CDK2 inhibitors

Abstract

The present disclosure provides, in part, a compound represented by structural formula (I): JPEG2026501699000096.jpg65165 or a pharmaceutically acceptable salt thereof. Applicants have discovered novel compounds that are effective inhibitors of CDK2 (see Synthesis Examples 1-64). In particular, compounds of the present disclosure have been demonstrated to effectively inhibit CDK2. The compounds of the present disclosure (also referred to herein as "disclosed compounds"), or pharmaceutically acceptable salts thereof, effectively inhibit CDK2 (see Biological Example 1) and can be used to treat various cancers.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 478,404, filed January 4, 2023, the disclosure of which is incorporated herein by reference in its entirety for all purposes. [Background technology]

[0002] Cyclin-dependent kinases (CDKs) are serine / threonine protein kinases that play a central role in cell cycle progression. CDK levels remain relatively constant throughout the cell cycle, and selective activation of specific CDKs allows for the proper sequencing of steps in cell cycle progression. CDK activation requires heterodimerization with regulatory subunits known as cyclins. Cell cycle deregulation is a common feature of human cancers.

[0003] Cyclin-dependent kinase 2 (Cdk2) is involved in a range of biological activities. CDK2 is a key cell cycle regulator, active throughout late G1 and S phases. CDK2 participates in the DNA damage response (DDR) via the homologous recombination (HR) pathway. CDK2 also regulates aspects of the apoptotic pathway. Cyclin E1 (CCNE1), cyclin E2 (CCNE2), cyclin A1 (CCNA1), and cyclin A2 (CCNA2), as well as p21Cip1 / Waf1, p27Kip1, and p57Kip2 (cyclin-dependent kinase inhibitors of the cyclin-CDK2 complex), are key regulators of CDK2 activity. Dysregulation of CDK2 binding by cyclin E1, E2, A1, or A2, or the activity of cyclin-dependent kinase inhibitor proteins, can occur in cancer. (See S. Tadesse et al., Drug Discovery Today, Volume 25, Number 2, February 2020)

[0004] Dysregulation of CDK2 can occur through several mechanisms. Amplification and / or overexpression of CCNE1 has been identified in ovarian and breast cancer (see Scaltriti, M. et al., Proc. Natl Acad. Sci. USA 108, 3761-3766 (2011) and Etemadmoghadam, D. et al., Proc. Natl Acad. Sci. USA 110, 19489-19494 (2013)). Poor outcomes in gastric, endometrial, and other cancers are associated with overexpression and / or amplification of CCNE1 (see Ooi et al., Hum Pathol. (2017) 61:58-67 and Noske et al., Oncotarget (2017) 8: 14794-14805). These findings indicate that CDK2 is a potential target for cancers with unregulated CDK2 activity, but no drugs that selectively target CDK2 are currently approved, necessitating the development of new CDK2 inhibitors. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] S. Tadesse et al.,Drug Discovery Today,Volume 25,Number 2 February 2020 [Non-patent document 2] Scaltriti, M. et al., Proc. Natl Acad. Sci. USA 108, 3761-3766 (2011) [Non-patent document 3] Etemadmoghadam, D. et al. Proc. Natl Acad. Sci. USA 110, 19489-19494(2013) [Non-patent document 4] Ooi et al. Hum Pathol.(2017)61:58-67 [Non-patent document 5] Noske et al, Oncotarget(2017)8: 14794-14805 Summary of the Invention [Means for solving the problem]

[0006] Applicants have discovered novel compounds that are effective inhibitors of CDK2 (see Synthesis Examples 1-64). In particular, compounds of the present disclosure have been demonstrated to effectively inhibit CDK2. The compounds of the present disclosure (also referred to herein as "disclosed compounds"), or pharmaceutically acceptable salts thereof, effectively inhibit CDK2 (see Biological Example 1) and can be used to treat various cancers. Importantly, the disclosed compounds are selective CDK2 inhibitors, i.e., the disclosed compounds exhibit no or reduced activity against CDK family kinases, most notably CDK1. Advantages associated with such selectivity may include facilitated effective administration and reduced toxicity on CDK1-mediated targets. Some of the disclosed compounds also have the advantage of having high microsomal stability. The disclosed compounds may also have favorable toxicity profiles relative to other non-kinase targets.

[0007] In one aspect, the present disclosure provides a compound represented by the following structural formula (I): [ka] or a pharmaceutically acceptable salt thereof (the definition of each variable is provided below).

[0008] In another aspect, the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and one or more compounds disclosed herein or pharmaceutically acceptable salts thereof ("pharmaceutical composition of the present disclosure").

[0009] The present disclosure provides a method of treating a subject having cancer, the method comprising administering to the subject an effective amount of a compound of the present disclosure (e.g., a compound of Formula (I)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. In one embodiment, the cancer is selected from the group consisting of uterine cancer (including uterine carcinosarcoma (UCS) and uterine endometrial cancer (UCEC)), endometrial cancer, breast cancer (including invasive carcinoma of the breast (BRCA), TNBC (triple-negative breast cancer), HR+ breast cancer (hormone receptor-positive breast cancer), ER+ breast cancer (estrogen receptor-positive breast cancer), HR+HER2- breast cancer (hormone receptor-positive, human epidermal growth factor 2-negative breast cancer), ER+HER2- breast cancer (estrogen receptor-positive, human epidermal growth factor 2-negative breast cancer), HER2- breast cancer (human epidermal growth factor 2-negative breast cancer), HER2- low breast cancer (human epidermal growth factor 2-low level breast cancer), and HER2+ breast cancer (human epidermal growth factor 2-positive breast cancer)), ovarian cancer (e.g., For example, ovarian serous cystadenocarcinoma (OV), gastric cancer (including gastric adenocarcinoma (STAD)), gastric cancer (including gastrointestinal stromal tumor), colorectal cancer, pancreatic cancer (including pancreatic adenocarcinoma (PAAD)), kidney cancer, head and neck cancer, liver cancer, prostate cancer, skin cancer, leukemia (including AML (acute myeloid leukemia)), lymphoma (including B-cell lymphoma), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), sarcoma (SARC), esophageal cancer (including esophageal carcinoma (ESCA)), bladder cancer (including bladder urothelial carcinoma), lung cancer (including lung squamous cell carcinoma and non-small cell lung cancer, e.g., EGFRm (epidermal growth factor receptor mutant)+ non-small cell lung cancer), cholangiocarcinoma, adrenocortical carcinoma (ACC), or mesothelioma. In some embodiments, the cancer is breast cancer. In one embodiment, the subject has a CCNE1-amplified advanced / recurrent tumor. In one embodiment, the subject has CCNE1-amplified platinum-resistant or platinum-refractory ovarian cancer. In one embodiment, the subject has endometrial cancer (previously treated with platinum therapy, e.g., the patient has been previously treated with platinum therapy) that has progressed after two or more lines of therapy (including platinum therapy). In one embodiment, the subject has CCNE1-amplified endometrial cancer that has failed two or more lines of therapy (which may include previous platinum therapy).In one embodiment, the subject has gastric cancer that has progressed after two or more lines of therapy (including platinum therapy) (previously received platinum therapy, e.g., the patient has previously been treated with platinum therapy). In one embodiment, the subject has ER+ HER- breast cancer that has progressed despite treatment with one or more CDK4 / 6 inhibitors.

[0010] In one embodiment, the cancer described herein (e.g., a cancer described in paragraphs

[0009] ,

[0019] ,

[0119] to

[0128] ,

[0130] , and

[0132] to

[0147] , e.g., breast cancer) to be treated has amplification and / or overexpression of CCNE1.

[0011] In one embodiment, the cancer described herein (e.g., a cancer described in paragraphs

[0009] ,

[0019] ,

[0119] to

[0128] ,

[0130] , and

[0132] to

[0147] , e.g., breast cancer) to be treated does not have CCNE1 amplification and / or overexpression.

[0012] In some embodiments, the methods of treatment disclosed herein include administering an effective amount of palbociclib (e.g., Ibrance®), ribociclib, abemaciclib, tamoxifen, letrozole, olaparib (e.g., Lynparza®), niraparib, carboplatin, cisplatin, paclitaxel, gemcitabine, megestrol acetate, medroxyprogesterone acetate, capecitabine (e.g., Xeloda®), regorafenib (e.g., Stivarga®), afatinib (e.g., Giotrif®), osimertinib, or cisplatin. Therapeutic approaches include administering to the subject an EGFR inhibitor, such as rivaroxaban (e.g., Tagrisso®), gefitinib (e.g., Iressa®), erlotinib (e.g., Tarceva®), ramucirumab (e.g., Cyramza®), pralsetinib, ABT-263 (navitoclax), MK-1775 (adavosertib), BAY-1895344, beruzosertib, selarasertib, SRA-737, LY2603618 (ravusertib), or trastuzumab (e.g., Herceptin®), or a combination thereof. EGFR inhibitors include afatinib, osimertinib, lapatinib, erlotinib, dacomitinib, poziotinib, neratinib, gefitinib JBJ-04-125-02, alflutinib (AST2818), aumoretinib (formerly almonertinib) (HS10296), BBT-176, BI-4020, BPI-361175, BPI-D0316, CH7233163, gilteritinib, icotinib, JND-3229, lazertinib, and nafatinib. It may be selected from zarutinib (EGF816), avitinib, PCC-0208027, resivertinib (BPI-7711), TQB3804, zolifertinib (AZ-3759) or DZD9008, or from EGFR antibodies such as cetuximab, panitumumab, necitumumab, HLX07, JMT101, or from bispecific EGFR and MET antibodies (e.g., amivantamab ((JNJ-61186372, JNJ-372)).

[0013] The present disclosure also provides a method of inhibiting CDK2 in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the present disclosure (e.g., a compound of Formula (I)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0014] The present disclosure also provides the use of an effective amount of a compound of the present disclosure (e.g., a compound of Formula (I)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, for the preparation of a medicament for the treatment of cancer.

[0015] In another aspect, provided herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure for use in the treatment of cancer.

[0016] In one aspect, the present disclosure provides a method of treating a subject having or at risk of developing a disease or disorder associated with CDK2, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, wherein the subject has CCNE1 gene amplification and / or has a CCNE1 expression level higher than a control expression level of CCNE1. In some embodiments, the CDK2-associated disease or disorder is cancer.

[0017] The present disclosure also provides methods of treating a subject having or at risk of developing a disease or disorder associated with CDK2, the methods comprising administering a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein to the subject, wherein the subject has amplification of the CCNE1 gene and / or has a CCNE1 expression level that is similar to a control expression level of CCNE1. In some embodiments, the CDK2-associated disease or disorder is cancer.

[0018] Also provided herein is a method of treating a patient having an amplified expression level of CCNE1 and suffering from or at risk of developing a solid tumor cancer, the method comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0019] Contemplated solid tumor cancers may be at least one of the following: uterine cancer (including uterine carcinosarcoma and uterine endometrial cancer (UCEC)), endometrial cancer, breast cancer (including invasive breast cancer, TNBC (triple-negative breast cancer), ER (estrogen receptor)+HER2 (human epidermal growth factor 2)- breast cancer, HR (hormone receptor)+HER2 (human epidermal growth factor 2)- breast cancer, HER2- breast cancer, and HER2+ breast cancer), ovarian cancer (e.g., ovarian serous cyst, adenocarcinoma), gastric cancer (including gastric adenocarcinoma), gastric cancer (including gastrointestinal stromal tumor), colorectal cancer, pancreatic cancer, kidney cancer, head and neck cancer, liver cancer, prostate cancer, skin cancer, lymphoma (including B-cell lymphoma), sarcoma, esophageal cancer (including esophageal carcinoma and esophageal adenocarcinoma), bladder cancer (including bladder urothelial carcinoma (BLCA)), lung cancer (including squamous cell carcinoma of the lung and non-small cell lung cancer, e.g., EGFRm (epidermal growth factor receptor mutant)+ non-small cell lung cancer), cholangiocarcinoma, adrenocortical carcinoma, or mesothelioma. DETAILED DESCRIPTION OF THE INVENTION

[0020] (Detailed Description of the Invention) definition The term "halo" as used herein means halogen and includes chloro, fluoro, bromo and iodo.

[0021] The term "alkyl," used alone or as part of a larger moiety such as "alkoxy" or "haloalkyl," refers to a saturated aliphatic straight-chain or branched monovalent hydrocarbon group. Unless otherwise specified, alkyl groups typically have 1 to 4 carbon atoms (i.e., (C1-C4) alkyl). As used herein, a "(C1-C4) alkyl" group refers to a group having 1 to 4 carbon atoms in a straight-chain or branched arrangement. Examples include methyl, ethyl, n-propyl, iso-propyl, and the like.

[0022] The term "alkoxy" refers to an alkyl group attached through an oxygen linking atom, represented by -O-alkyl. For example, "(C1-C4)alkoxy" includes methoxy, ethoxy, propoxy, and butoxy.

[0023] The term "cycloalkyl" refers to a saturated hydrocarbon ring system. Unless otherwise specified, cycloalkyls have 3 to 10 carbon atoms. In some embodiments, cycloalkyls have 3 to 6 carbon atoms. For example, C3-C 10 Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentane, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[3.2.1]octane, bicyclo[4.1.1]octane, spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane, spiro[2.6]nonane, spiro[2.7]decane, spiro[3.3]heptane, spiro[3.4]octane, spiro[3.5]nonane, spiro[3.6]decane, spiro[4.4]nonane, spiro[4.5]decane, etc. Unless otherwise specified, "cycloalkyl" contains 3 to 10 carbon atoms.

[0024] The term "cycloalkoxy" refers to an --O-cycloalkyl group.

[0025] The term "heterocyclyl" or "heterocyclic" refers to a radical of a 4- to 12-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, quaternary nitrogen, nitrogen oxide (e.g., NO), oxygen, and sulfur (including sulfoxide and sulfone) ("4- to 12-membered heterocyclyl"). In some embodiments, a heterocyclyl is a 3- to 6-membered or 4- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, quaternary nitrogen, nitrogen oxide (e.g., NO), oxygen, and sulfur (including sulfoxide and sulfone). In some embodiments, a heterocyclyl has 1 to 2 ring heteroatoms, each heteroatom independently selected from nitrogen, quaternary nitrogen, nitrogen oxide (e.g., NO), oxygen, and sulfur (including sulfoxide and sulfone). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, valence permitting. Exemplary heterocyclyl groups include azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, azepanyl, oxepanyl, thiepanyl, tetrahydropyridinyl, 2-oxabicyclo[2.1.1]hexane, 5-oxabicyclo[2.1.1]hexane, 3-oxabicyclo[3.1.0]hexane, 2-oxabicyclo[2.1.1]heptane, 7-oxabicyclo[2.2.1]heptane, 3-oxabicyclo[3.1.1]heptane, 6-oxabicyclo[3.1.1]heptane, 2-oxabicyclo[2.2.2]octane, 7-oxabicyclo[4.1.1]octane, 8-oxabicyclo[3.2.1]octane, and the like.

[0026] The term "heteroaryl" refers to a radical of a 4- to 12-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π-electrons shared in the cyclic arrangement) having a given ring carbon atom and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be at a carbon or nitrogen atom, valence permitting. Heteroaryl bicyclic ring systems can contain one or more heteroatoms in one or both rings. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more aryl groups, where the point of attachment is at either the aryl or heteroaryl ring; in such cases, the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be in either ring, i.e., in either the ring with a heteroatom (e.g., 2-indolyl) or the ring without a heteroatom (e.g., 5-indolyl). Heteroaryl groups may be described as, for example, 6- to 10-membered heteroaryl. Here, the term "member" refers to a non-hydrogen ring atom within the moiety.

[0027] It will be apparent to one of ordinary skill in the art that certain compounds disclosed herein may exist in tautomeric forms, and all such tautomeric forms of the compounds are within the scope of this disclosure. The term "tautomers" refers to compounds that are interchangeable forms of a particular compound structure, with changes in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium due to the shifting of π electrons and atoms (usually H).

[0028] Compounds of the Disclosure In this specification, Disclosed are embodiments of compounds having the general structure of Formula (I). The present invention provides compounds of the present invention, or pharmaceutically acceptable salts thereof, for use in the treatment of cancer. These compounds are selective inhibitors of CDK2.

[0029] In a first embodiment, the present disclosure provides a compound represented by the following structural formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 is D, halo, CN, C1-C4 alkyl, C3-C 10 Cycloalkyl, C3-C 10 cycloalkoxy, and 4- to 12-membered heterocyclyl, provided that C1-C4 alkyl, C3-C 10 Cycloalkyl and C3-C 10 Each cycloalkoxy has 1 to 4 R c and 4-12 membered heterocyclyl is O, S, N, and NR d and further having 1 to 4 R on the ring carbons. c may be substituted with R 2 is C1-C4 alkyl or ring A, where C1-C4 alkyl is selected from 1 to 4 groups each independently selected from D, halo, CN, and OH, and / or O, S, N, and NR d and optionally substituted with one group of 5- to 6-membered heteroaryl having 1 to 3 ring heteroatoms, each independently selected from the group consisting of: R 3 is H, D, C1-C4 alkyl, C3-C 10 cycloalkyl and 4-12 membered heterocyclyl, provided that C1-C4 alkyl and C3-C 10 Cycloalkyl has 1 to 4 R c and 4- to 12-membered heterocyclyl is O, S, N, and NR d and further having 1 to 4 R on a ring atom. c may be substituted with, or R 2 and R 3form ring B together with the carbon atoms to which they are attached, provided that ring B is C3-C 10 cycloalkyl or 4- to 12-membered heterocyclyl, C3-C 10 Cycloalkyl has 1 to 4 R b and 4-12 membered heterocyclyl is O, S, N, and NR d and further having 1 to 4 R on a ring atom. b may be substituted with Ring A is C3 to C 10 selected from the group consisting of cycloalkyl, phenyl, naphthyl, 4- to 12-membered heterocyclyl, and 4- to 12-membered heteroaryl, provided that C3-C 10 Cycloalkyl, phenyl, and naphthyl have 1 to 4 R a and 4- to 12-membered heterocyclyl and 4- to 12-membered heteroaryl are each optionally substituted by O, S, N, and NR d and further having 1 to 4 R on a ring atom. a may be substituted with Each R a are independently selected from the group consisting of D, halo, OH, CN, C1-C4 alkyl, and C1-C4 alkoxy, or two R a forms =O, with the proviso that C1-C4 alkyl and C1-C4 alkoxy are each optionally substituted with 1 to 4 groups each independently selected from the group consisting of halo, OH, and CN; Each R b are independently selected from the group consisting of D, halo, OH, CN, C1-C4 alkyl, and C1-C4 alkoxy, or two R b forms =O, with the proviso that C1-C4 alkyl and C1-C4 alkoxy are each optionally substituted with 1 to 4 groups each independently selected from the group consisting of halo, OH, and CN; Each R care independently selected from the group consisting of D, halo, OH, CN, C1-C4 alkyl, and C1-C4 alkoxy, or two R c forms =O, with the proviso that C1-C4 alkyl and C1-C4 alkoxy are each optionally substituted with 1 to 4 groups each independently selected from the group consisting of halo, OH, and CN; Each R d are H, D, C(O)C 1~ C4 alkyl and C 1~ C4 alkyl, R 4 is selected from the group consisting of H, D, and C1-C4 alkyl, wherein C1-C4 alkyl is optionally substituted with 1 to 4 groups each independently selected from halo and OH; R 5 is selected from the group consisting of H, D, halo, CN, and C1-C4 alkyl, wherein C1-C4 alkyl is optionally substituted with 1 to 4 groups each independently selected from halo and OH; R 6 is selected from the group consisting of H, D, and C1-C4 alkyl; R 7 is selected from the group consisting of H, D, and C1-C4 alkyl.

[0030] In another aspect, the present disclosure provides a compound represented by the following structural formula (I-1): [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 is D, halo, CN, C1-C4 alkyl, C5-C 12 Alkoxy; C1-C4 alkoxy substituted with 1 to 4 groups independently selected from OH, CN, ═O, C1-C4 alkyl, and C1-C4 alkoxy; C3-C 10 Cycloalkyl, C3-C 10cycloalkoxy, and 4- to 12-membered heterocyclyl, provided that C1-C4 alkyl, C5-C8 alkoxy, C3-C 10 Cycloalkyl and C3-C 10 Cycloalkoxy is a group consisting of 1 to 4 R c and 4- to 12-membered heterocyclyl is O, S, N, and NR d and further having 1 to 4 R on the ring carbons. c may be substituted with R 2 is C1-C4 alkyl or ring A, where C1-C4 alkyl is selected from 1 to 4 groups each independently selected from D, halo, CN, and OH, and / or O, S, N, and NR d and optionally substituted with one group of 5- to 6-membered heteroaryl having 1 to 3 ring heteroatoms, each independently selected from the group consisting of: R 3 is H, D, C1-C4 alkyl, C3-C 10 cycloalkyl and 4-12 membered heterocyclyl, provided that C1-C4 alkyl and C3-C 10 Cycloalkyl has 1 to 4 R c and 4- to 12-membered heterocyclyl is O, S, N, and NR d and further having 1 to 4 R on a ring atom. c may be substituted with, or R 2 and R 3 form ring B together with the carbon atoms to which they are attached, provided that ring B is C3-C 10 cycloalkyl or 4- to 12-membered heterocyclyl, C3-C 10 Cycloalkyl has 1 to 4 R b and 4-12 membered heterocyclyl is O, S, N, and NR d and further having 1 to 4 R on a ring atom. b may be substituted with Ring A is C3 to C 10 selected from the group consisting of cycloalkyl, phenyl, naphthyl, 4- to 12-membered heterocyclyl, and 4- to 12-membered heteroaryl, provided that C3-C 10 Cycloalkyl, phenyl, and naphthyl have 1 to 4 R a and 4- to 12-membered heterocyclyl and 4- to 12-membered heteroaryl are each optionally substituted by O, S, N, and NR d and further having 1 to 4 R on a ring atom. a may be substituted with Each R a are independently selected from the group consisting of D, halo, OH, CN, C1-C4 alkyl, and C1-C4 alkoxy, or two R a forms =O, with the proviso that C1-C4 alkyl and C1-C4 alkoxy are each optionally substituted with 1 to 4 groups each independently selected from the group consisting of halo, OH, and CN; Each R b are independently selected from the group consisting of D, halo, OH, CN, C1-C4 alkyl, and C1-C4 alkoxy, or two R b forms =O, with the proviso that C1-C4 alkyl and C1-C4 alkoxy are each optionally substituted with 1 to 4 groups each independently selected from the group consisting of halo, OH, and CN; Each R c are independently selected from the group consisting of D, halo, OH, CN, C1-C4 alkyl, and C1-C4 alkoxy, or two R c forms =O, with the proviso that C1-C4 alkyl and C1-C4 alkoxy are each optionally substituted with 1 to 4 groups each independently selected from the group consisting of halo, OH, and CN; Each R d are H, D, C(O)C 1~ C4 alkyl and C 1~ C4 alkyl, R 4is selected from the group consisting of H, D, and C1-C4 alkyl, wherein C1-C4 alkyl is optionally substituted with 1 to 4 groups each independently selected from halo and OH; R 5 is selected from the group consisting of H, D, halo, CN, and C1-C4 alkyl, wherein C1-C4 alkyl is optionally substituted with 1 to 4 groups each independently selected from halo and OH; R 6 is selected from the group consisting of H, D, and C1-C4 alkyl; R 7 is selected from the group consisting of H, D, and C1-C4 alkyl.

[0031] In some embodiments, each R a are independently selected from the group consisting of halo, OH, CN, C1-C4 alkyl, and C1-C4 alkoxy, or two R a form =O, with the proviso that C1-C4 alkyl and C1-C4 alkoxy are each optionally substituted with 1 to 4 groups each independently selected from the group consisting of halo, OH, and CN, and each R b are independently selected from the group consisting of halo, OH, CN, C1-C4 alkyl, and C1-C4 alkoxy, or two R b form =O, with the proviso that C1-C4 alkyl and C1-C4 alkoxy are each optionally substituted with 1 to 4 groups each independently selected from the group consisting of halo, OH, and CN, and each R c are independently selected from the group consisting of halo, OH, CN, C1-C4 alkyl, and C1-C4 alkoxy, or two R c form =O, with the proviso that C1-C4 alkyl and C1-C4 alkoxy are each optionally substituted with 1 to 4 groups each independently selected from the group consisting of halo, OH, and CN, and / or each R d are independently H or C1-C6 alkyl.

[0032] In some embodiments, R 2is C1-C4 alkyl or ring A, where C1-C4 alkyl is 1 to 4 groups each independently selected from halo, CN, and OH, and / or O, S, N, and NR d and / or R 4 is selected from the group consisting of H, D; and C1-C4 alkyl optionally substituted with 1 to 4 groups each independently selected from halo and OH.

[0033] In some embodiments, R 1 is selected from the group consisting of CN, C1-C4 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, and 4-10 membered heterocyclyl, with the proviso that C1-C4 alkyl, C3-C8 cycloalkyl, and C3-C8 cycloalkoxy are selected from the group consisting of 1-3 R c and each of the 4- to 10-membered heterocyclyl groups may be substituted with O, S, N, and NR d and further having 1 to 3 R on a ring carbon. c may be substituted with

[0034] In some embodiments, R 1 is selected from the group consisting of halo, CN, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, and 4-6 membered heterocyclyl, provided that C1-C4 alkyl, C3-C6 cycloalkyl, and C3-C6 cycloalkoxy are selected from the group consisting of 1-4 R c and 4- to 6-membered heterocyclyl is O, S, N, and NR d and further having 1 to 4 R on the ring carbons. c In some embodiments, R 1 is C1-C4 alkyl. In some embodiments, R 1 is C1-C4 alkyl substituted with 1-4 halo. In some embodiments, R1 is methyl, ethyl, or propyl, each optionally substituted with 1 to 4 halo. In some embodiments, R 1 is methyl, ethyl, or propyl, each optionally substituted with 1-4 halo or D. In some embodiments, R 1 is selected from the group consisting of methyl, ethyl, isopropyl, CF, CHF, and CHF. In some embodiments, R 1 is selected from the group consisting of methyl, ethyl, isopropyl, CD, CDH, CDH, CF, CHF, and CHF. 1 is CD3. In some embodiments, R 1 is CN. In some embodiments, R 1 is C-C cycloalkyl. In some embodiments, R 1 is C-C cycloalkyl. In some embodiments, R 4 is a 4- to 6-membered heterocyclyl. In some embodiments, R 1 is halo. In some embodiments, R 1 are chloro, bromo, CN, methyl, ethyl, isopropyl, [ka] In some embodiments, R 1 is CN, methyl, ethyl, isopropyl, [ka] In some embodiments, R 1 isopropyl and [ka] In some embodiments, R 1 is isopropyl. In some embodiments, R 1 teeth, [ka] is.

[0035] In some embodiments, R 2 represents 1 to 4 groups independently selected from D, halo, CN, and OH, and / or O, S, N, and NR d In some embodiments, R is a C1-C4 alkyl optionally substituted with one group of 5-6 membered heteroaryl having 1-3 ring heteroatoms each independently selected from the group consisting of: 2 is C1-C4 alkyl optionally substituted with 1-4 OH. In some embodiments, R 2 is C1-C4 alkyl optionally substituted with 1-3 groups each independently selected from the group consisting of halo, CN, and OH. In some embodiments, R 2 is a C1-C4 alkyl substituted with OH.

[0036] In some embodiments, R 2 teeth, [ka] is selected from the group consisting of:

[0037] In some embodiments, R 2 is ring A, methyl, ethyl, CH(OH)CH3, CH2F, CHF2, CH2OH, CH(CH3)CH2OH, CH2CH2OH, [ka] In some embodiments, R 2 is ring A, [ka] is selected from the group consisting of:

[0038] In some embodiments, R 2 is ring A.

[0039] In some embodiments, ring A is selected from the group consisting of C-C cycloalkyl, phenyl, naphthyl, 4-10 membered heterocyclyl, and 4-10 membered heteroaryl, with the proviso that C-C cycloalkyl, phenyl, and naphthyl are selected from the group consisting of 1-3 R a and 4-10 membered heterocyclyl and 4-10 membered heteroaryl are each optionally substituted by O, S, N, and NR d and further having 1 to 3 R on a ring atom. a In some embodiments, Ring A is selected from the group consisting of C3-C6 cycloalkyl, phenyl, 4-8 membered heterocyclyl, and 6 membered heteroaryl, provided that 10 Cycloalkyl and phenyl have 1 to 4 R a and the 4-8 membered heterocyclyl and the 6 membered heteroaryl are each optionally substituted by O, S, N, and NR d and further having 1 to 4 R on a ring atom. a In some embodiments, ring A is selected from the group consisting of phenyl, 4-6 membered heterocyclyl, and 6 membered heteroaryl, and the phenyl is optionally substituted with 1-3 R a and 4-6 membered heterocyclyl and 6 membered heteroaryl are optionally substituted with O, S, N, and NR d and further having 1 to 3 R on a ring atom. a In some embodiments, ring A is selected from 4-8 membered heterocyclyl and 6 membered heteroaryl, where 4-8 membered heterocyclyl and 6 membered heteroaryl are selected from O, S, N, and NR d and further having 1 to 4 R on a ring atom. a In some embodiments, ring A is selected from 4-6 membered heterocyclyl and 6 membered heteroaryl, where 4-6 membered heterocyclyl and 6 membered heteroaryl are selected from O, S, N, and NRd and further having 1 to 3 R on a ring atom. a In some embodiments, ring A is selected from the group consisting of 6-membered heterocyclyl and 6-membered heteroaryl, wherein 6-membered heterocyclyl and 6-membered heteroaryl are selected from the group consisting of O, S, N, and NR d and further having 1 to 3 R on a ring atom. a may be substituted with

[0040] In some embodiments, Ring A is selected from the group consisting of phenyl, cyclopropyl, pyridyl, pyridazinyl, tetrahydropyranyl, tetrahydrofuranyl, piperidinyl, oxabicyclo[3.1.0]hexane, and oxabicyclo[2.2.2]octane, provided that phenyl and cyclopropyl are selected from the group consisting of 1 to 4 R a pyridyl, pyridazinyl, tetrahydropyranyl, tetrahydrofuranyl, piperidinyl, oxabicyclo[3.1.0]hexane, and oxabicyclo[2.2.2]octane may be substituted with 1 to 4 R on a ring atom; a In some embodiments, Ring A is selected from the group consisting of phenyl, pyridyl, tetrahydropyranyl, tetrahydrofuranyl, piperidinyl, and oxabicyclo[3.1.0]hexane, wherein phenyl is optionally substituted with 1 to 4 Ra piperidinyl may be substituted on its N with R d pyridyl, tetrahydropyranyl, tetrahydrofuranyl, piperidinyl, and oxabicyclo[3.1.0]hexane may be substituted with 1 to 4 R on a ring atom; a In some embodiments, Ring A is selected from the group consisting of phenyl, pyridyl, tetrahydropyranyl, tetrahydrofuranyl, and piperidinyl, provided that phenyl is substituted with 1 to 4 Ra piperidinyl may be substituted on its N with R dand pyridyl, tetrahydropyranyl, tetrahydrofuranyl, and piperidinyl may be substituted with 1 to 4 R on the ring carbons. a may be substituted with

[0041] In some embodiments, ring A is tetrahydropyranyl.

[0042] In some embodiments, ring A is pyridyl optionally substituted with halo.

[0043] In some embodiments, ring A is [ka] [ka] [ka] [ka] [ka] [ka] is selected from the group consisting of:

[0044] In some embodiments, ring A is [ka] is selected from the group consisting of:

[0045] In some embodiments, R a is selected from halo, OH, CN, C1-C4 alkyl, and C1-C4 alkoxy, wherein C1-C4 alkyl and C1-C4 alkoxy are each optionally substituted with 1 to 4 groups each independently selected from the group consisting of halo, OH, and CN. ais selected from the group consisting of fluoro, chloro, CN, OH, OCH3, methyl, CH2CN, CF3, and CHF2, or two R's attached to the same atom; a forms =O. In some embodiments, R a Halo and C 1~ In some embodiments, R is selected from C4 alkoxy. a is selected from the group consisting of fluoro, chloro and methoxy.

[0046] In some embodiments, R 3 is selected from H and C1-C4 alkyl. In some embodiments, R 3 is selected from the group consisting of H, methyl and ethyl.

[0047] In some embodiments, R c is selected from halo and OH. In some embodiments, R c is halo. In some embodiments, R c is fluoro. In some embodiments, R c is selected from OH and F. In some embodiments, R c is OH.

[0048] In some embodiments, R 2 and R 3 form ring B together with the carbon atoms to which they are attached, provided that ring B is C3-C 10 cycloalkyl or 4- to 12-membered heterocyclyl, C3-C 10 Cycloalkyl has 1 to 4 R b and 4-12 membered heterocyclyl is O, S, N, and NR d and further having 1 to 4 R on a ring atom. b may be substituted with

[0049] In some embodiments, R 2 and R 3together with the carbon atoms to which they are attached form ring B, provided that ring B is C3-C8 cycloalkyl or 4-10 membered heterocyclyl, and the C3-C8 cycloalkyl is selected from 1-4 R b and 4-10 membered heterocyclyl is O, S, N, and NR d and further having 1 to 4 R on a ring atom. b In some embodiments, Ring B is selected from C-C cycloalkyl and 4-6 membered heterocyclyl, provided that C-C cycloalkyl is substituted with 1-4 R b and 4-6 membered heterocyclyl is O, S, N, and NR d and further having 1 to 4 R on a ring atom. b may be substituted with

[0050] In some embodiments, Ring B is selected from cyclohexyl and piperidinyl, each optionally substituted with OH, provided that piperidinyl is optionally substituted on its nitrogen atom with C(O)C1-C4 alkyl. [ka] [ka] is selected from the group consisting of:

[0051] In some embodiments, Ring B is selected from cyclohexyl and piperidinyl, each optionally substituted with OH, provided that piperidinyl is optionally substituted on its nitrogen atom with C(O)C1-C4 alkyl. [ka] is selected from the group consisting of:

[0052] In some embodiments, R bis selected from the group consisting of OH, F, and CHOH. In some embodiments, R b is OH.

[0053] In some embodiments, R 4 is selected from the group consisting of H, methyl, ethyl, CH(OH)CH, CHF, CHF, CHOH, CH(CH)CHOH, and CHCHOH. In some embodiments, R 4 is C1-C4 alkyl substituted with OH or F. In some embodiments, R 4 H and C1 ~C4 In some embodiments, R 4 is H. In some embodiments, R 3 and R 4 are each independently H. In some embodiments, R 3 is C1-C4 alkyl, and R 4 is H.

[0054] In some embodiments, R d is selected from the group consisting of H, C1-C4 alkyl, and C(O)C1-C4 alkyl. In some embodiments, R d is selected from the group consisting of H, methyl, and C(O)CH. In some embodiments, R d H and C1 ~C4 In some embodiments, R d is H or methyl.

[0055] In some embodiments, R 5 is selected from the group consisting of H, halo, and C1-C4 alkyl, where C1-C4 alkyl is optionally substituted with 1 to 4 groups each independently selected from halo and OH. 5 is selected from the group consisting of H, halo, and C1-C4 alkyl. In some embodiments, R 5 is selected from the group consisting of H, chloro, and methyl. In some embodiments, R 5is selected from the group consisting of H, F, Cl, CN, methyl, and CH(OH)CH. In some embodiments, R 5 is H. In some embodiments, R 5 is C1-C4 alkyl.

[0056] In some embodiments, R 6 is H. In some embodiments, R 6 is D.

[0057] In some embodiments, R 7 is H. In some embodiments, R 7 is D. In some embodiments, R 7 H and C1 ~C4 In some embodiments, R 7 is selected from H and methyl.

[0058] In some embodiments of the compounds of Formula (I), R 1 is selected from the group consisting of CN, C1-C4 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, and 4-10 membered heterocyclyl, provided that C1-C4 alkyl, C3-C8 cycloalkyl, and C3-C8 cycloalkoxy are each selected from the group consisting of 1-3 R c and 4-6 membered heterocyclyl is O, S, N, and NR d and further having 1 to 3 R on a ring carbon. c may be substituted with R 2 is a C1-C4 alkyl or ring A, wherein the C1-C4 alkyl is optionally substituted with 1 to 3 groups independently selected from the group consisting of D, halo, CN, and OH; R 3is selected from the group consisting of H, C1-C4 alkyl, C3-C8 cycloalkyl, and 4-10 membered heterocyclyl, provided that C1-C4 alkyl, C3-C8 cycloalkyl, and 4-10 membered heterocyclyl are each independently selected from 1-3 R on a ring atom; c may be substituted with R 2 and R 3 together with the carbon atoms to which they are attached form ring B, provided that ring B is C3-C8 cycloalkyl or 4-10 membered heterocyclyl, and the C3-C8 cycloalkyl is b and 4-10 membered heterocyclyl is O, S, N, and NR d and further having 1 to 3 R on a ring atom. b may be substituted with Ring A is selected from the group consisting of C3-C8 cycloalkyl, phenyl, naphthyl, 4-10 membered heterocyclyl, and 4-10 membered heteroaryl, with the proviso that C3-C8 cycloalkyl, phenyl, and naphthyl are each independently selected from 1-3 R a and 4-10 membered heterocyclyl and 4-10 membered heteroaryl are each optionally substituted by O, S, N, and NR d and further having 1 to 3 R on a ring atom. a may be substituted with Each R a are independently selected from the group consisting of D, halo, OH, CN, C1-C4 alkyl, and C1-C4 alkoxy, or two R a forms =O, with the proviso that C1-C4 alkyl and C1-C4 alkoxy are each optionally substituted with 1 to 3 groups each independently selected from the group consisting of halo, OH, and CN; Each R b are independently selected from the group consisting of D, halo, OH, CN, C1-C4 alkyl, and C1-C4 alkoxy, or two R bforms =O, with the proviso that C1-C4 alkyl and C1-C4 alkoxy are each optionally substituted with 1 to 3 groups each independently selected from the group consisting of halo, OH, and CN; Each R c are independently selected from the group consisting of D, halo, OH, CN, C1-C4 alkyl, and C1-C4 alkoxy, or two R c forms =O, with the proviso that C1-C4 alkyl and C1-C4 alkoxy are each optionally substituted with 1 to 3 groups each independently selected from the group consisting of halo, OH, and CN; Each R d are independently H or C1-C4 alkyl, R 4 is selected from the group consisting of H, D, and C1-C4 alkyl; R 5 is selected from the group consisting of H, D, halo, CN, and C1-C4 alkyl, wherein C1-C4 alkyl is optionally substituted with 1 to 3 groups each independently selected from halo and OH; R 6 is selected from the group consisting of H, D, and C1-C4 alkyl; R 7 is selected from the group consisting of H, D, and C1-C4 alkyl.

[0059] In some embodiments, the present disclosure provides a compound represented by the following structural formula (II): [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined above.

[0060] In some embodiments, ring A is C3-C8 cycloalkyl optionally substituted with 1-3 groups each independently selected from the group consisting of halo, OH, ═O, CN, C1-C4 alkyl, and C1-C4 alkoxy, provided that C1-C4 alkyl and C1-C4 alkoxy are each optionally substituted with 1-3 groups each independently selected from the group consisting of halo, OH, and CN.

[0061] In some embodiments, ring A is C3-C8 cycloalkyl optionally substituted with 1-3 groups each independently selected from the group consisting of D, halo, OH, ═O, CN, C1-C4 alkyl, and C1-C4 alkoxy, provided that C1-C4 alkyl and C1-C4 alkoxy are each optionally substituted with 1-3 groups each independently selected from the group consisting of halo, OH, and CN.

[0062] In some embodiments, ring A is phenyl optionally substituted with 1-3 groups each independently selected from the group consisting of D, halo, OH, ═O, CN, C1-C4 alkyl, and C1-C4 alkoxy, provided that C1-C4 alkyl and C1-C4 alkoxy are each optionally substituted with 1-3 groups each independently selected from the group consisting of halo, OH, and CN.

[0063] In some embodiments, ring A is phenyl optionally substituted with 1-3 groups each independently selected from the group consisting of D, halo, OH, ═O, CN, C1-C4 alkyl, and C1-C4 alkoxy, provided that C1-C4 alkyl and C1-C4 alkoxy are each optionally substituted with 1-3 groups each independently selected from the group consisting of halo, OH, and CN.

[0064] In some embodiments, ring A is naphthyl optionally substituted with 1 to 3 groups each independently selected from the group consisting of D, halo, OH, ═O, CN, C1-C4 alkyl, and C1-C4 alkoxy, wherein C1-C4 alkyl and C1-C4 alkoxy are each optionally substituted with 1 to 3 groups each independently selected from the group consisting of halo, OH, and CN.

[0065] In some embodiments, ring A is a 4-10 membered heterocyclyl optionally substituted on ring atoms with 1-3 groups each independently selected from the group consisting of halo, OH, ═O, CN, C1-C4 alkyl, and C1-C4 alkoxy, provided that C1-C4 alkyl and C1-C4 alkoxy are each optionally substituted with 1-3 groups each independently selected from the group consisting of halo, OH, and CN.

[0066] In some embodiments, ring A is a 4-10 membered heterocyclyl optionally substituted on ring atoms with 1-3 groups each independently selected from the group consisting of D, halo, OH, ═O, CN, C1-C4 alkyl, and C1-C4 alkoxy, provided that C1-C4 alkyl and C1-C4 alkoxy are each optionally substituted with 1-3 groups each independently selected from the group consisting of halo, OH, and CN. In some embodiments, ring A is tetrahydropyranyl. In some embodiments, ring A is [ka] is.

[0067] In some embodiments, ring A is a 4-10 membered heteroaryl optionally substituted on ring atoms with 1-3 groups each independently selected from the group consisting of halo, OH, ═O, CN, C1-C4 alkyl, and C1-C4 alkoxy, provided that C1-C4 alkyl and C1-C4 alkoxy are each optionally substituted with 1-3 groups each independently selected from the group consisting of halo, OH, and CN.

[0068] In some embodiments, ring A is a 4-10 membered heteroaryl optionally substituted on ring atoms with 1-3 groups each independently selected from the group consisting of halo, OH, ═O, CN, C1-C4 alkyl, and C1-C4 alkoxy, provided that C1-C4 alkyl and C1-C4 alkoxy are each optionally substituted with 1-3 groups each independently selected from the group consisting of halo, OH, and CN. In some embodiments, ring A is pyridyl optionally substituted with halo. In some embodiments, ring A is [ka] is.

[0069] In some embodiments, the present disclosure provides a compound represented by the following structural formula (III): [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as defined above.

[0070] In some embodiments, Ring B is C3-C8 cycloalkyl optionally substituted with 1-3 groups each independently selected from the group consisting of halo, OH, ═O, CN, C1-C4 alkyl, and C1-C4 alkoxy, provided that C1-C4 alkyl and C1-C4 alkoxy are each optionally substituted with 1-3 groups each independently selected from the group consisting of halo, OH, and CN.

[0071] In some embodiments, Ring B is C3-C8 cycloalkyl optionally substituted with 1-3 groups each independently selected from the group consisting of D, halo, OH, ═O, CN, C1-C4 alkyl, and C1-C4 alkoxy, provided that C1-C4 alkyl and C1-C4 alkoxy are each optionally substituted with 1-3 groups each independently selected from the group consisting of halo, OH, and CN.

[0072] In some embodiments, Ring B is a 4-10 membered heterocyclyl optionally substituted on ring atoms with 1-3 groups each independently selected from the group consisting of halo, OH, ═O, CN, C1-C4 alkyl, and C1-C4 alkoxy, provided that C1-C4 alkyl and C1-C4 alkoxy are each optionally substituted with 1-3 groups each independently selected from the group consisting of halo, OH, and CN.

[0073] In some embodiments, Ring B is a 4-10 membered heterocyclyl optionally substituted on ring atoms with 1-3 groups each independently selected from the group consisting of D, halo, OH, ═O, CN, C1-C4 alkyl, and C1-C4 alkoxy, provided that C1-C4 alkyl and C1-C4 alkoxy are each optionally substituted with 1-3 groups each independently selected from the group consisting of halo, OH, and CN.

[0074] In some embodiments, R 2 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl, each of which may be substituted with 1 to 4 groups independently selected from the group consisting of halo, OH, CN, and 5- to 6-membered heteroaryl.

[0075] In some embodiments, R 2 is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl, each of which may be substituted with 1 to 4 groups independently selected from the group consisting of D, halo, OH, CN, and 5- to 6-membered heteroaryl.

[0076] In some embodiments, R 3 is selected from the group consisting of H, C1-C4 alkyl, C3-C8 cycloalkyl, and 4-10 membered heterocyclyl, provided that C1-C4 alkyl, C3-C8 cycloalkyl, and 4-10 membered heterocyclyl are selected from the group consisting of (R 3When is a 4- to 10-membered heterocyclyl, each ring atom may be optionally substituted with 1 to 3 groups each independently selected from halo and OH.

[0077] In some embodiments, R 3 is selected from the group consisting of H, C1-C4 alkyl, C3-C8 cycloalkyl, and 4-10 membered heterocyclyl, provided that C1-C4 alkyl, C3-C8 cycloalkyl, and 4-10 membered heterocyclyl are selected from the group consisting of (R 3 When R is a 4- to 10-membered heterocyclyl, it may each be substituted on a ring atom with 1 to 3 groups independently selected from D, halo, and OH. 3 is selected from the group consisting of H, D, and C1-C4 alkyl.

[0078] In some embodiments, R 3 is (R 3 When is oxetanyl, it is selected from the group consisting of H, methyl, ethyl, cyclopropyl, and oxetanyl, each of which may be substituted on a ring carbon with 1 to 3 groups each independently selected from halo and OH.

[0079] In some embodiments, R 3 is (R 3 When R is oxetanyl, it is selected from the group consisting of H, methyl, ethyl, cyclopropyl, and oxetanyl, each of which is optionally substituted on a ring carbon with 1-3 groups each independently selected from the group consisting of D, halo, and OH. 3 is H. In some embodiments, R 3 is D.

[0080] In some embodiments, R 4 is H or CH. In some embodiments, R 4 is selected from the group consisting of H, D, and CH. In some embodiments, R 4 is H. In some embodiments, R 4 is D.

[0081] In some embodiments, R 5 is selected from the group consisting of H, halo, CN, methyl and ethyl, wherein methyl and ethyl may be substituted with OH.

[0082] In some embodiments, R 5 is selected from the group consisting of H, D, halo, CN, methyl, and ethyl, provided that methyl and ethyl may be substituted with OH. In some embodiments, R 5 is selected from the group consisting of H, D, halo, and methyl. In some embodiments, R 5 is H. In some embodiments, R 5 is D.

[0083] In some embodiments, the compound is a compound of formula (IV): [ka] or a pharmaceutically acceptable salt thereof [In the formula, R 1 is selected from the group consisting of CN, C1-C4 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, and 4-10 membered heterocyclyl, provided that C1-C4 alkyl, C3-C8 cycloalkyl, and C3-C8 cycloalkoxy are each selected from the group consisting of 1-3 R c and 4-10 membered heterocyclyl is O, S, N, and NR d and has 1 to 3 ring heteroatoms independently selected from the group consisting of: R 2 is a C1-C4 alkyl or ring A, wherein the C1-C4 alkyl is optionally substituted with 1 to 3 groups independently selected from the group consisting of halo, CN, and OH; R 3 is H or C1-C4 alkyl, or R 2 and R 3form ring B together with the carbon atoms to which they are attached, with the proviso that ring B is C3-C8 cycloalkyl optionally substituted with 1 to 3 groups independently selected from the group consisting of halo, OH, ═O, CN, C1-C4 alkyl, and C1-C4 alkoxy; Ring A is selected from the group consisting of C3-C8 cycloalkyl, phenyl, naphthyl, 4-10 membered heterocyclyl, and 4-10 membered heteroaryl, with the proviso that C3-C8 cycloalkyl, phenyl, and naphthyl are each independently selected from 1-3 R a and 4-10 membered heterocyclyl and 4-10 membered heteroaryl are each optionally substituted by O, S, N, and NR d and further having 1 to 3 R on a ring atom. a may be substituted with Each R a are independently selected from the group consisting of halo, OH, CN, C1-C4 alkyl, and C1-C4 alkoxy, or two R a forms =O, with the proviso that C1-C4 alkyl and C1-C4 alkoxy are each optionally substituted with 1 to 3 groups each independently selected from the group consisting of halo, OH, and CN; Each R c are independently selected from the group consisting of halo, OH, CN, C1-C4 alkyl, and C1-C4 alkoxy, or two R c forms =O, with the proviso that C1-C4 alkyl and C1-C4 alkoxy are each optionally substituted with 1 to 3 groups each independently selected from the group consisting of halo, OH, and CN; Each R d are independently H or C1-C4 alkyl, R 4 is H or C1-C4 alkyl, R 5 is selected from the group consisting of H, halo, CN, and C1-C4 alkyl; R 7 is H or C1-C4 alkyl].

[0084] In some embodiments, R 1 is selected from the group consisting of CN, C1-C4 alkyl, and 4-10 membered heterocyclyl, and the C1-C4 alkyl and 4-10 membered heterocyclyl are optionally substituted with 1 to 3 Rc.

[0085] In some embodiments, R 2 is ring A, and ring A is selected from the group consisting of phenyl, 4- to 6-membered heterocyclyl, and 6-membered heteroaryl, and phenyl is selected from the group consisting of 1 to 3 R a and 4-6 membered heterocyclyl and 6 membered heteroaryl are optionally substituted with O, S, N, and NR d and further having 1 to 3 R on a ring atom. a may be substituted with

[0086] In some embodiments, the compound is a compound of formula (V): [ka] or a pharmaceutically acceptable salt thereof [In the formula, R 1 is selected from the group consisting of CN, C1-C4 alkyl, and 4-10 membered heterocyclyl, and the C1-C4 alkyl and 4-10 membered heterocyclyl are optionally substituted with 1 to 3 Rc. R 2 is ring A selected from the group consisting of phenyl, 4- to 6-membered heterocyclyl, and 6-membered heteroaryl, provided that phenyl is selected from the group consisting of 1 to 3 R a and 4-6 membered heterocyclyl and 6 membered heteroaryl are optionally substituted with O, S, N, and NR d and further having 1 to 3 R on a ring atom. a may be substituted with Each R a are independently selected from the group consisting of halo, OH, CN, C1-C4 alkyl, and C1-C4 alkoxy, or two Ra forms a=O, Each R c are independently selected from the group consisting of halo, OH, CN, C1-C4 alkyl, and C1-C4 alkoxy, or two R c forms a=O, Each R d are independently H or C1-C4 alkyl; R4 is H or C1-C4 alkyl].

[0087] In some embodiments, R 2 is ring A, and ring A is selected from the group consisting of 6-membered heterocyclyl and 6-membered heteroaryl, where 6-membered heterocyclyl and 6-membered heteroaryl are selected from the group consisting of O, S, N, and NR d and further having 1 to 3 R on a ring atom. a may be substituted with

[0088] In some embodiments, R 6 is H. In some embodiments, R 6 is D.

[0089] In some embodiments, R 7 is H. In some embodiments, R 7 is D.

[0090] In one embodiment, the compound is a compound selected from the table below, or a pharmaceutically acceptable salt thereof. [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4] [Table 8-5] [Table 8-6] [Table 8-7] [Table 8-8] [Table 8-9] [Table 8-10] [Table 8-11] [Table 8-12]

[0091] The term "pharmaceutically acceptable salt" refers to a pharmaceutical salt that is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, or allergic reaction, within the scope of sound medical judgment, and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describe pharmacologically acceptable salts in J. Pharm. Sci., 1977, 66, 1-19.

[0092] The present teachings include pharmaceutically acceptable salts of the compounds disclosed herein. Compounds having a basic group can form pharmaceutically acceptable salts with pharmaceutically acceptable acid(s). Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include salts of inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid, and sulfuric acid) and salts of organic acids (such as acetic acid, benzenesulfonic acid, benzoic acid, ethanesulfonic acid, methanesulfonic acid, and succinic acid). Compounds of the present teachings having an acidic group, such as a carboxylic acid, can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s). Suitable pharmaceutically acceptable base salts include ammonium salts, alkali metal salts (such as sodium salts and potassium salts), and alkaline earth metal salts (such as magnesium salts and calcium salts).

[0093] Compounds with one or more chiral centers can exist in various stereoisomeric forms; that is, each chiral center may have an R or S configuration, or a mixture of both. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomeric and enantiomeric forms of a compound. Enantiomers are stereoisomers that are mirror images of each other. Diastereomers are stereoisomers with two or more chiral centers that are neither identical nor mirror images of each other.

[0094] When the stereochemical configuration at a chiral center in a compound having one or more chiral centers is indicated by its chemical name (e.g., when the configuration is indicated by "R" or "S" in the chemical name) or structure (e.g., when the configuration is indicated by a "wedge" bond), the enrichment of the indicated configuration relative to the opposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99%, or 99.9% (except when the structure or name is accompanied by the designation "rac" or "racemic," as described in the following two paragraphs). The "enrichment of the indicated configuration relative to the opposite configuration" is a mole percent and is determined by dividing the number of compounds having the indicated stereochemical configuration at the chiral center(s) by the total number of all compounds having the same or opposite stereochemical configuration in the mixture.

[0095] When the stereochemical configuration at a chiral center in a compound is indicated by the chemical name (e.g., when the configuration is indicated by "R" or "S" in the name) or structure (e.g., when the configuration is indicated by a "wedge" bond), and the structure is accompanied by the designation "rac" or "racemic" or specified in the chemical name, a racemic mixture is intended.

[0096] When two stereoisomers are depicted by their chemical names or structures and the names or structures are connected by "or," either one or the other of the two stereoisomers is intended, but not both.

[0097] When a disclosed compound having a chiral center is represented by a structure without indicating the configuration at that chiral center, the structure is meant to encompass compounds having the S configuration at that chiral center, compounds having the R configuration at that chiral center, or compounds having a mixture of R and S configurations at that chiral center. When a disclosed compound having a chiral center is represented by a chemical name without indicating the configuration at that chiral center with "S" or "R," the chemical name is meant to encompass compounds having the S configuration at that chiral center, compounds having the R configuration at that chiral center, or compounds having a mixture of R and S configurations at that chiral center.

[0098] A racemic mixture means a mixture of 50% of one enantiomer and 50% of its corresponding enantiomer. The present teachings encompass all enantiomerically pure, enantiomerically enriched, diastereomerically pure, and diastereomerically enriched racemic and diastereomeric mixtures of the compounds disclosed herein.

[0099] Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high-performance liquid chromatography, crystallization of the compound as a chiral salt complex, or crystallization of the compound in a chiral solvent, etc. Enantiomers and diastereomers can also be obtained from diastereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

[0100] "Peak 1" in the experimental section refers to the target product compound obtained from chromatographic separation / purification, which elutes earlier than a second target product compound from the same aforementioned reaction, which is referred to as "Peak 2."

[0101] If a disclosed compound is designated by a name or structure that represents a single enantiomer, unless otherwise indicated, the compound is at least 60%, 70%, 80%, 90%, 99%, or 99.9% optically pure (also referred to as "enantiomerically pure"). Optical purity is the weight of the mixture of the named or represented enantiomer divided by the total weight of the mixture of both enantiomers.

[0102] When the stereochemistry of a disclosed compound is designated or depicted by structure, and this designated or depicted structure encompasses more than one stereoisomer (e.g., as in the case of a diastereomeric pair), it is to be understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers is included unless otherwise indicated. It is further to be understood that the stereoisomeric purity of the designated or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight. Stereoisomeric purity in this case is determined by dividing the total weight of the mixture of stereoisomers encompassed by the name or structure by the total weight of the mixture of all stereoisomers.

[0103] In the compounds of the present disclosure, any position specifically designated as "D" or "deuterium" is understood to have 50%, 80%, 90%, 95%, 98%, or 99% deuterium enrichment. "Deuterium enrichment" is a mole percent and is determined by dividing the number of compounds having deuterium at the indicated position by the total number of all compounds. If a position is designated as "H" or "hydrogen," the position has hydrogen at its natural abundance. If a position is unspecified as to whether hydrogen or deuterium is present, the position has hydrogen at its natural abundance. One specific and alternative embodiment is directed to compounds of the present disclosure having at least 5%, 10%, 25%, 50%, 80%, 90%, 95%, 98%, or 99% deuterium enrichment at one or more positions not specifically designated as "D" or "deuterium."

[0104] As used herein, many moieties (e.g., alkyl, alkoxy, cycloalkyl, or heterocyclyl) are referred to as "substituted" or "optionally substituted." When a moiety is modified by one of these terms, unless otherwise specified, it means that any portion of the moiety known to one of ordinary skill in the art to be available for substitution can be substituted, including one or more substituents. When more than one substituent is present, each substituent may be independently selected. Such substitution means are well known in the art and / or taught by this disclosure. An optional substituent may be any substituent suitable for attachment to the moiety.

[0105] The compounds of the present disclosure are CDK2 inhibitors. As used herein, the term "selective CDK2 inhibitor" refers to a compound that selectively inhibits CDK2 over other CDKs and kinomes. In other words, a selective CDK2 inhibitor has no or low activity against other CDKs and kinomes. The inhibitory activity of a selective CDK2 inhibitor against CDK2 is higher than that against other CDKs and many other kinases, and the IC 50 value( すなわち The compounds are more potent in terms of potency (IC50 values ​​are sub-nanomolar). Potency can be measured using known biochemical assays.

[0106] In some embodiments, compounds of the present disclosure are selective for CDK2 over CDK1. In some such embodiments, the compounds exhibit at least 10-fold selectivity for CDK2 over CDK1. In other embodiments, the compounds exhibit at least 20-fold selectivity for CDK2 over CDK1. In certain embodiments, the compounds exhibit at least 30-fold selectivity for CDK2 over CDK1. In certain embodiments, the compounds exhibit at least 40-fold selectivity for CDK2 over CDK1. In other embodiments, the compounds exhibit at least 50-fold selectivity for CDK2 over CDK1. For example, the compounds exhibit at least 100-fold selectivity for CDK2 over CDK1. In some embodiments, the compounds of the present disclosure are selective for CDK2 over CDK4 and / or CDK6. In some such embodiments, the compounds exhibit at least 10-fold selectivity for CDK2 over CDK4 and / or CDK6. In other embodiments, the compounds exhibit at least 20-fold selectivity for CDK2 over CDK4 and / or CDK6. In certain embodiments, the compounds exhibit at least 30-fold selectivity for CDK2 over CDK4 and / or CDK6.

[0107] Some compounds of the present disclosure have the advantage of good metabolic stability. One indicator of good metabolic stability is high microsomal stability. Hepatic metabolism is the predominant excretion route for small molecule drugs. The clearance of a compound via hepatic metabolism can be evaluated in vitro using human liver microsomes (HLM) or human hepatocytes. The compound is incubated with HLM plus appropriate cofactors or human hepatocytes, and the compound depletion is measured to determine the in vitro intrinsic clearance (Cl). The Cl is scaled to the total body clearance (CL) and the hepatic extraction ratio (ER) is determined by dividing the CL by the standard hepatic blood flow rate in humans. Compounds with low hepatic extraction ratios are considered to have good metabolic stability. In some embodiments, compounds of the present disclosure have a calculated ER of <0.3, <0.4, <0.5, or <0.6.

[0108] Pharmaceutical Composition Pharmaceutical compositions of the present disclosure (also referred to herein as "disclosed pharmaceutical compositions") comprise one or more pharmaceutically acceptable carrier(s) or diluent(s) and a compound of the present disclosure (e.g., a compound of Formula (I)) or a pharmaceutically acceptable salt thereof.

[0109] "Pharmaceutically acceptable carrier" and "pharmaceutically acceptable diluent" refer to substances that aid in the formulation and / or administration of, and / or absorption by, an active agent in a subject and that can be included in the pharmaceutical compositions of the present disclosure without causing significant adverse toxicological effects to the subject. Non-limiting examples of pharmaceutically acceptable carriers and / or diluents include water, NaCl, saline, lactated Ringer's solution, regular sucrose, regular glucose, binders, fillers, disintegrants, lubricants, coating agents, sweeteners, flavorings, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates (such as lactose, amylose, or starch), hydroxymethylcellulose, fatty acid esters, polyvinylpyrrolidine, coloring agents, and the like. Such preparations can be sterilized and, if necessary, mixed with auxiliary substances such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring agents, and / or flavoring agents that do not deleteriously react with or interfere with the activity of the compounds provided herein. Those skilled in the art will recognize that other pharmaceutical excipients are suitable for use with the disclosed compounds or pharmaceutically acceptable salts thereof.

[0110] Pharmaceutical compositions of the present disclosure may contain one or more pharmaceutically acceptable carriers and / or diluents therefor, examples of which include lactose, starch, cellulose, and dextrose. Other excipients, such as flavoring agents, sweeteners, and preservatives, such as methyl, ethyl, propyl, and butyl parabens, may also be included.

[0042] The Handbook of Pharmaceutical Excipients (5 thA more complete list of suitable excipients can be found in Remington's Pharmaceutical Sciences (2003-20th edition), Pharmaceutical Press (2005). A person skilled in the art would know how to prepare formulations suitable for various types of administration routes. Conventional procedures and ingredients for the selection and preparation of suitable formulations can be found, for example, in Remington's Pharmaceutical Sciences (2003-20th edition), and The United States Pharmacopeia: The National Formulary, 1999 (USP 24 NF19). A carrier, diluent, and / or excipient is "acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical composition and not deleterious to the recipient thereof.

[0111] Treatment methods The compounds disclosed herein inhibit CDK2 and are therefore useful for treating diseases in which CDK2 is dysregulated, such as cancer. The present disclosure provides a method for inhibiting CDK2 in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0112] In some embodiments, the disclosure provides a method of treating a CDK2-associated disease or disorder in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or any formula described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the CDK2-associated disease or disorder is associated with amplification of the cyclin E1 (CCNE1) gene and / or overexpression of CCNE1. In some embodiments, the disease or disorder is cancer.

[0113] A subject "in need of inhibiting CDK2" is a subject having a disease in which inhibiting CDK2 can achieve a beneficial therapeutic effect, e.g., slowing the progression of the disease, alleviating one or more symptoms associated with the disease, or extending the lifespan of a subject given the disease.

[0114] In some embodiments, the present disclosure provides a method of treating a disease / condition / cancer associated with or modulated by CDK2, wherein inhibition of said CDK2 is therapeutically beneficial, including but not limited to, treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0115] In another embodiment, the present disclosure provides a method of treating a subject having cancer, the method comprising administering to the subject an effective amount of a compound disclosed herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein. In another embodiment, the cancer is characterized by amplification and / or overexpression of CCNE1 or CCNE2.

[0116] Thus, in some embodiments of the method, the subject or patient has been previously determined to have amplification of the cyclin E1 (CCNE1) gene and / or a CCNE1 expression level higher than the control expression level of CCNE1 in a biological sample obtained from the subject or patient.

[0117] In another embodiment, the present disclosure provides a method for inhibiting the growth of tumor (e.g., cancer) cells in vitro. The method comprises contacting tumor (e.g., cancer) cells in vitro with a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In another embodiment, the present disclosure provides a method for inhibiting the growth of tumor (e.g., cancer) cells associated with amplification and / or overexpression of CCNE1 in a subject or patient. The method comprises administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject or patient in need thereof.

[0118] In another embodiment, the present disclosure provides a method of treating a subject having cancer, comprising administering to the subject an effective amount of a compound disclosed herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, in combination with other agents or standard cancer treatments, as described below.

[0119] As used herein, "cancer" refers to any malignant and / or invasive growth or tumor caused by abnormal cell proliferation. Cancers include solid tumors, named for the type of cell that forms them, and cancers of the blood, bone marrow, or lymphatic system. Examples of solid tumors include sarcomas and carcinomas. Blood cancers include, but are not limited to, leukemia, lymphoma, and myeloma. Cancer also includes primary cancers that begin at a specific site in the body, metastatic cancers that have spread from their original location to other parts of the body, recurrence of a first primary cancer after remission, and second primary cancers (new primary cancers in people with a history of a previous cancer of a different type from the latter). In some such embodiments, the cancer is characterized by amplification and / or overexpression of CCNE1 and / or CCNE2.

[0120] Cancers that may be treated according to the disclosed methods include breast cancer, ovarian cancer, bladder cancer, uterine cancer (e.g., uterine carcinosarcoma), prostate cancer, lung cancer (including NSCLC, SCLC, squamous cell carcinoma (e.g., lung squamous cell carcinoma (LUSC)) or adenocarcinoma (e.g., lung adenocarcinoma (LUAD))), esophageal cancer, head and neck cancer, colorectal cancer (e.g., colon cancer, colorectal adenocarcinoma (COADREAD)), renal cancer (including RCC), liver cancer (including HCC), pancreatic cancer, gastric cancer (i.e., cancer of the stomach), urothelial carcinoma, brain cancer, mesothelioma (MESO), skin cancer (e.g., melanoma), sarcoma, or thyroid cancer, as well as metastases (particularly brain metastases) of all of the listed cancers. In some embodiments, the cancer is characterized by overexpression and / or amplification of CCNE1 and / or CCNE2 as described herein. In some embodiments of the methods provided herein, the subject has been confirmed to have a cancer characterized by amplification and / or overexpression of CCNE1 and / or CCNE2.

[0121] In further embodiments of the methods provided herein, the cancer is breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, liver cancer, pancreatic cancer, or gastric cancer. In some such embodiments, the cancer is characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0122] In further embodiments of the methods provided herein, the cancer is selected from the group consisting of ovarian cancer, endometrial cancer, gastric cancer, esophageal cancer, triple-negative breast cancer, and pulmonary adenosarcoma. In some embodiments, the cancer is characterized by overexpression and / or amplification of CCNE1. In some embodiments, the cancer is progressing despite platinum therapy.

[0123] In some embodiments, the cancer is platinum-resistant and / or platinum-refractory, hi some embodiments, the cancer is progressing despite platinum therapy.

[0124] In some embodiments, the CDK2-associated disease or disorder is an adenocarcinoma, carcinoma, or cystadenocarcinoma.

[0125] In other embodiments, the cancer is breast cancer, including, for example, ER-positive / HR-positive, HER2-negative breast cancer; ER-positive / HR-positive, HER2-positive breast cancer; triple-negative breast cancer (TNBC) or inflammatory breast cancer. In some embodiments, the breast cancer is chemotherapy- or radiotherapy-resistant breast cancer, endocrine-resistant breast cancer, trastuzumab-resistant breast cancer, or breast cancer that exhibits primary or acquired resistance to CDK4 / CDK6 inhibition. In some embodiments, the breast cancer is advanced or metastatic breast cancer. In some embodiments of each of the foregoing, the breast cancer is characterized by amplification and / or overexpression of CCNE1 and / or CCNE2.

[0126] In some embodiments, the cancer is HR-positive breast cancer. In some embodiments, the breast cancer is ER-positive breast cancer. In some embodiments, the breast cancer is HR-positive, HER2-negative breast cancer. In some embodiments, the breast cancer is ER-positive, HER2-negative breast cancer. In some embodiments, the breast cancer is responsive to treatment with a CDK4 / 6 inhibitor. In some embodiments, the breast cancer is responsive to treatment with a CDK4 / 6 inhibitor. In some embodiments, the breast cancer has progressed despite treatment with a CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor is palbociclib. In some embodiments, the CDK4 / 6 inhibitor is ribociclib. In some embodiments, the breast cancer has progressed despite a first treatment with palbociclib, ribociclib, and / or fulvestrant and a second treatment with abemaciclib and / or fulvestrant. In some embodiments, the method further comprises administering an effective amount of a CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor is selected from palbociclib and ribociclib, or a combination thereof. In some embodiments, the CDK4 / 6 inhibitor is ribociclib. In one embodiment, the breast cancer has CCNE amplification and / or overexpression.

[0127] In some embodiments, the breast cancer is triple-negative breast cancer.

[0128] In some embodiments, the cancer is ovarian cancer. In some such embodiments, the cancer is ovarian cancer characterized by amplification and / or overexpression of CCNE1 and / or CCNE2. In some such embodiments, the cancer is (a) ovarian cancer; (b) a cancer characterized by amplification and / or overexpression of cyclin E1 (CCNE1) or cyclin E2 (CCNE2); or (c) both (a) and (b). In some embodiments, the cancer is ovarian cancer.

[0129] In some embodiments, a compound of the present disclosure is administered as a first-line therapy. In other embodiments, a compound of the present disclosure is administered as a second- (or later) line therapy. In some embodiments, a compound of the present disclosure is administered as a second- (or later) line therapy following treatment with an endocrine therapy and / or a CDK4 / CDK6 inhibitor. In some embodiments, a compound of the present disclosure is administered as a second- (or later) line therapy following treatment with an endocrine therapy, e.g., an aromatase inhibitor, a SERM, or a SERD. In some embodiments, a compound of the present disclosure is administered as a second- (or later) line therapy following treatment with a CDK4 / CDK6 inhibitor. In some embodiments, a compound of the present disclosure is administered as a second- (or later) line therapy following treatment with one or more chemotherapy regimens, e.g., including a taxane or platinum agent. In some embodiments, a compound of the present disclosure is administered as a second- (or later) line therapy following treatment with a HER2-targeted agent (e.g., trastuzumab).

[0130] In some embodiments, the CDK2-associated disease or disorder is N-myc-amplified neuroblastoma cells (see Molenaar, et al., Proc Natl Acad Sci USA 106(31):12968-12973), K-Ras-mutated lung cancer (see Hu, S., et al., Mol Cancer Ther, 2015.14(11):2576-85), and cancer with FBW7 mutation and CCNE1 overexpression (see Takada, et al., Cancer Res, 2017.77(18):4881-4893).

[0131] In some embodiments, compounds of the present disclosure can be used to treat sickle cell disease and sickle cell anemia.

[0132] Examples of cancers that can be treated using the compounds of the present disclosure include bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, stomach cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia including acute myeloid leukemia, chronic Cancers that can be treated include but are not limited to myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, childhood solid tumors, lymphocytic lymphoma, bladder cancer, kidney or urethral cancer, renal pelvis cancer, central nervous system (CNS) neoplasm, primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancer, including asbestos-induced cancer, and combinations of the above cancers.The compounds of the present disclosure are also useful for treating metastatic cancer.

[0133] In some embodiments, cancers treatable by the compounds of the present disclosure include, but are not limited to, melanoma (e.g., metastatic malignant melanoma, BRAF and HSP90 inhibition-resistant melanoma, cutaneous melanoma (SKCM)), renal cancer (e.g., clear cell carcinoma), prostate cancer (e.g., hormone-refractory prostate adenocarcinoma), breast cancer, colon cancer, lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), squamous cell head and neck cancer (e.g., head and neck squamous cell carcinoma (NHSC)), urothelial carcinoma (e.g., bladder), and cancers with high microsatellite instability (MSI high). Additionally, the present disclosure includes refractory or recurrent malignancies whose growth can be inhibited using the compounds of the present disclosure.

[0134] In some embodiments, cancers treatable using the compounds of the present disclosure include, but are not limited to, solid tumors (e.g., prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, kidney cancer, liver cancer, pancreatic cancer, stomach cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, sarcoma, bladder cancer, etc.), blood cancers (e.g., lymphoma, leukemia (acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML)), DLBCL, mantle cell lymphoma, non-Hodgkin's lymphoma (relapsed or refractory NHL and follicular lymphoma, including relapsed follicular), Hodgkin's lymphoma, or multiple myeloma), and combinations of the foregoing cancers.

[0135] In some embodiments, cancers treatable using compounds of the present disclosure include, but are not limited to, cholangiocarcinoma, bile duct carcinoma, triple-negative breast cancer, rhabdomyosarcoma, small cell lung cancer, leiomyosarcoma, hepatocellular carcinoma (e.g., liver hepatocellular carcinoma (LIHC)), Ewing's sarcoma, brain cancer, brain tumor, astrocytoma, neuroblastoma, neurofibroma, basal cell carcinoma, chondrosarcoma, epithelioid sarcoma, eye cancer, fallopian tube cancer, gastrointestinal cancer, gastrointestinal stromal tumor, hairy cell leukemia, intestinal cancer, islet cell carcinoma, oral cavity cancer, mouth cancer, throat cancer, laryngeal cancer, lip cancer, mesothelioma, neck cancer, nasal cavity cancer, eye cancer, ocular melanoma, pelvic cancer, rectal cancer, renal cell carcinoma, salivary gland cancer, paranasal sinus cancer, spinal cancer, tongue cancer, tubular adenocarcinoma, urethral cancer, and ureteral cancer.

[0136] In some embodiments, cancers treatable with the compounds of the present disclosure include Genomic Identification of Key Targets in Cancer (GISTIC) and Pheochromocytoma and Paraganglioma (PCPG).

[0137] In some embodiments, cancers treatable with compounds of the present disclosure include advanced / recurrent tumors; CCNE1-amplified platinum-resistant or platinum-refractory ovarian cancer; endometrial cancer that has progressed after two or more lines of therapy (previously received platinum therapy); and gastric cancer that has progressed after two or more lines of therapy (previously received platinum therapy); and ER+HER2-BC that has progressed despite CDK4 / 6i. In some embodiments, cancers treatable with compounds of the present disclosure include platinum-resistant or platinum-refractory CCNE1-amplified ovarian cancer; CCNE1-amplified endometrial cancer that has failed two or more lines of therapy; CCNE1-amplified advanced / recurrent tumors not belonging to other groups; ER+HER2-BC that has progressed despite CDK4 / 6i; platinum-resistant or platinum-refractory CCNE1-amplified ovarian cancer; and ER+HER2-BC that has progressed despite CDK4 / 6i.

[0138] In some embodiments, diseases and indications treatable using compounds of the present disclosure include, but are not limited to, hematological cancers, sarcomas, lung cancers, gastrointestinal cancers, genitourinary tract cancers, liver cancer, bone cancers, nervous system cancers, gynecological cancers, and skin cancers.

[0139] Exemplary hematological cancers include lymphomas and leukemias, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin's lymphoma (including relapsed or refractory NHL and relapsed follicular), Hodgkin's lymphoma, myeloproliferative disorders (e.g., primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocythemia (ET)), myelodysplastic syndromes (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), and multiple myeloma (MM).

[0140] Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdomyosarcoma, fibroma, lipoma, hamartoma, and teratoma.

[0141] Exemplary lung cancers include non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), bronchial carcinoma, squamous cell, small undifferentiated cell, large undifferentiated cell, adenocarcinoma, alveolar epithelial (bronchiolar) carcinoma, bronchial adenoma, chondroid hamartoma, and mesothelioma. Exemplary gastrointestinal cancers include esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (carcinoma, lymphoma, leiomyosarcoma), pancreatic cancer (tubular adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine cancer (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colon cancer (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), and colorectal cancer.

[0142] Exemplary genitourinary tract cancers include kidney cancer (adenocarcinoma, Wilms' tumor, [nephroblastoma]), bladder and urethral cancer (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate cancer (adenocarcinoma (PRAD), sarcoma), and testicular cancer (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoroid tumor, lipoma).

[0143] Exemplary liver cancers include hepatocarcinoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

[0144] Exemplary bone cancers include, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell chordoma, osteochondroma (osteochondral exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor.

[0145] Exemplary nervous system cancers include skull cancers (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meningeal cancers (meningioma, meningeal sarcoma, gliomatosis), brain cancers (astrocytoma, medulloblastoma, glioma, brain low-grade glioma (LGG), ependymoma, germ cell tumor (pinealoma), glioblastoma, glioblastoma multiforme (GBM), oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), and spinal cancers (neurofibroma, meningioma, glioma, sarcoma), as well as neuroblastoma and Lhermitte-Dacros disease.

[0146] Exemplary gynecological cancers include uterine cancer (endometrial cancer), cervical cancer (cervical carcinoma, cervical squamous cell carcinoma (CESC), preneoplastic cervical dysplasia), ovarian cancer (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulvar cancer (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, sarcoma botryoides (embryonal rhabdomyosarcoma)), and cancer of the fallopian tubes (epithelial carcinoma).

[0147] Exemplary skin cancers include melanoma, basal cell carcinoma, Merkel cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, lenticular dysplastic nevi, lipoma, hemangioma, dermatofibroma, and keloids. In some embodiments, diseases and indications treatable using the compounds of the present disclosure include, but are not limited to, sickle cell disease (e.g., sickle cell anemia), triple-negative breast cancer (TNBC), myelodysplastic syndrome, testicular cancer, bile duct cancer, esophageal cancer, and urothelial cancer. combination

[0148] The compounds of the present disclosure may be administered as single agents or in combination with other anti-cancer therapeutic agents, particularly standard of care agents appropriate for the particular cancer.

[0149] As used herein, the term "additional anti-cancer therapeutic agent" refers to any one or more therapeutic agents, other than the compounds of the present disclosure, that are or may be used in the treatment of cancer; in some embodiments, such additional anti-cancer therapeutic agents include compounds from the following classes: mitotic inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, antiangiogenic agents, topoisomerase I and II inhibitors, plant alkaloids, hormonal agents and antagonists, growth factor inhibitors, radiation, signal transduction inhibitors such as inhibitors of protein tyrosine kinases and / or serine / threonine kinases, cell cycle inhibitors, biological response modifiers, enzyme inhibitors, antisense oligonucleotides or oligonucleotide derivatives, cytotoxic agents, and immuno-oncology agents.

[0150] In some embodiments, the additional anti-cancer agent is an endocrine agent, such as an aromatase inhibitor, a SERD, or a SERM.

[0151] In some embodiments, the additional anticancer agent is a PIK3CA inhibitor, including but not limited to alpelisib (PIQRAY), BEBT-908, BPI-21668, buparlisib, inavolisib, TQB-3525, RLY-2608, milansertib, MEN-1611, LOXO-783, HS-10352, HH-CYH33, gedatolicib, and fimepinostat.

[0152] In some embodiments, the additional anti-cancer agent includes, but is not limited to, trastuzumab deruxtecan (Enhertu), trastuzumab duocarmazine, trastuzumab emtansine (Kadcyla), upifitamab rxodotin (Upifitamab Antibody-drug conjugates include rilsodotin, mirvetuximab sorafutansine, tisotumab vedotin (Tivdak), pralzatamaravtansine, sacituzumab govitecan or sacituzumab govitecan-hziy (Trodelvy), datopotamab deruxtecan, ladiratuzumab vedotin, patritumab deruxtecan, STRO-002, MORab-202, DS-6000, anetumab, avatansine, XMT-2056, and dicitamab vedotin (RC48-ADC, Aidexi).

[0153] In some embodiments, the additional anti-cancer agent is a PLK1 inhibitor, including but not limited to onvansertib, BI2536, BI6727, GSK461364A, TAK960, rigosertib.

[0154] In some embodiments, the additional anti-cancer agent is an estrogen PROTAC (ARV-471, H3B-5942).

[0155] In other embodiments, the compounds of the present disclosure may be administered in combination with standard of care agents. In some embodiments, the compounds of the present disclosure may be administered in combination with endocrine therapy, such as agents such as letrozole, fulvestrant, tamoxifen, exemestane, or anastrozole. In some embodiments, the compounds of the present disclosure may be administered in combination with chemotherapeutic agents (e.g., docetaxel, paclitaxel, cisplatin, carboplatin, capecitabine, gemcitabine, vinorelbine, or liposomal doxorubicin). In other embodiments, the compounds of the present disclosure may be administered in combination with anti-HER2 agents (e.g., trastuzumab or pertuzumab).

[0156] In some embodiments, a compound of the present disclosure (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) may be administered in combination with an effective amount of carboplatin, ribociclib, fulvestrant, or a combination thereof.

[0157] In some embodiments, the additional anti-cancer agent is an anti-angiogenic agent, including, for example, VEGF inhibitors, VEGFR inhibitors, TIE-2 inhibitors, PDGFR inhibitors, angiopoietin inhibitors, PKCb inhibitors, COX-2 (cyclooxygenase II) inhibitors, integrin (alpha-v / beta-3), MMP-2 (matrix metalloproteinase 2) inhibitors, and MMP-9 (matrix metalloproteinase 9) inhibitors. Preferred anti-angiogenic agents include sunitinib (Sutent™), bevacizumab (Avastin™), axitinib (AG13736), SU14813 (Pfizer), and AG13958 (Pfizer). Additional antiangiogenic agents include vatalanib (CGP79787), sorafenib (Nexavar™), pegaptanib octasodium (Macugen™), vandetanib (Zactima™), PF-0337210 (Pfizer), SU14843 (Pfizer), AZD2171 (AstraZeneca), ranibizumab (Lucentis™), Neovastat™ (AE941), tetrathiomolybdate (Coplexa™), AMG706 (Amgen), VEGF Trap (AVE0005), CEP7055 (Sanofi-Aventis), XL880 (Exelixis), telatinib (BAY57-9352), and CP-868,596 (Pfizer). Other antiangiogenic agents include enzastaurin (LY317615), midostaurin (CGP41251), perifosine (KRX0401), teprenone (Cerbex™), and UCN01 (Kyowa Hakko). Other examples of antiangiogenic agents include celecoxib (Celebrex™), parecoxib (Dynastat™), deracoxib (SC59046), lumiracoxib (Plaize™), valdecoxib (Bextra™), rofecoxib (Viox™), iguratimod (Kaleram™), IP751 (Invedas), SC-58125 (Pharmacia), and etoricoxib (Alkoxya™).Still further anti-angiogenic agents include exilind (Aptosin™), salsalate (Amigesic™), diflunisal (Drobid™), ibuprofen (Motrin™), ketoprofen (Ordis™), nabumetone (Rilafen™), piroxicam (Feldene™), naproxen (Aleve™, Naprosyn™), diclofenac (Voltaren™), indomethacin (Indocin™), sulindac (Clinoryl™), tolmetin (Tolectin™), etodolac (Rodyne™), ketorolac (Toradal™), and oxaprozin (Daypro™). Additional anti-angiogenic agents include ABT510 (Abbott), aplatastat (TMI005), AZD8955 (AstraZeneca), incyclinide (Metastat™), and PCK3145 (Procyon).

[0158] Still other antiangiogenic agents (including VEGFR / PDGFR inhibitors) include, but are not limited to, ponatinib (Iclusig), BT1718, anlotinib, lenvatinib (Lenvima), tivozanib (Fotivda), dovitinib, brolucizumab (Beovu), aflibercept (Eylea), and faricimab.

[0159] Additional antiangiogenic agents include acitretin (Neotigasone™), plitidepsin (Aplidine™), cilengitide (EMD121974), combretastatin A4 (CA4P), fenretinide (4HPR), halofuginone (Tempostatin™), Panzem™ (2-methoxyestradiol), PF-03446962 (Pfizer), revimastat (BMS275291), catumaxomab (Removab™), lenalidomide (Revlimid™), squalamine (Ebizon™), thalidomide (Thalomid™), Ukrain™ (NSC631570), Vitaxin™ (MEDI522), and zoledronic acid (Zometa™).

[0160] In other embodiments, the additional anticancer agent is a so-called signal transduction inhibitor (e.g., an agent that inhibits the intracellular transmission of regulatory molecules that govern fundamental processes of cell proliferation, differentiation, and survival). Signal transduction inhibitors include small molecules, antibodies, and antisense molecules. Signal transduction inhibitors include, for example, kinase inhibitors (e.g., tyrosine kinase inhibitors or serine / threonine kinase inhibitors) and cell cycle inhibitors. More specifically, signal transduction inhibitors include, for example, farnesyl protein transferase inhibitors, EGF inhibitors, ErbB-1 (EGFR), ErbB-2, pan erb, IGF1R inhibitors, MEK, c-Kit inhibitors, FLT-3 inhibitors, K-Ras inhibitors, PI3 kinase inhibitors, JAK inhibitors, STAT inhibitors, Raf kinase inhibitors, Akt inhibitors, mTOR inhibitors, P70S6 kinase inhibitors, inhibitors of the WNT pathway, and so-called multi-targeted kinase inhibitors. Additional examples of signal transduction inhibitors that may be used in conjunction with the compounds of the invention and pharmaceutical compositions described herein include BMS214662 (Bristol-Myers Squibb), lonafarnib (Salazar™), peritrexol (AG2037), matuzumab (EMD7200), nimotuzumab (TheraCIM h-R3™), panitumumab (Vectibix™), vandetanib (Zactima™), pazopanib (SB 786034), ALT110 (Alteris Therapeutics), BIBW2992 (Boehringer Ingelheim), and Cerven™ (TP38).Other examples of signal transduction inhibitors include gefitinib (Iressa™), cetuximab (Erbitux™), erlotinib (Tarceva™), trastuzumab (Herceptin™), sunitinib (Sutent™), imatinib (Gleevec™), crizotinib (Pfizer), lorlatinib (Pfizer), dacomitinib (Pfizer), bosutinib (Pfizer), gedatricisib (Pfizer), canertinib (CI1033), and pertuzumab. (Omnitarg™), lapatinib (Tykerb™), pelitinib (EKB569), miltefosine (Miltefosine™), BMS599626 (Bristol-Myers Squibb), Lapuleucel-T (Neuvenge™), Nuvax™ (E75 cancer vaccine), Osidem™ (IDM1), mubritinib (TAK-165), CP-724,714 (Pfizer), panitumumab (Vectibix™), ARRY142886 (Array Biopharm), everolimus (Celtican™), zotarolimus (Endeavor™), temsirolimus (Trisel™), AP23573 (ARIAD), and VX680 (Vertex), XL647 (Exelixis), sorafenib (Nexavar™), LE-AON (Georgetown University), and GI-4000 (Globelmmune). Other signal transduction inhibitors include ABT751 (Abbott), alvocidib (flavopiridol), BMS387032 (Bristol Myers), EM1421 (Erimos), indisulam (E7070), seliciclib (CYC200), BIO112 (Onc Bio), BMS387032 (Bristol-Myers Squibb), palbociclib (Pfizer), and AG024322 (Pfizer).

[0161] In other embodiments, the additional anticancer agent is a so-called classical antitumor agent. Classical antitumor agents include, but are not limited to, hormone regulators, such as hormones, antihormones, androgen agonists, androgen antagonists, and antiestrogenic therapeutic agents, histone deacetylase (HDAC) inhibitors, DNA methyltransferase inhibitors, silencing or gene activating agents, ribonucleases, proteomics, topoisomerase I inhibitors, camptothecin derivatives, topoisomerase II inhibitors, alkylating agents, antimetabolites, poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors (e.g., talazoparib, olaparib, rucaparib, niraparib, iniparib, veliparib, etc.), microtubulin inhibitors, antibiotics, plant-derived spindle inhibitors, platinum coordination compounds, gene therapy agents, antisense oligonucleotides, vascular targeting agents (VTAs), and statins.Examples of classical anti-tumor agents useful in combination therapy with the compounds of the present invention (which may be used in combination with one or more other drugs) include, but are not limited to, glucocorticoids (dexamethasone, prednisone, prednisolone, methylprednisolone, hydrocortisone, etc.), progestins such as medroxyprogesterone, megestrol acetate (MegaAce), mifepristone (RU-486), selective estrogen receptor modulators (SERMs; tamoxifen, raloxifene, lasofoxifene, afimoxifene, arzoxifene, bazedoxifene, fispemifene, ormeloxifene, ospemifene, tesmilifene, toremifene, trilostane, CHF4227 (Cheisi), etc.), selective estrogen receptor downregulators (SERDs; fulvestrant, LSZ102, G1T48, RAD1901, elastase, etc.). Trant, GDC-9545, Gildestrant, SAR439859, Amsenestrant, AZD9833, Camizetrant, LY3484356, Zn-c5, D-0502), Exemestane (Aromasin), Anastrozole (Arimidex), Atamestane, Fadrozole, Letrozole (Femara), Formestane; Gonadotropin-Releasing Hormone (GnRH; commonly luteinizing hormone-releasing hormone [ LHRH [also known as LHRH] agonists (such as buserelin (Suprefact), goserelin (Zoladex), leuprorelin (Lupron), and triptorelin (Trelstar)), abarelix (Plenaxis), cyproterone, flutamide (Eulexin), megestrol, nilutamide (Nilandrone), and osaterone, dutasteride, epristeride, finasteride, saw palmetto, PHL 00801, abarelix, goserelin, leuprorelin, triptorelin, bicalutamide; antiandrogens such as enzalutamide, abiraterone acetate, bicalutamide (Casodex); and combinations thereof.Other examples of classical antitumor agents that may be used in combination with the compounds of the present invention include suberanilide hydroxamic acid (SAHA, Merck Inc. / Aton Pharmaceuticals), depsipeptide (FR901228 or FK228), G2M-777, MS-275, pivaloyloxymethyl butyrate and PXD-101; onconase (ranpirnase), PS-341 (MLN-341), Velcade (bortezomib), 9-aminocamptothecin, belotecan, BN-80915 (Roche), camptothecin, diflomotecan, edotecarin, exatecan (Daiichi), gimatecan, 10-hydroxycamptothecin, irinotecan HCl (Camptosar), lurtotecan, olathecin (rubitecan, Supergen), SN-38, topotecan, camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin, irinotecan, SN-38, edotecarin, topotecan, aclarubicin, adriamycin, amonafide, amrubicin, annamycin, daunorubicin, doxorubicin, elsamitrucin, epirubicin, etoposide, idarubicin, galarubicin, hydroxycarbamide, nemorubicin, novantrone (mitoxantrone), pirarubicin, pisantrone, procarbazine, rebeccamycin, sobuzoxane, tafluposide, valrubicin, Zinecard (dexrazoxane), nitrogen mustard N-oxide, cyclophosphamide, AMD-473, altretamine, AP-5280, apaziquone, brostallicin, bendamustine These include, but are not limited to, busulfan, carboquone, carmustine, chlorambucil, dacarbazine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, lomustine, mafosfamide, mechlorethamine, melphalan, mitobronitol, mitolactol, mitomycin C, mitoxatrone, nimustine, ranimustine, temozolomide, thiotepa, and platinum-coordinated alkylating compounds (e.g., cisplatin, paraplatin (carboplatin), eptaplatin, lobaplatin, nedaplatin, eloxatin (oxaliplatin, Sanofi), streptozocin, satrplatin), and combinations thereof.

[0162] In still other embodiments, the additional anticancer agent is a so-called dihydrofolate reductase inhibitor (such as methotrexate and Nutrexin (trimetresate glucuronate)), a purine antagonist (such as 6-mercaptopurine riboside, mercaptopurine, 6-thioguanine, cladribine, clofarabine (Clolar), fludarabine, nelarabine, and raltitrexed), a pyrimidine antagonist (such as 5-fluorouracil (5-FU), Alimta (premetrexed disodium, LY231514, MTA), capecitabine (Xeloda™), cytosine arabinoside, Gemzar™ (gemcitabine, Eli Lilly), tegafur (UFT Orzel or Uforal, and the TS-1 combination of tegafur, gimestat, and otostat), doxifluridine, carmofur, cytarabine (including ocphosphate, phosphate stearate, sustained-release, and liposomal forms), enocitabine, 5-azacytidine (Vidaza), decitabine, and ethinylcytidine), and other antimetabolites, such as eflornithine, hydroxyurea, leucovorin, nolatrexed (Thymitac), triapine, trimetrexate, N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino)]-2-thenoyl)-L-glutamic acid, AG-014699 (Pfizer Inc.), ABT-472 (Abbott Laboratories), INO-1001 (Inotek Pharmaceuticals), KU-0687 (KuDOS Pharmaceuticals), and GPI 18180 (Guilford Pharm) Inc), and combinations thereof.

[0163] Other examples of classical antitumor cytotoxic agents include, but are not limited to, Abraxane (Abraxis BioScience, Inc.), vatabulin (Amgen), EPO906 (Novartis), vinflunine (Bristol-Myers Squibb), actinomycin D, bleomycin, mitomycin C, neocarzinostatin (zinostatin), vinblastine, vincristine, vindesine, vinorelbine (navelbine), docetaxel (Taxotere), ortataxel, paclitaxel (including taxoplexin, a DHA / paclitaxel conjugate), cisplatin, carboplatin, nedaplatin, oxaliplatin (eloxatin), satraplatin, camptosar, capecitabine (Xeloda), oxaliplatin (Eloplatin), cisplatin, ... Xatin), Taxotere alitretinoin, Canfosfamide (Telcyta™), DMXAA (Antisoma), Ibandronic acid, L-asparaginase, Pegaspargase (Oncaspar™), Efaproxiral (Efaproxyn™ - radiation therapy), Bexarotene (Targretin™), Tesmilifene (DPPE - enhances the effectiveness of cytotoxic drugs), Seratope™ (Biomira), Tretinoin (Vesanoid™), Tirapazamine (Trizaone™), Motexafin Gadolinium (Xcytrin™), Cotara™ (mAb), and NBI-3001 (Protox Therapeutics), Polyglutamic Acid-Paclitaxel (Xyotax™) and combinations thereof.Further examples of classical antitumor agents include Advexin (ING201), TNFerade (GeneVec, a compound that induces TNFα expression in response to radiation therapy), RB94 (Baylor College of Medicine), Genasense (Oblimmersen, Genta), combretastatin A4P (CA4P), Oxy-4503, AVE-8062, ZD-6126, TZT-1027, atorvastatin (Lipitor, Pfizer Inc.), provastatin (Pravachol, Bristol-Myers Squibb), lovastatin (Mevacor, Merck Inc.), simvastatin (Zocor, Merck Inc.), fluvastatin (Lescol, Novartis), cerivastatin (Baycol, Bayer), rosuvastatin (Crestor, AstraZeneca), lovostatin, niacin (Advicor, Kos Pharmaceuticals), Caduet, Lipitor, torcetrapib, and combinations thereof.

[0164] In other embodiments, the additional anticancer agent is an epigenetic modulator, such as an inhibitor or EZH2, Smalca4, PBRM1, ARID1A, ARID2, ARID1B, DNMT3A, TET2, MLL1 / 2 / 3, NSD1 / 2, SETD2, BRD4, DOT1L, HKMTsanti, PRMT1-9, LSD1, UTX, IDH1 / 2, or BCL6.

[0165] In further embodiments, the additional anti-cancer agent is an immunomodulatory agent, examples of which include, but are not limited to, inhibitors of CTLA-4 (e.g., ipilimumab), PD-1 or PD-L1 (e.g., pembrolizumab, nivolumab, avelumab, atezolizumab, durvalumab, cemiplimab, or dostarlimab), LAG-3 (e.g., leratolimab, TIM-3, TIGIT, 4-1BB, OX40, GITR, CD40, or CAR-T cell therapy).

[0166] In some embodiments, the additional anticancer agent is an EGFR inhibitor such as afatinib, an EGFR antibody such as osimertinib, lapatinib, erlotinib, dacomitinib, poziotinib, neratinib or gefitinib or cetuximab, panitumumab or necitumumab.

[0167] Alternatively, a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein can be combined with other anti-cancer agents that are not EGFR inhibitors, such as MEK inhibitors, including mutant MEK inhibitors (trametinib, cobimutetinib, binimetinib, selumetinib, refametinib); c-MET inhibitors, including mutant c-Met inhibitors (savolitinib, cabozantinib, foretinib) and MET antibodies (emibetuzumab); mitotic kinase inhibitors (palbociclib, ribociclib, abemaciclib, CDK4 / 6 inhibitors such as rivaciclib, relociclib, trilaciclib, dalpiciclib, BPI-16350; antiangiogenic agents such as bevacizumab and nintedanib; apoptosis inducers such as Bcl-2 inhibitors (e.g., venetoclax, obatoclax, navitoclax) and Mcl-1 inhibitors (e.g., AZD-5991, AMG-176, S-64315); and mTOR inhibitors (e.g., rapamycin, temsirolimus, everolimus, lidofolomus).

[0168] The compounds of the present disclosure, pharmaceutically acceptable salts thereof, or pharmaceutical compositions disclosed herein may be administered in combination with other anti-cancer drugs, including palbociclib (e.g., Ibrance®), ribociclib, abemaciclib, tamoxifen, letrozole, olaparib (e.g., Lynparza®), niraparib, carboplatin, cisplatin, paclitaxel, gemcitabine, megestrol acetate, medroxyprogesterone acetate, capecitabine (e.g., Xeloda®), regorafenib (e.g., Stivarga®), afatinib (e.g., Giotrif®), osimertinib (e.g., ribozyme), ribozyme inhibitors (e.g., ribozyme inhibitors ... , Tagrisso®), gefitinib (e.g., Iressa®), erlotinib (e.g., Tarceva®), ramucirumab (e.g., Cyramza®), EGFR inhibitors, pralsetinib, ABT-263 (navitoclax), MK-1775 (adavosertib), BAY-1895344, beruzosertib, selalasertib, SRA-737, LY2603618 (ravusertib), and trastuzumab (e.g., Herceptin®), or a combination thereof. EGFR inhibitors include afatinib, osimertinib, lapatinib, erlotinib, dacomitinib, poziotinib, neratinib, gefitinib JBJ-04-125-02, alflutinib (AST2818), aumoretinib (formerly almonertinib) (HS10296), BBT-176, BI-4020, BPI-361175, BPI-D0316, CH7233163, gilteritinib, icotinib, JND-3229, lazertinib, and nafatinib. It may be selected from zarutinib (EGF816), avitinib, PCC-0208027, resivertinib (BPI-7711), TQB3804, zolifertinib (AZ-3759) or DZD9008, or from EGFR antibodies such as cetuximab, panitumumab, necitumumab, HLX07, JMT101, or from bispecific EGFR and MET antibodies (e.g., amivantamab ((JNJ-61186372, JNJ-372)).

[0169] Biomarkers and Pharmacodynamic Markers The present disclosure further provides predictive markers (e.g., biomarkers and pharmacodynamic markers, such as gene copy number, gene sequence, expression level, or phosphorylation level) to identify human subjects having, suspected of having, or at risk of developing a CDK2-related disease or disorder that is likely to be responsive to administration of a CDK2 inhibitor (as used herein, "CDK2 inhibitor" refers to a compound of the present disclosure, or a pharmaceutically acceptable salt thereof).

[0170] CCNE1 In one embodiment, the biomarker is CCNE1. In particular, amplification of the cyclin E1 (CCNE1) gene and / or expression levels of CCNE1 in a biological sample would indicate that a patient or subject may benefit from administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0171] CCNE1 is a cell cycle factor essential for cell cycle regulation at the G1 / S transition (Ohtsubo et al., 1995, Mol. Cell. Biol. 15:2612-2624). CCNE1 acts as a regulatory subunit of CDK2 and interacts with CDK2 to form a serine / threonine kinase holoenzyme complex. The CCNE1 subunit of this holoenzyme complex provides substrate specificity for the complex (Honda et al., 2005, EMBO 24:452-463). CCNE1 is encoded by the cyclin E1 ("CCNE1") gene (GenBank accession number NM_001238). The amino acid sequence of human CCNE1 can be found in GenBank accession number NP_001229 / UniProtKB accession number P24864).

[0172] In one aspect, the present disclosure provides a method of treating a subject having or at risk of developing a disease or disorder associated with CDK2, the method comprising administering a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein to the subject, wherein the subject has amplification of the CCNE1 gene and / or has a CCNE1 expression level that is higher than a control expression level of CCNE1. In some embodiments, the CDK2-associated disease or disorder is cancer.

[0173] Also provided herein is a method of treating a patient having an amplified expression level of CCNE1 and suffering from or at risk of developing a solid tumor cancer, the method comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0174] Amplification of the CCNE1 gene and / or a CCNE1 expression level higher than a control expression level of CCNE1 indicates / predicts that a human subject having or at risk of developing a CDK2-related disease or disorder will respond to a CDK2 inhibitor. In some embodiments, the CCNE1 expression level may be the CCNE1 mRNA level. In other embodiments, the CCNE1 expression level may be the CCNE1 protein level.

[0175] Other biomarkers In some embodiments, a contemplated biomarker may be p16 (also known as cyclin-dependent kinase inhibitor 2A, cyclin-dependent kinase 4 inhibitor A, multiple tumor suppressor 1, and p16-INK4a), which acts as a negative regulator of normal cell proliferation by interacting with CDK4 and CDK6. In other embodiments, a contemplated biomarker may be phosphorylation of Rb at the serine corresponding to amino acid position 780. Rb is a regulator of the cell cycle and acts as a tumor suppressor. Rb is activated when phosphorylated by cyclin D-CDK4 / 6 at Ser780 and Ser795 and cyclin E / CDK2 at Ser807 and Ser811.

[0176] Contemplated biomarkers may also be selected from the group consisting of RB1, RBL1, RBL2, CDKN2A, CDKN1A, CDKN1B, FBXW7, CCNE1, CCNE2, CCNA1, CCNA2, CCND1, CCND2, CCND3, CDK2, CDK3, CDK4, CDK6, CDKN2A, CDNK1A, CDKN1B, E2F1, E2F2, E2F3, MYC, MYCL, MYCN, EZH2, ER, HER2, HER3, HPV+ and EGFR.

[0177] biological samples Biological samples suitable for the methods described herein include any sample containing blood or tumor cells obtained from or derived from a human subject in need of treatment.For example, biological samples can include tumor cells obtained from a biopsy of a patient suffering from a solid tumor.Tumor biopsies can be obtained by various means known in the art.Alternatively, blood samples can be obtained from patients suffering from blood cancer.

[0178] The biological sample can be obtained from a human subject having, suspected of having, or at risk of developing a CDK2-associated disease or disorder. In some embodiments, the CDK2-associated disease or disorder is cancer (e.g., as described above).

[0179] Methods of obtaining and / or storing samples that preserve the activity or integrity of molecules (e.g., nucleic acids or proteins) in the sample are well known to those of skill in the art. For example, a biological sample may be further contacted with one or more additional agents, such as buffers and / or inhibitors (including one or more of nuclease, protease, and phosphatase inhibitors), that preserve or minimize alteration of the molecules in the sample.

[0180] Administration method and dosage form The exact amount of compound administered to provide an "effective amount" to a subject will depend on the mode of administration, the type and severity of the cancer, and the subject's characteristics (such as overall health, age, sex, weight, and tolerance to drugs). Those skilled in the art will be able to determine appropriate dosages depending on these and other factors. When administered in combination with other therapeutic agents, for example, in combination with anti-cancer drugs, the "effective amount" of any additional therapeutic agent(s) will depend on the type of drug used. Appropriate dosages of approved therapeutic agents are known and can be adjusted by those skilled in the art depending on the condition of the subject, the type of condition(s) being treated, and the amount of compound of Formula (I) used, for example, by following dosages reported in the literature and recommended in the Physician's Desk Reference (57th Ed., 2003).

[0181] "Treating" or "treatment" refers to obtaining a desired pharmacological and / or physiological effect. The effect may be therapeutic, including partially or substantially achieving one or more of the following results: partially or substantially reducing the extent of the disease, condition, or cancer; ameliorating or improving clinical symptoms or indicators associated with the disease, condition, or cancer; delaying, inhibiting, or reducing the likelihood of progression of the disease, condition, or cancer; or reducing the likelihood of recurrence of the disease, condition, or cancer.

[0182] The term "effective amount" refers to an amount that, when administered to a subject, produces a beneficial or desired result (including a clinical result), e.g., inhibits, suppresses, or reduces the symptoms of the condition being treated in the subject compared to a control. For example, a therapeutically effective amount can be provided in a unit dosage form (e.g., 0.1 mg to about 50 g per day, alternatively 1 mg to about 5 grams per day, and further alternatively 10 mg to 1 gram per day).

[0183] As used herein, the terms "administer," "administering," "administration," and the like refer to methods that can be used to enable delivery of a composition to a desired site of biological action. These methods include, but are not limited to, intraarticular (in the joints), intravenous, intramuscular, intratumor, intradermal, intraperitoneal, subcutaneous, oral, topical, intrathecal, inhalation, transdermal, rectal, and the like. Administration techniques that can be used with the agents and methods described herein can be found, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.

[0184] Additionally, a compound of the present disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure may be co-administered with another therapeutic agent. As used herein, the terms "co-administered," "administered in combination with," and their grammatical equivalents are meant to encompass the administration of two or more therapeutic agents to a single subject, and are intended to include therapeutic regimens in which the agents are administered by the same or different routes of administration or at the same or different times. In some embodiments, one or more compounds of the present disclosure, pharmaceutically acceptable salts thereof, or a pharmaceutical composition of the present disclosure will be co-administered with another agent. These terms encompass administering two or more agents to a subject such that both agents and / or their metabolites are present in the subject at the same time. These include co-administration in separate compositions, administration at different times in separate compositions, and / or administration in a composition in which both agents are present. Thus, in some embodiments, a compound described herein and another agent(s) are administered in a single composition. In some embodiments, a compound described herein and another agent(s) are admixed in the composition.

[0185] The particular mode of administration and dosage regimen will be selected by the attending clinician, taking into account the specifics of the case (e.g., subject, disease, disease state involved, particular treatment). Treatment may involve daily or multiple daily or less-than-daily (weekly, monthly, etc.) administration over a period ranging from several days to several months, or even years. However, one of skill in the art will readily recognize appropriate and / or equivalent dosage amounts, looking at the dosage amounts of approved compositions for treating diseases using CDK2 inhibitors disclosed as guidance.

[0186] As will be understood by those skilled in the art, the compound of the present disclosure or its pharmaceutically acceptable salt can be administered to patients in various forms depending on the selected administration route.The compound of the present teachings may be administered, for example, orally, parenterally, bucally, sublingually, nasally, rectally, by patch, pump, or transdermal administration, and by pharmaceutical compositions formulated accordingly.Parenteral administration includes intravenous administration, intraperitoneal administration, subcutaneous administration, intramuscular administration, transepithelial administration, intranasal administration, intrapulmonary administration, intrathecal administration, rectal administration, and topical administration modes.Parenteral administration can be by continuous infusion over a selected period of time.

[0187] The pharmaceutical composition of the present disclosure is formulated to be compatible with its intended route of administration.In some embodiments, the composition is formulated according to conventional procedures as a pharmaceutical composition suitable for intravenous, subcutaneous, intramuscular, oral, intranasal or topical administration to humans.In a preferred embodiment, the pharmaceutical composition is formulated for intravenous administration.

[0188] Typically, for oral therapeutic administration, the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.

[0189] Typically, for parenteral administration, the solution of the compound of the present disclosure or its pharmaceutically acceptable salt can be prepared in water, generally mixed with a surfactant such as hydroxypropylcellulose.Dispersions can also be prepared in glycerol, liquid polyethylene glycol, DMSO, and their mixtures with or without alcohol, and in oils.These preparations contain preservatives to prevent the growth of microorganisms under normal storage and use conditions.

[0190] Typically, for injectable use, sterile aqueous solutions or dispersions and sterile powders of the compounds of the present disclosure are suitable for the extemporaneous preparation of sterile injectable solutions or dispersions.

[0191] The following examples are intended to be illustrative and not to limit the scope of the present disclosure in any way. [Example]

[0192] Example Preparation of Exemplary Compounds definition AcOH means acetic acid; t-AmOH means tert-amyl alcohol; Aq. means aqueous; Bn means benzyl; Boc means tert-butoxycarbonyl; Boc2O means di-tert-butyl dicarbonate; (BPin)2 means 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane; br means broad; Brettphos means 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl; BrettPhos Pd G3 means [(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate; n-BuOH means butan-1-ol; t-BuOH means tertiary butanol; t-BuOK means potassium tert-butoxide; t-BuXPhos Pd G3 means (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)palladium(II) methanesulfonate; °C means degrees Celsius; CDCl3 means deuterated chloroform; Cs2CO3 means cesium carbonate; CuCN means copper cyanide; d denotes chemical shift; d means double line; dd means double double line; dq means double quartet; dt means double triplet; DAST means diethylaminosulfur trifluoride; DBU means 1,8-diazabicyclo[5.4.0]undec-7-ene; DCM means dichloromethane; DEA means diethylamine; DEAD means diethyl azodicarboxylate; DIAD means diisopropyl azodicarboxylate; DIBAL-H means diisobutylaluminum hydride; DIPEA means N-ethyldiisopropylamine or N,N-diisopropylethylamine; DMA means N,N-dimethylacetamide; DMF means N,N-dimethylformamide; DMSO means dimethyl sulfoxide; DMSO-d6 means hexadeuterodimethyl sulfoxide; EA means ethyl acetate; Et means ethyl; Et2O means diethyl ether; EtOAc means ethyl acetate; EtOH means ethanol; Eq. means equivalent; g means grams; HATU means 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; HBF4 means tetrafluoroboric acid; HCl means hydrochloric acid; HCOH means formaldehyde; HCO2H means formic acid; Hept means seven lines; 1 H NMR means proton nuclear magnetic resonance; H2O means water; H2O2 means hydrogen peroxide; HPLC means high pressure liquid chromatography; h means hours; IPA means 2-propanol; K2CO3 means potassium carbonate; KI means potassium iodide; KOH means potassium hydroxide; K3PO4 means potassium phosphate tribasic; L means liter; LCMS means liquid chromatography mass spectrometry; LDA means lithium diisopropylamide; LiAlH4 means lithium aluminum hydride; LiOH means lithium hydroxide; m means multiplet; μm means micrometer; M means molar concentration; Me means methyl; MeCN means acetonitrile; MeI means iodomethane; MeLi means methyllithium; MeMgBr means methylmagnesium bromide; MeNH2 means methylamine; MeOH means methanol; MeOH-d4 means deuterated methanol; mg means milligrams; MgSO4 means magnesium sulfate; MHz means megahertz; mins means minutes; mL means milliliters; mmol means millimole; MPLC means medium pressure liquid chromatography; MS m / z means mass spectral peak; MTBE means methyl tert-butyl ether; N2 means nitrogen; NaBH4 means sodium borohydride; Na2CO3 means sodium carbonate; NaH means sodium hydride; NaHCO3 means sodium bicarbonate; NaOH means sodium hydroxide; Na2SO4 means sodium sulfate; NCS means N-chlorosuccinimide; NH3 means ammonia; NH4Cl means ammonium chloride; NH4HCO3 means ammonium carbonate; NH2OH means hydroxylamine; NH4OH is ammonium hydroxide; NMP means N-methylpyrrolidine; PE means petroleum ether; Pd(amphos)Cl2 means bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II); Pd(t-Bu3P)2 means bis(tri-tert-butylphosphine)palladium(0); Pd(OAc) means palladium acetate; Pd2(dba)3 means tris(dibenzylideneacetone)dipalladium(0); Pd(dppf)Cl2 means [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); Pd(PPh3)4 means tetrakis(triphenylphosphine)palladium(0); Pd(PPh3)Cl2 means palladium(II) bis(triphenylphosphine) dichloride; Pd / C means palladium on carbon; Pd(OH)2 means palladium hydroxide; PPh3 means triphenylphosphine; q means quartet; rt means room temperature; RT means retention time; RuPhos Pd G3 means (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate; s means single line; sat. means saturated; SFC means supercritical fluid chromatography; soln. means solution; t means triple line; TBAF means tetrabutylammonium fluoride; TBDMSCl means tert-butyl(chloro)dimethylsilane; TEA means triethylamine; TFA means trifluoroacetic acid; TfOH means trifluoroethanesulfonic acid; THF means tetrahydrofuran; TLC means thin layer chromatography; TsOH means p-toluenesulfonic acid; μL means microliter; μmol means micromolar; Xantphos means 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; Xantphos Pd G2 means chloro[(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2′-amino-1,1′-biphenyl)]palladium(II); Xantphos Pd G3 means [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate; XPhos Pd G2 means chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II).

[0193] The method for preparing the compound of the present invention can be carried out in a suitable solvent that can be easily selected by those skilled in the art of organic synthesis.A suitable solvent can be substantially non-reactive with the starting material (reactant), intermediate, or product at the temperature at which the reaction is carried out (for example, from the freezing point of the solvent to the boiling point of the solvent).A particular reaction can be carried out in one solvent or a mixture of multiple solvents.Depending on the specific reaction step, those skilled in the art can select a suitable solvent for the specific reaction step.

[0194] The preparation of the compounds of the present invention may involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be easily determined by those skilled in the art. The chemical properties of protecting groups can be found, for example, in Wuts and Greene, Protective Groups in Organic Synthesis, 5th ed., John Wiley & Sons: New Jersey, (2014), which is incorporated herein by reference in its entirety.

[0195] The reaction can be monitored according to any suitable method known in the art. For example, the formation of the product can be monitored by spectroscopic means such as nuclear magnetic resonance (NMR) spectroscopy (e.g., 1H or 13C), infrared (IR) spectroscopy, spectrocolorimetry (e.g., ultraviolet-visible), mass spectrometry (MS), or by chromatographic methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC).

[0196] Analytical instruments and methods for compound characterization: LC-MS: Liquid chromatography-mass spectrometry (LC-MS) data were acquired at 50°C using an Agilent Technologies 1200 Series LCMSD equipped with a reversed-phase column (Sunfire C18, 3.5 μm particle size, 4.6 × 50 mm) using API-ESI ionization. The mobile phase consisted of a solvent mixture of 0.01% TFA in water and 0.01% TFA in acetonitrile. A constant gradient was used, increasing from 5% to 95% organic phase within 1.3 minutes and holding at 95% organic phase for 1.7 minutes. The flow rate was constant at 2 mL / min. Alternatively, liquid chromatography-mass spectrometry (LC-MS) data were acquired at 45°C using an Agilent Technologies 1200 Series LCMSD equipped with a reversed-phase column (XBridge C18, 3.5 μm particle size, 4.6 × 50 mm) using API-ESI ionization. The mobile phase consisted of a solvent mixture of water and 10 mM NH4HCO3 in acetonitrile. A constant gradient was used, increasing from 5% to 95% organic within 1.4 min and remaining at 95% organic for 1.6 min. The flow rate was constant at 1.8 mL / min.

[0197] Preparative LC-MS: Preparative HPLC was performed on a Gilson 281 preparative system equipped with a Welch Xtimate 10u C18 100A, AXIA-packed, 250 x 21.2 mm reverse-phase column at 20°C. The mobile phase consisted of a solvent mixture of 0.1% formic acid in water and 0.1% formic acid in acetonitrile. A constant gradient of the mobile phase from 70% aqueous / 30% organic to 30% aqueous / 70% organic over 15 min was used. The flow rate was constant at 30 mL / min. Alternatively, the column (Welch Xtimate 10u C18 21.2 x 250 mm, 10 μm) was used, and the mobile phase consisted of a solvent mixture of water (10 mmol / L NH4HCO3 + 0.05% NH3.H2O) and acetonitrile. A constant gradient of mobile phase from 70% aqueous / 30% organic to 30% aqueous / 70% organic over 15 min was used, with a constant flow rate of 30 mL / min.

[0198] Silica gel chromatography: Silica gel chromatography was performed on a Biotage® Isolera One instrument or a Biotage® Isolera Prime instrument.

[0199] Proton NMR: H NMR spectra were acquired on a Bruker AVANCE III 400 MHz, 400 MHz NMR instrument (acquisition time = 3.16 seconds with a 1-second delay; 8-32 scans) or a Bruker AVANCE III 400 MHz, 400 MHz NMR instrument (acquisition time = 3.98 seconds with a 1-second delay; 8-32 scans) or a Bruker AVANCE III 500 MHz, 500 MHz NMR instrument (acquisition time = 3.17 seconds with a 1-second delay; 8-32 scans). Unless otherwise indicated, all protons in DMSO-d6 solvent are reported as parts per million (ppm) relative to residual DMSO (2.50 ppm).

[0200] SFC: Waters preparative systems (SFC80, SFC150, SFC200, SFC350).

[0201] Chiral HPLC: Gilson 281 (manufacturer: GILSON)

[0202] Those skilled in the art will recognize that gradients, column lengths, and flow rates can be varied, and that depending on the chemical species being analyzed, some conditions may be more suitable for compound characterization than others.

[0203] The following symbols refer to the preparative HPLC conditions used as shown in the preferred examples and preparations section. Individual gradients were optimized appropriately for each compound. [Table 2]

[0204] General Scheme According to a first process, compounds of formula (I') can be prepared from compounds of formula (IV') and (V'), and compounds of formula (IV') can be prepared from compounds of formula (II') and (III'), as shown in Scheme 1. [ka]

[0205] Pyrazolo[3,4-b]pyrazine (II') can undergo Mitsunobu reaction with alcohol (III') to give compound (IV'), where Hal is a halogen, preferably Br or Cl.

[0206] Compounds of formula (I') can be obtained from halide (IV') and amine (V') by a Buchwald-type palladium-catalyzed cross-coupling reaction using a suitable palladium catalyst in the presence of a suitable phosphine ligand, in the presence of a suitable inorganic base, in a solvent at elevated temperature.

[0207] According to a second process, compounds of formula (I') and (IV') can be prepared as shown in Scheme 2. [ka]

[0208] Pyrazolo[3,4-b]pyrazine (II') can undergo a Mitsunobu reaction with alcohol (VI') to give compound (VII'). PG is a suitable protecting group for a heteroatom, typically an N or O atom. Suitable protecting groups are THP for primary alcohols, Boc for primary or secondary amines, or an acetal group for ketones.

[0209] Compound (VIII') can be obtained from halide (VII') and amine (V') by a Buchwald-type palladium-catalyzed cross-coupling reaction using a suitable palladium catalyst in the presence of a suitable phosphine ligand, a suitable inorganic base, and a solvent at elevated temperature.

[0210] Compounds (IV') and (I') can be obtained from compounds (VII') and (VIII'), respectively, by removal of the Boc, THP, or acetal protecting group by treatment with an acid such as HCl or TFA.

[0211] Compounds (IV') and (I') can also undergo a reaction to give other compounds (IV') and (I'). For example, C1 ~ C3 These include reductive amination reactions with alkyl aldehydes, acetylation of primary or secondary amines with acetyl chloride, or reduction of ketones using NaBH4.

[0212] According to the third process, R 3 Compounds of formula (I') bearing a primary alcohol can be obtained by reduction of the appropriate methyl or ethyl ester with LiAlH4.

[0213] Compounds possessing one or more stereocenters can be separated into their separate stereoisomers by conventional methods such as chiral SFC or chiral HPLC methods as illustrated in the examples below.

[0214] Example 1. 3-(6-((5-isopropyl-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)propan-1-ol [ka]

[0215] Step 1: Synthesis of 3-(6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)propan-1-ol

[0216] To a mixture of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (200 mg, 1.29 mmol), propane-1,3-diol (146 mg, 1.93 mmol), and PPh3 (506 mg, 1.93 mmol) in THF (20 mL) was added DEAD (336 mg, 1.93 mmol) dropwise at 0 °C, and the reaction mixture was stirred for 1 h. The reaction was quenched with water and extracted with EtOAc. The combined organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (PE / EtOAc = 1 / 9) to give the title compound (170 mg, 62%) as a white solid. LCMS m / z = 213 [M+H] +

[0217] Step 2: Synthesis of 3-(6-((5-isopropyl-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)propan-1-ol

[0218] A mixture of 3-(6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)propan-1-ol (170 mg, 0.80 mmol), 5-(propan-2-yl)-1H-pyrazol-3-amine (128 mg, 1.03 mmol), t-BuXPhosPdG3 (126 mg, 0.16 mmol), and KOAc (234 mg, 2.40 mmol) in dioxane (2 mL) was stirred at 90 °C under N2 for 2 h. The reaction mixture was cooled to room temperature and concentrated to give a residue that was purified by column chromatography on silica gel (PE: EtOAc = 1:4) to give the crude product (70 mg), which was purified by preparative HPLC, Method A (25% to 45% B) to give the title product (43.1 mg, 17%) as a yellow solid. LCMS m / z = 302 [M+H] + . 1 H-NMR (500MHz, DMSO-d6) δ ppm 12.09 (s, 1H), 10.30 (s, 1H), 8.28 (s, 1H), 8.04(s, 1H), 6.68 (s, 1H), 4.60 (s, 1H), 4.37 (t, 2H), 3.45-3.42 (m, 2H), 2.99-2.91(m, 1H), 2.03-1.95 (m, 2H), 1.25 (d, 6H).

[0219] Example 2. (S)—N-(5-(difluoromethyl)-1H-pyrazol-3-yl)-1-(1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0220] Step 1: Synthesis of (S)-6-chloro-1-(1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine

[0221] To a solution of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (130 mg, 0.84 mmol), (R)-1-(pyridin-3-yl)propan-1-ol (124 mg, 0.84 mmol), and PPh3 (300 mg, 1.1 mmol) in THF (10 mL) was added DIAD (0.5 mL) at 0 °C, and the reaction mixture was stirred at 25 °C for 18 h. The reaction was quenched with water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography on silica gel eluting with EtOAc / PE (1 / 3) to give the title product (120 mg, 52% yield). LCMS m / z = 274 [M+H] +

[0222] Step 2. Synthesis of (S)—N-(5-(difluoromethyl)-1H-pyrazol-3-yl)-1-(1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

[0223] A mixture of (S)-6-chloro-1-(1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine (100 mg, 0.37 mmol), 5-(difluoromethyl)-1H-pyrazol-3-amine (84.9 mg, 0.57 mmol), tBuXPhos Pd G3 (61.1 mg, 0.07 mmol), and KOAc (112 mg, 1.15 mmol) in dioxane (10 mL) was stirred at 100 °C under N for 3 h. The reaction mixture was concentrated, and the residue was purified by preparative HPLC, method B (15% to 95% B) to give the title product as a yellow solid (33.3 mg, 25%). LCMS m / z = 357 [M+H] +.1H-NMR (400 MHz, DMSO-d6) δ ppm 13.40-13.05(m, 1H), 11.05-10.55 (m, 1H), 8.58 (d, 1H), 8.45 (dd, 1H), 8.25 (s, 1H), 8.21-8.15(m, 1H), 7.75-7.71 (m, 1H), 7.33 (dd, 1H), 7.24-6.95 (m, 1H), 6.85-6.51 (m, 1H),6.46-6.11 (m, 1H), 1.94 (d, 3H).

[0224] Examples 3 to 6

[0225] Each compound in the table below was prepared from 6-chloro-1H-pyrazolo[3,4-b]pyrazine and the appropriate alcohol in a two-step procedure similar to that described in Example 2. [Table 3-1] [Table 3-2]

[0226] Example 7. N-(5-Isopropyl-1H-pyrazol-3-yl)-3-methyl-1-(pyridin-3-ylmethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0227] Following the procedure described in Step 2 of Example 2, Step 1 of Example 4 and 5-(propan-2-yl)-1H-pyrazol-3-amine, the title compound was obtained (85.6 mg, 63%). LCMS m / z = 349 [M+H] +.1H-NMR (400 MHz, DMSO-d6) δ ppm 12.10 (brs, 1H), 10.32 (s, 1H), 8.60 (d, 1H), 8.47 (dd, 1H), 8.24 (s, 1H), 7.68-7.65 (m,1H), 7.33 (dd, 1H), 6.58 (s, 1H), 5.50 (s, 2H), 3.33 (s, 2H), 2.95 (septet, 1H), 2.41(s, 3H), 1.25 (d, 6H).

[0228] Example 8. 3-Methyl-N-(5-(oxetan-3-yl)-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0229] Following the procedure described in Step 2 of Example 2, Step 1 of Example 6 and 5-(oxetan-3-yl)-1H-pyrazol-3-amine, the title compound was obtained as a white solid (95.6 mg, 34%). LCMS m / z = 370 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6) δ ppm12.34 (br s, 1H), 10.33 (br s, 1H), 8.23 ​​(s, 1H), 6.90 (br s, 1H), 4.95-4.90 (m,2H), 4.72-4.67 (m, 2H), 4.40-4.34 (m, 1H), 4.22-4.16 (m, 2H), 3.85-3.79 (m, 2H),3.30-3.20 (m, 2H), 2.41 (s,3H), 2.22-2.15 (m,1H), 1.50-1.43 (m, 2H), 1.34-1.24(m, 2H).

[0230] Examples 9 and 10 (R)—N-(5-(isopropyl-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine and (S)—N-(5-isopropyl-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0231] Step 1: Synthesis of 6-chloro-1-((tetrahydro-2H-pyran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine

[0232] Following a procedure similar to that described in Step 1 of Example 2, the title compound was obtained as a white solid (1.2 g, 92%) from 6-chloro-1H-pyrazolo[3,4-b]pyrazine and (oxan-3-yl)methanol. LCMS m / z = 253 [M+H] + .

[0233] Step 2: Synthesis of (R)—N-(5-(isopropyl-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine and (S)—N-(5-isopropyl-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

[0234] A mixture of 6-chloro-1-((tetrahydro-2H-pyran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine (300 mg, 1.18 mmol), 5-(propan-2-yl)-1H-pyrazol-3-amine (176 mg, 1.41 mmol), t-BuXphosPdG (141 mg, 0.24 mmol), and KOAc (346 mg, 3.54 mmol) in dioxane (8 mL) was stirred at 90 °C under N for 8 h. The mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel eluting with EtOAc / PE (1 / 1) to give the crude product, which was purified by preparative HPLC method B (15% to 95% B) to give N-(5-isopropyl-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine (200 mg). This was separated by preparative SFC using a Daicel IC 20*250 mm column (10 μm, mobile phase: 45% (0.2% MeOH / NH3) at 100 g / min) under a back pressure of 100 bar to give (R)-N-(5-isopropyl-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or (S)-N-(5-isopropyl-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine (66.0 mg, 16%) as enantiomer 1 of peak 1. LCMS m / z = 342 [M+H] + .1H-NMR (400 MHz, DMSO-d6) δ ppm 12.12 (s,1H), 10.36 (s, 1H), 8.27 (s, 1H), 8.05 (s, 1H), 6.72 (s, 1H), 4.30-4.16 (m, 2H),3.70-3.60 (m, 2H), 3.38-3.33 (m, 1H), 3.28-3.23 (m, 1H), 3.01-2.95 (m, 1H), 2.27-2.20(m, 1H), 1.73-1.60 (m, 2H), 1.44-1.40 (m, 1H), 1.26 (d, 6H), 1.30-1.25 (m, 1H).

[0235] Further elution gave (S)—N-(5-(isopropyl-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or (R)—N-(5-isopropyl-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine as enantiomer 2 of peak 2 (51.0 mg, 12%). LCMS m / z = 342 [M+H] + 1H-NMR (400 MHz, DMSO-d6) δ ppm 12.12 (s,1H), 10.37 (s, 1H), 8.27 (s, 1H), 8.06 (s, 1H), 6.72 (s, 1H), 4.30-4.16 (m, 2H),3.70-3.60 (m, 2H), 3.38-3.33 (m, 1H), 3.28-3.23 (m, 1H), 3.01-2.95 (m, 1H), 2.27-2.20(m, 1H), 1.73-1.60 (m, 2H), 1.44-1.40 (m, 1H), 1.26 (d, 6H), 1.30-1.25 (m, 1H).

[0236] Examples 11 and 12. (R)—N-(5-isopropyl-1H-pyrazol-3-yl)-1-((tetrahydrofuran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine and (S)—N-(5-isopropyl-1H-pyrazol-3-yl)-1-((tetrahydrofuran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0237] Step 1: Synthesis of 6-chloro-1-((tetrahydrofuran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine

[0238] Following a procedure similar to that described in Step 1 of Example 2, the title compound was obtained as a white solid (1 g, 81%) from 6-chloro-1H-pyrazolo[3,4-b]pyrazine and (oxolan-3-yl)methanol. LCMS m / z = 239 [M+H] + .

[0239] Step 2: Synthesis of (R)—N-(5-isopropyl-1H-pyrazol-3-yl)-1-((tetrahydrofuran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine and (S)—N-(5-isopropyl-1H-pyrazol-3-yl)-1-((tetrahydrofuran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine Following the procedure described in Step 2 of Examples 9 and 10, 6-chloro-1-((tetrahydrofuran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine and 5-(propan-2-yl)-1H-pyrazol-3-amine gave N-(5-isopropyl-1H-pyrazol-3-yl)-1-((tetrahydrofuran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine (220 mg (53.8%)). This product was further separated by chiral preparative HPLC (IC20*250, 10 μm) (mobile phase: n-hexane (0.1% DEA):IPA (0.1% DEA) = 70:30 at 50 mL / min) to give (R)-N-(5-isopropyl-1H-pyrazol-3-yl)-1-((tetrahydrofuran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or (S)-N-(5-isopropyl-1H-pyrazol-3-yl)-1-((tetrahydrofuran-3-yl))methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine (77.1 mg, 18%) as enantiomer 1 of peak 1. LCMS m / z = 328 [M+H] + . 1H-NMR (400 MHz, DMSO-d6) δ ppm12.11 (s, 1H), 10.35 (s, 1H), 8.29 (s, 1H), 8.07 (s, 1H), 6.67 (s, 1H), 4.29 (d,2H), 3.82-3.76 (m, 1H), 3.68-3.56 (m, 3H), 2.97-2.93 (m, 1H), 2.85-2.82 (m, 1H),1.94-1.89 (m, 1H), 1.71-1.66 (m, 1H), 1.26 (d, 6H).

[0240] Further elution gave (S)—N-(5-isopropyl-1H-pyrazol-3-yl)-1-((tetrahydrofuran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine and (R)—N-(5-isopropyl-1H-pyrazol-3-yl)-1-((tetrahydrofuran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine (92.1 mg, 22%) as enantiomer 2 of peak 2. LCMS m / z = 328 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6) δ ppm12.11 (s, 1H), 10.34 (s, 1H), 8.29 (s, 1H), 8.08 (s, 1H), 6.68 (s, 1H), 4.30 (d,2H), 3.82-3.76 (m, 1H), 3.68-3.56 (m, 3H), 3.05-2.93 (m, 1H), 2.85-2.75 (m, 1H),1.94-1.89 (m, 1H), 1.71-1.60 (m, 1H), 1.26 (d, 6H).

[0241] Examples 13 and 14. (2S,3S)-3-(6-((5-isopropyl-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)pentan-2-ol and (2S,3R)-3-(6-((5-isopropyl-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)pentan-2-ol [ka]

[0242] Step 1: (2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propanoate methyl

[0243] A mixture of (S)-methyl 2-hydroxypropanoate (10.0 g, 96.1 mmol), 3,4-dihydro-2H-pyran (8.08 g, 96.1 mmol), and TsOH (1.65 g, 9.61 mmol) in DCM (100 mL) was stirred for 3 h. The reaction mixture was washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel eluted with EtOAc / PE (1 / 30) to give the title compound as a yellow oil (9.70 mg, 53% yield).

[0244] Step 2: Synthesis of (2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)pentan-3-ol

[0245] To a mixture of methyl (2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propanoate (700 mg, 3.72 mmol) in toluene (30 mL) was added DIBAL-H (1.5 M in toluene, 2.8 mL, 4.09 mmol) dropwise under N at −78 °C. After maintaining the reaction at −70 °C for 30 min, EtMgBr (1.0 M in THF, 6.0 mL, 6.0 mmol) was added and the reaction mixture was stirred for 20 min and allowed to warm slowly to room temperature. The reaction mixture was poured into ice water, and aqueous HCl (10%) was added until all precipitate dissolved. The aqueous phase was extracted with THF / toluene, and the combined organic layers were washed with water, aqueous NaOH (1 M), and brine, dried over MgSO, filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with EtOAc / PE (1 / 5) to give the title compound as a yellow oil (600 mg, 85% yield).

[0246] Step 3: Synthesis of 6-chloro-1-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)pentan-3-yl)-1H-pyrazolo[3,4-b]pyrazine

[0247] Following a procedure similar to that described in Step 1 of Example 1, the title compound was obtained as a yellow solid (180 mg, 28%) from 6-chloro-1H-pyrazolo[3,4-b]pyrazine and (2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)pentan-3-ol. LCMS m / z = 241 [M-84+H] + .

[0248] Step 4: N-(5-isopropyl-1H-pyrazol-3-yl)-1-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)pentan-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

[0249] A mixture of 6-chloro-1-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)pentan-3-yl)-1H-pyrazolo[3,4-b]pyrazine (180 mg, 0.55 mmol), 5-isopropyl-1H-pyrazol-3-amine (94 mg, 0.66 mmol), t-BuXPhos-G3-Pd (10 mg, 0.01 mmol), and KOAc (163 mg, 1.66 mmol) in dioxane (5.0 mL) was stirred at 90° C. overnight. The mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel eluting with EtOAc / PE (1 / 2) to give the product (90 mg, 37%) as a yellow solid.

[0250] Step 5: Synthesis of (2S,3S)-3-(6-((5-isopropyl-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)pentan-2-ol and (2S,3R)-3-(6-((5-isopropyl-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)pentan-2-ol

[0251] To a solution of N-(5-isopropyl-1H-pyrazol-3-yl)-1-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)pentan-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine (90 mg, 0.21 mmol) in DCM (10 mL) was added TFA (2 mL) at room temperature, and the reaction mixture was stirred for 4 hours. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC method B (15% to 95% B) to give (2S,3S)-3-(6-((5-isopropyl-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)pentan-2-ol or (2S,3R)-3-(6-((5-isopropyl-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)pentan-2-ol (9.7 mg, 13%) as enantiomer 1 of peak 1. LCMS m / z = 330 [M+H] + .1H-NMR (400 MHz, DMSO-d6) δ ppm 12.11 (brs, 1H), 10.29 (s, 1H), 8.28 (s, 1H), 8.07 (s, 1H), 6.62 (s, 1H), 5.07(d, 1H), 4.26-4.20(m, 1H), 4.06-4.00 (m, 1H), 2.96 (q, 1H), 2.19-2.02 (m, 2H), 1.26 (d, 6H), 0.76(d, 3H), 0.62 (t, 3H).

[0252] Further elution gave peak 2 as enantiomer 2, (2S,3R)-3-(6-((5-isopropyl-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)pentan-2-ol or (2S,3S)-3-(6-((5-isopropyl-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)pentan-2-ol (3.0 mg, 4%). LCMS m / z = 330 [M+H] +.1H-NMR (400 MHz, DMSO-d6) δ ppm 12.09 (brs, 1H), 10.23 (br s, 1H), 8.28 (s, 1H), 8.05 (s, 1H), 6.62 (s, 1H), 4.65 (d, 1H),4.35-4.29 (m, 1H), 4.18-4.13 (m, 1H), 2.97 (q, 1H), 2.07-1.86 (m, 2H), 1.25 (d,6H), 1.15 (d, 3H), 0.60 (t, 3H).

[0253] Example 15. (S)—N-(5-methyl-1H-pyrazol-3-yl)-1-(1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0254] A solution of Step 1 from Example 2 (500 mg, 1.83 mmol), 5-methyl-1H-pyrazol-3-amine (194 mg, 2 mmol), Pd(dba) (32.1 mg, 0.04 mmol), t-BuXphos (14.8 mg, 0.04 mmol), and KOAc (85.9 mg, 0.87 mmol) in dioxane (20 mL) was stirred at 100 °C for 18 h. The reaction mixture was concentrated, and the residue was purified by preparative HPLC, Method B (15% to 95% B) to give the title product as a pink solid (120 mg, 20%). LCMS m / z = 321 [M+H] + .1H-NMR (400 MHz, DMSO-d6) δ ppm 12.05 (s,1H), 10.32 (s, 1H), 8.60 (d, 1H), 8.47 (dd, 1H), 8.27 (s, 1H), 8.13 (s, 1H), 7.75-7.69(m, 1H), 7.34 (dd, 1H), 6.54 (s, 1H), 6.20-6.10 (m, 1H), 2.27 (s, 3H), 1.94 (d,3H).

[0255] Example 16. 1-(((1R,5S,6s)-3-oxabicyclo[3.1.0]hexan-6-yl)methyl)-N-(5-(oxetan-3-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0256] Step 1: Synthesis of 1-(((1R,5S,6s)-3-oxabicyclo[3.1.0]hexan-6-yl)methyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazine

[0257] Following a procedure similar to that described in Step 1 of Example 2, the title compound was obtained as a yellow solid (280 mg, 62%) from 6-chloro-1H-pyrazolo[3,4-b]pyrazine (280 mg, 1.81 mmol) and (1R,5S,6s)-3-oxabicyclo[3.1.0]hexan-6-ylmethanol. LCMS m / z = 251 [M+H] + .

[0258] Step 2: Synthesis of 1-(((1R,5S,6s)-3-oxabicyclo[3.1.0]hexan-6-yl)methyl)-N-(5-(oxetan-3-yl)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

[0259] Following a procedure similar to that described in Example 15, 1-(((1R,5S,6s)-3-oxabicyclo[3.1.0]hexan-6-yl)methyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazine and (5-(oxetan-3-yl)-1H-pyrazol-3-amine) gave the title compound as a yellow solid (45 mg, 32%). LCMS m / z = 354 [M+H] +.1H-NMR (400 MHz, DMSO-d6) δ ppm 12.41 (brs, 1H), 10.40 (br s, 1H), 8.30 (s, 1H), 8.06 (s, 1H), 6.88 (br s, 1H), 4.93-4.88(m, 2H), 4.71-4.67 (m, 2H), 4.37-4.28 (m, 3H), 3.66 (d, 2H), 3.51 (d, 2H), 1.83-1.78(m, 2H), 1.24-1.20 (m, 1H)

[0260] Example 17. N-(5-isopropyl-1H-pyrazol-3-yl)-5-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0261] Step 1: Synthesis of 6-chloro-5-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine

[0262] Following a procedure similar to that described in Step 1 of Example 1, the title compound was obtained as a yellow solid (50 mg, 39%) from 6-chloro-5-methyl-1H-pyrazolo[3,4-b]pyrazine and (oxan-4-yl)methanol. LCMS m / z = 267 [M+H] + .

[0263] Step 2: Synthesis of N-(5-isopropyl-1H-pyrazol-3-yl)-5-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine Following a procedure similar to that described in Example 15, 6-chloro-5-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine and (5-(propan-2-yl)-1H-pyrazol-3-amine) was prepared to give the title compound as a white solid (4.4 mg, 6%). LCMS m / z = 356 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6) δ ppm12.14 (s, 1H), 9.08 (s, 1H), 7.97 (s, 1H), 6.74 (s, 1H), 4.19 (d, 2H), 3.84-3.77(m, 2H), 3.31-3.20 (m, 2H), 3.02-2.92 (m, 1H), 2.57 (s, 3H), 2.22-2.17 (m, 1H),1.48-1.40 (m, 2H), 1.32-1.27 (m, 2H), 1.29 (d, 6H).

[0264] Example 18. N-(5-isopropyl-1H-pyrazol-3-yl)-5-methyl-1-(pyridin-3-ylmethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0265] Step 1: Synthesis of 6-chloro-5-methyl-1-(pyridin-3-ylmethyl)-1H-pyrazolo[3,4-b]pyrazine

[0266] Following a procedure similar to that described in Step 1 of Example 1, the title compound was obtained as a white solid (70 mg, 93%) from 6-chloro-5-methyl-1H-pyrazolo[3,4-b]pyrazine and (pyridin-3-yl)methanol. LCMS m / z = 260 [M+H] + .

[0267] Step 2: Synthesis of N-(5-isopropyl-1H-pyrazol-3-yl)-5-methyl-1-(pyridin-3-ylmethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

[0268] Following a procedure similar to that described in Example 15, 6-chloro-5-methyl-1-(pyridin-3-ylmethyl)-1H-pyrazolo[3,4-b]pyrazine and 5-(propan-2-yl)-1H-pyrazol-3-amine gave the title compound as a white solid (29.4 mg, 31%). LCMS m / z = 349 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6) δ ppm12.15 (br s, 1H), 9.10 (br s, 1H), 8.60-8.56 (m, 1H), 8.48-8.45 (m, 1H), 8.03 (s,1H), 7.63 (d, 1H), 7.35-7.31 (m, 1H), 6.80-6.50 (m, 1H), 5.57 (s, 2H), 2.96 (quintet, 1H), 2.57 (s, 3H), 1.25 (d, 6H).

[0269] Example 19. (S)-1-(1-(4-fluoropyridin-2-yl)ethyl)-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or (R)-1-(1-(4-fluoropyridin-2-yl)ethyl)-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0270] Step 1: Synthesis of 6-chloro-1-(1-(4-fluoropyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine

[0271] Following a procedure similar to that described in Step 1 of Example 1, the title compound was obtained as a yellow solid (130 mg, 36%) from 6-chloro-1H-pyrazolo[3,4-b]pyrazine and 1-(fluoropyridin-2-yl)ethan-1-ol. LCMS m / z=278 [M+H] + .

[0272] Step 2: Synthesis of (S)-1-(1-(4-fluoropyridin-2-yl)ethyl)-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or (R)-1-(1-(4-fluoropyridin-2-yl)ethyl)-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

[0273] A mixture of 6-chloro-1-(1-(4-fluoropyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine (100 mg, 0.36 mmol), 5-methyl-1H-pyrazol-3-amine (52.3 mg, 0.54 mmol), Pd(dba) (34 mg, 0.02 mmol), t-BuXphos (40 mg, 0.04 mmol), and KOAc (105 mg, 1.07 mmol) in dioxane (20 mL) was stirred at 100 °C overnight. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by preparative HPLC, method B (15% to 95% B) to give the racemic product. This was further separated by chiral preparative SFC (column: Daicel AD 20*250 mm, 10 μm, column temperature: 35 °C (mobile phase: CO / MeOH (0.2% MeOH / NH) = 65 / 35, flow rate: 100 g / min, back pressure: 100 bar) to give (S)-1-(1-(4-fluoropyridin-2-yl) ethyl)-N-(5-methyl-1H)-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or (R)-1-(1-(4-fluoropyridin-2-yl) ethyl)-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine (16.5 mg, 13%) as enantiomer 1 of peak 1. LCMS m / z = 339 [M + H] + . 1H-NMR (400 MHz, DMSO-d6) δ ppm12.05 (s, 1H), 10.31 (s, 1H), 8.28 (s, 1H), 8.17-8.14 (m, 1H), 8.12 (s, 1H), 7.92-7.87(m, 1H), 7.38-7.32 (m, 1H), 6.51 (s, 1H), 6.25-6.20 (m, 1H), 2.26 (s, 3H), 1.90(d, 3H).

[0274] Furthermore, as peak 2, (R)-1-(1-(4-fluoropyridin-2-yl)ethyl)-N-(5-methoxy-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or (S)-1-(1-(4-fluoropyridin-2-yl)ethyl)-N-(5-methoxy-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine was obtained.

[0275] Examples 20 and 21. (S)—N-(5-(1,1-difluoropropan-2-yl)-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine and (R)—N-(5-(1,1-difluoropropan-2-yl)-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0276] Step 1: Synthesis of phenethyl 2-(trifluoromethyl)acrylate

[0277] A mixture of 2-(trifluoromethyl)acrylic acid (30.0 g, 214 mmol), 2-phenylethanol (52.5 g, 430 mmol), and 4-methylbenzenesulfonic acid (74.0 g, 430 mmol) in toluene (800 mL) was stirred under N at 120° C. for 18 h. The reaction mixture was concentrated, and the residue was purified by column chromatography on silica gel eluting with EtOAc / PE (1:10 to 1:5) to give the title product (29.0 g, 56%) as a colorless oil. 1 H-NMR (400 MHz, CDCl3) δ ppm 7.34-7.21 (m,5H),6.67 (q,1H),6.41 (q,1H),4.46 (t,2H),3.02(t,2H).

[0278] Step 2: Synthesis of phenethyl 3,3,3-trifluoro-2-methylpropanoate. A mixture of phenethyl 2-(trifluoromethyl)acrylate (29.0 g, 119 mmol) and 10% Pd / C (approximately 55% water-wet, 6.0 g) in EtOAc (300 mL) was stirred under H at 20 °C for 18 hours. The mixture was filtered, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel eluting with EtOAc / PE (1:10 to 1:3) to give the title product (24.9 g, 85%) as a colorless oil. 1 H-NMR(400 MHz,CDCl3) δ ppm 7.34-7.20 (m,5H),4.42-4.35 (m,2H),3.22-3.13 (m,1H),2.97(t,2H),1.36 (d,3H)

[0279] Step 3: Synthesis of phenethyl 3,3-difluoro-2-methylacrylate. Under argon, a solution of 3,3,3-trifluoro-2-methylpropanoate (3.7 g, 15.0 mmol) in THF (150 mL) was cooled to −78 °C and treated dropwise with 1.0 M LiHMDS in n-hexane (18.0 mL, 18.0 mmol). After stirring at this temperature for 4 h, the solution was quenched with saturated aqueous NH₄Cl. The mixture was partitioned between EtOAc and water, and the layers were separated. The organic layer was washed successively with water and brine. The organic phase was dried over Na₂SO₄, filtered, and evaporated. The crude product was purified by column chromatography on silica gel eluting with 1:8 EtOAc / PE to give the title product (2.1 g, 62%) as a colorless oil. 1 H-NMR (500 MHz, CDCl3) δ ppm 7.34-7.19 (m,5H),4.38 (t,2H),2.98 (t,2H),1.77 (t,3H).

[0280] Step 4: Synthesis of phenethyl 3,3-difluoro-2-methylpropanoate. A solution of phenethyl 3,3-difluoro-2-methylacrylate (4.5 g, 19.9 mmol) and 10% Pd / C (approximately 55% water, 1.15 g) in EtOAc (90 mL) was stirred under H at 20 °C for 18 h. The reaction mixture was filtered, rinsing with MeOH. The filtrate was concentrated, and the residue was purified by column chromatography on silica gel eluting with EtOAc / PE (1:10 to 1:4) to afford the title product (3.3 g, 73%) as a colorless oil. 1 H-NMR (400 MHz, CDCl3) δ ppm 7.34-7.20 (m,5H),5.97 (dt,1H),4.37 (t,2H),2.96(t,2H),2.95-2.87 (m,1H)),1.25 (d, 3H).

[0281] Step 5: Synthesis of 5,5-difluoro-4-methyl-3-oxopentanenitrile. A solution of LDA (10.0 mmol, n-hexane solution) in THF (15 mL) was cooled to −78°C under argon and treated dropwise with MeCN (0.75 mL, 15.0 mmol) in THF (2 mL). The reaction mixture was stirred at −78°C for 1 h, followed by the dropwise addition of a solution of phenethyl 3,3-difluoro-2-methylpropanoate (1.6 g, 7.0 mmol) in THF (10 mL). The solution was stirred from −78°C to 20°C for 18 h and then quenched with water. The mixture was concentrated, and the residue was dissolved in water and washed with ether. The aqueous phase was acidified to pH = 3 with 1N HCl and extracted with EtOAc. The organic phase was washed successively with water and brine, dried over Na2SO4, filtered, and evaporated. The crude product was purified by column chromatography on silica gel eluting with EtOAc / PE (1:3) to afford the title product (580 mg, 56%) as a colorless oil. 1 H-NMR (400 MHz, CDCl3) δ ppm 5.91 (dt, 1H), 3.63 (s, 2H), 3.28-3.19 (m, 1H), 1.32 (d, 3H).

[0282] Step 6: Synthesis of 5-(1,1-difluoropropan-2-yl)-1H-pyrazol-3-amine. A solution of 5,5-difluoro-4-methyl-3-oxopentanenitrile (400 mg, 2.7 mmol), hydrazine hydrate (410 mg, 8.1 mmol), and HCl (2.7 mmol, 16N aqueous solution) in IPA (5 mL) was stirred at 90° C. for 18 hours in a sealed tube. The reaction mixture was diluted with MeOH, treated with solid Na2CO3, filtered, and the filtrate was evaporated and concentrated. The residue was purified by column chromatography on silica gel eluting with EtOAc / PE (0% to 100%) to give the title compound as a yellow oil (150 mg, 34%). LCMS m / z = 162 [M+H] + .

[0283] Step 7: Synthesis of 6-chloro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine

[0284] To a mixture of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (2.0 g, 12.9 mmol), (tetrahydro-2H-pyran-4-yl)methanol (1.78 g, 15.4 mmol), and PPh3 (4.38 g, 16.7 mmol) in toluene (20 mL) was added DIAD (234 mg, 1.16 mmol), and the reaction was stirred at 80 °C for 2 h. The reaction was quenched with water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography to give the title product (2.8 g, 86%) as a yellow oil. LCMS m / z = 253 [M+H] + .

[0285] Step 8: Synthesis of (S)—N-(5-(1,1-difluoropropan-2-yl)-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine and (R)—N-(5-(1,1-difluoropropan-2-yl)-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

[0286] A mixture of 6-chloro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine (150 mg, 0.59 mmol), 5-(1,1-difluoropropan-2-yl)-1H-pyrazol-3-amine (95.5 mg, 0.59 mmol), KOAc (173 mg, 1.77 mmol), and BrettPhosPdG4 (50 mg) in dioxane (10 mL) was stirred at 90 °C for 2 h. The mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel. The crude product was purified by preparative HPLC, method B (15% to 95% B) to give the racemic product (120 mg), which was then purified by chiral SFC (IC20*250 mm, 10 μm (Dacel), column temperature: 35 °C, mobile phase: CO2 / MeOH (0.2% Separation using MeOH / NH3) = 60 / 40, flow rate: 100 g / min, back pressure: 100 bar gave peak 1 (S)-N-(5-(1,1-difluoropropan-2-yl)-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or (R)-N-(5-(1,1-difluoropropan-2-yl)-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine (38.7 mg, 16%). LCMS m / z = 378 [M+H] + . 1H-NMR (400 MHz, DMSO-d6) δ ppm12.35 (br s, 1H), 10.43 (br s, 1H), 8.29 (s, 1H), 8.08 (s, 1H), 6.83 (br s, 1H),6.20 (t, 1H), 4.25 (d, 2H), 3.85-3.80 (s, 2H), 3.50-3.40 (m, 1H), 3.30-3.20 (m,2H), 2.24-2.20 (m, 1H), 1.50-1.40 (m, 2H), 1.39-1.33 (m, 3H), 1.35-1.22 (m, 2H). Furthermore, peak 2 was (R)—N-(5-(1,1-difluoropropan-2-yl)-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or (S)—N-(5-(1,1-difluoropropan-2-yl)-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine (32.7 mg, 14%). LCMS m / z = 378 [M+H] + . 1 H-NMR (500 MHz,DMSO-d6) δ ppm12.35 (br s,1H),10.43 (br s,1H),8.29 (s,1H),8.08 (s,1H),6.83 (br s, 1H), 6.20 (t,1H), 4.25 (d, 2H), 3.85-3.80 (s, 2H), 3.50-3.40 (m, 1H), 3.30-3.20 (m, 2H), 2.24-2.20(m, 1H), 1.50-1.40 (m, 2H), 1.39-1.33 (m, 3H), 1.35-1.22 (m, 2H).

[0287] Example 22 (S)-3-((1-(1-(2-fluoropyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)amino)-1H-pyrazole-5-carbonitrile [ka]

[0288] Step 1: Synthesis of S-6-chloro-1-(1-(2-fluoropyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine

[0289] DIAD (604 mg, 3.11 mmol) was added dropwise to an ice-cold solution of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (400 mg, 2.59 mmol), PPh3 (815 mg, 3.11 mmol), and (R)-1-(2-fluoropyridin-3-yl)ethan-1-ol (438 mg, 3.11 mmol) in THF (8 mL). The reaction mixture was allowed to warm slowly to room temperature and stirred overnight. The mixture was evaporated under reduced pressure, and the residue was purified by Isco (0-60% EtOAc / Hex) to give a viscous oil. This was further purified by reverse-phase Isco (0-100% MeCN / water with 0.1% TFA). The product-containing fractions were partitioned between DCM and NaHCO3, the layers were separated, and the organic layer was dried over Na2SO4, filtered, and evaporated to give the title compound (320 mg, 44.5%) as a viscous oil. LCMS m / z = 278 [M+H] +

[0290] Step 2: Synthesis of (S)-3-((1-(1-(2-fluoropyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)amino)-1H-pyrazole-5-carbonitrile

[0291] (S)-6-chloro-1-(1-(2-fluoropyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine (90 mg, 0.32 mmol), 3-amino-1H-pyrazole-5-carbonitrile (39 mg, 0.36 mmol), tBuBrettPhos Pd G4 (14 mg, 16 μmol), and KOAc (95 mg, 0.97 mmol) in dioxane (1 mL) were combined under N2 and heated at 90 °C for 1 h. The mixture was evaporated to give the crude product, which was purified by reverse-phase Isco (0–80% MeCN / water (with 0.1% TFA)). The product-containing fractions were washed with NaHCO3 and extracted with 10% MeOH / DCM (×2). The combined organic extracts were dried over Na2SO4, filtered, and evaporated to give the title compound (68.3 mg of a pale yellow solid). LCMS m / z = 350 [M+H] + .1H NMR (500 MHz, DMSO-d6) δ 13.87 (d, 1H),10.93 (d, 1H), 8.36 - 8.13 (m, 3H), 7.96 (dt, 1H), 7.57 - 6.80 (m, 2H), 6.70 - 6.29(m, 1H), 1.90 (d, 3H).

[0292] Example 23 (S)-1-(1-(2-methoxypyridin-3-yl)ethyl)-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0293] Step 1: Synthesis of S-6-chloro-1-(1-(2-methoxypyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine

[0294] Following a procedure similar to that described in Step 1 of Example 2, 6-chloro-1H-pyrazolo[3,4-b]pyrazine and (R)-1-(2-methoxypyridin-3-yl)ethan-1-ol gave the title compound as a white solid (437 mg, 58.3%). LCMS = 290 [M+H]+ .

[0295] Step 2: Synthesis of (S)-1-(1-(2-methoxypyridin-3-yl)ethyl)-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

[0296] Following a procedure similar to that described in Step 2 of Example 22, (S)-6-chloro-1-(1-(2-methoxypyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine and 5-methyl-1H-pyrazol-3-amine gave the title compound as a pale yellow solid (50.5 mg, 41.8%). LCMS m / z = 352 [M+H] + .1H NMR (500 MHz, DMSO-d6) δ 12.04 (s, 1H),10.29 (s, 1H), 8.26 (s, 1H), 8.13 (s, 1H), 8.07 (dd, 1H), 7.46 (d, 1H), 6.93 (dd,1H), 6.53 (s, 1H), 6.29 (q, 1H), 3.96 (s, 3H), 2.28 (s, 3H), 1.83 (d, 3H).

[0297] Examples 24-25

[0298] Using the same two-step procedure described in Example 23, each compound in the table below was prepared from 6-chloro-1H-pyrazolo[3,4-b]pyrazine and the appropriate pyrazole. [Table 4]

[0299] Example 26 (S)-1-(1-(2-chloropyridin-3-yl)ethyl)-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0300] Following a procedure similar to that described in Step 2 of Example 22, Step 1 of Example 24 and 5-methyl-1H-pyrazol-3-amine, the title compound was obtained as a pale yellow solid (29.6 mg, 29.9%). LCMS m / z = 355 [M+H] + 1H NMR (500 MHz, DMSO-d6) δ 12.04 (s, 1H),10.34 (s, 1H), 8.34 (dd, 1H), 8.26 (s, 1H), 8.18 (s, 1H), 7.69 (d, 1H), 7.40 (dd,1H), 6.59 (s, 1H), 6.33 (q, 1H), 2.26 (s, 3H), 1.90 (d, 3H).

[0301] Example 27 (S)-3-chloro-N-(5-methyl-1H-pyrazol-3-yl)-1-(1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0302] Step 1: Synthesis of 3,6-dichloro-1H-pyrazolo[3,4-b]pyrazine

[0303] HBF (1.27 mL, 1.78 mmol) followed by NCS (864 mg, 6.47 mmol) were added to a suspension of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (0.5 g, 3.24 mmol) in MeCN (12 mL), and the reaction mixture was heated at 90 °C overnight. The mixture was concentrated in vacuo, 1 M NaOH (9.5 mL) was added to neutralize the solution, and the resulting suspension was filtered, washed with water, and dried by suction to give the title compound (596 mg, 97%) as a pale yellow solid. LCMS m / z = 189 [M+H] +

[0304] Step 2: Synthesis of (S)-3,6-dichloro-1-(1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine

[0305] Following a procedure similar to that described in Step 1 of Example 2, 3,6-dichloro-1H-pyrazolo[3,4-b]pyrazine and (R)-1-(pyridin-3-yl)ethan-1-ol gave the title compound as an off-white solid (230 mg, 49.3%). LCMS m / z = 296 [M+H] +

[0306] Step 3: Synthesis of (S)-3-chloro-N-(5-methyl-1H-pyrazol-3-yl)-1-(1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

[0307] (S)-3,6-Dichloro-1-(1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine (83 mg, 0.28 mmol), 5-methyl-1H-pyrazol-3-amine (30 mg, 0.31 mmol), tBuBrettPhosPdG4 (12 mg, 14 μmol), and KOAc (83 mg, 0.85 mmol) in dioxane (1 mL) were combined under N2 and heated at 90 °C for 1 h. The mixture was evaporated to give the crude product, which was purified by reverse-phase Isco (0–80% MeCN / water (with 0.1% TFA)). The product-containing fractions were concentrated and washed with 10% MeOH / DCM (3 × 10 mL). The solid remaining in the separatory funnel was filtered, washed with water, and dried to give the title compound as an off-white solid (9.7 mg, 9.7%). LCMS m / z = 355, 357 [M+H] + ;1H NMR (500 MHz, DMSO-d6) δ 12.11 (s,1H), 10.57 (s, 1H), 8.62 (s, 1H), 8.48 (d, 1H), 8.29 (s, 1H), 7.74 (d, 1H), 7.37(dd, 1H), 6.54 (s, 1H), 6.12 (q, 1H), 2.28 (s, 3H), 1.92 (d, 3H).

[0308] Example 28 (S)-3-chloro-1-(1-(2-fluoropyridin-3-yl)ethyl)-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0309] Step 1: Synthesis of (S)-3,6-dichloro-1-(1-(2-fluoropyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine

[0310] Following a procedure similar to that described in Step 1 of Example 2, 3,6-dichloro-1H-pyrazolo[3,4-b]pyrazine and (R)-1-(2-fluoropyridin-3-yl)ethan-1-ol, the title compound was obtained as an off-white solid (182 mg, 51.7% yield). LCMS m / z = 314 [M+H] +

[0311] Step 2: Synthesis of (S)-3-chloro-1-(1-(2-fluoropyridin-3-yl)ethyl)-N-(5-methyl-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

[0312] A mixture of (S)-3,6-dichloro-1-(1-(2-fluoropyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine (80 mg, 0.256 mmol), 5-methyl-1H-pyrazol-3-amine (27 mg, 0.28 mmol), tBuBrettPhosPdG4 (11 mg, 13 μmol), and KOAc (75 mg, 0.77 mmol) in dioxane (1 mL) was stirred at 90 °C under N2 for 1 h. The mixture was evaporated, and the residue was purified by Isco (0-10% MeOH / DCM) to give the title compound as a pale yellow solid (28.7 mg, 30%). LCMS m / z = 373 [M+H] +.1H NMR (500 MHz, DMSO-d6) δ 12.13 (s, 1H),10.58 (s, 1H), 8.30 (s, 1H), 8.18 (d, 1H), 7.97 (t, 1H), 7.38 (t, 1H), 6.51 (s,1H), 6.21 (q, 1H), 2.27 (s, 3H), 1.89 (d, 3H)

[0313] Example 29 (S)—N-(5-isopropyl-1H-pyrazol-3-yl)-1-(1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0314] Step 1 from Example 2 (53 mg, 0.20 mmol), 5-isopropyl-1H-pyrazol-3-amine (31 mg, 0.25 mmol), tBurettPhos Pd G3 (8.72 mg, 10.2 μmol), and KOAc (60 mg, 0.61 mmol) in dioxane (1 mL) were combined under N and heated at 90 °C for 1 h. The cooled mixture was diluted with 5% MeOH / DCM and washed with water. The organic layer was dried over NaSO, filtered, and evaporated to give the crude product, which was purified by Isco chromatography (0-10% MeOH / DCM) to give the title compound as a yellow solid (21 mg, 29.5%). LCMS m / z = 349 [M+H] + .1H NMR (500 MHz, DMSO-d6)δ 12.09 (s, 1H), 10.32 (s, 1H), 8.59 (d, 1H), 8.45 (dd, 1H), 8.26 (s, 1H), 8.12(s, 1H), 7.69 (dt, 1H), 7.33 (dd, 1H), 6.58 (s, 1H), 6.07 (d, 1H), 3.02 - 2.92 (m,1H), 1.97 (d, 3H), 1.28 (dd, 6H)

[0315] Example 30. N-(5-Isopropyl-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0316] Step 7 from Examples 20 and 21 (34 mg, 0.14 mmol), 5-isopropyl-1H-pyrazol-3-amine (20 mg, 0.16 mmol), tBurettPhos Pd G3 (5.75 mg, 6.7 μmol), and KOAc (40 mg, 0.40 mmol) in dioxane (1 mL) were combined under N and heated at 90 °C for 1 h. The cooled mixture was diluted with DCM and washed with water, and the organic layer was dried over NaSO, filtered, and evaporated to give the crude product, which was purified by Isco chromatography (0-10% MeOH / DCM) to give the title compound as a yellow solid (24.9 mg, 54.2%). LCMS m / z = 342 [M+H] + .1H NMR (400 MHz, DMSO-d6) δ 12.06 (s, 1H),10.26 (s, 1H), 8.26 (s, 1H), 8.02 (s, 1H), 6.67 (s, 1H), 4.19 (d, 2H), 3.79 (d,2H), 3.26 - 3.18 (m, 2H), 2.94 (p, 1H), 2.27 - 2.12 (m, 1H), 1.49 - 1.37 (m, 2H),1.33 - 1.21 (m, 8H).

[0317] Examples 31 to 37

[0318] Following procedures similar to those described in Example 30, each compound in the table below was prepared from the appropriate 6-chloro-1H-pyrazolo[3,4-b]pyrazine and pyrazole. [Table 5-1] [Table 5-2] [Table 5-3] A—The crude product was purified by reverse-phase ISCO (MeCN / water with 0.1% TFA). The product-containing fractions were washed with NaHCO and extracted with 10% MeOH / DCM. The combined organic extracts were dried over NaSO and evaporated to give the title compound.

[0319] Example 38 (1r,4r)-4-(6-((5-(oxetan-3-yl)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclohexan-1-ol [ka]

[0320] Step 1: Synthesis of 6-chloro-1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazolo[3,4-b]pyrazine

[0321] The title compound was obtained as a colorless oil that solidified on standing from 6-chloro-1H-pyrazolo[3,4-b]pyrazine and 1,4-dioxaspiro[4,5]decan-8-ol according to a procedure similar to that described in Step 1 of Example 2. LCMS m / z = 295 [M+H] +

[0322] Step 2: Synthesis of 4-(6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclohexan-1-one

[0323] A solution of 6-chloro-1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazolo[3,4-b]pyrazine (270 mg, 0.92 mmol) in THF (3 mL) and 1M HCl (3 mL) was stirred at room temperature for 72 hours. The solution was heated at 60° C. for 1 hour and then concentrated in vacuo. The residue was neutralized with aqueous NaHCO3, the resulting suspension was filtered, and the solid was washed with water and dried to give the title compound as a white solid (194 mg, 84%). LCMS m / z = 251 [M+H] +

[0324] Step 3: Synthesis of (1r,4r)-4-(6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclohexan-1-ol

[0325] To an ice-cold solution of 4-(6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclohexan-1-one (160 mg, 0.64 mmol) in MeOH (4 mL) was added NaBH4 (36 mg, 0.96 mmol), and the reaction mixture was stirred for 1 h. The mixture was evaporated under reduced pressure, followed by the addition of saturated ammonium chloride solution and water. The resulting suspension was stirred for 5 min, filtered, washed with water, and dried under suction to give a white solid, which was recrystallized from MeCN to give the title compound (90 mg) as white needles. LCMS m / z = 253 [M+H] +

[0326] Step 4: Synthesis of (1r,4r)-4-(6-((5-(oxetan-3-yl)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclohexan-1-ol

[0327] Following the procedure described in Example 33, (1r,4r)-4-(6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclohexan-1-ol and 5-(oxetan-3-yl)-1H-pyrazol-3-amine gave the title compound as an off-white solid (27.3 mg, 38%). LCMS m / z = 356 [M+H] +.1H NMR (500 MHz, DMSO-d6) δ 12.32 (s, 1H),10.42 (s, 1H), 8.26 (s, 1H), 8.01 (s, 1H), 6.77 (s, 1H), 4.93 (dd, 2H), 4.79 - 4.64(m, 3H), 4.53 (d, 1H), 4.39 - 4.28 (m, 1H), 3.55 (d,), 2.15- 1.92 (m, 6H), 1.49- 1.36 (m, 2H).

[0328] Example 39 (1r,4r)-4-(6-((5-methyl-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclohexan-1-ol [ka]

[0329] Step 2 from Example 38 (72 mg, 0.29 mmol), 5-methyl-1H-pyrazol-3-amine (30 mg, 0.31 mmol), tBurettPhos Pd G3 (12 mg, 14 μmol), and KOAc (84 mg, 0.86 mmol) in dioxane (1 mL) were combined under N and heated at 90 °C for 1 h. The mixture was evaporated under reduced pressure, and the residue was purified by reverse-phase Isco chromatography (0-80% MeCN / 0.1% TFA in water). The product-containing fractions were partitioned between NaHCO3 and 10% MeOH / DCM. The biphasic mixture was filtered, and the resulting solid was washed with water and dried to give the title compound as a yellow solid (28.5 mg, 31.9%). LCMS m / z = 314 [M+H] + .1H NMR (500 MHz,DMSO-d6) δ 11.99 (s,1H),10.24(s,1H),8.29 (s,1H),8.00 (s,1H),6.53 (s,1H),4.71 (s, ,1H), 4.58~4.45 (m,1H), 3.58 (d, 1H), 2.27(s, 3H), 2.15~1.88 (m, 6H), 1.51~1.37 (m, 2H)

[0330] Example 40. (R)—N-(5-isopropyl-1H-pyrazol-3-yl)-1-(1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0331] Step 1: Synthesis of (R)-6-chloro-1-(1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine

[0332] Following a procedure similar to that described in Step 1 of Example 22, the title compound was obtained as a colorless oil from 6-chloro-1H-pyrazolo[3,4-b]pyrazine and (S)-1-(pyridin-3-yl)ethan-1-ol. LCMS m / z = 260 [M+H] + .

[0333] Step 2: Synthesis of (R)—N-(5-isopropyl-1H-pyrazol-3-yl)-1-(1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

[0334] (R)-6-chloro-1-(1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine (51 mg, 0.20 mmol), 5-isopropyl-1H-pyrazol-3-amine (29 mg, 0.24 mmol), tBuBrettPhos Pd G3 (8.39 mg, 9.8 μmol), and KOAc (58 mg, 0.59 mmol) in dioxane (1 mL) were combined under N and heated at 90 °C for 1 h. The mixture was diluted with 5% MeOH / DCM and washed with water. The organic layer was dried over NaSO, filtered, and evaporated to give the crude product, which was purified by reverse-phase Isco (0–60% MeCN / water with 0.1% TFA). The product-containing fractions were evaporated, the residue was dissolved in 20% MeOH / DCM, an excess of carbonate resin and Na2SO4 was added, and the mixture was stirred for 15 min. The mixture was filtered and evaporated to give the title compound as a pale yellow solid (37.6 mg, 53.9%). LCMS m / z = 349 [M+H] + .1H NMR (500 MHz, DMSO-d6) δ 12.09 (s, 1H),10.32 (s, 1H), 8.59 (d, 1H), 8.45 (dd, 1H), 8.26 (s, 1H), 8.12 (s, 1H), 7.69 (dt,1H), 7.33 (dd, 1H), 6.58 (s, 1H), 6.07 (d, 1H), 3.02 - 2.92 (m, 1H), 1.97 (d, 3H),1.28 (dd, 6H).

[0335] Example 41 (S)—N-(5-(oxetan-3-yl)-1H-pyrazol-3-yl)-1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0336] Step 1: Synthesis of (S)-6-chloro-1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine

[0337] DIAD (298 mg, 1.47 mmol) was added dropwise to an ice-cold solution of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (175 mg, 1.13 mmol), PPh3 (386 mg, 1.47 mmol), and (R)-1-(tetrahydro-2H-pyran-4-yl)ethan-1-ol (192 mg, 1.47 mmol) in THF (4 mL). The reaction mixture was then slowly warmed to room temperature and stirred overnight. The mixture was evaporated under reduced pressure, and the residue was purified by ISCO (0-10% MeOH / DCM). The product was further purified by ISCO (0-100% EtOAc / Hex) to give the title compound (208 mg, 68.9%) as a colorless viscous oil. LCMS m / z = 267 [M+H] +

[0338] Step 2: Synthesis of (S)—N-(5-(oxetan-3-yl)-1H-pyrazol-3-yl)-1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

[0339] (S)-6-chloro-1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine (62 mg, 0.23 mmol), 5-(oxetan-3-yl)-1H-pyrazol-3-amine (36 mg, 0.26 mmol), tBuBrettPhos Pd G3 (9.93 mg, 12 μmol), and KOAc (68 mg, 0.70 mmol) in dioxane (1 mL) were combined under N2 and heated at 90 °C for 1 h. The mixture was evaporated to give the crude product, which was purified by reverse-phase Isco (0–80% MeCN / water with 0.1% TFA). The product-containing fractions were neutralized with NaHCO3 and extracted with 10% MeOH / DCM (2×). The combined organic extracts were dried over Na2SO4, filtered and evaporated to give the title compound as a yellow oil (40.8 mg, 48%). LCMS m / z = 370 [M+H] +.1H NMR (500 MHz, DMSO-d6) δ 12.37 (s, 1H),10.36 (s, 1H), 8.31 (s, 1H), 8.08 (s, 1H), 6.90 (s, 1H), 4.93 (dd, 2H), 4.74 - 4.66(m, 2H), 4.57 (s, 1H), 4.35 (t, 1H), 3.89 (ddd, 1H), 3.78 - 3.68 (m, 1H), 3.13 (td,1H), 2.17 (d, 1H), 1.82 - 1.72 (m, 1H), 1.54 (d, 3H), 1.32 (qd, 1H), 1.16 (qd, 1H),0.90 (d, 1H).

[0340] Examples 42 to 53

[0341] Using a two-step procedure similar to that described in Example 41, each compound in the table below was prepared from 6-chloro-1H-pyrazolo[3,4-b]pyrazine, the appropriate alcohol, and 5-(oxetan-3-yl)-1H-pyrazol-3-amine. [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] [Table 6-6] A-Reaction was carried out at 80°C.

[0342] Examples 54 to 57

[0343] Following a procedure similar to that described in Step 2 of Example 41, each compound in the table below was prepared from the appropriate 6-chloro-1H-pyrazolo[3,4-b]pyrazine and pyrazole. [Table 7-1] [Table 7-2]

[0344] Example 58. 1-(4-(6-((5-isopropyl-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)piperidin-1-yl)ethan-1-one [ka]

[0345] Step 1: Synthesis of tert-butyl 4-(6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)piperidine-1-carboxylate

[0346] Following a procedure similar to that described in Step 1 of Example 2, 6-chloro-1H-pyrazolo[3,4-b]pyrazine and tert-butyl 4-hydroxypiperidine-1-carboxylate gave the title compound as a pale yellow solid (204 mg, 78%).

[0347] Step 2: Synthesis of 6-chloro-1-(piperidin-4-yl)-1H-pyrazolo[3,4-b]pyrazine

[0348] tert-Butyl 4-(6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)piperidine-1-carboxylate (425 mg, 1.26 mmol) was dissolved in DCM (3 mL) and TFA (0.97 mL), and the reaction mixture was stirred at room temperature for 2 hours. The mixture was evaporated, and the residue was partitioned between DCM and dilute aqueous NaOH, and the layers were separated. The organic layer was dried over Na2SO4, filtered, and evaporated to give the title compound (260 mg, 87%) as a pale yellow solid. LCMS m / z = 238 [M+H]+

[0349] Step 3: Synthesis of 1-(4-(6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)piperidin-1-yl)ethan-1-one

[0350] A solution of 6-chloro-1-(piperidin-4-yl)-1H-pyrazolo[3,4-b]pyrazine (100 mg, 0.42 mmol) and TEA (88 μL, 0.63 mmol) in DCM (3 mL) was cooled in an ice bath. Acetyl chloride (36 μL, 0.51 mmol) was added, and the reaction mixture was allowed to warm slowly to room temperature overnight. The mixture was diluted with DCM, washed with water, brine, and dried over Na2SO4. The mixture was filtered and evaporated to give the crude product, which was triturated with ether, filtered, and dried to give the title compound (115 mg, 98%) as an off-white solid. LCMS m / z = 280 [M+H] +

[0351] Step 4: Synthesis of 1-(4-(6-((5-isopropyl-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)piperidin-1-yl)ethan-1-one

[0352] Following a procedure similar to that described in Step 2 of Example 41, 1-(4-(6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)piperidin-1-yl)ethan-1-one and 5-isopropyl-1H-pyrazol-3-amine gave the title compound as an off-white solid (22.2 mg, 35.9%). LCMS m / z = 369 [M+H] + .1H NMR (500 MHz, DMSO-d6) δ 12.10 (s, 1H),10.29 (s, 1H), 8.32 (s, 1H), 8.05 (s, 1H), 6.58 (s, 1H), 4.78 (s, 1H), 4.54 (d,1H), 4.00 (d, 1H), 3.01 - 2.92 (m, 1H), 2.79 (d, 1H), 2.18 (d, 1H), 2.05 (d, 6H),1.26 (d, 6H).

[0353] Example 59 (S)-1-(3-(6-((5-isopropyl-1H-pyrazolo-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)piperidin-1-yl)ethan-1-one [ka]

[0354] Following a four-step procedure similar to that described in Example 58, the title compound was obtained from (R)-tert-butyl 3-hydroxypiperidine-1-carboxylate and 6-chloro-1H-pyrazolo[3,4-b]pyrazine as a pale yellow solid. LCMS m / z = 369 [M+H] + .1H NMR (500 MHz, DMSO-d6) δ 12.10 (d, 1H),10.33 (d, 1H), 8.31 (d, 1H), 8.08 (d, 1H), 6.63 (s, 1H), 4.68 - 4.57 (m, 1H), 4.48(br s, 0.5H), 4.30 (d, 0.5H), 4.06 - 3.96 (m, 0.5H), 3.89 (d, 0.5H), 3.63 - 3.52(m, 0.5H), 3.13 (t, 0.5H), 3.05 (t, 0.5H), 2.96 (p, 1H), 2.79 - 2.71 (m, 0.5H) 2.39- 2.25 (m, 1H), 2.17 (d, 1H), 2.06 (s, 1.5H), 1.98 (s, 1.5H), 1.90 (dd, 1H), 1.64(d, 0.5H), 1.53 (d, 0.5H), 1.29 - 1.21 (m, 7H).

[0355] Example 60 (R)-3-(6-((5-isopropyl-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)-2-methylpropan-1-ol [ka]

[0356] Step 1: Synthesis of methyl (R)-3-(6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)-2-methylpropanoate

[0357] Following a procedure similar to that described in Step 1 of Example 2, the title compound was obtained as a white solid (200 mg, 40%) from 6-chloro-1H-pyrazolo[3,4-b]pyrazine and methyl (R)-3-hydroxy-2-methylpropanoate. LCMS m / z = 255 [M+H] + .

[0358] Step 2: (R)-3-(6-((5-isopropyl-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)-2-methylpropanoate methyl

[0359] Under nitrogen, a mixture of (R)-methyl 3-(6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)-2-methylpropanoate (100 mg, 0.39 mmol), 5-isopropyl-1H-pyrazol-3-amine (49 mg, 0.39 mmol), t-BuXphos (17 mg, 0.04 mmol), Pd(dba) (18 mg, 0.02 mmol), and KOAc (98 mg, 1.0 mmol) in dioxane (3 mL) was stirred at 90 °C for 5 h. The reaction mixture was concentrated to give a residue, which was purified by column chromatography on silica gel (PE:EA = 10:1 to 1:3) to give the title compound (70 mg, 52%) as a yellow paste. LCMS m / z = 344 [M+H] + .

[0360] Step 3: (R)-3-(6-((5-isopropyl-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)-2-methylpropan-1-ol

[0361] To a solution of (R)-methyl 3-(6-((5-isopropyl-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)-2-methylpropanoate (70 mg, 0.20 mmol) in THF (5 mL) was added LiAlH4 (17 mg, 0.45 mmol) at 0 °C, and the reaction mixture was stirred at 20 °C for 5 h. The reaction was quenched with MeOH (5 drops) and then concentrated. The residue was purified by preparative HPLC method B (15% to 95% B) to give the title compound (38 mg, 59%) as a yellow solid. LCMS m / z = 316 [M+H] + .1H-NMR (500 MHz, DMSO-d6) δ ppm 12.09 (brs, 1H), 10.31 (br s, 1H), 8.27 (s, 1H), 8.04 (s, 1H), 6.70 (s, 1H), 4.65 (s, 1H),4.37-4.30 (m, 1H), 4.15-4.09 (m, 1H), 3.35-3.29 (m, 2H), 3.00-2.90 (m, 1H), 2.25-2.20(m, 1H), 1.26 (d, 6H), 0.82 (d, 3H).

[0362] Example 61 (S)-3-(6-((5-isopropyl-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)-2-methylpropan-1-ol [ka]

[0363] Step 1: Synthesis of methyl (S)-3-(6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)-2-methylpropanoate

[0364] Following a procedure similar to that described in Step 1 of Example 1, the title compound was obtained as a pale yellow oil (200 mg, 24%) from 6-chloro-2H-pyrazolo[3,4-b]pyrazine and methyl (2S)-3-hydroxy-2-methylpropanoate. LCMS m / z = 255 [M+H] + .

[0365] Step 2: Synthesis of methyl (S)-3-(6-((5-isopropyl-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)-2-methylpropanoate

[0366] Following a procedure similar to that described in Step 2 of Example 60, (S)-methyl 3-(6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)-2-methylpropanoate and 5-(propan-2-yl)-1H-pyrazol-3-amine gave the title compound as a yellow oil (200 mg, 74%). LCMS m / z = 344 [M+H] +

[0367] Step 3: Synthesis of (S)-3-(6-((5-isopropyl-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)-2-methylpropan-1-ol

[0368] Following a procedure similar to that described in Step 3 of Example 60, (S)-methyl 3-(6-((5-isopropyl-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)-2-methylpropanoate gave the title compound as a yellow solid (78.3 mg, 43%). LCMS m / z = 316 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6) δ ppm12.10 (s, 1H), 10.31 (s, 1H), 8.28 (s, 1H), 8.04 (s, 1H), 6.71 (s, 1H), 4.65 (t,1H), 4.38-4.30 (m, 1H), 4.18-4.10 (m, 1H), 3.36-3.30 (m, 2H), 2.98-2.90 (m, 1H),2.30-2.21 (m, 1H), 1.26 (d, 6H), 0.82 (d, 3H).

[0369] Example 62. N-(5-Isopropyl-1H-pyrazol-3-yl)-1-(piperidin-4-ylmethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0370] Step 1: Synthesis of tert-butyl 4-((6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)piperidine-1-carboxylate

[0371] Following a procedure similar to that described in Step 1 of Example 1, 6-chloro-1H-pyrazolo[3,4-b]pyrazine and tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate gave the title compound as a white solid (1.0 g, 98%). LCMS m / z = 252 [M-Boc+H] + .

[0372] Step 2: Synthesis of tert-butyl 4-((6-((5-isopropyl-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)piperidine-1-carboxylate

[0373] Following a procedure similar to that described in Step 2 of Example 1, tert-butyl 4-((6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)piperidine-1-carboxylate and 5-(propan-2-yl)-1H-pyrazol-3-amine gave the title compound as a white solid (350 mg, 47%). LCMS m / z = 441 [M+H] +

[0374] Step 3: Synthesis of N-(5-isopropyl-1H-pyrazol-3-yl)-1-(piperidin-4-ylmethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

[0375] To a mixture of tert-butyl 4-((6-((5-isopropyl-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)piperidine-1-carboxylate (350 mg, 0.79 mmol) in dioxane (8 mL) was added HCl-dioxane (4.0 M, 8 mL) and the reaction mixture was stirred at room temperature under N for 8 hours. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC method B (15%-95% B) to give the title compound as a white solid (51 mg, 19%). LCMS m / z = 341 [M+H] + . 1 H-NMR (500 MHz, DMSO-d6) δ ppm10.42 (s, 1H), 8.28 (s, 1H), 8.04 (s, 1H), 6.66 (s, 1H), 4.21-4.19 (m, 2H,), 3.93(br s, 1H), 2.98-2.90 (m, 2H), 2.65-2.60 (m, 1H), 2.53-2.50 (m, 1H), 2.11-2.08 (m,1H), 1.50-1.47 (m, 2H), 1.25 (d, 6H), 1.16-1.12 (m, 3H).

[0376] Example 63 (R)—N-(5-isopropyl-1H-pyrazol-3-yl)-1-(piperidin-3-ylmethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0377] Step 1: Synthesis of tert-butyl (R)-3-((6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)piperidine-1-carboxylate

[0378] Following a procedure similar to that described in Step 1 of Example 1, 6-chloro-1H-pyrazolo[3,4-b]pyrazine and tert-butyl (R)-3-(hydroxymethyl)piperidine-1-carboxylate gave the title compound as an oil (550 mg, 80%). LCMS m / z = 352 [M+H]+

[0379] Step 2: Synthesis of tert-butyl (R)-3-((6-((5-isopropyl-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)piperidine-1-carboxylate

[0380] Following a procedure similar to that described in Step 2 of Example 1, (R)-tert-butyl 3-((6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)piperidine-1-carboxylate and 5-(propan-2-yl)-1H-pyrazol-3-amine gave the title compound as a yellow solid (100 mg, 41%). LCMS m / z = 441 [M+H] + .

[0381] Step 3: Synthesis of (R)—N-(5-isopropyl-1H-pyrazol-3-yl)-1-(piperidin-3-ylmethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine

[0382] Following a procedure similar to that described in Example 62, (R)-tert-butyl 3-((6-((5-isopropyl-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)piperidine-1-carboxylate gave the title compound as a yellow solid (32.3 mg, 41%). LCMS m / z = 341 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6) δ ppm12.50-11.95 (br, 1H), 10.37 (s, 1H), 8.27 (s, 1H), 8.06 (s, 1H), 6.70 (br s, 1H),4.27-4.15 (m, 2H), 2.98-2.81 (m, 3H), 2.52-2.45 (m, 2H), 2.15 (s, 1H), 1.63 (s,2H), 1.39-1.36 (m, 1H), 1.27 (d, 6H), 1.21-1.05 (m, 2H).

[0383] Example 64. N-(5-Isopropyl-1H-pyrazol-3-yl)-1-((1-methylpiperidin-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0384] To a mixture of the compound from Example 62 (119 mg, 0.35 mmol) in DCM (1 mL) and MeOH (1 mL) was added HOAc (0.2 mL), followed by aqueous HCHO (0.2 mL). After stirring at room temperature for 1 h, NaBHCN (87.5 mg, 1.39 mmol) was added, and the reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated in vacuo, and the residue was purified by preparative HPLC, Method B (15% to 95% B) to give the title compound as a white solid (35 mg, 28%). LCMS m / z = 355 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6) δ ppm12.50-11.90 (br s, 1H), 10.60-10.10 (br s, 1H), 8.27 (s, 1H), 8.03 (s, 1H), 6.68(s, 1H), 6.10 (br s, 1H), 4.19 (d, 2H), 2.98-2.93 (m, 1H), 2.73-2.65 (m, 2H), 2.09(s, 3H), 1.94-1.92 (m, 1H), 1.80-1.72 (m, 2H), 1.53-1.45 (m, 2H), 1.25 (d, 6H),1.25-1.20 (m, 2H).

[0385] Biological Example 1. The inhibitory effects of the compounds of the present disclosure were measured by a biochemical assay. This assay measured the enzymatic phosphorylation activity of a CDK enzyme in a complex with a cyclin protein, phosphorylating 7.5 micromolar fluorescently labeled peptide substrate 5-FAM-QSPKKG-CONH2 (FL-peptide 18, Perkin Elmer, 760362) in the presence of adenosine-5'-triphosphate (ATP) and various concentrations of test compound in 100 mM 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid (HEPES), pH 7.5, 10 mM MgCl2, 0.015% Brij®-35, 1 mM dithiothreitol (DTT), and 1.0% dimethyl sulfoxide (DMSO). The assay was performed at the Km of ATP for the CDK enzyme in the complex with the cyclin protein, or at 1.0 mM ATP. The reaction was allowed to proceed at room temperature (25 °C) until 10%-20% of the total peptide was phosphorylated and terminated with 35 mM 2,2',2'',2''-(ethane-1,2-diyldinitrilo)tetraacetic acid (EDTA). Products were detected using a caliper mobility shift detection method, in which the phosphorylated peptide (product) and substrate were separated and measured by electrophoresis. The apparent IC was calculated by plotting percent activity against the logarithmic concentration of compound and the points. 50 These assays used the following CDK enzymes in complex with different cyclin proteins: CDK1 / Cyclin B1, GST-tagged (BPS, 40454), 1.5 nM used in the assay CDK2 / Cyclin E (Eurofins, 14-475), 1.25 nM used in the assay

[0386] The biological assay data for the test compounds are shown in Table 1 below. [Table 1-1] [Table 1-2]

Claims

1. A compound of formula (I), 【Chemistry 54】 or a pharmaceutically acceptable salt thereof, R １ D, Halo, CN, C １ ~C ４ Alkyl, C ３ ~C １０ Cycloalkyl, C ３ ~C １０ cycloalkoxy, and 4- to 12-membered heterocyclyl, provided that １ ~C ４ alkyl, the C ３ ~C １０ Cycloalkyl, and the C ３ ~C １０ Each cycloalkoxy has 1 to 4 R ｃ and said 4- to 12-membered heterocyclyl is selected from O, S, N, and NR ｄ and 1 to 4 ring heteroatoms each independently selected from the group consisting of: ｃ may be substituted with R ２ is C １ ~C ４ alkyl or ring A, provided that said C １ ~C ４ Alkyl is 1 to 4 groups independently selected from D, halo, CN, and OH, and / or O, S, N, and NR ｄ and optionally substituted with one group of 5-6 membered heteroaryl having 1-3 ring heteroatoms each independently selected from the group consisting of: R ３ H, D, C １ ~C ４ Alkyl, C ３ ~C １０ cycloalkyl and 4- to 12-membered heterocyclyl, provided that １ ~C ４ Alkyl and the C ３ ~C １０ Cycloalkyl is 1 to 4 R ｃ and the 4- to 12-membered heterocyclyl is selected from O, S, N, and NR ｄ and further having 1 to 4 R on a ring atom. ｃ may be substituted with, or R ２ and R ３ form a ring B together with the carbon atom to which they are attached, provided that said ring B is C ３ ~C １０ cycloalkyl or 4- to 12-membered heterocyclyl, ３ ~C １０ Cycloalkyl is one to four R ｂ and said 4- to 12-membered heterocyclyl is selected from O, S, N, and NR ｄ and further having 1 to 4 R on a ring atom. ｂ may be substituted with Ring A is C ３ ~C １０ is selected from the group consisting of cycloalkyl, phenyl, naphthyl, 4- to 12-membered heterocyclyl, and 4- to 12-membered heteroaryl, provided that ３ ~C １０ Cycloalkyl, phenyl, and naphthyl are each 1 to 4 R ａ and the 4- to 12-membered heterocyclyl and the 4- to 12-membered heteroaryl are each optionally substituted with O, S, N, and NR ｄ and further having 1 to 4 R on a ring atom. ａ may be substituted with Each R ａ D, halo, OH, CN, C １ ~C ４ Alkyl, and C １ ~C ４ or two R bonded to the same atom independently selected from the group consisting of alkoxy; ａ forms =O, provided that said C １ ~C ４ Alkyl and the C １ ~C ４ each alkoxy is optionally substituted with 1 to 4 groups independently selected from the group consisting of halo, OH, and CN; Each R ｂ D, halo, OH, CN, C １ ~C ４ Alkyl, and C １ ~C ４ or two R bonded to the same atom independently selected from the group consisting of alkoxy; ｂ forms =O, provided that said C １ ~C ４ Alkyl and the C １ ~C ４ each alkoxy is optionally substituted with 1 to 4 groups independently selected from the group consisting of halo, OH, and CN; Each R ｃ D, halo, OH, CN, C １ ~C ４ Alkyl, and C １ ~C ４ or two R bonded to the same atom independently selected from the group consisting of alkoxy; ｂ forms =O, provided that said C １ ~C ４ Alkyl and the C １ ~C ４ each alkoxy is optionally substituted with 1 to 4 groups independently selected from the group consisting of halo, OH, and CN; Each R ｄ are H, D, C(O)C １～ C ４ Alkyl, and C １～ C ４ independently selected from the group consisting of alkyl, R ４ are H, D, and C １ ~C ４ alkyl, provided that said C １ ~C ４ The alkyl is optionally substituted with 1 to 4 groups independently selected from halo and OH; R ５ H, D, halo, CN, and C １ ~C ４ alkyl, provided that said C １ ~C ４ The alkyl is optionally substituted with 1 to 4 groups independently selected from halo and OH; R ６ are H, D, and C １ ~C ４ is selected from the group consisting of alkyl, R ７ are H, D, and C １ ~C ４ alkyl].

2. Each R ａ Halo, OH, CN, C １ ~C ４ Alkyl, and C １ ~C ４ or two R bonded to the same atom independently selected from the group consisting of alkoxy; ａ forms =O, provided that said C １ ~C ４ Alkyl and the C １ ~C ４ each alkoxy is optionally substituted with 1 to 4 groups independently selected from the group consisting of halo, OH, and CN; Each R ｂ Halo, OH, CN, C １ ~C ４ Alkyl, and C １ ~C ４ or two R bonded to the same atom independently selected from the group consisting of alkoxy; ｂ forms =O, provided that said C １ ~C ４ Alkyl and the C １ ~C ４ each alkoxy is optionally substituted with 1 to 4 groups independently selected from the group consisting of halo, OH, and CN; Each R ｃ Halo, OH, CN, C １ ~C ４ Alkyl, and C １ ~C ４ or two R bonded to the same atom independently selected from the group consisting of alkoxy; ｃ forms =O, provided that said C １ ~C ４ Alkyl and the C １ ~C ４ The alkoxy may each be optionally substituted with 1 to 4 groups each independently selected from the group consisting of halo, OH, and CN; and / or Each R ｄ are independently H or C １ ~C ６ 2. The compound of claim 1, wherein the aryl group is alkyl.

3. R ２ But C １ ~C ４ alkyl or ring A, provided that said C １ ~C ４ Alkyl is 1 to 4 groups independently selected from halo, CN, and OH, and / or O, S, N, and NR ｄ and optionally substituted with one group of 5-6 membered heteroaryl having 1-3 ring heteroatoms each independently selected from the group consisting of: R ４ C, which may be substituted with 1 to 4 groups independently selected from H, D; and halo and OH; １ ~C ４ 3. The compound of claim 1 or 2, wherein the compound is selected from the group consisting of alkyl.

4. R １ But, Haro, CN, C １ ~C ４ Alkyl, C ３ ~C ６ Cycloalkyl, C ３ ~C ６ cycloalkoxy, and 4- to 6-membered heterocyclyl, provided that １ ~C ４ alkyl, the C ３ ~C ６ Cycloalkyl, and the C ３ ~C ６ Cycloalkoxy is a group having 1 to 4 R ｃ and the 4-6 membered heterocyclyl is selected from O, S, N, and NR ｄ and 1 to 4 ring heteroatoms each independently selected from the group consisting of: ｃ The compound according to any one of claims 1 to 3, optionally substituted with

5. R １ But C １ ~C ４ The compound according to any one of claims 1 to 4, which is alkyl.

6. R １ CN, methyl, ethyl, isopropyl, 【Transformation 55】 The compound according to any one of claims 1 to 4, selected from the group consisting of:

7. Compound of formula (II): 【Transformation 56】 or a pharmaceutically acceptable salt thereof.

8. Ring A is D, halo, OH, ═O, CN, C １ ~C ４ Alkyl and C １ ~C ４ C optionally substituted with 1 to 3 groups independently selected from the group consisting of alkoxy ３ ~C ８ cycloalkyl, provided that said C １ ~C ４ Alkyl and the C １ ~C ４ The compound of any one of claims 1 to 7, wherein each alkoxy is optionally substituted with 1 to 3 groups each independently selected from the group consisting of halo, OH, and CN.

9. Ring A is D, halo, OH, ═O, CN, C １ ~C ４ Alkyl and C １ ~C ４ phenyl optionally substituted with 1 to 3 groups independently selected from the group consisting of alkoxy, １ ~C ４ Alkyl and the C １ ~C ４ The compound of any one of claims 1 to 7, wherein each alkoxy is optionally substituted with 1 to 3 groups each independently selected from the group consisting of halo, OH, and CN.

10. Ring A is D, halo, OH, ═O, CN, C １ ~C ４ Alkyl and C １ ~C ４ naphthyl optionally substituted with 1 to 3 groups independently selected from the group consisting of alkoxy, １ ~C ４ Alkyl and the C １ ~C ４ The compound of any one of claims 1 to 7, wherein each alkoxy is optionally substituted with 1 to 3 groups each independently selected from the group consisting of halo, OH, and CN.

11. Ring A is D, halo, OH, ═O, CN, C １ ~C ４ Alkyl, and C １ ~C ４ 4- to 10-membered heterocyclyl optionally substituted on ring atoms with 1 to 3 groups each independently selected from the group consisting of alkoxy, provided that １ ~C ４ Alkyl and the C １ ~C ４ The compound of any one of claims 1 to 7, wherein each alkoxy is optionally substituted with 1 to 3 groups each independently selected from the group consisting of halo, OH, and CN.

12. Ring A is D, halo, OH, ═O, CN, C １ ~C ４ Alkyl, and C １ ~C ４ 4-10 membered heteroaryl optionally substituted on ring atoms with 1 to 3 groups each independently selected from the group consisting of alkoxy, provided that １ ~C ４ Alkyl and the C １ ~C ４ The compound of any one of claims 1 to 7, wherein each alkoxy is optionally substituted with 1 to 3 groups each independently selected from the group consisting of halo, OH, and CN.

13. Compounds of formula (III): 【Chemistry 57】 or a pharmaceutically acceptable salt thereof.

14. Ring B is D, halo, OH, ═O, CN, C １ ~C ４ Alkyl, and C １ ~C ４ C optionally substituted with 1 to 3 groups independently selected from the group consisting of alkoxy ３ ~C ８ cycloalkyl, provided that said C １ ~C ４ Alkyl and the C １ ~C ４ The compound of claim 13, wherein each alkoxy is optionally substituted with 1 to 3 groups each independently selected from the group consisting of halo, OH, and CN.

15. Ring B is D, halo, OH, ═O, CN, C １ ~C ４ Alkyl, and C １ ~C ４ 4- to 10-membered heterocyclyl optionally substituted on ring atoms with 1 to 3 groups each independently selected from the group consisting of alkoxy, provided that １ ~C ４ Alkyl and the C １ ~C ４ The compound of claim 13, wherein each alkoxy is optionally substituted with 1 to 3 groups each independently selected from the group consisting of halo, OH, and CN.

16. R ２ is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl, each of which may be substituted with 1 to 4 groups independently selected from the group consisting of D, halo, OH, CN, and 5- to 6-membered heteroaryl.

17. R ３ But H, D, C １ ~C ４ Alkyl, C ３ ~C ８ cycloalkyl, and 4- to 10-membered heterocyclyl, １ ~C ４ alkyl, the C ３ ~C ８ Cycloalkyl and the 4- to 10-membered heterocyclyl are (R ３ 17. The compound of any one of claims 1 to 12 and 16, wherein, when is a 4- to 10-membered heterocyclyl, it is optionally substituted on the ring carbons with 1 to 3 groups each independently selected from the group consisting of D, halo, and OH.

18. R ３ However, H, D, and C １ ~C ４ The compound of any one of claims 1 to 12, 16, and 17, wherein the compound is selected from the group consisting of alkyl.

19. R ４ H, D, and CH ３ The compound according to any one of claims 1 to 18, selected from the group consisting of:

20. R ５ The compound of any one of claims 1 to 19, wherein is selected from the group consisting of H, D, halo, and methyl.

21. Compound of formula (IV): 【Chemistry 58】 or a pharmaceutically acceptable salt thereof. [In the formula, R １ is CN, C １ ~C ４ Alkyl, C ３ ~C ８ Cycloalkyl, C ３ ~C ８ cycloalkoxy, and 4- to 10-membered heterocyclyl, provided that １ ~C ４ alkyl, the C ３ ~C ８ Cycloalkyl, and the C3 to C ８ Cycloalkoxy is a group having 1 to 3 R ｃ and the 4- to 10-membered heterocyclyl is selected from O, S, N, and NR ｄ and each of the ring heteroatoms is independently selected from the group consisting of: R ２ is C １ ~C ４ alkyl or ring A, provided that said C １ ~C ４ The alkyl is optionally substituted with 1 to 3 groups independently selected from the group consisting of halo, CN, and OH; R ３ is H or C １ ~C ４ is alkyl, or R ２ and R ３ form a ring B together with the carbon atom to which they are attached, provided that said ring B is not a halo, OH, ═O, CN, C １ ~C ４ Alkyl, and C １ ~C ４ C optionally substituted with 1 to 3 groups independently selected from the group consisting of alkoxy ３ ~C ８ is cycloalkyl, Ring A is C ３ ~C ８ is selected from the group consisting of cycloalkyl, phenyl, naphthyl, 4- to 10-membered heterocyclyl, and 4- to 10-membered heteroaryl, provided that ３ ~C ８ The cycloalkyl, the phenyl, and the naphthyl each have 1 to 3 R ａ and the 4- to 10-membered heterocyclyl and the 4- to 10-membered heteroaryl are each optionally substituted with O, S, N, and NR ｄ and further having 1 to 3 R on a ring atom. ａ may be substituted with Each R ａ Halo, OH, CN, C １ ~C ４ Alkyl, and C １ ~C ４ or two R bonded to the same atom independently selected from the group consisting of alkoxy; ａ forms =O, provided that said C １ ~C ４ Alkyl and the C １ ~C ４ each alkoxy is optionally substituted with 1 to 3 groups independently selected from the group consisting of halo, OH, and CN; Each R ｃ Halo, OH, CN, C １ ~C ４ Alkyl, and C １ ~C ４ or two R bonded to the same atom independently selected from the group consisting of alkoxy; ｃ forms =O, provided that said C １ ~C ４ Alkyl and the C １ ~C ４ each alkoxy is optionally substituted with 1 to 3 groups independently selected from the group consisting of halo, OH, and CN; Each R ｄ are independently H or C １ ~C ４ is alkyl, R ４ is H or C １ ~C ４ is alkyl, R ５ is H, halo, CN, and C １ ~C ４ is selected from the group consisting of alkyl, R ７ is H or C １ ~C ４ alkyl].

22. Compound of formula (V): 【Chemistry 59】 or a pharmaceutically acceptable salt thereof. [In the formula, R １ is CN, C １ ~C ４ alkyl, and 4- to 10-membered heterocyclyl, １ ~C ４ The alkyl and the 4- to 10-membered heterocyclyl may be substituted with 1 to 3 Rc. R ２ is ring A selected from the group consisting of phenyl, 4- to 6-membered heterocyclyl, and 6-membered heteroaryl, provided that said phenyl is selected from the group consisting of 1 to 3 R ａ and the 4- to 6-membered heterocyclyl and the 6-membered heteroaryl are optionally substituted with O, S, N, and NR ｄ and further having 1 to 3 R on a ring atom. ａ may be substituted with Each R ａ Halo, OH, CN, C １ ~C ４ Alkyl, and C １ ~C ４ or two R bonded to the same atom independently selected from the group consisting of alkoxy; ａ forms a=O, Each R ｃ Halo, OH, CN, C １ ~C ４ Alkyl, and C １ ~C ４ or two R bonded to the same atom independently selected from the group consisting of alkoxy; ｃ forms a=O, Each R ｄ are independently H or C １ ~C ４ is alkyl, R4 is H or C １ ~C ４ alkyl].

23. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof.

24. A method for treating cancer, comprising administering an effective amount of the compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 23 to a subject in need of cancer treatment.

25. 25. The method of claim 24, wherein the cancer is breast cancer.

26. 26. The method of claim 25, wherein the breast cancer is progressing despite treatment with a CDK4 / 6 inhibitor.

27. 27. The method of claim 25 or 26, further comprising administering an effective amount of a CDK4 / 6 inhibitor.

28. 25. The method of claim 24, wherein the cancer is selected from the group consisting of ovarian cancer, endometrial cancer, gastric cancer, esophageal cancer, triple-negative breast cancer, and pulmonary adenosarcoma.

29. 29. The method of claim 28, wherein the cancer has CCNE1 overexpression and / or amplification.

30. 30. The method of claim 28 or 29, wherein the cancer is progressing despite platinum-based therapy.

31. 31. The method of any one of claims 24-26 and 28-30, further comprising administering to the subject an effective amount of carboplatin, ribociclib, fulvestrant, or a combination thereof.

32. The method according to any one of claims 24 to 26 and 28 to 30, wherein the compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 23, is administered to the subject in combination with an effective amount of carboplatin, ribociclib, fulvestrant, or a combination thereof.

33. A method for treating a patient having an amplified expression level of CCNE1 and suffering from or at risk of developing a solid tumor cancer, the method comprising administering to the patient a therapeutically effective amount of a compound described in any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in claim 23.

34. 34. The method of claim 33, wherein the solid tumor cancer is at least one of uterine cancer (including uterine carcinosarcoma and endometrial cancer), endometrial cancer, breast cancer (including invasive breast cancer, triple-negative breast cancer (TNBC), estrogen receptor (ER)+ human epidermal growth factor 2 (HER2)- breast cancer, and HER2+ breast cancer), ovarian cancer (including, for example, ovarian serous cystadenocarcinoma), gastric cancer (gastric adenocarcinoma)), gastric cancer (including gastrointestinal stromal tumor), colorectal cancer, pancreatic cancer, kidney cancer, head and neck cancer, liver cancer, prostate cancer, skin cancer, lymphoma (including B-cell lymphoma), sarcoma, esophageal cancer (including esophageal carcinoma), bladder cancer (including bladder urothelial carcinoma), lung cancer (including lung squamous cell carcinoma and non-small cell lung cancer, e.g., epidermal growth factor receptor mutant (EGFRm)+ non-small cell lung cancer), cholangiocarcinoma, adrenocortical carcinoma, or mesothelioma.

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