Inhibitors of CDK2

Abstract

The present invention is directed to the compounds of Formula (A) - inhibitors of CDK2. The inhibitors described herein can be useful in the treatment of diseases or disorders associated with CDK2, such as cancer. In particular, the invention is concerned with compounds and pharmaceutical compositions inhibiting CDK2, methods of treating diseases or disorders associated with CDK2, and methods of synthesizing these compounds.

Description

Inhibitors of CDK2 CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the priority and benefit of U.S. Provisional Patent Application Serial No. 63 / 554,997, filed on February 17, 2024, entitled ‘Inhibitors of CDK2.' The disclosure of this provisional application is incorporated herein by reference in its entirety for all purposes.FIELD OF INVENTION

[0002] The present invention is directed to inhibitors of CDK2. The inhibitors described herein can be useful in the treatment of diseases or disorders associated with CDK2, such as autoimmune disease, Alzheimer disease, and coronavirus infection by inducing durable responses. In particular, the invention is concerned with compounds and pharmaceutical compositions inhibiting CDK2, methods of treating diseases or disorders associated with CDK2, and methods of synthesizing these compounds.BACKGROUND

[0003] Cyclin-dependent kinase 2 (CDK2) plays a pivotal part in cell cycle regulation and is involved in a range of biological processes. CDK2 interacts with and phosphorylates proteins in pathways such as DNA damage, intracellular transport, protein degradation, signal transduction, DNA and RNA metabolism and translation. CDK2andits regulatory subunits are deregulated in many human cancers and there is emerging evidence suggesting CDK2 inhibition elicits antitumor activity in a subset of tumors with defined genetic features. Previous CDK2 inhibitors were nonspecific and limited by off-target effects. The development of new-generation CDK2 inhibitors represents a therapeutic opportunity for CDK2-dependent cancers.

[0004] Cyclin-dependent kinase 2 (CDK2) is a key cell cycle regulator, with roles in inactivating phosphorylation of the RB 1 (pRb) tumor suppressor family and in controlling both Gl / S and G2 / M transitions. In addition to promoting cell cycle progression, CDK2 has been described to play a positive role in cell cycle arrest in the DNA damage response (DDR), in particular at the G2 / M checkpoint.

[0005] Over the past decade, the clinical development of CDK4 / 6 inhibitors has led to practice-changing outcomes in breast cancer treatment. This has energized the field and increased interest in therapeutically targeting other members of the CDK family. CDK2was an early focus for anticancer drug discovery in the 1990s but the initial excitement was dampened owing to off-target effects of the early drugs. Interest in CDK2 inhibition has now reignited with the identification of more functions for CDK2 that impact cancer biology and the possibility of developing inhibitors with greater specificity to CDK2.

[0006] The broad functionality of CDK2 in proliferative and pro-survival pathways highlights it as an ideal target for mechanism-based and low-toxicity therapeutic strategies in cancer treatment. In addition to the roles and potential avenues for intervention discussed above, there is developing evidence that CDK2 activity also impacts cell differentiation and the adaptive immune response. Importantly, CDK2 inhibition appears to have most potential in particular molecular landscapes or cancer subtypes

[0007] All of the CDK2 inhibitors identified to date are nonselective leading to a promiscuous mode of action. In this context, it is important to note that specific cancers can benefit from the selective inhibition of CDK2 in combination with other CDKs, which broadens the spectrum for drug development. For example, endocrine-resistant cancers could benefit from a double blockade of CDK2 / CDK4 action because these cancers are so highly dependent on the Gl / S axis. Cancers that show cyclin El amplification and CDK2 dependency could benefit from CDK2 / CDK7 blockade, to directly inhibit CDK2 and then prevent the activation of residual CDK2 via CDK7 inhibition. There is already evidence that this approach will have some success because combination of CDK2 and PI3K inhibitors have demonstrated high in vitro efficacy in colorectal cancer cell lines

[0075] , and the combination of CDK1 / CDK2 inhibitors (e.g., roscovitine) with PI3K was synthetically lethal in human glioma xenograft models

[0076] , Consequently, the availability of a broad spectrum of inhibitors of either high specificity or selective targeting would be a maj or step forward in the search for new, effective, targeted cancer therapies, especially in those subtypes with CDK2 dependency, such as MYC-amplified cancers. Highly specific CDK2 inhibitors will bring additional benefit in defining further unique roles of CDK2 in cancer development, which will aid the ongoing identification of cancer subtypes that are susceptible to CDK2 inhibition.SUMMARY

[0008] A first aspect of the invention relates to compounds of Formula (A):or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein: each bond - is selected from a single bond and a double bond; each Q is independently selected from CH and N if the bond - is a double bond, and each Q is dependently selected from CH2 and NH if the bond - is a single bond;RQis selected from H, R1, R7and -N(R6)-L6-Rn; k is an integer selected from 1, 2, and 3; r is an integer selected from 0, 1, and 2; p is an integer selected from 0 and 1;R1is selected from -OH, -CN, halogen, Ci-Ce alkyl, Ci-Ce alkoxy, -S(O)2N(R6)2, - S(O)2Ci-C6alkyl, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, Ci-Ce alkyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl; each R2is independently selected from H, Ci-Ce alkyl;R3is selected from H, Ci-Ce alkyl, -NHC(O)Ci-Ce alkyl, -NHC(O)O-CI-C6 alkyl; each R6is independently selected from H, Ci-Ce alkyl, C3-C10 cycloalkyl, - C(O)OCi-Ce alkyl, or aryl, wherein the alkyl, cycloalkyl or aryl is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NH2, - N(Ci-Ce alkyl)2, Ci-Ce alkoxy, -(CH2)P-aryl;R7is -L-R8, L2-R10;L is selected from bond, -O(CH2)V-, -S-, -NR6(CH2)v(O)p(CH2)p-, -C(O)-, -(O)p- S(O)2-, -NH(CO)(CH2)P-, -NHS(O)2(CH2)P-, -NHC(O)NH-, -NHC(O)O(CH2)P, -(CH2)d-, - CH=CH-, -C=C-;L2is selected from C(O), S(O)2, NR6C(O), NR6S(O)2,NR6C(O)O;L6is selected from C(O), S(O)2, NR6C(O), NR6S(O)2;R8selected from C3-C10 cycloalkyl, 4-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from R9; each R9is independently selected from halogen, oxo, -OH, -N(R6)2, -CN, Ci-Ce alkyl, Ci-Ce alkoxy, -NHC(O)Ci-Ce alkyl, C3-C10 cycloalkyl, -(O)p-(CH2)p-aryl, -NR6-aryl, -C(O)Ci-C6 alkyl, heterocyclyl, -S(O)2heteroaryl, heteroaryl, wherein the alkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more substitutients independently selected from halogen, Ci-Ce alkyl, N(R6)2;R10is selected from Ci-Ce alkyl, Ci-Ce alkoxy, -N(R6)2, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from R9;R11is selected from Ci-Ce alkyl, Ci-Ce alkoxy, -N(R6)2, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from R9.

[0009] Another aspect of the invention relates to compounds of Formula (I):or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein: each R1is independently selected from halogen, Ci-Ce alkoxy; each R2is independently selected from H, Ci-Ce alkyl;R3is selected from H, Ci-Ce alkyl, -NHC(O)Ci-Ce alkyl, -NHC(O)O-CI-C6 alkyl;R4is selected from H, halogen, Ci-Ce alkyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, C3- C10 cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, -N(R6)2, -OC(O)N(R6)2, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, Ci-Ce alkyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, andR?is selected from H, halogen, Ci-Ce alkyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, C3- C10 cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, -N(R6)2, -OC(O)N(R6)2, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, Ci-Ce alkyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl andR4and R5together with the atoms to which they are attached and any intervening atoms, form 4-10 membered heterocycle, 5-10 membered heteroarene wherein the heterocycle or heteroarene is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, Ci-Ce alkyl, Ci-Ce halogenalkyl, Ci- C<, alkoxy, C3-C10 cycloalkyl, aryl; each R6is independently selected from H, Ci-Ce alkyl, C3-C10 cycloalkyl, - C(O)OCi-Ce alkyl, or aryl, wherein the alkyl, cycloalkyl or aryl is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NH2, - N(CI-C6 alkyl)2, Ci-Ce alkoxy, -(CH2)P-aryl; n is an integer selected from 1 and 2; p is an integer selected from 0 and 1;provided that when n is 1 and R1is Br, then at least one from substitutients R4and R5is different from H.

[0010] Another aspect of the invention relates to compounds of Formula (II):or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein: each W is independently selected from N, CH, provided that at least one W is N and provided that at least two W are CH; each R1is independently selected from halogen, Ci-Ce alkoxy, C3-C7 cycloalkyl, oxo, aryl, 5-10 membered heteroaryl;R2is selected from H, Ci-Ce alkyl;R3is selected from H, Ci-Ce alkyl, -NHC(O)Ci-Ce alkyl, -NHC(O)O-CI-C6 alkyl;R4is selected from H, halogen, Ci-Ce alkyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, C3- C10 cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, -N(R6)2, -OC(O)N(R6)2, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, Ci-Ce alkyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, andR?is selected from H, halogen, Ci-Ce alkyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, C3- C10 cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, -N(R6)2, -OC(O)N(R6)2, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selectedfrom halogen, OH, NH2, CN, Ci-Ce alkyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl,C2-C6 alkynyl, heterocycle, aryl, heteroaryl andR4and R3together with the atoms to which they are attached and any intervening atoms, form 4-10 membered heterocycle, 5-10 membered heteroarene wherein the heterocycle or heteroarene is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, Ci-Ce alkyl, Ci-Ce halogenalkyl, Ci- Ce alkoxy, C3-C10 cycloalkyl, aryl; each R6is independently selected from H, Ci-Ce alkyl, C3-C10 cycloalkyl, - C(O)OCi-Ce alkyl, or aryl, wherein the alkyl, cycloalkyl or aryl is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NH2, - N(Ci-Ce alkyl)2, Ci-Ce alkoxy, -(CH2)P-aryl; p is an integer selected from 0 and 1; m is an integer selected from 0, 1, 2 and 3.

[0011] Another aspect of the invention relates to compounds of Formula (III):or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein:R1is selected from -OH, -CN, Ci-Ce alkyl, Ci-Ce alkoxy, -S(O)2N(R6)2, -S(O)2Ci- Ce alkyl, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, Ci-Ce alkyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl;R2is selected from H, Ci-Ce alkyl;R3is selected from H, Ci-Ce alkyl, -NHC(O)CI-C6 alkyl, -NHC(O)O-Ci-Ce alkyl; each R6is independently selected from H, Ci-Ce alkyl, C3-C10 cycloalkyl; k is an integer selected from 1, 2, and 3; n is an integer selected from 0, 1, and 2.

[0012] Another aspect of the invention relates to compounds of Formula (IV):or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein: each R1is independently selected from halogen, Ci-Ce alkyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, Ci-Ce alkyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl;R2is selected from H, Ci-Ce alkyl;R3is selected from H, CI-CG alkyl, -NHC(O)CI-C6 alkyl, -NHC(O)O-CI-C6 alkyl; each R6is independently selected from H, Ci-Ce alkyl, C3-C10 cycloalkyl, - C(O)OCi-Ce alkyl, or aryl, wherein the alkyl, cycloalkyl or aryl is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NH2, - N(Ci-Ce alkyl)2, Ci-Ce alkoxy, -(CH2)P-aryl;R7is -L-R8;L is selected from a bond, -O(CH2)V-, -S-, -NR6(CH2)V(O)P(CH2)P-, -C(O)-, -(O)p- S(O)2-, -NH(CO)(CH2)P-, -NHS(O)2(CH2)P-, -NHC(O)NH-, -NHC(O)O(CH2)P, -(CH2)d-, - CH=CH-, -C=C-;R8is selected from C3-C10 cycloalkyl, 4-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl orheteroaryl is optionally substituted with one or more substituents independently selected from R9; each R9is independently selected from halogen, oxo, -OH, -N(R6)2, -CN, Ci-Ce alkyl, Ci-Ce alkoxy, -NHC(O)Ci-Ce alkyl, -NHC(O)OCi-Ce alkyl, C3-C10 cycloalkyl, - (O)P-(CH2)p-aryl, -NR6-aryl, -C(O)Ci-C6alkyl, heterocyclyl, -S(O)2Ci-C6alkyl, -S(O)2heteroaryl, heteroaryl, wherein the alkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more substitutients independently selected from halogen, Ci-Ce alkyl, N(R6)2; each p is an integer independently selected from 0 and 1; k is an integer selected from 0, 1, and 2; v is an integer selected from 0, 1, and 2; d is an integer selected from 1 and 2.

[0013] Another aspect of the invention relates to compound of Formula (V):or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein: each V is independently selected from NH and CH2;R2is selected from H, Ci-Ce alkyl;R3is selected from H, Ci-Ce alkyl, -NHC(O)Ci-Ce alkyl, -NHC(O)O-Ci-Ce alkyl; each R6is independently selected from H, Ci-Ce alkyl, C3-C10 cycloalkyl, - C(O)OCi-C6 alkyl, or aryl, wherein the alkyl, cycloalkyl or aryl is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NH2, - N(Ci-Ce alkyl)2, Ci-Ce alkoxy, -(CH2)P-aryl;R7is -L2-R10;L2is selected from C(O), S(O)2, NR6C(O), NR6S(O)2,NR6C(O)O;R10is selected from Ci-Ce alkyl, Ci-Ce alkoxy, -N(R6)2, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from R9; each R9is independently selected from halogen, oxo, -OH, -N(R6)2, -CN, Ci-Ce alkyl, Ci-C6alkoxy, -NHC(O)CI-C6alkyl, -NHC(O)OCI-C6alkyl, C3-C10 cycloalkyl, - (O)p-(CH2)p-aryl, -NR6-aryl, -C(O)Ci-C6 alkyl, heterocyclyl, -S(O)2 heteroaryl, heteroaryl, wherein the alkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more substitutients independently selected from halogen, Ci-Ce alkyl, N(R6)2; p is an integer selected from 0 and 1; k is an integer selected from 0, 1, and 2.

[0014] Another aspect of the invention relates to compound of Formula (VI):or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein:R2is selected from H, Ci-Ce alkyl;R3is selected from H, Ci-Ce alkyl, -NHC(O)Ci-Ce alkyl, -NHC(0)0-CI-C6 alkyl; each R6is independently selected from H, Ci-Ce alkyl, C3-C10 cycloalkyl, - C(O)OCi-C6 alkyl, or aryl, wherein the alkyl, cycloalkyl or aryl is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NH2, - N(Ci-Ce alkyl)2, Ci-Ce alkoxy, -(CH2)P-aryl;L6is selected from C(O), S(O)2;R11is selected from Ci-Ce alkyl, Ci-Ce alkoxy, -N(R6)2, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from R9; each R9is independently selected from halogen, oxo, -OH, -N(R6)2, -CN, Ci-Ce alkyl, Ci-Ce alkoxy, -NHC(O)Ci-Ce alkyl, -NHC(O)OCi-Ce alkyl, C3-C10 cycloalkyl, -(0)p-(CH2)p-aryl, -NR6-aryl, -C(0)Ci-C6 alkyl, heterocyclyl, -S(O)2 heteroaryl, heteroaryl, wherein the alkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more substitutients independently selected from halogen, Ci-Ce alkyl, N(R6)2; k is an integer selected from 0, 1, and 2; p is an integer selected from 0 and 1.

[0015] Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0016] Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0017] Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0018] Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (III), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0019] Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (IV), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0020] Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (V), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0021] Another aspect of the invention is directed to pharmaceutical compositions comprising a compound of Formula (VI), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof and a pharmaceutically acceptable carrier. The pharmaceutical acceptable carrier may further include an excipient, diluent, or surfactant.

[0022] Another aspect of the invention relates to a method of treating a cancer disease or disorder. The method comprises administering to a patient in need of a treatment for cancer diseases or disorders an effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0023] Another aspect of the invention relates to a method of treating a cancer disease or disorder. The method comprises administering to a patient in need of a treatment for cancer diseases or disorders an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0024] Another aspect of the invention relates to a method of treating a cancer disease or disorder. The method comprises administering to a patient in need of a treatment for cancer diseases or disorders an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0025] Another aspect of the invention relates to a method of treating a cancer disease or disorder. The method comprises administering to a patient in need of a treatment for cancer diseases or disorders an effective amount of a compound of Formula (III), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0026] Another aspect of the invention relates to a method of treating a cancer disease or disorder. The method comprises administering to a patient in need of a treatment for cancer diseases or disorders an effective amount of a compound of Formula (IV), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0027] Another aspect of the invention relates to a method of treating a cancer disease or disorder. The method comprises administering to a patient in need of a treatment for cancer diseases or disorders an effective amount of a compound of Formula (V), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0028] Another aspect of the invention relates to a method of treating a cancer disease or disorder. The method comprises administering to a patient in need of a treatment for cancer diseases or disorders an effective amount of a compound of Formula (VI), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0029] Another aspect of the invention is directed to a method of inhibiting of CDK2. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0030] Another aspect of the invention is directed to a method of inhibiting of CDK2. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0031] Another aspect of the invention is directed to a method of inhibiting of CDK2. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0032] Another aspect of the invention is directed to a method of inhibiting of CDK2. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (III), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0033] Another aspect of the invention is directed to a method of inhibiting of CDK2. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (IV), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0034] Another aspect of the invention is directed to a method of inhibiting of CDK2. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (V), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0035] Another aspect of the invention is directed to a method of inhibiting of CDK2. The method involves administering to a patient in need thereof an effective amount of a compound of Formula (VI), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0036] Another aspect of the present invention relates to compounds of Formula (A), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting CDK2.

[0037] Another aspect of the present invention relates to compounds of Formula (I), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting CDK2.

[0038] Another aspect of the present invention relates to compounds of Formula (II), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting CDK2.

[0039] Another aspect of the present invention relates to compounds of Formula (III), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting CDK2.

[0040] Another aspect of the present invention relates to compounds of Formula (IV), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers,or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting CDK2.

[0041] Another aspect of the present invention relates to compounds of Formula (V), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting CDK2.

[0042] Another aspect of the present invention relates to compounds of Formula (VI), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for inhibiting CDK2.

[0043] Another aspect of the present invention relates to the use of compounds of Formula (A), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of diseases and disorders associated with CDK2.

[0044] Another aspect of the present invention relates to the use of compounds of Formula(I), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of diseases and disorders associated with CDK2.

[0045] Another aspect of the present invention relates to the use of compounds of Formula(II), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of diseases and disorders associated with CDK2.

[0046] Another aspect of the present invention relates to the use of compounds of Formula(III), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of diseases and disorders associated with CDK2.

[0047] Another aspect of the present invention relates to the use of compounds of Formula(IV), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of diseases and disorders associated with CDK2.

[0048] Another aspect of the present invention relates to the use of compounds of Formula(V), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of diseases and disorders associated with CDK2.

[0049] Another aspect of the present invention relates to the use of compounds of Formula(VI), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of diseases and disorders associated with CDK2.

[0050] Another aspect of the present invention relates to compounds of Formula (A), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0051] Another aspect of the present invention relates to compounds of Formula (I), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0052] Another aspect of the present invention relates to compounds of Formula (II), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0053] Another aspect of the present invention relates to compounds of Formula (III), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0054] Another aspect of the present invention relates to compounds of Formula (IV), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0055] Another aspect of the present invention relates to compounds of Formula (V), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers,or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0056] Another aspect of the present invention relates to compounds of Formula (VI), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, for use in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0057] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0058] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0059] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0060] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a compound of Formula (III), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0061] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a compound of Formula (IV), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0062] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a compound of Formula (V), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0063] Another aspect of the invention is directed to a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof. The method involves administering to a patient in need of the treatment an effective amount of a compound of Formula (VI), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0064] Another aspect of the present invention relates to the use of compounds of Formula (A), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein.

[0065] Another aspect of the present invention relates to the use of compounds of Formula(I), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein.

[0066] Another aspect of the present invention relates to the use of compounds of Formula(II), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein.

[0067] Another aspect of the present invention relates to the use of compounds of Formula(III), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein.

[0068] Another aspect of the present invention relates to the use of compounds of Formula(IV), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein.

[0069] Another aspect of the present invention relates to the use of compounds of Formula(V), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein.

[0070] Another aspect of the present invention relates to the use of compounds of Formula(VI), or pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, tautomers, or pharmaceutical compositions thereof, in the treatment of a disease or disorder disclosed herein.

[0071] The present invention further provides methods of treating a disease or disorder associated with CDK2, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0072] The present invention further provides methods of treating a disease or disorder associated with CDK2, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0073] The present invention further provides methods of treating a disease or disorder associated with CDK2, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0074] The present invention further provides methods of treating a disease or disorder associated with CDK2, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (III), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0075] The present invention further provides methods of treating a disease or disorder associated with CDK2, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (IV), or a pharmaceutically acceptablesalt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0076] The present invention further provides methods of treating a disease or disorder associated with CDK2, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (V), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0077] The present invention further provides methods of treating a disease or disorder associated with CDK2, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (VI), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0078] The present invention provides inhibitors of CDK2 that are therapeutic agents in the treatment of diseases and disorders.

[0079] The present invention further provides compounds and compositions with an improved efficacy and safety profile relative to known inhibitors of CDK2. The present disclosure also provides agents with novel mechanisms of action toward CDK2 in the treatment of various types of diseases.

[0080] The present invention further provides methods of treating a disease or disorder associated with CDK2, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0081] The present invention further provides methods of treating a disease or disorder associated with CDK2, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0082] The present invention further provides methods of treating a disease or disorder associated with CDK2, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (II), or a pharmaceutically acceptablesalt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0083] The present invention further provides methods of treating a disease or disorder associated with CDK2, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (III), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0084] The present invention further provides methods of treating a disease or disorder associated with CDK2, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (IV), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0085] The present invention further provides methods of treating a disease or disorder associated with CDK2, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (V), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0086] The present invention further provides methods of treating a disease or disorder associated with CDK2, comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (VI), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0087] The present invention further provides methods of treating blood diseases, cancer diseases, ear diseases, endocrine diseases, eye diseases, fetal diseases, gastrointestinal diseases; genetic diseases, immune diseases, liver diseases, mental diseases, metabolic diseases, nephrological diseases, neuronal diseases, rare diseases, reproductive diseases, respiratory diseases, skin diseases comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0088] The present invention further provides methods of treating blood diseases, cancer diseases, ear diseases, endocrine diseases, eye diseases, fetal diseases, gastrointestinal diseases; genetic diseases, immune diseases, liver diseases, mental diseases, metabolic diseases, nephrological diseases, neuronal diseases, rare diseases, reproductive diseases, respiratory diseases, skin diseases comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0089] The present invention further provides methods of treating blood diseases, cancer diseases, ear diseases, endocrine diseases, eye diseases, fetal diseases, gastrointestinal diseases; genetic diseases, immune diseases, liver diseases, mental diseases, metabolic diseases, nephrological diseases, neuronal diseases, rare diseases, reproductive diseases, respiratory diseases, skin diseases comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0090] The present invention further provides methods of treating blood diseases, cancer diseases, ear diseases, endocrine diseases, eye diseases, fetal diseases, gastrointestinal diseases; genetic diseases, immune diseases, liver diseases, mental diseases, metabolic diseases, nephrological diseases, neuronal diseases, rare diseases, reproductive diseases, respiratory diseases, skin diseases comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (III), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0091] The present invention further provides methods of treating blood diseases, cancer diseases, ear diseases, endocrine diseases, eye diseases, fetal diseases, gastrointestinal diseases; genetic diseases, immune diseases, liver diseases, mental diseases, metabolic diseases, nephrological diseases, neuronal diseases, rare diseases, reproductive diseases, respiratory diseases, skin diseases comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (IV), or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0092] The present invention further provides methods of treating blood diseases, cancer diseases, ear diseases, endocrine diseases, eye diseases, fetal diseases, gastrointestinal diseases; genetic diseases, immune diseases, liver diseases, mental diseases, metabolic diseases, nephrological diseases, neuronal diseases, rare diseases, reproductive diseases, respiratory diseases, skin diseases comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (V), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0093] The present invention further provides methods of treating blood diseases, cancer diseases, ear diseases, endocrine diseases, eye diseases, fetal diseases, gastrointestinal diseases; genetic diseases, immune diseases, liver diseases, mental diseases, metabolic diseases, nephrological diseases, neuronal diseases, rare diseases, reproductive diseases, respiratory diseases, skin diseases comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (VI), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0094] The present invention further provides methods of treating a disease, disorder, or condition selected from: Breast Cancer (BC); Colorectal Cancer (CRC); Lung Cancer (LNCR); Retinoblastoma (RBI); Pancreatic Cancer (PNCA); Prostate Cancer (PC); Ovarian Cancer (OC); Hepatocellular Carcinoma (HCC); Gastric Cancer (GASC); Bladder Cancer (BLC); Endometrial Cancer (ENDMC); Glioblastoma (GBM); Adenocarcinoma; Squamous Cell Carcinoma; Ataxia-Telangiectasia (AT) comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0095] The present invention further provides methods of treating a disease, disorder, or condition selected from: Breast Cancer (BC); Colorectal Cancer (CRC); Lung Cancer (LNCR); Retinoblastoma (RBI); Pancreatic Cancer (PNCA); Prostate Cancer (PC); Ovarian Cancer (OC); Hepatocellular Carcinoma (HCC); Gastric Cancer (GASC); Bladder?3Cancer (BLC); Endometrial Cancer (ENDMC); Glioblastoma (GBM); Adenocarcinoma; Squamous Cell Carcinoma; Ataxia-Telangiectasia (AT) comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0096] The present invention further provides methods of treating a disease, disorder, or condition selected from: Breast Cancer (BC); Colorectal Cancer (CRC); Lung Cancer (LNCR); Retinoblastoma (RBI); Pancreatic Cancer (PNCA); Prostate Cancer (PC); Ovarian Cancer (OC); Hepatocellular Carcinoma (HCC); Gastric Cancer (GASC); Bladder Cancer (BLC); Endometrial Cancer (ENDMC); Glioblastoma (GBM); Adenocarcinoma; Squamous Cell Carcinoma; Ataxia-Telangiectasia (AT) comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula(II), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0097] The present invention further provides methods of treating a disease, disorder, or condition selected from: Breast Cancer (BC); Colorectal Cancer (CRC); Lung Cancer (LNCR); Retinoblastoma (RBI); Pancreatic Cancer (PNCA); Prostate Cancer (PC); Ovarian Cancer (OC); Hepatocellular Carcinoma (HCC); Gastric Cancer (GASC); Bladder Cancer (BLC); Endometrial Cancer (ENDMC); Glioblastoma (GBM); Adenocarcinoma; Squamous Cell Carcinoma; Ataxia-Telangiectasia (AT) comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula(III), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0098] The present invention further provides methods of treating a disease, disorder, or condition selected from: Breast Cancer (BC); Colorectal Cancer (CRC); Lung Cancer (LNCR); Retinoblastoma (RBI); Pancreatic Cancer (PNCA); Prostate Cancer (PC); Ovarian Cancer (OC); Hepatocellular Carcinoma (HCC); Gastric Cancer (GASC); Bladder Cancer (BLC); Endometrial Cancer (ENDMC); Glioblastoma (GBM); Adenocarcinoma; Squamous Cell Carcinoma; Ataxia-Telangiectasia (AT) comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula(IV), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0099] The present invention further provides methods of treating a disease, disorder, or condition selected from: Breast Cancer (BC); Colorectal Cancer (CRC); Lung Cancer (LNCR); Retinoblastoma (RBI); Pancreatic Cancer (PNCA); Prostate Cancer (PC); Ovarian Cancer (OC); Hepatocellular Carcinoma (HCC); Gastric Cancer (GASC); Bladder Cancer (BLC); Endometrial Cancer (ENDMC); Glioblastoma (GBM); Adenocarcinoma; Squamous Cell Carcinoma; Ataxia-Telangiectasia (AT) comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula(V), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0100] The present invention further provides methods of treating a disease, disorder, or condition selected from: Breast Cancer (BC); Colorectal Cancer (CRC); Lung Cancer (LNCR); Retinoblastoma (RB I); Pancreatic Cancer (PNCA); Prostate Cancer (PC); Ovarian Cancer (OC); Hepatocellular Carcinoma (HCC); Gastric Cancer (GASC); Bladder Cancer (BLC); Endometrial Cancer (ENDMC); Glioblastoma (GBM); Adenocarcinoma; Squamous Cell Carcinoma; Ataxia-Telangiectasia (AT) comprising administering to a patient suffering from at least one of said diseases or disorders a compound of Formula(VI), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0101] In some aspects, the present disclosure provides a compound obtainable by, or obtained by, a method for preparing compounds described herein (e.g., a method comprising one or more steps described in General Procedure).

[0102] In some aspects, the present disclosure provides a compound obtainable by, or obtained by, a method for preparing compounds described herein (e.g., a method comprising one or more steps described in Synthesis of the Representative Examples of the compound, examples 1-89).

[0103] In some aspects, the present disclosure provides an intermediate as described herein, being suitable for use in a method for preparing a compound as described herein (e.g., the intermediate is selected from the intermediates described in Preparative part - compounds P1-P65).

[0104] In some aspects, the present disclosure provides a method of preparing compounds of the present disclosure.

[0105] In some aspects, the present disclosure provides a method of preparing compounds of the present disclosure, comprising one or more steps described herein.

[0106] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents and other references mentioned herein are incorporated by reference. The references cited herein are not admitted to be prior art to the claimed invention. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting. In the case of conflict between the chemical structures and names of the compounds disclosed herein, the chemical structures will control.

[0107] Other features and advantages of the disclosure will be apparent from the following detailed description and claimsDETAILED DESCRIPTION

[0108] The present disclosure provides methods of treating, preventing, or ameliorating a disease or disorder associated with the CDK2 by administering to a subject in need thereof a therapeutically effective amount of a compound as disclosed herein.

[0109] The details of the disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, illustrative methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.All patents and publications cited in this specification are incorporated herein by reference in their entireties.Definitions

[0110] The articles "a" and "an" are used in this disclosure to refer to one or more than one ( / .<?., to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.[oni] The term "and / or" is used in this disclosure to mean either "and" or "or" unless indicated otherwise.

[0112] The term “optionally substituted” is understood to mean that a given chemical moiety (e.g, an alkyl group) can (but is not required to) be bonded other substituents (e.g., heteroatoms). For instance, an alkyl group that is optionally substituted can be a fully saturated alkyl chain (i.e., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have one or more substituents different from hydrogen. For instance, it can, at any point along the chain be bounded to a halogen atom, a hydroxyl group, or any other substituent described herein. Thus, the term “optionally substituted” means that a given chemical moiety has the potential to contain other functional groups but does not necessarily have any further functional groups. Suitable substituents used in the optional substitution of the described groups include, without limitation, halogen, oxo, - OH, -CN, -COOH, -CH2CN, -O-(CI-C6) alkyl, (Ci-C6) alkyl, (Ci-C6) alkoxy, (Ci-C6) haloalkyl, (Ci-Ce) haloalkoxy, -O-(C2-Ce) alkenyl, -O-(C2-Ce) alkynyl, (C2-C6) alkenyl, (C2-C6) alkynyl, -OH, -OP(O)(OH)2, -OC(O)(Ci-C6) alkyl, -C(O)(Ci-C6) alkyl, - OC(O)O(C1-C6) alkyl, -NH2, -NH((CI-C6) alkyl), -N((CI-C6) alkyl)2, -NHC(O)(CI-C6) alkyl, -C(O)NH(CI-C6) alkyl, -S(O)2(Ci-C6) alkyl, -S(O)NH(Ci-C6)alkyl, and - S(O)N((Ci-C6)alkyl)2. The substituents can themselves be optionally substituted. “Optionally substituted” as used herein also refers to substituted or unsubstituted whose meaning is described below.

[0113] As used herein, the term “substituted” means that the specified group or moiety bears one or more suitable substituents wherein the substituents may connect to the specified group or moiety at one or more positions. For example, an aryl substituted with a cycloalkyl may indicate that the cycloalkyl connects to one atom of the aryl with a bond or by fusing with the aryl and sharing two or more common atoms.

[0114] As used herein, the term “unsubstituted” means that the specified group bears no substituents.

[0115] Unless otherwise specifically defined, the term "aryl1' refers to cyclic, aromatic hydrocarbon groups that have 1 to 3 aromatic rings, including monocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl. Where containing two aromatic rings (bicyclic, etc.), the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl). The aryl group may be optionally substituted by one or more substituents, e.g., 1 to 5 substituents, at any point of attachment. Exemplary substituents include, but are not limited to, -H, -halogen, -O-(Ci-Ce)alkyl, (Ci-Ce)alkyl, - O-(C2-C6)alkenyl, -O-(C2-C6) alkynyl, (C2-C6)alkenyl, (C2-C6)alkynyl, -OH, - OP(O)(OH)2, -OC(O)(Ci-C6)alkyl, -C(O)(Ci-C6) alkyl, -OC(O)O(Ci-C6)alkyl, -NH2, - NH((Ci-C6)alkyl), -N((Ci-C6)alkyl)2, -S(O)2-(Ci-C6) alkyl, -S(O)NH(Ci-C6)alkyl, and - S(O)N((Ci-C6)alkyl)2. The substituents can themselves be optionally substituted. Furthermore, when containing two fused rings the aryl groups herein defined may have one or more saturated or partially unsaturated ring fused with a fully unsaturated aromatic ring. Exemplary ring systems of these aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl, indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, and the like.

[0116] Unless otherwise specifically defined, "heteroaryl" means a monovalent monocyclic or a polycyclic aromatic radical of 5 to 24 ring atoms, containing one or more ring heteroatoms selected from N, O, S, P, or B, the remaining ring atoms being C. A polycyclic aromatic radical includes two or more fused rings and may further include two or more spiro-fused rings, e.g., bicyclic, tricyclic, tetracyclic, and the like. Unless otherwise specifically defined, “fused” means two rings sharing two ring atoms. Unless otherwise specifically defined, “spiro-fused” means two rings sharing one ring atom. Heteroaryl as herein defined also means a bicyclic heteroaromatic group wherein the heteroatom is selected from N, O, S, P, or B. Heteroaryl as herein defined also means a tricyclic heteroaromatic group containing one or more ring heteroatoms selected from N, O, S, P, or B. Heteroaryl as herein defined also means a tetracyclic heteroaromatic group containing one or more ring heteroatoms selected from N, O, S, P, or B. The aromatic radical is optionally substituted independently with one or more substituents described herein.Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2- yl, quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole, benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl, imidazo[l,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[l,2-a]pyridinyl, indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl, thieno[2,3-c]pyridinyl, thieno[2,3- b]pyridinyl, benzothiazolyl, indolyl, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl, benzo[de]isoquinolinyl, pyrido[4,3-b][l,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazolo[l,5-a]pyridinyl, [l,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, imidazo[5,4- b]pyridinyl, pyrrolo[l,2-a]pyrimidinyl, tetrahydro pyrrolo[l,2-a]pyrimidinyl, 3,4-dihydro- 2H-l-pyrrolo[2,l-b]pyrimidine, dibenzo[b,d]thiophene, pyridin-2-one, furo[3,2- c]pyridinyl, furo[2,3-c]pyridinyl, lH-pyrido[3,4-b][l,4]thiazinyl, benzooxazolyl, benzoisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl, furo[3,2- b]pyridine, [l,2,4]triazolo[l,5-a]pyridinyl, benzo [ l,2,3]triazolyl, imidazo[l,2- a]pyrimidinyl, [l,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][l,2,5]thiadiazolyl, benzo[c] [ 1 ,2,5]oxadiazole, 1 ,3 -dihy dro-2H-benzo[d]imidazol -2-one, 3 ,4-dihy dro-2H- pyrazolo [l,5-b][l,2]oxazinyl, 4,5,6,7-tetrahydropyrazolo[l,5-a]pyridinyl, thiazolo[5,4- d]thiazolyl, imidazo[2,l-b][l,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl, and derivatives thereof. Furthermore, when containing two or more fused rings, the heteroaryl groups defined herein may have one or more saturated or partially unsaturated ring fused with one or more fully unsaturated aromatic ring. In heteroaryl ring systems containing more than two fused rings, a saturated or partially unsaturated ring may further be fused with a saturated or partially unsaturated ring described herein. Furthermore, when containing three or more fused rings, the heteroaryl groups defined herein may have one or more saturated or partially unsaturated ring spiro-fused. Any saturated or partially unsaturated ring described herein is optionally substituted with one or more oxo. Exemplary ring systems of these heteroaryl groups include, for example, indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl,tetrahydroquinolinyl, dihydrobenzothiazine, 3,4-dihydro-lH-isoquinolinyl, 2,3- dihydrobenzofuranyl, benzofuranonyl, indolinyl, oxindolyl, indolyl, l,6-dihydro-7H- pyrazolo[3,4-c]pyridin-7-onyl, 7,8-dihydro-6H-pyrido[3,2-b]pyrrolizinyl, 8H-pyrido[3,2- b]pyrrolizinyl, l,5,6,7-tetrahydrocyclopenta[b]pyrazolo[4,3-e]pyridinyl, 7,8-dihydro-6H- pyrido[3,2-b]pyrrolizine, pyrazolo[l,5-a]pyrimidin-7(4H)-only, 3,4-dihydropyrazino[l,2- a]indol-l(2H)-onyl, benzofc] [l,2]oxaborol-l(377)-olyl, 6,6a,7,8-tetrahydro-977- pyrido[2,3-Z>]puyrrolo[l,2-d][l,4]oxazin-9-onyl, or 6a’,7’-dihydro-6’H,9’H- spiro[cyclopropane-l,8’-pyrido[2,3-Z>]pyrrolo[l,2-d][l,4]oxazin]-9’-onyl.

[0117] Halogen or “halo” refers to fluorine, chlorine, bromine, or iodine.

[0118] Alkyl refers to a straight or branched chain saturated hydrocarbon containing 1-12 carbon atoms. Examples of a (Ci-Ce) alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl f / .w-propyl), isobutyl f / .w-butyl), sec -butyl, te / 7-butyl, isopentyl f / .w-pentyl), neopentyl ( / / co-pentyl), and isohexyl ( / .w-hexyl).

[0119] “Alkoxy” refers to a straight or branched chain saturated hydrocarbon containing1-12 carbon atoms containing a terminal “O” in the chain, i.e., -O(alkyl). Examples of alkoxy groups include without limitation, methoxy, ethoxy, propoxy, butoxy, / c / V-butoxy, or pentoxy groups.

[0120] “Alkenyl” refers to a straight or branched chain unsaturated hydrocarbon containing2-12 carbon atoms. The “alkenyl” group contains at least one double bond in the chain. The double bond of an alkenyl group can be unconjugated or conjugated to another unsaturated group. Examples of alkenyl groups include ethenyl, propenyl, / / -butcnyl, iso- butenyl, pentenyl, or hexenyl. An alkenyl group can be unsubstituted or substituted. Alkenyl, as herein defined, may be straight or branched.

[0121] “Alkynyl” refers to a straight or branched chain unsaturated hydrocarbon containing 2-12 carbon atoms. The “alkynyl” group contains at least one triple bond in the chain. Examples of alkenyl groups include ethynyl, propargyl, / / -butynyl, Ao-butynyl, pentynyl, or hexynyl. An alkynyl group can be unsubstituted or substituted.

[0122] The term “alkylene”, “alkylenyl” or “alkanediyl” refers to a divalent alkyl radical. Any of the above-mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl. As herein defined, alkylene may also be a Ci- Ce alkylene. An alkylene may further be a C1-C4 alkylene. Typical alkylene groups include,but are not limited to, -CH2-, -CH(CH3)-, -C(CH3)2-, -CH2CH2-, -CH2CH(CH3)-, - CH2C(CH3)2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, and the like.

[0123] “Cycloalkyl” means mono or polycyclic saturated carbon rings containing 3-18 carbon atoms. Polycyclic cycloalkyl may be fused bicyclic cycloalkyl, bridged bicyclic cycloalkyl, or spiro-fused bicyclic cycloalkyl. A polycyclic cycloalkyl comprises at least one non-aromatic ring. Examples of cycloalkyl groups include, without limitations, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl, norbornyl, norborenyl, 1,2,3,4-tetrahydronaphthyl, 2,3-dihydro-lH-indenyl, spiro[3.5]nonyl, spiro [5.5]undecyl, bicyclo[l. l. l]pentanyl, bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl.

[0124] “Heterocyclyl”, “heterocycle” or “heterocycloalkyl” mono or polycyclic rings containing 3-24 atoms which include carbon and one or more heteroatoms selected from N, O, S, P, or B and wherein the rings are not aromatic. The heterocycloalkyl ring structure may be substituted by one or more substituents. The substituents can themselves be optionally substituted. Examples of heterocyclyl rings include, but are not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, oxazolidinonyl, and homotropanyl.

[0125] The term “aromatic” means a planar ring having An + 2 electrons in a conjugated system. As used herein, “conjugated system” means a system of connected p-orbitals with delocalized electrons, and the system may include lone electron pairs.

[0126] The term “haloalkyl” as used herein refers to an alkyl group, as defined herein, which is substituted one or more halogen. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc.

[0127] The term “haloalkoxy” as used herein refers to an alkoxy group, as defined herein, which is substituted with one or more halogen. Examples of haloalkyl groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc.

[0128] The term “cyano” as used herein means a substituent having a carbon atom joined to a nitrogen atom by a triple bond, z.e., C=N.

[0129] “Spirocycloalkyl” or “spirocyclyl” means carbogenic bicyclic ring systems with both rings connected through a single atom. The ring can be different in size and nature, or identical in size and nature. Examples include spiropentane, spriohexane, spiroheptane, spirooctane, spirononane, or spirodecane. One or both of the rings in a spirocycle can be fused to another ring carbocyclic, heterocyclic, aromatic, or heteroaromatic ring. One or more of the carbon atoms in the spirocycle can be substituted with a heteroatom (e.g, O, N, S, or P). A (C3-C12) spirocycloalkyl is a spirocycle containing between 3 and 12 carbon atoms. One or more of the carbon atoms can be substituted with a heteroatom.

[0130] The term “spiroheterocycloalkyl”, “spiroheterocycle”, or “spiroheterocyclyl” is understood to mean a spirocycle wherein at least one of the rings is a heterocycle (e.g., at least one of the rings is furanyl, morpholinyl, or piperidinyl).

[0131] The term "solvate" refers to a complex of variable stoichiometry formed by a solute and solvent. Such solvents for the purpose of the disclosure may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH, DMSO, and AcOH. Solvates wherein water is the solvent molecule are typically referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water, as well as compositions containing variable amounts of water.

[0132] The term "isomer" refers to compounds that have the same composition and molecular weight but differ in physical and / or chemical properties. The structural difference may be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). With regard to stereoisomers, the compounds of Formula (A) and in particular compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V) or Formula (VI) may have one or more asymmetric carbon atom and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers.

[0133] The present disclosure also contemplates isotopically-labelled compounds of Formula I (e.g, those labeled with2H and14C). Deuterated (z.e.,2H or D) and carbon- 14 (z.e.,14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.Isotopically labelled compounds of Formula (A) and in particular compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI) can generally be prepared by following procedures analogous to those disclosed in the Schemes and / or in the Examples herein below, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent.

[0134] The disclosure also includes pharmaceutical compositions comprising a therapeutically effective amount of a disclosed compound and a pharmaceutically acceptable carrier. Representative "pharmaceutically acceptable salts" include, e.g., water- soluble and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2,2- disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methyl sulfate, mucate, napsylate, nitrate, N- methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate, pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p- toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosalicylate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts.

[0135] A "patient" or “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon, or rhesus.

[0136] An "effective amount" when used in connection with a compound is an amount effective for treating or preventing a disease in a subject as described herein.

[0137] The term "carrier", as used in this disclosure, encompasses carriers, excipients, and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject.

[0138] The term "treating" with regard to a subject, refers to improving at least one symptom of the subject's disorder. Treating includes curing, improving, or at least partially ameliorating the disorder.

[0139] The term "disorder" is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.

[0140] The term "administer", "administering", or "administration" as used in this disclosure refers to either directly administering a disclosed compound or pharmaceutically acceptable salt of the disclosed compound or a composition to a subject, or administering a prodrug derivative or analog of the compound or pharmaceutically acceptable salt of the compound or composition to the subject, which can form an equivalent amount of active compound within the subject's body.

[0141] The term "prodrug," as used in this disclosure, means a compound which is convertible in vivo by metabolic means (e.g., by hydrolysis) to a disclosed compound.

[0142] The term “salt’ refers to pharmaceutically acceptable salts.

[0143] The term “pharmaceutically acceptable salt” also refers to a salt of the compositions of the present disclosure having an acidic functional group, such as a carboxylic acid functional group, and a base.

[0144] “ CDK2 inhibitor” as used herein refer to compounds of Formula A and / or compositions comprising a compound of Formula A which inhibits CDK2.

[0145] “ CDK2 inhibitor” as used herein refer to compounds of Formula I and / or compositions comprising a compound of Formula I which inhibits CDK2.

[0146] “CDK2 inhibitor” as used herein refer to compounds of Formula II and / or compositions comprising a compound of Formula II which inhibits CDK2.

[0147] “ CDK2 inhibitor” as used herein refer to compounds of Formula III and / or compositions comprising a compound of Formula III which inhibits CDK2.

[0148] “ CDK2 inhibitor” as used herein refer to compounds of Formula IV and / or compositions comprising a compound of Formula IV which inhibits CDK2.

[0149] “ CDK2 inhibitor” as used herein refer to compounds of Formula V and / or compositions comprising a compound of Formula V which inhibits CDK2.

[0150] “CDK2 inhibitor” as used herein refer to compounds of Formula VI and / or compositions comprising a compound of Formula VI which inhibits CDK2.

[0151] The amount of compound of composition described herein needed for achieving a therapeutic effect may be determined empirically in accordance with conventional procedures for the particular purpose. Generally, for administering therapeutic agents (e.g. compounds or compositions of Formula A, I, II, III, IV, V, or VI (and / or additional agents) described herein) for therapeutic purposes, the therapeutic agents are given at a pharmacologically effective dose. A “pharmacologically effective amount,” “pharmacologically effective dose,” “therapeutically effective amount,” or “effective amount” refers to an amount sufficient to produce the desired physiological effect or amount capable of achieving the desired result, particularly for treating the disorder or disease. An effective amount as used herein would include an amount sufficient to, for example, delay the development of a symptom of the disorder or disease, alter the course of a symptom of the disorder or disease (e.g., slow the progression of a symptom of the disease), reduce or eliminate one or more symptoms or manifestations of the disorder or disease, and reverse a symptom of a disorder or disease. For example, administration of therapeutic agents to a subj ect suffering from cancer provides a therapeutic benefit not only when the underlying condition is eradicated or ameliorated, but also when the subject reports a decrease in the severity or duration of the symptoms associated with the disease, e.g., a decrease in tumor burden, a decrease in circulating tumor cells, an increase in progression free survival. Therapeutic benefit also includes halting or slowing the progression of the underlying disease or disorder, regardless of whether improvement is realized.Compounds of the Present Disclosure

[0152] In some embodiments, the present disclosure provides compounds of Formula (A) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof:wherein R1, R2, R3, Q, RQ, r and k are as described herein.

[0153] It is understood that, for a compound of Formula (A), R1, R2, R3, Q, RQ, r and k can each be, where applicable, selected from the groups described herein, and any group described herein for any R1, R2, R3, Q, RQ, r and k can be combined, where applicable, with any group described herein for one or more of the remainders of R1, R2, R3, Q, R(), r and k.

[0154] In some embodiments, the present disclosure provides compounds of Formula (I) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof:wherein R1, R2, R3, R4, R5and n are as described herein.

[0155] It is understood that, for a compound of Formula (I), R1, R2, R3, R4, R5and n can each be, where applicable, selected from the groups described herein, and any group described herein for any R1, R2, R3, R4, R5and n can be combined, where applicable, with any group described herein for one or more of the remainders of R1, R2, R3, R4, R5and n.

[0156] In some embodiments, the present disclosure provides compounds of Formula (11) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof:wherein R1, R2, R3, R4, R5, W and m are as described herein.

[0157] It is understood that, for a compound of Formula (II), R1, R2, R3, R4, R5, W and m can each be, where applicable, selected from the groups described herein, and any group described herein for any R1, R2, R3, R4, R5, W and m can be combined, where applicable, with any group described herein for one or more of the remainders of R1, R2, R3, R4, R3, W and m.

[0158] In some embodiments, the present disclosure provides compounds of Formula (III) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof:wherein R1, R2, R3, k and n are as described herein.

[0159] It is understood that, for a compound of Formula (III), R1, R2, R3, k and n can each be, where applicable, selected from the groups described herein, and any group described herein for any R1, R2, R3, k and n can be combined, where applicable, with any group described herein for one or more of the remainders of R1, R2, R3, k and n.

[0160] In some embodiments, the present disclosure provides compounds of Formula (IV) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof:wherein R1, R2, R3, R7, k and p are as described herein.

[0161] It is understood that, for a compound of Formula (IV), R1, R2, R3, R7, k and p can each be, where applicable, selected from the groups described herein, and any group described herein for any R1, R2, R3, R7, k and p can be combined, where applicable, with any group described herein for one or more of the remainders of R1, R2, R3, R7, k and p.

[0162] In some embodiments, the present disclosure provides compounds of Formula (V) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof:wherein R2, R3, R7, V, k and p are as described herein.

[0163] It is understood that, for a compound of Formula (V), R2, R3, R7, V, k and p can each be, where applicable, selected from the groups described herein, and any group described herein for any R2, R3, R7, V, k and p can be combined, where applicable, with any group described herein for one or more of the remainders of R2, R3, R7, V, k and p.

[0164] In some embodiments, the present disclosure provides compounds of Formula (VI) and salts, stereoisomers, solvates, prodrugs, isotopic derivatives, and tautomers thereof:wherein R2, R3, R6, R11, L6and kare as described herein.

[0165] It is understood that, for a compound of Formula (VI), R2, R3, R6, R11, L6and k can each be, where applicable, selected from the groups described herein, and any group described herein for any R2, R3, R6, R11, L6and k can be combined, where applicable, with any group described herein for one or more of the remainders of R2, R3, R6, R11, L6and k.

[0166] In some embodiments, the compound is of Formula (I-A):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0167] In some embodiments, the compound is of Formula (I-A-l):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0168] In some embodiments, the compound is of Formula (I-B):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0169] In some embodiments, the compound is of Formula (I-B-l):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0170] In some embodiments, the compound is of Formula (I-B-2):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0171] In some embodiments, the compound is of Formula (I-B-3):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0172] In some embodiments, the compound is of Formula (I-C):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0173] In some embodiments, the compound is of Formula (I-C-l):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0174] In some embodiments, the compound is of Formula (I-C-2):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0175] In some embodiments, the compound is of Formula (I-C-3):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0176] In some embodiments, the compound is of Formula (I-D):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0177] In some embodiments, the compound is of Formula (I-D-l):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0178] In some embodiments, the compound is of Formula (I-D-2):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0179] In some embodiments, the compound is of Formula (I-E):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0180] In some embodiments, the compound is of Formula (I-E-l):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0181] In some embodiments, the compound is of Formula (I-E-2):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0182] In some embodiments, the compound is of Formula (I-F):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0183] In some embodiments, the compound is of Formula (I-F-l):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0184] In some embodiments, the compound is of Formula (I-G):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0185] In some embodiments, the compound is of Formula (I-G-l):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof

[0186] In some embodiments, the compound is of Formula (I-H):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0187] In some embodiments, the compound is of Formula (I-H-l):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0188] In some embodiments, the compound is of Formula (II-A):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0189] In some embodiments, the compound is of Formula (II-B):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0190] In some embodiments, the compound is of Formula (II-B-1):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0191] In some embodiments, the compound is of Formula (II-B-2):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0192] In some embodiments, the compound is of Formula (II-B-3):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0193] In some embodiments, the compound is of Formula (II-B-3-a):or tautomer thereof.

[0194] In some embodiments, the compound is of Formula (II-C):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0195] In some embodiments, the compound is of Formula (II-C-1):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0196] In some embodiments, the compound is of Formula (II-C-2):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0197] In some embodiments, the compound is of Formula (II-C-3):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0198] In some embodiments, the compound is of Formula (II-C-3-a):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0199] In some embodiments, the compound is of Formula (II-D):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0200] In some embodiments, the compound is of Formula (II-D-I):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0201] In some embodiments, the compound is of Formula (II-D-l-a):or tautomer thereof.

[0202] In some embodiments, the compound is of Formula (II-D-I-b):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0203] In some embodiments, the compound is of Formula (II-D-I-c):or tautomer thereof.

[0204] In some embodiments, the compound is of Formula (II-D-2):or tautomer thereof.

[0205] In some embodiments, the compound is of Formula (II-D-2-a):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0206] In some embodiments, the compound is of Formula (II-D-3):or tautomer thereof.

[0207] In some embodiments, the compound is of Formula (II-D-3-a):or tautomer thereof.

[0208] In some embodiments, the compound is of Formula (II-D-4):or tautomer thereof.

[0209] In some embodiments, the compound is of Formula (II-D-4-a):or tautomer thereof.

[0210] In some embodiments, the compound is of Formula (III-A):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0211] In some embodiments, the compound is of Formula (III-B):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0212] In some embodiments, the compound is of Formula (III-C):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0213] In some embodiments, the compound is of Formula (IV-A):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0214] In some embodiments, the compound is of Formula (IV-A-1):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0215] In some embodiments, the compound is of Formula (IV-A-l-a):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0216] In some embodiments, the compound is of Formula (IV-A-2):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0217] In some embodiments, the compound is of Formula (IV-A-2-a):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0218] In some embodiments, the compound is of Formula (IV-B):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0219] In some embodiments, the compound is of Formula (IV-B-1):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0220] In some embodiments, the compound is of Formula (IV-B-l-a):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0221] In some embodiments, the compound is of Formula (IV-B-2): r2O v M R p N H (IV-B-2), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0222] In some embodiments, the compound is of Formula (IV-B-2-a):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0223] In some embodiments, the compound is of Formula (IV-C):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0224] In some embodiments, the compound is of Formula (IV-C-1):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0225] In some embodiments, the compound is of Formula (IV-C-l-a):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0226] In some embodiments, the compound is of Formula (IV-C-l-b):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0227] In some embodiments, the compound is of Formula (IV-C-l-c):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0228] In some embodiments, the compound is of Formula (IV-C-1 -d):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0229] In some embodiments, the compound is of Formula (IV-C-2):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0230] In some embodiments, the compound is of Formula (IV-C-2-a):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0231] In some embodiments, the compound is of Formula (IV-C-2-b):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0232] In some embodiments, the compound is of Formula (IV-C-2-c):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0233] In some embodiments, the compound is of Formula (IV-C-2-d):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0234] In some embodiments, the compound is of Formula (IV-C-3):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0235] In some embodiments, the compound is of Formula (IV-C-3-a):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0236] In some embodiments, the compound is of Formula (V-A):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0237] In some embodiments, the compound is of Formula (V-B):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0238] In some embodiments, the compound is of Formula (V-B-l):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0239] In some embodiments, the compound is of Formula (V-B-l-a):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0240] In some embodiments, the compound is of Formula (V-B-2):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0241] In some embodiments, the compound is of Formula (V-B-2-a):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0242] In some embodiments, the compound is of Formula (V-B-3):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0243] In some embodiments, the compound is of Formula (V-B-3-a):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0244] In some embodiments, the compound is of Formula (V-C):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0245] In some embodiments, the compound is of Formula (VI-A):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0246] In some embodiments, the compound is of Formula (VI-B):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0247] In some embodiments, the compound is of Formula (VI-B-1):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0248] In some embodiments, the compound is of Formula (VI-B-l-a):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0249] In some embodiments, the compound is of Formula (VI-B-l-b):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0250] In some embodiments, the compound is of Formula (VI-B-l-c):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0251] In some embodiments, the compound is of Formula (Vl-B-2):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0252] In some embodiments, the compound is of Formula (VI-B-2-a):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0253] In some embodiments, the compound is of Formula (VI-B-2-c):R2OX X tX vcXR6 H(VI-B-2-c), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0254] In some embodiments, the compound is of Formula (VI-C):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0255] In some embodiments, the compound is of Formula (VI-C-1):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0256] In some embodiments, the compound is of Formula (VI-C-1-a):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0257] In some embodiments, the compound is of Formula (VI-C-1-b):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0258] In some embodiments, the compound is of Formula (VI-C-l-c):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0259] In some embodiments, the compound is of Formula (VI-C-2):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0260] In some embodiments, the compound is of Formula (Vl-C-2-b):or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0261] In some embodiments, the compound is of Formula (A). In some embodiments, the compound is of Formula (I). In some embodiments, the compound is of Formula (II). In some embodiments, the compound is of Formula (III). In some embodiments, the compound is of Formula (IV). In some embodiments, the compound is of Formula (V). In some embodiments, the compound is of Formula (VI).

[0262] In some embodiments, the compound is of Formula (A), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0263] In some embodiments, the compound is of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0264] In some embodiments, the compound is of Formula (II), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0265] In some embodiments, the compound is of Formula (III), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0266] In some embodiments, the compound is of Formula (IV), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0267] In some embodiments, the compound is of Formula (V), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0268] In some embodiments, the compound is of Formula (VI), or a pharmaceutically acceptable salt, stereoisomer, solvate, prodrug, isotopic derivative, or tautomer thereof.

[0269] In some embodiments, R1is selected from -OH, -CN, halogen, Ci-Ce alkyl, Ci-Ce alkoxy, -S(O)2N(R6)2, -S(O)2Ci-C6 alkyl, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, Ci-Ce alkyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl.

[0270] In some embodiments, R1is selected from halogen, Ci-Ce alkoxy.

[0271] In some embodiments, R1is selected from halogen, Ci-Ce alkoxy, C3-C7 cycloalkyl, oxo, aryl, 5-10 membered heteroaryl.

[0272] In some embodiments, R1is -OH.

[0273] In some embodiments, R1is -CN.

[0274] In some embodiments, R1is Ci-Ce alkyl optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, Ci-Ce alkyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl.

[0275] In some embodiments, R1is Ci-Ce alkyl.

[0276] In some embodiments, R1is selected from methyl, ethyl, n-propyl, z-propyl, zz-butyl, z-butyl, sec-butyl, Zez'Z-butyl, zz-pentyl, zz-hexyl.

[0277] In some embodiments, R1is methyl.

[0278] In some embodiments, R1is -CF3.

[0279] In some embodiments, R1is halogen.

[0280] In some embodiments, R1is F.

[0281] In some embodiments, R1is Cl.

[0282] In some embodiments, R1is Br.

[0283] In some embodiments, R1is C3-C10 cycloalkyl optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, Ci-Ce alkyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl.

[0284] In some embodiments, R1is C3-C10 cycloalkyl.

[0285] In some embodiments, R1is cyclopropyl.

[0286] In some embodiments, R1is oxo.

[0287] In some embodiments, R1is aryl.

[0288] In some embodiments, R1is phenyl.

[0289] In some embodiments, R1is Ci-Ce alkoxy optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, Ci-Ce alkyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl.

[0290] In some embodiments, R1is selected from halogen, Ci-Ce alkoxy.

[0291] In some embodiments, R1is Ci-Ce alkoxy.

[0292] In some embodiments, R1is methoxy.

[0293] In some embodiments, R1is -OCH2CH3.

[0294] In some embodiments, R1is -O-CH(CH02.

[0295] In some embodiments, R1is -O-CH2CF3.

[0296] In some embodiments,

[0297] In some embodiments, R1is -S(O)2Ci-Cs alkyl.

[0298] In some embodiments, R1is -S(O)2CH3.

[0299] In some embodiments, R1is -S(O)2CH2CH3.

[0300] In some embodiments, R1is -S(O)2N(R6)2.

[0301] In some embodiments, R1is -S(O)2NH2.

[0302] In some embodiments, R1is -S(O)2N(H)CH3.

[0303] In some embodiments, R1is -S(O)2N(H)CH2CH3.

[0304] In some embodiments, R1is -S(O)2N(H)CH(CH3)2.

[0305] In some embodiments, R1is -S(O)2N(CH3)2.

[0306] In some embodiments, R2is selected from H, Ci-Ce alkyl.

[0307] In some embodiments, R2is H.

[0308] In some embodiments, R2is Ci-Ce alkyl.

[0309] In some embodiments, R2is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl.

[0310] In some embodiments, R2is selected from methyl, ethyl, / / -propyl, / -propyl, / / -butyl, / -butyl, sec-butyl, tert-butyl, / / -pentyl, / / -hexyl.

[0311] In some embodiments, R2is methyl.

[0312] In some embodiments, R3is selected from H, Ci-Ce alkyl, -NHC(O)Ci-Ce alkyl, - NHC(O)O-CI-C6alkyl.

[0313] In some embodiments, R3is H.

[0314] In some embodiments, R3is Ci-Ce alkyl.

[0315] In some embodiments, R3is selected from methyl, ethyl, propyl, butyl, pentyl, hexyl.

[0316] In some embodiments, R3is selected from methyl, ethyl, / / -propyl, / -propyl, / / -butyl, / ’-butyl, scc-butyl, tert-butyl, / / -pentyl, / / -hexyl.

[0317] In some embodiments, R3is methyl.

[0318] In some embodiments, R3is -NHC(O)Ci-Ce alkyl.

[0319] In some embodiments, R3is -NHC(O)CH3.

[0320] In some embodiments, R3is -NHC(O)O-CI-C6 alkyl.

[0321] In some embodiments, R3is -NHC(O)O-CH3.

[0322] In some embodiments, R4is selected from H, halogen, Ci-Ce alkyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, -NR6R7, - OC(O)NR6R7, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, Ci-Ce alkyl, Ci-Cealkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, and

[0323] In some embodiments, R4is H.

[0324] In some embodiments, R4is halogen.

[0325] In some embodiments, R4is Cl.

[0326] In some embodiments, R4is Ci-Ce alkoxy optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, Ci-Ce alkyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, and

[0327] In some embodiments, R4is Ci-Ce alkoxy.

[0328] In some embodiments, R4is methoxy.

[0329] In some embodiments, R4is ethoxy.

[0330] In some embodiments,

[0331] In some embodiments,

[0332] In some embodiments,

[0333] In some embodiments, R4is -NR6R7.

[0334] In some embodiments, R4is -N(CH3)2.

[0335] In some embodiments, R4is -OC(O)NR6R7.

[0336] In some embodiments, R4is -OC(O)N(CH3)2.

[0337] In some embodiments, R~ is selected from H, halogen, Ci-Ce alkyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, -NR6R7, - OC(O)NR6R7, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl,heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, Ci-Ce alkyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl and

[0338] In some embodiments, R5is H.

[0339] In some embodiments, R5is Ci-Ce alkyl.

[0340] In some embodiments, R5is halogen.

[0341] In some embodiments, R5is Cl.

[0342] In some embodiments, R5is Ci-Ce alkoxy optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, Ci-Ce alkyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, and

[0343] In some embodiments, R3is Ci-Ce alkoxy.

[0344] In some embodiments, R5is methoxy.

[0345] In some embodiments, R5is ethoxy.

[0346] In some embodiments,

[0347] In some embodiments,

[0348] In some embodiments,

[0350] In some embodiments, R5is -NR6R7.

[0351] In some embodiments,

[0352] In some embodiments,

[0353] In some embodiments,

[0354] In some embodiments, R5is heterocycle optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, Ci-Ce alkyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl and,

[0356] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form 4-10 membered heterocycle, 5-10 membered heteroarene wherein the heterocycle or heteroarene is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, Ci-Ce alkyl, Ci-Ce halogenalkyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, aryl.

[0357] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form

[0358] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form

[0359] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form

[0360] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form

[0361] In some embodiments, R4and R3together with the atoms to which they are attached and any intervening atoms, form

[0362] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form

[0363] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form

[0364] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form

[0365] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form

[0366] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form

[0367] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form

[0368] In some embodiments, R4and R3together with the atoms to which they are attached and any intervening atoms, form

[0369] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form

[0370] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form

[0371] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form

[0372] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form

[0373] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form

[0374] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form

[0375] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form

[0376] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form

[0377] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form

[0378] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form

[0379] In some embodiments, R4and R5together with the atoms to which they are attached and any intervening atoms, form.

[0380] In some embodiments, R6is selected from H, Ci-Ce alkyl, C3-C10 cycloalkyl, - C(O)OCi-Ce alkyl, or aryl, wherein the alkyl, cycloalkyl or aryl is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NH2, - N(Ci-Ce alkyl)2, Ci-Ce alkoxy, -(CH2)P-aryl .

[0381] In some embodiments, R6is H.

[0382] In some embodiments, R6is Ci-Ce alkyl.

[0383] In some embodiments, R6is -CH3.

[0384] In some embodiments, R6is -CH2CH3.

[0385] In some embodiments,

[0386] In some embodiments, R6is Ci-Ce alkyl optionally substituted with one or more substitutients independently selected from halogen, CN, OH.

[0387] In some embodiments,

[0388] In some embodiments, R6is -CF3.

[0389] In some embodiments, R6is aryl.

[0390] In some embodiments,

[0391] In some embodiments, R6is Ci-Ce alkyl-C(O)-, wherein alkyl is optionally substituted with one or more substitutients independently selected from halogen, CN, OH.

[0392] In some embodiments, R6is CH3C(O)-.

[0393] In some embodiments, R6is (CH3)2CHC(O)-.

[0394] In some embodiments, R6is (CH.3)3C(O)-.

[0395] In some embodiments, R6is CHF2C(O)-.

[0396] In some embodiments, R6is CF3C(O)-.

[0397] In some embodiments, R6is CF3CF2C(O)-.

[0398] In some embodiments, R7is -L-R8.

[0399] In some embodiments, L is selected from bond, -O(CH2)v-, -S-, - NR6(CH2)V(O)P(CH2)P-, -C(O)-, -(O)p-S(O)2-, -NH(CO)(CH2)P-, -NHS(O)2(CH2)P-, - NHC(O)NH-, -NHC(O)O(CH2)P, -(CH2)d-, -CH=CH-, -C=C-.

[0400] In some embodiments, L is a bond.

[0401] In some embodiments, L is a single bond.

[0402] In some embodiments, L is -0(CH2)v.

[0403] In some embodiments, L is O.

[0404] In some embodiments, L is -O-CH2-.

[0405] In some embodiments, L is NR6(CH2)V(O)P(CH2)P-.

[0406] In some embodiments, L is NH.

[0407] In some embodiments, L is N(C2Hs).

[0408] In some embodiments, L is -NH-CH2-.

[0409] In some embodiments, L is -NH-C(0)-0-CH2-.

[0410] In some embodiments, L is -NHS(O)2(CH2)P-.

[0411] In some embodiments, L is -NHS(O)2-.

[0412] In some embodiments, L is -NHS(O)2CH2-.

[0413] In some embodiments, L is -S-.

[0414] In some embodiments, L is -(O)P-S(O)2-.

[0415] In some embodiments, L is S(O)2.

[0416] In some embodiments, L is -O-S(O)2-.

[0417] In some embodiments, L is -C(O)-.

[0418] In some embodiments, L is -NH(CO)(CH2)P-.

[0419] In some embodiments, L is -NH(CO)-.

[0420] In some embodiments, L is -NHC(O)NH-.

[0421] In some embodiments, L is -C=C-.

[0422] In some embodiments, L is -CH=CH-.

[0423] In some embodiments, L is -(CH2)d-.

[0424] In some embodiments, L is -CH2-CH2-.

[0425] In some embodiments, L is -NH(CO)(CH2)P-.

[0426] In some embodiments, L is -NH(CO)CH2-.

[0427] In some embodiments, R8is selected from C3-C10 cycloalkyl, 4-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from R9.

[0428] In some embodiments, R8is C3-C10 cycloalkyl optionally substituted with one or more substituents independently selected from R9.

[0429] In some embodiments,

[0430] In some embodiments,

[0431] In some embodiments,

[0432] In some embodiments,

[0433] In some embodiments,

[0434] In some embodiments, R8is 4-10 membered heterocyclyl optionally substituted with one or more substituents independently selected from R9.

[0435] In some embodiments,

[0436] In some embodiments,

[0437] In some embodiments,

[0438] In some embodiments,

[0439] In some embodiments,

[0440] In some embodiments,

[0441] In some embodiments,

[0442] In some embodiments,

[0443] In some embodiments,

[0444] In some embodiments,

[0445] In some embodiments,

[0446] In some embodiments,

[0447] In some embodiments,

[0448] In some embodiments, R8is 6-10 membered aryl optionally substituted with one or more substituents independently selected from R9.

[0449] In some embodiments,

[0450] In some embodiments,

[0451] In some embodiments,

[0452] In some embodiments,

[0453] In some embodiments,

[0454] In some embodiments,

[0455] In some embodiments,

[0456] In some embodiments,

[0457] In some embodiments,

[0458] In some embodiments, R8is 5-10 membered heteroaryl optionally substituted with one or more substituents independently selected from R9.

[0459] In some embodiments,

[0470] In some embodiments,

[0471] In some embodiments,

[0472] In some embodiments,

[0473] In some embodiments,

[0474] In some embodiments,

[0475] In some embodiments,

[0476] In some embodiments,

[0477] In some embodiments,

[0478] In some embodiments,

[0479] In some embodiments,

[0480] In some embodiments,

[0481] In some embodiments,

[0484] In some embodiments,

[0489] In some embodiments,

[0494] In some embodiments,

[0495] In some embodiments,

[0496] In some embodiments,

[0497] In some embodiments,

[0498] In some embodiments,

[0499] In some embodiments,

[0500] In some embodiments,

[0501] In some embodiments,

[0502] In some embodiments,

[0503] In some embodiments,

[0504] In some embodiments,

[0505] In some embodiments,

[0506] In some embodiments,

[0507] In some embodiments,

[0508] In some embodiments,

[0509] In some embodiments,

[0510] In some embodiments,

[0511] In some embodiments,

[0512] In some embodiments,

[0513] In some embodiments,

[0514] In some embodiments,

[0515] In some embodiments,

[0516] In some embodiments,

[0517] In some embodiments,

[0518] In some embodiments,

[0519] In some embodiments,

[0520] In some embodiments,

[0521] In some embodiments,

[0522] In some embodiments,

[0523] In some embodiments,

[0524] In some embodiments,

[0525] In some embodiments,

[0526] In some embodiments,

[0527] In some embodiments,

[0528] In some embodiments,

[0529] In some embodiments,

[0530] In some embodiments,

[0531] In some embodiments,

[0532] In some embodiments,

[0533] In some embodiments,

[0534] In some embodiments,

[0535] In some embodiments,

[0536] In some embodiments,

[0537] In some embodiments,

[0538] In some embodiments,

[0539] In some embodiments,

[0540] In some embodiments,

[0541] In some embodiments,

[0542] In some embodiments,

[0543] In some embodiments,

[0544] In some embodiments, each R9is independently selected from halogen, oxo, -OH, -N(R6)2, -CN, CI-C6alkyl, Ci-C6alkoxy, -NHC(O)CI-C6alkyl, -NHC(O)OCI-C6alkyl, C3- Cio cycloalkyl, -(O)p-(CH2)P-aryl, -NR6-aryl, -C(O)Ci-Ce alkyl, heterocyclyl, -S(O)2-Ci- C<, alkyl, -S(O)2-heteroaryl, heteroaryl, wherein the alkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more substitutients independently selected from halogen, Ci-C6alkyl, N(R6)2.

[0545] In some embodiments, R9is -OH.

[0546] In some embodiments, R9is oxo.

[0547] In some embodiments, R9is halogen.

[0548] In some embodiments, R9is -F.

[0549] In some embodiments, R9is -Cl.

[0550] In some embodiments, R9is -CN.

[0551] In some embodiments, R9is Ci-Ce alkyl.

[0552] In some embodiments, R9is methyl.

[0553] In some embodiments, R9is ethyl.

[0554] In some embodiments, R9is iso-propyl.

[0555] In some embodiments, R9is Ci-Ce alkyl optionally substituted with one or more substitutients independently selected from halogen, Ci-Ce alkyl, N(R6)2.

[0556] In some embodiments, R9is -CHF2.

[0557] In some embodiments, R9is -N(R6)2.

[0558] In some embodiments, R9is -NH2.,

[0565] In some embodiments,

[0566] In some embodiments, R9is Ci-Ce alkoxy.

[0567] In some embodiments, R9is methoxy.

[0568] In some embodiments, R9is ethoxy.

[0569] In some embodiments, R9is / .w-propoxy.

[0570] In some embodiments, R9is -NHC(O)Ci-Ce alkyl.

[0571] In some embodiments, R9is -NHC(O)CH3.

[0572] In some embodiments, R9is -S(O)2-Ci-C6 alkyl.

[0573] In some embodiments, R9is -S(O)2CH3.

[0574] In some embodiments, R9is -S(O)2-heteroaryl.

[0575] In some embodiments,

[0576] In some embodiments, R9is heterocyclyl.

[0577] In some embodiments,

[0578] In some embodiments,

[0579] In some embodiments,

[0580] In some embodiments,

[0581] In some embodiments,

[0582] In some embodiments, R9is -NHC(O)OCi-Ce alkyl.

[0583] In some embodiments, R9is -NHC(O)OC2Hs.

[0584] In some embodiments, R9is -(O)p-(CH2)P-aryl.

[0585] In some embodiments,

[0586] In some embodiments, R9is C3-C10 cycloalkyl.

[0587] In some embodiments,

[0588] In some embodiments, R9is -C(O)Ci-Ce alkyl.

[0589] In some embodiments, R9is -C(O)CH3.

[0590] In some embodiments, R10is selected from Ci-Ce alkyl, Ci-Ce alkoxy, -N(R6)2, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from R9.

[0591] In some embodiments, R10is Ci-Ce alkyl.

[0592] In some embodiments, R10is methyl.

[0593] In some embodiments, R10is zso-butyl.

[0594] In some embodiments, R10is -N(R6)2.

[0595] In some embodiments, R10is -N(CH3)2.

[0596] In some embodiments, R10is aryl.

[0597] In some embodiments, R10is phenyl.

[0598] In some embodiments, R10is heteroaryl.

[0599] In some embodiments,

[0600] In some embodiments, R10is Ci-Ce alkoxy.

[0601] In some embodiments, R10is methoxy.

[0602] In some embodiments, R11is selected from Ci-Ce alkyl, Ci-Ce alkoxy, -N(R6)2, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from R9.

[0603] In some embodiments, R11is Ci-Ce alkyl.

[0604] In some embodiments, R11is -CH3.

[0605] In some embodiments, R11is -CH2CH3.

[0606] In some embodiments,

[0607] In some embodiments,

[0608] In some embodiments,

[0609] In some embodiments,

[0610] In some embodiments,

[0611] In some embodiments,

[0612] In some embodiments,

[0613] In some embodiments, R11is Ci-Ce alkoxy.

[0614] In some embodiments, R11is -OCH3.

[0615] In some embodiments, R11is -OCH2CH3.

[0616] In some embodiments,

[0617] In some embodiments,

[0618] In some embodiments, R11is -N(R6)2.

[0619] In some embodiments, R11is -N(CH3)2.

[0620] In some embodiments, L2is selected from C(O), S(O)2, NR6C(O), NR6S(O)2, NR6C(O)O.

[0621] In some embodiments, L2is C(O).

[0622] In some embodiments, L2is NHC(O).

[0623] In some embodiments, L2is N(CH3)C(O).

[0624] In some embodiments, L2is S(O)2.

[0625] In some embodiments, L2is NHS(O)2.

[0626] In some embodiments, L2is N(CH3)S(O)2.

[0627] In some embodiments, L6is selected from C(O), S(O)2.

[0628] In some embodiments, L6is C(O).

[0629] In some embodiments, L6is S(O)2.

[0630] In some embodiments, V is NH.

[0631] In some embodiments, V is CH2.

[0632] In some embodiments, W is N.

[0633] In some embodiments, W is CH.

[0634] In some embodiments, the compound is selected from the compounds described in Table 1 and pharmaceutically acceptable salts, stereoisomers, solvates, prodrugs, isotopic derivatives, or tautomers thereof.

[0635] In some embodiments, the compound is selected from the compounds described in Table 1 and prodrugs and pharmaceutically acceptable salts thereof.

[0636] In some embodiments, the compound is selected from the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0637] In some embodiments, the compound is selected from the prodrugs of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0638] In some embodiments, the compound is selected from the compounds described inTable 1

[0639] Table 1 Certain examples of the compound of Formula A

[0640] In some embodiments, the compound is a pharmaceutically acceptable salt of any one of the compounds described in Table 1.

[0641] In some embodiments, the compound is a lithium salt, sodium salt, potassium salt, calcium salt, or magnesium salt of any one of the compounds described in Table 1.

[0642] In some embodiments, the compound is a salt of any one of acid described in the Table 2 and any one of the compounds described in Table 1.

[0643] Table 2. Pharmaceutical acceptable acid forming salts with the Compound of Formula (A), (I)-(VI).

[0644] In some embodiments, the compound is a salt of acetic acid and any one of the compounds described in Table 1.

[0645] In some embodiments, the compound is a salt of adipic acid and any one of the compounds described in Table 1.

[0646] In some embodiments, the compound is a salt of ascorbic acid (L) and any one of the compounds described in Table 1.

[0647] In some embodiments, the compound is a salt of hydrobromic acid and any one of the compounds described in Table 1.

[0648] In some embodiments, the compound is a salt of hydrochloric acid and any one of the compounds described in Table 1.

[0649] In some embodiments, the compound is a salt of citric acid and any one of the compounds described in Table 1.

[0650] In some embodiments, the compound is a salt of glutamic acid and any one of the compounds described in Table 1.

[0651] In some embodiments, the compound is a salt of oxalic acid and any one of the compounds described in Table 1.

[0652] In some embodiments, the compound is a salt of formic acid and any one of the compounds described in Table 1.

[0653] In some embodiments, the compound is a salt of sulfuric acid and any one of the compounds described in Table 1.

[0654] In some aspects, the present disclosure provides a compound being an isotopic derivative (e.g., isotopically labeled compound) of any one of the compounds of the Formulae disclosed herein.

[0655] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1 and prodrugs and pharmaceutically acceptable salts thereof.

[0656] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0657] In some embodiments, the compound is an isotopic derivative of any one of prodrugs of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0658] In some embodiments, the compound is an isotopic derivative of any one of the compounds described in Table 1.

[0659] It is understood that the isotopic derivative can be prepared using any of a variety of art-recognized techniques. For example, the isotopic derivative can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examples described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0660] In some embodiments, the isotopic derivative is a deuterium labeled compound.

[0661] In some embodiments, the isotopic derivative is a deuterium labeled compound of any one of the compounds of the Formulae disclosed herein.

[0662] The term “isotopic derivative”, as used herein, refers to a derivative of a compound in which one or more atoms are isotopically enriched or labelled. For example, an isotopic derivative of a compound of Formula (I)-(VI) is isotopically enriched with regard to, or labelled with, one or more isotopes as compared to the corresponding compound of Formula (I)-(VI). In some embodiments, the isotopic derivative is enriched with regard to, or labelled with, one or more atoms selected from2H,13C,14C,15N,180,29Si,31P, and34S. In some embodiments, the isotopic derivative is a deuterium labeled compound (i.e., being enriched with2H with regard to one or more atoms thereof).

[0663] In some embodiments, the compound is a deuterium labeled compound of any one of the compounds described in Table 1 and prodrugs and pharmaceutically acceptable salts thereof.

[0664] In some embodiments, the compound is a deuterium labeled compound of any one of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0665] In some embodiments, the compound is a deuterium labeled compound of any one of the prodrugs of the compounds described in Table 1 and pharmaceutically acceptable salts thereof.

[0666] In some embodiments, the compound is a deuterium labeled compound of any one of the compounds described in Table 1.

[0667] It is understood that the deuterium labeled compound comprises a deuterium atom having an abundance of deuterium that is substantially greater than the natural abundance of deuterium, which is 0.015%.

[0668] In some embodiments, the deuterium labeled compound has a deuterium enrichment factor for each deuterium atom of at least 3500 (52.5% deuterium incorporation at each deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Asused herein, the term “deuterium enrichment factor” means the ratio between the deuterium abundance and the natural abundance of a deuterium.

[0669] It is understood that the deuterium labeled compound can be prepared using any of a variety of art-recognized techniques. For example, the deuterium labeled compound can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examples described herein, by substituting a deuterium labeled reagent for a nondeuterium labeled reagent.

[0670] A compound of the disclosure or a pharmaceutically acceptable salt or solvate thereof that contains the aforementioned deuterium atom(s) is within the scope of the disclosure. Further, substitution with deuterium ( / .<?.,2H) may afford certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements.

[0671] In some embodiments, the compound is a18F labeled compound.

[0672] In some embodiments, the compound is a123I labeled compound, a124I labeled compound, a125I labeled compound, a129I labeled compound, a131I labeled compound, a135I labeled compound, or any combination thereof.

[0673] In some embodiments, the compound is a33S labeled compound, a34S labeled compound, a35S labeled compound, a36S labeled compound, or any combination thereof.

[0674] It is understood that the18F,123I,124I,125I,129I,131I,135I,33S,34S,35S, and / or36S labeled compound, can be prepared using any of a variety of art-recognized techniques. For example, the deuterium labeled compound can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examples described herein, by substituting a18F,123I,124I,125I,129I,131I,1351,33S,34S,3?S, and / or36S labeled reagent for a non-isotope labeled reagent.

[0675] A compound of the disclosure or a pharmaceutically acceptable salt or solvate thereof that contains one or more of the aforementioned18F,123I,124I,125I,129I,131I,133I,33S,34S,35S, and36S atom(s) is within the scope of the disclosure. Further, substitution with isotope (e.g,,18F,123I,124I,123I,129I,131I,1351,33S,34S,33S, and / or36S) may afford certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements.

[0676] For the avoidance of doubt, it is to be understood that, where in this specification a group is qualified by “described herein”, the said group encompasses the first occurring and broadest definition as well as each and all of the particular definitions for that group.

[0677] The various functional groups and substituents making up the compounds of the Formula (A) are typically chosen such that the molecular weight of the compound does not exceed 1000 Daltons. More usually, the molecular weight of the compound will be less than 900, for example less than 800, or less than 750, or less than 700, or less than 650 Daltons. More conveniently, the molecular weight is less than 600 and, for example, is 550 Daltons or less, for example 500 Daltons or less, for example 450 Daltons or less.

[0678] A suitable pharmaceutically acceptable salt of a compound of the disclosure is, for example, an acid-addition salt of a compound of the disclosure, which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric methane sulfonate or maleic acid. In addition, a suitable pharmaceutically acceptable salt of a compound of the disclosure which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a pharmaceutically acceptable cation, for example a salt with methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[0679] It will be understood that the compounds of any one of the Formulae disclosed herein and any pharmaceutically acceptable salts thereof, comprise stereoisomers, mixtures of stereoisomers, polymorphs of all isomeric forms of said compounds.

[0680] As used herein, the term “isomerism” means compounds that have identical molecular formulae but differ in the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereoisomers,” and stereoisomers that are non-superimposable mirror images of each other are termed “enantiomers” or sometimes optical isomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a “racemic mixture.”

[0681] As used herein, the term “chiral center” refers to a carbon atom bonded to four nonidentical substituents.

[0682] As used herein, the term “chiral isomer” means a compound with at least one chiral center. Compounds with more than one chiral center may exist either as an individual diastereomer or as a mixture of diastereomers, termed “diastereomeric mixture.” When one chiral center is present, a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0683] As used herein, the term “geometric isomer” means the diastereomers that owe their existence to hindered rotation about double bonds or a cycloalkyl linker (e.g., 1,3- cyclobutyl). These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.

[0684] It is to be understood that the compounds of the present disclosure may be depicted as different chiral isomers or geometric isomers. It is also to be understood that when compounds have chiral isomeric or geometric isomeric forms, all isomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any isomeric forms, it being understood that not all isomers may have the same level of activity.

[0685] It is to be understood that the structures and other compounds discussed in this disclosure include all atropic isomers thereof. It is also to be understood that not all atropic isomers may have the same level of activity.

[0686] As used herein, the term “atropic isomers” are a type of stereoisomer in which the atoms of two isomers are arranged differently in space. Atropic isomers owe their existence to a restricted rotation caused by hindrance of rotation of large groups about a central bond. Such atropic isomers typically exist as a mixture, however as a result of recent advances inchromatography techniques, it has been possible to separate mixtures of two atropic isomers in select cases.

[0687] As used herein, the term “tautomer” is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solutions where tautomerisation is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that are interconvertible by tautomerisations is called tautomerism. Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs. Ring-chain tautomerism arises as a result of the aldehyde group (-CHO) in a sugar chain molecule reacting with one of the hydroxy groups (-OH) in the same molecule to give it a cyclic (ring-shaped) form as exhibited by glucose.

[0688] It is to be understood that the compounds of the present disclosure may be depicted as different tautomers. It should also be understood that when compounds have tautomeric forms, all tautomeric forms are intended to be included in the scope of the present disclosure, and the naming of the compounds does not exclude any tautomer form. It will be understood that certain tautomers may have a higher level of activity than others.

[0689] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric centre, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterised by the absolute configuration of its asymmetric centre and is described by the R- and 5-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarised light and designated as dextrorotatory or levorotatory ( / .<?., as (+) or (-)-isomers respectively). A chiral compound can exist as either individualenantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

[0690] The compounds of this disclosure may possess one or more asymmetric centres; such compounds can therefore be produced as individual (R)- or (^-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form. Some of the compounds of the disclosure may have geometric isomeric centres (E- and Z- isomers). It is to be understood that the present disclosure encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof that possess inflammasome inhibitory activity.

[0691] The present disclosure also encompasses compounds of the disclosure as defined herein which comprise one or more isotopic substitutions.

[0692] It is to be understood that the compounds of any Formula described herein include the compounds themselves, as well as their salts, and their solvates, if applicable. A salt, for example, can be formed between an anion and a positively charged group (e.g., amino) on a substituted compound disclosed herein. Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalenesulfonate, and acetate (e g-, trifluoroacetate).

[0693] As used herein, the term “pharmaceutically acceptable anion” refers to an anion suitable for forming a pharmaceutically acceptable salt. Likewise, a salt can also be formed between a cation and a negatively charged group (e.g., carboxylate) on a substituted compound disclosed herein. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion, and an ammonium cation such as tetramethylammonium ion or diethylamine ion. The substituted compounds disclosed herein also include those salts containing quaternary nitrogen atoms.

[0694] It is to be understood that the compounds of the present disclosure, for example, the salts of the compounds, can exist in either hydrated or unhydrated (the anhydrous) form or as solvates with other solvent molecules. Nonlimiting examples of hydrates include monohydrates, dihydrates, etc. Nonlimiting examples of solvates include ethanol solvates, acetone solvates, etc.

[0695] As used herein, the term “solvate” means solvent addition forms that contain either stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H2O.

[0696] As used herein, the term “analog” refers to a chemical compound that is structurally similar to another but differs slightly in composition (as in the replacement of one atom by an atom of a different element or in the presence of a particular functional group, or the replacement of one functional group by another functional group). Thus, an analog is a compound that is similar or comparable in function and appearance, but not in structure or origin to the reference compound.

[0697] As used herein, the term “derivative” refers to compounds that have a common core structure and are substituted with various groups as described herein.

[0698] As used herein, the term “bioisostere” refers to a compound resulting from the exchange of an atom or of a group of atoms with another, broadly similar, atom or group of atoms. The objective of a bioisosteric replacement is to create a new compound with similar biological properties to the parent compound. The bioisosteric replacement may be physicochemically or topologically based. Examples of carboxylic acid bioisosteres include, but are not limited to, acyl sulfonamides, tetrazoles, sulfonates and phosphonates. See, e.g., Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

[0699] It is also to be understood that certain compounds of any one of the Formulae disclosed herein may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. A suitable pharmaceutically acceptable solvate is, for example, a hydrate such as hemi-hydrate, a mono-hydrate, a di-hydrate or a tri-hydrate. It is to be understoodthat the disclosure encompasses all such solvated forms that possess inflammasome inhibitory activity.

[0700] It is also to be understood that certain compounds of any one of the Formulae disclosed herein may exhibit polymorphism, and that the disclosure encompasses all such forms, or mixtures thereof, which possess inflammasome inhibitory activity. It is generally known that crystalline materials may be analysed using conventional techniques such as X-Ray Powder Diffraction analysis, Differential Scanning Calorimetry, Thermal Gravimetric Analysis, Diffuse Reflectance Infrared Fourier Transform (DRIFT) spectroscopy, Near Infrared (NIR) spectroscopy, solution and / or solid state nuclear magnetic resonance spectroscopy. The water content of such crystalline materials may be determined by Karl Fischer analysis.

[0701] Compounds of any one of the Formulae disclosed herein may exist in a number of different tautomeric forms and references to compounds of Formula (A), (I), (II), (III), (IV), (V) and (VI) include all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all others are nevertheless embraced by Formula (A), (I), (II), (III), (IV), (V), (VI). Examples of tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / aci -nitro.keto enol enolate

[0702] Compounds of any one of the Formulae disclosed herein containing an amine function may also form A -oxi des. A reference herein to a compound of Formula (I)-(VI) that contains an amine function also includes the A-oxide. Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an A-oxide. Particular examples of A -oxi des are the A-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle. A-oxides can be formed by treatment of the corresponding amine with an oxidising agent such as hydrogen peroxide or a peracid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March,4th Edition, Wiley Interscience, pages. More particularly, / V-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with meta-chloroperoxybenzoic acid (m-CPBA), for example, in an inert solvent such as di chloromethane.

[0703] The compounds of any one of the Formulae disclosed herein may be administered in the form of a prodrug which is broken down in the human or animal body to release a compound of the disclosure. A prodrug may be used to alter the physical properties and / or the pharmacokinetic properties of a compound of the disclosure. A prodrug can be formed when the compound of the disclosure contains a suitable group or substituent to which a property-modifying group can be attached. Examples of prodrugs include derivatives containing in vivo cleavable alkyl or acyl substituents at the ester or amide group in any one of the Formulae disclosed herein.

[0704] Accordingly, the present disclosure includes those compounds of any one of the Formulae disclosed herein as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a prodrug thereof. Accordingly, the present disclosure includes those compounds of any one of the Formulae disclosed herein that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of any one of the Formulae disclosed herein may be a synthetically produced compound or a metabolically-produced compound.

[0705] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein is one that is based on reasonable medical judgment as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity. Various forms of prodrug have been described, for example in the following documents: a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32,692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, A C S. Symposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0706] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof. An in vivo cleavable ester or ether of a compound of any one of the Formulae disclosed herein containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester forming groups for a hydroxy group include Ci-Cio alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, Ci-Cio alkoxycarbonyl groups such as ethoxycarbonyl, A,V-(Ci-Ce alkyl)2carbamoyl, 2- dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, A-alkylaminomethyl, N,N- dialkylaminomethyl, morpholinomethyl, piperazin- 1-ylmethyl and 4-(CI-C4 alkyl)piperazin-l-ylmethyl. Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include a-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0707] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as ammonia, a Ci-4alkylamine such as methylamine, a (C1-C4 alkyl)2amine such as dimethylamine, N- ethyl-V-methylamine or diethylamine, a C1-C4 alkoxy-C2-C4 alkylamine such as 2-methoxyethylamine, a phenyl-Ci-C4 alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.

[0708] A suitable pharmaceutically acceptable prodrug of a compound of any one of the Formulae disclosed herein that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof. Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with C1-C10 alkanoyl groups such asan acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, A -alkyl ami nomethyl, A(A'-di alkyl ami nomethyl, morpholinomethyl, piperazin- 1-ylmethyl and 4-(CI-C4 alkyl)piperazin-l-ylmethyl.

[0709] The in vivo effects of a compound of any one of the Formulae disclosed herein may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of any one of the Formulae disclosed herein. As stated hereinbefore, the in vivo effects of a compound of any one of the Formulae disclosed herein may also be exerted by way of metabolism of a precursor compound (a prodrug).Method of Synthesizing the Compounds

[0710] The compounds of the present invention may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are depicted in the Schemes given below.

[0711] The compounds of Formula (A), in particular Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V) or Formula (VI) may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthetic schemes. In the schemes described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection processes, as well as the reaction conditions and order of those skilled in the art will recognize if a stereocenter exists in the compounds of Formula (A), (I)-(III). Accordingly, the present invention includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compounds but the individual enantiomers and / or diastereomers as well. When a compound is desired as a single enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, forexample, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994).

[0712] The compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, and / or enzymatic processes.Preparation of Compounds

[0713] The compounds of the present invention can be prepared in a number of ways well known to those skilled in the art of organic synthesis. By way of example, compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Suitable methods include but are not limited to those methods described below. Compounds of the present invention can be synthesized by following the steps outlined in General Procedures which comprise different sequences of assembling intermediates or compounds. Starting materials are either commercially available or made by known procedures in the reported literature or as illustrated below.GENERAL PROCEDURE

[0714] In general, the compounds of the present disclosure can be prepared according to reactions presented at the Scheme 1.

[0715] Scheme 1

[0716] It must be understood that any of the compounds at the Scheme 1 any of substitutients in these compounds can be further modified at any step of presented sequences to provide modified derivatives of these compounds useful for preparation of compounds of Formula (A), Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), or Formula (VI).

[0717] All reagents may be commercially available compounds itself or products of synthesis from commercially available reagents. For preparation these reagents may be used one step or multi step synthetic procedures, including but not limited procedures described herein in preparative part.

[0718] It should be obvious for specialist in this field that any of compound of Formula (A), (I), (II), (III), (IV), (V) or (VI) obtained according to the procedures described above may be a subject for further transformation and modification that will led to obtain other compound of Formula (A), (I), (II), (III), (IV), (V) or (VI).Biological Assays

[0719] Compounds designed, selected and / or optimized by methods described above, once produced, can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds have biological activity. For example, the molecules can be characterized by conventional assays, including but not limited to those assays described below, to determine whether they have a predicted activity, binding activity and / or binding specificity.

[0720] Furthermore, high-throughput screening can be used to speed up analysis using such assays. As a result, it can be possible to rapidly screen the molecules described herein for activity, using techniques known in the art. General methodologies for performing high- throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. High-throughput assays can use one or more different assay techniques including, but not limited to, those described below.

[0721] Various in vitro or in vivo biological assays may be suitable for detecting the effect of the compounds of the present disclosure. These in vitro or in vivo biological assays can include, but are not limited to, enzymatic activity assays, electrophoretic mobility shift assays, reporter gene assays, in vitro cell viability assays, and the assays described herein. Pharmaceutical Compositions

[0722] In some aspects, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure as an active ingredient. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound of each of the formulae described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the present disclosure provides a pharmaceutical composition comprising at least one compound selected from Table 1.

[0723] As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

[0724] Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspendingagents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component. In tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. Solid form preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

[0725] Liquid formulations also are suitable for oral administration include liquid formulation including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions. These include solid form preparations which are intended to be converted to liquid form preparations shortly before use. Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethyl cellulose, and other well-known suspending agents.

[0726] The compounds of the present invention may be formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol. Examples of oily or nonaqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form,obtained by aseptic isolation of sterile solid or by lyophilization from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water.

[0727] The compounds of present disclosure can be formulated for oral administration in forms such as tablets, capsules (each of which includes sustained release or timed-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. The compounds of present disclosure on can also be formulated for intravenous (bolus or in-fusion), intraperitoneal, topical, subcutaneous, intramuscular or transdermal (e.g., patch) administration, all using forms well known to those of ordinary skill in the pharmaceutical arts.

[0728] The formulation of the present disclosure may be in the form of an aqueous solution comprising an aqueous vehicle. The aqueous vehicle component may comprise water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from the group consisting of a solubility enhancing agent, chelating agent, preservative, tonicity agent, viscosity / suspending agent, buffer, and pH modifying agent, and a mixture thereof.

[0729] Any suitable solubility enhancing agent can be used. Examples of a solubility enhancing agent include cyclodextrin, such as those selected from the group consisting of hydroxypropyl-P-cyclodextrin, methyl-P-cyclodextrin, randomly methylated-P- cyclodextrin, ethylated-P-cyclodextrin, triacetyl-P-cyclodextrin, peracetylated-P- cyclodextrin, carboxymethyl-P-cyclodextrin, hydroxyethyl-P-cyclodextrin, 2-hydroxy-3- (trimethylammonio)propyl-P-cyclodextrin, glucosyl-P-cyclodextrin, sulfated P- cyclodextrin (S-P-CD), maltosyl-P-cyclodextrin, P-cyclodextrin sulfobutyl ether, branched-P-cyclodextrin, hydroxypropyl-y-cyclodextrin, randomly methylated-y- cyclodextrin, and trimethyl-'y-cyclodextrin, and mixtures thereof.

[0730] Any suitable chelating agent can be used. Examples of a suitable chelating agent include those selected from the group consisting of ethylenedi aminetetraacetic acid and metal salts thereof, di sodium edetate, trisodium edetate, and tetrasodium edetate, and mixtures thereof.

[0731] Any suitable preservative can be used. Examples of a preservative include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethoniumchloride, cetyl pyridinium chloride, benzyl bromide, phenylmercury nitrate, phenylmercury acetate, phenylmercury neodecanoate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl-p-hydroxybenzoate, and sorbic acid, and mixtures thereof.

[0732] In some embodiments, examples of a preservative include those selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetyl pyridinium chloride, benzyl bromide, phenylmercury nitrate, merthiolate, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl p-hydroxybenzoate, propylaminopropyl biguanide, and butyl-p-hydroxybenzoate, and sorbic acid, and mixtures thereof.

[0733] The aqueous vehicle may also include a tonicity agent to adjust the tonicity (osmotic pressure). The tonicity agent can be selected from the group consisting of a glycol (such as propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and a mixture thereof. In some embodiments, the tonicity agent is selected from the group consisting of a glycol (such as propylene glycol, triethylene glycol), glycerol, dextrose, glycerin, mannitol, potassium chloride, and sodium chloride, and a mixture thereof.

[0734] The aqueous vehicle may also contain a viscosity / suspending agent. Suitable viscosity / suspending agents include those selected from the group consisting of cellulose derivatives, such as methyl cellulose, ethyl cellulose, hydroxyethylcellulose, polyethylene glycols (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethyl cellulose, hydroxypropylmethyl cellulose, and cross-linked acrylic acid polymers (carbomers), such as polymers of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol (Carbopols - such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974 and Carbopol 974P), and a mixture thereof.

[0735] In order to adjust the formulation to an acceptable pH (typically a pH range of about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), the formulation may contain a pH modifying agent. The pH modifying agent istypically a mineral acid or metal hydroxide base, selected from the group of potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, and preferably sodium hydroxide and / or hydrochloric acid. These acidic and / or basic pH modifying agents are added to adjust the formulation to the target acceptable pH range. Hence it may not be necessary to use both acid and base - depending on the formulation, the addition of one of the acid or base may be sufficient to bring the mixture to the desired pH range.

[0736] The aqueous vehicle may also contain a buffering agent to stabilize the pH. When used, the buffer is selected from the group consisting of a phosphate buffer (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), a borate buffer (such as boric acid, or salts thereof including disodium tetraborate), a citrate buffer (such as citric acid, or salts thereof including sodium citrate), and s-aminocaproic acid, and mixtures thereof.

[0737] The formulation may further comprise a wetting agent. Suitable classes of wetting agents include those selected from the group consisting of polyoxypropylenepolyoxyethylene block copolymers (poloxamers), polyethoxylated ethers of castor oils, polyoxyethylenated sorbitan esters (polysorbates), polymers of oxyethylated octyl phenol (Tyloxapol), polyoxyl 40 stearate, fatty acid glycol esters, fatty acid glyceryl esters, sucrose fatty esters, and polyoxyethylene fatty esters, and mixtures thereof.

[0738] Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or com starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0739] According to a further aspect of the disclosure there is provided a pharmaceutical composition which comprises a compound of the disclosure as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.

[0740] In some embodiments, a pharmaceutical composition described herein may further comprise one or more additional pharmaceutically active agents.

[0741] The compositions of the disclosure may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).

[0742] The compositions of the disclosure may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and / or preservative agents.

[0743] A therapeutically effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat or prevent a CDK2 related condition referred to herein, slow its progression and / or reduce the symptoms associated with the condition.

[0744] A therapeutically effective amount of a compound of the present disclosure for use in therapy is an amount sufficient to treat an CDK2 related condition referred to herein, slow its progression and / or reduce the symptoms associated with the condition.

[0745] The size of the dose for therapeutic or prophylactic purposes of a compound of Formula (A), (I), (II), (III), (IV), (V) and / or (VI) will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or subject and the route of administration, according to well-known principles of medicine.Methods of Use

[0746] In some aspects, the present disclosure provides a method of inhibiting of CDK2 (e.g., in vitro or in vivo), comprising contacting a cell with a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof.

[0747] In some aspects, the present disclosure provides a method of treating or preventing a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0748] In some aspects, the present disclosure provides a method of treating a disease or disorder disclosed herein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0749] In some embodiments, the disease or disorder is associated with CDK2. In some embodiments, the disease or disorder is a disease or disorder in which CDK2 is implicated.

[0750] The compounds of the invention are also useful in treating diseases associated with CDK2. For example, diseases and conditions treatable according to the methods of the invention include Breast Cancer (BC); Colorectal Cancer (CRC); Lung Cancer (LNCR); Retinoblastoma (RBI); Pancreatic Cancer (PNCA); Prostate Cancer (PC); Ovarian Cancer (OC); Hepatocellular Carcinoma (HCC); Gastric Cancer (GASC); Bladder Cancer (BLC); Endometrial Cancer (ENDMC); Glioblastoma (GBM); Adenocarcinoma; Squamous Cell Carcinoma; Ataxia-Telangiectasia (AT).

[0751] The method of treatment comprises administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (A), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0752] In some embodiments, the method of treatment comprises administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0753] In some embodiments, the method of treatment comprises administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (II), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0754] In some embodiments, the method of treatment comprises administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (III), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0755] In some embodiments, the method of treatment comprises administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (IV), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0756] In some embodiments, the method of treatment comprises administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (V), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0757] In some embodiments, the method of treatment comprises administering to a patient suffering from at least one of said diseases or disorders a compound of Formula (VI), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0758] In some embodiments, the disease or disorder is Breast Cancer (BC).

[0759] In some embodiments, the disease or disorder is Colorectal Cancer (CRC).

[0760] In some embodiments, the disease or disorder is Lung Cancer (LNCR).

[0761] In some embodiments, the disease or disorder is Retinoblastoma (RBI).

[0762] In some embodiments, the disease or disorder is Pancreatic Cancer (PNCA).

[0763] In some embodiments, the disease or disorder is Prostate Cancer (PC).

[0764] In some embodiments, the disease or disorder is Ovarian Cancer (OC).

[0765] In some embodiments, the disease or disorder is Hepatocellular Carcinoma (HCC).

[0766] In some embodiments, the disease or disorder is Gastric Cancer (GASC).

[0767] In some embodiments, the disease or disorder is Bladder Cancer (BLC).

[0768] In some embodiments, the disease or disorder is Endometrial Cancer (ENDMC).

[0769] In some embodiments, the disease or disorder is Glioblastoma (GBM).

[0770] In some embodiments, the disease or disorder is Adenocarcinoma.

[0771] In some embodiments, the disease or disorder is Squamous Cell Carcinoma.

[0772] In some embodiments, the disease or disorder is Ataxia-Telangiectasia (AT).

[0773] In some aspects, the present disclosure provides a method of treating or preventing a cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0774] In some aspects, the present disclosure provides a method of treating a cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0775] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in inhibiting of CDK2 (e.g., in vitro or in vivo).

[0776] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing a disease or disorder disclosed herein.

[0777] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating a disease or disorder disclosed herein.

[0778] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating or preventing a cancer in a subject in need thereof.

[0779] In some aspects, the present disclosure provides a compound of the present disclosure or a pharmaceutically acceptable salt thereof for use in treating cancer in a subject in need thereof.

[0780] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting of CDK2 (e.g., in vitro or in vivo).

[0781] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing a disease or disorder disclosed herein.

[0782] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease or disorder disclosed herein.

[0783] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing cancer in a subject in need thereof.

[0784] In some aspects, the present disclosure provides use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer in a subject in need thereof.

[0785] The present disclosure provides compounds that function as inhibitors of CDK2 (e.g., in vitro or in vivo). The present disclosure therefore provides a method of inhibiting of CDK2 in vitro or in vivo, said method comprising contacting a cell with a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, as defined herein.

[0786] In some embodiments, the inhibitor of CDK2 is a compound of the present disclosure.

[0787] Effectiveness of compounds of the disclosure can be determined by industry- accepted assays / disease models according to standard practices of elucidating the same as described in the art and are found in the current general knowledge.

[0788] The present disclosure also provides a method of treating a disease or disorder in which CDK2 is implicated in a subject in need of such treatment, said method comprising administering to said subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

[0789] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.Routes of Administration

[0790] The compounds of the disclosure or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically / peripherally or topically (i.e., at the site of desired action).

[0791] Routes of administration include, but are not limited to, oral (e.g. by ingestion); buccal; sublingual; transdermal (including, e.g., by a patch, plaster, etc.); transmucosal (including, e.g., by a patch, plaster, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or insufflation therapy using, e.g., via an aerosol, e.g., through the mouth or nose); rectal (e.g., by suppository or enema); vaginal (e.g., by pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intra-arterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrastemal; by implant of a depot or reservoir, for example, subcutaneously or intramuscularly.EXAMPLESGeneral synthetical procedures and examples of the compound’s preparation.

[0792] All reagents were commercial and were used without further purification. Yields refer to purified and spectroscopically pure compounds. Thin layer chromatography (TLC) was performed using Merck TLC Aluminum sheets silica gel 60 F254 plates and visualized by fluorescence quenching under UV light. Flash chromatography was performed using silica gel (Chromatorex, MB 70-40 / 75, 40-75 pm) purchased by Fuji Silysia Chemicals. NMR spectra were recorded on a Varian-400MR operating at 400 MHz for1H. Chemical shifts are reported in ppm with the solvent resonance as the internal standard. Data is reported as follows: s = singlet, br. = broad, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublets; coupling constants in Hz; integration. The purities were recorded on Waters e2695 separations Module / 2998 PDA Detector HPLC system (Column: XBridge Cl 8, 5 pm, 4.6 mm (ID) x 150 mm (L), Eluent: the mixture of mobile phase A and B, mobile phase A: 100% acetonitrile; mobile phase B: pure water containing 0.1% formic acid and 10 mM NI LOAc, Flow rate: 0.5 mL / min. detection: UV, 254 nm)

[0793] Abbreviations used in the following examples and elsewhere herein are:AA acetic acidACN acetonitrileaq. aqueous anh. anhydrous br. broadBSA bovine serum albuminBTMA-ICk benzyltrimethylammonium di chloroiodide d dupletDCM dichloromethaneDIPA diisopropylamineDIPEA A,A-diisopropylethylamineDMAP dimethyl aminopyridineDMF A'r,Af-di methyl formamideDMSO dimethyl sulfoxideEA ethyl acetate eq equivalentFA formic acidFBS fetal bovine serum h hour(s)HPLC high pressure (or performance) liquid chromatographyLCMS liquid chromatography mass spectrometry m multiplet M molar MHz megahertz min minutes NBS A'-bromosuccinimide NMR nuclear magnetic resonance Pd?(dba),3 tris(dibenzylideneacetone)dipalladium(0)Pd(dppf)C12xDCM [1,1 '-Bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane q quadruplet rt room temperature s singlet s solid sat. saturated t temperature, tripletTEA tri ethylamineTHF tetrahydrofuranTLC thin layer chromatographySynthesis of Building BlocksSynthesis of 2-(2,3-dihydrobenzo[ / >][l,4]dioxin-6-yl)acetic acid (P3)P2 P3

[0794] Preparation 1. Methyl 2-(3,4-dihydroxyphenyl)acetate (Pl).To a solution of 2-(3,4-dihydroxyphenyl)acetic acid (25 g, 149 mmol, 1 eq) in MeOH (300 mL) sulfuric acid (14.6 g, 149 mmol, 1 eq) was added, and the mixture was heated under reflux for 24 h. The solvent was evaporated in vacuo, and sat. solution of NaHCCh (200 mL) was added to the mixture. The aq. layer was extracted with EA (3 x 150 mL), the organic layers were combined, dried over anh. Na2SC>4, filtered and concentrated in vacuo to give Pl (27 g, yield 97%).Analytical data: *HNMR (400 MHz, DMSO-rfc), 8: 8.81 (s, 2H), 6.65 (d, J = 8Hz, 2H), 6.48 (d, J = 8.4 Hz, 1H), 3.58 (s, 3H), 3.44 (s, 2H). LCMS (ESI): calc, for C9H10O4 182.18; found, 183.4 [M+H]+.

[0795] Preparation 2. Methyl 2-(2,3-dihydrobenzo[Z>][l,4]dioxin-6-yl)acetate (P2).To a solution of Pl (27 g, 148 mmol, 1 eq) in acetone (600 mL) K2CO3 (61.2 g, 444 mmol, 3 eq) and 1,2-dibromoethane (61.2 g, 326 mmol, 2.2 eq) were added. The reaction mixture was heated under reflux for 48 h. The reaction process was controlled by LCMS. After completion of the process K2CO3 (10.2 g, 74 mmol, 0.5 eq) and 1,2-dibromoethane (13.9 g, 74 mmol, 0.5 eq) were added, and the reaction mixture was heated under reflux for 24 h. Then the medium was filtered through a pad of Celite, the filtrate was concentrated in vacuo. The crude product was purified by flash chromatography (DCM as an eluent) to give P2 (26.6 g, yield 86%).Analytical data: 'H NMR (400 MHz, DMSO-dg), 8: 6.78 (d, J= 8Hz, 1H), 6.75 (s, 1H), 6.69 (d, J = 8.4Hz, 1H), 4.21 (s, 4H), 3.59 (s, 3H), 3.53 (s, 2H). LCMS (ESI): calc, for C11H12O4208.22; found, 209.4 [M+H]+.

[0796] Preparation 3. 2-(2,3-Dihydrobenzo[Z>][l,4]dioxin-6-yl)acetic acid (P3).To a solution of P2 (26.6 g, 128 mmol, 1 eq) in THF (300 mL) 2 N solution of LiOH (10.7 g, 256 mmol, 2 eq) in water (223 mL) was added. The reaction mixture was stirred at rt for 12 h and then concentrated in vacuo to remove THF. The aq. solution was then acidified until pH 2 by addition of 1 M aq. solution of KHSO4. The resulting mixture was extracted with EA (3 x 300 mL), and the combined organic layers were washed with brine, dried over anh. Na2SC>4, filtered and concentrated in vacuo to give P3 (24.4 g, yield 92%).Analytical data: 'H NMR (400 MHz, DMSO-tL), 8: 12.77 (s, 1H), 6.78 (d, J = 8.8Hz, 1H), 6.74 (s, 1H), 6.68 (d, J = 8Hz, 1H), 4.19 (s, 4H), 3.42 (s, 2H). LCMS (ESI): calc, for C10H10O4 194.19; found, 195.6 [M+H]+.Synthesis of 6-bromo-17 / -indazol-3 -amine (P4).

[0797] Preparation 4. 6-Bromo-l / / -indazol-3-amine (P4).To a solution of 4-bromo-2-fluorobenzonitrile (15 g, 76 mmol, 1 eq) in EtOH (100 mL) hydrazine hydrate (11 g, 277 mmol, 3.6 eq) was added. The reaction mixture was heated under reflux for 12 h, cooled to rt and filtered. The formed precipitate was washed with hexane and dried to give P4 (8.1 g, yield 54%).Analytical data:NMR (400 MHz, DMSO-de), 8: 11.50 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.42 (s, 1H), 7.02 (d, J = 8.8Hz, 1H), 5.44 (s, 2H). LCMS (ESI): calc, for C7H6BrN3 212.05; found, 213.3 [M+H]+.Synthesis of 7V-(6-bromo-l-(2-(2,3-dihydrobenzo[ / >][l,4]dioxin-6-yl)acetyl)-4-fluoro-l / / - indazol-3-yl)-2-(2,3-dihydrobenzo[ / >][l,4]dioxin-6-yl)acetamide (P6)

[0798] Preparation 5. 6-Bromo-4-fluoro-l / / -indazol-3-amine (P5).A mixture of 4-bromo-2,6-difluorobenzonitrile (1 g, 4.59 mmol, 1 eq) and hydrazine hydrate (688 mg, 13.77 mmol, 3 eq) in w-BuOH (30 mL) was heated under reflux for 24 h. The reaction mixture was then diluted with water (20 mL) and extracted with EA (3 x 40 mL). The organic layers were combined, dried over anh. Na2SO4, filtered and concentrated in vacuo. The title compound was purified by silica gel column chromatography (9: 1 EA / MeOH as an eluent) to give P5 as a white solid (790 mg, yield 75%).Analytical data: *H NMR (400 MHz, DMSO-cL), 5: 11.81 (s, 1H), 7.27 (d, J = 1.3 Hz, 1H), 6.84 (d, J= 9.9 Hz, 1H), 5.22 (br. s, 2H).

[0799] Preparation 6. A-(6-Bromo-l-(2-(2,3-dihydrobenzo[Z>][l,4]dioxin-6-yl)acetyl)-4- fluoro-l / / -indazol-3-yl)-2-(2,3-dihydrobenzo[Z>][l,4]dioxin-6-yl)acetamide (P6).To a solution of acid P3 (500 mg, 2 mmol, 2 eq) in pyridine (5 mL) within a 10 mL screwtop vial P5 (230 mg, 1 mmol, 1 eq) was added, followed by DIPEA (900 pL, 6 mmol, 6 eq) and TBTU (1002 mg, 3 mmol, 3 eq) at rt. The reaction mixture was stirred overnight at room temperature, then diluted with water (50 mL) and extracted with EA (3 x 50 ml). The organic layers were combined, washed with water and brine, dried over anh. Na2SC>4 and concentrated in vacuo. The crude product was purified by silica gel column chromatography (EA as an eluent) to give P6 (600 mg, yield 87%).Synthesis of 7-Bromo-4-fluoro-l / / -indazol-3-amine (P7)

[0800] Preparation 7. A mixture of 3-bromo-2,6-difluorobenzonitrile (500 mg, 2.29 mmol, 1 eq) and hydrazine hydrate (344 mg, 6.6 mmol, 3 eq) in w-BuOH (20 mL) was heated under reflux for 24 h. The reaction mixture was then diluted with water (20 mL) and extracted with EA (3 x 40 mL). The organic layers were combined, dried over anh. Na2SC>4, fdtered and concentrated in vacuo. The title compound was purified by silica gel column chromatography (9: 1 EA / MeOH as an eluent) to give P7 as a white solid (240 mg, yield 48%).Analytical data: *HNMR (400 MHz, DMSO-t / e), 8: 9.09 (br. s, 1H), 7.36(dd, J = 8.2, 4.2 Hz, 1H), 6.58 (dd, J = 9.9, 8.23 Hz, 1H), 4.36 (br. s, 2H).Synthesis of 2-(2,3 -dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)-A-(l -(2-(2,3 - dihydrobenzo[6][l,4]dioxin-6-yl)acetyl)-4,6-difluoro-177-indazol-3-yl)acetamide (P9)

[0801] Preparation 8. 4,6-Difluoro-ll / -indazol-3-amine (P8).A mixture of 2,4,6-trifluorobenzonitrile P8 (1 g, 6.37 mmol, 1 eq) and hydrazine hydrate (640 mg, 12.7 mmol, 2 eq) in w-BuOH (20 mL) was heated under reflux for 24 h. Thereaction mixture was then diluted with water (20 mL) and extracted with EA (3 x 40 mL). The organic layers were combined, dried over anh. Na2SC>4, fdtered and concentrated in vacuo. The title compound was purified by silica gel column chromatography (9: 1 EA / MeOH as an eluent) to give P8 as a white solid (460 mg, yield 42%).Analytical data: 'H NMR (400 MHz, DMSO-^e), 8: 11.75 (s, 1H), 6,84 (dd, J = 9.6, 2.1 Hz, 1H), 6.63 (t, J = 10.1 Hz, 1H), 5.18 (br. s, 2H).

[0802] Preparation 9. 2-(2,3-Dihydrobenzo[ / >][l,4]dioxin-6-yl)-A-(l-(2-(2,3- dihydrobenzo[6][l,4]dioxin-6-yl)acetyl)-4,6-difluoro-17 / -indazol-3-yl)acetamide (P9).To a solution of acid P3 (600 mg, 2.36 mmol, 1.83 eq) in pyridine (5 mL) within a 10 mL screw-top vial P8 (200 mg, 1.29 mmol, 1 eq) was added, followed by TEA (600 pL, 3.57 mmol, 2.77 eq) and TBTU (1140 mg, 3.64 mmol, 2,82 eq) at rt. The mixture was stirred at rt overnight. The resulting mixture was then diluted with water (50 mL) and extracted with EA (3 x 50 mL). The organic layers were combined and washed with water and brine, dried over anh. Na2SC>4, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (EA as an eluent) to give P9 (560 mg, yield 88%).Synthesis of A-[6-cyclopropyl- 1 -[2-(2, 3 -dihydro- 1 ,4-benzodioxin-6- yl)acetyl]pyrazolo[4,3-c]pyridin-3-yl]-2-(2,3-dihydro-l,4-benzodioxin-6-yl)acetamide (P12)

[0803] Preparation 10. 4-Chloro-6-cyclopropyl-pyridine-3-carbonitrile (PIO).A suspension of 4,6-dichloropyridine-3-carbonitrile (1 g, 5.78 mmol, 1 eq), cyclopropyl boronic acid (500 mg, 5.78 mmol, 1 eq), CS2CO3 (3.77 g, 11.6 mmol, 2 eq) and bis(triphenylphosphine) palladium(II)dichloride (405 mg, 0.58 mmol, 0.1 eq) in dry dioxane (30 mb) was heated under reflux for 16 h. Then the reaction mixture was cooled to rt, dioxane was removed in vacuo. The residue was dissolved in EA, washed with brine, the organic layer was dried over anh. Na?SO4 and filtered. All volatiles were removed in vacuo, and the crude product was purified by silica gel column chromatography (10: 1 hexane / EA as an eluent) to give P10 (320 mg, yield 30%).Analytical data: ' H NMR (400 MHz, CDCI3), 5: 8.62 (s, 1H), 7.32 (s, 1H), 2.04 (m, 1H), 1.15 (m, 4H).

[0804] Preparation 11. 6-Cyclopropyl-17 / -pyrazolo[4,3-c]pyridin-3 -amine (PH).A mixture of PIO (320 mg, 1.79 mmol, 1 eq) and hydrazine hydrate (900 mg, 17.9 mmol, 10 eq) in «-BuOH (7 mL) was heated to 90°C under stirring for 5 h. The reaction mixture was then cooled to rt, all volatiles were removed in vacuo, and the residue was triturated in ACN (20 mL) to give Pll (110 mg, yield 35%).Analytical data: *H NMR (400 MHz, DMSO-^), 8: 12.69 (br. s, 1H), 9.15 (s, 1H), 6.37 (br. s, 2H), 2.31 (m, 1H), 1.55 - 0.13 (m, 4H).

[0805] Preparation 12. A-[6-Cyclopropyl-l-[2-(2,3-dihydro-l,4-benzodioxin-6- yl)acetyl]pyrazolo[4,3-c]pyridin-3-yl]-2-(2,3-dihydro-l,4-benzodioxin-6-yl)acetamide(P12).To a solution of acid P3 (123 mg, 0.64 mmol, 2 eq) in dry DMA (3 mL) within a 10 mL screw-top vial Pll (55 mg, 0.32 mmol, 1 eq) was added, followed by DIPEA (170 pL, 0.96 mmol, 3 eq) and TBTU (250 mg, 0.78 mmol, 2,5 eq) at rt. The reaction mixture was stirred overnight at rt. The resulting mixture was then diluted with EA (3 x 50 mL). The organic layer was washed with brine and sat. solution of Nal ICO3 in water. Combined organic layers were dried over anh. Na2SC>4, filtered and concentrated in vacuo. The title compound Pll (200 mg, yield 120%) was used in the next step without purification.Synthesis of 4-m ethyl- l / 7-indazol-3 -amine (P13)

[0806] Preparation 13. 4-Methyl-l / 7-indazol-3 -amine (P13).A mixture of 2-fluoro-6-methylbenzonitrile (500 mg, 3.7 mmol, 1 eq) and hydrazine hydrate (555 mg, 11.1 mmol, 3 eq) in n-BuOH (20 mL) was heated under reflux for 24 h. The reaction mixture was then diluted with water (20 mL) and extracted with EA (3 x 40 mL). The organic layers were combined, dried over anh. Na2SC>4, filtered and concentrated in vacuo. The title compound was purified by silica gel column chromatography (9: 1 EA / MeOH as an eluent) to give P13 as a white solid (196 mg, yield 36%).Analytical data: 'H NMR (400 MHz, DMSO-^), 8: 11.20 (s, 1H), 7.28 (d, J = 8.3 Hz, 1H), 7.03-7.00 (m, 1H), 6.57 (d, J = 8.3 Hz, 1H), 4.79 (s, 2H), 2.47 (s, 3H).Synthesis of 6-cyclopropyl-l / / -indazol-3 -amine (P15)

[0807] Preparation 14. 4-Cyclopropyl-2-fluorobenzonitrile (P14).To a solution of 4-bromo-2 -fluorobenzonitrile (500 mg, 2.5 mmol, 1 eq) in dioxane (3 mL) in 10 mL vial, cyclopropyl boronic acid (258 mg, 3 mmol, 1.2 eq), tetrakis(triphenylphosphine)palladium(0) (57 mg, 0.05 mmol, 0.02 eq) and CS2CO3 (1625 mg, 5 mmol, 2 eq) were added. The vial was purged with nitrogen, sealed and heated to 100°C under stirring for 4 h. The reaction mixture was diluted with EA (40 mL) and washed with water (2 x 5 mL). The organic layer was dried over anh. Na2SC>4, filtered and concentrated in vacuo. The crude 4-cyclopropyl-2-fluorobenzonitrile P14 (400 mg, yield 99%) was used in the next step without purification.

[0808] Preparation 15. 6-Cyclopropyl-l / / -indazol-3 -amine (Pl 5).A mixture of P14 (400 mg, 2.5 mmol, 1 eq) and hydrazine hydrate (375 mg, 7.5 mmol, 3 eq) in w-BuOH (20 mL) was heated under reflux for 24 h. The reaction mixture was then diluted with water (20 mL) and extracted with EA (3 x 40 mL). The organic layers were combined, dried over anh. Na?SO4, filtered and concentrated in vacuo. The title compound was purified by silica gel column chromatography (9: 1 EA / MeOH as an eluent) to give P15 as a white solid (209 mg, yield 48%).Analytical data: 'l l NMR (400 MHz, DMSO-tffc), 8: 11.05 (s, 1H), 7.53 (d, J = 8.3 Hz, 1H), 6.90 (s, 1H), 6.62 (d, J = 8.3 Hz, 1H), 5.11 (s, 2H), 2.00-1.96 (m, 1H), 0.97-0.92 (m, 2H), 0.70-0.66 (m, 2H).Synthesis of 2-(2,3-dihydrobenzo[Z>][l,4]dioxin-6-yl)-A-(l-(2-(2,3- dihydrobenzo[Z>] [ 1 ,4]dioxin-6-yl)acetyl)-4-(l / / -pyrazol- 1 -yl)- l / / -indazol-3 -yl)acetamide (P18)

[0809] Preparation 16. 2-Fluoro-6-(177-pyrazol-l-yl)benzonitrile (P16).A mixture of 2,6-difluorobenzonitrile (2 g, 14.4 mmol, 1 eq), pyrazole (980 mg, 14.4 mmol, 1 eq) and K2C 0.3(2 g, 15 mmol, 1,04 eq) inDMF (20 mL) was heated to 70°C under stirring for 2 h. The reaction mixture was diluted with water (20 mL) and extracted with EA (3 x 40 mL). The organic layers were combined, dried over anh. Na?SO4 and concentrated in vacuo. The crude product was purified by silica gel column chromatography (1:3 EA / hexane as an eluent) to give P16 (101 mg, yield 74%) as a white solid.Analytical data: ' H NMR (400 MHz, DMSO-cL), 8: 8.17 (d, J=3.2 Hz, 1H), 7.82 (d, J = 1.71 Hz, 1H), 7.71-7.65 (m, 1H), 7.63-7.61 (m, 1H), 7.19 (td, J = 7.0, 1.3 Hz, 1H), 6.56 (dd, J = 2.6, 1.7 Hz, 1H).

[0810] Preparation 17. 4-(l / 7-Pyrazol-l-yl)-l / / -indazol-3-amine (P17).A mixture of P16 (500 mg, 2.67 mmol, 1 eq) and hydrazine hydrate (534 mg, 10.68 mmol, 4 eq) in / / -BuOH (20 mL) was heated under reflux for 24 h. The reaction mixture was then diluted with water (20 mL) and extracted with EA (3 x 40 mL). The organic layers werecombined, dried over anh. Na2SC>4, filtered and concentrated in vacuo. The title compound was purified by silica gel column chromatography (9:1 EA / MeOH as an eluent) to give P17 as a white solid (501 mg, yield 94%).Analytical data: 'H NMR (400 MHz, DMSO-^e), 5: 9.16 (br. s, 1H), 7.95 (d, J = 2.5 Hz, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.33 (t, J = 9.0 Hz, 1H), 7.27-7.24 (m, 2H), 6.99 (d, J = 8.0 Hz, 1H), 6.52 (t, J = 2.4 Hz, 1H), 5.52 (br. s, 2H).

[0811] Preparation 18. 2-(2,3-Dihydrobenzo[ / >][l,4]dioxin-6-yl)-A-(l-(2-(2,3- dihydrobenzo[ / >][l,4]dioxin-6-yl)acetyl)-4-(l / 7-pyrazol-l-yl)-l / / -indazol-3-yl)acetamide (P18)To a solution of acid P3 (500 mg, 2.60 mmol, 2 eq) in pyridine (5 mb) within a 10 mb screw-top vial P17 (256 mg, 1.29 mmol, 1 eq) was added, followed by DIPEA (670 pL, 3.87 mmol, 3 eq) and TBTU (900 mg, 2.80 mmol, 2.17 eq) at rt. The reaction mixture was stirred overnight at rt. The resulting mixture was then diluted with water (50 mb) and extracted with EA (3 x 50 mb). The organic layers were combined and washed with water and brine, dried over anh. Na2SC>4, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (EA as an eluent) to give P18 (110 mg, yield 15%).Synthesis of 2-(2,3-dihydrobenzo[Z>][l,4]dioxin-6-yl)-A-(l-(2-(2,3- dihydrobenzo[ / >][l,4]dioxin-6-yl)acetyl)-5-(pyridin-3-yl)-l / 7-indazol-3-yl)acetamide(P21)

[0812] Preparation 19. 2-Fluoro-5-(pyridin-3-yl)benzonitrile (P19).To a solution of 5-bromo-2-fluorobenzonitrile (400 mg, 2 mmol, 1 eq) in 3 mL of dioxane in 10 mL vial 3-pyridine boronic acid (250 mg, 2.2 mmol, 1.1 eq), tetrakis(triphenylphosphine)palladium(0) (57 mg, 0.05 mmol, 0.025 eq) and 2 M solution of K2CO3 (552 mg, 4 mmol, 2 eq) in water (2 mL) were added. The vial was purged with nitrogen, sealed and heated to 100°C under stirring for 4 h. The reaction mixture was diluted with EA (40 mL) and washed with water (2 x 5 mL). The organic layer was dried over anh. Na2SC>4, filtered and concentrated in vacuo. The crude product P19 (394 mg, yield 99%) was used in the next step without purification.

[0813] Preparation 20. 5-(Pyridin-2-yl)-177-indazol-3-amine (P20).A mixture of P19 (390 mg, 2 mmol, 1 eq) and hydrazine hydrate (300 mg, 6 mmol, 3 eq) in / 7-BUOH (30 mL) was heated under reflux for 24 h. The reaction mixture was then diluted with water (20 mL) and extracted with EA (3 x 40 mL). The organic layers were combined, dried over anh. Na2SC>4, filtered and concentrated in vacuo. The crude product was purifiedby silica gel column chromatography (9: 1 EA / MeOH as an eluent) to give P20 as a white solid (270 mg, yield 64%).Analytical data: ’H NMR (400 MHz, DMSO-^), 5: (d, J = 7.8 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.47-7.46 (m, 1H), 7.35 (d, J = 8.6 Hz, 1H), 5.35 (br. s, 2H).

[0814] Preparation 21. 2-(2,3-Dihydrobenzo[Z>][l,4]dioxin-6-yl)-A-(l-(2-(2,3- dihydrobenzo[Z>][l,4]dioxin-6-yl)acetyl)-5-(pyridin-3-yl)-177-indazol-3-yl)acetamide (P21).To a solution of acid P3 (308 mg, 1.24 mmol, 2 eq) in pyridine (5 mL) within a 10 mL screw-top vial P20 (130 mg, 0.62 mmol, 1 eq) was added, followed by DIPEA (600 pL, 3.57 mmol, 5.76 eq) and TBTU (597 mg, 1 .86 mmol, 3 eq) at rt. The reaction mixture was stirred overnight at rt. The resulting mixture was then diluted with water (50 mL) and extracted with EA (3 x 50 mL). The organic layers were combined and washed with water and brine, dried over anh. Na2SC>4, filtered and concentrated in vacuo. The title compound was purified by silica gel column chromatography (EA as an eluent) to give P21 (115 mg, yield 42%).Synthesis of 6-phenyl-l / f-indazol-3-amine (P23)P22 P23

[0815] Preparation 22. 3-Fluoro-[l,l'-biphenyl]-4-carbonitrile (P22).To a solution of 4-bromo-2-fluorobenzonitrile (200 mg, 1 mmol, 1 eq) in dioxane (3 mL) in 10 mL vial phenyl boronic acid (146 mg, 1.2 mmol, 1.2 eq), tetrakis(triphenylphosphine)palladium(0) (57 mg, 0.05 mmol, 0.05 eq) and the solution of K2CO3 (276 mg, 2 mmol, 2 eq) in water (1 mL) were added. The vial was purged with nitrogen, sealed and heated to 100°C under stirring for 4 h. The reaction mixture was diluted with EA (40 mL) and washed with water (2 x 5 mL). The organic layer was dried over anh. Na2SC>4 and concentrated in vacuo. The crude product P22 (197 mg, yield 99%) was used in the next step without purification.

[0816] Preparation 23. 6-Phenyl-l / / -indazol-3 -amine (P23).A mixture of P22 (197 mg, 1 mmol, 1 eq) and hydrazine hydrate (150 mg, 3 mmol, 3 eq) in w-BuOH (20 mL) was heated under reflux for 24 h. The reaction mixture was then diluted with water (20 mL) and extracted with EA (3 x 40 mL). The organic layers were combined, dried over anh. Na2SC>4, filtered and concentrated in vacuo. The title compound was purified by silica gel column chromatography (9: 1 EA / MeOH as an eluent) to give P23 as a white solid (110 mg, yield 55%).Analytical data: ’H NMR (400 MHz, DMSO-<A), 8: 11.40 (s, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 7.8 Hz, 2H), 7.47 (t, J = 7.8 Hz, 2H), 7.41 (d, J = 0.5 Hz, 1H), 7.36 (dd, J = 8.4, 1.3 Hz, 1H), 5.33 (s, 2H).Synthesis of 2-(2,3-dihydrobenzo[Z>][l,4]dioxin-6-yl)-A-(l-(2-(2,3- dihydrobenzo[Z>][l,4]dioxin-6-yl)acetyl)-5-(5-fluoropyridin-3-yl)-17 / -indazol-3- yl)acetamide (P26)

[0817] Preparation 24. 2-Fluoro-5-(5-fluoropyridin-3-yl) benzonitrile (P24).To a solution of 3-cyano-4-fluorophenyl)boronic acid (402 mg, 2 mmol, 1 eq) in dioxane (3 mL) in 10 mL vial 3-bromo-5-fluoropyridine (352 mg, 2 mmol, 1 eq), tetrakis(triphenylphosphine)palladium(0) (57 mg, 0.05 mmol, 0.025 eq) and 2 M solution of K2CO3 (552 mg, 4 mmol, 2 eq) in water (2 mL) were added. The vial was purged with nitrogen, sealed and heated to 100°C under stirring for 4 h. The reaction mixture was diluted with EA (40 mL) and washed with water (2 x 5 mL). The organic layer was dried over anh. Na2SO4, filtered and concentrated in vacuo. The crude product P24 (432 mg, yield 99%) was used in the next step without purification.

[0818] Preparation 25. 5-(5-Fluoropyridin-3-yl)-l / 7-indazol-3-amine (P25).A mixture of P24 (432 mg, 2 mmol, 1 eq) and hydrazine hydrate (300 mg, 6 mmol, 3 eq) in «-BuOH (30 mL) was heated under reflux for 24 h. The reaction mixture was then diluted with water (20 mL) and extracted with EA (3 x 40 mL). The organic layers were combined, dried over anh. Na2SC>4, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (9: 1 EA / MeOH as an eluent) to give P25 as a white solid (190 mg, yield 42%).Analytical data: *HNMR (400 MHz, DMSO-de), 5: 11.47 (s, 1H), 8.78 (s, 1H), 8.47-8.46 (m, 1H), 8.17 (s, 1H), 7.95-7.91 (m, 1H), 7.64 (dt, J = 8.7, 1.4 Hz, 1H), 7.34 (d, J = 10.2 Hz, 1H), 5.34 (br. s, 2H).

[0819] Preparation 26. 2-(2,3-Dihydrobenzo[Z>][l,4]dioxin-6-yl)-A-(l-(2-(2,3- dihydrobenzo[ / >][l,4]dioxin-6-yl)acetyl)-5-(5-fluoropyridin-3-yl)-177-indazol-3- yl)acetamide (P26).To a solution of acid P3 (215 mg, 0.88 mmol, 2 eq) in pyridine (5 mL) within a 10 mL screw-top vial P25 (100 mg, 0.44 mmol, 1 eq) was added, followed by DIPEA (310 pL, 1.76 mmol, 4 eq) and TBTU (357 mg, 1.1 mmol, 2.5 eq) at rt. The reaction mixture was stirred overnight at rt. The resulting mixture was then diluted with water (50 mL) and extracted with EA (3 x 50 mL). The organic layers were combined and washed with water and brine, dried over anh. Na2SC>4, filtered and concentrated in vacuo. The crude product P26 was used in the next step without purification.Synthesis of 5-(6-morpholino-3-pyridyl)-l / 7-indazol-3-amine (P28)

[0820] Preparation 27. 2-Fluoro-5-(6-morpholino-3-pyridyl)benzonitrile (P27).A mixture of 4-(5-bromo-2-pyridyl)morpholine (570 mg, 2.3 mmol, 1.1 eq), (3-cyano-4- fluoro-phenyl)boronic acid (350 mg, 2.1 mmol, 1 eq), K2CO3 (585 mg, 4.2 mmol, 2 eq) and tetrakis(triphenylphosphine)palladium(0) (122 mg, 0.1 mmol, 0.05 eq) were stirred at 85°C in a mixture of dioxane / water = 10 / 1 (8 mb) for 16 h. All volatiles were removed in vacuo, the crude product was purified by silica gel column chromatography (1 / 1 hexane / EA as an eluent) to give P27 (462 mg, yield 77%).Analytical data: 'H NMR (400 MHz, DMSO-de), 8: 8.47 (dd, J = 2.6, 0.8 Hz, 1H), 8.15 (dd, J = 6.1, 2.4 Hz, 1H), 8.00 (ddd, J = 8.9, 5.2, 2.5 Hz, 1H), 7.90 (dd, J = 8.9, 2.7 Hz, 1H), 7.52 (t, J = 9.1 Hz, 1H), 6.88 (dd, J = 8.9, 0.8 Hz, 1H), 3.71 - 3.62 (m, 4H), 3.52 - 3.45 (m, 4H).

[0821] Preparation 28. 5-(6-Morpholino-3-pyridyl)-l / / -indazol-3-amine (P28).A mixture of P27 (462 mg, 1.74 mmol, 1 eq) and hydrazine hydrate (0.85 mL, 17.4 mmol, 10 eq) in w-BuOH (10 mL) was heated to 90°C under stirring for 3 h in a closed vial. Then the reaction mixture was cooled to rt, the formed precipitate was collected on fdter, washed with ether and dried at 60°C to provide P28 (314 mg, yield 65.5%).Analytical data:XH NMR (400 MHz, DMSO-^), 8: 8.41 (d, J = 2.5 Hz, 1H), 7.89 (dd, J = 1.9, 0.8 Hz, 1H), 7.81 (dd, J = 8.8, 2.6 Hz, 1H), 7.46 (dd, J = 8.7, 1.8 Hz, 1H), 7.25 (dd, J = 8.6, 0.7 Hz, 1H), 6.88 (dd, J = 8.8, 0.8 Hz, 1H), 5.25 (s, 2H), 3.73 - 3.66 (m, 4H), 3.48 - 3.41 (m, 4H).Synthesis of 5-[6-(l-piperidyl)-3-pyridyl]-l / / -indazol-3-amine (P30)

[0822] Preparation 29. 2-Fluoro-5-[6-(l-piperidyl)-3-pyridyl]benzonitrile (P29).The mixture of 5-bromo-2-(l-piperidyl)pyridine (650 mg, 2.7 mmol, 1.1 eq), (3-cyano-4- fluorophenyl)boronic acid (410 mg, 2.7 mmol, 1 eq), K2CO3 (750 mg, 5.43 mmol, 2 eq) and tetrakis(triphenylphosphine)palladium(0) (145 mg, 0.125 mmol, 0.05 eq) were stirred at 85°C in dioxane / water 10 / 1 (8 mL) for 16 h. All volatiles were removed in vacuo, the crude product was purified by silica gel column chromatography (DCM as an eluent) to give P29 (575 mg, yield 82%).Analytical data: 'HNMR (400 MHz, DMSO4), 8: 8.46 (d, 1H), 8.14 (dd, 1H), 8.00 (ddd, 1H), 7.86 (dd, 1H), 7.53 (t, 1H), 6.87 (dd, 1H), 3.62 - 3.55 (m, 4H), 1.59 (m, 6H).

[0823] Preparation 30. 5-[6-(l-Piperidyl)-3-pyridyl]-lZ / -indazol-3-amine (P30).A mixture of P29 (570 mg, 2.03 mmol, 1 eq) and hydrazine hydrate 4 (1.3 g, 20.3 mmol, 10 eq) in w-BuOH (10 mL) was heated to 90°C under stirring for 5 h in a closed vial. Then the reaction mixture was cooled to rt, the formed precipitate was collected on filter, washed with Et2O and dried at 60°C to provide 30 (393 mg, yield 66%).Analytical data: 'l l NMR (400 MHz, DMSO-cL), 8: 11.29 (s, 1H), 8.40 (d, 1H), 7.99 - 7.85 (m, 1H), 7.78 (dd, 1H), 7.48 (dd, 1H), 7.28 (d, 1H), 6.88 (d, 1H), 5.26 (s, 2H), 3.55 (t, 4H), 1.61 (m, 6H).Synthesis of 5-[6-(4-methylpiperazin-l-yl)-3-pyridyl]-17 / -indazol-3-amine (P32)

[0824] Preparation 31. 2-Fluoro-5-[6-(4-methylpiperazin-l-yl)-3-pyridyl]benzonitrile(P31)The mixture of l-(5-bromopyridin-2-yl)-4-methylpiperazine (545 mg, 2.1 mmol, 1.1 eq), 3-cyano-4-fluorophenyl)boronic acid (312 mg, 1.9 mmol, 1 eq), K2CO3 (587 mg, 3.8 mmol, 2 eq) and tetrakis(triphenylphosphine)palladium(0) (123 mg, 0.1 mmol, 0.05 eq) were stirred at 85°C in a mixture of solvents dioxane / water 10 / 1 (8 mL) for 16 h. All volatiles were removed in vacuo, the crude product was purified by silica gel column chromatography (EA with 5 >10% MeOH as an eluent) to give P31 (510 mg, yield 89%). Analytical data: 'H NMR (400 MHz, DMSO-tL), 5: 8.44 (d, J = 2.7 Hz, 1H), 8.13 (ddd, J = 6.2, 2.5, 1.1 Hz, 1H), 7.98 (dddd, J = 8.9, 5.2, 2.6, 1.2 Hz, 1H), 7.86 (ddd, J = 9.0, 2.7, 1.2 Hz, 1H), 7.53 - 7.46 (m, 1H), 6.87 (d, J = 9.0 Hz, 1H), 3.52 (t, J = 5.1 Hz, 4H), 2.36 (t, J = 5.1 Hz, 4H), 2.25 - 2.10 (m, 3H).

[0825] Preparation 32. 5-[6-(4-Methylpiperazin-l-yl)-3-pyridyl]-U / -indazol-3-amine (P32).A mixture of P31 (510 mg, 1.72 mmol, 1 eq) and hydrazine hydrate (0.83 mL, 17.2 mmol, 10 eq) in M-BUOH (10 mL) was heated to 90°C under stirring for 3 h in a closed vial. Then the reaction mixture was cooled to rt, the formed precipitate was collected on fdter, washed with Et2O and dried at 60°C to provide P32 (244 mg, yield 46%).Analytical data: 'H NMR (400 MHz, DMSO-^), 5: 8.38 (d, J = 2.5 Hz, 1H), 7.91 - 7.86 (m, 1H), 7.77 (dd, J = 8.9, 2.6 Hz, 1H), 7.45 (dd, J = 8.7, 1.7 Hz, 1H), 7.24 (d, J = 8.6 Hz,1H), 6.89 (d, J = 8.9 Hz, 1H), 5.33 (s, 2H), 3.51 - 3.44 (m, 4H), 2.41 - 2.34 (m, 4H), 2.19 (s, 3H).Synthesis of 5-[6-(4-isopropylpiperazin-l-yl)-3-pyridyl]-17 / -indazol-3-amine (P34)

[0826] Preparation 33. 2-Fluoro-5-[6-(4-isopropylpiperazin-l-yl)-3-pyridyl]benzonitrile (P33).The mixture of l-(5-bromopyri din-2 -yl)-4-isopropylpiperazine (545 mg, 1.92 mmol, 1.1 eq), 3-cyano-4-fluorophenyl)boronic acid (290 mg, 1.76 mmol, 1 eq), K2CO3 (485 mg, 3.52 mmol, 2 eq) and tetrakis(triphenylphosphine)palladium(0) (100 mg, 0.088 mmol, 0.05 eq) was stirred at 85°C in dioxane / water 10 / 1 (8 mL) for 16 h. All volatiles were removed in vacuo, the residue was dissolved in EA, the formed precipitate was filtered and discarded. The filtrate was concentrated in vacuo, the crude product was purified by silicagel column chromatography (EA to EA / MeOH 10 / 1 as an eluent) to give P33 (547 mg, yield 96%).Analytical data: *H NMR (400 MHz, DMSO-tfc), 5: 8.48 (d, 1H), 8.33 - 8.12 (m, 1H), 8.02 (m, 1H), 7.89 (dd, 1H), 7.67 - 7.48 (m, 3H), 6.89 (d, 1H), 3.58 - 3.51 (m, 4H), 2.69 (m, 1H), 2.56 - 2.52 (m, 4H), 1.01 (d, 6H).

[0827] Preparation 34. 5-[6-(4-Isopropylpiperazin-l-yl)-3-pyridyl]-l / 7-indazol-3-amine (P34).A mixture of P33 (540 mg, 1.67 mmol, 1 eq) and hydrazine hydrate (1050 mg, 16.7 mmol, 10 eq) was heated to 90°C under stirring for 8 h in a closed vial. All volatiles were removed in vacuo, the residue was triturated in Et2O and dried at 60°C to provide P34 (313 mg, yield 56%).Analytical data: *H NMR (400 MHz, DMSO-^), 5: 11.30 (s, 1H), 8.41 (s, 1H), 7.91 (s, 1H), 7.80 (dd, 1H), 7.48 (dd, 1H), 7.28 (d, 1H), 6.89 (d, 1H), 5.26 (s, 2H), 3.50 (m, 4H), 2.70 (m, 1H), 2.55 (m, 4H), 1.02 (d, 6H).Synthesis of / V-(6-acetamido-l-(2-(2,3-dihydrobenzo[Z>][l,4]dioxin-6-yl)acetyl)-177- indazol-3-yl)-2-(2,3-dihydrobenzo[Z>][l,4]dioxin-6-yl)acetamide (P38)

[0828] Preparation 35. 6-Nitro-l / / -indazol-3-amine (P35).To a solution of 2-fluoro-4-nitrobenzonitrile (3 g, 18 mmol, 1 eq) in EtOH (100 mL) hydrazine hydrate (2.7 g, 54 mmol, 3 eq) was added. The reaction mixture was heated under reflux for 12 h. Then the mixture was cooled to rt and filtered, the formed precipitate was washed with hexane and dried to give P35 (2.4 g, yield 73%).Analytical data: 'H NMR (400 MHz, DMSO-t / e), 5: 12.10 (s, 1H), 8.12 (s, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 5.71 (s, 2H). LCMS (ESI): calc, for C7H6N4O2 178.14; found, 179.6 [M + H]+.

[0829] Preparation 36. 2-(2,3-Dihydrobenzo[Z>][l,4]dioxin-6-yl)-JV-(l-(2-(2,3- dihydrobenzo[ / >][l,4]dioxin-6-yl)acetyl)-6-nitro-177-indazol-3-yl)acetamide (P36).To a solution of P35 (1.33 g, 7.5 mmol, 1 eq) in dioxane (20 mL) DIPEA (2.9 g, 22.5 mmol, 3 eq), POCI3 (2.88 g, 18.8 mmol, 2.5 eq) and acid P3 (3.2 g, 16.5 mmol, 2.2 eq) were added. The reaction mixture was stirred at rt for 12 h. Then the mixture was concentrated in vacuo, sat. solution of Nal ICO3 in water (20 mL) was added, and theformed precipitate was filtered, washed with acetone and air dried to give P36 (2.7 g, yield 68%).Analytical data: ’H NMR (400 MHz, DMSO-tfc), 5: 9.03 (s, 1H), 8.22 (s, 2H), 6.90 (s, 2H), 6.82 (m, 5H), 4.35 (s, 2H), 4.21 (m, 8H), 3.72 (s, 2H). LCMS (ESI): calc, for C26H20N4O8 516.47; found, 517.6 [M + H]+.

[0830] Preparation 37. A-(6-Amino-l-(2-(2,3-dihydrobenzo[Z>][l,4]dioxin-6-yl)acetyl)- 17 / -indazol-3-yl)-2-(2,3-dihydrobenzo[ / >][l,4]dioxin-6-yl)acetamide (P37).To a solution of P36 (2.7 g, 5 mmol) in MeOH (150 ml) Pd / C (0.54 g) was added. The reaction mixture was stirred at rt for 12 h under atmosphere of hydrogen. Then the reaction mixture was filtered through a pad of Celite, the filtrate was concentrated in vacuo to give P37 (2.3 g, yield 92%).Analytical data: ’H NMR (400 MHz, DMSO-tL), 5: 10.81 (s, 1H), 7.57 (d, J = 9.6 Hz, 1H), 7.39 (s, 1H), 6.86 (s, 2H), 6.80 (m, 5H), 5.86 (s, 2H), 4.21 (m, 8H), 3.64 (s, 2H), 3.59 (s, 2H). LCMS (ESI): calc, for C27H24N4O6 500.52; found, 501.6 [M + H]+.

[0831] Preparation 38. A-(6-Acetamido-l-(2-(2,3-dihydrobenzo[Z>][l,4]dioxin-6- yl)acetyl)-l / 7-indazol-3-yl)-2-(2,3-dihydrobenzo[ / >][l,4]dioxin-6-yl)acetamide (P38).To a solution of P37 (0.1 g, 0.2 mmol, 1 eq) in THF (5 mb) NaH (0.006 g, 0.26 mmol, 1.3 eq) was added. The reaction mixture was stirred for 10 min and after that acetyl chloride (0.02 g, 0.26 mmol, 1 .3 eq) was added. The reaction mixture was stirred at rt for 12 h and then poured onto crushed ice. The crude product was extracted with EA, and the combined organic layers were washed with brine, dried over anh. Na2SC>4, filtered and concentrated in vacuo to afford P38 (0.091 g, yield 84%).Analytical data: LCMS (ESI): calc, for C29H26N4O7 542.55; found, 543.6 [M + H]+.Synthesis of A-(3-(2-(2,3-Dihydrobenzo[A][ l,4]dioxin-6-yl)acetamido)-l -('2-(2,3- dihydrobenzo[6][l,4]dioxin-6-yl)acetyl)-l / / -indazol-6-yl)-3-methylbutanamide (P39)

[0832] Preparation 39. A-(3-(2-(2,3-Dihydrobenzo[ / i][l,4]dioxin-6-yl)acetamido)-l-(2- (2,3-dihydrobenzo[Z>][l,4]dioxin-6-yl)acetyl)-l / / -indazol-6-yl)-3-methylbutanamide (P39).To a solution of P37 (0.1 1 g, 0.22 mmol, 1 eq) in THF (5 mL) NaH (0.007 g, 0.29 mmol, 1.3 eq) was added. The reaction mixture was stirred at rt for 10 min, and after that iso- pentanoyl chloride (0.035 g, 0.29 mmol, 1.3 eq) was added. The reaction mixture was stirred at rt for 12 h. Then the mixture was poured onto crushed ice, extracted with EA, and the combined organic layers were washed with brine, dried over anh. Na2SC>4, filtered, the filtrate was concentrated in vacuo to afford P39 (0.105 g, yield 82%).Analytical data: LCMS (ESI): calc, for C32H32N4O7 584.63; found, 585.7 [M + H]+.Synthesis of 2-(2,3-Dihydrobenzo[Z>][l,4]dioxin-6-yl)-A-(l-(2-(2,3- dihydrobenzo[Z>][l,4]dioxin-6-yl)acetyl)-6-(methylsulfonamido)-l / f-indazol-3- yl)acetamide (P40)

[0833] Preparation 40. 2-(2,3-Dihydrobenzo[Z>][l,4]dioxin-6-yl)-A-(l-(2-(2,3- dihydrobenzo[ / >][l,4]dioxin-6-yl)acetyl)-6-(methylsulfonamido)-177-indazol-3- yl)acetamide (P40).To a solution of P37 (0.096 g, 0.19 mmol, 1 eq) in THF (5 mL) NaH (0.006 g, 0.24 mmol, 1.25 eq) was added. The reaction mixture was stirred at rt for 10 min, and after that methanesulfonyl chloride (0.027 g, 0.24 mmol, 1.25 eq) was added. The reaction mixture was stirred at rt for 12 h. Then the mixture was poured onto crushed ice, extracted with EA, and the combined organic layers were washed with brine, dried over anh. Na2SC>4, filtered, and concentrated in vacuo to afford P40 (0.1 g, yield 91%).Analytical data: LCMS (ESI): calc, for C28H26N4O8S 578.61; found, 579.7 [M + H]+.Synthesis of 2-(2,3-Dihydrobenzo[Z»][l,4]dioxin-6-yl)-A-(l-(2-(2,3- dihydrobenzo[Z>][l,4]dioxin-6-yl)acetyl)-6-(phenylsulfonamido)-17T-indazol-3- yl)acetamide (P41)

[0834] Preparation 41. 2-(2,3-Dihydrobenzo[Z>][l,4]dioxin-6-yl)-A-(l-(2-(2,3- dihydrobenzo[ / >][l,4]dioxin-6-yl)acetyl)-6-(phenylsulfonamido)-l / / -indazol-3- yl)acetamide (P41).To a solution of P37 (0.095 g, 0.19 mmol, 1 eq) in THF (5 mb) NaH (0.006 g, 0.25 mmol, 1.3 eq) was added. The reaction mixture was stirred at rt for 10 min and after that benzenesulfonyl chloride (0.043 g, 0.25 mmol, 1.3 eq) was added. The reaction mixture was stirred at rt for 12 h. Then the mixture was poured onto crushed ice, extracted with EA, and the combined organic layers were washed with brine, dried over anh. Na2SC>4, filtered and concentrated in vacuo to afford P41 (0.1 g, yield 83%).Analytical data: LCMS (ESI): calc, for QsIEsN^sS 640.68; found, 641.7 [M + H]+.Synthesis of 2-(2,3-dihydrobenzo[Z>][l,4]dioxin-6-yl)-A-(l-(2-(2,3- dihydrobenzo[6][l,4]dioxin-6-yl)acetyl)-6-((2-methylpropyl)sulfonamido)-l / 7-indazol-3- yl)acetamide (P42)

[0835] Preparation 42. 2-(2,3-Dihydrobenzo[Z>][l,4]dioxin-6-yl)-A-(l-(2-(2,3- dihydrobenzo[Z»][l,4]dioxin-6-yl)acetyl)-6-((2-methylpropyl)sulfonamido)-l / 7-indazol-3- yl)acetamide (P42).To a solution of P37 (0.09 g, 0.18 mmol, 1 eq) in THF (5 mL) NaH (0.0056 g, 0.23 mmol, 1.3 eq) was added. The reaction mixture was stirred at rt for 10 min and after that 2- m ethylpropane- 1 -sulfonyl chloride (0.037 g, 0.23 mmol, 1.3 eq) was added. The reaction mixture was stirred at rt for 12 h. Then the mixture was poured onto crushed ice, extracted with EA, and the combined organic layers were washed with brine, dried over anh. Na2SO4, fdtered, and concentrated in vacuo to afford P42 (0.1 g, yield 89%).Analytical data: LCMS (ESI): calc, for C31H32N4O8S 620.69; found, 621.7 [M + H]+.Synthesis of 2-(2,3-dihydrobenzo[Z>][l,4]dioxin-6-yl)-A-(l-(2-(2,3- dihydrobenzo[ / >][l,4]dioxin-6-yl)acetyl)-6-((phenylmethyl)sulfonamido)-l / 7-indazol-3- yl)acetamide (P43)

[0836] Preparation 43. 2-(2,3-Dihydrobenzo[Z>][l,4]dioxin-6-yl)-2V-(l-(2-(2,3- dihydrobenzo[Z>][l,4]dioxin-6-yl)acetyl)-6-((phenylmethyl)sulfonamido)-17 / -indazol-3- yl)acetamide (P43).To a solution of P37 (0.105 g, 0.21 mmol, 1 eq) in THF (5 mL) NaH (0.0064 g, 0.27 mmol, 1.3 eq) was added. The reaction mixture was stirred at rt for 10 min and after that benzylsulfonyl chloride (0.052g, 0.27 mmol, 1.3 eq) was added. The reaction mixture was stirred at rt for 12 h. Then the reaction mixture was poured onto crushed ice, extracted with EA, and the combined organic layers were washed with brine, dried over anh. Na2SC>4, fdtered, and concentrated in vacuo to afford P43 (0.109 g, yield 79%).Analytical data: LCMS (ESI): calc, for C34H3oN408S 654.70; found, 655.8 [M + H]+.Synthesis of 2-(2,3-dihydro-l,4-benzodioxin-6-yl)-N-[l-(2,3-dihydro-l,4-benzodioxin-6- ylacetyl)-6-(methylthio)-17 / -indazol-3-yl]acetamide (P47)

[0837] Preparation 44. l-Bromo-2-fluoro-4-(methylthio)benzene (P44).A mixture of (4-bromo-3-fluorophenyl)amine (7.38 g, 38.8 mmol, 1 eq), isopentyl nitrite (6.83 g, 58.2 mmol, 1.5 eq) in dimethyl disulfide (40 mL) was heated to 90°C under stirring for 2 h. The solvent was evaporated in vacuo, and the crude product was purified by silica gel column chromatography on silica gel (5% EA in hexane as an eluent) to give P44 (8.1 g, yield 94%).Analytical data: 'H NMR (400 MHz, CDCh), 5: 7.43 (dd, J = 8.3, 7.3 Hz, 1H), 7.06 - 6.96 (m, 1H), 6.91 (dd, J = 8.4, 2.1 Hz, 1H).

[0838] Preparation 45. 2-Fluoro-4-(methylthio)benzonitrile (P45).A mixture of P44 (1.9 g, 8.6 mmol, 1 eq) and CuCN (1.54 g, 17.2 mmol, 2 eq) in DMF (20 mL) was stirred at 120°C for 15 h. The mixture was quenched with water, extracted with Et2O, the organic layers were combined, dried over anh. Na2SC>4, and solvent wasevaporated in vacuo. The crude product was purified by silica gel column chromatography on silica gel (5-10% EA in hexane as an eluent) to give P45 (0.62 g, yield 43%).Analytical data: ’HNMR (400 MHz, CDCI3), 5: 7.49 (dd, J = 8.2, 6.8 Hz, 1H), 7.06 (dd, J = 8.3, 1.7 Hz, 1H), 7.01 (dd, J = 9.9, 1.7 Hz, 1H).

[0839] Preparation 46. 6-(Methylthio)-l / f-indazol-3 -amine (P46).A mixture of P45 (0.62 g, 3.7 mmol, 1 eq) and hydrazine hydrate (1.11 g, 22.2 mmol) in i- PrOH (20 mb) was stirred under reflux for 15 h. Then the solvent was evaporated in vacuo, and the residue was passed through silica gel (10-15% MeOH in CHCI3 as an eluent) to afford the title compound P46 (0.39 g, yield 60%).Analytical data: ' H NMR (400 MHz, DMSO4), 5: 11.27 (s, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.00 (s, 1H), 6.79 (d, J = 8.4 Hz, 1H), 5.30 (s, 2H), 3.33 (d, J = 1.1 Hz, 3H).

[0840] Preparation 47. 2-(2,3-Dihydro-l,4-benzodioxin-6-yl)-A-[l-(2,3-dihydro-l,4- benzodioxin-6-ylacetyl)-6-(methylthio)-177-indazol-3-yl]acetamide (P47).To a mixture of P46 (0.15 g, 0.84 mmol, 1 eq), acid P3 (0.36 g, 1.85 mmol, 2.2 eq) and DIPEA (0.32 g, 2.52 mmol, 3 eq) in dioxane (30 mL) POCI3 (0.32 g, 2.1 mmol, 2.5 eq) was added, and the mixture was stirred at rt for 15 h. The formed precipitate was filtered and discarded, and the filtrate was evaporated in vacuo. The residue was dissolved in CHCI3 (30 mL), washed with sat. solution of NaHCCh in water, dried over anh. Na2SC>4, and the solvent was evaporated in vacuo. The crude product was purified by silica gel column chromatography on silica gel (20-50% EA in hexane as an eluent) to give the title compound P47 (0.27 g, yield 60%).Analytical data: LCMS (ESI): calc, for C28H25N3O6S 531.58; found, 532.1 [M + H]+.Synthesis of 6-(pyrrolidin-l-ylsulfonyl)-177-indazol-3-amine (P51)

[0841] Preparation 48. 4-[(4-Chlorobenzyl)thio]-2-fluorobenzonitrile (P48).To a solution of 4-bromo-2-fluorobenzonitrile (4 g, 20 mmol, 1 eq), (4- chlorophenyl)methanethiol (3.8 g, 24 mmol, 1.2 eq) and Xantphos (2.3 g, 4 mmol, 0.2 eq) in dioxane (100 mL) Pd2(dba)s (1.47 g, 1.6 mmol, 0.08 eq) were added. The reaction mixture was purged with argon, and it was heated to 100°C under stirring for 2 h. After completion of the process water (100 mL) was added, the title product was extracted with EA (3 x 100 mL), the combined organic layers were dried over anh. Na2SC>4 and passed through a pad of silica gel (EA as an eluent). The fdtrate was evaporated, the residue was suspended in Et2O, the formed precipitate was filtered, washed with Et2O and dried to give P48 (3.8 g, yield 69%).Analytical data:TH NMR (400 MHz, DMSO-de), 5: 7.87 - 7.72 (m, 1H), 7.52 (dd, J = 10.6, 1.5 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.5 Hz, 2H), 7.31 (dd, J = 8.3, 1.6 Hz, 1H), 4.43 (s, 2H).

[0842] Preparation 49. 4-Cyano-3 -fluorobenzenesulfonyl chloride (P49).To a solution of P48 (1.88 g, 6.77 mmol, 1 eq) in a mixture of AA-THF-water (40: 10: 10, 35 mL), A-chlorosuccinimide (1.81 g, 13.54 mmol, 2 eq) was added portionwise at rt. In 2 h the initially formed suspension turned into a transparent solution. The mixture was quenched with water (100 mL) and extracted with EA (3 x 100 mL). The combined organic layers were dried over anh. Na2SC>4 and concentrated in vacuo. The crude product waspurified on a silica gel column (20-65% EA in hexane as an eluent) to afford P49 (1.04 g, yield 69%).Analytical data: *HNMR (400 MHz, CDCh) 5 (ppm): 8.03 - 7.90 (m, 2H), 7.42 - 7.29 (m, 1H).

[0843] Preparation 50. 2-Fluoro-4-(pyrrolidin-l-ylsulfonyl)benzonitrile (P50).To a mixture of P49 (0.39 g, 1.78 mmol, 1 eq) and KHCO3 (1.78 g, 17.8 mmol, 10 eq) in a mixture of solvents THF-water (1 : 1, 25 mL) pyrrolidine (0.19 g, 2.67 mmol, 1.5 eq) was added, and the mixture was stirred at rt for 15 h. The mixture was diluted with water (50 mL), extracted with EA (3 x 50 mL), the combined organic layers were dried over anh. Na2SC>4 and filtered. The solvent was evaporated in vacuo. The residue was suspended in a mixture of solvents Et2O-hexane, 1 :3, the formed pellet was filtered, washed with hexane and dried to give P50 (0.34 g, yield 75%).Analytical data: 'HNMR (400 MHz, DMSO-t76), 8: 8.20 (dd, J = 7.9, 6.5 Hz, 1H), 7.96 (d, J = 8.7 Hz, 1H), 7.81 (dd, J = 8.1, 1.2 Hz, 1H), 3.21 (t, J = 6.7 Hz, 4H), 2.50 (d, J = 1.5 Hz, 4H), 1.78 - 1.55 (m, 4H).

[0844] Preparation 51. 6-(Pyrrolidin-l-yl sulfonyl)- 177-indazol-3 -amine (P51).To a solution of P50 (0.34 g, 1.34 mmol, 1 eq) in z-PrOH (10 mL) hydrazine hydrate (0.41 g, 8.04 mmol, 6 eq) was added, and the mixture was heated under reflux for 15 h. Then the formed precipitate was filtered, washed with z-PrOH and dissolved in a mixture of 10% MeOH in CHCI3 (1 mL). The solution was passed through a pad of silica gel eluting with (a mixture of 10% MeOH in CHCI3 as an eluent) The filtrate was evaporated, the residual solid was washed with Et2O and dried to afford P51 (0.23g, yield 65%).Analytical data:JH NMR (400 MHz, DMSO-t / e), 6: 11.86 (s, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 1.4 Hz, 1H), 7.28 (dd, J = 8.4, 1.5 Hz, 1H), 5.60 (s, 2H), 3.15 (s, 4H), 1.71 - 1.53 (m, 4H).Synthesis of A-(6-bromo-l-(2-(2,3-dihydrobenzo[ / >][l,4]dioxin-6-yl)acetyl)-lH-indazol- 3-yl)-2-(2,3 -dihy drobenzo[b] [ 1 ,4]dioxin-6-yl)acetamide (P52)

[0845] Preparation 52. A-(6-bromo-l-(2-(2,3-dihydrobenzo[Z>][l,4]dioxin-6-yl)acetyl)- 17 / -indazol-3-yl)-2-(2,3-dihydrobenzo[Z»][l,4]dioxin-6-yl)acetamide (P52).To a solution of P4 (2 g, 9.4 mmol, 1 eq) in dioxane (25 mL) DIPEA (3.7 g, 28 mmol, 3 eq), POCI3 (3.6 g, 24 mmol, 2.55 eq), acid P3 (4 g, 21 mmol, 2.23 eq) was added. The reaction mixture was stirred at rt for 12 h. Then the solvent was evaporated in vacuo, the sat. solution of NaHCCh (25 mL) was added, the formed precipitate was filtered, washed with acetone and air dried to give P52 (2.04 g, yield 38%).Analytical data: ’H NMR (400 MHz, DMSO-<76), 8: 11.19 (s, 1H), 8,45 (s, 1H), 7.95 (d, J = 8.7 Hz, 1H), 757 (d, J = 7.6 Hz, 1H), 6.88 (s, 2H), 6.81 (m, 4H), 4.30 (s, 2H), 4.22 (m, 8H), 3.70 (s, 2H). LCMS (ESI): calc, for C27H22BrN3O6 564.40; found, 565.3 [M + H]+.Synthesis of iV-(5-amino-l -(2-(2,3-dihydrobenzo[Z>][l ,4]dioxin-6-yl)acetyl)-lH-indazol- 3-yl)-2-(2,3 -dihydrobenzo[b] [ 1 ,4]dioxin-6-yl)acetamide (P54)

[0846] Preparation 53. 2-(2,3-Dihydrobenzo[b][l,4]dioxin-6-yl)-A-(l-(2-(2,3- dihydrobenzo[Z>][l,4]dioxin-6-yl)acetyl)-5-nitro-l / f-indazol-3-yl)acetamide (P53).To a solution of 5-nitro-l / / -indazol-3-amine (1 g, 5.6 mmol, 1 eq) and DIPEA (2.17 g, 16.8 mmol, 3 eq) in dioxane (25 mL) acid P3 (2.28 g, 11.78 mmol, 2.1 eq) and POCI3 (2.15 g, 1.3 mL, 14 mmol, 2.5 eq) were added. The reaction mixture was heated to 50°C under stirring overnight, cooled and poured into sat. solution of NaHCCh in water (250 ml). The formed precipitate was filtered, washed with water, Et2O and air dried to give P53 (2.9 g, yield 67%).Analytical data: 'HNMR (400 MHz, DMSO-^e), 8: 9.09 (s, 1H), 8.44 (s, 2H), 6.90-6.78 (m, 6H), 4.34 (s, 2H), 4.26-4.18 (m, 8H), 3.73 (s, 2H).

[0847] Preparation 54. A-(5-Amino-l-(2-(2,3-dihydrobenzo[Z>][l,4]dioxin-6-yl)acetyl)- l / / -indazol-3-yl)-2-(2,3-dihydrobenzo[Z>][l,4]dioxin-6-yl)acetamide (P54).To a solution of P53 (1.7 g, 3.2 mmol, 1 eq) was dissolved in mixture MeOH / THF (1 : 1, 100 mL). Pd / C (0.2 g) was added and the mixture was stirred under atmosphere of hydrogen at rt for 24 h. The catalyst was removed by filtration and the solution was evaporated to dryness w vacuo to afford P54 (1.2 g, yield 74%).Analytical data: LCMS (ESI): calc, for C27H24N4O6 500.51; found, 501 [M + H]+.Synthesis of l / / -pyrazolo[3,4-c]pyridin-3-amine (P55)

[0848] Preparation 55. 177-Pyrazolo[3,4-c]pyridin-3-amine (P55).To a solution of 3-fluoroisonicotinonitrile (2 g, 16 mmol, 1 eq) in EtOH (25 mL) hydrazine hydrate (2.5 g, 0.05 mol, 3.1 eq) was added, and the reaction mixture was heated under reflux overnight. The solvent was removed in vacuo, and water (15 mL) was added to the residue. The formed precipitate was filtered, washed with water and dried. The title compound P55 (2 g, yield 91%) was used in the next step without purification.Analytical data: 'HNMR (400 MHz, DMSO-tZc), 6: 11.9 (br. s, NH), 8.71 (br. s, 1H), 8.03 (d, J = 5.6 Hz, 1H), 7.65 (d, J = 5.6 Hz, 1H), 5.57 (br. s, 2H). LCMS (ESI): calc, for C6H6N4134.15; found, 135 [M + H]+.Synthesis of A-(5-bromo-l-(2-(3,4-dihydro-2Z7-benzo[Z>][l,4]dioxepin-7-yl)acetyl)-l / 7- indazol-3-yl)-2-(3,4-dihydro-27 / -benzo[Z>][l,4]dioxepin-7-yl)acetamide (P57)

[0849] Preparation 56. 5-Bromo-l / f-indazol-3-amine (P56).To a solution of 2-fluoro-5-bromo benzonitrile (2 g, 0.01 mol, 1 eq) in EtOH (25 mL) hydrazine hydrate (1.5 g, 0.03 mol, 3 eq) was added, and the reaction mixture was heated under reflux overnight. Then the solvent was removed in vacuo, and the water ( 15 mL) was added to the residue. The formed precipitate was filtered, washed by water and dried. The crude product P56 (2.05 g, yield 99%) was used in the next step without purification.Analytical data: ' H NMR (400 MHz, DMSO-tL), 8: 11.6 (br. s, 1H), 7.93 (br. s, 1H), 7.31 (dd, J = 2 Hz, J = 10.4 Hz, 1H), 7.2 (dd, J = 0.5 Hz, J = 8.6 Hz, 1H), 5.42 (br. s, 2H). LCMS (ESI): calc, for C7H6BrN3212.05; found, 213 [M + H]+.

[0850] Preparation 57. Ar-(5-Bromo-l-(2-(3,4-dihydro-2 / Z-benzo[Z>][l,4]dioxepin-7- yl)acetyl)-l / f-indazol-3-yl)-2-(3,4-dihydro-27 / -benzo[Z>][l,4]dioxepin-7-yl)acetamide (P57).To a solution of P56 (1 g, 4.7 mmol, 1 eq) and DIPEA (1.82 g, 14.2 mmol, 3,02 eq) in dioxane (25 mL) 2-(3,4-dihydro-2Z / -benzo[Z>][l,4]dioxepin-7-yl)acetic acid (2.16 g, 10.4 mmol, 2.2 eq) and then POCI3 (2.07 g, 13.5 mmol, 1.25 mL, 2.9 eq) were added. The reaction mixture was heated to 50°C under stirring overnight, cooled and poured into sat. solution of NaHCCL in water (250 mL). The formed precipitate was fdtered, washed with water, Et2O and dried to give P57 (2.44 g, yield 87.3%).Analytical data: 'H NMR (400 MHz, DMSO-^), 5: 11.19 (br. s, 1H), 8.24-8.22 (m, 2H), 7.79 (dd, J = 1.6 Hz, J = 10.8 Hz, 1H), 7.02-6.88 (m, 6H), 4.34 (s, 2H), 4.15-4.075 (m, 8H),3.73 (s, 2H), 2.13-2.05 (m, 2H). LCMS (ESI): calc, for C29H26BrN3O6592.45; found, 593.5 [M + H]+.Synthesis of A-(5-bromo-l-(2-(2,3-dihydrobenzo[Z>][l,4]dioxin-6-yl)acetyl)-177-indazol- 3-yl)-2-(2,3-dihydrobenzo[Z>][l,4]dioxin-6-yl)acetamide (P58)

[0851] Preparation 58. A-(5-Bromo-l-(2-(2,3-dihydrobenzo[ / >][l,4]dioxin-6-yl)acetyl)- l / / -indazol-3-yl)-2-(2,3-dihydrobenzo[Z>][l,4]dioxin-6-yl)acetamide (P58).To a solution of P56 (2.4 g, 11.7 mmol, 1 eq) and DIPEA (1.82 g, 14.2 mmol, 1.2 eq) in dioxane (25 mL) P3 (5 g, 25.7 mmol, 2.2 eq) and then POCI3 (4.48 g, 29.2 mmol, 2.7 mL, 2.5 eq) were added. The reaction mixture was heated to 50°C under stirring overnight, cooled and poured into sat. solution of NaHCCE in water (250 mL). The formed precipitate was fdtered, washed with water, Et20 and dried to give P58 (4.6 g, yield 69.7%).Analytical data: ’H NMR (400 MHz, DMSO-t76), 8: 8.23-8.21 (m, 2H), 7.78 (dd, J = 2.4 Hz, J = 10.8 Hz, 1H), 7.02-6.88 (m, 6H), 4.30 (s, 2H), 4.25-4.15 (m, 8H), 3.69 (s, 2H). LCMS (ESI): calc, for C27H22BrN3O6564.39; found, 565.5 [M + H]+.Synthesis of A-(5-bromo-6-chl oro-1 -(2-(2,3-dihydrobenzo[Z>][l,4]dioxin-6-yl)acetyl)- l / 7-indazol-3-yl)-2-(2,3-dihydrobenzo[Z>][l,4]dioxin-6-yl)acetamide (P62)

[0852] Preparation 59. 5-Bromo-4-chloro-2 -fluorobenzamide (P59).To a solution of 5-bromo-4-chloro-2-fluorobenzoic acid (0.25 g, 0.99 mmol, 1 eq) in toluene (100 mL) SOCh (0.3 g, 2.52 mmol, 2.55 eq) was added, and the mixture was heated under reflux for 2 h. After completion of the process the mixture was concentrated in vacuo, the residue was diluted with DCM. The obtained solution was added dropwise to NH4OH (10 mL) with ice cooling. The resulting mixture was stirred at rt for 15 min, and then the organic layer was separated, dried over anh. Na2SC>4 and filtered. The filtrate was concentrated in vacuo to give P59 (0.23 g, yield 92%) as a white solid.Analytical data: 'H NMR (400 MHz, DMSO-t / 6), 8: 7,97 (d, J = 7,1 Hz, 1H), 7,81 (m, 3H).

[0853] Preparation 60. 5-Bromo-4-chloro-2 -fluorobenzonitrile (P60).To a solution of P59 (0.23 g, 0.91 mmol, 1 eq) in DCM (50 mL) Burgess reagent (0.47 g, 1.97 mmol, 2.16 eq) was added, and the reaction mixture was stirred overnight at rt. The reaction mixture was diluted with sat. solution of NaHCO? in water. The organic layer wasseparated, washed with brine, dried over anh. Na2SC>4 and filtered. The filtrate was concentrated in vacuo to give P60 (0.2 g, yield 95%) as a solid.Analytical data: ’HNMR (400 MHz, DMSO-t / e), 5: 8.51 (d, J = 6.6 Hz, 1H), 8.08 (d, J =9.1 Hz, 1H).

[0854] Preparation 61. 5-Bromo-6-chloro-l / / -indazol-3-amine (P61).To a solution of P60 (0.2 g, 0.85 mmol, 1 eq) in EtOH (15 mL) hydrazine hydrate (2.5 mL, 51 mmol, 60 eq) was added, and the reaction mixture was heated under reflux overnight. Then the solvent was evaporated in vacuo, and water (10 mL) was added to the residue. The formed precipitate was filtered, washed with water and air dried to give P61 (0.19 g, yield 90%) as a white solid.Analytical data: ‘HNMR (400 MHz, DMSO-^), 8: 11,66 (s, 1H), 8,15 (s, 1H), 7,51 (s, 1H), 5,56 (s, 2H).

[0855] Preparation 62. A-(5-Bromo-6-chloro-l-(2-(2,3-dihydrobenzo[Z>][l,4]dioxin-6- yl)acetyl)-17 / -indazol-3-yl)-2-(2,3-dihydrobenzo[Z>][l,4]dioxin-6-yl)acetamide (P62).To a solution of P61 (0.19 g, 0.77 mmol, 1 eq) in dioxane (20 mL) P3 (0.33 g 1.70 mmol,2.2 eq) and DIPEA (0.3 g, 2.33 mmol, 3 eq) were added. Then to the reaction mixture POCI3 (0.3 g, 1.95 mmol, 2.53 eq) was added dropwise. The reaction mixture was stirred at rt overnight, the solvent was concentrated in vacuo. The residue was diluted with DCM and washed with sat. solution of NaHCCL in water and brine. The organic layer was separated, dried over anh. Na2SC>4, filtered, the filtrate was concentrated in vacuo. The crude product was purified by silica gel column chromatography (0-10% EA in DCM) to give P62 (0.21 g, yield 45%) as a solid.Analytical data: ‘H NMR (400 MHz, CDCI3) 8 (ppm): 11,27 (s, 1H), 8,47 (s, 1H), 8,46 (s, 1H), 6,88 (m, 2H), 6,81 (m, 4H), 4,29 (s, 2H), 4,22 (m, 8H), 3,70 (s, 2H).Synthesis of A-(5-amino- 1 -(2-(3 ,4-dihydro-2 / / -benzo[b] [ 1 ,4]dioxepin-7-yl)acetyl)-l / / - indazol-3-yl)-2-(3,4-dihydro-2Z / -benzo[Z>][l,4]dioxepin-7-yl)acetamide (P65)

[0856] Preparation 63. 5-Nitro-177-indazol-3-amine (P63).To a solution of 2-fluoro-5-nitro benzonitrile (1.66 g, 0.01 mol, 1 eq) in EtOH (25 mL) hydrazine hydrate (1.5 g, 0.03 mol, 3 eq) was added, and the reaction mixture was heated under reflux overnight. Then the solvent was evaporated in vacuo, and water (15 mL) was added to the residue. The formed precipitate was filtered, washed with water and air dried to give P63 (2 g, yield 97%).Analytical data: 'H NMR (400 MHz, DMSO-tL), 8: 12.2 (br. s, 1H), 8.89 (br. s, 1H), 8.04 (dd, J = 2 Hz, J = 11.2 Hz, 1H), 7.34 (d, J = 9.2 Hz, 1H), 5.98 (br. s, 2H). LCMS (ESI): calc, for C7H6N4O2 178.15; found, 179 [M + H]+.

[0857] Preparation 64. 2-(3,4-Dihydro-2 / / -benzo[Z>][l,4]dioxepin-7-yl)-7V-(l-(2-(3,4- dihydro-2 / 7-benzo[Z>][l,4]dioxepin-7-yl)acetyl)-5-nitro-17 / -indazol-3-yl)acetamide (P64). To a solution of P63 (1 g, 5.6 mmol, 1 eq) and DIPEA (2.8 g, 22.4 mmol, 4 eq) in dioxane (25 mL) 2-(3,4-dihydro-277-benzo[Z>][l,4]dioxepin-7-yl)acetic acid (2.56 g, 12.24 mmol, 2.2 eq) and POCI3 (2.6 g, 1.56 mL, 17 mmol, 3 eq) were added. The reaction mixture washeated to 50°C under stirring overnight, cooled and poured into sat. solution of NaHCO.i in water (250 mL). The formed precipitate was filtered, washed with water, Et2O and dried to give P64 (2.4 g, yield 82%).Analytical data: 'H NMR (400 MHz, DMSO4), 8: 11.05 (br. s, 1H), 8 9.1 (br. s, 1H), 8.5 (s, 2H), 7.016-6.93 (m, 6H), 4.38 (s, 2H), 4.15-4.05 (m, 8H), 3.77 (s, 2H), 2.14-2.05 (m, 2H). LCMS (ESI): calc, for C29H26N4O8 558.55; found, 559.5 [M + H]+.

[0858] Preparation 65. A'-(5-Amino- l -(2-(3,4-dihydro-27 / -benzo[bj[l,4]dioxepin-7- yl)acetyl)-l / 7-indazol-3-yl)-2-(3,4-dihydro-2 / 7-benzo[ / >][l,4]dioxepin-7-yl)acetamide (P65)To a solution of P64 (2.4 g, 4.3 mmol, 1 eq) in MeOH (100 mL) Pd / C (0.25 g, 10%) was added, and the mixture was stirred under atmosphere of hydrogen for 24 h. The catalyst was removed by filtration, and the filtrate was evaporated in vacuo to afford P65 (1.6 g, yield 72%).Analytical data: 'HNMR (400 MHz, DMSO-dk), 8: 10.19 (br. s, 1H), 7.13 (d, J = 8.8 Hz, 1H), 7.1-6.6 (m, 10H), 4.38 (s, 2H), 4.19-4.02 (m, 8H), 3.65 (s, 2H), 2.09-0.7 (m, 2H). LCMS (ESI): calc, for C29H28N4O6 528.57; found, 529.5 [M + H]+.Examples of the Final Compound

[0859] In the Table 3 presented certain non-limiting examples of the compound of Formula (A).

[0860] Table 3. Selected examples of the compound of Formula (A) and LCMS (ESI) dataZ12.Synthesis of the Representative Examples of the compound

[0861] Example 1. 2-(2,34)ihydrobenzo[6][l,4]dioxin-6-yl)JV-(5-fluoro-l / / -indazol-3- yl)acetamide (Compound 1021).To a solution of P3 (150 mg, 0.77 mmol, 1 eq) in pyridine (8 mL) 5-fluoro-lZ7-indazol-3- amine (116 mg, 0.77 mmol, 1 eq) was added, followed by DIPEA (134 pL, 0.77 mmol, 1 eq) and dropwise addition of T3P (490 mg, 1.54 mmol, 2 eq, 50% in EA). The mixture was stirred overnight at rt, diluted with water (50 mL) and extracted with EA (3 x 25 mL). The organic layers were combined and washed with water and brine, dried over anh. ISfeSCU, filtered and concentrated in vacuo. The crude product was purified by HPLC to give 1021 as a white solid (18 mg, yield 7%).Analytical data: *HNMR (400 MHz, DMSO-t76), 5: 12.74 (s, 1H), 10.54 (s, 1H), 7.46 - 7.36 (m, 2H), 7.23 - 7.13 (m, 1H), 6.85 (s, 1H), 6.78 (s, 2H), 4.18 (s, 4H), 3.55 (s, 2H).

[0862] Example 2. 2-(2,3-Dihydrobenzo[Z>][l,4]dioxin-6-yl)-A-(6-fluoro-lZ7-indazol-3- yl)acetamide (Compound 1026).P3 1026HTo a solution of acid P3 (150 mg, 0.77 mmol, 1 eq) in pyridine (8 mL) 6-fluoro-l / 7-indazol- 3-amine (116 mg, 0.77 mmol, 1 eq) was added, followed by DIPEA (134 pL, 0.77 mmol, 1 eq) and dropwise addition of (490 mg, 1.54 mmol, 2 eq, 50% in EA). The mixture was stirred overnight at rt, diluted then with water (50 mL) and extracted with EA (3 x 25 mL). The organic layers were combined and washed with water and brine, dried over anh. Na2SO4, filtered and concentrated in vacuo. The crude product was purified by HPLC to give 1026 as a white solid (20 mg, yield 8 %).Analytical data: 'H NMR (400 MHz, DMSO-dg), 8: 12.67 (s, 1H), 10.56 (s, 1H), 7.78 - 7.70 (m, 1H), 7.19 - 7.12 (m, 1H), 6.92 - 6.86 (m, 1H), 6.85 (s, 1H), 6.78 (s, 2H), 4.18 (s, 4H).

[0863] Example 3. A-(6-Bromo-177-indazol-3-yl)-2-(l,3-dimethyl-2-oxo-2,3-dihydro- l / / -benzo[<7]imidazol-5-yl)acetamide (Compound 1058).1058HTo a solution of 2-(l,3-dimethyl-2-oxo-2,3-dihydro-l / / -benzo[d]imidazol-5-yl)acetic acid (110 mg, 0.5 mmol, 1 eq) in pyridine (4 mL) P4 (110 mg, 0.52 mmol, 1.04 eq) was added, followed by DIPEA (174 pL, 1 mmol, 2 eq) and dropwise addition of T3P (318 mg, 1 mmol, 2 eq, 50% in EA). The mixture was stirred overnight at rt, then diluted with water (50 mL) and extracted with EA (3 x 25 mL). The organic layers were combined, washed with water and brine, dried over anh. Na2SC>4, filtered and concentrated in vacuo. The crude product was purified by HPLC to give 1058 as a white solid (9 mg, yield 13%).Analytical data: *HNMR (400 MHz, DMSO-^), 8: 12.76 (s, 1H), 10.66 (s, 1H), 7.76 - 7.49 (m, 2H), 7.15 - 6.94 (m, 4H), 3.70 (s, 2H), 3.27 (d, J = 3.3 Hz, 6H).

[0864] Example 4. 2-(2,3-Dihydrobenzo[Z>][l,4]dioxin-6-yl)-A-(5-methyl-lZ / -indazol-3- yl)acetamide (Compound 3003).P3 3003To a solution of acid P3 (150 mg, 0.77 mmol, 1 eq) in pyridine (8 mL) 5-methyl-l / f- indazol-3-amine (113 mg, 0.77 mmol, 1 eq) was added, followed by DIPEA (134 pL, 0.77 mmol, 1 eq) and dropwise addition of T3P (490 mg, 1.54 mmol, 2 eq, 50% in EA). The mixture was stirred overnight at rt, diluted then with water (50 mL) and extracted with EA (3 x 25 mL). The organic layers were combined and washed with water and brine, dried over anh. NazSCU, filtered and concentrated in vacuo. The crude product was purified by HPLC to give 1089 as a white solid (24 mg, yield 10%).Analytical data: 'H NMR (400 MHz, DMSO-t / e), 5: 12.48 (s, 1H), 10.37 (s, 1H), 7.42 (s, 1H), 7.28 (d, J = 8.5 Hz, 1H), 7.15 - 7.08 (m, 1H), 6.86 (s, 1H), 6.79 (s, 2H), 4.19 (s, 4H), 3.54 (s, 2H), 2.32 (s, 3H).

[0865] Example 5. 2-(2,3-Dihydrobenzo[ / i][l,4]dioxin-6-yl)-A-(6-methyl-l / / -indazol-3- yl)acetamide (Compound 3004).To a solution of acid P3 (150 mg, 0.77 mmol, 1 eq) in pyridine (8 mL) 6-m ethyl- 1H- indazol-3-amine (113 mg, 0.77 mmol, 1 eq) was added, followed by DIPEA (134 pL, 0.77 mmol, 1 eq) and dropwise addition of T3P (490 mg, 1.54 mmol, 2 eq, 50% in EA). The mixture was stirred overnight at rt, diluted then with water (50 mL) and extracted with EA (3 x 25 mL). The organic layers were combined and washed with water and brine, dried over anh. Na2SC>4, filtered and concentrated in vacuo. The crude product was purified by HPLC and crystallized from EA to give compound 1090 as a white solid (10 mg, yield 4%).Analytical data: 'H NMR (400 MHz, DMSO-^,), 8: 12.42 (s, 1H), 10.42 (s, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.14 (s, 1H), 6.87 - 6.75 (m, 4H), 4.18 (s, 4H), 3.53 (s, 2H), 2.36 (s, 3H).

[0866] Example 6. A-(6-Cyano-l / / -indazol-3-yl)-2-(2,3-dihydrobenzo[Z>][l,4]dioxin-6- yl)acetamide (Compound 1093).To a solution of acid P3 (150 mg, 0.77 mmol, 1 eq) in pyridine (8 mL) 3-amino-l / f- indazole-6-carbonitrile (122 mg, 0.77 mmol, 1 eq) was added, followed by DIPEA (134 pL, 0.77 mmol, 1 eq) and dropwise addition of T3P (490 mg, 1.54 mmol, 2 eq, 50% in EA). The mixture was stirred overnight at rt, diluted then with water (50 mL) and extracted with EA (3 x 25 mL). The organic layers were combined and washed with water and brine, dried over anh. Na2SO4, filtered and concentrated in vacuo. The crude product was purified by crystallization from EA to give compound 1093 as a white solid (56 mg, yield 22%).Analytical data: *HNMR (400 MHz, DMSO-rfc), 8: 13.22 (s, 1H), 10.72 (s, 1H), 8.05 - 8.00 (m, 1H), 7.89 (dd, J = 8.5, 0.9 Hz, 1H), 7.32 (dd, J = 8.5, 1.4 Hz, 1H), 6.85 (s, 1H), 6.78 (s, 1H), 4.18 (s, 4H), 3.57 (s, 2H).

[0867] Example 7. A-(5-Cyano-l / / -indazol-3-yl)-2-(2,3-dihydrobenzo[Z>][l,4]dioxin-6- yl)acetamide (Compound 1094).P3 1094 HTo a solution of P3 (150 mg, 0.77 mmol, 1 eq) in pyridine (8 mL) 3-amino-l / / -indazole- 5-carbonitrile (122 mg, 0.77 mmol, 1 eq) was added, followed by DIPEA (134 pL, 0.77 mmol, 1 eq) and dropwise addition of T3P (490 mg, 1.54 mmol, 2 eq, 50% in EA). The mixture was stirred overnight at rt, then diluted with water (50 mL) and extracted with EA(3 x 25 mL). The organic layers were combined and washed with water and brine, dried over anh. NazSCU, filtered and concentrated in vacuo. The crude product was purified by crystallization from EA to give 1094 as a white solid (56 mg, yield 22%).Analytical data: 'H NMR (400 MHz, DMSO-<A), 5: 13.17 (s, 1H), 10.84 (s, 1H), 8.35 (d, J = 1.2 Hz, 1H), 7.63 - 7.53 (m, 2H), 4.18 (s, 4H), 3.58 (s, 2H).

[0868] Example 8. 2-(2,3-Dihydrobenzo[Z>][l,4]dioxin-6-yl)-A-(4-(2,2,2- trifluoroethoxy)-17 / -indazol-3-yl)acetamide (Compound 3025).P3 3025 HTo a solution of acid P3 (150 mg, 0.77 mmol, 1 eq) in pyridine (8 mL) 4-(2,2,2- trifluoroethoxy)-l / / -indazol-3-amine (122 mg, 0.77 mmol, 1 eq) was added, followed by DLPEA (134 pL, 0.77 mmol, 1 eq) and dropwise addition of T3P (490 mg, 1.54 mmol, 2 eq, 50% in EA). The mixture was stirred overnight at rt, then diluted with water (50 mL) and extracted with EA (3 x 25 mL). The organic layers were combined and washed with water and brine, dried over anh. Na2SC>4, filtered and concentrated in vacuo. The crude product was purified by crystallization from EA to give 3025 as a white solid (40 mg, yield 13%).Analytical data: 'H NMR (400 MHz, DMSO-t76), 5: 12.79 (s, 1H), 9.80 (s, 1H), 7.22 (t, J = 8.0 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 6.81 - 6.69 (m, 3H), 6.57 (d, J = 7.7 Hz, 1H), 4.68 (q, J = 8.8 Hz, 2H), 4.17 (s, 4H), 3.44 (s, 2H).

[0869] Example 9. A-(6-Bromo-4-fluoro-l / 7-indazol-3-yl)-2-(2,3- dihydrobenzo[6][l,4]dioxin-6-yl)acetamide (Compound 1034).To a solution of P6 (600 mg, 0.88 mmol) in THF (20 mL) 0.1 N solution of LiOH in water (8 mL) was added. The mixture was stirred at rt for 2 h. After completion of the process (control by HPLC) the mixture was diluted with EA, washed with water twice, dried over anh. Na2SC>4, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC to give 1034 as a white solid (64 mg, yield 15%).Analytical data: 'H NMR (400 MHz, DMSO-<A), 8: 13.09 (s, 1H), 10.15(s, 1H), 7.54 (d, J= 1.4 Hz, 1H), 7.05 (dd, J = 9.6, 1.4 Hz, 1H), 6.84 (br. s, 1H), 6.78 (s, 2H), 4.22 (s, 4H), 3.54 (s, 2H).

[0870] Example 10. A-(7-Bromo-4-fluoro-lLf-indazol-3-yl)-2-(2,3- dihydrobenzo[ / >][l,4]dioxin-6-yl)acetamide (Compound 1035).To a solution of acid P3 (203 mg, 1.05 mmol, 1.15 eq) in pyridine (5 mL) within a 10 mL screw-top vial P7 (209 mg, 0.91 mmol, 1 eq) was added, followed by TEA (550 pL, 3 mmol, 3.3 eq) and TBTU (481 mg, 1.5 mmol, 1.65 eq) at rt. The mixture was stirred overnight at rt. The resulting mixture was then diluted with water (50 mL) and extracted with EA (3 x 50 mL). The organic layers were combined and washed with water and brine.The crude product was purified by preparative HPLC to give 1035 as a white solid (41 mg, yield 10%).Analytical data:JH NMR (400 MHz, DMSO-tL), 8: 13.40(s, 1H), 10.19 (s, 1H), 7.53- 7.49 (m, 1H), 6.83-6.78 (m, 4H), 4,23 (s, 4H), 3.56 (s, 2H).

[0871] Example 11. A-(4,6-Difluoro-lLf-indazol-3-yl)-2-(2,3- dihydrobenzo[Z’][l,4]dioxin-6-yl)acetamide (Compound 1037).To a solution of P9 (560 mg, 0.88 mmol, 1 eq) in THF (20 mL) 0.1 N solution of LiOH in water (8 mL) was added. The reaction mixture was stirred for 2 h After completion of the process (control by HPLC) the solution was diluted with EA, washed with water twice, dried over anh. Na2SO4, filtered and concentrated in vacuo. Purification of the crude product was achieved through preparative HPLC to give 1037 as a white solid (33 mg, yield 7%).Analytical data: 'HNMR (400 MHz, DMSO-J6), 8: 13.04 (s, 1H), 10.12(s, 1H), 7.12 (dd, J = 9.2, 2.0 Hz, 1H), 6.87-6.82 (m, 2H), 6.78 (br. s, 2H), 4.22 (s, 4H), 3.54 (s, 2H).

[0872] Example 12. A-(5-Chloro-l / 7-indazol-3-yl)-2-(3,4-dihydro-2 / f- benzo[Z>][l,4]dioxepin-7-yl)acetamide (Compound 1038).1038To a solution of 2-(3,4-dihydro-2 / 7-benzo[Z>][l,4]dioxepin-7-yl)acetic acid (150 mg, 0.72 mmol, 1 eq) in pyridine (5 mL) within a 10 mL screw-top vial 5-chloro-177-indazol-3- amine (168 mg, 0.72 mmol, 1 eq) was added, followed by TEA (150 pL, 1.08 mmol, 1.5 eq) and TBTU (321 mg, 1.08 mmol, 1,5 eq) at rt. The reaction mixture was stirred overnight at rt. The resulting mixture was then diluted with water (50 mL) and extracted with EA (3 x 50 mL). The organic layers were combined and washed with water and brine, dried over anh. Na2SC>4, fdtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (0-50% EA / hexane as an eluent) followed by preparative HPLC to give 1038 as a white solid (6 mg, yield 2%).

[0873] Example 13. 2-(3,4-Dihydro-2Z / -benzo[Z>][l,4]dioxepin-7-yl)-A-(5-fluoro-l / / - indazol-3-yl)acetamide (Compound 1039).2-(3,4-Dihydro-2Z7-benzo[Z>][l,4]dioxepin-7-yl)acetic acid (150 mg, 0.7 mmol, 1 eq), 5- fluoro-l / 7-indazol-3 -amine (109 mg, 0.7 mmol, 1 eq) and TEA (200 pL, 1.4 mmol, 2 eq) were mixed in pyridine (3 mL) within a 10 mL screw-top vial, then TBTU (463 mg, 1.4 mmol, 2 eq) was added. The reaction mixture was stirred overnight at rt. The resulting mixture was then diluted with water (3 mL) and extracted with EA (5 mL). The organic layers were combined and washed with water and brine, dried over anh. Na2SO4, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC to give 1039 as a white solid (55 mg, yield 20%).Analytical data: 'HNMR (400 MHz, DMSO-<76), 5: 12.68 (s, 1H), 10.47 (s, 1H), 7.42 (td, J = 9.4, 3.4 Hz, 2H), 7.18 (td, J = 9.0, 2.5 Hz, 1H), 6.98 - 6.93 (m, 1H), 6.90 (s, 2H), 4.08 (dt, J = 8.1, 5.4 Hz, 4H), 3.58 (s, 2H), 2.11 - 2.01 (m, 2H).

[0874] Example 14. 2-(3,4-Dihydro-2Z / -benzo[Z>][l,4]dioxepin-7-yl)-A-(6-fluoro-lff- indazol-3-yl)acetamide (Compound 1045).1045 H2-(3,4-Dihydro-277-benzo[Z)][l,4]dioxepin-7-yl)acetic acid (150 mg, 0.7 mmol, 1 eq), 6- fluoro-l / f-indazol-3-amine (109 mg, 0.7 mmol, 1 eq) and TEA (200 pL, 1.4 mmol, 2 eq) were mixed in pyridine (3 mb) within a 10 mb screw-top vial, then TBTU (463 mg, 1.4 mmol, 2 eq) was added, at it. The reaction mixture was stirred overnight at rt. The resulting mixture was then diluted with water (3 mb) and extracted with EA (5 mb). The organic layers were combined and washed with water and brine, dried over anh. Na2SC>4, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC to give 1045 as a white solid (36 mg, yield 14%).Analytical data:1HNMR (400 MHz, DMSO-Je), 5: 12.61 (s, 1H), 10.48 (s, 1H), 7.76 (dd, J = 8.8, 5.7 Hz, 1H), 7.14 (dt, J = 9.4, 1.9 Hz, 1H), 6.95 (s, 1H), 6.91 - 6.82 (m, 3H), 4.08 (q, J = 5.5 Hz, 4H), 3.58 (s, 2H), 2.06 (tt, J = 6.3, 3.4 Hz, 2H).

[0875] Example 15. A-(6-Bromo-l / / -indazol-3-yl)-2-(3,4-dihydro-2 / 7- benzo[Z>][l,4]dioxepin-7-yl)acetamide (Compound 1046).P4 1046 HTo a solution of 2-(3,4-dihydro-2 / f-benzo[Z>][l,4]dioxepin-7-yl)acetic acid (150 mg, 0.72 mmol, 1 eq) in pyridine (10 mb) P4 (153 mg, 0.72 mmol, 1 eq) was added, followed byTEA (150 pL, 1.08 mmol, 1.5 eq) and TBTU (347 mg, 1.08 mmol, 1,5 eq) at rt. The reaction mixture was stirred overnight at rt. The resulting mixture was then diluted with water (50 mL) and extracted with EA (3 x 50 mL). The organic layers were combined and washed with water and brine, dried over anh. Na2SC>4, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (0-50% EA / hexane as an eluent) and washed by hexane to give 1046 as a white solid (33 mg, yield 12%). Analytical data: 'HNMR (400 MHz, DMSO4), 5: 12.69 - 12.64 (m, 1H), 10.50 (s, 1H), 7.70 (dd, J = 8.8, 2.7 Hz, 1H), 7.64 - 7.58 (m, 1H), 7.13 (dq, J = 8.7, 1.7 Hz, 1H), 6.94 (s, 1H), 6.88 (d, J = 2.8 Hz, 2H), 4.08 (m, 4H), 3.59 (d, J = 2.8 Hz, 2H), 2.06 (td, J = 5.6, 2.7 Hz, 2H).

[0876] Example 16. / V-(6-Bromo-l-methyl-l / / -indazol-3-yl)-2-(3,4-dihydro-2 / 7- benzo[Z>][l,4]dioxepin-7-yl)acetamide (Compound 1049).To a solution of 2-(3,4-dihydro-2 / / -benzo[Z>][l,4]dioxepin-7-yl)acetic acid (150 mg, 0.77 mmol, 1 eq) in pyridine (10 mL) 6-bromo-l -methyl- l / / -indazol-3 -amine (174 mg, 0.77 mmol, 1.1 eq) was added, followed by TEA (150 pL, 1.08 mmol, 1.5 eq) and TBTU (347 mg, 1.08 mmol, 1,5 eq) at rt. The reaction mixture was stirred overnight at rt. The resulting mixture was then diluted with water (50 mL) and extracted with EA (3 x 25 mL). The organic layers were combined and washed with water and brine, dried over anh. Na2SO4, fdtered and concentrated in vacuo. The crude product was purified by recrystallization from EA / hexane to give 1049 as a white solid (19 mg, yield 6%).Analytical data: 'H NMR (400 MHz, DMSO-tL), 5: 10.65 (s, 1H), 7.87 (d, J = 1.7 Hz, 1H), 7.68 (d, J = 8.7 Hz, 1H), 7.15 (dd, J = 8.8, 1.7 Hz, 1H), 6.84 (s, 1H), 6.77 (s, 2H), 4.18 (s, 4H), 3.90 (s, 3H).

[0877] Example 17. A-(6-Cyclopropyl-l / 7-pyrazolo[4,3-c]pyridin-3-yl)-2-(2,3- dihydrobenzo[ / >][l,4]dioxin-6-yl)acetamide (Compound 2011).To a stirred solution of P12 (200 mg, 0.38 mmol, 1 eq) in a mixture of solvents MeOH / water 10 / 1 (5 mL) LiOH (14 mg, 0.58 mmol, 1.5 eq) was added. The resulting suspension was stirred at rt for 1 h. Then the reaction mixture was slightly acidified by adding AA, and all volatiles were removed in vacuo. The residue was washed by ACN several times, redissolved in DMSO and purified by preparative HPLC to give 2011 (15 mg, yield 14%).Analytical data: 'H NMR (400 MHz, DMSO-^e), 8: 12.65 (s, 1H), 10.71 (s, 1H), 9.00 (s, 1H), 7.20 (d, 1H), 6.88 (s, 1H), 6.85 - 6.76 (m, 2H), 4.22 (s, 3H), 3.61 (s, 2H), 2.14 (m, 1H), 1.00 - 0.86 (m, 4H).

[0878] Example 18. 2-(2,3-Dihydrobenzo[Z>][l,4]dioxin-6-yl)-A-(4-methyl-17T-indazol-3-yl)acetamide (Compound 3002).To a solution of acid P3 (288 mg, 1.15 mmol, 1 eq) in pyridine (5 mL) within a 10 mL screw-top vial P13 (170 mg, 1.15 mmol, 1 eq) was added, followed by TEA (520 pL, 3.5 mmol, 3.04 eq) and TBTU (552 mg, 1.7 mmol, 1,1 eq) at rt. The reaction mixture was stirred overnight at rt. The resulting mixture was then diluted with water (50 mL) and extracted with EA (3 x 25 mL). The organic layers were combined and washed with waterand brine, dried over anh. Na2SC>4, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC to give 3002 as a white solid (34 mg, yield 8%).Analytical data: 'H NMR (400 MHz, DMSO-tL), 5: 12.67 (s, 1H), 9.86 (s, 1H), 7.26 (d, J = 8.4 Hz, 1H), 7.18 (t, J = 6.7 Hz, 1H), 6.88 (s, 1H), 6.81-6.77 (m, 3H), 4.22 (s, 4H), 3.54 (s, 2H), 2.33 (s, 3H).

[0879] Example 19. 2-(3,4-Dihydro-2 / / -benzo[Z»][l,4]dioxepin-7-yl)-A-(l / / -indazol-3- yl)acetamide (Compound 3005).To a solution of 2-(3,4-dihydro-2 / / -benzo[Z>][l,4]dioxepin-7-yl)acetic acid (208 mg, 1 mmol, 1 eq) in pyridine (5 mL) within a 10 mL screw-top vial 177-indazol-3 -amine (133 mg, 1 mmol, 1 eq) was added, followed by TEA (150 pL, 1.08 mmol, 1.08 eq) and TBTU (802 mg, 2.5 mmol, 2,5 eq) at rt. The reaction mixture was stirred overnight at rt. The resulting mixture was then diluted with water (50 mL) and extracted with EA (3 x 50 mL). The organic layers were combined and washed with water and brine, dried over anh. Na2SC>4, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography to give 3005 as a white solid (48 mg, yield 15%).Analytical data: 'HNMR (400 MHz, DMSO-tL), 5: 12.56 (s, 1H), 10.46 - 10.28 (m, 1H), 7.68 (dd, J = 8.3, 2.8 Hz, 1H), 7.46 - 7.17 (m, 2H), 7.10 - 6.62 (m, 4H), 4.11 - 4.02 (m, 4H), 3.58 (d, J = 3.3 Hz, 2H), 2.06 (q, J = 4.2 Hz, 2H).

[0880] Example 20. 2-(3,4-Dihydro-2 / / -benzo[Z>][l,4]dioxepin-7-yl)-A-(5-methyl-l / 7- indazol-3-yl)acetamide (Compound 3011).To a solution of 2-(3,4-dihydro-2Z7-benzo[Z>][l,4]dioxepin-7-yl)acetic acid (150 mg, 0.72 mmol, 1 eq) in pyridine (10 mL) 5-methyl-l / 7-indazol-3-amine (106 mg, 0.72 mmol, 1 eq) was added, followed by TEA (150 pL, 1.08 mmol, 1.5 eq) and TBTU (347 mg, 1.08 mmol, 1.5 eq) at rt. The reaction mixture was stirred overnight at rt. The resulting mixture was then diluted with water (50 mL) and extracted with EA (3 x 50 mL). The organic layers were combined and washed with water and brine, dried over anh. Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (0-50% EA\hexane as an eluent) and washed by hexane to give 3011 as a white solid (11 mg, yield 5%).Analytical data: 'H NMR (400 MHz, DMSO-de), 5: 12.40 (s, 1H), 10.27 (s, 1H), 7.43 (s, 1H), 7.28 (dd, J = 8.5, 2.6 Hz, 1H), 7.11 (d, J = 8.6 Hz, 1H), 6.96 (s, 1H), 6.89 (s, 2H), 4.09 (s, 1H), 3.58 (s, 1H), 2.32 (s, 2H), 2.10 - 2.01 (m, 3H).

[0881] Example 21. 2-(3,4-Dihydro-2 / / -benzo[Z>][l,4]dioxepin-7-yl)-A-(6-methyl-l / 7- indazol-3-yl)acetamide (Compound 3012).3012To a solution of 2-(3,4-dihydro-2 / f-benzo[Z>][l,4]dioxepin-7-yl)acetic acid (150 mg, 0.72 mmol, 1 eq) in pyridine (10 mL) 6-methyl-17 / -indazol-3 -amine (106 mg, 0.72 mmol, 1 eq) was added, followed by TEA (150 pL, 1.08 mmol, 1.5 eq) and TBTU (348 mg, 1.08 mmol, 1.5 eq) at rt. The reaction mixture was stirred overnight at rt. The resulting mixture was then diluted with water (50 mL) and extracted with EA (3 x 50 mL). The organic layerswere combined and washed with water and brine, dried over anh. Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (0-50% EA\hexane as an eluent) and washed by hexane to give 3012 as a white solid (30 mg, yield 13%).Analytical data: 'HNMR (400 MHz, DMSO-tL), 8: 12.42 (d, J = 2.9 Hz, 1H), 10.44 (d, J = 2.8 Hz, 1H), 7.58 (dd, J = 8.4, 2.8 Hz, 1H), 7.14 (s, 1H), 6.96 (d, J = 2.6 Hz, 1H), 6.89 (d, J = 2.8 Hz, 2H), 6.81 (dd, J = 8.4, 2.7 Hz, 1H), 4.08 (s, 1H), 3.57 (s, 1H), 2.09 - 2.01 (m, 1H).

[0882] Example 22. A-(6-Cyclopropyl-177-indazol-3-yl)2-(2,3- dihydrobenzo[ / >][l,4]dioxin-6-yl)acetamide (Compound 4004).To a solution of acid P3 (234 mg, 1.21 mmol, 1 eq) in pyridine (5 mL) within a 10 mL screw-top vial P15 (209 mg, 1.21 mmol, 1 eq) was added, followed by TEA (468 pL, 3.63 mmol, 3 eq) and TBTU (582 mg, 1.81 mmol, 1.5 eq) at rt. The reaction mixture was stirred overnight at rt. The resulting mixture was then diluted with water (50 mL) and extracted with EA (3 x 50 mL). The organic layers were combined and washed with water and brine, dried over anh. NazSCU, fdtered and concentrated in vacuo. The crude product was purified by preparative HPLC to give 4004 as a white solid (21 mg, yield 5%).Analytical data: 'H NMR (400 MHz, DMSO-^), 8: 12.32 (s, 1H), 10.32 (s, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.08 (s, 1H), 6.88 (s, 1H), 6.83-6.78 (m, 2H), 6.74 (d, J = 8.3 Hz, 1H), 5.22 (s, 4H), 3.57 (s, 2H), 2.06-2.00 (m, 1H), 1.00-0.95 (m, 2H), 0.73-0.69 (m, 2H).

[0883] Example 23. A-(4-(17 / -Pyrazol-l-yl)-lLf-indazol-3-yl)-2-(2,3- dihydrobenzo[ / >][l,4]dioxin-6-yl)acetamide (Compound 4017).To a solution of P18 (110 mg, 0.2 mmol, 1 eq) in THF (20 mL) 0.1 N solution of LiOH in water (3 mL) was added. The reaction mixture was stirred for 2 h before completion (control by HPLC). The solution was diluted with EA, washed with water 2 times, dried over anh. Na2SC>4. The crude product was purified by preparative HPLC to give 4017 as a white solid (38 mg, yield 51%).Analytical data: ’H NMR (400 MHz, DMSO-tL), 5: 12.98 (s, 1H), 10.04 (s, 1H), 8.16 (s, 1H), 7.77 (s, 1H), 7.49 (dd, J = 8.5, 1.8 Hz, 1H), 7.40 (td, J = 8.4, 2.6 Hz, 1H), 7.22 (dd, J = 7.1, 1.8 Hz, 1H), 6.73-6.60 (m, 2H), 6.50-6.48 (m, 1H), 4.17 (s, 4H), 3.35 (s, 2H).

[0884] Example 24. 2-(2,3-Dihydrobenzo[Z>][l,4]dioxin-6-yl)-A-(5-(pyridin-3-yl)-l / 7- indazol-3-yl)acetamide (Compound 4028).To a solution of P21 (115 mg, 0.17 mmol) THF (10 mL) 0.1 N solution of LiOH in water (1.7 mL) was added. The reaction mixture was stirred for 2 h before completion (control by HPLC). The reaction mixture was diluted with EA, washed with water twice, dried over anh. Na2SO4. The crude product was purified by preparative HPLC to give 4028 (10 mg, yield 13%) as a white solid.Analytical data: 'HNMR (400 MHz, DMSO-Je), 5: 12.71 (s, 1H), 10.47 (s, 1H), 8.83 (d, J = 2.6 Hz, 1H), 8.54 (dd, J = 4.7, 1.5 Hz, 1H), 8.04 (s, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.69 (dd, J = 8.8, 1.8 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.57-7.48 (dd, J = 8.0, 4.5 Hz, 1H), 6.91 (br. s, 1H), 6.83-6.79 (m, 2H), 4.22 (s, 4H), 3.63 (s, 2H).

[0885] Example 25. 2-(2,3-Dihydrobenzo[Z>][l,4]dioxin-6-yl)-A-(6-phenyl-l / / -indazol-3- yl)acetamide (Compound 4045).To a solution of P3 (97 mg, 0.5 mmol, 0.96 eq) in pyridine (5 mL) within a 10 mL screwtop vial P23 (110 mg, 0.52 mmol, 1 eq) was added, followed by TEA (115 pL, 0.79 mmol, 1.52 eq) and TBTU (253 mg, 0.79 mmol, 1.52 eq) at rt. The reaction mixture was stirred overnight at rt. The resulting mixture was then diluted with water (50 mL) and extracted with EA (3 x 50 mL). The organic layers were combined and washed with water and brine, dried over anh. Na2SO4, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC to give 4045 as a white solid (12 mg, yield 7%).Analytical data: ’H NMR (400 MHz, DMSO-tfc), 5: 12.64 (s, 1H), 10.44 (s, 1H), 7.82- 7.33 (m, 8H), 6.90-6.82 (m, 3H), 4.23 (s, 4H), 3.62 (s, 2H).

[0886] Example 26. 2-(2,3-Dihydrobenzo[Z>][l,4]dioxin-6-yl)-A-(5-(5-fluoropyridin-3- yl)-17 / -indazol-3-yl)acetamide (Compound 4065).P26 (300 mg, 0.44 mmol) was dissolved in THF (10 mL) before 0.1 N solution of LiOH in water (1.7 mL) was added. The reaction mixture was stirred for 2 h before completion (control by HPLC). Then the solution was diluted with EA (50 mL), washed with water (2 x 20 mL), dried over anh. Na2SC>4. Purification of the crude product was achieved through preparative HPLC to give 4065 as a white solid (10 mg, yield 5%).Analytical data: 'H NMR (400 MHz, DMSO-tL), 5: 12.76 (s, 1H), 10.46 (s, 1H), 8.72 (s, 1H), 8.53 (d, J = 2.7 Hz, 1H), 8.11 (s, 1H), 7.93 (d, J =10.6 Hz, 1H), 7.71 (d, J = 8.6 Hz, 1H), 7.58 (d, J = 8.6 Hz, 1H), 6.91 (br. s, 1H), 6.83-6.79 (m, 2H), 4.22 (s, 4H), 3.64 (s, 2H).

[0887] Example 27. 2-(3,4-Dihydro-27 / -benzo[6][l,4]dioxepin-7-yl)-A-(6-phenyl-l / 7- indazol-3-yl)acetamide (Compound 4081).4081HTo a solution of 2-(3,4-dihydro-2 / / -benzo[ / >][l,4]dioxepin-7-yl)acetic acid (109 mg, 0.52 mmol, 1 eq) in pyridine (5 mL) within a 10 mL screw-top vial P23 (110 mg, 0.52 mmol, 1 eq) was added, followed by TEA (115 pL, 0.79 mmol, 1.52 eq) and TBTU (253 mg, 0.79 mmol, 2.08 eq) at rt. The reaction mixture was stirred overnight at rt. The resulting mixture was then diluted with water (50 mL) and extracted with EA (3 x 50 mL). The organic layers were combined and washed with water and brine, dried over anh. Na2SC>4, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC to give 4081 as a white solid (30 mg, yield 13%).Analytical data:1HNMR (400 MHz, DMSO-t / e), 5: 12.64 (s, 1H), 10.46 (s, 1H), 7.84 (dd, J = 8.4, 2.7 Hz, 1H), 7.72-7.70 (m, 2H), 7.62 (s, 1H), 7.51-7.46 (m, 2H), 7.40-7.33 (m, 2H), 4.14-4.10 (m, 4H), 3.64 (s, 2H), 2.12-2.08 (m, 2H).

[0888] Example 28. A-(5-Bromo-l / / -pyrazolo[3,4-Z>]pyridin-3-yl)-2-(2,3- dihydrobenzo[ / >][l,4]dioxin-6-yl)acetamide (Compound 2007).A mixture of 5-bromo-l / 7-pyrazolo[3,4-Z>]pyridin-3-amine (100 mg, 0.47 mmol, 1 eq), acid P3 (100 mg, 0.51 mmol, 1.1 eq) and CDI (152 mg, 0.94 mmol, 2 eq) in molten imidazole (320 mg, 4.7 mmol, 10 eq) was heated to 100°C under stirring for 5 h. Thereaction mixture was cooled to rt, dissolved in EA (50 mL) and washed with water (2 x 10 mL). The organic layers were combined, dried over anh. Na2SC>4 and filtered. All volatiles were removed in vacuo. The title product was purified by silica gel column chromatography (EA as an eluent) followed by crystallization from EtOH to give 2007 (14 mg, yield 8%).Analytical data: *HNMR (400 MHz, DMSO-tL), 5: 13.36 (s, 1H), 10.84 (s, 1H), 8.55 (m, 1H), 8.50 (m, 1H), 6.84 (s, 1H), 6.77 (m, 2H), 4.18 (s, 4H), 3.57 (s, 2H).

[0889] Example 29. A-(4-Chloro-17 / -pyrazolo[3,4-c]pyridin-3-yl)-2-(2,3- dihydrobenzo[Z>][l,4]dioxin-6-yl)acetamide (Compound 2008).A mixture of 4-chloro-17 / -pyrazolo[3,4-c]pyridin-3-amine (100 mg, 0.6 mmol, 1 eq), acid P3 (130 mg, 0.66 mmol, 1.1 eq) and CDI (193 mg, 1.2 mmol, 2 eq) in molten imidazole (400 mg, 6 mmol, 10 eq) was heated to 100°C under stirring for 3 h. The reaction mixture was cooled to rt, dissolved in EA (50 mL) and washed with water (2 x 10 mL). The organic layers were combined, dried over anh. Na2SC>4 and filtered. All volatiles were removed in vacuo. The title product was purified by silica gel column chromatography (15: 1 EA / MeOH as an eluent), to give 2008 (57 mg, yield 30%).Analytical data: 'H NMR (400 MHz, DMSO-t / e), 5: 13.67 (s, 1H), 10.06 (s, 1H), 8.89 (s, 1H), 8.13 (s, 1H), 6.84 (m, 1H), 6.76 (m, 2H), 4.19 (s, 4H), 3.53 (s, 2H).

[0890] Example 30. 2-(2,3-Dihydrobenzo[A][ l,4]dioxin-6-yl)- / V-(4,6-dimethyl- l / 7- pyrazolo[3,4-b]pyridin-3-yl)acetamide (Compound 2009).A mixture of4,6-dimethyl-l / f-pyrazolo[3,4-Z>]pyridin-3-amine (100 mg, 0.62 mmol, 1 eq), acid P3 (131 mg, 0.68 mmol, 1.1 eq) and CDI (200 mg, 1.24 mmol, 2 eq) in molten imidazole (419 mg, 6.2 mmol, 10 eq) was heated to 100°C under stirring for 3 h. The reaction mixture was cooled to rt, dissolved in EA and washed with water. The organic layers were combined, dried over anh. Na2SC>4 and fdtered. All volatiles were removed in vacuo. The crude product was purified by silica gel column chromatography (20: 1 EA / MeOH as an eluent), followed by crystallization from EtOH to give 2009 (3 mg, yield 1%).Analytical data: 'H NMR (400 MHz, DMSO-tfc), 8: 12.96 (s, 1H), 9.98 (s, 1H), 6.84 (s, 1H), 6.75 (m, 3H), 4.18 (s, 4H), 3.50 (s, 2H), 2.45 (s, 3H), 2.24 (s, 3H).

[0891] Example 31. A-(5-Bromo-4,6-dimethyl-l / / -pyrazolo[3,4-Z>]pyridin-3-yl)-2-(2,3- dihydrobenzo[Z>][l,4]dioxin-6-yl)acetamide (Compound 2012).A mixture of 5-bromo-4,6-dimethyl-l / / -pyrazolo[3,4- / >]pyridin-3-amine (50 mg, 0.21 mmol, 1 eq), acid P3 (40 mg, 0.21 mmol, 1 eq) and CDI (70 mg, 0.42 mmol, 2 eq) in molten imidazole (300 mg, mmol, ) was heated to 100°C under stirring for 1 h. The reaction mixture was cooled to rt and triturated in EA. The formed precipitate was collected and purified by preparative HPLC to give 2012 (3 mg, yield 4%).Analytical data: *HNMR (400 MHz, DMSO-dc), 5: 13.28 (s, 1H), 10.12 (s, 1H), 6.84 (m, 3H), 4.22 (s, 4H), 3.56 (s, 2H), 2.68 (s, 3H), 2.37 (s, 3H).

[0892] Example 32. 2-(2, 3 -Dihydrobenzo[Z>][l,4]dioxin-6-yl)-A-(5 -phenyl- 1H- pyrazolo[3,4-Z>]pyridin-3-yl)acetamide (Compound 2013).A mixture of 5-phenyl-l / / -pyrazolo[3,4-Z>]pyridin-3-amine (66 mg, 0.314 mmol, 1 eq), acid P3 (61 mg, 0.314 mmol, 1 eq) and CDI (100 mg, 0.63 mmol, 2 eq) in molten imidazole (300 mg) was heated to 100°C under stirring for 1.5 h. The reaction mixture was cooled to rt and triturated in EA. The formed precipitate was collected on a filter and discarded; filtrate was dried over anh. JSfeSCU, all volatiles were removed in vacuo. The crude product was purified by silica gel column chromatography (4: 1 EA / hexane as an eluent) to give 2013 (13 mg, yield 11%).Analytical data: 'HNMR (400 MHz, DMSO4), 8: 13.21 (s, 1H), 10.77 (s, 1H), 8.77 (d, 1H), 8.55 (d, 1H), 7.74 - 7.61 (m, 2H), 7.50 (dd, 2H), 7.44 - 7.35 (m, 1H), 6.89 (s, 1H), 6.86 - 6.74 (m, 2H), 4.21 (s, 4H), 3.64 (s, 2H).

[0893] Example 33. 2-(2,3-Dihydrobenzo[A][ l,4]dioxin-6-yl)- / V-(5-(6- morpholinopyri din-3 -yl)- 17 / -i ndazol -3 -yl)acetami de (Compound 4166).A mixture of P28 (100 mg, 0.34 mmol, 1 eq), acid P3 (72 mg, 0.37 mmol, 1.1 eq) and CD1 (110 mg, 0.68 mmol, 2 eq) in molten imidazole (230 mg, 3.4 mmol, 10 eq) was heated to 100°C under stirring for 2 h. The reaction mixture was cooled to rt, dissolved in EA (50 mL) and washed with water (2 x 10 mL). The organic layers were combined, dried over anh. NazSCE, filtered. All volatiles were removed in vacuo. The crude product was purified by silica gel column chromatography (EA as an eluent), followed by crystallization from EtOH to give 4166 (8 mg, yield 5%).Analytical data: 'HNMR (400 MHz, DMSO-^), 8: 12.57 (s, 1H), 10.38 (s, 1H), 8.35 (d, J = 2.6 Hz, 1H), 7.82 (d, J = 1.7 Hz, 1H), 7.75 (dd, J = 8.8, 2.6 Hz, 1H), 7.54 (dd, J = 8.7, 1.8 Hz, 1H), 7.44 (d, J = 8.7 Hz, 1H), 6.91 - 6.84 (m, 2H), 6.77 (t, J = 7.7 Hz, 2H), 4.18 (s, 4H), 3.72 - 3.65 (m, 4H), 3.57 (s, 2H), 3.48 - 3.41 (m, 4H).

[0894] Example 34. 2-(2,3-Dihydrobenzo[Z>][l,4]dioxin-6-yl)-Ar-(5-(6-(piperidin-l- yl)pyridin-3-yl)-l / / -indazol-3-yl)acetamide (Compound 4167).A mixture of P30 (100 mg, 0.34 mmol, 1 eq), acid P3 (66 mg, 0.34 mmol, 1 eq) and CDI (110 mg, 0.68 mmol, 2 eq) in molten imidazole (400 mg) was heated to 100°C under stirring for 2 h. The reaction mixture was cooled to rt, dissolved in EA (50 mL) and washed with water (2 x 10 mL). The organic layers were combined, dried over anh. Na2SC>4, fdtered. The crude product was purified by preparative HPLC to give 4167 (17 mg, yield 11%).Analytical data: 'H NMR (400 MHz, DMSO-t / 6), 8: 12.55 (s, 1H), 10.35 (s, 1H), 8.31 (d, 1H), 7.90 - 7.77 (m, 1H), 7.70 (dd, 1H), 7.54 (dd, 1H), 7.44 (dd, 1H), 4.19 (s, 4H), 3.58 (s, 2H), 3.55 - 3.48 (m, 4H), 1.75 - 1.36 (m, 6H).

[0895] Example 35. 2-(2,3-Dihydrobenzo[ / >][l,4]dioxin-6-yl)-A-(5-(6-(4- methylpiperazin-l-yl)pyridin-3-yl)-l / / -indazol-3-yl)acetamide (Compound 4177).A mixture of P32 (140 mg, 0.45 mmol, 1 eq), acid P3 (97 mg, 0.50 mmol, 1.1 eq) and CDI(150 mg, 0.9 mmol, 2 eq) in molten imidazole (310 mg, 4.5 mmol, 10 eq) was heated to 100°C under stirring for 5 h. The reaction mixture was cooled to rt, dissolved in EA (50 mL) and washed with water (2 x 10 mL). The organic layers were combined, dried over anh. Na2SC>4, filtered. All volatiles were removed in vacuo. The crude product was purified by silica gel column chromatography (1 / 1 DCM / MeOH as an eluent), followed by crystallization from EtOH to give 4177 (28 mg, yield 12.6%).Analytical data: 'H NMR (400 MHz, DMSO-tfc), 5: 12.57 (s, 1H), 10.38 (s, 1H), 8.33 (d, J = 2.6 Hz, 1H), 7.82 (s, 1H), 7.73 (dd, J = 8.8, 2.6 Hz, 1H), 7.54 (dd, J = 8.7, 1.7 Hz, 1H), 7.45 (d, J = 8.7 Hz, 1H), 6.91 - 6.84 (m, 2H), 6.78 (t, J = 7.5 Hz, 2H), 4.19 (s, 4H), 3.58 (s, 2H), 3.49 (t, J = 5.1 Hz, 4H), 2.39 (t, J = 5.1 Hz, 4H), 2.20 (s, 3H).

[0896] Example 36. 2-(2,3-Dihydrobenzo[Z>][l,4]dioxin-6-yl)-A-(5-(6-(4- isopropylpiperazin-l-yl)pyridin-3-yl)-l / / -indazol-3-yl)acetamide (Compound 4183).A mixture of 5-(6-(4-isopropylpiperazin-l-yl)pyridin-3-yl)-l / 7-indazol-3-amine P34 (100 mg, 0.3 mmol, 1 eq), acid P3 (58 mg, 0.3 mmol, 1 eq) and CDI (100 mg, 0.6 mmol, 2 eq) in molten imidazole (300 mg) was heated to 100°C under stirring for 3 h. The reaction mixture was cooled to rt, dissolved in EA (50 mL) and washed with water (2 x 10 mL). The organic layers were combined, dried over anh. Na2SC>4, filtered. All volatiles were removed in vacuo. The crude product was purified by preparative HPLC to give 4183 (65 mg, yield 43%).Analytical data: 'H NMR (400 MHz, DMSO-rfc), 5: 12.59 (s, 1H), 10.39 (s, 1H), 8.36 (d, 1H), 7.85 (d, 1H), 7.75 (dd, 1H), 7.57 (dd, 1H), 7.48 (d, 1H), 6.96 - 6.71 (m, 4H), 4.22 (s, 4H), 3.61 (s, 2H), 3.51 (m, 4H), 2.69 (m, 1H), 2.59 - 2.52 (m, 4H), 1.02 (d, 6H).

[0897] ExampleA-(6- Acetamido- 17f-indazol-3-yl)-2-(2,3 - dihydrobenzo[ / >][l,4]dioxin-6-yl)acetamide (Compound 6002).To a solution of P38 (0.091 g, 0.16 mmol, 1 eq) inMeOH (5 mL) K2CO3 (0.22 g, 1.6 mmol, 10 eq) was added. The reaction mixture was stirred at rt overnight. Then the mixture was filtered through a pad of Celite and the solvent was evaporated in vacuo. The product was purified by preparative RP-HPLC to give 6002 (0.011 g, yield 18%).

[0898] Example 38. A-(3-(2-(2,3-Dihydrobenzo[ / >][l,4]dioxin-6-yl)acetamido)-l / f- indazol-6-yl)-3-methylbutanamide (Compound 6015).To a solution of P39 (0.105 g, 0.17 mmol, 1 eq) inMeOH (5 mL)K2COs (0.23 g, 1.7 mmol, 10 eq) was added. The reaction mixture was stirred overnight at rt. Then the mixture was filtered through a pad of Celite, and the solvent was evaporated in vacuo. The crude product was purified by preparative RP-HPLC to afford 6015 (0.015 g, yield 21%).Analytical data: 'H NMR (400 MHz, DMSO-^e), 8: 12.43 (s, 1H), 10.49 (s, 1H), 9.95 (s, 1H), 8.07 (d, J = 1.7 Hz, 1H), 7.64 (d, J = 8.9 Hz, 1H), 6.95 (dd, J = 8.9, 1.7 Hz, 1H), 6.91 - 6.75 (m, 3H), 4.22 (s, 4H), 3.56 (s, 2H), 2.21 (d, J = 7.1 Hz, 2H), 2.17 - 2.00 (m, 1H), 0.94 (d, J = 6.6 Hz, 6H).

[0899] Example 39. 2-(2,3-Dihydrobenzo[Z»][l,4]dioxin-6-yl)-Az-(6-(methylsulfonamido)- l / / -indazol-3-yl)acetamide (Compound 6007).To a solution of P40 (0.1 g, 0.17 mmol, 1 eq) in MeOH (5 mb) K2CO3 (0.24 g, 1.7 mmol, 10 eq) was added. The reaction mixture was stirred overnight at rt. Then the mixture was filtered through a pad of Celite and the solvent was evaporated in vacuo. The crude product was purified by preparative RP-HPLC to afford 6007 (0.009 mg, yield 13%).

[0900] Example 40. 2-(2,3-Dihydrobenzo[Z>][l,4]dioxin-6-yl)-2V-(6-(phenylsulfonamido)- l / / -indazol-3-yl)acetamide (Compound 4141).To a solution of P41 (0.1 g, 0.16 mmol, 1 eq) in MeOH (5 mb) K2CO3 (0.22 g, 1.6 mmol, 10 eq) was added. The reaction mixture was stirred overnight at rt. Then the mixture was fdtered through a pad of Celite, and the solvent was evaporated in vacuo. The crude product was purified by preparative RP-HPLC to afford 4141 (0.019 g, yield 26%).Analytical data: 'H NMR (400 MHz, DMSO-rfc), 8: 12.43 (s, 1H), 10.48 (s, 1H), 10.39 (s, 1H), 7.81 - 7.70 (m, 2H), 7.64 - 7.46 (m, 4H), 7.12 (d, J = 1.9 Hz, 1H), 6.90 - 6.67 (m, 4H), 4.21 (s, 4H), 3.53 (s, 2H).

[0901] Example 41. 2-(2,3-Dihydrobenzo[Z>][l,4]dioxin-6-yl)-2V-(6-((2- methylpropyl)sulfonamido)-l / 7-indazol-3-yl)acetamide (Compound 6021).To a solution of P42 (0.1 g, 0.16 mmol, 1 eq) in MeOH (5 mL) K2CO3 (0.22 g, 1.6 mmol, 10 eq) was added. The reaction mixture was stirred overnight at rt. Then the mixture was fdtered through a pad of Celite, and the solvent was evaporated in vacuo. The crude product was purified by preparative RP-HPLC to give 6021 (0.007 g, yield 10%).

[0902] Example 42. 2-(2,3-Dihydrobenzo[Z>][l,4]dioxin-6-yl)-JV-(6-((phenylmethyl)sulfonamido)-l / / -indazol-3-yl)acetamide (Compound 4156).To a solution of P43 (0.109 g, 0.16 mmol, 1 eq) in MeOH (5 mL) K2CO3 (0.23 g, 1.6 mmol, 10 eq) was added. The reaction mixture was stirred overnight at rt. Then the mixture was filtered through a pad of Celite, and the solvent was evaporated in vacuo. The crude product was purified by preparative RP-HPLC to give 4156 (0.012 g, yield 15%).Analytical data: 'HNMR (400 MHz, DMSO-fifc), 5: 12.48 (s, 1H), 10.52 (s, 1H), 9.96 (s, 1H), 7.68 (d, J = 8.9 Hz, 1H), 7.40 - 7.30 (m, 3H), 7.30 - 7.18 (m, 3H), 6.94 - 6.76 (m, 4H), 4.46 (s, 2H), 4.22 (s, 4H), 3.57 (s, 2H).

[0903] Example 43. 2-(2,3-Dihydrobenzo[Z>][l,4]dioxin-6-yl)-2V-(5-(hexylsulfonamido)- l / 7-indazol-3-yl)acetamide (Compound 3019).To a solution of P47 (0.27 g, 0.51 mmol, 1 eq) in DCM (20 mL), 70% m- chloroper oxy benzoic acid (0.5 g, 2.04 mmol, 4 eq) was added, and the mixture was stirred at rt for 15 h. The solution was washed with aq JSfeSCh and NaHCCh, water, dried over anh. Na2SO4 and evaporated in vacuo. The residue was dissolved in MeOH (20 mL), K2CO3 (0.31 g, 2.25 mmol, 4.41 eq) was added, and the mixture was stirred at rt for 1 h. The formed precipitate was filtered and discarded, the filtrate was evaporated in vacuo. The crude product was purified by preparative RP-HPLC to give the title compound 3019 (0.071g, yield 41%).Analytical data: *HNMR (400 MHz, DMSO-^), 5: 13.25 (s, 1H), 10.75 (s, 1H), 8.04 - 7.93 (m, 2H), 7.59 - 7.48 (m, 1H), 6.95 - 6.78 (m, 3H), 4.22 (s, 4H), 3.61 (s, 2H), 3.25 (s, 3H).

[0904] Example 44. 2-(2,3-Dihydrobenzo[Z>][l,4]dioxin-6-yl)-A-(6-(pyrrolidin-l- ylsulfonyl)-l / / -indazol-3-yl)acetamide (Compound 4089).To a solution of P51 (0.15 g, 0.56 mmol, 1 eq) and DIPEA (0.22 g, 1.69 mmol, 3.02 eq) in dioxane (10 mb) acid P3 (0.11 g, 0.56 mmol, 1 eq) was added, following by addition of POCh (0.31 g, 1.12 mmol, 2 eq). The reaction mixture was heated to 50°C under stirring for 15 h, cooled and poured into sat. solution of NaHCCh in water. The formed precipitate was fdtered, washed with water, Et20 and dried to give 4089 (0.06 g, yield 25%).Analytical data: ’HNMR (400 MHz, DMSO-fifc), 5: 13.12 (s, 1H), 10.71 (s, 1H), 7.96 (d, J = 8.6 Hz, 1H), 7.86 (d, J = 1.5 Hz, 1H), 7.42 (dd, J = 8.7, 1.6 Hz, 1H), 6.94 - 6.75 (m, 3H), 4.22 (s, 4H), 3.61 (s, 2H), 3.23 - 3.08 (m, 4H), 1.75 - 1.56 (m, 4H).

[0905] Example 45. 2-(2,3-Dihydrobenzo[Z>][l,4]dioxin-6-yl)-A-(6-(pyridin-3-yl)-l / 7- indazol-3-yl)acetamide (Compound 4030).To a solution of P52 (0.26 g, 0.46 mmol, 1 eq) in mixture of solvents dioxane-water (10 mL + 0.5 mL) K2CO3 (0.13 g, 0.94 mmol, 2.04 eq) and 3-pyridine boronic acid (0.07 g, 0.57 mmol, 1.24 eq) and tetrakis(triphenylphosphine)palladium(0) (0.5% mol) were added under N2, and the reaction mixture was heated to 100°C under stirring for 8 h. After completion of the process the mixture was cooled to rt and diluted with EA (10 mL). The resulting mixture was filtered through a pad of Celite, and filtrate was concentrated in vacuo. The crude product was purified by preparative HPLC to give the title compound 4030 (29 mg, yield 16%).Analytical data: 'HNMR (400 MHz, DMSO-fik), 5: 12.88 (s, 1H), 10.63 (s, 1H), 9.07 (d, J = 2.3 Hz, 1H), 8.69 (d, J = 4.9 Hz, 1H), 8.40 (d, J = 8.1 Hz, 1H), 7.88 (d, J = 8.6 Hz, 1H), 7.77 (s, 1H), 7.71 (dd, J = 8.0, 5.1 Hz, 1H), 7.42 (d, J = 8.6 Hz, 1H), 7.01 - 6.77 (m, 3H), 4.22 (s, 4H), 3.61 (s, 2H).

[0906] Example 46. A-(5-Acetamido-l / 7-indazol-3-yl)-2-(2,3- dihydrobenzo[Z>][l,4]dioxin-6-yl)acetamide (Compound 6001).To a solution of P54 (0.15 g, 0.3 mmol, 1 eq) in dioxane (3 mL) TEA (0.04 g, 0.06 mL, 0.45 mmol, 1.5 eq) and then acetyl chloride (0.03 g, 0.36 mmol, 1.2 eq) were added, and the reaction mixture was stirred overnight at rt. The solvent was removed, the residue was dissolved in MeOH (2 mL). To the mixture K2CO3 (0.165 g, 1.2 mmol, 4 eq) was added, and the suspension was stirred overnight at rt. The mixture was diluted with EA (10 mL) and fdtered through a pad of Celite. The fdtrate was washed with water, the organic layer was separated, dried over anh. Na2SO4 and concentrated in vacuo. The crude product was purified by preparative HPLC to give 6001.

[0907] Example 47. 2-(2,3-Dihydrobenzo[Z>][l,4]dioxin-6-yl)-A-(5-(methylsulfonamido)- 17 / -indazol-3-yl)acetamide (Compound 6006).To a solution of P54 (0.15 g, 0.3 mmol, 1 eq) in ACN (3 mL) TEA (0.06 mL, 0.45 mmol, 1.5 eq) and then methanesulfonyl chloride (0.04 g, 0.36 mmol, 1.2 eq) were added. The reaction mixture was stirred overnight at rt. Then the solvent was removed, the residue wasdissolved in MeOH (2 mL). To the mixture K2CO3 (0.165 g, 1.2 mmol, 4 eq) was added, and the suspension was stirred overnight at rt. The mixture was diluted with EA (10 mL) and filtered through a pad of Celite. The filtrate was washed with water, the organic layer was separated, dried over anh. Na2SC>4 and concentrated in vacuo. The crude product was purified by preparative HPLC to give 6006.Analytical data: ’H NMR (400 MHz, DMSO-t / 6), 5: 12.68 (s, 1H), 10.50 (s, 1H), 9.44 (s, 1H), 7.62 (s, 1H), 7.41 (d, J = 8.9 Hz, 1H), 7.24 (d, J = 9.1 Hz, 1H), 6.93 - 6.74 (m, 3H), 4.22 (s, 4H), 3.58 (s, 2H), 2.88 (s, 3H).

[0908] Example 48. 2-(2,3-Dihydrobenzo[^][l,4]dioxin-6-yl)-A-(5-(3-methyl-2-oxo-2,3- dihydrobenzo[< / ]oxazole-6-sulfonamido)-l / 7-indazol-3-yl)acetamide (Compound 4185).Analytical data: ’H NMR (400 MHz, DMSO-tfc), 5: 12.59 (s, 1H), 10.43 (s, 1H), 9.96 (s, 1H), 7.58 (d, J = 1.7 Hz, 1H), 7.54 (dd, J = 8.2, 1.7 Hz, 1H), 7.50 - 7.41 (m, 1H), 7.33 - 7.22 (m, 2H), 7.05 (dd, J = 8.9, 2.0 Hz, 1H), 6.94 - 6.76 (m, 3H), 4.22 (s, 4H), 3.54 (s, 2H), 3.30 (s, 3H).

[0909] Example 49. A-(5-(Cyclopropanesulfonamido)-lZ7-indazol-3-yl)-2-(2,3- dihydrobenzo[ / >][l,4]dioxin-6-yl)acetamide (Compound 4051).Analytical data: 'H NMR (400 MHz, DMSO-tZ6), 8: 12.66 (s, 1H), 10.48 (s, 1H), 9.44 (s, 1H), 7.62 (d, J = 1.9 Hz, 1H), 7.39 (d, J = 8.9 Hz, 1H), 7.25 (dd, J = 8.9, 2.0 Hz, 1H), 6.93 - 6.66 (m, 3H), 4.21 (s, 4H), 3.58 (s, 2H), 2.47 - 2.38 (m, 1H), 0.95 - 0.77 (m, 4H).

[0910] Example 50. 2-(2,3-Dihydrobenzo[Z>][l,4]dioxin-6-yl)-A-(5-(thiophene-2- sulfonamido)-177-indazol-3-yl)acetamide (Compound 4106).H 4106Analytical data: 'H NMR (400 MHz, DMSO-<76), 8: 12.64 (s, 1H), 10.46 (s, 1H), 10.11 (s, 1H), 7.82 (dd, J = 5.0, 1.4 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H), 7.41 (dd, J = 3.7, 1.3 Hz, 1H), 7.32 (d, J = 8.9 Hz, 1H), 7.12 - 7.00 (m, 2H), 6.92 - 6.74 (m, 3H), 4.22 (s, 4H), 3.56 (s, 2H).

[0911] Example 51. 2-(2,3-Dihydrobenzo[^][l,4]dioxin-6-yl)-A-(5-(3,5- dimethylisoxazole-4-sulfonamido)-177-indazol-3-yl)acetamide (Compound 4161).H 4161Analytical data:1H NMR (400 MHz, DMSO-tC), 8: 12.64 (s, 1H), 10.45 (s, 1H), 10.20 (s, 1H), 7.42 (s, 1H), 7.34 (d, J = 8.9 Hz, 1H), 7.03 (dd, J = 8.9, 2.0 Hz, 1H), 6.92 - 6.76 (m, 3H), 4.22 (s, 4H), 3.56 (s, 2H), 2.31 (s, 3H), 2.16 (s, 3H).

[0912] Example 52. A-(5-(4-Cyclohexylphenylsulfonamido)-177-indazol-3-yl)-2-(2,3- dihydrobenzo[ / >][l,4]dioxin-6-yl)acetamide (Compound 4186).Analytical data: 'H NMR (400 MHz, DMSO-^), 5: 12.59 (s, 1H), 10.41 (s, 1H), 9.94 (s, 1H), 7.59 (d, J = 8.3 Hz, 2H), 7.47 (s, 1H), 7.36 - 7.22 (m, 3H), 7.05 (dd, J = 9.0, 2.0 Hz, 1H), 6.92 - 6.76 (m, 3H), 4.23 (s, 4H), 3.55 (s, 2H), 3.43 - 3.16 (m, 1H), 1.81 - 1.61 (m, 5H), 1.43 - 1.14 (m, 5H).

[0913] Example 53. 2-(2,3-Dihydrobenzo[Z>][l,4]dioxin-6-yl)-jV-(5-(2,3- dihydrobenzo[Z>][l,4]dioxine-6-sulfonamido)-l / / -indazol-3-yl)acetamide (Compound 4181)H 4181Analytical data: 'H NMR (400 MHz, DMSO-tfc), 5: 12.61 (s, 1H), 10.43 (s, 1H), 9.79 (s, 1H), 7.47 (d, J = 2.0 Hz, 1H), 7.30 (d, J = 8.9 Hz, 1H), 7.18 - 7.09 (m, 2H), 7.06 (dd, J = 9.0, 2.0 Hz, 1H), 6.93 - 6.85 (m, 2H), 6.85 - 6.75 (m, 2H), 4.29 - 4.16 (m, 8H), 3.56 (s, 2H).

[0914] Example 54. 2-(2,3-Dihydrobenzo[b][l,4]dioxin-6-yl)-7V-(5-(3,5-dimethyl-177- pyrazole-4-sulfonamido)-l / 7-indazol-3-yl)acetamide (Compound 4157).Analytical data: ’H NMR (400 MHz, DMSO-t / e), 5: 12.61 (s, 1H), 10.40 (s, 1H), 9.67 (s, 1H), 7.45 (d, J = 2.3 Hz, 1H), 7.30 (d, J = 8.9 Hz, 1H), 7.02 (dd, J = 9.0, 2.0 Hz, 1H), 6.93 - 6.72 (m, 3H), 4.22 (s, 4H), 3.55 (s, 2H), 2.10 (s, 6H).

[0915] Example 55. 2-(2,3-Dihydrobenzo[Z’][l,4]dioxin-6-yl)-A-(5-(pyridine-3- sulfonamido)-l / / -indazol-3-yl)acetamide (Compound 4150).H 4150Analytical data: 'HNMR (400 MHz, DMSO-de), 5: 12.31 (s, 1H), 10.19 (s, 1H), 8.77 (d, J = 2.3 Hz, 1H), 8.60 - 8.50 (m, 1H), 8.03 - 7.90 (m, 1H), 7.37 (dd, J = 7.9, 4.8 Hz, 1H), 7.18 (s, 1H), 7.13 (d, J = 8.9 Hz, 1H), 6.96 (dd, J = 8.9, 2.0 Hz, 1H), 6.92 - 6.77 (m, 3H), 4.23 (s, 4H), 3.54 (s, 2H).

[0916] Example 56. jV-(3-(2-(2,3-Dihydrobenzo[Z>][l,4]dioxin-6-yl)acetamido)-l / 7- indazol-5-yl)isobutyramide (Compound 6009).To a solution of P54 (0.19 g, 0.77 mmol, 1 eq) in dioxane (2 mL) DIPEA (0.3 g, 2.33 mmol, 3 eq) and z-butyric acid (0.09 g, 1 mmol, 1.3 eq) were added. Then to the reaction mixture POCh (0.18 g, 1.2 mmol, 1.6 eq) was added dropwise. The mixture was stirred overnight at rt. After completion of the process the solvent was evaporated in vacuo. The residue was diluted with DCM (10 mL) and washed with sat. aq. solution of NaHCCh and brine. The organic layer was separated, dried over anh. Na2SO4, filtered, and then concentrated in vacuo. The crude product was purified by preparative HPLC to give 6009. Analytical data: 'H NMR (400 MHz, DMSO-zfc), 5: 12.56 (s, 1H), 10.41 (s, 1H), 9.77 (s, 1H), 7.93 (s, 1H), 7.53 (dd, J = 8.9, 2.0 Hz, 1H), 7.34 (d, J = 8.9 Hz, 1H), 6.92 - 6.66 (m, 3H), 4.22 (s, 4H), 3.58 (s, 2H), 2.70 - 2.53 (m, 1H), 1.09 (d, J = 6.8 Hz, 6H).

[0917] Example 57. A-(5-(3-Cyclopentylureido)-17f-indazol-3-yl)-2-(2,3- dihydrobenzo[ / >][l,4]dioxin-6-yl)acetamide (Compound 4117).Analytical data: ’H NMR (400 MHz, DMSO-zfc), 5: 12.45 (s, 1H), 10.36 (s, 1H), 8.19 (s, 1H), 7.60 (s, 1H), 7.38 (dd, J = 9.0, 1.9 Hz, 1H), 7.29 (d, J = 8.9 Hz, 1H), 6.93 - 6.75 (m, 3H), 5.97 (d, J = 7.2 Hz, 1H), 4.22 (s, 4H), 4.00 - 3.79 (m, 1H), 3.56 (s, 2H), 1.93 - 1.72 (m, 2H), 1.72 - 1.44 (m, 4H), 1.43 - 1.18 (m, 2H).

[0918] Example 58. 2-(2,3-Dihydrobenzo[Z>][l,4]dioxin-6-yl)-7V-(5-(2-(pyridin-3- yl)acetamido)-l / / -indazol-3-yl)acetamide (Compound 4146).H 4146Analytical data: 'H NMR (400 MHz, DMSO-t / 6), 8: 12.60 (s, 1H), 10.46 (s, 1H), 10.26 (s, 1H), 8.73 (d, J = 2.1 Hz, 1H), 8.67 (d, J = 5.2 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H), 7.93 (d, J = 2.0 Hz, 1H), 7.73 (dd, J = 7.9, 5.2 Hz, 1H), 7.55 (dd, J = 9. 1, 2.0 Hz, 1H), 7.37 (d, J = 9.0 Hz, 1H), 6.91 - 6.66 (m, 3H), 4.21 (s, 4H), 3.84 (s, 2H), 3.57 (s, 2H).

[0919] Example 59. Ethyl 3-(2-(2,3-dihydrobenzo[Z>][l,4]dioxin-6-yl)acetamido)-l / 7- indazol-5-ylcarbamate (Compound 6010).Analytical data: 'HNMR (400 MHz, DMSO-t / e), 8: 12.54 (s, 1H), 10.36 (s, 1H), 9.45 (s, 1H), 7.81 (s, 1H), 7.34 (s, 2H), 6.93 - 6.75 (m, 3H), 4.22 (s, 4H), 4.10 (q, J = 7.0 Hz, 2H), 3.57 (s, 2H), 1.23 (t, J = 7.1 Hz, 3H).

[0920] Example 60. 2-(2,3-Dihydrobenzo[6][l,4]dioxin-6-yl)-JV-(17 / -pyrazolo[3,4- c]pyri din-3 -yl)acetamide (Compound 2002).To a solution of P55 (1 g, 7.4 mmol, 1 eq) and DIPEA (2.8 g, 22.4 mmol, 3.03 eq) in dioxane (25 mL) acid P3 (1.5 g, 7.8 mmol, 1.05 eq) and then POCh (1.4 g, 0.8 mb, 9 mmol, 1.2 eq) were added. The reaction mixture was heated to 50°C under stirring overnight, cooled and poured into sat. solution of NaHCCh in water (250 mL). The formed precipitate was fdtered, washed with water, dried to give 2002 (1.8 g, yield 77.8%).Analytical data: ’H NMR (400 MHz, DMSO-t / 6), 5: 13.94 (s, 1H), 11.07 (s, 1H), 9.27 (s, 1H), 8.23 (d, J = 6.1 Hz, 1H), 8.10 (d, J = 6.2 Hz, 1H), 6.94 - 6.72 (m, 3H), 4.22 (s, 4H), 3.64 (s, 2H).

[0921] Example 61. 2-(2,3-Dihydrobenzo[^][l,4]dioxin-6-yl)-A-(6-(l-methyl-177- pyrazol-4-ylsulfonyl)-4,5,6,7-tetrahydro-l / / -pyrazolo[3,4-c]pyridin-3-yl)acetamide (Compound 5015).To a solution of 2002 (1.7 g, 3.2 mmol, 1 eq) in a mixture of MeOH / THF (1 : 1, 100 mL). Pd / C (0.2 g) was added, and the mixture was stirred at rt under atmosphere of hydrogen for 24 h. Then the catalyst was removed by filtration, and the solution was concentrated in vacuo to dryness to afford PP (1.2 g, yield 74%).To a solution of PP (0.15 g, 0.4 mmol, 1 eq) in pyridine (3 mL) 1 -methyl- 17 / -pyrazole-4- sulfonyl chloride (0.1 g, 0.57 mmol, 1.43 eq) was added, and the reaction mixture was heated to 50°C under stirring overnight. The solvent was removed, the crude product was purified by preparative HPLC to give 5015.

[0922] Example 62. 2-(2,3-Dihydrobenzo[Zi][l,4]dioxin-6-yl)-Ar-(6-(isobuthylsulfonyl)- 4,5,6,7-tetrahydro-177-pyrazolo[3,4-c]pyridin-3-yl)acetamide (Compound 5010).Analytical data: ’H NMR (400 MHz, DMSO-tfc), 8: 10.13 (s, 1H), 6.86 - 6.69 (m, 3H), 4.28 (s, 2H), 4.21 (s, 4H), 3.47 (s, 2H), 3.38 (t, J = 5.7 Hz, 2H), 2.96 (d, J = 6.5 Hz, 2H), 2.47 - 2.39 (m, 2H), 2.10 (h, J = 6.7 Hz, 1H), 1.02 (d, J = 6.7 Hz, 6H).

[0923] Example 63. 2-(2,3-Dihydrobenzo[Z>][l,4]dioxin-6-yl)-JV-(6-(phenylsulfonyl)- 4,5,6,7-tetrahydro-l / 7-pyrazolo[3,4-c]pyridin-3-yl)acetamide (Compound 5013).Analytical data: ’H NMR (400 MHz, DMSO-tL), 8: 10.10 (s, 1H), 7.86 - 7.76 (m, 2H), 7.73 - 7.66 (m, 1H), 7.66 - 7.57 (m, 2H), 6.83 - 6.66 (m, 3H), 4.20 (s, 4H), 4.12 (s, 2H), 3.44 (s, 2H), 3.25 (t, J = 5.9 Hz, 2H), 2.42 (t, J = 5.9 Hz, 2H).

[0924] Example 64. 3-(2-(2,3-Dihydrobenzo[Z>][l,4]dioxin-6-yl)acetamido)-l / 7- pyrazolo[3,4-c]pyridine 6-oxide (Compound 2004).To a solution of 2002 (0.2 g, 0.6 mmol, 1 eq) in DCM (3 mL) MCPBA (0.29 g, 1.2 mmol, 2 eq) was added, and the reaction mixture was stirred overnight at rt. Then to reaction mixture 3 mL of sat. solution of Na2CCh in water was added, and the mixture was stirred at rt for 1 h. The organic layer was separated, dried over anh. Na2SC>4 and concentrated in vacuo. The crude product was purified by preparative HPLC to give 2004.Analytical data: 'H NMR (400 MHz, DMSO-rfc), 8: 10.85 (s, 1H), 8.50 (s, 1H), 7.80 (d, J = 7.0 Hz, 1H), 7.70 (d, J = 7.2 Hz, 1H), 6.92 - 6.74 (m, 3H), 4.21 (s, 4H), 3.58 (s, 2H).

[0925] Example 65. Ar-(5-Chloro-l / / -pyrazolo[3,4-Z>]pyridin-3-yl)-2-(2,3- dihydrobenzo[Z>][l,4]dioxin-6-yl)acetamide (Compound 2006).To a mixture of 5-chloro-l / / -pyrazolo[3,4-Z>]pyridin-3-amine (40 mg, 0.24 mmol, 1 eq), acid P3 (55.3 mg, 0.28 mmol, 1.17 eq) and DIPEA (45.9 mg, 0.36 mmol, 1.5 eq) in dioxane (2 mL) POCI3 (47.3 mg, 0.31 mmol, 1.3 eq) was added dropwise. The reaction mixture was stirred overnight at rt and quenched with 0.1 N solution of LiOH in water. The crude product was extracted with EA (3 x 20 mL). The organic layers were combined, washed with water and brine, concentrated in vacuo and purified by silica gel column chromatography (1 : 1 EA / hexane as an eluent) to afford 2006 as a white solid (20 mg, yield 24%).Analytical data: 'H NMR (400 MHz, DMSO-tL), 8: 13.35 (br. s, 1H), 10.8 (br. s, 1H), 8.55-8.25 (m, 2H), 7.01-6.65 (m, 3H), 4.17 (m, 4H), 2.76 (m, 2H).

[0926] Example 66. 2-(2,3-Dihydrobenzo[Z>][l,4]dioxin-6-yl)-A-(4-morpholino-177- indazol-3-yl)acetamide (Compound 4024).To a mixture of 5-chloro-4-morpholino-12 / -indazol-3-amine (50 mg, 0.23 mmol, 1 eq), 89 mg (458 mmol) of acid P3 (89 mg, 0.46 mmol, 2 eq) and DIPEA (88.8 mg, 0.69 mmol, 3 eq) in dioxane (2 mL) POCI3 (91.32 mg, 0.6 mmol, 2.6 eq) was added dropwise. Thereaction mixture was stirred overnight at rt and quenched with 0.1 N solution of Li OH in water. The crude product was extracted with EA (3 x 20 mL). The organic layers were combined, washed with water and brine, concentrated in vacuo and purified by silica gel column chromatography (1 : 1 EA / hexane as an eluent) to afford 4024 as a white solid (20 mg, yield 22%).Analytical data: 'H NMR (400 MHz, DMSO-de), 6: 12.72 (br. s, 1H), 9.66 (br. s, 1H), 7.4-6.3 (m, 6H), 4.17 (m, 4H), 3.75-3.25 (m, 6H), 2.95 (m, 4H).

[0927] Example 67. 2-(3,4-Dihydro-2 / / -benzo[ / >][l,4]dioxepin-7-yl)-A-(5-phenyl-l / 7- indazol-3-yl)acetamide (Compound 4080).To a solution of P57 (0.16 g, 0.27 mmol, 1 eq), phenylboronic acid (66 mg, 0.54 mmol, 2 eq), and tetrakis(triphenylphosphine)palladium(0) (32 mg, 0.027 mmol, 0.1 eq) in dioxane (3 mL) a solution of K2CO3 (77 mg, 0.54 mmol, 2 eq) in water (0.2 mL) was added. The reaction mixture was heated to 100°C under stirring for overnight under N2. Then the mixture was diluted with EA (10 mL) and filtered through a pad of Celite. The filtrate was washed with water, the organic layer was dried over anh. Na2SC>4 and concentrated in vacuo. The residue was purified by preparative HPLC to give 4080 (51.4 mg, yield 47.7%).

[0928] Example 68. 2-(3,4-Dihydro-2 / 7-benzo[Z>][l,4]dioxepin-7-yl)-A-(5-(pyridin-3-yl)- l / / -indazol-3-yl)acetamide (Compound 4062).4062 HAnalytical data: *HNMR (400 MHz, DMSO-^e), 5: 12.89 (s, 1H), 10.70 (s, 1H), 9.01 (d, J = 2.3 Hz, 1H), 8.70 (dd, J = 5.2, 1.5 Hz, 1H), 8.46 - 8.34 (m, 1H), 8.15 (d, J = 1.8 Hz, 1H), 7.77 (ddd, J = 19.2, 8.4, 3.5 Hz, 2H), 7.60 (d, J = 8.8 Hz, 1H), 7.06 - 6.87 (m, 3H), 4.10 (q, J = 6.1 Hz, 4H), 3.65 (s, 2H), 2.08 (t, J = 5.5 Hz, 2H).

[0929] Example 69. 2-(3,4-Dihydro-2 / 7-benzo[Z>][l,4]dioxepin-7-yl)-jV-(5-(4-(dimethylamino)phenyl)-17 / -indazol-3-yl)acetamide (Compound 4143).4143 HAnalytical data: *HNMR (400 MHz, DMSO-<76), 8: 12.61 (s, 1H), 10.52 (s, 1H), 7.87 7.77 (m, 1H), 7.57 (dd, J = 8.9, 1.7 Hz, 1H), 7.51 - 7.37 (m, 3H), 7.07 - 6.88 (m, 3H), 6.87 - 6.74 (m, 2H), 4.10 (q, J = 6.0 Hz, 4H), 3.63 (s, 2H), 2.93 (s, 6H), 2.18 - 2.02 (m, 2H).

[0930] Example 70. 2-(3,4-Dihydro-2Z7-benzo[Z>][l,4]dioxepin-7-yl)-jV-(5-(3-(dimethylamino)phenyl)-l / 7-indazol-3-yl)acetamide (Compound 4144).Analytical data: 'H NMR (400 MHz, DMSO-^,), 8: 12.72 (s, 1H), 10.58 (s, 1H), 7.92 (d, J = 1.7 Hz, 1H), 7.63 (dd, J = 8.7, 1.7 Hz, 1H), 7.50 (d, J = 8.7 Hz, 1H), 7.33 (t, J = 7.9 Hz, 1H), 7.15 - 6.73 (m, 6H), 4.15 - 4.01 (m, 4H), 3.63 (s, 2H), 3.02 (s, 6H), 2.08 (t, J = 5.5 Hz, 2H).

[0931] Example 71. 2-(3,4-Dihydro-2 / 7-benzo[6][l,4]dioxepin-7-yl)-A-(5-(pyrimidin-5- yl)-l / 7-indazol-3-yl)acetamide (Compound 4075).Analytical data: ’H NMR (400 MHz, DMSO-fifc), 8: 12.87 (s, 1H), 10.65 (s, 1H), 9.16 (s, 1H), 9.07 (s, 2H), 8.12 (d, J = 1.7 Hz, 1H), 7.75 (dd, J = 8.6, 1.8 Hz, 1H), 7.60 (d, J = 8.7 Hz, 1H), 7.07 - 6.87 (m, 3H), 4.10 (dt, J = 8.3, 5.4 Hz, 4H), 3.65 (s, 2H), 2.15 - 2.02 (m, 2H).

[0932] Example 72. Ar-(5-(3-Acetamidophenyl)-l / 7-indazol-3-yl)-2-(3,4-dihydro-2 / 7- benzo[ / >][l ,4]dioxepin-7-yl)acetamide (Compound 4151).4151 HAnalytical data: ’H NMR (400 MHz, DMSO-tffc), 8: 12.74 (s, 1H), 10.62 (s, 1H), 10.03 (s, 1H), 7.95 (s, 1H), 7.81 (s, 1H), 7.63 - 7.47 (m, 3H), 7.36 (t, J = 7.9 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 7.06 - 6.88 (m, 3H), 4.16 - 4.02 (m, 4H), 3.64 (s, 2H), 2.15 - 1.99 (m, 5H).

[0933] Example 73. 2-(3,4-Dihydro-2 / Abenzo[Z>][l,4]dioxepin-7-yl)-7V-(5-(6- methoxypyridin-3-yl)-l / / -indazol-3-yl)acetamide (Compound 4102).4102 HAnalytical data: 'HNMR (400 MHz, DMSO-t / e), 5: 12.74 (s, 1H), 10.60 (s, 1H), 8.39 (d, J = 2.5 Hz, 1H), 8.03 - 7.86 (m, 2H), 7.61 (d, J = 8.7 Hz, 1H), 7.52 (d, J = 8.7 Hz, 1H), 7.02 (s, 1H), 6.98 - 6.86 (m, 3H), 4.10 (d, J = 6.2 Hz, 4H), 3.89 (s, 3H), 3.63 (s, 2H), 2.16 - 1.87 (m, 2H).

[0934] Example 74. 2-(3,4-Dihydro-2 / / -benzo[Z>][l,4]dioxepin-7-yl)-7V-(5-(l-methyl-l / Z- indol-5-yl)-177-indazol-3-yl)acetamide (Compound 4163).4163 HAnalytical data: 'HNMR (400 MHz, DMSO-^), 5: 12.64 (s, 1H), 10.53 (s, 1H), 7.93 (s, 1H), 7.74 (s, 1H), 7.66 (d, J = 8.7 Hz, 1H), 7.50 (dd, J = 8.6, 5.7 Hz, 2H), 7.40 (d, J = 8.5 Hz, 1H), 7.34 (d, J = 3.1 Hz, 1H), 7.11 - 6.86 (m, 3H), 6.48 (d, J = 3.1 Hz, 1H), 4.09 (q, J = 5.7 Hz, 4H), 3.82 (s, 3H), 3.64 (s, 2H), 2.15 - 2.00 (m, 2H).

[0935] Example 75. (E)-2-(3,4-Dihydro-2 / / -benzo[Z>][l,4]dioxepin-7-yl)-A-(5-styryl-l / / - indazol-3-yl)acetamide (Compound 4128).4128 HAnalytical data: ’HNMR (400 MHz, DMSO<A), 5: 12.74 (s, 1H), 10.58 (s, 1H), 7.84 (s, 1H), 7.70 (dd, J = 9.0, 1.6 Hz, 1H), 7.65 - 7.55 (m, 2H), 7.44 (d, J = 8.8 Hz, 1H), 7.40 - 7.32 (m, 2H), 7.30 (s, 1H), 7.28 - 7.16 (m, 1H), 7.12 (d, J = 16.5 Hz, 1H), 7.02 (s, 1H), 7.00 - 6.89 (m, 2H), 4.11 (dt, J = 9.4, 5.3 Hz, 4H), 3.64 (s, 2H), 2.15 - 2.02 (m, 2H).

[0936] Example 76. 2-(3,4-Dihydro-27 / -benzo[6][l,4]dioxepin-7-yl)-A-(5-phenethyl-177- indazol-3-yl)acetamide (Compound 4129).To a solution of 4128 (0.1 g, 0.15 mmol, 1 eq) in MeOH (5 mL) Pd / C (0.01 g) was added. The reaction mixture was stirred at rt under atmosphere of hydrogen for 8 h. The catalyst was removed by filtration, and the solvent was evaporated in vacuo. The crude product was purified by preparative HPLC to give 4129.

[0937] Example 77. 2-(3,4-Dihydro-27 / -benzo[Z>][l,4]dioxepin-7-yl)-2V-(5-(phenylethynyl)-17 / -indazol-3-yl)acetamide (Compound 4130).4130 HA mixture of P57 (0.15 g, 0.25 mmol, 1 eq), TEA (0.35 mL, 2.5 mmol, 10 eq), triphenylphosphine (0.026 g, 0.1 mmol, 0.4 eq), Pd2(dba).3 (0.023 g, 0.05 mmol, 0.2 eq) and phenylacetylene (0.05 g, 0.5 mmol, 2 eq) in dried ACN (2 mL) was heated under reflux overnight under N2. After completion of the process the mixture was quenched with water (20 mL) and extracted with EA (3 x 30 mL). The organic layers were combined and dried over anh. Na2SC>4, filtered, and concentrated in vacuo. The residue was diluted in MeOH (2 mL), and K2CO3 (0.138 g, 1 mmol, 4 eq) was added. The reaction mixture was stirred at rt for 2 h. Then the mixture was diluted with water (30 mL), and MeOH was removed in vacuo. The crude product was extracted by EA (3 x 30 mL), dried over anh. Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC to give 4130Analytical data: 'HNMR (400 MHz, DMSO-fifc), 5: 12.89 (s, 1H), 10.69 (s, 1H), 8.01 (s, 1H), 7.60 - 7.52 (m, 2H), 7.52 - 7.45 (m, 2H), 7.45 - 7.37 (m, 3H), 7.13 - 6.88 (m, 3H), 4.10 (dt, J = 9.1, 5.4 Hz, 4H), 3.64 (s, 2H), 2.08 (t, J = 5.5 Hz, 2H).

[0938] Example 78. 2-(3,4-Dihydro-2J / -benzo[Z>][l,4]dioxepin-7-yl)-A-(5-(furan-2-yl)- 17 / -indazol-3-yl)acetamide (Compound 4044).To a mixture of P57 (0.15 g, 0.25 mmol, 1 eq), 2-(tributylstannyl)furan (0.18 g, 0.5 mmol, 2 eq) in anh. dioxane (5 mL) tetrakis(triphenylphosphine)palladium(0) (29 mg) was added. The reaction mixture was heated under reflux for 16 h. After the process was completed (control by TLC-analysis), the reaction mixture was cooled, and the solvent was evaporated in vacuo. The residue was diluted with EA and filtered through a pad of Celite. Then the filtrate was washed with water, brine, dried over anh. Na?SO4 and filtered. The solvent was evaporated in vacuo. The residue was dissolved in MeOH (10 mL), and K2CO3 (0.138 g, 1 mmol, 4 eq) was added to the solution. The suspension was stirred at rt for 2 h. The solvent was removed in vacuo, the crude product was purified by preparative HPLC to give 4044.

[0939] Example 79. 2-(3,4-Dihydro-277-benzo[Z>][l,4]dioxepin-7-yl)-A-(5-(thiazol-5-yl)- l / 7-indazol-3-yl)acetamide (Compound 4032).Analytical data: ’HNMR (400 MHz, DMSO-tL), 5: 12.84 (s, 1H), 10.65 (s, 1H), 9.03 (s, 1H), 8.19 (s, 1H), 8.00 (d, J = 1.7 Hz, 1H), 7.70 (dd, J = 8.7, 1.8 Hz, 1H), 7.51 (d, J = 8.7Hz, 1H), 7.07 - 6.88 (m, 3H), 4.11 (dt, J = 8.6, 5.4 Hz, 4H), 3.64 (s, 2H), 2.09 (t, J = 5.5 Hz, 2H).

[0940] Example 80. 2-(2,3-Dihydrobenzo[Zi][l,4]dioxin-6-yl)-A-(5-(3-(dimethylamino)phenyl)-17 / -indazol-3-yl)acetamide (Compound 4110).4110 HTo a mixture of P58 (0.16 g, 0.27 mmol, 1 eq), 3-A,A-dimethyl)phenylboronic acid (89.1 mg, 0.54 mmol, 2 eq) and tetrakis(triphenylphosphine)palladium(0) (32 mg, 0.027 mmol, 0.1 eq) in dioxane (3 mL) a solution of K2CO3 (77 mg, 0.54 mmol,) in water (0.2 mL) was added. The reaction mixture was heated to 100°C under stirring overnight under N2. Then the mixture was diluted with EA (10 mL) and filtered through a pad of Celite. The filtrate was washed with water, the organic layer was separated, dried over anh. Na2SC>4 and concentrated in vacuo. The crude product was purified by preparative HPLC to give 4110. Analytical data: 'H NMR (400 MHz, DMSO-t / e), 5: 12.72 (s, 1H), 10.56 (s, 1H), 7.91 (s, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.50 (d, J = 8.7 Hz, 1H), 7.33 (t, J = 7.9 Hz, 1H), 7.13 - 6.99 (m, 2H), 6.96 - 6.86 (m, 2H), 6.86 - 6.75 (m, 2H), 4.21 (s, 4H), 3.60 (s, 2H), 3.02 (s, 6H).

[0941] Example 81. A-(5-Cyclopropyl-17 / -indazol-3-yl)-2-(2,3- dihydrobenzo[ / >][l,4]dioxin-6-yl)acetamide (Compound 4003).Analytical data:10.52 (s, 1H), 7.46 -126 (m, 2H), 7.03 (d, J = 8.7 Hz, 1H), 6.90 (s, 1H), 6.82 (d, J = 3.8 Hz, 2H), 4.22 (s, 4H),3.58 (s, 2H), 1.97 (d, J = 9.8 Hz, 1H), 0.96 - 0.84 (m, 2H), 0.58 (d, J = 5.8 Hz, 2H).

[0942] Example 82. A-(6-Chloro-5-(pyridin-3-yl)-l / 7-indazol-3-yl)-2-(2,3- dihydrobenzo[ / >][l,4]dioxin-6-yl)acetamide (Compound 4068).To a mixture of P62 (0.06 g, 0.1 mmol, 1 eq) in a mixture of dioxane / water (10 mL / 0.5 mL) K2CO3 (0.02 g, 0.15 mmol, 1.5 eq) and 3-pyridine boronic acid (14 mg, 0.11 mmol,1.1 eq) were added. After then tetrakis(triphenylphosphine)palladium(0) (0.5% mol) was added under N2, and the reaction mixture was heated to 100°C under stirring for 8 h. After the completion of the process the mixture was diluted with EA (10 mL) and filtered through a pad of Celite. The filtrate was washed with water, the organic layer was separated, dried over anh. TsfeSCU and concentrated in vacuo. The crude product was purified by preparative HPLC to give 4068 (21 mg, yield 50%).Analytical data: *HNMR (400 MHz, DMSO-tfc), 5: 12.95 (s, 1H), 10.76 (s, 1H), 8.76 - 8.64 (m, 2H), 8.05 (dt, J= 7.9, 1.9 Hz, 1H), 7.93 (s, 1H), 7.72 (s, 1H), 7.66 (dd, J= 7.9,5.1 Hz, 1H), 6.89 - 6.72 (m, 3H), 4.19 (s, 4H), 3.58 (s, 2H).

[0943] Example 83. Ar-(5-Bromo-6-chloro-l / 7-indazol-3-yl)-2-(2,3- dihydrobenzo[Z>][l,4]dioxin-6-yl)acetamide (Compound 1036).To a solution of P62 (0.15 g, 0.25 mmol, 1 eq) in MeOH (15 mL) K2CO3 (0.07g, 0.50 mmol, 2 eq) was added, and the reaction mixture was stirred at rt for 3 h. Then the mixture was filtered through a pad of Celite, and filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC to give 1036 (44 mg, yield 42%). Analytical data: 'H NMR (400 MHz, DMSO-^e), 5: 12.95 (s, 1H), 10.76 (s, 1H), 8.24 (s, 1H), 7.75 (s, 1H), 6.96 - 6.70 (m, 3H), 4.22 (s, 4H), 3.59 (s, 2H).

[0944] Example 84. Benzyl 3-(2-(3,4-dihydro-2 / / -benzo[Z>][l,4]dioxepin-7- yl)acetamido)-17f-indazol-5-ylcarbamate (Compound 4169).4169To a solution of P65 (0.1 g, 0.29 mmol, 1 eq) in DCM (2 mL) TEA (0.1 mL, 0.6 mmol, 2 eq) was added, and the solution was cooled to -5°C. Then benzyl chloroformate (0.05 g, 0.3 mmol, 1 eq) was added to the solution, and the reaction mixture was stirred overnight at rt. After completion of the process the solvent was evaporated in vacuo, the residue was dissolved in MeOH (2 mL). To the obtained solution K2CO3 (0.042 g, 0.3 mmol, 1 eq) was added, and the mixture was stirred overnight at rt. After that the mixture was diluted with EA (10 mL) and filtered through a pad of Celite. The filtrate was washed with water, the organic layer was dried over anh. Na2SO4, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC to give 4169 (24 mg, yield 12,5%).Analytical data: ’H NMR (400 MHz, DMSO-t / 6), 5: 12.57 (s, 1H), 10.41 (s, 1H), 9.64 (s, 1H), 7.84 (s, 1H), 7.48 - 7.21 (m, 7H), 7.04 - 6.87 (m, 3H), 5.14 (s, 2H), 4.18 - 4.02 (m, 4H), 3.60 (s, 2H), 2.08 (t, J = 5.6 Hz, 2H).

[0945] Example 85. A-(5-Acetamido-17 / -indazol-3-yl)-2-(3,4-dihydro-2J7- benzo[Z>][l,4]dioxepin-7-yl)acetamide (Compound 6003).To a solution of P65 (0.3 g, 0.56 mmol, 1 eq) in dioxane (3 mL) TEA (0.12 mL, 0.85 mmol, 1.52 eq) and then acetyl chloride (0.05 g, 0.6 mmol, 1.07 eq) were added. The reaction mixture was stirred overnight at rt. Then the solvent was removed in vacuo, the residue was dissolved in MeOH (2 mL), K2CO3 (0.3 g, 2.2 mmol, 3.9 eq) was added, and the mixture was stirred overnight at rt. Then the mixture was diluted with EA (10 mL) and filtered through a pad of Celite. The filtrate was washed with water, the organic layer was dried over anh. Na?SO4 and concentrated in vacuo. The crude product was purified by preparative HPLC to give 6003 (76 mg, yield 35.7%).Analytical data: 'HNMR (400 MHz, DMSO-d6), 8: 12.56 (s, 1H), 10.44 (s, 1H), 9.87 (s, 1H), 7.87 (s, 1H), 7.53 (d, J = 9.1 Hz, 1H), 7.35 (d, J = 9.0 Hz, 1H), 7.04 - 6.89 (m, 3H), 4.19 - 4.02 (m, 4H), 3.60 (s, 2H), 2.09 (t, J = 5.6 Hz, 2H), 2.01 (s, 3H).

[0946] Example 86. A-(3-(2-(3,4-Dihydro-277-benzo[6][l,4]dioxepin-7-yl)acetamido)- l / / -indazol-5-yl)benzamide (Compound 4134).H 4134Analytical data: 'H NMR (400 MHz, DMSO-t / 6), 8: 12.64 (s, 1H), 10.48 (s, 1H), 10.26 (s, 1H), 8.10 (s, 1H), 8.03 - 7.91 (m, 2H), 7.66 (dd, J = 9.0, 2.0 Hz, 1H), 7.62 - 7.47 (m,3H), 7.42 (d, J = 8.9 Hz, 1H), 7.05 - 6.82 (m, 3H), 4.18 - 4.02 (m, 4H), 3.62 (s, 2H), 2.14 - 1.95 (m, 2H).

[0947] Example 87. 2-(3,4-Dihydro-2 / / -benzo[Z>][l,4]dioxepin-7-yl)- / V-(5-(phenylsulfonamido)-177-indazol-3-yl)acetamide (Compound 4155).To a solution of P65 (0.2 g, 0.37 mmol, 1 eq) in ACN (3 mL) TEA (0.08 mL, 0.56 mmol, 1.5 eq) and then benzensulfonyl chloride (0.087 g, 0.49 mmol, 1.32 eq) were added. The reaction mixture was stirred overnight at rt. After completion of the process the solvent was removed in vacuo, the residue was dissolved in MeOH (2 mL), K2CO3 (0.26 g, 1.9 mmol, 5.13 eq) was added, and the mixture was stirred overnight at rt. Then the mixture was diluted with EA and filtered through a pad of Celite. The filtrate was washed with water, the organic layer was dried over anh. Na2SC>4 and concentrated in vacuo. The crude product was purified by preparative HPLC to give 4155 (76 mg, yield 42.9%).Analytical data: 'HNMR (400 MHz, DM SO-6 / 4), 5: 12.62 (s, 1H), 10.46 (s, 1H), 9.99 (s, 1H), 7.73 - 7.61 (m, 2H), 7.61 - 7.51 (m, 1H), 7.51 - 7.40 (m, 3H), 7.28 (d, J = 8.9 Hz, 1H), 7.02 (dd, J = 8.9, 2.0 Hz, 1H), 7.00 - 6.87 (m, 3H), 4.12 (dt, J = 10.5, 5.4 Hz, 4H), 3.59 (s, 2H), 2.16 - 2.02 (m, 2H).

[0948] Example 88. 2-(3,4-Dihydro-277-benzo[Z>][l,4]dioxepin-7-yl)-A-(5-(methylsulfonamido)-17 / -indazol-3-yl)acetamide (Compound 6011).6011 HAnalytical data: 'H NMR (400 MHz, DMSO-t / e), 5: 12.69 (s, 1H), 10.53 (s, 1H), 9.44 (s, 1H), 7.62 (d, J = 2.0 Hz, 1H), 7.41 (d, J = 8.9 Hz, 1H), 7.24 (dd, J = 8.9, 2.0 Hz, 1H), 7.04 - 6.91 (m, 3H), 4.18 - 4.01 (m, 4H), 3.61 (s, 2H), 2.87 (s, 3H), 2.08 (t, J = 5.5 Hz, 2H).

[0949] Example 89. 2-(3,4-Dihydro-277-benzo[Z>][l,4]dioxepin-7-yl)-A-(5-(l-methyl-l / 7- pyrazole-4-sulfonamido)-l / / -indazol-3-yl)acetamide (Compound 4159).Analytical data: 'HNMR (400 MHz, DMSO-^e), 5: 12.64 (s, 1H), 10.52 (s, 1H), 9.81 (s, 1H), 8.04 (s, 1H), 7.58 (s, 1H), 7.51 (d, J = 1.9 Hz, 1H), 7.32 (d, J = 8.9 Hz, 1H), 7.08 (dd, J = 8.9, 2.1 Hz, 1H), 7.03 - 6.88 (m, 3H), 4.17 - 4.03 (m, 4H), 3.76 (s, 3H), 3.61 (s, 2H), 2.15 - 2.02 (m, 2H).

[0950] Example 90. A-(6-bromo- 1 -methyl- 1 H-indazol -3 -yl)-2-(2,3 - dihydrobenzo[b][l,4]dioxin-6-yl)acetamide (Compound 1049a).Analytical data: 'H NMR (400 MHz, DMSO-Z)6), 8: 10.65 (s, 1H), 7.87 (d, J = 1.7 Hz, 1H), 7.68 (d, J = 8.7 Hz, 1H), 7.15 (dd, J = 8.8, 1.7 Hz, 1H), 6.84 (s, 1H), 6.77 (s, 2H), 4.18 (s, 4H), 3.90 (s, 3H).

[0951] Example 91. A-(6-cyano-lH-indazol-3-yl)-2-(2,3-dihydrobenzo[b][l,4]dioxin-6- yl)acetamide (Compound 3007).Analytical data: 'H NMR (400 MHz, DMSO-Pe), 8: 13.22 (s, 1H), 10.72 (s, 1H), 8.05 - 8.00 (m, 1H), 7.89 (dd, J = 8.5, 0.9 Hz, 1H), 7.32 (dd, J = 8.5, 1.4 Hz, 1H), 6.85 (s, 1H), 6.78 (s, 1H), 4.18 (s, 4H), 3.57 (s, 2H).

[0952] Example 92. 'H NMR spectra of certain examples of the present disclosure.Biological Assays

[0953] Example A. Primary Assay Used to Determine Potency of CDK2 / CyclinA2 enzymatic activity Inhibition.

[0954] Compound activity was determined using recombinant CDK2 / CyclinA2 proteins (SignalChem, Cat# C29-10G), Histone Hl Peptide (SignalChem, Cat# H10-58) and ATP from ADP-Glo™ Kinase Assay kit (Promega, Cat# V9102) in an in vitro enzymatic reaction. Final concentrations were 0.1 ng / pL, 0.05 pg / pL and 5 pM, respectively. The reaction was carried out in assay buffer: 40 mM TRIS-HC1 pH 7.4-7.6, 20 mM MgCU, 0.05 mM DTT, 0.1 mg / mL BSA. The compounds were dispensed on a 384-well Diamond Well Plate (Axygen, Cat# P-384-120SQ-C-S) at 80x solutions of compounds in DMSO. 2x CDK2 / CyclinA2 -Hi stone Hl Peptide mix was prepared in assay buffer and 4 pL of mixture per well was added into 384-well white Reaction plate with NBS (Coming, Cat# 4513). 4 pL of Histone Hl Peptide w / o CDK2 / CyclinA2 was used for negative control. Plates were centrifuged for 1 min at 200 g. Then 80x solutions of compounds in DMSO were diluted down to 2x solutions in 2x ATP and 4 pL of these solutions were added into wells with 4 pL of CDK2 / CyclinA2 -Histone Hl Peptide mix. Plates were centrifuged for 1 min at 200 g and incubated for 1 h at rt. Then 4 pL of ADP-Glo reagent (Promega, ADP- Glo™ Kinase Assay, Cat# V9102) per well was added. Plates were incubated for 30 minat rt. Then 8 pL of Kinase detection reagent (Promega, ADP-Glo™ Kinase Assay, Cat# V9102) per well was added and the Luminescence was measured using microplate reader ClarioStarPlus (BMG). The % inhibition was then used to calculate the IC50 values in GraphPad Prism using four-parametric ...

Claims

CLAIMSWhat is claimed is:

1. A compound of F ormul a (A) :or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein: each bond - is selected from a single bond and a double bond; each Q is independently selected from CH and N if the bond - is a double bond, and each Q is dependently selected from CH2 and NH if the bond - is a single bond;RQis selected from H, R1, R7and -N(R6)-L6-Rn; k is an integer selected from 1, 2, and 3; r is an integer selected from 0, 1, and 2; p is an integer selected from 0 and 1;R1is selected from -OH, -CN, halogen, Ci-Ce alkyl, Ci-Ce alkoxy, -S(O)2N(R6)2, - S(O)2Ci-Ce alkyl, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, Ci-Ce alkyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl; each R2is independently selected from H, Ci-Ce alkyl;R3is selected from H, Ci-Ce alkyl, -NHC(O)Ci-Ce alkyl, -NHC(O)O-Ci-Ce alkyl; each R6is independently selected from H, Ci-Ce alkyl, C3-C10 cycloalkyl, - C(O)OCi-Ce alkyl, or aryl, wherein the alkyl, cycloalkyl or aryl is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NH2, - N(Ci-Ce alkyl)2, Ci-Ce alkoxy, -(CH2)P-aryl;R7is -L-R8, L2-R10;L is selected from bond, -O(CH2)V-, -S-, -NR6(CH2)V(O)P(CH2)P-, -C(O)-, -(O)p- S(O)2-, -NH(CO)(CH2)P-, -NHS(O)2(CH2)P-, -NHC(O)NH-, -NHC(O)O(CH2)P, -(CH2)d-, - CH=CH-, -C=C-;L2is selected from C(O), S(O)2, NR6C(O), NR6S(O)2,NR6C(O)O;L6is selected from C(O), S(O)2, NR6C(O), NR6S(O)2;R8selected from C3-C10 cycloalkyl, 4-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from R9; each R9is independently selected from halogen, oxo, -OH, -N(R6)2, -CN, Ci-Ce alkyl, Ci-Ce alkoxy, -NHC(O)CI-C6 alkyl, C3-C10 cycloalkyl, -(O)p-(CH2)p-aryl, -NR6-aryl, -C(O)Ci-Ce alkyl, heterocyclyl, -S(O)2heteroaryl, heteroaryl, wherein the alkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more substitutients independently selected from halogen, Ci-Ce alkyl, N(R6)2;R10is selected from Ci-Ce alkyl, Ci-Ce alkoxy, -N(R6)2, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from R9;R11is selected from Ci-Ce alkyl, Ci-Ce alkoxy, -N(R6)2, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from R9.

2. The compound of claim 1, wherein the compound is of Formula (I):or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein: each R1is independently selected from halogen, Ci-Ce alkoxy; each R2is independently selected from H, Ci-Ce alkyl;R3is selected from H, Ci-Ce alkyl, -NHC(O)CI-C6 alkyl, -NHC(O)O-CI-C6 alkyl;R4is selected from H, halogen, Ci-Ce alkyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, C3- C10 cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, -N(R6)2, -OC(O)N(R6)2, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, Ci-Ce alkyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, andR5is selected from H, halogen, Ci-Ce alkyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, C3- C10 cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, -N(R6)2, -OC(O)N(R6)2, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, Ci-Ce alkyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl andR4and R3together with the atoms to which they are attached and any intervening atoms, form 4-10 membered heterocycle, 5-10 membered heteroarene wherein the heterocycle or heteroarene is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, Ci-Ce alkyl, Ci-Ce halogenalkyl, Ci- Ce alkoxy, C3-C10 cycloalkyl, aryl; each R6is independently selected from H, Ci-Ce alkyl, C3-C10 cycloalkyl, - C(O)OCi-Ce alkyl, or aryl, wherein the alkyl, cycloalkyl or aryl is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NH2, - N(Ci-Ce alkyl)2, Ci-Ce alkoxy, -(CH2)P-aryl; n is an integer selected from 1 and 2;p is an integer selected from 0 and 1; provided that when n is i and R1is Br, then at least one from substitutients R4and R?is different from H.

3. The compound of claim 1, wherein the compound is of Formula (II):wherein: each W is independently selected from N, CH, provided that at least one W is N and provided that at least two W are CH; each R1is independently selected from halogen, Ci-Ce alkoxy, C3-C7 cycloalkyl, oxo, aryl, 5-10 membered heteroaryl;R2is selected from H, Ci-Ce alkyl;R3is selected from H, Ci-Ce alkyl, -NHC(O)Ci-Ce alkyl, -NHC(O)O-CI-C6 alkyl;R4is selected from H, halogen, Ci-Ce alkyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, C3- C10 cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, -N(R6)2, -OC(O)N(R6)2, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, Ci-Ce alkyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, andR?is selected from H, halogen, Ci-Ce alkyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, C3- C10 cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, -N(R6)2, -OC(O)N(R6)2, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, orheteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, Ci-Ce alkyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl andR4and R5together with the atoms to which they are attached and any intervening atoms, form 4-10 membered heterocycle, 5-10 membered heteroarene wherein the heterocycle or heteroarene is optionally substituted with one or more substituents independently selected from halogen, oxo, OH, CN, Ci-Ce alkyl, Ci-Ce halogenalkyl, Ci- Ce alkoxy, C3-C10 cycloalkyl, aryl; each R6is independently selected from H, Ci-Ce alkyl, C3-C10 cycloalkyl, - C(O)OCi-Ce alkyl, or aryl, wherein the alkyl, cycloalkyl or aryl is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NH2, - N(Ci-Ce alkyl)2, Ci-Ce alkoxy, -(CH2)P-aryl; p is an integer selected from 0 and 1; m is an integer selected from 0, 1, 2 and 3.

4. The compound of claim 1, wherein the compound is of Formula (III):or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein:R1is selected from -OH, -CN, CI-CG alkyl, CI-CG alkoxy, -S(O)2N(R6)2, -S(O)2Ci- CG alkyl, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selectedfrom halogen, OH, NH2, CN, Ci-Ce alkyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl;R2is selected from H, Ci-Ce alkyl;R3is selected from H, Ci-Ce alkyl, -NHC(O)Ci-Ce alkyl, -NHC(O)O-Ci-Ce alkyl; each R6is independently selected from H, Ci-Ce alkyl, C3-C10 cycloalkyl; k is an integer selected from 1, 2, and 3; n is an integer selected from 0, 1, and 2.

5. The compound of claim 1, wherein the compound is of Formula (IV):or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein: each R1is independently selected from halogen, Ci-Ce alkyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, heterocycle, cycloalkyl, aryl, or heteroaryl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, CN, Ci-Ce alkyl, Ci-Ce alkoxy, C3-C10 cycloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, heterocycle, aryl, and heteroaryl;R2is selected from H, Ci-Ce alkyl;R3is selected from H, Ci-Ce alkyl, -NHC(O)CI-C6 alkyl, -NHC(O)O-CI-C6 alkyl; each R6is independently selected from H, Ci-Ce alkyl, C3-C10 cycloalkyl, - C(O)OCi-C6 alkyl, or aryl, wherein the alkyl, cycloalkyl or aryl is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NH2, - N(Ci-Ce alkyl)2, Ci-Ce alkoxy, -(CH2)P-aryl;R7is -L-R8;L is selected from a bond, -O(CH2)v-, -S-, -NR6(CH2)V(O)P(CH2)P-, -C(O)-, -(O)p- S(O)2-, -NH(CO)(CH2)P-, -NHS(O)2(CH2)P-, -NHC(O)NH-, -NHC(O)O(CH2)P, -(CH2)d-, - CH=CH-, -C=C~,R8is selected from C3-C10 cycloalkyl, 4-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl, wherein the cycloalkyl, heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from R9; each R9is independently selected from halogen, oxo, -OH, -N(R6)2, -CN, Ci-Ce alkyl, Ci-C6alkoxy, -NHC(O)CI-C6alkyl, -NHC(O)OCI-C6alkyl, C3-C10 cycloalkyl, - (O)p-(CH2)p-aryl, -NR6-aryl, -C(O)Ci-C6 alkyl, heterocyclyl, -S(O)2 Ci-Ce alkyl, -S(O)2 heteroaryl, heteroaryl, wherein the alkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more substitutients independently selected from halogen, Ci-Ce alkyl, N(R6)2; each p is an integer independently selected from 0 and 1; k is an integer selected from 0, 1, and 2; v is an integer selected from 0, 1, and 2; d is an integer selected from 1 and 2.

6. The compound of claim 1, wherein the compound is of Formula (V):or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein: each V is independently selected from NH and CH2;R2is selected from H, Ci-Ce alkyl;R3is selected from H, Ci-Ce alkyl, -NHC(O)Ci-Ce alkyl, -NHC(O)O-CI-C6 alkyl; each R6is independently selected from H, Ci-Ce alkyl, C3-C10 cycloalkyl, - C(O)OCi-C6 alkyl, or aryl, wherein the alkyl, cycloalkyl or aryl is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NH2, - N(Ci-Ce alkyl)2, Ci-Ce alkoxy, -(CH2)P-aryl;R7is -L2-R10;L2is selected from C(O), S(O)2, NR6C(O), NR6S(O)2,NR6C(O)O;R10is selected from Ci-Ce alkyl, Ci-Ce alkoxy, -N(R6)2, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from R9; each R9is independently selected from halogen, oxo, -OH, -N(R6)2, -CN, Ci-Ce alkyl, Ci-C6alkoxy, -NHC(O)CI-C6alkyl, -NHC(O)OCI-C6alkyl, C3-C10 cycloalkyl, - (O)p-(CH2)p-aryl, -NR6-aryl, -C(O)Ci-C6 alkyl, heterocyclyl, -S(O)2 heteroaryl, heteroaryl, wherein the alkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more substitutients independently selected from halogen, Ci-Ce alkyl, N(R6)2; p is an integer selected from 0 and 1; k is an integer selected from 0, 1, and 2.

7. The compound of claim 1, wherein the compound is of Formula (VI):or a pharmaceutically acceptable salt, prodrug, stereoisomer, solvate, or tautomer thereof, wherein:R2is selected from H, Ci-Ce alkyl;R3is selected from H, Ci-C6alkyl, -NHC(O)CI-C6alkyl, -NHC(O)O-CI-C6alkyl; each R6is independently selected from H, Ci-Ce alkyl, C3-C10 cycloalkyl, - C(O)OCi-Ce alkyl, or aryl, wherein the alkyl, cycloalkyl or aryl is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NH2, - N(Ci-Ce alkyl)2, Ci-Ce alkoxy, -(CH2)P-aryl;L6is selected from C(O), S(O)2;R11is selected from Ci-Ce alkyl, Ci-Ce alkoxy, -N(R6)2, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents independently selected from R9;each R9is independently selected from halogen, oxo, -OH, -N(R6)2, -CN, Ci-Ce alkyl, Ci-C6alkoxy, -NHC(O)CI-C6alkyl, -NHC(O)OCI-C6alkyl, C3-C10 cycloalkyl, - (O)p-(CH2)p-aryl, -NR6-aryl, -C(O)Ci-C6 alkyl, heterocyclyl, -S(O)2 heteroaryl, heteroaryl, wherein the alkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more substitutients independently selected from halogen, Ci-Ce alkyl, N(R6)2; k is an integer selected from 0, 1, and 2; p is an integer selected from 0 and 1.

8. A compound is selected from:or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof.

9. A pharmaceutical composition comprising the compound of any one of claims 1-8 or a pharmaceutically acceptable salt, stereoisomer, solvate, or tautomer thereof, and a pharmaceutically acceptable carrier.

10. The pharmaceutical composition of claim 9, further comprising one or more additional pharmaceutically active agents.

11. A method of inhibiting of CDK2 in a cell, comprising contacting the cell with a compound of any one of claims 1-8 or a pharmaceutical composition of claim 9 or 10.

12. The method of claim 11, wherein the contacting is in vitro or in vivo.

13. A method for the treatment or prevention of a disease or disorder associated with CDK2 comprising administering to a subject in need thereof a compound of any one of claims 1-8 or a pharmaceutical composition of claim 9 or 10.

14. The method of claim 13, wherein the disease or disorder is selected from the group consisting of Breast Cancer (BC); Colorectal Cancer (CRC); Lung Cancer (LNCR); Retinoblastoma (RBI); Pancreatic Cancer (PNCA); Prostate Cancer (PC); Ovarian Cancer (OC); Hepatocellular Carcinoma (HCC); Gastric Cancer (GASC); Bladder Cancer (BLC); Endometrial Cancer (ENDMC); Glioblastoma (GBM); Adenocarcinoma; Squamous Cell Carcinoma; Ataxia-Telangiectasia (AT).

15. The method of claim 13, wherein the disease or disorder is cancer.

16. The method of any one of claims 11-15, wherein the subject is a mammal.

17. The method of claim 16, wherein the subject is a human.

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