Substituted pyrazolo[3,4-b]pyridin-6-carboxylic acids and method of use

Information

  • Patent Grant
  • 9796711
  • Patent Number
    9,796,711
  • Date Filed
    Friday, October 7, 2016
    7 years ago
  • Date Issued
    Tuesday, October 24, 2017
    6 years ago
Abstract
The present invention provides for compounds of formula (I)
Description
BACKGROUND OF THE INVENTION

Cystic fibrosis (CF) is a disease caused by mutations in the Or gene which induces defects in the CFTR protein, its production and/or its function. Cystic fibrosis is the most common fatal genetic disease in humans, and affects ˜0.04% of white individuals. For example, in the United States, about one in every 2,500 infants is affected, and up to 10 million people carry a single copy of the defective gene without apparent ill effects; moreover subjects bearing a single copy of the gene exhibit increased resistance to cholera and to dehydration resulting from diarrhea. In contrast, individuals with two copies of the CF associated gene suffer from the debilitating and fatal effects of CF, including chronic lung infections.


In cystic fibrosis patients, mutations in endogenous respiratory epithelial CFTR lead to a failure to confer chloride and bicarbonate permeability to epithelial cells in lung and other tissues, thus leading to reduced apical anion secretion and disruptions of the ion and fluid transport. This decrease in anion transport causes an enhanced mucus and pathogenic agent accumulation in the lung triggering microbial infections that ultimately cause death in CF patients.


Beyond respiratory disease, CF patients also suffer from gastrointestinal problems and pancreatic insufficiency that result in death if left untreated. Furthermore, female subjects with cystic fibrosis suffer from decreased fertility, whilst males with cystic fibrosis are infertile.


A variety of disease causing mutations has been identified through sequence analysis of the CFTR gene of CF chromosomes. ΔF508-CFTR, the most common CF mutation (present in at least 1 allele in ˜90% of CF patients) and occurring in approximately 70% of the cases of cystic fibrosis, contains a single amino acid deletion of phenylalanine 508. The F508del misfolding originates in the first nucleotide-binding domain (NBD1), which induces a global conformational change in CFTR through NBD1's interactions with other domains. This deletion prevents the nascent protein from folding correctly, whereby the protein in turn cannot exit the endoplasmic reticulum (ER) and being transported to the plasma membrane, and then is rapidly degraded. As a result, the number of channels present in the membrane is far less than in cells expressing wild-type CFTR. In addition to impaired trafficking, the mutation results in defective channel gating.


Accordingly, there is a need for novel compounds able to modulate CFTR. In particular, the present invention discloses compounds that may act as CFTR modulators for the treatment of cystic fibrosis. The present invention also provides methods for the preparation of these compounds, pharmaceutical compositions comprising these compounds and methods for the treatment of cystic fibrosis by administering the compounds of the invention.


SUMMARY

In one aspect the present invention provides for compounds of formula (I)




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or a pharmaceutically acceptable salt thereof, wherein

    • R1 is G1A, -G1B-G1C, -G1B-L1A-G1C, C1-C6 haloalkyl, C1-C6 alkyl, —(C1-C6 alkylenyl)-CN, —(C1-C6 alkylenyl)-G1D, or -G1D-O-benzyl;
    • L1A is —O— or —O—(C1-C3 alkylenyl)-; wherein the left end of the L1A moiety is attached to G1B.
    • G1A is phenyl, aryl, 5-6 membered monocyclic heteroaryl, 4-7 membered monocyclic heterocycle, fused bicyclic heterocycle, or C3-C6 monocyclic cycloalkyl; wherein each G1A is optionally substituted with 1, 2, 3, or 4 independently selected R1a groups;
    • G1B is phenyl or 5-6 membered monocyclic heteroaryl; wherein each G1B is optionally substituted with 1, 2, 3, or 4 independently selected R1b groups;
    • G1C is 4-7 membered monocyclic heterocycle which is optionally substituted with 1, 2, 3, or 4 independently selected R1c groups;
    • G1D, at each occurrence, is a 4-7 membered monocyclic heterocycle, 5-6 membered monocyclic heteroaryl, or a C3-C6 monocyclic cycloalkyl; wherein each G1D is optionally substituted with 1, 2, 3, or 4 independently selected R1d groups;
    • R2 is C2-C4 alkenyl, C1-C6 alkyl, C1-C6 haloalkyl, —OR2xa, —(C1-C6 alkylenyl)-OR2xb, —(C1-C6 alkylenyl)-N(R2xb)2, —C(O)OR2xb, —C(O)N(R2xb)2, or -G2A;
    • R2xa is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or G2B;
    • R2xb, at each occurrence, is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl;
    • G2A and G2B are each independently 4-7 membered monocyclic heterocycle or C3-C6 monocyclic cycloalkyl; wherein G2A and G2B are each optionally substituted with 1, 2, or 3 independently selected R2a groups;
    • R3 is halogen, G3A, -G3B-L1-G3C, -G3B-L3-G3C-L4-G3F, —(C1-C6 alkylenyl)-G3E, —OR3a, —N(R3a)(R3b), —N(R3b)C(O)G3D, or —C(O)G3D;
    • R3a, at each occurrence, is independently G3E, C1-C6 haloalkyl, or C1-C6 alkyl; wherein the C1-C6 haloalkyl and the C1-C6 alkyl are each optionally substituted with one or two substituents independently selected from the group consisting of G3E, —OR3xa, —C(O)G3D, —N(R3xb)2, and —S(O)2R3xc;
    • R3xa, R3xb, and R3xc, at each occurrence, are each independently hydrogen, C1-C6 haloalkyl, C1-C6 alkyl, G3E, —(C1-C6 alkylenyl)-OR3ya, or —(C1-C6 alkylenyl)-N(R3ya)2; wherein R3ya, at each occurrence, is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl;
    • R3b, at each occurrence, is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl;
    • L1 is a bond, C1-C6 alkylenyl, (C1-C6 alkylenyl)r-L2-(C1-C6 alkylenyl)s, or O—(C1-C6 alkylenyl)-C(O), wherein the left end of the L1 moiety is attached to G3B;
    • L2 is O, N(Rx), C(O), N(Rx)C(O), or C(O)N(Rx); wherein each Rx is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl;
    • L3 is a bond or C1-C6 alkylenyl;
    • L4 is a bond, C1-C6 alkylenyl, O, N(R2x), C(O), N(R2x)C(O), or C(O)N(R2x); wherein each R2x is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl;
    • r is 0 or 1;
    • s is 0 or 1;
    • G3A, G3B, and G3C, are each independently C3-C11 cycloalkyl, phenyl, 5-6 membered monocyclic heteroaryl, or 4-11 membered heterocycle, wherein G3A, G3B, and G3C are each optionally substituted with 1, 2, 3, or 4 independently selected Re groups;
    • G3D, at each occurrence, is 4-7 membered monocyclic heterocycle which is optionally substituted with 1, 2, 3, or 4 independently selected Re groups;
    • G3E, at each occurrence, is independently C3-C8 monocyclic cycloalkyl or 4-11 membered heterocycle; wherein each G3E is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of Re and G3F;
    • G3F, at each occurrence, is independently a 4-7 membered monocyclic heterocycle or a C3-C6 monocyclic cycloalkyl; wherein each G3F is optionally substituted with 1, 2, 3, or 4 independently selected Re groups;
    • Re, at each occurrence, is independently C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl, C1-C6 haloalkyl, halogen, oxo, —CN, —N3, NO2, —ORf, —OC(O)Rg, —OC(O)NRfRh, —SRf, —S(O)2Rf, —S(O)2NRfRh, —C(O)Rf, —C(O)ORf, —C(O)NRfRh, —C(O)N(Rh)S(O)2Rf, —N(Rf)2, —N(Rh)C(O)Rf, —N(Rh)S(O)2Rg, —N(Rh)C(O)O(Rg), —N(Rh)C(O)NRfRh, or —N(Rh)S(O)2NRfRh; wherein the C1-C6 haloalkyl and the C1-C6 alkyl are each optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, —CN, NO2, —ORf, —OC(O)Rg, —OC(O)NRfRh, —SRf, —S(O)2Rf, —S(O)2NRfRh, —C(O)Rf, —C(O)ORf, —C(O)NRfRh, —C(O)N(Rh)S(O)2Rf, —N(Rf)2, —N(Rh)C(O)Rf, —N(Rh)S(O)2Rg, —N(Rh)C(O)O(Rg), —N(Rh)C(O)NRfRh, and —N(Rh)S(O)2NRfRh;
    • Rf, at each occurrence, is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, —(C1-C6 alkylenyl)-CN, —(C1-C6 alkylenyl)-ORm, —(C1-C6 alkylenyl)-OC(O)Rn, —(C1-C6 alkylenyl)-OC(O)N(Rm)2, —(C1-C6 alkylenyl)-SRm, —(C1-C6 alkylenyl)-S(O)2Rm, —(C1-C6 alkylenyl)-S(O)2N(Rm)2, —(C1-C6 alkylenyl)-C(O)Rm, —(C1-C6 alkylenyl)-C(O)ORm, —(C1-C6 alkylenyl)-C(O)N(Rm)2, —(C1-C6 alkylenyl)-C(O)N(Rm)S(O)2Rn, —(C1-C6 alkylenyl)-N(Rm)2, —(C1-C6 alkylenyl)-N(Rm)C(O)Rn, —(C1-C6 alkylenyl)-N(Rm)S(O)2Rn, —(C1-C6 alkylenyl)-N(Rm)C(O)O(Rn), —(C1-C6 alkylenyl)-N(Rm)C(O)N(Rm)2, or —(C1-C6 alkylenyl)-N(Rm)S(O)2N(Rm)2;
    • Rg, at each occurrence, is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, —(C1-C6 alkylenyl)-CN, —(C1-C6 alkylenyl)-ORm, —(C1-C6 alkylenyl)-OC(O)Rn, —(C1-C6 alkylenyl)-OC(O)N(Rm)2, —(C1-C6 alkylenyl)-SRm, —(C1-C6 alkylenyl)-S(O)2Rm, —(C1-C6 alkylenyl)-S(O)2N(Rm)2, alkylenyl)-C(O)Rm, —(C1-C6 alkylenyl)-C(O)ORm, —(C1-C6 alkylenyl)-C(O)N(Rm)2, —(C1-C6 alkylenyl)-C(O)N(Rm)S(O)2Rn, —(C1-C6 alkylenyl)-N(Rm)2, —(C1-C6 alkylenyl)-N(Rm)C(O)Rn, —(C1-C6 alkylenyl)-N(Rm)S(O)2Rn, —(C1-C6 alkylenyl)-N(Rm)C(O)O(R″), —(C1-C6 alkylenyl)-N(Rm)C(O)N(Rm)2, or —(C1-C6 alkylenyl)-N(Rm)S(O)2N(Rm)2;
    • Rh, at each occurrence, is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or —(C1-C6 alkylenyl)-ORm;
    • R1a, R1b, R1c, R1d, and R2a, at each occurrence, are each independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, oxo, —CN, NO2, —ORm, —OC(O)Rn, —OC(O)N(Rm)2, —SRm, —S(O)2Rm, —S(O)2N(Rm)2, —C(O)Rm, —C(O)ORm, —C(O)N(Rm)2, —C(O)N(Rm)S(O)2Rn, —N(Rm)2, —N(Rm)(alkoxyalkyl), —N(alkoxyalkyl)2, —N(Rm)C(O)Rn, —N(Rm)S(O)2Rn, —N(Rm)C(O)O(Rn), —N(Rm)C(O)N(Rm)2, —N(Rm)S(O)2N(Rm)2, —(C1-C6 alkylenyl)-CN, —(C1-C6 alkylenyl)-ORm, —(C1-C6 alkylenyl)-OC(O)Rn, —(C1-C6 alkylenyl)-OC(O)N(Rm)2, —(C1-C6 alkylenyl)-SRm, —(C1-C6 alkylenyl)-S(O)2Rm, —(C1-C6 alkylenyl)-S(O)2N(Rm)2, —(C1-C6 alkylenyl)-C(O)Rm, —(C1-C6 alkylenyl)-C(O)ORm, —(C1-C6 alkylenyl)-C(O)N(Rm)2, —(C1-C6 alkylenyl)-C(O)N(Rm)S(O)2Rn, —(C1-C6 alkylenyl)-N(Rm)2, —(C1-C6 alkylenyl)-N(Rm)C(O)Rn, —(C1-C6 alkylenyl)-N(Rm)S(O)2Rn, —(C1-C6 alkylenyl)-N(Rm)C(O)O(Rn), —(C1-C6 alkylenyl)-N(Rm)C(O)N(Rn)2, or —(C1-C6 alkylenyl)-N(Rm)S(O)2N(Rn)2;
    • Rm, at each occurrence, is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl;
    • Rn, at each occurrence, is independently C1-C6 alkyl or C1-C6 haloalkyl; and
    • R4 is hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl;
    • with the proviso that when R1 is C1-C6 alkyl or G1A, wherein G1A is optionally substituted phenyl, optionally substituted 5-6 membered monocyclic heteroaryl, or optionally substituted 4-7 membered monocyclic heterocycle, R2 is C1-C6 alkyl, and R3 is G3A, then G3A is not optionally substituted phenyl or optionally substituted 5-6 membered monocyclic heteroaryl.


Another aspect of the invention relates to pharmaceutical compositions comprising a compound of the invention, and a pharmaceutical carrier. Such compositions can be administered in accordance with a method of the invention, typically as part of a therapeutic regimen for treatment or prevention of conditions and disorders related to Cystic Fibrosis Transmembrane Conductance Regulator activity. In a particular aspect, the pharmaceutical compositions may additionally comprise further therapeutically active ingredients suitable for use in combination with the compounds of the invention. In a more particular aspect, the further therapeutically active ingredient is an agent for the treatment of cystic fibrosis.


Moreover, the compounds of the invention, useful in the pharmaceutical compositions and treatment methods disclosed herein, are pharmaceutically acceptable as prepared and used.


Yet another aspect of the invention relates to a method for treating, or preventing conditions and disorders related to Cystic Fibrosis Transmembrane Conductance Regulator activity in mammals. More particularly, the method is useful for treating or preventing conditions and disorders related to cystic fibrosis, Sjögren's syndrome, pancreatic insufficiency, chronic obstructive lung disease, or chronic obstructive airway disease. Accordingly, the compounds and compositions of the invention are useful as a medicament for treating or preventing Cystic Fibrosis Transmembrane Conductance Regulator modulated disease.


The compounds, compositions comprising the compounds, methods for making the compounds, and methods for treating or preventing conditions and disorders by administering the compounds are further described herein.


In a particular aspect, the compounds of the invention are provided for use in the treatment of cystic fibrosis. In a particular aspect, the compounds of the invention are provided for use in the treatment of cystic fibrosis caused by class I, II, III, IV, V, and/or VI mutations.


The present invention also provides pharmaceutical compositions comprising a compound of the invention, and a suitable pharmaceutical carrier for use in medicine. In a particular aspect, the pharmaceutical composition is for use in the treatment of cystic fibrosis.


These and other objects of the invention are described in the following paragraphs. These objects should not be deemed to narrow the scope of the invention.







DETAILED DESCRIPTION OF THE INVENTION

Described herein are compounds of formula (I)




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wherein R1, R2, R3, and R4 are defined above in the Summary of the Invention and below in the Detailed Description. Further, compositions comprising such compounds and methods for treating conditions and disorders using such compounds and compositions are also described.


Compounds included herein may contain one or more variable(s) that occur more than one time in any substituent or in the formulae herein. Definition of a variable on each occurrence is independent of its definition at another occurrence. Further, combinations of sub stituents are permissible only if such combinations result in stable compounds. Stable compounds are compounds, which can be isolated from a reaction mixture.


Definitions


It is noted that, as used in this specification and the intended claims, the singular form “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a compound” includes a single compound as well as one or more of the same or different compounds; reference to “a pharmaceutically acceptable carrier” means a single pharmaceutically acceptable carrier as well as one or more pharmaceutically acceptable carriers, and the like.


As used in the specification and the appended claims, unless specified to the contrary, the following terms have the meaning indicated:


The term “alkenyl” as used herein, means a straight or branched hydrocarbon chain containing from 2 to 10 carbons and containing at least one carbon-carbon double bond. The term “C2-C6 alkenyl” means an alkenyl group containing 2-6 carbon atoms. Non-limiting examples of C2-C6 alkenyl include buta-1,3-dienyl, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, and 5-hexenyl.


The term “alkoxy” as used herein, means a C1-C6 alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.


The term “alkoxyalkyl” as used herein, means an alkoxy group, as defined herein, appended to the parent molecular moiety through a C1-C6 alkyl group, as defined herein. Non-limiting examples of alkoxyalkyl include tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl, and methoxymethyl.


The term “alkyl” as used herein, means a saturated, straight or branched hydrocarbon chain radical. In some instances, the number of carbon atoms in an alkyl moiety is indicated by the prefix “Cx-Cy”, wherein x is the minimum and y is the maximum number of carbon atoms in the substituent. Thus, for example, “C1-C6 alkyl” means an alkyl substituent containing from 1 to 6 carbon atoms and “C1-C3 alkyl” means an alkyl substituent containing from 1 to 3 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 3,3-dimethylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-methylpropyl, 2-methylpropyl, 1-ethylpropyl, and 1,2,2-trimethylpropyl. The terms “alkyl,” “C1-C6 alkyl,” “C1-C4 alkyl,” and “C1-C3 alkyl” used herein are unsubstituted, unless otherwise indicated.


The term “alkylene” or “alkylenyl” means a divalent radical derived from a straight or branched, saturated hydrocarbon chain, for example, of 1 to 10 carbon atoms or of 1 to 6 carbon atoms (C1-C6 alkylenyl) or of 1 to 4 carbon atoms or of 1 to 3 carbon atoms (C1-C3 alkylenyl) or of 2 to 6 carbon atoms (C2-C6 alkylenyl). Examples of C1-C6 alkylenyl include, but are not limited to, —CH2—, —CH2CH2—, —C(CH3)2—CH2CH2CH2—, —C(CH3)2—CH2CH2—, —CH2CH2CH2CH2—, and —CH2CH(CH3)CH2—.


The term “C2-C6 alkynyl” as used herein, means a straight or branched chain hydrocarbon radical containing from 2 to 6 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of C2-C6 alkynyl include, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.


The term “aryl” as used herein, means a phenyl fused to a C3-C6 monocyclic cycloalkyl or a phenyl fused to a C4-C7 monocyclic cycloalkenyl. Example of an aryl group includes, but is not limited to, bicyclo[4.2.0]octa-1,3,5-trien-3-yl.


The term “C3-C11 cycloalkyl” as used herein, means a hydrocarbon ring radical containing 3-11 carbon atoms, zero heteroatom, and zero double bond. The C3-C11 cycloalkyl group may be a single-ring (monocyclic) or have two or more rings (bicyclic or polycyclic). Monocyclic cycloalkyl groups typically contain from 3 to 8 carbon ring atoms (C3-C8 monocyclic cycloalkyl), and even more typically 3-6 carbon ring atoms (C3-C6 monocyclic cycloalkyl). Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups contain two or more rings, and bicyclic cycloalkyls contain two rings. In certain embodiments, the polycyclic cycloalkyl groups contain 2 or 3 rings. The rings within the polycyclic and the bicyclic cycloalkyl groups may be in a bridged, fused, or spiro orientation, or combinations thereof. In a spirocyclic cycloalkyl, one atom is common to two different rings. An example of a spirocyclic cycloalkyl is spiro[4.5]decane. In a bridged cycloalkyl, the rings share at least two non-adjacent atoms. Examples of bridged cycloalkyls include, but are not limited to, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.1]nonyl, bicyclo[4.2.1]nonyl, tricyclo[3.3.1.03,7]nonyl(octahydro-2,5-methanopentalenyl or noradamantyl), tricyclo[3.3.1.13,7]decyl(adamantyl), and tricyclo[4.3.1.13,8]undecyl(homoadamantyl). In a fused ring cycloalkyl, the rings share one common bond. Examples of fused-ring cycloalkyl include, but not limited to, decalin (decahydronaphthyl) and bicyclo[2.2.0]octyl.


The term “C4-C7 monocyclic cycloalkenyl” as used herein, means cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptyl.


The term “halo” or “halogen” as used herein, means Cl, Br, I, and F.


The term “haloalkyl” as used herein, means an alkyl group, as defined herein, in which one, two, three, four, five or six hydrogen atoms are replaced by halogen. The term “C1-C6 haloalkyl” means a C1-C6 alkyl group, as defined herein, in which one, two, three, four, five, or six hydrogen atoms are replaced by halogen. The term “C1-C3 haloalkyl” means a C1-C3 alkyl group, as defined herein, in which one, two, three, four, or five hydrogen atoms are replaced by halogen. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, 2,2-difluoroethyl, fluoromethyl, 2,2,2-trifluoroethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, 2-chloro-3-fluoropentyl, trifluorobutyl, and trifluoropropyl. The terms “haloalkyl,” “C1-C3 haloalkyl,” and “C1-C6 haloalkyl” used herein are unsubstituted, unless otherwise indicated.


The term “4-11 membered heterocycle” as used herein, means a hydrocarbon ring radical of 4-11 carbon ring atoms wherein at least one carbon atom is replaced by a heteroatom(s) independently selected from the group consisting of O, N, and S. The 4-11 membered heterocycle ring may be a single ring (monocyclic) or have two or more rings (bicyclic or polycyclic). In certain embodiments, the monocyclic heterocycle is a four-, five-, six-, seven-, or eight-membered hydrocarbon ring wherein at least one carbon ring atom is replaced by a heteroatom(s) independently selected from the group consisting of O, N, and S. In certain embodiments, the monocyclic heterocycle is a 4-7 membered hydrocarbon ring wherein at least one carbon ring atom is replaced by a heteroatom(s). A four-membered monocyclic heterocycle contains zero or one double bond, and one heteroatom selected from the group consisting of O, N, and S. A five-membered monocyclic heterocycle contains zero or one double bond and one, two, or three heteroatoms selected from the group consisting of O, N, and S. Examples of five-membered monocyclic heterocycles include those containing in the ring: 1 O; 1 S; 1 N; 2 N; 3 N; 1 S and 1 N; 1 S, and 2 N; 1 O and 1 N; or 1 O and 2 N. Non limiting examples of 5-membered monocyclic heterocyclic groups include 1,3-dioxolanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, imidazolidinyl, oxazolidinyl, imidazolinyl, imidazolidinyl, isoxazolidinyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, tetrahydrothienyl, thiazolinyl, and thiazolidinyl. A six-membered monocyclic heterocycle contains zero, one, or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. Examples of six-membered monocyclic heterocycles include those containing in the ring: 1 O; 2 O; 1 S; 2 S; 1 N; 2 N; 3 N; 1 S, 1 O, and 1 N; 1 S and 1 N; 1 S and 2 N; 1 S and 1 O; 1 S and 2 O; 1 O and 1 N; and 1 O and 2 N. Examples of six-membered monocyclic heterocycles include dihydropyridinyl, 1,6-dihydropyrimidinyl, dihydropyranyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,4-dithianyl, hexahydropyrimidine, imidazolidinyl, morpholinyl, oxazolidinyl, piperazinyl, piperidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, tetrahydrothiopyranyl, thiomorpholinyl, thioxanyl, and trithianyl. Seven- and eight-membered monocyclic heterocycles contains zero, one, two, or three double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. Examples of monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, 1,4-diazepanyl, 1,2-dihydropyridinyl, 1,6-dihydropyrimidinyl, dihydropyranyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,4-dioxanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, 1,4-oxazepanyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, oxetanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyridinyl, tetrahydropyranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, thiopyranyl, and trithianyl. Polycyclic heterocycle groups contain two or more rings, and bicyclic heterocycles contain two rings. In certain embodiments, the polycyclic heterocycle groups contain 2 or 3 rings. The rings within the polycyclic and the bicyclic heterocycle groups may be in a bridged, fused, or spiro orientation, or combinations thereof. In a spirocyclic heterocycle, one atom is common to two different rings. Non limiting examples of the spirocyclic heterocycle include 2-azaspiro[3.3]heptyl, 5-azaspiro[2.4]heptyl, 5-azaspiro[2.5]octyl, 2-azaspiro[3.5]nonyl, 2-azaspiro[3.4]octyl, 3-azaspiro[5.5]undecyl, 5-azaspiro[3.4]octyl, 2-oxaspiro[3.3]heptyl, 2-oxa-6-azaspiro[3.3]heptyl, 2-oxa-6-azaspiro[3.4]octyl, 6-oxa-2-azaspiro[3.4]octyl, 6-azaspiro[3.4]octyl, 7-azaspiro[3.5]nonyl, 8-azaspiro[4.5]decyl, 1-oxa-7-azaspiro[4.4]nonyl, 1-oxa-7-azaspiro[3.5]nonyl, 1-oxa-8-azaspiro[4.5]decyl, 1-oxa-3,8-diazaspiro[4.5]decyl, 1-oxa-4,9-diazaspiro[5.5]undecyl, 2-oxa-7-azaspiro[3.5]nonyl, 5-oxa-2-azaspiro[3.5]nonyl, 5-oxa-2-azaspiro[3.4]octyl, 6-oxa-2-azaspiro[3.5]nonyl, 7-oxa-2-azaspiro[3.5]nonyl, 8-oxa-2-azaspiro[4.5]decyl, 2,7-diazaspiro[4.4]nonyl, 1,4-dioxa-8-azaspiro[4.5]decyl, 1,4-dioxa-7-azaspiro[4.4]nonyl, 1,3,8-triazaspiro[4.5]decyl, 2-oxa-5,8-diazaspiro[3.5]nonyl, 2,8-diazaspiro[4.5]decyl and 3,9-diazaspiro[5.5]undecyl. In a fused ring heterocycle, the rings share one common bond. Examples of fused bicyclic heterocycles are a 4-6 membered monocyclic heterocycle fused to a phenyl group, or a 4-6 membered monocyclic heterocycle fused to a C3-C6 monocyclic cycloalkyl, or a 4-6 membered monocyclic heterocycle fused to a C4-C7 monocyclic cycloalkenyl, or a 4-6 membered monocyclic heterocycle fused to a 4-7 membered monocyclic heterocycle. Examples of fused bicyclic heterocycles include, but are not limited to, 3-azabicyclo[3.1.0]hexyl, benzo[d][1,3]dioxolyl, benzopyranyl, benzothiopyranyl, indolinyl, decahydropyrrolo[3,4-b]azepinyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydro-1H-indolyl, isoindolinyl, 3,4-dihydroisoquinolin-2(1H)-yl, 2,3,4,6-tetrahydro-1H-pyrido[1,2-a]pyrazin-2-yl, hexahydropyrano[3,4-b][1,4]oxazin-1(5H)-yl, hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl, hexahydrocyclopenta[c]pyrrol-3a(1H)-yl, hexahydro-1H-oxazolo[3,4-a]pyrazinyl, octahydroimidazo[1,5-a]pyrazinyl, hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl, and octahydropyrrolo[3,4-c]pyrrolyl. In a bridged heterocycle, the rings share at least two non-adjacent atoms. Examples of such bridged heterocycles include, but are not limited to, azabicyclo[2.2.1]heptyl (including 2-azabicyclo[2.2.1]hept-2-yl), 2-oxa-5-azabicyclo[2.2.1]heptyl, 8-azabicyclo[3.2.1]octyl, octahydro-2,5-epoxypentalene, 8-oxa-3-azabicyclo[3.2.1]octyl, hexahydro-1H-1,4-methanocyclopenta[c]furan, aza-admantane (1-azatricyclo[3.3.1.13,7]decane), and oxa-adamantane (2-oxatricyclo[3.3.1.13,7]decane). The nitrogen and sulfur heteroatoms in the heterocycle rings may optionally be oxidized (e.g. 1,1-dioxidotetrahydrothienyl, 1,1-dioxido-1,2-thiazolidinyl, 1,1-dioxidothiomorpholinyl)) and the nitrogen atoms may optionally be quaternized.


The term “5-11 membered heteroaryl” as used herein, means a monocyclic heteroaryl and a bicyclic heteroaryl. The monocyclic heteroaryl is a five- or six-membered ring. The five-membered ring contains two double bonds. The five membered ring may contain one heteroatom selected from O or S; or one, two, three, or four nitrogen atoms and optionally one oxygen or one sulfur atom. The six-membered ring contains three double bonds and one, two, three or four nitrogen atoms. Examples of 5-6 membered monocyclic heteroaryl include, but are not limited to, furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, 1,3-oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, 1,3-thiazolyl, thienyl, triazolyl, and triazinyl. The bicyclic heteroaryl consists of a monocyclic heteroaryl fused to a phenyl, or a monocyclic heteroaryl fused to a C3-C6 monocyclic cycloalkyl, or a monocyclic heteroaryl fused to C4-C7 monocyclic cycloalkenyl, or a monocyclic heteroaryl fused to a monocyclic heteroaryl, or a monocyclic heteroaryl fused to a 4-7 membered monocyclic heterocycle. Representative examples of bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzoxadiazolyl, phthalazinyl, 2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl, 6,7-dihydro-pyrazolo[1,5-a]pyrazin-5(4H)-yl, 6,7-dihydro-1,3-benzothiazolyl, imidazo[1,2-a]pyridinyl, indazolyl, indolyl, isoindolyl, isoquinolinyl, naphthyridinyl, pyridoimidazolyl, quinolinyl, 2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl, thiazolo[5,4-b]pyridin-2-yl, thiazolo[5,4-d]pyrimidin-2-yl, and 5,6,7,8-tetrahydroquinolin-5-yl. The nitrogen atom in the heteroaryl rings may optionally be oxidized and may optionally be quaternized.


The phenyl, the cycloalkyls, the cycloalkenyls, the heterocycles, and the heteroaryls, including the exemplary rings, are optionally substituted unless otherwise indicated; and are attached to the parent molecular moiety through any substitutable atom contained within the ring system.


The term “heteroatom” as used herein, means a nitrogen, oxygen, and sulfur.


The term “oxo” as used herein, means a═O group.


The term “radiolabel” means a compound of the invention in which at least one of the atoms is a radioactive atom or a radioactive isotope, wherein the radioactive atom or isotope spontaneously emits gamma rays or energetic particles, for example alpha particles or beta particles, or positrons. Examples of such radioactive atoms include, but are not limited to, 3H (tritium), 14C, 11C, 15O, 18F, 35 s, 123I and 125I.


A moiety is described as “substituted” when a non-hydrogen radical is in the place of hydrogen radical of any substitutable atom of the moiety. Thus, for example, a substituted heterocycle moiety is a heterocycle moiety in which at least one non-hydrogen radical is in the place of a hydrogen radical on the heterocycle. It should be recognized that if there are more than one substitution on a moiety, each non-hydrogen radical may be identical or different (unless otherwise stated).


If a moiety is described as being “optionally substituted,” the moiety may be either (1) not substituted or (2) substituted. If a moiety is described as being optionally substituted with up to a particular number of non-hydrogen radicals, that moiety may be either (1) not substituted; or (2) substituted by up to that particular number of non-hydrogen radicals or by up to the maximum number of substitutable positions on the moiety, whichever is less. Thus, for example, if a moiety is described as a heteroaryl optionally substituted with up to 3 non-hydrogen radicals, then any heteroaryl with less than 3 substitutable positions would be optionally substituted by up to only as many non-hydrogen radicals as the heteroaryl has substitutable positions. To illustrate, tetrazolyl (which has only one substitutable position) would be optionally substituted with up to one non-hydrogen radical. To illustrate further, if an amino nitrogen is described as being optionally substituted with up to 2 non-hydrogen radicals, then a primary amino nitrogen will be optionally substituted with up to 2 non-hydrogen radicals, whereas a secondary amino nitrogen will be optionally substituted with up to only 1 non-hydrogen radical.


The terms “treat”, “treating”, and “treatment” refer to a method of alleviating or abrogating a disease and/or its attendant symptoms. In certain embodiments, “treat,” “treating,” and “treatment” refer to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, “treat”, “treating”, and “treatment” refer to modulating the disease or disorder, either physically (for example, stabilization of a discernible symptom), physiologically (for example, stabilization of a physical parameter), or both. In a further embodiment, “treat”, “treating”, and “treatment” refer to slowing the progression of the disease or disorder.


The terms “prevent”, “preventing”, and “prevention” refer to a method of preventing the onset of a disease and/or its attendant symptoms or barring a subject from acquiring a disease. As used herein, “prevent”, “preventing” and “prevention” also include delaying the onset of a disease and/or its attendant symptoms and reducing a subject's risk of acquiring or developing a disease or disorder.


The phrase “therapeutically effective amount” means an amount of a compound, or a pharmaceutically acceptable salt thereof, sufficient to prevent the development of or to alleviate to some extent one or more of the symptoms of the condition or disorder being treated when administered alone or in conjunction with another therapeutic agent for treatment in a particular subject or subject population. The “therapeutically effective amount” may vary depending on the compound, the disease and its severity, and the age, weight, health, etc., of the subject to be treated. For example in a human or other mammal, a therapeutically effective amount may be determined experimentally in a laboratory or clinical setting, or may be the amount required by the guidelines of the United States Food and Drug Administration, or equivalent foreign agency, for the particular disease and subject being treated.


The term “subject” is defined herein to refer to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, pigs, horses, dogs, cats, rabbits, rats, mice and the like. In one embodiment, the subject is a human. The terms “human,” “patient,” and “subject” are used interchangeably herein.


The term ‘one or more’ refers to one to four. In one embodiment it refers to one or three. In another embodiment it refers to one to three. In a further embodiment it refers to one to two. In yet other embodiment it refers to two. In yet other further embodiment it refers to one.


As used herein, “Class I mutation(s)” refers to mutations which interfere with protein synthesis. They result in the introduction of a premature signal of termination of translation (stop codon) in the mRNA. The truncated CFTR proteins are unstable and rapidly degraded, so, the net effect is that there is no protein at the apical membrane. In particular, Class I mutation(s) refers to p.Gly542X (G542X), W1282X, c.489+1G>T (621+1G>T), or c.579+1G>T (711+1G>T) mutation. More particularly, Class I mutation(s) refers to G542X; or W1282X mutations.


As used herein, “Class II mutation(s)” refers to mutations which affect protein maturation. These lead to the production of a CFTR protein that cannot be correctly folded and/or trafficked to its site of function on the apical membrane. In particular, Class II mutation(s) refers to p.Phe508del (F508del), p.Ile507del, or p.Asn1303Lys (N1303K) mutations. More particularly, Class II mutation(s) refers to F508del or N1303K mutations.


As used herein, “Class III mutation(s)” refers to mutations which alter the regulation of the CFTR channel. The mutated CFTR protein is properly trafficked and localized to the plasma membrane but cannot be activated, or it cannot function as a chloride channel. In particular, Class III mutation(s) refers to p.Gly551Asp (G551D), G551S, R553G, G1349D, S1251N, G178R, S549N mutations. More particularly, Class III mutation(s) refers to G551D, R553G, G1349D, S1251N, G178R, or S549N mutations.


As used herein, “Class IV mutation(s)” refers to mutations which affect chloride conductance. The CFTR protein is correctly trafficked to the cell membrane but generates reduced chloride flow or a “gating defect” (most are missense mutations located within the membrane-spanning domain). In particular, Class IV mutation(s) refers to p.Arg117His (R117H), R347P, or p.Arg334Trp (R334W) mutations.


As used herein, “Class V mutation(s)” refers to mutations which reduce the level of normally functioning CFTR at the apical membrane or result in a “conductance defect” (for example partially aberrant splicing mutations or inefficient trafficking missense mutations). In particular, Class V mutation(s) refers to c.1210-12T[5] (5T allele), c.S3140-26A>G (3272-26A>G), c.3850-2477C>T (3849+10kbC>T) mutations.


As used herein, “Class VI mutation(s)” refers to mutations which decrease the stability of the CFTR which is present or which affect the regulation of other channels, resulting in inherent instability of the CFTR protein. In effect, although functional, the CFTR protein is unstable at the cell surface and it is rapidly removed and degraded by cell machinery. In particular, Class VI mutation(s) refers to Rescued F508del, 120del23, N287Y, 4326delITC, or 4279insA mutations. More particularly, Class VI mutation(s) refers to Rescued F508del mutations.


Compounds


Compounds of the invention have the general formula (I) as described above.


Particular values of variable groups in compounds of formula (I) are as follows. Such values may be used where appropriate with any of the other values, definitions, claims or embodiments defined hereinbefore or hereinafter.


In certain embodiments of formula (I), R1 is —(C1-C6 alkylenyl)-CN, —(C1-C6 alkylenyl)-G1D, or -G1D-O-benzyl.


In certain embodiments of formula (I), R1 is G1A, -G1B-G1C, -G1B-L1A-G1C, C1-C6 haloalkyl, or C1-C6 alkyl.


In certain embodiments of formula (I), R1 is G1A, -G1B-G1C, C1-C6 haloalkyl, or C1-C6 alkyl.


In certain embodiments of formula (I), R1 is G1A.


In certain embodiments of formula (I), R1 is G1A wherein G1A is phenyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, dihydropyridinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothienyl, piperidinyl, 1,3-benzodioxolyl, bicyclo[4.2.0]octa-1,3,5-trien-3-yl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.


In certain embodiments of formula (I), R1 is G1A wherein G1A is phenyl, pyrazolyl, pyridinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothienyl, piperidinyl, cyclopropyl, cyclopentyl, or cyclohexyl.


In certain embodiments of formula (I), R1 is G1A wherein G1A is phenyl, pyridinyl, or cyclohexyl.


In certain embodiments of formula (I), R1 is G1A wherein G1A is 4-7 membered monocyclic heterocycle. In some such embodiments, the 4-7 membered monocyclic heterocycle is pyrrolidinyl, piperidinyl, tetrahydrofuranyl, or tetrahydropyranyl. In some such embodiments, the 4-7 membered monocyclic heterocycle is tetrahydrofuranyl or tetrahydropyranyl.


In certain embodiments of formula (I), R1 is G1A wherein G1A is C3-C6 monocyclic cycloalkyl. In some such embodiments, the C3-C6 monocyclic cycloalkyl is cyclopropyl, cyclopentyl, or cyclohexyl. In some such embodiments, the C3-C6 monocyclic cycloalkyl is cyclopentyl or cyclohexyl. In some such embodiments, the C3-C6 monocyclic cycloalkyl is cyclohexyl. In some such embodiments, the C3-C6 monocyclic cycloalkyl is cyclopropyl. In some such embodiments, the C3-C6 monocyclic cycloalkyl is cyclopentyl.


In certain embodiments of formula (I), R1 is G1A wherein G1A is phenyl or 5-6 membered monocyclic heteroaryl. In some such embodiments, the 5-6 membered monocyclic heteroaryl is pyrazolyl, pyridazinyl, pyrimidinyl, or pyridinyl. In some such embodiments, the 5-6 membered monocyclic heteroaryl is pyrazolyl or pyridinyl. In some such embodiments, the 5-6 membered monocyclic heteroaryl is pyridinyl.


In certain embodiments of formula (I), R1 is G1A wherein G1A is phenyl.


In certain embodiments of formula (I), R1 is G1A wherein G1A is 5-6 membered monocyclic heteroaryl. In some such embodiments, the 5-6 membered monocyclic heteroaryl is pyrazolyl, pyridazinyl, pyrimidinyl, or pyridinyl. In some such embodiments, the 5-6 membered monocyclic heteroaryl is pyrazolyl or pyridinyl. In some such embodiments, the 5-6 membered monocyclic heteroaryl is pyridinyl.


In certain embodiments, G1A, including the exemplary rings, are optionally substituted with 1, 2, 3, or 4 independently selected R1a groups.


In certain embodiments, G1A, including the exemplary rings, are optionally substituted with 1, 2, or 3 independently selected R1a groups.


In certain embodiments, G1A, including the exemplary rings, are optionally substituted with 1 or 2 independently selected R1a groups.


In certain embodiments, G1A, including the exemplary rings, are unsubstituted.


In certain embodiments, each R1a is independently C1-C6 alkyl, halogen, C1-C6 haloalkyl, oxo, —CN, —S(O)2Rm, —S(O)2N(Rm)2, —C(O)Rm, —C(O)ORm, —C(O)N(Rm)2, —N(Rm)2, —N(Rm)(alkoxyalkyl), —N(alkoxyalkyl)2, or —(C1-C6 alkylenyl-CN).


In certain embodiments, each R1a is independently C1-C6 alkyl, halogen, C1-C6 haloalkyl, —CN, —ORm, —N(Rm)2, —N(Rm)(alkoxyalkyl), or —N(alkoxyalkyl)2.


In certain embodiments, each R1a is independently C1-C3 alkyl, halogen, C1-C3 haloalkyl, —CN, —ORm, or —N(Rm)2.


In certain embodiments of formula (I), R1 is -G1B-G1C.


In certain embodiments of formula (I), Gm is phenyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyridazinyl.


In certain embodiments of formula (I), Gm is phenyl, pyridinyl, or pyrimidinyl.


In certain embodiments of formula (I), G1B is phenyl or pyridinyl.


In certain embodiments of formula (I), G1B is phenyl.


In certain embodiments of formula (I), G1C is azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl.


In certain embodiments of formula (I), G1B, including the exemplary rings, are optionally substituted with 1, 2, or 3 independently selected R1b groups.


In certain embodiments of formula (I), G1B, including the exemplary rings, are optionally substituted with 1 or 2 independently selected R1b groups.


In certain embodiments of formula (I), G1B, including the exemplary rings, are unsubstituted.


In certain embodiments, each R1b is independently C1-C6 alkyl, halogen, C1-C6 haloalkyl, or —ORm.


In certain embodiments of formula (I), G1C, including the exemplary rings, are optionally substituted with 1, 2, or 3 independently selected R1c groups.


In certain embodiments of formula (I), Gm, including the exemplary rings, are optionally substituted with 1 or 2 independently selected R1c groups.


In certain embodiments of formula (I), G1C, including the exemplary rings, are unsubstituted.


In certain embodiments, each R1c is independently C1-C6 alkyl, halogen, C1-C6 haloalkyl, or —ORm.


In certain embodiments of formula (I), R1 is C1-C6 alkyl. In some such embodiments, R1 is —C(CH3)3, —C(H)(CH3)2, or —CH2—CH(CH3)2. In some such embodiments, R1 is —C(H)(CH3)2, or —CH2—CH(CH3)2. In some such embodiments, R1 is —CH2—CH(CH3)2.


In certain embodiments of formula (I), R1 is -G1B-L1A-G1C. In some such embodiments, G1B is optionally substituted 5-6 membered heteroaryl. In some such embodiments, G1B is optionally substituted pyridinyl.


In certain embodiments of formula (I), R1 is —(C1-C6 alkylenyl)-G1D. In some such embodiments, G1D is optionally substituted C3-C6 monocyclic cycloalkyl. In some such embodiments, G1D is optionally substituted cyclobutyl. In some such embodiments, G1D is unsubstituted cyclobutyl. In some such embodiments, the optional substituents of G1D are independently C1-C6 alkyl, halogen, C1-C6 haloalkyl, or —ORm.


In certain embodiments of formula (I), R2 is C2-C4 alkenyl, C1-C6 alkyl, C1-C6 haloalkyl, —OR2xa, or G2A.


In certain embodiments of formula (I), R2 is C1-C6 alkyl, C1-C6 haloalkyl, —OR2xa, or G2A.


In certain embodiments of formula (I), R2 is —OR2xa or G2A.


In certain embodiments of formula (I), R2 is C1-C6 alkyl, C1-C6 haloalkyl, or G2A.


In certain embodiments of formula (I), R2 is C1-C6 alkyl or G2A.


In certain embodiments of formula (I), R2 is —CH3, —C(H)(CH3)2, —C(CH3)3, or G2A.


In certain embodiments of formula (I), R2 is —CH3, —C(H)(CH3)2, or G2A.


In certain embodiments of formula (I), R2 is —C(H)(CH3)2 or G2A.


In certain embodiments of formula (I), R2 is C1-C6 alkyl.


In certain embodiments of formula (I), R2 is —CH3, —C(H)(CH3)2, or —C(CH3)3.


In certain embodiments of formula (I), R2 is —CH3 or —C(H)(CH3)2.


In certain embodiments of formula (I), R2 is G2A.


In certain embodiments, G2A is a C3-C6 monocyclic cycloalkyl. In some such embodiments, G2A is cyclopropyl or cyclobutyl. In some such embodiments, G2A is cyclobutyl.


In certain embodiments, G2A is a 4-7 membered monocyclic heterocycle. In some such embodiments, G2A is azetidinyl, oxetanyl, pyrrolidinyl, or tetrahydrofuranyl. In some such embodiments, G2A is azetidinyl or oxetanyl. In some such embodiments, G2A is azetidinyl.


In certain embodiments of formula (I), G2A is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, cyclopropyl, or cyclobutyl.


In certain embodiments, G2A is azetidinyl, pyrrolidinyl, cyclopropyl, or cyclobutyl.


In certain embodiments, G2A is azetidinyl or cyclobutyl.


In certain embodiments, G2A is azetidinyl.


In certain embodiments, G2A is cyclobutyl.


In certain embodiments of formula (I), G2A, including the exemplary rings, are optionally substituted with 1, 2, or 3 independently selected R2a groups.


In certain embodiments of formula (I), G2A, including the exemplary rings, are optionally substituted with 1 or 2 independently selected R2a groups.


In certain embodiments of formula (I), G2A, including the exemplary rings, are unsubstituted.


In certain embodiments of formula (I), R2 is —OR2xa.


In certain embodiments of formula (I), R2 is —OR2xa wherein R2xa C1-C6 alkyl or G2B.


In certain embodiments of formula (I), R2 is —OR2xa wherein R2xa G2B.


In certain embodiments of formula (I), G2B is a 4-7 membered monocyclic heterocycle.


In certain embodiments of formula (I), G2B is azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, or tetrahydropyranyl.


In certain embodiments of formula (I), G2B is azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, or tetrahydrofuranyl.


In certain embodiments of formula (I), G2B is azetidinyl or oxetanyl.


In certain embodiments of formula (I), G2B is azetidinyl.


In certain embodiments of formula (I), G2B is oxetanyl.


In certain embodiments of formula (I), G2B is a C3-C6 monocyclic cycloalkyl.


In certain embodiments of formula (I), G2B is cyclobutyl.


In certain embodiments, G2B, including the exemplary rings, are optionally substituted with 1, 2, or 3 independently selected R2a groups.


In certain embodiments, G2B, including the exemplary rings, are optionally substituted with 1 or 2 independently selected R2a groups.


In certain embodiments, G2B, including the exemplary rings, are unsubstituted.


In certain embodiments of formula (I), each R2a is independently C1-C6 alkyl, halogen, C1-C6 haloalkyl, oxo, —CN, —C(O)Rm, —C(O)ORm, or —(C1-C6 alkylenyl-CN).


In certain embodiments of formula (I), each R2a is independently C1-C3 alkyl, halogen, C1-C3 haloalkyl, —ORm, or —C(O)ORm.


In certain embodiments of formula (I), R2 is —(C1-C6 alkylenyl)-OR2xb, —(C1-C6 alkylenyl)-N(R2xb)2, —C(O)OR2xb, or —C(O)N(R2xb)2.


In certain embodiments of formula (I), R3 is G3A, -G3B-L1-G3C, -G3B-L3-G3C-L4-G3F, —(C1-C6 alkylenyl)-G3E, —OR3a, or —N(R3a)(R3b).


In certain embodiments of formula (I), R3 is G3A, -G3B-L1-G3C, —OR3a, or —N(R3a)(R3b).


In certain embodiments of formula (I), R3 is G3A, -G3B-L1-G3C, or —OR3a.


In certain embodiments of formula (I), R3 is G3A or -G3B-L1-G3C.


In certain embodiments of formula (I), R3 is G3A.


In certain embodiments of formula (I), R3 is G3A wherein G3A is phenyl, 5-6 membered monocyclic heteroaryl, or 4-11 membered heterocycle.


In certain embodiments of formula (I), R3 is G3A wherein G3A is phenyl or 5-6 membered monocyclic heteroaryl.


In certain embodiments of formula (I), R3 is G3A wherein G3A is phenyl, pyrazolyl, pyrrolyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl.


In certain embodiments of formula (I), R3 is G3A wherein G3A is phenyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl.


In certain embodiments of formula (I), R3 is G3A wherein G3A is phenyl, pyridinyl, or pyrimidinyl.


In certain embodiments of formula (I), R3 is G3A wherein G3A is phenyl.


In certain embodiments of formula (I), R3 is G3A wherein G3A is pyridinyl.


In certain embodiments of formula (I), R3 is G3A wherein G3A is a 4-11 membered heterocycle.


In certain embodiments of formula (I), R3 is G3A wherein G3A is azetidinyl, pyrrolidinyl, piperidinyl, dihydropyranyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyridinyl, azepanyl, 1,4-oxazepanyl, 1,4-diazepanyl, 2-azaspiro[3.3]heptyl, 2-oxaspiro[3.3]heptyl, 5-azaspiro[2.4]heptyl, 2-azaspiro[3.4]octyl, 5-azaspiro[2.5]octyl, 5-azaspiro[3.4]octyl, 5-oxa-2-azaspiro[3.5]nonyl, 6-oxa-2-azaspiro[3.4]octyl, 6-oxa-2-azaspiro[3.5]nonyl, 7-oxa-2-azaspiro[3.5]nonyl, 1-oxa-7-azaspiro[3.5]nonyl, 1-oxa-7-azaspiro[4.4]nonyl, 1,4-dioxa-7-azaspiro[4.4]nonyl, 2-oxa-7-azaspiro[3.5]nonyl, 7-azaspiro[3.5]nonyl, 2,7-diazaspiro[4.4]nonyl, 2-azaspiro[3.5]nonyl, 1,3,8-triazaspiro[4.5]decyl, 8-azaspiro[4.5]decyl, 8-oxa-2-azaspiro[4.5]decyl, 1-oxa-8-azaspiro[4.5]decyl, 1-oxa-3,8-diazaspiro[4.5]decyl, 1-oxa-4,9-diazaspiro[5.5]undecyl, 1,4-dioxa-8-azaspiro[4.5]decyl, 3-azaspiro[5.5]undecyl, 3-azabicyclo[3.1.0]hexyl, 8-azabicyclo[3.2.1]octyl, 3,9-diazaspiro[5.5]undecyl, 2,8-diazaspiro[4.5]decyl, octahydropyrrolo[3,4-c]pyrrolyl, hexahydro-1H-oxazolo[3,4-a]pyrazinyl, octahydropyrrolo[1,2-a]pyrazinyl, octahydroimidazo[1,5-a]pyrazinyl, octahydro-1H-pyrrolo[3,2-c]pyridinyl, hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl, octahydropyrrolo[3,4-b]azepin-7(1H)-yl, or isoindolinyl.


In certain embodiments of formula (I), R3 is G3A wherein G3A is a 4-7 membered monocyclic heterocycle.


In certain embodiments of formula (I), R3 is G3A wherein G3A is azetidinyl, pyrrolidinyl, piperidinyl, dihydropyranyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyridinyl, azepanyl, 1,4-oxazepanyl, or 1,4-diazepanyl.


In certain embodiments of formula (I), R3 is G3A wherein G3A is azetidinyl, piperidinyl, or piperazinyl.


In certain embodiments of formula (I), R3 is G3A wherein G3A is piperidinyl or piperazinyl.


In certain embodiments of formula (I), R3 is G3A wherein G3A is piperidinyl.


In certain embodiments, each of the aforementioned G3A, including the exemplary rings, are optionally substituted with 1, 2, 3, or 4 independently selected Re groups.


In certain embodiments, each of the aforementioned G3A, including the exemplary rings, are optionally substituted with 1, 2, or 3 independently selected Re groups.


In certain embodiments, each of the aforementioned G3A, including the exemplary rings, are optionally substituted with 1 or 2 independently selected Re groups.


In certain embodiments, G3A, including the exemplary rings, are unsubstituted.


In certain embodiments, each of the optional substituents of G3A is independently C1-C6 alkyl, C1-C6 haloalkyl, halogen, oxo, —CN, —N3, —ORf, —S(O)2Rf, —C(O)Rf, —C(O)ORf, —C(O)NRfRh, —N(Rf)2, —N(Rh)C(O)Rh, —N(Rh)S(O)2Rg, or —N(Rh)C(O)O(Rg); wherein the C1-C6 haloalkyl and the C1-C6 alkyl are each optionally substituted with 1 or 2 substituents independently selected from the group consisting of —CN, —ORf, —N(Rf)2, —C(O)N(Rf)2, and —N(Rh)C(O)O(Rg).


In certain embodiments, each of the optional substituents of G3A is independently C1-C6 alkyl, C1-C6 haloalkyl, halogen, oxo, —CN, —N3, —ORf, —S(O)2Rf, —C(O)ORf, —N(Rf)2, or —N(Rh)C(O)Rh; wherein the C1-C6 haloalkyl and the C1-C6 alkyl are each optionally substituted with 1 or 2 substituents independently selected from the group consisting of —CN, —ORf, and —N(Rf)2; and each Rf is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, —(C1-C6 alkylenyl)-ORm, or —(C1-C6 alkylenyl)-N(Rm)2.


In certain embodiments, each of the optional substituents of G3A is independently C1-C6 alkyl, C1-C6 haloalkyl, halogen, —CN, —ORf, or —N(Rf)2; wherein the C1-C6 haloalkyl and the C1-C6 alkyl are each optionally substituted with 1 or 2 substituents independently selected from the group consisting of —ORf and —N(Rf)2; and each Rf is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, —(C1-C6 alkylenyl)-ORm, or —(C1-C6 alkylenyl)-N(Rm)2.


In certain embodiments of formula (I), R3 is -G3B-L1-G3C.


In certain embodiments of formula (I), R3 is -G3B-L3-G3C-L4-G3F or —(C1-C6 alkylenyl)-G3E.


In certain embodiments of formula (I), G3B is phenyl, 5-6 membered monocyclic heteroaryl, or 4-7 membered monocyclic heterocycle.


In certain embodiments of formula (I), G3B is phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, 1,4-diazepanyl, octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl, 1-oxa-8-azaspiro[4.5]decyl, or 3,9-diazaspiro[5.5]undecyl.


In certain embodiments of formula (I), G3B is phenyl, pyridinyl, pyrimidinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or 1,4-diazepanyl.


In certain embodiments of formula (I), G3B is a 4-7 membered monocyclic heterocycle.


In certain embodiments of formula (I), G3B is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or 1,4-diazepanyl.


In certain embodiments of formula (I), G3B is piperidinyl or piperazinyl.


In certain embodiments of formula (I), G3B is piperidinyl.


In certain embodiments of formula (I), G3B is piperazinyl.


In certain embodiments of formula (I), G3C is C3-C6 monocyclic cycloalkyl, phenyl, 5-6 membered monocyclic heteroaryl, or 4-11 membered heterocycle.


In certain embodiment of formula (I)s, G3C is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, 1,3-dioxolanyl, 1,4-diazepanyl, 1,4-oxazepanyl, oxazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, thiomorpholinyl, morpholinyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 3-azabicyclo[3.1.0]hexyl, hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl, 2-oxa-6-azaspiro[3.3]heptyl, 6-oxa-2-azaspiro[3.5]nonyl, 2-oxa-5,8-diazaspiro[3.5]nonyl, 6-oxa-2-azaspiro[3.4]octyl, 2-oxa-6-azaspiro[3.4]octyl, 8-oxa-3-azabiclo[3.2.1]octyl, or 2-oxa-7-azaspiro[3.5]nonyl.


In certain embodiments of formula (I), G3C is a 4-7 membered monocyclic heterocycle.


In certain embodiments of formula (I), G3C is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, oxazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, thiomorpholinyl, or morpholinyl.


In certain embodiments of formula (I), G3C is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydropyranyl, or morpholinyl.


In certain embodiments of formula (I), G3C is pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl.


In certain embodiments, each of the aforementioned G3B and G3C, including the exemplary rings, are optionally substituted with 1, 2, 3, or 4 independently selected Re groups.


In certain embodiments, each of the aforementioned G3B and G3C, including the exemplary rings, are optionally substituted with 1, 2, or 3 independently selected Re groups.


In certain embodiments, each of the aforementioned G3B and G3C, including the exemplary rings, are optionally substituted with 1 or 2 independently selected Re groups.


In certain embodiments, G3B and G3C, including the exemplary rings, are unsubstituted.


In certain embodiments, each of the optional substituents of G3B is independently C1-C6 alkyl, C1-C6 haloalkyl, halogen, —ORf, or —CN. In some such embodiments, Rf is hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl.


In certain embodiments, each of the optional substituents of G3B is independently —CH3, —CH2F, —CHF2, —CF3, or F.


In certain embodiments, each of the optional substituents of G3C is independently C1-C6 alkyl, C1-C6 haloalkyl, halogen, oxo, or —CN.


In certain embodiments, each of the optional substituents of G3C is independently —CH3, —C(CH3)3, —CH2F, —CHF2, —CF3, —CH2CH2CF3, F, or —CN.


In certain embodiments, L1 is a bond, C1-C3 alkylenyl, or (C1-C3 alkylenyl)r-L2-(C1-C3 alkylenyl)s.


In certain embodiments, L1 is a bond.


In certain embodiments, L1 is C1-C3 alkylenyl.


In certain embodiments, L2 is O, N(Rx), or C(O).


In certain embodiments, L2 is O or N(Rx).


In certain embodiments of formula (I), R3 is —OR3a.


In certain embodiments of formula (I), R3 is —OR3a wherein R3a is G3E, C1-C6 haloalkyl, or C1-C6 alkyl; wherein the C1-C6 haloalkyl and the C1-C6 alkyl are each substituted with one or two substituents independently selected from the group consisting of G3E, —OR3xa, —C(O)G3D, —N(R3xb)2, and —S(O)2R3xc.


In certain embodiments of formula (I), R3 is —OR3a wherein R3a is G3E.


In certain embodiments of formula (I), R3 is —OR3a wherein R3a is C1-C6 haloalkyl or C1-C6 alkyl; wherein the C1-C6 haloalkyl and the C1-C6 alkyl are each substituted with one substituent selected from the group consisting of —OR3xa and —N(R3xb)2.


In certain embodiments of formula (I), R3 is —OR3a wherein R3a is C1-C6 haloalkyl or C1-C6 alkyl; wherein the C1-C6 haloalkyl and the C1-C6 alkyl are each substituted with one G3E.


In certain embodiments, G3E is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, imidazolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, thiomorpholinyl, morpholinyl, 1,3-dioxolanyl, azepanyl, 1,4-diazepanyl, 1,3-dioxanyl, 1,4-dioxanyl, 2-oxaspiro[3.3heptyl, 8-azaspiro[4.5]decyl, 5-azaspiro[3.4]octyl, 8-azabicyclo[3.2.1]octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl.


In certain embodiments, G3E is a 4-11 membered heterocycle.


In certain embodiments, G3E is oxetanyl, pyrrolidinyl, tetrahydrofuranyl, imidazolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, thiomorpholinyl, morpholinyl, 1,3-dioxolanyl, azepanyl, 1,4-diazepanyl, 1,3-dioxanyl, 1,4-dioxanyl, or 8-azaspiro[4.5]decyl.


In certain embodiments, G3E is a 4-7 membered monocyclic heterocycle.


In certain embodiments, G3E is oxetanyl, pyrrolidinyl, tetrahydrofuranyl, imidazolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, thiomorpholinyl, morpholinyl, 1,3-dioxolanyl, azepanyl, 1,4-diazepanyl, 1,3-dioxanyl, or 1,4-dioxanyl.


In certain embodiments, G3E is tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, thiomorpholinyl, morpholinyl, or 1,4-dioxanyl.


In certain embodiments, G3E is piperidinyl, piperazinyl, tetrahydropyranyl, or morpholinyl.


In certain embodiments, G3E is tetrahydropyranyl.


In certain embodiments, each of the aforementioned G3E, including the exemplary rings, is optionally substituted with 1, 2, 3, or 4 independently selected Re groups.


In certain embodiments, each of the aforementioned G3E, including the exemplary rings, is optionally substituted with 1, 2, or 3 independently selected Re groups.


In certain embodiments, each of the aforementioned G3E, including the exemplary rings, is optionally substituted with 1 or 2 independently selected Re groups.


In certain embodiments, G3E, including the exemplary rings, is unsubstituted.


In certain embodiments, each of the aforementioned G3E, including the exemplary rings, is substituted with one G3F; and said G3E is optionally further substituted with 1 or 2 independently selected Re groups. In some such embodiments, G3F is azetidinyl, oxetanyl, thiomorpholinyl, piperidinyl, or cyclohexyl.


In certain embodiments, each of the optional substituents of G3E is independently C1-C6 alkyl or C1-C6 haloalkyl, wherein the C1-C6 alkyl and C1-C6 haloalkyl are each optionally substituted with 1 or 2 substituents independently selected from the group consisting of —CN, —ORf, and —N(Rf)2.


In certain embodiments of formula (I), R3 is —N(R3a)(R3b).


In certain embodiments of formula (I), R3 is —N(R3a)(R3b) wherein R3a is G3E, C1-C3 haloalkyl, or C1-C3 alkyl; wherein the C1-C3 haloalkyl and the C1-C3 alkyl are each substituted with one substituent independently selected from the group consisting of G3E, —OR3xa and —N(R3xb)2. In some such embodiments, R3xa, at each occurrence, is independently hydrogen, C1-C3 haloalkyl, or C1-C3 alkyl; and R3xb, at each occurrence, is independently hydrogen, C1-C3 haloalkyl, C1-C3 alkyl; and G3E. In some such embodiments, G3E is optionally substituted C3-C6 monocyclic cycloalkyl or optionally substituted 4-7 membered monocyclic heterocycle. In some such embodiments, G3E is cyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, or morpholinyl.


In certain embodiments of formula (I), R3 is -G3B-L3-G3C-L4-G3F.


In certain embodiments of formula (I), R3 is -G3B-L3-G3C-L4-G3F wherein L4 is a bond, C1-C6 alkylenyl, N(R2x), or C(O). In some such embodiments, G3B is phenyl, 5-6 membered monocyclic heteroaryl, or 4-7 membered monocyclic heterocycle, each of which is optionally substituted; and G3C is optionally substituted 4-7 membered monocyclic heterocycle.


In certain embodiments of formula (I), R3 is —(C1-C6 alkylenyl)-G3E.


In certain embodiments of formula (I), R3 is —N(R3b)C(O)G3D or —C(O)G3D.


In certain embodiments of formula (I), R4 is hydrogen or C1-C3 alkyl.


In certain embodiments of formula (I), R4 is hydrogen.


Various embodiments of substituents R1, R2, R3, R4, G1A, R1a, G1B, G1C, R1b, R1c, G1D, R1d, G2A, G2B, R2a, R2xa, G3A, G3B, G3C, G3D, G3E, Re, Rf, L1, L2, L1A, L3, L4, R3a, and R3b have been discussed above. These substituents embodiments can be combined to form various embodiments of the invention. All embodiments of present compounds, formed by combining the substituent embodiments discussed above are within the scope of Applicant's invention, and some illustrative embodiments of present compounds are provided below.


In one embodiment, the invention is directed to compounds wherein R1 is G1A or -G1B-G1C; and R2 is C2-C4 alkenyl, C1-C6 alkyl, C1-C6 haloalkyl, —OR2xa, or G2A.


In one embodiment, the invention is directed to compounds wherein R1 is G1A or -G1B-G1C; and R3 is G3A, -G3B-L1-G3C, —OR3a, or —N(R3a)(R3b).


In one embodiment, the invention is directed to compounds wherein R1 is G1A or -G1B-G1C; R2 is C2-C4 alkenyl, C1-C6 alkyl, C1-C6 haloalkyl, —OR2xa, or G2A; and R3 is G3A, -G3B-L1-G3C, —OR3a, —N(R3a)(R3b).


In one embodiment, the invention is directed to compounds wherein R1 is G1A or -G1B-G1C; G1A is phenyl or 5-6 membered monocyclic heteroaryl; R2 is C1-C6 alkyl; R3 is G3A, -G3B-L1-G3C, —OR3a, —N(R3a)(R3b); and G3A is a 4-11 membered heterocycle.


In one embodiment, the invention is directed to compounds wherein R1 is G1A or -G1B-G1C; G1A is phenyl or 5-6 membered monocyclic heteroaryl; R2 is —OR2xa or G2A; R2xa is G2B; and R3 is G3A, -G3B-L1-G3C, —OR3a, or —N(R3a)(R3b).


In one embodiment, the invention is directed to compounds wherein R1 is G1A or -G1B-G1C; G1A is phenyl or 5-6 membered monocyclic heteroaryl; R2 is G2A; G2A is C3-C6 monocyclic cycloalkyl; and R3 is G3A, -G3B-L1-G3C, —OR3a, —N(R3a)(R3b).


In one embodiment, the invention is directed to compounds wherein R1 is G1A or -G1B-G1C; R2 is C1-C6 alkyl or G2A; and R3 is G3A, -G3B-L1-G3C, or —OR3a.


In one embodiment, the invention is directed to compounds wherein R1 is G1A; G1A is phenyl or 5-6 membered monocyclic heteroaryl; R2 is C1-C6 alkyl; R3 is G3A; and G3A is a 4-7 membered monocyclic heterocycle.


In one embodiment, the invention is directed to compounds wherein R1 is G1A; G1A is phenyl or 5-6 membered monocyclic heteroaryl; R2 is G2A; G2A is C3-C6 monocyclic cycloalkyl; R3 is G3A; and G3A is a phenyl, 5-6 membered monocyclic heteroaryl, or 4-11 membered heterocycle.


In one embodiment, the invention is directed to compounds wherein R1 is G1A; G1A is phenyl or 5-6 membered monocyclic heteroaryl; R2 is G2A; G2A is C3-C6 monocyclic cycloalkyl; R3 is G3A; and G3A is a 4-7 membered monocyclic heterocycle.


In one embodiment, the invention is directed to compounds wherein R1 is G1A; G1A is phenyl or 5-6 membered monocyclic heteroaryl; R2 is C1-C6 alkyl or G2A; G2A is C3-C6 monocyclic cycloalkyl; and R3 is -G3B-L1-G3C.


In one embodiment, the invention is directed to compounds wherein R1 is G1A; G1A is phenyl or 5-6 membered monocyclic heteroaryl; R2 is C1-C6 alkyl or G2A; G2A is C3-C6 monocyclic cycloalkyl; R3 is -G3B-L1-G3C; L1 is a bond, C1-C3 alkylenyl, or (C1-C3 alkylenyl)r-L2-(C1-C3 alkylenyl)s; L2 is O, N(Rx), or C(O); and G3B is phenyl, 5-6 membered monocyclic heteroaryl, or 4-7 membered monocyclic heterocycle.


In one embodiment, the invention is directed to compounds wherein R1 is G1A; G1A is phenyl or 5-6 membered monocyclic heteroaryl; R2 is C1-C6 alkyl or G2A; G2A is C3-C6 monocyclic cycloalkyl; R3 is -G3B-L1-G3C; L1 is a bond, C1-C3 alkylenyl, or (C1-C3 alkylenyl)r-L2-(C1-C3 alkylenyl)s; L2 is O or N(Rx); and G3B is 4-7 membered monocyclic heterocycle.


In one embodiment, the invention is directed to compounds wherein R1 is G1A; G1A is phenyl or 5-6 membered monocyclic heteroaryl; R2 is C1-C6 alkyl or G2A; G2A is C3-C6 monocyclic cycloalkyl; R3 is —OR3a; and R3a is G3E, C1-C6 haloalkyl, or C1-C6 alkyl; wherein the C1-C6 haloalkyl and the C1-C6 alkyl are each substituted with one or two substituents independently selected from the group consisting of G3E, —OR3xa, —C(O)G3D, —N(R3xb)2, and —S(O)2R3xc.


In one embodiment, the invention is directed to compounds wherein R1 is G1A; G1A is phenyl or 5-6 membered monocyclic heteroaryl; R2 is C1-C6 alkyl or G2A; G2A is C3-C6 monocyclic cycloalkyl; R3 is —OR3a; and R3a is C1-C6 haloalkyl or C1-C6 alkyl; wherein the C1-C6 haloalkyl and the C1-C6 alkyl are each substituted with one G3E.


In one embodiment, the invention is directed to compounds wherein R1 is G1A; G1A is phenyl or 5-6 membered monocyclic heteroaryl; R2 is C1-C6 alkyl or G2A; G2A is C3-C6 monocyclic cycloalkyl; R3 is —OR3a; R1a is C1-C6 haloalkyl or C1-C6 alkyl; wherein the C1-C6 haloalkyl and the C1-C6 alkyl are each substituted with one G3E; and G3E is a 4-7 membered monocyclic heterocycle.


In one embodiment, the invention is directed to compounds wherein R1 is -G1B-G1C; R2 is C1-C6 alkyl or G2A; and R3 is G3A, -G3B-L1-G3C, or —OR3a.


In one embodiment, the invention is directed to compounds wherein R1 is -G1B-G1C; R2 is C1-C6 alkyl or G2A; R3 is G3A; and G3A is phenyl, 5-6 membered monocyclic heteroaryl, or 4-11 membered heterocycle.


In one embodiment, the invention is directed to compounds wherein R1 is -G1B-G1c; R2 is C1-C6 alkyl or G2A; R3 is G3A; and G3A is 4-7 membered monocyclic heterocycle.


In one embodiment, the invention is directed to compounds wherein R1 is -G1B-G1C. R2 is C1-C6 alkyl or G2A; R3 is -G3B-L1-G3C; and G3B is phenyl, 5-6 membered monocyclic heteroaryl, or 4-7 membered monocyclic heterocycle.


In one embodiment, the invention is directed to compounds wherein R1 is -G1B-G1C; R2 is C1-C6 alkyl or G2A; R3 is -G3B-L1-G3C; L1 is a bond, C1-C3 alkylenyl, or (C1-C3 alkylenyl)r-L2-(C1-C3 alkylenyl)s; L2 is O or N(Rx); and G3B is 4-7 membered monocyclic heterocycle.


In one embodiment, the invention is directed to compounds wherein R1 is G1A or -G1B-G1C; R2 is C1-C6 alkyl or G2A; and R3 is G3B-L3-G3C or —(C1-C6 alkylenyl)-G3E.


In one embodiment, the invention is directed to compounds wherein R1 is G1A; G1A is optionally substituted phenyl or optionally substituted 5-6 membered monocyclic heteroaryl; R2 is C1-C6 alkyl or G2A wherein G2A is optionally substituted C3-C6 monocyclic cycloalkyl; R3 is -G3B-L3-G3C-L4-G3F or —(C1-C6 alkylenyl)-G3E; and L4 is a bond, C1-C6 alkylenyl, N(R2x), or C(O).


In one embodiment, the invention is directed to compounds wherein

    • R1 is G1A, -G1B-G1C, -G1B-L1A-G1C, C1-C6 haloalkyl, C1-C6 alkyl, —(C1-C6 alkylenyl)-CN, —(C1-C6 alkylenyl)-G1D, or -G1D-O-benzyl;
    • G1A is phenyl, 5-6 membered monocyclic heteroaryl, 4-7 membered monocyclic heterocycle, or C3-C6 monocyclic cycloalkyl; wherein each G1A is optionally substituted with 1, 2, 3, or 4 independently selected R1a groups;
    • G1B is phenyl or 5-6 membered monocyclic heteroaryl; wherein each G1B is optionally substituted with 1, 2, 3, or 4 independently selected R1b groups;
    • G1C is 4-7 membered monocyclic heterocycle which is optionally substituted with 1, 2, 3, or 4 independently selected R1c groups;
    • G1D, at each occurrence, is a 4-7 membered monocyclic heterocycle, or a C3-C6 monocyclic cycloalkyl; wherein each G1D is optionally substituted with 1, 2, 3, or 4 independently selected R1d groups;
    • R2 is C2-C4 alkenyl, C1-C6 alkyl, C1-C6 haloalkyl, —OR2xa, —(C1-C6 alkylenyl)-OR2xb, —(C1-C6 alkylenyl)-N(R2xb)2, —C(O)OR2xb, —C(O)N(R2xb)2, or -G2A;
    • R2xa is C1-C6 alkyl, C1-C6 haloalkyl, or G2B;
    • R2xb, at each occurrence, is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl;
    • G2A and G2B are each independently 4-7 membered monocyclic heterocycle or C3-C6 monocyclic cycloalkyl; wherein G2A and G2B are each optionally substituted with 1, 2, or 3 independently selected R2a groups;
    • R3 is G3A, -G3B-L1-G3C, —OR3a, —N(R3a)(R3b), —N(R3b)C(O)G3D, or —C(O)G3D;
    • R3a, at each occurrence, is independently G3E, C1-C6 haloalkyl, or C1-C6 alkyl; wherein the C1-C6 haloalkyl and the C1-C6 alkyl are each optionally substituted with one or two substituents independently selected from the group consisting of G3E, —OR3xa, —C(O)G3D, —N(R3xb)2, and —S(O)2R3xc;
    • R3xa, R3xb, and R3xc, at each occurrence, are each independently hydrogen, C1-C6 haloalkyl, C1-C6 alkyl, G3E, —(C1-C6 alkylenyl)-OR3ya, or —(C1-C6 alkylenyl)-N(R3ya)2; wherein R3ya, at each occurrence, is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl;
    • R3b, at each occurrence, is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl;
    • L1 is a bond, C1-C6 alkylenyl, (C1-C6 alkylenyl)r-L2-(C1-C6 alkylenyl)s, or O—(C1-C6 alkylenyl)-C(O), wherein the left end of the L1 moiety is attached to G3B;
    • L2 is O, N(Rx), C(O), N(Rx)C(O), or C(O)N(Rx); wherein each Rx is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl;
    • r is 0 or 1;
    • s is 0 or 1;
    • G3A, G3B, and G3C, are each independently C3-C11 cycloalkyl, phenyl, 5-6 membered monocyclic heteroaryl, or 4-11 membered heterocycle, wherein G3A, G3B, and G3C are each optionally substituted with 1, 2, 3, or 4 independently selected Re groups;
    • G3D, at each occurrence, is 4-7 membered monocyclic heterocycle which is optionally substituted with 1, 2, 3, or 4 independently selected Re groups;
    • G3E, at each occurrence, is independently C3-C8 monocyclic cycloalkyl or 4-11 membered heterocycle; wherein each G3E is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of Re and G3F;
    • G3F, at each occurrence, is independently a 4-7 membered monocyclic heterocycle or a C3-C6 monocyclic cycloalkyl; wherein each G3F is optionally substituted with 1, 2, 3, or 4 independently selected Re groups;
    • Re, at each occurrence, is independently C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl, C1-C6 haloalkyl, halogen, oxo, —CN, —N3, NO2, —ORf, —OC(O)Rg, —OC(O)NRfRh, —SRf, —S(O)2Rf, —S(O)2NRfRh, —C(O)Rf, —C(O)ORf, —C(O)NRfRh, —C(O)N(Rh)S(O)2Rf, —N(Rf)2, —N(Rh)C(O)Rf, —N(Rh)S(O)2Rg, —N(Rh)C(O)O(Rg), —N(Rh)C(O)NRfRh, or —N(Rh)S(O)2NRfRh; wherein the C1-C6 haloalkyl and the C1-C6 alkyl are each optionally substituted with 1 or 2 substituents independently selected from the group consisting of halogen, —CN, NO2, —ORf, —OC(O)Rg, —OC(O)NRfRh, —SRf, —S(O)2Rf, —S(O)2NRfRh, —C(O)R, —C(O)OR, —C(O)NRfRh, —C(O)N(Rh)S(O)2Rf, —N(Rf)2, —N(Rh)C(O)Rf, —N(Rh)S(O)2Rg, —N(Rh)C(O)O(Rg), —N(Rh)C(O)NRfRh, and —N(Rh)S(O)2NRfRh;
    • Rf, at each occurrence, is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, —(C1-C6 alkylenyl)-CN, —(C1-C6 alkylenyl)-ORm, —(C1-C6 alkylenyl)-OC(O)Rn, —(C1-C6 alkylenyl)-OC(O)N(Rm)2, —(C1-C6 alkylenyl)-SRm, —(C1-C6 alkylenyl)-S(O)2Rm, —(C1-C6 alkylenyl)-S(O)2N(Rm)2, —(C1-C6 alkylenyl)-C(O)Rm, —(C1-C6 alkylenyl)-C(O)ORm, —(C1-C6 alkylenyl)-C(O)N(Rm)2, —(C1-C6 alkylenyl)-C(O)N(Rm)S(O)2Rn, —(C1-C6 alkylenyl)-N(Rm)2, —(C1-C6 alkylenyl)-N(Rm)C(O)Rn, —(C1-C6 alkylenyl)-N(Rm)S(O)2Rn, —(C1-C6 alkylenyl)-N(Rm)C(O)O(Rn), —(C1-C6 alkylenyl)-N(Rm)C(O)N(Rm)2, or —(C1-C6 alkylenyl)-N(Rm)S(O)2N(Rm)2;
    • Rg, at each occurrence, is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, —(C1-C6 alkylenyl)-CN, —(C1-C6 alkylenyl)-ORm, —(C1-C6 alkylenyl)-OC(O)Rn, —(C1-C6 alkylenyl)-OC(O)N(Rm)2, —(C1-C6 alkylenyl)-SRm, —(C1-C6 alkylenyl)-S(O)2Rm, —(C1-C6 alkylenyl)-S(O)2N(Rm)2, alkylenyl)-C(O)Rm, —(C1-C6 alkylenyl)-C(O)ORm, —(C1-C6 alkylenyl)-C(O)N(Rm)2, —(C1-C6 alkylenyl)-C(O)N(Rm)S(O)2Rn, —(C1-C6 alkylenyl)-N(Rm)2, —(C1-C6 alkylenyl)-N(Rm)C(O)Rn, —(C1-C6 alkylenyl)-N(Rm)S(O)2Rn, —(C1-C6 alkylenyl)-N(Rm)C(O)O(R″), —(C1-C6 alkylenyl)-N(Rm)C(O)N(Rm)2, or —(C1-C6 alkylenyl)-N(Rm)S(O)2N(Rm)2;
    • Rh, at each occurrence, is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or —(C1-C6 alkylenyl)-ORm;
    • R1a, R1b, R1c, R1d, and R2a, at each occurrence, are each independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogen, C1-C6 haloalkyl, oxo, —CN, NO2, —ORm, —OC(O)Rn, —OC(O)N(Rm)2, —SRm, —S(O)2Rm, —S(O)2N(Rm)2, —C(O)Rm, —C(O)ORm, —C(O)N(Rm)2, —C(O)N(Rm)S(O)2Rn, —N(Rm)2, —N(Rm)(alkoxyalkyl), —N(alkoxyalkyl)2, —N(Rm)C(O)Rn, —N(Rm)S(O)2Rn, —N(Rm)C(O)O(Rn), —N(Rm)C(O)N(Rm)2, —N(Rm)S(O)2N(Rm)2, —(C1-C6 alkylenyl)-CN, —(C1-C6 alkylenyl)-ORm, —(C1-C6 alkylenyl)-OC(O)Rn, —(C1-C6 alkylenyl)-OC(O)N(Rm)2, —(C1-C6 alkylenyl)-SRm, —(C1-C6 alkylenyl)-S(O)2Rm, —(C1-C6 alkylenyl)-S(O)2N(Rm)2, —(C1-C6 alkylenyl)-C(O)Rm, —(C1-C6 alkylenyl)-C(O)ORm, —(C1-C6 alkylenyl)-C(O)N(Rm)2, —(C1-C6 alkylenyl)-C(O)N(Rm)S(O)2Rn, —(C1-C6 alkylenyl)-N(Rm)2, —(C1-C6 alkylenyl)-N(Rm)C(O)Rn, —(C1-C6 alkylenyl)-N(Rm)S(O)2Rn, —(C1-C6 alkylenyl)-N(Rm)C(O)O(Rn), —(C1-C6 alkylenyl)-N(Rm)C(O)N(Rn)2, or —(C1-C6 alkylenyl)-N(Rm)S(O)2N(Rn)2;
    • Rm, at each occurrence, is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl;
    • Rn, at each occurrence, is independently C1-C6 alkyl or C1-C6 haloalkyl; and
    • R4 is hydrogen, C1-C3 alkyl, or C1-C3 haloalkyl;
    • with the proviso that when R1 is C1-C6 alkyl or G1A, wherein G1A is optionally substituted phenyl, optionally substituted 5-6 membered monocyclic heteroaryl, or optionally substituted 4-7 membered monocyclic heterocycle, R2 is C1-C6 alkyl, and R3 is G3A, then G3A is not optionally substituted phenyl or optionally substituted 5-6 membered monocyclic heteroaryl.


Exemplary compounds of formula (I) include, but are not limited to:

  • 3-methyl-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclohexyl-4-(4-methoxyphenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclopentyl-4-(4-methoxyphenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(2-cyanoethyl)-4-(4-methoxyphenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(morpholin-4-yl)phenyl]-1-phenyl-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-4-[4-(morpholin-4-yl)phenyl]-1-[5-(trifluoromethyl)-1H-pyrazol-3-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-1-phenyl-4-[4-(piperidin-1-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-4-[4-(4-methylpiperazin-1-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(3,5-difluorophenyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(3-chlorophenyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(3-fluorophenyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-1-(3-methylphenyl)-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(1,1-dioxo-1λ6,4-thiazinan-4-yl)phenyl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-4-[2-(morpholin-4-yl)pyrimidin-5-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-(ethoxycarbonyl)-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclohexyl-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(3-bromophenyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-(hydroxymethyl)-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(3-methylphenyl)-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(3-methoxyphenyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-4-[4-(morpholin-4-yl)phenyl]-1-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-4-[4-(morpholin-4-yl)phenyl]-1-(oxan-4-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-phenyl-3-(propan-2-yl)-4-[4-(pyrrolidin-1-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-1-phenyl-4-[4-(pyrrolidin-1-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[2-chloro-4-(morpholin-4-yl)phenyl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-4-[4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(3-fluoropyrrolidin-1-yl)phenyl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(4-acetylpiperazin-1-yl)phenyl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(3,5-dimethylphenyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-4-[4-(morpholin-4-yl)phenyl]-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-1-[3-(morpholin-4-yl)phenyl]-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[2-methoxy-4-(morpholin-4-yl)phenyl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclopropyl-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-4-[4-(morpholin-4-yl)phenyl]-1-[3-(trifluoromethoxy)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-[3-(dimethylamino)phenyl]-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(3,4-difluorophenyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-[3-(methanesulfonyl)phenyl]-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-1-(1-methylpiperidin-4-yl)-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-tert-butyl-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(2-chloropyridin-4-yl)-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3,5-dimethyl-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(3,5-dichlorophenyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-4-[4-(morpholin-4-yl)phenyl]-1-(3-sulfamoylphenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-1-(1-methyl-1H-pyrazol-4-yl)-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-[1-(tert-butoxycarbonyl)azetidin-3-yl]-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(morpholin-4-yl)phenyl]-1-phenyl-3-(prop-1-en-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(3-cyanophenyl)-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-4-[6-(morpholin-4-yl)pyridin-3-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(2-methoxypyridin-4-yl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(3-fluoro-5-methoxyphenyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-{4-[4-(methanesulfonyl)piperazin-1-yl]phenyl}-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclohexyl-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-(methylcarbamoyl)-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-(1-hydroxy-2-methylpropan-2-yl)-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(2-fluoropyridin-4-yl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-4-[4-(morpholin-4-yl)phenyl]-1-(2-oxo-1,2-dihydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(3-carbamoylphenyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(4-tert-butylpiperazin-1-yl)phenyl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(6-methoxypyridin-3-yl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclohexyl-4-[2-(dimethylamino)pyrimidin-5-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-(2-hydroxypropan-2-yl)-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-carbamoyl-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclohexyl-3-methyl-4-[2-(morpholin-4-yl)pyrimidin-5-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[3-bromo-4-(morpholin-4-yl)phenyl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclopentyl-4-[2-(dimethylamino)pyrimidin-5-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(morpholin-4-yl)phenyl]-1-(oxan-3-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclopentyl-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-{4-[4-(methoxycarbonyl)piperazin-1-yl]phenyl}-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(1-acetylpiperidin-4-yl)-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-{4-[3-(dimethylamino)azetidin-1-yl]phenyl}-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(3,3-dimethylazetidin-1-yl)phenyl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclohexyl-3-methyl-4-[6-(morpholin-4-yl)pyridin-3-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclohexyl-4-[2-(dimethylamino)pyrimidin-5-yl]-3-methyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-[1-(tert-butoxycarbonyl)pyrrolidin-2-yl]-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclopentyl-4-[6-(morpholin-4-yl)pyridin-3-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-(1-acetylazetidin-3-yl)-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[2-(morpholin-4-yl)pyrimidin-5-yl]-1-phenyl-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclohexyl-4-[2-(morpholin-4-yl)pyrimidin-5-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclohexyl-4-[6-(morpholin-4-yl)pyridin-3-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-1-phenyl-4-{4-[4-(3,3,3-trifluoropropyl)piperazin-1-yl]phenyl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclopentyl-4-[6-(dimethylamino)pyridin-3-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-[3-(dimethylamino)phenyl]-4-[2-(morpholin-4-yl)pyrimidin-5-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-[3-(dimethylamino)phenyl]-4-[6-(morpholin-4-yl)pyridin-3-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-[1-(methoxycarbonyl)azetidin-3-yl]-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-[(dimethylamino)methyl]-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[2-(dimethylamino)pyrimidin-5-yl]-1-[3-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[6-(dimethylamino)pyridin-3-yl]-1-[3-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-[3-(dimethylamino)phenyl]-3-methyl-4-[2-(morpholin-4-yl)pyrimidin-5-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-tert-butyl-1-cyclopentyl-4-[2-(dimethylamino)pyrimidin-5-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-(1-hydroxy-2-methylpropan-2-yl)-4-[6-(morpholin-4-yl)pyridin-3-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclohexyl-4-[6-(dimethylamino)pyridin-3-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-1-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-[1-(cyanomethyl)piperidin-4-yl]-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(cyclobutylamino)phenyl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(3,3-difluoroazetidin-1-yl)phenyl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-{4-[4-(cyanomethyl)piperazin-1-yl]phenyl}-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclohexyl-4-[6-(dimethylamino)pyridin-3-yl]-3-methyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-tert-butyl-1-cyclopentyl-4-[2-(morpholin-4-yl)pyrimidin-5-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(3-fluorophenyl)-3-methyl-4-[6-(morpholin-4-yl)pyridin-3-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-4-[6-(morpholin-4-yl)pyridin-3-yl]-1-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-[1-(tert-butoxycarbonyl)pyrrolidin-2-yl]-4-[6-(morpholin-4-yl)pyridin-3-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(2,4-difluorophenyl)-3-methyl-4-[6-(morpholin-4-yl)pyridin-3-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(2,4-difluorophenyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclopentyl-3-methyl-4-[6-(morpholin-4-yl)pyridin-3-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-{4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(4,4-difluoropiperidin-1-yl)phenyl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(4-cyanopiperidin-1-yl)phenyl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-4-{4-[methyl(oxan-4-yl)amino]phenyl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(3,3-difluoropyrrolidin-1-yl)phenyl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-4-{4-[(oxetan-3-yl)amino]phenyl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-(3-methyloxetan-3-yl)-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(2,6-dimethylmorpholin-4-yl)phenyl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-{4-[cyclobutyl(methyl)amino]phenyl}-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-{4-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]phenyl}-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-4-(morpholin-4-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid; 4-[4-(2,2-dimethylmorpholin-4-yl)phenyl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(morpholin-4-yl)phenyl]-1-(oxolan-3-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-[3-(morpholin-4-yl)phenyl]-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-(methoxymethyl)-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-1-phenyl-4-(piperidin-1-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(3-hydroxyazetidin-1-yl)phenyl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(3-fluoroazetidin-1-yl)phenyl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-4-[4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-4-{4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]phenyl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-(1-methylcyclopropyl)-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-tert-butyl-1-cyclohexyl-4-[4-(dimethylamino)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(4-acetylpiperazin-1-yl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-{4-[2-(hydroxymethyl)morpholin-4-yl]phenyl}-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-4-[4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(azetidin-1-yl)phenyl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(cyanomethyl)piperazin-1-yl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(4-hydroxypiperidin-1-yl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(1-acetylpiperidin-4-yl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[1-(cyanomethyl)piperidin-4-yl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-4-{4-[methyl(oxetan-3-yl)amino]phenyl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-[1-(cyanomethyl)pyrrolidin-3-yl]-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-[1-(methoxycarbonyl)pyrrolidin-3-yl]-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(4-methoxypiperidin-1-yl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(4-hydroxypiperidin-1-yl)phenyl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-4-{4-[(oxan-4-yl)amino]phenyl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(methanesulfonyl)piperazin-1-yl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-tert-butyl-1-cyclohexyl-4-[2-(dimethylamino)pyrimidin-5-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-[1-(cyanomethyl)azetidin-3-yl]-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-tert-butyl-1-cyclohexyl-4-[2-(morpholin-4-yl)pyrimidin-5-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-4-(2-oxopiperidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-[3-(azetidin-1-yl)phenyl]-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(cyclohexylmethoxy)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(3-hydroxypyrrolidin-1-yl)phenyl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-4-[4-(2-oxa-7-azaspiro[3.5]nonan-7-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-{4-[(3S)-3-cyanopyrrolidin-1-yl]phenyl}-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(3-acetamidopyrrolidin-1-yl)phenyl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1-[3-(pyrrolidin-1-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-1-phenyl-4-(piperidine-1-carbonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4,4-difluorocyclohexyl)-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-[3-(3,3-dimethylazetidin-1-yl)phenyl]-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1-[1-(2,2,2-trifluoroethyl)piperidin-3-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(3-methylphenyl)-4-(piperidin-1-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-[(1R,3R)-3-(benzyloxy)cyclohexyl]-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-[3-(3-methoxyazetidin-1-yl)phenyl]-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-[3-(3-fluoropyrrolidin-1-yl)phenyl]-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclohexyl-4-[2-(dimethylamino)pyrimidin-5-yl]-3-[1-(methoxycarbonyl)azetidin-3-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-[3-(3-fluoroazetidin-1-yl)phenyl]-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-4-{6-[methyl(oxan-4-yl)amino]pyridin-3-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclohexyl-4-{6-[methyl(oxan-4-yl)amino]pyridin-3-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclohexyl-4-{6[(2-methoxyethyl)(methyl)amino]pyridin-3-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(4-acetamidophenyl)-1-cyclohexyl-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-{3-[(2-methoxyethyl)(methyl)amino]phenyl}-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(3-methylphenyl)-3-(propan-2-yl)-4-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(3-fluoroazetidin-1-yl)-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(4-cyanopiperidin-1-yl)phenyl]-1-[3-(dimethylamino)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-1-[3-(dimethylamino)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-1-[3-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-{6-[(2-methoxyethyl)(methyl)amino]pyridin-3-yl}-1-[3-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-1-cyclohexyl-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclohexyl-4-[6-(3,3-difluoropyrrolidin-1-yl)pyridin-3-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{6-[methyl(oxan-4-yl)amino]pyridin-3-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclohexyl-4-{4-[(2-methoxyethyl)(methyl)amino]phenyl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(4-cyanopiperidin-1-yl)phenyl]-1-cyclohexyl-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(morpholin-4-yl)phenyl]-3-(oxolan-2-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-{6-[methyl(oxan-4-yl)amino]pyridin-3-yl}-1-[3-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-{4-[(2-methoxyethyl)(methyl)amino]phenyl}-1-[3-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-[3-(dimethylamino)phenyl]-4-{6-[methyl(oxan-4-yl)amino]pyridin-3-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(3-methoxypiperidin-1-yl)-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(4-cyanopiperidin-1-yl)-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(4-methoxypiperidin-1-yl)-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclohexyl-3-cyclopropyl-4-[6-(dimethylamino)pyridin-3-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • rac-1-[(1R,3R)-3-hydroxycyclohexyl]-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • rac-1-[(1R,3S)-3-hydroxycyclohexyl]-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclohexyl-4-[6-(2,6-dimethylmorpholin-4-yl)pyridin-3-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclohexyl-4-[6-(2,2-dimethylmorpholin-4-yl)pyridin-3-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(3-hydroxypiperidin-1-yl)phenyl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[2-(4-cyanopiperidin-1-yl)pyrimidin-5-yl]-1-[3-(dimethylamino)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-[3-(dimethylamino)phenyl]-4-{2-[methyl(oxan-4-yl)amino]pyrimidin-5-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(morpholin-4-yl)phenyl]-1-[2-(morpholin-4-yl)pyridin-4-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(3-methylphenyl)-4-(2-oxa-7-azaspiro[3.5]nonan-7-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[6-(4-cyano-4-methylpiperidin-1-yl)pyridin-3-yl]-1-cyclohexyl-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[2-(4-cyanopiperidin-1-yl)pyrimidin-5-yl]-1-[3-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-[(1R,3S)-3-methoxycyclohexyl]-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(4-cyanopiperidin-1-yl)phenyl]-1-[3-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-[3-(dimethylamino)phenyl]-4-{4-[methyl(oxan-4-yl)amino]phenyl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-{4-[methyl(oxan-4-yl)amino]phenyl}-1-[3-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[(2-methoxyethyl)(methyl)amino]-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(4,4-difluoropiperidin-1-yl)-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(morpholin-4-yl)phenyl]-1-[5-(morpholin-4-yl)pyridin-3-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(3-methoxyazetidin-1-yl)-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(hydroxymethyl)piperidin-1-yl]-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-[(1R,3R)-3-methoxycyclohexyl]-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(3-methylphenyl)-3-(propan-2-yl)-4-[3-(trifluoromethyl)pyrrolidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[5-(tert-butoxycarbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-{4-[3-(dimethylamino)pyrrolidin-1-yl]phenyl}-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(3-cyanopyrrolidin-1-yl)-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(4-cyanopiperidin-1-yl)phenyl]-3-cyclobutyl-1-cyclohexyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-cyclobutyl-1-cyclohexyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(4-cyanopiperidin-1-yl)phenyl]-3-(propan-2-yl)-1-[3-(pyrrolidin-1-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-(propan-2-yl)-1-[3-(pyrrolidin-1-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclohexyl-4-[6-(3-fluoropiperidin-1-yl)pyridin-3-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclohexyl-4-[6-(3-methoxypyrrolidin-1-yl)pyridin-3-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-[3-(3-hydroxyazetidin-1-yl)phenyl]-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[5-(cyanomethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(methoxymethyl)piperidin-1-yl]-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(2-methoxyethyl)piperidin-1-yl]-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-chloropyridin-2-yl)-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-{2-[(2-methoxyethyl)(methyl)amino]pyrimidin-5-yl}-1-[3-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-{2-[methyl(oxan-4-yl)amino]pyrimidin-5-yl}-1-[3-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-{4-[4-(cyanomethyl)piperazin-1-yl]phenyl}-1-(3-methoxyphenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(5-acetylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[1-(tert-butoxycarbonyl)octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[2-(4-cyanopiperidin-1-yl)pyrimidin-5-yl]-1-cyclohexyl-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclohexyl-4-{2-[methyl(oxan-4-yl)amino]pyrimidin-5-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclohexyl-4-{2-[(2-methoxyethyl)(methyl)amino]pyrimidin-5-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-{4-[(2-methoxyethyl)(methyl)amino]phenyl}-3-(propan-2-yl)-1-[3-(pyrrolidin-1-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-[3-(azetidin-1-yl)phenyl]-4-{6-[(2-methoxyethyl)(methyl)amino]pyridin-3-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-[3-(azetidin-1-yl)phenyl]-4-{4-[methyl(oxan-4-yl)amino]phenyl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(morpholin-4-yl)phenyl]-1-[4-(morpholin-4-yl)pyridin-2-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(3-fluorophenyl)-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(3,4-difluorophenyl)-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(morpholin-4-yl)phenyl]-1-[6-(morpholin-4-yl)pyridin-2-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(3,5-difluorophenyl)-4-{4-[methyl(oxan-4-yl)amino]phenyl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(3,5-difluorophenyl)-4-{6-[methyl(oxan-4-yl)amino]pyridin-3-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(4-cyanopiperidin-1-yl)phenyl]-3-cyclobutyl-1-[3-(pyrrolidin-1-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-cyclobutyl-1-[3-(pyrrolidin-1-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-{4-[methyl(oxan-4-yl)amino]phenyl}-3-(propan-2-yl)-1-[3-(pyrrolidin-1-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-{6-[methyl(oxan-4-yl)amino]pyridin-3-yl}-3-(propan-2-yl)-1-[3-(pyrrolidin-1-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{4-[methyl(oxan-4-yl)amino]phenyl}-1-[3-(pyrrolidin-1-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{6-[methyl(oxan-4-yl)amino]pyridin-3-yl}-1-[3-(pyrrolidin-1-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-{6-[(2-methoxyethyl)(methyl)amino]pyridin-3-yl}-3-(propan-2-yl)-1-[3-(pyrrolidin-1-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclohexyl-4-{4-[methyl(oxan-4-yl)amino]phenyl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(1-acetyloctahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[1-(cyanomethyl)octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(methanesulfonyl)piperidin-1-yl]-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(3-methylphenyl)-4-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[2-(4-cyanopiperidin-1-yl)pyrimidin-5-yl]-3-(propan-2-yl)-1-[3-(pyrrolidin-1-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-(propan-2-yl)-1-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(4-cyanopiperidin-1-yl)phenyl]-3-(propan-2-yl)-1-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(3-methylphenyl)-4-(8-oxa-2-azaspiro[4.5]decan-2-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(4-cyanopiperidin-1-yl)-1-cyclohexyl-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclohexyl-4-(4-methoxypiperidin-1-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclohexyl-4-(piperidin-1-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclohexyl-4-[4-(hydroxymethyl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-[6-(dimethylamino)pyridin-2-yl]-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(3,5-difluorophenyl)-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1-[3-(trifluoromethoxy)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-[3-(dimethylamino)phenyl]-3-(propan-2-yl)-4-[3-(trifluoromethyl)pyrrolidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(1,1-difluoro-5-azaspiro[2.4]heptan-5-yl)-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[3-(methanesulfonyl)pyrrolidin-1-yl]-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(2-azaspiro[3.3]heptan-2-yl)-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(3-methylphenyl)-4-(5-oxa-2-azaspiro[3.5]nonan-2-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-{6-[bis(2-methoxyethyl)amino]pyridin-3-yl}-1-cyclohexyl-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclohexyl-4-{6-[methyl(oxolan-3-yl)amino]pyridin-3-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{2-[methyl(oxan-4-yl)amino]pyrimidin-5-yl}-1-[3-(pyrrolidin-1-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(3,4-difluorophenyl)-4-{4-[methyl(oxan-4-yl)amino]phenyl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-1-(3,4-difluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-{2-[methyl(oxan-4-yl)amino]pyrimidin-5-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-{2-[methyl(oxan-4-yl)amino]pyrimidin-5-yl}-3-(propan-2-yl)-1-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(4-cyanopiperidin-1-yl)phenyl]-1-(3,5-difluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(3-fluorophenyl)-4-{6-[methyl(oxan-4-yl)amino]pyridin-3-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(3-fluorophenyl)-4-{4-[methyl(oxan-4-yl)amino]phenyl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-1-(3-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(4-cyanopiperidin-1-yl)phenyl]-1-(3-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-{6-[methyl(oxan-4-yl)amino]pyridin-3-yl}-3-(propan-2-yl)-1-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-4-(4-methyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[3-(methoxymethyl)-3-methylazetidin-1-yl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-4-(3-oxohexahydroimidazo[1,5-a]pyrazin-2(3H)-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(methoxymethyl)piperidin-1-yl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(4-acetamidopiperidin-1-yl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-4-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[3-(methoxymethyl)azetidin-1-yl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[(3R)-3-methoxypyrrolidin-1-yl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[(3S)-3-methoxypyrrolidin-1-yl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(4-fluoropiperidin-1-yl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[(3R)-3-fluoropyrrolidin-1-yl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(3,3-difluoropyrrolidin-1-yl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[(3S)-3-fluoropyrrolidin-1-yl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-4-(3-oxotetrahydro-3H-[1,3]oxazolo[3,4-a]pyrazin-7(1H)-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-4-[3-(morpholin-4-yl)azetidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-{4-[(methanesulfonyl)amino]piperidin-1-yl}-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(3-azabicyclo[3.1. O]hexan-3-yl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-1-phenyl-4-[4-(pyrrolidine-1-carbonyl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-4-(6-oxa-2-azaspiro[3.4]octan-2-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(2-azaspiro[3.4]octan-2-yl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-4-(6-oxa-2-azaspiro[3.5]nonan-2-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(2-azaspiro[3.5]nonan-2-yl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(5-azaspiro[2.5]octan-5-yl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-4-(1-oxa-7-azaspiro[4.4]nonan-7-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-4-(5-oxa-2-azaspiro[3.5]nonan-2-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-4-(6-oxo-2,7-diazaspiro[4.4]nonan-2-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-{4-[(1S)-2-(dimethylamino)-1-fluoroethyl]piperidin-1-yl}-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-4-(1,4-oxazepan-4-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(3-fluorophenyl)-4-{2-[methyl(oxan-4-yl)amino]pyrimidin-5-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(3,5-difluorophenyl)-4-{2-[methyl(oxan-4-yl)amino]pyrimidin-5-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(2-methoxyethoxy)piperidin-1-yl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(dimethylcarbamoyl)piperidin-1-yl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(methanesulfonyl)-1,4-diazepan-1-yl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(3-methoxypropyl)piperazin-1-yl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-4-[4-(morpholine-4-carbonyl)piperazin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-{4-[2-(dimethylamino)-2-oxoethyl]piperazin-1-yl}-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[2-(4-cyanopiperidin-1-yl)pyrimidin-5-yl]-1-(2,4-difluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-1-(2,4-difluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(4-cyanopiperidin-1-yl)phenyl]-1-(2,4-difluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-[3-(dimethylamino)phenyl]-4-(piperidin-1-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(4-cyanopiperidin-1-yl)-1-[3-(dimethylamino)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-[3-(dimethylamino)phenyl]-4-(4-methoxypiperidin-1-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-[3-(dimethylamino)phenyl]-4-[4-(hydroxymethyl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-(1-methylcyclobutyl)-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-{[cis-3-(1,1-dioxo-1λ6,4-thiazinan-4-yl)cyclobutyl]oxy}-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[2-(1,1-dioxo-1λ6,4-thiazinan-4-yl)ethoxy]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[(2S)-2-fluoro-2-(oxan-4-yl)ethoxy]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[(2R)-2-fluoro-2-(oxan-4-yl)ethoxy]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-4-{[(3S)-1-methylpyrrolidin-3-yl]oxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-4-{[(3R)-1-methylpyrrolidin-3-yl]oxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-4-[(1-methylpiperidin-4-yl)oxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-{[cis-3-(dimethylamino)cyclobutyl]oxy}-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-4-[(oxetan-3-yl)oxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid; 3-methyl-1-phenyl-4-[2-(pyrrolidin-1-yl)ethoxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-4-{[(3R)-1-methylpiperidin-3-yl]oxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-4-[(2-oxaspiro[3.3]heptan-6-yl)oxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-1-phenyl-4-{[trans-3-(piperidin-1-yl)cyclobutyl]oxy}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-1-phenyl-4-{[cis-3-(piperidin-1-yl)cyclobutyl]oxy}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[2-(3,3-difluorocyclobutyl)ethoxy]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(fluoromethyl)piperidin-1-yl]-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(3-fluorophenyl)-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(3,4-difluorophenyl)-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclohexyl-4-(1-methyl-1H-pyrrol-3-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclohexyl-4-(1,3-dimethyl-1H-pyrazol-4-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(3,5-difluorophenyl)-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-(morpholin-4-yl)phenyl]-1-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(3-fluoro-4-methylphenyl)-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-(morpholin-4-yl)phenyl]-1-[4-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-[4-(dimethylamino)phenyl]-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(4-methoxypiperidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(3-methyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-8-yl)-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(3-azaspiro[5.5]undecan-3-yl)-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclohexyl-3-(propan-2-yl)-4-[1-(propan-2-yl)-1H-pyrazol-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclohexyl-4-(1-methyl-1H-pyrrol-2-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclohexyl-3-(propan-2-yl)-4-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclohexyl-4-(1-oxo-2,3-dihydro-1H-isoindol-5-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-1-(oxan-3-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[2-(3-cyanopiperidin-1-yl)pyrimidin-5-yl]-1-cyclohexyl-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{4-[2-oxo-2-(pyrrolidin-1-yl)ethoxy]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-[3-(dimethylamino)phenyl]-4-[4-(methoxymethyl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-(propan-2-yl)-1-[2-(pyrrolidin-1-yl)pyridin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclohexyl-4-(1-methyl-1H-pyrazol-5-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]-1-cyclohexyl-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-phenyl-4-{4-[(propan-2-yl)oxy]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[3-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(2-{[1-(tert-butoxycarbonyl)piperidin-4-yl](methyl)amino}pyrimidin-5-yl)-1-cyclohexyl-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-4-[(3-methyloxetan-3-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[(4-methoxycyclohexyl)oxy]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[2-fluoro-2-(oxan-4-yl)ethoxy]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[(3-fluoro-1-methylpyrrolidin-3-yl)methoxy]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[(2S)-2-fluoro-2-(1-methylpiperidin-4-yl)ethoxy]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[(2R)-2-fluoro-2-(1-methylpiperidin-4-yl)ethoxy]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-{[3-fluoro-1-(oxetan-3-yl)piperidin-3-yl]methoxy}-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[(3,3-difluorocyclopentyl)methoxy]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-methyl-4-[2-oxo-2-(piperidin-1-yl)ethoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-{[1-(methanesulfonyl)cyclobutyl]methoxy}-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-{2-[cyclopropyl(2-methylpropyl)amino]ethoxy}-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[(3,3-difluoro-1-methylcyclobutyl)methoxy]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-{[1-(fluoromethyl)cyclopropyl]methoxy}-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-{[1-(2-methoxyethyl)cyclopropyl]methoxy}-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[(2,2-difluorocyclopentyl)methoxy]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(morpholin-4-yl)phenyl]-1-phenyl-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-[4-(methoxymethyl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(4-cyanopiperidin-1-yl)phenyl]-3-(propan-2-yl)-1-[2-(pyrrolidin-1-yl)pyridin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-(4-methoxypiperidin-1-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-[4-(hydroxymethyl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(4-butoxypiperidin-1-yl)-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-[4-(2-methylpropoxy)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-(4-methoxy-4-methylpiperidin-1-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-(1-oxa-7-azaspiro[3.5]nonan-7-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[3-(difluoromethyl)piperidin-1-yl]-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-(6-oxa-2-azaspiro[3.5]nonan-2-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-(1-oxa-8-azaspiro[4.5]decan-8-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclohexyl-3-(propan-2-yl)-4-(2,2,6,6-tetramethyl-3,6-dihydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-(2-methoxyethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(2-azaspiro[3.4]octan-2-yl)-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(3-azabicyclo[3.1.0]hexan-3-yl)-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(cyclohexylmethoxy)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-phenyl-4-(piperidin-1-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid; 4-(2-azaspiro[3.5]nonan-2-yl)-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(4-cyanopiperidin-1-yl)-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-(methanesulfonyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(4-methoxypiperidin-1-yl)-3-(propan-2-yl)-1-[2-(pyrrolidin-1-yl)pyridin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-cyclobutyl-1-[2-(pyrrolidin-1-yl)pyridin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[2-(oxan-4-yl)ethoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(2S)-2-fluoro-2-(oxan-4-yl)ethoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-cyclobutyl-1-[2-(morpholin-4-yl)pyridin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(oxan-4-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[3-(methoxymethyl)azetidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(5-azaspiro[2.5]octan-5-yl)-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-(3,3-difluorocyclobutyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-(cis-3-methoxycyclobutyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(2-methoxyethyl)(methyl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(1,1-difluoro-5-azaspiro[2.4]heptan-5-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(5-oxa-2-azaspiro[3.5]nonan-2-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(2-azaspiro[3.3]heptan-2-yl)-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-{4-[(benzyloxy)methyl]piperidin-1-yl}-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(cis-4-methoxycyclohexyl)oxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(trans-4-methoxycyclohexyl)oxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-(3,3-dimethylcyclobutyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclohexyl-4-[4-(methoxymethyl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-(cis-3-fluorocyclobutyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-(trans-3-fluorocyclobutyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(2R)-2-fluoro-2-(oxan-4-yl)ethoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(3,3-difluorocyclopentyl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[2-(1,1-dioxo-1λ6,4-thiazinan-4-yl)ethoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-1-[2-(morpholin-4-yl)pyridin-4-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-[4-(2-methoxypropan-2-yl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[(cis-3-tert-butoxycyclobutyl)(methyl)amino]-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(3-methylazetidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(3,3-difluoropyrrolidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-phenyl-4-[3-(trifluoromethyl)pyrrolidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-phenyl-4-[4-(pyrrolidin-1-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(4-fluoropiperidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(3 S,4S)-3,4-dihydroxypyrrolidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{4-[2-(dimethylamino)ethyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{4-[2-(diethylamino)ethyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-(cyclopropylmethyl)piperazin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(4-cyclobutylpiperazin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(3-fluoro-3-methylazetidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(8-azaspiro[4.5]decan-8-yl)-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(3,3-difluoro-1-oxa-8-azaspiro[4.5]decan-8-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(1′-methyl[4,4′-bipiperidin]-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{4-[(1R)-2-(dimethylamino)-1-fluoroethyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{4-[(1S)-2-(dimethylamino)-1-fluoroethyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{4-[(1S)-1-fluoro-2-hydroxyethyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{4-[(1R)-1-fluoro-2-hydroxyethyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{4-fluoro-4-[(2-methoxyethoxy)methyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[3-(ethoxymethyl)-3-fluoropiperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-(ethoxymethyl)-4-fluoropiperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{3-fluoro-3-[(2-methoxyethoxy)methyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-fluoro-4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(3R,4R)-3-fluoro-4-hydroxypiperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(3R,4R)-4-fluoro-3-hydroxypiperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-phenyl-4-[3-(piperidin-1-yl)azetidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(3R)-3-(methanesulfonyl)pyrrolidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(3-methoxypiperidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-oxo-1-(propan-2-yl)-1,3,8-triazaspiro[4.5]decan-8-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-phenyl-4-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-(3-hydroxypropyl)piperazin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{4-[2-oxo-2-(pyrrolidin-1-yl)ethyl]piperazin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(azepan-1-yl)-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{4-[2-(morpholin-4-yl)-2-oxoethyl]piperazin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(3,3-difluoro-1-methylcyclobutyl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[2-(3,3-difluorocyclobutyl)ethoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{2-[(oxetan-3-yl)(propan-2-yl)amino]ethoxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[(1-acetyl-4-fluoropiperidin-4-yl)methoxy]-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{[(2S)-oxolan-2-yl]methoxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[2-(3-methoxyazetidin-1-yl)-2-oxoethoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(2R)-2-fluoro-2-(1-methylpiperidin-4-yl)ethoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{2-[(oxetan-3-yl)oxy]ethoxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{2-[1-(2-methoxyethyl)cyclopropyl]ethoxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{[1-(2-methoxyethyl)cyclopropyl]methoxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(2,2-difluorocyclopentyl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[3-(morpholin-4-yl)propoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[2-(1,3-dioxan-2-yl)ethoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(3-fluoropropoxy)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(3-methyloxetan-3-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(1,3-dimethoxypropan-2-yl)oxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{[cis-3-(dimethylamino)cyclobutyl]oxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(2-methyl-1,3-dioxan-5-yl)oxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{[(3S)-1-methylpiperidin-3-yl]oxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(2-oxaspiro[3.3]heptan-6-yl)oxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{[(3R)-1-methylpiperidin-3-yl]oxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-[(1-acetylazetidin-3-yl)oxy]-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-(1-methoxyethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-phenyl-4-[4-(1,1,1-trifluoro-2-methoxypropan-2-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[3-(diethylcarbamoyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(4-hydroxypiperidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{4-[2-(1,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)ethyl]piperazin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(4aS,7aR)-4-methyl-3-oxohexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(3-oxopiperazin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(5aS,8aS)-2-oxooctahydropyrrolo[3,4-b]azepin-7(1H)-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(2R)-4,4-difluoro-2-(hydroxymethyl)pyrrolidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(2S,4S)-4-fluoro-2-(hydroxymethyl)pyrrolidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[3-fluoro-3-(methoxymethyl)pyrrolidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(3R,4S)-3-fluoro-4-hydroxypiperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[3-(ethoxymethyl)-3-fluoropyrrolidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[3-(hydroxymethyl)-3-methylazetidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(3S)-3-methoxypyrrolidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[3-(2,2-difluoroethoxy)azetidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(2R,4S)-4-fluoro-2-(hydroxymethyl)pyrrolidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(7S,8aS)-7-fluorohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(4aS,7aS)-4-methyl-3-oxohexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-fluoro-4-(hydroxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(1-oxa-7-azaspiro[4.4]nonan-7-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{4-[(methanesulfonyl)amino]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-(1-fluoro-2-hydroxyethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[3-(methoxymethyl)-3-methylazetidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(3R)-3-methoxypyrrolidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-(methanesulfonyl)piperazin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-{6-[bis(2-methoxyethyl)amino]pyridin-3-yl}-1-[2-(morpholin-4-yl)pyridin-4-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(methoxymethyl)piperidin-1-yl]-1-[2-(morpholin-4-yl)pyridin-4-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-methoxy-4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(3S)-3-fluoropyrrolidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(3,3-difluoroazetidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[3-(2-oxo-1,3-oxazolidin-3-yl)azetidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(3-ethyl-3-fluoroazetidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[2-(hydroxymethyl)morpholin-4-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{3-fluoro-3-[(2-methoxyethoxy)methyl]pyrrolidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(cis-3-hydroxycyclobutyl)(methyl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(6-oxa-2-azaspiro[3.4]octan-2-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(3R,4S)-4-fluoro-3-hydroxypiperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(3-hydroxy-3-methylazetidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(6-oxo-2,7-diazaspiro[4.4]nonan-2-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(2S)-4,4-difluoro-2-(hydroxymethyl)pyrrolidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-(ethoxycarbonyl)piperazin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{4-[2-(cyclohexylamino)-2-oxoethyl]piperazin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(3R)-3-fluoropyrrolidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(3-methoxyazetidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(2-hydroxy-7-azaspiro[3.5]nonan-7-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(3R)-3-(hydroxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(1,4-oxazepan-4-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-hydroxy-4-(2-hydroxyethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(cyclobutylmethyl)-4-[4-(methoxymethyl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(methoxymethyl)piperidin-1-yl]-1-(2-methylpropyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • rac-4-[(3aR,7aS)-1-(tert-butoxycarbonyl)octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-1-phenyl-3-[(pyrrolidin-3-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-(trans-3-methylcyclobutyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-{[1-(tert-butoxycarbonyl)pyrrolidin-3-yl]oxy}-4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-{[1-(tert-butoxycarbonyl)piperidin-4-yl]oxy}-4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{methyl[(oxan-4-yl)methyl]amino}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-phenyl-4-[4-(2-propoxyethyl)piperazin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-phenyl-4-{2-[(piperidin-1-yl)methyl]morpholin-4-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-phenyl-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{4-[3-(morpholin-4-yl)propyl]piperazin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{4-[2-(dimethylamino)-2-oxoethyl]piperazin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(2-cyanoethyl)piperazin-1-yl]-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{2-[(dimethylamino)methyl]morpholin-4-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(4-methylpiperazin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(methyl {[1-(2-methylpropyl)piperidin-4-yl]methyl}amino)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{methyl[2-(morpholin-4-yl)ethyl]amino}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-(2-ethoxyethyl)piperazin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{4-[2-(methylamino)-2-oxoethyl]piperazin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{4-[(morpholin-4-yl)acetyl]piperazin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-(2-methoxyethyl)piperazin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{4-[(oxolan-2-yl)methyl]-1,4-diazepan-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-phenyl-4-{3-[(propan-2-yl)oxy]azetidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-phenyl-4-{4-[2-(pyrrolidin-1-yl)ethyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{4-[2-(morpholin-4-yl)ethyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-([1,4′-bipiperidin]-1′-yl)-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(3R)-3-(morpholin-4-yl)pyrrolidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(4,4-difluorocyclohexyl)oxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(oxan-4-yl)oxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{[(1S,2S)-2-methoxycyclohexyl]oxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(3-ethyloxetan-3-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{[(3R)-oxolan-3-yl]oxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{[(3S)-oxolan-3-yl]oxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-methoxy-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(cyclobutyloxy)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[2-(2-methoxyethoxy)ethoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[(3aR,7aS)-1-acetyloctahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[(3aS,7aR)-1-acetyloctahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(methoxymethyl)piperidin-1-yl]-1-[2-(morpholin-4-yl)pyrimidin-4-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{[(oxan-4-yl)methyl]amino}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-[(oxolan-3-yl)oxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-[(oxetan-3-yl)oxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{methyl[(1-methylpiperidin-3-yl)methyl]amino}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(4,4-difluoropiperidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[3-fluoro-3-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-phenyl-4-[2-(trifluoromethyl)morpholin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(cyclopentyloxy)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-{[cis-3-(azetidin-1-yl)cyclobutyl]oxy}-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(1-cyclohexylazetidin-3-yl)oxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(3,3-difluorocyclobutyl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(1-methylazetidin-3-yl)oxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-[3-(dimethylamino)phenyl]-4-[(oxan-4-yl)methoxy]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclohexyl-4-[(oxan-4-yl)methoxy]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-[2-(oxan-4-yl)ethoxy]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-(2-methoxypropan-2-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[3-(dimethylamino)propoxy]-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-[3-(morpholin-4-yl)propoxy]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-[(3-methyloxetan-3-yl)methoxy]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-[(oxolan-2-yl)methoxy]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • rac-3-cyclobutyl-1-phenyl-4-[(3aR,7aS)-1-{[(propan-2-yl)oxy]carbonyl}octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-(dimethylamino)butoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[(1-acetylpiperidin-4-yl)oxy]-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-phenyl-4-(2,2,2-trifluoroethoxy)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{2-[2-(dimethylamino)ethoxy]ethoxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{[(2S)-1-(dimethylamino)propan-2-yl]oxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(4,4-difluorocyclohexyl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{[(2R)-5-oxopyrrolidin-2-yl]methoxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{[(3S)-6-oxopiperidin-3-yl]oxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(5-ethyl-1,3-dioxan-5-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{[(3-endo)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl]oxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(5-methyl-1,3-dioxan-5-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)ethoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[3-(diethylamino)propoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{2-[cyclohexyl(oxetan-3-yl)amino]ethoxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{[4-fluoro-1-(methanesulfonyl)piperidin-4-yl]methoxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{[4-(methanesulfonyl)oxan-4-yl]methoxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-phenyl-4-[2-(pyrrolidin-1-yl)ethoxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[2-(methanesulfonyl)-2-methylpropoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(1-methylcyclopropyl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[2-(1-methylcyclopropyl)ethoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{[1-(methanesulfonyl)cyclobutyl]methoxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(2-cyclohexylethoxy)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[3-(4-methylpiperazin-1-yl)propoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[3-(dimethylamino)propoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[3-(dimethylamino)-2,2-dimethylpropoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[2-(dimethylamino)ethoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-{[1,3-bis(dimethylamino)propan-2-yl]oxy}-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-phenyl-4-[2-(piperidin-1-yl)ethoxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[2-(2-oxoimidazolidin-1-yl)ethoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-{[1,3-bis(morpholin-4-yl)propan-2-yl]oxy}-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-phenyl-4-[3-(piperidin-1-yl)propoxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[2-(azepan-1-yl)ethoxy]-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[2-(4-methyl-1,4-diazepan-1-yl)ethoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{[(2s,4r)-5-methyl-5-azaspiro[3.4]octan-2-yl]oxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(1-{3-[(diethylamino)methyl]oxetan-3-yl}azetidin-3-yl)oxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-phenyl-4-{[1-(propan-2-yl)piperidin-4-yl]oxy}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(cycloheptyloxy)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid; 3-cyclobutyl-4-(cyclooctyloxy)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid; 3-cyclobutyl-4-{[(3R)-1-methylpyrrolidin-3-yl]oxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{[(3S)-1-methylpyrrolidin-3-yl]oxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[(3,3-difluoro-1-methylcyclobutyl)methoxy]-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-[3-(piperidin-1-yl)propoxy]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[(1,3-dimethoxypropan-2-yl)oxy]-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-({[(2S)-oxolan-2-yl]methyl}amino)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-[4-(2-hydroxypropan-2-yl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(4-fluorophenyl)-4-[(oxan-4-yl)methoxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-(2-hydroxypropan-2-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(dimethylamino)piperidin-1-yl]-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-(1′-methyl[4,4′-bipiperidin]-1-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[(1-acetylpiperidin-4-yl)methoxy]-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-{[1-(methoxycarbonyl)piperidin-4-yl]methoxy}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-[(oxane-4-carbonyl)amino]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(cyanomethyl)-4-hydroxypiperidin-1-yl]-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(ethoxymethyl)-4-fluoropiperidin-1-yl]-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-{4-fluoro-4-[(2-methoxyethoxy)methyl]piperidin-1-yl}-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[(3R,4R)-3-fluoro-4-hydroxypiperidin-1-yl]-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-fluoro-4-(methoxymethyl)piperidin-1-yl]-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-{3-fluoro-3-[(2-methoxyethoxy)methyl]piperidin-1-yl}-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[(3S)-3-{[(tert-butoxycarbonyl)amino]methyl}pyrrolidin-1-yl]-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[(3R)-3-{[(tert-butoxycarbonyl)amino]methyl}pyrrolidin-1-yl]-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(1,1-dioxo-1λ6,4-thiazinan-4-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[(3R)-3-{[(tert-butoxycarbonyl)(methyl)amino]methyl}pyrrolidin-1-yl]-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[(3S)-3-{[(tert-butoxycarbonyl)(methyl)amino]methyl}pyrrolidin-1-yl]-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{(3S)-3-[(methylamino)methyl]pyrrolidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(2,6-dimethylpyridin-4-yl)-4-[4-(methoxymethyl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-(2-methoxypyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-phenyl-4-[3-(pyrrolidin-1-yl)azetidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{4-[(oxolan-2-yl)methyl]piperazin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-(1-methoxypropan-2-yl)piperazin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{4-[1-(morpholin-4-yl)ethyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{4-[(1,3-dioxolan-2-yl)methyl]piperazin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-(2-methoxyethoxy)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-phenyl-4-{4-[(piperidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{4-[2-(4-methylpiperidin-1-yl)ethyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-(2,6-dimethylmorpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-(diethylamino)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[{3-[cyclohexyl(methyl)amino]propyl}(methyl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-phenyl-4-[4-(propan-2-yl)-1,4-diazepan-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(3aR,6aS)-5-(2-methylpropyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-([1,4′-bipiperidin]-1′-yl)-3-cyclobutyl-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{4-[4-(2-methoxyethyl)piperazin-1-yl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{4-[2-(4-methylpiperazin-1-yl)ethyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-(ethoxyacetyl)piperazin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(3R)-3-(2-oxopyrrolidin-1-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(4′-methyl[1,4′-bipiperidin]-1′-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{4-[(2-methylpropoxy)carbonyl]piperazin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(4-methyl-1,4-diazepan-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(4-acetylpiperazin-1-yl)-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-(3-methoxypropyl)piperazin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(4-cyclopentyl-1,4-diazepan-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(3R)-3-hydroxypiperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-phenyl-4-(4-propylpiperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-(dimethylcarbamoyl)piperazin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[3-(morpholin-4-yl)azetidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(4-butyl-1,4-diazepan-1-yl)-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[3-(morpholine-4-carbonyl)[1,4′-bipiperidin]-1′-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-phenyl-4-(4-propyl-1,4-diazepan-1-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-phenyl-4-[(3R)-3-(piperidin-1-yl)pyrrolidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(7-cyano-5-oxa-2-azaspiro[3.4]octan-2-yl)-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{4-[3-(4-methyl-1,4-diazepan-1-yl)-3-oxopropyl]piperazin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-(dimethylcarbamoyl)-4-(2-oxopyrrolidin-1-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-(cyclohexylmethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(6-oxa-2-azaspiro[3.5]nonan-2-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-(2-hydroxyethyl)piperazin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[3-(4-methylmorpholin-2-yl)azetidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(3-{4-[methyl(oxetan-3-yl)amino]piperidin-1-yl}azetidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{3-[4-(morpholin-4-yl)piperidin-1-yl]azetidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{4-[1-(2-ethoxyethyl)piperidin-4-yl]piperazin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{4-[1-(2-hydroxypropyl)piperidin-4-yl]piperazin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{4-[3-(dimethylamino)propyl]piperazin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{4-[4-(2-ethoxyethyl)piperazin-1-yl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-phenyl-4-{4-[2-(piperidin-1-yl)ethoxy]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{4-[3-(diethylamino)propyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-phenyl-4-{4-[3-(piperidin-1-yl)propyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-phenyl-4-{4-[3-(pyrrolidin-1-yl)propyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{4-[ethyl(oxetan-3-yl)amino]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{4-[methyl(oxetan-3-yl)amino]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[1′-(oxetan-3-yl)[4,4′-bipiperidin]-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-(dimethylamino)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-(4-methylpiperazine-1-carbonyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-[3-(4-methylmorpholin-2-yl)azetidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-{4-[1-(2-ethoxyethyl)piperidin-4-yl]piperazin-1-yl}-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-{4-[1-(2-hydroxypropyl)piperidin-4-yl]piperazin-1-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(1-cyclopropylpiperidin-4-yl)piperazin-1-yl]-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-{4-[4-(oxetan-3-yl)piperazin-1-yl]piperidin-1-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-{4-[4-(2-ethoxyethyl)piperazin-1-yl]piperidin-1-yl}-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-{4-[4-(2-methoxyethyl)piperazin-1-yl]piperidin-1-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-{4-[3-(diethylamino)propyl]piperidin-1-yl}-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-{4-[3-(piperidin-1-yl)propyl]piperidin-1-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-3-(propan-2-yl)-4-{4-[3-(pyrrolidin-1-yl)propyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-{4-[ethyl(oxetan-3-yl)amino]piperidin-1-yl}-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-{4-[methyl(oxetan-3-yl)amino]piperidin-1-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-[1′-(oxetan-3-yl)[4,4′-bipiperidin]-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl]-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-[4-(4-methylpiperazine-1-carbonyl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-(3-{4-[methyl(oxetan-3-yl)amino]piperidin-1-yl}azetidin-1-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-{3 [4-(morpholin-4-yl)piperidin-1-yl]azetidin-1-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-{4-[3-(dimethylamino)propyl]piperazin-1-yl}-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-[4-methyl-4-(4-methylpiperazin-1-yl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-{4-[2-(piperidin-1-yl)ethoxy]piperidin-1-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-5-methyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclohexyl-4-[4-(4-methylpiperazine-1-carbonyl)phenyl]-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-[3-(morpholin-4-yl)azetidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-3-(propan-2-yl)-4-(4-propyl-1,4-diazepan-1-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(4-cyclobutyl-1,4-diazepan-1-yl)-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(4-butyl-1,4-diazepan-1-yl)-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-(4-methyl-1,4-diazepan-1-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(4-acetylpiperazin-1-yl)-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(4-ethylpiperazin-1-yl)-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-[4-(2-hydroxyethyl)piperazin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(dimethylcarbamoyl)piperazin-1-yl]-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(ethoxyacetyl)piperazin-1-yl]-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-[4-(3-methoxypropyl)piperazin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-3-(propan-2-yl)-4-(4-propylpiperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-{4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-{4-[3-(4-methyl-1,4-diazepan-1-yl)-3-oxopropyl]piperazin-1-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(cyclohexylmethyl)piperidin-1-yl]-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-[(3R)-3-hydroxypiperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-(4′-methyl[1,4′-bipiperidin]-1′-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-{4-[2-(4-methylpiperazin-1-yl)ethyl]piperidin-1-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-[(3R)-3-(piperidin-1-yl)pyrrolidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(diethylamino)piperidin-1-yl]-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(4-tert-butylpiperazin-1-yl)-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-3-(propan-2-yl)-4-{4-[1-(pyrrolidin-1-yl)ethyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-{4-[(piperidin-1-yl)methyl]piperidin-1-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-{4-[(1-methylpiperidin-3-yl)methyl]piperazin-1-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-{4-[(oxolan-2-yl)methyl]piperazin-1-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-[4-(1-methoxypropan-2-yl)piperazin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-3-(propan-2-yl)-4-[3-(pyrrolidin-1-yl)azetidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-3-(propan-2-yl)-4-[4-(propan-2-yl)-1,4-diazepan-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-[(3aR,6aS)-5-(2-methylpropyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(4-ethyl-1,4-diazepan-1-yl)-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-(4-hydroxy-4-{[methyl(propan-2-yl)amino]methyl}piperidin-1-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-{4-[methyl(propan-2-yl)amino]piperidin-1-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-{4-[2-(diethylamino)ethyl]piperazin-1-yl}-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(4-{[(3R)-3-(methoxymethyl)pyrrolidin-1-yl]methyl}piperidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(4-{[(3R)-3-methoxypyrrolidin-1-yl]methyl}piperidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(4-{[(3S)-3-(methoxymethyl)pyrrolidin-1-yl]methyl}piperidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(4-fluorophenyl)-4-{4-[1-(morpholin-4-yl)ethyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-cyclohexyl-4-{4-[(morpholin-4-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-cyclohexyl-4-{4-[2-(morpholin-4-yl)ethyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-(cyclobutyloxy)-1-cyclohexyl-4-{4-[(morpholin-4-yl)methyl]phenyl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-cyclohexyl-4-[4-(pyridin-4-yl)piperazin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(4-fluorophenyl)-4-{4-[2-(morpholin-4-yl)ethyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-3-(propan-2-yl)-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-phenyl-4-{4-[1-(pyrrolidin-1-yl)ethyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(3-oxo-2,8-diazaspiro[4.5]decan-2-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-{4-[(2-methylpropoxy)carbonyl]piperazin-1-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(2-methoxypyridin-4-yl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-[2-(oxan-4-yl)pyridin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-phenyl-4-[4-(propan-2-yl)piperazin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-[2-(oxan-4-yl)pyridin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(3-methylphenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(4-fluorophenyl)-4-{4-[(morpholin-4-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(3-methoxyphenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-[4-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(4-fluoro-3-methylphenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(3-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{4-[(3-fluoroazetidin-1-yl)methyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{4-[(3,3-difluoropyrrolidin-1-yl)methyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{4-[(3-methoxyazetidin-1-yl)methyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{4-[(3,3-difluoropiperidin-1-yl)methyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(4-{[3-(methoxymethyl)azetidin-1-yl]methyl}piperidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(4-{[(3R)-3-fluoropyrrolidin-1-yl]methyl}piperidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(4-{[(3S)-3-fluoropyrrolidin-1-yl]methyl}piperidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{4-[(1,4-oxazepan-4-yl)methyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(4-{[3-(2,2-difluoroethoxy)azetidin-1-yl]methyl}piperidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{4-[(6-oxa-2-azaspiro[3.5]nonan-2-yl)methyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{4-[(6-oxa-2-azaspiro[3.4]octan-2-yl)methyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(4-{[(7S,8aS)-7-fluorohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]methyl}piperidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{4-[(4-formyl-1,4-diazepan-1-yl)methyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{4-[(2-oxa-7-azaspiro[3.5]nonan-7-yl)methyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{4-[(4-methoxypiperidin-1-yl)methyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{4-[(2-oxa-6-azaspiro[3.4]octan-6-yl)methyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{4-[(4-formylpiperazin-1-yl)methyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-{4-[(3-azabicyclo[3.1.0]hexan-3-yl)methyl]piperidin-1-yl}-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-{4-[(5-methyl-6-oxo-2-oxa-5,8-diazaspiro[3.5]nonan-8-yl)methyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(3-fluoropyrrolidin-1-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(3-cyanoazetidin-1-yl)piperidin-1-yl]-3-cyclobutyl-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(3-methoxypyrrolidin-1-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(4-fluoro[1,4′-bipiperidin]-1′-yl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(4,4-difluoro[1,4′-bipiperidin]-1′-yl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(2-cyanomorpholin-4-yl)piperidin-1-yl]-3-cyclobutyl-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(4-fluorophenyl)-4-{4-[2-(methoxymethyl)morpholin-4-yl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(4-fluorophenyl)-4-{4-[methyl(oxan-4-yl)amino]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-{2-[(propan-2-yl)oxy]pyridin-4-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-[2-(benzyloxy)pyridin-4-yl]-3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(4-fluorophenyl)-4-[(morpholin-4-yl)methyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(4-fluorophenyl)-4-[(4-methylpiperazin-1-yl)methyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(4-fluorophenyl)-4-{[4-(methoxymethyl)piperidin-1-yl]methyl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(4-cyano[1,4′-bipiperidin]-1′-yl)-3-cyclobutyl-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclohexyl-4-{4-[4-(dimethylamino)piperidine-1-carbonyl]phenyl}-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(4-fluorophenyl)-4-[3-(pyrrolidin-1-yl)-1-oxa-8-azaspiro[4.5]decan-8-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclohexyl-3-[(propan-2-yl)oxy]-4-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-cyclohexyl-4-[4-(2-methylpyridin-4-yl)piperazin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-cyclohexyl-4-{6-[4-(propan-2-yl)piperazin-1-yl]pyridin-3-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-cyclohexyl-4-{4-[1-(morpholin-4-yl)ethyl]phenyl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-cyclohexyl-4-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-cyclohexyl-4-[6-(4-cyclopropylpiperazin-1-yl)pyridin-3-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(4-fluorophenyl)-4-{4-[3-(trifluoromethyl)pyrrolidin-1-yl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[4-(3-cyanopyrrolidin-1-yl)piperidin-1-yl]-3-cyclobutyl-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(3-cyano[1,4′-bipiperidin]-1′-yl)-3-cyclobutyl-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(3-fluoro[1,4′-bipiperidin]-1′-yl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(3-methoxyazetidin-1-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(4-fluorophenyl)-4-[3-(trifluoromethyl)[1,4′-bipiperidin]-1′-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(4-fluorophenyl)-4-(3-methoxy[1,4′-bipiperidin]-1′-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-(2,2-dimethylmorpholin-4-yl)piperidin-1-yl]-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-cyclohexyl-4-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-cyclohexyl-4-{6-[4-(2-methoxyethyl)piperazin-1-yl]pyridin-3-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(4-fluorophenyl)-4-{4-[4-(propan-2-yl)piperazin-1-yl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-cyclohexyl-4-{4-[4-(propan-2-yl)piperazin-1-yl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[(3S)-4-benzyl-3-methylpiperazin-1-yl]-3-cyclobutyl-1-cyclohexyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-[(3R)-4-benzyl-3-methylpiperazin-1-yl]-3-cyclobutyl-1-cyclohexyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclohexyl-4-[4-(4-methylpiperazin-1-yl)phenyl]-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclohexyl-4-{4-[(4-cyclopropylpiperazin-1-yl)methyl]phenyl}-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(2-hydroxypyridin-4-yl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl]-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(9-cyclopropyl-3,9-diazaspiro[5.5]undecan-3-yl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(4-fluorophenyl)-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-[2-(difluoromethoxy)pyridin-4-yl]-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(4-fluorophenyl)-4-[9-(propan-2-yl)-3,9-diazaspiro[5.5]undecan-3-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid
  • 3-cyclobutyl-4-{4-[4-(ethoxycarbonyl)piperazin-1-yl]piperidin-1-yl}-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(4-fluorophenyl)-4-(4-methoxy[1,4′-bipiperidin]-1′-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(4-fluorophenyl)-4-{[4-(morpholin-4-yl)piperidin-1-yl]methyl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(9-cyclobutyl-3,9-diazaspiro[5.5]undecan-3-yl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(4-fluorophenyl)-4-{4-[(2-methoxyethyl)(methyl)amino]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(4-fluorophenyl)-4-{4-[4-(2-methoxyethyl)piperazin-1-yl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(4-fluorophenyl)-4-[9-(2-methoxyethyl)-3,9-diazaspiro[5.5]undecan-3-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(4-fluorophenyl)-4-(4-hydroxy[1,4′-bipiperidin]-1′-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(4-fluorophenyl)-4-{4-[4-(oxetan-3-yl)piperazin-1-yl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(4-fluorophenyl)-4-[1-(propan-2-yl)octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-(1-cyclobutyloctahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(4-fluorophenyl)-4-[1-(oxetan-3-yl)octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(4-fluorophenyl)-4-[1-(oxan-4-yl)octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(4-fluorophenyl)-4-[9-(oxetan-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(3,5-difluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(3,4-difluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(4-fluoro-3-methoxyphenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-[3-(difluoromethoxy)phenyl]-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(bicyclo[4.2.0]octa-1,3,5-trien-3-yl)-3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(3-fluoro-4-methoxyphenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(3-fluoro-5-methoxyphenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-[4-(difluoromethoxy)phenyl]-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-[3-(1,1-difluoroethyl)phenyl]-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(2,5-difluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-[6-(2-fluoroethoxy)pyridin-3-yl]-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-{2-[(oxan-4-yl)oxy]pyridin-4-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-{2-[(oxan-4-yl)methoxy]pyridin-4-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(2,4-difluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(2,2-difluoro-2H-1,3-benzodioxol-4-yl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 4-(4-cyanophenyl)-1-cyclohexyl-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-{6-[(propan-2-yl)oxy]pyridin-2-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-3-hydroxy-4-(4-methoxy[1,4′-bipiperidin]-1′-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-(4-fluorophenyl)-4-(4-methoxy[1,4′-bipiperidin]-1′-yl)-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 1-cyclohexyl-4-(4-{[3-(dimethylamino)azetidin-1-yl]methyl}phenyl)-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-1-(4-fluorophenyl)-4-(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;
  • 3-cyclobutyl-4-[4-(ethoxycarbonyl)piperazin-1-yl]-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid; and
  • 3-cyclobutyl-1-(4-fluorophenyl)-4-{4-[(2-methylpropoxy)carbonyl]piperazin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid.


Compounds of the invention are named by using Name 2015 naming algorithm by Advanced Chemical Development, Struct=Name naming algorithm as part of CHEMDRAW® ULTRA v. 12.0.2.1076, or Accelrys Draw 4.2.


Compounds of the invention may exist as stereoisomers wherein asymmetric or chiral centers are present. These stereoisomers are “R” or “S” depending on the configuration of sub stituents around the chiral carbon atom. The terms “R” and “S” used herein are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, in Pure Appl. Chem., 1976, 45: 13-30. The invention contemplates various stereoisomers and mixtures thereof and these are specifically included within the scope of this invention. Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers. Individual stereoisomers of compounds of the invention may be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by methods of resolution well-known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and optional liberation of the optically pure product from the auxiliary as described in Furniss, Hannaford, Smith, and Tatchell, “Vogel's Textbook of Practical Organic Chemistry”, 5th edition (1989), Longman Scientific & Technical, Essex CM20 2JE, England, or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns or (3) fractional recrystallization methods.


Compounds of the invention may exist as cis or trans isomers, wherein substituents on a ring may attached in such a manner that they are on the same side of the ring (cis) relative to each other, or on opposite sides of the ring relative to each other (trans). For example, cyclobutane may be present in the cis or trans configuration, and may be present as a single isomer or a mixture of the cis and trans isomers. Individual cis or trans isomers of compounds of the invention may be prepared synthetically from commercially available starting materials using selective organic transformations, or prepared in single isomeric form by purification of mixtures of the cis and trans isomers. Such methods are well-known to those of ordinary skill in the art, and may include separation of isomers by recrystallization or chromatography.


It should be understood that the compounds of the invention may possess tautomeric forms, as well as geometric isomers, and that these also constitute an aspect of the invention.


The present disclosure includes all pharmaceutically acceptable isotopically-labelled compounds of formula (I) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature. Examples of isotopes suitable for inclusion in the compounds of the disclosure include isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as 36Cl, fluorine, such as 18F, iodine, such as 123I and 125I, nitrogen, such as 13N and 15N, oxygen, such as 15O, 17O and 18O, phosphorus, such as 32P, and sulphur, such as 35S. Certain isotopically-labelled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e. 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, i.e. 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as 11C, 18F, 15O and 13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of formula (I) may generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.


Thus, the formula drawings within this specification can represent only one of the possible tautomeric, geometric, or stereoisomeric forms. It is to be understood that the invention encompasses any tautomeric, geometric, or stereoisomeric form, and mixtures thereof, and is not to be limited merely to any one tautomeric, geometric, or stereoisomeric form utilized within the formula drawings.


Compounds of formula (I) may be used in the form of pharmaceutically acceptable salts. The phrase “pharmaceutically acceptable salt” means those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio.


Pharmaceutically acceptable salts have been described in S. M. Berge et al. J. Pharmaceutical Sciences, 1977, 66: 1-19.


Compounds of formula (I) may contain either a basic or an acidic functionality, or both, and can be converted to a pharmaceutically acceptable salt, when desired, by using a suitable acid or base. The salts may be prepared in situ during the final isolation and purification of the compounds of the invention.


Examples of acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isothionate), lactate, malate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides such as, but not limited to, methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as, but not limited to, decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained. Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid and such organic acids as acetic acid, fumaric acid, maleic acid, 4-methylbenzenesulfonic acid, succinic acid, and citric acid.


Basic addition salts may be prepared in situ during the final isolation and purification of compounds of this invention by reacting a carboxylic acid-containing moiety with a suitable base such as, but not limited to, the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as, but not limited to, lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine and the like. Other examples of organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like.


The term “pharmaceutically acceptable prodrug” or “prodrug” as used herein, refers to derivatives of the compounds of the invention which have cleavable groups. Such derivatives become, by solvolysis or under physiological conditions, the compounds of the invention which are pharmaceutically active in vivo. Prodrugs of the compounds of the invention are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use.


The invention contemplates compounds of formula (I) formed by synthetic means or formed by in vivo biotransformation of a prodrug.


Compounds described herein may exist in unsolvated as well as solvated forms, including hydrated forms, such as hemi-hydrates. In general, the solvated forms, with pharmaceutically acceptable solvents such as water and ethanol among others are equivalent to the unsolvated forms for the purposes of the invention.


Pharmaceutical Compositions


When employed as a pharmaceutical, a compound of the invention is typically administered in the form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier. The phrase “pharmaceutical composition” refers to a composition suitable for administration in medical or veterinary use.


The pharmaceutical compositions that comprise a compound of formula (I), alone or in combination with further therapeutically active ingredient, may be administered to the subjects orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments or drops), bucally or as an oral or nasal spray. The term “parenterally” as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.


The term “pharmaceutically acceptable carrier” as used herein, means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which may serve as pharmaceutically acceptable carriers are sugars such as, but not limited to, lactose, glucose and sucrose; starches such as, but not limited to, corn starch and potato starch; cellulose and its derivatives such as, but not limited to, sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as, but not limited to, cocoa butter and suppository waxes; oils such as, but not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols; such a propylene glycol; esters such as, but not limited to, ethyl oleate and ethyl laurate; agar; buffering agents such as, but not limited to, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as, but not limited to, sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants may also be present in the composition, according to the judgment of the formulator.


Pharmaceutical compositions for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous diluents, solvents, or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), vegetable oils (such as olive oil), injectable organic esters (such as ethyl oleate), and suitable mixtures thereof. Proper fluidity may be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.


These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption, such as aluminum monostearate and gelatin.


In some cases, in order to prolong the effect of the drug, it may be desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally-administered drug form may be accomplished by dissolving or suspending the drug in an oil vehicle.


Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release may be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.


The injectable formulations may be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.


Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In certain embodiments, solid dosage forms may contain from 1% to 95% (w/w) of a compound of formula (I). In certain embodiments, the compound of formula (I), or pharmaceutically acceptable salts thereof, may be present in the solid dosage form in a range of from 5% to 70% (w/w). In such solid dosage forms, the active compound may be mixed with at least one inert, pharmaceutically acceptable carrier, such as sodium citrate or dicalcium phosphate and/or a), fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.


The pharmaceutical composition may be a unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampules. Also, the unit dosage form may be a capsule, tablet, cachet, or lozenge itself, or it may be the appropriate number of any of these in packaged form. The quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 1000 mg, from 1 mg to 100 mg, or from 1% to 95% (w/w) of a unit dose, according to the particular application and the potency of the active component. The composition may, if desired, also contain other compatible therapeutic agents.


The dose to be administered to a subject may be determined by the efficacy of the particular compound employed and the condition of the subject, as well as the body weight or surface area of the subject to be treated. The size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects that accompany the administration of a particular compound in a particular subject. In determining the effective amount of the compound to be administered in the treatment or prophylaxis of the disorder being treated, the physician may evaluate factors such as the circulating plasma levels of the compound, compound toxicities, and/or the progression of the disease, etc.


For administration, compounds may be administered at a rate determined by factors that may include, but are not limited to, the LD50 of the compound, the pharmacokinetic profile of the compound, contraindicated drugs, and the side-effects of the compound at various concentrations, as applied to the mass and overall health of the subject. Administration may be accomplished via single or divided doses.


The compounds utilized in the pharmaceutical method of the invention may be administered at the initial dosage of about 0.001 mg/kg to about 100 mg/kg daily. In certain embodiments, the daily dose range is from about 0.1 mg/kg to about 10 mg/kg. The dosages, however, may be varied depending upon the requirements of the subject, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Treatment may be initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired.


Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such carriers as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.


The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well-known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.


The active compounds may also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned carriers.


Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, and fatty acid esters of sorbitan and mixtures thereof.


Besides inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.


Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth and mixtures thereof.


Compositions for rectal or vaginal administration are preferably suppositories which may be prepared by mixing the compounds with suitable non-irritating carriers or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.


Compounds may also be administered in the form of liposomes. Liposomes generally may be derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals which are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes may be used. The present compositions in liposome form may contain, in addition to a compound of the invention, stabilizers, preservatives, excipients, and the like. Examples of lipids include, but are not limited to, natural and synthetic phospholipids, and phosphatidyl cholines (lecithins), used separately or together.


Methods to form liposomes have been described, see example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.


Dosage forms for topical administration of a compound described herein include powders, sprays, ointments, and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propellants which may be required. Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.


A compound of the invention may also be administered in sustained release forms or from sustained release drug delivery systems.


Methods of Use


The compounds and compositions using any amount and any route of administration may be administered to a subject for the treatment or prevention of cystic fibrosis, pancreatic insufficiency, Sjögren's Syndrome (SS), chronic obstructive lung disease (COLD), or chronic obstructive airway disease (COAD).


The term “administering” refers to the method of contacting a compound with a subject. Thus, the compounds may be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, parentally, or intraperitoneally. Also, the compounds described herein may be administered by inhalation, for example, intranasally. Additionally, the compounds may be administered transdermally, topically, and via implantation. In certain embodiments, the compounds and compositions thereof may be delivered orally. The compounds may also be delivered rectally, bucally, intravaginally, ocularly, or by insufflation. CFTR-modulated disorders and conditions may be treated prophylactically, acutely, and chronically using compounds and compositions thereof, depending on the nature of the disorder or condition. Typically, the host or subject in each of these methods is human, although other mammals may also benefit from the administration of compounds and compositions thereof as set forth hereinabove.


Compounds of the invention are useful as modulators of CFTR. Thus, the compounds and compositions are particularly useful for treating or lessening the severity or progression of a disease, disorder, or a condition where hyperactivity or inactivity of CFTR is involved. Accordingly, the invention provides a method for treating cystic fibrosis, pancreatic insufficiency, Sjögren's Syndrome (SS), chronic obstructive lung disease (COLD), or chronic obstructive airway disease (COAD) in a subject, wherein the method comprises the step of administering to said subject a therapeutically effective amount of a compound of formula (I) or a preferred embodiment thereof as set forth above, with or without a pharmaceutically acceptable carrier. Particularly, the method is for the treatment or prevention of cystic fibrosis. In a more particular embodiment, the cystic fibrosis is caused by a Class I, II, III, IV, V, and/or VI mutation.


In another embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention for use in medicine. In a particular embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the treatment of cystic fibrosis, pancreatic insufficiency, Sjögren's Syndrome (SS), chronic obstructive lung disease (COLD) or chronic obstructive airway disease (COAD). In a more particular embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the treatment of cystic fibrosis. In a more particular embodiment, the cystic fibrosis is caused by a Class I, II, III, IV, V, and/or VI mutation.


One embodiment is directed to the use of a compound according to formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament. The medicament optionally can comprise one or more additional therapeutic agents. In some embodiments, the medicament is for use in the treatment of cystic fibrosis, pancreatic insufficiency, Sjögren's Syndrome (SS), chronic obstructive lung disease (COLD) or chronic obstructive airway disease (COAD). In a particular embodiment, the medicament is for use in the treatment of cystic fibrosis. In a more particular embodiment, the cystic fibrosis is caused by a Class I, II, III, IV, V, and/or VI mutation.


This invention also is directed to the use of a compound according to formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cystic fibrosis, Sjögren's syndrome, pancreatic insufficiency, chronic obstructive lung disease, and chronic obstructive airway disease. The medicament optionally can comprise one or more additional therapeutic agents. In a particular embodiment, the invention is directed to the use of a compound according to formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of cystic fibrosis. In a more particular embodiment, the cystic fibrosis is caused by a Class I, II, III, IV, V, and/or VI mutation.


In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents. In a particular embodiment, the other therapeutic agent is a cystic fibrosis treatment agent. In a more particular embodiment, the cystic fibrosis is caused by a Class I, II, III, IV, V, and/or VI mutation.


The present compounds or pharmaceutically acceptable salts thereof may be administered as the sole active agent or it may be co-administered with other therapeutic agents, including other compounds or pharmaceutically acceptable salts thereof that demonstrate the same or a similar therapeutic activity and that are determined to be safe and efficacious for such combined administration. The term “co-administered” means the administration of two or more different therapeutic agents to a subject in a single pharmaceutical composition or in separate pharmaceutical compositions. Thus co-administration involves administration at the same time of a single pharmaceutical composition comprising two or more therapeutic agents or administration of two or more different compositions to the same subject at the same or different times.


The compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with a therapeutically effective amount of one or more additional therapeutic agents to treat a CFTR mediated disease, where examples of the therapeutic agents include, but are not limited to antibiotics (for example, aminoglycosides, colistin, aztreonam, ciprofloxacin, and azithromycin), expectorants (for example, hypertonic saline, acetylcysteine, dornase alfa, and denufosol), pancreatic enzyme supplements (for example, pancreatin, and pancrelipase), epithelial sodium channel blocker (ENaC) inhibitors, CFTR modulators (for example, CFTR potentiators, CFTR correctors), and CFTR amplifiers. In one embodiment, the CFTR mediated disease is cystic fibrosis, chronic obstructive pulmonary disease (COPD), dry eye disease, pancreatic insufficiency, or Sjogren's syndrome. In one embodiment, the CFTR mediated disease is cystic fibrosis. In one embodiment, the CFTR mediated disease is cystic fibrosis. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with one or two CFTR modulators and one CFTR amplifier. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with one potentiator, one or more correctors, and one CFTR amplifier. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with one or more CFTR modulators. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with one CFTR modulators. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with two CFTR modulators. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with three CFTR modulators. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with one potentiator and one or more correctors. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with one potentiator and one corrector. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with one potentiator and two correctors. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with one potentiator. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with one or more correctors. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with one corrector. In one embodiment, the compounds of the invention or pharmaceutically acceptable salts thereof may be co-administered with two correctors.


Examples of CFTR potentiators include, but are not limited to, Ivacaftor (VX-770), CTP-656, NVS-QBW251, FD1860293, PTI-808, GLPG2451, GLPG1837, and N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-5-carboxamide. Examples of potentiators are also disclosed in publications: WO2005120497, WO2008147952, WO2009076593, WO2010048573, WO2006002421, WO2011072241, WO2011113894, WO2013038373, WO2013038378, WO2013038381, WO2013038386, WO2013038390, WO2014180562, WO2015018823; and U.S. application Ser. Nos. 14/271,080, 14/451,619, and 15/164,317.


In one embodiment, the potentiator can be selected from the group consisting of:

  • Ivacaftor (VX-770, N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide);
  • CTP-656;
  • NVS-QBW251,
  • FD1860293;
  • PTI-808;
  • GLPG1837;
  • GLPG2451;
  • 2-(2-fluorobenzamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide;
  • N-(3-carbamoyl-5,5,7,7-tetramethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-5-carboxamide;
  • 2-(2-hydroxybenzamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide;
  • 2-(1-hydroxycyclopropanecarboxamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide;
  • 5,5,7,7-tetramethyl-2-(2-(trifluoromethyl)benzamido)-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide;
  • 2-(2-hydroxy-2-methylpropanamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide;
  • 2-(1-(hydroxymethyl)cyclopropanecarboxamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide;
  • 2-(3-hydroxy-2,2-dimethylpropanamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide;
  • N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-5-methyl-1H-pyrazole-3-carboxamide;
  • N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-5-cyclopropyl-1H-pyrazole-3-carboxamide;
  • N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-5-isopropyl-1H-pyrazole-3-carboxamide;
  • N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-5-(trifluoromethyl)-1H-pyrazole-3-carboxamide;
  • 5-tert-butyl-N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-3-carboxamide;
  • N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-5-ethyl-1H-pyrazole-3-carboxamide;
  • N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-3-ethyl-4-methyl-1H-pyrazole-5-carboxamide;
  • 2-(2-hydroxypropanamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide;
  • N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-4-chloro-1H-pyrazole-3-carboxamide;
  • N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-1,4,6,7-tetrahydropyrano[4,3-c]pyrazole-3-carboxamide;
  • 4-bromo-N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-3-carboxamide;
  • N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-4-chloro-5-methyl-1H-pyrazole-3-carboxamide;
  • N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-4-methyl-1H-pyrazole-3-carboxamide;
  • 2-(2-hydroxy-3,3-dimethylbutanamido)-5,5,7,7-tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxamide;
  • 2-[(2-hydroxy-4-methyl-pentanoyl)amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide;
  • 5-(2-methoxy-ethoxy)-1H-pyrazole-3-carboxylic acid (3-carbamoyl-5,5,7,7-tetramethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl)-amide;
  • N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-4-(3-methoxypropyl)-1H-pyrazole-3-carboxamide;
  • N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-4-(2-ethoxyethyl)-1H-pyrazole-3-carboxamide;
  • 2-[[(2S)-2-hydroxy-3,3-dimethyl-butanoyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide;
  • 2-[[(2R)-2-hydroxy-3,3-dimethyl-butanoyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide;
  • 2-[(2-hydroxy-2,3,3-trimethyl-butanoyl)amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide;
  • [5-[(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)carbamoyl]pyrazol-1-yl]methyl dihydrogen phosphate;
  • [3-[(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)carbamoyl]pyrazol-1-yl]methyl dihydrogen phosphate;
  • N-(3-carbamoyl-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-2-yl)-4-(1,4-dioxan-2-yl)-1H-pyrazole-3-carboxamide;
  • 5,5,7,7-tetramethyl-2-[[(2S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propanoyl]amino]-4H-thieno[2,3-c]pyran-3-carboxamide;
  • 2-[[(2S)-2-hydroxypropanoyl]amino]-5,5,7,7-tetramethyl-4H-thieno[2,3-c]pyran-3-carboxamide;
  • 3-amino-N-(2-hydroxy-2-methylpropyl)-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide;
  • 3-amino-N-[(4-hydroxy-1-methylpiperidin-4-yl)methyl]-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide;
  • 3-amino-N-(3-hydroxy-2,2-dimethylpropyl)-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide;
  • 3-amino-5-[(4-fluorophenyl)sulfonyl]-N-[(1-hydroxycyclopropyl)methyl]pyridine-2-carboxamide;
  • 3-amino-5-[(4-fluorophenyl)sulfonyl]-N-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]pyridine-2-carboxamide;
  • 3-amino-5-[(3-fluorophenyl)sulfonyl]-N-(2-hydroxy-2-methylpropyl)pyridine-2-carboxamide;
  • 3-amino-N-[2-(cyclopropylamino)-2-oxoethyl]-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide;
  • (3-amino-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridin-2-yl)(azetidin-1-yl)methanone;
  • (3-amino-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridin-2-yl)[3-(hydroxymethyl)azetidin-1-yl]methanone;
  • (3-amino-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridin-2-yl)(3-fluoroazetidin-1-yl)methanone;
  • 3-amino-N-[(2R)-2-hydroxy-3-methoxypropyl]-5-{[4-(trifluoromethyl)phenyl]sulfonyl}pyridine-2-carboxamide;
  • (3-amino-5-{[2-fluoro-4-(trifluoromethoxy)phenyl]sulfonyl}pyridin-2-yl)(3-hydroxyazetidin-1-yl)methanone;
  • (3-amino-5-{[2-(trifluoromethoxy)phenyl]sulfonyl}pyridin-2-yl)(3,3-difluoroazetidin-1-yl)methanone;
  • rac-3-amino-N-[(3R,4S)-4-hydroxytetrahydro-2H-pyran-3-yl]-5-{[2-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide;
  • 3-amino-5-[(4,4-difluoropiperidin-1-yl)sulfonyl]-N-(3,3,3-trifluoro-2-hydroxypropyl)pyridine-2-carboxamide;
  • (3-amino-5-{[2-(trifluoromethoxy)phenyl]sulfonyl}pyridin-2-yl)[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]methanone;
  • 3-amino-N-(2-hydroxy-4-methylpentyl)-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide;
  • (3-amino-5-{[4-(trifluoromethyl)phenyl]sulfonyl}pyridin-2-yl)(3-hydroxy-3-methylazetidin-1-yl)methanone;
  • 3-amino-N-(3,3,3-trifluoro-2-hydroxypropyl)-5-{[4-(trifluoromethyl)piperidin-1-yl]sulfonyl}pyridine-2-carboxamide;
  • 3-amino-N-[2-hydroxy-1-(4-methoxyphenyl)ethyl]-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide;
  • 3-amino-5-[(3,3-difluoroazetidin-1-yl)sulfonyl]-N-(3,3,3-trifluoro-2-hydroxypropyl)pyridine-2-carboxamide;
  • 3-amino-5-{[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl}-N-[(2S)-2-hydroxypropyl]pyridine-2-carboxamide;
  • 3-amino-5-{[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl}-N-[(2R)-2-hydroxy-3-methoxypropyl]pyridine-2-carboxamide;
  • 3-amino-N-[2-oxo-2-(propan-2-ylamino)ethyl]-5-{[4-(trifluoromethyl)phenyl]sulfonyl}pyridine-2-carboxamide;
  • (3-amino-5-{[4-(trifluoromethyl)phenyl]sulfonyl}pyridin-2-yl)[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]methanone;
  • 3-amino-5-{[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl}-N-[(3R)-tetrahydrofuran-3-ylmethyl]pyridine-2-carboxamide;
  • (3-amino-5-{[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl}pyridin-2-yl)[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]methanone;
  • 3-amino-5-{[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl}-N-[(3S)-tetrahydrofuran-3-ylmethyl]pyridine-2-carboxamide;
  • 3-amino-5-{[2-fluoro-4-(trifluoromethoxy)phenyl]sulfonyl}-N-[(3S)-tetrahydrofuran-3-ylmethyl]pyridine-2-carboxamide;
  • 3-amino-N-[2-hydroxy-3-(2,2,2-trifluoroethoxy)propyl]-5-{[4-(trifluoromethyl)phenyl]sulfonyl}pyridine-2-carboxamide;
  • 3-amino-N-(3-tert-butoxy-2-hydroxypropyl)-5-{[2-fluoro-4-(trifluoromethyl)phenyl]sulfonyl}pyridine-2-carboxamide;
  • [3-amino-5-(phenylsulfonyl)pyridin-2-yl][3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]methanone;
  • {3-amino-5-[(3-fluorophenyl)sulfonyl]pyridin-2-yl}[3-hydroxy-3-(trifluoromethyl)azetidin-1-yl]methanone; and
  • 3-amino-N-[(2S)-2-hydroxypropyl]-5-{[4-(trifluoromethoxy)phenyl]sulfonyl}pyridine-2-carboxamide.


Non-limiting examples of correctors include Lumacaftor (VX-809), 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-{1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl}cyclopropanecarboxamide (VX-661), VX-983, GLPG2222, GLPG2665, GLPG2737, GLPG2851, VX-152, VX-440, FDL169, FDL304, FD2052160, and FD2035659. Examples of correctors are also disclosed in US20160095858A1, and U.S. application Ser. Nos. 14/925,649, 14/926,727, 15/205,512, 62/239,647, and 62/309,794.


In one embodiment, the corrector(s) can be selected from the group consisting of:

  • Lumacaftor (VX-809);
  • 1-(2,2-difluoro-1,3-benzodioxol-5-yl)-N-{1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl}cyclopropanecarboxamide (VX-661);
  • PTI-801;
  • VX-983;
  • VX-152;
  • VX-440;
  • FDL169
  • FDL304;
  • FD2052160;
  • FD2035659;
  • GLPG2665;
  • GLPG2737;
  • GLPG2851;
  • 3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid;
  • 3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]benzoic acid;
  • 3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-methyl-3,4-dihydro-2H-chromen-2-yl]benzoic acid;
  • 3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methyl-3,4-dihydro-2H-chromen-2-yl]benzoic acid;
  • 3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid;
  • 3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]cyclohexanecarboxylic acid;
  • 3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic acid;
  • 3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]cyclohexanecarboxylic acid;
  • 3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-fluoro-3,4-dihydro-2H-chromen-2-yl]benzoic acid;
  • 3-({3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methyl-3,4-dihydro-2H-chromen-2-yl]benzoyl}amino)-1-methylcyclopentanecarboxylic acid;
  • 3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methyl-3,4-dihydro-2H-chromen-2-yl]-N-[(2R)-2,3-dihydroxypropyl]benzamide;
  • 3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(2-methoxyethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic acid;
  • 3-[(2R,4R)-7-(benzyloxy)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]benzoic acid;
  • 3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(2-fluoroethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic acid;
  • 3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(trifluoromethyl)-3,4-dihydro-2H-chromen-2-yl]benzoic acid;
  • 3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(trifluoromethyl)-3,4-dihydro-2H-chromen-2-yl]cyclohexanecarboxylic acid;
  • 4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid;
  • 3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-8-fluoro-3,4-dihydro-2H-chromen-2-yl]benzoic acid;
  • 4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-3,4-dihydro-2H-chromen-2-yl]benzoic acid;
  • 4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic acid;
  • rac-3-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoic acid;
  • rac-4-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoic acid;
  • 3-[(2S,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoic acid;
  • 3-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoic acid;
  • rac-3-[(2R,4S,6S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-phenyhetrahydro-2H-pyran-2-yl]benzoic acid;
  • 3-[(2S,4R,6R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-phenyhetrahydro-2H-pyran-2-yl]benzoic acid;
  • 3-[(2R,4S,6S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-6-phenyhetrahydro-2H-pyran-2-yl]benzoic acid;
  • 4-[(2R,4S)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)tetrahydro-2H-pyran-2-yl]benzoic acid;
  • 4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-cyclobutyl-N-(methanesulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carb oxamide;
  • 3-cyclobutyl-N-(methanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
  • 4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-cyclobutyl-N-(methanesulfonyl)-1-[2-(morpholin-4-yl)pyridin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxamid;
  • N-(methanesulfonyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1-[2-(morpholin-4-yl)pyridin-4-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
  • 3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-N-[2-(morpholin-4-yl)ethanesulfonyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
  • 3-cyclobutyl-N-[2-(dimethylamino)ethanesulfonyl]-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
  • 1-(4-fluorophenyl)-N-(methanesulfonyl)-4-(1′-methyl[4,4′-bipiperidin]-1-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
  • 3-cyclobutyl-N-(methanesulfonyl)-4-{4-[2-(morpholin-4-yl)ethyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carb oxamide;
  • 3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-N-(oxolane-3-sulfonyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
  • 3-cyclobutyl-N-(dimethyl sulfamoyl)-1-(4-fluorophenyl)-4-(4-methoxy[1,4′-bipiperidin]-1′-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
  • 3-cyclobutyl-N-(morpholine-4-sulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carb oxamide;
  • 3-cyclobutyl-N-(morpholine-4-sulfonyl)-1-phenyl-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
  • 3-cyclobutyl-N-(methanesulfonyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxamide;
  • 5-[(2R,4R)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]pyrazine-2-carboxylic acid;
  • 6-[(2R,4R)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]pyridine-3-carboxylic acid;
  • trans-4-[(2S,4S)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic acid;
  • 6-[(2R,4R)-7-(difluoromethoxy)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]pyridine-3-carboxylic acid;
  • trans-4-[(2S,4S)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic acid;
  • ethyl trans-4-[(2S,4S)-7-(difluoromethoxy)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylate;
  • cis-4-[(2R,4R)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic acid;
  • trans-4-[(2S,4S)-7-(difluoromethoxy)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic acid;
  • 1-[(2R,4R)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]cyclopropane-1-carboxylic acid;
  • trans-4-[(2R,4R)-4-{[(5S)-2,2-difluoro-5-methyl-6,7-dihydro-2H,5H-indeno[5,6-d][1,3]dioxole-5-carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic acid;
  • trans-4-[(2R,4R)-4-{[(5S)-2,2-difluoro-5-methyl-6,7-dihydro-2H,5H-indeno[5,6-d][1,3]dioxole-5-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic acid;
  • trans-4-[(2R,4R)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-7-methoxy-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic acid;
  • trans-4-[(2R,4R)-7-(difluoromethoxy)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic acid; and
  • trans-4-[(2R,4R)-4-{[(7R)-2,2-difluoro-7-methyl-6,7-dihydro-2H-furo[2,3-f][1,3]benzodioxole-7-carbonyl]amino}-7-(trifluoromethoxy)-3,4-dihydro-2H-1-benzopyran-2-yl]cyclohexane-1-carboxylic acid.


In one embodiment, the additional therapeutic agent is a CFTR amplifier. CFTR amplifiers enhance the effect of known CFTR modulators, such as potentiators and correctors. Examples of CFTR amplifier include PTI130 and PTI-428. Examples of amplifiers are also disclosed in publications: WO2015138909 and WO2015138934.


In one embodiment, the additional therapeutic agent is a CFTR stabilizer. CFTR stabilizers enhance the stability of corrected CFTR that has been treated with a corrector, corrector/potentiator or other CFTR modulator combination(s). An example of a CFTR stabilizer is cavosonstat. Examples of stabilizers are also disclosed in publication: WO2012048181.


In one embodiment, the additional therapeutic agent is an agent that reduces the activity of the epithelial sodium channel blocker (ENaC) either directly by blocking the channel or indirectly by modulation of proteases that lead to an increase in ENaC activity (e.g., serine proteases, channel-activating proteases). Exemplary of such agents include camostat (a trypsin-like protease inhibitor), QAU145, 552-02, GS-9411, INO-4995, Aerolytic, amiloride, and VX-371. Additional agents that reduce the activity of the epithelial sodium channel blocker (ENaC) can be found, for example, in PCT Publication No. WO2009074575 and WO2013043720; and U.S. Pat. No. 8,999,976.


In one embodiment, the ENaC inhibitor is VX-371.


In one embodiment, the ENaC inhibitor is SPX-101 (S18).


In one embodiment, the In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents. In a particular embodiment, the additional therapeutic agents are selected from the group consisting of CFTR modulators and CFTR amplifiers. In a further embodiment, the additional therapeutic agents are CFTR modulators. In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, one potentiator, and one or more additional correctors.


This invention also is directed to kits that comprise one or more compounds and/or salts of the invention, and, optionally, one or more additional therapeutic agents.


This invention also is directed to methods of use of the compounds, salts, compositions, and/or kits of the invention to, with or without one or more additional therapeutic agents, for example, modulate the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein, and treat a disease treatable by modulating the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein (including cystic fibrosis, Sjögren's syndrome, pancreatic insufficiency, chronic obstructive lung disease, and chronic obstructive airway disease).


EXAMPLES

Chemical Synthetic Procedures


General


The compounds of the invention can be better understood in connection with the following synthetic schemes and methods which illustrate a means by which the compounds may be prepared.


The compounds of this invention can be prepared by a variety of synthetic procedures. Representative procedures are shown in, but are not limited to, Schemes 1-6. In Schemes 1-6, the variables R1, R2, R3 and R4 are as described in the Summary.


Optimum reaction conditions and reaction times for each individual step may vary depending on the particular reactants employed and substituents present in the reactants used. Unless otherwise specified, solvents, temperatures and other reaction conditions may be readily selected by one of ordinary skill in the art. Specific procedures are provided in the Synthetic Examples section. Reactions may be further processed in the conventional manner, e.g. by eliminating the solvent from the residue and further purified according to methodologies generally known in the art such as, but not limited to, crystallization, distillation, extraction, trituration and chromatography. Unless otherwise described, the starting materials and reagents are either commercially available or may be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature.


Routine experimentations, including appropriate manipulation of the reaction conditions, reagents and sequence of the synthetic route, protection of any chemical functionality that may not be compatible with the reaction conditions, and deprotection at a suitable point in the reaction sequence of the method are included in the scope of the invention. Suitable protecting groups and the methods for protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which can be found in T. Greene and P. Wuts, Protecting Groups in Organic Synthesis (3rd ed.), John Wiley & Sons, NY (1999), which is incorporated herein by reference in its entirety. Synthesis of the compounds of the invention can be accomplished by methods analogous to those described in the synthetic schemes described hereinabove and in specific examples.


Starting materials, if not commercially available, can be prepared by procedures selected from standard organic chemical techniques, techniques that are analogous to the synthesis of known, structurally similar compounds, or techniques that are analogous to the above described schemes or the procedures described in the synthetic examples section.


When an optically active form of a compound is required, it can be obtained by carrying out one of the procedures described herein using an optically active starting material (prepared, for example, by asymmetric induction of a suitable reaction step), or by resolution of a mixture of the stereoisomers of the compound or intermediates using a standard procedure (such as chromatographic separation, recrystallization or enzymatic resolution).


Similarly, when a pure geometric isomer of a compound is required, it can be prepared by carrying out one of the above procedures using a pure geometric isomer as a starting material, or by resolution of a mixture of the geometric isomers of the compound or intermediates using a standard procedure such as chromatographic separation.


The compounds of the invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e. reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) were given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.


The following methods are presented with details as to the preparation of a compound of the invention as defined hereinabove and the comparative examples. A compound of the invention may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis.


All reagents were of commercial grade and were used as received without further purification, unless otherwise stated. Commercially available anhydrous solvents were used for reactions conducted under inert atmosphere. Reagent grade solvents were used in all other cases, unless otherwise specified. Column chromatography was performed on silica gel 60 (35-70 μm). Thin layer chromatography was carried out using pre-coated silica gel F-254 plates (thickness 0.25 mm). 1H NMR spectra were recorded on a Bruker Advance 300 NMR spectrometer (300 MHz). Chemical shifts (δ) for 1H NMR spectra were reported in parts per million (ppm) relative to tetramethylsilane (δ 0.00) or the appropriate residual solvent peak, i.e. CHCl3 (δ 7.27), as internal reference. Multiplicities were given as singlet (s), doublet (d), triplet (t), quartet (q), quintuplet (quin), multiplet (m) and broad (br). Electrospray MS spectra were obtained on a Waters platform LC/MS spectrometer or with Waters Acquity H-Class UPLC coupled to a Waters Mass detector 3100 spectrometer. Columns used: Waters Acquity UPLC BEH C18 1.7 μm, 2.1 mm ID×50 mm L, Waters Acquity UPLC BEH C18 1.7 μm, 2.1 mm ID×30 mm L, or Waters Xterra® MS 5 μm C18, 100×4.6 mm. The methods were using either MeCN/H2O gradients (H2O contains either 0.1% TFA or 0.1% NH3) or Methanol/H2O gradients (H2O contains 0.05% TFA). Microwave heating was performed with a Biotage® Initiator. Electrospray MS spectra were obtained on Waters Acquity UPLC systems coupled to Waters SQD or SQD2 mass spectrometers. Columns used: Waters Acquity UPLC BEH C18 1.7 μm, 2.1 mm ID×50 mm L or Waters Acquity UPLC BEH C18 1.7 μm, 2.1 mm ID×30 mm L. The methods were using MeCN/H2O gradients (both MeCN and H2O contained either 0.1% formic acid or 0.05% NH3).


For the compounds purified by preparative chromatography, an XSelect™ CSH Prep Guard Column, C18 19×10 mm 5 μm (Waters) with an XSelect™ CSH Prep OBD Column, C18 19×100 mm 5 μm (Waters) and a gradient of 0.1% formic acid in water (A) and acetonitrile (B) at a flow rate of 20 mL/minute is used. Alternatively, an XBridge™ Prep Guard Column, C18 19×10 mm 5 μm (Waters) with a XBridge™ Prep OBD Column, C18 19×100 mm 5 μm (Waters) and a gradient of 0.5% NH3 in water (A) and acetonitrile (B) at a flow rate of 20 mL/minute is used. After elution, the solvent was removed under vacuum to provide the product. For the compounds purified by preparative chromatography, an XBridge™ Prep Guard Column, C18 19×10 mm 5 μm (Waters) with a XBridge™ Prep OBD Column, C18 30×100 mm 5 μm (Waters) and a gradient of 0.1% formic acid in water (A) and acetonitrile (B) at a flow rate of 50 mL/minute were used. Alternatively, a gradient of 0.1% DEA in water (A) and acetonitrile (B) at a flow rate of 50 mL/minute was used on the same references of guard column and column. After elution, the solvent was removed under vacuum to provide the dry product.


Alternatively, compounds were purified by automated reversed phase HPLC, using a Phenomenex® Luna® C8(2), 5 μm, 100 Å, 50×30 mm, with a SecurityGuard™ 15×30 mm guard column, and a gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B), at a flow rate of 40 mL/min (0-1.0 minute 10% A, 1.0-9.0 minutes linear gradient 10-100% A, 9.0-9.5 minutes 100% A, 9.5-10.0 minutes linear gradient 100-10% A). After elution, solvent was removed under vacuum to provide the pure product.


Alternatively, compounds were purified by automated reversed phase HPLC, using a C18 column, and a gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B), at a flow rate of 50 mL/min (0-0.5 minute 10% A, 0.5-6.0 minutes linear gradient 10-100% A, 6.0-7.0 minutes 100% A, 7.0-8.0 minutes linear gradient 100-10% A). After elution, solvent was removed under vacuum to provide the pure product.


Racemic mixtures were separated on an Agilent HP1100 system with UV detection. Column used: Chiralpak® IA (10×250 mm, 5 μm). Solvents used: iPrOH and tBME. Enantiomeric purity was determined on an Agilent HP1100 system with UV detection. Column used: Chiralpak IA (4.6×250 mm, 5 μm). Solvents used: iPrOH and tBME.


List of abbreviations used in the experimental section:













Abbreviation
Definition







Bn
benzyl


Boc
tert-butoxycarbonyl


Et
ethyl


Me
methyl


Ph
phenyl


Pr
propyl


Tf
trifluoromethanesulfonyl


OTf
trifluormethanesulfonate


TMS
trimethylsilyl


DCM
dichloromethane


MeCN
acetonitrile


DMA
N,N-dimethylacetamide


DMF
N,N-dimethylformamide


AcOH or HOAc
acetic acid


eq or equiv
equivalents


TFA
trifluoroacetic acid


THF
tetrahydrofuran


NMR
nuclear magnetic resonance


DMSO
dimethyl sulfoxide


LC/MS or LCMS
liquid chromatography-mass spectrometry


EtOAc
ethyl acetate


EtOH
ethanol


MeOH
methanol


tBuOH or t-BuOH
tert-butanol


tBME or MTBE
tert-butyl methyl ether


s
singlet


br s
broad singlet


d
duplet


dd
double duplet


m
multiplet


min
minute


h
hours


mL
milliliter


μL
microliter


g
gram


mg
milligram


kg
kilogram


RT
room(ambient) temperature


Et3N or NEt3
triethylamine


DIPEA
diisopropylethylamine


TMEDA
tetramethylethylenediamine


DME
1,2-Dimethoxyethane


DMAP
dimethylaminopyridine


EDC
N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide


mmol
millimoles


HPLC
high pressure liquid chromatography


HOBt
1-hydroxybenzotriazole hydrate


MS
mass spectrum


NMR
nuclear magnetic resonance


TLC
thin layer chromatography


NMP
N-methylpyrrolidone


ppm
parts per million


psi
pounds per square inch


Pd(OAc)2
palladium(II) acetate


Xantphos
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene


SM
starting material


Sphos
2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl


Cpd
compound


Int
intermediate


MW
molecular weight


Mes
molecular weight measured


NA
not active


Pd(dppf)Cl2
[1,1′-



bis(diphenylphosphino)ferrocene]



dichloropalladium(II)


Pd(dppf)Cl2•CH2Cl2
[1,1′-


or
bis(diphenylphosphino)ferrocene]


Pd(dppf)Cl2•DCM
dichloropalladium(II)



complex with dichloromethane


μm
micrometer


iPrOH
iso-propanol


DBU
1,8-diazabicycloundec-7-ene


DPPA
diphenylphosphoryl azide


LiHMDS
lithium hexamethyldisilazide or lithium



bis(trimethylsilyl)amide


KHMDS
potassium hexamethyldisilazide or potassium



bis(trimethylsilyl)amide


BINAP
1,1′-binaphthyl-2,2′-diamine


rac-BINAP
rac-1,1′-binaphthyl-2,2′-diamine


TfOH
trifluoromethanesulfonic acid


Tf2O
trifluoromethanesulfonic anhydride


XPhos
2-dicyclohexylphosphino-2′,4′,6′-



triisopropylbiphenyl


XPhos Pd G1
(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,



1′-biphenyl)[2-(2-aminoethyl)phenyl)]palladium



(II) chloride


K2CO3
potassium carbonate


MgSO4
magnesium sulfate


NaHCO3
sodium hydrogencarbonate


Na2CO3
sodium bicarbonate


Na2SO4
sodium sulfate


CO
carbon monoxide


NaCl
sodium chloride


NaH
sodium hydride


LiOH
lithium hydroxide










Synthetic Preparation of the Compounds of the Invention




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General Synthetic Routes


The compounds of the invention and the comparative examples can be produced according to the following schemes.




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Method A: Synthesis of Benzyl Esters



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To a solution of the carboxylic acid (1.0 equiv) in either dry DMF or dry acetonitrile is added K2CO3 (1.3 equiv) followed by benzylbromide (1.1 equiv). The reaction mixture is heated at a temperature ranging from RT to 85° C. from 2 h to 4 days, and then partitioned between brine and either ethyl acetate or dichloromethane. The organic layer is separated, washed with brine and saturated ammonium chloride, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue is purified by flash chromatography on silica gel (eluent system: heptane/ethyl acetate) to afford the titled compound.


Illustrative Synthesis of Intermediate BE01: 1-Methyl-cyclobutanecarboxylic acid benzyl ester



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To a solution of 1-methylcyclobutanecarboxylic acid (CAS:32936-76-8, 0.5 g, 4.38 mmol, 1.0 equiv) in dry DMF was added K2CO3 (0.787 g, 5.69 mmol, 1.3 equiv) followed by benzylbromide (CAS: 100-39-0, 0.57 mL, 4.82 mmol, 1.1 equiv). The reaction mixture was stirred at RT for 2.5 h and then diluted with ethyl acetate and brine. The organic layer was separated, washed with a saturated solution of ammonium chloride and brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (eluent system: heptane/ethyl acetate gradient from 100/0 to 90/10) to afford the titled compound.









TABLE I







List of benzyl esters












Int.
Structure
Name
SM
method
MW





BE01


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1-Methyl- cyclobutanecarboxylic acid benzyl ester
32936-76- 8
A, Specific example
204





BE02


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3-Methoxy- cyclobutanecarboxylic acid benzyl ester
552849- 35-1
A
220





BE03


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3-Fluoro- cyclobutanecarboxylic acid benzyl ester
122665- 96-7
A
208





BE04


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3-Methyl- cyclobutanecarboxylic acid benzyl ester
87863-09- 0
A
204





BE05


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Benzyl 3- methyloxetane-3- carboxylate
28562-68- 7
A
206









Method B: Cyanoketone Formation



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A flame-dried round bottom flask is cooled down to RT under nitrogen. A solution of 1 M LiHMDS in THF (1.5 equiv) is introduced into the flask, and then it is cooled down to −78° C. (acetone/dry ice bath). Dry MeCN (from 1.5 to 1.7 equiv) is then added dropwise under nitrogen, and the reaction mixture is stirred for 30 min at −78° C. At this point a solution of ester (1.0 equiv) in dry THF is added dropwise, and then the reaction mixture is stirred at −78° C. for 1-2 h. The reaction mixture is quenched with cold H2O, partitioned between ethyl acetate (or diethyl ether) and H2O. The organic layer is separated, and the aqueous layer is extracted with ethyl acetate (or diethyl ether). The aqueous fraction is then acidified to pH=1-3 with 2 N HCl and extracted with ethyl acetate (or diethyl ether or DCM). The combined organic layers are then washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the titled compound which is used as such or purified by flash chromatography on silica gel.


Illustrative Synthesis of CK01: Cyclobutyl-3-oxo-propionitrile



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A 1 L 4 neck round bottom flask was equipped with 2 dropping funnels and a septum on top of the apparatus. The whole system was flame-dried (heat gun) for 10 minutes under vacuum and then cooled down to RT under a positive stream of nitrogen (balloon). A low-temperature thermometer was adapted under a positive stream of nitrogen, then a 1 N LiHMDS solution in THF (468.0 mL, 468.0 mmol, 1.5 equiv) was cannulated into the flask using a positive stream of nitrogen. The solution was cooled down to −78° C. (dry ice/acetone cooling bath) as confirmed with the thermometer. Dry MeCN (24.4 mL, 468.0 mmol, 1.5 equiv) was added via syringe into the first dropping funnel, and then added dropwise (over 20 min) into the reaction mixture. After the end of the addition, the mixture was stirred at −78° C. for 1 h. At this point, cyclobutanecarboxylic acid ethyl ester (CAS:14924-53-9, 43.1 mL, 312.1 mmol, 1.0 equiv) as a solution in dry THF (106 mL) was introduced into the second dropping funnel. This solution was slowly added over 2 h into the reaction mixture at −78° C. The mixture was stirred at −78° C. for 2 h. The reaction mixture was poured into 300 mL of cold water, stirred for 30 min and allowed to warm to RT. The mixture was then partitioned between ethyl acetate and H2O. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×300 mL). The combined organic phases were discarded. The aqueous layer was then acidified with 100 mL of 2 N HCl, then extracted with ethyl acetate (3×300 mL), washed with 50 mL of brine, dried over MgSO4, filtered and concentrated in vacuo to afford the titled compound which was used without further purification.









TABLE II







List of cyanoketones













Int.
Structure
Name
SM
method
MW
Mes
















29509- 06-6


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4-Methyl-3-oxo- pentanenitrile


111






CK01, 118431- 89-3


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3-Cyclobutyl-3- oxo-propionitrile
14924- 53-9
B, Specific example
123






59997- 51-2


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4,4-Dimethyl-3- oxo-pentanenitrile


125






887594- 13-0


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3-(2-Cyano- acetyl)-azetidine- 1-carboxylic acid tert-butyl ester


224






118431- 88-2


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3-Cyclopropyl-3- oxo-propionitrile


109






CK02


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3-(1-Methyl- cyclobutyl)-3- oxo-propionitrile
BE01
B
137
138





CK03


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3-(cis-3-Methoxy- cyclobutyl)-3- oxo-propionitrile
BE02
B
153






29509- 06-6


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4-Methyl-3-oxo- pentanenitrile


111






1234616- 26-2


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3-(3,3-Difluoro- cyclobutyl)-3- oxo-propionitrile


159






CK04


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3-(3,3-Dimethyl- cyclobutyl)-3- oxo-propionitrile
3854- 83-9
B
151






CK05


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3-(3-Fluoro- cyclobutyl)-3- oxo-propionitrile
BE03
B
141.15






CK06


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3-(trans-3- Methyl- cyclobutyl)-3- oxo-propionitrile
BE04
B
137.18






CK07


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3-Oxo-3- tetrahydrofuran-2- yl-propanenitrile
37443- 42-3
B
139






CK08


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3-(3- Methyloxetan-3- yl)-3-oxo- propanenitrile
BE05
B
139









Method C: Hydrazine Formation



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Method C1: Reductive Amination

To a Solution of Ketone (1 Equiv) and Tert-Butyl Carbazate (CAS: 870-46-2, 1.0 Equiv) in anhydrous dichloromethane at 0° C. is added acetic acid (2.0 equiv) and sodium triacetoxyborohydride (CAS: 56553-60-7, 3.0 equiv). The reaction mixture is warmed up to RT and stirred for 1 h to several days (up to 8). The reaction mixture is then basified with a solution of 2 M sodium hydroxide and a saturated solution of sodium hydrogencarbonate. The two phases are separated, and the aqueous phase is extracted with dichloromethane. The combined organic phases are washed with a saturated solution of sodium hydrogencarbonate and brine, dried over MgSO4, filtered and concentrated in vacuo to afford the tert-butoxy carbonyl hydrazine which is used as such or purified by flash chromatography on silica gel.


Method C2: Reductive Amination

To the ketone (1 equiv) in anhydrous methanol at RT is added tert-butyl carbazate (CAS: 870-46-2, 1.0 equiv). The reaction mixture is stirred for 20 minutes at RT, then acetic acid (3.0 equiv) and sodium cyanoborohydride (CAS: 25895-60-7, 1.5 equiv) are added. The reaction mixture is stirred at RT for 1 h to several days (up to 8). The reaction mixture is then basified with a solution of 2 M sodium hydroxide and a saturated solution of sodium hydrogencarbonate. The two phases are separated, and the aqueous phase is extracted with dichloromethane. The combined organic phases are washed with a saturated solution of sodium hydrogencarbonate and brine, dried over MgSO4, filtered and concentrated in vacuo to afford the tert-butoxy carbonyl hydrazine which is used as such or purified by flash chromatography on silica gel.


Method C3: Tert-Butoxy Carbonyl-deprotection

To a solution of a tert-butoxy carbonyl hydrazine intermediate from Methods C1 or C2 in anhydrous dichloromethane at RT is added 4 M HCl in dioxane (20 equiv). The reaction mixture is stirred at RT until the reaction is finished. The solids are collected by filtration, washed twice with diethyl ether, and dried in vacuo to afford the hydrazine which is used as such.


Method C4: Tert-Butoxy Carbonyl-deprotection

A tert-butoxy carbonyl hydrazine intermediate from Methods C1 or C2 is stirred at RT in a 1:1 mixture of dichloromethane and trifluoroacetic acid until the reaction is finished. The reaction mixture is concentrated in vacuo. The residue is taken up three times with toluene and concentrated in vacuo to afford the hydrazine which is used as such.


Illustrative Synthesis of H01: (Tetrahydro-Pyran-3-Yl)-Hydrazine Di-Hydrochloride Salt



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Step 1: tert-butyl N-(tetrahydropyran-3-ylamino)carbamate

To a solution of dihydro-2H-pyran-3(4H)-one (CAS: 23462-75-1, 0.6 g, 5.99 mmol, 1.0 equiv) and tert-butyl carbazate (CAS: 870-46-2, 0.792 g, 5.99 mmol, 1.0 equiv) in anhydrous dichloromethane (20 mL) at 0° C. was added acetic acid (0.685 mL, 11.98 mmol, 2.0 equiv) and sodium triacetoxyborohydride (CAS: 56553-60-7, 3.81 g, 17.97 mmol, 3.0 equiv). The reaction mixture was warmed up to RT and stirred for 24 h. The reaction mixture was then basified with a solution of 2 M sodium hydroxide (45 mL) and a saturated solution of sodium hydrogencarbonate (30 mL). The two phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with a saturated solution of sodium hydrogencarbonate and brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (eluent system: heptane/ethyl acetate 70/30) to afford tert-butyl 2-(oxan-3-yl)hydrazine-1-carboxylate.


Step 2: (Tetrahydro-pyran-3-yl)-hydrazine di-hydrochloride salt

To a solution of tert-butyl 2-(oxan-3-yl)hydrazine-1-carboxylate from Step 1 (0.534 g, 2.46 mmol, 1 equiv) in anhydrous dichloromethane (1.74 mL) at RT was added 4 M HCl in dioxane (12.34 mL, 49.38 mmol, 20 equiv). The reaction mixture was stirred at RT overnight, and then the solid was collected by filtration. The solid was washed twice with diethyl ether and dried in vacuo to afford the titled compound, H01.


Illustrative Synthesis of H02: 4,4-Difluoro-cyclohexyl)-hydrazine bis(trifluoroacetate)



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Step 1: tert-butyl N-[(4,4-difluorocyclohexyl)amino]carbamate

To 4,4-difluorocyclohexanone (CAS: 22515-18-0, 0.4 g, 2.98 mmol, 1.0 equiv) in anhydrous methanol (8.5 mL) at RT was added tert-butyl carbazate (CAS: 870-46-2, 0.394 g, 2.98 mmol, 1.0 equiv). The reaction mixture was stirred for 20 minutes at RT, and then acetic acid (0.51 mL, 8.95 mmol, 3.0 equiv) and sodium cyanoborohydride (CAS: 25895-60-7, 0.281 g, 4.47 mmol, 1.5 equiv) were added. The reaction mixture was stirred at RT overnight. The reaction mixture was then basified with a solution of 2 M sodium hydroxide (22 mL) and a saturated solution of sodium hydrogencarbonate (15 mL). The two phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with a saturated solution of sodium hydrogencarbonate and brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (eluent system: heptane/ethyl acetate gradient from 100/0 to 50/50) to afford tert-butyl 2-(4,4-difluorocyclohexyl)hydrazine-1-carboxylate.


Step 2: 4,4-Difluoro-cyclohexyl)-hydrazine bis(trifluoroacetate)

The tert-butyl 2-(4,4-difluorocyclohexyl)hydrazine-1-carboxylate intermediate from Step 1 (0.2 g, 0.8 mmol, 1 equiv) was stirred at RT in a 1:1 mixture of dichloromethane (0.65 mL) and trifluoroacetic acid (0.65 mL) for 1.5 h. The reaction mixture was concentrated in vacuo. The residue was taken up three times with toluene and concentrated in vacuo to afford the titled compound, H02.


Synthesis of H04: (2,4-Dimethoxy-benzyl)-hydrazine di-hydrochloride salt



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Step 1: tert-butyl N-[(E)-(2,4-dimethoxyphenyl)methyleneamino]carbamate

To 2,4-dimethoxybenzaldehyde (CAS: 613-45-6, 37.82 g, 228 mmol, 1.0 equiv) in methanol at RT was added tert-butyl carbazate (CAS: 870-46-2, 30.08 g, 228 mmol, 1.0 equiv) and MgSO4 (18.9 g). The reaction mixture was stirred at RT overnight. The reaction mixture was filtered through a pad of diatomaceous earth. The solids were washed with dichloromethane, and the filtrate was concentrated in vacuo. The residue was taken up in diethyl ether (120 mL) and stirred at RT. The resulting slurry was filtered. The solid was washed three times with diethyl ether and dried in vacuo to afford tert-butyl 2-[(2,4-dimethoxyphenyl)methylidene]hydrazine-1-carboxylate.


Step 2: tert-butyl N-[(E)-(2,4-dimethoxyphenyl)methylamino]carbamate

A 2-L round bottom flask under nitrogen atmosphere was charged with methanol (1.3 L), 10% palladium on carbon (13.6 g), and tert-butyl 2-[(2,4-dimethoxyphenyl)methylidene]hydrazine-1-carboxylate from Step 1 (68.41 g, 228 mmol, 1 equiv). The reaction mixture was placed under vacuum then filled with hydrogen and kept under a hydrogen atmosphere (balloon). The reaction mixture was stirred at RT for 5 h. The reaction mixture was filtered through a pad of diatomaceous earth. The solids were washed with methanol, and the filtrate was concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (eluent system: heptane/ethyl acetate, gradient from 50/50 to 40/60) to afford tert-butyl 2-[(2,4-dimethoxyphenyl)methyl]hydrazine-1-carboxylate.


Step 3: (2,4-Dimethoxy-benzyl)-hydrazine di-hydrochloride salt

A 2-L round bottom flask was charged with tert-butyl 2-[(2,4-dimethoxyphenyl)methyl]hydrazine-1-carboxylate from Step 2 (59.8 g, 211 mmol, 1.0 equiv), then a solution of 4 M HCl in dioxane (600 mL, 2400 mmol, 11.35 equiv) was added. The reaction mixture was stirred at RT overnight. The reaction mixture was filtered. The solid was washed three times with diethyl ether and dried in vacuo to afford the titled compound, H04.


Synthesis of H05: 4-(3-hydrazinylphenyl)morpholine



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A solution of sodium nitrite (221 mg, 3.2 mmol) in water (1.5 mL) was added dropwise at −5° C. to a solution of 3-morpholin-4-ylaniline (CAS: 159724-40-0, 475 mg, 2.7 mmol). The reaction mixture was stirred for 1 hour, and a solution of tin (II) chloride dihydrate in concentrated HCl (3 mL) was added dropwise. The reaction mixture was allowed to warm to RT for 1 hour. The precipitate was filtered, washed with petroleum ether and partitioned between water and ethyl acetate. The aqueous phase was basified to pH 9-10 and extracted three times with ethyl acetate. The combined aqueous layer was evaporated under reduced pressure. The titled compound was used as such without further purification.









TABLE III







List of Hydrazines













Int.
Structure
Name
SM
method
MW
Mes





H01


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(Tetrahydro-pyran- 3-yl)-hydrazine di-hydrochloride salt
23462- 75-1
C1, C3 Specific example
116






H02


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(4,4-Difluoro- cyclohexyl)- hydrazine di-trifluoroacetic acid salt
22515- 18-0
C2, C4 Specific example
150






H03


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(Tetrahydro-furan- 3-yl)-hydrazine di-hydrochloride salt
22929- 52-8
C2, C3
102






H04


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(2,4-Dimethoxy- benzyl)-hydrazine di-hydrochloride salt
613- 45-6
Specific example
182
183





H05


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4-(3- Hydrazinylphenyl) morpholine
15972 4-40-0
Specific example
193
194





H06


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(3- Benzyloxycyclohexyl) hydrazine
12399 0-98- 7
C2, C3
220
221





H07


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Benzyl 4- hydrazinopiperidine- 1-carboxylate
19099- 93-5
C2, C3
249
250





H08


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Benzyl 3- hydrazinopyrrolidine- 1-carboxylate
13031 2-02-6
C2, C3
235
236





H09


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Benzyl 3- hydrazinopiperidine- 1-carboxylate
61995- 20-8
C2, C4
249
250









Method D: Aryl Hydrazones Formation



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An aryl bromide (1.05 equiv), benzophenone hydrazone (CAS: 5350-57-2, 1.0 equiv) and rac-BINAP (CAS: 98327-87-8, 0.06 equiv) are introduced in a round bottom flask at RT and suspended in anhydrous toluene. The slurry is purged with argon (bubbling). Then palladium(II) acetate (CAS: 3375-31-3, 0.02 equiv) and sodium tert-butoxide (CAS: 865-48-5, 1.3 equiv) are added, and the resulting slurry is purged with argon again. The reaction mixture is heated at 100° C. until the reaction is finished. The reaction mixture is cooled down to RT and filtered through a pad of diatomaceous earth. Solids were washed with ethyl acetate, and the filtrate is concentrated in vacuo. The titled compound is obtained from the crude filtrate either by precipitation from a suitable solvent or by purification by flash chromatography on silica gel (eluent system: heptane/ethyl acetate).


Illustrative Synthesis of ArH01: [3-(N′-Benzhydrylidene-hydrazino)-phenyl]-dimethyl-amine



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3-Bromo-N,N-dimethylaniline (CAS:16518-62-0, 18.55 mL, 130 mmol, 1.05 equiv), benzophenone hydrazone (CAS: 5350-57-2, 24.29 g, 124 mmol, 1.0 equiv) and rac-BINAP (CAS: 98327-87-8, 4.62 g, 7.43 mmol, 0.06 equiv) were combined in a round bottom flask at RT and suspended in anhydrous toluene (80 mL). The slurry was purged with argon (bubbling), and then palladium(II) acetate (CAS: 3375-31-3, 0.556 g, 2.48 mmol, 0.02 equiv) and sodium tert-butoxide (CAS: 865-48-5, 15.46 g, 161 mmol, 1.3 equiv) were added. The resulting slurry was purged with argon again, and the reaction mixture was heated at 100° C. for 1.5 h. The reaction mixture was cooled down to RT and filtered through a pad of diatomaceous earth. The solids were washed with ethyl acetate, and the filtrate was concentrated in vacuo. The residue was taken up in diethyl ether, and stirred at RT. The resulting slurry was filtered. The collected solid was washed twice with diethyl ether and dried in vacuo to afford the titled compound.









TABLE IV







List of Arylhydrazones













Int.
Structure
Name
SM
method
MW
Mes





ArH01


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[3-(N- Benzhydrylidene- hydrazino)-phenyl]- dimethyl-amine
16518- 62-0
D
315
316





ArH02


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N-Benzhydrylidene-N′- (3-morpholin-4-yl- phenyl)-hydrazine
197846- 82-5
D
357
358





ArH03


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N-Benzhydrylidene-N′- (3-fluoro-5-methoxy- phenyl)-hydrazine
29578- 39-0
D
320
321





ArH04


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N-Benzhydrylidene-N′- (6-fluoro-pyridin-2-yl)- hydrazine
144100- 07-2
D
291
292





ArH05


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N-Benzhydrylidene-N′- (2-chloro-pyridin-4-yl)- hydrazine
73583- 37-6
D
308
309





ArH06


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N- (benzhydrylideneamino)- 5-morpholino- pyridin-3-amine
200064- 13-7
D
358
359





ArH07


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N- (benzhydrylideneamino)- 4-chloro-pyridin-2- amine
22918- 01-0
D
307
308









Methods E1-E7: Synthesis of Aminopyrazoles
Method E1: Cyclization of Hydrazines with 3-aminocrotononitrile



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3-Aminocrotononitrile (CAS: 1118-61-2, 1.1 equiv), the hydrazine hydrochloride (1.0 equiv) and few drops of 1 N HCl solution are heated in EtOH at reflux until the reaction is finished. The reaction mixture is cooled down to RT and then is diluted with a saturated solution of sodium hydrogencarbonate. The aqueous phase is extracted with dichloromethane. The combined organic phases are filtered through a phase separator and concentrated under vacuum to afford the aminopyrazole which is used as such.


Illustrative Synthesis of AMP01: 5-Methyl-2-(3-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylamine



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3-Aminocrotononitrile (CAS: 1118-61-2, 0.5 g, 6.09 mmol, 1.1 eq;), 3-(trifluoromethoxy)phenylhydrazine hydrochloride (1.27 g, 5.54 mmol, 1.0 equiv) and two drops of 1 N HCl solution were heated in EtOH (1.5 mL) at reflux overnight. The reaction mixture was diluted with a saturated solution of sodium hydrogencarbonate, and the aqueous phase was extracted with dichloromethane. The combined organic phases were filtered through a phase separator and concentrated under vacuum to afford the titled compound which was used as such.


Method E2: Cyclization of Hydrochloride Salts of Hydrazines with Cyano Ketones



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A round bottom flask is charged with the cyanoketone (from 1.0 to 1.5 equiv), the hydrazine hydrochloride or dihydrochloride (1 equiv) and EtOH. This mixture is stirred at a temperature ranging from RT to refluxing ethanol until the reaction is finished. Then the reaction mixture is concentrated in vacuo to afford a crude mixture which is used as such or undergoes one of the following processes:


Either the crude mixture is taken up in a suitable solvent. The resulting slurry is filtered, and the solids are washed with the same solvent and dried in vacuo to afford the aminopyrazole as its hydrochloride salt which is used as such or is taken up in either ethyl acetate or dichloromethane and basified with a saturated solution of either potassium carbonate or sodium hydrogencarbonate. The two phases are separated, and the aqueous phase is extracted with either ethyl acetate or dichloromethane. The combined organic phases are washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the aminopyrazole as its free base which is used as such or further purified by flash chromatography on silica gel.


Or alternatively this crude mixture is partitioned between water and either ethyl acetate or dichloromethane. The two phases are separated, and the aqueous phase is washed with either ethyl acetate or dichloromethane, basified with a saturated solution of sodium hydrogencarbonate and extracted with either ethyl acetate or dichloromethane. The combined organic phases are washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the aminopyrazole as its free base which is used as such or further purified by flash chromatography on silica gel.


Or alternatively the crude mixture is partitioned between a saturated aqueous solution of NaHCO3 and dichloromethane. The organic phase is separated using a phase separator and concentrated in vacuo to afford the titled compound as its free base which is used as such or further purified by flash chromatography on silica gel.


Illustrative Synthesis of AMP29: 5-Cyclobutyl-2-phenyl-2H-pyrazol-3-ylamine



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A round bottom flask was charged with 3-cyclobutyl-3-oxo-propionitrile CK01 (19.6 g, 159 mmol, 1.1 equiv), phenylhydrazine hydrochloride (CAS: 59-88-1, 20.92 g, 145 mmol, 1.0 equiv) and EtOH (210 mL). The reaction mixture was stirred at reflux for 1 h. Then the reaction mixture was concentrated in vacuo to afford a crude mixture which was taken up in diethyl ether. The resulting slurry was filtered, and the solid was washed with diethyl ether and dried in vacuo to afford the titled compound as its hydrochloride salt which was taken up in dichloromethane and basified with a saturated solution of sodium hydrogencarbonate. The two phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the titled compound as its free base.


Illustrative Synthesis of AMP35: 5-cyclobutyl-2-cyclohexyl-2H-pyrazol-3-ylamine



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A round bottom flask was charged with 3-cyclobutyl-3-oxo-propionitrile ([118431-89-3], 20.4 g, 166 mmol), cyclohexylhydrazine hydrochloride ([24214-73-1], 25 g, 166 mmol) and EtOH (200 mL). The reaction mixture was refluxed overnight and cooled down to RT. Next, the mixture was concentrated and water (150 mL) was added. The pH was modified till pH=7 with a saturated aqueous K2CO3 solution. Subsequently, the aqueous phase was extracted with DCM. The obtained organic phase was dried and concentrated to give a yellow solid. Trituration with MTBE gave the titled compound.


Illustrative Synthesis of AMP93: 3-cyclobutyl-1-(4-fluorophenyl)-1H-pyrazol-5-amine



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A round bottom flask was charged with 3-cyclobutyl-3-oxo-propionitrile (CK01, 10 g, 81.4 mmol), 4-fluorophenylhydrazine hydrochloride ([823-85-8], 12 g, 74 mmol) and EtOH (35 mL). The reaction mixture was refluxed for 2 hours and cooled down to RT. Half of the solvent was removed in vacuo. The mixture was vigorously stirred and diisopropyl ether (350 mL) was added. The stirring was continued for 1 hour, and the formed precipitate was filtered, washed with diisopropyl ether and dried at 40° C. under reduced pressure to give the titled compound.


Illustrative Synthesis of AMP94: 1-tert-butyl-3-cyclobutyl-1H-pyrazol-5-amine



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A round bottom flask was charged with 3-cyclobutyl-3-oxo-propionitrile (CK01, 12.3 g, 0.1 mol), tert-butylhydrazine hydrochloride ([7400-27-3], 13.5 g, 0.11 mol) and EtOH (150 mL). The reaction mixture was refluxed for 20 hours and cooled down to RT. Half of the solvent was removed by concentration in vacuo, and the mixture was cooled in an ice bath. The formed precipitate was collected by filtration and washed successively with diethyl ether and n-pentane. The filtrate was allowed to stand for 1 hour, and the formed precipitate was again collected by filtration and washed with diethyl ether and n-pentane. The combined solids were stirred in ethyl acetate and a saturated solution of NaHCO3. The organic phase was dried over sodium sulfate, filtered and evaporated under reduced pressure to give the titled compound.


Method E3: Cyclization of Cyano Ketones with Hydrazines Either as Free Base, Hydrochloride or TFA Salt, in the Presence of an Organic Base



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To the hydrazine either as free base or as a hydrochloride or a trifluoroacetic acid mono or di-salt (1 equiv) and the cyanoketone (from 1.0 to 1.5 equiv) in ethanol or toluene at RT is added DIPEA (from 0 to 2.0 equiv). Then the reaction mixture is heated at reflux until the reaction is finished. The reaction mixture is concentrated in vacuo to afford a crude mixture which is used as such or purified by flash chromatography on silica gel to afford the aminopyrazole as its free base.


Illustrative Synthesis of AMP26: 2-Cyclopentyl-5-isopropyl-2H-pyrazol-3-ylamine



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To cyclopentylhydrazine hydrochloride (CAS: 24214-72-0, 0.35 g, 2.56 mmol, 1.0 equiv) and 4-methyl-3-oxo-pentanenitrile (CAS: 29509-06-6, 0.33 mL, 2.82 mmol, 1.1 equiv) in toluene (12.8 mL) at RT was added DIPEA (0.82 mL, 5.12 mmol, 2.0 equiv). Then the reaction mixture was heated at reflux for 1.5 h. The reaction mixture was cooled down to RT and concentrated in vacuo to afford a crude mixture which was purified by flash chromatography on silica gel (eluent system: heptane/ethyl acetate gradient from 100/0 to 30/70) to afford the titled compound.


Method E4: Cyclization of Arylhydrazones with Cyanoketones



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To the arylhydrazone (1 equiv) and the cyanoketone (from 1.0 to 2 equiv) in ethanol at RT is added an aqueous solution of 2 M HCl or 12 M HCl (5 equiv). Then the reaction mixture is heated at reflux until the reaction is finished. Then the reaction mixture is cooled down to RT and undergoes one of the following processes.


The reaction mixture is concentrated to dryness in vacuo to afford a crude mixture. The aminopyrazole is obtained from this crude mixture by precipitation from a suitable solvent to afford the aminopyrazole as its hydrochloride salt and used as such.


Ethanol from the reaction mixture is removed in vacuo. The resulting aqueous residue is diluted with an aqueous solution of 2 M HCl, washed with dichloromethane, then basified with a saturated solution of sodium hydrogencarbonate and extracted with dichloromethane. The combined organic phases are washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the aminopyrazole as a free base which is used as such or further purified by flash chromatography on silica gel.


Illustrative Synthesis of AMP06: 2-(3-Dimethylamino-phenyl)-5-isopropyl-2H-pyrazol-3-ylamine



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To [3-(N-benzhydrylidene-hydrazino)-phenyl]-dimethyl-amine (ArH01, 25.57 g, 81 mmol, 1 equiv) and 4-methyl-3-oxo-pentanenitrile (CAS: 29509-06-6, 10.57 mL, 89.2 mmol, 1.1 equiv) in ethanol (255 mL) at RT was added an aqueous solution of 2 M HCl (203 mL, 405 mmol, 5 equiv). Then the reaction mixture was heated at reflux overnight. The reaction mixture was cooled down to RT, and ethanol from the reaction mixture was removed in vacuo. The resulting aqueous residue was diluted with an aqueous solution of 2 M HCl, washed with dichloromethane, then basified with a saturated solution of sodium hydrogencarbonate and extracted twice with dichloromethane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the titled compound which was used as such.


Method E5: SNAr on 2-(2-chloro-pyridin-4-yl)-yl-2H-pyrazol-3-ylamine intermediates



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A sealed tube is charged with the 2-(2-chloro-pyridin-4-yl)-yl-2H-pyrazol-3-ylamine intermediate (1 equiv), the amine (from 10 to 15 equiv), DIPEA (3 equiv) and DMA. This mixture is heated at a temperature ranging from 130° C. to 160° C. until the reaction is finished. Then the reaction mixture is cooled down to RT and partitioned between ethyl acetate and water. The two phases are separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The substituted aminopyrazole is obtained from the crude mixture either by precipitation or by purification by flash chromatography on silica gel.


Illustrative Synthesis of AMP22: 5-Isopropyl-2-(2-pyrrolidin-1-yl-pyridin-4-yl)-2H-pyrazol-3-ylamine



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A sealed tube was charged with 2-(2-chloro-pyridin-4-yl)-yl-2H-pyrazol-3-ylamine intermediate (AMP20, 1.2 g, 5.07 mmol, 1 equiv), pyrrolidine (CAS: 123-75-1, 4 mL, 50.7 mmol, 10 equiv), DIPEA (2.6 mL, 15.2 mmol, 3 equiv) and DMA (10 mL). This mixture was heated at 130° C. for 2 h. Then the reaction mixture was cooled down to RT, and additional pyrrolidine (CAS: 123-75-1, 1 mL, 12.67 mmol, 2.5 equiv) was introduced, and the reaction mixture was heated at 130° C. for 30 minutes. Then the reaction mixture was cooled down to RT and partitioned between ethyl acetate and water. The two phases were separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with water (three times) and brine, dried over MgSO4, filtered and concentrated in vacuo. The crude mixture was purified by flash chromatography on silica gel (eluent system: dichloromethane/methanol gradient from 100/0 to 97/3) to afford the titled compound.


Method E6: Buchwald Coupling



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To the 2-(3-bromo-phenyl)-2H-pyrazol-3-ylamine hydrochloride salt intermediate (1 equiv) in anhydrous THF at RT under a nitrogen atmosphere is added the amine (1.2 equiv), a solution of 1 N LiHMDS in THF (5 equiv) and XPhos Pd G1 (CAS 1028206-56-5, 0.1 equiv). The reaction mixture is stirred at RT until the reaction is finished. The reaction mixture is hydrolyzed with a saturated solution of ammonium chloride and diluted with dichloromethane. The two phases are separated, and the aqueous phase is extracted with dichloromethane. The combined organic phases are washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The substituted aminopyrazole is obtained from the crude mixture by purification with flash chromatography on silica gel (eluent system: heptane/ethyl acetate).


Illustrative Synthesis of AMP11: 5-Isopropyl-2-(3-pyrrolidin-1-yl-phenyl)-2H-pyrazol-3-ylamine



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To 2-(3-bromo-phenyl)-5-isopropyl-2H-pyrazol-3-ylamine hydrochloride salt (AMP05, 0.5 g, 1.58 mmol, 1 equiv) in anhydrous THF (5 mL) at RT under nitrogen atmosphere was added pyrrolidine (CAS: 123-75-1, 0.16 mL, 1.9 mmol, 1.2 equiv), a solution of 1 N LiHMDS in THF (8 mL, 8 mmol, 5 equiv) and XPhos Pd G1 (CAS 1028206-56-5, 0.117 g, 0.16 mmol, 0.1 equiv). The reaction mixture was stirred at RT for 5 h. The reaction mixture was treated with a saturated solution of ammonium chloride and diluted with dichloromethane. The two phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude mixture was purified by flash chromatography on silica gel (eluent system: heptane/ethyl acetate gradient from 100/0 to 65/35) to afford the titled compound.


Method E7: O-Alkylation of 5-aminopyrazol-3-ol Analogues



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A suspension of 5-aminopyrazol-3-ol derivative (1 equiv), cesium carbonate (1.2 equiv) and 2-bromopropane (1 equiv) in N-methylpyrrolidine is stirred at RT for 20 to 72 hours. The reaction mixture is diluted with DCM and washed with water. The organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure. The O-alkylated product is purified by flash column chromatography on silica gel.


Illustrative Synthesis of AMP96: 1-(4-fluorophenyl)-3-[(propan-2-yl)oxy]-1H-pyrazol-5-amine



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A suspension of 5-amino-1-(4-fluorophenyl)-1H-pyrazol-3-ol ([1247169-18-1], 800 mg, 4.14 mmol), cesium carbonate (2.15 g, 4.97 mmol) and 2-bromopropane (516 μL, 4.14 mmol) in N-methylpyrrolidine (8 mL) was stirred at RT for 20 hours. The reaction mixture was diluted with DCM and washed with water. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate/n-heptane to yield the titled compound.


Synthesis of Intermediates: AMP18 [6-(5-Amino-3-isopropyl-pyrazol-1-yl)-pyridin-2-yl]-dimethyl-amine and AMP19 5-Isopropyl-2-(6-morpholin-4-yl-pyridin-2-yl)-2H-pyrazol-3-ylamine



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A sealed tube was charged with 2-(6-fluoro-pyridin-2-yl)-5-isopropyl-2H-pyrazol-3-ylamine (AMP17, 0.2 g, 0.91 mmol, 1 equiv), morpholine (CAS: 110-91-8, 0.12 mL, 1.37 mmol, 1.5 equiv), DIPEA (0.19 mL, 1.09 mmol, 1.2 equiv) and DMF (2 mL). This mixture was heated at 100° C. overnight. Then the reaction mixture was cooled down to RT and partitioned between ethyl acetate and water. The two phases were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water (three times) and brine, dried over MgSO4, filtered and concentrated in vacuo. The crude mixture was purified by flash chromatography on silica gel (eluent system: heptane/ethyl acetate gradient from 100/0 to 60/40) to afford the two titled compounds.


Synthesis of AMP51B: ethyl 5-(tert-butoxycarbonylamino)-1-phenyl-pyrazole-3-carboxylate



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Di-tert-butyl dicarbonate (613 mg, 2.8 mmol) and DMAP (686 mg, 5.6 mmol) were added at RT to a stirring solution of ethyl 5-amino-1-phenyl-1H-pyrazole-3-carboxylate (CAS: 866837-96-9, 500 mg, 2.2 mmol) in DCM (11 mL). The reaction mixture was stirred for 20 hours and diluted with DCM. The organic phase was washed with a saturated aqueous solution of NaHCO3, separated using a phase separator, and concentrated under reduced pressure. The crude sample was purified by flash column chromatography using a gradient of petroleum ether/ethyl acetate to give the titled compound.


Synthesis of AMP53: (5-amino-1-phenyl-pyrazol-3-yl)methanol



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A solution of ethyl 5-amino-1-phenyl-1H-pyrazole-3-carboxylate (CAS: 866837-96-9, 300 mg, 1.3 mmol) in THF (6.5 mL), under nitrogen atmosphere was cooled down to −78° C. Diisobutylaluminum hydride (1 M in toluene, 2.9 mL, 2.9 mmol) was added dropwise to the solution, and the stirring at −78° C. was continued for 1 hour. Methanol was added, and the reaction mixture was stirred for 30 minutes warming to RT. DCM was added, and the organic phase was washed with water. The organic phase was separated using a phase separator and concentrated under reduced pressure. The titled compound was used as such without any further purification.


Synthesis of AMP66: 2-(5-amino-1-phenyl-pyrazol-3-yl)propan-2-ol



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Step 1: tert-butyl N-[5-(1-hydroxy-1-methyl-ethyl)-2-phenyl-pyrazol-3-yl]carbamate

A solution of AMP51B (100 mg, 0.3 mmol) in THF (1.5 mL), under nitrogen atmosphere was cooled down in an ice bath. Methylmagnesium iodide (3 M in diethyl ether, 0.2 mL, 0.6 mmol) was added dropwise to the solution, and the stirring at 0° C. was continued for 20 minutes. The reaction mixture was allowed to warm to RT for 2.5 hours. LCMS analysis only showed little conversion. The reaction mixture was cooled in an ice bath and 2 equivalents of methylmagnesium iodide (3 M in diethyl ether, 0.2 mL, 0.6 mmol) were again added. The reaction mixture was stirred at RT for 2 hours. LCMS analysis still showed some starting ester left. An additional 2 equivalents of methylmagnesium iodide (3 M in diethyl ether, 0.2 mL, 0.6 mmol) were again added at RT, and the stirring was continued for 1 hour. The reaction mixture was quenched with a saturated aqueous solution of NH4Cl and extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of NaHCO3, dried over sodium sulfate, filtered and concentrated under reduced pressure. The tertiary alcohol compound was used as such without any further purification.


Step 2: 2-(5-amino-1-phenyl-pyrazol-3-yl)propan-2-ol

Trifluoroacetic acid (0.3 mL, 3.9 mmol) was added to a solution of the tertiary alcohol from the previous step (96 mg, 0.3 mmol) in DCM (3 mL). The solution was stirred at RT for 1.5 hours. Trifluoroacetic acid (0.3 mL, 3.9 mmol) was added again, and the solution was heated at 35° C. for 2 hours. The reaction mixture was cooled down to RT, diluted with DCM and washed twice with a saturated aqueous solution of NaHCO3. The organic phase was separated using a phase separator and concentrated in vacuo to give the titled compound.


Synthesis of AMP68: 5-amino-N-methyl-1-phenyl-pyrazole-3-carboxamide



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Step 1: 5-(tert-butoxycarbonylamino)-1-phenyl-pyrazole-3-carboxylic acid

A solution of AMP51B (300 mg, 0.9 mmol) in 2 N NaOH (2 mL, 4 mmol) and ethanol (4.5 mL) was heated at 70° C. for 3 hours. The reaction mixture was acidified to pH 5-6 and extracted with DCM. The organic phase was separated using a phase separator and concentrated under reduced pressure. The intermediate carboxylic acid was used as such without any further purification.


Step 2: tert-butyl N-[5-(methylcarbamoyl)-2-phenyl-pyrazol-3-yl]carbamate

A suspension of EDC.HCl (126 mg, 066 mmol), the carboxylic acid from the previous step (200 mg, 0.66 mmol), and HOBt (107 mg, 0.8 mmol) in DCM (3 mL) was stirred at 0° C. for 15 minutes. 2 M Methylamine in methanol (1 mL, 2 mmol) was added, and the stirring was continued at RT for 20 hours. The solution was diluted with DCM and washed with water. The organic phase was separated using a phase separator, and the volatiles were removed under reduced pressure. The intermediate methyl amide was used as such without any further purification.


Step 3: 5-amino-N-methyl-1-phenyl-pyrazole-3-carboxamide

Trifluoroacetic acid (0.6 mL, 7.8 mmol) was added to a solution of the compound from Step 2 (210 mg, 0.66 mmol) in DCM (6 mL). The solution was stirred at RT for 1.5 hours. Trifluoroacetic acid (0.3 mL, 3.9 mmol) was added again, and the solution was heated at 35° C. for 2 hours. The reaction mixture was cooled down to RT, diluted with DCM and washed twice with a saturated aqueous solution of NaHCO3. The organic phase was separated using a phase separator and concentrated in vacuo to give the titled compound.


Synthesis of AMP74: 5-amino-1-phenyl-pyrazole-3-carboxamide



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Step 1: tert-butyl N-(5-carbamoyl-2-phenyl-pyrazol-3-yl)carbamate

AMP51B (200 mg, 0.6 mmol) in 7 N ammonia in methanol (1 mL) was heated at 70° C. for 5 hours. The reaction mixture was cooled to RT, and the volatiles were removed under reduced pressure. The intermediate carboxamide was used as such without any further purification.


Step 2: 5-amino-1-phenyl-pyrazole-3-carboxamide

Trifluoroacetic acid (0.6 mL, 7.8 mmol) was added to a solution of the compound from Step 1 (181 mg, 0.6 mmol) in DCM (6 mL). The solution was stirred at RT for 1.5 hours. Trifluoroacetic acid (0.3 mL, 3.9 mmol) was added again, and the solution was heated at 35° C. for 2 hours. The reaction mixture was cooled down to RT, diluted with DCM and washed twice with a saturated aqueous solution of NaHCO3. The organic phase was separated using a phase separator and concentrated in vacuo to give the titled compound.


Synthesis of AMP86: 5-(methylaminomethyl)-2-phenyl-pyrazol-3-amine



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Step 1: tert-butyl N-(5-formyl-2-phenyl-pyrazol-3-yl)carbamate

A solution of AMP51B (842 mg, 2.5 mmol) in DCM (8 mL), under nitrogen atmosphere was cooled down to −78° C. 1 M Diisobutylaluminum hydride in toluene (3.3 mL, 3.3 mmol) was added dropwise to the solution, and the stirring at −78° C. was continued for 3 hours. 1 M Diisobutylaluminum hydride in toluene (3.3 mL, 3.3 mmol) is again added and the stirring at −78° C. was continued for another 2 hours. Methanol was added, and the reaction mixture was stirred for 30 minutes warming to RT. 1 M HCl was added, and the reaction mixture was extracted with DCM. The organic phase was separated using a phase separator and concentrated under reduced pressure. The aldehyde compound was used as such without any further purification.


Step 2: tert-butyl N-[5-(methylaminomethyl)-2-phenyl-pyrazol-3-yl]carbamate

A solution of 2 M methyl amine in THF (0.2 mL, 0.4 mmol) was added at RT to a stirring solution of the aldehyde from Step 1 (100 mg, 0.35 mmol) in methanol (2 mL). After 16 hours, sodium borohydride (13 mg, 0.35 mmol) was added, and the stirring at RT was continued for 5 hours. 1 M HCl was added to the reaction mixture, and the two phases were separated. The aqueous phase was basified with a solution of 2 N NaOH and extracted with DCM. The organic phase was filtered through a phase separator and concentrated under reduced pressure to give the methylamine.


Step 3: 5-(methylaminomethyl)-2-phenyl-pyrazol-3-amine

Trifluoroacetic acid (0.3 mL, 3.9 mmol) was added to a solution of the methylamine from Step 2 (106 mg, 0.35 mmol) in DCM (3 mL). The solution was stirred at 35° C. for 2.5 hours. The reaction mixture was cooled down to RT, diluted with DCM and washed twice with a saturated aqueous solution of NaHCO3. The organic phase was separated using a phase separator and concentrated in vacuo to give the titled compound.









TABLE V







List of aminopyrazoles













Int
Structure
Name
SM
method
MW
Mes
















70373- 98-7


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5-Amino-1- phenyl-1,2- dihydro-pyrazol- 3-one


175






826-85- 7


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2-Phenyl-2H- pyrazol-3- ylamine


159






1131- 18-6


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5-Methyl-2- phenyl-2H- pyrazol-3- ylamine


173






345-07- 3


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5-Methyl-2-(3- trifluoromethyl- phenyl)-2H- pyrazol-3- ylamine


241






866472- 29-9


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2-(3-Chloro-4- methyl- phenyl)-5- methyl-2H- pyrazol-3- ylamine


221






380569- 79-0


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2-(2,4- Difluoro- phenyl)-5- methyl-2H- pyrazol-3- ylamine


209






123279 6-65-4


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2-(3,5- Difluoro- phenyl)-5- methyl-2H- pyrazol-3- ylamine


209






890010- 89-6


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2-(3,5- Dimethyl- phenyl)-5- methyl-2H- pyrazol-3- ylamine


201






92721- 83-0


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5-Methyl-2-m- tolyl-2H- pyrazol-3- ylamine


187






56547- 82-1


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2-Cyclohexyl- 5-methyl-2H- pyrazol-3- ylamine


179






40401- 41-0


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2-(3-Chloro- phenyl)-5- methyl-2H- pyrazol-3- ylamine


207






105438- 45-7


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2-(3-Fluoro- phenyl)-5- methyl-2H- pyrazol-3- ylamine


191






497141- 59-0


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5-Methyl-2-(4- trifluoromethoxy- phenyl)- 2H-pyrazol-3- ylamine


257






92721- 94-3


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2-(3-Methoxy- phenyl)-5- methyl-2H- pyrazol-3- ylamine


203






3524- 36-5


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2-Isobutyl-5- methyl-2H- pyrazol-3-yl amine


153






1124- 16-9


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2-Isopropyl-5- methyl-2H- pyrazol-3- ylamine


139






436088- 86-7


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5-Amino-1- cyclohexyl- 1H-pyrazol-3- ol


181






124716 9-18-1


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5-Amino-1-(4- fluorophenyl)- 1H-pyrazol-3- ol


193






AMP01


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5-Methyl-2-(3- trifluorometho xy-phenyl)- 2H-pyrazol-3- ylamine
133115- 55-6, 1118-61-2
E1 Specific example
257
258





AMP02


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2-(3,4- Difluoro- phenyl)-5- methyl-2H- pyrazol-3- ylamine
161886- 22-2, 1118-22-2
E1
209
210





AMP03


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2-(3-Fluoro- 5-methoxy- phenyl)-5- methyl-2H- pyrazol-3- ylamine
ArH03, 1118-61-2
E4
221
222


AMP04


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5-Isopropyl-2- phenyl-2H- pyrazol-3- ylamine
100-63-0, 29509-06- 6
E3
201
202





AMP05


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2-(3-Bromo- phenyl)-5- isopropyl-2H- pyrazol-3- ylamine
27246-81- 7, 29509- 06-6
E2
280
281





AMP06


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2-(3- Dimethylamino- phenyl)-5- isopropyl-2H- pyrazol-3- ylamine
ArH01, 29509-06- 6
E4 Specific example
244
245





AMP07


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5-Isopropyl-2- m-tolyl-2H- pyrazol-3- ylamine
637-04-7, 29509-06- 6
E2
215
216





AMP08


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5-Isopropyl-2- (3- trifluoromethyl- phenyl)-2H- pyrazol-3- ylamine
368-78-5, 29509-06- 6
E3
269
270





AMP09


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2-(3,5- Difluoro- phenyl)-5- isopropyl-2H- pyrazol-3- ylamine
134993- 88-7, 29509-06- 6
E2
237
238





AMP10


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5-Isopropyl-2- (3-morpholin- 4-yl-phenyl)- 2H-pyrazol-3- ylamine
ArH02, 29509-06- 6
E4
286
287





AMP11


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5-Isopropyl-2- (3-pyrrolidin- 1-yl-phenyl)- 2H-pyrazol-3- ylamine
AMP05
E6 Specific example
270
271





AMP12


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2-(3-Fluoro- phenyl)-5- isopropyl-2H- pyrazol-3- ylamine
502496- 27-7, 2950906- 6
E2
219
220





AMP13


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2-(4-Fluoro- phenyl)-5- isopropyl-2H- pyrazol-3- ylamine
823-85-8, 29509-06- 6
E2
219
220





AMP14


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2-(2,4- Difluoro- phenyl)-5- isopropyl-2H- pyrazol-3- ylamine
51523-79- 6, 29509- 06-6
E2
237
238





AMP15


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2-Cyclopropyl- 5-methyl-2H- pyrazol-3- ylamine
213764- 25-1, 1118-61-2
E1
137
138





AMP16


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5-Isopropyl-2- (6-methoxy- pyridin-3-yl)- 2H-pyrazol-3- ylamine
179543- 88-5, 29509-06- 6
E2
232
233





AMP17


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2-(6-Fluoro- pyridin-2-yl)- 5-isopropyl- 2H-pyrazol-3- ylamine
ArH04, 29509-06- 6
E4
220
221





AMP18


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[6-(5-Amino- 3-isopropyl- pyrazol-1-yl)- pyridin-2-yl]- dimethyl- amine
AMP17
Specific example
245
246





AMP19


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5-Isopropyl-2- (6-morpholin- 4-yl-pyridin-2- yl)-2H- pyrazol-3- ylamine
AMP17
Specific example
287
288





AMP20


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2-(2-Chloro- pyridin-4-yl)- 5-isopropyl- 2H-pyrazol-3- ylamine
ArH05, 29509-06- 6
E4
237
238





AMP21


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5-Isopropyl-2- (2-morpholin- 4-yl-pyridin-4- yl)-2H- pyrazol-3- ylamine
AMP20
E5
287
288





AMP22


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5-Isopropyl- 2-(2-pyrrolidin- 1-yl-pyridin-4- yl)-2H- pyrazol-3- ylamine
AMP20 Specific example
E5
271
272





AMP23


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2-Cyclohexyl- 5-isopropyl- 2H-pyrazol-3- ylamine
30929-57- 8, 29509- 06-6
E2
207
208





AMP24


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2-(4,4- Difluoro- cyclohexyl)-5- isopropyl-2H- pyrazol-3- ylamine
H02, 29509-06- 6
E3
243
244





AMP25


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5-Isopropyl-2- (tetrahydro- pyran-3-yl)- 2H-pyrazol-3- ylamine
H01, 29509-06- 6
E3
209
210





AMP26


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2-Cyclopentyl- 5-isopropyl- 2H-pyrazol-3- ylamine
24214-72- 0, 29509- 06-6
E3 Specific example
193
194





AMP27


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5-Isopropyl-2- (tetrahydro- furan-3-yl)- 2H-pyrazol-3- ylamine
H03, 29509-06- 6
E3
195
196





AMP28


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2-(2,4- Dimethoxy- benzyl)-5- isopropyl-2H- pyrazol-3- ylamine
H04, 29509-06- 6
E2
275
276





AMP29


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5-Cyclobutyl- 2-phenyl-2H- pyrazol-3- ylamine
59-88-1, CK01
E2 Specific example
213
214





AMP30


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2-(3-Bromo- phenyl)-5- cyclobutyl-2H- pyrazol-3 ylamine
27246-81- 7, CK01
E3
292
293





AMP31


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5-Cyclobutyl- 2-(3- pyrrolidin-1- yl-phenyl)-2H- pyrazol-3- ylamine
AMP30
E6
282
283





AMP32


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2-(2-Chloro- pyridin-4-yl)- 5-cyclobutyl- 2H-pyrazol-3- ylamine
700811- 29-6, CK01
E3
248
249





AMP33


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5-Cyclobutyl- 2-(2- morpholin-4- yl-pyridin-4- yl)-2H- pyrazol-3- ylamine
AMP32
E5
299
300





AMP34


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5-Cyclobutyl- 2-(2- pyrrolidin-1- yl-pyridin-4- yl)-2H- pyrazol-3- ylamine
AMP32
E5
283
284





AMP35


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5-Cyclobutyl- 2-cyclohexyl- 2H-pyrazol-3- ylamine
30929-57- 8, CK01
E2, Specific Example
219
220





AMP36


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5-Cyclobutyl- 2-(2,4- dimethoxy- benzyl)-2H- pyrazol-3- ylamine
H04, CK01
E2
287
288





AMP37


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5-tert-Butyl-2- cyclopentyl- 2H-pyrazol-3- ylamine
24214-72- 0, 599917- 51-2
E2
207
208





AMP38


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3-(5-Amino-1- cyclohexyl- 1H-pyrazol-3- yl)-azetidine-1- carboxylic acid tert-butyl ester
30929-57- 8, 887594- 13-0
E2
320
321





AMP39


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2-Cyclohexyl- 5-cyclopropyl- 2H-pyrazol-3- ylamine
30929-57- 8, 118431- 88-2
E2
205
206





AMP40


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3-[5-Amino-1- (3,5-difluoro- phenyl)-1H- pyrazol-3-yl]- azetidine-1- carboxylic acid tert-butyl ester
134993- 88-7, 887594- 13-0
E2
350
2951





AMP41


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5-(1-Methyl- cyclobutyl)-2- phenyl-2H- pyrazol-3- ylamine
100-63-0, CK02
E3
227
228





AMP42


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5-(3-Methoxy- cyclobutyl)-2- phenyl-2H- pyrazol-3- ylamine
59-88-1, CK03
E2
243






AMP43


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5-(3,3- Difluoro- cyclobutyl)-2- phenyl-2H- pyrazol-3- ylamine
59-88-1, 1234616- 26-2
E2
249






AMP44


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5-(3,3- Dimethyl- cyclobutyl)-2- phenyl-2H- pyrazol-3- ylamine
59-88-1, CK04
E2
241






AMP45


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5-(3-Fluoro- cyclobutyl)-2- phenyl-2H- pyrazol-3- ylamine
59-88-1, CK05
E2
231






AMP46


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5-(3-Methyl- cyclobutyl)-2- phenyl-2H- pyrazol-3- ylamine
59-88-1, CK06
E2
227






AMP47


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2-Cyclopentyl- 5-methyl- pyrazol-3- amine
24214-72- 0, 1118- 61-2
E1
165






AMP48 61255- 82-1


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3-(5-Amino-3- methyl- pyrazol-1- yl)propanenitrile


150






AMP49 76606- 39-8


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2-(4- Fluorophenyl)- 5-methyl- pyrazol-3- amine


191






AMP50


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5-Methyl-2-[5- (trifluorometh yl)-1H- pyrazol-3- yl]pyrazol-3- amine
1418117- 75-5, 1118-61-2
E1
231
232





AMP51 866837- 96-9


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Ethyl 5-amino- 1-phenyl- pyrazole-3- carboxylate


231






AMP51 B


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Ethyl 5-(tert- butoxycarbonyl amino)-1- phenyl- pyrazole-3- carboxylate
866837- 96-9
Specific example
331
332





AMP52 956329- 14-9


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2-(3- Bromophenyl)- 5-methyl- pyrazol-3- amine


252






AMP53


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(5-Amino-1- phenyl- pyrazol-3- yl)methanol
866837- 96-9 (AMP51)
Specific example
189
190





AMP54 124707 5-24-6


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5-Methyl-2- tetrahydropyran- 4-yl-pyrazol- 3-amine


181






AMP55


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5-Methyl-2-(3- morpholinophenyl) pyrazol-3- amine
H05, 1118-61-2
E1
258
259





AMP56


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2-[3- (Dimethylamino) phenyl]-5- methyl- pyrazol-3- amine
940924- 81-2, 1118-61-2
E1
216
217





AMP57


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5-Methyl-2-(3- methylsulfonyl phenyl)pyrazol- 3-amine
312303- 93-8, 1118-61-2
E1
251
252





AMP58 3524- 43-4


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5-Methyl-2-(1- methyl-4- piperidyl)pyrazol- 3-amine


194






AMP59


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5-tert-Butyl-2- phenyl- pyrazol-3- amine
100-63-0, 59997-51- 2
E2
215
216





AMP60


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2-(2-Chloro-4- pyridyl)-5- isopropyl- pyrazol-3- amine
700811- 29-6, 29509-06- 6
E2
236
237





AMP61


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5-Isopropyl-2- [4- (trifluoromethoxy) phenyl]pyra zol-3-amine
13957-54- 5, 29509- 06-6
E2
285
286





AMP62


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2-(3,5- Dichlorophenyl)- 5-methyl- pyrazol-3- amine
39943-56- 1, 1118- 61-2
E1
242
243





AMP63


embedded image


3-(5-Amino-3- methyl- pyrazol-1- yl)benzenesul- fonamide
131774- 72-6, 1118-61-2
E1
252
253





AMP64


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5-Methyl-2-(1- methylpyrazol- 4-yl)pyrazol-3- amine
268521- 80-7, 1118-61-2
E1
177
178





AMP65


embedded image


tert-Butyl 3-(5- amino-1- phenyl- pyrazol-3- yl)azetidine-1 carboxylate
100-63-0, 887594- 13-0
E2
314
315





AMP66


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2-(5-Amino-1- phenyl- pyrazol-3- yl)propan-2-ol
AMP51B
Specific example
217
218





AMP67


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3-(5-Amino-3- isopropyl- pyrazol-1- yl)benzonitrile
17672-26- 3, 29509- 06-6
E2
226
227





AMP68


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5-Amino-N- methyl-1- phenyl- pyrazole-3- carboxamide
AMP51B
Specific example
216
217





AMP69


embedded image


2-(5-Amino-1- phenyl- pyrazol-3-yl)- 2-methyl- propan-1-ol
100-63-0, 489432- 33-9
E2
231
232





AMP70


embedded image


2-(2-Fluoro-4- pyridyl)-5- methyl- pyrazol-3- amine
837364- 87-1, 1118-61-2
E1
192
193





AMP71


embedded image


4-(5-Amino-3- methyl- pyrazol-1-yl)- 1H-pyridin-2- one
106689- 41-2, 1118-61-2
E1
190
191





AMP72


embedded image


3-(5-Amino-3- methyl- pyrazol-1- yl)benzamide
473927- 51-4, 1118-61-2
E1
216
217





AMP73


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2-(6-Methoxy- 3-pyridyl)-5- methyl- pyrazol-3- amine
160664- 95-9, 1118-61-2
E1
204
205





AMP74


embedded image


5-Amino-1- phenyl- pyrazole-3- carboxamide
AMP51B
Specific example
202
203





AMP75


embedded image


tert-Butyl 2-(5- amino-1- phenyl- pyrazol-3- yl)pyrrolidine- 1-carboxylate
100-63-0, 173690- 69-2
E2
328
329





AMP77


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5- (Methoxymeth yl)-2-phenyl- pyrazol-3- amine
100-63-0, 739366- 02-0
E2
203
204





AMP78


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5-(1- Methylcyclo propyl)-2- phenyl- pyrazol-3- amine
100-63-0, 88485-78- 3
E3
213
214





AMP79


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5-tert-Butyl-2- cyclohexyl- pyrazol-3- amine
30929-57- 8, 599917- 51-2
E2
221
222





AMP80


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2-Phenyl-5- tetrahydrofuran- 2-yl-pyrazol- 3-amine
100-63-0, CK07
E2
229
230





AMP81


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5-Isopropyl-2- (5-morpholino- 3- pyridyl)pyrazol- 3-amine
ArH06, 29509-06- 6
E4
287
288





AMP82


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2-(4-Chloro-2- pyridyl)-5- isopropyl- pyrazol-3- amine
ArH07, 29509-06- 6
E4
236
237





AMP83


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2-(3,4- Difluorophenyl)- 5-isopropyl- pyrazol-3- amine
875664- 54-3, 29509-06- 6
E2
273
274





AMP84


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5-Isopropyl-2- [3- (trifluoromethyl) phenyl]pyraz ol-3-amine
368-78-5, 29509-06- 6
E2
269
270





AMP85


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5-(3- Methyloxetan- 3-yl)-2-phenyl- pyrazol-3- amine
100-63-0, CK08
E2
229
230





AMP86


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5- (Methylamino methyl)-2- phenyl- pyrazol-3- amine
AMP51B
Specific example
202
203





AMP87


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2-(3- Methoxyphenyl)- 5-methyl- pyrazol-3- amine
39232-91- 2, 1118- 61-2
E1
203
204





AMP88 70373- 98-7


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5-Amino-1- phenyl-1,2- dihydro-3H- pyrazol-3-one


175






AMP89


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2-(3- Benzyloxycyclo- hexyl)-5- isopropyl- pyrazol-3- amine
H06, 29509-06- 6
E3
313
314





AMP90


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Benzyl 4-(5- amino-3- isopropyl- pyrazol-1- yl)piperidine- 1-carboxylate
H07, 29509-06- 6
E3
342
343





AMP91


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Benzyl 3-(5- amino-3- isopropyl- pyrazol-1- yl)pyrrolidine- 1-carboxylate
H08, 29509-06- 6
E3
328
329





AMP92


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Benzyl 3-(5- amino-3- isopropyl- pyrazol-1- yl)piperidine- 1-carboxylate
H09, 29509-06- 6
E3
342
343





AMP93


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3-Cyclobutyl- 1-(4- fluorophenyl)- 1H-pyrazol-5- amine
118431- 89-3, 823- 85-8
Specific example
231
232





AMP94


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1-tert-Butyl-3- cyclobutyl-1H- pyrazol-5- amine
7400-27- 3, 118431- 89-3
Specific example
193
194





AMP95


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1-Cyclohexyl- 3-[(propan-2- yl)oxy]-1H- pyrazol-5- amine
436088- 86-7
E7
223
224





AMP96


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1-(4- Fluorophenyl)- 3-[(propan-2- yl)oxy]-1H- pyrazol-5- amine
1247169- 18-1
E7, Specific example
235
236






1(M − tBu + H)+







Method F: Synthesis of Aldehydes by SN—Ar



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  • A is either CH or N

  • LG is F, Cl, or Br



A solution of the aldehyde (1 equiv), the amine (1.3 to 2 equiv) and the base (DIPEA or K2CO3) (2 equiv) is prepared in acetonitrile, DMSO or DMA. This mixture is heated under thermal conditions or under microwave irradiations at a temperature ranging from 85° C. to 150° C. The reaction is worked up either by filtration of the base when needed or by diluting the reaction mixture with ethyl acetate or DCM and washing the organic phase with water and brine. In all cases, the organic phase is concentrated under reduced pressure, and the crude residue is used as such or purified either by flash column chromatography or precipitation to give the titled compound.


Illustrative Synthesis of ALD02: 5′-Formyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carbonitrile



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A solution of 2-chloropyridine-5-carboxaldehyde (CAS: 23100-12-1, 25.1 g, 177.4 mmol), 4-cyanopiperidine (CAS: 4395-98-6, 25.4 g, 230.6 mmol) and DIPEA (62 mL, 354.7 mmol) in acetonitrile (250 mL) was refluxed for 20 hours. The reaction mixture was cooled to RT, and the mixture was concentrated under reduced pressure. The residue was dissolved in DCM (500 mL) and washed successively with a saturated aqueous solution of Na2CO3 (250 mL) and brine (250 mL). The organic phase was stirred for 2 minutes with 10 g of silica gel, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting mixture was dissolved in DCM (150 mL) and poured into a stirring solution of diisopropyl ether (1.5 L). The mixture was stirred vigorously for 4 hours. The precipitate was collected by filtration, washed with diisopropyl ether, and dried at 40° C. under reduced pressure to give the titled compound.









TABLE VI







List of aldehydes













Int.
Structure
Name
SM
method
MW
Mes





ALD01


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6-[(2-Methoxy- ethyl)-methyl- amino]- pyridine-3- carbaldehyde
23100- 12-1
F
194
195





ALD02


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5′-Formyl-3,4,5,6- tetrahydro-2H-[1, 2′]bipyridinyl-4- carbonitrile
23100- 12-1
F Specific example
215
216





ALD03


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6-[Methyl- (tetrahydro-pyran- 4-yl)-amino]- pyridine-3- carbaldehyde
23100- 12-1
F
220
221





ALD04


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4-[(2-Methoxy- ethyl)-methyl- amino]- benzaldehyde
459-57- 4
F
193
194





ALD05


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1-(4-Formyl- phenyl)-piperidine- 4-carbonitrile
459-57- 4
F
214
215





ALD06


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2-[Methyl- (tetrahydro-pyran- 4-yl)-amino]- pyrimidine-5- carbaldehyde
933702- 55-7
F
221
222





ALD07


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1-(5-Formyl- pyrimidin-2-yl)- piperidine-4- carbonitrile
933702- 55-7
F
216
217





ALD08


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4-[Methyl- (tetrahydro-pyran- 4-yl)-amino]- benzaldehyde
459-57- 4
F
219
220





ALD09


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2-[(2-Methoxy- ethyl)-methyl- amino]-pyrimidine- 5-carbaldehyde
933702- 55-7
F
195
196





ALD10


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6-Dimethylamino- pyridine-3- carbaldehyde
23100- 12-1
F
150
151





ALD11 1204- 86-0


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4- morpholinobenzal- dehyde


191






ALD12


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6-[bis(2- methoxyethyl)ami- no]pyridine-3- carbaldehyde
23100- 12-1
F
238
239









Methods G1-G3: Synthesis of Alkylidene Pyruvate
Method G1: Synthesis of Alkylidene Pyruvate



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  • A is either N or CH

  • A′ is either Re or L1-G3C as described in the Summary



A solution of potassium hydroxide (from 1.5 to 2 equiv) in water is added dropwise at 0° C. to a solution of aldehyde (1 equiv) and pyruvic acid (CAS 127-17-3, from 1 eq to 1.5 equiv) in methanol. The reaction is warmed up to RT and then heated at 40° C. for 1 h to several days. Then the reaction mixture undergoes one of the following processes:

    • Either the formed precipitate is collected by filtration, suspended in an aqueous acidic solution, collected by filtration again, and dried in vacuo to give the titled compound.
    • Or alternatively, methanol is removed in vacuo, and the resulting suspension is filtered. The solid is taken up in water and either ethyl acetate or dichloromethane and acidified to pH=3-5 with either acetic acid or an aqueous solution of 2 M HCl. The two phases are separated, and the aqueous phase is extracted with either ethyl acetate or dichloromethane. The combined organic phases are washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to afford the titled compound which is used as such or further purified by precipitation.


Illustrative Synthesis of ALP19: (E)-4-(4-Bromo-phenyl)-2-oxo-but-3-enoic acid



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A solution of potassium hydroxide (6.9 g, 121.6 mmol) in water (45 mL) was added at 0° C. to a stirring solution of 4-bromobenzaldehyde (CAS 1122-91-4, 15 g, 81.1 mmol) and pyruvic acid (CAS 127-17-3, 5.7 mL, 81.1 mmol) in methanol (105 mL) over a 5 minutes period. The reaction mixture was then heated at 40° C. for 4 hours, cooled down to RT and poured into ice/water (300 mL). The precipitate was stirred for 10 minutes, collected by filtration, washed with water and n-heptane, and air dried for 1 hour. The solid was suspended in aqueous 2 N HCl and stirred for 10 minutes. The precipitate was collected by filtration and dried at 40° C. under reduced pressure to afford the titled compound.


Method G2: Synthesis of Alkylidene Pyruvate



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  • A is either N or CH

  • A′ is either Re or L1-G3C as described in the Summary



Triflic acid (CAS 1493-13-6, from 1.35 eq to 2.5 equiv) is added dropwise to a solution of aldehyde (1 equiv), triethyl orthoformate (CAS 122-51-0, from 1.1 eq to 1.3 equiv) and ethyl pyruvate (CAS 617-35-6, from 1.5 to 3.5 equiv) in chloroform. The solution is refluxed for 30 minutes to 24 h. The reaction mixture is cooled down to RT, diluted with dichloromethane, basified with a saturated aqueous solution of Na2CO3 or NaHCO3. The two phases are separated, and the aqueous phase is extracted with dichloromethane. The combined organic phases are dried over sodium sulfate, filtered and concentrated under reduced pressure. This crude mixture is purified either by flash chromatography on silica gel or by precipitation to afford the titled compound.


Illustrative Synthesis of ALP09: ethyl(E)-4-[6-(4-cyano-1-piperidyl)-3-pyridyl]-2-oxo-but-3-enoate



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Triflic acid (CAS 1493-13-6, 26.7 mL, 301 mmol) was added dropwise to a solution of intermediate ALD02 (32.4 g, 150.5 mmol), triethyl orthoformate (CAS 122-51-0, 32.6 g, 195.7 mmol) and ethyl pyruvate (CAS 617-35-6, 41.7 mL, 376.3 mmol) in chloroform (180 mL). The solution was refluxed for 30 minutes and then cooled to RT. The reaction mixture was diluted with DCM (500 mL) and washed successively with a saturated aqueous solution of Na2CO3 (400 mL) and brine (400 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude sample was purified by flash column chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate to yield the titled compound.


Method G3: Synthesis of Alkylidene Pyruvate



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In a round bottom flask, under a nitrogen atmosphere, a suspension of 4-ethynylbenzene derivative (1 equiv.), 50% ethyl glyoxalate in toluene (2 equiv), morpholine ([110-91-8], 2 equiv), copper (I) bromide ([7787-70-4], 0.5 equiv) in dioxane is heated to 85° C. for 3 to 20 hours. The reaction mixture is cooled to RT, and the solvent was evaporated under reduced pressure. The residue is suspended in a mixture of DCM or DCM/2-propanol (95/5) and is washed twice with water. The organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude sample is purified by flash chromatography eluting with ethyl acetate/n-heptane/DCM.


Illustrative Synthesis of ALP36: ethyl 4-(4-formylphenyl)-2-oxobut-3-enoate



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In a round bottom flask, under a nitrogen atmosphere, a suspension of 4-ethynylbenzaldehyde ([63697-96-1], 5 g, 38.4 mmol), 50% ethyl glyoxalate in toluene ([924-44-7], 15.7 mL, 15.7 g, 76.8 mmol), morpholine ([110-91-8], 6.7 mL, 76.8 mmol), copper(I) bromide ([7787-70-4], 2.8 g, 19.2 mmol) in dioxane (50 mL) was heated to 85° C. for 3 hours. The reaction mixture was cooled to RT, and the volatiles were removed under reduced pressure. The residue was suspended in a mixture of DCM/2-propanol (200 mL, 95/5) and washed twice with water (50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate/n-heptane to yield the titled compound.


Synthesis of ALP 31: (E)-4-[4-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)phenyl]-2-oxo-but-3-enoic acid



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Nitrogen was bubbled for 5 minutes into a suspension of ALP19 (100 mg, 0.4 mmol), 1-methyl-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (CAS: 454482-11-2, 109 mg, 0.5 mmol), Pd(dppf)Cl2.DCM (20 mg, 0.02 mmol), and cesium carbonate (240 mg, 0.7 mmol) in dioxane/water (2/1 v/v, 2 mL). The reaction mixture was heated at 90° C. for 1 hour and cooled to RT. The volatiles were removed under reduced pressure, and the crude residue was suspended in water (20 mL). The aqueous solution was acidified with a citric acid solution to pH 5. The precipitate was filtered, washed with water and dried at 40° C. under reduced pressure to give the titled compound as the citrate salt. No further purification was performed and the compound was used as such in the next step.


Synthesis of ALP38: 4-Cyano-4-[4-((E)-3-ethoxycarbonyl-3-oxo-propenyl)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester



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Step 1: 4-Cyano-4-{4-[(triisopropylsilanyl)-ethynyl]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester

Nitrogen was bubbled for 5 minutes through a suspension of tert-butyl 4-(4-bromophenyl)-4-cyanopiperidine-1-carboxylate ([847615-14-9], 547 mg, 1.5 mmol), tetrakis(triphenylphosphine)palladium(0) ([14221-01-3], 90 mg, 77 μmol), copper(I) iodide ([7681-65-4], 8 mg, 42 μmol), lithium chloride ([7447-41-8], 8 mg, 189 μmol), and (triisopropylsilyl)acetylene ([89343-06-6], 670 μL, 3 mmol) in triethylamine (8 mL). The tube was sealed and heated at 100° C. for 6 hours. The mixture was then concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography eluting with ethyl acetate/n-heptane to give the titled compound.


Step 2: 4-Cyano-4-(4-ethynyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester

The compound from Step 1 (700 mg, 1.5 mmol) was dissolved in anhydrous THF (10 mL) and 1 M tetra-n-butylammonium fluoride in THF (1.7 mL, 1.7 mmol) was added. The reaction mixture was stirred at RT for 2 hours and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography eluting with ethyl acetate/n-heptane to give the titled compound.


Step 3: 4-Cyano-4-[4-((E)-3-ethoxycarbonyl-3-oxo-propenyl)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester

In a round bottom flask, under a nitrogen atmosphere, a suspension of the compound from Step 2 (270 mg, 0.58 mmol), 50% ethyl glyoxalate in toluene ([924-44-7], 232 μL, 1.16 mmol), morpholine ([110-91-8], 101 μL, 1.16 mmol), and copper(I) bromide ([7787-70-4], 42 mg, 0.29 mmol) in dioxane (5 mL) was heated to 85° C. for 20 hours. The reaction mixture was cooled down to RT and 50% ethyl glyoxalate in toluene ([924-44-7], 232 1.16 mmol), morpholine ([110-91-8], 101 μL, 1.16 mmol), and copper(I) bromide ([7787-70-4], 42 mg, 0.29 mmol) were added again, and the sealed tube was heated at 100° C. for 1 hour. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was suspended in DCM (20 mL) and washed with water (15 mL). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with ethyl acetate/n-heptane to yield the titled compound.


Synthesis of ALP 39: methyl(3E)-4-(4-bromophenyl)-2-oxobut-3-enoate



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EDC.HCl ([25952-538], 7.3 g, 38 mmol) was added at RT to a stirred solution of ALP19 (8.05 g, 32 mmol) in a mixture of dichloromethane/methanol (1/1; 160 mL). The reaction mixture was stirred at RT for 20 hours. The mixture was diluted with DCM (200 mL) and washed with a saturated aqueous solution of NaHCO3 (100 mL). The aqueous phase was extracted again with DCM (200 mL). The combined organic phases were dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash column chromatography eluting with dichloromethane to yield the titled compound.









TABLE VII







List of alkylidene pyruvates













Int.
Structure
Name
SM
method
MW
Mes
















ALP01


embedded image


(E)-4-(4- morpholinophenyl)- 2-oxo-but-3- enoic acid
1204- 86-0
G1
261
262





ALP02


embedded image


(E)-4-[4- (dimethylamino) phenyl]-2-oxo-but- 3-enoic acid
100-10- 7
G1
219
220





ALP03


embedded image


(E)-4-[2- (dimethylamino) pyrimidin-5-yl]-2- oxo-but-3-enoic acid
55551- 49-0
G1
221
222





ALP04


embedded image


(E)-4-(2- morpholino- pyrimidin- 5-yl)-2-oxo- but-3-enoic acid
842974- 69-0
G1
263
264





ALP05


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(E)-4-(6- morpholino-3- pyridyl)-2-oxo- but-3-enoic acid
173282- 60-5
G1
262
263





ALP06


embedded image


(E)-4-(4- methoxyphenyl)- 2-oxo-but-3-enoic acid
123-11- 5
G1
206
207





ALP07


embedded image


(E)-4-(6-Chloro- pyridin-3-yl)-2- oxo-but-3-enoic acid
23100- 12-1
G1
211- 213
212- 214





ALP08


embedded image


ethyl (E)-4-[6-[2- methoxyethyl (methyl) amino]-3- pyridyl]-2-oxo- but-3-enoate
ALD01
G2
291
292





ALP09


embedded image


ethyl (E)-4-[6-(4- cyano-1- piperidyl)-3- pyridyl]-2-oxo- but-3-enoate
ALD02
G2 Specific example
313
314





ALP10


embedded image


ethyl (E)-4-[6- [methyl(tetrahydro pyran-4- yl)amino]-3- pyridyl]-2-oxo- but-3-enoate
ALD03
G2
318
319





ALP11


embedded image


ethyl (E)-4-[4-[2- methoxyethyl(meth- yl)amino]phenyl]- 2-oxo-but-3- enoate
ALD04
G2
291
292





ALP12


embedded image


ethyl (E)-4-[4-(4- cyano-1- piperidyl)phenyl]- 2-oxo-but-3- enoate
ALD05
G2
312
313





ALP13


embedded image


ethyl (E)-4-[2- [methyl(tetrahydro pyran-4- yl)amino]pyrimidin- 5-yl]-2-oxo-but- 3-enoate
ALD06
G2
319
320





ALP14


embedded image


ethyl (E)-4-[2-(4- cyano-1- piperidyl)pyrimidin- 5-yl]-2-oxo-but- 3-enoate
ALD07
G2
314
315





ALP15


embedded image


ethyl (E)-4-[4- [methyl(tetrahydro pyran-4- yl)amino]phenyl]- 2-oxo-but-3- enoate
ALD08
G2
317
318





ALP16


embedded image


ethyl (E)-4-[2-[2- methoxyethyl (methyl)amino] pyrimidin- 5-yl]-2-oxo- but-3-enoate
ALD09
G2
293
294





ALP17


embedded image


ethyl (E)-4-(2,6- difluoro-4- methoxy-phenyl)- 2-oxo-but-3- enoate
256417- 10-4
G2
270
271





ALP18


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(E)-4-(4- morpholin-4-yl- phenyl)-2-oxo- but-3-enoic acid ethyl ester
ALD11 (1204- 86-0)
G2
289
290





ALP19


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(E)-4-(4-bromo- phenyl)-2-oxo- but-3-enoic acid
1122- 91-4
G1 Specific example
255
255- 257





ALP20


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(E)-4-(6- dimethylamino- pyridin-3-yl)-2- oxo-but-3-enoic acid ethyl ester
ALD10
G2
248
249





ALP21


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(E)-4-(6- dimethylamino- pyridin-3-yl)-2- oxo-but-3-enoic acid
ALD10
G1
220
221





ALP22


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(E)-4-(2- morpholin-4-yl- pyrimidin-5-yl)-2- oxo-but-3-enoic acid ethyl ester
842974- 69-0
G2
291
292





ALP23


embedded image


(E)-4-{6-[bis-(2- methoxy-ethyl)- amino]-pyridin-3- yl}-2-oxo-but-3- enoic acid ethyl ester
ALD12
G2
336
337





ALP24


embedded image


(E)-4-(4- acetylamino- phenyl)-2-oxo- but-3-enoic acid ethyl ester
122-85- 0
G2
261
262





ALP25


embedded image


(E)-4-(4- dimethylamino- phenyl)-2-oxo- but-3-enoic acid ethyl ester
100-10- 7
G2
247
248





ALP26


embedded image


(E)-4-(6- morpholin-4-yl- pyridin-3-yl)-2- oxo-but-3-enoic acid ethyl ester
173282- 60-5
G2
290
291





ALP27


embedded image


(E)-4-[4-(4- methylpiperazin- 1-yl)phenyl]-2- oxo-but-3-enoic acid
27913- 99-1
G1
274
275





ALP28


embedded image


(E)-4-[4-(1,1- dioxo-1,4- thiazinan-4- yl)phenyl]-2-oxo- but-3-enoic acid
27913- 96-8
G1
309
310





ALP29


embedded image


(E)-2-oxo-4-(4- pyrrolidin-1- ylphenyl)but-3- enoic acid
51980- 54-2
G1
245
246





ALP30


embedded image


(E)-4-(2-chloro-4- morpholino- phenyl)-2-oxo- but-3-enoic acid
886501- 36-6
G1
295
295- 297





ALP31


embedded image


(E)-4-[4-[1- methyl-3,6- dihydro-2H- pyridin-4- yl)phenyl]-2-oxo- but-3-enoic acid
ALP19
Specific example
271
272





ALP32


embedded image


(E)-4-(2-methoxy- 4-morpholino- phenyl)-2-oxo- but-3-enoic acid
404009- 68-3
G1
291
292





ALP33


embedded image


(E)-3-methyl-4-(4- morpholinophenyl)- 2-oxo-but-3- enoic acid
1204- 86-0
G1
275
276





ALP34


embedded image


(E)-4-(3-bromo-4- morpholino- phenyl)-2-oxo- but-3-enoic acid
404009- 68-3
G1
339
340- 342





ALP35


embedded image


(E)-2-oxo-4-[4-(1- piperidyl)phenyl] but-3-enoic acid
10338- 57-5
G1
259
260





ALP36


embedded image


ethyl 4-(4- formylphenyl)-2- oxobut-3-enoate
63697- 96-1
G3 Specific example
232






ALP37


embedded image


ethyl 4-(4- cyanophenyl)-2- oxobut-3-enoate
3032- 92-6
G3
229






ALP38


embedded image


4-Cyano-4-[4- ((E)-3- ethoxycarbonyl-3- oxo-propenyl)- phenyl]- piperidine-1- carboxylic acid tert-butyl ester
847615- 14-9
Specific example
412
NA





ALP39


embedded image


methyl (3E)-4-(4- bromophenyl)-2- oxobut-3-enoate
ALP19
Specific example
269
268- 270









Methods H1-H3: Synthesis of Halogenated Pyrazolopyridine
Method H1: Synthesis of Halogenated Pyrazolopyridine (Route 1)
Illustrative Synthesis of HP01: ethyl 4-chloro-3-isopropyl-1-(m-tolyl)pyrazolo[3,4-b]pyridine-6-carboxylate



embedded image


embedded image


Step 1: 6-Hydroxy-3-isopropyl-1-m-tolyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester

5-Isopropyl-2-m-tolyl-2H-pyrazol-3-ylamine hydrochloride (AMP07, 14.97 g, 59.7 mmol) was dissolved in AcOH (100 mL). Diethyloxalacetate sodium salt (CAS: 40876-98-0, 15 g, 71.6 mmol, 1.2 equiv) was added, and the reaction mixture was refluxed overnight. The reaction mixture was cooled down to RT, poured into water (400 mL) and diluted with ethyl acetate. The two phases were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic layers were concentrated in vacuo, and the resulting residue was taken up twice with cyclohexane (2×200 mL) and concentrated in vacuo again. The residue was suspended in a mixture of ethanol/water (100 mL/20 mL), and the resulting precipitate was collected by filtration and washed with heptane. The solid was dried under vacuum to provide the titled compound.


Step 2: 3-Isopropyl-1-m-tolyl-6-trifluoromethanesulfonyloxy-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester

6-Hydroxy-3-isopropyl-1-m-tolyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester (14.25 g, 42 mmol) was suspended in acetonitrile under nitrogen atmosphere. Pyridine (3.8 mL, 46.2 mmol, 1.1 equiv) was added. The reaction mixture was cooled to 0° C., and trifluoromethanesulfonic anhydride (CAS 358-23-6, 7.8 mL, 46.2 mmol, 1.1 equiv) was added dropwise over 20 min. The reaction mixture was then warmed up to RT over 20 min. Water was added (200 mL), and the suspension was filtered. The solid was washed successively with water and ethanol (40 mL) and then dried in vacuo to afford the titled compound.


Step 3: 6-Iodo-3-isopropyl-1-m-tolyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester

3-Isopropyl-1-m-tolyl-6-trifluoromethanesulfonyloxy-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester (13.0 g, 27.6 mmol) was suspended in acetonitrile. Sodium iodide (20.7 g, 138 mmol, 5 equiv) was added. The reaction mixture was cooled to 0° C., trifluoromethanesulfonic acid (5.4 mL, 60.7 mmol, 2.2 equiv) was added dropwise. The reaction mixture was stirred at RT overnight. At this point, the reaction was not complete and additional trifluoromethanesulfonic acid (2 mL, 22.6 mmol, 0.8 equiv) was added and stirring was continued for 1 hour. Water was added to the reaction mixture, and the suspension was filtered. The solid was washed with ethanol (10 mL) and dried in vacuo to afford the titled compound.


Step 4: 6-Iodo-3-isopropyl-1-m-tolyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid

6-Iodo-3-isopropyl-1-m-tolyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester (8.73 g, 4.63 mmol) was suspended in ethanol (10 mL). An aqueous solution of 2 M sodium hydroxide (10 mL, 20 mmol, 4.3 equiv) was added, and the reaction mixture was stirred at 70° C. until complete conversion. Then the reaction mixture was cooled down to 0° C., and an aqueous solution of 2 M HCl was added until pH<2 was reached. The resulting suspension was filtered, and the solid was dried in vacuo to afford the titled compound.


Step 5: (6-Iodo-3-isopropyl-1-m-tolyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-carbamicacid tert-butyl ester

6-Iodo-3-isopropyl-1-m-tolyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (8.12 g, 19.3 mmol) was suspended in toluene (43 mL). tert-Butanol (3.1 mL, 32.6 mmol, 2.0 equiv), triethylamine (4.54 mL, 32.6 mmol, 2.0 equiv) and diphenylphosphoryl azide (CAS 26386-88-9, 5 mL, 23.1 mmol, 1.2 equiv) were successively added. The reaction mixture was refluxed for 30 minutes. The reaction mixture was cooled down to RT and partitioned between ethyl acetate and water. The aqueous phase was further extracted with ethyl acetate. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was suspended in ethanol. The resulting precipitate was collected by filtration, washed with ethanol and dried under vacuum to provide the titled compound.


Step 6: (6-Cyano-3-isopropyl-1-m-tolyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-carbamic acid tert-butyl ester

(6-Iodo-3-isopropyl-1-m-tolyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-carbamicacid tert-butyl ester (7.56 g, 15.4 mmol) was solubilized in dry dimethylformamide (20 mL) in a sealed vial. Zinc cyanide (CAS 557-21-1, 1.1 g, 9.2 mmol, 0.6 equiv) was added, and the reaction mixture was degassed with argon (bubbling) for 5 minutes.


Tetrakis(triphenylphosphine)palladium(0) (CAS 14221-01-3, 0.9 g, 0.77 mmol, 0.05 equiv) was added, and the reaction mixture was degassed again with argon (bubbling) for 5 minutes. The vial was sealed, and the reaction mixture was stirred at 110° C. for 2 hour. The reaction mixture was cooled down to room temperature and diluted with water and ethyl acetate. The aqueous phase was further extracted with ethyl acetate. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated to a volume of 10 mL. Ethanol (10 mL) was added, and the suspension was stirred at 0° C. for 10 min. The resulting precipitate was collected by filtration, washed with ethanol and dried under vacuum to provide the titled compound.


Step 7: 4-Amino-3-isopropyl-1-m-tolyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid hydrochloride salt

(6-Cyano-3-isopropyl-1-m-tolyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-carbamic acid tert-butyl ester (4.8 g, 12.26 mmol) was suspended in 6 M HCl (50 mL). The reaction mixture was refluxed for 24 h. The reaction mixture was cooled to 0° C., and the obtained suspension was filtered. The solid was washed with diisopropyl ether and dried in vacuo to yield the titled compound.


Step 8: 4-Amino-3-isopropyl-1-m-tolyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid ethyl ester

4-Amino-3-isopropyl-1-m-tolyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid hydrochloride salt (4.23 g, 12.26 mmol) was solubilized in ethanol (150 mL). Thionyl chloride (CAS 7719-09-7, 1.34 mL, 18.39 mmol, 1.5 equiv) was carefully added. The reaction mixture was refluxed for 24 hours. The reaction mixture was cooled down to RT and concentrated in vacuo. The residue was taken up in ethanol (85 mL) and thionyl chloride (CAS 7719-09-7, 2.32 mL, 31.86 mmol, 2.6 equiv) was carefully added at RT. The mixture was refluxed for 6 hours. The reaction mixture was cooled down to RT and concentrated in vacuo. The crude mixture was diluted with ethyl acetate, basified with a saturated solution of sodium hydrogencarbonate. This mixture was filtered through a pad of Celpure® P65. Solids were washed with ethyl acetate. The two phases of the filtrate were separated, and the aqueous fraction was further extracted with ethyl acetate. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent system: heptane/ethyl acetate gradient from 95/5 to 80/20) to afford the titled compound.


Step 9: 4-Chloro-3-isopropyl-1-m-tolyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid ethyl ester

Copper(II) chloride (CAS 7447-39-4, 1.045 g, 7.77 mmol, 1.0 equiv) was suspended in acetonitrile (33 mL). Isopentylnitrite (CAS 110-46-3, 1.57 mL, 11.65 mmol, 1.5 equiv) was added, and the reaction mixture was stirred at RT for 30 minutes. 4-Amino-3-isopropyl-1-m-tolyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid ethyl ester (2.63 g, 7.77 mmol, 1.0 equiv) was added. The reaction mixture was stirred at 75° C. for 2.5 h. The reaction mixture was cooled down to 0° C., and the resulting suspension was filtered. The solid was washed with cold acetonitrile and dried in vacuo to afford the titled compound. The filtrate was concentrated in vacuo and purified by flash chromatography on silica gel (eluent system: heptane/ethyl acetate gradient from 100/0 to 98/2) to provide additional titled compound.


Method H1′: Alternative Conditions for Chlorination Route 1 Step 9



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To the 4-amino intermediate (1 equiv) in acetonitrile at RT is added isopentylnitrite (CAS 110-46-3, from 3 to 6 eq) followed by copper(I) chloride (CAS 7758-89-6, from 3 to 6 equiv), and the reaction mixture is stirred at RT for 1 h to 24 h. The reaction mixture is diluted with dichloromethane and with a saturated solution of sodium hydrogencarbonate. The two phases are separated, and the aqueous phase is extracted with dichloromethane. The combined organic phases are washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue is purified by flash chromatography on silica gel to afford the titled compound.


Illustrative Synthesis of HP03: ethyl 4-chloro-1-[3-(dimethylamino)phenyl]-3-isopropyl-pyrazolo[3,4-b]pyridine-6-carboxylate



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To 4-amino-1-(3-dimethylamino-phenyl)-3-isopropyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid ethyl ester (1 g, 2.74 mmol, 1 equiv) in acetonitrile (10 mL) at RT was added isopentylnitrite (CAS 110-46-3, 1.1 mL, 8.21 mmol, 3 equiv) followed by copper(I) chloride (CAS 7758-89-6, 0.82 g, 8.21 mmol, 3 equiv), and the reaction mixture was stirred at RT for 1 h. The reaction mixture was diluted with dichloromethane and with a saturated solution of sodium hydrogencarbonate. The two phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (eluent system: heptane/ethyl acetate gradient from 100/0 to 90/10) to afford the titled compound.


Synthesis of HP13: ethyl 4-chloro-3-methyl-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylate



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Step 1: 6-Hydroxy-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester

5-Amino-3-methyl-1-phenylpyrazole (CAS: 1131-18-6, 6.83 g, 39.4 mmol) was dissolved in AcOH (70 mL). Diethyloxalacetate sodium salt (CAS: 40876-98-0, 9.12 g, 44.4 mmol, 1.1 equiv) was added, and the reaction mixture was refluxed until complete conversion. The reaction mixture was concentrated in vacuo, and the residue was taken up in cyclohexane (2×100 mL) and concentrated in vacuo again. The residue was suspended in a mixture of MeOH/water (150 mL/100 mL). The resulting precipitate was collected by filtration and washed with heptane. The solid was dried under vacuum to provide the titled compound.


Step 2: 6-Bromo-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester

6-Hydroxy-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester (7.27 g, 24.5 mmol) was solubilized in anisole (30 mL). Phosphorous(V) oxybromide (CAS 7789-59-5, 8.23 g, 29.3 mmol, 1.2 equiv) was added, and the reaction mixture was refluxed at 140° C. for 1 h. The reaction mixture was cooled down to room temperature and basified with a saturated solution of sodium hydrogencarbonate. The reaction mixture was extracted twice with ethyl acetate, and the combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by filtration on a pad of silica gel (200 g), heptane/EtOAc 100/0 to 90/10) to give the titled compound.


Step 3: 6-Bromo-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid

6-Bromo-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester (3.90 g, 10.8 mmol) was suspended in ethanol (20 mL). An aqueous solution of 1 M sodium hydroxide (20 mL, 20 mmol, 1.9 equiv) was added, and the reaction mixture was stirred at 70° C. for 30 min. The reaction mixture was then concentrated in vacuo. The residue was acidified with an aqueous solution of 2 M HCl and extracted with ethyl acetate. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to yield the titled compound.


Step 4: (6-Bromo-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-carbamic acid tert-butyl ester

6-Bromo-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (3.50 g, 10.4 mmol) was suspended in toluene (35 mL). tert-Butanol (2 mL, 21.6 mmol, 2.1 equiv), triethylamine (4.4 mL, 31.2 mmol, 3.0 equiv) and diphenylphosphoryl azide (CAS 26386-88-9, 3.2 mL, 14.8 mmol, 1.4 equiv) were successively added. The reaction mixture was refluxed for 1.5 h. The reaction mixture was cooled down to RT and concentrated in vacuo, then partitioned between ethyl acetate and water. The aqueous phase was further extracted with ethyl acetate. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by filtration on a pad of silica gel (200 g, heptane/EtOAc 100/0 to 90/10) to give the titled compound.


Step 5: (6-Cyano-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-carbamic acid tert-butyl ester

(6-Bromo-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-carbamic acid tert-butyl ester (4.16 g, 10.3 mmol) was solubilized in dry dimethylformamide (20 mL) in a sealed vial. Zinc cyanide (CAS 557-21-1, 0.727 g, 6.2 mmol, 0.6 equiv) was added, and the reaction mixture was degassed with argon for 5 minutes. Tetrakis(triphenylphosphine)palladium(0) (CAS 14221-01-3, 0.595 g, 0.5 mmol, 0.05 equiv) was added, and the vial was sealed. The reaction mixture was stirred at 100° C. for 1 hour. The reaction was not complete. Additional tetrakis(triphenylphosphine)palladium(0) (CAS 14221-01-3, 0.595 g, 0.5 mmol, 0.05 equiv) and zinc cyanide (CAS 14221-01-3, 0.485 g, 4.1 mmol, 0.4 equiv) were added at RT, and the vial was sealed again. The reaction mixture was stirred at 100° C. for one hour and cooled down to room temperature. Water was added to the reaction mixture and precipitation occurred. The suspension was filtered, and the cake was washed with water. The solid residue was taken up with dichloromethane and with an aqueous solution of 0.5 M NaOH. The organic phase was separated, dried over Na2SO4, filtered and concentrated. The residue was purified by filtration on a pad of silica gel (150 g, heptane/EtOAc 100/0 to 60/40) to give the titled compound mixed with (6-cyano-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-carbonitrile. The mixture was engaged in the next step without further purification.


Step 6: 4-Amino-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid hydrochloride salt

A mixture of (6-cyano-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-carbamic acid tert-butyl ester and (6-cyano-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-carbonitrile (3.5 g) was suspended in 6 M HCl (50 mL). The reaction mixture was refluxed for 18 h. The reaction mixture was cooled to 0° C. and the obtained suspension was filtered. The solid was washed with an aqueous solution of 0.1 M HCl. The filtrate was concentrated in vacuo and precipitation occurred. The solid was also collected by filtration. The combined solids were dried in vacuo to yield the titled compound.


Step 7: 4-Amino-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid ethyl ester

4-Amino-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid hydrochloride salt (2.03 g, 7.6 mmol) was solubilized in ethanol (40 mL). Thionyl chloride (CAS 7719-09-7, 1.16 mL, 15.9 mmol, 2.1 equiv) was carefully added. The reaction mixture was refluxed for 24 hours. The reaction mixture was concentrated in vacuo and partitioned between ethyl acetate and aqueous saturated NaHCO3. The aqueous phase was further extracted with ethyl acetate. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo to give the titled compound.


Step 8: 4-Chloro-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid ethyl ester

Copper(II) chloride (CAS 7447-39-4, 0.908 g, 6.75 mmol, 1.0 equiv) was added to acetonitrile (50 mL). Isopentylnitrite (CAS 110-46-3, 1.4 mL, 10.1 mmol, 1.5 equiv) was added, and the reaction mixture was stirred at 75° C. for 5 minutes. 4-Amino-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid ethyl ester (2.0 g, 6.75 mmol, 1.0 equiv) dissolved in acetonitrile (50 mL) was added. The reaction mixture was stirred at 75° C. for 2.5 h. The reaction mixture was cooled down and concentrated in vacuo. Water was added to the residue, and the mixture was extracted with ethyl acetate. Copper salts prevented clean extraction. The suspension was filtered through diatomaceous earth. The organic phase was dried over Na2SO4, filtered and concentrated. The residue was suspended in ethanol (10 mL) and filtered. The solid was dried in vacuo to give the titled compound. The copper salts on the diatomaceous earth were washed with dichloromethane. The filtrate was concentrated to provide additional titled compound.


Method H2: Synthesis of Halogenated Pyrazolopyridine (Route 2)
Illustrative Synthesis of HP02: methyl 4-chloro-3-cyclobutyl-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylate



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Step 1: 3-cyclobutyl-1-phenyl-pyrazolo[3,4-b]pyridine-4,6-diol

To a mixture of 3-cyclobutyl-1-phenyl-1H-pyrazol-5-amine (AMP29, 74.0 g, 347 mmol) in oxydibenzene (450.0 g, 2.64 mol) was added diethyl malonate (CAS 105-53-3, 139.0 g, 867 mmol). The system was heated at 130-150° C. for 40 h. By this time solid had precipitated and heating was stopped. Two more reactions were set up as described above. All three reaction mixtures were combined. The combined mixture was cooled to below 40° C. and diluted with about 1.8 L of diethyl ether, and the resulting suspension was stirred for 2 h and then filtered. The collected solids were rinsed with diethyl ether (1 L). The solids were dried on the filter to give the titled compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.28 (s, 1H), 8.18 (d, J=7.9 Hz, 2H), 7.58-7.39 (m, 2H), 7.21 (t, J=7.1 Hz, 1H), 5.85 (s, 1H), 3.88 (quin, J=8.4 Hz, 1H), 2.44-2.22 (m, 4H), 2.07-1.78 (m, 2H).


Step 2: 4,6-dichloro-3-cyclobutyl-1-phenyl-pyrazolo[3,4-b]pyridine

A mixture of 3-cyclobutyl-1-phenyl-pyrazolo[3,4-b]pyridine-4,6-diol (60.0 g, 213 mmol) in phenyl dichlorophosphate (CAS 770-12-7,135 g, 640 mmol) was stirred at 170° C. for 15 h. Two more reactions were set up as described above. All three reaction mixtures were combined and poured into ice water (5 L) keeping the internal temperature <10° C. The mixture was neutralized with concentrated NH4OH (500 mL) to pH 6-7, then the suspension was stirred for 2 h. As the pH increased and with continued stirring, the semi-solid suspension becomes a flowing solid. The solid was collected by filtration. The wet solid was dissolved in dichloromethane (3 L) and filtered through a short path of silica gel (2 kg), eluting with dichloromethane (15 L). The filtrate was concentrated to a solid which was triturated with acetonitrile (1.5 L) and collected by filtration to give the titled compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.20 (d, J=7.9 Hz, 2H), 7.51 (t, J=7.5 Hz, 2H), 7.35-7.27 (m, 1H), 7.16 (s, 1H), 4.15 (quin, J=8.4 Hz, 1H), 2.63-2.41 (m, 4H), 2.20-2.07 (m, 1H), 2.00 (s, 1H).


Step 3: methyl 4-chloro-3-cyclobutyl-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylate

To a mixture of 4,6-dichloro-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine (50.0 g, 157 mmol) in methanol (700 mL) was added triethylamine (31.8 g, 314 mmol) and Pd(dppf)Cl2.DCM (CAS 95464-05-4, 6.4 g, 7.86 mmol). The system was heated at 60° C. under CO (30 psi) for 40 h. Two more reactions were set up as described above. All three reaction mixtures were combined and concentrated to give a semisolid which was dissolved in dichloromethane (3 L) and filtered through a 2 kg plug of silica gel. After concentration, about 130 g of solid was obtained. This solid was taken up in 1.3 L of ethyl acetate with heating. This solution was stirred at room temperature. Solids came out over a couple of minutes, and then 1.3 L of hexane was added in a thin stream via addition funnel with stirring for 2 hours. The solids were collected by filtration to give the titled compound. 1H NMR (400 MHz, CDCl3) δ ppm 8.38-8.27 (m, 2H), 7.95 (s, 1H), 7.53 (t, J=7.9 Hz, 2H), 7.35-7.27 (m, 1H), 4.21 (q, J=8.6 Hz, 1H), 4.08-4.03 (m, 1H), 2.66-2.40 (m, 4H), 2.22-1.93 (m, 2H).


Illustrative Synthesis of HP17: 4-chloro-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid



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Step 1: 4-hydroxy-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one

A solution of 5-amino-3-methyl-1-phenylpyrazole (CAS 1131-18-6, 6 g, 34.6 mmol) and diethyl malonate (5.28 mL, 34.6 mmol) in diphenyl ether (25 mL) was heated at reflux for 22 hours. Solids gradually precipitated from the reaction mixture. The reaction mixture was cooled to RT, diluted with diethyl ether (50 mL), and stirred at RT for 1 h. The solid was collected by filtration, washed with diethyl ether (25 mL), and dried in a vacuum oven at 50° C. for 16 hours. The filtrate was concentrated in vacuo to remove diethyl ether, and the resulting solution (of some unreacted starting material) in diphenyl ether solution was heated to reflux for 2 hours. Then the reaction mixture was cooled to RT, diluted with diethyl ether (25 mL) and filtered to give additional solid product. The filter cake was washed with diethyl ether (2×25 mL), air dried, and combined with first lot of solid, and this was dried under vacuum to give a total of 4.25 g of the titled compound (51% yield). 1H NMR (501 MHz, DMSO-d6) δ ppm 2.50 (s, 3H), 5.86 (s, 1H), 7.21 (tt, J=7.4, 1.2 Hz, 1H), 7.39-7.49 (m, 2H), 8.11-8.23 (m, 2H), 10.88 (s, 1H), 11.32 (s, 1H).


Step 2: 3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4,6-diylbis(trifluoromethanesulfonate)

To a cold (<0° C.) suspension of 4-hydroxy-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (4.25 g, 17.62 mmol) in acetonitrile (100 mL) was added pyridine (3.56 mL, 44.0 mmol) and trifluoromethanesulfonic anhydride (5.21 mL, 30.8 mmol) in a dropwise manner. The cooling bath was removed, and the reaction mixture stirred at RT for 2 hours. The reaction mixture was then diluted with water (100 mL) and stirred for 5 min. The resulting precipitates were collected by filtration, washed with water and dried in a vacuum oven at 50° C. for 16 h to give 8.0 gm of the titled compound (90% Yield). 1H NMR (400 MHz, CDCl3) δ ppm 2.78 (s, 3H), 7.03 (s, 1H), 7.35-7.42 (m, 1H), 7.50-7.58 (m, 2H), 8.08-8.15 (m, 2H).


Step 3: 4,6-dichloro-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine

A mixture of 3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4,6-diyl bis(trifluoromethanesulfonate) (8.00 g, 15.83 mmol) and 4.0 N hydrochloric acid in dioxane (39.6 mL, 158 mmol) was stirred in a sealed tube at 120° C. for 6 hours. The reaction mixture was concentrated in vacuo and purified by flash chromatography using a 120 g silica gel cartridge, eluting with 0-3.5% MTBE/heptanes to afford 3.41 g of the titled compound (78% yield). Note that the reaction can also be run at 100° C. for 16 hours instead of 120° C. 1H NMR (400 MHz, CDCl3) δ ppm 2.81 (s, 3H), 7.21 (s, 1H), 7.31-7.38 (m, 1H), 7.54 (t, 2H), 8.17 (d, 2H).


Step 4: methyl 4-chloro-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylate

To a 250 mL stainless steel pressure bottle was added 4,6-dichloro-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine (3.4063 g, 12.25 mmol), Pd-dppf (Heraeus) (0.179 g, 0.245 mmol), MeOH (70 mL), and triethylamine (3.41 mL, 24.49 mmol). The pressure bottle reactor was degassed with argon several times, followed by addition of carbon monoxide, and the reaction was heated to 100° C. for 30 minutes, maintaining the reaction under 60 psi pressure of carbon monoxide. The reaction mixture was concentrated in vacuo and purified by flash chromatography using a 120 g silica gel cartridge, eluting with 100% DCM to obtain 3.09 g of the titled compound (84% yield). Note that lowering the reaction temperature from 100° C. to 50° C., and increasing the reaction time from 30 minutes to 2 hours, also gives desired product. 1H NMR (400 MHz, CDCl3) δ ppm 2.86 (s, 3H), 4.05 (s, 3H), 7.29-7.37 (m, 1H), 7.49-7.60 (m, 2H), 7.98 (s, 1H), 8.24-8.32 (m, 2H).


Step 5: 4-chloro-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid

To a solution of methyl 4-chloro-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylate (3.09 g, 10.24 mmol) in tetrahydrofuran (76 mL) was added potassium trimethylsilanolate (1.577 g, 12.29 mmol), and the resulting suspension was stirred at 50° C. for 1 hour. The reaction mixture was acidified with concentrated aqueous HCl to pH 1, and the mixture was partitioned between MTBE and water. The organic extract were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain 2.90 g of the titled compound (99% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.71 (s, 3H), 7.30-7.37 (m, 1H), 7.50-7.59 (m, 2H), 7.87 (s, 1H), 8.16-8.23 (m, 2H), 13.75 (s, 1H).


Illustrative Synthesis of HP19: Methyl 4-chloro-3-cyclobutyl-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylate



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Step 1: 3-Cyclobutyl-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-4,6-diol

A mixture of 3-cyclobutyl-1-(4-fluorophenyl)-1H-pyrazol-5-amine (AMP93, 5 g, 18.6 mmol) and diethyl malonate ([105-53-3], 8.5 mL, 55.8 mmol) was heated at 100° C. for 30 minutes and then at 170° C. for 3 hours. The reaction mixture was cooled down to RT and dissolved in dichloromethane (60 mL). The resultant solution was poured into a stirred solution of n-heptane (700 mL). The precipitate was collected by filtration, washed with n-heptane and dried at 40° C. under reduced pressure to give the titled compound.


Step 2: 4,6-Dichloro-3-cyclobutyl-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine

A three-neck round-bottom flask equipped with a Dean-Stark apparatus was charged with phenyl dichlorophosphate ([770-12-7], 854 g, 4.05 mol). 3-Cyclobutyl-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-4,6-diol (404 g, 1.35 mol) was added in portions over a period of 5 minutes. The temperature was increased to 170° C. over a period of 1 hour, and the stirring at 170° C. was continued for 21 hours. The reaction mixture was cooled down to 50° C. and added slowly to a stirred aqueous 4 N NaOH (5 L) keeping the temperature below 20° C. The suspension was stirred for 1 hour at 10-15° C., and then cold water (3 L) was added. The precipitate was collected by filtration, washed with water and dried at 40° C. under reduced pressure to give the titled compound.


Step 3: methyl 4-chloro-3-cyclobutyl-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylate

A pressured vessel was charged with 4,6-dichloro-3-cyclobutyl-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine (5 g, 14.9 mmol), Pd(dppf)Cl2.DCM (CAS 95464-05-4, 218 mg, 0.3 mmol), and sodium acetate (1.8 g, 22.3 mmol) in dioxane/methanol (1:1, 25 mL). The system was loaded with CO (4 bars) and heated at 40° C. for 2 hours. The vessel was cooled to RT, and the conversion was monitored by LCMS. The reaction vessel was charged again with CO (4 bars) and heated at 40° C. The sequence was repeated until full conversion was observed. The crude mixture was concentrated under reduced pressure and purified by flash column chromatography eluting with a mixture of n-heptane/dichloromethane (90/10 to 30/70) to give the titled compound.


Method H3: Synthesis of Halogenated Pyrazolopyridine (Route 3)



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Step 1: Diethyl but-2-enedioate

To a suspension of aminopyrazole (1 equiv) in ethanol (150 mL) is added diethyl acetylenedicarboxylate (1.1 equiv). The reaction mixture is stirred at room temperature for 4 hours. The reaction mixture is concentrated. The crude residue is purified by silica gel column chromatography (heptane/EtOAc 100/0 to 70/30) to give the titled compound.


Step 2: Pyrazolopyridine formation

The diethyl but-2-enedioate is heated under air atmosphere at 190-195° C. for one hour. The reaction mixture is cooled to room temperature and is partitioned between dichloromethane and water. The aqueous phase is separated and extracted two times with dichloromethane. The combined organic phases were dried, filtered and concentrated in vacuo. The crude residue can be purified by silica gel column chromatography to provide the pyrazolopyridine.


Step 3: Chlorination

A solution of the above pyrazolopyridine (1 equiv) in phosphorus(V) oxychloride (32 equiv) was stirred at 115° C. for 1 h. The reaction mixture is then cooled to room temperature and concentrated in vacuo. The residue is dissolved in ethyl acetate, and the reaction mixture is added dropwise to a solution of saturated of sodium hydrogencarbonate till total neutralization of phosphorus(V) oxychloride (pH 8). The aqueous phase is separated and extracted two times with ethyl acetate. The combined organic phases are washed with brine, dried, filtered and concentrated in vacuo. The crude residue can be purified by silica gel column chromatography to provide the chlorinated pyrazolopyridine from which the dimethoxybenzyl group has also been removed.


Illustrative Synthesis of HP08: 4-Chloro-3-isopropyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid ethyl ester



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Step 1: 2-[2-(2,4-Dimethoxy-benzyl)-5-isopropyl-2H-pyrazol-3-ylamino]-but-2-enedioic acid diethyl ester

To a suspension of 2-(2,4-dimethoxy-benzyl)-5-isopropyl-2H-pyrazol-3-ylamine (AMP28, 18.14 g, 65.88 mmol) in ethanol (150 mL) was added diethyl acetylenedicarboxylate (CAS: 762-21-0, 11.60 mL, 72.47 mmol). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated. The crude residue was purified by silica gel column chromatography (heptane/EtOAc 100/0 to 70/30) to give the titled compound.


Step 2: Compound HP06: 1-(2,4-Dimethoxy-benzyl)-4-hydroxy-3-isopropyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid ethyl ester

2-[2-(2,4-Dimethoxy-benzyl)-5-isopropyl-2H-pyrazol-3-ylamino]-but-2-enedioic acid diethyl ester (13.46 g, 30.21 mmol) was heated under air atmosphere at 190-195° C. for one hour. The reaction mixture cooled to room temperature and was partitioned between dichloromethane and water. The aqueous phase was separated and extracted two times with dichloromethane. The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (heptane/EtOAc 100/0 to 60/40) to provide the titled compound.


Step 3: Compound HP08: 4-Chloro-3-isopropyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid ethyl ester

A solution of 1-(2,4-dimethoxy-benzyl)-4-hydroxy-3-isopropyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid ethyl ester (HP06, 4.02 g, 10.06 mmol) in phosphorus(V) oxychloride (CAS 100025-87-3, 30 mL, 322 mmol) was stirred at 115° C. for 1 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate, and the reaction mixture was added dropwise to a solution of saturated of sodium hydrogencarbonate till total neutralization of phosphorus(V) oxychloride (pH 8). The aqueous phase was separated and extracted two times with ethyl acetate. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (heptane/EtOAc 100/0 to 75/25) to provide the titled compound.


Illustrative Synthesis of HP20: ethyl 1-tert-butyl-3-cyclobutyl-4-[(trifluoromethanesulfonyl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate



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Step 1: diethyl 2-[(1-tert-butyl-3-cyclobutyl-1H-pyrazol-5-yl)amino]but-2-enedioate

In an amber round bottom flask, diethyl acetylenedicarboxylate ([762-21-0], 14.8 mL, 87 mmol) was added to a suspension of AMP94 (15.2 g, 78.8 mmol) in ethanol (200 mL). The reaction mixture was stirred at room temperature for 20 hours, and the mixture was concentrated in vacuo. The crude residue was purified by silica gel column chromatography (heptane/dichloromethane 100/0 to 0/100) to give the titled compound.


Step 2: ethyl 1-tert-butyl-3-cyclobutyl-4-hydroxy-1H-pyrazolo[3,4-b]pyridine-6-carboxylate

In a sealed tube, a suspension of diethyl 2-[(1-tert-butyl-3-cyclobutyl-1H-pyrazol-5-yl)amino]but-2-enedioate (5 g, 13.8 mmol) in Dowtherm® A (5 mL) was heated at 185-190° C. for 24 hours. The reaction mixture was cooled to room temperature and was partitioned between n-heptane and acetonitrile. The acetonitrile phase was separated and evaporated under reduced pressure. The crude sample was purified by silica gel column chromatography (dichloromethane/n-heptane) to give the titled compound.


Step 3: ethyl 1-tert-butyl-3-cyclobutyl-4-[(trifluoromethanesulfonyl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate

Trifluoromethanesulfonic anhydride ([358-23-6], 1.9 mL, 11.3 mmol) was added dropwise to a solution of ethyl 1-tert-butyl-3-cyclobutyl-4-hydroxy-1H-pyrazolo[3,4-b]pyridine-6-carboxylate (2.5 g, 7.89 mmol) and pyridine (1.9 mL, 23.5 mmol) in acetonitrile (80 mL), maintaining the temperature around 20-25° C. The reaction mixture was stirred at RT for 20 hours. Then solid sodium hydrogencarbonate and few milliliters of water were added, and the reaction mixture was concentrated in vacuo. The residue was taken up in dichloromethane and water. The two phases were separated, and the aqueous phase was again extracted with dichloromethane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (n-heptane/ethyl acetate) to yield the titled compound.


Synthesis of HP12: methyl 4-chloro-1-cyclohexyl-3-isopropyl-pyrazolo[3,4-b]pyridine-6-carboxylate



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Step 1: 1-cyclohexyl-3-isopropyl-pyrazolo[3,4-b]pyridine-4,6-diol

A mixture of AMP23 (5.0 g, 24.1 mmol) and diethylmalonate (CAS 105-53, 37.36 mL, 48.2 mmol, 2.0 equiv) was stirred at 190° C. for 2 hours. The reaction mixture was then cooled to RT, and diethyl ether was added. The obtained suspension was filtered; the solid was washed with pentane and dried in vacuo to give the titled compound.


Step 2: [1-cyclohexyl-3-isopropyl-6-(trifluoromethylsulfonyloxy)pyrazolo[3,4-b]pyridin-4-yl]trifluoromethanesulfonate

Trifluoromethanesulfonic anhydride (CAS 358-23-6, 6.26 mL, 37.2 mmol, 1.75 equiv) was added dropwise at 0° C. to a solution of 1-cyclohexyl-3-isopropyl-pyrazolo[3,4-b]pyridine-4,6-diol (5.85 g, 21.2 mmol) and pyridine (4.3 mL, 53.1 mmol, 2.5 equiv) in acetonitrile (145 mL). The reaction mixture was stirred at RT for 16 hours. Dichloromethane and water were added to the reaction mixture. The two phases were separated, and the organic phase was washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was taken up in toluene and concentrated again in vacuo to give the titled compound.


Step 3: 4,6-dichloro-1-cyclohexyl-3-isopropyl-pyrazolo[3,4-b]pyridine

A mixture of [1-cyclohexyl-3-isopropyl-6-(trifluoromethylsulfonyloxy)pyrazolo[3,4-b]pyridin-4-yl]trifluoromethanesulfonate (10.86 g, 20.1 mmol) and 4 N HCl in dioxane (50 mL, 200 mmol, 10 equiv) was stirred at 100° C. for 16 hours in a sealed tube. The reaction mixture was cooled to RT and concentrated in vacuo. The residue was purified by chromatography on silica gel (heptane/dichloromethane 100/0 to 80/20) to yield the titled compound.


Step 4: HP12: methyl 4-chloro-1-cyclohexyl-3-isopropyl-pyrazolo[3,4-b]pyridine-6-carboxylate

Triethylamine (1.9 mL, 13.6 mmol, 2.0 equiv) and Pd(dppf)Cl2 (CAS: 72287-26-4, 100 mg, 0.14 mmol, 0.02 equiv) were added to a solution of 4,6-dichloro-1-cyclohexyl-3-isopropyl-pyrazolo[3,4-b]pyridine (2.13 g, 6.82 mmol) in methanol (55 mL). The system was filled at RT with CO (40 psi) and heated at 100° C. for 1 hour. The reaction mixture was cooled down to RT and concentrated in vacuo. The residue was purified by chromatography on silica gel (heptane/ethyl acetate 100/0 to 90/10) to yield the titled compound.


Synthesis of HP14: ethyl 3-cyclobutyl-1-[(2,4-dimethoxyphenyl)methyl]-4-(trifluoromethylsulfonyloxy)pyrazolo[3,4-b]pyridine-6-carboxylate



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Trifluoromethanesulfonic anhydride (CAS 358-23-6, 92 μL, 0.56 mmol, 1.45 equiv) was added dropwise at RT to a solution of HP15 (160 mg, 0.39 mmol, 1 equiv) and pyridine (46 μL, 0.58 mmol, 1.5 equiv) in acetonitrile (4 mL). The reaction mixture was stirred at RT for 3 h. Then solid sodium hydrogencarbonate and few milliliters of water were added, and the reaction mixture was concentrated in vacuo. The residue was taken up in dichloromethane and water. The two phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (eluent system: heptane/dichloromethane gradient from 100/0 to 0/100) to yield the titled compound.


Synthesis of HP18: 4-chloro-3-methyl-1-phenyl-pyrazolo[3,4-b]pyridine-6-carbonitrile



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Step 1: 6-Hydroxy-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester

5-Amino-3-methyl-1-phenylpyrazole (CAS: 1131-18-6, 6.83 g, 39.4 mmol) was dissolved in AcOH (70 mL). Diethyloxalacetate sodium salt (CAS: 40876-98-0, 9.12 g, 44.4 mmol, 1.1 equiv) was added, and the reaction mixture was refluxed till the conversion (followed by LCMS) was total. The reaction mixture was concentrated, and the residue was taken up in cyclohexane (2×100 mL) and concentrated. The residue was triturated in MeOH/water (150 mL/100 mL). The resulting precipitate was collected by filtration and washed with heptane. The solid was dried to provide the titled compound.


Step 2: 6-Bromo-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester

6-Hydroxy-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester (7.27 g, 24.5 mmol) was solubilized in anisole (30 mL). Phosphorous(V) oxybromide (8.23 g, 29.3 mmol, 1.2 equiv) was added, and the reaction mixture was refluxed at 140° C. for 1 h. The reaction mixture was cooled to room temperature and saturated NaHCO3 was added. The reaction mixture was extracted twice with ethyl acetate, and the combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by filtration on a pad of silica gel (200 g), heptane/EtOAc 100/0 to 90/10) to give the titled compound.


Step 3: 6-Bromo-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid

6-Bromo-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester (3.90 g, 10.8 mmol) was suspended in ethanol (20 mL). 1 M NaOH (20 mL, 20 mmol, 1.9 equiv) was added, and the reaction mixture was stirred at 70° C. for 30 min. The reaction mixture was then concentrated. The residue was acidified with 2 M HCl and extracted with ethyl acetate. The organic phase was dried over Na2SO4, filtered and concentrated yielding the titled compound.


Step 4: 6-bromo-3-methyl-1-phenyl-pyrazolo[3,4-b]pyridin-4-amine

6-Bromo-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (3.50 g, 10.4 mmol) was suspended in toluene (35 mL). tert-Butanol (2 mL, 21.6 mmol, 2.1 equiv), triethylamine (4.4 mL, 31.2 mmol, 3.0 equiv) and diphenylphosphoryl azide (3.2 mL, 14.8 mmol, 1.4 equiv) were successively added. The reaction mixture was refluxed for 1.5 h. The reaction mixture was concentrated and then partitioned between ethyl acetate and water. The aqueous phase was further extracted with ethyl acetate. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified on a silica cake (200 g, heptane/EtOAc 100/0 to 90/10) to give the titled compound.


Step 5: 6-bromo-4-chloro-3-methyl-1-phenyl-pyrazolo[3,4-b]pyridine

Copper(II) chloride (28 mg, 0.21 mmol) and isopentylnitrite (71 μL, 0.53 mmol) in acetonitrile (4 mL) were heated at 70° C. for 5 minutes. The compound from Step 4 (107 mg, 0.35 mmol) was solubilized in acetonitrile (4 mL) and added to the previous solution. The heating at 70° C. was continued and copper (II) chloride (28 mg, 0.21 mmol) was added two times every hour. After 2.5 hours, the reaction mixture was left cooling to RT, and the mixture was concentrated under reduced pressure. Water was added, and the aqueous phase was extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with n-heptane/ethyl acetate to give the titled compound.


Step 6: 4-chloro-3-methyl-1-phenyl-pyrazolo[3,4-b]pyridine-6-carbonitrile

The compound from Step 5 (192 mg, 0.6 mmol) was solubilized in dry dimethylformamide (1 mL) in a vial. Zinc cyanide (35 mg, 0.3 mmol) was added, and the reaction mixture was degassed with argon for 5 minutes. Tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.06 mmol) was added, and the vial was sealed. The reaction mixture was stirred at 100° C. for 0.5 hour. The reaction mixture was cooled to room temperature, and the crude mixture was partitioned between a saturated aqueous solution of NaHCO3 and ethyl acetate. The organic phase was washed with a saturated aqueous solution of NaCl, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography eluting with n-heptane/ethyl acetate to give the titled compound.


Synthesis of Intermediate HP21: 1-(4-fluorophenyl)-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-4,6-diol



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In a sealed tube, a suspension of AMP96 (215 mg, 0.91 mmol) and diethyl malonate ([105-53-3], 418 μL, 2.75 mmol) in Dowtherm® A was heated at 200° C. 4 hours. The reaction mixture was cooled down to 70-80° C. and poured into stirred n-heptane (200 mL). The resultant precipitate was collected by filtration, washed with n-heptane and dried at 40° C. under reduced pressure to give the titled compound.


Synthesis of Intermediate HP22: 1-(4-fluorophenyl)-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-4,6-diyl bis(trifluoromethanesulfonate)



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Trifluoromethanesulfonic anhydride ([358-23-6], 302 μL, 1.8 mmol) was added dropwise to a solution of HP21 (270 mg, 0.9 mmol) and pyridine (220 μL, 2.25 mmol) in acetonitrile (5 mL), maintaining the temperature around 20-25° C. The reaction mixture was stirred at RT for 20 hours. The reaction was diluted with DCM and extracted twice with a saturated aqueous solution of NaHCO3. The organic phase was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (n-heptane/ethyl acetate) to yield the titled compound.


Synthesis of HP25: methyl 4-chloro-3-cyclobutyl-1-cyclohexyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylate



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Step 1: 3-cyclobutyl-1-cyclohexyl-4-hydroxy-3aH-pyrazolo[3,4-b]pyridin-6-one

A mixture of 5-cyclobutyl-2-cyclohexyl-2H-pyrazol-3-ylamine (AMP35, 10 g, 45.7 mmol) and diethyl malonate ([105-53-3], 27.7 mL, 183 mmol) in diphenylether (50 mL) was heated at 130° C. over approximately 60 hours. The reaction mixture was cooled down to RT and quenched with 0.5 M NaOH solution (100 mL, 50 mmol). Extraction with EtOAc gave an aqueous phase that was acidified with a 12 M HCl solution (4.3 mL, 51.6 mmol) giving rise to a suspension. This suspension was extracted with EtOAc. The obtained organic layer was dried and concentrated to give the titled compound that was used as such.


Step 2: 4,6-dichloro-3-cyclobutyl-1-cyclohexyl-pyrazolo[3,4-b]pyridine

The 3-cyclobutyl-1-cyclohexyl-4-hydroxy-3aH-pyrazolo[3,4-b]pyridin-6-one (5.15 g, 17.9 mmol) was suspended in phenyl dichlorophosphate ([770-12-7], 8.01 mL, 53.8 mmol). The mixture was heated at 130° C. overnight. Next, the mixture was diluted in DCM and poured into ice water. After increasing the pH till 7-8 with a saturated NH4OH solution, the biphasic mixture was stirred for 30 minutes. Subsequently, the organic phase was separated, dried and concentrated to give a residue. This residue was purified by chromatography using a petroleum ether/EtOAc gradient (100/0 to 90/10). This resulted in the titled compound that was used as such.


Step 3: methyl 4-chloro-3-cyclobutyl-1-cyclohexyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylate

In a Parr apparatus, 4,6-dichloro-3-cyclobutyl-1-cyclohexyl-pyrazolo[3,4-b]pyridine (2.17 g, 6.72 mmol) was dissolved in MeOH (50 mL) together with Pd(dppf)Cl2.DCM (CAS 95464-05-4, 275 mg, 0.33 mmol) and triethylamine (1.87 mL, 13.4 mmol). The system was loaded with CO (5 bar) and heated at 45° C. for 18 hours. After cooling down the mixture till RT, the mixture was concentrated, and the obtained residue was purified by chromatography using a petroleum ether/EtOAc gradient (100/0 till 95/5). This yielded the titled compound.


Illustrative Synthesis of HP27: 4-chloro-1-(4-fluorophenyl)-5-methyl-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid



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Step 1: 1-(4-fluorophenyl)-4-hydroxy-5-methyl-3-(propan-2-yl)-1,7-dihydro-6H-pyrazolo[3,4-b]pyridin-6-one

To a flask containing 2-(4-fluoro-phenyl)-5-isopropyl-2H-pyrazol-3-ylamine (8.0 g, 36.5 mmol, AMP13) in oxydibenzene (62.1 g, 365 mmol) was added diethyl 2-methylmalonate (4.0 g, 22.96 mmol). The reaction mixture was heated at 130° C. for 20 hours and then at 150° C. for 35 hours before being returned to room temperature. Heptane was added (180 mL), and the suspension was stirred at room temperature overnight. The solids were collected by filtration, washed with heptane (30 mL), and dried to give the titled compound. 1H NMR (400 MHz, CD3OD) δ ppm 7.80-7.75 (m, 2H), 7.26-7.20 (m, 2H), 3.50 (hept, J=7.0 Hz, 1H), 2.05 (s, 3H), 1.40 (d, J=7.0 Hz, 6H); MS (DCI) m/z 302 (M+H)+.


Step 2: 4,6-dichloro-1-(4-fluorophenyl)-5-methyl-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine

To a flask containing 1-(4-fluorophenyl)-4-hydroxy-5-methyl-3-(propan-2-yl)-1,7-dihydro-6H-pyrazolo[3,4-b]pyridin-6-one (4.5 g, 14.93 mmol) under nitrogen was added phenyl phosphorodichloridate (6.30 g, 29.9 mmol). The reaction mixture was heated to 180° C. and stirred for five hours before being cooled to room temperature, diluted with EtOAc (50 mL) and poured into ice water (50 g). The resulting biphasic mixture was stirred ten minutes, and then the separated aqueous layer was further extracted twice. The combined organic phases were washed with 10% aqueous sodium bicarbonate (30 mL) and brine, dried (Na2SO4), filtered and concentrated. The residue was slurried with acetonitrile (100 mL) at RT overnight. The solids were collected by filtration with an acetonitrile rinse and dried under vacuum to give the titled compound. 1H NMR (400 MHz, CDCl3) δ ppm 8.19-8.14 (m, 2H), 7.22-7.16 (m, 2H), 3.77 (hept, J=6.8 Hz, 1H), 2.58 (s, 3H), 1.47 (d, J=6.8 Hz, 6H); MS (DCI) m/z 338 (M+H)+.


Step 3: methyl 4-chloro-1-(4-fluorophenyl)-5-methyl-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylate

To 4,6-dichloro-1-(4-fluorophenyl)-5-methyl-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine (1.0 g, 2.96 mmol) and Pd-dppf (Heraeus) (45 mg, 0.062 mmol) in a 50 mL Hast C reactor was added MeOH (15 mL) and NEt3 (0.845 mL, 6.06 mmol). The reactor was flushed with argon several times followed by carbon monoxide, then heated at 60° C. for 8 hours at 70 psi. The reaction mixture was concentrated and filtered through silica (CH2Cl2). The filtrate was concentrated and filtered again through silica (50% CH2Cl2/heptane). The filtrate from this second column was concentrated, and the resulting solids were slurried in 1:3 MTBE/heptane, collected by filtration, rinsed with more 1:3 solution and dried under vacuum to give the titled compound. 1H NMR (400 MHz, CDCl3) δ ppm 8.26-8.20 (m, 2H), 7.22-7.15 (m, 2H), 4.02 (s, 3H), 3.83 (hept, J=6.9 Hz, 1H), 2.58 (s, 3H), 1.49 (d, J=6.9 Hz, 6H); MS (DCI) m/z 362 (M+H)+.


Step 4: 4-chloro-1-(4-fluorophenyl)-5-methyl-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid

Methyl 4-chloro-1-(4-fluorophenyl)-5-methyl-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylate (543 mg, 1.5 mmol) was sonicated in DMSO (3.0 mL). The suspension was treated with aqueous 3 M NaOH (1.0 mL, 3 mmol), then stirred at RT for 100 minutes and quenched with aqueous 1 M citric acid (3.0 mL). The mixture was extracted thrice with 1:2 EtOAc/MTBE, and the combined extracts were washed with aqueous 0.5 M citric acid, dried (Na2SO4), concentrated and chromatographed on silica (20% EtOAc in 1:1 CH2Cl2/heptane) to give the titled compound. 1H NMR (400 MHz, CDCl3) δ ppm 7.98-7.91 (m, 2H), 7.28-7.22 (m, 2H), 3.87 (hept, J=6.8 Hz, 1H), 2.94 (s, 3H), 1.50 (d, J=6.8 Hz, 6H).









TABLE VIII







List of halogenated pyrazolopyridine













Int.
Structure
Name
SM
method
MW
Mes





HP01


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ethyl 4-chloro- 3-isopropyl-1- (m- tolyl)pyrazolo [3,4-b]pyridine- 6-carboxylate
AMP07
H1 Specific example

  357- 359


  358- 360






HP02


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methyl 4- chloro-3- cyclobutyl-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
AMP29
H2 Specific example

  341- 343


  342- 344






HP03


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ethyl 4-chloro- 1-[3- (dimethylamino) phenyl]-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
AMP06
H1 (steps 1 to 8) and H1′ (step 9) Specific example

  386- 388


  387- 389






HP04


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ethyl 4-chloro- 1-cyclohexyl- 3-isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
AMP23
H1 (steps 1 to 8) and H1′ (step 9)

  349- 351


  350- 352






HP05


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methyl 4- chloro-1-(4- fluorophenyl)- 3-isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
AMP13
H2

  347- 349


  348- 350






HP06


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ethyl 1-[(2,4- dimethoxyphen- yl)methyl]-4- hydroxy-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
AMP28
H3 (steps 1 & 2 only)
399
400





HP07


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4-chloro-1-[3- (dimethylamino) phenyl]-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP03
J1

  358- 360


  359- 361






HP08


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ethyl 4-chloro- 3-isopropyl- 1H- pyrazolo[3,4- b]pyridine-6- carboxylate
AMP28
H3 Specific example

  267- 269


  268- 270






HP09


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ethyl 4-chloro- 1-(4- fluorophenyl)- 3-isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP08, 1765- 93-1
I4

  361- 363


  362- 364






HP10


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4-chloro-3- cyclobutyl-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP02
J1

  327- 329


  328- 330






HP11


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4-chloro-1-(4- fluorophenyl)- 3-isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP05
J1

  333- 335


  334- 336






HP12


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methyl 4- chloro-1- cyclohexyl-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
AMP23
Specific example

  335- 337


  336- 338






HP13


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ethyl 4-chloro- 3-methyl-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
1131- 18-6
Specific example

  315- 317


  316- 318






HP14


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ethyl 3- cyclobutyl-1- [(2,4- dimethoxyphen- yl)methyl]-4- (trifluoromethyl- sulfonyloxy) pyrazolo[3,4- b]pyridine-6- carboxylate
HP15
Specific example
543
544





HP15


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ethyl 3- cyclobutyl-1- [(2,4- dimethoxyphen- yl)methyl]-4- hydroxy- pyrazolo[3,4- b]pyridine-6- carboxylate
AMP36
H3 (steps 1 & 2 only)1
411
412





HP16


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4-chloro-3- isopropyl-1- (m- tolyl)pyrazolo [3,4-b]pyridine- 6-carboxylic acid
HP01
J1

  329- 331


  330- 332






HP17


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4-chloro-3- methyl-1- phenyl-1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP13
J1 Specific example
287






HP18


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4-chloro-3- methyl-1- phenyl- pyrazolo[3,4- b]pyridine-6- carbonitrile
1131- 18-6
Specific example

  268- 270


  269- 271






HP19


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methyl 4- chloro-3- cyclobutyl-1- (4- fluorophenyl)- 1H- pyrazolo[3,4- b]pyridine-6- carboxylate
AMP93
Specific example
359 and 361
360 and 362





HP20


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ethyl 1-tert- butyl-3- cyclobutyl-4- [(trifluorometh- anesulfonyl) oxy]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
AMP94
Specific example
449
450





HP21


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1-(4- fluorophenyl)- 3-[(propan-2- yl)oxy]-1H- pyrazolo[3,4- b]pyridine-4,6- diol
AMP96
Specific example
303
304





HP22


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1-(4- fluorophenyl)- 3-[(propan-2- yl)oxy]-1H- pyrazolo[3,4- b]pyridine-4,6- diyl bis(trifluoro- methanesulfonate)
HP21
Specific example
567
568





HP25


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methyl 4- chloro-3- cyclobutyl-1- cyclohexyl- 1H- pyrazolo[3,4- b]pyridine-6- carboxylate
AMP35
Specific example
347
348





HP26


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4-chloro-3- cyclobutyl-1- (4- fluorophenyl)- 1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP19
J1
345
346





HP27


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4-chloro-1-(4- fluorophenyl)- 5-methyl-3- (propan-2-yl)- 1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
AMP13
Specific example
347
346 (M − H)





HP28


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4-chloro-1- cyclohexyl-3- (propan-2-yl)- 1H- pyrazolo[3,4- b]pyridine-6- carboxylic acid
HP12
J1

  321- 323


  322- 324







1Step 2 performed in Dowtherm ™ at 160° C. for 48 h.







Synthesis of Esters and the Intermediates to Prepare Them
Synthesis of AMI01: 4-(methoxymethyl)piperidin-4-ol hydrochloride



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Step 1: 4-Hydroxy-4-methoxymethyl-piperidine-1-carboxylic acid tert-butyl ester

A suspension of tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (CAS: 147804-30-6, 200 mg, 0.94 mmol) and sodium methoxide (61 mg, 1.13 mmol) in methanol (2 mL) was placed in a sealed tube and was heated at 100° C. for 20 hours. The reaction mixture was cooled to RT, acidified with acetic acid to pH 5-6, diluted with DCM and washed with water. The organic phase was separated using a phase separator and concentrated in vacuo. The titled compound was used as such in the next step without any further purification.


Step 2: 4-Methoxymethyl-piperidin-4-ol hydrochloride

4-Hydroxy-4-methoxymethyl-piperidine-1-carboxylic acid tert-butyl ester (206 mg, 0.84 mmol) was dissolved in dioxane (2 mL). 4 M HCl in dioxane (1.05 mL, 4.2 mmol) was added, and the solution was stirred at RT for 20 hours. The solvent was evaporated under reduced pressure. The titled compound was used as such in the next step without any further purification.


Synthesis of AMI02: 4-[(1,1-dioxo-1,4-thiazinan-4-yl)methyl]piperidin-4-ol hydrochloride



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Step 1: tert-butyl 4-[(1,1-dioxo-1,4-thiazinan-4-yl)methyl]-4-hydroxy-piperidine-1-carboxylate

A solution of tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (CAS: 147804-30-6, 150 mg, 0.7 mmol) and thiomorpholine 1,1-dioxide (CAS: 39093-93-1, 380 mg, 2.8 mmol) in ethanol (2 mL) was placed in a sealed tube and was heated at 75° C. for 20 hours. The reaction mixture was cooled to RT, diluted with DCM and washed with water. The organic phase was separated using a phase separator and concentrated in vacuo. The titled compound was obtained by flash column chromatography eluting with DCM/MeOH.


Step 2: 4-[(1,1-dioxo-1,4-thiazinan-4-yl)methyl]piperidin-4-ol hydrochloride

tert-Butyl 4-[(1,1-dioxo-1,4-thiazinan-4-yl)methyl]-4-hydroxy-piperidine-1-carboxylate (215 mg, 0.62 mmol) was dissolved in dioxane (2 mL). 4 M HCl in dioxane (0.89 mL, 3.6 mmol) was added, and the solution was stirred at RT for 20 hours. The solvent was evaporated under reduced pressure. The titled compound was used as such in the next step without any further purification.


Synthesis of AMI03: (2S)-2-fluoro-N,N-dimethyl-2-(4-piperidyl)ethanamine hydrochloride



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Step 1: (S)-tert-butyl 4-(1-fluoro-2-oxoethyl)piperidine-1-carboxylate

To a suspension of N-fluoro-N-(phenyl sulfonyl)benzenesulfonamide ((CAS 133745-75-2, 347 g, 1100 mmol) and (5R)-(+)-2,2,3-trimethyl-5-benzyl-4-imidazolidinone dichloroacetic acid (CAS 857303-87-8, 76 g, 220 mmol) in THF and isopropyl alcohol at −20° C. was added a solution of tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (250 g, 1100 mmol, CAS: 142374-19-4) in THF. The mixture was stirred at 10° C. for 16 h, diluted with hexane at −78° C. and filtered through silica, washed with hexane, then with saturated aqueous NaHCO3 solution, dried, filtered, and concentrated to give (S)-tert-butyl 4-(1-fluoro-2-oxoethyl)piperidine-1-carboxylate.


Step 2: (S)-tert-butyl 4-(1-fluoro-2-hydroxyethyl)piperidine-1-carboxylate

A solution of (S)-tert-butyl 4-(1-fluoro-2-oxoethyl)piperidine-1-carboxylate (10 g, 40.8 mmol) in dichloromethane (280 mL) and ethanol (220 mL) was stirred at 10° C. Then, sodium borohydride (CAS 16940-66-2, 4.0 g, 105.7 mmol, 2.6 equiv) was added. The mixture was stirred at 10° C. for 1 hour, was diluted with water and extracted with dichloromethane. The organic layer was dried, filtered and concentrated, and the residue was purified by chromatography on silica gel (petroleum ether:ethyl acetate) to give (S)-tert-butyl 4-(1-fluoro-2-hydroxyethyl)piperidine-1-carboxylate.


Step 3: (S)-tert-butyl 4-(2-(benzylamino)-1-fluoroethyl)piperidine-1-carboxylate

Trifluoromethanesulfonic anhydride (CAS 358-23-6, 5.70 g, 20.22 mmol, 1.0 equiv) was added to a solution of (S)-tert-butyl 4-(1-fluoro-2-hydroxyethyl)piperidine-1-carboxylate (5 g, 20.22 mmol) and 2,6-dimethylpyridine (CAS 108-48-5, 2.166 g, 20.22 mmol, 1.0 equiv) in dichloromethane at 0° C. The mixture was stirred at 0° C. for 0.5 h. A separated round bottom flask was charged with benzylamine (2.166 g, 20.22 mmol, 1.0 equiv) in dichloromethane at 0° C. The solution of the triflate was then added slowly at 0° C. The reaction mixture was stirred at 25° C. for 12 hours, quenched with a saturated aqueous solution of sodium hydrogencarbonate, and extracted with dichloromethane. The organic fraction was concentrated. The residue was purified on silica gel chromatography, eluting with acetone/dichloromethane to give (S)-tert-butyl 4-(2-(benzylamino)-1-fluoroethyl)piperidine-1-carboxylate.


Step 4: (S)-tert-butyl 4-(2-amino-1-fluoroethyl)piperidine-1-carboxylate

To a solution of (S)-tert-butyl 4-(2-(benzylamino)-1-fluoroethyl)piperidine-1-carboxylate (4.5 g, 13.38 mmol) in methanol was added Pd/C, then the solution was stirred at 35° C. under hydrogen atmosphere (45 psi) for 12 hours. The mixture was filtered and concentrated to give (S)-tert-butyl 4-(2-amino-1-fluoroethyl)piperidine-1-carboxylate.


Step 5: (S)-tert-butyl 4-(2-(dimethylamino)-1-fluoroethyl)piperidine-1-carboxylate

To a mixture of (S)-tert-butyl 4-(2-amino-1-fluoroethyl)piperidine-1-carboxylate (3.0 g, 12.18 mmol) in methanol was added paraformaldehyde (CAS 30525-89-4, 1.828 g, 60.9 mmol, 5.0 equiv) followed by three drops of acetic acid. The reaction mixture stirred for 1 hour. Then sodium cyanoborohydride (CAS 25895-60-7, 1.148 g, 18.27 mmol, 1.5 equiv) was added, and the mixture was stirred for 12 hours. The reaction mixture was filtered and concentrated, and the residue was purified by column chromatography on silica gel (DCM/MeOH) to afford (S)-tert-butyl 4-(2-(dimethylamino)-1-fluoroethyl)piperidine-1-carboxylate.


Step 6: (S)-2-fluoro-N,N-dimethyl-2-(piperidin-4-yl)ethanamine hydrochloride

To a solution of (S)-tert-butyl 4-(2-(dimethylamino)-1-fluoroethyl)piperidine-1-carboxylate (2 g, 7.29 mmol) in MeOH was added 4 N hydrogen chloride in methanol (10 mL, 40 mmol, 5.5 equiv), and the mixture was stirred at RT for 2 hours. Then the solution was concentrated to give (S)-2-fluoro-N,N-dimethyl-2-(piperidin-4-yl)ethanamine hydrochloride.


Synthesis of AMI04: 4-(ethoxymethyl)-4-fluoro-piperidine



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Step 1: 1-tert-butyl 4-ethyl 4-fluoropiperidine-1,4-dicarboxylate

In a 100 mL round-bottomed flask was combined 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (1 g, 3.89 mmol) and THF (10 mL). The solution was cooled to −78° C., and sodium hexamethyldisilazide (6 mL of 1 M THF solution, 6.00 mmol) was added slowly via syringe. After 60 min, N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (2 g, 6.34 mmol) in THF (3 mL) was added. After 2 h, dichloromethane/water (1:1, 40 mL) was added. The aqueous layer was extracted with dichloromethane, and the combined organic fractions were dried over Na2SO4, filtered, and concentrated in vacuo.


Step 2: tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate

A solution of 1-tert-butyl 4-ethyl 4-fluoropiperidine-1,4-dicarboxylate (1.5 g, 5.45 mmol) in THF (5 mL) was cooled to 0° C., and then 1 M LiAlH4 in THF (3.81 mL, 3.81 mmol) was added dropwise. The reaction mixture was warmed up to RT and stirred for 2 h. Water (0.9 mL) was added to the reaction mixture dropwise followed by 2 N NaOH (0.3 mL). The mixture was stirred for another 30 minutes, and then solid removed by filtration through diatomaceous earth and washed with EtOAc. The filtrate was washed with brine, dried over Na2SO4, and concentrated from acetonitrile under vacuum several time to remove the water to afford tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate.


Step 3: tert-butyl 4-(ethoxymethyl)-4-fluoropiperidine-1-carboxylate

tert-Butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (30 g, 129 mmol) was first treated with sodium hydride (6.17 g, 154 mmol) DMF (500 mL), and then iodoethane (24.07 g, 154 mmol) was added at room temperature. The reaction mixture was stirred at 25° C. for 12 h. The mixture was washed with H2O and extracted with EtOAc, and then the combined organic phases were washed with H2O, and brine. The organic fraction was dried Na2SO4, filtered and concentrated to give tert-butyl 4-(ethoxymethyl)-4-fluoropiperidine-1-carboxylate (26.9 g, 103 mmol, 80% purity).


Step 4: 4-(ethoxymethyl)-4-fluoro-piperidine

A mixture of tert-butyl 4-(ethoxymethyl)-4-fluoropiperidine-1-carboxylate 26.9 g, 103 mmol) in ethyl acetate (200 mL) was made acidic by addition of HCl in ethyl acetate solution at 0° C. Then the mixture was allowed to warm to 15° C. and stirred at 15° C. for 3 h. The reaction mixture was concentrated under vacuum to yield 4-(ethoxymethyl)-4-fluoropiperidine as a hydrochloride salt (15.27 g, 95 mmol, 92% yield).


Synthesis of AMI05: 4-fluoro-4-(2-methoxyethoxymethy)piperidine



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Step 1: tert-butyl 4-fluoro-4-((2-methoxyethoxy)methyl)piperidine-1-carboxylate

To a mixture of tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (30 g, 129 mmol, prepared as described in the synthesis of AMI04) in DMF (400 mL) was added sodium hydride (6.43 g, 161 mmol) at 0° C. After 15 minutes, 1-bromo-2-methoxyethane (35.7 g, 257 mmol) was added at 0° C., and the mixture was stirred at 25° C. for 12 h. The mixture was quenched with 200 mL of aqueous NH4Cl at 5° C. The organic layer was separated, washed with water and brine, dried over Na2SO4, and concentrated. After column chromatography on silica gel (petroleum ether/EtOAc=10:1 to petroleum ether/EtOAc=2:1), tert-butyl 4-fluoro-4-((2-methoxyethoxy)methyl)piperidine-1-carboxylate (20.5 g, 70.4 mmol, 54.% yield) was obtained.


Step 2: 4-fluoro-4-(2-methoxyethoxymethy)piperidine

A solution of tert-butyl 4-fluoro-4-((2-methoxyethoxy)methyl)piperidine-1-carboxylate (20 g, 68.6 mmol) in 200 mL EtOAc was made acidic with HCl in EtOAc at room temperature. After TLC on silica gel (petroleum ether/EtOAc=1:1) showed that the reaction was complete, the mixture was concentrated to afford the titled compound as a hydrochloride salt (15 g, 65.9 mmol, 96% yield).


Synthesis of AMI07: 4-fluoro-4-(methoxymethyl)piperidine



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Step 1: tert-butyl 4-fluoro-4-(methoxymethyl)piperidine-1-carboxylate

To a mixture of tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (30 g, 129 mmol, prepared as described in the synthesis of AMI04) and NaH (3.09 g, 129 mmol) in THF (500 mL) was added iodomethane (41.9 g, 295 mmol) at room temperature, and then the mixture was stirred at 25° C. for 12 h, The reaction mixture was diluted with water and extracted with EtOAc. The combined organic phases were washed with water and brine. The organic fraction was dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified on a silica gel column eluted with petroleum ether/EtOAc=2:1 to give tert-butyl 4-fluoro-4-(methoxymethyl)piperidine-1-carboxylate (25 g, 101 mmol, 79% yield).


Step 2: 4-fluoro-4-(methoxymethyl)piperidine

A mixture of tert-butyl 4-fluoro-4-(methoxymethyl)piperidine-1-carboxylate (25 g, 101 mmol) in EtOAc (300 mL) was made acidic with HCl in EtOAc at 0° C., and the mixture was allowed to warm to 15° C. and stirred at 15° C. for 3 h. The reaction mixture was concentrated under vacuum to yield the titled compound as a hydrochloride salt (13 g, 70.8 mmol, 70.0% yield).


Synthesis of AMI08: 3-fluoro-3-(2-methoxyethoxymethy)piperidine



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Step 1: tert-butyl 3-fluoro-3-((2-methoxyethoxy)methyl)piperidine-1-carboxylate

To a mixture of tert-butyl 3-fluoro-3-(hydroxymethyl)piperidine-1-carboxylate (25 g, 107 mmol) in THF (300 mL) was added NaH (2.57 g, 107 mmol) at 0° C. After 15 minutes, 1-bromo-2-methoxyethane (29.8 g, 214 mmol) was added at 0° C. The mixture was stirred at 25° C. for 12 h, and then the reaction was quenched by the addition of saturated aqueous NH4Cl and extracted with EtOAc. The combined organic phases were washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuum. The residue was added to a silica gel column eluted with hexanes:ethyl acetate (2:1) to give tert-butyl 3-fluoro-3-((2-methoxyethoxy)methyl)piperidine-1-carboxylate (22 g, 76 mmol, 70.5% yield).


Step 2: 3-fluoro-3-(2-methoxyethoxymethyl)piperidine

A mixture of tert-butyl 3-fluoro-3-((2-methoxyethoxy)methyl)piperidine-1-carboxylate (25 g, 86 mmol) in EtOAc (200 mL) was made acidic with HCl in EtOAc at 0° C. The mixture was allowed to warm to 15° C. and stirred at 15° C. for 3 h. The reaction mixture was concentrated under vacuum to the titled compound as a hydrochloride salt (15 g, 65.9 mmol, 77% yield).


Synthesis of AMI09: 2-(4-hydroxy-4-piperidyl)acetonitrile hydrochloride



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Step 1: tert-butyl 4-(cyanomethyl)-4-hydroxy-piperidine-1-carboxylate

A flame-dried round bottom flask was cooled down to RT under argon. A solution of 1 M LiHMDS in THF (1.51 mL, 3.02 mmol, 2.0 equiv) was introduced into the flask and cooled down to −78° C. (acetone/dry ice bath). Dry MeCN (157 μL, 3.02 mmol, 2.0 equiv) in anhydrous THF (5 mL) was then added dropwise under argon, and the reaction mixture was stirred for 45 minutes at −78° C. At this point, a solution of 1-(tert-butoxycarbonyl)-4-piperidone (300 mg, 1.51 mmol, 1.0 equiv) in dry THF (5 mL) was added dropwise, and the reaction mixture was stirred at −78° C. for 1 h. The reaction mixture was quenched with an aqueous saturated solution of ammonium chloride and diluted with ethyl acetate. The two phases were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford tert-butyl 4-(cyanomethyl)-4-hydroxypiperidine-1-carboxylate which was used as such in the next step.


Step 2: 2-(4-hydroxy-4-piperidyl)acetonitrile hydrochloride

tert-Butyl 4-(cyanomethyl)-4-hydroxypiperidine-1-carboxylate (226 mg, 0.94 mmol, 1 equiv) was dissolved in dioxane (2.5 mL). 4 M HCl in dioxane (1.41 mL, 1.88 mmol, 6 equiv) was added, and the solution was stirred at RT for 5 days. The reaction mixture was concentrated under reduced pressure. The titled compound was used as such without any further purification.


Synthesis of AMI10: 4-methoxy-1,4′-bipiperidine



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Step 1: benzyl 4-methoxy-[1,4′-bipiperidine]-1′-carboxylate

To a solution of benzyl 4-oxopiperidine-1-carboxylate ([19099-93-5], 40 gram, 171 mmol) and 4-methoxypiperidine ([4045-24-3], 24.6 gram) in dichloromethane (800 mL) was added acetic acid (10.8 mL, 189 mmol) and sodium triacetoxyborohydride (54.5 gram, 257 mmol). The mixture was stirred at 0° C. for 120 minutes. Next, the mixture was washed with a saturated aqueous K2CO3 solution. The organic phase was separated and concentrated to give a residue that was purified by chromatography on silica gel using a gradient elution with CH2Cl2 to CH2Cl2/CH3OH (100/0 to 97/2.5) to give the titled compound.


Step 2: 4-methoxy-1,4′-bipiperidine

Benzyl 4-methoxy-[1,4′-bipiperidine]-1′-carboxylate (23 gram, 69 mmol) was dissolved in CH3OH (350 mL). The solution was flushed with N2 and 10% Pd/C (7.3 gram, 6.9 mmol) was added. After applying a balloon with H2, the mixture was stirred at ambient temperature overnight. Next, the mixture was filtered through diatomaceous earth, and the resulting filtrate was concentrated to give the titled compound.


Synthesis of AMI11: 1-piperidin-1-ium-4-ylpiperidine-4-carbonitrile chloride



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Step 1: tert-butyl 4-(4-cyano-1-piperidyl)piperidine-1-carboxylate

A suspension of 4-cyanopiperidine ([4395-98-6], 500 mg, 4.5 mmol), tert-butyl 4-oxopiperidine-1-carboxylate ([79099-07-3], 900 mg, 4.5 mmol) and AcOH (0.27 mL) in DCM (66 mL) was cooled at 0° C. Next, sodium triacetoxyborohydride ([56553-60-7], 955 mg, 4.5 mmol) was added portion wise. After overnight stirring, the reaction was diluted with 60 mL of water together with a 1 N citric acid solution to bring down the pH till 3-4. The organic layer was separated and discarded. Next, the aqueous layer was brought to neutral pH with a saturated aqueous NaHCO3 solution. After extraction with DCM, the organic phase was concentrated to give the titled compound.


Step 2: 1-piperidin-1-ium-4-ylpiperidine-4-carbonitrile chloride

tert-Butyl 4-(4-cyano-1-piperidyl)piperidine-1-carboxylate (662 mg, 2.26 mmol) was dissolved in DCM and trifluoroacetic acid ([76-05-1], 0.93 mL) was added. After overnight stirring, the mixture was concentrated to dryness. The obtained residue was suspended in 4 N HCl in dioxane. The addition of ethanol gave a suspension which was filtered to give the titled compound as a precipitate.


Synthesis of ALC02: (2R)-2-fluoro-2-tetrahydropyran-4-yl-ethanol



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Step 1: (2R)-2-fluoro-2-tetrahydropyran-4-yl-acetaldehyde

To a mixture of (R)-5-benzyl-2,2,3-trimethylimidazolidin-4-one dichloroacetic acid salt (CAS 857303-87-8, 2.71 g, 7.80 mmol, 0.2 equiv) and N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (CAS 133745-75-2, 12.30 g, 39 mmol, 1.0 equiv) in THF (200 mL) and isopropyl alcohol (25 mL) was slowly added at −20° C. a solution 2-(tetrahydro-2H-pyran-4-yl)acetaldehyde (5 g, 39 mmol, CAS 65626-23-5) in THF (25 mL). The mixture was stirred at −20° C. for 12 hours, then diluted with hexane (800 mL) cooled to −78° C. and filtered through silica, washed with hexane. The filtrate was concentrated to give (R)-2-fluoro-2-(tetrahydro-2H-pyran-4-yl)acetaldehyde.


Step 2: (2R)-2-fluoro-2-tetrahydropyran-4-yl-ethanol

To a solution of (R)-2-fluoro-2-(tetrahydro-2H-pyran-4-yl)acetaldehyde (4 g, 27.4 mmol) in dichloromethane (48 mL) and ethanol (40 mL) was added sodium borohydride (CAS 16940-66-2, 2.59 g, 68.4 mmol, 2.5 equiv). The mixture was stirred at 25° C. for 12 hours, then diluted with water and extracted with dichloromethane. The organic layer was dried, filtered, concentrated and purified by chromatography (petroleum ether, ethylate) to give (2R)-2-fluoro-2-tetrahydropyran-4-yl-ethanol.


Synthesis of ALC03: 1-[4-fluoro-4-(hydroxymethyl)-1-piperidyl]ethanone



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Step 1: tert-butyl 4-(bromomethyl)-4-fluoropiperidine-1-carboxylate

To a mixture of tert-butyl 4-methylenepiperidine-1-carboxylate (159635-49-1, 50 g, 253 mmol) and triethylamine trihydrofluoride (102 g, 634 mmol) in dichloromethane (1 L) was added 1-bromopyrrolidine-2,5-dione (67.7 g, 380 mmol) at 0° C. After 15 min, stirring was continued at 20° C. for 3 h. Then the mixture was poured into ice-water, neutralized with aqueous 28% ammonia and extracted with dichloromethane. The combined extracts were washed with ˜0.1 N HCl and with 5% aqueous sodium hydrogencarbonate solution, dried with sodium sulfate, filtered and concentrated. The residue was purified by column chromatography to provide tert-butyl 4-(bromomethyl)-4-fluoropiperidine-1-carboxylate (60.1 g, 203 mmol, 80% yield).


Step 2: tert-butyl 4-(acetoxymethyl)-4-fluoropiperidine-1-carboxylate

To a mixture of tert-butyl 4-(bromomethyl)-4-fluoropiperidine-1-carboxylate (50 g, 169 mmol) and potassium iodide (7.01 g, 42.2 mmol) in dimethyl formamide (1.5 L) was added potassium acetate (249 g, 2532 mmol) at room temperature. The mixture was stirred at 120-140° C. for 12 h, then cooled, diluted with water, and extracted with ethyl acetate. The combined organic phases were washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by chromatography on a silica gel column eluted with hexanes:ethyl acetate to give tert-butyl 4-(acetoxymethyl)-4-fluoropiperidine-1-carboxylate (42 g, 153 mmol, 90% yield).


Step 3: (4-fluoropiperidin-4-yl)methyl acetate hydrochloride

To a mixture of tert-butyl 4-(acetoxymethyl)-4-fluoropiperidine-1-carboxylate (50 g, 182 mmol) in ethyl acetate (400 mL) was added a solution of HCl (1 L) at 0° C. The mixture was allowed to warm to 15° C. and stirred at 15° C. overnight. The reaction mixture was concentrated under vacuum, and the residue washed with dichloromethane. Then the precipitate was collected by filtration to obtain (4-fluoropiperidin-4-yl)methyl acetate hydrochloride (33 g, 156 mmol, 86% yield).


Step 4: (1-acetyl-4-fluoropiperidin-4-yl)methyl acetate

To a solution of (4-fluoropiperidin-4-yl)methyl acetate hydrochloride (30 g, 142 mmol) and triethylamine (59.3 mL, 425 mmol) in dichloromethane (300 mL) was added acetyl chloride (16.69 g, 213 mmol) at 0° C. The mixture was stirred overnight at 20° C., then diluted with dichloromethane and washed with water. The dichloromethane layer was concentrated to give crude (1-acetyl-4-fluoropiperidin-4-yl)methyl acetate (21 g, 97 mmol, 68.2% yield).


Step 5: 1-[4-fluoro-4-(hydroxymethyl)-1-piperidyl]ethanone

(1-Acetyl-4-fluoropiperidin-4-yl)methyl acetate (30.8 g, 142 mmol) was dissolved in 3:1 THF:water (400 mL) at 0° C., and then lithium hydroxide (6.80 g, 284 mmol) was added in one portion. The reaction mixture was stirred for 1 hour at 0° C. The mixture was poured into ethyl acetate and water, shaken, and the layers separated. The aqueous layer was extracted with ethyl acetate. The ethyl acetate extracts were combined, dried over Na2SO4, and concentrated under reduced pressure. The residue was titrated with CH2Cl2 and cyclohexane to afford 1-[4-fluoro-4-(hydroxymethyl)-1-piperidyl]ethanone (19 g, 108 mmol, 76% yield).


Alternatively, 1-[4-fluoro-4-(hydroxymethyl)-1-piperidyl]ethanone is available by treatment of commercially available (4-fluoropiperidin-4-yl)methanol (CAS: 949100-11-2) with acetic anhydride.


Synthesis of ALC04: 2-[isopropyl(oxetan-3-yl)amino]ethanol



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2-[Isopropyl(oxetan-3-yl)amino]ethanol is available by the reaction of (isopropylamino)ethanol (CAS: 109-56-8) with 1 equivalent of 3-oxetanone (CAS: 6704-31-0) in a solvent such as isopropanol or THF with a reducing agent such as sodium borohydride or sodium triacetoxyborohydride, followed by distillation.


Synthesis of ALC05: 2-(oxetan-3-yloxy)ethanol



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Step 1: 3-(2-(benzyloxy)ethoxy)oxetane

1.0 M Lithium bis(trimethylsilyl)amide in THF (31.1 mL, 31.1 mmol, 1.2 equiv) was added dropwise at RT to a solution of oxetan-3-ol (1.92 g, 25.9 mmol) and ((2-bromoethoxy)methyl)benzene (6.13 g, 28.5 mmol, 1.1 equiv) in dioxane (15 mL). The mixture was stirred at ambient temperature for 2 hours. DMF (20 mL) was added along with sodium iodide, and the reaction mixture was stirred at ambient temperature overnight, then stirred at 70° C. for 20 hours. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and aqueous citric acid. The organic layer was washed twice with brine, then dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (dichloromethane and ethyl acetate) to give 3-(2-(benzyloxy)ethoxy)oxetane.


Step 2: 2-(oxetan-3-yloxy)ethanol

To a solution of 3-(2-(benzyloxy)ethoxy)oxetane (1.40 g, 6.72 mmol) in THF (28 mL) was added 20% palladium hydroxide on carbon (0.178 g, 0.645 mmol) in a 50 mL pressure bottle, and the mixture was stirred for 4 h under a hydrogen atmosphere. The reaction mixture was filtered free of catalyst and solids, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with a mixture of ethyl acetate and dichloromethane to give the titled compound.


Synthesis of Intermediate BF01: potassium trifluorido{[4-(methoxymethyl)piperidin-1-yl]methyl}borate



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4-(Methoxymethyl)piperidine hydrochloride ([916317-00-5], 1.0 g, 6.03 mmol,), potassium bromomethyl trifluoroborate (1.21 g, 6.03 mmol), KHCO3 (1.2 g, 12.1 mmol) and KI (100 mg, 0.6 mmol) were stirred under N2 in dry THF (8 mL) at 80° C. for 4 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was suspended in dry acetone and filtered. The filtrate was treated with diethyl ether, and the resulting precipitate was collected by filtration and dried to afford the titled compound, which was used as such in the next step.









TABLE IX







List of BF3 salts













Int.
Structure
Name
SM
method
MW
Mes





BF01


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potassium trifluorido{[4- (methoxymeth- yl)piperidin-1- yl]methyl}borate
916317- 00-5 and 888711- 44-2
Specific example
249

















TABLE X







List of amines













Int.
Structure
Name
SM
method
MW
Mes





AMI01


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4- (methoxymeth- yl)piperidin-4- ol hydrochloride
147804- 30-6
Specific example
181






AMI02


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4-[(1,1-dioxo- 1,4-thiazinan- 4- yl)methyl] piperidin-4-ol hydrochloride
147804- 30-6
Specific example
284






AMI03


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(2S)-2-fluoro- N,N-dimethyl- 2-(4- piperidyl)ethan- amine hydrochloride
142374- 19-4
Specific example
210






AMI04


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4- (ethoxymethyl)- 4-fluoro- piperidine
142851- 03-4
Specific example
161






AMI05


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4-fluoro-4-(2- methoxyethoxy- methyl)piperidine
614730- 97-1
Specific example
191






AMI06 955082- 95-8 or 955028- 84-9 (HCl salt)


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(3R,4R)-3- fluoropiperidin- 4-ol


119






AMI07


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4-fluoro-4- (methoxymeth- yl)piperidine
614730- 97-1
Specific example
147






AMI08


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3-fluoro-3-(2- methoxyethoxy- methyl)piperidine
1209781- 11- 2
Specific example
191






AMI09


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2-(4-hydroxy- 4- piperidyl)aceto- nitrile hydrochloride
79099- 07-3
Specific example
140






AMI10


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4-methoxy- 1,4′- bipiperidine
19099- 93-5 and 4045- 24-3
Specific example
198






AMI11


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1-piperidin- 1-ium-4- ylpiperidine- 4- carbonitrile chloride
79099- 07-3 and 4395- 98-6
Specific example
249
















TABLE XI







List of alcohols













Int.
Structure
Name
SM
method
MW
Mes





ALC01


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(2S)-2-fluoro- 2- tetrahydropyran- 4-yl-ethanol

Analogous to ALC02
148






ALC02


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(2R)-2-fluoro- 2- tetrahydropyran- 4-yl-ethanol
65626- 23-5
Specific example
148






ALC03


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1-[4-fluoro-4- (hydroxymethyl)- 1- piperidyl]ethan- one
159635- 49-1
Specific example
175






ALC04


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2- [isopropyl(oxetan- 3- yl)amino]ethan- ol

Specific example
159






ALC05


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2-(oxetan-3- yloxy)ethanol

Specific example
118






ALC06


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(1- cyclobutyl- 4- piperidyl) methanol
6457- 49-4 and 1191- 95-3
I30
169
170





ALC07


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(1- cyclohexyl- 4- piperidyl) methanol
6457- 49-4 and 108- 94-1
I30
197
198





ALC08


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(1- tetrahydro- pyran-4-yl-4- piperidyl) methanol
6457- 49-4 and 29943- 42-8
I30
199
200





ALC09


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(1- cyclopropyl- 4- piperidyl) methanol
6457- 49-4 and 27374- 25-0
I26
155
156









Synthesis of BOR1: 1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]piperidine-4-carbonitrile



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Step 1: 1-(5-bromo-2-pyridyl)piperidine-4-carbonitrile

Potassium carbonate (35.3 g, 256 mmol) was added at RT to a solution of 5-bromo-2-fluoropyridine (CAS: 766-11-0, 15 g, 85 mmol) and 4-cyanopiperidine (CAS: 4395-98-6, 14.1 g, 128 mmol) in DMSO (100 mL). The reaction mixture was heated at 100° C. for 6 hours and cooled down to RT. Water (200 mL) was added, and the precipitate was collected by filtration, washed with water and dried at 40° C. under reduced pressure.


Step 2: 1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]piperidine-4-carbonitrile

Potassium acetate (13.6 g, 138 mmol) in a round bottom flask was dried at 100° C. under a flow of nitrogen. The solid was left under nitrogen cooling down to RT. Anhydrous dioxane (250 mL) was added, and nitrogen was bubbled through the suspension for 30 minutes. Palladium(II) acetate (760 mg, 3.4 mmol), Sphos (CAS: 657408-07-6, 3.5 g, 8.5 mmol), bis(pinacolato)diboron (CAS: 73183-34-3, 25.8 g, 101.2 mmol), and the compound from Step 1 (15 g, 56.4 mmol) were successively added, and nitrogen was bubbled for another 1 hour at RT. The reaction mixture was heated at 60° C. for 28 hours, and then cooled down to RT. The precipitate was filtered and washed with ethyl acetate (250 mL). The organic phase was washed twice with water (2×250 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was stirred in cyclohexane, and the precipitate was filtered to yield the titled compound.


Method K: Pinacol Ester Synthesis



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Step 1: SNAr

A solution of halogenated derivative (1 equiv), amine (1.1 equiv) and DIPEA (from 1.1 to 2.1 equiv) in acetonitrile is heated at 80° C. for 4 hours. Amine (from 0.5 to 1.1 equiv) and DIPEA (from 1 to 2.1 equiv) can be added in one or two times over a period of 18 to 22 hours. The reaction mixture is cooled down to RT, diluted with DCM and washed with water. The organic phase is separated using a phase separator and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with n-heptane/ethyl acetate to give the substituted product.


Step 2: Borylation

Potassium acetate (1.5 equiv) in a sealed tube is dried at 80° C. under a flow of argon. The solid is left cooling down to RT. Dioxane is added, and nitrogen is bubbled through the suspension for 15 minutes. Palladium(II) acetate (0.05 equiv), Sphos (CAS: 657408-07-6, 0.13 equiv), bis(pinacolato)diboron (CAS: 73183-34-3, 1.2 equiv), and the compound from previous step (1 equiv) are successively added, and nitrogen is bubbled for another 1 hour at RT. The reaction mixture is heated at 100° C. for 20 hours and then cooled down to RT. The precipitate is filtered and washed with ethyl acetate. The filtrate is washed twice with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue is either used as such or stirred in cyclohexane and the solid collected by filtration to yield the pinacol ester.


Illustrative Synthesis of BOR2: 1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]piperidine-3-carbonitrile



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Step 1: 1-(5-bromopyrimidin-2-yl)piperidine-3-carbonitrile

A solution of 5-bromo-2-chloropyrimidine (CAS: 32779-36-5, 300 mg, 1.55 equiv), 3-cyanopiperidine hydrochloride (CAS:828300-57-8, 250 mg, 1.7 mmol) and DIPEA (567 μL, 3.3 mmol) in acetonitrile (3 mL) was heated at 80° C. for 4 hours. 3-Cyanopiperidine hydrochloride (CAS:828300-57-8, 125 mg, 0.85 mmol) and DIPEA (567 μL, 3.3 mmol) were again added, and the stirring at 80° C. was continued for 20 hours. The reaction mixture was diluted with DCM and washed with water. The organic phase was separated using a phase separator and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with n-heptane/ethyl acetate to give the titled compound.


Step 2: 1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]piperidine-3-carbonitrile

Potassium acetate (449 mg, 4.6 mmol) in a sealed tube was dried at 80° C. under a flow of argon. The solid was left cooling down to RT. Dioxane (13 mL) was added, and nitrogen was bubbled through the suspension for 15 minutes. Palladium(II) acetate (34 mg, 0.15 mmol), Sphos (CAS: 657408-07-6, 156 mg, 0.4 mmol), bis(pinacolato)diboron (CAS: 73183-34-3, 928 mg, 3.6 mmol), and the compound from previous step (1.13 g, 3.05 mmol) were successively added, and nitrogen was bubbled for another 1 hour at RT. The reaction mixture was heated at 100° C. for 20 hours and then cooled down to RT. The precipitate was collected by filtration and washed with ethyl acetate. The organic phase was washed twice with water, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the titled compound which was used as such without any further purification.









TABLE XII







Pinacol ester coupling reagents













Int.
Structure
Name
SM
method
MW
Mes





BOR1


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1-[5-(4,4,5,5- tetramethyl- 1,3,2- dioxaborolan- 2-yl)-2- pyridyl]piperidine- 4- carbonitrile
766- 11-0, 4395- 98-6
Specific example
313
314





BOR2


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1-[5-(4,4,5,5- tetramethyl- 1,3,2- dioxaborolan- 2-yl)pyrimidin- 2- yl]piperidine- 3-carbonitrile
32779- 36-5, 828300- 57-8
K
314
315





BOR3


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tert-butyl 4- [methyl-[5- (4,4,5,5- tetramethyl- 1,3,2- dioxaborolan- 2-yl)pyrimidin- 2- yl]amino]piper- idine-1- carboxylate
32779- 36-5, 147539- 41-1
K
418
419









Method I1-I35: Synthesis of Esters
Method I1: Cyclization of Alkylidene Pyruvates and Aminopyrazoles



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  • A is either N or CH

  • A′ is either Re or L1-G3C as described in the Summary



The alkylidene pyruvate (1 to 1.5 equiv) and the aminopyrazole (1 to 1.5 equiv) in acetic acid or DMF are stirred under air at temperatures ranging from RT to reflux for 1 h to several days. Alternatively, the reaction mixture is heated under microwave irradiation at 150° C. for 20 minutes to 2 h followed either by stirring under air in an opened flask at temperatures ranging from RT to 90° C. for 1 h to several days or by removal of the solvent in vacuo, dilution of the residue in ethanol and stirring at reflux for 1 h to several days. Then volatiles are removed in vacuo to afford the titled compound which is used as such or alternatively worked up by dilution with an organic solvent, washed successively with a basic aqueous solution and brine, dried over sodium sulfate, filtered and concentrated in vacuo and used as such or further purified either by precipitation, by preparative HPLC or by flash chromatography on silica gel.


Alternatively, the alkylidene pyruvate (1 equiv) and the aminopyrazole (1 equiv) in N-methylpyrrolidone can be heated at 80 to 100° C. over 8 to 24 hours. Next, the reaction mixture is cooled down to room temperature and a base such as Cs2CO3 (2-6 equiv) is added. The resulting mixture is stirred open to the air until full oxidation is observed.


Illustrative Synthesis of E018: 4-(4-Cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl)-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid ethyl ester



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The alkylidene pyruvate ALP09 (47.1 g, 150.5 mmol) and the aminopyrazole AMP29 (30 g, 140.7 mmol) were dissolved in acetic acid (240 mL) in an opened round bottom flask equipped with a condenser. The solution was heated at 80° C. for 40 hours and then left cooling down to RT. The mixture was concentrated under reduced pressure, and the crude residue was diluted with DCM (400 mL). The organic phase was washed successively with a saturated aqueous solution of Na2CO3 and a saturated aqueous solution of NaCl, dried over sodium sulfate, filtered and concentrated in vacuo. The crude sample was purified by flash column chromatography eluting with dichloromethane/ethyl acetate. The solid was stirred for 10 minutes in methanol, filtered and dried at 40° C. under reduced pressure to give the titled compound.


Illustrative Synthesis of E425: ethyl 1-cyclohexyl-4-(4-formylphenyl)-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate



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A solution of ALP36 (116 mg, 0.5 mmol) and AMP95 (112 mg, 0.5 mmol) in N-methylpyrrolidine (2 mL) was heated at 100° C. for 20 hours in a sealed tube. The volatiles were removed in vacuo, and the residue was purified by flash chromatography on silica gel eluted with ethyl acetate/n-heptane (0/1 to 1/0) to give the titled compound.


Illustrative Synthesis of E505: methyl 4-(4-bromophenyl)-1-cyclohexyl-3-hydroxy-1H-pyrazolo[3,4-b]pyridine-6-carboxylate



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5-Amino-1-cyclohexyl-1H-pyrazol-3-ol ([436088-86-7], 5.54 g, 30.5 mmol,) and (E)-methyl-4-(4-bromophenyl)-2-oxobut-3-enoate ([608128-34-3], 8.22 g, 30.5 mmol,) in NMP (60 mL,) were heated overnight at 90° C. Next, the reaction mixture was cooled down to room temperature and Cs2CO3 (30 g, 91.6 mmol) was added. The resulting mixture was stirred open to the air until full oxidation to the titled compound was observed. The obtained solution was used as such for alkylation.


Method I2: Suzuki Coupling



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Method I2A

Argon is bubbled through a suspension of halogenated derivative (1 equiv), boronic acid or ester (1.3 equiv), palladium(II) acetate (0.05 equiv), Sphos (CAS: 657408-07-6, 0.12 equiv) and potassium phosphate tribasic (CAS: 7778-53-2, 3 equiv) in dioxane/water at room temperature for 15 minutes. The reaction mixture is heated at 100° C. for 30 minutes to 1 h and then cooled down to RT. The mixture is filtered, and the filtrate is either concentrated in vacuo or diluted with ethyl acetate and washed with water and brine. The organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure. The coupled compound is obtained after purification by flash column chromatography.


Illustrative Synthesis of E252: ethyl 4-[6-(4-cyano-1-piperidyl)-3-pyridyl]-3-isopropyl-1-(m-tolyl)pyrazolo[3,4-b]pyridine-6-carboxylate



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Argon was bubbled into a suspension of HP01 (30 mg, 0.1 mmol), BOR1 (39 mg, 0.12 mmol), palladium(II) acetate (1.1 mg, 0.005 mmol), Sphos (CAS: 657408-07-6, 5 mg, 0.01 mmol) and potassium phosphate tribasic (CAS: 7778-53-2, 60 mg, 0.29 mmol) in dioxane/water (0.7 mL/0.2 mL) at room temperature for 15 minutes. The reaction mixture was heated at 100° C. for 1 h and then cooled down to RT. The mixture was filtered; the filtrate was diluted with ethyl acetate and washed with water and brine. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The titled compound was obtained after purification by flash column chromatography eluting with n-heptane/ethyl acetate.


Method I2B

Nitrogen is bubbled into a suspension of halogenated derivative (1 equiv), boronic acid or ester (from 1.3 to 1.5 equiv), Pd(dppf)Cl2.DCM (CAS: 95464-05-4, 0.1 equiv), and potassium carbonate (1.5 equiv) in dioxane/water at room temperature for 15 minutes. The reaction mixture is heated at a temperature ranging from 80° C. to 110° C. for 2 to 20 hours, and cooled down to RT. The mixture is filtered, and the filtrate is either concentrated in vacuo and purified by flash column chromatography or worked up by diluting with ethyl acetate and washing with water and brine. The organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure. The coupled compound is obtained after purification by flash column chromatography or used as such in the next step.


Illustrative Synthesis of E308: ethyl 1-cyclohexyl-4-(1,3-dimethylpyrazol-4-yl)-3-isopropyl-pyrazolo[3,4-b]pyridine-6-carboxylate



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Nitrogen was bubbled into a suspension of HP04 (50 mg, 0.14 mmol), 1,3-dimethylpyrazole-4-boronic pinacol ester (CAS: 1046832-21-6, 41 mg, 0.19 mmol), Pd(dppf)Cl2.DCM (CAS: 95464-05-4, 12 mg, 0.014 mmol), and potassium carbonate (30 mg, 0.21 mmol) in dioxane/water (1 mL/0.3 mL) at room temperature for 15 minutes. The reaction mixture was heated at 110° C. for 2 hours, and cooled down to RT. The mixture was filtered and concentrated in vacuo. The titled compound was obtained after purification by flash column chromatography eluting with n-heptane/ethyl acetate.


Method I3: Nucleophilic Substitutions of Amines



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A mixture of the chloride or triflate pyrazolopyridine intermediate (1.0 equiv), the amine as free base or hydrochloride salt (from 1 to 10 equiv) and DIPEA (from 1 to 15 equiv) in anhydrous acetonitrile and DMSO in a sealed tube or a round bottom flask is heated at a temperature ranging from 50 to 130° C. for 1 h to several days (up to 8 days). The reaction mixture is cooled to RT, and volatiles are removed in vacuo. The resulting residue is either purified by precipitation or by flash chromatography on silica gel to afford the titled compound or alternatively partitioned between either dichloromethane or ethyl acetate and water. The two phases are then separated, and the aqueous phase is extracted with either ethyl acetate or dichloromethane. The combined organic phases are washed with brine, dried over MgSO4, filtered and concentrated in vacuo and the resulting crude mixture is either used as such or purified by flash chromatography on silica gel to afford the titled compound.


Illustrative Synthesis of E092: methyl 1-(4-fluorophenyl)-3-isopropyl-4-[4-(methoxymethyl)-1-piperidyl]pyrazolo[3,4-b]pyridine-6-carboxylate



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A mixture of HP05 (6.71 g, 19.29 mmol, 1.0 equiv), 4-(methoxymethyl)piperidine hydrochloride (CAS 916317-00-5, 6.39 g, 38.58 mmol, 2 equiv) and DIPEA (10.1 mL, 57.88 mmol, 3 equiv) in anhydrous DMSO (65 mL) was heated at 100° C. for 20 h. The reaction mixture was cooled to RT, partitioned between ethyl acetate (300 mL) and a mixture of water and a saturated solution of NaCl 1:1 (300 mL). The two phases were separated, and the aqueous phase was extracted with ethyl acetate (150 mL). The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude mixture was purified by flash chromatography on silica gel eluting with n-heptane/ethyl acetate to afford the titled compound.


Method I4: Chan-Lam Coupling



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To a solution of ethyl 1H-pyrazolo[3,4-b]pyridine-6-carboxylate intermediate (1.0 equiv) in dichloromethane at RT is added the aryl boronic acid (2.0 to 3.0 equiv), copper(II) acetate (CAS 142-71-2, 1.5 equiv) and pyridine (4.0 equiv). The reaction mixture is stirred at room temperature under air for 1 h to 48 h. Then the reaction mixture is filtered on a pad of diatomaceous earth. Solids are washed with dichloromethane, and the filtrate is concentrated in vacuo. The resulting residue is purified by flash chromatography on silica gel to afford the titled compound.


Illustrative Synthesis of E111: ethyl 1-(2-fluoro-4-pyridyl)-3-isopropyl-4-(4-methoxy-1-piperidyl)pyrazolo[3,4-b]pyridine-6-carboxylate



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To a solution of ethyl 3-isopropyl-4-(4-methoxy-1-piperidyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylate (E109, 70 mg, 0.20 mmol, 1.0 equiv) in dichloromethane (2 mL) at RT was added (2-fluoropyridin-4-yl)boronic acid (CAS: 401815-98-3, 56 mg, 0.40 mmol, 2.0 equiv), copper(II) acetate (CAS 142-71-2, 54 mg, 0.30 mmol, 1.5 equiv) and pyridine (64 μL, 0.80 mmol, 4.0 equiv). The reaction mixture was stirred at room temperature under air overnight. The reaction mixture was filtered on a pad of diatomaceous earth. Solids were washed with dichloromethane, and the filtrate was concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (eluent system: heptane/ethyl acetate: 100/0 to 70/30) to give the titled compound.


Method I5: Nucleophilic Substitution



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  • A is CH or N

  • LG1 and LG2 are independently F, Cl or Br



To a solution of ethyl 1H-pyrazolo[3,4-b]pyridine-6-carboxylate intermediate (1.0 equiv) in anhydrous DMF or THF under nitrogen atmosphere at 0° C. is added sodium hydride (60% in mineral oil, from 1.2 equiv to 1.5 equiv), and the mixture is stirred 5 minutes at 0° C. Then an aromatic halide (2.0 equiv) is added, and the reaction mixture is warmed up to RT and stirred overnight. The reaction mixture is partitioned between water and ethyl acetate and acidified to pH 5 with AcOH. The two phases are separated. The organic phase is washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the titled compound which is used as such or purified by flash chromatography on silica gel.


Illustrative Synthesis of E133: ethyl 1-(6-bromo-2-pyridyl)-3-isopropyl-4-(4-methoxy-1-piperidyl)pyrazolo[3,4-b]pyridine-6-carboxylate



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To a solution of ethyl 3-isopropyl-4-(4-methoxy-1-piperidyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylate (E109, 245 mg, 0.71 mmol, 1.0 equiv) in anhydrous DMF (3 mL) under nitrogen atmosphere at 0° C. was added sodium hydride (60% in mineral oil, 34 mg, 0.85 mmol, 1.2 equiv), and the mixture was stirred 5 minutes at 0° C. Then 2-bromo-6-fluoropyridine (CAS 144100-07-2, 250 mg, 1.42 mmol, 2.0 equiv) was added, and the reaction mixture was warmed up to RT and stirred overnight. The reaction mixture was partitioned between water and ethyl acetate and acidified to pH 5 with AcOH. The two phases were separated. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the titled compound which was used as such.


Method I6: Alkylation



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To a suspension of ethyl 3-isopropyl-4-[4-(methoxymethyl)-1-piperidyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate E148 (1.0 equiv) in anhydrous DMF under nitrogen atmosphere is added potassium carbonate (1.2 equiv), then alkyl bromide (1.1 equiv). The reaction mixture is stirred at room temperature overnight. Then cesium carbonate (1.2 equiv) and potassium iodide (0.1 equiv) are added, and the reaction mixture is stirred at room temperature for 24 h. The mixture is partitioned between water and ethyl acetate. The aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude mixture is purified by flash chromatography on silica gel to afford the titled compound.


Illustrative Synthesis of E154: ethyl 1-(cyclobutylmethyl)-3-isopropyl-4-[4-(methoxymethyl)-1-piperidyl]pyrazolo[3,4-b]pyridine-6-carboxylate



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To a suspension of ethyl 3-isopropyl-4-[4-(methoxymethyl)-1-piperidyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate E148 (100 mg, 0.28 mmol, 1.0 equiv) in anhydrous DMF (2 mL) under nitrogen atmosphere was added potassium carbonate (47 mg, 0.34 mmol, 1.2 equiv) and then (bromomethyl)cyclobutane (CAS: 17247-58-4, 35 μL, 0.31 mmol, 1.1 equiv). The reaction mixture was stirred at room temperature overnight. Then cesium carbonate (111 mg, 0.34 mmol, 1.2 equiv) and potassium iodide (5 mg, 0.028 mmol, 0.1 equiv) were added, and the reaction mixture was stirred at room temperature for 24 h. The mixture was partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude mixture was purified by flash chromatography on silica gel (eluent system: heptane/ethyl acetate gradient from 100/0 to 75/25) to afford the titled compound.


Method I7: Buchwald Coupling
Illustrative Synthesis of E157: ethyl 3-isopropyl-4-[4-(methoxymethyl)-1-piperidyl]-1-(1-methyl-6-oxo-pyridazin-3-yl)pyrazolo[3,4-b]pyridine-6-carboxylate



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A suspension of ethyl 3-isopropyl-4-[4-(methoxymethyl)-1-piperidyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate E148 (100 mg, 0.28 mmol, 1.0 equiv) in anhydrous toluene (1 mL) was degassed with nitrogen (bubbling) at room temperature for 5 minutes. Then to this suspension was added 6-bromo-2-methyl-pyridazin-3-one (CAS 1123169-25-4, 58 mg, 0.31 mmol, 1.1 equiv), cesium carbonate (365 mg, 1.12 mmol, 4.0 equiv), Xantphos (CAS 161265-03-8, 16 mg, 0.028 mmol, 0.1 equiv), and palladium(II) acetate (CAS 3375-31-3, 3 mg, 0.014 mmol, 0.05 equiv). The mixture was purged again with nitrogen at RT for 10 minutes, and then the mixture was stirred at reflux overnight. The reaction mixture was cooled down and concentrated in vacuo. The residue was partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude mixture was purified by flash chromatography on silica gel (eluent system: heptane/ethyl acetate gradient from 100/0 to 0/100) to afford the titled compound.


Method I8: Buchwald Coupling



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A suspension of aryl bromide intermediate (1.0 equiv), XPhos Pd G1 (CAS 1028206-56-5, 0.1 equiv) and sodium tert-butoxide (CAS: 865-48-5, 1.3 equiv) in anhydrous toluene is degassed with argon (bubbling) at room temperature for 15 minutes. Amine (1.3 equiv) is added, and the mixture is purged with argon at RT for 2 minutes. The reaction mixture is stirred at 100° C. for 30 minutes to 24 h. The reaction mixture is concentrated in vacuo, and the residue is partitioned between water and dichloromethane and filtered on a pad of Celpure P65®. Solids were washed with dichloromethane and water, and the two phases of the filtrate are separated. The aqueous layer is extracted with dichloromethane. The combined organic phases are washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The titled compound is obtained from the crude mixture either by precipitation or by purification by flash chromatography on silica gel.


Illustrative Synthesis of E002: ethyl 1-[3-(azetidin-1-yl)phenyl]-3-isopropyl-4-(4-morpholinophenyl)pyrazolo[3,4-b]pyridine-6-carboxylate



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A suspension of ethyl 1-(3-bromophenyl)-3-isopropyl-4-(4-morpholinophenyl)pyrazolo[3,4-b]pyridine-6-carboxylate E001 (60 mg, 0.115 mmol, 1.0 equiv), XPhos Pd G1 (CAS 1028206-56-5, 9 mg, 0.011 mmol, 0.1 equiv), and sodium tert-butoxide (CAS: 865-48-5, 14 mg, 0.149 mmol, 1.3 equiv) in anhydrous toluene (1.2 mL) was degassed with argon (bubbling) at room temperature for 15 minutes. Azetidine (13 μL, 0.149 mmol, 1.3 equiv) was added, and the mixture was purged with argon at RT for 2 minutes. The reaction mixture was stirred at 100° C. for 1 hour. The reaction mixture was concentrated in vacuo; the residue was partitioned between water and dichloromethane, and then was filtered on a pad of Celpure P65®. Solids were washed with dichloromethane and water, and the two phases of the filtrate were separated. The aqueous layer was extracted with dichloromethane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent system: dichloromethane/methanol gradient from 100/0 to 90/10). The obtained solid was suspended in ethanol, filtered, washed with diethyl ether and dried in vacuo to afford the titled compound.


Method I9: Esterification



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To the acid (1 equiv) in either ethanol or methanol at RT is added concentrated sulfuric acid (catalytic amount). The reaction mixture is refluxed for 1 h to several days (up to 8 days). Then the reaction mixture is cooled down to RT. The resulting suspension is filtered; the solid is washed with either ethanol or methanol and then dried in vacuo. The crude solid is purified by flash chromatography on silica gel (eluent system: heptane/ethyl acetate) to give the titled compound.


Alternatively, if no suspension is formed when cooling down the reaction mixture, the solvent is removed in vacuo. The resulting residue is taken up in dichloromethane and basified with a saturated solution of NaHCO3. The two phases are separated, and the aqueous phase is extracted with dichloromethane. The combined organic phases are washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the titled compound which is used as such or further purified by flash chromatography on silica gel.


Illustrative Synthesis of E001 ethyl 1-(3-bromophenyl)-3-isopropyl-4-(4-morpholinophenyl)pyrazolo[3,4-b]pyridine-6-carboxylate



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Concentrated sulfuric acid (0.23 mL) was added to a suspension of A117 (2.56 g, 4.9 mmol) in absolute ethanol (64 mL) at RT. The reaction mixture was refluxed for 5 hours. The reaction mixture was cooled down to RT, and the obtained suspension was filtered. The cake was washed with ethanol and dried in vacuo. The solid residue was purified by chromatography on silica gel (heptane/ethyl acetate 100/0 to 70/30) to give the titled compound.


Method I10: Buchwald Coupling on the Aryl Linker



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To the amine (from 1.3 to 2 equiv), E010 (1 equiv) and sodium tert-butoxide (CAS: 865-48-5, from 1.3 to 3 equiv) is added degassed anhydrous toluene. The reaction mixture is purged with argon, XPhos Pd G1 (CAS 1028206-56-5, 0.1 equiv) is added, and the mixture is purged again with argon. The reaction mixture is stirred at a temperature ranging from 90° C. to 110° C. for 1 h to 24 h. The reaction mixture is cooled down and filtered on a pad of diatomaceous earth. Solids are washed with organic solvents, and the combined filtrates are concentrated in vacuo. The resulting residue is purified by flash chromatography on silica gel to afford the titled compound.


Illustrative Synthesis of E011: ethyl 4-[4-[3-(dimethylamino)azetidin-1-yl]phenyl]-3-methyl-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylate



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To N,N-imethylazetidin-3-amine hydrochloride (CAS: 935670-07-8, 40 mg, 0.194 mmol, 1.3 equiv), E010 (100 mg, 0.23 mmol, 1 equiv) and sodium tert-butoxide (CAS: 865-48-5, 57 mg, 0.598 mmol, 2.6 equiv) was added degassed toluene (2 mL). The reaction mixture was purged with argon, XPhos Pd G1 (CAS 1028206-56-5, 17 mg, 0.023 mmol, 0.1 equiv) was added and the mixture was purged again with argon. The reaction mixture was stirred at 100° C. for 1 hour. The reaction mixture was cooled down and filtered on a pad of diatomaceous earth. Solids were washed with toluene, ethyl acetate and dichloromethane, and the combined filtrates were concentrated in vacuo. The residue was purified by flash chromatography on silica gel (dichloromethane/methanol 98/2) to afford the titled compound.


Method I11A: Sulfonyl Derivatives



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A solution of amine (1 equiv) and triethyl amine (3.3 equiv) in DCM is cooled in an ice bath and a sulfonyl chloride derivative (1.1 equiv) is added. The reaction mixture is stirred at a temperature ranging from 0° C. to RT until complete conversion. The organic phase is diluted with DCM, washed with a saturated aqueous solution of NaHCO3 and a saturated aqueous solution of NaCl. The organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude sample can be purified by flash column chromatography to give the titled compound or used as such in the next step.


Illustrative Synthesis of E201: ethyl 3-methyl-4-[4-(4-methylsulfonylpiperazin-1-yl)phenyl]-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylate



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A solution of E324 (44 mg, 0.1 mmol) and triethyl amine (46 μL, 0.33 mmol) in DCM (0.5 mL) was cooled in an ice bath, and methanesulfonyl chloride (9 μL, 0.11 mmol) was added. The reaction mixture was stirred for 20 minutes in an ice bath and then left warming to RT for 2 hours. The organic phase was diluted with DCM (10 mL) and washed successively with a saturated aqueous solution of NaHCO3 and a saturated aqueous solution of NaCl. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude sample was purified by flash column chromatography eluting with a gradient of DCM and methanol to give the titled.


Method H1B: Acylation



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Acetyl chloride (2 equiv) is added at RT to a solution of amine (1 equiv) and triethylamine (2 equiv) in DCM. The solution is stirred until conversion was obtained. The organic phase is diluted with DCM, washed with a saturated aqueous solution of NaHCO3 and a saturated aqueous solution of NaCl. The organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude sample can be purified by flash column chromatography to give the titled compound or used as such in the next step.


Illustrative Synthesis of E204: ethyl 1-(1-acetyl-4-piperidyl)-3-isopropyl-4-(4-morpholinophenyl)pyrazolo[3,4-b]pyridine-6-carboxylate



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Acetyl chloride (21 μL, 0.3 mmol) was added at RT to a solution of E325 (70 mg, 0.15 mmol) and triethyl amine (21 μL, 0.3 mmol) in DCM (1.5 mL). The solution was stirred for 3 hours. The solution was diluted with DCM, washed with a saturated aqueous solution of NaHCO3 and a saturated aqueous solution of NaCl. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude sample was purified by flash column chromatography eluting with a gradient of DCM and methanol to give the titled compound.


Synthesis of E176: methyl 4-[(1-acetyl-4-piperidyl)methoxy]-1-(4-fluorophenyl)-3-isopropyl-pyrazolo[3,4-b]pyridine-6-carboxylate



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To E177 (0.1 g, 0.23 mmol, 1 equiv) in anhydrous dichloromethane (2 mL) at RT was added acetyl chloride (CAS 75-36-5, 19 μL, 0.28 mmol, 1.2 equiv) followed by triethylamine (47 μL, 0.345 mmol, 1.5 equiv). The reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with dichloromethane and water. The two phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (eluent system: heptane/ethyl acetate gradient from 100/0 to 0/100) to afford the titled compound.


Synthesis of E178: methyl 1-(4-fluorophenyl)-3-isopropyl-4-[(1-methoxycarbonyl-4-piperidyl)methoxy]pyrazolo[3,4-b]pyridine-6-carboxylate



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To E177 (0.1 g, 0.23 mmol, 1 equiv) in anhydrous dichloromethane (2 mL) at RT was added methyl chloroformate (CAS: 79-22-1, 19 μL, 0.28 mmol, 1.2 equiv) followed by triethylamine (47 μL, 0.345 mmol, 1.5 equiv). The reaction mixture was stirred at RT for 2 h. The reaction mixture was diluted with dichloromethane and water. The two phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (eluent system: heptane/ethyl acetate gradient from 100/0 to 50/50) to afford the titled compound.


Synthesis of E042: ethyl 4-(4-acetamidophenyl)-1-(3,5-difluorophenyl)-3-(1-methoxycarbonylazetidin-3-yl)pyrazolo[3,4-b]pyridine-6-carboxylate



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Diisopropylethylamine (0.045 mL, 0.26 mmol, 2.0 equiv) and 4-(dimethylamino)pyridine (CAS 1122-58-3, 3 mg, 0.026, 0.2 equiv) were added to a solution of E043 (65 mg, 0.13 mmol, 1 equiv) in dichloromethane (1 mL) at RT. The reaction mixture was cooled to 0° C. and methyl chloroformate (CAS: 79-22-1, 0.010 mL, 0.13 mmol, 1.0 equiv) was added. The reaction mixture was stirred at RT for 45 min then partitioned between dichloromethane and water. The organic phase was separated, washed with water, dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography (DCM/MeOH: 100/0 to 93/7) to give the titled compound.


Synthesis of E129: methyl 3-cyclobutyl-4-(1-methoxycarbonyl-3,3a,4,6,7,7a-hexahydro-2H-pyrrolo[3,2-c]pyridin-5-yl)-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylate



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To E130 (31 mg, 0.073 mmol, 1 equiv) in anhydrous dichloromethane (0.5 mL) at 0° C. was added triethylamine (31 μL, 0.219 mmol, 3 equiv) followed by methyl chloroformate (CAS: 79-22-1, 7 μL, 0.088 mmol, 1.2 equiv). The reaction mixture was stirred at RT for 1.5 h. The reaction mixture was diluted with dichloromethane and water. The two phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (eluent system: dichloromethane/methanol, gradient from 100/0 to 98/2) to afford the titled compound.


Synthesis of E132: methyl 4-(1-acetyl-3,3a,4,6,7,7a-hexahydro-2H-pyrrolo[3,2-c]pyridin-5-yl)-3-cyclobutyl-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylate



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To E130 (31 mg, 0.073 mmol, 1 equiv) in anhydrous dichloromethane (2 mL) at 0° C. was added (31 μL, 0.219 mmol, 3 equiv) followed by acetyl chloride (CAS 75-36-5, 5 μL, 0.088 mmol, 1.2 equiv). The reaction mixture was stirred at RT for 1.5 h. The reaction mixture was diluted with dichloromethane and water. The two phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (eluent system: dichloromethane/methanol, gradient from 100/0 to 96/4) to afford the titled compound.


Method I12: Nucleophilic Substitution



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To a solution of the intermediate ester (1.0 equiv) in anhydrous DMSO, are added the amine (from 2.0 to 3.0 equiv) and K2CO3 (3.0 equiv). The reaction mixture is stirred at 100° C. overnight. The reaction mixture is cooled down to RT, poured into water and extracted with ethyl acetate. The combined organic layers are washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue is purified by silica gel chromatography to afford the titled compound.


Illustrative Synthesis of E110: ethyl 3-isopropyl-4-(4-methoxy-1-piperidyl)-1-(2-pyrrolidin-1-yl-4-pyridyl)pyrazolo[3,4-b]pyridine-6-carboxylate



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To a solution of ethyl 1-(2-fluoro-4-pyridyl)-3-isopropyl-4-(4-methoxy-1-piperidyl)pyrazolo[3,4-b]pyridine-6-carboxylate E111 (50 mg, 0.11 mmol, 1.0 equiv) in anhydrous DMSO (1 mL), were added pyrrolidine (18 μL, 0.22 mmol, 2.0 equiv) and K2CO3 (46 mg, 0.33 mmol, 3.0 equiv). The reaction mixture was stirred at 100° C. overnight. The reaction mixture was cooled down to RT, poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (heptane/ethyl acetate: 100/0 to 40/60) to afford the titled compound.


Method I13: O-Alkylation of the Pyrazole



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Intermediate E153 (1.0 equiv), the alkyl iodide (from 3 to 5.7 equiv) and cesium carbonate (from 3 to 5.7 equiv) are charged in a sealed vial. NMP is added, and the vial is sealed. The reaction mixture is stirred at 130° C. for 1 hour. The reaction mixture is cooled down to RT and partitioned between water and ethyl acetate. The phases are separated, and the aqueous phase is extracted with ethyl acetate. The combined organic phases are washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the titled compound which is used as such or purified by flash chromatography on silica gel.


Illustrative Synthesis of E152: ethyl 3-[(1-tert-butoxycarbonyl-4-piperidyl)oxy]-4-[6-(4-cyano-1-piperidyl)-3-pyridyl]-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylate



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Intermediate E153 (110 mg, 0.23 mmol), N-Boc-4-iodo-piperidine (CAS: 301673-14-3, 410 mg, 1.32 mmol, 5.7 equiv) and cesium carbonate (430 mg, 1.32 mmol, 5.7 equiv) were charged in a sealed vial. NMP (2.9 mL) was added, and the vial was sealed. The reaction mixture was stirred at 130° C. for 1 hour. The reaction mixture was cooled down to RT and partitioned between water and ethyl acetate. The phases were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (heptane/ethyl acetate: gradient from 100/0 to 2:1) to give the titled compound.


Method I14: Mitsunobu Reaction



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Diisopropyl azodicarboxylate (CAS: 2446-83-5, 0.606 mL, 3.075 mmol, 1.5 equiv) is added dropwise to a stirred solution of the intermediate phenol HP (1 equiv), tetrahydropyran-4-methanol (CAS: 14774-37-9, from 1.5 to 2.0 equiv) and triphenylphosphine (CAS: 603-35-0, 1.5 equiv) in tetrahydrofuran under nitrogen atmosphere. The reaction mixture is stirred at RT for 1 to 3 h. The solvent is removed under reduced pressure, and the resulting crude sample is purified by flash column chromatography on silica gel (eluent system: heptane/ethyl acetate) to yield the titled compound.


Illustrative Synthesis of E183 ethyl 1-[(2,4-dimethoxyphenyl)methyl]-3-isopropyl-4-(tetrahydropyran-4-ylmethoxy)pyrazolo[3,4-b]pyridine-6-carboxylate



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Diisopropyl azodicarboxylate (CAS: 2446-83-5, 0.606 mL, 3.075 mmol, 1.5 equiv) was added dropwise to a stirred solution of HP06 (820 mg, 2.05 mmol), tetrahydropyran-4-methanol (CAS: 14774-37-9, 477 mg, 4.1 mmol, 2.0 equiv) and triphenylphosphine (CAS: 603-35-0, 806 mg, 3.075 mmol, 1.5 equiv) in tetrahydrofuran (20 mL) under nitrogen atmosphere. The reaction mixture was stirred at RT for 1 hour. The solvent was removed under reduced pressure, and the crude sample was purified by flash column chromatography on silica gel eluting with n-heptane/ethyl acetate from 90/10 to 1/1 to yield the titled compound.


Method I15: Dimethoxybenzyl Group Removal



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Trifluoroacetic acid or a mixture of dichloromethane and trifluoroacetic acid is added to the (2,4-dimethoxyphenyl)methyl]pyrazolo[3,4-b]pyridine compound. The reaction mixture is stirred at RT for several hours. Then the titled compound is isolated by precipitation in diethyl ether directly from the reaction mixture or after removal of volatiles and is used as such or is taken up in dichloromethane and basified with a saturated solution of sodium hydrogencarbonate. The phases are separated and the aqueous phase is extracted with dichloromethane. The combined organic phases are washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the titled compound which is used as such or further purified by silica gel chromatography.


Alternatively the reaction mixture is concentrated in vacuo. The residue is taken up in dichloromethane and basified with a saturated solution of sodium hydrogencarbonate. The phases are separated and the aqueous phase is extracted with dichloromethane. The combined organic phases are washed with brine, dried over MgSO4, filtered and concentrated in vacuo which was used as such or purified by precipitation or by flash chromatography on silica gel.


Illustrative Synthesis of compound E055: ethyl 3-isopropyl-4-(4-morpholinophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylate



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Trifluoroacetic acid (4.24 mL, 55.4 mmol, 71 equiv) was added to compound E056 (424 mg, 0.78 mmol). The reaction mixture was stirred at RT for 3 hours. Diethyl ether (20 mL) was added to the reaction mixture which was vigorously stirred for 5 minutes. The resulting suspension was filtered, and the cake was washed with diethyl ether. The solid was partitioned between dichloromethane and a saturated solution of sodium hydrogencarbonate and vigorously stirred. The suspension was filtered, and the solids were washed with dichloromethane. The two phases of the filtrate were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo to yield the titled compound which was used without further purification.


Method I16: Ullmann Coupling
Synthesis of E171: ethyl 3-cyclobutyl-1-(4-fluorophenyl)-4-(tetrahydropyran-4-ylmethoxy)pyrazolo[3,4-b]pyridine-6-carboxylate



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A degassed solution of trans-N,N′-dimethyl-1,2-cyclohexane (CAS: 67579-81-1, 0.002 mL, 0.01 mmol, 0.15 equiv) and 1-fluoro-4-iodobenzene (CAS: 352-34-1, 0.007 mL, 0.06 mmol, 0.7 equiv) in toluene (2 mL) was added to a mixture of E172 (30 mg, 0.08 mmol), K3PO4 (35 mg, 0.167 mmol, 2.0 equiv) and CuI (1 mg, 0.005 mmol, 0.07 equiv). The vial was sealed and the reaction mixture was stirred at 110° C. for 16 hours. The reaction mixture was cooled down to RT and partitioned between water and ethyl acetate. The organic phase was separated, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (dichloromethane/heptane/ethyl acetate: 100/0/0 to 0/70/30) to give the titled compound.


Method I17: O-Alkylation of Pyrazole
Synthesis of Compound E090: isopropyl 3-isopropoxy-4-(4-morpholinophenyl)-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylate



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To a solution of AI15 (330 mg, 0.79 mmol) and 2-iodopropane (CAS 75-30-9, 0.19 mL, 1.90 mmol, 2.4 equiv) in anhydrous NMP (4 mL) was added cesium carbonate (775 mg, 2.38 mmol, 3.0 equiv), and the reaction mixture was stirred at 130° C. for 16 hours. The reaction mixture was cooled down to RT and partitioned between dichloromethane and a saturated solution of sodium hydrogencarbonate. The organic phase was separated, washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/ethyl acetate: 80/20 to 70/30) to give the titled compound.


Synthesis of Intermediate E506: methyl 4-(4-bromophenyl)-1-cyclohexyl-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate



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To a solution containing methyl 4-(4-bromophenyl)-1-cyclohexyl-3-hydroxy-1H-pyrazolo[3,4-b]pyridine-6-carboxylate (30.5 mmol, E505) was added isopropyl bromide ([75-26-3], 5.73 mL, 61.1 mmol) and Cs2CO3 (2.70 g, 8.28 mmol), and the resulting mixture stirred under N2 at 60° C. for 1 hour. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with brine ((2×)) and concentrated. The obtained residue was purified by column chromatography using a petroleum ether/EtOAc gradient (95/5 till 90/10) to afford the titled compound.


Synthesis of Intermediate E507: methyl 4-(4-bromophenyl)-3-(cyclobutyloxy)-1-cyclohexyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylate



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To a solution containing methyl 4-(4-bromophenyl)-1-cyclohexyl-3-hydroxy-1H-pyrazolo[3,4-b]pyridine-6-carboxylate (5.52 mmol, E505) was added cyclobutyl bromide ([4399-47-7], 1.04 mL, 11.0 mmol) and Cs2CO3 (5.40 g, 11.0 mmol), and the resulting mixture stirred under N2 at 60° C. for 1 hour. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with brine ((2×)) and concentrated. The obtained residue was purified by column chromatography using a petroleum ether/EtOAc gradient (95/5 till 90/10) to afford the titled compound.


Method I18: Alkylation



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An amine (1 equiv) is alkylated with a halogenated alkyl derivative (1.2 to 1.5 equiv) and potassium carbonate (3 equiv) in DMF at RT or at 100° C. for 20 hours. The reaction mixture is diluted with ethyl acetate and washed with water and/or a saturated aqueous solution of NaHCO3 and/or a saturated aqueous solution of NaCl. The organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude sample is purified by flash column chromatography to give the titled compound.


Illustrative Synthesis of E208: ethyl 1-[1-(cyanomethyl)-4-piperidyl]-3-isopropyl-4-(4-morpholinophenyl)pyrazolo[3,4-b]pyridine-6-carboxylate



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A suspension of E325 (70 mg, 0.15 mmol), bromoacetonitrile (12 μL, 0.17 mmol) and potassium carbonate (61 mg, 0.44 mmol) in DMF (1 mL) was stirred at RT for 20 hours. The reaction mixture was diluted with ethyl acetate and washed successively with water, a saturated aqueous solution of NaHCO3 and a saturated aqueous solution of NaCl. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude sample was purified by flash column chromatography eluting with a gradient of DCM and methanol to give the titled compound.


Illustrative Synthesis of E210: ethyl 4-[4-[4-(cyanomethyl)piperazin-1-yl]phenyl]-3-methyl-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylate



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A suspension of E324 (70 mg, 0.15 mmol), bromoacetonitrile (16 μL, 0.24 mmol) and potassium carbonate (65 mg, 0.47 mmol) in DMF (2 mL) was stirred at 80° C. for 20 hours. The reaction mixture was cooled down to RT, diluted with ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude sample was purified by flash column chromatography eluting with a gradient of ethyl acetate and n-heptane to give the titled compound.


Method I19: NaH Alkylation

To a solution of the corresponding amine (1.0 equiv) in anhydrous DMF under a nitrogen atmosphere at 0° C. is added sodium hydride (1.5 equiv). The resulting solution is stirred at 0° C. or at room temperature for 5 to 30 min, and then methyl iodide (1.5 equiv) is added. The reaction mixture is stirred at room temperature or heated to 55° C. until completion. The mixture is then quenched by addition of water, and extracted with EtOAc. The combined organic phases are washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue is purified by silica gel chromatography or by preparative HPLC.


Illustrative Synthesis of intermediate E218: methyl 4-[4-[cyclobutyl(methyl)amino]phenyl]-3-methyl-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylate



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To a solution of E337 (21 mg, 0.049 mmol, 1.0 equiv) in anhydrous DMF (4.4 mL) under a nitrogen atmosphere was added sodium hydride (60% in oil, 3 mg, 0.074 mmol, 1.5 equiv). The resulting solution was stirred at 55° C. for 3 min, and then methyl iodide (4.6 μL, 0.074 mmol, 1.5 equiv) was added. The reaction mixture was stirred at 55° C. for 5 min, and then at room temperature overnight. The mixture was quenched by addition of water and extracted with EtOAc. The combined organic phases were washed with a saturated NaHCO3 solution and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was finally purified by silica gel chromatography (heptane/EtOAc: 100/0 to 65/35) to afford the titled compound.


Method I20: Deprotection of Amine by Hydrogenolysis

A suspension of the corresponding ester (1.0 equiv) and Pd/C (10%) in THF/EtOH is hydrogenated until completion. The reaction mixture is filtered over Celpure® and washed with DCM and MeOH, and the filtrate is concentrated in vacuo. The crude residue is then used directly in the next step or purified by silica gel chromatography or preparative HPLC.


Illustrative Synthesis of intermediate E328: ethyl 3-isopropyl-4-(4-morpholinophenyl)-1-pyrrolidin-3-yl-pyrazolo[3,4-b]pyridine-6-carboxylate



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A suspension of ester E340 (180 mg, 0.30 mmol, 1.0 equiv) and Pd/C (10%, 18 mg) in THF/EtOH (2 mL/1 mL) was hydrogenated overnight. The reaction mixture was filtered over Celpure® and washed with DCM and EOH, and the filtrate was concentrated in vacuo to afford the titled compound.


Method I21: Tert-Butoxy Carbonyl (Boc) Deprotection
Method I21A: Trifluoroacetic Acid Treatment

Trifluoroacetic acid (from 30 to 33 equiv) is added to a solution of tert-butoxycarbonyl protected compound (1 equiv) in DCM. The solution is stirred at RT until complete deprotection. The reaction mixture is diluted with DCM and washed with a saturated aqueous solution of NaHCO3. The organic phase is dried over sodium sulfate, filtered and concentrated in vacuo to give the titled compound.


Illustrative Synthesis of E327: ethyl 3-methyl-1-phenyl-4-(4-piperidyl)pyrazolo[3,4-b]pyridine-6-carboxylate



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Trifluoroacetic acid (470 μL, 6.1 mmol) was added to a solution of E339 (95 mg, 0.2 mmol) in DCM (5 mL). The solution was stirred at RT for 1.5 hours. The reaction mixture was diluted with DCM (30 mL) and washed with a saturated aqueous solution of NaHCO3. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo to give the titled compound.


Method I21B: Hydrochloric Acid Treatment

The tert-butoxycarbonyl-protected compound (1 equiv) is dissolved in dioxane. 4 M HCl in dioxane (from 4 equiv to 8 equiv) is added, and the solution was stirred at RT until complete deprotection. The solvent is concentrated under reduced pressure to give the titled compound. The solution can also be worked up by dilution with DCM and washing with a saturated aqueous solution of NaHCO3. The organic phase is separated using a phase separator and concentrated under reduced pressure. The titled compound is used as such in the next step without any further purification.


Illustrative Synthesis of E332: ethyl 4-(2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrol-5-yl)-3-isopropyl-1-(m-tolyl)pyrazolo[3,4-b]pyridine-6-carboxylate



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E264 (58 mg, 0.11 mmol) was dissolved in dioxane (2 mL). 4 M HCl in dioxane (110 μL, 0.44 mmol) was added, and the solution was stirred at RT for 18 hours. The reaction mixture was diluted with DCM and washed with a saturated aqueous solution of NaHCO3. The organic phase is separated using a phase separator and concentrated under reduced pressure. The titled compound is used as such in the next step without any further purification.


Method I22: Buchwald Coupling



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To the amine or amide (from 1 to 1.2 equiv), the halogenated scaffold (1 equiv) and cesium carbonate (1.5 equiv) is added degassed dioxane. The reaction mixture is purged with argon, tris(dibenzylideneacetone)dipalladium(0) (CAS: 51364-51-3, 0.05 equiv) or palladium(II) acetate (0.05 equiv) and Xantphos (CAS: 161265-03-8, from 0.75 to 0.2 equiv) are added, and the mixture is purged again with argon. The reaction mixture is stirred at a temperature ranging from 100° C. to 110° C. for 30 minutes to 1.5 hours. The reaction mixture is cooled down and filtered over a diatomaceous earth pad. Solids are washed with organic solvents, and the combined filtrates are concentrated in vacuo. Alternatively the crude sample can be poured into water and extracted with ethyl acetate. The organic phase is washed with a saturated aqueous solution of NaCl, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue is purified by flash chromatography on silica gel to afford the coupled compound.


Illustrative Synthesis of intermediate E322: methyl 1-(4-fluorophenyl)-3-isopropyl-4-(tetrahydropyran-4-carbonylamino)pyrazolo[3,4-b]pyridine-6-carboxylate



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To tetrahydropyran-4-carboxamide (CAS 344329-76-6, 45 mg, 0.34 mmol), HP05 (100 mg, 0.29 mmol) and cesium carbonate (140 mg, 0.43 mmol) was added degassed dioxane (1 mL). The reaction mixture was purged with argon, tris(dibenzylideneacetone)dipalladium(0) (CAS: 51364-51-3, 3 mg, 0.01 mmol) and Xantphos (CAS: 161265-03-8.12 mg, 0.02 mmol)) were added, and the mixture was purged again with argon. The reaction mixture was heated at 100° C. for 30 minutes, cooled down to RT and filtered over a diatomaceous earth pad. Solids were washed with ethyl acetate, and the combined filtrates were concentrated in vacuo. The resulting residue was purified by flash column chromatography eluting with n-heptane/ethyl acetate to afford the titled compound.


Method I23: General Method for Oxidation



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Dess Martin's periodinane (1 to 2 eq) is added at RT to a stirred solution of alcohol (1 eq) in dichloromethane. After 0.5 to 2 hours, the reaction mixture is diluted with dichloromethane. A solution of 20% Na2S2O3 in water and a saturated aqueous solution of NaHCO3 (1:1) is added and the stirring is continued for 30 minutes. The organic phase is separated, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the titled compound. The compound can be used as such or purified by flash column chromatography.


Synthesis of Compound E353: Methyl 3-cyclobutyl-1-(4-fluorophenyl)-4-(4-oxopiperidin-1-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylate



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Dess-Martin periodinane (4 g, 9.4 mmol) was added at RT to a stirred solution of E352 (3.6 g, 8.6 mmol) in dichloromethane (40 mL). After 30 minutes, the reaction mixture was diluted with dichloromethane (50 mL). A solution of 20% aqueous Na2S2O3 and a saturated aqueous solution of NaHCO3 (1:1, 50 mL) were added, and the stirring was continued for 30 minutes. The organic phase was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the titled compound.


Method I24: Coupling of Amines



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EDC.HCl ([25952-538], 1.2 equiv) is added at RT to a stirring solution of carboxylic acid (1 equiv), amine (4 equiv) and 4-(dimethylamino)pyridine ([1122-58-3], 2 equiv) in dichloromethane. The reaction mixture is stirred at RT for 20 hours. The solvent is evaporated under reduced pressure. The residue is purified flash column chromatography eluting with ethyl acetate/n-heptane and/or DCM/MeOH to yield the desired compound.


Illustrative Synthesis of E439: ethyl 4-{4-[5-(tert-butoxycarbonyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carbonyl]phenyl}-1-cyclohexyl-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate



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EDC.HCl ([25952-538], 18 mg, 74 μmol) was added at RT to a stirred solution of E438 (30 mg, 62 μmol), tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate ([141449-85-6], 52 mg, 248 μmol) and 4-(dimethylamino)pyridine ([1122-58-3], 17 mg, 124 μmol) in dichloromethane (5 mL). The reaction mixture was stirred at RT for 20 hours. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with ethyl acetate/n-heptane to yield the titled compound.


Synthesis of E441: ethyl 1-cyclohexyl-4-{4-[3-(dimethylamino)azetidine-1-carbonyl]phenyl}-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate



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EDC.HCl ([25952-538], 24 mg, 125 μmol) was added at RT to a stirred solution of E438 (40 mg, 89 μmol), N,N-dimethylazetidin-3-amine hydrochloride ([935670-07-8], 49 mg, 358 triethylamine (50 μL, 358 μmol) and 4-(dimethylamino)pyridine ([1122-58-3], 24 mg, 196 μmol) in dichloromethane (15 mL). The reaction mixture was stirred at RT for 20 hours. The mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with ethyl acetate/DCM/MeOH (1/0/0 to 0/8/2) to yield the titled compound.


Method I25: Tert-Butoxycarbonyl (Boc) Deprotection



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To a solution of the Boc-protected amine (1 eq) in dichloromethane at 0° C., TFA (76-05-1, 7 eq) is added. The resulting mixture is stirred at room temperature overnight. After dilution with DCM, the mixture is extracted with K2CO3 solution. The obtained organic phase is concentrated to give the desired product that is used as such.


Method I26: Reductive Amination to Install a Cyclopropyl Group



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The amine (1 eq) is mixed with (1-ethoxycyclopropoxy)trimethylsilane ([27374-25-0], 2 eq), AcOH (1.6 eq) and NaBH3CN (1.5 eq) in a mixture of THF/MeOH (1/1). The resulting mixture is stirred overnight at 50° C. After cooling the mixture down to room temperature, the reaction is quenched by the addition of water. Next, 1 M NaOH solution is added, and the mixture is stirred for another 15 minutes. After dilution with DCM, the organic layer is separated, dried and concentrated to give the titled compound.


Illustrative Synthesis of compound E465: methyl 3-cyclobutyl-4-[4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl]-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylate



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Methyl 3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(piperazin-1-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate (200 mg, 0.41 mmol, E496) was mixed with (1-ethoxycyclopropoxy)trimethylsilane ([27374-25-0], 163 μL, 0.81 mmol), AcOH (26 μL, 0.65 mmol) and sodium cyanoborohydride ([25895-60-7], 38 mg, 0.61 mmol) in a mixture of THF/MeOH (1/1, 1 mL). The resulting mixture was stirred overnight at 50° C. After cooling the mixture down to room temperature, the reaction was quenched by the addition of water. Next, 1 M NaOH solution was added, and the mixture was stirred for another 15 minutes. After dilution with DCM, the organic layer was separated, dried and concentrated to give the titled compound.


Method I27: Amine Alkylation



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The amine (1 eq) is mixed with 1-bromo-2-methoxyethane ([6482-24-2], 1.1 eq) and K2CO3 (2 eq) in MeCN. The resulting mixture is heated at reflux overnight at 50° C. After cooling down, the mixture is used as such in the next step.


Method I28: Amino-Carbonylation



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A is CH or N

In a Parr reactor, the arylbromide (1 eq) is mixed with an amine (2 eq), Et3N (4 eq) and Xantphos Pd G3 (0.03 eq) in dioxane. A CO pressure of 5 bar is applied and the mixture is heated at 100° C. overnight. Concentration gives a residue that is re-dissolved in DCM. Extraction with water gives an organic phase that is concentrated to give a residue that is used as such in the next step.


Illustrative Synthesis of compound E474: methyl 1-cyclohexyl-4-[4-(4-methylpiperazine-1-carbonyl)phenyl]-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate



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A Parr reactor was loaded with E506 (0.50 mmol, 250 mg), 1-methylpiperazine dihydrochloride ([34352-59-5], 1.0 mmol, 173 mg) and [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate] (0.015 mmol, 14 mg). The reactor was evacuated and back-filled with N2, Et3N (4.0 equiv, 2.0 mmol, 279 μL) and 1,4-dioxane (dry, 8 mL/mmol, 4 mL) were added, and the reaction mixture was heated to 100° C. under a CO atmosphere (5 bar) overnight. The reaction mixture was concentrated in vacuo, and the residue was partitioned between H2O and dichloromethane. The organic phase was dried and concentrated in vacuo to give the titled compound which was used as such in the next step.


Method I29: Alternative Buchwald Coupling on the Aryl Linker



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A tube is loaded with the arylbromide (1 eq). The amine (1.2 eq) is added together with (RuPhos) palladium(II) phenethylamine chloride (1:1 MTBE solvate, 0.1 eq), NaOtBu (1.2 eq) in dioxane. The resulting suspension is put under a N2 atmosphere and stirred at 100° C. Next, the mixture is diluted with water and acidified with a 1 N citric acid solution till pH 3-4. Extraction with DCM gives the crude product that is either used as such or purified by chromatography. During this method, it is possible that partial hydrolysis of the ester to the corresponding acid occurs.


Illustrative Synthesis of compound E502: methyl 1-cyclohexyl-4-[4-(4-methylpiperazin-1-yl)phenyl]-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate



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A tube was loaded with the E506 (100 mg, 0.21 mmol). 1-Methylpiperazine ([109-01-3], 28 μL, 0.25 mmol) was added together with (RuPhos) palladium(II) phenethylamine chloride (1:1 MTBE solvate, 17 mg, 0.02 mmol), and NaOtBu (25 mg, 0.25 mmol) in dioxane (1 mL). The resulting suspension was put under a N2 atmosphere and stirred at 100° C. Next, the mixture was diluted with water and acidified with a 1 N citric acid solution till pH 3-4. Extraction with DCM gave the titled compound that was used as such. Partial hydrolysis of the ester to the corresponding acid was observed.


Method I30: Alternative Reductive Amination



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A solution of the amine (1 eq), the ketone (2 eq) and AcOH (1.5 eq) in DCM is cooled to 0° C. Next, sodium triacetoxyborohydride ([56553-60-7], 2 eq) is added portionwise, and the reaction is stirred overnight at ambient temperature. Subsequently, the mixture is diluted with saturated NaHCO3 solution and extracted with DCM. The organic phase is concentrated to give the alkylated amine that is used as such or purified by chromatography.


Illustrative example of compound E469: methyl 3-cyclobutyl-1-(4-fluorophenyl)-4-[9-(oxetan-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate



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A solution of the methyl 3-cyclobutyl-4-(3,9-diazaspiro[5.5]undecan-3-yl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylate (200 mg, 0.42 mmol, E500), 3-oxetanone ([6704-31-0], 54 μL, 0.84 mmol) and AcOH (36 μL) in DCM (3 mL) was cooled at 0° C. Next, sodium triacetoxyborohydride ([56553-60-7], 178 mg, 0.84 mmol) was added portion wise and the reaction was stirred overnight at ambient temperature. Subsequently, the mixture was diluted with sat. NaHCO3 solution and extracted with DCM. The organic phase was evaporated to give the titled compound.


Method I31: Carbamate Synthesis



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To a solution of the amine (1 eq) in DCM is added trimethylamine (2 eq) and then methyl chloroformate ([79-22-1], 2 eq). The mixture is stirred at RT overnight. Next, the reaction mixture is diluted with saturated NaHCO3 solution and extracted with DCM. After concentration, the carbamate is obtained that is used as such or purified by chromatography.


Illustrative example of compound E486: methyl 3-cyclobutyl-1-(4-fluorophenyl)-4-{4-[4-(methoxycarbonyl)piperazin-1-yl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylate



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To a solution of the E498 (118 mg, 0.239 mmol) in DCM (1 mL) was added triethylamine (67 μL, 0.478 mmol) and then methyl chloroformate (37 μL, 0.478 mmol). The mixture was stirred at RT overnight. Next, the reaction mixture was diluted with saturated NaHCO3 solution and extracted with DCM. After concentration, the titled compound was obtained that was used as such.


Method I32: Amide Synthesis Using Acetyl Chloride



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To a solution of the amine (1 eq) in DCM is added trimethylamine (2 eq) and then acetyl chloride ([75-36-5], 2 eq). The mixture is stirred at RT overnight. Next, the reaction mixture is diluted with saturated NaHCO3 solution extracted with DCM. After concentration, the amide is obtained that is used as such or purified by chromatography.


Illustrative example of compound E487: methyl 4-[4-(4-acetylpiperazin-1-yl)piperidin-1-yl]-3-cyclobutyl-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylate



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To a solution of the E498 (118 mg, 0.239 mmol) in DCM (1 mL) was added triethylamine (67 μL, 0.478 mmol) and then acetyl chloride ([75-36-5], 0.478 mmol). The mixture was stirred at RT overnight. Next, the reaction was diluted with saturated NaHCO3 solution and extracted with DCM. After concentration, the titled compound was obtained that was used as such.


Method I33: General Method for Reductive Amination



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A suspension of ketone (1 eq), amine (1.5 to 3 eq) and triethylamine (1 to 2 eq) in dichloromethane is stirred at RT for 5 minutes. Acetic acid (1 to 2 eq) is added, and the stirring at RT is continued for 30 minutes. Sodium triacetoxyborohydride (1 to 3 eq) is then added, and the stirring is continued for 20 hours. The reaction mixture is diluted with dichloromethane and washed with a saturated aqueous solution of NaHCO3. The organic phase is separated, dried over sodium sulfate and concentrated under reduced pressure. The crude sample is used as such or purified by flash column chromatography.


Illustrative Synthesis of E354: methyl 3-cyclobutyl-1-(4-fluorophenyl)-4-{4-[2-(methoxymethyl)morpholin-4-yl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylate



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A suspension of E353 (0.1 g, 0.24 mmol), 2-(methoxymethyl)morpholine ([156121-15-2], 63 mg, 0.47 mmol) and triethylamine (33 μL, 0.24 mmol) in dichloromethane (2 mL) was stirred at RT for 5 minutes. Acetic acid (21 μL, 0.35 mmol) was added, and the stirring at RT was continued for 30 minutes. Sodium triacetoxyborohydride (76 mg, 0.35 mmol) was then added, and the stirring was continued for 20 hours. The reaction mixture was diluted with dichloromethane (3 mL) and washed with a saturated aqueous solution of NaHCO3 (2 mL). The organic phase was separated using a phase separator and concentrated in vacuo to give the titled compound.


Method I34: Reductive Amination on Aldehydes



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A suspension of amine hydrochloride or free base (1 to 2 equiv) and triethylamine (from 1 to 2 equiv) in 1,2-dichloroethane is stirred at RT for 10 minutes. Aldehyde (1 equiv), sodium triacetoxyborohydride (2 equiv), and acetic acid (0.6 to 4 equiv) are successively added, and the stirring at RT is continued for 20 hours. Starting reagents can be added until full conversion is observed. The reaction mixture is diluted with DCM, washed with a saturated aqueous solution of NaHCO3 and/or a saturated aqueous solution of NH4Cl and a phosphate buffer (pH 6.2). The organic phase is dried over sodium sulfate and concentrated under reduced pressure. The residue is used as such or purified by flash column chromatography to yield the reductively aminated compound.


Illustrative Synthesis of E426: ethyl 1-cyclohexyl-4-(4-{[3-(dimethylamino)azetidin-1-yl]methyl}phenyl)-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate



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A suspension of 3-(dimethylamino)azetidine dihydrochloride ([124668-49-1], 17 mg, 124 μmol) and triethylamine (35 μL, 248 μmol) in 1,2-dichloroethane (2 mL) was stirred at RT for 10 minutes. Aldehyde E425 (54 mg, 124 μmol), sodium triacetoxyborohydride (53 mg, 248 μmol), and acetic acid (29 μL, 496 μmol) were successively added, and the stirring at RT was continued for 20 hours. The reaction mixture was diluted with DCM and washed with a saturated aqueous solution of NaHCO3. The organic phase was separated, dried over sodium sulfate and concentrated under reduced pressure. The residue was used as such or purified by flash column chromatography eluted with n-heptane/ethyl acetate/DCM/MeOH (100/0/0/0/0 to 0/100/0/0 and to 0/0/90/10) to yield the titled compound.


Method I35: Suzuki with Alkyl-BF3 Salts



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    • LG3 is a leaving group suitable for the coupling reaction

    • Gx is -G3B or -G3B-L1-G3C





The aryl halide (1 eq) is mixed together with the alkyl-BF3 salt (1.5 eq), Pd(dppf)Cl2.DCM (CAS 95464-05-4, 0.05 eq) and CS2CO3 (3 eq) in a mixture of THF/H2O (10/1). The mixture is put under N2 atmosphere and heated at 80° C. overnight. Concentration, possibly followed by chromatographic purification, gives the titled compound.


Synthesis of E199: methyl 4-(4-azidophenyl)-1-[3-(dimethylamino)phenyl]-3-isopropyl-pyrazolo[3,4-b]pyridine-6-carboxylate



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Intermediate E200 (0.5 g, 1.013 mmol, 1.0 equiv) and sodium azide (CAS 26628-22-8, 132 mg, 2.026 mmol, 2 equiv) were put in a sealed vial. A 2:1 mixture of ethanol and water (2 mL) was added, and the vial was purged with nitrogen. Then copper(I) iodide (CAS 7681-65-4, 20 mg, 0.101 mmol, 0.1 equiv), sodium ascorbate (CAS 134-03-2, 11 mg, 0.051 mmol, 0.05 equiv) and N,N-dimethylethylenediamine (CAS 110-70-3, 45 μL, 0.405 mmol, 0.2 equiv) were added, and the vial was sealed. The reaction mixture was heated under microwave irradiation at 80° C. for 45 minutes. Volatiles were removed in vacuo. The resulting aqueous residue was diluted with ethyl acetate. The two phases were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the titled compound which was used as such.


Synthesis of E247: ethyl 3-methyl-1-phenyl-4-(piperidine-1-carbonyl)pyrazolo[3,4-b]pyridine-6-carboxylate



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To a solution of acid E330 (0.09 mmol, 30 mg, 1.0 equiv) in THF were added piperidine (11 μL, 0.11 mmol, 1.2 equiv), HATU (42 mg, 0.11 mmol, 1.2 equiv), and DIPEA (19 μL, 0.11 mmol, 1.2 equiv). The solution was stirred at room temperature for 1 h then quenched by addition of a saturated NH4Cl solution and extracted with DCM. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was finally purified by silica gel chromatography (heptane/EtOAc: 100/0 to 70/30) to afford the titled compound.


Synthesis of E197: methyl 4-(1-tert-butoxycarbonyl-4-piperidyl)-1-(4-fluorophenyl)-3-isopropyl-pyrazolo[3,4-b]pyridine-6-carboxylate



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Step 1: methyl 4-(1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridin-4-yl)-1-(4-fluorophenyl)-3-isopropyl-pyrazolo[3,4-b]pyridine-6-carboxylate E198

A suspension of methyl 4-chloro-1-(4-fluorophenyl)-3-isopropyl-pyrazolo[3,4-b]pyridine-6-carboxylate HP05 (2.0 g, 5.75 mmol, 1.0 equiv), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (3.6 g, 11.5 mmol, 2.0 equiv), K2CO3 (2.4 g, 17.25 mmol, 3.0 equiv) and Pd(dppf)2Cl2 (939 mg, 1.15 mmol, 0.2 equiv) in anhydrous DMF (15 mL) was degassed with N2 at room temperature for 2 minutes. The reaction mixture was heated at reflux overnight. The mixture was cooled to RT, and the mixture was poured into 150 mL of iced water. The aqueous phase was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude was purified by silica gel chromatography (heptane/ethyl acetate: 100/0 to 80/20) to give E198.


Step 2: methyl 4-(1-tert-butoxycarbonyl-4-piperidyl)-1-(4-fluorophenyl)-3-isopropyl-pyrazolo[3,4-b]pyridine-6-carboxylate

A suspension of E198 (2.44 g, 4.93 mmol, 1.0 equiv) and PtO2 (1.2 g) in AcOH was hydrogenated overnight. The reaction mixture was filtered over Celpure® and washed with ethyl acetate, and the filtrate was concentrated. The residue was purified by silica gel chromatography (heptane/ethyl acetate: 100/0 to 80/20) to give the titled compound.


Synthesis of E339: ethyl 4-(1-tert-butoxycarbonyl-4-piperidyl)-3-methyl-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylate



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Step 1: ethyl 4-(1-tert-butoxycarbonyl-3,6-dihydro-2H-pyridin-4-yl)-3-methyl-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylate

A suspension of HP13 (167 mg, 0.53 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (164 mg, 0.53 mmol), K3PO4 (225 mg, 1.06 mmol) and Pd(PPh3)2Cl2 (37 mg, 0.05 mmol) in DME/EtOAc (3 mL, 2/1) was degassed with N2 at room temperature for 2 minutes. The reaction mixture was heated at 110° C. for 2 hours and cooled down to RT. The solution was diluted with 0.1 M HCl (5 mL) and extracted twice with ethyl acetate (2×10 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with n-heptane/ethyl acetate to give the titled compound.


Step 2: ethyl 4-(1-tert-butoxycarbonyl-4-piperidyl)-3-methyl-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylate

A solution of the compound from Step 1 (110 mg, 0.24 mmol, 1.0 equiv) in a mixture of ethanol/ethyl acetate (25 mL, 1/1) was hydrogenated using a 10% palladium over charcoal cartridge in continuous flow an H-Cube® system (20 bars, RT, 3 hours). The volatiles were removed under reduced pressure to yield the titled compound E339.


Synthesis of E330: 6-ethoxycarbonyl-3-methyl-1-phenyl-pyrazolo[3,4-b]pyridine-4-carboxylic acid



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Step 1: ethyl 6-hydroxy-3-methyl-1-phenyl-pyrazolo[3,4-b]pyridine-4-carboxylate

5-Amino-3-methyl-1-phenylpyrazole (CAS: 1131-18-6, 10 g, 57.7 mmol) was dissolved in AcOH (100 mL). Diethyloxalacetate sodium salt (CAS: 40876-98-0, 13.4 g, 63.5 mmol) was added, and the reaction mixture was refluxed for 1.5 hours. Diethyloxalacetate sodium salt (CAS: 40876-98-0, 1.3 g, 6.3 mmol) was again added, and the reflux was continued for another 30 minutes. The reaction mixture was cooled down to RT and poured into cold water (300 mL). The precipitate was filtered, washed with water and air dried for 20 hours to yield the titled compound.


Step 2: ethyl 3-methyl-1-phenyl-6-(trifluoromethylsulfonyloxy)pyrazolo[3,4-b]pyridine-4-carboxylate

A suspension of the compound from Step 1 (13.7 g, 46 mmol) in pyridine (4.1 mL, 50.7 mmol) and acetonitrile (200 mL) was cooled in an ice bath. Triflic anhydride (8.5 mL, 50.7 mL) was added dropwise over a 30 minutes period. The reaction mixture was left warming to RT over a 20 minutes period and water (200 mL) was added. The precipitate was filtered, washed with water and ethanol, and dried at 40° C. under reduced pressure to give the titled compound.


Step 3: ethyl 6-cyano-3-methyl-1-phenyl-pyrazolo[3,4-b]pyridine-4-carboxylate

Compound from Step 2 (9.2 g, 21.4 mmol) was placed in a vial and solubilized in dry dimethylformamide (40 mL). Zinc cyanide (2.5 g, 21.4 mmol) was added, and argon was bubbled into the reaction mixture for 5 minutes. Tetrakis(triphenylphosphine)palladium(0) (2.5 g, 2.1 mmol) was added, and the vial was sealed. The reaction mixture was stirred at 100° C. for 2 hours and then was cooled to room temperature. The crude mixture was poured into water, and the precipitate was filtered. The solid was suspended in ethyl acetate and filtered again. The organic phase was washed with a saturated aqueous solution of NaCl, dried over sodium sulfate, filtered and concentrated under reduced pressure to a volume of approximately 20 mL. n-Heptane (100 mL) was added, and the precipitate was filtered, washed with n-heptane and dried to give the titled compound.


Step 4: 4-(hydroxymethyl)-3-methyl-1-phenyl-pyrazolo[3,4-b]pyridine-6-carbonitrile

Sodium borohydride (1.2 g, 31.7 mmol) was added portionwise to a suspension of the compound from Step 3 (4.9 g, 15.8 mmol) in THF (20 mL) followed by addition of ethanol (50 mL). The reaction mixture was stirred at RT for 2 hours and was quenched with a saturated aqueous solution of NH4Cl. The aqueous phase was extracted with ethyl acetate, and the organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified over a silica gel pad eluting with DCM and n-heptane to give the titled compound.


Step 5: 4-(hydroxymethyl)-3-methyl-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylic acid

The compound of Step 4 (1.32 g, 5 mmol) was solubilized in dioxane (10 mL) and a 6 M HCl solution in water (20 mL) was added. The solution was refluxed for 20 hours and cooled down to RT. The precipitate was filtered and washed with ethanol. The filtrate was concentrated under reduced pressure to give the titled compound which was used as such without any further purification.


Step 6: ethyl 4-(hydroxymethyl)-3-methyl-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylate

The compound from Step 5 (1.4 g, 5 mmol) was dissolved in ethanol (60 mL) and thionyl chloride (0.6 mL, 7.5 mmol) was added. The solution was refluxed for 4 hours and then cooled to RT. The volatiles were removed under reduced pressure, and the crude sample was purified by flash column chromatography eluting with DCM and methanol to yield the titled compound.


Step 7: 6-ethoxycarbonyl-3-methyl-1-phenyl-pyrazolo[3,4-b]pyridine-4-carboxylic acid

The compound from Step 6 (139 mg, 0.45 mmol) was dissolved in DCM (5 mL) and Dess-Martin's periodinane (227 mg, 0.54 mmol) was added at RT. The reaction mixture was stirred for 30 minutes. The precipitate was filtered, and the filtrate was concentrated under reduced pressure. The residue was solubilized in DMF (5 mL) and Oxone® (2×166 mg, 1.08 mmol) was added over a period of 30 minutes. The stirring at RT was continued for another 30 minutes, and water was added until a precipitate was formed. The precipitate was collected by filtration, washed with water and dried at 40° C. under reduced pressure to give the titled compound, E330.


Synthesis of E390: ethyl 3-cyclobutyl-1-[2-(3,6-dihydro-2H-pyran-4-yl)pyridin-4-yl]-4-[4-(methoxymethyl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate and E391: ethyl 3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-[2-(oxan-4-yl)pyridin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate



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Step 1: E390: ethyl 3-cyclobutyl-1-[2-(3,6-dihydro-2H-pyran-4-yl)pyridin-4-yl]-4-[4-(methoxymethyl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate

In a sealed tube, a suspension of E389 (110 mg, 0.23 mmol), 3,6-dihydro-2H-pyran-4-boronic pinacol ester (72 mg, 0.34 mmol), K3PO4 (146 mg, 0.69 mmol) and Pd(Amphos)C12 ([887919-35-9], 16 mg, 23 μmol) in dioxane (3 mL) and water (0.5 mL) was degassed with N2 at room temperature for 2 minutes. The reaction mixture was heated at 100° C. for 3 hours. The mixture was cooled to RT and then concentrated under reduced pressure. The crude sample was purified by flash column chromatography eluted with ethyl acetate/n-heptane (0/1 to I/O) to give the titled compound E390.


Step 2: E391: ethyl 3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-[2-(oxan-4-yl)pyridin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate

A suspension of E390 (60 mg, 0.11 mmol) and palladium hydroxide on carbon (20 mg) in ethanol was hydrogenated for 6 hours. The reaction mixture was filtered over Celpure® and washed with ethyl acetate. The filtrate was concentrated in vacuo to give the titled compound E391.


Synthesis of E393: ethyl 3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate



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Trifluoromethanesulfonic acid (860 μL, 10 mmol) was added dropwise at RT to a solution of E392 (1 g, 2 mmol) in dichloromethane (10 mL). The reaction mixture was stirred for 4 hours and poured into a mixture of saturated aqueous NaHCO3 and water (1:1, 10 mL). The aqueous phase was extracted twice with dichloromethane/isopropanol (95/5, 20 mL). The combined organic phases were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the titled compound as a colorless solid.


Synthesis of E402: ethyl 3-cyclobutyl-1-(2-hydroxypyridin-4-yl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate



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A suspension of E401 (75 mg, 0.12 mmol) and palladium hydroxide on carbon (10 mg) in THF was hydrogenated for 20 hours. The reaction mixture was filtered over Celpure® that was washed with dichloromethane/methanol. The filtrate was concentrated in vacuo to give the titled compound E402.


Synthesis of E407: ethyl 3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-[2-(oxan-4-yl)pyridin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate



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Step 1: ethyl 3-cyclobutyl-1-[2-(3,6-dihydro-2H-pyran-4-yl)pyridin-4-yl]-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate

In a sealed tube, a suspension of E406 (110 mg, 0.21 mmol), 3,6-dihydro-2H-pyran-4-boronic pinacol ester (72 mg, 0.34 mmol), K3PO4 (146 mg, 0.69 mmol) and Pd(Amphos)Cl2 ([887919-35-9], 16 mg, 23 μmol) in dioxane (3 mL) and water (0.5 mL) was degassed with N2 at room temperature for 2 minutes. The reaction mixture was heated at 100° C. for 20 hours. The mixture was cooled to RT, and the mixture was concentrated under reduced pressure. The crude sample was purified by flash column chromatography eluted with n-heptane/ethyl acetate/DCM/MeOH (1/0/0/0 to 40/40/10/1) to give the titled compound.


Step 2: ethyl 3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-[2-(oxan-4-yl)pyridin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate

A suspension of ethyl 3-cyclobutyl-1-[2-(3,6-dihydro-2H-pyran-4-yl)pyridin-4-yl]-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate (54 mg, 0.94 mmol) and palladium hydroxide on carbon (15 mg) in ethanol/THF (1:1, 10 mL) was hydrogenated for 6 hours. The reaction mixture was filtered over Celpure® that was washed with ethyl acetate, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography eluted with n-heptane/ethyl acetate/DCM/MeOH (100/0/0/0/0 to 0/100/0/0 and to 0/0/90/10) to give the titled compound E407.


Synthesis of E413: methyl 3-cyclobutyl-1-(4-fluorophenyl)-4-(piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylate



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Step 1: methyl 4-[1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]-3-cyclobutyl-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylate

A suspension of methyl 4-chloro-3-cyclobutyl-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylate (HP19, 2.0 g, 5.75 mmol, 1.0 equiv), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (CAS 286961-14-6, 3.6 g, 11.5 mmol, 2.0 equiv), K2CO3 (2.4 g, 17.25 mmol, 3.0 equiv) and Pd(dppf)Cl2 (CAS: 72287-26-4, 939 mg, 1.15 mmol, 0.2 equiv) in anhydrous DMF (15 mL) was degassed with nitrogen at room temperature for 2 minutes. The reaction mixture was refluxed for 20 hours. The mixture was cooled to RT, poured into 150 mL of iced water and diluted with ethyl acetate. The two phases were separated, and the aqueous phase was extracted again with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (heptane/ethyl acetate: 100/0 to 80/20) to give the titled compound.


Step 2: methyl 4-[1-(tert-butoxycarbonyl)piperidin-4-yl]-3-cyclobutyl-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylate

A suspension of compound from Step 1 (2.44 g, 4.93 mmol, 1.0 equiv) and platinum (IV) oxide (CAS 1314-15-4, 1.2 g) in acetic acid (240 mL) was stirred at RT under a hydrogen atmosphere (balloon) for 20 hours. The reaction mixture was filtered over Celpure® P65. Solids were washed with ethyl acetate, and the filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (heptane/ethyl acetate: 100/0 to 80/20) to give the title compound.


Step 3: methyl 3-cyclobutyl-1-(4-fluorophenyl)-4-(piperidin-4-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylate

Methyl 4-[1-(tert-butoxycarbonyl)piperidin-4-yl]-3-cyclobutyl-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylate (2.75 g, 5.4 mmol, 1 equiv) was dissolved in 4 M HCl in dioxane (40 mL, 162.2 mmol, 30 equiv), and the solution was stirred at RT for 2 hours. The solvent was concentrated under reduced pressure. The residue was dissolved in a minimum of methanol and poured into diethyl ether (500 mL). The precipitate was filtered, washed with diethyl ether and dried at 40° C. under reduced pressure to give the titled compound, E413.


Synthesis of E427 and compound 923: ethyl 4-(4-cyanophenyl)-1-cyclohexyl-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate and 4-(4-cyanophenyl)-1-cyclohexyl-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid



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A solution of ALP37 (1 g, 4.4 mmol) and 5-amino-1-cyclohexyl-1H-pyrazol-3-ol ([436088-86-7], 796 mg, 4.4 mmol) in N-methylpyrrolidine (7 mL) was heated at 90° C. for 5 hours in a sealed tube. The reaction mixture was cooled to RT. Cesium carbonate (4.3 g, 13.2 mmol) and 2-bromopropane (984 μL, 8.8 mmol) were added, and the tube was sealed. The reaction mixture was heated at 90° C. for 2 hours and then left stirring at RT for 20 hours. The volatiles were removed in vacuo, and the residue was purified by flash chromatography on silica gel eluted with ethyl acetate/n-heptane (0/1 to I/O) to give the titled compound, E427, and the carboxylic acid compound 923.


Synthesis of E428: ethyl 1-(6-bromopyridin-2-yl)-3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate



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To a solution of E393 (67 mg, 0.16 mmol) in DMA (3 mL) under a nitrogen atmosphere at RT was added sodium hydride (60% in mineral oil, 8 mg, 0.2 mmol), and the mixture was stirred 10 minutes. Then 2-bromo-6-fluoropyridine ([144100-07-2], 56 mg, 0.32 mmol) was added, and the reaction mixture was stirred overnight. The reaction mixture was quenched with a saturated aqueous solution of NH4Cl and extracted with DCM. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate/DCM/MeOH (100/0/0 to 0/90/10) to afford the titled compound.


Synthesis of E429: methyl 1-(4-fluorophenyl)-4-(4-methoxy[1,4′-bipiperidin]-1′-yl)-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate



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A pressure vessel was charged with AI25 (145 mg, 240 μmol), Pd(dppf)Cl2.DCM ([95464-05-4], 4 mg, 4.8 μmol), and triethylamine (66 μL, 500 μmol) in MeOH (5 mL). The system was loaded with CO (6 bars) and heated at 100° C. for 1 hour. The vessel was cooled down to RT, and the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with a mixture of ethyl acetate/DCM/MeOH (100/0/0 to 0/90/10) to give the titled compound.


Synthesis of E430: methyl 3-cyclobutyl-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylate



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In a sealed tube, a suspension of HP02 (1 g, 2.92 mmol), 1,4-dioxa-spiro[4,5]dec-7-en-8-boronic acid, pinacol ester ([680596-79-6], 1.01 g, 3.8 mmol), K3PO4 (1.86 g, 8.77 mmol), Pd(OAc)2 ([3375-31-3], 330 mg, 0.14 mmol), and SPhos ([657408-07-6], 150 mg, 0.365 mmol) in toluene (22 mL) and water (6 mL) was degassed with N2 at room temperature for 5 minutes. The reaction mixture was stirred at RT for 2 hours. Additional Pd(OAc)2 ([3375-31-3], 330 mg, 0.14 mmol) and SPhos ([657408-07-6], 150 mg, 0.365 mmol) were added. The stirring at RT was continued for 20 hours. Pd(OAc)2 ([3375-31-3], 165 mg, 0.07 mmol) and SPhos ([657408-07-6], 75 mg, 0.18 mmol) were again added, and the reaction mixture was heated at 100° C. for 1 hour. The reaction mixture was cooled to RT, diluted with ethyl acetate and filtered. The filtrate was washed successively with water and a saturated aqueous solution of NaCl. The organic phase was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel eluting with ethyl acetate/n-heptane to give the titled compound.


Synthesis of E431: methyl 3-cyclobutyl-4-(1,4-dioxaspiro[4.5]decan-8-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylate



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A suspension of E430 (823 mg, 1.85 mmol) and palladium hydroxide on carbon ([12135-22-7], 280 mg) in THF/MeOH (25 mL, 2/1) was hydrogenated for 20 hours. The reaction mixture was filtered over Celpure® which was washed with DCM. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography eluting with ethyl acetate/n-heptane to give the titled compound E431.


Synthesis of E432: methyl 3-cyclobutyl-1-[(3E,5Z)-hepta-1,3,5-trien-4-yl]-4-(4-oxocyclohexyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylate



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The ester, E431 (732 mg, 1.64 mmol), was dissolved in DCM and TFA (2.2 mL, 3 volumes) was added dropwise at RT. The solution was stirred for 48 hours and then diluted with DCM. The mixture was washed with a saturated aqueous solution of NaHCO3. The organic phase was separated, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with ethyl acetate/n-heptane to give the titled compound E432.


Synthesis of E438: 4-{1-cyclohexyl-6-(ethoxycarbonyl)-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridin-4-yl}benzoic acid



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A mixture of aldehyde E425 (27 mg, 62 μmol), sulfamic acid ([226-18-8], 17 mg, 168 μmol), and sodium chlorite ([7758-19-2], 17 mg, 188 μmol) in THF/water (3.3 mL, 10/1) was stirred at RT for 1 hour. The reaction mixture was diluted with DCM (20 mL) and washed with water (20 mL). The organic phase was dried over sodium sulfate, filtered and evaporated under reduced pressure. The titled compound was used as such in the next step.


Synthesis of E444: ethyl 1-cyclohexyl-4-{4-[(8-methyl-2-oxa-5,8-diazaspiro[3.5]nonan-5-yl)methyl]phenyl}-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate



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Iodomethane (3 μL, 48 μmol) was added at RT to a stirred suspension of E443 (22 mg, 40 μmol) and cesium carbonate (33 mg, 100 μmol) in DMF (2 mL). The reaction mixture was stirred for 20 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with ethyl acetate/DCM/MeOH (100/0/0 to 0/90/10) to give the titled compound.


Synthesis of E445: ethyl 4-[4-(4-cyano-1-methylpiperidin-4-yl)phenyl]-1-cyclohexyl-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate



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Step 1: ethyl 4-{4-[1-(tert-butoxycarbonyl)-4-cyanopiperidin-4-yl]phenyl}-1-cyclohexyl-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate

A solution of ALP38 (305 mg, 0.74 mmol) and AMP95 (575 mg, 0.77 mmol) in N-methylpyrrolidine (4 mL) was heated at 110° C. for 24 hours in an opened vessel. The reaction mixture was cooled to RT, and the mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic phase was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate/n-heptane to give the titled compound.


Step 2: ethyl 4-[4-(4-cyanopiperidin-4-yl)phenyl]-1-cyclohexyl-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate

Trifluoroacetic acid (1 mL) was added to a solution of the tert-butoxycarbonyl protected compound from Step 1 (230 mg, 0.37 mmol) in DCM (10 mL). The solution was stirred at RT for 2 hours. The reaction mixture was diluted with toluene (5 mL) and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate, water, and a phosphate buffer solution (pH 6.2). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate/n-heptane to give the titled compound.


Step 3: ethyl 4-[4-(4-cyano-1-methylpiperidin-4-yl)phenyl]-1-cyclohexyl-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate

Iodomethane (2 μL, 32 μmol) was added at RT to a stirred suspension of the compound from Step 2 (15 mg, 29 μmol) and cesium carbonate (33 mg, 100 μmol) in DMF (2 mL). The reaction mixture was stirred for 2 hours. The reaction mixture was partitioned between water and DCM. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with ethyl acetate/DCM/MeOH (100/0/0 to 0/90/10) to give the titled compound.


Synthesis of E509: methyl 3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate



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Step 1: 4-[1-(2,6-dichloropyridin-4-yl)piperidin-4-yl]morpholine

N-Ethyl-N-isopropylpropan-2-amine (22.91 mL, 132 mmol) was added to a suspension of 2,4,6-trichloropyridine (12 g, 65.8 mmol) and 4-(piperidin-4-yl)morpholine (13.44 g, 79 mmol) in acetonitrile (120 mL). The reaction mixture was heated to 60° C. and stirred for 16 hours. Upon cooling to room temperature, the precipitate was collected by filtration. The crude solid was then precipitated from EtOAc to give the titled compound. 1H NMR (400 MHz, CDCl3) δ ppm 6.59 (s, 2H), 3.89-3.79 (m, 2H), 3.77-3.69 (m, 4H), 2.96 (ddd, J=13.3, 11.8, 2.8 Hz, 2H), 2.60-2.52 (m, 4H), 2.45 (tt, J=10.8, 3.7 Hz, 1H), 1.95 (ddd, J=12.9, 3.9, 1.9 Hz, 2H), 1.61-1.48 (m, 2H); MS (APCI+) m/z 316.2 (M+H)+.


Step 2: cyclobutyl{2,6-dichloro-4-[4-(morpholin-4-yl)piperidin-1-yl]pyridin-3-yl}methanone

n-Butyllithium (19.2 mL, 26.9 mmol) was added in 5 mL portions to a stirred solution of 4-[1-(2,6-dichloropyridin-4-yl)piperidin-4-yl]morpholine (7.95 g, 25.1 mmol) in THF (160 mL) at −78° C. After stirring at this temperature for 1.5 hours, cyclobutanecarbonyl chloride (1.42 g, 11.9 mmol) was added rapidly, and the reaction mixture was stirred for 10 minutes. To obtain higher conversion, sequential additions of n-butyllithium and cyclobutanecarbonyl chloride were performed in the same manner. Addition 1: n-butyllithium (13.0 mL, 18.2 mmol) and cyclobutanecarbonyl chloride (0.97 g, 8.1 mmol); Addition 2: n-butyllithium (9.2 mL, 12.9 mmol) and cyclobutanecarbonyl chloride (0.68 g, 5.6 mmol); Addition 3: n-butyllithium (6.9 mL, 9.7 mmol) and cyclobutanecarbonyl chloride (0.51 g, 4.2 mmol); Addition 4: n-butyllithium (5.7 mL, 8.0 mmol) and cyclobutanecarbonyl chloride (0.41 g, 3.4 mmol). Upon completion of the last addition, the excess n-butyl lithium was quenched with water (200 mL), and the mixture was extracted with ethyl acetate (3×100 mL). The combined organic fractions were washed with brine (100 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (0-5% 95/5 MeOH/30% aqueous NH3 in DCM) to give the titled compound. 1H NMR (400 MHz, CDCl3) δ ppm 6.76 (s, 1H), 3.80-3.65 (m, 5H), 3.50-3.40 (m, 2H), 2.98-2.76 (m, 2H), 2.62-2.50 (m, 4H), 2.50-2.37 (m, 2H), 2.29 (tt, J=11.0, 3.8 Hz, 1H), 2.22-2.08 (m, 2H), 2.08-1.93 (m, 2H), 1.93-1.83 (m, 2H), 1.52 (dddd, J=14.8, 12.8, 7.5, 3.8 Hz, 2H); MS (APCI+) m/z 398.2 (M+H)+.


Step 3: 6-chloro-3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine

Hydrazine (35% in water, 3.10 mL, 33.9 mmol) was added to cyclobutyl{2,6-dichloro-4-[4-(morpholin-4-yl)piperidin-1-yl]pyridin-3-yl}methanone (4.5 g, 11.30 mmol) in EtOH (32 mL). The reaction mixture was heated to reflux for 14 hours. Upon cooling to −5° C., the precipitate was isolated by filtration. The filter cake was rinsed with cold EtOH to give the titled compound. 1H NMR (400 MHz, CDCl3) δ ppm 10.21 (br s, 1H), 6.45 (s, 1H), 3.94-3.76 (m, 5H), 3.63 (d, J=12.4 Hz, 2H), 2.84 (td, J=12.4, 2.3 Hz, 2H), 2.71-2.59 (m, 4H), 2.58-2.44 (m, 2H), 2.44-2.31 (m, 3H), 2.14-1.97 (m, 4H), 1.85-1.70 (m, 2H); MS (APCI+) m/z 376.2 (M+H)+.


Step 4: methyl 3-cyclobutyl-4-(4-morpholinopiperidin-1-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylate

Into a 600 mL Parr reactor was charged 6-chloro-3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine (3.4 g, 9.05 mmol), followed by THF (170 mL) and MeOH (170 mL). 1,1′-Bis(diphenylphosphino)ferrocene-palladium (II) dichloride dichloromethane complex (0.739 g, 0.905 mmol), and triethylamine (2.52 mL, 18.09 mmol) were added to give a suspension. The reaction vessel was purged with argon followed by CO, pressurized to 100 psig with CO, and heated to 80° C. After 8 hours, the reaction mixture was cooled to room temperature, diluted with CH2Cl2 (800 mL), and filtered. The filtrate was concentrated in vacuo, and the residue was dissolved in CH2Cl2 (800 mL). The organic mixture was washed with saturated aqueous NaHCO3 (300 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was slurried in EtOAc to give the titled compound. 1H NMR (400 MHz, CDCl3) δ ppm 10.98 (br s, 1H), 7.37 (s, 1H), 4.08 (s, 3H), 3.96 (p, J=8.4 Hz, 1H), 3.83-3.76 (m, 4H), 3.70 (d, J=12.3 Hz, 2H), 2.92 (t, J=11.8 Hz, 2H), 2.66 (t, J=4.7 Hz, 4H), 2.55 (dq, J=11.3, 9.0 Hz, 2H), 2.44-2.31 (m, 3H), 2.15-2.00 (m, 4H), 1.88-1.74 (m, 2H); MS (APCI+) m/z 400.3 (M+H)+.









TABLE XIII







List of esters













Int.
Structure
Name
SM
method
MW
Mes





E001


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ethyl 1-(3- bromophenyl)-3- isopropyl-4-(4- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylate
AI17
I9
548- 550
549- 551





E002


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ethyl 1-[3-(azetidin- 1-yl)phenyl]-3- isopropyl-4-(4- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylate
E001, 935670- 07-8
I8
525
526





E003


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ethyl 1-cyclohexyl- 3-isopropyl-4-(2- morpholinopyrimidin- 5-yl)pyrazolo[3,4- b]pyridine-6- carboxylate
ALP22, AMP23
I1
478
479





E004


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ethyl 3-methyl-1- phenyl-4-(1- piperidyl)pyrazolo[3, 4-b]pyridine-6- carboxylate
HP13, 98-77-1
I3
364
365





E005


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ethyl 3-isopropyl-4- (4-morpholinophenyl)- 1-(3-pyrrolidin-1- ylphenyl)pyrazolo[3, 4-b]pyridine-6- carboxylate
E001
I8
539
540





E006


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ethyl 4-[4- (dimethylamino) phenyl]-3-methyl-1- phenyl-pyrazolo[3,4- b]pyridine-6- carboxylate
ALP25, 1131-18- 6
I1
400
401





E007


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ethyl 3-isopropyl-4- (6-morpholino-3- pyridyl)-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
ALP26, AMP04
I1
471
472





E008


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ethyl 3-isopropyl-1- [3-(3- methoxyazetidin-1- yl)phenyl]-4-(4- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylate
E001, 110925- 17-2
I8
555
556





E009


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ethyl 3-methyl-4-(6- morpholino-3- pyridyl)-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
ALP26, 1131-18- 6
I1
443
444





E010


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ethyl 4-(4- bromophenyl)-3- methyl-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
AI16
I9
435- 437
436- 438





E011


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ethyl 4-[4-[3- (dimethylamino) azetidin-1-yl]phenyl]- 3-methyl-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
E010, 138022- 85-2
I10
455
456





E012


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ethyl 1-[3-(3,3- dimethylazetidin-1- yl)phenyl]-3- isopropyl-4-(4- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylate
E001, 19816- 92-3
I8
553
554





E013


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ethyl 1-[3-(3- fluoropyrrolidin-1- yl)phenyl]-3- isopropyl-4-(4- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylate
E001, 116574- 74-4
I8
553
558





E014


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ethyl 1-cyclohexyl- 3-isopropyl-4-[6- [methyl (tetrahydropyran- 4-yl)amino]-3- pyridyl]pyrazolo[3,4- b]pyridine-6- carboxylate
ALP10, AMP23
I1
505
506





E015


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ethyl 1-[3- (dimethylamino) phenyl]-3-isopropyl- 4-(6-morpholino-3- pyridyl)pyrazolo[3,4- b]pyridine-6- carboxylate
ALP26, AMP06
I1
514
515





E016


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ethyl 1-[3- (dimethylamino) phenyl]-3-isopropyl- 4-(2-morpholino- pyrimidin- 5-yl)pyrazolo[3,4- b]pyridine-6- carboxylate
ALP22, AMP06
I1
515
516





E017


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ethyl 3-cyclobutyl-4- [6-[2- methoxyethyl(methyl) amino]-3-pyridyl]- 1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
ALP08, AMP26
I1
485
486





E018


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ethyl 4-[6-(4-cyano- 1-piperidyl)-3- pyridyl]-3- cyclobutyl-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
ALP09, AMP29
I1
506
507





E019


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ethyl 3-cyclobutyl-4- [6-[methyl (tetrahydropyran- 4-yl)amino]-3- pyridyl]-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
ALP10, AMP29
I1
511
512





E020


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ethyl 3-cyclobutyl-4- [4-[2- methoxyethyl(methyl) amino]phenyl]-1- phenyl-pyrazolo[3,4- b]pyridine-6- carboxylate
ALP11, AMP29
I1
484
485





E021


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ethyl 4-(4- acetamidophenyl)-1- cyclohexyl-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
ALP24, AMP23
I1
448
449





E022


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ethyl 4-[4-(4-cyano- 1-piperidyl)phenyl]- 1-cyclohexyl-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
ALP12, AMP23
I1
499
500





E023


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ethyl 4-[4-(4-cyano- 1-piperidyl)phenyl]- 1-[3-(dimethylamino) phenyl]-3-isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
ALP12, AMP06
I1
536
537





E024


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ethyl 1-[3- (dimethylamino) phenyl]-3- isopropyl-4-[4-[2- methoxyethyl(methyl) amino]phenyl] pyrazolo [3,4-b]pyridine-6- carboxylate
ALP11, AMP06
I1
515
516





E025


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ethyl 4-[6-(4-cyano- 1-piperidyl)-3- pyridyl]-1-[3- (dimethylamino) phenyl]-3-isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
ALP09, AMP06
I1
537
538





E026


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ethyl 1-[3- (dimethylamino) phenyl]-3-isopropyl- 4-[6-[2- methoxyethyl(methyl) amino]-3- pyridyl]pyrazolo[3,4- b]pyridine-6- carboxylate
ALP08, AMP06
I1
516
517





E027


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ethyl 4-[6-(4-cyano- 1-piperidyl)-3- pyridyl]-3-isopropyl- 1-(3-morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylate
ALP09, AMP10
I1
579
580





E028


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ethyl 3-isopropyl-4- [6-[2- methoxyethyl(methyl) amino]-3-pyridyl]- 1-(3-morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylate
ALP08, AMP10
I1
558
559





E029


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ethyl 3-isopropyl-4- [6-[methyl (tetrahydropyran- 4-yl)amino]-3- pyridyl]-1-(3- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylate
ALP10, AMP10
I1
584
585





E030


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ethyl 3-isopropyl-4- [4-[2- methoxyethyl(methyl) amino]phenyl]-1-(3- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylate
ALP11, AMP10
I1
557
558





E031


embedded image


ethyl 1-[3- (dimethylamino) phenyl]-3-isopropyl- 4-[6-[methyl (tetrahydropyran- 4-yl)amino]-3- pyridyl]pyrazolo[3,4- b]pyridine-6- carboxylate
ALP10, AMP06
I1
542
543





E032


embedded image


ethyl 1-[3- (dimethylamino) phenyl]-3-isopropyl- 4-[2-[methyl (tetrahydropyran-4- yl)amino]pyrimidin- 5-yl]pyrazolo[3,4- b]pyridine-6- carboxylate
ALP13, AMP06
I1
543
544





E033


embedded image


ethyl 1-cyclohexyl- 3-cyclopropyl-4-[6- (dimethylamino)-3- pyridyl]pyrazolo[3,4- b]pyridine-6- carboxylate
ALP20, AMP39
I1
433
434





E034


embedded image


ethyl 4-[2-(4-cyano-1- piperidyl)pyrimidin- 5-yl]-1-[3- (dimethylamino) phenyl]-3-isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
ALP14, AMP06
I1
538
539





E035


embedded image


ethyl 1-[3- (dimethylamino) phenyl]-3-isopropyl- 4-[4-[methyl (tetrahydropyran-4- yl)amino]phenyl] pyrazolo [3,4-b]pyridine- 6-carboxylate
ALP15, AMP06
I1
541
542





E036


embedded image


ethyl 3-isopropyl-4- [4-[methyl (tetrahydropyran-4- yl)amino]phenyl]-1- (3-morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylate
ALP15, AMP10
I1
583
584





E037


embedded image


ethyl 4-[2-(4-cyano-1- piperidyl)pyrimidin- 5-yl]-3-isopropyl-1- (3-morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylate
ALP14, AMP10
I1
580
581





E038


embedded image


ethyl 4-[4-[3- (dimethylamino) pyrrolidin-1-yl] phenyl]- 3-methyl-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
E010, 69478- 75-7
I10
469
470





E039


embedded image


ethyl 3-isopropyl-1- (m-tolyl)-4-(1- piperidyl)pyrazolo[3, 4-b]pyridine-6- carboxylate
HP01, 98-77-1
I3
406
407





E040


embedded image


ethyl 4-[4-(4-cyano- 1-piperidyl)phenyl]- 3-cyclobutyl-1- cyclohexyl- pyrazolo[3,4- b]pyridine-6- carboxylate
ALP12, AMP35
I1
511
512





E041


embedded image


ethyl 4-[6-(4-cyano- 1-piperidyl)-3- pyridyl]-3- cyclobutyl-1- cyclohexyl- pyrazolo[3,4- b]pyridine-6- carboxylate
ALP09, AMP35
I1
512
513





E042


embedded image


ethyl 4-(4- acetamidophenyl)-1- (3,5-difluorophenyl)- 3-(1-methoxycarbonyl- azetidin-3- yl)pyrazolo[3,4- b]pyridine-6- carboxylate
E043
I11B
549
550





E043


embedded image


ethyl 4-(4- acetamidophenyl)-3- (azetidin-3-yl)-1- (3,5-difluorophenyl) pyrazolo [3,4-b]pyridine-6- carboxylate
E044
I21A
491
492





E044


embedded image


ethyl 4-(4- acetamidophenyl)-3- (1-tert- butoxycarbonyl- azetidin-3-yl)-1-(3,5- difluorophenyl) pyrazolo [3,4-b]pyridine-6- carboxylate
ALP24, AMP40
I1
591
592





E045


embedded image


ethyl 3-isopropyl-4- [4-[2- methoxyethyl(methyl) amino]phenyl]-1-(3- pyrrolidin-1- ylphenyl)pyrazolo[3, 4-b]pyridine-6- carboxylate
ALP11, AMP11
I1
541
542





E046


embedded image


ethyl 3-isopropyl-4- [4-[methyl (tetrahydropyran-4- yl)amino]phenyl]-1- (3-pyrrolidin-1- ylphenyl)pyrazolo[3, 4-b]pyridine-6- carboxylate
ALP15, AMP11
I1
567
568





E047


embedded image


ethyl 3-cyclobutyl-4- [4-[methyl (tetrahydropyran-4- yl)amino]phenyl]-1- (3-pyrrolidin-1- ylphenyl)pyrazolo[3, 4-b]pyridine-6- carboxylate
ALP15, AMP31
I1
580
581





E048


embedded image


ethyl 3-isopropyl-4- (4-methoxy-1- piperidyl)-1-(m- tolyl)pyrazolo[3,4- b]pyridine-6- carboxylate
HP01, 4045-24- 3
I3
436
437





E049


embedded image


ethyl 4-[2-(4-cyano- 1-piperidyl)pyrimidin- 5-yl]-1-cyclohexyl- 3-isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
ALP14, AMP23
I1
501
502





E050


embedded image


ethyl 1-cyclohexyl- 3-isopropyl-4-[2-[2- methoxyethyl(methyl) amino]pyrimidin-5- yl]pyrazolo[3,4- b]pyridine-6- carboxylate
ALP16, AMP23
I1
480
481





E051


embedded image


ethyl 1-cyclohexyl- 3-isopropyl-4-[2- [methyl (tetrahydropyran-4- yl)amino]pyrimidin- 5-yl]pyrazolo[3,4- b]pyridine-6- carboxylate
ALP13, AMP23
I1
506
507





E052


embedded image


ethyl 4-[6-(4-cyano- 1-piperidyl)-3- pyridyl]-3-isopropyl- 1-[3-(trifluoromethyl) phenyl]pyrazolo[3,4- b]pyridine-6- carboxylate
ALP09, AMP08
I1
562
563





E053


embedded image


ethyl 1-[6- (dimethylamino)-2- pyridyl]-3-isopropyl- 4-(4-morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylate
ALP18, AMP18
I1
514
515





E054


embedded image


ethyl 3-isopropyl-4- (4-morpholinophenyl)- 1-[3-(trifluoromethoxy) phenyl]pyrazolo[3,4- b]pyridine-6- carboxylate
E055, 179113- 90-7
I4
554
555





E055


embedded image


ethyl 3-isopropyl-4- (4-morpholinophenyl)- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E056
I15
394
395





E056


embedded image


ethyl 1-[(2,4- dimethoxyphenyl) methyl]-3-isopropyl- 4-(4-morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylate
ALP18, AMP28
I1
544
545





E057


embedded image


ethyl 1-(3,4- difluorophenyl)-3- isopropyl-4-(4- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylate
E055
I4
506
507





E058


embedded image


ethyl 3-isopropyl-4- (4-morpholinophenyl)- 1-(6-morpholino-2- pyridyl)pyrazolo[3,4- b]pyridine-6- carboxylate
ALP18, AMP19
I1
556
557





E059


embedded image


ethyl 4-(2,6-difluoro- 4-methoxy-phenyl)- 1-(3-fluoro-5- methoxy-phenyl)-3- methyl-pyrazolo[3,4- b]pyridine-6- carboxylate
ALP17, AMP03
I1
471
472





E060


embedded image


ethyl 4-[4-(4-cyano- 1-piperidyl)phenyl]- 1-(3,5- difluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
ALP12, AMP09
I1
529
530





E061


embedded image


ethyl 4-[4-(4-cyano- 1-piperidyl)phenyl]- 1-(3-fluorophenyl)- 3-isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
ALP12, AMP12
I1
511
512





E062


embedded image


ethyl 3-isopropyl-4- [4-[2- methoxyethyl(methyl) amino]phenyl]-1-[3- (trifluoromethyl) phenyl]pyrazolo[3,4- b]pyridine-6- carboxylate
ALP11, AMP08
I1
540
541





E063


embedded image


ethyl 3-isopropyl-4- [6-[methyl (tetrahydropyran- 4-yl)amino]-3- pyridyl]-1-[3- (trifluoromethyl) phenyl]pyrazolo[3,4- b]pyridine-6- carboxylate
ALP10, AMP08
I1
567
568





E064


embedded image


ethyl 1-(4- fluorophenyl)-3- isopropyl-4-[2- [methyl (tetrahydropyran-4- yl)amino]pyrimidin- 5-yl]pyrazolo[3,4- b]pyridine-6- carboxylate
ALP13, AMP13
I1
518
519





E065


embedded image


ethyl 4-[4-(4-cyano- 1-piperidyl)phenyl]- 3-isopropyl-1-[3- (trifluoromethyl) phenyl] pyrazolo[3,4- b]pyridine-6- carboxylate
ALP12, AMP08
I1
561
562





E066


embedded image


ethyl 3-isopropyl-4- (4-morpholinophenyl)- 1-(2-morpholino-4- pyridyl)pyrazolo[3,4- b]pyridine-6- carboxylate
ALP18, AMP21
I1
556
557





E067


embedded image


ethyl 3-(1- methylcyclobutyl)-4- (4-morpholinophenyl)- 1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
ALP18, AMP41
I1
496
497





E068


embedded image


ethyl 4-[2-(4-cyano- 1-piperidyl)pyrimidin- 5-yl]-1-(2,4- difluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
ALP14, AMP14
I1
531
532





E069


embedded image


ethyl 4-[6-(4-cyano- 1-piperidyl)-3- pyridyl]-1-(2,4- difluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
ALP09, AMP14
I1
530
531





E070


embedded image


ethyl 4-[4-(4-cyano- 1-piperidyl)phenyl]- 1-(2,4- difluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
ALP12, AMP14
I1
529
530





E071


embedded image


methyl 3-cyclobutyl- 4-(4-methoxy-1- piperidyl)-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
420
421





E072


embedded image


ethyl 1-[3- (dimethylamino) phenyl]-3-isopropyl-4- [4-(methoxymethyl)- 1-piperidyl]pyrazolo[3, 4-b]pyridine-6- carboxylate
HP03
I3
479
480





E073


embedded image


ethyl 4-[6-(4-cyano- 1-piperidyl)-3- pyridyl]-3-isopropyl- 1-tetrahydropyran-3- yl-pyrazolo[3,4- b]pyridine-6- carboxylate
ALP09, AMP25
I1
502
503





E074


embedded image


ethyl 4-[4-(3- benzyloxypyrrolidin- 1-yl)phenyl]-3- methyl-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
AI12
I9
532
533





E075


embedded image


ethyl 4-(2,2-difluoro- 5-azaspiro[2.4]heptan- 5-yl)-3-isopropyl-1- (m-tolyl) pyrazolo[3,4- b]pyridine-6- carboxylate
HP01
I3
454
455





E076


embedded image


ethyl 1-cyclohexyl- 3-isopropyl-4-(4- methoxy-1- piperidyl)pyrazolo[3, 4-b]pyridine-6- carboxylate
HP04
I3
428
429





E077


embedded image


methyl 3-cyclobutyl- 4-(4-isopropoxy-1- piperidyl)-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
448
449





E078


embedded image


methyl 3-cyclobutyl- 1-phenyl-4-(4- propoxy-1- piperidyl)pyrazolo[3, 4-b]pyridine-6- carboxylate
HP02
I3
448
449





E079


embedded image


methyl 3-cyclobutyl- 4-[3- (methoxymethyl)-1- piperidyl]-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
434
435





E080


embedded image


methyl 3-cyclobutyl- 4-[4-(2-oxo-2- pyrrolidin-1-yl- ethoxy)-1-piperidyl]- 1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
517
518





E081


embedded image


ethyl 1-[3- (dimethylamino) phenyl]-3-isopropyl- 4-(4-methoxy-1- piperidyl)pyrazolo[3, 4-b]pyridine-6- carboxylate
HP03
I3
465
466





E082


embedded image


ethyl 3-isopropyl-4- [4-(methoxymethyl)- 1-piperidyl]-1-(m- tolyl)pyrazolo[3,4- b]pyridine-6- carboxylate
HP01
I3
450
451





E083


embedded image


ethyl 1-[3- (dimethylamino) phenyl]-3-isopropyl- 4-(1- piperidyl)pyrazolo[3, 4-b]pyridine-6- carboxylate
HP03
I3
435
436





E084


embedded image


ethyl 4-[6-(4-cyano- 1-piperidyl)-3- pyridyl]-3-isopropyl- 1-(2-pyrrolidin-1-yl- 4- pyridyl)pyrazolo[3,4- b]pyridine-6- carboxylate
ALP09, AMP22
I1
564
565





E085


embedded image


methyl 3-cyclobutyl- 4-(1-oxa-7- azaspiro[3.5]nonan- 7-yl)-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
432
433





E086


embedded image


ethyl 4-(4-cyano-1- piperidyl)-1-[3- (dimethylamino) phenyl]-3-isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP03
I3
460
461





E087


embedded image


ethyl 3-isopropyl-4- [4-(2-methoxyethyl)- 1-piperidyl]-1-(m- tolyl)pyrazolo[3,4- b]pyridine-6- carboxylate
HP01
I3
464
465





E088


embedded image


ethyl 3-isopropyl-4- (3-methoxy-1- piperidyl)-1-(m- tolyl)pyrazolo[3,4- b]pyridine-6- carboxylate
HP01
I3
436
437





E089


embedded image


ethyl 3-isopropyl-4- (4-methylsulfonyl-1- piperidyl)-1-(m- tolyl)pyrazolo[3,4- b]pyridine-6- carboxylate
HP01
I3
484
485





E090


embedded image


isopropyl 3- isopropoxy-4-(4- morpholinophenyl)- 1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
AI15
I17
500
501





E091


embedded image


methyl 1-(4- fluorophenyl)-3- isopropyl-4-(4- methoxy-1- piperidyl)pyrazolo[3, 4-b]pyridine-6- carboxylate
HP05
I3
426
427





E092


embedded image


methyl 1-(4- fluorophenyl)-3- isopropyl-4-[4- (methoxymethyl)-1- piperidyl]pyrazolo[3, 4-b]pyridine-6- carboxylate
HP05
I3
440
441





E093


embedded image


ethyl 4-[4-(4-cyano- 1-piperidyl)phenyl]- 3-isopropyl-1-(2- pyrrolidin-1-yl-4- pyridyl)pyrazolo[3,4- b]pyridine-6- carboxylate
ALP12, AMP22
I1
563
564





E094


embedded image


ethyl 3-isopropyl-4-[2- methoxyethyl(methyl) amino]-1-(m- tolyl)pyrazolo[3,4- b]pyridine-6- carboxylate
HP01
I3
410
411





E095


embedded image


ethyl 3-isopropyl-1- (m-tolyl)-4-(8-oxa-2- azaspiro[4.5]decan- 2-yl)pyrazolo[3,4- b]pyridine-6- carboxylate
HP01
I3
462
463





E096


embedded image


methyl 4-(4-butoxy- 1-piperidyl)-1-(4- fluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP05
I3
468
467





E097


embedded image


methyl 1-(4- fluorophenyl)-3- isopropyl-4-(4- methoxy-4-methyl-1- piperidyl)pyrazolo[3, 4-b]pyridine-6- carboxylate
HP05
I3
440
441





E098


embedded image


methyl 1-(4- fluorophenyl)-4-(4- isobutoxy-1- piperidyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP05
I3
468
469





E099


embedded image


methyl 1-(4- fluorophenyl)-3- isopropyl-4-(1-oxa-7- azaspiro[3.5]nonan- 7-yl)pyrazolo[3,4- b]pyridine-6- carboxylate
HP05
I3
438
439





E100


embedded image


methyl 4-[3- (difluoromethyl)-1- piperidyl]-1-(4- fluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP05
I3
446
447





E101


embedded image


methyl 1-(4- fluorophenyl)-3- isopropyl-4-(6-oxa-2- azaspiro[3.5]nonan- 2-yl)pyrazolo[3,4- b]pyridine-6- carboxylate
HP05
I3
438
439





E102


embedded image


methyl 1-(4- fluorophenyl)-3- isopropyl-4-(1-oxa-8- azaspiro[4.5]decan- 8-yl)pyrazolo[3,4- b]pyridine-6- carboxylate
HP05
I3
452
453





E103


embedded image


methyl 3-cyclobutyl- 1-phenyl-4-(1- piperidyl)pyrazolo[3, 4-b]pyridine-6- carboxylate
HP02
I3
390
391





E104


embedded image


methyl 3-cyclobutyl- 4-[4-(2- methoxyethyl)-1- piperidyl]-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
448
449





E105


embedded image


methyl 4-(2- azaspiro[3.4]octan-2- yl)-3-cyclobutyl-1- phenyl-pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
416
417





E106


embedded image


methyl 3-cyclobutyl- 4-[4- (methoxymethyl)-1- piperidyl]-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
434
435





E107


embedded image


methyl 4-(3- azabicyclo[3.1.0] hexan-3-yl)-3- cyclobutyl-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
388
389





E108


embedded image


ethyl 1-(2-bromo-4- pyridyl)-3-isopropyl- 4-(4-methoxy-1- piperidyl)pyrazolo[3, 4-b]pyridine-6- carboxylate
E109
I4
501-503
502-504





E109


embedded image


ethyl 3-isopropyl-4- (4-methoxy-1- piperidyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP08
I3
346
347





E110


embedded image


ethyl 3-isopropyl-4- (4-methoxy-1- piperidyl)-1-(2- pyrrolidin-1-yl-4- pyridyl)pyrazolo[3,4- b]pyridine-6- carboxylate
E111
I12
492
493





E111


embedded image


ethyl 1-(2-fluoro-4- pyridyl)-3-isopropyl- 4-(4-methoxy-1- piperidyl)pyrazolo[3, 4-b]pyridine-6- carboxylate
E109
I4
441
442





E112


embedded image


ethyl 4-[6-(4-cyano- 1-piperidyl)-3- pyridyl]-3- cyclobutyl-1-(2- pyrrolidin-1-yl-4- pyridyl)pyrazolo[3,4- b]pyridine-6- carboxylate
ALP09, AMP34
I1
576
577





E113


embedded image


methyl 3-cyclobutyl- 4-(4-methylsulfonyl- 1-piperidyl)-1- phenyl-pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
468
469





E114


embedded image


methyl 4-(4-cyanol-1- piperidyl)-3- cyclobutyl-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
415
416





E115


embedded image


methyl 4-(2- azaspiro[3.5]nonan- 2-yl)-3-cyclobutyl-1- phenyl-pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
430
431





E116


embedded image


methyl 3-cyclobutyl- 4-[3-(methoxymethyl) azetidin- 1-yl]-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
406
407





E117


embedded image


ethyl 4-[6-(4-cyano- 1-piperidyl)-3- pyridyl]-3-(3- methoxycyclobutyl)- 1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
ALP09, AMP42
I1
536
537





E118


embedded image


ethyl 4-[6-(4-cyano- 1-piperidyl)-3- pyridyl]-3-(3,3- difluorocyclobutyl)- 1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
ALP09, AMP43
I1
542
543





E119


embedded image


ethyl 4-[6-(4-cyano- 1-piperidyl)-3- pyridyl]-3-(3,3- dimethylcyclobutyl)- 1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
ALP09, AMP44
I1
534
535





E120


embedded image


ethyl 4-[6-(4-cyano- 1-piperidyl)-3- pyridyl]-3-(3- fluorocyclobutyl)-1- phenyl-pyrazolo[3,4- b]pyridine-6- carboxylate
ALP09, AMP45
I1
524
525





E121


embedded image


ethyl 4-[6-(4-cyano- 1-piperidyl)-3- pyridyl]-3- cyclobutyl-1-(2- morpholino-4- pyridyl)pyrazolo[3,4- b]pyridine-6- carboxylate
ALP09, AMP33
I1
592
593





E122


embedded image


methyl 3-cyclobutyl- 4-(2,2-difluoro-5- azaspiro[2.4]heptan- 5-yl)-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
438
439





E123


embedded image


methyl 3-cyclobutyl- 4-(5-oxa-2- azaspiro[3.5]nonan- 2-yl)-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
432
433





E124


embedded image


methyl 3-cyclobutyl- 4-(7-oxa-2- azaspiro[3.5]nonan- 2-yl)-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
432
433





E125


embedded image


methyl 4-(5- azaspiro[2.5]octan-5- yl)-3-cyclobutyl-1- phenyl-pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
416
417





E126


embedded image


methyl 3-cyclobutyl- 4-[2- methoxyethyl(methyl) amino]-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
394
395





E127


embedded image


methyl 4-[4- (benzyloxymethyl)- 1-piperidyl]-3- cyclobutyl-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
510
511





E128


embedded image


methyl 4-(2- azaspiro[3.3]heptan- 2-yl)-3-cyclobutyl-1- phenyl-pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
402
403





E129


embedded image


methyl 3-cyclobutyl- 4-(1- methoxycarbonyl- 3,3a,4,6,7,7a- hexahydro-2H- pyrrolo[3,2- c]pyridin-5-yl)-1- phenyl-pyrazolo[3,4- b]pyridine-6- carboxylate
E130
I11B
489
490





E130


embedded image


methyl 4- (1,2,3,3a,4,6,7,7a- octahydropyrrolo[3,2- c]pyridin-5-yl)-3- cyclobutyl-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
E131
I21B
431
432





E131


embedded image


methyl 4-(1-tert- butoxycarbonyl- 3,3a,4,6,7,7a- hexahydro-2H- pyrrolo[3,2- c]pyridin-5-yl)-3- cyclobutyl-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
531
532





E132


embedded image


methyl 4-(1-acetyl- 3,3a,4,6,7,7a- hexahydro-2H- pyrrolo[3,2- c]pyridin-5-yl)-3- cyclobutyl-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
E130
I11B
473
474





E133


embedded image


ethyl 1-(6-bromo-2- pyridyl)-3-isopropyl- 4-(4-methoxy-1- piperidyl)pyrazolo[3, 4-b]pyridine-6- carboxylate
E109
I5
501- 503
502- 504





E134


embedded image


methyl 1-cyclohexyl- 4-[4- (hydroxymethyl)-1- piperidyl]-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP12
I3
414
415





E135


embedded image


methyl 3-cyclobutyl- 4-[4-[(1S)-2- (dimethylamino)-1- fluoro-ethyl]-1- piperidyl]-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02, AMI03
I3
479
480





E136


embedded image


methyl 1-(4- fluorophenyl)-4-[4- (1-hydroxy-1- methyl-ethyl)-1- piperidyl]-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP05
I3
454
455





E137


embedded image


ethyl 1-(3- fluorophenyl)-3- isopropyl-4-[6- [methyl (tetrahydropyran- 4-yl)amino]-3- pyridyl]pyrazolo[3,4- b]pyridine-6- carboxylate
ALP10, AMP12
I1
517
518





E138


embedded image


ethyl 4-[6-(4-cyano- 1-piperidyl)-3- pyridyl]-3-isopropyl- 1-(2-morpholino-4- pyridyl)pyrazolo[3,4- b]pyridine-6- carboxylate
ALP09, AMP21
I1
580
581





E139


embedded image


methyl 3-cyclobutyl- 4-[4-(cyclopentoxy)- 1-piperidyl]-1- phenyl-pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
474
475





E140


embedded image


methyl 3-cyclobutyl- 4-[4-(cyclohexoxy)- l-piperidyl]-1- phenyl-pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
488
489





E141


embedded image


methyl 3-cyclobutyl- 4-[4- (cyclopropylmethoxy)- 1-piperidyl]-1- phenyl-pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
460
461





E142


embedded image


ethyl 4-(4-cyano-1- piperidyl)-1-(4- fluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP09
I3
435
436





E143


embedded image


methyl 3-cyclobutyl- 4-[4-(1- hydroxyethyl)-1- piperidyl]-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
434
435





E144


embedded image


methyl 3-cyclobutyl- 1-phenyl-4-[4-(2,2,2- trifluoro-1-hydroxy- 1-methyl-ethyl)-1- piperidyl]pyrazolo[3, 4-b]pyridine-6- carboxylate
HP02
I3
502
503





E145


embedded image


ethyl 4-[6-[bis(2- methoxyethyl)amino]- 3-pyridyl]-3- cyclobutyl-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
ALP23, AMP29
I1
529
530





E146


embedded image


methyl 3-cyclobutyl- 4-[4-hydroxy-4- (methoxymethyl)-1- piperidyl]-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02, AMI01
I3
450
451





E147


embedded image


ethyl 1-(2-fluoro-4- pyridyl)-3-isopropyl- 4-[4- (methoxymethyl)-1- piperidyl]pyrazolo[3, 4-b]pyridine-6- carboxylate
E148
I4
455
456





E148


embedded image


ethyl 3-isopropyl-4- [4-(methoxymethyl)- 1-piperidyl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP08
I3
360
361





E149


embedded image


ethyl 4-[6-[bis(2- methoxyethyl)amino]- 3-pyridyl]-3- isopropyl-1-(2- morpholino-4- pyridyl)pyrazolo[3,4- b]pyridine-6- carboxylate
ALP23, AMP21
I1
603
604





E150


embedded image


methyl 3-cyclobutyl- 4-[4-[(1,1-dioxo-1,4- thiazinan-4- yl)methyl]-4- hydroxy-1- piperidyl]-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02, AMI02
I3
553
554





E151


embedded image


ethyl 4-[6-(4-cyano- 1-piperidyl)-3- pyridyl]-3-(3- methylcyclobutyl)-1- phenyl-pyrazolo[3,4- b]pyridine-6- carboxylate
ALP09, AMP46
I1
520
521





E152


embedded image


ethyl 3-[(1-tert- butoxycarbonyl-4- piperidyl)oxy]-4-[6- (4-cyano-1- piperidyl)-3- pyridyl]-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
E153
I3
651






E153


embedded image


ethyl 4-[6-(4-cyano- 1-piperidyl)-3- pyridyl]-3-oxo-1- phenyl-2H- pyrazolo[3,4- b]pyridine-6- carboxylate
ALP09, 70373- 98-7
I1
468
469





E154


embedded image


ethyl 1- (cyclobutylmethyl)- 3-isopropyl-4-[4- (methoxymethyl)-1- piperidyl]pyrazolo[3, 4-b]pyridine-6- carboxylate
E148
I6
428
429





E155


embedded image


ethyl 1-isobutyl-3- isopropyl-4-[4- (methoxymethyl)-1- piperidyl]pyrazolo[3, 4-b]pyridine-6- carboxylate
E148
I6
416
417





E156


embedded image


methyl 1-(4- fluorophenyl)-3- isopropyl-4-[4- (2,2,2- trifluoroethyl)piperazin- 1-yl]pyrazolo[3,4- b]pyridine-6- carboxylate
HP05
I3
479
480





E157


embedded image


ethyl 3-isopropyl-4- [4-(methoxymethyl)- 1-piperidyl]-1-(1- methyl-6-oxo- pyridazin-3- yl)pyrazolo[3,4- b]pyridine-6- carboxylate
E148
I7
468
469





E158


embedded image


methyl 3-cyclobutyl- 4-(4- isopropylpiperazin- 1-yl)-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
433
434





E159


embedded image


ethyl 4-[6-(4-cyano- 1-piperidyl)-3- pyridyl]-1-phenyl-3- tetrahydrofuran-3- yloxy-pyrazolo[3,4- b]pyridine-6- carboxylate
E153
I13
538
539





E160


embedded image


ethyl 3-isopropyl-4- [4-(methoxymethyl)- 1-piperidyl]-1-(2- morpholinopyrimidin- 4-yl)pyrazolo[3,4- b]pyridine-6- carboxylate
E161
I12
523
524





E161


embedded image


ethyl 1-(2- chloropyrimidin-4- yl)-3-isopropyl-4-[4- (methoxymethyl)-1- piperidyl]pyrazolo[3, 4-b]pyridine-6- carboxylate
E148
I5
472- 474
473- 475





E162


embedded image


methyl 4-(4- cyclobutylpiperazin- 1-yl)-1-(4- fluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP05
I3
451
452





E163


embedded image


methyl 3-cyclobutyl- 4-[4-(1-hydroxy-1- methyl-ethyl)-1- piperidyl]-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
448
449





E164


embedded image


ethyl 4-[6-(4-cyano- 1-piperidyl)-3- pyridyl]-3-(oxetan-3- yloxy)-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
E153
I13
524
525





E165


embedded image


methyl 1-(4- fluorophenyl)-3- isopropyl-4-[2- methoxyethyl(methyl) amino]pyrazolo[3,4- b]pyridine-6- carboxylate
HP05
I3
400
401





E166


embedded image


methyl 1-(4- fluorophenyl)-4-[4- (1-hydroxy-1- methyl-ethyl)-1- piperidyl]-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP05
I3
454
455





E167


embedded image


ethyl 3-cyclobutyl-1- (4-fluorophenyl)-4- [4-(methoxymethyl)- 1-piperidyl]pyrazolo[3, 4-b]pyridine-6- carboxylate
E168
I4
466
467





E168


embedded image


ethyl 3-cyclobutyl-4- [4-(methoxymethyl)- 1-piperidyl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E169
I15
372
373





E169


embedded image


ethyl 3-cyclobutyl-1- [(2,4- dimethoxyphenyl) methyl]-4-[4- (methoxymethyl)-1- piperidyl]pyrazolo[3, 4-b]pyridine-6- carboxylate
HP14
I3
522
523





E170


embedded image


methyl 3-cyclobutyl- 4-[4-(1-hydroxy-1- methyl-ethyl)-1- piperidyl]-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
448
449





E171


embedded image


ethyl 3-cyclobutyl-1- (4-fluorophenyl)-4- (tetrahydropyran-4- ylmethoxy)pyrazolo [3,4-b]pyridine-6- carboxylate
E172
I16
453
454





E172


embedded image


ethyl 3-cyclobutyl-4- (tetrahydropyran-4- ylmethoxy)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E173
I15
359
360





E173


embedded image


ethyl 3-cyclobutyl-1- [(2,4- dimethoxyphenyl) methyl]-4- (tetrahydropyran-4- ylmethoxy)pyrazolo [3,4-b]pyridine-6- carboxylate
HP15
I14
509
510





E174


embedded image


methyl 4-[4- (dimethylamino)-1- piperidyl]-1-(4- fluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP05
I3
439
440





E175


embedded image


methyl 1-(4- fluorophenyl)-3- isopropyl-4-[4-(1- methyl-4-piperidyl)-1- piperidyl]pyrazolo[3, 4-b]pyridine-6- carboxylate
HP05
I3
493
494





E176


embedded image


methyl 4-[(l-acetyl-4- piperidyl)methoxy]- 1-(4-fluorophenyl)- 3-isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
E177
I11B
468
469





E177


embedded image


methyl 1-(4- fluorophenyl)-3- isopropyl-4-(4- piperidylmethoxy) pyrazolo[3,4- b]pyridine-6- carboxylate
AI22
I9
426
427





E178


embedded image


methyl 1-(4- fluorophenyl)-3- isopropyl-4-[(1- methoxycarbonyl-4- piperidyl)methoxy] pyrazolo[3,4- b]pyridine-6- carboxylate
E177
I11B
484
485





E179


embedded image


methyl 4-[4- (cyanomethyl)-4- hydroxy-1- piperidyl]-3- cyclobutyl-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02, AMI09
I3
445
446





E180


embedded image


methyl 3-cyclobutyl- 1-phenyl-4-[4-(2,2,2- trifluoroethyl)piperazin- 1-yl]pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
473
474





E181


embedded image


ethyl 1-(2-fluoro-4- pyridyl)-3-isopropyl- 4-(tetrahydropyran-4- ylmethoxy)pyrazolo [3,4-b]pyridine-6- carboxylate
E182
I4
442
443





E182


embedded image


ethyl 3-isopropyl-4- (tetrahydropyran-4- ylmethoxy)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E183
I15
347
348





E183


embedded image


ethyl l-[(2,4- dimethoxyphenyl) methyl]-3-isopropyl-4- (tetrahydropyran-4- ylmethoxy)pyrazolo [3,4-b]pyridine-6- carboxylate
HP06
I14
497
498





E184


embedded image


methyl 4-(4- ethoxycarbonyl- piperazin- 1-yl)-1-(4- fluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP05
I3
469
470





E185


embedded image


methyl 1-(4- fluorophenyl)-3- isopropyl-4-(3- methyl-2-oxo-1-oxa- 3,8- diazaspiro[4.5]decan- 8-yl)pyrazolo[3,4- b]pyridine-6- carboxylate
HP05
I3
481
482





E186


embedded image


methyl 1-(4- fluorophenyl)-3- isopropyl-4-[3- (trifluoromethyl) piperazin-1- yl]pyrazolo[3,4- b]pyridine-6- carboxylate
HP05
I3
465
466





E187


embedded image


methyl 1-(4- fluorophenyl)-3- isopropyl-4-[4-(2- methoxyethyl) piperazin-1- yl]pyrazolo[3,4- b]pyridine-6- carboxylate
HP05
I3
455
456





E188


embedded image


methyl 4-(2,4-dioxo- 1,3,8- triazaspiro[4.5]decan- 8-yl)-1-(4- fluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP05
I3
480
481





E189


embedded image


methyl 4-[4- (ethoxymethyl)-4- fluoro-1-piperidyl]- 1-(4-fluorophenyl)- 3-isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP05, AMI04
I3
472
473





E190


embedded image


methyl 4-[4-fluoro- 4-(2- methoxyethoxymethyl)- 1-piperidyl]-1-(4- fluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP05, AMI05
I3
502
503





E191


embedded image


methyl 4-[(3R,4R)-3- fluoro-4-hydroxy-1- piperidyl]-1-(4- fluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP05, AMI06
I3
430
431





E192


embedded image


methyl 4-[4-fluoro- 4-(methoxymethyl)- 1-piperidyl]-1-(4- fluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP05, AMI07
I3
458
459





E193


embedded image


methyl 4-[3-fluoro- 3-(2- methoxyethoxymethyl)- 1-piperidyl]-1-(4- fluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP05, AMI08
I3
502
503





E194


embedded image


methyl 1-(4- fluorophenyl)-3- isopropyl-4-[4-(1- piperidyl)-1- piperidyl]pyrazolo[3, 4-b]pyridine-6- carboxylate
HP05
I3
479
480





E195


embedded image


ethyl 1-(2,6- dimethyl-4-pyridyl)- 3-isopropyl-4-[4- (methoxymethyl)-1- piperidyl]pyrazolo[3, 4-b]pyridine-6- carboxylate
E148
I4
465
466





E196


embedded image


methyl 3-cyclobutyl- 4-(1,1-dioxo-1,4- thiazinan-4-yl)-1- phenyl-pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
440
441





E197


embedded image


methyl 4-(1-tert- butoxycarbonyl-4- piperidyl)-1-(4- fluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
E198
Specific example
496
497





E198


embedded image


methyl 4-(1-tert- butoxycarbonyl-3,6- dihydro-2H-pyridin- 4-yl)-1-(4- fluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP05
I2, Specific example
494
495





E199


embedded image


methyl 4-(4- azidophenyl)-1-[3- (dimethylamino) phenyl]-3-isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
E200
Specific example
455
456





E200


embedded image


methyl 4-(4- bromophenyl)-1-[3- (dimethylamino) phenyl]-3-isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
608128- 34-3, AMP06
I1
492- 494
493- 495





E201


embedded image


ethyl 3-methyl-4-[4-(4- methylsulfonyl- piperazin- 1-yl)phenyl]-1- phenyl-pyrazolo[3,4- b]pyridine-6- carboxylate
E324
I11A
519
520





E202


embedded image


ethyl 4-[4-(4-tert- butylpiperazin-1- yl)phenyl]-3-methyl- 1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
E010
I10
497
498





E203


embedded image


ethyl 4-[4-(4- methoxycarbonyl- piperazin-1-yl)phenyl]- 3-methyl-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
E324
I11B
499
500





E204


embedded image


ethyl 1-(1-acetyl-4- piperidyl)-3- isopropyl-4-(4- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylate
E325
I11B
519
520





E205


embedded image


ethyl 4-[4-(3,3- dimethylazetidin-1- yl)phenyl]-3-methyl- 1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
E010
I10
440
441





E206


embedded image


ethyl 3-methyl-1- phenyl-4-[4-[4- (3,3,3- trifluoropropyl) piperazin-1- yl]phenyl]pyrazolo[3, 4-b]pyridine-6- carboxylate
E324
I18
537
538





E208


embedded image


ethyl 1-[1- (cyanomethyl)-4- piperidyl]-3- isopropyl-4-(4- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylate
E325
I18
516
517





E209


embedded image


ethyl 4-[4-(3,3- difluoroazetidin-1- yl)phenyl]-3-methyl- 1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
E010
I10
448
449





E210


embedded image


ethyl 4-[4-[4- (cyanomethyl) piperazin- 1-yl]phenyl]-3- methyl-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
E324
I18
480
481





E211


embedded image


ethyl 4-[4-[4-(2- hydroxyethyl) piperazin- 1-yl]phenyl]-3- methyl-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
E324
I18
485
486





E212


embedded image


ethyl 4-[4-(4,4- difluoro-1- piperidyl)phenyl]-3- methyl-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
E010
I10
476
477





E213


embedded image


ethyl 4-[4-(4-cyano- 1-piperidyl)phenyl]- 3-methyl-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
E010
I10
465
466





E214


embedded image


ethyl 3-methyl-4-[4- [methyl (tetrahydropyran-4- yl)amino]phenyl]-1- phenyl-pyrazolo[3,4- b]pyridine-6- carboxylate
E010
I10
470
471





E215


embedded image


ethyl 4-[4-(3,3- difluoropyrrolidin-1- yl)phenyl]-3-methyl- 1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
E010
I10
462
463





E216


embedded image


ethyl 3-methyl-4-[4- (oxetan-3- ylamino)phenyl]-1- phenyl-pyrazolo[3,4- b]pyridine-6- carboxylate
E010
I10
428
429





E217


embedded image


ethyl 4-[4-(2,6- dimethylmorpholin- 4-yl)phenyl]-3- methyl-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
E010
I10
470
471





E218


embedded image


methyl 4-[4- [cyclobutyl(methyl) amino]phenyl]-3- methyl-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
E337
I18
426
427





E219


embedded image


ethyl 4-[4-[(3R,4R)- 3,4- dihydroxypyrrolidin- 1-yl]phenyl]-3- methyl-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
E010
I10
458
459





E220


embedded image


ethyl 3-isopropyl-4-(4- morpholinophenyl)- 1-[1-(2,2,2- trifluoroethyl)-4- piperidyl]pyrazolo[3, 4-b]pyridine-6- carboxylate
E325
I18
559
560





E221


embedded image


ethyl 4-[4-(2,2- dimethylmorpholin- 4-yl)phenyl]-3- methyl-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
E010
I10
470
471





E222


embedded image


ethyl 3-isopropyl-1-(3- morpholinophenyl)- 4-(4- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylate
E001
I8
555
556





E223


embedded image


ethyl 4-[4-(3- hydroxyazetidin-1- yl)phenyl]-3-methyl- 1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
E010
I10
428
429





E224


embedded image


ethyl 4-[4-(3- fluoroazetidin-1- yl)phenyl]-3-methyl- 1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
E010
I10
430
431





E225


embedded image


ethyl 3-methyl-4-[4- (2-oxa-6- azaspiro[3.3]heptan- 6-yl)phenyl]-1- phenyl-pyrazolo[3,4- b]pyridine-6- carboxylate
E010
I10
454
455





E226


embedded image


ethyl 3-methyl-4-[4- [(1S,4S)-2-oxa-5- azabicyclo[2.2.1] heptan-5-yl]phenyl]-1- phenyl-pyrazolo[3,4- b]pyridine-6- carboxylate
E010
I10
454
455





E227


embedded image


ethyl 4-(4- acetylpiperazin-1- yl)-3-methyl-1- phenyl-pyrazolo[3,4- b]pyridine-6- carboxylate
HP13
I3
407
408





E228


embedded image


ethyl 4-[4-[2- (hydroxymethyl) morpholin-4-yl] phenyl]- 3-methyl-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
E010
I10
472
473





E229


embedded image


ethyl 3-methyl-4-[4- (8-oxa-3- azabicyclo[3.2.1] octan-3-yl)phenyl]-1- phenyl-pyrazolo[3,4- b]pyridine-6- carboxylate
E010
I10
468
469





E230


embedded image


ethyl 4-[4-(azetidin- 1-yl)phenyl]-3- methyl-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
E010
I10
412
413





E231


embedded image


ethyl 4-[4- (cyanomethyl) piperazin- 1-yl]-3-methyl- 1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
E512
I18
404
405





E232


embedded image


ethyl 4-(4-hydroxy- 1-piperidyl)-3- methyl-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP13
I3
380
381





E233


embedded image


ethyl 4-(1-acetyl-4- piperidyl)-3-methyl- 1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
E327
I11B
406
407





E234


embedded image


ethyl 4-[1- (cyanomethyl)-4- piperidyl]-3-methyl- 1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
E327
I18
403
404





E235


embedded image


ethyl 3-methyl-4-[4- [methyl(oxetan-3- yl)amino]phenyl]-1- phenyl-pyrazolo[3,4- b]pyridine-6- carboxylate
E338
I19
442
443





E236


embedded image


ethyl 1-[1- (cyanomethyl) pyrrolidin-3-yl]-3- isopropyl-4-(4- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylate
E328
I18
502
503





E237


embedded image


ethyl 3-isopropyl-1-(1- methoxycarbonyl- pyrrolidin-3-yl)-4-(4- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylate
E328
I11B
521
522





E238


embedded image


ethyl 4-(4-hydroxy- 1-piperidyl)-3- methyl-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP13
I3
380
381





E239


embedded image


ethyl 4-[4-(4- hydroxy-1- piperidyl)phenyl]-3- methyl-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
E350
I20
456
457





E240


embedded image


ethyl 3-methyl-1- phenyl-4-[4- (tetrahydropyran-4- ylamino)phenyl] pyrazolo [3,4-b]pyridine- 6-carboxylate
E010
I10
46
457





E241


embedded image


ethyl 3-methyl-4-(4- methylsulfonyl- piperazin-1-yl)-1- phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
E512
I11A
443
444





E242


embedded image


ethyl 3-[1- (cyanomethyl)azetidin- 3-yl]-4-(4- morpholinophenyl)- 1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
E329
I18
508
509





E243


embedded image


ethyl 3-methyl-4-(2- oxo-1-piperidyl)-1- phenyl-pyrazolo[3,4- b]pyridine-6- carboxylate
HP13
I22
378
379





E244


embedded image


ethyl 4-[4-(3- hydroxypyrrolidin-1- yl)phenyl]-3-methyl- 1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
E074
I20
442
443





E245


embedded image


ethyl 3-methyl-4-[4- (2-oxa-7- azaspiro[3.5]nonan- 7-yl)phenyl]-1- phenyl-pyrazolo[3,4- b]pyridine-6- carboxylate
E010
I10
482
483





E246


embedded image


ethyl 4-[4-[(3S)-3- cyanopyrrolidin-1- yl]phenyl]-3-methyl- 1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
E010
I10
451
452





E247


embedded image


ethyl 3-methyl-1- phenyl-4- (piperidine-1- carbonyl)pyrazolo[3, 4-b]pyridine-6- carboxylate
E330
Specific example
392
393





E248


embedded image


ethyl 3-isopropyl-4-(4- morpholinophenyl)- 1-[1-(2,2,2- trifluoroethyl)-3- piperidyl]pyrazolo[3, 4-b]pyridine-6- carboxylate
E331
I18
559
560





E249


embedded image


ethyl 1-[3- (benzyloxy) cyclohexyl]- 4-[4-(morpholin- 4-yl)phenyl]-3- (propan-2-yl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
AI07
I9
582
583





E250


embedded image


ethyl 3-isopropyl-1- (m-tolyl)-4- pyrrolidin-1-yl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP01
I3
396
397





E251


embedded image


ethyl 4-(3- fluoroazetidin-1-yl)- 3-isopropyl-1-(m- tolyl)pyrazolo[3,4- b]pyridine-6- carboxylate
HP01
I3
396
397





E252


embedded image


ethyl 4-[6-(4-cyano- 1-piperidyl)-3- pyridyl]-3-isopropyl- 1-(m- tolyl)pyrazolo[3,4- b]pyridine-6- carboxylate
HP01, BOR1
I2A
508
509





E253


embedded image


ethyl 4-[6-(4-cyano- 1-piperidyl)-3- pyridyl]-1- cyclohexyl-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
AMP23, ALP09
I1
500
501





E254


embedded image


ethyl 1-cyclohexyl- 3-isopropyl-4-[4-[2- methoxyethyl(methyl) amino]phenyl]pyrazolo [3,4-b]pyridine- 6-carboxylate
AMP23, ALP11
I1
478
479





E255


embedded image


ethyl 4-(4-cyano-1- piperidyl)-3- isopropyl-1-(m- tolyl)pyrazolo[3,4- b]pyridine-6- carboxylate
HP01
I3
431
432





E256


embedded image


ethyl rac-1-[(1R,3R)-3- hydroxycyclohexyl]- 4-[4-(morpholin-4- yl)phenyl]-3- (propan-2-yl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E249
I20
492
493





E257


embedded image


ethyl rac-1-[(1R,3S)-3- hydroxycyclohexyl]- 4-[4-(morpholin-4- yl)phenyl]-3- (propan-2-yl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E249
I20
492
493





E258


embedded image


ethyl 4-[4-(4-cyano- 1-piperidyl)phenyl]- 3-isopropyl-1-(3- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylate
AMP10, ALP12
I1
578
579





E259


embedded image


ethyl 4-(4,4-difluoro- 1-piperidyl)-3- isopropyl-1-(m- tolyl)pyrazolo[3,4- b]pyridine-6- carboxylate
HP01
I3
442
443





E260


embedded image


ethyl 3-isopropyl-4-(4- morpholinophenyl)- 1-(5-morpholino-3- pyridyl)pyrazolo[3,4- b]pyridine-6- carboxylate
AMP81, ALP18
I1
556
557





E261


embedded image


ethyl 3-isopropyl-4- (3-methoxyazetidin- 1-yl)-1-(m- tolyl)pyrazolo[3,4- b]pyridine-6- carboxylate
HP01
I3
408
409





E262


embedded image


ethyl 4-[4- (hydroxymethyl)-1- piperidyl]-3- isopropyl-1-(m- tolyl)pyrazolo[3,4- b]pyridine-6- carboxylate
HP01
I3
436
437





E263


embedded image


ethyl 3-isopropyl-1- (m-tolyl)-4-[3- (trifluoromethyl) pyrrolidin-1- yl]pyrazolo[3,4- b]pyridine-6- carboxylate
HP01
I3
459
460





E264


embedded image


ethyl 4-(5-tert- butoxycarbonyl- 1,3,3a,4,6,6a- hexahydropyrrolo[3, 4-c]pyrrol-2-yl)-3- isopropyl-1-(m- tolyl)pyrazolo[3,4- b]pyridine-6- carboxylate
HP01
I3
533
534





E265


embedded image


ethyl 4-(3- cyanopyrrolidin-1- yl)-3-isopropyl-1- (m- tolyl)pyrazolo[3,4- b]pyridine-6- carboxylate
HP01
I3
417
418





E266


embedded image


ethyl 4-[4-(4-cyano- 1-piperidyl)phenyl]- 3-isopropyl-1-(3- pyrrolidin-1- ylphenyl)pyrazolo[3, 4-b]pyridine-6- carboxylate
AMP11, ALP12
I1
562
563





E267


embedded image


ethyl 4-[6-(4-cyano- 1-piperidyl)-3- pyridyl]-3-isopropyl- 1-(3-pyrrolidin-1- ylphenyl)pyrazolo[3, 4-b]pyridine-6- carboxylate
AMP11, ALP09
I1
563
564





E268


embedded image


ethyl 4-[2- (cyanomethyl)- 1,3,3a,4,6,6a- hexahydropyrrolo[3, 4-c]pyrrol-5-yl]-3- isopropyl-1-(m- tolyl)pyrazolo[3,4- b]pyridine-6- carboxylate
E332
I18
472
473





E269


embedded image


ethyl 1-(4-chloro-2- pyridyl)-3-isopropyl- 4-(4- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylate
AMP82, ALP18
I1
556
557





E270


embedded image


ethyl 3-isopropyl-4- [2-[2- methoxyethyl(methyl) amino]pyrimidin-5- yl]-1-(3- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylate
AMP10, ALP16
I1
556
557





E271


embedded image


ethyl 3-isopropyl-4- [2- [methyl (tetrahydropyran-4- yl)amino]pyrimidin- 5-yl]-1-(3- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylate
AMP10, ALP13
I1
585
586





E272


embedded image


methyl 4-{4-[4- (cyanomethyl) piperazin- 1-yl]phenyl}-1- (3-methoxyphenyl)- 3-methyl-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E333
I18
496
497





E273


embedded image


ethyl 4-(5-acetyl- 1,3,3a,4,6,6a- hexahydropyrrolo[3, 4-c]pyrrol-2-yl)-3- isopropyl-1-(m- tolyl)pyrazolo[3,4- b]pyridine-6- carboxylate
E332
I11B
475
476





E274


embedded image


ethyl 4-(1-tert- butoxycarbonyl- 3,3a,4,6,7,7a- hexahydro-2H- pyrrolo[3,2- c]pyridin-5-yl)-3- isopropyl-1-(m- tolyl)pyrazolo[3,4- b]pyridine-6- carboxylate
HP01
I3
547
548





E275


embedded image


ethyl 1-(3- fluorophenyl)-3- isopropyl-4-(4- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylate
E334
I4
488
489





E276


embedded image


ethyl 1-(3,5- difluorophenyl)-3- isopropyl-4-[4- [methyl (tetrahydropyran-4- yl)amino]phenyl] pyrazolo[3,4- b]pyridine-6- carboxylate
AMP09, ALP15
I1
534
535





E277


embedded image


ethyl 1-(3,5- difluorophenyl)-3- isopropyl-4-[6- [methyl (tetrahydropyran- 4-yl)amino]-3- pyridyl]pyrazolo[3,4- b]pyridine-6- carboxylate
AMP09, ALP10
I1
535
536





E278


embedded image


ethyl 4-[4-(4-cyano- 1-piperidyl)phenyl]- 3-cyclobutyl-1-(3- pyrrolidin-1- ylphenyl)pyrazolo[3, 4-b]pyridine-6- carboxylate
AMP34, ALP12
I1
574
575





E279


embedded image


ethyl 4-[6-(4-cyano- 1-piperidyl)-3- pyridyl]-3- cyclobutyl-1-(3- pyrrolidin-1- ylphenyl)pyrazolo[3, 4-b]pyridine-6- carboxylate
AMP34, ALP09
I1
575
576





E280


embedded image


ethyl 3-isopropyl-4- [6-[methyl (tetrahydropyran- 4-yl)amino]-3- pyridyl]-1-(3- pyrrolidin-1- ylphenyl)pyrazolo[3, 4-b]pyridine-6- carboxylate
AMP11, ALP10
I1
568
569





E281


embedded image


ethyl 3-cyclobutyl-4- [6-[methyl (tetrahydropyran- 4-yl)amino]-3- pyridyl]-1-(3- pyrrolidin-1- ylphenyl)pyrazolo[3, 4-b]pyridine-6- carboxylate
AMP34, ALP10
I1
580
581





E282


embedded image


ethyl 3-isopropyl-4- [6-[2- methoxyethyl(methyl) amino]-3-pyridyl]- 1-(3-pyrrolidin-1- ylphenyl)pyrazolo[3, 4-b]pyridine-6- carboxylate
AMP11, ALP08
I1
542
543





E283


embedded image


ethyl 1-cyclohexyl- 3-isopropyl-4-[4- [methyl (tetrahydropyran-4- yl)amino]phenyl] pyrazolo[3,4- b]pyridine-6- carboxylate
AMP23, ALP15
I1
504
505





E284


embedded image


ethyl 4-(1-acetyl- 3,3a,4,6,7,7a- hexahydro-2H- pyrrolo[3,2- c]pyridin-5-yl)-3- isopropyl-1-(m- tolyl)pyrazolo[3,4- b]pyridine-6- carboxylate
E349
I11B
489
490





E285


embedded image


ethyl 4-[1- (cyanomethyl)- 3,3a,4,6,7,7a- hexahydro-2H- pyrrolo[3,2- c]pyridin-5-yl]-3- isopropyl-1-(m- tolyl)pyrazolo[3,4- b]pyridine-6- carboxylate
E349
I18
486
487





E286


embedded image


ethyl 3-isopropyl-1- (m-tolyl)-4-(7-oxa-2- azaspiro[3.5]nonan- 2-yl)pyrazolo[3,4- b]pyridine-6- carboxylate
HP01
I3
448
449





E287


embedded image


ethyl 4-[2-(4-cyano- 1- piperidyl)pyrimidin- 5-yl]-3-isopropyl-1- (3-pyrrolidin-1- ylphenyl)pyrazolo[3, 4-b]pyridine-6- carboxylate
AMP11, ALP17
I1
564
565





E288


embedded image


ethyl 4-(4-cyano-1- piperidyl)-1- cyclohexyl-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP04
I3
423
424





E289


embedded image


ethyl 1-cyclohexyl- 3-isopropyl-4-(1- piperidyl)pyrazolo[3, 4-b]pyridine-6- carboxylate
HP04
I3
398
399





E290


embedded image


ethyl 1-cyclohexyl- 4-[4- (hydroxymethyl)-1- piperidyl]-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP04
I3
428
429





E291


embedded image


ethyl 1-(3,5- difluorophenyl)-3- isopropyl-4-(4- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylate
E334
I4
506
507





E292


embedded image


ethyl 1-[3- (dimethylamino) phenyl]-3-isopropyl-4- [3-(trifluoromethyl) pyrrolidin-1- yl]pyrazolo[3,4- b]pyridine-6- carboxylate
HP03
I3
489
490





E293


embedded image


ethyl 3-isopropyl-4-(3- methylsulfonyl- pyrrolidin- 1-yl)-1-(m- tolyl)pyrazolo[3,4- b]pyridine-6- carboxylate
HP01
I3
470
471





E294


embedded image


ethyl 4-(2- azaspiro[3.3]heptan- 2-yl)-3-isopropyl-1- (m-tolyl)pyrazolo[3,4- b]pyridine-6- carboxylate
HP01
I3
418
419





E295


embedded image


ethyl 3-isopropyl-1- (m-tolyl)-4-(5-oxa-2- azaspiro[3.5]nonan- 2-yl)pyrazolo[3,4- b]pyridine-6- carboxylate
HP01
I3
448
449





E296


embedded image


ethyl 3-cyclobutyl-4- [2-[methyl (tetrahydropyran-4- yl)amino]pyrimidin- 5-yl]-1-(3- pyrrolidin-1- ylphenyl)pyrazolo[3, 4-b]pyridine-6- carboxylate
AMP34, ALP13
I1
581
582





E297


embedded image


ethyl 1-(3,4- difluorophenyl)-3- isopropyl-4-[4- [methyl (tetrahydropyran-4- yl)amino]phenyl] pyrazolo[3,4- b]pyridine-6- carboxylate
AMP83, ALP15
I1
534
535





E298


embedded image


ethyl 4-[6-(4-cyano- 1-piperidyl)-3- pyridyl]-1-(3,4- difluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
AMP83, ALP09
I1
530
531





E299


embedded image


ethyl 3-isopropyl-4- [2-[methyl (tetrahydropyran-4- yl)amino]pyrimidin- 5-yl]-1-[3- (trifluoromethyl) phenyl]pyrazolo[3,4- b]pyridine-6- carboxylate
AMP84, ALP13
I1
568
569





E300


embedded image


ethyl 1-(3- fluorophenyl)-3- isopropyl-4-[4- [methyl (tetrahydropyran-4- yl)amino]phenyl] pyrazolo[3,4- b]pyridine-6- carboxylate
AMP12, ALP15
I1
516
517





E301


embedded image


ethyl 4-[6-(4-cyano- 1-piperidyl)-3- pyridyl]-1-(3- fluorophenyl)-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
AMP12, ALP09
I1
512
513





E302


embedded image


ethyl 1-(3- fluorophenyl)-3- isopropyl-4-[2- [methyl (tetrahydropyran-4- yl)amino]pyrimidin- 5-yl]pyrazolo[3,4- b]pyridine-6- carboxylate
AMP12, ALP13
I1
518
519





E303


embedded image


ethyl 1-(3,5- difluorophenyl)-3- isopropyl-4-[2- [methyl (tetrahydropyran-4- yl)amino]pyrimidin- 5-yl]pyrazolo[3,4- b]pyridine-6- carboxylate
AMP09, ALP13
I1
536
537





E304


embedded image


ethyl 1-[3- (dimethylamino) phenyl]-4-[4- (hydroxymethyl)-1- piperidyl]-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP03
I3
465
466





E305


embedded image


ethyl 3-cyclobutyl-1- (3-fluorophenyl)-4- (4-morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylate
E335
I4
500
501





E306


embedded image


ethyl 3-cyclobutyl-1- (3,4-difluorophenyl)- 4-(4- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylate
E335
I4
518
519





E307


embedded image


ethyl 1-cyclohexyl- 3-isopropyl-4-(1- methylpyrrol-3- yl)pyrazolo[3,4- b]pyridine-6- carboxylate
HP04
I2A
394
395





E308


embedded image


ethyl 1-cyclohexyl- 4-(1,3- dimethylpyrazol-4- yl)-3-isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP04
I2B
409
410





E309


embedded image


ethyl 3-cyclobutyl-1- (3,5-difluorophenyl)- 4-(4- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylate
E335
I4
518
519





E310


embedded image


ethyl 3-cyclobutyl-4- (4-morpholinophenyl)- 1-[3-(trifluoromethyl) phenyl]pyrazolo[3,4- b]pyridine-6- carboxylate
E335
I4
550
551





E311


embedded image


ethyl 3-cyclobutyl-1- (3-fluoro-4-methyl- phenyl)-4-(4- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylate
E335
I4
514
515





E312


embedded image


ethyl 3-cyclobutyl-4- (4-morpholinophenyl)- 1-[4-(trifluoromethyl) phenyl]pyrazolo[3,4- b]pyridine-6- carboxylate
E335
I4
550
551





E313


embedded image


ethyl 3-cyclobutyl-1- [4-(dimethylamino) phenyl]-4-(4- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylate
E335
I4
525
526





E314


embedded image


ethyl 1-cyclohexyl- 3-isopropyl-4-(1- isopropylpyrazol-4- yl)pyrazolo[3,4- b]pyridine-6- carboxylate
HP04
I2B
423
424





E315


embedded image


ethyl 4-[2-(3-cyano-1- piperidyl)pyrimidin- 5-yl]-1-cyclohexyl- 3-isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP04, BOR2
I2A
501
502





E316


embedded image


ethyl 1-cyclohexyl- 3-isopropyl-4-(2- methylpyrazol-3- yl)pyrazolo[3,4- b]pyridine-6- carboxylate
HP04
I2B
395
396





E317


embedded image


ethyl 4-(1-tert- butoxycarbonyl-3,6- dihydro-2H-pyridin- 4-yl)-1-cyclohexyl- 3-isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP04
I2B
496
497





E318


embedded image


ethyl 4-[2-[(1-tert- butoxycarbonyl-4- piperidyl)-methyl- amino]pyrimidin-5- yl]-1-cyclohexyl-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP04, BOR3
I2A
605
606





E319


embedded image


methyl 1-(4- fluorophenyl)-4-[4- (hydroxymethyl)-1- piperidyl]-3- isopropyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP05
I3
426
427





E320


embedded image


ethyl 1-cyclohexyl- 3-isopropyl-4- (2,2,6,6-tetramethyl- 3H-pyran-4- yl)pyrazolo[3,4- b]pyridine-6- carboxylate
HP04
I2B
453
454





E321


embedded image


ethyl 3-(1-tert- butoxycarbonyl- pyrrolidin-3-yl)oxy- 4-[6-(4-cyano-1- piperidyl)-3- pyridyl]-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
E336
I13
637
638





E322


embedded image


methyl 1-(4- fluorophenyl)-3- isopropyl-4- (tetrahydropyran-4- carbonylamino) pyrazolo [3,4-b]pyridine-6- carboxylate
HP05
I22
440
441





E323


embedded image


methyl 4-[4- (cyanomethyl)-4- hydroxy-1- piperidyl]-3- cyclobutyl-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
445
446





E324


embedded image


ethyl 3-methyl-1- phenyl-4-(4- piperazin-1- ylphenyl)pyrazolo[3, 4-b]pyridine-6- carboxylate
E010
I10
441
442





E325


embedded image


ethyl 1-(1- benzyloxycarbonyl- 4-piperidyl)-3- isopropyl-4-(4- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylate
E348
I20
477
478





E326


embedded image


ethyl 3-methyl-4-[4- (morpholin-4- yl)phenyl]-1-(2-oxo- 1,2-dihydropyridin- 4-yl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
AMP71, ALP18
I1
431
432





E327


embedded image


ethyl 3-methyl-1- phenyl-4-(4- piperidyl)pyrazolo[3, 4-b]pyridine-6- carboxylate
E339
I21A
364
365





E328


embedded image


ethyl 3-isopropyl-4-(4- morpholinophenyl)- 1-pyrrolidin-3-yl- pyrazolo[3,4- b]pyridine-6- carboxylate
E340
I20
463
464





E329


embedded image


ethyl 3-(azetidin-3- yl)-4-(4- morpholinophenyl)- 1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
E341
121A
469
470





E330


embedded image


6-ethoxycarbonyl-3- methyl-1-phenyl- pyrazolo[3,4- b]pyridine-4- carboxylic acid
1131-18- 6
Specific example
325
326





E331


embedded image


ethyl 3-isopropyl-4-(4- morpholinophenyl)- 1-(3- piperidyl)pyrazolo[3, 4-b]pyridine-6- carboxylate
E342
I20
463
464





E332


embedded image


ethyl 4- (2,3,3a,4,6,6a- hexahydro-1H- pyrrolo[3,4-c]pyrrol- 5-yl)-3-isopropyl-1- (m- tolyl)pyrazolo[3,4- b]pyridine-6- carboxylate
E264
I21B
433
434





E333


embedded image


methyl 1-(3- methoxyphenyl)-3- methyl-4-(4- piperazin-1- ylphenyl)pyrazolo[3, 4-b]pyridine-6- carboxylate
E343
I10
457
458





E334


embedded image


ethyl 3-isopropyl-4-(4- morpholinophenyl)- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E344
I15
394
395





E335


embedded image


ethyl 3-cyclobutyl-4-(4- morpholinophenyl)- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E345
I15
406
407





E336


embedded image


ethyl 4-[6-(4-cyano- 1-piperidyl)-3- pyridyl]-3-oxo-1- phenyl-2H- pyrazolo[3,4- b]pyridine-6- carboxylate
70373- 98-7 (AMP88), ALP09
I1
468
469





E337


embedded image


methyl 4-[4- (cyclobutylamino) phenyl]-3-methyl-1- phenyl-pyrazolo[3,4- b]pyridine-6- carboxylate
E010
I10
426
427





E338


embedded image


ethyl 3-methyl-4-[4- (oxetan-3- ylamino)phenyl]-1- phenyl-pyrazolo[3,4- b]pyridine-6- carboxylate
E010
I10
428
429





E339


embedded image


ethyl 4-(1-tert- butoxycarbonyl-4- piperidyl)-3-methyl- 1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
HP13
Specific example
464
465





E340


embedded image


ethyl 1-(1- benzyloxycarbonyl- pyrrolidin-3-yl)-3- isopropyl-4-(4- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylate
AI09
I9
597
598





E341


embedded image


ethyl 3-(1-tert- butoxycarbonyl- azetidin-3-yl)-4-(4- morpholinophenyl)- 1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
AMP65, ALP18
I1
569
570





E342


embedded image


ethyl 1-(1- benzyloxycarbonyl- 3-piperidyl)-3- isopropyl-4-(4- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylate
AI10
I9
611
612





E343


embedded image


methyl 4-(4- bromophenyl)-1-(3- methoxyphenyl)-3- methyl-pyrazolo[3,4- b]pyridine-6- carboxylate
92721- 94-3, ALP39
I1
452
453





E344


embedded image


ethyl 1-[(2,4- dimethoxyphenyl) methyl]-3-isopropyl-4- (4-morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylate
AMP28, ALP18
I1
544
545





E345


embedded image


ethyl 3-cyclobutyl-1- [(2,4- dimethoxyphenyl) methyl]-4-(4- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylate
AMP36, ALP18
I1
556
557





E346


embedded image


ethyl 1-(3- bromophenyl)-3- isopropyl-4-[6-[2- methoxyethyl(methyl) amino]-3- pyridyl]pyrazolo[3,4- b]pyridine-6- carboxylate
AMP05, ALP08
I1
552
553





E347


embedded image


ethyl 1-(3- bromophenyl)-3- isopropyl-4-[4- [methyl (tetrahydropyran-4- yl)amino]phenyl] pyrazolo[3,4- b]pyridine-6- carboxylate
AMP05, ALP15
I1
577
578





E348


embedded image


ethyl 1-(1- benzyloxycarbonyl- 4-piperidyl)-3- isopropyl-4-(4- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylate
AI08
I9
611
612





E349


embedded image


ethyl 4-(1-acetyl- 3,3a,4,6,7,7a- hexahydro-2H- pyrrolo[3,2- c]pyridin-5-yl)-3- isopropyl-1-(m- tolyl)pyrazolo[3,4- b]pyridine-6- carboxylate
E274
I21B
447
448





E350


embedded image


ethyl 4-[4-(4- benzyloxy-1- piperidyl)phenyl]-3- methyl-1-phenyl- pyrazolo[3,4- b]pyridine-6- carboxylate
E010
I10
546
547





E351


embedded image


ethyl 3-isopropyl-1- [3-[2- methoxyethyl(methyl) amino]phenyl]-4-(4- morpholinophenyl) pyrazolo[3,4- b]pyridine-6- carboxylate
E001
I8
557
558





E352


embedded image


methyl 3-cyclobutyl- 1-(4-fluorophenyl)- 4-(4- hydroxypiperidin-1- yl)-1H-pyrazolo[3,4- b]pyridine-6- carboxylate
HP19
I3
424
425





E353


embedded image


methyl 3-cyclobutyl- 1-(4-fluorophenyl)- 4-(4-oxopiperidin-1- yl)-1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E352
I23
422
423





E354


embedded image


methyl 3-cyclobutyl- 1-(4-fluorophenyl)- 4-{4-[2- (methoxymethyl) morpholin-4- yl]piperidin-1-yl}- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E353
I33
537
538





E355


embedded image


methyl 3-cyclobutyl- 1-(4-fluorophenyl)- 4-[4-(3- fluoropyrrolidin-1- yl)piperidin-1-yl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E353
I33
495
496





E356


embedded image


methyl 4-[4-(3- cyanoazetidin-1- yl)piperidin-1-yl]-3- cyclobutyl-1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E353
I33
488
489





E357


embedded image


methyl 3-cyclobutyl- 1-(4-fluorophenyl)- 4-[4-(3- methoxypyrrolidin- 1-yl)piperidin-1-yl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E353
I33
507
508





E358


embedded image


methyl 3-cyclobutyl- 4-(4,4-difluoro[1,4′- bipiperidin]-1′-yl)-1- (4-fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E353
I33
527
528





E359


embedded image


methyl 4-[4-(2- cyanomorpholin-4- yl)piperidin-1-yl]-3- cyclobutyl-1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E353
I33
518
519





E360


embedded image


methyl 3-cyclobutyl- 1-(4-fluorophenyl)- 4-[4-(2-oxa-5- azabicyclo[2.2.1] heptan-5-yl)piperidin-1- yl]-1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E353
I33
505
506





E361


embedded image


methyl 3-cyclobutyl- 1-(4-fluorophenyl)- 4-{4-[methyl(oxan-4- yl)amino]piperidin- 1-yl}-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E353
I33
521
522





E362


embedded image


methyl 3-cyclobutyl- 1-(4-fluorophenyl)- 4-{4-[3- (trifluoromethyl) pyrrolidin-1-yl] piperidin- 1-yl}-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E353
I33
545
546





E363


embedded image


methyl 4-[4-(3- cyanopyrrolidin-1- yl)piperidin-1-yl]-3- cyclobutyl-1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E353
I33
502
503





E364


embedded image


methyl 4-(3- cyano[1,4′- bipiperidin]-1′-yl)-3- cyclobutyl-1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E353
I33
516
517





E365


embedded image


methyl 3-cyclobutyl- 4-(3-fluoro[1,4′- bipiperidin]-1′-yl)-1- (4-fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E353
I33
509
510





E366


embedded image


methyl 3-cyclobutyl- 1-(4-fluorophenyl)- 4-[4-(3- methoxyazetidin-1- yl)piperidin-1-yl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E353
I33
493
494





E367


embedded image


methyl 3-cyclobutyl- 1-(4-fluorophenyl)- 4-[3- (trifluoromethyl)[1,4′- bipiperidin]-1′-yl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E353
I33
559
560





E368


embedded image


methyl 3-cyclobutyl- 1-(4-fluorophenyl)- 4-(3-methoxy[1,4′- bipiperidin]-1′-yl)- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E353
I33
521
522





E369


embedded image


methyl 3-cyclobutyl- 4-[4-(2,2- dimethylmorpholin- 4-yl)piperidin-1-yl]- 1-(4-fluorophenyl)- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E353
I33
521
522





E370


embedded image


methyl 3-cyclobutyl- 4-{4-[4- (ethoxycarbonyl) piperazin- 1-yl]piperidin- 1-yl}-1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E353
I33
564
565





E371


embedded image


methyl 3-cyclobutyl- 1-(4-fluorophenyl)- 4-[1-(propan-2- yl)octahydro-5H- pyrrolo[3,2- c]pyridin-5-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E514
I33
491
492





E372


embedded image


methyl 3-cyclobutyl- 4-(1- cyclobutyloctahydro- 5H-pyrrolo[3,2- c]pyridin-5-yl)-1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E514
I33
503
504





E373


embedded image


methyl 3-cyclobutyl- 1-(4-fluorophenyl)- 4-[1-(oxetan-3- yl)octahydro-5H- pyrrolo[3,2- c]pyridin-5-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E514
I33
505
506





E374


embedded image


methyl 3-cyclobutyl- 1-(4-fluorophenyl)- 4-[1-(oxan-4- yl)octahydro-5H- pyrrolo[3,2- c]pyridin-5-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E514
I33
533
534





E375


embedded image


methyl 3-cyclobutyl- 4-(4-fluoro[1,4′- bipiperidin]-1′-yl)-1- (4-fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E353
I33
509
510





E376


embedded image


methyl 3-cyclobutyl- 1-(4-fluorophenyl)- 4-{4-[(2- methoxyethyl)(methyl) amino]piperidin- 1-yl}-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E353
I33
495
496





E377


embedded image


methyl 3-cyclobutyl- 1-(4-fluorophenyl)- 4-[4-(morpholin-4- yl)piperidin-1-yl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
HP19
I3
493
494





E378


embedded image


methyl 4-([1,4′- bipiperidin]-1′-yl)-3- cyclobutyl-1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP19
I3
491
492





E379


embedded image


methyl 3-cyclobutyl- 1-(4-fluorophenyl)- 4-(3-hydroxy-1-oxa- 8-azaspiro[4.5]decan- 8-yl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP19
I3
480
481





E380


embedded image


methyl 3-cyclobutyl- 1-(4-fluorophenyl)- 4-(3-oxo-1-oxa-8- azaspiro[4.5]decan- 8-yl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E379
I23
478
479





E381


embedded image


methyl 3-cyclobutyl- 1-(4-fluorophenyl)- 4-[3-(pyrrolidin-1- yl)-1-oxa-8- azaspiro[4.5]decan- 8-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E380
I33
533
534





E382


embedded image


methyl 3-cyclobutyl- 1-(4-fluorophenyl)- 4-{4-[2-(morpholin- 4-yl)ethyl]piperidin- 1-yl}-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP19
I3
521
522





E383


embedded image


methyl 3-cyclobutyl- 4-{4-[2-(4- methylpiperidin-1- yl)ethyl]piperidin-1- yl}-1-phenyl-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
515
516





E384


embedded image


methyl 3-cyclobutyl- 4-[4-(4- cyclopropylpiperazin- 1-yl)piperidin-1-yl]- 1-phenyl-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
514
515





E385


embedded image


methyl 3-cyclobutyl- 1-phenyl-4-[4- (propan-2- yl)piperazin-1-yl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
433
434





E388


embedded image


ethyl 3-cyclobutyl-4- [4- (methoxymethyl) piperidin-1-yl]-1-(2- methoxypyridin-4- yl)-1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E168
I4
479
480





E389


embedded image


ethyl 1-(2- chloropyridin-4-yl)- 3-cyclobutyl-4-[4- (methoxymethyl) piperidin-1-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E168
I4
484- 486
485- 487





E390


embedded image


ethyl 3-cyclobutyl-1- [2-(3,6-dihydro-2H- pyran-4-yl)pyridin-4- yl]-4-[4- (methoxymethyl) piperidin-1-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E389
Specific example
531
532





E391


embedded image


ethyl 3-cyclobutyl-4- [4- (methoxymethyl) piperidin-1-yl]-1-[2- (oxan-4-yl)pyridin-4- yl]-1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E390
Specific example
533
534





E392


embedded image


ethyl 1-tert-butyl-3- cyclobutyl-4-[4- (morpholin-4- yl)piperidin-1-yl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
HP20
I3
469
470





E393


embedded image


ethyl 3-cyclobutyl-4- [4-(morpholin-4- yl)piperidin-1-yl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E392
Specific example
413
414





E394


embedded image


ethyl 3-cyclobutyl-1- (2-methoxypyridin- 4-yl)-4-[4- (morpholin-4- yl)piperidin-1-yl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E393
I4
520
521





E395


embedded image


ethyl 3-cyclobutyl-1- (3-methylphenyl)-4- [4-(morpholin-4- yl)piperidin-1-yl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E393
I4
503
504





E396


embedded image


ethyl 3-cyclobutyl-1- (3-methoxyphenyl)- 4-[4-(morpholin-4- yl)piperidin-1-yl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E393
I4
519
520





E397


embedded image


ethyl 3-cyclobutyl-4- [4-(morpholin-4- yl)piperidin-1-yl]-1- [4-(trifluoromethyl) phenyl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E393
I4
557
558





E398


embedded image


ethyl 3-cyclobutyl-1- (4-fluoro-3- methylphenyl)-4-[4- (morpholin-4- yl)piperidin-1-yl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E393
I4
521
522





E399


embedded image


ethyl 3-cyclobutyl-4- [4-(morpholin-4- yl)piperidin-1-yl]-1- [3-(trifluoromethyl) phenyl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E393
I4
557
558





E400


embedded image


ethyl 3-cyclobutyl-4- [4-(morpholin-4- yl)piperidin-1-yl]-1- {2-[(propan-2- yl)oxy]pyridin-4-yl}- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E393
I4
548
549





E401


embedded image


ethyl 1-[2- (benzyloxy)pyridin- 4-yl]-3-cyclobutyl-4- [4-(morpholin-4- yl)piperidin-1-yl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E393
I4
596
597





E402


embedded image


ethyl 3-cyclobutyl-1- (2-hydroxypyridin-4- yl)-4-[4-(morpholin- 4-yl)piperidin-1-yl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E401
Specific example
506
507





E403


embedded image


ethyl 3-cyclobutyl-1- [2-(difluoromethoxy) pyridin-4-yl]-4-[4- (morpholin-4- yl)piperidin-1-yl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E393
I4
556
557





E404


embedded image


ethyl 3-cyclobutyl-1- (3-fluorophenyl)-4- [4-(morpholin-4- yl)piperidin-1-yl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E393
I4
507
508





E405


embedded image


ethyl 3-cyclobutyl-1- (2,2-difluoro-2H-1,3- benzodioxol-5-yl)-4- [4-(morpholin-4- yl)piperidin-1-yl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E393
I4
569
570





E406


embedded image


ethyl 1-(2- chloropyridin-4-yl)- 3-cyclobutyl-4-[4- (morpholin-4- yl)piperidin-1-yl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E393
I4
525- 527
526- 528





E407


embedded image


ethyl 3-cyclobutyl-4- [4-(morpholin-4- yl)piperidin-1-yl]-1- [2-(oxan-4- yl)pyridin-4-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E406
Specific example
574
575





E408


embedded image


methyl 3-cyclobutyl- 4-[4-(ethoxymethyl)- 4-fluoropiperidin-1- yl]-1-phenyl-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02, AMI04
I3
466
467





E409


embedded image


methyl 3-cyclobutyl- 4-{4-fluoro-4-[(2- methoxyethoxy)methyl] piperidin-1-yl}-1- phenyl-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02, AMI05
I3
496
497





E410


embedded image


methyl 3-cyclobutyl- 4-{3-fluoro-3-[(2- methoxyethoxy)methyl] piperidin-1-yl}-1- phenyl-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02, AMI08
I3
496
497





E411


embedded image


methyl 3-cyclobutyl- 4-[4-fluoro-4- (methoxymethyl) piperidin-1-yl]-1- phenyl-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02, AMI07
I3
452
453





E412


embedded image


methyl 3-cyclobutyl- 4-{4-[2-(4- methylpiperidin-1- yl)ethyl]piperidin-1- yl}-1-phenyl-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
I3
515
516





E413


embedded image


methyl 3-cyclobutyl- 1-(4-fluorophenyl)- 4-(piperidin-4-yl)- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
HP19
Specific example
408
409





E414


embedded image


methyl 3-cyclobutyl- 4-[1-(4,4- difluorocyclohexyl) piperidin-4-yl]-1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E413
I18
526
527





E415


embedded image


methyl 3-cyclobutyl- 1-(4-fluorophenyl)- 4-[1-(propan-2- yl)piperidin-4-yl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E413
I18
450
451





E416


embedded image


methyl 3-cyclobutyl- 1-(4-fluorophenyl)- 4-[1-(oxan-4- yl)piperidin-4-yl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E413
I18
492
493





E417


embedded image


methyl 3-cyclobutyl- 1-(4-fluorophenyl)- 4-{1-[(oxan-4- yl)methyl]piperidin- 4-yl}-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E413
I18
506
507





E418


embedded image


methyl 3-cyclobutyl- 4-{1-[(2,5- dimethoxyoxolan-3- yl)methyl]piperidin- 4-yl}-1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E413
I18
552
553





E419


embedded image


methyl 3-cyclobutyl- 1-(4-fluorophenyl)- 4-[1-(3,3,3- trifluoropropyl) piperidin-4-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E413
I18
504
505





E421


embedded image


methyl 3-cyclobutyl- 4-[1- (cyclopropylmethyl) piperidin-4-yl]-1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E413
I18
462
463





E422


embedded image


ethyl 1-(2- chloropyrimidin-4- yl)-3-cyclobutyl-4- [4-(morpholin-4- yl)piperidin-1-yl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E393
I5
525
526





E424


embedded image


methyl 3-cyclobutyl- 1-(4-fluorophenyl)- 4-(4-methoxy[1,4′- bipiperidin]-1′-yl)- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
HP19, AMI10
I3
521
522





E425


embedded image


ethyl 1-cyclohexyl- 4-(4-formylphenyl)- 3-[(propan-2- yl)oxy]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
ALP36, AMP95
Specific example
435
436





E426


embedded image


ethyl 1-cyclohexyl- 4-(4-{[3- (dimethylamino) azetidin-1- yl]methyl}phenyl)-3- [(propan-2-yl)oxy]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E425
I34
519
520





E427


embedded image


ethyl 4-(4- cyanophenyl)-1- cyclohexyl-3- [(propan-2-yl)oxy]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
436088- 86-7, ALP37
Specific example
432
433





E428


embedded image


ethyl 1-(6- bromopyridin-2-yl)- 3-cyclobutyl-4-[4- (morpholin-4- yl)piperidin-1-yl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E393
Specific example
568- 570
569- 571





E429


embedded image


methyl 1-(4- fluorophenyl)-4-(4- methoxy[1,4′- bipiperidin]-1′-yl)-3- [(propan-2-yl)oxy]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
AI25
Specific example
525
526





E430


embedded image


methyl 3-cyclobutyl- 4-(1,4- dioxaspiro[4.5]dec- 7-en-8-yl)-1-phenyl- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
HP02
Specific example
445
446





E431


embedded image


methyl 3-cyclobutyl- 4-(1,4- dioxaspiro[4.5]decan- 8-yl)-1-phenyl-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E430
Specific example
447
448





E432


embedded image


methyl 3-cyclobutyl- 4-(4-oxocyclohexyl)- 1-phenyl-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E431
Specific example
403
404





E433


embedded image


methyl 3-cyclobutyl- 4-[4-(morpholin-4- yl)cyclohexyl]-1- phenyl-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E432
I33
474
475





E434


embedded image


methyl 3-cyclobutyl- 1-(4-fluorophenyl)- 4-{4-[4-(propan-2- yl)piperazin-1- yl]piperidin-1-yl}- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E353
I33
534
535





E435


embedded image


ethyl 1-cyclohexyl- 3-[(propan-2- yl)oxy]-4-(4-{[4- (propan-2- yl)piperazin-1- yl]methyl}phenyl)- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E425
I34
547
548





E436


embedded image


ethyl 1-cyclohexyl- 4-{4-[(4- methoxypiperidin-1- yl)methyl]phenyl}-3- [(propan-2-yl)oxy]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E425
I34
534
535





E437


embedded image


ethyl 1-cyclohexyl- 4-{4-[(5- methylhexahydro- pyrrolo [3,4-c]pyrrol- 2(1H)- yl)methyl]phenyl}-3- [(propan-2-yl)oxy]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E425
I34
545
546





E438


embedded image


4-{1-cyclohexyl-6- (ethoxycarbonyl)-3- [(propan-2-yl)oxy]- 1H-pyrazolo[3,4- b]pyridin-4- yl}benzoic acid
E425
Specific example
451
452





E439


embedded image


ethyl 4-{4-[5-(tert- butoxycarbonyl) hexahydropyrrolo[3,4- c]pyrrole-2(1H)- carbonyl]phenyl}-1- cyclohexyl-3- [(propan-2-yl)oxy]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E438
I24
645
646





E440


embedded image


ethyl 1-cyclohexyl- 4-[4-(5- methylhexahydro- pyrrolo[3,4-c]pyrrole- 2(1H- carbonyl)phenyl]-3- [(propan-2-yl)oxy]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E438
I24
559
560





E441


embedded image


ethyl 1-cyclohexyl- 4-{4-[3- (dimethylamino) azetidine-1- carbonyl]phenyl}-3- [(propan-2-yl)oxy]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E438
I24, Specific example
533
534





E442


embedded image


ethyl 4-(4-{[8-(tert- butoxycarbonyl)-2- oxa-5,8- diazaspiro[3.5]nonan- 5-yl]methyl}phenyl)-1- cyclohexyl-3- [(propan-2-yl)oxy]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E425
I34
647
648





E443


embedded image


ethyl 1-cyclohexyl- 4-{4-[(2-oxa-5,8- diazaspiro[3.5]nonan- 5-yl)methyl]phenyl}-3- [(propan-2-yl)oxy]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E442
I21A
547
548





E444


embedded image


ethyl 1-cyclohexyl- 4-{4-[(8-methyl-2- oxa-5,8- diazaspiro[3.5]nonan- 5-yl)methyl]phenyl}-3- [(propan-2-yl)oxy]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E443
Specific example
561
562





E445


embedded image


ethyl 4-[4-(4-cyano- 1-methylpiperidin-4- yl)phenyl]-1- cyclohexyl-3- [(propan-2-yl)oxy]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
ALP38, AMP 95
Specific example
529
530





E460


embedded image


methyl 3-cyclobutyl- 1-(4-fluorophenyl)- 4-{4-[1-(morpholin- 4-yl)ethyl]piperidin- 1-yl}-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP19, 436852- 25-4
I3
521
522





E461


embedded image


methyl 3-cyclobutyl- 1-cyclohexyl-4-[4- (2-methylpyridin-4- yl)piperazin-1-yl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
HP25, 98010- 38-9
I3
488
489





E462


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methyl 3-cyclobutyl- 1-cyclohexyl-4-{4- [4-(propan-2- yl)piperazin-1- yl]piperidin-1-yl}- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
HP25, 202991- 78-4
I3
522
523





E463


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methyl 4-[(3S)-4- benzyl-3- methylpiperazin-1- yl]-3-cyclobutyl-1- cyclohexyl-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP25, 511254- 92-57
I3
501
502





E464


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methyl 4-[(3R)-4- benzyl-3- methylpiperazin-1- yl]-3-cyclobutyl-1- cyclohexyl-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP25, 1588480- 39-0
I3
501
502





E465


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methyl 3-cyclobutyl- 4-[4-(4- cyclopropylpiperazin- 1-yl)piperidin-1-yl]- 1-(4-fluorophenyl)- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E496
I26
517
518





E466


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methyl 3-cyclobutyl- 4-(9-cyclopropyl- 3,9-diazaspiro[5.5] undecan-3-yl)-1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E500
I26
517
518





E467


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methyl 3-cyclobutyl- 1-(4-fluorophenyl)- 4-{4-[(pyrrolidin-1- yl)methyl]piperidin- 1-yl}-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP19, 683772- 11-5
I3
491
492





E468


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methyl 3-cyclobutyl- 1-(4-fluorophenyl)- 4-{4-[4-(2- methoxyethyl) piperazin- 1-yl]piperidin-1- yl}-1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E496, 6482-24- 2
I27
550
551





E469


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methyl 3-cyclobutyl- 1-(4-fluorophenyl)- 4-[9-(oxetan-3-yl)- 3,9-diazaspiro[5.5] undecan-3-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E500, 6704-31- 0
I30
533
534





E470


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methyl 3-cyclobutyl- 1-(4-fluorophenyl)- 4-{4-[4-(oxetan-3- yl)piperazin-1- yl]piperidin-1-yl}- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E496, 6704-31- 0
I30
548
549





E471


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methyl 3-cyclobutyl- 1-(4-fluorophenyl)- 4-[(morpholin-4- yl)methyl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP19, 936329- 94-1
I35
424
425





E472


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methyl 3-cyclobutyl- 1-(4-fluorophenyl)- 4-[(4- methylpiperazin-1- yl)methyl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP19, 1015484- 22-6
I35
438
439





E473


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methyl 1-cyclohexyl- 4-{4-[(morpholin-4- yl)methyl]phenyl}-3- [(propan-2-yl)oxy]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E506, 1268340- 94-8
I35
493
493





E474


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methyl 1-cyclohexyl- 4-[4-(4- methylpiperazine-1- carbonyl)phenyl]-3- [(propan-2-yl)oxy]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E506, 34352- 59-5
I28
519
520





E475


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methyl 3-cyclobutyl- 1-cyclohexyl-4-[4- (pyridin-4- yl)piperazin-1-yl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
HP25, 1008-91- 9
I3
474
475





E476


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methyl 3- (cyclobutyloxy)-1- cyclohexyl-4-{4- [(morpholin-4- yl)methyl]phenyl}- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E507, 1268340- 94-8
I35
504
505





E477


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methyl 1-cyclohexyl- 4-{4-[4- (dimethylamino) piperidine-1- carbonyl]phenyl}-3- [(propan-2-yl)oxy]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E506, 4318-42- 7
I28
548
549





E478


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methyl 1-cyclohexyl- 4-{4-[(piperidin-1- yl)methyl]phenyl}-3- [(propan-2-yl)oxy]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E506, 1268340- 93-7
I35
491
492





E479


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methyl 1-cyclohexyl- 4-{4-[(4- methylpiperazin-1- yl)methyl]phenyl}-3- [(propan-2-yl)oxy]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E506, 1015484- 22-6
I35
506
507





E480


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methyl 1-cyclohexyl- 3-[(propan-2- yl)oxy]-4-{4- [(pyrrolidin-1- yl)methyl]phenyl}- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E506, 888711- 53-3
I35
477
477





E481


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methyl 3-cyclobutyl- 1-(4-fluorophenyl)- 4-{[4- (methoxymethyl) piperidin-1-yl]methyl}- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
HP19, BF01
I35
466
467





E482


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methyl 1-cyclohexyl- 4-{4-[(4- cyclopropylpiperazin- 1-yl)methyl]phenyl}-3- [(propan-2-yl)oxy]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E494
I26
531
532





E483


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methyl 1-cyclohexyl- 3-[(propan-2- yl)oxy]-4-{4-[4- (propan-2- yl)piperazin-1- yl]phenyl}-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E506, 4318-42- 7
I29
519
520





E484


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methyl 1-cyclohexyl- 4-[4-(4- cyclopropylpiperazin- 1-yl)phenyl]-3- [(propan-2-yl)oxy]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E506, 20327- 23-5
I29
517
518





E485


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methyl 4-(4- cyano[1,4′- bipiperidin]-1′-yl)-3- cyclobutyl-1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP19, AMI11
I3
516
517





E486


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methyl 3-cyclobutyl- 1-(4-fluorophenyl)- 4-{4-[4- (methoxycarbonyl) piperazin-1- yl]piperidin-1-yl}- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E498
I31
550
551





E487


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methyl 4-[4-(4- acetylpiperazin-1- yl)piperidin-1-yl]-3- cyclobutyl-1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E498
I32
534
535





E488


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methyl 3-cyclobutyl- 1-cyclohexyl-4-{4- [(morpholin-4- yl)methyl]piperidin- 1-yl}-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP25, 81310- 62-5
I3
495
496





E489


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methyl 3-cyclobutyl- 1-cyclohexyl-4-{4- [2-(morpholin-4- yl)ethyl]piperidin-1- yl}-1H-pyrazolo[3,4- b]pyridine-6- carboxylate
HP25, 500357- 64-2
I3
509
510





E490


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methyl 3-cyclobutyl- 1-cyclohexyl-4-[4- (morpholin-4- yl)piperidin-1-yl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
HP25, 53617- 35-9
I3
481
482





E491


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methyl 3-cyclobutyl- 1-(4-fluorophenyl)- 4-{4-[(morpholin-4- yl)methyl]piperidin- 1-yl}-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP19, 202991- 78-4
I3
507
508





E492


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methyl 3-cyclobutyl- 1-(4-fluorophenyl)- 4-(4-hydroxy[1,4′- bipiperidin]-1′-yl)- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
HP19, 202991- 78-4
I3
507
508





E494


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methyl 1-cyclohexyl- 4-{4-[(piperazin-1- yl)methyl]phenyl}-3- [(propan-2-yl)oxy]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E495
I25
491
492





E495


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methyl 4-(4-{[4- (tert- butoxycarbonyl) piperazin-1- yl]methyl}phenyl)-1- cyclohexyl-3- [(propan-2-yl)oxy]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E506, 936329- 97-4
I35
591
592





E496


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methyl 3-cyclobutyl- 1-(4-fluorophenyl)- 4-[4-(piperazin-1- yl)piperidin-1-yl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E497
I25
492
493





E497


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methyl 4-{4-[4-(tert- butoxycarbonyl) piperazin-1- yl]piperidin- 1-yl}-3-cyclobutyl- 1-(4-fluorophenyl)- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
HP19, 205059- 24-1
I3
592
593





E498


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methyl 3-cyclobutyl- 1-(4-fluorophenyl)- 4-[4-(piperazin-1- yl)piperidin-1-yl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E499
I25
492
493





E499


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methyl 4-{4-[4-(tert- butoxycarbonyl) piperazin-1- yl]piperidin- 1-yl}-3-cyclobutyl- 1-(4-fluorophenyl)- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
HP19, 205059- 24-1
I3
592
593





E500


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methyl 3-cyclobutyl- 4-(3,9- diazaspiro[5.5] undecan-3-yl)-1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E501
I25
477
478





E501


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tert-butyl 9-[3- cyclobutyl-1-(4- fluorophenyl)-6- (methoxycarbonyl)- 1H-pyrazolo[3,4- b]pyridin-4-yl]-3,9- diazaspiro[5.5] undecane-3-carboxylate
HP19 173405- 78-2
I3
577
578





E502


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methyl 1-cyclohexyl- 4-[4-(4- methylpiperazin-1- yl)phenyl]-3- [(propan-2-yl)oxy]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E506, 109-01-3
I29
491
492





E503


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methyl 3-cyclobutyl- 1-(4-fluorophenyl)- 4-[9-(2- methoxyethyl)-3,9- diazaspiro[5.5] undecan-3-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E500, 6482-24- 2
I27
535
536





E504


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methyl 3-cyclobutyl- 4-(9-cyclobutyl-3,9- diazaspiro[5.5] undecan-3-yl)-1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E500, 1191-95- 3
I33
531
532





E505


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methyl 4-(4- bromophenyl)-1- cyclohexyl-3- hydroxy-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
436088- 86-7, 608128- 34-3
I1, Specific example
430






E506


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methyl 4-(4- bromophenyl)-1- cyclohexyl-3- [(propan-2-yl)oxy]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E505, 75- 26-3
I17, Specific example
472






E507


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methyl 4-(4- bromophenyl)-3- (cyclobutyloxy)-1- cyclohexyl-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E505, 4399-47- 4
I17, Specific example
484






E508


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methyl 3-cyclobutyl- 1-(4-fluorophenyl)- 4-[9-(propan-2-yl)- 3,9-diazaspiro[5.5] undecan-3-yl]-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E500, 67-64-1
I30
519
520





E509


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methyl 3-cyclobutyl- 4-[4-(morpholin-4- yl)piperidin-1-yl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
53617- 35-9, 16063- 69-7, 5006-22- 4, 301-01-2, 630-08-0
Specific example
399
400





E510


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methyl 3-cyclobutyl- 1-[3- (difluoromethoxy) phenyl]-4-[4- (morpholin-4- yl)piperidin-1-yl]- 1H-pyrazolo[3,4- b]pyridine-6- carboxylate
E509
Specific example
541
542





E511


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ethyl 4-[4-(tert- butoxycarbonyl) piperazin-1-yl]-3- methyl-1-phenyl-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP13
I3
465
466





E512


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ethyl 3-methyl-1- phenyl-4-(piperazin- 1-yl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E511
I21B
365
366





E513


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methyl 4-[1-(tert- butoxycarbonyl) octahydro-5H- pyrrolo[3,2- c]pyridin-5-yl]-3- cyclobutyl-1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylatee
HP19
I3
549
550





E514


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methyl 3-cyclobutyl- 1-(4-fluorophenyl)- 4-(octahydro-5H- pyrrolo[3,2- c]pyridin-5-yl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
E513
I21A
449
450





E515


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methyl 3-cyclobutyl- 1-(4-fluorophenyl)- 4-(9-methyl-3,9- diazaspiro[5.5] undecan-3-yl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP19, 13323- 45-0
I3
491
492





E516


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methyl 3-cyclobutyl- 4-[4- (ethoxycarbonyl) piperazin-1-yl]-1-(4- fluorophenyl)-1H- pyrazolo[3,4- b]pyridine-6- carboxylate
HP19, 120-43-4
I3
481
482





E517


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methyl 3-cyclobutyl- 1-(4-fluorophenyl)- 4-{4-[(2- methylpropoxy) carbonyl]piperazin-1- yl}-1H-pyrazolo[3,4- b]pyridine-6- carboxylate
HP19, 23672- 96-0
I3
509
510









Methods J1-22: Synthesis of Carboxylic Acids
Method J1: Synthesis of Carboxylic Acids by Saponification of Ester



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To the intermediate ester (1 equiv) in THF or in a mixture of THF/methanol or in dioxane/water at RT is added either aqueous 1-2 N sodium hydroxide or lithium hydroxide monohydrate (from 1 to 5 equiv). The reaction mixture is stirred at a temperature ranging from RT to 70° C. for 1 hour to several days (up to 8 days). The volatiles are removed under reduced pressure, and the resulting mixture is acidified with either aqueous 1-2 N HCl or acetic acid. If a filterable suspension is obtained, the precipitate is collected by filtration, washed with water and dried in vacuo to afford the titled compound which is used as such or further purified either by preparative HPLC or flash chromatography on silica gel. In other cases, the mixture is partitioned between water and either dichloromethane or ethyl acetate. The two phases are separated, and the aqueous phase is extracted either with dichloromethane, methanol/dichloromethane or ethyl acetate. The combined organic phases are washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the titled compound which is used as such or further purified either by preparative HPLC or flash chromatography on silica gel.


Illustrative Synthesis of compound 182: 4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid



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Intermediate E018 (30.7 g, 60.3 mmol) was dissolved in a mixture of THF/methanol (1/1; 1 L), and 2 N sodium hydroxide (109 mL, 218 mmol) in water was added at RT. The solution was stirred for 1 hour. The volatiles were removed under reduced pressure, and the resulting mixture was diluted with water (300 mL). The aqueous phase was acidified with aqueous 2 N HCl (110 mL), and the precipitate was filtered, washed with water and dried at 40° C. under reduced pressure to give the titled compound.


Method J1A: Synthesis of Carboxylic Acids by Saponification of Ester



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To the ester intermediate (1 equiv) in THF or ethanol or methanol or a mixture of the cited solvents at RT is added either aqueous 1 N or 2 N sodium hydroxide 1 (from 1 to 10 equiv). The reaction mixture is stirred at RT until complete conversion is observed. Sodium hydroxide can be added to allow the full conversion of the starting ester. The volatiles are removed under reduced pressure, and the resulting mixture is acidified with either aqueous 1 N or 2 N HCl. If a filterable suspension is obtained, the precipitate is collected by filtration, washed with water and dried in vacuo to afford the titled compound which is used as such or further purified either by preparative HPLC or flash chromatography on silica gel. In other cases, the mixture is partitioned between a phosphate buffer (pH 6.2) and either dichloromethane or chloroform or a mixture of dichloromethane/isopropanol. The organic phases are separated, dried over MgSO4, filtered and concentrated in vacuo to afford the titled compound which is used as such or further purified either by preparative HPLC or flash chromatography on silica gel.


Illustrative Synthesis of compound 820: 3-cyclobutyl-1-(3-methylphenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid



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Ester E395 (40 mg, 80 μmol) was dissolved in a mixture of THF/ethanol (1/1; 6 mL) and 1 N sodium hydroxide (0.5 mL, 500 μmol) in water was added at RT. The solution was stirred for 4 hours. Aqueous 1 N HCl (0.5 mL, 500 μmol) and a phosphate buffer were added (pH 6.2).


The solvent was partially removed under reduced pressure, and the resulting mixture was extracted twice with chloroform. The combined organic phases were dried over magnesium sulfate, filtered and evaporated under reduced pressure to give the titled compound.


Method J2: Synthesis of Acids



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  • A is either N or CH

  • A′ is either Re or L1-G3C as described in the Summary



The alkylidene pyruvate (1 to 1.5 equiv) and the aminopyrazole (1 to 1.5 equiv) in acetic acid are stirred under air at temperatures ranging from RT to reflux for 1 h to several days. Alternatively, the alkylidene pyruvate (1 to 1.5 equiv) and the aminopyrazole (1 to 1.5 equiv) in DMF or acetic acid are heated under microwave irradiation at 150° C. for 20 minutes to 2 h followed by stirring under air in an opened flask at temperatures ranging from RT to 90° C. for 1 h to several days with or without dilution of the reaction mixture with a large amount of ethanol or methanol. Then the reaction mixture is filtered, and the solid is washed with solvents, and dried in vacuo to afford the titled compound which is used as such or purified by precipitation, by preparative HPLC or by flash chromatography on silica gel. Alternatively, the reaction mixture is concentrated in vacuo to afford a crude mixture which is used as such or further purified either by precipitation, by preparative HPLC or by flash chromatography on silica gel.


Illustrative Synthesis of compound 1: 3-methyl-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid



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ALP01 (261 mg, 1 mmol, 1 equiv) and 3-methyl-1-phenyl-1H-pyrazol-5-amine (CAS 1131-18-6, 173 mg, 1 mmol, 1 equiv) were introduced in a sealed tube. DMF (2 mL) was added, and the vial was sealed. The reaction mixture was heated under microwave irradiation at 150° C. for 1 h. Then after cooling down to RT, the vial was opened, diluted with a large amount of ethanol, and stirred vigorously under air at RT overnight. The resulting suspension was filtered. The solid was washed with ethanol, and dried in vacuo to afford the titled compound.


Method J3: Nucleophilic Substitution on the Central Core with Alcohols



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To a solution of alcohol (3.0-4.0 equiv) in anhydrous THF under nitrogen atmosphere at RT is added 60% sodium hydride in mineral oil (6.0 equiv), and the mixture is stirred at room temperature for 30 minutes. Then the aryl chloride intermediate HP (1.0 equiv) is added, the reaction mixture is stirred at room temperature for 5 minutes, and then heated at reflux for 1 h to 24 h. The reaction mixture is cooled to 0° C., diluted with heptane, quenched with water and acidified with 2 N HCl (6.0 equiv). Volatiles are removed in vacuo. The resulting aqueous residue is filtered, and the solid is washed with water and with a mixture of heptane/Et2O (1/1), and dried in vacuo to afford the titled compound which is used as such or purified by silica gel chromatography. Alternatively, the aqueous residue is diluted with dichloromethane. The two phases are separated and the aqueous phase is extracted with dichloromethane. The combined organic phases are washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the titled compound which is used as such or purified by silica gel chromatography. As another alternative, the compounds can be purified by preparative HPLC.


Alternatively, to a solution of alcohol (2.0 equiv) in anhydrous DMF is added 1 M potassium tert-butoxide (3-4 equiv), and the mixture is stirred at room temperature for several minutes. Then the aryl chloride intermediate HP (1.0 equiv) is added, and then the reaction mixture is heated at 40-60° C. for 1 h to 24 h. After cooling to ambient temperature, the product can be precipitated from an appropriate solvent or purified chromatographically.


Illustrative Synthesis of compound 417: 3-cyclobutyl-4-[(oxan-4-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid



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To a solution of tetrahydropyran-4-ylmethanol (CAS: 14774-37-9, 54 mg, 0.457 mmol, 3.0 equiv) in anhydrous THF (1 mL) under nitrogen atmosphere was added 60% sodium hydride in mineral oil (37 mg, 0.915 mmol, 6.0 equiv), and the mixture was stirred at room temperature for 30 minutes. HP10 (50 mg, 0.152 mmol, 1.0 equiv) was added; the reaction mixture was stirred at room temperature for 5 minutes and then heated at reflux for 3 hours. The reaction mixture was cooled to 0° C., diluted with heptane (1 mL), quenched with water (1 mL) and acidified with 2 N HCl (0.46 mL, 6.0 equiv). Volatiles were removed in vacuo. The resulting aqueous suspension was diluted with a mixture heptane/Et2O: 1/1 (1 mL) and filtered. The solid was washed with water and with a mixture heptane/Et2O 1/1 and dried in vacuo. The crude solid was purified by silica gel chromatography (eluent system: DCM/(DCM/MeOH/AcOH/H2O: 90/10/1/1) gradient from 100/0 to 90/10) to give the titled compound.


Illustrative Synthesis of compound 487: 3-cyclobutyl-4-[3-(morpholin-4-yl)propoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid



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3-Morpholinopropan-1-ol (73 mg, 0.50 mmol) was dissolved into anhydrous DMF (830 μL), treated with 1 M KOtBu in THF (830 μL, 0.83 mmol), stirred three minutes, treated further with intermediate HP10 (82 mg, 0.25 mmol), and heated at 50° C. for about an hour. More DMF (570 μL) was added and heating was continued overnight. The mixture was brought to room temperature, diluted with MeCN and filtered with a MeCN rinse. The collected solids were mixed with acetic acid into DMSO, and diluted with water to precipitate solids which were collected by filtration, rinsed with water and dried under vacuum to give the titled compound (65 mg).


Illustrative Synthesis of compound 375: 3-methyl-4-[(3-methyloxetan-3-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid



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To a 4-mL vial equipped with stir bar was added (3-methyloxetan-3-yl)methanol (50 mg, 4 equiv, 0.5 mmol) followed by sodium hydride (20 mg, 6 equiv, 0.73 mmol) in 500 μL of THF, and the mixture was allowed to stir for 30 minutes at room temperature. To this mixture was then added a solution of 4-chloro-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid (HP17, 35 mg, 0.12 mmol) in 500 μL THF, and this mixture was heated at 80° C. for 30 minutes. After completion of reaction, the mixture was concentrated and the residue was dissolved in 1:1 MeOH:DMSO and purified by reverse phase HPLC (C18, 0-100% CH3CN/water (0.1% TFA)). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/min (0-0.5 min 10% A, 0.5-6.0 min linear gradient 10-100% A, 6.0-7.0 min 100% A, 7.0-8.0 min linear gradient 100-10% A) to afford the titled compound.


Method J4: Buchwald Coupling on the Central Core



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To a degassed solution of the aryl chloride intermediate HP (1.0 equiv) and the amine as free base or hydrochloride salt (1.5 equiv) in anhydrous THF at RT under nitrogen atmosphere in a sealed vial is added XPhos Pd G1 (CAS 1028206-56-5, 0.1 equiv) followed by 1 N LiHMDS in THF (from 3 to 5 equiv). The reaction mixture is purged with nitrogen and the vial is sealed. The reaction mixture is stirred at 100° C. for 1 h to 24 h. Then the reaction mixture is cooled down and volatiles are removed in vacuo. The resulting residue is taken up in dichloromethane and water and acidified with acetic acid. The two phases are separated and the aqueous phase is extracted with dichloromethane. The combined organic layers are washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue is purified by flash chromatography on silica gel to afford the titled compound.


Illustrative Synthesis of intermediate AI13: 3-cyclobutyl-4-[4-(fluoromethyl)-1-piperidyl]-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylic acid



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To a degassed solution of HP10 (64 mg, 0.194 mmol, 1.0 equiv) and 4-(fluoromethyl)piperidine hydrochloride (CAS 259143-04-9, 45 mg, 0.292 mmol, 1.5 equiv) in anhydrous THF (2 mL) at RT under nitrogen atmosphere in a sealed vial was added XPhos Pd G1 (CAS 1028206-56-5, 14 mg, 0.019 mmol, 0.1 equiv) followed by 1 N LiHMDS in THF (0.97 mL, 0.97 mmol, 5.0 equiv). The reaction mixture was purged with nitrogen, and the vial was sealed. The reaction mixture was stirred at 100° C. overnight. Then the reaction mixture was cooled down and volatiles were removed in vacuo. The resulting residue was taken up in dichloromethane and water and acidified with acetic acid. The two phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel (eluent system: dichloromethane/methanol gradient from 100/0 to 95/5) to afford the titled compound.


Method J5: Buchwald Coupling on the Aryl Linker



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To a degassed solution of pyridyl chloride (1.0 equiv) and amine (1.5 equiv) in anhydrous THF at RT under nitrogen atmosphere is added 1 N LiHMDS in THF (from 3 to 4.5 equiv) followed by XPhos Pd G1 (CAS 1028206-56-5, 0.1 equiv). The reaction mixture is stirred at room temperature for 1 h to 24 h. The mixture is quenched with acetic acid and diluted with water and dichloromethane. The organic layer is separated, washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to afford the titled compound which is used as such or further purified by preparative HPLC or by flash chromatography on silica gel. The cross-coupling reaction can be performed on either a carboxylic acid or ester. In some instances, an ester starting material is concomitantly hydrolyzed to the corresponding carboxylic acid product under the reaction conditions.


Illustrative Synthesis of compound 196: 1-cyclohexyl-4-[6-(2,6-dimethylmorpholin-4-yl)pyridin-3-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid



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To a degassed solution of AI14 (75 mg, 0.188 mmol, 1.0 equiv) and 2,6-dimethylmorpholine (CAS 141-91-3, 32 μL, 0.26 mmol, 1.5 equiv) in anhydrous THF (0.7 mL) at RT under nitrogen atmosphere was added 1 N LiHMDS in THF (765 μL, 0.765 mmol, 4.5 equiv) followed by XPhos Pd G1 (CAS 1028206-56-5, 12.5 mg, 0.017 mmol, 0.1 equiv). The reaction mixture was stirred at room temperature for 1 h. The mixture was quenched with AcOH and diluted with water and dichloromethane. The organic layer was separated, washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (eluent system: dichloromethane/methanol, gradient from 100/0 to 95/5) to afford the titled compound.


Method J6: Nucleophilic Substitution on the R1 Part



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To the intermediate fluoropyridine (1.0 equiv) in anhydrous DMSO is added the amine (from 2.0 to 10.0 equiv) and K2CO3 (from 3.0 to 10 equiv). The reaction mixture is stirred at 100° C. overnight. If the reaction is not complete, additional amine (from 2.0 to 10 equiv) and K2CO3 (from 0 to 10 equiv) are added, and the reaction mixture is stirred at 100° C. until the reaction is finished. Then the reaction mixture is cooled down to RT, diluted with water and extracted with ethyl acetate. The combined organic layers are washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the titled compound which is used as such or purified by flash chromatography on silica gel.


Illustrative Synthesis of compound 525: 4-[4-(methoxymethyl)piperidin-1-yl]-1-[2-(morpholin-4-yl)pyridin-4-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid



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To E147 (144 mg, 0.32 mmol, 1.0 equiv) in anhydrous DMSO (1.5 mL) was added morpholine (56 μL, 0.64 mmol, 2.0 equiv) and K2CO3 (133 mg, 0.96 mmol, 3.0 equiv). The reaction mixture was stirred at 100° C. overnight. Additional morpholine (56 μL, 0.64 mmol, 2.0 equiv) and K2CO3 (133 mg, 0.96 mmol, 3.0 equiv) were added, and the reaction mixture was stirred at 100° C. for 24 h. Then additional morpholine (56 μL, 0.64 mmol, 2.0 equiv) was added again, and the reaction mixture was stirred at 100° C. for 5 days. Then the reaction mixture was cooled down to RT, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (eluent system: dichloromethane/methanol, gradient 100/0 to 95/5 with 0.1% AcOH) to afford the titled compound.


Method J7: Buchwald Coupling on the Phenyl or Heteroaryl Halogen



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To a degassed solution of the aromatic bromide intermediate (1.0 equiv) and the amine as free base or hydrochloride salt (from 1.5 to 2 equiv) in anhydrous THF at RT under nitrogen atmosphere in a sealed vial is added XPhos Pd G1 (CAS 1028206-56-5, 0.1 equiv) followed by 1 N LiHMDS in THF (from 3 to 5 equiv). The reaction mixture is purged with nitrogen, and the vial is sealed. The reaction mixture is stirred at a temperature ranging from RT to 100° C. for 1 h to 3 h. If the reaction is not complete, additional amine (from 1.0 to 3.0 equiv), LiHMDS (from 1.5 to 6.0 equiv) and XPhos Pd G1 (CAS 1028206-56-5, from 0.05 to 0.2 equiv) are added at RT. The reaction mixture is purged again with nitrogen and the vial is sealed. The reaction mixture is stirred at a temperature ranging from RT to 100° C. for 1 h to 3 h. Then the reaction mixture is cooled down and volatiles are removed in vacuo. The resulting residue is taken up in dichloromethane and water and acidified with acetic acid. The two phases are separated, and the aqueous phase is extracted with dichloromethane. The combined organic layers are washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue is purified by flash chromatography on silica gel to afford the titled compound.


Illustrative Synthesis of compound 239: 1-[3-(azetidin-1-yl)phenyl]-4-{6-[(2-methoxyethyl)(methyl)amino]pyridin-3-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid



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To a degassed solution of A105 (38 mg, 0.7 mmol, 1.0 equiv) and azetidine (7 μL, 0.10 mmol, 1.5 equiv) in anhydrous THF (0.3 mL) at RT under nitrogen atmosphere in a sealed vial was added XPhos Pd G1 (CAS 1028206-56-5, 5 mg, 0.007 mmol, 0.1 equiv) followed by 1 N LiHMDS in THF (315 μL, 0.315 mmol, 4.5 equiv). The reaction mixture was purged with nitrogen and stirred at RT overnight. Additional azetidine (3.5 μL, 0.05 mmol, 0.5 equiv) and XPhos Pd G1 (CAS 1028206-56-5, 5 mg, 0.007 mmol, 0.1 equiv) were added at RT. The reaction mixture was purged again with nitrogen and stirred for 2 h. Then the reaction mixture was cooled down and volatiles were removed in vacuo. The resulting residue was taken up in dichloromethane and water and acidified with acetic acid. The two phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by preparative HPLC to deliver the titled compound.


Method J8: Tandem Methylation and Saponification



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60% NaH in mineral oil (6.0 equiv) is added to a solution of an ester/alcohol or a 2-oxo-1,2-dihydropyridin-4-yl/ester (1 equiv) in THF. The reaction mixture is stirred at RT for 5 minutes, and a C1-C6 alkyl halide (6.0 equiv) was added. The reaction mixture was stirred at RT for 1-24 hours and then concentrated. The residue was purified by silica gel chromatography to give the ether/carboxylic acid or the 1-methyl-2-oxo-1,2-dihydropyridin-4-yl/carboxylic acid.


Illustrative Synthesis of compound 431: 1-cyclohexyl-4-[4-(methoxymethyl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid



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60% NaH in mineral oil (24 mg, 0.60 mmol, 6.0 equiv) was added to a solution of E134 (42 mg, 0.10 mmol) in THF (1 mL). The reaction mixture was stirred at RT for 5 minutes, and methyl iodide (0.037 mL, 0.60 mmol, 6.0 equiv) was added. The reaction mixture was stirred at RT for 16 hours and then concentrated. The residue was purified by silica gel chromatography (DCM/MeOH: 100/0 to 90/10) to give the titled compound.


Method J9: Acylation of Amine



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A heterocyclic amine at either the R2 or R3 positions can be reacted with an acid chloride or chloroformate dissolved is solvents such as dichloromethane, tetrahydrofuran or DMF at 0° C. to ambient temperature over 0.5-4 hours in the presence a tertiary amine base or an inorganic carbonate base. The reaction mixture is extractively worked up and/or purified chromatographically either by flash chromatography or by preparative HPLC.


Illustrative Synthesis of compound 166: 1-cyclohexyl-4-[2-(dimethylamino)pyrimidin-5-yl]-3-[1-(methoxycarbonyl)azetidin-3-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid



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Diisopropylethylamine (0.55 mL, 3.12 mmol, 6.0 equiv) and DMAP (13 mg, 0.104 mmol, 0.2 equiv) were added to a solution of AI21 (220 mg, 0.52 mmol, 1 equiv) in dichloromethane (2 mL). The mixture was cooled to 0° C. and methyl chloroformate (CAS: 79-22-1, 81 μL, 0.104 mmol, 2.0 equiv) was added. The reaction mixture was warmed up to RT and stirred for 1.5 h. The reaction mixture was partitioned between dichloromethane and water. The two phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phase were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC to afford the titled compound.


Synthesis of Compounds 587 and 588: 4-[(3aR,7aS)-1-acetyloctahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid and 4-[(3aS,7aR)-1-acetyloctahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid



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Step 1: sodium rac-3-cyclobutyl-4-[(3aR,7aS)-octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylate

rac-4-[(3aR,7aS)-1-(tert-Butoxycarbonyl)octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid (Compound 549, 1.00 g, <1.9 mmol) was dissolved into anhydrous CH2Cl2 (8.0 mL), treated with TFA (2.0 mL), stirred at room temperature for two hours and then concentrated. The residue was redissolved into CH2Cl2, treated with aqueous K2HPO4 and basified to pH 11+ with aqueous NaOH. Brine was added, and the mixture was extracted with 10% MeOH/CH2Cl2. The separated organic phase was dried (Na2SO4), passed through a short column of Na2SO4 and concentrated to give the titled compound (452 mg).



1H NMR (500 MHz, methanol-d4) δ ppm 1.69-1.77 (m, 1H), 1.98-2.21 (m, 5H), 2.40-2.66 (m, 6H), 2.94-3.01 (m, 2H), 3.15-3.3 (m, 3H), 3.32-3.36 (m, 1H), 4.07-4.15 (m, 1H), 7.24-7.28 (m, 1H), 7.38 (s, 1H), 7.47-7.51 (m, 2H), 8.35-8.38 (m, 2H); MS (ESI) m/z 418 (M+H)+.


Step 2: 4-[(3aR,7aS)-1-acetyloctahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid and 4-[(3aS,7aR)-1-acetyloctahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid

Sodium rac-3-cyclobutyl-4-[(3aR,7aS)-octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylate (209 mg, 0.50 mmol) and N-methylmorpholine (220 μL, 2.0 mmol) were suspended in DMF (2.5 mL) and chilled with a water ice bath. A solution of acetyl chloride (50 μL, 0.70 mmol) in dichloromethane (500 μL) was added dropwise, and the mixture was stirred for two minutes before the bath was removed. The cloudy solution was stirred another thirty minutes at room temperature before being diluted with EtOAc and placed directly on silica for chromatography (EtOAc, then 0 to 20% MeOH/MeCN, then 0.1% TFA/19.9% MeOH/80% MeCN) to give rac-4-[(3aR,7aS)-1-acetyloctahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid (236 mg).


The racemate was then subjected to preparative supercritical fluid chromatography set to maintain a maximum back pressure of 100 MPa using a Chiralcel® OJ-H (21×250 mm) column with the sample at a concentration of 10 mg/mL in methanol using 35% methanol in CO2 at a flow rate of 45 mL/minute to provide both enantiomers separately. The first enantiomer eluted (retention time=5.4 minutes, compound 588), and the second enantiomer eluted (retention time=7.4 minutes, compound 587) as the titled compounds (stereochemistry arbitrarily assigned).


Synthesis of Compound 610: rac-3-cyclobutyl-1-phenyl-4-[(3aR,7aS)-1-{[(propan-2-yl)oxy]carbonyl}octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid



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Sodium rac-3-cyclobutyl-4-[(3aR,7aS)-octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylate (˜0.1 mmol, Step 1 in the preparation of compounds 587 and 588) was dissolved into THF (1.0 mL), treated with 1 M aqueous Na2CO3 (150 μL, 0.15 mmol) followed by 1 M isopropyl chloroformate in toluene (300 μL, 0.3 mmol) and stirred about 12 minutes before being quenched with 3 M aqueous NaOH (50 μL) and diisopropylamine (50 μL). The mixture was stirred thoroughly and then acidified with TFA (10 drops). Sodium chloride was added, and the wet salts were separated and extracted with EtOAc. The combined organic phases were concentrated and chromatographed quickly on silica (EtOAc/CH2Cl2). Fractions containing product were concentrated and purified by preparative HPLC on a Waters® Sunfire™ C8 column (30×150 mm) with a 60 to 100% gradient of acetonitrile in 0.1% aqueous TFA at 50 mL/min to give the titled compound (10 mg).


Method J10: Nucleophilic Substitution on the Central Core with Amines



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A mixture of the chloride or triflate intermediate HP (1.0 equiv), the amine as free base or hydrochloride salt (from 1 to 10 equiv) and DIPEA (from 1 to 15 equiv) in acetonitrile, N,N-dimethylacetamide or a mixture of anhydrous acetonitrile and DMSO in a sealed tube or a round bottom flask is heated at a temperature ranging from 50 to 150° C. for 1 h to several days (up to 8 days). The reaction mixture is cooled to RT. The resulting residue is either purified by precipitation or by flash chromatography on silica gel or preparative HPLC to afford the titled compound or alternatively partitioned between either dichloromethane or ethyl acetate and water. The two phases are then separated, and the aqueous phase is extracted with either ethyl acetate or dichloromethane. The combined organic phases are dried, filtered and concentrated in vacuo, and the resulting crude mixture is either used as such or purified by flash chromatography on silica gel to afford the titled compound.


Alternatively, a mixture of the chloride or triflate intermediate HP (1.0 equiv), the amine as free base or hydrochloride salt (from 1 to 10 equiv) and triethylamine (from 1 to 15 equiv) in N,N-dimethylacetamide is heated with microwave irradiation at a temperature ranging from 130 to 150° C. for 5 to 20 min. DBU (1 to 2 equiv) was added, and the reaction mixture is again heated with microwave irradiation for 1 to 4 hours at 130 to 150° C. Upon cooling, solids are collected and then precipitated from a solvent such as acetonitrile or purified by preparative HPLC.


Illustrative Synthesis of compound 576: 4-([1,4′-bipiperidin]-1′-yl)-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid



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A suspension of intermediate HP10 (328 mg, 1.0 mmol), 1,4′-bipiperidine (253 mg, 1.50 mmol) and triethylamine (350 μL, 2.5 mmol) in anhydrous DMA (800 μL) was heated in a Biotage® Initiator microwave synthesizer at 150° C. for fifteen minutes. DBU (180 μL, 1.2 mmol) was added, and the reaction mixture was heated with microwave irradiation at 150° C. for one hour and 45 minutes, brought to room temperature, diluted with water (8 mL) and washed with 1:2 EtOAc/MTBE. The aqueous phase was acidified with 3 M aqueous citric acid (400 μL) to precipitate the product, which was collected by filtration, washed with water and dried under vacuum to give the titled compound (423 mg).


Illustrative Synthesis of compound 560: 3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid



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A suspension of intermediate HP10 (230 mg, 0.70 mmol), 4-(piperidin-4-yl)morpholine (177 mg, 1.05 mmol) and triethylamine (245 μL, 1.76 mmol) in anhydrous DMA (600 μL) was heated in a Biotage® Initiator microwave synthesizer at 140° C. for five minutes. DBU (105 μL, 0.70 mmol) was added, and the reaction mixture was heated with microwave irradiation at 140° C. for three hours, brought to room temperature and filtered through a C18 column (MeOH/H2O). The filtrate was concentrated, and the residual solids were washed with EtOAc, boiled in MeCN and allowed to cool to room temperature. The solid was collected by filtration, rinsed with acetonitrile and dried under vacuum to give the titled compound (305 mg).


Illustrative Synthesis of compound 575: 3-cyclobutyl-4-{4-[2-(morpholin-4-yl)ethyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid



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A suspension of intermediate HP10 (164 mg, 0.50 mmol), 4-(2-(piperidin-4-yl)ethyl)morpholine (149 mg, 0.75 mmol) and triethylamine (175 μL, 1.26 mmol) in anhydrous DMA (400 μL) was heated in a Biotage® Initiator microwave synthesizer at 150° C. for fifteen minutes. DBU (90 μL, 0.60 mmol) was added, and the reaction mixture was heated by microwave irradiation at 150° C. for one hour, brought to room temperature, diluted with water (8 mL) and concentrated. The residue was slurried in acetonitrile and the solids were collected by filtration to give the titled compound (155 mg).


Illustrative Synthesis of compound 544: 3-cyclobutyl-4-[(3R)-3-(hydroxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid



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A suspension of 4-chloro-3-cyclobutyl-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylic acid (HP10, 164 mg, 0.50 mmol), (R)-piperidin-3-ylmethanol (86 mg, 0.75 mmol) and triethylamine (175 μL, 1.26 mmol) in anhydrous DMA (400 μL) was heated in a microwave reactor at 150° C. for fifteen minutes. DBU (90 μL, 0.60 mmol) was added, and the reaction mixture was heated in the reactor at 150° C. for one hour, brought to room temperature, diluted with water (8 mL), concentrated, and purified by preparative HPLC on a Waters® T3 column (30 mm×100 mm) with a 20 to 100% gradient of acetonitrile in 10 mM aqueous ammonium acetate to give the titled compound (156 mg).


Illustrative Synthesis of compound 549: rac-4-[(3aR,7aS)-1-(tert-butoxycarbonyl)octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid



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Intermediate HP10 (164 mg, 0.50 mmol), the tert-butyl rac-(3aR,7aS)-octahydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (181 mg, 0.80 mmol, CAS#848410-13-9) and diisopropylethylamine (175 μL, 1.0 mmol) were heated in DMSO (350 μL) at 120° C. for a day, brought to room temperature, and partitioned between EtOAc and 2:1 water/brine (600 μL). The aqueous phase was separated and extracted thrice with EtOAc, and the combined organic phases were acidified with TFA, concentrated and chromatographed on silica (0.1% TFA in 1:1 EtOAc/heptane) to give the titled compound (274 mg).


Synthesis of Compound 288: 3-methyl-4-(4-methyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid



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To a 4 mL vial equipped with a stir bar was added 4-chloro-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid (40 mg, 0.14 mmol, HP17 dissolved in 400 μL of acetonitrile. To this solution, was then added 4-methyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one (153 mg, 5 eq, 0.7 mmol) followed by diisopropylethylamine (145 μL, 6 equiv, 0.83 mmol), and the mixture was heated at 100° C. with stirring for 16 hours. After completion of the reaction, the mixture was concentrated. The residue was dissolved in DMSO and purified by reverse phase HPLC (C18, 0-100% CH3CN/water (0.1% TFA)). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/min (0-0.5 min 10% A, 0.5-6.0 min linear gradient 10-100% A, 6.0-7.0 min 100% A, 7.0-8.0 min linear gradient 100-10% A). to afford the title compound.


Illustrative Synthesis of compound 571: 3-cyclobutyl-4-[4-(2-methoxyethyl)piperazin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid



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A suspension of intermediate HP10 (164 mg, 0.50 mmol), 1-(2-methoxyethyl)piperazine (108 mg, 0.75 mmol) and triethylamine (175 μL, 1.26 mmol) in anhydrous DMA (400 μL) was heated in a Biotage® Initiator microwave synthesizer at 150° C. for fifteen minutes. DBU (90 μL, 0.60 mmol) was added, and the reaction mixture was heated by microwave irradiation at 150° C. for one hour, brought to room temperature, diluted with water (8 mL) and concentrated. The residue was chromatographed on a C18 column (0 to 50% MeOH/H2O), and the impure product was purified by preparative HPLC on a Waters® Sunfire™ C8 column (30×150 mm) with a 30 to 60% gradient of acetonitrile in 10 mM aqueous ammonium acetate at 50 mL/min to give the titled compound (147 mg).


Illustrative Synthesis of compound 590: 3-cyclobutyl-4-{[(oxan-4-yl)methyl]amino}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid



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Intermediate HP10 (82 mg, 0.25 mmol), 4-aminomethyltetrahydropyran (40 mg, 0.35 mmol), DBU (67 μL, 0.45 mmol) and TMEDA (53 μL, 0.35 mmol) were placed into anhydrous DMA (170 μL) and heated in a Biotage® Initiator microwave synthesizer at 150° C. for one hour. More DBU (11 μL, 0.07 mmol) was added, and the reaction mixture was heated another hour at 160° C. before being brought to room temperature. The reaction mixture was diluted with dichloromethane and washed with water, which was separated and back-extracted with more CH2Cl2. The organic phases were washed with brine, which was separated and back-extracted with CHCl3. The combined organic phases were dried (Na2SO4), concentrated and purified by preparative HPLC on a Waters® Sunfire™ C8 column (30×150 mm) with a 45 to 75% gradient of acetonitrile in 0.1% aqueous TFA at 50 mL/min to give the titled compound (26 mg).


Illustrative Synthesis of compound 655: 3-cyclobutyl-4-({[(2S)-oxolan-2-yl]methyl}amino)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid



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A mixture of intermediate HP10 (82 mg, 0.25 mmol), (S)-(tetrahydrofuran-2-yl)methanamine (40 mg, 0.40 mmol) and triethylamine (88 μL, 0.63 mmol) in anhydrous DMA (200 μL) was heated in a Biotage® Initiator microwave synthesizer at 120° C. for ten minutes. DBU (38 μL, 0.25 mmol) was added, and the reaction mixture was heated at 150° C. for three hours, then brought to room temperature, loaded on silica with EtOAc and eluted (0 to 10% MeOH/MeCN then 0.4% TFA/19.6% MeOH/80% MeCN). The impure product was then purified by preparative HPLC on a Waters® Sunfire™ C8 column (30×150 mm) with a 45 to 75% gradient of acetonitrile in 0.1% aqueous TFA at 50 mL/min to give the titled compound (41 mg).


Illustrative Synthesis of compound 671: 4-[(3S)-3-{[(tert-butoxycarbonyl)amino]methyl}pyrrolidin-1-yl]-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid



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A suspension of intermediate HP02 (230 mg, 0.70 mmol), (R)-tert-butyl(pyrrolidin-3-ylmethyl)carbamate (˜200 mg, 1.0 mmol) and triethylamine (245 μL, 1.76 mmol) in anhydrous DMA (600 μL) was heated in a Biotage® Initiator microwave synthesizer at 150° C. for fifteen minutes. DBU (125 μL, 0.84 mmol) was added, and the reaction mixture was heated at 150° C. with microwave irradiation for one hour, brought to room temperature, treated with acetic acid (200 μL) and chromatographed on silica (100% MeCN then 0.2% HOAc in 1:9 MeOH/MeCN). The appropriate fractions were concentrated, and the residue was swirled with water/methanol until a precipitate formed. The solid was collected by filtration, rinsed with methanol/water and dried under vacuum to give the titled compound (291 mg).


Illustrative Synthesis of compound 672: 4-[(3R)-3-{[(tert-butoxycarbonyl)amino]methyl}pyrrolidin-1-yl]-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid



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A suspension of intermediate HP02 (230 mg, 0.70 mmol), (S)-tert-butyl(pyrrolidin-3-ylmethyl)carbamate (˜200 mg, 1.0 mmol) and triethylamine (245 μL, 1.76 mmol) in anhydrous DMA (600 μL) was heated in a Biotage® Initiator microwave synthesizer at 150° C. for fifteen minutes. DBU (125 μL, 0.84 mmol) was added, and the reaction mixture was heated at 150° C. with microwave irradiation for one hour, brought to room temperature, treated with acetic acid (200 μL) and chromatographed on silica (100% MeCN then 0.2% HOAc in 1:9 MeOH/MeCN). The appropriate fractions were concentrated, and the residue was swirled with water/methanol until a precipitate formed. The solid was collected by filtration, rinsed with methanol/water and dried under vacuum to give the titled compound (292 mg).


Illustrative Synthesis of compound 763: 1-(4-fluorophenyl)-5-methyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid



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A suspension of HP27 (70 mg, <0.20 mmol), 4-morpholinopiperidine (51 mg, 0.30 mmol) and triethylamine (70 μL, 0.50 mmol) in anhydrous DMA (170 μL) was heated in a microwave reactor at 150° C. for fifteen minutes. DBU (30 μL, 0.20 mmol) was added, and the reaction mixture was heated at 180° C. for an hour and then at 200° C. for 2.5 hours. The reaction mixture was brought to room temperature and purified by preparative HPLC on a Waters® Sunfire™ C8 column (30×150 mm) with a 25 to 35% gradient of acetonitrile in 10 mM aqueous ammonium acetate to give the titled compound.


Illustrative Synthesis of compound 811: 1-(4-fluorophenyl)-3-(propan-2-yl)-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid



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A suspension of the chloropyrazolopyridine, HP11 (267 mg, 0.80 mmol), 4-(pyrrolidin-1-ylmethyl)piperidine (202 mg, 1.20 mmol) and triethylamine (280 μL, 2.0 mmol) in anhydrous DMA (700 μL) was heated in a microwave reactor at 150° C. for fifteen minutes. DBU (145 μL, 0.96 mmol) was added and the reaction mixture was heated at 150° C. for 1 hour and 45 minutes, brought to room temperature, diluted with water (7 mL) and washed with 1:2 EtOAc/MTBE. The aqueous phase was acidified with 3 M aqueous citric acid (400 μL) and cooled with a water ice bath to initiate precipitation. The mixture was stirred at room temperature, and when most of the initial gum had solidified, then the suspension was cooled with a water ice bath. The solids were collected by filtration, rinsed with water and chromatographed on silica (20% MeOH/CH3CN then 1% concentrated aqueous NH4OH/9% H2O/CH3CN) to give the titled compound.


Illustrative Synthesis of compound AI27: 3-cyclobutyl-4-[4-(hydroxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid



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To a solution of HP10 (0.502 g, 1.532 mmol) and 4-piperidinemethanol (0.441 g, 3.83 mmol) in N,N-dimethylacetamide (DMA, 1.5 mL) was added diisopropylethylamine (1.5 mL, 8.59 mmol), and the reaction mixture was then stirred at 150° C. for 12 hours. The reaction mixture was then partitioned between dichloromethane and 1 N HCl. The organic fraction was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified on silica gel, eluting with a gradient of 0-5% MeOH/DCM to give the titled compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.41 (qd, J=12.2, 3.7 Hz, 2H), 1.60 (dtdd, J=13.2, 10.0, 6.2, 3.6 Hz, 1H), 1.83 (dd, J=13.3, 3.4 Hz, 2H), 1.87-2.12 (m, 3H), 2.36 (dtd, J=11.8, 8.5, 3.1 Hz, 2H), 2.51 (dd, J=9.3, 2.3 Hz, 1H), 2.76-2.96 (m, 2H), 3.54 (dd, J=9.4, 6.2 Hz, 2H), 3.94 (p, J=8.4 Hz, 1H), 4.55 (s, 1H), 7.24-7.33 (m, 2H), 7.47-7.58 (m, 2H), 8.30 (d, J=8.0 Hz, 2H).


Method J11: Reductive Amination

To a solution of amine (1 equiv) in anhydrous methanol at RT is added paraformaldehyde (CAS: 30525-89-4, 5.0 equiv). A drop of acetic acid is added, and the reaction mixture is stirred for 1 h at RT. Sodium cyanoborohydride (CAS: 25895-60-7, 7 mg, 0.1 mmol, 5 equiv) is then introduced and the reaction mixture is stirred at RT until completion. The reaction mixture is then partitioned between DCM and water. The two phases are separated, and the aqueous phase is extracted with dichloromethane. The combined organic phases are washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the alkylated amine compound which is used as such or purified by flash chromatography on silica gel or preparative HPLC.


Illustrative Synthesis of compound 87: 3-[(dimethylamino)methyl]-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid



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To a solution of A102 (9 mg, 0.02 mmol, 1 equiv) in anhydrous methanol at RT was added paraformaldehyde (CAS: 30525-89-4, 4 mg, 0.1 mmol, 5.0 equiv). A drop of acetic acid was added, and the reaction mixture was stirred for 1 h at RT. Sodium cyanoborohydride (CAS: 25895-60-7, 7 mg, 0.1 mmol, 5 equiv) was then introduced. The reaction mixture was stirred at RT overnight. The reaction mixture was then partitioned between DCM and water. The two phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC to afford the titled compound.


Method J12: Tandem Nucleophilic Substitution on the Central Core and Hydrolysis

To a solution of intermediate halogenated pyrazolopyridine (1.0 equiv) in anhydrous DMSO is added morpholine (2.0 equiv), and the reaction mixture is stirred at 100° C. until completion. The reaction mixture is added to water and extracted with ethyl acetate. The organic layer is washed with brine, dried over MgSO4, filtered and concentrated. The crude is used directly in the next step without further purification.


The crude residue is suspended in a 6 N HCl aqueous solution, and the resulting mixture is heated to reflux overnight. The mixture is cooled to room temperature, quenched by addition of a saturated NaHCO3 solution and extracted with EtOAc. The combined organic phases are washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue is purified by silica gel chromatography or by preparative HPLC.


Illustrative Synthesis of compound 118: 3-methyl-4-(morpholin-4-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid



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Step 1: 3-methyl-4-morpholino-1-phenyl-pyrazolo[3,4-b]pyridine-6-carbonitrile

To a solution of HP18 (21 mg, 0.08 mmol, 1.0 equiv) in anhydrous DMSO (0.5 mL) was added morpholine (14 μL, 0.16 mmol, 2.0 equiv), and the reaction mixture was stirred at 100° C. for 1 h. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude residue was used directly in the next step without further purification.


Step 2: 3-methyl-4-(morpholin-4-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid

The crude residue was suspended in a 6 N HCl aqueous solution, and the resulting mixture was heated to reflux overnight. The mixture was cooled to room temperature, quenched by addition of a saturated NaHCO3 solution and extracted with EtOAc. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH: 100/0 to 95/5) to deliver the titled compound.


Method J13: Alkylation of Alcohols and Carbamates

To a solution of the corresponding alcohol or carbamate (1.0 equiv) in anhydrous DMF under a nitrogen atmosphere at 0° C. is added sodium hydride or KHMDS (1-3 equiv). The resulting solution is stirred at 0° C. for 30 min, and then methyl iodide (1-4 equiv) is added. The reaction mixture is stirred at 0° C. to room temperature until completion. The mixture is then quenched by addition of a saturated NH4Cl solution and filtered. The filtrate is concentrated in vacuo. The residue is dissolved in water, and the pH is adjusted to 4-5 with acetic acid. The resulting mixture is stirred at RT for 1 h. If a filterable suspension is obtained, the suspension formed is collected by filtration, washed with water and dried in vacuo. The crude solid is then purified by silica gel flash chromatography or preparative HPLC. In other cases, the mixture is extracted with EtOAc. The combined organic phases are washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue is purified by silica gel chromatography or by preparative HPLC.


Illustrative Synthesis of compound 143: 4-(4-methoxypiperidin-1-yl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid



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To a solution of ethyl 4-(4-hydroxy-1-piperidyl)-3-methyl-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylate E238 (218 mg, 0.57 mmol, 1.0 equiv) in anhydrous DMF (4.4 mL) under a nitrogen atmosphere was added sodium hydride (60% in oil, 30 mg, 0.74 mmol, 1.3 equiv). The resulting solution was stirred at 0° C. for 30 min, and then methyl iodide (47 μL, 0.31 mmol, 1.3 equiv) was added. The reaction mixture was stirred at 0° C. for 1 h. Then sodium hydride (60 mg, 1.48 mmol, 2.6 equiv) and methyl iodide (181 μL, 2.96 mmol, 5.0 equiv) were added, and the reaction mixture was stirred at 0° C. for 2 h. The mixture was quenched by addition of a saturated NH4Cl solution and filtered. The filtrate was concentrated in vacuo. The residue was dissolved in water, and the pH was adjusted to 4-5 with acetic acid. The resulting mixture was stirred at room temperature for 1 h. The suspension that formed was filtered, and the solids were washed with water and dried in vacuo. The crude solid was then purified by silica gel flash chromatography (heptane/EtOAc/AcOH: 100/0/0.5 to 30/70/0.5) to afford the titled compound.


Synthesis of Compound 674: 4-[(3R)-3-{[(tert-butoxycarbonyl)(methyl)amino]methyl}pyrrolidin-1-yl]-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid



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4-[(3S)-3-{[(tert-Butoxycarbonyl)amino]methyl}pyrrolidin-1-yl]-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid (compound 671, 148 mg, 0.30 mmol) was placed under nitrogen, dissolved into anhydrous DMF (3.0 mL) and cooled with a water ice bath. 1 M KHMDS in THF (900 μL, 0.90 mmol) was added dropwise over a few minutes, and after a few more minutes, iodomethane (75 μL, 1.2 mmol) which had previously been passed through basic alumina was added dropwise over several minutes too. A few minutes later the reaction vial was removed from the bath and the contents were stirred at room temperature for two hours before being treated with 3 M aqueous NaOH (300 μL). After 45 minutes, the reaction mixture was filtered through silica (0 then 0.5% HOAc/EtOAc) and concentrated. The concentrate was diluted with water and extracted thrice with MTBE. The combined organic phases were washed with water then brine, dried (Na2SO4) and concentrated to give the titled compound (141 mg).


Synthesis of Compound 675: 4-[(3S)-3-{[(tert-butoxycarbonyl)(methyl)amino]methyl}pyrrolidin-1-yl]-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid



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4-[(3R)-3-{[(tert-Butoxycarbonyl)amino]methyl}pyrrolidin-1-yl]-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid (compound 672, 148 mg, 0.30 mmol) was placed under nitrogen, dissolved into anhydrous DMF (3.0 mL) and cooled with a water ice bath. 1 M KHMDS in THF (900 μL, 0.90 mmol) was added dropwise over a few minutes, and after a few more minutes, iodomethane (75 μL, 1.2 mmol) which had previously been passed through basic alumina was added dropwise over several minutes too. A few minutes later the reaction vial was removed from the bath and the contents were stirred at room temperature for two hours before being treated with 3 M aqueous NaOH (300 μL). After 45 minutes the reaction mixture was filtered through silica (0 then 0.5% HOAc/EtOAc) and concentrated. The concentrate was diluted with water and extracted thrice with MTBE. The combined organic phases were washed with water then brine, dried (Na2SO4) and concentrated to give the titled compound (154 mg).


Method J14: Debenzylation by Hydrogenolysis

A suspension of the corresponding benzyl ether (1.0 equiv) and Pd/C (10%) in THF/MeOH is hydrogenated until completion. The reaction mixture is filtered over Celpure® and washed with DCM and MeOH, and the filtrate is concentrated in vacuo. The crude residue is then purified by silica gel chromatography or preparative HPLC.


Illustrative Synthesis of compound 198: 4-[4-(3-hydroxypiperidin-1-yl)phenyl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid



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A suspension of AI03 (29 mg, 0.56 mmol, 1.0 equiv) and Pd/C (10%, 20 mg) in THF/MeOH (2 mL/2 mL) was hydrogenated overnight. The reaction mixture was filtered over Celpure® and washed with DCM and MeOH, and the filtrate was concentrated in vacuo. The crude was purified by silica gel chromatography (DCM/MeOH: 100/0 to 90/10) to give the titled compound.


Method J15: Deprotection of Amine by Hydrolysis

To a solution of the corresponding acid (1.0 equiv) in DCM is added trifluoroacetic acid (10% by volume). The reaction mixture is stirred at RT until completion and then concentrated in vacuo. The residue is purified by silica gel chromatography or preparative HPLC to deliver the titled compound.


Illustrative Synthesis of compound 550: 4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-1-phenyl-3-[(pyrrolidin-3-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid



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To a solution of compound 552 (30 mg, 0.049 mmol, 1.0 equiv) in DCM (1 mL) was added trifluoroacetic acid (0.1 mL, 10% by volume). The reaction mixture was stirred at RT until completion, and then concentrated in vacuo. The residue was purified by preparative HPLC to deliver the titled compound.


Synthesis of Compound 676: 3-cyclobutyl-4-{(3S)-3-[(methylamino)methyl]pyrrolidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid



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4-[(3R)-3-{[(tert-Butoxycarbonyl)(methyl)amino]methyl}pyrrolidin-1-yl]-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid (Compound 674, 17 mg, 34 μmol) was dissolved into anhydrous dichloromethane (0.8 mL), treated with TFA (0.2 mL) stirred at room temperature for about 100 minutes, and then concentrated under vacuum. The residue was passed through a C18 column (1 g Burdick and Jackson® column, 13 mm diameter) eluted with 30 to 60% MeOH/H2O to give the titled compound (15 mg).


Method J16: Tandem Nucleophilic Substitution/Saponification



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  • Rm: isopropyl, ethyl



The intermediate ester (1 equiv.) is suspended in a mixture of appropriate alcohol for the nucleophilic substitution and THF. 1 N NaOH (from 17 to 19 equiv) is added, and the reaction mixture is stirred at RT or 50° C. until full conversion is observed. 1 N HCl (2 equiv) and a phosphate buffer solution (pH 6.2) are added. The mixture is concentrated under reduced pressure, and the crude residue is partitioned between water and dichloromethane. The organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure to give the titled compound.


Illustrative Synthesis of compound AI29: 3-cyclobutyl-1-(2-ethoxypyrimidin-4-yl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid



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The intermediate ester E422 (30 mg, 57 μmol) was suspended in a mixture of ethanol (8 mL) and THF (3 mL). 1 N NaOH (1 mL, 1 mmol) was added, and the reaction mixture was stirred at RT for 2 hours. 1N HCl (1 mL, 1 mmol) and a phosphate buffer solution (pH 6.2, 5 mL) were added. The mixture was concentrated under reduced pressure, and the crude residue was partitioned between water and dichloromethane. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to give the titled compound.


Method J17: SNAr on Fluoropyridine



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The (6-fluoro-pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid (1 eq) is heated together with the amine (1.05 eq) and DIPEA (1.25 eq) in NMP at 100° C. for 18 hours. Mixture is diluted with EtOAc and water. Isolation of the organic layer and subsequent concentration yields the desired product.


Illustrative Synthesis of compound 868: 3-Cyclobutyl-1-cyclohexyl-4-[6-(4-cyclopropylpiperazin-1-yl)-pyridin-3-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid



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3-Cyclobutyl-1-cyclohexyl-4-(6-fluoro-pyridin-3-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid (200 mg, 0.51 mmol) was heated together with 1-cyclopropylpiperazine ([20327-23-5], 64 μL, 0.53 mmol) and DIPEA (110 μL, 0.64 mmol) in NMP (2 mL) at 100° C. for 18 hours. Mixture was diluted with EtOAc and water. Isolation of the organic layer and subsequent concentration yielded the titled compound.


Method J18: Suzuki with Alkyl-BF3 Salts



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    • LG3 is a leaving group suitable for the coupling reaction

    • Gx is -G3A or -G3B-L1-G3C





The aryl halide (1 eq) is mixed together with the alkyl-BF3 salt (1.5 eq), Pd(dppf)Cl2.DCM (CAS 95464-05-4, 0.05 eq) and CS2CO3 (3 eq) in a mixture of THF/H2O (10/1). The mixture is put under N2 atmosphere and heated at 80° C. overnight.


If the method is performed on an ester, the ester can be subsequently hydrolyzed to the acid by the addition of LiOH (2 eq) and heating at 50° C. The titled compound is isolated by acidifying with citric acid till pH=6 and extraction with EtOAc. Concentration, possibly followed by chromatographic purification, gives the titled compound.


Illustrative Synthesis of compound 893: 3-Cyclobutyl-1-(4-fluoro-phenyl)-4-(4-morpholin-4-yl-piperidin-1-ylmethyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid



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HP19 (352 mg, 0.98 mmol) was mixed together with potassium trifluorido{[4-(morpholin-4-yl)piperidin-1-yl]methyl}borate (426 mg, 1.47 mmol), Pd(dppf)Cl2.DCM (CAS 95464-05-4, 40 mg, 0.05 mmol) and Cs2CO3 (959 mg, 2.94 mmol) in a mixture of THF/H2O (10/1, 5 mL). The mixture was put under a N2 atmosphere and heated at 80° C. overnight.


Next, LiOH (82 mg, 2 mmol) was added, and the mixture was heated at 50° C. The titled compound was isolated by acidifying with citric acid till pH=6 and extraction with EtOAc. Concentration, followed by automated preparative chromatographic purification, gave the titled compound.


Method J19: Suzuki and Subsequent Hydrolysis



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The aryl chloride (1 eq) is mixed with the boronic ester (or acid) (1.5 eq), Pd(dppf)Cl2.DCM (CAS 95464-05-4, 0.1 eq) and DIPEA (3 eq) in a mixture of water/dioxane (1/2). The resulting mixture is stirred at 120° C. for 18 hours. Next, LiOH (2 eq) is added, and the mixture is heated at 40° C. After acidifying with 2 M HCl solution, extraction with EtOAc gives an organic phase that is concentrated to give the titled compound.


Method J20: Oxidation of Primary Alcohols to Aldehydes



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The primary alcohol is combined with dimethyl sulfoxide and treated with triethylamine (1.5-5 equiv) and pyridine sulfur trioxide complex (1.5-5 equiv) with stirring at ambient temperature. The reaction mixture is stirred for 30 minutes to 2 hours. Additional triethylamine and pyridine sulfur trioxide complex are added as needed to give complete conversion. The reaction mixture is partitioned between dichloromethane and aqueous 1 N HCl. The organic fraction is dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel column chromatography.


Illustrative Synthesis of AI28: 3-cyclobutyl-4-(4-formylpiperidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid



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To a solution of AI27 (1.685 g, 4.15 mmol) in DMSO (15 mL) were added triethylamine (1.444 mL, 10.36 mmol) and pyridine sulfur trioxide complex (1.649 g, 10.36 mmol). The reaction mixture was stirred at RT for one hour to give a mixture of the aldehyde and starting alcohol. More triethylamine (0.3 mL, 0.5 equivalents) and pyridine sulfur trioxide complex (0.33 gm, 0.5 eq) were added to the reaction mixture, which was stirred at 25° C. for 30 minutes. More triethylamine (0.15 mL, 0.25 equivalents) and pyridine sulfur trioxide complex (0.165 gm, 0.25 equivalents) were added, and the reaction stirred at 25° C. for one hour. The reaction mixture was then partitioned between dichloromethane and 1 N aqueous HCl. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified on silica gel eluting with a gradient of 0-5% MeOH/dichloromethane to give the titled compound. 1H NMR (400 MHz, CDCl3) δ ppm 1.97 (dtd, J=14.1, 10.7, 3.8 Hz, 2H), 2.11 (dddd, J=14.6, 9.5, 8.0, 3.7 Hz, 2H), 2.16-2.31 (m, 2H), 2.45 (dddd, J=9.2, 8.0, 6.6, 4.1 Hz, 1H), 2.62 (dddd, J=18.0, 14.8, 11.2, 6.7 Hz, 3H), 3.10 (td, J=12.7, 11.7, 2.8 Hz, 2H), 3.66 (dt, J=12.4, 4.1 Hz, 2H), 3.98 (p, J=8.4 Hz, 1H), 7.38 (tt, J=7.5, 1.1 Hz, 1H), 7.50 (d, J=0.9 Hz, 1H), 7.52-7.62 (m, 2H), 8.05 (dq, J=7.7, 1.1 Hz, 2H), 9.82 (s, 1H).


Method J21: Reductive Amination of Aldehydes



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To a mixture of aldehyde (1 equiv) in dichloroethane is added N,N-diisopropylethylamine (2 equiv). Molecular sieves and amine or amine hydrochloride (1-2 equiv) are added followed by stirring at ambient temperature for 1-5 hours. Sodium triacetoxyborohydride (1-3 equiv) is added followed by stirring for 8 hours to 4 days. The reaction mixture is filtered. The filtrate is concentrated, and the residue can be purified by preparative HPLC.


Alternatively, a mixture of aldehyde (1 equiv), amine or amine hydrochloride (1-2 equiv), acetic acid, and reductant (sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride; 1-6 equiv; solid or on a solid support, i.e. resin) in dichloroethane, dichloromethane, or a mixture of dichloromethane and methanol is stirred at ambient temperature for 1-24 hours. The reaction mixture is can be purified by preparative HPLC.


Illustrative Synthesis of compound 802: 3-cyclobutyl-4-(4-{[(3R)-3-(methoxymethyl)pyrrolidin-1-yl]methyl}piperidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid



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To a suspension of AI28 (0.05 g, 0.124 mmol) in dichloroethane (1 mL) was added N,N-diisopropylethylamine (0.043 mL, 0.247 mmol). Molecular sieves were then added to the reaction mixture followed by addition of (R)-3-(methoxymethyl)pyrrolidine hydrochloride (0.019 g, 0.124 mmol), and the reaction mixture was stirred at 25° C. for three hours. Sodium triacetoxyborohydride (0.039 g, 0.185 mmol) was added to the reaction mixture, which was then stirred at 25° C. for 2 days. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was then purified by preparative HPLC on a Waters® Sunfire™ C8 column (30×150 mm) with an escalating gradient of acetonitrile in 10 mM aqueous ammonium acetate to give the titled compound.


Method J22: Cross-Coupling to Pyrazole and Ester Hydrolysis



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Under an inert atmosphere (glovebox) are combined a palladium catalyst such as tris(dibenzylideneacetone)dipalladium(0) (0.02 to 0.1 equiv), a ligand such as di-tert-butyl(2′,4′,6′-triisopropyl-3,4,5,6-tetramethyl-[1,1′-biphenyl]-2-yl)phosphine (0.05 to 0.3 equiv), and cesium carbonate (1 to 4 equiv) in toluene. The mixture can be heated at 50-100° C. for 20-60 minutes. The pyrazolopyridine (1 equiv) and an aryl halide or heteroaryl halide are added, and the mixture can be heated at 50-100° C. overnight. The reaction mixture is dried, and the intermediate ester can be hydrolyzed with a base such as aqueous 0.5 to 2 N lithium hydroxide, sodium hydroxide or potassium hydroxide at room temperature over 4-24 hours. Upon reaction completion, the coupled/hydrolyzed product can be isolated by preparative chromatography.


Illustrative Synthesis of compound 910: 3-cyclobutyl-1-[3-(difluoromethoxy)phenyl]-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid and intermediate E510: methyl 3-cyclobutyl-1-[3-(difluoromethoxy)phenyl]-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate



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A nitrogen-purged mixture of tris(dibenzylideneacetone)dipalladium(0) (0.0193 g, 0.021 mmol), and di-tert-butyl(2′,4′,6′-triisopropyl-3,4,5,6-tetramethyl-[1,1′-biphenyl]-2-yl)phosphine (0.0251 g, 0.052 mmol) in toluene (2.2 mL) was stirred for 20 minutes and then added to an nitrogen-purged mixture of methyl 3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate (0.1760 g, 0.441 mmol, E509), 1-bromo-3-(difluoromethoxy)benzene (0.1179 g, 0.529 mmol), and Cs2CO3 (0.2143 g, 0.658 mmol). The mixture was heated to 70° C. overnight, diluted with water, extracted with DCM (3×8 mL), dried (Na2SO4), and concentrated. The residue was chromatographed on silica (30-60% EtOAc/DCM to 4% MeOH/DCM) and re-chromatographed (2.5-4% iPrOH/DCM) to give methyl 3-cyclobutyl-1-[3-(difluoromethoxy)phenyl]-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate (E510). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.28-8.16 (m, 2H), 7.58 (t, J=8.2 Hz, 1H), 7.51-7.03 (m, 3H), 3.95 (dq, J=18.1, 9.8, 8.5 Hz, 1H), 3.88 (s, 3H), 3.63-3.48 (m, 6H), 2.91 (t, J=11.9 Hz, 2H), 2.53-2.48 (m, 4H), 2.46-2.28 (m, 2H), 2.12-1.88 (m, 4H), 1.63 (td, J=13.1, 12.6, 6.4 Hz, 2H); MS (APCI+) m/z 542.4 (M+H)+. 1008161A 1 N aqueous solution of sodium hydroxide (0.14 mL, 0.140 mmol) was added to a mixture of methyl 3-cyclobutyl-1-[3-(difluoromethoxy)phenyl]-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylate (E510, 0.0647 g, 0.119 mmol) in methanol (0.14 mL) and tetrahydrofuran (0.40 mL), The mixture was stirred for 2 hours, diluted with water, and extracted with DCM that was back-extracted with water (2×). The aqueous layer was neutralized with 1 N HCl (0.17 mL), and extracted with DCM, dried (Na2SO4), and concentrated to give 3-cyclobutyl-1-[3-(difluoromethoxy)phenyl]-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid.


Synthesis of acid compound 24: 1-phenyl-3-(propan-2-yl)-4-[4-(pyrrolidin-1-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid



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Aldehyde (CAS 51980-54-2, 219 mg, 1.25 mmol, 1 equiv), pyruvic acid (81 μL, 1.25 mmol, 1 equiv), and pyrazole AMP04 (251 mg, 1.25 mmol, 1 equiv) were introduced in a sealed tube. Acetic acid (5 mL) was added, and the vial was sealed. The reaction mixture was heated under microwave irradiation at 160° C. for 20 min. Then after cooling down to RT, the vial was opened, and the volatiles were evaporated under reduced pressure. The resulting crude mixture was diluted in methanol and purified by preparative HPLC to afford the titled compound.


Synthesis of acid AI11: 3-(azetidin-3-yloxy)-4-(4-morpholinophenyl)-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylic acid



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Step 1: (1-tert-butoxycarbonylazetidin-3-yl) 3-(1-tert-butoxycarbonylazetidin-3-yl)oxy-4-(4-morpholinophenyl)-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylate

To a solution of acid AI15 (100 mg, 2.4 mmol, 1.0 equiv) in anhydrous NMP (4.4 mL) were added cesium carbonate (235 mg, 0.72 mmol, 3.0 equiv) and 3-iodo-azetidine-1-carboxylic acid tert-butyl ester (210 mg, 0.72 mmol, 3.0 equiv). The resulting solution was stirred at 130° C. under microwave irradiation for 30 min twice. The mixture was then poured into water and extracted with EtOAc. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (DCM/MeOH: 100/0 to 95/5) to deliver the bis-alkylated compound.


Step 2: 3-(1-tert-butoxycarbonylazetidin-3-yl)oxy-4-(4-morpholinophenyl)-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylic acid

The previous intermediate (0.033 mmol, 1.0 eq) was dissolved in methanol (2 mL) and 2N NaOH (66 μL, 0.13 mmol, 4.0 eq) in water was added at RT. The solution was stirred for 2 h. The volatiles were evaporated under reduced pressure, and the resulting mixture was diluted with water. The aqueous phase was acidified with aqueous 2 N HCl (70 μL) and extracted with EtOAc. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was directly used in the next step without purification.


Step 3: 3-(azetidin-3-yloxy)-4-(4-morpholinophenyl)-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylic acid

To a solution of the previous acid (1.0 equiv) in DCM (1 mL) was added trifluoroacetic acid (1 mL, 50% volume). The reaction mixture was stirred at RT for 1.5 h and then concentrated in vacuo. The crude residue was directly used in the next step without purification.


Synthesis of AI23: 1-(6-bromopyridin-2-yl)-3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid



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Ester E428 (46 mg, 81 μmol) was dissolved in a mixture of THF/2-propanol (1/2; 9 mL), and 1 N sodium hydroxide (1 mL, 1 mmol) in water was added at RT. The solution was stirred for 2 hours. Aqueous 1 N HCl (1 mL, 1 mmol) was added, and then a phosphate buffer was added (pH 6.2). The solvent was partially removed under reduced pressure, and the resulting mixture was extracted twice with DCM. The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the titled compound that was used without further purification.


Synthesis of AI25: 1-(4-fluorophenyl)-4-(4-methoxy[1,4′-bipiperidin]-1′-yl)-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridin-6-yl trifluoromethanesulfonate



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A mixture of HP22 (29 mg, 50 μmol), 4-methoxy-1-piperidin-4-ylpiperidine hydrochloride ([930603-98-8], 14 mg, 50 μmol) and DIPEA (35 μL, 200 μmol) in anhydrous DMSO (1 mL) was heated at 100° C. for 2 hours. The reaction mixture was cooled to RT and partitioned between ethyl acetate (50 mL) and water (30 mL). The organic phase was separated, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with n-heptane/ethyl acetate and DCM/MeOH to afford the titled compound.


Synthesis of AI26: 1-(4-fluorophenyl)-4-(4-methoxy[1,4′-bipiperidin]-1′-yl)-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carbonitrile



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Compound AI25 (16 mg, 26 μmol) was solubilized in dry dimethylformamide (1 mL) in a vial. Zinc cyanide (3.5 mg, 30 μmol) was added, and the reaction mixture was degassed with argon for 5 minutes. Tetrakis(triphenylphosphine)palladium(0) (4 mg, 3 μmol) was added, and the vial was sealed. The reaction mixture was stirred at 120° C. for 2 hours. The reaction mixture was cooled to room temperature, and the mixture was partitioned between a saturated aqueous solution of NaHCO3 and DCM. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography eluting with ethyl acetate/DCM/MeOH to give the titled compound.


Synthesis of Compound 924: 3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-{6-[(propan-2-yl)oxy]pyridin-2-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid



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Sodium hydride (60% in mineral oil, 100 mg, 2 mmol) was added at 0° C. to 2-propanol (3 mL) under a nitrogen atmosphere. The tube was sealed and then heated at 90° C. for 5 minutes. The reaction mixture was cooled to RT, and a solution of AI23 (30 mg, 55 μmol) in 2-propanol (2 mL) was added dropwise. The reaction mixture was stirred at 90° C. for 1 hour. The reaction mixture was quenched with a saturated aqueous solution of NH4Cl. A phosphate buffer was added (pH 6.2), and the aqueous phase was extracted twice with DCM/2-propanol (50 mL, 95/5). The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with DCM/MeOH/1% AcOH to afford the titled compound.


Synthesis of Compound 925: 1-(4-fluorophenyl)-3-hydroxy-4-(4-methoxy[1,4′-bipiperidin]-1′-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid



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In a sealed tube, compound AI26 (11 mg, 22 μmol) was dissolved in 6 N HCl (3 mL, 18 mmol). The solution was heated at 100° C. for 5 hours and then cooled to RT. The reaction mixture was partitioned between a phosphate buffer solution (pH 6.2) and a mixture of DCM/2-propanol (100 mL, 85/15). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with DCM/MeOH/water/AcOH from 90/10/1/1 to 85/15/2/2 to yield the titled compound.









TABLE XIV







Table of intermediate acids













Int
Structure
Name
SM
Method
MW
Mes





AI01


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3-(azetidin- 3-yl)-4-(4- morpholino- phenyl)-1- phenyl- pyrazolo[3,4- b]pyridine- 6-carboxylic acid
47
J15
455
456





AI02


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3- (methylamino- methyl)-4- (4- morpholino- phenyl)-1- phenyl- pyrazolo[3,4- b]pyridine- 6-carboxylic acid
AMP86, ALP01
J2
442
443





AI03


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4-[4-(3- benzyloxy- 1- piperidyl) phenyl]-3- methyl-1- phenyl- pyrazolo[3,4- b]pyridine- 6-carboxylic acid
E010
J5
518
519





AI04


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4-(6-chloro- 3-pyridyl)- 3-methyl-1- phenyl- pyrazolo[3,4- b]pyridine- 6-carboxylic acid
1131- 18-6, ALP07
J2
364
364- 366





AI05


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1-(3- bromo- phenyl)-3- isopropyl-4- [6-[2- methoxy- ethyl(methyl) amino]-3- pyridyl] pyrazolo[3,4- b]pyridine- 6-carboxylic acid
E346
J1
523
524





AI06


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1-(3- bromo- phenyl)-3- isopropyl-4- [4- [methyl(tetra- hydropyran- 4- yl)amino] phenyl] pyrazolo[3,4- b]pyridine- 6-carboxylic acid
E347
J1
548
549





AI07


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1-(3- benzyloxy- cyclohexyl)-3- isopropyl-4- (4- morpholino- phenyl) pyrazolo[3,4- b]pyridine- 6-carboxylic acid
AMP89, ALP01
J2
554
555





AI08


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1-(1- benzyloxy- carbonyl-4- piperidyl)-3- isopropyl-4- (4- morpholino- phenyl) pyrazolo[3,4- b]pyridine- 6-carboxylic acid
AMP90, ALP01
J2
583
584





AI09


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1-(1- benzyloxy- carbonyl- pyrrolidin-3- yl)-3- isopropyl-4- (4- morpholino- phenyl) pyrazolo[3,4- 6]pyridine- 6-carboxylic acid
AMP91, ALP01
J2
569
570





AI10


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1-(1- benzyloxy- carbonyl-3- piperidyl)-3- isopropyl-4- (4- morpholino- phenyl) pyrazolo[3,4- b]pyridine- 6-carboxylic acid
AMP92, ALP01
J2
583
584





AI11


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3-(azetidin- 3-yloxy)-4- (4- morpholino- phenyl)-1- phenyl- pyrazolo[3,4- b]pyridine- 6-carboxylic acid
AI15
Specific example
471
472





AI12


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4-[4-(3- benzyloxy- pyrrolidin-1- yl)phenyl]- 3-methyl-1- phenyl- pyrazolo[3,4- b]pyridine- 6-carboxylic acid
E010
J5
504
505





AI13


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3- cyclobutyl- 4-[4- (fluoro- methyl)-1- piperidyl]-1- phenyl- pyrazolo[3,4- b]pyridine- 6-carboxylic acid
HP10
J4, Specific example
408
409





AI14


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4-(6-chloro- 3-pyridyl)- 1- cyclohexyl- 3-isopropyl- pyrazolo[3,4- b]pyridine- 6-carboxylic acid
ALP07, AMP23
J2
398- 400
399- 401





AI15


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4-(4- morpholino- phenyl)-3- oxo-1- phenyl-2H- pyrazolo[3,4- b]pyridine- 6-carboxylic acid
ALP01, 70373- 98-7
J2
416
417





AI16


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4-(4- bromo- phenyl)-3- methyl- 1-phenyl- pyrazolo[3,4- b]pyridine- 6-carboxylic acid
ALP19, 1131- 18-6
J2
407- 409
408- 410





AI17


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1-(3- bromo- phenyl)-3- isopropyl-4- (4- morpholino- phenyl) pyrazolo[3,4- b]pyridine- 6-carboxylic acid
ALP01, AMP05
J2
520- 522
521- 523





AI18


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4-[6-(4- cyano-1- piperidyl)-3- pyridyl]-3- (3- fluorocyclo- butyl)-1- phenyl- pyrazolo[3,4- b]pyridine- 6-carboxylic acid
E120
J1
496
497





AI19


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1-[3-(3- benzyloxy- azetidin-1- yl)phenyl]- 3-isopropyl- 4-(4- morpholino- phenyl) pyrazolo[3,4- b]pyridine- 6-carboxylic acid
AI17
J7
603
604





AI21


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3-(azetidin- 3-yl)-1- cyclohexyl- 4-[2- (dimethyl- amino) pyrimidin-5- yl]pyrazolo [3,4-b] pyridine- 6-carboxylic acid
ALP03, AMP38
J2
421
422





AI22


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4-[(1-tert- butoxy- carbonyl-4- piperidyl) methoxy]-1- (4- fluorophenyl)- 3-isopropyl- pyrazolo[3,4- b]pyridine- 6-carboxylic acid
HP11
J3
512
513





AI23


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1-(6- bromo- pyridin- 2-yl)-3- cyclobutyl- 4-[4- (morpholin- 4- yl)piperidin- 1-yl]-1H- pyrazolo[3,4- b]pyridine- 6-carboxylic acid
E428
Specific example
540- 542
541- 543





AI24


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3- cyclobutyl- 1- cyclohexyl- 4-(6- fluoropyridin- 3-yl)-1H- pyrazolo[3,4- b]pyridine- 6-carboxylic acid
HP25, 351019- 18-6
J19
394
395





AI25


embedded image


1-(4- fluorophenyl)- 4-(4- methoxy[1,4′- bipiperidin]- 1′-yl)-3- [(propan-2- yl)oxy]-1H- pyrazolo[3,4- b]pyridin-6- yl trifluoro- methane- sulfonate
HP22
Specific example
615
617





AI26


embedded image


1-(4- fluorophenyl)- 4-(4- methoxy[1,4′- bipiperidin]- 1′-yl)-3- [(propan-2- yl)oxy]-1H- pyrazolo[3,4- b]pyridine- 6- carbonitrile
AI25
Specific example
492
493





AI27


embedded image


3- cyclobutyl- 4-[4- (hydroxy- methyl) piperidin- 1-yl]-1- phenyl-1H- pyrazolo[3,4- b]pyridine- 6-carboxylic acid
HP10
J10, Specific example
406
407





AI28


embedded image


3- cyclobutyl- 4-(4- formyl- piperidin- 1-yl)-1- phenyl-1H- pyrazolo[3,4- b]pyridine- 6-carboxylic acid
AI27
J20, Specific example
404
405





AI29


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3- cyclobutyl- 1-(2- ethoxy- pyrimidin- 4-yl)-4-[4- (morpholin- 4- yl)piperidin- 1-yl]-1H- pyrazolo[3,4- b]pyridine- 6-carboxylic acid
E422
Specific example
507
















TABLE XV







Final Compounds












Cpd
Name
SM
Method
MW
Mes















1
3-methyl-4-[4-(morpholin-4-
ALP01,
J2
414
415



yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-
1131-18-






b]pyridine-6-carboxylic acid
6





2
1-cyclohexyl-4-(4-methoxyphenyl)-3-
56547-
J2
364
365



methyl-1H-pyrazolo[3,4-b]pyridine-6-
82-1,






carboxylic acid
ALP06





3
1-cyclopentyl-4-(4-methoxyphenyl)-
AMP47,A
J2
352
353



3-methyl-1H-pyrazolo[3,4-b]pyridine-
LP06






6-carboxylic acid






4
1-(2-cyanoethyl)-4-(4-
61255-
J2
336
337



methoxyphenyl)-3-methyl-1H-
82-1






pyrazolo[3,4-b]pyridine-6-carboxylic
(AMP48),






acid
ALP06





5
4-[4-(morpholin-4-yl)phenyl]-1-
AMP04,
J2
444
445



phenyl-3-(propan-2-yl)-1H-
ALP01






pyrazolo[3,4-b]pyridine-6-carboxylic







acid






6
1-(4-fluorophenyl)-3-methyl-4-[4-
76606-
J2
432
433



(morpholin-4-yl)phenyl]-1H-
39-8






pyrazolo[3,4-b]pyridine-6-carboxylic
(AMP49),






acid
ALP01





7
3-methyl-4-[4-(morpholin-4-
AMP50,
J2
472
473



yl)phenyl]-1-[5-(trifluoromethyl)-1H-
ALP01






pyrazol-3-yl]-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






8
3-methyl-1-phenyl-4-[4-(piperidin-1-
1131-18-
J2
411
412



yl)phenyl]-1H-pyrazolo[3,4-
6 , ALP35






b]pyridine-6-carboxylic acid






9
3-methyl-4-[4-(4-methylpiperazin-1-
1131-18-
J2
427
428



yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-
6, ALP27






b]pyridine-6-carboxylic acid






10
1-(3,5-difluorophenyl)-3-methyl-4-[4-
ALP01,
J2
450
451



(morpholin-4-yl)phenyl]-1H-
1232796-






pyrazolo[3,4-b]pyridine-6-carboxylic
65-4






acid






11
1-(3-chlorophenyl)-3-methyl-4-[4-
ALP01,
J2
448
449



(morpholin-4-yl)phenyl]-1H-
40401-






pyrazolo[3,4-b]pyridine-6-carboxylic
41-0






acid






12
1-(3-fluorophenyl)-3-methyl-4-[4-
ALP01,
J2
432
433



(morpholin-4-yl)phenyl]-1H-
105438-






pyrazolo[3,4-b]pyridine-6-carboxylic
45-7






acid






13
3-methyl-1-(3-methylphenyl)-4-[4-
92721-
J2
428
429



(morpholin-4-yl)phenyl]-1H-
83-0,






pyrazolo[3,4-b]pyridine-6-carboxylic
ALP01






acid






14
4-[4-(1,1-dioxo-1λ6,4-thiazinan-4-
1131-18-
J2
462
463



yl)phenyl]-3-methyl-1-phenyl-1H-
6,






pyrazolo[3,4-b]pyridine-6-carboxylic
ALP28






acid






15
3-methyl-4-[2-(morpholin-4-
1131-18-
J2
416
417



yl)pyrimidin-5-yl]-1-phenyl-1H-
6,






pyrazolo[3,4-b]pyridine-6-carboxylic
ALP04






acid






16
3-(ethoxycarbonyl)-4-[4-(morpholin-
866837-
J2
473
475



4-yl)phenyl]-1-phenyl-1H-
96-9






pyrazolo[3,4-b]pyridine-6-carboxylic
(AMP51),






acid
ALP01





17
1-cyclohexyl-3-methyl-4-[4-
ALP01,
J2
420
421



(morpholin-4-yl)phenyl]-1H-
56547-






pyrazolo[3,4-b]pyridine-6-carboxylic
82-1






acid






18
1-(3-bromophenyl)-3-methyl-4-[4-
956329-
J2
493
494



(morpholin-4-yl)phenyl]-1H-
14-9






pyrazolo[3,4-b]pyridine-6-carboxylic
(AMP52),






acid
ALP01





19
3-(hydroxymethyl)-4-[4-(morpholin-
AMP53,
J2
430
431



4-yl)phenyl]-1-phenyl-1H-
ALP01






pyrazolo[3,4-b]pyridine-6-carboxylic







acid






20
1-(3-methylphenyl)-4-[4-(morpholin-
AMP07,
J2
456
457



4-yl)phenyl]-3-(propan-2-yl)-1H-
ALP01






pyrazolo[3,4-b]pyridine-6-carboxylic







acid






21
1-(3-methoxyphenyl)-3-methyl-4-[4-
ALP01,
J2
444
445



(morpholin-4-yl)phenyl]-1H-
92721-






pyrazolo[3,4-b]pyridine-6-carboxylic
94-3






acid






22
3-methyl-4-[4-(morpholin-4-
ALP01,
J2
482
483



yl)phenyl]-1-[3-
345-07-3






(trifluoromethyl)phenyl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






23
3-methyl-4-[4-(morpholin-4-
1247075-
J2
422
423



yl)phenyl]-1-(oxan-4-yl)-1H-
24-6






pyrazolo[3,4-b]pyridine-6-carboxylic
(AMP54),






acid
ALP01





24
1-phenyl-3-(propan-2-yl)-4-[4-
AMP 04,
Specific
426
427



(pyrrolidin-1-yl)phenyl]-1H-
51980-
example





pyrazolo[3,4-b]pyridine-6-carboxylic
54-2






acid






25
3-methyl-1-phenyl-4-[4-(pyrrolidin-1-
1131-18-
J2
398
399



yl)phenyl]-1H-pyrazolo[3,4-
6,






b]pyridine-6-carboxylic acid
ALP29





26
4-[2-chloro-4-(morpholin-4-
1131-18-
J2
448
449



yl)phenyl]-3-methyl-1-phenyl-1H-
6,






pyrazolo[3,4-b]pyridine-6-carboxylic
ALP30






acid






27
3-methyl-4-[4-(1-methyl-1,2,3,6-
1131-18-
J2
424
425



tetrahydropyridin-4-yl)phenyl]-1-
6,






phenyl-1H-pyrazolo[3,4-b]pyridine-6-
ALP31






carboxylic acid






28
4-[4-(3-fluoropyrrolidin-1-yl)phenyl]-
AI16
J5
416
417



3-methyl-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






29
4-[4-(4-acetylpiperazin-1-yl)phenyl]-
AI16
J5
455
456



3-methyl-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






30
1-(3,5-dimethylphenyl)-3-methyl-4-
ALP01,
J2
442
443



[4-(morpholin-4-yl)phenyl]-1H-
890010-






pyrazolo[3,4-b]pyridine-6-carboxylic
89-6






acid






31
3-methyl-4-[4-(morpholin-4-
ALP01,
J2
498
415



yl)phenyl]-1-[4-
497141-






(trifluoromethoxy)phenyl]-1H-
59-0






pyrazolo[3,4-b]pyridine-6-carboxylic







acid






32
3-methyl-1-[3-(morpholin-4-
AMP55,
J2
499
500



yl)phenyl]-4-[4-(morpholin-4-
ALP01






yl)phenyl]-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






33
4-[2-methoxy-4-(morpholin-4-
1131-18-
J2
444
445



yl)phenyl]-3-methyl-1-phenyl-1H-
6,






pyrazolo[3,4-b]pyridine-6-carboxylic
ALP32






acid






34
1-cyclopropyl-3-methyl-4-[4-
ALP01,
J2
378
379



(morpholin-4-yl)phenyl]-1H-
AMP15






pyrazolo[3,4-b]pyridine-6-carboxylic







acid






35
3-methyl-4-[4-(morpholin-4-
ALP01,
J2
498




yl)phenyl]-1-[3-
AMP01






(trifluoromethoxy)phenyl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






36
1-[3-(dimethylamino)phenyl]-3-
AMP56,
J2
457
458



methyl-4-[4-(morpholin-4-yl)phenyl]-
ALP01






1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






37
1-(3,4-difluorophenyl)-3-methyl-4-[4-
ALP01,
J2
450
451



(morpholin-4-yl)phenyl]-1H-
AMP02






pyrazolo[3,4-b]pyridine-6-carboxylic







acid






38
1-[3-(methanesulfonyl)phenyl]-3-
AMP57,
J2
492
493



methyl-4-[4-(morpholin-4-yl)phenyl]-
ALP01






1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






39
3-methyl-1-(1-methylpiperidin-4-yl)-
3524-43-
J2
435
436



4-[4-(morpholin-4-yl)phenyl]-1H-
4






pyrazolo[3,4-b]pyridine-6-carboxylic
(AMPS 8),






acid
ALP01





40
3-tert-butyl-4-[4-(morpholin-4-
AMP59,
J2
456
457



yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-
ALP01






b]pyridine-6-carboxylic acid






41
1-(2-chloropyridin-4-yl)-4-[4-
AMP60,
J2
478
478-



(morpholin-4-yl)phenyl]-3-(propan-2-
ALP01


480



yl)-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






42
3,5-dimethyl-4-[4-(morpholin-4-
1131-18-
J2
428
429



yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-
6,






b]pyridine-6-carboxylic acid
ALP33





43
4-[4-(morpholin-4-yl)phenyl]-3-
AMP61,
J2
526
527



(propan-2-yl)-1-[4-
ALP01






(trifluoromethoxy)phenyl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






44
1-(3,5-dichlorophenyl)-3-methyl-4-[4-
AMP62,
J2
482
483



(morpholin-4-yl)phenyl]-1H-
ALP01






pyrazolo[3,4-b]pyridine-6-carboxylic







acid






45
3-methyl-4-[4-(morpholin-4-
AMP63,
J2
493
494



yl)phenyl]-1-(3-sulfamoylphenyl)-
ALP01






1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






46
3-methyl-1-(1-methyl-1H-pyrazol-4-
AMP64,
J2
418
419



yl)-4-[4-(morpholin-4-yl)phenyl]-1H-
ALP01






pyrazolo[3,4-b]pyridine-6-carboxylic







acid






47
3-[1-(tert-butoxycarbonyl)azetidin-3-
AMP65,
J2
555
556



yl]-4-[4-(morpholin-4-yl)phenyl]-1-
ALP01






phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






48
4-[4-(morpholin-4-yl)phenyl]-1-
AMP66,
J2
440
441



phenyl-3-(prop-1-en-2-yl)-1H-
ALP01






pyrazolo[3,4-b]pyridine-6-carboxylic







acid






49
1-(3-cyanophenyl)-4-[4-(morpholin-
AMP67,
J2
467
468



4-yl)phenyl]-3-(propan-2-yl)-1H-
ALP01






pyrazolo[3,4-b]pyridine-6-carboxylic







acid






50
3-methyl-4-[6-(morpholin-4-
E009
J1
415
416



yl)pyridin-3-yl]-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






51
1-(2-methoxypyridin-4-yl)-3-methyl-
57
J6
445
446



4-[4-(morpholin-4-yl)phenyl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






52
1-(3-fluoro-5-methoxyphenyl)-3-
AMP03,
J2
462
463



methyl-4-[4-(morpholin-4-yl)phenyl]-
ALP01






1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






53
4-{4-[4-(methanesulfonyl)piperazin-
E201
J1
491
492



1-yl]phenyl}-3-methyl-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






54
1-cyclohexyl-4-[4-(morpholin-4-
AMP23,
J2
448
449



yl)phenyl]-3-(propan-2-yl)-1H-
ALP01






pyrazolo[3,4-b]pyridine-6-carboxylic







acid






55
3-(methylcarbamoyl)-4-[4-
AMP68,
J2
457
458



(morpholin-4-yl)phenyl]-1-phenyl-
ALP01






1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






56
3-(1-hydroxy-2-methylpropan-2-yl)-
AMP69,
J2
473
473



4-[4-(morpholin-4-yl)phenyl]-1-
ALP01






phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






57
1-(2-fluoropyridin-4-yl)-3-methyl-4-
AMP70,
J2
433
434



[4-(morpholin-4-yl)phenyl]-1H-
ALP01






pyrazolo[3,4-b]pyridine-6-carboxylic







acid






58
3-methyl-4-[4-(morpholin-4-
AMP71,
J2
431
432



yl)phenyl]-1-(2-oxo-1,2-
ALP01






dihydropyridin-4-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






59
1-(3-carbamoylphenyl)-3-methyl-4-
AMP72,
J2
457
458



[4-(morpholin-4-yl)phenyl]-1H-
ALP01






pyrazolo[3,4-b]pyridine-6-carboxylic







acid






60
4-[4-(4-tert-butylpiperazin-1-
E202
J1
469
470



yl)phenyl]-3-methyl-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






61
1-(6-methoxypyridin-3-yl)-3-methyl-
AMP73,
J2
445
446



4-[4-(morpholin-4-yl)phenyl]-1H-
ALP01






pyrazolo[3,4-b]pyridine-6-carboxylic







acid






62
1-cyclohexyl-4-[2-
ALP03,
J2
408
409



(dimethylamino)pyrimidin-5-yl]-3-
AMP23






(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






63
3-(2-hydroxypropan-2-yl)-4-[4-
AMP66,
J2
459
460



(morpholin-4-yl)phenyl]-1-phenyl-
ALP01






1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






64
3-carbamoyl-4-[4-(morpholin-4-
AMP74,
J2
443
444



yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-
ALP01






b]pyridine-6-carboxylic acid






65
1-cyclohexyl-3-methyl-4-[2-
56547-
J2
422
423



(morpholin-4-yl)pyrimidin-5-yl]-1H-
82-1,






pyrazolo[3,4-b]pyridine-6-carboxylic
ALP04






acid






66
4-[3-bromo-4-(morpholin-4-
56547-
J2
493
493-



yl)phenyl]-3-methyl-1-phenyl-1H-
82-1,


495



pyrazolo[3,4-b]pyridine-6-carboxylic
ALP34






acid






67
1-cyclopentyl-4-[2-
AMP26,
J2
394
395



(dimethylamino)pyrimidin-5-yl]-3-
ALP03






(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






68
4-[4-(morpholin-4-yl)phenyl]-1-
ALP01,
J2
450
451



(oxan-3-yl)-3-(propan-2-yl)-1H-
AMP25






pyrazolo[3,4-b]pyridine-6-carboxylic







acid






69
1-cyclopentyl-4-[4-(morpholin-4-
AMP26,
J2
434
435



yl)phenyl]-3-(propan-2-yl)-1H-
ALP01






pyrazolo[3,4-b]pyridine-6-carboxylic







acid






70
4-{4-[4-(methoxycarbonyl)piperazin-
E203
J1
471
472



1-yl]phenyl}-3-methyl-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






71
1-(1-acetylpiperidin-4-yl)-4-[4-
E204
J1
491
492



(morpholin-4-yl)phenyl]-3-(propan-2-







yl)-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






72
4-{4-[3-(dimethylamino)azetidin-1-
E011
J1
427
428



yl]phenyl 1-3-methyl-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






73
4-[4-(3,3-dimethylazetidin-1-
E205
J1
412
413



yl)phenyl]-3-methyl-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






74
1-cyclohexyl-3-methyl-4-[6-
ALP05,
J2
421
422



(morpholin-4-yl)pyridin-3-yl]-1H-
56547-






pyrazolo[3,4-b]pyridine-6-carboxylic
82-1






acid






75
1-cyclohexyl-4-[2-
ALP03,
J2
380
381



(dimethylamino)pyrimidin-5-yl]-3-
56547-






methyl-1H-pyrazolo[3,4-b]pyridine-6-
82-1






carboxylic acid






76
3-[1-(tert-butoxycarbonyl)pyrrolidin-
AMP75,
J2
569
570



2-yl]-4-[4-(morpholin-4-yl)phenyl]-1-
ALP01






phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






77
1-cyclopentyl-4-[6-(morpholin-4-
AMP26,
J2
436
438



yl)pyridin-3-yl]-3-(propan-2-yl)-1H-
ALP05






pyrazolo[3,4-b]pyridine-6-carboxylic







acid






78
3-(1-acetylazetidin-3-yl)-4-[4-
AI01
J9
497
498



(morpholin-4-yl)phenyl]-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






79
4-[2-(morpholin-4-yl)pyrimidin-5-yl]-
ALP04,
J2
444
445



1-phenyl-3-(propan-2-yl)-1H-
AMP04






pyrazolo[3,4-b]pyridine-6-carboxylic







acid






80
1-cyclohexyl-4-[2-(morpholin-4-
E003
J1
450
451



yl)pyrimidin-5-yl]-3-(propan-2-yl)-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






81
1-cyclohexyl-4-[6-(morpholin-4-
ALP05,
J2
449
450



yl)pyridin-3-yl]-3-(propan-2-yl)-1H-
AMP23






pyrazolo[3,4-b]pyridine-6-carboxylic







acid






82
3-methyl-1-phenyl-4-{4-[4-(3,3,3-
E206
J1
509
510



trifluoropropyl)piperazin-1-







yl]phenyl}-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






83
1-cyclopentyl-4-[6-
ALP21,
J2
393
394



(dimethylamino)pyridin-3-yl]-3-
AMP26






(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






84
1-[3-(dimethylamino)phenyl]-4-[2-
E016
J1
487
488



(morpholin-4-yl)pyrimidin-5-yl]-3-







(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






85
1-[3-(dimethylamino)phenyl]-4-[6-
E015
J1
486
487



(morpholin-4-yl)pyridin-3-yl]-3-







(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






86
3-[1-(methoxycarbonyl)azetidin-3-
AI01
J9
513
514



yl]-4-[4-(morpholin-4-yl)phenyl]-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






87
3-[(dimethylamino)methyl]-4-[4-
A102
J11
457
458



(morpholin-4-yl)phenyl]-1-phenyl-

Specific





1H-pyrazolo[3,4-b]pyridine-6-

example





carboxylic acid






88
4-[2-(dimethylamino)pyrimidin-5-yl]-
ALP03,
J2
487
488



1-[3-(morpholin-4-yl)phenyl]-3-
AMP 10






(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






89
4-[6-(dimethylamino)pyridin-3-yl]-1-
ALP21,
J2
486
487



[3-(morpholin-4-yl)phenyl]-3-
AMP10






(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






90
1-[3-(dimethylamino)phenyl]-3-
AMP56,
J2
459
460



methyl-4-[2-(morpholin-4-
ALP04






yl)pyrimidin-5-yl]-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






91
3-tert-butyl-1-cyclopentyl-4-[2-
AMP37,
J2
408
409



(dimethylamino)pyrimidin-5-yl]-1H-
ALP03






pyrazolo[3,4-b]pyridine-6-carboxylic







acid






92
3-(1-hydroxy-2-methylpropan-2-yl)-
AMP69,
J2
474
456



4-[6-(morpholin-4-yl)pyridin-3-yl]-1-
ALP05


(M-18)



phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






93
1-cyclohexyl-4-[6-
ALP21,
J2
407
408



(dimethylamino)pyridin-3-yl]-3-
AMP23






(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






94
3-methyl-1-(1-methyl-2-oxo-1,2-
E326
J8
445
446



dihydropyridin-4-yl)-4-[4-







(morpholin-4-yl)phenyl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






95
1-[1-(cyanomethyl)piperidin-4-yl]-4-
E208
J1
488
489



[4-(morpholin-4-yl)phenyl]-3-







(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






96
4-[4-(cyclobutylamino)phenyl]-3-
E010
J5
398
399



methyl-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






97
4-[4-(3,3-difluoroazetidin-1-
E209
J1
420
421



yl)phenyl]-3-methyl-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






98
4-{4-[4-(cyanomethyl)piperazin-1-
E210
J1
452
453



yl]phenyl}-3-methyl-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






99
1-cyclohexyl-4-[6-
56547-
J2
379
380



(dimethylamino)pyridin-3-yl]-3-
82-1,






methyl-1H-pyrazolo[3,4-b]pyridine-6-
ALP21






carboxylic acid






100
3-tert-butyl-1-cyclopentyl-4-[2-
AMP37,
J2
450
451



(morpholin-4-yl)pyrimidin-5-yl]-1H-
ALP04






pyrazolo[3,4-b]pyridine-6-carboxylic







acid






101
1-(3-fluorophenyl)-3-methyl-4[6-
105438-
J2
433
434



(morpholin-4-yl)pyridin-3-yl]-1H-
45-77,






pyrazolo[3,4-b]pyridine-6-carboxylic
ALP05






acid






102
3-methyl-4-[6-(morpholin-4-
ALP05,
J2
483
484



yl)pyridin-3-yl]-1-[3-
345-07-3






(trifluoromethyl)phenyl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






103
3-[1-(tert-butoxycarbonyl)pyrrolidin-
AMP75,
J2
570
571



2-yl]-4-[6-(morpholin-4-yl)pyridin-3-
ALP05






yl]-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






104
1-(2,4-difluorophenyl)-3-methyl-4-[6-
ALP05,
J2
451
452



(morpholin-4-yl)pyridin-3-yl]-1H-
380569-






pyrazolo[3,4-b]pyridine-6-carboxylic
79-9






acid






105
1-(2,4-difluorophenyl)-3-methyl-4-[4-
ALP01,
J2
450
451



(morpholin-4-yl)phenyl]-1H-
380569-






pyrazolo[3,4-b]pyridine-6-carboxylic
79-9






acid






106
1-cyclopentyl-3-methyl-4[6-
AMP47,
J2
407
408



(morpholin-4-yl)pyridin-3-yl]-1H-
ALP05






pyrazolo[3,4-b]pyridine-6-carboxylic







acid






107
4-{4-[4-(2-hydroxyethyl)piperazin-1-
E211
J1
457
458



yl]phenyl 1-3-methyl-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






108
4-[4-(4,4-difluoropiperidin-1-
E212
J1
448
449



yl)phenyl]-3-methyl-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






109
4-[4-(4-cyanopiperidin-1-yl)phenyl]-
E213
J1
437
438



3-methyl-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






110
3-methyl-4-{4-[methyl(oxan-4-
E214
J1
442
443



yl)amino]phenyl}-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






111
4-[4-(3,3-difluoropyrrolidin-1-
E215
J1
434
435



yl)phenyl]-3-methyl-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






112
3-methyl-4-{4-[(oxetan-3-
E216
J1
400
401



yl)amino]phenyl}-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






113
3-(3-methyloxetan-3-yl)-4-[4-
AMP85,
J2
470
471



(morpholin-4-yl)phenyl]-1-phenyl-
ALP01






1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






114
4-[4-(2,6-dimethylmorpholin-4-
E217
J1
442
443



yl)phenyl]-3-methyl-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






115
4-{4-
E218
J1
412
413



[cyclobutyl(methyl)amino]phenyl}-3-







methyl-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






116
4-{4-[(3R,4R)-3,4-
E219
J1
430
431



dihydroxypyrrolidin-1-yl]phenyl}-3-







methyl-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






117
4-[4-(morpholin-4-yl)phenyl]-3-
E220
J1
531
532



(propan-2-yl)-1-[1-(2,2,2-







trifluoroethyl)piperidin-4-yl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






118
3-methyl-4-(morpholin-4-yl)-1-
HP18
J12
338
339



phenyl-1H-pyrazolo[3,4-b]pyridine-6-

Specific





carboxylic acid

example




119
4-[4-(2,2-dimethylmorpholin-4-
E221
J1
442
443



yl)phenyl]-3-methyl-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






120
4-[4-(morpholin-4-yl)phenyl]-1-
ALP01,
J2
436
437



(oxolan-3-yl)-3-(propan-2-yl)-1H-
AMP27






pyrazolo[3,4-b]pyridine-6-carboxylic







acid






121
1-[3-(morpholin-4-yl)phenyl]-4-[4-
E222
J1
528
529



(morpholin-4-yl)phenyl]-3-(propan-2-







yl)-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






122
3-(methoxymethyl)-4-[4-(morpholin-
AMP77,
J2
444
445



4-yl)phenyl]-1-phenyl-1H-
ALP01






pyrazolo[3,4-b]pyridine-6-carboxylic







acid






123
3-methyl-1-phenyl-4-(piperidin-1-yl)-
E004
J1
336
337



1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






124
4-[4-(3-hydroxyazetidin-1-yl)phenyl]-
E223
J1
400
401



3-methyl-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






125
4-[4-(3-fluoroazetidin-1-yl)phenyl]-3-
E224
J1
436
437



methyl-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






126
3-methyl-4-[4-(2-oxa-6-
E225
J1
426
427



azaspiro[3.3]heptan-6-yl)phenyl]-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






127
3-methyl-4-{4-[(1S,4S)-2-oxa-5-
E226
J1
426
427



azabicyclo[2.2.1]heptan-5-







yl]phenyl}-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






128
4-(3,6-dihydro-2H-pyran-4-yl)-3-
HP13
J19
335
336



methyl-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






129
3-(1-methylcyclopropyl)-4-[4-
AMP78,
J2
454
455



(morpholin-4-yl)phenyl]-1-phenyl-
ALP01






1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






130
3-cyclobutyl-4-[4-(morpholin-4-
ALP01,
J2
454
455



yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-
AMP29






b]pyridine-6-carboxylic acid






131
3-tert-butyl-1-cyclohexyl-4-[4-
AMP79,
J2
420
421



(dimethylamino)phenyl]-1H-
ALP02






pyrazolo[3,4-b]pyridine-6-carboxylic







acid






132
4-(4-acetylpiperazin-1-yl)-3-methyl-
E227
J1
379
380



1-phenyl-1H-pyrazolo[3,4-b]pyridine-







6-carboxylic acid






133
4-{4-[2-(hydroxymethyl)morpholin-
E228
J1
444
445



4-yl]phenyl}-3-methyl-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






134
3-methyl-4-[4-(8-oxa-3-
E229
J1
440
441



azabicyclo[3.2.1]octan-3-yl)phenyl]-







1-phenyl-1H-pyrazolo[3,4-b]pyridine-







6-carboxylic acid






135
4-[4-(azetidin-1-yl)phenyl]-3-methyl-
E230
J1
384
385



1-phenyl-1H-pyrazolo[3,4-b]pyridine-







6-carboxylic acid






136
4[4-(cyanomethyl)piperazin-1-yl]-3-
E231
J1
376
377



methyl-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






137
4-(4-hydroxypiperidin-1-yl)-3-
E232
J1
352
353



methyl-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






138
4-(1-acetylpiperidin-4-yl)-3-methyl-1-
E233
J1
378
379



phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






139
4-[1-(cyanomethyl)piperidin-4-yl]-3-
E234
J1
375
376



methyl-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






140
3-methyl-4-{4-[methyl(oxetan-3-
E235
J1
414
415



yl)amino]phenyl}-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






141
1-[1-(cyanomethyl)pyrrolidin-3-yl]-4-
E236
J1
474
475



[4-(morpholin-4-yl)phenyl]-3-







(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






142
1-[1-(methoxycarbonyl)pyrrolidin-3-
E237
J1
493
494



yl]-4-[4-(morpholin-4-yl)phenyl]-3-







(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






143
4-(4-methoxypiperidin-1-yl)-3-
E238
J13
366
367



methyl-1-phenyl-1H-pyrazolo[3,4-

Specific





b]pyridine-6-carboxylic acid

example




144
4-[4-(4-hydroxypiperidin-1-
E239
J1
428
429



yl)phenyl]-3-methyl-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






145
3-methyl-4-{4-[(oxan-4-
E240
J1
428
429



yl)amino]phenyl}-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






146
4-[4-(methanesulfonyl)piperazin-1-
E241
J1
415
416



yl]-3-methyl-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






147
3-tert-butyl-1-cyclohexyl-4-[2-
AMP79,
J2
423
424



(dimethylamino)pyrimidin-5-yl]-1H-
ALP03






pyrazolo[3,4-b]pyridine-6-carboxylic







acid






148
3-[1-(cyanomethyl)azetidin-3-yl]-4-
E242
J1
494
495



[4-(morpholin-4-yl)phenyl]-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






149
3-tert-butyl-1-cyclohexyl-4-[2-
AMP79,
J2
464
465



(morpholin-4-yl)pyrimidin-5-yl]-1H-
ALP04






pyrazolo[3,4-b]pyridine-6-carboxylic







acid






150
3-methyl-4-(2-oxopiperidin-1-yl)-1-
E243
J1
350
351



phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






151
1-[3-(azetidin-1-yl)phenyl]-4-[4-
E002
J1
497
498



(morpholin-4-yl)phenyl]-3-(propan-2-







yl)-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






152
4-(cyclohexylmethoxy)-3-methyl-1-
HP17
J3
365
366



phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






153
4-[4-(3-hydroxypyrrolidin-1-
E244
J1
414
415



yl)phenyl]-3-methyl-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






154
3-methyl-4-[4-(2-oxa-7-
E245
J1
455
456



azaspiro[3.5]nonan-7-yl)phenyl]-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






155
4-{4-[(3S)-3-cyanopyrrolidin-1-
E246
J1
423
424



yl]phenyl}-3-methyl-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






156
4-[4-(3-acetamidopyrrolidin-1-
E010
J5
455
456



yl)phenyl]-3-methyl-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






157
4-[4-(morpholin-4-yl)phenyl]-3-
E005
J1

512



(propan-2-yl)-1-[3-(pyrrolidin-1-







yl)phenyl]-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






158
3-methyl-1-phenyl-4-(piperidine-1-
E247
J1
364
365



carbonyl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






159
1-(4,4-difluorocyclohexyl)-4-[4-
ALP01,
J2
484
485



(morpholin-4-yl)phenyl]-3-(propan-2-
AMP24






yl)-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






160
1-[3-(3,3-dimethylazetidin-1-
E012
J1
525
526



yl)phenyl]-4-[4-(morpholin-4-







yl)phenyl]-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






161
4-[4-(morpholin-4-yl)phenyl]-3-
E248
J1
531
532



(propan-2-yl)-1-[1-(2,2,2-







trifluoroethyl)piperidin-3-yl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






162
1-(3-methylphenyl)-4-(piperidin-1-
E039
J1

379



yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






163
1-[(1R,3R)-3-(benzyloxy)cyclohexyl]-
E249
J1
554
555



4-[4-(morpholin-4-yl)phenyl]-3-







(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






164
1-[3-(3-methoxyazetidin-1-
E008
J1
527
528



yl)phenyl]-4-[4-(morpholin-4-







yl)phenyl]-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






165
1-[3-(3-fluoropyrrolidin-1-yl)phenyl]-
E013
J1
529
530



4-[4-(morpholin-4-yl)phenyl]-3-







(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






166
1-cyclohexyl-4-[2-
AI21
J9,
480




(dimethylamino)pyrimidin-5-yl]-3-[1-

Specific





(methoxycarbonyl)azetidin-3-yl]-1H-

example





pyrazolo[3,4-b]pyridine-6-carboxylic







acid






167
1-[3-(3-fluoroazetidin-1-yl)phenyl]-4-
E001
J5
515
516



[4-(morpholin-4-yl)phenyl]-3-







(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






168
3-methyl-4-{6-[methyl(oxan-4-
AI04
J5
443
444



yl)amino]pyridin-3-yl}-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






169
1-cyclohexyl-4-{6-[methyl(oxan-4-
E014
J1
477
478



yl)amino]pyridin-3-yl}-3-(propan-2-







yl)-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






170
1-cyclohexyl-4-{6-[(2-
AI14
J5
452
453



methoxyethyl)(methyl)amino]pyridin-







3-yl}-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






171
4-(4-acetamidophenyl)-1-cyclohexyl-
E021
J1
420
421



3-(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






172
1-{3-[(2-
E351
J1
529
530



methoxyethyl)(methyl)amino]phenyl}-







4[4-(morpholin-4-yl)phenyl]-3-







(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






173
1-(3-methylphenyl)-3-(propan-2-yl)-
E250
J1
364
365



4-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






174
4-(3-fluoroazetidin-1-yl)-1-(3-
E251
J1
368
369



methylphenyl)-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






175
4-[6-(4-cyanopiperidin-1-yl)pyridin-
E252
J1
480
481



3-yl]-1-(3-methylphenyl)-3-(propan-







2-yl)-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






176
4-[4-(4-cyanopiperidin-1-yl)phenyl]-
E023
J1
508
509



143-(dimethylamino)phenyl]-3-







(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






177
4-[6-(4-cyanopiperidin-1-yl)pyridin-
E025
J1
509
510



3-yl]-143-(dimethylamino)phenyl]-3-







(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






178
4-[6-(4-cyanopiperidin-1-yl)pyridin-
E027
J1
551
551



3-yl]-143-(morpholin-4-yl)phenyl]-3-







(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






179
4-{6-[(2-
E028
J1
530
530



methoxyethyl)(methyl)amino]pyridin-







3-yl}-143-(morpholin-4-yl)phenyl]-







3-(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






180
4-[6-(4-cyanopiperidin-1-yl)pyridin-
E253
J1
472
473



3-yl]-1-cyclohexyl-3-(propan-2-yl)-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






181
1-cyclohexyl-4-[6-(3,3-
AI14
J5
469
470



difluoropyrrolidin-1-yl)pyridin-3-yl]-







3-(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






182
4-[6-(4-cyanopiperidin-1-yl)pyridin-
E018
J1
478
479



3-yl]-3-cyclobutyl-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






183
3-cyclobutyl-4-{6-[methyl(oxan-4-
E019
J1
483
484



yl)amino]pyridin-3-yl}-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






184
1-cyclohexyl-4-{4-[(2-
E254
J1
450
451



methoxyethyl)(methyl)amino]phenyl}-







3-(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






185
4-[4-(4-cyanopiperidin-1-yl)phenyl]-
E022
J1
471
472



1-cyclohexyl-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






186
4-[4-(morpholin-4-yl)phenyl]-3-
AMP80,
J2
470
471



(oxolan-2-yl)-1-phenyl-1H-
ALP01






pyrazolo[3,4-b]pyridine-6-carboxylic







acid






187
4-{6-[methyl(oxan-4-
E029
J1
556
557



yl)amino]pyridin-3-yl}-1-[3-







(morpholin-4-yl)phenyl]-3-(propan-2-







yl)-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






188
4-{4-[(2-
E030
J1
529
530



methoxyethyl)(methyl)amino]phenyl}-







1[3-(morpholin-4-yl)phenyl]-3-







(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






189
1-[3-(dimethylamino)phenyl]-4-{6-
E031
J1
514
515



[methyl(oxan-4-yl)amino]pyridin-3-







yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






190
4-(3-methoxypiperidin-1-yl)-1-(3-
E088
J1
408
409



methylphenyl)-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






191
4-(4-cyanopiperidin-1-yl)-1-(3-
E255
J1
403
404



methylphenyl)-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






192
4-(4-methoxypiperidin-1-yl)-1-(3-
E048
J1
408
409



methylphenyl)-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






193
1-cyclohexyl-3-cyclopropyl-4-[6-
E033
J1
405
406



(dimethylamino)pyridin-3-yl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






194
rac-1-[(1R,3R)-3-
E256
J1
464
465



hydroxycyclohexyl]-4-[4-(morpholin-







4-yl)phenyl]-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






195
rac-1-[(1R,3S)-3-hydroxycyclohexyl]-
E257
J1
464
465



4-[4-(morpholin-4-yl)phenyl]-3-







(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






196
1-cyclohexyl-4-[6-(2,6-
AI14
J5,
477
478



dimethylmorpholin-4-yl)pyridin-3-

Specific





yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-

example





b]pyridine-6-carboxylic acid






197
1-cyclohexyl-4-[6-(2,2-
AI14
J5
477
478



dimethylmorpholin-4-yl)pyridin-3-







yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






198
4-[4-(3-hydroxypiperidin-1-
AI03
J14,
428
429



yl)phenyl]-3-methyl-1-phenyl-1H-

Specific





pyrazolo[3,4-b]pyridine-6-carboxylic

example





acid






199
4-[2-(4-cyanopiperidin-1-
E034
J1
510
511



yl)pyrimidin-5-yl]-1-[3-







(dimethylamino)phenyl]-3-(propan-2-







yl)-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






200
1-[3-(dimethylamino)phenyl]-4-{2-
E032
J1
515
516



[methyl(oxan-4-yl)amino]pyrimidin-







5-yl}-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






201
4-[4-(morpholin-4-yl)phenyl]-1-[2-
E066
J1
528
529



(morpholin-4-yl)pyridin-4-yl]-3-







(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






202
1-(3-methylphenyl)-4-(2-oxa-7-
HP16
J4
420
421



azaspiro[3.5]nonan-7-yl)-3-(propan-2-







yl)-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






203
4-[6-(4-cyano-4-methylpiperidin-1-
AI14
J5
486
487



yl)pyridin-3-yl]-1-cyclohexyl-3-







(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






204
4-[2-(4-cyanopiperidin-1-
E037
J1
552
553



yl)pyrimidin-5-yl]-1-[3-(morpholin-4-







yl)phenyl]-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






205
1-[(1R,3S)-3-methoxycyclohexyl]-4-
E257
J13
478
479



[4-(morpholin-4-yl)phenyl]-3-







(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






206
4-[4-(4-cyanopiperidin-1-yl)phenyl]-
E258
J1
550
551



1-[3-(morpholin-4-yl)phenyl]-3-







(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






207
1-[3-(dimethylamino)phenyl]-4-{4-
E035
J1
513
514



[methyl(oxan-4-yl)amino]phenyl}-3-







(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






208
4-{4-[methyl(oxan-4-
E036
J1
555
556



yl)amino]phenyl}-1-[3-(morpholin-4-







yl)phenyl]-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






209
4-[(2-methoxyethyl)(methyl)amino]-
E094
J1
382
383



1-(3-methylphenyl)-3-(propan-2-yl)-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






210
4-(4,4-difluoropiperidin-1-yl)-1-(3-
E259
J1
414
415



methylphenyl)-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






211
4-[4-(morpholin-4-yl)phenyl]-1-[5-
E260
J1
528
529



(morpholin-4-yl)pyridin-3-yl]-3-







(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






212
4-(3-methoxyazetidin-1-yl)-1-(3-
E261
J1
380
381



methylphenyl)-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






213
4-[4-(hydroxymethyl)piperidin-1-yl]-
E262
J1
408
409



1-(3-methylphenyl)-3-(propan-2-yl)-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






214
1-[(1R,3R)-3-methoxycyclohexyl]-4-
E256
J13
478
479



[4-(morpholin-4-yl)phenyl]-3-







(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






215
1-(3-methylphenyl)-3-(propan-2-yl)-
E263
J1
432
433



4-[3-(trifluoromethyl)pyrrolidin-1-yl]-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






216
4-[5-(tert-
E264
J1
505
506



butoxycarbonyl)hexahydropyrrolo[3,4-







c]pyrrol-2(1H)-yl]-1-(3-







methylphenyl)-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






217
4-{4-[3-(dimethylamino)pyrrolidin-1-
E038
J1
441
442



yl]phenyl}-3-methyl-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






218
4-(3-cyanopyrrolidin-1-yl)-1-(3-
E265
J1
389
390



methylphenyl)-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






219
4-[4-(4-cyanopiperidin-1-yl)phenyl]-
E040
J1
483
484



3-cyclobutyl-1-cyclohexyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






220
4-[6-(4-cyanopiperidin-1-yl)pyridin-
E041
J1
484
485



3-yl]-3-cyclobutyl-1-cyclohexyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






221
4-[4-(4-cyanopiperidin-1-yl)phenyl]-
E266
J1
535
536



3-(propan-2-yl)-1-[3-(pyrrolidin-1-







yl)phenyl]-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






222
4-[6-(4-cyanopiperidin-1-yl)pyridin-
E267
J1
536
537



3-yl]-3-(propan-2-yl)-1-[3-







(pyrrolidin-1-yl)phenyl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






223
1-cyclohexyl-4-[6-(3-fluoropiperidin-
AI14
J5
465
466



1-yl)pyridin-3-yl]-3-(propan-2-yl)-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






224
1-cyclohexyl-4-[6-(3-
AI14
J5
463
464



methoxypyrrolidin-1-yl)pyridin-3-yl]-







3-(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






225
1-[3-(3-hydroxyazetidin-1-yl)phenyl]-
AI19
J14
513
514



4-[4-(morpholin-4-yl)phenyl]-3-







(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






226
4-[5-
E268
J1
444
445



(cyanomethyl)hexahydropyrrolo[3,4-







c]pyrrol-2(1H)-yl]-1-(3-







methylphenyl)-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






227
4-[4-(methoxymethyl)piperidin-1-yl]-
E082
J1
422
423



1-(3-methylphenyl)-3-(propan-2-yl)-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






228
4-[4-(2-methoxyethyl)piperidin-1-yl]-
E087
J1
436
437



1-(3-methylphenyl)-3-(propan-2-yl)-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






229
1-(4-chloropyridin-2-yl)-4-[4-
E269
J1
477
478



(morpholin-4-yl)phenyl]-3-(propan-2-







yl)-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






230
4-{2-[(2-
E270
J1
532
533



methoxyethyl)(methyl)amino]pyrimid







in-5-yl}-1-[3-(morpholin-4-







yl)phenyl]-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






231
4-{2-[methyl(oxan-4-
E271
J1
558
559



yl)amino]pyrimidin-5-yl}-1-[3-







(morpholin-4-yl)phenyl]-3-(propan-2-







yl)-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






232
4-{4-[4-(cyanomethyl)piperazin-1-
E272
J1
482
483



yl]phenyl}-1-(3-methoxyphenyl)-3-







methyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






233
4-(5-acetylhexahydropyrrolo[3,4-
E273
J1
447
448



c]pyrrol-2(11/)-yl)-1-(3-







methylphenyl)-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






234
4-[1-(tert-butoxycarbonyl)octahydro-
E274
J1
520
521



5H-pyrrolo[3,2-c]pyridin-5-yl]-1-(3-







methylphenyl)-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






235
4-[2-(4-cyanopiperidin-1-
E049
J1
473
474



yl)pyrimidin-5-yl]-1-cyclohexyl-3-







(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






236
1-cyclohexyl-4-{2-[methyl(oxan-4-
E051
J1
478
479



yl)amino]pyrimidin-5-yl}-3-(propan-







2-yl)-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






237
1-cyclohexyl-4-{2-[(2-
E050
J1
452
453



methoxyethyl)(methyl)amino]pyrimid







in-5-yl}-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






238
4-{4-[(2-
E045
J1
513
514



methoxyethyl)(methyl)amino]phenyl}-







3-(propan-2-yl)-1-[3-(pyrrolidin-1-







yl)phenyl]-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






239
1-[3-(azetidin-1-yl)phenyl]-4-{6-[(2-
AI05
J7,
501
502



methoxyethyl)(methyl)amino]pyridin-

Specific





3-yl}-3-(propan-2-yl)-1H-

example





pyrazolo[3,4-b]pyridine-6-carboxylic







acid






240
1-[3-(azetidin-1-yl)phenyl]-4-{4-
AI06
J7
526
527



[methyl(oxan-4-yl)amino]phenyl}-3-







(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






241
4-[4-(morpholin-4-yl)phenyl]-1-[4-
229
J7
528
529



(morpholin-4-yl)pyridin-2-yl]-3-







(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






242
1-(3-fluorophenyl)-4-[4-(morpholin-
E275
J1
460
461



4-yl)phenyl]-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






243
1-(3,4-difluorophenyl)-4-[4-
E057
J1
478
479



(morpholin-4-yl)phenyl]-3-(propan-2-







yl)-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






244
4-[4-(morpholin-4-yl)phenyl]-1-[6-
E058
J1
528
529



(morpholin-4-yl)pyridin-2-yl]-3-







(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






245
1-(3,5-difluorophenyl)-4-{4-
E276
J1
507
508



[methyl(oxan-4-yl)amino]phenyl}-3-







(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






246
1-(3,5-difluorophenyl)-4-{6-
E277
J1
508
509



[methyl(oxan-4-yl)amino]pyridin-3-







yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






247
4-[4-(4-cyanopiperidin-1-yl)phenyl]-
E278
J1
547
548



3-cyclobutyl-1-[3-(pyrrolidin-1-







yl)phenyl]-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






248
4-[6-(4-cyanopiperidin-1-yl)pyridin-
E279
J1
548
549



3-yl]-3-cyclobutyl-143-(pyrrolidin-1-







yl)phenyl]-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






249
4-{4-[nethyl(oxan-4-
E046
J1
539
540



yl)amino]phenyl}-3-(propan-2-yl)-1-







[3-(pyrrolidin-1-yl)phenyl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






250
4-{6-[methyl(oxan-4-
E280
J1
541
542



yl)amino]pyridin-3-yl}-3-(propan-2-







yl)-1[3-(pyrrolidin-1-yl)phenyl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






251
3-cyclobutyl-4-{4-[methyl(oxan-4-
E047
J1
551
552



yl)amino]phenyl}-1-[3-(pyrrolidin-1-







yl)phenyl]-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






252
3-cyclobutyl-4-{6-[methyl(oxan-4-
E281
J1
552
553



yl)amino]pyridin-3-yl}-1-[3-







(pyrrolidin-1-yl)phenyl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






253
4-{6-[(2-
E282
J1
514
515



methoxyethyl)(methyl)amino]pyridin-







3-yl}-3-(propan-2-yl)-1-[3-







(pyrrolidin-1-yl)phenyl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






254
1-cyclohexyl-4-{4-[methyl(oxan-4-
E283
J1
476
477



yl)amino]phenyl}-3-(propan-2-yl)-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






255
4-(1-acetyloctahydro-5H-pyrrolo[3,2-
E284
J1
461
462



c]pyridin-5-yl)-1-(3-methylphenyl)-3-







(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






256
4-[1-(cyanomethyl)octahydro-5H-
E285
J1
458
459



pyrrolo[3,2-c]pyridin-5-yl]-1-(3-







methylphenyl)-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






257
4-[4-(methanesulfonyl)piperidin-1-
E089
J1
456
457



yl]-1-(3-methylphenyl)-3-(propan-2-







yl)-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






258
1-(3-methylphenyl)-4-(7-oxa-2-
E286
J1
420
421



azaspiro[3.5]nonan-2-yl)-3-(propan-2-







yl)-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






259
4-[2-(4-cyanopiperidin-1-
E287
J1
536
537



yl)pyrimidin-5-yl]-3-(propan-2-yl)-1-







[3-(pyrrolidin-1-yl)phenyl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






260
4-[6-(4-cyanopiperidin-1-yl)pyridin-
E052
J1
534
535



3-yl]-3-(propan-2-yl)-1-[3-







(trifluoromethyl)phenyl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






261
4-[4-(4-cyanopiperidin-1-yl)phenyl]-
E065
J1
533
533



3-(propan-2-yl)-1-[3-







(trifluoromethyl)phenyl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






262
1-(3-methylphenyl)-4-(8-oxa-2-
E095
J1
434
435



azaspiro[4.5]decan-2-yl)-3-(propan-2-







yl)-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






263
4-(4-cyanopiperidin-1-yl)-1-
E288
J1
395
396



cyclohexyl-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






264
1-cyclohexyl-4-(4-methoxypiperidin-
E076
J1
400
401



1-yl)-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






265
1-cyclohexyl-4-(piperidin-1-yl)-3-
E289
J1
370
371



(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






266
1-cyclohexyl-4-[4-
E290
J1
400
401



(hydroxymethyl)piperidin-1-yl]-3-







(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






267
1-[6-(dimethylamino)pyridin-2-yl]-4-
E053
J1
486
487



[4-(morpholin-4-yl)phenyl]-3-







(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






268
1-(3,5-difluorophenyl)-4-[4-
E291
J1
478
479



(morpholin-4-yl)phenyl]-3-(propan-2-







yl)-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






269
4-[4-(morpholin-4-yl)phenyl]-3-
E054
J1
526
527



(propan-2-yl)-1-[3-







(trifluoromethoxy)phenyl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






270
1-[3-(dimethylamino)phenyl]-3-
E292
J1
461
462



(propan-2-yl)-4-[3-







(trifluoromethyl)pyrrolidin-1-yl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






271
4-(1,1-difluoro-5-azaspiro[2.4]heptan-
E075
J1
426
427



5-yl)-1-(3-methylphenyl)-3-(propan-







2-yl)-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






272
4-[3-(methanesulfonyl)pyrrolidin-1-
E293
J1
442
443



yl]-1-(3-methylphenyl)-3-(propan-2-







yl)-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






273
4-(2-azaspiro[3.3]heptan-2-yl)-1-(3-
E294
J1
390
391



methylphenyl)-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






274
1-(3-methylphenyl)-4-(5-oxa-2-
E295
J1
420
421



azaspiro[3.5]nonan-2-yl)-3-(propan-2-







yl)-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






275
4-{6-[bis(2-
AI14
J5
495
496



methoxyethyl)amino]pyridin-3-yl}-1-







cyclohexyl-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






276
1-cyclohexyl-4-{6-[methyl(oxolan-3-
AI14
J5
463
464



yl)amino]pyridin-3-yl}-3-(propan-2-







yl)-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






277
3-cyclobutyl-4-{2-[methyl(oxan-4-
E296
J1
554
555



yl)amino]pyrimidin-5-yl}-1-[3-







(pyrrolidin-1-yl)phenyl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






278
1-(3,4-difluorophenyl)-4-{4-
E297
J1
506
507



[methyl(oxan-4-yl)amino]phenyl}-3-







(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






279
4-[6-(4-cyanopiperidin-1-yl)pyridin-
E298
J1
502
503



3-yl]-1-(3,4-difluorophenyl)-3-







(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






280
1-(4-fluorophenyl)-4-{2-
E064
J1
490
491



[methyl(oxan-4-yl)amino]pyrimidin-







5-yl}-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






281
4-{2-[methyl(oxan-4-
E299
J1
540
541



yl)amino]pyrimidin-5-yl}-3-(propan-







2-yl)-1[3-(trifluoromethyl)phenyl]-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






282
4-[4-(4-cyanopiperidin-1-yl)phenyl]-
E060
J1
501
502



1-(3,5-difluorophenyl)-3-(propan-2-







yl)-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






283
1-(3-fluorophenyl)-4-{6-
E137
J1
489
490



[methyl(oxan-4-yl)amino]pyridin-3-







yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






284
1-(3-fluorophenyl)-4-{4-
E300
J1
488
489



[nethyl(oxan-4-yl)amino]phenyl}-3-







(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






285
4-[6-(4-cyanopiperidin-1-yl)pyridin-
E301
J1
484
485



3-yl]-1-(3-fluorophenyl)-3-(propan-2-







yl)-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






286
4-[4-(4-cyanopiperidin-1-yl)phenyl]-
E061
J1
483
484



1-(3-fluorophenyl)-3-(propan-2-yl)-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






287
4-{6-[methyl(oxan-4-
E063
J1
539
540



yl)amino]pyridin-3-yl}-3-(propan-2-







yl)-1[3-(trifluoromethyl)phenyl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






288
3-methyl-4-(4-methyl-3-oxo-1-oxa-
HP17
J10,
435
436



4,9-diazaspiro[5.5]undecan-9-yl)-1-

Specific





phenyl-1H-pyrazolo[3,4-b]pyridine-6-

example





carboxylic acid






289
4-[3-(methoxymethyl)-3-
HP17
J10
366
367



methylazetidin-1-yl]-3-methyl-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






290
3-methyl-4-(3-
HP17
J10
392
393



oxohexahydroimidazo[1,5-a]pyrazin-







2(3H)-yl)-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






291
4-[4-(methoxymethyl)piperidin-1-yl]-
HP17
J10
380
381



3-methyl-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






292
4-(4-acetamidopiperidin-1-yl)-3-
HP17
J10
393
394



methyl-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






293
3-methyl-4-(7-oxa-2-
HP17
J10
378
379



azaspiro[3.5]nonan-2-yl)-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






294
4-[3-(methoxymethyl)azetidin-1-yl]-
HP17
J10
352
353



3-methyl-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






295
4-[(3R)-3-methoxypyrrolidin-1-yl]-3-
HP17
J10
352
353



methyl-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






296
4-[(3S)-3-methoxypyrrolidin-1-yl]-3-
HP17
J10
352
353



methyl-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






297
4-(4-fluoropiperidin-1-yl)-3-methyl-
HP17
J10
354
355



1-phenyl-1H-pyrazolo[3,4-b]pyridine-







6-carboxylic acid






298
4-[(3R)-3-fluoropyrrolidin-1-yl]-3-
HP17
J10
340
342



methyl-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






299
4-(3,3-difluoropyrrolidin-1-yl)-3-
HP17
J10
358
359



methyl-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






300
4-[(3S)-3-fluoropyrrolidin-1-yl]-3-
HP17
J10
340
341



methyl-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






301
3-methyl-4-(3-oxotetrahydro-3H-
HP17
J10
393
394



[1,3]oxazolo[3,4-a]pyrazin-7(1H)-yl)-







1-phenyl-1H-pyrazolo[3,4-b]pyridine-







6-carboxylic acid






302
3-methyl-4-[3-(morpholin-4-
HP17
J10
393
394



yl)azetidin-1-yl]-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






303
4-{4-
HP17
J10
429
430



[(methanesulfonyl)amino]piperidin-1-







yl}-3-methyl-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






304
4-(3-azabicyclo[3.1.0]hexan-3-yl)-3-
HP17
J10
334
335



methyl-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






305
3-methyl-1-phenyl-4-[4-(pyrrolidine-
HP17
J10
433
434



1-carbonyl)piperidin-1-yl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






306
3-methyl-4-(6-oxa-2-
HP17
J10
364
365



azaspiro[3.4]octan-2-yl)-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






307
4-(2-azaspiro[3.4]octan-2-yl)-3-
HP17
J10
362
363



methyl-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






308
3-methyl-4-(6-oxa-2-
HP17
J10
378
379



azaspiro[3.5]nonan-2-yl)-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






309
4-(2-azaspiro[3.5]nonan-2-yl)-3-
HP17
J10
376
377



methyl-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






310
4-(5-azaspiro[2.5]octan-5-yl)-3-
HP17
J10
362
363



methyl-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






311
3-methyl-4-(1-oxa-7-
HP17
J10
378
379



azaspiro[4.4]nonan-7-yl)-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






312
3-methyl-4-(5-oxa-2-
HP17
J10
378
378



azaspiro[3.5]nonan-2-yl)-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






313
3-methyl-4-(6-oxo-2,7-
HP17
J10
391
392



diazaspiro[4.4]nonan-2-yl)-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






314
4-{4-[(1S)-2-(dimethylamino)-1-
HP17
J10
425
426



fluoroethyl]piperidin-1-yl}-3-methyl-







1-phenyl-1H-pyrazolo[3,4-b]pyridine-







6-carboxylic acid






315
3-methyl-4-(1,4-oxazepan-4-yl)-1-
HP17
J10
352
353



phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






316
1-(3-fluorophenyl)-4-{2-
E302
J1
490
491



[methyl(oxan-4-yl)amino]pyrimidin-







5-yl}-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






317
1-(3,5-difluorophenyl)-4-{2-
E303
J1
508
509



[methyl(oxan-4-yl)amino]pyrimidin-







5-yl}-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






318
4-[4-(2-methoxyethoxy)piperidin-1-
HP17
J10
410
411



yl]-3-methyl-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






319
4-[4-(dimethylcarbamoyl)piperidin-1-
HP17
J10
407
408



yl]-3-methyl-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






320
4-[4-(methanesulfonyl)-1,4-diazepan-
HP17
J10
429
430



1-yl]-3-methyl-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






321
4-[4-(3-methoxypropyl)piperazin-1-
HP17
J10
409
410



yl]-3-methyl-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






322
3-methyl-4-[4-(morpholine-4-
HP17
J10
450
451



carbonyl)piperazin-1-yl]-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






323
4-{4-[2-(dimethylamino)-2-
HP17
J10
422
423



oxoethyl]piperazin-1-yl}-3-methyl-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






324
3-methyl-4-[4-(morpholin-4-
HP17
J10
421
422



yl)piperidin-1-yl]-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






325
4-[2-(4-cyanopiperidin-1-
E068
J1
503
504



yl)pyrimidin-5-yl]-1-(2,4-







difluorophenyl)-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






326
4-[6-(4-cyanopiperidin-1-yl)pyridin-
E069
J1
502
503



3-yl]-1-(2,4-difluorophenyl)-3-







(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






327
4-[4-(4-cyanopiperidin-1-yl)phenyl]-
E070
J1
501
502



1-(2,4-difluorophenyl)-3-(propan-2-







yl)-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






328
1-[3-(dimethylamino)phenyl]-4-
E083
J1
407
408



(piperidin-1-yl)-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






329
4-(4-cyanopiperidin-1-yl)-1-[3-
E086
J1
432
433



(dimethylamino)phenyl]-3-(propan-2-







yl)-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






330
1-[3-(dimethylamino)phenyl]-4-(4-
E081
J1
437
438



methoxypiperidin-1-yl)-3-(propan-2-







yl)-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






331
1-[3-(dimethylamino)phenyl]-4-[4-
E304
J1
437
438



(hydroxymethyl)piperidin-1-yl]-3-







(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






332
3-(1-methylcyclobutyl)-4-[4-
E067
J1
468
469



(morpholin-4-yl)phenyl]-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






333
4-{[cis-3-(1,1-dioxo-1λ6,4-thiazinan-
HP17
J3
456
457



4-yl)cyclobutyl]oxy}-3-methyl-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






334
4-[2-(1,1-dioxo-lλ6,4-thiazinan-4-
HP17
J3
430
431



yl)ethoxy]-3-methyl-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






335
4-[(2S)-2-fluoro-2-(oxan-4-
HP17
J3
399
400



yl)ethoxy]-3-methyl-I-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






336
4-[(2R)-2-fluoro-2-(oxan-4-
HP17
J3
399
400



yl)ethoxy]-3-methyl-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






337
3-methyl-4-{[(3S)-1-
HP17
J3
352
353



methylpyrrolidin-3-yl]oxy}-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






338
3-methyl-4-{[(3R)-1-
HP17
J3
352
353



methylpyrrolidin-3-yl]oxy}-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






339
3-methyl-4-[(1-methylpiperidin-4-
HP17
J3
366
367



yl)oxy]-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






340
4-{[cis-3-
HP17
J3
366
367



(dimethylamino)cyclobutyl]oxy}-3-







methyl-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






341
3-methyl-4-[(oxetan-3-yl)oxy]-1-
HP17
J3
325
326



phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






342
3-methyl-1-phenyl-4-[2-(pyrrolidin-1-
HP17
J3
366
367



yl)ethoxy]-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






343
3-methyl-4-{[(3R)-1-methylpiperidin-
HP17
J3
366
367



3-yl]oxy}-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






344
3-methyl-4-[(2-oxaspiro[3.3]heptan-
HP17
J3
365
366



6-yl)oxy]-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






345
3-methyl-1-phenyl-4-{[trans-3-
HP17
J3
406
407



(piperidin-1-yl)cyclobutyl]oxy}-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






346
3-methyl-1-phenyl-4-{[cis-3-
HP17
J3
406
407



(piperidin-1-yl)cyclobutyl]oxy}-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






347
4-[2-(3,3-difluorocyclobutyl)ethoxy]-
HP17
J3
387
388



3-methyl-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






348
4-[4-(fluoromethyl)piperidin-1-yl]-1-
HP16
J4
410
411



(3-methylphenyl)-3-(propan-2-yl)-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






349
3-cyclobutyl-1-(3-fluorophenyl)-4-[4-
E305
J1
472
473



(morpholin-4-yl)phenyl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






350
3-cyclobutyl-1-(3,4-difluorophenyl)-
E306
J1
490
491



4-[4-(morpholin-4-yl)phenyl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






351
1-cyclohexyl-4-(1-methyl-1H-pyrrol-
E307
J1
366
367



3-yl)-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






352
1-cyclohexyl-4-(1,3-dimethyl-1H-
E308
J1
381
382



pyrazol-4-yl)-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






353
3-cyclobutyl-1-(3,5-difluorophenyl)-
E309
J1
490
491



4-[4-(morpholin-4-yl)phenyl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






354
3-cyclobutyl-4-[4-(morpholin-4-
E310
J1
522
523



yl)phenyl]-1-[3-







(trifluoromethyl)phenyl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






355
3-cyclobutyl-1-(3-fluoro-4-
E311
J1
486
487



methylphenyl)-4-[4-(morpholin-4-







yl)phenyl]-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






356
3-cyclobutyl-4-[4-(morpholin-4-
E312
J1
522
523



yl)phenyl]-1-[4-







(trifluoromethyl)phenyl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






357
3-cyclobutyl-1-[4-
E313
J1
497
498



(dimethylamino)phenyl]-4-[4-







(morpholin-4-yl)phenyl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






358
3-cyclobutyl-4-(4-methoxypiperidin-
E071
J1
406
407



1-yl)-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






359
4-(3-methyl-2-oxo-1-oxa-3,8-
HP16
J4
463
464



diazaspiro[4.5]decan-8-yl)-1-(3-







methylphenyl)-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






360
4-(3-azaspiro[5.5]undecan-3-yl)-1-(3-
HP16
J4
447
448



methylphenyl)-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






361
1-cyclohexyl-3-(propan-2-yl)-4-[1-
E314
J1
395
396



(propan-2-yl)-1H-pyrazol-4-yl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






362
1-cyclohexyl-4-(1-methyl-1H-pyrrol-
HP04
J4
366
367



2-yl)-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






363
1-cyclohexyl-3-(propan-2-yl)-4-(1H-
HP04
J4
353
354



pyrazol-4-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






364
1-cyclohexyl-4-(1-oxo-2,3-dihydro-
HP04
J4
418
419



1H-isoindol-5-yl)-3-(propan-2-yl)-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






365
4-[6-(4-cyanopiperidin-1-yl)pyridin-
E073
J1
474
475



3-yl]-1-(oxan-3-yl)-3-(propan-2-yl)-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






366
4-[2-(3-cyanopiperidin-1-
E315
J1
473
474



yl)pyrimidin-5-yl]-1-cyclohexyl-3-







(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






367
3-cyclobutyl-4-{4-[2-oxo-2-
E080
J1
503
504



(pyrrolidin-1-yl)ethoxy]piperidin-1-







yl}-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






368
1-[3-(dimethylamino)phenyl]-4-[4-
E072
J1
451
452



(methoxymethyl)piperidin-1-yl]-3-







(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






369
4-[6-(4-cyanopiperidin-1-yl)pyridin-
E084
J1
536
537



3-yl]-3-(propan-2-yl)-1-[2-







(pyrrolidin-1-yl)pyridin-4-yl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






370
1-cyclohexyl-4-(1-methyl-1H-
E316
J1
367
368



pyrazol-5-yl)-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






371
4-[1-(tert-butoxycarbonyl)-1,2,3,6-
E317
J1
467
468



tetrahydropyridin-4-yl]-1-cyclohexyl-







3-(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






372
3-cyclobutyl-1-phenyl-4-{4-[(propan-
E077
J1
434
435



2-yl)oxy]piperidin-1-yl}-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






373
3-cyclobutyl-4-[3-
E079
J1
420
421



(methoxymethyl)piperidin-1-yl]-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






374
4-(2-{[1-(tert-
E318
J1
577
578



butoxycarbonyl)piperidin-4-







yl](methyl)amino}pyrimidin-5-yl)-1-







cyclohexyl-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






375
3-methyl-4-[(3-methyloxetan-3-
HP17
J3,
353
354



yl)methoxy]-1-phenyl-1H-

Specific





pyrazolo[3,4-b]pyridine-6-carboxylic

example





acid






376
4-[(4-methoxycyclohexyl)oxy]-3-
HP17
J3
381
382



methyl-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






377
4-[2-fluoro-2-(oxan-4-yl)ethoxy]-3-
HP17
J3
399
400



methyl-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






378
4-[(3-fluoro-1-methylpyrrolidin-3-
HP17
J3
384
385



yl)methoxy]-3-methyl-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






379
4-[(2S)-2-fluoro-2-(1-
HP17
J3
412
413



methylpiperidin-4-yl)ethoxy]-3-







methyl-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






380
4-[(2R)-2-fluoro-2-(1-
HP17
J3
412
413



methylpiperidin-4-yl)ethoxy]-3-







methyl-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






381
4-{[3-fluoro-1-(oxetan-3-yl)piperidin-
HP17
J3
440
441



3-yl]methoxy}-3-methyl-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






382
4-[(3,3-
HP17
J3
387
387



difluorocyclopentyl)methoxy]-3-







methyl-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






383
3-methyl-4-[2-oxo-2-(piperidin-1-
HP17
J3
394
395



yl)ethoxy]-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






384
4-{[1-
HP17
J3
415
416



(methanesulfonyl)cyclobutyl]methoxy}-







3-methyl-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






385
4-{2-[cyclopropyl(2-
HP17
J3
408
409



methylpropyl)amino]ethoxy}-3-







methyl-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






386
4-[(3,3-difluoro-1-
HP17
J3
387
388



methylcyclobutyl)methoxy]-3-







methyl-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






387
4-{[1-
HP17
J3
355
356



(fluoromethyl)cyclopropyl]methoxy}-







3-methyl-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






388
4-{[1-(2-
HP17
J3
381
382



methoxyethyl)cyclopropyl]methoxy}-







3-methyl-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






389
4-[(2,2-
HP17
J3
387
388



difluorocyclopentyl)methoxy]-3-







methyl-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






390
4-[4-(morpholin-4-yl)phenyl]-1-
E090
J1
458
459



phenyl-3-[(propan-2-yl)oxy]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






391
1-(4-fluorophenyl)-4-[4-
E092
J1
426
427



(methoxymethyl)piperidin-1-yl]-3-







(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






392
4-[4-(4-cyanopiperidin-1-yl)phenyl]-
E093
J1
535
536



3-(propan-2-yl)-1-[2-(pyrrolidin-1-







yl)pyridin-4-yl]-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






393
1-(4-fluorophenyl)-4-(4-
E091
J1
412
413



methoxypiperidin-1-yl)-3-(propan-2-







yl)-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






394
1-(4-fluorophenyl)-4-[4-
E319
J1
425
426



(hydroxymethyl)piperidin-1-yl]-3-







(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






395
4-(4-butoxypiperidin-1-yl)-1-(4-
E096
J1
454
455



fluorophenyl)-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






396
1-(4-fluorophenyl)-4-[4-(2-
E098
J1
454
455



methylpropoxy)piperidin-1-yl]-3-







(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






397
1-(4-fluorophenyl)-4-(4-methoxy-4-
E097
J1
426
427



methylpiperidin-1-yl)-3-(propan-2-







yl)-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






398
1-(4-fluorophenyl)-4-(1-oxa-7-
E099
J1
424
425



azaspiro[3.5]nonan-7-yl)-3-(propan-2-







yl)-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






399
4-[3-(difluoromethyl)piperidin-1-yl]-
E100
J1
432
433



1-(4-fluorophenyl)-3-(propan-2-yl)-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






400
1-(4-fluorophenyl)-4-(6-oxa-2-
E101
J1
424
425



azaspiro[3.5]nonan-2-yl)-3-(propan-2-







yl)-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






401
1-(4-fluorophenyl)-4-(1-oxa-8-
E102
J1
438
439



azaspiro[4.5]decan-8-yl)-3-(propan-2-







yl)-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






402
1-cyclohexyl-3-(propan-2-yl)-4-
E320
J1
425
426



(2,2,6,6-tetramethyl-3,6-dihydro-2H-







pyran-4-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






403
3-cyclobutyl-4-[4-(2-
E104
J1
434
435



methoxyethyl)piperidin-1-yl]-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






404
4-(2-azaspiro[3.4]octan-2-yl)-3-
E105
J1
402
403



cyclobutyl-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






405
3-cyclobutyl-4-[4-
E106
J1
420
421



(methoxymethyl)piperidin-1-yl]-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






406
4-(3-azabicyclo[3.1.0]hexan-3-yl)-3-
E107
J1
374
375



cyclobutyl-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






407
3-cyclobutyl-4-(cyclohexylmethoxy)-
HP10
J3
405
406



1-phenyl-1H-pyrazolo[3,4-b]pyridine-







6-carboxylic acid






408
3-cyclobutyl-1-phenyl-4-(piperidin-1-
E103
J1
376
377



yl)-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






409
4-(2-azaspiro[3.5]nonan-2-yl)-3-
E115
J1
416
417



cyclobutyl-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






410
4-(4-cyanopiperidin-1-yl)-3-
E114
J1
401
402



cyclobutyl-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






411
3-cyclobutyl-4-[4-
E113
J1
454
455



(methanesulfonyl)piperidin-1-yl]-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






412
4-(4-methoxypiperidin-1-yl)-3-
E110
J1
464
465



(propan-2-yl)-1-[2-(pyrrolidin-1-







yl)pyridin-4-yl]-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






413
4-[6-(4-cyanopiperidin-1-yl)pyridin-
E112
J1
548
549



3-yl]-3-cyclobutyl-1-[2-(pyrrolidin-1-







yl)pyridin-4-yl]-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






414
3-cyclobutyl-4-[2-(oxan-4-yl)ethoxy]-
HP10
J3
421
422



1-phenyl-1H-pyrazolo[3,4-b]pyridine-







6-carboxylic acid






415
3-cyclobutyl-4-[(2S)-2-fluoro-2-
HP10,
J3
439
440



(oxan-4-yl)ethoxy]-1-phenyl-1H-
ALC01






pyrazolo[3,4-b]pyridine-6-carboxylic







acid






416
4-[6-(4-cyanopiperidin-1-yl)pyridin-
E121
J1
564
565



3-yl]-3-cyclobutyl-1-[2-(morpholin-4-







yl)pyridin-4-yl]-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






417
3-cyclobutyl-4-[(oxan-4-yl)methoxy]-
HP10
J3,
407
408



1-phenyl-1H-pyrazolo[3,4-b]pyridine-

Specific





6-carboxylic acid

example




418
3-cyclobutyl-4-[3-
E116
Jl
392
393



(methoxymethyl)azetidin-1-yl]-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






419
4-(5-azaspiro[2.5]octan-5-yl)-3-
E125
Jl
402
403



cyclobutyl-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






420
4-[6-(4-cyanopiperidin-1-yl)pyridin-
E118
Jl
514
515



3-yl]-3-(3,3-difluorocyclobutyl)-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






421
4-[6-(4-cyanopiperidin-1-yl)pyridin-
E117
Jl
508
509



3-yl]-3-(cis-3-methoxycyclobutyl)-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






422
3-cyclobutyl-4-[(2-
E126
Jl
380
381



methoxyethyl)(methyl)amino]-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






423
3-cyclobutyl-4-(1,1-difluoro-5-
E122
Jl
424
425



azaspiro [2. 4]heptan-5-yl)-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






424
3-cyclobutyl-4-(5-oxa-2-
E123
J1
418
419



azaspiro[3.5]nonan-2-yl)-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






425
3-cyclobutyl-4-(7-oxa-2-
E124
J1
418
419



azaspiro[3.5]nonan-2-yl)-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






426
4-(2-azaspiro[3.3]heptan-2-yl)-3-
E128
J1
388
389



cyclobutyl-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






427
4-{4-[(benzyloxy)methyl]piperidin-1-
E127
J1
496
497



yl}-3-cyclobutyl-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






428
3-cyclobutyl-4-[(cis-4-
HP10
J3
421
422



methoxycyclohexyl)oxy]-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






429
3-cyclobutyl-4-[(trans-4-
HP10
J3
421
422



methoxycyclohexyl)oxy]-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






430
4-[6-(4-cyanopiperidin-1-yl)pyridin-
E119
J1
506
507



3-yl]-3-(3,3-dimethylcyclobutyl)-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






431
1-cyclohexyl-4-[4-
E134
J8,
414
415



(methoxymethyl)piperidin-1-yl]-3-

Specific





(propan-2-yl)-1H-pyrazolo[3,4-

example





b]pyridine-6-carboxylic acid






432
4-[6-(4-cyanopiperidin-1-yl)pyridin-
AI18
Separation
496
497



3-yl]-3-(cis-3-fluorocyclobutyl)-1-

by prep





phenyl-1H-pyrazolo[3,4-b]pyridine-6-

HPLC





carboxylic acid






433
4-[6-(4-cyanopiperidin-1-yl)pyridin-
AI18
Separation
496
497



3-yl]-3-(trans-3-fluorocyclobutyl)-1-

by prep





phenyl-1H-pyrazolo[3,4-b]pyridine-6-

HPLC





carboxylic acid






434
3-cyclobutyl-4-[(2R)-2-fluoro-2-
HP10,
J3
439
440



(oxan-4-yl)ethoxy]-1-phenyl-1H-
ALC02






pyrazolo[3,4-b]pyridine-6-carboxylic







acid






435
3-cyclobutyl-4-[(3,3-
HP10
J3
427
428



difluorocyclopentyl)methoxy]-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






436
3-cyclobutyl-4-[2-(1,1-dioxo-lλ6,4-
HP10
J3
470
471



thiazinan-4-yl)ethoxy]-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






437
4-[6-(4-cyanopiperidin-1-yl)pyridin-
E138
J1
552
553



3-yl]-1-[2-(morpholin-4-yl)pyridin-4-







yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






438
1-(4-fluorophenyl)-4-[4-(2-
E136
J8
454
455



methoxypropan-2-yl)piperidin-1-yl]-







3-(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






439
4-[(cis-3-tert-
HP10
J10
448
449



butoxycyclobutyl)(methyl)amino]-3-







cyclobutyl-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






440
3-cyclobutyl-4-(3-methylazetidin-1-
HP10
J10
362
363



yl)-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






441
3-cyclobutyl-4-(3,3-
HP10
J10
398
399



difluoropyrrolidin-1-yl)-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






442
3-cyclobutyl-1-phenyl-4-[3-
HP10
J10
430
431



(trifluoromethyl)pyrrolidin-1-yl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






443
3-cyclobutyl-1-phenyl-4-[4-
HP10
J10
445
446



(pyrrolidin-1-yl)piperidin-1-yl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






444
3-cyclobutyl-4-(4-fluoropiperidin-1-
HP10
J10
394
395



yl)-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






445
3-cyclobutyl-4-[(3R,4R)-3,4-
HP10
J10
394
395



dihydroxypyrrolidin-1-yl]-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






446
3-cyclobutyl-4-[(3S,4S)-3,4-
HP10
J10
394
395



dihydroxypyrrolidin-1-yl]-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






447
3-cyclobutyl-4-{4-[2-
HP10
J10
447
448



(dimethylamino)ethyl]piperidin-1-







yl}-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






448
3-cyclobutyl-4-{4-[2-
HP10
J10
475
476



(diethylamino)ethyl]piperidin-1-yl}-







1-phenyl-1H-pyrazolo[3,4-b]pyridine-







6-carboxylic acid






449
3-cyclobutyl-4-[4-
HP10
J10
431
432



(cyclopropylmethyl)piperazin-1-yl]-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






450
3-cyclobutyl-4-(4-
HP10
J10
431
432



cyclobutylpiperazin-1-yl)-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






451
3-cyclobutyl-4-(3-fluoro-3-
HP10
J10
380
381



methylazetidin-1-yl)-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






452
4-(8-azaspiro[4.5]decan-8-yl)-3-
HP10
J10
430
431



cyclobutyl-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






453
3-cyclobutyl-4-(3,3-difluoro-1-oxa-8-
HP10
J10
468
469



azaspiro[4.5]decan-8-yl)-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






454
3-cyclobutyl-4-(1′-methyl[4,4′-
HP10
J10
473
474



bipiperidin]-1-yl)-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






455
3-cyclobutyl-4-{4-[(1R)-2-
HP10
J10
465
466



(dimethylamino)-1-







fluoroethyl]piperidin-1-yl}-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






456
3-cyclobutyl-4-{4-[(1S)-2-
E135
J1
465
466



(dimethylamino)-1-







fluoroethyl]piperidin-1-yl}-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






457
3-cyclobutyl-4-{4-[(1S)-1-fluoro-2-
HP10
J10
438
439



hydroxyethyl]piperidin-1-yl}-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






458
3-cyclobutyl-4-{4-[(1R)-1-fluoro-2-
HP10
J10
438
439



hydroxyethyl]piperidin-1-yl}-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






459
3-cyclobutyl-4-{4-fluoro-4-[(2-
HP10
J10
482
483



methoxyethoxy)methyl]piperidin-1-







yl}-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






460
3-cyclobutyl-4-[3-(ethoxymethyl)-3-
HP10
J10
452
453



fluoropiperidin-1-yl]-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






461
3-cyclobutyl-4-[4-(ethoxymethyl)-4-
HP10
J10
452
453



fluoropiperidin-1-yl]-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






462
3-cyclobutyl-4-{3-fluoro-3-[(2-
HP10
J10
482
483



methoxyethoxy)methyl]piperidin-1-







yl}-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






463
3-cyclobutyl-4-[4-fluoro-4-
HP10
J10
438
439



(methoxymethyl)piperidin-1-yl]-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






464
3-cyclobutyl-4-[(3R,4R)-3-fluoro-4-
HP10
J10
410
411



hydroxypiperidin-1-yl]-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






465
3-cyclobutyl-4-[(3R,4R)-4-fluoro-3-
HP10
J10
410
411



hydroxypiperidin-1-yl]-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






466
3-cyclobutyl-1-phenyl-4-[3-
HP10
J10
431
432



(piperidin-1-yl)azetidin-1-yl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






467
3-cyclobutyl-4-[(3R)-3-
HP10
J10
440
441



(methanesulfonyl)pyrrolidin-1-yl]-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






468
3-cyclobutyl-4-(3-methoxypiperidin-
HP10
J10
406
407



1-yl)-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






469
3-cyclobutyl-4-[4-oxo-1-(propan-2-
HP10
J10
488
489



yl)-1,3,8-triazaspiro[4.5]decan-8-yl]-







1-phenyl-1H-pyrazolo[3,4-b]pyridine-







6-carboxylic acid






470
3-cyclobutyl-1-phenyl-4-[4-(2,2,2-
HP10
J10
459
460



trifluoroethyl)piperazin-1-yl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






471
3-cyclobutyl-4-[4-(3-
HP10
J10
435
436



hydroxypropyl)piperazin-1-yl]-1-







phenyl-1H-pyrazolo[3 ,4-b]pyridine-6-







carboxylic acid






472
3-cyclobutyl-4-{4-[2-oxo-2-
HP10
J10
488
489



(pyrrolidin-1-yl)ethyl]piperazin-1-







yl}-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






473
4-(azepan-1-yl)-3-cyclobutyl-1-
HP10
J10
390
391



phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






474
3-cyclobutyl-4-{4-[2-(morpholin-4-
HP10
J10
504
505



yl)-2-oxoethyl]piperazin-1-yl}-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






475
3-cyclobutyl-4-[(7R,8aS)-7-
HP10
J10
433
434



hydroxyhexahydropyrrolo[1,2-







a]pyrazin-2(1H)-yl]-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






476
3-cyclobutyl-4-[(3,3-difluoro-1-
HP10
J3
427
428



methylcyclobutyl)methoxy]-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






477
3-cyclobutyl-4-[2-(3,3-
HP10
J3
427
428



difluorocyclobutyl)ethoxy]-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






478
3-cyclobutyl-4-{2-[(oxetan-3-
HP10
J3
450
451



yl)(propan-2-yl)amino]ethoxy}-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






479
4-[(1-acetyl-4-fluoropiperidin-4-
HP10
J3
466
467



yl)methoxy]-3-cyclobutyl-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






480
3-cyclobutyl-4-{[(2S)-oxolan-2-
HP10
J3
393
394



yl]methoxy}-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






481
3-cyclobutyl-4-[2-(3-
HP10
J3
436
437



methoxyazetidin-1-yl)-2-oxoethoxy]-







1-phenyl-1H-pyrazolo[3,4-b]pyridine-







6-carboxylic acid






482
3-cyclobutyl-4-[(2R)-2-fluoro-2-(1-
HP10
J3
452
453



methylpiperidin-4-yl)ethoxy]-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






483
3-cyclobutyl-4-{2-[(oxetan-3-
HP10
J3
409
410



yl)oxy]ethoxy}-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






484
3-cyclobutyl-4-{2-[1-(2-
HP10
J3
435
436



methoxyethyl)cyclopropyl]ethoxyl}-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






485
3-cyclobutyl-4-{[1-(2-
HP10
J3
421
422



methoxyethyl)cyclopropyl]methoxyl}-







1-phenyl-1H-pyrazolo[3,4-b]pyridine-







6-carboxylic acid






486
3-cyclobutyl-4-[(2,2-
HP10
J3
427
428



difluorocyclopentyl)methoxy]-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






487
3-cyclobutyl-4-[3-(morpholin-4-
HP10
J3,
436
437



yl)propoxy]-1-phenyl-1H-

Specific





pyrazolo[3,4-b]pyridine-6-carboxylic

example





acid






488
3-cyclobutyl-4-[2-(1,3-dioxan-2-
HP10
J3
423
424



yl)ethoxy]-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






489
3-cyclobutyl-4-(3-fluoropropoxy)-1-
HP10
J3
369
369



phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






490
3-cyclobutyl-4-[(3-methyloxetan-3-
HP10
J3
393
394



yl)methoxy]-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






491
3-cyclobutyl-4-[(1,3-
HP10
J3
411
412



dimethoxypropan-2-yl)oxy]-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






492
3-cyclobutyl-4-{[cis-3-
HP10
J3
406
407



(dimethylamino)cyclobutyl]oxy}-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






493
3-cyclobutyl-4-[(2-methyl-1,3-
HP10
J3
409
410



dioxan-5-yl)oxy]-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






494
3-cyclobutyl-4-{[(3S)-1-
HP10
J3
406
407



methylpiperidin-3-yl]oxy}-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






495
3-cyclobutyl-4-[(2-
HP10
J3
405
406



oxaspiro[3.3]heptan-6-yl)oxy]-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






496
3-cyclobutyl-4-{[(3R)-1-
HP10
J3
406
407



methylpiperidin-3-yl]oxy}-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






497
3-[(1-acetylazetidin-3-yl)oxy]-4-[4-
AI11
J9
513
514



(morpholin-4-yl)phenyl]-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






498
3-cyclobutyl-4-[4-(1-
E143
J8
434
435



methoxyethyl)piperidin-1-yl]-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






499
3-cyclobutyl-1-phenyl-4-[4-(1,1,1-
E144
J8
502
503



trifluoro-2-methoxypropan-2-







yl)piperidin-1-yl]-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






500
3-cyclobutyl-4-[3-
HP10
J10
475
476



(diethylcarbamoyl)piperidin-1-yl]-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






501
3-cyclobutyl-4-(4-hydroxypiperidin-
HP10
J10
392
393



1-yl)-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






502
3-cyclobutyl-4-{4-[2-(1,4-dimethyl-6-
HP10
J10
527
528



oxo-1,6-dihydropyrimidin-5-







yl)ethyl]piperazin-1-yl}-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






503
3-cyclobutyl-4-[(4aS,7aR)-4-methyl-
HP10
J10
447
448



3-oxohexahydropyrrolo[3,4-







b][1,4]oxazin-6(2H)-yl]-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






504
3-cyclobutyl-4-(3-oxopiperazin-1-yl)-
HP10
J10
391
392



1-phenyl-1H-pyrazolo[3,4-b]pyridine-







6-carboxylic acid






505
3-cyclobutyl-4-[(5aS,8aS)-2-
HP10
J10
445
446



oxooctahydropyrrolo[3,4-b]azepin-







7(1H)-yl]-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






506
3-cyclobutyl-4-[(2R)-4,4-difluoro-2-
HP10
J10
428
429



(hydroxymethyl)pyrrolidin-1-yl]-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






507
3-cyclobutyl-4-[(2S,4S)-4-fluoro-2-
HP10
J10
410
411



(hydroxymethyl)pyrrolidin-1-yl]-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






508
3-cyclobutyl-4-[3-fluoro-3-
HP10
J10
424
425



(methoxymethyl)pyrrolidin-1-yl]-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






509
3-cyclobutyl-4-[(3R,4S)-3-fluoro-4-
HP10
J10
410
411



hydroxypiperidin-1-yl]-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






510
3-cyclobutyl-4-[3-(ethoxymethyl)-3-
HP10
J10
438
439



fluoropyrrolidin-1-yl]-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






511
3-cyclobutyl-4-[3-(hydroxymethyl)-3-
HP10
J10
392
393



methylazetidin-1-yl]-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






512
3-cyclobutyl-4-[(3S)-3-
HP10
J10
392
393



methoxypyrrolidin-1-yl]-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






513
3-cyclobutyl-4-[3-(2,2-
HP10
J10
428
429



difluoroethoxy)azetidin-1-yl]-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






514
3-cyclobutyl-4-[(2R,4S)-4-fluoro-2-
HP10
J10
410
411



(hydroxymethyl)pyrrolidin-1-yl]-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






515
3-cyclobutyl-4-[(7S,8aS)-7-
HP10
J10
435
436



fluorohexahydropyrrolo[1,2-







a]pyrazin-2(11/)-yl]-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






516
3-cyclobutyl-4-[(4aS,7aS)-4-methyl-
HP10
J10
447
448



3-oxohexahydropyrrolo[3,4-







b][1,4]oxazin-6 (2H)-yl]-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






517
3-cyclobutyl-4-[4-fluoro-4-
HP10
J10
424
425



(hydroxymethyl)piperidin-1-yl]-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






518
3-cyclobutyl-4-(1-oxa-7-
HP10
J10
418
419



azaspiro[4.4]nonan-7-yl)-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






519
3-cyclobutyl-4-{4-
HP10
J10
469
470



[(methanesulfonyl)amino]piperidin-1-







yl}-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






520
3-cyclobutyl-4-[4-(1-fluoro-2-
HP10
J10
438
439



hydroxyethyl)piperidin-1-yl]-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






521
3-cyclobutyl-4-[3-(methoxymethyl)-
HP10
J10
406
407



3-methylazetidin-1-yl]-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






522
3-cyclobutyl-4-[(3R)-3-
HP10
J10
392
393



methoxypyrrolidin-1-yl]-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






523
3-cyclobutyl-4-[4-
HP10
J10
455
456



(methanesulfonyl)piperazin-1-yl]-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






524
4-{6-[bi s(2-
E149
J1
575
576



methoxyethyl)amino]pyridin-3-yl}-1-







[2-(morpholin-4-yl)pyridin-4-yl]-3-







(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






525
4-[4-(methoxymethyl)piperidin-1-yl]-
E147
J6,
494
495



142-(morpholin-4-yl)pyridin-4-yl]-3-

Specific





(propan-2-yl)-1H-pyrazolo[3,4-

example





b]pyridine-6-carboxylic acid






526
3-cyclobutyl-4-[4-methoxy-4-
E146
J8
450
451



(methoxymethyl)piperidin-1-yl]-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






527
3-cyclobutyl-4-[(3S)-3-
HP10
J10
380
381



fluoropyrrolidin-1-yl]-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






528
3-cyclobutyl-4-(3,3-difluoroazetidin-
HP10
J10
384
385



1-yl)-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






529
3-cyclobutyl-4-[3-(2-oxo-1,3-
HP10
J10
433
434



oxazolidin-3-yl)azetidin-1-yl]-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






530
3-cyclobutyl-4-(3-ethyl-3-
HP10
J10
394
395



fluoroazetidin-1-yl)-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






531
3-cyclobutyl-4-[2-
HP10
J10
408
409



(hydroxymethyl)morpholin-4-yl]-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






532
3-cyclobutyl-4-{3-fluoro-3-[(2-
HP10
J10
468
469



methoxyethoxy)methyl]pyrrolidin-1-







yl}-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






533
3-cyclobutyl-4-[(cis-3-
HP10
J10
392
393



hydroxycyclobutyl)(methyl)amino]-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






534
3-cyclobutyl-4-(6-oxa-2-
HP10
J10
404
405



azaspiro[3.4]octan-2-yl)-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






535
3-cyclobutyl-4-[(3R,4S)-4-fluoro-3-
HP10
J10
410
411



hydroxypiperidin-1-yl]-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






536
3-cyclobutyl-4-(3-hydroxy-3-
HP10
J10
378
379



methylazetidin-1-yl)-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






537
3-cyclobutyl-4-(6-oxo-2,7-
HP10
J10
431
432



diazaspiro[4.4]nonan-2-yl)-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






538
3-cyclobutyl-4-[(2S)-4,4-difluoro-2-
HP10
J10
428
429



(hydroxymethyl)pyrrolidin-1-yl]-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






539
3-cyclobutyl-4-[4-
HP10
J10
449
450



(ethoxycarbonyl)piperazin-1-yl]-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






540
3-cyclobutyl-4-{4-[2-
HP10
J10
516
517



(cyclohexyl amino)-2-







oxoethyl]piperazin-1-yl}-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






541
3-cyclobutyl-4-[(3R)-3-
HP10
J10
380
381



fluoropyrrolidin-1-yl]-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






542
3-cyclobutyl-4-(3-methoxyazetidin-1-
HP10
J10
378
379



yl)-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






543
3-cyclobutyl-4-(2-hydroxy-7-
HP10
J10
432
433



azaspiro[3.5]nonan-7-yl)-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






544
3-cyclobutyl-4-[(3R)-3-
HP10
J10,
406
407



(hydroxymethyl)piperidin-1-yl]-1-

Specific





phenyl-1H-pyrazolo[3,4-b]pyridine-6-

example





carboxylic acid






545
3-cyclobutyl-4-(1,4-oxazepan-4-yl)-1-
HP10
J10
392
393



phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






546
3-cyclobutyl-4-[4-hydroxy-4-(2-
HP10
J10
436
437



hydroxyethyl)piperidin-1-yl]-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






547
1-(cyclobutylmethyl)-4-[4-
E154
J1
400
401



(methoxymethyl)piperidin-1-yl]-3-







(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






548
4-[4-(methoxymethyl)piperidin-1-yl]-
E155
J1
388
389



1-(2-methylpropyl)-3-(propan-2-yl)-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






549
rac-4-[(3aR,7aS)-1-(tert-
HP10
J10,
517
518



butoxy carbonyl)octahydro-5H-

Specific





pyrrolo[3,2-c]pyridin-5-yl]-3-

example





cyclobutyl-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






550
4-[6-(4-cyanopiperidin-1-yl)pyridin-
552
J15,
509
510



3-yl]-1-phenyl-3-[(pyrrolidin-3-

Specific





yl)oxy]-1H-pyrazolo[3,4-b]pyridine-

example





6-carboxylic acid






551
4-[6-(4-cyanopiperidin-1-yl)pyridin-
E151
J1
492
493



3-yl]-3-(trans-3-methylcyclobutyl)-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






552
3-{[1-(tert-
E321
J1
609
610



butoxycarbonyl)pyrrolidin-3-yl]oxy}-







4-[6-(4-cyanopiperidin-1-yl)pyridin-







3-yl]-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






553
3-{[1-(tert-butoxycarbonyl)piperidin-
E152
J1
623
624



4-yl]oxy}-4-[6-(4-cyanopiperidin-1-







yl)pyridin-3-yl]-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






554
3-cyclobutyl-4-{methyl[(oxan-4-
HP10
J10
420
421



yl)methyl]amino}-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






555
3-cyclobutyl-1-phenyl-4-[4-(2-
HP10
J10
463
464



propoxyethyl)piperazin-1-yl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






556
3-cyclobutyl-1-phenyl-4-{2-
HP10
J10
475
476



[(piperidin-1-yl)methyl]morpholin-4-







yl}-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






557
3-cyclobutyl-1-phenyl-4-{4-
HP10
J10
459
460



[(pyrrolidin-1-yl)methyl]piperidin-1-







yl}-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






558
3-cyclobutyl-4-{4-[3-(morpholin-4-
HP10
J10
504
505



yl)propyl]piperazin-1-yl}-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






559
3-cyclobutyl-4-{4-[2-
HP10
J10
462
463



(dimethylamino)-2-







oxoethyl]piperazin-1-yl}-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






560
3-cyclobutyl-4-[4-(morpholin-4-
HP10
J10,
461
462



yl)piperidin-1-yl]-1-phenyl-1H-

Specific





pyrazolo[3,4-b]pyridine-6-carboxylic

example





acid






561
4-[4-(2-cyanoethyl)piperazin-1-yl]-3-
HP10
J10
430
431



cyclobutyl-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






562
3-cyclobutyl-4-{2-
HP10
J10
435
436



[(dimethylamino)methyl]morpholin-







4-yl}-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






563
3-cyclobutyl-4-(4-methylpiperazin-1-
HP10
J10
391
392



yl)-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






564
3-cyclobutyl-4-(methyl{[1-(2-
HP10
J10
475
476



methylpropyl)piperidin-4-







yl]methyl}amino)-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






565
3-cyclobutyl-4-{methyl[2-
HP10
J10
435
436



(morpholin-4-yl)ethyl]amino}-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






566
3-cyclobutyl-4-[4-(2-
HP10
J10
449
450



ethoxyethyl)piperazin-1-yl]-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






567
3-cyclobutyl-4-[(3R)-3-
HP10
J10
405
406



(dimethylamino)pyrrolidin-1-yl]-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






568
3-cyclobutyl-4-[(3S)-3-
HP10
J10
405
406



(dimethylamino)pyrrolidin-1-yl]-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






569
3-cyclobutyl-4-{4-[2-(methylamino)-
HP10
J10
448
449



2-oxoethyl]piperazin-1-yl}-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






570
3-cyclobutyl-4-{4-[(morpholin-4-
HP10
J10
504
505



yl)acetyl]piperazin-1-yl}-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






571
3-cyclobutyl-4-[4-(2-
HP10
J10,
435
436



methoxyethyl)piperazin-1-yl]-1-

Specific





phenyl-1H-pyrazolo[3,4-b]pyridine-6-

example





carboxylic acid






572
3-cyclobutyl-4-{4-[(oxolan-2-
HP10
J10
475
476



yl)methyl]-1,4-diazepan-1-yl}-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






573
3-cyclobutyl-1-phenyl-4-{3-[(propan-
HP10
J10
406
407



2-yl)oxy]azetidin-1-yl}-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






574
3-cyclobutyl-1-phenyl-4-{4-[2-
HP10
J10
473
474



(pyrrolidin-1-yl)ethyl]piperidin-1-yl}-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






575
3-cyclobutyl-4-{4-[2-(morpholin-4-
HP10
J10,
489
490



yl)ethyl]piperidin-1-yl}-1-phenyl-1H-

Specific





pyrazolo[3,4-b]pyridine-6-carboxylic

example





acid






576
4-([1,4′-bipiperidin]-1′-yl)-3-
HP10
J10,
459
460



cyclobutyl-1-phenyl-1H-pyrazolo[3,4-

Specific





b]pyridine-6-carboxylic acid

example




577
3-cyclobutyl-4-[(3R)-3-(morpholin-4-
HP10
J10
447
448



yl)pyrrolidin-1-yl]-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






578
3-cyclobutyl-4-[(4,4-
HP10
J3
427
428



difluorocyclohexyl)oxy]-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






579
3-cyclobutyl-4-[(oxan-4-yl)oxy]-1-
HP10
J3
393
394



phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






580
3-cyclobutyl-4-{[(1S,2S)-2-
HP10
J3
421
422



methoxycyclohexyl]oxy}-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






581
3-cyclobutyl-4-[(3-ethyloxetan-3-
HP10
J3
407
408



yl)methoxy]-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






582
3-cyclobutyl-4-{[(3R)-oxolan-3-
HP10
J3
379
380



yl]oxy}-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






583
3-cyclobutyl-4-{[(3S)-oxolan-3-
HP10
J3
379
380



yl]oxy 1-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






584
3-cyclobutyl-4-methoxy-1-phenyl-
HP10
J3
323
324



1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






585
3-cyclobutyl-4-(cyclobutyloxy)-1-
HP10
J3
363
364



phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






586
3-cyclobutyl-4-[2-(2-
HP10
J3
411
412



methoxyethoxy)ethoxy]-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






587
4-[(3aR,7aS)-1-acetyloctahydro-5H-
549
J15, J9
459
458



pyrrolo[3,2-c]pyridin-5-yl]-3-

Specific





cyclobutyl-1-phenyl-1H-pyrazolo[3 ,4-

example





b]pyridine-6-carboxylic acid






588
4-[(3aS,7aR)-1-acetyloctahydro-5H-
549
J15, J9
459
458



pyrrolo[3,2-c]pyridin-5-yl]-3-

Specific





cyclobutyl-1-phenyl-1H-pyrazolo[3 ,4-

example





b]pyridine-6-carboxylic acid






589
4-[4-(methoxymethyl)piperidin-1-yl]-
E160
J1
495
496



142-(morpholin-4-yl)pyrimidin-4-yl]-







3-(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






590
3-cyclobutyl-4-{[(oxan-4-
HP10
J10,
406
407



yl)methyl]amino}-1-phenyl-1H-

Specific





pyrazolo[3,4-b]pyridine-6-carboxylic

example





acid






591
4-[6-(4-cyanopiperidin-1-yl)pyridin-
E159
J1
510
511



3-yl]-3-[(oxolan-3-yl)oxy]-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






592
4-[6-(4-cyanopiperidin-1-yl)pyridin-
E164
J1
496
497



3-yl]-3-[(oxetan-3-yl)oxy]-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






593
3-cyclobutyl-4-{methyl [(1-
HP10
J10
433
434



methylpiperidin-3-yl)methyl]amino}-







1-phenyl-1H-pyrazolo[3,4-b]pyridine-







6-carboxylic acid






594
3-cyclobutyl-4-(4,4-difluoropiperidin-
HP10
J10
412
413



1-yl)-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






595
3-cyclobutyl-4-[3-fluoro-3-
HP10
J10
438
439



(methoxymethyl)piperidin-1-yl]-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






596
3-cyclobutyl-1-phenyl-4-[2-
HP10
J10
446
447



(trifluoromethyl)morpholin-4-yl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






597
3-cyclobutyl-4-(cyclopentyloxy)-1-
HP10
J3
377
378



phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






598
4-{[cis-3-(azetidin-1-
HP10
J3
418
419



yl)cyclobutyl]oxy}-3-cyclobutyl-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






599
3-cyclobutyl-4-[(1-
HP10
J3
446
447



cyclohexylazetidin-3-yl)oxy]-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






600
3-cyclobutyl-4-[(3,3-
HP10
J3
413
414



difluorocyclobutyl)methoxy]-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






601
3-cyclobutyl-4-[(1-methylazetidin-3-
HP10
J3
378
379



yl)oxy]-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






602
1-[3-(dimethylamino)phenyl]-4-
HP07
J3
438
439



[(oxan-4-yl)methoxy]-3-(propan-2-







yl)-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






603
1-cyclohexyl-4-[(oxan-4-
HP28
J3
401
402



yl)methoxy]-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






604
1-(4-fluorophenyl)-4-[2-(oxan-4-
HP11
J3
427
428



yl)ethoxy]-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






605
3-cyclobutyl-4-[4-(2-methoxypropan-
E163
J8
448
449



2-yl)piperidin-1-yl]-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






606
4-[3-(dimethylamino)propoxy]-1-(4-
HP11
J3
400
401



fluorophenyl)-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






607
1-(4-fluorophenyl)-4-[3-(morpholin-
HP11
J3
442
443



4-yl)propoxy]-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






608
1-(4-fluorophenyl)-4-[(3-
HP11
J3
399
400



methyloxetan-3-yl)methoxy]-3-







(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






609
1-(4-fluorophenyl)-4-[(oxolan-2-
HP11
J3
399
400



yl)methoxy]-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






610
rac-3-cyclobutyl-1-phenyl-4-
587 Step1
J9,
503
504



[(3aR,7aS)-1-{[(propan-2-

Specific





yl)oxy]carbonyl}octahydro-5H-

example





pyrrolo[3,2-c]pyridin-5-yl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






611
3-cyclobutyl-4-[4-
HP10
J3
408
409



(dimethylamino)butoxy]-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






612
4-[(1-acetylpiperidin-4-yl)oxy]-3-
HP10
J3
434
435



cyclobutyl-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






613
3-cyclobutyl-1-phenyl-4-(2,2,2-
HP10
J3
391
392



trifluoroethoxy)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






614
3-cyclobutyl-4-{2-[2-
HP10
J3
424
425



(dimethylamino)ethoxy]ethoxy}-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






615
3-cyclobutyl-4-{[(2S)-1-
HP10
J3
394
395



(dimethylamino)propan-2-yl]oxy}-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






616
3-cyclobutyl-4-[(4,4-
HP10
J3
441
442



difluorocyclohexyl)methoxy]-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






617
3-cyclobutyl-4-{[(2R)-5-
HP10
J3
406
407



oxopyrrolidin-2-yl]methoxy}-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






618
3-cyclobutyl-4-{[(4R)-2,2-dimethyl-
HP10
J3
423
424



1,3-dioxolan-4-yl]methoxy}-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






619
3-cyclobutyl-4-{[(3S)-6-oxopiperidin-
HP10
J3
406
407



3-yl]oxy}-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






620
3-cyclobutyl-4-[(5-ethyl-1,3-dioxan-
HP10
J3
437
438



5-yl)methoxy]-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






621
3-cyclobutyl-4-{[(3-endo)-8-methyl-
HP10
J3
432
433



8-azabicyclo[3.2.1]octan-3-yl]oxy}-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






622
3-cyclobutyl-4-[(5-methyl-1,3-
HP10
J3
423
424



dioxan-5-yl)methoxy]-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






623
3-cyclobutyl-4-[2-(1,4-dioxa-8-
HP10
J3
478
479



azaspiro[4.5]decan-8-yl)ethoxy]-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






624
3-cyclobutyl-4-[3-
HP10
J3
422
423



(diethylamino)propoxy]-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






625
3-cyclobutyl-4-{2-
HP10
J3
490
491



[cyclohexyl(oxetan-3-







yl)amino]ethoxy}-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






626
3-cyclobutyl-4-{[4-fluoro-1-
HP10
J3
502
503



(methanesulfonyl)piperidin-4-







yl]methoxy}-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






627
3-cyclobutyl-4-{[4-
HP10
J3
485
486



(methanesulfonyl)oxan-4-







yl]methoxy}-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






628
3-cyclobutyl-1-phenyl-4-[2-
HP10
J3
406
407



(pyrrolidin-1-yl)ethoxy]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






629
3-cyclobutyl-4-[2-(methanesulfonyl)-
HP10
J3
443
444



2-methylpropoxy]-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






630
3-cyclobutyl-4-[(1-
HP10
J3
377
378



methylcyclopropyl)methoxy]-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






631
3-cyclobutyl-4-[2-(1-
HP10
J3
391
392



methylcyclopropyl)ethoxy]-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






632
3-cyclobutyl-4-{[1-
HP10
J3
455
456



(methanesulfonyl)cyclobutyl]methoxy}-







1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






633
3-cyclobutyl-4-(2-cyclohexylethoxy)-
HP10
J3
419
420



1-phenyl-1H-pyrazolo[3,4-b]pyridine-







6-carboxylic acid






634
3-cyclobutyl-4-[3-(4-methylpiperazin-
HP10
J3
449
450



1-yl)propoxy]-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






635
3-cyclobutyl-4-[3-
HP10
J3
394
395



(dimethylamino)propoxy]-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






636
3-cyclobutyl-4-[3-(dimethylamino)-
HP10
J3
422
423



2,2-dimethylpropoxy]-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






637
3-cyclobutyl-4-[2-
HP10
J3
380
381



(dimethylamino)ethoxy]-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






638
4-{[1,3-bis(dimethylamino)propan-2-
HP10
J3
437
438



yl]oxy}-3-cyclobutyl-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






639
3-cyclobutyl-1-phenyl-4-[2-
HP10
J3
420
421



(piperidin-1-yl)ethoxy]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






640
3-cyclobutyl-4-[2-(2-
HP10
J3
421
422



oxoimidazolidin-1-yl)ethoxy]-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






641
4-{[1,3-bis(morpholin-4-yl)propan-2-
HP10
J3
521
522



yl]oxy}-3-cyclobutyl-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






642
3-cyclobutyl-1-phenyl-4-[3-
HP10
J3
434
435



(piperidin-1-yl)propoxy]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






643
4-[2-(azepan-1-yl)ethoxy]-3-
HP10
J3
434
435



cyclobutyl-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






644
3-cyclobutyl-4-[2-(4-methyl-1,4-
HP10
J3
449
450



diazepan-1-yl)ethoxy]-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






645
3-cyclobutyl-4-{[(2s,4r)-5-methyl-5-
HP10
J3
432
433



azaspiro[3.4]octan-2-yl]oxy}-1-







phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






646
3-cyclobutyl-4-[(1-{3-
HP10
J3
505
507



[(diethylamino)methyl]oxetan-3-







yl}azetidin-3-yl)oxy]-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






647
3-cyclobutyl-1-phenyl-4-{[1-(propan-
HP10
J3
434
435



2-yl)piperidin-4-yl]oxy}-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






648
3-cyclobutyl-4-(cycloheptyloxy)-1-
HP10
J3
405
406



phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






649
3-cyclobutyl-4-(cyclooctyloxy)-1-
HP10
J3
419
420



phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






650
3-cyclobutyl-4-{[(3R)-1-
HP10
J3
392
393



methylpyrrolidin-3-yl]oxy}-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






651
3-cyclobutyl-4-{[(3S)-1-
HP10
J3
392
393



methylpyrrolidin-3-yl]oxy}-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






652
4-[(3,3-difluoro-1-
HP11
J3
433
434



methylcyclobutyl)methoxy]-1-(4-







fluorophenyl)-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






653
1-(4-fluorophenyl)-4-[3-(piperidin-1-
HP11
J3
440
441



yl)propoxy]-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






654
4-[(1,3-dimethoxypropan-2-yl)oxy]-1-
HP11
J3
417
418



(4-fluorophenyl)-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






655
3-cyclobutyl-4-({[(2S)-oxolan-2-
HP10
J10,
392
393



yl]methyl}amino)-1-phenyl-1H-

Specific





pyrazolo[3,4-b]pyridine-6-carboxylic

example





acid






656
1-(4-fluorophenyl)-4-[4-(2-
E166
J1
440
441



hydroxypropan-2-yl)piperidin-1-yl]-







3-(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






657
3-cyclobutyl-1-(4-fluorophenyl)-4-[4-
E167
J1
438
439



(methoxymethyl)piperidin-1-yl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






658
3-cyclobutyl-1-(4-fluorophenyl)-4-
E171
J1
425
426



[(oxan-4-yl)methoxy]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






659
3-cyclobutyl-4-[4-(2-hydroxypropan-
E170
J1
434
435



2-yl)piperidin-1-yl]-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






660
4-[4-(dimethylamino)piperidin-1-yl]-
E174
J1
425
426



1-(4-fluorophenyl)-3-(propan-2-yl)-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






661
1-(4-fluorophenyl)-4-(1′-methyl [4,4′-
E175
J1
479
480



bipiperidin]-1-yl)-3-(propan-2-yl)-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






662
4-[(1-acetylpiperidin-4-yl)methoxy]-
E176
J1
454
455



1-(4-fluorophenyl)-3-(propan-2-yl)-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






663
1-(4-fluorophenyl)-4-{[1-
E178
J1
470
471



(methoxycarbonyl)piperidin-4-







yl]methoxy}-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






664
1-(4-fluorophenyl)-4-[(oxane-4-
E322
J1
426
427



carbonyl)amino]-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






665
4-[4-(cyanomethyl)-4-
E179
J1
431
432



hydroxypiperidin-1-yl]-3-cyclobutyl-







1-phenyl-1H-pyrazolo[3,4-b]pyridine-







6-carboxylic acid






666
4-[4-(ethoxymethyl)-4-
E189
J1
458
459



fluoropiperidin-1-yl]-1-(4-







fluorophenyl)-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






667
4-{4-fluoro-4-[(2-
E190
J1
488
489



methoxyethoxy)methyl]piperidin-1-







yl}-1-(4-fluorophenyl)-3-(propan-2-







yl)-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






668
4-[(3R,4R)-3-fluoro-4-
E191
J1
416
417



hydroxypiperidin-1-yl]-1-(4-







fluorophenyl)-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






669
4-[4-fluoro-4-
E192
J1
444
445



(methoxymethyl)piperidin-1-yl]-1-(4-







fluorophenyl)-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






670
4-{3-fluoro-3-[(2-
E193
J1
488
489



methoxyethoxy)methyl]piperidin-1-







yl}-1-(4-fluorophenyl)-3-(propan-2-







yl)-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






671
4-[(3S)-3-{[(tert-
HP10
J10,
491
492



butoxycarbonyl)amino]methyl}pyrrol

Specific





idin-1-yl]-3-cyclobutyl-1-phenyl-1H-

example





pyrazolo[3,4-b]pyridine-6-carboxylic







acid






672
4-[(3R)-3-{[(tert-
HP10
J10,
491
492



butoxycarbonyl)amino]methyl}pyrrol

Specific





idin-1-yl]-3-cyclobutyl-1-phenyl-1H-

example





pyrazolo[3,4-b]pyridine-6-carboxylic







acid






673
3-cyclobutyl-4-(1,1-dioxo-1λ6,4-
E196
J1
426
427



thiazinan-4-yl)-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






674
4-[(3R)-3-{[tert-
671
J13,
505
506



butoxycarbonyl)(methyl)amino]methyl}

Specific





pyrrolidin-1-yl]-3-cyclobutyl-1-

example





phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






675
4-[(3S)-3-{[tert-
672
J13,
505
506



butoxycarbonyl)(methyl)amino]methyl}

Specific





pyrrolidin-1-yl]-3-cyclobutyl-1-

example





phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






676
3-cyclobutyl-4-{(3S)-3-
674
J15,
405
406



[(methylamino)methyl]pyrrolidin-1-

Specific





yl}-1-phenyl-1H-pyrazolo[3,4-

example





b]pyridine-6-carboxylic acid






677
1-(2,6-dimethylpyridin-4-yl)-4-[4-
E195
J1
437
438



(methoxymethyl)piperidin-1-yl]-3-







(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






678
3-cyclobutyl-4-[4-
E388
J1
451
452



(methoxymethyl)piperidin-1-yl]-1-(2-







methoxypyridin-4-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






679
3-cyclobutyl-1-(4-fluorophenyl)-4-[4-
E377
J1
479
480



(morpholin-4-yl)piperidin-1-yl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






680
3-cyclobutyl-1-phenyl-4-[3-
HP10,
J10
417
418



(pyrrolidin-1-yl)azetidin-1-yl]-1H-
149105-






pyrazolo[3,4-b]pyridine-6-carboxylic
96-4






acid






681
3-cyclobutyl-4-{4-[(oxolan-2-
HP10,
J10
461
462



yl)methyl]piperazin-1-yl}-1-phenyl-
82500-






1H-pyrazolo[3,4-b]pyridine-6-
35-4






carboxylic acid






682
3-cyclobutyl-4-[4-(1-methoxypropan-
HP10,
J10
449
450



2-yl)piperazin-1-yl]-1-phenyl-1H-
682802-






pyrazolo[3,4-b]pyridine-6-carboxylic
89-7






acid






683
3-cyclobutyl-4-{4-[1-(morpholin-4-
HP10,
J10
489
490



yl)ethyl]piperidin-1-yl}-1-phenyl-1H-
733733-






pyrazolo[3,4-b]pyridine-6-carboxylic
37-4






acid






684
3-cyclobutyl-4-{4-[(1,3-dioxolan-2-
HP10,
J10
463
464



yl)methyl]piperazin-1-yl}-1-phenyl-
682802-






1H-pyrazolo[3,4-b]pyridine-6-
92-2






carboxylic acid






685
3-cyclobutyl-4-[4-(2-
HP10,
J10
450
451



methoxyethoxy)piperidin-1-yl]-1-
70978-






phenyl-1H-pyrazolo[3,4-b]pyridine-6-
88-0






carboxylic acid






686
3-cyclobutyl-1-phenyl-4-{4-
HP10,
J10
473
474



[(piperidin-1-yl)methyl]piperidin-1-
32470-






yl}-1H-pyrazolo[3,4-b]pyridine-6-
52-3






carboxylic acid






687
3-cyclobutyl-4-{4-[2-(4-
E383
J1
501
502



methylpiperidin-1-yl)ethyl]piperidin-







1-yl}-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






688
3-cyclobutyl-4-[4-(2,6-
HP10,
J10
489
490



dimethylmorpholin-4-yl)piperidin-1-
551923-






yl]-1-phenyl-1H-pyrazolo[3,4-
15-0






b]pyridine-6-carboxylic acid






689
3-cyclobutyl-4-[4-
HP10,
J10
447
448



(diethylamino)piperidin-1-yl]-1-
143300-






phenyl-1H-pyrazolo[3,4-b]pyridine-6-
64-5






carboxylic acid






690
3-cyclobutyl-4-[{3-
HP10,
J10
475
476



[cyclohexyl(methyl)amino]propyl}
91336-






(methyl)amino]-1-phenyl-1H-
67-3






pyrazolo[3,4-b]pyridine-6-carboxylic







acid






691
3-cyclobutyl-1-phenyl-4-[4-(propan-
HP10,
J10
433
434



2-yl)-1,4-diazepan-1-yl]-1H-
59039-






pyrazolo[3,4-b]pyridine-6-carboxylic
61-1






acid






692
3-cyclobutyl-4-[(3aR,6aS)-5-(2-
HP10,
J10
459
460



methylpropyl)hexahydropyrrolo[3,4-
1690154-






c]pyrrol-2(1H)-yl]-1-phenyl-1H-
42-7






pyrazolo[3,4-b]pyridine-6-carboxylic







acid






693
4-([1,4′-bipiperidin]-1′-yl)-3-
E378
J1
477
478



cyclobutyl-1-(4-fluorophenyl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






694
3-cyclobutyl-4-{4-[4-(2-
HP10
J10
518
519



methoxyethyl)piperazin-1-







yl]piperidin-1-yl}-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






695
3-cyclobutyl-4-{4-[2-(4-
HP10,
J10
502
503



methylpiperazin-1-yl)ethyl]piperidin-
775288-






1-yl}-1-phenyl-1H-pyrazolo[3,4-
46-5






b]pyridine-6-carboxylic acid






696
3-cyclobutyl-4-[4-
HP10,
J10
463
464



(ethoxyacetyl)piperazin-1-yl]-1-
95550-






phenyl-1H-pyrazolo[3,4-b]pyridine-6-
07-5






carboxylic acid






697
3-cyclobutyl-4-[(3R)-3-(2-
HP10,
J10
459
460



oxopyrrolidin-1-yl)piperidin-1-yl]-1-
1240347-






phenyl-1H-pyrazolo[3,4-b]pyridine-6-
02-7






carboxylic acid






698
3-cyclobutyl-4-(4′-methyl [1,4′-
HP10,
J10
473
474



bipiperidin]-1′-yl)-1-phenyl-1H-
801979-






pyrazolo[3,4-b]pyridine-6-carboxylic
80-6






acid






699
3-cyclobutyl-4-(9-methyl-3,9-
HP10,
J10
459
460



diazaspiro[5.5]undecan-3-yl)-1-
13323-






phenyl-1H-pyrazolo[3,4-b]pyridine-6-
45-0






carboxylic acid






700
3-cyclobutyl-4-(1,4-dioxa-8-
HP10,
J10
434
435



azaspiro[4.5]decan-8-yl)-1-phenyl-
177-11-7






1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






701
3-cyclobutyl-4-{4-[(2-
HP10,
J10
477
478



methylpropoxy)carbonyl]piperazin-1-
23672-






yl}-1-phenyl-1H-pyrazolo[3,4-
96-0






b]pyridine-6-carboxylic acid






702
3-cyclobutyl-4-(4-methyl-1,4-
HP10,
J10
405
406



diazepan-1-yl)-1-phenyl-1H-
4318-37-






pyrazolo[3,4-b]pyridine-6-carboxylic
0






acid






703
4-(4-acetylpiperazin-1-yl)-3-
HP10,
J10
419
420



cyclobutyl-1-phenyl-1H-pyrazolo[3,4-
13889-






b]pyridine-6-carboxylic acid
98-0





704
3-cyclobutyl-4-[4-(3-
HP10,
J10
449
450



methoxypropyl)piperazin-1-yl]-1-
88708-






phenyl-1H-pyrazolo[3,4-b]pyridine-6-
40-1






carboxylic acid






705
3-cyclobutyl-4-(4-cyclopentyl-1,4-
HP10,
J10
459
460



diazepan-1-yl)-1-phenyl-1H-
245070-






pyrazolo[3,4-b]pyridine-6-carboxylic
83-1






acid






706
3-cyclobutyl-4-[(3R)-3-
HP10,
J10
392
393



hydroxypiperidin-1-yl]-1-phenyl-1H-
62414-






pyrazolo[3,4-b]pyridine-6-carboxylic
68-0






acid






707
3-cyclobutyl-1-phenyl-4-(4-
HP10,
J10
419
420



propylpiperazin-1-yl)-1H-
21867-






pyrazolo[3,4-b]pyridine-6-carboxylic
64-1






acid






708
3-cyclobutyl-4-[4-
HP10,
J10
448
449



(dimethylcarbamoyl)piperazin-1-yl]-
41340-






1-phenyl-1H-pyrazolo[3,4-b]pyridine-
78-7






6-carboxylic acid






709
3-cyclobutyl-4-[3-(morpholin-4-
HP10,
J10
433
434



yl)azetidin-1-yl]-1-phenyl-1H-
302355-






pyrazolo[3,4-b]pyridine-6-carboxylic
79-9






acid






710
4-(4-butyl-1,4-diazepan-1-yl)-3-
HP10,
J10
447
448



cyclobutyl-1-phenyl-1H-pyrazolo[3,4-
3619-75-






b]pyridine-6-carboxylic acid
8





711
3-cyclobutyl-4-[3-(morpholine-4-
HP10,
J10
572
573



carbonyl)[1,4′-bipiperidin]-1′-yl]-1-
954213-






phenyl-1H-pyrazolo[3,4-b]pyridine-6-
76-4






carboxylic acid






712
3-cyclobutyl-1-phenyl-4-(4-propyl-
HP10,
J10
433
434



1,4-diazepan-1-yl)-1H-pyrazolo[3,4-
3619-74-






b]pyridine-6-carboxylic acid
7





713
3-cyclobutyl-4-(1,4-dioxa-7-
HP10,
J10
420
421



azaspiro[4.4]nonan-7-yl)-1-phenyl-
176-33-0






1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






714
3-cyclobutyl-4-{4-[2-(2-
HP10,
J10
465
466



hydroxyethoxy)ethyl]piperazin-1-yl}-
13349-






1-phenyl-1H-pyrazolo[3,4-b]pyridine-
82-1






6-carboxylic acid






715
3-cyclobutyl-1-phenyl-4-[(3R)-3-
HP10,
J10
445
446



(piperidin-1-yl)pyrrolidin-1-yl]-1H-
913812-






pyrazolo[3,4-b]pyridine-6-carboxylic
09-6






acid






716
4-(7-cyano-5-oxa-2-
HP10
J10
429
430



azaspiro[3.4]octan-2-yl)-3-cyclobutyl-







1-phenyl-1H-pyrazolo[3,4-b]pyridine-







6-carboxylic acid






717
3-cyclobutyl-4-{4-[3-(4-methyl-1,4-
HP10,
J10
545
546



diazepan-1-yl)-3-
775288-






oxopropyl]piperazin-1-yl}-1-phenyl-
10-3






1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






718
3-cyclobutyl-4-[4-
HP10,
J10
530
531



(dimethylcarbamoyl)-4-(2-
945833-






oxopyrrolidin-1-yl)piperidin-1-yl]-1-
47-6






phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






719
3-cyclobutyl-4-[4-
HP10,
J10
472
473



(cyclohexylmethyl)piperidin-1-yl]-1-
78197-






phenyl-1H-pyrazolo[3,4-b]pyridine-6-
28-1






carboxylic acid






720
3-cyclobutyl-4-(6-oxa-2-
HP10,
J10
418
419



azaspiro[3.5]nonan-2-yl)-1-phenyl-
1214875-






1H-pyrazolo[3,4-b]pyridine-6-
08-7






carboxylic acid






721
3-cyclobutyl-4-[(8aR)-
HP10,
J10
417
418



hexahydropyrrolo[1,2-a]pyrazin-
96193-






2(1H)-yl]-1-phenyl-1H-pyrazolo[3,4-
27-0






b]pyridine-6-carboxylic acid






722
3-cyclobutyl-4-[4-(2-
HP10,
J10
421
422



hydroxyethyl)piperazin-1-yl]-1-
103-76-4






phenyl-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






723
3-cyclobutyl-4-[3-(4-
HP10
J10
447
448



methylmorpholin-2-yl)azetidin-1-yl]-







1-phenyl-1H-pyrazolo[3,4-b]pyridine-







6-carboxylic acid






724
3-cyclobutyl-4-(3-{4-[methyl(oxetan-
HP10,
J10
516
517



3-yl)amino]piperidin-1-yl}azetidin-1-
1799768-






yl)-1-phenyl-1H-pyrazolo[3,4-
53-8






b]pyridine-6-carboxylic acid






725
3-cyclobutyl-4-{3-[4-(morpholin-4-
HP10,
J10
516
517



yl)piperidin-1-yl]azetidin-1-yl}-1-
1799768-






phenyl-1H-pyrazolo[3,4-b]pyridine-6-
55-0






carboxylic acid






726
3-cyclobutyl-4-{4-[1-(2-
HP10
J10
532
533



ethoxyethyl)piperidin-4-yl]piperazin-







1-yl}-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






727
3-cyclobutyl-4-{4-[1-(2-
HP10
J10
518
519



hydroxypropyl)piperidin-4-







yl]piperazin-1-yl}-1-phenyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






728
3-cyclobutyl-4-{4-[3-
HP10,
J10
462
463



(dimethylamino)propyl]piperazin-1-
877-96-3






yl}-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






729
3-cyclobutyl-4-{4-[4-(2-
HP10
J10
532
533



ethoxyethyl)piperazin-1-yl]piperidin-







1-yl}-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






730
3-cyclobutyl-1-phenyl-4-{4-[2-
HP10,
J10
503
504



(piperidin-1-yl)ethoxy]piperidin-1-
917003-






yl}-1H-pyrazolo[3,4-b]pyridine-6-
52-2






carboxylic acid






731
3-cyclobutyl-4-{4-[3-
HP10,
J10
489
490



(diethylamino)propyl]piperidin-1-yl}-
127425-






1-phenyl-1H-pyrazolo[3,4-b]pyridine-
06-3






6-carboxylic acid






732
3-cyclobutyl-1-phenyl-4-{4-[3-
HP10,
J10
501
502



(piperidin-1-yl)propyl]piperidin-1-
122373-






yl}-1H-pyrazolo[3,4-b]pyridine-6-
82-4






carboxylic acid






733
3-cyclobutyl-1-phenyl-4-{4-[3-
HP10,
J10
487
488



(pyrrolidin-1-yl)propyl]piperidin-1-
933746-






yl}-1H-pyrazolo[3,4-b]pyridine-6-
67-9






carboxylic acid






734
3-cyclobutyl-4-{4-[ethyl(oxetan-3-
HP10,
J10
475
476



yl)amino]piperidin-1-yl}-1-phenyl-
1799768-






1H-pyrazolo[3,4-b]pyridine-6-
49-2






carboxylic acid






735
3-cyclobutyl-4-{4-[methyl(oxetan-3-
HP10,
J10
461
462



yl)amino]piperidin-1-yl}-1-phenyl-
1257293-






1H-pyrazolo[3,4-b]pyridine-6-
68-7






carboxylic acid






736
3-cyclobutyl-4-[1′-(oxetan-3-yl)[4,4′-
HP10,
J10
515
516



bipiperidin]-1-yl]-1-phenyl-1H-
1628468-






pyrazolo[3,4-b]pyridine-6-carboxylic
88-1






acid






737
3-cyclobutyl-4-[4-
HP10,
J10
419
420



(dimethylamino)piperidin-1-yl]-1-
50533-






phenyl-1H-pyrazolo[3,4-b]pyridine-6-
97-6






carboxylic acid






738
3-cyclobutyl-4-[4-(4-
E384
J1
500
501



cyclopropylpiperazin-1-yl)piperidin-







1-yl]-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






739
3-cyclobutyl-4-[4-(4-
HP10,
J10
502
503



methylpiperazine-1-
63214-






carbonyl)piperidin-1-yl]-1-phenyl-
56-2






1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






740
1-(4-fluorophenyl)-4-[3-(4-
HP11
J10
453
454



methylmorpholin-2-yl)azetidin-1-yl]-







3-(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






741
4-{4-[1-(2-ethoxyethyl)piperidin-4-
HP11
J10
538
539



yl]piperazin-1-yl}-1-(4-







fluorophenyl)-3-(propan-2-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






742
1-(4-fluorophenyl)-4-{4-[1-(2-
HP11
J10
524
525



hydroxypropyl)piperidin-4-







yl]piperazin-1-yl}-3-(propan-2-yl)-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






743
4-[4-(1-cyclopropylpiperidin-4-
HP11,
J10
506
507



yl)piperazin-1-yl]-1-(4-fluorophenyl)-
775287-






3-(propan-2-yl)-1H-pyrazolo[3,4-
98-4






b]pyridine-6-carboxylic acid






744
1-(4-fluorophenyl)-4-{4-[4-(oxetan-3-
HP11,
J10
522
523



yl)piperazin-1-yl]piperidin-1-yl}-3-
1628468-






(propan-2-yl)-1H-pyrazolo[3,4-
86-9






b]pyridine-6-carboxylic acid






745
4-{4-[4-(2-ethoxyethyl)piperazin-1-
HP11
J10
538
539



yl]piperidin-1-yl}-1-(4-fluorophenyl)-







3-(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






746
1-(4-fluorophenyl)-4-{4-[4-(2-
HP11
J10
524
525



methoxyethyl)piperazin-1-







yl]piperidin-1-yl}-3-(propan-2-yl)-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






747
4-{4-[3-
HP11,
J10
495
496



(diethylamino)propyl]piperidin-1-yl}-
127425-






1-(4-fluorophenyl)-3-(propan-2-yl)-
06-3






1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






748
1-(4-fluorophenyl)-4-{4-[3-
HP11,
J10
507
508



(piperidin-1-yl)propyl]piperidin-1-
122373-






yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-
82-4






b]pyridine-6-carboxylic acid






749
1-(4-fluorophenyl)-3-(propan-2-yl)-4-
HP11,
J10
493
494



{4-[3-(pyrrolidin-1-
933746-






yl)propyl]piperidin-1-yl}-1H-
67-9






pyrazolo[3,4-b]pyridine-6-carboxylic







acid






750
4-{4-[ethyl(oxetan-3-
HP11,
J10
481
482



yl)amino]piperidin-1-yl}-1-(4-
1799768-






fluorophenyl)-3-(propan-2-yl)-1H-
49-2






pyrazolo[3,4-b]pyridine-6-carboxylic







acid






751
1-(4-fluorophenyl)-4-{4-
HP11,
J10
467
468



[methyl(oxetan-3-yl)amino]piperidin-
1257293-






1-yl}-3-(propan-2-yl)-1H-
68-7






pyrazolo[3,4-b]pyridine-6-carboxylic







acid






752
1-(4-fluorophenyl)-4-[1′-(oxetan-3-
HP11,
J10
521
522



yl)[4,4′-bipiperidin]-1-yl]-3-(propan-
1628468-






2-yl)-1H-pyrazolo[3,4-b]pyridine-6-
88-1






carboxylic acid






753
1-(4-fluorophenyl)-4-[4-(4-
HP11,
J10
480
481



methylpiperazin-1-yl)piperidin-1-yl]-
53617-






3-(propan-2-yl)-1H-pyrazolo[3,4-
36-0






b]pyridine-6-carboxylic acid






754
4-[4-(4-cyclopropylpiperazin-1-
HP11,
J10
506
507



yl)piperidin-1-yl]-1-(4-fluorophenyl)-
775288-






3-(propan-2-yl)-1H-pyrazolo[3,4-
31-8






b]pyridine-6-carboxylic acid






755
1-(4-fluorophenyl)-4-[4-(4-
HP11,
J10
508
509



methylpiperazine-1-
63214-






carbonyl)piperidin-1-yl]-3-(propan-2-
56-2






yl)-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






756
1-(4-fluorophenyl)-4-[4-(morpholin-
HP11,
J10
467
468



4-yl)piperidin-1-yl]-3-(propan-2-yl)-
442563-






1H-pyrazolo[3,4-b]pyridine-6-
55-5






carboxylic acid






757
3-cyclobutyl-4-[4-(4-methylpiperazin-
HP10,
J10
474
475



1-yl)piperidin-1-yl]-1-phenyl-1H-
53617-






pyrazolo[3,4-b]pyridine-6-carboxylic
36-0






acid






758
1-(4-fluorophenyl)-4-(3-{4-
HP11,
J10
522
523



[methyl(oxetan-3-yl)amino]piperidin-
1799768-






1-yl}azetidin-1-yl)-3-(propan-2-yl)-
53-8






1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






759
1-(4-fluorophenyl)-4-{3-[4-
HP11,
J10
522
523



(morpholin-4-yl)piperidin-1-
1799768-






yl]azetidin-1-yl}-3-(propan-2-yl)-1H-
55-0






pyrazolo[3,4-b]pyridine-6-carboxylic







acid






760
4-{4-[3-
HP11,
J10
468
469



(dimethylamino)propyl]piperazin-1-
877-96-3






yl}-1-(4-fluorophenyl)-3-(propan-2-







yl)-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






761
1-(4-fluorophenyl)-4-[4-methyl-4-(4-
HP11,
J10
494
495



methylpiperazin-1-yl)piperidin-1-yl]-
930604-






3-(propan-2-yl)-1H-pyrazolo[3,4-
01-6






b]pyridine-6-carboxylic acid






762
1-(4-fluorophenyl)-4-{4-[2-
HP11,
J10
509
510



(piperidin-1-yl)ethoxy]piperidin-1-
917003-






yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-
52-2






b]pyridine-6-carboxylic acid






763
1-(4-fluorophenyl)-5-methyl-4-[4-
HP27,
J10,
481
482



(morpholin-4-yl)piperidin-1-yl]-3-
53617-
Specific





(propan-2-yl)-1H-pyrazolo[3,4-
35-9
example





b]pyridine-6-carboxylic acid






764
1-cyclohexyl-4-[4-(4-
E474
J1
506
506



methylpiperazine-1-carbonyl)phenyl]-







3-[(propan-2-yl)oxy]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






765
1-(4-fluorophenyl)-4-[3-(morpholin-
HP11,
J10
439
440



4-yl)azetidin-1-yl]-3-(propan-2-yl)-
302355-






1H-pyrazolo[3,4-b]pyridine-6-
79-9






carboxylic acid






766
1-(4-fluorophenyl)-3-(propan-2-yl)-4-
HP11,
J10
439
440



(4-propyl-1,4-diazepan-1-yl)-1H-
3619-74-






pyrazolo[3,4-b]pyridine-6-carboxylic
7






acid






767
4-(4-cyclobutyl-1,4-diazepan-1-yl)-1-
HP11,
J10
451
452



(4-fluorophenyl)-3-(propan-2-yl)-1H-
851049-






pyrazolo[3,4-b]pyridine-6-carboxylic
21-3






acid






768
4-(4-butyl-1,4-diazepan-1-yl)-1-(4-
HP11,
J10
453
454



fluorophenyl)-3-(propan-2-yl)-1H-
3619-75-






pyrazolo[3,4-b]pyridine-6-carboxylic
8






acid






769
1-(4-fluorophenyl)-4-(4-methyl-1,4-
HP11,
J10
411
412



diazepan-1-yl)-3-(propan-2-yl)-1H-
4318-37-






pyrazolo[3,4-b]pyridine-6-carboxylic
0






acid






770
1-(4-fluorophenyl)-4-[(8aR)-
HP11,
J10
423
424



hexahydropyrrolo[1,2-a]pyrazin-
96193-






2(1H)-yl]-3-(propan-2-yl)-1H-
27-0






pyrazolo[3,4-b]pyridine-6-carboxylic







acid






771
4-(4-acetylpiperazin-1-yl)-1-(4-
HP11,
J10
425
426



fluorophenyl)-3-(propan-2-yl)-1H-
13889-






pyrazolo[3,4-b]pyridine-6-carboxylic
98-0






acid






772
4-(4-ethylpiperazin-1-yl)-1-(4-
HP11,
J10
411
412



fluorophenyl)-3-(propan-2-yl)-1H-
5308-25-






pyrazolo[3,4-b]pyridine-6-carboxylic
8






acid






773
1-(4-fluorophenyl)-4-[4-(2-
HP11,
J10
427
428



hydroxyethyl)piperazin-1-yl]-3-
103-76-4






(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






774
4-[4-(dimethylcarbamoyl)piperazin-1-
HP11,
J10
454
455



yl]-1-(4-fluorophenyl)-3-(propan-2-
41340-






yl)-1H-pyrazolo[3,4-b]pyridine-6-
78-7






carboxylic acid






775
4-[4-(ethoxyacetyl)piperazin-1-yl]-1-
HP11,
J10
469
470



(4-fluorophenyl)-3-(propan-2-yl)-1H-
95550-






pyrazolo[3,4-b]pyridine-6-carboxylic
07-5






acid






776
1-(4-fluorophenyl)-4-[4-(3-
HP11,
J10
455
456



methoxypropyl)piperazin-1-yl]-3-
88708-






(propan-2-yl)-1H-pyrazolo[3,4-
40-1






b]pyridine-6-carboxylic acid






777
1-(4-fluorophenyl)-3-(propan-2-yl)-4-
HP11,
J10
425
426



(4-propylpiperazin-1-yl)-1H-
21867-






pyrazolo[3,4-b]pyridine-6-carboxylic
64-1






acid






778
1-(4-fluorophenyl)-4-{4-[2-(2-
HP11,
J10
471
472



hydroxyethoxy)ethyl]piperazin-1-yl}-
13349-






3-(propan-2-yl)-1H-pyrazolo[3,4-
82-1






b]pyridine-6-carboxylic acid






779
1-(4-fluorophenyl)-4-{4-[3-(4-
HP11,
J10
551
552



methyl-1,4-diazepan-1-yl)-3-
775288-






oxopropyl]piperazin-1-yl}-3-(propan-
10-3






2-yl)-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






780
4-[4-(cyclohexylmethyl)piperidin-1-
HP11,
J10
478
479



yl]-1-(4-fluorophenyl)-3-(propan-2-
78197-






yl)-1H-pyrazolo[3,4-b]pyridine-6-
28-1






carboxylic acid






781
1-(4-fluorophenyl)-4-(9-methyl-3,9-
HP11,
J10
465
466



diazaspiro[5.5]undecan-3-yl)-3-
13323-






(propan-2-yl)-1H-pyrazolo[3,4-
45-0






b]pyridine-6-carboxylic acid






782
4-(1,4-dioxa-8-azaspiro[4.5]decan-8-
HP11,
J10
440
441



yl)-1-(4-fluorophenyl)-3-(propan-2-
177-11-7






yl)-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






783
1-(4-fluorophenyl)-4-[(3R)-3-
HP11,
J10
398
399



hydroxypiperidin-1-yl]-3-(propan-2-
62414-






yl)-1H-pyrazolo[3,4-b]pyridine-6-
68-0






carboxylic acid






784
1-(4-fluorophenyl)-4-(4′-methyl [1,4′-
HP11,
J10
479
480



bipiperidin]-1′-yl)-3-(propan-2-yl)-
801979-






1H-pyrazolo[3,4-b]pyridine-6-
80-6






carboxylic acid






785
1-(4-fluorophenyl)-4-{4-[2-(4-
HP11,
J10
508
509



methylpiperazin-1-yl)ethyl]piperidin-
775288-






1-yl}-3-(propan-2-yl)-1H-
46-5






pyrazolo[3,4-b]pyridine-6-carboxylic







acid






786
1-(4-fluorophenyl)-4-[(3R)-3-
HP11,
J10
451
452



(piperidin-1-yl)pyrrolidin-1-yl]-3-
913812-






(propan-2-yl)-1H-pyrazolo[3,4-
09-6






b]pyridine-6-carboxylic acid






787
4-[4-(diethylamino)piperidin-1-yl]-1-
HP11,
J10
453
454



(4-fluorophenyl)-3-(propan-2-yl)-1H-
143300-






pyrazolo[3,4-b]pyridine-6-carboxylic
64-5






acid






788
4-(4-tert-butylpiperazin-1-yl)-1-(4-
HP11,
J10
439
440



fluorophenyl)-3-(propan-2-yl)-1H-
38216-






pyrazolo[3,4-b]pyridine-6-carboxylic
72-7






acid






789
1-(4-fluorophenyl)-3-(propan-2-yl)-4-
HP11,
J10
479
480



{4-[1-(pyrrolidin-1-yl)ethyl]piperidin-
933682-






1-yl}-1H-pyrazolo[3,4-b]pyridine-6-
80-5






carboxylic acid






790
1-(4-fluorophenyl)-4-{4-[(piperidin-
HP11,
J10
479
480



1-yl)methyl]piperidin-1-yl}-3-
32470-






(propan-2-yl)-1H-pyrazolo[3,4-
52-3






b]pyridine-6-carboxylic acid






791
1-(4-fluorophenyl)-4-{4-[(1-
HP11,
J10
494
495



methylpiperidin-3-
496808-






yl)methyl]piperazin-1-yl}-3-(propan-
03-8






2-yl)-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






792
1-(4-fluorophenyl)-4-{4-[(oxolan-2-
HP11,
J10
467
468



yl)methyl]piperazin-1-yl}-3-(propan-
82500-






2-yl)-1H-pyrazolo[3,4-b]pyridine-6-
35-4






carboxylic acid






793
1-(4-fluorophenyl)-4-[4-(1-
HP11,
J10
455
456



methoxypropan-2-yl)piperazin-1-yl]-
682802-






3-(propan-2-yl)-1H-pyrazolo[3,4-
89-7






b]pyridine-6-carboxylic acid






794
1-(4-fluorophenyl)-3-(propan-2-yl)-4-
HP11,
J10
423
424



[3-(pyrrolidin-1-yl)azetidin-1-yl]-1H-
149105-






pyrazolo[3,4-b]pyridine-6-carboxylic
96-4






acid






795
1-(4-fluorophenyl)-3-(propan-2-yl)-4-
HP11,
J10
439
440



[4-(propan-2-yl)-1,4-diazepan-1-yl]-
59039-






1H-pyrazolo[3,4-b]pyridine-6-
61-1






carboxylic acid






796
1-(4-fluorophenyl)-4-[(3aR,6aS)-5-(2-
HP11,
J10
465
466



methylpropyl)hexahydropyrrolo[3,4-
1690154-






c]pyrrol-2(1H)-yl]-3-(propan-2-yl)-
42-7






1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






797
4-(4-ethyl-1,4-diazepan-1-yl)-1-(4-
HP11,
J10
425
426



fluorophenyl)-3-(propan-2-yl)-1H-
3619-73-






pyrazolo[3,4-b]pyridine-6-carboxylic
6






acid






798
1-(4-fluorophenyl)-4-(4-hydroxy-4-
HP11,
J10
483
484



{[methyl(propan-2-
1248808-






yl)amino]methyl}piperidin-1-yl)-3-
74-3






(propan-2-yl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






799
1-(4-fluorophenyl)-4-{4-
HP11,
J10
453
454



[methyl(propan-2-yl)amino]piperidin-
790205-






1-yl}-3-(propan-2-yl)-1H-
01-5






pyrazolo[3,4-b]pyridine-6-carboxylic







acid






800
4-[4-[2-
HP11,
J10
482
483



(diethylamino)ethyl]piperazin-1-yl}-
4038-92-






1-(4-fluorophenyl)-3-(propan-2-yl)-
0






1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






801
1-(4-fluorophenyl)-4-[4-(1-
HP11,
J10
480
481



methylpiperidin-4-yl)piperazin-1-yl]-
23995-






3-(propan-2-yl)-1H-pyrazolo[3,4-
88-2






b]pyridine-6-carboxylic acid






802
3-cyclobutyl-4-(4-{[(3R)-3-
AI28,
J21,
503
504



(methoxymethyl)pyrrolidin-1-
955400-
Specific





yl]methyl}piperidin-1-yl)-1-phenyl-
18-7
example





1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






803
3-cyclobutyl-4-(4-{[(3R)-3-
AI28,
J21
489
490



methoxypyrrolidin-1-
474707-






yl]methyl}piperidin-1-yl)-1-phenyl-
30-7






1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






804
3-cyclobutyl-4-(4-{[(3S)-3-
AI28,
J21
503
504



(methoxymethyl)pyrrolidin-1-
1421050-






yl]methyl}piperidin-1-yl)-1-phenyl-
43-2






1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






805
3-cyclobutyl-1-(4-fluorophenyl)-4-{4-
E460
J1
507
508



[1-(morpholin-4-yl)ethyl]piperidin-1-







yl}-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






806
3-cyclobutyl-1-cyclohexyl-4-{4-
E488
J1
481
482



[(morpholin-4-yl)methyl]piperidin-1-







yl}-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






807
3-cyclobutyl-1-cyclohexyl-4-{4-[2-
E489
J1
495
496



(morpholin-4-yl)ethyl]piperidin-1-







yl}-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






808
3-(cyclobutyloxy)-1-cyclohexyl-4-{4-
E476
J1
491
491



[(morpholin-4-yl)methyl]phenyl}-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






809
3-cyclobutyl-1-cyclohexyl-4-[4-
E475
J1
461
461



(pyridin-4-yl)piperazin-1-yl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






810
3-cyclobutyl-1-(4-fluorophenyl)-4-{4-
E382
J1
507
508



[2-(morpholin-4-yl)ethyl]piperidin-1-







yl}-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






811
1-(4-fluorophenyl)-3-(propan-2-yl)-4-
HP11,
J10,
465
466



{4-[(pyrrolidin-1-yl)methyl]piperidin-
683772-
Specific





1-yl}-1H-pyrazolo[3,4-b]pyridine-6-
11-4
example





carboxylic acid






812
3-cyclobutyl-1-phenyl-4-{4-[1-
HP10,
J10
473
474



(pyrrolidin-1-yl)ethyl]piperidin-1-yl}-
933682-






1H-pyrazolo[3,4-b]pyridine-6-
80-5






carboxylic acid






813
3-cyclobutyl-4-(3-oxo-2,8-
HP10,
J10
445
446



diazaspiro[4.5]decan-2-yl)-1-phenyl-
561314-






1H-pyrazolo[3,4-b]pyridine-6-
57-6






carboxylic acid






814
1-(4-fluorophenyl)-4-{4-[(2-
HP11,
J10
483
484



methylpropoxy)carbonyl]piperazin-1-
23672-






yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-
96-0






b]pyridine-6-carboxylic acid






816
3-cyclobutyl-1-(2-methoxypyridin-4-
E394
J1A
492
493



yl)-4-[4-(morpholin-4-yl)piperidin-1-







yl]-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






817
3-cyclobutyl-4-[4-
E391
J1A
505
506



(methoxymethyl)piperidin-1-yl]-1-[2-







(oxan-4-yl)pyridin-4-yl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






818
3-cyclobutyl-1-phenyl-4-[4-(propan-
E385
J1
419
420



2-yl)piperazin-1-yl]-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






819
3-cyclobutyl-4-[4-(morpholin-4-
E407
J1A
546
547



yl)piperidin-1-yl]-1-[2-(oxan-4-







yl)pyridin-4-yl]-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






820
3-cyclobutyl-1-(3-methylphenyl)-4-
E395
J1A
475
476



[4-(morpholin-4-yl)piperidin-1-yl]-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






821
3-cyclobutyl-1-(4-fluorophenyl)-4-{4-
E491
J1
493
494



[(morpholin-4-yl)methyl]piperidin-1-







yl}-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






822
3-cyclobutyl-1-(3-methoxyphenyl)-4-
E396
J1A
491
492



[4-(morpholin-4-yl)piperidin-1-yl]-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






823
3-cyclobutyl-4-[4-(morpholin-4-
E397
J1A
529
530



yl)piperidin-1-yl]-1-[4-







(trifluoromethyl)phenyl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






824
3-cyclobutyl-1-(4-fluoro-3-
E398
J1A
493
494



methylphenyl)-4-[4-(morpholin-4-







yl)piperidin-1-yl]-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






825
3-cyclobutyl-1-(3-fluorophenyl)-4-[4-
E404
J1A
479
480



(morpholin-4-yl)piperidin-1-yl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






826
3-cyclobutyl-4-[4-(morpholin-4-
E399
J1A
529
530



yl)piperidin-1-yl]-1-[3-







(trifluoromethyl)phenyl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






827
3-cyclobutyl-4-{4-[(3-fluoroazetidin-
AI28,
J21
463
464



1-yl)methyl]piperidin-1-yl}-1-phenyl-
690257-






1H-pyrazolo[3,4-b]pyridine-6-
76-2






carboxylic acid






828
3-cyclobutyl-4-{4-[(3,3-
AI28,
J21
495
496



difluoropyrrolidin-1-
316131-






yl)methyl]piperidin-1-yl}-1-phenyl-
01-8






1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






829
3-cyclobutyl-4-{4-[(3-
AI28,
J21
475
476



methoxyazetidin-1-
110925-






yl)methyl]piperidin-1-yl}-1-phenyl-
17-2






1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






830
3-cyclobutyl-4-{4-[(3,3-
AI28,
J21
509
510



difluoropiperidin-1-
363179-






yl)methyl]piperidin-1-yl}-1-phenyl-
66-2






1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






831
3-cyclobutyl-4-(4-{[3-
AI28,
J21
489
490



(methoxymethyl)azetidin-1-
942400-






yl]methyl}piperidin-1-yl)-1-phenyl-
33-1






1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






832
3-cyclobutyl-4-(4-{[(3R)-3-
AI28,
J21
477
478



fluoropyrrolidin-1-
136725-






yl]methyl}piperidin-1-yl)-1-phenyl-
55-8






1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






833
3-cyclobutyl-4-(4-{[(3S)-3-
AI28,
J21
477
478



fluoropyrrolidin-1-
136725-






yl]methyl}piperidin-1-yl)-1-phenyl-
54-7






1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






834
3-cyclobutyl-4-{4-[(1,4-oxazepan-4-
AI28,
J21
489
490



yl)methyl]piperidin-1-yl}-1-phenyl-
5638-60-






1H-pyrazolo[3,4-b]pyridine-6-
8






carboxylic acid






835
3-cyclobutyl-4-(4-{[3-(2,2-
AI28,
J21
525
526



difluoroethoxy)azetidin-1-
1342279-






yl]methyl}piperidin-1-yl)-1-phenyl-
77-9






1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






836
3-cyclobutyl-4-{4-[(6-oxa-2-
AI28,
J21
515
516



azaspiro[3.5]nonan-2-
1214875-






yl)methyl]piperidin-1-yl}-1-phenyl-
08-7






1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






837
3-cyclobutyl-4-{4-[(6-oxa-2-
AI28,
J21
501
502



azaspiro[3.4]octan-2-
410070-






yl)methyl]piperidin-1-yl}-1-phenyl-
90-5






1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






838
3-cyclobutyl-4-(4-{[(7S,8aS)-7-
AI28,
J21
532
533



fluorohexahydropyrrolo[1,2-
1808069-






a]pyrazin-2(1H)-yl]methyl]piperidin-
12-6






1-yl)-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






839
3-cyclobutyl-4-{4-[(4-formyl-1,4-
AI28,
J21
516
517



diazepan-1-yl)methyl]piperidin-1-yl1-
29053-






1-phenyl-1H-pyrazolo[3,4-b]pyridine-
62-1






6-carboxylic acid






840
3-cyclobutyl-4-{4-[(2-oxa-7-
AI28,
J21
515
516



azaspiro[3.5]nonan-7-
241820-






yl)methyl]piperidin-1-yl}-1-phenyl-
91-7






1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






841
3-cyclobutyl-4-{4-[(4-
AI28,
J21
503
504



methoxypiperidin-1-
4045-24-






yl)methyl]piperidin-1-yl}-1-phenyl-
3






1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






842
3-cyclobutyl-4-{4-[(2-oxa-6-
AI28,
J21
501
502



azaspiro[3.4]octan-6-
220290-






yl)methyl]piperidin-1-yl}-1-phenyl-
68-6






1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






843
3-cyclobutyl-4-{4-[(4-
AI28,
J21
502
503



formylpiperazin-1-
7755-92-






yl)methyl]piperidin-1-yl}-1-phenyl-
2






1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






844
4-{4-[(3-azabicyclo[3.1.0]hexan-3-
AI28,
J21
471
472



yl)methyl]piperidin-1-yl}-3-
285-59-6






cyclobutyl-1-phenyl-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






845
3-cyclobutyl-4-{4-[(5-methyl-6-oxo-
AI28
J21
544
545



2-oxa-5,8-diazaspiro[3.5]nonan-8-







yl)methyl]piperidin-1-yl}-1-phenyl-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






846
3-cyclobutyl-1-(4-fluorophenyl)-4-[4-
E355
J1
481
482



(3-fluoropyrrolidin-1-yl)piperidin-1-







yl]-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






847
4-[4-(3-cyanoazetidin-1-yl)piperidin-
E356
J1
474
475



1-yl]-3-cyclobutyl-1-(4-







fluorophenyl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






848
3-cyclobutyl-1-(4-fluorophenyl)-4-[4-
E357
J1
493
494



(3-methoxypyrrolidin-1-yl)piperidin-







1-yl]-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






849
3-cyclobutyl-4-(4-fluoro[1,4′-
E375
J1
495
496



bipiperidin]-1′-yl)-1-(4-fluorophenyl)-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






850
3-cyclobutyl-4-(4,4-difluoro[1,4′-
E358
J1
513
514



bipiperidin]-1′-yl)-1-(4-fluorophenyl)-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






851
4-[4-(2-cyanomorpholin-4-
E359
J1
504
505



yl)piperidin-1-yl]-3-cyclobutyl-1-(4-







fluorophenyl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






852
3-cyclobutyl-1-(4-fluorophenyl)-4-[4-
E360
J1
491
492



(2-oxa-5-azabicyclo[2.2.1]heptan-5-







yl)piperidin-1-yl]-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






853
3-cyclobutyl-1-(4-fluorophenyl)-4-{4-
E354
J1
523
523



[2-(methoxymethyl)morpholin-4-







yl]piperidin-1-yl}-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






854
3-cyclobutyl-1-(4-fluorophenyl)-4-{4-
E361
J1
507
508



[methyl(oxan-4-yl)amino]piperidin-1-







yl}-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






855
3-cyclobutyl-4-[4-(morpholin-4-
E400
J1A
520
521



yl)piperidin-1-yl]-1-{2-[(propan-2-







yl)oxy]pyridin-4-yl}-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






856
1-[2-(benzyloxy)pyridin-4-yl]-3-
E401
J1A
568
569



cyclobutyl-4-[4-(morpholin-4-







yl)piperidin-1-yl]-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






857
3-cyclobutyl-1-(4-fluorophenyl)-4-
E471
J1
410
411



[(morpholin-4-yl)methyl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






858
3-cyclobutyl-1-(4-fluorophenyl)-4-
E472
J1
423
424



[(4-methylpiperazin-1-yl)methyl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






859
3-cyclobutyl-1-(4-fluorophenyl)-4-
E481
J1
453
453



{[4-(methoxymethyl)piperidin-1-







yl]methyl}-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






860
4-(4-cyano[1,4′-bipiperidin]-1′-yl)-3-
E485
J1
502
503



cyclobutyl-1-(4-fluorophenyl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






861
1-cyclohexyl-4-{4-[4-
E477
J1
534
535



(dimethylamino)piperidine-1-







carbonyl]phenyl}-3-[(propan-2-







yl)oxy]-1H-pyrazolo[3,4-b]pyridine-







6-carboxylic acid






862
3-cyclobutyl-1-(4-fluorophenyl)-4-[3-
E381
J1
519
520



(pyrrolidin-1-yl)-1-oxa-8-







azaspiro[4.5]decan-8-yl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






863
1-cyclohexyl-3-[(propan-2-yl)oxy]-4-
E483
J1
505
506



{4-[4-(propan-2-yl)piperazin-1-







yl]phenyl}-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






864
3-cyclobutyl-1-cyclohexyl-4-[4-(2-
E461
J1
474
475



methylpyridin-4-yl)piperazin-1-yl]-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






865
3-cyclobutyl-1-cyclohexyl-4-{6-[4-
AI24,
J17
502
503



(propan-2-yl)piperazin-1-yl]pyridin-
4318-42-






3-yl}-1H-pyrazolo[3,4-b]pyridine-6-
7






carboxylic acid






866
3-cyclobutyl-1-cyclohexyl-4-{4-[1-
HP25,
J19
488
489



(morpholin-4-yl)ethyl]phenyl}-1H-
1206594-






pyrazolo[3,4-b]pyridine-6-carboxylic
12-8






acid






867
3-cyclobutyl-1-cyclohexyl-4-{4-[4-
HP25,
J19
501
502



(propan-2-yl)piperazin-1-yl]phenyl}-
1073354-






1H-pyrazolo[3,4-b]pyridine-6-
18-3






carboxylic acid






868
3-cyclobutyl-1-cyclohexyl-4-[6-(4-
AI24,
J17,
500
501



cyclopropylpiperazin-1-yl)pyridin-3-
20327-
Specific





yl]-1H-pyrazolo[3,4-b]pyridine-6-
23-5
example





carboxylic acid






869
3-cyclobutyl-1-(4-fluorophenyl)-4-{4-
E362
J1
531
532



[3-(trifluoromethyl)pyrrolidin-1-







yl]piperidin-1-yl 1-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






870
4-[4-(3-cyanopyrrolidin-1-
E363
J1
488
489



yl)piperidin-1-yl]-3-cyclobutyl-1-(4-







fluorophenyl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






871
4-(3-cyano[1,4′-bipiperidin]-1′-yl)-3-
E364
J1
502
503



cyclobutyl-1-(4-fluorophenyl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






872
3-cyclobutyl-4-(3-fluoro[1,4′-
E365
J1
495
496



bipiperidin]-1′-yl)-1-(4-fluorophenyl)-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






873
3-cyclobutyl-1-(4-fluorophenyl)-4-[4-
E366
J1A
479
480



(3-methoxyazetidin-1-yl)piperidin-1-







yl]-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






874
3-cyclobutyl-1-(4-fluorophenyl)-4-[3-
E367
J1A
545
546



(trifluoromethyl)[1,4′-bipiperidin]-1′-







yl]-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






875
3-cyclobutyl-1-(4-fluorophenyl)-4-(3-
E368
J1A
507
508



methoxy[1,4′-bipiperidin]-1′-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






876
3-cyclobutyl-4-[4-(2,2-
E369
J1A
507
508



dimethylmorpholin-4-yl)piperidin-1-







yl]-1-(4-fluorophenyl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






877
3-cyclobutyl-1-cyclohexyl-4-[6-(4-
AI24,
J17
474
475



methylpiperazin-1-yl)pyridin-3-yl]-
109-01-3






1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






878
3-cyclobutyl-1-cyclohexyl-4-{6-[4-
AI24,
J17
518
519



(2-methoxyethyl)piperazin-1-
13484-






yl]pyridin-3-yl}-1H-pyrazolo[3,4-
40-7






b]pyridine-6-carboxylic acid






879
3-cyclobutyl-1-(4-fluorophenyl)-4-{4-
E434
J1
520
521



[4-(propan-2-yl)piperazin-1-







yl]piperidin-1-yl}-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






880
3-cyclobutyl-1-cyclohexyl-4-{4-[4-
E462
J1
508
509



(propan-2-yl)piperazin-1-yl]piperidin-







1-yl}-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






881
4-[(3S)-4-benzyl-3-methylpiperazin-
E463
J1
487
488



1-yl]-3-cyclobutyl-1-cyclohexyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






882
4-[(3R)-4-benzyl-3-methylpiperazin-
E464
J1
487
488



1-yl]-3-cyclobutyl-1-cyclohexyl-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






883
1-cyclohexyl-4-[4-(4-
E506,
J5
477
478



methylpiperazin-1-yl)phenyl]-3-
109-01-3






[(propan-2-yl)oxy]-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






884
1-cyclohexyl-4-{4-[(4-
E482
J1
518
518



cyclopropylpiperazin-1-







yl)methyl]phenyl}-3-[(propan-2-







yl)oxy]-1H-pyrazolo[3,4-b]pyridine-







6-carboxylic acid






885
3-cyclobutyl-1-(2-hydroxypyridin-4-
E402
J1A
478
479



yl)-4-[4-(morpholin-4-yl)piperidin-1-







yl]-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






886
3-cyclobutyl-4-[4-(4-
E465
J1
518
519



cyclopropylpiperazin-1-yl)piperidin-







1-yl]-1-(4-fluorophenyl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






887
3-cyclobutyl-4-(9-cyclopropyl-3,9-
E466
J1
503
504



diazaspiro[5.5]undecan-3-yl)-1-(4-







fluorophenyl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






888
3-cyclobutyl-1-(4-fluorophenyl)-4-{4-
E467
J1
477
478



[(pyrrolidin-1-yl)methyl]piperidin-1-







yl}-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






889
3-cyclobutyl-1-[2-
E403
J1A
528
529



(difluoromethoxy)pyridin-4-yl]-4-[4-







(morpholin-4-yl)piperidin-1-yl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






890
3-cyclobutyl-1-(4-fluorophenyl)-4-[9-
E508
J1′
505
506



(propan-2-yl)-3,9-







diazaspiro[5.5]undecan-3-yl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






891
3-cyclobutyl-4-{4-[4-
E370
J1A
550
551



(ethoxycarbonyl)piperazin-1-







yl]piperidin-1-yl}-1-(4-fluorophenyl)-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






892
3-cyclobutyl-1-(4-fluorophenyl)-4-(4-
E424
J1
507
508



methoxy[1,4′-bipiperidin]-1′-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






893
3-cyclobutyl-1-(4-fluorophenyl)-4-
HP19,
J18,
493
494



{[4-(morpholin-4-yl)piperidin-1-
888711-
Specific





yl]methyl}-1H-pyrazolo[3,4-
44-2
example





b]pyridine-6-carboxylic acid






894
3-cyclobutyl-4-(9-cyclobutyl-3,9-
E504
J1
517
518



diazaspiro[5.5]undecan-3-yl)-1-(4-







fluorophenyl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






895
3-cyclobutyl-1-(4-fluorophenyl)-4-{4-
E376
J1A
481
482



[(2-methoxyethyl)







(methyl)amino]piperidin-







1-yl}-1H-pyrazolo[3,4-b]pyridine-







6-carboxylic acid






896
3-cyclobutyl-1-(4-fluorophenyl)-4-{4-
E468
J1
536
537



[4-(2-methoxyethyl)piperazin-1-







yl]piperidin-1-yl}-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






897
3-cyclobutyl-1-(4-fluorophenyl)-4-[9-
E503
J1
521
522



(2-methoxyethyl)-3,9-







diazaspiro[5.5]undecan-3-yl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






898
3-cyclobutyl-1-(4-fluorophenyl)-4-(4-
E492
J1
493
494



hydroxy[1,4′-bipiperidin]-1′-yl)-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






899
3-cyclobutyl-1-(4-fluorophenyl)-4-{4-
E470
J1
534
535



[4-(oxetan-3-yl)piperazin-1-







yl]piperidin-1-yl}-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






900
3-cyclobutyl-1-(4-fluorophenyl)-4-[1-
E371
J1
477
478



(propan-2-yl)octahydro-5H-







pyrrolo[3,2-c]pyridin-5-yl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






901
3-cyclobutyl-4-(1-
E372
J1
489
490



cyclobutyloctahydro-5H-pyrrolo[3,2-







c]pyridin-5-yl)-1-(4-fluorophenyl)-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






902
3-cyclobutyl-1-(4-fluorophenyl)-4-[1-
E373
J1
491
492



(oxetan-3-yl)octahydro-5H-







pyrrolo[3,2-c]pyridin-5-yl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






903
3-cyclobutyl-1-(4-fluorophenyl)-4-[1-
E374
J1
519
520



(oxan-4-yl)octahydro-5H-pyrrolo[3,2-







c]pyridin-5-yl]-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






904
3-cyclobutyl-1-(4-fluorophenyl)-4-[9-
E469
J1
519
520



(oxetan-3-yl)-3,9-







diazaspiro[5.5]undecan-3-yl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






905
3-cyclobutyl-1-(3,5-difluorophenyl)-
E509
J22
541
498



4-[4-(morpholin-4-yl)piperidin-1-yl]-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






906
3-cyclobutyl-1-(2,2-difluoro-2H-1,3-
E405
J1A
541
542



benzodioxo1-5-yl)-4-[4-(morpholin-4-







yl)piperidin-1-yl]-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






907
3-cyclobutyl-1-(3,4-difluorophenyl)-
E509
J22
497
498



4-[4-(morpholin-4-yl)piperidin-1-yl]-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






908
3-cyclobutyl-1-(4-fluoro-3-
E509
J22
509
510



methoxyphenyl)-4-[4-(morpholin-4-







yl)piperidin-1-yl]-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






909
3-cyclobutyl-4-[4-(morpholin-4-
E509
J22
545
546



yl)piperidin-1-yl]-1-[4-







(trifluoromethoxy)phenyl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






910
3-cyclobutyl-1-[3-
E509
J22,
527
528



(difluoromethoxy)phenyl]-4-[4-

Specific





(morpholin-4-yl)piperidin-1-yl]-1H-

example





pyrazolo[3,4-b]pyridine-6-carboxylic







acid






911
1-(bicyclo[4.2.0]octa-1,3,5-trien-3-
E509
J22
487
488



yl)-3-cyclobutyl-4-[4-(morpholin-4-







yl)piperidin-1-yl]-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






912
3-cyclobutyl-1-(3-fluoro-4-
E509
J22
509
510



methoxyphenyl)-4-[4-(morpholin-4-







yl)piperidin-1-yl]-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






913
3-cyclobutyl-1-(3-fluoro-5-
E509
J22
509
510



methoxyphenyl)-4-[4-(morpholin-4-







yl)piperidin-1-yl]-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






914
3-cyclobutyl-1-[4-
E509
J22
527
528



(difluoromethoxy)phenyl]-4-[4-







(morpholin-4-yl)piperidin-1-yl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






915
3-cyclobutyl-143-(1,1-
E509
J22
525
526



difluoroethyl)phenyl]-4-[4-







(morpholin-4-yl)piperidin-1-yl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






916
3-cyclobutyl-1-(2,5-difluorophenyl)-
E509
J22
497
498



4-[4-(morpholin-4-yl)piperidin-1-yl]-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






917
3-cyclobutyl-146-(2-
E509
J22
524
525



fluoroethoxy)pyridin-3-yl]-4-[4-







(morpholin-4-yl)piperidin-1-yl]-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






918
3-cyclobutyl-4-[4-(morpholin-4-
E509
J22
562
563



yl)piperidin-1-yl]-1-{2-[(oxan-4-







yl)oxy]pyridin-4-yl}-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






919
3-cyclobutyl-4-[4-(morpholin-4-
E509
J22
576
577



yl)piperidin-1-yl]-1-{2-[(oxan-4-







yl)methoxy]pyridin-4-yl}-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






920
3-cyclobutyl-1-(2,4-difluorophenyl)-
E509
J22
497
498



4-[4-(morpholin-4-yl)piperidin-1-yl]-







1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






921
3-cyclobutyl-1-(2,2-difluoro-2H-1,3-
E509
J22
541
542



benzodioxo1-4-yl)-4-[4-(morpholin-4-







yl)piperidin-1-yl]-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






923
4-(4-cyanophenyl)-1-cyclohexyl-3-
436088-
Specific
404
405



[(propan-2-yl)oxy]-1H-pyrazolo[3,4-
86-7,
example





b]pyridine-6-carboxylic acid
ALP37





924
3-cyclobutyl-4-[4-(morpholin-4-
AI23
Specific
520
521



yl)piperidin-1-yl]-1-{6-[(propan-2-

example





yl)oxy]pyridin-2-yl}-1H-







pyrazolo[3,4-b]pyridine-6-carboxylic







acid






925
1-(4-fluorophenyl)-3-hydroxy-4-(4-
AI26
Specific
469
470



methoxy[1,4′-bipiperidin]-1′-yl)-1H-

example





pyrazolo[3,4-b]pyridine-6-carboxylic







acid






926
1-(4-fluorophenyl)-4-(4-
E429
J1A
511
512



methoxy[1,4′-bipiperidin]-1′-yl)-3-







[(propan-2-yl)oxy]-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






927
1-cyclohexyl-4-(4-{[3-
E426
J1A
491
492



(dimethylamino)azetidin-1-







yl]methyl}phenyl)-3-[(propan-2-







yl)oxy]-1H-pyrazolo[3,4-b]pyridine-







6-carboxylic acid






928
3-cyclobutyl-1-(4-fluorophenyl)-4-(9-
E515
J1
477
478



methyl-3,9-diazaspiro[5.5]undecan-3-







yl)-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






929
3-cyclobutyl-4-[4-
E516
J1
467
468



(ethoxycarbonyl)piperazin-1-yl]-1-(4-







fluorophenyl)-1H-pyrazolo[3,4-







b]pyridine-6-carboxylic acid






930
3-cyclobutyl-1-(4-fluorophenyl)-4-{4-
E517
J1
495
496



[(2-







methylpropoxy)carbonyl]piperazin-1-







yl}-1H-pyrazolo[3,4-b]pyridine-6-







carboxylic acid






aEster hydrolysis occurred under the reaction conditions.














TABLE XVI








1H NMR data of selected final compounds









Cpd

1H NMR






 28
(400 MHz, MeOD-d4) δ ppm 8.39 (dd, J = 8.7, 1.0 Hz, 2 H), 7.75-7.85 (m, 1 H),



7.44-7.62 (m, 4 H), 7.23-7.38 (m, 1 H), 6.78 (d, J = 8.7 Hz, 2 H), 5.43 (dt,



J = 53.4, 3.4 Hz, 1 H), 3.47-3.77 (m, 4 H), 2.41 (s, 3 H), 2.39-2.34 (m, 2 H)


 53
(400 MHz, DMSO-d6) δ ppm 8.43 (d, J = 7.7 Hz, 2 H), 7.40-7.62 (m, 5 H), 7.30 (t,



J = 7.3 Hz, 1 H), 7.16 (d, J = 8.9 Hz, 2 H), 3.34-3.47 (m, 4 H), 3.28 (m , 4 H), 2.96



(s, 3 H), 2.32 (s, 3 H)


 60
(400 MHz, DMSO-d6) δ ppm 8.35 (d, J = 7.9 Hz, 2 H), 7.76 (s, 1 H), 7.59 (t, J =



7.9 Hz, 2 H), 7.53 (d, J = 8.7 Hz, 2 H), 7.29-7.44 (m, 1 H), 7.12 (d, J = 8.7 Hz, 2 H),



3.32-3.31 (m, J = 5.5 Hz, 4 H), 2.68-2.74 (m, 4 H), 2.40 (s, 3 H), 1.10 (s, 9 H)


 68
(400 MHz, CDCl3) δ ppm 7.93 (s, 1 H), 7.38-7.52 (m, 2 H), 6.98-7.10 (m, 2 H),



5.08 (tt, J = 10.9, 4.3 Hz, 1 H), 4.04-4.20 (m, 2 H), 3.81-4.00 (m, 5 H), 3.60 (td,



J = 11.2, 3.4 Hz, 1 H), 3.28-3.37 (m, 4 H), 3.19 (quin, J = 6.8 Hz, 1 H), 2.34-2.57



(m, 1 H), 2.25 (m, J = 12.6 Hz, 1 H), 1.86-2.08 (m, 2 H), 1.16 (dd, J = 6.8, 2.0 Hz,



6 H)


 69
(400 MHz, CDCl3) δ ppm 7.90 (s, 1 H), 7.39-7.51 (m, 2 H), 6.95-7.10 (m, 2 H),



5.43 (quin, J = 7.3 Hz, 1 H), 3.86-4.03 (m, 4 H), 3.26-3.40 (m, 4 H), 3.18 (quin,



J = 6.8 Hz, 1 H), 2.12-2.30(m, 4H), 1.94-2.12(m, 2 H), 1.70-1.89 (m, 2H),



1.16 (d, J = 6.8 Hz, 6 H)


 70
(400 MHz, CDCl3) δ ppm 8.01-8.21 (m, 3 H), 7.56-7.70 (m, 2 H), 7.51 (d, J = 8.5



Hz, 2 H), 7.37-7.45 (m, 1 H), 7.10 (d, J = 8.7 Hz, 2 H), 3.78 (br. s., 3 H), 3.72 (d,



J = 4.6 Hz, 4 H), 3.28-3.46 (m, 4 H), 2.49 (s, 3 H)


 71
(400 MHz, CDCl3) δ ppm 7.94 (s, 1 H), 7.41-7.51 (m, 2 H), 7.05 (m, 2 H), 5.15



(ddd, J = 10.9, 6.6, 4.5 Hz, 1 H), 4.80 (d, J = 13.7 Hz, 1 H), 4.08 (d, J = 14.8 Hz,



1 H),



3.84-3.99 (m, 4 H), 3.35-3.48 (m, 1 H), 3.25-3.35 (m, 4 H), 3.19 (dt, J = 13.6,



6.8 Hz, 1 H), 2.91-3.07 (m, 1 H), 2.26-2.48 (m, 2 H), 2.24 (s, 3 H), 2.11 (t,



J = 14.2 Hz, 2 H), 1.15 (dd, J = 6.8, 4.3 Hz, 6 H)


 73
(400 MHz, DMSO-d6) δ ppm 8.34 (d, J = 8.0 Hz, 2 H), 7.75 (s, 1 H), 7.59 (m,



J = 7.9, 7.9 Hz, 2 H), 7.48 (d, J = 8.4 Hz, 2 H), 7.25-7.44 (m, 1 H), 6.58 (d, J = 8.5



Hz, 2 H), 3.66 (s, 4H), 2.41 (s, 3 H), 1.33 (s, 6 H)


 80
(400 MHz, CDCl3) δ ppm 8.49 (s, 1 H), 7.83 (s, 1 H), 4.97-4.62 (m, 1 H), 4.01-



3.88 (m, 4 H), 3.88-3.71 (m, 4 H), 3.14 (quin, J = 6.8 Hz, 1 H), 2.28-1.90 (m, 6



H), 1.81 (d, J = 13.0 Hz, 1 H), 1.63-1.32 (m, 3 H), 1.28-1.08 (m, 6 H)


 82
(400 MHz, DMSO-d6) δ ppm 8.37 (d, J = 7.9 Hz, 2 H), 7.73 (s, 1 H), 7.44-7.66 (m,



4 H), 7.29-7.37 (m, 1 H), 7.13 (m, J = 8.0 Hz, 2 H), 3.33-3.51 (m, 8 H), 2.60 (br.



s., 4 H), 2.38 (s, 3 H)


 85
(400 MHz, CDCl3) δ ppm 8.41 (d, J = 2.2 Hz, 1 H), 7.98 (s, 1 H), 7.73 (dd, J = 8.9,



2.4 Hz, 1 H), 7.32-7.54 (m, 3 H), 6.69-6.91 (m, 2 H), 3.86-4.07 (m, 4 H), 3.54-



3.78 (m, 4 H), 3.27 (quin, J = 6.8 Hz, 1 H), 3.09 (s, 6 H), 1.26 (d, J = 6.8 Hz, 6 H)


 95
(400 MHz, CDCl3) 6 ppm 7.93 (s, 1 H), 7.45 (d, J = 8.7 Hz, 2 H), 7.05 (d, J = 8.7



Hz, 2 H), 4.88-5.04 (m, 1 H), 3.88-4.03 (m, 4 H), 3.68 (s, 2 H), 3.28-3.41 (m, 4 H),



3.19 (dt, J = 13.5, 6.8 Hz, 1 H), 3.08 (d, J = 11.6 Hz, 2 H), 2.66-2.82 (m, 2 H),



2.46-2.64 (m, 2 H), 2.13 (d, J = 10.9 Hz, 2 H), 1.16 (d, J = 6.8 Hz, 6 H)


 96
(400 MHz, CDCl3) 6 ppm 8.21-7.89 (m, 3 H), 7.58 (t, J = 7.7 Hz, 2 H), 7.45-7.31



(m, 3 H), 6.68-6.67 (m, 1 H), 6.69 (d, J = 8.4 Hz, 2 H), 4.03 (t, J = 7.4 Hz, 1 H),



2.65-2.39 (m, 5 H), 1.99-1.78 (m, 4 H)


 97
(400 MHz, DMSO-d6) δ ppm 8.26-8.42 (m, 2 H), 7.78 (s, 1 H), 7.51-7.67 (m, 4



H), 7.28-7.43 (m, 1 H), 6.77 (d, J = 8.6 Hz, 2 H), 4.41 (t, J = 12.4 Hz, 4 H), 2.39 (s,



3H)


 98
(400 MHz, DMSO-d6) δ ppm 8.35 (m, 2 H), 7.77 (s, 1 H), 7.45-7.66 (m, 4 H),



7.31-7.39 (m, 1 H), 7.16 (d, J = 8.7 Hz, 2 H), 4.09 (br. s., 4 H), 3.84 (s, 2 H), 2.59-



2.78 (m, 4 H), 2.39 (s, 3 H)


108
(400 MHz, DMSO-d6) δ ppm 8.35 (d, J = 8.1 Hz, 2 H), 7.79 (s, 1 H), 7.49-7.66 (m,



4 H), 7.28-7.45 (m, 1 H), 7.21 (d, J = 8.5 Hz, 2 H), 3.51 (s, 4 H), 2.40 (s, 3 H),



1.96-2.20 (m, 4 H)


109
(400 MHz, DMSO-d6) δ ppm 8.34 (d, J = 7.9 Hz, 2 H), 7.78 (s, 1 H), 7.46-7.66 (m,



4 H), 7.29-7.43 (m, 1 H), 7.15 (d, J = 8.7 Hz, 2H), 3.47-3.62 (m, 2H), 3.15-



3.24 (m, 2 H), 3.04-3.12 (m, 1H), 2.39 (s, 3 H), 1.95-2.18 (m, 2 H), 1.76-1.93



(m, 2 H)


110
(400 MHz, CDCl3) 6 ppm 8.02-8.14 (m, 3 H), 7.61 (t, J = 7.9 Hz, 2 H), 7.49 (d,



J = 8.9 Hz, 2 H), 7.35-7.46 (m, 1 H), 6.97 (d, J = 8.9 Hz, 2 H), 4.17 (dd, J = 11.3,



4.4 Hz, 2 H), 3.93-4.09 (m, 1 H), 3.52-3.66 (m, 2 H), 2.96 (s, 3 H), 2.55 (s, 3 H),



1.89-2.07 (m, 2 H), 1.80 (dd, J = 12.6, 1.9 Hz, 2 H)


111
(400 MHz, DMSO-d6) δ ppm 8.27-8.43 (m, 2 H), 7.77 (s, 1 H), 7.48-7.67 (m, 4



H), 7.29-7.44 (m, 1 H), 6.81 (d, J = 8.7 Hz, 2 H), 3.82 (t, J = 13.3 Hz, 2 H), 3.61 (t,



J = 7.3 Hz, 2 H), 2.60 (tt, J = 14.5, 7.2 Hz, 2 H), 2.40 (s, 3 H)


112
(400 MHz, CDCl3) δ ppm 8.20-7.94 (m, 3 H), 7.58 (t, J = 7.8 Hz, 2 H), 7.41 (d,



J = 8.4 Hz, 3 H), 6.66 (d, J = 8.4 Hz, 2 H), 5.08 (t, J = 6.6 Hz, 2 H), 4.74 (br. s.,



1 H), 4.67-4.55 (m, 2 H), 4.53-4.41 (m, 1 H), 2.47 (s, 3 H)


113
(400 MHz, DMSO-d6) δ ppm 8.31 (d, J = 8.2 Hz, 2 H), 7.72 (s, 1 H), 7.61 (t, J = 7.5



Hz, 2 H), 7.45-7.24 (m, 3 H), 7.12 (d, J = 8.0 Hz, 2 H), 5.03 (d, J = 5.5 Hz, 2 H),



4.04 (d, J = 5.5 Hz, 2 H), 3.79 (br. s., 4 H), 3.25 (br. s., 4 H), 1.44 (s, 3 H)


115
(400 MHz, CDCl3) δ ppm 8.20-7.89 (m, 3 H), 7.66-7.50 (m, 2 H), 7.48-7.32



(m, 3 H), 6.90 (d, J = 8.7 Hz, 2 H), 4.19 (t, J = 8.5 Hz, 1 H), 3.11-2.84 (m, 3 H),



2.51 (s, 3 H), 2.41-2.31 (m, 2 H), 2.27-2.12 (m, 2 H), 1.86-1.69 (m, 2 H)


116
(400 MHz, METHANOL-d4) δ ppm 8.32 (d, J = 7.5 Hz, 2 H), 7.86 (s, 1 H), 7.54 (t,



J = 7.2 Hz, 2 H), 7.45 (d, J = 8.0 Hz, 2 H), 7.22-7.37 (m, 1 H), 6.76 (d, J = 8.2 Hz,



2 H), 4.28 (br. s., 2 H), 3.62-3.82 (m, 2 H), 3.36-3.42 (m, 2 H), 2.42 (br. s., 3 H)


117
(400 MHz, CDCl3) δ ppm 7.91 (br. s., 1 H), 7.44 (br. s., 2 H), 7.04 (br. s., 2 H),



4.89 (br. s., 1 H), 3.94 (br. s., 4 H), 3.32 (br. s., 4 H), 2.97-3.23 (m, 4 H), 2.72 (br.



s., 2 H), 2.55 (br. s., 2H), 2.39 (s, 1 H), 1.88-2.15 (m, 2H), 1.00-1.22 (m, 6 H)


118
(400 MHz, CDCl3) δ ppm 7.97 (d, J = 7.9 Hz, 2 H), 7.54 (t, J = 7.9 Hz, 2 H), 7.48



(s, 1 H), 7.37 (t, J = 7.9 Hz, 1 H), 3.98-3.94 (m, 4 H), 3.40-3.37 (m, 4 H),



2.75 (s, 3 H)


119
(400 MHz, CDCl3) δ ppm 7.98-8.15 (m, 3 H), 7.61 (t, J = 7.9 Hz, 2 H), 7.37-7.55



(m, 3 H), 7.06 (d, J = 8.7 Hz, 2 H), 3.88-4.05 (m, 2 H), 3.22-3.34 (m, 2 H), 3.15



(s, 2 H), 2.51 (s, 3 H), 1.41 (s, 6 H)


120
(300 MHz, CDCl3) δ ppm 7.94 (s, 1 H), 7.46 (m, J = 8.8 Hz, 2 H), 7.06 (m, J = 8.8



Hz, 2 H), 5.61-5.80 (m, 1 H), 4.26-4.38 (m, 2 H), 4.07-4.24 (m, 2 H), 3.88-



4.03 (m, 4 H), 3.28-3.40 (m, 4 H), 3.20 (dt, J = 13.7, 6.8 Hz, 1 H), 2.42-2.70 (m,



2 H), 1.06-1.24 (m, 6 H)


121
(300 MHz, CDCl3) δ ppm 7.98 (s, 1 H), 7.59-7.57 (m, 2 H), 7.46-7.42 (m, 3 H),



7.03 (d, J = 8.6 Hz, 2 H), 6.94-6.90 (m, 1 H), 3.94-3.89 (m, 8H), 3.32-3.18 (m,



9 H), 1.20 (d, J = 6.8 Hz, 6 H)


122
(400 MHz, DMSO-d6) δ ppm 8.31 (d, J = 8.5 Hz, 2 H), 7.83 (s, 1 H), 7.72-7.55



(m, 4 H), 7.49-7.33 (m, 1 H), 7.14 (d, J = 8.4 Hz, 2 H), 4.51 (s, 2 H), 3.79 (d,



J = 3.8 Hz, 4 H), 3.26 (d, J = 4.1 Hz, 4 H), 3.15 (s, 3 H)


123
(400 MHz, CDCl3) δ ppm 7.98 (d, J = 7.7 Hz, 2 H), 7.52 (t, J = 7.7 Hz, 2 H), 7.46



(s, 1 H), 7.35 (t, J = 7.7 Hz, 1 H), 3.37-3.34 (m, 4 H), 2.75 (s, 3 H), 1.86-1.81



(m, 4 H), 1.75-1.69 (m, 2H)


124
(400 MHz, CDCl3) δ ppm 8.07 (d, J = 1.2 Hz, 1 H), 8.05 (d, J = 1.0 Hz, 1 H), 8.02



(s, 1 H), 7.58 (t, J = 7.9 Hz, 2 H), 7.45-7.38 (m, 3 H), 6.65-6.57 (m, 2 H), 4.91-



4.81 (m, 1 H), 4.34-4.26 (m, 2H), 3.84 (dd, J = 9.0, 4.4 Hz, 2 H), 2.47 (s, 3 H)



(2xOH missing)


125
(400 MHz, CDCl3) δ ppm 8.06 (d, J = 7.8 Hz, 2 H), 8.02 (s, 1 H), 7.58 (t, J = 7.8



Hz, 2 H), 7.48-7.36 (m, 3 H), 6.62 (d, J = 8.6 Hz, 2 H), 5.62-5.39 (m, 1 H), 4.38-



4.25 (m, 2 H), 4.18-4.02 (m, 2 H), 2.47 (s, 3 H) (OH missing)


126
(400 MHz, CDCl3) δ ppm 8.05 (dd, J = 8.4, 1.1 Hz, 2 H), 8.01 (s, 1 H), 7.61-7.53



(m, 2 H), 7.45-7.36 (m, 3 H), 6.63-6.55 (m, 2 H), 4.90 (s, 4 H), 4.16 (s, 4 H), 2.45



(s, 3 H) (OH missing)


127
(400 MHz, CDCl3) δ ppm 10.75 (br. s., 1 H), 8.16-7.92 (m, 3 H), 7.66-7.51 (m, 2



H), 7.49-7.33 (m, 3 H), 6.74 (d, J = 7.8 Hz, 2 H), 4.74 (br. s., 1 H), 4.54 (br. s., 1



H), 4.12-3.85 (m, 2 H), 3.64 (d, J = 8.8 Hz, 1 H), 3.31 (d, J = 9.0 Hz, 1 H), 2.50 (s,



3 H), 2.07 (d, J = 9.3 Hz, 2 H) (OH missing)


128
(300 MHz, CDCl3) δ ppm 8.05-7.80 (m, 3 H), 7.56-7.40 (m, 2 H), 7.34-7.26



(m, 1 H), 6.02-5.94 (m, 1 H), 4.45-4.35 (m, 2 H), 4.08-3.96 (m, 2 H), 2.66 (s,



3 H),2.61-2.52 (m, 2H)


129
(400 MHz, DMSO-d6) δ ppm 8.49-8.07 (m, 2 H), 7.80 (s, 1 H), 7.65-7.51 (m, 4



H), 7.39-7.29 (m, 1 H), 7.13 (d, J = 8.9 Hz, 2 H), 3.84-3.70 (m, 4 H), 3.29-3.17



(m, 4 H), 1.36-1.21 (m, 2 H), 0.81 (s, 3 H), 0.68-0.57 (m, 2 H)


130
(400 MHz, DMSO-d6) δ ppm 13.50 (s, 1 H), 8.37 (d, J = 8.1 Hz, 2 H), 7.74 (s, 1 H),



7.60 (t, J = 7.8 Hz, 2 H), 7.47 (d, J = 8.5 Hz, 2 H), 7.37 (t, J = 7.3 Hz, 1 H), 7.14 (d,



J = 8.7 Hz, 2 H), 3.83-3.76 (m, 4 H), 3.69 (pent, J = 8.4 Hz, 1 H), 3.29-3.22 (m, 4



H), 2.34-2.21 (m, 2 H), 2.00-1.89 (m, 2 H), 1.88-1.74 (m, 2 H)


131
(400 MHz, CDCl3) δ ppm 7.78 (s, 1 H), 7.25-7.10 (m, 2 H), 6.78 (d, J = 8.7 Hz, 2



H), 5.01-4.53 (m, 1 H), 3.16-2.93 (m, 6H), 2.22-1.91 (m, 6H), 1.81 (d, J = 12.6



Hz, 1 H), 1.65-1.47 (m, 2 H), 1.46-1.27 (m, 1 H), 1.24-1.08 (m, 9 H)


132
(300 MHz, DMSO-d6) δ ppm 13.31 (s, 1 H), 8.29 (d, J = 7.6 Hz, 2 H), 7.55 (t, J =



7.6 Hz, 2 H), 7.35-7.29 (m, 2H), 3.74-3.66 (m, 4H), 3.38-3.30 (m, 4H), 2.71 (s,



3 H), 2.08 (s, 3 H)


133
(400 MHz, CDCl3) δ ppm 10.71 (s, 1 H), 8.05 (br. s., 3 H), 7.76-6.95 (m, 5 H),



6.86-6.24 (m, 2 H), 4.02 (br. s., 4 H), 2.48 (br. s., 8 H)


134
(400 MHz, CDCl3) δ ppm 8.13-7.97 (m, 3 H), 7.58 (t, J = 7.9 Hz, 2 H), 7.47 (d, J =



8.6 Hz, 2 H), 7.42-7.35 (m, 1 H), 6.95 (d, J = 8.8 Hz, 2 H), 4.69 (s, 1 H), 4.56 (br.



s., 2H), 3.52-3.40 (m, 2H), 3.15 (dd, J = 11.5, 2.4 Hz, 2H), 2.55-2.42 (m, 3 H),



2.11-1.91 (m, 4 H)


135
(400 MHz, methano-d4) δ ppm 8.34 (d, J = 8.1 Hz, 2 H), 7.84 (s, 1 H), 7.54 (t, J =



7.9 Hz, 2 H), 7.44 (d, J = 8.3 Hz, 2 H), 7.37-7.26 (m, 1 H), 6.64 (d, J = 8.6 Hz, 2



H), 3.99 (t, J = 7.2 Hz, 4 H), 2.52-2.35 (m, 5 H) (OH missing)


136
(400 MHz, DMSO-d6) δ ppm 8.28 (d, J = 7.6 Hz, 2 H), 7.55 (t, J = 7.6 Hz, 2 H),



7.34-7.29 (m, 2 H), 3.87 (s, 2 H), 3.38-3.33 (m, 4 H), 2.78-2.73 (m, 4 H), 2.70



(s, 3 H)


137
(400 MHz, DMSO-d6) δ ppm 8.29 (d, J = 7.7 Hz, 2 H), 7.54 (t, J = 7.7 Hz, 2 H),



7.34-7.32 (m, 2 H), 4.82 (s, 1 H), 3.80-3.70 (m, 1 H), 3.58-3.50 (m, 2 H), 3.11-



3.06 (m, 2 H), 2.68 (s, 3 H), 1.99-1.92 (m, 2 H), 1.69-1.58 (m, 2 H)


138
(400 MHz, CDCl3) δ ppm 8.04 (d, J = 7.6 Hz, 2 H), 7.94 (s, 1 H), 7.54 (t, J = 7.6



Hz, 2 H), 7.37 (t, J = 7.6 Hz, 1 H), 4.95-4.87 (m, 1H), 4.11-4.04 (m, 1H), 3.63-3.54



(m, 1H), 3.35-3.24 (m, 1H), 2.84 (s, 3 H), 2.79-2.68 (m, 1 H), 2.19 (s, 3 H),



2.07-1.74 (m, 4 H)


139
(400 MHz, DMSO-d6) δ ppm 8.28 (d, J = 7.6 Hz, 2 H), 7.97 (s, 1 H), 7.57 (t, J = 7.6



Hz, 2 H), 7.35 (t, J = 7.6 Hz, 1 H), 3.81 (s, 2 H), 3.40-3.28 (m, 1 H), 3.02-2.96



(m, 2 H), 2.79 (s, 3 H), 2.47-2.39 (m, 2 H), 2.01-1.93 (m, 2 H), 1.90-1.78 (m, 2H)


140
(400 MHz, CDCl3) δ ppm 8.22-7.87 (m, 3 H), 7.58 (t, J = 7.9 Hz, 2 H), 7.49-7.33



(m, 3 H), 6.78 (d, J = 8.7 Hz, 2 H), 5.03-4.72 (m, 5 H), 3.09 (s, 3 H), 2.48 (s, 3 H)


141
(400 MHz, CDCl3) δ ppm 7.94 (s, 1 H), 7.39-7.54 (m, 2 H), 7.06 (d, J = 8.9 Hz, 2



H), 5.60-5.83 (m, 1 H), 3.91-4.03 (m, 4 H), 3.82 (s, 2 H), 3.29-3.48 (m, 5 H),



3.13-3.29 (m, 3 H), 2.99-3.13 (m, 1 H), 2.48-2.69 (m, 2 H), 1.18 (dd, J = 6.7, 4.9



Hz, 6 H)


142
(400 MHz, CDCl3) δ ppm 7.95 (s, 1 H), 7.44 (d, J = 8.8 Hz, 2 H), 7.05 (d, J = 8.8



Hz, 2H), 5.46-5.78 (m, 1 H), 4.14 (m, J = 12.2 Hz, 1 H), 3.89-4.03 (m, 6 H), 3.59-



3.87 (m, 4 H), 3.28-3.40 (m, 4H), 3.22-3.13 (m, 1 H), 2.69-2.58 (m, J = 6.8 Hz, 1



H), 2.50-2.41 (m, 1 H), 1.14 (m, J = 6.8 Hz, 6 H)


143
(400 MHz, DMSO-d6) δ ppm 8.30 (d, J = 7.6 Hz, 2 H), 7.54 (t, J = 7.6 Hz, 2 H),



7.33-7.22 (m, 2 H), 3.54-3.42 (m, 3 H), 3.31 (s, 3 H), 3.16-3.08 (m, 2 H), 2.68



(s, 3 H), 2.11-2.02 (m, 2 H), 1.74-1.64 (m, 2 H)


144
(400 MHz, DMSO-d6) δ ppm 8.34 (d, J = 7.9 Hz, 2 H), 7.78 (s, 1 H), 7.60 (t, J = 7.9



Hz, 2 H), 7.51 (d, J = 8.7 Hz, 2 H), 7.29-7.42 (m, 1 H), 7.12 (d, J = 8.9 Hz, 2 H),



4.73 (br. s., 1 H), 3.60-3.78 (m, 3 H), 2.86-3.11 (m, 2H), 2.40 (s, 3 H), 1.74-



1.96 (m, 2 H), 1.39-1.62 (m, 2 H)


145
(400 MHz, CDCl3) δ ppm 8.06 (dd, J = 18.3, 11.0 Hz, 4 H), 7.58 (t, J = 7.6 Hz, 2



H), 7.40 (d, J = 8.1 Hz, 3 H), 6.76 (d, J = 8.1 Hz, 2 H), 4.69 (br. s., 1 H), 4.06



(d, J = 11.0 Hz, 2 H), 3.71-3.48 (m, 3 H), 2.50 (s, 3 H), 2.12 (d, J = 12.5 Hz, 2 H),



1.76-1.60 (m, 2 H)


146
(400 MHz, DMSO-d6) δ ppm 8.28 (d, J = 7.6 Hz, 2 H), 7.55 (t, J = 7.7 Hz, 2 H),



7.35-7.30 (m, 2 H), 3.44-3.37 (m, 8 H), 2.99 (s, 3 H), 2.71 (s, 3 H)


147
(400 MHz, CDCl3) δ ppm 8.30 (bs, 2 H), 7.75 (s, 1 H), 4.87 (tt, J = 11.2, 4.2 Hz,



1 H), 2.23-1.85 (m, 6 H), 1.81 (d, J = 12.8 Hz, 1 H), 1.63-1.48 (m, 2 H), 1.45-1.30



(m, 1 H), 1.25 (s, 9H)


148
(400 MHz, DMSO-d6) δ ppm 8.53-8.14 (m, 2 H), 7.76 (s, 1 H), 7.61 (t, J = 8.0 Hz,



2 H), 7.48 (d, J = 8.7 Hz, 2 H), 7.42-7.30 (m, 1 H), 7.15 (d, J = 8.9 Hz, 2 H), 3.93-



3.83 (m, 1 H), 3.82-3.73 (m, 4 H), 3.56 (s, 2 H), 3.45-3.39 (m, 2 H), 3.28-3.19



(m, 6 H)


149
(400 MHz, DMSO-d6) δ ppm 8.61-8.38 (m, 2 H), 7.55 (s, 1 H), 5.13-4.73 (m, 1



H), 3.83-3.74 (m, 4 H), 3.72-3.63 (m, 4 H), 2.01-1.82 (m, 6 H), 1.73 (d, J = 13.0



Hz, 1H), 1.59-1.44 (m, 2 H), 1.36-1.23 (m, 1H), 1.20-1.12 (m, 9 H)


150
(400 MHz, CDCl3) δ ppm 8.02-7.96 (m, 2 H), 7.82 (s, 1 H), 7.53-7.46 (m, 2 H),



7.36-7.29 (m, 1H), 3.95-3.55 (m, 2 H), 3.70-3.62 (m, 2 H), 2.59 (s, 3 H), 2.10-



1.96 (m, 4 H)


151
(300 MHz, CDCl3) δ ppm 7.97 (s, 1 H), 7.44 (d, J = 8.7 Hz, 2 H), 7.41-7.35 (m, 2



H), 7.13-7.10 (m, 1 H), 7.04 (d, J = 8.7 Hz, 2 H), 6.49-6.42 (m, 1 H), 4.02-3.88



(m, 8 H), 3.36-3.28 (m, 4H), 3.22 (hept, J = 6.7 Hz, 1 H), 2.42 (p, J = 7.2 Hz, 2 H),



1.19 (d, J = 6.7 Hz, 6 H).


152
(400 MHz, CDCl3) δ ppm 8.00 (d, J = 7.6 Hz, 2 H), 7.53 (t, J = 7.6 Hz, 2 H), 7.47



(s, 1 H), 7.35 (t, J = 7.6 Hz, 1 H), 4.10 (d, J = 6.0 Hz, 2 H), 2.75 (s, 3 H), 2.05-1.65



(m, 7 H), 1.40-1.12 (m, 4 H)


153
(400 MHz, CDCl3) δ ppm 8.00-8.12 (m, 3 H), 7.61 (t, J = 8.0 Hz, 2 H), 7.49 (d,



J = 8.7 Hz, 2 H), 7.39-7.44 (m, 1 H), 6.74 (d, J = 8.7 Hz, 2 H), 3.60-3.75 (m, 2 H),



3.48-3.56 (m, 6H), 2.54 (s, 3 H)


154
(400 MHz, methanol-d4) δ ppm 8.34 (d, J = 7.1 Hz, 2 H), 7.85 (s, 1 H), 7.54 (t, J =



7.9 Hz, 2 H), 7.48 (d, J = 8.6 Hz, 2 H), 7.40-7.26 (m, 1 H), 7.16 (d, J = 9.0 Hz, 2



H), 4.53 (s, 4H), 3.40-3.33 (m, 4H), 2.40 (s, 3 H), 2.11-1.99 (m, 4H) (OH



missing)


155
(400 MHz, CDCl3) δ ppm 8.11-7.99 (m, 3 H), 7.63-7.54 (m, 2 H), 7.51-7.44 (m, 2



H), 7.42-7.34 (m, 1 H), 6.79-6.66 (m, 2 H), 3.83-3.75 (m, 1 H), 3.74-3.61 (m, 2 H),



3.55 (dt, J = 9.5, 6.8 Hz, 1 H), 3.41-3.29 (m, 1 H), 2.56-2.35 (m, 5 H) (OH



missing)


156
(400 MHz, CDCl3) δ ppm 8.12-7.97 (m, 3 H), 7.58 (t, J = 7.9 Hz, 2 H), 7.47 (d, J =



8.8 Hz, 2 H), 7.41-7.35 (m, 1 H), 6.72 (d, J = 8.8 Hz, 2 H), 5.67 (d, J = 7.3 Hz, 1



H), 4.71 (d, J = 5.9 Hz, 1 H), 3.72 (dd, J = 10.1, 6.0 Hz, 1 H), 3.63-3.53 (m, 1 H),



3.51-3.43 (m, 1 H), 3.31 (dd, J = 10.1, 3.5 Hz, 1 H), 2.50 (s, 3 H), 2.40 (dd, J =



13.8, 5.7 Hz, 1 H), 2.13-1.98 (m, 4 H) (OH missing)


157
(400 MHz, CDCl3) δ ppm 7.96 (s, 1 H), 7.45 (d, J = 8.6 Hz, 2 H), 7.37 (t, J = 8.1 Hz,



1 H), 7.28 (d, J = 8.1 Hz, 1 H), 7.26-7.23 (m, 1 H), 7.04 (d, J = 8.6 Hz, 2 H), 6.60-



6.56 (m, 1 H), 3.95-3.91 (m, 4H), 3.39-3.36 (m, 4H), 3.31-3.29 (m, 4H), 3.22



(hept, J = 6.8 Hz, 1 H), 2.07-2.04 (m, 4H), 1.20 (d, J = 6.8 Hz, 6 H)


158
(400 MHz, CDCl3) δ ppm 8.01 (d, J = 7.6 Hz, 2 H), 7.96 (s, 1 H), 7.55 (t, J = 7.6



Hz, 2 H), 7.38(t, J = 7.6 Hz, 1 H), 3.88-3.85 (m, 2 H), 3.28-3.20 (m, 2 H), 2.63 (s, 3



H), 1.83-1.70 (m, 4 H), 1.60-1.44 (m, 2 H)


159
(400 MHz, CDCl3) δ ppm 7.94 (s, 1 H), 7.46 (d, J = 8.9 Hz, 2 H), 7.06 (d, J = 8.5



Hz, 2 H), 5.05 (t, J = 9.6 Hz, 1 H), 3.85-4.00 (m, 4 H), 3.29-3.40 (m, 4 H), 3.20 (dt,



J = 13.7, 6.8 Hz, 1 H), 2.33-2.63 (m, 4 H), 1.95 -2.22 (m, 4 H), 1.16 (d, J = 6.8 Hz,



6H)


160
(300 MHz, CDCl3) δ ppm 7.98 (s, 1 H), 7.46 (d, J = 8.8 Hz, 2 H), 7.36-7.41 (m, 2



H), 7.12 (s, 1 H), 7.05 (d, J = 8.8 Hz, 2 H), 6.40-6.49 (m, 1 H), 3.90-3.98 (m, 4



H), 3.68 (s, 3 H), 3.29-3.35 (m, 3 H), 3.16-3.28 (m, 1 H), 1.37 (s, 6 H), 1.27 (s, 2



H), 1.21 (d, J = 6.7 Hz, 6 H)


161
(300 MHz, CDCl3) δ ppm 7.82 (s, 1 H), 7.35 (d, J = 8.8 Hz, 2 H), 6.98 (d, J = 8.5



Hz, 2 H), 4.91 -5.16 (m, 1 H), 3.68-3.96 (m, 4 H), 3.18-3.29 (m, 4 H), 2.82-3.17



(m, 6 H), 2.34-2.63 (m, 1 H), 1.96-2.16 (m, 2 H), 1.69-1.93 (m, 2 H), 1.05 (d,



J = 6.7 Hz, 6 H)


162
(300 MHz, CDCl3) δ ppm 7.82-7.77 (m, 2 H), 7.51 (s, 1 H), 7.40 (t, J = 7.8 Hz, 1



H), 7.17-7.14 (m, 1 H), 3.49 (hept, J = 6.8 Hz, 1 H), 3.32-3.28 (m, 4 H), 2.46 (s,



3 H), 1.88-1.78 (m, 4 H), 1.76-1.66 (m, 2H), 1.47 (d, J = 6.8 Hz, 6 H).


164
(300 MHz, CDCl3) δ ppm 7.97 (br. s., 1 H), 7.44 (br. s., 4 H), 7.16 (br. s., 1 H),



7.04 (br. s., 2 H), 6.47 (br. s., 1 H), 4.39 (br. s., 1 H), 4.19 (br. s., 2 H), 3.74-3.99



(m, 5 H), 3.33 (d, J = 16.1 Hz, 8 H), 1.08-1.31 (m, 8 H)


165
(300 MHz, CDCl3) δ ppm 7.98 (s, 1 H), 7.36-7.50 (m, 4 H), 7.05 (d, J = 8.8 Hz, 2



H), 6.54-6.64 (m, 1 H), 5.29-5.55 (m, 1 H), 3.85-3.99 (m, 4 H), 3.67-3.80 (m,



1 H), 3.52-3.67 (m, 3 H), 3.29-3.38 (m, 4 H), 3.18-3.27 (m, 1 H), 1.56 (br. s., 3



H), 1.22 (d, J = 7.0 Hz, 6 H)


166
(400 MHz, methanol-d4) δ ppm 8.50 (s, 2 H), 7.80 (s, 1 H), 5.2-5.10 (m, 1 H), 4.23



(br. s., 2 H), 4.13-4.01 (m, 3 H), 3.72-3.61 (m, 3 H), 3.32-3.25 (m, 6 H), 2.18-1.91



(m, 6 H), 1.82 (d, J = 13.0 Hz, 1 H), 1.71-1.54 (m, 2 H), 1.43 (tt, J = 12.8, 3.3 Hz,



1 H) (OH missing)


167
(300 MHz, CDCl3) δ ppm 7.97 (s, 1 H), 7.50 (s, 1 H), 7.45 (d, J = 8.8 Hz, 2 H), 7.37



(s, 1 H), 7.19 (s, 1 H), 7.04 (d, J = 8.8 Hz, 2 H), 6.40-6.49 (m, 1 H), 5.31-5.61 (m,



1 H), 4.20-4.35 (m, 2 H), 4.05-4.13 (m, 1 H), 3.97-4.05 (m, 1 H), 3.90-3.96



(m, 4 H), 3.27-3.35 (m, 4 H), 3.22 (s, 1 H), 2.79-2.92 (m, 1 H), 1.20 (d, J = 6.7



Hz, 6 H)


168
(400 MHz, CDCl3) δ ppm 8.52-8.22 (m, 1 H), 8.05 (d, J = 7.5 Hz, 2 H), 8.01 (s, 1



H), 7.70 (dd, J = 8.7, 2.6 Hz, 1 H), 7.63-7.49 (m, 2 H), 7.46-7.34 (m, 1 H), 6.68



(d, J = 8.7 Hz, 1 H), 4.96 (tt, J = 12.0, 4.1 Hz, 1 H), 4.12 (dd, J = 11.4, 4.4 Hz, 2



H), 3.63 (td, J = 11.9, 1.9 Hz, 2 H), 3.10-2.90 (m, 3 H), 2.55 (s, 3 H), 2.03-1.85 (m,



2 H), 1.73 (dd, J = 12.4, 2.3 Hz, 2 H)


169
(400 MHz, CDCl3) δ ppm 8.32 (d, J = 2.6 Hz, 1 H), 7.84 (s, 1 H), 7.63 (dd, J = 8.8,



2.5 Hz, 1 H), 6.64 (d, J = 8.9 Hz, 1 H), 5.02-4.67 (m, 2 H), 4.12 (dd, J = 11.4, 4.4



Hz, 2 H), 3.76-3.53 (m, 2 H), 3.20 (quin, J = 6.8 Hz, 1 H), 2.99 (s, 3 H), 2.26-



1.86 (m, 8 H), 1.81 (d, J = 12.8 Hz, 1 H), 1.73 (dd, J = 12.4, 2.5 Hz, 2 H), 1.63-1.48



(m, 2 H), 1.46-1.31 (m, 1 H), 1.19 (d, J = 6.8 Hz, 6 H)


170
(400 MHz, CDCl3) δ ppm 8.36-8.20 (m, 1 H), 7.85 (s, 1 H), 7.61 (dd, J = 8.7, 2.6



Hz, 1 H), 6.65 (d, J = 8.9 Hz, 1 H), 4.95-4.68 (m, 1 H), 3.92-3.80 (m, 2 H), 3.71-



3.57 (m, 2 H), 3.40 (s, 3 H), 3.24-3.08 (m, 4 H), 2.20-1.90 (m, 6 H), 1.81 (d,



J = 12.5 Hz, 1 H), 1.64-1.48 (m, 2 H), 1.18 (d, J = 6.7 Hz, 6 H)


171
(400 MHz, CDCl3) δ ppm 7.87 (s, 1 H), 7.70 (d, J = 8.3 Hz, 2 H), 7.46 (d, J = 8.6



Hz, 2 H), 7.37 (br. s., 1 H), 4.92-4.79 (m, 1 H), 3.73 (q, J = 6.9 Hz, 1 H), 3.12-3.00



(m, 1 H), 2.25 (s, 3 H), 2.19-1.94 (m, 2 H), 1.81 (d, J = 12.2 Hz, 2 H), 1.62-1.48



(m, 2 H), 1.44-1.37 (m, 2 H), 1.31-1.22 (m, 1 H), 1.11 (d, J = 6.6 Hz, 6 H) (OH



missing)


172
(300 MHz, CDCl3) δ ppm 8.52 (s, 1 H), 8.22 (s, 1 H), 7.99 (d, J = 8.8 Hz, 2 H),



7.86-7.94 (m, 2 H), 7.58 (d, J = 8.8 Hz, 2 H), 7.25 (td, J = 4.6, 2.5 Hz, 1 H), 4.41-



4.50 (m, 4 H), 4.12-4.23 (m, 4 H), 3.92 (s, 3 H), 3.82-3.88 (m, 4 H), 3.70-3.80 (m, 1



H), 3.61 (s, 3 H), 1.78-1.83 (m, 1 H), 1.74 (d, J = 6.7 Hz, 6 H)


173
(400 MHz, DMSO-d6) δ ppm 8.22 (d, J = 8.2 Hz, 1 H), 8.10 (s, 1 H), 7.40 (t, J = 7.9



Hz, 1 H), 6.93-7.17 (m, 2 H), 3.48-3.70 (m, 5 H), 2.41 (s, 3 H), 1.99 (d, J = 5.6



Hz, 4 H), 1.37 (d, J = 6.7 Hz, 6 H)


174
(300 MHz, CDCl3) δ ppm 7.73-7.90 (m, 2 H), 7.44 (t, J = 7.8 Hz, 1 H), 7.20 (d,



J = 7.3 Hz, 1 H), 7.01 (s, 1 H), 5.43-5.47 (m, 0.5 H), 5.61-5.66 (m, 0.5 H), 4.41-



4.77 (m, 4 H), 3.38 (quin, J = 6.7 Hz, 1 H), 2.51 (s, 3 H), 1.42-1.56 (m, 6 H)


175
(300 MHz, CDCl3) δ ppm 8.36 (d, J = 2.0 Hz, 1 H), 7.95 (s, 1 H), 7.88-7.82 (m, 2



H), 7.67 (dd, J = 8.7, 2.0 Hz, 1H), 7.44 (t, J = 7.7 Hz, 1 H), 7.21-7.19 (m, 1 H),



6.81 (d, J = 8.7 Hz, 1 H), 4.00-3.92 (m, 2 H), 3.70-3.62 (m, 2 H), 3.23 (hept,



J = 6.8 Hz, 1 H), 3.02-2.90 (m, 1 H), 2.49 (s, 3 H), 2.14-1.94 (m, 4 H), 1.25 (d,



J = 6.8 Hz, 6 H)


176
(400 MHz, CDCl3) δ ppm 7.89 (s, 1 H), 7.25-7.47 (m, 5 H), 6.85-7.05 (m, 2 H),



6.46-6.71 (m, 1 H), 3.41-3.63 (m, 2 H), 3.17-3.22 (m, 3 H), 3.13 (m, 6 H), 2.82



(dt, J = 7.9, 3.8 Hz, 1 H), 1.86-2.18 (m, 4 H), 1.04-1.27 (m, 6 H)



(400 MHz, CDCl3) δ ppm 8.29 (d, J = 2.4 Hz, 1 H), 7.86 (d, J = 0.5 Hz, 1 H), 7.61



177 (dd, J = 8.7, 2.3 Hz, 1 H), 7.23-7.41 (m, 3 H), 6.59-6.83 (m, 2 H), 3.89 (ddd,



J = 13.6, 7.3, 3.5 Hz, 2 H), 3.44-3.71 (m, 2 H), 3.15 (quin, J = 6.8 Hz, 1 H), 2.98 (s,



6 H), 2.89 (dt, J = 7.8, 3.7 Hz, 1 H), 1.76-2.08 (m, 4 H), 1.03-1.30 (m, 6 H)


178
(400 MHz, CDCl3) δ ppm 8.29 (d, J = 2.4 Hz, 1 H), 7.88 (s, 1 H), 7.62 (dd, J = 8.8,



2.4 Hz, 1 H), 7.45-7.57 (m, 2 H), 7.28-7.42 (m, 1 H), 6.84-6.90 (m, 1 H), 6.75



(d, J = 8.8 Hz, 1 H), 3.77-4.02 (m, 6 H), 3.60 (ddd, J = 13.7, 7.6, 3.7 Hz, 2 H),



3.05-3.25 (m, 5 H), 2.75-2.98 (m, 1 H), 1.78-2.11 (m, 4 H), 1.04-1.27 (m, 6 H)


179
(400 MHz, CDCl3) δ ppm 8.26 (d, J = 2.0 Hz, 1 H), 7.88 (s, 1 H), 7.46-7.64 (m, 3



H), 7.29-7.44 (m, 1 H), 6.79-6.92 (m, 1 H), 6.62 (d, J = 8.8 Hz, 1 H), 3.73-3.89



(m, 6 H), 3.53 -3.67 (m, 2 H), 3.33 (s, 3H), 3.20-3.23 (m, 4 H), 3.14 (s, 3H),



1.09-1.27 (m, 6 H)


180
(400 MHz, CDCl3) δ ppm 8.34 (d, J = 2.4 Hz, 1 H), 7.85 (s, 1 H), 7.66 (dd, J = 8.8,



2.5 Hz, 1 H), 6.79 (d, J = 8.7 Hz, 1 H), 3.96 (ddd, J = 13.7, 7.2, 3.6 Hz, 2 H), 3.75-



3.54 (m, 2 H), 3.15 (dt, J = 13.4, 6.8 Hz, 1 H), 3.00-2.86 (m, 1 H), 2.22-1.92 (m,



10 H), 1.81 (d, J = 12.6 Hz, 1 H), 1.65-1.48 (m, 3 H), 1.33-1.22 (m, 1 H), 1.18 (d,



J = 6.7 Hz, 6 H)


181
(400 MHz, CDCl3) δ ppm 8.34 (d, J = 2.2 Hz, 1 H), 7.85 (d, J = 1.0 Hz, 1 H), 7.67



(dd, J = 8.7, 2.2 Hz, 1 H), 6.51 (d, J = 8.7 Hz, 1 H), 4.93-4.68 (m, 1 H), 3.96 (t,



J = 13.1 Hz, 2 H), 3.81 (t, J = 7.3 Hz, 2 H), 3.15 (dt, J = 13.4, 7.0 Hz, 1 H), 2.57 (tt,



J = 13.7, 7.0 Hz, 2 H), 2.20-1.93 (m, 7 H), 1.81 (d, J = 12.8 Hz, 1 H), 1.64-1.49



(m, 1 H), 1.45-1.33 (m, 1 H), 1.20-1.13 (m, 6 H)


182
(400 MHz, CDCl3) δ ppm 8.34 (d, J = 2.4 Hz, 1 H), 8.11 (dd, J = 8.6, 1.1 Hz, 2 H),



7.98 (s, 1 H), 7.68 (dd, J = 8.8, 2.5 Hz, 1 H), 7.63-7.56 (m, 2 H), 7.45-7.37 (m, 1



H), 6.83 (d, J = 8.7 Hz, 1 H), 3.99 (ddd, J = 13.6, 7.4, 3.6 Hz, 2 H), 3.77-3.62 (m, 3



H), 2.98 (dt, J = 7 .7 , 3.7 Hz, 1 H), 2.44 (td, J = 9.1, 2.3 Hz, 2 H), 2.18-1.83



(m, 8 H)


183
(400 MHz, CDCl3) δ ppm 8.32 (d, J = 2.2 Hz, 1 H), 8.18-8.07 (m, 2 H), 7.98 (s, 1



H), 7.71-7.49 (m, 3 H), 7.46-7.34 (m, 1 H), 6.67 (d, J = 8.8 Hz, 1 H), 5.07-4.91



(m, 1 H), 4.13 (dd, J = 11.5, 4.6 Hz, 2 H), 3.82-3.72 (m, 1 H), 3.64 (td, J = 11.9, 1.7



Hz, 2 H), 3.02 (s, 3 H), 2.53-2.33 (m, 2 H), 2.21-2.07 (m, 2 H), 2.02-1.84 (m, 4



H), 1.74 (dd, J = 12.3, 2.3 Hz, 2 H)


184
(400 MHz, CDCl3) δ ppm 7.87 (s, 1 H), 7.45-7.33 (m, 2 H), 6.83 (d, J = 8.8 Hz, 2



H), 4.82 (tt, J = 11.5, 3.8 Hz, 1 H), 3.63 (s, 4 H), 3.45-3.38 (m, 3 H), 3.24 (quin,



J = 6.8 Hz, 1 H), 3.05-3.15 (m, 3 H), 1.94-2.20 (m, 6 H), 1.86-1.76 (m, 1 H),



1.63-1.48 (m, 2 H), 1.45-1.33 (m, 1 H), 1.16 (d, J = 6.8 Hz, 6 H)


185
(400 MHz, CDCl3) δ ppm 7.87 (s, 1 H), 7.42 (d, J = 8.7 Hz, 2 H), 7.04 (d, J = 8.7



Hz, 2 H), 4.83 (tt, J = 11.4, 3.9 Hz, 1 H), 3.63-3.49 (m, 2 H), 3.35-3.22 (m, 2 H),



3.20-3.05 (m, 1 H), 2.94-2.76 (m, 1 H), 2.19-1.93 (m, 7 H), 1.91-1.76 (m, 5 H),



1.65-1.45 (m, 2H), 1.13 (d, J = 6.8 Hz, 6 H)


186
(400 MHz, CDCl3) δ ppm 8.09-8.02 (m, 3 H), 7.63 (d, J = 8.0 Hz, 2 H), 7.56 (t,



J = 7.5 Hz, 2 H), 7.40 (t, J = 7.0 Hz, 1 H), 7.04 (d, J = 8.2 Hz, 2 H), 5.17 (t, J =



6.5 Hz, 1 H), 4.09 (q, J = 6.8 Hz, 1 H), 3.94-3.88 (m, 4 H), 3.85 (q, J = 7.0 Hz,



1 H), 3.34-3.27 (m, 4 H), 2.42-2.30 (m, 1 H), 2.20-2.09 (m, 1 H), 2.05-1.86



(m, 2 H)


187
(400 MHz, CDCl3) δ ppm 8.27 (d, J = 2.4 Hz, 1 H), 7.88 (s, 1 H), 7.46-7.72 (m, 3



H), 7.37 (t, J = 8.1 Hz, 1 H), 6.85 (dd, J = 8.1, 2.0 Hz, 1 H), 6.59 (d, J = 8.8 Hz,



1 H), 4.87 (tt, J = 11.8, 4.0 Hz, 1 H), 3.98-4.19 (m, 2 H), 3.75-3.93 (m, 4H), 3.55



(td, J = 11.8, 1.6 Hz, 2H), 3.10-3.35 (m, 5 H), 2.93 (s, 3 H), 1.76-2.01 (m, 2H),



1.65 (dd, J = 12.3, 2.3 Hz, 2 H), 1.05-1.34 (m, 6 H)


188
(400 MHz, CDCl3) δ ppm 7.90 (s, 1 H), 7.50-7.69 (m, 2 H), 7.27-7.44 (m, 3 H),



6.68 -6.91 (m, 3 H), 3.74-3.94 (m, 4 H), 3.56 (s, 4 H), 3.33 (s, 3H), 3.23-3.28 (



m, 1H), 3.18-3.21 (m, 4 H), 3.01 (s, 3 H), 1.15 (d, J = 6.8 Hz, 6 H)


189
(400 MHz, CDCl3) δ ppm 8.11 -8.34 (m, 1 H), 7.87 (s, 1 H), 7.59 (dd, J = 8.8, 2.4



Hz, 1 H), 7.24-7.42 (m, 3 H), 6.63-6.72 (m, 1 H), 6.58 (d, J = 8.8 Hz, 1 H), 4.87



(t, J = 3.9 Hz, 1 H), 3.89-4.14 (m, 2 H), 3.55 (td, J = 11.9, 2.0 Hz, 2 H), 3.14-3.28



(m, 1 H), 2.99 (s, 6 H), 2.93 (s, 3 H), 1.79-1.99 (m, 2 H), 1.65 (dd, J = 12.5, 2.2



Hz, 2 H), 1.15-1.22 (m, 6 H)


190
(300 MHz, CDCl3) δ ppm 7.75-7.85 (m, 2 H), 7.55 (s, 1 H), 7.43 (t, J = 7.8 Hz, 1



H), 7.18 (d, J = 7.6 Hz, 1 H), 3.75 (d, J = 11.7 Hz, 1 H), 3.45-3.60 (m, 3 H), 3.43 (s,



3 H), 3.02-3.17 (m, 1 H), 2.96 (dd, J = 11.7, 8.5 Hz, 1 H), 2.49 (s, 3 H), 2.18 (d,



J = 12.3 Hz, 1 H), 1.94-2.07 (m, 1 H), 1.72-1.89 (m, 1 H), 1.53-1.65 (m, 2 H),



1.49 (dd, J = 8.1, 6.9 Hz, 6 H)


191
(400 MHz, CDCl3) δ ppm 7.65-7.81 (m, 2 H), 7.51 (br. s., 1 H), 7.20-7.30 (m, 1



H), 6.93 (br. s., 1 H), 3.30-3.51 (m, 3 H), 3.10 (br. s., 2 H), 2.83 (br. s., 1 H), 2.35



(br. s., 3 H), 2.01-2.20 (m, 4 H), 1.46 (d, J = 6.5 Hz, 6 H), 1.22-1.32 (m, 1 H)


192

1H NMR (300 MHz, CDCl3) δ ppm 7.75-7.87 (m, 2 H), 7.54 (s, 1 H), 7.42 (t,




J = 7.9 Hz, 1 H), 7.18 (d, J = 7.6 Hz, 1 H), 3.46-3.67 (m, 4 H), 3.44 (s, 3 H), 3.10-



3.23 (m, 2 H), 2.48 (s, 3 H), 2.07-2.22 (m, 2 H), 1.81-1.96 (m, 2 H), 1.49 (d,



J = 6.7 Hz, 6 H)


193
(400 MHz, CDCl3) δ ppm 8.52 (d, J = 2.2 Hz, 1 H), 7.88 (s, 1 H), 7.79 (dd, J = 8.8,



2.2 Hz, 1H), 6.64 (d, J = 8.8 Hz, 1 H), 4.82-4.74 (m, 1 H), 3.20 (s, 6 H), 2.12-



1.76 (m, 8 H), 1.58-1.46 (m, 2 H), 1.40-1.32 (m, 1 H), 1.06-1.02 (m, 2 H),



0.91-0.87 (m, 2 H).


194
(400 MHz, CDCl3) δ ppm 7.86 (s, 1 H), 7.41 (d, J = 8.2 Hz, 2 H), 7.00 (d, J = 8.2



Hz, 2 H), 5.42-5.32 (m, 1 H), 4.48-4.48 (m, 1 H), 3.96-3.88 (m, 4 H), 3.32-3.26



(m, 4 H), 3.14 (hept, J = 6.6 Hz, 1 H), 2.42-2.32 (m, 1 H), 2.18-1.96 (m, 4 H),



1.88-1.68 (m, 3 H), 1.11 (d, J = 6.6 Hz, 6H)


195
(300 MHz, CDCl3) δ ppm 7.89 (s, 1 H), 7.42 (d, J = 8.7 Hz, 2 H), 7.01 (d, J = 8.7



Hz, 2 H), 5.12-5.01 (m, 1 H), 4.02-3.88 (m, 5 H), 3.32-3.27 (m, 4 H), 3.17 (hept,



J = 6.8 Hz, 1 H), 2.40-2.16 (m, 2 H), 2.04-1.88(m, 4 H), 1.66-1.50 (m, 2 H),



1.13 (d, J = 6.8 Hz, 6H)


196
(400 MHz, CDCl3) δ ppm 8.33 (d, J = 2.4 Hz, 1 H), 7.83 (s, 1 H), 7.63 (dd,J = 8.8,



2.4 Hz, 1H), 6.75 (d, J = 8.8 Hz, 1 H), 4.88-4.79 (m, 1 H), 4.20-4.14 (m, 2 H),



3.82-3.74 (m, 2 H), 3.15 (hept, J = 6.8 Hz, 1 H), 2.65 (dd,J = 12.8, 10.6 Hz, 2H),



2.18-1.92(m, 6H), 1.84-1.76(m, 1 H), 1.60-1.48 (m, 2 H), 1.44-1.35 (m, 1



H), 1.31 (d, J = 6.3 Hz, 6 H), 1.16 (d, J = 6.8 Hz, 6 H)


197
(400 MHz, CDCl3) δ ppm 8.32 (d, J = 1.9 Hz, 1 H), 7.85 (s, 1 H), 7.64 (dd, J = 8.8,



2.5 Hz, 1 H), 6.74 (d, J = 8.7 Hz, 1 H), 4.85 (tt, J = 11.5, 4.2 Hz, 1 H), 3.97-3.85 (m,



2 H), 3.69-3.58 (m, 2 H), 3.56-3.44 (m, 2 H), 3.17 (quin, J = 6.8 Hz, 1 H), 2.13-



2.07 (m, 6 H), 2.07-1.92 (m, 4 H), 1.88-1778 (m, 1 H), 1.61-1.47 (m, 2 H), 1.44-



1.36 (m, 1 H), 1.31-1.22 (m, 2H), 1.21-1.14 (m, 6H)


198
(400 MHz, CD30D) δ ppm 8.29 (d, J = 8.1 Hz 2 H), 7.84 (s, 1 H), 7.51 (t, J = 7.8



Hz, 2 H), 7.42 (d, J = 8.5 Hz, 2 H), 7.31 (t, J = 7.3 Hz, 1 H), 7.09 (d, J = 8.1 Hz, 2



H), 3.84-3.70 (m, 2 H), 3.61-3.52 (m, 1 H), 2.93-2.84 (m, 1 H), 2.82-2.74 (m, 1 H),



2.36 (s, 3 H), 2.06-1.98 (m, 1 H), 1.95-1.86 (m, 1 H), 1.74-1.62 (m, 1 H), 1.53-1.41



(m, 1 H)


199
(400 MHz, CDCl3) δ ppm 8.52 (s, 2 H), 7.92 (s, 1 H), 7.43-7.32 (m, 3 H), 6.78-



6.73 (m, 1 H), 4.26-4.18 (m, 2H), 3.95-3.87 (m, 2 H), 3.20 (pent, J = 6.8 Hz, 1 H),



3.05 (s, 6 H), 3.02-2.95 (m, 1 H), 2.10-1.92 (m, 4 H), 1.30 (d, J = 6.8 Hz, 6 H)


200
(400 MHz, CDCl3) δ ppm 8.52 (s, 2 H), 7.92 (s, 1 H), 7.43-7.33 (m, 3 H), 6.76-



6.71 (m, 1 H), 5.06-4.96 (m, 1H), 4.16-4.08 (m, 2 H), 3.61 (t, J = 11.7 Hz, 2 H),



3.25 (sept, J = 6.8 Hz, 1 H), 3.16 (s, 3 H), 3.05 (s, 6 H), 2.03-1.90 (m, 2 H), 1.78-



1.69 (m, 2 H), 1.30 (d, J = 6.7 Hz, 6 H)


201
(400 MHz, CDCl3) δ ppm 8.43 (d, J = 5.2 Hz, 1 H), 8.08 (s, 1 H), 7.47 (d, J = 8.7



Hz, 2 H), 7.08 (d, J = 8.9 Hz, 2 H), 3.86-4.04 (m, 8 H), 3.76 (br. s., 4 H), 3.52



(q, J = 7.0 Hz, 1 H), 3.32-3.41 (m, 4 H), 3.27 (dt, J = 13.6, 6.7 Hz, 1 H), 1.08-1.34



(m, 7 H)


202
(400 MHz, CDCl3) δ ppm 7.81 (d, J = 8.1 Hz, 1 H), 7.78 (s, 1 H), 7.52 (s, 1 H), 7.43



(t, J = 7.8 Hz, 1 H), 7.19 (d, J = 7.7 Hz, 1 H), 4.55 (s, 3 H), 3.46 (d, J = 6.7 Hz, 1



H), 3.26 (br. s., 2 H), 2.48 (s, 2 H), 2.11-2.20 (m, 3 H), 1.49 (d, J = 6.9 Hz, 5 H)


203
(400 MHz, CDCl3) δ ppm 8.34 (d, J = 2.2 Hz, 1 H), 7.85 (s, 1 H), 7.65 (dd, J = 8.7,



2.6 Hz, 1 H), 6.80 (d, J = 8.7 Hz, 1 H), 4.95-4.77 (m, 1 H), 4.44 (d, J = 14.2 Hz, 2



H), 3.41-3.22 (m, 2 H), 3.15 (quin, J = 6.8 Hz, 1 H), 2.19-1.87 (m, 11 H), 1.81 (d,



J = 13.1 Hz, 1 H), 1.71-1.50 (m, 3 H), 1.44-1.23 (m, 2 H), 1.22-1.09 (m, 6 H)


204
(400 MHz, CDCl3) δ ppm 8.51 (s, 2 H), 7.93 (s, 1 H), 7.60-7.55 (m, 2 H), 7.45 (t,



J = 8.1 Hz, 1 H), 6.96-6.92 (m, 1 H), 4.26-4.18 (m, 2H), 3.95-3.87 (m, 6 H), 3.29-



3.25 (m, 4H), 3.21 (sept, J = 6.8 Hz, 1 H), 3.02-2.95 (m, 1 H), 2.11-1.92 (m, 4H),



1.29 (d, J = 6.8 Hz, 6 H)


205
(300 MHz, CDCl3) δ ppm 7.87 (s, 1 H), 7.42 (d, J = 8.7 Hz, 2 H), 7.02 (d, J = 8.7



Hz, 2 H), 4.92-4.80 (m, 1 H), 3.94-3.88 (m, 4 H), 3.48-3.36 (m, 4 H), 3.32-3.24



(m, 4 H), 3.14 (hept, J = 6.8 Hz, 1 H), 2.47-2.35 (m, 1 H), 2.25-1.92(m, 5 H),



1.60-1.25 (m, 3 H), 1.12 (d, J = 6.8 Hz, 6H)


206
(400 MHz, CDCl3) δ ppm 7.98 (s, 1 H), 7.55-7.63 (m, 2 H), 7.40-7.51 (m, 3 H),



7.07 (d, J = 8.8 Hz, 2 H), 6.94 (dd, J = 7.5, 1.8 Hz, 1 H), 3.86-3.96 (m, 4 H), 3.52-



3.65 (m, 2 H), 3.18-3.36 (m, 7 H), 2.90 (tt, J = 7.8, 4.0 Hz, 1 H), 2.01-2.20 (m, 4



H), 1.21 (d, J = 6.8 Hz, 6 H)


207
(400 MHz, CDCl3) δ ppm 7.89 (s, 1 H), 7.24-7.43 (m, 5 H), 6.85 (d, J = 8.8 Hz, 2



H), 6.66 (td, J = 4.6, 2.6 Hz, 1 H), 3.98-4.19 (m, 2 H), 3.84-3.98 (m, 1 H), 3.40-



3.57 (m, 2 H), 3.25 (dt, J = 13.6, 6.8 Hz, 1 H), 2.98 (s, 6 H), 2.85 (s, 3 H), 1.87 (qd,



J = 12.3, 4.5 Hz, 2 H), 1.70 (dd, J = 12.5, 2.2 Hz, 2 H), 1.11-1.22 (m, 6 H)


208
(400 MHz, CDCl3) δ ppm 7.90 (s, 1 H), 7.48-7.66 (m, 2 H), 7.25-7.46 (m, 3 H),



6.68-6.90 (m, 3 H), 3.98-4.14 (m, 2 H), 3.86-3.95 (m, 1 H), 3.76-3.86 (m, 4



H), 3.49 (td, J = 11.9, 1.7 Hz, 2 H), 3.22-3.30 (m, 1 H), 3.14-3.22 (m, 4 H), 2.85



(s, 3 H), 1.87 (qd, J = 12.3, 4.5 Hz, 2 H), 1.70 (dd, J = 12.6, 2.1 Hz, 2 H), 1.16 (d,



J = 6.8 Hz, 6 H)


209
(400 MHz, CDCl3) δ ppm 7.75 (d, J = 14.7 Hz, 2 H), 7.48 (s, 1 H), 7.35 (br. s., 1 H),



7.09 (br. s., 1 H), 3.63 (br. s., 4 H), 3.45-3.56 (m, 1 H), 3.30 (s, 3 H), 3.14 (br. s.,



3 H), 2.43 (br. s., 3 H), 1.46 (d, J = 6.8 Hz, 7 H)


210
(400 MHz, CDCl3) δ ppm 7.76-7.84 (m, 2 H), 7.58 (s, 1 H), 7.44 (t, J = 7.9 Hz, 1



H), 7.20 (d, J = 7.7 Hz, 1 H), 3.46-3.52 (m, 4 H), 3.40-3.46 (m, 1 H), 2.49 (s, 3



H), 2.21-2.36 (m, 4 H), 1.49-1.60 (m, 7 H)


211
(400 MHz, DMSO-d6) δ ppm 9.03 (d, J = 1.7 Hz, 1 H), 8.20-8.41 (m, 2 H), 7.76 (s,



1 H), 7.52 (d, J = 8.7 Hz, 2 H), 7.14 (d, J = 8.9 Hz, 2 H), 3.80 (dt, J = 9.3, 4.8 Hz, 8



H), 3.17-3.42 (m, 9 H), 1.14 (d, J = 6.8 Hz, 6 H)


212
(300 MHz, CDCl3) δ ppm 7.74-7.86 (m, 2 H), 7.41 (t, J = 7.9 Hz, 1 H), 7.16 (d,



J = 7.3 Hz, 1 H), 6.95 (s, 1 H), 4.52-4.60 (m, 2 H), 4.36-4.45 (m, 1 H), 4.21-4.30



(m, 2 H), 3.31-3.44 (m, 4 H), 2.47 (s, 3 H), 1.47 (d, J = 6.7 Hz, 6 H)


213
(300 MHz, CDCl3) δ ppm 7.75-7.85 (m, 2 H), 7.54 (s, 1 H), 7.42 (t, J = 7.8 Hz, 1



H), 7.18 (d, J = 7.6 Hz, 1 H), 3.75 (d, J = 12.3 Hz, 2 H), 3.66 (d, J = 6.5 Hz, 2 H),



3.42-3.53 (m, 1 H), 2.93-3.07 (m, 2 H), 2.48 (s, 3 H), 1.99 (d, J = 11.4 Hz, 2 H),



1.80 (d, J = 11.4 Hz, 1 H), 1.60 (td, J = 12.3, 3.7 Hz, 4 H), 1.49 (d, J = 6.7 Hz, 6 H)


214
(300 MHz, CDCl3) δ ppm 7.86 (s, 1 H), 7.42 (d, J = 8.7 Hz, 2 H), 7.01 (d, J = 8.7



Hz,2H), 5.27-5.16 (m, 1 H), 3.94-3.88 (m, 4 H), 3.84-3.78 (m, 1 H), 3.40 (s, 3 H),



3.30-3.27 (m, 4 H), 3.15 (hept, J = 6.8 Hz, 1 H), 2.30-1.49 (m, 8 H), 1.12 (d,



J = 6.8 Hz, 6 H)


215
(300 MHz, CDCl3) δ ppm 7.70-7.83 (m, 2 H), 7.38 (t, J = 7.8 Hz, 1 H), 7.27 (s, 1



H), 7.14 (d, J = 7.6 Hz, 1 H), 3.67-3.85 (m, 4 H), 3.47 (quin, J = 6.7 Hz, 1 H), 3.02-



3.20 (m, 1 H), 2.45 (s, 3 H), 2.18-2.41 (m, 2 H), 1.44 (dd, J = 14.8, 6.6 Hz, 6 H)


216
(300 MHz, CDCl3) δ ppm 7.75-7.84 (m, 2 H), 7.41 (t, J = 7.8 Hz, 1 H), 7.27 (s, 1



H), 7.17 (d, J = 7.6 Hz, 1 H), 3.91 (br. s., 2 H), 3.46-3.73 (m, 5 H), 3.37 (br. s., 2



H), 3.08 (br. s., 2 H), 2.48 (s, 3 H), 1.41-1.51 (m, 15 H)


217
(400 MHz, DMSO-d6) δ ppm 8.33 (d, J = 8.3 Hz 2 H), 7.77 (s, 1 H), 7.63-7.52 (m, 4



H), 7.35 (t, J = 7.4 Hz, 1 H), 6.81 (d, J = 8.6 Hz, 2 H), 4.05-3.91 (m, 1 H), 3.78-3.71



(m, 1 H), 3.65-3.55 (m, 2 H), 3.42-3.27 (m, 1 H), 2.83 (s, 6 H), 2.53-2.42 (m, 1 H),



2.40 (s, 3 H), 2.35-2.23 (m, 1 H)


218
(300 MHz, CDCl3) δ ppm 7.74-7.84 (m, 2 H), 7.38-7.47 (m, 1 H), 7.31 (s, 1 H),



7.18 (d, J = 7.6 Hz, 1 H), 3.88-4.03 (m, 3 H), 3.70-3.81 (m, 1 H), 3.49 (dt,



J = 13.3, 6.7 Hz, 1 H), 3.35 (quin, J = 6.3 Hz, 1 H), 2.43-2.54 (m, 5 H), 1.81-2.12



(m, 1 H), 1.43-1.51 (m, 6 H)


219
(400 MHz, CDCl3) δ ppm 7.78 (s, 1 H), 7.32 (d, J = 8.6 Hz, 2 H), 6.96 (d, J = 8.6



Hz, 2 H), 4.77 (tt, J = 11.6, 3.9 Hz, 1 H), 3.43-3.58 (m, 3 H), 3.13-3.27 (m, 2 H),



2.75-2.87 (m, 1 H), 2.15-2.31 (m, 2 H), 1.84-2.14 (m, 12 H), 1.66-1.82 (m, 3 H),



1.48 (q, J = 12.9 Hz, 2 H), 1.23-1.38 (m, 1 H)


220
(400 MHz, CDCl3) δ ppm 8.30 (d, J = 2.2 Hz, 1 H), 7.84 (s, 1 H), 7.63 (dd, J = 8.8,



2.4 Hz, 1 H), 6.80 (d, J = 8.8 Hz, 1 H), 4.80-4.93 (m, 1 H), 3.96 (ddd, J = 13.6, 7.3,



3.5 Hz, 2 H), 3.55-3.71 (m, 3 H), 2.96 (dt, J = 7.9, 3.8 Hz, 1 H), 2.33 (dq, J = 11.5,



9.0 Hz, 2 H), 1.75-2.22 (m, 16 H), 1.47-1.63 (m, 2 H), 1.29-1.45 (m, 1 H)


221
(400 MHz, CDCl3) δ ppm 7.97 (s, 1 H), 7.45 (d, J = 8.6 Hz, 2 H), 7.39 (t, J = 1.0



Hz,1 H), 7.22-7.32 (m, 2 H), 7.06 (d, J = 8.6 Hz, 2 H), 6.59 (dd, J = 8.2, 2.1 Hz, 1



H), 3.53-3.63 (m, 2 H), 3.35-3.43 (m, 4 H), 3.26-3.34 (m, 2 H), 3.17-3.26 (m, 1



H), 2.85 -2.94 (m, 1 H), 2.00-2.19 (m, 8 H), 1.21 (d, J = 6.8 Hz, 6 H)


222
(400 MHz, CDCl3) δ ppm 8.29 (d, J = 2.4 Hz, 1 H), 7.87 (s, 1 H), 7.62 (dd, J = 8.8,



2.4 Hz, 1 H), 7.27-7.35 (m, 1 H), 7.12-7.23 (m, 2 H), 6.74 (d, J = 8.8 Hz, 1 H),



6.51 (dd, J = 8.2, 2.1 Hz, 1 H), 3.90 (ddd, J = 13.6, 7.3, 3.8 Hz, 2 H), 3.59 (ddd,



J = 13.6, 7.6, 3.5 Hz, 2 H), 3.25-3.36 (m, 4 H), 3.08-3.22 (m, 1 H), 2.89 (t, J = 3.9



Hz, 1 H), 1.87-2.07 (m, 8 H), 1.18 (d, J = 6.6 Hz, 6 H)


223
(400 MHz, CDCl3) δ ppm 8.33 (d, J = 2.4 Hz, 1 H), 7.84 (s, 1 H), 7.63 (dd, J = 8.8,



2.5 Hz, 1 H), 6.80 (d, J = 8.7 Hz, 1 H), 4.93-4.78 (m, 1 H), 4.74 (d, J = 3.8 Hz, 1 H),



3.97-3.80 (m, 2 H), 3.77-3.66 (m, 1 H), 3.65-3.57 (m, 1 H), 3.18 (quin, J = 6.8



Hz, 1 H), 2.22-1.91 (m, 8 H), 1.81 (d, J = 12.3 Hz, 1 H), 1.74-1.64 (m, 1 H), 1.60-



1.47 (m, 2H), 1.45-1.34 (m, 1 H), 1.32-1.24 (m, 1 H), 1.18 (d, J = 6.7 Hz, 6 H)


224
(400 MHz, CDCl3) δ ppm 8.32 (d, J = 2.4 Hz, 1 H), 7.84 (s, 1 H), 7.61 (dd, J = 8.6,



2.3 Hz, 1 H), 6.51 (d, J = 8.5 Hz, 1 H), 4.94-4.73 (m, 1 H), 4.26-4.07 (m, 1 H),



3.80-3.57 (m, 4 H), 3.43 (d, J = 0.7 Hz, 3 H), 3.29-3.06 (m, 1 H), 2.33-2.13 (m,



3 H), 2.09-1.93 (m, 4 H), 1.81 (d, J = 12.1 Hz, 1 H), 1.61-1.49 (m, 2 H), 1.45-



1.24 (m, 2 H), 1.18 (d, J = 6.8 Hz, 6 H)


225
(300 MHz, CDCl3) δ ppm 7.94-8.04 (m, 1 H), 7.42-7.49 (m, 3 H), 7.33-7.42



(m, 1 H), 7.18 (t, J = 2.1 Hz, 1 H), 7.05 (d, J = 8.8 Hz, 2 H), 6.47 (dd, J = 7.9,



1.2 Hz, 1 H), 4.75-4.89 (m, 1 H), 4.27 (t, J = 7.3 Hz, 2 H), 3.89-3.98 (m, 4 H),



3.80 (dd, J = 8.4, 4.5 Hz, 2 H), 3.28-3.37 (m, 4 H), 3.16-3.27 (m, 1 H), 1.21 (d, J =



6.7 Hz, 6 H)


226
(300 MHz, CDCl3) δ ppm 7.76-7.87 (m, 2 H), 7.36-7.47 (m, 2 H), 7.17 (d, J = 7.3



Hz, 1 H), 3.68-3.84 (m, 4 H), 3.55 (dt, J = 13.5, 6.7 Hz, 1 H), 3.36 (dd, J = 10.6, 4.4



Hz, 2 H), 3.06 (br. s., 2 H), 2.81-2.91 (m, 2 H), 2.71-2.79 (m, 2 H), 2.48 (s, 3 H),



1.43-1.55 (m, 6H)


227
(300 MHz, CDCl3) δ ppm 7.49-7.61 (m, 2 H), 7.27 (s, 1 H), 7.16 (t, J = 7.8 Hz, 1



H), 6.91 (d, J = 7.6 Hz, 1 H), 3.47 (d, J = 12.3 Hz, 2 H), 3.22 (quin, J = 6.7 Hz, 1



H), 3.15 (s, 3 H), 3.11 (d, J = 6.5 Hz, 2 H), 2.73 (td, J = 12.3, 1.8 Hz, 2 H), 2.22 (s,



3 H), 1.56-1.76 (m, 3 H), 1.19-1.38 (m, 8 H)


228
(300 MHz, CDCl3) δ ppm 7.76-7.86 (m, 2 H), 7.51 (s, 1 H), 7.41 (t, J = 7.8 Hz, 1



H), 7.16 (d, J = 7.3 Hz, 1 H), 3.64-3.77 (m, 2 H), 3.42-3.55 (m, 3 H), 3.38 (s, 3



H), 2.89-3.05 (m, 2 H), 2.47 (s, 3 H), 1.84-1.99 (m, 2 H), 1.61-1.77 (m, 3 H),



1.43-1.60 (m, 8 H)


230
(400 MHz, CDCl3) δ ppm 8.51 (s, 2 H), 7.94 (s, 1 H), 7.58-7.54 (m, 2 H), 7.45 (t,



J = 8.3 Hz, 1 H), 6.96-6.92 (m, 1 H), 3.97-3.89 (m, 6H), 3.68 (t J = 5.5 Hz, 2 H),



3.41 (s, 3 H), 3.34 (s, 3 H), 3.29-3.21 (m, 5 H), 1.29 (d, J = 6.8 Hz, 6 H)


231
(400 MHz, CDCl3) δ ppm 8.52 (s, 2 H), 7.94 (s, 1 H), 7.62-7.53 (m, 2 H), 7.48-



7.40 (m, 1 H), 6.97-6.89 (m, 1 H), 5.06-4.95 (m, 1 H), 4.16-4.08 (m, 2 H), 3.94-



3.87 (m, 4 H), 3.62 (t, J = 11.7 Hz, 2 H), 3.32-3.19 (m, 5 H), 3.17 (s, 3 H), 2.04-



1.91 (m, 2 H),1.78-1.70 (m, 2 H), 1.30 (d, J = 6.9 Hz, 6 H)


232
(400 MHz, methanol-d4) δ ppm 8.05 (s, 1 H), 7.97 (d, J = 7.6 Hz, 1 H), 7.88 (s, 1



H), 7.51 (d, J = 8.8 Hz, 2 H), 7.44 (t, J = 8.2 Hz, 1 H), 7.18 (d, J = 8.8 Hz, 2 H),



6.92-6.85 (m, 1 H), 3.92 (s, 3 H), 3.81-3.74 (m, 2 H), 3.51-3.46 (m, 1 H), 3.44-



3.38 (m, 3 H), 2.84-2.75 (m, 4 H), 2.41 (s, 3 H)



(OH missing)


233
(300 MHz, CDCl3) δ ppm 7.74-7.91 (m, 2 H), 7.41 (t, J = 7.8 Hz, 1 H), 7.27 (s, 1



H), 7.16 (d, J = 7.3 Hz, 1 H), 3.94 (ddd, J = 10.4, 7.2, 3.2 Hz, 2 H), 3.75-3.86 (m, 2



H), 3.39-3.68 (m, 5 H), 3.16-3.27 (m, 1 H), 3.04-3.16 (m, 1 H), 2.47 (s, 3 H),



2.11 (s, 3 H), 1.45 (dd, J = 6.7, 5.0 Hz, 6H)


234
(300 MHz, CDCl3) δ ppm 7.73-7.86 (m, 2 H), 7.55 (s, 1 H), 7.42 (t, J = 7.8 Hz, 1



H), 7.18 (d, J = 7.3 Hz, 1 H), 3.91-4.03 (m, 1 H), 3.49 (dt, J = 13.5, 6.7 Hz, 6 H),



3.00 (br. s., 1 H), 2.56 (d, J = 4.4 Hz, 1 H), 2.48 (s, 3 H), 2.06-2.31 (m, 2 H), 1.89-



2.02 (m, 2 H), 1.40-1.57 (m, 15 H)


235
(400 MHz, CDCl3) δ ppm 8.48 (s, 2 H), 7.82 (s, 1 H), 4.89-4.79 (m, 1 H), 4.25-



4.16 (m, 2 H), 3.93-3.84 (m, 2 H), 3.12 (sept, J = 6.7 Hz, 1 H), 3.01-2.93 (m, 1 H),



2.17-1.91 (m, 9 H), 1.84-1.76 (m, 1 H), 1.61-1.18 (m, 4 H), 1.21 (d, J = 6.8 Hz, 6 H)


236
(400 MHz, CDCl3) δ ppm 8.48 (s, 2 H), 7.82 (s, 1 H), 5.04-4.94 (m, 1 H), 4.89-



4.79 (m, 1 H), 4.15-4.07 (m, 2 H), 3.61 (t, J = 11.8 Hz, 2 H), 3.24-3.09 (m, 4 H),



2.17-1.90 (m, 6 H), 1.84-1.68 (m, 2 H), 1.61-1.24 (m, 6 H), 1.22 (d, J = 6.9 Hz, 6 H)


237
(400 MHz, CDCl3) δ ppm 8.47 (s, 2 H), 7.82 (s, 1 H), 4.89-4.79 (m, 1 H), 3.93 (t,



J = 5.5 Hz, 2 H), 3.67 (t, J = 5.5 Hz, 2 H), 3.40 (s, 3 H), 3.32 (s, 3 H), 3.16 (sept,



J = 6.8 Hz, 1 H), 2.18-1.93 (m, 5H), 1.84-1.76(m, 1H), 1.61-1.24 (m, 4 H), 1.21



(d, J = 6.8 Hz, 6 H)


238
(400 MHz, CDCl3) δ ppm 7.99 (s, 1 H), 7.37-7.50 (m, 3 H), 7.33 (d, J = 8.4 Hz, 1



H), 6.88 (d, J = 8.5 Hz, 2 H), 6.61 (d, J = 7.3 Hz, 2 H), 3.67 (s, 4 H), 3.40-3.48 (m,



7H), 3.35 (dd, J = 13.7, 6.9 Hz, 1 H), 3.13 (s, 3 H), 2.10 (br. s., 4 H), 1.26 (d, J = 6.8



Hz, 6 H)


239
(400 MHz CDCl3) δ ppm 8.37 (s, 1 H), 7.93 (s, 1 H), 7.75-7.57 (m, 1 H), 6.94-



6.72 (m, 1 H), 6.67 (d, J = 8.7 Hz, 1 H), 6.62-6.41 (m, 1 H), 5.91-5.58 (m, 1 H),



3.93-3.82 (m, 2 H), 3.79 (br. s., 4 H), 3.75-3.63 (m, 2 H), 3.42 (s, 3 H), 3.25-



3.19 (m, 1 H), 3.21 (s, 3 H), 2.39-2.23 (m, 2 H), 1.22 (s, 6 H)


240
(400 MHz, CDCl3) δ ppm 7.94 (s, 1 H), 7.45 (d, J = 8.5 Hz, 2 H), 6.99 (d, J = 10.8



Hz, 2 H), 6.92 (d, J = 8.7 Hz, 2 H), 6.72 (br. s., 1 H), 6.17-5.84 (m, 1 H), 4.13 (dd,



J = 11.4, 4.2 Hz, 2 H), 3.96 (tt, J = 11.5, 3.8 Hz, 1 H), 3.84 (t, J = 6.8 Hz, 4 H),



3.56 (t, J = 11.3 Hz, 2 H), 3.32-3.17 (m, 1 H), 2.91 (s, 3 H), 2.35 (quin, J = 7.1



Hz, 2 H), 2.03-1.85 (m, 2 H), 1.82-1.70 (m, 2 H), 1.21 (d, J = 7.0 Hz, 6 H)


241
(400 MHz, CDCl3) δ ppm 8.45-8.64 (m, 1 H), 8.10 (s, 1 H), 7.37-7.51 (m, 3 H),



7.06 (d, J = 8.9 Hz, 2 H), 6.75 (dd, J = 6.4, 2.5 Hz, 1 H), 3.94 (dt, J = 9.5, 4.9 Hz,



8 H), 3.46-3.62 (m, 4 H), 3.31-3.41 (m, 4 H), 3.18-3.31 (m, 1 H), 1.13-1.26 (m,



6 H), 1.09-1.30 (d, J = 6.8 Hz, 6 H)


242
(400 MHz, CDCl3) δ ppm 7.99-8.09 (m, 2 H), 7.93 (d, J = 10.4 Hz, 1 H), 7.52-



7.63 (m, 1 H), 7.48 (d, J = 8.5 Hz, 2 H), 6.97-7.14 (m, 3 H), 3.85-4.01 (m, 4 H),



3.33-3.42 (m, 4 H), 3.27 (dt, J = 13.6, 6.8 Hz, 1 H), 1.24 (d, J = 6.7 Hz, 6 H)


243
(400 MHz, CDCl3) δ ppm 8.06 (s, 1 H), 7.91-8.05 (m, 2 H), 7.48 (d, J = 8.6 Hz, 2



H), 7.35-7.45 (m, 1 H), 7.08 (d, J = 8.7 Hz, 2 H), 3.87-4.03 (m, 4 H), 3.32-3.40



(m, 4 H), 3.27 (dt, J = 13.5, 6.9 Hz, 1 H), 1.23 (d, J = 6.7 Hz, 6 H)


244
(400 MHz, CDCl3) δ ppm 8.02 (s, 1 H), 7.75 (t, J = 8.0 Hz, 1 H), 7.46 (d, J = 8.7



Hz, 2 H), 7.23-7.39 (m, 1 H), 7.07 (d, J = 8.7 Hz, 2 H), 6.63 (d, J = 8.4 Hz, 1 H),



3.94 (s, 8 H), 3.60-3.77 (m, 4 H), 3.31-3.40 (m, 4 H), 3.25 (dt, J = 13.6, 6.8 Hz, 1



H), 1.22 (d, J = 6.7 Hz, 6 H)


245
(400 MHz, CDCl3) δ ppm 8.05 (s, 1 H), 7.91-7.75 (m, 2 H), 7.42 (d, J = 8.9 Hz, 2



H), 6.93 (d, J = 8.7 Hz, 2 H), 6.84-6.68 (m, 1 H), 4.14 (dd, J = 10.8, 4.9 Hz, 2 H),



3.98 (tt, J = 11.7, 3.9 Hz, 1 H), 3.66-3.45 (m, 2 H), 3.33 (dt, J = 13.7, 6.8 Hz, 1H),



3.00-2.83 (m, 3 H), 1.95 (qd, J = 12.3, 4.6 Hz, 2 H), 1.83-1.73 (m, 2 H), 1.25-



1.08 (m, 6 H)


246
(400 MHz, CDCl3) δ ppm 8.34 (d, J = 2.0 Hz, 1 H), 8.03 (s, 1 H), 7.86 (d, J = 6.3



Hz,2 H), 7.65 (dd, J = 8.6, 2.1 Hz, 1 H), 6.81 (t, J = 8.7 Hz, 1 H), 6.67 (d, J = 8.9



Hz, 1 H), 4.95 (t, J = 11.7 Hz, 1 H), 4.12 (dd, J = 11.4, 4.4 Hz, 2 H), 3.63 (t, J =



11.2 Hz, 2 H), 3.39-3.19(m, 1 H), 3.06-2.89 (m, 3 H), 2.08-1.86(m, 2H), 1.79-1.64



(m, 2 H), 1.34-1.09 (m, 6 H)


247
(400 MHz, CDCl3) δ ppm 7.96 (s, 1 H), 7.43 (d, J = 8.6 Hz, 2 H), 7.38 (d, J = 8.1



Hz, 1 H), 7.29-7.34 (m, 1 H), 7.25-7.29 (m, 1 H), 7.07 (d, J = 8.6 Hz, 2 H), 6.59 (dd,



J = 7.8, 2.0 Hz, 1 H), 3.54-3.72 (m, 3 H), 3.35-3.44 (m, 4 H), 3.25-3.35 (m, 2



H), 2.90 (dt, J = 7.9, 3.8 Hz, 1 H), 2.41 (dq, J = 11.5, 9.0 Hz, 2 H), 1.96-2.20 (m, 10



H), 1.81-1.94 (m, 2 H)


248
(400 MHz, CDCl3) δ ppm 8.34 (d, J = 2.4 Hz, 1 H), 7.94 (s, 1 H), 7.67 (dd, J = 8.7,



2.6 Hz, 1 H), 7.35-7.43 (m, 1 H), 7.28-7.33 (m, 1 H), 7.26 (t, J = 2.1 Hz, 1 H),



6.83 (d, J = 8.8 Hz, 1 H), 6.59 (dd, J = 8.1, 1.7 Hz, 1 H), 3.98 (ddd, J = 13.6, 7.3,



3.5 Hz, 2 H), 3.63-3.75 (m, 3 H), 3.33-3.45 (m, 4 H), 2.92-3.02 (m, 1 H), 2.37-



2.51 (m, 2 H), 1.84-2.15 (m, 12 H)


249
(400 MHz, CDCl3) δ ppm 7.97 (s, 1 H), 7.44 (d, J = 8.6 Hz, 2 H), 7.34-7.41 (m, 1



H), 7.25-7.33 (m, 2 H), 6.93 (d, J = 8.6 Hz, 2 H), 6.57 (dd, J = 8.3, 1.5 Hz, 1 H),



4.14 (dd, J = 11.5, 4.4 Hz, 2 H), 3.92-4.03 (m, 1 H), 3.57 (t, J = 11.1 Hz, 2 H),



3.26-3.43 (m, 5 H), 2.93 (s, 3 H), 2.07 (dt, J = 6.4, 3.4 Hz, 4 H), 1.95 (qd, J = 12.2,



4.4 Hz, 2 H), 1.78 (dd, J = 12.3, 1.8 Hz, 2 H), 1.24 (d, J = 6.8 Hz, 6 H)


250
(400 MHz, CDCl3) δ ppm 7.99 (s, 1 H), 7.37-7.50 (m, 3 H), 7.33 (d, J = 8.4 Hz, 1



H), 6.88 (d, J = 8.5 Hz, 2 H), 6.61 (d, J = 7.3 Hz, 2 H), 3.67 (s, 4 H), 3.40-3.48 (m, 7



H), 3.35 (dd, J = 13.7, 6.9 Hz, 1 H), 3.13 (s, 3 H), 2.10 (br. s., 4 H), 1.26 (d, J = 6.8



Hz, 6 H)


251
(400 MHz, CDCl3) δ ppm 7.96 (s, 1 H), 7.36-7.45 (m, 3 H), 7.30-7.35 (m, 1 H),



7.29 (t, J = 2.1 Hz, 1 H), 6.94 (d, J = 8.8 Hz, 2 H), 6.54-6.62 (m, 1 H), 4.14 (dd,



J = 11.4, 4.3 Hz, 2 H), 3.92-4.04 (m, 1 H), 3.75 (q, J = 8.4 Hz, 1 H), 3.52-3.62(m,



2 H), 3.35-3.44 (m, 4 H), 2.94 (s, 3 H), 2.37-2.50 (m, 2 H), 2.03-2.12 (m, 6 H),



1.84-1.99 (m, 4 H), 1.79 (dd, J = 12.6, 2.1 Hz, 2 H)


252
(400 MHz, CDCl3) δ ppm 8.32 (d, J = 2.4 Hz, 1 H), 7.94 (s, 1 H), 7.64 (dd, J = 8.8,



2.7 Hz, 1 H), 7.36-7.42 (m, 1 H), 7.29-7.34 (m, 1 H), 7.24-7.28 (m, 1 H), 6.67



(d, J = 8.8 Hz, 1 H), 6.59 (dt, J = 7.0, 1.3 Hz, 1 H), 4.98 (tt, J = 11.9, 4.0 Hz, 1 H),



4.13 (dd, J = 11.5, 4.4 Hz, 2H), 3.75 (quin, J = 8.4 Hz, 1 H), 3.64 (td, J = 11.9, 1.7



Hz, 2 H), 3.35 -3.44 (m, 4 H), 3.02 (s, 3 H), 2.38-2.50 (m, 2 H), 2.03-2.17 (m, 6



H), 1.85-2.01 (m, 4 H), 1.74 (dd, J = 12.2, 2.2 Hz, 2 H)


253
(400 MHz, CDCl3) δ ppm 8.34 (d, J = 1.9 Hz, 1 H), 7.95 (s, 1 H), 7.65 (dd, J = 8.7,



2.0 Hz, 1 H), 7.34-7.44 (m, 1 H), 7.21-7.33 (m, 2 H), 6.68 (d, J = 8.7 Hz, 1 H),



6.58 (d, J = 7.5 Hz, 1 H), 3.87 (t, J = 5.5 Hz, 2 H), 3.67 (t, J = 5.5 Hz, 2 H), 3.34-



3.45 (m, 7 H), 3.29 (dt, J = 13.5, 6.8 Hz, 1 H), 3.21 (s, 3 H), 2.07 (br. s., 4 H),



1.26 (d, J = 6.7 Hz, 6 H)


254
(400 MHz, CDCl3) δ ppm 7.87 (s, 1 H), 7.40 (d, J = 8.9 Hz, 2 H), 6.90 (d, J = 8.9



Hz, 2 H), 4.93-4.73 (m, 1 H), 4.21-4.05 (m, 2 H), 4.00-3.85 (m, 1 H), 3.56 (td,



J = 11.9, 1.7 Hz, 2 H), 3.24 (dt, J = 13.6, 6.8 Hz, 1 H), 3.02-2.76 (m, 3 H), 2.28-



1.72 (m, 10 H), 1.62-1.48 (m, 2 H), 1.45-1.33 (m, 1 H), 1.18-1.06 (m, 6 H)


255
(300 MHz, CDCl3) δ ppm 7.74-7.86 (m, 2 H), 7.51-7.62 (m, 1 H), 7.43 (t, J = 7.9



Hz, 1 H), 7.19 (d, J = 7.6 Hz, 1 H), 3.91-4.37 (m, 1 H), 3.33-3.75 (m, 7 H), 2.82-



3.05 (m, 1 H), 2.27-2.52 (m, 5 H), 1.87-2.17 (m, 5 H), 1.41-1.58 (m, 6 H)


256
(300 MHz, CDCl3) δ ppm 7.68-7.83 (m, 2 H), 7.51 (s, 1 H), 7.34 (br. s., 1 H),



7.07 (br. s., 1 H), 3.65-3.75 (m, 2 H), 3.31-3.53 (m, 3 H), 3.15 (br. s., 2 H), 2.90-



3.06 (m, 2 H), 2.68-2.78 (m, 1 H), 2.61 (br. s., 1 H), 2.39-2.48 (m, 3 H), 1.98-



2.18 (m, 2 H), 1.88 (d, J = 12.3 Hz, 1 H), 1.42-1.54 (m, 7 H)


257
(300 MHz, CDCl3) δ ppm 7.74-7.85 (m, 2 H), 7.56 (s, 1 H), 7.43 (t, J = 7.9 Hz, 1



H), 7.19 (d, J = 7.6 Hz, 1 H), 3.87 (d, J = 12.6 Hz, 2 H), 3.43 (quin, J = 6.8 Hz, 1



H), 3.09-3.22 (m, 1 H), 2.95-3.08 (m, 5 H), 2.49 (s, 3 H), 2.34-2.43 (m, 2 H), 2.11-



2.28 (m, 2 H), 1.51 (d, J = 6.7 Hz, 6 H)


258
(300 MHz, CDCl3) δ ppm 7.72-7.87 (m, 2 H), 7.41 (t, J = 7.8 Hz, 1 H), 7.16 (d,



J = 7.3 Hz, 1 H), 6.96 (s, 1 H), 4.14 (s, 4 H), 3.68-3.79 (m, 4 H), 3.40 (quin, J = 6.7



Hz, 1 H), 2.48 (s, 3 H), 1.85-1.97 (m, 4 H), 1.42-1.54 (m, 6 H)


259
(400 MHz, CDCl3) δ ppm 8.52 (s, 2 H), 7.92 (s, 1 H), 7.38 (t, J = 8.0 1 H), 7.28-



7.24 (m, 1 H), 7.21-7.19 (m, 1 H), 6.61-6.57 (m, 1 H), 4.26-4.18 (m, 2 H), 3.95-



3.87 (m, 2 H), 3.40-3.35 (m, 4 H), 3.20 (sept, J = 6.8 Hz, 1 H), 3.02-2.95 (m, 1 H),



2.10-1.92 (m, 8 H), 1.30 (d, J = 6.8 Hz, 6 H)


260
(400 MHz, CDCl3) δ ppm 8.43-8.51 (m, 2 H), 8.38 (d, J = 2.4 Hz, 1 H), 7.97-8.04



(m, 1 H), 7.65-7.75 (m, 2 H), 7.56-7.64 (m, 1 H), 6.84 (d, J = 8.8 Hz, 1 H), 3.97



(ddd, J = 13.6, 7.3, 3.5 Hz, 2 H), 3.68 (ddd, J = 13.6, 7.7, 3.7 Hz, 2 H), 3.25 (quin,



J = 6.8 Hz, 1 H), 2.98 (tt, J = 7 .7 , 4.0 Hz, 1 H), 1.94-2.15 (m, 4 H), 1.26 (d, J = 6.8



Hz, 6 H)


261
(400 MHz, CDCl3) δ ppm 8.46 (s, 1 H), 8.43 (d, J = 8.3 Hz, 1 H), 8.04 (s, 1 H),



7.66-7.75 (m, 1 H), 7.58-7.65 (m, 1 H), 7.45 (d, J = 8.6 Hz, 2 H), 7.08 (d, J = 8.8



Hz, 2 H), 3.53-3.64 (m, 2 H), 3.19-3.37 (m, 3 H), 2.86-2.95 (m, 1 H), 2.00-2.20 (m,



4 H), 1.22 (d, J = 6.8 Hz, 6 H)


262
(400 MHz, CDCl3) δ ppm 7.77-7.90 (m, 2 H), 7.44 (t, J = 7.9 Hz, 1 H), 7.25-7.30



(m, 1 H), 7.19 (d, J = 7.7 Hz, 1 H), 3.78-3.88 (m, 4 H), 3.67-3.77 (m, 2 H), 3.49-



3.64 (m, 3 H), 2.50 (s, 3 H), 2.03 (t, J = 7.0 Hz, 2 H), 1.72 (t, J = 4.8 Hz, 4 H), 1.48



(d, J = 6.7 Hz, 6 H)


263
(400 MHz, CDCl3) δ ppm 7.43 (s, 1 H), 4.74 (tt, J = 11.5, 4.0 Hz, 1 H), 3.48-3.59



(m, 2 H), 3.32 (dt, J = 13.6, 6.8 Hz, 1 H), 3.20 (t, J = 9.0 Hz, 2 H), 2.91 (tt, J = 8.1,



4.1 Hz, 1 H), 1.90-2.27 (m, 10 H), 1.79 (d, J = 12.8 Hz, 1 H), 1.45-1.59 (m, 2 H),



1.34-1.45 (m, 7H)


264
(400 MHz, CDCl3) δ ppm 7.41 (s, 1 H), 4.72 (tt, J = 11.5, 3.9 Hz, 1 H), 3.51-3.58



(m, 2 H), 3.47 (tt, J = 8.1, 3.9 Hz, 1 H), 3.34-3.43 (m, 4 H), 3.08 (ddd, J = 12.3, 9.3,



2.9 Hz, 2 H), 1.74-2.15 (m, 11 H), 1.44-1.58 (m, 2 H), 1.33-1.42 (m, 7 H)


265
(400 MHz, CDCl3) δ ppm 7.39 (s, 1 H), 4.71 (tt, J = 11.5, 3.9 Hz, 1 H), 3.75 (ddd,



J = 6.6, 4.2, 2.6 Hz, 1 H), 3.40 (dt, J = 13.6, 6.8 Hz, 1 H), 3.21-3.31 (m, 4 H), 1.64-



2.12 (m, 13 H), 1.44-1.58 (m, 2 H), 1.36-1.43 (m, 6 H)


266
(400 MHz, CDCl3) δ ppm 7.41 (s, 1 H), 4.72 (tt, J = 11.5, 3.9 Hz, 1 H), 3.71 (d,



J = 12.5 Hz, 2 H), 3.64 (d, J = 6.3 Hz, 2 H), 3.38 (quin, J = 6.8 Hz, 1 H), 2.93 (td,



J = 12.2, 1.9 Hz, 2 H), 2.01-2.13 (m, 2 H), 1.95 (dd, J = 13.1, 2.6 Hz, 6 H), 1.72-



1.83 (m, 2 H), 1.45-1.61 (m, 4 H), 1.32-1.43 (m, 7 H)


267
(400 MHz, CDCl3) δ ppm 7.91 (s, 1 H), 7.48-7.66 (m, 1 H), 7.29-7.46 (m, 2 H),



7.10 (d, J = 7.6 Hz, 1 H), 6.97 (d, J = 8.8 Hz, 2 H), 6.41 (d, J = 8.3 Hz, 1 H), 3.77-



4.02 (m, 4 H), 3.22-3.25 (m, 5 H), 3.05 (s, 6H), 1.12 (d, J = 6.8 Hz, 6 H)


268
(400 MHz, CDCl3) δ ppm 8.08 (s, 1 H), 7.88 (d, J = 6.3 Hz, 2 H), 7.38-7.56 (m, 2



H), 6.99-7.15 (m, 2 H), 6.83 (t, J = 8.8 Hz, 1 H), 3.85-4.05 (m, 4 H), 3.32-3.41



(m, 4 H), 3.27 (dt, J = 13.6, 6.8 Hz, 1 H), 1.23 (d, J = 6.8 Hz, 6 H)


269
(400 MHz, CDCl3) δ ppm 8.10-8.25 (m, 2 H), 8.07 (s, 1 H), 7.63 (t, J = 8.3 Hz, 1



H), 7.48 (d, J = 8.5 Hz, 2 H), 7.26 (d, J = 8.2 Hz, 1 H), 7.08 (d, J = 8.5 Hz, 2 H),



3.89-4.08 (m, 4 H), 3.33-3.41 (m, 4 H), 3.28 (dt, J = 13.5, 6.8 Hz, 1 H), 1.26



(d, J = 6.8 Hz, 6 H)


270
(300 MHz, CDCl3) δ ppm 7.20-7.38 (m, 4 H), 6.53-6.74 (m, 1 H), 3.64-3.90



(m, 4 H), 3.47 (dt, J = 13.1, 6.5 Hz, 1 H), 2.91-3.18 (m, 6 H), 2.27 (d, J = 5.6 Hz, 2



H), 1.45 (dd, J = 14.5, 6.6 Hz, 6 H), 1.21-1.30 (m, 1 H)


271
(300 MHz, CDCl3) δ ppm 7.69-7.85 (m, 2 H), 7.36 (t, J = 7.8 Hz, 1 H), 7.22-7.29



(m, 1 H), 7.10 (d, J = 7.6 Hz, 1 H), 3.75-3.86 (m, 3 H), 3.64-3.73 (m, 1 H), 3.47



(quin, J = 6.7 Hz, 1 H), 2.43 (s, 3 H), 2.32 (dt, J = 12.5, 6.2 Hz, 1 H), 2.06-2.22 (m,



1 H), 1.37-1.55 (m, 8 H)


272
(300 MHz, CDCl3) δ ppm 7.60-7.83 (m, 2 H), 7.33 (t, J = 7.8 Hz, 1 H), 7.24 (s, 1



H), 7.09 (d, J = 7.6 Hz, 1 H), 3.62-4.15 (m, 5 H), 3.36-3.55 (m, 1 H), 2.94 (s, 3



H), 2.43-2.70 (m, 2 H), 2.41 (s, 3 H), 1.27-1.53 (m, 6 H)


275
(400 MHz CDCl3) δ ppm 8.29 (d, J = 2.0 Hz, 1 H), 7.85 (s, 1 H), 7.65-7.49 (m, 1



H), 6.73 (d, J = 8.5 Hz, 1 H), 4.94-4.73 (m, 1 H), 3.95-3.74 (m, 4 H), 3.70-3.60



(m, 4 H), 3.40 (s, 4 H), 3.21 (quin, J = 6.8 Hz, 1 H), 2.20-1.92 (m, 6 H), 1.81 (d,



J = 12.6 Hz, 1 H), 1.63-1.48 (m, 3 H), 1.46-1.35 (m, 1 H), 1.31-1.24 (m, 1 H),



1.19 (d, J = 6.8 Hz, 6 H)


276
(400 MHz, CDCl3) δ ppm 8.32 (d, J = 2.0 Hz, 1 H), 7.85 (s, 1 H), 7.64 (dd, J = 8.7,



2.6 Hz, 1 H), 6.65 (d, J = 8.7 Hz, 1 H), 5.59 (dd, J = 8.7, 5.3 Hz, 1 H), 4.93-4.76



(m, 1 H), 4.14 (td, J = 8.6, 4.5 Hz, 1 H), 3.91 (d, J = 5.6 Hz, 1 H), 3.78 (q, J = 8.0



Hz, 1 H), 3.20 (dt, J = 13.7, 6.8 Hz, 1 H), 3.06 (s, 2 H), 2.45-2.28 (m, 1 H), 2.21-



2.07 (m, 3 H), 2.07-1.92 (m, 5 H), 1.81 (d, J = 12.5 Hz, 1 H), 1.63-1.48 (m, 2 H),



1.46-1.35 (m, 1 H), 1.32-1.23 (m, 1 H), 1.19 (d, J = 6.8 Hz, 6 H)


277
(400 MHz, CDCl3) δ ppm 8.47 (s, 2 H), 7.91 (s, 1 H), 7.33-7.22 (m, 2 H), 7.10-



7.08 (m, 1 H), 6.56-6.52 (m, 1 H), 5.05-4.95 (m, 1 H), 4.11 (dd, J = 11.3, 4.3 Hz, 2



H), 3.7 (pent, J = 8.4 Hz, 1 H), 3.62 (t, J = 11.7 Hz, 2 H), 3.37-3.30 (m, 4 H), 3.15



(s, 3 H), 2.49-2.38 (m, 2 H), 2.15-1.82 (m, 10H), 1.77-1.70 (m, 2 H)


278
(400 MHz, DMSO-d6) δ ppm 8.59 (ddd, J = 12.6, 7.4, 2.4 Hz, 1 H), 8.35-8.14 (m,



1 H), 7.81-7.56 (m, 2 H), 7.42 (d, J = 8.5 Hz, 2 H), 7.08-6.87 (m, 2 H), 4.04 (t,



J = 11.6 Hz, 1 H), 3.95 (dd, J = 11.0, 4.0 Hz, 2 H), 3.50 (t, J = 11.1 Hz, 2 H), 3.33-



3.21 (m, 1 H), 2.88-2.77 (m, 3 H), 1.80 (qd, J = 12.0, 4.4 Hz, 2 H), 1.62 (d, J = 10.9



Hz, 2 H), 1.13 (d, J = 6.8 Hz, 6 H)


279
(400 MHz, DMSO-d6) δ ppm 8.59 (ddd, J = 12.5, 7.4, 2.4 Hz, 1 H), 8.32 (d, J = 2.2



Hz, 1 H), 8.29-8.21 (m, 1 H), 7.80 (dd, J = 8.7, 2.2 Hz, 1 H), 7.72 (s, 1 H), 7.70-



7.58 (m, 1 H), 7.03 (d, J = 8.9 Hz, 1 H), 4.05-3.85 (m, 2 H), 3.58-3.42(m, 2 H),



3.21-3.07 (m, 2 H), 1.97 (td, J = 6.4, 2.8 Hz, 2 H), 1.83-1.65 (m, 2 H), 1.13 (d,



J = 6.7 Hz, 6 H)


280
(400 MHz, CDCl3) δ ppm 8.51 (s, 2 H), 8.06-7.98 (m, 2 H), 7.96 (s, 1 H), 7.31-



7.18 (m, 2 H), 5.06-4.95 (m, 1H), 4.16-4.08 (m, 2 H), 3.62 (t, J = 11.7 Hz, 2 H),



3.26 (sept, J = 6.8 Hz, 1 H), 3.17 (s, 3 H), 2.04-1.90 (m, 2 H), 1.78-1.69 (m, 2 H),



1.29 (d, J = 6.8 Hz, 6 H)


281
(400 MHz, CDCl3) δ ppm 8.52 (s, 2 H), 8.44 (s, 1 H), 8.40 (d, J = 8.0 Hz, 1 H), 7.99



(s, 1 H), 7.70 (t, J = 7.6 Hz, 1 H), 7.63 (d, J = 7.7 Hz, 1 H), 5.06-4.95 (m, 1H), 4.16-



4.08 (m, 2 H), 3.62 (t, J = 11.7 Hz, 2 H), 3.27 (sept, J = 6.8 Hz, 1 H), 3.17 (s, 3 H),



2.04-1.90 (m, 2 H), 1.78-1.69 (m, 2 H), 1.31 (d, J = 6.8 Hz, 6 H)


282
(400 MHz, CDCl3) δ ppm 8.04 (s, 1 H), 7.84-7.94 (m, 2 H), 7.43 (d, J = 8.5 Hz, 2



H), 7.07 (d, J = 8.5 Hz, 2 H), 6.77 (t, J = 8.6 Hz, 1 H), 3.52-3.64 (m, 2 H), 3.27-



3.38 (m, 2 H), 3.22 (dt, J = 13.5, 6.8 Hz, 1 H), 2.85-2.96 (m, 1 H), 2.01-2.21 (m,



4 H), 1.19 (d, J = 6.8 Hz, 6 H)


283
(300 MHz, CDCl3) δ ppm 8.35 (d, J = 2.3 Hz, 1 H), 7.97-8.06 (m, 2 H), 7.86-7.96



(m, 1 H), 7.66 (dd, J = 8.8, 2.3 Hz, 1 H), 7.47-7.58 (m, 1 H), 7.01-7.13 (m, 1 H),



6.67 (d, J = 8.8 Hz, 1 H), 4.95 (ddd, J = 11.7, 7.8, 4.0 Hz, 1 H), 4.12 (dd, J = 11.4,



4.4 Hz, 2 H), 3.54-3.70 (m, 2 H), 3.30 (quin, J = 6.7 Hz, 1 H), 2.96-3.05 (m, 3 H),



1.95 (qd, J = 12.3, 4.7 Hz, 2 H), 1.65-1.78 (m, 2 H), 1.21-1.29 (m, 6 H)


284
(300 MHz, CDCl3) δ ppm 7.99-8.06 (m, 2 H), 7.91 (dd, J = 10.3, 2.1 Hz, 1 H),



7.48-7.58 (m, 1 H), 7.43 (d, J = 8.8 Hz, 2 H), 7.07 (td, J = 8.3, 2.2 Hz, 1 H), 6.93 (d,



J = 8.8 Hz, 2 H), 4.14 (dd, J = 11.4, 4.4 Hz, 2 H), 3.91-4.05 (m, 1 H), 3.50-3.63



(m, 2 H), 3.33 (quin, J = 6.7 Hz, 1 H), 2.93 (s, 3 H), 1.85-2.03 (m, 2 H), 1.72-1.84



(m, 2 H), 1.23 (d, J = 6.7 Hz, 6 H)


285
(300 MHz, CDCl3) δ ppm 8.36 (d, J = 2.3 Hz, 1 H), 7.96-8.09 (m, 2 H), 7.91 (dt,



J = 10.3, 2.2 Hz, 1 H), 7.69 (dd, J = 8.8, 2.3 Hz, 1 H), 7.53 (td, J = 8.2, 6.5 Hz, 1 H),



7.08 (td, J = 8.2, 2.1 Hz, 1 H), 6.83 (d, J = 8.8 Hz, 1 H), 3.97 (ddd, J = 13.6, 7.1,



3.7 Hz, 2 H), 3.68 (ddd, J = 13.5, 7.5, 3.4 Hz, 2 H), 3.24 (quin, J = 6.8 Hz, 1 H),



2.88-3.06 (m, 1 H), 1.89-2.19 (m, 4 H), 1.20-1.29 (m, 6 H)


286
(300 MHz, CDCl3) δ ppm 8.04 (br. s., 1 H), 8.02 (s, 1 H), 7.91 (d, J = 10.3 Hz, 1 H),



7.48-7.58 (m, 1 H), 7.44 (d, J = 8.2 Hz, 2 H), 7.06 (d, J = 8.2 Hz, 3 H), 3.49-3.65



(m, 2 H), 3.13-3.38 (m, 3 H), 2.90 (dd, J = 7.6, 3.5 Hz, 1 H), 1.96-2.21 (m, 4 H),



1.20 (d, J = 6.7 Hz, 6 H)


287
(400 MHz, CDCl3) δ ppm 8.29-8.52 (m, 3 H), 8.01 (s, 1 H), 7.54-7.75 (m, 3 H),



6.68 (d, J = 8.9 Hz, 1 H), 4.94 (t, J = 11.6 Hz, 1 H), 4.13 (dd, J = 11.3, 3.6 Hz, 2H),



3.63 (t, J = 11.4 Hz, 2 H), 3.31 (dt, J = 13.4, 6.5 Hz, 1 H), 3.02 (s, 3 H), 1.95 (qd,



J = 12.1, 4.3 Hz, 2 H), 1.74 (d, J = 11.1 Hz, 2 H), 1.27 (d, J = 6.7 Hz, 6 H)


288
(501 MHz, pyridine-d5) δ ppm 8.95-8.82 (m, 2H), 7.81 (s, 1H), 7.55-7.46 (m,



2H), 7.27 (d, J = 7.4 Hz, 1H), 4.38 (s, 2H), 3.34 (dt, J = 12.9, 3.9 Hz, 2H), 3.23



(dd, J = 11.8, 2.6 Hz, 2H), 3.18 (s, 2H), 3.01 (s, 3H), 2.77 (s, 3H), 2.09-1.90 (m,



2H), 1.88-1.69 (m, 2H)


289
(501 MHz, pyridine-d5) δ ppm 8.96-8.85 (m, 2H), 7.54-7.41 (m, 2H), 7.25 (s,



1H), 7.23 (d, J = 7.4 Hz, 1H), 4.16 (d, J = 8.1 Hz, 2H), 3.84 (d, J = 7.9 Hz, 2H),



3.33 (s, 3H), 3.31 (s, 2H), 2.65 (s, 3H), 1.32 (s, 3H)


290
(501 MHz, pyridine-d5) δ ppm 8.87-8.82 (m, 2H), 7.79 (s, 1H), 7.51 (dd, J = 8.6,



7.3 Hz, 2H), 7.32 -7.23 (m, 1H), 4.24 (dd, J = 13.2, 2.9 Hz, 1H), 3.99 (ddt, J =



11.8, 8.1, 3.9 Hz, 1H), 3.62 (t, J = 9.0 Hz, 1H), 3.49 -3.40 (m, 1H), 3.27 (td, J =



12.5, 3.3 Hz, 1H), 3.14 (dd, J = 9.1, 4.3 Hz, 1H), 2.95-2.77 (m, 2H), 2.74 (s, 3H)


291
(501 MHz, pyridine-d5) δ ppm 8.91-8.83 (m, 2H), 7.76 (s, 1H), 7.54-7.45 (m,



2H), 7.25 (tt, J = 7.1, 1.2 Hz, 1H), 3.57 (dq, J = 11.3, 3.2, 2.4 Hz, 2H), 3.32 (s,



3H), 3.24 (d, J = 6.0 Hz, 2H), 2.77 (td, J = 12.3, 2.3 Hz, 2H), 2.73 (s, 3H), 1.90-



1.68 (m, 3H), 1.61-1.42 (m, 2H)


292
(500 MHz, pyridine-d5) δ ppm 8.85 (d, J = 8.0 Hz, 2H), 7.74 (s, 1H), 7.50 (dd, J =



8.6, 7.4 Hz, 2H), 7.24 (t, J = 7.3 Hz, 1H), 4.29 (dt, J = 7.6, 4.0 Hz, 1H), 3.54 (dd,



J = 12.9, 3.8 Hz, 2H), 2.93 (ddd, J = 12.1, 10.1, 2.5 Hz, 2H), 2.67 (s, 3H), 2.16 (s,



5H), 1.81 (td, J = 11.4, 7.8 Hz, 2H)


293
(500 MHz, pyridine-d5) δ ppm 8.94 (d, J = 8.1 Hz, 2H), 8.91 (s, 2H), 7.53 -



(m, 1H), 7.26 (d, J = 4.9 Hz, 1H), 7.24 (s, 1H), 3.95 (s, 4H), 3.69 (t, J = 5.3 Hz,



4H), 2.70 (s, 3H), 1.79 (t, J = 5.2 Hz, 4H)


294
(400 MHz, pyridine-d5) δ ppm 8.93 -8.85 (m, 2H), 7.52 -7.41 (m, 2H), 7.23 (d, J =



6.9 Hz, 2H), 4.22 (t, J = 8.4 Hz, 2H), 4.02 (dd, J = 8.3, 5.5 Hz, 2H), 3.48 (d, J =



6.2 Hz, 2H), 3.32 (s, 3H), 2.93 (t, J = 5.8 Hz, 1H), 2.63 (s, 3H)


295
(400 MHz, pyridine-d5) δ ppm 8.95 -8.85 (m, 2H), 7.54 -7.44 (m, 3H), 7.29 -



7.22 (m, 1H), 3.98 (dp, J = 4.5, 2.4 Hz, 1H), 3.81 -3.63 (m, 3H), 3.49 (ddd, J =



10.6, 6.8, 2.5 Hz, 1H), 3.29 (s, 3H), 2.75 (s, 3H), 2.19 -



J = 12.8, 9.7, 8.2, 4.4 Hz, 1H)


296
(400 MHz, pyridine-d5) δ ppm 8.96-8.86 (m, 2H), 7.53-7.45 (m, 3H), 7.28-



7.22 (m, 1H), 3.98 (tt, J = 4.5, 2.4 Hz, 1H), 3.83-3.63 (m, 3H), 3.49 (ddd, J =



10.6, 6.8, 2.6 Hz, 1H), 3.29 (s, 3H), 2.75 (s, 3H), 2.14-2.04 (m, 1H), 1.99-1.84



(m, 1H)


297
(400 MHz, pyridine-d5) δ ppm 8.85 (d, J = 8.1 Hz, 2H), 7.50 (dd, J = 8.2, 2.3 Hz,



2H), 7.27 (dd, J = 9.1, 7.3 Hz, 1H), 4.95-4.77 (m, 1H), 3.39-3.30 (m, 2H), 3.13



(dt, J = 12.0, 5.2 Hz, 2H), 2.72 (s, 3H), 2.13-1.89 (m, 4H)


298
(400 MHz, pyridine-d5) δ ppm 8.94-8.83 (m, 2H), 7.53-7.43 (m, 3H), 7.25 (d, J =



7.3 Hz, 1H), 5.33 (d, J = 2.9 Hz, 1H), 3.94-3.76 (m, 3H), 3.64-3.51 (m, 1H),



2.76 (s, 3H), 2.28 (dt, J = 15.6, 7.6 Hz, 1H), 2.16-1.94 (m, 1H)


299
(400 MHz, pyridine-d5) δ ppm 8.86 (dt, J = 8.8, 1.8 Hz, 2H), 7.51 (s, 3H), 7.31-



7.23 (m, 1H), 4.10 (t, J = 12.7 Hz, 2H), 3.77 (t, J = 7.2 Hz, 2H), 2.76 (s, 3H),



2.57-2.50 (m, 2H)


300
(400 MHz, pyridine-d5) δ ppm 8.93-8.85 (m, 2H), 7.53-7.44 (m, 3H), 7.29-



7.23 (m, 1H), 5.47- 5.26 (m, 1H), 3.94-3.79 (m, 3H), 3.65-3.49 (m, 1H), 2.75



(s, 3H), 2.29 (ddt, J = 15.9, 14.1, 4.0 Hz, 1H), 2.1 (m, 1H)


301
(400 MHz, pyridine-d5) δ ppm 8.88-8.78 (m, 2H), 7.78 (s, 1H), 7.53-7.47 (m,



2H), 7.27 (t, J = 7.5 Hz, 1H), 4.48 (d, J = 10.1 Hz, 1H), 4.12-4.01 (m, 4H), 3.60-



3.44 (m, 2H), 3.34 (td, J = 12.6, 3.6 Hz, 1H), 2.88 (td, J = 12.2, 3.5 Hz, 1H), 2.81-



2.76 (m, 1H), 2.74 (s, 4H)


302
(400 MHz, pyridine-d5) δ ppm 8.95-8.86 (m, 2H), 7.53-7.47 (m, 2H), 7.27 (s,



1H), 7.26-7.23 (m, 1H), 4.24 (t, J = 7.8 Hz, 2H), 4.11 (dd, J = 8.5, 5.1 Hz, 2H),



3.78 (q, J = 4.4 Hz, 4H), 3.20 (tt, J = 7.1, 5.0 Hz, 1H), 2.71 (s, 3H), 2.37 (t, J = 4.6



Hz, 4H)


303
(400 MHz, pyridine-d5) δ ppm 8.85 (d, J = 7.8 Hz, 2H), 7.77 (s, 1H), 7.52-7.46



(m, 2H), 7.26 (d, J = 7.4 Hz, 1H), 3.90-3.78 (m, 1H), 3.61 (d, J = 12.6 Hz, 2H),



3.26 (s, 3H), 3.01-2.92 (m, 2H), 2.71 (s, 3H), 2.33 (dd, J = 13.0, 3.9 Hz, 2H),



2.02 (td, J = 11.2, 7.7 Hz, 2H)


304
(400 MHz, pyridine-d5) δ ppm 8.93-8.82 (m, 2H), 7.55-7.45 (m, 3H), 7.24 (d, J =



7.4 Hz, 1H), 3.74 (d, J = 9.9 Hz, 2H), 3.50 (dt, J = 10.0, 1.8 Hz, 2H), 2.74 (s,



3H), 1.53 (dt, J = 7.3, 2.9 Hz, 2H), 0.63 (td, J = 7.7, 4.8 Hz, 1H), 0.21 (q, J = 4.2



Hz, 1H)


305
(400 MHz, pyridine-d5) δ ppm 8.92-8.81 (m, 2H), 7.78 (s, 1H), 7.52-7.44 (m,



2H), 7.25 (d, J = 7.4 Hz, 1H), 3.66 (d, J = 12.4 Hz, 2H), 3.57 (t, J = 6.9 Hz, 2H),



3.43 (t, J = 6.7 Hz, 2H), 2.92-2.80 (m, 2H), 2.71 (s, 3H), 2.68-258 (m, 1H),



2.26 (q, J = 13.3, 11.9 Hz, 2H), 2.03-1.90 (m, 2H), 1.77 (p, J = 6.9 Hz, 2H), 1.63



(q, J = 6.9 Hz, 2H)


306
(400 MHz, pyridine-d5) δ ppm 8.96-8.85 (m, 2H), 7.54-7.45 (m, 2H), 7.27-



7.22 (m, 2H), 4.19-4.10 (m, 4H), 3.98 (s, 2H), 3.88 (t, J = 7.0 Hz, 2H), 2.66 (s,



3H), 2.13 (t, J = 7.0 Hz, 2H)


307
(400 MHz, pyridine-d5) δ ppm 8.96-8.82 (m, 2H), 7.54-7.44 (m, 2H), 7.24 (d, J =



7.3 Hz, 1H), 3.99 (s, 4H), 2.68 (s, 3H), 1.75 (s, 4H), 1.57-1.48 (m, 4H)


308
(400 MHz, pyridine-d5) δ ppm 8.98-8.87 (m, 2H), 7.54-7.44 (m, 2H), 7.24 (d, J =



4.1 Hz, 2H), 4.01 (d, J = 8.2 Hz, 2H), 3.86 (d, J = 8.2 Hz, 2H), 3.74 (s, 2H), 3.60



(t, J = 5.2 Hz, 2H), 2.66 (s, 3H), 1.78 (t, J = 6.0 Hz, 2H), 1.52 (p, J = 5.3 Hz, 2H)


309
(400 MHz, pyridine-d5) 6 9.00-8.88 (m, 2H), 7.53-7.44 (m, 2H), 7.24 (d, J = 8.0



Hz, 2H), 3.84 (s, 4H), 2.69 (s, 3H), 1.60 (t, J = 5.6 Hz, 4H), 1.35 (dq, J = 27.9, 5.8



Hz, 6H)


310
(400 MHz, pyridine-d5) δ ppm 8.88-8.80 (m, 2H), 7.52-7.42 (m, 3H), 7.27 (dd,



J = 12.8, 7.2 Hz, 1H), 3.29-3.23 (m, 2H), 2.96 (s, 2H), 2.73 (d, J = 7.7 Hz, 5H),



1.92-1.73 (m, 2H), 1.39 (t, J = 5.9 Hz, 2H), 0.50-0.30 (m, 4H)


311
(400 MHz, pyridine-d5) δ ppm 8.92-8.85 (m, 2H), 7.53-7.46 (m, 3H), 7.27-



7.22 (m, 1H), 3.95-3.79 (m, 3H), 3.68-3.54 (m, 3H), 2.75 (s, 3H), 1.94-1.79



(m, 5H)


312
(400 MHz, pyridine-d5) δ ppm 8.98-8.85 (m, 2H), 7.52-7.44 (m, 2H), 7.28 (s,



1H), 7.24 (d, J = 7.3 Hz, 1H), 4.20 (d, J = 8.6 Hz, 2H), 4.08 (d, J = 8.6 Hz, 2H),



3.65 (t, J = 5.1 Hz, 2H), 2.68 (s, 3H), 1.81-1.71 (m, 2H), 1.55 (tt, J = 8.1, 3.7 Hz,



2H), 1.43 (p, J = 5.9 Hz, 2H)


313
(400 MHz, pyridine-d5) δ ppm 8.90 (dd, J = 7.6, 1.6 Hz, 2H), 7.55 (s, 1H), 7.52-



7.45 (m, 2H), 7.23 (s, 1H), 4.17 (d, J = 9.8 Hz, 1H), 3.92-3.79 (m, 1H), 3.75-



3.68 (m, 1H), 3.58 (d, J = 9.8 Hz, 1H), 3.36 (t, J = 6.7 Hz, 2H), 2.76 (s, 3H), 2.49-



2.41 (m, 1H), 2.11 (ddt, J = 17.2, 12.8, 6.8 Hz, 2H), 1.94 (ddd, J = 11.4, 6.6, 3.4



Hz, 1H)


314
(400 MHz, pyridine-d5) δ ppm 8.91-8.82 (m, 2H), 7.77 (s, 1H), 7.51 (dd, J = 8.6



7.3 Hz, 2H), 7.25 (s, 1H), 4.86-4.66 (m, 1H), 3.63 (s, 2H), 2.90-2.68 (m, 7H),



2.47 (s, 6H), 2.0 (m, 2) 1.73 (td, J = 12.0, 10.5, 6.0 Hz, 3H)


315
(400 MHz, pyridine-d5) δ ppm 8.91-8.82 (m, 2H), 7.78 (s, 1H), 7.51 (dd, J = 8.6,



7.3 Hz, 2H), 7.21 (s, 1H), 3.91-3.77 (m, 4H), 3.74-3.60 (m, 4H), 2.72 (s, 3H),



1.96 (p, J = 5.5 Hz, 2H)


316
(400 MHz, CDCl3) δ ppm 8.52 (s, 2 H), 8.00 (d, J = 8.0 Hz, 1 H), 7.97 (s, 1 H), 7.90



(d, J = 10.3 Hz, 1 H), 7.57-7.48 (m, 1 H), 7.12-7.03 (m, 1 H), 5.06-4.95 (m, 1H),



4.16-4.08 (m, 2 H), 3.62 (t, J = 11.7 Hz, 2 H), 3.25 (sept, J = 6.8 Hz, 1 H), 3.17 (s, 3



H), 2.04-1.90 (m, 2 H), 1.78-1.70 (m, 2 H), 1.29 (d, J = 6.8 Hz, 6 H)


317
(400 MHz, DMSO-d6) δ ppm 8.69 (s, 2 H), 8.22 (d, J = 8.4 Hz, 2 H), 7.85 (s, 1 H),



7.22 (t, J = 9.3 Hz, 1 H), 4.96-4.86 (m, 1H), 4.01-3.93 (m, 2 H), 3.46 (t, J = 11.7 Hz,



2 H), 3.18 (sept, J = 6.8 Hz, 1 H), 3.10 (s, 3 H), 1.94-1.80 (m, 2 H), 1.66-1.58 (m, 2



H), 1.19 (d, J = 6.8 Hz, 6 H)


318
(400 MHz, pyridine-d5) δ ppm 8.68 (d, J = 8.2 Hz, 2H), 7.72 (s, 1H), 7.43 (t, J =



7.8 Hz, 2H), 7.19 (t, J = 7.3 Hz, 1H), 3.68 (dd, J = 5.6, 4.2 Hz, 2H), 3.59 (dd, J =



6.2, 3.9 Hz, 3H), 3.51 (ddd, J = 12.1, 7.0, 3.7 Hz, 2H), 3.34 (s, 3H), 3.06 (ddd, J =



12.2, 8.5, 3.3 Hz, 2H), 2.71 (s, 3H), 2.02 (ddt, J = 10.8, 7.0, 3.5 Hz, 2H), 1.84 (dtd,



J = 12.0, 8.0, 3.4 Hz, 2H)


319
(400 MHz, pyridine-d5) δ ppm 8.68 (d, J = 8.1 Hz, 2H), 7.72 (s, 1H), 7.69 (s, 1H),



7.43 (t, J = 7.8 Hz, 2H), 7.19 (t, J = 7.4 Hz, 1H), 3.66 (dd, J = 9.6, 5.9 Hz, 2H),



2.95 (s, 8H), 2.79 (ddt, J = 10.8, 8.2, 4.0 Hz, 1H), 2.70 (s, 3H), 2.24-2.07 (m,



2H), 1.89 (dd, J = 14.0, 3.6 Hz, 2H)


320
(400 MHz, pyridine-d5) δ ppm 8.68 (d, J = 8.1 Hz, 2H), 7.72 (s, 1H), 7.44 (t, J =



7.9 Hz, 2H), 7.21 (d, J = 7.4 Hz, 1H), 3.70 (s, 4H), 3.65-3.56 (m, 2H), 3.54 (t, J =



6.1 Hz, 2H), 2.94 (s, 3H), 2.70 (s, 3H), 2.05 (q, J = 5.8 Hz, 2H)


321
(400 MHz, pyridine-d5) δ ppm 8.70 (s, 2H), 7.69 (s, 1H), 7.44 (t, J = 7.8 Hz, 2H),



7.20 (t, J = 7.4 Hz, 1H), 3.46 (t, J = 6.3 Hz, 2H), 3.32 (t, J = 4.9 Hz, 4H), 3.30 (s,



3H), 2.74 (s, 3H), 2.68 (t, J = 4.8 Hz, 4H), 2.56 (t, J = 7.2 Hz, 2H), 1.84 (p, J = 6.7



Hz, 2H)


322
(400 MHz, pyridine-d5) δ ppm 8.69 (s, 2H), 7.72 (s, 1H), 7.44 (t, J = 7.8 Hz, 2H),



7.20 (t, J = 7.4 Hz, 1H), 3.73-3.65 (m, 4H), 3.54 (dd, J = 6.4, 3.6 Hz, 4H), 3.41-



3.33 (m, 4H), 3.27 (dd, J = 6.2, 3.8 Hz, 4H), 2.73 (s, 3H)


323
(400 MHz, pyridine-d5) δ ppm 8.70-8.64 (m, 2H), 7.72 (s, 1H), 7.43 (t, J = 7.8



Hz, 2H), 7.19 (t, J = 7.4 Hz, 1H), 3.34 (s, 2H), 3.32-3.26 (m, 4H), 2.96 (s, 5H),



2.83 (dd, J = 6.1, 3.8 Hz, 4H), 2.72 (s, 3H)


324
(400 MHz, pyridine-d5) δ ppm 8.70 (d, J = 8.0 Hz, 2H), 7.72 (s, 1H), 7.44 (t, J =



7.9 Hz, 2H), 7.20 (t, J = 7.4 Hz, 1H), 3.81-3.70 (m, 4H), 3.64 (d, J = 12.5 Hz,



2H), 2.88 (t, J = 12.0 Hz, 2H), 2.75 (s, 3H), 2.61-2.51 (m, 4H), 2.35 (s, 1H), 1.92



(d, J = 11.5 Hz, 2H)


325
(300 MHz, CDCl3) δ ppm 8.53 (s, 2 H), 7.96 (s, 1 H), 7.68-7.58 (m, 1 H), 7.16-



7.07 (m, 3 H), 4.27-4.17 (m, 2 H), 3.97-3.86 (m, 2 H), 3.23 (sept, J = 6.8 Hz, 1 H),



3.04-2.94 (m, 1 H), 2.12-1.91 (m, 4 H), 1.28 (d, J = 6.8 Hz, 6 H)


326
(300 MHz, CDCl3) δ ppm 8.40-8.35 (m, 1 H), 7.97 (s, 1 H), 7.74-7.58 (m, 2 H),



7.16-7.06 (m, 2 H), 6.83 (d, J = 8.8 Hz, 1 H), 4.03-3.91 (m, 2 H), 3.75-3.62 (m, 2



H), 3.25 (sept, J = 6.8 Hz, 1 H), 3.02-2.91 (m, 1 H), 2.15-1.93 (m, 4 H), 1.23 (d,



J = 6.8 Hz, 6 H)


327
(400 MHz, CDCl3) δ ppm 10.64 (s, 1 H), 7.99 (s, 1 H), 7.67-7.60 (m, 1 H), 7.45 (d,



J = 8.3 Hz, 2 H), 7.14-7.04 (m, 4 H), 3.62-3.54 (m, 2 H), 3.34-3.27 (m, 2 H), 3.24



(sept, J = 6.8 Hz, 1 H), 2.93-2.86 (m, 1 H), 2.18-2.00 (m, 4 H), 1.19 (d, J =



6.8 Hz, 6 H)


328
(400 MHz, CDCl3) δ ppm 7.51 (s, 1 H), 7.38 (t, J = 8.0 Hz, 2 H), 7.32 (d, J = 7.8



Hz, 1 H), 6.76-6.69 (m, 1 H), 3.54-3.46 (m, 1 H), 3.27-3.35 (m, 4 H), 3.05 (s, 6 H),



1.89-1.80 (m, 4 H), 1.77-1.69 (m, 2 H), 1.49 (d, J = 6.9 Hz, 6 H)


329
(400 MHz, CDCl3) δ ppm 7.55 (s, 1 H), 7.28-7.45 (m, 4 H), 6.74 (dd, J = 8.1, 2.4



Hz, 1 H), 3.51-3.64 (m, 2 H), 3.36-3.46 (m, 1 H), 3.25 (t, J = 9.2 Hz, 2 H), 3.00-



3.10 (m, 6 H), 2.87-2.97(m, 1 H), 2.09-2.31 (m, 4H), 1.47-1.57(m, 6 H)


330
(400 MHz, CDCl3) δ ppm 7.53 (s, 1 H), 7.35-7.43 (m, 2 H), 7.32 (d, J = 7.7 Hz, 1



H), 6.73 (d, J = 6.7 Hz, 1 H), 3.55-3.64 (m, 2 H), 3.46-3.55 (m, 2 H), 3.44 (s, 3



H), 3.15 (ddd, J = 12.3, 9.1, 2.9 Hz, 2 H), 3.05 (s, 6 H), 2.14 (ddd, J = 9.6, 6.4, 3.2



Hz, 2 H), 1.81-1.95 (m, 2 H), 1.48 (d, J = 6.7 Hz, 6 H)


331
(400 MHz, CDCl3) δ ppm 7.53 (s, 1 H), 7.28-7.41 (m, 3 H), 6.72 (dd, J = 7.9, 1.7



Hz, 1 H), 3.70-3.80 (m, 3 H), 3.66 (d, J = 6.3 Hz, 2 H), 3.43-3.51 (m, 1 H), 3.04



(s, 6 H), 2.94-3.03 (m, 2 H), 1.92-2.04 (m, 2 H), 1.98 (d, J = 11.3 Hz, 2 H), 1.57



(dd, J = 12.4, 3.5 Hz, 2 H), 1.43-1.53 (m, 6 H)



(300 MHz, CDCl3) δ ppm 7.84 (d, J = 7.6 Hz, 2 H), 7.72 (s, 1 H), 7.33 (br. s., 2 H),



332 7.08-7.20 (m, 3 H), 6.79 (d, J = 7.9 Hz, 2 H), 3.63-3.88 (m, 4 H), 2.96-3.23 (m,



4 H), 2.25-2.56 (m, 2H), 1.65-1.90 (m, 1 H), 1.38-1.60 (m, 3 H), 1.15 (s, 3 H)


333
(400 MHz, pyridine-d5) δ ppm 8.84 (d, J = 7.7 Hz, 2H), 7.68 (s, 1H), 7.52-7.44



(m, 2H), 7.25 (t, J = 7.3 Hz, 1H), 4.70 (p, J = 7.0 Hz, 1H), 3.30 (t, J = 5.2 Hz, 4H),



2.90 (dd, J = 7.1, 3.6 Hz, 4H), 2.81-2.69 (m, 5H), 2.64 (p, J = 7.6 Hz, 1H), 2.13



(ddd, J = 11.3, 9.1, 5.3 Hz, 2H)


334
(400 MHz, pyridine-d5) δ ppm 8.83 (d, J = 8.0 Hz, 2H), 7.84 (s, 1H), 7.56-7.46



(m, 2H), 7.25 (t, J = 7.4 Hz, 1H), 4.35 (t, J = 5.3 Hz, 2H), 3.46-3.37 (m, 4H),



3.28 (dd, J = 6.9, 3.6 Hz, 4H), 3.06 (t, J = 5.3 Hz, 2H), 2.74 (s, 3H)


335
(400 MHz, pyridine-d5) δ ppm 8.82 (d, J = 7.9 Hz, 2H), 7.90 (s, 1H), 7.52-7.45



(m, 2H), 7.25 (t, J = 7.3 Hz, 1H), 4.67-4.45 (m, 2H), 4.09-3.98 (m, 2H), 3.43



(dddd, J = 11.8, 8.9, 5.8, 2.6 Hz, 2H), 2.80 (s, 3H), 2.16 (ddh, J = 14.9, 7.4, 3.6 Hz,



1H), 1.87-1.71 (m, 1H), 1.71-1.51 (m, 3H)


336
(400 MHz, pyridine-d5) δ ppm 8.82 (d, J = 8.3 Hz, 2H), 7.90 (s, 1H), 7.50 (t, J =



7.9 Hz, 2H), 7.25 (t, J = 7.3 Hz, 1H), 4.60-4.45 (m, 1H), 4.08 (dq, J = 10.3, 4.6,



3.7 Hz, 2H), 3.42 (ddt, J = 11.8, 6.2, 2.6 Hz, 2H), 2.80(s, 3H), 2.25-2.05 (m,



1H), 1.82 (ddd, J = 13.2, 4.0, 2.1 Hz, 1H), 1.62 (dtd, J = 20.0, 12.1, 4.5 Hz, 3H)


337
(400 MHz, pyridine-d5) δ ppm 8.86-8.78 (m, 2H), 7.78 (s, 1H), 7.49 (dd, J = 8.6,



7.3 Hz, 2H), 7.25 (d, J = 7.4 Hz, 1H), 3.29 (t, J = 4.4 Hz, 2H), 3.13 (dt, J = 9.5, 7.1



Hz, 1H), 2.93-2.78 (m, 1H), 2.76 (s, 3H), 2.59 (s, 3H), 2.52-2.41 (m, 1H)


338
(400 MHz, pyridine-d5) δ ppm 8.81 (d, J = 7.7 Hz, 2H), 7.73 (s, 1H), 7.51-7.43



(m, 2H), 7.25 (t, J = 7.4 Hz, 1H), 5.43-5.28 (m, 1H), 3.56-3.38 (m, 2H), 3.28



(dt, J = 10.1, 7.3 Hz, 1H), 2.77 (s, 3H), 2.71 (s, 3H), 2.59-2.48 (m, 1H), 2.34-



2.22 (m, 1H)


339
(400 MHz, pyridine-d5) δ ppm 8.89-8.77 (m, 2H), 7.80 (s, 1H), 7.54-7.46 (m,



2H), 7.26 (t, J = 7.4 Hz, 1H), 4.96 (dt, J = 5.4, 2.6 Hz, 1H), 3.14 (d, J = 8.2 Hz,



4H), 2.72 (d, J = 3.1 Hz, 6H), 2.38 (td, J = 8.4, 4.2 Hz, 2H), 2.19 (dt, J = 14.5, 4.8



Hz, 2H)


340
(400 MHz, pyridine-d5) δ ppm 8.87-8.78 (m, 2H), 7.64 (s, 1H), 7.51-7.43 (m,



2H), 7.24 (d, J = 7.4 Hz, 1H), 4.80-4.67 (m, 1H), 2.94-2.74 (m, 6H), 2.67-



2.53 (m, 2H), 2.45 (s, 6H)


341
(400 MHz, pyridine-d5) δ ppm 8.81 (d, J = 7.7 Hz, 2H), 7.52-7.45 (m, 2H), 7.42



(s, 1H), 7.25 (t, J = 7.2 Hz, 1H), 5.09 (t, J = 6.9 Hz, 2H), 4.91 (dd, J = 7.7, 5.0 Hz,



2H), 2.78 (s, 3H)


342
(400 MHz, pyridine-d5) δ ppm 8.82 (d, J = 8.0 Hz, 2H), 7.84 (s, 1H), 7.48 (d, J =



8.3 Hz, 2H), 7.54-7.40 (m, 1H), 4.52 (t, J = 5.5 Hz, 2H), 3.21 (t, J = 5.2 Hz, 2H),



2.87 (s, 3H), 2.77 (s, 3H), 2.54 ?


343
(400 MHz, pyridine-d5) δ ppm 8.84 (d, J = 7.9 Hz, 2H), 7.88 (s, 1H), 7.53-7.41



(m, 2H), 7.21 (s, 1H), 4.87 (d, J = 3.3 Hz, 1H), 2.92 (d, J = 11.6 Hz, 1H), 2.79 (s,



3H), 2.25 (s, 4H), 2.00 (s, 2H), 1.82 (s, 1H), 1.61 (s, 2H)


344
(400 MHz, pyridine-d5) δ ppm 8.83 (d, J = 7.9 Hz, 2H), 7.64 (s, 1H), 7.50 (dd, J =



8.6, 7.3 Hz, 2H), 7.25 (t, J = 7.3 Hz, 1H), 4.86 (p, J = 6.6 Hz, 1H), 4.70 (d, J = 6.8



Hz, 4H), 2.87-2.78 (m, 2H), 2.77 (s, 3H), 2.49-2.38 (m, 2H)


345
(400 MHz, pyridine-d5) δ ppm 8.87-8.78 (m, 2H), 7.60 (s, 1H), 7.50 (dp, J = 8.3,



6.6 Hz, 2H), 7.25 (dd, J = 8.1, 6.7 Hz, 1H), 3.50 (d, J = 8.2 Hz, 1H), 2.94 (s, 2H),



2.76 (s, 3H), 2.64 (s, 3H), 2.58 ?



(s, 2H)


346
(400 MHz, pyridine-d5) δ ppm 8.82 (d, J = 8.0 Hz, 2H), 7.67 (s, 1H), 7.41 (s, 2H),



7.23 (s, 1H), 4.73 (q, J = 7.1 Hz, 1H), 2.80 (s, 4H), 2.49 (s, 5H), 1.61 (q, J = 5.8



Hz, 3H), 1.36 (s, 2H)


347
(400 MHz, pyridine-d5) δ ppm 8.84 (d, J = 8.1 Hz, 2H), 7.78 (s, 1H), 7.50 (t, J =



7.9 Hz, 2H), 7.25 (t, J = 7.3 Hz, 1H), 4.17 (dt, J = 19.1, 6.2 Hz, 2H), 2.86-2.71



(m, 5H), 2.38 (ddt, J = 15.3, 12.2, 8.1 Hz, 3H), 2.00 (q, J = 6.3 Hz, 2H)



(400 MHz,methanol-d4) δ ppm 8.12-8.01 (m, 2 H), 7.50 (s, 1 H), 7.39 (t, J = 7.7



Hz, 1 H), 7.14 (d, J = 7.3 Hz, 1 H), 4.45 (d, J = 5.6 Hz, 1 H), 4.34 (d, J = 5.4 Hz, 1



348 H), 3.69 (d, J = 12.2 Hz, 2 H), 3.56 (quin, J = 6.8 Hz, 1 H), 3.02-2.90 (m, 2 H),



2.46(s, 3 H), 2.02-1.88 (m, 3 H), 1.71-1.57 (m, 2 H), 1.53-1.42(m, 6 H) (OH



missing)


349
(300 MHz, CDCl3) δ ppm 7.77-7.92 (m, 2 H), 7.74 (dt, J = 10.3, 2.2 Hz, 1 H),



7.18-7.46 (m, 3 H), 6.79-6.98 (m, 3 H), 3.68-3.86 (m, 4 H), 3.38-3.54 (m, 1 H),



3.05-3.20 (m, 4 H), 2.10-2.38 (m, 2 H), 1.79-2.00 (m, 2 H), 1.61-1.79 (m, 2 H)


350
(300 MHz, CDCl3) δ ppm 7.90-8.16 (m, 3 H), 7.32-7.52 (m, 3 H), 6.91-7.17



(m, 2 H), 3.85-4.03 (m, 4 H), 3.71 (quin, J = 8.3 Hz, 1 H), 3.24-3.43 (m, 4 H),



2.31 -2.57 (m, 2 H), 2.00-2.19 (m, 2 H), 1.80-2.00 (m, 2 H)


351
(400 MHz, MeOD-d4) δ ppm 7.67 (s, 1 H), 7.09-6.91 (m, 1 H), 6.85-6.68 (m, 1



H), 6.44-6.24 (m, 1 H), 5.10 (br. s., 1 H), 3.67-3.47 (m, 1 H), 2.19-1.83 (m, 10



H), 1.81-1.69 (m, 1 H), 1.67-1.47 (m, 1 H), 1.45-1.30 (m, 1 H), 1.21 (d, J = 6.8



Hz, 6 H)


352
(400 MHz, MeOD-d4) δ ppm 7.72 (s, 1 H), 7.60 (s, 1 H), 5.27-5.00 (m, 1 H), 3.93



(s, 3 H), 3.08 (quin, J = 6.8 Hz, 1 H), 2.16 (s, 3 H), 2.05 (d, J = 11.8 Hz, 1 H), 1.99-



1.87(m, 5H), 1.81-1.72(m, 1 H), 1.68-1.50 (m, 2 H), 1.44-1.27(m, 1 H), 1.15



(d, J = 6.8 Hz, 6 H)


353
(300 MHz, CDCl3) δ ppm 7.96 (s, 1 H), 7.80 (d, J = 6.5 Hz, 2 H), 7.34 (d, J = 8.5



Hz, 2 H), 6.97 (d, J = 8.5 Hz, 2 H), 6.72 (t, J = 8.9 Hz, 1 H), 3.78-3.96 (m, 4 H),



3.59 (t, J = 8.4 Hz, 1 H), 3.14-3.31 (m, 4 H), 2.18-2.46 (m, 2 H), 1.90-2.08 (m, 2 H),



1.66-1.90 (m, 2 H)


354
(300 MHz, CDCl3) δ ppm 8.30-8.57 (m, 2 H), 7.97 (br. s., 1 H), 7.47-7.74 (m, 2



H), 7.37 (d, J = 8.5 Hz, 2 H), 7.00 (d, J = 8.5 Hz, 2 H), 3.78-4.01 (m, 4 H), 3.57-



3.71 (m, 1 H), 3.27 (br. s., 4 H), 2.26-2.47 (m, 2 H), 1.99 (br. s., 2 H), 1.76-1.92



(m, 2 H)


355
(400 MHz, CDCl3) δ ppm 8.03 (s, 1 H), 7.75-7.96 (m, 2 H), 7.35-7.51 (m, 3 H),



7.09 (d, J = 8.7 Hz, 2 H), 3.90-4.03 (m, 4 H), 3.63-3.79 (m, 1 H), 3.26-3.43 (m,



4 H), 2.31-2.52 (m, 5 H), 2.01-2.14(m, 2H), 1.82-1.99(m, 2H)


356
(400 MHz, CDCl3) δ ppm 8.38 (d, J = 8.1 Hz, 2 H), 8.03 (s, 1 H), 7.83 (d, J = 7.8



Hz, 2 H), 7.42 (d, J = 7.8 Hz, 2 H), 7.06 (d, J = 8.2 Hz, 2 H), 4.01-3.86 (m, 4 H),



3.68 (t, J = 8.1 Hz, 1 H), 3.33 (br. s., 4 H), 2.50-2.29 (m, 2 H), 2.05 (br. s., 2 H),



1.97-1.80 (m, 2 H)


357
(400 MHz, CDCl3) δ ppm 7.94 (s, 1 H), 7.81 (d, J = 8.1 Hz, 2 H), 7.44 (d, J = 7.9 Hz,



2 H), 7.13-7.00 (m, 2 H), 6.89 (d, J = 7.8 Hz, 2 H), 4.00-3.87 (m, 4 H), 3.74-3.58



(m, 1 H), 3.32 (br. s., 4 H), 3.05 (br. s., 6 H), 2.49-2.33 (m, 2 H), 2.04 (br. s., 2



H), 1.95-1.80 (m, 2 H)


358
(400 MHz, CDCl3) δ ppm 8.05 (dd, J = 8.7, 1.2 Hz, 2 H), 7.56 (t, J = 8.2 Hz, 2 H),



7.48 (s, 1 H), 7.37 (t, J = 7.3 Hz, 1 H), 4.01 (quin, J = 8.4 Hz, 1 H), 3.48-3.65 (m, 3



H), 3.45 (s, 3 H), 3.15 (ddd, J = 12.4, 9.1, 3.1 Hz, 2 H), 2.64 (quind, J = 9.0, 9.0, 9.0,



9.0, 3.0 Hz, 2 H), 2.35-2.50 (m, 2 H), 2.01-2.22 (m, 4 H), 1.82-1.98 (m, 2 H)


359
(400 MHz, MeOD-d4) δ ppm 8.12-8.00 (m, 2 H), 7.57-7.48 (m, 1 H), 7.39 (t, J =



7.7 Hz, 1 H), 7.14 (d, J = 7.3 Hz, 1 H), 3.70 (dt, J = 12.2, 6.0 Hz, 1 H), 3.64-3.44



(m, 5 H), 2.87 (s, 3 H), 2.46 (s, 3 H), 2.21-2.01 (m, 1 H), 1.93 (br. s., 1 H), 1.47



(ddd, J = 16.7, 6.7, 2.3 Hz, 4 H), 1.12 (d, J = 6.1 Hz, 6 H)


360
(400 MHz, CDCl3) δ ppm 7.71 (d, J = 6.9 Hz, 1 H), 7.66 (br. s., 1 H), 7.59 (s, 1 H),



7.21 (br. s., 1 H), 6.91 (br. s., 1 H), 3.43-3.59 (m, 1 H), 3.16-3.36 (m, 4 H), 2.77



(q, J = 7.2 Hz, 2H), 2.36 (s, 3 H), 1.71 (br. s., 4H), 1.35-1.59 (m, 11 H), 1.22 (t,



J = 7.2 Hz, 3H)


361
(400 MHz, MeOD-d4) δ ppm 8.10 (s, 1 H), 7.86-7.62 (m, 2 H), 5.22-4.96 (m, 1



H), 4.66 (dt, J = 13.4, 6.7 Hz, 1 H), 3.37 (quin, J = 6.8 Hz, 1 H), 2.13-1.99 (m, 2 H),



1.94 (d, J = 11.1 Hz, 4 H), 1.78 (d, J = 12.8 Hz, 1 H), 1.61-1.53 (m, 6H), 1.52-



1.44 (m, 1 H), 1.41-1.26 (m, 3 H), 1.21 (d, J = 6.8 Hz, 5 H)


362
(400 MHz, CDCl3) δ ppm 7.86 (s, 1 H), 7.01-6.68 (m, 1 H), 6.47-6.14 (m, 2 H),



5.01-4.59 (m, 1 H), 3.55 (s, 3 H), 3.14 (dt, J = 13.7, 6.8 Hz, 1 H), 2.28-1.89 (m, 6



H), 1.81 (d, J = 12.8 Hz, 1 H), 1.27-1.61 (m, 3 H), 1.14 (d, J = 6.8 Hz, 6 H)


363
(400 MHz, CDCl3) δ ppm 8.15-7.65 (m, 3 H), 6.62(s, 1 H), 4.85 (ddd, J = 11.4,



7.5, 4.2 Hz, 1 H), 3.70 (dt, J = 13.5, 6.8 Hz, 1 H), 2.21-1.92 (m, 6 H), 1.81 (d,



J = 12.8 Hz, 1 H), 1.62-1.46 (m, 2 H), 1.34-1.45 (m, 1 H), 1.13 (d, J =



6.8 Hz, 6 H)


364
(400 MHz, CDCl3) δ ppm 8.13-7.97 (m, 1 H), 7.92 (s, 1 H), 7.71-7.55 (m, 2 H),



6.50 (s, 1 H), 4.88 (tt, J = 11.5, 4.1 Hz, 1 H), 4.58 (s, 2 H), 2.90 (quin, J = 6.8 Hz, 1



H), 2.25-1.95 (m, 6 H), 1.82 (d, J = 13.1 Hz, 1 H), 1.66-1.49 (m, 2 H), 1.41 (t,



J = 12.5 Hz, 1 H), 1.10 (d, J = 6.8 Hz, 6 H)


365
(400 MHz, CDCl3) δ ppm 8.32 (d, J = 2.3 Hz, 1 H), 7.87 (s, 1 H), 7.64 (dd, J = 8.8,



2.4 Hz, 1 H), 6.79 (d, J = 8.9 Hz, 1 H), 5.11-5.01 (m, 1 H), 4.12-4.01 (m, 2H), 3.99-



3.91 (m, 2 H), 3.87 (t, J = 10.6 Hz, 1 H), 3.69-3.52 (m, 3 H), 3.14 (sept, J = 6.8 Hz, 1



H), 2.99-2.91 (m, 1 H), 2.49-2.37 (m, 1 H), 2.25-2.17 (m, 1 H), 2.11-1.88 (m, 6 H),



1.16 (dd, J = 6.8, 2.3 Hz, 6 H)


366
(400 MHz, methanol-d4) δ ppm 8.56 (d, J = 1.5 Hz, 2 H), 7.77 (d, J = 1.7 Hz, 1 H),



5.17-5.05 (m, 1 H), 4.35 (dd, J = 13.3, 6.2 Hz, 1 H), 4.18-4.01 (m, 2 H), 3.88-3.74



(m, 1 H), 3.14 (dt, J = 13.6, 6.8 Hz, 1 H), 3.04 (dt, J = 6.5, 3.1 Hz, 1 H), 2.17-2.01



(m, 4 H), 1.96 (d, J = 12.2 Hz, 4 H), 1.90-1.76 (m, 2 H), 1.75-1.54 (m, 2 H), 1.45-



1.26 (m, 2 H), 1.24-1.14 (m, 6 H) (OH missing)


367
(400 MHz, methanol-d4) δ ppm 8.31 (dd, J = 8.6, 1.0 Hz, 2 H), 7.53 (t, J = 8.1 Hz,



2 H), 7.45 (s, 1 H), 7.37-7.27 (m, 1 H), 4.27 (s, 2 H), 4.16-4.05 (m, 1 H), 3.75 (dt,



J = 8.0, 3.9 Hz, 1 H), 3.60-3.42 (m, 6 H), 3.18-3.06 (m, 2 H), 2.69-2.56 (m, 2 H),



2.53-2.42 (m, 2 H), 2.26-2.16 (m, 2 H), 2.14-1.86 (m, 8 H)


369
(400 MHz, CDCl3) δ ppm 9.76 (s, 1 H), 8.45 (s, 1 H), 8.31 (d, J = 2.3 Hz, 1 H), 8.22



(d, J = 6.8 Hz, 1 H), 8.09-8.03 (m, 1 H), 8.01 (s, 1 H), 7.67 (dd, J = 8.8, 2.4 Hz, 1 H),



6.80 (d, J = 8.9 Hz, 1 H), 3.98-3.90 (m, 2 H), 3.77-3.71 (m, 4 H), 3.68-3.60 (m, 2



H), 3.17 (sept, J = 6.7 Hz, 1 H), 2.99-2.91 (m, 1 H), 2.14-1.93 (m, 8 H), 1.17 (d,



J = 6.8 Hz, 6 H)


370
(400 MHz, CDCl3) δ ppm 7.90 (s, 1 H), 7.65 (d, J = 1.9 Hz, 1 H), 6.44 (d, J = 1.9 Hz,



1 H), 4.99-4.71 (m, 1 H), 3.75 (s, 3 H), 2.87 (quin, J = 6.9 Hz, 1 H), 2.27-1.91



(m, 6 H), 1.82 (d, J = 12.8 Hz, 1 H), 1.66-1.32 (m, 3 H), 1.14 (d, J = 7.0 Hz, 6 H)


371
(400 MHz, CDCl3) δ ppm 7.89-7.59(m, 1 H), 5.84 (br. s., 1 H), 4.80 (tt, J = 11.6,



4.0 Hz, 1 H), 4.13 (d, J = 1.7 Hz, 2 H), 3.72 (t, J = 5.3 Hz, 2 H), 3.31 (dt, J = 13.7, 6.8



Hz, 1 H), 2.55 (d, J = 1.5 Hz, 2 H), 2.22-1.90 (m, 7 H), 1.80 (d, J = 12.8 Hz, 1 H),



1.64-1.44 (m, 11 H), 1.38-1.17 (m, 6H)


372
(400 MHz, CD30D) δ ppm 8.30 (d, J = 8.1 Hz, 2 H), 7.44-7.56 (m, 2 H), 7.22-



7.42 (m, 2 H), 3.90-4.12 (m, 1 H), 3.73-3.90 (m, 1 H), 3.56-3.73 (m, 1 H), 3.37-



3.54 (m, 2 H), 2.85-3.12 (m, 2 H), 2.48 -2.65 (m, 2 H), 2.34-2.48 (m, 2 H),



1.95-2.18 (m, 4H), 1.64-1.90 (m, 2H), 1.05-1.31 (m, 6H)


373
(400 MHz, CD30D) δ ppm 8.31 (d, J = 8.2 Hz, 2 H), 7.53 (t, J = 8.0 Hz, 2 H), 7.45



(s, 1H), 7.31 (t, J = 7.4, 1 H), 4.10 (pent, J = 8.3 Hz, 1 H), 3.76-3.70 (m, 2 H), 3.63-



3.56 (m, 1 H), 3.41 (dd, J = 9.4, 5.0 Hz, 1 H), 3.35 (s, 3 H), 2.97-2.88 (m, 1 H),



2.74-2.60 (m, 2 H), 2.56-2.46 (m, 3 H), 2.25-1.83 (m, 6 H), 1.36-1.20 (m, 1 H)


374
(400 MHz, CD30D) δ ppm 8.50 (d, J = 4.3 Hz, 2 H), 7.73 (s, 1 H), 5.16-5.04 (m,



1H), 4.97-4.84 (m, 1 H), 4.29-4.20 (m, 2 H), 3.18-3.08 (m, 1 H), 3.10 (d, J = 2.3 Hz,



3 H), 3.00-2.82 (m, 2 H), 2.12-2.00 (m, 2 H), 1.98-1.88 (m, 4 H), 1.84-1.70 (m, 5



H), 1.65-1.52 (m, 2 H), 1.49 (s, 9 H)1.43-1.26 (m, 1 H), 1.19 (d, J = 6.6 Hz, 6 H)


375
(400 MHz, pyridine-d5) δ ppm 8.67 (d, J = 8.3 Hz, 2H), 7.72 (s, 1H), 7.44 (t, J =



7.8 Hz, 2H), 7.2 (t, 1H), 4.71 (d, J = 5.8 Hz, 2H), 4.46 (d, J = 5.9 Hz, 2H), 4.27 (s,



2H), 2.73 (s, 3H), 1.41 (s, 3H)


376
(400 MHz, pyridine-d5) δ ppm 8.67 (d, J = 8.1 Hz, 2H), 7.72 (s, 1H), 7.42 (t, J =



7.9 Hz, 2H), 7.2 (t, 1H), 3.29 (s, 4H), 2.73 (s, 3H), 2.07 (dd,J = 8.5, 5.6 Hz, 2H),



1.90-1.82 (m, 2H), 1.82-1.67 (m, 4H)


377
(400 MHz, pyridine-d5) δ ppm 8.67 (d, 2H), 7.72 (s, 1H), 7.43 (t, J = 7.9 Hz, 2H),



7.20 (t, J = 7.4 Hz, 1H), 4.62-4.43 (m, 3H), 4.01 (dq,J = 11.4, 3.6, 2.6 Hz, 2H),



3.40 (tt, J = 11.9, 3.2 Hz, 2H), 2.77 (s, 3H), 2.14 (dp, J = 16.6, 5.7, 5.3 Hz, 1H),



1.89-1.72 (m, 1H), 1.72-1.50 (m, 3H)


378
(400 MHz, pyridine-d5) δ ppm 8.67 (d, 2H), 7.75 (s, 1H), 7.48-7.36 (m, 2H), 7.19



(t, J = 7.4 Hz, 1H), 4.49 (d, J = 19.9 Hz, 2H), 3.09-2.92 (m, 2H), 2.79 (d, J = 9.1



Hz, 1H), 2.75 (s, 3H), 2.36 (s, 3H), 2.26 (m, 1H), 2.20 (m, 1H)


379
(400 MHz, pyridine-d5) δ ppm 8.64 (d, 2H), 7.75 (s, 1H), 7.48-7.36 (m, 2H), 7.20



(t, J = 7.4 Hz, 2H), 4.89-4.70 (m, 1H), 4.67-4.44 (m, 2H), 3.26 (d, J = 11.8 Hz,



2H), 2.74 (s, 3H), 2.58-2.42 (m, 5H), 2.14-1.85 (m, 4H), 1.80 (dt, J = 12.6, 3.0



Hz, 1H)


380
(400 MHz, pyridine-d5) δ ppm 8.66 (d, 2H), 7.75 (s, 1H), 7.46-7.37 (m, 2H), 7.20



(t, J = 7.3 Hz, 1H), 4.81 (ddt, J = 47.6, 6.5, 2.8 Hz, 1H), 4.63-4.44 (m, 2H), 3.27



(d, J = 11.9 Hz, 2H), 2.74 (s, 3H), 2.52 (d, J = 1.4 Hz, 5H), 2.11 ?



1.80 (dt, J = 13.9, 3.2 Hz, 1H)


381
(400 MHz, pyridine-d5) δ ppm 8.66 (d, 2H), 7.79 (s, 1H), 7.43 (t, J = 7.9 Hz, 2H),



7.19 (t, J = 7.4 Hz, 1H), 4.67-4.48 (m, 6H), 3.57 (p, J = 6.5 Hz, 1H), 2.77 (s, 3H),



2.74-2.55 (m, 2H), 2.30 (td, J = 6.8, 3.8 Hz, 2H), 1.93 (dddd, J = 32.0, 19.5, 9.0,



5.6 Hz, 3H)


382
(400 MHz, pyridine-d5) δ ppm 8.71-8.65 (m, 2H), 7.68 (s, 1H), 7.48-7.38 (m,



2H), 7.26-7.17 (m, 1H), 4.16 (d, J = 6.3 Hz, 2H), 2.72 (s, 5H), 2.46-2.36 (m,



1H), 2.25-2.07 (m, 3H), 200 (dtd, J = 13.0, 8.1, 4.1 Hz, 1H), 1.71 (dq, J = 13.0,



8.7 Hz, 1H)


383
(400 MHz, pyridine-d5) δ ppm 8.71-8.65 (m, 2H), 8.43 (s, 1H), 7.43 (t, J = 7.8



Hz, 2H), 7.19 (t, J = 7.4 Hz, 1H), 6.25 (s, 2H), 3.55 (d, J = 42.8 Hz, 4H), 2.94 (s,



3H), 1.42 (m, 6H)


384
(400 MHz, pyridine-d5) δ ppm 8.67 (d, J = 8.1 Hz, 2H), 7.82 (s, 1H), 7.45 (t, J =



7.9 Hz, 2H), 7.21 (t, J = 7.4 Hz, 1H), 4.86 (s, 2H), 3.07 (s, 3H), 3.01 ?



2H), 2.73 (s, 3H), 2.46-2.28 (m, 2H), 2.12 (p, J = 8.2 Hz, 2H)


385
(400 MHz, pyridine-d5) δ ppm 8.69-8.66 (m, 2H), 7.77 (s, 1H), 7.48-7.37 (m,



2H), 7.19 (t, J = 7.4 Hz, 1H), 4.42 (t, J = 5.9 Hz, 2H), 3.11 (t, J = 5.9 Hz, 2H), 2.79



(s, 3H), 2.48 (d, J = 7.3 Hz, 2H), 1.95-1.79 (m, 2H), 0.89 (d, J = 6.5 Hz, 6H),



0.51-0.43 (m, 4H)


386
(400 MHz, pyridine-d5) δ ppm 8.68 (d, J = 8.1 Hz, 2H), 7.70 (s, 1H), 7.44 (t, J =



7.8 Hz, 2H), 7.20 (t, J = 7.5 Hz, 1H), 4.13 (s, 2H), 2.88-2.76 (m, 2H), 2.73 (s,



3H), 2.41 (td, J = 14.3, 9.2 Hz, 2H), 1.36 (s, 3H)


387
(400 MHz, pyridine-d5) δ ppm 8.67 (d, J = 8.2 Hz, 2H), 7.68 (s, 1H), 7.43 (t, J =



7.8 Hz, 2H), 7.19 (t, J = 7.4 Hz, 1H), 4.49 (d, J = 48.7 Hz, 2H), 4.25 (s, 2H), 2.75



(s, 3H), 0.86-0.68 (m, 4H)


388
(400 MHz, pyridine-d5) δ ppm 8.69-8.66 (m, 2H), 7.68 (s, 1H), 7.45-7.36 (m,



2H), 7.19 (t, J = 7.4 Hz, 1H), 4.15 (s, 2H), 3.56 (t, J = 6.6 Hz, 2H), 3.26 (s, 3H),



2.78 (s, 3H), 1.87 (t, J = 6.6 Hz, 2H), 0.73-0.56 (m, 4H)


389
(400 MHz, pyridine-d5) δ ppm 8.68-8.65 (m, 2H), 7.73 (s, 1H), 7.43 (dd, J = 8.6,



7.3 Hz, 2H), 7.19 (t, J = 7.4 Hz, 1H), 4.47 (dd, J = 9.9, 7.1 Hz, 1H), 4.31 (dd, J =



10.0, 6.1 Hz, 1H), 2.76 (s, 4H), 2.21-1.99 (m, 3H), 1.78-1.59 (m, 3H)


390
(400 MHz, CDCl3) δ ppm 8.06 (m, 3H), 7.77 (d, J = 8.2 Hz, 2H), 7.52 (t, J = 7.3 Hz,



2H), 7.30 (m, 1H), 7.00 (d, J = 8.5 Hz, 2H), 5.27 (spt, J = 6.1, 1H), 3.92 (t, J = 4.7,



4H), 3.81 (t, J = 4.5, 4H), 1.45 (d, J = 6.2, 6H)


391
(400 MHz, methanol-d4) δ ppm 8.38-8.27 (m, 2 H), 7.53 (s, 1 H), 7.32-7.23 (m, 2



H), 3.70 (d, J = 12.2 Hz, 2 H), 3.63-3.53 (m, 1 H), 3.43-3.38 (m, 5 H), 3.05-2.92



(m, 2 H), 2.03-1.84 (m, 3 H), 1.68-1.54 (m, 2 H), 1.50 (d, J = 6.8 Hz, 6 H) (OH



missing)


392
(400 MHz, CDCl3) δ ppm 8.19 (d, J = 5.7 Hz, 1 H), 7.89 (s, 1 H), 7.81 (dd, J = 5.8,



1.8 Hz, 1 H), 7.43 (d, J = 1.6 Hz, 1 H), 7.41 (d, J = 8.7 Hz, 2 H), 7.01 (d, J = 8.7 Hz, 2



H),3.59-3.49 (m, 6 H), 3.28-3.20 (m, 2 H), 3.14 (sept, J = 6.8 Hz, 1 H), 2.90-2.83



(m, 1 H), 2.16-1.99 (m, 8 H), 1.15 (d, J = 6.8 Hz, 6 H)


393
(400 MHz, MeOD-d4) δ ppm 8.31-8.40 (m, 2 H), 7.46 (s, 1 H), 7.17-7.26 (m, 2



H), 3.46-3.62 (m, 4 H), 3.42 (s, 3 H), 3.03-3.13 (m, 2 H), 2.16 (t, J = 5.8 Hz, 2



H), 1.74-1.89 (m, 2 H), 1.47 (d, J = 6.8 Hz, 6 H)


394
(400 MHz, methanol-d4) δ ppm 8.36-8.23 (m, 2 H), 7.51 (s, 1 H), 7.25 (t, J = 8.8



Hz, 2 H), 3.69 (d, J = 12.5 Hz, 2 H), 3.61-3.50 (m, 3 H), 2.96 (t, J = 11.4 Hz, 2 H),



1.95 (d, J = 13.2 Hz, 2 H), 1.82-1.66 (m, 1 H), 1.62-1.52 (m, 2 H), 1.47 (d, J = 7.0



Hz, 6 H) (2xOH missing)


395
(400 MHz, MeOD-d4) δ ppm 8.14-8.46 (m, 2 H), 7.51 (d, J = 1.7 Hz, 1 H), 7.08-



7.34(m, 2 H), 3.44-3.70(m, 6 H), 2.96-3.23 (m, 2H), 2.15 (d, J = 10.5 Hz, 2 H),



1.73-1.93 (m, 2 H), 1.53-1.69 (m, 2 H), 1.25-1.53 (m, 8 H), 0.99 (t, J = 7.3 Hz,



3 H)


396
(400 MHz, MeOD-d4) δ ppm 8.17-8.40 (m, 2 H), 7.42-7.60 (m, 1 H), 7.14-7.34



(m, 2 H), 3.45-3.64 (m, 4 H), 3.00-3.26 (m, 2 H), 2.14 (br. s., 2 H), 1.74-1.98



(m, 3 H), 1.50 (dd, J = 6.6, 1.7 Hz, 6 H), 0.98 (dd, J = 6.6, 1.0 Hz, 6 H)


398
(400 MHz, CDCl3) δ ppm 8.01 (dd, J = 8.6, 4.7 Hz, 2 H), 7.57 (s, 1 H), 7.26 (t,



J = 8.6 Hz, 2 H), 4.65 (t, J = 7.7 Hz, 2 H), 3.40-3.57 (m, 3 H), 3.35 (d, J = 5.5 Hz, 2



H), 2.54 (t, J = 7.8 Hz, 2 H), 2.23 (br. s., 2 H), 2.05-2.18 (m, 2 H), 1.50 (d, J = 6.7



Hz, 6 H)


399
(400 MHz, CDCl3) δ ppm 7.96 (br. s., 2 H), 7.57 (br. s., 1 H), 7.18 (br. s., 2 H),



5.52-5.94 (m, 1 H), 3.73 (d, J = 8.0 Hz, 1 H), 3.59 (br. s., 1 H), 3.36-3.51 (m, 1



H),2.91 (d, J = 11.9 Hz, 2 H), 2.36 (br. s., 1H), 1.95-2.11 (m, 2 H), 1.79-1.94



(m, 2 H), 1.48 (t, J = 6.1 Hz, 6 H)


400
(400 MHz, CDCl3) δ ppm 8.02-7.92 (m, 2 H), 7.24-7.16 (m, 2 H), 6.94 (s, 1 H),



4.14 (d, J = 8.2 Hz, 2 H), 4.0 (d, J = 8.2 Hz, 2 H), 3.78 (s, 2 H), 3.71-3.64(m, 2 H),



3.39 (hept, J = 6.7Hz, 1 H), 1.94-1.88 (m, 2 H), 1.72-1.64 (m, 2 H), 1.44 (d,



J = 6.7 Hz, 6 H)


401
(400 MHz, CDCl3) δ ppm 7.94-8.04 (m, 2 H), 7.55 (s, 1 H), 7.19-7.26 (m, 2 H),



3.91 (t, J = 6.7 Hz, 2 H), 3.33-3.55 (m, 5 H), 2.02 (quin, J = 7.1 Hz, 2 H), 1.79-



1.93 (m, 6 H), 1.43-1.51 (m, 6 H)


403
(400 MHz, CDCl3) δ ppm 8.05 (d, J = 7.7 Hz, 2 H), 7.55 (t, J = 7.9 Hz, 2 H), 7.47 (s,



1 H), 7.33-7.40 (m, 1 H), 3.99 (t, J = 8.4 Hz, 1 H), 3.69 (d, J = 12.6 Hz, 2 H), 3.52



(t, J = 6.2 Hz, 2 H), 3.39 (s, 3 H), 2.92-3.03 (m, 2 H), 2.57-2.70 (m, 2 H), 2.38-



2.50 (m, 2 H), 2.01 -2.14 (m, 2 H), 1.94 (d, J = 11.8 Hz, 2 H), 1.63-1.80 (m, 3 H),



1.47-1.61 (m, 2 H)


405
(400 MHz, CDCl3) δ ppm 8.02-8.08 (m, 2 H), 7.51-7.60 (m, 2 H), 7.48 (s, 1 H),



7.32-7.41 (m, 1 H), 3.99 (quin, J = 8.4 Hz, 1 H), 3.72 (d, J = 12.5 Hz, 2 H), 3.35-



3.45 (m, 5 H), 2.98 (td, J = 12.4, 2.1 Hz, 2 H), 2.57-2.71 (m, 2 H), 2.38-2.51 (m,



2 H), 2.02-2.18 (m, 2 H), 1.84-2.01 (m, 3 H), 1.51-1.66 (m, 2 H)


406
(400 MHz, CDCl3) δ ppm 8.00-8.07 (m, 2 H), 7.49-7.58 (m, 2 H), 7.31-7.39



(m, 1 H), 7.25 (s, 1 H), 3.86-4.00 (m, 3 H), 3.68 (d, J = 10.2 Hz, 2 H), 2.56-2.69



(m, 2 H), 2.41 -2.53 (m, 2 H), 1.97-2.15 (m, 2 H), 1.68-1.76 (m, 2 H), 0.73-



0.82 (m, 1 H), 0.33 (q, J = 4.1 Hz, 1 H)


407
(300 MHz, DMSO-d6) δ ppm 8.33 (d, J = 7.7 Hz, 2 H), 7.56 (t, J = 7.7 Hz, 2 H),



7.40 (s, 1 H), 7.32 (t, J = 7.6 Hz, 1 H), 4.16 (d, J = 5.4 Hz, 2 H), 4.02 (p, J =



8.4 Hz, 1 H), 2.49-2.34 (m, 4 H), 2.16-2.02 (m, 1 H) 2.00-1.64 (m, 7 H),



1.40-1.10 (m, 5 H)


408
(400 MHz, CDCl3) δ ppm 8.01-8.15 (m, 2 H), 7.53-7.64 (m, 2 H), 7.50 (s, 1 H),



7.34-7.43 (m, 1 H), 3.94-4.13 (m, 1 H), 3.27-3.40 (m, 4 H), 2.58-2.75 (m, 2



H), 2.38-2.54 (m, 2 H), 2.02-2.22 (m, 2 H), 1.85-1.97 (m, 4 H), 1.67-1.82 (m,



2H)


409
(400 MHz, CDCl3) δ ppm 8.02-8.16 (m, 2 H), 7.50-7.64 (m, 2 H), 7.32-7.42



(m, 1 H), 6.93 (s, 1 H), 4.00-4.11 (m, 4H), 3.91 (quip, J = 7.9 Hz, 1 H), 2.58-2.72



(m, 2 H), 2.41 -2.55 (m, 2 H), 2.01-2.19(m, 2 H), 1.72-1.84(m, 4 H), 1.40-



1.63 (m, 6 H)


410
(400 MHz, CDCl3) δ ppm 8.00-8.10 (m, 2 H), 7.52-7.61 (m, 2 H), 7.50 (s, 1 H),



7.34-7.43 (m, 1 H), 3.96 (quip, J = 8.4 Hz, 1 H), 3.51-3.63 (m, 2 H), 3.18-3.32



(m, 2 H), 2.90-3.02 (m, 1 H), 2.58-2.73 (m, 2 H), 2.38-2.51 (m, 2 H), 2.03-



2.33 (m, 6 H)


411
(400 MHz, CDCl3) δ ppm 7.97-8.13 (m, 2 H), 7.51-7.65 (m, 3 H), 7.37-7.49



(m, 1 H), 3.95-4.09 (m, 2 H), 3.89 (d, J = 12.7 Hz, 2 H), 3.10-3.27 (m, 2 H),



3.03 -3.08 (m, 3 H), 2.59-2.77 (m, 2 H), 2.36-2.56 (m, 4 H), 2.02-2.32 (m, 4 H)


412
(300 MHz, CDCl3) δ ppm 8.26 (d, J = 6.2 Hz, 1 H), 7.66-7.43 (m, 3 H), 3.70-3.37



(m, 12 H), 3.25-3.06 (m, 2 H), 2.20-2.01 (m, 6 H), 1.89 (dt, J = 8.2, 4.4 Hz, 2 H),



1.54-1.40 (m, 6 H)


413
(400 MHz, CDCl3) δ ppm 8.46 (s, 1 H), 8.27 (d, J = 2.2 Hz, 1 H), 8.21 (d, J = 6.5 Hz,



1 H), 7.99 (d, J = 6.8 Hz, 1 H), 7.95 (s, 1 H), 7.63 (dd, J = 8.8, 2.2 Hz, 1 H), 6.79 (d,



J = 8.8 Hz, 1 H), 3.99-3.89 (m, 2 H), 3.76-3.55 (m, 7 H), 2.99-2.91 (m, 1 H), 2.38-



2.26 (m, 2 H), 2.12-1.80 (m, 12 H)


414
(300 MHz, CDCl3) δ ppm 8.04 (d, J = 7.5 Hz, 2 H), 7.54 (t, J = 7.5 Hz, 2 H), 7.48 (s,



1 H), 7.36 (t, J = 7.6 Hz, 1 H), 4.37 (t, J = 6.3 Hz, 2 H), 4.12-3.98 (m, 3 H), 3.43



(td, J = 11.8, 2.1 Hz, 2H), 2.65-2.37 (m, 4 H), 2.22-1.80 (m, 5 H), 1.76-1.68



(m, 2 H), 1.52-1.36 (m, 2 H)


415
(400 MHz, CDCl3) δ ppm 10.75 (br. s., 1 H), 8.06 (d, J = 7.7 Hz, 2 H), 7.56 (t,



J = 7.9 Hz, 2 H), 7.48 (s, 1 H), 7.34-7.42 (m, 1 H), 4.62-4.84 (m, 1 H), 4.39-4.58



(m, 2 H), 4.02-4.17 (m, 3 H), 3.41-3.54 (m, 2 H), 2.54-2.67 (m, 2 H), 2.42-



2.54 (m, 2 H), 2.09-2.25 (m, 2 H), 1.96-2.09 (m, 1 H), 1.91 (d, J = 13.3 Hz, 1 H),



1.54-1.72 (m, 3 H)


416
(400 MHz, CDCl3) δ ppm 8.73 (s, 1 H), 8.31 (d, J = 2.3 Hz, 1 H), 8.23 (d, J = 6.9 Hz,



1 H), 8.01 (d, J = 6.7 Hz, 1 H), 7.95-7.90 (m, 2 H), 7.21 (d, J = 8.9 Hz, 1 H), 4.07-



3.98 (m, 2 H), 3.82 (s, 8 H), 3.71 (pent, J = 8.2 Hz, 1 H), 3.60-3.51 (m, 2 H), 3.27-



3.18 (m, 1 H), 2.36-2.24 (m, 2 H), 2.05-1.75 (m, 8 H)


417
(400 MHz, CDCl3) δ ppm 8.05 (d, J = 7.6 Hz, 2 H), 7.55 (t, J = 7.6 Hz, 2 H), 7.49 (s,



1 H), 7.36 (t, J = 7.6 Hz, 1 H), 4.17 (d, J = 6.4 Hz, 2 H), 4.12-4.02 (m, 3 H), 3.56-



3.48 (m, 2 H), 2.63 -2.62 (m, 2 H), 2.51-2.40 (m, 2 H), 2.31-1.96(m, 3H),



1.88-1.79 (m, 2 H), 1.65-1.52 (m, 2 H)


418
(400 MHz, CDCl3) δ ppm 7.98-8.16 (m, 2 H), 7.48-7.65 (m, 2 H), 7.32-7.43



(m, 1 H), 6.85-6.95 (m, 1 H), 4.35-4.53 (m, 2 H), 4.12-4.24 (m, 2 H), 3.83-



3.96 (m, 1 H), 3.59-3.72 (m, 2 H), 3.40-3.51 (m, 3 H), 3.11 (ddd, J = 8.4, 5.6, 2.4



Hz, 1 H), 2.57-2.73 (m, 2 H), 2.37-2.56 (m, 2 H), 1.96-2.17 (m, 2 H)


419
(400 MHz, CDCl3) δ ppm 8.08 (dd, J = 8.6, 1.0 Hz, 2 H), 7.50-7.67 (m, 2 H), 7.33-



7.48 (m, 2 H), 3.93-4.15 (m, 1 H), 3.38-3.49 (m, 2 H), 3.15 (s, 2 H), 2.58-2.73



(m, 2 H), 2.40-2.55 (m, 2 H), 1.96-2.20 (m, 4 H), 1.54-1.67 (m, 2 H), 0.40-



0.58 (m, 4 H)


420
(400 MHz, CDCl3) δ ppm 8.32 (d, J = 2.3 Hz, 1 H), 8.09 (dd, J = 8.5, 1.1 Hz, 2 H),



8.02 (s, 1 H), 7.66 (dd, J = 8.7, 2.6 Hz, 1 H), 7.63-7.57 (m, 2 H), 7.47-7.40 (m, 1



H), 6.84 (d, J = 8.7 Hz, 1 H), 3.98 (ddd, J = 13.7, 7.4, 3.7 Hz, 2 H), 3.71 (ddd, J =



13.7, 7.6, 3.5 Hz, 2 H), 3.55 (td, J = 8.5, 2.6 Hz, 1 H), 3.08-2.92 (m, 3 H), 2.75-



2.59 (m, 2 H), 2.14-1.95 (m, 4 H) (OH missing)


421
(400 MHz, CDCl3) δ ppm 8.40-8.16 (m, 1 H), 8.15-7.81 (m, 3 H), 7.72-7.35 (m, 3



H), 7.33-7.08 (m, 1 H), 6.89-6.60 (m, 1 H), 4.06-3.44 (m, 4 H), 3.35-2.76 (m, 4 H),



2.50-2.17 (m, 4 H), 2.15-1.74 (m, 5 H), 1.35-1.03 (m, 1 H) (OH missing)


422
(400 MHz, METHANOL-d4) δ ppm 8.30 (dd, J = 8.6, 1.0 Hz, 2 H), 7.49-7.60 (m,



2H), 7.41 (s, 1 H), 7.21-7.37 (m, 1 H), 4.11 (quin, J = 8.3 Hz, 1 H), 3.29(s, 3 H),



3.05-3.19 (m, 3 H), 2.43-2.66 (m, 4 H), 1.92-2.23 (m, 2 H)


423
(400 MHz, CDCl3) δ ppm 8.05 (d, J = 7.7 Hz, 2 H), 7.55 (t, J = 7.9 Hz, 2 H), 7.33-



7.41 (m, 1 H), 7.23 (s, 1 H), 3.93 (quin, J = 8.1 Hz, 1 H), 3.79-3.88 (m, 3 H), 3.71



(dd, J = 10.6, 5.1 Hz, 1 H), 2.57-2.72 (m, 2 H), 2.31-2.50 (m, 3 H), 2.13-2.23



(m, 1 H), 1.99-2.12 (m, 2 H), 1.47-1.59 (m, 2 H)


424
(400 MHz, CDCl3) δ ppm 8.06 (d, J = 7.7 Hz, 2 H), 7.54 (t, J = 7.9 Hz, 2 H), 7.35 (t,



J = 7.3 Hz, 1 H), 6.95 (s, 1 H), 4.27 (d, J = 8.5 Hz, 2 H), 4.18 (d, J = 7.9 Hz, 2 H), 3.86



(quin, J = 7.9 Hz, 1 H), 3.74 (t, J = 5.1 Hz, 2 H), 2.55-2.69 (m, 2 H), 2.40-2.52 (m,



2 H), 2.00-2.15 (m, 2 H), 1.85-1.93 (m, 2 H), 1.69-1.79 (m, 2 H), 1.57-1.68



(m, 2 H)


425
(400 MHz, CDCl3) δ ppm 8.06 (d, J = 7.7 Hz, 2 H), 7.54 (t, J = 7.9 Hz, 2 H), 7.35 (t,



J = 7.2 Hz, 1 H), 6.94 (s, 1 H), 4.12 (s, 4 H), 3.87 (quin, J = 7.9 Hz, 1 H), 3.69-3.74



(m, 4 H), 2.55-2.68 (m, 2 H), 2.40-2.52(m, 2 H), 2.01-2.14(m, 2 H), 1.83-



1.95 (m, 4 H)


426
(400 MHz, CDCl3) δ ppm 8.06 (d, J = 7.7 Hz, 2 H), 7.54 (t, J = 7.9 Hz, 2 H), 7.34 (t,



J = 7.3 Hz, 1 H), 6.88 (s, 1 H), 4.32 (s, 4 H), 3.88 (quin, J = 7.9 Hz, 1 H), 2.54-2.69



(m, 2 H), 2.40-2.52 (m, 2 H), 2.31 (t, J = 7.6 Hz, 4 H), 2.01-2.14 (m, 2H), 1.95



(quin, J = 7.7 Hz, 2 H)


427
(300 MHz, CDCl3) δ ppm 8.09-8.01 (m, 2 H), 7.58-7.51 (m, 2 H), 7.46 (s, 1 H),



7.40-7.28 (m, 6 H), 4.57 (s, 2 H), 3.97 (p, J = 8.4 Hz, 1 H), 3.72-3.68 (m, 2 H),



3.46 (d, J = 6.0 Hz, 2 H), 3.04-2.92 (m, 2 H), 2.69-2.55 (m, 2 H), 2.48-2.36 (m,



2H), 2.14-1.90(m, 5H), 1.58-1.50 (m, 2 H)


428
(300 MHz, CDCl3) δ ppm 8.04 (d, J = 7.6 Hz, 2 H), 7.54 (t, J = 7.6 Hz, 2 H), 7.46 (s,



1 H), 7.35 (t, J = 7.6 Hz, 1 H), 4.84-4.74 (m, 1 H), 3.97 (p, J = 8.8 Hz, 1 H), 3.46-



3.36 (m, 4 H), 2.64-2.50 (m, 2 H), 2.48-2.37 (m, 2 H), 2.28-2.16 (m, 2 H),



2.14-1.94 (m, 4 H), 1.84-1.71 (m, 2 H), 1.69-1.56 (m, 2H)


429
(300 MHz, CDCl3) δ ppm 8.04 (d, J = 7.6 Hz, 2 H), 7.54 (t, J = 7.6 Hz, 2 H), 7.46 (s,



1 H), 7.35 (t, J = 7.6 Hz, 1 H), 4.82-4.72 (m, 1 H), 4.09 (p, J = 8.5 Hz, 1 H), 3.43-



3.38 (m, 4 H), 2.64-2.39 (m, 4 H), 2.20-1.76 (m, 10H)


430
(400 MHz, CDCl3) δ ppm 8.34 (d, J = 2.3 Hz, 1 H), 8.15-8.08 (m, 2 H), 7.99 (s, 1



H), 7.67 (dd, J = 8.8, 2.5 Hz, 1 H), 7.62-7.55 (m, 2 H), 7.43-7.37 (m, 1 H), 6.83 (d,



J = 8.7 Hz, 1 H), 3.99 (ddd, J = 13.6, 7.3, 3.6 Hz, 2 H), 3.68 (ddd, J = 13.7, 7.8, 3.6



Hz, 2 H), 3.65-3.56 (m, 1 H), 3.03-2.92 (m, 1 H), 2.23-2.14 (m, 2 H), 2.13-1.93 (m,



4 H), 1.87-1.75 (m, 2 H), 1.10 (d, J = 14.4 Hz, 6 H) (OH missing)


431
(300 MHz, CDCl3) δ ppm 7.40 (s, 1 H), 4.76-4.57 (m, 1 H), 3.69 (d, J = 12.0 Hz, 2



H), 3.45-3.28 (m, 6 H), 2.93 (t, J = 11.3 Hz, 2 H), 2.13-1.70 (m, 10 H), 1.65-1.31



(m, 11 H)


432
(400 MHz, CDCl3) δ ppm 8.34 (d, J = 2.3 Hz, 1 H), 8.15-8.08 (m, 2 H), 7.99 (s, 1



H), 7.67 (dd, J = 8.8, 2.5 Hz, 1 H), 7.62-7.55 (m, 2 H), 7.43-7.37 (m, 1 H), 6.83 (d,



J = 8.7 Hz, 1 H), 3.99 (ddd, J = 13.6, 7.3, 3.6 Hz, 2 H), 3.68 (ddd, J = 13.7, 7.8, 3.6



Hz, 2 H), 3.65-3.56 (m, 1 H), 3.03-2.92 (m, 1 H), 2.23-2.14 (m, 2 H), 2.13-1.93 (m,



4 H), 1.87-1.75 (m, 2 H), 1.10 (d, J = 14.4 Hz, 6 H) (OH missing)


433
(400 MHz, CDCl3) δ ppm 8.31 (d, J = 2.4 Hz, 1 H), 8.10 (d, J = 7.7 Hz, 2 H), 8.01



(s, 1 H), 7.64 (dd, J = 8.9, 2.6 Hz, 1 H), 7.60 (t, J = 7.9 Hz, 2 H), 7.46-7.39 (m, 1



H), 6.83 (d, J = 8.9 Hz, 1 H), 5.43-5.20 (m, 1 H), 3.99 (ddd, J = 13.7, 7.3, 3.8 Hz, 2



H), 3.85-3.74 (m, 1 H), 3.70 (ddd, J = 13.6, 7.6, 3.6 Hz, 2 H), 2.98 (dq, J = 7.8, 3.8



Hz, 1 H), 2.77 (tdd, J = 14.0, 14.0, 6.8, 4.7 Hz, 2 H), 2.59-2.39 (m, 2 H), 2.15-1.93



(m, 4 H) (OH missing)


434
(300 MHz, CDCl3) δ ppm 8.04 (d, J = 7.6 Hz, 2 H), 7.55 (t, J = 7.6 Hz, 2 H), 7.47 (s,



1 H), 7.37 (t, J = 7.6 Hz, 1 H), 4.85-4.61 (m, 1 H), 4.55-4.38 (m, 2 H), 4.16-



4.05 (m, 3 H), 3.52-3.40 (m, 2 H), 2.68-2.40 (m, 4 H), 2.24-1.84 (m, 4 H),



1.72-1.56 (m, 3 H)


435
(300 MHz, CDCl3) δ ppm 8.04 (d, J = 7.5 Hz, 2 H), 7.55 (t, J = 7.6 Hz, 2 H), 7.48 (s,



1 H), 7.37 (t, J = 7.6 Hz, 1 H), 4.32-4.21 (m, 2 H), 4.05 (p, J = 8.4 Hz, 1 H), 2.89-



2.76(m, 1 H), 2.64-2.38 (m, 5 H), 2.32-1.94 (m, 6 H), 1.85-1.72 (m, 1H)


436
(300 MHz, DMSO) δ ppm 8.33 (d, J = 7.5 Hz, 2 H), 7.56 (t, J = 7.5 Hz, 2 H), 7.45 (s,



1 H), 7.32 (t, J = 7.6 Hz, 1 H), 4.44 (t, J = 5.2 Hz, 2 H), 4.03 (p, J = 8.8 Hz, 1 H), 3.16



-3.04 (m, 10 H), 2.49-2.36 (m, 4 H), 2.16-1.88 (m, 2 H)


437
(400 MHz, DMSO-d6) δ ppm 8.55 (s, 1 H), 8.31 (s, 1 H), 8.16 (d, J = 5.8 Hz, 1 H),



7.92-7.85 (m, 2 H), 7.79 (d, J = 8.7 Hz, 1 H), 7.03 (d, J = 8.7 Hz, 1 H), 4.07-3.97 (m,



2 H), 3.90-3.84 (m, 4 H), 3.67-3.45 (m, 6 H), 3.32-3.20 (m, 1 H), 3.15-3.06 (m, 1



H), 2.12-2.03 (m, 2 H), 1.95-1.85 (m, 2 H), 1.21 (d, J = 6.8 Hz, 6 H)


438
(300 MHz, CD30D) δ ppm 8.34-8.26 (m, 2 H), 7.48 (s, 1 H), 7.24 (t, J = 8.8 Hz, 2



H), 3.76-3.67 (m, 2 H), 3.55 (pent, J = 6.8 Hz, 1 H), 3.24 (s, 3 H), 2.96-2.84 (m, 2



H), 1.94-1.84 (m, 2 H), 1.81-1.55 (m, 3 H), 1.47 (d, J = 6.8 Hz, 6 H), 1.20 (s, 6 H)


439
(400 MHz, pyridine-d5) δ ppm 8.88-8.77 (m, 2H), 7.65 (s, 1H), 7.48-7.40 (m,



2H), 7.21-7.16 (m, 1H), 4.00 (m, 1H), 3.85 (m, 1H), 3.48 (m, 1H), 2.83 (s, 3H),



2.67-2.52 (m, 4H), 2.41 (qd, J = 8.1, 4.0 Hz, 2H), 2.10 (qd, J = 8.5, 2.9 Hz, 2H),



1.96 (ddd, J = 18.0, 10.7, 7.8 Hz, 2H), 1.12 (s, 9H)


440
(400 MHz, pyridine-d5) δ ppm 8.93-8.84 (m, 2H), 7.47-7.37 (m, 2H), 7.21-



7.16 (m, 2H), 4.18 (t, J = 8.1 Hz, 2H), 3.88-3.73 (m, 1H), 3.64 (dd, J = 8.0, 5.6



Hz, 2H), 2.63 (ddt, J = 16.3, 8.4, 4.8 Hz, 3H), 2.39 (dddd, J = 11.7, 8.2, 4.7, 2.1



Hz, 2H), 2.05-1.86 (m, 2H), 1.10 (d, J = 6.8 Hz, 3H)


441
(400 MHz, pyridine-d5) δ ppm 8.86-8.78 (m, 2H), 7.53 (s, 1H), 7.49-7.41 (m,



2H), 7.24-7.16 (m, 1H), 4.01-3.86 (m, 3H), 3.65 (t, J = 7.1 Hz, 2H), 2.69-2.57



(m, 2H), 2.49 (tt, J = 13.5, 7.0 Hz, 2H), 2.40 (ddq, J = 11.8, 10.2, 4.7, 3.9 Hz, 2H),



2.02-1.83 (m, 2H)


442
(400 MHz, pyridine-d5) δ ppm 8.92-8.79 (m, 2H), 7.52 (s, 1H), 7.49-7.42 (m,



2H), 7.24-7.16 (m, 1H), 3.91 (p, J = 8.0 Hz, 1H), 3.75 ?



3.44 (m, 2H), 3.22 (dt, J = 16.5, 8.1 Hz, 1H), 2.73 (dq, J = 10.6, 8.5 Hz, 1H), 2.66-



2.54 (m, 1H), 2.46-2.32 (m, 2H), 2.21-2.11 (m, 1H),2.11-2.01 (m, 1H),



1.99-1.86 (m, 2H)


443
(400 MHz, pyridine-d5) δ ppm 8.84-8.75 (m, 2H), 7.70 (s, 1H), 7.49-7.41 (m,



2H), 7.20 (tt, J = 7.3, 1.2 Hz, 1H), 4.12 (m, J = 8.4 Hz, 1H), 3.53 (d, J = 12.4 Hz,



2H), 3.27 (s, 3H), 3.05 (s, 1H), 2.79-2.61 (m, 4H), 2.51 (dtd, J = 11.5, 8.4, 3.2



Hz, 2H), 2.42-2.28 (m, 2H), 2.28 ?



4H)


444
(400 MHz, pyridine-d5) δ ppm 8.84-8.76 (m, 2H), 7.73 (s, 1H), 7.47-7.40 (m,



2H), 7.26-7.17 (m, 1H), 4.91-4.74 (m, 1H), 4.00 (p, J = 8.3 Hz, 1H), 3.28 (s,



2H), 3.08-2.98 (m, 2H), 2.67 (pd, J = 9.1, 2.4 Hz, 2H), 2.39 (dqd, J = 12.0, 6.1,



2.5 Hz, 2H), 2.16-1.93 (m, 6H)


445
(400 MHz, pyridine-d5) δ ppm 8.91-8.79 (m, 2H), 7.51 (p, J = 1.1 Hz, 1H), 7.48-



7.39 (m, 2H), 7.17 (dt, J = 7.3, 1.2 Hz, 1H), 4.79 (d, J = 3.3 Hz, 2H), 4.37 (dd, J



= 10.5, 3.5 Hz, 2H), 3.99 (q, J = 8.0 Hz, 1H), 3.80 (d, J = 10.5 Hz, 2H), 2.74-2.62



(m, 1H), 2.62-2.53 (m, 1H), 2.44 (tdt, J = 11.4, 8.0, 3.8 Hz, 1H), 2.33 (dh, J =



12.2, 4.1 Hz, 1H), 1.95-1.74 (m, 2H)


446
(400 MHz, pyridine-d5) δ ppm 8.92-8.78 (m, 2H), 7.63 (s, 1H), 7.52 (t, J = 1.2



Hz, 2H), 7.43 (dd, J = 8.6, 7.3 Hz, 2H), 7.21-7.16 (m, 1H), 4.79 (d, J = 3.2 Hz,



2H), 4.37 (dd, J = 10.5, 3.5 Hz, 2H), 4.00 (p, J = 8.0 Hz, 1H), 3.80 (d, J = 10.4 Hz,



2H), 2.76-2.64 (m, 1H), 2.64-2.51 (m, 1H), 2.51-2.37 (m, 1H), 2.33 (dp, J =



12.1, 4.2 Hz, 1H), 1.96-1.75 (m, 2H)


447
(400 MHz, pyridine-d5) δ ppm 8.86-8.78 (m, 2H), 7.70 (s, 1H), 7.50-7.41 (m,



2H), 7.24-7.16 (m, 1H), 4.02 (t, J = 8.3 Hz, 1H), 3.44 (d, J = 12.0 Hz, 2H), 3.20-



3.04 (m, 2H), 2.80 (s, 6H), 2.68 (ddd, J = 11.6, 7.4, 2.9 Hz, 4H), 2.53-2.32 (m,



2H), 2.11-1.93 (m, 2H), 1.67 (d, J = 8.5 Hz, 2H), 1.42 (s, 3H)


448
(400 MHz, pyridine-d5) δ ppm 8.82 (ddd, J = 8.5, 2.1, 1.1 Hz, 2H), 7.73 (d, J =



12.4 Hz, 1H), 7.48-7.42 (m, 2H), 7.25-7.16 (m, 1H), 4.01 (dq, J = 22.4, 8.3 Hz,



1H), 3.69 (s, 1H), 3.46 (d, J = 12.1 Hz, 1H), 3.34 (t, J = 5.6 Hz, 1H), 3.31-3.22



(m, 1H), 3.14 (q, J = 7.3 Hz, 4H), 2.79-2.55 (m, 3H), 2.45-2.31 (m, 3H), 2.08-



1.91 (m, 2H), 1.86-1.67 (m, 1H), 1.48 (dd, J = 12.4, 4.0 Hz, 1H), 1.20 (t, J = 7.4



Hz, 5H)


449
(400 MHz, pyridine-d5) δ ppm 8.87-8.74 (m, 2H), 7.76 (s, 1H), 7.49-7.43 (m,



2H), 7.23-7.18 (m, 1H), 4.08 (p, J = 8.3 Hz, 1H), 3.35 (t, J = 4.8 Hz 4H), 2.93 (t,



J = 4.7 Hz, 4H), 2.68 (pd, J = 9.0, 2.4 Hz, 2H), 2.49-2.36 (m, 4H), 2.08-1.93



(m, 2H), 1.08-0.83 (m, 1H), 0.55-0.42 (m, 2H), 0.22-0.12 (m, 2H)


450
(400 MHz, pyridine-d5) δ ppm 8.85-8.77 (m, 2H), 7.75 (s, 1H), 7.49-7.41 (m,



2H), 7.20 (tt, J = 7.5, 1.2 Hz, 1H), 4.08 (p, J = 8.3 Hz, 1H), 3.25 (t, J = 4.8 Hz,



4H), 2.82 (p, J = 7.8 Hz, 1H), 2.69 (dq, J = 11.6, 9.0 Hz, 2H), 2.59 (t, J = 4.7 Hz,



4H), 2.43 (ddd, J = 9.6, 7.7, 5.3 Hz, 2H), 2.06-1.86 (m, 6H), 1.67-1.52 (m, 2H)


451
(400 MHz, pyridine-d5) δ ppm 8.90-8.81 (m, 2H), 7.48-7.39 (m, 2H), 7.24 (s,



1H), 7.21-7.16 (m, 1H), 4.42 (d, J = 9.7 Hz, 1H), 4.37 (d, J = 9.6 Hz, 1H), 4.17



(ddd, J = 18.2, 9.4, 1.4 Hz, 2H), 3.78 (p, J = 7.8 Hz, 1H), 2.69-2.53 (m, 2H), 2.47-



2.34 (m, 2H), 2.03-1.86 (m, 2H), 1.60 (d, J = 21.6 Hz, 3H)


452
(400 MHz, pyridine-d5) δ ppm 8.86-8.78 (m, 2H), 7.75 (s, 1H), 7.49-7.42 (m,



2H), 7.23-7.16 (m, 1H), 4.09 (p, J = 8.4 Hz, 1H), 3.10-3.02 (m, 4H), 2.71 (pd, J =



9.0, 2.5 Hz, 2H), 2.44 (dddd, J = 14.0, 11.8, 5.9, 2.5 Hz, 2H), 2.09-1.96 (m,



2H), 1.61-1.51 (m, 8H), 1.42-1.35 (m, 4H)


453
(400 MHz, pyridine-d5) δ ppm 8.88-8.76 (m, 2H), 7.76 (s, 1H), 7.49-7.41 (m,



2H), 7.20 (td, J = 7.4, 1.1 Hz, 1H), 4.16-3.97 (m, 3H), 3.32-3.11 (m, 4H), 2.69



(pd, J = 9.0, 2.5 Hz, 2H), 2.47-2.33 (m, 4H), 2.00 (dtd, J = 13.6, 8.8, 8.0, 5.5 Hz



6H)


454
(400 MHz, pyridine-d5) δ ppm 8.88-8.78 (m, 2H), 7.74 (s, 1H), 7.49-7.43 (m,



2H), 7.26-7.17 (m, 1H), 4.05 (p, J = 8.3 Hz, 1H), 3.48 (s, 4H), 2.77-2.55 (m,



9H), 2.50-2.37 (m, 1H), 2.08-1.96 (m, 2H), 1.79-1.63 (m, 6H), 1.44-1.30



(m, 2H), 1.14 (dd, J = 18.5, 8.6 Hz, 1H)


455
(400 MHz, pyridine-d5) δ ppm 8.86-8.77 (m, 2H), 7.73 (s, 1H), 7.49-7.42 (m,



2H), 7.20 (tt, J = 7.3, 1.2 Hz, 1H), 4.97-4.75 (m, 1H), 4.12-3.98 (m, 1H), 3.52



(t, J = 11.1 Hz, 2H), 3.09-3.00 (m, 1H), 2.97 (d, J = 5.1 Hz, 1H), 2.80-2.61 (m,



4H), 2.53 (s, 6H), 2.37 (s, 2H), 2.04-1.88 (m, 3H), 1.88-1.69 (m, 4H)


456
(400 MHz, pyridine-d5) δ ppm 8.86-8.77 (m, 2H), 7.73 (s, 1H), 7.71 (s, 1H), 7.48-



7.41 (m, 2H), 7.28-7.15 (m, 2H), 4.04 (t, J = 8.3 Hz, 1H), 3.52 (t, J = 11.0 Hz,



2H), 3.06-2.94 (m, 2H), 2.68 (tdd, J = 12.2, 9.1, 5.2 Hz, 4H), 2.53 (s, 6H), 2.40



(s, 2H), 2.07-1.88 (m, 3H), 1.75 (s, 4H)


457
(400 MHz, pyridine-d5) δ ppm 8.85-8.78 (m, 2H), 7.45 (dd, J = 8.4, 7.3 Hz, 2H),



7.19 (td, J = 7.5, 1.1 Hz, 1H), 6.61 (s, 3H), 4.64 (dtd, J = 48.5, 6.6, 5.9, 3.2 Hz,



1H), 4.16-3.99 (m, 3H), 3.53 (t, J = 11.0 Hz, 2H), 2.80-2.60 (m, 4H), 2.47-



2.34 (m, 2H), 2.08 (d, J = 13.4 Hz, 2H), 2.04-1.93 (m, 2H), 1.87-1.69 (m, 3H),-



0.07 (d, J = 0.8 Hz, 1H)


458
(400 MHz, pyridine-d5) δ ppm 8.89-8.75 (m, 2H), 7.73 (s, 1H), 7.48-7.42 (m,



2H), 7.22-7.16 (m, 1H), 4.78-4.52 (m, 1H), 4.16-4.01 (m, 3H), 3.53 (s, 2H),



2.71 (ddtd, J = 29.2, 17.9, 9.0, 8.1, 2.6 Hz, 4H), 2.41 (qq, J = 8.1, 4.4 Hz, 2H),



2.15-2 05 (m, 2H), 2.05-1.93 (m, 2H), 1.78 (ddt, J = 15 4, 12.6, 7 6 Hz, 3H)


459
(400 MHz, pyridine-d5) δ ppm 8.85-8.76 (m, 2H), 7.77 (s, 1H), 7.48-7.40 (m,



2H), 7.20 (tt, J = 7.3, 1.2 Hz, 1H), 4.03 (p, J = 8.3 Hz, 1H), 3.72-3.67 (m, 3H),



3.64 (s, 1H), 3.55-3.51 (m, 2H), 3.38-3.32 (m, 2H), 3.27 (s, 3H), 3.25-3.14



(m, 2H), 2.67 (dq, J = 11.6, 9.0 Hz, 2H), 2.43 ?



2.02-1.90 (m, 2H)


460
(400 MHz, pyridine-d5) δ ppm 8.86-8.75 (m, 2H), 7.82 (s, 1H), 7.47-7.41 (m,



2H), 7.19 (tt, J = 7.2, 1.2 Hz, 1H), 4.19 (p, J = 8.4 Hz, 1H), 3.79 (dd, J = 12.9, 8.8



Hz, 1H), 3.62-3.47 (m, 2H), 3.43-3.34 (m, 3H), 3.25 (d, J = 12.9 Hz, 1H), 3.18



(d, J = 12.9 Hz, 1H), 2.93 (t, J = 11.5 Hz, 1H), 2.68 (dp, J = 18.8, 9.2 Hz, 2H),



2.49 (ddtd, J = 22.0, 11.1, 7.8, 7.3, 3.7 Hz, 2H), 2.17 (m, 1H), 2.17-1.92 (m, 4H),



1.80-1.57 (m, 2H), 1.06 (t, J = 7.0 Hz, 3H)


461
(400 MHz, pyridine-d5) δ ppm 8.87-8.75 (m, 2H), 7.79 (s, 1H), 7.71 (s, 1H), 7.49-



7.43 (m, 2H), 7.20 (tt, J = 7.5, 1.2 Hz, 1H), 4.05 (p, J = 8.3 Hz, 1H), 3.58 (s, 1H),



3.56-3.45 (m, 3H), 3.42-3.31 (m, 2H), 3.21 (ddt, J = 12.1, 7.9, 3.2 Hz, 2H),



2.68 (pd, J = 9.0, 2.5 Hz, 2H), 2.42-2.33 (m, 2H), 2.16-1.89(m, 6H), 1.14 (t, J =



7.0 Hz, 3H)


462
(400 MHz, pyridine-d5) δ ppm 8.87-8.75 (m, 2H), 7.81 (s, 1H), 7.46-7.39 (m,



1H), 7.19 (tt, J = 7.3, 1.2 Hz, 1H), 4.18 (p, J = 8.3 Hz, 1H), 3.71 (s, 1H), 3.69-



3.56 (m, 3H), 3.56-3.36 (m, 3H), 3.22 (s, 3H), 2.75-2.58 (m, 2H), 2.50 (ddt, J =



15.8, 8.3, 4.0 Hz, 2H), 2.02 (ddq, J = 18.5, 14.9, 10.9 Hz, 3H), 1.79-1.57 (m, 2H)


463
(400 MHz, pyridine-d5) δ ppm 8.85-8.76 (m, 2H), 7.78 (d, J = 1.2 Hz, 1H), 7.49-



7.42 (m, 2H), 7.20 (tt, J = 7.4, 1.2 Hz, 1H), 4.04 (p, J = 8.4 Hz, 1H), 3.47 (s, 2H),



3.39-3.30 (m, 5H), 3.23-3.14 (m, 2H), 2.68 (dq, J = 11.8, 9.1 Hz, 2H), 2.46-



2.34 (m, 2H), 2.14-1.89 (m, 6H)


464
(400 MHz, pyridine-d5) δ ppm 8.85-8.74 (m, 2H), 7.81 (s, 1H), 7.49-7.40 (m,



2H), 7.23-7.17 (m, 1H), 4.80 (dddd, J = 50.4, 10.0, 7.6, 4.9 Hz, 1H), 4.43-4.32



(m, 1H), 4.11 (q, J = 8.4 Hz, 1H), 3.89 (dtd, J = 11.8, 4.6, 1.9 Hz, 1H), 3.50-3.40



(m, 1H), 3.11 (dd, J = 12.4, 9.3 Hz, 1H), 3.05-2.92 (m, 1H), 2.69 (ddd, J = 19.6,



10.5, 8.7 Hz, 2H), 2.55 (ddt, J = 11.5, 8.1, 4.1 Hz, 1H), 2.41 (qt, J = 7.7, 3.3 Hz,



1H), 2.31 (ddt, J = 11.5, 8.8, 4.2 Hz, 1H), 2.16-2.01 (m, 1H), 1.94 (qd, J = 8.5,



7.9, 4.4 Hz, 2H)


465
(400 MHz, pyridine-d5) δ ppm 8.85-8.74 (m, 2H), 7.81 (s, 1H), 7.49-7.40 (m,



2H), 7.23-7.17 (m, 1H), 4.80 (dddd, j = 50.4, 10.0, 7.6, 4.9 Hz, 1H), 4.43-4.32



(m, 1H), 4.11 (q, J = 8.4 Hz, 1H), 3.89 (dtd, J = 11.8, 4.6, 1.9 Hz, 1H), 3.50-3.40



(m, 1H), 3.11 (dd, J = 12.4, 9.3 Hz, 1H), 3.05-2.92 (m, 1H), 2.69 (ddd, j = 19.6,



10.5, 8.7 Hz, 2H), 2.55 (ddt, J = 11.5, 8.1, 4.1 Hz, 1H), 2.41 (qt, J = 7.7, 3.3 Hz,



1H), 2.31 (ddt, J = 11.5, 8.8, 4.2 Hz, 1H), 2.16-2.01 (m, 1H), 1.94 (qd, J = 8.5,



7.9, 4.4 Hz, 2H)


466
(400 MHz, pyridine-d5) δ ppm 8.90-8.82 (m, 2H), 7.51-7.40 (m, 3H), 7.22-



7.16 (m, 1H), 6.78 (s, 8H), 4.23 (t, J = 7.7 Hz, 2H), 4.08 (dd, J = 8.3, 5.5 Hz, 2H),



3.88 (p, J = 7.7 Hz, 1H), 3.20 (tt, J = 7.2, 5.4 Hz, 1H), 2.71-256 (m, 2H), 2.49-



2.35 (m, 3H), 2.27 (s, 3H), 2.05-1.85 (m, 3H), 1.51 (t, J = 5.8 Hz, 4H), 1.35-



1.27 (m, 2H)


467
(400 MHz, pyridine-d5) δ ppm 8.82 (dt, J = 8.6, 1.0 Hz, 2H), 7.56 (s, 1H), 7.49-



7.42 (m, 2H), 7.19 (t, J = 7.3 Hz, 1H), 4.26 (qd, J = 6.3, 4.3 Hz, 2H), 4.03 ?



(m, 2H), 3.78 (ddd, J = 9.8, 7.7, 5.6 Hz, 1H), 3.53 (dt, J = 9.7, 7.1 Hz, 1H), 3.24 (s,



3H), 2.74-2.54 (m, 3H), 2.54-2.36 (m, 3H), 1.95-1.85 (m, 2H)


468
(400 MHz, pyridine-d5) δ ppm 8.86-8.75 (m, 2H), 7.77 (s, 1H), 7.48-7.40 (m,



2H), 7.20 (dt, J = 7.4, 1.2 Hz, 1H), 4.07 (p, J = 8.4 Hz, 1H), 3.57 (dd, J = 11.6, 3.6



Hz, 1H), 3.43 (dt, J = 8.1, 4.0 Hz, 1H), 3.30 (s, 3H), 3.21 (d, J = 12.3 Hz, 1H),



2.96-2.73 (m, 2H), 2.68 (ddd, J = 17.4, 10.3, 8 6 Hz, 2H), 2.45 (ddtd, J = 22.7, 11.3,



7.9, 3.8 Hz, 2H), 2.12-1.93 (m, 3H), 1.84-1.75 (m, 1H), 1.61 (dt, J = 13.5, 10.1



Hz, 1H), 1.42 (d, J = 10.7 Hz, 1H)


469
(400 MHz, pyridine-d5) δ ppm 8.89-8.76 (m, 2H), 7.84 (s, 1H), 7.48-7.39 (m,



2H), 7.19 (t, J = 7.4 Hz, 1H), 4.32 (s, 2H), 4.14 (p, J = 8.3 Hz, 1H), 3.96 (ddd, J =



12.6, 9.8, 3.2 Hz, 2H), 3.58-3.38 (m, 2H), 3.21 (hept, J = 6.5 Hz, 1H), 2.71



(dq, J = 11.5, 9.0 Hz, 2H), 2.54-2.36 (m, 2H), 2.21-1.92 (m, 6H), 1.07 (d, J =



6.5 Hz, 6H)


470
(400 MHz, pyridine-d5) δ ppm 8.85-8.76 (m, 2H), 7.73 (s, 1H), 7.49-7.42 (m,



2H), 7.23-7.17(m, 1H), 4.05 (p, J = 8.3 Hz, 1H), 3.25-3.12 (m, 6H), 2 88 (t, J =



4.7 Hz, 4H), 2.68 (pd, J = 9.0, 2.5 Hz, 2H), 2.45-2.37 (m, 2H), 2.08-1.96 (m,



2H)


471
(400 MHz, pyridine-d5) δ ppm 8.87-8.75 (m, 2H), 7.73 (s, 1H), 7.48-7.43 (m,



2H), 7.23-7.18 (m, 1H), 4.06 (p, J = 8.3 Hz, 1H), 3.92 (t, J = 6.0 Hz, 2H), 3.31



(t, J = 4.8 Hz, 4H), 2.89 (dt, J = 14.4, 5.9 Hz, 5H), 2.68 (dq, J = 11.6, 9.0 Hz,



2H), 2.47-2.33 (m, 2H), 1.99 (dtd, J = 9.0, 7.1, 5.4 Hz, 4H)


472
(400 MHz, pyridine-d5) δ ppm 8.83-8.75 (m, 2H), 7.73 (s, 1H), 7.48-7.42 (m,



2H), 7.22-7.16 (m, 1H), 4.08 (p, J = 8.3 Hz, 1H), 3.49 (t, J = 6.9 Hz, 2H), 3.39 (t,



J = 6.8 Hz, 2H), 3.35 (s, 2H), 3.23 (t, J = 4.6 Hz, 4H), 2.94 (t, J = 4.6 Hz, 4H),



2.66 (dq, J = 11.5, 9.0 Hz, 2H), 2.46-2.33 (m, 2H), 2.04-1.90 (m, 2H), 1.68 (p,



J = 6.8 Hz, 2H), 1.55 (p, J = 6.8 Hz, 2H)


473
(400 MHz, pyridine-d5) δ ppm 8.90-8.80 (m, 2H), 7.71 (s, 1H), 7.69 (s, 1H), 7.49-



7.42 (m, 2H), 7.22-7.16 (m, 1H) 3.91 (p, J = 8.2 Hz, 1H), 3.50-3.40 (m, 4H),



2.64 (pd, J = 8.9, 2.4 Hz, 2H), 2.38 (dqd, J = 12.1, 6.2, 2.5 Hz, 2H), 2.00-1.90



(m, 2H), 1.63 (h, J = 4.0, 3.4 Hz, 4H), 1.49-1.40 (m, 4H)


474
(400 MHz, pyridine-d5) δ ppm 8.84-8.74 (m, 2H), 7.78 (d, J = 1.2 Hz, 1H), 7.49-



7.42 (m, 2H), 7.20 (dd, J = 8.1, 6.7 Hz, 1H), 4.07 (p, J = 8.3 Hz, 1H), 3.65 (dt, J =



25.4, 4.1 Hz, 8H), 3.43 (s, 2H), 3.20 (t, J = 4.5 Hz, 4H), 2.84 (t, J = 4.7 Hz, 4H),



2.66 (dq, J = 11.5, 8.9 Hz, 2H), 2.46-2.34 (m, 2H), 2.05-1.92 (m, 2H)


475
(400 MHz, pyridine-d5) δ ppm 8.86-8.75 (m, 2H), 7.77 (s, 1H), 7.49-7.43 (m,



2H), 7.21 (t, J = 7.4 Hz, 1H), 4.83 (td, J = 6.7, 6.2, 4.1 Hz, 1H), 4.06 (p, J = 8.3



Hz, 1H), 3.83 (dd, J = 9.9, 6.6 Hz, 1H), 3.66 (dt, J = 11.6, 2.2 Hz, 1H), 3.57-3.48



(m, 1H), 3.36-3.19 (m, 3H), 3.04-2.92 (m, 2H), 2.85 (dd, J = 9.9, 4.8 Hz, 1H),



2.74-2.59 (m, 2H), 2.48-2.33 (m, 2H), 2.15 (ddd, J = 12.8, 6.0, 1.7 Hz, 1H),



2.10-1.87 (m, 3H)


476
(400 MHz, pyridine-d5) δ ppm 8.85-8.77 (m, 2H), 7.75 (s, 1H),, 7.49-7.43 (m,



2H), 7.20 (t, J = 7.4 Hz, 1H), 4.05 (s, 3H), 2.86-2.71 (m, 2H), 2.64 (dq, J = 11.5,



8.9 Hz, 2H), 2.44 (dtd, J = 13.4, 9.1, 8.2, 4.3 Hz, 4H), 2.13-1.94 (m, 2H), 1.33 (s,



3H)


477
(400 MHz, pyridine-d5) δ ppm 8.85-8.76 (m, 2H), 7.73 (s, 1H), 7.50-7.38 (m,



2H), 7.26-7.17 (m, 1H), 4.10 (t, J = 6.2 Hz, 3H), 2.85-2.72 (m, 1H), 2.65 (dq, J =



11.5, 9.0 Hz, 2H), 2.33 (s, 3H), 1.99 (q, J = 6.1, 4.6 Hz, 4H)


478
(400 MHz, pyridine-d5) δ ppm 8.84-8.77 (m, 2H), 7.82 (s, 1H), 7.49-7.41 (m,



2H), 7.25-7.15 (m, 1H), 4.82-4.65 (m, 4H), 4.2 (t, J = 6.2 Hz, 2H), 4.20-4.10



(m, 2H), 3.12 (t, J = 6.2 Hz, 2H), 2.90 (h, J = 6.6 Hz, 1H), 2.66 (pd, J = 9.2, 2.5



Hz, 2H), 2.55-2.43 (m, 2H), 2.10-1.99 (m, 1H), 1.99-1.89 (m, 1H), 0.1 (d, J =



6.6 Hz, 6H)


479
(400 MHz, pyridine-d5) δ ppm 8.79 (d, J = 8.0 Hz, 2H), 7.81 (s, 1H), 7.45 (t, J =



7.9 Hz, 2H), 7.20 (t, J = 7.4 Hz, 1H), 4.69 (s, 1H), 4.37 (d, J = 19.0 Hz, 2H), 4.13



(p, J = 8.4 Hz, 1H), 3.72 (d, J = 13.9 Hz, 1H), 3.09 (t, J = 11.9 Hz, 1H), 2.65 (d, J =



8.6 Hz, 2H), 2.11 (s, 6H)


480
(400 MHz, pyridine-d5) δ ppm 8.83-8.74 (m, 2H), 7.79 (s, 1H), 7.46-7.39 (m,



2H), 7.20-7.16 (m, 1H), 4.34 (qd, J = 6.8, 4.7 Hz, 1H), 4.25-4.09 (m, 3H), 3.86



(dt, J = 8.3, 6.7 Hz, 1H), 3.78-3.69 (m, 1H), 2.73-2.60 (m, 2H), 2.48 (dddd, J =



12.0, 8.4, 7.0, 3.7 Hz, 2H), 2.12-1.90 (m, 3H), 1.88-1.60 (m, 3H)


481
(400 MHz, pyridine-d5) δ ppm 8.75 (dt, J = 8.6, 1.7 Hz, 2H), 7.92 (s, 1H), 7.42



(ddd, J = 9.6, 5.7, 2.2 Hz, 2H), 7.23-7.16 (m, 1H), 4.43-4.03 (m, 1H), 4.27-



4.11 (m, 2H), 4.09-3.88 (m, 2H), 3.08 (s, 3H), 2.68 (dq, J = 11.9, 9.1 Hz, 2H),



2.57-2.38 (m, 2H), 2.06- 1.79 (m, 2H)


482
(400 MHz, pyridine-d5) δ ppm 8.83-8.75 (m, 2H), 7.81 (s, 1H), 7.48-7.40 (m,



2H), 7.22-7.17 (m, 1H), 4.87 (ddd, J = 47.9, 7.0, 5.0 Hz, 1H), 4.62-4.40 (m,



2H), 4.14 (p, J = 8.7 Hz, 1H), 3.42-3.28 (m, 2H), 2.65 (dtd, J = 12.1, 9.1, 2.8 Hz,



2H), 2.56 (s, 5H), 2.47 (dtd, J = 11.8, 8.4, 2.9 Hz, 2H), 2.15-1.88 (m, 6H), 1.76



(d, J = 13.2 Hz, 1H)


483
(400 MHz, pyridine-d5) δ ppm 8.83-8.75 (m, 2H), 7.77 (s, 1H), 7.46-7.37 (m,



2H), 7.23-7.17 (m, 1H), 4.36-4.20 (m, 2H), 4.13-4.06 (m, 2H), 3.84-3.60



(m, 6H), 2.73-2.58 (m, 2H), 2.48 (dtd, J = 17.1, 9.5, 8.7, 4.7 Hz, 2H), 2.13-1.85



(m, 2H)


484
(400 MHz, pyridine-d5) δ ppm 8.88-8.75 (m, 2H), 7.81 (s, 1H), 7.49-7.36 (m,



2H), 7.24-7.15 (m, 1H), 4.34 (t, J = 7.0 Hz, 2H), 4.18 (t, J = 8.6 Hz, 1H), 3.46 (t,



J = 6.6 Hz, 2H), 3.26 (s, 3H), 2.66 (pd, J = 9.1, 2.5 Hz, 2H), 2.47 (dtt, J = 11.8,



8.5, 2.6 Hz, 2H), 2.10-1.98 (m, 1H), 1.90 (t, J = 7.0 Hz, 2H), 1.61 (t, J = 6.6 Hz,



2H), 0.41 (dt, J = 6.8, 1.6 Hz, 4H)


485
(400 MHz, pyridine-d5) δ ppm 8.85-8.76 (m, 2H), 7.72 (s, 1H), 7.48-7.39 (m,



2H), 7.21-7.16 (m, 1H), 4.17 (dd, J = 9.0, 8.0 Hz, 1H), 4.04 (s, 2H), 3.53 (t, J =



6.6 Hz, 2H), 3.24(s, 3H), 2.68 (dq, J = 11.5, 9.1 Hz, 2H), 2.57-2.40 (m, 2H),



2.16-1.92 (m, 2H), 1.88 (t, J = 6.7 Hz, 2H), 0.60 (dt, J = 9.7, 1.7 Hz, 4H)


486
(400 MHz, pyridine-d5) δ ppm 8.82-8.76 (m, 2H), 7.78 (s, 1H), 7.47-7.39 (m,



2H), 7.19 (t, J = 7.4 Hz, 1H), 4.42 (dd, J = 9.7, 7.5 Hz, 1H), 4.26-4.11 (m, 2H),



2.80 (dt, J = 14.8, 7.7 Hz, 1H), 2.89-2.58 (m, 2H), 2.48 (dd, J = 6.0, 3.0 Hz, 2H),



2.22-1.92 (m, 5H), 1.71- 1.51 (m, 3H)


487
(400 MHz, DMSO-d6) δ ppm 8.38-8.28 (m, 2H), 7.61-7.52 (m, 2H), 7.41 (s, 1H),



7.36-7.29 (m, 1H), 4.43-4.34 (m, 2H), 4.08-3.98 (m, 1H), 3.62-3.58 (m, 4H), 2.57-



2.35 (m, 10H), 2.15-1.89 (m, 4H)


488
(400 MHz, pyridine-d5) δ ppm 8.83-8.75 (m, 2H), 7.77 (s, 1H), 7.45-7.39 (m,



2H), 7.22-7.15 (m, 1H), 4.90 (t, J = 5.1 Hz, 2H), 4.38 (t, J = 6.5 Hz, 2H), 4.24-



4.07 (m, 1H), 4.07-3.98 (m, 2H), 3.71 (td, J = 12.2, 2.4 Hz, 2H), 2.65 (pd, J =



9.1, 2.5 Hz, 2H), 2.45 (dtd, J = 12.0, 8.5, 3.1 Hz, 2H), 2.30 (td, J = 6.4, 5.0 Hz,



2H), 2.12-1.90 (m, 3H), 1.11 (ddt, J = 12.4,3.0, 1.5 Hz, 1H)


489
(400 MHz, pyridine-d5) δ ppm 8.83-8.74 (m, 2H), 7.73 (s, 1H), 7.44 (dd, J = 8.6,



7.3 Hz, 2H), 7.18 (td, J = 7.3, 1.1 Hz, 1H), 4.73 (t, J = 5.8 Hz, 1H), 4.61 (t, J = 5.8



Hz, 1H), 4.25 (t, J = 6.1 Hz, 2H), 4.07 (t, J = 8.5 Hz, 1H), 2.63 (pd, J = 9.1, 2.5 Hz,



2H), 2.42 (qd, J = 8.8, 4.5 Hz, 2H), 2.17 (dp, J = 24.4, 6.0 Hz, 2H), 2.10- 1.84 (m,



2H)


490
(400 MHz, pyridine-d5) δ ppm 8.84-8.77 (m, 2H), 7.79 (s, 1H), 7.45 (t, J = 7.8



Hz, 2H), 7.20 (t, J = 7.3 Hz, 1H), 4.71 (d, J = 5.9 Hz, 2H), 4.47 (d, J = 5.9 Hz,



2H), 4.19 (s, 2H), 4.10 (q, J = 8.4 Hz, 1H), 2.66-2.55 (m, 2H), 2.55-2.38 (m,



3H), 2.10-1.88 (m, 2H), 1.37 (s, 3H)


491
(400 MHz, pyridine-d5) δ ppm 8.85-8.74 (m, 2H), 8.01 (s, 1H), 7.46-7.39 (m,



2H), 7.20-7.16 (m, 1H), 4.16 (p, J = 8.6 Hz, 1H), 3.75 (d, J = 4.8 Hz, 4H), 3.29



(s, 6H), 2.68 (pd, J = 9.2, 2.5 Hz, 2H), 2.46 (dtd, J = 12.1, 8.6, 3.3 Hz, 2H), 2.13-



1.88 (m, 2H)


492
(400 MHz, pyridine-d5) δ ppm 8.85-8.76 (m, 2H), 7.62 (s, 1H), 7.46-7.36 (m,



2H), 7.19 (dt, J = 7.4, 1.2 Hz, 1H), 4.65 (p, J = 7.2 Hz, 1H), 4.11 (d, J = 34.0 Hz,



1H), 4.11 (t, J = 8.5 Hz, 1H), 2.76-2.56 (m, 4H), 2.50-2.36 (m, 2H), 2.23 (d, J =



9.5 Hz, 2H), 2.15 (s, 5H), 2.1(m, 1H), 2.00- 1.88 (m, 1H)


493
(400 MHz, pyridine-d5) δ ppm 8.83-8.75 (m, 2H), 7.69 (s, 1H), 7.48-7.38 (m,



2H), 7.25-7.16 (m, 1H), 4.77 (q, J = 5.0 Hz, 1H), 4.62 (d, J = 1.8 Hz, 1H), 4.43-



4.34 (m, 2H), 4.29 (q, J = 8.7 Hz, 1H), 3.98 (dq, J = 13.1, 1.6 Hz, 2H), 2.76 (qd,



J = 9.2, 2.5 Hz, 2H), 2.62-2.50 (m, 2H), 2.13-1.96 (m, 2H), 1.38 (d, J = 5.0 Hz,



3H)


494
(400 MHz, pyridine-d5) δ ppm 8.85-8.76 (m, 2H), 7.82 (s, 1H), 7.47-7.39 (m,



2H), 7.21-7.15 (m, 1H), 4.84 (dt, J = 8.0, 3.9 Hz, 1H), 4.14 (p, J = 8.7 Hz, 1H),



2.95 (d, J = 10.9 Hz, 1H), 2.64 (ddd, J = 19.1, 9.6, 2.6 Hz, 2H), 2.52-2.37 (m,



4H), 2.22 (s, 3H), 2.16 (d, J = 10.0 Hz, 1H), 1.96 (s, 2H), 1.80-1.67 (m, 1H),



1.64-1.48 (m, 2H)


495
(400 MHz, pyridine-d5) δ ppm 8.83-8.74 (m, 2H), 7.59 (s, 1H), 7.48-7.41 (m,



2H), 7.23-7.17 (m, 1H), 4.81 (p, J = 6.6 Hz, 1H), 4.64 (s, 4H), 4.24-4.00 (m,



1H), 2.83-2.73 (m, 2H), 2.64 (pd, J = 9.1, 2.4 Hz, 2H), 2.50-2.34 (m, 4H), 2.05



(dt, J = 10.8, 8.8 Hz, 1H), 2.00-1.89 (m, 1H)


496
(400 MHz, pyridine-d5) δ ppm 8.84-8.75 (m, 2H), 7.82 (s, 1H), 7.47-7.40 (m,



2H), 7.24-7.16 (m, 1H), 4.83 (dt, J = 8.1, 4.0 Hz, 1H), 4.14 (t, J = 8.6 Hz, 1H),



2.93 (d, J = 11.2 Hz, 1H), 2.65 (dtd, J = 18.0, 9.0, 2.6 Hz, 2H), 2.43 (ddd, J = 11.0,



8.6, 3.6 Hz, 4H), 2.21 (s, 3H), 2.14 (d, J = 9.0 Hz, 2H), 2.06 (dt, J = 10.9, 8.9 Hz,



1H), 1.96 (d, J = 8.8 Hz, 2H), 1.74 (s, 1H), 1.57 (q, J = 9.4 Hz, 2H)


498
(400 MHz, CDCl3) δ ppm 8.06 (d, J = 7.1 Hz, 2 H), 7.55 (t, J = 8.3 Hz, 2 H), 7.47 (s,



1 H), 7.36 (tt, J = 7.5, 1.1 Hz, 1 H), 3.99 (quin, J = 8.3 Hz, 1 H), 3.74 (d, J = 12.5 Hz,



2 H), 3.40 (s, 3 H), 3.23 (quin, J = 6.0 Hz, 1 H), 2.87-3.01 (m, 2 H), 2.56-2.71 (m,



2 H), 2.37-2.51 (m, 2 H), 2.00-2.17 (m, 3 H), 1.77-1.91 (m, 1 H), 1.51-1.74



(m, 3 H), 1.22 (d, J = 6.4 Hz, 3 H)


499
(400 MHz, CDCl3) δ ppm 8.06 (d, J = 8.1 Hz, 2 H), 7.55 (t, J = 8.3 Hz, 2 H), 7.47 (s,



1 H), 7.37 (t, J = 7.3 Hz, 1 H), 3.98 (quin, J = 8.4 Hz, 1 H), 3.70-3.85 (m, 2 H), 3.45



(s, 3 H), 2.95 (t, J = 12.3 Hz, 2 H), 2.64 (quin, J = 9.0 Hz, 2 H), 2.34-2.53 (m, 2 H),



1.90-2.20 (m, 5 H), 1.77 (quind, J = 12.8, 3.9 Hz, 2 H), 1.42 (s, 3 H)


500
(400 MHz, pyridine-d5) δ ppm 8.84-8.76 (m, 2H), 7.80 (s, 1H), 7.48-7.39 (m,



2H), 7.19 (tt, J = 7.1, 1.2 Hz, 1H), 4.06 (s,1H), 3.77 (dd, J = 13.4, 3.2 Hz, 1H),



3.55-3.27 (m, 7H), 3.20-3.05 (m, 1H), 2.79-2.62 (m, 3H), 2.38 (s, 2H), 2.00



(td, J = 9.3, 4.5 Hz, 3H), 1.87-1.75 (m, 2H), 1.75-1.66 (m, 1H), 1.07 (dt, J =



14.1, 7.0 Hz, 6H)


501
(400 MHz, pyridine-d5) δ ppm 8.86-8.79 (m, 2H), 7.77 (s, 1H), 7.47-7.40 (m,



2H), 7.17 (s, 1H), 4.09 (t, J = 8.2 Hz, 2H), 3.60-3.46 (m, 2H), 2.96 (dd, J = 11.8,



8.7 Hz, 2H), 2.68 (dq, J = 11.4, 8.9 Hz, 2H), 2.41 (d, J = 5.1 Hz, 2H), 2.16 (s, 2H),



1.99 (dd, J = 8.4, 5.1 Hz, 4H)


502
(400 MHz, pyridine-d5) δ ppm 8.85-8.77 (m, 2H), 8.16 (s, 1H), 7.75 (s, 1H), 7.71



(s, 1H), 7.48-7.41(m, 2H), 7.20 (tt, J = 7.4, 1.2 Hz, 1H), 4.08 (t, J = 8.3 Hz, 1H),



3.37 (s, 3H), 3.25 (t, J = 4.7 Hz, 4H), 2.92 (dd, J = 9.0, 6.1 Hz, 2H), 2.84 (t, J = 4.6



Hz, 4H), 2.77-2.63 (m, 4H), 2.48-2.39 (m, 2H), 2.37 (s, 3H), 2.08-1.93 (m,



2H)


503
(400 MHz, pyridine-d5) δ ppm 8.89-8.80 (m, 2H), 7.49-7.41 (m, 2H), 7.20 (tt, J =



7.5, 1.2 Hz, 1H), 4.52-4.35 (m, 2H), 4.27 (d, J = 16.2 Hz, 1H), 4.08 (dd, J =



11.9, 4.3 Hz, 1H), 3.97-3.79 (m, 4H), 3.63 (d, J = 11.7 Hz, 1H), 3.55 (s, 1H),



3.04 (s, 3H), 2.75 (dd, J = 10.5, 8.3 Hz, 1H), 2.63 (s, 1H), 2.58 (q, J = 9.3, 8.5 Hz,



1H), 2.45 (dt, J = 11.1, 3.6 Hz, 1H), 2.32 (dp, J = 12.5, 4.3 Hz, 1H), 1.97 (dtd, J =



17.2, 9.0, 8.5, 4.4 Hz, 1H), 1.87 (dt, J = 10.9, 8.5 Hz, 1H)


504
(400 MHz, pyridine-d5) δ ppm 8.83-8.76 (m, 2H), 7.84 (s, 1H), 7.49-7.41 (m,



2H), 7.20 (tt, J = 7.5, 1.2 Hz, 2H), 4.15 (s, 1H), 4.05 (s, 2H), 3.59 (s, 2H), 3.45



(t, J = 5.4 Hz, 2H), 2.68 (dd, J = 11.3, 8.7 Hz, 2H), 1.95 (t, J = 5.4 Hz, 2H)


505
(400 MHz, pyridine-d5) δ ppm 8.90-8.80 (m, 2H), 8.44 (s, 1H), 8.41 (d, J = 3.8



Hz, 1H), 7.50-7.43 (m, 2H), 7.24-7.17 (m, 1H), 4.24 (d, J = 5.1 Hz, 1H), 4.03



(dd, J = 10.9, 5.6 Hz, 1H), 3.88 (t, J = 8.0 Hz, 1H), 3.69 (dd, J = 10.8, 1.8 Hz, 1H),



3.42 (dd, J = 9.0, 2.7 Hz, 2H), 2.63 (td, J = 19.4, 18.9, 8.6 Hz, 4H), 2.33 (d, J = 8.8



Hz, 2H), 1.98-1.86 (m, 2H), 1.75 (dt, J = 12.7, 7.0 Hz, 2H), 1.58 (d, J = 7.7 Hz,



2H)


506
(400 MHz, pyridine-d5) δ ppm 8.84-8.75 (m, 2H), 7.91 (s, 1H), 7.49-7.41 (m,



2H), 7.20 (td, J = 7.4, 1.3 Hz, 1H), 4.71 (tt, J = 7.9, 4.1 Hz, 1H), 4.45 (ddd, J =



25.1, 11.1, 6.3 Hz, 1H), 4.06 (dd, J = 11.6, 4.8 Hz, 1H), 3.94-3.84 (m, 3H), 2.92



(ddd, J = 25.5, 11.4, 7.8 Hz, 1H), 2.77 (d, J = 7.8 Hz, 1H), 2.61 (ddd, J = 11.5, 8.2,



3.6 Hz, 2H), 2.41 ?


507
(400 MHz, pyridine-d5) δ ppm 8.85-8.77 (m, 2H), 7.90 (s, 1H), 7.47-7.41 (m,



2H), 7.23-7.17 (m, 1H), 5.29 (ddd, J = 9.5, 5.9, 3.7 Hz, 1H), 4.50 (p, J = 5.5 Hz



1H), 4.20 (ddd, J = 20.4, 11.3, 3.5 Hz, 1H), 4.14-3.95 (m, 3H), 3.59 (ddd, J =



21.6, 11.4, 5.4 Hz, 1H), 2.72-2.45 (m, 5H), 2.37 (ddd, J = 10.7, 5.2, 2.9 Hz, 1H),



1.98-1.85 (m, 2H)


508
(400 MHz, pyridine-d5) δ ppm 8.88-8.78 (m, 2H), 7.53 (s, 1H), 7.49-7.41 (m,



2H), 7.19 (tt, J = 7.3, 1.2 Hz, 1H), 4.10-3.76 (m, 4H), 3.72-3.61 (m, 2H), 3.53



(ddd, J = 10.0, 8.5, 2.2 Hz, 1H), 3.34 (s, 3H), 2.82-2.67 (m, 1H), 2.67 ?



1H), 2.49 (dt, J = 11.1, 3.8 Hz, 1H), 2.34 (ddt, J = 16.4, 8.5, 4.2 Hz, 1H), 2.29-



2.06 (m, 2H), 2.02- 1.85 (m, 2H)


509
(400 MHz, pyridine-d5) δ ppm 8.85-8.76 (m, 2H), 7.82 (s, 1H), 7.49-7.41 (m,



2H), 7.23-7.17 (m, 1H), 4.28 (dd, J = 20.2, 7.5 Hz, 1H), 4.15 (t, J = 8.4 Hz, 1H),



3.86 (dt, J = 12.7, 6.5 Hz, 1H), 3.56 (dd, J = 10.7, 6.2 Hz, 1H), 3.36 (dd, J = 21.4,



11.5 Hz, 1H), 3.07 (t, J = 9.8 Hz, 1H), 2.68 (dd, J = 9.1, 2.6 Hz, 2H), 2.50-2.29



(m, 1H), 2.14-2.04 (m, 1H), 1.97 (ddt, J = 11.0, 8.1, 4.1 Hz, 2H)


510
(400 MHz, pyridine-d5) δ ppm 8.92-8.81 (m, 2H), 7.54 (s, 1H), 7.48-7.42 (m,



2H), 7.22-7.16 (m, 1H), 4.04 (d, J = 11.9 Hz, 1H), 3.99-3.82 (m, 4H), 3.79-



3.63 (m, 2H), 3.51 (dqd, J = 13.9, 7.7, 7.0, 2.5 Hz, 3H), 2.77 (dq, J = 10.6, 8.8 Hz,



1H), 2.67-2.57 (m, 1H), 2.52 (dp, J = 12.0, 4.0 Hz, 1H), 2.40-2.28 (m, 1H),



2.28-2.09 (m, 2H), 2.01-1.83 (m, 2H), 1.13 (t, J = 7.0 Hz, 3H)


511
(400 MHz, pyridine-d5) δ ppm 8.97-8.78 (m, 2H), 7.46-7.40 (m, 2H), 7.28 (s,



1H), 7.20-7.16 (m, 1H), 4.31 (d, J = 7.8 Hz, 2H), 3.87 (d, J = 7.7 Hz, 3H), 3.80



(s, 2H), 2.66-2.56 (m, 2H), 2.46-2.35 (m, 2H), 2.01-1.81 (m, 2H), 1.38 (s, 3H)


512
(400 MHz, pyridine-d5) δ ppm 8.92- 8.81 (m, 2H), 7.47-7.41 (m, 2H), 7.19 (dt,



J= 7.4, 1.2 Hz, 1H), 4.03-3.86 (m, 2H), 3.68 (ddd, J = 20.9, 10.2, 3.6 Hz, 2H),



3.57 (dt, J = 10.9, 1.8 Hz, 1H), 3.38 (ddd, J = 9.4, 8.1, 3.1 Hz, 1H), 3.22 (s, 3H),



2.74-2.59 (m, 2H), 2.47-2.29 (m, 2H), 2.00-1.82 (m, 3H)


513
(400 MHz, pyridine-d5) δ ppm 8.91-8.81 (m, 2H), 7.47-7.42 (m, 2H), 7.22 (s,



1H), 7.20-7.16 (m, 1H), 6.28 (s, 1H), 4.53 (ddd, J = 6.6, 3.9, 2.4 Hz, 1H), 4.43-



4.32 (m, 2H), 4.23-4.11 (m, 2H), 3.90-3.74 (m, 3H), 2.68-2.53 (m, 2H), 2.39



(tdd, J = 11.7, 8.7, 5.4 Hz, 2H), 2.03- 1.81 (m, 2H)


514
(400 MHz, pyridine-d5) δ ppm 8.87-8.75 (m, 2H), 7.93 (s, 1H), 7.46-7.37 (m,



2H), 7.19 (dt, J = 7.4, 1.2 Hz, 1H), 4.72 (tt, J = 8.0, 3.9 Hz, 1H), 4.28-4.04 (m,



2H), 3.95-3.75 (m, 3H), 2.68-2.41 (m, 5H), 2.27 (dt, J = 11.1, 3.7 Hz, 1H), 1.95-



1.80 (m, 2H)


515
(400 MHz, pyridine-d5) δ ppm 8.87-8.77 (m, 2H), 7.75 (s, 1H), 7.49-7.43 (m,



2H), 7.24-7.18 (m, 1H), 4.04 (p, J = 8.3 Hz, 1H), 3.51 (dt, J = 11.2, 2.2 Hz, 1H),



3.43 (dd, J = 11.4, 1.9 Hz, 1H), 3.31 (dd, J = 21.8, 11.2 Hz, 1H), 3.11-2.98 (m,



2H), 2.81 (dd, J = 11.3, 9.8 Hz, 1H), 2.73 ?



2.36-2.21 (m, 3H), 2.08-1.98 (m, 2H), 1.73 (d, J = 36.1 Hz, 1H)


516
(400 MHz, pyridine-d5) δ ppm 8.92- 8.82 (m, 2H), 7.53 (s, 1H), 7.51-7.46 (m,



2H), 7.21 (t, J = 7.4 Hz, 1H), 4.63-4.49 (m, 2H), 4.21 (td, J = 9.6, 7.1 Hz, 1H),



3.87 (ddt, J = 14.9, 10.2, 4.4 Hz, 3H), 3.71 (ddd, J = 8.6, 6.9, 4.6 Hz, 2H), 3.61



(dd, J = 11.0, 8.5 Hz, 1H), 2.95 (s, 3H), 2.82-2.71 (m, 1H), 2.67-2.51 (m, 1H),



2.39 (dddt, J = 26.8, 11.0, 7.7, 4.1 Hz, 2H), 2.03-1.83 (m, 2H)


517
(400 MHz, pyridine-d5) δ ppm 8.88-8.74 (m, 2H), 7.80 (s, 1H), 7.49-7.43 (m,



2H), 7.20 (td, J = 7.4, 1.2 Hz, 1H), 4.06 (t, J = 8.3 Hz, 1H), 3.97 (d, J = 19.8 Hz,



2H), 3.47-3.37 (m, 2H), 3.25 (td, J = 11.8, 4.2 Hz, 2H), 2.68 (pd, J = 9.0, 2.5 Hz,



2H), 2.38 (dtd, J = 12.0, 8.4,3.1 Hz, 2H), 2.19 (dtd, J = 26.1, 13.7, 11.7, 7.0 Hz,



4H), 2.04-1.86 (m, 2H)


518
(400 MHz, pyridine-d5) δ ppm 8.90-8.81 (m, 2H), 7.50 (s, 1H), 7.47-7.41 (m,



2H), 7.22-7.16 (m, 1H), 3.91 (q, J = 8.0 Hz, 1H), 3.83 (td, J = 9.6, 6.8 Hz, 1H),



3.77- 3.71 (m, 2H), 3.54 (s, 2H), 3.46 (ddd, J = 9.5, 8.0, 3.1 Hz, 1H), 2.72 (dq, J =



10.8, 8.7 Hz, 1H), 2.66 ?


519
6.7, 3.0 Hz, 1H), 1.97-1.82 (m, 4H), 1.83-1.70 (m, 4H)



(400 MHz, pyridine-d5) δ ppm 8.87-8.77 (m, 2H), 7.73 (s, 1H), 7.49-7.41 (m,



2H), 7.25-7.17 (m, 1H), 4.00 (t, J = 8.4 Hz, 1H), 3.78 (dt, J = 13.9, 5.3 Hz, 1H),



3.49 (d, J = 12.6 Hz, 2H), 3.21 (s, 3H), 2.93-2.81 (m, 2H), 2.66 (dq, J = 11.6, 9.1



Hz, 2H), 2.42-2.26 (m, 4H), 2.09- 1.81 (m, 4H)


520
(400 MHz, pyridine-d5) δ ppm 8.87-8.74 (m, 2H), 7.73 (s, 1H), 7.49-7.42 (m,



2H), 7.22-7.17 (m, 1H), 4.64 (dddd, J = 48.5, 6.8, 5.2, 3.2 Hz, 1H), 4.17-4.01



(m, 3H), 3.53 (s, 2H), 2.82-2.60 (m, 4H), 2.41 (dq, J = 8.1, 3.7 Hz, 2H), 2.18-



2.03 (m, 2H), 2.03-1.91 (m, 2H), 1.87-1.68 (m, 3H)


521
(400 MHz, pyridine-d5) δ ppm 8.92-8.83 (m, 2H), 7.47-7.39 (m, 2H), 7.23 (s,



1H), 7.18 (dt, J = 7.4, 1.2 Hz, 1H), 4.11 (d, J = 7.8 Hz, 2H), 3.85 (q, J = 7.8 Hz,



1H), 3.80 (d, J = 7.8 Hz, 2H), 3.27 (s, 5H), 2.63 (dddd, J = 16.5, 8.9, 7.6, 2.2 Hz,



2H), 2.47-2.35 (m, 1H), 2.02-1.85 (m, 2H), 1.28 (s, 3H)


522
(400 MHz, pyridine-d5) δ ppm 8.93-8.81 (m, 2H), 7.50 (s, 1H), 7.47-7.41 (m,



2H), 7.20-7.15 (m, 1H), 3.97-3.87 (m, 2H), 3.76-3.62 (m, 2H), 3.57 (dt, J =



10.9, 1.8 Hz, 1H), 3.42-3.32 (m, 1H), 3.22 (s, 3H), 2.74-2.58 (m, 2H), 2.46-



2.30 (m, 2H), 2.06 (dddd, J = 13.4, 6.2, 3.8, 1.9 Hz, 1H), 1.99-1.80 (m, 3H)


523
(400 MHz, pyridine-d5) δ ppm 8.86-8.75 (m, 2H), 7.73 (s, 1H), 7.47 (ddd, J =



8.6, 5.7, 1.9 Hz, 2H), 7.21 (td, J = 7.4, 1.3 Hz, 1H), 4.02 (p, J = 8.2 Hz, 1H), 3.64



(t, J = 4.8 Hz, 4H), 3.25 (dd, J = 5.9, 3.7 Hz, 4H), 3.10 (s, 3H), 2.73-2.61 (m,



2H), 2.36 (dtd, J = 12.0, 8.5, 3.7 Hz, 2H), 2.07-1.87 (m, 2H)


524
(400 MHz, CDCl3) δ ppm 8.34 (d, J = 5.6 Hz, 1 H), 8.29 (d, J = 2.2 Hz, 1 H), 8.00 (s,



1 H), 7.66 (d, J = 5.5 Hz, 1 H), 7.62 (d, J = 2.4 Hz, 1 H), 7.60-7.58 (m, 1 H), 6.76 (d,



J = 8.9 Hz, 1 H), 3.90-3.86 (m, 4 H), 3.84 (t, J = 5.8 Hz, 4 H), 3.68-3.61 (m, 8 H),



3.39 (s, 6 H), 3.28 (sept, J = 6.7 Hz, 1 H), 1.25 (d, J = 6.7 Hz, 6 H)


525
(300 MHz, CDCl3) δ ppm 8.32 (d, J = 5.6 Hz, 1 H), 7.65-7.54 (m, 2 H), 7.49 (d,



J = 1.5 Hz, 1 H), 3.95-3.81 (m, 4 H), 3.72 (d, J = 12.0 Hz, 2 H), 3.67-3.56 (m, 4 H),



3.52-3.29 (m, 6 H), 3.10-2.92 (m, 2 H), 2.04-1.82-(m, 3 H), 1.66-1.38 (m, 8 H)


526
(400 MHz, CDCl3) δ ppm 8.05 (d, J = 8.1 Hz, 2 H), 7.54 (t, J = 8.0 Hz, 2 H), 7.49 (s,



1H), 7.35 (t, J = 7.4, 1 H), 3.97 (pent, J = 8.4 Hz, 1 H), 3.48-3.41 (m, 2 H), 3.45 (s, 2



H), 3.44 (s, 3 H), 3.37-3.29 (m, 2 H), 3.33 (s, 3 H), 2.69-2.57 (m, 2 H), 2.48-2.38



(m, 2 H), 2.16-1.98 (m, 4 H), 1.89-1.79 (m, 2 H)


527
(400 MHz, pyridine-d5) δ ppm 8.94-8.79 (m, 2H), 7.49-7.40 (m, 2H), 7.22-



7.15 (m, 1H), 3.97-3.86 (m, 1H), 3.76 (dddd, J = 24.7, 22.9, 10.9, 7.5 Hz, 3H),



3.47-3.37 (m, 1H), 2.72-2.59 (m, 2H), 2.43 (dtt, J = 11.9, 8.0, 3.9 Hz, 1H), 2.37-



2.26 (m, 1H), 2.26-2.17 (m, 1H),2.01-1.84 (m, 2H)



(400 MHz, pyridine-d5) δ ppm 8.85-8.77 (m, 2H), 7.48-7.41 (m, 2H), 7.31 (s,



528 1H), 7.20 (td, J = 7.3, 1.2 Hz, 1H), 4.63 (t, J = 12.2 Hz, 4H), 3.78 (p, J = 7.7 Hz,



1H), 2.68-2.55 (m, 2H), 2.48-2.33 (m, 2H), 2.04-1.83 (m, 2H)


529
(400 MHz, pyridine-d5) δ ppm 8.88 (s, 2H), 8.90-8.80 (m, 2H), 7.49-7.42 (m,



2H), 7.25 (s, 1H), 7.21-7.17 (m, 1H), 4.51-4.33 (m, 4H), 4.28 (dd, J = 8.8, 7.0



Hz, 2H), 3.87-3.75 (m, 1H), 3.74-3.67 (m, 2H), 2.71-2.54 (m, 2H), 2.45-



2.32 (m, 2H), 2.03-1.81 (m, 1H)


530
(400 MHz, pyridine-d5) δ ppm 8.88-8.78 (m, 2H), 7.48-7.40 (m, 2H), 7.26 (s,



1H), 7.22-7.15 (m, 1H), 4.35 (ddd, J = 20.8, 9.5, 1.3 Hz, 2H), 4.21 (ddd, J = 18.4,



9.4, 1.4 Hz, 2H), 3.82 (s, 1H), 2.72-2.55 (m, 2H), 2.40 (dddd, J = 13.4, 8.4, 6.7,



3.7 Hz, 2H), 2.02-1.82 (m, 4H), 0.95 (t, J = 7.4 Hz, 3H)


531
(400 MHz, pyridine-d5) δ ppm 8.81 (dd, J = 8.4, 1.3 Hz, 2H), 7.79 (s, 1H), 7.49-



7.42 (m, 2H), 7.23-7.17 (m, 1H), 4.18-4.00 (m, 4H), 3.94 (ddd, J = 12.6, 10.3,



3.9 Hz, 2H), 3.75 (dt, J = 12.2, 2.1 Hz, 1H), 3.28 (d, J = 11.9 Hz, 1H), 3.05-2.88



(m, 2H), 2.68 (td, J = 12.0, 11.5, 8.6 Hz, 2H), 2.61-2.37 (m, 2H), 2.07-1.93 (m,



2H)


532
(400 MHz, pyridine-d5) δ ppm 8.85 (dt, J = 8.6, 1.0 Hz, 2H), 7.52 (s, 1H), 7.48-



7.41 (m, 2H), 7.19 (tt, J = 7.5, 1.1 Hz, 1H), 3.98 (d, J = 5.4 Hz, 1H), 3.96-3.78



(m, 5H), 3.70 (td, J = 4.1, 1.7 Hz, 2H), 3.55-3.48 (m, 3H), 3.26 (d, J = 0.7 Hz,



3H), 2.81-2.70 (m, 1H), 2.67-2.58 (m, 1H), 2.54 (dt, J = 7.6, 4.2 Hz, 1H), 2.36



(dtt, J = 11.7, 8.3, 3.9 Hz, 1H), 2.30-2.09 (m, 2H), 1.95 (ddt, J = 10.8, 5.3, 3.3



Hz, 2H)


533
(400 MHz, pyridine-d5) δ ppm 8.87-8.78 (m, 2H), 7.71 (s, 1H), 7.67 (s, 1H),



7.48 -7.41 (m, 2H), 7.25-7.16 (m, 1H), 4.26 (p, J = 7.4 Hz, 1H), 4.07-3.89 (m, 1H),



3.48 (tt, J = 8.8, 6.7 Hz, 1H), 2.89-2.78 (m, 5H), 2.60 (dq, J = 11.6, 9.1 Hz, 2H),



2.40 (dddd, J = 14.5, 12.1, 7.5, 2.9 Hz, 2H), 2.25 (qd, J = 8.6, 2.8 Hz, 2H), 2.05-



1.88 (m, 2H)


534
(400 MHz, pyridine-d5) δ ppm 8.88 (dd, J = 8.4, 1.4 Hz, 2H), 7.46 (dd, J = 8.4, 7.2



Hz, 2H), 7.23-7.16 (m, 2H), 4.15-4.05 (m, 4H), 3.94 (s, 2H), 3.82 (t, J = 7.0 Hz,



3H), 2.63 (dq, J = 10.9, 8.5 Hz, 2H), 2.40 (dtd, J = 11.6, 8.3, 4.8 Hz, 2H), 2.09 (t,



J= 7.0 Hz, 2H), 2.01-1.83 (m, 2H)


535
(400 MHz, pyridine-d5) δ ppm 8.81 (dd, J = 8.7, 1.3 Hz, 2H), 7.83 (s, 1H), 7.48-



7.42 (m, 2H), 7.20 (tt, J = 7.4, 1.2 Hz, 1H), 4.39-4.27 (m, 1H), 4.14 (q, J = 8.3



Hz, 1H), 3.66 (dd, J = 12.0, 4.2 Hz, 1H), 3.58-3.51 (m, 1H), 3.31 (t, J = 10.9 Hz,



1H), 3.20 (dt, J = 12.5, 4.7 Hz, 1H), 2.79-2.60 (m, 2H), 2.57 (dt, J = 11.4, 4.5 Hz,



1H), 2.43 (dp, J = 12.5, 4.1 Hz, 1H), 2.35-2.23 (m, 1H), 2.11-1.92 (m, 3H)


536
(400 MHz, pyridine-d5) δ ppm 8.93-8.79 (m, 2H), 7.44 (dd, J = 8.5, 7.3 Hz, 2H),



7.18 (d, J = 7.4 Hz, 1H), 4.40 (d, J = 8.2 Hz, 2H), 4.23 (d, J = 8.2 Hz, 2H), 3.95-



3.75 (m, 1H), 2.65-2.56 (m, 2H), 2.45-2.25 (m, 2H), 1.98-1.84 (m, 2H), 1.68



(s, 3H)


537
(400 MHz, pyridine-d5) δ ppm 8.91-8.82 (m, 2H), 7.54 (s, 1H), 7.48-7.41 (m,



2H), 7.22-7.16 (m, 1H), 4.09 (d, J = 9.8 Hz, 1H), 3.98 (p, J = 8.0 Hz, 1H), 3.76-



3.63 (m, 2H), 3.45 (d, J = 9.8 Hz, 1H), 3.30 (t, J = 6.7 Hz, 2H), 2.72-2.60 (m,



2H), 2.51-2.34 (m, 3H), 2.03 (td, J = 6.6, 2.9 Hz, 2H), 1.89 (qdd, J = 10.8, 6.9,



2.7 Hz, 3H)


538
(400 MHz, pyridine-d5) δ ppm 8.79 (dd, J = 8.6, 1.3 Hz, 2H), 7.90 (s, 1H), 7.46-



7.40 (m, 2H), 7.19 (td, J = 7.4, 1.2 Hz, 1H), 4.77-4.68 (m, 1H), 4.06 (dd, J =



11.4, 4.8 Hz, 1H), 3.97-3.83 (m, 3H), 3.15-2.70 (m, 1H), 2.61 (s, 2H), 2.54-



2.42 (m, 1H), 2.33 (dd, J = 7.7, 4.5 Hz, 1H), 2.00-1.82 (m, 2H)


539
(400 MHz, pyridine-d5) δ ppm 8.84-8.75 (m, 2H), 7.71 (s, 1H), 7.49-7.43 (m,



2H), 7.23-7.18 (m, 1H), 4.24 (q, J = 7.1 Hz, 2H), 4.15-3.96 (m, 1H), 3.07 (t, J =



5.0 Hz, 4H), 2.68 (dq, J = 11.5, 8.9 Hz, 2H), 2.48-2.34 (m, 2H), 2.03 (dtd, J =



15.2, 10.3, 9.2, 5.1 Hz, 2H), 1.21 (t, J = 7.1 Hz, 3H)


540
(400 MHz, pyridine-d5) δ ppm 8.84-8.76 (m, 2H), 7.71 (d, J = 9.4 Hz, 2H), 7.49-



7.43 (m, 2H), 7.23-7.17 (m, 1H), 4.05 (dq, J = 10.4, 8.2 Hz, 2H), 3.29 (s, 2H),



3.15 (t, J = 4.6 Hz, 4H), 2.77 (t, J = 4.7 Hz, 3H), 2.66 (qd, J = 8.9, 2.5 Hz, 2H),



2.41 (ddtd, J = 12.0, 8.5, 6.1, 2.5 Hz, 2H), 2.08-1.90 (m, 4H), 1.58 (dt, J = 12.9,



3.5 Hz, 2H), 1.42 (d, J = 13.5 Hz, 1H), 1.34-1.15 (m, 4H), 1.10-0.99 (m, 1H)


541
(400 MHz, pyridine-d5) δ ppm 8.90-8.81 (m, 2H), 7.48-7.42 (m, 2H), 7.21-



7.15 (m, 1H), 3.95-3.85 (m, 1H), 3.85-3.68 (m, 3H), 3.44 (ddd, J = 10.2, 9.0,



1.7 Hz, 1H), 2.71-2.60 (m, 2H), 2.43 (dtt, J = 11.7, 8.0, 4.0 Hz, 1H), 2.38-2.26



(m, 1H), 2.26-2.05 (m, 1H), 2.12-2.00 (m, 1H), 2.00-1.86 (m, 2H)


542
(400 MHz, pyridine-d5) δ ppm 8.91-8.81 (m, 2H), 7.47-7.40 (m, 2H), 7.21 (s,



1H), 7.18 (d, J = 7.4 Hz, 1H), 4.30 (dd, J = 8.6, 6.5 Hz, 2H), 4.10 (dd, J = 9.0, 3.7



Hz, 2H), 3.23 (s, 3H), 2.69-2.55 (m, 2H), 2.46-2.32 (m, 2H), 2.03-1.86 (m,



2H)


543
(400 MHz, pyridine-d5) δ ppm 8.86-8.78 (m, 2H), 7.72 (s, 1H), 7.48-7.41 (m,



2H), 7.19 (t, J = 7.4 Hz, 1H), 4.61 (p, J = 7.2 Hz, 1H), 4.07 (p, J = 8.3 Hz, 1H),



3.02 (dt, J = 23.2, 5.5 Hz, 4H), 2.70 (dq, J = 11.5, 9.0 Hz, 2H), 2.48-2.34 (m,



4H), 2.09-1.96 (m, 4H), 1.78 (t, J = 5.5 Hz, 2H), 1.72 (t, J = 5.4 Hz, 2H)


544
(400 MHz, pyridine-d5) δ ppm 8.86-8.78 (m, 2H), 7.80 (s, 1H), 7.48-7.40 (m,



2H), 7.19 (t, J = 7.4 Hz, 1H), 4.13 (p, J = 8.3 Hz, 1H), 3.89-3.74 (m, 2H), 3.68



(dd, J = 10.7, 7.5 Hz, 1H), 3.40 (d, J = 12.3 Hz, 1H), 2.81-2.38 (m, 6H), 2.24-



2.14 (m, 1H), 2.10-1.85 (m, 3H), 1.79-1.66 (m, 2H), 1.21 (qd, J = 11.4, 4.9 Hz,



1H)


545
(400 MHz, pyridine-d5) δ ppm 8.92-8.78 (m, 2H), 7.72 (s, 1H), 7.49-7.42 (m,



2H), 7.22-7.16 (m, 1H), 3.93 (q, J = 8.2 Hz, 1H), 3.85-3.80 (m, 2H), 3.78 (t, J =



5.6 Hz, 2H), 3.65-3.59 (m, 2H), 3.59-3.53 (m, 2H), 2.63 (dq, J = 11.6, 9.0 Hz,



2H), 2.39 (ttd, J = 12.1, 8.4, 7.1, 4.3 Hz, 2H), 2.01-1.87 (m, 4H)


546
(400 MHz, pyridine-d5) δ ppm 8.86-8.78 (m, 2H), 7.84 (s, 1H), 7.45 (dd, J = 8.6,



7.3 Hz, 2H), 7.26-7.17 (m, 1H), 4.25 (t, J = 6.4 Hz, 2H), 4.12 (q, J = 8.3 Hz, 1H),



3.56 (s, 2H), 3.36 (dt, J = 12.1, 4.0 Hz, 2H), 2.69 (pd, J = 9.0, 2.5 Hz, 2H), 2.51-



2.39 (m, 2H), 2.16-1.91 (m, 8H)


547
(400 MHz, CDCl3) δ ppm 7.39 (s, 1 H), 4.43 (d, J = 7.2 Hz, 2 H), 3.72-3.66 (m, 2



H), 3.42-3.32 (m, 6 H), 2.98-2.86 (m, 3 H), 2.04-1.82 (m, 9 H), 1.58-1.46



(m, 2 H), 1.39 (d, J = 6.8 Hz, 6 H)


548
(400 MHz, CDCl3) δ ppm 7.41 (s, 1 H), 4.24 (d, J = 7.3 Hz, 2 H), 3.70 (d, J = 12.5



Hz, 2 H), 3.42-3.31 (m, 6 H), 2.94 (td, J = 12.3, 2.1 Hz, 2 H), 2.36 (s, 1 H), 1.93 (d,



J = 13.0 Hz, 3 H), 1.53 (dd, J = 11.9, 3.2 Hz, 2 H), 1.45-1.39 (m, 6 H), 0.92



(d, J = 6.8 Hz, 6 H)


549
(501 MHz, methanol-d4) δ ppm 1.50 (s, 9H), 1.94 2.27 (m, 6H), 2.42-2.51 (m, 2H),



2.52-2.66 (m, 3H), 2.95-3.06 (m, 1H), 3.37-3.58 (m, 5H), 3.94-4.00 (m, 1H), 4.02-



4.07 (m, 1H), 7.31-7.35 (m, 1H), 7.44 (s, 1H), 7.50-7.55 (m, 2H), 8.24-8.28 (m,



2H)


551
(400 MHz, DMSO-d6) δ ppm 8.28-8.43 (m, 3 H), 7.70-7.82 (m, 2 H), 7.55-7.65



(m, 2 H), 7.26-7.41 (m, 1 H), 6.99-7.12 (m, 1 H), 3.89-4.07 (m, 2 H), 3.65-



3.79 (m, 1 H), 3.43-3.56 (m, 2 H), 3.11-3.25 (m, 1 H), 2.53-2.63 (m, 1 H), 2.28-



2.46 (m, 2 H), 1.90-2.05 (m, 3 H), 1.69-1.83 (m, 2 H), 1.52-1.66 (m, 1 H),



1.05 (d, J = 6.7 Hz, 3 H)


552
400 MHz, CDCl3) δ ppm 8.55 (br. s., 1 H), 8.01 (br. s., 3 H), 7.85 (br. s., 1 H), 7.49



(br. s., 2 H), 7.27 (s, 1 H), 6.75 (br. s., 1 H), 5.69-5.48 (m, 1 H), 3.95 (br. s., 2 H),



3.89-3.59 (m, 4H), 3.58-3.42 (m, 2H), 2.94 (br. s., 1 H), 2.25 (br. s., 2H), 2.11-



1.87 (m, 4 H), 1.54-1.36 (m, 9 H) (OH missing)


554
(400 MHz, pyridine-d5) δ ppm 8.87-8.79 (m, 2H), 7.75 (s, 1H), 7.48-7.41 (m,



2H), 7.21-7.17 (m, 1H), 4.00 (t, J = 8.3 Hz, 1H), 3.92-3.82 (m, 2H), 3.27-3.17



(m, 4H), 2.97 (s, 3H), 2.65 (qd, J = 8.9, 2.6 Hz, 2H), 2.52-2.37 (m, 2H), 2.04-



1.92 (m, 3H), 1.49-1.41 (m, 2H), 1.09 (qd, J = 12.1, 4.5 Hz, 2H)


555
(400 MHz, pyridine-d5) δ ppm 8.86-8.74 (m, 2H), 7.74 (s, 1H), 7.49-7.42 (m,



2H), 7.20 (tt, J = 7.4, 1.2 Hz, 1H), 4.08 (p, J = 8.3 Hz, 1H), 3.63 (t, J = 5.6 Hz,



2H), 3.33 (t, J = 6.5 Hz, 2H), 3.27 (t, J = 4.8 Hz, 4H), 2.89 (t, J = 4.7 Hz, 4H), 2.81



(t, J = 5.6 Hz, 2H), 2.68 (dq, J = 11.6, 9.1 Hz, 2H), 2.42 (ddt, J = 8.6, 6.0, 2.7 Hz,



2H), 2.08-1.93 (m, 2H), 1.61-1.49 (m, 2H), 0.87 (t, J = 7.4 Hz, 3H)


556
(400 MHz, pyridine-d5) δ ppm 8.85-8.75 (m, 2H), 7.75 (s, 1H), 7.49-7.43 (m,



2H), 7.24-7.17 (m, 1H), 4.41 (dtd, J = 10.6, 5.5, 2.2 Hz, 1H), 4.17-4.01 (m,



1H), 4.01-3.89 (m, 2H), 3.50 (d, J = 11.8 Hz, 1H), 3.26 (dd, J = 12.1, 2.1 Hz,



1H), 3.15-2.81 (m, 7H), 2.81-2.64 (m, 2H), 2.62-2.52 (m, 2H), 2.47 (dqd, J =



14.9, 8.0, 7.1, 3.8 Hz, 1H), 2.14-1.97 (m, 2H), 1.66 (p, J = 5.7 Hz, 4H), 1.30 (s,



2H)


557
(400 MHz, pyridine-d5) δ ppm 8.90-8.76 (m, 2H), 7.71 (s, 1H), 7.49-7.41 (m,



2H), 7.23-7.17 (m, 1H), 4.03 (p, J = 8.3 Hz, 1H), 3.47 (d, J = 12.3 Hz, 2H), 2.93



(d, J = 6.8 Hz, 2H), 2.79-2.61 (m, 4H), 2.44 (pd, J = 7.6, 6.9, 3.3 Hz, 2H), 2.15-



1.99 (m, 4H), 1.9 (m, 1H), 1.89- 1.79 (m, 4H), 1.59 (qd, J = 12.3, 3.6 Hz, 2H)


558
(400 MHz, pyridine-d5) δ ppm 8.84-8.76 (m, 2H), 7.73 (s, 1H), 7.49-7.42 (m,



2H), 7.23-7.18 (m, IH), 4.07 (p, J = 8.4 Hz, 1H), 3.85 (t, J = 4.8 Hz, 4H), 3.26 (t,



J = 4.7 Hz, 4H), 2.91-2.74 (m, 10H), 2.74-2.62 (m, 2H), 2.59 (t, J = 7.0 Hz,



2H), 2.51-2.34 (m, 2H), 2.10-1.88 (m, 4H)


559
(400 MHz, pyridine-d5) δ ppm 8.84-8.74 (m, 2H), 7.73 (s, 1H), 7.48-7.42 (m,



2H), 7.22-7.17 (m, 1H), 4.07 (p, J = 8.3 Hz, 1H), 3.38 (s, 2H), 3.20 (t, J = 4.7 Hz,



4H), 2.94 (s, 3H), 2.89 (s, 3H), 2.86 (t, J = 4.7 Hz, 4H), 2.66 (dq, J = 11.6, 9.0 Hz,



2H), 2.41 (ddd, J = 14.4, 8.3, 3.0 Hz, 2H), 2.04- 1.93 (m, 2H)


560
(400 MHz, DMSO-d6, 90° C.) δ ppm 8.34-8.30 (m, 2H), 7.54-7.48 (m, 2H), 7.30-



7.25 (m, 2H), 4.00 (p, J = 8.1 Hz, 1H), 3.62-3.58 (m, 4H), 3.56-3.53 (m, 2H), 2.97-



2.89 (m, 1H), 2.76-2.68 (m, 1H), 2.56-2.51 (m, 4H), 2.45-2.41 (m, 3H), 2.11-1.94



(m, 4H), 1.85-1.77 (m, 1H), 1.74-1.63 (m, 2H), 1.55-1.44 (m, 1H)


561
(400 MHz, pyridine-d5) δ ppm 8.87-8.78 (m, 2H), 7.72 (s, 1H), 7.49-7.42 (m,



2H), 7.20 (t, J = 7.4 Hz, 1H), 4.05 (p, J = 8.4 Hz, 1H), 3.17 (t, J = 4.7 Hz, 4H),



2.68 (td, J = 8.4, 7.2, 3.6 Hz, 10H), 2.41 (dqd, J = 12.2, 6.2, 2.4 Hz, 2H), 2.08-



1.96 (m, 2H)


562
(400 MHz, pyridine-d5) δ ppm 8.84-8.75 (m, 2H), 7.75 (s, 1H), 7.46 (dd, J = 8.6,



7.3 Hz, 2H), 7.21 (td, J = 7.4, 1.2 Hz, 1H), 4.32 (qt, J = 5.9, 2.1 Hz, 1H), 4.11-



3.88 (m, 3H), 3.78-3.53 (m, 1H), 3.50 (d, J = 12.1 Hz, 1H), 3.27 (d, J = 12.2 Hz,



1H), 3.00-2.88 (m, 3H), 2.72 (ddd, J = 12.2, 9.6, 4.4 Hz, 2H), 2.64 (s, 6H), 2.47



(dqd, J = 28.4, 8.0, 4.2 Hz, 2H), 2.14-1.97 (m, 2H)


563
(400 MHz, pyridine-d5) δ ppm 8.84-8.75 (m, 2H), 7.73 (s, 1H), 7.48-7.41 (m,



2H), 7.21 (dt, J = 7.5, 1.3 Hz, 1H), 4.06 (p, J = 8.3 Hz, 1H), 3.22 (t, J = 4.8 Hz,



4H), 2.74-2.64 (m, 2H), 2.62 (dd, J = 6.6, 3.2 Hz, 4H), 2.30 (s, 3H), 2.10- 1.94



(m, 2H)


564
(400 MHz, pyridine-d5) δ ppm 8.83 (dt, J = 8.6, 1.2 Hz, 2H), 7.73 (d, J = 1.0 Hz,



1H), 7.48-7.43(m, 2H), 7.19 (td, J =7.4, 1.2 Hz, 1H), 3.98 (q, .7=8.2 Hz, 1H),



3.21 (d, J = 7.2 Hz, 3H), 2.94 (d, J = 1.0 Hz, 3H), 2.64 (dq, J = 11.1, 8.6 Hz, 2H),



2.52-2.40 (m, 4H), 2.05-1.91 (m, 3H), 1.89-1.66 (m, 3H), 1.56 (d, J = 13.4



Hz, 2H), 0.83 (dd, J = 6.7, 1.0 Hz, 6H)


565
(400 MHz, pyridine-d5) δ ppm 8.87-8.79 (m, 2H), 7.78 (s, 1H), 7.46-7.38 (m,



2H), 7.18 (tt, J = 7.3, 1.2 Hz, 1H), 4.05 (p, J = 8.4 Hz, 1H), 3.59- 3.43 (m, 6H),



2.95 (s, 3H), 2.66 (pd, J = 9.1, 2.4 Hz, 2H), 2.55-2.41 (m, 4H), 2.30-2.21 (m.



4H), 2.07-1.91 (m, 2H)


566
(400 MHz, pyridine-d5) δ ppm 8.84-8.77 (m, 2H), 7.73 (s, 1H), 7.71 (s, 1H), 7.48



2H), 3.42 (q, J = 7.0 Hz, 2H), 3.26 (t, J = 4.7 Hz, 4H), 2.86 (t, J = 4.7 Hz, 4H),



2.78 (t, J = 5.7 Hz, 2H), 2.68 (pd, J = 9.1, 2.5 Hz, 2H), 2.47-2.35 (m, 2H), 1.99



(dtd, J = 15.0, 10.5, 9.8, 6.7 Hz, 2H), 1.13 (t, J = 7.0 Hz, 3H)


567
(400 MHz, pyridine-d5) δ ppm 8.94-8.81 (m, 2H), 7.50 (s, 1H), 7.49-7.43 (m,



2H), 7.23-7.16(m, 1H), 3.95 (p, .7=7.9 Hz, 1H), 3.81 -3.74(m, 1H), 3.68-



3.63 (m, 1H), 3.52-3.44 (m, 2H), 3.11 (p, J = 7.6 Hz, 1H), 2.74-2.60 (m, 2H),



2.46 (s, 7H), 2.23-2.04 (m, 2H), 2.04-1.87 (m, 2H)


568
(400 MHz, pyridine-d5) δ ppm 8.91-8.79 (m, 2H), 7.50 (s, 1H), 7.49-7.43 (m,



2H), 7.19 (tt, J = 7.4, 1.2 Hz, 1H), 3.96 (p, J = 8.0 Hz, 1H), 3.80 (dd, J = 9.7, 8.2



Hz, 1H), 3.67 (dd, J = 9.6, 6.8 Hz, 1H), 3.53-3.46 (m, 2H), 2.75-2.60 (m, 2H),



2.47 (s, 8H), 2.20-2.04 (m, 2H), 2.03-1.93 (m, 2H)


569
(400 MHz, pyridine-d5) δ ppm 8.86-8.74 (m, 2H), 7.66 (s, 1H), 7.48-7.43 (m,



2H), 7.20 (tt, J = 7.4, 1.2 Hz, 1H), 4.03 (t, J = 8.3 Hz, 1H), 3.27 (s, 2H), 3.07 (t, J =



4.7 Hz, 3H), 2.93 (d, J = 4.8 Hz, 3H), 2.72 (t, J = 4.6 Hz, 4H), 2.65 (qd, J = 8.9,



2.5 Hz, 2H), 2.39 (dqd, J = 12.0, 6.1, 2.2 Hz, 2H), 2.09- 1.96 (m, 2H)


570
(400 MHz, pyridine-d5) δ ppm 8.86-8.76 (m, 2H), 7.74 (s, 1H), 7.71 (s, 1H), 7.49



3.75 (s, 1H), 3.71 (t, J = 4.6 Hz, 4H), 3.40 (s, 2H), 3.17 (dt, J = 27.8, 4.9 Hz, 4H),



2.68 (pd, J = 9.1, 2.4 Hz, 2H), 2.63-2.57 (m, 4H), 2.43 (qd, J = 8.3, 5.7 Hz, 2H),



2.10-1.96 (m, 2H)


571
(501 MHz, DMSO-d6) δ ppm 8.35-8.32 (m, 2H), 7.59-7.54 (m, 2H), 7.33 (tt, J =



7.3, 1.2 Hz, 1H), 7.31 (s, 1H), 4.01 (tt, J = 8.4, 8.4 Hz, 1H), 3.51 (t, J = 5.7 Hz,



3H), 3.27 (s, 3H), 3.26-3.21 (m, 4H), 2.76-2.69 (m, 4H), 2.62 (t, J = 5.7 Hz, 2H),



2.55-2.36 (m, 4H), 2.11-1.93 (m, 2H)


572
(400 MHz, pyridine-d5) δ ppm 8.84 (dt, J = 8.7, 1.1 Hz, 2H), 7.45 (dd, J = 8.4, 7.2



Hz, 2H), 7.19 (td, J = 7.4, 1.2 Hz, 1H), 4.15 (p, J = 6.2 Hz, 1H), 3.94 (p, J = 8.1



Hz, 1H), 3.83 (t, J = 4.6 Hz, 2H), 3.81-3.72 (m, 1H), 3.63 (td, J = 7.9, 6.1 Hz,



1H), 3.55 (dd, J = 6.8, 3.1 Hz, 2H), 3.21 (dt, J = 14.3, 4.5 Hz, 1H), 3.03 (ddq, J =



31.1, 12.8, 7.3, 5.9 Hz, 3H), 2.80 (d, J = 5.6 Hz, 2H), 2.62 (ddt, J = 13.5, 8.8, 4.3



Hz, 2H), 2.41 (dt, J = 12.0, 3.9 Hz, 2H), 2.07-1.88 (m, 4H), 1.83 (dtd, J = 11.8,



7.2, 4.9 Hz, 1H), 1.71-1.54 (m, 2H), 1.40 (dq, J = 12.1, 8.1 Hz, 1H), 1.4(m, 1H)


573
(400 MHz, pyridine-d5) δ ppm 8.96- 8.79 (m, 2H), 7.45 (ddt, J = 8.6, 7.6, 1.4 Hz,



2H), 7.23 (d, J = 0.9 Hz, 1H), 7.21-7.15 (m, 2H), 4.45-4.32 (m, 3H), 4.1 (dd, J =



8.6, 3.6 Hz, 2H), 3.88-3.74 (m, 1H), 3.64-3.50 (m, 1H), 2.69-2.57 (m, 2H),



2.41-2.31 (m, 2H), 2.01-1.84 (m, 2H), 1.11 (dd, J = 6.1, 0.9 Hz, 6H)


574
(400 MHz, pyridine-d5) δ ppm 8.90-8.79 (m, 2H), 7.71 (s, 1H), 7.48-7.43 (m,



2H), 7.20 (tt, J = 7.4, 1.2 Hz, 1H), 4.03 (t, J = 8.3 Hz, 1H), 3.44 (d, J = 12.0 Hz,



2H), 3.05 (t, J = 8.1 Hz, 2H), 2.77-2.60 (m, 4H), 2.46-2.35 (m, 2H), 2.08-1.97



(m, 2H), 1.82 (d, J = 4.0 Hz, 4H), 1.69 (d, J = 9.2 Hz, 4H), 1.44 (s, 3H)


575
(400 MHz, DMSO-d6, 120° C.) δ ppm 8.32 (d, J = 8.1 Hz, 2H), 7.54-7.48 (m, 2H),



7.32-7.26 (m, 2H), 4.02 (p, J = 8.1 Hz, 1H), 3.63-3.58 (m, 2H), 3.00-2.91 (m, 2H),



2.63-2.57 (m, 4H), 2.56-2.41 (m, 5H), 2.16-1.91 (m, 4H), 1.82-1.69 (m, 2H), 1.60-



1.51 (m, 4H), 1.48-1.39 (m, 2H)


576
(400 MHz, DMSO-d6, 120° C.) δ ppm 8.32 (d, J = 8.1 Hz, 2H), 7.54-7.48 (m, 2H),



7.32-7.26 (m, 2H), 4.02 (p, J = 8.1 Hz, 1H), 3.63-3.58 (m, 2H), 3.00-2.91 (m, 2H),



2.63-2.57 (m, 4H), 2.56-2.41 (m, 5H), 2.16-1.91 (m, 4H), 1.82-1.69 (m, 2H), 1.60-



1.51 (m, 4H), 1.48-1.39 (m, 2H)


577
(400 MHz, DMSO-d6) δ ppm 8.35-8.22 (m, 2H), 7.63-7.52 (m, 2H), 7.46 (s,



1H), 7.39-7.29 (m, 1H), 5.09 (s, 1H), 4.08-3.95 (m, 1H), 2.50-2.32 (m, 4H),



2.25-1.86 (m, 10H)


578
(400 MHz, DMSO-d6) δ ppm 8.30- 8.23 (m, 2H), 7.60- 7.51 (m, 2H), 7.44 (s,



1H), 7.40-7.28 (m, 1H), 5.09 (tt, J = 8.0, 4.0 Hz, 1H), 4.13-3.98 (m, 1H), 3.89



(ddd, J = 11.6, 6.0, 3.9 Hz, 2H), 3.65-3.58 (m, 2H), 2.49-2.34 (m, 4H), 2.10



(dtd, J = 14.1, 8.7, 7.3, 3.7 Hz, 3H), 1.99- 1.85 (m, 1H), 1.77 (dtd, J = 12.2, 8.0,



3.9 Hz, 2H)


579
(400 MHz, DMSO-d6) δ ppm 8.33-8.21 (m, 2H), 7.56 (dd, J = 8.6, 7.3 Hz, 2H),



7.48 (s, 1H), 7.41-7.28 (m, 1H), 4.70 (ddd, J = 9.3, 7.8, 4.4 Hz, 1H), 4.15 - 3.94



(m, 1H), 3.44 (d, J = 11.9 Hz, 1H), 3.28 (s, 3H), 2.49-2.34 (m, 3H), 2.17-2.01



(m, 3H), 1.99-1.85 (m, 1H), 1.69 (dd, J = 9.8, 5.3 Hz, 2H), 1.61-1.25 (m, 4H)


580
(400 MHz, DMSO-d6) δ ppm 8.32-8.24 (m, 2H), 7.65-7.53 (m, 2H), 7.49 (s,



1H), 7.38-7.29 (m, IH), 4.58 (d, J = 6.1 Hz, 2H), 4.44 (d,./ = 5.4 Hz, 4H), 4.10-



3.95 (m, 1H), 2.38 (dddd, J = 24.3, 11.6, 9.3, 5.4 Hz, 4H), 2.08-1.97 (m, 1H),



1.97-1.79 (m, 3H), 0.95 (t, J = 7.5 Hz, 3H)


581
(400 MHz, DMSO-d6) δ ppm 8.32- 8.20 (m, 2H), 7.63-7.51 (m, 2H), 7.39-7.30



(m, 2H), 5.46 (t, J = 4.1 Hz, 1H), 4.07-3.96 (m, 3H), 3.96-3.81 (m, 2H), 2.47-



2.27 (m, 4H), 2.20-2.00 (m, 2H), 2.00-1.80 (m, 1H)


582
(400 MHz, DMSO-d6) δ ppm 8.31-8.20 (m, 2H), 7.66-7.50 (m, 2H), 7.45-7.30



(m, 2H), 5.46 (dd, J = 5.8, 3.1 Hz, 1H), 4.11-3.95 (m, 3H), 3.94-3.83 (m, 2H),



2.49-2.29 (m, 5H), 2.23-2.02 (m, 2H), 2.00-1.81 (m, 1H)


583
(400 MHz, DMSO-d6) δ ppm 8.34-8.23 (m, 2H), 7.64-7.50 (m, 2H), 7.41 (s,



1H), 7.38-7.28 (m, 1H), 4.09 (s, 3H), 4.04-3.95 (m, 1H), 2.49-2.33 (m, 4H),



2.10 (dq, J = 10.9, 8.7 Hz, 1H), 2.01-1.84 (m, 1H)


584
(400 MHz, DMSO-d6) δ ppm 8.29-8.20 (m, 2H), 7.64-7.52 (m, 2H), 7.33 (t, J =



7.4 Hz, 1H), 7.23 (s, 1H), 5.10 (p, J = 7.1 Hz, 1H), 4.12-3.93 (m, 1H), 2.50-



2.38 (m, 4H), 2.27-2.06 (m, 3H), 2.10-1.85 (m, 2H), 1.85- 1.71 (m, 1H)


585
(400 MHz, DMSO-d6) δ ppm 8.31-8.21 (m, 2H), 7.56 (dd, J = 8.6, 7.3 Hz, 2H),



7.41 (s, 1H), 7.37-7.24 (m, 1H), 4.50-4.38 (m, 2H), 4.02 (p, J = 8.8 Hz, 1H),



3.94-3.86 (m, 2H), 3.65-3.59 (m, 2H), 3.56-3.44 (m, 2H), 3.24 (s, 3H), 2.50-



2.36 (m, 4H), 2.07 (dp, J = 10.6, 8.9 Hz, 1H), 2.00- 1.85 (m, 1H)


586
(400 MHz, DMSO-d6, 120° C.) δ ppm 1.98 (s, 3H), 1.88-2.22 (m, 6H), 2.40-2.59



(m, 4H), 2.98-3.07 (m, 1H), 3.15-3.19 (m, 1H), 3.31-3.61 (m, 4H), 3.78-3.83 (m,



1H), 3.99-4.13 (m, 2H), 7.27-7.32 (m, 1H), 7.34 (s, 1H), 7.49-7.55 (m, 2H), 8.29-



8.35 (m, 2H)



(400 MHz, DMSO-d6, 120° C.) δ ppm 1.98 (s, 3H), 1.88-2.22 (m, 6H), 2.40-2.59


587
(m, 4H), 2.98-3.07 (m, 1H), 3.15-3.19 (m, 1H), 3.31-3.61 (m, 4H), 3.78-3.83 (m,



1H), 3.99-4.13 (m, 2H), 7.27-7.32 (m, 1H), 7.34 (s, 1H), 7.49-7.55 (m, 2H), 8.29-



8.35 (m, 2H)


588
(400 MHz, pyridine-d5) δ ppm 8.87-8.79 (m, 2H), 7.75 (s, 1H), 7.48-7.41 (m,



2H), 7.21-7.17 (m, 1H), 4.00 (t, J = 8.3 Hz, 1H), 3.92 - 3.82 (m, 2H), 3.27 -3.17



(m, 4H), 2.97 (s, 3H), 2.65 (qd, J = 8.9, 2.6 Hz, 2H), 2.52 ?



1.92 (m, 3H), 1.49- 1.41 (m, 2H), 1.09 (qd, J = 12.1, 4.5 Hz, 2H)


589
H NMR (300 MHz, CDCl3) δ ppm 8.45 (d, J = 5.6 Hz, 1 H), 7.62 (s, 1 H), 7.23 (d,



J = 5.3 Hz, 1 H), 3.90-4.00 (m, 4 H), 3.75-3.90 (m, 6 H), 3.40-3.49 (m, 1H),



3.38 (s, 3 H), 3.34 (d, J = 5.9 Hz, 2 H), 3.12 (t, J = 12.6 Hz, 2 H), 1.80-2.03 (m, 3



H), 1.48-1.63 (m, 2 H), 1.45 (d, J = 6.7 Hz, 6 H)


590
(400 MHz, DMSO-d6) δ ppm 1.22-1.35 (m, 2H), 1.60-1.68 (m, 2H), 1.87-2.02 (m,



2H), 2.03-2.16 (m, 1H), 2.40-2.48 (m, 4H), 3.24-3.33 (m, 4H), 3.83-3.90 (m, 2H),



4.15-4.25 (m, 1H), 6.33-6.38 (m, 1H), 6.99 (s, 1H), 7.25-7.30 (m, 1H), 7.50-7.56



(m, 2H), 8.34-8.38 (m, 2H)


591
(400 MHz, CDCl3) δ ppm 8.54 (d, J = 2.4 Hz, 1 H), 8.31 (dd, J = 8.8, 1.0 Hz, 2 H),



8.08 (dd, J = 9.0, 2.2 Hz, 1 H), 7.87 (s, 1 H), 7.60-7.51 (m, 2 H), 7.33-7.25 (m, 1



H), 7.13 (d, J = 9.5 Hz, 1 H), 5.56 (td, J = 4.2, 2.2 Hz, 1 H), 4.04-3.92 (m, 4 H),



3.88-3.75 (m, 2 H), 3.59-3.46 (m, 2 H), 3.20 (tt, J = 8.6, 4.2 Hz, 1 H), 2.36-2.24



(m, 1 H), 2.22-2.08 (m, 1 H), 2.00 (ddd, J = 9.7, 6.1, 3.3 Hz, 2 H), 1.85-1.73 (m, 2



H) (OH missing)


592
(400 MHz, CDCl3) δ ppm 8.68 (d, J = 2.2 Hz, 1 H), 8.07 (s, 1 H), 8.04-7.95 (m, 3



H), 7.55 (t, J = 7.9 Hz, 2 H), 7.39-7.31 (m, 1 H), 6.82 (d, J = 8.9 Hz, 1 H), 5.79-



5.68 (m, 1 H), 5.08 (t, J = 7.3 Hz, 2 H), 4.83 (dd, J = 8.3, 5.0 Hz, 2 H), 3.99 (ddd,



J = 13.7, 7.3, 3.6 Hz, 2 H), 3.70 (ddd, J = 13.7, 7.7, 3.6 Hz, 2 H), 2.97 (tt, J = 7.8,



4.1 Hz, 1 H), 1.93-2.13 (m, 4 H) (OH missing)


593
(400 MHz, pyridine-d5) δ ppm 8.90-8.79 (m, 2H), 7.76 (s, 1H), 7.46-7.40 (m,



2H), 7.19 (d, J = 7.5 Hz, 1H), 4.02 (p, J = 8.3 Hz, 1H), 3.23 (d, J = 7.3 Hz, 2H),



2.94 (s, 3H), 2.78-2.56 (m, 3H), 2.55-2.37 (m, 3H), 2.06 (d, J = 6.2 Hz, 6H),



1.56 (t, J = 10.1 Hz, 2H), 1.43 (h, J = 3.9 Hz, 2H), 0.78 (d, J = 11.6 Hz, 1H)


594
(400 MHz, pyridine-d5) δ ppm 8.80 (d, J = 8.1 Hz, 1H), 7.77 (s, 1H), 7.46 (t, J =



7.9 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 3.99 (q, J = 8.5 Hz, 1H), 3.24 (t, J = 5.6 Hz,



2H), 2.78-2.58 (m, 1H), 2.39 (ddp, J = 12.3, 7.9, 4.9, 4.3 Hz, 1H), 2.24 (dt, J =



13.6, 7.5 Hz, 2H), 2.10-1.97 (m, 1H)


595
(400 MHz, pyridine-d5) δ ppm 8.83-8.75 (m, 2H), 7.83 (s, 1H), 7.49-7.40 (m,



2H), 7.19 (t, J = 7.5 Hz, 1H), 4.17 (t, J = 8.3 Hz, 1H), 3.76 (dd, J = 12.8, 8.9 Hz,



1H), 3.56-3.39 (m, 2H), 3.26 (s, 2H), 3.20-3.06 (m, 1H), 2.89 (t, J = 11.5 Hz,



1H), 2.67 (dt, J = 25.3, 9.4 Hz, 1H), 2.47 (ddt, J = 19.2, 12.1, 4.2 Hz, 1H), 2.07 (s,



2H), 2.01-1.86 (m, 1H), 1.82-1.56 (m, 1H)


596
(400 MHz, pyridine-d5) δ ppm 8.81 (d, J = 8.1 Hz, 2H), 7.83 (s, 1H), 7.22 (m, 2H),



4.57 (d, J = 8.9 Hz, 1H), 4.15-3.93 (m, 4H), 3.61 (d, J = 11.8 Hz, 1H), 3.28 (d,



J = 12.6 Hz, 2H), 3.11 (t, J = 11.1 Hz, 2H), 3.05-2.95 (m, 1H), 2.66 (dq, J = 18.7,



9.5 Hz, 2H), 2.56-2.33 (m, 2H), 2.10-1.92 (m, 2H)


597
(400 MHz, DMSO-d6) δ ppm 8.32-8.20 (m, 2H), 7.62-7.46 (m, 2H), 7.46-7.29



(m, 2H), 5.22 (tt, J = 5.8, 2.3 Hz, 1H), 4.05-3.90 (m, 1H), 2.49-2.31 (m, 4H),



2.17-1.95 (m, 3H), 1.95-1.83 (m, 3H), 1.83-1.65 (m, 4H)


598
(400 MHz, DMSO-d6) δ ppm 8.28-8.23 (m, 2H), 7.57 (dd, J = 8.6, 7.4 Hz, 2H),



7.42-7.31 (m, 1H), 7.23 (s, 1H), 4.97 (p, J = 6.9 Hz, 1H), 3.84 (q, J = 7.9 Hz,



1H), 3.06-2.94 (m, 2H), 2.48-2.27 (m, 7H), 2.13 (dq, J = 11.0, 8.7 Hz, 1H),



1.95 (s, 1H)


599
(400 MHz, DMSO-d6) δ ppm 8.34-8.20 (m, 2H), 7.58 (dd, J = 8.6, 7.4 Hz, 2H),



7.39-7.29 (m, 1H), 7.13 (s, 1H), 5.46 (td, J = 6.5, 3.2 Hz, 1H), 4.71 (dd, J = 12.2,



6.5 Hz, 2H), 4.39 (dd, J = 12.4, 4.2 Hz, 2H), 4.24-4.07 (m, 1H), 3.20 (td, J = 7.3,



3.5 Hz, 1H), 2.46 (dd, J = 10.7, 6.9 Hz, 4H), 2.18-2.06 (m, 1H), 2.04-1.91 (m,



3H), 1.85-1.74 (m, 2H), 1.62 (d, J = 12.3 Hz, 1H), 1.32-1.04 (m, 5H)


600
(400 MHz, DMSO-d6) δ ppm 8.34-8.21 (m, 2H), 7.56 (dd, J = 8.6, 7.4 Hz, 2H),



7.40 (s, 1H), 7.33 (t, J = 7.4 Hz, 1H), 4.39 (d, J = 4.8 Hz, 2H), 4.02 (p, J = 8.5 Hz,



1H), 2.80-2.58 (m, 4H), 2.45-2.31 (m, 3H), 2.12-1.98 (m, 1H), 1.92 (s, 1H)


601
(400 MHz, DMSO-d6) δ ppm 8.32-8.23 (m, 2H), 7.57 (dd, J = 8.4, 7.5 Hz, 2H),



7.35 (t, J = 7.4 Hz, 1H), 7.09 (s, 1H), 5.42 (s, 1H), 4.55 (s, 2H), 4.20-4.06 (m,



2H), 2.85 (s, 3H), 2.46 (s, 1H), 2.24-2.07 (m, 1H), 1.96 (s, 1H), 1.19 (d, J = 27.6



Hz, 3H)


602
(300 MHz, CDCl3) δ ppm 7.49 (s, 1 H), 7.29-7.45 (m, 3 H), 6.73 (d, J = 6.7 Hz, 1



H), 4.21 (d, J = 6.5 Hz, 2 H), 4.09 (d, J = 7.9 Hz, 2 H), 3.40-3.69 (m, 3 H), 3.05 (s, 6



H), 2.26 (br. s., 1 H), 1.84 (d, J = 10.9 Hz, 2 H), 1.54-1.74 (m, 2 H), 1.48 (d, J = 6.7



Hz, 6 H)


603
(300 MHz, CDCl3) δ ppm 7.44 (s, 1 H), 4.83 (d, J = 3.5 Hz, 1 H), 4.19-4.00 (m, 4



H), 3.59-3.36 (m, 3 H), 3.13 (q, J = 7.3 Hz, 4 H), 2.29-1.30 (m, 17 H)


604
(300 MHz, CDCl3) δ ppm 7.99 (q, J = 4.7 Hz, 2 H), 7.52 (s, 1 H), 7.23 (d, J = 8.2 Hz,



2 H), 4.40 (t, J = 6.2 Hz, 2 H), 4.02 (dd, J = 11.4, 3.5 Hz, 2 H), 3.59 (quin, J = 7.0 Hz,



1 H), 3.42 (td, J = 11.7, 1.8 Hz, 2 H), 1.79-2.02 (m, 3 H), 1.72 (d, J = 13.8 Hz, 2 H),



1.47 (d, J = 6.7 Hz, 6 H), 1.36-1.44 (m, 2 H)


605
(400 MHz, CDCl3) δ ppm 8.05 (d, J = 8.0 Hz, 2 H), 7.54 (t, J = 8.0 Hz, 2 H), 7.46 (s,



1H), 7.35 (t, J = 7.5, 1 H), 3.98 (pent, J = 8.3 Hz, 1 H), 3.80-3.73 (m, 2 H), 3.25 (s, 3



H), 2.97-2.88 (m, 2 H), 2.68-2.57 (m, 2 H), 2.49-2.39 (m, 2 H), 2.15-2.00 (m, 2 H),



1.95-1.87 (m, 2 H), 1.75-1.58 (m, 3 H), 1.21 (s, 6 H)


606
(300 MHz, CDCl3) δ ppm 8.06 (br. s., 2 H), 7.47 (br. s., 1 H), 7.08 (t, J = 8.8 Hz, 2



H), 4.50 (br. s., 2 H), 3.52 (d, J = 14.7 Hz, 1 H), 3.11 (br. s., 2 H), 2.71 (br. s., 6 H),



2.34 (br. s., 2 H), 1.50 (d, J = 6.2 Hz, 6 H)


607
(300 MHz, CDCl3) δ ppm 8.01-7.89 (m, 2 H), 7.47 (s, 1 H), 7.18 (t, J = 8.7 Hz, 2



H), 4.45 (t, J = 6.0 Hz, 2 H), 3.93 (br. s., 4 H), 3.55 (d, J = 7.0 Hz, 1 H), 2.75-2.98



(m, 6 H), 2.36 (br. s., 2 H), 1.48 (d, J = 7.0 Hz, 6 H)


608
(300 MHz, CDCl3) δ ppm 8.07-7.92 (m, 2 H), 7.58 (s, 1 H), 7.25-7.18 (m, 2 H),



4.71 (d, J = 6.2 Hz, 2 H), 4.57 (d, J = 6.2 Hz, 2 H), 4.43 (s, 2 H), 3.66-3.50



(m, 1 H), 1.69-1.40 (m, 14 H)


609
(300 MHz, CDCl3) δ ppm 8.05-7.93 (m, 2 H), 7.53 (s, 1 H), 7.27-7.16 (m, 2 H),



4.50-4.37 (m, 1 H), 4.34 (dd, J = 5.0, 1.2 Hz, 2 H), 4.02-3.85 (m, 2 H), 3.65-3.53



(m, 1 H), 2.20 (d, J = 7.0 Hz, 1 H), 2.09-1.95 (m, 2 H), 1.94-1.78 (m, 2 H), 1.55-



1.43 (m, 6 H)


610
(400 MHz, DMSO-d6) δ ppm 1.23 (d, J = 6.2 Hz, 6H), 1.89-2.20 (m, 6H), 2.41-



2.61 (m, 4H), 3.01-3.11 (m, 2H), 3.36-3.53 (m, 5H), 3.91-3.98 (m, 1H), 4.03 (p,



J = 8.0 Hz, 1H), 4.83 (hept, J = 6.2 Hz, 1H), 7.27-7.32 (m, 1H), 7.33 (s, 1H),



7.49-7.55 (m, 2H), 8.30-8.34 (m, 2H)


611
(400 MHz, DMSO-d6) δ ppm 8.30-8.23 (m, 2H), 7.63-7.51 (m, 2H), 7.41 (s,



1H), 7.38-7.30 (m, 1H), 4.36 (t, J = 5.9 Hz, 2H), 4.02 (td, J = 8.5, 1.0 Hz, 1H),



3.19-3.13 (m, 2H), 2.80 (s, 6H), 2.49-2.32 (m, 4H), 2.15-2.03 (m, 1H), 1.89



(dddd, J = 22.8, 13.0, 6.8, 3.6 Hz, 5H)


612
(400 MHz, DMSO-d6) δ ppm 8.32-8.23 (m, 2H), 7.63-7.52 (m, 2H), 7.45 (s,



1H), 7.34 (td, J = 7.3, 1.2 Hz, 1H), 5.19-5.06 (m, 1H), 4.04 (dd, J = 8.9, 7.8 Hz,



1H), 3.50 (d, J = 9.7 Hz, 1H), 2.48-2.34 (m, 4H), 2.16-1.98 (m, 5H), 1.92 (s,



1H), 1.82 (d, J = 8.9 Hz, 1H), 1.70 (s, 1H)



(400 MHz, DMSO-d6) δ ppm 8.31-8.21 (m, 2H), 7.61-7.50 (m, 3H), 7.38-7.31



613 (m, 1H), 5.17 (q, J = 8.6 Hz, 2H), 3.98 (qd, J = 8.9, 8.0 Hz, 1H), 2.48-2.32 (m,



4H), 2.09 (dq, J = 10.9, 8.8 Hz, 1H), 1.92 (td, J = 11.5, 10.2, 6.7 Hz, 1H)


614
(400 MHz, DMSO-d6) δ ppm 8.30-8.23 (m, 2H), 7.57 (dd, J = 8.6, 7.4 Hz, 2H),



7.44 (s, 1H), 7.40-7.29 (m, 1H), 4.59-4.47 (m, 2H), 4.06-3.93 (m, 4H), 3.84



(dd, J = 5.7, 4.4 Hz, 3H), 3.30 (dd, J = 5.7, 4.3 Hz, 2H), 2.80 (s, 6H), 2.50-2.37



(m, 4H), 2.14-2.01 (m, 1H), 1.91 (s, 1H)


615
(400 MHz, DMSO-d6) δ ppm 8.30-8.21 (m, 2H), 7.62-7.53 (m, 3H), 7.40-7.30



(m, 1H), 5.43 (ddd, J = 8.7, 6.1, 2.4 Hz, 1H), 4.16-4.02 (m, 1H), 3.65 (dd, J =



14.0, 8.9 Hz, 2H), 3.52 (dd, J = 14.0, 2.2 Hz, 1H), 2.90 (s, 5H), 2.58 (dd, J = 10.7,



8.7 Hz, 1H), 2.51-2.21 (m, 5H), 2.12(dp, J = 10.7, 8.7Hz, 1H), 1.93 (dddd, J =



13.8, 8.4, 6.3, 3.4 Hz, 1H), 1.37 (d, J = 6.1 Hz, 3H)


616
(400 MHz, DMSO-d6) δ ppm 8.28 (dd, J = 8.6, 1.2 Hz, 2H), 7.56 (dd, J = 8.6, 7.4



Hz, 2H), 7.42-7.29 (m, 2H), 4.24 (d, J = 5.5 Hz, 2H), 4.09-3.95 (m, 1H), 2.41



(dd, J = 12.8, 9.1 Hz, 3H), 2.12-2.01 (m, 4H), 1.94 (s, 3H), 1.53 (q, J = 12.7, 11.9



Hz, 2H)


617
(400 MHz, DMSO-d6) δ ppm 8.32-8.24 (m, 2H), 7.61-7.52 (m, 2H), 7.41 (s,



1H), 7.38-7.29 (m, 1H), 4.30 (d, J = 4.5 Hz, 2H), 4.12-4.00 (m, 2H), 2.41 -



2.22 (m, 6H), 2.13-1.99 (m, 2H), 1.91 (t, J = 9.6 Hz, 1H)


618
(400 MHz, DMSO-d6) δ ppm 8.32-8.24 (m, 2H), 7.64-7.52 (m, 2H), 7.44 (s,



1H), 7.41-7.29 (m, 1H), 4.57 (dt, J = 10.0, 6.0 Hz, 1H), 4.45 (dd, J = 10.5, 3.6



Hz, 1H), 4.35 (dd, J = 10.5, 5.5 Hz, 1H), 4.29-4.12 (m, 1H), 4.06 (p, J = 8.6 Hz,



1H), 4.00-3.86 (m, 1H), 2.52-2.34 (m, 15H), 2.07 (dt, J = 19.7, 9.1 Hz, 1H),



1.93 (s, 1H), 1.39 (s, 2H), 1.33 (s, 2H)


619
(400 MHz, DMSO-d6) δ ppm 8.31 ?



1H), 7.38-7.29 (m, 1H), 5.29 (s, 1H), 3.96 (p, J = 8.6 Hz, 1H), 3.61 (dd, J = 13.6,



3.1 Hz, 1H), 3.47 (d, J = 13.6 Hz, 1H), 2.44 (ddd, J = 20.4, 8.8, 3.0 Hz, 2H), 2.39-



2.30 (m, 4H), 2.20 (s, 1H), 2.13-1.96 (m, 1H), 1.90 (d, J = 10.3 Hz, 1H)


620
(400 MHz, DMSO-d6) δ ppm 8.36-8.25 (m, 2H), 7.65-7.46 (m, 3H), 7.35 (t, J =



7.4 Hz, 1H), 4.92 (d, J = 6.0 Hz, 1H), 4.70 (d, J = 6.2 Hz, 1H), 4.42 (s, 2H), 4.09-



3.94 (m, 3H), 2.41 (dd, J = 20.0, 9.6 Hz, 4H), 2.06 (dd, J = 19.4, 8.6 Hz, 2H), 1.49



(q, J = 7.6 Hz, 2H), 0.85 (t, J = 7.6 Hz, 3H)


621
(400 MHz, DMSO-d6) δ ppm 8.31-8.23 (m, 2H), 7.63-7.53 (m, 2H), 7.40-7.29



(m, 2H), 5.07 (s, 1H), 4.06 (p, J = 8.2 Hz, 1H), 3.94 (s, 2H), 2.74 (s, 2H), 2.43



(q, J = 8.7 Hz, 4H), 2.39-2.24 (m, 6H), 2.14-2.00 (m, 1H), 1.98 (s, 1H)


622
(400 MHz, DMSO-d6) δ ppm 8.36- 8.26 (m, 2H), 7.65-7.52 (m, 2H), 7.51-7.30



(m, 2H), 4.92 (d, J = 6.1 Hz, 1H), 4.72 (d, J = 6.1 Hz, 1H), 4.38 (s, 2H), 4.12-



3.92 (m, 3H), 3.63 (d, J = 11.5 Hz, 2H), 2.47-2.36 (m, 4H), 2.17-1.91 (m, 2H),



1.02 (s, 3H)


623
(400 MHz, DMSO-d6) δ ppm 8.31-8.24 (m, 2H), 7.58 (dd, J = 8.6, 7.4 Hz, 2H),



7.47 (s, 1H), 7.40-7.31 (m, 1H), 4.71 (t, J = 5.0 Hz, 2H), 3.95 (s, 4H), 3.45 (s,



4H), 2.43 (dtd, J = 12.9, 8.7, 8.2, 4.1 Hz, 4H), 2.17-2.02 (m, 1H), 1.95 (t, J = 5.8



Hz, 5H)


624
(501 MHz, DMSO-d6) δ ppm 8.35-8.29 (m, 2H), 7.66-7.55 (m, 2H), 7.44 (s,



1H), 7.38 (td, J = 7.4, 1.1 Hz, 1H), 4.45 (td, J = 6.0, 2.5 Hz, 2H), 4.16-4.02 (m,



1H), 3.32 (dd, J = 7.1, 4.2 Hz, 1H), 3.24 (q, J = 7.2 Hz, 3H), 2.51-2.38 (m, 4H),



2.27 (ddt, J = 21.0, 13.5, 6.4 Hz, 2H), 2.15-2.04 (m, 1H), 2.04-1.94 (m, 1H),



1.27 (dt, J = 21.6, 7.2 Hz, 6H)


625
(501 MHz, DMSO-d6) δ ppm 8.34-8.28 (m, 2H), 7.60 (dd, J = 8.6, 7.4 Hz, 2H),



7.45 (s, 1H), 7.42-7.34 (m, IH), 4.46 (t, J = 6.0 Hz, 2H), 4.13 - 4.03 (m, 1H),



3.36-3.29 (m, 2H), 3.24 (q, J = 7.3 Hz, 4H), 2.51-2.39 (m, 4H), 2.30 (s, 2H),



2.11 (dp, J = 10.8, 8.9 Hz, 1H), 1.29 (t, J = 7.3 Hz, 6H)


626
(501 MHz, DMSO-d6) δ ppm 8.34-8.27 (m, 2H), 7.64-7.56 (m, 2H), 7.50 (s,



1H), 7.42-7.34 (m, 1H), 4.58(s, 1H), 4.53 (s, 1H), 4.11-4.01 (m, 1 H), 3.60 (d, J =



12.0 Hz, 1H), 3.07 (td, J = 12.2, 2.8 Hz, 2H), 2.95 (s, 3H), 2.50-2.39 (m, 4H),



2.20 (t, J = 12.0 Hz, 2H), 2.16-1.89 (m, 4H)


627
(400 MHz, DMSO-d6) δ ppm 1.23 (d, J = 6.2 Hz, 6H), 1.89-2.20 (m, 6H), 2.41-



2.61 (m, 4H), 3.01-3.11 (m, 2H), 3.36-3.53 (m, 5H), 3.91-3.98 (m, 1H), 4.03



(p, J = 8.0 Hz, 1H), 4.83 (hept, J = 6.2 Hz, 1H), 7.27-7.32 (m, 1H), 7.33 (s, 1H),



7.49-7.55 (m, 2H), 8.30-8.34 (m, 2H)


628
(501 MHz, DMSO-d6) δ ppm 8.35-8.25 (m, 2H), 7.61 (dd, J = 8.6, 7.4 Hz, 2H),



7.50 (s, 1H), 7.45-7.31 (m, 1H), 4.71 (t, J = 5.0 Hz, 2H), 4.12 (pd, J = 8.5, 1.0



Hz, 1H), 2.51-2.37 (m, 4H), 2.17- 1.90 (m, 5H)


629
(501 MHz, DMSO-d6) δ ppm 8.35-8.27 (m, 2H), 7.64-7.56 (m, 2H), 7.54 (s,



1H), 7.42-7.35 (m, 1H) , 4.57 (s, 2H), 4.23-4.12 (m, 1H), 3.09 (s, 3H), 2.54-



2.40 (m, 4H), 2.15-2.03 (m, 1H), 2.03-1.92 (m, 1H), 1.57 (s, 6H)


630
(501 MHz, DMSO-d6) δ ppm 8.34-8.25 (m, 2H), 7.63-7.53 (m, 2H), 7.40-7.30



(m, 2H), 4.15 (s, 2H), 4.08 (dd, J = 9.0, 8.0 Hz, 1H), 2.48-2.36 (m, 4H), 2.13 (dq,



J = 10.9, 8.8 Hz, 2H), 1.32 (s, 3H), 0.73-0.59 (m, 2H), 0.59-0.47 (m, 2H)


631
(501 MHz, DMSO-d6) δ ppm 8.34-8.28 (m, 2H), 7.63-7.56 (m, 2H), 7.45 (s,



1H), 7.40-7.33 (m, 1H), 4.44 (t, J = 6.7 Hz, 2H), 4.13-4.02 (m, 1H), 2.54-2.36



(m, 4H), 2.10 (ddt, J = 17.9, 10.8, 8.9 Hz, 1H), 1.87 (t, J = 6.7 Hz, 2H), 1.16 (s,



3H), 0.48-0.40 (m, 2H), 0.40-0.32 (m, 2H)


632
(501 MHz, DMSO-d6) δ ppm 8.35-8.28 (m, 2H), 8.03 (s, 1H), 7.67-7.54 (m,



2H), 7.41 (ddt, J = 8.6, 7.4, 1.2 Hz, 1H), 4.86 (s, 2H), 4.28-4.17 (m, 1H), 4.10 (s,



2H), 2.64 (dt, J = 10.7, 5.4 Hz, 2H), 2.51-2.41 (m, 4H), 2.19-2.12 (m, 3H), 2.12-



1.91 (m, 3H)


633
(501 MHz, DMSO-d6) δ ppm 8.30 (dd, J = 8.7, 1.2 Hz, 2H), 7.59 (dd, J = 8.6, 7.4



Hz, 2H), 7.43 (s, 1H), 7.36 (tt, J = 7.3, 1.2 Hz, 1H), 4.38 (t, J = 6.4 Hz, 2H), 4.09-



3.98 (m, 1H), 2.52-2.35 (m, 4H), 2.10 (dp, J = 11.0, 8.9 Hz, 1H), 1.99-1.90 (m,



1H), 1.84-1.69 (m, 6H), 1.68- 1.55 (m, 2H), 1.30- 1.12 (m, 3H), 1.08-0.97



(m, 2H)


634
(501 MHz, DMSO-d6) δ ppm 8.30 (dd, J = 8.6, 1.4 Hz, 2H), 7.60 (dd, J = 8.7, 7.3



Hz, 2H), 7.44 (s, 1H), 7.40-7.34 (m, 1H). 4.44 (t, J = 6.2 Hz, 2H), 4.11 - 4.00 (m.



1H), 3.27 (t, J = 7.7 Hz, 2H), 2.91 (s, 3H), 2.52-2.37 (m, 4H), 2.29 (s, 2H), 2.13



(dp, J = 10.9, 8.8 Hz, 1H), 1.99-1.91 (m, 1H)


635
(501 MHz, DMSO-d6) δ ppm 8.34-8.27 (m, 2H), 7.64-7.56 (m, 2H), 7.44 (s,



1H), 7.41-7.34 (m, 1H), 4.43 (W= 6.2 Hz, 2H), 4.07 (pd, J = 8.5, 1.1 Hz, 1H),



3.35-3.28 (m, 2H), 2.89 (s, 6H), 2.49-2.39 (m, 4H), 2.35-2.25 (m, 2H), 2.14



(dp, J = 10.9, 8.8 Hz, 1H), 2.02-1.91 (m, 1H)


636
(501 MHz, DMSO-d6) δ ppm 8.34-8.28 (m, 2H), 7.61 (dd, J = 8.5, 7.3 Hz, 2H),



7.48 (s, 1H), 7.42-7.35 (m, 1H), 4.23 (s, 2H), 4.08 (pd, J = 8.2, 1.0 Hz, 1H), 3.33



(s, 2H), 2.94 (s, 6H), 2.51-2.41 (m,4H), 2.19-2.06 (m, 1H), 2.04-1.91 (m,



1H), 1.29 (s, 6H)


637
(501 MHz, DMSO-d6) δ ppm 8.34-8.27 (m, 2H), 7.65-7.57 (m, 2H), 7.50 (s,



1H), 7.42-7.35 (m, 1H), 4.73 (dd, J = 6.7, 3.3 Hz, 2H), 4.11 (pd, J = 8.4, 1.1 Hz,



1H), 3.72 (dd, J = 5.6, 4.2 Hz, 2H), 2.99 (s, 6H), 2.53-2.43 (m, 3H), 2.47 -



(m, 1H), 2.13 (dp, J = 10.8, 8.8 Hz, 1H), 1.97 (dddd, J = 13.3, 8.3, 4.6, 2.3 Hz, 1H)


638
(501 MHz, DMSO-d6) δ ppm 8.32-8.25 (m, 2H), 7.75 (s, 1H), 7.66-7.58 (m,



2H), 7.44-7.36 (m, 1H), 5.83 (p, J = 5.3 Hz, 1H), 4.13 (pd, J = 8.4, 1.0 Hz, 1H),



3.74-3.68 (m, 3H), 2.94(s, 12H), 2.50-2.41 (m, 4H), 2.15 (dp, J = 10.9, 8.7 Hz,



1H), 2.04-1.92 (m, 1H)


639
(501 MHz, DMSO-d6) δ ppm 8.34-8.27 (m, 2H), 7.64-7.57 (m, 2H), 7.50 (s,



1H), 7.42-7.35 (m, 1H), 4.74 (t, J = 5.0 Hz, 2H), 4.16-4.00 (m, 1H), 3.69 (t, J =



5.0 Hz, 2H), 3.61 (d, J = 12.0 Hz, 2H), 3.20-3.11 (m, 2H), 2.53-2.38 (m, 4H),



2.12 (dp, J = 10.8, 8.7 Hz, 1H), 2.03-1.88 (m, 3H), 1.72 (q, J = 14.1, 13.5 Hz,



3H), 1.49 (t, J = 13.2 Hz, 1H)


640
(501 MHz, DMSO-d6) δ ppm 8.34-8.27 (m, 2H), 7.64-7.55 (m, 2H), 7.45 (s,



1H), 7.42-7.33 (m, 1H), 4.46 (t, J = 5.3 Hz, 2H), 4.13 - 4.02 (m, 1H), 3.62 (t, J =



5.2 Hz, 2H), 3.52 (dd, J = 9.1, 6.7 Hz, 2H), 3.29 (dd, J = 8.9, 6.8 Hz, 2H), 2.50-



2.37 (m, 4H), 2.18-2.05 (m, 1H), 1.98-1.87(m, 1H)


641
(501 MHz, DMSO-d6) δ ppm 8.33-8.27 (m, 2H), 7.67 (s, 1H), 7.60 (dd, J = 8.6,



7.4 Hz, 2H), 7.38 (tt, J = 7.4, 1.1 Hz, 1H), 5.44 (s, 1H), 4.15-4.04 (m, 1H), 3.63



(s, 7H), 3.13 (s, 3H), 2.92 (s, 2H), 2.84 (s, 2H), 2.58 (s, 2H), 2.46 (dd, J = 10.7,



6.8 Hz, 4H), 2.21-2.08 (m, 1H), 1.96 (d, J = 7.9 Hz, 1H)


642
(501 MHz, DMSO-d6) δ ppm 8.37-8.26 (m, 2H), 7.60 (dd, J = 8.6, 7.4 Hz, 2H),



7.45 (s, 1H), 7.42-7.31 (m, 1H), 4.44 (t, J = 6.2 Hz, 2H), 4.13-4.03 (m, 1H),



3.53 (d, J = 12.2 Hz, 2H), 3.38-3.23 (m, 2H), 2.98 (td, J = 12.4, 3.0 Hz, 2H),



2.51 2.03-1.84 (m, 3H), 1.82-1.64 (m, 3H), 1.53-1.37 (m, 1H)


643
(501 MHz, DMSO-d6) δ ppm 8.35-8.25 (m, 2H), 7.61 (dd, J = 8.6, 7.3 Hz, 2H),



7.51 (s, 1H), 7.44-7.32 (m, 1H), 4.75 (t, J = 5.2 Hz, 2H), 4.17-4.00 (m, 1H),



3.47 (d, J = 86.5 Hz, 4H), 2.50-2.35 (m, 4H), 2.12 (dp, J = 10.8, 8.8 Hz, 1H),



2.03-1.75 (m, 5H), 1.69 (s, 4H)


644
(501 MHz, DMSO-d6) δ ppm 8.34-8.27 (m, 2H), 7.65-7.57 (m, 2H), 7.50 (s,



1H), 7.42-7.35 (m, 1H), 4.74 (t, J = 5.0 Hz, 2H), 4.18-4.03 (m, 1H), 3.71 (s,



2H), 3.61 (s, 2H), 2.91 (s, 3H), 2.54-2.47 (m, 2H), 2.47-2.40 (m, 2H), 2.21 (d, J =



22.4 Hz, 2H), 2.18-2.08 (m, 1H), 2.03-1.92 (m, 1H)


645
(501 MHz, DMSO-d6) δ ppm 8.32-8.24 (m, 2H), 7.66-7.54 (m, 2H), 7.43-7.34



(m, 1H), 7.21 (s, 1H), 5.23 (tt, J = 7.6, 3.8 Hz, 1H), 4.08 (pd, J = 8.6, 1.1 Hz, 1H),



3.60-3.20 (m, 2H), 2.89 (s, 3H), 2.52-2.41(m, 5H), 2.30-2.09 (m, 2H), 2.09-



1.88 (m, 3H)


646
(501 MHz, DMSO-d6) δ ppm 8.32-8.26 (m, 2H), 7.60 (dd, J = 8.6, 7.3 Hz, 2H),



7.42-7.35 (m, 1H), 7.21 (s, 1H), 5.47-5.32 (m, 1H), 4.70 (d, J = 7.7 Hz, 2H),



4.55 (d, J = 7.7 Hz, 2H), 4.15-4.04 (m, 3H), 3.68 (dd, J = 9.0, 4.7 Hz, 2H), 3.47



(s, 2H), 3.13-3.06 (m, 4H), 2.61-2.49 (m, 5H), 2.46 (tt, J = 8.8, 1.7 Hz, 2H),



2.16 (dp, J = 11.0, 9.0 Hz, 1H), 2.03-1.93 (m, 1H), 1.24 (t, J = 7.2 Hz, 6H)


647
(501 MHz, DMSO-d6) δ ppm 8.29 (td, J = 8.7, 1.3 Hz, 2H), 7.64-7.55 (m, 2H)



7.47 (s, 1H), 7.38 (td, J = 7.4, 3.6 Hz, 1H), 5.17 (tt, J = 10.5, 4.7 Hz, 1H), 4.06 (dp,



J = 36.5, 8.4 Hz, 1H), 3.56 (ddd, J = 30.8, 15.4, 9.5 Hz, 2H), 3.48-3.42 (m, 1H),



3.28 (td, J = 13.0, 2.6 Hz, 1H), 3.18 (td, J = 13.0, 3.2 Hz, 1H), 2.55-2.36 (m, 4H),



2.36-1.91 (m, 4H), 1.33 (dd, J = 20.4, 6.7 Hz, 6H)


648
(501 MHz, DMSO-d6) δ ppm 8.33-8.27 (m, 2H), 7.59 (dd, J = 8.6, 7.4 Hz, 2H),



7.37 (s, 2H), 5.00 (tt, J = 7.8, 4.5 Hz, 1H), 4.10-3.99 (m, 1H), 2.54-2.36 (m,



4H), 2.18-2.05 (m, 3H), 1.98-1.86 (m, 3H), 1.74 (td, J = 9.3, 8.4, 4.7 Hz, 2H),



1.67-1.53 (m, 6H)


649
(501 MHz, DMSO-d6) δ ppm 8.33-8.26 (m, 2H), 8.10 (s, 1H), 7.65-7.57 (m,



2H), 7.44-7.35 (m, 1H), 4.57 (dd, J = 11.2, 3.1 Hz, 1H), 4.22 (p, J = 8.1 Hz, 1H),



2.79-2.67 (m, 1H), 2.67-2.61 (m, 1H), 2.61-2.55 (m, 2H), 2.55-2.36 (m,



4H), 2.32-1.98 (m, 5H), 1.95 (d, J = 11.9 Hz, 1H), 1.78 (s, 1H), 1.62 (s, 2H), 1.39



(s, 1H)


650
(501 MHz, DMSO-d6) δ ppm 8.33-8.26 (m, 2H), 7.64-7.56 (m, 2H), 7.42-7.34



(m, 2H), 5.60 (s, 1H), 4.14 (s, 1H), 3.52 (s, 1H), 2.98 (d, J = 6.2 Hz, 3H), 2.46



(ddd, J = 12.4, 9.0, 5.0 Hz, 4H), 2.20-2.07 (m, 1H), 1.96 (s, 1H), 1.58-1.43 (m,



1H)


651
(501 MHz, DMSO-d6) δ ppm 8.33-8.26 (m, 2H), 7.64-7.56 (m, 2H), 7.42-7.34



(m, 2H), 5.60 (s, 1H), 4.14 (s, 1H), 2.99 (d, J = 24.0 Hz, 3H), 2.51 (dd, J = 9.0, 2.2



Hz, 1H), 2.46 (ddd, J = 15.5, 7.8, 3.6 Hz, 4H), 2.31 (s, 1H), 2.15 (dq, J = 10.8, 8.8



Hz, 1H), 1.97 (dt, J = 10.2, 5.4 Hz, 1H)


652
(400 MHz, CDCl3) δ ppm 8.04-7.94 (m, 2 H), 7.53 (s, 1 H), 7.27-7.18 (m, 2 H),



4.25 (s, 2 H), 3.67-3.49 (m, 1 H), 2.78 (d, J = 13.7 Hz, 2 H), 2.58-2.37 (m, 2 H),



1.55-1.42 (m, 9 H)


653
(400 MHz, CDCl3) δ ppm 8.10 (dd, J = 8.9, 4.8 Hz, 2 H), 7.42 (s, 1 H), 7.07 (t,



J = 8.7 Hz, 2 H), 4.45 (t, J = 5.6 Hz, 2 H), 3.43-3.60 (m, 2 H), 2.92-3.27 (m, 5 H),



2.32-2.46 (m, 2 H), 1.97 (br. s., 4 H), 1.47 (d, J = 6.8 Hz, 6 H), 1.27 (br. s., 4 H),



0.89 (t, J = 6.7 Hz, 2 H)


655
(501 MHz, DMSO-d6) δ ppm 8.38-8.32 (m, 2H), 7.58-7.50 (m, 2H), 7.36-7.26 (m,



1H), 7.23-7.05 (m, 1H), 6.19-6.13 (m, 1H), 4.16-4.00 (m, 3H), 3.85-3.79 (m, 1H),



3.68 (dd, J = 8.0, 6.7 Hz, 1H), 3.51-3.44 (m, 1H), 3.42-3.36 (m, 1H), 2.50-2.39 (m,



4H), 2.15-1.65 (m, 5H)


656
(400 MHz, CD30D) δ ppm 8.00-7.95 (m, 2 H), 7.53 (s, 1 H), 7.23 (t, J = 8.6 Hz, 2



H), 3.83-3.76 (m, 2 H), 3.47 (pent, J = 6.8 Hz, 1 H), 3.00-2.92 (m, 2 H), 2.02-1.95



(m, 2 H), 1.71-1.43 (m, 4 H), 1.47 (d, J = 6.6 Hz, 6 H), 1.29 (s, 6 H)


657
(400 MHz, CDCl3) δ ppm 7.98-8.05 (m, 2 H), 7.47 (s, 1 H), 7.23 (t, J = 8.7 Hz, 2



H), 3.98 (t, J = 8.4 Hz, 1 H), 3.71 (d, J = 12.5 Hz, 2 H), 3.35-3.43 (m, 5 H), 2.98 (td,



J = 12.3, 1.8 Hz, 2 H), 2.55-2.67 (m, 2 H), 2.37-2.49 (m, 2 H), 2.02-2.16 (m, 2



H), 1.86-2.01 (m, 3 H), 1.52-1.65 (m, 2 H)


658
(400 MHz, CDCl3) δ ppm 7.95-8.09 (m, 2 H), 7.49 (s, 1 H), 7.17-7.30 (m, 2 H),



5.01 (dtd, J = 12.5, 6.2, 6.2, 2.4 Hz, 1 H), 4.01-4.21 (m, 5 H), 3.52 (td, J = 11.7, 2.0



Hz, 2 H), 2.38-2.66 (m, 4 H), 1.95-2.32 (m, 3 H), 1.84 (dd, J = 13.0, 1.7 Hz, 2 H),



1.51-1.68 (m, 2 H)


659
(400 MHz, CDCl3) δ ppm 8.05 (d, J = 8.1 Hz, 2 H), 7.55 (t, J = 7.9 Hz, 2 H), 7.47 (s,



1H), 7.36 (t, J = 7.4, 1 H), 3.99 (pent, J = 8.3 Hz, 1 H), 3.82-3.75 (m, 2 H), 2.99-2.90



(m, 2 H), 2.69-2.57 (m, 2 H), 2.50-2.40 (m, 2 H), 2.16-1.95 (m, 4 H), 1.73-1.44 (m,



4H), 1.30 (m, 6 H)


660
(300 MHz, CDCl3) δ ppm 8.22-8.09 (m, 2 H), 7.63 (s, 1 H), 7.24-7.12 (m, 2 H),



3.54 (br. s., 4 H), 3.46-3.36 (m, 1 H), 3.38-3.27 (m, 1 H), 3.13 (br. s., 4 H), 1.49



(d, J = 6.7 Hz, 6 H), 1.37 (d, J = 6.7 Hz, 6 H)


661
(300 MHz, CDCl3) δ ppm 8.06-7.94 (m, 2 H), 7.53 (s, 1 H), 7.23 (t, J = 8.7 Hz, 2



H), 3.75 (d, J = 12.3 Hz, 2 H), 3.58 (d, J = 11.2 Hz, 2 H), 3.44 (dd, J = 13.8, 7.0 Hz, 1



H), 2.96 (br. s., 2 H), 2.79 (s, 3 H), 2.70 (br. s., 2 H), 2.17-1.88 (m, 6 H), 1.61-



1.41 (m, 11 H)


662
(400 MHz, CDCl3) δ ppm 8.06-7.90 (m, 2 H), 7.51 (s, 1 H), 7.26-7.18 (m, 2 H),



4.77 (d, J = 13.7 Hz, 1 H), 4.22 (d, J = 6.3 Hz, 2 H), 3.95 (d, J = 13.8 Hz, 1 H), 3.56



(quin, J = 6.9 Hz, 1 H), 3.27-3.12 (m, 1 H), 2.75-2.60 (m, 1 H), 2.35-2.18 (m, 1



H), 2.15 (s, 3 H), 1.98 (t, J = 15.1 Hz, 2 H), 1.86 (dt, J = 6.7, 3.3 Hz, 1 H), 1.51-1.35



(m, 6 H)


663
(400 MHz, CDCl3) δ ppm 8.04-7.94 (m, 2 H), 7.51 (s, 1 H), 7.26-7.18 (m, 2 H),



4.20 (d, J = 6.3 Hz, 2 H), 3.80-3.70 (m, 4 H), 3.56 (quin, J = 6.9 Hz, 1 H), 2.88 (t,



J = 11.4 Hz, 2 H), 2.26-2.12 (m, 1 H), 1.97-1.80 (m, 3 H), 1.50-1.44(m, 8H)


664
(300 MHz, DMSO-d6) δ ppm 10.08 (s, 1 H), 8.34 (dd, J = 8.9, 4.9 Hz, 2H), 8.18



(s, 1 H), 7.44 (t, J = 8.9 Hz, 2 H), 4.01-3.92 (m, 2 H), 3.79 (hept, J = 6.8 Hz, 1 H),



3.48-3.36 (m, 2 H), 2.92-2.80 (m, 1 H), 1.90-1.66 (m, 4H), 1.37 (d, J = 6.8 Hz,



6H)


665
(400 MHz, CDCl3) δ ppm 8.04 (d, J = 8.1 Hz, 2 H), 7.56 (t, J = 7.9 Hz, 2 H), 7.52 (s,



1H), 7.38 (t, J = 7.4, 1 H), 3.95 (pent, J = 8.4 Hz, 1 H), 3.57-3.49 (m, 2 H), 3.44-3.35



(m, 2 H), 2.70 (s, 2 H), 2.72-2.58 (m, 2 H), 2.47-2.38 (m, 2 H), 2.15-1.97 (m, 4 H),



1.71-1.41 (m, 3 H)


666
(300 MHz, CDCl3) δ ppm 8.05-7.93 (m, 2 H), 7.59 (s, 1 H), 7.27-7.17 (m, 2 H),



3.68-3.51 (m, 6 H), 3.50-3.31 (m, 3 H), 2.11 (d, J = 11.7 Hz, 4 H), 1.48 (d, J = 6.7



Hz, 6 H), 1.27 (t, J = 7.0 Hz, 3 H)


667
(300 MHz, CDCl3) δ ppm 8.05-7.92 (m, 2 H), 7.58 (s, 1 H), 7.26-7.17 (m, 2 H),



3.82-3.67 (m, 4 H), 3.66-3.51 (m, 5 H), 3.48-3.37 (m, 4 H), 2.22-2.03 (m, 2 H),



1.86 (dt, J = 6.7, 3.3 Hz, 2 H), 1.48 (d, J = 6.7 Hz, 6 H)



(300 MHz, DMSO-d6) δ ppm 8.30-8.45 (m, 2 H), 7.29-7.43 (m, 2 H), 7.28 (s, 1



H), 5.43 (d, J = 4.7 Hz, 1 H), 4.34-4.69 (m, 1 H), 3.38-3.82 (m, 3 H), 2.89-3.13



668 (m, 2 H), 2.06 (d, J = 5.3 Hz, 1 H), 1.55-1.78 (m, 1 H), 1.40 (dd, J = 6.7, 1.8 Hz, 6



H)


669
(300 MHz, CDCl3) δ ppm 8.04-7.93 (m, 2 H), 7.58 (s, 1 H), 7.26-7.18 (m, 2 H),



3.64-3.30 (m, 10 H), 2.17-1.89 (m, 4 H), 1.48 (d, J = 6.7 Hz, 6 H)


670
(300 MHz, CDCl3) δ ppm 8.05-7.93 (m, 2 H), 7.57 (s, 1 H), 7.26-7.16 (m, 2 H),



3.75-3.52(m, 8H), 3.37(s, 3H), 3.34-3.02 (m, 2 H), 2.31-2.00 (m, 2 H), 1.90-



1.80 (m, 2 H), 1.47 (dd, J = 8.8, 6.7 Hz, 6 H)


671
(400 MHz, DMSO-d6, 90° C.) δ ppm 8.37-8.33 (m, 2H), 7.54-7.48 (m, 2H), 7.30-



7.25 (m, 1H), 7.02 (s, 1H), 6.69-6.60 (m, 1H), 4.04 (p, J = 7.7 Hz, 1H), 3.68-3.56



(m, 3H), 3.38 (dd, J = 10.0, 7.0 Hz, 1H), 3.16-3.02 (m, 2H), 2.57-2.37 (m, 4H),



2.14-1.91 (m, 3H), 1.82-1.72 (m, 1H), 1.41-1.36 (m, 10H)


672
(400 MHz, DMSO-d6, 90° C.) δ ppm 8.37-8.33 (m, 2H), 7.54-7.48 (m, 2H), 7.30-



7.25 (m, 1H), 7.02 (s, 1H), 6.69-6.60 (m, 1H), 4.04 (p, J = 7.8 Hz, 1H), 3.68-3.56



(m, 3H), 3.38 (dd, J = 10.0, 7.0 Hz, 1H), 3.16-3.01 (m, 2H), 2.57-2.38 (m, 4H),



2.14-1.91 (m, 3H), 1.82-1.72 (m, 1H), 1.41-1.36 (m, 10H)


674
(400 MHz, CDCl3) δ ppm 8.07-8.03 (m, 2H), 7.57-7.49 (m, 2H), 7.34 (t, J = 7.4



Hz, 1H), 7.17 (s, 1H), 3.95 (p, J = 8.0 Hz, 1H), 3.79-3.63 (m, 3H), 3.56-3.27 (m,



3H), 2.92 (bs, 3H), 2.72-2.49 (m, 3H), 2.49-2.35 (m, 2H), 2.24-2.13 (m, 1H), 2.08-



1.96 (m, 2H), 1.90-1.79 (m, 1H), 1.52-1.34 (m, 9H)


675
(501 MHz, CDCl3) δ ppm 8.06-8.03 (m, 2H), 7.55-7.51 (m, 2H), 7.36-7.32 (m,



1H), 7.17 (s, 1H), 3.95 (tt, J = 8.0, 7.9 Hz, 1H), 3.78-3.65 (m, 3H), 3.55-3.28 (m,



3H), 2.92 (bs, 3H), 2.72-2.49 (m, 3H), 2.48-2.37 (m, 2H), 2.24-2.14 (m, 1H), 2.08-



1.96 (m, 2H), 1.89-1.81 (m, 1H), 1.52-1.35 (m, 9H)


676
(400 MHz, CDCl3) δ ppm 9.76-9.37 (m, 2H), 7.90-7.80 (m, 2H), 7.54-7.43 (m,



2H), 7.38-7.30 (m, 1H), 6.99 (bs, 1H), 4.0-3.4 (m, 5H), 3.25-3.09 (m, 2H), 3.01-



2.87 (m, 1H), 2.82-2.69 (m, 3H), 2.56-2.41 (m, 2H), 2.41-2.23 (m, 3H), 2.07-1.72



(m, 3H)


677
(300 MHz, CDCl3) δ ppm 8.23 (br. s., 2 H), 7.65 (s, 1 H), 3.69 (d, J = 12.1 Hz, 2 H),



3.43-3.52 (m, 1 H), 3.40 (s, 3 H), 3.36 (d, J = 5.9 Hz, 2 H), 2.99 (br. s., 2 H), 2.81



(s, 6 H), 1.95 (d, J = 12.8 Hz, 3 H), 1.48 (d, J = 6.6 Hz, 8 H)


678
(400 MHz, CDCl3) δ ppm 8.30 (d, J = 5.6 Hz, 1 H), 7.86 (dd, J = 5.7, 1.8 Hz, 1 H),



7.67 (d, J = 1.7 Hz, 1 H), 7.54 (s, 1 H), 4.04 (s, 3 H), 3.97 (quin, J = 8.3 Hz, 1 H),



3.70 (d, J = 12.5 Hz, 2 H), 3.28-3.46 (m, 5 H), 2.91-3.06 (m, 2 H), 2.54-2.68 (m,



2 H), 2.37-2.50 (m, 2 H), 2.05-2.19 (m, 2 H), 1.84-2.02 (m, 3 H), 1.24-1.32



(m, 2 H)


679
(300 MHz, CDCl3) δ ppm 7.97-8.23 (m, 2 H), 7.19 (s, 1 H), 6.82-7.09 (m, 2 H),



3.73-3.86 (m, 2 H), 3.54-3.69 (m, 4 H), 3.47 (d, J = 12.5 Hz, 2 H), 2.60-2.76 (m,



2 H), 2.46-2.54 (m, 3 H), 2.33-2.45 (m, 3 H), 2.12-2.29 (m, 3 H), 1.77-1.99



(m, 3 H), 1.48-1.73 (m, 2 H)


680
(400 MHz, pyridine-d5) δ ppm 8.88 (m, 2H), 7.46 (d, J = 1.9 Hz, 2H), 7.24 (s, 1H),



7.18 (dt, J = 7.5, 1.2 Hz, 1H), 4.24 (t, J = 7.7 Hz, 2H), 4.16 (d, J = 5.0 Hz, 2H),



3.87 (m, 1H), 3.40 (ddd, J = 7.2, 4.9, 2.2 Hz, 1H), 2.73-2.57 (m, 2H), 2.53-2.41



(m, 6H), 2.40 (m, 1H), 2.03-1.91 (m, 2H), 1.66 (p, J = 3.0 Hz, 4H)


681
(400 MHz, pyridine-d5) δ ppm 8.86-8.77 (m, 2H), 7.74 (s, 1H), 7.71 (d, 2H), 7.49-



7.42 (m, 2H), 7.19 (t, J = 7.4 Hz, 1H), 4.16-4.02 (m, 2H), 3.89-3.75 (m, 1H),



3.66 (td, J = 7.9, 6.2 Hz, 1H), 3.22 (dt, J = 6.4, 3.2 Hz, 4H), 2.89 (dt, J = 9.9, 4.6



Hz, 2H), 2.75 (dt, J = 11.3, 5.1 Hz, 2H), 2.70-2.61 (m, 2H), 2.57 (dd, J = 5.5, 2.9



Hz, 2H), 2.48-2.35 (m, 2H), 2.00 (tt, J = 9.0, 6.2 Hz, 2H), 1.90-1.79 (m, 1H),



1.67 (tt, J = 12.8, 5.9 Hz, 2H), 1.55-1.41 (m, 1H)


682
(400 MHz, pyridine-d5) δ ppm 8.93-8.81 (m, 2H), 7.75 (s, 1H), 7.55-7.49 (m,



2H), 7.24-7.16 (m, 1H), 4.11 (t, J = 8.3 Hz, 1H), 3.51 (dd, J = 9.6, 5.7 Hz, 1H),



3.31 (dd, J = 9.7, 5.8 Hz, 1H), 3.27 (s, 4H), 3.22 (d, J = 4.8 Hz, 3H), 2.90 (dd, J =



12.1, 6.4 Hz, 2H), 2.82-2.69 (m, 1H), 2.55-2.43 (m, 2H), 2.08-1.94 (m, 2H),



1.09 (d, J = 6.7 Hz, 3H)


683
(400 MHz, pyridine-d5) δ ppm 8.89 (dd, J = 8.4, 1.3 Hz, 2H), 7.84 (s, 1H), 7.55-



7.48 (m, 2H), 7.26 (t, J = 7.3 Hz, 1H), 4.17 (p, J = 8.3 Hz, 1H), 3.85-3.69 (m,



4H), 3.67-3.56 (m, 2H), 2.77 (ddd, J= 18.1, 9.4, 6.8 Hz, 4H), 2.64 - 2.42 (m.



4H), 2.41-2.20 (m, 4H), 2.07(td, J = 8.9, 5.8 Hz, 2H), 1.86- 1.74 (m, 1H), 1.52



(td, J = 20.7, 17.7, 10.9 Hz, 3H), 0.93 (d, J = 6.6 Hz, 3H)


684
(400 MHz, pyridine-d5) δ ppm 8.84-8.77 (m, 2H), 7.73 (s, 1H), 7.48-7.42 (m,



2H), 7.22-7.17 (m, 1H), 5.19 (t, J = 4.3 Hz, 1H), 4.08 (q, J = 8.3 Hz, 1H), 3.96-



3.86 (m, 2H), 3.79-3.68 (m, 2H), 3.21 (t, J = 4.7 Hz, 4H), 2.83 (dd, J = 22.2, 4.5



Hz, 6H), 2.66 (dq, J = 11.5, 9.0 Hz, 2H), 2.41 (ddt, J = 11.9, 8.4, 5.8 Hz, 2H),



2.06-1.93 (m, 2H)


685
(400 MHz, pyridine-d5) δ ppm 8.86-8.77 (m, 2H), 7.73 (s, 1H), 7.46 (dd, J = 8.6,



7.3 Hz, 2H), 7.20 (tt, J = 7.3, 1.2 Hz, 1H), 4.03 (t, J = 8.4 Hz, 1H), 3.67 (dd, J =



5.9, 3.7 Hz, 2H), 3.57 (dd, J = 5.9, 3.7 Hz, 3H), 3.39 (dd, J = 12.3, 5.8 Hz, 2H),



3.31 (s, 3H), 2.91 (ddd, J = 12.1, 8.8, 2.9 Hz, 2H), 2.67 (qd, J = 9.0, 2.6 Hz, 2H),



2.40 (dd, J = 10.5, 6.6 Hz, 2H), 2.08-1.95 (m, 4H), 1.91-1.82 (m, 2H), 1.81 (s,



2H)


686
(400 MHz, pyridine-d5) δ ppm 8.94-8.84 (m, 2H), 7.78 (s, 1H), 7.53 (dd, J = 8.6,



7.3 Hz, 2H), 7.31-7.24 (m, 1H), 4.12 (p, J = 8.3 Hz, 1H), 3.56 (d, J = 12.2 Hz,



2H), 3.02-2.68 (m, 9H),2.51 (qq, J = 8.1, 3.4 Hz, 2H), 2.22-1.97 (m, 4H), 1.78



(s, 3H), 1.65 (q, J = 12.4, 11.9 Hz, 2H), 1.42 (s, 2H)


687
(400 MHz, pyridine-d5) δ ppm 8.94 (s, 2H), 8.92-8.84 (m, 2H), 7.78 (s, 1H), 7.54



2H), 3.33 (m, 2H), 2.86 (s, 2H), 2.75 (td, J = 8.7, 2.6 Hz, 4H), 2.55-2.34 (m, 4H),



2.20-2.01 (m, 2H), 2.00 (m, 2H), 1.84- 1.66 (m, 4H), 1.63-1.28 (m, 8H), 0.83



(d, J = 6.4 Hz, 3H)


688
(400 MHz, pyridine-d5) δ ppm 8.85-8.78 (m, 2H), 7.76 (s, 1H), 7.49-7.43 (m,



2H), 7.20 (tt, J = 7.3, 1.2 Hz, 1H), 4.11 (t, J = 8.3 Hz, 1H), 3.72 (ddd, J = 13.5, 7.3,



3.5 Hz, 2H), 3.61-3.50 (m, 2H), 2.91-2.61 (m, 5H), 2.50-2.40 (m, 3H), 2.33 (t,



J = 11.1 Hz, 2H), 2.15-1.82 (m, 7H), 1.15 (d, J = 6.3 Hz, 6H)


689
(400 MHz, pyridine-d5) δ ppm 8.87-8.76 (m, 2H), 7.73 (s, 1H), 7.49-7.42 (m,



2H), 7.21 (d, J = 7.4 Hz, 1H), 4.10 (p, J = 8.4 Hz, 1H), 3.57 (d, J = 12.5 Hz, 2H),



3.09 (d, 1H), 2.90 (s, 3H), 2.81-2.59 (m, 5H), 2.52-2.38 (m, 3H), 2.06 (d, J =



8.2 Hz, 6H), 1.16 (d, J = 7.1 Hz, 4H)


690
(400 MHz, pyridine-d5) δ ppm 8.85-8.74 (m, 2H), 7.73 (s, 1H), 7.50-7.42 (m,



2H), 7.24-7.17 (m, 1H), 4.05 (p, J = 8.3 Hz, 1H), 3.37 (t, J = 6.9 Hz, 2H), 2.97 (s,



5H), 2.62 (d, J = 9.4 Hz, 4H), 2.44 (s, 4H), 2.15 (m, 2H), 2.10-2.00 (m, 1H), 1.94



(d, J = 12.0 Hz, 2H), 1.58 (d, J = 13.1 Hz, 2H), 1.30 (dt, J = 35.1, 12.6 Hz, 3H),



1.06 (q, J = 12.8 Hz, 2H), 0.95-0.71 (m, 1H)


691
(400 MHz, pyridine-d5) δ ppm 8.84-8.76 (m, 2H), 7.68 (s, 1H), 7.49-7.41 (m,



2H), 7.20 (tt, J = 7.3, 1.2 Hz, 1H), 4.11 (d, J = 6.6 Hz, 2H), 3.96 (q, J = 8.2 Hz,



1H), 3.62-3.48 (m, 3H), 3.43 (d, J = 6.7 Hz, 2H), 3.25 (s, 2H), 2.62 (pd, J = 8.9,



2.3 Hz, 2H), 2.45 (qd, J = 8.4, 4.3 Hz, 2H), 2.27 (Sm 2H), 2.14-1.88 (m, 2H),



1.19 (d, J = 6.6 Hz, 6H)


692
(400 MHz, pyridine-d5) δ ppm 8.90-8.78 (m, 2H), 7.63 (s, 1H), 7.45 (dd, J = 8.6,



7.3 Hz, 2H), 7.19 (t, J = 7.4 Hz, 1H), 4.07 (p, J = 8.2 Hz, 1H), 3.54 (dd, J = 10.1,



7.3 Hz, 2H), 3.23 (dd, J = 10.2, 4.1 Hz, 2H), 2.82 (s, 2H), 2.67 (ddd, J = 17.7, 8.8,



2.5 Hz, 4H), 2.52 (d, J = 9.0 Hz, 4H), 2.21 (d, J = 7.4 Hz, 2H), 2.09-1.93 (m,



2H), 1.68 (m, J = 6.8 Hz, 1H), 0.86 (d, J = 6.6 Hz, 6H)


693
(300 MHz, CDCl3) δ ppm 8.14-8.27 (m, 2 H), 7.32 (s, 1 H), 7.01-7.24 (m, 2 H),



3.92 (s, 1 H), 3.61 (d, J = 12.5 Hz, 2 H), 2.72-2.90 (m, 2 H), 2.47-2.65 (m, 6 H),



2.27-2.45 (m, 3 H), 1.91-2.11 (m, 4 H), 1.66-1.88 (m, 2 H), 1.52-1.66 (m, 4



H), 1.43 (d, J = 5.0 Hz, 2 H)


694
(400 MHz, pyridine-d5) δ ppm 8.92-8.82 (m, 2H), 7.79 (d, J = 7.8 Hz, 1H), 7.57-



7.48 (m, 2H), 7.27 (dd, J = 8.1, 6.8 Hz, 1H), 4.12 (q, J = 8.4 Hz, 1H), 3.59 (q, J =



5.7 Hz, 4H), 3.29 (m, 2H), 2.90-2.69 (m, 14H), 2.51 (d, J = 5.7 Hz, 4H), 2.07 (dt,



J = 15.2, 9.1 Hz, 4H), 1.86 (m, 2H)


695
(400 MHz, pyridine-d5) δ ppm 8.86-8.79 (m, 2H), 7.73 (s, 1H), 7.48-7.41 (m,



2H), 7.20 (td, J = 7.3, 1.3 Hz, 1H), 4.06 (t, J = 8.4 Hz, 1H), 3.46 (d, J = 11.9 Hz,



2H), 2.96 (s, 2H), 2.88 (s, 2H), 2.76-2.65 (m, 4H), 2.59 (s, 2H), 2.48 (s, 3H), 2.43



(dd, J = 5.2, 2.7 Hz, 1H), 2.02 (td, J = 9.1, 5.9 Hz, 2H), 1.71 (d, J = 9.5 Hz, 2H),



1.53 (d, J = 6.7 Hz, 2H), 1.42 (m, 2H)


696
(400 MHz, pyridine-d5) δ ppm 8.80 (dd, J = 8.5, 1.2 Hz, 2H), 7.71 (s, 1H), 7.49-



7.42 (m, 2H), 7.21 (tt, J = 7.5, 1.1 Hz, 1H), 4.36 (s, 2H), 4.03 (t, J = 8.3 Hz, 1H),



3.92 (s, 2H), 3.75 (s, 2H), 3.60 (q, J = 7.0 Hz, 2H), 3.11 (s, 3H), 2.67 (dq, J = 11.7,



9.1 Hz, 2H), 2.47-2.34 (m, 2H), 2.08- 1.95 (m, 2H), 1.22- 1.14 (m, 3H)


697
(400 MHz, pyridine-d5) δ ppm 8.85-8.78 (m, 2H), 7.75 (s, 1H), 7.49-7.42 (m,



2H), 7.23-7.16 (m, 1H), 4.56 (tt, J = 11.4, 3.9 Hz, 1H), 4.13 (p, J = 8.3 Hz, 1H),



3.49 (dd, J = 11.2, 3.9 Hz, 1H), 3.32 (d, J = 12.0 Hz, 1H), 3.24-3.12 (m, 2H),



2.76 (td, J = 11.0, 10.3, 7.6 Hz, 2H), 2.65-2.40 (m, 4H), 2.38-2.14 (m, 3H),



2.01 (td, J = 11.4, 10.4, 7.0 Hz, 1H), 1.83- 1.64(m, 6H), 1.50 (qd, J = 12.2, 4.9



Hz, 1H)


698
(400 MHz, pyridine-d5) δ ppm 8.85-8.78 (m, 2H), 7.73 (s, 1H), 7.51 (m, 2H),



7.23-7.16 (m, 1H), 4.17 (d, J = 8.4 Hz, 1H), 3.39 (bs, 2H), 2.93 (s, 2H), 2.74 (dd,



J = 8.9, 2.6 Hz, 3H), 2.54 (d, J = 9.2 Hz, 2H), 2.43 (s, 1H), 2.05 (q, J = 9.3 Hz,



1H), 1.74 (d, J = 57.9 Hz, 5H), 1.32 (s, 2H), 1.09 (bs, 2H)


699
(400 MHz, pyridine-d5) δ ppm 8.86-8.78 (m, 2H), 7.74 (s, 1H), 7.71 (s, 1H), 7.49-



7.43 (m, 2H), 7.24-7.17 (m, 1H), 4.04 (p, J = 8.3 Hz, 1H), 3.04 (d, J = 5.8 Hz,



7H), 2.68 (s, 4H), 2.47-2.34 (m, 2H), 2.09 -1.95 (m, 2H), 1.85-1.76 (m, 4H),



1.66 (t, J = 5.3 Hz, 4H)


700
(400 MHz, pyridine-d5) δ ppm 8.85-8.77 (m, 2H), 7.76 (s, 1H), 7.49-7.41 (m,



2H), 7.19 (ddd, J = 8.5, 6.8, 1.1 Hz, 1H), 3.92 (d, J = 0.8 Hz, 4H), 3.31 (bs, 3H),



2.67 (pd, J = 9.1, 2.2 Hz, 2H), 2.45 ?


701
(400 MHz, pyridine-d5) δ ppm 8.84-8.75 (m, 2H), 7.73 (s, 1H), 7.71 (s, 1H), 7.46



(dd, J = 8.6, 7.3 Hz, 2H), 7.21 (td, J = 7.3, 1.3 Hz, 1H), 4.03 (dd, J = 7.5, 2.9 Hz,



3H), 3.77 (s, 4H), 3.10 (t, J = 5.0 Hz, 4H), 2.74-2.58 (m, 2H), 2.47-2.33 (m,



2H), 2.01 (ddd, J = 9.3, 7.5, 5.5 Hz, 2H), 1.95-1.85 (m, 1H), 0.88 (d, J = 6.7 Hz,



6H)


702
(400 MHz, pyridine-d5) δ ppm 8.84-8.77 (m, 2H), 7.67 (s, 1H), 7.49-7.43 (m,



2H), 7.20 (tt, J = 7.2, 1.2 Hz, 1H), 4.07-4.00 (m, 2H), 4.00-3.86 (m, 1H), 3.61-



3.52 (m, 3H), 3.43-3.36 (m, 2H), 3.25-3.17 (m, 2H), 2.75 (s, 3H), 2.61 (dq, J =



11.5, 9.0 Hz, 2H), 2.48-2.35 (m, 2H), 2.19 (s, 2H), 2.07-1.89 (m, 2H)


703
(400 MHz, pyridine-d5) δ ppm 8.85-8.75 (m, 2H), 7.70 (s, 1H), 7.51 (t, J = 1.3



Hz, 2H), 7.21 (t, J = 7.4 Hz, 1H), 4.02 (q, J = 8.3 Hz, 1H), 3.91 (t, J = 5.0 Hz, 2H),



3.59 (t, J = 5.0 Hz, 2H), 3.06 (d, J = 5.1 Hz, 4H), 2.68 (dq, J = 11.5, 9.0 Hz, 2H),



2.46-2.32 (m, 2H), 2.16 (s, 3H), 2.12-1.85 (m, 2H)


704
(400 MHz, pyridine-d5) δ ppm 8.85-8.79 (m, 2H), 7.74 (s, 1H), 7.49-7.41 (m,



2H), 7.28-7.15 (m, 1H), 4.08 (p, J = 8.3 Hz, 1H), 3.41 (t, J = 6.3 Hz, 2H), 3.26 (s,



3H), 3.20 (t, J = 4.7 Hz, 4H), 2.76-2.61 (m, 6H), 2.51 (t, J = 7.3 Hz, 2H), 2.47-



2.37 (m, 2H), 2.07- 1.97 (m, 2H), 1.81 (p, J = 6.6 Hz, 2H)


705
(400 MHz, pyridine-d5) δ ppm 8.87-8.79 (m, 2H), 7.71 (s, 1H), 7.46 (dd, J = 8.6,



7.3 Hz, 2H), 7.24-7.17 (m, 1H), 4.00-3.86 (m, 3H), 3.61-3.53 (m, 2H), 3.11



(s, 2H), 2.99 (s, 1H), 2.63 (dq, J = 11.6, 9.0 Hz, 2H), 2.49-2.37 (m, 2H), 2.07 (d,



J = 6.6 Hz, 2H), 1.97 (dd, J = 11.9, 8.9 Hz, 2H), 1.85- 1.75 (m, 2H), 1.56 (dd, J =



5.8, 3.6 Hz, 1H), 1.37 (dq, J = 10.3, 4.9, 4.2 Hz, 2H)


706
(400 MHz, pyridine-d5) δ ppm 8.90- 8.86 (m, 2H), 7.88 (s, 1H), 7.51 (t, J = 7.9



Hz, 2H), 7.25 (s, 1H), 4.31 ?



12.1 Hz, 1H), 3.07 (dd, J = 11.7, 9.0 Hz, 1H), 2.90 (t, J = 11.1 Hz, 1H), 2.79-2.70



(m, 2H), 2.61 (d, J = 10.3 Hz, 1H), 2.52-2.43 (m, 1H), 2.28 (d, J = 12.1 Hz, 1H),



2.09-1.98 (m, 2H), 1.91 (s, 1H), 1.82-1.57 (m, 2H)


707
(400 MHz, pyridine-d5) δ ppm 8.85-8.78 (m, 2H), 7.74 (s, 1H), 7.49-7.43 (m,



2H), 7.20 (t, 1H), 4.09 (t, J = 8.3 Hz, 1H), 3.22 (bs, 4H), 2.68 (ddd, J = 18.2, 9.1,



3.6 Hz, 5H), 2.44 (ddd, J = 10.2, 8.1, 5.8 Hz, 2H), 2.37-2.29 (m, 2H), 2.09-1.96



(m, 2H), 1.48 (h, J = 7.3 Hz, 2H), 0.86 (t, J = 7.3 Hz, 3H)


708
(400 MHz, pyridine-d5) δ ppm 8.88 (m, 2H), 7.73 (s, 1H), 7.51 (d, J = 1.8 Hz, 2H),



7.32 (d, J = 16.1 Hz, 1H), 4.05 (q, J = 8.3 Hz, 1H), 3.49 (s, 4H), 3.14 (t, J = 4.8



Hz, 4H), 2.80 (s, 6H), 2.68 (dd, J = 8.9, 2.6 Hz, 2H), 2.52 ?



1.98 (m, 2H)


709
(400 MHz, pyridine-d5) δ ppm 8.91-8.83 (m, 2H), 7.49-7.40 (m, 2H), 7.31 (s,



1H), 7.26 (s, 1H), 7.22-7.16 (m, 1H), 4.21 (t, J = 7.7 Hz, 2H), 4.06 (dd, J = 8.3,



5.2 Hz, 2H), 3.88 (t, J = 7.8 Hz, 1H), 3.72 (t, J = 4.6 Hz, 4H), 3.26-3.08 (m, 1H),



2.70-2.58 (m, 2H), 2.49-2.36 (m, 2H), 2.33 (t, J = 4.5 Hz, 3H), 2.11-1.89 (m,



2H)


710
(400 MHz, pyridine-d5) δ ppm 8.87-8.80 (m, 2H), 7.71 (s, 1H), 7.49-7.42 (m,



2H), 7.19 (t, J = 7.4 Hz, 1H), 4.02- 3.85 (m, 3H), 3.61-3.53 (m, 2H), 3.06 (s,



2H), 2.91 (d, J = 6.1 Hz, 2H), 2.63 (dq, J = 11.5, 8.9, 7.6 Hz, 4H), 2.41 (ddt, J =



12.0, 8.2, 6.2 Hz, 2H), 2.08-1.93 (m, 4H), 1.59- 1.46 (m, 2H), 1.21 (h, J = 7.3



Hz, 2H), 0.79 (t, J = 7.3 Hz, 3H)


711
(400 MHz, pyridine-d5) δ ppm 8.84-8.75 (m, 2H), 7.70 (s, 1H), 7.49-7.42 (m,



2H), 7.23-7.16(m, 1H),4.05 (d,J = 8.2 Hz, 1H), 3.90-3.73 (m, 1H), 3.61-



3.48(m, 10H), 3.32-3.14 (m, 2H), 2.82-2.73 (m, 3H), 2.66 (dq, J = 11.2, 8.7



Hz, 2H), 2.48-2.35 (m, 2H), 2.33-2.07 (m, 5H), 2.07-1.88 (m, 3H), 1.80 (s,



4H)


712
(400 MHz, pyridine-d5) δ ppm 8.87-8.79 (m, 2H), 7.70 (s, 1H), 7.49-7.42 (m,



2H), 7.19 (td, J = 7.3, 1.2 Hz, 1H), 4.01-3.85 (m, 3H), 3.60-3.52 (m, 2H), 3.07



(s, 2H), 2.93 (d, J = 6.2 Hz, 2H), 2.63 (td, J = 8.7, 2.7 Hz, 4H), 2.48-2.35 (m,



2H), 2.09-1.99 (m, 2H), 1.96 (dd, J = 10.9, 6.4 Hz, 2H), 1.63-1.49 (m, 2H),



0.78 (t, J = 7.4 Hz, 3H)


713
(400 MHz, pyridine-d5) δ ppm 8.88-8.81 (m, 2H), 7.46-7.40 (m, 2H), 7.19 (d, J



= 7.3 Hz, 2H), 3.91 (bs, 6H), 3.70 (s, 2H), 3.63 (t, J = 7.1 Hz, 2H), 2.65 (dq, J =



11.5, 8.8 Hz, 2H), 2.44-2.33 (m, 2H), 2.18 (t, J = 7.1 Hz, 2H), 1.97-1.84 (m,



2H)


714
(400 MHz, pyridine-d5) δ ppm 8.84-8.76 (m, 2H), 7.71 (s, 1H), 7.49-7.42 (m,



2H), 7.22-7.16 (m, 1H), 4.07 (q, J = 8.3 Hz, 1H), 4.01-3.94 (m, 2h), 3.74 (dt, J =



11.7, 5.3 Hz, 4H), 3.25 (t, J = 4.7 Hz, 4H), 2.86 (t, J = 4.7 Hz, 4H), 2.80 (t, J =



5.7 Hz, 2H), 2.66 (dq, J = 11.5, 9.0 Hz, 2H), 2.41 (ddd, J = 11.0, 6.2, 2.5 Hz, 2H),



2.06-1.93 (m, 2H)


715
(400 MHz, pyridine-d5) δ ppm 8.91-8.84 (m, 2H), 7.49-7.42 (m, 2H), 7.21-



7.16 (m, 1H), 3.96 (p, J = 8.0 Hz, 1H), 3.77-3.60 (m, 2H), 3.58-3.41 (m, 3H),



3.00 (d, J = 8.6 Hz, 1H), 2.71-2.57 (m, 4H), 2.54-2.36 (m, 4H), 2.13 (m,



1H),1.97 (tt, J = 9.0, 6.1 Hz, 3H), 1.58 (t, J = 5.9 Hz, 4H), 1.32 (s, 2H)



(400 MHz, pyridine-d5) δ ppm 8.89-8.81 (m, 2H), 7.47-7.41 (m, 2H), 7.22 (s,



1H), 7.21-7.16 (m, 1H), 4.49-4.38 (m, 2H), 4.36-4.30 (m, 1H), 4.24 (dd, J =



716 8.9, 1.0 Hz, 1H), 4.19-4.09 (m, 2H), 3.82- 3.72 (m, 1H), 3.57-3.46 (m, 1H),



2.61 (ddd, J = 13.3, 6.7, 3.9 Hz, 4H), 2.38 (dddd, J = 12.0, 10.6, 5.8, 3.2 Hz, 2H),



1.91 (ttd, J = 19.3, 8.4, 7.4, 3.5 Hz, 2H)


717
(400 MHz, pyridine-d5) δ ppm 8.84-8.77 (m, 2H), 7.73 (s, 1H), 7.46-7.41 (m,



1H), 7.20 (td, J = 7.4, 1.3 Hz, 1H), 4.06 (td, J = 8.3, 2.4 Hz, 1H), 3.96 (dd, J = 6.8,



3.3 Hz, 1H), 3.83 (bs, 1H), 3.72 (t, J = 6.3 Hz, 1H), 3.57-3.46 (m, 2H), 3.22 (ddd,



J = 23.9, 11.9, 5.3 Hz, 7H), 3.13-2.94 (m, 3H), 2.84 (dq, J = 11.8, 7.5, 5.8 Hz,



4H), 2.79-2.60 (m, 6H), 2.46-2.34 (m, 2H), 2.19 (p, J = 6.1 Hz, 1H), 2.01 (ddt,



J = 9.1, 6.3, 3.8 Hz, 3H)


718
(400 MHz, pyridine-d5) δ ppm 8.84-8.76 (m, 2H), 7.76 (s, 1H), 7.44 (dd, J = 8.7,



7.3 Hz, 2H), 7.21-7.16 (m, 1H), 4.09 (p, J = 8.3 Hz, 1H), 3.66- 3.55 (m, 2H),



3.51-3.39 (m, 4H), 2.96 (s, 6H), 2.67 (dd, J = 11.8, 9.0 Hz, 4H), 2.48-2.36 (m,



2H), 2.36-2.25 (m, 4H), 2.05-1.89 (m, 2H), 1.89- 1.76 (m, 2H)


719
(400 MHz, pyridine-d5) δ ppm 8.88 (m, 2H), 7.52 (d, J = 7.9 Hz, 1H), 4.11 (m,



1H), 3.51 (d, 2H), 2.89-2.71 (m, 4H), 2.46 (bs, 2H), 2.04 (dd, J = 9.2, 6.1 Hz,



2H), 1.79-1.36 (m, 7H), 1.38 (q, J = 14.5, 14.1 Hz, 4H), 1.22- 1.01 (m, 5H),



0.82 (d, J = 11.3 Hz, 2H)


720
(400 MHz, pyridine-d5) δ ppm 8.92-8.84 (m, 2H), 7.48-7.41 (m, 2H), 7.23 (s,



1H), 7.21-7.16 (m, 1H), 3.96 (d, J = 8.1 Hz, 2H), 3.89-3.81 (m, 1H), 3.79 (d, J =



8.1 Hz, 2H), 3.70 (s, 2H), 3.54 (t, J = 5.2 Hz, 2H), 2.70-2.56 (m, 2H), 2.40



(ddddd, J = 10.3, 8.4, 6.8, 4.8, 2.2 Hz, 2H), 2.03-1.81 (m, 2H), 1.72 (t, J = 6.0



Hz, 2H), 1.46 (p, J = 5.4 Hz, 2H)


721
(400 MHz, pyridine-d5) δ ppm 8.85-8.77 (m, 2H), 7.76 (s, 1H), 7.49-7.42 (m,



2H), 7.20 (t, J = 7.4 Hz, 1H), 4.07 (p, J = 8.3 Hz, 1H), 3.58-3.52 (m, 1H), 3.44



(d, J = 12.2 Hz, 1H), 3.11-2.98 (m, 3H), 2.69 (dt, J = 10.2, 8.6 Hz, 3H), 2.53-



2.38 (m, 4H), 2.30 (d, J = 7.0 Hz, 1H), 2.14 (q, J = 8.7 Hz, 1H), 2.09-1.97 (m,



2H), 1.72 (dtd, J = 16.0, 8.3, 6.6, 4.8 Hz, 2H), 1.62-1.52 (m, 1H), 1.38 (td, J =



10.9, 6.1 Hz, 1H)


722
(400 MHz, pyridine-d5) δ ppm 8.84-8.77 (m, 2H), 7.73 (s, 1H), 7.71 (s, 1H), 7.46



(ddd, J = 8.6, 5.7, 1.9 Hz, 2H), 7.24-7.17 (m, 1H), 4.07 (q, J = 8.2 Hz, 1H), 4.00



(t, J = 5.8 Hz, 2H), 3.25-3.15 (m, 4H), 2.82 (dt, J = 11.9, 5.3 Hz, 5H), 2.67 (dq, J



= 11.5, 9.0 Hz, 2H), 2.45-2.35 (m, 2H), 2.06-1.95 (m, 2H)


723
(400 MHz, pyridine-d5) δ ppm 9.00-8.85 (m, 2H), 7.44 (dd, J = 1.1 Hz, 2H), 7.23



(s, 1H), 7.17 (m, 1H), 4.25 (dd, J = 7.3, 5.1 Hz, 3H), 4.21-4.10 (m, 1H), 3.88 (d,



J = 7.9 Hz, 2H), 3.85-3.72 (m, 3H), 2.82 (s, 1H), 2.78 (dd, J = 8.1, 5.9 Hz, 1H),



2.72-2.58 (m, 3H), 2.52-2.39 (m, 2H), 2.09 (s, 3H), 2.05-1.92 (m, 3H), 1.78 (t,



1H)


724
(400 MHz, pyridine-d5) δ ppm 8.97-8.90 (m, 2H), 7.55-7.47 (m, 2H), 7.38 (s,



1H), 7.31-7.23 (m, 1H), 4.79 (t, J = 6.4 Hz, 2H), 4.66 (t, J = 6.5 Hz, 2H), 4.31 (t,



J = 7.8 Hz, 2H), 4.13 (dd, J = 8.2, 5.4 Hz, 2H), 3.98 (h, J = 8.0, 7.4 Hz, 2H), 3.32-



3.20(m, 1H), 2.92 (d, J = 11.3 Hz, 2H), 2.72 (dq, J = 11.6, 8.6 Hz, 2H), 2.57-



2.46 (m, 3H), 2.40 (q, J = 6.5, 5.3 Hz, 1H), 2.20 (s, 2H), 2.13-1.96 (m, 2H), 1.89-



1.77 (m, 3H), 1.71-1.56 (m, 3H)


725
(400 MHz, pyridine-d5) δ ppm 8.90-8.83 (m, 2H), 7.48-7.40 (m, 2H), 7.25 (s,



1H), 7.20-7.16 (m, 1H), 4.23 (t, J = 7.7 Hz, 2H), 4.04 (dd, J = 8.3, 5.4 Hz, 2H),



3.95-3.83 (m, 5H), 3.28-3.09 (m, 1H), 2.90 (t, J = 4.8 Hz, 6H), 2.73-2.58 (m,



3H), 2.43 (dddd, J = 13.4, 8.4, 6.6, 3.5 Hz, 2H), 2.04-1.90 (m, 4H), 1.81 (d, J =



6.7 Hz, 6H)


726
(400 MHz, pyridine-d5) δ ppm 8.84-8.79 (m, 2H), 7.74 (s, 1H), 7.47 (m, 2H),



7.22 (t, 1H), 4.10 (t, J = 8.3 Hz, 1H), 3.70 (t, J = 5.3 Hz, 2H), 3.44-3.34 (m, 4H),



3.22- 3.15 (m, 4H), 3.03 (s, 2H), 2.71 (dt, J = 19.3, 6.8 Hz, 7H), 2.44 (q, J = 12.5,



10.6 Hz, 3H), 2.05 (d, J = 15.5 Hz, 2H), 1.94 (dd, J = 10.9, 7.5 Hz, 4H), 1.09 (d, J =



7.0 Hz, 3H)


727
(400 MHz, pyridine-d5) δ ppm 8.85-8.79 (m, 2H), 7.74 (s, 1H), 7.71 (m, 2H),



7.49-7.40 (t, 1H), 7.20 (t, J = 7.3 Hz, 1H), 4.35 (m, 1H), 4.11 (t, J = 8.3 Hz, 1H),



3.47 (t, J = 14.6 Hz, 2H), 3.21-3.15 (m, 4H), 2.73 (s, 8H), 2.52-2.34 (m, 4H),



2.10-1.99 (m, 2H), 1.91 (s, 4H), 1.23 (d, J = 6.3 Hz, 3H)


728
(400 MHz, pyridine-d5) δ ppm 8.84-8.77 (m, 2H), 7.70 (s, 1H), 7.49-7.42 (m,



2H), 7.20 (t, J = 7.4 Hz, 1H), 4.06 (t, J = 8.3 Hz, 1H), 3.17 (ddd, J = 17.1, 8.6, 5.0



Hz, 6H), 2.82 (s, 6H), 2.75 ?



11.1,6.2, 5.3, 2.7 Hz, 4H)


729
(400 MHz, pyridine-d5) δ ppm 8.88 (s, 2H), 8.85-8.78 (m, 2H), 7.73 (s, 1H), 7.71



(s, 1H), 7.48-7.42 (m, 3H), 7.20 (t, J = 7.4 Hz, 1H), 4.15-4.02 (m, IH), 3.59 (t,



J = 5.7 Hz, 2H), 3.52 (d, J = 12.5 Hz, 2H), 3.36 (t, J = 7.0 Hz, 2H), 2.92-2.62



14H), 2.44 (s, 3H), 2.10-1.91 (m, 5H), 1.83 (s, 2H), 1.09 (t, J = 7.0 Hz, 3H)


730
(400 MHz, pyridine-d5) δ ppm 8.94-8.82 (m, 2H), 7.80 (s, 1H), 7.52 (dd, J = 8.6,



7.3 Hz, 1H), 7.27 (d, J = 7.5 Hz, 1H), 4.10 (t, J = 8.3 Hz, 1H), 3.92 (t, J = 5.4 Hz,



2H), 3.60 (dd, J = 8.0, 4.0 Hz, 1H), 3.45 m, 2H), 3.42 (d, J = 7.0 Hz, 2H), 3.15 (m,



2H), 3.07-2.92 (m, 4H), 2.75 (td, J = 8.9, 2.5 Hz, 2H), 2.55-2.40 (m, 2H), 2.10-



1.99 (m, 2H), 1.88 (d, J = 17.0 Hz, 2H), 1.78-1.68 (m, 4H), 1.37 (m, 2H)


731
(400 MHz, pyridine-d5) δ ppm 8.88 (s, 2H), 8.90-8.77 (m, 2H), 7.72 (s, 1H), 7.49-



7.43 (m, 2H), 7.20 (td, J = 7.3, 1.2 Hz, 1H), 4.05 (p, J = 8.4 Hz, 1H), 3.45 (d, J =



12.3 Hz, 2H), 3.16-2.98 (m, 6H), 2.68 (ddd, J = 14.8, 10.1, 4.3 Hz, 4H), 2.42 (td,



J = 8.0, 7.2, 4.4 Hz, 2H), 2.02 (td, J = 9.1, 6.0 Hz, 2H), 1.86- 1.75 (m, 2H), 1.72



(d, J = 11.8 Hz, 2H), 1.45- 1.32 (m, 2H), 1.21 (q, J = 7.0 Hz, 8H)


732
(400 MHz, pyridine-d5) δ ppm 8.97-8.85 (m, 2H), 7.79 (d, J = 8.3 Hz, 1H), 7.56-



7.46 (m, 2H), 7.26 (t, J = 7.4 Hz, 1H), 4.13 (t, J = 8.4 Hz, 1H), 3.53 (d, J = 12.2



Hz, 2H), 2.76 (td, J = 11.1, 10.4, 4.5 Hz, 7H), 2.56-2.43 (m, 2H), 2.10 (dd, J =



9.1, 5.9 Hz, 2H), 1.83-1.59 (m, 7H), 1.44 (d, J = 27.3 Hz, 4H), 1.29 (t, J = 7.8



Hz, 2H)


733
(400 MHz, pyridine-d5) δ ppm 8.96-8.82 (m, 2H), 7.80 (s, 1H), 7.78 (s, 1H), 7.56-



7.49 (m, 2H), 7.26 (t, J = 7.4 Hz, 1H), 4.12 (p, J = 8.4 Hz, 1H), 3.52 (d, J = 12.2



Hz, 2H), 3.18 (s, 2H), 3.00 (t, J = 7.9 Hz, 2H), 2.81 ?



2H), 2.18-1.95 (m, 2H), 1.93- 1.72 (m, 7H), 1.50- 1.25 (m, 5H)


734
(400 MHz, pyridine-d5) δ ppm 8.93-8.83 (m, 2H), 7.74 (s, 1H), 7.51 (t, J = 1.3



Hz, 2H), 7.20 (t, 1H), 4.74 (t, J = 6.5 Hz, 2H), 4.17-4.08 (m, 2H), 3.53 (d, J =



12.2 Hz, 2H), 2.87-2.64 (m, 7H), 2.59-2.37 (m, 2H), 2.05 (s, 2H), 1.76 (d, J =



26.8 Hz, 4H), 0.99 (t, J = 7.1 Hz, 3H)


735
(400 MHz, pyridine-d5) δ ppm 8.91-8.74 (m, 2H), 7.71 (s, 1H), 7.49-7.40 (m,



2H), 7.20 (t, J = 7.4 Hz, 1H), 4.74 (t, J = 6.3 Hz, 2H), 4.64 (t, J = 6.4 Hz, 2H), 4.07



(t, J = 8.3 Hz, 1H), 3.94 (t, J = 6.9 Hz, 1H), 3.50 (d, 2H), 2.68 (d, J = 8.8 Hz, 3H),



2.42 (m, 3H), 2.15 (s, 3H), 2.02 (td, J = 9.2, 5.4 Hz, 2H), 1.72 (q, J = 4.1 Hz, 4H)


736
(400 MHz, pyridine-d5) δ ppm 8.85-8.79 (m, 2H), 7.76 (s, 1H), 7.47-7.40 (m,



2H), 7.22-7.17 (m, 1H), 4.65 (m, 4H), 4.09 (p, J = 8.3 Hz, 1H), 3.53 (d, J = 12.1



Hz, 2H), 3.31 (d, J = 6.4 Hz, 1H), 2.85-2.67 (m, 5H), 2.58-2.44 (m, 2H), 2.08



(d, J = 8.1 Hz, 2H), 1.77 (m, 2H), 1.74- 1.60 (m, 5H), 1.43 (t, J = 11.4 Hz, 2H),



1.28 (q, J = 11.0 Hz, 2H), 1.14(m, 1H), 1.03 (m, 1H)


737
(400 MHz, pyridine-d5) δ ppm 8.90-8.74 (m, 2H), 7.71 (s, 1H), 7.48-7.39 (m,



2H), 7.30 (t, 1H), 7.25-7.16 (m, 1H), 4.05 (m, 1H), 3.55 (d 2H), 2.82-2.55 (m,



4H), 2.49 (m, 5H), 2.19- 1.92 (m, 4H)


738
(400 MHz, pyridine-d5) δ ppm 8.87-8.77 (m, 2H), 7.73 (s, 1H), 7.45 (dd, J = 8.6,



7.3 Hz, 2H), 7.20 (t, J = 7.4 Hz, 1H), 4.08 (p, J = 8.3 Hz, 1H), 3.53 (d, J = 12.2 Hz,



2H), 2.92-2.67 (m, 10H), 2.57 (m, 1H), 2.50-2.34 (m, 1H), 2.04 (d, J = 7.8 Hz,



2H), 1.89 (q, J = 11.7 Hz, 2H), 1.60 (tt, J = 6.7, 3.6 Hz, 1H), 0.56-0.35 (m, 4H)


739
(400 MHz, pyridine-d5) δ ppm 8.91-8.83 (m, 2H), 7.80 (d, J = 13.2 Hz, 1H), 7.55-



7.46 (m, 2H), 7.26 (dd, J = 8.1, 6.8 Hz, 1H), 4.13 (q, J = 8.3 Hz, 1H), 3.83 (s,



2H), 3.64 (d, J = 11.0 Hz, 4H), 2.89 (dd, J = 12.9, 10.4 Hz, 3H), 2.72 (dq, J = 11.0,



8.8 Hz, 2H), 2.55-2.25 (m, 8H), 2.22 (s, 3H), 2.07-1.91 (m, 4H)


740
(400 MHz, pyridine-d5) δ ppm 8.86-8.77 (m, 2H), 7.34 (s, 1H), 7.24 (t, 2H), 4.40



2.88 (q, J = 7.8 Hz, 1H), 2.79 (d, J = 11.1 Hz, 1H), 2.65 (m, 1H), 2.30 (s, 3H), 2.14



(td, J = 11.4, 3.4 Hz, 1H), 1.91-1.79 (m, 2H), 1.50 (dd, J = 6.7, 1.5 Hz, 6H)


741
(400 MHz, pyridine-d5) δ ppm 8.78-8.70 (m, 2H), 7.81 (s, 1H), 7.29-7.13 (t,



2H), 3.74 (t, J = 5.1 Hz, 2H), 3.59 (q, J = 6.8 Hz, 1H), 3.54 (d, J = 8.1 Hz, 2H),



3.52-3.36 (m, 2H), 3.353.18 (m, 6H), 2.83 (s, 1H), 2.69 (t, J = 4.5 Hz, 4H),



2.43 (d, J = 6.3 Hz, 2H), 1.96 (s, 3H), 1.56 (d, J = 6.7 Hz, 6H), 1.07 (t, J = 7.0 Hz,



3H)


742
(400 MHz, pyridine-d5) δ ppm 8.73 (m, 2H), 7.81 (s, 1H), 7.22 (t, 2H), 4.45 (d, J =



6.3 Hz, 1H), 3.60 (dq, J = 14.8, 8.5, 8.1 Hz, 3H), 3.21 (s, 4H), 2.97 (d, J = 6.3 Hz,



2H), 2.70 (s, 4H), 2.56-2.40 (m, 3H), 2.15- 1.94 (m, 4H), 1.57 (d, J = 6.7 Hz,



6H), 1.42 (d, J = 13.4 Hz, 2H), 1.22 (d, J = 6.2 Hz, 3H)


743
(400 MHz, pyridine-d5) δ ppm 8.71 (dd, J = 9.2, 4.9 Hz, 2H), 7.81 (s, 1H), 7.23-



7.17 (m, 2H), 3.67-3.54 (m, 1H), 3.41-3.25 (m, 4H), 2.79 (t, J = 4.7 Hz, 4H),



2.62-2.41 (m, 4H), 1.81 (dd, J = 42.8, 11.7 Hz, 5H), 1.57 (d, J = 6.7 Hz, 7H),



0.74 (d, J = 3.4 Hz, 2H), 0.46 (d, J = 1.9 Hz, 2H)


744
(400 MHz, pyridine-d5) δ ppm 8.74-8.68 (m, 2H), 7.81 (s, 1H), 7.24-7.16 (m,



2H), 4.61 (p, J = 6.2 Hz, 3H), 3.58 (dd, J = 12.3, 5.1 Hz, 3H), 3.34 (p, J = 6.3 Hz,



1H), 2.73 (s, 5H), 2.37 (s, 4H), 1.99 (d, J = 12.1 Hz, 2H), 1.80 (s, 3H), 1.56 (d, J =



6.8 Hz, 6H)


745
(400 MHz, pyridine-d5) δ ppm 8.78-8.67 (m, 4H), 7.79 (s, 1H), 7.24-7.16 (m,



2H), 3.66-3.51 (m, 5H), 3.35 (q, J = 7.0 Hz, 2H), 2.98 (s, 3H), 2.88 (dd, J = 13.0,



7.6 Hz, 5H), 2.82-2.67 (m, 2H), 2.57 (s, 1H), 1.98 (d, J = 12.7 Hz, 2H), 1.81 (dd,



J = 14.0, 8.1 Hz, 2H), 1.55 (d, J = 6.7 Hz, 6H), 1.08 (t, J = 7.0 Hz, 3H)


746
(400 MHz, pyridine-d5) δ ppm 8.78-8.67 (m, 2H), 7.79 (s, 1H), 7.20 (t, J = 8.8



Hz, 2H), 3.61-3.51 (m, 5H), 3.20 (s, 3H), 2.88 (s, 5H), 2.84-2.71 (m, 4H), 2.55



(s, 1H), 1.98 (d, J = 12.2 Hz, 2H), 1.91-1.70 (m, 2H), 1.55 (d, J = 6.8 Hz, 6H)


747
(400 MHz, pyridine-d5) δ ppm 8.76-8.69 (m, 2H), 7.79 (s, 1H), 7.22-7.16 (m,



2H), 3.58-3.42 (m, 3H), 3.12 (q, J = 7.3 Hz, 4H), 3.05-2.93 (m, 2H), 2.71 (t, J =



11.4 Hz, 2H), 1.80 (s, 2H), 1.70 (d, J = 10.2 Hz, 2H), 1.54 (d, J = 6.7 Hz, 6H), 1.32



(m, 4H), 1.20 (t, J = 7.2 Hz, 8H)


748
(400 MHz, pyridine-d5) δ ppm 8.76-8.68 (m, 2H), 7.79 (s, 1H), 7.23-7.17 (m,



2H), 3.49 (d, J = 12.3 Hz, 2H), 2.95 (s, 4H), 2.71 (t, J = 11.2 Hz, 2H), 1.69 (d, J =



12.2 Hz, 4H), 1.54 (d, J = 6.8 Hz, 6H), 1.32 (s, 4H), 1.17 (d, J = 7.2 Hz, 2H)


749
(400 MHz, pyridine-d5) δ ppm 8.76-8.68 (m, 2H), 7.79 (s, 1H), 7.19 (t, J = 8.8



Hz, 2H), 3.48 (d, J = 12.1 Hz, 2H), 3.19 (s, 4H), 3.03-2.94 (m, 2H), 2.70 (t, J =



11.4 Hz, 2H), 1.81 (dq, J = 9.2, 4.4, 3.9 Hz, 6H), 1.67 (d, J = 11.4 Hz, 2H), 1.54



(d, J = 6.7 Hz, 6H), 1.47-1.04 (m, 7H)


750
(400 MHz, pyridine-d5) δ ppm 8.83-8.75 (m, 2H), 7.88 (s, 1H), 7.33-7.22 (m,



2H), 4.80 (t, J = 6.5 Hz, 2H), 4.71 (dd, J = 7.1, 6.0 Hz, 2H), 4.21 (p, J = 7.1 Hz,



1H), 3.76-3.55 (m, 3H), 2.80 (t, J = 11.4 Hz, 2H), 2.68 (d, J = 7.1 Hz, 2H), 1.77



(d, J = 7.0 Hz, 3H), 1.63 (d, J = 6.7 Hz, 6H), 1.04 (t, J = 7.1 Hz, 3H)


751
(400 MHz, pyridine-d5) δ ppm 8.79-8.69 (m, 2H), 7.80 (s, 1H), 7.20 (t, 2H), 4.73



(t, J = 6.4 Hz, 2H), 4.63 (t, J = 6.5 Hz, 2H), 3.92 (t, J = 6.9 Hz, 1H), 3.63-3.49



(m, 3H), 2.77-2.66 (m, 2H), 2.58-2.32 (m, 1H), 2.13 (s, 3H), 1.70 (q, J = 3.6



Hz, 4H), 1.56 (d, J = 6.7 Hz, 6H)


752
(400 MHz, pyridine-d5) δ ppm 8.78-8.68 (m, 2H), 7.82 (s, 1H), 7.25 ?



2H), 4.63 (dt, J = 16.5, 6.2 Hz, 3H), 3.66-3.49 (m, 2H), 3.32 (p, J = 6.6 Hz, 1H),



2.70 (s, 3H), 1.77- 1.64 (m, 2H), 1.66-1.54 (m, 7H), 1.41 (d, J = 11.1 Hz, 3H),



1.31-1.19 (m, 2H), 1.14 (d, J = 8.5 Hz, 1H), 1.01 (m, 1H)


753
(400 MHz, pyridine-d5) δ ppm 8.75-8.68 (m, 2H), 7.80 (s, 1H), 7.24-7.16 (m,



2H), 3.62-3.48 (m, 3H), 2.96-2.74 (m, 8H), 2.51 (s, 3H), 2.42 (d, J = 8.7 Hz,



1H), 1.89 (d, J = 12.2 Hz, 2H), 1.80- 1.66 (m, 2H), 1.54 (d, J = 6.7 Hz, 6H)


754
(400 MHz, pyridine-d5) δ ppm 8.70 (ddd, J = 10.8, 5.4, 3.0 Hz, 2H), 7.78 (s, 1H),



7.25-7.16 (m, 2H), 3.64-3.52 (m, 3h), 2.93 (s, 2H), 2.86 (d, J = 4.7 Hz, 4H),



2.83-2.72 (m, 2H), 2.10 (d, J = 12.1 Hz, 2H), 2.04-1.90 (m, 2H), 1.56 (d, J =



6.7 Hz, 6H), 0.44 (q, J = 3.9, 3.2 Hz, 2H), 0.40-0.31 (m, 2H)


755
(400 MHz, pyridine-d5) δ ppm 8.70 (td, J = 4.9, 2.5 Hz, 2H), 7.80 (s, 1H), 7.23-



7.16 (m, 2H), 3.83 (s, 2H), 3.67 (s, 2H), 3.64-3.53 (m, 3H), 2.85 (td, J = 11.0,



9.9, 4.2 Hz, 3H), 2.57 (s, 2H), 2.44 (d, J = 9.3 Hz, 2H), 2.29 (s, 3H), 2.25-2.15



(m, 2H), 1.92 (d, J = 12.5 Hz, 2H), 1.50 (d, J = 6.8 Hz, 6H)


756
(500 MHz, DMSO-d6) δ ppm 8.34-8.30 (m, 2H), 7.43-7.39 (m, 2H), 7.38 (s, 1H),



3.67-3.60 (m, 6H), 3.46 (hept, J = 6.7 Hz, 1H), 2.97-2.89 (m, 2H), 2.64-2.59 (m,



4H), 2.51-2.44 (m, 1H), 2.06-2.00 (m, 2H), 1.70-1.60 (m, 2H), 1.42 (d, J = 6.7 Hz,



6H)


757
(400 MHz, pyridine-d5) δ ppm 8.93-8.82 (m, 2H), 7.79 (d, J = 10.5 Hz, 2H), 7.53



(t, J = 7.9 Hz, 2H), 7.27 (t, J = 7.4 Hz, 1H), 4.13 (t, J = 8.4 Hz, 1H), 3.58 (d, J =



12.6 Hz, 2H), 2.87-2.67 (m, 11H), 2.46 (d, J = 32.7 Hz, 6H), 2.09-1.95 (m, 3H),



1.85 (d, J = 5.7 Hz, 2H)


758
(400 MHz, pyridine-d5) δ ppm 8.87-8.78 (m, 2H), 7.38 (s, 1H), 7.26 (d, J = 8.8



Hz, 2H), 4.81 (t, J = 6.4 Hz, 2H), 4.66 (t, J = 6.5 Hz, 2H), 4.34 (q, J = 11.2, 9.4



Hz, 2H), 4.19 (dd, J = 8.2, 5.4 Hz, 2H), 4.01 (t, J = 6.9 Hz, 1H), 3.60-3.43 (m,



1H), 3.47-3.17 (m, 1H), 2.92 (d, J = 11.1 Hz, 2H), 2.55-2.37 (m, 1H), 2.38 (m,



1H), 2.21 (s, 3H), 1.68 (m, 3H), 1.54 (d, J = 6.7 Hz, 7H)


759
(400 MHz, pyridine-d5) δ ppm 8.87-8.78 (m, 2H), 7.36 (s, 1H), 7.25 (t, J = 8.8



Hz, 2H), 4.34 (t, J = 7.6 Hz, 2H), 4.17 (dd, J = 8.1, 5.5 Hz, 2H), 3.82 (t, J = 4.6 Hz,



4H), 3.52 (p, J = 6.8 Hz, 1H), 3.27 (q, J = 6.3 Hz, 1H), 2.92 (d, J = 10.8 Hz, 2H),



2.70 (s, 3H), 2.40 (t, J = 11.7 Hz, 1H), 1.98- 1.82 (m, 4H), 1.70 (td, J = 12.7, 9.2



Hz, 2H), 1.54 (d, J = 6.6 Hz, 6H)


760
(400 MHz, pyridine-d5) δ ppm 8.74-8.68 (m, 2H), 7.78 (s, 1H), 7.25-7.16 (m,



2H), 3.55-3.50 (m, 1H), 3.18 (dt, J = 7.7, 4.7 Hz, 5H), 2.83 (s, 5H), 2.58 (s, 3H),



2.41 (q, J = 6.6 Hz, 2H), 2.01 (q, J = 7.9, 7.2 Hz, 2H), 1.97 (s, 2H), 1.54 (d, J = 6.8



Hz, 6H)


761
(400 MHz, pyridine-d5) δ ppm 8.79-8.70 (m, 2H), 7.82 (s, 1H), 7.23-7.17 (m,



2H), 3.70-3.50 (m, 1H), 3.27 (t, J = 10.2 Hz, 2H), 3.09 (s, 5H), 2.82 (s, 3H), 2.68



(s, 3H), 1.97 (s, 2H), 1.90 (d, J = 11.1 Hz, 2H), 1.80 (s, 2H), 1.67- 1.53 (m, 8H),



0.86 (s, 3H)


762
(400 MHz, pyridine-d5) δ ppm 8.75-8.68 (m, 2H), 7.80 (s, 1H), 7.22-7.16 (m,



2H), 3.92 (t, J = 5.1 Hz, 2H), 3.54 (d, J = 6.6 Hz, 1H), 3.39 (q, J = 6.1, 4.0 Hz,



2H), 3.27 (t, J = 5.1 Hz, 2H), 3.13 (s, 2H), 2.95 (td, J = 9.6, 8.8, 4.9 Hz, 2H), 2.00



(d, J = 12.7 Hz, 2H), 1.73 (s, 7H), 1.53 (d, J = 6.7 Hz, 6H), 1.31 (s, 2H)


763
(400 MHz, DMSO-d6/F3CCOOD, 120° C.) δ ppm 8.26-8.15 (m, 2H), 7.31-7.23 (m,



2H), 3.96-3.86 (m, 4H), 3.72 (hept, J = 6.9 Hz, 1H), 3.54-3.31 (m, 9H), 2.56-2.42



(m, 3H), 2.27-2.20 (m, 2H), 1.95-1.83 (m, 2H), 1.45-1.40 (m, 6H)


764
(400 MHz, CDCl3) δ ppm 13.17 (br s, 1H-NH), 7.88 (s, 1H), 7.80 (d, 2H), 7.55 (d,



2H), 5.06 (septet, 1H), 4.75-4.83 (m, 1H), 3.90-4.11 (m, 3H), 3.49-3.63 (m, 2H),



2.84-2.95 (m + s, 2 + 3H), 1.91-2.04 (m, 6H), 1.76 (d, 1H), 1.46-1.56 (m, 2H), 1.30



(d + m, 6 + 1H), OH not observed


765
(400 MHz, pyridine-d5) δ ppm 8.81 - 8.72 (m, 2H), 7.31 (s, 1H), 7.23-7.16 (m,



2H), 4.25 (t, J = 7.6 Hz, 2H), 4.11 (dd, J = 8.2, 5.3 Hz, 2H), 3.72 (t, J = 4.6 Hz,



4H), 3.45 (p, J = 6.7 Hz, 1H), 3.19 (ddd, J = 7.1, 5.2, 1.9 Hz, 1H), 2.33 (s, 4H),



1.47 (d, J = 6.7 Hz, 6H)


766
(400 MHz, pyridine-d5) δ ppm 8.76-8.68 (m, 2H), 7.78 (s, 1H), 7.25-7.17 (m,



2H), 4.01 (d, J = 8.6 Hz, 2H), 3.57 (dt, J = 21.7, 6.5 Hz, 3H), 3.41-3.34 (m, 2H),



3.21 (t, J = 5.2 Hz, 2H), 2.88-2.79 (m, 2H), 2.18 (p, J = 5.6 Hz, 2H), 1.74-1.59



(m, 2H), 1.47 (d, J = 6.7 Hz, 6H), 0.76 (t, J = 7.4 Hz, 3H)


767
(400 MHz, pyridine-d5) δ ppm 8.77-8.67 (m, 2H), 7.78 (s, 1H), 7.25-7.16 (m,



2H), 3.97 (d, J = 8.6 Hz, 2H), 3.63-3.51 (m, 3H), 3.26 (p, J = 8.1 Hz, 1H), 3.11



(d, J = 7.0 Hz, 2H), 2.96 (t, J = 5.3 Hz, 2H), 2.32-2.20 (m, 2H), 2.13 (p, J = 5.2



Hz, 2H), 2.01 (dtd, J = 11.4, 8.8, 8.4, 2.3 Hz, 2H), 1.64 (s, 1H), 1.66-1.55 (m,



1H), 1.48 (d, J = 6.7 Hz, 7H)


768
(400 MHz, pyridine-d5) δ ppm 8.77-8.68 (m, 2H), 7.79 (s, 1H), 7.26-7.16 (m,



2H), 4.01 (d, J = 7.8 Hz, 2H), 3.64- 3.51 (m, 3H), 3.40-3.33 (m, 2H), 3.20 (t, J =



5.3 Hz, 2H), 2.92-2.83 (m, 2H), 2.19 (q, J = 5.9, 5.3 Hz, 2H), 1.69- 1.56 (m,



2H), 1.48 (d, J = 6.7 Hz, 6H), 1.19 (h, J = 7.4 Hz, 2H), 0.76 (t, J = 7.4 Hz, 3H)


769
(400 MHz, pyridine-d5) δ ppm 8.75-8.67 (m, 2H), 7.76 (s, 1H), 7.21 (d, J = 8.8



Hz, 2H), 4.05-3.98 (m, 2H), 3.63-3.48 (m, 4H), 3.41-3.34 (m, 2H), 3.24-



3.16 (m, 2H), 2.74 (s, 3H), 2.16 (p, J = 5.2 Hz, 2H), 1.46 (d, J = 6.7 Hz, 6H)


770
(400 MHz, pyridine-d5) δ ppm 8.76-8.69 (m, 2H), 7.84 (s, 1H), 7.25 ?



2H), 3.55 (ddd, J = 23.7, 13.2, 8.4 Hz, 3H), 3.20-3.02 (m, 3H), 2.93 ?



1H), 2.62 ?



(dtd, J = 11.6, 5.8, 3.2 Hz, 2H), 1.66- 1.49 (m, 7H), 1.41 (qd, J = 11.1, 5.5 Hz,



1H)


771
(400 MHz, pyridine-d5) δ ppm 8.74-8.68 (m, 2H), 7.77 (s, 1H), 7.23-7.17 (m,



2H), 3.87 (t, J = 5.0 Hz, 2H), 3.58-3.46 (m, 3H), 3.09 (t, J = 5.1 Hz, 4H), 2.15 (s,



3H), 1.54 (d, J = 6.7 Hz, 6H)


772
(400 MHz, pyridine-d5) δ ppm 8.75-8.67 (m, 2H), 7.81 (s, 1H), 7.25-7.16 (m,



2H), 3.56 (p, J = 6.7 Hz, 1H), 3.34 (t, J = 4.8 Hz, 4H), 2.78 (t, J = 4.6 Hz, 4H),



2.54 (q, J = 7.2 Hz, 2H), 1.54 (d, J = 6.7 Hz, 6H), 1.08 (t, J = 7.2 Hz, 3H)



(400 MHz, pyridine-d5) δ ppm 8.66 (m, 2H), 7.80 (s, 1H), 7.19 (t, J = 8.8 Hz, 2H),



773 3.98 (t, J = 5.8 Hz, 2H), 3.56 (dt, J = 14.1, 7.4 Hz, 2H), 3.24 (t, J = 4.8 Hz, 4H),



2.76 (q, J = 5.9, 4.9 Hz, 6H), 1.54 (d, J = 6.7 Hz, 6H)


774
(400 MHz, pyridine-d5) δ ppm 8.74-8.66 (m, 2H), 7.80 (s, 1H), 7.24-7.16 (m,



2H), 3.58-3.50 (m, 1H), 3.44 (dd, J = 6.4, 3.3 Hz, 4H), 3.18 (t, J = 4.8 Hz, 4H),



2.80 (s, 6H), 1.53 (d, J = 6.7 Hz, 6H)


775
(400 MHz, pyridine-d5) δ ppm 8.74-8.68 (m, 2H), 7.78 (s, 1H), 7.24-7.16 (m,



2H), 4.35 (s, 2H), 3.88 (s, 1H), 3.71 (s, 2H), 3.65-3.48 (m, 3H), 3.14 (d, J = 9.2



Hz, 4H), 1.54 (d, J = 6.8 Hz, 6H), 1.17 (t, J = 7.0 Hz, 3H)


776
(400 MHz, pyridine-d5) δ ppm 8.75-8.67 (m, 3H), 7.81 (s, 1H), 7.22-7.16 (m,



2H), 3.58 (hept, J = 7.0 Hz, 1H), 3.40 (t, J = 6.3 Hz, 2H), 3.25 (s, 6H), 2.64 (t, J =



4.5 Hz, 4H), 2.51 (t, J = 7.3 Hz, 2H), 1.87- 1.75 (m, 2H), 1.55 (d, J = 6.8 Hz, 6H)


777
(400 MHz, pyridine-d5) δ ppm 8.76-8.68 (m, 2H), 7.82 (s, 1H), 7.20 (t, J = 8.8



Hz, 2H), 3.59 (p, J = 6.7 Hz, 1H), 3.25 (s, 4H), 2.63 ?



(m, 2H), 1.56 (d, J = 6.8 Hz, 6H), 1.49- 1.39 (m, 2H), 0.86 (t, J = 7.3 Hz, 3H)


778
(400 MHz, pyridine-d5) δ ppm 8.75-8.67 (m, 2H), 7.79 (s, 1H), 7.26-7.16 (m,



2H), 4.01-3.93 (m, 2H), 3.73 (q, J = 5.5, 5.0 Hz, 4H), 3.63-3.47 (m, 1H), 3.27



(t, J = 4.7 Hz, 4H), 2.77 (dt, J = 22.4, 5.2 Hz, 6H), 1.53 (d, J = 6.7 Hz, 6H)


779
(400 MHz, pyridine-d5) δ ppm 8.75-8.68 (m, 2H), 7.80 (s, 1H), 7.20 (t, J = 8.8



Hz, 2H), 3.97 (dd, J = 6.4, 3.3 Hz, 1H), 3.90-3.84 (m, 1H), 3.76-3.67 (m, 1H),



3.60-3.47 (m, 3H), 3.28 (dt, J = 25.2, 5.5 Hz, 7H), 3.07 (dt, J = 17.5, 7.3 Hz, 3H),



2.90-2.69 (m, 9H), 2.22 (p, J = 6.0 Hz, 1H), 2.05 (dt, J = 11.9, 6.4 Hz, 1H), 1.53



(dd, J = 6.8, 1.7 Hz, 6H)


780
(400 MHz, pyridine-d5) δ ppm 8.66 (m, 2H), 7.83 (s, 1H), 7.20 (t, J = 8.8 Hz, 2H),



3.53 (d, J = 12.1 Hz, 3H), 2.76 (dd, J = 12.8, 10.5 Hz, 2H), 1.74-1.43 (m, 12H),



1.47-1.14 (m, 3H), 1.09 (q, J = 7.0, 6.3 Hz, 5H), 0.81 (d, J = 10.7 Hz, 2H)


781
(400 MHz, pyridine-d5) δ ppm 8.75-8.67 (m, 2H), 7.81 (s, 1H), 7.25 ?



2H), 3.55 (p, J = 6.7 Hz, 1H), 3.08 (t, J = 5.5 Hz, 4H), 2.88 (s, 4H), 2.59 (s, 3H),



1.73 (t, J = 5.8 Hz, 4H), 1.61 (d, J = 5.6 Hz, 4H), 1.55 (d, J = 6.8 Hz, 6H)


782
(400 MHz, pyridine-d5) δ ppm 8.68 (s, 2H), 7.84 (s, 1H), 7.19 (t, J = 8.8 Hz, 2H),



3.91 (s, 4H), 3.65-3.50 (m, 1H), 3.35 (dd, J = 6.7, 4.5 Hz, 4H), 1.97 (t, J = 5.6



Hz, 4H), 1.51 (d, J = 6.7 Hz, 6H)


783
(400 MHz, pyridine-d5) δ ppm 8.74-8.68 (m, 2H), 7.87 (s, 1H), 7.23-7.16 (m,



2H), 4.19 (tt, J = 8.8, 4.1 Hz, 1H), 3.88 (dd, J = 12.2, 4.0 Hz, 1H), 3.63 (p, J = 6.7



Hz, 1H), 3.35 (d, J = 12.5 Hz, 1H), 3.01 (dd, J = 11.6, 9.1 Hz, 1H), 2.28-2.11 (m,



1H), 1.83 (dt, J = 12.3, 3.7 Hz, 1H), 1.76-1.55 (m, 2H), 1.50 (d, J = 6.8 Hz, 6H)


784
(400 MHz, pyridine-d5) δ ppm 8.69 (td, J = 4.9, 2.4 Hz, 2H), 7.79 (s, 1H), 7.24-



7.16 (m, 2H), 3.68 (p, J = 6.7 Hz, 1H), 3.54-3.46 (m, 2H), 2.91 (t, J = 11.9 Hz,



3H), 2.61 (s, 2H), 1.94-1.71 (m, 5H), 1.64 (d, J = 6.7 Hz, 6H), 1.24 (m, 5H)


785
(400 MHz, pyridine-d5) δ ppm 8.76-8.67 (m, 2H), 7.80 (s, 1H), 7.26-7.15 (m,



2H), 3.63-3.46 (m, 2H), 3.01 (s, 2H), 2.91 (s, 2H), 2.73 (t, J = 11.2 Hz, 2H), 2.59



(t, J = 7.7 Hz, 2H), 2.51 (s, 3H), 1.69 (d, J = 8.9 Hz, 2H), 1.59- 1.46 (m, 6H), 1.40



(d, J = 8.1 Hz, 2H)


786
(400 MHz, pyridine-d5) δ ppm 8.80-8.71 (m, 2H), 7.58 (s, 1H), 7.23 ?



2H), 3.95 (t, J = 9.0 Hz, 1H), 3.81 (dd, J = 9.4, 7.0 Hz, 1H), 3.66-3.48 (m, 3H),



3.27 (t, J = 7.7 Hz, 1H), 2.85-2.64 (m, 4H), 2.28-2.13 (m, 2H), 1.63 (h, J = 5.7,



5.2 Hz, 4H), 1.55 (d, J = 6.6 Hz, 3H), 1.38 (d, J = 6.8 Hz, 3H), 1.31 (td, J = 11.7,



10.9, 5.9 Hz, 2H)


787
(400 MHz, pyridine-d5) δ ppm 8.74-8.66 (m, 2H), 7.51 (p, J = 1.1 Hz, 1H), 7.25-



7.17 (m, 2H), 3.67-3.61 (m, 2H), 3.61 - 3.42 (m, 2H), 3.19 (q, J = 12 Hz, 4H),



2.82 (td, J = 12.3, 2.5 Hz, 2H), 2.23 (dtd, J = 27.6, 12.0, 3.6 Hz, 4H), 1.56 (d, J =



6.7 Hz, 6H), 1.28 (t, J = 7.2 Hz, 6H)


788
(400 MHz, pyridine-d5) δ ppm 8.74-8.67 (m, 2H), 7.51 (p, J = 1.1 Hz, 1H), 7.25-



7.12 (m, 2H), 3.56 (dq, .7=6.8, 5.0,3.4 Hz, 5H), 3.19 (t,J = 4.7 Hz, 4H), 1.52 (d.



J = 6.7 Hz, 6H), 1.23 (s, 9H)


789
(400 MHz, pyridine-d5) δ ppm 8.75-8.68 (m, 2H), 7.76 (s, 1H), 7.24-7.15 (m,



2H), 3.61-3.48 (m, 3H), 3.29 (s, 2H), 3.08 (t, J = 5.8 Hz, 1H), 2.73 (dddd, J =



14.6, 11.5, 6.9, 2.7 Hz, 2H), 2.17 (d, J = 13.1 Hz, 1H), 2.01 (d, J = 14.2 Hz, 1H),



1.86 (s, 3H), 1.75-1.61 (m, 3H), 1.54 (dd, J = 6.8, 3.9 Hz, 6H), 1.27 (d, J = 6.7



Hz, 3H)


790
(400 MHz, pyridine-d5) δ ppm 8.74-8.68 (m, 2H), 7.76 (s, 1H), 7.19 (t, J = 8.8



Hz, 2H), 3.55 (td, J = 12.9, 12.1, 5.7 Hz, 2H), 2.88 (s, 1H), 2.79 (dd, J = 12.2, 2.0



Hz, 2H), 2.75 (d, J = 5.1 Hz, 2H), 1.98 (d, J = 11.6 Hz, 2H), 1.71 (s, 2H), 1.54



(d, J = 6.8 Hz, 6H), 1.33 (s, 1H)


791
(400 MHz, pyridine-d5) δ ppm 8.74-8.67 (m, 2H), 7.52 (s, 1H), 7.25-7.14 (m,



2H), 3.80 (s, 1H), 3.55 (hept, J = 6.8 Hz, 1H), 3.42 (s, 1H), 3.16 (d, J = 6.2 Hz,



3H), 2.81 (s, 3H), 2.70 (s, 2H), 2.51-2.40 (m, 3H), 2.22-2.16 (m, 1H), 2.08-



1.86 (m, 1H), 1.66 (d, J = 12.2 Hz, 2H), 1.54 (dd, J = 6.7, 1.6 Hz, 6H), 0.94 (d, J =



12.1 Hz, 1H)


792
(400 MHz, pyridine-d5) δ ppm 8.75-8.66 (m, 2H), 7.81 (s, 1H), 7.25-7.16 (m,



2H), 4.19-4.07 (m, 1H), 3.87-3.76 (m, 1H), 3.70-3.51 (m, 2H), 3.38-3.24



(m, 4H), 2.96 (q, J = 6.8, 4.6 Hz, 2H), 2.83 (dt, J = 7.9, 3.5 Hz, 2H), 2.67-2.57



(m, 2H), 1.86 (dtd, J = 11.8, 7.4, 6.6, 4.7 Hz, 1H), 1.74- 1.57 (m, 2H), 1.56-1.40



(m, 7H)


793
(400 MHz, pyridine-d5) δ ppm 8.75-8.68 (m, 2H), 7.82 (s, 1H), 7.25-7.16 (m,



2H), 3.61 (p, J = 6.8 Hz, 1H), 3.49 (dd, J = 9.7, 5.7 Hz, 1H), 3.43 (s, 1H), 3.35-



3.23 (m, 8H), 2.95-2.81 (m, 5H), 1.55 (dd, J = 6.7, 1.3 Hz, 6H), 1.08 (d, J =6.7



Hz, 3H)


794
(400 MHz, pyridine-d5) δ ppm 8.78-8.70 (m, 2H), 7.33 (d, J = 15.7 Hz, 1H), 7.18



(d, J = 8.8 Hz, 2H), 4.36-4.22 (m, 4H), 3.53 (m, 1H), 3.42 (p, J = 6.7 Hz, 1H0,



2.60 (s, 4H), 1.73-1.64 (m, 4H), 1.45 (d, J = 6.6 Hz, 6H)


795
(400 MHz, pyridine-d5) δ ppm 8.74-8.68 (m, 2H), 7.51 (s, 1H), 7.22-7.13 (m,



2H), 4.15-4.08 (m, 2H), 3.63 - 3.47 (m, 6H), 3.32 (s, 2H), 2.29 (d, J = 5.9 Hz,



2H), 1.48 (d, J = 6.7 Hz, 6H), 1.21 (d, J = 6.6 Hz, 6H)


796
(400 MHz, pyridine-d5) δ ppm 8.76-8.68 (m, 2H), 7.74 (s, 1H), 7.19 (t, J = 8.7



Hz, 2H), 3.69-3.59 (m, 1H), 3.47 (dd, J = 10.7, 5.8 Hz, 2H), 3.35 (dd, J = 10.4,



3.0 Hz, 2H), 3.03-2.97 (m, 2H), 2.83-2.76 (m, 2H), 2.48 (d, J = 7.3 Hz, 2H),



1.80 (hept, J = 6.8 Hz, 1H), 1.52 (d, J = 6.8 Hz, 6H), 0.88 (d, J = 6.4 Hz, 6H)


797
(400 MHz, pyridine-d5) δ ppm 8.75-8.67 (m, 2H), 7.51 (s, 1H), 7.25-7.16 (m,



2H), 4.12-4.05 (m, 2H), 3.63-3.45 (m, 5H), 3.39 - 3.32 (m, 2H), 3.11 (q, J = 7.3



Hz, 2H), 2.26 (p, J = 5.1 Hz, 2H), 1.47 (d, J = 6.7 Hz, 6H), 1.23 (t, J = 7.2 Hz, 3H)


798
(400 MHz, pyridine-d5) δ ppm 8.75-8.68 (m, 2H), 7.52 (t, J = 1.2 Hz, 1H), 7.22-



7.17 (m, 2H), 3.68-3.48 (m, 4H), 3.48-3.38 (m, 2H), 3.22 (s, 2H), 2.94 (s, 3H),



2.20 (d, J = 12.8 Hz, 2H), 2.03 (td, J = 12.6, 4.1 Hz, 2H), 1.49 (d, J = 6.7 Hz, 6H),



1.24 (d, J = 6.6 Hz, 6H)


799
(400 MHz, pyridine-d5) δ ppm 8.69 (td, J = 4.9, 2.5 Hz, 2H), 7.77 (s, 1H), 7.24-



7.16 (m, 2H), 3.72 (m,1H), 3.67-3.56 (m, 3H), 3.23 (s, 1H), 2.78 (td, J = 12.4, 2.6



Hz, 2H), 2.64 (s, 3H), 2.23 (s, 2H), 1.59 (d, J = 6.7 Hz, 6H), 1.21 (d, J = 6.5 Hz,



6H)


800
(400 MHz, pyridine-d5) δ ppm 8.76-8.69 (m, 2H), 7.52 (s, 1H), 7.25-7.16 (m,



2H),3.54 /(m, 1H), 3.33-3.20 (m, 9H), 2.90 (t, J = 6.1 Hz, 2H), 2.74-2.67 (m,



3H), 1.54 (d, J = 6.7 Hz, 6H), 1.24 (t, J = 7.3 Hz, 6H)


801
(400 MHz, pyridine-d5) δ ppm 8.76-8.68 (m, 2H), 7.81 (s, 1H), 7.26-7.17 (m,



2H), 3.57 (p, J = 6.8 Hz, 1H), 3.46 (s, 1H), 3.19 (t, J = 4.6 Hz, 4H), 2.90 (s, 1H),



2.75 (s, 3H), 2.65 (t, J = 4.7 Hz, 4H), 2.44 (d, J = 7.5 Hz, 1H), 2.06 (qd, J = 10.3,



5.1 Hz, 2H), 1.94 (d, J = 14.0 Hz, 2H), 1.55 (d, J = 6.7 Hz, 6H)


802
(400 MHz, DMSO-d6) δ ppm 1.29 1.57 (m, 4H), 1.66 2.10 (m, 6H), 2.25 2.40 (m,



3H), 2.64 (d, J = 7.1 Hz, 2H), 2.82 (q, J = 15.7, 13.7 Hz, 4H), 2.94 (t, J = 8.6 Hz,



1H), 3.23 (s, 3H), 3.23 3.32 (m, 2H), 3.50 (d, J = 11.9 Hz, 2H), 3.94 (p, J = 8.4 Hz,



1H), 7.27 (s, 1H), 7.30 (d, J = 7.4 Hz, 1H), 7.53 (t, J = 7.9 Hz, 2H), 8.28 8.38 (m,



2H)


803
(501 MHz, DMSO-d6) δ ppm 1.40 (qd, J = 12.1, 6.5 Hz, 2H), 1.72 (dtt, J = 16.1,



7.7, 3.7 Hz, 2H), 1.85-2.09 (m, 5H), 2.36 (dddd, J = 11.7, 8.5, 6.1, 2.8 Hz, 3H),



2.53-2.64 (m, 2H), 2.64-2.74 (m, 1H), 2.84 (td, J = 10.5, 8.7, 4.3 Hz, 3H), 3.15



(s, OH), 3.17 (s, 3H), 3.51 (d, J = 12.0 Hz, 2H), 3.87-4.03 (m, 2H), 7.28 (s, 1H),



7.30 (dt, J = 7.4, 1.2 Hz, 1H), 7.48-7.58 (m, 2H), 8.27-8.38 (m, 2H)


804
(501 MHz, DMSO-d6) δ ppm 1.35-1.56 (m, 3H), 1.86-2.05 (m, 6H), 2.29-2.40



(m, 2H), 2.40-2.48 (m, 2H), 2.49-2.57 (m, 1H), 2.59-2.70 (m, 2H), 2.72-



2.89 (m, 5H), 2.95 (t, J = 8.9 Hz, 1H), 3.23 (s, 4H), 3.24-3.30 (m, 2H), 3.51



(d, J = 12.0 Hz, 2H), 3.94 (p, J = 8.3 Hz, 1H), 7.27 (s, 1H), 7.28-7.31 (m, 1H),



7.48-7.57 (m, 2H), 8.28-8.37 (m, 2H)


805
(400 MHz, DMSO-d6) δ ppm 8.41-8.37 (m, 2H), 8.27 (s, 1H), 7.42-7.35 (m, 2H),



7.24 (s, 1H), 4.02-3.94 (m, 1H), 3.63-3.50 (m, 7H), 2.86-2.76 (m, 2H), 2.58-2.50



(m, 2H), 2.49-2.31 (m, 6H), 2.18-2.15 (m, 1H), 2.11-1.92 (m, 2H), 1.86-1.82 (m,



1H), 1.62-1.53 (m, 1H), 1.45-1.34 (m, 2H), 0.95 (d, 3H)


808
(400 MHz, CDCl3) δ ppm 13.46 (br s, 1H-NH), 7.91 (s, 1H), 7.83 (brs, 4H), 5.07



(septet, 1H), 4.71-4.79 (m, 1H), 4.22-4.39 (m, 4H), 3.98 (d, 2H), 3.62-3.77 (m,



1H), 3.38-3.41 (m, 2H), 2.86-2.98 (m, 2H), 2.39-2.47 (m, 2H), 1.89-2.09 (m, 6H),



1.77-1.85 (m, 2H), 1.62-1.71 (m, 2H), 1.47-1.59 (m, 2H), 1.28-1.41 (m, 2H)


811
(400 MHz, DMSO-d6, 90° C.) δ ppm 8.33 (dd, J = 8.8, 4.9 Hz, 2H), 7.38 7.28 (m,



3H), 3.60 3.53 (m, 2H), 3.49 (hept, J = 6.8 Hz, 1H), 2.98 2.89 (m, 2H), 2.52 2.45



(m, 4H), 1.98 1.90 (m, 2H), 1.81 1.68 (m, 6H), 1.47 1.35 (m, 9H)


812
(400 MHz, pyridine-d5) δ ppm 8.86-8.76 (m, 2H), 7.72 (s, 1H), 7.48-7.40 (m,



2H), 7.25-7.17 (m, 1H), 4.07 (p, J = 8.2 Hz, 1H), 3.55 (t, J = 11.0 Hz, 2H), 3.00



(bs, 2H), 2.70 (t, J = 8.9 Hz, 4H), 2.05 (td, J = 10.1, 8.7, 6.5 Hz, 2H), 1.79 (d, J =



5.8 Hz, 7H), 1.17 (d, J = 6.5 Hz, 3H)


813
(400 MHz, pyridine-d5) δ ppm 8.85-8.78 (m, 2H), 8.44 (s, 1H), 8.41 (s, 1H), 7.73



(s, 1H), 7.71 (s, 1H), 7.48 ?



1H), 3.24 (s, 2H), 3.07 (q, J = 5.9 Hz, 4H), 2.70 (pd, J = 9.0, 2.4 Hz, 2H), 2.48-



2.39 (m, 2H), 2.38 (s, 2H), 2.03 (td, J = 8.7, 8.2, 5.5 Hz, 2H), 1.80 (t, J = 5.5 Hz,



4H)


814
(400 MHz, pyridine-d5) δ ppm 8.83-8.75 (m, 2H), 7.87 (s, 1H), 7.28 (d, J = 8.8



Hz, 2H), 4.10 (d, J = 6.6 Hz, 2H), 3.80 (s, 4H), 3.20 (t, J = 5.0 Hz, 4H), 1.99



(p, J = 6.6 Hz, 1H), 1.62 (d, J = 6.8 Hz, 6H), 0.94 (d, J = 6.7 Hz, 6H)


817
(400 MHz, CDCl3) δ ppm 8.69 (d, J = 5.6 Hz, 1 H), 7.97-8.17 (m, 2 H), 7.47-7.59



(m, 1 H), 4.08-4.25 (m, 2 H), 3.98 (quin, J = 8.3 Hz, 1 H), 3.55-3.77 (m, 4 H),



3.28-3.48 (m, 5 H), 3.04-3.17 (m, 1 H), 2.88-3.04 (m, 2 H), 2.56-2.72 (m, 2



H), 2.34-2.53 (m, 2 H), 2.05-2.22 (m, 3 H), 1.80-2.03 (m, 8 H)


819
(300 MHz, CDCl3) δ ppm 8.68 (d, J = 5.1 Hz, 1 H), 8.18-8.39 (m, 2 H), 7.57 (s, 1



H), 4.59 (s, 2 H), 4.16 (d, J = 10.6 Hz, 3 H), 3.96-4.06 (m, 2 H), 3.89 (br. s., 4 H),



3.77 (d, J = 12.1 Hz, 2 H), 3.65 (d, J = 14.3 Hz, 3 H), 2.96-3.21 (m, 4H), 2.81 (br.



s., 4 H), 2.54-2.70 (m, 3 H), 2.47 (br. s., 2 H), 1.78-2.25 (m, 4 H)


823
(300 MHz, CDCl3) δ ppm 8.47 (d, J = 8.4 Hz, 2 H), 7.73 (d, J = 8.8 Hz, 2 H),



7.53 (s,1H), 3.87-4.08 (m, 5 H), 3.76 (d, J = 12.1 Hz, 2 H), 3.02 (t, J = 11.9 Hz,



3 H), 2.90(br. s., 4 H), 2.70-2.78 (m, 1 H), 2.56-2.69 (m, 2 H), 2.36-2.52



(m, 2 H), 1.84-2.25 (m, 5 H)


824
(400 MHz, CDCl3) δ ppm 7.74-7.92 (m, 2 H), 7.47 (s, 1 H), 7.15 (t, J = 9.2 Hz, 1



H), 4.00 (t, J = 8.4 Hz, 1 H), 3.85 (t, J = 4.5 Hz, 4 H), 3.75 (d, J = 12.7 Hz, 2 H),



2.98 (t, J = 11.7 Hz, 2H), 2.75 (br. s., 4H), 2.62 (td, J = 9.2, 2.4 Hz, 2H),



2.45-2.55 (m, 1 H), 2.32-2.44 (m, 5H), 1.99-2.20 (m, 4H), 1.75-1.94 (m, 2 H)


825
(400 MHz, CDCl3) δ ppm 7.93-8.11 (m, 2 H), 7.38-7.54 (m, 2 H), 7.00 (td,



J = 8.2, 2.0 Hz, 1 H), 3.90-4.04 (m, 1 H), 3.80-3.90 (m, 4 H), 3.74 (d, J = 12.5 Hz,



2 H), 2.98 (t, J = 11.9 Hz, 2 H), 2.80 (br. s., 4 H), 2.53-2.68 (m, 3 H), 2.42 (dd,



J = 7.8, 3.9 Hz, 2 H), 1.99-2.24 (m, 4 H), 1.80-1.95 (m, 2 H)


826
(400 MHz, CDCl3) δ ppm 8.61 (s, 1 H), 8.53 (d, J = 8.3 Hz, 1 H), 7.55-7.64 (m, 1



H), 7.45-7.54 (m, 2 H), 3.92-4.04 (m, 2 H), 3.92 (br. s., 3 H), 3.73 (d, J = 12.0



Hz, 2H), 2.98 (t, J = 11.9 Hz, 2H), 2.88 (br. s., 4H), 2.73 (t, J = 10.8 Hz, 1 H),



2.50 -2.65 (m, 2 H), 2.32-2.47 (m, 2 H), 2.13-2.24 (m, 2 H), 1.82-2.10 (m, 4 H)


827
(400 MHz, pyridine-d5) δ ppm 8.86-8.78 (m, 2H), 7.73 (s, 1H), 7.20 (td, J = 7.3,



1.2 Hz, 2H), 4.06 (p, J = 8.3 Hz, 1H), 3.66-3.54 (m, 2H), 3.46 (d, J = 11.8 Hz,



2H), 3.26-3.19 (m, 1H), 3.18-3.11 (m, 1H), 2.68 (dt, J = 11.2, 8.7 Hz, 3H),2.41



(d, J = 9.7 Hz, 2H), 2.36 (d, J = 4.7 Hz, 2H), 2.05-1.96 (m, 2H), 1.82 (d, J = 7.2



Hz, 1H), 1.45 (s, 2H)


828
(400 MHz, pyridine-d5) δ ppm 8.86-8.79 (m, 2H), 7.75 (s, 1H), 7.49-7.41 (m,



2H), 7.22-7.16 (m, 1H), 4.07 (t, J = 8.3 Hz, 1H), 3.49 (d, J = 12.2 Hz, 2H), 2.92



(t, J = 13.4 Hz, 2H), 2.78-2.57 (m, 6H), 2.42(s, 2H), 2.30-2.18 (m, 4H), 2.06-



1.93 (m, 2H), 1.86 (d, J = 11.8 Hz, 2H), 1.56 (td, J = 7.2, 3.5 Hz, 1H), 1.50-1.36



(m, 2H)


829
(400 MHz, pyridine-d5) δ ppm 8.85-8.78 (m, 2H), 7.71 (s, 1H), 7.47-7.41 (m,



2H), 7.23 ?



Hz, 2H), 3.33 (d, J = 7.8 Hz, 2H), 3.13 (s, 3H), 2.72-2.63 (m, 6H), 2.46-2.38



(m, 2H), 2.01 (td, J = 9.1, 4.5 Hz, 2H), 1.88 (d, J = 13.1 Hz, 2H), 1.66 (s, 2H),



1.58-1.39 (m, 2H)


830
(400 MHz, pyridine-d5) δ ppm 8.86-8.78 (m, 2H), 7.75 (s, 1H), 7.49-7.41 (m,



2H), 7.19 (tt, J = 7.1, 1.2 Hz, 1H), 4.06 (t, J = 8.3 Hz, 1H), 3.49 (d, J = 12.2 Hz,



2H), 2.79 ?



2H), 2.04-1.91 (m, 2H), 1.86 (dd, J = 13.3, 8.7 Hz, 4H), 1.69- 1.61 (m, 3H),



1.43 (qd, J = 11.9, 3.7 Hz, 2H)


831
(400 MHz, pyridine-d5) δ ppm 8.84-8.77 (m, 2H), 7.68 (s, 1H), 7.45 (dd, J = 8.6,



7.3 Hz, 2H), 7.19 (td, J = 7.3, 1.2 Hz, 1H), 4.10 (s, 1H), 4.00 (q, J = 8.3 Hz, 1H),



3.74 (d, J = 8.7 Hz, 2H), 3.44 (d, J = 12.3 Hz, 2H), 3.33 (d, J = 5.1 Hz, 2H), 3.22



(s, 3H), 3.02 (d, J = 7.1 Hz, 1H), 2.90 (d, J = 6.5 Hz, 2H), 2.68 (dd, J = 11.9, 9.5



Hz, 4H), 2.46-2.32 (m, 2H), 2.09-1.96 (m, 2H), 1.90 (d, J = 13.3 Hz, 3H), 1.63-



1.45 (m, 2H)


832
(400 MHz, pyridine-d5) δ ppm 8.86 (d, J = 18.7 Hz, 2H), 7.75 (s, 1H), 7.26-7.16



(m, 2H), 4.07 (p, J = 8.2 Hz, 1H), 3.50 (s, 1H), 3.00-2.90 (dddd, 1H), 2.83-2.60



(m, 6H), 2.38 (d, J = 30.3 Hz, 2H), 1.99 (dd, J = 8.8, 5.5 Hz, 4H), 1.60 (d, J = 7.5



Hz, 1H), 1.45 (q, J = 10.6 Hz, 2H)


833
(400 MHz, pyridine-d5) δ ppm 8.93-8.85 (m, 2H), 7.81 (s, 1H), 7.56-7.47 (m,



2H), 7.36-7.23 (m, 2H), 4.13 (t, J = 8.3 Hz, 1H), 3.55 (d, J = 11.9 Hz, 2H), 3.01



(dd, J = 26.2, 11.4 Hz, 1H), 2.90-2.80 (m, 1H), 2.74 (dd, J = 19.9, 9.5 Hz, 5H),



2.54-2.42 (m, 2H), 2.39 (d, J = 7.2 Hz, 2H), 2.16- 1.88 (m, 6H), 1.78-1.60 (m,



1H), 1.53 (dd, J = 12.5, 9.0 Hz, 2H)


834
(400 MHz, pyridine-d5) δ ppm 8.87-8.79 (m, 2H), 7.76 (s, 1H), 7.47-7.40 (m,



2H), 7.23-7.18 (m, 1H), 4.09 (m, 1H), 3.78 (d, J = 1.1 Hz, 4H), 3.52 (d, J = 12.2



Hz, 2H), 2.75 (s, 8H), 2.44 (d, J = 7.2 Hz, 4H), 2.04 (m, 1H), 2.02-1.85 (m, 5H),



1.66 (s, 1H), 1.47 (q, J = 10.5 Hz, 2H)


835
(400 MHz, pyridine-d5) δ ppm 8.88 (s, 2H), 7.73 (s, 1H), 7.45 (dd, J = 8.6, 7.4 Hz,



2H), 7.20 (d, J = 7.5 Hz, 1H), 6.17 (tt, J = 55.2, 3.8 Hz, 1H), 4.28 (t, J = 5.8 Hz,



1H), 4.04 (q, J = 8.3 Hz, 1H), 3.79- 3.56 (m, 4H), 3.46 (d, J = 12.3 Hz, 2H), 3.13



(t, J = 7.0 Hz, 2H), 2.69 (s, 4H), 2.52-2.38 (m, 4H), 2.12- 1.93 (m, 2H), 1.85 (d,



J = 11.4 Hz, 2H), 1.49 (d, J = 9.6 Hz, 3H)


836
(400 MHz, pyridine-d5) δ ppm 8.92-8.78 (m, 2H), 7.72 (s, 1H), 7.45 (dd, J = 8.6,



7.3 Hz, 2H), 7.19 (t, J = 7.4 Hz, 2H), 4.11-3.94 (m, 1H), 3.76 (d, J = 6.1 Hz, 2H),



3.68-3.34 (m, 7H), 2.70 (d, J = 12.0 Hz, 5H), 2.43 (d, J = 10.0 Hz, 2H), 2.06-



1.95 (m, 2H), 1.90 (d, J = 12.9 Hz, 2H), 1.73 (m, 3H), 1.52 (d, J = 11.9 Hz, 2H),



1.38 (m, 2H)


837
(400 MHz, pyridine-d5) δ ppm 8.84-8.80 (m, 2H), 7.72 (d, J = 9.9 Hz, 1H), 7.45



(dd, J = 8.5, 7.3 Hz, 2H), 7.20 (t, J = 7.2 Hz, 1H), 4.07 (q, J = 8.4 Hz, 1H), 3.89 (s,



2H), 3.71 (t, J = 7.0 Hz, 2H), 3.56-3.43 (m, 2H), 3.29 (s, 4H), 2.70 (q, J = 11.9,



10.8 Hz, 4H), 2.42 (m, 4H), 2.02 (s, 1H), 1.98 (m, 1H), 1.88 (d, J = 11.2 Hz, 2H),



1.48 (dd, J = 23.1, 10.6 Hz, 3H), 1.23 (dd, J = 12.4, 9.1 Hz, 1H)


838
(400 MHz, pyridine-d5) δ ppm 8.83 (d, J = 1.3 Hz, 2H), 7.75 (s, 1H), 7.48-7.41



(m, 2H), 7.23-7.16 (m, 1H), 5.21-5.00 (m, 1H), 4.08 (p, J = 8.3 Hz, 1H), 3.53



(d, 2H), 3.36-3.24 (m, 1H), 3.22 (d, 1H), 2.97 m, 2H), 2.74 (dd, J = 30.1, 11.4



Hz, 4H), 2.44-2.18 (m, 6H), 2.16- 1.91 (m, 4H), 1.99 (m,4H), 1.78 (d, J = 11.4



Hz, 2H), 1.50 (d, J = 11.2 Hz, 2H)


839
(400 MHz, pyridine-d5) δ ppm 8.83 (dt, J = 8.7, 1.3 Hz, 2H), 8.25 (d, J = 12.3 Hz,



1H), 7.75 (d, J = 2.8 Hz, 1H), 7.45 (dt, J = 7.2, 1.7 Hz, 2H), 7.25-7.21 (m, 1H),



4.08 (td, J = 8.3, 3.3 Hz, 1H), 3.68-3.60 (m, 1H), 3.59-3.52 (m, 2H), 3.49 (s,



1H), 3.43-3.33 (m, 1H), 3.27 (t, J = 6.0 Hz, 1H), 2.77-2.67 (m, 4H), 2.57 (m,



3H), 2.35 (dd, J = 12.4, 7.0 Hz, 2H), 2.07-1.96 (m, 2H), 1.85 (d, J = 12.9 Hz,



2H), 1.75 (d, J = 28.2 Hz, 1H), 1.43 (d, J = 11.5 Hz, 2H)


840
(400 MHz, pyridine-d5) δ ppm 8.91-8.82 (m, 2H), 7.76 (s, 1H), 7.51 (m, 2H),



7.31 (s, 1H), 4.4 (s, 4H), 4.09 (d, J = 8.4 Hz, 1H), 3.54 (d, J = 6.6 Hz, 2H), 2.75 (t,



J = 12.9 Hz, 4H), 2.43 (m, 2H), 2.24 (m, 6H), 2.01 (d, 2H), 1.89- 1.74 (m, 5H),



1.64-1.37 (m, 2H), 1.21 (d, J = 7.8 Hz, 1H)


841
(400 MHz, pyridine-d5) δ ppm 8.89-8.77 (m, 2H), 7.73 (s, 1H), 7.45 (dd, J = 8.6,



7.4 Hz, 2H), 7.19 (t, J = 7.4 Hz, 2H), 4.06 (m, 1H), 3.50 (d, J = 12.2 Hz, 2H), 3.21



(s, 4H), 2.89 (bs, 2H), 2.77-2.66 (m, 3H), 2.45 (m, 6H), 1.96 (s, 6H), 1.75 (m,



3H), 1.59-1.43 (m, 2H)


842
(400 MHz, pyridine-d5) δ ppm 8.81 (ddt, J = 7.0, 4.1, 1.1 Hz, 2H), 7.70 (s, 1H),



7.45 (ddt, J = 9.0, 7.3, 1.9 Hz, 2H), 7.19 (tt, J = 7.2, 1.2 Hz, 1H), 4.68 (d, J = 6.0



Hz, 2H), 4.59 (d, J = 6.0 Hz, 2H), 4.09-3.99 (m, 2H), 3.64 (bs, 1H), 3.48 (t, J =



14.0 Hz, 2H), 3.14(s, 2H), 2.89-2.59 (m, 6H), 2.51-2.34 (m,2H), 2.17 (dt, J =



21.4, 7.1 Hz, 2H), 2.01 (ddd, J = 19.3, 14.6, 9.0 Hz, 4H), 1.8 (bs, 1H), 1.69-1.46



(m, 2H)


843
(400 MHz, pyridine-d5) δ ppm 8.87-8.79 (m, 2H), 7.76 (s, 1H), 7.49-7.43 (m,



2H), 7.20 (tt, J = 7.5, 1.2 Hz, 1H), 4.08 (t, J = 8.3 Hz, 1H), 3.61 (t, J = 5.1 Hz, 2H),



3.57-3.48 (m, 2H), 3.26 (t, J = 5.0 Hz, 2H), 2.81 ?



2.27 (dt, J = 8.0, 5.0 Hz, 4H), 2.14 (d, J = 7.2 Hz, 2H), 2.06-1.95 (m, 2H), 1.85



(d, J = 12.6 Hz, 2H), 1.65 (m, 1H), 1.53-1.32 (m, 2H)


844
(400 MHz, pyridine-d5) δ ppm 8.85-8.78 (m, 2H), 7.73 (s, 1H), 7.48-7.41 (m,



2H), 7.19 (tt, J = 7.3, 1.2 Hz, 1H), 4.05 (p, J = 8.3 Hz, 1H), 3.47 (d, J = 12.2 Hz,



2H), 3.19 (s, 2H), 2.75-2.61 (m, 4H), 2.50-2.3 (m, 5H), 2.00 (tt, J = 7.9, 5.9



Hz, 2H), 1.86 (d, J = 12.8 Hz, 2H), 1.65 (s, 1H), 1.51-1.37 (m, 2H), 1.33 (d, J =



7.1 Hz, 2H), 0.91 (d, J = 4.4 Hz, 1H), 0.36 (td, J = 7.8, 4.4 Hz, 1H)


845
(400 MHz, pyridine-d5) δ ppm 8.89-8.75 (m, 2H), 7.77 (s, 1H), 7.46 (dd, J = 8.6,



7.3 Hz, 2H), 7.23-7.18 (m, 2H), 4.86 (d, J = 7.1 Hz, 2H), 4.48 (d, J = 7.0 Hz,



2H), 4.17-3.97 (m, 1H), 3.50 (d, J = 12.2 Hz, 2H), 3.22 (d, J = 20.7 Hz, 5H), 2.90



(s, 2H), 2.72 (d, J = 11.5 Hz, 4H), 2.44 (d, J = 8.9 Hz, 2H), 2.20 (d, J = 7.2 Hz,



2H), 2.06-1.95 (m, 2H), 1.84 (d, J = 12.9 Hz, 2H), 1.67 (bs, 1H), 1.53-1.35 (m,



2H), 1.39 (m, 1H)


846
(300 MHz, DMSO-d6) δ ppm 8.17 (dd, J = 9.1, 5.0 Hz, 2 H), 7.23 (t, J = 8.8 Hz, 2



H), 7.13 (s, 1 H), 5.14 (br. s., 0.5 H), 4.95 (br. s., 0.5 H), 3.68-3.88 (m, 1 H), 3.34



(d, J = 12.0 Hz, 4 H), 2.66-2.87 (m, 4 H), 2.57 (d, J = 11.7 Hz, 1 H), 2.42-2.53 (m,



1 H), 2.05-2.29 (m, 4 H), 1.60-2.02 (m, 5 H), 1.50 (d, J = 10.3 Hz, 2 H)


847
(400 MHz, DMSO-d6) δ ppm 8.21-8.43 (m, 2 H), 7.35-7.46 (m, 2 H), 7.31 (s, 1



H), 3.95 (quin, J = 8.3 Hz, 1 H), 3.41-3.58 (m, 5 H), 3.17-3.38 (m, 4 H), 2.95 (t,



J = 10.2 Hz, 2 H), 2.26-2.44 (m, 3 H), 2.02-2.16 (m, 1 H), 1.91-2.01 (m, 1H),



1.85 (d, J = 10.6 Hz, 2 H), 1.43 (q, J = 9.3 Hz, 2 H)


848
(400 MHz, DMSO-d6) δ ppm 8.24-8.41 (m, 2 H), 7.30-7.45 (m, 2 H), 7.30 (s, 1



H), 3.82-4.05 (m, 3 H), 3.53 (br. s., 2 H), 3.20 (s, 3 H), 2.83-2.99 (m, 3 H), 2.76



(q, J = 7.5 Hz, 1 H), 2.57-2.70 (m, 2 H), 2.28-2.45 (m, 4 H), 1.88-2.13 (m, 5 H),



1.61-1.77 (m, 3 H)


849
(400 MHz, DMSO-d6) δ ppm 8.28-8.41 (m, 2 H), 7.34-7.50 (m, 2 H), 7.30 (s, 1



H), 4.76 (dt, J = 7.0, 3.5 Hz, 0.5 H), 4.63 (dt, J = 7.0, 3.4 Hz, 0.5 H), 3.98 (quin,



J = 8.3 Hz, 1 H), 3.59 (d, J = 11.9 Hz, 3 H), 2.90 (t, J = 11.6 Hz, 2 H), 2.76 (br. s., 2



H), 2.47-2.54 (m, 3 H), 2.31-2.46 (m, 3H), 1.99-2.15 (m, 1 H), 1.81-1.99(m,



5 H), 1.56-1.79 (m, 4 H)


850
(400 MHz, DMSO-d6) δ ppm 8.22-8.43 (m, 2 H), 7.35-7.49 (m, 2 H), 7.30 (s, 1



H), 3.98 (t, J = 8.3 Hz, 1 H), 3.59 (d, J = 11.9 Hz, 2 H), 2.91 (t, J = 11.5 Hz, 2 H),



2.64-2.74 (m, 4 H), 2.55-2.64 (m, 1 H), 2.45 (m, 1 H), 2.32-2.44 (m, 2 H), 2.03-



2.15 (m, 2 H), 1.87-2.01 (m, 7 H), 1.63-1.81 (m, 2 H)


851
(400 MHz, DMSO-d6) δ ppm 8.25-8.42 (m, 2 H), 7.35-7.50 (m, 2 H), 7.31 (s, 1



H), 4.99 (t, J = 3.2 Hz, 1 H), 3.98 (t, J = 8.3 Hz, 1 H), 3.74-3.88 (m, 2 H), 3.49-



3.67(m, 3 H), 2.86-3.01 (m, 4 H), 2.77 (d, J = 11.6 Hz, 1 H), 2.69 (dd, J = 12.0, 3.2



Hz, 1 H), 2.32-2.49 (m, 3 H), 2.00-2.14 (m, 1 H), 1.98 (d, J = 8.5 Hz, 3 H), 1.57-



1.80 (m, 3 H)


853
(400 MHz, DMSO-d6) δ ppm 8.26-8.43 (m, 2 H), 7.41 (t, J = 8.9 Hz, 2 H), 7.30 (s,



1 H), 3.98 (s, 1 H), 3.75-3.86 (m, 1 H), 3.58 (d, J = 10.4 Hz, 4 H), 3.50 (d, J = 1.9



Hz, 2 H), 3.28-3.40 (m, 4 H), 2.89 (d, J = 11.1 Hz, 3 H), 2.74-2.84 (m, 1 H), 2.33-



2.47 (m, 4H), 2.17-2.29 (m, 1 H), 1.89-2.12 (m, 5 H), 1.52-1.76 (m, 2 H)


854
(400 MHz, DMSO-d6) δ ppm 8.28-8.42 (m, 2 H), 7.34-7.47 (m, 2 H), 7.28 (s, 1



H), 3.98 (t, J = 8.4 Hz, 1 H), 3.89 (dd, J = 10.9, 3.4 Hz, 2 H), 3.48-3.63 (m, 2 H),



3.32 (t, J = 11.0 Hz, 3 H), 2.80-3.01 (m, 4 H), 2.35-2.47 (m, 3 H), 2.30 (s, 3 H),



1.87-2.10 (m, 4 H), 1.64-1.84 (m, 4 H), 1.46-1.60 (m, 2 H)


855
(300 MHz, CDCl3) δ ppm 8.29 (d, J = 5.9 Hz, 1 H), 7.88 (dd, J = 5.9, 1.8 Hz, 1 H),



7.63 (d, J = 1.8 Hz, 1 H), 7.56 (s, 1 H), 5.42 (quin, J = 6.1 Hz, 1 H), 3.91-4.06 (m,



1H), 3.86 (br. s., 4 H), 3.76 (d, J = 13.2 Hz, 2 H), 3.03 (t, J = 11.6 Hz, 2 H), 2.75 (br.



s., 4 H), 2.55-2.69 (m, 3 H), 2.37-2.53 (m, 2 H), 2.02-2.22 (m, 4 H), 1.75-1.96



(m, 2 H), 1.44 (d, J = 6.2 Hz, 6 H)


856
(400 MHz, CDCl3) δ ppm 8.31 (d, J = 5.9 Hz, 1 H), 7.91 (dd, J = 5.7, 1.8 Hz, 1 H),



7.72 (d, J = 1.7 Hz, 1 H), 7.48-7.57 (m, 3 H), 7.33-7.46 (m, 3 H), 5.49 (s, 2 H),



3.97 (t, J = 8.3 Hz, 1 H), 3.75-3.86 (m, 5 H), 3.66 (br. s., 1 H), 3.01 (t, J = 12.7 Hz,



1 H), 2.54-2.72 (m, 6 H), 2.33-2.52 (m, 4 H), 1.99-2.20 (m, 6 H)


861
(400 MHz, CDCl3) δ ppm 8.33 (s, 1H-NH), 7.83 (s, 1H), 7.78 (d, 2H), 7.46 (d,



2H), 5.02 (septet, 1H), 4.91-4.95 (m, 1H), 3.36-3.41 (m, 2H), 2.84 (s, 2H), 2.76 (s,



6H), 2.36-2.40 (m, 1H), 2.14-2.17 (m, 2H), 1.87-2.05 (m, 7H), 1.71-1.74 (m, 3H),



1.45-1.50 (m, 2H), 1.28 (d, 6H). Note: HNMR of zwitterion


862
(400 MHz, CDCl3) δ ppm 8.17-8.35 (m, 2 H), 7.46 (s, 1 H), 7.03-7.25 (m, 2 H),



4.01-4.19 (m, 2 H), 3.95 (quin, J = 8.4 Hz, 1 H), 3.50-3.67 (m, 1 H), 3.30-3.46



(m, 2 H), 3.01-3.28 (m, 6 H), 2.47-2.60 (m, 2 H), 2.27-2.38 (m, 3 H), 2.17 (dd,



J = 13.0, 9.4 Hz, 2H), 1.90-2.11 (m, 8H), 1.73-1.86 (m, 1 H)


869
(400 MHz, CDCl3) δ ppm 7.92-8.09 (m, 2 H), 7.42-7.52 (m, 1 H), 7.12-7.34



(m, 2 H), 4.01 (quin, J = 8.4 Hz, 1 H), 3.69 (d, J = 12.5 Hz, 2 H), 3.09-3.21 (m, 1



H), 2.85-3.09 (m, 4 H), 2.54-2.71 (m, 4 H), 2.28-2.49 (m, 3 H), 1.97-2.24 (m,



6 H), 1.73-1.97 (m, 2 H)


870
(400 MHz, CDCl3) δ ppm 7.94-8.08 (m, 2 H), 7.49 (s, 1 H), 7.16-7.33 (m, 2 H),



4.00 (t, J = 8.4 Hz, 1 H), 3.69 (d, J = 12.7 Hz, 2 H), 2.98-3.19 (m, 4 H), 2.75-2.94



(m, 3 H), 2.56-2.70 (m, 2 H), 2.38-2.52 (m, 3 H), 2.27-2.36 (m, 1 H), 2.17-



2.25 (m, 1 H), 2.02-2.16 (m, 4 H), 1.78-1.97 (m, 2 H)


871
(300 MHz, CDCl3) δ ppm 7.80-8.02 (m, 2 H), 7.34-7.46 (m, 1 H), 7.01-7.25



(m, 2 H), 3.90 (quin, J = 8.3 Hz, 1 H), 3.67 (d, J = 12.8 Hz, 2 H), 2.83-3.00 (m, 3



H), 2.70-2.79 (m, 1 H), 2.61-2.70 (m, 2 H), 2.43-2.59 (m, 4 H), 2.38 (dd, J = 7.9,



4.2 Hz, 2 H), 1.42-2.12 (m, 10H)


872
(300 MHz, CDCl3) δ ppm 7.93 (dd, J = 9.0, 5.0 Hz, 2 H), 7.39 (s, 1 H), 7.04-7.25



(m, 2 H), 4.64-4.78 (m, 1 H), 4.45-4.60 (m, 1 H), 3.82-4.01 (m, 1 H), 3.57-



3.75 (m, 2 H), 2.90 (br. s., 3 H), 2.26-2.68 (m, 8 H), 1.91-2.12 (m, 4 H), 1.70-



1.86 (m, 3 H), 1.41-1.66 (m, 2 H)


873
(400 MHz, CDCl3) δ ppm 7.93-8.14 (m, 2 H), 7.39-7.50 (m, 1 H), 7.19 (t, J = 8.6



Hz, 2H), 4.11-4.24 (m, 1 H), 3.86-4.05 (m, 3 H), 3.66 (d, J = 12.7 Hz, 2H), 3.31



(s, 3 H), 3.06-3.22 (m, 2 H), 2.91-3.05 (m, 2 H), 2.50-2.69 (m, 3 H), 2.29-2.45



(m, 2 H), 1.93-2.21 (m, 6 H)


874
(400 MHz, CDCl3) δ ppm 7.93-8.13 (m, 2 H), 7.48 (s, 1 H), 7.19-7.35 (m, 2 H),



3.99 (t, J = 8.3 Hz, 1 H), 3.76 (d, J = 12.5 Hz, 2 H), 3.25 (d, J = 10.3 Hz,



1 H), 3.10 (d, J = 10.5 Hz, 1 H), 2.99 (t, J = 12.0 Hz, 2 H), 2.55-2.70



(m, 3 H), 2.45 (dtd, J = 11.9, 8.0, 8.0, 3.7 Hz, 3 H), 2.26 (q, J = 11.2 Hz, 2 H),



1.97-2.16 (m, 5 H), 1.79-1.94



(m, 3 H), 1.68 (d, J = 12.7 Hz, 1 H), 1.32-1.38 (m, 1 H)


875
(400 MHz, CDCl3) δ ppm 8.00-8.24 (m, 2 H), 7.47 (s, 1 H), 7.18 (t, J = 8.6 Hz, 2



H), 3.98 (t, J = 8.3 Hz, 1 H), 3.73 (d, J = 12.0 Hz, 2 H), 3.51-3.63 (m, 1 H), 3.44 (s,



3 H), 3.31 (d, J = 7.3 Hz, 1 H), 3.08 (br. s., 1 H), 2.83-3.03 (m, 3 H), 2.61 (quin,



J = 9.0 Hz, 2 H), 2.31-2.52 (m, 4 H), 2.00-2.20 (m, 5 H), 1.85-1.99 (m, 3 H),



1.78 (d, J = 10.3 Hz, 1H), 1.28-1.35 (m, 1H)


876
(400 MHz, CDCl3) δ ppm 7.95-8.06 (m, 2 H), 7.48 (s, 1 H), 7.10-7.31 (m, 2 H),



3.99 (quin, J = 8.3 Hz, 1 H), 3.77-3.85 (m, 2 H), 3.74 (d, J = 12.5 Hz, 2 H), 3.02 (t,



J = 11.2 Hz, 2 H), 2.55-2.71 (m, 4 H), 2.33-2.52 (m, 5H), 1.96-2.20 (m, 4 H),



1.82 (q, J = 10.6 Hz, 2 H), 1.21-1.35 (m, 6 H)


884
(400 MHz, CDCl3) δ ppm 7.90 (s, 1H), 7.74 (d, 2H), 7.50 (d, 2H), 5.01 (septet,



1H), 4.85-4.93 (m, 1H), 3.86 (br s, 2H), 2.77-3.03 (m, 8H), 1.74-2.05 (m, 9H),



1.45-1.58 (m, 2H), 1.23-1.38 (m, 1H), 1.30 (d, 6H), 0.54-0.70 (m, 4H),



zwitterionic proton not observed. Note: HNMR of zwitterion


885
(400 MHz, CDCl3) δ ppm 7.83 (dd, J = 7.3, 2.2 Hz, 1 H), 7.76 (d, J = 2.0 Hz, 1 H),



7.45 (s, 1 H), 7.41 (d, J = 7.3 Hz, 1 H), 3.95 (t, J = 8.3 Hz, 1 H), 3.75-3.81 (m, 4 H),



3.64 (d, J = 12.7 Hz, 2 H), 2.87-2.97 (m, 2 H), 2.62-2.67 (m, 4 H), 2.51-2.60 (m,



2 H), 2.32-2.46 (m, 4H), 2.00-2.12(m, 4H), 1.70-1.85 (m, 2H)


886
(400 MHz, DMSO-d6) δ ppm 8.37-8.32 (m, 2H), 7.44-7.39 (m, 2H), 7.32 (s, 1H),



4.01-3.93 (m, 1H), 3.63-3.57 (m, 2H), 2.96-2.90 (m, 2H), 2.77-2.60 (m, 9H), 2.52-



2.40 (m, 3H), 2.11-1.94 (m, 5H), 1.79-1.69 (m, 3H), 0.47-0.42 (m, 2H), 0.35-0.31



(m, 2H)


888
(400 MHz, DMSO-d6) δ ppm 8.38-8.34 (m, 2H), 7.41-7.36 (m, 2H), 7.27 (s, 1H),



4.00-3.91 (m, 1H), 3.54-3.48 (m, 2H), 2.87-2.75 (m, 5H), 2.67-2.63 (m, 2H),



2.52-2.32 (m, 5H), 2.05-1.91 (m, 4H), 1.85-1.78 (m, 5H), 1.51-1.39 (m, 2H)


889
(400 MHz, CDCl3) δ ppm 8.23 (d, J = 4.6 Hz, 2 H), 7.50 (s, 1 H), 7.54 (s, 1 H),



3.83-4.04 (m, 6 H), 3.74 (d, J = 11.5 Hz, 2 H), 3.03 (br. s., 2 H), 2.85 (br. s., 4 H),



2.50-2.73 (m, 3 H), 2.42 (d, J = 8.1 Hz, 2 H), 2.18 (d, J = 12.2 Hz, 2 H),



2.03-2.13 (m, 2H), 1.93 (br. s., 2 H)


891
(400 MHz, CDCl3) δ ppm 7.91-8.09 (m, 2 H), 7.48 (s, 1 H), 7.12-7.34 (m, 2 H),



4.18 (q, J = 7.1 Hz, 2 H), 3.99 (quin, J = 8.4 Hz, 1 H), 3.75 (d, J = 12.5 Hz, 2 H),



3.57 (br. s., 4 H), 2.99 (t, J = 11.6 Hz, 2 H), 2.57-2.75 (m, 6 H), 2.36-2.57 (m, 3 H),



2.00-2.18 (m, 4 H), 1.75-1.93 (m, 2 H), 1.16-1.37 (m, 3 H)


892
(400 MHz, CDCl3) δ ppm 12.29 (1H, s), 7.94 (2H, m), 7.37 (1H, s), 7.16 (2H, m),



3.89 (1H,m), 3.80 (2H,d), 3.65 (1H,$), 3.35 (6H, s), 3.19 (2H,m), 3.03 (2H,m),



2.56 (6H,m), 2.50 (2H,m), 2.12 (6H, m)


894
(400 MHz, DMSO-d6) δ ppm 13.36 (br s, 1H), 10.36 (br s, 1H), 8.38-8.32 (m, 2H),



7.46-7.39 (m, 2H), 7.35 (s, 1H), 4.02-3.93 (m, 1H), 3.74-3.64 (m, 1H), 3.27-3.16



(m, 6H), 2.94-2.82 (m, 2H), 2.56-2.26 (m, 5H), 2.20-1.84 (m, 9H), 1.79-1.61 (m,



6H)


895
(400 MHz, CDCl3) δ ppm 8.10 (br. s., 2 H), 7.49 (s, 1 H), 7.19 (t, J = 7.5 Hz, 2 H),



4.00 (quin, J = 8.4 Hz,1 H), 3.75 (d, J = 11.5 Hz, 2 H), 3.56-3.69 (m, 2 H), 3.41 (s, 3



H), 2.84-3.09 (m, 5 H), 2.52-2.71 (m, 5 H), 2.45 (dd, J = 7 .7 , 4.3 Hz, 2 H), 2.00-



2.19(m, 4 H), 1.78-1.97(m, 2 H)


896
(400 MHz, DMSO-d6) δ ppm 8.37-8.33 (m, 2H), 7.47-7.42 (m, 2H), 7.35 (s, 1H),



4.03-3.90 (m, 1H), 3.91-3.36 (m, 12H), 3.50-3.30 (m, 6H), 3.00-2.95 (m, 2H),



2.54-1.91 (m, 10H)


897
(400 MHz, DMSO-d6) δ ppm 13.37 (br s, 1H), 9.98 (br s, 1H), 8.38-8.32 (m, 2H),



7.47-7.39 (m, 2H), 7.33 (s, 1H), 4.01-3.92 (m, 1H), 3.74-3.70 (m, 2H), 3.40-3.20



(m, 11H), 3.16-3.07 (m, 2H), 2.56-2.36 (m, 3H), 2.19-1.83 (m, 7H), 1.79-1.61 (m,



4H)


900
(400 MHz, DMSO-d6) δ ppm 8.23-8.45 (m, 2 H), 7.39 (t, J = 8.9 Hz, 2 H), 7.30 (s,



1 H), 3.98 (quin, J = 8.2 Hz, 1 H), 3.05-3.19 (m, 4 H), 2.84 (d, J = 6.7 Hz, 1 H),



2.47-2.54 (m, 3 H), 2.31 -2.46 (m, 3 H), 2.02-2.14 (m, 3 H), 1.80-2.00 (m, 4



H), 1.60 (d, J = 5.8 Hz, 1 H), 1.17 (d, J = 6.3 Hz, 3 H), 1.06 (d, J = 6.1 Hz, 3 H)


901
(400 MHz, DMSO-d6) δ ppm 8.28-8.44 (m, 2 H), 7.40 (t, J = 8.6 Hz, 2 H), 7.29 (s,



1 H), 3.96-4.00 ( t, 1 H), 2.91-3.14(m, 4H), 2.77 (br. s, 1 H), 2.29-2.46 (m, 5



H), 1.99-2.16 (m, 7 H), 1.96 (br. s., 5 H), 1.67 (br. s., 2 H), 1.43 (br. s, 1 H)


902
(400 MHz, CDCl3) δ ppm 7.89-8.13 (m, 2 H), 7.47 (s, 1 H), 7.02-7.35 (m, 2 H),



4.60-5.09 (m, 4 H), 4.05-4.32 (m, 1 H), 3.94 (quin, J = 8.4 Hz, 1 H), 3.67 (br. s., 1



H), 3.50 (d, J = 4.1 Hz, 3 H), 3.34 (br. s., 2 H), 2.54-2.74 (m, 3 H), 2.44 (dtd,



J = 11.3, 7.7, 7.7, 3.9 Hz, 3 H), 1.75-2.20 (m, 6 H)


903
(400 MHz, DMSO-d6) δ ppm 8.23-8.41 (m, 2 H), 7.40 (t, J = 8.9 Hz, 2 H), 7.28 (s,



1 H), 3.99 (s, 1 H), 3.77-3.91 (m, 2 H), 3.01-3.25 (m, 7 H), 2.68-2.96 (m, 4 H),



2.29-2.46 (m, 3 H), 1.37-2.13 (m, 11 H)


904
(400 MHz, DMSO-d6) δ ppm 8.38-8.34 (m, 2H), 7.43-7.37 (m, 2H), 7.31 (s, 1H),



4.54-4.50 (m, 2H), 4.44-4.40 (m, 2H), 4.00-3.91 (m, 1H), 3.44-3.39 (m, 2H), 3.20-



3.16 (m, 4H), 2.47-2.38 (m, 3H), 2.26-2.18 (m, 4H), 2.11-1.93 (m, 2H), 1.70-1.62



(m, 4H), 1.60-1.51 (m, 4H)


905
(400 MHz, pyridine-d5) δ ppm 8.70 (d, J = 2.3 Hz, 2H), 7.77 (s, 1H), 6.88 (d, J =



2.4 Hz, 1H), 4.03 (p, J = 8.3 Hz, 1H), 3.75 (t, J = 4.6 Hz, 4H), 3.52 (d, J = 12.4 Hz,



2H), 2.77 (dd, J = 12.8, 10.6 Hz, 2H), 2.71-2.58 (m, 2H), 2.54 (s, 4H), 2.43 (s,



3H), 2.28 (m, 1H), 2.07- 1.97 (m, 2H), 1.94 (d, J = 12.6 Hz, 2H), 1.79- 1.70 (m,



2H)


906
(400 MHz, pyridine-d5) δ ppm 8.72 (d, J = 2.1 Hz, 1H), 8.53 (dd, J = 8.8, 2.2 Hz,



1H), 7.76 (s, 1H), 7.20 (d, J = 8.8 Hz, 1H), 4.06 (t, J = 8.3 Hz, 1H), 3.76 (t, J = 4.6



Hz, 4H), 3.54 (d, J = 12.3 Hz, 2H), 2.83-2.61 (m, 4H), 2.56 (t, J = 4.6 Hz, 4H),



2.43 (s, 11H), 2.38-2.24 (m, 1H), 2.09-1.92 (m, 4H), 1.85-1.70 (m, 2H)


907
(400 MHz, pyridine-d5) δ ppm 8.86 (ddd, J = 12.7, 7.3, 2.6 Hz, 1H), 8.61 (ddt, J =



8.6, 4.2, 2.0 Hz, 1H), 7.76 (s, 1H), 7.31 (dt, J = 10.3, 8.9 Hz, 1H), 4.06 (t, J = 8.3



Hz, 1H), 3.76 (t, J = 4.6 Hz, 4H), 3.54 (d, J = 12.3 Hz, 2H), 2.83-2.73 (m, 2H),



2.67 (dq, J = 11.6, 9.1 Hz, 2H), 2.56 (t, J = 4.6 Hz, 4H), 2.52 ?



(dd, J = 10.1, 5.9 Hz, 1H), 2.09- 1.99 (m, 2H), 1.95 (d, J = 12.8 Hz, 2H), 1.84-



1.70 (m, 2H)


908
(400 MHz, pyridine-d5) δ ppm 8.81 (dd, J = 7.9, 2.5 Hz, 1H), 8.29 (dd, J = 3.9, 2.5



Hz, 1H), 8.27 (dd, J = 3.9, 2.5 Hz, 1H), 7.76 (s, 1H), 7.29 (dd, J = 11.0, 8.8 Hz,



1H), 4.09 (t, J = 8.3 Hz, 1H), 3.95 (s, 3H), 3.75 (t, J = 4.6 Hz, 4H), 3.55 (d, J =



12.4 Hz, 2H), 2.80-2.66 (m, 4H), 2.54 (s, 4H), 2.43 (s, 6H), 2.29 (t, J = 10.9 Hz,



1H), 2.05-1.90 (m, 4H), 1.82-1.68 (m, 2H)


909
(400 MHz, pyridine-d5) δ ppm 8.91-8.82 (m, 2H), 7.76 (s, 1H), 7.37 (d, J = 8.7



Hz, 2H), 4.07 (p, J = 8.3 Hz, 1H), 3.77 (t, J = 4.6 Hz, 4H), 3.54 (d, J = 12.3 Hz,



2H), 2.82 ?



(m, 1H), 2.10- 1.92 (m, 4H), 1.79 (tt, J = 12.1, 6.1 Hz, 2H)


910
(400 MHz, pyridine-d5) δ ppm 8.88 (s, 1H), 8.86 (t, J = 2.3 Hz, 1H), 8.84-8.72



(m, 1H), 7.75 (s, 1H), 7.44 (t, J = 8.2 Hz, 1H), 7.10 (dd, J = 8.1, 2.5 Hz, 2H), 4.05



(t, J = 8.3 Hz, 1H), 3.75 (t, J = 4.6 Hz, 4H), 3.52 (d, J = 12.3 Hz, 2H), 2.82-2.59



(m, 4H), 2.55 (t, J = 4.7 Hz, 4H), 2.50 ?



1.70 (m, 3H)


911
(400 MHz, pyridine-d5) 68.86 (d, 1H), 8.84-8.72 (m, 1H), 7.74 (s, 1H), 7.34 (s,



1H), 4.11 (d, J = 8.3 Hz, 1H), 3.75 (d, J = 4.8 Hz, 4H), 3.53 (d, 2H), 2.94 (s, 4H),



2.89-2.66 (m, 4H), 2.52 (t, J = 4.6 Hz, 6H), 2.05 (d, J = 6.1 Hz, 1H), 1.98 (m,



4H), 1.75 (dd, J = 23.3, 11.6 Hz, 2H), 1.22 (d, J = 9.2 Hz, 2H)


912
(400 MHz, pyridine-d5) δ ppm 8.70 (dd, J = 13.1, 2.6 Hz, 1H), 8.60 (ddd, J = 8.9,



2.6, 1.5 Hz, 1H), 7.75 (s, 1H), 7.71 (s, 1H), 7.05 (t, J = 9.2 Hz, 1H), 4.07 (t, J = 8.3



Hz, 1H), 3.75 (t, J = 4.6 Hz, 4H), 3.70 (s, 3H), 3.54 (d, J = 12.4 Hz, 2H), 2.82-



2.62 (m, 4H), 2.54 (t, J = 4.6 Hz, 4H), 2.48 ?



2.06-1.90 (m, 4H), 1.82- 1.72 (m, 2H)


913
(400 MHz, pyridine-d5) δ ppm 8.62 (d, J = 2.2 Hz, 1H), 8.44 (dt, J = 10.8, 2.1 Hz,



1H), 8.44 (s, 1H), 7.75 (s, 1H), 7.71 (s, 1H), 6.73 (dt, J = 10.6, 2.4 Hz, 1H), 4.05 (t,



J = 8.3 Hz, 1H), 3.97 (s, 1H), 3.79 (s, 3H), 3.75 (t, J = 4.6 Hz, 4H), 3.52 (d, J =



12.3 Hz, 2H), 2.81-2.60 (m, 4H), 2.54 (t, J = 4.6 Hz, 4H), 2.50-2.39 (m, 4H),



2.34-2.23 (m, 2H), 2.07- 1.90 (m, 4H), 1.82-1.68 (m, 3H)


914
(400 MHz, pyridine-d5) δ ppm 8.84-8.75 (m, 2H), 7.76 (s, 1H), 7.37-7.29 (m,



2H), 7.16 (s, 1H), 4.07 (t, J = 8.4 Hz, 1H), 3.76 (t, J = 4.6 Hz, 4H), 3.54 (d, J =



12.3 Hz, 2H), 2.82-2.62 (m, 4H), 2.56 (t, J = 4.6 Hz, 4H), 2.44 (dq, J = 9.2, 6.8,



5.4 Hz, 2H), 2.40-2.25 (m, 1H), 2.07-1.91 (m, 4H), 1.79 (td, J = 12.0, 11.4, 3.5



Hz, 2H)


915
(400 MHz, pyridine-d5) δ ppm 9.16 (d, J = 2.0 Hz, 1H), 9.01-8.90 (m, 1H), 7.76



(s, 1H), 7.71 (s, 1H), 7.48 (t, J = 7.9 Hz, 1H), 4.07 (d, J = 8.4 Hz, 1H), 3.75 (t, J =



4.6 Hz, 4H), 3.54 (d, J = 12.3 Hz, 2H), 2.82-2.62 (m, 4H), 2.55 (s, 4H), 2.43 (s,



7H), 2.30 (s, 1H), 2.25 (s, 1H), 2.02 (d, J = 18.4 Hz, 3H), 1.94 (d, J = 10.0 Hz,



4H), 1.78 (dd, J = 13.9, 7.7 Hz, 2H)


916
(400 MHz, pyridine-d5) δ ppm 7.84 (ddd, J = 8.9, 5.8, 3.2 Hz, 1H), 7.75 (s, 1H),



7.30 (s, 1H), 7.14 (q, J = 1.0 Hz, 1H), 7.04 (ddt, J = 8.9, 6.7, 3.4 Hz, 1H), 4.07 (t, J =



8.3 Hz, 1H), 3.74 (t, J = 4.6 Hz, 4H), 3.56 (d, 1H), 2.87-2.62 (m, 3H), 2.52 (t, J =



4.6 Hz, 4H), 2.43 (s, 3H), 2.25 (d, J = 11.5 Hz, 1H), 1.79 (m, 2H), 1.81-1.62



(m, 2H)


917
(400 MHz, pyridine-d5) δ ppm 9.57 (d, J = 2.6 Hz, 1H), 8.82 (dd, J = 8.9, 2.7 Hz,



1H), 7.75 (s, 1H), 6.95 (d, J = 9.0 Hz, 1H), 4.73-4.65 (m, 2H), 4.63-4.57 (m,



1H), 3.76 (t, J = 4.6 Hz, 4H), 3.56 (d, J = 12.4 Hz, 3H), 2.83-2.59 (m, 4H), 2.56



(t, J = 4.6 Hz, 6H), 2.43 (m, 7H), 2.26 (s, 2H), 2.08-1.91 (m, 4H), 1.77 (q, J =



11.4 Hz, 2H)


918
(400 MHz, pyridine-d5) δ ppm 8.72 (dd, J = 5.8, 1.9 Hz, 1H), 8.44 (s, 1H), 8.41 (d,



J = 1.8 Hz, 1H), 8.34 (d, J = 5.8 Hz, 1H), 7.77 (s, 1H), 4.03 (p, J = 8.3 Hz, 1H),



3.94 (dt, J = 11.5, 4.4 Hz, 2H), 3.76 (t, J = 4.6 Hz, 4H), 3.49 (ddd, J = 11.7, 9.5,



2.9 Hz, 4H), 2.77 (t, J = 11.7 Hz, 2H), 2.70-2.59 (m, 2H), 2.56 (t, J = 4.6 Hz,



4H), 2.43 (s, 12H), 2.26 (s, 1H), 2.05 (ddt, J = 12.8, 8.5, 5.1 Hz, 4H), 1.95 (d, J =



12.1 Hz, 2H), 1.80 (dtd, J = 17.2, 8.9, 4.0 Hz, 4H)


919
(400 MHz, pyridine-d5) δ ppm 8.70 (dd, J = 5.7, 1.8 Hz, 1H), 8.52-8.42 (m, 1H),



8.36 (d, J = 5.8 Hz, 1H), 7.77 (s, 1H), 4.30 (d, J = 6.5 Hz, 2H), 4.09-3.98 (m,



1H), 3.95-3.87 (m, 2H), 3.75 (t, J = 4.5 Hz, 4H), 3.51 (d, J = 12.3 Hz, 2H), 3.28



(td, J = 11.7, 2.1 Hz, 2H), 2.82-2.60 (m, 4H), 2.54 (s, 4H), 2.43 (s, 12H), 2.28 (d,



J = 10.6 Hz, 1H), 2.26 (s, 1H), 2.06-1.90 (m, 5H), 1.82-1.71 (m, 2H), 1.58 (dd,



J = 11.3, 2.9 Hz, 2H), 1.43-1.32(m, 2H)


920
(400 MHz, pyridine-d5) δ ppm 7.97 (td, J = 8.7, 6.0 Hz, 1H), 7.82 (s, 1H), 7.20-



7.15 (m, 1H), 7.13-7.04 (m, 1H), 4.14 (p, J = 8.4 Hz, 1H), 3.81 (t, J = 4.6 Hz,



4H), 3.61 (d, J = 12.3 Hz, 2H), 2.87-2.66 (m, 4H), 2.61-2.43 (m, 6H), 2.31 (t, J =



10.9 Hz, 1H), 2.09-1.92 (m, 4H), 1.80 (d, J = 11.6 Hz, 2H)


921
(400 MHz, pyridine-d5) δ ppm 8.28 (dd, J = 8.5, 1.1 Hz, 1H), 7.83 (s, 1H), 7.19 (d,



J = 11.9 Hz, 1H), 7.07 (dd, J = 8.0, 1.1 Hz, 1H), 4.12 (p, J = 8.2 Hz, 1H), 3.86-



3.73 (m, 4H), 3.61 (d, J = 12.3 Hz, 2H), 2.89-2.73 (m, 4H), 2.58-2.46 (m, 6H),



2.38-2.27 (m, 1H), 2.14 (s, 2H), 2.09-1.89 (m, 3H), 1.87-1.67 (m, 2H)


923
(300 MHz, CDCl3) δ ppm 7.93 (s, 1 H), 7.74-7.89 (m, 4 H), 5.10 (dt, J = 12.2, 6.2



Hz, 1 H), 4.78 (dt, J = 10.3, 5.1 Hz, 1 H), 1.89-2.10 (m, 7 H), 1.81 (d, J = 12.5 Hz, 1



H), 1.45-1.63 (m, 2 H), 1.34 (d, J = 6.2 Hz, 6 H)


926
(400 MHz, CDCl3) δ ppm 8.04-8.36 (m, 2 H), 6.99-7.19 (m, 1 H), 5.26 (dt,



J = 12.1, 6.2 Hz, 2 H), 4.20 (d, J = 11.2 Hz, 2 H), 3.51 (br. s., 1 H), 3.26-3.40 (m, 3



H), 3.13 (br. s., 4H), 2.98 (t, J = 11.9 Hz, 2H), 2.29 (br. s., 2H), 2.18 (d, J = 9.8 Hz,



2 H), 1.84-2.05 (m, 5 H), 1.19-1.35 (m, 6H)


929

1H NMR (400 MHz, CDCl3) 8 ppm 7.92-8.07 (m, 2 H), 7.49 (s, 1 H), 7.21-7.29




(m, 2 H), 4.23 (q, J = 7.1 Hz, 2 H), 3.99 (t, J = 8.4 Hz, 1 H), 3.71-3.87 (m, 4 H),



3.22-3.40 (m, 4 H), 2.55-2.68 (m, 2 H), 2.36-2.49 (m, 2 H), 1.99-2.19 (m, 2



H), 1.09-1.38 (m, 3 H)


930

IH NMR (400 MHz, CDCl3) 8 ppm 7.96-8.02 (m, 2 H), 7.49 (s, 1 H), 7.22-7.27




(m, 2 H), 4.04-3.92 (m, 3 H), 3.75-3.82 (m, 4 H), 3.28-3.34 (m, 4 H), 2.57-



2.68 (m, 2 H), 2.38-2.48 (m, 2 H), 1.94-2.15 (m, 3 H), 0.97 (d, J = 6.7 Hz, 6 H)









Determination of Biological Activity

Cellular Assays


Measuring CFTR Cell Surface Expression of CFTR-ΔF508 Using PathHunter® U2OS CFTR-ΔF508 Cells


The PathHunter® U2OS CFTR-ΔF508 cell assay (DiscoveRx) measures the expression of CFTR-ΔF508 at the plasma membrane. CFTR-ΔF508 has a folding defect leading to absence of protein at the plasma membrane. This assay is used to evaluate the capacity of compounds to increase the expression of CFTR-ΔF508 at the plasma membrane. The CFTR-ΔF508 is tagged with a ProLink™ peptide which can complement with plasma membrane expressed enzyme acceptor protein (EA-MEM). When both the ProLink™ and EA-MEM acceptor are in close proximity, i.e. both are located at the plasma membrane, a functional enzyme is formed of which the activity can be measured. The amount of CFTR-ΔF508 that can be rescued to the plasma membrane is correlated with the amount of functional enzyme that can be measured.


There are several ways to measure the capacity of compounds to rescue CFTR-ΔF508 to the plasma membrane; either compounds are evaluated on their own and the impact on plasma membrane levels is measured or compounds are evaluated in combination with a co-corrector, i.e. a compound that rescues CFTR-ΔF508 to the plasma membrane but rescue can be enhanced by addition of compounds due to a complementary mode of action.


Activity of Compounds in Combination with Co-Corrector:


For this purpose, PathHunter® U2OS CFTR-ΔF508 cells (DiscoveRx; custom made were cultured in AssayComplete™ U2OS Cell Culture medium (DiscoveRx; 92-0018GK3) as per manufacturer's instructions. For compound testing, cells were seeded in white 384-well plates (Greiner; 781080) at five thousand cells/well in 25 μL AssayComplete™ Cell Plating 5 Reagent (DiscoveRx; 93-0563R5A) and incubated overnight at 37° C., 5% CO2. On day two, 5 μL of test compounds diluted in Cell Plating 5 Reagent were added to the cells with a final dimethyl sulfoxide (DMSO) concentration of 0.1%. In order to measure synergy with a co-corrector (3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid), 3 μM of co-corrector was added along with test compounds. All cell plates contained 3 μM of co-corrector or DMSO as positive and negative controls, respectively. Cells were incubated with compounds for twenty to twenty-four hours at 37° C., 5% CO2. On day three, plates were placed at room temperature for thirty minutes and then 15 μL of substrate (PathHunter® Flash Detection Kit, DiscoveRx; 93-0247) was added per well. After one hour of incubation at room temperature in the dark, the luminescence signal was measured on a plate reader (Envision®, Perkin Elmer). Raw data were normalized to percentage activity values using the equation: 100×(Sample−Negative control)/(Positive control−Negative Control).


Activity of Compounds for their Intrinsic Corrector Capacity:


For this purpose PathHunter® U2OS CFTR-ΔF508 cells (DiscoveRx; custom made as described above) were cultured in AssayComplete™ U2OS Cell Culture medium (DiscoveRx; 92-0018GK3) as per manufacturer's instructions. For compound testing, cells were seeded in white 384-well plates (Greiner; 781080) at five thousand cells/well in 25 μL AssayComplete™ Cell Plating 5 Reagent (DiscoveRx; 93-0563R5A) and incubated overnight at 37° C., 5% CO2. On day two, 5 μL of test compounds diluted in Cell Plating 5 Reagent were added to the cells with a final DMSO concentration of 0.1%. All cell plates contained 3 μM corrector (3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid) or DMSO as positive and negative controls, respectively. Cells were incubated with compounds for twenty to twenty-four hours at 37° C., 5% CO2. On day three, plates were placed at room temperature for thirty minutes and then 15 μL of substrate (PathHunter® Flash Detection Kit, DiscoveRx; 93-0247) was added per well. After one hour of incubation at room temperature in the dark, the luminescence signal was measured on a plate reader (Envision®, Perkin Elmer). Raw data were normalized to percentage activity values using the equation: 100×(Sample−Negative control)/(Positive control−Negative Control).


Activity of Compounds in Presence of Human Serum


To evaluate the impact of plasma protein binding of compounds on their biological activity, the PathHunter® U2OS CFTR-ΔF508 assay was run in the presence of 40% human serum (Sigma; H4522). For this purpose PathHunter® U2OS CFTR-ΔF508 cells (DiscoveRx; custom made) were cultured in AssayComplete™ U2OS Cell Culture medium (DiscoveRx; 92-0018GK3) as per manufacturer's instructions. For compound testing, cells were seeded in white 384-well plates (Greiner; 781080) at five thousand cells/well in 25 μL AssayComplete™ Cell Plating 5 Reagent (DiscoveRx; 93-0563R5A) containing 40% human serum and incubated overnight at 37° C., 5% CO2. On day two, 5 μL of test compounds diluted in Cell Plating 5 Reagent were added to the cells with a final DMSO concentration of 0.1%. All cell plates contained 3 μM corrector (4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid) or DMSO as positive and negative controls respectively. Cells were incubated with compounds for twenty to twenty-four hours at 37° C., 5% CO2. On day three, plates were placed at room temperature for thirty minutes, and then 15 μL of substrate (PathHunter® Flash Detection Kit, DiscoveRx; 93-0247) was added per well. After one hour of incubation at room temperature in the dark, the luminescence signal was measured on a plate reader (Envision®, Perkin Elmer). Raw data were normalized to percentage activity values using the equation: 100×(Sample−Negative control)/(Positive control−Negative Control).


Activity of Compounds in Presence of Human Serum


To evaluate the impact of plasma protein binding of compounds on their biological activity, the PathHunter® U2OS CFTR-ΔF508 was run in the presence of 40% human serum (Sigma; H4522). For this purpose PathHunter® U2OS CFTR-ΔF508 cells (DiscoveRx; custom made) were cultured in AssayComplete™ U2OS Cell Culture medium (DiscoveRx; 92-0018GK3) as per manufacturer's instructions. For compound testing, cells were seeded in white 384-well plates (Greiner; 781080) at five thousand cells/well in 25 μL AssayComplete™ Cell Plating 5 Reagent (DiscoveRx; 93-0563R5A) and incubated overnight at 37° C., 5% CO2. On day two, the medium was replaced with 25 μL of primary human airway epithelial cell air-liquid interface medium or ALI medium, a 50:50 mixture of DMEM (Dulbecco's Modified Eagle Medium, Invitrogen; 41966-029) and LHC Basal Medium (Invitrogen; 12677-019) with additives as described in Table XVII) and containing 40% human serum. One hour later, 5 μL of test compounds diluted in ALI medium were added to the cells with a final DMSO concentration of 0.1%. All cell plates contained 3 μM corrector (4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid) or DMSO as positive and negative controls respectively. Cells were incubated with compounds for twenty to twenty-four hours at 37° C., 5% CO2. On day three, plates were placed at room temperature for thirty minutes and then washed twice with PBS (phosphate buffered saline) followed by the addition of 15 μL of substrate (PathHunter® Flash Detection Kit, DiscoveRx; 93-0247) per well. After one hour of incubation at room temperature in the dark, the luminescence signal was measured on a plate reader (Envision®, Perkin Elmer). Raw data were normalized to percentage activity values using the equation: 100×(Sample−Negative control)/(Positive control−Negative Control).












TABLE XVII






Final





concentration


Ingredient
in medium
Provider
Cat#



















BSA
0.5
mg/mL
Sigma
A7638


bovine pituitary
10
μg/mL
Sigma
P1476


extract


Insulin
0.87
μM
Sigma
I9278


transferrin
0.125
μM
Sigma
T0665


hydrocortisone
0.21
μM
Sigma
H0396


triiodothyronine
0.01
μM
Sigma
T6397


Epinephrine
0.01
μM
Sigma
E4250


epidermal growth
5
ng/mL
Invitrogen
PHG0313


factor










All-trans
  5 × 10−8 M
Sigma
R-2625


retinoic acid











o-Phosphoethanolamine
0.5
μM
Sigma
P-0503


ethanolamine
0.5
μM
Sigma
E0135


zinc sulfate
3.0
μM
Sigma
Z0251


(ZnSO4•7H2O)


pen/strep
100
U/mL
Sigma
15140-122










ferrous sulfate
1.5 × 10−6 M
Sigma
F8048


magnesium chloride
  6 × 10−4 M
Sigma
M2670


hexahydrate


calcium chloride
1.1 × 10−4 M
Fluka
21097


dihydrate


Trace elements:












sodium selenite
30
nM
Sigma
S5261


manganese chloride
1
nM
Sigma
M8054


tetrahydrate


sodium metasilicate
500
nM
Sigma
S5904


nonahydrate


ammonium molybdate
1
nM
Sigma
M1019


tetrahydrate


ammonium metavanadate
5
nM
Sigma
398128


nickel(II)sulfate
1
nM
Fluka
72280


hexahydrate


(Sigma)
(N4882)


tin(II) chloride
0.5
nM
Sigma
243523


dihydrate










Measuring CFTR Cell Surface Levels Using HRP-Tagged AF508-CFTR Expressing CFBE Cells


The HRP-tagged AF508-CFTR cell assay measures the expression of CFTR-ΔF508 at the plasma membrane. CFTR-ΔF508 has a folding defect leading to absence of protein at the plasma membrane. This assay is used to evaluate the capacity of compounds to increase the expression of CFTR-ΔF508 at the plasma membrane. The CFTR-ΔF508 is tagged with HRP (horse radish peroxidase enzyme) within the ECL4 (Extracellular loop 4) of CFTR (Phuan, P.-W. et al. Synergy-based small-molecule screen using a human lung epithelial cell line yields AF508-CFTR correctors that augment VX-809 maximal efficacy. Mol. Pharmacol. 86, 42-51 (2014)). When HRP-tagged AF508-CFTR is present at the plasma membrane, the HRP enzyme activity can be measured. The amount of CFTR-ΔF508 that can be rescued to the plasma membrane is correlated with the amount of functional enzyme that can be measured.


There are several ways to measure the capacity of compounds to rescue CFTR-ΔF508 to the plasma membrane; either compounds are evaluated on their own and the impact on plasma membrane levels is measured or compounds are evaluated in combination with a co-corrector, i.e. a compound that rescues CFTR-ΔF508 to the plasma membrane but rescue can be enhanced by addition of compounds due to a complementary mode of action.


Activity of Compounds in Combination with Co-Corrector:


For this purpose doxycycline-inducible AF508-CFTR-HRP expressing CFBE4lo-cells (obtained from Gergely Lukacs, McGill University) were maintained in MEM (Minimum Essential Medium, Gibco; 31095) supplemented with 10% fetal bovine serum (Hyclone; SV30160.03) under puromycin (3 μg/mL) and G418 selection (0.2 mg/mL). For compound testing, cells were seeded at 4000 cells/well in white 384-well plates (Greiner; 781080) in 50 μL of medium containing 0.5 μg/mL doxycycline and incubated for 68 hours at 37° C., 5% CO2. On day four, 10 μL of test compounds diluted in PBS (phosphate buffered saline) were added to the plates at a final DMSO concentration of 0.1%. In order to measure compound synergy with a co-corrector, 3 μM co-corrector (3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid) was added along with test compounds. All compound plates contained negative controls (DMSO) and positive controls (3 μM co-corrector). Cell plates were incubated at 33° C., 5% CO2 for 20 hours. On day five, the cells were washed five times with phosphate-buffered saline, and HRP activity was assayed by the addition of 50 μL/well of HRP substrate (SuperSignal™ West Pico Chemiluminescent Substrate, Thermo Scientific; 34080). After incubation for 15 minutes in the dark, the chemiluminescence was measured using a plate reader (EnVision®, Perkin Elmer). Raw data were normalized to percentage activity values using the equation: 100×(Sample−Negative control)/(Positive control−Negative Control).









TABLE XVIII







Illustrative EC50 measured by CFTR cell surface


levels using HRP-tagged ΔF508-CFTR expressing


CFBE cells in the presence of a co-corrector.









Compound #
% Activation
EC50 (nM)












1
354.48
1040.5


2
198.6
2970


5
389.8
371


13
363.7
723


15
282.5
2600


17
272.5
1135


20
450.9
371


22
310.95
995.5


26
258.4
1088


32
399.6
1393


36
364.5
3340


40
340.8
392.5


41
301.2
526.9


43
360.8
371


47
390.5
566.6


50
313.2
2125


54
392.6
376.13


60
143.1
>10000


61
253.6
2349


62
349.9
1694.5


63
294.35
3340


64
113.3
>10000


65
258.2
2312


66
131.3
>10000


67
280.35
1256.5


68
274.9
1389


69
366.8
993.2


70
355.6
649


71
126.8
>10000


72
308.1
3340


73
303.9
3251


74
257.2
1484


75
254
1152


76
244.2
430.1


77
343.4
1111


78
132
>10000


79
256.45
5282.9


80
341.92
2932.5


81
398.25
570.45


82
335.65
971.45


83
332.65
1055


84
541.12
734.1


85
504.7
701.9


86
300.25
2552.5


87
148.9
3340


88
453.15
524.75


89
482.05
1238


90
367.15
882.75


91
176.6
3340


92
99.81
>10000


93
379.57
491.23


94
119.4
>10000


95
145.4
3340


96
329.75
1197.5


97
268
1158.8


98
350.65
833.7


99
247.8
1096


100
310
457.25


101
331.65
998.8


102
384
949.3


103
302
694.5


104
308.55
1006.2


105
383.25
878.75


106
237.45
2621.5


107
164.5
3340


108
329.7
752


109
398.15
752


110
397.65
536.5


111
299.8
423.85


112
378.1
2373.5


113
277
1168


114
460.85
1238.9


115
354
1277.5


116
262.7
3340


117
229.45
765.35


118
165.25
3340


119
413.2
624.2


120
231.45
3136.5


121
603.1
758.3


122
311.75
1767


123
267.95
2692


124
371.1
1884.5


125
351.8
1231


126
319.25
837.25


127
401.3
719.15


128
175.85
3340


129
380
390.35


130
430.55
407.38


131
388.7
620.05


132
156.4
3340


133
280.3
3340


134
362.2
556.4


135
355.55
1461.5


136
189.95
3340


137
158.05
3340


138
133.3
>10000


139
104.1
>10000


140
362.05
941.15


141
121.5
>10000


142
135.2
5555


143
246.8
2420


144
338.4
2617.5


145
368.6
850.1


146
134.9
>10000


147
318.9
830.55


148
238.75
3340


149
296
448.95


150
115.3
>10000


151
562.6
643.77


152
253.1
2090.5


153
386.85
1203


154
353.7
747.95


155
399.6
908.75


156
411.55
3163.5


157
621
485.15


158
112.2
>10000


159
415.33
754.8


160
544.87
329.33


161
333.87
794.67


162
399.73
807.87


163
554.5
422.6


164
608.5
375.3


165
533.35
515.3


166
241.5
3260


167
568.2
535


168
379.07
696.9


169
436.5
302.22


170
482.4
503.55


171
450.73
1065.3


172
513.1
480.25


173
380.52
2529.2


174
260.12
2538.5


175
522.6
531.9


176
619.28
448.45


177
606.47
689.27


178
591
458.3


179
548
977.65


180
524.85
686.75


181
397.95
1058.8


182
452.88
365.64


183
469.58
459.58


184
377.4
677.15


185
478.6
519.9


186
378.4
1260


187
522
564.95


188
432.9
498.7


189
590.78
292.3


190
301.85
634.32


191
375.1
481.28


192
439.45
273.5


193
402.32
424.72


194
233.9
1247


195
174.9
3340


196
520.8
596.25


197
445.2
432.45


198
364
1012


199
602.4
917.4


200
594.2
514.07


201
439.85
287.75


202
309.3
608.6


203
361.75
756.25


204
589.7
843.6


205
261.5
818.8


206
661.63
245.77


207
674.35
379.9


208
673.2
646.85


209
411.9
787


210
261
3340


211
289.75
1092.2


212
386.9
1490


213
456.97
382.5


214
323
608.85


215
347.15
915.3


216
431.7
1110


217
342.3
1468


218
380.9
932.5


219
474.5
365.25


220
470.77
369.23


221
645.97
283


222
612.47
268.17


223
484.45
686.6


224
396.65
895.65


225
395.7
901.4


226
352.2
1345.2


227
452.6
339.75


228
475.1
397.1


229
298
1559.6


230
507.3
514.3


231
625.45
569.55


232
380.95
1284.6


233
249.55
3340


234
510.27
367.63


235
403.1
743.15


236
423.62
637.92


237
372.97
324.1


238
613.4
539.75


239
495.85
712.85


240
609.05
515.7


241
259.75
2139.6


242
394.12
338.22


243
402.73
407.5


244
514.48
458.18


245
508.37
626.73


246
457.57
467.03


247
569.07
332.3


248
606.83
421.9


249
596.2
287.7


250
622.03
508.27


251
577.73
352.9


252
630.25
505.05


253
568.13
425


254
417.67
333.07


255
302.97
293.77


256
362.25
2051.5


257
440.2
787.9


258
364.3
918.7


259
673.9
1013.4


260
554.15
516.9


261
519.37
552.93


262
375.95
853.15


263
334.25
1134.5


264
428.47
463.45


265
397.8
1388.5


266
405.3
1048.3


267
498.35
412.25


268
425.68
393.9


269
452.33
390.9


270
430.4
529.05


271
323.5
395.87


272
319.6
3340


273
311.05
985.3


274
301.45
901.9


275
371.35
735.9


276
407.8
372.03


277
608.57
515.43


278
446.55
676.35


279
427.65
498.5


280
440.83
248.57


281
425.85
908.4


282
476.23
340.6


283
435.2
367.17


284
435.23
282.07


285
428
260.77


286
448.23
256.5


287
464.35
428.7


288
128
7505


289
172.8
1832.5


290
127.35
7505


291
349.55
1402.5


292
141.1
4175


293
264.9
2505


294
225.5
2505


295
172.1
2505


296
164
2505


297
184.07
3340


298
206.45
2439.5


299
194.8
2505


300
165
2505


301
117.35
7505


302
131.6
7505


303
123.5
7505


304
254.9
1987.5


305
170.5
1445


306
147.8
2505


307
233.4
1543.3


308
221.85
2505


309
237.3
1331.1


310
199.65
1605.5


311
195.5
2142.8


312
185
2319.5


313
132.2
7505


314
250.1
2505


315
150.3
4175


316
435.6
308.17


317
433.4
972.25


318
323.72
1860.5


319
270.75
4175


320
166.3
3340


321
196.85
2505


322
154.55
3340


323
128.4
>10000


324
279.1
2505


325
389.75
779.25


326
360.83
573.93


327
335.63
241.2


328
422.25
463.1


329
454.57
307


330
509.93
197.03


331
513.57
390.03


332
346.12
917.14


333
150.85
4105.5


334
226.6
1898


335
259.25
1382.5


336
297.8
1321.8


337
139.85
4175


338
135.7
7505


339
126.85
7505


340
146
4175


341
149.55
4093.5


342
138.5
3373


343
104.7
7505


344
218.25
1767


345
129.4
4175


346
151.2
4175


347
259.55
1408


348
410.3
369.93


349
382.73
236.33


350
397.5
316.33


351
256.6
1525


352
210.15
1431.5


353
438.65
458.55


354
429.9
322.8


355
360.63
556.2


356
331.9
428.35


357
274.8
805.67


358
370.47
205.65


359
349.55
2181


360
293
1033.6


361
227.65
1156.6


362
170.85
1803.5


363
187.2
2333


364
282.3
1638.7


365
278.05
1539


366
385.85
602.25


367
406.35
668.55


368
515.5
289.5


369
389.2
470.55


370
133
>10000


371
283.6
1105


372
388.6
126.5


373
306.9
303.95


374
297.35
463.5


375
184.1
1670


376
289.4
1138.8


377
295.65
1499.5


378
140.5
3340


379
128.5
5010


380
141.7
950.3


381
182.9
1670


382
268.1
1407


383
129.7
5010


384
123
5010


385
238.75
1670


386
250.65
1439.5


387
224.5
1670


388
171.6
1462.5


389
280.6
1287.6


390
362
271.6


391
528.7
374.43


392
519.35
323


393
454.3
313.7


394
392.57
676.97


395
480.35
549.05


396
409.8
301.15


397
217.3
298.75


398
275.7
737.23


399
336.55
475.25


400
283.65
980.15


401
306.07
653.43


402
214.5
1110


403
507.25
310.8


404
275.95
849.1


405
512.4
226.42


406
359.55
640.65


407
323.95
662.45


408
346.95
617.25


409
249.3
1110


410
317.5
227.6


411
456
976.05


412
387.2
307.4


413
392.2
337.9


414
295.15
372.7


415
334.35
248.95


416
369.5
784.95


417
322
317.8


418
342.25
597.6


419
293.9
508.9


420
411.25
289.05


421
368.65
722.9


422
336.05
1002.6


423
299.25
920.15


424
254.9
829.4


425
262.45
349.05


426
253.5
897.4


427
418.9
577.15


428
296
380.2


429
268.2
370.45


430
342.17
243.4


431
416.6
424.8


432
388.23
297.5


433
369.1
367.5


434
342.8
327.63


435
290.05
453.25


436
157.15
2505


437
419.53
795.4


438
507.27
387.16


439
312.85
1110


440
308.95
1931.5


441
289.75
1507


442
321.95
654.65


443
317.25
1474.5


444
282.8
542.85


445
127.85
>10000


446
171.35
3340


447
415.6
724.45


448
387.15
646.5


449
298.55
918.25


450
377.1
455.7


451
234.95
874.1


452
282.3
1110


453
275.35
655.8


454
470.3
636.35


455
421.5
451.75


456
414.5
335.3


457
430.85
392.25


458
399.6
278.1


459
319.8
379.8


460
322.2
327.85


461
328.05
342.85


462
316.85
318.3


463
341.85
373.2


464
328.25
407.65


465
244.6
703.45


466
271.1
1290


467
274.35
3340


468
297.2
370.5


469
360.3
716.05


470
311.25
427.15


471
259.9
2986


472
292.55
1384.6


473
280.9
545.4


474
301.35
2251.5


475
163.35
2716


476
297.8
385.85


477
266.3
500.5


478
292
409.4


479
317.77
1846


480
270.4
363.75


481
210.3
3045.5


482
284.7
708.77


483
267
366.85


484
226.6
369.35


485
242.05
334.75


486
299
335.15


487
316.5
490.65


488
261.9
462.25


489
274.95
769.75


490
311.1
296.3


491
256.5
965.53


492
239.55
2508.5


493
286.5
396.35


494
196.7
1159


495
235.15
307.4


496
145.5
2130.6


497
157.55
3340


498
435.9
87.785


499
435.6
199.84


500
289
296.05


501
367.65
353.45


502
327
1349


503
220.8
3192


504
138.9
>10000


505
118.3
>10000


506
137.7
>10000


507
218.3
2523


508
271.8
451


509
344.6
1668


510
313.2
397.4


511
214.6
1031


512
286.4
1417


513
349.6
472.1


514
178.2
3330


515
173.5
3330


516
275.5
723.2


517
303.2
575.1


518
237
530.9


519
340.6
3330


520
450.25
241.45


521
216.55
289.55


522
294.1
1079


523
320.1
630.3


524
354.25
261.05


525
311.3
936.3


526
284.5
370


527
291.2
1033


528
209.2
1939


529
126.7
>10000


530
254.15
542.4


531
223.4
1450


532
271.77
348.8


533
315.85
1227.5


534
281.95
893.2


535
205.9
1411


536
209.35
2467


537
191.2
3330


538
312.05
1538


539
564.8
197.67


540
314.05
323.6


541
287.85
799.2


542
290.6
1779


543
304.9
242.25


544
273
457.35


545
247.05
563


546
246.6
3330


547
318.7
1881


548
306
3330


549
467.2
61.66


550
122.4
>10000


551
424.35
87.225


552
396.65
396.25


553
419.05
118.55


554
365.83
1719.1


555
310.65
169.45


556
324
682.15


557
418.2
200.5


558
322.5
777.9


559
352.47
2050


560
437.33
171.23


561
348
426.7


562
347
920.97


563
272.97
2230


564
369.1
2453


565
319.8
1934.6


566
365.3
406.6


567
302.8
2112


568
279.9
2484


569
259.37
3063


570
254
3330


571
334.05
328.4


572
330.8
1190


573
376
299.2


574
469.5
189.63


575
431.9
208.7


576
390.78
396.45


577
300.47
1149.2


578
301.55
224.2


579
263.5
267.15


580
288
311.5


581
377.8
203.3


582
307.5
613.6


583
287.75
460.05


584
202.2
2882


585
245.3
2489


586
322.2
1999.8


587
360.33
2424.8


588
469.3
2422.5


589
451.75
303.45


590
310.45
2028.8


591
286.4
450.1


592
279
583.9


593
313.3
1166


594
269.8
621.4


595
383.8
206.8


596
299.4
522.1


597
342.5
229.9


598
274.4
3330


599
248.4
376.1


600
334.3
383.4


601
173.6
2484


602
393.4
133.8


603
273.3
869.7


604
292.2
255.75


605
531.3
43.56


606
199.7
1772


607
305.5
1980


608
338.1
683


609
336.4
1042


610
539.05
44.755


611
278.1
2933


612
266.9
1176.5


613
292
739.4


614
176.9
3330


615
216.65
2334


616
389.95
83.345


617
127.3
>10000


618
315.25
350.95


619
134.1
>10000


620
323.25
169.95


621
294.75
3144


622
275.2
67.53


623
308.3
501.2


624
281.85
2211


625
326.75
125.7


626
398.15
1008


627
126.25
>10000


628
217.7
3330


629
252.2
2161


630
323.7
254.35


631
283
177.2


632
129.55
>10000


633
279.27
713.53


634
294.7
2569


635
233.85
2114.5


636
391.3
790.05


637
174.45
3011


638
175.15
6665


639
261.7
1672.5


640
137.45
>10000


641
239.75
2269.5


642
281.95
2404


643
271.8
1261.5


644
196.3
3330


645
270.05
408.85


646
198
3330


647
301.3
2007.8


648
296.1
202.95


649
314.65
224.8


650
193.6
3330


651
187.9
2198


652
310.6
202.7


653
260.3
3330


654
245.5
3330


655
340.2
1128


656
415.7
190.6


657
543
305.7


658
345.9
455.25


659
424.5
69.535


660
284.47
3330


661
522.3
226.8


662
310.6
2301


663
315.5
90.88


664
120.6
>10000


665
330.43
1858.5


666
338.35
252.95


667
339.85
462


668
341.65
2361.5


669
315.5
795.4


670
397.3
218.25


671
357.4
942.85


672
343.15
552.95


673
163.25
3330


674
323.85
380.45


675
303.65
1054.8


676
164.55
892.2


677
260.45
6546.5


678
373.3
91.755


679
503.6
299.27


680
236.7
1362


681
373.05
197.3


682
368.9
115.95


683
600.53
60.673


684
384.65
235.8


685
510.3
245.15


686
431.1
237.4


687
454
89.717


688
532.6
246.9


689
329
802.75


690
318.25
2757.6


691
280.7
5000


692
381.4
931.25


693
392.45
324.6


694
421.9
534.7


695
385.5
118.5


696
346.8
1670


697
217.3
1273


698
242.7
745


699
432
169.03


700
290.9
128.1


701
498.5
36.07


702
214.1
1670


703
374.6
386


704
344.1
408.9


705
249.8
1670


706
284.4
488.2


707
326.3
341.2


708
314.8
147.3


709
223.9
1670


710
282.6
1350


711
248.8
1111


712
242.9
607.8


713
243.5
659.2


714
212.5
1408


715
261.4
1272


716
282.9
771.5


717
124.6
5000


718
209.8
1670


720
263.1
356.1


721
302.1
510.3


722
247
1670


723
344.8
1053


724
208.5
1670


725
173.2
868.7


726
409.6
311.3


727
348
1670


728
221.6
1670


729
530.4
1670


730
418.7
71.54


731
399.5
94.54


732
409.6
119.2


733
396.9
85.09


734
415
243.8


735
437.7
224.5


736
511.6
42.2


737
343.3
1670


738
472.1
110.5


739
327.2
1670


740
194.7
423.6


741
303
668.5


742
126.1
5000


743
330.5
1242


744
337.3
735.2


745
457.5
191.3


746
418.4
549.3


747
475.3
1670


749
387
277


750
394.1
502.8


751
400.2
1587


752
530.9
103.6


753
377.6
300.8


754
467.3
153


755
270.9
1670


756
446
401.1


757
489.6
402.2


758
139.5
811.6


759
207
1670


760
131.6
5000


761
284
1670


762
442.6
462.1


763
276.3
1670


764
255.65
2405


765
181.3
737.6


766
213.4
1182


767
210.1
1670


768
256.5
1670


769
157.2
1578


770
234.5
899.5


771
290.8
1670


772
226.6
1359


773
141.8
5000


774
375.6
1670


775
262.4
1670


776
261.4
531.4


777
254.9
955.3


778
149
1670


779
121.2
5000


780
429.5
124.4


781
368.7
1562


782
345.2
272.2


783
283.6
1670


784
225.6
1670


785
482.8
558.3


786
221.6
907


787
309.9
1295


788
329.4
1670


789
460.95
917.65


790
419.1
181.4


791
307.5
1670


792
321
709.9


793
363.5
1670


794
168.7
788.1


795
175.3
1670


796
358
1670


797
178.6
1670


798
186.5
863.6


799
306.6
1670


800
214.8
1488


801
253.1
1670


802
439.7
771.3


803
436
671.73


804
365
231.05


805
671
47.395


806
435.5
224.6


807
389.35
72.515


808
297
263.8


809
452.2
183.7


810
468.7
88.415


811
408.4
1078


816
359.9
67.64


817
384.9
46.36


819
313.1
3330


820
499.75
122.9


821
545.15
134.45


822
472.75
1136.6


823
375.2
146.85


824
535.65
277.05


825
455.85
143.95


826
528.15
101.81


827
453.25
92.96


828
518.35
47.94


829
411.7
344.4


830
588.2
63.15


831
402.5
406.7


832
526.6
1070


833
443.15
141.55


834
403
114.5


835
466.9
67.625


836
325.3
408.8


838
411.8
114.6


839
437.3
179.8


840
368.8
249.9


841
457.1
313.9


842
370
582.5


843
499.3
207.2


844
429.2
205.5


845
499.6
1085


846
495.1
968.1


847
503.8
286.2


848
405.2
427


849
458.6
230.61


850
615.6
88.86


851
559.8
123.3


852
391.4
3330


853
509.5
177.3


854
380.7
3330


855
490.9
87.15


856
416.9
88.31


857
232.2
2437


858
168.6
3175.5


859
291.4
2564


860
576.25
416.7


861
155.4
10000


862
359.6
636.15


863
320.9
369.93


864
458.6
105.33


865
306.8
1124.6


866
298.3
150.95


867
290.65
317.15


868
337.8
176.25


869
513.05
37.715


870
611.45
170.95


871
681.7
156.21


872
548.45
172


873
332.45
1845.2


874
608.35
83.045


875
450.3
819.25


876
562.35
267.15


877
374.57
605.13


878
391.3
99.645


879
446.25
196.18


880
446.95
693.2


881
242.75
699.85


882
363.85
371.85


883
380.9
238.1


884
377.6
213.75


885
255.5
2451.5


886
551.77
511


887
375.13
203.6


888
430
332.8


889
449.8
241.3


890
406.67
225.04


891
564.5
51.04


892
428.72
601.79


893
236.6
3330


894
371.3
218.25


895
429.4
3330


896
513.5
699.8


897
354.93
185.83


898
393.6
3330


899
351.9
308.7


900
389.73
216.03


901
432.3
150.6


902
411.75
114.25


903
480.55
108.4


904
372.85
101.82


905
466.55
144.85


906
485.34
72.824


907
483.65
182.62


908
486.75
171.25


909
498.4
56.175


910
499.9
79.065


911
405.9
73.96


912
397.9
267


913
531.4
163.25


914
429.25
172.95


915
587.95
50.215


916
362.05
1377


917
306.95
1670


918
352.1
479


919
416.35
255.65


923
263
380.46


924
609.82
136.48


925
126.05
10000


926
486.6
339.85


927
362.92
1104


928
362.2
2413


929
560
83.25










Activity of Compounds for their Intrinsic Corrector Capacity:


For this purpose doxycycline-inducible AF508-CFTR-HRP expressing CFBE4lo-cells (obtained from Gergely Lukacs, McGill University) were maintained in MEM (Gibco; 31095) supplemented with 10% fetal bovine serum (Hyclone; SV30160.03) under puromycin (3 μg/mL) and G418 selection (0.2 mg/mL). For compound testing, cells were seeded at 4000 cells/well in white 384-well plates (Greiner; 781080) in 50 μL medium containing 0.5 μg/mL doxycycline and incubated for 68 hours at 37° C., 5% CO2. On day four, 10 μL test compounds diluted in PBS were added to the plates at a final DMSO concentration of 0.1%. All compound plates contained negative controls (DMSO) and positive controls (3 μM corrector, 3-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid). Cell plates were incubated at 33° C., 5% CO2 for 20 hours. On day five, the cells were washed five times with phosphate-buffered saline, and HRP activity was assayed by the addition of 50 μL/well of HRP substrate (SuperSignal™ West Pico Chemiluminescent Substrate, Thermo Scientific; 34080). After incubation for 15 minutes in the dark, chemiluminescence was measured using a plate reader (EnVision®, Perkin Elmer). Raw data were normalized to percentage activity values using the equation: 100×(Sample−Negative control)/(Positive control−Negative Control).









TABLE XIX







Illustrative EC50 measured by CFTR cell surface levels


using HRP-tagged ΔF508-CFTR expressing CFBE cells.









Compound #
% Activation
EC50 (nM)












1
151.61
1382.8


2
49.03
2653


3
46.83
3340


4
3.339
>10000


5
183.67
495.43


6
119.05
818.25


7
5.355
>10000


8
91.055
753.75


9
31.76
3340


10
116.55
866.85


11
134.3
1379


12
117.2
951.45


13
159.23
997.17


14
58.56
3340


15
98.68
2667


16
92.93
3340


17
99.207
2188.4


18
126.8
783


19
23.76
>10000


20
199.98
521.82


21
103.72
1057.8


22
131.28
1006.6


23
8.185
>10000


24
134.1
1829


25
93.1
1502


26
83.24
1272.5


27
41.145
6670


28
129.5
1176


29
146.1
3113


30
119.1
1206


31
96.335
521.8


32
176.7
637.62


33
90.265
1526.5


34
22.74
>10000


35
110.15
736.8


36
118.9
1996.3


37
112.9
1110


38
23.86
>10000


39
−2.469
>10000


40
154.82
537.03


41
110.52
957.1


42
74.83
3340


43
187.4
407.77


44
117.2
2202


45
5.851
>10000


46
15.23
>10000


47
183.2
608.4


48
163.7
988.7


49
107
1110


50
132.05
2801.8


51
41.22
1177


52
87.35
2679


53
72.97
3340


54
167.9
763.25


55
0.088
>10000


56
53.1
3340


57
68.57
3340


58
4.754
>10000


59
13.69
>10000


60
14.9
>10000


61
96.05
3340


62
159.65
2628.5


63
108.18
3340


64
3.754
>10000


65
103.02
3340


66
13.06
>10000


67
117.6
1593


68
106.65
1738


69
150.25
970


70
160.8
909.6


71
17.23
>10000


72
91.87
2246


73
110.1
3165


74
116.7
2560


75
117.1
3132


76
117.9
834.5


77
139.5
1172.1


78
10.784
>10000


79
195.9
696.6


80
184.8
611.45


81
193.6
744.4


82
135.95
1008.2


83
142.25
1467


84
289.83
829.22


85
314.6
919.7


86
129.75
3340


87
28.91
>10000


88
288.95
693.15


89
310.15
2529.5


90
169.65
1040


91
43.54
3340


92
2.873
>10000


93
175.6
679.6


94
3.061
>10000


95
16.66
>10000


96
141.5
1526


97
96.51
1525.5


98
165.8
1147


99
80.69
1528


100
115.7
980.9


101
143.75
1606


102
153
1044.8


103
115.65
703


104
130.4
1242.5


105
179.05
949.45


106
73
3340


107
20.98
>10000


108
145.5
904.35


109
235.9
885


110
212.25
705.05


111
110.34
458.7


112
200.55
2469


113
110.35
1668


114
251.05
805.95


115
152.3
1870.5


116
81.72
3340


117
70.77
1104


118
26.575
6670


119
207.25
915.35


120
70.235
3340


121
401.5
528.4


122
147.6
2991


123
107.95
3275.5


124
190.5
3077


125
168.75
1763


126
156.45
1693.5


127
221.4
1785.5


128
33.92
3340


129
178.3
414.25


130
237.68
488.98


131
153.75
899.4


132
13.45
>10000


133
74.96
3340


134
153.25
982.2


135
165.1
2195.5


136
40.405
3340


137
27.985
>10000


138
12.11
>10000


139
−0.041
>10000


140
178
1500


141
5.399
>10000


142
17.605
>10000


143
109.45
2285.5


144
212.6
2924.5


145
190.2
1432


146
8.92
>10000


147
114.65
1054


148
79.64
3340


149
112.95
652.6


150
6.341
>10000


151
322.03
354.5


152
75.36
2631


153
198.45
1526


154
153.9
918.2


155
203.65
1350.5


156
175.5
3340


157
388.2
459.35


158
1.521
>10000


159
150.16
736.56


160
318.83
446.77


161
111.83
921.17


162
147.97
992.4


163
232.43
525.1


164
359.9
675.07


165
350.4
793.55


166
68.01
3340


167
301.1
595.77


168
190.23
1291.2


169
217.88
448.36


170
208.6
737.7


171
199.67
1189


172
339.33
615.15


173
182.82
2946.5


174
90.21
3242.2


175
321.67
808.5


176
382.28
527.65


177
364.43
701.37


178
415
627.6


179
329.25
2820.5


180
249.55
971.55


181
149.2
1222.4


182
251.7
538.32


183
252.9
528.3


184
170.25
942.15


185
237.8
1110


186
168.7
1871


187
367.4
674


188
282.4
635.65


189
385.02
513.5


190
136.12
929


191
208.12
997.92


192
276.92
424.25


193
194.98
633.2


194
86.36
1712


195
27.46
>10000


196
251.45
555.4


197
219.25
644.35


198
220
1120


199
356.9
1223.7


200
330.83
437.77


201
251.3
596.3


202
136.8
794.8


203
162.5
842.95


204
402.1
1110


205
109
1110


206
466.87
323.13


207
384.15
581.4


208
413.75
603.35


209
165.6
1359


210
66.65
1176


211
94.07
2169.5


212
139.7
2638


213
247.33
678.73


214
154
819.8


215
165.95
1034.4


216
161
1014


217
129.7
1523


218
169.4
2305


219
248.7
517.6


220
245.37
786.37


221
429
314.83


222
429.93
433.47


223
246.95
714.3


224
189.6
1179


225
251.5
1984


226
189.05
3340


227
305.45
665.7


228
297.15
680.35


229
130.65
2145


230
368.85
1490


231
419
732.8


232
215.6
1684


233
72.33
3030.5


234
292.97
463.7


235
206.8
832


236
213.68
656


237
227
510.4


238
393.7
827.25


239
327.55
874.6


240
380.6
587.7


241
60.46
3340


242
206.5
603.32


243
224.73
659.6


244
320.17
472.95


245
267.15
777.45


246
212.75
463.5


247
390.27
419.9


248
405.93
550.1


249
410.6
474.72


250
394.7
456.23


251
389.2
438.27


252
398.4
698.4


253
375.87
655.73


254
234.6
611.4


255
120.77
441.57


256
180
3340


257
260.4
2532.5


258
169.7
1286


259
438.95
1129.8


260
326.4
783.6


261
314.07
702.33


262
164.4
915.6


763
161.25
1630.5


264
213.88
746.78


265
132.05
1245


266
197.55
1246.3


267
318.9
806.8


268
251.82
615.82


269
264.3
580.67


270
236.02
698.38


271
144.2
923.87


272
135.5
3340


273
100.16
1018.4


274
114.64
1078


275
173.8
923.1


276
206.93
503.93


277
356.47
513.03


278
259.1
990.85


279
257.8
900.5


280
238.6
485.4


281
226.7
1293.5


282
269.33
492.23


283
233.17
648.7


284
240.8
500.83


285
255.73
654.87


286
259.83
543.67


287
234.95
535.1


288
20.49
7505


289
46.35
2505


290
12.145
7505


291
168.85
1714


292
15.095
7505


293
90.275
2505


294
73.275
2505


295
46.475
2505


296
29.42
4175


297
50.78
2226.7


298
52.345
2505


299
51.845
2505


300
41.065
2505


301
12.64
7505


302
18.02
7505


303
10.878
7505


304
98.425
2505


305
29.97
3115.5


306
22.69
7505


307
77.423
1921


308
59.78
2505


309
67.305
1334.5


310
88.73
1892


311
53.7
2505


312
61.325
2505


313
11.239
7505


314
92.46
2505


315
24.61
3434


316
218.87
564.63


317
216.25
694.7


318
134.15
2626.5


319
80.905
2505


320
19.37
>10000


321
39.85
2505


322
12.25
>10000


323
8.143
>10000


324
93.32
2505


325
177.1
1197


326
180.53
976.93


327
176
368.7


328
196.9
671.3


329
239.4
557.63


330
326.43
405.1


331
311.73
1045.6


332
167.75
337


333
27.26
4175


334
36.645
4175


335
100.33
1610.5


336
118.2
1370


337
15.48
7505


338
12.64
7505


339
15.162
7505


340
18.86
7505


341
25.115
4175


342
19.4
7505


343
11.085
7505


344
69.225
2505


345
23.411
4175


346
20.555
7505


347
79.835
1413.5


348
217.2
553.33


349
208.2
460.07


350
211
425.8


351
84.055
1610.5


352
55.175
1511


353
224.1
506.5


354
212.07
450.5


355
180.03
740.4


356
152.8
489.45


357
113.47
885.07


358
205.07
410.5


359
142
2040.5


360
96.335
1166.6


361
80.015
1537.5


362
44.405
2029.5


363
56.625
2465


364
118.28
2277


365
147.55
2549


366
199.1
435.75


367
239.55
1008.8


368
357.3
520.6


369
251.6
843.25


370
19.18
>10000


371
116.35
1306.5


372
179
262.3


373
126.3
468.8


374
114.2
594.75


375
36.645
3340


376
109.7
1605.5


377
95.185
1670


378
14.56
5010


379
4.874
5010


380
14.735
5010


381
17.695
5010


382
80.645
1670


383
16.587
5010


384
8.1785
5010


385
54.89
1670


386
64.285
1307.6


387
65.365
1670


388
50.555
1670


389
101.73
1670


390
177.8
585.35


391
306.23
589.73


392
302
345.4


393
258.8
557.6


394
235.1
1493


395
223.6
437.7


396
209.3
403


397
73.11
644.65


398
96.49
1289.3


399
137.6
823.5


400
111.35
1346


401
136.97
1096.8


402
43.815
714.6


403
293.4
408.15


404
104.91
910.5


405
298.75
346.8


406
182.5
822.95


407
125.25
925.4


408
141.15
931.7


409
75.39
1073.5


410
155.63
557


411
280.85
3340


412
215.6
460.05


413
216.65
527.45


414
120.3
691.8


415
168.85
487.15


416
179.1
1254.5


417
134.8
545.75


418
144.95
1219.8


419
136
982.95


420
211.15
534.05


421
184.4
1292.5


422
131.9
1616


423
113.4
934.4


424
86.32
1075.6


425
123.35
990


426
76.06
998.1


427
200.4
663.35


428
128.05
977.7


429
114.95
979


430
175.73
372.53


431
198.57
542.6


432
197.97
560.57


433
185.45
628.95


434
154.17
580.67


435
116.7
773.3


436
24.16
4175


437
247.47
1225.5


438
277.03
330.87


439
120.85
1122


440
104.7
1922.5


441
111.85
2051


442
137.7
1075


443
146.9
2301


444
111.15
1108.4


446
20.695
>10000


447
243.3
1124.5


448
239.2
1075.2


449
139.3
1353


450
165.85
1089.9


451
71.425
1286.5


452
74.98
1110


453
110.68
716.15


454
253.5
997.9


455
288.4
1113.8


456
253.65
844.8


457
240.3
607.4


458
216.4
484.5


459
152.05
652.9


460
138.15
642.45


461
158.55
818.15


462
156.2
486.3


463
157.75
686.4


464
163.6
1144.5


465
91.04
1849.5


466
116.25
2327


467
97.95
3340


468
120.3
618.45


469
198.95
1121.2


470
147.5
735.55


471
106.45
3340


472
144
2493


473
102.9
1020.4


474
125.3
3340


475
35.755
6670


476
121.45
513.15


477
97.78
1018.5


478
125.2
828.05


479
114.41
1853.2


480
115.15
862.35


481
48.6
3340


482
144.75
1640


483
142.4
897.2


484
113.5
1110


485
107.5
1067


486
127
602.9


487
142.7
834.9


488
95.49
755


489
106.4
1859


490
144.95
399.65


491
82.97
2276.3


492
84.2
2370


493
129.05
644.7


494
65.56
3282


495
95.96
1110


496
32.84
3340


497
24.76
>10000


498
244.33
325.83


499
242.93
392.96


500
132.8
466.5


501
152.7
629.2


502
152
3340


503
65.78
3340


504
19.62
>10000


505
-6.616
>10000


506
40.12
3340


507
132.8
2167


508
104.6
1110


509
123.6
1241


510
99.8
1110


511
56.48
3340


512
103
1166


513
141.7
371


514
37.34
3340


515
15.59
>10000


516
123.4
1112


517
82.63
646.3


518
62.95
371


519
149.3
3340


520
213.9
583


521
58.57
487.8


522
114
478.7


523
136.2
2848


524
134.7
453.7


525
232.2
415.8


526
97.7
406.1


527
100.1
1162


528
80.74
3330


529
5.039
>10000


530
90.17
718.2


531
91.66
3330


532
107.05
707.25


533
114.5
3213


534
111
3330


535
56.68
2845


536
49.72
3330


537
45.36
3330


538
124.6
2431


539
366.3
370


540
142.2
452.1


541
120.7
987.9


542
104.6
1842


543
129.15
303.85


544
129.55
803.05


545
109.4
1146.4


546
87.52
3330


547
120.7
3330


548
88.93
2540


549
302.2
211


550
4.775
>10000


551
223.1
370


552
156.1
370


553
189.7
370


555
152
330.7


556
140.1
838.2


557
221.7
443.7


558
121.3
1374


560
265.05
393.05


561
174.8
1593


562
154.7
1765


566
150.5
387.6


571
189.6
812.2


573
149.7
974.4


574
294
479.5


575
268.4
512


576
175.2
495.95


577
108
3026


578
118.2
334.3


579
97.37
237.5


580
88.82
333.4


581
146
249.7


582
92.03
903


583
134.7
1017


587
149.5
3330


588
232.6
3330


589
232.15
457.5


590
141.3
2611


591
106.3
925.7


592
116.6
1159


594
75.66
786.8


595
162.8
347


596
99.54
735.2


599
81.59
357.3


602
159.3
256.3


603
92.66
1761


604
142.9
738.5


605
292.8
82.08


610
262.4
122.8


611
104.6
3330


612
109.5
3330


613
99.78
1596


614
32.02
3330


615
44.6
3330


616
144.2
116.5


617
7.139
>10000


618
105.9
546.6


619
7.484
>10000


620
147.4
249.5


621
89.46
3330


622
124.5
164.7


623
106.8
1158


624
98.14
3330


625
135.2
300.25


626
223.1
2713


627
9.221
>10000


628
67.69
3183


629
94.42
3330


630
136.15
308.05


631
99.143
345.9


632
18.94
>10000


633
66.87
665.5


634
122.2
3330


635
86.1
3330


636
184.1
617


637
49.14
3330


638
24.93
>10000


639
96.54
2211


640
13.97
>10000


641
65.07
3330


642
125.9
3330


643
95.84
2895


644
42.75
3330


645
111.55
1067.3


646
45.39
3330


647
119.9
2180


648
90.745
262.9


649
107.6
432.2


650
45.88
3330


651
54.22
3330


652
130.6
333.9


654
66.19
3330


655
165.6
3098


656
287.7
437.5


661
315
565


671
190.1
1609


672
141.6
748.5


674
158.5
520.8


675
118.8
658.8


676
35.03
5000


677
67.38
1573


678
181.5
230.4


679
279.5
370.2


681
220.95
408.5


682
172.9
180.1


683
395.1
140.7


684
230.2
380.2


685
260.5
164.2


686
240.4
1670


687
264.95
171.2


688
322.5
247.3


689
182.7
1568


690
136.1
1670


692
208.1
1670


693
185.9
1269


694
177.4
486.7


699
247.63
621.83


738
267.6
245.45


745
239.3
573.1


753
215
1028


754
254.1
385.3


757
208.45
318.8


764
85.92
3330


765
45.48
1670


766
54.3
1670


767
59.96
1670


768
79.69
1584


769
19.25
5000


770
85.33
1670


771
94.91
1670


772
53.82
1670


773
16.13
5000


774
163
1670


775
93.07
1670


776
113.2
1670


777
95
1670


778
9.442
5000


779
6.923
5000


780
233.5
249.2


781
154
1670


782
174.4
673.4


783
95.05
1670


784
38.94
1224


785
264.9
621.6


786
67.03
1165


787
121.5
770.7


788
115.7
1670


789
257.05
477.05


790
193.7
293.7


791
79.95
1670


792
170.1
1431


793
157.7
1670


794
58.82
1670


795
47.22
1670


796
169.7
1670


797
31.52
5000


798
58.3
1670


799
114
1670


800
45.22
1670


801
67.99
1670


802
218
462


803
229.35
1016.3


804
191.15
488.65


805
364
72.75


810
277.6
203.8


811
120.4
889.6


817
168
152.3


819
174.7
3330


820
351.3
284.6


822
272.3
300.7


823
188.7
258.2


824
338.9
179.6


825
289
207.3


826
314.4
156.9


827
265.4
257.2


828
283.5
83.17


829
170.7
381.1


830
353.9
115


831
231.3
1455


832
250.5
150.7


833
231.9
187.1


834
227.9
240.6


835
291.5
163.1


836
137.3
485.6


838
240.3
269.1


839
275.7
921


840
164.4
400.1


841
225
532.2


842
162.5
627.9


843
264.2
365.8


844
184.9
209.9


845
273.7
1465


846
317.9
874.2


847
279.1
539.5


848
249
1201


849
249.1
660.35


850
234.4
74.1


851
342.9
243.7


852
120.6
1714


853
290.9
261.3


854
131.1
2075


855
304.2
197.3


856
230.7
247.7


857
60.01
3330


858
29.24
10000


859
89.07
2232


860
383
516.9


861
31.08
10000


862
186.5
637.35


863
156.35
499.05


864
337.7
1007


865
146.9
439.5


866
99.71
277.4


867
125.2
1413


868
140.3
239.3


869
299.1
112.9


870
304.4
1037


871
355.1
275


872
368.7
591.4


873
139.8
3340


874
330.7
169.6


875
270.7
1598


876
324.4
300.6


877
162.65
347.55


878
181.05
221.4


879
279.6
355.2


880
259.5
168.6


883
160.6
329.7


884
140.6
298.5


885
66.2
3340


886
236.05
466.5


887
191.35
361.15


889
229.2
404.4


890
179
741.6


891
367.25
93.145


892
196.44
603.24


893
55.75
3142


894
164
304


895
178.2
1284


896
358.8
1634


897
151.25
348.45


898
231.6
3236


899
210.9
3096


900
183.97
432.57


901
199.2
87.56


902
193.9
229.9


903
275.8
331.2


904
200.1
236.65


905
278.8
362.4


906
276.92
145.54


907
270.7
259.7


908
220.2
256.2


909
277.7
134.1


910
286.2
186.7


911
222.45
189.85


912
212.4
720.2


913
326.3
1148


914
228.2
546


915
386.2
394.1


916
165.25
1670


917
116.67
1662.5


918
149.75
711.5


919
198.2
490.4


923
60.466
355.12


924
374.45
419.67


925
11.745
10000


926
240.2
520.75


927
150.78
1246.6


928
284.7
4031.5


929
474.3
181.1


930
434.3
240.3










YFP-Halide Influx Assay for the CFTR-ΔF508 Mutation


The YFP halide influx assay measures the functionality of the Cystic Fibrosis Transmembrane Conductance regulator (CFTR) channels in the cystic fibrosis bronchial epithelium cell line CFBE4lo-. The fluorescence of the yellow fluorescent protein (YFP) variant YFP H148Q, I152L or variant YFP H148Q, I152L & F47L is substantially quenched by iodine, a halide that is efficiently transported by CFTR. The assay is thus used to evaluate the effect of corrector compounds on CFTR channel function by measuring the extent of YFP signal quenching. (Galietta, L. J. V., Haggie, P. M., Verkman, A. S., 2001. Green fluorescent protein-based halide indicators with improved chloride and iodide affinities. FEBS Lett. 499, 220-224. doi: 10.1016/S0014-5793(01)02561-3; Nagai, T., Ibata, K., Park, E. S., Kubota, M., Mikoshiba, K., Miyawaki, A., 2002. A variant of yellow fluorescent protein with fast and efficient maturation for cell-biological applications. Nat. Biotechnol. 20, 87-90. doi:10.1038/nbt0102-87). For this purpose, CFBE4lo-cells were seeded in 96-well plates (6000 CFBE cells/well). One day after seeding, the CFBE cells were transduced with adenoviral vectors that direct the expression of the CFTR ΔF508 mutant and of the YFP reporter. Cells were treated with test compounds for 24 hours at 37° C. to allow trafficking of corrected CFTR to the membrane. The next day the CFTR channels were activated by treatment with the cAMP inducer forskolin (10.67 μM) and potentiator, N-(3-carbamoyl-5,5,7,7-tetramethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-5-carboxamide (0.5 μM), in 1×D-PBS (from Gibco, Cat n#14090-091) for 20 minutes prior to addition of an Isolution (137 mM NaI, 2.7 mM KI, 1.76 mM KH2PO4, 10.1 mM Na2HPO4, 5 mM glucose). The F induced quenching of fluorescence is recorded immediately after injection of for 7 seconds. The capacity of a compound to increase number of channels, and therefore overall halide influx is directly correlated with the decrease in fluorescence, and is expressed as (1-(fluorescence after 7 seconds (F)/fluorescence before injection (F0))) and an EC50 can be derived from a (1-F/F0) vs compound concentration plot.


TECC Assay


Primary Bronchial Epithelial Cells Protocol


The TECC (Tranepithelial Clamp Circuit, EP-design) assay measures the functionality of the cystic fibrosis Transmembrane Conductance regulator (CFTR) by measuring the short circuit current (Isc) generated over the basolateral and apical membrane of lung epithelial cells. In TECC the transepithelial potential PD and transepithelial resistance (Rt)) are measured in an open circuit and transformed to Ieq using Ohm's law. 24 Wells can be measured simultaneously allowing a higher throughput compared to Ussing chambers.


For this purpose, bronchial epithelial cells isolated from CF patients homozygous for the CFTR ΔF508 mutation (hAEC-CF, Epithelix, Geneva, Switzerland; McGill University, Montreal, Qc; Asterand, Detroit, Mich.; University of North Carolina, Chapel Hill, N.C.) are plated on type IV collagen-coated Transwell® supports (Costar). Human airway epithelia are generated by provision of an air-liquid interface for 21 days to form well-differentiated polarized cultures that resemble in vivo pseudo-stratified ciliated epithelium (Fulcher, M. L., Gabriel, S., Burns, K. A., Yankaskas, J. R., Randell, S. H., 2005. Well-differentiated human airway epithelial cell cultures. Methods Mol. Med. 107, 183-206). The differentiated cells are treated with test corrector compound(s) (corrector alone or in combination with co-corrector, 4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-methoxy-3,4-dihydro-2H-chromen-2-yl]benzoic acid (G924806/A-1618261) (“acute”) or test corrector compounds, co-corrector and potentiator, N-(3-carbamoyl-5,5,7,7-tetramethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-5-carboxamide GLPG1837, (“chronic”) for 24 hours basolaterally to allow sufficient expression of properly folded CFTR protein on the membrane. All compound plates contained negative controls (DMSO) and positive controls. All compound plates contained negative controls (DMSO) and positive controls (0.15 μM, 4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic acid).


For electrophysiological recording of the “acute” experiments, the human airway epithelia are mounted in the TECC heating plate and kept at 37° C. The epithelia are bathed in a NaCl-Ringer solution (120 mM NaCl, 25 mM NaHCO3, 1.2 mM CaCl2, 1.2 mM MgCl2, 0.8 mM KH2PO4, 0.8 mM K2HPO4, pH 7.4, 5 mM glucose) on both the basolateral and apical sides. Apical amiloride is used to inhibit the endogenous epithelial sodium channel (ENaC) currents while forskolin is applied on both apical and basolateral side to stimulate CFTR. CFTR activity is measured by addition of forskolin followed by addition of a potentiator, N-(3-carbamoyl-5,5,7,7-tetramethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-5-carboxamide, on both sides. Measurements are done during a 20 minute timeframe with recordings every 2 minutes. The increase in Ieq is used as a measure for the increased CFTR activity, EC50 values can be generated by measuring impact of different concentrations of compound on Ieq on primary cells, for this purpose each transwell is treated with a different compound concentration for 24 hours. Inhibitor-172, an inhibitor specific for CFTR, is used to test the specificity of the tested compounds. Raw data were normalized to percentage activity values using the equation: 100×(Sample−Negative control)/(Positive control−Negative Control).









TABLE XX







Illustrative acute TECC assay response with and


without the presence of a co-corrector.









Compound
% Activity at
% Activity at 3 μM


#
10 μM (Ieq*)
with co-corrector (Ieq)





 89
147.6



123
100.6



151
100.6



169

279.1


213

199.4


220

122.9


222

221.3





*Ieq refers to calculations based on the maximum current.






For electrophysiological recording of the “chronic” experiments, the human airway epithelia are mounted in the TECC heating plate for electrophysiological measurement and kept at 37° C. The epithelia are bathed in a NaCl-Ringer solution (120 mM NaCl, 25 mM NaHCO3, 1.2 mM CaCl2, 1.2 mM MgCl2, 0.8 mM KH2PO4, 0.8 mM K2HPO4, pH 7.4, 5 mM glucose) on both the basolateral and apical sides. Test compounds (corrector, co-corrector, 4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic acid, and potentiator, N-(3-carbamoyl-5,5,7,7-tetramethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-5-carboxamide), are re-added to the recording solution prior to measurement. Apical amiloride is used to inhibit the endogenous ENaC currents while forskolin is applied on both apical and basolateral side to stimulate CFTR. Measurements are done during a 20 minute timeframe with recordings every 2 minutes. The increase in Ieq is used as a measure for the increased CFTR activity, EC50 values can be generated by measuring impact of different concentrations of compound on Ieq on primary cells, for this purpose each transwell is treated with a different compound concentration. Inhibitor-172, an inhibitor specific for CFTR, is used to test the specificity of the tested compounds. Raw data were normalized to percentage activity values using the equation: 100×(Sample−Negative control)/(Positive control−Negative Control).









TABLE XXI







Illustrative chronic TECC assay response.













%

%
%




Activity
EC50
Activity
Activity
EC50


Compound
at 1 μM
(nM)
at 1 μM
at 3 μM
(nM)


#
(Ieq*)
(Ieq)
(AUC**)
(AUC)
(AUC)















191
220
50





192
235
<30





201


254

<30


204
241
<30





205
140
>1000





213
390
>300





220
720
120





227
300
30





228
280
<30





244
210
<30





268
267
25





456




120


539


557




557


262
384



560

<30





574


190




575


290

100


576


183




610


471




656




48


657




78


679


373.3333

28


683


196.675




687


263.3333

53.52


699




162


738


230

23.01


754


190




789


235




790


220

120.3


803


161.4501




804


290




809


186.6667




810


191.4768




849


256.6667

15.6


878


170




886


282.5409




887


273.3871

1340


890


366.6667




892


188.3291

900.1


894


300




897


375




898



150.7853
2639


910



531.5026



915



423.3333



924



235.9027
10.56


927




1936





*Ieq refers to calculations based on the maximum current.


**AUC is the full area under the curve upon forskolin stimulation.






Information on protein binding of compounds can be retrieved from incubation of compounds in the presence of 40% human serum. For this purpose the differentiated cells are treated basolaterally with test compounds in medium containing 40% human serum (Sigma; H4522) for 24 hours. For electrophysiological recording, the human airway epithelia are mounted in the TECC heating plate and kept at 37° C. The epithelia are bathed in a NaCl-Ringer solution (120 mM NaCl, 25 mM NaHCO3, 1.2 mM CaCl2, 1.2 mM MgCl2, 0.8 mM KH2PO4, 0.8 mM K2HPO4, pH 7.4, 5 mM glucose) on both the basolateral and apical sides. Test compounds (corrector, co-corrector, 4-[(2R,4R)-4-({[1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropyl]carbonyl}amino)-7-(difluoromethoxy)-3,4-dihydro-2H-chromen-2-yl]benzoic acid, and potentiator, N-(3-carbamoyl-5,5,7,7-tetramethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-5-carboxamide), are re-added to the recording solution prior to measurement. Apical amiloride is used to inhibit the endogenous ENaC currents while forskolin is applied on both apical and basolateral side to stimulate CFTR. Measurements are done during a 20 minute timeframe with recordings every 2 minutes. The increase in Ieq is used as a measure for the increased CFTR activity, EC50 values can be generated by measuring impact of different concentrations of compound on Ieq on primary cells, for this purpose each transwell is treated with a different compound concentration. Inh-172, an inhibitor specific for CFTR, is used to test the specificity of the tested compounds.


It is understood that the foregoing detailed description and accompanying examples are merely illustrative and are not to be taken as limitations upon the scope of the invention, which is defined solely by the appended claims and their equivalents. Various changes and modifications to the described embodiments will be apparent to those skilled in the art. Such changes and modifications, including without limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations, or methods, or any combination of such changes and modifications of use of the invention, may be made without departing from the spirit and scope thereof.

Claims
  • 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof,
  • 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is G1A, -G1B-G1C, C1-C6 haloalkyl, or C1-C6 alkyl.
  • 3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is G1A.
  • 4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is -G1B-G1C.
  • 5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R2 is C2-C4 alkenyl, C1-C6 alkyl, C1-C6 haloalkyl, —OR2xa, or G2A.
  • 6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R2 is C1-C6 alkyl, C1-C6 haloalkyl, or G2A.
  • 7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R3 is G3A, -G3B-L1-G3C, —OR3a, or —N(R3a)(R3b).
  • 8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is G1A or -G1B-G1C; andR2 is C2-C4 alkenyl, C1-C6 alkyl, C1-C6 haloalkyl, —OR2xa, or G2A.
  • 9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is G1A or G1B-G1C; andR3 is G3A, -G3B-L1-G3C, —OR3a, or —N(R3a)(R3b).
  • 10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is G1A or -G1B-G1C;R2 is C2-C4 alkenyl, C1-C6 alkyl, C1-C6 haloalkyl, —OR2xa, or G2A; andR3 is G3A, -G3B-L1-G3C, —OR3a, or —N(R3a)(R3b).
  • 11. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein G1A is optionally substituted phenyl or optionally substituted 5-6 membered monocyclic heteroaryl;R2 is C1-C6 alkyl; andG3A is an optionally substituted 4-11 membered heterocycle.
  • 12. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein G1A is optionally substituted phenyl or optionally substituted 5-6 membered monocyclic heteroaryl;R2 is —OR2xa or G2A; andR2xa is G2B.
  • 13. The compound of claim 12 or a pharmaceutically acceptable salt thereof, wherein R2 is G2A; andG2A is optionally substituted C3-C6 monocyclic cycloalkyl.
  • 14. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is G1A or -G1B-G1C;R2 is C1-C6 alkyl or G2A; andR3 is G3A, -G3B-L1-G3C, or —OR3a.
  • 15. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is G1A;G1A is optionally substituted phenyl or optionally substituted 5-6 membered monocyclic heteroaryl;R2 is C1-C6 alkyl;R3 is G3A; andG3A is an optionally substituted 4-7 membered monocyclic heterocycle.
  • 16. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is G1A;G1A is optionally substituted phenyl or optionally substituted 5-6 membered monocyclic heteroaryl;R2 is G2A;G2A is optionally substituted C3-C6 monocyclic cycloalkyl;R3 is G3A; andG3A is optionally substituted phenyl, optionally substituted 5-6 membered monocyclic heteroaryl, or optionally substituted 4-11 membered heterocycle.
  • 17. The compound of claim 16 or a pharmaceutically acceptable salt thereof, wherein G3A is an optionally substituted 4-7 membered monocyclic heterocycle.
  • 18. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is G1A;G1A is optionally substituted phenyl or optionally substituted 5-6 membered monocyclic heteroaryl;R2 is C1-C6 alkyl or G2A;G2A is optionally substituted C3-C6 monocyclic cycloalkyl; andR3 is -G3B-L1-G3C.
  • 19. The compound of claim 18 or a pharmaceutically acceptable salt thereof, wherein L1 is a bond, C1-C3 alkylenyl, or (C1-C3 alkylenyl)r-L2-(C1-C3 alkylenyl)s;L2 is O, N(Rx), or C(O); andG3B is optionally substituted phenyl, optionally substituted 5-6 membered monocyclic heteroaryl, or optionally substituted 4-7 membered monocyclic heterocycle.
  • 20. The compound of claim 19 or a pharmaceutically acceptable salt thereof, wherein L2 is O or N(Rx); andG3B is an optionally substituted 4-7 membered monocyclic heterocycle.
  • 21. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is G1A;G1A is optionally substituted phenyl or optionally substituted 5-6 membered monocyclic heteroaryl;R2 is C1-C6 alkyl or G2A;G2A is optionally substituted C3-C6 monocyclic cycloalkyl;R3 is —OR3a; andR3a is G3E, C1-C6 haloalkyl, or C1-C6 alkyl; wherein the C1-C6 haloalkyl and the C1-C6 alkyl are each substituted with one or two substituents independently selected from the group consisting of G3E, —OR3xa, —C(O)G3D, —N(R3xb)2, and —S(O)2R3xc.
  • 22. The compound of claim 21 or a pharmaceutically acceptable salt thereof, wherein R3a is C1-C6 haloalkyl or C1-C6 alkyl; wherein the C1-C6 haloalkyl and the C1-C6 alkyl are each substituted with one G3E.
  • 23. The compound of claim 22 or a pharmaceutically acceptable salt thereof, wherein G3E is an optionally substituted 4-7 membered monocyclic heterocycle.
  • 24. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is -G1B-G1C;R2 is C1-C6 alkyl or G2A; andR3 is G3A, -G3B-L1-G3C, or —OR3a.
  • 25. The compound of claim 24 or a pharmaceutically acceptable salt thereof, wherein R3 is G3A; andG3A is optionally substituted phenyl, optionally substituted 5-6 membered monocyclic heteroaryl, or optionally substituted 4-11 membered heterocycle.
  • 26. The compound of claim 24 or a pharmaceutically acceptable salt thereof, wherein R3 is G3A; andG3A is optionally substituted 4-7 membered monocyclic heterocycle.
  • 27. The compound of claim 24 or a pharmaceutically acceptable salt thereof, wherein R3 is -G3B-L1-G3C; andG3B is optionally substituted phenyl, optionally substituted 5-6 membered monocyclic heteroaryl, or optionally substituted 4-7 membered monocyclic heterocycle.
  • 28. The compound of claim 24 or a pharmaceutically acceptable salt thereof, wherein R3 is -G3B-L1-G3C;L1 is a bond, C1-C3 alkylenyl, or (C1-C3 alkylenyl)r-L2-(C1-C3 alkylenyl)s;L2 is O or N(Rx); andG3B is optionally substituted 4-7 membered monocyclic heterocycle.
  • 29. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R3 is -G3B-L3-G3C-L4-G3F or —(C1-C6 alkylenyl)-G3E.
  • 30. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is G1A or -G1B-G1C;R2 is C1-C6 alkyl or G2A; andR3 is -G3B-L3-G3C-L4-G3F or —(C1-C6 alkylenyl)-G3E.
  • 31. The compound of claim 30 or a pharmaceutically acceptable salt thereof, wherein R1 is G1A;G1A is optionally substituted phenyl or optionally substituted 5-6 membered monocyclic heteroaryl;G2A is optionally substituted C3-C6 monocyclic cycloalkyl; andL4 is a bond, —(C1-C6 alkylenyl), N(R2x), or C(O).
  • 32. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: 3-methyl-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclohexyl-4-(4-methoxyphenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclopentyl-4-(4-methoxyphenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(2-cyanoethyl)-4-(4-methoxyphenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(morpholin-4-yl)phenyl]-1-phenyl-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-4-[4-(morpholin-4-yl)phenyl]-1-[5-(trifluoromethyl)-1H-pyrazol-3-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-1-phenyl-4-[4-(piperidin-1-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-4-[4-(4-methylpiperazin-1-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(3,5-difluorophenyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(3-chlorophenyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(3-fluorophenyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-1-(3-methylphenyl)-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(1,1-dioxo-1λ6,4-thiazinan-4-yl)phenyl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-4-[2-(morpholin-4-yl)pyrimidin-5-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-(ethoxycarbonyl)-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclohexyl-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(3-bromophenyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-(hydroxymethyl)-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(3-methylphenyl)-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(3-methoxyphenyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-4-[4-(morpholin-4-yl)phenyl]-1-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-4-[4-(morpholin-4-yl)phenyl]-1-(oxan-4-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-phenyl-3-(propan-2-yl)-4-[4-(pyrrolidin-1-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-1-phenyl-4-[4-(pyrrolidin-1-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[2-chloro-4-(morpholin-4-yl)phenyl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-4-[4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(3-fluoropyrrolidin-1-yl)phenyl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(4-acetylpiperazin-1-yl)phenyl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(3,5-dimethylphenyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-4-[4-(morpholin-4-yl)phenyl]-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-1-[3-(morpholin-4-yl)phenyl]-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[2-methoxy-4-(morpholin-4-yl)phenyl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclopropyl-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-4-[4-(morpholin-4-yl)phenyl]-1-[3-(trifluoromethoxy)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-[3-(dimethylamino)phenyl]-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(3,4-difluorophenyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-[3-(methanesulfonyl)phenyl]-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-1-(1-methylpiperidin-4-yl)-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-tert-butyl-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(2-chloropyridin-4-yl)-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3,5-dimethyl-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(3,5-dichlorophenyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-4-[4-(morpholin-4-yl)phenyl]-1-(3-sulfamoylphenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-1-(1-methyl-1H-pyrazol-4-yl)-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-[1-(tert-butoxycarbonyl)azetidin-3-yl]-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(morpholin-4-yl)phenyl]-1-phenyl-3-(prop-1-en-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(3-cyanophenyl)-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-4-[6-(morpholin-4-yl)pyridin-3-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(2-methoxypyridin-4-yl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(3-fluoro-5-methoxyphenyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-{4-[4-(methanesulfonyl)piperazin-1-yl]phenyl}-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclohexyl-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-(methylcarbamoyl)-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-(1-hydroxy-2-methylpropan-2-yl)-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(2-fluoropyridin-4-yl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-4-[4-(morpholin-4-yl)phenyl]-1-(2-oxo-1,2-dihydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(3-carbamoylphenyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(4-tert-butylpiperazin-1-yl)phenyl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(6-methoxypyridin-3-yl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclohexyl-4-[2-(dimethylamino)pyrimidin-5-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-(2-hydroxypropan-2-yl)-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-carbamoyl-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclohexyl-3-methyl-4-[2-(morpholin-4-yl)pyrimidin-5-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[3-bromo-4-(morpholin-4-yl)phenyl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclopentyl-4-[2-(dimethylamino)pyrimidin-5-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(morpholin-4-yl)phenyl]-1-(oxan-3-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclopentyl-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-{4-[4-(methoxycarbonyl)piperazin-1-yl]phenyl}-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(1-acetylpiperidin-4-yl)-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-{4-[3-(dimethylamino)azetidin-1-yl]phenyl}-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(3,3-dimethylazetidin-1-yl)phenyl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclohexyl-3-methyl-4-[6-(morpholin-4-yl)pyridin-3-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclohexyl-4-[2-(dimethylamino)pyrimidin-5-yl]-3-methyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-[1-(tert-butoxycarbonyl)pyrrolidin-2-yl]-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclopentyl-4-[6-(morpholin-4-yl)pyridin-3-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-(1-acetylazetidin-3-yl)-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[2-(morpholin-4-yl)pyrimidin-5-yl]-1-phenyl-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclohexyl-4-[2-(morpholin-4-yl)pyrimidin-5-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclohexyl-4-[6-(morpholin-4-yl)pyridin-3-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-1-phenyl-4-{4-[4-(3,3,3-trifluoropropyl)piperazin-1-yl]phenyl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclopentyl-4-[6-(dimethylamino)pyridin-3-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-[3-(dimethylamino)phenyl]-4-[2-(morpholin-4-yl)pyrimidin-5-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-[3-(dimethylamino)phenyl]-4-[6-(morpholin-4-yl)pyridin-3-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-[1-(methoxycarbonyl)azetidin-3-yl]-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-[(dimethylamino)methyl]-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[2-(dimethylamino)pyrimidin-5-yl]-1-[3-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[6-(dimethylamino)pyridin-3-yl]-1-[3-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-[3-(dimethylamino)phenyl]-3-methyl-4-[2-(morpholin-4-yl)pyrimidin-5-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-tert-butyl-1-cyclopentyl-4-[2-(dimethylamino)pyrimidin-5-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-(1-hydroxy-2-methylpropan-2-yl)-4-[6-(morpholin-4-yl)pyridin-3-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclohexyl-4-[6-(dimethylamino)pyridin-3-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-1-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-[1-(cyanomethyl)piperidin-4-yl]-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(cyclobutylamino)phenyl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(3,3-difluoroazetidin-1-yl)phenyl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-{4-[4-(cyanomethyl)piperazin-1-yl]phenyl}-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclohexyl-4-[6-(dimethylamino)pyridin-3-yl]-3-methyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-tert-butyl-1-cyclopentyl-4-[2-(morpholin-4-yl)pyrimidin-5-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(3-fluorophenyl)-3-methyl-4-[6-(morpholin-4-yl)pyridin-3-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-4-[6-(morpholin-4-yl)pyridin-3-yl]-1-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-[1-(tert-butoxycarbonyl)pyrrolidin-2-yl]-4-[6-(morpholin-4-yl)pyridin-3-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(2,4-difluorophenyl)-3-methyl-4-[6-(morpholin-4-yl)pyridin-3-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(2,4-difluorophenyl)-3-methyl-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclopentyl-3-methyl-4-[6-(morpholin-4-yl)pyridin-3-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-{4-[4-(2-hydroxyethyl)piperazin-1-yl]phenyl}-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(4,4-difluoropiperidin-1-yl)phenyl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(4-cyanopiperidin-1-yl)phenyl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-4-{4-[methyl(oxan-4-yl)amino]phenyl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(3,3-difluoropyrrolidin-1-yl)phenyl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-4-{4-[(oxetan-3-yl)amino]phenyl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-(3-methyloxetan-3-yl)-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(2,6-dimethylmorpholin-4-yl)phenyl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-{4-[cyclobutyl(methyl)amino]phenyl}-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-{4-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]phenyl}-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-4-(morpholin-4-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(2,2-dimethylmorpholin-4-yl)phenyl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(morpholin-4-yl)phenyl]-1-(oxolan-3-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-[3-(morpholin-4-yl)phenyl]-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-(methoxymethyl)-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-1-phenyl-4-(piperidin-1-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(3-hydroxyazetidin-1-yl)phenyl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(3-fluoroazetidin-1-yl)phenyl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-4-[4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-4-{4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]phenyl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(3,6-dihydro-2H-pyran-4-yl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-(1-methylcyclopropyl)-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-tert-butyl-1-cyclohexyl-4-[4-(dimethylamino)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(4-acetylpiperazin-1-yl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-{4-[2-(hydroxymethyl)morpholin-4-yl]phenyl}-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-4-[4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(azetidin-1-yl)phenyl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(cyanomethyl)piperazin-1-yl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(4-hydroxypiperidin-1-yl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(1-acetylpiperidin-4-yl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[1-(cyanomethyl)piperidin-4-yl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-4-{4-[methyl(oxetan-3-yl)amino]phenyl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-[1-(cyanomethyl)pyrrolidin-3-yl]-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-[1-(methoxycarbonyl)pyrrolidin-3-yl]-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(4-methoxypiperidin-1-yl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(4-hydroxypiperidin-1-yl)phenyl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-4-{4-[(oxan-4-yl)amino]phenyl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(methanesulfonyl)piperazin-1-yl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-tert-butyl-1-cyclohexyl-4-[2-(dimethylamino)pyrimidin-5-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-[1-(cyanomethyl)azetidin-3-yl]-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-tert-butyl-1-cyclohexyl-4-[2-(morpholin-4-yl)pyrimidin-5-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-4-(2-oxopiperidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-[3-(azetidin-1-yl)phenyl]-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(cyclohexylmethoxy)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(3-hydroxypyrrolidin-1-yl)phenyl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-4-[4-(2-oxa-7-azaspiro[3.5]nonan-7-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-{4-[(3S)-3-cyanopyrrolidin-1-yl]phenyl}-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(3-acetamidopyrrolidin-1-yl)phenyl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1-[3-(pyrrolidin-1-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-1-phenyl-4-(piperidine-1-carbonyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4,4-difluorocyclohexyl)-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-[3-(3,3-dimethylazetidin-1-yl)phenyl]-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1-[1-(2,2,2-trifluoroethyl)piperidin-3-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(3-methylphenyl)-4-(piperidin-1-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-[(1R,3R)-3-(benzyloxy)cyclohexyl]-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-[3-(3-methoxyazetidin-1-yl)phenyl]-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-[3-(3-fluoropyrrolidin-1-yl)phenyl]-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclohexyl-4-[2-(dimethylamino)pyrimidin-5-yl]-3-[1-(methoxycarbonyl)azetidin-3-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-[3-(3-fluoroazetidin-1-yl)phenyl]-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-4-{6-[methyl(oxan-4-yl)amino]pyridin-3-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclohexyl-4-{6-[methyl(oxan-4-yl)amino]pyridin-3-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclohexyl-4-{6-[(2-methoxyethyl)(methyl)amino]pyridin-3-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(4-acetamidophenyl)-1-cyclohexyl-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-{3-[(2-methoxyethyl)(methyl)amino]phenyl}-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(3-methylphenyl)-3-(propan-2-yl)-4-(pyrrolidin-1-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(3-fluoroazetidin-1-yl)-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(4-cyanopiperidin-1-yl)phenyl]-1-[3-(dimethylamino)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-1-[3-(dimethylamino)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-1-[3-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-{6-[(2-methoxyethyl)(methyl)amino]pyridin-3-yl}-1-[3-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-1-cyclohexyl-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclohexyl-4-[6-(3,3-difluoropyrrolidin-1-yl)pyridin-3-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{6-[methyl(oxan-4-yl)amino]pyridin-3-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclohexyl-4-{4-[(2-methoxyethyl)(methyl)amino]phenyl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(4-cyanopiperidin-1-yl)phenyl]-1-cyclohexyl-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(morpholin-4-yl)phenyl]-3-(oxolan-2-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-{6-[methyl(oxan-4-yl)amino]pyridin-3-yl}-1-[3-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-{4-[(2-methoxyethyl)(methyl)amino]phenyl}-1-[3-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-[3-(dimethylamino)phenyl]-4-{6-[methyl(oxan-4-yl)amino]pyridin-3-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(3-methoxypiperidin-1-yl)-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(4-cyanopiperidin-1-yl)-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(4-methoxypiperidin-1-yl)-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclohexyl-3-cyclopropyl-4-[6-(dimethylamino)pyridin-3-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;rac-1-[(1R,3R)-3-hydroxycyclohexyl]-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;rac-1-[(1R,3S)-3-hydroxycyclohexyl]-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclohexyl-4-[6-(2,6-dimethylmorpholin-4-yl)pyridin-3-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclohexyl-4-[6-(2,2-dimethylmorpholin-4-yl)pyridin-3-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(3-hydroxypiperidin-1-yl)phenyl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[2-(4-cyanopiperidin-1-yl)pyrimidin-5-yl]-1-[3-(dimethylamino)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-[3-(dimethylamino)phenyl]-4-{2-[methyl(oxan-4-yl)amino]pyrimidin-5-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(morpholin-4-yl)phenyl]-1-[2-(morpholin-4-yl)pyridin-4-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(3-methylphenyl)-4-(2-oxa-7-azaspiro[3.5]nonan-7-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[6-(4-cyano-4-methylpiperidin-1-yl)pyridin-3-yl]-1-cyclohexyl-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[2-(4-cyanopiperidin-1-yl)pyrimidin-5-yl]-1-[3-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-[(1R,3S)-3-methoxycyclohexyl]-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(4-cyanopiperidin-1-yl)phenyl]-1-[3-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-[3-(dimethylamino)phenyl]-4-{4-[methyl(oxan-4-yl)amino]phenyl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-{4-[methyl(oxan-4-yl)amino]phenyl}-1-[3-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[(2-methoxyethyl)(methyl)amino]-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(4,4-difluoropiperidin-1-yl)-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(morpholin-4-yl)phenyl]-1-[5-(morpholin-4-yl)pyridin-3-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(3-methoxyazetidin-1-yl)-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(hydroxymethyl)piperidin-1-yl]-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-[(1R,3R)-3-methoxycyclohexyl]-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(3-methylphenyl)-3-(propan-2-yl)-4-[3-(trifluoromethyl)pyrrolidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[5-(tert-butoxycarbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-{4-[3-(dimethylamino)pyrrolidin-1-yl]phenyl}-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(3-cyanopyrrolidin-1-yl)-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(4-cyanopiperidin-1-yl)phenyl]-3-cyclobutyl-1-cyclohexyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-cyclobutyl-1-cyclohexyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(4-cyanopiperidin-1-yl)phenyl]-3-(propan-2-yl)-1-[3-(pyrrolidin-1-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-(propan-2-yl)-1-[3-(pyrrolidin-1-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclohexyl-4-[6-(3-fluoropiperidin-1-yl)pyridin-3-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclohexyl-4-[6-(3-methoxypyrrolidin-1-yl)pyridin-3-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-[3-(3-hydroxyazetidin-1-yl)phenyl]-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[5-(cyanomethyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(methoxymethyl)piperidin-1-yl]-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(2-methoxyethyl)piperidin-1-yl]-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-chloropyridin-2-yl)-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-{2-[(2-methoxyethyl)(methyl)amino]pyrimidin-5-yl}-1-[3-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-{2-[methyl(oxan-4-yl)amino]pyrimidin-5-yl}-1-[3-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-{4-[4-(cyanomethyl)piperazin-1-yl]phenyl}-1-(3-methoxyphenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(5-acetylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[1-(tert-butoxycarbonyl)octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[2-(4-cyanopiperidin-1-yl)pyrimidin-5-yl]-1-cyclohexyl-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclohexyl-4-{2-[methyl(oxan-4-yl)amino]pyrimidin-5-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclohexyl-4-{2-[(2-methoxyethyl)(methyl)amino]pyrimidin-5-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-{4-[(2-methoxyethyl)(methyl)amino]phenyl}-3-(propan-2-yl)-1-[3-(pyrrolidin-1-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-[3-(azetidin-1-yl)phenyl]-4-{6-[(2-methoxyethyl)(methyl)amino]pyridin-3-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-[3-(azetidin-1-yl)phenyl]-4-{4-[methyl(oxan-4-yl)amino]phenyl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(morpholin-4-yl)phenyl]-1-[4-(morpholin-4-yl)pyridin-2-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(3-fluorophenyl)-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(3,4-difluorophenyl)-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(morpholin-4-yl)phenyl]-1-[6-(morpholin-4-yl)pyridin-2-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(3,5-difluorophenyl)-4-{4-[methyl(oxan-4-yl)amino]phenyl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(3,5-difluorophenyl)-4-{6-[methyl(oxan-4-yl)amino]pyridin-3-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(4-cyanopiperidin-1-yl)phenyl]-3-cyclobutyl-1-[3-(pyrrolidin-1-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-cyclobutyl-1-[3-(pyrrolidin-1-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-{4-[methyl(oxan-4-yl)amino]phenyl}-3-(propan-2-yl)-1-[3-(pyrrolidin-1-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-{6-[methyl(oxan-4-yl)amino]pyridin-3-yl}-3-(propan-2-yl)-1-[3-(pyrrolidin-1-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{4-[methyl(oxan-4-yl)amino]phenyl}-1-[3-(pyrrolidin-1-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{6-[methyl(oxan-4-yl)amino]pyridin-3-yl}-1-[3-(pyrrolidin-1-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-{6-[(2-methoxyethyl)(methyl)amino]pyridin-3-yl}-3-(propan-2-yl)-1-[3-(pyrrolidin-1-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclohexyl-4-{4-[methyl(oxan-4-yl)amino]phenyl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(1-acetyloctahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[1-(cyanomethyl)octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(methanesulfonyl)piperidin-1-yl]-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(3-methylphenyl)-4-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[2-(4-cyanopiperidin-1-yl)pyrimidin-5-yl]-3-(propan-2-yl)-1-[3-(pyrrolidin-1-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-(propan-2-yl)-1-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(4-cyanopiperidin-1-yl)phenyl]-3-(propan-2-yl)-1-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(3-methylphenyl)-4-(8-oxa-2-azaspiro[4.5]decan-2-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(4-cyanopiperidin-1-yl)-1-cyclohexyl-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclohexyl-4-(4-methoxypiperidin-1-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclohexyl-4-(piperidin-1-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclohexyl-4-[4-(hydroxymethyl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-[6-(dimethylamino)pyridin-2-yl]-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(3,5-difluorophenyl)-4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(morpholin-4-yl)phenyl]-3-(propan-2-yl)-1-[3-(trifluoromethoxy)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-[3-(dimethylamino)phenyl]-3-(propan-2-yl)-4-[3-(trifluoromethyl)pyrrolidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(1,1-difluoro-5-azaspiro[2.4]heptan-5-yl)-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[3-(methanesulfonyl)pyrrolidin-1-yl]-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(2-azaspiro[3.3]heptan-2-yl)-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(3-methylphenyl)-4-(5-oxa-2-azaspiro[3.5]nonan-2-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-{6-[bis(2-methoxyethyl)amino]pyridin-3-yl}-1-cyclohexyl-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclohexyl-4-{6-[methyl(oxolan-3-yl)amino]pyridin-3-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{2-[methyl(oxan-4-yl)amino]pyrimidin-5-yl}-1-[3-(pyrrolidin-1-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(3,4-difluorophenyl)-4-{4-[methyl(oxan-4-yl)amino]phenyl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-1-(3,4-difluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-{2-[methyl(oxan-4-yl)amino]pyrimidin-5-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-{2-[methyl(oxan-4-yl)amino]pyrimidin-5-yl}-3-(propan-2-yl)-1-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(4-cyanopiperidin-1-yl)phenyl]-1-(3,5-difluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(3-fluorophenyl)-4-{6-[methyl(oxan-4-yl)amino]pyridin-3-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(3-fluorophenyl)-4-{4-[methyl(oxan-4-yl)amino]phenyl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-1-(3-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(4-cyanopiperidin-1-yl)phenyl]-1-(3-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-{6-[methyl(oxan-4-yl)amino]pyridin-3-yl}-3-(propan-2-yl)-1-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-4-(4-methyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[3-(methoxymethyl)-3-methylazetidin-1-yl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-4-(3-oxohexahydroimidazo[1,5-a]pyrazin-2(3H)-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(methoxymethyl)piperidin-1-yl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(4-acetamidopiperidin-1-yl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-4-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[3-(methoxymethyl)azetidin-1-yl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[(3R)-3-methoxypyrrolidin-1-yl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[(3S)-3-methoxypyrrolidin-1-yl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(4-fluoropiperidin-1-yl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[(3R)-3-fluoropyrrolidin-1-yl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(3,3-difluoropyrrolidin-1-yl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[(3S)-3-fluoropyrrolidin-1-yl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-4-(3-oxotetrahydro-3H-[1,3]oxazolo[3,4-a]pyrazin-7(1H)-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-4-[3-(morpholin-4-yl)azetidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-{4-[(methanesulfonyl)amino]piperidin-1-yl}-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(3-azabicyclo[3.1.0]hexan-3-yl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-1-phenyl-4-[4-(pyrrolidine-1-carbonyl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-4-(6-oxa-2-azaspiro[3.4]octan-2-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(2-azaspiro[3.4]octan-2-yl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-4-(6-oxa-2-azaspiro[3.5]nonan-2-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(2-azaspiro[3.5]nonan-2-yl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(5-azaspiro[2.5]octan-5-yl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-4-(1-oxa-7-azaspiro[4.4]nonan-7-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-4-(5-oxa-2-azaspiro[3.5]nonan-2-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-4-(6-oxo-2,7-diazaspiro[4.4]nonan-2-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-{4-[(1S)-2-(dimethylamino)-1-fluoroethyl]piperidin-1-yl}-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-4-(1,4-oxazepan-4-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(3-fluorophenyl)-4-{2-[methyl(oxan-4-yl)amino]pyrimidin-5-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(3,5-difluorophenyl)-4-{2-[methyl(oxan-4-yl)amino]pyrimidin-5-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(2-methoxyethoxy)piperidin-1-yl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(dimethylcarbamoyl)piperidin-1-yl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(methanesulfonyl)-1,4-diazepan-1-yl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(3-methoxypropyl)piperazin-1-yl]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-4-[4-(morpholine-4-carbonyl)piperazin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-{4-[2-(dimethylamino)-2-oxoethyl]piperazin-1-yl}-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[2-(4-cyanopiperidin-1-yl)pyrimidin-5-yl]-1-(2,4-difluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-1-(2,4-difluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(4-cyanopiperidin-1-yl)phenyl]-1-(2,4-difluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-[3-(dimethylamino)phenyl]-4-(piperidin-1-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(4-cyanopiperidin-1-yl)-1-[3-(dimethylamino)phenyl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-[3-(dimethylamino)phenyl]-4-(4-methoxypiperidin-1-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-[3-(dimethylamino)phenyl]-4-[4-(hydroxymethyl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-(1-methylcyclobutyl)-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-{[cis-3-(1,1-dioxo-1λ6,4-thiazinan-4-yl)cyclobutyl]oxy}-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[2-(1,1-dioxo-1λ6,4-thiazinan-4-yl)ethoxy]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[(2S)-2-fluoro-2-(oxan-4-yl)ethoxy]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[(2R)-2-fluoro-2-(oxan-4-yl)ethoxy]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-4-{[(3S)-1-methylpyrrolidin-3-yl]oxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-4-{[(3R)-1-methylpyrrolidin-3-yl]oxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-4-[(1-methylpiperidin-4-yl)oxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-{[cis-3-(dimethylamino)cyclobutyl]oxy}-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-4-[(oxetan-3-yl)oxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-1-phenyl-4-[2-(pyrrolidin-1-yl)ethoxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-4-{[(3R)-1-methylpiperidin-3-yl]oxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-4-[(2-oxaspiro[3.3]heptan-6-yl)oxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-1-phenyl-4-{[trans-3-(piperidin-1-yl)cyclobutyl]oxy}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-1-phenyl-4-{[cis-3-(piperidin-1-yl)cyclobutyl]oxy}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[2-(3,3-difluorocyclobutyl)ethoxy]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(fluoromethyl)piperidin-1-yl]-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(3-fluorophenyl)-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(3,4-difluorophenyl)-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclohexyl-4-(1-methyl-1H-pyrrol-3-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclohexyl-4-(1,3-dimethyl-1H-pyrazol-4-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(3,5-difluorophenyl)-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-(morpholin-4-yl)phenyl]-1-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(3-fluoro-4-methylphenyl)-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-(morpholin-4-yl)phenyl]-1-[4-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-[4-(dimethylamino)phenyl]-4-[4-(morpholin-4-yl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(4-methoxypiperidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(3-methyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-8-yl)-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(3-azaspiro[5.5]undecan-3-yl)-1-(3-methylphenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclohexyl-3-(propan-2-yl)-4-[1-(propan-2-yl)-1H-pyrazol-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclohexyl-4-(1-methyl-1H-pyrrol-2-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclohexyl-3-(propan-2-yl)-4-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclohexyl-4-(1-oxo-2,3-dihydro-1H-isoindol-5-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-1-(oxan-3-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[2-(3-cyanopiperidin-1-yl)pyrimidin-5-yl]-1-cyclohexyl-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{4-[2-oxo-2-(pyrrolidin-1-yl)ethoxy]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-[3-(dimethylamino)phenyl]-4-[4-(methoxymethyl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-(propan-2-yl)-1-[2-(pyrrolidin-1-yl)pyridin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclohexyl-4-(1-methyl-1H-pyrazol-5-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl]-1-cyclohexyl-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-phenyl-4-{4-[(propan-2-yl)oxy]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[3-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(2-{[1-(tert-butoxycarbonyl)piperidin-4-yl](methyl)amino}pyrimidin-5-yl)-1-cyclohexyl-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-4-[(3-methyloxetan-3-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[(4-methoxycyclohexyl)oxy]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[2-fluoro-2-(oxan-4-yl)ethoxy]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[(3-fluoro-1-methylpyrrolidin-3-yl)methoxy]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[(2S)-2-fluoro-2-(1-methylpiperidin-4-yl)ethoxy]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[(2R)-2-fluoro-2-(1-methylpiperidin-4-yl)ethoxy]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[3-fluoro-1-(oxetan-3-yl)piperidin-3-yl]methoxy-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[(3,3-difluorocyclopentyl)methoxy]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-methyl-4-[2-oxo-2-(piperidin-1-yl)ethoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[1-(methanesulfonyl)cyclobutyl]methoxy-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-{2-[cyclopropyl(2-methylpropyl)amino]ethoxy}-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[(3,3-difluoro-1-methylcyclobutyl)methoxy]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-{[1-(fluoromethyl)cyclopropyl]methoxy}-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-{[1-(2-methoxyethyl)cyclopropyl]methoxy}-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[(2,2-difluorocyclopentyl)methoxy]-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(morpholin-4-yl)phenyl]-1-phenyl-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-[4-(methoxymethyl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(4-cyanopiperidin-1-yl)phenyl]-3-(propan-2-yl)-1-[2-(pyrrolidin-1-yl)pyridin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-(4-methoxypiperidin-1-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-[4-(hydroxymethyl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(4-butoxypiperidin-1-yl)-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-[4-(2-methylpropoxy)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-(4-methoxy-4-methylpiperidin-1-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-(1-oxa-7-azaspiro[3.5]nonan-7-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[3-(difluoromethyl)piperidin-1-yl]-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-(6-oxa-2-azaspiro[3.5]nonan-2-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-(1-oxa-8-azaspiro[4.5]decan-8-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclohexyl-3-(propan-2-yl)-4-(2,2,6,6-tetramethyl-3,6-dihydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-(2-methoxyethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(2-azaspiro[3.4]octan-2-yl)-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(3-azabicyclo[3.1.0]hexan-3-yl)-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(cyclohexylmethoxy)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-phenyl-4-(piperidin-1-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(2-azaspiro[3.5]nonan-2-yl)-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(4-cyanopiperidin-1-yl)-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-(methanesulfonyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(4-methoxypiperidin-1-yl)-3-(propan-2-yl)-1-[2-(pyrrolidin-1-yl)pyridin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-cyclobutyl-1-[2-(pyrrolidin-1-yl)pyridin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[2-(oxan-4-yl)ethoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(2S)-2-fluoro-2-(oxan-4-yl)ethoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-cyclobutyl-1-[2-(morpholin-4-yl)pyridin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(oxan-4-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[3-(methoxymethyl)azetidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(5-azaspiro[2.5]octan-5-yl)-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-(3,3-difluorocyclobutyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-(cis-3-methoxycyclobutyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(2-methoxyethyl)(methyl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(1,1-difluoro-5-azaspiro[2.4]heptan-5-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(5-oxa-2-azaspiro[3.5]nonan-2-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(2-azaspiro[3.3]heptan-2-yl)-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-{4-[(benzyloxy)methyl]piperidin-1-yl}-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(cis-4-methoxycyclohexyl)oxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(trans-4-methoxycyclohexyl)oxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-(3,3-dimethylcyclobutyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclohexyl-4-[4-(methoxymethyl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-(cis-3-fluorocyclobutyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-(trans-3-fluorocyclobutyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(2R)-2-fluoro-2-(oxan-4-yl)ethoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(3,3-difluorocyclopentyl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[2-(1,1-dioxo-1λ6,4-thiazinan-4-yl)ethoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-1-[2-(morpholin-4-yl)pyridin-4-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-[4-(2-methoxypropan-2-yl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[(cis-3-tert-butoxycyclobutyl)(methyl)amino]-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(3-methylazetidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(3,3-difluoropyrrolidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-phenyl-4-[3-(trifluoromethyl)pyrrolidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-phenyl-4-[4-(pyrrolidin-1-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(4-fluoropiperidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(3S,4S)-3,4-dihydroxypyrrolidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{4-[2-(dimethylamino)ethyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{4-[2-(diethylamino)ethyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-(cyclopropylmethyl)piperazin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(4-cyclobutylpiperazin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(3-fluoro-3-methylazetidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(8-azaspiro[4.5]decan-8-yl)-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(3,3-difluoro-1-oxa-8-azaspiro[4.5]decan-8-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(1′-methyl[4,4′-bipiperidin]-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{4-[(1R)-2-(dimethylamino)-1-fluoroethyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{4-[(1S)-2-(dimethylamino)-1-fluoroethyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{4-[(1S)-1-fluoro-2-hydroxyethyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{4-[(1R)-1-fluoro-2-hydroxyethyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{4-fluoro-4-[(2-methoxyethoxy)methyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[3-(ethoxymethyl)-3-fluoropiperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-(ethoxymethyl)-4-fluoropiperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{3-fluoro-3-[(2-methoxyethoxy)methyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-fluoro-4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(3R,4R)-3-fluoro-4-hydroxypiperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(3R,4R)-4-fluoro-3-hydroxypiperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-phenyl-4-[3-(piperidin-1-yl)azetidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(3R)-3-(methanesulfonyl)pyrrolidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(3-methoxypiperidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-oxo-1-(propan-2-yl)-1,3,8-triazaspiro[4.5]decan-8-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-phenyl-4-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-(3-hydroxypropyl)piperazin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{4-[2-oxo-2-(pyrrolidin-1-yl)ethyl]piperazin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(azepan-1-yl)-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{4-[2-(morpholin-4-yl)-2-oxoethyl]piperazin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(7R,8aS)-7-hydroxyhexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(3,3-difluoro-1-methylcyclobutyl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[2-(3,3-difluorocyclobutyl)ethoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{2-[(oxetan-3-yl)(propan-2-yl)amino]ethoxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[(1-acetyl-4-fluoropiperidin-4-yl)methoxy]-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{[(2S)-oxolan-2-yl]methoxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[2-(3-methoxyazetidin-1-yl)-2-oxoethoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(2R)-2-fluoro-2-(1-methylpiperidin-4-yl)ethoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{2-[(oxetan-3-yl)oxy]ethoxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{2-[1-(2-methoxyethyl)cyclopropyl]ethoxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{[1-(2-methoxyethyl)cyclopropyl]methoxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(2,2-difluorocyclopentyl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[3-(morpholin-4-yl)propoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[2-(1,3-dioxan-2-yl)ethoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(3-fluoropropoxy)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(3-methyloxetan-3-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(1,3-dimethoxypropan-2-yl)oxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{[cis-3-(dimethylamino)cyclobutyl]oxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(2-methyl-1,3-dioxan-5-yl)oxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{[(3S)-1-methylpiperidin-3-yl]oxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(2-oxaspiro[3.3]heptan-6-yl)oxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{[(3R)-1-methylpiperidin-3-yl]oxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-[(1-acetylazetidin-3-yl)oxy]-4-[4-(morpholin-4-yl)phenyl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-(1-methoxyethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-phenyl-4-[4-(1,1,1-trifluoro-2-methoxypropan-2-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[3-(diethylcarbamoyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(4-hydroxypiperidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{4-[2-(1,4-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)ethyl]piperazin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(4aS,7aR)-4-methyl-3-oxohexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(3-oxopiperazin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(5 aS,8aS)-2-oxooctahydropyrrolo[3,4-b]azepin-7(1H)-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(2R)-4,4-difluoro-2-(hydroxymethyl)pyrrolidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(2S,4S)-4-fluoro-2-(hydroxymethyl)pyrrolidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[3-fluoro-3-(methoxymethyl)pyrrolidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(3R,4S)-3-fluoro-4-hydroxypiperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[3-(ethoxymethyl)-3-fluoropyrrolidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[3-(hydroxymethyl)-3-methylazetidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(3S)-3-methoxypyrrolidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[3-(2,2-difluoroethoxy)azetidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(2R,4S)-4-fluoro-2-(hydroxymethyl)pyrrolidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(7S,8aS)-7-fluorohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(4aS,7aS)-4-methyl-3-oxohexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-fluoro-4-(hydroxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(1-oxa-7-azaspiro[4.4]nonan-7-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{4-[(methanesulfonyl)amino]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-(1-fluoro-2-hydroxyethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[3-(methoxymethyl)-3-methylazetidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(3R)-3-methoxypyrrolidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-(methanesulfonyl)piperazin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-{6-[bis(2-methoxyethyl)amino]pyridin-3-yl}-1-[2-(morpholin-4-yl)pyridin-4-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(methoxymethyl)piperidin-1-yl]-1-[2-(morpholin-4-yl)pyridin-4-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-methoxy-4-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(3S)-3-fluoropyrrolidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(3,3-difluoroazetidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[3-(2-oxo-1,3-oxazolidin-3-yl)azetidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(3-ethyl-3-fluoroazetidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[2-(hydroxymethyl)morpholin-4-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{3-fluoro-3-[(2-methoxyethoxy)methyl]pyrrolidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(cis-3-hydroxycyclobutyl)(methyl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(6-oxa-2-azaspiro[3.4]octan-2-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(3R,4S)-4-fluoro-3-hydroxypiperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(3-hydroxy-3-methylazetidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(6-oxo-2,7-diazaspiro[4.4]nonan-2-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(2S)-4,4-difluoro-2-(hydroxymethyl)pyrrolidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-(ethoxycarbonyl)piperazin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{4-[2-(cyclohexylamino)-2-oxoethyl]piperazin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(3R)-3-fluoropyrrolidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(3-methoxyazetidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(2-hydroxy-7-azaspiro[3.5]nonan-7-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(3R)-3-(hydroxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(1,4-oxazepan-4-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-hydroxy-4-(2-hydroxyethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(cyclobutylmethyl)-4-[4-(methoxymethyl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(methoxymethyl)piperidin-1-yl]-1-(2-methylpropyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;rac-4-[(3aR,7aS)-1-(tert-butoxycarbonyl)octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-1-phenyl-3-[(pyrrolidin-3-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-(trans-3-methylcyclobutyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-{[1-(tert-butoxycarbonyl)pyrrolidin-3-yl]oxy}-4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-{[1-(tert-butoxycarbonyl)piperidin-4-yl]oxy}-4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{methyl[(oxan-4-yl)methyl]amino}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-phenyl-4-[4-(2-propoxyethyl)piperazin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-phenyl-4-{2-[(piperidin-1-yl)methyl]morpholin-4-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-phenyl-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{4-[3-(morpholin-4-yl)propyl]piperazin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{4-[2-(dimethylamino)-2-oxoethyl]piperazin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(2-cyanoethyl)piperazin-1-yl]-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{2-[(dimethylamino)methyl]morpholin-4-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(4-methylpiperazin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(methyl {[1-(2-methylpropyl)piperidin-4-yl]methyl}amino)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{methyl[2-(morpholin-4-yl)ethyl]amino}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-(2-ethoxyethyl)piperazin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(3R)-3-(dimethylamino)pyrrolidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{4-[2-(methylamino)-2-oxoethyl]piperazin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{4-[(morpholin-4-yl)acetyl]piperazin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-(2-methoxyethyl)piperazin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{4-[(oxolan-2-yl)methyl]-1,4-diazepan-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-phenyl-4-{3-[(propan-2-yl)oxy]azetidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-phenyl-4-{4-[2-(pyrrolidin-1-yl)ethyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{4-[2-(morpholin-4-yl)ethyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-([1,4′-bipiperidin]-1′-yl)-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(3R)-3-(morpholin-4-yl)pyrrolidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(4,4-difluorocyclohexyl)oxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(oxan-4-yl)oxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{[(1S,2S)-2-methoxycyclohexyl]oxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(3-ethyloxetan-3-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{[(3R)-oxolan-3-yl]oxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{[(3S)-oxolan-3-yl]oxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-methoxy-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(cyclobutyloxy)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[2-(2-methoxyethoxy)ethoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[(3aR,7aS)-1-acetyloctahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[(3aS,7aR)-1-acetyloctahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(methoxymethyl)piperidin-1-yl]-1-[2-(morpholin-4-yl)pyrimidin-4-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{[(oxan-4-yl)methyl]amino}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-[(oxolan-3-yl)oxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[6-(4-cyanopiperidin-1-yl)pyridin-3-yl]-3-[(oxetan-3-yl)oxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{methyl[(1-methylpiperidin-3-yl)methyl]amino}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(4,4-difluoropiperidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[3-fluoro-3-(methoxymethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-phenyl-4-[2-(trifluoromethyl)morpholin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(cyclopentyloxy)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-{[cis-3-(azetidin-1-yl)cyclobutyl]oxy}-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(1-cyclohexylazetidin-3-yl)oxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(3,3-difluorocyclobutyl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(1-methylazetidin-3-yl)oxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-[3-(dimethylamino)phenyl]-4-[(oxan-4-yl)methoxy]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclohexyl-4-[(oxan-4-yl)methoxy]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-[2-(oxan-4-yl)ethoxy]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-(2-methoxypropan-2-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[3-(dimethylamino)propoxy]-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-[3-(morpholin-4-yl)propoxy]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-[(3-methyloxetan-3-yl)methoxy]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-[(oxolan-2-yl)methoxy]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;rac-3-cyclobutyl-1-phenyl-4-[(3aR,7aS)-1-{[(propan-2-yl)oxy]carbonyl}octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-(dimethylamino)butoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[(1-acetylpiperidin-4-yl)oxy]-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-phenyl-4-(2,2,2-trifluoroethoxy)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{2-[2-(dimethylamino)ethoxy]ethoxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{[(2S)-1-(dimethylamino)propan-2-yl]oxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(4,4-difluorocyclohexyl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{[(2R)-5-oxopyrrolidin-2-yl]methoxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{[(3S)-6-oxopiperidin-3-yl]oxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(5-ethyl-1,3-dioxan-5-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{[(3-endo)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl]oxy}-1-phenyl-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(5-methyl-1,3-dioxan-5-yl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[2-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)ethoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[3-(diethylamino)propoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{2-[cyclohexyl(oxetan-3-yl)amino]ethoxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{[4-fluoro-1-(methanesulfonyl)piperidin-4-yl]methoxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{[4-(methanesulfonyl)oxan-4-yl]methoxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-phenyl-4-[2-(pyrrolidin-1-yl)ethoxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[2-(methanesulfonyl)-2-methylpropoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(1-methylcyclopropyl)methoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[2-(1-methylcyclopropyl)ethoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{[1-(methanesulfonyl)cyclobutyl]methoxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(2-cyclohexylethoxy)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[3-(4-methylpiperazin-1-yl)propoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[3-(dimethylamino)propoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[3-(dimethylamino)-2,2-dimethylpropoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[2-(dimethylamino)ethoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-{[1,3-bis(dimethylamino)propan-2-yl]oxy}-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-phenyl-4-[2-(piperidin-1-yl)ethoxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[2-(2-oxoimidazolidin-1-yl)ethoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-{[1,3-bis(morpholin-4-yl)propan-2-yl]oxy}-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-phenyl-4-[3-(piperidin-1-yl)propoxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[2-(azepan-1-yl)ethoxy]-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[2-(4-methyl-1,4-diazepan-1-yl)ethoxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{[(2s,4r)-5-methyl-5-azaspiro[3.4]octan-2-yl]oxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(1-{3-[(diethylamino)methyl]oxetan-3-yl}azetidin-3-yl)oxy]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-phenyl-4-{[1-(propan-2-yl)piperidin-4-yl]oxy}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(cycloheptyloxy)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(cyclooctyloxy)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{[(3R)-1-methylpyrrolidin-3-yl]oxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{[(3S)-1-methylpyrrolidin-3-yl]oxy}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[(3,3-difluoro-1-methylcyclobutyl)methoxy]-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-[3-(piperidin-1-yl)propoxy]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[(1,3-dimethoxypropan-2-yl)oxy]-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-({[(2S)-oxolan-2-yl]methyl}amino)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-[4-(2-hydroxypropan-2-yl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(methoxymethyl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(4-fluorophenyl)-4-[(oxan-4-yl)methoxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-(2-hydroxypropan-2-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(dimethylamino)piperidin-1-yl]-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-(1′-methyl[4,4′-bipiperidin]-1-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[(1-acetylpiperidin-4-yl)methoxy]-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-{[1-(methoxycarbonyl)piperidin-4-yl]methoxy}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-[(oxane-4-carbonyl)amino]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(cyanomethyl)-4-hydroxypiperidin-1-yl]-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(ethoxymethyl)-4-fluoropiperidin-1-yl]-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-{4-fluoro-4-[(2-methoxyethoxy)methyl]piperidin-1-yl}-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[(3R,4R)-3-fluoro-4-hydroxypiperidin-1-yl]-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-fluoro-4-(methoxymethyl)piperidin-1-yl]-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-{3-fluoro-3-[(2-methoxyethoxy)methyl]piperidin-1-yl}-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[(3S)-3-{[(tert-butoxycarbonyl)amino]methyl}pyrrolidin-1-yl]-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[(3R)-3-{[(tert-butoxycarbonyl)amino]methyl}pyrrolidin-1-yl]-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(1,1-dioxo-1λ6,4-thiazinan-4-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[(3R)-3-{[(tert-butoxycarbonyl)(methyl)amino]methyl}pyrrolidin-1-yl]-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[(3S)-3-{[(tert-butoxycarbonyl)(methyl)amino]methyl}pyrrolidin-1-yl]-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{(3S)-3-[(methylamino)methyl]pyrrolidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(2,6-dimethylpyridin-4-yl)-4-[4-(methoxymethyl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-(2-methoxypyridin-4-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-phenyl-4-[3-(pyrrolidin-1-yl)azetidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{4-[(oxolan-2-yl)methyl]piperazin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-(1-methoxypropan-2-yl)piperazin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{4-[1-(morpholin-4-yl)ethyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{4-[(1,3-dioxolan-2-yl)methyl]piperazin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-(2-methoxyethoxy)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-phenyl-4-{4-[(piperidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{4-[2-(4-methylpiperidin-1-yl)ethyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-(2,6-dimethylmorpholin-4-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-(diethylamino)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[{3-[cyclohexyl(methyl)amino]propyl}(methyl)amino]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-phenyl-4-[4-(propan-2-yl)-1,4-diazepan-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(3aR,6aS)-5-(2-methylpropyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-([1,4′-bipiperidin]-1′-yl)-3-cyclobutyl-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{4-[4-(2-methoxyethyl)piperazin-1-yl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{4-[2-(4-methylpiperazin-1-yl)ethyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-(ethoxyacetyl)piperazin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(3R)-3-(2-oxopyrrolidin-1-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(4′-methyl[1,4′-bipiperidin]-1′-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{4-[(2-methylpropoxy)carbonyl]piperazin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(4-methyl-1,4-diazepan-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(4-acetylpiperazin-1-yl)-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-(3-methoxypropyl)piperazin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(4-cyclopentyl-1,4-diazepan-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(3R)-3-hydroxypiperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-phenyl-4-(4-propylpiperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-(dimethylcarbamoyl)piperazin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[3-(morpholin-4-yl)azetidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(4-butyl-1,4-diazepan-1-yl)-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[3-(morpholine-4-carbonyl)[1,4′-bipiperidin]-1′-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-phenyl-4-(4-propyl-1,4-diazepan-1-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-phenyl-4-[(3R)-3-(piperidin-1-yl)pyrrolidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(7-cyano-5-oxa-2-azaspiro[3.4]octan-2-yl)-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{4-[3-(4-methyl-1,4-diazepan-1-yl)-3-oxopropyl]piperazin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-(dimethylcarbamoyl)-4-(2-oxopyrrolidin-1-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-(cyclohexylmethyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(6-oxa-2-azaspiro[3.5]nonan-2-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-(2-hydroxyethyl)piperazin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[3-(4-methylmorpholin-2-yl)azetidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(3-{4-[methyl(oxetan-3-yl)amino]piperidin-1-yl}azetidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{3-[4-(morpholin-4-yl)piperidin-1-yl]azetidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{4-[1-(2-ethoxyethyl)piperidin-4-yl]piperazin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{4-[1-(2-hydroxypropyl)piperidin-4-yl]piperazin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{4-[3-(dimethylamino)propyl]piperazin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{4-[4-(2-ethoxyethyl)piperazin-1-yl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-phenyl-4-{4-[2-(piperidin-1-yl)ethoxy]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{4-[3-(diethylamino)propyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-phenyl-4-{4-[3-(piperidin-1-yl)propyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-phenyl-4-{4-[3-(pyrrolidin-1-yl)propyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{4-[ethyl(oxetan-3-yl)amino]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{4-[methyl(oxetan-3-yl)amino]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[1′-(oxetan-3-yl)[4,4′-bipiperidin]-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-(dimethylamino)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-(4-methylpiperazine-1-carbonyl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-[3-(4-methylmorpholin-2-yl)azetidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-{4-[1-(2-ethoxyethyl)piperidin-4-yl]piperazin-1-yl}-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-{4-[1-(2-hydroxypropyl)piperidin-4-yl]piperazin-1-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(1-cyclopropylpiperidin-4-yl)piperazin-1-yl]-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-{4-[4-(oxetan-3-yl)piperazin-1-yl]piperidin-1-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-{4-[4-(2-ethoxyethyl)piperazin-1-yl]piperidin-1-yl}-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-{4-[4-(2-methoxyethyl)piperazin-1-yl]piperidin-1-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-{4-[3-(diethylamino)propyl]piperidin-1-yl}-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-{4-[3-(piperidin-1-yl)propyl]piperidin-1-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-3-(propan-2-yl)-4-{4-[3-(pyrrolidin-1-yl)propyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-{4-[ethyl(oxetan-3-yl)amino]piperidin-1-yl}-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-{4-[methyl(oxetan-3-yl)amino]piperidin-1-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-[1′-(oxetan-3-yl)[4,4′-bipiperidin]-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl]-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-[4-(4-methylpiperazine-1-carbonyl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-(3-{4-[methyl(oxetan-3-yl)amino]piperidin-1-yl}azetidin-1-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-{3-[4-(morpholin-4-yl)piperidin-1-yl]azetidin-1-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-{4-[3-(dimethylamino)propyl]piperazin-1-yl}-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-[4-methyl-4-(4-methylpiperazin-1-yl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-{4-[2-(piperidin-1-yl)ethoxy]piperidin-1-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-5-methyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclohexyl-4-[4-(4-methylpiperazine-1-carbonyl)phenyl]-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-[3-(morpholin-4-yl)azetidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-3-(propan-2-yl)-4-(4-propyl-1,4-diazepan-1-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(4-cyclobutyl-1,4-diazepan-1-yl)-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(4-butyl-1,4-diazepan-1-yl)-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-(4-methyl-1,4-diazepan-1-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-[(8aR)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(4-acetylpiperazin-1-yl)-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(4-ethylpiperazin-1-yl)-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-[4-(2-hydroxyethyl)piperazin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(dimethylcarbamoyl)piperazin-1-yl]-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(ethoxyacetyl)piperazin-1-yl]-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-[4-(3-methoxypropyl)piperazin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-3-(propan-2-yl)-4-(4-propylpiperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-{4-[2-(2-hydroxyethoxy)ethyl]piperazin-1-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-{4-[3-(4-methyl-1,4-diazepan-1-yl)-3-oxopropyl]piperazin-1-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(cyclohexylmethyl)piperidin-1-yl]-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-[(3R)-3-hydroxypiperidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-(4′-methyl[1,4′-bipiperidin]-1′-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-{4-[2-(4-methylpiperazin-1-yl)ethyl]piperidin-1-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-[(3R)-3-(piperidin-1-yl)pyrrolidin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(diethylamino)piperidin-1-yl]-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(4-tert-butylpiperazin-1-yl)-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-3-(propan-2-yl)-4-{4-[1-(pyrrolidin-1-yl)ethyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-{4-[(piperidin-1-yl)methyl]piperidin-1-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-{4-[(1-methylpiperidin-3-yl)methyl]piperazin-1-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-{4-[(oxolan-2-yl)methyl]piperazin-1-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-[4-(1-methoxypropan-2-yl)piperazin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-3-(propan-2-yl)-4-[3-(pyrrolidin-1-yl)azetidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-3-(propan-2-yl)-4-[4-(propan-2-yl)-1,4-diazepan-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-[(3aR,6aS)-5-(2-methylpropyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(4-ethyl-1,4-diazepan-1-yl)-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-(4-hydroxy-4-{[methyl(propan-2-yl)amino]methyl}piperidin-1-yl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-{4-[methyl(propan-2-yl)amino]piperidin-1-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-{4-[2-(diethylamino)ethyl]piperazin-1-yl}-1-(4-fluorophenyl)-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(4-{[(3R)-3-(methoxymethyl)pyrrolidin-1-yl]methyl}piperidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(4-{[(3R)-3-methoxypyrrolidin-1-yl]methyl}piperidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(4-{[(3S)-3-(methoxymethyl)pyrrolidin-1-yl]methyl}piperidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(4-fluorophenyl)-4-{4-[1-(morpholin-4-yl)ethyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-cyclohexyl-4-{4-[(morpholin-4-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-cyclohexyl-4-{4-[2-(morpholin-4-yl)ethyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-(cyclobutyloxy)-1-cyclohexyl-4-{4-[(morpholin-4-yl)methyl]phenyl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-cyclohexyl-4-[4-(pyridin-4-yl)piperazin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(4-fluorophenyl)-4-{4-[2-(morpholin-4-yl)ethyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-3-(propan-2-yl)-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-phenyl-4-{4-[1-(pyrrolidin-1-yl)ethyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(3-oxo-2,8-diazaspiro[4.5]decan-2-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-{4-[(2-methylpropoxy)carbonyl]piperazin-1-yl}-3-(propan-2-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(2-methoxypyridin-4-yl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-(methoxymethyl)piperidin-1-yl]-1-[2-(oxan-4-yl)pyridin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-phenyl-4-[4-(propan-2-yl)piperazin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-[2-(oxan-4-yl)pyridin-4-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(3-methylphenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(4-fluorophenyl)-4-{4-[(morpholin-4-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(3-methoxyphenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-[4-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(4-fluoro-3-methylphenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(3-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{4-[(3-fluoroazetidin-1-yl)methyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{4-[(3,3-difluoropyrrolidin-1-yl)methyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{4-[(3-methoxyazetidin-1-yl)methyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{4-[(3,3-difluoropiperidin-1-yl)methyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(4-{[3-(methoxymethyl)azetidin-1-yl]methyl}piperidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(4-{[(3R)-3-fluoropyrrolidin-1-yl]methyl}piperidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(4-{[(3S)-3-fluoropyrrolidin-1-yl]methyl}piperidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{4-[(1,4-oxazepan-4-yl)methyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(4-{[3-(2,2-difluoroethoxy)azetidin-1-yl]methyl}piperidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{4-[(6-oxa-2-azaspiro[3.5]nonan-2-yl)methyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{4-[(6-oxa-2-azaspiro[3.4]octan-2-yl)methyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(4-{[(7S,8aS)-7-fluorohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]methyl}piperidin-1-yl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{4-[(4-formyl-1,4-diazepan-1-yl)methyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{4-[(2-oxa-7-azaspiro[3.5]nonan-7-yl)methyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{4-[(4-methoxypiperidin-1-yl)methyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{4-[(2-oxa-6-azaspiro[3.4]octan-6-yl)methyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{4-[(4-formylpiperazin-1-yl)methyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-{4-[(3-azabicyclo[3.1.0]hexan-3-yl)methyl]piperidin-1-yl}-3-cyclobutyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-{4-[(5-methyl-6-oxo-2-oxa-5,8-diazaspiro[3.5]nonan-8-yl)methyl]piperidin-1-yl}-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(3-fluoropyrrolidin-1-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(3-cyanoazetidin-1-yl)piperidin-1-yl]-3-cyclobutyl-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(3-methoxypyrrolidin-1-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(4-fluoro[1,4′-bipiperidin]-1′-yl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(4,4-difluoro[1,4′-bipiperidin]-1′-yl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(2-cyanomorpholin-4-yl)piperidin-1-yl]-3-cyclobutyl-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(4-fluorophenyl)-4-{4-[2-(methoxymethyl)morpholin-4-yl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(4-fluorophenyl)-4-{4-[methyl(oxan-4-yl)amino]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-{2-[(propan-2-yl)oxy]pyridin-4-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-[2-(benzyloxy)pyridin-4-yl]-3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(4-fluorophenyl)-4-[(morpholin-4-yl)methyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(4-fluorophenyl)-4-[(4-methylpiperazin-1-yl)methyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(4-fluorophenyl)-4-{[4-(methoxymethyl)piperidin-1-yl]methyl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(4-cyano[1,4′-bipiperidin]-1′-yl)-3-cyclobutyl-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclohexyl-4-{4-[4-(dimethylamino)piperidine-1-carbonyl]phenyl}-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(4-fluorophenyl)-4-[3-(pyrrolidin-1-yl)-1-oxa-8-azaspiro[4.5]decan-8-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclohexyl-3-[(propan-2-yl)oxy]-4-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-cyclohexyl-4-[4-(2-methylpyridin-4-yl)piperazin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-cyclohexyl-4-{6-[4-(propan-2-yl)piperazin-1-yl]pyridin-3-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-cyclohexyl-4-{4-[1-(morpholin-4-yl)ethyl]phenyl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-cyclohexyl-4-{4-[4-(propan-2-yl)piperazin-1-yl]phenyl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-cyclohexyl-4-[6-(4-cyclopropylpiperazin-1-yl)pyridin-3-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(4-fluorophenyl)-4-{4-[3-(trifluoromethyl)pyrrolidin-1-yl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[4-(3-cyanopyrrolidin-1-yl)piperidin-1-yl]-3-cyclobutyl-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(3-cyano[1,4′-bipiperidin]-1′-yl)-3-cyclobutyl-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(3-fluoro[1,4′-bipiperidin]-1′-yl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(3-methoxyazetidin-1-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(4-fluorophenyl)-4-[3-(trifluoromethyl)[1,4′-bipiperidin]-1′-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(4-fluorophenyl)-4-(3-methoxy[1,4′-bipiperidin]-1′-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-(2,2-dimethylmorpholin-4-yl)piperidin-1-yl]-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-cyclohexyl-4-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-cyclohexyl-4-{6-[4-(2-methoxyethyl)piperazin-1-yl]pyridin-3-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(4-fluorophenyl)-4-{4-[4-(propan-2-yl)piperazin-1-yl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-cyclohexyl-4-{4-[4-(propan-2-yl)piperazin-1-yl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[(3S)-4-benzyl-3-methylpiperazin-1-yl]-3-cyclobutyl-1-cyclohexyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-[(3R)-4-benzyl-3-methylpiperazin-1-yl]-3-cyclobutyl-1-cyclohexyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclohexyl-4-[4-(4-methylpiperazin-1-yl)phenyl]-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclohexyl-4-{4-[(4-cyclopropylpiperazin-1-yl)methyl]phenyl}-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(2-hydroxypyridin-4-yl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-(4-cyclopropylpiperazin-1-yl)piperidin-1-yl]-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(9-cyclopropyl-3,9-diazaspiro[5.5]undecan-3-yl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(4-fluorophenyl)-4-{4-[(pyrrolidin-1-yl)methyl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-[2-(difluoromethoxy)pyridin-4-yl]-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(4-fluorophenyl)-4-[9-(propan-2-yl)-3,9-diazaspiro[5.5]undecan-3-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid3-cyclobutyl-4-{4-[4-(ethoxycarbonyl)piperazin-1-yl]piperidin-1-yl}-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(4-fluorophenyl)-4-(4-methoxy[1,4′-bipiperidin]-1′-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(4-fluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]methyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(9-cyclobutyl-3,9-diazaspiro[5.5]undecan-3-yl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(4-fluorophenyl)-4-{4-[(2-methoxyethyl)(methyl)amino]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(4-fluorophenyl)-4-{4-[4-(2-methoxyethyl)piperazin-1-yl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(4-fluorophenyl)-4-[9-(2-methoxyethyl)-3,9-diazaspiro[5.5]undecan-3-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(4-fluorophenyl)-4-(4-hydroxy[1,4′-bipiperidin]-1′-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(4-fluorophenyl)-4-{4-[4-(oxetan-3-yl)piperazin-1-yl]piperidin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(4-fluorophenyl)-4-[1-(propan-2-yl)octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-(1-cyclobutyloctahydro-5H-pyrrolo[3,2-c]pyridin-5-yl)-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(4-fluorophenyl)-4-[1-(oxetan-3-yl)octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(4-fluorophenyl)-4-[1-(oxan-4-yl)octahydro-5H-pyrrolo[3,2-c]pyridin-5-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(4-fluorophenyl)-4-[9-(oxetan-3-yl)-3,9-diazaspiro[5.5]undecan-3-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(3,5-difluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(3,4-difluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(4-fluoro-3-methoxyphenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-[4-(trifluoromethoxy)phenyl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-[3-(difluoromethoxy)phenyl]-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(bicyclo[4.2.0]octa-1,3,5-trien-3-yl)-3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(3-fluoro-4-methoxyphenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(3-fluoro-5-methoxyphenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-[4-(difluoromethoxy)phenyl]-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-[3-(1,1-difluoroethyl)phenyl]-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(2,5-difluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-[6-(2-fluoroethoxy)pyridin-3-yl]-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-{2-[(oxan-4-yl)oxy]pyridin-4-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-{2-[(oxan-4-yl)methoxy]pyridin-4-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(2,4-difluorophenyl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(2,2-difluoro-2H-1,3-benzodioxol-4-yl)-4-[4-(morpholin-4-yl)piperidin-1-yl]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;4-(4-cyanophenyl)-1-cyclohexyl-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-(morpholin-4-yl)piperidin-1-yl]-1-{6-[(propan-2-yl)oxy]pyridin-2-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-3-hydroxy-4-(4-methoxy[1,4′-bipiperidin]-1′-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-(4-fluorophenyl)-4-(4-methoxy[1,4′-bipiperidin]-1′-yl)-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;1-cyclohexyl-4-(4-{[3-(dimethylamino)azetidin-1-yl]methyl}phenyl)-3-[(propan-2-yl)oxy]-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-1-(4-fluorophenyl)-4-(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid;3-cyclobutyl-4-[4-(ethoxycarbonyl)piperazin-1-yl]-1-(4-fluorophenyl)-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid; and3-cyclobutyl-1-(4-fluorophenyl)-4-{4-[(2-methylpropoxy)carbonyl]piperazin-1-yl}-1H-pyrazolo[3,4-b]pyridine-6-carboxylic acid.
  • 33. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.
  • 34. A method for treating cystic fibrosis in a subject comprising administering a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
  • 35. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, one potentiator, and one or more additional correctors.
  • 36. A method for treating cystic fibrosis in a subject comprising administering a compound of claim 1 or a pharmaceutically acceptable salt thereof, one potentiator, and one or more additional correctors, to a subject in need thereof.
  • 37. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents.
  • 38. The pharmaceutical composition of claim 37 wherein the additional therapeutic agents are selected from the group consisting of CFTR modulators and CFTR amplifiers.
  • 39. The pharmaceutical composition of claim 37 wherein the additional therapeutic agents are CFTR modulators.
  • 40. A method for treating cystic fibrosis in a subject comprising administering a compound of claim 1 or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents.
  • 41. The method of claim 40 wherein the additional therapeutic agents are selected from the group consisting of CFTR modulators and CFTR amplifiers.
  • 42. The method of claim 40 wherein the additional therapeutic agents are CFTR modulators.
CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No. 62/239,475, filed Oct. 9, 2015, which is incorporated herein by reference for all purposes.

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Related Publications (1)
Number Date Country
20170101406 A1 Apr 2017 US
Provisional Applications (1)
Number Date Country
62239475 Oct 2015 US