CDK2 inhibitors

Abstract

The present disclosure provides compounds of structural formula (I): The present invention provides a compound useful for treating cancer, represented by TIFF2024524373000349.tif50165, or a pharma- ceutically acceptable salt thereof.

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 / 215,901, filed June 28, 2021, 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 have 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 ordering of steps in cell cycle progression. Activation of CDKs 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 is involved in the DNA damage response (DDR) via the homologous recombination (HR) pathway. CDK2 also controls 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 the main regulators of CDK2 activity. In cancer, dysregulation of CDK2 binding by cyclins E1, E2, A1 or A2, or activity of cyclin-dependent kinase inhibitor proteins can occur. (See S. Tadesse et al., Drug Discovery Today, Volume 25, Number 2 February 2020)

[0004] Dysregulation of CDK2 can occur by 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 outcome in gastric, endometrial and other cancers has been 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, thus 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

[0006] Applicants have discovered novel compounds that are effective inhibitors of CDK2 (see Synthesis Examples 1-227). In particular, compounds of the present disclosure have been demonstrated to effectively inhibit CDK2. Compounds of the present disclosure (also referred to herein as "disclosed compounds"), or pharma- ceutically 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 have no or low activity against CDK family kinases, most notably CDK1. Advantages associated with such selectivity may include facilitating effective administration and reducing toxicity on CDK1-mediated targets. Some of the disclosed compounds also have the advantage of having high microsomal stability. Compounds of the present disclosure may also have favorable toxicity profiles associated with other non-kinase targets.

[0007] In one embodiment, the present disclosure provides a compound having the following structural formula (I): [ka] or a pharma- ceutically acceptable salt thereof. The definitions of each variable are provided below.

[0008] In another aspect, the present disclosure provides a compound represented by the following structural formula (Ia): [ka] or a pharma- ceutically acceptable salt thereof. The definitions of each variable are provided below.

[0009] In another aspect, the present disclosure provides a pharmaceutical composition comprising a pharma- ceutical carrier or diluent and one or more compounds disclosed herein or a pharma- ceutical acceptable salt thereof ("pharmaceutical composition of the present disclosure").

[0010] 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 Formula (Ia)) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. In one embodiment, the cancer is uterine cancer (including uterine carcinosarcoma (UCS), uterine endometrial carcinoma (UCEC)), endometrial cancer, breast cancer (including breast invasive carcinoma (BRCA), triple negative breast cancer (TNBC), hormone receptor positive breast cancer (HR+ breast cancer), estrogen receptor positive breast cancer (ER+ breast cancer), hormone receptor positive human epidermal growth factor 2 negative breast cancer (HR+HER2- breast cancer), estrogen receptor positive human epidermal growth factor 2 negative breast cancer (ER+HER2- breast cancer), human epidermal growth factor 2 negative breast cancer (HER2- breast cancer), human epidermal growth factor 2 low expressing breast cancer (HER2 low expressing breast cancer), human epidermal growth factor 2 positive breast cancer (HER2+ breast cancer)), ovarian cancer (e.g., ovarian The cancer is selected from the group consisting of serous cystadenocarcinoma (OV), gastric cancer (including gastric adenocarcinoma (STAD)), gastric cancer (including gastrointestinal stromal tumors), colorectal cancer, pancreatic cancer (including pancreatic adenocarcinoma (PAAD)), renal cancer, head and neck cancer, liver cancer, prostate cancer, skin cancer, leukemia (including acute myeloid leukemia (AML)), 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., epidermal growth factor receptor mutant (EGFRm)+ 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 progressive / 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 was 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 (previously treated with platinum therapy, e.g., the patient was previously treated with platinum therapy) that has progressed after two or more lines of therapy (including platinum therapy). In one embodiment, the subject has ER+HER- breast cancer that has progressed despite treatment with one or more CDK4 / 6 inhibitors.

[0011] In one embodiment, the cancer to be treated as described herein (eg, a cancer described in paragraphs 0010, 0020, 0120-0129, 0131, and 0133-0148, eg, breast cancer) has CCNE1 amplification and / or overexpression.

[0012] In one embodiment, the cancer treated as described herein (eg, a cancer described in paragraphs 0010, 0020, 0120-0129, 0131, and 0133-0148, eg, breast cancer) does not have CCNE1 amplification and / or overexpression.

[0013] The therapeutic methods disclosed herein further include administering to the patient 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 (e.g., sirolimus), or combinations thereof. , 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, selarasertib, SRA-737, LY2603618 (ravusertib), or trastuzumab (e.g., Herceptin®), or a combination thereof, are administered to the subject. EGFR inhibitors include afatinib, osimertinib, lapatinib, erlotinib, dacomitinib, poziotinib, neratinib, gefitinibJBJ-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, resibertinib (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)).

[0014] The present disclosure also provides a method of inhibiting CDK2 in a subject in need thereof, 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 Formula (Ia)) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0015] 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 Formula (Ia)) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, for the preparation of a medicament for the treatment of cancer.

[0016] In another aspect, provided herein is a compound of Formula (I) or Formula (Ia) of the present disclosure, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition for use in the treatment of cancer.

[0017] In one aspect, the 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 pharma- ceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, wherein the subject has an amplification of the CCNE1 gene 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.

[0018] The present disclosure also 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 pharma- ceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, wherein the subject has an amplification of the CCNE1 gene and / or has a CCNE1 expression level similar to a control expression level of CCNE1. In some embodiments, the disease or disorder associated with CDK2 is cancer.

[0019] 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 pharma- ceutical acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0020] Contemplated solid tumor cancers include uterine cancer (including uterine carcinosarcoma, uterine endometrial carcinoma (UCEC)), endometrial cancer, breast cancer (including breast invasive carcinoma, triple negative breast cancer (TNBC), estrogen receptor (ER)+ human epidermal growth factor 2 (HER2)- breast cancer, hormone receptor (HR)+ human epidermal growth factor 2 (HER2)- breast cancer, HER2- breast cancer, and HER2+ breast cancer), ovarian cancer (e.g., ovarian serous cystadenocarcinoma), gastric cancer (gastric adenocarcinoma), stomach cancer, (including gastrointestinal stromal tumors), colorectal cancer, pancreatic cancer, renal 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 lung squamous cell carcinoma and non-small cell lung cancer, e.g., epidermal growth factor receptor mutant (EGFRm)+ non-small cell lung cancer), bile duct carcinoma, adrenal cortical carcinoma, or mesothelioma. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0021] definition The term "halo" as used herein means halogen and includes chloro, fluoro, bromo and iodo.

[0022] The term "alkyl" used alone or as part of a larger moiety such as "alkoxy" or "haloalkyl" means a saturated aliphatic straight or branched chain monovalent hydrocarbon group. Unless otherwise specified, an alkyl group typically has 1 to 4 carbon atoms, i.e., (C1-C4) alkyl. As used herein, a "(C1-C4) alkyl" group means a group having 1 to 4 carbon atoms in a linear or branched arrangement. Examples include methyl, ethyl, n-propyl, iso-propyl, and the like.

[0023] 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.

[0024] The term "cycloalkyl" refers to a monocyclic saturated hydrocarbon ring system. Unless otherwise specified, cycloalkyl has 3 to 10 carbon atoms. In some embodiments, cycloalkyl has 3 to 6 carbon atoms. For example, C3-C 10 Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Unless otherwise specified, "cycloalkyl" has from 3 to 10 carbon atoms.

[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 1-4 ring heteroatoms, each heteroatom being 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 non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom being independently selected from nitrogen, quaternary nitrogen, nitrogen oxide (e.g., NO), oxygen, and sulfur (including sulfoxide and sulfone). In some embodiments, a heterocyclyl has 1-2 ring heteroatoms, each heteroatom being 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 can be at a carbon or nitrogen atom, where valence permits. Exemplary heterocyclyl groups include azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, azepanyl, oxepanyl, thiepanyl, tetrahydropyridinyl, and the like.

[0026] The term "heteroaryl" refers to a group of 4-12 membered monocyclic or bicyclic 4n+2 aromatic ring systems (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be at a carbon or nitrogen atom, where valence permits. Heteroaryl bicyclic ring systems can contain one or more heteroatoms in one or both rings. "Heteroaryl" also includes ring systems in which the heteroaryl ring as defined above is fused with one or more aryl groups, and the point of attachment is on either the aryl or heteroaryl ring, in such instances the number of ring members designates 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 at either ring. That is, it can be in a ring that has a heteroatom (e.g., 2-indolyl) or a ring that does not contain a heteroatom (e.g., 5-indolyl). Heteroaryl groups may be described as, for example, 6-10 membered heteroaryl, where the term "membered" refers to a non-hydrogen ring atom in 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 and that differ in the placement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium with the shift of π electrons and atoms (usually H).

[0028] Compounds of the Disclosure Disclosed herein are embodiments of compounds having the general structure of formula (I) or formula (Ia).The present invention provides the compounds of the present invention or their pharma- ceutically acceptable salts for use in treating 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 pharma- ceutically acceptable salt thereof, wherein R 1 is a C1-C4 alkyl optionally substituted with 1 to 4 halo; R 2 is C1-C4 alkyl or ring A, where C1-C4 alkyl is 1-4 groups each independently selected from halo, CN, and OH, and / or O, S, and NR d and each of the 5- to 6-membered heteroaryl groups having 1 to 3 ring heteroatoms independently selected from the group consisting of R 3 is H, C1-C4 alkyl, C3-C 10 cycloalkyl and 4-12 membered heterocyclyl, wherein C1-C4 alkyl and C3-C 10 Cycloalkyl has 1 to 4 R c wherein 4-12 membered heterocyclyl is selected from O, S and NR d and then 1 to 4 R on the ring carbons. c or R 2 and R 3 together with the carbon atom to which they are attached form ring B, where ring B is C3-C 10 cycloalkyl or 4-12 membered heterocyclyl, where C 10 Cycloalkyl is 1 to 4 R b wherein the 4- to 12-membered heterocyclyl is optionally substituted by NR d , 1 to 4 ring heteroatoms each independently selected from the group consisting of O and S, followed by 1 to 4 R b may be substituted with Ring A is C3~C 10 cycloalkyl, phenyl, naphthyl, 4-12 membered heterocyclyl, and 4-12 membered heteroaryl, wherein C 10 Cycloalkyl, phenyl and naphthyl each have 1 to 4 R a wherein the 4- to 12-membered heterocyclyl and the 4- to 12-membered heteroaryl are optionally substituted with O, S, and NR d and then 1 to 4 R on the ring carbons. 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, where 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 halo, OH, CN, C1-C4 alkyl, and C1-C4 alkoxy, or two R b forms =O, where 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 halo, OH, CN, C1-C4 alkyl, and C1-C4 alkoxy, or two R c forms =O, where 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; or Each R d are independently H or C1-C6 alkyl; R 4is H or C1-C4 alkyl optionally substituted with 1 to 4 groups each independently selected from halo and OH; R 5 is selected from the group consisting of H, halo, CN, and C1-C4 alkyl, where C1-C4 alkyl is optionally substituted with 1 to 4 groups each independently selected from halo and OH.

[0030] In another embodiment, the present disclosure provides a compound represented by the following structural formula (Ia): [ka] or a pharma- ceutically acceptable salt thereof, wherein R 1 is a C1-C4 alkyl optionally substituted with 1 to 4 groups each independently selected from halo and D; R 2 is C1-C4 alkyl or ring A, where C1-C4 alkyl is 1-4 groups each independently selected from halo, D, CN and OH, and / or O, S and NR d and each of the 5- to 6-membered heteroaryl groups having 1 to 3 ring heteroatoms independently selected from the group consisting of R 3 is H, D, C1-C4 alkyl, C3-C 10 cycloalkyl and 4-12 membered heterocyclyl, wherein C1-C4 alkyl and C3-C 10 Cycloalkyl is 1 to 4 R c wherein 4-12 membered heterocyclyl is O, S, or NR d and then 1 to 4 R on the ring carbons. c or R 2 and R 3 together with the carbon atom to which they are attached form ring B, where ring B is C3-C 10cycloalkyl or 4-12 membered heterocyclyl, where C 10 Cycloalkyl is 1 to 4 R b wherein the 4- to 12-membered heterocyclyl is optionally substituted by NR d , 1 to 4 ring heteroatoms each independently selected from the group consisting of O and S, followed by 1 to 4 R b may be substituted with Ring A is C3~C 10 cycloalkyl, phenyl, naphthyl, 4-12 membered heterocyclyl, and 4-12 membered heteroaryl, wherein C 10 Cycloalkyl, phenyl and naphthyl each have 1 to 4 R a wherein the 4- to 12-membered heterocyclyl and the 4- to 12-membered heteroaryl are optionally substituted with O, S, and NR d and then 1 to 4 R on the ring carbons. 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, where 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, where 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 cforms =O, where 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; or Each R d is independently selected from the group consisting of H, D, and C1-C6 alkyl; R 4 is selected from the group consisting of C1-C4 alkyl optionally substituted with 1-4 groups each independently selected from halo, D, and OH, H, and D; R 5 is selected from the group consisting of H, D, halo, CN, and C1-C4 alkyl, where C1-C4 alkyl is optionally substituted with 1 to 4 groups each independently selected from halo and OH; R 6 is H or D, R 7 is H or D).

[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, where 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, where 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 cform =O, where 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, or each R d are independently H or C1-C6 alkyl.

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

[0033] In some embodiments, R 1 is methyl or ethyl, each of which is optionally substituted with 1 to 4 halo.

[0034] In some embodiments, R 1 is methyl or ethyl, each of which is optionally substituted with 1 to 4 halo or D.

[0035] In some embodiments, R 1 is selected from the group consisting of methyl, ethyl, CF3, CH2F and CHF2.

[0036] In some embodiments, R 1 is selected from the group consisting of methyl, ethyl, CD3, CD2H, CDH2, CF3, CH2F and CHF2.

[0037] In some embodiments, R 1 is CHF2.

[0038] In some embodiments, R 1is CD3.

[0039] In some embodiments, R 2 is ring A, methyl, ethyl, CH(OH)CH3, CH2F, CHF2, CH2OH, CH(CH 3) CH2OH, CH2, CH2OH, [ka] is selected from the group consisting of:

[0040] In some embodiments, ring A is [ka] [ka] [ka] [ka] [ka] is selected from the group consisting of:

[0041] In some embodiments, R a is selected from the group consisting of fluoro, chloro, CN, OH, OCH3, methyl, CH2CN, CF3, and CHF2, or two R a forms =O.

[0042] In some embodiments, R 3 are H, methyl, ethyl, CH(OH)CH3, CH2F, CHF2, CH2OH, CH(CH 3) CH2OH, CH2,CH2OH, [ka] is selected from the group consisting of:

[0043] In some embodiments, R c is selected from OH and F.

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

[0045] In some embodiments, R b is selected from the group consisting of OH, F, and CHOH.

[0046] In some embodiments, R 4 are H, methyl, ethyl, CH(OH)CH3, CH2F, CHF2, CH2OH, CH(CH 3) Selected from the group consisting of CH2OH, CH2 and CH2OH.

[0047] In some embodiments, R 4 is C1-C4 alkyl substituted with OH or F.

[0048] In some embodiments, R d is H or methyl.

[0049] In some embodiments, R 5 is selected from the group consisting of H, F, Cl, CN, methyl and CH(OH)CH3.

[0050] In some embodiments, the present disclosure provides a compound represented by the following structural formula (IIa): [ka] or a pharma- ceutically acceptable salt thereof.

[0051] In some embodiments, the present disclosure provides a compound represented by the following structural formula (II): [ka] or a pharma- ceutically acceptable salt thereof.

[0052] In some embodiments, ring A is a 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, where 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.

[0053] In some embodiments, ring A is a 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, where 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.

[0054] In some embodiments, ring A is phenyl 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, where 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.

[0055] 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, where 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.

[0056] In some embodiments, ring A is a 4-10 membered heterocyclyl optionally substituted on ring carbons with 1-3 groups each independently selected from the group consisting of halo, OH, ═O, CN, C1-C4 alkyl, and C1-C4 alkoxy, where 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.

[0057] In some embodiments, ring A is a 4-10 membered heterocyclyl optionally substituted on ring carbons with 1-3 groups each independently selected from the group consisting of D, halo, OH, =O, CN, C1-C4 alkyl, and C1-C4 alkoxy, where 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.

[0058] In some embodiments, ring A is [ka] It is.

[0059] In some embodiments, Ring A is a 4-10 membered heteroaryl optionally substituted on the ring carbons with 1-3 groups each independently selected from the group consisting of halo, OH, ═O, CN, C1-C4 alkyl, and C1-C4 alkoxy, where 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.

[0060] In some embodiments, ring A is a 4-10 membered heteroaryl optionally substituted on the ring carbons with 1-3 groups each independently selected from the group consisting of D, halo, OH, =O, CN, C1-C4 alkyl, and C1-C4 alkoxy, where 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, the present disclosure provides a compound represented by the following structural formula (IIIa): [ka] or a pharma- ceutically acceptable salt thereof.

[0062] In some embodiments, the present disclosure provides a compound represented by the following structural formula (III): [ka] or a pharma- ceutically acceptable salt thereof.

[0063] In some embodiments, Ring B is a 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, where 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 B is a 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, where 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.

[0065] In some embodiments, Ring B is a 4-10 membered heterocyclyl optionally substituted on the ring carbons with 1-3 groups each independently selected from the group consisting of halo, OH, ═O, CN, C1-C4 alkyl, and C1-C4 alkoxy, where 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 B is a 4-10 membered heterocyclyl optionally substituted on the ring carbons with 1-3 groups each independently selected from the group consisting of D, halo, OH, =O, CN, C1-C4 alkyl, and C1-C4 alkoxy, where 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.

[0067] 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 is optionally substituted with 1 to 4 groups each independently selected from the group consisting of halo, OH, CN, and 5- to 6-membered heteroaryl.

[0068] 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 is optionally substituted with 1 to 4 groups each independently selected from the group consisting of D, halo, OH, CN, and 5- to 6-membered heteroaryl.

[0069] In some embodiments, R 3 is selected from the group consisting of H, C1-C4 alkyl, C3-C8 cycloalkyl, and 4-10 membered heterocyclyl, where C1-C4 alkyl, C3-C8 cycloalkyl, and 4-10 membered heterocyclyl are each represented by (R 3When is a 4-10 membered heterocyclyl, it is optionally substituted on the ring carbons with 1 to 3 groups each independently selected from halo and OH.

[0070] In some embodiments, R 3 is selected from the group consisting of H, D, C1-C4 alkyl, C3-C8 cycloalkyl, and 4-10 membered heterocyclyl, where C1-C4 alkyl, C3-C8 cycloalkyl, and 4-10 membered heterocyclyl are each represented by (R 3 When is a 4-10 membered heterocyclyl, it may be substituted on the ring carbons with 1 to 3 groups independently selected from the group consisting of D, halo and OH.

[0071] In some embodiments, R 3 is selected from the group consisting of H, methyl, ethyl, cyclopropyl, and oxetanyl, each of which is (R 3 When is oxetanyl, it may be substituted on the ring carbons with 1 to 3 groups each independently selected from halo and OH.

[0072] In some embodiments, R 3 is selected from the group consisting of H, D, methyl, ethyl, cyclopropyl, and oxetanyl, each of which is (R 3 When is oxetanyl, it may be substituted on the ring carbons with 1 to 3 groups independently selected from the group consisting of D, halo, and OH.

[0073] In some embodiments, R 3 is H.

[0074] In some embodiments, R 3 is D.

[0075] In some embodiments, R 4 is H or CH3.

[0076] In some embodiments, R 4 is selected from the group consisting of H, D and CH3.

[0077] In some embodiments, R 4 is H.

[0078] In some embodiments, R 4 is D.

[0079] 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.

[0080] In some embodiments, R 5 is selected from the group consisting of H, D, halo, CN, methyl and ethyl, wherein methyl and ethyl may be substituted with OH.

[0081] In some embodiments, R 5 is H.

[0082] In some embodiments, R 5 is D.

[0083] In some embodiments, the compound has formula IVa-1 or IVb-1, i.e. [ka] or a pharma- ceutically acceptable salt thereof.

[0084] In some embodiments, the compound is represented by formula IVa or IVb, i.e. [ka] or a pharma- ceutically acceptable salt thereof.

[0085] In some embodiments, the compounds are represented by formulas Va-1, Vb-1, Vc-1, and Vd-1, i.e. [ka] or a pharma- ceutically acceptable salt thereof.

[0086] In some embodiments, R 6 is H. In some embodiments, R 6 is D.

[0087] In some embodiments, R 7 is H. In some embodiments, R 7 is D.

[0088] In some embodiments, the compounds are represented by formulas Va, Vb, Vc, and Vd, i.e. [ka] or a pharma- ceutically acceptable salt thereof.

[0089] In one embodiment, the compound is a compound selected from the table below, or a pharma- ceutically acceptable salt thereof.

[0090] [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8]

Table 3-9

Table 3-10

Table 3-11

Table 3-12

Table 3-13

Table 3-14

Table 3-15

Table 3-16

Table 3-17

Table 3-18

Table 3-19

Table 3-20

Table 3-21

Table 3-22

Table 3-23

Table 3-24

Table 3-25

Table 3-26

Table 3-27

Table 3-28

Table 3-29

Table 3-30

Table 3-31

Table 3-32

Table 3-33

Table 3-34

Table 3-35

Table 3-36

Table 3-37

Table 3-38

Table 3-39

Table 3-40

Table 3-41

Table 3-42

Table 3-43

Table 3-44

Table 3-45

Table 3-46

Table 3-47

Table 3-48

Table 3-49

Table 3-50

Table 3-51

Table 3-52

Table 3-53

Table 3-54

Table 3-55

Table 3-56

Table 3-57

Table 3-58

Table 3-59

[0091] In this specification, [ka] Also contemplated is a compound represented by: or a pharma- ceutically acceptable salt thereof.

[0092] The term "pharmaceutical acceptable salt" refers to a pharmaceutical salt that is suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, and 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, S.M. Berge et al. describes pharmacologically acceptable salts in J. Pharm. Sci., 1977, 66, 1-19.

[0093] The present teachings include pharma- ceutically acceptable salts of the compounds disclosed herein. Compounds having a basic group can form pharma- ceutically acceptable salts with pharma- ceutically acceptable acid(s). Suitable pharma- ceutically 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 pharma- ceutically acceptable salts with pharma- ceutically acceptable base(s). Suitable pharma- ceutically 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).

[0094] Compounds with one or more chiral centers can exist in various stereoisomeric forms, i.e., each chiral center can 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.

[0095] 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 in the chemical name by "R" or "S") or structure (e.g., when the configuration is indicated by a "wedge" bond), the enrichment of the indicated configuration compared to the opposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99% or 99.9% (unless the structure or name is accompanied by the designation "rac" or "racemic", as described in the following two paragraphs). "Enrichment of the indicated configuration compared to the opposite configuration" is a mole percentage 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.

[0096] A racemic mixture is intended when the stereochemical configuration at a chiral center in a compound is indicated by the chemical name (e.g., when the configuration is indicated in the name by "R" or "S") or by the 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.

[0097] 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.

[0098] When a disclosed compound having a chiral center is depicted 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 depicted by its chemical name without indicating the configuration at that chiral center with "S" or "R," the 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.

[0099] A racemic mixture means a mixture that is 50% of one enantiomer and 50% of its corresponding enantiomer. The present teachings encompass all enantiomerically pure, enantiomerically enriched, diastereomerically pure, diastereomerically enriched racemic and diastereomeric mixtures of the compounds disclosed herein.

[0100] Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or stereoisomers by well-known methods, examples of which include 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.

[0101] "Peak 1" in the experimental section refers to a target reaction product compound obtained from chromatographic separation / purification that elutes earlier than a second target reaction product compound from the same aforementioned reaction, which is referred to as "Peak 2."

[0102] If a disclosed compound is designated by a name or structure that denotes 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 named or indicated enantiomer in a mixture divided by the total weight of both enantiomers in the mixture.

[0103] When the stereochemistry of a disclosed compound is designated or depicted by structure, and the 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.

[0104] In the compounds of the present disclosure, any position specifically designated as "D" or "deuterium" is understood to have deuterium enrichment of 50%, 80%, 90%, 95%, 98% or 99%. "Deuterium enrichment" is a molar percentage 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 deuterium enrichment of at least 5%, 10%, 25%, 50%, 80%, 90%, 95%, 98% or 99% at one or more positions not specifically designated as "D" or "deuterium".

[0105] 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 part of the moiety known to one of skill in the art to be available for substitution may 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 suitable substituent for attachment to the moiety.

[0106] 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, selective CDK2 inhibitors have no or low activity against other CDKs and kinomes. The inhibitory activity of selective CDK2 inhibitors against CDK2 is higher than that against other CDKs and many other kinases, and is generally higher than that against other kinases, and is generally higher than that against other kinases, and is generally higher than that against other kinases. 50 value (i.e., IC 50 The potency can be measured using known biochemical assays.

[0107] In some embodiments, the compounds of the present disclosure are selective for CDK2 versus CDK1. In some such embodiments, the compounds exhibit at least 10-fold selectivity for CDK2 versus CDK1. In other embodiments, the compounds exhibit at least 20-fold selectivity for CDK2 versus CDK1. In certain embodiments, the compounds exhibit at least 30-fold selectivity for CDK2 versus CDK1. In certain embodiments, the compounds exhibit at least 40-fold selectivity for CDK2 versus CDK1. In other embodiments, the compounds exhibit at least 50-fold selectivity for CDK2 versus CDK1. For example, the compounds exhibit at least 100-fold selectivity for CDK2 versus CDK1. In some embodiments, the compounds of the present disclosure are selective for CDK2 versus CDK4 and / or CDK6. In some such embodiments, the compounds exhibit at least 10-fold selectivity for CDK2 versus 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.

[0108] 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 by 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 (Clint). The Clint 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 ratio are considered to have good metabolic stability. In some embodiments, the compounds of the present disclosure have a calculated ER of <0.3, <0.4, <0.5, <0.6.

[0109] Pharmaceutical Compositions A pharmaceutical composition of the present disclosure (also referred to herein as the "disclosed pharmaceutical composition") comprises one or more pharma- ceutically acceptable carrier(s) or diluent(s) and a compound of the present disclosure (e.g., a compound of Formula (I) or Formula (Ia)), or a pharma- ceutically acceptable salt thereof.

[0110] "Pharmaceutically acceptable carrier" and "Pharmaceutically acceptable diluent" refer to substances that aid in the formulation and / or administration of an active agent to a subject and / or its absorption by 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, coatings, sweeteners, flavorings, salt solutions (such as Ringer's solution), alcohol, oils, gelatin, carbohydrates (such as lactose, amylose or starch), hydroxymethylcellulose, fatty acid esters, polyvinylpyrrolidine, and coloring agents. Such preparations can be sterilized and, if desired, mixed with auxiliary agents, examples of which include lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring agents and / or aromatic substances, which 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 pharma-ceutically acceptable salts thereof.

[0111] The pharmaceutical compositions of the present disclosure may contain one or more pharma- ceutically 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. thA more complete list of suitable excipients is provided in Remington's Pharmaceutical Sciences (ed., Pharmaceutical Press (2005)). A person skilled in the art would know how to prepare suitable formulations for various types of administration routes. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, 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.

[0112] 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 the compounds disclosed herein, their pharma- ceutically acceptable salts, or pharmaceutical compositions disclosed herein.

[0113] In some embodiments, the disclosure provides a method of treating a disease or disorder associated with CDK2 in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (I) or Formula (Ia) or any formula described herein, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disease or disorder associated with CDK2 is associated with amplification of the cyclin E1 (CCNE1) gene and / or overexpression of CCNE1. In some embodiments, the disease or disorder is cancer.

[0114] 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 subject's lifespan in view of the disease.

[0115] In some embodiments, the present disclosure provides a method for treating a disease / condition / or cancer associated with or regulated by CDK2, where 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 pharma- ceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0116] In another embodiment, the 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 pharma- ceutically 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.

[0117] 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 a control expression level of CCNE1 in a biological sample obtained from the subject or patient.

[0118] In another embodiment, the present disclosure provides a method for inhibiting the proliferation 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 Formula (Ia) or a pharmaceutically acceptable salt thereof. In another embodiment, the present disclosure provides a method for inhibiting the proliferation 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 Formula (Ia) or a pharmaceutically acceptable salt thereof to a subject or patient in need thereof.

[0119] In another embodiment, the 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 pharma- ceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, in combination with other agents or standard cancer treatments, as described below.

[0120] As used herein, "cancer" refers to any malignant and / or invasive growth or tumor caused by abnormal cell proliferation. Cancer includes solid tumors, named for the type of cells that form them, 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 where they began 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 than the latter). In some such embodiments, the cancer is characterized by amplification and / or overexpression of CCNE1 and / or CCNE2.

[0121] 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, metastases of all of the cancers listed (especially brain metastases). 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 identified as having a cancer characterized by amplification and / or overexpression of CCNE1 and / or CCNE2.

[0122] 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 and / or overexpression of CCNE1 and / or CCNE2.

[0123] 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 lung adenosarcoma. In some embodiments, the cancer is characterized by CCNE1 overexpression and / or amplification. In some embodiments, the cancer has progressed despite platinum-based therapy.

[0124] In some embodiments, the cancer is platinum-resistant and / or platinum-refractory, hi some embodiments, the cancer has progressed despite platinum therapy.

[0125] In some embodiments, the disease or disorder associated with CDK2 is an adenocarcinoma, carcinoma or cystadenocarcinoma cystadenocarcinoma.

[0126] 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 exhibiting 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.

[0127] 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 resistant 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 breast cancer has progressed despite a first treatment with palbociclib 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 some embodiments, the breast cancer has CCNE amplification and / or overexpression.

[0128] In some embodiments, the breast cancer is triple-negative breast cancer.

[0129] 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) characterized by amplification and / or overexpression of cyclin E1 (CCNE1) or cyclin E2 (CCNE2), or (c) both (a) and (b). In some such embodiments, the cancer is ovarian cancer.

[0130] In some embodiments, the compounds of the present disclosure are administered as first-line therapy. In other embodiments, the compounds of the present disclosure are administered as second (or later) line therapy. In some embodiments, the compounds of the present disclosure are administered as second (or later) line therapy following treatment with an endocrine therapeutic agent and / or a CDK4 / CDK6 inhibitor. In some embodiments, the compounds of the present disclosure are administered as second (or later) line therapy following treatment with an endocrine therapeutic agent, such as an aromatase inhibitor, a SERM or a SERD. In some embodiments, the compounds of the present disclosure are administered as second (or later) line therapy following treatment with a CDK4 / CDK6 inhibitor. In some embodiments, the compounds of the present disclosure are administered as second (or later) line therapy following treatment with one or more chemotherapy regimens, such as, for example, a taxane or a platinum agent. In some embodiments, the compounds of the present disclosure are administered as second (or later) line therapy following treatment with a HER2-targeted agent (e.g., trastuzumab).

[0131] In some embodiments, the disease or disorder associated with CDK2 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).

[0132] In some embodiments, compounds of the present disclosure can be used to treat sickle cell disease and sickle cell anemia.

[0133] Examples of cancers treatable 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 carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, 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 urethra cancer, renal pelvis carcinoma, central nervous system (CNS) neoplasms, primary CNS lymphomas, tumor angiogenesis, spinal axis tumors, brainstem gliomas, pituitary adenomas, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancers, including asbestos-induced cancers, and combinations of the above cancers.The compounds of the present disclosure are also useful for treating metastatic cancers.

[0134] 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 (MSIhigh). Additionally, the present disclosure includes refractory or recurrent malignant tumors whose growth can be inhibited using the compounds of the present disclosure.

[0135] 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, gastric 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), etc.), DLBCL, mantle cell lymphoma, non-Hodgkin's lymphoma (follicular lymphoma, including relapsed or refractory NHL and relapsed follicular), Hodgkin's lymphoma, or multiple myeloma), and combinations of such cancers.

[0136] In some embodiments, cancers treatable using the 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., hepatocellular carcinoma of the liver (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 cancer, oral cavity cancer, throat cancer, laryngeal cancer, lip cancer, mesothelioma, cervical 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.

[0137] 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).

[0138] In some embodiments, cancers treatable with the compounds of the present disclosure include progressive / recurrent tumors, CCNE1-amplified platinum-resistant or platinum-refractory ovarian cancer, endometrial cancer that has progressed after two or more lines of therapy (previously treated with platinum therapy), gastric cancer that has progressed after two or more lines of therapy (previously treated with platinum therapy), and ER+HER2- breast cancer that has progressed despite CDK4 / 6i. In some embodiments, cancers treatable with the 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 progressive / recurrent tumors not belonging to other groups, ER+HER2- breast cancer that has progressed despite CDK4 / 6i, platinum-resistant or platinum-refractory CCNE1-amplified ovarian cancer, and ER+HER2- breast cancer that has progressed despite CDK4 / 6i.

[0139] In some embodiments, diseases and indications treatable using compounds of the present disclosure include, but are not limited to, blood cancers, sarcomas, lung cancer, gastrointestinal cancer, genitourinary tract cancer, liver cancer, bone cancer, nervous system cancer, gynecological cancer, and skin cancer.

[0140] 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).

[0141] Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdomyosarcoma, fibroma, lipoma, hamartoma, and teratoma.

[0142] Exemplary lung cancers include non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), bronchial carcinoma, squamous cell, small cell undifferentiated, large cell undifferentiated, adenocarcinoma, alveolar epithelial (bronchiolar) carcinoma, bronchial adenoma, chondroitin 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.

[0143] 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, adenoid tumor, lipoma).

[0144] Exemplary liver cancers include hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

[0145] 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 tumor chordoma, osteochondroma (osteochondral exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor.

[0146] Exemplary nervous system cancers include skull cancer (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meningeal cancer (meningioma, meningeal sarcoma, gliomatosis), brain cancer (astrocytoma, medulloblastoma, glioma, brain low-grade glioma (LGG), ependymoma, germinoma (pinealoma), glioblastoma, glioblastoma multiforme (GBM), oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), and spinal cancer (neurofibroma, meningioma, glioma, sarcoma), as well as neuroblastoma and Lhermitte-Dacros disease.

[0147] Exemplary gynecologic cancers include uterine cancer (endometrial carcinoma), 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).

[0148] Exemplary skin cancers include melanoma, basal cell carcinoma, Merkel cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, lenticular dysplastic nevus, lipoma, hemangioma, dermatofibroma, and keloid. 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, cholangiocarcinoma, esophageal cancer, and urothelial carcinoma.

[0149] combination The compounds of the present disclosure may be administered as single agents or in combination with other anti-cancer therapeutics, particularly standard of care agents appropriate for the particular cancer.

[0150] 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.

[0151] In some embodiments, the additional anti-cancer agent is an endocrine agent, such as an aromatase inhibitor, a SERD or a SERM.

[0152] In some embodiments, the additional anticancer agent is a PIK3CA inhibitor, including but not limited to alpelisib (PIQRAY), BEBT-908, BPI-21668, bupallisib, inavolisib, TQB-3525, RLY-2608, milansertib, MEN-1611, LOXO-783, HS-10352, HH-CYH33, gedatolicib, and fimepinostat.

[0153] In some embodiments, the additional anticancer agent is an antibody-drug conjugate, including trastuzumab deruxtecan (Enhertu), trastuzumab duocarmazine, trastuzumab emtansine (Kadcyla), upifitamab rilsodotin, mirvetuximab sorafutansine, tisotumab vedotin (Tivdak), pralzatamab ravtansine, or sacituzumab. These include, but are not limited to, govitecan or sacituzumab govitecan-hziy (Trodelvy), datopotamab deruxtecan, ladiratuzumab vedotin, patritumab deruxtecan, STRO-002, MORab-202, DS-6000, anetumab, avtansine, XMT-2056, and dicitamab vedotin (RC48-ADC, Aidexi).

[0154] In some embodiments, the additional anti-cancer agent is a PLK1 inhibitor, including but not limited to onvansertib, BI2536, BI6727, GSK461364A, TAK960, rigosertib.

[0155] In some embodiments, the additional anti-cancer agent is an estrogen PROTAC (ARV-471, H3B-5942).

[0156] In other embodiments, the compounds of the present disclosure may be administered in combination with standard care agents.In some embodiments, the compounds of the present disclosure may be administered in combination with endocrine therapy, such as drugs 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 invention may be administered in combination with anti-HER2 agents (e.g., trastuzumab or pertuzumab).

[0157] In some embodiments, a compound of the present disclosure (e.g., Formula (I), Formula (Ia), Formula (II), Formula (IIa), Formula (III), Formula (IIIa), Formula (IVa), Formula (IVb), Formula (IVa-1), Formula (IVb-1), Formula (Va), Formula (Vb), Formula (Vc), Formula (Vd), Formula (Va-1), Formula (Vb-1), Formula (Vc-1) or Formula (Vd-1)) or a pharma- ceutically acceptable salt thereof may be administered in combination with an effective amount of carboplatin, ribociclib, fulvestrant, or a combination thereof.

[0158] 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 (Coprexa™), 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 (Selbex™), and UCN01 (Kyowa Hakko). Other examples of antiangiogenic agents include celecoxib (Cerelecbrex™), parecoxib (Dynastat™), dracoxib (SC59046), lumiracoxib (Preige™), valdecoxib (Bextra™), rofecoxib (Vioxx™), iguratimod (Careram™), IP751 (Investdus), SC-58125 (Pharmacia), and etoricoxib (Arcoxia™).Further antiangiogenic agents include excisulind (Aptosyn™), salsalate (Amigesic™), diflunisal (Dolobid™), ibuprofen (Motrin™), ketoprofen (Ordis™), nabumetone (Rilafen™), piroxicam (Feldene™), naproxen (Aleve™, Naprosyn™), diclofenac (Voltaren™), indomethacin (Indocin™), sulindac (Clinoryl™), tolmetin (Tolectin™), etodolac (Lodine™), ketorolac (Toradol™), and oxaprozin (Daypro™). Further anti-angiogenic agents include ABT510 (Abbott), aplatast (TMI005), AZD8955 (AstraZeneca), inciclinide (Metastat™), and PCK3145 (Procyon).

[0159] Further 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.

[0160] Further antiangiogenic agents include acitretin (Neotigasone™), plitidepsin (Aplidine™), cilentide (EMD121974), combretastatin A4 (CA4P), fenretinide (4HPR), halofuginone (Tempostatin™), Panzem™ (2-methoxyestradiol), PF-03446962 (Pfizer), revimastat (BMS275291), catumaxomab (Removab™), lenalidomide (Revlimid™), squalamine (EVIZON™), thalidomide (Thalomid™), Ukraine™ (NSC631570), Vitaxin™ (MEDI522), and zoledronic acid (Zometa™).

[0161] In other embodiments, the additional anticancer agent is a so-called signal transduction inhibitor (e.g., inhibiting the way in which regulatory molecules governing the fundamental processes of cell proliferation, differentiation and survival are transmitted within the cell). 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, Panerb, IGF1R inhibitors, Mec, 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 (SB786034), 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), pertuzumab (Omni targ™), lapatinib (Tycerb™), pelitinib (EKB569), miltefosine (Miltefosine™), BMS599626 (Bristol-Myers Squibb), Lapuleucel-T (Neuvenge™), NeuVax™ (E75 cancer vaccine), Osidem™ (IDM1), mubritinib (TAK-165), CP-724,714 (Pfizer), panitumumab (Vectibix™), ARRY142886 (Array Biopharm), everolimus (Certican™), zotarolimus (Endeavor™), temsirolimus (Trisel™), AP23573 (ARIAD), and VX680 (Vertex), XL647 (Exelixis), sorafenib (Nexavar™), LE-AON (Georgetown University), and GI-4000 (Globermune). Other signal transduction inhibitors include ABT751 (Abbott), alvocidib (flavopiridol), BMS387032 (Bristol Myers), EM1421 (Erimos), indiculam (E7070), seliciclib (CYC200), BIO112 (Onc Bio), BMS387032 (Bristol-Myers Squibb), palbociclib (Pfizer), and AG024322 (Pfizer).

[0162] 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 agents or gene activators, ribonucleases, proteomics, topoisomerase I inhibitors, camptothecin derivatives, topoisomerase II inhibitors, alkylating agents, metabolic antagonists, 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 (VTA) and statins.Examples of classical antitumor agents used in combination therapy with the compounds of the present invention (which may be used in combination with one or more other agents) include glucocorticoids (e.g., dexamethasone, prednisone, prednisolone, methylprednisolone, hydrocortisone, etc.), progestins such as medroxyprogesterone, megestrol acetate (Megaace), mifepristone (RU-486), selective estrogen receptor modulators (SERMs; tamoxifen, raloxifene, lasofoxifene, afimostat, cyclosporine ... xifene, arzoxifene, bazedoxifene, fispemifene, ormeloxifene, ospemifene, tesmilifene, toremifene, trilostane, CHF4227 (Cheisi), etc.), selective estrogen receptor downregulators (SERDs; fulvestrant, LSZ102, G1T48, RAD1901, elaestrant, GDC-9545, gylidestrant, SAR439859, amcenestrant, AZD9833, camizant, LY348 4356, Zn-c5, D-0502, etc.), exemestane (Aromasin), anastrozole (Arimidex), atamestane, fadrozole, letrozole (Femara), formestane; gonadotropin-releasing hormone (GnRH; also commonly known as luteinizing hormone-releasing hormone [LHRH]) agonists (such as buserelin (Suprefact), goserelin (Zoladex), leuprorelin (Lupron), and triptorelin (Trelstar)); These include, but are not limited to, abarelix (Plenaxis), cyproterone, flutamide (Eurexin), megestrol, nilutamide (Nilandrone) and osaterone, dutasteride, epristeride, finasteride, saw palmetto, PHL00801, 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 invention include suberanilide hydroxamic acid (SAHA, Merck Inc. / Aton Pharmaceuticals), depsipeptide (FR901228 or FK228), G2M-777, MS-275, pivaloyloxymethylbutyrate 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, riboflavin ... Can HCl (Camptosar), Lurtotecan, Oracecin (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, Novant Lon (mitoxantrone), pirarubicin, pisanthrone, procarbazine, rebeccamycin, sobuzoxane, tafluposide, valrubicin, Zinecard (dexrazoxane), nitrogen mustard N-oxide, cyclophosphamide, AMD-473, altretamine, AP-5280, apaziquone, brostallicin, bendamustine, busulfan, carboquone, carmustine, chlorambucil, dacarbazine, estramustine, fotemustine, glufosfamide, ifosfamidis These include, but are not limited to, cisplatin, 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, satorplatin), and combinations thereof.

[0163] In yet other embodiments, the additional anticancer drug is a so-called dihydrofolate reductase inhibitor (such as methotrexate and Nutrexin (trimethresate glucuronate)), a purine antagonist (such as 6-mercaptopurine riboside, mercaptopurine, 6-thioguanine, cladribine, clofarabine (Clolar), fludarabine, nelarabine, 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 GPI18180 (Guilford Pharm) Inc), and combinations thereof.

[0164] Other examples of classical antitumor cytotoxic agents include Abraxane (Abraxis BioScience, Inc.), butabulin (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 (Etoposide), cyclosporine (cyclosporine ... These include, but are not limited to, loxatin), taxotere alitretinoin, canfosfamide (Telcyta™), DMXAA (Antisoma), ibandronic acid, L-asparaginase, pegaspargas (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 (Oblimasen, Genta), combretastatin A4P (CA4P), Oxy-4503, AVE-8062, ZD-6126, TZT-1027, atorvastatin (Lipitor, Pfizer Inc.), pravastatin (Pravachol, Bristol-Myers Squibb), lovastatin (Mevacor, Merck Inc.), simvastatin (Zocor, Merck Inc.), fluvastatin (Lescol, Novartis), cerivastatin (Baycor, Bayer), rosuvastatin (Crestor, AstraZeneca), lovostatin, niacin (Advicor, Kos Pharmaceuticals), Caduet, Lipitor, Torcetrapib and combinations thereof.

[0165] 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.

[0166] 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.

[0167] In some embodiments, the additional anti-cancer 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.

[0168] Alternatively, the compounds of the present disclosure, pharma- ceutically acceptable salts thereof, or pharmaceutical compositions disclosed herein can be administered in combination with other anti-cancer agents that are not EGFR inhibitors, e.g., in combination with MEK, examples of which include mutant MEK inhibitors (trametinib, cobimutetinib, binimetinib, selumetinib, refametinib); c-MET, mutant c-Met inhibitors (savolitinib, cabozantinib, foretinib) and MET antibodies (emibetuzumab); mitotic kinase inhibitors (palbociclib, ribavirinib ... CDK4 / 6 inhibitors such as bocilib, abemaciclib, relociclib, trilaciclib, dalpiciclib, BPI-16350; antiangiogenic agents (e.g., bevacizumab, 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, lidforolimus).

[0169] The compound of the present disclosure, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein may be administered in the form of 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 ( For example, it may be administered in combination with a second agent selected from the group consisting of Tagrisso®), gefitinib (e.g., Iressa®), erlotinib (e.g., Tarceva®), ramucirumab (e.g., Cyramza®), an EGFR inhibitor, pralsetinib, ABT-263 (navitoclax), MK-1775 (adavosertib), BAY-1895344, beruzosertib, selarasertib, SRA-737, LY2603618 (ravusertib) and trastuzumab (e.g., Herceptin®), or a combination thereof. EGFR inhibitors include afatinib, osimertinib, lapatinib, erlotinib, dacomitinib, poziotinib, neratinib, gefitinibJBJ-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, resibertinib (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)).

[0170] 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 levels, or phosphorylation levels) to identify human subjects having, suspected of having, or at risk of developing a CDK2-related disease or disorder that is likely to be effective against administration of a CDK2 inhibitor (as used herein, "CDK2 inhibitor" refers to a compound of the present disclosure, or a pharmaceutically acceptable salt thereof).

[0171] 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 Formula (Ia) or a pharma- ceutical acceptable salt thereof.

[0172] CCNE1 is a cell cycle factor essential for cell cycle control 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 No. NM_001238). The amino acid sequence of human CCNE1 is available in GenBank Accession No. NP_001229 / UniProtKB Accession No. P24864).

[0173] In one aspect, the 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 pharma- ceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, wherein the subject has an amplification of the CCNE1 gene 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.

[0174] 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 pharma- ceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0175] 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 disease or disorder associated with CDK2 will respond to a CDK2 inhibitor. In some embodiments, the expression level of CCNE1 may be the level of CCNE1 mRNA. In other embodiments, the expression level of CCNE1 may be the level of CCNE1 protein.

[0176] 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.

[0177] 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.

[0178] Biological samples Biological samples suitable for the methods described herein include any sample containing blood or tumor cells obtained or derived from a human subject in need of treatment.For example, biological samples can include tumor cells 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.

[0179] The biological sample can be obtained from a human subject having, suspected of having, or at risk of developing a disease or disorder associated with CDK2. In some embodiments, the disease or disorder associated with CDK2 is cancer (such as those described above).

[0180] 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 can 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), which preserve or minimize alteration of the molecules in the sample.

[0181] Method of administration 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 characteristics of the subject (such as overall health, age, sex, weight, and tolerance to the drug). Those skilled in the art will be able to determine the appropriate dosage depending on these and other factors. When administered in combination with other therapeutic agents, for example, in combination with an anti-cancer drug, 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 according to the subject's condition, the type of condition(s) being treated, and the amount of compound of formula (I) or formula (Ia) used, for example, by following dosages reported in the literature and recommended in the Physician's Desk Reference (57th Ed., 2003).

[0182] "Treating" or "treatment" refers to obtaining a desired pharmacological and / or physiological effect, which effect is 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; slowing, 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.

[0183] 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).

[0184] As used herein, the terms "administer," "administering," "administration," and the like refer to methods that may 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 may be employed with the agents and methods described herein are described, 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.

[0185] Additionally, the compounds of the present disclosure, their pharma- ceutically acceptable salts, or pharmaceutical compositions of the present disclosure can be co-administered with other therapeutic agents. As used herein, the terms "co-administered" and "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, their pharma- ceutically acceptable salts, or pharmaceutical compositions of the present disclosure will be co-administered with other agents. These terms encompass the administration of two or more agents to a subject, thereby resulting in the simultaneous presence of both agents and / or their metabolites in the subject. They 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, the compounds described herein and the other agent(s) are administered in a single composition. In some embodiments, the compounds described herein and the other agent(s) are mixed in the composition.

[0186] The particular mode of administration and dosage regimen will be selected by the attending clinician, taking into consideration the particulars 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, and in some cases years. However, those skilled in the art will readily recognize appropriate and / or equivalent dosages, looking at the dosages of approved compositions for treating diseases using CDK2 inhibitors disclosed as a guide.

[0187] As will be understood by those skilled in the art, the compounds of the present disclosure or their pharma- ceutically acceptable salts can be administered to patients in various forms depending on the selected administration route.The compounds of the present teachings can be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump or transdermal administration, and by pharmaceutical compositions formulated accordingly.Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, intranasal, pulmonary, intrathecal, rectal and topical modes of administration.Parenteral administration can be by continuous infusion over a selected period of time.

[0188] 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 that is compatible with intravenous, subcutaneous, intramuscular, oral, intranasal or topical administration to humans.In a preferred embodiment, the pharmaceutical composition is formulated for intravenous administration.

[0189] Typically, for oral therapeutic administration, the compounds of the present disclosure, or pharma- ceutically acceptable salts thereof, will be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.

[0190] In general, for parenteral administration, the solution of the compound of the present disclosure or its pharma- ceutically acceptable salt can be prepared in water, generally mixed with a suitable surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycol, DMSO, and mixtures thereof with or without alcohol, and in oils. These preparations contain a preservative to prevent the growth of microorganisms under normal storage and use conditions.

[0191] 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. EXAMPLES

[0192] The following examples are intended to be illustrative and not to limit the scope of the disclosure in any way. Preparation of Exemplary Compounds definition AcOH means acetic acid; t-AmOH means tert-amyl alcohol; Aq. means aqueous solution; Bn means benzyl; Boc, meaning tert-butoxycarbonyl; BocO 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 wide line; Brettphos means 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl; BrettPhos Pd G3 means [(2-di-cyclohexylphosphino-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 Celsius; CDCl3 means deuterated chloroform; Cs2CO3 means cesium carbonate; CuCN means copper cyanide; δ means chemical shift; d means double line; dd means double double line; dq means quadruple doublet; dt means triple doublet; 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 dimethylsulfoxide; DMSO-d6 means hexadeuterodimethylsulfoxide; 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 liters; LCMS means liquid chromatography mass spectrometry; LDA means lithium diisopropylamide; LiAlH4 means lithium aluminum hydride; LiOH means lithium hydroxide; m means multiplet; 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 spectrum 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 charcoal; 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 singlet; 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 compounds 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 materials (reactants), intermediates or products at the temperature at which the reaction is carried out (e.g., temperatures ranging from the freezing point of the solvent to the boiling point of the solvent).A given reaction can be carried out in one solvent or a mixture of more than one solvent.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 necessity of protection and deprotection, and the selection of suitable protecting groups, can be easily determined by those skilled in the art. The chemical nature of protecting groups is described, 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., UV-vis), mass spectrometry (MS), or by chromatographic methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC). Analytical instruments and methods for compound characterization:

[0196] LC-MS: Liquid chromatography mass spectrometry (LC-MS) data was acquired using an Agilent Technologies 1200 Series LCMSD. The LCMSD utilizes API-ESI ionization and is equipped with a (Sunfire C18, 3.5um particle size, 4.6x50mm dimensions) reversed phase column at 50 degrees Celsius. 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 that increased from 5% to 95% organic within 1.3 minutes and was 95% organic for 1.7 minutes. The flow rate was constant at 2mL / min. Alternatively, liquid chromatography mass spectrometry (LC-MS) data was acquired using an Agilent Technologies 1200 Series LCMSD. The LCMSD utilizes API-ESI ionization and is equipped with a (XBridge C18, 3.5um particle size, 4.6x50mm dimensions) reversed phase column at 45 degrees Celsius. The mobile phase consisted of a solvent mixture of 10 mM NH4HCO3 in water and acetonitrile. A constant gradient was used, increasing from 5% to 95% organic in 1.4 min and then 95% organic for 1.6 min. The flow rate was constant at 1.8 mL / min.

[0197] Prep LC-MS: Preparative HPLC was performed on a Gilson 281 preparative system equipped with a Welch Xtimate 10u C18 100A, AXIA packed, 250x21.2mm reversed phase column at 20 degrees Celsius. The mobile phase consisted of a mixture of solvents 0.1% formic acid in water and 0.1% formic acid in acetonitrile. A constant gradient of the mobile phase from 70% water / 30% organic to 30% water / 70% organic over a period of 15 minutes was utilized. The flow rate was constant at 30mL / min. Alternatively, the column (Welch Xtimate 10u C18 21.2x250mm,10um) was equipped and the mobile phase consisted of a mixture of solvents water (10mmol / L NH4HCO3+0.05%NH3.H2O) and acetonitrile. A constant gradient of the mobile phase from 70% water / 30% organic to 30% water / 70% organic over a period of 15 minutes was used. The flow rate was constant at 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: 1H NMR spectra were run on a Bruker AVANCE III 400MHz, 400MHz NMR instrument (acquisition time = 3.16 seconds with 1 second delay; 8-32 scans) or a Bruker AVANCE III 400MHz, 400MHz NMR instrument (acquisition time = 3.98 seconds with 1 second delay; 8-32 scans) or a Bruker AVANCE III 500MHz, 500MHz NMR instrument (acquisition time = 3.17 seconds with 1 second delay; 8-32 scans). Unless otherwise indicated, all protons in DMSO-d6 solvent were reported as parts per million (ppm) relative to residual DMSO (2.50 ppm).

[0200] SFC: Waters fractionation system (SFC80, SFC150, SFC200, SFC350).

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

[0202] Those skilled in the art will recognize that variations in gradients, column lengths and flow rates are possible 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 4]

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

[0205] Compounds of formula (I') may be prepared from compounds of formula (II') and (III') according to process step (a) Buchwald-Hartwig cross coupling. Typical conditions include reaction of an amine of formula (III') with a chloride of formula (II') in the presence of a suitable inorganic base and a suitable catalyst in a suitable solvent at elevated temperature. Preferred conditions include the reaction of compounds of formula (II') and (III') in the presence of BrettPhos Pd G3, tBuBrettPhos Pd G3, BrettPhos Pd G4, tBuBrettPhos Pd G4, t-BuXphos Pd G3, tBuXPhos Pd G4 or Xantphos Pd G3 or Pd2(dba)3 / tBuXPhos in the presence of a suitable base such as Cs2CO3, K2CO3, K3PO4 or KOAc in a suitable solvent such as dioxane, toluene, t-AmOH, NMP or DMF at between 90°C and 130°C.

[0206] According to a second process, compounds of formula (II') may be prepared from compounds of formulae (IV') and (V'), as shown in Scheme 2. [ka]

[0207] A compound of formula (II') (wherein R 3 or R 4 wherein at least one of is H) may be prepared from compounds of formula (IV') and (V') according to process step (b) Mitsunobu reaction. Typical conditions include reaction of compound of formula (IV') and alcohol of formula (V') in the presence of a suitable azodicarboxylate such as DIAD or DEAD in the presence of PPh3 in a suitable solvent such as THF or toluene at between 0°C and 80°C.

[0208] Alternatively, a compound of formula (II') (wherein R 3 and R 4 are not H), may be prepared from compounds of formula (IV') and (V') according to process step (c) alkylation reaction. Typical conditions include reaction of compounds of formula (IV') and (V') in the presence of an acid catalyst such as TfOH in a suitable polar aprotic solvent such as DCM at between 0° C. and room temperature.

[0209] According to a third process, compounds of formula (II') may be prepared from compounds of formulae (IV') and (VI'), as shown in Scheme 3. [ka]

[0210] Compounds of formula (II') may be prepared from compounds of formula (IV') and (VI') by process step (d), an epoxide ring-opening reaction. Typical conditions include reaction of compounds of formula (IV') and (VI') in the presence of a suitable inorganic base, such as K2CO3, in a suitable polar aprotic solvent, such as MeCN, at between room temperature and elevated temperatures (such as 90°C).

[0211] Compounds of formula (II'), (IV'), (V') and (VI') are either commercially available or may be prepared by methods known in the literature or by analogy with the methods described in the experimental section below.

[0212] Compounds of formula (I'), (II') and (IV') may be converted to alternative compounds of formula (I'), (II') and (IV') by standard chemical transformations known to those skilled in the art. Examples of these transformations include, but are not limited to, the following:

[0213] Reduction of ketones to secondary alcohols using NaBH4, fluorination using Selectfluor or DAST, chlorination using NCS in conjunction with HBF4, conversion of aryl iodides to ketones using the Stille method, or conversion of iodo groups to nitriles using CuCN.

[0214] Those skilled in the art will appreciate that the preparation of compounds of formula (I') may require the use of appropriate protecting group strategies. Typical protecting groups may include carbamates, preferably Boc, for the protection of amines, including pyrazoles, or TIPS or benzyl groups for the protection of primary or secondary alcohols.

[0215] It will further be understood that it may be necessary or desirable to carry out the transformations in an order other than that illustrated in the Schemes, or to modify one or more of the transformations to provide desired compounds of the invention.

[0216] preparation Preparation 1 3,6-Dichloro-1H-pyrazolo[3,4-b]pyrazine [ka]

[0217] BF4 (852 mg, 9.71 mmol) was added followed by NCS (864 mg, 6.47 mmol) to a suspension of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (500 mg, 6.47 mmol) in MeCN (12 mL) and the reaction was heated at 90° C. overnight. The cooled mixture was concentrated in vacuo and 1 M NaOH (9.5 mL) was added to neutralize the solution. The resulting suspension was filtered off, washed with water and dried to give the title compound as a pale yellow solid (596 mg). LCMS m / z = 191 [M+H] + .

[0218] Preparation 2 6-Chloro-3-iodo-1H-pyrazolo[3,4-b]pyrazine [ka]

[0219] HBF4 (1.704 g, 194 mmol) and 1-iodopyrrolidine-2,5-dione (2.91 g, 12.9 mmol) were added to a solution of 6-chloro-1H-pyrazole[3,4-b]pyrazine (1.0 g, 6.47 mmol) in MeCN and the reaction was heated to 80° C. for 2 h. The cooled reaction was concentrated in vacuo and the residue was diluted with water, then NaOH (2.5 mL) and sodium thiosulfate were added until the reddish color turned uniformly pale yellow. The mixture was filtered, washed with water and dried to give the title compound (1.71 g, 94% yield). LCMS m / z = 281 [M+H] + .

[0220] Preparation 3 6-Chloro-3-fluoro-1H-pyrazolo[3,4-b]pyrazine [ka]

[0221] A mixture of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (500 mg, 3.23 mmol) and Selectfluor (2.28 g, 6.46 mmol) in MeCN (8 mL) and water (2 mL) was stirred in a sealed tube at 100° C. for 15 h. The cooled reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography on silica gel eluting with EtOAc / PE (1 / 1) to give the title compound as a yellow solid (120 mg, 22% yield). LCMS m / z = 173 [M+H] + .

[0222] Preparation 4 Methyl (2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propanoate [ka]

[0223] A mixture of methyl (S)-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 in vacuo. The residue was purified by flash chromatography on silica gel eluted with EtOAc / PE (1 / 30) to give the title compound as a yellow oil (9.70 g, 53% yield).

[0224] Preparation 5 Methyl (2R)-2-((tetrahydro-2H-pyran-2-yl)oxy)propanoate [ka]

[0225] Following the procedure described in Preparation 4, methyl (R)-2-hydroxypropanoate gave the title compound as a yellow oil (97.7 g, 53%).

[0226] Preparation 6 (2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)pentan-3-ol [ka]

[0227] DIBAL-H (1.5M in toluene, 2.8mL, 4.2mmol) was added dropwise to a mixture of methyl (2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)propanoate (Preparation 4, 700mg, 3.72mmol) in toluene (30mL) under N2 at -78°C and the mixture was stirred at -70°C for 30 minutes. Ethylmagnesium bromide (1.0M in THF, 6.0mL, 6.0mmol) was added and the reaction was stirred at -70°C for 20 minutes and slowly warmed to room temperature. The reaction mixture was poured into ice water and aqueous HCl (10%) was added until all precipitate was dissolved. The aqueous phase was extracted with THF / toluene and the combined organic layers were washed with water, aqueous NaOH (1M) and brine, dried over MgSO4, filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc / PE (1 / 5) to give the title compound as a yellow oil (600 mg, 85% yield).

[0228] Preparation 7 (2R)-2-((tetrahydro-2H-pyran-2-yl)oxy)pentan-3-ol [ka]

[0229] Following the procedure described in Preparation 7, methyl (2R)-2-((tetrahydro-2H-pyran-2-yl)oxy)propanoate (Preparation 5) gave the title compound as a yellow oil (600 mg, 85%).

[0230] Preparation 8 4-Vinyltetrahydro-2H-pyran [ka]

[0231] To a mixture of sodium hydride (2.08 g, 52.5 mmol) in THF (25 mL) was added methyltriphenylphosphanium bromide (18.70 g, 52.5 mmol) and the mixture was heated at reflux for 2 h. After cooling to room temperature, oxane-4-carbaldehyde (5.00 g, 43.8 mmol) was added and the reaction was stirred at room temperature for 15 h. The reaction was diluted with ether and washed with aqueous NaHCO3 and brine. The organic layer was concentrated in vacuo and the residue was purified by flash chromatography on silica gel eluting with EtOAc / PE (1 / 5) to give the title compound as a colorless oil (0.9 g, 18% yield). 1H-NMR(500MHz,DMSO-d6) δ ppm 5.83-5.75(m,1H),5.02-4.93(m,2H),3.85-3.82(m,2H),3.34-3.29(m,2H),2.19-2.14(m,1H),1.32-1.24(m,4H).

[0232] Preparation 9 (S)-1-(tetrahydro-2H-pyran-4-yl)ethane-1,2-diol [ka]

[0233] To a mixture of AD-mix-alpha (12.7 g, 16 mmol) in t-BuOH:H2O 1:1 (150 mL) was added 4-vinyltetrahydro-2H-pyran (Preparation 8, 0.9 g, 8 mmol) at 0 °C and the solution was allowed to warm to room temperature. The reaction was covered with aluminum foil to protect from light and then stirred at room temperature for 2 days. The mixture was cooled to 0 °C, sodium sulfite (15 g) was added and the mixture was stirred at room temperature for 1 h. EtOAc was added, the layers were separated and the aqueous layer was extracted with EtOAc (2x) and DCM:MeOH 10:1. The combined organic layers were dried and evaporated under reduced pressure to give the title compound as a yellow oil (0.6 g, 51% yield). LCMS m / z = 147 [M+H] + .

[0234] Preparation 10 (S)-1-(tetrahydro-2H-pyran-4-yl)-2-((triisopropylsilyl)oxy)ethan-1-ol [ka]

[0235] To a mixture of (1S)-1-(tetrahydro-2H-pyran-4-yl)ethane-1,2-diol (Preparation 9, 600 mg, 4.10 mmol) and 1H-imidazole (830 mg, 12.2 mmol) in DCM (6 mL) was added chlorotris(propan-2-yl)silane (790 mg, 4.10 mmol) at 0° C. and the reaction was stirred at room temperature for 15 h. The reaction mixture was diluted with DCM and washed with water. The organic layer was evaporated in vacuo and the residue was purified by flash chromatography on silica gel eluting with EtOAc / PE (1 / 5) to give the title compound as a yellow oil (0.7 g, 56% yield). LCMS m / z = 303 [M+H] + .

[0236] Preparation 11 2,2-Difluoro-1-(tetrahydro-2H-pyran-4-yl)ethan-1-ol [ka]

[0237] A mixture of tetrahydro-2H-pyran-4-carbaldehyde (500 mg, 4.38 mmol), (difluoromethyl)trimethylsilane (543 mg, 4.38 mmol) and CsF (1.99 g, 13.14 mmol) in DMF (5 mL) was stirred overnight. TBAF (5 eq.) was added and the reaction was stirred at room temperature for 1 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 in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc / PE (1 / 4) to give the title compound (230 mg, 31% yield). LCMS m / z = 167 [M+H] + .

[0238] Preparation 12 1-(Tetrahydro-2H-pyran-3-yl)ethan-1-ol [ka]

[0239] To a solution of tetrahydro-2H-pyran-3-carbaldehyde (500 mg, 4.38 mmol) in THF (20 mL) was added MeMgBr (1 M in THF, 4.4 mL, 4.4 mmol) at 0° C., the reaction was stirred at this temperature for 30 min, then warmed to room temperature and stirred for an additional 2 h. The resulting mixture was quenched with water and extracted with EtOAc. The organic layer was evaporated under reduced pressure to give the crude title compound, which was used directly in the next step.

[0240] Preparation 13 2-(oxiran-2-yl)pyridine [ka]

[0241] To a solution of H2O (25 mL) and dioxane (90 mL) was added 2-ethenylpyridine (14 g, 133 mmol) and AcOH (7.98 g, 133 mmol), then 1-bromopyrrolidine-2,5-dione (25.9 g, 146 mmol) was added slowly and the mixture was stirred for 1 h. Na2CO3 (42.2 g, 399 mmol) was added and the reaction was stirred for 1 h. The mixture was diluted with EtOAc and washed with water. The organic layer was concentrated in vacuo to about 20 mL and then purified by flash chromatography on silica gel eluting with EtOAc / PE (1 / 2) to give the title compound as a yellow oil (14 g, 87%). LCMS m / z = 122 [M+H] + .

[0242] Preparation 14 3-(oxiran-2-yl)pyridine [ka]

[0243] Following the procedure described in Preparation 13, 3-ethenylpyridine gave the title compound as a yellow oil (4 g, 35% yield). LCMS m / z = 122 [M+H] + .

[0244] Preparation 15 2-Fluoro-1-(pyridin-2-yl)ethan-1-ol [ka]

[0245] A mixture of 2-(oxiran-2-yl)pyridine (Preparation 13, 8 g, 66.0 mmol) and 1M TBAF / THF (120 mL) was heated under reflux for 1 day. The cooled reaction mixture was diluted with EtOAc and washed with water. The organic layer was concentrated in vacuo to approximately 20 mL and then purified by flash chromatography on silica gel eluting with EtOAc / PE (1 / 3) to give the title compound as a yellow oil (1 g, 11% yield). LCMS m / z = 142 [M+H] + .

[0246] Preparation 16 2-Fluoro-1-(pyridin-3-yl)ethan-1-ol [ka]

[0247] Following the procedure described in Preparation 15, 3-(oxiran-2-yl)pyridine (Preparation 14) gave the title compound as a yellow oil (120 mg, 3% yield). LCMS m / z = 142 [M+H] + .

[0248] Preparation 17 1-(4-fluoropyridin-3-yl)ethan-1-one [ka]

[0249] Part 1. To a solution of 4-fluoropyridine-3-carboxylic acid (300 mg, 2.12 mmol), methoxy(methyl)amine hydrochloride (310 mg, 3.18 mmol) and DIPEA (548 mg, 4.24 mmol) in DMF (5 mL) was added HATU (965 mg, 2.54 mmol) and the reaction was stirred at room temperature for 15 h. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography on silica gel eluting with EtOAc / PE (1 / 1) to give 4-fluoro-N-methoxy-N-methylnicotinamide (250 mg, 64% yield) as a yellow solid.

[0250] Part 2. To a mixture of 4-fluoro-N-methoxy-N-methylpyridine-3-carboxamide (Part 1, 200 mg, 1.08 mmol) in THF (5 mL) was added MeMgBr (2M in THF, 2.2 mL, 4.4 mmol) at 0° C. and the reaction was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic layer was concentrated and the residue was purified by flash chromatography on silica gel eluting with EtOAc / PE (1 / 1) to give the title compound as a yellow oil (150 mg, 80% yield). LCMS m / z = 140 [M+H] + .

[0251] Preparation 18 1-(4-fluoropyridin-3-yl)ethan-1-ol [ka]

[0252] To a mixture of 1-(4-fluoropyridin-3-yl)ethan-1-one (Preparation 17, 150 mg, 1.07 mmol) in MeOH (4 mL) was added NaBH4 (162 mg, 4.28 mmol) and the reaction was stirred at room temperature for 10 min. The reaction mixture was diluted with EtOAc and washed with water. The organic layer was concentrated in vacuo and the residue was purified by flash chromatography on silica gel eluting with EtOAc / PE (2 / 1) to give the title compound as a yellow oil (100 mg, 66% yield). LCMS m / z = 142 [M+H] + .

[0253] Preparation 19 1-(4-fluoropyridin-2-yl)ethan-1-ol [ka]

[0254] To a solution of 4-fluoropyridine-2-carbaldehyde (2.5 g, 19.9 mmol) in THF (50 mL) at 0° C. was added MeMgBr (2 M in THF, 15 mL, 30 mmol) and the reaction was stirred for 2 h. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic layer was concentrated in vacuo and the residue was purified by flash chromatography on silica gel eluting with EtOAc / PE (2 / 1) to give the title compound as a yellow oil (1.7 g, 64%). LCMS m / z = 142 [M+H] + .

[0255] Preparations 20 and 21 (S)-2-Fluoro-1-phenylethan-1-ol and (R)-2-Fluoro-1-phenylethan-1-ol [ka]

[0256] A mixture of styrene (10.0 g, 96.01 mmol) and Selectfluor reagent (51.0 g, 144.02 mmol) in MeCN / H2O (100 mL / 50 mL) was heated at 90 °C overnight under N2. The reaction mixture was concentrated in vacuo and the residue was extracted with EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel eluted with EtOAc / PE (1 / 20 to 1 / 5) to give 2-fluoro-1-phenylethan-1-ol (2.50 g, 73% yield) as a yellow oil. 1H-NMR (400 MHz, DMSO-d6) δ ppm: 7.40-7.25 (m, 5H), 5.72 (d, 1H), 4.86-4.80 (m, 1H), 4.50-4.01 (m, 2H).

[0257] This is further purified by SFC using a column of OD-H 20x250mm, 10μm (Daicel), mobile phase: CO2 / MeOH (0.2% MeOH / NH3) = 85 / 15 at 70g / min to give:

[0258] Enantiomer 1: (S)-2-fluoro-1-phenylethan-1-ol or (R)-2-fluoro-1-phenylethan-1-ol, 300 mg.

[0259] Enantiomer 2: (R)-2-fluoro-1-phenylethan-1-ol or (S)-2-fluoro-1-phenylethan-1-ol (300 mg).

[0260] Preparation 22 Oxetan-3-yl(phenyl)methanol [ka]

[0261] Phenyllithium (13 mL, 17.4 mmol) was slowly added to a solution of oxetane-3-carbaldehyde (500 mg, 5.80 mmol) in THF (10 mL) under N2 at -78 °C, and the reaction was stirred at -78 °C for 30 min and at room temperature for another 2 h. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic layer was evaporated under reduced pressure to give the title compound (1.2 g, crude).

[0262] Preparation 23 (S)-1-Phenyl-2-((triisopropylsilyl)oxy)ethan-1-ol [ka]

[0263] To a mixture of (S)-1-phenylethane-1,2-diol (1.50 g, 10.8 mmol) and 1H-imidazole (2.20 g, 32.5 mmol) in DMF (10 mL) was added chlorotriisopropylsilane (2.09 g, 10.8 mmol) dropwise at 25° C. and the reaction was stirred overnight. The reaction was diluted with DCM, washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc / PE (1 / 30) to give the title compound as a yellow oil (900 mg, 28% yield).

[0264] Preparation 24 4-((triisopropylsilyl)oxy)butan-2-ol [ka]

[0265] To a mixture of butane-1,3-diol (2 g, 22.1 mmol) and 1H-imidazole (4.51 g, 66.3 mmol) in DCM (30 mL) was added chlorotris(propan-2-yl)silane (4.26 g, 22.1 mmol) at 0° C. and the reaction was stirred at room temperature for 15 h. The reaction mixture was diluted with DCM, washed with water and the organic layer was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc / PE (1 / 5) to give the title compound as a colorless oil (2 g, 37% yield). LCMS m / z = 247 [M+H] + .

[0266] Preparation 25 (S)-1-(pyridin-3-yl)ethane-1,2-diol [ka]

[0267] Following a procedure similar to that described in Preparation 9, 3-vinylpyridine gave the title compound as a yellow oil (700 mg, 38% yield). LCMS m / z = 140 [M+H] + .

[0268] Preparation 26 (S)-1-(pyridin-3-yl)-2-((triisopropylsilyl)oxy)ethan-1-ol [ka]

[0269] Following the procedure described in Preparation 23, (1S)-1-(pyridin-3-yl)ethane-1,2-diol (Preparation 25) gave the title compound as a yellow oil (700 mg, 47% yield). LCMS m / z = 296 [M+H] + .

[0270] Preparation 27 (2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)methanol [ka]

[0271] To a solution of ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropane-1-carboxylate (300 mg, 1.24 mmol) in THF (20 mL) was added LiAlH4 (150 mg, 3.72 mmol) at 0 °C and the reaction was stirred for 18 h. The reaction mixture was quenched with Na2SO4·10H2O, the mixture was filtered and the filtrate was evaporated under reduced pressure to give the title compound (206 mg, crude) as a yellow oil, which was used directly in the next step.

[0272] Preparation 28 Methyl 2-(hydroxymethyl)-4-methyl-4-nitropentanoate [ka]

[0273] To a solution of 2-nitropropane (917 mg, 10.3 mmol) in THF (8 mL) was added DBU (131 mg, 0.861 mmol). After stirring at 65° C. for 10 min, methyl 2-(hydroxymethyl)prop-2-enoate (1 g, 8.61 mmol) was added dropwise. The reaction mixture was stirred at 80° C. for 2 h and then at 25° C. for 16 h. The reaction was diluted with EtOAc, washed with water and brine, and the organic layer was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc / PE (1 / 4) to give the title compound as a yellow oil (900 mg, 51% yield).

[0274] Preparation 29 3-(Hydroxymethyl)-5,5-dimethylpyrrolidin-2-one [ka]

[0275] To a solution of methyl 2-(hydroxymethyl)-4-methyl-4-nitropentanoate (Preparation 28, 350 mg, 1.70 mmol) in EtOH (5 mL) was added Raney Ni (100 mg) and the reaction was stirred at 25° C. under 2 bar H2 for 16 h. The reaction was filtered and the filtrate was evaporated under reduced pressure to give the title compound as a white solid (200 mg, 82% yield). LCMS m / z = 144 [M+H] + .

[0276] Preparation 30 tert-Butyl 3-amino-5-(difluoromethoxy)-1H-pyrazole-1-carboxylate [ka]

[0277] To a solution of 5-(difluoromethoxy)-1H-pyrazol-3-amine (24 g, 64.39 mmol, 40% purity) in DCM (200 mL) was added KOH (4.5 M, 114.47 mL) and Boc2O (28.10 g, 128.77 mmol) and the reaction was heated at 50 °C for 16 h. The reaction mixture was extracted with DCM (40 mL x 3) and the combined organic layers were washed with brine (40 mL x 3), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (ISCO 0-13% EtOAc / PE) to give the title compound as a white solid (5 g, 31.16% yield). 1H NMR (400MHz, DMSO-d6) δ ppm 7.52-7.11 (m, 1H), 6.66 (br s, 2H), 5.12 (s, 1H), 1.52-1.61 (m, 9H).

[0278] Preparation 31 (S)-6-chloro-1-(1-(2-fluoropyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine [ka]

[0279] A mixture of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (400 mg, 2.59 mmol), (R)-1-(2-fluoropyridin-3-yl)ethan-1-ol (438 mg, 3.11 mmol) and PPh3 (815 mg, 2.59 mmol) in THF (8 mL) was cooled in an ice bath. DIAD (628 mg, 3.11 mmol) was added dropwise and the reaction was allowed to warm slowly to room temperature and stirred overnight. The mixture was concentrated in vacuo and the residue was preloaded onto silica gel and purified by Isco chromatography (0 to 60% EtOAc / Hex) to give a colorless oil. This was further purified by reverse phase Isco (0 to 100% MeCN / 0.1% TFA in water). The product was neutralized using NaHCO3 and extracted with DCM (3x). The combined organic extracts were evaporated under reduced pressure to give the title compound as a colorless oil (320 mg, 44.6% yield). LCMS m / z = 278 [M+H] + .

[0280] Preparation 32 (R)-6-Chloro-1-(1-cyclopropylethyl)-1H-pyrazolo[3,4-b]pyrazine [ka]

[0281] A mixture of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (300 mg, 1.94 mmol), (S)-1-cyclopropylethan-1-ol (167 mg, 1.94 mmol) and PPh3 (611 mg, 2.329 mmol) in THF was cooled in an ice bath. DIAD (471 mg, 2.329 mmol) was added dropwise and the reaction was allowed to warm slowly to room temperature. The mixture was concentrated in vacuo and the residue was preloaded onto silica gel and purified by Isco chromatography (0 to 60% EtOAc / Hex) to give a colorless oil. This was further purified by reverse phase Isco (0 to 100% MeCN / 0.1% TFA in water) to give the title compound as a colorless oil (70 mg).

[0282] Preparation 33 (S)-6-Chloro-1-(1-cyclopropylethyl)-1H-pyrazolo[3,4-b]pyrazine [ka]

[0283] Following a procedure similar to that described in Preparation 32, 6-chloro-1H-pyrazolo[3,4-b]pyrazine and (R)-1-cyclopropylethan-1-ol afforded the title compound as a colorless oil (152 mg, 35.2% yield). 1 H NMR (500MHz, CDCl3) δ:8.51(d,1H),8.28(s,1H),4.22(p,1H),1.71(dd,3H),0.70(p,1H),0.41(t,2H),0.35(t,2H).

[0284] Preparation 34 4-((6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)thiazole [ka]

[0285] Following a procedure similar to that described in Preparation 32, 6-chloro-1H-pyrazolo[3,4-b]pyrazine and thiazol-4-ylmethanol gave the title compound as a colorless oil that solidified on standing (242 mg, 49.5% yield). LCMS m / z = 252,253 [M+H] + .

[0286] Preparation 35 5-((6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)thiazole [ka]

[0287] Following a procedure similar to that described in Preparation 32, 6-chloro-1H-pyrazolo[3,4-b]pyrazine and thiazol-5-ylmethanol gave the title compound as a white solid (243 mg, 49.5% yield). LCMS m / z = 252,253 [M+H] + .

[0288] Preparation 36 6-Chloro-1-((2-fluoropyridin-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine [ka]

[0289] A mixture of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (200 mg, 1.294 mmol), (2-fluoropyridin-3-yl)methanol (197 mg, 1.553 mmol) and PPh3 (407 mg, 1.553 mmol) in THF (5 mL) was cooled in an ice bath. DIAD (314 mg, 1.553 mmol) was added dropwise and the reaction was allowed to warm slowly to room temperature. The mixture was concentrated in vacuo and the residue was preloaded onto silica gel and purified by Isco chromatography (0 to 100% EtOAc / Hex) to give the title compound as a colorless oil that solidified on standing (216 mg, 63.5% yield). LCMS m / z = 264 [M+H] + .

[0290] Preparation 37~57

[0291] Following a procedure similar to that described in Preparation 36, the compounds in the following table were prepared from 6-chloro-1H-pyrazolo[3,4-b]pyrazine and the appropriate alcohol. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6]

[0292] Preparation 58~61

[0293] Following a procedure similar to that described in Preparation 36, the compounds in the following table were prepared from 6-chloro-3-iodo-1H-pyrazolo[3,4-b]pyrazine and the appropriate alcohol. [Table 6]

[0294] Preparation 62 (S)-3,6-Dichloro-1-(1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine [ka]

[0295] A mixture of 3,6-dichloro-1H-pyrazolo[3,4-b]pyrazine (300 mg, 1.587 mmol), (R)-1-(pyridin-3-yl)ethan-1-ol (215 mg, 1.746 mmol) and PPh3 (500 mg, 1.905 mmol) in THF (8 mL) was cooled in an ice bath. DIAD (385 mg, 1.905 mmol) was added dropwise and the reaction was allowed to warm slowly to room temperature. The mixture was concentrated in vacuo and the residue was preloaded onto silica gel and purified by Isco chromatography (0 to 40% EtOAc / Hex). The product was further purified by Isco (0-60% EtOAc / DCM) to give the title compound as an off-white solid (230 mg). LCMS m / z = 296 [M+H] + .

[0296] Preparation 63 (S)-3,6-Dichloro-1-(1-(2-fluoropyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine [ka]

[0297] A mixture of 3,6-dichloro-1H-pyrazolo[3,4-b]pyrazine (213 mg, 1.127 mmol), (R)-1-(2-fluoropyridin-3-yl)ethan-1-ol (175 mg, 1.24 mmol) and PPh3 (355 mg, 1.352 mmol) in THF (8 mL) was cooled in an ice bath. DIAD (273 mg, 1.352 mmol) was added dropwise and the reaction was allowed to warm slowly to room temperature. The mixture was concentrated in vacuo and the residue was preloaded onto silica gel and purified by Isco chromatography (0 to 40% EtOAc / Hex) to give the title compound as a white solid (182 mg). LCMS m / z = 314 [M+H] + .

[0298] Preparation 64 4-((6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)pyrrolidin-2-one [ka]

[0299] To a mixture of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (300 mg, 1.94 mmol), 4-(hydroxymethyl)pyrrolidin-2-one (246 mg, 2.135 mmol) and PPh3 (611 mg, 2.329 mmol) in THF (10 mL) was added DIAD (471 mg, 2.329 mmol) dropwise at 0° C. and the reaction was allowed to warm to room temperature. The reaction was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with MeOH / DCM (0 to 5%) to give the title compound as an off-white solid (152 mg). LCMS m / z = 252 [M+H] + .

[0300] Preparation 65 6-Chloro-1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazolo[3,4-b]pyrazine [ka]

[0301] A mixture of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (300 mg, 1.94 mmol), 1,4-dioxaspiro[4.5]decan-8-ol (368 mg, 2.34 mmol) and PPh3 (611 mg, 2.34 mmol) in THF (8 mL) was cooled in an ice bath. DIAD (471 mg, 2.34 mmol) was added dropwise and the reaction was allowed to warm slowly to room temperature. The mixture was concentrated in vacuo and the residue was preloaded onto silica gel and purified by Isco chromatography (0 to 50% EtOAc / Hex) to give the title compound (324 mg) as a colorless oil that crystallized on standing. LCMS m / z = 295 [M+H] + .

[0302] Preparation 66 4-(6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclohexan-1-one [ka]

[0303] To a solution of 6-chloro-1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazolo[3,4-b]pyrazine (Preparation 65, 270 mg, 0.92 mmol) in THF (3 mL) was added 1M HCl (2.75 mL) and the solution was stirred at room temperature overnight. The reaction was heated to 60° C. for 1 h and then cooled to room temperature. The reaction mixture was concentrated in vacuo and the residue was neutralized using aqueous NaHCO3. The resulting suspension was filtered, washed with water and dried to give the title compound as a white solid (194 mg, 77.3%). LCMS m / z = 251 [M+H] + .

[0304] Preparation 67 (1r,4r)-4-(6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclohexan-1-ol [ka]

[0305] To an ice-cold solution of 4-(6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclohexan-1-one (Preparation 66, 160 mg, 0.638 mmol) in MeOH (4 mL) was added NaBH4 (36 mg, 0.957 mmol) and the reaction was stirred for 1 h. The mixture was concentrated in vacuo and saturated aqueous NH4Cl was added, followed by water. The resulting suspension was stirred for several minutes, then filtered, washed with water and sucked dry to give a white solid (130 mg). This was recrystallized from MeCN to give the title compound as white needles (90 mg). LCMS m / z = 253 [M+H] + .

[0306] Preparation 68 3,6-Dichloro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine [ka]

[0307] To a solution of 6-chloro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine (Preparation 87, 209 mg, 0.827 mmol) in MeCN (2 mL) was added NCS (221 mg, 1.654 mmol) and HBF4 (218 mg, 2.481 mmol) and the reaction was heated at 90° C. overnight. The cooled mixture was concentrated in vacuo and the resulting slurry was neutralized with 1M NaOH (150 μL), diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated to give the crude product, which was purified by Isco chromatography (0 to 25% EtOAc / Hex) to give the title compound as a white solid (135 mg, 56.8%). LCMS m / z = 289 [M+H] + .

[0308] Preparation 69 6-Chloro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile [ka]

[0309] To a solution of 6-chloro-3-iodo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine (Preparation 61, 209 mg, 0.552 mmol) in DMSO (1.5 mL) was added CuCN (54 mg, 0.607 mmol) and the reaction was heated at 150° C. for 1.5 h. The cooled mixture was diluted with water and extracted with EtOAc. The biphasic mixture was filtered through Celite® and the filtrate was separated. The organic layer was washed with water, then with brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by Isco chromatography (0 to 40% EtOAc / Hex) to give the title compound as a white solid (62 mg, 40.4%). LCMS m / z = 278 [M+H] + .

[0310] Preparation 70 (S)-6-Chloro-1-(1-(2-fluoropyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile [ka]

[0311] Following the procedure described in Preparation 69, (S)-6-chloro-1-(1-(2-fluoropyridin-3-yl)ethyl)-3-iodo-1H-pyrazolo[3,4-b]pyrazine (Preparation 58) gave the title compound as a white solid (105 mg, 46.7% yield). LCMS m / z = 303 [M+H] + .

[0312] Preparation 71 (S)-6-Chloro-1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine-3-carbonitrile [ka]

[0313] Following the procedure described in Preparation 69, (S)-6-chloro-3-iodo-1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine (Preparation 59) gave the title compound as a white solid (170 mg, 37.9% yield). LCMS m / z = 292 [M+H] + .

[0314] Preparation 72 1-(6-chloro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethan-1-one [ka]

[0315] A mixture of 6-chloro-3-iodo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine (Preparation 61, 1.0 g, 2.64 mmol), tributyl(1-ethoxyvinyl)stannane (1.002 g, 2.77 mmol) and Pd(PPh3)Cl in dioxane (10 mL) 2( A mixture of 1M HCl (93 mg, 0.132 mmol) was stirred at 90° C. overnight. The reaction was cooled to 60° C., 1M HCl (2.6 mL) was added, and the mixture was stirred for 45 min. The mixture was cooled to room temperature, 1M NaOH (2.6 mL) was added, the mixture was diluted with EtOAc, and the layers were separated. The organic layer was washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude product was purified by Isco chromatography (0 to 100% EtOAc / Hex) to afford the title compound as a pale yellow crystalline solid (697 mg, 90% yield). LCMS m / z = 295 [M+H] + .

[0316] Preparation 73 (S)-1-(6-chloro-1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethan-1-one [ka]

[0317] Following the procedure described in Preparation 72, (S)-6-chloro-3-iodo-1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine (Preparation 59) gave the title compound as an off-white solid (634 mg, 80% yield). LCMS m / z = 309 [M+H] + .

[0318] Preparation 74 (S)-1-(6-chloro-1-(1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethan-1-one [ka]

[0319] Following the procedure described in Preparation 72, (S)-6-chloro-3-iodo-1-(1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine (Preparation 60) gave the title compound as a pale yellow crystalline solid (697 mg, 88% yield). LCMS m / z = 302 [M+H] + .

[0320] Preparation 75 1-(6-chloro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethan-1-ol [ka]

[0321] To a solution of 1-(6-chloro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethan-1-one (Preparation 72, 352 mg, 1.194 mmol) in MeOH (7 mL) at -40 °C was added NaBH4 (45 mg, 1.194 mmol) and the reaction was allowed to warm slowly to room temperature. Saturated aqueous NH4Cl and water were added and the mixture was concentrated in vacuo. The resulting aqueous slurry was partitioned between water and DCM, the layers were separated and the organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by Isco chromatography (0 to 100% EtOAc / Hex) to give the title compound as an off-white solid (217 mg, 61.2%). LCMS m / z = 297 [M+H] + .

[0322] Preparation 76 1-(6-chloro-1-((S)-1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethan-1-ol [ka]

[0323] Following a procedure similar to that described in Preparation 75, (S)-1-(6-chloro-1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethan-1-one (Preparation 73) gave the title compound as a colorless viscous oil (412 mg, 81% yield).

[0324] Preparation 77 1-(6-chloro-1-((S)-1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethan-1-ol [ka]

[0325] To a solution of (S)-1-(6-chloro-1-(1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-3-yl)ethan-1-one (Preparation 74, 297 mg, 0.98 mmol) dissolved in MeOH (5 mL) was added NaBH4 (45 mg, 1.18 mmol), cooled in an ice bath, and the reaction was stirred for 20 min. The reaction was quenched with saturated aqueous NH4Cl, then water, and the mixture was extracted with DCM. The combined organic extracts were dried (Na2SO4), filtered, and evaporated under reduced pressure. The crude product was purified by Isco chromatography (0 to 5% MeOH / DCM) to give the title compound as a tan foam (103 mg, 34.4%). LCMS m / z = 304 [M+H] + .

[0326] Preparation 78 4-((6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)tetrahydro-2H-pyran-4-ol [ka]

[0327] A mixture of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (175 mg, 1.132 mmol), 1,6-dioxaspiro[2.5]octane (155 mg, 1.359 mmol) and K2CO3 (313 mg, 2.265 mmol) in MeCN (3 mL) was heated at 90° C. for 2 days. The cooled mixture was diluted with EtOAc, filtered and the filtrate was evaporated under reduced pressure to give the crude product. This was purified by Isco chromatography (0 to 100% EtOAc / Hex) to give 33 mg of 4-((6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)tetrahydro-2H-pyran-4-ol as a colorless oil (which crystallized on standing) and 36 mg of 4-((6-chloro-2H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)tetrahydro-2H-pyran-4-ol as a colorless oil (which crystallized on standing). NOE analysis confirmed the structure assignment. LCMS m / z = 269,270 [M+H] + .

[0328] Preparation 79 6-Chloro-1-(2-cyclopropylpropan-2-yl)-1H-pyrazolo[3,4-b]pyrazine [ka]

[0329] To a solution of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (1.35 g, 8.78 mmol) and 2-cyclopropylpropan-2-ol (440 mg, 4.39 mmol) in DCM (30 ml) was added trifluoromethanesulfonic acid (658 mg, 4.39 mmol) dropwise at 0° C. and the reaction was stirred at 0° C. for 30 min. The reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was concentrated in vacuo and the residue was purified by silica gel chromatography eluting with PE / EtOAc (9 / 1) to give the title compound as a colorless oil (320 mg, 31% yield). 1H-NMR (400MHz, DMSO-d6) δ ppm 8.69 (s, 1H), 8.48 (s, 1H), 1.69 (s, 6H), 1.65-1.58 (m, 1H), 0.42-0.40 (m, 4H).

[0330] Preparation 80 6-Chloro-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyrazine [ka]

[0331] To a mixture of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (200 mg, 1.29 mmol), tetrahydro-2H-pyran-4-ol (197 mg, 1.93 mmol) and PPh3 (506 mg, 1.93 mmol) in THF (10 mL) was added DIAD (390 mg, 1.93 mmol) dropwise at 0° C. and the reaction was stirred overnight at room temperature under N2. 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 in vacuo. The residue was purified by column chromatography on silica gel eluting with EtOAc / PE (1 / 4) to give the title compound as a yellow solid (150 mg, 49% yield). LCMS m / z = 239 [M+H] + .

[0332] Preparation 81 (S)-6-Chloro-1-(1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine [ka]

[0333] To a mixture of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (1.0 g, 6.46 mmol), (R)-1-(pyridin-3-yl)ethan-1-ol (1.19 g, 9.69 mmol) and PPh3 (2.54 g, 9.69 mmol) in THF (30 mL) was added DIAD (1.95 g, 9.69 mmol) dropwise at 0° C. and the reaction was stirred overnight. 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 in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc / PE (1 / 4) to give the title compound as a yellow solid (1.5 g, 89% yield). LCMS m / z = 260 [M+H] + .

[0334] Preparation 82 (S)-6-Chloro-1-(1-(pyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine [ka]

[0335] To a mixture of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (900 mg, 5.82 mmol), (R)-1-(pyridin-2-yl)ethan-1-ol (859 mg, 6.98 mmol) and PPh3 (2.28 g, 8.73 mmol) in THF (20 mL) was added DIAD (1.76 g, 8.73 mmol) dropwise at 0° C. and the reaction was stirred at room temperature overnight. 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 in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc / PE (1 / 5) to give the title compound as a yellow solid (900 mg, 59% yield). LCMS m / z = 260 [M+H] + .

[0336] Preparation 83 6-Chloro-1-(1-(4-fluoropyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine [ka]

[0337] To a mixture of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (200 mg, 1.29 mmol), 1-(4-fluoropyridin-2-yl)ethanol (200 mg, 1.40 mmol) and PPh3 (510 mg, 1.94 mmol) in THF (10 mL) was added DIAD (254 mg, 1.94 mmol) dropwise at 0° C. and the reaction was stirred overnight. 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 in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc / PE (1 / 10) to give the title compound as a yellow solid (120 mg, 29% yield). LCMS m / z = 278 [M+H] + .

[0338] Preparation 84 6-Chloro-1-(2-fluoro-1-(pyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine [ka]

[0339] To a mixture of 2-fluoro-1-(pyridin-2-yl)ethan-1-ol (Preparation 15, 400 mg, 2.83 mmol), 6-chloro-1H-pyrazolo[3,4-b]pyrazine (437 mg, 2.83 mmol) and PPh3 (1.11 g, 4.24 mmol) in THF (10 mL) was slowly added DIAD (857 mg, 4.24 mmol) and the reaction was stirred at room temperature for 15 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 in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc / PE (1 / 1) to give the title compound as a colorless oil (400 mg, 51%). LCMS m / z = 278 [M+H] + .

[0340] Preparation 85 6-Chloro-1-(2-fluoro-1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine [ka]

[0341] To a mixture of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (120 mg, 0.776 mmol), 2-fluoro-1-(pyridin-3-yl)ethan-1-ol (Preparation 16, 109 mg, 0.776 mmol) and PPh3 (304 mg, 1.16 mmol) in toluene (5 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 in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc / PE (2 / 1) to give the title compound as a colorless oil (180 mg, 84% yield). LCMS m / z = 278 [M+H] + .

[0342] Preparation 86 6-Chloro-1-(1-(pyridazin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine [ka]

[0343] To a mixture of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (850 mg, 5.49 mmol), 1-(pyridazin-3-yl)ethan-1-ol (681 mg, 5.49 mmol) and PPh3 (2.15 g, 8.23 ​​mmol) in THF (10 mL) was added DIAD (1.66 g, 8.23 ​​mmol) dropwise at 0° C. and the reaction 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 in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc / PE (1 / 4) to give the title compound as a yellow solid (550 mg, 38% yield). LCMS m / z = 261,263 [M+H] + .

[0344] Preparation 87 6-Chloro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine [ka]

[0345] To a mixture of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (1.0 g, 6.5 mmol), (tetrahydro-2H-pyran-4-yl)methanol (1.13 g, 9.75 mmol) and PPh3 (2.56 g, 9.75 mmol) in THF (30 mL) was added DIAD (1.96 g, 9.75 mmol) at 0° C. and the reaction was stirred at room temperature under N2 overnight. 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 in vacuo. The residue was purified by column chromatography on silica gel eluted with EtOAc / PE (1 / 3) to give the title compound as a white solid (1.57 g, 95% yield). LCMS m / z = 253 [M+H]+.

[0346] Preparation 88 6-Chloro-1-(1-(tetrahydrofuran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine [ka]

[0347] To a mixture of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (200 mg, 3.34 mmol), 1-(tetrahydrofuran-3-yl)ethanol (400 mg, 3.40 mmol) and PPh3 (1.02 g, 3.88 mmol) in THF (10 mL) was added DIAD (508 mg, 3.88 mmol) dropwise at 0° C. and the reaction was stirred at room temperature overnight. 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 in vacuo. The residue was purified by column chromatography on silica gel eluting with EtOAc / PE (1 / 10) to give the title compound as a yellow solid (240 mg, 29% yield). LCMS m / z = 253 [M+H] + .

[0348] Preparation 89 6-Chloro-1-(1-(tetrahydro-2H-pyran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine [ka]

[0349] To a mixture of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (300 mg, 1.94 mmol), PPh3 (760 mg, 2.90 mmol) and 1-(tetrahydro-2H-pyran-3-yl)ethan-1-ol (Preparation 12, 377 mg, 2.90 mmol) in THF (8 mL) was added DIAD (586 mg, 2.90 mmol) at 0° C. and the reaction was stirred overnight. 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 in vacuo. The residue was purified by column chromatography on silica gel eluting with EtOAc / PE (1 / 4) to give the title compound as a yellow oil (323 mg, 62% yield). LCMS m / z = 267 [M+H] + .

[0350] Preparation 90 (S)-6-Chloro-1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine [ka]

[0351] To a mixture of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (250 mg, 1.62 mmol), (R)-1-(tetrahydro-2H-pyran-4-yl)ethan-1-ol (200 mg, 1.70 mmol) and PPh3 (636 mg, 2.43 mmol) in THF (10 mL) was added DIAD (422 mg, 2.43 mmol) dropwise at 0° C. and the reaction was stirred overnight. 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 in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc / PE (1 / 10) to give the title compound as a yellow solid (80 mg, 19% yield). LCMS m / z = 267 [M+H] + .

[0352] Preparation 91 (R)-6-Chloro-1-(1-(tetrahydro-2H-pyran-4-yl)-2-((triisopropylsilyl)oxy)ethyl)-1H-pyrazolo[3,4-b]pyrazine [ka]

[0353] To a mixture of (S)-1-(tetrahydro-2H-pyran-4-yl)-2-((triisopropylsilyl)oxy)ethan-1-ol (Preparation 10, 700 mg, 2.31 mmol), 6-chloro-1H-pyrazolo[3,4-b]pyrazine (357 mg, 2.31 mmol) and PPh3 (907 mg, 3.46 mmol) in toluene (5 mL) was added DIAD (699 mg, 3.46 mmol) at 0° C. and the reaction was stirred at 80° C. for 4 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 in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc / PE (1 / 1) to give the title compound as a yellow oil (700 mg, 69% yield). LCMS m / z = 439 [M+H] + .

[0354] Preparation 92 6-Chloro-1-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)pentan-3-yl)-1H-pyrazolo[3,4-b]pyrazine [ka]

[0355] To a mixture of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (400 mg, 2.59 mmol), (2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)pentan-3-ol (Preparation 6, 730 mg, 3.88 mmol) and PPh3 (784 mg, 3.88 mmol) in THF (10 mL) was added DIAD (1.02 g, 3.88 mmol) dropwise at 0° C., and the reaction was then stirred overnight. 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 in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc / PE (1 / 10) to give the title compound as a yellow solid (180 mg, 21% yield). LCMS m / z = 241 [M-84+H] + .

[0356] Preparation 93 6-Chloro-1-(2,2-difluoro-1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine [ka]

[0357] To a mixture of 2,2-difluoro-1-(tetrahydro-2H-pyran-4-yl)ethan-1-ol (Preparation 11, 200 mg, 1.20 mmol), tetrahydro-2H-pyran-4-ol (185 mg, 1.20 mmol) and PPh3 (471 mg, 1.8 mmol) in THF (10 mL) was added DIAD (363 mg, 1.8 mmol) dropwise at 0° C. and the reaction was stirred overnight. 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 in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc / PE (1 / 4) to give the title compound as a yellow solid (250 mg, 69% yield). LCMS m / z = 303 [M+H] + .

[0358] Preparation 94 trans-rac-2-((6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclopropane-1-carbonitrile [ka]

[0359] Trans-racemic

[0360] To a mixture of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (794 mg, 5.14 mmol), trans-2-(hydroxymethyl)cyclopropane-1-carbonitrile (500 mg, 5.14 mmol) and PPh3 (1.61 g, 6.16 mmol) in toluene (10 mL) was added DIAD (1.24 g, 6.16 mmol) dropwise at 0° C. and the reaction was stirred at 80° C. overnight. 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 in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc / PE (1 / 4) to give the title compound as a white solid (400 mg, 33% yield). LCMS m / z = 234 [M+H] + .

[0361] Preparation 95~182

[0362] To a mixture of 6-chloro-1H-pyrazolo[3,4-b]pyrazine, 6-chloro-3-methyl-1H-pyrazolo[3,4-b]pyrazine or 6-chloro-3-fluoro-1H-pyrazolo[3,4-b]pyrazine (Preparation 3) (1 eq.) (as indicated in the table), the appropriate alcohol (1.0-3.0 eq.) and PPh3 (1.5-2.0 eq.) in THF was added dropwise at 0° C. with DIAD (1.5-2.0 eq.) and the reaction was stirred at room temperature until the starting material was consumed. 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 in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc / PE to give the title compound. [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4]

Table 7-5

Table 7-6

Table 7-7

Table 7-8

Table 7-9

Table 7-10

Table 7-11

Table 7-12

Table 7-13

Table 7-14

Table 7-15

Table 7-16

Table 7-17

Table 7-18

Table 7-19

Table 7-20

Table 7-21

[0363] A-Toluene was the solvent and the reaction was stirred at 80° C. until all starting material was consumed.

[0364] Preparations 183 and 184 trans-rac-1-(1-(1,4-dioxan-2-yl)ethyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazine and cis-rac-1-(1-(1,4-dioxan-2-yl)ethyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazine [ka]

[0365] Trans-racemic and cis-racemic

[0366] DEAD (783 mg, 4.5 mmol) was added dropwise to an ice-cold solution of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (540 mg, 3.5 mmol), 1-(1,4-dioxan-2-yl)ethan-1-ol (400 mg, 3.0 mmol) and PPh3 (917 mg, 3.5 mmol) in THF (10 mL) and the reaction was stirred at 20° C. overnight. 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 in vacuo. The residue was purified by flash chromatography on silica gel (PE:EtOAc=4:1) to provide:

[0367] Product 1: trans-rac-1-(1-(1,4-dioxan-2-yl)ethyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazine or cis-rac-1-(1-(1,4-dioxan-2-yl)ethyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazine (90 mg, 11% yield)

[0368] Product 2: cis-rac-1-(1-(1,4-dioxan-2-yl)ethyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazine or trans-rac-1-(1-(1,4-dioxan-2-yl)ethyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazine (230 mg, 29% yield). LCMS m / z = 269,271 [M+H] + .

[0369] Preparation 185 2-((6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclopropan-1-ol [ka]

[0370] To a solution of 6-chloro-1-((2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyrazine (Preparation 164, 80 mg, 0.239 mmol) in AcOH (2 mL) at 0° C. was added H2O2 (30 wt%, 1 mL) and the reaction was stirred at 25° C. for 18 h. The reaction was concentrated in vacuo and the residue was purified by flash chromatography on silica gel eluting with EtOAc / PE (1 / 5) to give the title compound as a yellow solid (20 mg, 37% yield). LCMS m / z = 225 [M+H] + .

[0371] Preparation 186 6-Chloro-1-(2-(tetrahydro-2H-pyran-4-yl)propan-2-yl)-1H-pyrazolo[3,4-b]pyrazine [ka]

[0372] To a solution of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (426 mg, 2.76 mmol) and 2-(oxan-4-yl)propan-2-ol (200 mg, 1.38 mmol) in DCM (15 mL) was added trifluoromethanesulfonic acid (621 mg, 4.14 mmol) dropwise at 0° C., and the reaction was stirred at 0° C. for 30 min. The reaction mixture was quenched with saturated aqueous NaHCO3, extracted with EtOAc, and the organic layer was concentrated in vacuo. The residue was purified by silica gel chromatography eluting with PE / EtOAc (10 / 1) to give the title compound as a white solid (70 mg, 18% yield). LCMS m / z = 281 [M+H] + .

[0373] Preparation 187 N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)pentan-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0374] A mixture of 6-chloro-1-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)pentan-3-yl)-1H-pyrazolo[3,4-b]pyrazine (Preparation 92, 180 mg, 0.554 mmol), 5-(difluoromethoxy)-1H-pyrazol-3-amine (124 mg, 0.831 mmol), BrettPhos Pd G4 (19.5 mg, 20 μmol) and KOAc (163 mg, 1.66 mmol) in dioxane (5.0 mL) was stirred at 90° C. overnight under N2. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc / PE (1 / 1) to give the title compound as a yellow oil (90 mg, 37% yield). LCMS m / z = 438 [M+H] + .

[0375] Preparation 188 N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((2R)-2-((tetrahydro-2H-pyran-2-yl)oxy)pentan-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0376] The title compound was obtained from 6-chloro-1-((2R)-2-((tetrahydro-2H-pyran-2-yl)oxy)pentan-3-yl)-1H-pyrazolo[3,4-b]pyrazine (Preparation 112) and 5-(difluoromethoxy)-1H-pyrazol-3-amine according to the procedure described in Preparation 187 (80 mg, 66% yield). LCMS m / z = 438 [M+H] + .

[0377] Preparation 189 Methyl (S)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)-2-methylpropanoate [ka]

[0378] Following the procedure described in Preparation 187, methyl (S)-3-(6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)-2-methylpropanoate (Preparation 105) and 5-(difluoromethoxy)-1H-pyrazol-3-amine gave the title compound as a yellow oil (70 mg, 48% yield). LCMS m / z = 368 [M+H] + .

[0379] Preparation 190 (R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(tetrahydro-2H-pyran-4-yl)-2-((triisopropylsilyl)oxy)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0380] A mixture of (R)-6-chloro-1-(1-(tetrahydro-2H-pyran-4-yl)-2-((triisopropylsilyl)oxy)ethyl)-1H-pyrazolo[3,4-b]pyrazine (Preparation 91, 600 mg, 1.36 mmol), 5-(difluoromethoxy)-1H-pyrazol-3-amine (243 mg, 1.63 mmol), KOAc (400 mg, 4.08 mmol) and BrettPhos Pd G4 (100 mg, 0.11 mmol) in dioxane (8 mL) was stirred at 90° C. for 2 h under N2. The cooled reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography on silica gel eluting with EtOAc / PE (2 / 1) to give the title compound as a yellow solid (600 mg, 80% yield). LCMS m / z = 552 [M+H] + .

[0381] Preparation 191 1-(((1r,3r)-3-(benzyloxy)cyclobutyl)methyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0382] A mixture of 1-((trans-3-(benzyloxy)cyclobutyl)methyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazine (Preparation 177, 400 mg, 1.21 mmol), 5-(difluoromethoxy)-1H-pyrazol-3-amine (216 mg, 1.45 mmol), t-BuXPhos Pd G3 (96.6 mg, 12.1 μmol) and KOAc (355 mg, 3.62 mmol) in dioxane (10 mL) under N2 was stirred at 100° C. overnight. The cooled mixture was concentrated in vacuo and the residue was purified by flash chromatography on silica gel eluting with EtOAc / PE (1 / 1) to give the title compound as a yellow solid (350 mg, 65% yield). LCMS m / z = 442 [M+H] + .

[0383] Preparation 192 (R)-6-Chloro-1-((tetrahydrofuran-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine [ka]

[0384] To an ice-cold solution of 6-chloro-1H-pyrazolo[3,4-b]pyrazine (300 mg, 1.94 mmol), R)-(tetrahydrofuran-3-yl)methanol (198 mg, 1.94 mmol) and PPh3 (611 mg, 2.33 mmol) in THF (10 mL) was added DIAD (471 mg, 2.33 mmol). The resulting mixture was slowly warmed until it reached 5° C., at which point the reaction was complete. The reaction mixture was evaporated to dryness in vacuo and the residue was purified by Isco chromatography (0-40% EtOAc / Hex) to give the title compound as a colorless viscous oil (381 mg, 82%). LCMS m / z = 239 [M+H] + .

[0385] Preferred embodiment Example 1

[0386] (S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0387] A mixture of (S)-6-chloro-1-(1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine (Preparation 81, 600 mg, 2.4 mmol), 5-(difluoromethoxy)-1H-pyrazol-3-amine (413 mg, 2.77 mmol), Pd2(dba)3 (423 mg, 0.46 mmol), tBuXPhos (196 mg, 0.46 mmol) and KOAc (453 mg, 4.62 mmol) in dioxane (15 mL) was degassed with N2 (x3) and then heated at 100 °C under N2 overnight. The reaction mixture was cooled to room temperature and concentrated to give a residue that was purified by flash chromatography (SiO2; 50% EtOAc / PE) and then by preparative HPLC-1 to give the title compound as a yellow solid (168 mg, 18%). LCMS m / z = 373 [M+H]+;1H NMR(400MHz,DMSO-d6) δ:12.29(s,1H),10.86(s,1H),8.59(s,1H),8.45(d,1H),8.23(s,1H),8.21(s,1H),7.7 4(d,1H),7.36-7.32(m,1H),7.31(t,1H),6.65-6.60(m,1H),5.92(s,1H),1.92(d,3H).

[0388] Example 2

[0389] N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0390] A mixture of 6-chloro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine (Preparation 87, 780 mg, 3.09 mmol), 5-(difluoromethoxy)-1H-pyrazol-3-amine (554 mg, 3.72 mmol), tBuXphos Pd G3 (150 mg, 0.19 mmol) and KOAc (892 mg, 9.08 mmol) in dioxane (15 mL) was stirred at 90° C. for 6 h under N2. The reaction mixture was evaporated to dryness in vacuo and the residue was purified by preparative HPLC-4 to give the title compound as a white solid (361.4 mg, 32%). LCMS m / z = 366 [M+H] + ; 1 H NMR(400MHz,DMSO-d6) δ:12.21(s,1H),10.82(s,1H),8.19(s,1H),8.17(s,1H),7.32(t,1H),5.98(d,1H),4. 40(d,2H),3.87-3.75(m,2H),3.29-3.16(m,2H),2.24-2.11(m,1H),1.46-1.29(m,4H).

[0391] Example 3

[0392] (1r,4r)-4-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclohexan-1-ol [ka]

[0393] (1r,4r)-4-(6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclohexan-1-ol (Preparation 67, 45 mg, 0.178 mmol), 5-(difluoromethoxy)-1H-pyrazol-3-amine (29 mg, 0.196 mmol) in dioxane (1 mL), tA mixture of BuBrettPhos Pd G3 (7.61 mg, 8.9 mmol) and KOAc (52 mg, 0.534 mmol) was stirred at 90 °C for 1 h. The reaction mixture was evaporated to dryness and the residue was dissolved in DMSO, filtered and purified by reverse phase Isco (0 to 80% MeCN / H2O (+0.1% TFA)). The appropriate fractions were treated with NaHCO3 and extracted with 10% MeOH / DCM (4x). The combined organics were dried (Na2SO4) and evaporated to dryness in vacuo to give the title compound as a pale yellow solid (21.3 mg, 33%). LCMS m / z = 366 [M+H] + ; 1 H NMR(500MHz,DMSO-d6) δ:12.22(s,1H),10.72(s,1H),8.19(s,1H),8.13(s,1H),7.31(t,1H),5.96(s,1H),4. 95-4.82(m,1H),4.69(d,1H),3.61-3.49(m,1H),2.07-1.84(m,6H),1.56-1.41(m,2H).

[0394] Example 4

[0395] (S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(pyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0396] A mixture of (S)-6-chloro-1-(1-(pyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine (Preparation 82, 980 mg, 3.77 mmol), 5-(difluoromethoxy)-1H-pyrazol-3-amine (562 mg, 3.77 mmol), t-BuXPhos Pd G4 (100 mg, 0.126 mmol) and KOAc (1.10 g, 11.3 mmol) in dioxane (10 mL) was stirred at 100° C. overnight under N2. The reaction mixture was cooled to room temperature, concentrated in vacuo and the residue was purified by flash chromatography (SiO2, 4:1 EtOAc / PE) followed by preparative HPLC-1 to give the title compound as a yellow solid (205 mg, 14%). LCMS m / z = 373 [M+H] + ; 1 H NMR(400MHz,DMSO-d6) δ:8.55(d,1H),8.20(s,1H),8.19(s,1H),7.74-7.69(m,1H),7.29(t,1H),7 .28-7.25(m,1H),7.07(d,1H),6.45-6.40(m,1H),5.86(s,1H),1.95(d,3H).

[0397] Examples 5 and 6

[0398] (2S,3R)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)pentan-2-ol and (2S,3S)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)pentan-2-ol [ka]

[0399] To a mixture of N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((2S)-2-((tetrahydro-2H-pyran-2-yl)oxy)pentan-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine (Preparation 187, 90 mg, 0.205 mmol) in DCM (20 mL) at 0° C. was added TFA (200 mg, 2.06 mmol) and the resulting mixture was stirred at 25° C. for 5 h. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by preparative HPLC-1 followed by further purification by chiral-SFC (Daicel IC 20×250 mm, 10 mm; 40% MeOH in CO2 (+0.2% MeOH / NH3)) to give the title compound as a white solid.

[0400] Peak 1, Example 5, (2S,3R)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)pentan-2-ol or (2S,3S)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)pentan-2-ol (17.8 mg): LCMS m / z = 354 [M+H]+; 1H NMR (400MHz, DMSO-d6) δ: 12.19 (br s, 1H), 10.90 (br s,1H),8.22(s,1H),8.18(s,1H),7.31(t,1H),6.01(s,1H),5.06(d,1H),4.60 -4.53(m,1H),4.02-3.98(m,1H),2.14-1.99(m,2H),0.79(d,3H),0.61(t,3H).

[0401] Peak 2, Example 6, (2S,3S)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)pentan-2-ol or (2S,3R)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)pentan-2-ol (6.4 mg): LCMS m / z = 354 [M+H]+ ; 1 H NMR(400MHz,DMSO-d6) δ:12.23(br s,1H),10.92(br s,1H),8.20(s,1H),8.16(s,1H),7.31(t,1H),5.94(s,1H),4.80-4.60( m,2H),4.20-4.00(m,1H),2.10-1.80(m,2H),1.43(d,3H),0.59(t,3H).

[0402] Example 7

[0403] N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((2-fluoropyridin-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0404] 6-chloro-1-((2-fluoropyridin-3-yl)methyl)-1H-pyrazolo[3,4-b]pyrazine (Preparation 36, 65 mg, 0.247 mmol), 5-(difluoromethoxy)-1H-pyrazol-3-amine (40 mg, 0.271 mmol) in dioxane (1 mL), t A mixture of BuBrettPhos Pd G3 (10.5 mg, 12 mmol) and KOAc (73 mg, 0.740 mmol) was stirred at 80 °C overnight. The reaction mixture was evaporated to dryness and the residue was dissolved in DMSO, filtered and purified by reverse phase Isco (0 to 80% MeCN / H2O (+0.1% TFA)). The appropriate fractions were treated with NaHCO3 and extracted with 10% MeOH / DCM (4x). The combined organics were dried (Na2SO4) and evaporated to dryness in vacuo to give the title compound as an off-white solid (33 mg, 36%). LCMS m / z = 376 [M+H] + ; 1H NMR(500MHz,DMSO-d6) δ:12.27(s,1H),10.88(s,1H),8.23(s,1H),8.22(s,1H),8.17(d,1H),7.72-7.63(m,1H),7.47-7.12(m,2H),5.89(s,1H),5.83(s,2H).

[0405] Example 8

[0406] (S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(2-fluoropyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0407] (S)-6-chloro-1-(1-(2-fluoropyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine (Preparation 31, 73 mg, 0.263 mmol), 5-(difluoromethoxy)-1H-pyrazol-3-amine (43 mg, 0.289 mmol) in dioxane (1 mL), t A mixture of BuBrettPhos Pd G3 (11 mg, 13 mmol) and KOAc (77 mg, 0.789 mmol) was stirred at 90 °C for 1 h. The reaction mixture was evaporated to dryness and the residue was dissolved in DMSO, filtered and purified by reverse phase Isco (0 to 80% MeCN / H2O (+0.1% TFA)). The appropriate fractions were treated with NaHCO3 and extracted with 10% MeOH / DCM (4x). The combined organics were dried (Na2SO4) and evaporated to dryness in vacuo to give the title compound as a yellow solid (26 mg, 30%). LCMS m / z = 391 [M+H] + ; 1 H NMR(500MHz,DMSO-d6) δ:12.24(s,1H),10.82(s,1H),8.23(s,1H),8.22(s,1H),8.16(d,1H),7 .91(ddd,1H),7.47-7.12(m,2H),6.65(q,1H),5.95(d,1H),1.89(d,3H).

[0408] Examples 9, 10, 11 and 12

[0409] N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((S)-1-((S)-tetrahydrofuran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine and N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((R)-1-((R)-tetrahydrofuran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine and and N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((R)-1-((S)-tetrahydrofuran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine and N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((S)-1-((R)-tetrahydrofuran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0410] Part 1. A mixture of 6-chloro-1-(1-(tetrahydrofuran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine (Preparation 88, 240 mg, 0.94 mmol), 5-(difluoromethoxy)-1H-pyrazol-3-amine (212 mg, 1.42 mmol), BrettPhos Pd G4 (40 mg, 0.42 mmol) and KOAc (280 mg, 1.42 mmol) in dioxane (5 mL) was stirred at 90° C. overnight under N2. The reaction mixture was cooled to room temperature, evaporated to dryness in vacuo and the residue was purified by flash chromatography on silica gel (50% EtOAc / PE) and then by preparative HPLC-1 to give:

[0411] Intermediate peak 1 (100 mg, 29%) and intermediate peak 2 (130 mg, 37%) as yellow solids.

[0412] Part 2. Middle peak 1 from Part 1 was purified by preparative SFC (Daicel OD; 20x250 mm, 10 mm; 40% MeOH in CO2 (0.2% MeOH / NH3)) to give:

[0413] Peak 1, Example 9, N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((S)-1-((S)-tetrahydrofuran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((R)-1-((R)-tetrahydrofuran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((R)-1-((S)-tetrahydrofuran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((S)-1-((R)-tetrahydrofuran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine (30.5 mg); LCMS m / z = 366 [M+H]+;1H NMR(400MHz,DMSO-d6) δ:12.22(br s,1H),10.93(br s,1H),8.22(s,1H),8.17(s,1H),7.31(t,1H),5.95(s,1H),5.15-5.05(m,1H),3.89-3. 85(m,1H),3.67-3.51(m,3H),2.83-2.77(m,1H),2.83-2.77(m,1H),1.53-1.38(m,5H).

[0414] Peak 2, Example 10, N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((R)-1-((R)-tetrahydrofuran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((S)-1-((S)-tetrahydrofuran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or is N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((R)-1-((S)-tetrahydrofuran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((S)-1-((R)-tetrahydrofuran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine (29.6 mg); LCMS m / z = 366 [M+H]+;1H NMR(400MHz,DMSO-d6) δ:12.22(br s,1H),10.93(br s,1H),8.22(s,1H),8.17(s,1H),7.31(t,1H),5.95(s,1H),5.15-5.05(m,1H),3.89-3. 85(m,1H),3.67-3.51(m,3H),2.83-2.77(m,1H),2.83-2.77(m,1H),1.53-1.38(m,5H).

[0415] Part 3. Middle peak 2 from Part 1 was purified by preparative SFC (Daicel OZ; 20x250 mm, 10 mm; 30% MeOH in CO2 (0.2% MeOH / NH3)) to give:

[0416] Peak 3, Example 11, N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((R)-1-((S)-tetrahydrofuran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((S)-1-((R)-tetrahydrofuran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or is N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((S)-1-((S)-tetrahydrofuran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((R)-1-((R)-tetrahydrofuran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine (45.4 mg); LCMS m / z = 366 [M+H] + ; 1 H NMR(400MHz,DMSO-d6) δ:12.35-11.90(br s,1H),11.05-10.65(br s,1H),8.20(s,1H),8.16(s,1H),7.30(t,1H),5.97(s,1H),5.08-5.03(m,1H),3.80-3.75(m,1H),3.68-3.64(m, 1H),3.35-3.30(m,1H),3.23-3.18(m,1H),2.86-2.83(m,1H),2.10-2.07(m,1H),1.80-1.75(m,1H),1.50(d,3H).

[0417] Peak 4, Example 12, N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((S)-1-((R)-tetrahydrofuran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((R)-1-((S)-tetrahydrofuran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or is N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((S)-1-((S)-tetrahydrofuran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((R)-1-((R)-tetrahydrofuran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine (48.1 mg); LCMS m / z = 366 [M+H] + ; 1 H NMR(400MHz,DMSO-d6) δ:12.35-11.90(br,1H),11.05-10.65(br,1H),8.20(s,1H),8.16(s,1H),7.30(t,1H),5.97(s,1H),5.08-5.03(m,1H),3.80-3.75(m ,1H),3.68-3.64(m,1H),3.35-3.30(m,1H),3.23-3.18(m,1H),2.86-2.83(m,1H),2.10-2.07(m,1H),1.80-1.75(m,1H),1.50(d,3H).

[0418] Examples 13 and 14

[0419] (S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(4-fluoropyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine and (R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(4-fluoropyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0420] A mixture of 6-chloro-1-(1-(4-fluoropyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine (Preparation 147, 120 mg, 0.43 mmol), 5-(difluoromethoxy)-1H-pyrazol-3-amine (96 mg, 0.64 mmol), BrettPhos Pd G4 (20 mg, 0.021 mmol) and KOAc (127 mg, 1.30 mmol) in dioxane (5 mL) was stirred under N2 at 90° C. overnight. The reaction mixture was cooled to room temperature and evaporated to dryness in vacuo. The residue was purified by flash chromatography (SiO2, 50% EtOAc / PE) and then by preparative HPLC-1 to give N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(4-fluoropyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine as a yellow solid (60 mg, 35%). The racemate was separated by chiral preparative SFC (Daicel OX 20x250mm, 10mm; 35% MeOH in CO2 (0.2% MeOH / NH3)) to give the title compound as a white solid.

[0421] Peak 1, Example 13, (S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(4-fluoropyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or (R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(4-fluoropyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine (8.8 mg, 5%). LCMS m / z = 391 [M+H]+;1H NMR(400MHz,DMSO-d6) δ:11.80-11.40(br s,1H),8.21(s,1H),8.20(s,1H),8.15(d,1H),7.92-7.86(m,1H),7.35- 7.32(m,1H),7.33(t,1H),6.62-6.59(m,1H),5.98(s,1H),1.89(d,3H).

[0422] Peak 2, Example 14, (R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(4-fluoropyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or (S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(4-fluoropyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine (8.3 mg, 5%). LCMS m / z = 391 [M+H] + ; 1 H NMR(400MHz,DMSO-d6) δ:12.24(s,1H),10.82(s,1H),8.21(s,1H),8.20(s,1H),8.15(d,1H),7.92-7.86(m ,1H),7.35-7.32(m,1H),7.33(t,1H),6.62-6.59(m,1H),5.98(s,1H),1.89(d,3H).

[0423] Examples 15 and 16

[0424] (R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(2-fluoro-1-(pyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine and (S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(2-fluoro-1-(pyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0425] A mixture of 6-chloro-1-(2-fluoro-1-(pyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine (Preparation 84, 400 mg, 1.44 mmol), 5-(difluoromethoxy)-1H-pyrazol-3-amine (256 mg, 1.72 mmol), KOAc (422 mg, 4.31 mmol) and BrettPhos Pd G4 (80 mg) in dioxane (5 mL) was heated to 90° C. for 2 h. The mixture was concentrated in vacuo and the residue was purified by flash chromatography (SiO 2 , 3:1 EtOAc / PE) to give N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(2-fluoro-1-(pyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine (100 mg, 18%). This was separated by chiral-SFC (Daicel AD-H, 20x250mm, 10mm; 30% MeOH in CO2) to give:

[0426] Peak 1, Example 15, (R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(2-fluoro-1-(pyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or (S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(2-fluoro-1-(pyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine white solid (20.2 mg, 3%): LCMS m / z = 391 [M+H]+; 1H NMR (500MHz, DMSO-d6) δ:12.36(s,1H),10.93(s,1H),8.58(d,1H),8.27(s,1H),7.80-7.70(m,1H),7.36-7.34(m ,1H),7.33(t,1H),7.12-7.10(m,1H),6.92-6.89(m,1H),5.84(s,1H),5.50-5.34(m,2H).

[0427] Peak 2, Example 16, (S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(2-fluoro-1-(pyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or (R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(2-fluoro-1-(pyridin-2-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine white solid (13.2 mg, 2%): LCMS m / z = 391 [M+H] + ; 1 H NMR(500MHz,DMSO-d6) δ:12.36(s,1H),10.92(s,1H),8.59(d,1H),8.27(s,1H),8.23(s,1H),7.73(td,1H),7.33( dd,1H),7.30(t,1H),7.11(d,1H),6.92-6.88(m,1H),5.85-5.83(m,1H),5.48-5.30(m,2H).

[0428] Example 17

[0429] (S)-3-Chloro-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(2-fluoropyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0430] (S)-3,6-dichloro-1-(1-(2-fluoropyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine (Preparation 63, 89 mg, 0.285 mmol), 5-(difluoromethoxy)-1H-pyrazol-3-amine (47 mg, 0.314 mmol) in dioxane (1 mL), tA mixture of BuBrettPhos Pd G3 (12 mg, 14 mmol) and KOAc (84 mg, 0.855 mmol) was stirred at 90° C. for 1 h. The reaction mixture was evaporated to dryness and the residue was dissolved in DCM, filtered and purified by Isco (0-10% MeOH / DCM) to give the title compound as a pale yellow solid (46.4 mg, 38%). LCMS m / z = 425 [M+H] + ;1H NMR(500MHz,DMSO-d6) δ:12.31(s,1H),11.06(s,1H),8.25(s,1H),8.18(d,1H),8.04-7.93(m,1H),7.50-7.11(m,2H),6.67(q,1H),5.99(d,1H),1.87(d,3H).

[0431] Examples 18 and 19

[0432] (S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(2-fluoro-1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine and (R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(2-fluoro-1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0433] A mixture of 6-chloro-1-(2-fluoro-1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine (Preparation 85, 180 mg, 0.65 mmol), 5-(difluoromethoxy)-1H-pyrazol-3-amine (115 mg, 0.78 mmol), KOAc (190 mg, 1.94 mmol) and BrettPhos Pd G4 (40 mg) in dioxane (5 mL) was stirred at 90 °C for 2 h. The mixture was evaporated to dryness in vacuum, and the residue was purified by flash chromatography (SiO2, 3:1 EtOAc / PE) and then by preparative HPLC-1 to give N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(2-fluoro-1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine (ca. 100 mg), which was separated by chiral preparative SFC (Daicel AD, 20x250mm, 10mm; 35% MeOH in CO2 (0.2% MeOH / NH3)) to give the title compound.

[0434] Peak 1, Example 18, (S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(2-fluoro-1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or (R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(2-fluoro-1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine (25.9 mg, 10%): LCMS m / z = 391 [M+H]+; 1H NMR (500MHz, DMSO-d6) δ:12.34(s,1H),10.94(s,1H),8.72(s,1H),8.53-8.50(m,1H),8.30(s,1H),8.22(s,1H),7.8 6(d,1H),7.38(dd,1H),7.33(t,1H),6.96-6.90(m,1H),5.90-5.87(m,1H),5.39-5.05(m,2H).

[0435] Peak 2, Example 19, (R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(2-fluoro-1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or (S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(2-fluoro-1-(pyridin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine (30.7 mg, 12%): LCMS m / z = 391 [M+H]+; 1H NMR (500MHz, DMSO-d6) δ:12.50-11.90(br,1H),11.30-10.85(br,1H),8.72-8.70(m,1H),8.53-8.51(m,1H),8.27(s,1H),8. 19(s,1H),7.86(d,1H),7.39(dd,1H),7.32(t,1H),6.96-6.90(m,1H),5.91(s,1H),5.41-5.05(m,2H).

[0436] Examples 20 and 21

[0437] (S)-4-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)pyrrolidin-2-one and (R)-4-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)pyrrolidin-2-one [ka]

[0438] A mixture of 4-((6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)pyrrolidin-2-one (Preparation 64, 152 mg, 0.60 mmol), 5-(difluoromethoxy)-1H-pyrazol-3-amine (99 mg, 0.66 mmol), KOAc (178 mg, 1.81 mmol) and BrettPhos Pd G4 (26 mg) in dioxane (2 mL) was stirred for 2 h at 90° C. The mixture was diluted with 5% MeOH / DCM and washed with water. The combined organics were dried (Na2SO4) and evaporated to dryness in vacuo and the residue purified by Isco chromatography (SiO2, 0-10% MeOH / DCM) to give 4-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)pyrrolidin-2-one (89 mg, 40%). The racemate was separated by chiral preparative SFC (Daicel AD, 20x250mm, 10mm; 40% MeOH in CO2 (0.2% MeOH / NH3)) to give the title compound.

[0439] Peak 1, Example 20, (S)-4-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)pyrrolidin-2-one or (R)-4-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)pyrrolidin-2-one (yellow solid, 30.5 mg, 68%); LCMS m / z = 365 [M+H] + ; 1 H NMR(500MHz,DMSO-d6) δ:12.64-11.74(br s,1H),11.74-10.38(br s,1H),8.18(s,1H),8.16(s,1H),7.78(s,1H),7.30(t,1H),5.86(s,1H),4.82-4.72(m,1H),4.53(dd ,1H),3.11-3.07(m,1H),2.96-2.92(m,1H),2.89-2.83(m,1H),2.04-1.97(m,1H),1.87-1.79(m,1H).

[0440] Peak 2, Example 21, (R)-4-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)pyrrolidin-2-one or (S)-4-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)pyrrolidin-2-one (yellow solid, 33.2 mg, 74%); LCMS m / z = 365 [M+H] + ; 1 H NMR(500MHz,DMSO-d6) δ:12.35(s,1H),10.85(s,1H),8.18(s,1H),8.17(s,1H),7.78(s,1H),7.30(t,1H,),5.83(s,1H),4.82-4.77(m,1 H),4.53(dd,1H),3.11-3.06(m,1H),2.96-2.92(m,1H),2.89-2.83(m,1H),2.04-1.97(m,1H),1.86-1.81(m,1H).

[0441] Example 22

[0442] (S)-N-(5-Methoxy-1H-pyrazol-3-yl)-1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0443] A mixture of (S)-6-chloro-1-(1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine (Preparation 90, 350 mg, 1.31 mmol), 5-methoxy-1H-pyrazol-3-amine hydrochloride (294 mg, 1.97 mmol), BrettPhos Pd G4 (20 mg, 0.21 mmol) and KOAc (643 mg, 6.56 mmol) in dioxane (10 mL) was stirred at 90° C. overnight under N2. The reaction mixture was cooled to room temperature and evaporated to dryness in vacuo. The residue was purified by flash chromatography (SiO2, 50% EtOAc / PE) and then by preparative HPLC-1 to give the title compound as a white solid (116 mg, 25%). LCMS m / z = 344 [M+H] + ; 1 H NMR(400MHz,DMSO-d6) δ:12.10-11.60(m,1H),10.59(br s,1H),8.16(s,1H),8.12(s,1H),5.62(br s,1H),4.93(s,1H),3.90-3.81(m,1H),3.81(s,3H),3.76-3.71(m,1H),3.30-3.20(m,1H),3.15-3.11(m,1H) ,2.00-1.96(m,1H),1.71-1.66(m,1H),1.47(d,3H),1.40-1.25(m,1H),1.25-1.11(m,1H),0.93-0.85(m,1H).

[0444] Example 23

[0445] 1-(2-Cyclopropylpropan-2-yl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0446] A mixture of 6-chloro-1-(2-cyclopropylpropan-2-yl)-1H-pyrazolo[3,4-b]pyrazine (Preparation 79, 100 mg, 0.422 mmol), 5-(difluoromethoxy)-1H-pyrazol-3-amine (62.9 mg, 0.422 mmol), BrettPhos Pd G4 (64.6 mg, 0.042 mmol) and KOAc (123 mg, 1.26 mmol) in dioxane (2 mL) was degassed with N2 (x3) and heated at 90 °C under N2 for 3 h. The reaction mixture was cooled to room temperature and evaporated to dryness in vacuo. The residue was purified by flash column chromatography (50% EtOAc / PE) and then by preparative HPLC-1 to give the title compound as a yellow solid (25.2 mg, 17%). LCMS m / z = 349 [M+H] + ; 1 H NMR(500MHz,DMSO-d6) δ:12.30-11.48(br,1H),11.06-10.26(br,1H),8.19(s,1H),8.07(s,1H),7 .22(t,1H),6.22(s,1H),1.68(s,6H),1.65-1.62(m,1H),0.36-0.33(m,4H).

[0447] Examples 24 and 25

[0448] (S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(pyridazin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine and (R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(pyridazin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0449] A mixture of 6-chloro-1-(1-(pyridazin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine (Preparation 86, 1.1 g, 4.23 mmol), 5-(difluoromethoxy)-1H-pyrazol-3-amine (693 mg, 4.65 mmol), BrettPhos Pd G4 (195 mg, 0.21 mmol) and KOAc (1.24 g, 12.7 mmol) in dioxane (20 mL) was degassed with N2 (x3) and then heated at 100 °C under N2 overnight. The reaction mixture was cooled to room temperature and evaporated to dryness in vacuo. The residue was purified by flash chromatography (SiO2, 4:1 EtOAc / PE) and then by preparative HPLC-1 to give N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(pyridazin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine (600 mg, 38%). The racemate (600 mg) was separated by chiral-SFC (Daicel AD 20x250 mm, 10 mm; 40% MeOH in CO2 (0.2% MeOH / NH3)) to give the title compound as a white solid.

[0450] Peak 1, Example 24, (S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(pyridazin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or (R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(pyridazin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine (297 mg): LCMS m / z = 374 [M+H] + ; 1 H NMR(400MHz,DMSO-d6) δ:12.29(s,1H),10.88(s,1H),9.15(t,1H),8.25(s,1H),8.23(s,1H),7.63 (dd,1H),7.37(d,1H),7.31(t,1H),6.83(q,1H),5.87(s,1H),2.02(d,3H).

[0451] Peak 2, Example 25, (R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(pyridazin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or (S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(pyridazin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine (269 mg, 89%): LCMS m / z = 374 [M+H] + ; 1 H NMR(400MHz,DMSO-d6) δ:12.28(br s,1H),10.87(br s,1H),9.14(dd,1H),8.24(s,1H),8.22(s,1H),7.62(dd,1H),7.36(dd,1H,),7.30(t,1H),6.83-6.80(m,1H),5.85(s,1H),2.00(d,3H).

[0452] Examples 26 and 27

[0453] (1R,2R)-2-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclopropane-1-carbonitrile and (1S,2S)-2-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclopropane-1-carbonitrile [ka]

[0454] A mixture of trans-rac-2-((6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclopropane-1-carbonitrile (Preparation 94, 370 mg, 1.58 mmol), 5-(difluoromethoxy)-1H-pyrazol-3-amine (235 mg, 1.58 mmol), BrettPhos Pd G4 (145 mg, 0.158 mmol) and KOAc (465 mg, 4.74 mmol) in dioxane (10 mL) was stirred at 100° C. overnight under N2. The reaction mixture was cooled to room temperature and concentrated to give a residue that was purified by flash chromatography (SiO2, 50% EtOAc / PE) and preparative HPLC-1 to give a racemic mixture of the title compounds (200 mg, 36%). The racemic mixture was separated by chiral-SFC (Daicel OD, 20x250mm, 10mm; 30% IPA in CO2 (+0.2% MeOH / NH3)) to give the title compound as a yellow solid.

[0455] Peak 1, Example 26, (1R,2R)-2-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclopropane-1-carbonitrile or (1S,2S)-2-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclopropane-1-carbonitrile (83.6 mg): LCMS m / z = 347 [M+H] + ; 1 H NMR(400MHz,DMSO-d6) δ:12.24(s,1H),10.84(s,1H),8.21(s,1H),8.20(s,1H),7.32(t,1H),5.8 8(s,1H),4.51(d,2H),1.98(m,1H),1.85(m,1H),1.30(m,1H),1.19(m,1H).

[0456] Peak 2, Example 27, (1S,2S)-2-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclopropane-1-carbonitrile or (1R,2R)-2-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclopropane-1-carbonitrile (90.6 mg): LCMS m / z = 347 [M+H] + ; 1 H NMR(400MHz,DMSO-d6) δ:12.25(s,1H),10.84(s,1H),8.21(s,1H),8.20(s,1H),7.32(t,1H),5.88(s,1H),4. 51(d,2H),2.02-1.95(m,1H),1.88-1.83(m,1H),1.33-1.28(m,1H),1.21-1.15(m,1H).

[0457] Examples 28 and 29

[0458] (S)-1-(2,2-difluoro-1-(tetrahydro-2H-pyran-4-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine and (R)-1-(2,2-difluoro-1-(tetrahydro-2H-pyran-4-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0459] A mixture of 6-chloro-1-(2,2-difluoro-1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine (Preparation 93, 230 mg, 0.76 mmol), 5-(difluoromethoxy)-1H-pyrazol-3-amine (113 mg, 0.76 mmol), BrettPhos Pd G4 (165 mg, 0.1 mmol) and KOAc (223 mg, 2.28 mmol) in dioxane (5 mL) was degassed with N2 (x3) and then heated at 90 °C under N2 overnight. The reaction mixture was cooled to room temperature and concentrated to give a residue which was purified by flash column chromatography on silica gel followed by preparative HPLC-3 to give 1-(2,2-difluoro-1-(tetrahydro-2H-pyran-4-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine (150 mg, 48%). The racemic material was separated by chiral-SFC to give the title compound as a yellow solid.

[0460] Peak 1, Example 28, (S)-1-(2,2-difluoro-1-(tetrahydro-2H-pyran-4-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or (R)-1-(2,2-difluoro-1-(tetrahydro-2H-pyran-4-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine (55.4 mg): LCMS m / z = 416 [M+H]+; 1H NMR (400MHz, DMSO-d6) δ: 12.27 (br s, 1H), 10.95 (br s,1H),8.27(s,1H),8.22(s,1H),7.31(t,1H),6.57(dt,1H),5.82(s,1H),5.59-5.55(m,1H),3 .89-3.73(m,2H),3.32-3.19(m,1H),1.84-1.80(m,1H),1.50-1.21(m,3H),1.01-0.97(m,1H).

[0461] Peak 2, Example 29, (R)-1-(2,2-difluoro-1-(tetrahydro-2H-pyran-4-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or (S)-1-(2,2-difluoro-1-(tetrahydro-2H-pyran-4-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine (60.6 mg): LCMS m / z = 416 [M+H] + ; 1 H NMR(400MHz,DMSO-d6) δ:12.27(br s,1H),10.95(br s,1H),8.27(s,1H),8.22(s,1H),7.31(t,1H),6.57(dt,1H),5.82(s,1H),5.59-5.55(m,1H),3 .89-3.73(m,2H),3.32-3.19(m,1H),1.84-1.80(m,1H),1.50-1.21(m,3H),1.01-0.97(m,1H).

[0462] Example 30

[0463] (R)-2-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)-2-(tetrahydro-2H-pyran-4-yl)ethan-1-ol [ka]

[0464] A mixture of (R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(tetrahydro-2H-pyran-4-yl)-2-((triisopropylsilyl)oxy)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine (Preparation 190, 500 mg, 0.906 mmol) and 1M TBAF / THF was heated to reflux for 0.5 h. The reaction mixture was diluted with EtOAc and washed with H2O. The combined organics were evaporated to dryness in vacuo and the residue was purified by flash chromatography (SiO2, 5:1 EtOAc / PE) and then by preparative HPLC-1 to give the title compound as a white solid (250 mg, 70%). LCMS m / z = 396 [M+H] + ; 1 H NMR(400MHz,DMSO-d6) δ:12.16(s,1H),10.75(s,1H),8.19(s,1H),8.17(s,1H),7.30(t,1H),5. 97(s,1H),4.81-4.79(m,1H),4.68-4.65(m,1H),3.94-3.85(m,2H),3.84- 3.81(m,1H),3.72-3.67(m,1H),3.33-3.25(m,1H),3.17-3.11(m,1H),2. 21-2.18(m,1H),1.77-1.74(m,1H),1.45-1.35(m,2H),0.86-0.83(m,1H).

[0465] Example 31

[0466] (R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(2-fluoro-1-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0467] To a mixture of (R)-2-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)-2-(tetrahydro-2H-pyran-4-yl)ethan-1-ol (Example 30, 140 mg, 0.354 mmol) in DCM (2 mL) was added DAST (114 mg, 0.708 mmol) at 0° C., and the resulting mixture was stirred for 2 h. The reaction mixture was diluted with EtOAc, washed with aqueous NaHCO3, and concentrated in vacuo. The residue was purified by preparative HPLC-1 to give the title compound as a white solid (10 mg, 7%). LCMS m / z = 398 [M+H] + ; 1 H NMR(400MHz,DMSO-d6) δ:12.21(br,s,1H),10.84(br s,1H),8.23(s,1H),8.21(s,1H),7.31(t,1H),5.90(s,1H),5.40-5.30( m,1H),5.00-4.97(m,1H),4.89-4.85(m,1H),3.88-3.84(m,1H),3.72-3. 69(m,1H),3.33-3.28(m,1H),3.20-3.12(m,1H),2.21-2.18(m,1H),1.7 7-1.74(m,1H),1.45-1.40(m,1H),1.40-1.35(m,1H),0.86-0.83(m,1H).

[0468] Examples 32 and 33

[0469] (S)-N-(5-methoxy-1H-pyrazol-3-yl)-1-(1-(pyridazin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine and (R)-N-(5-methoxy-1H-pyrazol-3-yl)-1-(1-(pyridazin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0470] A mixture of 6-chloro-1-(1-(pyridazin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine (Preparation 86, 2.0 g, 7.67 mmol), 5-methoxy-1H-pyrazol-3-amine (867 mg, 7.67 mmol), BrettPhos Pd G4 (352 mg, 0.383 mmol) and KOAc (3.00 g, 60.6 mmol) in dioxane (20 mL) was stirred at 100 °C overnight under N2. The reaction mixture was evaporated to dryness in vacuo and the residue was purified by flash chromatography (SiO2, 50% EtOAc / PE) and then by preparative HPLC-1 to give racemic N-(5-methoxy-1H-pyrazol-3-yl)-1-(1-(pyridazin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine (800 mg, 30%). The racemate (800 mg) was separated by chiral-SFC (Daicel AD 20x250 mm, 10 mm; 40% MeOH in CO2 (0.2% MeOH / NH3)) to give the title compound as a yellow solid.

[0471] Peak 1, Example 32, (S)-N-(5-methoxy-1H-pyrazol-3-yl)-1-(1-(pyridazin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or (R)-N-(5-methoxy-1H-pyrazol-3-yl)-1-(1-(pyridazin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine (266 mg): LCMS m / z = 338 [M+H] + ; 1 H NMR(400MHz,DMSO-d6) δ:11.76(br s,1H),10.57(br s,1H),9.14(dd,1H),8.22(s,1H),8.20(s,1H),7.61(dd,1H),7.36(dd,1H),6.70-6.52(m,1H),5.70-5.52(m,1H),3.82(s,3H),2.01(d,3H).

[0472] Peak 2, Example 33, (R)-N-(5-methoxy-1H-pyrazol-3-yl)-1-(1-(pyridazin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or (S)-N-(5-methoxy-1H-pyrazol-3-yl)-1-(1-(pyridazin-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine (346 mg): LCMS m / z = 338 [M+H] + ; 1 H NMR(400MHz,DMSO-d6) δ:11.75(br s,1H),10.58(br s,1H),9.14(dd,1H),8.22(s,1H),8.20(s,1H),7.61(dd,1H),7.36(dd,1H),6.70-6.52(m,1H),5.70-5.52(m,1H),3.82(s,3H),2.01(d,3H).

[0473] Examples 34-140

[0474] Using methods similar to those described for Example 8, the title compounds were prepared from the appropriate amine (amine-1, amine-2 or amine-3), the appropriate chloride (RCl) and the appropriate Pd catalyst system, and purified by ISCO or HPLC as shown in the table below.

[0475] Amine-1: 5-(difluoromethoxy)-1H-pyrazol-3-amine; Amine-2: 5-ethoxy-1H-pyrazol-3-amine; Amine-3: 5-methoxy-1H-pyrazol-3-amine [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

Table 8-13

Table 8-14

Table 8-15

Table 8-16

Table 8-17

Table 8-18

Table 8-19

Table 8-20

Table 8-21

Table 8-22

Table 8-23

Table 8-24

Table 8-25

Table 8-26

Table 8-27

Table 8-28

Table 8-29

Table 8-30

Table 8-31

Table 8-32

Table 8-33

Table 8-34

Table 8-35

Table 8-36

Table 8-37

Table 8-38

Table 8-39

Table 8-40

Table 8-41

Table 8-42

Table 8-43

Table 8-44

Table 8-45

Table 8-46

Table 8-47

Table 8-48

Table 8-49

Table 8-50

Table 8-51

Table 8-52

Table 8-53

Table 8-54

Table 8-55

Table 8-56

[0476] Examples 141 to 197

[0477] Using methods similar to those described in Examples 32 and 33, the title compounds were prepared using the appropriate amine (RNH2) and chloride (RCl) and the appropriate catalyst system as shown in the table below. [Table 9-1] [Table 9-2] [Table 9-3] [Table 9-4] [Table 9-5] [Table 9-6] [Table 9-7] [Table 9-8] [Table 9-9] [Table 9-10] [Table 9-11]

Table 9-12

Table 9-13

Table 9-14

Table 9-15

Table 9-16

Table 9-17

Table 9-18

Table 9-19

Table 9-20

Table 9-21

Table 9-22

Table 9-23

Table 9-24

Table 9-25

Table 9-26

Table 9-27

Table 9-28

[0478] Example 198

[0479] (R)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)-2-methylpropan-1-ol [ka]

[0480] Part 1. A mixture of methyl (R)-3-(6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)-2-methylpropanoate (Preparation 95, 100 mg, 0.39 mmol), 5-(difluoromethoxy)-1H-pyrazol-3-amine (59 mg, 0.39 mmol), t-BuXphos Pd G3 (31 mg, 0.04 mmol) and KOAc (98 mg, 1.0 mmol) in dioxane (3 mL) was stirred at 100 °C for 3 h under N2. The reaction mixture was cooled to room temperature and concentrated to give a residue which was purified by flash column chromatography (SiO2, 0-75% EtOAc / PE) to give (R)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)-2-methylpropanoate (80 mg, 56%). LCMS m / z = 368 [M+H] + .

[0481] Part 2. To a solution of (R)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)-2-methylpropanoate (part 1, 80 mg, 0.22 mmol) in THF (5 mL) at 0 °C, LiAlH4 (17 mg, 0.45 mmol) was added and then stirred at 20 °C for 5 h. The reaction mixture was quenched with MeOH (5 drops) and then concentrated in vacuo. The residue was purified by flash chromatography (SiO2, 30-90% EtOAc / PE) and then by preparative HPLC-1 to give the title compound as a yellow solid (30 mg, 41%). LCMS m / z = 340 [M+H] + ; 1 H NMR(500MHz,DMSO-d6) δ:12.31(br s,1H),10.82(br s,1H),8.19(s,1H),8.15(s,1H),7.29(t,1H),5.93(s,1H),4.90(s,1H) ,4.44-4.30(m,2H),3.39-3.27(m,2H),2.19-2.12(m,1H),0.81(d,3H).

[0482] Example 199

[0483] (S)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)-2-methylpropan-1-ol [ka]

[0484] The title compound was prepared from methyl (S)-3-(6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)-2-methylpropanoate (Preparation 105) and 5-(difluoromethoxy)-1H-pyrazol-3-amine using a two-part procedure similar to that described for Example 198. Purification by preparative HPLC-5 afforded the title compound (46.4 mg, 34%). LCMS m / z = 340 [M+H] + ; 1H NMR(400MHz,DMSO-d6) δ:8.17(s,1H),8.13(s,1H),7.28(t,1H),5.95(s,1H),4.43-4.29(m,2H),3.30-3.26(m,2H),2.16-2.13(m,1H),0.81(d,3H).

[0485] Example 200

[0486] (S)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(piperidin-3-ylmethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0487] Part 1. A mixture of tert-butyl (S)-3-((6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)piperidine-1-carboxylate (Preparation 104, 300 mg, 0.85 mmol), 5-(difluoromethoxy)-1H-pyrazol-3-amine (190 mg, 1.28 mmol), BrettPhos Pd G4 (20 mg, 0.21 mmol) and KOAc (251 mg, 2.56 mmol) in dioxane (5 mL) was stirred at 90 °C overnight under N2. The reaction mixture was cooled to room temperature and concentrated to give a residue which was purified by flash column chromatography (SiO2, 80% EtOAc / PE) to give tert-butyl (S)-3-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)piperidine-1-carboxylate (250 mg, 63%). LCMS m / z = 413 [M+H] + .

[0488] Part 2. To a solution of tert-butyl (S)-3-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)piperidine-1-carboxylate (Part 1, 250 mg, 0.53 mmol) in THF (20 mL) was added TFA (0.5 mL) at 25° C. and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated to dryness in vacuo and the residue was purified by preparative HPLC-4 to give the title compound (24.4 mg, 12%). LCMS m / z = 365 [M+H] + ; 1 H NMR(400MHz,DMSO-d6) δ:8.16(s,1H),8.11(s,1H),7.27(t,1H),6.15-6.12(m,1H),4.58-3.97(m,2H),2.80-2 .60(m,1H),2.49-2.23(m,3H),1.77-1.52(m,2H),1.45-1.32(m,2H),1.20-1.12(m,1H).

[0489] Examples 201 and 202

[0490] (2R,3S)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)pentan-2-ol and (2R,3R)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)pentan-2-ol [ka]

[0491] To a solution of N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((2R)-2-((tetrahydro-2H-pyran-2-yl)oxy)pentan-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine (Preparation 188, 250 mg, 0.53 mmol) in THF (20 mL) was added TFA (0.5 mL) at 25° C., and the resulting reaction mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated to dryness in vacuo, and the residue was purified by preparative HPLC-4 to give the mixture of title compounds (16.0 mg, 12%). The mixture was separated by chiral-SFC (Daicel IC, 20×250 mm, 10 mm; 30% MeOH in CO2 (0.2% MeOH / NH3)) to give the title compounds.

[0492] Peak 1, Example 201, (2R,3S)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)pentan-2-ol or (2R,3R)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)pentan-2-ol (8 mg): LCMS m / z = 354 [M+H]+; 1H NMR (400MHz, DMSO-d6) δ: 12.18 (br s, 1H), 10.91 (br s,1H),8.22(s,1H),8.16(s,1H),7.31(t,1H),6.01-5.99(m,1H),5.06(d,1H),4. 60-4.53(m,1H),4.02-3.98(m,1H),2.14-1.99(m,2H),0.79(d,3H),0.61(t,3H).

[0493] Peak 2, Example 202, (2R,3R)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)pentan-2-ol and (2R,3S)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)pentan-2-ol, white solid (8 mg): LCMS m / z = 354 [M+H] + ; 1 H NMR(400MHz,DMSO-d6) δ:12.18(br s,1H),10.91(br s,1H),8.22(s,1H),8.16(s,1H),7.31(t,1H),6.00(br s,1H),5.06(d,1H),4.70-4.60(m,1H),4.05-3.95(m,1H),2.25-1.90(m,2H),0.79(d,3H),0.61(t,3H).

[0494] Example 203

[0495] (R)-2-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)-2-phenylethan-1-ol [ka]

[0496] Part 1. A mixture of (R)-6-chloro-1-(1-phenyl-2-((triisopropylsilyl)oxy)ethyl)-1H-pyrazolo[3,4-b]pyrazine (Preparation 130, 700 mg, 1.62 mmol), 5-(difluoromethoxy)-1H-pyrazol-3-amine (363 mg, 2.44 mmol), BrettPhos Pd G4 (20 mg, 0.21 mmol) and KOAc (478 mg, 4.87 mmol) in dioxane (20 mL) was stirred at 90 °C overnight under N2. The reaction mixture was cooled to room temperature and concentrated in vacuo to give a residue which was purified by flash column chromatography (SiO2, 66% EtOAc / PE) to give (R)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-phenyl-2-((triisopropylsilyl)oxy)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine as a yellow solid (260 mg, 29%). LCMS m / z = 544 [M+H] + .

[0497] Part 2. A solution of Part 1 compound (250 mg, 0.20 mmol) in TBAF / THF (3 mL) was stirred at room temperature overnight. The reaction mixture was evaporated to dryness and the residue was purified by preparative HPLC-4 to give the title compound as a white solid (116 mg, 62%). LCMS m / z = 388 [M+H] + ; 1 H NMR(400MHz,DMSO-d6) δ:12.21(br s,1H),10.77(br s,1H),8.22(s,1H),8.20(s,1H),7.43-7.23(m,5H),7.31(t,1H),6.23-6.19(m,1H),6.01(br s,1H),5.03(t,1H),4.40-4.35(m,1H),4.08-4.01(m,1H).

[0498] Example 204

[0499] (R)-2-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)-2-(pyridin-3-yl)ethan-1-ol [ka]

[0500] The title compound was prepared from (R)-6-chloro-1-(1-(pyridin-3-yl)-2-((triisopropylsilyl)oxy)ethyl)-1H-pyrazolo[3,4-b]pyrazine (Preparation 137) and 5-(difluoromethoxy)-1H-pyrazol-3-amine using a two-part method similar to that described for Example 203. Purification by preparative HPLC-1 afforded the title compound as a white solid (78.8 mg, 45%). LCMS m / z = 389 [M+H] + ; 1 H NMR(400MHz,DMSO-d6) δ:12.28(s,1H),10.83(s,1H),8.68(d,1H),8.48(dd,1H),8.24(s,1H),8.20(s,1H),7.85(d,1H),7.35( dd,1H),7.32(t,1H),6.39-6.35(m,1H),5.94(s,1H),5.14(t,1H),4.33-4.30(m,1H),4.14-4.08(m,1H).

[0501] Examples 205 and 206

[0502] (S)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)butan-1-ol and (R)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)butan-1-ol [ka]

[0503] The title compound was prepared from 6-chloro-1-(4-((triisopropylsilyl)oxy)butan-2-yl)-1H-pyrazolo[3,4-b]pyrazine (Preparation 167) and 5-(difluoromethoxy)-1H-pyrazol-3-amine using a two-part method similar to that described for Example 203. Preparative HPLC-1 followed by preparative SFC (Daicel OZ 20x250mm, 10mm; 20% MeOH in CO2 (0.2% MeOH / NH3).

[0504] Peak 1, Example 205, (S)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)butan-1-ol or (R)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)butan-1-ol, white solid; LCMS m / z = 340 [M+H]+; 1H NMR (500MHz, DMSO-d6) δ: 12.23 (br s, 1H), 10.79 (br s,1H),8.19(s,1H),8.15(s,1H),7.29(t,1H),5.96(s,1H),5.25-5.19(m,1H),4.66 -4.60(m,1H),3.33-3.24(m,1H),3.18-3.10(m,1H),2.06-1.90(m,2H),1.49(d,3H).

[0505] Peak 2, Example 206, (R)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)butan-1-ol or (S)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)butan-1-ol, white solid; LCMS m / z = 340 [M+H] + ; 1H NMR(400MHz,DMSO-d6) δ:12.22(s,1H),10.77(s,1H),8.19(s,1H),8.16(s,1H),7.29(t,1H),5.95(s,1H),5. 25-5.19(m,1H),3.33-3.24(m,1H),3.18-3.10(m,1H),2.06-1.90(m,2H),1.49(d,3H).

[0506] Examples 207, 208, 209 and 210

[0507] (1S,3R)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclopentan-1-ol and (1R,3S)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclopentan-1-ol and and (1R,3R)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclopentan-1-ol and (1S,3S)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclopentan-1-ol [ka]

[0508] Part 1. A mixture of 3-(6-chloro-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclopentan-1-ol (Preparation 132, 200 mg, 0.837 mmol), 5-(difluoromethoxy)-1H-pyrazol-3-amine (124 mg, 0.837 mmol), t-BuXPhos Pd G3 (66.5 mg, 0.0837 mmol) and KOAc (246 mg, 2.51 mmol) in dioxane (10 mL) was degassed with N2 (3x) and then heated at 100 °C under N2 for 3 h. The reaction mixture was cooled to room temperature and concentrated to give a residue that was purified by flash column chromatography on silica gel (80% EtOAc / PE) to give a residue that was further purified by preparative HPLC-3 to give intermediate 1 (150 mg, 50%) and intermediate 2 (50 mg, 16%).

[0509] Part 2. Intermediate 1 was further purified by chiral-SFC (Daicel IG, 20x250mm, 10mm; 25% MeOH in CO2 (0.2% MeOH / NH3)) to give peak 1 and peak 2 as yellow solids.

[0510] Peak 1, Example 207, (1S,3R)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclopentan-1-ol or (1R,3S)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclopentan-1-ol or is (1R,3R)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclopentan-1-ol or (1S,3S)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclopentan-1-ol (51.4 mg); LCMS m / z = 352 [M+H] + ; 1H NMR(400MHz,DMSO-d6) δ:12.27(s,1H),10.74(s,1H),8.19(s,1H),8.15(s,1H),7.31(t,1H),5.93(s,1H),5.67-5.63(m,1H),4.74(d,1H) ,4.43-4.40(m,1H),2.34-2.25(m,1H),2.23-2.15(m,1H),2.15-2.01(m,2H),1.95-1.90(m,1H),1.65-1.60(m,1H).

[0511] Peak 2, Example 208, (1R,3S)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclopentan-1-ol or (1S,3R)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclopentan-1-ol or or (1R,3R)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclopentan-1-ol or (1S,3S)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclopentan-1-ol (63 mg); LCMS m / z = 352 [M+H] + ; 1 H NMR(400MHz,DMSO-d6) δ:12.27(s,1H),10.74(s,1H),8.19(s,1H),8.15(s,1H),7.31(t,1H),5.93(s,1H),5.67-5.63(m,1H),4.74(d,1H) ,4.43-4.40(m,1H),2.34-2.25(m,1H),2.23-2.15(m,1H),2.15-2.01(m,2H),1.95-1.90(m,1H),1.65-1.60(m,1H).

[0512] Part 3. Intermediate 2 was further purified by chiral-SFC (Daicel IG, 20x250mm, 10mm; 20% MeOH in CO2 (0.2% MeOH / NH3)) to give peak 3 and peak 4 as yellow solids.

[0513] Peak 3, Example 209, (1R,3R)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclopentan-1-ol or (1S,3S)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclopentan-1-ol or is (1S,3R)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclopentan-1-ol or (1R,3S)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclopentan-1-ol (16.7 mg); LCMS m / z = 352 [M+H]+;1H NMR(400MHz,DMSO-d6) δ:12.25(br s,1H),10.95(br s,1H),8.19(s,1H),8.16(s,1H),7.31(t,1H),5.89(s,1H),5.37(m,1H),4. 99(s,1H),4.25(s,1H),2.42(m,1H),2.20(m,1H),2.03(m,2H),1.80(m,2H).

[0514] Peak 4, Example 210, (1S,3S)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclopentan-1-ol or (1R,3R)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclopentan-1-ol or is (1S,3R)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclopentan-1-ol or (1R,3S)-3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclopentan-1-ol (17.4 mg); LCMS m / z = 352 [M+H] + ; 1 H NMR(400MHz,DMSO-d6) δ:12.25(br s,1H),10.95(br s,1H),8.19(s,1H),8.16(s,1H),7.31(t,1H),5.89(s,1H),5.37(s,1H),4. 99(s,1H),4.25(s,1H),2.42(m,1H),2.20(m,1H),2.03(m,2H),1.80(m,2H).

[0515] Examples 211, 212, 213 and 214

[0516] 1-((S)-1-((R)-1,4-dioxan-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine and 1-((S)-1-((S)-1,4-dioxan-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine and 1-((R)-1-((R)-1,4-dioxan-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine and 1-((R)-1-((S)-1,4-dioxan-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0517] Part 1. A mixture of trans-rac-1-(1-(1,4-dioxan-2-yl)ethyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazine or cis-rac-1-(1-(1,4-dioxan-2-yl)ethyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazine (product 1, preparations 183 and 184, 100 mg, 0.37 mmol), 5-(difluoromethoxy)-1H-pyrazol-3-amine (75 mg, 0.5 mmol), BrettPhos Pd G4 (92 mg, 0.1 mmol) and KOAc (80 mg, 0.8 mmol) in dioxane (3 mL) was stirred at 100° C. for 2 h under N2. The reaction mixture was cooled to room temperature and evaporated to dryness in vacuo to give a residue which was purified by flash column chromatography on silica gel (10:1 PE / EtOAc) to give intermediate A as a yellow solid (50 mg, 35%). LCMS m / z = 382 [M+H]+.

[0518] Part 2. Using a method similar to that described in Part 1 above, intermediate B was prepared from a mixture of cis-rac-1-(1-(1,4-dioxan-2-yl)ethyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazine or trans-rac-1-(1-(1,4-dioxan-2-yl)ethyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazine (product 2, preparations 183 and 184) and 5-(difluoromethoxy)-1H-pyrazol-3-amine (yellow solid, 210 mg, 42%). LCMS m / z = 382 [M+H]+.

[0519] Part 3. Intermediate A (Part 1) was separated by chiral-SFC (Daicel OJ, 20x250 mm, 10 mm; 15% MeOH in CO2 (0.2% MeOH / NH3)) to give:

[0520] Peak 1, Example 211, 1-((S)-1-((S)-1,4-dioxan-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or 1-((R)-1-((R)-1,4-dioxan-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or is 1-((S)-1-((R)-1,4-dioxan-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or 1-((R)-1-((S)-1,4-dioxan-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine (15.2 mg); LCMS m / z = 382 [M+H] + ; 1H NMR(400MHz,DMSO-d6) δ:12.31(br s,1H),10.88(br s,1H),8.22(s,1H),8.20(s,1H),7.31(t,1H),5.95(s,1H),5.18(s,1H),3.89-3.81(m,2H) ,3.67-3.58(m,2H),3.45-3.38(m,1H),3.27-3.20(m,1H),3.14-3.09(m,1H),1.53(d,3H).

[0521] Peak 2, Example 212, 1-((R)-1-((R)-1,4-dioxan-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or 1-((S)-1-((S)-1,4-dioxan-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or is 1-((S)-1-((R)-1,4-dioxan-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or 1-((R)-1-((S)-1,4-dioxan-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine (44.9 mg); LCMS m / z = 382 [M+H]+;1H NMR(400MHz,DMSO-d6) δ:12.31(br s,1H),10.88(br s,1H),8.22(s,1H),8.20(s,1H),7.31(t,1H),5.95(s,1H),5.18(s,1H),3.89-3.81(m,2H) ,3.67-3.58(m,2H),3.45-3.38(m,1H),3.27-3.20(m,1H),3.14-3.09(m,1H),1.53(d,3H).

[0522] Part 4. Intermediate product B (Part 2) was separated by chiral-SFC (Daicel OJ, 20x250 mm, 10 mm; 15% MeOH in CO2 (0.2% MeOH / NH3)) to give:

[0523] Peak 3, Example 213, 1-((S)-1-((R)-1,4-dioxan-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or 1-((R)-1-((S)-1,4-dioxan-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or is 1-((R)-1-((R)-1,4-dioxan-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or 1-((S)-1-((S)-1,4-dioxan-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine (15.2 mg); LCMS m / z = 382 [M+H] + ; 1 H NMR(400MHz,DMSO-d6) δ:12.27(br s,1H),10.83(br s,1H),8.19(s,1H),8.15(s,1H),7.31(t,1H),5.92(s,1H),5.20(s,1H) ,3.94-3.90(m,2H),3.63-3.56(m,2H),3.40-3.31(m,3H),1.41(d,3H).

[0524] Peak 4, Example 214, 1-((R)-1-((S)-1,4-dioxan-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or 1-((S)-1-((R)-1,4-dioxan-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or is 1-((R)-1-((R)-1,4-dioxan-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or 1-((S)-1-((S)-1,4-dioxan-2-yl)ethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine (15.2 mg); LCMS m / z = 382 [M+H] + ; 1 H NMR(400MHz,DMSO-d6) δ:12.27(br s,1H),10.83(br s,1H),8.19(s,1H),8.15(s,1H),7.31(t,1H),5.92(s,1H),5.20(s,1H) ,3.94-3.90(m,2H),3.63-3.56(m,2H),3.40-3.31(m,3H),1.41(d,3H).

[0525] Examples 215, 216, 217 and 218

[0526] N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((S)-1-((R)-tetrahydro-2H-pyran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine and N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((R)-1-((R)-tetrahydro-2H-pyran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine and and N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((S)-1-((S)-tetrahydro-2H-pyran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine and N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((R)-1-((S)-tetrahydro-2H-pyran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0527] Part 1. To a solution of 6-chloro-1-(1-(tetrahydro-2H-pyran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazine (Preparation 89, 300 mg, 1.12 mmol)) and 5-(difluoromethoxy)-1H-pyrazol-3-amine (250 mg, 1.68 mmol) in dioxane (10 mL) was added tBuXPhos Pd G3 (177 mg, 0.224 mmol) and KOAc (219 mg, 2.24 mmol) at ambient temperature, and the resulting mixture was purged with N2 and then stirred at 100 °C for 2 h. The reaction mixture was evaporated to dryness and the residue was purified by preparative HPLC-1 to give N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(tetrahydro-2H-pyran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine as a white solid (44 mg, 10%). LCMS m / z = 380 [M+H]+.

[0528] Part 2. N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(1-(tetrahydro-2H-pyran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine (Part 1) was further purified by chiral-SFC (Daicel OJ; 20x250mm, 10mm; 15% MeOH in CO2 (0.2% MeOH / NH3)) to give the title compound. LCMS m / z = 380 [M+H]+.

[0529] Peak 1, Example 215, N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((S)-1-((R)-tetrahydro-2H-pyran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((R)-1-((R)-tetrahydro-2H-pyran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((S)-1-((S)-tetrahydro-2H-pyran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((R)-1-((S)-tetrahydro-2H-pyran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine (0.9 mg): 1H NMR(400MHz,DMSO-d6) δ:12.19(s,1H),10.76(s,1H),8.20(s,1H),8.17(s,1H),7.30(t,1H),5.97(s,1H),5.05-5.01(m,1H),3.96(dd,1H),3. 67(d,1H),3.32-3.21(m,2H),2.07-2.05(m,1H),1.46(d,3H),1.35-1.23(m,2H),1.15-1.12(m,1H),1.05-0.99(m,1H).

[0530] Peak 2, Example 216, N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((R)-1-((R)-tetrahydro-2H-pyran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((S)-1-((R)-tetrahydro-2H-pyran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((S)-1-((S)-tetrahydro-2H-pyran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((R)-1-((S)-tetrahydro-2H-pyran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine (2.8 mg): 1 H NMR(400MHz,DMSO-d6) δ:12.40-12.30(br,1H),10.95-10.72(br,1H),8.20(s,1H),8.17(s,1H),7.30(t,1H),5.97(s,1H),5.05-5.01(m,1H),3.96(dd ,1H),3.68(dd,1H),3.32-3.21(m,2H),2.07-2.05(m,1H),1.46(d,3H),1.35-1.23(m,2H),1.15-1.12(m,1H),1.05-0.99(m,1H).

[0531] Peak 3, Example 217, N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((S)-1-((S)-tetrahydro-2H-pyran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((R)-1-((R)-tetrahydro-2H-pyran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((R)-1-((S)-tetrahydro-2H-pyran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((S)-1-((R)-tetrahydro-2H-pyran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine (3.5 mg): 1 H NMR(400MHz,DMSO-d6) δ:12.40-12.30(br s,1H),10.95-10.72(br s,1H),8.20(s,1H),8.17(s,1H),7.30(t,1H),5.97(s,1H),5.02-4.95(m,1H),3.69(d,1H),3.32-3.23(m,1H),3.15-3. 12(m,1H),3.02-2.96(m,1H),2.13-2.10(m,1H),1.98-1.95(m,1H),1.66-1.60(m,1H),1.53(d,3H),1.48-1.33(m,2H).

[0532] Peak 4, Example 218, N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((R)-1-((S)-tetrahydro-2H-pyran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((R)-1-((R)-tetrahydro-2H-pyran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((S)-1-((S)-tetrahydro-2H-pyran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine or N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((S)-1-((R)-tetrahydro-2H-pyran-3-yl)ethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine (5.6 mg): 1 H NMR(400MHz,DMSO-d6) δ:12.19(s,1H),10.80(s,1H),8.20(s,1H),8.17(s,1H),7.31(t,1H),5.97(s,1H),4.99(s,1H),3.70-3.68(m,1H),3.32-3.23(m,1 H),3.15-3.12(m,1H),3.02-2.96(m,1H),2.13-2.10(m,1H),1.98-1.95(m,1H),1.66-1.60(m,1H),1.53(d,3H),1.48-1.33(m,2H).

[0533] Example 219

[0534] (3-(6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)cyclobutyl)methanol [ka]

[0535] Part 1. A mixture of 1-(3-((benzyloxy)methyl)cyclobutyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazine (Preparation 176, 410 mg, 1.24 mmol), 5-(difluoromethoxy)-1H-pyrazol-3-amine (184 mg, 1.24 mmol), KOAc (364 mg, 3.72 mmol) and BrettPhos Pd G4 (114 mg, 0.124 mmol) in dioxane (12 mL) was stirred at 90 °C for 14 h under N2. The reaction mixture was concentrated in vacuo and the residue was purified by flash chromatography on silica gel (33% EtOAc / PE) to give 1-(3-((benzyloxy)methyl)cyclobutyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine as a white solid (230 mg, 42%). LCMS m / z = 442 [M+H]+.

[0536] Part 2. A mixture of 1-(3-((benzyloxy)methyl)cyclobutyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine (Part 1, 200 mg, 0.453 mmol) and Pd / C (10% wet, 80 mg) in EtOAc (18 mL) under H2 was stirred at ambient temperature for 14 h. The reaction mixture was filtered through a pad of Celite®. The filtrate was concentrated and the residue was purified by preparative HPLC-2 to give the title compound as a white solid (59 mg, 37%). LCMS m / z = 352 [M+H]+;1H NMR(400MHz,DMSO-d6) δ:12.26(br s,1H),10.75(br s,1H),8.20(s,1H),8.18(s,1H),7.31(t,1H),5.92(s,1H),5.63(s,1H) ,4.73(t,1H),3.64-3.61(m,2H),2.69-2.67(m,3H),2.30-2.25(m,2H).

[0537] Example 220

[0538] (1r,3r)-3-((6-((5-(difluoromethoxy)-1H-pyrazol-3-yl)amino)-1H-pyrazolo[3,4-b]pyrazin-1-yl)methyl)cyclobutan-1-ol [ka]

[0539] To a solution of 1-(((1r,3r)-3-(benzyloxy)cyclobutyl)methyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine (Preparation 191, 350 mg, 0.792 mmol) in MeOH (10 mL) at 25° C., Pd / C (200 mg) was added and the mixture was stirred under H2 for 1 h. The reaction mixture was filtered and the filtrate was concentrated to give a residue which was purified by preparative HPLC-3 to give the title compound as a yellow solid (66.6 mg, 23%). LCMS m / z = 352 [M+H] + ; 1 H NMR(400MHz,DMSO-d6) δ:11.70-10.85(m,2H),8.18(s,1H),8.12(s,1H),7.30(t,1H),6.01(s,1H),5.01-4.93(m,1 H),4.50(d,2H),4.28-4.21(m,1H),2.68-2.60(m,1H),2.09-2.01(m,2H),1.93-1.86(m,2H).

[0540] Example 221

[0541] 1-(3-oxabicyclo[3.1.0]hexan-1-ylmethyl)-N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0542] Part 1: 3-Oxabicyclo[3.1.0]hexan-1-ylmethanol (85.5 mg, 0.75 mmol) and 6-chloro-1H-pyrazolo[3,4-b]pyrazine (77.0 mg, 0.50 mmol) were dissolved in THF (6 mL), DIAD (121.2 mg, 0.60 mmol) and triphenylphosphine resin (83.3 mg, 3.0 mmol / g, 0.25 mmol) were added under N2, and the reaction mixture was shaken at 30 °C for 16 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with EtOAc (5 mL) and partitioned between EtOAc (5 mL) and H2O (5 mL). The combined organics were washed (2×2.5 mL), dried (NaSO) and concentrated under reduced pressure to give 1-(3-oxabicyclo[3.1.0]hexan-1-ylmethyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazine, which was used in Part 2 without further purification.

[0543] Part 2. Under N2, a mixture of tert-butyl 3-amino-5-(difluoromethoxy)-1H-pyrazole-1-carboxylate (Preparation 30, 99.6 mg, 0.40 mmol), 1-(3-oxabicyclo[3.1.0]hexan-1-ylmethyl)-6-chloro-1H-pyrazolo[3,4-b]pyrazine (Part 1, 0.40 mmol), K3PO4 (253.2 mg, 1.20 mmol) and XantPhos Pd G3 (19.0 mg, 0.015 mmol) was combined in t-AmOH (5 mL) at room temperature and the resulting mixture was stirred at 100° C. for 2 h under N2. The reaction mixture was diluted with EtOAc (5 mL) and washed with water (3×5 mL). The combined organics were dried (Na2SO4) and evaporated to give tert-butyl 3-((1-(3-oxabicyclo[3.1.0]hexan-1-ylmethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)amino)-5-(difluoromethoxy)-1H-pyrazole-1-carboxylate, which was used in Part 3 without further purification.

[0544] Part 3. tert-Butyl 3-((1-(3-oxabicyclo[3.1.0]hexan-1-ylmethyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl)amino)-5-(difluoromethoxy)-1H-pyrazole-1-carboxylate (Part 2, 0.30 mmol) was dissolved in DCM (1.5 mL), HCl-dioxane (1.5 mL, 4 M) was added at room temperature, and the resulting mixture was stirred at 30° C. for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC to give the title compound (10.8 mg, 6%). LCMS m / z = 364 [M+H] + .

[0545] Example 222

[0546] N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(pyridazin-3-ylmethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0547] The title compound was prepared from pyridazin-3-ylmethanol, 6-chloro-1H-pyrazolo[3,4-b]pyrazine and tert-butyl 3-amino-5-(difluoromethoxy)-1H-pyrazole-1-carboxylate (Preparation 30) using a three-part protocol similar to that described for Example 221 (13.9, 8%). LCMS m / z = 360 [M+H] + .

[0548] Example 223

[0549] N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(pyrazin-2-ylmethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0550] The title compound was prepared from pyrazin-2-ylmethanol, 6-chloro-1H-pyrazolo[3,4-b]pyrazine and tert-butyl 3-amino-5-(difluoromethoxy)-1H-pyrazole-1-carboxylate (Preparation 30) using a three-part protocol similar to that described for Example 221 (12.4 mg, 7%). LCMS m / z = 360 [M+H] + .

[0551] Example 224

[0552] N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(pyridin-3-ylmethyl-d2)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0553] Part 1: To a solution of nicotinic acid (1.33 g, 10.8 mmol) in THF at 0° C. was added LiAlD4 (0.5 g, 11.9 mmol) and stirred at room temperature for 15 h. D2O (0.5 mL) was added, followed by 15% NaOD in D2O (0.5 mL), followed by D2O (1.5 mL). Filtration and concentration of the filtrate gave pyridin-3-ylmethan-d2-ol as a pale yellow oil (0.84 g, 70%). MS (ES+) C6H5D2NO calculated: 111, observed: 112 [M+H] + .

[0554] Part 2. Under nitrogen atmosphere, DIAD (937 mg, 3.58 mmol) was added dropwise to a stirred solution of pyridin-3-ylmethan-d2-ol (part 1, 200 mg, 1.79 mmol), 6-chloro-1H-pyrazolo[3,4-b]pyrazine (276 mg, 1.79 mmol) and PPh3 (541 mg, 2.68 mmol) in THF (10 mL) at 0 °C. The resulting mixture was stirred at room temperature under N2 for 2 h. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography eluting with PE / EA (10:1 to 5:1) to give 6-chloro-1-(pyridin-3-ylmethyl-d2)-1H-pyrazolo[3,4-b]pyrazine as a pale yellow oil (210 mg, 47% yield). MS (ES+) C11H6D2ClN5 calculated: 247, observed: 248 [M+H]+.

[0555] Part 3: A mixture of 6-chloro-1-(pyridin-3-ylmethyl-d2)-1H-pyrazolo[3,4-b]pyrazine (Part 2, 210 mg, 847 μmol), 5-(difluoromethoxy)-1H-pyrazol-3-amine (126 mg, 847 μmol), KOAc (248 mg, 2.54 mmol) and Brett Phos Pd G4 (40 mg) in dioxane (6 mL) was stirred at 100° C. for 2 h under N2. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography eluting with PE / EA (2:1 to 1:1) to give the crude product (180 mg). The crude product was purified by preparative HPLC (mobile phase: A=water (0.1% NH4HCO3), B=acetonitrile; gradient: B=15% to 95% in 18 min; column: Xtimate 10um 150A 21.2×250mm) to give the title product as a white solid (145.7 mg, 47.5% yield). MS (ES+) C15H10D2F2N8O theoretical: 360, observed: 361 [M+H]+. 1H-NMR(400MHz,DMSO-d6) δ ppm 12.31(s,1H),10.88(s,1H),8.57(s,1H),8.47(d,J = 4.8Hz, 1H), 8.21-8.19 (m, 2H), 7.67-7.64 (m, 1H), 7.50-7.12 (m, 2H), 5.88 (s, 1H).

[0556] Example 225

[0557] N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-(ethyl-1,1-d2)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka] The title compound was prepared from 1-hydroxyethane-1,1-d2, chloro-1H-pyrazolo[3,4-b]pyrazine and 5-(difluoromethoxy)-1H-pyrazol-3-amine following a three-part protocol similar to that described for Example 224 (49 mg, 30%). MS (ES+) C11H9D2F2N7O theoretical: 297, observed: 298 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ ppm 12.21 (s, 1H), 10.72 (s, 1H), 8.18 (s, 1H), 8.10 (s, 1H), 7.32 (t, J = 73.6 Hz, 1H), 5.91 (s, 1H), 1.34 (s, 3H).

[0558] Example 226

[0559] N-(5-(difluoromethoxy)-1H-pyrazol-3-yl)-1-((tetrahydro-2H-pyran-4-yl)methyl-d2)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0560] The title compound was prepared from methyl tetrahydro-2H-pyran-4-carboxylate, chloro-1H-pyrazolo[3,4-b]pyrazine and 5-(difluoromethoxy)-1H-pyrazol-3-amine using a three-part protocol similar to that described for Example 224 (86.9 mg, 23%). MS(ES+)C 15 H 15 D2F2N7O2 theoretical value: 367, observed value: 368 [M+H]+ . 1 H-NMR(400MHz,DMSO-d6) δ ppm 11.21(br.s.,1H),8.19(s,1H),8.15(s,1H),7.32(t,J = 73.6Hz,1H),6.01(s,1H),3.83-3.79(m,2H),3.25-3.19(m,2H),2.17-2.12(m,1H),1.40-1.30(m,4H).

[0561] Example 227

[0562] N-(5-(methoxy-d3)-1H-pyrazol-3-yl)-1-(pyridin-3-ylmethyl)-1H-pyrazolo[3,4-b]pyrazin-6-amine [ka]

[0563] Part 1: To a mixture of methan-d3-ol-d (1.0 g, 27.7 mmol) and triethylamine (5.6 g, 55.4 mmol) in DCM (10 mL) was added methanesulfonyl chloride (3.1 g, 27.7 mmol) dropwise at 0° C. and then stirred at room temperature for 1 h. The reaction was diluted with DCM and washed with water and brine. The organic layer was concentrated. The residue was used directly in the next step (Part 3).

[0564] Part 2: A mixture of 5-amino-2,4-dihydro-3H-pyrazol-3-one (11.0 g, 0.11 mol) and isobenzofuran-1,3-dione (17.0 g, 0.11 mol) in HOAc (200 mL) was stirred at 120° C. for 2 h. The reaction mixture was cooled to room temperature. The precipitate was collected by filtration to give 2-(5-oxo-4,5-dihydro-1H-pyrazol-3-yl)isoindoline-1,3-dione as a grey solid (20.0 g, 80% yield). MS (ES+) calculated for C11H7N3O3: 229, observed: 230 [M+H]+.

[0565] Part 3: A mixture of 2-(5-oxo-4,5-dihydro-1H-pyrazol-3-yl)isoindoline-1,3-dione (Part 2, 1.0 g, 4.36 mmol), methyl-d3 methanesulfonate (Part 1, 1.2 g, 8.72 mmol) and K2CO3 (493 mg, 4.36 mmol) in DMF (10 mL) was stirred at 35 °C overnight. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with DCM / MeOH 4:1 to give 2-(5-(methoxy-d3)-1H-pyrazol-3-yl)isoindoline-1,3-dione as a yellow oil (2.8 g, crude). MS (ES+) C12H6D3N3O3 calculated: 246, observed: 247 [M+H]+.

[0566] Part 4: To a mixture of 2-(5-(methoxy-d3)-1H-pyrazol-3-yl)isoindoline-1,3-dione (Part 3, 2.8 g, crude) in EtOH (6 mL) was added hydrazine hydrate (2 mL) and then stirred at 70° C. for 2 h. The reaction mixture was purified by flash chromatography on silica gel eluting with DCM / MeOH=2:1 to give 5-(methoxy-d3)-1H-pyrazol-3-amine as a yellow oil (0.8 g). MS (ES+) C4H4D3N3O calculated: 116, observed: 117 [M+H]+.

[0567] Part 5: A mixture of methyl 6-chloro-1-(pyridin-3-ylmethyl)-1H-pyrazolo[3,4-b]pyrazine (Preparation 35, 400 mg, 1.63 mmol), 5-(methoxy-d3)-1H-pyrazol-3-amine (Part 4, 0.8 g, crude), BrettPhos Pd G4 (24 mg, 0.24 mmol) and potassium acetate (479 mg, 4.89 mmol) in dioxane (10 mL) was stirred at 90° C. overnight under N2. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by preparative HPLC (mobile phase: A=water (0.1% NH4HCO3), B=acetonitrile; gradient: B=15% to 95% in 18 min; column: Xtimate 10 um 150A 21.2×250 mm) to give the title product (19.9 mg, 4% yield). MS (ES+) C15H11D3N8O theoretical: 325, found: 326 [M+H]+.1H-NMR (400MHz, DMSO-d6) δ ppm 11.79 (br.s, 1H), 10.67 (br.s, 1H), 8.58 (s, 1H), 8.47 (d, J = 4.0Hz, 1H), 8.21 (s, 1H), 8.15 (s, 1H), 7.64 (d, J = 7.6Hz, 1H), 7.34 (dd, J = 4.8Hz, 7.6Hz, 1H), 5.75 (s, 2H), 5.59 (br.s, 1H).

[0568] Biological Example 1. The inhibitory effect of the compounds of the present disclosure is measured by a biochemical assay, which measures the enzymatic phosphorylation activity of CDK enzyme in complex with cyclin protein to phosphorylate 7.5 micromolar fluorescently labeled peptide substrate 5-FAM-QSPKKG-CONH2 (FL-peptide 18, PerkinElmer, 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), 1.0% dimethylsulfoxide (DMSO). The assay is performed at the Km of ATP of CDK enzyme in complex with 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-diylnitrilo)tetraacetic acid (EDTA). The products were detected using a caliper mobility shift detection method, in which the phosphorylated peptides (products) and substrates were separated by electrophoresis and measured. Percent activity was plotted against the log concentration of compound and points to obtain a visually clear IC. 50 These assays used the following CDK enzymes in complexes with different cyclin proteins: CDK1 / cyclin B1, GST-tag (BPS, 40454), 1.5 nM used in the assay CDK2 / cyclin E (Eurofins, 14-475), 1.25 nM was used in the assay

[0569] Biological assay data for the test compounds are shown below in Table 1. For inhibitory activity against CDK2 / cyclin E mutants, the following designations are used: ≦10 nM=A; >10-20 nM=B; >20-30 nM=C; >30-100 nM=D; >100=E. For inhibition of CDK1 / cyclin B1, GST-tag, ≧500 nM=A; <100-500 nM=B; <100 nM=C. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7]

[0570] Additional compounds not disclosed herein were also tested in the assay described in Biological Example 1, and all but one had inhibitory activity against CDK2 / cyclin E1 less than 10 micromolar. One compound that had inhibitory activity against CDK2 / cyclin E1 greater than 10 micromolar is shown in Table 2. [Table 2]

Claims

1. The compound of formula (Ia), 【Chemical 144】 or a pharmaceutically acceptable salt thereof (wherein, R １ is C which may be substituted with 1 to 4 groups independently selected from halo and D １ to C ４ alkyl, R ２ is C １ to C ４ alkyl or ring A, where the C １ to C ４ alkyl is independently selected from 1 to 4 groups selected from halo, D, CN and OH, and / or NR ｄ and may be substituted with one group of 5- to 6-membered heteroaryl having 1 to 3 ring heteroatoms independently selected from the group consisting of N, O, and S R ３ is selected from the group consisting of H, D, C １ to C ４ alkyl, C ３ to C １０ cycloalkyl and 4- to 12-membered heterocyclyl, where the C １ to C ４ alkyl and the C ３ to C １０ cycloalkyl may each be substituted with 1 to 4 R ｃ s, where the 4- to 12-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from the group consisting of NR ｄ , N, O, and S, and is then optionally substituted on the ring carbon with 1 to 4 R ｃ s, or R ２ and R ３ together with the carbon atom to which they are attached form ring B, where ring B is C ３ -C １０ cycloalkyl or 4- to 12-membered heterocyclyl, where said C ３ -C １０ cycloalkyl may be substituted with 1 to 4 R ｂ s, where said 4- to 12-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from the group consisting of NR ｄ , N, O and S, and may then be substituted on the ring carbon with 1 to 4 R ｂ s, Ring A is C ３ to C １０ selected from the group consisting of cycloalkyl, phenyl, naphthyl, 4- to 12-membered heterocyclyl, and 4- to 12-membered heteroaryl, wherein said C ３ to C １０ cycloalkyl, said phenyl, and said naphthyl may each be substituted with 1 to 4 Rs ａ and wherein said 4- to 12-membered heterocyclyl and said 4- to 12-membered heteroaryl each independently have 1 to 4 ring heteroatoms selected from the group consisting of NR ｄ , N, O, and S, and may then be substituted with 1 to 4 Rs ａ on the ring carbon, Each R ａ is independently selected from the group consisting of D, halo, OH, CN, C １ ~C ４ alkyl and C １ ~C ４ alkoxy, or two Rs bonded to the same atom form =O, where the C ａ ~C １ ~C ４ alkyl and the C １ ~C ４ alkoxy may each be substituted with 1 to 4 groups independently selected from the group consisting of halo, OH, and CN, Each R ｂ is independently selected from the group consisting of D, halo, OH, CN, C １ ~C ４ alkyl and C １ ~C ４ alkoxy, or two Rs bonded to the same atom form =O, where the C ｂ ~C １ ~C ４ alkyl and the C １ ~C ４ alkoxy may each be substituted with 1 to 4 groups independently selected from the group consisting of halo, OH, and CN, Each R ｃ is independently selected from the group consisting of D, halo, OH, CN, C １ ~C ４ alkyl and C １ ~C ４ alkoxy, or two Rs bonded to the same atom form =O, where the C ｃ ~C １ ~C ４ alkyl and the C １ ~C ４ alkoxy may each be substituted with 1 to 4 groups independently selected from the group consisting of halo, OH, and CN, or Each R ｄ is independently selected from the group consisting of H, D and C １ to C ６ alkyl, R ４ is C which may be substituted with 1 to 4 groups independently selected from halo, D and OH １ -C ４ -alkyl, and is selected from the group consisting of H and D R ５ is selected from the group consisting of H, D, halo, CN and C １ to C ４ alkyl, wherein said C １ to C ４ alkyl may be substituted with 1 to 4 groups independently selected from halo and OH, R ６ is H or D, R ７ is H or D).

2. R １ is methyl, ethyl, CF ３ , CH ２ F and CHF ２ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of.

3. The compound is a compound of formula (IIa): 【Chemical 145】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is the compound of formula (IIa).

4. Ring A is a 4- to 10-membered heterocyclyl optionally substituted on a ring carbon with 1 to 3 groups each independently selected from the group consisting of D, halo, OH, =O, CN, C １ ~C ４ alkyl and C １ ~C ４ alkoxy, and is a compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein said C １ ~C ４ alkyl and said C １ ~C ４ alkoxy may each be substituted with 1 to 3 groups each independently selected from the group consisting of halo, OH and CN.

5. Ring A is a 4- to 10-membered heteroaryl independently selected from 1 to 3 groups each consisting of D, halo, OH, ═O, CN, C １ ~C ４ alkyl and C １ ~C ４ alkoxy, and is optionally substituted on the ring carbon, and the C １ ~C ４ alkyl and the C １ ~C ４ alkoxy may each be substituted with 1 to 3 groups independently selected from the group consisting of halo, OH and CN. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

6. The compound is a compound of formula (IIIa): 【Chemical 148】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is the compound of formula (IIIa).

7. R ３ is selected from the group consisting of H, D, methyl, ethyl, cyclopropyl and oxetanyl, each of which (when R ３ is oxetanyl, on the ring carbon) may be independently substituted with 1 to 3 groups each selected from the group consisting of D, halo and OH, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

8. R ４ is the compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of H, D and CH ３ ​

9. R ５ is selected from the group consisting of H, D, halo, CN, methyl and ethyl, wherein the methyl and the ethyl may be substituted with OH, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

10. The compound is a compound of formula (IVa-1) or (IVb-1): 【Chemical 150】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is the compound of formula (IVa-1) or (IVb-1).

11. The compound is selected from the compounds of formula (Va-1), (Vb-1), (Vc-1) and (Vd-1): 【Chemical 152】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the compounds of formula (Va-1), (Vb-1), (Vc-1) and (Vd-1).

12. The compound of formula (I), 【Chemical 143】 or a pharmaceutically acceptable salt thereof (wherein, R １ is C which may be substituted with 1 to 4 halos １ to C ４ alkyl, R ２ is C １ to C ４ alkyl or ring A, where said C １ to C ４ alkyl is independently selected from 1 to 4 groups selected from halo, CN and OH, and / or NR ｄ and is optionally substituted with one group of a 5- to 6-membered heteroaryl having 1 to 3 ring heteroatoms independently selected from the group consisting of N, O, and S. R ３ is selected from the group consisting of H, C １ -C ４ alkyl, C ３ -C １０ cycloalkyl and 4- to 12-membered heterocyclyl, wherein the C １ -C ４ alkyl and the C ３ -C １０ cycloalkyl may each be substituted with 1 to 4 R ｃ s, wherein the 4- to 12-membered heterocyclyl has 1 to 4 ring heteroatoms independently selected from the group consisting of NR ｄ , N, O, and S, and may then be substituted with 1 to 4 R ｃ s on the ring carbon, or R ２ and R ３ together with the carbon atom to which they are attached form ring B, where ring B is C ３ -C １０ cycloalkyl or 4- to 12-membered heterocyclyl, where said C ３ -C １０ cycloalkyl may be substituted with 1 to 4 R ｂ groups, where said 4- to 12-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from the group consisting of NR ｄ , N, O, and S, and may then be substituted on the ring carbon with 1 to 4 R ｂ groups, Ring A is C ３ to C １０ selected from the group consisting of cycloalkyl, phenyl, naphthyl, 4- to 12-membered heterocyclyl, and 4- to 12-membered heteroaryl, wherein said C ３ to C １０ cycloalkyl, said phenyl, and said naphthyl may each be substituted with 1 to 4 Rs ａ and wherein said 4- to 12-membered heterocyclyl and said 4- to 12-membered heteroaryl each independently have 1 to 4 ring heteroatoms selected from the group consisting of NR ｄ , N, O, and S, and may then be substituted with 1 to 4 Rs ａ on the ring carbon, Each R ａ is independently selected from the group consisting of halo, OH, CN, C １ ~C ４ alkyl and C １ ~C ４ alkoxy, or two Rs bonded to the same atom form =O, where the C ａ ~C １ alkyl and the C ４ ~C １ alkoxy may each be substituted with 1 to 4 groups independently selected from the group consisting of halo, OH, and CN, ４ ​ Each R ｂ is independently selected from the group consisting of halo, OH, CN, C １ ~C ４ alkyl and C １ ~C ４ alkoxy, or two Rs bonded to the same atom form =O, where the C ｂ ~C １ alkyl and the C ４ ~C １ ~C ４ alkoxy may each be substituted with 1 to 4 groups independently selected from the group consisting of halo, OH and CN, Each R ｃ is halo, OH, CN, C １ ~C ４ Alkyl and C １ ~C ４ or two R bonded to the same atom are independently selected from the group consisting of alkoxy; ｃ forms =O, wherein said C １ ~C ４ Alkyl and the C １ ~C ４ Each alkoxy is optionally substituted with 1 to 4 groups each independently selected from the group consisting of halo, OH, and CN; or Each R ｄ is independently H or C １ -C ６ alkyl, R ４ is C which may be substituted with 1 to 4 groups independently selected from H, halo and OH respectively １ -C ４ -alkyl, R ５ is selected from the group consisting of H, halo, CN and C １ to C ４ alkyl, wherein said C １ to C ４ alkyl may be substituted with 1 to 4 groups independently selected from halo and OH).

13. The pharmaceutically acceptable salt of the compound represented by the following structural formula: 【Chemical 154】

14. The compound represented by the following structural formula:

15. 【Chemical 155】 A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof.

16. A composition for treating a subject suffering from solid tumor cancer, comprising the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof.

17. The solid tumor cancer includes at least one of uterine cancer (including uterine carcinosarcoma, endometrial carcinoma of the uterine body), endometrial cancer, breast cancer (including breast invasive carcinoma, triple negative breast cancer (TNBC), estrogen receptor (ER)+ human epidermal growth factor 2 (HER2)- breast cancer, and HER2+ breast cancer), ovarian cancer (e.g., 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 squamous cell carcinoma of the lung and non-small cell lung cancer, e.g., epidermal growth factor receptor variant (EGFRm)+ non-small cell lung cancer), cholangiocarcinoma, adrenocortical carcinoma, or mesothelioma. The composition according to claim 16.

18. The composition according to claim 16, wherein the solid tumor cancer is breast cancer. ​ ​ The composition according to claim 16, wherein the solid tumor cancer is a hormone receptor positive / human epidermal growth factor 2 negative (HR+ / HER2−) breast cancer. The composition according to claim 16, wherein the solid tumor cancer is endometrial cancer. The composition according to claim 16, wherein the solid tumor cancer is ovarian cancer. The composition according to claim 16, wherein the solid tumor cancer has amplification and / or overexpression of CCNE1 or CCNE2.

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