HETEROCYCLIC KINASE INHIBITORS AND PRODUCTS AND USES THEREOF

Abstract

Compounds are provided having the structure of Formula (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein A, X, R3, R5, R6, R7, R8, Y2, Y4, Y6, Y7, Y8, Y9, m, and n are as defined herein. Such compounds inhibit tyrosine kinase receptors, particularly the platelet derived growth factor receptor-alpha (PDGFR-α) and/or the platelet derived growth factor receptor-beta (PDGFR-β). Products containing such compounds, as well as methods for their use and preparation, are also provided.

Description

FIELD OF THE INVENTION

The present invention relates generally to tyrosine kinase receptor modulators, and particularly to compounds that modulate the platelet derived growth factor receptor (PDGFR), as well as to products containing the same and to methods of their use and preparation.

BACKGROUND

Receptor tyrosine kinases are transmembrane polypeptides that regulate the regeneration, remodeling, development, and differentiation of cells. Among the receptor tyrosine kinases is the platelet derived growth factor receptor (PDGFR), which is associated with pulmonary diseases, tissue fibrosis, and solid tumors.

Among the pulmonary diseases, pulmonary hypertension (PH) is a rare disorder of the pulmonary vasculature that is associated with high morbidity and mortality. The pathology of the disease includes plexiform lesions of disorganized angiogenesis and abnormal neointimal cellular proliferation, which obstruct blood flow through the pulmonary arterioles. Known kinase receptor inhibitors, and in particular known PDGFR inhibitors, are not orally available and or are associated with with off-target effects that can contribute to PH development and/or are associated with dose limiting side effects. Accordingly, there remains a need in the art for agents that can be administered orally and can inhibit PDGFRα and/or PDGFRβ with improved potency and selectivity over other kinases known to be involved with dose-limiting side effects (e.g. cKit, FLT3, and VEGFR2).

BRIEF SUMMARY

In one embodiment, compounds are provided having the structure of Formula (I):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein:

X is —C(O)NH—, —C(R¹⁰R¹¹)C(O)NH—, —NHC(O)NH—, or —NHC(O)—;

ring A is carbocycle or heterocycle;

Y² is a bond, —CR²═, NR², or —N═;

Y⁴ is a bond, —CR⁴═, —NR⁴—, or —N═;

R² or R⁴, together with R³ and the atoms to which they are attached, form ring B;

R² is H, halogen, cyano, alkyl, haloalkyl, alkoxy, —NH₂, —NHR⁹, or —NR⁹R⁹ when R³ and R⁴ form ring B;

R⁴ is H, halogen, cyano, alkyl, haloalkyl, alkoxy, —NH₂, —NHR⁹, or —NR⁹R⁹ when R³ and R² form ring B;

ring B is a 5- to 6-membered carbocycle or 5- to 6-membered heterocycle, wherein ring B is substituted by (R⁹)_p;

Y⁶, Y⁷, Y⁸, and Y⁹ are each, independently, —CH═, —CR⁷═, or N;

R⁵ is H, alkyl, haloalkyl, or hydroxyalkyl;

R⁶ is H, alkyl, haloalkyl, or hydroxyalkyl;

or R⁵ and R⁶, together with the carbon atom they are attached to, form a 3- to 5-membered carbocycle or heterocycle;

R⁷ is, at each occurrence, independently halogen, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy;

or R⁶ and one R⁷, together with the atoms to which they are attached, form a 5- to 6-membered carbocycle;

R⁸ is, at each occurrence, independently halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —C(O)R^a, —OC(O)R^a, —C(O)OR^a, —OC(O)OR^a, —C(O)NR^aR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, C_1-4 alkyl, C_1-4 alkenyl, C_1-4 alkynyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁸ together form ═O;

R⁹ is, at each occurrence, halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, alkyl, alkenyl, alkynyl, haloalkyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁹ together form ═O;

R¹⁰ is H, alkyl, or haloalkyl;

R¹¹ is H, alkyl, or haloalkyl;

wherein R⁷, R⁸, and R⁹ are each, independently, optionally substituted with one or more R;

R is —OR^a, —C(O)R^a, —NR^aR^b, halogen, cyano, alkyl, haloalkyl, alkoxy, carbocycle, heterocycle, carbocyclalkyl, or heterocyclealkyl;

R^a is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

R^b is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

or R^a and R^b, together with the nitrogen atom to which they are attached, form C_4-8 cycloalkyl, or 4- to 8-membered saturated heterocycle;

m is 0-5, wherein m is 1-5 when ring B is a 6-membered carbocycle;

n is 0-5;

p is 0-5; and

q is 0-2.

In another embodiment, compounds are provided having the structure listed in Table 5, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof.

In another embodiment, a substantially enantiomerically pure form of a compound is provided having the structure listed in Table 5 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof.

In another embodiment, a composition is provided comprising a compound having the structure of any one of Formulas (I)-(XX), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

In another embodiment, a method for inhibiting PDGF receptor α is provided, comprising contacting the PDGF receptor α with an effective amount of a compound having the structure of any one of Formulas (I)-(XX), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, or a composition comprising the same.

In another embodiment, a method for inhibiting PDGF receptor β is provided, comprising contacting the PDGF receptor β with an effective amount of a compound having the structure of any one of Formulas (I)-(XX), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, or a composition comprising the same.

In another embodiment, a method for treating a PDGF receptor α-dependent condition is provided, comprising administering to a subject in need thereof an effective amount of a compound having the structure of any one of Formulas (I)-(XX), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, or a composition comprising the same.

In another embodiment, a method for treating a PDGF receptor β-dependent condition is provided, comprising administering to a subject in need thereof an effective amount of a compound having the structure of any one of Formulas (I)-(XX), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, or a composition comprising the same.

In another embodiment, a method for treating a pulmonary disorder is provided, comprising administering to a subject in need thereof an effective amount of a compound having the structure of any one of Formulas (I)-(XX), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, or a composition comprising the same. In one embodiment, the pulmonary disorder is pulmonary hypertension. In a further embodiment, pulmonary hypertension is pulmonary arterial hypertension.

In another embodiment, a method for treating systemic sclerosis is provided, comprising administering to a subject in need thereof an effective amount of a compound having the structure of any one of Formulas (I)-(XX), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, or a composition comprising the same.

In another embodiment, a method for treating tissue fibrosis is provided, comprising administering to a subject in need thereof an effective amount of a compound having the structure of any one of Formulas (I)-(XX), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, or a composition comprising the same.

In another embodiment, a method for treating solid tumors is provided, comprising administering to a subject in need thereof an effective amount of a compound having the structure of any one of Formulas (I)-(XX), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, or a composition comprising the same.

DETAILED DESCRIPTION

Unless specifically defined otherwise, the technical terms, as used herein, have their normal meaning as understood in the art. The following explanations of terms and methods are provided to better describe the present compounds, compositions and methods, and to guide those of ordinary skill in the art in the practice of the present disclosure. It is also to be understood that the terminology used in the disclosure is for the purpose of describing particular embodiments and examples only and is not intended to be limiting.

As used herein, the singular terms “a,” “an,” and “the” include plural referents unless context clearly indicates otherwise. Similarly, the word “or” is intended to include “and” unless the context clearly indicates otherwise. Also, as used herein, the term “comprises” means “includes.” Thus the phrase “comprising A or B” means including A, B, or A and B.

As mentioned above, the invention relates to compounds that modulate one or both of the PDGF receptor α and the PDGF receptor β. As used herein, a “modulator” of the PDGF receptor α and the PDGF receptor β is a compound which, when administered to a subject, provides the desired modulation of the target receptor. For example, the compound may function as a full or partial antagonist or agonist of the receptor, either by interacting directly or indirectly with the target receptor.

In one embodiment, compounds are provided having the structure of Formula (I):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein:

X is —C(O)NH—, —C(R¹⁰R¹¹)C(O)NH—, —NHC(O)NH—, or —NHC(O)—;

ring A is carbocycle or heterocycle;

Y² is a bond, —CR²═, —NR²—, or —N═;

Y⁴ is a bond, —CR⁴═, —NR⁴—, or —N═;

R² or R⁴, together with R³ and the atoms to which they are attached, form ring B;

R² is H, halogen, cyano, alkyl, haloalkyl, alkoxy, —NH₂, —NHR⁹, or —NR⁹R⁹ when R³ and R⁴ form ring B;

R⁴ is H, halogen, cyano, alkyl, haloalkyl, alkoxy, —NH₂, —NHR⁹, or —NR⁹R⁹ when R³ and R² form ring B;

ring B is a 5- to 6-membered carbocycle or 5- to 6-membered heterocycle, wherein ring B is substituted by (R⁹)_p;

Y⁶, Y⁷, Y⁸, and Y⁹ are each, independently, —CH═, —CR⁷═, or N;

R⁵ is H, alkyl, haloalkyl, or hydroxyalkyl;

R⁶ is H, alkyl, haloalkyl, or hydroxyalkyl;

or R⁵ and R⁶, together with the carbon atom they are attached to, form a 3- to 5-membered carbocycle or heterocycle;

R⁷ is, at each occurrence, independently halogen, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy;

or R⁶ and one R⁷, together with the atoms to which they are attached, form a 5- to 6-membered carbocycle;

R⁸ is, at each occurrence, independently halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —C(O)R^a, —OC(O)R^a, —C(O)OR^a, —OC(O)OR^a, —C(O)NR^aR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, C_1-4 alkyl, C_1-4 alkenyl, C_1-4 alkynyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁸ together form ═O;

R⁹ is, at each occurrence, halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, alkyl, alkenyl, alkynyl, haloalkyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁹ together form ═O;

R¹⁰ is H, alkyl, or haloalkyl;

R¹¹ is H, alkyl, or haloalkyl;

wherein R⁷, R⁸, and R⁹ are each, independently, optionally substituted with one or more R;

R is —OR^a, —C(O)R^a, —NR^aR^b, halogen, cyano, alkyl, haloalkyl, alkoxy, carbocycle, heterocycle, carbocyclalkyl, or heterocyclealkyl;

R^a is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

R^b is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

or R^a and R^b, together with the nitrogen atom to which they are attached, form C_4-8 cycloalkyl, or 4- to 8-membered saturated heterocycle;

m is 0-5, wherein m is 1-5 when ring B is a 6-membered carbocycle;

n is 0-5;

p is 0-5; and

q is 0-2.

As used herein, “alkyl” means a straight chain or branched saturated hydrocarbon group. “Lower alkyl” means a straight chain or branched alkyl group having from 1 to 8 carbon atoms, in some embodiments from 1 to 6 carbon atoms, in some embodiments from 1 to 4 carbon atoms, and in some embodiments from 1 to 2 carbon atoms. Examples of straight chain lower alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched lower alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups.

“Alkenyl” groups include straight and branched chain and cyclic alkyl groups as defined above, except that at least one double bond exists between two carbon atoms. Thus, alkenyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to —CH═CH₂, —CH═CH(CH₃), —CH═C(CH₃)₂, —C(CH₃)═CH₂, —C(CH₃)═CH(CH₃), —C(CH₂CH₃)═CH₂, —CH═CHCH₂CH₃, —CH═CH(CH₂)₂CH₃, —CH═CH(CH₂)₃CH₃, —CH═CH(CH₂)₄CH₃, vinyl, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among others.

“Alkynyl” groups include straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms. Thus, alkynyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to —C≡CH, —C≡C(CH₃), —C≡C(CH₂CH₃), —CH₂C≡CH, —CH₂C≡C(CH₃), and —CH₂C≡C(CH₂CH₃), among others.

As used herein, “alkylene” means a divalent alkyl group. Examples of straight chain lower alkylene groups include, but are not limited to, methylene (i.e., —CH₂—), ethylene (i.e., —CH₂CH₂—), propylene (i.e., —CH₂CH₂CH₂—), and butylene (i.e., —CH₂CH₂CH₂CH₂—). As used herein, “heteroalkylene” is an alkylene group of which one or more carbon atoms is replaced with a heteroatom such as, but not limited to, N, O, S, or P.

“Alkoxy” refers to an alkyl as defined above joined by way of an oxygen atom (i.e., —O-alkyl). Examples of lower alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, n-butoxy, isopropoxy, sec-butoxy, tert-butoxy, and the like.

The terms “carbocyclic” and “carbocycle” denote a ring structure wherein the atoms of the ring are carbon. Carbocycles may be monocyclic or polycyclic. Carbocycle encompasses both saturated and unsaturated rings. Carbocycle encompasses both fused and spirocyclic rings. Carbocycle encompasses both cycloalkyl and aryl groups. In some embodiments, the carbocycle has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms is 4, 5, 6, or 7. Unless specifically indicated to the contrary, the carbocyclic ring can be substituted with as many as N substituents wherein N is the size of the carbocyclic ring with for example, alkyl, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.

“Cycloalkyl” groups are alkyl groups forming a ring structure, which can be substituted or unsubstituted. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 3 to 6, or 3 to 7. Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like. Cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above. Representative substituted cycloalkyl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups or mono-, di- or tri-substituted norbornyl or cycloheptyl groups, which can be substituted with, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.

“Aryl” groups are cyclic aromatic hydrocarbons that do not contain heteroatoms. Thus aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, aryl groups contain 6-14 carbons in the ring portions of the groups. The terms “aryl” and “aryl groups” include include fused rings wherein at least one ring, but not necessarily all rings, are aromatic, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like).

“Carbocyclealkyl” refers to an alkyl as defined above with one or more hydrogen atoms replaced with carbocycle. Examples of carbocyclealkyl groups include, but are not limited to benzyl and the like.

As used herein, “heterocycle” or “heterocyclyl” groups include aromatic and non-aromatic ring compounds (heterocyclic rings) containing 3 or more ring members, of which one or more is a heteroatom such as, but not limited to, N, O, S, or P. A heterocycle group as defined herein can be a heteroaryl group or a partially or completely saturated cyclic group including at least one ring heteroatom. In some embodiments, heterocycle groups include 3 to 20 ring members, whereas other such groups have 3 to 15 ring members. At least one ring contains a heteroatom, but every ring in a polycyclic system need not contain a heteroatom. Heterocycle encompasses both fused and spirocyclic rings. For example, a dioxolanyl ring and a benzdioxolanyl ring system (methylenedioxyphenyl ring system) are both heterocycle groups within the meaning herein. A heterocycle group designated as a C₂-heterocycle can be a 5-membered ring with two carbon atoms and three heteroatoms, a 6-membered ring with two carbon atoms and four heteroatoms and so forth. Likewise a C₄-heterocycle can be a 5-membered ring with one heteroatom, a 6-membered ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms. A saturated heterocyclic ring refers to a heterocyclic ring containing no unsaturated carbon atoms.

“Heteroaryl” groups are aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S. A heteroaryl group designated as a C₂-heteroaryl can be a 5-membered ring with two carbon atoms and three heteroatoms, a 6-membered ring with two carbon atoms and four heteroatoms and so forth. Likewise a C₄-heteroaryl can be a 5-membered ring with one heteroatom, a 6-membered ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms. Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, and quinazolinyl groups. The terms “heteroaryl” and “heteroaryl groups” include fused ring compounds such as wherein at least one ring, but not necessarily all rings, are aromatic, including tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl and 2,3-dihydro indolyl.

“Heterocyclealkyl” refers to an alkyl as defined above with one or more hydrogen atoms replaced with heterocycle. Examples of heterocyclealkyl groups include, but are not limited to morpholinoethyl and the like.

“Halo” or “halogen” refers to fluorine, chlorine, bromine and iodine.

“Haloalkyl” refers to an alkyl as defined above with one or more hydrogen atoms replaced with halogen. Examples of lower haloalkyl groups include, but are not limited to, —CF₃, —CH₂CF₃, and the like.

“Haloalkoxy” refers to an alkoxy as defined above with one or more hydrogen atoms replaced with halogen. Examples of lower haloalkoxy groups include, but are not limited to —OCF₃, —OCH₂CF₃, and the like.

“Hydroxyalkyl” refers to an alkyl as defined above with one or more hydrogen atoms replaced with —OH. Examples of lower hydroxyalkyl groups include, but are not limited to —CH₂OH, —CH₂CH₂OH, and the like.

As used herein, the term “optionally substituted” refers to a group (e.g., an alkyl, carbocycle, or heterocycle) having 0, 1, or more substituents, such as 0-25, 0-20, 0-10 or 0-5 substituents. Substituents include, but are not limited to —OR^a, —NR^aR^b, —S(O)₂R^a or —S(O)₂OR^a, halogen, cyano, alkyl, haloalkyl, alkoxy, carbocycle, heterocycle, carbocyclalkyl, or heterocyclealkyl, wherein each R^a and R^b is, independently, H, alkyl, haloalkyl, carbocycle, or heterocycle, or R^a and R^b, together with the atom to which they are attached, form a 3-8 membered carbocycle or heterocycle.

In one embodiment, compounds are provided having the structure of Formula (I):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein A, X, R³, R⁵, R⁶, R⁷, R⁸, R⁹, Y², Y⁴, Y⁶, Y⁷, Y⁸, Y⁹, m, and n are as defined above. In one embodiment, ring A is a monocyclic carbocycle. In another embodiment, ring A is a polycyclic carbocycle. In one embodiment, ring A is a monocyclic heterocycle. In another embodiment, ring A is a polycyclic heterocycle.

In one embodiment, compounds are provided having the structure of Formula (I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein ring A is a monocyclic heterocycle. In one embodiment, ring A is pyrrolidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, oxatriazolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, thiatriazolyl, piperidinyl, piperazinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, 2H-pyranyl, tetrahydro-2H-pyranyl, or morpholinyl.

In one embodiment, compounds are provided having the structure of Formula (I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein ring A is a polycyclic heterocycle. In one embodiment, ring A is indolyl, benzimidazolyl, indazolyl, benzotriazolyl, 1H-pyrrolo [3,2-b]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl, [1,2,3]triazolo[4,5-b]pyridinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-purinyl, indolizinyl, pyrrolo[1,2-a]pyrimidinyl, pyrrolo[1,2-a]pyrazinyl, pyrrolo[1,2-c]pyriminyl, pyrrolo[1,2-b]pyridazinyl, imidazo[4,5-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, imidazo[1,5-a]pyridinyl, imidazo[1,5-b]pyridazinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-c]pyrimidinyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[4,3-a]pyridinyl, [1,2,3-triazolo[1,5-a]pyridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrido[2,3-b]pyrazinyl, pteridinyl, pyrido[3,4-d]pyridazinyl, 1,6-naphthyridinyl, 1,8-naphthyridinyl, 9H-carbazolyl, benzoxazolyl, dibenzofuranyl, benzothiphenyl, or dibenzothiophenyl.

In one embodiment, compounds are provided having the structure of Formula (I), wherein Y² is C, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof. In another embodiment, Y² is N. In another embodiment, Y² is a bond.

In one embodiment, compounds are provided having the structure of Formula (I), wherein Y⁴ is C, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof. In another embodiment, Y⁴ is N. In another embodiment, Y⁴ is a bond.

In one embodiment, compounds are provided wherein R² and R³, together with the atoms to which they are attached, form ring B and having the structure of Formula (II):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein:

X is —C(O)NH—, —C(R¹⁰R¹¹)C(O)NH—, —NHC(O)NH—, or —NHC(O)—;

ring A is carbocycle or heterocycle;

Y² is C or N;

Y⁴ is a bond, —CR⁴═, or —N═;

R⁴ is H, halogen, cyano, alkyl, haloalkyl, alkoxy, —NH₂, —NHR⁹, or —NR⁹R⁹;

ring B is a 5- to 6-membered carbocycle or 5- to 6-membered heterocycle;

Y⁶, Y⁷, Y⁸, and Y⁹ are each, independently, —CH═, —CR⁷═, or N;

R⁵ is H, alkyl, haloalkyl, or hydroxyalkyl;

R⁶ is H, alkyl, haloalkyl, or hydroxyalkyl;

or R⁵ and R⁶, together with the carbon atom they are attached to, form a 3- to 5-membered carbocycle or heterocycle;

R⁷ is, at each occurrence, independently halogen, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy;

or R⁶ and one R⁷, together with the atoms to which they are attached, form a 5- to 6-membered carbocycle;

R⁸ is, at each occurrence, independently halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —C(O)R^a, —OC(O)R^a, —C(O)OR^a, —OC(O)OR^a, —C(O)NR^aR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, C_1-4 alkyl, C_1-4 alkenyl, C_1-4 alkynyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁸ together form ═O;

R⁹ is, at each occurrence, halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, alkyl, alkenyl, alkynyl, haloalkyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁹ together form ═O;

R¹⁰ is H, alkyl, or haloalkyl;

R¹¹ is H, alkyl, or haloalkyl;

wherein R⁷, R⁸, and R⁹ are each, independently, optionally substituted with one or more R;

R is —OR^a, —C(O)R^a, —NR^aR^b, halogen, cyano, alkyl, haloalkyl, alkoxy, carbocycle, heterocycle, carbocyclalkyl, or heterocyclealkyl;

R^a is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

R^b is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

or R^a and R^b, together with the nitrogen atom to which they are attached, form C_4-8 cycloalkyl, or 4- to 8-membered saturated heterocycle;

m is 0-5, wherein m is 1-5 when ring B is a 6-membered carbocycle;

n is 0-5;

p is 0-5; and

q is 0-2.

In one embodiment, compounds are provided having the structure of Formula (III):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein:

X is —C(O)NH—, —C(R¹⁰R¹¹)C(O)NH—, —NHC(O)NH—, or —NHC(O)—;

ring A is carbocycle or heterocycle;

Y² is C or N;

Y⁴ is a bond, —CR⁴═, or —N═;

R⁴ is H, halogen, cyano, alkyl, haloalkyl, alkoxy, —NH₂, —NHR⁹, or —NR⁹R⁹;

Q¹ and Q² are each, independently, C or N;

Q³ and Q⁴ are each, independently, a bond, C, N, S, or O;

Y⁶, Y⁷, Y⁸, and Y⁹ are each, independently, —CH═, —CR⁷═, or N;

R⁵ is H, alkyl, haloalkyl, or hydroxyalkyl;

R⁶ is H, alkyl, haloalkyl, or hydroxyalkyl;

or R⁵ and R⁶, together with the carbon atom they are attached to, form a 3- to 5-membered carbocycle or heterocycle;

R⁷ is, at each occurrence, independently halogen, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy;

or R⁶ and one R⁷, together with the atoms to which they are attached, form a 5- to 6-membered carbocycle;

R⁸ is, at each occurrence, independently halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —C(O)R^a, —OC(O)R^a, —C(O)OR^a, —OC(O)OR^a, —C(O)NR^aR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, C_1-4 alkyl, C_1-4 alkenyl, C_1-4 alkynyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁸ together form ═O;

R⁹ is, at each occurrence, halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, alkyl, alkenyl, alkynyl, haloalkyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁹ together form ═O;

R¹⁰ is H, alkyl, or haloalkyl;

R¹¹ is H, alkyl, or haloalkyl;

wherein R⁷, R⁸, and R⁹ are each, independently, optionally substituted with one or more R;

R is —OR^a, —C(O)R^a, —NR^aR^b, halogen, cyano, alkyl, haloalkyl, alkoxy, carbocycle, heterocycle, carbocyclalkyl, or heterocyclealkyl;

R^a is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

R^b is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

or R^a and R^b, together with the nitrogen atom to which they are attached, form C_4-8 cycloalkyl, or 4- to 8-membered saturated heterocycle;

m is 0-5, wherein m is 1-5 when Q¹, Q², Q³, and Q⁴ are each C;

n is 0-5;

p is 0-5; and

q is 0-2.

In one embodiment, compounds are provided having the structure of Formula (IV):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein:

X is —C(O)NH—, —C(R¹⁰R¹¹)C(O)NH—, —NHC(O)NH—, or —NHC(O)—;

ring A is carbocycle or heterocycle;

Y² is C or N;

Y⁴ is a bond, —CR⁴═, or —N═;

R⁴ is H, halogen, cyano, alkyl, haloalkyl, alkoxy, —NH₂, —NHR⁹, or —NR⁹R⁹;

Q¹ and Q² are each, independently, C or N;

Q³ and Q⁴ are each, independently, a bond, C, N, S, or O;

R⁵ is H, alkyl, haloalkyl, or hydroxyalkyl;

R⁶ is H, alkyl, haloalkyl, or hydroxyalkyl;

or R⁵ and R⁶, together with the carbon atom they are attached to, form a 3- to 5-membered carbocycle or heterocycle;

R⁷ is, at each occurrence, independently halogen, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy;

or R⁶ and one R⁷, together with the atoms to which they are attached, form a 5- to 6-membered carbocycle;

R⁸ is, at each occurrence, independently halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —C(O)R^a, —OC(O)R^a, —C(O)OR^a, —OC(O)OR^a, —C(O)NR^aR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, C_1-4 alkyl, C_1-4 alkenyl, C_1-4 alkynyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁸ together form ═O;

R⁹ is, at each occurrence, halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, alkyl, alkenyl, alkynyl, haloalkyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁹ together form ═O;

R¹⁰ is H, alkyl, or haloalkyl;

R¹¹ is H, alkyl, or haloalkyl;

wherein R⁷, R⁸, and R⁹ are each, independently, optionally substituted with one or more R;

R is —OR^a, —C(O)R^a, —NR^aR^b, halogen, cyano, alkyl, haloalkyl, alkoxy, carbocycle, heterocycle, carbocyclalkyl, or heterocyclealkyl;

R^a is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

R^b is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

or R^a and R^b, together with the nitrogen atom to which they are attached, form C_4-8 cycloalkyl, or 4- to 8-membered saturated heterocycle;

m is 0-5, wherein m is 1-5 when Q¹, Q², Q³, and Q⁴ are each C;

n is 0-5;

p is 0-5; and

q is 0-2.

In one embodiment, compounds are provided having the structure of Formula (V):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein:

X is —C(O)NH—, —C(R¹⁰R¹¹)C(O)NH—, —NHC(O)NH—, or —NHC(O)—;

Y² is C or N;

Y⁴ is a bond, —CR⁴═, or —N═;

R⁴ is H, halogen, cyano, alkyl, haloalkyl, alkoxy, —NH₂, —NHR⁹, or —NR⁹R⁹;

Q¹ and Q² are each, independently, C or N;

Q³ and Q⁴ are each, independently, C, N, S, or O; Z¹, Z², Z³, Z⁴, and Z⁵ are each, independently, a bond, C, N, S, or O;

R⁵ is H, alkyl, haloalkyl, or hydroxyalkyl;

R⁶ is H, alkyl, haloalkyl, or hydroxyalkyl;

or R⁵ and R⁶, together with the carbon atom they are attached to, form a 3- to 5-membered carbocycle or heterocycle;

R⁷ is, at each occurrence, independently halogen, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy;

or R⁶ and one R⁷, together with the atoms to which they are attached, form a 5- to 6-membered carbocycle;

R⁸ is, at each occurrence, independently halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —C(O)R^a, —OC(O)R^a, —C(O)OR^a, —OC(O)OR^a, —C(O)NR^aR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, C_1-4 alkyl, C_1-4 alkenyl, C_1-4 alkynyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁸ together form ═O;

R⁹ is, at each occurrence, halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, alkyl, alkenyl, alkynyl, haloalkyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁹ together form ═O;

R¹⁰ is H, alkyl, or haloalkyl;

R¹¹ is H, alkyl, or haloalkyl;

wherein R⁷, R⁸, and R⁹ are each, independently, optionally substituted with one or more R;

R is —OR^a, —C(O)R^a, —NR^aR^b, halogen, cyano, alkyl, haloalkyl, alkoxy, carbocycle, heterocycle, carbocyclalkyl, or heterocyclealkyl;

R^a is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

R^b is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

or R^a and R^b, together with the nitrogen atom to which they are attached, for, C_4-8 cycloalkyl, or 4- to 8-membered saturated heterocycle;

m is 0-5, wherein m is 1-5 when Q¹, Q², Q³, and Q⁴ are each C;

n is 0-5;

p is 0-5; and

q is 0-2.

In one embodiment, compounds are provided having the structure of Formula (VI):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein:

X is —C(O)NH—, —C(R¹⁰R¹¹)C(O)NH—, —NHC(O)NH—, or —NHC(O)—;

Y⁴ is a bond, —CR⁴═, or —N═;

R⁴ is H, halogen, cyano, alkyl, haloalkyl, alkoxy, —NH₂, —NHR⁹, or —NR⁹R⁹;

Z¹, Z², Z³, Z⁴, and Z⁵ are each, independently, a bond, C, N, S, or O;

R⁵ is H, alkyl, haloalkyl, or hydroxyalkyl;

R⁶ is H, alkyl, haloalkyl, or hydroxyalkyl;

or R⁵ and R⁶, together with the carbon atom they are attached to, form a 3- to 5-membered carbocycle or heterocycle;

R⁷ is, at each occurrence, independently halogen, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy;

or R⁶ and one R⁷, together with the atoms to which they are attached, form a 5- to 6-membered carbocycle;

R⁸ is, at each occurrence, independently halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —C(O)R^a, —OC(O)R^a, —C(O)OR^a, —OC(O)OR^a, —C(O)NR^aR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, C_1-4 alkyl, C_1-4 alkenyl, C_1-4 alkynyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁸ together form ═O;

R⁹ is, at each occurrence, halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, alkyl, alkenyl, alkynyl, haloalkyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁹ together form ═O;

R¹⁰ is H, alkyl, or haloalkyl;

R¹¹ is H, alkyl, or haloalkyl;

wherein R⁷, R⁸, and R⁹ are each, independently, optionally substituted with one or more R;

R is —OR^a, —C(O)R^a, —NR^aR^b, halogen, cyano, alkyl, haloalkyl, alkoxy, carbocycle, heterocycle, carbocyclalkyl, or heterocyclealkyl;

R^a is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

R^b is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

or R^a and R^b, together with the nitrogen atom to which they are attached, form C_4-8 cycloalkyl, or 4- to 8-membered saturated heterocycle;

m is 0-5, wherein m is 1-5 when Z³ is N;

n is 0-5;

p is 0-5; and

q is 0-2.

In one embodiment, compounds are provided wherein Y² is C and Q⁴ is a bond and having the structure of Formula (VII):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein:

X is —C(O)NH—, —C(R¹⁰R¹¹)C(O)NH—, —NHC(O)NH—, or —NHC(O)—;

ring A is carbocycle or heterocycle;

Y² is C or N;

Y⁴ is a bond, —CR⁴═, or —N═;

R⁴ is H, halogen, cyano, alkyl, haloalkyl, alkoxy, —NH₂, —NHR⁹, or —NR⁹R⁹;

Q¹ and Q² are each, independently, C or N; Q³ is C, N, S, or O;

R⁵ is H, alkyl, haloalkyl, or hydroxyalkyl;

R⁶ is H, alkyl, haloalkyl, or hydroxyalkyl;

or R⁵ and R⁶, together with the carbon atom they are attached to, form a 3- to 5-membered carbocycle or heterocycle;

R⁷ is, at each occurrence, independently halogen, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy;

or R⁶ and one R⁷, together with the atoms to which they are attached, form a 5- to 6-membered carbocycle;

R⁸ is, at each occurrence, independently halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —C(O)R^a, —OC(O)R^a, —C(O)OR^a, —OC(O)OR^a, —C(O)NR^aR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, C_1-4 alkyl, C_1-4 alkenyl, C_1-4 alkynyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁸ together form ═O;

R⁹ is, at each occurrence, halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, alkyl, alkenyl, alkynyl, haloalkyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁹ together form ═O;

R¹⁰ is H, alkyl, or haloalkyl;

R¹¹ is H, alkyl, or haloalkyl;

wherein R⁷, R⁸, and R⁹ are each, independently, optionally substituted with one or more R;

R is —OR^a, —C(O)R^a, —NR^aR^b, halogen, cyano, alkyl, haloalkyl, alkoxy, carbocycle, heterocycle, carbocyclalkyl, or heterocyclealkyl;

R^a is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

R^b is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

or R^a and R^b, together with the nitrogen atom to which they are attached, form C_4-8 cycloalkyl, or 4- to 8-membered saturated heterocycle;

m is 0-5;

n is 0-5;

p is 0-5; and

q is 0-2.

In one embodiment, compounds are provided having the structure of Formula (VIII):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein:

X is —C(O)NH—, —C(R¹⁰R¹¹)C(O)NH—, —NHC(O)NH—, or —NHC(O)—;

Y⁴ is a bond, —CR⁴═, or —N═;

R⁴ is H, halogen, cyano, alkyl, haloalkyl, alkoxy, —NH₂, —NHR⁹, or —NR⁹R⁹;

Q¹ and Q² are each, independently, C or N;

Q³ is C, N, S, or O;

Z¹, Z², Z³, Z⁴, and Z⁵ are each, independently, a bond, C, N, S, or O;

R⁵ is H, alkyl, haloalkyl, or hydroxyalkyl;

R⁶ is H, alkyl, haloalkyl, or hydroxyalkyl;

or R⁵ and R⁶, together with the carbon atom they are attached to, form a 3- to 5-membered carbocycle or heterocycle;

R⁷ is, at each occurrence, independently halogen, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy;

or R⁶ and one R⁷, together with the atoms to which they are attached, form a 5- to 6-membered carbocycle;

R⁸ is, at each occurrence, independently halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —C(O)R^a, —OC(O)R^a, —C(O)OR^a, —OC(O)OR^a, —C(O)NR^aR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, C_1-4 alkyl, C_1-4 alkenyl, C_1-4 alkynyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁸ together form ═O;

R⁹ is, at each occurrence, halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, alkyl, alkenyl, alkynyl, haloalkyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁹ together form ═O;

R¹⁰ is H, alkyl, or haloalkyl;

R¹¹ is H, alkyl, or haloalkyl;

wherein R⁷, R⁸, and R⁹ are each, independently, optionally substituted with one or more R;

R is —OR^a, —C(O)R^a, —NR^aR^b, halogen, cyano, alkyl, haloalkyl, alkoxy, carbocycle, heterocycle, carbocyclalkyl, or heterocyclealkyl;

R^a is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

R^b is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

or R^a and R^b, together with the nitrogen atom to which they are attached, form C_4-8 cycloalkyl, or 4- to 8-membered saturated heterocycle;

m is 0-5;

n is 0-5;

p is 0-5; and

q is 0-2.

In one embodiment, compounds are provided having the structure of Formula (VIII-A):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein:

X is —C(O)NH—, —C(R¹⁰R¹¹)C(O)NH—, —NHC(O)NH—, or —NHC(O)—;

Y⁴ is —CR⁴═, or —N═;

R⁴ is H, halogen, cyano, alkyl, haloalkyl, alkoxy, —NH₂, —NHR⁹, or —NR⁹R⁹;

Z¹, Z², Z³, Z⁴, and Z⁵ are each, independently, a bond, C, N, S, or O;

R⁵ is H, alkyl, haloalkyl, or hydroxyalkyl;

R⁶ is H, alkyl, haloalkyl, or hydroxyalkyl;

or R⁵ and R⁶, together with the carbon atom they are attached to, form a 3- to 5-membered carbocycle or heterocycle;

R⁷ is, at each occurrence, independently halogen, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy;

or R⁶ and one R⁷, together with the atoms to which they are attached, form a 5- to 6-membered carbocycle;

R⁸ is, at each occurrence, independently halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —C(O)R^a, —OC(O)R^a, —C(O)OR^a, —OC(O)OR^a, —C(O)NR^aR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, C_1-4 alkyl, C_1-4 alkenyl, C_1-4 alkynyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁸ together form ═O;

R^9a is H, halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, alkyl, alkenyl, alkynyl, haloalkyl, carbocycle, carbocyclealkyl, heterocycle, or heterocyclealkyl;

R^9b is H, halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, alkyl, alkenyl, alkynyl, haloalkyl, carbocycle, carbocyclealkyl, heterocycle, or heterocyclealkyl;

R^9c is H, —S(O)_qR^a, —S(O)_qNR^aR^b, alkyl, alkenyl, alkynyl, haloalkyl, carbocycle, carbocyclealkyl, heterocycle, or heterocyclealkyl;

R¹⁰ is H, alkyl, or haloalkyl;

R¹¹ is H, alkyl, or haloalkyl;

wherein R⁷, R⁸, R^9a, R^9b, and R^9c are each, independently, optionally substituted with one or more R;

R is —OR^a, —C(O)R^a, —NR^aR^b, halogen, cyano, alkyl, haloalkyl, alkoxy, carbocycle, heterocycle, carbocyclalkyl, or heterocyclealkyl;

R^a is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

R^b is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

or R^a and R^b, together with the nitrogen atom to which they are attached, form C_4-8 cycloalkyl, or 4- to 8-membered saturated heterocycle;

m is 0-5;

n is 0-5; and

q is 0-2.

In one embodiment, compounds are provided having the structure of Formula (VIII-B):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein:

X is —C(O)NH—, —C(R¹⁰R¹¹)C(O)NH—, —NHC(O)NH—, or —NHC(O)—;

Y⁴ is —CR⁴═, or —N═;

R⁴ is H, halogen, cyano, alkyl, haloalkyl, alkoxy, —NH₂, —NHR⁹, or —NR⁹R⁹;

Z¹, Z², Z³, Z⁴, and Z⁵ are each, independently, a bond, C, N, S, or O;

R⁵ is H, alkyl, haloalkyl, or hydroxyalkyl;

R⁶ is H, alkyl, haloalkyl, or hydroxyalkyl;

or R⁵ and R⁶, together with the carbon atom they are attached to, form a 3- to 5-membered carbocycle or heterocycle;

R⁷ is, at each occurrence, independently halogen, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy;

or R⁶ and one R⁷, together with the atoms to which they are attached, form a 5- to 6-membered carbocycle;

R⁸ is, at each occurrence, independently halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —C(O)R^a, —OC(O)R^a, —C(O)OR^a, —OC(O)OR^a, —C(O)NR^aR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, C_1-4 alkyl, C_1-4 alkenyl, C_1-4 alkynyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁸ together form ═O;

R^9a is H, halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, alkyl, alkenyl, alkynyl, haloalkyl, carbocycle, carbocyclealkyl, heterocycle, or heterocyclealkyl;

R^9c is H, —S(O)_qR^a, —S(O)_qNR^aR^b, alkyl, alkenyl, alkynyl, haloalkyl, carbocycle, carbocyclealkyl, heterocycle, or heterocyclealkyl;

R¹⁰ is H, alkyl, or haloalkyl;

R¹¹ is H, alkyl, or haloalkyl;

wherein R⁷, R⁸, R^9a, and R^9c are each, independently, optionally substituted with one or more R;

R is —OR^a, —C(O)R^a, —NR^aR^b, halogen, cyano, alkyl, haloalkyl, alkoxy, carbocycle, heterocycle, carbocyclalkyl, or heterocyclealkyl;

R^a is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

R^b is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

or R^a and R^b, together with the nitrogen atom to which they are attached, form C_4-8 cycloalkyl, or 4- to 8-membered saturated heterocycle;

m is 0-5;

n is 0-5; and

q is 0-2.

In one embodiment, compounds are provided having the structure of Formula (VIII-C):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein:

X is —C(O)NH—, —C(R¹⁰R¹¹)C(O)NH—, —NHC(O)NH—, or —NHC(O)—;

Y⁴ is —CR⁴═, or —N═;

R⁴ is H, halogen, cyano, alkyl, haloalkyl, alkoxy, —NH₂, —NHR⁹, or —NR⁹R⁹;

Z¹, Z², Z³, Z⁴, and Z⁵ are each, independently, a bond, C, N, S, or O;

R⁵ is H, alkyl, haloalkyl, or hydroxyalkyl;

R⁶ is H, alkyl, haloalkyl, or hydroxyalkyl;

or R⁵ and R⁶, together with the carbon atom they are attached to, form a 3- to 5-membered carbocycle or heterocycle;

R⁷ is, at each occurrence, independently halogen, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy;

or R⁶ and one R⁷, together with the atoms to which they are attached, form a 5- to 6-membered carbocycle;

R⁸ is, at each occurrence, independently halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —C(O)R^a, —OC(O)R^a, —C(O)OR^a, —OC(O)OR^a, —C(O)NR^aR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, C_1-4 alkyl, C_1-4 alkenyl, C_1-4 alkynyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁸ together form ═O;

R^9a is H, halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, alkyl, alkenyl, alkynyl, haloalkyl, carbocycle, carbocyclealkyl, heterocycle, or heterocyclealkyl;

R^9b is H, halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, alkyl, alkenyl, alkynyl, haloalkyl, carbocycle, carbocyclealkyl, heterocycle, or heterocyclealkyl;

R¹⁰ is H, alkyl, or haloalkyl;

R¹¹ is H, alkyl, or haloalkyl;

wherein R⁷, R⁸, R^9a, and R^9b are each, independently, optionally substituted with one or more R;

R is —OR^a, —C(O)R^a, —NR^aR^b, halogen, cyano, alkyl, haloalkyl, alkoxy, carbocycle, heterocycle, carbocyclalkyl, or heterocyclealkyl;

R^a is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

R^b is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

or R^a and R^b, together with the nitrogen atom to which they are attached, form C_4-8 cycloalkyl, or 4- to 8-membered saturated heterocycle;

m is 0-5;

n is 0-5; and

q is 0-2.

In one embodiment, compounds are provided having the structure of Formula (VIII-D):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein:

X is —C(O)NH—, —C(R¹⁰R¹¹)C(O)NH—, —NHC(O)NH—, or —NHC(O)—;

Y⁴ is —CR⁴═, or —N═;

R⁴ is H, halogen, cyano, alkyl, haloalkyl, alkoxy, —NH₂, —NHR⁹, or —NR⁹R⁹;

Z¹, Z², Z³, Z⁴, and Z⁵ are each, independently, a bond, C, N, S, or O;

R⁵ is H, alkyl, haloalkyl, or hydroxyalkyl;

R⁶ is H, alkyl, haloalkyl, or hydroxyalkyl;

or R⁵ and R⁶, together with the carbon atom they are attached to, form a 3- to 5-membered carbocycle or heterocycle;

R⁷ is, at each occurrence, independently halogen, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy;

or R⁶ and one R⁷, together with the atoms to which they are attached, form a 5- to 6-membered carbocycle;

R⁸ is, at each occurrence, independently halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —C(O)R^a, —OC(O)R^a, —C(O)OR^a, —OC(O)OR^a, —C(O)NR^aR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, C_1-4 alkyl, C_1-4 alkenyl, C_1-4 alkynyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁸ together form ═O;

R^9a is H, —S(O)_qR^a, —S(O)_qNR^aR^b, alkyl, alkenyl, alkynyl, haloalkyl, carbocycle, carbocyclealkyl, heterocycle, or heterocyclealkyl;

R^9b′, and R^9b″ are each, independently, halogen, cyano, alkyl, alkenyl, alkynyl, carbocycle, heterocycle, carbocyclealkyl, heterocyclealkyl, or R^9b′ and R^9b″ together form ═O, or R^9b′ and R^9b″ together with the carbon to which they are attached form a 3-7 membered carbocycle or heterocycle;

R^9c is H, —S(O)_qR^a, —S(O)_qNR^aR^b, alkyl, alkenyl, alkynyl, haloalkyl, carbocycle, carbocyclealkyl, heterocycle, or heterocyclealkyl;

R¹⁰ is H, alkyl, or haloalkyl;

R¹¹ is H, alkyl, or haloalkyl;

wherein R⁷, R⁸, R^9a, R^9b′, R^9b″, and R^9c are each, independently, optionally substituted with one or more R;

R is —OR^a, —C(O)R^a, —NR^aR^b, halogen, cyano, alkyl, haloalkyl, alkoxy, carbocycle, heterocycle, carbocyclalkyl, or heterocyclealkyl;

R^a is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

R^b is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

or R^a and R^b, together with the nitrogen atom to which they are attached, form C_4-8 cycloalkyl, or 4- to 8-membered saturated heterocycle;

m is 0-5;

n is 0-5; and

q is 0-2.

In one embodiment, compounds are provided having the structure of Formula (VIII-E):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein:

X is —C(O)NH—, —C(R¹⁰R¹¹)C(O)NH—, —NHC(O)NH—, or —NHC(O)—;

Y⁴ is —CR⁴═, or —N═;

R⁴ is H, halogen, cyano, alkyl, haloalkyl, alkoxy, —NH₂, —NHR⁹, or —NR⁹R⁹;

Z¹, Z², Z³, Z⁴, and Z⁵ are each, independently, a bond, C, N, S, or O;

R⁵ is H, alkyl, haloalkyl, or hydroxyalkyl;

R⁶ is H, alkyl, haloalkyl, or hydroxyalkyl;

or R⁵ and R⁶, together with the carbon atom they are attached to, form a 3- to 5-membered carbocycle or heterocycle;

R⁷ is, at each occurrence, independently halogen, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy;

or R⁶ and one R⁷, together with the atoms to which they are attached, form a 5- to 6-membered carbocycle;

R⁸ is, at each occurrence, independently halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —C(O)R^a, —OC(O)R^a, —C(O)OR^a, —OC(O)OR^a, —C(O)NR^aR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, C_1-4 alkyl, C_1-4 alkenyl, C_1-4 alkynyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁸ together form ═O;

R^9a is H, —S(O)_qR^a, —S(O)_qNR^aR^b, alkyl, alkenyl, alkynyl, haloalkyl, carbocycle, carbocyclealkyl, heterocycle, or heterocyclealkyl;

R^9c is H, halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, alkyl, alkenyl, alkynyl, haloalkyl, carbocycle, carbocyclealkyl, heterocycle, or heterocyclealkyl;

R¹⁰ is H, alkyl, or haloalkyl;

R¹¹ is H, alkyl, or haloalkyl;

wherein R⁷, R⁸, R^9a, and R^9c are each, independently, optionally substituted with one or more R;

R is —OR^a, —C(O)R^a, —NR^aR^b, halogen, cyano, alkyl, haloalkyl, alkoxy, carbocycle, heterocycle, carbocyclalkyl, or heterocyclealkyl;

R^a is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

R^b is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

or R^a and R^b, together with the nitrogen atom to which they are attached, form C_4-8 cycloalkyl, or 4- to 8-membered saturated heterocycle;

m is 0-5;

n is 0-5; and

q is 0-2.

In one embodiment, compounds are provided having the structure of Formula (VIII-F):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein:

X is —C(O)NH—, —C(R¹⁰R¹¹)C(O)NH—, —NHC(O)NH—, or —NHC(O)—;

Y⁴ is —CR⁴═, or —N═;

R⁴ is H, halogen, cyano, alkyl, haloalkyl, alkoxy, —NH₂, —NHR⁹, or —NR⁹R⁹;

Z¹, Z², Z³, Z⁴, and Z⁵ are each, independently, a bond, C, N, S, or O;

R⁵ is H, alkyl, haloalkyl, or hydroxyalkyl;

R⁶ is H, alkyl, haloalkyl, or hydroxyalkyl;

or R⁵ and R⁶, together with the carbon atom they are attached to, form a 3- to 5-membered carbocycle or heterocycle;

R⁷ is, at each occurrence, independently halogen, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy;

or R⁶ and one R⁷, together with the atoms to which they are attached, form a 5- to 6-membered carbocycle;

R⁸ is, at each occurrence, independently halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —C(O)R^a, —OC(O)R^a, —C(O)OR^a, —OC(O)OR^a, —C(O)NR^aR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, C_1-4 alkyl, C_1-4 alkenyl, C_1-4 alkynyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁸ together form ═O;

R^9a is H, —S(O)_qR^a, —S(O)_qNR^aR^b, alkyl, alkenyl, alkynyl, haloalkyl, carbocycle, carbocyclealkyl, heterocycle, or heterocyclealkyl;

R^9b and R^9c are each, independently, H, halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, alkyl, alkenyl, alkynyl, haloalkyl, carbocycle, carbocyclealkyl, heterocycle, or heterocyclealkyl;

R¹⁰ is H, alkyl, or haloalkyl;

R¹¹ is H, alkyl, or haloalkyl;

wherein R⁷, R⁸, R^9a, R^9b, and R^9c are each, independently, optionally substituted with one or more R;

R is —OR^a, —C(O)R^a, —NR^aR^b, halogen, cyano, alkyl, haloalkyl, alkoxy, carbocycle, heterocycle, carbocyclalkyl, or heterocyclealkyl;

R^a is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

R^b is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

or R^a and R^b, together with the nitrogen atom to which they are attached, form C_4-8 cycloalkyl, or 4- to 8-membered saturated heterocycle;

m is 0-5;

n is 0-5; and

q is 0-2.

In one embodiment, compounds are provided having the structure of Formula (VIII-G):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein:

X is —C(O)NH—, —C(R¹⁰R¹¹)C(O)NH—, —NHC(O)NH—, or —NHC(O)—;

Y⁴ is —CR⁴═, or —N═;

R⁴ is H, halogen, cyano, alkyl, haloalkyl, alkoxy, —NH₂, —NHR⁹, or —NR⁹R⁹;

Z¹, Z², Z³, Z⁴, and Z⁵ are each, independently, a bond, C, N, S, or O;

R⁵ is H, alkyl, haloalkyl, or hydroxyalkyl;

R⁶ is H, alkyl, haloalkyl, or hydroxyalkyl;

or R⁵ and R⁶, together with the carbon atom they are attached to, form a 3- to 5-membered carbocycle or heterocycle;

R⁷ is, at each occurrence, independently halogen, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy;

or R⁶ and one R⁷, together with the atoms to which they are attached, form a 5- to 6-membered carbocycle;

R⁸ is, at each occurrence, independently halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —C(O)R^a, —OC(O)R^a, —C(O)OR^a, —OC(O)OR^a, —C(O)NR^aR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, C_1-4 alkyl, C_1-4 alkenyl, C_1-4 alkynyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁸ together form ═O;

R^9a is H, —S(O)_qR^a, —S(O)_qNR^aR^b, alkyl, alkenyl, alkynyl, haloalkyl, carbocycle, carbocyclealkyl, heterocycle, or heterocyclealkyl;

R^9b is H, halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, alkyl, alkenyl, alkynyl, haloalkyl, carbocycle, carbocyclealkyl, heterocycle, or heterocyclealkyl;

R¹⁰ is H, alkyl, or haloalkyl;

R¹¹ is H, alkyl, or haloalkyl;

wherein R⁷, R⁸, R^9a, and R^9b are each, independently, optionally substituted with one or more R;

R is —OR^a, —C(O)R^a, —NR^aR^b, halogen, cyano, alkyl, haloalkyl, alkoxy, carbocycle, heterocycle, carbocyclalkyl, or heterocyclealkyl;

R^a is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

R^b is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

or R^a and R^b, together with the nitrogen atom to which they are attached, form C_4-8 cycloalkyl, or 4- to 8-membered saturated heterocycle;

m is 0-5;

n is 0-5; and

q is 0-2.

In one embodiment, compounds are provided having the structure of Formula (VIII-H):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein:

X is —C(O)NH—, —C(R¹⁰R¹¹)C(O)NH—, —NHC(O)NH—, or —NHC(O)—;

Y⁴ is —CR⁴═, or —N═;

Y⁵ is O, or S;

R⁴ is H, halogen, cyano, alkyl, haloalkyl, alkoxy, —NH₂, —NHR⁹, or —NR⁹R⁹;

Z¹, Z², Z³, Z⁴, and Z⁵ are each, independently, a bond, C, N, S, or O;

R⁵ is H, alkyl, haloalkyl, or hydroxyalkyl;

R⁶ is H, alkyl, haloalkyl, or hydroxyalkyl;

or R⁵ and R⁶, together with the carbon atom they are attached to, form a 3- to 5-membered carbocycle or heterocycle;

R⁷ is, at each occurrence, independently halogen, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy;

or R⁶ and one R⁷, together with the atoms to which they are attached, form a 5- to 6-membered carbocycle;

R⁸ is, at each occurrence, independently halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —C(O)R^a, —OC(O)R^a, —C(O)OR^a, —OC(O)OR^a, —C(O)NR^aR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, C_1-4 alkyl, C_1-4 alkenyl, C_1-4 alkynyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁸ together form ═O;

R^9a and R^9b are each, independently, H, halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_cR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, alkyl, alkenyl, alkynyl, haloalkyl, carbocycle, carbocyclealkyl, heterocycle, or heterocyclealkyl;

R¹⁰ is H, alkyl, or haloalkyl;

R¹¹ is H, alkyl, or haloalkyl;

wherein R⁷, R⁸, R^9a, and R^9b are each, independently, optionally substituted with one or more R;

R is —OR^a, —C(O)R^a, —NR^aR^b, halogen, cyano, alkyl, haloalkyl, alkoxy, carbocycle, heterocycle, carbocyclalkyl, or heterocyclealkyl;

R^a is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

R^b is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

or R^a and R^b, together with the nitrogen atom to which they are attached, form C_4-8 cycloalkyl, or 4- to 8-membered saturated heterocycle;

m is 0-5;

n is 0-5; and

q is 0-2.

In one embodiment, compounds are provided wherein Y⁴ is a bond and having the structure of Formula (IX):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein:

X is —C(O)NH—, —C(R¹⁰R¹¹)C(O)NH—, —NHC(O)NH—, or —NHC(O)—;

ring A is carbocycle or heterocycle;

Y² is C or N;

Q¹ and Q² are each, independently, C or N;

Q³ and Q⁴ are each, independently, C, N, S, or O;

R⁵ is H, alkyl, haloalkyl, or hydroxyalkyl;

R⁶ is H, alkyl, haloalkyl, or hydroxyalkyl;

or R⁵ and R⁶, together with the carbon atom they are attached to, form a 3- to 5-membered carbocycle or heterocycle;

R⁷ is, at each occurrence, independently halogen, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy;

or R⁶ and one R⁷, together with the atoms to which they are attached, form a 5- to 6-membered carbocycle;

R⁸ is, at each occurrence, independently halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —C(O)R^a, —OC(O)R^a, —C(O)OR^a, —OC(O)OR^a, —C(O)NR^aR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, C_1-4 alkyl, C_1-4 alkenyl, C_1-4 alkynyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁸ together form ═O;

R⁹ is, at each occurrence, halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, alkyl, alkenyl, alkynyl, haloalkyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁹ together form ═O;

wherein R⁷, R⁸, and R⁹ are each, independently, optionally substituted with one or more R;

R is —OR^a, —C(O)R^a, —NR^aR^b, halogen, cyano, alkyl, haloalkyl, alkoxy, carbocycle, heterocycle, carbocyclalkyl, or heterocyclealkyl;

R^a is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

R^b is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

or R^a and R^b, together with the nitrogen atom to which they are attached, form C_4-8 cycloalkyl, or 4- to 8-membered saturated heterocycle;

m is 0-5, wherein m is 1-5 when Q¹, Q², Q³, and Q⁴ are each C;

n is 0-5;

p is 0-5; and

q is 0-2.

In one embodiment, compounds are provided having the structure of Formula (X):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein:

X is —C(O)NH—, —C(R¹⁰R¹¹)C(O)NH—, —NHC(O)NH—, or —NHC(O)—;

Y² is C or N;

Q¹ and Q² are each, independently, C or N;

Q³ and Q⁴ are each, independently, C, N, S, or O;

Z¹, Z², Z³, Z⁴, and Z⁵ are each, independently, a bond, C, N, S, or O;

R⁵ is H, alkyl, haloalkyl, or hydroxyalkyl;

R⁶ is H, alkyl, haloalkyl, or hydroxyalkyl;

or R⁵ and R⁶, together with the carbon atom they are attached to, form a 3- to 5-membered carbocycle or heterocycle;

R⁷ is, at each occurrence, independently halogen, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy;

or R⁶ and one R⁷, together with the atoms to which they are attached, form a 5- to 6-membered carbocycle;

R⁸ is, at each occurrence, independently halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —C(O)R^a, —OC(O)R^a, —C(O)OR^a, —OC(O)OR^a, —C(O)NR^aR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, C_1-4 alkyl, C_1-4 alkenyl, C_1-4 alkynyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁸ together form ═O;

R⁹ is, at each occurrence, halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, alkyl, alkenyl, alkynyl, haloalkyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁹ together form ═O;

wherein R⁷, R⁸, and R⁹ are each, independently, optionally substituted with one or more R;

R is —OR^a, —C(O)R^a, —NR^aR^b, halogen, cyano, alkyl, haloalkyl, alkoxy, carbocycle, heterocycle, carbocyclalkyl, or heterocyclealkyl;

R^a is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

R^b is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

or R^a and R^b, together with the nitrogen atom to which they are attached, form C_4-8 cycloalkyl, or 4- to 8-membered saturated heterocycle;

m is 0-5, wherein m is 1-5 when Q¹, Q², Q³, and Q⁴ are each C;

n is 0-5;

p is 0-5; and

q is 0-2.

In one embodiment, compounds are provided having the structure of Formula (XI):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein:

X is —C(O)NH—, —C(R¹⁰R¹¹)C(O)NH—, —NHC(O)NH—, or —NHC(O)—;

Z¹, Z², Z³, Z⁴, and Z⁵ are each, independently, a bond, C, N, S, or O;

R⁵ is H, alkyl, haloalkyl, or hydroxyalkyl;

R⁶ is H, alkyl, haloalkyl, or hydroxyalkyl;

or R⁵ and R⁶, together with the carbon atom they are attached to, form a 3- to 5-membered carbocycle or heterocycle;

R⁷ is, at each occurrence, independently halogen, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy;

or R⁶ and one R⁷, together with the atoms to which they are attached, form a 5- to 6-membered carbocycle;

R⁸ is, at each occurrence, independently halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —C(O)R^a, —OC(O)R^a, —C(O)OR^a, —OC(O)OR^a, —C(O)NR^aR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, C_1-4 alkyl, C_1-4 alkenyl, C_1-4 alkynyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁸ together form ═O;

R⁹ is, at each occurrence, halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, alkyl, alkenyl, alkynyl, haloalkyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁹ together form ═O;

wherein R⁷, R⁸, and R⁹ are each, independently, optionally substituted with one or more R;

R is —OR^a, —C(O)R^a, —NR^aR^b, halogen, cyano, alkyl, haloalkyl, alkoxy, carbocycle, heterocycle, carbocyclalkyl, or heterocyclealkyl;

R^a is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

R^b is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

or R^a and R^b, together with the nitrogen atom to which they are attached, form C_4-8 cycloalkyl, or 4- to 8-membered saturated heterocycle;

m is 1-5;

n is 0-5;

p is 0-5; and

q is 0-2.

In one embodiment, compounds are provided having the structure of Formula (XII):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein:

X is —C(O)NH—, —C(R¹⁰R¹¹)C(O)NH—, —NHC(O)NH—, or —NHC(O)—;

ring A is carbocycle or heterocycle;

Y² is a bond, —CR²═, or —N═;

Y⁴ is C or N;

R² is H, halogen, cyano, alkyl, haloalkyl, alkoxy, —NH₂, —NHR⁹, or —NR⁹R⁹;

ring B is a 5- to 6-membered carbocycle or 5- to 6-membered heterocycle, wherein ring B is substituted by (R⁹)_p;

Y⁶, Y⁷, Y⁸, and Y⁹ are each, independently, —CH═, —CR⁷═, or N;

R⁵ is H, alkyl, haloalkyl, or hydroxyalkyl;

R⁶ is H, alkyl, haloalkyl, or hydroxyalkyl;

or R⁵ and R⁶, together with the carbon atom they are attached to, form a 3- to 5-membered carbocycle or heterocycle;

R⁷ is, at each occurrence, independently halogen, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy;

or R⁶ and one R⁷, together with the atoms to which they are attached, form a 5- to 6-membered carbocycle;

R⁸ is, at each occurrence, independently halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —C(O)R^a, —OC(O)R^a, —C(O)OR^a, —OC(O)OR^a, —C(O)NR^aR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, C_1-4 alkyl, C_1-4 alkenyl, C_1-4 alkynyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁸ together form ═O;

R⁹ is, at each occurrence, halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, alkyl, alkenyl, alkynyl, haloalkyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁹ together form ═O;

wherein R⁷, R⁸, and R⁹ are each, independently, optionally substituted with one or more R;

R is —OR^a, —C(O)R^a, —NR^aR^b, halogen, cyano, alkyl, haloalkyl, alkoxy, carbocycle, heterocycle, carbocyclalkyl, or heterocyclealkyl;

R^a is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

R^b is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

or R^a and R^b, together with the nitrogen atom to which they are attached, form C_4-8 cycloalkyl, or 4- to 8-membered saturated heterocycle;

m is 0-5, wherein m is 1-5 when ring B is a 6-membered carbocycle;

n is 0-5;

p is 0-5; and

q is 0-2.

In one embodiment, compounds are provided having the structure of Formula (XIII):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein:

X is —C(O)NH—, —C(R¹⁰R¹¹)C(O)NH—, —NHC(O)NH—, or —NHC(O)—;

ring A is carbocycle or heterocycle;

Y² is a bond, —CR²═, or —N═;

Y⁴ is C or N;

R² is H, halogen, cyano, alkyl, haloalkyl, alkoxy, —NH₂, —NHR⁹, or —NR⁹R⁹;

Q¹ and Q² are each, independently, C or N;

Q³ and Q⁴ are each, independently, a bond, C, N, S, or O;

Y⁶, Y⁷, Y⁸, and Y⁹ are each, independently, —CH═, —CR⁷═, or N;

R⁵ is H, alkyl, haloalkyl, or hydroxyalkyl;

R⁶ is H, alkyl, haloalkyl, or hydroxyalkyl;

or R⁵ and R⁶, together with the carbon atom they are attached to, form a 3- to 5-membered carbocycle or heterocycle;

R⁷ is, at each occurrence, independently halogen, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy;

or R⁶ and one R⁷, together with the atoms to which they are attached, form a 5- to 6-membered carbocycle;

R⁸ is, at each occurrence, independently halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —C(O)R^a, —OC(O)R^a, —C(O)OR^a, —OC(O)OR^a, —C(O)NR^aR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, C_1-4 alkyl, C_1-4 alkenyl, C_1-4 alkynyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁸ together form ═O;

R⁹ is, at each occurrence, halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, alkyl, alkenyl, alkynyl, haloalkyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁹ together form ═O;

wherein R⁷, R⁸, and R⁹ are each, independently, optionally substituted with one or more R;

R is —OR^a, —C(O)R^a, —NR^aR^b, halogen, cyano, alkyl, haloalkyl, alkoxy, carbocycle, heterocycle, carbocyclalkyl, or heterocyclealkyl;

R^a is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

R^b is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

or R^a and R^b, together with the nitrogen atom to which they are attached, form C_4-8 cycloalkyl, or 4- to 8-membered saturated heterocycle;

m is 0-5, wherein m is 1-5 when Q¹, Q², Q³, and Q⁴ are each C;

n is 0-5;

p is 0-5; and

q is 0-2.

In one embodiment, compounds are provided having the structure of Formula (XIV):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein:

X is —C(O)NH—, —C(R¹⁰R¹¹)C(O)NH—, —NHC(O)NH—, or —NHC(O)—;

ring A is carbocycle or heterocycle;

Y² is a bond, —CR²═, or —N═;

Y⁴ is C or N;

R² is H, halogen, cyano, alkyl, haloalkyl, alkoxy, —NH₂, —NHR⁹, or —NR⁹R⁹;

Q¹ and Q² are each, independently, C or N;

Q³ and Q⁴ are each, independently, a bond, C, N, S, or O;

R⁵ is H, alkyl, haloalkyl, or hydroxyalkyl;

R⁶ is H, alkyl, haloalkyl, or hydroxyalkyl;

or R⁵ and R⁶, together with the carbon atom they are attached to, form a 3- to 5-membered carbocycle or heterocycle;

R⁷ is, at each occurrence, independently halogen, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy;

or R⁶ and one R⁷, together with the atoms to which they are attached, form a 5- to 6-membered carbocycle;

R⁸ is, at each occurrence, independently halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —C(O)R^a, —OC(O)R^a, —C(O)OR^a, —OC(O)OR^a, —C(O)NR^aR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, C_1-4 alkyl, C_1-4 alkenyl, C_1-4 alkynyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁸ together form ═O;

R⁹ is, at each occurrence, halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, alkyl, alkenyl, alkynyl, haloalkyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁹ together form ═O;

wherein R⁷, R⁸, and R⁹ are each, independently, optionally substituted with one or more R;

R is —OR^a, —C(O)R^a, —NR^aR^b, halogen, cyano, alkyl, haloalkyl, alkoxy, carbocycle, heterocycle, carbocyclalkyl, or heterocyclealkyl;

R^a is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

R^b is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

or R^a and R^b, together with the nitrogen atom to which they are attached, form C_4-8 cycloalkyl, or 4- to 8-membered saturated heterocycle;

m is 0-5, wherein m is 1-5 when Q¹, Q², Q³, and Q⁴ are each C;

n is 0-5;

p is 0-5; and

q is 0-2.

In one embodiment, compounds are provided having the structure of Formula (XV):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein:

X is —C(O)NH—, —C(R¹⁰R¹¹)C(O)NH—, —NHC(O)NH—, or —NHC(O)—;

Y² is a bond, —CR²═, or —N═;

Y⁴ is C or N;

R² is H, halogen, cyano, alkyl, haloalkyl, alkoxy, —NH₂, —NHR⁹, or —NR⁹R⁹;

Q¹ and Q² are each, independently, C or N;

Q³ and Q⁴ are each, independently, C, N, S, or O;

Z¹, Z², Z³, Z⁴, and Z⁵ are each, independently, a bond, C, N, S, or O;

R⁵ is H, alkyl, haloalkyl, or hydroxyalkyl;

R⁶ is H, alkyl, haloalkyl, or hydroxyalkyl;

or R⁵ and R⁶, together with the carbon atom they are attached to, form a 3- to 5-membered carbocycle or heterocycle;

R⁷ is, at each occurrence, independently halogen, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy;

or R⁶ and one R⁷, together with the atoms to which they are attached, form a 5- to 6-membered carbocycle;

R⁸ is, at each occurrence, independently halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —C(O)R^a, —OC(O)R^a, —C(O)OR^a, —OC(O)OR^a, —C(O)NR^aR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, C_1-4 alkyl, C_1-4 alkenyl, C_1-4 alkynyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁸ together form ═O;

R⁹ is, at each occurrence, halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, alkyl, alkenyl, alkynyl, haloalkyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁹ together form ═O;

wherein R⁷, R⁸, and R⁹ are each, independently, optionally substituted with one or more R;

R is —OR^a, —C(O)R^a, —NR^aR^b, halogen, cyano, alkyl, haloalkyl, alkoxy, carbocycle, heterocycle, carbocyclalkyl, or heterocyclealkyl;

R^a is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

R^b is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

or R^a and R^b, together with the nitrogen atom to which they are attached, form C_4-8 cycloalkyl, or 4- to 8-membered saturated heterocycle;

m is 0-5, wherein m is 1-5 when Q¹, Q², Q³, and Q⁴ are each C;

n is 0-5;

p is 0-5; and

q is 0-2.

In one embodiment, compounds are provided having the structure of Formula (XVI):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein:

X is —C(O)NH—, —C(R¹⁰R¹¹)C(O)NH—, —NHC(O)NH—, or —NHC(O)—;

Y² is a bond, —CR²═, or —N═;

R² is H, halogen, cyano, alkyl, haloalkyl, alkoxy, —NH₂, —NHR⁹, or —NR⁹R⁹;

Q¹ and Q² are each, independently, C or N;

Q³ and Q⁴ are each, independently, C, N, S, or O;

Z¹, Z², Z³, Z⁴, and Z⁵ are each, independently, a bond, C, N, S, or O;

R⁵ is H, alkyl, haloalkyl, or hydroxyalkyl;

R⁶ is H, alkyl, haloalkyl, or hydroxyalkyl;

or R⁵ and R⁶, together with the carbon atom they are attached to, form a 3- to 5-membered carbocycle or heterocycle;

R⁷ is, at each occurrence, independently halogen, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy;

or R⁶ and one R⁷, together with the atoms to which they are attached, form a 5- to 6-membered carbocycle;

R⁸ is, at each occurrence, independently halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —C(O)R^a, —OC(O)R^a, —C(O)OR^a, —OC(O)OR^a, —C(O)NR^aR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, C_1-4 alkyl, C_1-4 alkenyl, C_1-4 alkynyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁸ together form ═O;

R⁹ is, at each occurrence, halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, alkyl, alkenyl, alkynyl, haloalkyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁹ together form ═O;

wherein R⁷, R⁸, and R⁹ are each, independently, optionally substituted with one or more R;

R is —OR^a, —C(O)R^a, —NR^aR^b, halogen, cyano, alkyl, haloalkyl, alkoxy, carbocycle, heterocycle, carbocyclalkyl, or heterocyclealkyl;

R^a is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

R^b is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

or R^a and R^b, together with the nitrogen atom to which they are attached, form C_4-8 cycloalkyl, or 4- to 8-membered saturated heterocycle;

m is 0-5, wherein m is 1-5 when Q¹, Q², Q³, and Q⁴ are each C;

n is 0-5;

p is 0-5; and

q is 0-2.

In one embodiment, compounds are provided having the structure of Formula (XVII):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein:

X is —C(O)NH—, —C(R¹⁰R¹¹)C(O)NH—, —NHC(O)NH—, or —NHC(O)—;

ring A is carbocycle or heterocycle;

Y² is a bond, —CR²═, or —N═;

Y⁴ is C or N;

R² is H, halogen, cyano, alkyl, haloalkyl, alkoxy, —NH₂, —NHR⁹, or —NR⁹R⁹;

Q¹ and Q² are each, independently, C or N;

Q³ is C, N, S, or O;

R⁵ is H, alkyl, haloalkyl, or hydroxyalkyl;

R⁶ is H, alkyl, haloalkyl, or hydroxyalkyl;

or R⁵ and R⁶, together with the carbon atom they are attached to, form a 3- to 5-membered carbocycle or heterocycle;

R⁷ is, at each occurrence, independently halogen, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy;

or R⁶ and one R⁷, together with the atoms to which they are attached, form a 5- to 6-membered carbocycle;

R⁸ is, at each occurrence, independently halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —C(O)R^a, —OC(O)R^a, —C(O)OR^a, —OC(O)OR^a, —C(O)NR^aR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, C_1-4 alkyl, C_1-4 alkenyl, C_1-4 alkynyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁸ together form ═O;

R⁹ is, at each occurrence, halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, alkyl, alkenyl, alkynyl, haloalkyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁹ together form ═O;

wherein R⁷, R⁸, and R⁹ are each, independently, optionally substituted with one or more R;

R is —OR^a, —C(O)R^a, —NR^aR^b, halogen, cyano, alkyl, haloalkyl, alkoxy, carbocycle, heterocycle, carbocyclalkyl, or heterocyclealkyl;

R^a is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

R^b is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

or R^a and R^b, together with the nitrogen atom to which they are attached, form C_4-8 cycloalkyl, or 4- to 8-membered saturated heterocycle;

m is 0-5;

n is 0-5;

p is 0-5; and

q is 0-2.

In one embodiment, compounds are provided having the structure of Formula (XVIII):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein:

X is —C(O)NH—, —C(R¹⁰R¹¹)C(O)NH—, —NHC(O)NH—, or —NHC(O)—;

Y² is a bond, —CR²═, or —N═;

R² is H, halogen, cyano, alkyl, haloalkyl, alkoxy, —NH₂, —NHR⁹, or —NR⁹R⁹;

Q¹ and Q² are each, independently, C or N;

Q³ is C, N, S, or O;

Z¹, Z², Z³, Z⁴, and Z⁵ are each, independently, a bond, C, N, S, or O;

R⁵ is H, alkyl, haloalkyl, or hydroxyalkyl;

R⁶ is H, alkyl, haloalkyl, or hydroxyalkyl;

or R⁵ and R⁶, together with the carbon atom they are attached to, form a 3- to 5-membered carbocycle or heterocycle;

R⁷ is, at each occurrence, independently halogen, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy;

or R⁶ and one R⁷, together with the atoms to which they are attached, form a 5- to 6-membered carbocycle;

R⁸ is, at each occurrence, independently halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —C(O)R^a, —OC(O)R^a, —C(O)OR^a, —OC(O)OR^a, —C(O)NR^aR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, C_1-4 alkyl, C_1-4 alkenyl, C_1-4 alkynyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁸ together form ═O;

R⁹ is, at each occurrence, halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, alkyl, alkenyl, alkynyl, haloalkyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁹ together form ═O;

wherein R⁷, R⁸, and R⁹ are each, independently, optionally substituted with one or more R;

R is —OR^a, —C(O)R^a, —NR^aR^b, halogen, cyano, alkyl, haloalkyl, alkoxy, carbocycle, heterocycle, carbocyclalkyl, or heterocyclealkyl;

R^a is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

R^b is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

or R^a and R^b, together with the nitrogen atom to which they are attached, form C_4-8 cycloalkyl, or 4- to 8-membered saturated heterocycle;

m is 0-5;

n is 0-5;

p is 0-5; and

q is 0-2.

In one embodiment, compounds are provided having the structure of Formula (XVIII-A):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein:

X is —C(O)NH—, —C(R¹⁰R¹¹)C(O)NH—, —NHC(O)NH—, or —NHC(O)—;

Y² is a bond, —CR²═, or —N═;

R² is H, halogen, cyano, alkyl, haloalkyl, alkoxy, —NH₂, —NHR⁹, or —NR⁹R⁹;

Z¹, Z², Z³, Z⁴, and Z⁵ are each, independently, a bond, C, N, S, or O;

R⁵ is H, alkyl, haloalkyl, or hydroxyalkyl;

R⁶ is H, alkyl, haloalkyl, or hydroxyalkyl;

or R⁵ and R⁶, together with the carbon atom they are attached to, form a 3- to 5-membered carbocycle or heterocycle;

R⁷ is, at each occurrence, independently halogen, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy;

or R⁶ and one R⁷, together with the atoms to which they are attached, form a 5- to 6-membered carbocycle;

R⁸ is, at each occurrence, independently halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —C(O)R^a, —OC(O)R^a, —C(O)OR^a, —OC(O)OR^a, —C(O)NR^aR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, C_1-4 alkyl, C_1-4 alkenyl, C_1-4 alkynyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁸ together form ═O;

R^9a is H, —S(O)_qR^a, —S(O)_qNR^aR^b, alkyl, alkenyl, alkynyl, haloalkyl, carbocycle, carbocyclealkyl, heterocycle, or heterocyclealkyl;

R^9b and R^9c are each, independently, H, halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, alkyl, alkenyl, alkynyl, haloalkyl, carbocycle, carbocyclealkyl, heterocycle, or heterocyclealkyl;

wherein R⁷, R⁸, R^9a, R^9b, and R^9c are each, independently, optionally substituted with one or more R;

R is —OR^a, —C(O)R^a, —NR^aR^b, halogen, cyano, alkyl, haloalkyl, alkoxy, carbocycle, heterocycle, carbocyclalkyl, or heterocyclealkyl;

R^a is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

R^b is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

or R^a and R^b, together with the nitrogen atom to which they are attached, form C_4-8 cycloalkyl, or 4- to 8-membered saturated heterocycle;

m is 0-5;

n is 0-5; and

q is 0-2.

In one embodiment, compounds are provided having the structure of Formula (XVIII-B):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein:

X is —C(O)NH—, —C(R¹⁰R¹¹)C(O)NH—, —NHC(O)NH—, or —NHC(O)—;

Y² is a bond, —CR²═, or —N═;

R² is H, halogen, cyano, alkyl, haloalkyl, alkoxy, —NH₂, —NHR⁹, or —NR⁹R⁹;

Z¹, Z², Z³, Z⁴, and Z⁵ are each, independently, a bond, C, N, S, or O;

R⁵ is H, alkyl, haloalkyl, or hydroxyalkyl;

R⁶ is H, alkyl, haloalkyl, or hydroxyalkyl;

or R⁵ and R⁶, together with the carbon atom they are attached to, form a 3- to 5-membered carbocycle or heterocycle;

R⁷ is, at each occurrence, independently halogen, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy;

or R⁶ and one R⁷, together with the atoms to which they are attached, form a 5- to 6-membered carbocycle;

R⁸ is, at each occurrence, independently halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —C(O)R^a, —OC(O)R^a, —C(O)OR^a, —OC(O)OR^a, —C(O)NR^aR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, C_1-4 alkyl, C_1-4 alkenyl, C_1-4 alkynyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁸ together form ═O;

R⁹ is, at each occurrence, halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, alkyl, alkenyl, alkynyl, haloalkyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl;

R^9a is H, —S(O)_qR^a, —S(O)_qNR^aR^b, alkyl, alkenyl, alkynyl, haloalkyl, carbocycle, carbocyclealkyl, heterocycle, or heterocyclealkyl;

R^9c is H, halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, alkyl, alkenyl, alkynyl, haloalkyl, carbocycle, carbocyclealkyl, heterocycle, or heterocyclealkyl;

wherein R⁷, R⁸, and R⁹, R^9a, and R^9c are each, independently, optionally substituted with one or more R;

R is —OR^a, —C(O)R^a, —NR^aR^b, halogen, cyano, alkyl, haloalkyl, alkoxy, carbocycle, heterocycle, carbocyclalkyl, or heterocyclealkyl;

R^a is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

R^b is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

or R^a and R^b, together with the nitrogen atom to which they are attached, form C_4-8 cycloalkyl, or 4- to 8-membered saturated heterocycle;

m is 0-5;

n is 0-5; and

q is 0-2.

In one embodiment, compounds are provided having the structure of Formula (XIX):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein:

X is —C(O)NH—, —C(R¹⁰R¹¹)C(O)NH—, —NHC(O)NH—, or —NHC(O)—;

ring A is carbocycle or heterocycle;

Y⁴ is C or N;

Q¹ and Q² are each, independently, C or N;

Q³ and Q⁴ are each, independently, C, N, S, or O;

R⁵ is H, alkyl, haloalkyl, or hydroxyalkyl;

R⁶ is H, alkyl, haloalkyl, or hydroxyalkyl;

or R⁵ and R⁶, together with the carbon atom they are attached to, form a 3- to 5-membered carbocycle or heterocycle;

R⁷ is, at each occurrence, independently halogen, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy;

or R⁶ and one R⁷, together with the atoms to which they are attached, form a 5- to 6-membered carbocycle;

R⁸ is, at each occurrence, independently halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —C(O)R^a, —OC(O)R^a, —C(O)OR^a, —OC(O)OR^a, —C(O)NR^aR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, C_1-4 alkyl, C_1-4 alkenyl, C_1-4 alkynyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁸ together form ═O;

R⁹ is, at each occurrence, halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, alkyl, alkenyl, alkynyl, haloalkyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁹ together form ═O;

wherein R⁷, R⁸, and R⁹ are each, independently, optionally substituted with one or more R;

R is —OR^a, —C(O)R^a, —NR^aR^b, halogen, cyano, alkyl, haloalkyl, alkoxy, carbocycle, heterocycle, carbocyclalkyl, or heterocyclealkyl;

R^a is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

R^b is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

or R^a and R^b, together with the nitrogen atom to which they are attached, form C_4-8 cycloalkyl, or 4- to 8-membered saturated heterocycle;

m is 0-5, wherein m is 1-5 when Q¹, Q², Q³, and Q⁴ are each C;

n is 0-5;

p is 0-5; and

q is 0-2.

In one embodiment, compounds are provided having the structure of Formula (XX):

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein:

X is —C(O)NH—, —C(R¹⁰R¹¹)C(O)NH—, —NHC(O)NH—, or —NHC(O)—;

Y⁴ is C or N;

Q¹ and Q² are each, independently, C or N;

Q³ and Q⁴ are each, independently, C, N, S, or O;

Z¹, Z², Z³, Z⁴, and Z⁵ are each, independently, a bond, C, N, S, or O;

R⁵ is H, alkyl, haloalkyl, or hydroxyalkyl;

R⁶ is H, alkyl, haloalkyl, or hydroxyalkyl;

or R⁵ and R⁶, together with the carbon atom they are attached to, form a 3- to 5-membered carbocycle or heterocycle;

R⁷ is, at each occurrence, independently halogen, cyano, alkyl, haloalkyl, alkoxy, or haloalkoxy;

or R⁶ and one R⁷, together with the atoms to which they are attached, form a 5- to 6-membered carbocycle;

R⁸ is, at each occurrence, independently halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —C(O)R^a, —OC(O)R^a, —C(O)OR^a, —OC(O)OR^a, —C(O)NR^aR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, C_1-4 alkyl, C_1-4 alkenyl, C_1-4 alkynyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁸ together form ═O;

R⁹ is, at each occurrence, halogen, cyano, —OR^a, —S(O)_qR^a, —S(O)_qNR^aR^b, —NR^aS(O)_qR^b, —NR^aR^b, —OC(O)NR^aR^b, —NR^aC(O)R^b, —NR^aC(O)OR^b, alkyl, alkenyl, alkynyl, haloalkyl, carbocycle, carbocyclealkyl, heterocycle, heterocyclealkyl, or two R⁹ together form ═O;

wherein R⁷, R⁸, and R⁹ are each, independently, optionally substituted with one or more R;

R is —OR a, —C(O)R^a, —NR^aR^b, halogen, cyano, alkyl, haloalkyl, alkoxy, carbocycle, heterocycle, carbocyclalkyl, or heterocyclealkyl;

R^a is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

R^b is H, alkyl, haloalkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

or R^a and R^b, together with the nitrogen atom to which they are attached, form C_4-8 cycloalkyl, or 4- to 8-membered saturated heterocycle;

m is 0-5, wherein m is 1-5 when Q¹, Q², Q³, and Q⁴ are each C;

n is 0-5;

p is 0-5; and

q is 0-2.

In one embodiment, compounds are provided having the structure of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIII-A), (VIII-B), (VIII-C), (VIII-D), (VIII-E), (VIII-F), (VIII-G), (VIII-H), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII A), (XVIII B), (XIX), or (XX), as applicable, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein X is —C(O)NH—. In specific embodiments, compounds of Formulas (VIII-A), (VIII-B), (VIII-C), (VIII-D), (VIII-E), (VIII-F), (VIII-G), (VIII-H), (XI), (XVI), (XVIII-A), (XVIII-B), and (XX) are provided having the structure of any one of Formulas (VIII-A-1), (VIII-B-1), (VIII-C-1), (VIII-D-1), (VIII-E-1), (VIII-F-1), (VIII-G-1), (VIII-H-1), (XI-1), (XVI-1), (XVIII-A-1), (XVIII-B-1), or (XX-1) as shown in Table 1, below:

TABLE 1
EMBODIMENTS WHERE X IS —C(O)NH—
Formula Structure
(VIII-A-1)
(VIII-B-1)
(VIII-C-1)
(VIII-D-1)
(VIII-E-1)
(VIII-F-1)
(VIII-G-1)
(VIII-H-1)
(XI-1)
(XVI-1)
(XVIII-A-1)
(XVIII-B-1)
(XX-1)

In one embodiment, compounds are provided having the structure of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIII-A), (VIII-B), (VIII-C), (VIII-D), (VIII-E), (VIII-F), (VIII-G), (VIII-H), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII A), (XVIII B), (XIX), or (XX), as applicable, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein X is —C(R¹⁰R¹¹)C(O)NH—. In specific embodiments, compounds of Formulas (VIII-A), (VIII-B), (VIII-C), (VIII-D), (VIII-E), (VIII-F), (VIII-G), (VIII-H), (XI), (XVI), (XVIII-A), (XVIII-B), and (XX) are provided having the structure of any one of Formulas (VIII-A-2), (VIII-B-2), (VIII-C-2), (VIII-D-2), (VIII-E-2), (VIII-F-2), (VIII-G-2), (VIII-H-2), (XI-2), (XVI-2), (XVIII-A-2), (XVIII-B-2), or (XX-2) as shown in Table 2, below:

TABLE 2
EMBODIMENTS WHERE X IS —C(R10R11)C(O)NH—
Formula Structure
(VIII-A-2)
(VIII-B-2)
(VIII-C-2)
(VIII-D-2)
(VIII-E-2)
(VIII-F-2)
(VIII-G-2)
(VIII-H-2)
(XI-2)
(XVI-2)
(XVIII-A-2)
(XVIII-B-2)
(XX -2)

In one embodiment, compounds are provided having the structure of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIII-A), (VIII-B), (VIII-C), (VIII-D), (VIII-E), (VIII-F), (VIII-G), (VIII-H), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII A), (XVIII B), (XIX), or (XX), as applicable, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein X is —NHC(O)NH—. In specific embodiments, compounds of Formulas (VIII-A), (VIII-B), (VIII-C), (VIII-D), (VIII-E), (VIII-F), (VIII-G), (VIII-H), (XI), (XVI), (XVIII-A), (XVIII-B), and (XX) are provided having the structure of any one of Formulas (VIII-A-3), (VIII-B-3), (VIII-C-3), (VIII-D-3), (VIII-E-3), (VIII-F-3), (VIII-G-3), (VIII-H-3), (XI-3), (XVI-3), (XVIII-A-3), (XVIII-B-3), or (XX-3) as shown in Table 3, below:

TABLE 3
EMBODIMENTS WHERE X IS —NHC(O)NH—
Formula Structure
(VIII-A-3)
(VIII-B-3)
(VIII-C-3)
(VIII-D-3)
(VIII-E-3)
(VIII-F-3)
(VIII-G-3)
(VIII-H-3)
(XI-3)
(XVI-3)
(XVIII-A-3)
(XVIII-B-3)
(XX-3)

In one embodiment, compounds are provided having the structure of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIII-A), (VIII-B), (VIII-C), (VIII-D), (VIII-E), (VIII-F), (VIII-G), (VIII-H), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII A), (XVIII B), (XIX), or (XX), as applicable, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein X is —NHC(O)—. In specific embodiments, compounds of Formulas (VIII-A), (VIII-B), (VIII-C), (VIII-D), (VIII-E), (VIII-F), (VIII-G), (VIII-H), (XI), (XVI), (XVIII-A), (XVIII-B), and (XX) are provided having the structure of any one of Formulas (VIII-A-4), (VIII-B-4), (VIII-C-4), (VIII-D-4), (VIII-E-4), (VIII-F-4), (VIII-G-4), (VIII-H-4), (XI-4), (XVI-4), (XVIII-A-4), (XVIII-B-4), or (XX-4) as shown in Table 4, below:

TABLE 4
EMBODIMENTS WHERE X IS —NHC(O)—
Formula Structure
(VIII-A-4)
(VIII-B-4)
(VIII-C-4)
(VIII-D-4)
(VIII-E-4)
(VIII-F-4)
(VIII-G-4)
(VIII-H-4)
(XI-4)
(XVI-4)
(XVIII-A-4)
(XVIII-B-4)
(XX-4)

In one embodiment, compounds are provided having the structure of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIII-A), (VIII-B), (VIII-C), (VIII-D), (VIII-E), (VIII-F), (VIII-G), (VIII-H), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII A), (XVIII B), (XIX), or (XX), as applicable, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein R⁵ is H and R⁶ is alkyl. In one embodiment, R⁶ is methyl.

In one embodiment, compounds are provided having the structure of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIII-A), (VIII-B), (VIII-C), (VIII-D), (VIII-E), (VIII-F), (VIII-G), (VIII-H), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII-A), (XVIII-B), (XIX), or (XX), as applicable, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein n is 0. In one embodiment, n is 1 or 2.

In one embodiment, compounds are provided having the structure of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIII-A), (VIII-B), (VIII-C), (VIII-D), (VIII-E), (VIII-F), (VIII-G), (VIII-H), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII A), (XVIII B), (XIX), or (XX), as applicable, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein m is 0. In one embodiment, m is 1 or 2.

In one embodiment, compounds are provided having the structure of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIII-A), (VIII-B), (VIII-C), (VIII-D), (VIII-E), (VIII-F), (VIII-G), (VIII-H), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII A), (XVIII B), (XIX), or (XX), as applicable, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R⁸ is alkyl. In one embodiment, at least one R⁸ is methyl, ethyl, iso-propyl, n-propyl, or t-butyl.

In one embodiment, compounds are provided having the structure of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIII-A), (VIII-B), (VIII-C), (VIII-D), (VIII-E), (VIII-F), (VIII-G), (VIII-H), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII A), (XVIII B), (XIX), or (XX), as applicable, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R⁸ is alkyl substituted with halogen. In one embodiment, at least one R⁸ is difluoromethyl, trifluoromethyl, 2-fluoroethyl, or 2,2-difluoroethyl.

In one embodiment, compounds are provided having the structure of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIII-A), (VIII-B), (VIII-C), (VIII-D), (VIII-E), (VIII-F), (VIII-G), (VIII-H), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII A), (XVIII B), (XIX), or (XX), as applicable, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R⁸ is alkyl substituted with —OR^a and R^a is H or alkyl. In one embodiment, at least one R⁸ is hydroxymethyl, 2-hydroxyethyl, hydroxybutyl, or methoxymethyl.

In one embodiment, compounds are provided having the structure of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIII-A), (VIII-B), (VIII-C), (VIII-D), (VIII-E), (VIII-F), (VIII-G), (VIII-H), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII A), (XVIII B), (XIX), or (XX), as applicable, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R⁸ is carbocycle. In one embodiment, at least one R⁸ is cyclopropyl or cyclobutyl.

In one embodiment, compounds are provided having the structure of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIII-A), (VIII-B), (VIII-C), (VIII-D), (VIII-E), (VIII-F), (VIII-G), (VIII-H), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII A), (XVIII B), (XIX), or (XX), as applicable, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one of R⁸ is heterocycle.

In one embodiment, compounds are provided having the structure of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIII-A), (VIII-B), (VIII-C), (VIII-D), (VIII-E), (VIII-F), (VIII-G), (VIII-H), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII A), (XVIII B), (XIX), or (XX), as applicable, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R⁸ is —OR^a. In one embodiment, at least one R^a is alkyl. In one embodiment, at least one R^a is haloalkyl. In one embodiment, at least one R^a is carbocycle.

In one embodiment, compounds are provided having the structure of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIII-A), (VIII-B), (VIII-C), (VIII-D), (VIII-E), (VIII-F), (VIII-G), (VIII-H), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII A), (XVIII B), (XIX), or (XX), as applicable, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R⁸ is Nine′ in one embodiment, at least one R^a is H and at least one R^b is alkyl. In one embodiment, at least one R^a is H and at least one R^b is haloalkyl.

In one embodiment, compounds are provided having the structure of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIII-A), (VIII-B), (VIII-C), (VIII-D), (VIII-E), (VIII-F), (VIII-G), (VIII-H), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII A), (XVIII B), (XIX), or (XX), as applicable, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R⁸ is cyano.

In one embodiment, compounds are provided having the structure of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIII-A), (VIII-B), (VIII-C), (VIII-D), (VIII-E), (VIII-F), (VIII-G), (VIII-H), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII A), (XVIII B), (XIX), or (XX), as applicable, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R⁸ is halogen. In one embodiment, at least one R⁸ is Cl.

In one embodiment, compounds are provided having the structure of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIII-A), (VIII-B), (VIII-C), (VIII-D), (VIII-E), (VIII-F), (VIII-G), (VIII-H), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII A), (XVIII B), (XIX), or (XX), as applicable, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein p is 0. In one embodiment, p is 1 or 2.

In one embodiment, compounds are provided having the structure of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIII-A), (VIII-B), (VIII-C), (VIII-D), (VIII-E), (VIII-F), (VIII-G), (VIII-H), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII A), (XVIII B), (XIX), or (XX), as applicable, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R⁹ is halogen. In one embodiment, at least one of R⁹ is Cl or Br.

In one embodiment, compounds are provided having the structure of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIII-A), (VIII-B), (VIII-C), (VIII-D), (VIII-E), (VIII-F), (VIII-G), (VIII-H), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII A), (XVIII B), (XIX), or (XX), as applicable, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R⁹ is alkyl. In one embodiment, at least one of R⁹ is methyl or ethyl.

In one embodiment, compounds are provided having the structure of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIII-A), (VIII-B), (VIII-C), (VIII-D), (VIII-E), (VIII-F), (VIII-G), (VIII-H), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII A), (XVIII B), (XIX), or (XX), as applicable, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R⁹ is carbocycle. In one embodiment, at least one of R⁹ is phenyl.

In one embodiment, compounds are provided having the structure of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIII-A), (VIII-B), (VIII-C), (VIII-D), (VIII-E), (VIII-F), (VIII-G), (VIII-H), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII A), (XVIII B), (XIX), or (XX), as applicable, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R⁹ is heterocycle.

In one embodiment, compounds are provided having the structure of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIII-A), (VIII-B), (VIII-C), (VIII-D), (VIII-E), (VIII-F), (VIII-G), (VIII-H), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII A), (XVIII B), (XIX), or (XX), as applicable, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R⁹ is —OR^a. In one embodiment, R^a is, at each occurrence, independently H or alkyl.

In one embodiment, compounds are provided having the structure of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIII-A), (VIII-B), (VIII-C), (VIII-D), (VIII-E), (VIII-F), (VIII-G), (VIII-H), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII A), (XVIII B), (XIX), or (XX), as applicable, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R⁹ is optionally substituted with carbocycle or heterocycle.

In one embodiment, compounds are provided having the structure of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIII-A), (VIII-B), (VIII-C), (VIII-D), (VIII-E), (VIII-F), (VIII-G), (VIII-H), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII A), (XVIII B), (XIX), or (XX), as applicable, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R⁹ is optionally substituted with —OR^a. In one embodiment, R^a is, at each occurrence, independently H or alkyl.

In one embodiment, compounds are provided having the structure of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIII-A), (VIII-B), (VIII-C), (VIII-D), (VIII-E), (VIII-F), (VIII-G), (VIII-H), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII A), (XVIII B), (XIX), or (XX), as applicable, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein two R⁹ together form ═O.

Representative compounds having the structure of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIII-A), (VIII-B), (VIII-C), (VIII-D), (VIII-E), (VIII-F), (VIII-G), (VIII-H), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII A), (XVIII B), (XIX), or (XX), as applicable, include the compounds listed in Table 5 below, as well as pharmaceutically acceptable isomers, racemates, hydrates, solvates, isotopes, or salts thereof.

TABLE 5
REPRESENTATIVE COMPOUNDS
Cmpd
No	Structure	Name
1		(S)-5-methyl-N-(3-(1-((5- methyl-5H-pyrrolo[2,3-b] pyrazin-3-yl)amino)ethyl) phenyl)nicotinamide
2		(S)-5-methyl-N-(3-(1-(quinolin- 3-ylamino)ethyl)phenyl) nicotinamide
3		(S)-N-(3-(1-((1,5-naphthyridin- 3-yl)amino)ethyl)phenyl)-5- methylnicotinamide
4		(S)-5-methyl-N-(3-(1- (quinoxalin-2-ylamino)ethyl) phenyl)nicotinamide
5		(S)-5-methyl-N-(3-(1-(pyrido [2,3-b]pyrazin-3-ylamino)ethyl) phenyl)nicotinamide
6		(S)-N-(3-(1-((1-(3,4- dimethoxyphenyl)-1H-pyrrolo [3,2-b]pyridin-6-yl)amino)ethyl) phenyl)-5-methylnicotinamide
7		(S)-N-(3-(1-((1-ethyl-1H- pyrazolo[4,3]pyridin-6-yl) amino)ethyl)phenyl)-5- methylnicotinamide
8		(S)-5-methyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)nicotinamide
9		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-5- methylnicotinamide
10		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)-6- (trifluoromethyl)nicotinamide
11		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[4,3-b]pyridin-6-yl) amino)ethyl)phenyl)-5- methylnicotinamide
12		(S)-5-methyl-n-(3-(1-((3- methyl-2-oxo-2,3-dihydro-1H- imidazo[4,5-b]pyrazin-5-yl) amino)ethyl)phenyl) nicotinamide
13		(S)-5-methyl-N-(3-(1-((3- methyl-1H-pyrrolo[2,3-b] pyridin-5-yl)amino)ethyl) phenyl)nicotinamide
14		(S)-5-methyl-N-(3-(1-((3- methyl-1H-pyrazolo[3,4-b] pyridin-5-yl)amino)ethyl) phenyl)nicotinamide
15		(S)-5-methyl-N-(3-(1-((7- methyl-5H-pyrrolo[2,3-b] pyrazin-2-yl)amino)ethyl) phenyl)nicotinamide
16		(S)-5-methyl-N-(3-(1-((3- methyl-1H-pyrazolo[3,4-b] pyrazin-5-yl)amino)ethyl) phenyl)nicotinamide
17		(S)-5-methyl-N-(3-(1-((6- methylfuro[2,3-b]pyrazin-3-yl)- amino)ethyl)phenyl) nicotinamide
18		(S)-5-methyl-N-(3-(1-((2- methylthieno[3,2-b]pyridin-6- yl)amino)ethyl)phenyl) nicotinamide
19		(S)-5-methyl-N-(3-(1-((6- methylthieno[2,3-b]pyrazin-3- yl)amino)ethyl)phenyl) nicotinamide
20		(S)-5-methyl-N-(3-(1- (pyrazolo[1,5-a]pyridin-3- ylamino)ethyl)phenyl) nicotinamide
21		(S)-5-methyl-N-(3-(1-((1-(1- methyl-1H-pyrazol-4-yl)-1H- pyrazolo[3,4-c]pyridin-4-yl) amino)ethyl)phenyl) nicotinamide
22		(S)-5-methyl-N-(3-(1-((2- methylfuro[3,2-b]pyridin-6-yl) amino)ethyl)phenyl) nicotinamide
23		(S)-N-(3-(1-((1H-imidazo[4,5-b] pyrazin-5-yl)amino)ethyl) phenyl)-5-methylnicotinamide
24		(S)-N-(3-(1-((2-ethyl-3H- imidazo[4,5-b]pyridin-6-yl) amino)ethyl)phenyl)-5- methylnicotinamide
25		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-2-(5- methylpyridin-2-yl)acetamide
26		(S)-5-methyl-N-(3-(1- (pyrido[2,3-b]pyrazin-2- ylamino)ethyl)phenyl) nicotinamide
27		(S)-N-(3-(1-((5- methoxyquinolin-3-yl)amino) ethyl)phenyl)-5- methylnicotinamide
28		(S)-N-(3-(1-((7- methoxyquinolin-3-yl)amino) ethyl)phenyl)-5- methylnicotinamide
29		(S)-N-(3-(1-((5-fluoroquinolin- 3-yl)amino)ethyl)phenyl)-5- methylnicotinamide
30		(S)-N-(3-(1-((6,7- difluoroquinolin-3-yl)amino) ethyl)phenyl)-5- methylnicotinamide
31		5-methyl-N-(3-((quinoxalin-2- ylamino)methyl)phenyl) nicotinamide
32		(S)-N-(3-(1-((7- methoxyquinoxalin-2-yl)amino) ethyl)phenyl)-5- methylnicotinamide
33		(S)-N-(3-(1-((6- methoxyquinoxalin-2-yl)amino) ethyl)phenyl)-5- methylnicotinamide
34		(S)-5-methyl-N-(3-(1-((7- (trifluoromethyl)quinoxalin-2- yl)amino)ethyl)phenyl) nicotinamide
35		(S)-5-methyl-N-(3-(1-((6- (trifluoromethyl)quinoxalin-2- yl)amino)ethyl)phenyl) nicotinamide
36		(S)-N-(3-(1-((6,7- difluoroquinoxalin-2-yl)amino) ethyl)phenyl)-5- methylnicotinamide
37		(S)-N-(3-(1-((8- chloroquinoxalin-2-yl)amino) ethyl)phenyl)-5- methylnicotinamide
38		(S)-5-methyl-N-(3-(1-((7- methylquinoxalin-2-yl)amino) ethyl)phenyl)nicotinamide
39		(S)-N-(3-(1-((7- bromoquinoxalin-2-yl)amino) ethyl)phenyl)-5- methylnicotinamide
40		(S)-N-(3-(1-((6- fluoroquinoxalin-2-yl)amino) ethyl)phenyl)-5- methylnicotinamide
41		(S)-N-(3-(1-((7- cyclopropylquinoxalin-2-yl) amino)ethyl)phenyl)-5- methylnicotinamide
42		(S)-5-methyl-N-(3-(1-((7-(1- methyl-1H-pyrazol-4-yl) quinoxalin-2-yl)amino)ethyl) phenyl)nicotinamide
43		N-(4-methoxy-3-((quinoxalin-2- ylamino)methyl)phenyl)-5- methylnicotinamide
44		(S)-5-methyl-N-(3-(1-((5,6,7,8- tetrahydroquinoxalin-2-yl) amino)ethyl)phenyl) nicotinamide
45		(S)-N-(3-1-((3,4-dihydro-2H- pyrido[3,2-b][1,4]oxazin-7-yl) amino)ethyl)phenyl)-5- methylnicotinamide
46		(S)-1-methyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-1H-pyrrolo[3,2-b] pyridine-6-carboxamide
47		(S)-1-methyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-1H-pyrazolo[3,4-b] pyridine-6-carboxamide
48		(S)-1-methyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-1H-pyrazolo[4,3-b] pyridine-6-carboxamide
49		(S)-N-(3-(1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl) thieno[3,2-b]pyridinc-6- carboxamide
50		(S)-1-methyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-1H-indole-6- carboxamide
51		(S)-1-methyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-1H-indole-6- carboxamide
52		N-(3-((S)-1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-2- (trifluoromethyl)cyclopropane- 1-carboxamide
53		(1S,2R)-N-(3-((S)-1-((1 methyl- 1H-pyrazolo[3,4-d]pyrazin-6-yl) amino)ethyl)phenyl)-2- (trifluoromethyl)cyclopropane- 1-carboxamide
54		N-(3-((S)-1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-3- (trifluoromethyl)piperidine-1- carboxamide
55		(S)-N-(3-(1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-3,4- dihydroisoquinoline-2(1H)- carboxamide
56		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-3,4- dihydro-2H-pyrano[2,3-b] pyridine-6-carboxamide
57		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)quinoline- 3-carboxamide
58		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-6,7- dihydro-5H-cyclope3nta[6] pyridine-3-carboxamide
59		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)- 3,4-dihydro-2H-pyrano[2,3-b] pyridine-6-carboxamide
60		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-1H- pyrazolo[3,4-b]pyridine-5- carboxamide
61		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-3-methyl- 1H-pyrazolo[3,4-b]pyridine-5- carboxamide
62		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-1-methyl- 1H-pyrazolo[4,3-b]pyridine-6- carboxamide
63		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl) quinoline-3-carboxamide
64		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl) benzo[d][1,3]dioxole-5- carboxamide
65		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-1-methyl- 1H-pyrrolo[3,2-b]pyridine-6- carboxamide
66		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-1,2,3,4- tetrahydroisoquinoline-6- carboxamide
67		(S)-N-(3-(1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-1-oxo-1,3- dihydroisobenzofuran-5- carboxamide
68		(S)-N-(3-(1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-2,3- dihydrobenzo[b][1,4]dioxine-6- carboxamide
69		(S)-N-(3-(1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-2,3- dihydro-[1,4]dioxino[2,3-b] pyridine-7-carboxamide
70		(S)-N-(3-(1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-3,4- dihydro-2H-pyrano[2,3-b] pyridine-6-carboxamide
71		(S)-N-(3-(1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)chromane- 6-carboxamide
72		(S)-N-(3-(1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-2- oxochromane-6-carboxamide
73		(S)-1-methyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-1H-benzo[d]imidazole- 6-carboxamide
74		(S)-1-ethyl-N-(3-(1-((1-methyl- 1H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-1H- benzo[d]imidazole-6- carboxamide
75		(S)-N-(3-(1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-8-oxo-5,8- dihydro-6H-pyrano[3,4-b] pyridine-3-carboxamide
76		3-methyl-N-(3-((S)-1-((1- methyl-N-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-1-oxo-1,3- dihydroisobenzofuran-5- carboxamide
77		(S)-1-methyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-1H-imidazo[4,5-b] pyridine-6-carboxamide
78		(S)-N-(3-(1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-1- oxoisochromane-6-carboxamide
79		(S)-N-(3-(1-((1-methyl-1H- pyrazolo[3,4-d]pyrazin-6-yl) amino)ethyl)phenyl)-3,4- dihydro-2H-benzo[b] [1,4]thiazine-7-carboxamide
80		(S)-5-methyl-N-(3-(1-((1- methyl-1H-pyrrolo[3,2-b] pyridin-6-yl)amino)ethyl) phenyl)nicotinamide
81		(S)-N-(3-(1-((1-(3,4- dimethoxybenzyl)-1H-pyrrolo [3,2-b]pyridin-6-yl)amino)ethyl) phenyl)-5-methylnicotinamide
82		(S)-N-(3-(1-((5-ethyl-5H- pyrrolo[2,3-b]pyrazin-3-yl) amino)ethyl)phenyl)-5- methylnicotinamide
83		(S)-N-(3-(1-((5-(2- hydroxyethyl)-5H-pyrrolo[2,3- 6]pyrazin-3-yl)amino)ethyl) phenyl)-5-methylnicotinamide
84		(S)-N-(3-(1-((5-(2- methoxyethyl)-5H-pyrrolo [2,3-b]pyrazin-3-yl)amino) ethyl)phenyl)-5- methylnicotinamide
85		(S)-5-methyl-N-(3-(1-((5-(2- morpholinoethyl)-5H-pyrrolo [2,3-b]pyrazin-3-yl)amino) ethyl)phenyl)nicotinamide
86		(S)-5-methyl-N-(3-(1-((5-(1- methyl-1H-pyrazol-4-yl)-5H- pyrrolo[2,3-b]pyrazin-3-yl) amino)ethyl)phenyl) nicotinamide
87		(S)-N-(3-(1-((5-(3,4- dimethoxyphenyl)-5H-pyrrolo [2,3-b]|pyrazin-3-yl)amino) ethyl)phenyl)-5- methylnicotinamide
88		(S)-N-(3-(1-((5-(3,4- dimethoxybenzyl)-5H-pyrrolo [2,3-b]pyrazin-3-yl)amino) ethyl)phenyl)-5- methylnicotinamide
89		(S)-5-methyl-N-(3-(1-((1- methyl-1H-pyrazolo[4,3-b] pyridin-6-yl)amino)ethyl) phenyl)nicotinamide
90		(S)-N-(3-(1-((1H-pyrazolo[3,4- b]pyrazin-6-yl)amino)ethyl) phenyl)-5-methylnicotinamide
91		(S)-N-(3-(1-((1H-pyrazolo[3,4- b]pyrazin-6-yl)amino)ethyl) phenyl)-5-ethylnicotinamide
92		(S)-N-(3-(1-((1H-pyrazolo[3,4- b]pyrazin-6-yl)amino)ethyl) phenyl)-5-(hydroxymethyl) nicotinamide
93		(S)-N-(3-(1-((1H-pyrazolo[3,4- b]pyrazin-6-yl)amino)ethyl) phenyl)-5- cyclopropylnicotinamide
94		(S)-N-(3-(1-((1H-pyrazolo[3,4- b]pyrazin-6-yl)amino)ethyl) phenyl)-5-(2-fluoropropan-2-yl) nicotinamide
95		(S)-N-(3-(1-((1H-pyrazolo[3,4- 6]pyrazin-6-yl)amino)ethyl) phenyl)-5-(2-hydroxypropan-2- yl)nicotinamide
96		(S)-N-(3-(1-((1H-pyrazolo[3,4- b]pyrazin-6-yl)amino)ethyl) phenyl)-5- cyclobutylnicotinamide
97		(S)-N-(3-(1-((1H-pyrazolo[3,4- b]pyrazin-6-yl)amino)ethyl) phenyl)-5-(oxetan-3-yl) nicotinamide
98		(S)-N-(3-(1-((1H-pyrazolo[3,4- b]pyrazin-6-yl)amino)ethyl) phenyl)-5-methyl-6- (trifluoromethyl)nicotinamide
99		(S)-N-(3-(1-((1H-pyrazolo[3,4 b]pyrazin-6-yl)amino)ethyl) phenyl)-6-(trifluoromethyl) nicotinamide
100		(S)-N-(3-(1-((1H-pyrazolo[3,4- b]pyrazin-6-yl)amino)ethyl) phenyl)-1-isopropyl-1H- pyrazole-4-carboxamide
101		(S)-N-ethyl-N-(3-(1-((1-methyl- 1H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl) nicotinamide
102		(S)-N-(3-(1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-5- (trifluoromethyl)nicotinamide
103		(S)-5-(difluoromethyl)-N-(3-(1- ((1-methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)nicotinamide
104		(S)-5-methoxy-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)nicotinamide
105		(S)-5-cyclopropyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)nicotinamide
106		(S)-5-(hydroxymethyl)-N-(3-(1- ((1-methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)nicotinamide
107		(S)-5-(2-hydroxypropan-2-yl)- N-(3-(1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl) nicotinamide
108		(S)-5-(2-fluoropropan-2-yl)-N- (3-(1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl) nicotinamide
109		(S)-5-chloro-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)nicotinamide
110		(S)-5-cyclobutyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)nicotinamide
111		(S)-5-bromo-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)nicotinamide
112		(S)-5-(methoxymethyl)-N-(3-(1- ((1-methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)nicotinamide
113		(S)-5-ethynyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)nicotinamide
114		(S)-N-(3-(1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-5-(oxetan- 3-yl)nicotinamide
115		(S)-N-(3-(1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-6- (trifluoromethyl)nicotinamide
116		(S)-6-cyclopropyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)nicotinamide
117		(S)-6-cyano-N-(3-(1-((1-methyl- 1H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl) nicotinamide
118		(S)-6-(difluoromethoxy)-N-(3- (1-((1-methyl-1H-pyrazolo[3,4- 6]pyrazin-6-yl)amino)ethyl) phenyl)nicotinamide
119		(S)-N-(3-(1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-6- (trifluoromethoxy)nicotinamide
120		(S)-N-(3-(1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-6- (methylamino)nicotinamide
121		(S)-6-(cyclopropylamino)-N-(3- (1-((1-methyl-1H-pyrazolo[3,4- 6]pyrazin-6-yl)amino)ethyl) phenyl)nicotinamide
122		(S)-6-methoxy-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)nicotinamide
123		(S)-6-cyclobutyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)nicotinamide
124		(S)-6-methyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-5-(trifluoromethyl) nicotinamide
125		(S)-5-methyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-6-(trifluoromethyl) nicotinamide
126		(S)-2-methyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-5-(trifluoromethyl) nicotinamide
127		(S)-6-cyano-5-methyl-N-(3-(1- ((1-methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)nicotinamide
128		(S)-6-methoxy-5-methyl-N-(3- (1-((1-methyl-1H-pyrazolo[3,4- b]pyrazin-6-yl)amino)ethyl) phenyl)nicotinamide
129		(S)-6-ethoxy-5-methyl-N-(3-(1- ((1-methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)nicotinamide
130		(S)-5-methyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-6-(methylamino) nicotinamide
131		(S)-4-fluoro-N-(3-(1-((1-methyl- 1H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl) nicotinamide
132		(S)-6-methyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)pyridazine-4- carboxamide
133		(S)-5-methyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)thiophene-2- carboxamide
134		(S)-5-(difluoromethyl)-N-(3-(1- ((1-methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)thiophene-2- carboxamide
135		(S)-5-chloro-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)thiophene-2- carboxamide
136		(S)-5-cyclopropyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)thiophene-2- carboxamide
137		(S)-N-(3-(1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-5- (trifluoromethyl)thiophene-2- carboxamide
138		(S)-2-methyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)thiazole-5-carboxamide
139		(S)-N-(3-(1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-2- (trifluoromethyl)thiazole-5- carboxamide
140		(S)-2-cyclopropyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)thiazole-5-carboxamide
141		(S)-2-(difluoromethyl)-N-(3-(1- ((1-methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)thiazole-5-carboxamide
142		(S)-5-isopropyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)isoxazole-3- carboxamide
143		(S)-5-(tert-butyl)-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)isoxazole-3- carboxamide
144		(S)-5-cyclopropyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)isoxazole-3- carboxamide
145		(S)-3-isopropyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)isoxazole-5- carboxamide
146		(S)-1-methyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-1H-pyrazole-4- carboxamide
147		(S)-1-isopropyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-1H-pyrazole-4- carboxamide
148		(S)-1-(tert-butyl)-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-1H-pyrazole-4- carboxamide
149		(S)-1-(difluoromethyl)-N-(3-(1- ((1-methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-1H-pyrazole-4- carboxamide
150		(S)-1-cyclopropyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-1H-pyrazole-4- carboxamide
151		(S)-1-cyclobutyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-1H-pyrazole-4- carboxamide
152		(S)-1-(cyclopropylmethyl)-N-(3- (1-((1-methyl-1H-pyrazolo[3,4- b]pyrazin-6-yl)amino)ethyl) phenyl)-1H-pyrazole-4- carboxamide
153		(S)-1-ethyl-N-(3-(1-((1-methyl- 1H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-1H- pyrazole-4-carboxamide
154		(S)-1-(2-fluoroethyl)-N-(3-(1- ((1-methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-1H-pyrazole-4- carboxamide
155		(S)-1-(difluoromethyl)-N-(3-(1- ((1-methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-1H-pyrazole-3- carboxamide
156		(S)-1-isopropyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-1H-pyrazole-3- carboxamide
157		(S)-1-isobutyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-1H-pyrazole-3- carboxamide
158		(S)-1-(2,2-difluoroethyl)-N-(3- (1-((1-methyl-1H-pyrazolo[3,4- b]pyrazin-6-yl)amino)ethyl) phenyl)-1H-pyrazole-3- carboxamide
159		(S)-3-(tert-butyl)-1-methyl-N- (3-(1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-1H- pyrazole-5-carboxamide
160		(S)-1-methyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-3-(trifluoromethyl)-1H- pyrazole-5-carboxamide
161		(S)-5-isopropyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-1H-pyrazole-3- carboxamide
162		(S)-5-isopropyl-1-methyl-N-(3- (1-((1-methyl-1H-pyrazolo[3,4- b]pyrazin-6-yl)amino)ethyl) phenyl)-1H-pyrazole-3- carboxamide
163		(S)-1-ethyl-5-isopropyl-N-(3-(1- ((1-methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-1H-pyrazole-3- carboxamide
164		(S)-1-methyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-5-(trifluoromethyl)-1H- pyrazole-3-carboxamide
165		(S)-3-isopropyl-1-methyl-N-(3- (1-((1-methyl-1H-pyrazolo[3,4- 6]pyrazin-6-yl)amino)ethyl) phenyl)-1H-pyrazole-5- carboxamide
166		(S)-5-(tert-butyl)-1-methyl-N- (3-(1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-1H- pyrazole-3-carboxamide
167		(S)-1-ethyl-3-isopropyl-N-(3-(1- ((1-methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-1H-pyrazole-5- carboxamide
168		(S)-4-methyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-1H-pyrazole-1- carboxamide
169		(S)-1-methyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-1H-pyrrolo[2,3-b] pyridine-5-carboxamide
170		N-(3-fluoro-5-(1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-5- methylnicotinamide
171		(S)-N-(3-fluoro-5-(1-((1-methyl- 1H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-5- methylnicotinamide
172		(S)-N-(3-fluoro-3-(1-((1-methyl- 1H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-5- methylnicotinamide
173		(S)-N-(2-fluoro-3-(1-((1-methyl- 1H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-5- methylnicotinamide
174		(S)-5-methyl-N-(5-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) pyridin-3-yl)nicotinamide
175		(S)-5-methyl-N-(6-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) pyridin-2-yl)nicotinamide
176		(S)-N-(3-(1-((1-ethyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-5- methylnicotinamide
177		(S)-N-(3-(1-((1-cyclopropyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-5- methylnicotinamide
178		(S)-N-(3-(1-((1-cyclobutyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-5- methylnicotinamide
179		(S)-5-methyl-N-(3-(1-((1- (oxetan-3-yl)-1H-pyrazolo[3,4- b]pyrazin-6-yl)amino)ethyl) phenyl)nicotinamide
180		(S)-5-methyl-N-(3-(1-((1- (tetrahydro-2H-pyran-4-yl)-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl) nicotinamide
181		(S)-N-(3-(1-((1- (cyclopropylmethyl)-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-5- methylnicotinamide
182		5-methyl-N-(3-((1S)-1-((1- (tetrahydrofuran-3-yl)-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl) nicotinamide
183		(S)-N-(3-(1-((1-(2,2- difluoroethyl)-1H-pyrazolo[3,4- b]pyrazin-6-yl)amino)ethyl) phenyl)-5-methylnicotinamide
184		(S)-5-methyl-N-(3-(1-((1- (methyl-d3)-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)nicotinamide
185		(S)-N-(3-(1-((1-(3,4- dimethoxyphenyl)-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-5- methylnicotinamide
186		(S)-5-methyl-N-(3-(1-((1-(1- methyl-1H-pyrazol-4-yl)-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl) nicotinamide
187		(S)-5-chloro-6-methoxy-N-(3- (1-((1-methyl-1H-pyrazolo[3,4- b]pyrazin-6-yl)amino)ethyl) phenyl)nicotinamide
188		(S)-3-fluoro-4-methyl-N-(3-(1- ((1-methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)benzamide
189		(S)-3-fluoro-4-methoxy-N-(3-(1- ((1-methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)benzamide
190		(S)-6-(difluoromethyl)-5- methyl-N-(3-(1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl) nicotinamide
191		(S)-4-chloro-3-fluoro-N-(3-(1- ((1-methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)benzamide
192		(S)-6-fluoro-5-methyl-N-(3-(1- ((1-methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)nicotinamide
193		(S)-4-cyano-3-methyl-N-(3-(1- ((1-methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)benzamide
194		(S)-6-(ethylamino)-5-methyl-N- (3-(1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl) nicotinamide
195		(S)-5-methyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-6-(4-methylpiperazin-1- yl)nicotinamide
196		(S)-4-ethoxy-3-methyl-N-(3-(1- ((1-methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)benzamide
197		methyl (S)-2-bromo-4-((3-(1- ((1-methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)carbamoyl)benzoate
198		(S)-6-(isopropylamino)-5- methyl-N-(3-(1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl) nicotinamide
199		methyl (S)-2-methyl-4-((3-(1- ((1-methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)carbamoyl)benzoate
200		(S)-6-chloro-5-methyl-N-(3-(1- ((1-methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)nicotinamide
201		(S)-6-cyclopropyl-N-(4-fluoro- 3-(1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl) nicotinamide
202		(S)-6-(difluoromethoxy)-N-(4- fluoro-3-(1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl) nicotinamide
203		(S)-3,4-dimethoxy-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)benzamide
204		(S)-6-isopropyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)nicotinamide
205		(S)-5,6-dimethoxy-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)nicotinamide
206		(S)-5,6-dimethyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)nicotinamide
207		(S)-6-ethyl-N-(3-(1-((1-methyl- 1H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl) nicotinamide
208		(S)-3-methyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-4-((4-methylpiperazin- 1-yl)methyl)benzamide
209		(S)-3-methyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-4-(morpholinomethyl) benzamide
210		(S)-4-methoxy-3-methyl-N-(3- (1-((1-methyl-1H-pyrazolo[3,4- b]pyrazin-6-yl)amino)ethyl) phenyl)benzamide
211		methyl (S)-4-((3-(1-((1-methyl- 1H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)carbamoyl) benzoate
212		methyl (S)-5-((3-(1-((1-methyl- 1H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)carbamoyl) picolinate
213		(S)-1-cyclobutyl-N-(4-fluoro-3- (1-((1-methyl-1H-pyrazolo[3,4- b]pyrazin-6-yl)amino)ethyl) phenyl)-1H-pyrazole-4- carboxamide
214		(S)-4-((3-(1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)carbamoyl) phenyl acetate
215		(S)-3-((3-(1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)carbamoyl) phenyl acetate
216		(S)-5-methyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-6-(prop-1-en-2-yl) nicotinamide
217		(S)-ethyl (4-((3-(1-((1-methyl- 1H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)carbamoyl) phenyl) carbonate
218		(S)-N-(3-(1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-6- (methylthio)nicotinamide
219		(S)-N-(3-(1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-4- (methylthio)benzamide
220		(S)-N-(3-(1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-4- (methylsulfonyl)benzamide
221		(S)-N-(3-(1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-6- (methylsulfonyl)nicotinamide
222		(S)-3-methyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-4- (methylthio)benzamide
223		(S)-5-methyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-6- (methylthio)nicotinamide
224		(S)-N-(3-(1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-3- (methylthio)benzamide
225		(S)-N-(3-(1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-5- (methylthio)benzamide
226		(S)-N-(3-(1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-3- (methylsulfonyl)benzamide
227		(S)-N-(3-(1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-5- (methylsulfonyl)nicotinamide
228		(S)-N-(4-fluoro-3-(1-((1-methyl- 1H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-3-methyl- 4-((4-methylpiperazin-1-yl) methyl)benzamide
229		(S)-6-isobutoxy-5-methyl-N-(3- (1-((1-methyl-1H-pyrazolo[3,4- b]pyrazin-6-yl)amino)ethyl) phenyl)nicotinamide
230		(S)-5-(ethoxymethyl)-N-(3-(1- ((1-methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)nicotinamide
231		(S)-6-isopropyl-5-methyl-N-(3- (1-((1-methyl-1H-pyrazolo[3,4- 6]pyrazin-6-yl)amino)ethyl) phenyl)nicotinamide
232		(S)-N-(4-fluoro-3-(1-((1-methyl- 1H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-6- (isopropylamino)-5- methylnicotinamide
233		(S)-6-ethyl-5-methyl-N-(3-(1- ((1-methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)nicotinamide
234		(S)-3,4-dimethyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)benzamide
235		(S)-6-(ethylamino)-N-(4-fluoro- 3-(1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-5- methylnicotinamide
236		(S)-4-chloro-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-3- (methylthio)benzamide
237		(S)-3-methyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-4- (thiomorpholinomethyl) benzamide
238		(S)-N-(3-(1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-4-((4- methylpiperazin-1-yl)methyl)-3- (methylthio)benzamide
239		(S)-5-methyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-6-(morpholinomethyl) nicotinamide
240		(S)-4-hydroxy-3-methyl-N-(3- (1-((1-methylH-pyrazolo[3,4- b]pyrazin-6-yl)amino)ethyl) phenyl)benzamide
241		(S)-5-hydroxy-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)nicotinamide
242		(S)-5-ethoxy-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)nicotinamide
243		(S)-5-methyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-6-((4-methylpiperazin- 1-yl)methyl)nicotinamide
244		(S)-5-methyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-6- (thiomorpholinomethyl) nicotinamide
245		(S)-5-methyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-6-vinylnicotinamide
246		(S)-3-methyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-4-vinylbenzamide
247		(S)-6-methoxy-N-(3-(1-((1- methyl-1-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-5-(trifluoromethyl) nicotinamide
248		(S)-6-isopropoxy-5-methyl-N- (3-(1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl) nicotinamide
249		(S)-6-chloro-5-methoxy-N-(3- (1-((1-methyl-1H-pyrazolo[3,4- b]pyrazin-6-yl)amino)ethyl) phenyl)nicotinamide
250		(S)-5-fluoro-6-methyl-N-(3-(1- ((1-methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)nicotinamide
251		(S)-4-ethyl-3-methyl-N-(3-(1- ((1-methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)benzamide
252		(S)-5-methoxy-6-methyl-N-(3- (1-((1-methyl-1H-pyrazolo[3,4- b]pyrazin-6-yl)amino)ethyl) phenyl)nicotinamide
253		(S)-6-hydroxy-5-methyl-N-(3- (1-((1-methyl-1H-pyrazolo[3,4- b]pyrazin-6-yl)amino)ethyl) phenyl)nicotinamide
254		propyl (S)-2-methyl-4-((3-(1- ((1-methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)carbamoyl)benzoate
255		ethyl (S)-2-methyl-4-((3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)carbamoyl)benzoate
256		1-acetoxyethyl 2-methyl-4-((3- ((S)-1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)carbamoyl) benzoate
257		2-hydroxyethyl (S)-2-methyl-4- ((3-(1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)carbamoyl) benzoate
258		isopropyl (S)-2-methyl-4-((3-(1- ((1-methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)carbamoyl)benzoate
259		(S)-5-methyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-6-(2-oxa-6- azaspiro[3.3]heptan-6-yl) nicotinamide
260		(S)-5-methyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-6- thiomorpholinonicotinamide
261		methyl (S)-2-methoxy-4-((3-(1- ((1-methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)carbamoyl)benzoate
262		(S)-5-chloro-6-isobutoxy-N-(3- (1-((1-methyl-1H-pyrazolo[3,4- b]pyrazin-6-yl)amino)ethyl) phenyl)nicotinamide
263		isobutyl (S)-2-methyl-4-((3-(1- ((1-methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)carbamoyl)benzoate
264		2-morpholinoethyl (S)-2- methyl-4-((3-(1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)carbamoyl) benzoate
265		(S)-1-ethyl-N-(3-(1-((1-methyl- 1H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-1H- imidazo[4,5-b]pyridine-6- carboxamide
266		2-aminoethyl (S)-2-methyl-4- ((3-(1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)carbamoyl) benzoate
267		(5-methyl-2-oxo-1,3-dioxol-4- yl)methyl (S)-2-methyl-4-((3-(1- ((1-methyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)carbamoyl)benzoate
268		2-(pyrrolidin-1-yl)ethyl (S)-2- methyl-4-((3-(1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)carbamoyl) benzoate
269		(S)-N-(3-(1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-3,4- bis(methylthio)benzamide
270		1-methylpiperidin-4-yl (S)-2- methyl-4-((3-(1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)carbamoyl) benzoate
271		(S)-5-methyl-N-(3-(1-((1- phenyl-1H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)nicotinamide
272		(S)-5-methyl-N-(3-(1-((1- (pyridin-2-yl)-1H-pyrazolo[3,4- b]pyrazin-6-yl)amino)ethyl) phenyl)nicotinamide
273		(S)-5-methyl-N-(3-(1-((1- (pyridin-3-yl)-1H-pyrazolo[3,4- b]pyrazin-6-yl)amino)ethyl) phenyl)nicotinamide
274		(S)-5-methyl-N-(3-(1-((2- methyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)nicotinamide
275		(S)-N-(3-(1-((2- (cyclopropylmethyl)-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-5- methylnicotinamide
276		(S)-N-(3-(1-((2-isobutyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-5- methylnicotinamide
277		(S)-N-(3-(1-((2-(2-fluoroethyl)- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-5- methylnicotinamide
278		(S)-5-methyl-N-(3-(1-((2-(2- morpholinoethyl)-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl) nicotinamide
279		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-5- methoxynicotinamide
280		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-5-(2- fluoropropan-2-yl)nicotinamide
281		(S)-5-chloro-N-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl) nicotinamide
282		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-6- (trifluoromethoxy)nicotinamide
283		(S)-6-cyclopropyl-N-(3-(1-((2- ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)nicotinamide
284		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-6- (trifluoromethyl)nicotinamide
285		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-6- methoxynicotinamide
286		(S)-6-ethoxy-N-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl) nicotinamide
287		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-6- isopropoxynicotinamide
288		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-5-methyl- 6-(trifluoromethyl)nicotinamide
289		(S)-6-cyano-N-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-5- methylnicotinamide
290		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-6- methoxy-5-methylnicotinamide
291		(S)-5-cyclopropyl-N-(3-(1-((2- ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)thiophene-2- carboxamide
292		(S)-5-(difluoromethyl)-N-(3-(1- ((2-ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)thiophene-2- carboxamide
293		(S)-5-chloro-N-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)thiophene- 2-carboxamide
294		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-2- methylthiazole-5-carboxamide
295		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-2- (trifluoromethyl)thiazole-5- carboxamide
296		(S)-2-cyclopropyl-N-(3-(1-((2- ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)thiazole-5-carboxamide
297		(S)-1-ethyl-N-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-1H- pyrazole-4-carboxamide
298		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-1-(2- fluoroethyl)-1H-pyrazole-4- carboxamide
299		(S)-1-cyclopropyl-N-(3-(1-((2- ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-1H-pyrazole-4- carboxamide
300		(S)-1-(cyclopropylmethyl)-N-(3- (1-((2-ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-1H-pyrazole-4- carboxamide
301		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-1- isopropyl-1H-pyrazole-4- carboxamide
302		(S)-6-cyclopropyl-N-(3-(1-((2- ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl)-4- fluorophenyl)nicotinamide
303		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)-6- (trifluoromethoxy)nicotinamide
304		(S)-6-(difluoromethoxy)-N-(3- (1-((2-ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl)-4- fluorophenyl)nicotinamide
305		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-1- isopropyl-1H-pyrazole-3- carboxamide
306		(S)-6-cyano-N-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)-5- methylnicotinamide
307		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)-2- methylthiazole-5-carboxamide
308		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)-2- (trifluoromethyl)thiazole-5- carboxamide
309		(S)-2-cyclopropyl-N-(3-(1-((2- ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl)-4- fluorophenyl)thiazole-5- carboxamide
310		(S)-1-ethyl-N-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)- 1H-pyrazole-4-carboxamide
311		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)-1- (2-fluoroethyl)-1H-pyrazole-4- carboxamide
312		(S)-1-cyclopropyl-N-(3-(1-((2- ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl)-4- fluorophenyl)-1H-pyrazole-4- carboxamide
313		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)-1- isopropyl-1H-pyrazole-4- carboxamide
314		(S)-6-ethoxyN-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-5- methylnicotinamide
315		(S)-6-(cyclopropylmethoxy)-N- (3-(1-((2-ethyl-2H-pyrazolo[3,4- b]pyrazin-6-yl)amino)ethyl) phenyl)-5-methylnicotinamide
316		(S)-6-ethoxy-N-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)-5- methylnicotinamide
317		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)-6- methoxy-5-methylnicotinamide
318		(S)-6-(cyclopropylmethoxy)-N- (3-(1-((2-ethyl-2H-pyrazolo[3,4- b]pyrazin-6-yl)amino)ethyl)-4- fluorophenyl)-5- methylnicotinamide
319		(S)-2-(difluoromethyl)-N-(3-(1- ((2-ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)thiazole-5-carboxamide
320		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)-6- (pyrrolidin-1-yl)nicotinamide
321		(S)-6-cyclopropyl-N-(3-(1-((2- ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-5-methylnicotinamide
322		(S)-6-cyclopropyl-N-(3-(1-((2- ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl)-4- fluorophenyl)-5- methylnicotinamide
323		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-5-methyl- 6-(pyrrolidin-1-yl)nicotinamide
324		(S)-2-bromo-N-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)thiazole-5- carboxamide
325		(S)-N-( 3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-2- methoxythiazole-5-carboxamide
326		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-2- (pyrrolidin-1-yl)thiazole-5- carboxamide
327		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-6- isopropoxy-5- methylnicotinamide
328		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-5,6- dimethylnicotinamide
329		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-6-fluoro-5- methylnicotinamide
330		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-4-fluoro-3- methylbenzamide
331		(S)-4-cyano-N-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-3- methylbenzamide
332		(S)-3-chloro-N-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-4- methylbenzamide
333		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-6- (ethylamino)-5- methylnicotinamide
334		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-6-(1H- imidazol-1-yl)-5- methylnicotinamide
335		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)-5- methyl-6-(trifluoromethyl) nicotinamide
336		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)-5- methyl-6-(pyrrolidin-1-yl) nicotinamide
337		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)-6- (methylamino)nicotinamide
338		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-2- (methoxymethyl)thiazole-5- carboxamide
339		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-2- morpholinothiazole-5- carboxamide
340		(S)-2-(dimethylamino)-N-(3-(1- ((2-ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)thiazole-5-carboxamide
341		(S)-2-ethyl-N-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)thiazole-5- carboxamide
342		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-2-(1- methyl-1H-pyrazol-4-yl) thiazole-5-carboxamide
343		(S)-3-chloro-N-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-4- fluorobenzamide
344		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-3-fluoro-4- methylbenzamide
345		(S)-4-chloro-N-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-3- methylbenzamide
346		(S)-4-cyano-N-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)benzamide
347		(S)-4-chloro-N-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-3- fluorobenzamide
348		(S)-6-(dimethylamino)-N-(3-(1- ((2-ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-5-methylnicotinamide
349		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-2- isopropylthiazole-5- carboxamide
350		(S)-6-bromo-N-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-5- methylnicotinamide
351		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-5-methyl- 6-((tetrahydro-2H-pyran-4-yl) amino)nicotinamide
352		(S)-6-(cyclopropylamino)-N-(3- (1-((2-ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-5-methylnicotinamide
353		(S)-6-(difluoromethyl)-N-(3-(1- ((2-ethyl-2H-pyrazolo[3,4-b)] pyrazin-6-yl)amino)ethyl) phenyl)-5-methylnicotinamide
354		(S)-5-chloro-N-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-6- isopropoxynicotinamide
355		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-5- fluoronicotinamide
356		(S)-5-chloro-N-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-6- methoxynicotinamide
357		(S)-4,5-dichloro-N-(3-(1-((2- ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)thiophene-2- carboxamide
358		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-5-methyl- 6-morpholinonicotinamide
359		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-3-fluoro-4- methoxybenzamide
360		(S)-3-chloro-N-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-4- morpholinobenzamide
361		(S)-3-chloro-N-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-4-(4- methylpiperazin-1-yl)benzamide
362		(S)-2-ethoxy-N-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)thiazole-5- carboxamide
363		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-2- (hydroxymethyl)thiazole-5- carboxamide
364		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-2- (ethylamino)thiazole-5- carboxamide
365		(S)-N5-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)thiazole- 2,5-dicarboxamide
366		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-3-fluoro-4- morpholinobenzamide
367		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-3-fluoro-4- (4-methylpiperazin-1-yl) benzamide
368		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)furan-3- carboxamide
369		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-5- methylfuran-2-carboxamide
370		(S)-2-acetamido-N-(3-(1-((2- ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)thiazole-5-carboxamide
371		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-6- (isopropylamino)-5- methylnicotinamide
372		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-6- morpholinonicotinamide
373		(S)-4-((dimethylamino)methyl)- N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)benzamide
374		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-4- (morpholinomethyl)benzamide
375		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-6- (pyrrolidin-1-yl)nicotinamide
376		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-4-((4- methylpiperazin-1-yl)methyl) benzamide
377		(S)-6-(dimethylamino)-N-(3-(1- ((2-ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)nicotinamide
378		tert-butyl (S)-4-(5-((3-(1-((2- ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)carbamoyl)pyridin-2-yl) piperazine-1-carboxylate
379		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)-5- methyl-6-(methylamino) nicotinamide
380		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-5-methyl- 6-(methylamino)nicotinamide
381		N-(3-((S)-1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-2-(1- hydroxyethyl)thiazole-5- carboxamide
382		(S)-N-(3-(1-((2- (cyclopropylmethyl)-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)-2- (trifluoromethyl)thiazole-5- carboxamide
383		(S)-6-chloro-N-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-5- methylnicotinamide
384		(S)-4-(dimethylamino)-N-(3-(1- ((2-ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-3-methylbenzamide
385		(S)-6-(cyclopropylamino)-N-(3- (1-((2-ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)nicotinamide
386		(S)-N-(3-(1-((2-ethyl-2H- pvrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-3-methyl- 4-morpholinobenzamide
387		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-6-((4- methylpiperazin-1-yl)methyl) nicotinamide
388		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-6- (pyrrolidin-1-ylmethyl) nicotinamide
389		(S)-3-chloro-N-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-4- (pyrrolidin-1-yl)benzamide
390		(S)-N-(3-(1-((2- (cyclobutylmethyl)-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)-2- (trifluoromethyl)thiazole-5- carboxamide
391		(S)-N-(3-(1-((2-(azetidin-3- ylmethyl)-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl)-4- fluorophenyl)-2- (trifluoromethyl)thiazole-5- carboxamide
392		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-6-((2- methoxyethyl)amino)-5- methylnicotinamide
393		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-6- (methylamino)nicotinamide
394		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-6- (ethylamino)nicotinamide
395		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-6- (isopropylamino)nicotinamide
396		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-5-methyl- 6-(4-methylpiperazin-1-yl) nicotinamide
397		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-6- (piperazin-1-yl)nicotinamide
398		(S)-2-cyclopentyl-N-(3-(1-((2- ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)thiazole-5-carboxamide
399		(S)-N-(3-(1-((2-cyclopropyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)-2- (trifluoromethyl)thiazole-5- carboxamide
400		(S)-2-(1,3-dioxolan-2-yl)-N-(3- (1-((2-ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)thiazole-5-carboxamide
401		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-4-formyl- 3-methylbenzamide
402		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-3-methyl- 4-((4-methylpiperazin-1-yl) methyl)benzamide
403		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-3-methyl- 4-(morpholinomethyl) benzamide
404		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-3-methyl- 4-(pyrrolidin-1-ylmethyl) benzamide
405		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-4- (isopropylamino)-3- methylbenzamide
406		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-5-methyl- 6-(3-(pyrrolidin-1-yl) propoxy)nicotinamide
407		(S)-1-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-3-(6- (trifluoromethoxy)pyridin-3-yl) urea
408		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)propyl)phenyl)-5- methylnicotinamide
409		(S)-N-(3-(1-((2-(2- (dimethylamino)ethyl)-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)-2- (trifluoromethyl)thiazole-5- carboxamide
410		N-(4-fluoro-3-((1S)-1-((2- (pyrrolidin-3-ylmethyl)-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-5- methylnicotinamide
411		N-(4-fluoro-3-((1S)-1-((2- (morpholin-2-ylmethyl)-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-5- methylnicotinamide
412		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)-3- methyl-4-(4-methylpiperazin-1- yl)benzamide
413		(S)-3-chloro-N-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)-4- (4-methylpiperazin-1-yl) benzamide
414		(S)-4-((2-oxa-6- azaspiro[3.3]heptan-6-yl) methyl)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-3- methylbenzamide
415		(S)-4-((2-oxa-6- azaspiro[3.3]heptan-6-yl) methyl)-3-chloro-N-(3-(1-((2- ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)benzamide
416		(S)-3-chloro-N-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-4- (morpholinomethyl)benzamide
417		(S)-3-chloro-N-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-4-((4- methylpiperazin-1-yl)methyl) benzamide
418		(S)-3-chloro-N-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-4- (pyrrolidin-1-ylmethyl) benzamide
419		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-5-fluoro-6- methylnicotinamide
420		(S)-5-chloro-N-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-6- (ethylamino)nicotinamide
421		(S)-5-chloro-N-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-6-(4- methylpiperazin-1-yl) nicotinamide
422		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-6-(4- methylpiperazin-1-yl)-5- (trifluoromethyl)nicotinamide
423		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-4-((4- methylpiperazin-1-yl)methyl)-3- (trifluoromethyl)benzamide
424		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-4- (morpholinomethyl)-3- (trifluoromethyl)benzamide
425		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-4- (pyrrolidin-1-ylmethyl)-3- (trifluoromethyl)benzamide
426		(S)-3-chloro-N-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)-4- (pyrrolidin-1-ylmethyl) benzamide
427		(S)-3-chloro-N-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)-4- (morpholinomethyl)benzamide
428		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)-4- (morpholinomethyl)-3- (trifluoromethyl)benzamide
429		(S)-3-chloro-N-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)-4- ((4-methylpiperazin-1-yl) methyl)benzamide
430		(S)-3-chloro-N-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)-4- ((1-methylpiperidin-4-yl) oxy)benzamide
431		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)-4- ((1-methylpiperidin-4-yl)oxy)- 3-(trifluoromethyl)benzamide
432		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)-5- methyl-6-(4-methylpiperazin-1- yl)nicotinamide
433		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)-4- (4-methylpiperazin-1-yl)-3- (trifluoromethyl)benzamide
434		(S)-5-methyl-N-(3-(1-((2- phenyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)nicotinamide
435		(S)-4-((1H-imidazol-1-yl) methyl)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-3- methylbenzamide
436		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-4-(4- methylpiperazin-1-yl)-3- (trifluoromethyl)benzamide
437		(S)-3-chloro-N-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-4- (trifluoromethoxy)benzamide
438		(S)-3-chloro-N-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-4- (trifluoromethyl)benzamide
439		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-3-methyl- 4-(trifluoromethyl)benzamide
440		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-3- methoxy-4-(trifluoromethyl) benzamide
441		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-3-fluoro-4- (pyrrolidin-1-yl)benzamide
442		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-2,2- difluorobenzo[d][1,3]dioxole-5- carboxamide
443		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)-4- (pyrrolidin-1-ylmethyl)-3- (trifluoromethyl)benzamide
444		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)-4- ((4-methylpiperazin-1-yl) methyl)-3-(trifluoromethyl) benzamide
445		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)-6- (4-methylpiperazin-1-yl)-5- (trifluoromethyl)nicotinamide
446		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)-3- methyl-4-(morpholinomethyl) benzamide
447		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)-3- methyl-4-((1-methylpiperidin-4- yl)oxy)benzamide
448		(S)-5-methyl-N-(3-(1-((2- (pyridin-2-yl)-2H-pyrazolo[3,4- b]pyrazin-6-yl)amino)ethyl) phenyl)nicotinamide
449		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-2- methylisoindoline-5- carboxamide
450		(S)-3-chloro-4- (difluoromethoxy)-N-(3-(1-((2- ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)benzamide
451		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-2-(2- fluorophenyl)acetamide
452		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-3-methyl- 4-(trifluoromethoxy)benzamide
453		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-4- (trifluoromethyl)benzamide
454		(S)-2-(2,3-difluorophenyl)-N-(3- (1-((2-ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)acetamide
455		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-methylphenyl)- 6-(trifluoromethyl)nicotinamide
456		(S)-5-chloro-N-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)-6- (4-methylpiperazin-1-yl) nicotinamide
457		(S)-N-(3-(1-((2-ethyl-2H- pvrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)-3 methyl-4-((4-methylpiperazin-1- yl)methyl)benzamide
458		(S)-N-(4-chloro-3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-6- (trifluoromethyl)nicotinamide
459		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-(trifluoromethyl) phenyl)-6-(trifluoromethyl) nicotinamide
460		(S)-4-((2-oxa-6- azaspiro[3.4]octan-6-yl)methyl)- N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-3- methylbenzamide
461		(S)-4-((1,1-difluoro-5- azaspiro[2.3]hexan-5-yl)methyl)- 1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-3- methylbenzamide
462		(S)-4-((4-cyclopropylpiperazin- 1-yl)methyl)-N-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-3- methylbenzamide
463		(S)-5-methyl-N-(3-(1-((2- (pyridin-3-yl)-2H-pyrazolo[3,4- b]pyrazin-6-yl)amino)ethyl) phenyl)nicotinamide
464		3-chloro-N-(3-((S)-1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-4-(((R)-3- fluoropyrrolidin-1-yl)methyl) benzamide
465		4-((R)-3-aminopyrrolidine-1- carbonyl)-N-(3-((S)-1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-3- methylbenzamide
466		(S)-3-chloro-N-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-4-(4- methylpiperazine-1-carbonyl) benzamide
467		4-((R)-3-aminopyrrolidine-1- carbonyl)-3-chloro-N-(3-((5)-1- ((2-ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)benzamide
468		(S)-4-((2-oxa-6- azaspiro[3.3]heptan-6-yl) methyl)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-3- fluorobenzamide
469		N-(3-((S)-1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-4-(((R)-3- fluoropyrrolidin-1-yl)methyl)-3- methylbenzamide
470		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)-3- methyl-4-(pyrrolidin-1- ylmethyl)benzamide
471		N-(3-((S)-1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-4-(((S)-3- hydroxypyrrolidin-1-yl)methyl)- 3-methylbenzamide
472		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-3-methyl- 4-(4-methylpiperazine-1- carbonyl)benzamide
473		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-3-methyl- 4-((6-methyl-2,6- diazaspiro[3.3]heptan-2-yl) methyl)benzamide
474		(S)-4-((3,3-difluoropiperidin-1- yl)methyl)-N-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-3- methylbenzamide
475		N-(3-((S)-1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-3-methyl- 4-(((1R,5S)-3-methyl-3,8- diazabicyclo[3.2.1]octan-8-yl) methyl)benzamide
476		(S)-4-((4,4-difluoropiperidin-1- yl)methyl)-N-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-3- methylbenzamide
477		4-((3-azabicyclo[3.1.0]hexan-3- yl)methyl)-N-(3-((5)-1-((2- ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-3-methylbenzamide
478		4-(((2S,6R)-2,6- dimethylmorpholino)methyl)-N- (3-((S)-1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-3- methylbenzamide
479		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-3-methyl- 4-((4-methyl-3-oxopiperazin-1- yl)methyl)benzamide
480		(S)-4-((2-oxa-7- azaspiro[3.5]nonan-7-yl)methyl)- N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-3- methylbenzamide
481		(S)-4-((2-oxa-6- azaspiro[3.5]nonan-6-yl)methyl)- N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-3- methylbenzamide
482		N-(3-((S)-1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) annno)ethyl)phenyl)-4-(((R)-3- hydroxypyrrolidin-1-yl)methyl)- 3-methylbenzamide
483		3-chloro-N-(3-((S)-1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-4-(((R)-3- hydroxypyrrolidin-1-yl)methyl) benzamide
484		3-chloro-N-(3-((S)-1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-4-(((S)-3- fluoropyrrolidin-1-yl)methyl) benzamide
485		(S)-4-(azetidin-1-ylmethyl)-N- (3-(1-((2-ethyl-2H-pyrazolo[3,4- b]pyrazin-6-yl)amino)ethyl) phenyl)-3-methylbenzamide
486		(S)-4-(azetidin-1-ylmethyl)-3- chloro-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)benzamide
487		(S)-3-chloro-N-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-4-((3- hydroxyazetidin-1-yl)methyl) benzamide
488		(S)-3-chloro-N-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-5-fluoro-4- (pyrrolidin-1-ylmethyl) benzamide
489		(S)-3-chloro-N-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-5-fluoro-4- ((4-methylpiperazin-1-yl) methyl)benzamide
490		(S)-4-((2-oxa-6- azaspiro[3.3]heptan-6-yl) methyl)-3-chloro-N-(3-(1-((2- ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-5-fluorobenzamide
491		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4,5- difluorophenyl)-6- (trifluoromethyl)nicotinamide
492		(S)-N-(5-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-2,4- difluorophenyl)-6- (trifluoromethyl)nicotinamide
493		N-(3-((S)-1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-4-(((S)-3- fluoropyrrolidin-1-yl)methyl)-3- methylbenzamide
494		3-chloro-N-(3-((5)-1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-4-(((S)-3- hydroxypyrrolidin-1-yl)methyl) benzamide
495		(S)-3-chloro-N-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-4-((3- fluoroazetidin-1-yl)methyl) benzamide
496		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-4-((3- hydroxyazetidin-1-yl)methyl)-3- methylbenzamide
497		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-4-((3- fluoroazetidin-1-yl)methyl)-3- methylbenzamide
498		(S)-3-ethyl-N-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-4-((4- methylpiperazin-1-yl)methyl) benzamide
499		(S)-4-((2-oxa-6- azaspiro[3,3]heptan-6-yl) methyl)-3-ethyl-N-(3-(1-((2- ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)benzamide
500		(S)-6-((2-oxa-6- azaspiro[3.3]heptan-6-yl) methyl)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-5- fluoronicotinamide
501		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[4,3-b]pyridin-6-yl) amino)ethyl)-4-methylphenyl)- 5-methylnicotinamide
502		(S)-3-cyclopropyl-N-(3-(1-((2- ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-4-((4-methylpiperazin- 1-yl)methyl)benzamide
503		(S)-6-((2-oxa-6- azaspiro[3.3]heptan-6-yl) methyl)-5-chloro-N-(3-(1-((2- ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)nicotinamide
504		(S)-3-(difluoromethyl)-N-(3-(1- ((2-ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)-4-((4-methylpiperazin- 1-yl)methyl)benzamide
505		(S)-4-((2-oxa-6- azaspiro[3.3]heptan-6-yl) methyl)-3-cyclopropyl-N-(3-(1- ((2-ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)benzamide
506		(S)-4-((2-oxa-6- azaspiro[3.3]heptan-6-yl) methyl)-3-(difluoromethyl)-N- (3-(1-((2-ethyl-2H-pyrazolo[3,4- b]pyrazin-6-yl)amino)ethyl) phenyl)benzamide
507		(S)-3-chloro-N-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-methylphenyl)- 4-fluorobenzamide
508		(S)-4-chloro-N-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-methylphenyl)- 3-methylbenzamide
509		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-methylphenyl)- 5,6-dimethylnicotinamide
510		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-methylphenyl)- 5-methylnicotinamide
511		(S)-6-(difluoromethoxy)-N-(3- (1-((2-ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl)-4- methylphenyl)nicotinamide
512		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-methylphenyl)- 6-fluoro-5-methylnicotinamide
513		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-methylphenyl)- 6-(ethylamino)-5- methylnicotinamide
514		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-methylphenyl)- 5-methyl-6-(4-methylpiperazin- 1-yl)nicotinamide
515		(S)-6-(cyclopropylamino)-N-(3- (1-((2-ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl)-4- methylphenyl)-5- methylnicotinamide
516		(S)-N-(4-ethyl-3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-6- (trifluoromethyl)nicotinamide
517		(S)-6-((2-oxa-6- azaspiro[3.3]heptan-6-yl) methyl)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-5- methylnicotinamide
518		(S)-3-chloro-N-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-methylphenyl)- 5-fluoro-4-((4-methylpiperazin- 1-yl)methyl)benzamide
519		(S)-4-(azetidin-1-ylmethyl)-3- chloro-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-methylphenyl)- 5-fluorobenzamide
520		(S)-3-chloro-N-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-methylphenyl)- 5-fluoro-4-(morpholinomethyl) benzamide
521		3-chloro-N-(3-((S)-1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-methylphenyl)- 5-fluoro-4-(((R)-3- hydroxypyrrolidin-1-yl)methyl) benzamide
522		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-methylphenyl)- 3-methyl-4-(pyrrolidin-1- ylmethyl)benzamide
523		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-methylphenyl)- 3-methyl-4-(morpholinomethyl) benzamide
524		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-methylphenyl)- 3-methyl-4-((4-methylpiperazin- 1-yl)methyl)benzamide
525		(S)-4-(azetidin-1-ylmethyl)-N- (3-(1-((2-ethyl-2H-pyrazolo[3,4- b]pyrazin-6-yl)amino)ethyl)-4- methylphenyl)-3-fluoro-5- methylbenzamide
526		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-methylphenyl)- 3-fluoro-5-methyl-4- (morpholinomethyl)benzamide
527		N-(3-((S)-1-((2-ethyl-2H- pvrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-methylphenyl)- 3-fluoro-4-(((R)-3- hydroxypyrrolidin-1-yl)methyl)- 5-methylbenzamide
528		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-methylphenyl)- 3-fluoro-5-methyl-4-((4- methylpiperazin-1-yl)methyl) benzamide
529		(S)-N-(3-(1-((1H-pyrazolo[3,4- b]pyrazin-5-yl)amino)ethyl) phenyl)-5-methylnicotinamide
530		(S)-N-(3-(1-((1H-pyrazolo[3,4- b]pyrazin-5-yl)amino)ethyl) phenyl)-5-isopropylisoxazole-3- carboxamide
531		(S)-5-methoxy-N-(3-(1-((3- methyl-1H-pyrazolo[3,4-b] pyrazin-5-yl)amino)ethyl) phenyl)nicotinamide
532		(S)-5-(difluoromethyl)-N-(3-(1- ((3-methyl-1H-pyrazolo[3,4-b] pyrazin-5-yl)amino)ethyl) phenyl)nicotinamide
533		(S)-5-chloro-N-(3-(1-((3- methyl-1H-pyrazolo[3,4-b] pyrazin-5-yl)amino)ethyl) phenyl)nicotinamide
534		(S)-N-(3-(1-((3-methyl-1H- pyrazolo[3,4-b]pyrazin-5-yl) amino)ethyl)phenyl)-6- (trifluoromethyl)nicotinamide
535		(S)-6-cyclopropyl-N-(3-(1-((3- methyl-1H-pyrazolo[3,4-b] pyrazin-5-yl)amino)ethyl) phenyl)nicotinamide
536		(S)-N-(3-(1-((3-methyl-1H- pyrazolo[3,4-b]pyrazin-5-yl) amino)ethyl)phenyl)-6- (trifluoromethoxy)nicotinamide
537		(S)-6-ethoxy-N-(3-(1-((3- methyl-1H-pyrazolo[3,4-b] pyrazin-5-yl)amino)ethyl) phenyl)nicotinamide
538		(S)-5-methyl-N-(3-(1-((3- methyl-1H-pyrazolo[3,4-b] pyrazin-5-yl)amino)ethyl) phenyl)-6-(trifluoromethyl) nicotinamide
539		(S)-5-(difluoromethyl)-N-(3-(1- ((3-methyl-1H-pyrazolo[3,4-b] pyrazin-5-yl)amino)ethyl) phenyl)thiophene-2- carboxamide
540		(S)-N-(3-(1-((3-methyl-1H- pyrazolo[3,4-b]pyrazin-5-yl) amino)ethyl)phenyl)-2- (trifluoromethyl)thiazole-5- carboxamide
541		(S)-2-cyclopropyl-N-(3-(1-((3- methyl-1H-pyrazolo[3,4-b] pyrazin-5-yl)amino)ethyl) phenyl)thiazole-5-carboxamide
542		(S)-5-isopropyl-N-(3-(1-((3- methyl-1H-pyrazolo[3,4-b] pyrazin-5-yl)amino)ethyl) phenyl)isoxazole-3- carboxamide
543		(S)-1-cyclopropyl-N-(3-(1-((3- methyl-1H-pyrazolo[3,4-b] pyrazin-5-yl)amino)ethyl) phenyl)-1H-pyrazole-4- carboxamide
544		(S)-1-(2-fluoroethyl)-N-(3-(1- ((3-methyl-1H-pyrazolo[3,4-b] pyrazin-5-yl)amino)ethyl) phenyl)-1H-pyrazole-4- carboxamide
545		(S)-1-ethyl-N-(3-(1-((3-methyl- 1H-pyrazolo[3,4-b]pyrazin-5-yl) amino)ethyl)phenyl)-1H- pyrazole-4-carboxamide
546		(S)-1-(difluoromethyl)-N-(3-(1- ((3-methyl-1H-pyrazolo[3,4-b] pyrazin-5-yl)amino)ethyl) phenyl)-1H-pyrazole-4- carboxamide
547		(S)-1-methyl-N-(3-(1-((3- methyl-1H-pyrazolo[3,4-b] pyrazin-5-yl)amino)ethyl) phenyl)-5-(trifluoromethyl)-1H- pyrazole-3-carboxamide
548		(S)-1-methyl-N-(3-(1-((3- methyl-1H-pyrazolo[3,4-b] pyrazin-5-yl)amino)ethyl) phenyl)-3-(trifluoromethyl)-1H- pyrazole-5-carboxamide
549		(S)-N-(3-(1-((3-bromo-1H- pyrazolo[3,4-b]pyrazin-5-yl) amino)ethyl)phenyl)-5- methylnicotinamide
550		(S)-N-(3-(1-((3-chloro-1H- pyrazolo[3,4-b]pyrazin-5-yl) amino)ethyl)phenyl)-5- methylnicotinamide
551		(S)-5-methyl-N-(3-(1-((3-(1- methyl-1H-pyrazol-4-yl)-1H- pyrazolo[3,4-b]pyrazin-5-yl) amino)ethyl)phenyl) nicotinamide
552		(S)-N-(3-(1-((5H-pyrrolo[2,3-b] pyrazin-2-yl)amino)ethyl) phenyl)-5-methylnicotinamide
553		(S)-N-(3-(1-((5H-pyrrolo[2,3-b] pyrazin-2-yl)amino)ethyl) phenyl)-5-isopropylisoxazole-3- carboxamide
554		(S)-5-isopropyl-N-(3-(1-((7- methyl-5H-pyrrolo[2,3-b] pyrazin-2-yl)amino)ethyl) phenyl)isoxazole-3- carboxamide
555		(S)-5-methoxy-N-(3-(1-((7- methyl-5H-pyrrolo[2,3-b] pyrazin-2-yl)amino)ethyl) phenyl)nicotinamide
556		(S)-5-(difluoromethyl)-N-(3-(1- ((7-methyl-5H-pyrrolo[2,3-6] pyrazin-2-yl)amino)ethyl) phenyl)nicotinamide
557		(S)-N-(3-(1-((7-methyl-5H- pyrrolo[2,3-b]pyrazin-2-yl) amino)ethyl)phenyl)-6- (trifluoromethyl)nicotinamide
558		(S)-6-cyclopropyl-N-(3-(1-((7- methyl-5H-pyrrolo[2,3-b] pyrazin-2-yl)amino)ethyl) phenyl)nicotinamide
559		(S)-5-methyl-N-(3-(1-((7- methyl-5H-pyrrolo[2,3-b] pyrazin-2-yl)amino)ethyl) phenyl)-6-(trifluoromethyl) nicotinamide
560		(S)-5-(difluoromethyl)-N-(3-(1- ((7-methyl-5H-pyrrolo[2,3-b] pyrazin-2-yl)amino)ethyl) phenyl)thiophene-2- carboxamide
561		(S)-1-(difluoromethyl)-N-(3-(1- ((7-methyl-5H-pyrrolo[2,3-b] pyrazin-2-yl)amino)ethyl) phenyl)-1H-pyrazole-4- carboxamide
562		(S)-1-methyl-N-(3-(1-((7- methyl-5H-pyrrolo[2,3-b] pyrazin-2-yl)amino)ethyl) phenyl)-3-(trifluoromethyl)-1H- pyrazole-5-carboxamide
563		(S)-5-methyl-N-(3-(1-((7-(1- methyl-H-pyrazol-4-yl)-5H- pyrrolo[2,3-b]pyrazin-2-yl) amino)ethyl)phenyl) nicotinamide
564		(S)-N-(3-(1-((7-ethyl-5H- pyrrolo[2,3-b]pyrazin-2-yl) amino)ethyl)phenyl)-5- methylnicotinamide
565		(S)-5-chloro-N-(3-(1-((7- methyl-5H-pyrrolo[2,3-b] pyrazin-2-yl)amino)ethyl) phenyl)nicotinamide
566		(S)-6-methoxy-N-(3-(1-((7-(1- methyl-1H-pyrazol-4-yl)-5H- pyrrolo[2,3-b]pyrazin-2-yl) amino)ethyl)phenyl) nicotinamide
567		(S)-1-methyl-N-(3-(1-((7- methyl-5H-pyrrolo[2,3-b] pyrazin-2-yl)amino)ethyl) phenyl)-5-(trifluoromethyl)-1H- pyrazole-3-carboxamide
568		(S)-N-(3-(1-((7-methyl-5H- pyrrolo[2,3-b]pyrazin-2-yl) amino)ethyl)phenyl)-6- (trifluoromethoxy)nicotinamide
569		(S)-N-(3-(1-((7-cyclopropyl-5H- pyrrolo[2,3-b]pyrazin-2-yl) amino)ethyl)phenyl)-5- methylnicotinamide
570		(S)-6-ethoxy-N-(3-(1-((7- methyl-5H-pyrrolo[2,3-b] pyrazin-2-yl)amino)ethyl) phenyl)nicotinamide
571		(S)-2-cyclopropyl-N-(3-(1-((7- methyl-5H-pyrrolo[2,3-b] pyrazin-2-yl)amino)ethyl) phenyl)thiazole-5-carboxamide
572		(S)-N-(3-(1-((7-methyl-5H- pyrrolo[2,3-b]pyrazin-2-yl) amino)ethyl)phenyl)-2- (trifluoromethyl)thiazole-5- carboxamide
573		(s)-1-cyclopropyl-N-(3-(1-((7- methyl-5H-pyrrolo[2,3-b] pyrazin-2-yl)amino)ethyl) phenyl)-1H-pyrazole-4- carboxamide
574		(S)-1-ethyl-N-(3-(1-((7-methyl- 5H-pyrrolo[2,3-b]pyrazin-2-yl) amino)ethyl)phenyl)-1H- pyrazole-4-carboxamide
575		(S)-1-(2-fluoroethyl)-N-(3-(1- ((7-methyl-5H-pyrrolo[2,3-b] pyrazin-2-yl)amino)ethyl) phenyl)-1H-pyrazole-4- carboxamide
576		(S)-5-methyl-N-(3-(1-((7-(1- methyl-1H-pyrazol-4-yl)-5H- pyrrolo[2,3-b]pyrazin-2-yl) amino)ethyl)phenyl)-6- (trifluoromethyl)nicotinamide
577		(S)-5-methyl-N-(3-(1-((7-(1- methyl-1H-pyrazol-4-yl)-5H- pyrrolo[2,3-b]pyrazin-2-yl) amino)ethyl)phenyl)-6- (pyrrolidin-1-yl)nicotinamide
578		(S)-2-cyclopropyl-N-(3-(1-((7- (1-methyl-1H-pyrazol-4-yl)-5H- pyrrolo[2,3-b]pyrazin-2-yl) amino)ethyl)phenyl)thiazole-5- carboxamide
579		(S)-6-methoxy-5-methyl-N-(3- (1-((7-(1-methyl-1H-pyrazol-4- yl)-5H-pyrrolo[2,3-b]pyrazin-2- yl)amino)ethyl)phenyl) nicotinamide
580		(S)-N-(3-(1-((7-(1-methyl-1H- pyrazol-4-yl)-5H-pyrrolo[2,3-b] pyrazin-2-yl)amino)ethyl) phenyl)-6-(trifluoromethyl) nicotinamide
581		(S)-1-cyclopropyl-N-(3-(1-((7- (1-methyl-1H-pyrazol-4-yl)-5H- pyrrolo[2,3-b]pyrazin-2-yl) amino)ethyl)phenyl)-1H- pyrazole-4-carboxamide
582		(S)-N-(3-(1-((7-(1-methyl-1H- pyrazol-4-yl)-5H-pyrrolo[2,3-b] pyrazin-2-yl)amino)ethyl) phenyl)-2-(trifluoromethyl) thiazole-5-carboxamide
583		(S)-2-methyl-N-(3-(1-((7-(1- methyl-1H-pyrazol-4-yl)-5H- pyrrolo[2,3-b]pyrazin-2-yl) amino)ethyl)phenyl)thiazole-5- carboxamide
584		(S)-1-methyl-N-(3-(1-((7-(1- methyl-1H-pyrazol-4-yl)-5H- pyrrolo[2,3-b]pyrazin-2-yl) amino)ethyl)phenyl)-3- (trifluoromethyl)-1H-pyrazole- 5-carboxamide
585		(S)-N-(3-(1-((7-(1-methyl-1H- pyrazol-4-yl)-5H-pyrrolo[2,3-b] pyrazin-2-yl)amino)ethyl) phenyl)-6-(pyrrolidin-1-yl) nicotinamide
586		(S)-5-methoxy-N-(3-(1-((7-(1- methyl-1H-pyrazol-4-yl)-5H- pyrrolo[2,3-b]pyrazin-2-yl) amino)ethyl)phenyl) nicotinamide
587		(S)-5-methyl-N-(3-(1-((7-(1- methyl-1H-pyrazol-4-yl)-5H- pyrrolo[2,3-b]pyrazin-2-yl) amino)ethyl)phenyl)-6- (methylamino)nicotinamide
588		(S)-1-isopropyl-N-(3-(1-((7-(1- methyl-1H-pyrazol-4-yl)-5H- pyrrolo[2,3-b]pyrazin-2-yl) amino)ethyl)phenyl)-1H- pyrazole-4-carboxamide
589		(1R,2R)-N-(3-((S)-1-((7-(1- methyl-1H-pyrazol-4-yl)-5H- pyrrolo[2,3-b]pyrazin-2-yl) amino)ethyl)phenyl)-2- (trifluoromethyl)cyclopropane- 1-carboxamide
590		(1R,2S)-N-(3-((5)-1-((7-(1- methyl-1H-pyrazol-4-yl)-5H- pyrrolo[2,3-b]pyrazin-2-yl) amino)ethyl)phenyl)-2- (trifluoromethyl)cyclopropane- 1-carboxamide
591		(S)-5-methyl-N-(3-(1-((7- (pyridin-3-yl)-5H-pyrrolo[2,3-b] pyrazin-2-yl)amino)ethyl) phenyl)nicotinamide
592		(S)-5-methyl-N-(3-(1-((7- (pyridin-4-yl)-5H-pyrrolo[2,3-b] pyrazin-2-yl)amino)ethyl) phenyl)nicotinamide
593		(S)-5-methyl-N-(3-(1-((7- (pyrimidin-5-yl)-5H-pyrrolo [2,3-b]pyrazin-2-yl)amino) ethyl)phenyl)nicotinamide
594		(S)-N-(3-(1-((5H-pyrrolo[2,3-b] pyrazin-2-yl)amino)ethyl) phenyl)-6- cyclopropylnicotinamide
595		(S)-N-(3-(1-((5H-pyrrolo[2,3-b] pyrazin-2-yl)amino)ethyl) phenyl)-6- (difluoromethoxy)nicotinamide
596		(S)-N-(3-(1-((5H-pyrrolo[2,3-b] pyrazin-2-yl)amino)ethyl)-4- fluorophenyl)-6- (difluoromethoxy)nicotinamide
597		(S)-N-(3-(1-((5H-pyrrolo[2,3-b] pyrazin-2-yl)amino)ethyl)-4- fluorophenyl)-1-cyclobutyl-1H- pyrazole-4-carboxamide
598		(S)-N-(3-(1-((5H-pyrrolo[2,3-b] pyrazin-2-yl)amino)ethyl) phenyl)-1-cyclobutyl-1H- pyrazole-4-carboxamide
599		(S)-N-(3-(1-((5H-pyrrolo[2,3-b] pyrazin-2-yl)amino)ethyl)-4- fluorophenyl)-6- cyclopropylnicotinamide
600		(S)-N-(3-(1-((3H-imidazo[4,5-b] pyridin-6-yl)amino)ethyl) phenyl)-5-methylnicotinamide
601		(S)-N-(3-(1-((2-cyclopropyl-3H- imidazo[4,5-6]pyridin-6-yl) amino)ethyl)phenyl)-5- methylnicotinamide
602		(S)-5-methyl-N-(3-(1-((2-(1- methyl-1H-pyrazol-4-yl)-3H- imidazo[4,5-b]pyridin-6-yl) amino)ethyl)phenyl) nicotinamide
603		(S)-5-methyl-N-(3-(1-((2-(1- methyl-1H-pyrazol-4-yl)-1H- imidazo[4,5-b]pyrazin-5-yl ) amino)ethyl)phenyl) nicotinamide
604		(S)-N-(3-(1-(furo[3,2-b]pyridin- 6-ylamino)ethyl)phenyl)-5- methylnicotinamide
605		(S)-N-(3-(1-(furo[2,3-b]pyrazin- 3-ylamino)ethyl)phenyl)-5- methylnicotinamide
606		(S)-5-methyl-N-(3-(1- (thieno[3,2-b]pyridin-6- ylamino)ethyl)phenyl) nicotinamide
607		(S)-5-methyl-N-(3-(1- (thieno[2,3-b]pyridin-3- ylamino)ethyl)phenyl) nicotinamide
608		(S)-6-(difluoromethoxy)-N-(3- (1-((6-methylthieno[2,3-b] pyrazin-3-yl)amino)ethyl) phenyl)nicotinamide
609		(S)-1-cyclobutyl-N-(3-(1-((6- methylthieno[2,3-b]pyrazin-3- yl)amino)ethyl)phenyl)-1H- pyrazole-4-carboxamide
610		(S)-6-cyclopropyl-N-(3-(1-((6- methylthieno[2,3-b]pyrazin-3- yl)amino)ethyl)phenyl) nicotinamide
611		(S)-6-(difluoromethoxy)-N-(4- fluoro-3-(1-((6- methylthieno[2,3-b]pyrazin-3- yl)amino)ethyl)phenyl) nicotinamide
612		(S)-6-cyclopropyl-N-(4-fluoro- 3-(1-((6-methylthieno[2,3-b] pyrazin-3-yl)amino)ethyl) phenyl)nicotinamide
613		(S)-1-cyclobutyl-N-(4-fluoro-3- (1-((6-methylthieno[2,3-b] pyrazin-3-yl)amino)ethyl) phenyl)-1H-pyrazole-4- carboxamide
614		(S)-N-(4-fluoro-3-(1-((6- methylfuro[2,3-b]pyrazin-3-yl) amino)ethyl)phenyl)-6- (trifluoromethyl)nicotinamide
615		(S)-N-(4-fluoro-3-(1-((6- methylthieno[2,3-b]pyrazin-3- yl)amino)ethyl)phenyl)-6- (trifluoromethyl)nicotinamide
616		(S)-N-(3-(1-((6- cyclopropylthieno[2,3-b] pyrazin-3-yl)amino)ethyl)-4- fluorophenyl)-6- (trifluoromethyl)nicotinamide
617		(S)-N-(4-fluoro-3-(1-(furo[2,3- b]pyrazin-3-ylamino)ethyl) phenyl)-6-(trifluoromethyl) nicotinamide
618		(S)-N-(3-(1-((6-(difluoromethyl) thieno[2,3-b]pyrazin-3-yl) amino)ethyl)-4-fluorophenyl)-6- (trifluoromethyl)nicotinamide
619		(S)-N-(3-(1-((6-ethylfuro[2,3-b] pyrazin-3-yl)amino)ethyl)-4- fluorophenyl)-6- (trifluoromethyl)nicotinamide
620		(S)-N-(3-(1-((6-ethylthieno[2,3- b]pyrazin-3-yl)amino)ethyl)-4- fluorophenyl)-6- (trifluoromethyl)nicotinamide
621		(S)-2-(3-chlorophenyl)-N-(3-(1- ((2-ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)acetamide
622		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-2-(m-tolyl) acetamide
623		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-2-(5- fluoropyridin-3-yl)acetamide
624		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-2-(pyridin- 3-yl)acetamide
625		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-2-(3- fluorophenyl)acetamide
626		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-2-(3- fluoro-4-methoxyphenyl) acetamide
627		(S)-2-(4-chloro-3-fluorophenyl)- N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)acetamide
628		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-2-(3- fluoro-4-(trifluoromethyl) phenyl)acetamide
629		(S)-2-(1-methyl-1H-pyrazol-4- yl)-N-(3-(1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)acetamide
630		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-2-(3- (trifluoromethyl)phenyl) acetamide
631		(S)-2-(3-chloro-4-fluorophenyl)- N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)acetamide
632		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-2-(4- fluoro-3-methylphenyl) acetamide
633		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-2- phenylacetamide
634		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)-2- (m-tolyl)acetamide
635		(S)-2-(3-chlorophenyl)-N-(3-(1- ((2-ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl)-4- fluorophenyl)acetamide
636		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)-2- (3-(trifluoromethyl)phenyl) acetamide
637		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)-2- phenylacetamide
638		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-2-(4- fluorophenyl)acetamide
639		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-2-(3- fluoro-5-methylphenyl) acetamide
640		(S)-2-(2,5-difluorophenyl)-N-(3- (1-((2-ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)acetamide
641		(S)-2-(3-chloro-5-fluorophenyl)- N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)acetamide
642		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-2-(6- (trifluoromethyl)pyridin-2-yl) acetamide
643		(S)-2-(3,5-difluorophenyl)-N-(3- (1-((2-ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)acetamide
644		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-2-(pyridin- 4-yl)acetamide
645		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-2-(pyridin- 2-yl)acetamide
646		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-2-(3- fluoro-5-((4-methylpiperazin-1- yl)methyl)phenyl)acetamide
647		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-2-(5- fluoropyridin-2-yl)acetamide
648		(S)-2-(3,4-difluorophenyl)-N-(3- (1-((2-ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)acetamide
649		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)-2- (5-fluoropyridin-2-yl)acetamide
650		(S)-2-(5-chloropyridin-2-yl)-N- (3-(1-((2-ethyl-2H-pyrazolo[3,4- b]pyrazin-6-yl)amino)ethyl)-4- fluorophenyl)acetamide
651		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)-2- (6-methylpyridin-3-yl) acetamide
652		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)-2- (5-methylpyridin-3-yl) acetamide
653		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)-2- (5-fluoropyridin-3-yl)acetamide
654		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)-2- (5-(trifluoromethyl)pyridin-2-yl) acetamide
655		(S)-2-(5-cyclopropylpyridin-2- yl)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl) acetamide
656		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-methylphenyl)- 2-(5-fluoropyridin-2-yl) acetamide
657		(S)-2-(5-chloropyridin-2-yl)-N- (3-(1-((2-ethyl-2H-pyrazolo[3,4- b]pyrazin-6-yl)amino)ethyl)-4- methylphenyl)acetamide
658		(S)-2-(6-cyclopropylpyridin-3 - yl)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl) acetamide
659		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-methylphenyl)- 2-(5-fluoropyridin-3-yl) acetamide
660		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-methylphenyl)- 2-(5-methylpyridin-2-yl) acetamide
661		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-methylphenyl)- 2-(5-(trifluoromethyl)pyridin-2- yl)acetamide
662		(S)-2-(5-cyclopropylpyridin-2- yl)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-methylphenyl) acetamide
663		(S)-2-(5-chloropyridin-3-yl)-N- (3-(1-((2-ethyl-2H-pyrazolo[3,4- b]pyrazin-6-yl)amino)ethyl)-4- fluorophenyl)acetamide
664		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-methylphenyl)- 2-(6-methylpyridin-3-yl) acetamide
665		(S)-2-(6-cyclopropylpyridin-3- yl)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-methylphenyl) acetamide
666		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-methylphenyl)- 2-(5-methylpyridin-3-yl) acetamide
667		(S)-2-(5-cyclobutylpyridin-2-yl)- N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl) acetamide
668		(S)-2-(5-chloro-6- methylpyridin-2-yl)-N-(3-(1-((2- ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl)-4- fluorophenyl)acetamide
669		(S)-2-(5-cyclobutylpyridin-2-yl)- N-(3-(1-((2-ethyl 2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-methylphenyl) acetamide
670		(S)-2-(5-chloro-6- methylpyridin-2-yl)-N-(3-(1-((2- ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl)-4- methylphenyl)acetamide
671		(S)-2-(6-cyclobutylpyridin-3-yl)- N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl) acetamide
672		(S)-2-(6-cyclobutylpyridin-3-yl)- N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-methylphenyl) acetamide
673		(S)-2-(5-chloropyridin-3-yl)-N- (3-(1-((2-ethyl-2H-pyrazolo[3,4- b]pyrazin-6-yl)amino)ethyl)-4- methylphenyl)acetamide
674		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)-2- (5-fluoro-6-methylpyridin-2-yl) acetamide
675		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-methylphenyl)- 2-(5-fluoro-6-methylpyridin-2- yl)acetamide
676		(S)-2-(4-chloropyridin-2-yl)-N- (3-(1-((2-ethyl-2H-pyrazolo[3,4- b]pyrazin-6-yl)amino)ethyl) phenyl)acetamide
677		(6)-2-(4-chloropyridin-2-yl)-N- (3-(1-((2-ethyl-2H-pyrazolo[3,4- b]pyrazin-6-yl)amino)ethyl)-4- methylphenyl)acetamide
678		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-2-(4- methylpyridin-2-yl)acetamide
679		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-methylphenyl)- 2-(4-methylpyridin-2-yl) acetamide
680		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-methylphenyl)- 2-(4-methyl-3-(4- methylpiperazin-1-yl)phenyl) acetamide
681		(S)-2-(5-chloropyridin-2-yl)-N- (3-(1-((2-ethyl-2H-pyrazolo[3,4- b]pyrazin-6-yl)amino)ethyl) phenyl)acetamide
682		(S)-2-(5-cyclopropylpyridin-2- yl)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)acetamide
683		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)-2- (5-(2-fluoropropan-2-yl)pyridin- 2-yl)acetamide
684		(S)-2-(5-cyanopyridin-2-yl)-N- (3-(1-((2-ethyl-2H-pyrazolo[3,4- b]pyrazin-6-yl)amino)ethyl)-4- methylphenyl)acetamide
685		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)-2- (5-(trifluoromethyl)pyridin-3-yl) acetamide
686		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-2-(5- fluoro-4-methylpyridin-2-yl) acetamide
687		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-methylphenyl)- 2-(5-fluoro-4-methylpyridin-2- yl)acetamide
688		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-2-(5- (trifluoromethyl)pyridin-2-yl) acetamide
689		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)-2- (5-methylpyridin-2-yl) acetamide
690		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-methylphenyl)- 2-(5-(2-fluoropropan-2-yl) pyridin-2-yl)acetamide
691		(S)-2-(6-cyclopropyl-5- fluoropyridin-3-yl)-N-(3-(1-((2- ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl)-4- fluorophenyl)acetamide
692		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-methylphenyl)- 2-(5-(trifluoromethyl)pyridin-3- yl)acetamide
693		(S)-2-(4,5-dimethylpyridin-2-yl)- N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)acetamide
694		(S)-2-(4,5-dimethylpyridin-2-yl)- N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-methylphenyl) acetamide
695		(S)-2-(5-chloro-4- methylpyridin-2-yl)-N-(3-(1-((2- ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)acetamide
696		(S)-2-(5-chloro-4- methylpyridin-2-yl)-N-(3-(1-((2- ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl)-4- methylphenyl)acetamide
697		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-2-(5- methoxypyridin-2-yl)acetamide
698		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-methylphenyl)- 2-(5-methoxypyridin-2-yl) acetamide
699		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) ainino)ethyl)phenvl)-2-(5- fluoro-6-methylpyridin-2-yl) acetamide
700		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-methylphenyl)- 2-(2-fluorophenyl)acetamide
701		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-methylphenyl)- 2-(4-fluorophenyl)acetamide
702		(S)-2-(2,5-difluorophenyl)-N-(3- (1-((2-ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl)-4- methylphenyl)acetamide
703		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)-2- (5-(2-hydroxypropan-2-yl) pyridin-2-yl)acetamide
704		(S)-2-(5-cyanopyridin-2-yl)-N- (3-(1-((2-ethyl-2H-pyrazolo[3,4- b]pyrazin-6-yl)amino)ethyl)-4- fluorophenyl)acetamide
705		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-methylphenyl)- 2-(5-(2-hydroxypropan-2-yl) pyridin-2-yl)acetamide
706		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-fluorophenyl)-2- (5-fluoro-6-methylpyridin-3-yl) acetamide
707		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-methylphenyl)- 2-(5-fluoro-6-methylpyridin-3- yl)acetamide
708		(S)-2-(6-cyclopropyl-5- fluoropyridin-3-yl)-N-(3-(1-((2- ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl)-4- methylphenyl)acetamide
709		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-2-(5- isopropylpyridin-2-yl)acetamide
710		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-methylphenyl)- 2-(5-isopropylpyridin-2-yl) acetamide
711		(S)-2-(5-cyclobutylpyridin-2-yl)- N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)acetamide
712		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-2-(5- ethylpyridin-2-yl)acetamide
713		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-methylphenyl)- 2-(5-ethylpyridin-2-yl) acetamide
714		(S)-N-(3-(1-((2H-pyrazolo[3,4- b]pyrazin-6-yl)amino)ethyl) phenyl)-2-(5-methylpyridin-2- yl)acetamide
715		N-(3-((S)-1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-2-hydroxy- 2-(5-methylpyridin-2-yl) acetamide
716		(S)-2-(5,6-dimethylpyridin-2-yl)- N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)acetamide
717		(S)-2-(5,6-dimethylpyridin-2-yl)- N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-methylphenyl) acetamide
718		(S)-2-(6,7-dihydro-5H- cyclopenta[b]pyridin-2-yl)-N- (3-(1-((2-ethyl-2H-pyrazolo[3,4- b]pyrazin-6-yl)amino)ethyl) phenyl)acetamide
719		(S)-2-(6,7-dihydro-5H- cyclopenta[b]pyridin-2-yl)-N- (3-(1-((2-ethyl-2H-pyrazolo[3,4- b]pyrazin-6-yl)amino)ethyl)-4- methylphenyl)acetamide
720		(S)-2-(3,4-dihydro-2H- pyrano[2,3-b]pyridin-7-yl)-N- (3-(1-((2-ethyl-2H-pyrazolo[3,4- b]pyrazin-6-yl)amino)ethyl) phenyl)acetamide
721		(S)-2-(3,4-dihydro-2H- pyrano[2,3-b]pyridin-7-yl)N- (3-(1-((2-ethyl-2H-pyrazolo[3,4- b]pyrazin-6-yl)amino)ethyl)-4- methylphenyl)acetamide
722		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-methylphenyl)- 2-(5-methyl-4-((4- methylpiperazin-1-yl)methyl) pyridin-2-yl)acetamide
723		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-2-(5,6,7,8- tetrahydroquinolin-2-yl) acetamide
724		(S)-N-(5-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-2,4- difluorophenyl)-2-(5- methylpyridin-2-yl)acetamide
725		(S)-2-(6-cyclobutyl-5- fluoropyridin-3-yl)-N-(3-(1-((2- ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl)-4- fluorophenyl)acetamide
726		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-methylphenyl)- 2-(5-fluoro-6-((4- methylpiperazin-1-yl)methyl) pyridin-2-yl)acetamide
727		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-methylphenyl)- 2-(5-methyl-4-(pyrrolidin-1- ylmethyl)pyridin-2-yl)acetamide
728		(S)-N-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-4-methylphenyl)- 2-(5,6,7,8-tetrahydroquinolin-2- yl)acetamide
729		(S)-1-(3-(1-((1-methyl-1H- pyrazolo[3,4]pyrazin-6-yl) amino)ethyl)phenyl)-3- phenylurea
730		(S)-1-(3-(1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-3-(pyridin- 3-yl)urea
731		(S)-1-(3-(1-((1-methyl-1H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-3-(5- methylpyridin-3-yl)urea
732		(S)-1-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-3-(5- methylpyridin-3-yl)urea
733		(S)-1-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-3-(1- isopropyl-1H-pyrazol-4-yl)urea
734		(S)-1-(6-cyclopropyl-5- methylpyridin-3-yl)-3-(3-(1-((2- ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)urea
735		(S)-1-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-3-(4- methylpyridin-2-yl)urea
736		(S)-1-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-3-(6- (trifluoromethyl)pyridin-3-yl) urea
737		(S)-1-(6-cyclopropylpyridin-3- yl)-3-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)urea
738		(S)-1-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-3-(6- (methylamino)pyridin-3-yl)urea
739		(S)-1-(6-(dimethylamino) pyridin-3-yl)-3-(3-(1-((2-ethyl- 2H-pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)urea
740		(S)-1-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-3-(1- isobutyl-1H-pyrazol-4-yl)urea
741		(S)-1-(1-(cyclopropylmethyl)- 1H-pyrazol-4-yl)-3-(3-(1-((2- ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)urea
742		(S)-1-(6-(dimethylamino)-5- methylpyridin-3-yl)-3-(3-(1-((2- ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl) phenyl)urea
743		(S)-1-(3-(1-((2-ethyl-2H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)phenyl)-3-(5- methyl-6-(methylamino)pyridin- 3-yl)urea
744		(S)-3-(1-((1-methyl-H- pyrazolo[3,4-b]pyrazin-6-yl) amino)ethyl)-N-(5- methylpyridin-3-yl)benzamide
745		(S)-5-methyl-N-(3-(1-((5-(1- methyl-1H-pyrazol-4-yl) pyrazolo[1,5-a]pyridin-3-yl) amino)ethyl)phenyl) nicotinamide
746		(S)-5-methyl-N-(3-(1-((6-(1- methyl-1H-pyrazol-4-yl) pyrazolo[1,5-a]pyridin-3-yl) amino)ethyl)phenyl) nicotinamide
747		(S)-5-methyl-N-(3-(1-((2- methyl-2H-pyrazolo[3,4-c] pyridin-4-yl)amino)ethyl) phenyl)nicotinamide
748		(S)-5-methyl-N-(3-(1-((1-(1- methyl-1H-pyrazol-4-yl)-1H- pyrrolo[2,3-c]pyridin-4-yl) amino)ethyl)phenyl) nicotinamide
749		(S)-N-(3-(1-((1H-pyrazolo[3,4- c]pyridin-4-yl)amino)ethyl) phenyl)-5-methylnicotinamide
750		(S)-5-methyl-N-(3-(1-((1- methyl-1H-pyrazolo[3,4-c] pyridin-4-yl)amino)ethyl) phenyl)nicotinamide
751		(S)-5-methyl-N-(3-(1-((3- methyl-1-(1-methyl-1H-pyrazol- 4-yl)-1H-pyrazolo[3,4-c] pyridin-4-yl)amino)ethyl) phenyl)nicotinamide

“Isomer” is used herein to encompass all chiral, diastereomeric or racemic forms of a structure, unless a particular stereochemistry or isomeric form is specifically indicated. Such compounds can be enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions, at any degree of enrichment. Both racemic and diastereomeric mixtures, as well as the individual optical isomers can be synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these are all within the scope of certain embodiments of the disclosure. The isomers resulting from the presence of a chiral center comprise a pair of non-superimposable isomers that are called “enantiomers.” Single enantiomers of a pure compound are optically active (i.e., they are capable of rotating the plane of plane polarized light and designated R or S).

“Isolated optical isomer” means a compound which has been substantially purified from the corresponding optical isomer(s) of the same formula. For example, the isolated isomer may be at least about 80%, at least 80% or at least 85% pure. In other embodiments, the isolated isomer is at least 90% pure or at least 98% pure, or at least 99% pure by weight.

“Substantially enantiomerically or diasteromerically” pure means a level of enantiomeric or diastereomeric enrichment of one enantiomer with respect to the other enantiomer or diasteromer of at least about 80%, and more specifically in excess of 80%, 85%, 90%, 95%, 98%, 99%, 99.5% or 99.9%.

The terms “racemate” and “racemic mixture” refer to an equal mixture of two enantiomers. A racemate is labeled “(±)” because it is not optically active (i.e., will not rotate plane-polarized light in either direction since its constituent enantiomers cancel each other out).

A “hydrate” is a compound that exists in combination with water molecules. The combination can include water in stoichiometric quantities, such as a monohydrate or a dihydrate, or can include water in random amounts. As the term is used herein a “hydrate” refers to a solid form; that is, a compound in a water solution, while it may be hydrated, is not a hydrate as the term is used herein.

A “solvate” is similar to a hydrate except that a solvent other that water is present. For example, methanol or ethanol can form an “alcoholate”, which can again be stoichiometric or non-stoichiometric. As the term is used herein a “solvate” refers to a solid form; that is, a compound in a solvent solution, while it may be solvated, is not a solvate as the term is used herein.

“Isotope” refers to atoms with the same number of protons but a different number of neutrons, and an isotope of a compound having the structure of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIII-A), (VIII-B), (VIII-C), (VIII-D), (VIII-E), (VIII-F), (VIII-G), (VIII-H), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII A), (XVIII B), (XIX), or (XX), includes any such compound wherein one or more atoms are replaced by an isotope of that atom. For example, carbon 12, the most common form of carbon, has six protons and six neutrons, whereas carbon 13 has six protons and seven neutrons, and carbon 14 has six protons and eight neutrons. Hydrogen has two stable isotopes, deuterium (one proton and one neutron) and tritium (one proton and two neutrons). While fluorine has a number of isotopes, fluorine 19 is longest-lived. Thus, an isotope of a compound having the structure of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIII-A), (VIII-B), (VIII-C), (VIII-D), (VIII-E), (VIII-F), (VIII-G), (VIII-H), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX) includes, but is not limited to, compounds having the structure of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIII-A), (VIII-B), (VIII-C), (VIII-D), (VIII-E), (VIII-F), (VIII-G), (VIII-H), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII), (XIX), or (XX) wherein one or more carbon 12 atoms are replaced by carbon-13 and/or carbon-14 atoms, wherein one or more hydrogen atoms are replaced with deuterium and/or tritium, and/or wherein one or more fluorine atoms are replaced by fluorine-19.

“Salt” generally refers to an organic compound, such as a carboxylic acid or an amine, in ionic form, in combination with a counter ion. For example, salts formed between acids in their anionic form and cations are referred to as “acid addition salts”. Conversely, salts formed between bases in the cationic form and anions are referred to as “base addition salts.”

The term “pharmaceutically acceptable” refers an agent that has been approved for human consumption and is generally non-toxic. For example, the term “pharmaceutically acceptable salt” refers to nontoxic inorganic or organic acid and/or base addition salts (see, e.g., Lit et al., Salt Selection for Basic Drugs, Int. J. Pharm., 33, 201-217, 1986) (incorporated by reference herein).

Pharmaceutically acceptable base addition salts of compounds of the disclosure include, for example, metallic salts including alkali metal, alkaline earth metal, and transition metal salts such as, for example, calcium, magnesium, potassium, sodium, and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,N′dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine.

Pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, and phosphoric acids. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, aromatic aliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenyl acetic, mandelic, hippuric, malonic, oxalic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, panthothenic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, βhydroxybutyric, salicylic, -galactaric, and galacturonic acid.

Although pharmaceutically unacceptable salts are not generally useful as medicaments, such salts may be useful, for example as intermediates in the synthesis of compounds having the structure of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIII-A), (VIII-B), (VIII-C), (VIII-D), (VIII-E), (VIII-F), (VIII-G), (VIII-H), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII A), (XVIII B), (XIX), or (XX), for example in their purification by recrystallization.

In certain embodiments, the disclosure provides a pharmaceutical composition comprising a compound having the structure of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIII-A), (VIII-B), (VIII-C), (VIII-D), (VIII-E), (VIII-F), (VIII-G), (VIII-H), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII A), (XVIII B), (XIX), or (XX), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, together with at least one pharmaceutically acceptable carrier, diluent, or excipient. For example, the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which can be in the form of an ampoule, capsule, sachet, paper, or other container. When the active compound is mixed with a carrier, or when the carrier serves as a diluent, it can be solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid carrier, for example contained in a sachet. Some examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid, or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose, and polyvinylpyrrolidone. Similarly, the carrier or diluent can include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.

As used herein, the term “pharmaceutical composition” refers to a composition containing one or more of the compounds described herein, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, homolog or salt thereof, formulated with a pharmaceutically acceptable carrier, which can also include other additives, and manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal. Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a tablet, capsule, caplet, gelcap, or syrup); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or in any other formulation described herein. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippencott Williams & Wilkins (2005) and in The United States Pharmacopeia: The National Formulary (USP 36 NF31), published in 2013.

In another embodiment, there are provided methods of making a composition of a compound described herein including formulating a compound of the disclosure with a pharmaceutically acceptable carrier or diluent. In some embodiments, the pharmaceutically acceptable carrier or diluent is suitable for oral administration. In some such embodiments, the methods can further include the step of formulating the composition into a tablet or capsule. In other embodiments, the pharmaceutically acceptable carrier or diluent is suitable for parenteral administration. In some such embodiments, the methods further include the step of lyophilizing the composition to form a lyophilized preparation.

As used herein, the term “pharmaceutically acceptable carrier” refers to any ingredient other than the disclosed compounds, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, homolog or salt thereof (e.g., a carrier capable of suspending or dissolving the active compound) and having the properties of being nontoxic and non-inflammatory in a patient. Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, or waters of hydration. Exemplary excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

The formulations can be mixed with auxiliary agents which do not deleteriously react with the active compounds. Such additives can include wetting agents, emulsifying and suspending agents, salt for influencing osmotic pressure, buffers and/or coloring substances, preserving agents, sweetening agents, or flavoring agents. The compositions can also be sterilized if desired.

The route of administration can be any route which effectively transports the active compound of the disclosure to the appropriate or desired site of action, such as oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, or parenteral, e.g., rectal, depot, subcutaneous, intravenous, inhalation of a dry powder form or a nebulized form, intraurethral, intramuscular, intranasal, ophthalmic solution, or an ointment, the oral route being preferred.

Dosage forms can be administered once a day, or more than once a day, such as twice or thrice daily. Alternatively, dosage forms can be administered less frequently than daily, such as every other day, or weekly, if found to be advisable by a prescribing physician. Dosing regimens include, for example, dose titration to the extent necessary or useful for the indication to be treated, thus allowing the patient's body to adapt to the treatment and/or to minimize or avoid unwanted side effects associated with the treatment. Other dosage forms include delayed or controlled-release forms. Suitable dosage regimens and/or forms include those set out, for example, in the latest edition of the Physicians' Desk Reference, incorporated herein by reference.

As used herein, the term “administering” or “administration” refers to providing a compound, a pharmaceutical composition comprising the same, to a subject by any acceptable means or route, including (for example) by oral, parenteral (e.g., intravenous), inhaled, or topical administration.

As used herein, the term “treatment” refers to an intervention that ameliorates a sign or symptom of a disease or pathological condition. As used herein, the terms “treatment”, “treat” and “treating,” with reference to a disease, pathological condition or symptom, also refers to any observable beneficial effect of the treatment. The beneficial effect can be evidenced, for example, by a delayed onset of clinical symptoms of the disease in a susceptible subject, a reduction in severity of some or all clinical symptoms of the disease, a slower progression of the disease, a reduction in the number of relapses of the disease, an improvement in the overall health or well-being of the subject, or by other parameters well known in the art that are specific to the particular disease. A prophylactic treatment is a treatment administered to a subject who does not exhibit signs of a disease or exhibits only early signs, for the purpose of decreasing the risk of developing pathology. A therapeutic treatment is a treatment administered to a subject after signs and symptoms of the disease have developed.

As used herein, the term “subject” refers to an animal (e.g., a mammal, such as a human). A subject to be treated according to the methods described herein may be one who has been diagnosed with a neurodegenerative disease involving demyelination, insufficient myelination, or underdevelopment of a myelin sheath, e.g., a subject diagnosed with multiple sclerosis or cerebral palsy, or one at risk of developing the condition. Diagnosis may be performed by any method or technique known in the art. One skilled in the art will understand that a subject to be treated according to the present disclosure may have been subjected to standard tests or may have been identified, without examination, as one at risk due to the presence of one or more risk factors associated with the disease or condition.

As used herein, the term “effective amount” refers to a quantity of a specified agent sufficient to achieve a desired effect in a subject being treated with that agent. Ideally, an effective amount of an agent is an amount sufficient to inhibit or treat the disease without causing substantial toxicity in the subject. The effective amount of an agent will be dependent on the subject being treated, the severity of the affliction, and the manner of administration of the pharmaceutical composition. Methods of determining an effective amount of the disclosed compound sufficient to achieve a desired effect in a subject will be understood by those of skill in the art in light of this disclosure.

In one embodiment, a method for inhibiting PDGF receptor α is provided, comprising contacting the PDGF receptor α with an effective amount of a compound having the structure of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIII-A), (VIII-B), (VIII-C), (VIII-D), (VIII-E), (VIII-F), (VIII-G), (VIII-H), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII A), (XVIII B), (XIX), or (XX), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, or a composition comprising the same.

In one embodiment, a method for inhibiting PDGF receptor β is provided, comprising contacting the PDGF receptor β with an effective amount of a compound having the structure of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIII-A), (VIII-B), (VIII-C), (VIII-D), (VIII-E), (VIII-F), (VIII-G), (VIII-H), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII A), (XVIII B), (XIX), or (XX), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, or a composition comprising the same.

In one embodiment, a method for treating a PDGF receptor α-dependent condition is provided, comprising administering to a subject in need thereof an effective amount of a compound having the structure of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIII-A), (VIII-B), (VIII-C), (VIII-D), (VIII-E), (VIII-F), (VIII-G), (VIII-H), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII A), (XVIII B), (XIX), or (XX), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, or a composition comprising the same.

In one embodiment, a method for treating a PDGF receptor β-dependent condition, comprising administering to a subject in need thereof an effective amount of a compound having the structure of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIII-A), (VIII-B), (VIII-C), (VIII-D), (VIII-E), (VIII-F), (VIII-G), (VIII-H), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII A), (XVIII B), (XIX), or (XX), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, or a composition comprising the same.

In one embodiment, a method for treating a pulmonary disorder is provided, comprising administering to a subject in need thereof an effective amount of a compound having the structure of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIII-A), (VIII-B), (VIII-C), (VIII-D), (VIII-E), (VIII-F), (VIII-G), (VIII-H), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII A), (XVIII B), (XIX), or (XX), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, or a composition comprising the same. In one embodiment, the pulmonary disorder is pulmonary hypertension.

In one embodiment, the pulmonary hypertension is pulmonary arterial hypertension. A method for treating pulmonary arterial hypertension is provided, comprising administering to a subject in need thereof an effective amount of a compound having the structure of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIII-A), (VIII-B), (VIII-C), (VIII-D), (VIII-E), (VIII-F), (VIII-G), (VIII-H), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII A), (XVIII B), (XIX), or (XX), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, or a composition comprising the same. In one embodiment, the pulmonary arterial hypertension is primary PAH, idiopathic PAH, heritable PAH, refractory PAH, BMPR2, AL 1, endoglin associated with hereditary hemorrhagic telangiectasia, endoglin not associated with hereditary hemorrhagic telangiectasia, drug-induced PAH, or toxin-induced PAH. In another embodiment, the pulmonary arterial hypertension is associated with systemic sclerosis, mixed connective tissue disease, HIV, hepatitis, or portal hypertension.

In one embodiment, the pulmonary hypertension is associated with myeloproliferative disorders. A method for treating pulmonary hypertension associated with myeloproliferative disorders is provided, comprising administering to a subject in need thereof an effective amount of a compound having the structure of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIII-A), (VIII-B), (VIII-C), (VIII-D), (VIII-E), (VIII-F), (VIII-G), (VIII-H), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII A), (XVIII B), (XIX), or (XX), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, or a composition comprising the same. In one embodiment, the myeloproliferative disorder associated pulmonary hypertension is Group 5 PAH.

In one embodiment, a method for treating a disease associated with tissue fibrosis, comprising administering to a subject in need thereof an effective amount of a compound having the structure of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIII-A), (VIII-B), (VIII-C), (VIII-D), (VIII-E), (VIII-F), (VIII-G), (VIII-H), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII A), (XVIII B), (XIX), or (XX), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, or a composition comprising the same. In one embodiment, the disease associated with tissue fibrosis is systemic sclerosis, interstitial lung disease, bronchiolitis obliterans with organizing pneumonia (BOOP), acute lung injury, glomerulonephritis, focal segmental glomerulosclerosis, stroke, or radiation induced fibrosis.

In one embodiment, a method for solid tumors, comprising administering to a subject in need thereof an effective amount of a compound having the structure of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIII-A), (VIII-B), (VIII-C), (VIII-D), (VIII-E), (VIII-F), (VIII-G), (VIII-H), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII A), (XVIII B), (XIX), or (XX), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, or a composition comprising the same. In one embodiment, the solid tumor is associated with an increased copy number of PDGF ligands. In another embodiment, the solid tumor is associated with PDGFRα or PDGFRβ amplification. In another embodiment, the solid tumor is associated with a translocation in the PDGFRα or PDGFRβ kinase domain.

Compounds having the structure of any one of Formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIII-A), (VIII-B), (VIII-C), (VIII-D), (VIII-E), (VIII-F), (VIII-G), (VIII-H), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XVIII A), (XVIII B), (XIX), or (XX), can be synthesized using standard synthetic techniques known to those of skill in the art. For examples, compounds of the present disclosure can be synthesized using the general synthetic procedures set forth in Schemes 1-3.

To this end, the reactions, processes and synthetic methods described herein are not limited to the specific conditions described in the following experimental section, but rather are intended as a guide to one with suitable skill in this field. For example, reactions may be carried out in any suitable solvent, or other reagents to perform the transformation[s] necessary. Generally, suitable solvents are protic or aprotic solvents which are substantially non-reactive with the reactants, the intermediates or products at the temperatures at which the reactions are carried out (i.e., temperatures which may range from the freezing to boiling temperatures). A given reaction may be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction, suitable solvents for a particular work-up following the reaction may be employed.

Unless otherwise indicated, conventional methods of mass spectroscopy (MS), liquid chromatography-mass spectroscopy (LCMS), NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology are employed. Compounds are prepared using standard organic chemistry techniques such as those described in, for example, March's Advanced Organic Chemistry, 7th Edition, John Wiley and Sons, Inc (2013). Alternate reaction conditions for the synthetic transformations described herein may be employed such as variation of solvent, reaction temperature, reaction time, as well as different chemical reagents and other reaction conditions. As necessary, the use of appropriate protecting groups may be required. The incorporation and cleavage of such groups may be carried out using standard methods described in Peter G. M. Wuts and Theodora W. Green, Protecting Groups in Organic Synthesis, 4th Edition, Wiley-Interscience. (2006). All starting materials and reagents are commercially available or readily prepared.

In some embodiments, arylamide derivatives H1 are synthesized as shown in Scheme 1.

In some embodiments, treatment of suitably N-protected 3-nitro-benzyl derivative A1 with a suitable reducing agent such as hydrogen gas in the presence of Pd/C or Pd(OH)₂/C and in the presence of a suitable solvent such as MeOH, EtOH, or EtOAc will afford the corresponding amino-derivative B1. Alternatively, treatment of A1 with SnCl₂ in the presence of a suitable solvent such as EtOH will afford B1. Treatment of B1 with a carboxylic acid derivative C1 using standard amide coupling conditions will directly afford amide-derivative E1. Alternatively, treatment of carboxylic acid derivative C1 with, for example, SOCl₂, or oxalyl chloride and catalytic DMF, in a suitable solvent such as DCM, or THF will afford acid chloride D1. Subsequent treatment of acid chloride D1 with amino-derivative B1 in the presence of a suitable base such as TEA, Hunig's base, NaHCO₃, or K₂CO₃, and in the presence of a suitable solvent such as DCM or THF, with or without an activating agent such as DMAP, with or without heating will afford amide-derivative E1. Subsequent removal of the N-protecting group (PG) of E1 using appropriate deprotection conditions, will afford amine F1. Treatment of amine F1 with aryl halide G1 (where X=Cl, Br, or I) with heating in the presence of a transition metal catalyst such as Pd[PPh₃]₄, Pd₂(dba)₃, Pd(OAc)₂, Pd(dppf)Cl₂, BrettPhos precatalyst, or CuI, with or without a suitable ligand, such as for example PPh₃, 2-(di-tert-butylphosphino)biphenyl, BrettPhos, BINAP, or trans-N,N-dimethyl-1,2-cyclohexanediamine, and in the presence of a suitable base such as NaO^tBu, Na₂CO₃, or DIEA, and in suitable solvents such as 1,4-dioxane, toluene, THF, acetonitrile, DMF, with or without water, will afford Ill. Alternatively, treatment of F1 with G1 (where X=F, Cl) with or without a base such as K₂CO₃, Cs₂CO₃, TEA, or DIEA, and in a suitable solvent such as THF, DMF, 1,4-dioxane, DMSO, or NMP, with or without heating, will afford Ill. Alternatively, compounds Ill may be prepared from A1 as follows. Removal of the N-protecting group (PG) of A1 using appropriate deprotection conditions, will afford amine I1. Treatment of amine I1 with aryl halide G1 (where X=F, Cl, Br, or I) using the appropriate conditions described above (for the conversion of F1 to H1), will afford J1. Treatment of J1 with a suitable reducing agent such as hydrogen gas in the presence of Pd/C or Pd(OH)₂/C and in the presence of a suitable solvent such as MeOH, EtOH, or EtOAc will afford the corresponding amino-derivative K1. Alternatively, treatment of J1 with SnCl₂ in the presence of a suitable solvent such as EtOH will afford K1. Subsequent treatment of K1 with either carboxylic acid derivative C1, or alternatively, acid chloride derivative D1, using the appropriate conditions described above (for the conversion of B1 to E1), will afford H1.

In some embodiments, arylamide derivatives H2 are synthesized as shown in Scheme 2.

In some embodiments, treatment of suitably N-protected 3-carboxylester-benzyl derivative A2 with a base such as LiOH or NaOH in the presence of water and a suitable solvent such as MeOH or THF, will afford the corresponding acid-derivative B2. Treatment of B2 with an amine D2 using standard amide coupling conditions will directly afford amide-derivative E2. Alternatively, treatment of carboxylic acid derivative B2 with, for example, SOCl₂, or oxalyl chloride and catalytic DMF, in a suitable solvent such as DCM, or THF will afford acid chloride C2. Subsequent treatment of acid chloride C2 with amino-derivative D2 in the presence of a suitable base such as TEA, Hunig's base, NaHCO₃, or K₂CO₃, and in the presence of a suitable solvent such as DCM or THF, with or without an activating agent such as DMAP, with or without heating will afford amide-derivative E2. Subsequent removal of the N-protecting group (PG) of E2 using appropriate deprotection conditions, will afford amine F2. Treatment of amine F2 with aryl halide G2 (where X=Cl, Br, or I) with heating in the presence of a transition metal catalyst such as Pd[PPh₃]₄, Pd₂(dba)₃, Pd(OAc)₂, Pd(dppf)Cl₂, BrettPhos precatalyst, or CuI, with or without a suitable ligand, such as for example PPh₃, 2-(di-tert-butylphosphino)biphenyl, BrettPhos, BINAP, or trans-N,N-dimethyl-1,2-cyclohexanediamine, and in the presence of a suitable base such as NaO^tBu, Na₂CO₃, or DIEA, and in suitable solvents such as 1,4-dioxane, toluene, THF, acetonitrile, DMF, with or without water, will afford H2. Alternatively, treatment of F2 with G2 (where X=F, Cl) with or without a base such as K₂CO₃, Cs₂CO₃, TEA, or DIEA, and in a suitable solvent such as THF, DMF, 1,4-dioxane, DMSO, or NMP, with or without heating, will afford H2. Alternatively, compounds H2 may be prepared from A2 as follows. Removal of the N-protecting group (PG) of A2 using appropriate deprotection conditions, will afford amine 12. Treatment of amine 12 with aryl halide G2 (where X=F, Cl, Br, or I) using the appropriate conditions described above (for the conversion of F2 to H2), will afford J2. Treatment of J2 with a base such as LiOH or NaOH in the presence of water and a suitable solvent such as MeOH or THF, will afford the corresponding acid-derivative K2. Conversion of K2 to H2, either directly or via acid chloride L2, may be achieved using the appropriate conditions described above (for the conversion of B2 to E2).

In some embodiments, arylurea derivatives J3 are synthesized as shown in Scheme 3.

In some embodiments, treatment of suitably N-protected 3-nitro-benzyl derivative A3 with a suitable reducing agent such as hydrogen gas in the presence of Pd/C or Pd(OH)₂/C and in the presence of a suitable solvent such as MeOH, EtOH, or EtOAc will afford the corresponding amino-derivative B3. Alternatively, treatment of A3 with SnCl₂ in the presence of a suitable solvent such as EtOH will afford B3. Treatment of B3 with an isocyanate derivative C3 in the presence of a suitable solvent such as DCM, THF, or DMF, with or without heating, will directly afford urea-derivative D3. Alternatively, treatment of amine B3 with a suitable substituted chloroformate derivative E3 (where R can be for example 4-nitrophenyl or isopropenyl) in the presence of a suitable base such as TEA, DIEA, or NaHCO₃, and in a suitable solvent such as DCM, EtOAc, or THF, will afford intermediate carbamate F3. Subsequent treatment of carbamate F3 with an amine G3 in a suitable solvent such as DCM, THF, or 1,4-dioxane, with or without a base such as TEA, DIEA, or DMAP, and with or without heating, will afford D3. Subsequent removal of the N-protecting group (PG) of D3 using appropriate deprotection conditions will afford amine H3. Treatment of amine H3 with aryl halide 13 (where X=Cl, Br, or I) with heating in the presence of a transition metal catalyst such as Pd[PPh₃]₄, Pd₂(dba)₃, Pd(OAc)₂, Pd(dppf)Cl₂, BrettPhos precatalyst, or CuI, with or without a suitable ligand, such as for example PPh₃, 2-(di-tert-butylphosphino)biphenyl, BrettPhos, BINAP, or trans-N,N-dimethyl-1,2-cyclohexanediamine, and in the presence of a suitable base such as NaO^tBu, Na₂CO₃, or DIEA, and in suitable solvents such as 1,4-dioxane, toluene, THF, acetonitrile, DMF, with or without water, will afford J3. Alternatively, treatment of H3 with I3 (where X=F, Cl) with or without a base such as K₂CO₃, Cs₂CO₃, TEA, or DIEA, and in a suitable solvent such as THF, DMF, 1,4-dioxane, DMSO, or NMP, with or without heating, will afford J3. Alternatively, compounds J3 may be prepared from A3 as follows. Removal of the N-protecting group (PG) of A3 using appropriate deprotection conditions, will afford amine K3. Treatment of amine K3 with aryl halide I3 (where X=F, Cl, Br, or I) using the appropriate conditions described above (for the conversion of H3 to J3), will afford L3. Treatment of L3 with a suitable reducing agent (as described above for the conversion of A3 to B3) will afford the corresponding amine M3. Conversion of M3 to J3, may be achieved using the appropriate conditions described above (for the conversion of B3 to D3).

EXAMPLES

The invention is further illustrated by the following examples. The examples below are non-limiting are merely representative of various aspects of the invention. Solid and dotted wedges within the structures herein disclosed illustrate relative stereochemistry, with absolute stereochemistry depicted only when specifically stated or delineated. The following examples were prepared according to the methods described in Schemes 1 through 3 using the appropriately substituted or modified intermediates.

Example 1

Synthesis of the hydrochloride salt of (5)-5-Methyl-N-(3-(1-((5-methyl-5H-pyrrolo[2,3-b] pyrazin-3-yl)amino)ethyl)phenyl)nicotinamide (Compound 1)

Step 1: Synthesis of (S)-1-(1-azidoethyl)-3-nitrobenzene (1-b)

To a stirred solution of (R)-1-(3-nitrophenyl)ethan-1-ol (1-a) (10.00 g, 0.059 mol) in THF at 0° C., was added DPPA (19.76 g, 0.072 mol). After 5 min, DBU (27.32 g, 0.179 mol) was added dropwise. The mixture was stirred at 20° C. for 16 h. The mixture was concentrated and the crude residue purified (silica gel; eluting with 2% EtOAc in petroleum ether) to afford compound 1-b (9.22 g, 80%) as a yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 8.35-8.12 (m, 2H), 7.88 (d, J=7.7 Hz, 1H), 7.72 (t, J=7.9 Hz, 1H), 5.10 (q, J=6.8 Hz, 1H), 1.53 (d, J=6.8 Hz, 3H).

Step 2: Synthesis of (S)-1-(3-nitrophenyl)ethan-1-amine (1-c)

To a mixture of compound (1-b) (9.22 g, 0.048 mol) in toluene (100 mL), was added water (30 mL) and PPh₃ (25.17 g, 0.095 mol). The mixture was stirred at 85° C. for 5 h. After cooling to rt, the mixture was diluted with aq. HCl (3N, 500 mL) and washed with EtOAc (500 mL×3). The aqueous layer was cooled to 0° C., and the pH was adjusted to 12 with aq. 30% NaOH. The aqueous layer was extracted with DCM (500 mL×3), and the combined organic phase dried (Na₂SO₄), filtered, and concentrated under reduced pressure to afford compound 1-c (7.25 g, 91%) as a yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ 8.28 (s, 1H), 8.07 (dd, J=8.2, 2.3 Hz, 1H), 7.83 (d, J=7.7 Hz, 1H), 7.60 (t, J=7.9 Hz, 1H), 4.17 (q, J=6.6 Hz, 1H), 1.29 (d, J=6.6 Hz, 3H). LCMS Mass: 167.1 (M⁺+H).

Step 3: Synthesis of tert-butyl (S)-(1-(3-nitrophenyl)ethyl)carbamate (1-d)

To a stirred solution of compound (1-c) (3.00 g, 18.1 mmol) in DCM (40 mL), was added TEA (3.64 g, 36.0 mmol) and (Boc)₂O (5.89 g, 27.0 mmol). The mixture was stirred at rt for 16 h. The mixture was concentrated under reduced pressure and partitioned between water (100 mL) and EtOAc (80 mL). The organic layer was separated, dried (Na₂SO₄), filtered, and was concentrated under reduced pressure. The crude residue was purified (silica gel; eluting with 0-10% EtOAc in petroleum ether) to afford compound 1-cl (3.90 g, 81%) as an off-white solid. ¹H NMR (400 MHz, CDCl₃): δ 8.17 (s, 1H), 8.11 (d, J=8.1 Hz, 1H), 7.64 (d, J=7.6 Hz, 1H), 7.50 (t, J=7.9 Hz, 1H), 4.88 (s, 2H), 1.47 (d, J=6.6 Hz, 3H), 1.42 (s, 9H); LCMS Mass: 211.1 (MH⁺−56) and 167.1 (MH⁺-100).

Step 4: Synthesis of tert-butyl (S)-(1-(3-aminophenyl)ethyl)carbamate (1-e)

To a stirred solution of compound (1-d) (3.90 g, 14.6 mmol) in methanol (50 mL), was added Pd/C (400 mg). The mixture was stirred at rt for 16 h under H₂ (1 atmosphere pressure). The reaction mixture was filtered through Celite, and the solid residue was washed with methanol (20 mL). The filtrate was concentrated to dryness under reduced pressure to afford compound 1-e (3.40 g, 98%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 7.13 (t, J=7.7 Hz, 1H), 6.79-6.69 (m, 2H), 6.69-6.59 (m, 1H), 4.80 (s, 1H), 4.69 (s, 1H), 4.20-3.25 (brs, 2H), 1.41 (s, 12H); LCMS Mass: 181.1 (MH⁺−56).

Step 5: Synthesis of tert-butyl (S)-(1-(3-(5-methylnicotinamido)phenyl)ethyl)carbamate (1-f)

To a stirred solution of 5-methylnicotinic acid (3.21 g, 23.4 mmol) in DMF (50 mL) at rt, was added HATU (11.90 g, 31.2 mmol) and the mixture was stirred at rt for 20 min. Compound (1-e) (3.40 g, 15.6 mmol) and DIPEA (6.05 g, 46.8 mmol) were added and the mixture stirred at rt for 16 h. The reaction mixture was partitioned between water (200 mL) and EtOAc (120 mL). The organic layer was separated and washed with brine (100 mL×2). The organic layer was separated, dried (Na₂SO₄), filtered, and was concentrated under reduced pressure. The crude residue was purified (silica gel; eluting with 0-50% EtOAc in petroleum ether) to afford compound 1-f (4.80 g, 92%) as an off-white solid. ¹H NMR (400 MHz, CDCl₃): δ 8.98 (s, 1H), 8.56 (s, 1H), 8.48 (brs, 1H), 8.13 (s, 1H), 7.60-7.57 (m, 2H), 7.31 (t, J=7.8 Hz, 1H), 7.10 (d, J=7.6 Hz, 1H), 4.95 (d, J=5.6 Hz, 1H), 4.75 (s, 1H), 2.43 (s, 3H), 1.45 (d, J=7.0 Hz, 3H), 1.41 (s, 9H); LCMS Mass: 356.1 (M⁺+H).

Step 6: Synthesis of (S)—N-(3-(1-aminoethyl)phenyl)-5-methylnicotinamide (1-g)

To a stirred solution of compound (1-f) (4.80 g, 13.5 mmol) in DCM (40 mL), was added 4 M HCl in 1,4-dioxane (4 mL) and the mixture was stirred at rt for 16 h. The mixture was evaporated under reduced pressure and the crude residue was adjusted to pH 8 with saturated aq. Na₂CO₃. The mixture was dissolved in methanol and purified (C-18 reverse-phase column chromatography) to afford compound 1-g (2.40 g, 70%) as a yellow oil. ¹H NMR (400 MHz, DMSO-d₆): δ 10.36 (s, 1H), 8.91 (d, J=1.9 Hz, 1H), 8.60 (d, J=1.6 Hz, 1H), 8.12 (s, 1H), 7.75 (s, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.28 (t, J=7.8 Hz, 1H), 7.13 (d, J=7.7 Hz, 1H), 4.01 (q, J=6.6 Hz, 1H), 2.39 (s, 3H), 1.27 (d, J=6.6 Hz, 3H); LCMS Mass: 256.1 (M⁺+H).

Step 7: Synthesis of 3-chloro-5-methyl-5H-pyrrolo[2,3-b]pyrazine (1-i)

To a stirred solution of 3-chloro-5H-pyrrolo[2,3-b]pyrazine (1-h) (50 mg, 0.326 mmol) in DMF (3 mL) was added methyl iodide (231 mg, 1.628 mmol) and Cs₂CO₃ (212 mg, 0.651 mmol). The mixture was stirred at rt for 1 h. The mixture was evaporated under reduced pressure. The resulting mixture was partitioned between water (50 mL) and EtOAc (50 mL). The organic layer was separated, dried (Na₂SO₄), filtered, and was concentrated under reduced pressure. The crude residue was purified (C-18 reverse-phase column; eluting with 60% MeOH in water) to afford compound 1-i (23 mg, 42.0%) as an off white solid. LCMS Mass: 168.1 (M⁺+H).

Step 8: Synthesis of the hydrochloride salt of (S)-5-methyl-N-(3-(1-((5-methyl-5H-pyrrolo[2,3-b]pyrazin-3-yl)amino)ethyl)phenyl)nicotinamide (Compound 1)

To a stirred solution of compound (1-i) (23 mg, 0.137 mmol) in 1,4-dioxane (3 mL) at rt, was added (S)—N-(3-(1-aminoethyl)phenyl)-5-methylnicotinamide (1-g) (38 mg, 0.151 mmol), Pd₂(dba)₃ (13 mg, 0.014 mmol), BINAP (9 mg, 0.014 mmol) and t-BuONa (26 mg, 0.274 mmol). The mixture was heated to reflux under N₂ for 16 h. The reaction mixture was partitioned between brine (50 mL) and EtOAc (50 mL). The organic layer was separated, dried (Na₂SO₄), filtered, and was concentrated under reduced pressure. The crude residue was purified (Preparative HPLC; eluting with 0.1% HCl in H₂O/MeOH) to afford the hydrochloride salt of Compound 1 (18 mg, 34%). ¹H NMR (400 MHz, MeOH-d₄): δ 9.19 (s, 1H), 8.95 (s, 1H), 8.88 (s, 1H), 7.97 (s, 1H), 7.87 (s, 1H), 7.62-7.57 (m, 2H), 7.40-7.29 (m, 2H), 6.54 (d, J=3.7 Hz, 1H), 5.18 (q, J=6.9 Hz, 1H), 3.76 (s, 3H), 2.65 (s, 3H), 1.65 (d, J=6.9 Hz, 3H); LCMS Mass: 387.2 (M⁺+H).

Example 2

Synthesis of (S)-5-methyl-N-(3-(1-(quinolin-3-ylamino)ethyl)phenyl)nicotinamide (Compound 2)

To a stirred solution of 3-bromoquinoline (2-a) (25 mg, 0.120 mmol) in 1,4-dioxane (3 mL) at rt, was added (S)—N-(3-(1-aminoethyl)phenyl)-5-methylnicotinamide (1-g) (prepared as described in Example 1, Step 6) (34 mg, 0.132 mmol), Pd₂(dba)₃ (9.7 mg, 0.012 mmol), CyJohnPhos (4.2 mg, 0.012 mmol) and t-BuONa (2M, 90 μL). The mixture was heated to 100° C. under N₂ for 30 min. The reaction mixture was filtered and purified (Preparative HPLC; eluting with 0.1% TFA in H₂O/acetonitrile). The combined fractions were diluted with EtOAc and washed with saturated aq. NaHCO₃ and brine. The organic phase was dried (MgSO₄), filtered, and concentrated under reduced pressure to afford compound Compound 2 (32 mg, 66%). LCMS Mass: 383.2 (M⁺+H).

Example 3

Synthesis of (S)—N-(3-(1-((1,5-naphthyridin-3-yl)amino)ethyl)phenyl)-5-methylnicotinamide (Compound 3)

To a stirred solution of 3-bromo-1,5-naphthyridine (3-a) (25 mg, 0.120 mmol) in 1,4-dioxane (1 mL) at rt, was added (S)—N-(3-(1-aminoethyl)phenyl)-5-methylnicotinamide (1-g) (prepared as described in Example 1, Step 6) (34 mg, 0.132 mmol), Pd₂(dba)₃ (11 mg, 0.012 mmol), Josiphos (8 mg, 0.012 mmol) and t-BuONa (2M, 120 μL). The mixture was heated to reflux under N₂ for 16 h. The reaction mixture was filtered and purified (Preparative HPLC; eluting with 0.05% TFA in H₂O/acetonitrile). The combined fractions were diluted with EtOAc and washed with saturated aq. NaHCO₃ and brine. The organic phase dried (MgSO₄), filtered, and concentrated under reduced pressure to afford Compound 3 (7 mg, 15%). ¹H NMR (MeOH-d4, 300 MHz) δ 8.84 (d, 1H, J=1.7 Hz), 8.62 (d, 1H, J=2.7 Hz), 8.59 (dd, 1H, J=1.6, 4.4 Hz), 8.54 (d, 1H, J=1.4 Hz), 8.17 (dd, 1H, J=0.8, 8.3 Hz), 8.14 (s, 1H), 7.82 (s, 1H), 7.6-7.6 (m, 1H), 7.3-7.4 (m, 2H), 7.2-7.3 (m, 1H), 6.92 (d, 1H, J=2.6 Hz), 4.62 (q, 1H, J=6.8 Hz), 2.43 (s, 3H), 1.64 (d, 3H, J=6.8 Hz); LCMS Mass: 384.2 (M⁺+H).

Example 4

Synthesis of (5)-5-methyl-N-(3-(1-(quinoxalin-2-ylamino)ethyl)phenyl)nicotinamide trifluoroacetate (Compound 4)

To a stirred solution of 2-chloroquinoxaline (4-a) (25 mg, 0.152 mmol) in DMSO (1 mL) was added (S)—N-(3-(1-aminoethyl)phenyl)-5-methylnicotinamide (1-g) (prepared as described in Example 1, Step 6) (78 mg, 0.304 mmol). The reaction mixture was stirred at rt overnight and K₂CO₃ (31 mg, 0.228 mmol) was added. The reaction was heated to 80° C. for 6 h. The mixture was purified (Preparative HPLC; eluting with 0.1% TFA in H₂O/acetonitrile) to afford Compound 4 (8 mg, 10%). ¹H NMR (MeOH-d4, 300 MHz) δ 9.0-9.0 (m, 1H), 8.70 (d, 1H, J=1.2 Hz), 8.4-8.5 (m, 2H), 7.9-8.0 (m, 1H), 7.9-7.9 (m, 1H), 7.6-7.7 (m, 2H), 7.6-7.6 (m, 1H), 7.4-7.5 (m, 2H), 7.3-7.4 (m, 1H), 5.3-5.4 (m, 1H), 2.55 (s, 3H), 1.72 (d, 3H, J=6.8 Hz); LCMS Mass: 384.2 (M⁺+H).

Example 5

Synthesis of (S)-5-methyl-N-(3-(1-(pyrido[2,3-b]pyrazin-3-ylamino)ethyl)phenyl) nicotinamide (Compound 5)

To a stirred solution of 3-chloropyrido[2,3-b]pyrazine (5-a) (25 mg, 0.151 mmol) in 1,4-dioxane (1 mL) at rt, was added (S)—N-(3-(1-aminoethyl)phenyl)-5-methylnicotinamide (1-g) (prepared as described in Example 1, Step 6) (42 mg, 0.166 mmol), Pd₂(dba)₃ (14 mg, 0.015 mmol), Josiphos (9.7 mg, 0.015 mmol) and t-BuONa (2M, 151 μL). The mixture was heated to reflux under N₂ for 4 h. Additional Pd₂(dba)₃ (14 mg, 0.015 mmol), Josiphos (9.7 mg, 0.015 mmol) and t-BuONa (2M, 75 μL) were added to the reaction mixture and heating was continued for 16 h. The reaction mixture was filtered and purified (Preparative HPLC; eluting with 0.05% TFA in H₂O/acetonitrile). The material isolated was combined with batch 2 below.

To a second stirred solution of 3-chloropyrido[2,3-b]pyrazine (5-a) (40 mg, 0.241 mmol) in 1,4-dioxane (1 mL) at rt, was added (S)—N-(3-(1-aminoethyl)phenyl)-5-methylnicotinamide (1-g) (prepared as described in Example 1, Step 6) (42 mg, 0.166 mmol), Pd₂(dba)₃ (14 mg, 0.015 mmol), Josiphos (9.7 mg, 0.015 mmol) and t-BuONa (2M, 226 μL). The mixture was heated to reflux under N₂ for 2 h. [Pd(cinnamyl)Cl]₂ (7.8 mg, 0.015 mmol), tBuXPhos (6.4 mg, 0.015 mmol), and t-BuONa (2 M, 226 μL) were added and the reaction was heated at 100° C. for 16 h. The reaction mixture was filtered and purified (Preparative HPLC; eluting with 0.05% TFA in H₂O/acetonitrile). The combined fractions from both batches were diluted with EtOAc and washed with saturated aq. NaHCO₃ and brine. The organic phases were dried (MgSO₄), filtered, and concentrated under reduced pressure. The crude residue was purified (silica gel; eluting with 0-100% EtOAc in heptane followed by 10-30% MeOH in DCM) to afford Compound 5 (6 mg, 7%). ¹H NMR (MeOH-d4, 300 MHz) δ 8.85 (s, 1H), 8.5-8.6 (m, 2H), 8.48 (s, 1H), 8.15 (s, 1H), 8.00 (dd, 1H, J=1.7, 8.3 Hz), 7.84 (s, 1H), 7.5-7.6 (m, 2H), 7.2-7.4 (m, 2H), 5.33 (q, 1H, J=6.9 Hz), 2.44 (s, 3H), 1.63 (d, 3H, J=7.0 Hz); LCMS Mass: 385.20 (M⁺+H).

Example 6

Synthesis of the hydrochloride salt of (S)—N-(3-(1-((1-(3,4-dimethoxyphenyl)-1H-pyrrolo [3,2-b]pyridin-6-yl)amino)ethyl)phenyl)-5-methylnicotinamide (Compound 6)

Step 1: Synthesis of 6-bromo-1-(3,4-dimethoxyphenyl)-1H-pyrrolo[3,2-b]pyridine (6-b)

To a stirred solution of 6-bromo-1H-pyrrolo[3,2-b]pyridine (6-a) (400 mg, 2.030 mol) in 1,4-dioxane (8 mL) was added 4-iodo-1,2-dimethoxybenzene (536 mg, 2.030 mol), (1S,2S)—N¹,N²-dimethylcyclohexane-1,2-diamine (58 mg, 0.406 mmol), CuI (39 mg, 0.203 mmol) and Cs₂CO₃ (1.32 g, 4.060 mmol). The mixture was placed in a microwave and heated at 150° C. for 2 h. The mixture was concentrated and purified (silica gel; eluting with EtOAc/PE=1/50-1/10) to afford compound 6-b (206 mg, 31%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.63-8.40 (m, 1H), 8.22-8.02 (m, 1H), 7.94 (dd, J=26.8, 3.3 Hz, 1H), 7.14 (d, J=10.3 Hz, 3H), 6.86-6.74 (m, 1H), 3.83 (s, 6H); LCMS Mass: 333.0 (M⁺+H).

Step 2: Synthesis the hydrochloride salt of (S)—N-(3-(1-((1-(3,4-dimethoxyphenyl)-1H-pyrrolo[3,2-b]pyridin-6-yl)amino)ethyl)phenyl)-5-methylnicotinamide (Compound 6)

To a mixture of compound (6-b) (200 mg, 0.600 mmol) in 1,4-dioxane (5 mL) was added Pd₂(dba)₃ (55 mg, 0.060 mmol), (S)—N-(3-(1-aminoethyl)phenyl)-5-methylnicotinamide (1-g) (prepared as described in Example 1, Step 6) (153 mg, 0.600 mmol), Davephos (24 mg, 0.060 mmol) and t-BuONa (173 mg, 1.801 mmol). The mixture was stirred at 100° C. for 6 h under nitrogen atmosphere. The mixture was cooled to rt and concentrated and the residue was purified (reverse-phase HPLC; eluting with MeOH/water/HCl) to afford the hydrochloride salt of Compound 6 (8 mg) as a yellow solid. ¹H NMR (400 MHz, CD₃OD) δ 9.12 (s, 1H), 8.91 (s, 1H), 8.82 (s, 1H), 7.91 (s, 1H), 7.81 (s, 1H), 7.73 (d, J=3.4 Hz, 1H), 7.52 (d, J=5.6 Hz, 1H), 7.34 (s, 1H), 7.28 (t, J=7.9 Hz, 1H), 7.14 (d, J=7.7 Hz, 1H), 6.98 (d, J=8.5 Hz, 1H), 6.87 (d, J=2.1 Hz, 1H), 6.82-6.73 (m, 1H), 6.65 (d, J=3.3 Hz, 1H), 4.45 (q, J=6.6 Hz, 1H), 3.74 (s, 3H), 3.70 (s, 3H), 2.58 (s, 3H), 1.50 (d, J=6.7 Hz, 3H); LCMS Mass: 508.1 (M⁺+H).

Example 7

Synthesis of the hydrochloride salt of (S)—N-(3-(1-((1-ethyl-1H-pyrazolo[4,3-b]pyridin-6-yl)ethyl)phenyl)-5-methylnicotinamide (Compound 7)

To a stirred solution of 6-bromo-1-ethyl-1H-pyrazolo[4,3-b]pyridine (7-a) (80 mg, 0.35 mmol) and (S)—N-(3-(1-aminoethyl)phenyl)-5-methylnicotinamide (1-g) (prepared as described in Example 1, Step 6) (100 mg, 0.4 mmol) in toluene was added Pd₂(dba)₃ (32.05 mg, 0.035 mmol), t-BuONa (84 mg, 0.875 mmol) and 2-(di-tert-butylphosphino)biphenyl (10.5 mg, 0.035 mmol) and the mixture was stirred at 100° C. under N₂ atmosphere overnight. The mixture was extracted with DCM (20 mL×3). The organic phase was combined and dried (Na₂SO₄), filtered, and was concentrated under reduced pressure. The crude was purified (Reverse-Phase Preparative HPLC; eluting with 0.1% HCl in H₂O/MeOH) to afford afford the hydrochloride salt of Compound 7 (50 mg, 36%). ¹H NMR (400 MHz, CD₃OD) δ 9.21-9.15 (m, 1H), 8.93 (s, 1H), 8.87 (s, 1H), 8.37-8.32 (m, 1H), 8.11 (s, 1H), 8.00 (d, J=27.2 Hz, 1H), 7.53 (s, 1H), 7.39-7.35 (m, 2H), 7.33 (d, J=5.4 Hz, 1H), 4.74 (s, 1H), 4.42-4.34 (m, 2H), 2.61 (s, 3H), 1.63 (s, 3H), 1.33 (s, 3H); LCMS Mass: 401.3 (M⁺+H).

Example 8

Synthesis of the hydrochloride salt of (S)-5-methyl-N-(3-(1-((1-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)amino)ethyl)phenyl)nicotinamide (Compound 8)

Step 1: Synthesis of 6-chloro-1-methyl-1H-pyrazolo[3,4-b]pyrazine (8-b)

To a stirred solution of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (8-a) (100 mg, 0.64 mmol) in DMF (10 mL), was added Cs₂CO₃ (421 mg, 1.29 mmol) and iodomethane (459 mg, 3.23 mmol). The mixture was stirred at r.t for 2 h. The mixture was evaporated under reduced pressure. The reaction mixture was partitioned between water (50 mL) and EtOAc (50 mL). The organic layer was separated, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude residue was purified (silica gel; eluting with 0-30% EtOAc in PE), to afford compound 8-b (56 mg, 51%) as an off white solid. ¹H NMR (400 MHz, CDCl₃): δ 8.53 (s, 1H), 8.27 (s, 1H), 4.14 (s, 3H); LCMS Mass: 169.0 (M⁺+H).

Step 2: Synthesis of the hydrochloride salt of (S)-5-methyl-N-(3-(1-((1-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl)amino)ethyl)phenyl)nicotinamide (Compound 8)

To a stirred solution of 6-chloro-1-methyl-1H-pyrazolo[3,4-b]pyrazine (8-b) (50 mg, 0.29 mmol) in 1,4-dioxane (3 mL) was added (S)—N-(3-(1-aminoethyl)phenyl)-5-methylnicotinamide (1-g) (prepared as described in Example 1, Step 6) (90 mg, 0.35 mmol), Pd₂(dba)₃ (27 mg, 0.029 mmol), BINAP (18 mg, 0.029 mmol) and t-BuONa (85 mg, 0.89 mmol). The mixture was heated to reflux overnight under N₂ protection. The reaction mixture was partitioned between brine (50 mL) and EtOAc (50 mL). The organic layer was separated, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude residue was purified (Reverse-Phase Preparative HPLC; eluting with 0.1% HCl in H₂O/MeOH) to afford the hydrochloride salt of Compound 8 (9 mg, 8%) as a solid. 1H NMR (400 MHz, CD₃OD): δ 9.21 (s, 1H), 9.01 (s, 1H), 8.90 (s, 1H), 8.07 (s, 2H), 7.96 (s, 1H), 7.61-7.59 (m, 1H), 7.40-7.36 (m, 1H), 7.33-7.31 (m, 1H), 5.29-5.24 (q, 1H), 3.89 (s, 3H), 2.67 (s, 3H), 1.65-1.63 (d, 3H); LCMS Mass: 388.2 (M⁺+H).

Example 9

Synthesis of the hydrochloride salt of (S)—N-(3-(1-((2-ethyl-2H-pyrazolo[3,4-b]pyrazin-6-yl)amino)ethyl)phenyl)-5-methylnicotinamide (Compound 9)

Step 1: Synthesis of 6-chloro-2-ethyl-2H-pyrazolo[3,4-b]pyrazine (9-b)

To a stirred solution of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (9-a) (7.0 g, 45.3 mmol) in THF (100 mL) was added NaHMDS (1 M, 72.5 mL) followed by iodoethane (21.2 g, 136 mmol, 10.9 mL). The mixture was stirred at rt for 24 h. The reaction mixture was partitioned between water (100 mL) and EtOAc (100 mL). The organic layer was separated, dried (MgSO₄), filtered, and was concentrated under reduced pressure. The residue was triturated with ether/heptane (1:1) to give 4.4 g of compound 9-b. The filtrate was concentrated and purified (silica gel; eluting with 0-3% MeOH in DCM) to give an additional 1.1 g of material. The batches were combined to afford Compound 9-b (5.5 g, 67%) as a light brown solid. ¹H NMR (300 MHz, CDCl₃) δ ppm 8.50 (s, 1H) 8.26 (s, 1H) 4.56 (q, J=7.43 Hz, 2H) 1.71 (t, J=7.34 Hz, 3H); LCMS Mass: 182.9 (M⁺+H).

Step 2: Synthesis of (S)-2-ethyl-N-(1-(3-nitrophenyl)ethyl)-2H-pyrazolo[3,4-b]pyrazin-6-amine (9-d)

To a stirred solution of 6-chloro-2-ethyl-pyrazolo[3,4-b]pyrazine (9-b) (2.5 g, 13.7 mmol) in 1,4-dioxane (40 mL) at rt, was added (S)-1-(3-nitrophenyl)ethan-1-amine (1-c) prepared as described in Example 1, Step 2) (4.6 g, 27.4 mmol), t-BuONa (2.0 g, 20.5 mmol) and BrettPhos-Pd-G1 (1.09 g, 1.37 mmol). The mixture was heated to 90° C. under N₂ for 10 min. The reaction mixture was diluted with EtOAc (50 mL) and filtered through Celite. The filtrate was washed with brine (50 mL) and the aqueous layer was extracted with EtOAc (50 mL×2). The combined organic phase was washed with brine (50 mL), dried (MgSO₄), filtered, and concentrated under reduced pressure. The residue was purified (amine-functionalized silica; eluting with 0-100% EtOAc in heptane) to afford compound 9-d (1.7 g, 40%) as a brown solid. ¹H NMR (300 MHz, CDCl₃) δ ppm 8.27 (t, J=1.97 Hz, 1H) 8.04-8.14 (m, 1H) 7.94 (s, 1H) 7.93 (s, 1H) 7.80 (d, J=7.70 Hz, 1H) 7.49 (t, J=7.93 Hz, 1H) 5.46 (quin, J=6.85 Hz, 1H) 5.22 (br d, J=6.60 Hz, 1H) 4.33 (q, J=7.34 Hz, 2H) 1.65 (d, J=6.88 Hz, 3H) 1.56-1.61 (m, 3H); LCMS Mass: 313.89 (M⁺+H).

Step 3: Synthesis of (S)—N-(1-(3-aminophenyl)ethyl)-2-ethyl-2H-pyrazolo[3,4-b]pyrazin-6-amine (9-e)

To a stirred solution of (S)-2-ethyl-N-(1-(3-nitrophenyl)ethyl)-2H-pyrazolo[3,4-b]pyrazin-6-amine (9-d) (1.7 g, 5.44 mmol) in methanol (60 mL) was added Pd/C (680 mg). The mixture was stirred at rt for 16 h under H₂ (1 atmosphere pressure). The reaction mixture was filtered through Celite and washed with methanol (30 mL). The filtrate was concentrated to dryness under reduced pressure to afford compound 9-e (1.53 g, 99%) as a light brown solid. ¹H NMR (300 MHz, CDCl₃) δ ppm 7.91 (s, 1H) 7.81 (s, 1H) 7.10-7.17 (m, 1H) 6.82 (d, J=7.70 Hz, 1H) 6.76 (t, J=1.97 Hz, 1H) 6.59 (ddd, J=7.93, 2.29, 0.87 Hz, 1H) 5.29 (quin, J=6.85 Hz, 1H) 5.04 (br d, J=7.43 Hz, 1H) 4.34 (q, J=7.34 Hz, 2H) 3.68 (br s, 2H) 1.58-1.63 (m, 6H); LCMS Mass: 283.65 (M⁺+H).

Step 4: Synthesis of the hydrochloride salt of (S)—N-(3-(1-((2-ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl)phenyl)-5-methylnicotinamide (Compound 9)

To a stirred solution of 5-methylnicotinic acid (33 mg, 0.24 mmol) in DMF (3 mL), was added (S)—N-(1-(3-aminophenyl)ethyl)-2-ethyl-2H-pyrazolo[3,4-b]pyrazin-6-amine (9-e) (56 mg, 0.20 mmol) HATU (95 mg, 0.25 mmol) and DIPEA (62 mg, 0.48 mmol). The mixture stirred at r.t for 3 h. The reaction mixture was partitioned between water (30 mL) and EtOAc (50 mL). The organic layer was separated and washed by brine (10 mL×2). The organic layer was separated, dried (Na₂SO₄), filtered, and was concentrated under reduced pressure. The crude residue was purified (Prep-TLC; eluting with MeOH:DCM=1:15) to afford the free base. The free base was stirred with 4M HCl in 1,4-dioxane and concentrated to afford the hydrochloride salt of Compound 9 (50 mg, 57%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.82 (s, 1H), 9.19 (s, 1H), 8.88 (s, 1H), 8.72 (s, 1H), 8.38 (s, 2H), 8.11 (d, J=1.5 Hz, 1H), 7.81 (s, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.35 (t, J=7.8 Hz, 1H), 7.22 (d, J=7.7 Hz, 1H), 5.10 (s, 1H), 4.22 (q, J=7.2 Hz, 2H), 2.51 (s, 3H), 1.51 (d, J=6.8 Hz, 3H), 1.40 (dd, J=7.9, 6.4 Hz, 3H); LCMS Mass: 402.1 (M⁺+H).

Example 10

Synthesis of the hydrochloride salt of (S)—N-(3-(1-((2-ethyl-2H-pyrazolo[3,4-b]pyrazin-6-yl)amino)ethyl)-4-fluorophenyl)-6-(trifluoromethyl)nicotinamide (Compound 10)

Step 1: Synthesis of (S,E)-N-(1-(2-fluoro-5-nitrophenyl)ethylidene)-2-methylpropane-2-sulfinamide (10-b)

To a mixture of 1-(2-fluoro-5-nitrophenyl)ethan-1-one (10-a) (1.00 g, 5.46 mmol) in THF (10 mL) was added (S)-2-methylpropane-2-sulfinamide (0.99 g, 8.19 mmol) and Ti(OEt)₄ (2.45 g, 10.92 mmol). The mixture was stirred at 75° C. overnight. The mixture was cooled to room temperature and quenched with ice water (30 mL). EtOAc (100 mL) was added and the mixture was stirred at room temperature for 15 min. The mixture was filtered. The filtercake was washed with EtOAc (3×20 mL). The combined organic layers were washed with brine (30 mL) and dried over Na₂SO₄. The mixture was filtered and concentrated to dryness. The crude product was purified (silica gel; eluting with EtOAc:PE=1:8 to 1:4) to afford to compound 10-b (1.0 g, 64%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.56 (dd, J=6.4, 2.9 Hz, 1H), 8.32 (dt, J=9.1, 3.6 Hz, 1H), 7.29 (t, J=9.4 Hz, 1H), 2.81 (d, J=3.5 Hz, 3H), 1.34 (s, 9H); LCMS

Mass: 287.0 (M⁺+H).

Step 2: Synthesis of (S)—N—((S)-1-(2-fluoro-5-nitrophenyl)ethyl)-2-methylpropane-2-sulfinamide (10-c)

To a stirred solution of 10-b (800 mg, 2.79 mmol) in THF (10 mL) at −50° C., was added NaBH₄ (316 mg, 8.37 mmol). The mixture was stirred between 0° C. to r. t. for 3 h. The mixture was carefully quenched with sat. NH₄Cl solution (20 mL). The mixture was extracted with EtOAc (3×30 mL). The organic layer was washed with brine (15 mL) and dried over Na₂SO₄. The mixture was filtered, concentrated to dryness and purified (silica gel; eluting with EtOAc:PE=1:4 to 1:1) to afford compound 10-c (478 mg, 59%) as yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 9.16 (s, 1H), 8.32 (dd, J=6.2, 2.8 Hz, 1H), 8.19 (ddd, J=8.9, 4.2, 2.7 Hz, 1H), 7.21 (t, J=9.1 Hz, 1H), 4.84 (t, J=6.4 Hz, 1H), 1.59 (d, J=6.7 Hz, 3H), 1.24 (s, 9H); LCMS Mass: 289.0 (MH⁺).

Step 3: Synthesis of (S)—N—((S)-1-(5-amino-2-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (10-d)

To a stirred solution of 10-c (100 mg, 0.35 mmol) in a mixture of EtOH (2 mL) and water (1 mL), was added Fe (58 mg, 1.04 mmol) and NH₄Cl (56 mg, 1.04 mmol). The mixture was stirred at 80° C. for 2 h. The mixture was filtered and concentrated to dryness. The crude product was diluted with a mixture of DCM (20 mL) and water (10 mL). The aqueous phase was extracted with DCM (2×10 mL). The combined organic layers were washed with brine (15 mL) and was dried over Na₂SO₄. The mixture was purified (Prep-TLC; eluting with MeOH:DCM=1:20) to afford compound 10-d (67 mg, 75%) as yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 6.77 (dd, J=10.3, 8.7 Hz, 1H), 6.65 (dd, J=6.4, 2.8 Hz, 1H), 6.42 (ddd, J=8.7, 4.3, 2.9 Hz, 1H), 5.53 (d, J=6.6 Hz, 1H), 4.90 (s, 2H), 4.53 (m, 1H), 1.35 (d, J=6.8 Hz, 3H), 1.09 (s, 9H); LCMS Mass: 259.1 (MH⁺).

Step 4: Synthesis of tert-butyl (3-((S)-1-(((S)-tert-butylsulfinyl)amino)ethyl)-4-fluorophenyl)carbamate (10-e)

To a stirred solution of 10-d (6.4 g, 0.025 mol) in MeOH (150 mL), was added TEA (7.6 g, 0.075 mol) and (Boc)₂O (10.9 g, 0.050 mol). The mixture was stirred at r.t. for 2 h. The mixture was evaporated under reduced pressure. The reaction mixture was partitioned between water (150 mL) and EtOAc (150 mL). The organic layer was separated, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude residue was purified (silica gel; eluting with 30 to 40% EtOAc in PE) to afford compound 10-e (8.3 g, 93%) as an off-white solid. LCMS Mass: 359.2 (M⁺+H).

Step 5: Synthesis of tert-butyl (S)-(3-(1-aminoethyl)-4-fluorophenyl)carbamate (10-f)

To a mixture of 10-e (8.3 g, 0.023 mol) in THF (80 mL) was added water (16 mL) and 12 (1.7 g, 0.007 mol). The mixture was stirred at 50° C. for 5 h. The mixture was cooled to r.t. and then diluted with saturated aqueous citric acid solution. The mixture was washed with EtOAc (200 mL×3). The aqueous phase was cooled to 0° C., then the pH was adjusted to 10 with NaOH (30% in water). The mixture was extracted with EtOAc (200 mL×3). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated under reduced pressure to afford compound 10-f (5.5 g, 90%) as a yellow oil. LCMS Mass: 255.2 (M⁺+H).

Step 6: Synthesis of tert-butyl(S)-(3-(1-((2-ethyl-2H-pyrazolo[3,4-b]pyrazin-6-yl)amino) ethyl)-4-fluorophenyl)carbamate (10-g)

To a stirred solution of 10-f (5.5 g, 0.022 mol) in 1,4-dioxane (100 mL) was added 6-chloro-2-ethyl-2H-pyrazolo[3,4-b]pyrazine (9-b) (prepared as described in Example 9, Step 1) (4.3 g, 0.024 mol), BrettPhos Palladacycle (0.8 g, 0.001 mol) and t-BuONa (6.2 g, 0.065 mol). The mixture was stirred at 75° C. for 1.5 h under a N₂ atmosphere. The reaction mixture was partitioned between brine (200 mL) and EtOAc (200 mL). The organic layer was separated, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude residue was purified (silica gel; eluting with EtOAc/PE=1/1) to afford compound 10-g (5.5 g, 63%) as a yellow solid. LCMS Mass: 401.3 (M⁺+H).

Step 7: Synthesis of (S)—N-(1-(5-amino-2-fluorophenyl)ethyl)-2-ethyl-2H-pyrazolo[3,4-b] pyrazin-6-amine (10-h)

To a stirred solution of 10-g (5.5 g, 13.5 mmol) in MeOH (40 mL), was added 4 M HCl in 1,4-dioxane (40 mL) and the mixture was stirred at r.t for 2 h. The mixture was evaporated under reduced pressure. The mixture was diluted with 3M HCl (200 mL) and washed with EtOAc (200 mL×3). The aqueous phase was cooled to 0° C., then the pH was adjusted to 12 with NaOH (30% in water). The mixture was extracted with EtOAc (200 mL×3). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated under reduced pressure to afford compound 10-h (4.0 g, 96%) as yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.32 (s, 1H), 8.04 (s, 1H), 7.87 (d, J=7.1 Hz, 1H), 6.80 (dd, J=10.4, 8.6 Hz, 1H), 6.54 (dd, J=6.5, 2.8 Hz, 1H), 6.37 (ddd, J=8.6, 4.2, 2.9 Hz, 1H), 5.18 (p, J=6.8 Hz, 1H), 4.87 (s, 2H), 4.21 (q, J=7.2 Hz, 2H), 1.44-1.38 (m, 6H); LCMS Mass: 301.2 (M⁺+H).

Step 8: Synthesis of the hydrochloride salt of (S)—N-(3-(1-((2-ethyl-2H-pyrazolo[3,4-b] pyrazin-6-yl)amino)ethyl)-4-fluorophenyl)-6-(trifluoromethyl)nicotinamide (Compound 10)

To a stirred solution of 10-h (50 mg, 0.167 mmol) and 6-(trifluoromethyl) nicotinic acid (32 mg, 0.83 mmol) in DMF (4 mL), was added HATU (95 mg, 0.25 mmol) and DIEA (64 mg, 0.5 mmol). The mixture was stirred at r.t. for 2.5 h. The reaction mixture was diluted with water, and extracted with EtOAc. The organic phase was washed with water, then brine, dried over Na₂SO₄, and concentrated under reduced pressure. The obtained residue was purified (Preparative HPLC; eluting with 0.1% HCl in H2O/MeOH) to afford the hydrochloride salt of Compound 10 (28 mg, 33%). ¹H NMR (400 MHz, DMSO-d₆) δ 10.65 (s, 1H), 9.19 (d, J=2.1 Hz, 1H), 8.51 (dd, J=8.2, 2.1 Hz, 1H), 8.33 (s, 1H), 8.13 (d, J=6.7 Hz, 1H), 8.10 (s, 1H), 8.07 (dd, J=8.2, 0.9 Hz, 1H), 7.81 (dd, J=6.9, 2.7 Hz, 1H), 7.67 (dd, J=8.8, 4.5, 2.7 Hz, 1H), 7.22 (dd, J=10.1, 8.8 Hz, 1H), 5.29 (m, 1H), 4.21 (q, J=7.2 Hz, 2H), 1.51 (d, J=6.9 Hz, 3H), 1.40 (t, J=7.3 Hz, 3H). LCMS Mass: 474.2 (M⁺+H).

Example 11

Synthesis of the hydrochloride salt of (S)—N-(3-(1-((2-ethyl-2H-pyrazolo[4,3-b]pyridin-6-yl)amino)ethyl)phenyl)-5-methylnicotinamide (Compound 11)

Step 1: Synthesis of 6-bromo-2-ethyl-2H-pyrazolo[4,3-b]pyridine (11-b)

To a stirred solution of 6-bromo-1H-pyrazolo[4,3-b]pyridine (11-a) (1.00 g, 5.08 mmol) in DMF, was added cesium carbonate (3.3 g, 10.16 mmol) and bromoethane (1.1 g, 10.16 mmol) at r.t. The mixture was stirred at r.t. for 2 h. The mixture was concentrated and purified (silica gel; eluting with EtOAc/PE=1/1) to afford compound 11-b (420 mg, 37%) as a yellow solid and compound 11-c (640 mg, 56%) as a brown oil. Compound 11-b: ¹H NMR (400 MHz, DMSO-d₆) δ 8.77 (d, J=0.9 Hz, 1H), 8.53 (d, J=2.0 Hz, 1H), 8.43 (dd, J=2.1, 1.0 Hz, 1H), 4.49 (q, J=7.3 Hz, 2H), 1.52 (t, J=7.3 Hz, 3H); LCMS Mass: 226.1 (M⁺+H); Compound 11-c: ¹H NMR (400 MHz, CDCl₃) δ 8.47 (t, J=5.4 Hz, 1H), 8.09 (d, J=0.8 Hz, 1H), 7.83 (dd, J=1.8, 1.0 Hz, 1H), 4.28 (q, J=7.3 Hz, 2H), 1.42 (t, J=7.0 Hz, 3H); LCMS Mass: 226.1 (M⁺+H).

Step 2: Synthesis of the hydrochloride salt of (S)—N-(3-(1-((2-ethyl-2H-pyrazolo[4,3-b] pyridin-6-yl)amino)ethyl)phenyl)-5-methylnicotinamide (Compound 11)

To a stirred solution of 6-bromo-2-ethyl-2H-pyrazolo[4,3-b]pyridine (11-b) (80 mg, 0.35 mmol) and (S)—N-(3-(1-aminoethyl)phenyl)-5-methylnicotinamide (1-g) (prepared as described in Example 1, Step 6) (100 mg, 0.4 mmol) in toluene, was added Pd₂(dba)₃ (32.05 mg, 0.035 mmol), t-BuONa (84 mg, 0.875 mmol) and 2-(di-tert-butylphosphino)biphenyl (10.5 mg, 0.035 mmol) and the mixture was stirred at 100° C. under N₂ atmosphere overnight. The mixture was extracted with DCM (20 mL×3). The organic phase was combined and dried (Na₂SO₄), filtered, and was concentrated under reduced pressure. The crude was purified (Reverse-Phase Preparative HPLC; eluting with 0.1% HCl in H₂O/MeOH) to afford afford the hydrochloride salt of Compound 11 (20 mg, 14%) as a solid. ¹H NMR (400 MHz, CD₃OD) δ 9.19 (s, 1H), 8.99 (s, 1H), 8.90 (d, J=20.9 Hz, 1H), 8.62 (s, 1H), 8.56 (s, 1H), 7.91 (s, 1H), 7.65 (s, 1H), 7.36 (s, 1H), 7.31 (t, J=7.1 Hz, 1H), 7.26 (d, J=20.9 Hz, 1H), 4.67 (dd, J=13.4, 6.7 Hz, 1H), 4.53-4.46 (m, 2H), 2.64 (s, 3H), 1.62 (s, 3H), 1.56 (d, J=6.7 Hz, 3H); LCMS Mass: 401.2 (M⁺+H).

Example 12

Synthesis of the hydrochloride salt of (5)-5-methyl-N-(3-(1-((3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)amino)ethyl)phenyl)nicotinamide (Compound 12)

Step 1: Synthesis of 6-bromo-N2-methylpyrazine-2,3-diamine (12-b)

A solution of 3,5-dibromopyrazin-2-amine (12-a) (3 g, 11.96 mmol) in MeNH₂/THF (2 M) (30 mL) was stirred in a sealed tube at 100° C. overnight. The mixture was concentrated and was purified (silica gel; eluting with ethyl acetate:Petroleum ether=1:2) to afford compound 12-b (1.96 g, 81%) as a white solid. ¹H NMR (400 MHz, Chloroform-d) δ 7.46 (s, 1H), 4.49 (s, 1H), 3.03 (d, J=3.9 Hz, 3H). LCMS Mass: 203 (M⁺+H).

Step 2: Synthesis of 6-bromo-1-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one (12-c)

A solution of 12-b (737 mg, 3.65 mmol) and CDI (1.479 g, 9.12 mmol) in THF was stirred at 50° C. overnight. The mixture was cooled to r.t. and ethyl acetate (30 mL) and water (20 mL) were added. The organic layer was separated and concentrated, and the crude product was purified (Silica gel; eluting with EA:PE=1:4) to afford compound 12-c (800 mg, 96%) as a white solid. ¹H NMR (400 MHz, Chloroform-d) δ 9.33 (s, 1H), 8.05 (s, 1H), 3.49 (s, 3H); LCMS Mass: 229 (M⁺+H).

Step 3: Synthesis of 5-bromo-1-(4-methoxybenzyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one (12-d)

To a solution of 12-c (500 mg, 2.2 mmol), PMBCl (412 g, 2.64 mmol) and K₂CO₃ (456 mg, 3.3 mmol) in DMF was stirred at 70° C. for 2 h. The mixture was cooled down to r.t. and DCM (20 mL) and water (20 mL) were added. The organic layer was separated and concentrated to afford compound 12-d (500 mg, 65%) as a white solid. LCMS Mass: 348.9 (M⁺+H).

Step 4: Synthesis of (S)-1-(4-methoxybenzyl)-3-methyl-5-((1-(3-nitrophenyl)ethyl) amino)-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one (12-e)

To a stirred solution of 12-d (200 mg, 0.575 mmol) in toluene (8 mL) was added Cs₂CO₃ (561.75 mg, 1.725 mmol), (S)-1-(3-nitrophenyl)ethan-1-amine (1-c) (prepared as described in Example 1, Step 2) (105 mg, 0.63 mmol), BINAP (35.78 mg, 0.057 mmol) and Pd₂(dba)₃ (52.62 mg, 0.057 mmol). The mixture was heated to 100° C. overnight under a N₂ atmosphere. The reaction mixture was concentrated and the residue was dissolved in EtOAc (20 mL). The mixture was washed by water (40 mL) and then brine (40 mL). The organic layer was separated, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude residue was purified (silica gel; eluting with 0˜50% EtOAc in PE) to afford compound 12-e (100 mg, 40%) as an orange solid. LCMS Mass: 435.20 (M⁺+H).

Step 5: Synthesis of (5)-5-((1-(3-aminophenyl)ethyl)amino)-1-(4-methoxybenzyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyrazin-2-one (12-f)

To a stirred solution of 12-e (100 mg, 0.230 mmol) in methanol (10 mL), was added Pd/C (10 mg) and the mixture was stirred at r.t for 4 h under a H2 atmosphere. The reaction mixture was filtered through celite and the filter cake was washed with methanol (15 mL). The filtrate was concentrated to dryness under reduced pressure to afford compound 12-f (90 mg, 97%) as a yellow solid. LCMS Mass: 405.25 (M⁺+H).

Step 6: Synthesis of (S)—N-(3-(1-((1-(4-methoxybenzyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)amino)ethyl)phenyl)-5-methylnicotinamide (12-g)

To a stirred solution of 12-f (90 mg, 0.222 mmol) in DMF (2 mL), was added HATU (169.2 mg, 0.444 mmol), DIPEA (86.26 mg, 0.668 mmol) and 5-methylnicotinic acid (45.77 mg, 0.333 mmol) and the mixture stirred at r.t for 2 h. The reaction mixture was partitioned between water (40 mL) and EtOAc (20 mL). The organic layer was separated and washed with brine (25 mL×2). The organic layer was separated, dried (Na₂SO₄), filtered, and was concentrated under reduced pressure. The crude residue was purified (Reverse-Phase C18 column; eluting with 60% MeOH in water) to afford compound 12-g (100 mg, 86%) as yellow solid. LCMS Mass: 524.30 (M⁺+H).

Step 7: Synthesis of the hydrochloride salt of (S)-5-methyl-N-(3-(1-((3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)amino)ethyl)phenyl)nicotinamide (Compound 12)

A solution of 12-g (60 mg, 0.11 mmol) in trifluoromethanesulfonic acid (1 mL) was stirred at r.t for 1 h. The reaction mixture was concentrated and purified (Preparative Reverse-Phase HPLC; eluting with 0.1% HCl in H₂O/MeOH) to afford the hydrochloride salt of Compound 12 (1.5 mg, 3%) as a solid. ¹H NMR (400 MHz, CD₃OD): δ 9.17 (s, 1H), 8.96 (s, 1H), 8.88 (s, 1H), 7.84 (s, 1H), 7.56 (d, 1H), 7.36 (t, 1H), 7.62 (d, 1H), 7.22 (s, 1H), 5.34 (t, 1H), 3.32 (s, 3H), 2.66 (s, 3H), 1.59 (d, 3H). LCMS Mass: 404.25 (M⁺+H).

Example 13

Synthesis of the hydrochloride salt of (S)-5-methyl-N-(3-(1-((3-methyl-1H-pyrrolo[2,3-b] pyridin-5-yl)amino)ethyl)phenyl)nicotinamide (Compound 13)

Step 1: Synthesis of 5-bromo-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo [3,4-b]pyridine (13-b)

To a stirred solution of 5-bromo-3-methyl-1H-pyrrolo[2,3-b]pyridine (13-a) (300 mg, 1.421 mmol) in DCM (5 mL) was added (Boc)₂O (620 mg, 2.843 mmol), TEA (431 mg, 4.264 mmoL) and DMAP (17 mg, 0.142 mmoL). The mixture was stirred at 20° C. for 5 h. The mixture was concentrated and purified (silica gel; eluting with EtOAc/PE=1/50) to afford compound 13-b (350 mg, 79%) as an off-white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.38 (d, J=2.2 Hz, 1H), 8.16 (d, J=2.2 Hz, 1H), 7.53 (d, J=1.2 Hz, 1H), 2.25 (s, 3H), 1.66 (s, 9H); LCMS Mass: 311.05 (M⁺+H).

Step 2: Synthesis of the hydrochloride salt of (S)-5-methyl-N-(3-(1-((3-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)amino)ethyl)phenyl)nicotinamide (Compound 13)

To a mixture of 13-b (350 mg, 1.125 mmol) in 1, 4-dioxane (5 mL), was added Pd₂(dba)₃ (103 mg, 0.113 mmol), (S)—N-(3-(1-aminoethyl)phenyl)-5-methylnicotinamide (1-g) (prepared as described in Example 1, Step 6) (287 mg, 1.125 mmol), 2-(di-tert-butylphosphino)biphenyl (36 mg, 0.113 mmol) and t-BuONa (2M, THF) (1.7 ml, 3.375 mmol). The mixture was stirred at 80° C. for 2 h under a nitrogen atmosphere and was cooled down to room-temperature. The mixture was concentrated, and the residue was purified (reverse-phase column; eluting with MeOH/water/HCl) to afford the hydrochloride salt of Compound 13 (11 mg) as a yellow solid. ¹H NMR (400 MHz, CD₃OD) δ 9.21 (s, 1H), 9.01 (s, 1H), 8.90 (s, 1H), 7.94 (d, J=2.0 Hz, 2H), 7.73 (s, 1H), 7.65 (d, J=8.1 Hz, 1H), 7.40 (t, J=7.9 Hz, 1H), 7.33-7.25 (m, 2H), 4.72 (q, J=6.7 Hz, 1H), 2.67 (s, 3H), 2.27 (s, 3H), 1.70 (d, J=6.7 Hz, 3H); LCMS Mass: 386.30 (M⁺+H).

Example 14

Synthesis of the hydrochloride salt of (5)-5-methyl-N-(3-(1-((3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)amino)ethyl)phenyl)nicotinamide (Compound 14)

Step 1: Synthesis of 5-bromo-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo [3,4-b]pyridine (14-b)

To an ice cooled solution of 5-bromo-3-methyl-1H-pyrazolo[3,4-b] pyridine (14-a) (400 mg, 1.9 mmol) in THF (20 mL), was added NaH (112 mg, 2.8 mmol) and SEMCl (466.8 mg, 2.8 mmol) and the mixture was stirred between 0° C. and r.t. for 16 h. The reaction mixture was partitioned between water (20 mL) and EtOAc (100 mL). The organic layer was separated and washed with brine (10 mL×2). The organic layer was separated, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude residue was purified by C18 column chromatography to afford compound 14-b (270 mg, 41%) as an off-white solid. LCMS Mass: 342.0 and 344.5 (MH⁺).

Step 2: Synthesis of (S)-5-methyl-N-(3-(1-((3-methyl-1-((2-(trimethylsilyl)ethoxy) methyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)amino)ethyl)phenyl)nicotinamide (14-c)

To a stirred solution of 14-b (270 mg, 0.79 mmol) in toluene (10 mL) was added (S)—N-(3-(1-aminoethyl)phenyl)-5-methylnicotinamide (1-g) (prepared as described in Example 1, Step 6) (201 mg, 0.79 mmol), Pd₂(dba)₃ (72 mg, 0.079 mmol), 2-(di-tert-butylphosphino)biphenyl (47 mg, 0.16 mmol), and t-BuONa (0.8 mL, 1.6 mmol). The mixture was heated to reflux under N₂ atmosphere for 2 h. The reaction mixture was partitioned between brine (50 mL) and EtOAc (50 mL). The organic layer was separated, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude residue was purified by C18 column chromatography to afford compound 14-c (100 mg, 24%) as an off-white solid. LCMS Mass: 517.3 (M⁺+H).

Step 3: Synthesis of the hydrochloride salt of (S)-5-methyl-N-(3-(1-((3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)amino)ethyl)phenyl)nicotinamide (Compound 14)

To a stirred solution of 14-c (100 mg, 0.19 mmol) in DCM (10 mL) was added TFA (1 mL, 13.4 mmol). The mixture was stirred at r.t. O/N. The reaction mixture was concentrated under reduced pressure. The crude residue was purified (Preparative-HPLC; eluting with 0.1% HCl in H₂O/MeOH) to afford the hydrochloride salt of Compound 14 (18 mg, 34%) as a solid. ¹H NMR (400 MHz, CD₃OD) δ 9.24 (s, 1H), 9.04 (s, 1H), 8.93 (s, 1H), 8.38 (d, J=2.5 Hz, 1H), 8.09 (d, J=2.4 Hz, 1H), 7.97 (s, 1H), 7.72 (d, J=9.2 Hz, 1H), 7.43 (t, J=7.9 Hz, 1H), 7.29 (d, J=7.8 Hz, 1H), 4.85 (s, 1H), 2.69 (s, 3H), 2.58 (s, 3H), 1.81 (d, J=6.8 Hz, 3H); LCMS Mass: 387.2 (M⁺+H).

Example 15

Synthesis of the hydrochloride salt of (5)-5-methyl-N-(3-(1-((7-methyl-5H-pyrrolo[2,3-b] pyrazin-2-yl)amino)ethyl)phenyl)nicotinamide (Compound 15)

Step 1: Synthesis of N-allyl-3,5-dibromopyrazin-2-amine (15-b)

To a stirred solution of 3,5-dibromopyrazin-2-amine (15-a) (20 g, 0.079 mol) in THF at room temperature, was added LiHMDS (94.90 mL, 0.095 mol). After 2 h, 3-bromoprop-1-ene (19.10 g, 0.158 mol) was added. The mixture was stirred at r.t. for 16 h. The mixture was quenched with saturated NH₄Cl, and extracted with EtOAc. The organic layer was washed with brine. The mixture was concentrated and purified (Silica gel; eluting with EtOAc/PE=1/100) to afford compound 15-b (14 g, 60%) as a black oil. LCMS Mass: 293.8 (M⁺+H)

Step 2: Synthesis of 2-bromo-7-methyl-5H-pyrrolo[2,3-b]pyrazine (15-c)

To a stirred solution of 15-b (14 g, 0.048 mol) in DMF (100 mL) was added HCOONa (0.8 g, 0.012 mol), Pd(OAc)₂ (1.1 g, 0.005 mol), Bu₄NH₄Br (2.3 g, 0.007 mol) and TEA (11.6 g, 0.115 mol). The mixture was stirred at 50° C. for 18 h under a N₂ atmosphere. The reaction mixture was filtered through Celite and the filter cake was washed by methanol. The filtrate was concentrated under reduced pressure. The crude residue was purified (Silica gel; eluting with EtOAc/PE=1/2) to afford compound 15-c (1.6 g, 16%) as a black solid. LCMS Mass: 213.9 (M⁺+H).

Step 3: Synthesis of tert-butyl 2-bromo-7-methyl-5H-pyrrolo[2,3-b]pyrazine-5-carboxylate (15-d)

To a stirred solution of 15-c (1.6 g, 7.5 mmol) in DCM (30 mL), was added DMAP (0.4 g, 3.5 mmol), TEA (1.5 g, 15.1 mmol) and (Boc)₂O (3.3 g, 15.1 mmol) and the mixture was stirred at r.t. for 2 h. The mixture was evaporated under reduced pressure and the reaction mixture was partitioned between water (80 mL) and EtOAc (60 mL). The organic layer was separated, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude residue was purified (silica gel; eluting with 0 to 10% EtOAc in PE) to afford compound 15-d (1.76 g, 74%) as a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.43 (s, 1H), 7.90 (s, 1H), 2.32-2.28 (m, 3H), 1.67 (s, 9H); LCMS Mass: 256.0 (MH⁺−56).

Step 4: Synthesis of tert-butyl (S)-7-methyl-2-((1-(3-(5-methylnicotinamido)phenyl) ethyl)amino)-5H-pyrrolo[2,3-b]pyrazine-5-carboxylate (15-e)

To a stirred solution of 15-d (150 mg, 0.48 mmol) in toluene (15 mL), was added (S)—N-(3-(1-amino ethyl)phenyl)-5-methylnicotinamide (1-g) (prepared as described in Example 1, Step 6) (122 mg, 0.48 mmol), Pd₂(dba)₃ (44 mg, 0.048 mmol), BINAP (30 mg, 0.048 mmol) and Cs₂CO₃ (470 mg, 1.44 mmol). The mixture was heated to 100° C. for overnight under a N₂ atmosphere. The reaction mixture was partitioned between brine (100 mL) and EtOAc (50 mL). The organic layer was separated, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude residue was purified (silica gel; eluting with 0 to 50% EtOAc in PE) to afford compound 15-e (93 mg, 40%) as yellow solid. LCMS Mass: 487.30 (M⁺+H).

Step 5: Synthesis of the hydrochloride salt of (S)-5-methyl-N-(3-(1-((7-methyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)amino)ethyl)phenyl)nicotinamide (Compound 15)

To a stirred solution of compound 15-e (93 mg, 0.19 mmol) in DCM (5 mL), was added TFA (1 mL) and the mixture was stirred at r.t for 3 h. The mixture was evaporated under reduced pressure and the crude residue was purified (Preparative Reverse-Phase HPLC; eluting with 0.1% HCl in H₂O/MeOH) to afford the hydrochloride salt of Compound 15 (32 mg, 44%) as a solid. ¹H NMR (400 MHz, DMSO-d₆): δ 11.88 (s, 1H), 10.78 (s, 1H), 9.14 (s, 1H), 8.82 (s, 1H), 8.61 (s, 1H), 7.88 (s, 2H), 7.70-7.67 (d, 1H), 7.47 (s, 1H), 7.38-7.34 (t, 1H), 7.29-7.27 (d, 1H), 5.29 (m, 1H), 2.48 (s, 3H), 2.20 (s, 3H), 1.56-1.54 (d, 3H); LCMS Mass: 387.20 (M⁺+H).

Example 16

Synthesis of the hydrochloride salt of (S)-5-methyl-N-(3-(1-((3-methyl-1H-pyrazolo[3,4-b]pyrazin-5-yl)amino)ethyl)phenyl)nicotinamide (Compound 16)

Step 1: Synthesis of 3-methyl-1-trityl-1H-pyrazolo[3,4-b]pyrazine (16-b)

To a stirred solution of 3-methyl-1H-pyrazolo[3,4-b]pyrazine (16-a) (2.0 g, 14.9 mmol) in DMF (30 mL) was added trityl chloride (6.23 g, 22.4 mmol) and Cs₂CO₃ (9.72 g, 29.8 mmol). The mixture was stirred at r.t. for 2 h. The mixture was diluted with EtOAc (80 mL) and washed by water (200 mL), and brine (100 mL×2). The organic layer was separated, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude residue was purified (silica gel; eluting with 0˜10% EtOAc in PE) to afford compound 16-b (5.22 g, 93%) as an off white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.49 (d, 1H), 8.18 (d, 1H), 7.29-7.20 (m, 15H), 2.52 (s, 3H).

Step 2: Synthesis of 3-methyl-1-trityl-1H-pyrazolo[3,4-b]pyrazine 4-oxide (16-c)

To a stirred solution of 16-b (5.20 g, 13.8 mmol) in DCM (50 mL) was added 3-chlorobenzoperoxoic acid (3.58 g, 20.7 mmol). The mixture was stirred at r.t. for 16 h. The mixture was treated with saturated Na₂SO₃ (80 mL) and extracted with DCM (50 mL). The organic layer was washed by brine (100 mL). The organic layer was separated, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude residue was purified (silica gel; eluting with 0˜20% EtOAc in PE) to afford compound 16-c (4.19 g, 77%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.13-8.11 (m, 2H), 7.30-7.19 (m, 15H), 2.60 (s, 3H).

Step 3: Synthesis of 5-bromo-3-methyl-1H-pyrazolo[3,4-b]pyrazine (16-d)

To a stirred solution of 16-c (4.19 g, 10.6 mmol) in DMF (50 mL) was added POBr₃ (3.67 g, 12.8 mmol) at 0° C. The mixture was stirred at 90° C. for 2.5 h. The mixture was cooled down to r.t and the pH was adjusted to 8 with saturated aq Na₂CO₃ solution. The mixture was extracted with EtOAc (80 ml) and washed by water (100 ml×2), then brine (100 ml). The organic layer was separated, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude residue was purified (silica gel; eluting with 0˜20% EtOAc in PE) to afford compound 16-d (4.19 g, 77%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 13.92 (s, 1H), 8.68 (s, 1H), 2.52 (s, 3H); LCMS Mass: 212.95 (M⁺+H).

Step 4: Synthesis of tert-butyl 5-bromo-3-methyl-1H-pyrazolo[3,4-b]pyrazine-1-carboxylate (16-e)

To a stirred solution of 16-d (1.23 g, 5.77 mmol) in DCM (30 mL), was added TEA (1.46 g, 14.4 mmol) and (Boc)₂O (1.89 g, 8.66 mmol) and the mixture was stirred at r.t. for 2 h. The mixture was evaporated under reduced pressure and the reaction mixture was partitioned between water (100 mL) and EtOAc (80 mL). The organic layer was separated, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude residue was purified (silica gel; eluting with 0˜20% EtOAc in PE) to afford compound 16-e (1.02 g, 57%) as an off-white solid. ¹H NMR (400 MHz, CDCl₃): δ 8.69 (s, 1H), 2.67 (s, 3H), 1.72 (s, 9H).

Step 5: Synthesis of tert-butyl (S)-3-methyl-5-((1-(3-nitrophenyl)ethyl)amino)-1H-pyrazolo[3,4-b]pyrazine-1-carboxylate (16-f)

To a stirred solution of 16-e (626 mg, 2.0 mmol) in toluene (30 mL) was added (S)-1-(3-nitrophenyl)ethan-1-amine (1-c) (prepared as described in Example 1, Step 2) (332 mg, 2.0 mmol), Pd₂(dba)₃ (184 mg, 0.2 mmol), BINAP (125 mg, 0.2 mmol) and Cs₂CO₃ (1.95 g, 6.0 mmol). The mixture was heated to reflux overnight under a N₂ atmosphere. The reaction mixture was partitioned between brine (50 mL) and EtOAc (50 mL). The organic layer was separated, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude residue was purified (silica gel; eluting with 0˜50% EtOAc in PE) to afford compound 16-f (298 mg, 37%) as a yellow solid. ¹H NMR (400 MHz, CD₃OD): δ 8.34 (t, 1H), 8.10 (s, 1H), 8.08 (dd, 1H), 7.86 (d, 1H), 7.55 (t, 1H), 5.21 (q, 1H), 2.38 (s, 3H), 1.65 (s, 9H), 1.62 (d, 3H); LCMS Mass: 399.2 (M⁺+H).

Step 6: Synthesis of tert-butyl (S)-5-((1-(3-aminophenyl)ethyl)amino)-3-methyl-1H-pyrazolo[3,4-b]pyrazine-1-carboxylate (16-g)

To a stirred solution of 16-f (298 mg, 0.75 mmol) in methanol (20 mL), was added Pd/C (30 mg) and the mixture was stirred at r.t for 16 h under a H2 atmosphere. The reaction mixture was filtered through Celite and the filter cake was washed with methanol (20 mL). The filtrate was concentrated to dryness under reduced pressure to afford compound 16-g (250 mg, 91%) as a yellow solid, which was used directly without further purification. LCMS Mass: 368.2 (M⁺+H).

Step 7: Synthesis of tert-butyl (S)-3-methyl-5-((1-(3-(5-methylnicotinamido)phenyl) ethyl)amino)-1H-pyrazolo[3,4-b]pyrazine-1-carboxylate (16-h)

To a stirred solution of 5-methylnicotinic acid (44.6 mg, 0.32 mmol) in DMF (5 mL), was added HATU (155 mg, 0.41 mmol) and the mixture was stirred at r.t for 20 min. Compound 16-g (100 mg, 0.27 mmol) and DIPEA (105 mg, 0.81 mmol) were added and the mixture stirred at r.t for 16 h. The reaction mixture was partitioned between water (50 mL) and EtOAc (20 mL). The organic layer was separated and washed by brine (30 mL×2). The organic layer was separated, dried (Na₂SO₄), filtered, and was concentrated under reduced pressure. The crude residue was purified (silica gel; eluting with 0˜100% EtOAc in PE) to afford compound 16-h (96 mg, 73%) as a yellow oil. LCMS Mass: 488.30 (M⁺+H).

Step 8: Synthesis of the hydrochloride salt of (S)-5-methyl-N-(3-(1-((3-methyl-1H-pyrazolo[3,4-b]pyrazin-5-yl)amino)ethyl)phenyl)nicotinamide (Compound 16)

To a stirred solution of 16-h (96 mg, 13.5 mmol) in DCM (40 mL), was added 4 M HCl in 1,4-dioxane (4 mL) and the mixture was stirred at r.t for 16 h. The mixture was evaporated under reduced pressure and the crude residue was purified (Preparative Reverse-Phase HPLC; eluting with 0.1% HCl in H₂O/MeOH) to afford the hydrochloride salt of Compound 16 (38 mg, 49%) as a solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.86 (s, 1H), 9.22 (s, 1H), 8.89 (s, 1H), 8.77 (s, 1H), 8.12 (s, 1H), 7.87 (s, 1H), 7.69-7.67 (d, 2H), 7.34 (t, 1H), 7.27 (d, 1H), 5.23 (q, 1H), 2.52 (s, 3H), 2.36 (s, 3H), 1.53-1.51 (d, 3H); LCMS Mass: 388.2 (M⁺+H).

Example 17

Synthesis of the hydrochloride salt of (5)-5-methyl-N-(3-(1-((6-methylfuro[2,3-b] pyrazin-3-yl)amino)ethyl)phenyl)nicotinamide (Compound 17)

Step 1: Synthesis of (R)-1-(3-nitrophenyl)ethyl methanesulfonate (17-b)

To a stirred solution of (R)-1-(3-nitrophenyl)ethan-1-ol (17-a) (5.0 g, 29.91 mmol) in DCM (50 mL) at 0° C., was added methyl sulfonyl chloride (6.85 g, 59.82 mmol) and TEA (9.08 g, 89.73 mmol). The mixture was allowed to warm to r.t. and stirred for a further 16 h. The mixture was diluted with DCM (100 mL) and washed by water (200 mL), then brine (100 mL). The organic layer was separated, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude residue was purified (silica gel; eluting with 0˜20% EtOAc in PE) to afford compound 17-b (4.7 g, 64%) as a yellow oil, which was not purified further.

Step 2: Synthesis of 6-chloro-5-(prop-1-yn-1-yl)pyrazin-2-amine (17-d)

To a stirred solution of 5-bromo-6-chloropyrazin-2-amine (17-c) (4.8 g, 23.03 mmol) in DMF (50 mL), was added tributyl(prop-1-yn-1-yl)stannane (9.09 g, 27.64 mmol), Pd(PPh₃)₂Cl₂ (8.08 g, 11.51 mmol), CuI (2.19 g, 11.51 mmol) and TEA (6.99 g, 69.08 mmol) and the mixture was stirred at 90° C. for 16 h under a N₂ atmosphere. The reaction mixture was partitioned between water (250 mL) and EtOAc (150 mL). The organic layer was separated and washed by brine (200 mL×2). The organic layer was separated, dried (Na₂SO₄), filtered, and was concentrated under reduced pressure. The crude residue was purified (silica gel; eluting with 0˜20% EtOAc in PE) to afford compound 17-d (96 mg, 73%) as yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 7.83 (s, 1H), 3.39 (s, 2H), 2.13 (s, 3H); LCMS Mass: 168.05 (M⁺+H).

Step 3: Synthesis of 6-methylfuro[2,3-b]pyrazin-3-amine (17-e)

To a stirred solution of 17-d (1.77 g, 10.56 mmol) in DMSO/H₂O (30 mL), was added potassium hydroxide (1.19 g, 21.12 mmol) and the mixture was stirred at 100° C. for 16 h. The reaction mixture was partitioned between water (120 mL) and EtOAc (60 mL). The organic layer was separated and washed by brine (80 mL×2). The organic layer was separated, dried (Na₂SO₄), filtered, and was concentrated under reduced pressure. The crude residue was purified (silica gel; eluting with 0˜30% EtOAc in PE), to afford compound 17-e (871 mg, 55%) as yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 7.91 (s, 1H), 6.48 (m, 1H), 2.47 (s, 3H); LCMS Mass: 150.10 (M⁺+H).

Step 4: Synthesis of (S)-6-methyl-N-(1-(3-nitrophenyl)ethyl)furo[2,3-b]pyrazin-3-amine (17-f)

To a stirred solution of 17-e (871 mg, 5.83 mmol) in acetonitrile (20 mL) was added (R)-1-(3-nitrophenyl)ethyl methanesulfonate (17-b) (2.58 g, 10.50 mmol), and Cs₂CO₃ (5.70 g, 17.50 mmol). The mixture was heated to reflux overnight. The reaction mixture was concentrated and the residue was dissolved in EtOAc (20 mL). The mixture was washed by water (50 mL) and brine (50 mL). The organic layer was separated, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude residue was purified (silica gel; eluting with 0˜20% EtOAc in PE), to afford compound 17-f (156 mg, 9%) as yellow solid.

Step 5: Synthesis of (S)—N-(1-(3-aminophenyl)ethyl)-6-methylfuro[2,3-b]pyrazin-3-amine (17-g)

To a stirred solution of 17-f (156 mg, 0.523 mmol) in methanol (10 mL), was added Pd/C (15.6 mg) and the mixture was stirred at r.t for 16 h under a H2 atmosphere. The reaction mixture was filtered by celite and the filter cake was washed by methanol (10 mL). The filtrate was concentrated to dryness under reduced pressure to afford compound 17-g (110 mg, 86%) as yellow solid. LCMS Mass: 269.20 (M⁺+H).

Step 6: Synthesis of the hydrochloride salt of (S)-5-methyl-N-(3-(1-((6-methylfuro[2,3-b] pyrazin-3-yl)amino)ethyl)phenyl)nicotinamide (Compound 17)

To a stirred solution of 5-methylnicotinic acid (67 mg, 0.491 mmol) in DMF (2 mL), was added HATU (233.82 mg, 0.614 mmol) and the mixture was stirred at r.t for 20 min. Compound 17-g (110 mg, 0.409 mmol) and DIPEA (166.75 mg, 0.819 mmol) were added and the mixture stirred at r.t for 2 h. The reaction mixture was partitioned between water (40 mL) and EtOAc (20 mL). The organic layer was separated and washed by brine (20 mL×2). The organic layer was separated, dried (Na₂SO₄), filtered, and was concentrated under reduced pressure. The crude residue was purified (Preparative Reverse-Phase HPLC; eluting with 0.1% HCl in H₂O/MeOH) to afford the hydrochloride salt of Compound 17 (113 mg, 72%) as a solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.72 (s, 1H), 9.16 (s, 1H), 8.85 (d, 1H), 8.66 (s, 1H), 7.91 (s, 1H), 7.77 (t, 1H), 7.65 (d, 1H), 7.32 (d, 1H), 7.19 (d, 1H), 6.53 (d, 1H), 4.92 (q, 1H), 2.50 (s, 3H), 2.34 (d, 3H), 1.49-1.47 (d, 3H); LCMS Mass: 388.25 (M⁺+H).

Example 18

Synthesis of the hydrochloride salt of (S)-5-methyl-N-(3-(1-((2-methylthieno[3,2-b] pyridin-6-yl)amino)ethyl)phenyl)nicotinamide (Compound 18)

Step 1: Synthesis of 5-methylthiophen-3-amine hydrochloride (18-b)

To a stirred solution of tert-butyl (5-methylthiophen-3-yl)carbamate (18-a) (1.00 g, 0.004 mol) in DCM was added HCl in 1,4-dioxane (5 ml). The reaction was stirred at room temperature overnight. The reaction was concentrated directly to afford 5-methylthiophen-3-amine hydrochloride (750 mg, 74%) as a white solid (18-b), which was not purified further.

Step 2: Synthesis of 6-bromo-2-methylthieno[3,2-b]pyridine (18-c)

To a mixture of 18-b (100 mg, 0.671 mmol) and 2-bromomalonaldehyde (300 mg, 2.01 mmol) in HOAc (8 mL), was added HBr (2 mL) and PPh₃. The mixture was stirred at 130° C. overnight. After cooling to room temperature, the mixture was diluted with water and extracted with DCM (20 mL×3). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated under reduced pressure to afford compound 18-c (75 mg, 50%) as yellow oil. ¹H NMR (400 MHz, CD₃OD) δ 8.57 (s, 1H), 8.47 (s, 1H), 7.18 (s, 1H), 2.65 (s, 3H).

Step 3: Synthesis of the hydrochloride salt of (S)-5-methyl-N-(3-(1-((2-methylthieno[3,2-b]pyridin-6-yl)amino)ethyl)phenyl)nicotinamide (Compound 18)

To a stirred solution of 18-c (75 mg, 0.711 mmol) and (S)—N-(3-(1-aminoethyl)phenyl)-5-methylnicotinamide (1-g) (prepared as described in Example 1, Step 6) (70 mg, 0.274 mmol) in toluene (5 mL), was added Pd₂(dba)₃ (25 mg, 0.027), 2-(di-tert-butylphosphino)biphenyl (8.1 mg, 0.027 mmol) and t-BuONa (80 mg, 0.822 mmol). The mixture was heated to 100° C. overnight under a N₂ atmosphere. The reaction mixture was partitioned between brine (40 mL) and EtOAc (20 mL×3). The combined organic layers were separated, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude residue was purified (Preparative Reverse-Phase HPLC; eluting with 0.1% HCl in H₂O/MeOH) to afford the hydrochloride salt of Compound 18 (20 mg, 15%) as a solid. ¹H NMR (400 MHz, CD₃OD) δ 9.22 (s, 1H), 9.02 (s, 1H), 8.90 (s, 1H), 8.02 (d, J=8.3 Hz, 2H), 7.92 (s, 1H), 7.66 (d, J=7.5 Hz, 1H), 7.39 (t, J=7.4 Hz, 1H), 7.30 (d, J=7.3 Hz, 1H), 7.18 (s, 1H), 4.74-4.66 (m, 1H), 2.67 (s, 3H), 2.64 (s, 3H), 1.63 (d, J=5.3 Hz, 3H); LCMS Mass: 403.20 (M⁺+H).

Example 19

Synthesis of the hydrochloride salt of (S)-5-methyl-N-(3-(1-((6-methylthieno[2,3-b] pyrazin-3-yl)amino)ethyl)phenyl)nicotinamide (Compound 19)

Step 1: Synthesis of 6-methylthieno[2,3-b]pyrazin-3-amine (19-a)

To a stirred solution of compound 17-d (prepared as described in Example 17, Step 2) (1.5 g, 8.95 mmol) in DMF (30 mL), was added sodium sulfide pentahydrate (6.02 g, 35.8 mmol) and the mixture was stirred at 90° C. for 16 h. The reaction mixture was partitioned between water (150 mL) and EtOAc (80 mL). The organic layer was separated and washed by brine (100 mL×2). The organic layer was separated, dried (Na₂SO₄), filtered, and was concentrated under reduced pressure. The crude residue was purified (silica gel; eluting with 0˜40% EtOAc in PE) to afford compound 19-a (790 mg, 53%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃): δ 7.97 (s, 1H), 6.96 (d, 1H), 2.56 (d, 3H); LCMS Mass: 166.05 (M⁺+H).

Step 2: Synthesis of (S)-6-methyl-N-(1-(3-nitrophenyl)ethyl)thieno[2,3-b]pyrazin-3-amine (19-b)

To a stirred solution of 19-a (790 mg, 4.78 mmol) in acetonitrile (20 mL) was added 17-b (prepared as described in Example 17, Step 1) (2.35 g, 9.56 mmol) and Cs₂CO₃ (3.12 mg, 9.56 mmol). The mixture was heated to reflux for overnight. The reaction mixture was concentrated and the residue was dissolved in EtOAc (20 mL). The mixture was washed with water (50 mL) and then brine (50 mL). The organic layer was separated, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude residue was purified (silica gel; eluting with 0˜20% EtOAc in PE) to afford compound 19-b (160 mg, 11%) as a yellow oil. LCMS Mass: 315.10 (M⁺+H).

Step 3: Synthesis of (S)—N-(1-(3-aminophenyl)ethyl)-6-methylthieno[2,3-b]pyrazin-3-amine (19-c)

To a stirred solution of 19-b (135 mg, 0.43 mmol) in methanol (10 mL), was added Pd/C (13.5 mg) and the mixture was stirred at r.t for 16 h under a H2 atmosphere. The reaction mixture was filtered through Celite and the filter cake was washed by methanol (10 mL). The filtrate was concentrated to dryness under reduced pressure to afford compound 19-c (120 mg, 98%) as a yellow solid. The crude was used directly without further purification. LCMS Mass: 285.15 (M⁺+H).

Step 4: Synthesis of the hydrochloride salt of (S)-5-methyl-N-(3-(1-((6-methylthieno[2,3-b]pyrazin-3-yl)amino)ethyl)phenyl)nicotinamide (Compound 19)

To a stirred solution of 5-methylnicotinic acid (69 mg, 051 mmol) in DMF (5 mL), was added HATU (240 mg, 0.63 mmol) and the mixture was stirred at r.t for 20 min. Compound 19-c (120 mg, 0.42 mmol) and DIPEA (109 mg, 0.84 mmol) were added and the mixture stirred at r.t for 2 h. The reaction mixture was partitioned between water (50 mL) and EtOAc (20 mL). The organic layer was separated and washed by brine (20 mL×2). The organic layer was separated, dried (Na₂SO₄), filtered, and was concentrated under reduced pressure. The crude residue was purified (Preparative Reverse-Phase HPLC; eluting with 0.1% HCl in H₂O/MeOH) to afford the hydrochloride salt of Compound 19 (63 mg, 37%) as a solid. ¹H NMR (400 MHz, DMSO-d6): δ 10.86 (s, 1H), 9.23 (s, 1H), 8.91 (s, 1H), 8.80 (s, 1H), 8.02 (s, 1H), 7.80 (s, 1H), 7.69 (d, 1H), 7.33 (t, 1H), 7.21 (d, 1H), 6.95 (d, 1H), 5.04 (q, 1H), 2.52 (s, 3H), 2.46-2.45 (d, 3H), 1.50-1.38 (d, 3H). LCMS Mass: 404.20 (M⁺+H).

Example 20

Synthesis of the hydrochloride salt of (5)-5-methyl-N-(3-(1-(pyrazolo[1,5-a]pyridin-3-yl) amino)ethyl)phenyl)nicotinamide (Compound 20)

Step 1: Synthesis of (R)-1-(3-aminophenyl)ethan-1-ol (20-b)

To a stirred solution of (R)-1-(3-nitrophenyl)ethan-1-ol (20-a) (3.00 g, 17.0 mmol) in methanol (30 mL), was added Pd/C (400 mg) and the mixture was stirred at r.t for 16 h under H₂ (1 atmosphere). The reaction mixture was filtered through Celite and the filter cake was washed with methanol (20 mL). The filtrate was concentrated to dryness under reduced pressure to afford compound 20-b (2.43 g, 98%) as brown oil. The crude was used directly without further purification. ¹H NMR (400 MHz, CDCl₃) δ 7.13-7.10 (t, 1H), 6.74-6.73 (d, 1H), 6.70 (s, 1H), 6.59-6.58 (t, 1H), 4.80-4.76 (q, 1H), 2.81 (br m, 3H), 1.46-1.44 (d, 3H); LCMS Mass: 138.2 (M⁺+H).

Step 2: Synthesis of (R)—N-(3-(1-hydroxyethyl)phenyl)-5-methylnicotinamide (20-c)

To a mixture of 5-methylnicotinic acid (2.67 g, 19.4 mmol) in DCM (50 mL), was added HATU (7.40 g, 19.4 mmol) and the mixture was stirred at r.t for 20 min. Compound 20-b (2.43 g, 17.0 mmol) and DIPEA (4.57 g, 35.4 mmol) were added and the mixture stirred at r.t for 16 h. The reaction mixture was partitioned between water (200 mL) and DCM (120 mL). The organic layer was separated and washed by brine (100 mL×2). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude residue was purified (silica gel; eluting with 0˜50% EtOAc in PE) to afford compound 20-c (4.17 g, 92%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.35 (s, 1H), 8.91 (s, 1H), 8.60 (s, 1H), 8.12 (s, 1H), 7.75 (s, 1H), 7.67-7.65 (d, 1H), 7.31-7.28 (t, 1H), 7.09-7.08 (d, 1H), 5.19 (m, 1H), 4.71 (m, 1H), 2.39 (s, 3H), 1.34 (d, 3H).

Step 3: Synthesis of (R)-1-(3-(5-methylnicotinamido)phenyl)ethyl methanesulfonate (20-d)

To a stirred solution of 20-c (1.50 g, 5.85 mmol) in DCM (30 mL) at 0° C., was added methyl sulfonyl chloride (1.34 g, 11.7 mmol) and TEA (2.96 g, 29.26 mmol). The mixture was allowed to warm to r.t. and stirred for a further 16 h. The mixture was diluted with DCM (100 mL) and washed by water (200 mL), then brine (100 mL). The organic layer was separated, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude residue was purified (silica gel; eluting with 0˜50% EtOAc in PE) to afford compound 20-d (720 mg, 37%) as a yellow oil. ¹H NMR (400 MHz, CDCl₃): δ 9.08 (s, 1H), 8.57 (s, 1H), 8.15 (s, 1H), 7.82 (s, 1H), 7.67-7.64 (d, 1H), 7.37-7.33 (m, 3H), 5.11-5.06 (q, 1H), 2.70 (br s, 3H), 2.44 (s, 3H), 1.86-1.84 (d, 3H).

Step 4: Synthesis of 1,1-diphenyl-N-(pyrazolo[1,5-a]pyridin-3-yl)methanimine (20-f)

To a stirred solution of 3-bromopyrazolo[1,5-a]pyridine (20-e) (400 mg, 2.03 mmol) in toluene (15 mL), was added diphenylmethanimine (405 mg, 2.23 mmol), Pd₂(dba)₃ (186 mg, 0.20 mmol), BINAP (126 mg, 0.20 mmol), t-BuONa (585 mg, 6.09 mmol) and the mixture was stirred at 80° C. for 16 h under a N₂ atmosphere. The mixture was diluted with EtOAc (100 mL) and washed by water (200 mL), then brine (100 mL). The organic layer was separated, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude residue was purified (silica gel; eluting with 0˜20% EtOAc in PE) to afford compound 20-f (270 mg, 45%) as a yellow oil. ¹H NMR (400 MHz, DMSO-d₆): δ 7.52-7.51 (d, 1H), 7.11-7.09 (d, 1H), 6.99-6.98 (d, 2H), 6.75-6.74 (d, 3H), 6.61-6.56 (q, 3H), 6.47-6.44 (t, 3H), 6.09-6.06 (t, 1H), 5.62 (s, 1H); LCMS Mass: 298.1 (M+H⁺).

Step 5: Synthesis of pyrazolo[1,5-a]pyridin-3-amine hydrochloride (20-g)

To a stirred solution of 20-f (270 mg, 0.90 mmol) in methanol (10 mL), was added 2M HCl aqueous (5 mL) and the mixture was stirred at r.t for 2 h. The mixture was concentrated to afford compound 20-g (183 mg) as red solid that was not further purified. LCMS Mass: 134.1 (M⁺+H).

Step 6: Synthesis of the hydrochloride salt of (S)-5-methyl-N-(3-(1-(pyrazolo[1,5-a] pyridin-3-ylamino)ethyl)phenyl)nicotinamide (Compound 20)

To a stirred solution of 20-g (84 mg, 0.63 mmol) in acetonitrile (5 mL) was added 20-d (316 mg, 0.94 mmol), K₂CO₃ (261 mg, 1.89 mmol). The mixture was heated to reflux overnight. The reaction mixture was concentrated and the residue was dissolved in EtOAc (20 mL). The mixture was washed with water (50 mL), then brine (50 mL). The organic layer was separated, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude residue was purified (Preparative Reverse-Phase HPLC; eluting with 0.1% HCl in H₂O/MeOH) to afford the hydrochloride salt of Compound 20 (15 mg, 6%) as a solid. ¹H NMR (400 MHz, CD₃OD): δ 9.23 (s, 1H), 9.03 (s, 1H), 8.92 (s, 1H), 8.55-8.54 (d, 1H), 8.02 (s, 1H), 7.92 (s, 1H), 7.76-7.74 (d, 1H), 7.50-7.48 (d, 1H), 7.42-7.38 (t, 1H), 7.33-7.29 (t, 1H), 7.21-7.19 (d, 1H), 7.00-6.97 (t, 1H), 4.88 (s, 1H), 2.68 (s, 3H), 1.89-1.87 (d, 3H); LCMS Mass: 372.2 (M⁺+H).

Example 21

Synthesis of (S)—N-(3-(1-((1-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridin-4-yl) amino)ethyl)phenyl)nicotinamide (Compound 21)

Step 1: Synthesis of 4-bromo-1-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c]pyridine (21-d)

To a stirred solution of 4-bromo-2H-pyrazolo[3,4-c]pyridine (21-a) (250 mg, 1.27 mmol) in 2% Tween® 20/H₂O (3 mL) at rt, was added 4-iodo-1-methyl-(21-b) (317 mg, 1.52 mmol), CuI (161 mg, 0.254 mmol), Cs₂CO₃ (1.03 g, 3.17 mmol), and compound 21-c (181 mg, 1.27 mmol). The mixture was heated to 60° C. under N₂ for 2 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with saturated aq. NH₄Cl and then dried (MgSO₄), filtered, and concentrated under reduced pressure. The crude residue was purified (silica gel; eluting with 0-100% EtOAc in heptane) to afford compound 21-d (120 mg, 34%). LCMS Mass: 279.98 (M⁺+H).

Step 2: Synthesis of (S)—N-(3-(1-((1-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-c] pyridin-4-yl)amino)ethyl)phenyl)nicotinamide (Compound 21)

To a stirred solution of compound 21-d (120 mg, 0.431 mmol) in 1,4-dioxane (5 mL) at rt, was added (S)—N-(3-(1-aminoethyl)phenyl)-5-methylnicotinamide (1-g) (prepared as described in Example 1, Step 6) (100 mg, 0.392 mmol), Pd(dba)2 (23 mg, 0.039 mmol), Xantphos (23 mg, 0.039 mmol) and t-BuONa (2M, 392 μL). The mixture was heated to reflux under N₂ for 2 h. The mixture was diluted with EtOAc and washed with saturated aq. NH₄Cl and brine. The organic phase was dried (MgSO₄), filtered, and concentrated under reduced pressure. The residue was purified (Preparative HPLC; eluting with 0.05% TFA in H2O/acetonitrile) to afford Compound 21 (25 mg, 11%). 1H NMR (DMSO-d6, 300 MHz) δ 10.42 (s, 1H), 8.8-9.0 (m, 2H), 8.5-8.8 (m, 2H), 8.42 (s, 1H), 7.9-8.3 (m, 4H), 7.62 (d, 1H, J=8.8 Hz), 7.2-7.4 (m, 3H), 4.94 (br t, 1H, J=6.6 Hz), 3.95 (s, 3H), 2.39 (s, 3H), 1.64 (d, 3H, J=6.6 Hz); LCMS Mass: 453.36 (M++H).

Example 22

Synthesis of the hydrochloride salt of (5)-5-methyl-N-(3-(1-((2-methylfuro[3,2-b]pyridin-6-yl)amino)ethyl)phenyl)nicotinamide (Compound 22)

Step 1: Synthesis of 6-bromo-2-methylfuro[3,2-b]pyridine (22-b)

To a stirred solution of 5-bromo-2-iodopyridin-3-ol (22-a) (1.00 g, 0.003 mol) and TEA (1.01 g, 0.009 mol) in THF, was added Propyne (0.67 g, 0.015 mol), CuI (0.95 g, 0.005 mol) and Pd(PPh3)2Cl2 (25 mg, 0.0003 mol). The reaction mixture was stirred at room temperature under a nitrogen atmosphere overnight. The reaction was diluted with water, and extracted with EtOAc. The organic phase was washed with water and brine, then concentrated and purified by Prep-TLC to afford 6-bromo-2-methylfuro[3,2-b]pyridine (22-b) (412 mg, 58%) as a yellow oil.

Step 2: Synthesis of the hydrochloride salt of (S)-5-methyl-N-(3-(1-((2-methylfuro[3,2-b] pyridin-6-yl)amino)ethyl)phenyl)nicotinamide (Compound 22)

To a stirred solution of 22-b (150 mg, 0.711 mmol) and (S)—N-(3-(1-aminoethyl)phenyl)-5-methylnicotinamide (1-g) (prepared as described in Example 1, Step 6) (70 mg, 0.274 mmol) in toluene (5 mL) was added Pd₂(dba)₃ (25 mg, 0.027), 2-(di-tert-butylphosphino)biphenyl (8.1 mg, 0.027 mmol) and t-BuONa (80 mg, 0.822 mmol). The mixture was heated to 100° C. overnight under a nitrogen atmosphere. The reaction mixture was partitioned between brine (50 mL) and EtOAc (50 mL). The organic layer was separated, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude residue was purified (Preparative Reverse-Phase HPLC; eluting with 0.1% HCl in H₂O/MeOH) to afford the hydrochloride salt of Compound 22 (50 mg, 47%) as a solid. ¹H NMR (400 MHz, DMSO-d₆) δ 10.79 (s, 1H), 9.14 (s, 1H), 8.82 (s, 1H), 8.60 (s, 1H), 7.96 (s, 1H), 7.88 (s, 1H), 7.65 (d, J=8.9 Hz, 2H), 7.35 (t, J=7.8 Hz, 1H), 7.23 (d, J=7.7 Hz, 1H), 6.85 (s, 1H), 4.72-4.67 (m, 1H), 2.48-2.50 (2×s, 6H), 1.51 (d, J=6.6 Hz, 3H). LCMS 387.3 (M⁺+H).

Example 23

Synthesis of the hydrochloride salt of (S)—N-(3-(1-((1H-imidazo[4,5-b]pyrazin-5-yl) amino)ethyl)phenyl)-5-methylnicotinamide (Compound 23)

Step 1: Synthesis of 5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b] pyrazine (23-b)

To a stirred solution of 5-bromo-1H-imidazo[4,5-b]pyrazine (23-a) (300 mg, 1.515 mmol) and NaH (73 mg, 3.03 mmol) in DMF, was added SEMCl (505 mg, 3.03 mmol) and the mixture was stirred at r.t. for 1.5 h. The mixture was extracted with DCM (30 mL×3) and the combined organic layers were combined and dried (Na₂SO₄), filtered, and was concentrated under reduced pressure. The crude was purified (Preparative TLC; eluting with DCM:MeOH=20:1) to afford compound 23-b (320 mg, 64%) as a brown solid. ¹H NMR (400 MHz, CDCl₃) δ 8.46-8.41 (m, 2H), 5.64 (d, J=4.6 Hz, 2H), 3.60 (q, J=8.5 Hz, 2H), 0.91 (ddd, J=9.1, 7.7, 5.4 Hz, 2H), −0.06 (dd, J=4.3, 1.1 Hz, 9H); LCMS Mass: 329 (M⁺+H).

Step 2: Synthesis of -5-methyl-N-(3-(1-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyrazin-5-yl)amino)ethyl)phenyl)nicotinamide (23-c)

To a stirred solution of 23-b (100 mg, 0.3 mmol) and (S)—N-(3-(1-aminoethyl)phenyl)-5-methylnicotinamide (1-g) (prepared as described in Example 1, Step 6) (85.6 mg, 0.335 mmol) in toluene, was added Pd₂(dba)₃ (27.5 mg, 0.03 mmol), BINAP (18.7 mg, 0.03 mmol) and K₃PO₄ (191 mg) and the mixture was stirred at 100° C. under a N₂ atmosphere overnight. The reaction mixture was partitioned between brine (20 mL) and EtOAc (20 mL). The organic layer was separated, dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude residue was purified (Preparative TLC; eluting with DCM:MeOH=20:1) to afford afford Compound 23-c (91 mg, 60%) as a brown solid. LCMS Mass: 504.2 (M⁺+H).

Step 3: Synthesis of the Hydrochloride Salt of (S)—N-(3-(1-((1H-imidazo[4,5-b]pyrazin-5-yl)amino)ethyl)phenyl)-5-methylnicotinamide (Compound 23)

To a solution of 23-c (91 mg, 0.18 mmol) in 4 M HCl (3 mL) and MeOH (3 mL) was stirred at 80° C. for 3 h. The mixture was concentrated and was purified (Preparative Reverse-Phase HPLC; eluting with 0.1% HCl in H₂O/MeOH) to afford the hydrochloride salt of Compound 23 (15 mg, 22%) as a yellow solid. ¹H NMR (400 MHz, CD₃OD) δ 9.22 (s, 1H), 9.13 (s, 1H), 9.01 (s, 1H), 8.90 (s, 1H), 8.14 (s, 1H), 7.90 (t, J=1.8 Hz, 1H), 7.64-7.59 (m, 1H), 7.35 (t, J=7.8 Hz, 1H), 7.27 (d, J=7.6 Hz, 1H), 5.13 (q, J=6.9 Hz, 1H), 2.67 (s, 3H), 1.62 (d, J=6.9 Hz, 3H); LCMS Mass: 374.2 (M⁺+H).

Example 24

Synthesis of the hydrochloride salt of ((S)—N-(3-(1-((2-ethyl-3H-imidazo[4,5-b]pyridin-6-yl)amino)ethyl)phenyl)-5-methylnicotinamide (Compound 24)

Step 1: Synthesis of 6-bromo-2-ethyl-3H-imidazo[4,5-b]pyridine (24-b)

A solution of 5-bromopyridine-2,3-diamine (24-a) (500 mg, 2.66 mmol) in propionic acid (5 mL) was stirred at 140° C. overnight. The reaction mixture was concentrated and was purified by (silica gel; eluting with DCM:MeOH=20:1) to afford 24-b (390 mg, 65%) as a brown solid. ¹H NMR (400 MHz, Methanol-d₄) δ 8.35 (d, J=2.1 Hz, 1H), 8.07 (d, J=2.1 Hz, 1H), 2.96 (q, J=7.6 Hz, 2H), 1.41 (t, J=7.6 Hz, 3H); LCMS Mass: 226 (M⁺+H).

Step 2: Synthesis of 6-bromo-2-ethyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo [4,5-b]pyridine (24-c)

To a stirred solution of 24-b (200 mg, 0.89 mmol) and NaH (43 mg, 1.78 mg) in DMF (5 mL) at r.t., was added SEMCl (296.4 mg, 1.78 mmol) and the mixture was stirred at r.t. for 1.5 h. The mixture was extracted with DCM (30 mL×3). The combined organic layers were dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude was purified (Preparative TLC; eluting with DCM:MeOH=20:1) to afford compound 24-c (180 mg, 57%) as a brown solid. ¹H NMR (400 MHz, Chloroform-d) δ 8.54 (d, J=2.1 Hz, 1H), 7.85 (d, J=2.1 Hz, 1H), 5.44 (s, 2H), 3.55-3.49 (m, 2H), 2.99-2.95 (q, J=7.5 Hz, 2H), 1.49 (t, J=7.5 Hz, 3H), 0.93-0.88 (m, 2H), −0.03 (s, 9H). LCMS Mass: 356 (M⁺+H).

Step 3: Synthesis of (S)—N-(3-(1-((2-ethyl-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)amino)ethyl)phenyl)-5-methylnicotinamide (24-d)

To a stirred solution of 24-c (100 mg, 0.28 mmol) and (S)—N-(3-(1-aminoethyl)phenyl)-5-methylnicotinamide (1-g) (prepared as described in Example 1, Step 6) (79.1 mg, 0.31 mmol) in toluene was added Pd₂(dba)₃ (25.6 mg, 0.028 mmol), Jonhphos (8.36 mg, 0.028 mmol) and t-BuONa (in THF) (53.8 mg, 0.56 mmol). The mixture was stirred at 100° C. under a N₂ atmosphere overnight. The mixture was extracted with DCM (20 mL×3). The organic phase was combined and dried (Na₂SO₄), filtered, and concentrated under reduced pressure. The crude was purified (Preparative TLC; eluting with DCM:MeOH=20:1) to afford compound 24-d (45 mg, 30%) as a brown solid. LCMS Mass: 531.0 (M⁺+H).

Step 4: Synthesis of the hydrochloride salt of ((S)—N-(3-(1-((2-ethyl-3H-imidazo[4,5-b] pyridin-6-yl)amino)ethyl)phenyl)-5-methylnicotinamide (Compound 24)

A stirred solution of 24-d (45 mg, 0.085 mmol), 6M HCl (2 mL), and MeOH was heated at 80° C. for 3 h. The mixture was concentrated under reduced pressure and the residue was purified (Preparative Reverse-Phase HPLC; eluting with 0.1% HCl in H₂O/MeOH) to afford the hydrochloride salt of Compound 24 (5 mg, 15%) as a yellow solid. ¹H NMR (400 MHz, Methanol-d₄) δ 9.11 (s, 1H), 8.91 (s, 1H), 8.80 (s, 1H), 8.03 (d, J=2.3 Hz, 1H), 7.79 (t, J=1.8 Hz, 1H), 7.55 (dd, J=7.8, 1.8 Hz, 1H), 7.28 (t, J=7.8 Hz, 1H), 7.18 (d, J=7.6 Hz, 1H), 6.97 (d, J=2.4 Hz, 1H), 4.51 (q, J=6.7 Hz, 1H), 2.99 (q, J=7.6 Hz, 2H), 2.57 (s, 3H), 1.53 (d, J=6.6 Hz, 3H), 1.33 (t, J=7.5 Hz, 3H); LCMS Mass: 401.3 (M⁺+H).

Example 25

Synthesis of (S)—N-(3-(1-((2-ethyl-2H-pyrazolo[3,4-b]pyrazin-6-yl)amino)ethyl)phenyl)-2-(5-methylpyridin-2-yl)acetamide (Compound 25)

To a stirred solution of 2-(5-methyl-2-pyridyl)acetic acid (27 mg, 0.177 mmol) in DMA (1 mL) at rt, was added HATU (74 mg, 0.195 mmol) and DIPEA (35 mg, 46.8 mmol). The mixture was stirred at rt for 10 min. Compound 9-e (prepared as described in Example 9, Step 3) (50 mg, 0.177 mmol) was added and the reaction was stirred at rt for 16 h. The mixture was purified (Preparative HPLC; eluting with 0.1% FA in H₂O/acetonitrile) to give an off-white solid after lyophilization. The solid was dissolved in acetonitrile (2 mL) and 4 M HCl in 1,4-dioxane (0.186 mmol, 8.5 uL) was added. The reaction was stirred at rt for 1 h and lyophilized to afford Compound 25 (40 mg, 50%) as a light yellow solid. ¹H NMR (300 MHz, DMSO-d6) δ ppm 10.44 (s, 1H) 8.68 (s, 1H) 8.32 (s, 1H) 8.21 (br d, J=7.24 Hz, 1H) 8.03 (s, 1H) 7.97 (br d, J=6.79 Hz, 1H) 7.78 (d, J=8.16 Hz, 1H) 7.61 (s, 1H) 7.47 (br d, J=8.62 Hz, 1H) 7.27 (t, J=7.93 Hz, 1H) 7.12 (d, J=7.52 Hz, 1H) 5.04 (quin, J=6.79 Hz, 1H) 4.22 (q, J=7.40 Hz, 2H) 4.11 (s, 2H) 2.43 (s, 3H) 1.47 (d, J=6.97 Hz, 3H) 1.41 (t, J=7.24 Hz, 3H); LCMS 416.4 (M⁺+H).

Examples 26-751

Compound Nos. 2-751 listed in Table 6 below were prepared according to the methods described in Schemes 1 through 3 and Examples 1 through 25, as shown above, using the appropriately substituted or modified intermediates.

TABLE 6
COMPOUNDS PREPARED ACCORDING TO SYNTHETIC SCHEMES 1 THROUGH 3
			Observed
Cmpd			Mass
No	Structure	MW	(LCMS m/z)
26		384.43	385.19
27		412.48	413.24
28		412.48	413.14
29		400.44	401.13
30		418.44	419.12
31		369.42	370.18
32		413.47	414.21
33		413.47	414.25
34		451.44	452.23
35		451.44	453.03
36		419.43	420.22
37		417.89	420.04
38		397.47	398.15
39		462.34	464.05
40		401.44	402.41
41		423.51	424.24
42		463.53	464.25
43		399.44	400.11
44		387.48	388.27
45		389.45	390.14
46		426.47	428.03
47		427.46	427.80
48		427.46	428.80
49		429.50	431.00
50		425.49	426.20
51		425.49	426.30
52		404.4	405.20
53		404.4	405.20
54		447.47	448.30
55		427.51	428.30
56		443.51	444.20
57		437.5	438.2
58		427.5	428.3
59		461.49	462.2
60		427.46	428.2
61		441.49	442.2
62		441.49	442.3
63		455.49	456.2
64		430.46	432.4
65		440.5	441.3
66		441.53	442.5
67		428.44	429.1
68		430.46	431.1
69		431.45	432.3
70		429.47	430.2
71		428.49	429.1
72		442.47	443.3
73		426.47	427.2
74		440.5	441.9
75		443.46	443.2
76		442.47	443.3
77		427.46	428.1
78		442.47	444.1
79		445.54	446.1
80		385.46	386.14
81		521.61	522.10
82		400.48	401.30
83		416.47	417.25
84		430.5	431.25
85		485.58	486.35
86		452.51	453.30
87		508.57	509.10
88		522.6	523.10
89		386.45	387.13
90		373.41	374.30
91		387.45	388.00
92		389.42	390.00
93		399.46	400.20
94		419.46	420.25
95		417.47	418.25
96		413.49	414.30
97		415.46	416.25
98		441.42	442.20
99		427.39	428.20
100		390.45	391.20
101		401.47	402.25
102		441.41	442.15
103		423.42	424.71
104		403.44	404.73
105		413.49	414.25
106		403.45	404.25
107		431.5	432.30
108		433.49	434.25
109		407.86	408.22
110		427.51	428.00
111		452.31	454.10
112		417.46	419.00
113		397.43	398.90
114		429.48	430.25
115		441.41	442.15
116		413.49	414.25
117		398.43	399.00
118		439.43	440.20
119		457.42	458.20
120		402.46	403.10
121		428.5	429.00
122		403.45	404.00
123		427.51	428.30
124		455.44	456.20
125		455.44	456.15
126		455.44	456.15
127		412.46	413.15
128		417.47	418.25
129		431.5	432.20
130		416.49	417.25
131		391.41	392.20
132		388.43	389.30
133		392.48	393.15
134		428.46	429.20
135		412.9	412.90
136		418.52	419.15
137		446.45	447.15
138		393.47	394.00
139		447.44	448.15
140		419.51	420.25
141		429.45	430.00
142		405.45	406.15
143		419.48	420.25
144		403.44	404.20
145		405.45	406.15
146		376.41	377.20
147		404.47	405.20
148		418.49	419.40
149		412.40	413.94
150		402.45	403.86
151		416.48	417.82
152		416.48	417.97
153		390.44	391.66
154		408.43	409.70
155		412.40	413.98
156		404.47	405.62
157		418.49	419.50
158		426.42	428.00
159		432.52	433.25
160		444.41	445.15
161		404.47	405.20
162		418.49	419.25
163		432.52	433.25
164		444.41	445.20
165		418.49	419.30
166		432.52	433.25
167		432.52	433.30
168		376.42	377.25
169		426.47	427.20
170		405.44	406.20
171		405.44	406.15
172		405.44	406.00
173		405.44	406.10
174		388.44	389.10
175		388.44	389.15
176		401.47	402.25
177		413.47	414.10
178		427.51	428.25
179		429.48	430.30
180		457.53	458.29
181		427.51	428.30
182		443.51	444.30
183		437.45	438.25
184		390.47	391.15
185		509.56	510.40
186		453.5	454.3
187		437.88	438.5
188		404.44	405.1
189		420.44	421.5
190		437.44	438.8
191		424.86	425.5
192		405.43	407.1
193		411.46	413.3
194		430.5	432.1
195		485.58	486.6
196		430.5	431.5
197		509.35	511.3
198		444.53	446.38
199		444.48	445.2
200		421.88	422.7
201		431.46	432.3
202		457.41	458.2
203		432.47	433.1
204		415.49	416.2
205		433.46	434.3
206		401.46	402.3
207		401.46	402.2
208		498.62	499.6
209		485.58	486.9
210		416.47	417.6
211		430.46	432.1
212		431.45	433.03
213		434.47	435.3
214		430.46	431.1
215		430.46	431.1
216		427.5	428.3
217		460.48	461.1
218		419.5	420.5
219		418.51	419.5
220		450.51	451.1
221		451.5	452.6
222		432.54	433.6
223		433.53	435
224		418.51	419.6
225		419.5	420.5
226		450.51	452
227		451.5	452.8
228		516.61	517.3
229		459.54	460.3
230		431.49	432.2
231		429.52	430.2
232		462.52	463.3
233		415.49	416.3
234		400.48	401.1
235		448.5	449.2
236		452.96	453.5
237		501.65	502.6
238		530.69	531.6
239		486.57	487.6
240		402.45	403.6
241		389.41	390.1
242		417.46	418.4
243		499.61	500.6
244		502.63	503.6
245		413.47	414.2
246		412.49	413.3
247		471.43	472.2
248		445.52	446.3
249		437.88	438.1
250		405.43	406.6
251		414.5	415.3
252		417.46	418.2
253		403.44	404.2
254		472.54	473.3
255		458.51	459.2
256		516.55	517.2
257		474.51	475.3
258		472.54	473.3
259		484.55	485.4
260		488.61	489.5
261		460.48	461.5
262		479.96	480.2
263		486.56	487.3
264		543.62	544.3
265		441.49	442.3
266		473.53	474.2
267		542.54	543.3
268		527.62	528.4
269		464.61	465.1
270		527.62	528.3
271		449.51	450.1
272		450.49	451.1
273		450.49	451.2
274		387.44	388.22
275		427.51	428.30
276		429.53	430.30
277		419.46	420.25
278		486.58	487.30
279		417.47	418.20
280		447.52	448.30
281		421.89	422.20
282		471.44	472.25
283		427.51	428.00
284		455.45	456.20
285		417.47	418.20
286		431.5	432.30
287		445.53	446.25
288		469.47	470.20
289		426.48	427.25
290		431.5	432.20
291		432.55	433.10
292		442.49	443.20
293		426.92	427.20
294		407.5	407.90
295		461.47	461.90
296		433.53	434.25
297		404.48	405.30
298		422.47	423.20
299		416.49	417.30
300		430.52	431.20
301		418.51	419.20
302		445.5	446.20
303		489.43	490.20
304		471.44	472.25
305		418.51	419.25
306		444.47	445.20
307		425.49	426.20
308		479.46	480.10
309		451.52	452.25
310		422.47	423.10
311		440.46	441.30
312		434.48	435.30
313		436.5	437.30
314		445.52	446.3
315		471.55	472.3
316		463.51	464.2
317		449.48	450.3
318		489.54	490.3
319		443.47	444.3
320		474.53	475.3
321		441.53	442.3
322		459.52	460.4
323		470.57	471.3
324		472.36	474.1
325		423.49	424.2
326		462.57	463.3
327		459.54	460.3
328		415.49	416.3
329		419.45	420.9
330		418.47	420.16
331		425.49	426.9
332		434.92	435.3
333		444.53	445.7
334		467.53	468.3
335		487.45	488.2
336		488.56	489.4
337		434.47	435.2
338		437.52	438.2
339		478.57	479.3
340		436.53	437.2
341		421.52	422.3
342		473.55	474.3
343		438.88	439.8
344		418.47	420.13
345		434.92	435.7
346		411.46	413.36
347		438.88	439.4
348		444.53	445.3
349		435.54	436.2
350		480.36	480.2
351		500.59	501.3
352		456.54	458.07
353		451.47	453.42
354		479.96	480.8
355		405.43	407.1
356		451.91	452.7
357		461.37	464.4
358		486.57	487.3
359		434.47	436.1
360		506	508.2
361		519.04	519.4
362		437.52	438.1
363		423.49	424.1
364		436.53	437.3
365		436.49	437.2
366		489.54	490.9
367		502.59	503.4
368		376.41	378.1
369		390.44	392.2
370		450.52	451.1
371		458.56	459.3
372		472.54	473.3
373		443.54	444.4
374		485.58	486.4
375		456.54	457.4
376		498.62	499.4
377		430.5	431.3
378		571.67	572.4
379		448.5	449.3
380		430.5	431.2
381		437.52	438.2
382		505.49	506.2
383		435.91	438.2
384		443.54	444.3
385		442.52	443.3
386		485.58	486.4
387		499.61	500.4
388		470.57	471.3
389		490	490.3
390		519.52	520.2
391		520.51	521.2
392		474.56	475.7
393		416.48	417.3
394		430.5	431.3
395		444.53	445.7
396		499.61	500.6
397		471.56	472.4
398		461.58	462.3
399		491.46	492.2
400		465.53	467.4
401		428.49	429
402		512.65	513.3
403		499.61	500.1
404		483.61	484.6
405		457.57	458.2
406		528.65	529.8
407		486.45	487.2
408		415.49	416.3
409		522.52	523.2
410		474.53	475.3
411		490.53	491.2
412		516.61	517.25
413		537.03	537.1
414		511.62	512.2
415		532.04	532.2
416		520.02	520.2
417		533.07	533.4
418		504.03	504.2
419		419.45	420.2
420		464.95	465.1
421		520.03	520.2
422		553.58	554.3
423		566.62	567.3
424		553.58	554.2
425		537.58	538.3
426		522.02	522.35
427		538.02	538.2
428		571.57	572.3
429		551.06	551.4
430		552.04	552.3
431		585.59	586.2
432		517.6	518.2
433		570.58	571.2
434		449.51	450.1
435		480.56	481.1
436		552.59	553.2
437		504.89	505.7
438		488.89	489.6
439		468.47	470
440		484.47	485.9
441		473.54	475
442		466.44	467.5
443		555.57	556.3
444		584.61	585.3
445		571.57	572.3
446		517.6	518.3
447		531.62	532.4
448		450.49	451.5
449		441.53	442.3
450		486.9	487.1
451		418.47	419.1
452		484.47	485.6
453		454.45	455.6
454		436.46	437.5
455		469.46	470.15
456		538.02	538.1
457		530.64	531.2
458		489.88	490.2
459		523.43	524.1
460		525.64	526.1
461		531.6	532.2
462		538.68	538.4
463		450.49	451.3
464		522.02	522.3
465		512.61	513.2
466		547.05	548.1
467		533.02	533.1
468		515.58	516.1
469		501.6	503.2
470		501.6	502.1
471		499.61	500.4
472		526.63	526.3
473		524.66	526.3
474		533.61	534.5
475		538.68	539.5
476		533.61	534.5
477		495.62	496.5
478		527.66	529.2
479		526.63	527.5
480		539.67	540.3
481		539.67	540.5
482		499.61	550.15
483		520.02	520.3
484		522.02	522.1
485		469.58	470.1
486		490	490.3
487		506	506
488		522.02	522.1
489		551.06	551.1
490		550.03	550.15
491		491.42	492.2
492		491.42	492.1
493		501.6	502.2
494		520.02	520.1
495		507.99	508.1
496		485.58	486.1
497		487.57	488.2
498		526.67	527.3
499		525.64	526.2
500		516.57	517.2
501		414.5	415.2
502		538.68	539.5
503		533.02	533.1
504		548.63	549.3
505		537.65	538.2
506		547.6	548.2
507		452.91	453.4
508		448.95	450.6
509		429.52	430.2
510		415.49	416.5
511		467.47	469.1
512		433.48	435.2
513		458.56	459.5
514		513.64	514.5
515		470.57	471.4
516		483.49	484.1
517		512.61	513.2
518		565.08	565.2
519		522.02	522.2
520		552.04	552.2
521		552.04	552.2
522		497.63	498.5
523		513.63	514.3
524		526.67	527.7
525		501.6	502.1
526		531.62	532.1
527		531.62	532.2
528		544.66	545.2
529		373.42	374.20
530		391.44	392.20
531		403.45	404.20
532		423.43	424.20
533		407.86	408.15
534		441.42	442.20
535		413.49	414.20
536		457.42	458.20
537		417.47	418.30
538		455.45	456.20
539		428.46	429.15
540		447.44	448.20
541		419.51	420.25
542		405.46	406.25
543		402.46	403.20
544		408.44	409.25
545		390.45	391.20
546		412.4	413.20
547		444.42	445.25
548		444.42	445.25
549		452.32	454.20
550		407.86	408.1
551		453.5	454.2
552		372.42	373.15
553		390.44	391.20
554		404.46	405.20
555		402.46	403.00
556		422.44	423.20
557		440.43	441.00
558		412.5	413.10
559		454.46	455.00
560		427.47	427.90
561		411.42	412.20
562		443.43	444.20
563		452.52	453.30
564		400.48	401.3
565		406.87	407.2
566		468.51	469.3
567		443.42	444.2
568		456.42	457.1
569		412.49	413.2
570		416.47	417.2
571		418.51	419.1
572		446.45	447.1
573		401.46	402.2
574		389.45	390.2
575		407.44	408.2
576		520.51	521.3
577		521.62	522.3
578		484.58	485.2
579		482.54	483.3
580		506.48	507.2
581		467.53	468.3
582		512.51	513.2
583		458.54	459.3
584		509.49	510.3
585		507.59	508.3
586		468.51	469.3
587		481.55	482.3
588		469.54	470.3
589		469.46	470.3
590		469.46	470.3
591		449.51	450.3
592		449.51	450.2
593		450.49	451.3
594		398.46	399.2
595		424.4	425.2
596		442.39	443.2
597		419.45	420.3
598		401.46	402.2
599		416.45	417.1
600		372.42	373.1
601		412.49	413.2
602		452.51	453.3
603		453.5	454.1
604		372.43	373.10
605		373.42	374.20
606		388.49	389.10
607		389.48	390.15
608		455.48	456.2
609		432.54	433.2
610		429.54	430.1
611		473.47	474.1
612		447.53	448.2
613		450.53	451.1
614		459.4	460
615		475.46	476
616		501.5	502
617		445.37	446.1
618		511.44	512
619		473.42	474.4
620		489.49	490.1
621		434.92	435.9
622		414.5	416.08
623		419.45	420.2
624		401.46	402.2
625		418.47	420.2
626		448.49	450.6
627		452.91	455.4
628		486.46	488.6
629		390.44	391.1
630		468.47	470.26
631		452.91	454.1
632		432.49	434.2
633		400.48	401.8
634		432.49	433.3
635		452.91	453.2
636		486.46	487.2
637		418.47	419.3
638		418.47	419.1
639		432.49	433.5
640		436.46	437.1
641		452.91	453.2
642		469.46	470.5
643		436.46	437.1
644		401.46	402
645		401.46	402.1
646		530.64	531.2
647		419.45	420.4
648		436.46	438.3
649		437.44	438.1
650		453.9	454.1
651		433.48	434.1
652		433.48	434.1
653		437.44	438.2
654		487.45	488.1
655		459.52	460.1
656		433.48	434.1
657		449.94	450.1
658		459.52	460.2
659		433.48	434.2
660		429.52	430.2
661		483.49	484.2
662		455.55	456.2
663		453.9	454.2
664		429.52	430.1
665		455.55	455.2
666		429.52	430.1
667		473.54	474.5
668		467.93	468.1
669		469.58	470.3
670		463.96	464.1
671		473.54	474.3
672		469.58	470.1
673		449.94	450.2
674		451.47	452.1
675		447.51	448.1
676		435.91	436.2
677		449.94	450.2
678		415.49	416.1
679		429.52	430.1
680		526.67	527.3
681		435.91	436.1
682		441.53	442.3
683		479.52	480.3
684		440.5	441.1
685		487.45	488.2
686		433.48	434.3
687		447.51	448.2
688		469.46	470.1
689		433.48	434.3
690		475.56	476.4
691		477.51	478.2
692		483.49	484.1
693		429.52	430.1
694		443.54	444.1
695		449.94	450.3
696		463.96	464.2
697		431.49	432.1
698		445.52	446.3
699		433.48	434.1
700		432.49	433.1
701		432.49	433.1
702		450.48	451.1
703		477.53	478.2
704		444.46	445.1
705		473.57	474.1
706		451.47	452.1
707		447.51	448.1
708		473.54	474.1
709		443.54	444.1
710		457.57	458.1
711		455.55	456.2
712		429.52	430.1
713		443.54	444.1
714		387.44	388.2
715		431.49	432.2
716		429.52	430.1
717		443.54	444.1
718		441.53	442.2
719		455.55	456.2
720		457.53	458.1
721		471.55	472.1
722		541.69	542.4
723		455.55	456.2
724		451.47	452.2
725		491.54	492.3
726		545.65	546.2
727		512.65	513.4
728		469.58	470.1
729		387.45	388.25
730		388.44	389.30
731		402.46	403.25
732		416.48	417.3
733		433.51	434.2
734		456.54	457.3
735		416.48	417.2
736		470.45	471.1
737		442.52	443.2
738		431.49	432.2
739		445.52	446.3
740		447.53	448.3
741		445.52	446.1
742		459.55	460.3
743		445.52	446.3
744		387.44	389.46
745		451.52	452.10
746		451.52	452.20
747		386.45	387.22
748		451.52	452.29
749		372.42	373.17
750		386.45	387.23
751		466.54	467.29

Example 752

Biological Assays

Human PDGFRα Biochemical Inhibition Assay

The compounds described herein were tested for the ability to inhibit activity of PDGFRα which was achieved via use of an off-chip Mobility Shift Assay (MSA). Human PDGFRα, cytoplasmic domain [550-1089 (end) amino acids of accession number NP_006197.1 (SEQ ID NO: 1)] was expressed as N-terminal GST-fusion protein (89 kDa) using baculovirus expression system (SEQ ID NO: 2). GST-PDGFRα was purified by using glutathione sepharose chromatography.

Test compounds were dissolved in and diluted with dimethylsulfoxide (DMSO) to achieve 1 mM concentration. Then the solution was further diluted 25-fold with assay buffer to make the final test compound solution. The reference compound, Staurosporine, used as the assay positive control was prepared similarly. The 4× compound solution/substrate (CSKtide, 1000 nM)/ATP (Km ATP)/Mg Metal (5 mM) was prepared with kit buffer (20 mM HEPES, 0.01% Triton X-100, 5 mM DTT, pH 7.5), and 2× kinase solution was prepared with assay buffer (20 mM HEPES, 0.01% Triton X-100, 1 mM DTT, pH 7.5). The 5 μL of 4× compound solution, 5 mL of 4× Substrate/ATP/Metal solution, and 10 mL of 2× kinase solution were mixed and incubated in a well of polypropylene 384 well microplate for 1 hour at room temperature. 70 mL of Termination Buffer (QuickScout Screening Assist MSA; Carna Biosciences) was added to the well. The reaction mixture was applied to LabChip™ system (Perkin Elmer), and the product and substrate peptide peaks were separated and quantitated. The kinase reaction was evaluated by the product ratio calculated from peak heights of product(P) and substrate(S) peptides (P/(P+S)). The readout value of reaction control (complete reaction mixture) was set as a 0% inhibition, and the readout value of background (Enzyme(—)) was set as a 100% inhibition, then the percent inhibition of each test solution was calculated.

IC₅₀ values were calculated from concentration vs. % Inhibition curves by fitting to a four parameter logistic curve, and are provided for the compounds of the present invention in Table 5, below. With respect to PDGFRα activity: “+++” denotes an IC₅₀ of less than 300 nM; “++” denotes an IC₅₀ of from 300 nM to less than 1000 nM; and “+” denotes an IC₅₀ of 1000 nM or more.

Human PDGFRβ Biochemical Inhibition Assay

The compounds described herein were tested for the ability to inhibit activity of PDGFRβ which was achieved via use of an off-chip Mobility Shift Assay (MSA). Human PDGFRβ, cytoplasmic domain [557-1106 (end) amino acids of accession number NP_002600.1 (SEQ ID NO: 3)] was expressed as N-terminal GST-fusion protein (88 kDa) using baculovirus expression system (SEQ ID NO: 4). GST-PDGFRβ was purified by using glutathione sepharose chromatography. Test compounds were dissolved in and diluted with dimethylsulfoxide (DMSO) to achieve 1 mM concentration. Then the solution was further diluted 25-fold with assay buffer to make the final test compound solution. The reference compound, Staurosporine, used as the assay positive control was prepared similarly. The 4× compound solution/substrate (CSKtide, 1000 nM)/ATP (Km ATP)/Mg Metal (5 mM) was prepared with kit buffer (20 mM HEPES, 0.01% Triton X-100, 5 mM DTT, pH 7.5), and 2× kinase solution was prepared with assay buffer (20 mM HEPES, 0.01% Triton X-100, 1 mM DTT, pH 7.5). The 5 μL of 4× compound solution, 5 mL of 4× Substrate/ATP/Metal solution, and 10 mL of 2× kinase solution were mixed and incubated in a well of polypropylene 384 well microplate for 1 hour at room temperature. 70 mL of Termination Buffer (QuickScout Screening Assist MSA; Carna Biosciences) was added to the well. The reaction mixture was applied to LabChip™ system (Perkin Elmer), and the product and substrate peptide peaks were separated and quantitated. The kinase reaction was evaluated by the product ratio calculated from peak heights of product(P) and substrate(S) peptides (P/(P+S)). The readout value of reaction control (complete reaction mixture) was set as a 0% inhibition, and the readout value of background (Enzyme(−)) was set as a 100% inhibition, then the percent inhibition of each test solution was calculated.

IC₅₀ values were calculated from concentration vs. % Inhibition curves by fitting to a four parameter logistic curve, and are provided for the compounds of the present invention in Table 7, below. With respect to PDGFRβ activity: “+++” denotes an IC₅₀ of less than 300 nM; “++” denotes an IC₅₀ of from 300 nM to less than 1000 nM; and “+” denotes an IC₅₀ of 1000 nM or more.

TABLE 7
ACTIVITY OF REPRESENTATIVE COMPOUNDS
	PDGFRα	PDGFRβ
Cmpd No	IC50	IC50
1	+++	+++
2	+++	++
3	+++	+
4	+++	+++
5	+++	++
6	+++	+
7	+++	+
8	+++	+++
9	+++	++
10	+++	+++
11	+++	+++
12	+++	+++
13	Not Tested	Not Tested
14	+++	+++
15	+++	+++
16	+++	+++
17	+++	+++
18	+++	+++
19	+++	+++
20	+	+
21	+++	+++
22	+++	+++
23	++	++
24	++	++
25	+++	+
26	++	+
27	+++	+++
28	+++	+++
29	+++	+++
30	+++	++
31	+++	+++
32	+++	+++
33	+++	+++
34	+++	++
35	+++	+++
36	+++	+++
37	+++	+++
38	+++	+++
39	+++	+++
40	+++	+++
41	+++	+++
42	+++	+++
43	++	+
44	+++	+
45	++	+
46	+++	+++
47	+++	+++
48	+++	+++
49	+++	+++
50	+++	+++
51	+++	+++
52	++	+
53	+	+
54	+++	+++
55	+++	+++
56	+++	+++
57	+++	+++
58	+++	+++
59	+++	+++
60	+	+
61	++	+
62	++	+
63	+++	+++
64	+++	++
65	Not Tested	Not Tested
66	+++	++
67	+++	+++
68	+++	+++
69	+++	+++
70	+++	+++
71	+++	+++
72	+++	+++
73	+++	+++
74	+++	+++
75	Not Tested	Not Tested
76	+++	+++
77	+++	++
78	Not Tested	Not Tested
79	+++	+++
80	++	+
81	+	+
82	+++	++
83	+++	+
84	+++	++
85	+	+
86	+++	+++
87	+++	+++
88	+++	+
89	+++	++
90	+++	+++
91	+++	+++
92	+++	+
93	+++	+++
94	+++	+++
95	+++	+++
96	+++	+++
97	+++	+++
98	+++	+++
99	+++	+++
100	+++	+++
101	+++	+++
102	+++	+++
103	+++	+++
104	+++	+++
105	+++	+++
106	+++	++
107	+++	+++
108	+++	+++
109	+++	+++
110	Not Tested	Not Tested
111	+++	+++
112	+++	+++
113	+++	++
114	+++	+++
115	+++	+++
116	+++	+++
117	+++	+
118	+++	+++
119	+++	+++
120	+++	++
121	+++	+++
122	+++	++
123	+++	+++
124	+++	+++
125	+++	+++
126	++	+
127	+++	+++
128	+++	+++
129	+++	+++
130	+++	+++
131	++	+
132	+++	+
133	+++	+++
134	+++	+++
135	+++	+++
136	+++	+++
137	+++	+++
138	+++	+++
139	+++	+++
140	+++	+++
141	+++	+++
142	+++	+++
143	+++	+++
144	+++	+++
145	+++	+++
146	++	+
147	+++	+++
148	+++	+++
149	+++	+++
150	+++	+++
151	+++	+++
152	+++	+++
153	+++	+++
154	+++	+++
155	+++	+
156	+++	+++
157	+++	+++
158	+++	++
159	+++	+++
160	+++	+++
161	+++	+++
162	+++	+++
163	+++	+++
164	+++	+++
165	+++	+++
166	+++	+++
167	+++	+++
168	+++	+
169	+++	+++
170	+++	++
171	+++	+++
172	+++	+++
173	Not Tested	Not Tested
174	Not Tested	Not Tested
175	Not Tested	Not Tested
176	+++	+++
177	+++	+++
178	+++	+++
179	++	+
180	++	+
181	+++	+++
182	+++	+
183	+++	++
184	+++	+++
185	+++	+++
186	+++	+++
187	+++	+++
188	+++	+++
189	+++	+++
190	+++	+++
191	+++	+++
192	+++	+++
193	+++	+++
194	+++	+++
195	+++	+++
196	+++	+++
197	+++	+++
198	+++	+++
199	+++	+++
200	+++	+++
201	+++	+++
202	+++	+++
203	+++	+++
204	+++	+++
205	+++	+++
206	+++	+++
207	+++	+++
208	+++	+++
209	+++	+++
210	+++	+++
211	+++	+++
212	++	+
213	+++	+++
214	+++	+++
215	+++	+++
216	+++	+++
217	Not Tested	Not Tested
218	+++	+++
219	+++	+++
220	+++	++
221	+++	+++
222	+++	+++
223	+++	+++
224	+++	+++
225	+++	+++
226	+++	+++
227	+++	+++
228	+++	+++
229	+++	+++
230	+++	+++
231	+++	+++
232	+++	+++
233	+++	+++
234	+++	+++
235	Not Tested	Not Tested
236	+++	+++
237	+++	+++
238	+++	+++
239	+++	+++
240	+++	+++
241	+++	++
242	+++	+++
243	+++	+++
244	+++	+++
245	+++	+++
246	+++	+++
247	+++	+++
248	+++	+++
249	+++	+++
250	+++	+++
251	+++	+++
252	+++	+++
253	+++	+
254	+++	+++
255	+++	+++
256	+++	+++
257	+++	+++
258	+++	+++
259	+++	+++
260	+++	+++
261	+++	+++
262	+++	+++
263	+++	++
264	+++	+++
265	+++	+++
266	+++	+++
267	+++	+++
268	+++	+++
269	+++	+++
270	Not Tested	Not Tested
271	+++	+++
272	+++	+++
273	+++	+++
274	+++	+
275	+++	+++
276	++	++
277	+++	+++
278	++	+
279	+++	++
280	+++	+++
281	+++	++
282	+++	++
283	+++	+++
284	++	++
285	++	+
286	+++	++
287	+++	+++
288	+++	+++
289	+++	++
290	+++	+++
291	+++	+++
292	+++	+++
293	+++	+++
294	++	++
295	+++	+++
296	+++	+++
297	++	++
298	+++	++
299	+++	++
300	+++	+++
301	+++	+++
302	+++	+++
303	+++	+++
304	+++	+++
305	+++	++
306	+++	+++
307	+++	+++
308	+++	+++
309	+++	+++
310	+++	+++
311	+++	+++
312	+++	+++
313	+++	+++
314	+++	+++
315	+++	+++
316	+++	+++
317	+++	+++
318	+++	+++
319	+++	+++
320	+++	+++
321	+++	+++
322	+++	+++
323	+++	+++
324	+++	++
325	+	+
326	+++	+++
327	+++	+++
328	+++	+++
329	+++	+++
330	+++	+++
331	+++	+++
332	+++	+++
333	+++	++
334	+++	+++
335	+++	+++
336	+++	+++
337	+++	+++
338	+++	++
339	+++	++
340	+++	+++
341	+++	+++
342	++	+
343	+++	+++
344	+++	+++
345	+++	+++
346	++	++
347	+++	+++
348	+++	+++
349	+++	+++
350	+++	+++
351	++	+
352	+++	++
353	+++	+++
354	+++	+++
355	++	+
356	+++	+++
357	+++	+++
358	+++	+++
359	+++	+++
360	+++	+++
361	+++	++
362	+++	++
363	+	+
364	+++	++
365	+++	+++
366	+++	+++
367	++	+
368	+	+
369	+	+
370	++	+
371	+++	++
372	++	+
373	+++	+
374	++	++
375	+++	++
376	+++	+++
377	++	++
378	+++	++
379	+++	++
380	+++	++
381	+++	++
382	Not Tested	Not Tested
383	+++	+++
384	+++	+++
385	+++	++
386	+++	+++
387	+++	+
388	+	+
389	+++	+++
390	+++	+++
391	+++	+++
392	++	+
393	++	+
394	+++	+
395	+++	++
396	+++	+++
397	++	+
398	+++	+++
399	+++	+++
400	++	+
401	+++	+++
402	+++	+++
403	+++	+++
404	+++	+++
405	+++	+++
406	Not Tested	Not Tested
407	+++	+++
408	++	+
409	Not Tested	Not Tested
410	+++	+++
411	+++	+++
412	+++	+++
413	+++	+++
414	+++	+++
415	+++	+++
416	+++	+++
417	+++	+++
418	+++	+++
419	+++	++
420	+++	+++
421	+++	+++
422	+++	+++
423	+++	+++
424	+++	+++
425	+++	+++
426	+++	+++
427	+++	+++
428	+++	+++
429	+++	+++
430	+++	+++
431	+++	+++
432	+++	+++
433	+++	+++
434	+++	+++
435	+++	+++
436	+++	+++
437	+++	+++
438	+++	+++
439	+++	+++
440	+++	+++
441	+++	+++
442	+++	+++
443	+++	+++
444	+++	+++
445	+++	+++
446	+++	+++
447	+++	+++
448	Not Tested	Not Tested
449	++	+
450	+++	+++
451	+++	++
452	+++	+++
453	+++	+++
454	+++	++
455	+++	+++
456	+++	+++
457	+++	+++
458	+++	+++
459	+	+
460	+++	+++
461	+++	++
462	+++	+++
463	+++	+++
464	+++	+++
465	+++	+
466	+++	++
467	+++	+
468	++	+
469	+++	+++
470	+++	+++
471	++	+
472	+++	++
473	+++	+++
474	+++	+++
475	+++	+++
476	+++	++
477	+++	+++
478	+++	++
479	+++	+++
480	+++	++
481	+++	+++
482	+++	++
483	+++	+++
484	+++	+++
485	Not Tested	Not Tested
486	+++	+++
487	+++	+++
488	+++	+++
489	+++	+++
490	+++	+++
491	++	++
492	+++	++
493	+++	+++
494	+++	+++
495	+++	+++
496	+++	++
497	+++	+++
498	+++	+++
499	+++	+++
500	+	+
501	+++	+++
502	+++	+++
503	++	++
504	+++	+++
505	+++	+++
506	+++	+++
507	+++	+++
508	+++	+++
509	+++	+++
510	+++	+++
511	+++	+++
512	+++	+++
513	+++	+++
514	+++	+++
515	+++	+++
516	+	+
517	Not Tested	Not Tested
518	+++	+++
519	Not Tested	Not Tested
520	+++	+++
521	+++	+++
522	+++	+++
523	+++	+++
524	+++	+++
525	Not Tested	Not Tested
526	+++	+++
527	+++	+++
528	+++	+++
529	+++	+++
530	+++	+++
531	+++	+++
532	+++	+++
533	+++	+++
534	+++	+++
535	+++	+++
536	+++	+++
537	+++	+++
538	+++	+++
539	+++	+++
540	+++	+++
541	+++	+++
542	+++	+++
543	+++	+++
544	+++	+++
545	+++	+++
546	+++	+++
547	+++	+++
548	+++	+++
549	+++	+++
550	+++	+++
551	+++	+++
552	+++	+++
553	+++	+++
554	+++	+++
555	+++	+++
556	+++	+++
557	+++	+++
558	+++	+++
559	+++	+++
560	+++	+++
561	+++	+++
562	+++	++
563	+++	+++
564	+++	+++
565	+++	+++
566	+++	+++
567	+++	++
568	++	+
569	++	+++
570	+++	+++
571	+++	+++
572	+	++
573	+++	+++
574	+++	+++
575	+++	+++
576	+++	+++
577	+++	+++
578	+++	+++
579	+++	+++
580	++	+++
581	+++	+++
582	++	++
583	+++	+++
584	++	++
585	+++	+++
586	+++	+++
587	+++	+++
588	+++	+++
589	+	++
590	Not Tested	Not Tested
591	+++	+++
592	+++	+++
593	+++	+++
594	+++	+++
595	+++	+++
596	+++	+++
597	+++	+++
598	+++	+++
599	+++	+++
600	+++	++
601	+++	+++
602	+++	+++
603	+++	+++
604	+++	++
605	+++	+++
606	+++	+++
607	+++	+++
608	+++	+++
609	+++	+++
610	+++	+++
611	+++	+++
612	+++	+++
613	+++	+++
614	+++	+++
615	+++	+++
616	+++	+++
617	+++	+++
618	+++	+++
619	+++	+++
620	+++	+++
621	+++	+++
622	+++	+++
623	++	+
624	++	+
625	+++	++
626	+++	+
627	+++	++
628	+++	+
629	+++	+
630	+++	++
631	+++	+++
632	+++	+++
633	+++	++
634	+++	+++
635	+++	+++
636	+++	+++
637	+++	+++
638	+++	+++
639	+++	+++
640	+++	++
641	+++	+++
642	+++	++
643	+++	++
644	+	+
645	++	+
646	+++	++
647	+++	+
648	+++	+++
649	+++	++
650	+++	++
651	+++	+
652	+++	++
653	+++	+
654	+++	+
655	+++	+
656	+++	+++
657	+++	+++
658	++	+
659	+++	+++
660	+++	++
661	+++	++
662	+++	+
663	+++	++
664	+++	+
665	+++	+
666	+++	+++
667	+++	+
668	+++	+++
669	+++	++
670	+++	+++
671	+++	+
672	+++	+
673	+++	+++
674	+++	+++
675	+++	+++
676	++	+
677	+++	+++
678	+++	+
679	+++	+++
680	+++	+++
681	+++	+
682	++	+
683	++	+
684	Not Tested	Not Tested
685	+++	++
686	+++	++
687	+++	+++
688	+++	+
689	+++	+
690	++	+
691	+++	+
692	+++	+++
693	+++	+
694	+++	+++
695	+++	++
696	+++	+++
697	++	+
698	+++	++
699	+++	++
700	+++	+++
701	+++	+++
702	+++	+++
703	+	+
704	Not Tested	Not Tested
705	+	+
706	+++	+
707	+++	++
708	+++	++
709	++	+
710	+++	+
711	+++	+
712	+++	+
713	+++	++
714	Not Tested	Not Tested
715	Not Tested	Not Tested
716	+++	+
717	+++	+++
718	+++	+
719	+++	+++
720	+++	+
721	+++	+
722	+++	+
723	+++	+
724	+++	+
725	Not Tested	Not Tested
726	+++	++
727	+	+
728	+	+
729	+++	+++
730	+++	++
731	+++	+++
732	+++	++
733	+++	++
734	+++	+++
735	+++	+++
736	+++	+++
737	+++	+++
738	++	+
739	+++	+
740	+++	++
741	+++	+
742	+++	+++
743	+++	++
744	+++	+
745	+	+
746	+++	+++
747	+	+
748	+++	++
749	+	+
750	+	+
751	+	+

The various embodiments described above can be combined to provide further embodiments. All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the Application Data Sheet are incorporated herein by reference, in their entirety. Aspects of the embodiments can be modified, if necessary to employ concepts of the various patents, applications and publications to provide yet further embodiments.

These and other changes can be made to the embodiments in light of the above-detailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims, but should be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure.

This application claims the benefit of priority to U.S. Provisional Application No. 62/868,735, filed Jun. 28, 2019, which application is hereby incorporated by reference in its entirety.

Claims

1. A compound having the structure of Formula (I):

2. The compound of claim 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein ring A is a monocyclic carbocycle.

3. The compound of claim 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein ring A is a polycyclic carbocycle.

4. The compound of claim 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein ring A is a monocyclic heterocycle.

5. The compound of claim 4, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein ring A is pyrrolidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, oxatriazolyl, thiophenyl, thiazolyl, isothiazolyl, thiadiazolyl, thiatriazolyl, piperidinyl, piperazinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, 2H-pyranyl, tetrahydro-2H-pyranyl, or morpholinyl.

6. The compound of claim 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein ring A is a polycyclic heterocycle.

7. The compound of claim 6, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein ring A is indolyl, benzimidazolyl, indazolyl, benzotriazolyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[3,2-c]pyridinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl, [1,2,3]triazolo[4,5-b]pyridinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-purinyl, indolizinyl, pyrrolo[1,2-a]pyrimidinyl, pyrrolo[1,2-a]pyrazinyl, pyrrolo[1,2-c]pyriminyl, pyrrolo[1,2-b]pyridazinyl, imidazo[4,5-b]pyridinyl, pyrazolo[1,5-a]pyridinyl, imidazo[1,5-a]pyridinyl, imidazo[1,5-b]pyridazinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-c]pyrimidinyl, imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[4,3-a]pyridinyl, [1,2,3-triazolo[1,5-a]pyridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, pyrido[2,3-b]pyrazinyl, pteridinyl, pyrido[3,4-d]pyridazinyl, 1,6-naphthyridinyl, 1,8-naphthyridinyl, 9H-carbazolyl, benzoxazolyl, dibenzofuranyl, benzothiphenyl, or dibenzothiophenyl.

8. The compound of any one of claims 1-7, having the structure of Formula (II):

9. The compound of any one of claims 1-8, having the structure of Formula (III):

10. The compound of any one of claims 1-9, having the structure of Formula (IV):

11. The compound of any one of claims 1-10, having the structure of Formula (V):

12. The compound of any one of claims 1-11, having the structure of Formula (VI):

13. The compound of any one of claims 1-9, having the structure of Formula (VII):

14. The compound of any one of claims 1-9 or 13, having the structure of Formula (VIII):

15. The compound of any one of claims 1-9 or 13-14, having the structure of Formula (VIII-A):

16. The compound of any one of claims 1-9 or 13-14, having the structure of Formula (VIII-B):

17. The compound of any one of claims 1-9 or 13-14, having the structure of Formula (VIII-C):

18. The compound of any one of claims 1-9 or 13-14, having the structure of Formula (VIII-D):

19. The compound of any one of claims 1-9 or 13-14, having the structure of Formula (VIII-E)

20. The compound of any one of claims 1-9 or 13-14, having the structure of Formula (VIII-F):

21. The compound of any one of claims 1-9 or 13-14, having the structure of Formula (VIII-G):

22. The compound of any one of claims 1-9 or 13-14, having the structure of Formula (VIII-H):

23. The compound of any one of claims 1-7, having the structure of Formula (IX):

24. The compound of of any one of claims 1-7 or 23, having the structure of Formula (X):

25. The compound of of any one of claims 1-7 or 23-24, having the structure of Formula (XI):

26. The compound of any one of claims 1-11 or 23-24, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein Y2 is C.

27. The compound of any one of claims 1-11 or 23-24, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein Y2 is N.

28. The compound of any one of claims 1-22, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein Y4 is C.

29. The compound of any one of claims 1-22, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein Y4 is N.

30. The compound of any one of claims 1-7, having the structure of Formula (XII):

31. The compound of any one of claims 1-7 or 30, having the structure of Formula (XIII):

32. The compound of any one of claims 1-7 or 30-31, having the structure of Formula (XIV):

33. The compound of any one of claims 1-7 or 30-32, having the structure of Formula (XV):

34. The compound of any one of claims 1-7 or 30-33, having the structure of Formula (XVI):

35. The compound of any one of claims 1-7, having the structure of Formula (XVII):

36. The compound of any one of claims 1-7 or 35, having the structure of Formula (XVIII):

37. The compound of any one of claims 1-7 or 35-36; having the structure of Formula (XVIII-A):

38. The compound of any one of claims 1-7 or 35-36, having the structure of Formula (XVIII-B):

39. The compound of any one of claim 1-7, having the structure of Formula (XIX):

40. The compound of any one of claims 1-7 or 39, having the structure of Formula (XX):

41. The compound of any one of claims 1-40, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein X is —C(O)NH—.

42. The compound of any one of claims 1-40, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein X is —C(R10R11)C(O)NH—.

43. The compound of any one of claims 1-40, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein X is —NHC(O)NH—.

44. The compound of any one of claims 1-40, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein X is —NHC(O)—.

45. The compound of any one of claims 1-44, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein R5 is H and R6 is alkyl.

46. The compound of claim 45, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein R6 is methyl.

47. The compound of any one of claims 1-46, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein n is 0.

48. The compound of any one of claims 1-46, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein n is 1 or 2.

49. The compound of any one of claims 1-48, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein m is 0.

50. The compound of any one of claims 1-48, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein m is 1 or 2.

51. The compound of claim 50, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R8 is alkyl.

52. The compound of claim 51, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R8 is methyl, ethyl, iso-propyl, n-propyl, or t-butyl.

53. The compound of claim 50, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R8 is alkyl substituted with halogen.

54. The compound of claim 53, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R8 is difluoromethyl, trifluoromethyl, 2-fluoroethyl, or 2,2-difluoroethyl.

55. The compound of claim 50, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R8 is alkyl substituted with —ORa and Ra is H or alkyl.

56. The compound of claim 55, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R8 is hydroxymethyl, 2-hydroxyethyl, hydroxybutyl, or methoxymethyl.

57. The compound of claim 50, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R8 is carbocycle.

58. The compound of claim 57, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R8 is cyclopropyl or cyclobutyl.

59. The compound of claim 50, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one of R8 is heterocycle.

60. The compound of claim 50, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R8 is —ORa.

61. The compound of claim 60, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one Ra is alkyl.

62. The compound of claim 60, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one Ra is haloalkyl.

63. The compound of claim 60, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one Ra is carbocycle.

64. The compound of claim 50, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R8 is —NRaRb.

65. The compound of claim 64, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one Ra is H and at least one Rb is alkyl.

66. The compound of claim 64, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one Ra is H and at least one Rb is haloalkyl.

67. The compound of claim 50, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R8 is cyano.

68. The compound of claim 50, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R8 is halogen.

69. The compound of claim 68, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R8 is Cl.

70. The compound of any one of claims 1-69, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein p is 0.

71. The compound of any one of claims 1-69, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein p is 1 or 2.

72. The compound of claim 71, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R9 is halogen.

73. The compound of claim 72, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R9 is Cl or Br.

74. The compound of claim 71, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R9 is alkyl.

75. The compound of claim 74, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R9 is methyl or ethyl.

76. The compound of claim 74 or 75, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R9 is optionally substituted with carbocycle or heterocycle.

77. The compound of claim 74 or 75, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R9 is substituted with —ORa.

78. The compound of claim 71, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R9 is carbocycle.

79. The compound of claim 78, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R9 is phenyl.

80. The compound of claim 78 or 79, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R9 is substituted with —ORa.

81. The compound of claim 80, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein Ra is, at each occurrence, independently H or alkyl.

82. The compound of claim 71, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R9 is heterocycle.

83. The compound of claim 71, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein at least one R9 is —ORa.

84. The compound of claim 83, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein Ra is, at each occurrence, independently H or alkyl.

85. The compound of claim 71, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, wherein two R9 together form ═O.

86. A compound having a structure listed in Table 5, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof.

87. A substantially enantiomerically pure form of a compound having a structure listed in Table 5 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof.

88. A composition comprising a compound of any one of claims 1-87, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

89. A method for inhibiting PDGF receptor α, comprising contacting the PDGF receptor α with an effective amount of a compound of any one of claims 1-87, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, or a composition comprising the same.

90. A method for inhibiting PDGF receptor β, comprising contacting the PDGF receptor β with an effective amount of a compound of any one of claims 1-87, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, or a composition comprising the same.

91. A method for treating a PDGF receptor α-dependent condition, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-87, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, or a composition comprising the same.

92. A method for treating a PDGF receptor β-dependent condition, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-87, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, or a composition comprising the same.

93. A method for treating a pulmonary disorder, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-87, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, or a composition comprising the same.

94. The method of claim 93, wherein the pulmonary disorder is pulmonary hypertension.

95. The method of claim 94, wherein the pulmonary hypertension is pulmonary arterial hypertension.

96. The method of claim 95, wherein the pulmonary arterial hypertension is primary PAH, idiopathic PAH, heritable PAH, refractory PAH, BMPR2, AL 1, endoglin associated with hereditary hemorrhagic telangiectasia, endoglin not associated with hereditary hemorrhagic telangiectasia, drug-induced PAH, or toxin-induced PAH.

97. The method of claim 95, wherein the pulmonary arterial hypertension is associated with systemic sclerosis, mixed connective tissue disease, HIV, hepatitis, or portal hypertension.

98. The method of claim 94, wherein the pulmonary hypertension is associated with myeloproliferative disorders.

99. The method of claim 98, wherein the myeloproliferative disorder associated pulmonary hypertension is Group 5 PAH.

100. A method for treating a disease associated with tissue fibrosis, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-87, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, or a composition comprising the same.

101. The method of claim 100, wherein the disease associated with tissue fibrosis is systemic sclerosis, interstitial lung disease, bronchiolitis obliterans with organizing pneumonia (BOOP), acute lung injury, glomerulonephritis, focal segmental glomerulosclerosis, stroke, or radiation induced fibrosis.

102. A method for treating solid tumors, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-87, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, tautomer, isotope, or salt thereof, or a composition comprising the same.