Patent Application
20250009745
The present application claims the priorities of Chinese patent application 202110161786.5 filed on Feb. 5, 2021, Chinese patent application 202110483256.2 filed on Apr. 30, 2021, Chinese patent application 202111062178.5 filed on Sep. 10, 2021, Chinese patent application 202111398260.5 filed on Nov. 19, 2021 and Chinese patent application 202210048365.6 filed on Jan. 17, 2022. The contents of the above Chinese patent applications are incorporated herein by reference in its entirety.
The present disclosure belongs to the field of pharmaceutical chemistry, and particularly relates to a novel compound with CDK2/4/6 inhibitory activity, a pharmaceutical composition containing the compound, a useful intermediate for preparing the compound, and a method for treating cell proliferative diseases (such as cancer) using the compound of the present disclosure.
The cell cycle is the basic process of cell life activities, which controls the growth, proliferation, and differentiation of cells. Cyclin-dependent kinases (CDKs) are a class of important cellular enzymes that cooperate with cyclins and play an important role in the regulation of the cell cycle. Cyclin B/CDK1, cyclin A/CDK2, cyclin E/CDK2, cyclin D/CDK4, cyclin D/CDK6 and other possible heterodimers are important regulatory factors of different phases of the cell cycle (Harper, J. W., Adams, P. D., Cyclin-Dependent Kinases, Chem. Rev. 2001, 101, 2511-2526).
Serving as an important regulatory factor in the cell cycle, CDK2 forms a kinase complex with cyclin E or cyclin A, and plays a decisive role in the process of driving the cell cycle from G1 phase to S phase and maintaining S phase. The main mechanism is that cyclin E and CDK2 work together to phosphorylate the retinoblastoma susceptibility gene (Rb) protein. The phosphorylation of the Rb protein leads to the release of E2F (a transcription factor). The released E2F binds to the upstream of some genes (usually locates in the promoter region or enhancer region), initiating the transcriptional expression of those genes related to the cell cycle, so that the cells enter the S phase at the end of G1. Many studies have shown that the abnormal expression of CDK2 is closely related to the occurrence of cancer, such as ovarian cancer with CCNE1 amplification, KRAS mutant lung cancer, hormone-dependent breast and prostate cancer, etc. (Tadesse S, Anshabo A T, Portman N, Lim E, Tilley W, Caldon C E, Wang S, Targeting CDK2 in cancer: challenges and opportunities for therapy, Drug Discovery Today, 2020, 25, 406-413).
As the important role of cyclin-dependent kinases (CDKs) in cell cycle regulation has been identified, CDK inhibitors have become the current research hotspot of anti-tumor drugs. At present, several CDK inhibitors have been approved for marketing in the world, but most of them act on CDK4/6 targets, mainly targeting breast cancer, such as Palbociclib from Pfizer, Ribociclib from Novartis and abemaciclib from Eli Lilly. Multi-target inhibitors including fadraciclib, Roscovitine, and PF-06873600 that target CDK2 are in different clinical stages. Currently, no CDK2 inhibitor has been approved for marketing. Therefore, It is of great research significance to continue to develop novel CDK inhibitors, especially effective for CDK2 targets.
The present disclosure aims to provide a class of novel compounds with CDK2/4/6 inhibitory activity, a pharmaceutical composition containing the compound, a useful intermediate for preparing the compound, and a use of the compound in the manufacture of a medicament for the treatment of cancer.
The present disclosure provides a compound of formula (I-A),
a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof, a solvate thereof, or an isotope-labeled derivative thereof,
wherein
R1 is selected from halogen, —CN, —NO2 or C1-4 haloalkyl;
Z is selected from —CH— or N;
L is selected from a bond, —NRa—, —O—, —S—, —SO2—, —SO—, —CO—, —CRaRb— or —CH═, and the Ra and Rb are optionally and independently selected from H, C1-4 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, —SO2Rc, —SORc, —CORc, —(CH2)mNRaaRab or —(CH2)mC(O)NRaaRab, wherein the Rc is selected from H, C1-4 alkyl, and the Raa and Rab are optionally and independently selected from H, C1-4 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, or Raa and Rab together with the N atom to which they are attached form a 4- to 6-membered heterocycloalkyl;
R2 is selected from C1-4 alkyl, C3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, aryl or 5- to 6-membered heteroaryl, and the C1-4 alkyl, C3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, aryl and 5- to 6-membered heteroaryl are optionally substituted by one or more than one Rd; the Rd is optionally and independently selected from H, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, —(CH2)mOH, —(CH2)mNReRf, C3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl; the C3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl in Rd are optionally substituted by C1-4 alkyl, C1-4 haloalkyl, —OH or —NH2;
R3 is selected from C1-4 alkyl, C1-4 haloalkyl, —(CH2)mNReRf, —(CH2)mOH, -L1-aryl, -L1-(5- to 6-membered heteroaryl), -L1-(C3-6 cycloalkyl) or -L1-(3- to 6-membered heterocycloalkyl), and the aryl, 5- to 6-membered heteroaryl, C3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl are optionally substituted by one or more than one Rg, and the Rg can be Rga or Rgb;
Rga is optionally and independently selected from H, halogen, —OH, C1-4 alkyl, C1-4 haloalkyl, —(CH2)mNReRf, ReRfNC(O)—C1-4 alkyl-, —C1-4 alkyl-OH, —S(O)2-(5- to 6-membered heteroaryl) or C1-4 alkoxy;
Rgb is optionally and independently selected from -L2-(C3-6 cycloalkyl), -L2-(3- to 6-membered heterocycloalkyl), -L2-(3- to 6-membered heterocycloalkenyl), -L2-aryl, -L2-(5- to 6-membered heteroaryl), -L2-(7- to 11-membered spiroheterocyclyl), -L2-(6- to 14-membered fused heterocyclyl), wherein the C3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, 3- to 6-membered heterocycloalkenyl, aryl, 5- to 6-membered heteroaryl, 7- to 11-membered spiroheterocyclyl, -L2-(6- to 14-membered fused heterocyclyl) are optionally substituted by one or more than one Rgc, and the Rgc is optionally and independently selected from C1-4 alkyl, halogen, C1-4 haloalkyl, —(CH2)mNReRf, —(CH2)mOH or cyano, or any two Rgc are connected to form a C1-2 alkylene chain;
L1 is a bond or L1 is optionally and independently selected from C1-4 alkylene;
L2 is a bond or L2 is optionally and independently selected from C1-4 alkylene or NH;
Re and Rf are optionally and independently selected from H or C1-4 alkyl;
m is optionally and independently selected from 0, 1, 2, 3 or 4;
R4, R4′ and R5 are optionally and independently selected from H, OH, halogen, C1-4 alkyl, C1-4 haloalkyl or C1-4 alkoxy;
and when L is the bond, R2 is not
when L is —NH—, R2 is not
and when the compound of formula (I) is
R1 is not halogen.
In some embodiments of the present disclosure, the compound of formula (I-A), the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, the solvate thereof or the isotope-labeled derivative thereof, wherein the compound can be represented by formula (I-B),
wherein
R1 is selected from halogen, —CN, —NO2 or C1-4 haloalkyl;
Z is selected from —CH— or N;
L is selected from a bond, —NRa—, —O—, —S—, —SO2—, —SO—, —CO—, —CRaRb— or —CH═, and the Ra and Rb are optionally and independently selected from H, C1-4 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, —SO2Rc, —SORc, —CORc, —(CH2)mNRaaRab or —(CH2)mC(O)NRaaRab, wherein the Rc is selected from H, C1-4 alkyl, and the Raa and Rab are optionally and independently selected from H, C1-4 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, or Raa and Rab together with the N atom to which they are attached form a 4- to 6-membered heterocycloalkyl;
R2 is selected from C1-4 alkyl, C3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, aryl or 5- to 6-membered heteroaryl, and the C1-4 alkyl, C3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, aryl and 5- to 6-membered heteroaryl are optionally substituted by one or more than one Rd; the Rd is optionally and independently selected from H, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, —(CH2)mOH, —(CH2)mNReRf, C3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl; the C3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl in Rd are optionally substituted by C1-4 alkyl, C1-4 haloalkyl, —OH or —NH2;
R3 is selected from C1-4 alkyl, C1-4 haloalkyl, —(CH2)mNReRf, —(CH2)mOH, -L1-aryl, -L1-(5- to 6-membered heteroaryl), -L1-(C3-6 cycloalkyl) or -L1-(3- to 6-membered heterocycloalkyl), and the aryl, 5- to 6-membered heteroaryl, C3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl are optionally substituted by one or more than one Rg, and the Rg is Rga or Rgb;
Rga is optionally and independently selected from H, halogen, —OH, C1-4 alkyl, C1-4 haloalkyl, —(CH2)mNReRf, ReRfNC(O)—C1-4 alkyl-, —C1-4 alkyl-OH, —S(O)2-(5- to 6-membered heteroaryl) or C1-4 alkoxy;
Rgb is optionally and independently selected from -L2-(C3-6 cycloalkyl), -L2-(3- to 6-membered heterocycloalkyl), -L2-(3- to 6-membered heterocycloalkenyl), -L2-aryl, -L2-(5- to 6-membered heteroaryl), -L2-(7- to 11-membered spiroheterocyclyl), -L2-(6- to 14-membered fused heterocyclyl), wherein the C3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, 3- to 6-membered heterocycloalkenyl, aryl, 5- to 6-membered heteroaryl, 7- to 11-membered spiroheterocyclyl, 6- to 14-membered fused heterocyclyl in Rgb are optionally substituted by one or more than one Rgc;
Rgc is optionally and independently selected from C1-4 alkyl, halogen, C1-4 haloalkyl, —(CH2)mNReRf, —(CH2)mOH or cyano;
or any two Rgc are connected to form a C1-2 alkylene chain;
L1 is a bond or L1 is optionally and independently selected from C1-4 alkylene;
L2 is a bond or L2 is optionally and independently selected from C1-4 alkylene or NH;
Re and Rf are optionally and independently selected from H or C1-4 alkyl;
m is optionally and independently selected from 0, 1, 2, 3 or 4;
R4 and R5 are optionally and independently selected from H, OH, halogen, C1-4 alkyl, C1-4 haloalkyl or C1-4 alkoxy.
In some embodiments of the present disclosure, R1 is selected from —CN, —CF3 or —CHF2.
In some embodiments of the present disclosure, R1 is selected from —CN or —CF3.
In some embodiments of the present disclosure, R1 is selected from —CF3.
In some embodiments of the present disclosure, R1 is selected from —CN.
In some embodiments of the present disclosure, Z is selected from N.
In some embodiments of the present disclosure, L is selected from —NH—, —N(CH3)—, —O—, —CH2—, CH=, —N(CH(CH)2)—
—N(SO2CH3)—, —SO2—, —SO—, —N(CH2CF3)—,
In some embodiments of the present disclosure, L is selected from the bond or —S—.
In some embodiments of the present disclosure, L is selected from —NH— or —O—.
In some embodiments of the present disclosure, L is selected from —NH—.
In some embodiments of the present disclosure, L is selected from —O—.
In some embodiments of the present disclosure, -L2-(7- to 11-membered spiroheterocyclyl) in Rgb is selected from -L2-(7- to 11-membered azaspirocyclyl), and -L2-(6- to 14-membered fused heterocyclyl) is selected from -L2-(6- to 14-membered fused azacyclyl).
In some embodiments of the present disclosure, R2 is selected from methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl,
(for example
(for example
(for example
(for example
wherein M is optionally and independently selected from —O— or —NRa—, Ra and Rd are as defined in any embodiment of the present disclosure, and n is independently 0, 1, 2, 3 or 4.
In some embodiments of the present disclosure, the 3- to 6-membered heterocycloalkyl in Rd is 3- to 6-membered azacycloalkyl, for example
for another example
In some embodiments of the present disclosure, Rd is selected from H, —OH, —F, —N(CH3)CH3, —CH3, —OCH3, —CH2N(CH3)CH3 or
In some embodiments of the present disclosure, Rd is selected from —OH, —F, —CH3.
In some embodiments of the present disclosure, the 3- to 6-membered heterocycloalkyl in R2 is selected from 3- to 6-membered oxacycloalkyl, such as tetrahydrofuryl
In some embodiments of the present disclosure, R2 is selected from isopropyl, tert-butyl,
In some embodiments of the present disclosure, R2 is selected from
In some embodiments of the present disclosure, R2 is selected from
In some embodiments of the present disclosure, R2 is selected from
In some embodiments of the present disclosure, R3 is selected from methyl, isopropyl, —(CH2)3N(CH3)CH3,
wherein M, n, Rga, Rgc, L1, L2 are as defined in any embodiment of the present disclosure.
In some embodiments of the present disclosure, R3 is selected from
wherein n, Rga, Rgc are as defined in any embodiment of the present disclosure.
In some embodiments of the present disclosure, in R3, any two Rgc in
are connected to form the C1-2 alkylene chain, such as
wherein n, Rga, Rgc are as defined in any embodiment of the present disclosure.
In some embodiments of the present disclosure, in R3, any two Rgc in
are connected to form the C1-2 alkylene chain, such as
wherein n, Rga, Rgc are as defined in any embodiment of the present disclosure.
In some embodiments of the present disclosure, in R3, any two Rgc in
are connected to form the C1-2 alkylene chain, such as
wherein n, Rga, Rgc are as defined in any embodiment of the present disclosure.
In some embodiments of the present disclosure, ReRfNC(O)—C1-4 alkyl- in Rga is NH2COC(CH3)2—.
In some embodiments of the present disclosure, —S(O)2-(5- to 6-membered heteroaryl) in Rga is —S(O)2-(5- to 6-membered azaaryl), such as
In some embodiments of the present disclosure, Rga is selected from H, Br, F, —CH3, —CH(CH3)2, —CH2CH2N(CH3)CH3, —NH2, —CH2CH2OH, —C(CH3)2OH, NH2COC(CH3)2—,
In some embodiments of the present disclosure, L2 in Rgb is the bond or —(CH2)2—.
In some embodiments of the present disclosure, R2 is selected from
In some embodiments of the present disclosure, Rgb is selected from
In some embodiments of the present disclosure, Rgb is selected from
In some embodiments of the present disclosure, Rgc is selected from H, —CH3, F, —OH, —NH2, —N(CH3)CH3, CN, —CF3;
or any two Rgc are connected to form —CH2— or —CH2CH2— chain.
In some embodiments of the present disclosure, any two non-adjacent Rgc are connected to form a C1-2 alkylene chain.
In some embodiments of the present disclosure, any two non-adjacent Rgc are connected to form —CH2— or —CH2CH2— chain.
In some embodiments of the present disclosure, -L1-aryl in R3 is selected from -L1-phenyl.
In some embodiments of the present disclosure, -L1-(5- to 6-membered heteroaryl) in R3 is selected from -L1-(5- to 6-membered azaaryl), such as -L1-pyrazolyl, -L1-pyridyl.
In some embodiments of the present disclosure, L1 in R3 is the bond.
In some embodiments of the present disclosure, R3 is selected from methyl, isopropyl, —(CH2)3N(CH3)CH3,
In some embodiments of the present disclosure, R3 is selected from
In some embodiments of the present disclosure, R3 is selected from
In some embodiments of the present disclosure, R3 is selected from
In some embodiments of the present disclosure, R3 is selected from
In some embodiments of the present disclosure, R3 is selected from
In some embodiments of the present disclosure, R4 and R5 are optionally and independently selected from H, F, OH, CH3.
In some embodiments of the present disclosure, R4 and R5 are optionally and independently selected from H, F.
In some embodiments of the present disclosure, R4 and R5 are selected from H.
In some embodiments of the present disclosure, for the compounds of formula (I-A) and formula (I-B), the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, the solvate thereof or the isotope-labeled derivative thereof, wherein the compound can be represented by formula (II),
wherein
R1, R2, R3, R4, R5, L are as defined in any embodiment of the present disclosure.
In some embodiments of the present disclosure, for the compounds of formula (I-A) and formula (I-B), the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, the solvate thereof or the isotope-labeled derivative thereof, wherein the compound can be represented by any structure in formula (II-A), formula (II-B) and formula (II-C),
wherein
R1, R2, R4, R5, L, Rg, n are as defined in any embodiment of the present disclosure.
In some embodiments of the present disclosure, for the compounds of formula (I-A) and formula (I-B), the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, the solvate thereof or the isotope-labeled derivative thereof, wherein the compound can be represented by any one of the following structures,
wherein
Z1 is selected from C, CH or N;
Z2 is selected from CH2, NH or O;
R1, R2, R4, R5, L, n, Rga, Rgc are as defined in any embodiment of the present disclosure.
In some embodiments of the present disclosure, for the compounds of formula (I-A) and formula (I-B), the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, the solvate thereof or the isotope-labeled derivative thereof, wherein the compound can be represented by any one of the following structures,
wherein R1, L, Rd, M, h, R4, R5, Rga, Rgc, Z1, Z2 are as defined in any embodiment of the present disclosure.
In some embodiments of the present disclosure, for the compounds of formula (I-A) and formula (I-B), the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, the solvate thereof or the isotope-labeled derivative thereof, wherein the compound can be represented by any one of the following structures,
R1, L, Rd, n, R4, R5, Rga, Rgc are as defined in any embodiment of the present disclosure.
In some embodiments of the present disclosure, for the compounds of formula (I-A) and formula (I-B), the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, the solvate thereof or the isotope-labeled derivative thereof, wherein the compound can be represented by any one of the following structures,
wherein R3, Rgb, Rgc, n are as defined in any embodiment of the present disclosure.
In some embodiments of the present disclosure, the compound of formula (I-A), the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, the solvate thereof or the isotope-labeled derivative thereof, wherein the compound can be represented by formula (I),
wherein
R1 is selected from halogen, —CN, —NO2 or C1-4 haloalkyl;
Z is selected from —CH— or N;
L is selected from a bond, —NRa—, —O—, —S—, —SO2—, —SO—, —CO—, —CRaRb— or —CH═, and the Ra and Rb are optionally and independently selected from H, C1-4 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, —SO2Rc, —SORc, —CORc, —(CH2)mNRaaRab or —(CH2)mC(O)NRaaRab, wherein the Rc is selected from H, C1-4 alkyl, and the Raa and Rab are optionally and independently selected from H, C1-4 alkyl, C1-4 haloalkyl, C3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, or Raa and Rab together with the N atom to which they are attached form a 4- to 6-membered heterocycloalkyl;
R2 is selected from C1-4 alkyl, C3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, aryl or 5- to 6-membered heteroaryl, and the C1-4 alkyl, C3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, aryl and 5- to 6-membered heteroaryl are optionally substituted by one or more than one Rd; the Rd is optionally and independently selected from H, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, —(CH2)mOH, —(CH2)mNReRf, C3-6 cycloalkyl or 3- to 6-membered heterocycloalkyl; the C3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl in Rd are optionally substituted by C1-4 alkyl, C1-4 haloalkyl, —OH or —NH2;
R3 is selected from C1-4 alkyl, C1-4 haloalkyl, —(CH2)mNReRf, —(CH2)mOH, -L1-aryl, -L1-(5- to 6-membered heteroaryl), -L1-(C3-6 cycloalkyl) or -L1-(3- to 6-membered heterocycloalkyl), and the aryl, 5- to 6-membered heteroaryl, C3-6 cycloalkyl and 3- to 6-membered heterocycloalkyl are optionally substituted by one or more than one Rg, and the Rg can be Rga or Rgb;
Rga is optionally and independently selected from H, halogen, —OH, C1-4 alkyl, C1-4 haloalkyl, —(CH2)mNReRf, ReRfNC(O)—C1-4 alkyl-, —C1-4 alkyl-OH or —S(O)2-(5- to 6-membered heteroaryl);
Rgb is optionally and independently selected from -L2-(C3-6 cycloalkyl), -L2-(3- to 6-membered heterocycloalkyl), -L2-(3- to 6-membered heterocycloalkenyl), -L2-aryl, -L2-(5- to 6-membered heteroaryl), wherein the C3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, 3- to 6-membered heterocycloalkenyl, aryl, 5- to 6-membered heteroaryl are optionally substituted by one or more than one Rgc, and the Rgc is optionally and independently selected from C1-4 alkyl, halogen, C1-4 haloalkyl, —(CH2)mNReRf, or —(CH2)mOH;
L1 is a bond or L1 is optionally and independently selected from C1-4 alkylene;
L2 is a bond or L2 is optionally and independently selected from C1-4 alkylene;
Re and Rf are optionally and independently selected from H or C1-4 alkyl;
m is optionally and independently selected from 0, 1, 2, 3 or 4;
R4 and R5 are optionally and independently selected from H, OH, halogen, C1-4 alkyl, C1-4 haloalkyl or C1-4 alkoxy;
and when L is the bond, R2 is not
when L is —NH—, R2 is not
and when the compound of formula (I) is
R1 is not halogen.
In some embodiments of the present disclosure, R1 is selected from —CN, —CF3 or —CHF2.
In some embodiments of the present disclosure, R1 is selected from —CN or —CF3.
In some embodiments of the present disclosure, R1 is selected from —CN.
In some embodiments of the present disclosure, Z is selected from N.
In some embodiments of the present disclosure, L is selected from —NH—, —N(CH3)—, —O—, —CH2—, CH=, —N(CH(CH)2)—, —N(SO2CH3)—, —SO2—, —SO—, —N(CH2CF3)—, or
In some embodiments of the present disclosure, L is selected from —NH— or —O—.
In some embodiments of the present disclosure, L is selected from —NH—.
In some embodiments of the present disclosure, R2 is selected from methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl,
wherein M is optionally and independently selected from —O— or —NRa—, Ra and Rd are as defined in any embodiment of the present disclosure, and n is independently 0, 1, 2, 3 or 4.
In some embodiments of the present disclosure, Rd is selected from H, —OH, —F, —N(CH3)CH3, —CH3, —OCH3, —CH2N(CH3)CH3 or
In some embodiments of the present disclosure, Rd is selected from —OH, —F, —CH3.
In some embodiments of the present disclosure, R2 is selected from isopropyl, tert-butyl
In some embodiments of the present disclosure, R3 is selected from methyl, isopropyl, —(CH2)3N(CH3)CH3,
wherein M, n, Rga, Rgc, L1 are as defined in any embodiment of the present disclosure.
In some embodiments of the present disclosure, Rga is selected from H, Br, F, —CH3, —CH(CH3)2, —CH2CH2N(CH3)CH3, —NH2, —CH2CH2OH, —C(CH3)2OH, NH2COC(CH3)2—,
In some embodiments of the present disclosure, Rgb is selected from
In some embodiments of the present disclosure, Rgc is selected from H, —CH3, F, —OH, —NH2, —N(CH3)CH3.
In some embodiments of the present disclosure, R3 is selected from methyl, isopropyl, —(CH2)3N(CH3)CH3,
In some embodiments of the present disclosure, R4 and R5 are optionally and independently selected from H, F, OH, CH3.
In some embodiments of the present disclosure, R4 and R5 are optionally and independently selected from H, F.
In some embodiments of the present disclosure, for the compound, the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, the solvate thereof, or the isotope-labeled derivative thereof, wherein the compound can be represented by formula (II),
wherein
R1, R2, R3, R4, R5, L are as defined in any embodiment of the present disclosure.
In some embodiments of the present disclosure, for the compound, the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, the solvate thereof, or the isotope-labeled derivative thereof, wherein the compound can be represented by any one of the following structures,
wherein
R1, R2, R4, R5, L, Rg, n are as defined in any embodiment of the present disclosure;
In some embodiments of the present disclosure, for the compound, the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, the solvate thereof, or the isotope-labeled derivative thereof, wherein the compound can be represented by any one of the following structures,
wherein
Z1 is selected from C, CH or N;
Z2 is selected from CH2, NH or O;
R1, R2, R4, R5, L, Rg, n, Rga, Rgc are as defined in any embodiment of the present disclosure.
In some embodiments of the present disclosure, for the compound, the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, the solvate thereof, or the isotope-labeled derivative thereof, wherein the compound can be represented by any one of the following structures,
wherein R1, L, Rd, Rg, M, n, R4, R5, Rga, Rgc are as defined in any embodiment of the present disclosure.
In some embodiments of the present disclosure, for the compound, the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, the solvate thereof, or the isotope-labeled derivative thereof, wherein the compound can be represented by any one of the following structures,
R1, L, Rd, Rg, n, R4, R5, Rga, Rgc are as defined in any embodiment of the present disclosure.
The present disclosure further provides the following compound, a stereoisomer thereof, a tautomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof, a solvate thereof, or an isotope-labeled derivative thereof, wherein the compound can be selected from any one of the following structures,
The present disclosure also provides a pharmaceutical composition comprising the (preferably a therapeutically effective amount of) compound, the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, the solvate thereof, or the isotope-labeled derivative thereof; and a pharmaceutically acceptable carrier, diluent and excipient. The pharmaceutical composition can be formulated for specific routes of administration, such as oral administration, parenteral administration, rectal administration, and the like. Oral administration, for example, a tablet, a capsule (including a sustained release or timed release prescription), a pill, a powder, a granule, an elixir, a tincture, a suspension (including a nano-suspension, a micro-suspension, a spray-dried dispersant), a syrup and an emulsion; sublingual administration; buccal administration; parenteral administration, for example, by subcutaneous, intravenous, intramuscular, or intrasternal injection, or infusion techniques (for example, as a sterile injectable aqueous solution or non-aqueous solution or a suspension); nasal administration, including administration to the nasal mucosa, for example, by inhalation spray; topical administration, for example, in the form of a cream or an ointment; or rectal administration, for example, in the form of a suppository. They can be administered alone, but they are usually administered together with a pharmaceutical carrier selected according to the selected route of administration and standard pharmaceutical practice.
“Pharmaceutically acceptable carrier” refers to a medium generally acceptable in the art for delivering a biologically active agent to animals, particularly mammals, including, for example, an adjuvant, an excipient or a vehicle, such as a diluent, a preservative, a filler, a flow regulator, a disintegrant, a wetting agent, an emulsifier, a suspending agent, a sweetener, a flavor, a fragrance, an antibacterial agent, an antifungal agent, a lubricants agent and a dispersant, according to the mode of administration and the nature of dosage forms. The pharmaceutically acceptable carrier is formulated according to a number of factors that are within the purview of those skilled in the art. The factors include, but are not limited to, the type and nature of the active agent formulated, the subjects to which the composition containing the agent is to be administered, the expected route of administration of the composition, and the target therapeutic indication. The pharmaceutically acceptable carriers include both aqueous and non-aqueous media and various solid and semisolid dosage forms. In addition to the active agent, such carriers include many different ingredients and additives, and such additional ingredients included in prescriptions for a variety of reasons (e.g., stabilizing the active agent and an adhesive, etc.) are well known to those of ordinary skilled in the art.
It is certain that administration regimens for the compounds of the present disclosure may vary depending on known factors, such as the pharmacodynamic characteristics of a specific drug and its mode and route of administration, the species, age, sex, health, medical condition and weight of the recipient, nature and extent of symptoms, types of coexisting treatments, frequency of treatments, routes of administration, renal and hepatic function of the patient, and desired effects. A therapeutically effective amount of the compound, a pharmaceutical composition or a combination thereof depends on the species, weight, age and individual condition of the subject, the disorder or disease being treated or its severity. A physician, clinician or veterinarian of ordinary skill may readily determine the effective amount of each active ingredient required to prevent, treat or inhibit the progression of a disorder or disease.
Serving as an important regulator in the cell cycle, CDK2 forms a kinase complex with cyclin E or cyclin A, and plays a decisive role in the process of driving the cell cycle from G1 phase to S phase and maintaining S phase. The main mechanism is that cyclin E and CDK2 work together to phosphorylate the retinoblastoma susceptibility gene (Rb) protein. The phosphorylation of the Rb protein leads to the release of E2F (a transcription factor). The released E2F binds to the upstream of some genes (usually locates in the promoter region or enhancer region), initiating the transcriptional expression of those genes related to the cell cycle, so that the cells enter the S phase at the end of G1. Many studies have shown that the abnormal expression of CDK2 is closely related to the occurrence of cancer, such as ovarian cancer with CCNE1 amplification, KRAS mutant lung cancer, hormone-dependent breast and prostate cancer, etc. (Tadesse S, Anshabo A T, Portman N, Lim E, Tilley W, Caldon C E, Wang S, Targeting CDK2 in cancer: challenges and opportunities for therapy, Drug Discovery Today, 2020, 25, 406-413).
The present disclosure also provides a use of the compound, the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, the solvate thereof, or the isotope-labeled derivative thereof, or the pharmaceutical composition in the manufacture of a medicament (preferably a medicament for the treatment of CDK-mediated cancer).
The present disclosure also provides a method for the treatment of CDK-mediated cancer, comprising administering to a patient a therapeutically effective amount of the compound, the stereoisomer thereof, the tautomer thereof, the pharmaceutically acceptable salt thereof, the prodrug thereof, the hydrate thereof, the solvate thereof, or the isotope-labeled derivative thereof, or the pharmaceutical composition.
In some embodiments of the present disclosure, in the use, the cancer comprises ovarian cancer, breast cancer, acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).
The present disclosure also provides a compound of formula (III), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
wherein
X is selected from halogen, OH, —SO2Me,−OMs, OTf, OTs and H; preferably halogen (e.g. Cl);
Z, R1, R3, R4, R5 are as defined in any embodiment of the present disclosure.
In some embodiments of the present disclosure, the compound of formula (III) is selected from
wherein R1, X, Rga, Rgc and n are as defined in any embodiment of the present disclosure.
The present disclosure also provides compounds of formula (IV-1) and formula (IV-2), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
wherein X is selected from halogen, OH, —SO2Me,−OMs, OTf, OTs; preferably halogen (e.g. Br).
X is selected from halogen, OH, —SO2Me,—OMs, OTf, OTs; preferably halogen (e.g. Cl).
The above compounds are used to prepare CDK inhibitor compounds of formula (I-A), formula (I-B) and formula (I) in the present disclosure.
The compounds of the present disclosure have better CDK 2/4/6 kinase inhibitory activity, especially excellent in the inhibitory activity of CDK 2 kinase; the compounds of the present disclosure can selectively inhibit CDK 2/4/6 kinases and especially has good selectivity for CDK 2 kinase. Some compounds have inhibitory selectivity of nearly ten times, even tens of times, or 100 times or more on CDK 1/7/9 kinases compared with CDK 2 kinase.
The compounds of the present disclosure have better inhibitory activity toward cell proliferation, showing better tumor inhibitory activity and good tolerance in drug efficacy experiments in vivo.
Unless otherwise specified, the following terms and phrases when used herein have the following meanings. A specific term or phrase should not be considered indefinite or unclear in the absence of a particular definition, but should be understood in the ordinary sense.
The term “pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms, which are suitable for use in contact with human and animal tissues within the scope of reasonable medical judgment, without excessive toxicity, irritation, allergic reaction or other problems or complications, and is commensurate with a reasonable benefit/risk ratio.
The term “pharmaceutically acceptable salt” refers to a derivative prepared by the compound of the present disclosure with a relatively nontoxic acid or base. These salts may be prepared during the synthesis, separation and purification of the compound, or the free form of the purified compound may be used alone to react with a suitable acid or base. When the compound contains a relatively acidic functional group, the compound reacts with alkali metal, alkaline earth metal hydroxide or organic amine to obtain an alkali addition salt, including cations based on alkali metals and alkaline earth metals and non-toxic ammonium, quaternary ammonium and amine cations. Salts of amino acids are also covered. When the compound contains a relatively basic functional group, the compound reacts with an organic acid or an inorganic acid to obtain an acid addition salt.
The compounds provided by the present disclosure also include the form of prodrugs, which means that the compounds which are rapidly converted in vivo to the parent compound of the above formula are converted into the compounds of the present disclosure in the in vivo or in vitro environment by chemical or biochemical methods, such as hydrolysis in blood.
The compounds of the present disclosure may exist in unsolvated as well as solvated forms, and the solvated form includes a hydrate form. In general, the solvated form is equivalent to the unsolvated form, which is also encompassed within the scope of the present disclosure.
The compounds of the present disclosure have geometric isomers as well as stereoisomers, such as cis-trans isomers, enantiomers, diastereoisomers, and racemic mixtures thereof, and other mixtures, all of which are within the scope of the present disclosure.
The term “enantiomer” refers to stereoisomers that are mirror images of each other.
The term “diastereomer” refers to stereoisomers in which the molecules have two or more chiral centers and the relationship between the molecules is not mirror images.
The term “cis-trans isomer” refers to a configuration in which a double bond or a single bond of a ring-forming carbon atom in a molecule cannot rotate freely.
Unless otherwise specified, the term “tautomer” or “tautomeric form” means that isomers with different functional groups are in dynamic equilibrium at room temperature and are rapidly interconvertible. If tautomers are possible (e.g., in solution), then chemical equilibrium of the tautomers can be achieved. For example, keto-enol isomerization and imine-enamine isomerization.
Unless otherwise specified, the absolute configuration of a stereogenic center is represented by a wedged solid bond and a wedged dashed bond
and the relative configuration of a stereogenic center is represented by a straight solid bond
and a straight dashed bond
For example,
OH represents that the hydroxyl group and the amino group are located on the same side of cyclopentane, which can be
Stereoisomers of the compounds of the present disclosure may be prepared by chiral synthesis or chiral reagents or other conventional techniques. For example, an enantiomer of a certain compound of the present disclosure may be prepared by an asymmetric catalysis technique or a chiral auxiliary derivatization technique. Alternatively, compounds with a single stereo configuration may be obtained from a mixture by a chiral resolution technique. Alternatively, it can be prepared directly from chiral starting materials. Separation of optically pure compounds in the present disclosure is usually accomplished by preparative chromatography, and a chiral chromatographic column is used to achieve the purpose of separating chiral compounds.
The absolute stereo configuration of a compound may be confirmed by conventional technical means in the art. For example, a single crystal X-ray diffraction method may also confirm the absolute configuration of the compound by the chiral structure of the raw material and the reaction mechanism of asymmetric synthesis. Compounds marked herein as “absolute configuration not determined” are typically split from racemic compounds into single isomers by chiral preparative SFC, which are then characterized and tested.
For example, the cis-compound 11 shown below is split by SFC chiral preparation to obtain compound 12 and compound 13 in a single configuration. Compounds 12 and 13 are enantiomers of each other, but the absolute stereo configurations corresponding to compounds 12 and 13 cannot be determined.
The term “optically pure” or “enriched in enantiomers” refers to the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
It indicates that the carbon atom is a chiral carbon atom, and the structure represents an optically pure compound in which the stereo configuration of the carbon atom is (R) configuration or (S) configuration and a mixture thereof, and the ratio of the mixture may be 1:1 or other ratios. For example,
represents that the structure may be
or a mixture of the two, and when the ratio of the mixture is 1:1, the structure is a racemic compound
the present disclosure also comprises isotope-labeled compounds, including isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2H, 3H, 13C, 11C, 14C, 15N, 18O, 17O, 31P, 32p, 35S, 18F and 36Cl. Compounds of the present disclosure containing the above isotopes and/or other isotopes of other atoms are within the scope of the present disclosure.
The term “pharmaceutically acceptable carrier” refers to a medium generally acceptable in the art for delivering a biologically active agent to animals, particularly mammals, including, for example, an adjuvant, an excipient or a vehicle, such as a diluent, a preservative, a filler, a flow regulator, a disintegrant, a wetting agent, an emulsifier, a suspending agent, a sweetener, a flavor, a fragrance, an antibacterial agent, an antifungal agent, a lubricants agent and a dispersant, according to the mode of administration and the nature of dosage forms. The pharmaceutically acceptable carrier is formulated according to a number of factors that are within the purview of those skilled in the art. The factors include, but are not limited to, the type and nature of the active agent formulated, the subjects to which the composition containing the agent is to be administered, the expected route of administration of the composition, and the target therapeutic indication. The pharmaceutically acceptable carriers include both aqueous and non-aqueous media and various solid and semisolid dosage forms. In addition to the active agent, such carriers include many different ingredients and additives, and such additional ingredients included in prescriptions for a variety of reasons (e.g., stabilizing the active agent and an adhesive, etc.) are well known to those of ordinary skilled in the art.
The term “excipient” generally refers to a carrier, diluent and/or medium required to formulate an effective pharmaceutical composition.
The term “prophylactically or therapeutically effective amount” refers to a sufficient amount of the compound or the pharmaceutically acceptable salt thereof of the present disclosure, which is sufficient to treat a disorder at a reasonable effect/risk ratio suitable for any medical treatment and/or prophylaxis. It should be recognized that the total daily dose of the compound of formula I, or the pharmaceutically acceptable salt thereof and the composition thereof in the present disclosure, is required to be determined by the attending physician within the scope of reliable medical judgment. For any specific patient, the specific therapeutically effective dose level depends on a variety of factors, including a disorder being treated and the severity of the disorder; activity of a specific compound used; a specific composition used; age, weight, general health status, sex and diet of the patient; administration time, administration route and excretion rate of the specific compound used; duration of treatment; drugs used in combination or simultaneously with the specific compounds used; and similar factors known in the medical field.
The term “optionally substituted” means an atom can be substituted by a substituent or not, unless otherwise specified, the type and number of the substituent may be arbitrary as long as being chemically achievable. For example, the term “optionally substituted by one or more than one Rd” means that an atom may or may not be substituted by one or more than one Rd.
When any variable (such as Rd) occurs in the constitution or structure of the compound more than once, the definition of the variable at each occurrence is independent. For example,
indicates that the cyclopentyl is substituted by 3 Rd, and each Rd has an independent option.
When the number of a linking group is 0 or defined as a bond, such as —O(CH2)nCH3, n=0 indicates that the linking group is a single bond, i.e., —OCH3; for example, R3 is -L1-(C3-6 cycloalkyl), L1 is a bond or optionally and independently selected from C1-4 alkylene, when L1 is a bond, it indicates that L1 does not exist, i.e., R3 is —(C3-6 cycloalkyl).
When the bond of a substituent may be cross-connected to two atoms on a ring, the substituent may be bonded to any atom on the ring. For example, the structure moiety
indicates that the substituent R1 may be substituted at any position on a benzene ring.
When a listed substituent does not indicate through which atom it is attached to a compound included in the general formula but not specifically mentioned, such substituent may be bonded through any of its atoms. For example, pyrazole serves as a substituent indicates that any carbon atom on a pyrazole ring is connected to a substituted group; when or
appears in the structure, it indicates that the atom is a bonded atom, for example,
both indicate that the N atom on a morpholine ring is a bonded atom.
Unless otherwise specified, “ring” refers to saturated, partially saturated or unsaturated monocyclic and polycyclic rings, and the “polycyclic rings” include a linked ring, a spiro ring, a fused ring and a bridged ring. Representative “rings” include substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl, or heteroaryl. The term “hetero” refers to substituted or unsubstituted heteroatoms and oxidized forms of heteroatoms, the heteroatoms being generally selected from N, O, S, and the oxidized forms generally including NO, SO and S(O)2. Nitrogen atoms may be substituted, namely NR (R is H or other substituents defined herein); the number of atoms on the ring is usually defined as the number of the ring members, for example, “3- to 6-membered heterocycloalkyl” refers to a ring formed by 3 to 6 atoms arranged around it, and each ring optionally contains 1 to 3 heteroatoms, namely N, O, S, NO, SO, S(O)2 or NR, and each ring is optionally substituted by R, and R is a group as defined herein.
Unless otherwise specified, the term “aryl” refers to an unsaturated, usually aromatic, hydrocarbon group, which may be a single ring or multiple rings fused together. C5-10 aryl is preferred, C5-8 aryl is more preferred, monocyclic C5-6 aryl is most preferred; examples of aryl include, but are not limited to, phenyl, naphthyl.
Unless otherwise specified, the term “heteroaryl” refers to a stable monocyclic or polycyclic aromatic hydrocarbon group containing at least one heteroatom (N, O, S, NO, SO, S(O)2 or NR). 5- or 6-membered monocyclic heteroaryl is preferred. Examples of heteroaryl include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidinyl.
Unless otherwise specified, “cycloalkyl” refers to a saturated monocyclic or polycyclic hydrocarbon group. The cycloalkyl is preferably 3- to 8-membered monocycloalkyl, more preferably 3- to 6-membered monocycloalkyl. Examples of monocycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.
Unless otherwise specified, “heterocycloalkyl” refers to monoheterocycloalkyl and polyheterocycloalkyl containing a certain number of heteroatoms in the ring, and the heteroatoms are generally selected from N, O, S, NO, SO, S(O)2, and NR. The heterocycloalkyl is preferably 3- to 8-membered monoheterocycloalkyl, more preferably 3- to 6-membered monoheterocycloalkyl. Examples of monoheterocycloalkyl include, but are not limited to, oxiranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, 1,3-dioxolane, 1,4-dioxane, etc.
Unless otherwise specified, “heterocycloalkenyl” refers to cyclic monoalkenyl containing heteroatoms, including 3- to 10-membered heterocyclylalkenyl, preferably 3- to 6-membered heterocyclylalkenyl, most preferably 5- to 6-membered heterocyclylalkenyl. Examples of heterocycloalkenyl include, but are not limited to,
etc.
Unless otherwise specified, the term “alkyl” is used to refer to a linear or branched saturated hydrocarbyl. C1-6 alkyl is preferred, and C1-4 alkyl is more preferred. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, neopentyl, n-hexyl, etc.
Unless otherwise specified, “spiroheterocyclyl” refers to a spirocyclyl in which one or more carbon atoms in the spirocyclic skeleton structure are substituted by heteroatoms selected from N, O, and S. Spiroheterocyclyl is preferably 5- to 13-membered spiroheterocyclyl, 6- to 12-membered spiroheterocyclyl, or 7- to 11-membered spiroheterocyclyl. Examples of spiroheterocyclyl include, but are not limited to, 2-oxa-7-azaspiro[5.3]nonan-7-yl, 2-oxa-7-azaspiro[4.4]nonan-7-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 2-oxa-8-azaspiro[4.5]decan-8-yl, 1,4,9-triazaspiro[5.5]undecan-9-yl, 3-oxa-9-azaspiro[5.5]undecan-9-yl, 2,6-diazaspiro[3.3]heptan-2-yl, 2,7-diazaspiro[5.3]nonan-7-yl, 2,7-dioxaspiro[5.3]nonyl, 3,9-diazaspiro[5.5]undecan-3-yl, 1-oxa-4,9-diazaspiro[5.5]undecan-9-yl, 1-oxa-4,8-diazaspiro[5.4]decan-8-yl, 3-azaspiro[5.5]undecan-3-yl, 7-azaspiro[3.5]decan-7-yl, 1-oxa-4,9-diazaspiro[5.5]undecan-4-yl, 6-oxa-2,9-diazaspiro[4.5]decan-9-yl, 9-oxa-2,6-diazaspiro[4.5]decan-6-yl, 3-azaspiro[5.5]undecan-3-yl, 4-oxa-1,9-diazaspiro[5.5]undecan-9-yl.
Unless otherwise specified, the term “fused cyclyl” refers to a polycyclic hydrocarbon group sharing two adjacent carbon atoms, and the fused cyclyl is preferably C8-10 fused bicyclyl, more preferably a three-membered ring-fused a five-membered ring, a five-membered ring-fused a five-membered ring, a five-membered ring-fused a six-membered ring, etc., and examples of fused cyclyl include, but are not limited to, bicyclo[3.1.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[3.3.0]octyl, bicyclo[4.1.0]heptyl, bicyclo[4.2.0]octyl, bicyclo[4.3.0]nonyl, bicyclo[4.4.0]decyl, etc.
Unless otherwise specified, the term “fused heterocyclyl” means that the skeleton carbon atoms in the fused ring are substituted by 1 to 3 heteroatoms selected from N, O, and S. Examples of fused heterocyclyl include, but are limited to, 1,4-diazabicyclo[4.4.0]decan-4-yl, 1,4-diazabicyclo[4.3.0]-nonan-4-yl, 8-oxa-1,4-diazabicyclo[4.4.0]decan-4-yl, 1,4-diazabicyclo[4.4.0]decan-4-yl, 4,7-diazabicyclo[4.3.0]nonan-4-yl, 3,7-diazabicyclo[4.3.0]nonan-3-yl, 3,7-diazabicyclo[3.3.0]octan-3-yl, 3,7-diazabicyclo[4.4.0]decan-3-yl, 3,6-diazabicyclo[4.3.0]nonan-3-yl, 3,6-diazabicyclo[4.4.0]decan-3-yl, 3,6,9-triazabicyclo[4.4.0]decan-3-yl, 3,7-diazabicyclo[4.2.0]octan-3-yl and 3,7-diazabicyclo[3.3.0]octan-3-yl.
Unless otherwise specified, the term “alkylene” means a divalent hydrocarbon group with the specified number of carbon atoms, including straight chain alkylene and branched chain alkylene, preferably C1-6 alkylene, more preferably C1-4 alkylene. Examples of alkylene include, but are not limited to, —CH2—, —CH2CH2—, —CH2CH2CH2—, —CH2CH2CH2CH2—, —CH2CH(CH3)—, —CH2CH(CH3)CH2—, —CH2CH2CH(CH3)—, —CH2CH2CH(CH3)CH2— and —CH2CH2CH2CH(CH3)—, etc.
Unless otherwise specified, the term “alkoxy” refers to alkyl connected by an oxygen bridge, that is, a group obtained by substituting hydrogen atoms in hydroxyl with alkyl. C1-6 alkoxy is preferred, and C1-4 alkoxy is more preferred. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, neopentoxy and n-hexyloxy.
Unless otherwise specified, the term “halogen” refers to fluorine, chlorine, bromine or iodine atom.
Unless otherwise specified, the term “haloalkyl” refers to alkyl in which one or more hydrogen atoms are substituted by halogen atoms. C1-6 haloalkyl is preferred, and C1-4 haloalkyl is more preferred. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, tribromomethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, etc.
Unless otherwise specified, the term “C1-4 alkyl-OH” refers to a structure in which hydrogen atoms in a C1-4 alkyl are optionally substituted by hydroxyl. Examples of “C1-4 alkyl-OH” include, but are not limited to, —CH2OH, —CH2CH2OH, —CH(OH)CH3,—CH2CH2CH2OH, —CH2CH(OH)CH3,
—CH2CH2CH2CH2OH, —CH2CH(OH)CH2CH3, —CH2CH2CH(OH)CH3,
etc.
Unless otherwise specified, “” in the structure means that the bond can be a single bond or a double bond, for example, the structural moiety
can be
or can be
Specifically, all combinations of the substituent and/or the variant thereof herein are allowed only when such combinations result in a stable compound.
In the examples of the present disclosure, the nomenclature of the title compound is converted from the compound structure by means of Chemdraw. If there is any inconsistency between the compound name and the compound structure, it may be determined by synthesizing relevant information and reaction routes; if it cannot be confirmed by other methods, the given structural formula of the compound shall prevail.
The preparation methods of some compounds in the present disclosure refer to the preparation methods of the aforementioned similar compounds. Those skilled in the art should know that when using or referring to the preparation methods cited therein, the feed ratio of reactants, reaction solvent, reaction temperature, etc. may be appropriately adjusted according to the different reactants.
The compounds of the present disclosure can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific examples listed below, the examples formed by their combination with other chemical synthesis methods, and equivalent alternatives known to those skilled in the art, preferred embodiments include but are not limited to the examples of the present disclosure.
Abbreviations used in the examples of the present disclosure and their corresponding chemical names are as follows:
The structures of the compounds of the present disclosure were determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS), or ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). NMR chemical shift (δ) was given in units of parts per million (ppm). NMR was determined using a Bruker Neo 400M or Bruker Ascend 400 NMR instrument with deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD3OD), deuterated chloroform (CDCl3) and heavy water (D2O) as solvents and tetramethylsilane (TMS) as an internal standard.
Liquid chromatography-mass chromatography LC-MS was determined using an Agilent 1260-6125B single quadrupole mass spectrometer, and the column was Welch Biomate column (C18, 2.7 μm, 4.6*50 mm) or waters H-Class SQD2, and the column was Welch Ultimate column (XB—C18, 1.8 μm, 2.1*50 mm) mass spectrometer (ion source is electrospray ionization).
Ultra-performance liquid chromatography-mass spectrometry UPLC-MS was determined using a Waters UPLC H-class SQD mass spectrometer (an ion source was electrospray ionization).
HPLC was determined using Waters e2695-2998 or Waters ARC and Agilent 1260 or Agilent Poroshell HPH high performance liquid chromatography.
Waters 2555-2489 (10 μm, ODS 250 cm×5 cm) or GILSON Trilution LC was used as preparative HPLC, and the column was Welch XB—C18 column (5 μm, 21.2*150 mm).
Chiral HPLC was determined using waters aquity UPC2; the column was Daicel chiralpak AD-H (5 μm, 4.6*250 mm), Daicel chiralpak OD-H (5 μm, 4.6*250 mm), Daicel chiralpak IG-3 (3 μm, 4.6 * 150 mm), Chiral Technologies Europe AD-3 (3 μm, 3.0*150 mm) and Trefoil™ Technology Trefoil™ AMY1 (2.5 μm, 3.0*150 mm).
Supercritical fluid chromatography (SFC) was determined using waters SFC 80Q, and the column was Daicel Chiralcel OD/OJ/OZ (20×250 mm, 10 μm) or Daicel Chiralpak IC/IG/IH/AD/AS (20×250 mm, 10 μm).
GF254 silica gel plate from Yantai Jiangyou Silica Gel Development Co., Ltd. or Rushan Shangbang New Materials Co., Ltd. was used as a thin layer chromatography silica gel plate. The specification used for TLC was 0.15 mm to 0.20 mm. The specification used for preparative TLC was 20×20 cm. Column chromatography generally used 200 to 300 mesh silica gel from Yucheng Chemical as a carrier.
The starting materials in the examples of the present disclosure are known and commercially available, or can be synthesized by using or following methods known in the art.
Unless otherwise specified, all reactions in the present disclosure are carried out under continuous magnetic stirring and dry nitrogen or argon atmosphere. The solvent is a dry solvent, and the unit of reaction temperature is Celsius.
Step 1: 2,4-Dichloro-5-cyanopyrimidine (5.0 g, 28.4 mmol) was dissolved in a 1/1 mixed solvent (70 mL) of tert-butanol and 1,2-dichloroethane at room temperature. Subsequently, under cooling in an ice-water bath and nitrogen atmosphere, a tetrahydrofuran solution of zinc chloride (1 mol/L, 33.6 mL, 33.6 mmol) was slowly added dropwise to the above solution, and the reaction mixture was stirred for 1 hour under an ice-water bath. Under cooling in an ice-water bath, a solution of tert-butyl 4-aminopiperazine-1-carboxylate (5.9 g, 28.4 mmol) in a 1/1 mixed solvent of tert-butanol and 1,2-dichloroethane and a solution of triethylamine (3.6 mL, 33.6 mmol) in a 1/1 mixed solvent of tert-butanol and 1,2-dichloroethane were slowly added dropwise in portions to the above reaction mixture. The reaction mixture was heated to room temperature and stirred for 2 hours. Water (50 mL) was added to the reaction mixture to quench the reaction. The reaction mixture was concentrated under reduced pressure. The mixture was extracted with dichloromethane (40 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (30 mL) first, then dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 3.8 g of tert-butyl 4-((4-chloro-5-cyanopyrimidin-2-yl)amino)piperidine-1-carboxylate (1A-2).
MS (ESI) m/z: 338.1 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ 8.84-8.77 (m, 1H), 8.76 (s, 0.5H), 8.69 (s, 0.4H), 4.09-3.83 (m, 3H), 2.87 (br.s., 2H), 1.80 (d, J=10.9 Hz, 2H), 1.40 (s, 9H), 1.38-1.29 (m, 2H).
Step 2: Compound 1A-2 (1 g, 2.9 mmol) was dissolved in 1,4-dioxane (3 mL) at room temperature. Subsequently, a hydrogen chloride-dioxane solution (2 mol/L, 3 mL, 6 mmol) was added thereto. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain 700 mg of 4-chloro-2-(piperidin-4-ylamino)pyrimidine-5-carbonitrile (1A-3).
MS (ESI) m/z: 238.1 [M+H]+.
Step 3: Compound 1A-3 (700 mg, 2.9 mmol) was dissolved in dichloromethane (10 mL) at room temperature. Subsequently, N,N-diisopropylethylamine (1.08 g, 8.4 mmol) and 1-methyl-1H-pyrazole-4-sulfonyl chloride (637.0 mg, 3.5 mmol) were sequentially added to the above reaction mixture. The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and water (30 mL) was added to the resulting residue to quench the reaction. The mixture was extracted with dichloromethane (30 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (10 mL×3 times) first, then dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 740.0 mg of compound 4-chloro-2-((1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile (intermediate 1A).
MS (ESI) m/z: 382.0 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ 8.94-8.80 (m, 1H), 8.73 (s, 0.5H), 8.69 (s, 0.4H), 8.32 (s, 1H), 7.77 (s, 1H), 3.91 (s, 3H), 3.87-3.69 (m, 1H), 3.53-3.40 (m, 2H), 2.48-2.38 (m, 2H), 2.04-1.82 (m, 2H), 1.69-1.52 (m, 2H).
Step 1: 2,4-Dichloro-5-trifluoromethylpyrimidine (500 mg, 2.3 mmol) was dissolved in acetonitrile (10 mL) at room temperature. Subsequently, triethylamine (349.0 mg, 3.5 mmol) and 1-tert-butoxycarbonyl-4-amino-piperidine (552.0 mg, 2.8 mmol) were slowly added to the above solution under cooling in an ice-water bath. The reaction mixture was stirred for 1 hour under cooling in an ice-water bath. Water (30 mL) was added to the reaction mixture to quench the reaction. The mixture was concentrated under reduced pressure and extracted with ethyl acetate (8 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (30 mL) first, then dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 340 mg of tert-butyl 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate (1B-2).
MS (ESI) m/z: 325.0 [M+H-t-Bu]+.
1H NMR (400 MHz, DMSO-d6) δ 8.63 (s, 0.6H), 8.61-8.49 (m, 1.4H), 4.05-3.82 (m, 3H), 2.87 (br.s., 2H), 1.81 (d, J=11.4 Hz, 2H), 1.50-1.21 (m, 11H).
Step 2: Compound 1B-2 (130 mg, 0.3 mmol) was dissolved in 1,4-dioxane (1 mL) at room temperature. Subsequently, a hydrogen chloride-dioxane solution (4 mol/L, 2 mL, 8 mmol) was added to the above solution. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain 95.0 mg of 4-chloro-N-(piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (1B-3).
MS (ESI) m/z: 281.0 [M+H]+.
Step 3: Compound 1B-3 (95.0 mg, 0.3 mmol) was dissolved in dichloromethane (5 mL) at room temperature. Subsequently, N,N-diisopropylethylamine (132.0 mg, 1.0 mmol) and 1-methyl-1H-pyrazole-4-sulfonyl chloride (72.0 mg, 0.4 mmol) were sequentially added to the above reaction mixture under cooling in an ice-water bath. The reaction mixture was stirred at room temperature for 15 hours. Water (30 mL) was added to the reaction mixture to quench the reaction. The mixture was extracted with dichloromethane (10 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (10 mL×3 times) first, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 120.0 mg of 4-chloro-N-(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (intermediate 1B).
MS (ESI) m/z: 425.0 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ 8.69-8.52 (m, 2H), 8.32 (s, 1H), 7.77 (s, 1H), 3.91 (s, 3H), 3.86-3.66 (m, 1H), 3.51-3.39 (m, 2H), 2.48-2.32 (m, 2H), 1.97-1.86 (m, 2H), 1.66-1.50 (m, 2H).
Step 1: Compound 1-1 (9.0 g, 40.7 mmol) and diisopropylethylamine (5.3 g, 40.7 mmol) were dissolved in 90 mL of dichloromethane. Cyclopentylamine (3.64 g, 42.8 mmol) was slowly added dropwise to the above solution at 0° C. After the dropwise addition was completed, the reaction mixture was continued to stir at room temperature for 1 hour. Saturated sodium bicarbonate aqueous solution (40 mL) was added to the reaction mixture to quench the reaction. The mixture was extracted with dichloromethane (100 mL×2 times), and the organic phases were combined. The organic phases were washed with saturated brine first, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain 12.3 g of 4-(cyclopentylamino)-2-(((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile (1-2). This product was used directly in the next reaction step without purification.
MS (ESI) m/z: 270.0 [M+H]+.
Step 2: Compound 1-2 (12.3 g, 45.6 mmol) was dissolved in THF/water (2/1, 150 mL) at room temperature. Subsequently, lithium hydroxide monohydrate (3.83 g, 91.3 mmol) was added in portions to the above solution. The reaction mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure to remove tetrahydrofuran, and the solution was neutralized to pH=4 with 3 mol/L hydrochloric acid aqueous solution. The mixture was extracted with dichloromethane (100 mL×2 times), and the organic phases were combined. The organic phases were washed with saturated brine first, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain 7.5 g of 2-chloro-4-(cyclopentylamino)pyrimidine-5-carboxylic acid (1-3).
MS (ESI) m/z: 240.1 [M−H]−.
Step 3: N,N-Dimethylformamide (10 drops) and 1-3 (7.5 g, 31.1 mmol) were dissolved in dichloromethane (100 mL) at room temperature. The reaction mixture was cooled to 0° C., and then oxalyl chloride (5.75 mL, 68.5 mmol) was slowly added dropwise to the above reaction mixture within 20 minutes. The reaction mixture was warmed to room temperature and stirred for 2 hours. At 0° C., the above reaction mixture was added dropwise to ammonia water (100 mL) within 30 minutes. The reaction mixture was filtered and dried to obtain 6.0 g of 2-chloro-4-(cyclopentylamino)pyrimidine-5-carboxamide (1-4).
MS (ESI) m/z: 241.0 [M+H]+.
Step 4: 1-4 (400 mg, 1.8 mmol), 1-(methylsulfonyl)piperidin-4-amine (581 mg, 2.7 mmol) and cesium carbonate (1.77 g, 5.4 mmol) were dissolved in 1,4-dioxane (10 mL). The reaction mixture was heated to 120° C. and reacted for 3 hours, then cooled to room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with dichloromethane. The organic phases were combined, washed with saturated brine first, then dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 405 mg of 4-(cyclopentylamino)-2-(((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carboxamide (1-5).
MS (ESI) m/z: 383.4 [M+H]+.
Step 5: 1-5 (200 mg, 0.5 mmol) and triethylamine (636 mg, 6.3 mmol) were dissolved in THE (10 mL). At −65° C., trifluoroacetic anhydride (1.1 g, 5.2 mmol) was added to the reaction mixture. The reaction mixture was continued to stir for 30 minutes at −65° C. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture. The mixture was extracted with dichloromethane (100 mL×2 times). The organic phases were combined, washed with saturated brine first, then dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure to obtain 100 mg of N-(5-cyano-2-(((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-N-cyclopentyl-2,2,2-trifluoroacetamide (1-6).
MS (ESI) m/z: 461.2 [M+H]+.
Step 6: 1-6 (100 mg, 0.22 mmol) was dissolved in THE (5 mL) at room temperature, and ammonia water (5 mL) was added to the solution. After the reaction mixture was reacted at room temperature for 1 hour, water was added to quench the reaction. The mixture was extracted with dichloromethane (100 mL×2 times), and the organic phases were combined. The organic phases were washed with saturated brine first, then dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 40 mg of 4-(cyclopentylamino)-2-(((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile (compound 1).
MS (ESI) m/z: 365.4 [M+H]+.
1HNMR (400 MHz, DMSO-d6+TFA) δ 9.06-8.82 (m, 2H), 8.57 (br.s., 1H), 4.52-4.31 (m, 1H), 4.02-3.67 (m, 1H), 3.64-3.45 (m, 2H), 3.01-2.65 (m, 5H), 2.09-1.81 (m, 4H), 1.78-1.41 (m, 8H).
Step 1: Cyclopentylamine (830 mg, 9.8 mmol) was dissolved in THF (10 mL) at room temperature. At 0° C., sodium hydride (60% dispersed in mineral oil, 530 mg, 13.3 mmol) was slowly added to the above solution in portions, and the reaction mixture was continued to stir and react at 0° C. for 20 minutes. Subsequently, a solution of 2-1 (1.54 g, 8.9 mmol) in tetrahydrofuran (5 mL) was slowly added dropwise to the above reaction mixture at this temperature. After the dropwise addition was completed, the reaction mixture was stirred at room temperature for 1 hour. The reaction was quenched by adding saturated ammonium chloride aqueous solution. The mixture was extracted with dichloromethane (40 mL×2 times), and the organic phases were combined. The organic phases were washed with saturated brine first, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 810 mg of a mixture of 2-2A and 2-2B.
Step 2: The mixture of 2-2A and 2-2B (200 mg, 0.9 mmol), 1-(methylsulfonyl)piperidin-4-amine (400 mg, 2.25 mmol) and cesium carbonate (734 mg, 2.25 mmol) was dissolved in 1,4-dioxane (10 mL). The reaction system was heated to 120° C. and continued to stir for 5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove most of the solvent. The residue was extracted with dichloromethane (40 mL×2 times). The organic phase was combined, washed with saturated brine first, then dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 25 mg of 4-(cyclopentylamino)-6-((1-(methylsulfonyl)piperidin-4-yl)amino)nicotinamide (compound 2).
MS (ESI) m/z: 364.3 [M+H]+.
1HNMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 5.45 (s, 1H), 4.69 (d, J=5.2 Hz, 1H), 3.92-3.82 (m, 1H), 3.82-3.69 (m, 3H), 3.01-2.90 (m, 2H), 2.81 (s, 3H), 2.19-2.10 (m, 2H), 2.10-1.98 (m, 2H), 1.84-1.72 (m, 2H), 1.71-1.51 (m, 7H).
Step 1: Cyclopentanol (270 mg, 3.16 mmol) was dissolved in THF (10 mL) at room temperature. The reaction mixture was cooled to 0° C. Sodium hydride (60% dispersed in mineral oil, 130 mg, 3.16 mmol) was slowly added to the above solution in portions, and the reaction mixture was continued to stir and react at room temperature for 15 minutes. Subsequently, 1A-1 (0.5 g, 2.87 mmol) was slowly added dropwise to the above reaction mixture at 0° C. After the dropwise addition was completed, the reaction mixture was continued to stir at room temperature for 1 hour. The reaction was quenched by adding saturated ammonium chloride aqueous solution. The mixture was extracted with ethyl acetate, and the organic phases were combined. The organic phase was washed with saturated brine first, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain 420 mg of 2-chloro-4-(cyclopentyloxy)pyrimidine-5-carbonitrile (3-2). This product was directly used in the next reaction step without purification.
Step 2: 3-2 (400 mg, 1.79 mmol), 1-(methylsulfonyl)piperidin-4-amine (479 mg, 2.69 mmol) and cesium carbonate (1.24 g, 4.48 mmol) were dissolved in 1,4-dioxane (10 mL). The reaction system was heated to 120° C. and continued to stir for 3 hours. The reaction mixture was cooled to room temperature, and water (30 mL) and ethyl acetate (30 mL) were added thereto. The reaction mixture was filtered. The filter cake was washed with water, dried in vacuo and purified by preparative high-performance liquid chromatography to obtain mg of 4-(cyclopentyloxy)-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile (compound 3).
MS (ESI) m/z: 366.2 [M+H]+.
1HNMR (400 MHz, CDCl3+TFA) δ 8.55 (s, 1H), 5.66-5.56 (m, 1H), 4.21-4.08 (m, 1H), 3.76-3.59 (m, 2H), 3.22-3.07 (m, 2H), 2.96 (s, 3H), 2.13-1.87 (m, 10H), 1.77-1.73 (m, 2H).
Step 1: Compound 1-1 (1.0 g, 4.52 mmol), phenylboronic acid (0.55 g, 4.52 mmol), sodium carbonate (1.45 g, 13.57 mmol) and bis(triphenylphosphine)palladium(II) chloride (158 mg, 0.22 mmol) were dissolved in 1,4-dioxane/water (10/1, 10 mL). The reaction system was replaced three times with nitrogen. The reaction mixture was heated to 95° C. and continued to stir for 12 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and water (25 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (20 mL×2 times), and the organic phases were combined. The organic phases were washed with saturated brine first, then dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 0.65 g of ethyl 2-chloro-4-phenylpyrimidine-5-carboxylate (4-2).
MS (ESI) m/z: 263.2 [M+H]+.
Step 2: 4-2 (650 mg, 2.48 mmol), 1-(methylsulfonyl)piperidin-4-amine (880 mg, 4.95 mmol) and cesium carbonate (2.44 g, 7.45 mmol) were dissolved in 1,4-dioxane (10 mL). The reaction system was heated to 120° C. and continued to stir for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove most of the solvent. The residue was extracted with dichloromethane. The organic phase was combined, washed with saturated brine first, then dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 600 mg of ethyl 2-((1-(methylsulfonyl)piperidin-4-yl)amino)-4-phenylpyrimidine-5-carboxylate (4-3).
MS (ESI) m/z: 405.3 [M+H]+.
Step 3: Compound 4-3 (600 mg, 2.29 mmol) was dissolved in THF/water (2.5/1, 7.5 mL) at room temperature. Subsequently, lithium hydroxide monohydrate (290 mg, 2.85 mmol) was added to the above solution. The reaction mixture was stirred at room temperature for 3 hours and concentrated under reduced pressure to remove tetrahydrofuran, and the solution was neutralized to pH=4 with 3 mol/L hydrochloric acid aqueous solution. The mixture was extracted with dichloromethane (100 mL×2 times), and the organic phases were combined. The organic phases were washed with saturated brine first, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to obtain 450 mg of 2-((1-(methylsulfonyl)piperidin-4-yl)amino)-4-phenylpyrimidine-5-carboxylic acid (4-4).
MS (ESI) m/z: 377.2 [M+H]+.
Step 4: N,N-Dimethylformamide (1 drop) and 4-4 (200 mg, 0.53 mmol) were dissolved in dichloromethane (5 mL) at room temperature. The reaction mixture was cooled to 0° C., and then oxalyl chloride (203 mg, 1.6 mmol) was added dropwise to the above reaction mixture within 5 minutes. The reaction mixture was warmed to room temperature and stirred for 0.5 hours. At 0° C., the above reaction mixture was added dropwise to ammonia water (10 mL) within 30 minutes. The reaction mixture was filtrated and dried to obtain 155 mg of 2-((1-(methylsulfonyl)piperidin-4-yl)amino)-4-phenylpyrimidine-5-carboxamide (4-5).
MS (ESI) m/z: 376.2 [M+H]+.
Step 5: 4-5 (100 mg, 0.27 mmol) and triethylamine (300 mg, 3.24 mmol) were dissolved in THF (5 mL). The reaction system was cooled to −65° C., and trifluoroacetic anhydride (270 mg, 1.3 mmol) was slowly added dropwise to the solution. The reaction mixture was continued to stir and react at −65° C. for 30 minutes. The reaction was quenched by adding saturated sodium bicarbonate aqueous solution to the reaction mixture. The mixture was extracted with dichloromethane (100 mL×2 times), and the organic phases were combined. The organic phases were washed with saturated brine first, then dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 50 mg of 2-((1-(methylsulfonyl)piperidin-4-yl)amino)-4-phenylpyrimidine-5-carbonitrile (compound 4).
MS (ESI) m/z: 358.3 [M+H]+.
1HNMR (400 MHz, CDCl3) δ 8.63 (s, 0.6H), 8.56 (s, 0.5H), 8.01 (d, J=6.7 Hz, 1H), 7.96 (d, J=7.0 Hz, 1H), 7.64-7.48 (m, 3H), 5.87-5.67 (m, 1H), 4.22-4.05 (m, 1H), 3.80 (br.s., 2H), 2.93 (t, J=11.3 Hz, 2H), 2.83 (s, 3H), 2.26-2.14 (m, 2H), 1.86-1.54 (m, 2H).
Step 1: 1B-1 (100 mg, 0.92 mmol) and N,N-diisopropylethylamine (550 mg, 1.38 mmol) were dissolved in dichloromethane (5 mL) at 0° C. Cyclopentylamine (78.2 mg, 0.92 mmol) was slowly added dropwise to the reaction mixture at this temperature. After the dropwise addition was completed, the reaction mixture was continued to stir at room temperature for 1 hour. The reaction was quenched by adding saturated sodium bicarbonate aqueous solution to the reaction mixture. The mixture was extracted with dichloromethane (100 mL×2 times), and the organic phases were combined, washed with saturated brine first, then dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure to obtain 155 mg of a mixture of 5-2A and 5-2B. This mixture was directly used in the next reaction step without purification.
Step 2: 5-2A and 5-2B (150 mg, 0.57 mmol), 1-(methylsulfonyl)piperidin-4-amine (151 mg, 0.85 mmol) and cesium carbonate (372 mg, 1.14 mmol) were dissolved in 1,4-dioxane (10 mL). The reaction mixture was heated to 120° C. and reacted for 5 hours, then cooled to room temperature. The reaction mixture was concentrated under reduced pressure to remove most of the solvent, and the residue was extracted with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to obtain 22 mg of N4-cyclopentyl-N2-(1-(methylsulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidine-2,4-diamine (compound 5).
MS (ESI) m/z: 408.2 [M+H]+.
1HNMR (400 MHz, DMSO-d6) δ 8.04 (s, 0.4H), 7.99 (s, 0.6H), 7.39 (d, J=6.0 Hz, 0.6H), 7.21 (d, J=6.8 Hz, 0.6H), 6.26-6.10 (m, 1H), 4.55-4.46 (m, 0.4H), 4.43-4.29 (m, 0.6H), 3.92-3.73 (m, 1H), 3.62-3.46 (m, 2H), 2.67-2.72 (m, 5H), 2.03-1.78 (m, 4H), 1.76-1.39 (m, 8H).
Cyclopentanol (33.7 mg, 0.4 mmol) was dissolved in N,N-dimethylformamide (2 mL) at room temperature. Subsequently, sodium hydride (9.7 mg, 0.4 mmol) was added to the above reaction mixture under an ice bath and nitrogen atmosphere, and compound 1A (100.0 mg, 0.3 mmol) was added after the above reaction mixture was stirred for 15 minutes under an ice bath. The reaction mixture was heated to 100° C. and stirred for 1 hour. Water (10 mL) was added to the reaction mixture to quench the reaction. The mixture was extracted with ethyl acetate (30 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (10 mL×3 times) first, then dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to obtain 9.2 mg of 4-(cyclopentyloxy)-2-((1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile (compound 6).
MS (ESI) m/z: 432.2 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 0.4H), 8.43 (s, 0.6H), 8.33 (s, 0.5H), 8.31 (s, 0.5H), 8.27 (d, J=7.3 Hz, 0.6H), 8.11 (d, J=7.8 Hz, 0.4H), 7.79 (s, 0.5H), 7.77 (s, 0.4H), 5.48-5.38 (m, 1H), 3.91 (s, 3H), 3.78 (br.s, 1H), 3.53-3.40 (m, 2H), 2.44-2.30 (m, 2H), 2.02-1.84 (m, 4H), 1.78-1.51 (m, 8H).
(S)-3-Hydroxytetrahydrofuran (16.0 g, 0.2 mmol) was dissolved in N,N-dimethylformamide (1 mL) at room temperature under nitrogen atmosphere. Subsequently, sodium hydride (7.2 mg, 0.2 mmol, 60% dispersed in mineral oil) was added to the above solution under cooling in an ice-water bath. After the reaction mixture was stirred at room temperature for 10 minutes, compound 1B (50.0 mg, 0.1 mmol) was slowly added to the reaction mixture. The reaction system was heated to 100° C. and continued to stir for 1 hour. Water (20 mL) was added to the reaction mixture to quench the reaction. The mixture was extracted with ethyl acetate (5 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (20 mL×3 times) first, then dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to obtain 28.0 mg of (S)—N-(1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-4-((tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-amine (compound 7).
MS (ESI) m/z: 477.2 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ 8.41-8.27 (m, 2H), 8.03 (d, J=7.3 Hz, 0.6H), 7.88 (d, J=7.2 Hz, 0.4H), 7.78 (d, J=6.4 Hz, 1H), 5.65-5.50 (m, 1H), 4.03-3.85 (m, 4H), 3.85-3.66 (m, 4H), 3.55-3.42 (m, 2H), 2.48-2.30 (m, 2H), 2.29-2.14 (m, 1H), 2.07-1.85 (m, 3H), 1.70-1.50 (m, 2H).
Step 1: Compound 1A-3 (556.0 mg, 2.4 mmol) was dissolved in dichloromethane (3 mL) at room temperature. Subsequently, N,N-diisopropylethylamine (940.0 mg, 7.3 mmol) was added to the reaction mixture. p-Bromobenzenesulfonyl chloride (743.0 mg, 3.3 mmol) was added dropwise to the above solution at 0° C., and the reaction mixture was stirred overnight at room temperature. Water (20 mL) was added to the reaction mixture to quench the reaction. The mixture was extracted with ethyl acetate (30 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (30 mL) first, then dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 830.0 mg of 2-((1-((4-bromophenyl)sulfonyl)piperidin-4-yl)amino)-4-chloropyrimidine-5-carbonitrile (8-2).
MS (ESI) m/z: 456.0 [M+H]+.
Step 2: Compound 8-2 (100.0 mg, 0.2 mmol) was dissolved in N,N-dimethylacetamide(1 mL) at room temperature. Subsequently, N,N-diisopropylethylamine (85.0 mg, 0.7 mmol) and (S)-3-aminotetrahydrofuran (29.0 mg, 0.3 mmol) were sequentially added to the above reaction mixture. The reaction mixture was heated to 80° C. and stirred for 4 hours. Water (20 mL) was added to the reaction mixture to quench the reaction. The mixture was extracted with ethyl acetate (30 mL×3 times), and the organic phases were combined. The organic phases were washed with water (30 mL×3 times) and saturated brine (30 mL) first, then dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to obtain 95.0 mg of (S)-2-((1-((4-bromophenyl)sulfonyl)piperidin-4-yl)amino)-4-((tetrahydrofuran-3-yl)amino)pyrimidine-5-carbonitrile (8-3).
MS (ESI) m/z: 507.0 [M+H]+.
Step 3: Compound 8-3 (95.0 mg, 0.2 mmol) was dissolved in 1,4-dioxane/water (5/1 mL) at room temperature under nitrogen atmosphere. Subsequently, 1-methyl-4-pyrazole boronic acid pinacol ester (50.0 mg, 0.2 mmol), PdCl2(dppf) (15.0 mg, 0.02 mmol) and anhydrous sodium carbonate (42 mg, 0.4 mmol) were added to the above reaction mixture in portions. The reaction mixture was heated to 100° C. and stirred for 1 hour. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to obtain 35.6 mg of (S)-2-((1-((4-(1-methyl-1H-pyrazol-4-yl)phenyl)sulfonyl)piperidin-4-yl)amino)-4-((tetrahydrofuran-3-yl)amino)pyrimidine-5-carbonitrile (compound 8). ee value: 98.4%.
MS (ESI) m/z: 509.2 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 8.17 (s, 0.3H), 8.13 (s, 0.7H), 8.00 (s, 1H), 7.82 (s, 0.7H), 7.80 (s, 1.3H), 7.73-7.64 (m, 2.7H), 7.50 (d, J=5.9 Hz, 1H), 7.38 (d, J=6.8 Hz, 0.4H), 4.59-4.37 (m, 1H), 3.89 (s, 3H), 3.84-3.61 (m, 5H), 3.59-3.45 (m, 3H), 2.15-1.80 (m, 5H), 1.63-1.46 (m, 2H).
Step 1: 2,2,6,6-Tetramethylpiperidine (850.0 mg, 6.0 mmol) was dissolved in THF (10 mL) at room temperature. The mixture was cooled to −30° C., and then n-butyllithium (3.76 mL, 6.0 mmol) was slowly added dropwise to the above solution at −30° C. under nitrogen atmosphere. The reaction mixture was stirred at −30° C. for 30 minutes. After 30 minutes, the above solution was cooled to −78° C. A mixed solution of bis[(pinacolato)boryl]methane (1350.0 mg, 5.0 mmol) and tetrahydrofuran (5 mL), and another mixed solution of cyclopentanone (422 mg, 5.0 mmol) and tetrahydrofuran (5 mL) were slowly added dropwise in portions. The reaction mixture was stirred at room temperature for 18 hours. Ammonium chloride aqueous solution (10 mL) was added to the reaction mixture to quench the reaction. The mixture was concentrated under reduced pressure and extracted with ethyl acetate (40 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (30 mL) first, then dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 510 mg of 2-(cyclopentylidenemethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1A).
1H NMR (400 MHz, CDCl3) δ 5.27 (t, J=2.0 Hz, 1H), 2.52 (t, J=7.2 Hz, 2H), 2.36 (t, J=7.1 Hz, 2H), 1.77-1.59 (m, 4H), 1.25 (s, 12H).
Step 2: Compound 1A (100.0 mg, 0.3 mmol) was dissolved in 1,4-dioxane/water (5/1 mL) at room temperature under nitrogen atmosphere. Subsequently, 2-(cyclopentylidenemethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (62.0 mg, 0.3 mg mol), PdCl2(dppf) (20.0 mg, 0.03 mmol) and anhydrous sodium carbonate (56 mg, 0.5 mmol) were sequentially added to the above reaction mixture. The reaction mixture was heated to 100° C. and stirred for 1 hour. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to obtain 44 mg of 4-(cyclopentylidenemethyl)-2-((1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile (compound 9).
MS (ESI) m/z: 428.2 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ 8.58 (s, 0.3H), 8.55 (s, 0.7H), 8.35 (s, 0.7H), 8.32 (s, 0.3H), 8.16 (d, J=7.5 Hz, 0.7H), 7.95 (d, J=7.5 Hz, 0.4H), 7.79 (s, 0.6H), 7.77 (s, 0.4H), 6.47 (s, 0.7H), 6.42 (s, 0.4H), 3.91 (s, 3H), 3.83-3.70 (m, 1H), 3.56-3.45 (m, 2H), 2.96-2.76 (m, 2H), 2.59-2.53 (m, 2H), 2.44-2.35 (m, 2H), 2.01-1.86 (m, 2H), 1.77-1.52 (m, 6H).
4-(Cyclopentylidenemethyl)-2-((1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile (33 mg, 0.07 mmol) was dissolved in methanol (2 mL) at room temperature. Subsequently, 10% palladium-carbon (10 mg) was added to the above solution. After the reaction system was replaced with hydrogen for 3 times, the reaction mixture was stirred for 1 hour under hydrogen atmosphere. After filtration, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to obtain 3.6 mg of 4-(cyclopentylmethyl)-2-((1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile (compound 10).
MS (ESI) m/z: 430.2 [M+H]+.
1HNMR (400 MHz, DMSO-d6) δ 8.61 (s, 0.5H), 8.56 (s, 0.5H), 8.33 (s, 0.5H), 8.32 (s, 0.5H), 8.26 (d, J=8.0 Hz, 0.5H), 8.22 (d, J=7.2 Hz, 0.5H), 7.77 (d, J=6.8 Hz, 1H), 3.91 (s, 3H), 3.79 (br.s., 1H), 3.51-3.43 (m, 2H), 2.69-2.64 (m, 2H), 2.46-2.38 (m, 2H), 2.26-2.19 (m, 1H), 1.98-1.85 (m, 2H), 1.72-1.42 (m, 8H), 1.26-1.14 (m, 2H).
Step 1: Compound 1A-2 (80.0 mg, 0.2 mmol) was dissolved in N,N-dimethylformamide (1 mL) at room temperature. Subsequently, N,N-diisopropylethylamine (50.0 mg, 0.39 mmol) and (1,3-cis)-3-aminocyclopentanol hydrochloride (49.0 mg, 0.3 mmol) were sequentially added to the above reaction mixture. The reaction mixture was heated to 120° C. and stirred for 6 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was quenched with water (10 mL). The mixture was extracted with ethyl acetate (30 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (10 mL×3 times) first, then dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 53.0 mg of tert-butyl 4-((5-cyano-4-(((1,3-cis)-3-hydroxycyclopentyl)amino)pyrimidin-2-yl)amino)piperidine-1-carboxylate (11-2).
MS (ESI) m/z: 403.2 [M+H]+.
Step 2: Compound 11-2 (53.0 mg, 0.1 mmol) was dissolved in 1,4-dioxane (1 mL) at room temperature. Subsequently, a hydrogen chloride-dioxane solution (4 mol/L, 2 mL) was added thereto. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain 40.0 mg of 4-((1,3-cis)-3-hydroxycyclopentyl)amino)-2-(piperidin-4-ylamino)pyrimidine-5-carbonitrile (11-3).
MS (ESI) M/Z:303.2 [M+H]+.
Step 3: Compound 11-3 (40.0 mg, 0.1 mmol) was dissolved in dichloromethane (3 mL) at room temperature. Subsequently, N,N-diisopropylethylamine (50.0 mg, 0.6 mmol) was added thereto. 1-Methyl-1H-pyrazole-4-sulfonyl chloride (28.0 mg, 0.1 mmol) was added dropwise to the above solution at 0° C., and the reaction mixture was stirred overnight at room temperature. Water (20 mL) was added to the reaction mixture to quench the reaction. The mixture was extracted with ethyl acetate (30 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (30 mL) first, then dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to obtain 28.4 mg of 4-((1,3-cis)-3-hydroxycyclopentyl)amino)-2-((1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile (compound 11).
MS (ESI) m/z: 447.2 [M+H]+.
1HNMR (400 MHz, DMSO-d6) δ 8.32 (s, 0.6H), 8.31 (s, 0.4H), 8.17 (s, 0.4H), 8.13 (s, 0.5H), 7.78 (s, 0.6H), 7.76 (s, 0.4H), 7.65 (d, J=7.2 Hz, 0.6H), 7.48 (d, J=7.6 Hz, 0.4H), 7.07 (d, J=7.6 Hz, 0.6H), 7.01 (d, J=8.0 Hz, 0.4H), 4.81 (d, J=3.6 Hz, 0.5H), 4.77 (d, J=4.0 Hz, 0.7H), 4.51-4.29 (m, 1H), 4.17-4.08 (m, 1H), 3.90 (s, 3H), 3.72 (br.s., 1H), 3.51-3.39 (m, 3H), 2.41-2.31 (m, 1H), 2.05-1.79 (m, 4H), 1.76-1.46 (m, 6H).
Compound 11 was subjected to chiral resolution, and the resolution conditions were as follows: preparative column 0.46 cm I.D.*15 cmL; mobile phase: CO2:MeOH (0.1% DEA)=60:40; flow rate: 2.5 mL/min; detection wavelength: 254 nm. The product was collected and lyophilized under reduced pressure. A compound with a retention time of 3.77 minutes was obtained, and the ee value was 99.66%. The absolute configuration was not determined. It is an enantiomer of compound 13.
MS (ESI) m/z: 447.2 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 0.6H), 8.31 (s, 0.4H), 8.17 (s, 0.4H), 8.13 (s, 0.5H), 7.78 (s, 0.6H), 7.76 (s, 0.4H), 7.65 (d, J=7.2 Hz, 0.6H), 7.48 (d, J=7.6 Hz, 0.4H), 7.07 (d, J=7.6 Hz, 0.6H), 7.01 (d, J=8.0 Hz, 0.4H), 4.81 (d, J=3.6 Hz, 0.5H), 4.77 (d, J=4.0 Hz, 0.7H), 4.51-4.29 (m, 1H), 4.17-4.08 (m, 1H), 3.90 (s, 3H), 3.72 (br.s., 1H), 3.51-3.39 (m, 3H), 2.41-2.31 (m, 1H), 2.05-1.79 (m, 4H), 1.76-1.46 (m, 6H).
Compound 11 was subjected to chiral resolution, and the resolution conditions were as follows: preparative column 0.46 cm I.D.*15 cmL; mobile phase: CO2:MeOH (0.1% DEA)=60:40; flow rate: 2.5 mL/min; detection wavelength: 254 nm. The product was collected and lyophilized under reduced pressure. A compound with a retention time of 4.60 minutes was obtained, and the ee value was 99.88%. The absolute configuration was not determined. It was an enantiomer of compound 12.
MS (ESI) m/z: 447.2 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 0.6H), 8.31 (s, 0.4H), 8.17 (s, 0.4H), 8.13 (s, 0.5H), 7.78 (s, 0.6H), 7.76 (s, 0.4H), 7.65 (d, J=7.2 Hz, 0.6H), 7.48 (d, J=7.6 Hz, 0.4H), 7.07 (d, J=7.6 Hz, 0.6H), 7.01 (d, J=8.0 Hz, 0.4H), 4.81 (d, J=3.6 Hz, 0.5H), 4.77 (d, J=4.0 Hz, 0.7H), 4.51-4.29 (m, 1H), 4.17-4.08 (m, 1H), 3.90 (s, 3H), 3.72 (br.s., 1H), 3.51-3.39 (m, 3H), 2.41-2.31 (m, 1H), 2.05-1.79 (m, 4H), 1.76-1.46 (m, 6H).
Step 1: Compound (1R, 2R)-2-aminocyclopentanol hydrochloride (240.0 mg, 1.7 mmol) was dissolved in acetone/water (20 mL/1.4 mL) at room temperature. Subsequently, potassium carbonate (720.0 mg, 5.2 mmol) and benzyl bromide (0.4 mL, 3.5 mmol) were sequentially added to the above reaction mixture. The reaction mixture was heated to 56° C. and stirred for 16 hours. Water (20 mL) was added to the reaction mixture to quench the reaction. The mixture was concentrated under reduced pressure and extracted with ethyl acetate (30 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (30 mL) first, then dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 340 mg of (1R,2R)-2-(dibenzylamino)cyclopentan-1-ol (compound 14).
MS (ESI) m/z: 282.2 [M+H]+.
Step 2: Compound 14-2 (100.0 mg, 0.4 mmol) was dissolved in THE (5 mL) at room temperature. Subsequently, sodium hydride (27 mg, 0.7 mmol, 60% dispersed in mineral oil) was added in portions to the above solution under cooling in an ice-water bath. After the reaction mixture was stirred at room temperature for 30 minutes, iodomethane (99 mg, 0.7 mmol) was slowly added dropwise to the above reaction mixture. The reaction mixture was continued to stir overnight at room temperature. Water (10 mL) was added to the reaction system to quench. The mixture was extracted with ethyl acetate (20 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (10 mL) first, then dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 80 mg of (1R,2R)—N,N-dibenzyl-2-methoxycyclopentan-1-amine (14-3).
MS (ESI) m/z: 296.2 [M+H]+.
Step 3: Compound 14-3 (80 mg, 0.3 mmol) was dissolved in methanol (5 mL). Subsequently, 10% palladium/carbon (8 mg) was added to the above solution. After the reaction system was replaced with hydrogen three times, the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered through diatomite. The filter cake was washed with methanol (10 mL×3 times), and the resulting filtrate was concentrated under reduced pressure to obtain 46 mg of (1R,2R)-2-methoxycyclopentan-1-amine (14-4).
1H NMR (400 MHz, DMSO-d6) δ 8.26 (br. s., 2H), 3.80-3.68 (m, 1H), 3.37-3.27 (m, 1H), 3.25 (s, 3H), 2.06-1.86 (m, 2H), 1.79-1.47 (m, 4H).
Step 4: Compound 14-4 (70.0 mg, 0.2 mmol) was dissolved in N,N-dimethylacetamide (1 mL) at room temperature. Subsequently, N,N-diisopropylethylamine (70.0 mg, 0.6 mmol) and compound 1A (31.0 mg, 0.3 mmol) were sequentially added to the above reaction mixture. The reaction mixture was heated to 80° C. and stirred for 4 hours. Water (20 mL) was added to the reaction mixture to quench the reaction. The mixture was extracted with ethyl acetate (30 mL×3 times), and the organic phases were combined. The organic phases were washed with water (30 mL×3 times) and saturated brine (30 mL) first, then dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to obtain 31.5 mg of 4-((1R,2R)-2-methoxycyclopentyl)amino)-2-((1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile (compound 14).
MS (ESI) m/z: 461.2 [M+H]+.
1HNMR (400 MHz, DMSO-d6) δ 8.34 (s, 0.6H), 8.31 (s, 0.4H), 8.17 (s, 0.4H), 8.13 (s, 0.6H), 7.78 (s, 0.6H), 7.76 (s, 0.4H), 7.67 (d, J=7.4 Hz, 0.6H), 7.46 (d, J=7.8 Hz, 0.4H), 7.35 (d, J=7.6 Hz, 1H), 4.47-4.37 (m, 0.5H), 4.28-4.19 (m, 0.7H), 3.91 (s, 3H), 3.79-3.65 (m, 2H), 3.53-3.41 (m, 2H), 3.20 (s, 1.3H), 3.13 (s, 1.7H), 2.44-2.29 (m, 2H), 2.00-1.72 (m, 4H), 1.72-1.39 (m, 6H).
Step 1: Compound 1A-2 (605 mg, 1.79 mmol) was dissolved in N,N-dimethylacetamide (4 mL) at room temperature. Subsequently, cyclopentylamine (183.2 mg, 2.15 mmol) and N,N-diisopropylethylamine (463.9 mg, 3.59 mmol) were sequentially added to the reaction mixture. The reaction mixture was heated to 80° C. and stirred overnight. The reaction mixture was cooled to room temperature and quenched by adding water (40 mL). The mixture was extracted with dichloromethane (40 mL×3 times). The organic phases were combined, washed with saturated brine (100 mL) first, and then dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 580 mg of tert-butyl 4-((5-cyano-4-(cyclopentylamino)pyrimidin-2-yl)amino)piperidine-1-carboxylate (15-2).
MS (ESI) m/z: 387.2 [M+H]+.
Step 2: Compound 15-2 (580 mg, 1.50 mmol) was dissolved in 1,4-dioxane (3 mL) at room temperature. Subsequently, a hydrogen chloride-dioxane solution (3 mL, 6 mmol) was added thereto. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain 610 mg of 4-(cyclopentylamino)-2-(piperidin-4-ylamino)pyrimidine-5-carbonitrile (15-3).
MS (ESI) m/z: 287.2 [M+H]+.
Step 3: Compound 15-3 (610.0 mg, 2.13 mmol) was dissolved in dichloromethane (9 mL) at room temperature. Subsequently, N,N-diisopropylethylamine (826.0 mg, 6.39 mmol) was added thereto. p-Bromobenzenesulfonyl chloride (649.0 mg, 2.56 mmol) was added dropwise to the above solution at 0° C., and the reaction mixture was stirred at room temperature for 3 hours. Water (40 mL) was added to the reaction mixture to quench the reaction. The mixture was extracted with dichloromethane (40 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (100 mL) first, then dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 605.0 mg of 2-((1-((4-bromophenyl)sulfonyl)piperidin-4-yl)amino)-4-(cyclopentylamino)pyrimidine-5-carbonitrile (15-4).
MS (ESI) m/z: 505.0 [M+H]+.
Step 4: Compound 15-4 (300.0 mg, 0.59 mmol) was dissolved in 1,4-dioxane (4 mL) and water (0.4 mL) at room temperature. Subsequently, compound 15-1A (130.0 mg, 0.21 mmol), sodium carbonate (126 mg, 1.19 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (92 mg, 0.12 mmol) were sequentially added thereto, and the reaction mixture was stirred overnight at 100° C. After cooling the reaction mixture to room temperature, water (40 mL) was added to the reaction mixture to quench. The mixture was extracted with dichloromethane (40 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (100 mL) first, then dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 330.0 mg of tert-butyl 4-(4-((4-((5-cyano-4-(cyclopentylamino)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (15-5).
MS (ESI) m/z: 608.2 [M+H]+.
Step 5: Compound 15-5 (80 mg, 1.50 mmol) was dissolved in 1,4-dioxane (3 mL) at room temperature. Subsequently, a hydrogen chloride-dioxane solution (3 mL, 6 mmol) was added thereto. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was added with dichloromethane (20 mL×3 times) and concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to obtain 20.2 mg of 4-(cyclopentylamino)-2-((1-((4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile (compound 15).
MS (ESI) m/z: 508.2 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ 8.13 (s, 0.4H), 8.10 (s, 0.6H), 7.72-7.64 (m, 4H), 7.60 (d, J=7.2 Hz, 0.6H), 7.43 (d, J=7.8 Hz, 0.4H), 7.23 (d, J=6.6 Hz, 0.6H), 7.13 (d, J=7.6 Hz, 0.4H), 6.43 (s, 1H), 4.44-4.31 (m, 0.4H), 4.27-4.14 (m, 0.6H), 3.68 (br.s., 1H), 3.60-3.46 (m, 2H), 3.40 (br.s., 2H), 2.92 (s, 2H), 2.44-2.31 (m, 4H), 1.95-1.74 (m, 4H), 1.72-1.36 (m, 9H).
Compound 15 (70.0 mg, 0.14 mmol) was dissolved in methanol (4 mL) at room temperature. Subsequently, acetic acid (16.8 mg, 0.28 mmol) and formaldehyde aqueous solution (21 mg, 0.70 mmol) were sequentially added thereto, and the mixture was stirred at room temperature for 0.5 hours; then sodium triacetoxyborohydride (152.6 mg, 0.70 mmol) was added to the system, and the reaction was continued for 0.5 hours. The reaction mixture was added with dichloromethane (20 mL×3 times) and concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to obtain 9.8 mg of 4-(cyclopentylamino)-2-((1-((4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile (compound 16).
MS (ESI) m/z: 522.2 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ 8.13 (s, 0.4H), 8.10 (s, 0.6H), 7.73-7.64 (m, 4H), 7.60 (d, J=7.2 Hz, 0.6H), 7.43 (d, J=7.8 Hz, 0.4H), 7.23 (d, J=6.6 Hz, 0.6H), 7.13 (d, J=7.6 Hz, 0.4H), 6.41-6.35 (m, 1H), 4.42-4.30 (m, 0.4H), 4.27-4.14 (m, 0.6H), 3.68 (br.s., 1H), 3.60-3.43 (m, 2H), 3.05 (d, J=3.0 Hz, 2H), 2.62-2.54 (m, 2H), 2.51 (s, 2H), 2.47-2.31 (m, 2H), 2.28 (s, 3H), 1.95-1.75 (m, 4H), 1.70-1.35 (m, 8H).
Compound 16 (50.0 mg, 0.10 mmol) was dissolved in ethanol (4 mL) at room temperature. Subsequently, wet palladium on carbon (30 mg, 60%) was added thereto in portions, and stirred at room temperature for 6 hours. The reaction mixture was filtered, and the filter cake was washed with ethanol (20 mL×3 times). The filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to obtain 9.3 mg of 4-(cyclopentylamino)-2-((1-((4-(1-methylpiperidin-4-yl)phenyl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile (compound 17).
MS (ESI) m/z: 524.3 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ 8.13 (s, 0.4H), 8.10 (s, 0.6H), 7.72-7.58 (m, 2.5H), 7.52 (s, 1H), 7.50 (s, 1H), 7.43 (d, J=7.7 Hz, 0.4H), 7.24 (d, J=6.6 Hz, 0.6H), 7.13 (d, J=7.6 Hz, 0.4H), 4.44-4.30 (m, 0.4H), 4.26-4.13 (m, 0.6H), 3.67 (s, 1H), 3.60-3.44 (m, 2H), 2.87 (d, J=11.3 Hz, 2H), 2.69-2.55 (m, 2H), 2.44-2.30 (m, 2H), 2.19 (s, 3H), 2.04-1.33 (m, 17H).
Compound 15-4 (60.0 mg, 0.1 mmol) was dissolved in toluene (5 mL) at room temperature under nitrogen atmosphere. Subsequently, N-methylpiperazine (17.8 mg, 0.2 mmol), Pd2(dba)3 (11.0 mg, 0.01 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (11.4 mg, 0.02 mmol) and anhydrous cesium carbonate (78 mg, 0.2 mmol) were sequentially added to the above reaction mixture. The reaction mixture was heated to 100° C. and stirred for 18 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to obtain 6.3 mg of 4-(cyclopentylamino)-2-((1-((4-(4-methylpiperazin-1-yl)phenyl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile (compound 18).
MS (ESI) m/z: 525.2 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 0.4H), 8.10 (s, 0.6H), 7.61 (d, J=7.0 Hz, 0.6H), 7.51 (d, J=8.8 Hz, 2H), 7.43 (d, J=7.4 Hz, 0.4H), 7.24 (d, J=6.8 Hz, 0.6H), 7.13 (d, J=7.8 Hz, 0.4H), 7.07 (d, J=9.0 Hz, 2H), 4.45-4.30 (m, 0.4H), 4.28-4.13 (m, 0.6H), 3.74-3.58 (m, 1H), 3.55-3.39 (m, 2H), 3.31-3.25 (m, 2H), 2.45-2.26 (m, 7H), 2.22 (s, 3H), 1.94-1.76 (m, 4H), 1.72-1.61 (m, 2H), 1.60-1.34 (m, 7H).
Step 1: Methyl-1,2-cyclopentene oxide (70.0 mg, 0.7 mmol) was dissolved in ammonia water (1 mL) at room temperature. The reaction system was heated to 90° C. and reacted for 15 hours. A methanol solution of hydrochloric acid (4 mol) was added to the reaction mixture under an ice-water bath until pH=3. The reaction mixture was concentrated under reduced pressure to obtain 200 mg of compound 19-2, which was directly used in the next reaction step.
MS (ESI) m/z: 116.2 [M+H]+.
Step 2: Compound 19-2 (90.0 mg, 0.2 mmol) was dissolved in N,N-dimethylformamide (0.5 mL) at room temperature. Subsequently, N,N-diisopropylethylamine (91.0 mg, 0.7 mmol) and compound 1A (91.0 mg, 0.6 mmol) were added to the above solution. The reaction system was heated to 80° C. and continued to stir for 15 hours. Water (20 mL) was added to the reaction mixture to quench the reaction. The mixture was extracted with ethyl acetate (8 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (30 mL) first, then dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to obtain 35.0 mg of the final product 4-(trans-2-hydroxy-2-methylcyclopentyl)amino)-2-((1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile (compound 19).
MS (ESI) m/z: 461.2 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ 8.35-8.29 (m, 1H), 8.22-8.11 (m, 1H), 7.81-7.73 (m, 1H), 7.64 (d, J=7.2 Hz, 0.6H), 7.53 (d, J=7.6 Hz, 0.4H), 6.87 (d, J=8.0 Hz, 0.5H), 6.77 (d, J=8.4 Hz, 0.4H), 4.50 (s, 0.4H), 4.41 (s, 0.5H), 4.38-4.24 (m, 1H), 3.91 (s, 3H), 3.80-3.68 (m, 1H), 3.59-3.32 (m, 2H), 2.48-2.28 (m, 2H), 2.09-1.81 (m, 3H), 1.71-1.41 (m, 7H), 1.13-0.99 (m, 3H).
Compound 19 was subjected to chiral resolution, and the resolution conditions were as follows: preparative column IG 25*250 mm, 10 μm (Daicel); mobile phase: CO2:MeOH (0.2% ammonia methanol)=60:40; flow rate: 100 g/min; detection wavelength: 214 nm. The product was collected and lyophilized under reduced pressure. The resulting product was purified by preparative high performance liquid chromatography. A compound with a retention time of 4.05 minutes was obtained, and the ee value was 100%.
The absolute configuration was not determined. It was an enantiomer of compound 21.
MS (ESI) m/z: 461.2 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 0.5H), 8.31 (s, 0.5H), 8.21 (s, 0.4H), 8.18 (s, 0.5H), 7.77 (s, 0.5H), 7.79-7.75 (m, 1H), 7.72 (d, J=6.4 Hz, 0.6H), 7.61 (d, J=6.4 Hz, 0.5H), 7.05 (d, J=7.6 Hz, 0.6H), 6.84 (d, J=8.0 Hz, 0.5H), 4.39-4.28 (m, 1H), 3.91 (s, 3H), 3.78-3.75 (m, 1H), 3.53-3.38 (m, 2H), 2.46-2.28 (m, 2H), 2.07-1.83 (m, 3H), 1.69-1.45 (m, 7H), 1.12-1.00 (m, 3H).
Compound 19 was subjected to chiral resolution, and the resolution conditions were as follows: preparative column IG 25*250 mm, 10 μm (Daicel); mobile phase: CO2:MeOH (0.2% ammonia methanol)=60:40; flow rate: 100 g/min; detection wavelength: 214 nm. The product was collected and lyophilized under reduced pressure. The resulting product was purified by preparative high performance liquid chromatography. A compound with a retention time of 5.44 minutes was obtained, and the ee value was 100%.
The absolute configuration was not determined. It was an enantiomer of compound 20.
MS (ESI) m/z: 461.2 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 0.5H), 8.31 (s, 0.5H), 8.19 (s, 0.5H), 8.13 (s, 0.6H), 7.77 (s, 0.5H), 7.76 (s, 0.5H), 7.63 (d, J=7.6 Hz, 0.7H), 7.53 (d, J=7.6 Hz, 0.5H), 6.87 (d, J=7.6 Hz, 0.6H), 6.76 (d, J=8.0 Hz, 0.5H), 4.50 (s, 0.5H), 4.41 (s, 0.6H), 4.39-4.26 (m, 1H), 3.91 (s, 3H), 3.81-3.66 (m, 1H), 3.54-3.39 (m, 2H), 2.46-2.33 (m, 2H), 2.07-1.81 (m, 3H), 1.72-1.45 (m, 7H), 1.12-1.00 (m, 3H).
Step 1: Compound 15-4 (100.0 mg, 0.2 mmol) was dissolved in tetrahydrofuran (6 mL) at room temperature. Subsequently, a solution of n-butyllithium/n-hexane (2.5 mol/L, 0.8 mL, 2.0 mmol) was added thereto under nitrogen atmosphere at −78° C., and the reaction mixture was stirred at −78° C. for 10 minutes. N,N-Dimethylacetamide (146.2 mg, 2.4 mmol) was further added thereto. The reaction mixture was stirred at room temperature for 2 hours. Saturated ammonium chloride aqueous solution (20 mL) was added to the reaction mixture to quench the reaction. The mixture was extracted with ethyl acetate (10 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (30 mL) first, then dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 80.0 mg of 4-(cyclopentylamino)-2-(((1-((4-formylphenyl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile (22-2).
MS (ESI) m/z: 455.2 [M+H]+.
Step 2: Compound 22-2 (80.0 mg, 0.18 mmol) and N-methylpiperazine (18.0 mg, 0.18 mmol) were dissolved in 1,2-dichloroethane (1 mL) at room temperature. After the system was replaced with nitrogen three times, acetic acid (108.2 mg, 1.8 mmol) was added thereto under an ice-water bath. The reaction mixture was stirred at room temperature for 2 hours. Finally, sodium triacetoxyborohydride (114.4 mg, 0.54 mmol) was added thereto under an ice-water bath. The reaction mixture was stirred at room temperature for 2 hours. Saturated sodium bicarbonate aqueous solution (30 mL) was added to the reaction mixture to quench the reaction. The mixture was extracted with ethyl acetate (10 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (30 mL) first, then dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to obtain 12.2 mg of 4-(cyclopentylamino)-2-((1-((4-((4-methylpiperazin-1-yl)methyl)phenyl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile (compound 22).
MS (ESI) m/z: 539.2 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ 8.17 (s, 0.4H), 8.11 (s, 0.6H), 7.87-7.77 (m, 2H), 7.71-7.62 (m, 1.6H), 7.52-7.43 (m, 1.4H), 7.25 (d, J=6.6 Hz, 0.6H), 7.14 (d, J=7.6 Hz, 0.4H), 4.50-4.20 (m, 1H), 3.93-3.70 (m, 3H), 3.61 (d, J=12.4 Hz, 2H), 2.83-2.68 (m, 2H), 2.47-2.25 (m, 8H), 2.16 (s, 3H), 1.97-1.78 (m, 4H), 1.72-1.59 (m, 2H), 1.59-1.40 (m, 6H).
Step 1: A solution of 6-oxabicyclo[3.1.0]hexane (1000 mg, 12 mmol, 1.00 eq) and ammonia water (8 mL) was stirred at 90° C. for 3 hours in a sealed tube. The reaction mixture was cooled to room temperature, and the pH was adjusted to 2 with concentrated hydrochloric acid. A large amount of white solid precipitated out of the solution, and the mixture was filtered. 1600 mg of (1R,2R-trans)-2-aminocyclopentan-1-ol (23-2) was obtained.
MS (ESI) m/z: 102.2 [M+H]+.
Step 2: Compound 23-2 (1600 mg, 12 mmol) was dissolved in water/THF (20 mL/2 mL), and sodium hydroxide (960 mg, 24 mmol) and benzyloxycarbonyl chloride (2251 mg, 13.2 mmol) were added thereto at 0° C. The reaction mixture was warmed to room temperature and reacted for 4 hours. After quenching with water (60 mL), the reaction mixture was extracted with dichloromethane (3×20 mL). The organic phases were combined, washed with saturated brine (30 mL) first, then dried over anhydrous sodium sulfate and filtered. The residue was concentrated under reduced pressure and purified by silica gel column chromatography to obtain 800 mg of benzyl ((1R,2R-trans)-2-hydroxycyclopentyl)carbamate (23-3).
MS (ESI) m/z: 236.2 [M+H+].
1H NMR (400 MHz, DMSO-d6) δ 7.41-7.26 (m, 5H), 7.18 (d, J=7.2 Hz, 1H), 5.00 (s, 2H), 4.67 (d, J=4.3 Hz, 1H), 3.83-3.78 (m, 1H), 3.61-3.51 (m, 1H), 1.92-1.78 (m, 1H), 1.76-1.72 (m, 1H), 1.64-1.51 (m, 2H), 1.45-1.30 (m, 2H).
Step 3: Compound 23-3 (500 mg, 2.15 mmol) was dissolved in dichloromethane (15 mL). Methanesulfonyl chloride (365 mg, 3.23 mmol) and triethylamine (0.90 mL, 6.45 mmol) were sequentially added thereto at 0° C. The reaction mixture was warmed to room temperature and reacted for 1 hour. After quenching with water (60 mL), the reaction mixture was extracted with dichloromethane (3×20 mL). The organic phases were combined, washed with saturated brine (30 mL) first, then dried over anhydrous sodium sulfate, filtered and concentrated. The concentrated crude product and dimethylamine aqueous solution (10 mL) were stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent to obtain 360 mg of benzyl ((1R,2S-cis)-2-(dimethylamino)cyclopentyl)carbamate (23-4).
MS (ESI) m/z: 263.2 [M+H]+.
Step 4: Compound 23-4 (360 mg, 1.37 mmol) was dissolved in methanol (15 mL) under hydrogen atmosphere. Palladium/carbon (10%, 730 mg) was added thereto. The reaction mixture was stirred at room temperature for 3 hours. After filtration and concentration under reduced pressure, 150 mg of (1S,2R-cis)-N1, N1-dimethylcyclopentane-1,2-diamine (23-5) was obtained.
MS (ESI) m/z: 129.2 [M+H]+.
Step 5: Compound 23-5 (100 mg, 0.26 mmol) was dissolved in N,N-dimethylacetamide (1 mL) in a sealed tube. The mixture was added with diisopropylethylamine (67 mg, 0.52 mmol), and added with compound 1A (37 mg, 0.29 mmol). The mixture was heated to 80° C. and reacted for 2 hours. After quenching with water (60 mL), the reaction mixture was extracted with dichloromethane (3×20 mL). The organic phases were combined, washed with saturated brine (30 mL) first, then dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to obtain 8.0 mg of 4-((1S,2R-cis)-2-(dimethylamino)cyclopentyl)amino)-2-((1-((1-methyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile (compound 23).
MS (ESI) m/z: 474.2 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 0.6H), 8.31 (s, 0.4H), 8.16 (s, 0.4H), 8.11 (s, 0.6H), 7.80-7.75 (m, 1H), 7.64 (d, J=7.3 Hz, 0.5H), 7.46 (d, J=7.5 Hz, 0.4H), 7.34 (d, J=7.9 Hz, 0.5H), 7.24 (d, J=8.5 Hz, 0.4H), 4.49-4.29 (m, 1H), 3.91 (s, 3H), 3.78-3.65 (m, 1H), 3.61-3.39 (m, 2H), 2.91-2.76 (m, 1H), 2.45-2.30 (m, 2H), 2.15-2.05 (m, 6H), 1.97-1.82 (m, 3H), 1.75-1.41 (m, 7H).
n-BuLi (0.83 mL, 0.6 mmol, 2.5 mol/L in THF) was dissolved in THE (5 mL) at −78° C. under nitrogen atmosphere. Subsequently, compound 15-4 (400.0 mg, 0.8 mmol) was slowly added to the above reaction mixture. The reaction mixture was stirred for 1 hour, and then acetone (69.0 mg, 1.2 mmol) was slowly added dropwise thereto. The reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was cooled in an ice-water bath and quenched with saturated ammonium chloride aqueous solution. The mixture was extracted with ethyl acetate (40 mL×3 times). The organic phases were combined, washed with saturated brine (100 mL) first, then dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to obtain 30.2 mg of 4-(cyclopentylamino)-2-((1-((4-(2-hydroxypropan-2-yl)phenyl)sulfonyl)piperidin-4-yl)amino)pyrimidine-5-carbonitrile (compound 24).
MS (ESI) m/z: 485.0 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ 8.13 (s, 0.4H), 8.10 (s, 0.6H), 7.76-7.64 (m, 4H), 7.62 (d, J=7.1 Hz, 0.6H), 7.44 (d, J=7.9 Hz, 0.4H), 7.24 (d, J=6.5 Hz, 0.6H), 7.14 (d, J=7.4 Hz, 0.4H), 5.26 (s, 1H), 4.44-4.31 (m, 0.4H), 4.25-4.14 (m, 0.6H), 3.77-3.60 (m, 1H), 3.60-3.47 (m, 2H), 2.48-2.40 (m, 1H), 2.40-2.31 (m, 1H), 1.96-1.75 (m, 4H), 1.67-1.39 (m, 14H).
Step 1: (S)-(−)-3-Hydroxytetrahydrofuran (696.0 mg, 7.9 mmol) was dissolved in THF (30 mL) at room temperature under nitrogen atmosphere. Subsequently, sodium hydride (316.0 mg, 7.9 mmol, 60% dispersed in mineral oil) was added to the above solution under an ice-water bath. After the reaction mixture was stirred for 10 minutes under an ice-water bath, compound 1B-2 (2.0 g, 5.2 mmol) was slowly added to the reaction mixture. The reaction system was heated to 100° C. and stirred for 2 hours. The reaction mixture was cooled to room temperature. Water (50 mL) was added to the reaction mixture to quench the reaction. The mixture was extracted with ethyl acetate (15 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (50 mL) first, then dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 1.8 g of tert-butyl (S)-4-((4-((tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate (25-2).
MS (ESI) m/z: 433.0 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 0.4H), 8.31 (s, 0.6H), 8.01 (d, J=7.2 Hz, 0.6H), 7.82 (d, J=8.0 Hz, 0.4H), 5.62-5.55 (m, 1H), 3.99-3.84 (m, 4H), 3.83-3.73 (m, 3H), 3.00-2.75 (m, 2H), 2.32-2.18 (m, 1H), 2.06-1.95 (m, 1H), 1.90-1.77 (m, 2H), 1.40 (s, 9H), 1.39-1.30 (m, 2H).
Step 2: Compound 25-2 (1.8 g, 4.2 mmol) was dissolved in 1,4-dioxane (10 mL) at room temperature. Subsequently, a hydrogen chloride-dioxane solution (10 mL, 40 mmol) was added to the above solution. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain 1.38 g of (S)—N-(piperidin-4-yl)-4-((tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-amine (25-3).
MS (ESI) m/z: 333.0 [M+H]+.
Step 3: Compound 25-3 (700.0 mg, 2.1 mmol) was dissolved in dichloromethane (40 mL) at room temperature. Subsequently, N,N-diisopropylethylamine (812.0 mg, 6.3 mmol) and pyrazole-4-sulfonyl chloride (349.0 mg, 2.1 mmol) were sequentially added to the above reaction mixture under an ice-water bath. The reaction mixture was stirred at room temperature for 3 hours. Water (30 mL) was added to the reaction mixture to quench the reaction. The mixture was extracted with dichloromethane (20 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (10 mL×3 times) first, then dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 700.0 mg of (S)—N-(1-(((1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)-4-((tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-amine (compound 25).
MS (ESI) m/z: 462.8 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ 13.74 (s, 1H), 8.41-8.33 (m, 1H), 8.32-8.27 (m, 1H), 8.03 (d, J=7.3 Hz, 0.6H), 7.87 (d, J=7.6 Hz, 0.4H), 7.83 (s, 1H), 5.63-5.52 (m, 1H), 3.96-3.84 (m, 1H), 3.83-3.65 (m, 4H), 3.56-3.42 (m, 2H), 2.47-2.34 (m, 2H), 2.27-2.14 (m, 1H), 2.02-1.87 (m, 3H), 1.67-1.52 (m, 2H).
MS (ESI) m/z: 592.8 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ 14.19 (s, 1H), 8.92 (d, J=8.4 Hz, 1H), 8.78-8.35 (m, 2H), 8.31 (d, J=5.6 Hz, 1H), 8.23 (s, 0.6H), 8.21 (s, 0.4H), 8.05 (d, J=7.6 Hz, 0.6H), 7.88 (d, J=8.0 Hz, 0.4H), 5.63-5.51 (m, 1H), 3.95-3.89 (m, 1H), 3.84-3.71 (m, 4H), 3.59-3.48 (m, 2H), 2.65-2.53 (m, 2H), 2.27-2.15 (m, 1H), 2.03-1.87 (m, 3H), 1.67-1.51 (m, 2H).
Step 1: Compound 25 (100.0 mg, 0.2 mmol), triphenylphosphine (275.0 mg, 1.0 mmol) and 2-(tetrahydro-2H-pyran-2-yloxy)ethanol (63.0 mg, 0.4 mmol) were dissolved in tetrahydrofuran (5 mL). Subsequently, diisopropyl azodicarboxylate (212.1 mg, 1.0 mmol) was slowly added to the reaction mixture under an ice-water bath. The reaction mixture was stirred at room temperature for 18 hours. Water (20 mL) was added to the reaction mixture to quench the reaction. The mixture was extracted with ethyl acetate (5 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (20 mL) first, then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 60.0 mg of compound 27-2.
MS (ESI) m/z: 591.8 [M+H]+.
Step 2: Compound 27-2 (60.0 mg, 0.1 mmol) was dissolved in methanol (5 mL) at room temperature. Subsequently, p-toluenesulfonic acid (18.0 mg, 0.1 mmol) was added to the above reaction mixture. The reaction mixture was stirred at room temperature for 16 hours. Saturated sodium bicarbonate aqueous solution (5 mL) was added to the reaction mixture to quench the reaction. Water (10 mL) was added to the mixture. The mixture was extracted with ethyl acetate (20 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (10 mL×3 times) first, then dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to obtain 21.1 mg of (S)-2-(4-((4-((tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-1H-pyrazol-1-yl)ethanol (compound 27).
MS (ESI) m/z: 506.8 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ 8.34-8.26 (m, 2H), 8.03 (d, J=7.4 Hz, 0.6H), 7.87 (d, J=7.6 Hz, 0.4H), 7.81 (s, 0.5H), 7.80 (s, 0.4H), 5.61-5.51 (m, 1H), 4.95 (t, J=5.3 Hz, 1H), 4.21 (t, J=5.4 Hz, 2H), 3.95-3.85 (m, 1H), 3.83-3.66 (m, 6H), 3.56-3.44 (m, 2H), 2.46-2.35 (m, 2H), 2.26-2.13 (m, 1H), 2.04-1.87 (m, 3H), 1.68-1.52 (m, 2H).
Step 1: Compound 1B-3 (508 mg, 1.81 mmol) was dissolved in dichloromethane (30 mL) at room temperature. Subsequently, N,N-diisopropylethylamine (702 mg, 5.43 mmol) and 4-bromo-benzenesulfonyl chloride (508 mg, 2.00 mmol) were added thereto under an ice-water bath. After the reaction mixture was stirred at room temperature for 2 hours, the reaction was quenched by adding water (60 mL). The mixture was extracted with dichloromethane (20 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (30 mL) first, then dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 830 mg of N-(1-(1-(4-bromophenyl)sulfonyl)piperidin-4-yl)-4-chloro-5-(trifluoromethyl)pyrimidin-2-amine (99-1).
MS (ESI) m/z: 499.0 [M+H]+.
Step 2: (S)-3-Hydroxytetrahydrofuran (42 mg, 0.48 mmol) was dissolved in THF (2 mL) in a sealed jar. Subsequently, sodium hydride (21 mg, 0.88 mmol) was added thereto under an ice-water bath. After the reaction was carried out for 15 minutes, compound 99-1 (200 mg, 0.40 mmol) was added thereto. The reaction mixture was heated to 100° C. for 4 hours, and water (60 mL) was added to the reaction mixture to quench. The mixture was extracted with dichloromethane (20 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (30 mL) first, then dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 150 mg of (S)—N-(1-(((4-bromophenyl)sulfonyl)piperidin-4-yl)-4-((tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-amine (compound 99).
MS (ESI) m/z: 551.0 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.02 (d, J=7.4 Hz, 0.6H), 7.92-7.83 (m, 2.4H), 7.73-7.65 (m, 2H), 5.62-5.51 (m, 1H), 3.96-3.86 (m, 1H), 3.85-3.68 (m, 4H), 3.63-3.46 (m, 2H), 2.65-2.55 (m, 2H), 2.28-2.13 (m, 1H), 2.03-1.84 (m, 3H), 1.64-1.48 (m, 2H).
Step 1: Under nitrogen atmosphere, compound 99 (200 mg, 0.36 mmol), compound 15A-1 (79 mg, 0.44 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (26 mg, 0.036 mmol) and sodium carbonate (76 mg, 0.72 mmol) were dissolved in 1,4-dioxane/water (20 mL/2 mL). The reaction mixture was heated to 110° C. and stirred overnight. After the reaction mixture was cooled to room temperature, the reaction mixture was quenched by adding water (60 mL) and extracted with ethyl acetate (3×20 mL). The organic phases were combined, washed with saturated brine (60 mL) first, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel column chromatography to obtain 220 mg of tert-butyl (S)-4-(4-((4-((4-((tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (compound 100-1).
MS (ESI) m/z: 653.8 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.01 (d, J=7.2 Hz, 0.6H), 7.86 (d, J=7.4 Hz, 0.4H), 7.75-7.65 (m, 4H), 6.37 (s, 1H), 5.59-5.48 (m, 1H), 4.04 (s, 2H), 3.95-3.83 (m, 1H), 3.81-3.67 (m, 4H), 3.63-3.49 (m, 4H), 2.59-2.51 (m, 2H), 2.49-2.39 (m, 2H), 2.25-2.11 (m, 1H), 2.02-1.85 (m, 3H), 1.64-1.49 (m, 2H), 1.43 (s, 9H).
Step 2: Compound 100-1 (120 mg, 0.18 mmol) was dissolved in 1,4-dioxane (5 mL). Dioxane hydrochloride solution (4 mL) was added thereto, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to obtain 59.6 mg of (S)-4-((tetrahydrofuran-3-yl)oxy)-N-(1-((4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine hydrochloride (compound 100).
MS (ESI) m/z: 554.2 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ 9.65-9.30 (m, 2H), 8.30 (d, J=7.0 Hz, 1H), 8.16-8.06 (m, 0.5H), 8.10-7.86 (s, 0.5H), 7.80-7.76 (m, 3H), 6.41 (br.s., 1H), 5.55 (br.s., 1H), 3.97-3.84 (m, 1H), 3.84-3.66 (m, 5H), 3.66-3.46 (m, 2H), 3.31 (br.s., 2H), 2.70 (s, 2H), 2.64-2.55 (m, 1H), 2.47-2.38 (m, 1H), 2.27-2.11 (m, 1H), 2.02-1.83 (m, 3H), 1.67-1.49 (m, 2H).
Referring to the preparation method of Example 100, (S)-4-((tetrahydrofuran-3-yl)oxy)-N-(1-((4-(1,2,5,6-tetrahydropyridin-3-yl)phenyl)sulfonyl)piperidin-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (compound 112) was obtained.
MS (ESI) m/z: 554.1 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 8.01 (d, J=7.3 Hz, 0.6H), 7.86 (d, J=7.6 Hz, 0.4H), 7.73-7.57 (m, 4H), 6.45 (s, 1H), 5.62-5.50 (m, 1H), 3.95-3.84 (m, 1H), 3.82-3.65 (m, 4H), 3.62-3.47 (m, 4H), 2.81 (t, J=5.6 Hz, 2H), 2.57-2.51 (m, 2H), 2.46-2.39 (m, 1H), 2.26-2.12 (m, 3H), 2.02-1.83 (m, 3H), 1.63-1.47 (m, 2H).
Referring to the preparation method of Example 17, N-(1-((4-(piperidin-3-yl)phenyl)sulfonyl)piperidin-4-yl)-4-(((S)-tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-amine (compound 113) was obtained.
MS (ESI) m/z: 556.2 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.02 (d, J=7.3 Hz, 0.6H), 7.86 (d, J=7.1 Hz, 0.4H), 7.69-7.61 (m, 2H), 7.50 (d, J=8.3 Hz, 2H), 5.60-5.51 (m, 1H), 3.94-3.83 (m, 1H), 3.82-3.66 (m, 4H), 3.62-3.49 (m, 2H), 3.02-2.89 (m, 2H), 2.76-2.68 (m, 1H), 2.54-2.51 (m, 2H), 2.45-2.36 (m, 2H), 2.26-2.11 (m, 1H), 2.01-1.83 (m, 4H), 1.71-1.39 (m, 5H).
Compound 113 was subjected to chiral resolution, and the resolution conditions were as follows: preparative column: Daicel OZ (25*250 mm, 10 m), mobile phase: CO2/MeOH (0.2% ammonia methanol)=50/50; flow rate: 100 g/min; detection wavelength: 214 nm. The product was collected and lyophilized under reduced pressure. Compound 114 with a retention time of 2.374 minutes was obtained, and the ee value was 100%. The absolute configuration was not determined. It was an enantiomer of compound 115.
MS (ESI) m/z: 556.2 [M+H]+.
1H NMR (400 MHz, DMSO) δ 8.29 (s, 1H), 8.02 (d, J=7.2 Hz, 0.6H), 7.86 (d, J=7.7 Hz, 0.4H), 7.74-7.61 (m, 2H), 7.50 (d, J=8.3 Hz, 2H), 5.64-5.48 (m, 1H), 3.97-3.83 (m, 1H), 3.83-3.67 (m, 4H), 3.67-3.47 (m, 2H), 3.08-2.88 (m, 2H), 2.81-2.66 (m, 1H), 2.66-2.54 (m, 2H), 2.47-2.24 (m, 2H), 2.25-2.11 (m, 1H), 2.10-1.82 (m, 4H), 1.70-1.42 (m, 5H).
Compound 113 was subjected to chiral resolution, and the resolution conditions were as follows: preparative column: Daicel OZ (25*250 mm, 10 m), mobile phase: CO2/MeOH (0.2% ammonia methanol)=50/50; flow rate: 100 g/min; detection wavelength: 214 nm. The product was collected and lyophilized under reduced pressure. Compound 115 with a retention time of 3.247 minutes was obtained, and the ee value was 99.34%. The absolute configuration was not determined. It was an enantiomer of compound 114.
MS (ESI) m/z: 556.2 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.02 (d, J=7.3 Hz, 0.6H), 7.86 (d, J=7.5 Hz, 0.4H), 7.66 (t, J=6.7 Hz, 2H), 7.52 (d, J=12.0 Hz, 2H), 5.55 (d, J=4.3 Hz, 1H), 3.96-3.83 (m, 1H), 3.83-3.65 (m, 4H), 3.65-3.48 (m, 2H), 3.07-2.89 (m, 2H), 2.82-2.66 (m, 1H), 2.64-2.53 (m, 2H), 2.49-2.35 (m, 2H), 2.34-2.11 (m, 1H), 2.04-1.82 (m, 4H), 1.73-1.40 (m, 5H).
Step 1: Under nitrogen atmosphere, compound 99 (2.0 g, 3.7 mmol), compound tert-butyl piperazine-1-carboxylate (1.02 g, 5.5 mmol), tris(dibenzylideneacetone)dipalladium (338.8 mg, 0.37 mmol) and cesium carbonate (2.4 g, 7.4 mmol) were dissolved in 1,4-dioxane (100 mL). The reaction mixture was heated to 100° C. and stirred overnight. The reaction mixture was cooled to room temperature, concentrated under reduced pressure and extracted with ethyl acetate (3×20 mL). The organic phases were combined, washed with saturated brine (60 mL) first, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel column chromatography to obtain 1.35 g of compound tert-butyl (S)-4-(4-((4-((4-((tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperazine-1-carboxylate (compound 116-1).
MS (ESI) m/z: 657.2 [M+H]+.
Step 2: Compound 116-1 (1.35 g, 2.05 mmol) was dissolved in 1,4-dioxane (10 mL). Subsequently, a 1,4-dioxane hydrochloride solution (15 mL) was added thereto. After the reaction mixture was stirred overnight at room temperature, the reaction mixture was concentrated under reduced pressure. The reaction mixture was extracted with dichloromethane (3×100 mL), washed with saturated sodium bicarbonate aqueous solution (100 mL), and the organic phases were combined. The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was slurried with ethanol. 818 mg of ((S)—N-(1-(((4-(piperazin-1-yl)phenyl)sulfonyl)piperidin-4-yl)-4-((tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-amine (compound 116) was obtained.
MS (ESI) m/z: 557.2 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.01 (d, J=7.3 Hz, 0.6H), 7.86 (d, J=7.2 Hz, 0.4H), 7.51 (d, J=8.8 Hz, 2H), 7.05 (d, J=9.0 Hz, 2H), 5.62-5.49 (m, 1H), 3.95-3.83 (m, 1H), 3.83-3.65 (m, 4H), 3.57-3.43 (m, 2H), 3.27-3.17 (m, 4H), 2.89-2.76 (m, 4H), 2.46-2.33 (m, 3H), 2.26-2.12 (m, 1H), 2.02-1.83 (m, 3H), 1.64-1.46 (m, 2H).
Step 1: (S)-(−)-3-Hydroxytetrahydrofuran (365.0 mg, 0.83 mmol) was dissolved in THF (20 mL) at room temperature under nitrogen atmosphere. Subsequently, sodium hydride (335.0 mg, 1.1 mmol, 60% dispersed in mineral oil) was added to the above solution under an ice-water bath. After the reaction mixture was stirred for 10 minutes under an ice-water bath, compound 1B-2 (1.0 g, 0.55 mmol) was slowly added to the reaction mixture. The reaction system was heated to 100° C. and stirred for 2 hours. After the reaction mixture was cooled to room temperature, water (20 mL) was added to quench. The mixture was extracted with ethyl acetate (15 mL×3 times), and the organic phases were combined. The organic phase was washed with saturated brine (30 mL) first, dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 0.85 g of tert-butyl (S)-4-((4-((tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidine-1-carboxylate (compound 117-1).
MS (ESI) m/z: 433.0 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 0.4H), 8.31 (s, 0.5H), 8.01 (d, J=7.5 Hz, 0.5H), 7.82 (d, J=7.9 Hz, 0.4H), 5.61-5.55 (m, 1H), 3.99-3.85 (m, 3H), 3.82-3.68 (m, 3H), 2.89 (br.s., 2H), 2.31-2.16 (m, 1H), 2.06-1.95 (m, 2H), 1.91-1.76 (m, 2H), 1.43-1.30 (m, 11H).
Step 2: Compound 117-1 (0.85 g, 1.9 mmol) was dissolved in 1,4-dioxane (10 mL) at room temperature. Subsequently, a hydrogen chloride-dioxane solution (10 mL) was added to the above solution. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain 0.7 g of compound (S)—N-(piperidin-4-yl)-4-((tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-amine (compound 117-2).
MS (ESI) m/z: 333.4 [M+H]+.
Step 3: Compound 117-2 (150.0 mg, 2.0 mmol) was dissolved in dichloromethane (8 mL) at room temperature. Subsequently, N,N-diisopropylethylamine (774.0 mg, 6.0 mmol) and 6-chloropyridine-3-sulfonyl chloride (508 mg, 2.4 mmol) were sequentially added to the above reaction mixture under an ice-water bath. The reaction mixture was stirred at room temperature for 16 hours. Water (20 mL) was added to the reaction mixture to quench the reaction. The mixture was extracted with dichloromethane (10 mL×3 times), and the organic phases were combined. The organic phases were washed with saturated brine (20 mL) first, then dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 105 mg of (S)—N-(1-(((6-chloropyridin-3-yl)sulfonyl)piperidin-4-yl)-4-((tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-amine (compound 117-3).
MS (ESI) m/z: 508.0 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ 8.81-8.75 (m, 1H), 8.30 (s, 1H), 8.24-8.18 (m, 1H), 8.02 (d, J=7.4 Hz, 0.5H), 7.87-7.79 (m, 1.5H), 5.62-5.50 (m, 1H), 3.95-3.68 (m, 5H), 3.66-3.49 (m, 2H), 2.78-2.59 (m, 2H), 2.26-2.12 (m, 1H), 1.98-1.84 (m, 2H), 1.64-1.45 (m, 2H).
Step 4: (S)—N-(1-((6-Chloropyridin-3-yl)sulfonyl)piperidin-4-yl)-4-((tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-amine (100 mg, 0.20 mmol) was dissolved in n-butanol (1 mL) at room temperature. Subsequently, N,N-diisopropylethylamine (0.10 mL, 0.59 mmol) and tert-butyl (2S,6R)-2,6-dimethylpiperazine-1-carboxylate (63 mg, 0.30 mmol) were sequentially added to the above reaction mixture. The reaction mixture was stirred at 120° C. for 16 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 120 mg of compound tert-butyl (2S,6R)-2,6-dimethyl-4-(5-((4-(((S)-tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-ylsulfonyl)pyridin-2-ylpiperazine-1-carboxylate (compound 117-4).
MS (ESI) m/z: 686.2 [M+H]+.
Step 5: Compound 117-4 (120.0 mg, 0.18 mmol) was dissolved in 1,4-dioxane (0.5 mL) at room temperature. Subsequently, a hydrogen chloride-dioxane solution (1 mL) was added thereto. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and saturated sodium bicarbonate aqueous solution (3 mL) was added to the resulting residue to quench. The mixture was extracted with ethyl acetate (10 mL×3 times). The organic phases were combined, then dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to obtain 69.3 mg of N-(1-((6-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyridin-3-yl)sulfonyl)piperidin-4-yl)-4-((S)-tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-amine (compound 117).
MS (ESI) m/z: 586.2 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J=2.4 Hz, 1H), 8.29 (s, 1H), 8.02 (d, J=7.4 Hz, 0.6H), 7.87 (d, J=7.5 Hz, 0.4H), 7.71 (dd, J=9.2, 2.5 Hz, 1H), 6.95 (d, J=9.1 Hz, 1H), 5.60-5.52 (m, 1H), 4.31 (d, J=12.1 Hz, 2H), 3.95-3.85 (m, 1H), 3.84-3.68 (m, 4H), 3.58-3.44 (m, 2H), 2.75-2.67 (m, 2H), 2.59-2.54 (m, 2H), 2.46-2.34 (m, 3H), 2.26-2.12 (m, 1H), 2.04-1.81 (m, 3H), 1.64-1.48 (m, 2H), 1.03 (d, J=6.2 Hz, 6H).
Step 1: Under nitrogen atmosphere, compound 99 (25 g, 45.3 mmol), tert-butyl (2S,6S)-2,6-dimethylpiperazine-1-carboxylate (11.6 g, 45.3 mmol), tris(dibenzylideneacetone)dipalladium (4.1 g, 4.53 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (1.3 g, 9.02 mmol) and cesium carbonate (29.4 g, 90.6 mmol) were dissolved in 1,4-dioxane (1.25 L). The reaction mixture was heated to 100° C. and stirred overnight. The reaction mixture was concentrated under reduced pressure and extracted with ethyl acetate (3×100 mL). The organic phases were combined, washed with saturated brine (100 mL) first, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel column chromatography to obtain 18.1 g of tert-butyl (2S,6S)-2,6-dimethyl-4-(4-((S)-tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperazin-1-carboxylate (compound 168-1).
MS (ESI) m/z: 685.2 [M+H]+.
Step 2: Compound 168-1 (18.1 g, 26.4 mmol) was dissolved in 1,4-dioxane (100 mL). Subsequently, a 1,4-dioxane hydrochloride solution (100 mL) was added thereto. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure. Sodium bicarbonate aqueous solution (300 mL) was added to the resulting residue for washing. The mixture was extracted with ethyl acetate (200 mL×3 times). The organic phases were combined. The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 9.2 g of N-(1-((4-((3S,5S)-3,5-dimethylpiperazin-1-yl)phenyl)sulfonyl)piperidin-4-yl)-4-((S)-tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-amine (compound 168).
MS (ESI) m/z: 585.2 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.00 (d, J=7.1 Hz, 0.6H), 7.85 (d, J=6.9 Hz, 0.4H), 7.49 (d, J=8.8 Hz, 2H), 7.02 (d, J=9.0 Hz, 2H), 5.60-5.51 (m, 1H), 3.95-3.83 (m, 1H), 3.81-3.65 (m, 4H), 3.57-3.44 (m, 2H), 3.37-3.33 (m, 2H), 3.21-3.09 (m, 2H), 3.02-2.91 (m, 2H), 2.46-2.37 (m, 2H), 2.28-2.03 (m, 2H), 2.02-1.84 (m, 3H), 1.66-1.47 (m, 2H), 1.06 (d, J=6.4 Hz, 6H).
Step 1: Under nitrogen atmosphere, compound 99 (50 mg, 0.09 mmol), tert-butyl cis-2,6-dimethylpiperazine-1-carboxylate (23.1 mg, 0.108 mmol), tris(dibenzylideneacetone)dipalladium (8.2 mg, 0.009 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (8.6 mg, 0.018 mmol) and cesium carbonate (69.3 mg, 7.4 mmol) were dissolved in 1,4-dioxane (5 mL). The reaction mixture was heated to 100° C. and stirred overnight. The reaction mixture was concentrated under reduced pressure and extracted with ethyl acetate (3×10 mL). The organic phases were combined, washed with saturated brine (30 mL) first, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel column chromatography to obtain 40 mg of tert-butyl cis-2,6-dimethyl-4-(4-((4-((S)-tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)piperazine-1-carboxylate (Compound 169-1).
MS (ESI) m/z: 685.2 [M+H]+.
Step 2: Compound 169-1 (40 mg, 0.06 mmol) was dissolved in 1,4-dioxane (1 mL). Subsequently, a 1,4-dioxane hydrochloride solution (1 mL) was added thereto. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure. The reaction mixture was extracted with ethyl acetate (8×3 mL), washed with saturated sodium bicarbonate aqueous solution (30 mL). The organic phases were combined. The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography to obtain 6 mg of N-(1-((4-cis-3,5-dimethylpiperazin-1-yl)phenyl)sulfonyl)piperidin-4-yl)-4-((S′)-tetrahydrofuran-3-yl)oxy)-5-(trifluoromethyl)pyrimidin-2-amine (compound 169).
MS (ESI) m/z: 585.2 [M+H]+.
1H NNR (400 lIz, DMSO-dl6) 68.29 (s, 1H), 8.01 (d, J=7.3 Hz, 0.6H), 7.86 (d, J=7.0 Hz, 0.4H), 7.50 (d, J=8.8 Hz, 2H), 7.06 (d, J=9.1 Hz, 2H), 5.63-5.44 (i, 1H), 3.96-3.82 (m, 1H), 3.82-3.62 (m, 6H), 3.56-3.43 (m, 2H), 2.86-2.71 (i, 2H), 2.42-2.37 (m, 2H), 2.29-2.14 (m, 4H), 1.99-1.84 (m, 3H), 1.63-1.44 (m, 2H), 1.03 (d, J=6.2 Hz, 6H).
The compounds given in Table 1 were prepared by essentially the same methods as described in the examples.
1HNMR
1HNMR (400 MHz, CDCl3 + TFA) δ 8.30 (s, 1H), 6.33 (d, J = 7.7 Hz, 1H), 4.48-4.32 (m, 1H), 4.18-4.07 (m, 1H), 3.69-3.53 (m, 2H), 3.22-3.11 (m, 2H), 2.92 (s, 3H), 2.15-2.03 (m, 2H), 1.93-1.80 (m, 2H), 1.37 (d, J = 6.6 Hz, 6H).
1HNMR (400 MHz, DMSO-d6) δ 8.20 (s, 0.4H), 8.13 (s, 0.6H), 7.67 (d, J = 7.6 Hz, 0.6H), 7.49 (d, J = 7.6 Hz, 0.4H), 7.29 (d, J = 6.4 Hz, 0.6H), 7.17 (d, J = 8.0 Hz, 0.4H), 4.46- 4.37 (m, 0.4H), 4.35-4.25 (m, 0.6H), 4.00- 3.90 (m, 0.5H), 3.90-3.75 (m, 0.7H), 3.63 (d, J = 12.8 Hz, 2H), 3.32-3.26 (m, 1H), 3.05- 2.91 (m, 2H), 1.95-1.78 (m, 4H), 1.71-1.41 (m, 8H), 1.21 (d, J = 6.8 Hz, 6H).
1HNMR (400 MHz, CDCl3) δ 7.72 (s, 1H), 5.41-5.20 (m, 2H), 4.37-4.24 (m, 1H), 4.02- 3.88 (m, 1H), 3.71-3.56 (m, 2H), 3.12-2.97 (m, 2H), 2.82 (s, 3H), 2.18-1.98 (m, 4H), 1.83- 1.57 (m, 6H), 1.57-1.44 (m, 2H).
1HNMR (400 MHz, DMSO-d6) δ 8.33 (s, 0.6H), 8.31 (s, 0.4H), 8.16 (s, 0.4H), 8.11 (s, 0.6H), 7.78 (s, 0.6H), 7.76 (s, 0.4H), 7.63 (d, J = 7.2 Hz, 0.6H), 7.45 (d, J = 7.7 Hz, 0.4H), 7.26 (d, J = 7.2 Hz, 0.6H), 7.16 (d, J = 7.2 Hz, 0.4H), 4.38 (q, J = 7.4 Hz, 0.4H), 4.25 (q, J = 7.0 Hz, 0.6H), 3.91 (s, 3H), 3.81-3.62 (m, 1H), 3.55-3.36 (m, 2H), 2.47-2.40 (m, 1H), 2.35 (t, J = 11.0 Hz, 1H), 2.00-1.77 (m, 4H), 1.73-1.40 (m, 8H).
1H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 7.98 (s, 1H), 7.78 (s, 1H), 7.36 (d, J = 6.4 Hz, 0.6H), 7.18 (d, J = 6.8 Hz, 0.4H), 6.16 (br.s., 1H), 4.56-4.25 (m, 1H), 3.91 (s, 3H), 3.80- 3.62 (m, 1H), 3.58-3.38 (m, 2H), 2.48-2.28 (m, 2H), 2.05-1.78 (m, 4H), 1.75-1.39 (m, 8H).
1H NMR (400 MHz, CDCl3) δ 8.11-8.00 (m, 1H), 7.45 (br.s., 1H), 6.66 (d, J = 1.6 Hz, 1H), 541-5.00 (m, 2H), 4.37-4.24 (m, 1H), 4.01 (s, 3H), 3.95-3.75 (m, 2H), 3.65-3.53 (m, 1H), 3.03-2.88 (m, 1H), 2.79-2.60 (m, 1H), 2.15-1.97 (m, 4H), 1.83-1.55 (m, 6H), 1.55- 1.35 (s, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 0.4H), 8.11 (s, 0.6H), 7.86-7.77 (m, 2H), 7.60 (d, J = 7.2 Hz, 0.6H), 7.43 (d, J = 7.6 Hz, 0.4H), 7.25 (d, J = 6.5 Hz, 0.6H), 7.14 (d, J = 7.4 Hz, 0.4H), 4.46-4.33 (m, 0.4H), 4.30- 4.18 (m, 0.6H), 3.84-3.61 (m, 4H), 3.55 (d, J = 12.5 Hz, 2H), 2.73-2.54 (m, 2H), 1.96-1.77 (m, 4H), 1.74-1.60 (m, 2H), 1.60-1.40 (m, 6H).
1H NMR (400 MHz, DMSO-d6) δ 8.03-7.95 (m, 1H), 7.82 (s, 1H), 7.81 (s, 1H), 7.34 (d, J = 6.0 Hz, 0.6H), 7.16 (d, J = 6.0 Hz, 0.4H), 6.20- 6.10 (m, 1H), 4.54-4.26 (m, 1H), 3.72 (s, 3H), 3.69-3.61 (m, 1H), 3.60-3.49 (m, 2H), 2.70-2.53 (m, 2H), 1.99-1.80 (m, 4H), 1.73- 1.60 (m, 2H), 1.59-1.42 (m, 6H).
1H NMR (400 MHz, DMSO-d6) δ 8.77 (d, J = 4.4 Hz, 1H), 8.19-8.08 (m, 2H), 7.96-7.88 (m, 1H), 7.75-7.66 (m, 1H), 7.62 (d, J = 7.2 Hz, 0.6H), 7.44 (d, J = 7.6 Hz, 0.4H), 7.25 (d, J = 6.4 Hz, 0.6H), 7.14 (d, J = 7.6 Hz, 0.4H), 4.45-4.33 (m, 0.4H), 4.30 4.17 (m, 0.6H), 3.87-3.63 (m, 3H), 2.91-2.72 (m, 2H), 1.96- 1.76 (m, 4H), 1.74-1.60 (m, 2H), 1.59-1.39 (m, 6H).
1H NMR (400 MHz, CDCl3 + D2O) δ 8.12 (s, 1H), 7.73 (d, J = 9.4 Hz, 2H), 4.65-4.51 (m, 1H), 3.98 (s, 3H), 3.83 (br.s., 1H), 3.69 (br.s., 1H), 3.54 (br.s., 1H), 2.68 (br.s., 1H), 2.57- 2.41 (m, 1H), 2.33-2.01 (m, 5H), 2.00-1.52 (m, 5H).
1H NMR (400 MHz, DMSO-d6) δ 8.33-8.27 (m, 1.2H), 8.23 (s, 0.6H), 7.78 (s, 1H), 7.76 (s, 0.6H), 7.59 (d, J = 7.5 Hz, 0.4H), 4.70-4.58 (m, 1H), 4.35-4.24 (m, 1H), 3.91 (s, 3H), 3.89- 3.63 (m, 3H), 3.61-3.54 (m, 1H), 3.51-3.37 (m, 3H), 3.29-3.18 (m, 1H), 2.48-2.31 (m, 2H), 1.97-1.82 (m, 2H), 1.65-1.49 (m, 2H), 1.26 (t, J = 6.4 Hz, 3H).
1H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 0.6H), 8.31 (s, 0.4H), 8.23 (s, 0.3H), 8.18 (s, 0.6H), 7.78 (s, 0.6H), 7.76 (s, 0.3H), 7.66 (d, J = 7.2 Hz, 0.6H), 7.46 (d, J = 7.4 Hz, 0.3H), 5.06-4.79 (m, 1H), 3.90 (s, 3H), 3.81-3.60 (m, 1H), 3.52-3.39 (m, 2H), 3.04-2.95 (m, 3H), 2.48-2.30 (m, 2H), 1.98-1.75 (m, 4H), 1.73-1.46 (m, 8H).
1H NMR (400 MHz, DMSO-d6) δ 8.33 (d, J = 4.4 Hz, 1H), 8.26 (s, 1H), 7.95 (d, J = 6.9 Hz, 0.5H), 7.84-7.70 (m, 1.4H), 5.54-5.39 (m, 1H), 3.91 (s, 3H), 3.85-3.66 (m, 1H), 3.57- 3.41 (m, 2H), 2.49-2.29 (m, 2H), 2.04-1.80 (m, 4H), 1.77-1.49 (m, 8H).
1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 0.5H), 8.31 (s, 0.4H), 8.20 (s, 0.4H), 8.16 (s, 0.5H), 7.76 (s, 1H), 7.73 (d, J = 7.2 Hz, 0.6H), 7.60 (d, J = 6.7 Hz, 0.5H), 7.56 (d, J = 7.6 Hz, 0.4H), 7.49 (d, J = 7.6 Hz, 0.4H), 4.66-4.37 (m, 1H), 3.90 (s, 3H), 3.81-3.63 (m, 1H), 3.53- 3.39 (m, 2H), 2.47-2.31 (m, 3H), 2.31-2.13 (m, 2H), 2.11-1.76 (m, 5H), 1.64-1.49 (m, 2H).
1H NMR (400 M, DMSO-d6) δ 8.33 (s, 0.7H), 8.31 (s, 0.3H), 8.17 (s, 0.3H), 8.14 (s, 0.7H), 7.79 (s, 0.7H), 7.77 (s, 0.3H), 7.70 (d, J = 7.6 Hz, 0.7H), 7.47 (d, J = 7.6 Hz, 0.3H), 6.12 (s, 0.7H), 5.98 (s, 0.3H), 3.91 (s, 3H), 3.77-3.59 (m, 1H), 3.59-3.40 (m, 2H), 2.47-2.26 (m, 2H), 2.00-1.81 (m, 2H), 1.68-1.50 (m, 2H), 1.42 (s, 3H), 1.39 (s, 6H).
1H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 0.6H), 8.31 (s, 0.4H), 8.20 (s, 0.3H), 8.15 (s, 0.6H), 7.78 (s, 0.6H), 7.76 (s, 0.3H), 7.69 (d, J = 7.4 Hz, 0.6H), 7.56-7.48 (m, 1H), 7.41 (d, J = 6.5 Hz, 0.3H), 4.60-4.41 (m, 1H), 3.91 (s, 3H), 3.85-3.62 (m, 4H), 3.57-3.41 (m, 3H), 2.47-2.31 (m, 2H), 2.16-1.82 (m, 4H), 1.65- 1.48 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 0.6H), 8.31 (s, 0.4H), 8.20 (s, 0.3H), 8.15 (s, 0.6H), 7.78 (s, 0.6H), 7.76 (s, 0.3H), 7.69 (d, J = 7.4 Hz, 0.6H), 7.56-7.48 (m, 1H), 7.41 (d, J = 6.5 Hz, 0.3H), 4.60-4.41 (m, 1H), 3.91 (s, 3H), 3.85-3.62 (m, 4H), 3.57-3.41 (m, 3H), 2.47-2.31 (m, 2H), 2.16-1.82 (m, 4H), 1.65- 1.48 (m, 2H).
1H NMR (400 MHz, DMSO-d6 + TFA) δ 8.54- 8.41 (m, 2H), 8.34 (s, 1H), 7.79 (s, 1H), 4.26- 4.00 (m, 2H), 3.90 (s, 3H), 3.87-3.76 (m, 1H), 3.67-3.39 (m, 2H), 2.36-2.23 (m, 1H), 2.06-1.76 (m, 4H), 1.71-1.37 (m, 6H).
1H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 0.6H), 8.31 (s, 0.4H), 8.17 (s, 0.4H), 8.12 (s, 0.6H), 7.77 (s, 0.6H), 7.76 (s, 0.4H), 7.62 (d, J = 7.3 Hz, 0.6H), 7.47 (d, J = 7.6 Hz, 0.4H), 7.20 (d, J = 6.5 Hz, 0.6H), 7.12 (d, J = 7.4 Hz, 0.4H), 4.71 (d, J = 4.3 Hz, 0.4H), 4.65 (d, J = 4.2 Hz, 0.6H), 4.19-3.94 (m, 2H), 3.91 (s, 3H), 3.81-3.65 (m, 1H), 3.56-3.35 (m, 2H), 2.48-2.31 (m, 2H), 2.03-1.75 (m, 4H), 1.64- 1.49 (m, 4H), 1.49-1.35 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 0.6H), 8.31 (s, 0.4H), 8.21 (s, 0.4H), 8.16 (s, 0.6H), 7.78 (s, 0.6H), 7.76 (s, 0.4H), 7.71 (d, J = 7.2 Hz, 0.6H), 7.54 (d, J = 8.0 Hz, 0.4H), 6.41 (d, J = 5.6 Hz, 0.6H), 6.23 (d, J = 7.3 Hz, 0.4H), 5.09 (d, J = 4.1 Hz, 1H), 4.19-3.98 (m, 2H), 3.90 (s, 3H), 3.83-3.63 (m, 1H), 3.58- 3.38 (m, 2H), 2.47-2.30 (m, 2H), 2.02-1.82 (m, 3H), 1.82-1.66 (m, 2H), 1.64-1.35 (m, 5H).
1H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 0.6H), 8.31 (s, 0.4H), 8.21 (s, 0.4H), 8.16 (s, 0.6H), 7.78 (s, 0.6H), 7.76 (s, 0.4H), 7.71 (d, J = 7.2 Hz, 0.6H), 7.54 (d, J = 8.0 Hz, 0.4H), 6.41 (d, J = 6.1 Hz, 0.6H), 6.23 (d, J = 7.3 Hz, 0.4H), 5.09 (d, J = 4.2 Hz, 1H), 4.18-3.97 (m, 2H), 3.90 (s, 3H), 3.83-3.63 (m, 1H), 3.58- 3.38 (m, 2H), 2.47-2.30 (m, 2H), 2.02-1.82 (m, 3H), 1.82-1.66 (m, 2H), 1.64-1.35 (m, 5H).
1H NMR (400 MHz, DMSO-d6 + TFA) δ 8.71- 8.56 (m, 1H), 8.46 (s, 1H), 8.31 (s, 1H), 8.00 (s, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.5 Hz, 2H), 4.47-4.24 (m, 1H), 3.88 (s, 3H), 3.81 (br.s., 1H), 3.64 (d, J = 11.1 Hz, 1H), 3.53 (d, J = 12.0 Hz, 2H), 2.63-2.54 (m, 1H), 2.37-2.25 (m, 1H), 2.00-1.76 (m, 4H), 1.75- 1.35 (m, 8H).
1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.14 (s, 0.4H), 8.10 (s, 0.6H), 8.00 (s, 1H), 7.82 (s, 0.6H), 7.80 (s, 1.4H), 7.73-7.65 (m, 2H), 7.61 (d, J = 7.3 Hz, 0.6H), 7.45 (d, J = 7.9 Hz, 0.5H), 7.17 (d, J = 6.4 Hz, 0.6H), 7.10 (d, J = 7.4 Hz, 0.4H), 4.70 (d, J = 4.3 Hz, 0.4H), 4.61 (d, J = 4.2 Hz, 0.6H), 4.20-3.92 (m, 2H), 3.89 (s, 3H), 3.71 (br.s., 1H), 3.63-3.47 (m, 2H), 2.45-2.37 (m, 1H), 1.99-1.68 (m, 4H), 1.63- 1.32 (m, 6H).
1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 8.19 (s, 0.4H), 8.14 (s, 0.6H), 8.00 (s, 1H), 7.82 (s, 1H), 7.80 (s, 1H), 7.71-7.68 (m, 2.6H), 7.53 (d, J = 7.4 Hz, 0.4H), 6.39 (d, J = 6.3 Hz, 0.6H), 6.21 (d, J = 7.2 Hz, 0.4H), 5.07 (br.s., 1H), 4.10-3.98 (m, 2H), 3.89 (s, 3H), 3.81- 3.62 (m, 1H), 3.60-3.44 (m, 2H), 2.47-2.41 (m, 2H), 1.99-1.79 (m, 3H), 1.79-1.64 (m, 2H), 1.63-1.31 (m, 5H).
Absolute configuration not determined, enantiomer of compound 53
1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.15 (s, 0.4H), 8.11 (s, 0.6H), 7.76 (s, 1H), 7.62 (d, J = 7.0 Hz, 0.6H), 7.47 (d, J = 7.7 Hz, 0.4H), 7.27 (d, J = 6.9 Hz, 0.6H), 7.16 (d, J = 8.0 Hz, 0.4H), 4.75-4.62 (m, 0.4H), 4.53- 4.40 (m, 1.6H), 4.17 (br.s., 1H), 3.91 (s, 3H), 3.81-3.62 (m, 1H), 3.54-3.38 (m, 2H), 2.49- 2.29 (m, 2H), 2.08-1.67 (m, 6H), 1.62-1.35 (m, 4H).
Absolute configuration not determined, enantiomer of compound 52
1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.15 (s, 0.4H), 8.11 (s, 0.6H), 7.77 (s, 1H), 7.62 (d, J = 7.1 Hz, 0.6H), 7.47 (d, J = 7.8 Hz, 0.5H), 7.27 (d, J = 6.9 Hz, 0.6H), 7.16 (d, J = 7.9 Hz, 0.5H), 4.50-4.40 (m, 2H), 4.18 (s, 1H), 3.91 (s, 3H), 3.71 (br.s., 1H), 3.51-3.41 (m, 2H), 2.45-2.33 (m, 2H), 2.01-.1.35 (m, 10H).
1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 7.99 (s, 1H), 7.77 (s, 1H), 7.36 (d, J = 6.4 Hz, 0.6H), 7.21 (d, J = 6.8 Hz, 0.5H), 6.21-6.08 (m, 1H), 4.74-4.60 (m, 1H), 4.25-3.95 (m, 2H), 3.91 (s, 3H), 3.80-3.65 (m, 1H), 3.65- 3.57 (m, 3H), 2.42-2.28 (m, 1H), 2.08-1.73 (m, 4H), 1.72-1.50 (m, 4H), 1.50-1.35 (m, 2H).
Relative configuration (trans)
1H NMR (400 MHz, DMSO-d6) δ 8.46 (s, 0.4H), 8.43 (s, 0.6H), 8.33 (s, 0.6H), 8.31 (s, 0.4H), 8.28 (d, J = 7.3 Hz, 0.6H), 8.13 (d, J = 7.6 Hz, 0.4H), 7.79 (s, 0.6H), 7.77 (s, 0.5H), 5.56-5.42 (m, 1H), 4.64 (dd, J = 5.5, 3.7 Hz, 1H), 4.32-4.20 (m, 1H), 3.91 (s, 3H), 3.77 (br.s., 1H), 3.48 (t, J = 12.2 Hz, 2H), 2.43-2.30 (m, 2H), 2.26-2.07 (m, 1H), 2.03-1.79 (m, 5H), 1.74-1.45 (m, 4H).
Absolute configuration not determined, enantiomer of compound 57
1H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 0.4H), 8.43 (s, 0.7H), 8.33 (s, 0.6H), 8.31 (s, 0.4H), 8.28 (d, J = 7.9 Hz, 0.6H), 8.13 (d, J = 8.4 Hz, 0.4H), 7.78 (s, 0.6H), 7.77 (s, 0.4H), 5.57-5.42 (m, 1H), 4.69-4.59 (m, 1H), 4.26 (br.s., 1H), 3.91 (s, 3H), 3.76 (br.s., 1H), 3.54- 3.41 (m, 2H), 2.48-2.33 (m, 2H), 2.00-1.81 (m, 6H), 1.75-1.40 (m, 4H).
Absolute configuration not determined, enantiomer of compound 56
1H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 0.4H), 8.43 (s, 0.5H), 8.33 (s, 0.6H), 8.31 (s, 0.5H), 8.28 (d, J = 7.8 Hz, 0.6H), 8.13 (d, J = 7.9 Hz, 0.5H), 7.78 (s, 0.6H), 7.77 (s, 0.5H), 5.57-5.42 (m, 1H), 4.67-4.59 (m, 1H), 4.26 (br.s., 1H), 3.91 (s, 3H), 3.76 (br.s., 1H), 3.54- 3.41 (m, 2H), 2.48-2.33 (m, 2H), 2.06-1.79 (m, 6H), 1.75-1.44 (m, 4H).
Relative configuration (cis)
1H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 0.4H), 8.43 (s, 0.5H), 8.33 (s, 0.6H), 8.31 (s, 0.4H), 8.26 (d, J = 7.4 Hz, 0.6H), 8.09 (d, J = 7.7 Hz, 0.4H), 7.79 (s, 0.5H), 7.77 (s, 0.4H), 5.35-5.23 (m, 1H), 4.69 (d, J = 4.0 Hz, 0.5H), 4.66 (d, J = 4.0 Hz, 0.5H), 4.14-4.03 (m, 1H), 3.90 (s, 3H), 3.76 (br.s., 1H), 3.53-3.42 (m, 2H), 2.44-2.22 (m, 2H), 2.07-1.78 (m, 5H), 1.77-1.51 (m, 5H).
1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 8.14 (s, 0.4H), 8.10 (s, 0.6H), 8.00 (s, 1H), 7.82 (s, 0.8H), 7.80 (s, 1.1H), 7.72-7.65 (m, 2H), 7.61 (d, J = 7.2 Hz, 0.7H), 7.46 (d, J = 7.7 Hz, 0.5H), 7.17 (d, J = 6.3 Hz, 0.6H), 7.10 (d, J = 7.0 Hz, 0.8H), 4.69 (d, J = 4.1 Hz, 0.5H), 4.60 (d, J = 4.3 Hz, 0.6H), 4.18-4.07 (m, 0.5H), 4.05-3.93 (m, 1.5H), 3.89 (s, 3H), 3.78-3.63 (m, 1H), 3.62-3.51 (m, 2H), 2.46-2.37 (m, 2H), 2.05-1.68 (m, 4H), 1.63-1.34 (m, 6H).
1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 8.14 (s, 0.4H), 8.10 (s, 0.6H), 8.00 (s, 1H), 7.82 (s, 0.8H), 7.80 (s, 1.2H), 7.72-7.65 (m, 2H), 7.61 (d, J = 7.3 Hz, 0.6H), 7.46 (d, J = 7.9 Hz, 0.4H), 7.17 (d, J = 6.4 Hz, 0.6H), 7.10 (d, J = 7.4 Hz, 0.4H), 4.70 (d, J = 4.3 Hz, 0.4H), 4.61 (d, J = 4.2 Hz, 0.6H), 4.18-3.92 (m, 2H), 3.89 (s, 3H), 3.71 (br.s., 1H), 3.63-3.46 (m, 2H), 2.48-2.35 (m, 1H), 1.97-1.69 (m, 4H), 1.64- 1.47 (m, 4H), 1.46-1.31 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 8.19 (s, 0.4H), 8.15 (s, 0.5H), 8.00 (s, 1H), 7.81 (d, J = 8.2 Hz, 2H), 7.73-7.65 (m, 2.6H), 7.53 (d, J = 7.7 Hz, 0.4H), 6.39 (d, J = 6.2 Hz, 0.6H), 6.21 (d, J = 7.3 Hz, 0.4H), 5.07 (t, J = 4.8 Hz, 1H), 4.15-3.94 (m, 2H), 3.89 (s, 3H), 3.80-3.61 (m, 1H), 3.60-3.46 (m, 2H), 2.60- 2.53 (m, 1H), 2.48-2.39 (m, 1H), 1.97-1.80 (m, 3H), 1.79-1.63 (m, 2H), 1.63-1.33 (m, 5H).
Relative configuration (cis)
1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 8.15 (s, 0.4H), 8.11 (s, 0.6H), 8.00 (s, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.73-7.66 (m, 2H), 7.64 (d, J = 7.2 Hz, 0.6H), 7.47 (d, J = 7.9 Hz, 0.4H), 7.04 (d, J = 7.5 Hz, 0.6H), 7.00 (d, J = 8.2 Hz, 0.4H), 4.80 (d, J = 3.6 Hz, 0.4H), 4.75 (d, J = 4.0 Hz, 0.6H), 4.51-4.27 (m, 1H), 4.09 (br.s., 1H), 3.89 (s, 3H), 3.71 (br.s., 1H), 3.62- 3.47 (m, 2H), 2.49-2.37 (m, 2H), 2.03-1.77 (m, 4H), 1.73-1.48 (m, 6H).
Absolute configuration not determined, enantiomer of compound 83
1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.12 (s, 0.4H), 8.09 (s, 0.6H) 8.00 (s, 1H), 7.82 (s, 1H), 7.80 (s, 1H), 7.73-7.66 (m, 2H), 7.61 (d, J = 6.6 Hz, 0.6H), 7.46 (d, J = 8.2 Hz, 0.4H), 7.25 (d, J = 7.1 Hz, 0.6H), 7.15 (d, J = 8.2 Hz, 0.4H), 4.73-4.60 (m, 0.4H), 4.51- 4.33 (m, 1.6H), 4.20-4.11 (m, 1H), 3.89 (s, 3H), 3.82-3.62 (m, 1H), 3.62-3.46 (m, 2H), 2.47-2.34 (m, 2H), 2.04-1.62 (m, 6H), 1.60- 1.30 (m, 4H).
1H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 0.4H), 8.47 (s, 0.6H), 8.36-8.30 (m, 1.5H), 8.17 (d, J = 7.8 Hz, 0.4H), 7.79 (s, 0.6H), 7.77 (s, 0.4H), 5.55 (br.s., 1H), 3.91 (s, 3H), 3.90- 3.68 (m, 5H), 3.56-3.42 (m, 2H), 2.47-2.17 (m, 3H), 2.09-1.84 (m, 3H), 1.71-1.52 (m, 2H).
Relative configuration (cis)
Absolute configuration not determined, enantiomer of compound 67
1H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 0.4H), 8.44 (s, 0.5H), 8.32 (d, J = 6.0 Hz, 1H), 8.29 (d, J = 7.2 Hz, 0.5H), 8.14 (d, J = 7.7 Hz, 0.4H), 7.78 (d, J = 5.5 Hz, 1H), 5.18-5.12 (m, 0.5H), 5.11-5.06 (m, 0.6H), 4.94 (dd, J = 4.0 Hz, 2.7 Hz, 1H), 4.12-4.02 (m, 1H), 3.91 (s, 3H), 3.87-3.72 (m, 1H), 3.54-3.40 (m, 2H), 2.47-2.31 (m, 2H), 2.16-2.04 (m, 1H), 2.02- 1.76 (m, 3H), 1.75-1.45 (m, 6H).
Absolute configuration not determined, enantiomer of compound 66
1H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 0.4H), 8.44 (s, 0.5H), 8.32 (d, J = 6.0 Hz, 1H), 8.29 (d, J = 7.6 Hz, 0.5H), 8.14 (d, J = 7.2 Hz, 0.4H), 7.77 (d, J = 5.6 Hz, 1H), 5.18-5.12 (m, 0.5H), 5.11-5.05 (m, 0.6H), 4.93 (dd, J = 4.0 Hz, 2.8 Hz, 1H), 4.13-4.01 (m, 1H), 3.91 (s, 3H), 3.86-3.70 (m, 1H), 3.55-3.42 (m, 2H), 2.47-2.31 (m, 2H), 2.17-2.03 (m, 1H), 2.02- 1.78 (m, 3H), 1.77-1.46 (m, 6H).
Relative configuration (trans)
1H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 0.5H), 8.43 (s, 0.5H), 8.33 (d, J = 8.5 Hz, 1H), 8.22 (d, J = 7.3 Hz, 0.5H), 8.06 (d, J = 7.7 Hz, 0.5H), 7.78 (d, J = 7.5 Hz, 1H), 5.22-5.11 (m, 1H), 4.69 (dd, J = 10.6, 4.8 Hz, 1H), 4.20-4.08 (m, 1H), 3.91 (s, 3H), 3.86-3.66 (m, 1H), 3.54- 3.39 (m, 2H), 2.48-2.35 (m, 2H), 1.99-1.86 (m, 3H), 1.84-1.70 (m, 3H), 1.67-1.42 (m, 4H).
1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 0.6H), 8.31 (s, 0.4H), 8.18 (s, 0.4H), 8.13 (s, 0.6H), 7.78 (s, 0.6H), 7.76 (s, 0.4H), 7.63 (d, J = 7.3 Hz, 0.6H), 7.47 (d, J = 7.7 Hz, 0.4H), 6.85 (d, J = 7.8 Hz, 0.6H), 6.75 (d, J = 8.3 Hz, 0.4H), 4.78-4.68 (m, 1H), 4.29-4.07 (m, 1H), 3.92 (s, 3H), 3.81-3.62 (m, 1H), 3.53-3.33 (m, 4H), 2.46-2.30 (m, 2H), 1.90-1.79 (m, 2H), 1.65-1.49 (m, 2H), 1.09 (d, J = 6.6 Hz, 3H).
1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 0.6H), 8.31 (s, 0.4H), 8.18 (s, 0.4H), 8.13 (s, 0.6H), 7.78 (s, 0.6H), 7.76 (s, 0.4H), 7.63 (d, J = 7.3 Hz, 0.6H), 7.47 (d, J = 7.4 Hz, 0.4H), 6.85 (d, J = 7.9 Hz, 0.6H), 6.75 (d, J = 8.3 Hz, 0.4H), 4.78-4.68 (m, 1H), 4.29-4.07 (m, 1H), 3.91 (s, 3H), 3.79-3.62 (m, 1H), 3.53-3.33 (m, 4H), 2.46-2.30 (m, 2H), 2.04-1.79 (m, 2H), 1.59-1.56 (m, 2H), 1.09 (d, J = 6.6 Hz, 3H).
1H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 0.6H), 8.31 (s, 0.4H), 8.18 (s, 0.4H), 8.15 (s, 0.6H), 7.78 (s, 0.6H), 7.76 (s, 0.4H), 7.66 (d, J = 7.7 Hz, 0.6H), 7.48 (d, J = 7.6 Hz, 0.4H), 7.32 (d, J = 6.1 Hz, 0.6H), 7.18 (d, J = 6.8 Hz, 0.4H), 4.56-4.33 (m, 1H), 3.91 (s, 3H), 3.81- 3.65 (m, 1H), 3.52-3.39 (m, 2H), 2.79-2.62 (m, 1H), 2.47-2.34 (m, 5H), 2.22 (d, J = 9.1 Hz, 3H), 2.16-2.00 (m, 1H), 1.98-1.82 (m, 2H), 1.81-1.71 (m, 1H), 1.66-1.47 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 0.6H), 8.31 (s, 0.4H), 8.18 (s, 0.4H), 8.13 (s, 0.6H), 7.78 (s, 0.6H), 7.76 (s, 0.4H), 7.66 (d, J = 7.7 Hz, 0.6H), 7.48 (d, J = 7.6 Hz, 0.4H), 7.32 (d, J = 6.1 Hz, 0.7H), 7.18 (d, J = 6.8 Hz, 0.4H), 4.56-4.33 (m, 1H), 3.91 (s, 3H), 3.80- 3.64 (m, 1H), 3.56-3.41 (m, 2H), 2.80-2.62 (m, 2H), 2.47-2.28 (m, 4H), 2.26-21.5 (m, 3H), 2.15-2.00 (m, 1H), 1.98-1.82 (m, 2H), 1.82-1.71 (m, 1H), 1.65-1.49 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.49 (s, 0.4H), 8.45 (s, 0.6H), 8.36-8.28 (m, 1.5H), 8.12 (d, J = 7.6 Hz, 0.4H), 7.79 (s, 0.6H), 7.77 (s, 0.4H), 5.44-5.34 (m, 1H), 3.91 (s, 3H), 3.82-3.70 (m, 1H), 3.56-3.41 (m, 2H), 2.77- 2.59 (m, 4H), 2.47-2.27 (m, 3H), 2.22 (d, J = 4.4 Hz, 3H), 2.00-1.85 (m, 2H), 1.86-1.73 (m, 1H), 1.68-1.52 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 0.4H), 8.44 (s, 0.6H), 8.35-8.28 (m, 1.5H), 8.12 (d, J = 7.8 Hz, 0.4H), 7.79 (s, 0.6H), 7.77 (s, 0.4H), 5.44-5.33 (m, 1H), 3.91 (s, 3H), 3.85-3.69 (m, 1H), 3.57-3.42 (m, 2H), 2.79- 2.60 (m, 4H), 2.44-2.34 (m, 1H), 2.34-2.20 (m, 5H), 2.01-1.74 (m, 3H), 1.70-1.51 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 8.31 (s, 0.6H), 8.28 (s, 0.5H), 8.23 (s, 1H), 7.77 (s, 0.4H), 7.59 (d, J = 7.9 Hz, 0.4H), 4.70-4.58 (m, 1H), 4.35-4.24 (m, 1H), 3.91 (s, 3H), 3.89- 3.85 (m, 1H), 3.78-3.64 (m, 2H), 3.61-3.54 (m, 1H), 3.51-3.37 (m, 3H), 3.29-3.18 (m, 1H), 2.48-2.31 (m, 2H), 1.96-1.80 (m, 2H), 1.64-1.50 (m, 2H), 1.31-1.21 (m, 3H).
1H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 0.6H), 8.31 (s, 0.4H), 8.17 (s, 0.4H), 8.12 (s, 0.6H), 7.79 (s, 0.6H), 7.76 (s, 0.4H), 7.67- 7.57 (m, 1H), 7.51 (d, J = 8.0 Hz, 0.6H), 7.46 (d, J = 7.6 Hz, 0.4H), 4.60-4.32 (m, 1H), 3.91 (s, 3H), 3.71 (br.s., 1H), 3.52-3.41 (m, 2H), 2.47-2.30 (m, 2H), 2.20-2.03 (m, 4H), 1.98- 1.80 (m, 2H), 1.71-1.47 (m, 4H).
1H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 0.6H), 8.31 (s, 0.4H), 8.16 (s, 0.4H), 8.12 (s, 0.6H), 7.79 (s, 0.6H), 7.76 (s, 0.4H), 7.65- 7.56 (m, 1H), 7.50 (d, J = 7.2 Hz, 0.5H), 7.43 (d, J = 7.6 Hz, 0.5H), 5.04-4.98 (m, 1H), 4.03- 3.86 (m, 4H), 3.84-3.64 (m, 3H), 3.52-3.37 (m, 2H), 2.51-2.49 (m, 2H), 2.36 (t, J = 11.0 Hz, 1H), 2.00-1.79 (m, 4H), 1.64-1.48 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 0.6H), 8.31 (s, 0.4H), 8.23 (s, 0.4H), 8.18 (s, 0.6H), 7.90 (d, J = 7.6 Hz, 0.6H), 7.82 (d, J = 6.8 Hz, 0.4H), 7.79-7.71 (m, 1.5H), 7.58 (d, J = 8.0 Hz, 0.4H), 4.46-4.35 (m, 0.4H), 4.29- 4.15 (m, 0.6H), 3.90 (s, 3H), 3.79-3.66 (m, 1H), 3.55-3.39 (m, 2H), 2.93-2.70 (m, 4H), 2.48-2.30 (m, 2H), 1.97-1.81 (m, 2H), 1.67- 1.49 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 0.6H), 8.31 (s, 0.4H), 8.15 (s, 0.4H), 8.11 (s, 0.6H), 7.78 (s, 0.6H), 7.76 (s, 0.4H), 7.63 (dd, J = 6.9 Hz, 0.6H), 7.42 (d, J = 7.8 Hz, 0.4H), 7.15 (d, J = 7.2 Hz, 0.5H), 6.96 (d, J = 8.3 Hz, 0.5H), 4.05-3.94 (m, 0.5H), 3.90 (s, 3H), 3.85- 3.69 (m, 1H), 3.68-3.54 (m, 0.7H), 3.53- 3.58 (m, 2H), 2.47-2.29 (m, 2H), 2.00-1.82 (m, 2H), 1.82-1.65 (m, 4H), 1.65-1.51 (m, 3H), 1.44-1.27 (m, 2H), 1.27-1.02 (m, 3H).
1H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 0.7H), 8.31 (s, 0.3H), 8.23 (s, 0.3H), 8.18 (s, 0.7H), 8.11 (d, J = 8.0 Hz, 0.7H), 8.03 (d, J = 5.2 Hz, 0.3H), 7.79 (s, 0.7H), 7.76 (s, 0.3H), 7.72 (d, J = 7.2 Hz, 0.7H), 7.50 (d, J = 7.6 Hz, 0.3H), 5.04-4.79 (m, 1H), 4.72-4.61 (m, 2H), 4.58 (t, J = 6.5 Hz, 2H), 3.95-3.86 (m, 3H), 3.79-3.59 (m, 1H), 3.53-3.40 (m, 2H), 2.48-2.29 (m, 2H), 1.90-1.81 (m, 2H), 1.62- 1.47 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 0.5H), 8.31 (s, 0.4H), 8.18 (s, 0.4H), 8.14 (s, 0.5H), 7.78 (s, 0.5H), 7.76 (s, 0.4H), 7.68 (d, J = 6.9 Hz, 0.5H), 7.48 (d, J = 7.9 Hz, 0.4H), 7.32 (d, J = 7.2 Hz, 0.5H), 7.15 (d, J = 8.3 Hz, 0.5H), 4.26-4.12 (m, 0.4H), 4.10-3.97 (m, 0.6H), 3.91 (s, 3H), 3.89-3.80 (m, 2H), 3.79- 3.68 (m, 0.4H), 3.68-3.55 (m, 0.6H), 3.51- 3.40 (m, 2H), 3.30-3.22 (m, 2H), 2.45-2.29 (m, 2H), 1.95-1.80 (m, 2H), 1.75-1.51 (m, 6H).
1H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 0.7H), 8.31 (s, 0.3H), 8.26 (s, 0.3H), 8.21 (s, 0.7H), 7.77 (br.s., 1H), 7.69 (d, J = 7.0 Hz, 0.7H), 7.38 (d, J = 7.5 Hz, 0.3H), 4.40-4.14 (m, 1H), 3.90 (s, 3H), 3.78-3.57 (m, 1H), 3.55- 3.40 (m, 2H), 2.82 (br.s., 1H), 2.41-2.27 (m, 2H), 2.06-1.68 (m, 7H), 1.68-1.41 (m, 5H), 1.02-0.90 (m, 2H), 0.82-0.70 (m, 2H).
Absolute configuration not determined, enantiomer of compound 63
1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.12 (s, 0.4H), 8.09 (s, 0.6H), 8.00 (s, 1H), 7.82 (s, 1H), 7.80 (s, 1H), 7.69 (d, J = 7.9 Hz, 2H), 7.61 (d, J = 6.9 Hz, 0.6H), 7.46 (d, J = 8.0 Hz, 0.4H), 7.24 (d, J = 6.8 Hz, 0.6H), 7.15 (d, J = 7.1 Hz, 0.4H), 4.74-4.58 (m, 0.4H), 4.52- 4.38 (m, 1.6H), 4.15 (br.s., 1H), 3.89 (s, 3H), 3.68 (br.s., 1H), 3.62-3.48 (m, 2H), 2.46-2.37 (m, 1H), 2.05-1.62 (m, 7H), 1.62-1.33 (m, 4H).
1H NMR (400 MHz, DMSO-d6) δ 8.86 (s, 0.3H), 8.84 (s, 0.6H), 8.42-8.27 (m, 2.6H), 8.12 (d, J = 8.0 Hz, 0.3H), 7.79 (s, 0.7H), 7.77 (s, 0.3H), 4.52-4.43 (m, 0.3H), 4.43-4.31 (m, 0.7H), 3.91 (s, 3H), 3.84-3.72 (m, 1H), 3.55- 3.41 (m, 2H), 2.47-2.34 (m, 1H), 2.05-1.83 (m, 4H), 1.78-1.48 (m, 9H).
1H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 0.4H), 8.13 (s, 0.6H), 7.65 (d, J = 7.4 Hz, 0.6H), 7.47 (d, J = 7.7 Hz, 0.4H), 7.26 (d, J = 6.5 Hz, 0.6H), 7.15 (d, J = 8.0 Hz, 0.4H), 4.45- 4.26 (m, 1H), 4.05-3.80 (m, 1H), 3.70-3.56 (m, 2H), 3.05-2.83 (m, 3H), 2.89-2.76 (m, 2H), 2.14 (s, 3H), 1.94-1.82 (m, 8H), 1.71- 1.44 (m, 10H).
Absolute configuration not determined, enantiomer of compound 87
1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 8.15 (s, 0.4H), 8.11 (s, 0.6H), 8.00 (s, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.73-7.66 (m, 2H), 7.64 (d, J = 7.1 Hz, 0.6H), 7.47 (d, J = 8.2 Hz, 0.4H), 7.04 (d, J = 6.9 Hz, 0.6H), 7.00 (d, J = 8.4 Hz, 0.4H), 4.80 (d, J = 3.6 Hz, 0.4H), 4.75 (d, J = 3.3 Hz, 0.6H), 4.51-4.25 (m, 1H), 4.09 (br.s., 1H), 3.89 (s, 3H), 3.71 (br.s., 1H), 3.64- 3.47 (m, 2H), 2.49-2.37 (m, 2H), 2.04-1.77 (m, 4H), 1.74-1.48 (m, 6H).
Absolute configuration not determined, enantiomer of compound 86
1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 8.15 (s, 0.4H), 8.11 (s, 0.6H), 8.00 (s, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.73-7.66 (m, 2H), 7.64 (d, J = 7.1 Hz, 0.6H), 7.47 (d, J = 8.2 Hz, 0.4H), 7.04 (d, J = 6.9 Hz, 0.6H), 7.00 (d, J = 8.4 Hz, 0.4H), 4.80 (d, J = 3.6 Hz, 0.4H), 4.75 (d, J = 3.3 Hz, 0.6H), 4.51-4.25 (m, 1H), 4.09 (br.s. 1H), 3.89 (s, 3H), 3.71 (br.s., 1H), 3.64- 3.47 (m, 2H), 2.49-2.37 (m, 2H), 2.03-1.75 (m, 4H), 1.74-1.48 (m, 6H).
1H NMR (400 MHz, DMSO-d6) δ 8.39-8.26 (m, 2H), 8.03 (d, J = 7.2 Hz, 0.6H), 7.88 (d, J = 7.6 Hz, 0.4H), 7.79 (s, 0.6H), 7.77 (s, 0.4H), 5.65-5.50 (m, 1H), 3.96-3.87 (m, 4H), 3.83- 3.70 (m, 4H), 3.54-3.43 (m, 2H), 2.49-2.34 (m, 2H), 2.27-2.15 (m, 1H), 2.04-1.87 (m, 3H), 1.68-1.53 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 0.4H), 8.46 (s, 0.5H), 8.37-8.30 (m, 1.5H), 8.17 (d, J = 7.3 Hz, 0.4H), 7.79 (s, 0.6H), 7.77 (s, 0.4H), 6.06 (br.s., 1H), 5.59-5.52 (m, 1H), 3.91 (s, 3H), 3.89-3.69 (m, 5H), 3.55-3.43 (m, 2H), 2.46-2.35 (m, 1H), 2.29-2.16 (m, 1H), 2.06-1.87 (m, 3H), 1.67-1.52 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 0.4H), 8.10 (s, 0.6H), 7.61 (d, J = 6.9 Hz, 0.6H), 7.50 (d, J = 8.9 Hz, 2H), 7.43 (d, J = 7.3 Hz, 0.3H), 7.24 (d, J = 6.6 Hz, 0.6H), 7.13 (d, J = 7.7 Hz, 0.4H), 7.04 (d, J = 9.0 Hz, 2H), 4.43-4.28 (m, 0.4H), 4.27-4.14 (m, 0.7H), 3.74-3.57 (m, 1H), 3.54-3.37 (m, 2H), 3.26- 3.16 (m, 4H), 2.89-2.76 (m, 4H), 2.44-2.24 (m, 2H), 1.95-1.74 (m, 4H), 1.74-1.60 (m, 2H), 1.59-1.34 (m, 6H).
1H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 0.4H), 8.10 (s, 0.6H), 7.72-7.66 (m, 3H), 7.61 (d, J = 4.0 Hz, 0.6H), 7.45 (d, J = 4.0 Hz, 0.5H), 7.18 (d, J = 4.0 Hz, 0.7H), 7.11 (d, J = 6.4 Hz, 0.5H), 6.43 (s, 1H), 4.69 (d, J = 4.0 Hz, 0.4H), 4.61 (d, J = 4.0 Hz, 0.6H), 4.07-3.88 (m, 2H), 3.80-3.65 (m, 1H), 3.64-3.47 (m, 2H), 3.40 (s, 2H), 2.92 (t, J = 5.5 Hz, 2H), 2.43- 2.29 (m, 4H), 2.02-1.69 (m, 5H), 1.68-1.32 (m, 7H).
1HNMR (400 MHz, DMSO-d6) δ 8.17 (s, 0.4H), 8.13 (s, 0.6H), 7.68 (s, 4.5H), 7.51 (d, J = 5.5 Hz, 1H), 7.39 (d, J = 5.2 Hz, 0.5H), 6.49- 6.36 (m, 1H), 4.59-4.37 (m, 1H), 3.92-3.61 (m, 4H), 3.61-3.45 (m, 3H), 3.44-3.36 (m, 2H), 2.92 (t, J = 5.2 Hz, 2H), 2.44-2.23 (m, 4H), 2.07-1.79 (m, 4H), 1.63-1.46 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.74-7.61 (m, 3H), 7.45-7.37 (m, 1H), 7.30- 7.21 (m, 1H), 6.50-6.35 (m, 2H), 4.67-4.44 (m, 2H), 3.94-3.75 (m, 2H), 3.74-3.60 (m, 2H), 3.60-3.45 (m, 3H), 3.44-3.38 (m, 2H), 2.92 (t, J = 5.4 Hz, 2H), 2.42-2.34 (m, 2H), 2.17-1.83 (m, 5H), 1.61-1.47 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.14 (s, 0.4H), 8.10 (s, 0.5H), 7.61 (d, J = 7.2 Hz, 0.5H), 7.54 (d, J = 8.7 Hz, 2H), 7.43 (d, J = 7.8 Hz, 0.4H), 7.24 (d, J = 6.6 Hz, 0.5H), 7.13 (d, J = 7.6 Hz, 0.3H), 7.08 (d, J = 8.9 Hz, 2H), 4.46-4.27 (m, 0.4H), 4.27-4.11 (m, 0.6H), 3.79-3.70 (m, 4H), 3.69-3.56 (m, 1H), 3.55- 3.39 (m, 2H), 3.31-3.25 (m, 4H), 2.45-2.31 (m, 2H), 1.95-1.75 (m, 4H), 1.71-1.38 (m, 8H).
1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.21-8.10 (m, 1H), 8.00 (s, 1H), 7.84-7.78 (m, 2H), 7.74-7.64 (m, 2.6H), 7.50 (d, J = 5.5 Hz, 1H), 7.41-7.35 (m, 0.5H), 4.59-4.37 (m, 1H), 3.89 (s, 3H), 3.84-3.61 (m, 4H), 3.59- 3.45 (m, 3H), 2.48-2.38 (m, 2H), 2.17-1.78 (m, 4H), 1.63-1.46 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.44-8.30 (m, 2.6H), 8.22 (d, J = 7.8 Hz, 0.4H), 7.78 (s, 0.6H), 7.77 (s, 0.4H), 4.11-3.96 (m, 1H), 3.90 (s, 3H), 3.86-3.71 (m, 1H), 3.60-3.43 (m, 2H), 2.47-2.34 (m, 2H), 2.25-2.02 (m, 2H), 2.00-1.87 (m, 2H), 1.78-1.48 (m, 8H).
1H NMR (400 MHz, DMSO-d6) δ 9.08-9.01 (m, 1H), 8.97 (s, 0.5H), 8.92 (s, 0.5H), 8.33 (d, J = 7.7 Hz, 1H), 7.78 (d, J = 6.2 Hz, 1H), 4.28- 4.17 (m, 0.6H), 4.10-3.98 (m, 0.6H), 3.91 (s, 3h), 3.83 (br.s., 1H), 3.54-3.43 (m, 2H), 2.48- 2.39 (m, 2H), 2.06-1.86 (m, 6H), 1.76-1.55 (m, 6H).
1H NMR (400 MHz, DMSO-d6) δ 8.88 (d, J = 7.6 Hz, 0.6H), 8.82-8.74 (m, 1.3H), 8.32 (d, J = 4.0 Hz, 1H), 7.77 (d, J = 4.9 Hz, 1H), 3.91 (s, 3H), 3.81 (br.s., 1H), 3.58-3.40 (m, 3H), 2.48-2.39 (m, 2H), 2.13-1.87 (m, 4H), 1.85- 1.73 (m, 1H), 1.72-1.50 (m, 7H).
1H NMR (400 MHz, DMSO-d6 + D2O) δ 8.51- 8.39 (m, 1H), 7.72 (d, J = 8.2 Hz, 2H), 7.51 (d, J = 8.2 Hz, 2H), 4.46-4.23 (m, 1H), 3.89- 3.74 (m, 1H), 3.53-3.44 (m, 2H), 3.40-3.30 (m, 2H), 3.08-2.95 (m, 3H), 2.75-2.54 (m, 2H), 2.36-2.21 (m, 1H), 2.02-1.77 (m, 8H), 1.73-1.37 (m, 8H).
1H NMR (400 MHz, DMSO-d6) δ 7.97 (s, 1H), 7.78-7.61 (m, 4H), 7.40-7.30 (m, 0.6H), 7.23- 7.16 (m, 0.4H), 6.43 (s, 1H), 6.18-6.09 (m, 1H), 4.72-4.57 (m, 1H), 4.24-3.93 (m, 2H), 3.77-3.48 (m, 4H), 3.46-3.39 (m, 3H), 2.93 (t, J = 5.6 Hz, 2H), 2.42-2.33 (m, 2H), 2.06- 1.33 (m, 10H).
1H NMR (400 MHz, DMSO-d6) δ 8.22-8.08 (m, 2H), 7.60 (d, J = 7.3 Hz, 0.6H), 7.54 (d, J = 8.8 Hz, 2H), 7.43 (d, J = 7.8 Hz, 0.4H), 7.23 (d, J = 6.7 Hz, 0.6H), 7.13 (d, J = 7.2 Hz, 0.4H), 7.02 (d, J = 9.0 Hz, 2H), 4.44-4.14 (m, 1H), 3.87 (s, 2H), 3.73-3.60 (m, 1H), 3.59- 3.53 (m, 2H), 3.52-3.39 (m, 2H), 2.45-2.24 (m, 2H), 1.96-1.74 (m, 5H), 1.72-1.37 (m, 9H).
1H NMR (400 MHz, DMSO-d6) δ 8.48 (s, 0.3H), 8.45 (s, 0.6H), 8.32 (d, J = 6.8 Hz, 0.6H), 8.15 (d, J = 8.4 Hz, 0.3H), 7.69 (br.s., 3H), 6.44 (br.s., 1H), 6.08 (br.s., 1H), 5.58- 5.47 (m, 1H), 4.09-3.98 (m, 1H), 3.93-3.66 (m, 5H), 3.63-3.52 (m, 2H), 2.98-2.86 (m, 2H), 2.41-2.34 (m, 2H), 2.31-2.14 (m, 3H), 2.04-1.82 (m, 5H), 1.63-1.45 (s, 2H).
1H NMR (400 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.45-8.02 (m, 3H), 7.87 (d, J = 8.3 Hz, 2H), 7.76-7.63 (m, 2.5H), 7.50 (d, J = 5.6 Hz, 1H), 7.39 (d, J = 6.6 Hz, 0.4H), 4.58-4.50 (m, 0.4H), 4.47-4.37 (m, 0.6H), 3.96-3.44 (m, 7H), 2.45-2.37 (m, 1H), 2.20-1.79 (m, 5H), 1.64-1.45 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 0.3H), 8.14 (s, 0.6H), 7.86 (d, J = 8.5 Hz, 2H), 7.74-7.63 (m, 2.5H), 7.54-7.47 (m, 1H), 7.40 (d, J = 6.5 Hz, 0.3H), 4.59-4.38 (m, 1H), 3.96- 3.70 (m, 3H), 3.70-3.62 (m, 1H), 3.62-3.44 (m, 3H), 2.65-2.52 (m, 1H), 2.46-2.38 (m, 1H), 2.17-1.80 (m, 4H), 1.63-1.45 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.13 (s, 0.4H), 8.10 (s, 0.6H), 7.60 (d, J = 7.1 Hz, 0.6H), 7.48 (d, J = 8.8 Hz, 2H), 7.42 (d, J = 7.6 Hz, 0.4H), 7.24 (d, J = 6.3 Hz, 0.6H), 7.13 (d, J = 7.5 Hz, 0.4H), 7.05 (d, J = 9.1 Hz, 2H), 4.73 (d, J = 4.1 Hz, 1H), 4.43-4.31 (m, 0.4H), 4.26-4.14 (m, 0.6H), 3.79-3.57 (m, 4H), 3.55- 3.39 (m, 2H), 3.12-2.99 (m, 2H), 2.43-2.23 (m, 2H), 1.96-1.74 (m, 6H), 1.73-1.34 (m, 10H).
1H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 0.5H), 8.40 (s, 0.4H), 8.30 (s, 1H), 8.04 (d, J = 7.6 Hz, 0.5H), 7.87 (d, J = 7.6 Hz, 0.4H), 7.84 (s, 0.5H), 7.82 (s, 0.4H), 5.61-5.51 (m, 1H), 4.56-4.44 (m, 1H), 4.04-3.85 (m, 3H), 3.83- 3.66 (m, 4H), 3.55-3.41 (m, 5H), 2.43-2.34 (m, 1H), 2.26-2.14 (m, 1H), 2.08-1.86 (m, 7H), 1.67-1.52 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.78 (d, J = 4.6 Hz, 1H), 8.31 (s, 0.4H), 8.30 (s, 0.6H), 8.12 (t, J = 7.8 Hz, 1H), 8.03 (d, J = 7.4 Hz, 0.6H), 7.96-7.90 (m, 1H), 7.87 (d, J = 7.8 Hz, 0.5H), 7.76-7.68 (m, 1H), 5.61-5.50 (m, 1H), 3.97- 3.65 (m, 7H), 2.93-2.77 (m, 2H), 2.27-2.13 (m, 1H), 2.04-1.82 (m, 3H), 1.62-1.44 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.38 (d, J = 6.8 Hz, 1H), 8.30 (d, J = 2.0 Hz, 1H), 8.04 (d, J = 7.2 Hz, 0.6H), 7.87 (d, J = 7.2 Hz, 0.4H), 7.80 (d, J = 7.2 Hz, 1H), 5.62-5.52 (m, 1H), 4.66-4.53 (m, 1H), 3.97-3.66 (m, 5H), 3.58- 3.43 (m, 2H), 2.42-2.35 (m, 2H), 2.26-2.15 (m, 1H), 2.02-1.89 (m, 3H), 1.66-1.54 (m, 2H), 1.44 (d, J = 6.4 Hz, 6H).
Relative configuration (cis)
1H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 0.5H), 8.32 (s, 0.5H), 8.30 (s, 0.4H), 8.29 (s, 0.6H), 7.96 (d, J = 7.4 Hz, 0.5H), 7.81 (d, J = 7.8 Hz, 0.5H), 7.79 (s, 0.5H), 7.77 (s, 0.5H), 5.46-5.38 (m, 1H), 5.07 (d, J = 5.0 Hz, 0.4H), 5.02 (d, J = 5.2 Hz, 0.6H), 4.46-4.38 (m, 0.4H), 4.38-4.30 (m, 0.6H), 4.09-3.96 (m, 1H), 3.91 (s, 3H), 3.90-3.83 (m, 1H), 3.82- 3.67 (m, 2H), 3.58-3.40 (m, 3H), 2.47-2.35 (m, 2H), 2.04-1.87 (m, 2H), 1.66-1.51 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 0.6H), 8.31 (s, 0.4H), 8.24 (s, 0.4H), 8.19 (s, 0.6H), 7.78 (s, 0.6H), 7.76 (s, 0.4H), 7.68 (d, J = 7.3 Hz, 0.6H), 7.49 (d, J = 7.8 Hz, 0.4H), 4.95-4.78 (m, 1H), 4.47-4.33 (m, 1H), 3.91 (s, 3H), 3.80-3.59 (m, 1H), 3.52-3.36 (m, 2H), 3.03 (t, J = 12.8 Hz, 1H), 2.48-2.34 (m, 2H), 2.01-1.80 (m,2H), 1.76-1.48 (m, 7H), 1.48-1.32 (m, 1H), 1.21 (d, J = 6.8 Hz, 3H).
1H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 0.5H), 8.36 (s, 0.4H), 8.30 (s, 1H), 8.04 (d, J = 7.3 Hz, 0.5H), 7.87 (d, J = 7.6 Hz, 0.4H), 7.82 (s, 0.5H), 7.80 (s, 0.5H), 5.63-5.51 (m, 1H), 4.35-4.22 (m, 1H), 3.96-3.84 (m, 1H), 3.83- 3.67 (m, 4H), 3.55-3.42 (m, 2H), 3.03 (d, J = 12.5 Hz, 2H), 2.62-2.52 (m, 3H), 2.47-2.31 (m, 2H), 2.28-2.13 (m, 1H), 2.03-1.87 (m, 5H), 1.87-1.73 (m, 2H), 1.66-1.52 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 0.5H), 8.38 (s, 0.4H), 8.33 (s, 1H), 8.20 (d, J = 7.8 Hz, 0.5H), 8.05 (d, J = 8.2 Hz, 0.4H), 7.84 (s, 0.5H), 7.82 (s, 0.4H), 5.64-5.52 (m, 1H), 4.80-4.58 (m, 1H), 4.09 (br.s., 1H), 3.98-3.86 (m, 4H), 3.83-3.70 (m, 3H), 3.70-3.47 (m, 1H), 3.42-3.33 (m, 1H), 2.87-2.60 (m, 2H), 2.29-2.16 (m, 1H), 2.10-1.92 (m, 2H), 1.69- 1.57 (m, 1H).
1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.02 (d, J = 7.3 Hz, 0.6H), 7.86 (d, J = 7.5 Hz, 0.4H), 7.61 (t, J = 7.3 Hz, 1H), 7.58-7.50 (m, 2H), 6.21-6.13 (m, 1H), 5.60-5.55 (m, 1H), 3.96-3.86 (m, 1H), 3.85-3.68 (m, 4H), 3.64- 3.51 (m, 2H), 3.44-3.36 (m, 2H), 2.90 (t, J = 5.5 Hz, 2H), 2.69-2.53 (m, 3H), 2.38-2.30 (m, 2H), 2.26-2.13 (m, 1H), 2.01-1.85 (m, 3H), 1.64-1.50 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.02 (d, J = 7.3 Hz, 0.5H), 7.86 (d, J = 7.7 Hz, 0.4H), 7.66-7.47 (m, 3H), 5.60-5.51 (m, 1H), 3.96-3.85 (m, 1H), 3.85-3.67 (m, 4H), 3.63- 3.49 (m, 2H), 3.09-2.89 (m, 3H), 2.68-2.57 (m, 4H), 2.25-2.11 (m, 1H), 2.03-1.84 (m, 3H), 1.75-1.45 (m, 6H).
1H NMR (400 MHz, DMSO-d6) δ 8.32-8.26 (m, 1H), 8.23-8.18 (m, 1H), 8.02 (d, J = 7.4 Hz, 0.6H), 7.87 (d, J = 7.6 Hz, 0.4H), 7.65- 7.58 (m, 1H), 6.96 (s, 2H), 6.53 (d, J = 8.8 Hz, 1H), 5.61-5.51 (m, 1H), 3.95-3.85 (m, 1H), 3.84-3.66 (m, 4H), 3.53-3.42 (m, 2H), 2.47- 2.38 (m, 2H), 2.26-2.13 (m, 1H), 2.01-1.84 (m, 3H), 1.63-1.47 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.38-8.30 (m, 2H), 8.15 (d, J = 7.4 Hz, 0.6H), 8.00 (d, J = 7.7 Hz, 0.4H), 7.80-7.75 (m, 1H), 5.66- 5.50 (m, 1H), 5.41 (d, J = 3.0 Hz, 0.5H), 5.28 (d, J = 3.0 Hz, 0.5H), 4.25-4.15 (m, 1H), 4.04- 3.83 (m, 5H), 3.82-3.71 (m, 2H), 3.55-3.42 (s, 2H), 2.46-2.35 (m, 2H), 2.03-1.87 (m, 2H), 1.69-1.52 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.42-8.36 (m, 1H), 8.35-8.30 (m, 1H), 8.20 (d, J = 7.6 Hz, 0.5H), 8.05 (d, J = 7.2 Hz, 0.4H), 7.86- 7.81 (m, 1H), 5.64-5.53 (m, 1H), 4.78-4.70 (m, 0.5H), 4.67-4.57 (m, 0.5H), 4.22-4.02 (m, 1H), 4.01-3.87 (m, 4H), 3.83-3.69 (m, 3H), 3.67-3.47 (m, 2H), 2.89-2.72 (m, 2H), 2.28-2.16 (m, 1H), 2.10-1.93 (m, 2H), 1.73- 1.57 (m, 1H).
1H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 8.20 (s, 1H), 7.78 (s, 1H), 7.75 (d, J = 6.4 Hz, 0.5H), 7.58 (d, J = 7.2 Hz, 0.5H), 6.83 (t, J = 55.1 Hz, 1H), 5.51 (s, 1H), 3.98-3.87 (m, 4H), 3.86-3.66 (m, 4H), 3.53-3.42 (m, 2H), 2.44 2.34 (m, 2H), 2.28-2.13 (m, 1H), 2.04-1.87 (m, 3H), 1.66-1.50 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.35 (d, J = 4.4 Hz, 1H), 8.32 (d, J = 3.1 Hz, 1H), 8.13 (d, J = 7.2 Hz, 0.6H), 8.01 (d, J = 7.4 Hz, 0.4H), 7.81 (s, 0.6H), 7.78 (s, 0.4H), 5.59 (br.s., 1H), 5.00 (d, J = 18.7 Hz, 0.5H), 4.87 (d, J = 19.2 Hz, 0.5H), 4.11-3.87 (m, 5H), 3.87-3.69 (m, 4H), 3.67-3.55 (m, 1H), 2.84-2.56 (m, 2H), 2.30-2.11 (m, 1H), 2.04-1.89 (m, 2H), 1.82- 1.71 (m, 1H).
1H NMR (400 MHz, DMSO-d6) δ 8.35-8.22 (m, 2H), 8.03 (d, J = 7.5 Hz, 0.6H), 7.88 (d, J = 7.5 Hz, 0.4H), 7.75 (s, 0.4H), 7.74 (s, 0.6H), 7.20 (br.s., 1H), 5.62-5.49 (m, 1H), 4.77 (s, 2H), 3.97-3.83 (m, 1H), 3.84-3.66 (m, 4H), 3.51 (d, J = 8.4 Hz, 2H), 2.46-2.35 (m, 1H), 2.28-2.14 (m, 1H), 2.02-1.84 (m, 3H), 1.68- 1.51 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.43-8.25 (m, 2.5H), 8.15 (d, J = 9.5 Hz, 0.5H), 7.88 (s, 0.6H), 7.84 (s, 0.4H), 5.62 (s, 1H), 4.76-4.48 (m, 1H), 4.00-3.85 (m, 4H), 3.84-3.67 (m, 4H), 3.66-3.44 (m, 1H), 3.15-2.95 (m, 1H), 2.84-2.69 (m, 1H), 2.30-2.13 (m, 1H), 2.04- 1.78 (m, 3H).
1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.02 (d, J = 7.2 Hz, 0.6H), 7.86 (d, J = 7.1 Hz, 0.4H), 7.72-7.60 (m, 2H), 7.50 (d, J = 8.3 Hz, 2H), 5.54 (br.s., 1H), 3.96-3.82 (m, 1H), 3.82- 3.67 (m, 4H), 3.62-3.48 (m, 2H), 3.02 (d, J = 12.0 Hz, 2H), 2.76-2.65 (m, 1H), 2.64-2.54 (m, 3H), 2.45-2.35 (m, 1H), 2.27-2.11 (m, 1H), 2.03-1.84 (m, 3H), 1.77-1.64 (m, 2H), 1.64-1.45 (m, 4H).
1H NMR (400 MHz, DMSO-d6) δ 8.35 (br.s., 1H), 8.29 (s, 1H), 8.02 (d, J = 7.1 Hz, 0.6H), 7.87 (d, J = 7.0 Hz, 0.4H), 7.78-7.68 (m, 2H), 7.68-7.59 (m, 2H), 5.59-5.49 (m, 1H), 4.12- 3.95 (m, 3H), 3.94-3.66 (m, 7H), 3.63-3.49 (m, 3H), 2.46-2.36 (m, 1H), 2.27-2.11 (m, 1H), 2.01-1.84 (m, 3H), 1.64-1.49 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.01 (d, J = 7.3 Hz, 0.6H), 7.86 (d, J = 7.4 Hz, 0.4H), 7.50 (d, J = 8.9 Hz, 2H), 7.06 (d, J = 9.1 Hz, 2H), 5.60-5.50 (m, 1H), 3.97-3.83 (m, 3H), 3.81-3.64 (m, 4H), 3.55-3.42 (m, 2H), 2.85 (t, J = 11.5 Hz, 2H), 2.45-2.39 (m, 1H), 2.39-2.22 (m, 2H), 2.22-2.09 (m, 7H), 2.03- 1.78 (m, 5H), 1.63-1.48 (m, 2H), 1.48-1.33 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.01 (d, J = 7.3 Hz, 0.6H), 7.86 (d, J = 7.7 Hz, 0.4H), 7.49 (d, J = 8.9 Hz, 2H), 7.05 (d, J = 9.1 Hz, 2H), 5.62-5.49 (m, 1H), 4.39 (s, 1H), 3.96- 3.84 (m, 1H), 3.82-3.63 (m, 4H), 3.59-3.43 (m, 4H), 3.30-3.18 (m, 2H), 2.47-2.36 (m, 2H), 2.27-2.10 (m, 1H), 2.04-1.83 (m, 3H), 1.63-1.45 (m, 6H), 1.15 (s, 3H).
1H NMR (400 MHz, DMSO-d6) δ 8.35-8.22 (m, 2H), 8.03 (d, J = 7.5 Hz, 0.6H), 7.88 (d, J = 7.6 Hz, 0.4H), 7.74 (d, J = 5.9 Hz, 1H), 7.19 (br.s., 2H), 5.57 (d, J = 5.1 Hz, 1H), 4.77 (s, 2H), 3.95-3.84 (m, 1H), 3.84-3.67 (m, 4H), 3.51 (d, J = 9.7 Hz, 2H), 2.48-2.35 (m, 2H), 2.29-2.13 (m, 1H), 2.03-1.86 (m, 3H), 1.69- 1.49 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 0.3H), 8.18 (s, 0.6H), 7.74 (d, J = 7.2 Hz, 0.6H), 7.67 (d, J = 4.0 Hz, 4H), 7.56 (d, J = 7.9 Hz, 0.4H), 7.42 (d, J = 7.8 Hz, 0.7H), 7.32 (d, J = 8.7 Hz, 0.4H), 6.43 (br.s., 1H), 4.95-4.82 (m, 0.4H), 4.71-4.62 (m, 0.6H), 3.80-3.63 (m, 1H), 3.62-3.45 (m, 2H), 3.44-3.37 (m, 2H), 2.92 (t, J = 5.5 Hz, 2H), 2.46-2.34 (m, 4H), 2.19-1.68 (m, 8H), 1.66-1.40 (m, 3H).
1H NMR (400 MHz, DMSO-d6) δ 8.04 (br.s., 1H), 7.68 (s, 4H), 7.48 (d, J = 7.2 Hz, 0.6H), 7.31 (d, J = 7.5 Hz, 0.4H), 6.43 (s, 1H), 6.29 (d, J = 8.3 Hz, 0.6H), 6.16 (d, J = 8.6 Hz, 0.4H), 5.08-4.89 (m, 0.4H), 4.85-4.69 (m, 0.7H), 3.69 (br.s., 1H), 3.61-3.44 (m, 2H), 3.41 (d, J = 2.9 Hz, 2H), 2.93 (t, J = 5.6 Hz, 2H), 2.47-2.34 (m, 4H), 2.19-1.98 (m, 3H), 1.98-1.81 (m, 3H), 1.80-1.66 (m, 1H), 1.66- 1.40 (m, 3H).
1H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.67 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 8.2 Hz, 2.7H), 7.30 (s, 0.4H), 6.30 (d, J = 6.8 Hz, 0.6H), 6.18 (s, 0.4H), 5.05-4.89 (m, 0.4H), 4.84-4.67 (m, 0.6H), 3.70 (br.s., 1H), 3.59- 3.43 (m, 2H), 3.02 (d, J = 12.1 Hz, 2H), 2.75- 2.68 (m, 1H), 2.64-2.54 (m, 2H), 2.44-2.35 (m, 2H), 2.16-1.98 (m, 3H), 1.97-1.82 (m, 3H), 1.80-1.65 (m, 3H), 1.65-1.42 (m, 5H).
1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 0.3H), 8.18 (s, 0.6H), 7.75 (d, J = 7.3 Hz, 0.6H), 7.66 (t, J = 6.7 Hz, 2H), 7.56 (d, J = 7.7 Hz, 0.4H), 7.50 (d, J = 8.2 Hz, 2H), 7.42 (d, J = 7.9 Hz, 0.7H), 7.32 (d, J = 8.8 Hz, 0.4H), 4.93-4.82 (m, 0.4H), 4.74-4.57 (m, 0.6H), 3.70 (br.s., 1H), 3.62-3.43 (m, 2H), 3.02 (d, J = 12.4 Hz, 2H), 2.75-2.68 (m, 1H), 2.64-2.54 (m, 2H), 2.45-2.35 (m, 2H), 2.20-1.81 (m, 7H), 1.79-1.65 (m, 3H), 1.65-1.40 (m, 5H).
1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.01 (d, J = 7.7 Hz, 0.6H), 7.86 (d, J = 7.5 Hz, 0.4H), 7.39 (d, J = 8.7 Hz, 2H), 6.68 (d, J = 8.9 Hz, 2H), 6.53 (d, J = 7.6 Hz, 1H), 5.55 (br.s., 1H), 3.94-3.82 (m, 1H), 3.82-3.61 (m, 4H), 3.47 (d, J = 9.4 Hz, 2H), 2.95 (d, J = 12.6 Hz, 2H), 2.59-2.52 (m, 5H), 2.45-2.34 (m, 2H), 2.24-2.12 (m, 1H), 2.02-1.78 (m, 5H), 1.62- 1.42 (m, 2H), 1.31-1.25 (m, 1H).
1H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 8.00 (d, J = 7.1 Hz, 0.7H), 7.85 (d, J = 7.2 Hz, 0.4H), 7.49 (d, J = 8.8 Hz, 2H), 6.63 (d, J = 9.0 Hz, 2H), 5.54 (br.s., 1H), 5.03 (d, J = 3.6 Hz, 1H), 4.42 (br.s., 1H), 3.95-3.83 (m, 1H), 3.80- 3.61 (m, 4H), 3.54-3.41 (m, 3H), 3.41-3.34 (m, 2H), 3.16 (d, J = 10.9 Hz, 1H), 2.44-2.35 (m, 2H), 2.24-2.12 (m, 1H), 2.10-1.83 (m, 5H), 1.63-1.47 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 8.00 (d, J = 7.3 Hz, 0.6H), 7.85 (d, J = 6.9 Hz, 0.4H), 7.49 (d, J = 8.7 Hz, 2H), 6.63 (d, J = 8.9 Hz, 2H), 5.54 (br.s., 1H), 5.03 (d, J = 3.6 Hz, 1H), 4.42 (br.s., 1H), 3.96-3.81 (m, 1H), 3.80- 3.61 (m, 4H), 3.55-3.42 (m, 3H), 3.42-3.35 (m, 2H), 3.16 (d, J = 10.4 Hz, 1H), 2.46-2.35 (m, 2H), 2.26-2.12 (m, 1H), 2.12-1.83 (m, 5H), 1.63-1.49 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 5.28 (s, 1H), 8.04-7.96 (m, 1.5H), 7.86 (d, J = 7.3 Hz, 0.4H), 7.82 (d, J = 8.4 Hz, 2H), 7.73- 7.67 (m, 2H), 5.60-5.49 (d, J = 5.2 Hz, 1H), 3.96-3.83 (m, 4H), 3.82-3.65 (m, 4H), 3.58 (br.s., 2H), 2.59-2.52 (m, 2H), 2.24-2.11 (m, 1H), 2.02-1.85 (m, 3H), 1.64-1.47 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 801 (d, J = 7.3, Hz, 0.6H), 7.85 (d, J = 8.0 Hz, 0.4H), 7.52 (d, J = 8.8 Hz, 2H), 7.09 (d, J = 9.1 Hz, 2H), 5.59-5.49 (m, 1H), 3.95-3.84 (m, 1H), 3.81-3.64 (m, 4H), 3.64-3.45 (m, 4H), 3.30-3.20 (m, 2H), 3.15-3.08 (m, 1H), 2.43- 2.35 (m, 1H), 2.24-2.14 (m, 1H), 2.04-1.84 (m, 6H), 1.84-1.72 (m, 2H), 1.63-1.48 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.27 (s, 1H), 7.49 (d, J = 8.5 Hz, 2H), 6.52 (d, J = 8.6 Hz, 2H), 5.54 (d, J = 15.2 Hz, 1H), 4.07 (s, 4H), 4.00 (s, 4H), 3.93-3.80 (m, 1H), 3.80- 3.61 (m, 5H), 2.43-2.34 (m, 2H), 2.31-2.12 (m, 2H), 2.01-1.83 (m, 3H), 1.62-1.46 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.02 (d, J = 7.3 Hz, 0.6H), 7.86 (d, J = 7.6 Hz, 0.4H), 7.74-7.62 (m, 2H), 7.60-7.49 (m, 2H), 5.60-5.50 (m, 1H), 3.96-3.83 (m, 1H), 3.82- 3.66 (m, 4H), 3.62-3.50 (m, 2H), 3.27-3.15 (m, 2H), 3.04-2.85 (m, 2H), 2.70-2.60 (m, 1H), 2.58-2.53 (m, 1H), 2.47-2.35 (m, 1H), 2.25-2.11 (m, 2H), 2.02-1.84 (m, 3H), 1.76- 7.63 (m, 1H), 1.63-1.49 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 8.01 (d, J = 7.4 Hz, 0.6H), 7.86 (d, J = 7.4 Hz, 0.4H), 7.76-7.62 (m, 4H), 6.65 (s, 1H), 5.61- 5.49 (m, 1H), 4.47 (s, 0.4H), 4.27 (s, 0.4H), 3.99 (s, 1.6H), 3.94-3.80 (m, 3H), 3.80-3.66 (m, 4H), 3.64-3.49 (m, 2.5H), 2.53-2.51 (m, 2H), 2.23-2.12 (m, 1H), 2.00-1.85 (m, 3H), 1.62-1.49 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.00 (d, J = 7.1 Hz, 0.6H), 7.85 (d, J = 7.6 Hz, 0.4H), 7.54 (d, J = 8.9 Hz, 2H), 7.12 (d, J = 9.1 Hz, 2H), 5.61-5.50 (m, 1H), 3.96-3.61 (m, 7H), 3.51 (br.s., 3H), 3.08-2.87 (m, 4H), 2.85- 2.75 (m, 1H), 2.46-2.34 (m, 2H), 2.29-2.11 (m, 1H), 2.03-1.83 (m, 3H), 1.64-1.47 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 0.8H), 8.31 (s, 0.2H), 8.23 (s, 0.2H), 8.17 (s, 0.8H), 7.76 (s, 1H), 7.72 (d, J = 7.6 Hz, 0.8H), 7.41 (d, J = 7.9 Hz, 0.2H), 4.86-4.77 (m, 0.2H), 4.74-4.63 (m, 0.9H), 3.90 (s, 3H), 3.79- 3.61 (m, 1H), 3.58-3.40 (m, 4H), 2.38 (br.s., 2H), 2.31-2.14 (m, 3H), 2.05 (s, 5H), 1.96- 1.79 (m, 4H), 1.76-1.44 (m, 8H).
1H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 8.13 (s, 1H), 7.82 (s, 1H), 7.37 (d, J = 7.3 Hz, 1H), 4.33-4.23 (m, 1H), 4.15 (s, 2H), 3.92 (s, 3H), 3.42 (d, J = 11.9 Hz, 3H), 2.87 (s, 3H), 2.70-2.62 (m, 3H), 2.31-2.21 (m, 2H), 1.86- 1.70 (m, 4H), 1.68-1.60 (m, 2H), 1.59-1.37 (m, 6H).
1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 8.17-8.11 (m, 1H), 8.00 (s, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.75-7.65 (m, 3H), 7.13 (s, 0.8H), 7.02 (s, 0.3H), 3.89 (s, 3H), 3.87-3.73 (m, 2H), 3.72-3.58 (m, 4H), 3.57-3.50 (m, 1H), 2.41-2.35 (m, 2H), 1.94-1.82 (m, 3H), 1.63-1.45 (m, 3H), 1.44 (s, 1H), 1.39 (s, 2H).
Enantiomer of 152, absolute configuration unknown
1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.02 (d, J = 7.2 Hz, 0.6H), 7.86 (d, J = 7.0 Hz, 0.4H), 7.65 (t, J = 6.8 Hz, 2H), 7.53 (d, J = 8.3 Hz, 2H), 5.61-5.52 (m, 1H), 3.96-3.83 (m, 1H), 3.83-3.67 (m, 4H), 3.62-3.47 (m, 2H), 3.26-3.17 (m, 2H), 3.03-2.96 (m, 1H), 2.95- 2.86 (m, 1H), 2.58-2.52 (m, 3H), 2.44-2.37 (m, 1H), 2.25-2.11 (m, 2H), 2.03-1.85 (m, 3H), 1.76-1.65 (m, 1H), 1.64-1.50 (m, 2H).
Enantiomer of 151, absolute configuration unknown
1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.02 (d, J = 7.3 Hz, 0.6H), 7.86 (d, J = 7.2 Hz, 0.4H), 7.66 (t, J = 6.8 Hz, 2H), 7.53 (d, J = 8.3 Hz, 2H), 5.60-5.50 (m, 1H), 3.96-3.83 (m, 1H), 3.82-3.66 (m, 4H), 3.61-3.49 (m, 2H), 3.26-3.16 (m, 2H), 3.04-2.96 (m, 1H), 2.95- 2.86 (m, 1H), 2.60-2.52 (m, 3H), 2.45-2.36 (m, 1H), 2.24-2.11 (m, 2H), 2.04-1.84 (m, 3H), 1.74-1.65 (m, 1H), 1.65-1.50 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 2.5 Hz, 1H), 8.29 (s, 1H), 8.02 (d, J = 7.5 Hz, 0.6H), 7.87 (d, J = 7.7 Hz, 0.4H), 7.72 (dd, J = 9.1, 2.5 Hz, 1H), 6.92 (d, J = 9.2 Hz, 1H), 5.60- 5.53 (m, 1H), 3.95-3.86 (m, 1H), 3.83-3.69 (m, 4H), 3.63-3.54 (m, 4H), 3.54-3.44 (m, 2H), 2.82-2.72 (m, 4H), 2.58-2.52 (m, 3H), 2.25-2.14 (m, 1H), 2.02-1.86 (m, 3H), 1.64- 1.50 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.02 (d, J = 7.3 Hz, 0.6H), 7.87 (d, J = 7.3 Hz, 0.4H), 7.59-7.48 (m, 2H), 7.31 (d, J = 7.9 Hz, 1H), 5.65 (br.s., 1H), 5.60-5.52 (m, 1H), 3.96- 3.85 (m, 1H), 3.83-3.67 (m, 4H), 3.62-3.49 (m, 2H), 3.40-3.34 (m, 2H), 3.91 (t, J = 5.4 Hz, 2H), 2.64-2.55 (m, 2H), 2.45-2.39 (m, 1H), 2.35 (s, 3H), 2.25-2.11 (m, 3H), 2.02- 1.85 (m, 3H), 1.66-1.51 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 8.01 (d, J = 7.3 Hz, 0.6H), 7.86 (d, J = 7.6 Hz, 0.4H), 7.58-7.49 (m, 2H), 7.46 (d, J = 8.1 Hz, 1H), 5.60-5.50 (m, 1H), 3.95-3.83 (m, 1H), 3.81-3.66 (m, 4H), 3.61-3.47 (m, 2H), 3.10- 2.96 (m, 2H), 2.92-2.78 (m, 1H), 2.65-2.52 (m, 3H), 2.45-2.35 (m, 4H), 2.26-2.11 (m, 1H), 2.02-1.84 (m, 3H), 1.70-1.44 (m, 6H).
1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 0.4H), 8.30 (s, 0.6H), 8.19 (s, 0.6H), 8.17 (s, 0.4H), 8.03 (d, J = 7.6 Hz, 0.6H), 7.86 (d, J = 7.8 Hz, 0.4H), 7.80 (s, 0.5H), 7.78 (s, 0.5H), 5.61-5.50 (m, 1H), 4.79 (s, 1H), 4.10 (s, 2H), 3.95-3.83 (m, 1H), 3.82-3.65 (m, 4H), 3.57- 3.44 (m, 2H), 2.46-2.34 (m, 2H), 2.27-2.12 (m, 1H), 2.02-1.88 (m, 3H), 1.67-1.52 (m, 2H), 1.08 (s, 2H), 1.07 (s, 4H).
1H NMR (400 MHz, DMSO-d6) δ 8.37-8.33 (m, 1H), 8.32-8.28 (s, 1H), 8.03 (d, J = 7.3 Hz, 0.6H), 7.86 (d, J = 7.5 Hz, 0.4H), 7.79 (s, 0.5H), 7.78 (s, 0.5H), 5.60-5.51 (m, 1H), 4.26 (t, J = 6.3 Hz, 2H), 3.95-3.84 (m, 1H), 3.93- 3.65 (m, 4H), 3.55-3.43 (m, 2H), 2.71-2.62 (m, 2H), 2.45-2.35 (m, 2H), 2.27-2.10 (m, 7H), 2.03-1.86 (m, 3H), 1.67-1.51 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 8.19 (s, 1H), 7.78 (s, 1H), 7.42 (d, J = 7.4 Hz, 1H), 6.02 (s, 1H), 5.05 (s, 1H), 3.91 (s, 3H), 3.90-3.67 (m, 5H), 3.44 (d, J = 11.4 Hz, 2H), 2.47-2.40 (m, 2H), 2.29-2.19 (m, 1H), 2.03- 1.87 (m, 3H), 1.59-1.44 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 0.6H), 8.29 (s, 0.8H), 8.01 (d, J = 7.1 Hz, 0.4H), 7.86 (d, J = 7.6 Hz, 0.4H), 7.69-7.62 (m, 1.6H), 7.51 (s, 0.6H), 7.49 (s, 0.7H), 5.54 (s, 1H), 3.95-3.84 (m, 1H), 3.82-3.67 (m, 4H), 3.62-3.48 (m, 2H), 3.31-.25 (m, 2H), 2.96 (d, J = 12.4 Hz, 1H), 2.72-2.68 (m, 0.5H), 2.65-2.55 (m, 1.4H), 2.46-2.35 (m, 2H), 2.26-2.12 (m, 1H), 2.11-1.85 (m, 5H), 1.66-1.50 (m, 2H), 1.44-1.33 (m, 1H), 1.10- 0.99 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.02 (d, J = 7.6 Hz, 0.5H), 7.86 (d, J = 7.5 Hz, 0.4H), 7.76 (t, J = 7.6 Hz, 1H), 7.64-7.57 (m, 1H), 7.56-7.48 (m, 1H), 5.60-5.50 (m, 1H), 4.29-3.87 (m, 3H), 3.84-3.64 (m, 7H), 3.63- 3.51 (m, 2H), 2.65-2.58 (m, 1H), 2.27-2.13 (m, 1H), 2.02-1.84 (m, 3H), 1.63-1.49 (m, 2H), 1.34-1.17 (m, 1H).
1H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 8.23 (s, 1H), 8.21 (s, 1H), 8.01 (d, J = 7.1 Hz, 0.5H), 7.99-7.93 (m, 2H), 7.85 (d, J = 7.1 Hz, 0.4H), 5.59-5.49 (m, 1H), 3.95-3.83 (m, 1H), 3.83-3.68 (m, 4H), 3.68-3.56 (m, 2H), 2.65- 2.56 (m, 4H), 2.53-2.51 (m, 1H), 2.24-2.11 (m, 1H), 2.01-1.86 (m, 3H), 1.63-1.49 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.08-7.93 (m, 1H), 7.39 (d, J = 6.8 Hz, 0.5H), 7.22 (s, 0.4H), 6.26-6.06 (m, 1H), 4.55-4.30 (m, 1H), 3.99-3.76 (m, 1H), 3.60 (d, J = 10.3 Hz, 2H), 3.21-2.92 (m, 4H), 2.83 (d, J = 12.6 Hz, 1H), 2.55-2.52 (m, 1H), 2.39-2.27 (m, 1H), 2.18 (br.s., 1H), 2.05 (d, J = 12.5 Hz, 1H), 1.98- 1.76 (m, 4H), 1.74-1.30 (m, 10H).
1H NMR (400 MHz, DMSO-d6) δ 8.07-7.94 (m, 1H), 7.40 (d, J = 7.0 Hz, 0.5H), 7.22 (s, 0.4H), 6.22-6.10 (m, 1H), 4.56-4.30 (m, 1H), 3.98-3.78 (m, 1H), 3.66-3.55 (m, 2H), 3.21- 3.14 (m, 1H), 3.14-2.92 (m, 3H), 2.83 (d, J = 12.2 Hz, 1H), 2.54-2.52 (m, 1H), 2.39-2.28 (m, 1.5H), 2.26-2.14 (m, 0.6H), 2.05 (d, J = 12.3 Hz, 1H), 1.98-1.77 (m, 4H), 1.75-1.30 (m, 10H).
1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 7.98 (s, 1H), 7.78 (s, 1H), 6.94 (d, J = 7.1 Hz, 1H), 6.19 (d, J = 5.6 Hz, 1H), 5.60 (s, 1H), 3.99 (s, 1H), 3.91 (s, 3H), 3.89-3.73 (m, 2H), 3.75- 3.66 (m, 2H), 3.62-3.56 (m, 1H), 3.44 (d, J = 11.8 Hz, 2H), 2.45-2.40 (m, 2H), 2.21-2.10 (m, 1H), 2.03-1.86 (m, 3H), 1.54-1.43 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 8.00 (s, 1H), 7.95 (s, 1H), 7.81 (d, J = 8.5 Hz, 2H), 7.70 (d, J = 8.5 Hz, 2H), 6.91 (d, J = 7.4 Hz, 1H), 6.17 (d, J = 6.0 Hz, 1H), 5.57 (s, 1H), 3.97 (br.s., 1H), 3.89 (s, 3H), 3.86-3.76 (m, 2H), 3.74-3.64 (m, 2H), 3.60-3.48 (m, 3H), 2.57-2.53 (m, 1H), 2.19-2.08 (m, 1H), 2.04- 1.94 (m, 1H), 1.94-1.83 (m, 3H), 1.51-1.41 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 8.29 (s, 1H), 8.03 (d, J = 7.2 Hz, 0.6H), 7.87 (d, J = 7.4 Hz, 0.4H), 7.83-7.73 (m, 1H), 7.02 (d, J = 9.2 Hz, 1H), 5.64-5.50 (m, 1H), 4.47 (d, J = 12.3 Hz, 1H), 4.00 (d, J = 12.3 Hz, 1H), 3.96-3.86 (m, 1H), 3.84-3.69 (m, 4H), 3.59- 3.44 (m, 3H), 3.25-3.13 (m, 2H), 3.10-2.97 (m, 2H), 2.81-2.70 (m, 1H), 2.61-2.53 (m, 1H), 2.48-2.38 (m, 1H), 2.27-2.14 (m, 1H), 2.05-1.85 (m, 3H), 1.66-1.50 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.00 (d, J = 7.1 Hz, 0.6H), 7.85 (d, J = 6.9 Hz, 0.4H), 7.49 (d, J = 8.8 Hz, 2H), 7.02 (d, J = 9.0 Hz, 2H), 5.60-5.51 (m, 1H), 3.95-3.83 (m, 1H), 3.81-3.65 (m, 4H), 3.57-3.44 (m, 2H), 3.37-3.33 (m, 2H), 3.21-3.09 (m, 2H), 3.02- 2.91 (m, 2H), 2.46-2.37 (m, 2H), 2.28-2.03 (m, 2H), 2.02-1.84 (m, 3H), 1.66-1.47 (m, 2H), 1.06 (d, J = 6.4 Hz, 6H).
1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.01 (d, J = 7.3 Hz, 0.6H), 7.86 (d, J = 7.0 Hz, 0.4H), 7.50 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 9.1 Hz, 2H), 5.63-5.44 (m, 1H), 3.96-3.82 (m, 1H), 3.82-3.62 (m, 6H), 3.56-3.43 (m, 2H), 2.86-2.71 (m, 2H), 2.42-2.37 (m, 2H), 2.29- 2.14 (m, 4H), 1.99-1.84 (m, 3H), 1.63-1.44 (m, 2H), 1.03 (d, J = 6.2 Hz, 6H).
1H NMR (400 MHz, DMSO-d6) δ 8.35-8.31 (m, 1H), 8.29 (s, 1H), 8.02 (d, J = 7.2 Hz, 0.6H), 7.87 (d, J = 8.0 Hz, 0.4H), 7.73-7.65 (m, 1H), 6.93 (d, J = 9.2 Hz, 1H), 5.61-5.51 (m, 1H), 3.95-3.85 (m, 1H), 3.83-3.66 (m, 6H), 3.56-3.45 (m, 2H), 3.30-3.25 (m, 2H), 3.16-3.07 (m, 2H), 2.62-2.55 (m, 2H), 2.47- 2.39 (m, 1H), 2.26-2.15 (m, 1H), 2.02-1.85 (m, 3H), 1.66-149 (m, 2H), 1.01 (d, J = 6.4 Hz, 6H).
1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.01 (d, J = 7.3 Hz, 0.6H), 7.86 (d, J = 7.5 Hz, 0.4H), 7.56-7.44 (m, 2H), 7.13 (d, J = 8.1 Hz, 1H), 5.61-5.49 (m, 1H), 3.95-3.84 (m, 1H), 3.81-3.67 (m, 4H), 3.59-3.46 (m, 2H), 2.85 (br.s., 8H), 2.57-2.52 (m, 2H), 2.46-2.34 (m, 1H), 2.32 (s, 3H), 2.27-2.12 (m, 1H), 2.02- 1.84 (m, 3H), 1.64-1.49 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.01 (d, J = 7.4 Hz, 0.6H), 7.86 (d, J = 6.9 Hz, 0.4H), 7.49-7.39 (m, 2H), 7.18 (t, J = 8.7 Hz, 1H), 5.55 (br.s., 1H), 3.96-3.85 (m, 1H), 3.83- 3.68 (m, 4H), 3.60-3.45 (m, 2H), 3.14-2.99 (m, 4H), 2.89-2.76 (m, 4H), 2.62-2.52 (m, 2H), 2.46-2.39 (m, 1H), 2.26-2.13 (m, 1H), 2.02-1.83 (m, 3H), 1.63-1.47 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.89-8.72 (m, 1H), 8.29 (s, 1H), 8.11-8.05 (m, 1H), 8.02 (d, J = 7.6 Hz, 0.6H), 7.86 (d, J = 6.4 Hz, 0.4H), 7.77 (d, J = 8.2 Hz, 1H), 7.04-6.94 (m, 1H), 5.61-5.50 (m, 1H), 3.95-3.69 (m, 5H), 3.65-3.53 (m, 2H), 3.49-3.42 (m, 2H), 2.92 (t, J = 5.6 Hz, 2H), 2.65-2.56 (m, 3H), 2.46- 2.43 (m, 2H), 2.27-2.11 (m, 1H), 2.03-1.82 (m, 3H), 1.63-1.49 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.87-8.77 (m, 1H), 8.29 (s, 1H), 8.11-8.05 (m, 1H), 8.03 (d, J = 7.4 Hz, 0.6H), 7.87 (d, J = 6.9 Hz, 0.4H), 7.55 (d, J = 8.3 Hz, 1H), 5.61-5.50 (m, 1H), 3.95-3.85 (m, 1H), 3.83-3.68 (m, 4H), 3.65-3.52 (m, 2H), 3.10-3.00 (m, 2H), 2.95- 2.81 (m, 1H), 2.72-2.54 (m, 4H), 2.24-2.13 (m, 1H), 2.02-1.86 (m, 3H), 1.84-1.74 (m, 2H), 1.70-1.49 (m, 4H).
1H NMR (400 MHz, DMSO-d6) δ 8.39-8.34 (m, 1H), 8.29 (s, 1H), 8.02 (d, J = 7.6 Hz, 0.6H), 7.87 (d, J = 7.6 Hz, 0.4H), 7.76-7.70 (m, 1H), 5.61-5.51 (m, 1H), 3.95-3.86 (m, 1H), 3.82-3.70 (m, 4H), 3.61-3.49 (m, 2H), 3.24-3.18 (m, 4H), 2.88-2.81 (m, 4H), 2.60 (t, J = 10.4 Hz, 1H), 2.53-2.51 (m, 1H), 2.48- 2.43 (m, 1H), 2.30 (s, 3H), 2.25-2.15 (m, 1H), 2.01-1.87 (m, 3H), 1.64-1.51 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.30 (d, J = 7.0 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 7.6 Hz, 0.6H), 7.91-7.82 (m, 1.4H), 6.56 (s, 1H), 5.56 (s, 1H), 3.94-3.86 (m, 1H), 3.80-3.61 (m, 6H), 3.46-3.38 (m, 2H), 2.93 (t, J = 5.5 Hz, 2H), 2.88-2.76 (m, 2H), 2.41-2.35 (m, 2H), 2.26-2.09 (m, 1H), 2.02-1.80 (m, 3H), 1.62-1.40 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.31 (d, J = 5.6 Hz, 1H), 8.04 (d, J = 7.2 Hz, 0.6H), 7.96 (d, J = 8.1 Hz, 1H), 7.89-7.86 (m, 1H), 7.86-7.83 (m, 0.4H), 5.61-5.53 (m, 1H), 3.95-3.86 (m, 1H), 3.84-3.65 (m, 6H), 3.11 (d, J = 12.1 Hz, 2H), 2.94-2.76 (m, 3H), 2.69- 2.61 (m, 2H), 2.26-2.16 (m, 1H), 2.01-1.87 (m, 3H), 1.82-1.73 (m, 2H), 1.67-1.49 (m, 4H).
1H NMR (400 MHz, DMSO-d6) δ 8.40 (d, J = 2.8 Hz, 1H), 8.30 (d, J = 6.9 Hz, 1H), 8.02 (d, J = 7.3 Hz, 0.6H), 7.86 (d, J = 7.7 Hz, 0.4H), 7.67 (dd, J = 8.8, 3.4 Hz, 1H), 7.40 (dd, J = 9.0, 2.9 Hz, 1H), 5.68-5.44 (m, 1H), 3.96-3.84 (m, 1H), 3.85-3.69 (m, 4H), 3.69-3.54 (m, 2H), 3.30-3.25 (m, 4H), 2.87-2.79 (m, 4H), 2.79-2.68 (m, 2H), 2.26-2.13 (m, 1H), 2.02- 1.80 (m, 3H), 1.62-1.40 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.00 (d, J = 7.2 Hz, 0.6H), 7.86 (d, J = 7.6 Hz, 0.4H), 7.55 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 9.2 Hz, 2H), 5.61-5.50 (m, 1H), 3.96-3.83 (m, 1H), 3.81-3.62 (m, 6H), 3.56-3.44 (m, 6H), 2.57-2.52 (m, 1H), 2.47-2.37 (m, 2H), 2.35- 2.27 (m, 1H), 2.24-2.12 (m, 1H), 2.01-1.86 (m, 3H), 1.64-1.52 (m, 2H), 1.48 (d, J = 8.4 Hz, 1H).
1H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H), 8.29 (s, 1H), 8.02 (d, J = 7.0 Hz, 0.6H), 7.87 (d, J = 7.6 Hz, 0.4H), 7.79 (d, J = 10.1 Hz, 1H), 6.75 (d, J = 9.1 Hz, 1H), 5.61-5.49 (m, 1H), 3.93-3.47 (m, 15H), 2.45-2.37 (m, 2H), 2.27- 2.13 (m, 1H), 2.05-1.85 (m, 3H), 1.65-1.52 (m, 2H), 1.46 (d, J = 9.1 Hz, 1H).
1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 0.9H), 8.25 (s, 0.1H), 8.01 (d, J = 7.2 Hz, 0.6H), 7.86 (d, J = 7.2 Hz, 0.4H), 7.54-7.46 (m, 2H), 6.94 (d, J = 9.2 Hz, 2H), 5.60-5.52 (m, 1H), 3.95-3.84 (m, 1H), 3.81-3.67 (m, 4H), 3.64-3.58 (m, 2H), 3.56-3.52 (m, 2H), 3.51-3.46 (m, 2H), 2.90 (d, J = 11.2 Hz, 2H), 2.84-2.30 (m, 2H), 2.25-2.13 (m, 1H), 2.02- 1.85 (m, 3H), 1.77-1.63 (m, 4H), 1.61-1.50 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.39-8.33 (m, 1H), 8.29 (s, 1H), 8.02 (d, J = 7.2 Hz, 0.6H), 7.87 (d, J = 7.6 Hz, 0.4H), 7.76-7.69 (m, 1H), 6.81 (d, J = 9.2 Hz, 1H), 5.61-5.51 (m, 1H), 4.00-3.87 (m, 3H), 3.82-3.69 (m, 4H), 3.56-3.46 (m, 4H), 2.97 (d, J = 11.6 Hz, 2H), 2.59-2.55 (m, 2H), 2.46-2.41 (m, 1H), 2.26-2.14 (m, 1H), 2.03-1.85 (m, 3H), 1.74- 1.64 (m, 2H), 1.62-1.50 (m, 4H).
1H NMR (400 MHz, DMSO-d6) δ 8.34 (s, 1H), 8.29 (s, 1H), 8.03 (d, J = 7.0 Hz, 0.6H), 7.87 (d, J = 7.6 Hz, 0.4H), 7.68 (d, J = 9.1 Hz, 1H), 6.80 (d, J = 9.0 Hz, 1H), 5.51-5.52 (m, 1H), 4.75-4.38 (m, 2H), 3.97-3.85 (m, 1H), 3.80- 3.70 (m, 4H), 3.56-3.46 (m, 2H), 2.86-2.75 (m, 2H), 2.61-2.55 (m, 4H), 2.45-2.41 (m, 1H), 2.25-2.16 (m, 1H), 1.99-1.84 (m, 7H), 1.61-1.52 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.02 (d, J = 7.4 Hz, 0.6H), 7.86 (d, J = 7.6 Hz, 0.4H), 7.45 (t, J = 8.0 Hz, 1H), 7.24 (d, J = 8.1 Hz, 1H), 7.14-7.05 (m, 2H), 5.67-5.38 (m, 1H), 3.97-3.82 (m, 1H), 3.82-3.66 (m, 4H), 3.63-3.47 (m, 2H), 3.17-3.06 (m, 4H), 2.91- 2.76 (m, 4H), 2.59-2.51 (m, 2H), 2.47-2.38 (m, 1H), 2.25-2.12 (m, 1H), 2.02-1.85 (m, 3H), 1.65-1.48 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.01 (d, J = 6.8 Hz, 0.6H), 7.86 (d, J = 7.7 Hz, 0.4H), 7.51 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 9.1 Hz, 2H), 5.62-5.49 (m, 1H), 3.93-3.83 (m, 1H), 3.81-3.62 (m, 6H), 3.56-3.40 (m, 2H), 2.97 (d, J = 8.5 Hz, 1H), 2.75-2.69 (m, 3H), 2.46-2.34 (m, 3H), 2.27-2.09 (m, 1H), 2.02- 1.80 (m, 3H), 1.67-1.47 (m, 2H), 1.03 (d, J = 6.3 Hz, 3H).
1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.01 (d, J = 7.2 Hz, 0.6H), 7.86 (d, J = 8.0 Hz, 0.4H), 7.65-7.46 (m, 2H), 7.05 (d, J = 9.2 Hz, 2H), 5.63-5.50 (m, 1H), 3.93-3.84 (m, 1H), 3.80-3.66 (m, 6H), 3.55-3.46 (m, 2H), 3.01- 2.92 (m, 1H), 2.77-2.67 (m, 3H), 2.48-2.40 (m, 2H), 2.38-2.30 (m, 2H), 2.24-2.13 (m, 1H), 2.01-1.84 (m, 3H), 1.63-1.49 (m, 2H), 1.03 (d, J = 6.4 Hz, 3H).
1H NMR (400 MHz, DMSO-d6) δ 8.36 (d, J = 2.5 Hz, 1H), 8.29 (s, 1H), 8.02 (d, J = 7.3 Hz, 0.6H), 7.87 (d, J = 7.6 Hz, 0.4H), 7.76-7.67 (m, 1H), 6.94 (d, J = 9.2 Hz, 1H), 5.60-5.53 (m, 1H), 4.27 (t, J = 10.7 Hz, 2H), 3.98-3.85 (m, 1H), 3.85-3.66 (m, 4H), 3.49 (d, J = 10.9 Hz, 2H), 2.95 (d, J = 11.8 Hz, 1H), 2.84 (t, J = 12.1 Hz, 1H), 2.65-2.60 (m, 1H), 2.58-2.52 (m, 3H), 2.48-2.40 (m, 2H), 2.27-2.12 (m, 1H), 2.04-1.83 (m, 3H), 1.67-1.47 (m, 2H), 1.03 (d, J = 6.2 Hz, 3H).
1HNMR (400 MHz, DMSO-d6) δ 8.41-8.36 (m, 1H), 8.29 (s, 1H), 8.02 (d, J = 7.2 Hz, 0.6H), 7.87 (d, J = 7.6 Hz, 0.4H), 7.80-7.75 (m, 1H), 7.01 (d, J = 9.2 Hz, 1H), 5.61-5.51 (m, 1H), 4.44-4.32 (m, 2H), 3.95-3.85 (m, 1H), 3.82-3.67 (m, 4H), 3.58-3.47 (m, 2H), 3.20-3.14 (m, 1H), 3.07-2.94 (m, 2H), 2.87- 2.75 (m, 2H), 2.58-2.56 (m, 1H), 2.44-2.38 (m, 2H), 2.25-2.15 (m, 1H), 2.01-1.87 (m, 3H), 1.63-1.50 (m, 2H), 1.19-1.11 (m, 3H).
1H NMR (400 MHz, DMSO-d6) δ 8.43-8.39 (m, 0.2H), 8.38-8.33 (m, 0.8H), 8.30 (d, J = 4.8 Hz, 1H), 8.03 (d, J = 6.6 Hz, 0.6H), 7.87 (d, J = 7.7 Hz, 0.4H), 7.81-7.75 (m, 0.2H), 7.75-7.65 (m, 0.8H), 6.74 (d, J = 8.5 Hz, 0.2H), 6.58 (d, J = 8.8 Hz, 0.8H), 5.62-5.52 (m, 1H), 4.53-4.47 (m, 0.4H), 4.38 (d, J = 6.0 Hz, 1.8H), 3.94-3.86 (m, 1H), 3.81-3.69 (m, 4H), 3.58-3.48 (m, 2H), 3.41-3.34 (m, 1H), 3.29-3.25 (m, 1H), 2.80 (d, J = 12.8 Hz, 2H), 2.65-2.55 (m, 3H), 2.47-2.40 (m, 1H), 2.27- 2.12 (m, 1H), 2.03-1.78 (m, 4H), 1.64-1.44 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.02 (d, J = 7.5 Hz, 0.5H), 7.87 (d, J = 7.1 Hz, 0.4H), 7.56 (d, J = 5.8 Hz, 1H), 7.53-7.45 (m, 1H), 7.31 (d, J = 7.9 Hz, 1H), 5.68 (s, 1H), 5.60- 5.52 (m, 1H), 3.99-3.84 (m, 1H), 3.83-3.64 (m, 4H), 3.64-3.46 (m, 2H), 2.86 (t, J = 5.7 Hz, 2H), 2.64-2.52 (m, 3H), 2.47-2.38 (m, 2H), 2.36 (s, 3H), 2.24-2.15 (m, 1H), 2.15- 2.07 (m, 2H), 2.01-1.85 (m, 3H), 1.67-1.49 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.00 (d, J = 7.4 Hz, 0.6H), 7.85 (d, J = 7.6 Hz, 0.4H), 7.49 (d, J = 8.7 Hz, 2H), 6.73-6.62 (m, 2H), 5.59-5.50 (m, 1H), 3.96-3.82 (m, 1H), 3.82-3.60 (m, 4H), 3.58-3.46 (m, 4H), 3.28- 3.06 (m, 4H), 3.06-2.91 (m, 2H), 2.92-2.76 (m, 2H), 2.71-2.64 (m, 1H), 2.46-2.34 (m, 2H), 2.24-2.10 (m, 1H), 2.04-1.80 (m, 3H), 1.64-1.45 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.01 (d, J = 7.2 Hz, 0.6H), 7.86 (d, J = 7.6 Hz, 0.4H), 7.57-7.42 (m, 3H), 5.61-5.49 (m, 1H), 3.96-3.83 (m, 1H), 3.81-3.64 (m, 4H), 3.60- 3.45 (m, 2H), 3.00-2.82 (m, 3H), 2.60-2.52 (m, 3H), 2.46-2.36 (m, 5H), 2.56-2.12 (m, 1H), 2.00-1.85 (m, 3H), 1.85-1.76 (m, J = 11.2 Hz, 1H), 1.71-1.43 (m, 5H).
1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.02 (d, J = 7.1 Hz, 0.6H), 7.86 (d, J = 7.6 Hz, 0.4H), 7.70-7.59 (m, 1H), 7.58-7.44 (m, 2H), 5.66-5.43 (m, 1H), 3.96-3.84 (m, 1H), 3.85- 3.68 (m, 4H), 3.64-3.48 (m, 2H), 3.05-2.88 (m, 3H), 2.69-2.52 (m, 3H), 2.48-2.43 (m, 1H), 2.26-2.13 (m, 1H), 2.02-1.80 (m, 5H), 1.72-1.43 (m, 5H).
1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.02 (d, J = 7.5 Hz, 0.6H), 7.87 (d, J = 7.7 Hz, 0.4H), 7.39-7.33 (m, 1H), 7.32-7.25 (m, 1H), 7.22-7.16 (m, 1H), 5.91 (s, 1H), 5.61-5.51 (m, 1H), 3.94-3.83 (m, 4H), 3.82-3.67 (m, 4H), 3.65-3.51 (m, 2H), 3.41-3.34 (m ,2H), 2.86 (t, J = 5.5 Hz, 2H), 2.68-2.56 (m, 2H), 2.35-2.26 (m, 2H), 2.24-2.12 (m, 1H), 2.02- 1.85 (m, 3H), 1.65-1.48 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.01 (d, J = 7.0 Hz, 0.6H), 7.86 (d, J = 7.1 Hz, 0.4H), 7.47 (d, J = 8.5 Hz, 2H), 6.89 (d, J = 9.0 Hz, 2H), 5.63-5.47 (m, 1H), 4.25 (s, 2H), 3.96- 3.82 (m, 1H), 3.81-3.59 (m, 4H), 3.57-3.43 (m, 2H), 2.87 (d, J = 12.5 Hz, 2H), 2.47-2.34 (m, 5H), 2.25-2.13 (m, 1H), 2.00-1.83 (m, 7H), 1.64-1.47 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.02 (d, J = 7.5 Hz, 0.5H), 7.87 (d, J = 7.1 Hz, 0.4H), 7.56 (d, J = 5.8 Hz, 1H), 7.53-7.45 (m, 1H), 7.31 (d, J = 7.9 Hz, 1H), 5.68 (s, 1H), 5.60- 5.52 (m, 1H), 3.99-3.84 (m, 1H), 3.83-3.64 (m, 4H), 3.64-3.46 (m, 2H), 2.86 (t, J = 5.7 Hz, 2H), 2.64-2.52 (m, 3H), 2.47-2.38 (m, 2H), 2.36 (s, 3H), 2.24-2.15 (m, 1H), 2.15- 2.07 (m, 2H), 2.01-1.85 (m, 3H), 1.67-1.49 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.02 (d, J = 7.3 Hz, 0.6H), 7.86 (d, J = 7.4 Hz, 0.4H), 7.43 (d, J = 8.0 Hz, 1H), 7.34-7.27 (m, 1H), 7.17 (d, J = 7.6 Hz, 1H), 5.60-5.51 (m, 1H), 3.95-3.89 (m, 1H), 3.88 (s, 3H), 3.81- 3.68 (m, 5H), 3.63-3.51 (m, 3H), 3.02 (d, J = 11.8 Hz, 3H), 2.68-2.55 (m, 4H), 2.27-2.12 (m, 1H), 2.02-1.88 (m, 3H), 1.67-1.43 (m, 6H).
1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.24 (s, 0.8H), 8.01 (d, J = 7.2 Hz, 0.6H), 7.86 (d, J = 7.5 Hz, 0.4H), 7.51 (d, J = 8.8 Hz, 2H), 7.00 (d, J = 9.1 Hz, 2H), 5.60-5.50 (m, 1H), 4.13-4.05 (m, 1H), 3.94-3.83 (m, 2H), 3.81- 3.68 (m, 6H), 3.07-2.80 (m, 5H), 2.27-2.12 (m, 4H), 2.02-1.83 (m, 4H), 1.63-1.46 (m, 2H), 1.10 (d, J = 6.6 Hz, 3H).
1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.01 (d, J = 7.1 Hz, 0.6H), 7.86 (d, J = 7.7 Hz, 0.4H), 7.50 (d, J = 8.4 Hz, 2H), 6.99 (d, J = 9.0 Hz, 2H), 5.54 (s, 1H), 4.05 (s, 1H), 3.94-3.82 (m, 1H), 3.82-3.64 (m, 4H), 3.55-3.42 (m, 3H), 3.02-2.77 (m, 4H), 2.70-2.58 (m, 1H), 2.46-2.39 (m, 1H), 2.37-2.29 (m, 1H), 2.25- 2.13 (m, 1H), 2.02-1.85 (m, 3H), 1.63-1.47 (m, 2H), 1.24 (s, 1H), 1.09 (d, J = 6.5 Hz, 3H).
1H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.96-7.84 (m, 2.7H), 7.78-7.64 (m, 2.3H), 6.46-6.33 (m, 1H), 3.87-3.72 (m, 1H), 3.66- 3.52 (m, 2H), 2.95-2.74 (m, 2H), 2.62-2.54 (m, 2H), 2.47-2.43 (m, 2H), 1.99-1.83 (m, 2H), 1.82-1.46 (m, 6H).
1H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 1H), 7.87 (d, J = 8.0 Hz, 0.6H), 7.73-7.65 (m, 4.3H), 6.45-6.41 (m, 1H), 6.41-6.34 (m, 1H), 3.80-3.68 (m, 1H), 3.64-3.51 (m, 2H), 3.41 (d, J = 3.0 Hz, 2H), 2.95-2.86 (m, 2H), 2.77- 2.71 (m, 1H), 2.46-2.35 (m, 6H), 2.26-2.16 (m, 1H), 1.97-1.87 (m, 1H), 1.77-1.65 (m, 1H), 1.66-1.51 (m, 6H).
1H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 1H), 7.87 (d, J = 7.4 Hz, 0.6H), 7.72-7.63 (m, 0.3H), 7.50 (d, J = 9.0 Hz, 2H), 7.07 (d, J = 8.8 Hz, 2H), 6.43-6.33 (m, 1H), 3.82-3.65 (m, 3H), 3.60-3.47 (m, 2H), 2.95-2.69 (m, 4H), 2.37-2.24 (m, 5H), 2.23-1.99 (m, 1H), 1.95- 1.86 (m, 2H), 1.78-1.67 (m, 0.8H), 1.63- 1.50 (m, 5.2H), 1.04 (d, J = 6.2 Hz, 6H).
1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.01 (d, J = 7.6 Hz, 0.6H), 7.86 (d, J = 7.6 Hz, 0.4H), 7.77-7.64 (m, 4H), 6.41-6.36 (m, 1H), 5.60-5.51 (m, 1H), 3.94-3.84 (m, 1H), 3.80- 3.69 (m, 4H), 3.60-3.51 (m, 2H), 3.08-3.03 (m, 2H), 2.60-2.56 (m, 2H), 2.55-2.52 (m, 2H), 2.47-2.40 (m, 2H), 2.29 (s, 3H), 2.23- 2.13 (m, 1H), 2.00-1.85 (m, 3H), 1.62-1.49 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.01 (d, J = 7.2 Hz, 0.6H), 7.86 (d, J = 7.2 Hz, 0.4H), 7.55-7.49 (m, 2H), 7.11-7.04 (m, 2H), 5.59-5.51 (m, 1H), 3.94-3.84 (m, 1H), 3.80- 3.67 (m, 4H), 3.55-3.45 (m, 2H), 3.38-3.34 (m, 2H), 3.31-3.28 (m, 2H), 2.46-2.41 (m, 5H), 2.40-2.33 (m, 1H), 2.22 (s, 3H), 2.21- 2.12 (m, 1H), 2.00-1.85 (m, 3H), 1.62-1.50 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 1H), 7.87 (d, J = 7.3 Hz, 0.7H), 7.62 (d, J = 7.2 Hz, 0.4H), 7.48 (d, J = 9.0 Hz, 2H), 7.03 (d, J = 8.9 Hz, 2H), 6.39 (s, 1H), 3.78-3.65 (m, 1H), 3.59- 3.47 (m, 2H), 3.43-3.33 (m, 2H), 3.21-3.10 (m, 2H), 3.02-2.94 (m, 2H), 2.92-2.85 (m, 0.7H), 2.74 (brs, 1.4H), 2.39-1.99 (m, 4H), 1.96-1.85 (m, 2H), 1.81-1.67 (m, 1H), 1.66- 1.46 (m, 5H), 1.06 (d, J = 6.5 Hz, 6H).
1H NMR (400 MHz, DMSO-d6) δ 8.39-8.35 (m, 1H), 8.31-8.28 (m, 1H), 8.02 (d, J = 7.6 Hz, 0.6H), 7.87 (d, J = 8.0 Hz, 0.4H), 7.76- 7.71 (m, 1H), 6.96 (d, J = 9.2 Hz, 1H), 5.61- 5.51 (m, 1H), 3.94-3.87 (m, 1H), 3.79-3.71 (m, 4H), 3.67-3.62 (m, 4H), 3.53-3.47 (m, 2H), 2.58-2.54 (m, 1H), 2.48-2.42 (m, 1H), 2.41-2.37 (m, 4H), 2.26-2.18 (m, 4H), 2.01- 1.88 (m, 3H), 1.63-1.49 (m, 2H).
1H NMR (400 MHz, DMSO-d6) δ 8.81 (brs, 1H), 8.39 (s, 1H), 8.29 (s, 1H), 8.01 (d, J = 7.2 Hz, 0.6H), 7.86 (d, J = 7.6 Hz, 0.4H), 7.82- 7.76 (m, 1H), 7.06 (d, J = 9.2 Hz, 1H), 5.74- 5.44 (m, 1H), 4.00-3.87 (m, 3H), 3.84-3.70 (m, 4H), 3.68-3.60 (m, 2H), 3.57-3.48 (m, 4H), 2.60-2.53 (m, 1H), 2.48-2.38 (m, 1H), 2.27-2.14 (m, 1H), 2.02-1.86 (m, 3H), 1.63- 1.47 (m, 2H), 1.24 (d, J = 6.0 Hz, 6H).
1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.00 (d, J = 7.2 Hz, 0.6H), 7.85 (d, J = 7.7 Hz, 0.4H), 7.53 (d, J = 8.5 Hz, 2H), 7.09 (d, J = 8.9 Hz, 2H), 5.64-5.47 (m, 1H), 3.96-3.83 (m, 1H), 3.81-3.65 (m, 4H), 3.56-3.51 (m, 2H), 3.49-3.39 (m, 3H), 3.39-3.24 (m, 2H), 3.23- 3.14 (m, 2H), 2.48-2.40 (m, 1H), 2.40-2.26 (m, 1H), 2.25-2.11 (m, 1H), 2.02-1.84 (m, 3H), 1.65-1.48 (m, 2H), 1.21 (d, J = 6.4 Hz, 6H).
1H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 7.60 (d, J = 8.3 Hz, 2H), 6.89 (d, J = 7.7 Hz, 2H), 5.52 (br.s., 1H), 5.29 (br.s., 1H), 5.06 (br.s., 1H), 4.10-3.99 (m, 1H), 3.92-3.82 (m, 3H), 3.76 (br.s., 2H), 3.53 (br.s., 1H), 3.49- 3.27 (m, 4H), 3.14-2.99 (m, 2H), 2.66 (br.s., 1H), 2.44 (br.s., 1H), 2.30-1.94 (m, 5H), 1.26 (d, J = 5.0 Hz, 6H).
1H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.02 (d, J = 7.1 Hz, 0.6H), 7.87 (d, J = 7.1 Hz, 0.4H), 7.50 (d, J = 8.7 Hz, 2H), 7.06 (d, J = 9.0 Hz, 2H), 5.60-5.50 (m, 1H), 3.96-3.83 (m, 1.5H), 3.80-3.62 (m, 5.5H), 3.57-3.43 (m, 2H), 2.78 (br.s., 2H), 2.42-2.38 (m, 2H), 2.38- 2.22 (m, 3H), 2.22-2.11 (m, 1H), 2.01-1.81 (m, 3H), 1.64-1.48 (m, 2H), 1.03 (d, J = 6.2 Hz, 6H).
In this experiment, the method of capillary migration ability change assay (MSA) was used to test the inhibitory effect of the compounds on CDK1/CDK2/CDK4/CDK6/CDK7/CDK9 kinase activity, and the half maximal inhibitory concentration (IC50) of the compounds on CDK1/CDK2/CDK4/CDK6/CDK7/CDK9 kinase activity was obtained.
CDK1/CDK2/CDK4/CDK6/CDK7/CDK9 were purchased from Carna Company; Carliper substrate CTD3/substrate 18/substrate 8 were purchased from Gil Biochemical Company; Dinaciclib/Palbociclib were purchased from Selleckchem Company; DMSO was purchased from Sigma Company; 384-well plates were purchased from Corning Company.
% inhibition=(conversion %_max−conversion %_sample)/(conversion %_max−conversion %_min)×100% Calculation formula:
Where, conversion %_sample is the readings of conversion rate of the sample; conversion %_min: the average value of negative control wells, representing the readings of conversion rate of wells without enzyme activity; conversion %_max: the average value of positive control wells, representing the readings of conversion rate of wells without compound inhibition.
Taking the log value of the concentration as the X-axis, and the percentage inhibition rate as the Y-axis, the dose-effect curve was fitted using the log(inhibitor) vs. response—Variable slope of the analysis software GraphPad Prism 5 so as to obtain the IC50 value of each compound on the enzyme activity.
Y=Bottom+(Top−Bottom)/(1+10{circumflex over ( )}((Log IC50−X)*HillSlope)). Calculation formula:
Table 2 shows the inhibitory IC50 data of the compounds of the present disclosure on CDK kinase activity. Where, compounds with IC50<10 nM are marked with A, compounds with 10 nM≤IC50<50 nM are marked with B, compounds with 50 nM≤IC50<100 nM are marked with C, compounds with 100 nM≤IC50<1000 nM are marked with D, and compounds with IC50>1000 nM are marked with E. Where, compounds with IC50<10 nM can be specifically divided into compounds with IC50<0.5 nM represented by AA, compounds with 0.5 nM≤IC50<2.5 nM represented by AB, and compounds with 2.5 nM≤IC50<10 nM represented by AC.
Conclusion: The compounds of the present disclosure have better CDK 2/4/6 kinase inhibitory activity, especially excellent in the inhibitory activity of CDK 2 kinase; the compounds of the present disclosure can selectively inhibit CDK 2/4/6 kinases and especially has good selectivity for CDK 2 kinase. Some compounds have inhibitory selectivity of nearly ten times, even tens of times, or 100 times or more on CDK 1/7/9 kinases compared with CDK 2 kinase.
In this experiment, the CellTiter-Glo method was used to test the inhibitory effect of the compound on the proliferation of HCC1806/NIH:OVCAR-3 cells, and the half maximal inhibitory concentration IC50 (nM) of the compound on cells was obtained.
HCC1806 was purchased from Tongpai (Shanghai) Biotechnology Co., Ltd.; NIH:OVCAR-3 was purchased from ATCC Cell Bank in the United States.
1640 medium, fetal bovine serum (FBS), Penicillin-Streptomycin, GlutaMAX-I Supplement were purchased from GIBCO.
PF-06873600 was purchased from Selleck Company.
CellTiter-Glo reagent, purchased from Promega Company.
Data analysis was performed using GraphPad Prism 6 software to obtain the IC50 (nM) of the compounds.
Experimental results and conclusions: After testing, the compound of the present disclosure can have an IC50 of less than 100 nM on cell proliferation of the HCC1806/NIH:OVCAR-3 cell line and has a better inhibitory effect than that of the reference compound PF-06873600.
HCC1806 was purchased from Tongpai (Shanghai) Biotechnology Co., Ltd.; NIH:OVCAR-3 was purchased from ATCC Cell Bank in the United States.
1640 medium, fetal bovine serum (FBS), Penicillin-Streptomycin were purchased from GIBCO. PF-06873600 was purchased from MCE Company.
Cells in the logarithmic growth phase were collected and subcutaneously inoculated into the right flank of the BALB/c nude mice to establish a tumor model. The day of inoculation was named as DO. On the fourth day after inoculation (D4), when the average tumor volume reached about 150 mm3, the mice with moderate tumor volume were selected to enter the group, with 6 animals in each group. On the day of grouping, intragastric administration was started. Body weight data and tumor volume data were counted 2 to 3 times a week. Body weight-tumor growth curves was drawn. Tumor volume V=1/2×a×b2, wherein a and b represent the long diameter and short diameter of the tumor, respectively.
Experimental results and conclusions: After testing, the tumors of the treatment group administered with the compound of the present disclosure are effectively inhibited. Compared with the reference compound PF-06873600, the compound of the present disclosure has a better tumor inhibitory effect, and the body weight of the mice does not decrease significantly, showing good tolerance under all treatment regimens (10 mg/kg BID, 20 mg/kg BID, 30 mg/kg QD).
OVCAR-3 was purchased from ATCC Cell Bank in the United States. 1640 medium, fetal bovine serum (FBS), Penicillin-Streptomycin were purchased from GIBCO. PF-06873600 was purchased from MCE Company.
Cells in the logarithmic growth phase were collected and subcutaneously inoculated into the right flank of the BALB/c nude mice to establish a tumor model. The day of inoculation was named as DO. On the 27th day after inoculation (D27), when the average tumor volume reached about 180 mm3, the mice with moderate tumor volume were selected to enter the group, with 6 animals in each group. On the day of grouping, intragastric administration was started. The compounds were administered continuously to the mice for 21 days. Body weight data and tumor volume data were counted 2 to 3 times a week. Body weight-tumor growth curves was drawn. Tumor volume V=1/2×a×b2, wherein a and b represent the long diameter and short diameter of the tumor, respectively.
Experimental results and conclusions: After testing, the tumors of the treatment group administered with the compound of the present disclosure are effectively inhibited. Compared with the reference compound PF-06873600, the compound of the present disclosure has a better tumor inhibitory effect, and the body weight of the mice does not decrease significantly, showing good tolerance under all treatment regimens (5 mg/kg BID, 7.5 mg/kg BID, 10 mg/kg QD, 20 mg/kg QD).
| Number | Date | Country | Kind |
|---|---|---|---|
| 202110161786.5 | Feb 2021 | CN | national |
| 202110483256.2 | Apr 2021 | CN | national |
| 202111062178.5 | Sep 2021 | CN | national |
| 202111398260.5 | Nov 2021 | CN | national |
| 202210048365.6 | Jan 2022 | CN | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/CN2022/074491 | 1/28/2022 | WO |
