CDK2 inhibitors

Abstract

This disclosure, in part, describes a structural formula (I) that is useful for the treatment of cancer: The present invention provides compounds useful for the treatment of cancer, or pharmaceutically acceptable salts thereof, represented by TIFF2026514052000355.tif65165. The applicant has discovered novel compounds that are effective inhibitors of CDK2 (see, for example, Examples 1-258). In particular, the compounds of the present disclosure have been demonstrated to effectively inhibit CDK2. The compounds of the present disclosure (also referred to herein as “the Disclosed Compounds”) or pharmaceutically acceptable salts thereof effectively inhibit CDK2 (see Biological Example 1) and can be used in the treatment of various cancers. Importantly, the disclosed compounds are selective CDK2 inhibitors; that is, the disclosed compounds show little to no activity against CDK family kinases, most notably CDK1.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority and benefits of U.S. Provisional Patent Application No. 63 / 496,146 filed on 14 April 2023, U.S. Provisional Patent Application No. 63 / 591,862 filed on 20 October 2023, and U.S. Provisional Patent Application No. 63 / 564,604 filed on 13 March 2024, the contents of each of these, respectively, are incorporated herein by reference in whole. [Background technology]

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

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

[0004] CDK2 dysregulation can occur through several mechanisms. Amplification and / or overexpression of CCNE1 have been identified in ovarian and breast cancer (see Scaltriti, M. et al., Proc. Natl Acad. Sci. USA 108, 3761-3766 (2011), and Etemadmoghadam, D. et al. Proc. Natl Acad. Sci. USA 110, 19489-19494 (2013)). Poor outcomes in gastric cancer, endometrial cancer, and other cancers are associated with CCNE1 overexpression and / or amplification (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. Therefore, the development of new CDK2 inhibitors is needed. [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

Summary of the Invention

Means for Solving the Problems

[0006] The applicant has discovered a novel compound that is an effective inhibitor of CDK2 (see, for example, Examples 1 to 258). In particular, the compounds of the present disclosure have been demonstrated to effectively inhibit CDK2. The compounds of the present disclosure (also referred to herein as "disclosed compounds") or pharmaceutically acceptable salts thereof effectively inhibit CDK2 (see Biological Example 1) and can be used for the treatment of various cancers. Importantly, the disclosed compounds are selective CDK2 inhibitors, that is, the disclosed compounds do not show activity or have low activity against CDK family kinases, most notably CDK1. Advantages associated with such selectivity may include facilitation of effective dosing and reduction of on-target toxicity via CDK1. Some of the disclosed compounds also have the advantage of high microsomal stability. The compounds of the present disclosure may also have a favorable toxicity profile associated with other non-kinase targets.

[0007] In one aspect, the present disclosure provides a compound represented by the following structural formula (I):

Chemical Formula

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

[0009] This disclosure provides a method for treating a subject having cancer, the method comprising administering an effective amount of a compound of the Disclosure (e.g., a compound of formula (I)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Disclosure, to the subject. In one embodiment, cancer includes uterine cancer (including uterine carcinosarcoma (UCS), endometrial cancer of the uterine body (UCEC)), endometrial cancer, breast cancer (including invasive breast cancer (BRCA), TNBC (triple-negative breast cancer), HR+ breast cancer (hormone receptor-positive breast cancer), ER+ breast cancer (estrogen receptor-positive breast cancer), HR+HER2- breast cancer (hormone receptor-positive, human epidermal growth factor 2-negative breast cancer), ER+HER2- breast cancer (estrogen receptor-positive, human epidermal growth factor 2-negative breast cancer), HER2- breast cancer (human epidermal growth factor 2-negative breast cancer), HER2-low breast cancer (human epidermal growth factor 2-low level breast cancer), and HER2+ breast cancer (human epidermal growth factor 2-positive breast cancer)), ovarian cancer (e.g., ovarian serous These include cystadenocarcinoma (OV), gastric cancer (including gastric adenocarcinoma (STAD)), gastric cancer (including gastrointestinal stromal tumors), colorectal cancer, pancreatic cancer (including pancreatic adenocarcinoma (PAAD) and pancreatic ductal adenocarcinoma (PDAC)), kidney cancer, head and neck cancer, liver cancer, prostate cancer, skin cancer, leukemia (including AML (acute myeloid leukemia)), lymphoma (including B-cell lymphoma), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), sarcoma (SARC), esophageal cancer (including esophageal cancer (ESCA)), bladder cancer (including urothelial carcinoma of the bladder), lung cancer (including squamous cell carcinoma of the lung and non-small cell lung cancer, e.g., EGFRm (epidermal growth factor receptor variant) + 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-amplifying 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 that has progressed after two or more lines of treatment (including platinum therapy) (the patient has previously received platinum therapy, for example, the patient has been treated with platinum therapy before). In one embodiment, the subject has CCNE1-amplified endometrial cancer that has failed two or more lines of treatment (which may include previous platinum therapy).In one embodiment, the subject has gastric cancer that has progressed after two or more lines of treatment (including platinum therapy) (the patient has previously received platinum therapy, for example, the patient has been treated with platinum therapy before). In another embodiment, the subject has ER+HER- breast cancer that has progressed despite treatment with one or more CDK4 / 6 inhibitors.

[0010] [r] In one embodiment, the cancer described herein that is to be treated (for example, the cancers described in paragraphs

[0009] ,

[0019] ,

[0119] to

[0130] , and

[0132] to

[0148] , e.g., breast cancer) has amplification and / or overexpression of CCNE1.

[0011] In one embodiment, the cancers described herein that are to be treated (e.g., the cancers described in paragraphs

[0009] ,

[0019] ,

[0119] to

[0130] , and

[0132] to

[0148] , e.g., breast cancer) do not have CCNE1 amplification and / or overexpression.

[0012] In some embodiments, the therapeutic methods disclosed herein include effective doses of palbociclib (e.g., Ibrance®), ribociclib, abemaciclib, tamoxifen, letrozole, olaparib (e.g., Lymphalza®), niraparib, carboplatin, cisplatin, paclitaxel, gemcitabine, megestrol acetate, medroxyprogesterone acetate, capecitabine (e.g., Xeloda®), regorafenib (e.g., Stivarga®), afatinib (e.g., Giotrif®), osimertinib. This includes administering drugs such as bacon (e.g., Tagrisso®), gefitinib (e.g., Iressa®), erlotinib (e.g., Tarceva®), ramucirumab (e.g., Cyramza®), EGFR inhibitors, pralcetinib, ABT-263 (Navitoclax), MK-1775 (adavocertib), BAY-1895344, bezocertib, ceraracertib, SRA-737, LY2603618 (labcertib), or trastuzumab (e.g., Herceptin®), or combinations thereof, to the target population. EGFR inhibitors include afatinib, osimertinib, lapatinib, erlotinib, dacomitinib, poziotinib, neratinib, gefitinib (JBJ-04-125-02), alflutinib (AST2818), aumorertinib (formerly amonertinib) (HS10296), BBT-176, BI-4020, BPI-361175, BPI-D0316, CH7233163, gilteritinib, icotinib, JND-3229, razertinib, and na The antibody may be selected from zartinib (EGF816), abitinib, PCC-0208027, regibertinib (BPI-7711), TQB3804, zolifertinib (AZ-3759), or DZD9008, or from EGFR antibodies such as cetuximab, panitumumab, nesitumumab, HLX07, or JMT101, or from bispecific EGFR and MET antibodies (e.g., amivantamab ((JNJ-61186372, JNJ-372))).

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

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

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

[0016] In one embodiment, the Disclosure provides a method for treating a subject having or at risk of developing a CDK2-related disease or disorder, comprising administering a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, to the subject having an amplified CCNE1 gene and / or a CCNE1 expression level higher than the control expression level of CCNE1. In some embodiments, the CDK2-related disease or disorder is cancer.

[0017] This disclosure also provides a method for treating a subject having or at risk of developing a CDK2-related disease or disorder, the method comprising administering a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, to a subject having an amplification of the CCNE1 gene and / or a CCNE1 expression level similar to a control expression level of CCNE1. In some embodiments, the CDK2-related disease or disorder is cancer.

[0018] Furthermore, this specification also provides a method for treating patients who have amplified levels of CCNE1 expression and who have or are at risk of developing solid tumor cancer, the method comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0019] The targeted solid tumor cancer may be at least one of the following: uterine cancer (including uterine carcinosarcoma and endometrial carcinoma of the uterine body (UCEC)), endometrial cancer, breast cancer (including invasive breast cancer, TNBC (triple-negative breast cancer), ER (estrogen receptor) + HER2 (human epidermal growth factor 2)-breast cancer, HR (hormone receptor) + HER2 (human epidermal growth factor 2)-breast cancer, HER2-breast cancer, and HER2+ breast cancer), ovarian cancer (e.g., ovarian serous cysts) Adenocarcinoma), gastric cancer (including gastric adenocarcinoma), gastric cancer (including gastrointestinal stromal tumors), 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 cancer and esophageal adenocarcinoma), bladder cancer (including urothelial carcinoma of the bladder (BLCA)), lung cancer (squamous cell carcinoma of the lung and non-small cell lung cancer, e.g., EGFRm (epidermal growth factor receptor variant) + non-small cell lung cancer), cholangiocarcinoma, adrenocortical carcinoma, or mesothelioma. [Modes for carrying out the invention]

[0020] definition As used herein, the term "halo" means halogen, and includes chloro, fluoro, bromo, and iodine.

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

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

[0023] The term "aromatic ring system" is known in the art and refers to a monocyclic, bicyclic, or polycyclic hydrocarbon ring system in which at least one ring is aromatic.

[0024] The term "aryl" refers to a monovalent radical of an aromatic ring system. Typical aryl groups include complete aromatic ring systems, such as phenyl, cyclooctatetraene, indene, and naphthyl, as well as ring systems in which an aromatic carbon ring is fused to one or more non-aromatic carbon rings, such as indanyl, phthaliumidyl, naphthimidyl, or tetrahydronaphthyl. The number of ring members specifies the number of ring members in the fused ring system. An aryl group may be written, for example, as a 6- to 10-membered aryl, in which case the term "member" refers to a ring atom that is not a hydrogen atom within the part.

[0025] The term "cycloalkyl" refers to a saturated hydrocarbon ring system. Unless otherwise specified, cycloalkyls have 3 to 10 carbon atoms. In some embodiments, cycloalkyls have 3 to 6 carbon atoms. For example, C3-C 10Examples of cycloalkyl compounds include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentane, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[3.2.1]octane, bicyclo[4.1.1]octane, spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane, spiro[2.6]nonane, spiro[2.7]decane, spiro[3.3]heptane, spiro[3.4]octane, spiro[3.5]nonane, spiro[3.6]decane, spiro[4.4]nonane, and spiro[4.5]decane. Unless otherwise specified, "cycloalkyl" compounds have 3 to 10 carbon atoms.

[0026] The term "cycloalkoxy" refers to an -O-cycloalkyl group.

[0027] The term “heterocyclyl” or “heterocyclic” refers to a 4- to 12-membered non-aromatic ring system having a ring carbon atom and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, quaternary nitrogen, nitrogen oxides (e.g., NO), oxygen, and sulfur (including sulfoxides and sulfones) ("4- to 12-membered heterocyclyl"). In some embodiments, the heterocyclyl is a 3- to 6-membered or 4- to 6-membered non-aromatic ring system having a ring carbon atom and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, quaternary nitrogen, nitrogen oxides (e.g., NO), oxygen, and sulfur (including sulfoxides and sulfones). In some embodiments, the heterocyclyl has 1 to 2 ring heteroatoms, where each heteroatom is independently selected from nitrogen, quaternary nitrogen, nitrogen oxides (e.g., NO), oxygen, and sulfur (including sulfoxides and sulfones). In a heterocyclyl group containing one or more nitrogen atoms, the bond site can be a carbon or nitrogen atom, as long as the valence allows. Examples of heterocyclyl groups include azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, azepanyl, oxepanyl, thiepanyl, tetrahydropyridinyl, 2-oxabicyclo[2.1.1]hexane, 5-oxabicyclo[2.1.1]hexane, 3-oxabicyclo[3.1.0]hexane, 2-oxabicyclo[2.1.1]heptane, 7-oxabicyclo[2.2.1]heptane, 3-oxabicyclo[3.1.1]heptane, 6-oxabicyclo[3.1.1]heptane, 2-oxabicyclo[2.2.2]octane, 7-oxabicyclo[4.1.1]octane, and 8-oxabicyclo[3.2.1]octane.

[0028] The term "heteroaryl" refers to a radical of a 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having a ring carbon atom and 1 to 4 ring heteroatoms within an aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur (e.g., a monocyclic or bicyclic 4n+2 aromatic ring system). ("5-10 membered heteroaryl"). In a heteroaryl group containing one or more nitrogen atoms, the bond site can be a carbon or nitrogen atom, as long as the valence allows. A heteroaryl bicyclic system may contain one or more heteroatoms in one or both rings. "Heteroaryl" also includes ring systems in which the heteroaryl rings defined above are fused with one or more aryl groups, and where the bond site is located in an aryl or heteroaryl ring; in such cases, the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups where one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl), the bond site can be on either ring. That is, it can be on either a ring with a heteroatom (e.g., 2-indolyl) or a ring without a heteroatom (e.g., 5-indolyl). Heteroaryl groups are sometimes written as, for example, 6- to 10-membered heteroaryls, in which case the term "member" refers to a ring atom that is not a hydrogen atom within the part.

[0029] It will be apparent to those skilled in the art that certain compounds disclosed herein may exist in tautomeristic forms, and all such tautomeristic forms of compounds are within the scope of this disclosure. The term "tautomer" refers to a compound in which a particular compound structure is interchangeable, with altered substitutions of hydrogen atoms and electrons. Thus, the two structures may be in equilibrium through the transfer of π electrons and atoms (usually H).

[0030] Compounds of the Disclosure This specification discloses embodiments of compounds having the general structure of formula (I). The present invention provides compounds of the present invention or pharmaceutically acceptable salts thereof for use in the treatment of cancer. These compounds are selective inhibitors of CDK2.

[0031] In the first embodiment, the present disclosure provides a compound represented by the following structural formula (I):

Chemical formula

[0032] In some embodiments, the compound is the compound of formula (II): [ka] or a pharmaceutically acceptable salt thereof.

[0033] In some embodiments, X2 is -O-, -(CHR d ) n -, -NRb -, -NR b -(CHR c ) m -, and -O-(CHR c ) m - Selected from the group consisting of these.

[0034] In some embodiments, X 2 is -O-, -(CHR d )n-, -NR b -(CHR c )-, and -O-(CHR c Selected from the group consisting of )-.

[0035] In some embodiments, X2 is -O-, -CH2-, -NH-, -N(CH3)-, [ka] It is selected from the group consisting of the following.

[0036] In some embodiments, X2 is -O-, -CH2-, -NH-, -N(CH3)-, [ka] It is selected from the group consisting of the following.

[0037] In certain embodiments, X2 is -O-.

[0038] In some embodiments, the compound is the compound of formula (III): [ka] or a pharmaceutically acceptable salt thereof.

[0039] In some embodiments, ring B is a C3-C8 cycloalkyl or a 4-10 membered heterocycline, where the C3-C8 cycloalkyl has 1-4 R a They may be substituted with, and the 4-10 member heterocyclyls are O, S, N, and NR bEach ring has 1 to 4 ring heteroatoms independently selected from the group consisting of and further has 1 to 4 R on the ring carbon a It may be replaced with.

[0040] In some embodiments, ring B is a C3-C8 cycloalkyl or a 4-10 membered heterocycline, where the C3-C8 cycloalkyl may be substituted with 1-4 groups selected from the group consisting of -NH2, OH, and =O, and the 4-10 membered heterocycline may be O, S, N, and NR b Each ring heteroatom is independently selected from the group consisting of , and may be further substituted on the ring carbon with 1 to 4 groups selected from the group consisting of -NH2, OH, and =O.

[0041] In some embodiments, ring B is a C4-C6 cycloalkyl or a 4-8 membered heterocycline, and the C4-C6 cycloalkyl has 1-4 R a They may be substituted with, and 4-8 member heterocyclyls are O, S, N, and NR b Each ring has 1 to 4 ring heteroatoms independently selected from the group consisting of and further has 1 to 4 R on the ring carbon a It may be replaced with.

[0042] In some embodiments, ring B is a C4-C6 cycloalkyl or a 4-8 membered heterocycline, where the C4-C6 cycloalkyl may be substituted with 1-4 groups selected from the group consisting of -NH2, OH, and =O, and the 4-8 membered heterocycline may be O, S, N, and NR b Each ring heteroatom is independently selected from the group consisting of , and may be further substituted on the ring carbon with 1 to 4 groups selected from the group consisting of -NH2, OH, and =O.

[0043] In some embodiments, ring B is selected from the group consisting of cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, and 1,4-diazepanyl, and cyclopentyl and cyclohexyl have 1 to 4 R aThey may be substituted with R on their N atoms(s), and piperidinyl, piperazinyl, and 1,4-diazepanyl may be substituted with R on their N atoms(s). b It may also be substituted with, and furthermore, 1 to 4 R on the ring carbon a It may be replaced with.

[0044] In some embodiments, ring B is selected from the group consisting of cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, and 1,4-diazepanyl, and cyclopentyl and cyclohexyl may be substituted with 1 to 4 groups selected from the group consisting of -NH2, OH, and =O, and piperidinyl, piperazinyl, and 1,4-diazepanyl have R on the N atom. b It may be substituted with, and further substituted on the ring carbon with 1 to 4 groups selected from the group consisting of -NH2, OH, and =O.

[0045] In some embodiments, ring B is [ka] [ka] [ka] It is selected from the group consisting of the following.

[0046] In some embodiments, ring B is [ka] [ka] It is selected from the group consisting of the following.

[0047] In some embodiments, ring B is [ka] It is selected from the group consisting of the following.

[0048] In some embodiments, R 3 is selected from the group consisting of H, C1-C4 alkyl, CN, -SO2C1-C4 alkyl, and -S(O)NH-C1-C4 alkyl.

[0049] In some embodiments, R 3 is selected from the group consisting of H, methyl, ethyl, CN, -S(O)2CH3, and -S(O)NHCH3. In certain embodiments, R 3 is H.

[0050] In some embodiments, R 4 is selected from the group consisting of H, C1-C4 alkyl, and C3-C6 cycloalkyl.

[0051] In some embodiments, R 4 is selected from the group consisting of H, methyl, ethyl, and cyclopropyl. In certain embodiments, R 4 is H.

[0052] In some embodiments, R 5 is H.

[0053] In some embodiments, R c is selected from H and C1-C4 alkyl optionally substituted with 1 to 4 halos.

[0054] In some embodiments, R c is selected from the group consisting of H, methyl, ethyl, -CH2F, and -CF3.

[0055] In some embodiments, m is 1 or 2.

[0056] In some embodiments, the compound is a compound of formula (IVa):

Chemical formula

[0057] In some embodiments, R d This is selected from H and methyl.

[0058] In some embodiments, the compound is the compound of formula (IVb): [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, R 1 The group is selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, C3-C8 cycloalkyl, and 4-10 membered heterocyclyl, and C1-C4 alkyl, C1-C4 alkoxy, and C3-C8 cycloalkyl each have 1-3 R a They may be substituted with, and the 4-10 member heterocyclyls are O, S, N, and NR b Each ring has 1 to 3 ring heteroatoms independently selected from the group consisting of and further has 1 to 3 R on the ring carbon a It may be replaced with, X 2 -NR b -or-NR b -(C(R c )2) m -and, R 2 The C1-C4 alkyl group is selected from C1-C4 alkyl groups and ring A, and the C1-C4 alkyl group may be substituted with 1-3 groups independently selected from the group consisting of halo, CN, and OH. Ring A is selected from the group consisting of C3-C8 cycloalkyl, 4-10 membered heterocyclyl, 6-10 membered aryl, and 4-10 membered heteroaryl, and C3-C8 cycloalkyl and 6-10 membered aryl each have 1-3 R a They may be substituted with 4-10 member heterocyclyls and 4-10 member heteroaryls, O, S, N, and NR. b Each ring has 1 to 3 ring heteroatoms independently selected from the group consisting of and further has 1 to 3 R on the ring carbon a It may be replaced with, R 3 is H or C1-C4 alkyl, Each R a R is independently selected from the group consisting of halo, OH, CN, C1-C4 alkyl, and C1-C4 alkoxy, or two R atoms bonded to the same atom. a The O group forms an O group, and the C1-C4 alkyl and C1-C4 alkoxy groups may each be substituted with 1 to 3 groups independently selected from the group consisting of halo, OH, and CN. Each R b These are independently H or C1-C4 alkyl groups, and the C1-C4 alkyl groups may be substituted with 1-4 D atoms. Each R c These are independently H or C1-C4 alkyl groups. m is either 1 or 2.

[0059] In some embodiments, R 1 The group is selected from CN, C1-C4 alkyl, C1-C4 alkoxy, -C3-C6 cycloalkyl, -(CH2)-C3-C6 cycloalkyl, -O(CH2)-C3-C6 cycloalkyl, 4-6 membered heterocyclyl, -O-(4-6 membered heterocyclyl), -O(CH2)-(4-6 membered heterocyclyl), and -(CH2)-phenyl, and C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, and phenyl have 1-3 R a These may be substituted in each case, and the 4-6 member heterocyclyls are O, S, N, and NR. bEach ring has 1 to 3 ring heteroatoms independently selected from the group consisting of and further has 1 to 3 R on the ring carbon a It may be replaced with.

[0060] In some embodiments, R 1 The group is selected from the group consisting of CN, C1-C4 alkyl, C1-C4 alkoxy, -C3-C6 cycloalkyl, -(CH2)-C3-C6 cycloalkyl, -O(CH2)-C3-C6 cycloalkyl, 4- to 6-membered heterocyclyl, -O-(4- to 6-membered heterocyclyl), -O(CH2)-(4- to 6-membered heterocyclyl), and -(CH2)-phenyl. The C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, and phenyl may each be substituted with 1 to 3 groups selected from the group consisting of fluoro, OH, CN, methyl, and methoxy, and the 4- to 6-membered heterocyclyl may be O, S, N, and NR. b Each ring heteroatom is independently selected from the group consisting of , and may be further substituted on the ring carbon with 1 to 3 groups selected from the group consisting of fluoro, OH, CN, methyl, and methoxy.

[0061] In some embodiments, R 1 The group is selected from CN, C1-C4 alkyl, C1-C4 alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, -(CH2)-cyclopropyl, -O(CH2)-cyclopropyl, -O(CH2)-tetrahydrofuranyl, -O-tetrahydropyranyl, and -(CH2)-phenyl, and C1-C4 alkyl, C1-C4 alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, and phenyl have 1-3 R on the ring carbon. a It may be replaced with.

[0062] In some embodiments, R 1The group is selected from the group consisting of CN, C1-C4 alkyl, C1-C4 alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, -(CH2)-cyclopropyl, -O(CH2)-cyclopropyl, -O(CH2)-tetrahydrofuranyl, -O-tetrahydropyranyl, and -(CH2)-phenyl, and the C1-C4 alkyl, C1-C4 alkoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, and phenyl may be substituted on the ring carbon with 1 to 3 groups selected from the group consisting of fluoro, OH, CN, methyl, and methoxy.

[0063] In some embodiments, R 1 is a C1-C4 alkoxy substituted with 1-3 halos. In some embodiments, R 1 is a C1-C4 alkoxy substituted with 1-3 fluorocarbons. In some embodiments, R 1 It is -OCHF2.

[0064] In some embodiments, R 1 Methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -CD3, -CD2H, -CDH2, -CF3, -CH2F, -CHF2, CN, methoxy, ethoxy, isopropoxy, -OCHF2, [ka] [ka] [ka] It is selected from the group consisting of the following.

[0065] In some embodiments, R 1 methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -CHF2, CN, methoxy, ethoxy, isopropoxy, -OCHF2, [ka] [ka] [ka] It is selected from the group consisting of the following.

[0066] In some embodiments, R 1 methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -CHF2, CN, methoxy, ethoxy, isopropoxy, -OCHF2, [ka] [ka] It is selected from the group consisting of the following.

[0067] In some embodiments, R 2 This is a C1-C4 alkyl group that may be substituted with 1-4 groups independently selected from the group consisting of D, halo, CN, and OH.

[0068] In some embodiments, R 2 is a C1-C4 alkyl group which may be substituted with 1-4 OH groups. In some embodiments, R 2 This is a C1-C4 alkyl group that may be substituted with an OH group.

[0069] In some embodiments, R 2 This is ethyl, which may be substituted with an OH group.

[0070] In some embodiments, R 2 methyl, ethyl, -CH2F, -CHF2, [ka] It is selected from the group consisting of the following.

[0071] In some embodiments, R 2 is ethyl, [ka] Selected from the group consisting of R 2 is ethyl, [ka] It is selected from the group consisting of the following.

[0072] In some embodiments, ring A is O, S, N, and NR b A 4-10 membered heterocyclyl having 1-3 ring heteroatoms independently selected from the group consisting of, and further having 1-3 R on the ring carbon a It may be replaced with.

[0073] In some embodiments, ring A is selected from the group consisting of C3-C6 cycloalkyl, 4-10 membered heterocyclyl, and 4-10 membered heteroaryl, where the C3-C6 cycloalkyl has 1-3 R a They may be substituted with 4-10 member heterocyclyls and 4-10 member heteroaryls, O, S, N, and NR. b Each ring has 1 to 3 ring heteroatoms independently selected from the group consisting of and further has 1 to 3 R on the ring carbon a It may be replaced with.

[0074] In some embodiments, ring A is selected from the group consisting of C3-C6 cycloalkyl, 4-10 membered heterocyclyl, and 4-10 membered heteroaryl, where the C3-C6 cycloalkyl may be substituted with 1-3 groups selected from the group consisting of fluoro, CN, methyl, ethyl, isopropyl, methoxy, and oxo, and the 4-10 membered heterocyclyl and 4-10 membered heteroaryl may be O, S, N, and NR bEach ring has 1 to 3 ring heteroatoms independently selected from the group consisting of , and may further be substituted on the ring carbon with 1 to 3 groups selected from the group consisting of fluoro, CN, methyl, ethyl, isopropyl, methoxy, and oxo.

[0075] In some embodiments, ring A is cyclopropyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 1,4-dioxanyl, pyrrolidinyl, piperidinyl, 5-azabispiro[2.5]octanyl, 1-azabicyclo[2.2.1]heptanyl, quinuclidinyl, 3-azabicyclo[3.1.1]heptanyl, 8-azabicyclo[3.2.1]octanyl, azepanyl, 9-azabicyclo [3.3.1] Selected from the group consisting of nonanyl, 2-azaspiro[3.3]heptanyl, 3-azabicyclo[3.2.0]heptanyl, quinolyl, oxazolyl, phenyl, pyridyl, and pyridazyl, and cyclopropyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 1,4-dioxanyl, quinolyl, oxazolyl, phenyl, pyridyl, and pyridazyl, which have 1 to 4 R on the ring carbon. a Pyrrolidinyl, piperidinyl, 5-azabispiro[2.5]octanyl, 1-azabicyclo[2.2.1]heptanyl, quinuclidinyl, 3-azabicyclo[3.1.1.]heptanyl, 8-azabicyclo[3.2.1]octanyl, azepanyl, 9-azabicyclo[3.3.1]nonanyl, 2-azabispiro[3.3]heptanyl, and 3-azabicyclo[3.2.0]heptanyl may be substituted with R on its N atom. b It may also be substituted with, and furthermore, 1 to 4 R on the ring carbon a It may be replaced with.

[0076] In some embodiments, ring A is selected from the group consisting of cyclopropyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 1,4-dioxanyl, pyrrolidinyl, piperidinyl, 5-azabicyclo[2.5]octanyl, 1-azabicyclo[2.2.1]heptanyl, quinuclidinyl, 3-azabicyclo[3.1.1]heptanyl, 8-azabicyclo[3.2.1]octanyl, azepanyl, 9-azabicyclo[3.3.1]nonanyl, 2-azabicyclo[3.3]heptanyl, 3-azabicyclo[3.2.0]heptanyl, quinolyl, oxazolyl, phenyl, pyridyl, and pyridazyl, and cyclopropyl, cyclopentyl, cyclohexyl, oxetanyl Cetanyl, tetrahydrofuranyl, tetrahydropyranyl, 1,4-dioxanyl, quinolyl, oxazolyl, phenyl, pyridyl, and pyridazyl may be substituted on the ring carbon with 1 to 4 groups selected from the group consisting of fluoro, CN, methyl, ethyl, isopropyl, methoxy, and oxo, while pyrrolidinyl, piperidinyl, 5-azabispiro[2.5]octanyl, 1-azabicyclo[2.2.1]heptanyl, quinuclidinyl, 3-azabicyclo[3.1.1.]heptanyl, 8-azabicyclo[3.2.1]octanyl, azepanyl, 9-azabicyclo[3.3.1]nonanyl, 2-azabispiro[3.3]heptanyl, and 3-azabicyclo[3.2.0]heptanyl may be substituted on the N atom with R b It may be substituted with, and further substituted on the ring carbon with 1 to 4 groups selected from the group consisting of fluoro, CN, methyl, ethyl, isopropyl, methoxy, and oxo.

[0077] In some embodiments, ring A is piperidinyl, and R is located on its N atom. bIt may be substituted with, and further substituted on the ring carbon with 1 to 4 groups selected from the group consisting of fluoro, CN, methyl, ethyl, isopropyl, methoxy, and oxo. In some embodiments, ring A is piperidinyl and its N atom may be substituted with a C1-C4 alkyl group. In some embodiments, ring A is piperidinyl and its N atom may be substituted with a methyl group. In certain embodiments, ring A is piperidinyl substituted with a methyl group on its N atom.

[0078] In some embodiments, ring A is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] It is selected from the group consisting of the following.

[0079] In some embodiments, ring A is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] It is selected from the group consisting of the following.

[0080] In a particular embodiment, ring A is [ka] That is the case.

[0081] In some embodiments, R a is Halo, OH, CN, N(R) b )2. Selected from the group consisting of C1-C4 alkyl and C1-C4 alkoxy, or two R atoms bonded to the same atom a The group forms an O group, and the C1-C4 alkyl and C1-C4 alkoxy groups may each be substituted with 1 to 4 groups independently selected from the group consisting of D, halo, OH, and CN. In some embodiments, R a is Halo, OH, CN, N(R) b )2. Selected from the group consisting of C1-C4 alkyl and C1-C4 alkoxy, or two R atoms bonded to the same atom aHowever, it forms =O. In some embodiments, halo, OH, CN, C1-C4 alkyl, and C1-C4 alkoxy, or two R bonded to the same atom a However, it forms =O.

[0082] In some embodiments, R a The group consists of fluoro, chloro, OH, CN, methyl, ethyl, isopropyl, CD3, CD2H, CDH2, CF3, CHF2, CH2F, CH2CN, methoxy, ethoxy, and NH2, and has two R atoms bonded to the same atom. a In some embodiments, R a The group is selected from fluoro, OH, cyano, methyl, CD3, CF3, isopropyl, methoxy, oxo, and NH2.

[0083] In some embodiments, n is 1.

[0084] In some embodiments, the compound is a compound of formula (Va), [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, R 1 It is a C1-C4 alkyl or C1-C4 alkoxy, with 1-3 R a It may be replaced with, or O, S, N, and NR b A 4-10 membered heterocyclyl having 1-3 ring heteroatoms independently selected from the group consisting of, and further having 1-3 R on the ring carbon a It may be replaced with, R 2 R is a ring A selected from the group consisting of phenyl, 4-6 membered heterocyclyl, and 6 membered heteroaryl, where phenyl has 1-3 R a They may be substituted with, and 4-6 member heterocyclyls are O, S, N, and NR b Each ring has 1 to 3 ring heteroatoms independently selected from the group consisting of and further has 1 to 3 R on the ring carbona They may be substituted with, and the 6-membered heteroaryl has 1 to 3 ring heteroatoms independently selected from the group consisting of O, S, and N, and further 1 to 3 R on the ring carbon a It may be replaced with, R 3 is H or C1-C4 alkyl, Each R a R is independently selected from the group consisting of halo, OH, CN, C1-C4 alkyl, and C1-C4 alkoxy, or two R atoms bonded to the same atom. a However, it forms =O, Each R b These are independently H or C1-C4 alkyl groups.

[0085] In some embodiments, the compound is a compound of formula (VIa) or (VIb), [ka] or a pharmaceutically acceptable salt thereof.

[0086] In some embodiments, the compound is the compound of formula (Vb), [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, R 1 It is a C1-C4 alkyl or C1-C4 alkoxy, with 1-3 R a It may be replaced with, or O, S, N, and NR b A 4-10 membered heterocyclyl having 1-3 ring heteroatoms independently selected from the group consisting of, and further having 1-3 R on the ring carbon a It may be replaced with, R 2 R is a ring A selected from the group consisting of phenyl, 4-6 membered heterocyclyl, and 6 membered heteroaryl, where phenyl has 1-3 R a They may be substituted with, and 4-6 member heterocyclyls are O, S, N, and NR bEach ring has 1 to 3 ring heteroatoms independently selected from the group consisting of and further has 1 to 3 R on the ring carbon a They may be substituted with, and the 6-membered heteroaryl has 1 to 3 ring heteroatoms independently selected from the group consisting of O, S, and N, and further 1 to 3 R on the ring carbon a It may be replaced with, R 3 is H or C1-C4 alkyl, Each R a R is independently selected from the group consisting of halo, OH, CN, C1-C4 alkyl, and C1-C4 alkoxy, or two R atoms bonded to the same atom. a However, it forms =O, Each R b These are independently H or C1-C4 alkyl groups.

[0087] In some embodiments, the compound is a compound of formula (VIc) or (VId), [ka] or a pharmaceutically acceptable salt thereof.

[0088] In some embodiments, R b This is selected from H and methyl.

[0089] In one embodiment, the compound is a compound selected from the following two tables or a pharmaceutically acceptable salt thereof. [Table 2-1] [Table 2-2] [Table 2-3] [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 Table 3-60 Table 3-61 Table 3-62 Table 3-63 Table 3-64 Table 3-65 Table 3-66 Table 3-67 Table 3-68 Table 3-69 Table 3-70 [Table 3-71] [Table 3-72] [Table 3-73] [Table 3-74] [Table 3-75] [Table 3-76] [Table 3-77]

[0090] Previous examples 78 and 211 have been intentionally excluded, and previous examples 257 and 258 have been renumbered as examples 78 and 211, respectively. New examples 257, 258, and 259 have been added.

[0091] The term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable salt that, within the bounds of sound medical judgment, is suitable for use in contact with human and lower animal tissues without causing excessive toxicity, irritation, or allergic reactions, and that has a reasonable benefit-risk ratio. Pharmacologically acceptable salts are well known in the art. For example, SMBerge et al. describe pharmaceutically acceptable salts in J. Pharm. Sci., 1977, 66, 1-19.

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

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

[0094] If the stereochemical configuration at a chiral center in a compound having one or more chiral centers is indicated by its chemical name (e.g., if the configuration is indicated by "R" or "S" in the chemical name) or structure (e.g., if the configuration is indicated by a "wedge" bond), then the concentration 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). The "concentration of the indicated configuration relative to the opposite configuration" is expressed in mole percent and is determined by dividing the number of compounds having the stereochemical configuration indicated by the chiral center(s) by the total number of compounds in the mixture having the same or opposite stereochemical configurations.

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

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

[0097] If a disclosed compound having a chiral center is shown by structure without indicating the configuration at the chiral center, this structure means that it encompasses compounds having an S configuration at the chiral center, compounds having an R configuration at the chiral center, or compounds having a mixture of R and S configurations at the chiral center. If a disclosed compound having a chiral center is represented by its chemical name without indicating the configuration at the chiral center with "S" or "R", this chemical name means that it encompasses compounds having an S configuration at the chiral center, compounds having an R configuration at the chiral center, or compounds having a mixture of R and S configurations at the chiral center.

[0098] A racemic mixture means a mixture in which one enantiomer is 50% and its corresponding enantiomer is 50%. This instruction encompasses all enantiomerically pure, enantiomerically concentrated, diastereomerically pure, diastereomerically concentrated racemic and diastereomeric mixtures of the compounds disclosed herein.

[0099] Enantiomerous and diastereomerous mixtures can be decomposed into their enantiomers or stereoisomers by known methods, including chiral phase gas chromatography, chiral phase high-performance liquid chromatography, crystallization of compounds as chiral salt complexes, or crystallization of compounds in chiral solvents. Enantiomers and diastereomers can also be obtained from diastereomerically or enantiomerically pure intermediates, reagents, and catalysts by known asymmetric synthesis methods.

[0100] In the experimental section, "Peak 1" refers to the target reaction product obtained from chromatographic separation / purification. This reaction product elutes faster than the second target reaction product from the same aforementioned reaction. The second target product is called "Peak 2".

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

[0102] If the stereochemistry of a disclosed compound is specified or shown by structure, and this specified or shown structure encompasses two or more stereoisomers (for example, as in the case of a diastereomer pair), it should be understood that, unless otherwise indicated, it will contain one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers. It should further be understood that the stereoisogenic purity of the specified or shown stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight. In this case, the stereoisogenic purity is determined by dividing the total weight of the mixture of stereoisomers encompassed by name or structure by the total weight of the mixture of all stereoisomers.

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

[0104] As used herein, many parts (e.g., alkyl, alkoxy, cycloalkyl, or heterocyclyl) are referred to as “substituted” or “may be substituted.” When a part is modified by one of these terms, unless otherwise specified, it means that any part of the part known to those skilled in the art as being available for substitution may be substituted, and this includes one or more substituents. If more than one substituent is present, each substituent may be selected independently. Such substitution methods are well known in the art and / or taught herein. Any optional substituent may be any substituent suitable for bonding to this part.

[0105] The compounds disclosed herein are CDK2 inhibitors. As used herein, the term “selective CDK2 inhibitor” means a compound that selectively inhibits CDK2 more than other CDKs and quinomes. In other words, selective CDK2 inhibitors have no activity or low activity towards other CDKs and quinomes. The inhibitory activity of selective CDK2 inhibitors towards CDK2 is compared to their inhibitory activity towards other CDKs and many other kinases, with respect to IC2. 50 value( すなわち It is more effective in terms of having an IC50 value of less than nanomoles. Its effectiveness can be measured using known biochemical assays.

[0106] In some embodiments, the compounds of the present disclosure are selective to CDK2 compared to CDK1. In some such embodiments, the compounds exhibit at least 10 times greater selectivity to CDK2 compared to CDK1. In other embodiments, the compounds exhibit at least 20 times greater selectivity to CDK2 compared to CDK1. In certain embodiments, the compounds exhibit at least 30 times greater selectivity to CDK2 compared to CDK1. In certain embodiments, the compounds exhibit at least 40 times greater selectivity to CDK2 compared to CDK1. In other embodiments, the compounds exhibit at least 50 times greater selectivity to CDK2 compared to CDK1. For example, the compounds exhibit at least 100 times greater selectivity to CDK2 compared to CDK1. In some embodiments, the compounds of the present invention are selective to CDK2 compared to CDK4 and / or CDK6. In some such embodiments, the compounds exhibit at least 10 times greater selectivity to CDK2 compared to CDK4 and / or CDK6. In other embodiments, the compound exhibits at least 20 times greater selectivity for CDK2 compared to CDK4 and / or CDK6. In specific embodiments, the compound exhibits at least 30 times greater selectivity for CDK2 compared to CDK4 and / or CDK6.

[0107] Some compounds of this disclosure have the advantage of good metabolic stability. One indicator of good metabolic stability is high microsomal stability. Hepatic metabolism is the dominant excretion pathway for small molecule drugs. The clearance of compounds 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 consumption of the compound is measured to determine the intrinsic clearance (Clint) in vitro. Clint is scaled to systemic clearance (CL), and the hepatic extraction rate (ER) is determined by dividing CL by the standard human hepatic blood flow. Compounds with a low hepatic extraction rate are considered to have good metabolic stability. In some embodiments, the compounds of this disclosure have calculated ERs <0.3, <0.4, <0.5, and <0.6. In some embodiments, the compounds of this disclosure may eliminate certain side effects, such as drug interactions.

[0108] Pharmaceutical composition The pharmaceutical compositions of this disclosure (also referred to herein as “Disclosed Pharmaceutical Compositions”) comprise one or more pharmaceutically acceptable carriers or diluents and one of the compounds of this disclosure (e.g., compounds of formulas (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId)) or a pharmaceutically acceptable salt thereof.

[0109] "Pharmacopoeia-acceptable carriers" and "pharmacopoeia-acceptable diluents" refer to substances that can be included in the pharmaceutical compositions of this disclosure without causing significant adverse toxicity to the subject, while assisting the formulation and / or administration of the active agent to and / or absorption by the subject. Non-limiting examples of pharmacopoeia-acceptable carriers and / or diluents include water, NaCl, physiological saline, lactated Ringer's solution, usually sucrose, usually glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates (such as lactose, amylose, or starch), hydroxymethylcellulose, fatty acid esters, polyvinylpyrrolidine, and colorants. Such preparations can be sterilized and, if necessary, mixed with adjuvants such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts to affect osmotic pressure, buffers, colorants, and / or fragrances, which do not react adversely 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 compound or pharmaceutically acceptable salts thereof.

[0110] The pharmaceutical compositions of this disclosure may contain one or more pharmaceutically acceptable carriers and / or diluents therefor, examples of which include lactose, starch, cellulose, and dextrose. Other excipients such as flavoring additives and sweeteners, and preservatives such as methyl, ethyl, propyl, and butylparabens may also be included. Handbook of Pharmaceutical Excipients (5) thA more complete list of suitable excipients can be found in Ed., Pharmaceutical Press (2005). Those skilled in the art will know how to prepare formulations suitable for various routes of administration. Conventional procedures and components for the selection and preparation of suitable formulations are described, for example, in Remington's Pharmaceutical Sciences (2003-20th edition) and in The United States Pharmacopeia: The National Formulary (USP 24 NF19), published in 1999. Carriers, diluents, and / or excipients are “acceptable” in the sense that they are compatible with the other components of the pharmaceutical composition and are not harmful to its recipient. Treatment methods

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

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

[0113] A subject who "needs to inhibit CDK2" is a subject with a disease in which inhibiting CDK2 can achieve beneficial therapeutic effects, such as delaying disease progression, alleviating one or more disease-related symptoms, or extending the subject's lifespan considering the disease.

[0114] In some embodiments, the Disclosure provides methods for treating diseases / conditions / or cancers related to or modulated by CDK2, wherein inhibition of CDK2 is therapeutically beneficial, including, but not limited to, the treatment of cancer in subjects requiring treatment for cancer. The methods include administering an effective amount of one of the compounds disclosed herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein to a subject.

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

[0116] Therefore, in some embodiments of this method, the subject or patient is predetermined to have amplification of the cyclin E1 (CCNE1) gene and / or a CCNE1 expression level higher than the control expression level of CCNE1 in the biological sample obtained from that subject or patient.

[0117] In another embodiment, the Disclosure provides a method for inhibiting the growth of tumor (e.g., cancer) cells in vitro. This method involves contacting tumor (e.g., cancer) cells in vitro with a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof. In another embodiment, the Disclosure provides a method for inhibiting the growth of tumor (e.g., cancer) cells, involving amplification and / or overexpression of CCNE1 in a subject or patient. This method involves administering a therapeutically effective amount of a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId), or a pharmaceutically acceptable salt thereof, to a subject or patient in need.

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

[0119] As used herein, “cancer” means any malignant and / or invasive growth or tumor caused by abnormal cell proliferation. Cancers include solid tumors, blood, bone marrow, or lymphoid cancers, named after the type of cells that form them. Examples of solid tumors include sarcomas and carcinomas. Blood cancers include, but are not limited to, leukemia, lymphoma, and myeloma. Cancers also include primary cancers that occur in a specific site in the body, metastatic cancers that spread from the site of origin to other parts of the body, recurrence of the first primary cancer after remission, and secondary primary cancers (new primary cancers in people with a history of a different type of cancer than the latter). In some such embodiments, cancers are characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0120] Cancers treated according to the disclosed methods include breast cancer, ovarian cancer, bladder cancer, uterine cancer (e.g., uterine carcinosarcoma), prostate cancer (e.g., androgen receptor (AR)-dependent and AR-independent), lung cancer (including NSCLC, SCLC, squamous cell carcinoma (e.g., pulmonary 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)), kidney cancer (including RCC), liver cancer (including HCC), pancreatic cancer (including pancreatic adenocarcinoma (PAAD) and pancreatic ductal adenocarcinoma (PDAC)), gastric cancer (i.e., stomach cancer), urothelial carcinoma, brain cancer, mesothelioma (MESO), skin cancer (e.g., melanoma), sarcoma, or thyroid cancer, and metastases of all listed cancers (especially brain metastases).In one embodiment, cancer includes uterine cancer (including uterine carcinosarcoma (UCS) and endometrial carcinoma of the uterine body (UCEC)), endometrial cancer (including serous endometrial carcinoma (SEC)), breast cancer (invasive breast cancer (BRCA), TNBC (triple-negative breast cancer), HR+ breast cancer (hormone receptor-positive breast cancer), ER+ breast cancer (estrogen receptor-positive breast cancer), HR+ / HER2- breast cancer (hormone receptor-positive, human epidermal growth factor 2-negative breast cancer), ER+ / HER2- breast cancer (estrogen receptor-positive, human epidermal growth factor 2-negative breast cancer), PR+ / HER2- breast cancer (progesterone receptor-positive, human epidermal growth factor 2-negative breast cancer), HER2- breast cancer (human epidermal growth factor 2-negative breast cancer), HER2-low breast cancer (human epidermal growth factor 2-low level breast cancer), and HER2+ breast cancer (human epidermal growth factor 2-positive breast cancer)), ovarian cancer (e.g., ovarian serous cystadenocarcinoma (OV) and high-grade ovarian serous cystadenocarcinoma (OV)), and high-grade ovarian serous cystadenocarcinoma (OV) Malignant serous ovarian cancer (HGSOC), gastric cancer (including gastric adenocarcinoma (STAD)), gastric cancer (including gastrointestinal stromal tumors), colorectal cancer, pancreatic cancer (including pancreatic adenocarcinoma (PAAD) and pancreatic ductal adenocarcinoma (PDAC)), kidney cancer, head and neck cancer, liver cancer, prostate cancer (including androgen receptor (AR)-dependent, AR-independent, and castration-resistant prostate cancer (CRPC)), skin cancer, leukemia (including AML (acute myeloid leukemia)), lymphoma ( These include B-cell lymphoma, myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), sarcoma (SARC), esophageal cancer (including esophageal cancer (ESCA)), bladder cancer (including urothelial carcinoma of the bladder), lung cancer (squamous cell carcinoma of the lung, small cell lung cancer (SCLC), and non-small cell lung cancer (NSCLC), e.g., including EGFRm (epidermal growth factor receptor variant) + non-small cell lung cancer), cholangiocarcinoma, adrenocortical carcinoma (ACC), or mesothelioma. 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.

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

[0122] In further embodiments of the methods provided herein, the cancer is selected from the group consisting of breast cancer (including ER+ / HER2- breast cancer, HR+ / HER2- breast cancer, PR+ / HER2- breast cancer, and triple-negative breast cancer), endometrial cancer, esophageal cancer, gastric cancer, ovarian cancer, pancreatic cancer (including PDAC), and prostate cancer (including androgen receptor-positive (AR+) prostate cancer). In some embodiments of the methods provided herein, the cancer is selected from the group consisting of ovarian cancer, endometrial cancer, gastric cancer, esophageal cancer, triple-negative breast cancer, and pulmonary adenosarcoma. In some embodiments, the cancer is characterized by overexpression and / or amplification of CCNE1. In some embodiments, the cancer is progressing despite platinum therapy.

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

[0124] In some embodiments, the cancer is an adenocarcinoma, carcinoma, or cystadenoma.

[0125] In other embodiments, the cancer includes, 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 each of the aforementioned embodiments, the breast cancer is characterized by amplification and / or overexpression of CCNE1 and / or CCNE2.

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

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

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

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

[0130] In some embodiments, the cancer is lung cancer. In some such embodiments, the cancer is lung cancer characterized by amplification or overexpression of CCNE1 and / or CCNE2. In some such embodiments, the cancer is (a) lung cancer; (b) cancer characterized by amplification and / or overexpression of cyclin E1 (CCNE1) or cyclin E2 (CCNE2); or (c) both (a) and (b). In some embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In some embodiments, the lung cancer is small cell lung cancer (SCLC).

[0131] In some embodiments, the compounds of the Disclosure are administered as first-line therapy. In other embodiments, the compounds of the Disclosure are administered as second (or later)-line therapy. In some embodiments, the compounds of the Disclosure are administered as second (or later)-line therapy following treatment with endocrine agents and / or CDK4 / CDK6 inhibitors. In some embodiments, the compounds of the Disclosure are administered as second (or later)-line therapy following treatment with endocrine agents such as aromatase inhibitors, SERMs, or SERDs. In some embodiments, the compounds of the Disclosure are administered as second (or later)-line therapy following treatment with CDK4 / CDK6 inhibitors. In some embodiments, the compounds of the Disclosure are administered as second (or later)-line therapy following treatment with one or more chemotherapy regimens including, for example, taxanes, platinum-based drugs, pyrimidine antagonists, and / or gemcitabine. In some embodiments, the compounds of the Disclosure are administered as a second-line (or later-line) therapy following treatment with a HER2-targeted agent (e.g., trastuzumab). In some embodiments, the compounds of the Disclosure are administered as a second-line (or later-line) therapy following treatment with an EGFR inhibitor (e.g., osimertinib). In some embodiments, the compounds of the Disclosure are administered as a second-line (or later-line) therapy after treatment with a pyrimidine antagonist (e.g., 5-fluorouracil (5-FU)) and / or gemcitabine and / or a platinum-based agent (e.g., cisplatin).

[0132] In some embodiments, the cancers are N-myc-amplified neuroblastoma cells (see Molenaar, et al., Proc Natl Acad Sci USA 106(31):12968-12973), K-Ras mutant lung cancer (see Hu, S., et al., Mol Cancer Ther, 2015.14(11):2576-85), and cancers with FBW7 mutations and CCNE1 overexpression (see Takada, et al., Cancer Res, 2017.77(18):4881-4893).

[0133] Examples of cancers treatable with the compounds disclosed herein include bone cancer, pancreatic cancer, skin cancer, head and neck cancer, malignant melanoma of the skin or eye, uterine cancer, ovarian cancer, rectal cancer, anal cancer, gastric cancer, testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia including acute myeloid leukemia, and chronic bone cancer. Examples of environmentally induced cancers, including but not limited to myelic leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, childhood solid tumors, lymphocytic lymphoma, bladder cancer, kidney or urethral cancer, renal pelvis cancer, neoplasms of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axial tumors, brainstem gliomas, pituitary adenomas, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, asbestos-induced cancers, and combinations of the above cancers. The compounds of this disclosure are also useful in the treatment of metastatic cancers.

[0134] In some embodiments, cancers treatable with the compounds of the Disclosure include, but are not limited to, melanoma (e.g., metastatic melanoma, BRAF and HSP90 inhibitor-resistant melanoma, cutaneous melanoma (SKCM)), renal cell carcinoma (e.g., clear cell carcinoma), prostate cancer (e.g., hormone-resistant prostatic 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). Furthermore, the Disclosure includes refractory or recurrent malignancies whose growth can be inhibited by using the compounds of the Disclosure.

[0135] In some embodiments, cancers treatable with 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.), hematological cancers (e.g., lymphoma, leukemia (e.g., acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), etc.), DLBCL, mantle cell lymphoma, non-Hodgkin lymphoma (including relapsed or refractory NHL and relapsed follicular lymphoma), Hodgkin lymphoma or multiple myeloma), and combinations of the aforementioned cancers.

[0136] In some embodiments, cancers treatable with the compounds of the present disclosure include, but are not limited to, cholangiocarcinoma, 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 tumors, astrocytoma, neuroblastoma, neurofibroma, basal cell carcinoma, chondrosarcoma, epithelioid sarcoma, ocular cancer, fallopian tube cancer, gastrointestinal cancer, gastrointestinal stromal tumor, hairy cell leukemia, intestinal cancer, islet cell carcinoma, oral cancer, throat cancer, laryngeal cancer, lip cancer, mesothelioma, cervical cancer, nasal cavity cancer, eye cancer, melanoma of the eye, pelvic cancer, rectal cancer, renal cell carcinoma, salivary gland cancer, paranasal sinus cancer, spinal cord cancer, tongue cancer, tubular gland cancer, urethral cancer, and ureteral cancer.

[0137] In some embodiments, cancers treatable with the compounds of this disclosure include Genomic Identification of Significant Targets in Cancer (GISTIC), as well as pheochromocytoma and paraganglioma (PCPG).

[0138] In some embodiments, cancers treatable with the compounds of this disclosure include advanced / recurrent tumors, platinum-resistant or platinum-refractory ovarian cancer, endometrial cancer that has progressed after two or more lines of treatment (with a history of platinum therapy), gastric cancer that has progressed after two or more lines of treatment (with a history of platinum therapy), and HR+ / HER2-BC (including both ER+ HER2-BC and PR+ / HER2-BC) that has progressed despite CDK4 / 6i. In some embodiments, cancers treatable with the compounds of this disclosure include platinum-resistant or platinum-refractory CCNE1-amplified ovarian cancer, CCNE1-amplified endometrial cancer that has failed two or more lines of treatment, CCNE1-amplified advanced / recurrent tumors not belonging to the other group, HR+ / HER2-BC that has progressed despite CDK4 / 6i, and platinum-resistant or platinum-refractory CCNE1-amplified ovarian cancer. In one embodiment, the subject has a CCNE1-amplified advanced / recurrent tumor. In one embodiment, the subject has CCNE1-amplified platinum-resistant or platinum-refractory ovarian cancer. In one embodiment, the subject has endometrial cancer that has progressed after two or more lines of treatment (including platinum therapy) (the patient has previously received platinum therapy, for example, the patient has been treated with platinum therapy before). In one embodiment, the subject has CCNE1-amplified endometrial cancer that has failed two or more lines of treatment (which may include previous platinum therapy). In one embodiment, the subject has gastric cancer that has progressed after two or more lines of treatment (including platinum therapy) (the patient has previously received platinum therapy, for example, the patient has been treated with platinum therapy before). In one embodiment, the subject has HR+ / HER- breast cancer that has progressed despite treatment with one or more CDK4 / 6 inhibitors. In one embodiment, the subject has TNBC that has progressed despite one or more lines of treatment. In one embodiment, the subject has AR+ prostate cancer that has progressed despite one or more lines of treatment. In one embodiment, the subject has pancreatic cancer that has progressed despite one or more lines of treatment. In one embodiment, the subject has PDAC that has progressed despite one or more lines of treatment. In one embodiment, the subject suffers from lung cancer in which CCNE1 is amplified.In one embodiment, the subject has NSCLC that has progressed despite treatment with one or more EGFR inhibitors (e.g., osimertinib). In another embodiment, the subject has CCNE1-amplified NSCLC that has progressed despite treatment with one or more EGFR inhibitors (e.g., osimertinib).

[0139] In some embodiments, cancers treatable with the compounds of this disclosure include, but are not limited to, hematological cancers, sarcomas, lung cancers, gastrointestinal cancers, urogenital cancers, liver cancers, bone cancers, nervous system cancers, gynecological cancers, and skin cancers.

[0140] Exemplary blood cancers include lymphomas and leukemias, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin lymphoma (including relapsed or refractory NHL and relapsed follicular lymphoma), Hodgkin 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, rhabdomyosarcoma, fibroma, lipoma, hamartoma, and teratoma.

[0142] Examples of lung cancers include non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), bronchial cancer, squamous cell carcinoma, anaplastic small cell carcinoma, anaplastic large cell carcinoma, adenocarcinoma, alveolar epithelial (bronchiolar) carcinoma, bronchial adenoma, chondrodysartoma, and mesothelioma. Examples of 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), colorectal cancer (adenocarcinoma, tubular adenoma, chorioadenoma, hamartoma, leiomyoma), and colorectal cancer.

[0143] Exemplary urogenital 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, AR+ or AR-dependent prostate cancer, AR-independent prostate cancer, and CRPC), and testicular cancer (seminocarcinoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, and lipoma).

[0144] Typical liver cancers include 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 (reticular cell sarcoma), multiple myeloma, malignant giant cell chordoma, osteochondromas (osteochondrectomy), benign chondromas, chondroblastomas, chondromyxofibromas, osteoid osteomas, and giant cell tumors.

[0146] Exemplary neurological cancers include skull cancer (osteoma, hemangioma, granuloma, xanthomas, osteoosteitis), meningeal cancer (meningioma, meningiosarcoma, gliomatosis), brain cancer (astrocytoma, medulloblastoma, glioma, low-grade cerebral glioma (LGG), ependymoma, germ cell tumor (pineal glandoma), glioblastoma, glioblastoma multiforme (GBM), oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), and spinal cord cancer (neurofibroma, meningioma, glioma, sarcoma), as well as neuroblastoma and Lhermitt-Dacros disease.

[0147] Exemplary gynecological cancers include uterine cancer (endometrial cancer), cervical cancer (cervical cancer, squamous cell carcinoma of the cervix (CESC), preneoplastic cervical dysplasia), ovarian cancer (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiable cancer), granulosa-theca cell tumor, Sertoli-Leydig cell tumor, undifferentiated germ cell tumor, malignant teratoma), vulvar cancer (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, staphylosarcoma (embryonic rhabdomyosarcoma)), and fallopian tube cancer (epithelial malignant tumor).

[0148] Exemplary skin cancers include melanoma, basal cell carcinoma, Merkel cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic nevus moles, lipomas, hemangiomas, dermatofibromas, and keloids. In some embodiments, cancers treatable with the compounds of this disclosure include, but are not limited to, triple-negative breast cancer (TNBC), myelodysplastic syndrome, testicular cancer, cholangiocarcinoma, esophageal cancer, and urothelial carcinoma. combination

[0149] The compounds of this disclosure may be administered as a single agent or in combination with other anticancer agents, particularly a standard of care agents appropriate for specific cancers.

[0150] As used herein, the term “additional anticancer therapeutic agent” means any one or more therapeutic agents other than the compounds of this disclosure that are used or may be used to treat cancer. In some embodiments, such additional anticancer therapeutic agents include compounds belonging to the following classifications: mitotic inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, antiangiogenic agents, topoisomerase I and II inhibitors, plant alkaloids, hormones and antagonists, growth factor inhibitors, radiation, signaling inhibitors, e.g., inhibitors of protein tyrosine kinase and / or serine / threonine kinase, cell cycle inhibitors, biological reaction modifiers, enzyme inhibitors, antisense oligonucleotides or oligonucleotide derivatives, cytotoxic agents, immuno-oncological agents, etc.

[0151] In some embodiments, the additional anticancer agent is an endocrine agent such as an aromatase inhibitor, a selective estrogen receptor degrader (SERD), or a selective estrogen receptor modulator (SERM). In some embodiments, the additional anticancer agent is a SERD. In some embodiments, the SERD is fulvestrant.

[0152] In some embodiments, additional anticancer agents are PIK3CA inhibitors, including, but not limited to, alpelisib (PIQRAY), BEBT-908, BPI-21668, buparlicib, inavolicib, TQB-3525, RLY-2608, mirancertib, MEN-1611, LOXO-783, HS-10352, HH-CYH33, gedatricib, and fimepinostat. In some embodiments, the PIK3CA inhibitor is alpelisib.

[0153] In some embodiments, additional anticancer agents may include, but are not limited to, trastuzumab deruxtecan (Enhertu), trastuzumab duocalmazine, trastuzumab emtansine (Kadcyla), and upifitamab brilsodotin (Upifitamab This is an antibody-drug conjugate containing rilsodotin, milbetuximab sorafutansine, tisotumab vedotin (Tivdak), praluza tamaburabutansine, sacituzumab govitecan or sacituzumab govitecan-hziy (Trodelvy), datopotamab deruxtecan, radilatuzumab vedotin, patritumab deruxtecan, STRO-002, MORab-202, DS-6000, anetumab, avatansine, XMT-2056, and disitamab vedotin (RC48-ADC, Aidexi).

[0154] In some embodiments, additional anticancer agents are PLK1 inhibitors, including, but not limited to, onvancertib, BI2536, BI6727, GSK461364A, TAK960, and rigosertib.

[0155] In some embodiments, the additional anticancer agent is estrogen protac (ARV-471, H3B-5942).

[0156] In other embodiments, the compounds of the Disclosure may be administered in combination with standard care agents. In some embodiments, the compounds of the Disclosure may be administered in combination with endocrine therapies, such as drugs such as letrozole, fulvestrant, tamoxifen, exemestane, or anastrozole. In some embodiments, the compounds of the 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 Disclosure may be administered in combination with anti-HER2 agents (e.g., trastuzumab or pertuzumab).

[0157] In some embodiments, the compounds of the present disclosure (e.g., the compounds of formula (I) or pharmaceutically acceptable salts thereof) may be administered in combination with an effective amount of 5-FU, alpelisib, carboplatin, cisplatin, enzalutamide, fulvestrant, gemcitabine, osimertinib, ribociclib, or a combination thereof. In some embodiments, the compounds of the present disclosure may be administered in combination with an effective amount of carboplatin, ribociclib, fulvestrant, or a combination thereof.

[0158] In some embodiments, additional anticancer agents are anti-angiogenic agents, such as VEGF inhibitors, VEGFR inhibitors, TIE-2 inhibitors, PDGFR inhibitors, angiopoietin inhibitors, PKCb inhibitors, COX-2 (cyclooxygenase II) inhibitors, integrin (αv / β3), 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 anti-angiogenic agents include batalanib (CGP79787), sorafenib (Nexavar®), pegaptanib octasodium (Macugen®), vandetanib (Zactima®), PF-0337210 (Pfizer), SU14843 (Pfizer), AZD2171 (AstraZeneca), ranibizumab (Lucentis®), Neovastat® (AE941), tetrathiomolybdata (Coprexa®), AMG706 (Amgen), VEGF Trap (AVE0005), CEP7055 (Sanofi-Aventis), XL880 (Exelixis), teratinib (BAY57-9352), and CP-868,596 (Pfizer). Other anti-angiogenic agents include enzastaurin (LY317615), midostaurin (CGP41251), perifosin (KRX0401), teprenone (Selbex®), and UCN01 (Kyowa Hakko). Other examples of anti-angiogenic agents include celecoxib (Celebrex®), parecoxib (Dynastat®), delacoxib (SC59046), lumiracoxib (Preige®), valdecoxib (Bextra®), rofecoxib (Vioxx®), iguratimod (Careram®), IP751 (Invedus), SC-58125 (Pharmacia), and etoricoxib (Arcoxia®).Further anti-angiogenic drugs include exilind (Aptosyn®), sarsalat (Amigesic®), diflunisal (Dolobid®), ibuprofen (Motrin®), ketoprofen (Orudis®), nabumetone (Relafen®), piroxicam (Feldene®), naproxen (Aleve®, Naprosyn®), diclofenac (Voltaren®), indomethacin (Indocin®), sulindac (Clinoril®), tolmetin (Tolectin®), etodolac (Lodine®), ketorolac (Toradol®), and oxaprozin (Daypro®). Other anti-angiogenic agents include ABT510 (Abbott), aplatastat (TMI005), AZD8955 (AstraZeneca), incyclinide (Metastat®), and PCK3145 (Procyon).

[0159] Other anti-angiogenic 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 falisimab.

[0160] Other anti-angiogenic agents include acitretin (Neotigason®), pritchidepsin (aplidine®), sirengitide (EMD121974), combretastatin A4 (CA4P), fenretinide (4HPR), halofdinone (Tempostatin®), Panzem® (2-methoxyestradiol), PF-03446962 (Pfizer), levimast (BMS275291), catsumakisomab (Removab®), lenalidomide (Revlimid®), squalamine (EVIZON®), thalidomide (Thalomid®), Ukrain® (NSC631570), Vitaxin® (MEDI522), and zoledronic acid (Zometa®).

[0161] In other embodiments, additional anticancer agents are so-called signaling inhibitors (e.g., those that inhibit the way in which regulatory molecules governing the fundamental processes of cell proliferation, differentiation, and survival are transmitted within a cell). Examples of signaling inhibitors include small molecules, antibodies, and antisense molecules. Examples of signaling inhibitors include kinase inhibitors (e.g., tyrosine kinase inhibitors or serine / threonine kinase inhibitors) and cell cycle inhibitors. More specifically, examples of signaling inhibitors include farnesyl protein transferase inhibitors, EGF inhibitors, ErbB-1 (EGFR), ErbB-2, pan erb, IGF1R inhibitors, MEK, c-Kit inhibitors, FLT-3 inhibitors, K-Ras inhibitors, PI3 kinase inhibitors, JAK inhibitors, STAT inhibitors, Raf kinase inhibitors, Akt inhibitors, mTOR inhibitors, P70S6 kinase inhibitors, WNT pathway inhibitors, and so-called multi-target kinase inhibitors. Additional examples of signal transduction inhibitors that may be used in conjunction with the compounds of the present invention and the pharmaceutical compositions described herein include BMS214662 (Bristol-Myers Squibb), ronafarnib (Salazar®), peritrexol (AG2037), matuzumab (EMD7200), nimotuzumab (TheraCIM h-R3®), panitumumab (Vectibix®), vandetanib (Zactima®), pazopanib (SB 786034), ALT110 (Alteris Therapeutics), BIBW2992 (Boehringer Ingelheim), and Celven® (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), gedatricib (Pfizer), canertinib (CI1033), and pertuzumab. (Omnitarg(trademark)), Lapatinib (Tykerb(trademark)), Peritinib (EKB569), Miltefosine (Miltefosine(trademark)), BMS599626 (Bristol-Myers Squibb), Laprousel-T (Neuvenge(trademark)), Nuvacs(trademark) (E75 cancer vaccine), Osidem(trademark) (IDM1), Mbritinib (TAK-165), CP-724,714 (Pfizer), Panitumumab (Vectibix(trademark)), ARRY142886 (Array Examples include Biopharm, everolimus (Certican®), zotarolimus (Endeavor®), temsirolimus (Tricel®), AP23573 (ARIAD), and VX680 (Vertex), XL647 (Exelixis), sorafenib (Nexavar®), LE-AON (Georgetown University), and GI-4000 (Globelmmune). Other signal transduction inhibitors include ABT751 (Abbott), arbosidib (flavopyridol), BMS387032 (Bristol-Myers), EM1421 (Erimos), indislam (E7070), celicyclib (CYC200), BIO112 (Onc Bio), BMS387032 (Bristol-Myers Squibb), palbociclib (Pfizer), and AG024322 (Pfizer).

[0162] In other embodiments, additional anticancer agents are so-called classic antitumor agents. Classic antitumor agents include, but are not limited to, hormone regulators, e.g., hormones, antihormones, androgen agonists, androgen antagonists and anti-estrogen therapeutics, histone deacetylase (HDAC) inhibitors, DNA methyltransferase inhibitors, silencing agents or gene activators, ribonucleases, proteosomics, topoisomerase I inhibitors, camptothecin derivatives, topoisomerase II inhibitors, alkylating agents, antimetabolites, poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors (e.g., thalazoparib, olaparib, lucaparib, niraparib, iniparib, veliparib, etc.), microtubulin inhibitors, antibiotics, plant-derived spindle inhibitors, platinum-coordinate compounds, gene therapies, antisense oligonucleotides, vascular targeted drugs (VTAs), and statins.Examples of classic 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, but are not limited to, glucocorticoids (dexamethasone, prednisone, prednisolone, methylprednisolone, hydrocortisone, etc.), progestins such as medroxyprogesterone, megestrol acetate (Megaace), mifepristone (RU-486), selective estrogen receptor modulators (SERMs; tamoxifen, raloxifen, rasofoxifen, afimoxifen, aldoxifen, bazedoxifen, fispemifene, olmeroxifen, ospemifene, tesmillifen, toremifene, trilostane, CHF4227 (Cheisi), etc.), and selective estrogen receptor downregulators (SERDs, fulvestrant, LSZ102, G1T48, RAD1901, elastane). Trant, GDC-9545, Giledestrant, SAR439859, Amsenestrant, AZD9833, Kamizetrant, LY3484356, Zn-c5, D-0502), Exemestane (Aromasin), Anastrozole (Arimidex), Atamestan, Fadrozol, Letrozole (Femara), Formestan; Gonadotropin-releasing hormone (GnRH; Generally Luteinizing hormone-releasing hormone [ Examples include agonists (also known as LHRH) such as buserelin (Suprefact), goserelin (Zoladex), leuprorelin (Lupron), and triptorelin (Trelstar), avalerix (Plenaxis), cyproterone, flutamide (Eulexin), megestrol, nilutamide (nilandrone), and osaterone, dutasteride, epristeride, finasteride, saw palmetto, PHL 00801, avalerix, goserelin, leuprorelin, triptorelin, bicalutamide; antiandrogens such as enzalutamide, abiraterone acetate, and bicalutamide (Casodex); and combinations thereof.Other examples of classic antitumor agents used in combination with the compounds of the present invention include suberoranilide hydroxamic acid (SAHA, Merck Inc. / Aton). Pharmaceuticals), Depsipeptide (FR901228 or FK228), G2M-777, MS-275, Pivaloyloxymethyl Butyrate and PXD-101; Onconase (Rampillase), PS-341 (MLN-341), Velcade (Bortezomib), 9-Aminocamptothecin, Belotecan, BN-80915 (Roche), Camptothecin, Diflomothecan, Edotecarin, Exatecan (Daiichi), Gimatecan, 10-Hydroxycamptothecin, Irinotecan HCl (Camptosal), Lulutotecan, Orasecin (Rubitecan, Supergen), SN-38, Topotecan, Camptothecin, 10-Hydroxycamptothecin, 9-aminocamptothecin, irinotecan, SN-38, edotecarin, topotecan, acralubicin, adriamycin, amonafide, amrubicin, anamycin, daunorubicin, doxorubicin, erusamitrusine, epirubicin, etoposide, idarubicin, galarubicin, hydroxycarbamide, nemorubicin, novantrone (mitoxantrone), pirarubicin, pisanthrone, procarbazine, rebeccamycin, sobuzoxane, tafluposide, barrubicin, Zinecard (dexrazoxane), nitrogen mustard N-oxide, cyclophosphamide, AMD-473, altretamine, AP-5280, apadiquan, brostaricin, bendamstein This includes, but is not limited to, busulfan, carboquan, carmustine, chlorambucil, dacarbazine, estramustine, fotemustine, gluphosphamide, ifosfamide, KW-2170, lomustine, maphosphamide, mechloretamine, melphalan, mitobronitol, mitractol, mitomycin C, mitoxatron, nimustine, ranimustine, temozolomide, thiotepa, and platinum-coordinate alkylated compounds (e.g., cisplatin, paraplatin (carboplatin), eptaplatin, lobaplatin, nedaplatin, eloxatin (oxaliplatin, Sanofi), streptozosin, subtoruplatin) and combinations thereof.

[0163] In further embodiments, additional anticancer agents include so-called dihydrofolate reductase inhibitors (such as methotrexate and nutrexin (trimethrexate glucuronide)), purine antagonists (such as 6-mercaptopurine riboside, mercaptopurine, 6-thioguanine, cladribine, clofarabine (Clolar), fludarabine, nerarabine, and larcitrexed), pyrimidine antagonists (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, gimethat, and otostat), doxifluridine, carmofur, cytarabine (including ocphosphate, stearate phosphate, sustained-release, and liposomal forms), enocitabine, 5-azacitidine (Vidaza), decitabine, and ethinylcytidine), and other antimetabolites, such as eflornithine, hydroxyurea, leucovorin, nolatrexed (Thymitaq), triapines, trimethrexate, N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazoline-6-ylmethyl)-N-methylamino]-2-tenoyl)-L-glutamic acid, AG-014699 (Pfizer Inc.), ABT-472 (Abbott Laboratories), INO-1001 (Inotek These include KU-0687 (KuDOS Pharmaceuticals), GPI 18180 (Guilford Pharm Inc.), and combinations thereof. In some embodiments, the additional anticancer agent is a pyrimidine antagonist. In some embodiments, the pyrimidine antagonist is 5-FU.

[0164] Other examples of classic antitumor cytotoxic agents include, but are not limited to, Abraxis BioScience, Inc., Batablin (Amgen), EPO906 (Novartis), Vinflunin (Bristol-Myers Squibb Company), Actinomycin D, Bleomycin, Mitomycin C, Neocartinostatin (Dinostatin), Vinblastine, Vincristine, Vindesine, Vinorelbine (Navelbine), Docetaxel (Taxotere), Ortataxel, Paclitaxel (including Taxoplexin, a DHA / paclitaxel complex), Cisplatin, Carboplatin, Nedaplatin, Oxaliplatin (Eloxatin), Satraplatin, Camptosar, Capecitabine (Xeloda), Oxaliplatin (Eloxatin), and Taxotere Altretino Examples include camphosphamide (Telcyta®), DMXAA (Antisoma), ibandronate, L-asparaginase, pegaspar gauze (Oncaspar®), efaproxyl (Efaproxyn® - radiotherapy), bexarotene (Targretin®), tesmilifen (DPPE - enhances the effectiveness of cytotoxic drugs), Theratope® (Biomira), tretinoin (Vesanoid®), tirapazamine (Trizaone®), motexafingadolinium (Xcytrin®), Cotara® (mAb), and NBI-3001 (Protox Therapeutics), polyglutamic acid-paclitaxel (Xyotax®), and combinations thereof.Further examples of classic antitumor agents include Advexin (ING201), TNFerade (GeneVec, a compound that expresses TNFα in response to radiotherapy), RB94 (Baylor College of Medicine), Genasense (Obrimarcen, Genta), Combretastatin A4P (CA4P), Oxi-4503, AVE-8062, ZD-6126, TZT-1027, Atorvastatin (Lipitor, Pfizer Inc.), Provastatin (Pravachol, Bristol-Myers Squibb), Lovastatin (Mevacor, Merck Inc.), Simvastatin (Zocor, Merck Inc.), Fluvastatin (Lescol, Novartis), Cerivastatin (Baycol, Bayer), Rosuvastatin (Crestor, AstraZeneca), Lovostatin, Niacin (Advicor, Kos Examples include, but are not limited to, pharmaceuticals, Caduet, Lipitor, Torcetrapib, and combinations thereof.

[0165] In other embodiments, additional anticancer agents include epigenetic modulators, such as inhibitors or EZH2, Smarca 4, 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, additional anticancer agents include, but are not limited to, CTLA-4 inhibitors (e.g., ipilimumab), PD-1 or PD-L1 inhibitors (e.g., pembrolizumab, nivolumab, avelumab, atezolizumab, durvalumab, semiprimab, or dosterimab), LAG-3 inhibitors (e.g., relatrimab), TIM-3 inhibitors, TIGIT inhibitors, 4-1BB inhibitors, OX40 inhibitors, GITR inhibitors, CD40 inhibitors, or CAR-T cell therapy.

[0167] In some embodiments, the additional anticancer agent is an EGFR inhibitor, such as afatinib, osimertinib, lapatinib, erlotinib, dacomitinib, poziotinib, neratinib, or gefitinib, or an EGFR antibody, such as cetuximab, panitumumab, or nesitumumab. In some embodiments, the EGFR inhibitor is osimertinib.

[0168] Alternatively, the compounds of this disclosure, their pharmaceutically acceptable salts, or the pharmaceutical compositions disclosed herein may be combined with other anticancer agents that are not EGFR inhibitors, for example, MEK, e.g., mutant MEK inhibitors (trametinib, cobimtetinib, binimetinib, selumetinib, refametinib); c-MET, e.g., mutant c-Met inhibitors (savolitinib, cabozantinib, foretinib) and MET antibodies (emibetuzumab); mitotic kinase inhibitors (palbociclib, ribociclib, abemacicili CDK4 / 6 inhibitors such as palbociclib, trilaciclib, darpiciclib, and BPI-16350; anti-angiogenic agents, e.g., bevacizumab and nintedanib; apoptosis inducers, e.g., Bcl-2 inhibitors (e.g., venetoclax, ovatoclax, and navitoclax) and Mcl-1 inhibitors (e.g., AZD-5991, AMG-176, and S-64315); and mTOR inhibitors (e.g., rapamycin, temsirolimus, everolimus, and lidophorolimus). In some embodiments, the CDK4 / 6 inhibitor is palbociclib. In some embodiments, the CDK4 / 6 inhibitor is ribociclib.

[0169] The compounds of this disclosure, their pharmaceutically acceptable salts, or the pharmaceutical compositions disclosed herein can be administered in combination with a CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor is selected from the group consisting of palbociclib, ribociclib, abemaciclib, rerocilib, trilaciclib, darpiciclib, and BPI-16350. In some embodiments, the CDK4 / 6 inhibitor is ribociclib.

[0170] The compounds of this disclosure, their pharmaceutically acceptable salts, or the pharmaceutical compositions disclosed herein can be administered in combination with a CDK4 / 6 inhibitor and SERD. In some embodiments, the compounds of this disclosure, their pharmaceutically acceptable salts, or the pharmaceutical compositions disclosed herein can be administered in combination with ribociclib and fulvestrant. In some embodiments, the compounds of this disclosure, their pharmaceutically acceptable salts, or the pharmaceutical compositions disclosed herein can be administered in combination with a pyrimidine antagonist and gemcitabine. In some embodiments, the compounds of this disclosure can be administered in combination with a pyrimidine antagonist, gemcitabine, and a CDK4 / 6 inhibitor. In some embodiments, the combination further includes a platinum agent. In some embodiments, the compounds of this disclosure can be administered in combination with 5-FU, gemcitabine, ribociclib, and optionally cisplatin. In some embodiments, the compounds of this disclosure, their pharmaceutically acceptable salts, or the pharmaceutical compositions disclosed herein can be administered in combination with an EGFR inhibitor. In some embodiments, the compounds of the Disclosure, their pharmaceutically acceptable salts, or the pharmaceutical compositions disclosed herein may be administered in combination with osimertinib. In some embodiments, the compounds of the Disclosure, their pharmaceutically acceptable salts, or the pharmaceutical compositions disclosed herein may be administered in combination with a PARP-1 inhibitor. In some embodiments, the compounds of the Disclosure, their pharmaceutically acceptable salts, or the pharmaceutical compositions disclosed herein may be administered in combination with olaparib.

[0171] The compounds disclosed herein, their pharmaceutically acceptable salts, or the pharmaceutical compositions disclosed herein also include 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., gilotrif®), osimertinib (e.g., t It may also be administered in combination with an effective dose of a second drug selected from the group consisting of agrisso®, gefitinib (e.g., iressa®), erlotinib (e.g., tarceva®), ramucirumab (e.g., cyramza®), EGFR inhibitors, pralcetinib, ABT-263 (navitoclax), MK-1775 (adavocertib), BAY-1895344, bezocertib, ceraracertib, SRA-737, LY2603618 (rabucertib), and trastuzumab (e.g., herceptin®), or combinations thereof. EGFR inhibitors include afatinib, osimertinib, lapatinib, erlotinib, dacomitinib, poziotinib, neratinib, gefitinib (JBJ-04-125-02), alflutinib (AST2818), aumorertinib (formerly amonertinib) (HS10296), BBT-176, BI-4020, BPI-361175, BPI-D0316, CH7233163, gilteritinib, icotinib, JND-3229, razertinib, and na The antibody may be selected from zartinib (EGF816), abitinib, PCC-0208027, regibertinib (BPI-7711), TQB3804, zolifertinib (AZ-3759), or DZD9008, or from EGFR antibodies such as cetuximab, panitumumab, nesitumumab, HLX07, or JMT101, or from bispecific EGFR and MET antibodies (e.g., amivantamab ((JNJ-61186372, JNJ-372))).

[0172] Biomarkers and pharmacodynamic markers The Disclosure further provides predictive markers (e.g., biomarkers and pharmacodynamic markers, e.g., levels, gene copy number, gene sequence, expression level, phosphorylation level, or mutations) to identify human subjects who have, are suspected of having, or are at risk of developing CDK2-related diseases or disorders (e.g., cancer) for which administration of CDK2 inhibitors is likely to be effective (as used herein, “CDK2 inhibitor” means the compounds of the Disclosure or their pharmaceutically acceptable salts).

[0173] CCNE1 In one embodiment, the biomarker is CCNE1. In some embodiments, CCNE1 is absent. In some embodiments, loss of CCNE1 is a biomarker. In some embodiments, CCNE1 is mutated (e.g., loss-of-function mutation). In some embodiments, CCNE1 or mutated CCNE1 is functional. In some embodiments, CCNE1 is a biomarker for sensitivity to compounds of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or pharmaceutically acceptable salts thereof. In some embodiments, treatment with compounds of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or pharmaceutically acceptable salts thereof modulates the level of CCNE1. In some embodiments, the level of CCNE1 before and after treatment with a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof changes by at least 10%. In some embodiments, the level of CCNE1 before and after treatment with a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof changes by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the level of CCNE1 before and after treatment changes by approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the level of CCNE1 before and after treatment with a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof increases.In some embodiments, CCNE1 levels are reduced before and after treatment with compounds of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or pharmaceutically acceptable salts thereof.

[0174] In some embodiments, amplification of the cyclin E1 (CCNE1) gene and / or higher or excessive levels of CCNE1 expression in a biological sample would indicate that a patient or subject may benefit from the administration of a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof.

[0175] CCNE1 is an essential cell cycle factor for regulating the cell cycle during G1 / S transition (Ohtsubo et al., 1995, Mol.Cell.Biol.15:2612-2624). CCNE1 acts as a regulatory subunit of CDK2, interacting with CDK2 to form a serine / threonine kinase holoenzyme complex. The CCNE1 subunit of this holoenzyme complex provides substrate specificity for the complex (Honda et al., 2005, EMBO 24:452-463). CCNE1 is encoded by the cyclin E1 ("CCNE1") gene (GenBank accession number NM_001238). The amino acid sequence of human CCNE1 can be found at GenBank accession number NP_001229 / UniProtKB accession number P24864.

[0176] In one embodiment, the present disclosure provides a method for treating a subject who has or is at risk of developing a CDK2-related disease or disorder (e.g., cancer), the method comprising administering a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, to a subject in which the CCNE1 gene is amplified (e.g., based on copy number) and / or the level of CCNE1 is higher than the control level of CCNE1. In some embodiments, the CDK2-related disease or disorder is cancer.

[0177] Furthermore, this specification also provides a method for treating patients who have amplified levels of CCNE1 expression and who have or are at risk of developing solid tumor cancer, the method comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0178] In some embodiments, amplification of the CCNE1 gene and / or a level of CCNE1 higher than the control level of CCNE1 indicates / predicts that a human subject with cancer or at risk of developing cancer will respond to a CDK2 inhibitor (e.g., a compound disclosed herein or a pharmaceutically acceptable salt thereof). In some embodiments, the expression level of CCNE1 may be at the level of CCNE1 mRNA. In other embodiments, the expression level of CCNE1 may be at the level of CCNE1 protein. In some embodiments, the level of CCNE1 is regulated in response to administration of a therapeutically effective amount of a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId), or a pharmaceutically acceptable salt thereof, to the subject.

[0179] Other biomarkers In some embodiments, the intended biomarker is 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 some embodiments, treatment with a therapeutically effective amount of a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof modulates p16 levels. In some embodiments, p16 is absent. In some embodiments, loss of p16 is a biomarker. In some embodiments, p16 has a mutation (e.g., a loss-of-function mutation). In some embodiments, p16 or a p16 variant is functional. In some embodiments, p16 is a biomarker for sensitivity to a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof.

[0180] In some embodiments, the change in p16 levels before and after treatment of a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof indicates / predicts that a subject with or at risk of developing cancer responded to treatment with a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof. In some embodiments, the change in p16 levels before and after treatment with a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof changes by at least 10%. In some embodiments, the level of p16 before and after treatment with a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof changes by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the level of p16 before and after treatment changes by approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the level of p16 before and after treatment with a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof increases. In some embodiments, the level of p16 decreases before and after treatment with a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof.

[0181] In some embodiments, the intended biomarker is retinoblastoma protein (pRb or RB), which is encoded by the gene RB transcription corepressor 1 (RB1). In some embodiments, the intended biomarker is phosphorylation of Rb at any phosphorylation site. In some embodiments, the biomarker is phosphorylation at serine (Ser780 or S780) corresponding to amino acid position 780 and / or serine (Ser795 or S795) corresponding to amino acid position 795. In some embodiments, the intended biomarker is phosphorylation of Rb at serine (Ser807 or S807) corresponding to amino acid position 807 and / or serine (Ser811 or S811) corresponding to amino acid position 811. In some embodiments, the intended biomarker is phosphorylation of Rb at threonine (Thr821) corresponding to amino acid position 821 and / or threonine (Thr826) corresponding to amino acid position 826. Rb is a cell cycle regulator and acts as a tumor suppressor. Rb is activated when phosphorylated by cyclin D-CDK4 / 6 at Ser780 and Ser795, and by cyclin E / CDK2 at Ser807 and Ser811. In some embodiments, treatment with a therapeutically effective amount of a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof modulates the level of phosphorylated Rb. In some embodiments, phosphorylated Rb or RB is absent. In some embodiments, loss of phosphorylated Rb or RB is a biomarker. In some embodiments, RB has a mutation (e.g., a loss-of-function mutation). In some embodiments, the Rb or RB variant is functional. In some embodiments, phosphorylated Rb or RB is a biomarker for sensitivity to compounds of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or pharmaceutically acceptable salts thereof.

[0182] In some embodiments, changes in the levels of phosphorylated Rb or RB before and after treatment of a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof indicate / predict that a subject with or at risk of developing cancer responded to treatment with a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at any phosphorylation site before and after treatment with a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof changes by at least 10%. In some embodiments, the level of phosphorylated Rb at any phosphorylation site before and after treatment with a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof changes by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the level of phosphorylated Rb at any phosphorylation site before and after treatment changes by approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the level of phosphorylated Rb or RB at any phosphorylation site before and after treatment with a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof increases.In some embodiments, the level of phosphorylated Rb or RB at any phosphorylation site is reduced before and after treatment with a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof.

[0183] In some embodiments, the levels of phosphorylated Rb at Ser780 and / or Ser795 change by at least 10% before and after treatment with a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof. In some embodiments, the levels of phosphorylated Rb at Ser780 and / or Ser795 before and after treatment with a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof change by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the levels of phosphorylated Rb at Ser780 and / or Ser795 before and after treatment change by approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the levels of phosphorylated Rb at Ser780 and / or Ser795 before and after treatment with a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof increase.

[0184] In some embodiments, the levels of phosphorylated Rb at Ser780 and / or Ser795 are reduced before and after treatment with a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof. In some embodiments, the levels of phosphorylated Rb at Ser780 and / or Ser795 are reduced by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% before and after administration of a compound disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Ser780 and / or Ser795 decreases by at least 10% before and after administration of the compound disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Ser780 and / or Ser795 decreases by at least 20% before and after administration of the compound disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Ser780 and / or Ser795 decreases by at least 30% before and after administration of the compound disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Ser780 and / or Ser795 decreases by at least 40% before and after administration of the compound disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Ser780 and / or Ser795 decreases by at least 50% before and after administration of the compound disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Ser780 and / or Ser795 is reduced by at least 60% before and after administration of the compound disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Ser780 and / or Ser795 is reduced by at least 70% before and after administration of the compound disclosed herein or a pharmaceutically acceptable salt thereof.In some embodiments, the level of phosphorylated Rb at Ser780 and / or Ser795 is reduced by at least 80% before and after administration of the compound disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Ser780 and / or Ser795 is reduced by at least 90% before and after administration of the compound disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Ser780 and / or Ser795 is reduced by at least 100% before and after administration of the compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0185] In some embodiments, the levels of phosphorylated Rb at Ser807 and / or Ser811 change by at least 10% before and after treatment with a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof. In some embodiments, the levels of phosphorylated Rb at Ser807 and / or Ser811 before and after treatment with a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof change by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the levels of phosphorylated Rb at Ser807 and / or Ser811 before and after treatment change by approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the levels of phosphorylated Rb at Ser807 and / or Ser811 before and after treatment with a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof increase.

[0186] In some embodiments, the level of phosphorylated Rb at Ser807 and / or Ser811 is reduced before and after treatment with a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Ser807 and / or Ser811 is reduced by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% before and after administration of a compound disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Ser807 and / or Ser811 decreases by at least 10% before and after administration of the compound disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Ser807 and / or Ser811 decreases by at least 20% before and after administration of the compound disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Ser807 and / or Ser811 decreases by at least 30% before and after administration of the compound disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Ser807 and / or Ser811 decreases by at least 40% before and after administration of the compound disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Ser807 and / or Ser811 decreases by at least 50% before and after administration of the compound disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Ser807 and / or Ser811 is reduced by at least 60% before and after administration of the compound disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Ser807 and / or Ser811 is reduced by at least 70% before and after administration of the compound disclosed herein or a pharmaceutically acceptable salt thereof.In some embodiments, the level of phosphorylated Rb at Ser807 and / or Ser811 is reduced by at least 80% before and after administration of the compound disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Ser807 and / or Ser811 is reduced by at least 90% before and after administration of the compound disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Ser807 and / or Ser811 is reduced by at least 100% before and after administration of the compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0187] In some embodiments, the levels of phosphorylated Rb at Thr821 and / or Thr826 change by at least 10% before and after treatment with a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof. In some embodiments, the levels of phosphorylated Rb at Thr821 and / or Thr826 before and after treatment with a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof change by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the levels of phosphorylated Rb at Thr821 and / or Thr826 before and after treatment change by approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the levels of phosphorylated Rb at Thr821 and / or Thr826 before and after treatment with a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof increase.

[0188] In some embodiments, the levels of phosphorylated Rb at Thr821 and / or Thr826 are reduced before and after treatment with a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof. In some embodiments, the levels of phosphorylated Rb at Thr821 and / or Thr826 are reduced by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% before and after administration of a compound disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Thr821 and / or Thr826 decreases by at least 10% before and after administration of the compound disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Thr821 and / or Thr826 decreases by at least 20% before and after administration of the compound disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Thr821 and / or Thr826 decreases by at least 30% before and after administration of the compound disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Thr821 and / or Thr826 decreases by at least 40% before and after administration of the compound disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the level of phosphorylated Rb at Thr821 and / or Thr826 decreases by at least 50% before and after administration of the compound disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the levels of phosphorylated Rb at Thr821 and / or Thr826 are reduced by at least 60% before and after administration of the compounds disclosed herein or pharmaceutically acceptable salts thereof. In some embodiments, the levels of phosphorylated Rb at Thr821 and / or Thr826 are reduced by at least 70% before and after administration of the compounds disclosed herein or pharmaceutically acceptable salts thereof.In some embodiments, the levels of phosphorylated Rb at Thr821 and / or Thr826 are reduced by at least 80% before and after administration of the compounds disclosed herein or pharmaceutically acceptable salts thereof. In some embodiments, the levels of phosphorylated Rb at Thr821 and / or Thr826 are reduced by at least 90% before and after administration of the compounds disclosed herein or pharmaceutically acceptable salts thereof. In some embodiments, the levels of phosphorylated Rb at Thr821 and / or Thr826 are reduced by at least 100% before and after administration of the compounds disclosed herein or pharmaceutically acceptable salts thereof.

[0189] In some embodiments, the intended biomarker is TK1 (thymidine kinase 1). TK1 is involved in cell proliferation via the recovery of nucleotide thymidines in the DNA salvage pathway. Because TK1 is required for nucleotide formation outside of the S phase, it is important for cell repair after DNA damage. In some embodiments, treatment with a therapeutically effective amount of a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof modulates TK1 levels. In some embodiments, TK1 is absent. In some embodiments, loss of TK1 is a biomarker. In some embodiments, TK1 has a mutation (e.g., a loss-of-function mutation). In some embodiments, TK1 or a TK1 variant is functional. In some embodiments, TK1 is serum TK1. In some embodiments, TK1 is a biomarker for sensitivity to compounds of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or pharmaceutically acceptable salts thereof.

[0190] In some embodiments, the change in TK1 levels before and after treatment with a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof indicates / predicts that a subject with cancer or at risk of developing cancer responded to treatment with a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof. In some embodiments, the change in TK1 levels before and after treatment with a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof changes by at least 10%. In some embodiments, the level of TK1 before and after treatment with a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof changes by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the level of TK1 before and after treatment changes by approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the level of TK1 before and after treatment with a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof increases.

[0191] In some embodiments, the level of TK1 decreases before and after treatment with a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of TK1 decreases by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% before and after administration of a compound disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the level of TK1 decreases by at least 10% before and after administration of a compound disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the TK1 level before and after administration of the compound disclosed herein or a pharmaceutically acceptable salt thereof decreases by at least 20%. In some embodiments, the TK1 level before and after administration of the compound disclosed herein or a pharmaceutically acceptable salt thereof decreases by at least 30%. In some embodiments, the TK1 level before and after administration of the compound disclosed herein or a pharmaceutically acceptable salt thereof decreases by at least 40%. In some embodiments, the TK1 level before and after administration of the compound disclosed herein or a pharmaceutically acceptable salt thereof decreases by at least 50%. In some embodiments, the TK1 level before and after administration of the compound disclosed herein or a pharmaceutically acceptable salt thereof decreases by at least 60%. In some embodiments, the TK1 level before and after administration of the compound disclosed herein or a pharmaceutically acceptable salt thereof decreases by at least 70%. In some embodiments, the TK1 level before and after administration of the compound disclosed herein or a pharmaceutically acceptable salt thereof decreases by at least 80%. In some embodiments, the TK1 level before and after administration of the compounds disclosed herein or pharmaceutically acceptable salts thereof is reduced by at least 90%. In some embodiments, the TK1 level before and after administration of the compounds disclosed herein or pharmaceutically acceptable salts thereof is reduced by at least 100%.

[0192] In some embodiments, the intended biomarker is the growth marker Ki-67 (Ki-67). In some embodiments, treatment with a therapeutically effective amount of a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof modulates Ki-67 levels. In some embodiments, Ki-67 is absent. In some embodiments, loss of Ki-67 is the biomarker. In some embodiments, Ki-67 has a mutation (e.g., a loss-of-function mutation). In some embodiments, Ki-67 or a Ki-67 variant is functional. In some embodiments, Ki-67 is a biomarker for sensitivity to compounds of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or pharmaceutically acceptable salts thereof.

[0193] In some embodiments, the change in Ki-67 levels before and after treatment with a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof indicates / predicts that a subject with cancer or at risk of developing cancer responded to treatment with a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof. In some embodiments, the change in Ki-67 levels before and after treatment with a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof changes by at least 10%. In some embodiments, the level of Ki-67 before and after treatment with a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof changes by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the level of Ki-67 before and after treatment changes by approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the level of Ki-67 before and after treatment with a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof increases. In some embodiments, Ki-67 levels are reduced before and after treatment with compounds of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or pharmaceutically acceptable salts thereof.

[0194] In some embodiments, the intended biomarker is the cancer antigen 125 or (CA-125). In some embodiments, the cancer is ovarian cancer. In some embodiments, treatment with a therapeutically effective amount of a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof modulates the level of CA-125. In some embodiments, CA-125 is absent. In some embodiments, loss of CA-125 is the biomarker. In some embodiments, CA-125 has a mutation (e.g., a loss-of-function mutation). In some embodiments, CA-125 or a CA-125 variant is functional. In some embodiments, CA-125 is a biomarker for sensitivity to compounds of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or pharmaceutically acceptable salts thereof.

[0195] In some embodiments, changes in CA-125 levels before and after treatment with a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof indicate / predict that a subject with cancer or at risk of developing cancer responded to treatment with a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof. In some embodiments, changes in CA-125 levels before and after treatment with a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof change by at least 10%. In some embodiments, the level of CA-125 before and after treatment with a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof changes by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the level of CA-125 before and after treatment changes by approximately 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments, the level of CA-125 before and after treatment with a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof increases.

[0196] In some embodiments, the level of CA-125 decreases before and after treatment with a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof. In some embodiments, the level of CA-125 decreases by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% before and after administration of a compound disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the level of CA-125 decreases by at least 10% before and after administration of a compound disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the level of CA-125 decreases by at least 20% before and after administration of the compound disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the level of CA-125 decreases by at least 30% before and after administration of the compound disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the level of CA-125 decreases by at least 40% before and after administration of the compound disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the level of CA-125 decreases by at least 50% before and after administration of the compound disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the level of CA-125 decreases by at least 60% before and after administration of the compound disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the level of CA-125 decreases by at least 70% before and after administration of the compound disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the level of CA-125 decreases by at least 80% before and after administration of the compound disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the level of CA-125 decreases by at least 90% before and after administration of the compounds disclosed herein or pharmaceutically acceptable salts thereof. In some embodiments, the level of CA-125 decreases by at least 100% before and after administration of the compounds disclosed herein or pharmaceutically acceptable salts thereof.

[0197] Furthermore, the intended biomarker may be selected from the group consisting of RB1, RBL1, RBL2, CA-125, CDKN2A, CDKN1A, CDKN1B, FBXW7, CCNE1, CCNE2, CCNA1, CCNA2, CCND1, CCND2, CCND3, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK18, CDKN2A, CDNK1A, CDKN1B, CHK1, E2F1, E2F2, E2F3, Ki-67, MYC, MYCL, MYCN, p16, EZH2, ER, HER2, HER3, TK1, and EGFR. In some embodiments, a level of any one of the biomarkers disclosed herein may be modulated in response to treatment with a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof.

[0198] In another embodiment, the present invention provides a method for measuring changes in the levels of one or more biomarkers after administering a compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId) or a pharmaceutically acceptable salt thereof to a subject who has cancer or is at risk of developing cancer.

[0199] Biological samples Biological specimens suitable for the methods described herein include any specimens containing blood or tumor cells obtained from or derived from a human subject in need of treatment. For example, a biological specimen may include tumor cells obtained from a biopsy of a patient with a solid tumor. A tumor biopsy may be obtained by various means known in the art. Alternatively, a blood specimen may be obtained from a patient with a hematological malignancy.

[0200] Biological samples can be obtained from human subjects who have, are suspected of having, or are at risk of developing a CDK2-related disease or disorder. In some embodiments, the CDK2-related disease or disorder is cancer (e.g., as described above).

[0201] Methods for 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 skilled in the art. For example, a biological sample may be further exposed to one or more additional agents, such as buffers and / or inhibitors (including one or more nuclease, protease, and phosphatase inhibitors), that preserve or minimize changes in the molecules in the sample.

[0202] Method of administration and dosage form The precise amount of a compound administered to provide an "effective dose" to a subject will depend on the mode of administration, the type and severity of the cancer, and the subject's characteristics (such as overall health, age, sex, weight, and drug tolerance). A person skilled in the art will be able to determine the appropriate dosage based on these and other factors. When administered in combination with other therapeutic agents, for example, in combination with anticancer agents, the "effective dose" of any additional therapeutic agent(s) will depend on the type of drug used. Appropriate dosages of approved therapeutic agents are publicly known and can be adjusted by a person skilled in the art, depending on the subject's condition, the type of condition being treated, and the amount of compound of formula (I), (II), (III), (IVa), (IVb), (Va), (Vb), (VIa), (VIb), (VIc), or (VId), by following the dosages reported in the literature and recommended in Physician's Desk Reference (57th Ed., 2003).

[0203] "To treat" or "treatment" means to obtain a desired pharmacological and / or physiological effect. Such effect may be therapeutic, involving the achievement of one or more of the following outcomes, in part or substantially: namely, a partial or substantially reduction in the degree of disease, condition or cancer; improvement or enhancement of any clinical symptoms or indicators associated with disease, condition or cancer; delay, inhibit or reduce the likelihood of progression of disease, condition or cancer; or a reduction in the likelihood of recurrence of disease, condition or cancer.

[0204] The term "effective dose" refers to the amount administered to a subject that, when administered, produces a beneficial or desired outcome (including clinical outcomes), such as inhibiting, suppressing, or reducing the symptoms of the condition being treated in the subject compared to a control. For example, a therapeutically effective dose can be administered in unit dosage form (e.g., 0.1 mg to approximately 50 g per day, alternatively 1 mg to approximately 5 g per day, and even more alternatively 10 mg to 1 g per day).

[0205] As used herein, terms such as “administer,” “give delivery,” and “dosage” refer to methods that may be used to enable the delivery of a composition to a desired site of action. These methods include, but are not limited to, intraarticular (in the joints), intravenous, intramuscular, intratumor, intradermal, intraperitoneal, subcutaneous, oral, topical, intrathecal, inhalation, percutaneous, and rectal administration. Administration techniques that can be used in conjunction with the agents and methods described herein can be found, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current ed.), Mack Publishing Co., Easton, Pa.

[0206] Furthermore, the compounds of the Disclosure, their pharmaceutically acceptable salts, or the pharmaceutical compositions of the Disclosure may be administered co-administered with other therapeutic agents. As used herein, the terms “co-administered” and “administered in combination,” and their grammatical equivalents, mean 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 Disclosure, their pharmaceutically acceptable salts, or the pharmaceutical compositions of the Disclosure will be administered co-administered with other agents. These terms encompass the administration of two or more agents to a subject such that both agents and / or their metabolites are present in the subject at the same time. These include co-administration in separate compositions, administration in separate compositions at different times, and / or administration in a composition in which both agents are present. Thus, in some embodiments, the compounds and other agents described herein are administered in a single composition. In some embodiments, the compounds and other agents described herein are mixed in a composition.

[0207] Specific dosing regimens and dosage regimens are selected by the attending clinician, taking into account the details of the case (e.g., subject, disease, disease state involved, specific treatment). Treatment may involve daily or multiple daily doses or less than daily doses (weekly, monthly, etc.) over a period of several days to several months, and in some cases several years. However, those skilled in the art will immediately recognize appropriate and / or equivalent doses by looking at the dosages of approved compositions for treating diseases using CDK2 inhibitors disclosed as guidance.

[0208] As those skilled in the art will understand, the compounds of this disclosure or pharmaceutically acceptable salts thereof can be administered to patients in various forms depending on the selected route of administration. The compounds of this teaching may be administered, for example, orally, parenterally, buccally, sublingually, nasally, rectally, by patch, pump, or transdermally, and by pharmaceutical compositions formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, subarachnoid, rectal, and topical administration methods. Parenteral administration may be by continuous infusion over a selected period of time.

[0209] The pharmaceutical compositions of this disclosure are formulated to suit their intended route of administration. In some embodiments, the compositions are formulated according to conventional procedures as pharmaceutical compositions suitable for intravenous, subcutaneous, intramuscular, oral, intranasal, or topical administration to humans. In preferred embodiments, the pharmaceutical compositions are formulated for intravenous administration.

[0210] Typically, for oral therapeutic administration, the compounds of this disclosure, or pharmaceutically acceptable salts thereof, may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups, wafers, and the like.

[0211] Typically, for parenteral administration, solutions of the compounds of this disclosure, or pharmaceutically acceptable salts thereof, can be prepared in water, generally in appropriate mixture with a surfactant such as hydroxypropylcellulose. Alternatively, dispersions can be prepared in glycerol, liquid polyethylene glycol, DMSO, and mixtures thereof, with or without alcohol, as well as in oil. These preparations contain preservatives to inhibit microbial growth under normal storage and use conditions.

[0212] Typically, for injection applications, sterile aqueous solutions or dispersions of the compounds of this disclosure, and sterile powders, are suitable for immediate preparation of sterile injection solutions or dispersions.

[0213] The following examples are illustrative and not intended to limit the scope of this disclosure. [Examples]

[0214] Preparation of Exemplary Compounds definition AcOH means acetic acid; t-AmOH stands for tert-amyl alcohol; Aq. means water-based; Bn stands for benzyl; Boc stands for tert-butoxycarbonyl; Boc2O stands for di-tert-butyl dicarbonate; (BPin)2 stands for 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane; br means broad; Brettphos means 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl; BrettPhos Pd G3 means [(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate; n-BuOH means butan-1-ol; t-BuOH stands for 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 stands for Celsius temperature; CDCl3 means deuterated chloroform; Cs2CO3 means cesium carbonate; CuCN stands for copper cyanide; 'd' stands for chemical shift; 'd' means a double line; dd means double double lines; dq means double quadruple lines; dt means double or triple lines; DAST stands for diethylaminosulfur trifluoride; DBU stands for 1,8-diazabicyclo[5.4.0]undeca-7-ene; DCM stands for dichloromethane; DEA stands for diethylamine; DEAD refers to diethyl azodicarboxylate; DIAD stands for diisopropyl azodicarboxylate; DIBAL-H stands for diisobutylaluminum hydride; DIPEA means N-ethyldiisopropylamine or N,N-diisopropylethylamine; DMA stands for N,N-dimethylacetamide; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; DMSO-d6 stands for hexaduterodimethyl sulfoxide; EA stands for ethyl acetate; Et means ethyl; Et2O means diethyl ether; RINKAN means ethyl acetate; EtOH means ethanol; Eq. means equivalent; g stands for gram; HATU stands for 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; HBF4 stands for tetrafluoroboric acid; HCl means hydrochloric acid; HCOH stands for formaldehyde; HCO2H means formic acid; Hept means seven lines; 1 1H NMR stands for Proton Nuclear Magnetic Resonance; H2O means water; H2O2 stands for hydrogen peroxide; HPLC stands for High-Pressure Liquid Chromatography; h stands for time; IPA stands for 2-propanol; K2CO3 means potassium carbonate; KI stands for potassium iodide; KOH stands for potassium hydroxide; K3PO4 stands for tribasic potassium phosphate; L stands for liter; LCMS stands for Liquid Chromatography Mass Spectrometry; LDA stands for lithium diisopropylamide; LiAlH4 stands for lithium aluminum hydride; LiOH stands for lithium hydroxide; 'm' stands for multiplet; M stands for mole; Me means methyl; MeCN stands for acetonitrile; MeI stands for iodomethane; MeLi stands for methyllithium; MeMgBr stands for methylmagnesium bromide; MeNH2 means methylamine; MeOH stands for methanol; MeOH-d4 means deuterium methanol; mg means milligram; MgSO4 stands for magnesium sulfate; MHz stands for megahertz; "Mins" means minutes; mL stands for milliliter; "Molecular" means millimoles; MPLC stands for Medium Pressure Liquid Chromatography; MSm / z refers to the mass spectral peak; MTBE stands for methyl tert-butyl ether; N2 stands for nitrogen; NaBH4 stands for sodium borohydride; Na2CO3 means sodium carbonate; NaH stands for sodium hydride; NaHCO3 means sodium bicarbonate; NaOH stands for sodium hydroxide; Na2SO4 means sodium sulfate; NCS stands for N-chlorosuccinimide; NH3 stands for ammonia; NH4Cl stands for ammonium chloride; NH4HCO3 means ammonium carbonate; NH2OH stands for hydroxylamine; NH4OH is ammonium hydroxide; NMP stands for N-methylpyrrolidine; PE stands for petroleum ether; Pd(amphos)Cl2 means bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II); Pd(t-Bu3P)2 stands for bis(tri-tert-butylphosphine)palladium(0); Pd(OAc) stands for palladium acetate; Pd2(dba)3 means Tris(dibenzylideneacetone)dipalladium(0); Pd(dppf)Cl2 stands for [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); Pd(PPh3)4 stands for tetrakis(triphenylphosphine)palladium(0); Pd(PPh3)Cl2 stands for palladium(II) bis(triphenylphosphine) dichloride; Pd / C stands for palladium carbon; Pd(OH)2 stands for palladium hydroxide; PPh3 stands for triphenylphosphine; q means quadruple lines; rt means room temperature; RT stands for 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 a single line; sat. means saturation; SFC stands for supercritical fluid chromatography; "Solen" means solution; 't' means triple lines; TBAF stands for tetrabutylammonium fluoride; TBDMSCl stands for tert-butyl(chloro)dimethylsilane; TEA stands for triethylamine; TFA stands for trifluoroacetic acid; TfOH stands for trifluoroethanesulfonic acid; THF stands for tetrahydrofuran; TLC stands for Thin-Layer Chromatography; TsOH stands for p-toluenesulfonic acid; μL means microliter; μmol means micromoles; Xanthos means 4,5-bis(diphenylphosphin)-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 stands for chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II).

[0215] The method for preparing the compounds of the present invention may be carried out in a suitable solvent that can be readily selected by those skilled in organic synthesis. A suitable solvent may be substantially inactive with the starting materials (reactants), intermediates, or products at the temperature in which the reaction takes place (e.g., within the range from the freezing point to the boiling point of the solvent). A particular reaction may be carried out in one solvent or a mixture of several solvents. Depending on the specific reaction step, those skilled in the art can select a solvent suitable for that particular step.

[0216] The preparation of the compounds of the present invention may involve the protection and deprotection of various chemical groups. The need for protection and deprotection, as well as the selection of appropriate protecting groups, can be readily determined by those skilled in the art. The chemical properties of protecting groups can be found, for example, in Wuts and Greene, Protective Groups in Organic Synthesis, 5th ed., John Wiley & Sons: New Jersey, (2014), which is incorporated herein by reference in its entirety.

[0217] The reaction can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means such as nuclear magnetic resonance (NMR) spectroscopy (e.g., 1H or 13C), infrared (IR) spectroscopy, spectrophotometric methods (e.g., ultraviolet-visible), and mass spectrometry (MS), or by chromatographic methods such as high-performance liquid chromatography (HPLC) or thin-layer chromatography (TLC). Analytical instruments and methods for characterizing compounds:

[0218] LC-MS: Liquid chromatography-mass spectrometry (LC-MS) data were acquired at 50 degrees Celsius using an Agilent Technologies 1200 Series LCMSD equipped with a reversed-phase column (Sunfire C18, particle size 3.5 μm, dimensions 4.6 × 50 mm) employing the API-ESI ionization method. The mobile phase consisted of a solvent mixture of 0.01% TFA in water and 0.01% TFA in acetonitrile. A constant gradient was used, increasing from 5% to 95% organic phase within 1.3 minutes and maintaining 95% organic phase for 1.7 minutes. The flow rate was kept constant at 2 mL / min. Alternatively, liquid chromatography-mass spectrometry (LC-MS) data were acquired at 45 degrees Celsius using an Agilent Technologies 1200 Series LCMSD equipped with a reversed-phase column (XBridge C18, particle size 3.5 μm, dimensions 4.6 × 50 mm) employing the API-ESI ionization method. The mobile phase consisted of a mixture of water and 10 mM NH4HCO3 solvent in acetonitrile. A constant gradient was used, increasing from 5% to 95% organic within 1.4 minutes and remaining at 95% organic for 1.6 minutes. The flow rate was kept constant at 1.8 mL / min.

[0219] Preparative LC-MS: Preparative HPLC was performed at 20 degrees Celsius using a Gilson 281 preparative system equipped with a Welch Xtimate 10u C18 100A, AXIA packed, 250 × 21.2 mm reversed-phase column. The mobile phase consisted of a solvent mixture of 0.1% formic acid in water and 0.1% formic acid in acetonitrile. A constant gradient of the mobile phase from 70% aqueous / 30% organic to 30% aqueous / 70% organic was utilized over 15 minutes. The flow rate was kept constant at 30 mL / min. Alternatively, a column (Welch Xtimate 10u C18 21.2 × 250 mm, 10 μm) was used, and the mobile phase consisted of a solvent mixture of water (10 mmol / L NH4HCO3 + 0.05% NH3.H2O) and acetonitrile. A constant gradient of the mobile phase was utilized, changing from 70% aqueous / 30% organic phase to 30% aqueous / 70% organic phase over 15 minutes. The flow rate was kept constant at 30 mL / min.

[0220] Silica gel chromatography: Silica gel chromatography was performed using a Biotage® Isolera One instrument or a Biotage® Isolera Prime instrument.

[0221] Proton NMR: 1H NMR spectra were acquired using a Bruker AVANCE III 400 MHz, 400 MHz NMR instrument (acquisition time = 3.16 seconds with a 1-second delay; 8-32 scans), a Bruker AVANCE III 400 MHz, 400 MHz NMR instrument (acquisition time = 3.98 seconds with a 1-second delay; 8-32 scans), or a Bruker AVANCE III 500 MHz, 500 MHz NMR instrument (acquisition time = 3.17 seconds with a 1-second delay; 8-32 scans). Unless otherwise indicated, all protons in DMSO-d6 solvent were reported as parts per million (ppm) relative to residual DMSO (2.50 ppm).

[0222] SFC:Waters sorting system (SFC80, SFC150, SFC200, SFC350).

[0223] Chiral HPLC: Gilson 281 (Manufacturer / Supplier: GILSON)

[0224] Those skilled in the art will recognize that the gradient, column length, and flow rate can be changed, and that certain conditions may be more suitable than others for characterizing the chemical species being analyzed.

[0225] The following symbols refer to the preparative HPLC conditions used as shown in the Preferred Examples and Preparations section. Each gradient was appropriately optimized for each compound. [Table 4]

[0226] SFC conditions

[0227] Method A: Column: OD 20 × 250 mm, 10 μm (Daicel), Column temperature: 35°C, Mobile phase: CO2 / MeOH [0.2% NH3 (7M in MeOH)], Flow rate: 100 g / min, Back pressure: 100 bar, Uniform gradient optimized for each separation.

[0228] Method B: Column: IC 20×250mm, 10μm (Daicel), Column temperature: 35℃, Mobile phase: CO2 / MeOH (0.2% methanol ammonia), Flow rate: 100g / min, Back pressure: 100bar

[0229] Method C: Column: IG 20 x 250 mm, 10 μm (Daicel), column temperature: 35 °C, mobile phase: CO2 / MeOH [0.2% NH3 (7M in MeOH)], flow rate: 100 g / min, back pressure: 100 bar

[0230] Method D: Column: IG 20×250mm, 10μm (Daicel), Column temperature: 35℃, Mobile phase: CO2 / IPA [0.5% NH3 (7M in MeOH)], Flow rate: 100g / min, Back pressure: 100bar

[0231] Method E: Column: AD 20 x 250 mm, 10 μm (Daicel), column temperature: 35 °C, mobile phase: CO2 / MeOH [0.2% NH3 (7M in MeOH)], flow rate: 100 g / min, back pressure: 100 bar

[0232] Method F: Column: AD 20×250mm, 10μm (Daicel), Column temperature: 35℃, Mobile phase: CO2 / EtOH (0.5% methanol ammonia), Flow rate: 100g / min, Back pressure: 100bar

[0233] Method G: Column: OZ 20 x 250 mm, 10 μm (Daicel), column temperature: 35 °C, mobile phase: CO2 / EtOH [0.5% NH3 (7M in MeOH)], flow rate: 100 g / min, back pressure: 100 bar

[0234] Method H: Column: OJ 20×250mm, 10μm (Daicel), Column temperature: 35℃, Mobile phase: CO2 / MeOH (0.2%MeOH / NH3), Flow rate: 100g / min

[0235] Method I: Column: OX 20 x 250 mm, 10 μm (Daicel), column temperature: 35 °C, mobile phase: CO2 / EtOH [0.5% NH3 (7M in MeOH)], flow rate: 100 g / min, back pressure: 100 bar

[0236] Method J: Column: AS 20 x 250 mm, 10 μm (Daicel), column temperature: 35 °C, mobile phase: CO2 / MeOH [0.2% NH3 (7M in MeOH)], flow rate: 100 g / min, back pressure: 100 bar

[0237] General scheme [ka] Scheme 1 In Scheme 1, X 2 -O-, -NR b -, -NR b -(C(R c )2) m , -O(C(R c )2) m-, and -(C(R d )2) n It is -O-. Hal is a halide, preferably Br, Cl, or F. PG is a suitable protecting group for a heteroatom (generally N or O atom). Suitable protecting groups are THP or benzyl for primary alcohols, or Boc for primary or secondary amines.

[0238] The compound of formula (IV') may also be obtained by arylating compound (III') with aryl halide (II') in the presence of a suitable strong organic base or inorganic base, at an optionally suitable high temperature, and optionally under microwave irradiation.

[0239] The compound of formula (VI') may be obtained from a halide (IV') and an amine (V') by a Buchwald-type palladium-catalyzed cross-coupling reaction using a suitable palladium catalyst in a high-temperature solvent in the presence of a suitable phosphine ligand and a suitable inorganic base.

[0240] In the formula, PG is Boc, and the compound of formula (I) may be obtained by treating compound (VI') with an acid such as HCl or TFA. [ka] Scheme 2

[0241] In scheme 2, X 2 -O-, -NR b -, -NR b -(C(R c )2) m -, -O(C(R c )2) m -, and -(C(R d )2) n The compound of formula (VIII') may be obtained by arylating compound (VII') with an aryl(II') halide at an optional high temperature and under microwave irradiation in the presence of a suitable strong organic or inorganic base, provided that the compound is -O-.

[0242] Or, X 2 -O-, -NR b -, -NR b -(C(R c )2) m -, -O(C(R c )2) m -, and -(C(R d )2) n The compound is -O-, and the compound of formula (VIII') may be obtained by reacting compound (XIV') with compound (VII') under Mitsunobu conditions.

[0243] As described in Scheme 1, the compound of formula (I) may be obtained from the halide (VIII') and the amine (V') by a Buchwald-type palladium-catalyzed cross-coupling reaction. [ka] Scheme 2A

[0244] PG2 is a suitable pyrazole N protecting group, generally a t-butyl or tosyl group.

[0245] Alternatively, the pyrazole protecting group strategy shown in Scheme 2A, PG 2 It may be necessary to use the following. The compound of formula (XVIII') may be obtained by reacting the halide of formula (VIII') with the amine of formula (XVIII') under the Buchwald-type reaction conditions described in Scheme 1. The compound of formula (I) may be obtained by deprotecting the compound of formula (XVIII'). [ka] Scheme 3

[0246] The compound of formula (IX') may be obtained from the halide (II') by amination reaction with amine (V') at room temperature in the presence of an inorganic base and a suitable solvent.

[0247] In the formula, X2 -O-, -NR b -, -NR b -(C(R c )2) m -, -O(C(R c )2) m -, or -(C(R d )2) n Compound (I) may be obtained by arylating compound (VII') with an aryl halide (IX') in the presence of a suitable organic or inorganic base, optionally at high temperature, and optionally under microwave irradiation. [ka] Scheme 4

[0248] R 2 ' is, X 2 -R 2 It is an unsaturated precursor. B(Y)2 is a suitable boronic acid or boronic acid ester, for example, pinacol ester.

[0249] In scheme 4, X 2 is, -(C(R d )2) n - and R 2 is either C1-C4 alkyl or X 2 and R 2 These combine to form ring B bonded to pyrazine, where ring B is C3-C 10 The compounds of formula (XII'), which are cycloalkyl or 4-12 membered heterocyclils, may be obtained by a Suzuki-type palladium-catalyzed cross-coupling reaction from the halide of formula (II') and the boronic acid ester (X') in a high-temperature solvent, in the presence of a suitable phosphine ligand and a suitable inorganic base, using a suitable palladium catalyst.

[0250] As described in Scheme 1, the compound of formula (XIII') may be obtained from the halide of formula (XII') and the amine of formula (V') by a Buchwald-type palladium-catalyzed cross-coupling reaction.

[0251] Compound (I) may be obtained from compound (XIII') by a hydrogenation reaction using a suitable transition metal catalyst.

[0252] Alternatively, as described in relation to the synthesis of compounds (XII') and (XIII'), compound (I) (wherein X) can be synthesized from compounds of formulas (II'), (XI'), and (V'). 2 and R 2 These may combine to form a ring B bonded to pyrazine, in which case ring B is a 4-12 membered aryl or a 4-12 membered heteroaryl.

[0253] In the formula, X 1 is O,-O(C(R c )2) m A compound of formula (I') may be selected from the group consisting of - and prepared according to scheme 5. [ka] Scheme 5

[0254] PG 2 The preferred pyrazole N protecting group is generally a t-butyl or tosyl group.

[0255] As described in Scheme 1, the compound of formula (XVI') may be obtained from the halide of formula (VIII') and the amine of formula (XV') by a Buchwald-type palladium-catalyzed cross-coupling reaction.

[0256] Under Mitsunobu reaction conditions, alcohol R 1 X 1 The compound of formula (XVII') may be obtained by reacting H with the compound of formula (XVI'). Alternatively, in the presence of a suitable organic or inorganic base, for example, K2CO3, R 1 The compound of formula (XVII') may also be obtained by alkylating the compound of formula (XVI') with Hal.

[0257] The compound of formula (I') may be obtained from the compound of formula (XVII') by deprotecting the protecting group. In the formula, PG 2 This is t-butyl, which may be achieved by treatment with formic acid.

[0258] Scheme 6 Compounds of formula (I) may be converted to substitute compounds of formula (I) by standard chemical transformations known to those skilled in the art. Examples of these transformations include, but are not limited to, reductive amination reactions with C1-C3 alkylaldehydes in the presence of a suitable reducing agent such as NaCN(BH), Grignard reactions of carbonyl groups to obtain secondary or tertiary alcohols, conversion of primary alcohols to nitrile groups via tosylate, oxidation of thioalkyl groups to obtain sulfoxide groups, and reduction of carbonyl groups to obtain alcohols. Compounds of formulas (IV'), (VIII'), (XVIII'), (XVI'), and (XVII') may be converted to substitute compounds of formulas (IV'), (VIII'), (XVIII'), (XVI'), and (XVII') by standard chemical transformations, including those described in Scheme 6.

[0259] Compounds having one or more stereocenters may be separated into their separate stereoisomers by common methods such as chiral SFC or chiral HPLC, as shown in the following examples.

[0260] Those skilled in the art will understand that it may be necessary to utilize a suitable protecting group strategy to prepare the compound of formula (I). Common protecting groups include benzyl or carbamates, preferably Boc, for protecting primary or secondary aliphatic amines.

[0261] Example 1, N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(piperidine-4-yloxy)pyrazine-2-amine [ka]

[0262] Step 1: Synthesis of 4-((6-chloropyrazine-2-yl)oxy)piperidine-1-carboxylate tert-butyl

[0263] To a solution of 4-hydroxypiperidine-1-carboxylate tert-butyl (30.0 g, 149 mmol) in THF (500 mL), NaH (10.7 g, 267 mmol) was added at 0°C, and the solution was stirred for 1 hour. 2,6-dichloropyrazine (22.1 g, 149 mmol) was added, and the reaction mixture was stirred under N2 at room temperature for 16 hours. The reaction mixture was quenched with water and extracted with siRNA. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel eluted with siRNA / PE(1 / 1) to obtain the title product (40 g, 86%) as a yellow solid. LCMS m / z = 258 [M -56+H] + .

[0264] Step 2: Synthesis of 4-((6-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)piperidine-1-carboxylate tert-butyl A mixture of 4-((6-chloropyrazine-2-yl)oxy)piperidine-1-carboxylate tert-butyl (28.0 g, 89.2 mmol), 5-(difluoromethoxy)-1H-pyrazole-3-amine (13.2 g, 89.2 mmol), tBuXPhos Pd G3 (4.10 g, 4.46 mmol), and KOAc (26.2 g, 267 mmol) in dioxane (800 mL) was stirred under N2 at 100 °C for 16 hours. The reaction mixture was diluted with siRNA, washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel eluted with siRNA / PE(1 / 1) to obtain the title product (23.6 g, 61%) as a yellow solid. LCMS m / z = 427 [M + H] + .

[0265] Step 3: Synthesis of N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(piperidine-4-yloxy)pyrazine-2-amine A mixture of 4-((6-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)piperidine-1-carboxylate tert-butyl (23.6 g, 55.3 mmol) and TFA (80 mL) in DCM (300 mL) was stirred under N2 at 50°C for 3 hours. The reaction mixture was concentrated, and the residue was purified by preparative HPLC (Method A) to obtain the title product as a white solid (5.8 g, 31%). LCMS m / z = 327 [M + H] + .1H-NMR (400 MHz, DMSO-d6) δ ppm 10.39 (br s, 1H), 7.78 (s, 1H), 7.58 (s, 1H), 7.25 (t, 1H), 5.99 (s, 1H), 5.10-4.99 (m, 1H), 3.90-3.80 (m, 1H), 3.05-2.97 (m, 2H), 2.69-2.61 (m, 2H), 2.02-1.98 (m, 2H), 1.65-1.53 ​​(m, 2H).

[0266] Example 2, N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-((4-methylpiperidine-4-yl)oxy)pyrazine-2-amine [ka]

[0267] Step 1: Synthesis of 4-((6-bromopyrazine-2-yl)oxy)-4-methylpiperidine-1-carboxylate tert-butyl A mixture of 2-bromo-6-fluoropyrazine (200 mg, 1.14 mmol), 4-hydroxy-4-methylpiperidine-1-carboxylate tert-butyl (366 mg, 1.70 mmol), and sodium tert-butoxide (109 mg, 1.14 mmol) in DMA (2 mL) was irradiated with microwaves at 80°C for 40 minutes. The reaction mixture was diluted with ELISA and washed with water. The organic layer was concentrated to obtain the crude product (320 mg) as a brown oil, which was used directly in the next step.

[0268] Step 2: Synthesis of 4-((6-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-4-methylpiperidine-1-carboxylate tert-butyl A mixture of 4-((6-bromopyrazine-2-yl)oxy)-4-methylpiperidine-1-carboxylate tert-butyl (320 mg, crude), 5-(difluoromethoxy)-1H-pyrazole-3-amine (30.1 mg, 0.20 mmol), BrettPhos Pd G4 (31.1 mg, 20 μmol), and KOAc (117.6 mg, 1.20 mmol) in dioxane (3 mL) was stirred at 100 °C for 3 hours under N2. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography eluted with siRNA / PE(1 / 4) to obtain the title product (20 mg, 11%) as a yellow solid. LCMS m / z = 441 [M + H] + .

[0269] Step 3: Synthesis of N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-((4-methylpiperidine-4-yl)oxy)pyrazine-2-amine To a solution of 4-((6-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-4-methylpiperidine-1-carboxylate tert-butyl (20 mg, 45 μmol) in DCM (1 mL), TFA (0.3 mL) was added at 0°C, and the reaction mixture was stirred at room temperature for 15 minutes. The reaction mixture was concentrated, and the residue was purified by preparative HPLC (Method A) to obtain the title product (1.5 mg, 9%) as a yellow solid. LCMS m / z = 341 [M + H] + . 1 H-NMR (400 MHz, DMSO-d6) δ ppm 12.13 (br s, 1H), 9.74 (br s, 1H), 7.78 (s, 1H), 7.57 (s, 1H), 7.22 (t, 1H), 5.95 (s, 1H), 2.80-2.68 (m, 4H), 2.33-2.32 (m, 1H), 2.21-2.17 (m, 2H), 1.69-1.63 (m, 2H), 1.54 (s, 3H).

[0270] Example 3, N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(((2S,4R)-2-methylpiperidine-4-yl)oxy)pyrazine-2-amine [ka]

[0271] Step 1: Synthesis of (2S,4R)-4-((6-chloropyrazine-2-yl)oxy)-2-methylpiperidine-1-carboxylate tert-butyl The title compound was obtained from (2S,4R)-4-hydroxy-2-methylpiperidine-1-carboxylate tert-butyl and 2,6-dichloropyrazine as a yellow solid, 1.1 g, 76% concentration, following the procedure described in Step 1 of Example 1. LCMS m / z = 228 [M -100+H] + .

[0272] Step 2: Synthesis of (2S,4R)-4-((6-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-2-methylpiperidine-1-carboxylate tert-butyl The title compound was obtained from (2S,4R)-4-((6-chloropyrazine-2-yl)oxy)-2-methylpiperidine-1-carboxylate tert-butyl and 5-(difluoromethoxy)-1H-pyrazole-3-amine as a yellow solid, 750 mg, 51% concentration, according to the procedure described in Step 2 of Example 2. LCMS m / z = 441 [M + H] + .

[0273] Step 3: Synthesis of N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(((2S,4R)-2-methylpiperidine-4-yl)oxy)pyrazine-2-amine To a mixture of (2S,4R)-4-((6-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-2-methylpiperidine-1-carboxylate tert-butyl (470 mg, 1.06 mmol) in DCM (5 mL), 4 M HCl in dioxane (5.3 mL) was added, and the reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated, and the residue was purified by preparative HPLC (Method A) to obtain the title product as a white solid (226 mg, 62%). LCMS m / z = 341 [M + H] + . 1 H-NMR (400 MHz, DMSO-d6) δ ppm 12.11 (br s, 1H), 10.06 (br s, 1H), 7.76 (s, 1H), 7.60 (s, 1H), 7.24 (t, 1H), 5.95 (s, 1H), 5.30-5.25 (m, 1H), 2.94-2.67 (m, 4H), 1.87-1.78 (m, 2H), 1.68-1.62 (m, 1H), 1.39-1.32 (m, 1H), 0.96 (d, 3H).

[0274] Example 4,6-(((1R,3r,5S)-9-azabicyclo[3.3.1]nonane-3-yl)oxy)-N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)pyrazine-2-amineformate [ka]

[0275] Step 1: Synthesis of (1R,3r,5S)-3-((6-chloropyrazine-2-yl)oxy)-9-azabicyclo[3.3.1]nonane-9-carboxylate tert-butyl The title compound was obtained from (1R,3r,5S)-3-hydroxy-9-azabicyclo[3.3.1]nonane-9-carboxylate tert-butyl and 2,6-dichloropyrazine as 500 mg, 86% yellow oil by following the same procedure as described in Step 1 of Example 1. LCMS m / z = 354 [M +H] + .

[0276] Step 2: Synthesis of (1R,3r,5S)-3-((6-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-9-azabicyclo[3.3.1]nonane-9-carboxylate tert-butyl The title compound was obtained from (1R,3r,5S)-3-((6-chloropyrazine-2-yl)oxy)-9-azabicyclo[3.3.1]nonane-9-carboxylate tert-butyl and 5-(difluoromethoxy)-1H-pyrazole-3-amine as 300 mg, 91% yellow solid, following the same procedure as described in Step 2 of Example 2. LCMS m / z = 467 [M + H] + .

[0277] Step 3: Synthesis of 6-(((1R,3r,5S)-9-azabicyclo[3.3.1]nonane-3-yl)oxy)-N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)pyrazine-2-amine formate (1R,3r,5S)-3-((6-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-9-azabicyclo[3.3.1]nonane-9-carboxylate tert-butyl (200 mg, 0.43 mmol) was added to a 3 mL solution of DCM, to which a 1 mL solution of HCl-dioxane (6 M, 6.0 mmol) was added. The mixture was stirred at 25°C for 1 hour. The mixture was concentrated under vacuum, and the residue was purified by preparative HPLC (Method B) to obtain the title product (125.6 mg, 70%) as a white solid. LCMS m / z = 367 [M + H] + .1H-NMR (400 MHz, DMSO-d6) δ ppm 12.93 (br s, 1H), 11.26 (br s, 1H), 8.44 (s, 1H), 7.77 (s, 1H), 7.58 (s, 1H), 7.27 (t, 1H), 6.00 (s, 1H), 5.27 (quintet, 1H), 3.55 (s, 2H), 2.53-2.50 (m, 1H), 2.50-2.44 (m, 2H), 2.44-2.36 (m, 1H), 1.90-1.80 (m, 4H), 1.62-1.54 (m, 2H), 1.50-1.44 (m, 1H).

[0278] Examples 5 and 23, 6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octane-3-yl)oxy)-N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)pyrazine-2-amine hydrochloride and 6-(((1R,3r,5S)-8-azabicyclo[3.2.1]octane-3-yl)oxy)-N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)pyrazine-2-amine hydrochloride [ka]

[0279] Step 1: Synthesis of 3-((6-chloropyrazine-2-yl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl

[0280] 3-Hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl (99.9 mg, 0.44 mmol) was dissolved in THF (4 mL), and NaH (100 mg, 2.40 mmol, 60 wt% / mineral oil) was added. The mixture was shaken at 30°C for 0.5 hours. 2,6-Dichloropyrazine (59.6 mg, 0.40 mmol) was added, and the reaction mixture was shaken at 30°C for 2 hours. The reaction mixture was diluted with water (3 mL) and extracted with ELISA (10 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the title compound.

[0281] Step 2: Synthesis of (1R,3r,5S)-3-((6-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl and (1R,3s,5S)-3-((6-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl

[0282] A mixture of 5-(difluoromethoxy)-1H-pyrazole-3-amine (89.4 mg, 0.60 mmol), 3-((6-chloropyrazine-2-yl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl (crude, 0.40 mmol), KOAc (117.6 mg, 1.20 mmol), and Brettphos Pd G3 (18.12 mg, 0.02 mmol) in t-AmOH (3 mL) was stirred under N2 at 100°C for 2 hours. The cooled reaction mixture was diluted with RINKAN (5 mL) and washed with water (5 mL x 3). The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated to dryness to obtain the crude product. This was purified by preparative HPLC (Method A) to obtain 3-((6-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl. This product was then subjected to chiral SFC (column: IC). Separation was performed using a 20×250mm, 10μm (Daicel) column, at a column temperature of 35℃, mobile phase: CO2 / MeOH (0.2% MeOH / NH3) = 75 / 25, at 100g / min, and peak 1,(1R,3r,5S)-3-((6-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl or (1R,3s,5S)-3-((6-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-8 -Azabicyclo[3.2.1]octane-8-carboxylate tert-butyl and peak 2,(1R,3s,5S)-3-((6-((5-()difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl or (1R,3r,5S)-3-((6-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl were obtained. LCMS m / z = 453 [M +H] + .

[0283] Step 3: Synthesis of 6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octane-3-yl)oxy)-N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)pyrazine-2-amine hydrochloride or 6-(((1R,3r,5S)-8-azabicyclo[3.2.1]octane-3-yl)oxy)-N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)pyrazine-2-amine hydrochloride

[0284] To the DCM (2.0 mL) mixture of peak 1 (7.0 mg, 15.5 μmol) from step 2, 4 M HCl / dioxane (0.5 mL) was added under N2 at 0°C. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was evaporated under reduced pressure to obtain the title product of Example 23 (1.8 mg, 33%) as a yellow solid. LCMS m / z = 353 [M +H]+. 1HNMR (400 MHz, DMSO-d6) δ ppm 10.07 (s, 1H), 9.20 (s, 1H), 7.83 (s, 1H), 7.61 (s, 1H), 7.38 (s, 1H), 7.26 (t, 1H), 7.13 (s, 1H), 5.96 (s, 1H), 5.37-5.30 (m, 1H), 4.08-4.01 (m, 2H), 2.25-2.18 (m, 2H), 2.05-1.82 (m, 6H).

[0285] Step 4: Synthesis of 6-(((1R,3r,5S)-8-azabicyclo[3.2.1]octane-3-yl)oxy)-N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)pyrazine-2-amine hydrochloride or 6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octane-3-yl)oxy)-N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)pyrazine-2-amine hydrochloride

[0286] To the DCM (2 mL) solution of peak 2 (8.0 mg, 17.7 μmol) from step 2, HCl / dioxane (0.5 mL) was added, and the reaction mixture was stirred at 25°C for 2 hours. The mixture was concentrated to obtain the title product of Example 5 (3.4 mg, 54%) as a yellow solid. LCMS m / z = 353 [M +H]+. 1H-NMR (400 MHz, DMSO-d6) δ ppm 10.11 (br s, 1H), 9.02 (br s, 1H), 8.81 (br s, 1H), 7.84 (s, 1H), 7.66 (s, 1H), 7.28 (t, 1H), 5.92 (s, 1H), 5.35-5.30 (m, 1H), 5.30-5.25 (m, 1H), 4.01-3.96 (m, 2H), 2.35-1.97 (m, 8H).

[0287] Example 6, N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(((3S,4R)-3-methoxypiperidine-4-yl)oxy)pyrazine-2-amine [ka]

[0288] Step 1: (3S,4R)-4-((6-chloropyrazine-2-yl)oxy)-3-methoxypiperidine-1-carboxylate tert-butyl

[0289] To a solution of (3S,4R)-4-hydroxy-3-methoxypiperidine-1-carboxylate tert-butyl (0.50 g, 2.16 mmol) in THF (4.32 ml, 2.16 mmol), NaH (0.104 g, 4.32 mmol) was gradually added at 0°C. After stirring for 1 hour, 2,6-dichloropyrazine (0.32 g, 2.16 mmol) was added, and the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography on silica gel eluted with ethyl acetate / hexane (1 / 4) to obtain the title compound as a white solid (636 mg, 86%).

[0290] Step 2: (3S,4R)-4-((6-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-3-methoxypiperidine-1-carboxylate tert-butyl

[0291] A mixture of the compound from step 1 (0.318 g, 0.925 mmol), 5-(difluoromethoxy)-1H-pyrazole-3-amine (0.152 g, 1.02 mmol), Brettphos Pd G4 (21 mg, 0.023 mmol), and KOAc (0.182 g, 1.85 mmol) in dioxane (4.62 ml) was heated overnight at 100°C under N2. The reaction mixture was cooled to room temperature, concentrated, and the residue was purified by column chromatography on silica gel eluted with siRNA / hexane (5 / 1~1:5) to obtain the title compound (0.27 g, 64.0%).

[0292] Step 3: N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(((3S,4R)-3-methoxypiperidine-4-yl)oxy)pyrazine-2-amine

[0293] The compound from step 2 (0.27 g, 0.592 mmol) was dissolved in DCM (2 mL) and TFA (0.5 mL), and the reaction mixture was stirred overnight at room temperature. The reaction product was concentrated under vacuum, and the residue was purified by reverse-phase HPLC (Method A) to obtain the title compound (0.112 g, 34.0%). LCMS m / z = 357.1 [M + H] + .1H NMR (500 MHz, DMSO) δ ppm 10.20 (br s, 1H), 8.25 (s, 1H), 7.71 (s, 1H), 7.54 (d, J = 3.4 Hz, 1H), 7.18 (s, 1H), 5.87 (s, 1H), 5.27-5.17 (m, 1H), 3.41 (s, 3H), 2.95-2.77 (m, 2H), 2.69-2.61 (m, 2H), 1.84-1.79 (m, 2H), 1.66-1.61 (m, 2H).

[0294] Example 7, N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(((1R,2S,3R,5S)-2-methyl-8-azabicyclo[3.2.1]octane-3-yl)oxy)pyrazine-2-amine, and Example 128, N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(((1R,2S,3S,5S)-2-methyl-8-azabicyclo[3.2.1]octane-3-yl)oxy)pyrazine-2-amine [ka]

[0295] Step 1: Synthesis of (1R,2R,5S)-2-methyl-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl, (1S,2S,5R)-2-methyl-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl, (1R,2S,5S)-2-methyl-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl, and (1S,2R,5R)-2-methyl-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl

[0296] 1.9 g of 2-methyl-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl was separated by chiral preparative HPLC (column: IG 20 × 250 mm, 10 μm (Daicel), column temperature: 35 °C, mobile phase: CO2 / MeOH (0.2% MeOH / NH3) = 60 / 40, 100 g / min) to obtain peak 1 as a mixture of two isomers, peak 2 (600 mg) of (1R,2S,5S)-2-methyl-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl, and peak 3. Peak 2 was further purified by preparative HPLC (Method A) to obtain the title product (210 mg) as a yellow solid.

[0297] Step 2: Synthesis of (1R,2S,5S)-3-hydroxy-2-methyl-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl

[0298] To the MeOH (5 mL) mixture at peak 2 (210 mg, 0.88 mmol) of step 1, NaBH4 (33 mg, 0.88 mmol) was added at 0°C, and the reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was quenched with water at 0°C and concentrated under vacuum. The residue was partitioned into toluene and water, the layers were separated, the aqueous layer was extracted with toluene, and the combined organic phase was concentrated under vacuum. The residue was purified by silica gel chromatography eluting with toluene / PE(1 / 4) to obtain the title product (143 mg, 68%). LCMS m / z = 186 [M -56+H] + .

[0299] Step 3: Synthesis of (1R,2S,5S)-3-((6-chloropyrazine-2-yl)oxy)-2-methyl-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl

[0300] The title compound was obtained as a yellow solid, 195 mg, 93% in volume, from the compound of step 2 and 2,6-dichloropyrazine, following the same procedure as described in step 1 of Example 1. LCMS m / z = 298 [M -56+H] + .

[0301] Step 4: Synthesis of (1R,2S,5S)-3-((6-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-2-methyl-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl

[0302] The title compound was obtained as a brown oily substance (195 mg, 76%) from the compound of step 3 and 5-(difluoromethoxy)-1H-pyrazole-3-amine according to the procedure described in step 2 of Example 2. LCMS m / z = 467 [M + H] + .

[0303] Step 5: Synthesis of N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(((1R,2S,3S,5S)-2-methyl-8-azabicyclo[3.2.1]octane-3-yl)oxy)pyrazine-2-amine and N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(((1R,2S,3R,5S)-2-methyl-8-azabicyclo[3.2.1]octane-3-yl)oxy)pyrazine-2-amine

[0304] At 0°C, TFA (2.5 mL) was added to a mixture of the compound from step 4 (195 mg, 0.42 mmol) in DCM (5 mL), and the reaction mixture was heated to room temperature and stirred for 2 hours. The solution was concentrated under vacuum, and the residue was purified by preparative HPLC (Method A). The product was further purified by chiral preparative SFC (column: AS 20×250mm, 10μm (Daicel), column temperature: 35℃, mobile phase: CO2 / MeOH [0.2%NH3 (7M in MeOH)] = 75 / 25 100g / min), and peak 1, i.e., Example 128, N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(((1R,2S,3S,5S)-2-methyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyrazine-2-amine, 1H NMR (500 MHz, DMSO-d6): δ 12.15 (br s, 1H), 10.10 (br s, 1H), 7.75 (s, 1H), 7.56 (s, 1H), 7.24 (t, 1H), 5.98 (s, 1H), 4.85-4.78 (m, 1H), 3.56-3.52 (m, 1H), 2.10-2.04 (m, 1H), 1.98-1.90 (m, 1H), 1.84-1.70 (m, 2H), 1.66-1.56 (m, 2H), 1.48-1.40 (m, 1H), 0.87 (d, 3H).

[0305] And peak 2, i.e., Example 7 (15.7 mg, 10%), was obtained as an off-white solid. The structure of Example 7 was confirmed by X-ray crystallography. LCMS m / z = 367 [M +H]+. 1H NMR (500 MHz, DMSO-d6) δ 12.12 (br s, 1H), 10.26 (br s, 1H), 7.75 (s, 1H), 7.57 (s, 1H), 7.25 (t, 1H), 5.94 (s, 1H), 5.14-5.12 (m, 1H), 3.19 - 3.15 (m, 1H), 2.25 - 2.18 (m, 1H), 2.17 - 2.11 (m, 1H), 1.96 - 1.90 (m, 1H), 1.85 - 1.75 (m, 2H), 1.71 - 1.62 (m, 1H), 1.61 - 1.52 (m, 1H), 0.89 (d, 3H)

[0306] Example 8, N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-((1-methylpiperidine-4-yl)oxy)pyrazine-2-amine [ka]

[0307] Step 1: Synthesis of 2-chloro-6-((1-methylpiperidine-4-yl)oxy)pyrazine The title compound was obtained from 1-methylpiperidine-4-ol and 2,6-dichloropyrazine as 15 g, 64% pale yellow oily substance, following the same procedure as described in Step 1 of Example 1. LCMS m / z = 228 [M + H] + .

[0308] Step 2: Synthesis of N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-((1-methylpiperidine-4-yl)oxy)pyrazine-2-amine A mixture of 2-chloro-6-((1-methylpiperidine-4-yl)oxy)pyrazine (13.0 g, 57.0 mmol), 5-(difluoromethoxy)-1H-pyrazole-3-amine (8.49 g, 57.0 mmol), KOAc (10.20 g, 104 mmol), and BrettPhos Pd G4 (1.5 g, 0.97 mmol) in dioxane (220 mL) was stirred at 100 °C for 24 hours. The mixture was concentrated under vacuum, and the residue was purified by column chromatography on silica gel eluted with MeOH / DCM (1 / 5) to obtain the crude product (5.2 g). This was further purified by preparative HPLC (Method A) to obtain the title product (3.70 g, 19%). LCMS m / z = 341 [M + H] + . 1 H-NMR (400 MHz, DMSO-d6) δ ppm 11.93 (br s, 1H), 9.95 (br s, 1H), 7.77 (s, 1H), 7.59 (s, 1H), 7.24 (t, 1H), 5.97 (s, 1H), 4.93 (quintet, 1H), 2.70-2.55 (m, 2H), 2.24 (s, 3H), 2.26-2.12 (m, 2H), 2.00-1.93 (m, 2H), 1.75-1.63 (m, 2H).

[0309] Examples 9 and 97, (S)-6-((1-methylpiperidine-4-yl)oxy)-N-(5-(tetrahydrofuran-3-yl)-1H-pyrazole-3-yl)pyrazine-2-amine formate or (R)-6-((1-methylpiperidine-4-yl)oxy)-N-(5-(tetrahydrofuran-3-yl)-1H-pyrazole-3-yl)pyrazine-2-amine formate and (R)-6-((1-methylpiperidine-4-yl)oxy)-N-(5-(tetrahydrofuran-3-yl)-1H-pyrazole-3-yl)pyrazine-2-amine formate or (S)-6-((1-methylpiperidine-4-yl)oxy)-N-(5-(tetrahydrofuran-3-yl)-1H-pyrazole-3-yl)pyrazine-2-amine formate [ka]

[0310] Step 1 of Example 8 (200 mg, 878 μmol), a mixture of 5-(oxolan-3-yl)-1H-pyrazole-3-amine (160 mg, 1.05 mmol), BrettPhos-Pd-G4 (20 mg, 0.02 mmol), and KOAc (171 mg, 1.75 mmol) in 20 mL of dioxane was stirred under N2 at 120 °C for 15 hours. The cooled reaction mixture was diluted with Â, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method A) to obtain a racemic product (80 mg), which was then separated by chiral preparative SFC (column: OD 20 × 250 mm, 10 μm (Daicel), column temperature: 35 °C, mobile phase: CO2 / EtOH [0.5% NH3 (7 M in MeOH)] = 65 / 35 100 g / min, back pressure: 100 bar). Peak 1 of Example 9 (31.5 mg, 10%) was obtained. ¹H-NMR (400 MHz, DMSO-d6) δ ppm values ​​were 12.13 (br s, ¹H), 9.69 (br s, ¹H), 7.92 (s, ¹H), 7.45 (s, ¹H), 6.31 (s, ¹H), 4.95-4.90 (m, ¹H), 4.04-3.99 (m, ¹H). 3.90-3.85 (m, 1H), 3.83-3.77 (m, 1H), 3.63-3.55 (m, 1H), 3.42-3.37 (m, 1H), 2.75-2.65 (m, 2H), 2.33-2.25 (m, 1H), 2.23 (s, 3H), 2.20-2.04 (m, 2H), 2.03-1.93 (m, 3H), 1.74-1.69 (m, 2H).

[0311] And peak 2 (24.1 mg, 8%) of Example 97 was obtained. LCMS m / z = 345 [M +H]+. 1HNMR (400 MHz, DMSO-d6) δ ppm 11.93 (br s, 1H), 9.68 (br s, 1H), 7.93 (s, 1H), 7.46 (s, 1H), 6.31 (s, 1H), 4.95-4.90 (m, 1H), 4.04-3.99 (m, 1H), 3.90-3.85 (m, 1H), 3.83-3.77 (m, 1H), 3.63-3.55 (m, 1H), 3.42-3.37 (m, 1H), 2.75-2.65 (m, 2H), 2.33-2.25 (m, 1H), 2.23 (s, 3H), 2.20-2.04 (m, 2H), 2.03-1.93 (m, 3H), 1.74-1.69 (m, 2H).

[0312] Example 10, (S)-N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-((1-methylazepan-4-yl)oxy)pyrazine-2-amine or (R)-N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-((1-methylazepan-4-yl)oxy)pyrazine-2-amine and

[0313] Example 151, (R)-N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-((1-methylazepan-4-yl)oxy)pyrazine-2-amine or (S)-N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-((1-methylazepan-4-yl)oxy)pyrazine-2-amine [ka]

[0314] Step 1: Synthesis of 4-((6-chloropyrazine-2-yl)oxy)-1-methylazepane To a solution of 1-methylazepan-4-ol (1.0 g, 7.75 mmol) and 2,6-dichloropyrazine (1.25 g, 8.36 mmol) in THF (10 mL), NaH (200 mg, 8.36 mmol) was added at 0°C, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water and extracted with SiO2. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated to obtain the title compound (1.5 g, 79%), which was used directly in the next step. LCMS m / z = 242 [M + H] + .

[0315] Step 2: Synthesis of (R)-N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-((1-methylazepan-4-yl)oxy)pyrazine-2-amine or (S)-N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-((1-methylazepan-4-yl)oxy)pyrazine-2-amine A mixture of 4-((6-chloropyrazine)-2-yl)oxy)-1-methylazepane (500 mg, 2.07 mmol), 5-(difluoromethoxy)-1H-pyrazole-3-amine (463 mg, 3.11 mmol), Brettphos-Pd-G4 (50 mg, 0.03 mmol), and KOAc (608 mg, 6.21 mmol) in dioxane (20 mL) was stirred overnight at 90°C. The reaction mixture was cooled to room temperature, concentrated, and the residue was obtained, which was purified by preparative HPLC (Method A) to obtain a racemic product. This was then separated by chiral preparative SFC (column: OZ 20 × 250 mm, 10 μm (Daicel), column temperature: 35°C, mobile phase: CO2 / EtOH (0.5% NH3 (7 M in MeOH) = 70 / 30, 100 g / min).

[0316] Peak 1 of Example 151, LCMS m / z = 355 [M + H] + . 1H NMR (400 MHz, DMSO-d6) δ ppm 12.01 (br s, 1H), 10.06 (br s, 1H), 7.77 (s, 1H), 7.57 (s, 1H), 7.25 (t, 1H), 5.98 (s, 1H), 5.24-5.19 (m, 1H), 2.81-2.75 (m, 2H), 2.73-2.69 (m, 2H), 2.41 (s, 3H), 2.27-2.10 (m, 2H), 2.01-1.93 (m, 2H), 1.89-1.76 (m, 2H).

[0317] And peak 2 (10.6 mg, 1%) of Example 10 was obtained. LCMS m / z = 355 [M + H] + . 1 H-NMR (400 MHz, DMSO-d6) δ ppm 11.98 (br s, 1H), 10.05 (s, 1H), 7.77 (s, 1H), 7.58 (s, 1H), 7.26 (t, 1H), 5.97 (s, 1H), 5.26-5.20 (m, 1H), 3.00-2.89 (m, 2H), 2.79-2.67 (m, 2H), 2.45 (s, 3H), 2.15-2.09 (m, 2H), 1.96-1.91 (m, 2H), 1.87-1.77 (m, 2H)..

[0318] Example 11, N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(((2S,4R)-1,2-dimethylpiperidine-4-yl)oxy)pyrazine-2-amine [ka]

[0319] N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(((2S,4R)-2-methylpiperidine-4-yl)oxy)pyrazine-2-amine (Example 3, 500 mg, 1.46 mmol), acetic acid (0.2 mL), and a mixture of HCHO (0.2 mL) aqueous solution in MeOH (10 mL) were stirred at room temperature for 1 hour. NaBH3CN (135.8 mg, 2.19 mmol) was added, and the resulting mixture was stirred for 1 hour. The reaction mixture was concentrated, and the residue was purified by preparative HPLC (Method A) to obtain the title product (130.1 mg, 25%) as a white solid. LCMS m / z = 355 [M + H] + . 1 H-NMR (400 MHz, DMSO-d6) δ ppm 11.93 (br s, 1H), 9.98 (s, 1H), 7.77 (s, 1H), 7.59 (s, 1H), 7.24 (t, 1H), 5.95 (s, 1H), 5.23-5.17 (m, 1H), 2.60-2.54 (m, 1H), 2.38-2.27 (m, 2H), 2.19 (s, 3H), 1.89-1.80 (m, 3H), 1.60-1.50 (m, 1H), 0.98 (d, 3H).

[0320] Example 12, N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(((1R,3r,5S)-9-methyl-9-azabicyclo[3.3.1]nonane-3-yl)oxy)pyrazine-2-amine [ka]

[0321] The title compound was obtained from 6-(((1R,3r,5S)-9-azabicyclo[3.3.1]nonane-3-yl)oxy)-N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)pyrazine-2-amine (Example 4) as a white solid of 43.7 mg, 28% following the procedure described in Example 11. LCMS m / z = 381 [M + H] + . 1H-NMR (400 MHz, DMSO-d6) δ ppm 11.94 (br s, 1H), 9.96 (s, 1H), 7.77 (s, 1H), 7.57 (s, 1H), 7.23 (t, 1H), 6.02 (s, 1H), 5.31 (quintet, 1H), 2.98-2.92 (m, 2H), 2.50-2.40 (m, 2H), 2.39 (s, 3H), 2.24-2.16 (m, 1H), 1.95-1.85 (m, 2H), 1.54-1.40 (m, 3H), 1.25-1.11 (m, 2H).

[0322] Example 13, N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-((1-methylazepan-4-yl)oxy)pyrazine-2-amine [ka]

[0323] Step 1: Synthesis of 4-((6-chloropyrazine-2-yl)oxy)-1-methylazepane:

[0324] 1-Methylpiperidine-4-ol (92.65 mg, 0.81 mmol) was dissolved in THF (4 mL), and NaH (193.2 mg, 4.83 mmol, 60 wt% / mineral oil) was added. The mixture was shaken at 30°C for 0.5 hours. 2,6-Dichloropyrazine (119.1 mg, 0.81 mmol) was added, and the reaction mixture was shaken at 30°C for 2 hours. Water (3 mL) was added, and the mixture was extracted with ELISA (10 mL × 3). The combined organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the title product, which was used in the next step without further purification.

[0325] Step 2: Synthesis of N-(5-isopropyl-1H-pyrazole-3-yl)-6-((1-methylpiperidine-4-yl)oxy)pyrazine-2-amine

[0326] 5-Isopropyl-1H-pyrazole-3-amine (111.2 mg, 0.89 mmol), 2-chloro-6-((1-methylpiperidine-4-yl)oxy)pyrazine (crude, 0.40 mmol), KOAc (157.8 mg, 1.61 mmol), and tBuXPhos Pd G3 (31.97 mg, 0.04 mmol) were added in THF (4 mL), and the reaction mixture was stirred under N2 at 110°C for 5 hours. The reaction mixture was diluted with  (5 mL) and washed with water (5 mL x 3). The organic layer was dried over Na2SO4, filtered, and evaporated to dryness to obtain the crude product. This was purified by preparative HPLC (Method C) to obtain the title product (91.42 mg, yield 35.9%). LCMS: m / z = 317 [M + H] + .

[0327] Example 14, N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-((3,3-difluoropiperidine-4-yl)oxy)pyrazine-2-amine [ka]

[0328] Step 1: Synthesis of 4-((6-chloropyrazine-2-yl)oxy)-3,3-difluoropiperidine-1-carboxylate tert-butyl

[0329] The title product was obtained from tert-butyl 3,3-difluoro-4-hydroxypiperidine-1-carboxylate and 2,6-dichloropyrazine according to the procedure described in Step 1 of Example 13.

[0330] Step 2: Synthesis of 4-((6-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-3,3-difluoropiperidine-1-carboxylate tert-butyl

[0331] 5-(difluoromethoxy)-1H-pyrazole-3-amine (89.4 mg, 0.60 mmol), 4-((6-chloropyrazine-2-yl)oxy)-3,3-difluoropiperidine-1-carboxylate tert-butyl (crude, 0.40 mmol), KOAc (117.6 mg, 1.20 mmol), and BrettPhos Pd G3 (18.12 mg, 0.02 mmol) were added in t-AmOH (3 mL), and the reaction mixture was stirred under N2 at 100°C for 2 hours. The mixture was diluted with ELISA (5 mL) and washed with water (5 mL x 3). The organic layer was dried over Na2SO4, filtered, and evaporated to obtain the title product, which was used without further purification.

[0332] Step 3: Synthesis of N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-((3,3-difluoropiperidine-4-yl)oxy)pyrazine-2-amine

[0333] 4-((6-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-3,3-difluoropiperidine-1-carboxylate tert-butyl (crude, 0.40 mmol) was dissolved in DCM (3 mL), then TFA (1 mL) was added, and the reaction mixture was stirred at 30°C for 2 hours. The mixture was concentrated under reduced pressure, and the crude product was purified by preparative HPLC (Method C) to obtain the title product (28.65 mg, yield 19.8%). LCMS m / z = 363 [M + H] +

[0334] Example 15, Rac-6-(((1R,3s,5S)-8-azabicyclo[3.2.1]octan-3-yl)oxy)-N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)pyrazine-2-amine [ka]

[0335] The title compound was obtained from 2,6-dichloropyrazine, rac-(1R,3s,5S)-3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl, and 5-(difluoromethoxy)-1H-pyrazole-3-amine following the three-step procedure described in Example 14. LCMS m / z = 353 [M + H] +

[0336] Example 16, N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(piperidine-3-ylmethoxy)pyrazine-2-amine [ka]

[0337] Step 1: Synthesis of 3-(((6-chloropyrazine-2-yl)oxy)methyl)piperidine-1-carboxylate tert-butyl:

[0338] The crude title compound was obtained from tert-butyl 3-(hydroxymethyl)piperidine-1-carboxylate and 2,6-dichloropyrazine according to the procedure described in Step 1 of Example 13.

[0339] Step 2: Synthesis of 3-(((6-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)methyl)piperidine-1-carboxylate tert-butyl

[0340] 5-(difluoromethoxy)-1H-pyrazole-3-amine (89.4 mg, 0.60 mmol), 3-(((6-chloropyrazine-2-yl)oxy)methyl)piperidine-1-carboxylate tert-butyl (crude, 0.40 mmol), Cs2CO3 (390.9 mg, 1.20 mmol), and BrettPhos Pd G3 (18.12 mg, 0.02 mmol) were added in t-AmOH (3 mL), and the reaction mixture was stirred at 100°C under N2 for 2 hours. The reaction mixture was diluted with ELISA (5 mL) and washed with water (5 mL x 3). The organic layer was dried over Na2SO4, filtered, and evaporated to obtain the title product, which was used in the next step without further purification.

[0341] Step 3: Synthesis of N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(piperidine-3-ylmethoxy)pyrazine-2-amine The title compound was obtained from 3-(((6-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)methyl)piperidine-1-carboxylate tert-butyl according to the procedure described in step 3 of Example 14 (29.9 mg, 22%). LCMS m / z = 341 [M + H] + .

[0342] Example 17, (S)-5-((5-Methoxy-1H-pyrazole-3-yl)amino)-3-((1-(oxetan-3-yl)ethyl)amino)pyrazine-2-carbonitrile [ka]

[0343] Step 1: Synthesis of 3-chloro-5-((5-methoxy-1H-pyrazole-3-yl)aminopyrazine-2-carbonitrile

[0344] A mixture of 3,5-dichloropyrazine-2-carbonitrile (600 mg, 3.44 mmol), 5-methoxy-1H-pyrazole-3-amine hydrochloride (466 mg, 4.12 mmol), and NaHCO3 (1.15 g, 13.7 mmol) in DMA (20 mL) was stirred under N2 at room temperature for 4 hours. The reaction mixture was diluted with HCl and washed with water and brine. The organic layer was purified by column chromatography on silica gel eluted with HCl / PE(1 / 1) to obtain the title compound (130 mg, yield 15%) as a white solid. LCMS m / z = 251 [M + H] +

[0345] Step 2: (S)-5-((5-Methoxy-1H-pyrazole-3-yl)amino)-3-((1-(oxetane-3-yl)ethyl)amino)pyrazine-2-carbonitrile

[0346] A mixture of 3-chloro-5-((5-methoxy-1H-pyrazole-3-yl)amino)pyrazine-2-carbonitrile (130 mg, 0.5 mmol), 1-(oxetane-3-yl)ethane-1-amine (62.7 mg, 0.6 mmol), and DIPEA (199 mg, 1.55 mmol) in NMP (8 mL) was stirred under N2 at 100°C for 16 hours. The reaction mixture was purified by preparative HPLC (Method A) to obtain 5-((5-methoxy-1H-pyrazole-3-yl)amino)-3-((1-(oxetane-3-yl)ethyl)amino)pyrazine-2-carbonitrile (approximately 90 mg). This was further separated by chiral preparative HPLC (column: IC20×250mm, 10μm (Daicel), column temperature: 35°C, mobile phase: CO2 / MeOH (0.2%MeOH / NH3) = 65 / 35, flow rate: 80g / min) to obtain the title compound (35.6 mg, yield 21%) as a white solid. LCMS m / z = 316 [M +H] + . 1H-NMR (400 MHz, DMSO-d6) δ ppm 12.05 (br s, 1H), 10.36 (br s, 1H), 7.52 (s, 1H), 7.06 (s, 1H), 5.99 (br s, 1H), 4.69-4.57 (m, 3H), 4.36-4.26 (m, 2H), 3.81 (s, 3H), 3.21-3.12 (m, 1H), 1.12 (d, 3H).

[0347] Example 18, N2-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-N6-(1-methylpiperidine-4-yl)pyrazine-2,6-diamine [ka]

[0348] Step 1: Synthesis of 6-chloro-N-(1-methylpiperidine-4-yl)pyrazine-2-amine

[0349] A mixture of 2,6-dichloropyrazine (80.0 mg, 0.537 mmol), 1-methylpiperidine-4-amine (61.3 mg, 0.537 mmol), and DIPEA (207 mg, 1.65 mmol) in NMP (5 mL) was irradiated with microwaves at 100°C for 2 hours. The reaction mixture was diluted with DCM and washed with water and brine. The organic layer was concentrated, and the residue was purified by column chromatography on silica gel eluted with DCM / MeOH (10 / 1) to obtain the title compound (50.0 mg, yield 41%) as a colorless oil. LCMS m / z = 227 [M + H] +

[0350] Step 2: Synthesis of N2-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-N6-(1-methylpiperidine-4-yl)pyrazine-2,6-diamine

[0351] A mixture of 6-chloro-N-(1-methylpiperidine-4-yl)pyrazine-2-amine (50.0 mg, 0.22 mmol), 5-(difluoromethoxy)-1H-pyrazole-3-amine (32.8 mg, 0.22 mmol), BrettPhos Pd G4 (20.2 mg, 22.0 μmol), and KOAc (64.7 mg, 0.66 mmol) in dioxane (5 mL) was stirred under N2 at 100 °C for 16 hours. The reaction mixture was concentrated under vacuum, and the residue was purified by preparative HPLC (Method A) to obtain the title compound (11.7 mg, yield 15%) as a yellow solid. LCMS m / z = 340 [M + H] + . 1 H-NMR (400 MHz, DMSO-d6) δ ppm 11.99 (s, 1H), 9.82 (s, 1H), 7.31 (s, 1H), 7.30 (s, 1H), 7.24 (t, 1H), 6.90 (d, 1H), 5.66 (s, 1H), 3.48-3.45 (m, 1H), 2.77-2.74 (m, 2H), 2.20 (s, 3H), 2.10-2.05 (m, 2H), 1.93-1.88 (m, 2H), 1.50-1.42 (m, 2H).

[0352] Examples 19 and 20: (R)-N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(piperidine-3-yl)pyrazine-2-amine or (S)-N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(piperidine-3-yl)pyrazine-2-amine [ka]

[0353] Step 1: Synthesis of 5-(6-chloropyrazine-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate tert-butyl

[0354] A mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl (500 mg, 1.61 mmol), 2,6-dichloropyrazine (479 mg, 3.22 mmol), Pd(dppf)Cl2 (116 mg, 0.16 mmol), and KOAc (316 mg, 3.23 mmol) in dioxane (8 mL) and H2O (2 mL) was stirred at 100°C for 5 hours. The reaction mixture was cooled to room temperature, concentrated, and the residue was obtained. This residue was purified by silica gel column chromatography (PE:siRNA = 1:4) to obtain the title compound (380 mg, yield 80%) as a yellow solid. LCMS m / z = 296 [M -56+H] + .

[0355] Step 2: Synthesis of 5-(6-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl

[0356] A mixture of tert-butyl 5-(6-chloropyrazine-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate (300 mg, 1.01 mmol), 5-(difluoromethoxy)-1H-pyrazole-3-amine (195 mg, 1.31 mmol), BrettPhos Pd G4 (77.5 mg, 0.05 mmol), and KOAc (198 mg, 2.02 mmol) in dioxane (4 mL) was stirred under N2 at 100°C for 15 hours. The reaction mixture was cooled to room temperature, concentrated, and the residue was obtained. This residue was purified by silica gel column chromatography (PE:Â=1:4) to obtain the title compound (311 mg, yield 75%) as a yellow solid. LCMS m / z = 409 [M + H] +

[0357] Step 3: Synthesis of (R)-3-(6-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)piperidine-1-carboxylate tert-butyl and (S)-3-(6-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)piperidine-1-carboxylate tert-butyl

[0358] A mixture of 5-(6-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate tert-butyl (300 mg, 734 μmol) and PtO2 (49.9 mg, 220 μmol) in ELISA (6 mL) was stirred under an H2 balloon at room temperature for 24 hours. The reaction mixture was diluted with ELISA and filtered. The filtrate was concentrated under vacuum, and the residue was purified by preparative HPLC (Method A) to obtain 3-(6-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)piperidine-1-carboxylate tert-butyl (approximately 100 mg). This was then subjected to chiral preparative HPLC (column: IG 20 × 250 mm, 10 μm (Daicel), column temperature: 35°C). Separation was performed using mobile phase: CO2 / MeOH [0.2% NH3 (7M in MeOH)] = 80 / 20, flow rate: 100 g / min), and peak 1 was identified as (R)-3-(6-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)piperidine-1-carboxylate tert-butyl or (S)-3-(6-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)piperidine-1-carboxylate We obtained tert-butyl ruvonate (50 mg, 33% yield) and (S)-3-(6-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)piperidine-1-carboxylate tert-butyl or (R)-3-(6-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)piperidine-1-carboxylate tert-butyl (40 mg, 26% yield). LCMS m / z = 411 [M + H] +

[0359] Step 4: Synthesis of (R)-N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(piperidine-3-yl)pyrazine-2-amine or (S)-N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(piperidine-3-yl)pyrazine-2-amine

[0360] To a solution of (R)-3-(6-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)piperidine-1-carboxylate tert-butyl (peak 1) or (S)-3-(6-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)piperidine-1-carboxylate tert-butyl (peak 1) in DCM (1 mL), TFA (1 mL) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated under vacuum, and the residue was purified by preparative HPLC (Method A) to obtain the desired product of Example 20 (30.1 mg, yield 80%) as a white solid. LCMS m / z = 311 [M + H] + 1 H-NMR (400 MHz, DMSO-d6) δ ppm 10.37 (br s, 1H), 8.05 (s, 1H), 7.92 (s, 1H), 7.26 (t, 1H), 5.91 (s, 1H), 3.17-3.04 (m, 2H), 2.98-2.87 (m, 1H), 2.87-2.75 (m, 2H), 2.75-2.65 (m, 1H), 2.02-1.81 (m, 1H), 1.75-1.57 (m, 2H), 1.54-1.38 (m, 1H).

[0361] Step 5: Synthesis of (S)-N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(piperidine-3-yl)pyrazine-2-amine or (R)-N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(piperidine-3-yl)pyrazine-2-amine

[0362] To a solution of (S)-3-(6-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)piperidine-1-carboxylate tert-butyl (peak 2) or (R)-3-(6-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)piperidine-1-carboxylate tert-butyl (peak 2) in DCM (1 mL), TFA (1 mL) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated under vacuum, and the residue was purified by preparative HPLC (Method A) to obtain the desired product of Example 19 (16.8 mg, yield 55%) as a white solid. LCMS m / z = 311 [M + H] + 1 H-NMR (400 MHz, DMSO-d6) δ ppm 8.06 (s, 1H), 7.91 (s, 1H), 7.25 (t, 1H), 5.95 (s, 1H), 4.19-4.02 (m, 1H), 3.18-3.05 (m, 1H), 3.00-2.90 (m, 1H), 2.86-2.69 (m, 2H), 2.00-1.88 (m, 1H), 1.76-1.61 (m, 2H), 1.52-1.37 (m, 1H).

[0363] Example 21,6-(((1R,3s,5S)-9-azabicyclo[3.3.1]nonane-3-yl)oxy)-N-(5-isopropyl-1H-pyrazole-3-yl)pyrazine-2-amine [ka]

[0364] Step 1: Synthesis of (1R,3s,5S)-3-((6-chloropyrazine-2-yl)oxy)-9-azabicyclo[3.3.1]nonane-9-carboxylate tert-butyl

[0365] (1R,3s,5S)-3-hydroxy-9-azabicyclo[3.3.1]nonane-9-carboxylate tert-butyl (300 mg, 1.24 mmol) and 2,6-dichloropyrazine (184 mg, 1.24 mmol) were dissolved in THF (5 ml), to which 60% NaH (99.1 mg, 2.48 mmol) was added at 0°C, and the mixture was stirred at 0°C for 2 hours. LC-MS showed that the reaction products were completely converted. The reaction mixture was quenched with water and diluted with EA. The separated organic layer was washed with water and brine and evaporated under vacuum. The residue was purified by silica gel chromatography (PE / EA = 3 / 1) to obtain the title product (400 mg, yield 91%) as a colorless solid. LC-MS m / z = 298 [M -56+H] + .

[0366] Step 2: Synthesis of (1R,3s,5S)-3-((6-((5-isopropyl-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-9-azabicyclo[3.3.1]nonane-9-carboxylate tert-butyl

[0367] A mixture of (1R,3s,5S)-3-[(6-chloropyrazine-2-yl)oxy]-9-azabicyclo[3.3.1]nonane-9-carboxylate tert-butyl (180 mg, 508 μmol), 5-(propan-2-yl)-1H-pyrazole-3-amine (63.5 mg, 508 μmol), BrettPhos Pd G4 (78.0 mg, 50.8 μmol), and KOAC (149 mg, 1.52 mmol) in dioxane (5 ml) was stirred at 90°C for 2 hours. LC-MS showed that the reaction products were completely converted. The reaction mixture was concentrated, and the residue was purified by silica gel flash chromatography (PE / EA = 3 / 2) to obtain the title product (150 mg, yield 66%) as a colorless solid. LC-MS m / z = 443 [M + H] + .

[0368] Step 3: Synthesis of 6-(((1R,3s,5S)-9-azabicyclo[3.3.1]nonane-3-yl)oxy)-N-(5-isopropyl-1H-pyrazole-3-yl)pyrazine-2-amine

[0369] (1R,3s,5S)-3-[(6-{[5-(propan-2-yl)-1H-pyrazole-3-yl]amino}pyrazine-2-yl)oxy]-9-azabicyclo[3.3.1]nonane-9-carboxylate tert-butyl (150 mg, 338 μmol) was dissolved in DCM (2.0 mL), to which TFA (0.5 mL) was added at room temperature. The mixture was stirred at room temperature for 2 hours. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated and purified by preparative HPLC (mobile phase: A=water (0.1% NH4HCO3), B=acetonitrile; gradient: B=15%~95% over 18 min; column: Xtimate 10 μm 150A 21.2 × 250 mm) to obtain the title product (25.7 mg, yield 22%) as a yellow solid. LC-MS m / z = 343 [M + H] + . 1 H-NMR (400 MHz, DMSO-d6) δ ppm 12.01 (br. s., 1H), 9.58 (s, 1H), 7.88 (s, 1H), 7.38 (s, 1H), 6.24 (s, 1H), 5.84-5.75 (m, 1H), 3.27-3.25 (m, 2H), 2.91-2.86 (m, 1H), 2.19-2.14 (m, 2H), 1.82-1.68 (m, 6H), 1.63-1.60 (m, 3H), 1.21 (d, J = 7.2 Hz, 6H).

[0370] Example 22,6-(((1R,3r,5S)-9-azabicyclo[3.3.1]nonane-3-yl)oxy)-N-(5-isopropyl-1H-pyrazole-3-yl)pyrazine-2-amine [ka]

[0371] Step 1: Synthesis of (1R,3r,5S)-3-((6-bromopyrazine-2-yl)oxy)-9-azabicyclo[3.3.1]nonane-9-carboxylate tert-butyl To a mixture of (1R,3r,5S)-3-hydroxy-9-azabicyclo[3.3.1]nonane-9-carboxylate tert-butyl (750 mg, 3.10 mmol) and 2-bromo-6-fluoropyrazine (818 mg, 4.65 mmol) in anhydrous THF (10 mL), 60% NaH in mineral oil (186 mg, 4.65 mmol) was added at 0°C. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction product was quenched with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na₂SO₄, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography eluting with ethyl acetate / PE(1 / 2) to obtain the title compound (659 mg, 53%). LCMS m / z = 399 [M + H] + .

[0372] Step 2: Synthesis of (1R,3r,5S)-3-((6-((5-isopropyl-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-9-azabicyclo[3.3.1]nonane-9-carboxylate tert-butyl The title compound was obtained as 150 mg, 45% yellow solid from the compound of Step 1 and 5-(propan-2-yl)-1H-pyrazole-3-amine according to the procedure described in Step 2 of Examples 19 and 20. LCMS m / z = 443 [M + H] + .

[0373] Step 3: Synthesis of 6-(((1R,3r,5S)-9-azabicyclo[3.3.1]nonane-3-yl)oxy)-N-(5-isopropyl-1H-pyrazole-3-yl)pyrazine-2-amine The title compound was obtained from the compound in Step 2 as a white solid of 38.6 mg, 38%, following the procedure described in Step 3 of Example 3. LCMS m / z = 343 [M + H] + . 1H-NMR (400 MHz, DMSO-d6) δ ppm 11.92 (br s, 1H), 9.57 (s, 1H), 7.94 (s, 1H), 7.42 (s, 1H), 6.28 (s, 1H), 5.39-5.31 (m, 1H), 3.27-3.22 (m, 2H), 2.92-2.88 (m, 1H), 2.41-2.37 (m, 2H), 2.14-2.08 (m, 1H), 1.59-1.56 (m, 2H), 1.48-1.35 (m, 6H), 1.22 (d, 6H).

[0374] Example 23. See Example 5.

[0375] Example 24, N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(((3S,4S)-3-methoxypiperidine-4-yl)oxy)pyrazine-2-amine [ka]

[0376] The title compound was obtained from (3S,4S)-4-hydroxy-3-methoxypiperidine-1-carboxylate tert-butyl, 2,6-dichloropyrazine, and 5-(difluoromethoxy)-1H-pyrazole-3-amine according to the three-step procedure described in Example 6. LCMS m / z = 357 [M + H] + . 1 H-NMR (400 MHz, DMSO-d6) δ ppm 12.02 (br s, 1H), 10.04 (s, 1H), 7.78 (s, 1H), 7.62 (s, 1H), 7.24 (t, 1H), 5.94 (s, 1H), 4.96-4.90 (s, 1H), 3.31 (s, 3H), 3.26-3.21 (m, 1H), 2.94-2.90 (m, 1H), 2.57-2.55 (m, 1H), 2.48-2.42 (m, 1H), 2.07-2.00 (m, 1H), 1.56-1.50 (m, 1H).

[0377] Example 25, N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(((3R,4R)-3-methoxypiperidine-4-yl)oxy)pyrazine-2-amine [ka]

[0378] The title compound was obtained from (3R,4R)-4-hydroxy-3-methoxypiperidine-1-carboxylate tert-butyl, 2,6-dichloropyrazine, and 5-(difluoromethoxy)-1H-pyrazole-3-amine according to the three-step procedure described in Example 6. LCMS m / z = 357 [M + H] + . 1 H-NMR (400 MHz, DMSO-d6) δ ppm 13.06 (br s, 1H), 11.25 (s, 1H), 8.37 (s, 2H), 7.74 (s, 1H), 7.58 (s, 1H), 7.22 (t, 1H), 5.99 (s, 1H), 4.97-4.92 (m, 1H), 3.32 (s, 3H), 3.26-3.22 (m, 1H), 3.02-2.91 (m, 1H), 2.60-2.54 (m, 1H), 2.50-2.40 (m, 1H), 2.11-2.07 (m, 1H), 1.58-1.50 (m, 1H).

[0379] Example 26,6-(((1R,3s,5S)-9-azabicyclo[3.3.1]nonane-3-yl)oxy)-N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)pyrazine-2-amine [ka]

[0380] Step 1: Synthesis of (1R,3s,5S)-3-((6-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-9-azabicyclo[3.3.1]nonane-9-carboxylate tert-butyl The title compound was obtained as a yellow solid (563 mg, 77%) from step 1 of Example 21 and 5-(difluoromethoxy)-1H-pyrazole-3-amine, following the procedure described in step 2 of Examples 19 and 20. LCMS m / z = 467 [M + H] + .

[0381] Step 2: Synthesis of 6-(((1R,3s,5S)-9-azabicyclo[3.3.1]nonane-3-yl)oxy)-N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)pyrazine-2-amine The title compound was obtained from the compound in Step 1 as a white solid of 49.7 mg, 31%, following the procedure described in Step 3 of Example 3. LCMS m / z = 367 [M + H] + . 1 HNMR (400 MHz, DMSO-d6) δ ppm 10.56 (br s, 1H), 7.75 (s, 1H), 7.54 (s, 1H), 7.23 (t, 1H), 6.05 (s, 1H), 5.93-5.74 (m, 1H), 4.45-4.35 (m, 1H), 3.38-3.30 (m, 2H), 3.20-3.13 (m, 1H), 2.24-2.06 (m, 2H), 1.88-1.73 (m, 4H), 1.73-1.63 (m, 4H).

[0382] Example 27, N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(((1R,3s,5S)-9-methyl-9-azabicyclo[3.3.1]nonane-3-yl)oxy)pyrazine-2-amine [ka]

[0383] The title compound was obtained from Example 26 and HCHO as a white solid, 134.4 mg, 28% concentration, following the procedure described in Example 11. LCMS m / z = 381 [M + H] + . 1HNMR (400 MHz, DMSO-d6) δ ppm 9.94 (br s, 1H), 7.75 (s, 1H), 7.54 (s, 1H), 7.21 (t, 1H), 6.03 (s, 1H), 5.74-5.65 (m, 1H), 3.50-3.40 (m, 2H), 2.98-2.87 (m, 2H), 2.41 (s, 3H), 1.96-1.82 (m, 5H), 1.75-1.62 (m, 2H), 1.51-1.45 (m, 2H).

[0384] Example 28, (R)-6-(piperidine-4-yloxy)-N-(5-(tetrahydro-2H-pyran-3-yl)-1H-pyrazole-3-yl)pyrazine-2-amine or (S)-6-(piperidine-4-yloxy)-N-(5-(tetrahydro-2H-pyran-3-yl)-1H-pyrazole-3-yl)pyrazine-2-amine and

[0385] Example 29, (S)-6-(piperidine-4-yloxy)-N-(5-(tetrahydro-2H-pyran-3-yl)-1H-pyrazole-3-yl)pyrazine-2-amine or (R)-6-(piperidine-4-yloxy)-N-(5-(tetrahydro-2H-pyran-3-yl)-1H-pyrazole-3-yl)pyrazine-2-amine [ka]

[0386] Step 1: Synthesis of 3-oxo-3-(tetrahydro-2H-pyran-3-yl)propanenitrile A 15 mL solution of LDA (10.0 mmol, n-hexane solution) in THF was cooled to -78°C under Ar. MeCN (0.75 mL, 15.0 mmol) in 2 mL of THF was added dropwise, and the solution was stirred at -78°C for 1 hour. A 10 mL solution of methyl tetrahydro-2H-pyran-3-carboxylate (2.0 g, 13.0 mmol) in THF was added dropwise, and the reaction mixture was stirred at -78°C to 20°C for 18 hours. The reaction mixture was quenched with water and then concentrated under vacuum. The residue was dissolved in water, washed with Et2O, the aqueous phase was acidified to pH=3 with 1N HCl, and then extracted with siRNA. The organic phase was sequentially washed with water and brine, then dried over Na2SO4, filtered, and evaporated. The residue was purified by column chromatography using silica gel eluted with Â1 / 3 to obtain the title product (590 mg, 29%) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ ppm 4.02-3.98 (m, 1H), 3.86-3.81 (m, 1H), 3.66-3.61 (m, 1H), 3.54 (s, 2H), 3.51-3.45 (m, 1H), 2.87-2.80 (m, 1H), 2.03-1.99 (m, 1H), 1.85-1.54 (m, 3H).

[0387] Step 2: Synthesis of 5-(tetrahydro-2H-pyran-3-yl)-1H-pyrazole-3-amine A solution of 3-oxo-3-(tetrahydro-2H-pyran-3-yl)propanenitrile (590 mg, 2.7 mmol), hydrazine hydrate (410 mg, 8.1 mmol), and concentrated HCl (0.2 mL, 2.7 mmol) in IPA (5 mL) was stirred at 90°C for 18 hours. The reaction mixture was diluted with MeOH, treated with solid Na2CO3, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography eluting with Â1 / 5~4 / 1 to obtain the title compound (600 mg, 90%) as a yellow oil. LCMS m / z = 168 [M + H] + .

[0388] Step 3: Synthesis of (R)-4-((6-((5-(tetrahydro-2H-pyran-3-yl)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)piperidine-1-carboxylate tert-butyl and (S)-4-((6-((5-(tetrahydro-2H-pyran-3-yl)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)piperidine-1-carboxylate tert-butyl

[0389] 5-(tetrahydro-2H-pyran-3-yl)-1H-pyrazole-3-amine and, following the procedure described in Step 1 of Example 1 to Step 1 of Examples 24 and 25, peak 1,(R)-4-((6-((5-(tetrahydro-2H-pyran-3-yl)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)piperidine-1-carboxylate tert-butyl or (S)-4-((6-((5-(tetrahydro-2H-pyran-3-yl)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy (S) piperidine-1-carboxylate tert-butyl (100 mg, 35%) and peak 2,(S)-4-((6-((5-(tetrahydro-2H-pyran-3-yl)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy) piperidine-1-carboxylate tert-butyl or (R)-4-((6-((5-(tetrahydro-2H-pyran-3-yl)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy) piperidine-1-carboxylate tert-butyl (97 mg, 34%) were obtained. LCMS m / z = 445 [M + H] + .

[0390] Step 4: Synthesis of (R)-6-(piperidine-4-yloxy)-N-(5-(tetrahydro-2H-pyran-3-yl)-1H-pyrazole-3-yl)pyrazine-2-amine or (S)-6-(piperidine-4-yloxy)-N-(5-(tetrahydro-2H-pyran-3-yl)-1H-pyrazole-3-yl)pyrazine-2-amine The title compound (Example 28) was obtained as a white solid, 41.5 mg, 53%, from peak 1 of step 3, according to the method described in step 3 of Example 2. LCMS m / z = 345 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.07 (br s, 1H), 9.64 (s, 1H), 7.94 (s, 1H), 7.46 (s, 1H), 6.26 (s, 1H), 5.06-5.03 (m, 1H), 3.94-3.91 (m, 1H), 3.84-3.80 (m, 1H), 3.40-3.31 (m, 2H), 3.13-3.11 (m, 2H), 2.90-2.76 (m, 3H), 2.11-1.96 (m, 3H), 1.74-1.53 ​​(m, 6H).

[0391] Step 5: Synthesis of (S)-6-(piperidine-4-yloxy)-N-(5-(tetrahydro-2H-pyran-3-yl)-1H-pyrazole-3-yl)pyrazine-2-amine or (R)-6-(piperidine-4-yloxy)-N-(5-(tetrahydro-2H-pyran-3-yl)-1H-pyrazole-3-yl)pyrazine-2-amine The title compound (Example 29) was obtained as a white solid, 61 mg, 81% concentration, from peak 2 of step 3, following the procedure described in step 3 of Example 2. LCMS m / z = 345 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.06 (br s, 1H), 9.64 (s, 1H), 7.94 (s, 1H), 7.46 (s, 1H), 6.26 (s, 1H), 5.04-5.05 (m, 1H), 3.94-3.91 (m, 1H), 3.84-3.80 (m, 1H), 3.40-3.31 (m, 2H), 3.13-3.11 (m, 2H), 2.90-2.76 (m, 3H), 2.11-1.96 (m, 3H), 1.74-1.53 ​​(m, 6H).

[0392] Example 30, 6-(((1R,3r,5S)-9-methyl-9-azabicyclo[3.3.1]nonane-3-yl)oxy)-N-(5-((S)-tetrahydrofuran-3-yl)-1H-pyrazole-3-yl)pyrazine-2-amine or 6-(((1R,3r,5S)-9-methyl-9-azabicyclo[3.3.1]nonane-3-yl)oxy)-N-(5-((R)-tetrahydrofuran-3-yl)-1H-pyrazole-3-yl)pyrazine-2-amine [ka]

[0393] A mixture of Example 32 (80 mg, 215 μmol), formaldehyde (50 mg, 645 μmol), and NaCNBH3 (40 mg, 645 μmol) was stirred under N2 at room temperature for 16 hours. The reaction mixture was purified by preparative HPLC (Method A) to obtain the title product (17.5 mg, 21%) as a yellow solid. LCMS m / z = 385 [M + H]+ 1 H-NMR (400 MHz, DMSO-d6) δ ppm 12.09 (br s, 1H), 9.64 (s, 1H), 7.94 (s, 1H), 7.43 (s, 1H), 6.34 (s, 1H), 5.35-5.30 (m, 1H), 4.03-3.97 (m, 1H), 3.87-3.77 (m, 2H), 3.62-3.55 (m, 1H), 3.42-3.35 (m, 2H), 3.31-2.97 (m, 2H), 2.57-2.52(m, 1H), 2.40 (s, 3H), 2.33-2.22 (m, 1H), 2.20-2.08 (m, 1H), 1.99-1.86 (m, 3H), 1.51-1.40 (m, 3H), 1.10-1.01 (m, 2H).

[0394] Example 31, 6-(((1R,3r,5S)-9-methyl-9-azabicyclo[3.3.1]nonane-3-yl)oxy)-N-(5-((R)-tetrahydrofuran-3-yl)-1H-pyrazole-3-yl)pyrazine-2-amine or 6-(((1R,3r,5S)-9-methyl-9-azabicyclo[3.3.1]nonane-3-yl)oxy)-N-(5-((S)-tetrahydrofuran-3-yl)-1H-pyrazole-3-yl)pyrazine-2-amine [ka]

[0395] The title compound was obtained from Example 33 and formaldehyde as a yellow solid, 2.8 mg, 15% concentration, following the procedure described in Example 30. LCMS m / z = 385 [M +H]+ 1 H-NMR (400 MHz, DMSO-d6) δ ppm 12.09 (br, s, 1H), 9.64 (s, 1H), 7.94 (s, 1H), 7.43 (s, 1H), 6.34 (s, 1H), 5.35-5.30 (m, 1H), 4.03-3.97 (m, 1H), 3.87-3.77 (m, 2H), 3.62-3.55 (m, 1H), 3.42-3.35 (m, 2H), 3.31-2.97 (m, 2H), 2.57-2.52(m, 1H), 2.40 (s, 3H), 2.33-2.22 (m, 1H), 2.20-2.08 (m, 1H), 1.99-1.86 (m, 3H), 1.51-1.40 (m, 3H), 1.10-1.01 (m, 2H).

[0396] Examples 32 and 33, 6-(((1R,3r,5S)-9-azabicyclo[3.3.1]nonane-3-yl)oxy)-N-(5-((S)-tetrahydrofuran-3-yl)-1H-pyrazole-3-yl)pyrazine-2-amine and 6-(((1R,3r,5S)-9-azabicyclo[3.3.1]nonane-3-yl)oxy)-N-(5-((R)-tetrahydrofuran-3-yl)-1H-pyrazole-3-yl)pyrazine-2-amine [ka]

[0397] Step 1: Synthesis of (1R,3r,5S)-3-((6-((5-((S)-tetrahydrofuran-3-yl)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-9-azabicyclo[3.3.1]nonane-9-carboxylate tert-butyl and (1R,3r,5S)-3-((6-((5-((R)-tetrahydrofuran-3-yl)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-9-azabicyclo[3.3.1]nonane-9-carboxylate tert-butyl

[0398] Step 1 of Example 4 (400 mg, 1.13 mmol), a mixture of 5-(oxolan-3-yl)-1H-pyrazole-3-amine (258 mg, 1.69 mmol), BrettPhos Pd G4 (40 mg, 0.04 mmol), and KOAc (331 mg, 3.38 mmol) in dioxane (30 mL) was stirred under N2 at 100°C for 16 hours. The reaction mixture was diluted with  and washed with water and brine. The organic layer was purified by column chromatography using silica gel eluted with  / PE(10 / 1) to obtain the racemic product compound (380 mg) as a yellow solid. This was then subjected to chiral-SFC (column: IC) chromatography. 20×250mm, 10μm (Daicel), column temperature: 35℃, mobile phase: CO2 / [MeOH / MeCN[0.2%NH3 (7M in MeOH)] 1:1]=55 / 45, flow rate: 120g / min, back pressure: 100bar, peak 1 is (1R,3r,5S)-3-((6-((5-((S))-tetrahydrofuran-3-yl)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-9-azabicyclo[3.3.1]nonane-9-carboxylate tert-butyl or (1R,3r,5S)-3-((6-((5-((R)-tetrahydrofuran-3-yl)-1H-pyrazole-3-yl)amino)pyrazine-2-yl )oxy)-9-azabicyclo[3.3.1]nonane-9-carboxylate tert-butyl (180 mg) and peak 2 (1R,3r,5S)-3-((6-((5-((R)-tetrahydrofuran-3-yl)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-9-azabicyclo[3.3.1]nonane-9-carboxylate tert-butyl or (1R,3r,5S)-3-((6-((5-((S)-tetrahydrofuran-3-yl)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-9-azabicyclo[3.3.1]nonane-9-carboxylate tert-butyl (180 mg) were obtained. LCMS m / z = 471 [M + H] + .

[0399] Step 2: Synthesis of Example 32, 6-(((1R,3r,5S)-9-azabicyclo[3.3.1]nonane-3-yl)oxy)-N-(5-((S)-tetrahydrofuran-3-yl)-1H-pyrazole-3-yl)pyrazine-2-amine or 6-(((1R,3r,5S)-9-azabicyclo[3.3.1]nonane-3-yl)oxy)-N-(5-((R)-tetrahydrofuran-3-yl)-1H-pyrazole-3-yl)pyrazine-2-amine To a 3 mL solution of peak 1 (70 mg, 148 μmol) from step 1 in DCM, TFA (1 mL) was added, and the reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated, and the residue was purified by preparative HPLC (Method B) to obtain the title product (10.4 mg, 19%) as a white solid. LCMS m / z = 371 [M + H] + . 1 H-NMR (400 MHz, DMSO-d6) δ ppm 11.94 (br s, 1H), 9.71 (s, 1H), 8.36 (s, 1H), 7.96 (s, 1H), 7.46 (s, 1H), 6.31 (s, 1H), 5.25-5.20 (m, 1H), 4.01-3.97 (m, 1H), 3.88-3.83 (m, 1H), 3.81-3.74 (m, 1H), 3.58-3.50 (m, 1H), 3.41-3.35 (m, 1H), 2.47-2.44 (m, 2H), 2.33-2.24 (m, 3H), 2.00-1.94 (m, 2H), 1.78-1.66 (m, 4H), 1.53-1.45 (m, 3H).

[0400] Step 3: Synthesis of Example 33, 6-(((1R,3r,5S)-9-azabicyclo[3.3.1]nonane-3-yl)oxy)-N-(5-((S)-tetrahydrofuran-3-yl)-1H-pyrazole-3-yl)pyrazine-2-amine or 6-(((1R,3r,5S)-9-azabicyclo[3.3.1]nonane-3-yl)oxy)-N-(5-((R)-tetrahydrofuran-3-yl)-1H-pyrazole-3-yl)pyrazine-2-amine The title compound was obtained as a white solid of 9 mg, 16%, from peak 2 of step 1, following the procedure described in step 2. LCMS m / z = 371 [M + H] + . 1 H-NMR (400 MHz, DMSO-d6) δ ppm 11.94 (br s, 1H), 9.71 (s, 1H), 8.36 (s, 1H), 7.96 (s, 1H), 7.46 (s, 1H), 6.31 (s, 1H), 5.25-5.20 (m, 1H), 4.01-3.97 (m, 1H), 3.88-3.83 (m, 1H), 3.81-3.74 (m, 1H), 3.58-3.50 (m, 1H), 3.41-3.35 (m, 1H), 2.47-2.44 (m, 2H), 2.33-2.24 (m, 3H), 2.00-1.94 (m, 2H), 1.78-1.66 (m, 4H), 1.53-1.45 (m, 3H).

[0401] Example 34, N-(5-isopropyl-1H-pyrazole-3-yl)-6-(((1R,2R,3S,5S)-2-methyl-8-azabicyclo[3.2.1]octane-3-yl)oxy)pyrazine-2-amine or N-(5-isopropyl-1H-pyrazole-3-yl)-6-(((1R,2R,3R,5S)-2-methyl-8-azabicyclo[3.2.1]octane-3-yl)oxy)pyrazine-2-amine or N-(5-isopropyl-1H-pyrazole-3-yl)-6-(((1S,2S,3S,5R)-2-methyl-8-azabicyclo[3.2.1]octane-3-yl)oxy)pyrazine-2-amine N-(5-isopropyl-1H-pyrazole-3-yl)-6-(((1S,2S,3R,5R)-2-methyl-8-azabicyclo[3.2.1]octane-3-yl)oxy)pyrazine-2-amine or N-(5-isopropyl-1H-pyrazole-3-yl)-6-(((1S,2R,3S,5R)-2-methyl-8-azabicyclo[3.2.1]octane-3-yl)oxy)pyrazine-2-amine or N-(5-isopropyl-1H-pyrazole-3-yl)-6-(((1S,2R,3R,5R)-2-methyl-8-azabicyclo[3.2.1]octane-3-yl)oxy)pyrazine-2-amine and

[0402] Example 40, N-(5-isopropyl-1H-pyrazole-3-yl)-6-(((1R,2R,3R,5S)-2-methyl-8-azabicyclo[3.2.1]octane-3-yl)oxy)pyrazine-2-amine or N-(5-isopropyl-1H-pyrazole-3-yl)-6-(((1R,2R,3S,5S)-2-methyl-8-azabicyclo[3.2.1]octane-3-yl)oxy)pyrazine-2-amine or N-(5-isopropyl-1H-pyrazole-3-yl)-6-(((1S,2S,3S,5R)-2-methyl-8-azabicyclo[3.2.1]octane-3-yl)oxy)pyrazine-2-amine Pyrrazine-2-amine or N-(5-isopropyl-1H-pyrazole-3-yl)-6-(((1S,2S,3R,5R)-2-methyl-8-azabicyclo[3.2.1]octane-3-yl)oxy)pyrazine-2-amine or N-(5-isopropyl-1H-pyrazole-3-yl)-6-(((1S,2R,3S,5R)-2-methyl-8-azabicyclo[3.2.1]octane-3-yl)oxy)pyrazine-2-amine or N-(5-isopropyl-1H-pyrazole-3-yl)-6-(((1S,2R,3R,5R)-2-methyl-8-azabicyclo[3.2.1]octane-3-yl)oxy)pyrazine-2-amine [ka]

[0403] Step 1: Synthesis of (1R,2R,5S)-3-hydroxy-2-methyl-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl or (1S,2S,5R)-3-hydroxy-2-methyl-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl or (1S,2R,5R)-3-hydroxy-2-methyl-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl

[0404] To a 10 mL solution of Peak 1 (1.0 g, 4.17 mmol) from Step 1 of Examples 7 and 128, which is a mixture of the two enantiomers, NaBH4 (790 mg, 20.8 mmol) was added under N2 at 0°C. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was quenched with water and extracted with siRNA. The combined organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered, and the filtrate was evaporated under reduced pressure to obtain a mixture of the two title isomers (950 mg, 95%) as a colorless oil. LCMS m / z = 186 [M -56+H] + .

[0405] Step 2: (1R,2R,3S,5S)-3-((6-chloropyrazine-2-yl)oxy)-2-methyl-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl, (1R,2R,3R,5S)-3-((6-chloropyrazine-2-yl)oxy)-2-methyl-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl, (1S,2S,3S,5R)-3-((6-chloropyrazine-2-yl)oxy)-2-methyl-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl, Synthesis of (1S,2S,3R,5R)-3-((6-chloropyrazine-2-yl)oxy)-2-methyl-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl, (1S,2R,3R,5R)-3-((6-chloropyrazine-2-yl)oxy)-2-methyl-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl, or (1S,2R,3S,5R)-3-((6-chloropyrazine-2-yl)oxy)-2-methyl-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl

[0406] To a solution of the compound mixture from step 1 (0.95 g, 3.94 mmol) in THF (10 mL), 60% NaH (249 mg, 6.22 mmol) was added at 0°C, and the solution was stirred under N2 for 30 minutes. 2,6-Dichloropyrazine (614 mg, 4.14 mmol) was added, and the reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried on anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The crude product was purified by column chromatography on silica gel eluted with PE / ethyl(4 / 1) to obtain a racemic product (800 mg, 56%). This was converted to chiral SFC (column: IG 20×250mm, 10μm (Daicel), column temperature: 35℃, mobile phase: CO2 / MeOH [0.5%NH3 (7M in MeOH)] = 85 / 15, flow rate: 100g / min, back pressure: 100bar) to obtain peaks 1 (220mg), 2 (150mg), 3 (30mg), and 4 (190mg) as yellow solids.

[0407] Step 3: (1R,2R,3S,5S)-3-((6-((5-isopropyl-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-2-methyl-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl or (1R,2R,3R,5S)-3-((6-((5-isopropyl-1H-pyrazole-3-yl))amino)pyrazine-2-yl)oxy)-2-methyl-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl or (1S,2S,3S,5R)-3-((6-((5-isopropyl-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-2-methyl-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl Synthesis of (1S,2S,3R,5R)-3-((6-((5-isopropyl-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-2-methyl-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl or (1S,2R,3R,5R)-3-((6-((5-isopropyl-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-2-methyl-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl or (1S,2R,3S,5R)-3-((6-((5-isopropyl-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-2-methyl-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl

[0408] To a solution of peak 1 (130 mg, 368 μmol) of 5-isopropyl-1H-pyrazole-3-amine (46 mg, 368 μmol) in dioxane (4.0 mL), KOAc (108 mg, 1.10 mmol) and BrettPhos Pd G4 (33.2 mg) were added under N2 at room temperature. The reaction mixture was heated to 90°C and stirred for 18 hours. The reaction mixture was cooled to room temperature, diluted with dioxane, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with siRNA / PE(1 / 1) to obtain the title compound (120 mg, 74%) as a yellow oil. LCMS m / z = 443 [M + H] + .

[0409] Step 4: N-(5-isopropyl-1H-pyrazole-3-yl)-6-(((1R,2R,3S,5S)-2-methyl-8-azabicyclo[3.2.1]octane-3-yl)oxy)pyrazine-2-amine or N-(5-isopropyl-1H-pyrazole-3-yl)-6-(((1R,2R,3R,5S)-2-methyl-8-azabicyclo[3.2.1]octane-3-yl)oxy)pyrazine-2-amine or N-(5-isopropyl-1H-pyrazole-3-yl)-6-(((1S,2S,3S,5R)-2-methyl-8-azabicyclo[3.2.1]octane-3-yl)oxy)pyrazine-2-amine Synthesis of N-(5-isopropyl-1H-pyrazole-3-yl)-6-(((1S,2S,3R,5R)-2-methyl-8-azabicyclo[3.2.1]octane-3-yl)oxy)pyrazine-2-amine or N-(5-isopropyl-1H-pyrazole-3-yl)-6-(((1S,2R,3R,5R)-2-methyl-8-azabicyclo[3.2.1]octane-3-yl)oxy)pyrazine-2-amine or N-(5-isopropyl-1H-pyrazole-3-yl)-6-(((1S,2R,3S,5R)-2-methyl-8-azabicyclo[3.2.1]octane-3-yl)oxy)pyrazine-2-amine

[0410] To a solution of the compound from step 3 (120 mg, 271 μmol) in DCM (3.0 mL), TFA (1.0 mL) was added at room temperature, and the reaction mixture was stirred for 1 hour. The mixture was basicized to approximately pH 8 with 7NNH3 in MeOH. It was then concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method A) to obtain Example 34 (6.9 mg, 8%) as a white solid. LCMS m / z = 343 [M + H] + . 1HNMR (400 MHz, DMSO-d6) δ ppm 11.97 (br s, 1H), 9.55 (s, 1H), 7.88 (s, 1H), 7.40 (s, 1H), 6.22 (s, 1H), 4.89-4.85 (m, 1H), 3.47-3.40 (m, 1H), 3.27-3.23 (m, 1H), 2.95-2.90 (m, 1H), 2.06-2.01 (m, 1H), 1.89-1.84 (m, 2H), 1.76-1.70 (m, 2H), 1.63-1.40 (m, 2H), 1.23 (d, 6H), 0.85 (d, 3H).

[0411] Step 5: (1R,2R,3R,5S)-3-((6-((5-isopropyl-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-2-methyl-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl or (1R,2R,3S,5S)-3-((6-((5-isopropyl-1H-pyrazole-3-yl))amino)pyrazine-2-yl)oxy)-2-methyl-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl or (1S,2S,3S,5R)-3-((6-((5-isopropyl-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-2-methyl-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl Synthesis of (1S,2S,3R,5R)-3-((6-((5-isopropyl-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-2-methyl-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl or (1S,2R,3S,5R)-3-((6-((5-isopropyl-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-2-methyl-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl or (1S,2R,3R,5R)-3-((6-((5-isopropyl-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-2-methyl-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl

[0412] The title compound was obtained as 120 mg, 74% yellow oil from peak 2 of step 2 and 5-isopropyl-1H-pyrazole-3-amine according to the procedure described in step 3. LCMS m / z = 443 [M +H]+

[0413] Step 6: N-(5-isopropyl-1H-pyrazole-3-yl)-6-(((1R,2R,3R,5S)-2-methyl-8-azabicyclo[3.2.1]octane-3-yl)oxy)pyrazine-2-amine or N-(5-isopropyl-1H-pyrazole-3-yl)-6-(((1R,2R,3S,5S)-2-methyl-8-azabicyclo[3.2.1]octane-3-yl)oxy)pyrazine-2-amine or N-(5-isopropyl-1H-pyrazole-3-yl)-6-(((1S,2S,3S,5R)-2-methyl-8-azabicyclo[3.2.1]octane-3-yl)oxy)pyrazine-2-amine Synthesis of N-(5-isopropyl-1H-pyrazole-3-yl)-6-(((1S,2S,3R,5R)-2-methyl-8-azabicyclo[3.2.1]octane-3-yl)oxy)pyrazine-2-amine or N-(5-isopropyl-1H-pyrazole-3-yl)-6-(((1S,2R,3S,5R)-2-methyl-8-azabicyclo[3.2.1]octane-3-yl)oxy)pyrazine-2-amine or N-(5-isopropyl-1H-pyrazole-3-yl)-6-(((1S,2R,3R,5R)-2-methyl-8-azabicyclo[3.2.1]octane-3-yl)oxy)pyrazine-2-amine

[0414] The title compound (Example 40) was obtained from the compound in step 5 as a white solid, 20.4 mg, 22% concentration, following the procedure described in step 4. LCMS m / z = 343 [M + H] + . 1HNMR (400 MHz, DMSO-d6) δ ppm 11.98 (br s, 1H), 9.53 (s, 1H), 7.89 (s, 1H), 7.40 (s, 1H), 6.23 (s, 1H), 5.28-5.20 (m, 1H), 3.50-3.40 (m, 1H), 3.30-3.20 (m, 1H), 2.97-2.87 (m, 1H), 2.18-2.12 (m, 1H), 1.78-1.58 (m, 6H), 1.26-1.20 (m, 6H), 0.92-0.84 (m, 3H).

[0415] Example 35, N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(((3R,4S)-3-methoxypiperidine-4-yl)oxy)pyrazine-2-amine [ka]

[0416] The title compound was obtained from (3R,4S)-4-hydroxy-3-methoxypiperidine-1-carboxylate tert-butyl, 2,6-dichloropyrazine, and 5-(difluoromethoxy)-1H-pyrazole-3-amine using the same three-step procedure as described in Example 6. LCMS m / z = 357 [M + H] + .1H-NMR (400 MHz, DMSO-d6) δ ppm 12.08 (br s, 1H), 10.09 (br s, 1H), 7.78 (s, 1H), 7.61 (s, 1H), 7.25 (t, 1H), 5.94 (s, 1H), 5.28-5.23 (m, 1H), 3.50-3.45 (m, 1H), 3.25 (s, 3H), 3.00-2.95 (m, 1H), 2.90-2.85 (m, 1H), 2.73-2.65 (m, 1H), 2.58-2.53 (m, 1H), 1.90-1.85 (m, 1H), 1.70-1.62 (m, 1H).

[0417] Example 36, N-(5-isopropyl-1H-pyrazole-3-yl)-6-(((1R,2S,5S)-2-methyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyrazine-2-amine [ka]

[0418] Step 1: Synthesis of (1R,2S,5S)-3-((6-((5-isopropyl-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-2-methyl-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl

[0419] The title compound was obtained as 50 mg, 66% yellow solid from 5-isopropyl-1H-pyrazole-3-amine and from step 3 of Examples 7 and 128 and 5-isopropyl-1H-pyrazole-3-amine, following the same procedure as in step 2 of Example 37, except that the crude product was purified by column chromatography (DCM / MeOH) using silica gel. LCMS m / z = 443 [M +H]+.

[0420] Step 2: Synthesis of N-(5-isopropyl-1H-pyrazole-3-yl)-6-(((1R,2S,5S)-2-methyl-8-azabicyclo[3.2.1]octan-3-yl)oxy)pyrazine-2-amine

[0421] The title compound was obtained from the compound of Step 1 as a white solid of 5.4 mg, 14%, following the procedure described in Step 3 of Example 2. LCMS m / z = 343 [M +H]+. 1HNMR (400 MHz, DMSO-d6) δ ppm 11.93 (br s, 1H), 9.53 (br s, 1H), 7.97 (s, 1H), 7.44 (s, 1H), 6.18 (s, 1H), 5.15 (s, 1H), 3.13-3.12 (m, 1H), 2.93-2.86 (m, 1H), 2.24-2.10 (m, 2H), 1.96-1.78 (m, 3H), 1.69-1.51 (m, 2H), 1.21 (d, 6H), 0.89 (d, 3H).

[0422] Example 37, 6-((1-azabicyclo[2.2.1]heptan-4-yl)oxy)-N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)pyrazine-2-amine [ka]

[0423] Step 1: Synthesis of 4-((6-chloropyrazine-2-yl)oxy)-1-azabicyclo[2.2.1]heptane To a solution of bicyclo[2.2.1]heptan-1-ol (150 mg, 1.32 mmol) in anhydrous DMSO (8.0 mL), NaH (60% in mineral oil, 196 mg, 5.11 mmol) was added under N2 at 0°C. After stirring for 30 minutes, 2,6-dichloropyrazine (196 mg, 1.32 mmol) was added, and the reaction mixture was heated to 60°C and stirred overnight. The reaction mixture was quenched with water and extracted with RINKAN. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with MeOH (0.5% NH3) / DCM (1 / 4) to obtain the title compound (150 mg, 50%) as a white solid. LCMS m / z = 226 [M + H] + .

[0424] Step 2: Synthesis of 6-((1-azabicyclo[2.2.1]heptan-4-yl)oxy)-N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)pyrazine-2-amine

[0425] A solution of 4-((6-chloropyrazine-2-yl)oxy)-1-azabicyclo[2.2.1]heptane (200 mg, 886 μmol), 5-(difluoromethoxy)-1H-pyrazole-3-amine (132 mg, 886 μmol), KOAc (260 mg, 2.65 mmol), and BrettPhos Pd G4 (40.7 mg, 44.3 μmol) in dioxane (5 mL) was stirred at 100 °C for 18 hours under N2. The reaction mixture was cooled to room temperature, diluted with dioxane, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method A) to obtain the title compound (6.90 mg, 2.3%) as a yellow solid. LCMS m / z = 339 [M + H]+. 1 HNMR (400 MHz, DMSO-d6) δ ppm 12.22 (br s, 1H), 9.62 (s, 1H), 7.79 (s, 1H), 7.62 (s, 1H), 7.24 (t, 1H), 5.94 (s, 1H), 3.02-2.95 (m, 2H), 2.74-2.64 (m, 4H), 1.93-1.81 (m, 4H).

[0426] Example 38, 6-((2-azaspiro[3,3]heptan-6-yl)oxy)-N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)pyrazine-2-amine [ka]

[0427] Step 1: Synthesis of 6-((6-chloropyrazine-2-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl To a solution of tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (250 mg, 1.17 mmol) in anhydrous THF (10 mL), NaH (60% in mineral oil, 373 mg, 9.36 mmol) was added at 0°C. After stirring for 20 minutes, 2,6-dichloropyrazine (174 mg, 1.17 mmol) dissolved in anhydrous THF (2 mL) was added via syringe. The reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was quenched with saturated NH4Cl solution and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with PE / siRNA (1 / 1) to obtain the title compound as a yellow oil (300 mg, 78%). LCMS m / z = 270 [M -56+H] + .

[0428] Step 2: Synthesis of 6-((6-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-2-azaspiro[3.3]heptan-2-carboxylate tert-butyl The title compound was obtained from the compound of Step 1 and 5-(difluoromethoxy)-1H-pyrazole-3-amine as 250 mg, 62% brown oily substance according to the procedure described in Step 2 of Examples 19 and 20. LCMS m / z = 439 [M + H] + .

[0429] Step 3: Synthesis of 6-((2-azaspiro[3,3]heptan-6-yl)oxy)-N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)pyrazine-2-amine To a 5 mL solution of the compound from step 2 (250 mg, 570 μmol) in DCM, 2 mL of TFA was added under N2 conditions at 0°C. After addition, the resulting mixture was warmed to room temperature and stirred for 1.5 hours. The reaction mixture was basicized to approximately pH 10 with NH3 (7 M in MeOH). The precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method A) to obtain the title compound (33.2 mg, 17%) as a brown solid. LCMS m / z = 339 [M + H]+ . 1 HNMR (400 MHz, DMSO-d6) δ ppm 11.48 (br s, 1H), 8.44 (s, 1H), 7.75 (s, 1H), 7.53 (s, 1H), 7.26 (t, 1H), 6.05 (s, 1H), 5.09-5.04 (m, 1H), 3.94-3.89 (m, 4H), 2.76-2.71 (m, 2H), 2.33-2.29 (m, 2H).

[0430] Example 39, 6-((3-azabicyclo[3.2.0]heptan-6-yl)oxy)-N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)pyrazine-2-amine [ka]

[0431] Step 1: Synthesis of 6-((6-chloropyrazine-2-yl)oxy)-3-azabicyclo[3.2.0]heptane-3-carboxylate tert-butyl To a mixture of tert-butyl 6-hydroxy-3-azabicyclo[3.2.0]heptane-3-carboxylate (213 mg, 1 mmol) and 2,6-dichloropyrazine (150 mg, 1.00 mmol) in THF (20 mL), NaH (60% of mineral oil, 43.8 mg, 1.10 mmol) was added at 0°C, and the reaction mixture was stirred at room temperature under N2 for 1 hour. The reaction product was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel eluted with ethyl acetate / PE(1 / 5) to obtain the title compound as a yellow oil (300 mg, 92%). LCMS m / z = 270 [M -56+H] + .

[0432] Step 2: Synthesis of 6-((6-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-3-azabicyclo[3.2.0]heptane-3-carboxylate tert-butyl The title compound was obtained as 200 mg, 74% yellow solid from the compound of Step 1 and 5-(difluoromethoxy)-1H-pyrazole-3-amine according to the method described in Step 2 of Examples 19 and 20. LCMS m / z = 439 [M + H] + .

[0433] Step 3: Synthesis of 6-((3-azabicyclo[3.2.0]heptan-6-yl)oxy)-N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)pyrazine-2-amine To a 5 mL solution of the compound from step 2 (150 mg, 342 μmol) in DCM, 1.0 mL of TFA was added at 0°C, and the mixture was then stirred under N2 at 50°C for 5 hours. The reaction mixture was concentrated under vacuum, and the residue was purified by preparative HPLC (Method C) to obtain the title compound (39.6 mg, 34%) as a yellow solid. LCMS m / z = 339 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.11 (br s, 1H), 10.20 (br s, 1H), 7.82 (s, 1H), 7.62 (s, 1H), 7.27 (t, 1H), 5.96 (s, 1H), 5.20-5.13 (m, 1H), 3.64-3.40 (m, 1H), 3.28-3.22 (m, 2H), 3.03-2.99 (m, 1H), 2.88-2.75 (m, 3H), 2.67-2.55 (m, 1H), 1.99-1.86 (m, 1H).

[0434] See Example 40 and Example 34.

[0435] Example 41, (S)-6-((1-methylpiperidine-4-yl)oxy)-N-(5-((tetrahydrofuran-3-yl)methoxy)-1H-pyrazole-3-yl)pyrazine-2-amine [ka]

[0436] Step 1: Synthesis of 1-(tert-butyl)-5-((6-((1-methylpiperidine-4-yl)oxy)pyrazine-2-yl)amino)-1,2-dihydro-3H-pyrazole-3-one The title compound was obtained as 1.23 g, 89% yellow solid from step 1 of Example 8 and 5-amino-1-(tert-butyl)-1,2-dihydro-3H-pyrazole-3-one, following the procedure described in step 2 of Examples 19 and 20. LCMS m / z = 348 [M + H] + .

[0437] Step 2: Synthesis of (S)-N-(1-(tert-butyl)-3-((tetrahydrofuran-3-yl)methoxy)-1H-pyrazole-5-yl)-6-((1-methylpiperidine-4-yl)oxy)pyrazine-2-amine To a mixture of the compound from step 1 (240 mg, 0.7 mmol), (R)-(tetrahydrofuran-3-yl)methanol (70 mg, 0.7 mmol), and PPh3 (263 mg, 1.0 mmol) in THF (10 mL), DIAD (202 mg, 1.0 mmol) was added at 0°C, and the reaction mixture was stirred overnight under N2. The reaction product was quenched with water and extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel eluted with ethyl acetate / PE (0%~100%) to obtain the title compound (100 mg, 34%) as a yellow solid. LCMS m / z = 431 [M + H] + .

[0438] Step 3: Synthesis of (S)-6-((1-methylpiperidine-4-yl)oxy)-N-(5-((tetrahydrofuran-3-yl)methoxy)-1H-pyrazole-3-yl)pyrazine-2-amine The compound from step 2 (100 mg, 0.23 mmol) was dissolved in FA (3 mL) and stirred at 80°C for 16 hours. The reaction mixture was concentrated under vacuum, and the residue was purified by preparative HPLC (Method A) to obtain the title product (9.8 mg, 10%) as a yellow solid. LC-MS m / z = 375 [M + H]+. 1H-NMR (400 MHz, DMSO-d6) δ ppm 11.85-11.26 (m, 1H), 9.73 (br s, 1H), 7.81 (br s, 1H), 7.49 (s, 1H), 5.75 (br s, 1H), 4.93-4.87 (m, 1H), 4.05-3.94 (m, 2H), 3.80-3.75 (m, 2H), 3.68-3.63 (m, 1H), 3.54-3.49 (m, 1H), 2.78-2.61 (m, 3H), 2.18 (s, 3H), 2.14-2.07 (m, 2H), 2.02-1.97 (m, 3H), 1.69-1.55 (m, 3H).

[0439] Example 42, N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(((2R,4S)-2-isopropylpiperidine-4-yl)oxy)pyrazine-2-amine or N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(((2R,4R)-2-isopropylpiperidine-4-yl)oxy)pyrazine-2-amine [ka]

[0440] The title compound was obtained as 10.1 mg, 20% white solid from the compound of Example 96 and HCHO according to the procedure described in Example 11. LCMS m / z = 383 [M + H] + . 1HNMR (400 MHz, DMSO-d6) δ ppm 11.87 (br s, 1H), 9.99 (s, 1H), 7.77 (s, 1H), 7.57 (s, 1H), 7.25 (t, 1H), 5.97 (s, 1H), 4.91-4.81 (m, 1H), 2.89-2.83 (m, 1H), 2.76-2.72 (m, 1H), 2.68-2.52 (m, 2H), 2.14 (s, 3H), 2.05-1.95 (m, 2H), 1.83-1.78 (m, 1H), 1.63-1.53 (m, 1H), 1.25-1.13 (m, 1H), 0.83-0.77 (m, 6H).

[0441] Example 43, N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(((2R,4R)-2-isopropyl-1-methylpiperidine-4-yl)oxy)pyrazine-2-amine or N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(((2R,4S)-2-isopropyl-1-methylpiperidine-4-yl)oxy)pyrazine-2-amine [ka]

[0442] Step 1: Synthesis of (R)-2-isopropyl-4,6-dioxopiperidine-1-carboxylate tert-butyl To a 25 mL solution of (R)-3-((tert-butoxycarbonyl)amino)-4-methylpentanoic acid (3 g, 12.9 mmol) in DCM, 2,2-dimethyl-1,3-dioxane-4,6-dione (1.85 g, 12.9 mmol), EDCI (3.68 g, 19.3 mmol), and DMAP (2.35 g, 19.3 mmol) were added in an ice bath, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was washed with 1 N KHSO4, dried over Na2SO4, filtered, and the filtrate was concentrated. The residue was dissolved in ELISA and heated under reflux for 4 hours. The cooled reaction mixture was washed with 1 N KHSO4 and brine, dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography on silica gel eluted with PE / ELISA (2:1) to obtain the title compound (2 g, 60%). LCMS m / z = 200 [M -tBu+H] + .

[0443] Step 2: Synthesis of (2R,4R)-4-hydroxy-2-isopropyl-6-oxopiperidine-1-carboxylate tert-butyl or (2R,4S)-4-hydroxy-2-isopropyl-6-oxopiperidine-1-carboxylate tert-butyl To a 20 mL solution of the compound from step 1 (2 g, 7.83 mmol) in DCM, AcOH (1.5 mL) and NaBH4 (865 mg, 23.4 mmol) were added in an ice bath, and the reaction mixture was stirred at room temperature for 72 hours. The mixture was concentrated under vacuum, and the residue was purified by column chromatography on silica gel eluted with siRNA / PE(2 / 1) to obtain the title compound (500 mg, 24%) as a yellow oil. LCMS m / z = 202 [M -tBu+H]+.

[0444] Step 3: Synthesis of (2R,4S)-4-hydroxy-2-isopropylpiperidine-1-carboxylate tert-butyl or (2R,4R)-4-hydroxy-2-isopropylpiperidine-1-carboxylate tert-butyl To a solution of the compound from step 2 (400 mg, 1.55 mmol) in THF (20 mL), BH3.SMe2 (589 mg, 7.75 mmol) was added under N2 in an ice bath, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with MeOH and then concentrated under vacuum. The residue was diluted with siRNA, washed with water, sodium bicarbonate, and 1N KHSO4, dried over Na2SO4, filtered, and the residue was concentrated to obtain the title compound (200 mg, 53%) as a colorless oil.

[0445] Step 4: (2R,4R)-2-isopropyl-4-((4-nitrobenzoyl)oxy)piperidine-1-carboxylate tert-butyl or (2R,4S)-2-isopropyl-4-((4-nitrobenzoyl)oxy)piperidine-1-carboxylate tert-butyl To a solution of the compound from step 3 (300 mg, 1.23 mmol), 4-nitrobenzoic acid (307 mg, 1.84 mmol), and PPh3 (482 mg, 1.84 mmol) in THF (15 mL), DIAD (743 mg, 3.68 mmol) was added under N2 in an ice bath, and the reaction mixture was then stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum, and the residue was purified by column chromatography on silica gel eluted with siRNA / PE(1 / 4) to obtain the title compound (300 mg, 62%) as a yellow oil. LCMS m / z = 293 [M -100+H]+.

[0446] Step 5: Synthesis of (2R,4R)-4-hydroxy-2-isopropylpiperidine-1-carboxylate tert-butyl or (2R,4S)-4-hydroxy-2-isopropylpiperidine-1-carboxylate tert-butyl The compound from step 4 (250 mg, 637 μmol) and a mixture of LiOH (71.1 mg, 1.27 mmol) in MeOH (10 mL) and water (2 mL) were stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum, and the residue was purified by column chromatography on silica gel eluted with SiO / PE (1 / 1) to obtain the title compound (120 mg, 77%) as a colorless oil. LCMS m / z = 188 [M -tBu+H] + .

[0447] Step 6: Synthesis of (2R,4R)-4-((6-chloropyrazine-2-yl)oxy)-2-isopropylpiperidine-1-carboxylate tert-butyl or (2R,4S)-4-((6-chloropyrazine-2-yl)oxy)-2-isopropylpiperidine-1-carboxylate tert-butyl The title compound was obtained from the compound of step 5 and 2,6-dichloropyrazine as a yellow oily substance of 45 mg, 31%, following the procedure described in step 1 of Example 39. LCMS m / z = 300 [M -56+H]+.

[0448] Step 7: Synthesis of (2R,4R)-4-((6-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-2-isopropylpiperidine-1-carboxylate tert-butyl or (2R,4R)-4-((6-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-2-isopropylpiperidine-1-carboxylate tert-butyl

[0449] The title compound was obtained as 40 mg, 67% yellow solid from the compound of step 6 and 5-(difluoromethoxy)-1H-pyrazole-3-amine according to the procedure described in step 1 of Examples 19 and 20. LCMS m / z = 469 [M +H]+.

[0450] Step 8: Synthesis of N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(((2R,4R)-2-isopropylpiperidine-4-yl)oxy)pyrazine-2-aminetrifluoroacetate or N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(((2R,4S)-2-isopropylpiperidine-4-yl)oxy)pyrazine-2-aminetrifluoroacetate

[0451] The compound from step 7 (40 mg, 85.3 μmol) and a mixture of TFA (1 mL) and DCM (3 mL) were stirred at room temperature for 1 hour. The solvent was removed under vacuum to obtain the title compound (30 mg, crude) as a yellow oil. LCMS m / z = 369 [M + H]+.

[0452] Step 9: Synthesis of N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(((2R,4R)-2-isopropyl-1-methylpiperidine-4-yl)oxy)pyrazine-2-amine or N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(((2R,4S)-2-isopropyl-1-methylpiperidine-4-yl)oxy)pyrazine-2-amine The title compound was obtained as a white solid of 4.8 mg, 19%, from the compound in step 8 and HCHO, following the same procedure as described in Example 11, except that HPLC (Method B) was used. LCMS m / z = 383 [M + H] + . 1 H-NMR (400 MHz, DMSO-d6) δ ppm 11.92 (br s, 1H), 10.01 (br s, 1H), 8.14 (s, 1H), 7.78 (s, 1H), 7.62 (s, 1H), 7.25 (t, 1H), 5.95 (s, 1H), 5.33-5.28 (m, 2H), 2.85-2.80 (m, 1H), 2.71-2.57 (m, 1H), 2.37 (s, 3H), 2.35-2.29 (m, 1H), 2.15-2.08 (m, 1H), 1.94-1.80 (m, 3H), 1.63-1.56 (m, 1H), 0.85-0.75 (m, 6H).

[0453] Example 44, (R)-N-(5-(sec-butyl)-1H-pyrazole-3-yl)-6-((1-methylpiperidine-4-yl)oxy)pyrazine-2-amine or (S)-N-(5-(sec-butyl)-1H-pyrazole-3-yl)-6-((1-methylpiperidine-4-yl)oxy)pyrazine-2-amine and Example 45, (S)-N-(5-(sec-butyl)-1H-pyrazole-3-yl)-6-((1-methylpiperidine-4-yl)oxy)pyrazine-2-amine and (R)-N-(5-(sec-butyl)-1H-pyrazole-3-yl)-6-((1-methylpiperidine-4-yl)oxy)pyrazine-2-amine [ka]

[0454] From 5-(sec-butyl)-1H-pyrazole-3-amine and step 1 of Example 8, N-(5-(sec-butyl)-1H-pyrazole-3-yl)-6-((1-methylpiperidine-4-yl)oxy)pyrazine-2-amine was obtained (300 mg) according to the procedure described in step 2 of Example 37. This was separated by chiral SFC (column: AD 20 × 250 mm, 10 μm (Daicel), column temperature: 35 °C, mobile phase: CO2 / [MeOH / MeCN[0.2%NH3 (7M in MeOH)] 1:1] = 60 / 40, flow rate: 120 g / min, back pressure: 100 bar), and peak 1 of Example 45 (86.8 mg, 29%) was obtained as a yellow solid. 1 HNMR (400 MHz, DMSO-d6) δ ppm 11.95 (br s, 1H), 9.61 (s, 1H), 7.91 (s, 1H), 7.43 (s, 1H), 6.24 (s, 1H), 4.94-4.89 (m, 1H), 2.74-2.65 (m, 3H), 2.18 (s, 3H), 2.14-2.07 (m, 2H), 2.01-1.98 (m, 2H), 1.69-1.51 (m, 4H), 1.22 (d, 3H), 0.85 (t, 3H).

[0455] And peak 2 (94.5 mg, 31%) of Example 44 was obtained as a yellow solid. LCMS m / z = 331 [M + H] + . 1 HNMR (400 MHz, DMSO-d6) δ ppm 11.96 (br s, 1H), 9.62 (s, 1H), 7.92 (s, 1H), 7.43 (s, 1H), 6.25 (s, 1H), 4.95-4.89 (m, 1H), 2.74-2.66 (m, 3H), 2.18 (s, 3H), 2.11-2.06 (m, 2H), 2.02-1.97 (m, 2H), 1.73-1.55 (m, 4H), 1.22 (d, 3H), 0.85 (t, 3H).

[0456] Example 46, 3-((3-((6-((1-methylpiperidine-4-yl)oxy)pyrazine-2-yl)amino)-1H-pyrazole-5-yl)oxy)propan-1-ol [ka]

[0457] Step 1: Synthesis of 3-((1-(tert-butyl)-5-((6-((1-methylpiperidine-4-yl)oxy)pyrazine-2-yl)amino)-1H-pyrazole-3-yl)oxy)propan-1-ol To a stirred solution of Step 1 of Example 41 (150 mg, 432 μmol) and 3-bromopropan-1-ol (60.0 mg, 432 μmol) in DMF (3 mL), K2CO3 (178 mg, 1.29 mmol) was added at room temperature, and the reaction mixture was stirred under N2 at 35°C for 12 hours. The resulting mixture was diluted with HCl, washed with brine, and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain the title compound (110 mg, crude) as a yellow oil. LCMS m / z = 405 [M + H] + .

[0458] Step 2: Synthesis of 3-((5-((6-((1-methylpiperidine-4-yl)oxy)pyrazine-2-yl)amino)-1H-pyrazole-3-yl)oxy)propyl formate The compound from step 1 (70 mg, 538 μmol) was mixed with FA (3 mL) and stirred at 80°C for 1 hour under N2. The reaction mixture was concentrated under vacuum to obtain the title compound (70 mg, crude) as a yellow oil. LCMS m / z = 377 [M + H] + .

[0459] Step 3: Synthesis of 3-((3-((6-((1-methylpiperidine-4-yl)oxy)pyrazine-2-yl)amino)-1H-pyrazole-5-yl)oxy)propan-1-ol To a solution of the compound from step 2 (70 mg, 186 μmol) in MeOH (2 mL) and H2O (2 mL), NaOH (22.1 mg, 555 μmol) was added at room temperature, and the reaction mixture was stirred at 50°C for 1 hour. The mixture was purified by preparative HPLC (Method A) to obtain the title product (6.1 mg, 10%) as a yellow solid. LCMS m / z = 377 [M + H] + . 1 H-NMR (400 MHz, DMSO-d6) δ ppm 11.93 (br s, 1H), 9.77 (br s, 1H), 7.90 (s, 1H), 7.50 (s, 1H), 5.86 (s, 1H), 4.95-4.90 (m, 1H), 4.59-4.52 (m, 1H), 4.11 (t, 2H), 3.56-3.51 (m, 2H), 2.72-2.60 (m, 2H), 2.33 (s, 3H), 2.32-2.10 (m, 2H), 2.02-1.92 (m, 2H), 1.90-1.80 (m, 2H), 1.78-1.60 (m, 2H).

[0460] Examples 47 and 48, (R)-6-(piperidine-4-yloxy)-N-(5-(tetrahydrofuran-3-yl)-1H-pyrazole-3-yl)pyrazine-2-amine and (S)-6-(piperidine-4-yloxy)-N-(5-(tetrahydrofuran-3-yl)-1H-pyrazole-3-yl)pyrazine-2-amine [ka]

[0461] Step 1: Synthesis of (R)-4-((6-((5-(tetrahydrofuran-3-yl)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)piperidine-1-carboxylate tert-butyl and (S)-4-((6-((5-(tetrahydrofuran-3-yl)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)piperidine-1-carboxylate tert-butyl

[0462] From Step 1 of Example 1 and 5-(tetrahydrofuran-3-yl)-1H-pyrazole-3-amine, 4-((6-((5-(tetrahydrofuran-3-yl)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)piperidine-1-carboxylate tert-butyl was prepared according to the procedure described in Step 2 of Examples 19 and 20. The racemic product was converted to chiral-SFC (column: OZ 4.6 × 100 mm). Separation was performed using a 5μm column, 40°C column temperature, CO2 / MeOH mobile phase [0.2%NH3 (7M in MeOH)] = 50 / 50, flow rate: 100g / min, back pressure: 100bar) to obtain peak 1 (R)-4-((6-((5-(tetrahydrofuran-3-yl)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)piperidine-1-carboxylate tert-butyl or (S)-4-((6-((5-(tetrahydrofuran-3-yl)-1H-pyrazole-3-yl)amino)pyrazine-2 (S)-4-((6-((5-(tetrahydrofuran-3-yl)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)piperidine-1-carboxylate tert-butyl (140 mg) was obtained at peak 2. (R)-4-((6-((5-(tetrahydrofuran-3-yl)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)piperidine-1-carboxylate tert-butyl (140 mg) was obtained. LCMS m / z = 431 [M + H] +

[0463] Step 2: Synthesis of Example 48, (R)-6-(piperidine-4-yloxy)-N-(5-(tetrahydrofuran-3-yl)-1H-pyrazole-3-yl)pyrazine-2-amine or (S)-6-(piperidine-4-yloxy)-N-(5-(tetrahydrofuran-3-yl)-1H-pyrazole-3-yl)pyrazine-2-amine The title compound was obtained as a white solid, 52.7 mg, 48%, from peak 1 of step 1, following the procedure described in step 3 of Example 3. LCMS m / z = 331 [M +H]+. 1H-NMR (400 MHz, DMSO-d6) δ ppm 12.09 (br s, 1H), 9.68 (s, 1H), 7.92 (s, 1H), 7.45 (s, 1H), 6.30 (s, 1H), 5.01-4.95 (m, 1H), 4.03-3.98 (m, 1H), 3.92-3.77 (m, 2H), 3.60-3.53 (m, 1H), 3.45-3.35 (m, 2H), 3.02-2.99 (m, 2H), 2.62-2.56 (m, 2H), 2.33-2.25 (m, 1H), 2.02-1.91 (m, 3H), 1.55-1.48 (m, 2H).

[0464] Step 3: Synthesis of Example 47, (S)-6-(piperidine-4-yloxy)-N-(5-(tetrahydrofuran-3-yl)-1H-pyrazole-3-yl)pyrazine-2-amine or (R)-6-(piperidine-4-yloxy)-N-(5-(tetrahydrofuran-3-yl)-1H-pyrazole-3-yl)pyrazine-2-amine The title compound was obtained as a white solid, 60.2 mg, 56%, from peak 2 of step 1, following the procedure described in step 3 of Example 3. LCMS m / z = 331 [M +H]+. 1 H-NMR (400 MHz, DMSO-d6) δ ppm 12.07 (br s, 1H), 9.67 (s, 1H), 7.92 (s, 1H), 7.44 (s, 1H), 6.30 (s, 1H), 4.99-4.94 (m, 1H), 4.01 (t, 1H), 3.90-3.76 (m, 2H), 3.59 (t, 1H), 3.45-3.35 (m, 2H), 3.01-2.98 (m, 2H), 2.61-2.56 (m, 2H), 2.33-2.25 (m, 1H), 2.00-1.91 (m, 3H), 1.54-1.47 (m, 2H).

[0465] Example 49, (1R,3R)-1-methyl-3-(3-((6-((1-methylpiperidine-4-yl)oxy)pyrazine-2-yl)amino)-1H-pyrazole-5-yl)cyclopentan-1-ol or (1S,3R)-1-methyl-3-(3-((6-((1-methylpiperidine-4-yl)oxy)pyrazine-2-yl)amino)-1H-pyrazole-5-yl)cyclopentan-1-ol and

[0466] Example 50, (1S,3R)-1-methyl-3-(3-((6-((1-methylpiperidine-4-yl)oxy)pyrazine-2-yl)amino)-1H-pyrazole-5-yl)cyclopentan-1-ol or (1R,3R)-1-methyl-3-(3-((6-((1-methylpiperidine-4-yl)oxy)pyrazine-2-yl)amino)-1H-pyrazole-5-yl)cyclopentan-1-ol [ka]

[0467] Step 1: Synthesis of (R)-3,3-dimethoxycyclopentane-1-carboxylate methyl To a solution of (R)-3-oxocyclopentane-1-carboxylic acid (3 g, 23.4 mmol) and trimethoxymethane (14.8 g, 140 mmol) in MeOH (15 mL), 4-methylbenzene-1-sulfonic acid hydrate (89.0 mg, 0.47 mmol) was added under N2 at room temperature, and the reaction mixture was stirred for 24 hours. The reaction mixture was quenched with saturated NaHCO3 aqueous solution and then concentrated under vacuum. The aqueous layer was extracted with ELISA, the combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to obtain the title product (3.5 g, crude) as a yellow oil.

[0468] Step 2: Synthesis of (R)-3-(3,3-dimethoxycyclopentyl)-3-oxopropannitrile To a solution of MeCN (1.51 g, 37.0 mmol) in THF (15 mL), BuLi (2.5 M, 14.8 mL, 37.0 mmol) was added under N2 at -78°C. After stirring for 1 hour, (1R)-3,3-dimethoxycyclopentane-1-carboxylate methyl (3.5 g, 18.5 mmol) was added at -78°C, and the reaction mixture was stirred at 0°C for 2 hours. The reaction mixture was neutralized with 1 M HCl and extracted with toluene. The organic layer was washed with brine and concentrated to obtain the title product (3.5 g, crude) as a yellow oil.

[0469] Step 3: Synthesis of (R)-1-(tert-butyl)-3-(3,3-dimethoxycyclopentyl)-1H-pyrazole-5-amine To a solution of 10 mL of 1.65 g of tert-butyl hydrazine hydrochloride (1.65 g, 13.3 mmol), NaOH (531 mg, 13.3 mmol) was added at room temperature. After stirring for 1 hour, methyl(R)-3-(3,3-dimethoxycyclopentyl)-3-oxopropanenitrile (2.2 g, 11.1 mmol) was added, and the reaction mixture was stirred at 75°C for 18 hours. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to obtain the crude product (2.5 g) as a red oily substance.

[0470] Step 4: Synthesis of (R)-3-(5-amino-1-(tert-butyl)-1H-pyrazole-3-yl)cyclopentan-1-one To a solution of (R)-1-(tert-butyl)-3-(3,3-dimethoxycyclopentyl)-1H-pyrazole-5-amine (2.5 g, 9.35 mmol) in acetone (10 mL) and water (10 mL), 4-toluenesulfonic acid monohydrate (231 mg, 1.22 mmol) was added at room temperature, and the reaction mixture was stirred for 3 hours. The reaction mixture was concentrated under vacuum, the residue was neutralized with saturated NaHCO3 aqueous solution, and extracted with ELISA. The combined organic layers were washed with brine, dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum to obtain the title product (2.2 g, crude) as a red oil. LCMS m / z = 222 [M + H] + .

[0471] Step 5: Synthesis of (R)-3-(1-(tert-butyl)-3-((6-((1-methylpiperidine-4-yl)oxy)pyrazine-2-yl)amino)-1H-pyrazole-5-yl)cyclopentan-1-one The title compound was obtained as 1.7 g, 60% yellow solid by following the procedure described in Step 2 of Examples 19 and 20, starting from (R)-3-(5-amino-1-(tert-butyl)-1H-pyrazole-3-yl)cyclopentan-1-one and Step 1 of Example 8. LCMS m / z = 413 [M + H] + .

[0472] Step 6: Synthesis of (R)-3-(3-((6-((1-methylpiperidine-4-yl)oxy)pyrazine-2-yl)amino)-1H-pyrazole-5-yl)cyclopentan-1-one A mixture of (R)-3-(1-(tert-butyl)-3-((6-((1-methylpiperidine-4-yl)oxy)pyrazine-2-yl)amino)-1H-pyrazole-5-yl)cyclopentan-1-one (1.7 g, 4.12 mmol) in FA (10 mL) was heated to 80°C for 1 hour. The mixture was evaporated under reduced pressure. The residue was diluted with ELISA and washed with saturated NaHCO3 solution and brine. The organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel eluted with PE / ELISA (1 / 1) to obtain the title compound (1.0 g, 68%) as a yellow solid. LCMS m / z = 357 [M + H] + .

[0473] Step 7: Synthesis of (1R,3R)-1-methyl-3-(3-((6-((1-methylpiperidine-4-yl)oxy)pyrazine-2-yl)amino)-1H-pyrazole-5-yl)cyclopentan-1-ol and (1S,3R)-1-methyl-3-(3-((6-((1-methylpiperidine-4-yl)oxy)pyrazine-2-yl)amino)-1H-pyrazole-5-yl)cyclopentan-1-ol A solution of (R)-3-(3-((6-((1-methylpiperidine-4-yl)oxy)pyrazine-2-yl)amino)-1H-pyrazole-5-yl)cyclopentan-1-one (1 g, 2.80 mmol) in THF (20 mL) was cooled to -78 °C. CH3Li (1.6 M, 8.75 mL, 14 mmol) was added dropwise, and the reaction mixture was stirred for 2 hours. The reaction mixture was quenched with saturated NH4Cl solution and extracted with DCM. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (Method A), and the title product (121.9 mg, 12%) of peak 1 in Example 49 was obtained as a yellow solid. 1 H-NMR (400 MHz, DMSO-d6) δ ppm 11.87 (br s, 1H), 9.59 (s, 1H), 7.93 (s, 1H), 7.43 (s, 1H), 6.27 (s, 1H), 4.98-4.92 (m, 1H), 4.44 (s, 1H), 3.12-3.06 (m, 1H), 2.72-2.65 (m, 2H), 2.22-2.14 (m, 2H), 2.20 (s, 3H), 2.05-1.98 (m, 4H), 1.88-1.80 (m, 1H), 1.77-1.60 (m, 4H), 1.57-1.51 (m, 1H), 1.26 (s, 3H).

[0474] And peak 2 (15.7 mg, 1.5%) of Example 50 was obtained as a yellow solid. LCMS m / z = 373 [M + H] + . 1HNMR (400 MHz, DMSO-d6) δ ppm 11.87 (br s, 1H), 9.58 (s, 1H), 7.93 (s, 1H), 7.43 (s, 1H), 6.29 (s, 1H), 4.99-4.92 (m, 1H), 4.44 (s, 1H), 3.09-3.07 (m, 1H), 2.70-2.67 (m, 2H), 2.18 (s, 3H), 2.17 - 2.14 (m, 2H), 2.02 - 1.98 (m, 4H), 1.88-1.86 (m, 1H), 1.77-1.68 (m, 4H), 1.67-1.65 (m, 1H), 1.26 (s, 3H).

[0475] Example 51, (1S,3S)-1-methyl-3-(3-((6-((1-methylpiperidine-4-yl)oxy)pyrazine-2-yl)amino)-1H-pyrazole-5-yl)cyclopentan-1-ol or (1R,3S)-1-methyl-3-(3-((6-((1-methylpiperidine-4-yl)oxy)pyrazine-2-yl)amino)-1H-pyrazole-5-yl)cyclopentan-1-ol and

[0476] Example 52, (1R,3S)-1-methyl-3-(3-((6-((1-methylpiperidine-4-yl)oxy)pyrazine-2-yl)amino)-1H-pyrazole-5-yl)cyclopentan-1-ol or (1S,3S)-1-methyl-3-(3-((6-((1-methylpiperidine-4-yl)oxy)pyrazine-2-yl)amino)-1H-pyrazole-5-yl)cyclopentan-1-ol [ka]

[0477] Steps 1-6: Synthesis of (S)-3-(3-((6-((1-methylpiperidine-4-yl)oxy)pyrazine-2-yl)amino)-1H-pyrazole-5-yl)cyclopentan-1-one

[0478] The title compound was obtained from (1S)-3-oxocyclopentane-1-carboxylic acid as 120 mg of a yellow solid by following the same 6-step procedure as described in steps 1-6 of Examples 49 and 50.

[0479] Step 7: Synthesis of (1S,3S)-1-methyl-3-(3-((6-((1-methylpiperidine-4-yl)oxy)pyrazine-2-yl)amino)-1H-pyrazole-5-yl)cyclopentan-1-ol and (1R,3S)-1-methyl-3-(3-((6-((1-methylpiperidine-4-yl)oxy)pyrazine-2-yl)amino)-1H-pyrazole-5-yl)cyclopentan-1-ol

[0480] From (S)-3-(3-((6-((1-methylpiperidine-4-yl)oxy)pyrazine-2-yl)amino)-1H-pyrazole-5-yl)cyclopentan-1-one and CH3Li, peak 1 of Example 51 (11.5 mg, 9.2%) and peak 2 of Example 52 (18.4 mg, 14.7%) were obtained by following the procedure described in step 7 of Examples 49 and 50.

[0481] Peak 1: 1 H-NMR (400 MHz, DMSO-d6) δ ppm 11.95 (br s, 1H), 9.64 (s, 1H), 7.89 (s, 1H), 7.43 (s, 1H), 6.26 (s, 1H), 4.92-4.88 (m, 1H), 4.41 (s, 1H), 3.32-3.29 (m, 1H), 2.68-2.65 (m, 2H), 2.56 (s, 3H), 2.27 - 1.95 (m, 7H), 1.77 - 1.61 (m, 5H), 1.30 (s, 3H).

[0482] Peak 2. LCMS m / z = 373 [M + H] + . 1HNMR (400 MHz, DMSO-d6) δ ppm 11.89 (br s, 1H), 9.60 (s, 1H), 7.93 (s, 1H), 7.44 (s, 1H), 6.27 (s, 1H), 4.97-4.94 (m, 1H), 4.45 (s, 1H), 3.18-3.02 (m, 1H), 2.83- 2.70 (m, 2H), 2.28-2.22 (m, 5H), 2.08-1.94 (m, 4H), 1.90-1.83 (m, 1H), 1.81-1.64 (m, 4H), 1.61-1.45 (m, 1H), 1.27 (s, 3H).

[0483] Example 53, (S)-6-((1-methylpiperidine-4-yl)oxy)-N-(5-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-3-yl)pyrazine-2-amine or (R)-6-((1-methylpiperidine-4-yl)oxy)-N-(5-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-3-yl)pyrazine-2-amine and

[0484] Example 54, (R)-6-((1-methylpiperidine-4-yl)oxy)-N-(5-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-3-yl)pyrazine-2-amine or (S)-6-((1-methylpiperidine-4-yl)oxy)-N-(5-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-3-yl)pyrazine-2-amine [ka]

[0485] Step 1: Synthesis of 2-(trifluoromethyl)phenethyl acrylate

[0486] A mixture of 2-(trifluoromethyl)acrylic acid (30.0 g, 214 mmol), 2-phenylethanol (52.5 g, 430 mmol), and 4-methylbenzenesulfonic acid (74.0 g, 430 mmol) in toluene (800 mL) was stirred under N2 at 120 °C for 18 hours. The reaction mixture was concentrated, and the residue was purified by column chromatography on silica gel eluted with siRNA / PE (1:10~1:5) to obtain the title product (29.0 g, 56%) as a colorless oil. ¹H-NMR (400 MHz, CDCl₃) δ ppm 7.34-7.21 (m, 5H), 6.67 (q, 1H), 6.41 (q, 1H), 4.46 (t, 2H), 3.02 (t, 2H).

[0487] Step 2: Synthesis of phenethyl 3,3,3-trifluoro-2-methylpropanoate A mixture of phenethyl 2-(trifluoromethyl)acrylate (29.0 g, 119 mmol) and HCl (300 mL) of Pd / C (wet, 6.0 g) was stirred under H2 at 20°C for 18 hours. The reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by column chromatography on silica gel eluted with HCl / PE (1:10~1:3) to obtain the title product (24.9 g, 85%) as a colorless oil. ¹H-NMR (400 MHz, CDCl3) δ ppm 7.34-7.20 (m, 5H), 4.42-4.35 (m, 2H), 3.22-3.13 (m, 1H), 2.97 (t, 2H), 1.36 (d, 3H).

[0488] Step 3: Synthesis of 5,5,5-trifluoro-4-methyl-3-oxopentanenitrile The title compound was obtained from phenethyl 3,3,3-trifluoro-2-methylpropanoate and MeCN as 100 mg, 9% yellow oil by following the procedure described in Step 1 of Examples 28 and 29. ¹H-NMR (400 MHz, CDCl3) δ ppm 3.74-3.61 (m, 2H), 3.54-3.47 (m, 1H), 1.42 (d, 3H).

[0489] Step 4: Synthesis of 5-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-3-amine The title compound was obtained from 5,5,5-trifluoro-4-methyl-3-oxopentanenitrile and hydrazine hydrate as 120 mg, 37% yellow oily substance according to the procedure described in step 2 of Examples 28 and 29. LCMS m / z = 180 [M +H]+.

[0490] Step 5: Synthesis of (S)-6-((1-methylpiperidine-4-yl)oxy)-N-(5-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-3-yl)pyrazine-2-amine and (R)-6-((1-methylpiperidine-4-yl)oxy)-N-(5-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-3-yl)pyrazine-2-amine From Step 1 of Example 8 and 5-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-3-amine, 6-((1-methylpiperidine-4-yl)oxy)-N-(5-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-3-yl)pyrazine-2-amine was obtained as 85 mg, 41% yellow solid according to the procedure described in Step 2 of Examples 19 and 20. 85 mg of the racemic product was separated by prechiral SFC (Method E, 88 / 12), and peak 1 (20.7 mg) of Example 53 was obtained. ¹H-NMR (400 MHz, DMSO-d6) δ ppm values ​​were 12.43 (br s, ¹H), 9.76 (s, ¹H), 7.91 (s, ¹H), 7.47 (s, ¹H), 6.55-6.25 (m, ¹H), 4.95-4.88 (m, ¹H), 3.90-3.85 (m, ¹H), 2.72-2.65 (m, ²H), 2.17 (s, ³H), 2.15-2.07 (m, ²H), 1.99-1.95 (m, ²H), 1.73-1.63 (m, ²H). 1.46 (d, 3H).

[0491] And peak 2 (23.1 mg) of Example 54 was obtained. ¹H-NMR (400 MHz, DMSO-d6) δ ppm 12.42 (br s, 1H), 9.76 (s, 1H), 7.90 (s, 1H), 7.47 (s, 1H), 6.55-6.25 (m, 1H), 4.95-4.88 (m, 1H), 3.90-3.85 (m, 1H), 2.72-2.65 (m, 2H), 2.17 (s, 3H), 2.15-2.07 (m, 2H), 1.99-1.95 (m, 2H), 1.73-1.63 (m, 2H), 1.45 (d, 3H).

[0492] Example 55, (S)-N-(5-(2,2-difluorocyclobutyl)-1H-pyrazole-3-yl)-6-((1-methylpiperidine-4-yl)oxy)pyrazine-2-amine or (R)-N-(5-(2,2-difluorocyclobutyl)-1H-pyrazole-3-yl)-6-((1-methylpiperidine-4-yl)oxy)pyrazine-2-amine and

[0493] Example 56, (R)-N-(5-(2,2-difluorocyclobutyl)-1H-pyrazole-3-yl)-6-((1-methylpiperidine-4-yl)oxy)pyrazine-2-amine or (S)-N-(5-(2,2-difluorocyclobutyl)-1H-pyrazole-3-yl)-6-((1-methylpiperidine-4-yl)oxy)pyrazine-2-amine [ka]

[0494] Step 1: Synthesis of 2,2-difluorocyclobutane-1-carboxylate phenethyl

[0495] The title compound was obtained from 2,2-difluorocyclobutane-1-carboxylic acid and 2-phenylethanol as a colorless oily substance, 1.0 g, 57% concentration, following the procedure described in Step 1 of Examples 53 and 54. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.34-7.21 (m, 5H), 4.32-4.28 (m, 2H), 3.92-3.85 (m, 1H), 2.92-2.88 (m, 2H), 2.55-2.43 (m, 2H), 1.97-1.92 (m, 2H).

[0496] Step 2: Synthesis of 3-(2,2-difluorocyclobutyl)-3-oxopropannitrile

[0497] The title compound was obtained from MeCN and 2,2-difluorocyclobutane-1-carboxylic acid phenethyl as a colorless oil, 180 mg, 57% in volume, following the procedure described in Step 1 of Examples 28 and 29. 1 H NMR (500 MHz, CDCl3) δ ppm 3.98-3.88 (m, 1H), 3.63-3.53 (m, 2H), 2.65-2.49 (m, 2H), 2.37-2.30 (m, 1H), 1.98-1.92 (m, 1H)

[0498] Step 3: Synthesis of 5-(2,2-difluorocyclobutyl)-1H-pyrazole-3-amine The title compound was obtained from 3-(2,2-difluorocyclobutyl)-3-oxopropanenitrile and hydrazine hydrate as 330 mg, 54% yellow oily substance according to the procedure described in step 2 of Examples 28 and 29. 1 H NMR (500 MHz, DMSO-d6) δ ppm 11.30 (br s, 1H), 5.29 (s, 1H), 4.95-4.33 (m, 2H), 3.85-3.76 (m, 1H), 2.59-2.50 (m, 1H), 2.50-2.40 (m, 1H), 2.15-2.01 (m, 1H), 1.97-1.84 (m, 1H).

[0499] Step 4: (S)-N-(5-(2,2-difluorocyclobutyl)-1H-pyrazole-3-yl)-6-((1-methylpiperidine-4-yl)oxy)pyrazine-2-amine and (R)-N-(5-(2,2-difluorocyclobutyl)-1H-pyrazole-3-yl)-6-((1-methylpiperidine-4-yl)oxy)pyrazine-2-amine

[0500] From 5-(2,2-difluorocyclobutyl)-1H-pyrazole-3-amine and step 1 of Example 8, the title compound, namely peak 1 of Example 55 (70 mg, 24%) and peak 2 of Example 56 (15.9 mg, 5%), was obtained by following the same procedure as described in step 3 of Examples 28 and 29.

[0501] Peak 1:1H NMR (400 MHz, DMSO-d6) δ ppm 12.28 (br s, 1H), 9.75 (s, 1H), 7.90 (s, 1H), 7.45 (s, 1H), 6.43 (s, 1H), 4.96-4.85 (m, 1H), 4.12-3.98 (m, 1H), 2.77-2.58 (m, 3H), 2.28-2.20 (m, 1H), 2.17 (s, 3H), 2.13-2.08 (m, 2H), 2.01-1.95 (m, 3H), 1.71-1.63 (m, 2H).

[0502] Peak 2: LCMS m / z = 365 [M + H] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.30 (br s, 1H), 9.74 (s, 1H), 7.90 (s, 1H), 7.46 (s, 1H), 6.43 (s, 1H), 4.97-4.86 (m, 1H), 4.11-4.00 (m, 1H), 2.78-2.58 (m, 3H), 2.28-2.23 (m, 1H), 2.19 (s, 3H), 2.16-2.06 (m, 2H), 2.06-1.95 (m, 3H), 1.71-1.63 (m, 2H).

[0503] Example 57, (R)-N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-((4-methylazepan-4-yl)oxy)pyrazine-2-amine or (S)-N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-((4-methylazepan-4-yl)oxy)pyrazine-2-amine [ka]

[0504] Step 1: Synthesis of 4-((6-bromopyrazine-2-yl)oxy)-4-methylazepane-1-carboxylate tert-butyl

[0505] To a DMA (5.0 mL) solution of 2-bromo-6-fluoropyrazine (500 mg, 2.82 mmol) and 4-hydroxy-4-methylazepane-1-carboxylate tert-butyl (839 mg, 3.66 mmol), tert-butoxide sodium (271 mg, 2.82 mmol) was added, and the reaction mixture was irradiated with microwaves at 80°C for 40 minutes. After cooling to room temperature, the reaction product was diluted with ELISA and washed with water. The organic layer was evaporated under reduced pressure to obtain the title compound (1.0 g) as a brown oily substance.

[0506] Step 2: Synthesis of (R)-4-((6-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-4-methylazepan-1-carboxylate tert-butyl and (S)-4-((6-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-4-methylazepan-1-carboxylate tert-butyl

[0507] The title compound was obtained from 4-((6-bromopyrazine-2-yl)oxy)-4-methylazepane-1-carboxylate tert-butyl and 5-(difluoromethoxy)-1H-pyrazole-3-amine according to the procedure described in Step 1 of Examples 24 and 25, as peak 2 (18 mg, 6%). LCMS m / z = 455 [M + H]+ .

[0508] Step 3: Synthesis of (R)-N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-((4-methylazepan-4-yl)oxy)pyrazine-2-amine or (S)-N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-((4-methylazepan-4-yl)oxy)pyrazine-2-amine

[0509] The title compound was obtained as a yellow solid of 11.3 mg, 81%, by following the procedure described in Step 3 of Example 3, starting from Step 2. LCMS m / z = 355 [M + H] + .1H-NMR (400 MHz, DMSO-d6) δ ppm 12.15 (br s, 1H), 9.70 (br s, 1H), 7.80 (s, 1H), 7.58 (s, 1H), 7.23 (t, 1H), 5.91 (s, 1H), 3.21-3.01 (m, 4H), 2.47-2.33 (m, 2H), 2.08-1.99 (m, 1H), 1.85-1.77 (m, 2H), 1.74-1.58 (m, 1H)), 1.53 (s, 3H).

[0510] Example 58, (R)-6-((1-methylpiperidine-4-yl)oxy)-N-(5-((tetrahydrofuran-3-yl)methoxy)-1H-pyrazole-3-yl)pyrazine-2-amine [ka]

[0511] The title compound was obtained from (S)-(tetrahydrofuran-3-yl)methanol using the same two-step procedure as described in steps 2 and 3 of Example 41. LCMS m / z = 375 [M +H]+. 1H-NMR (400 MHz, DMSO-d6) δ ppm 11.87-11.26 (m, 1H), 9.73 (br s, 1H), 7.80 (br s, 1H), 7.50 (s, 1H), 5.78-5.73 (m, 1H), 4.93-4.87 (m, 1H), 4.05-3.94 (m, 2H), 3.80-3.75 (m, 2H), 3.68-3.63 (m, 1H), 3.54-3.49 (m, 1H), 2.78-2.61 (m, 3H), 2.18 (s, 3H), 2.14-2.07 (m, 2H), 2.02-1.97 (m, 3H), 1.69-1.55 (m, 3H).

[0512] Example 59, 6-((1-methylpiperidine-4-yl)oxy)-N-(5-((tetrahydro-2H-pyran-4-yl)oxy)-1H-pyrazole-3-yl)pyrazine-2-amine [ka]

[0513] Step 1: Synthesis of 2-(5-oxo-4,5-dihydro-1H-pyrazole-3-yl)isoindoline-1,3-dione A mixture of 5-amino-2,4-dihydro-3H-pyrazole-3-one (11.0 g, 0.11 mol) and isobenzofuran-1,3-dione (17.0 g, 0.11 mol) in AcOH (200 mL) was stirred at 120 °C for 2 hours. The reaction mixture was cooled to room temperature. The precipitate was collected by filtration to obtain the title compound (20.0 g, 80%) as a gray solid. LCMS m / z = 230 [M + H] + .

[0514] Step 2: Synthesis of 2-(5-((tetrahydro-2H-pyran-4-yl)oxy)-1H-pyrazole-3-yl)isoindoline-1,3-dione A mixture of the compound from step 1 (6 g, 26.1 mmol), 4-bromooxane (8.61 g, 52.2 mmol), and K2CO3 (10.8 g, 78.3 mmol) in DMF (15 mL) was stirred at 35°C for 16 hours. The mixture was diluted with SiO2, washed with water and brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography on silica gel eluted with SiO2 / PE(3 / 2) to obtain the title compound (320 mg, 4%) as a yellow oil. LCMS m / z = 314 [M + H] + .

[0515] Step 3: Synthesis of 5-((tetrahydro-2H-pyran-4-yl)oxy)-1H-pyrazole-3-amine Compound from step 2 (320 mg, 1.02 mmol) and N2H 4. A mixture of H2O (163 mg, 5.10 mmol) and EtOH (6 mL) was stirred at 70°C for 2 hours. The reaction mixture was concentrated under vacuum, and the residue was purified by column chromatography on silica gel eluted with MeOH / DCM (1 / 3) to obtain the title product (160 mg, crude) as a colorless oil. LCMS m / z = 184 [M + H]+.

[0516] Step 4: Synthesis of 5-((tetrahydro-2H-pyran-4-yl)oxy)-1-tosyl-1H-pyrazole-3-amine A mixture of the compound from step 3 (160 mg, crude), toluene (263 mg, 2.61 mmol), TsCl (165 mg, 873 μmol), and DMAP (10.6 mg, 87.3 μmol) in DCM (8 mL) was stirred at room temperature for 1 hour. The mixture was concentrated under vacuum, and the residue was purified by column chromatography on silica gel eluted with MeOH / DCM (1 / 8) to obtain the title compound (130 mg, 44%) as a yellow oil.

[0517] Step 5: Synthesis of 6-((1-methylpiperidine-4-yl)oxy)-N-(5-((tetrahydro-2H-pyran-4-yl)oxy)-1-tosyl-1H-pyrazole-3-yl)pyrazine-2-amine The title compound was obtained as 160 mg, 78% yellow solid from the compound obtained in Step 4 and Step 1 of Example 8, following the procedure described in Step 1 of Examples 19 and 20. LCMS m / z = 529 [M +H]+.

[0518] Step 6: Synthesis of 6-((1-methylpiperidine-4-yl)oxy)-N-(5-((tetrahydro-2H-pyran-4-yl)oxy)-1H-pyrazole-3-yl)pyrazine-2-amine The compound from step 5 (130 mg, 245 μmol) and KOH (27.4 mg, 490 μmol) were mixed in EtOH (10 mL) and stirred at 65°C for 1 hour. The mixture was concentrated under vacuum, and the residue was purified by column chromatography on silica gel eluted with MeOH / DCM (3 / 7) to obtain the title compound (4.6 mg, 5%) as a yellow solid. LCMS m / z = 375 [M + H] + . 1 H-NMR (400 MHz, CDCl3) δ ppm 7.74 (s, 1H), 7.68 (s, 1H), 6.86 (s, 1H), 5.37 (s, 1H), 4.95-4.90 (m, 1H), 4.67-4.61 (m, 1H), 3.99-3.90 (m, 2H), 3.59-3.53 (m, 2H), 2.73-2.67 (m, 2H), 2.46-2.40 (m, 2H), 2.34 (s, 3H), 2.10-2.05 (m, 4H), 1.97-1.87 (m, 2H), 1.84-1.74 (m, 2H).

[0519] Example 60, N-(5-methyl-1H-pyrazole-3-yl)-6-(quinuclidine-4-yloxy)pyrazine-2-amine [ka]

[0520] Step 1: Synthesis of 4-((6-chloropyrazine-2-yl)oxy)quinuclidine The title compound was obtained from 1-azabicyclo[2.2.2]octan-4-ol and 2,6-dichloropyrazine as a white solid, 230 mg, 82% concentration, following the procedure described in Step 1 of Example 37. LCMS m / z = 240 [M +H] +

[0521] Step 2: Synthesis of N-(5-methyl-1H-pyrazole-3-yl)-6-(quinuclidine-4-yloxy)pyrazine-2-amine A mixture of 4-((6-chloropyrazine-2-yl)oxy)quinuclidine (70 mg, 292 μmol), 5-methyl-1H-pyrazole-3-amine (28.3 mg, 292 μmol), KOAc (85.9 mg, 876 μmol), and BrettPhos Pd G4 (26.8 mg, 29.2 μmol) in dioxane (5 mL) was stirred at 90°C for 3 hours under N2. The reaction mixture was diluted with dioxane, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on a silica gel column eluted with MeOH / DCM (1 / 4). The product was further purified by preparative HPLC (Method A) to obtain the title compound (10.1 mg, 10%) as a white solid. LCMS m / z = 301 [M + H] + . 1 HNMR (400 MHz, DMSO-d6) δ ppm 11.88 (br s, 1H), 9.31 (s, 1H), 8.03 (s, 1H), 7.34 (s, 1H), 6.01 (s, 1H), 2.91-2.83 (m, 6H), 2.17 (s, 3H), 2.04-1.95 (m, 6H).

[0522] Example 61, N-(5-methoxy-1H-pyrazole-3-yl)-6-(quinuclidine-4-yloxy)pyrazine-2-amine [ka]

[0523] The title compound was obtained as 12.5 mg, 14% white solid from step 1 of Example 60 and 5-methoxy-1H-pyrazole-3-amine, following the procedure described in step 2 of Example 60. LCMS m / z = 317 [M +H] + . 1 HNMR (400 MHz, DMSO-d6) δ ppm 11.89-11.30 (m, 1H), 9.55-9.46 (m, 1H), 8.15-7.70 (m, 1H), 7.45 (s, 1H), 5.67 (s, 1H), 3.78 (s, 3H), 2.95-2.80 (m, 6H), 2.13-1.95 (m, 6H).

[0524] Example 62, N-(5-isopropyl-1H-pyrazole-3-yl)-6-(quinuclidine-4-yloxy)pyrazine-2-amine [ka]

[0525] The title compound was obtained as 10.2 mg, 10% yellow solid from step 1 of Example 60 and 5-isopropyl-1H-pyrazole-3-amine, following the procedure described in step 2 of Example 60. LCMS m / z = 329 [M +H] + 1 HNMR (400 MHz, DMSO-d6) δ ppm 11.94 (br s, 1H), 9.38 (s, 1H), 8.00 (s, 1H), 7.36 (s, 1H), 6.04 (s, 1H), 3.02-2.94 (m, 6H), 2.91-2.86 (m, 1H), 2.14-2.05 (m, 6H), 1.19 (d, 6H).

[0526] Example 63, (2R,3R)-3-((6-((5-(oxetan-3-yl)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)butan-2-ol [ka]

[0527] Step 1: Synthesis of (2R,3R)-3-((6-chloropyrazine-2-yl)oxy)butan-2-ol The title compound was obtained from (2R,3R)-butane-2,3-diol and 2,6-dichloropyrazine as a yellow solid, 219 mg, 50% concentration, following the procedure described in Step 1 of Example 5. LCMS m / z = 203 [M + H] + .

[0528] Step 2: Synthesis of (2R,3R)-3-((6-((5-(oxetan-3-yl)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)butan-2-ol The title compound was obtained as 110 mg, 35% white solid from (2R,3R)-3-((6-chloropyrazine-2-yl)oxy)butan-2-ol and 5-(oxetan-3-yl)-1H-pyrazole-3-amine according to the procedure described in step 2 of Examples 19 and 20. LCMS m / z = 306 [M + H] + . 1 NMR (400 MHz, DMSO-d6) δ ppm 12.18 (br s, 1H), 9.60 (br s, 1H), 8.02 (s, 1H), 7.46 (s, 1H), 6.49 (s, 1H), 5.01-4.96 (m, 1H), 4.90-4.85 (m, 2H), 4.84-4.80 (m, 1H), 4.66-4.60 (m, 2H), 4.31-4.26 (m, 1H), 3.82-3.79 (m, 1H), 1.24 (d, 3H), 1.10 (d, 3H).

[0529] Example 64, N-(5-benzyl-1H-pyrazole-3-yl)-6-((1-methylpiperidine-4-yl)oxy)pyrazine-2-amine [ka]

[0530] The title compound was obtained as a yellow solid of 44.5 mg, 46%, from step 1 of Example 8 and 5-benzyl-1H-pyrazole-3-amine, following the procedure described in step 2 of Example 37. LCMS m / z = 365 [M + H] + . 1 HNMR (400 MHz, DMSO-d6) δ ppm 12.15 (br s, 1H), 9.64 (s, 1H), 7.91 (s, 1H), 7.43 (s, 1H), 7.35-7.20 (m, 5H), 6.19 (s, 1H), 4.81-4.75 (m, 1H), 3.93 (s, 2H), 2.62-2.57 (m, 2H), 2.17 (s, 3H), 2.10-1.98 (m, 2H), 1.92-1.89 (m, 2H), 1.67-1.57 (m, 2H).

[0531] Example 65, N-(5-ethoxy-1H-pyrazole-3-yl)-6-((1-methylpiperidine-4-yl)oxy)pyrazine-2-amine [ka]

[0532] The title compound was obtained as a yellow solid, 54 mg, 43%, from step 1 of Example 8 and 5-ethoxy-1H-pyrazole-3-amine, following the same procedure as described in step 2 of Examples 19 and 20. LCMS m / z = 319 [M +H] + . 1 H-NMR (400 MHz, DMSO-d6) δ ppm 11.58 (br s, 1H), 9.69 (br s, 1H), 7.88 (br s, 1H), 7.50 (s, 1H), 5.76-5.70 (m, 1H), 4.95-4.90 (m, 1H), 4.10 (q, 2H), 2.70-2.62 (m, 2H), 2.18 (s, 3H), 2.17-2.08 (m, 2H), 2.01-1.95 (m, 2H), 1.75-1.65 (m, 2H), 1.30 (t, 3H).

[0533] Example 66, N-(5-isobutoxy-1H-pyrazole-3-yl)-6-((1-methylpiperidine-4-yl)oxy)pyrazine-2-amine [ka]

[0534] Step 1: Synthesis of 2-(5-isobutoxy-1H-pyrazole-3-yl)isoindoline-1,3-dione The title compound was obtained as 120 mg, 9% yellow oil from step 1 of Example 59 and 2-methylpropylmethanesulfonate, following the procedure of step 2 of Example 59. LCMS m / z = 286 [M +H]+.

[0535] Step 2: Synthesis of 5-isobutoxy-1H-pyrazole-3-amine 2-(5-isobutoxy-1H-pyrazole-3-yl)isoindorin-1,3-dione (120 mg, 420 μmol) and N2H4 . A mixture of H2O (13.4 mg, 420 μmol) and EtOH (4 mL) was stirred at 75°C for 2 hours. The reaction mixture was purified by preparative HPLC (Method A) to obtain the title product (60 mg, 92%) as a colorless oil. LCMS m / z = 156 [M + H] + .

[0536] Step 3: Synthesis of N-(5-isobutoxy-1H-pyrazole-3-yl)-6-((1-methylpiperidine-4-yl)oxy)pyrazine-2-amine The title compound was obtained as a yellow solid of 4.5 mg, 4%, by following the procedure described in Step 2 of Example 37, using 5-isobutoxy-1H-pyrazole-3-amine and Step 1 of Example 8. LCMS m / z = 347 [M +H] + . 1H-NMR (400 MHz, CDCl3) δ ppm 7.78 (s, 1H), 7.73 (br s, 1H), 7.66 (s, 1H), 5.49 (s, 1H), 4.99-4.90 (m, 1H), 3.89 (d, 2H), 2.81-2.64 (m, 2H), 2.45-2.30 (m, 2H), 2.33 (s, 3H), 2.14-2.02 (m, 3H), 1.95-1.83 (m, 2H), 1.01 (d, 6H).

[0537] Example 67, N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(((4S,6R)-6-methylazepan-4-yl)oxy)pyrazine-2-amine or N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(((4R,6R)-6-methylazepan-4-yl)oxy)pyrazine-2-amine or N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(((4R,6S)-6-methylazepan-4-yl)oxy)pyrazine-2-amine or N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(((4S,6S)-6-methylazepan-4-yl)oxy)pyrazine-2-amine and

[0538] Example 68, N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(((4R,6R)-6-methylazepan-4-yl)oxy)pyrazine-2-amine or N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(((4S,6R)-6-methylazepan-4-yl)oxy)pyrazine-2-amine or N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(((4R,6S)-6-methylazepan-4-yl)oxy)pyrazine-2-amine or N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(((4S,6S)-6-methylazepan-4-yl)oxy)pyrazine-2-amine [ka]

[0539] Step 1: Synthesis of (R)-3-methyl-5-oxoazepane-1-carboxylate tert-butyl and (S)-3-methyl-5-oxoazepane-1-carboxylate tert-butyl

[0540] 3-methyl-5-oxoazepane-1-carboxylate tert-butyl (1 g) was separated by SFC (Method C, 75 / 25) to obtain (R)-3-methyl-5-oxoazepane-1-carboxylate tert-butyl or (S)-3-methyl-5-oxoazepane-1-carboxylate tert-butyl (360 mg) with peak 1, and (S)-3-methyl-5-oxoazepane-1-carboxylate tert-butyl or (R)-3-methyl-5-oxoazepane-1-carboxylate tert-butyl (410 mg) with peak 2.

[0541] Step 2: Synthesis of (3R)-5-hydroxy-3-methylazepane-1-carboxylate tert-butyl or (3S)-5-hydroxy-3-methylazepane-1-carboxylate tert-butyl

[0542] To the stirred MeOH (5 ml) solution of peak 1 (360 mg, 1.58 mmol) from step 1, NaBH4 (508 mg, 13.4 mmol) was added under N2 at room temperature, and the reaction mixture was stirred for 0.5 hours. The mixture was diluted with ELISA, washed with water and brine, and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain the title compound (350 mg) as a pale yellow oil. LCMS m / z = 174 [M -56+H] + .

[0543] Step 3: Synthesis of (3R,5S)-5-((6-chloropyrazine-2-yl)oxy)-3-methylazepane-1-carboxylate tert-butyl, or (3R,5R)-5-((6-chloropyrazine-2-yl)oxy)-3-methylazepane-1-carboxylate tert-butyl, or (3S,5S)-5-((6-chloropyrazine-2-yl)oxy)-3-methylazepane-1-carboxylate tert-butyl, or (3S,5R)-5-((6-chloropyrazine-2-yl)oxy)-3-methylazepane-1-carboxylate tert-butyl

[0544] Following the procedure described in Step 1 of Example 5, (3R)-5-((6-chloropyrazine-2-yl)oxy)-3-methylazepane-1-carboxylate tert-butyl or (3S)-5-((6-chloropyrazine-2-yl)oxy)-3-methylazepane-1-carboxylate tert-butyl was obtained from the compound of Step 2 and 2,6-dichloropyrazine as 360 mg, 75% yellow oil. The racemic product was separated by chiral-SFC (Method E, 75 / 25) to obtain peak 1 (160 mg) and peak 2 (180 mg). LCMS m / z = 286 [M -56+H] + .

[0545] Step 4: (3R,5S)-5-((6-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-3-methylazepane-1-carboxylate tert-butyl, or (3R,5R)-5-((6-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-3-azepane-1-carboxylate tert-butyl Synthesis of (3S,5S)-5-((6-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-3-azepan-1-carboxylate tert-butyl, or (3S,5R)-5-((6-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-3-azepan-1-carboxylate tert-butyl

[0546] The title compound was obtained as a pale yellow solid, 160 mg, 64%, from peak 1 of step 3 and 5-(difluoromethoxy)-1H-pyrazole-3-amine, following the procedure described in step 2 of Examples 19 and 20. LCMS m / z = 455 [M + H] + .

[0547] Step 5: Synthesis of N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(((4S,6R)-6-methylazepan-4-yl)oxy)pyrazine-2-amine or N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(((4R,6R)-6-methylazepan-4-yl)oxy)pyrazine-2-amine or N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(((4R,6S)-6-methylazepan-4-yl)oxy)pyrazine-2-amine or N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(((4S,6S)-6-methylazepan-4-yl)oxy)pyrazine-2-amine

[0548] Except for using HPLC (Method B), the title compound (Example 67) was obtained from the compound in Step 4 as 11.3 mg, 14.5% yellow solid, following the same procedure as described in Step 3 of Example 3. LCMS m / z = 355 [M + H] + . 1 H-NMR (400 MHz, DMSO-d6) δ ppm 11.96 (br s, 1H), 8.39 (s, 1H), 7.73 (s, 1H), 7.53 (s, 1H), 7.26 (t, 1H), 6.01 (s, 1H), 5.16-5.11 (m, 1H), 3.09-2.97 (m, 3H), 2.66-2.54 (m, 1H), 2.37-2.28 (m, 1H), 2.20-2.04 (m, 1H), 2.03-1.86 (m, 2H), 1.67-1.61(m, 1H), 0.91 (d, 3H).

[0549] Step 6: (3R,5R)-5-((6-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-3-methylazepane-1-carboxylate tert-butyl, or (3R,5S)-5-((6-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-3-azepane-1-carboxylate tert-butyl Synthesis of (3S,5S)-5-((6-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-3-azepan-1-carboxylate tert-butyl, or (3S,5R)-5-((6-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-3-azepan-1-carboxylate tert-butyl

[0550] The title compound was obtained as 110 mg, 57% pale yellow oil from peak 2 of step 3 and 5-(difluoromethoxy)-1H-pyrazole-3-amine, following the procedure described in step 2 of Examples 19 and 20. LCMS m / z = 455 [M + H] + .

[0551] Step 7: Synthesis of N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(((4R,6R)-6-methylazepan-4-yl)oxy)pyrazine-2-amine or N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(((4S,6R)-6-methylazepan-4-yl)oxy)pyrazine-2-amine or N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(((4R,6S)-6-methylazepan-4-yl)oxy)pyrazine-2-amine or N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(((4S,6S)-6-methylazepan-4-yl)oxy)pyrazine-2-amine

[0552] The title product (Example 68) was obtained as a yellow solid (42.4 mg, 54%) from the product of step 6 according to the procedure described in step 5. LCMS m / z = 355 [M + H]+ . 1 H-NMR (400 MHz, DMSO-d6) δ ppm 11.75 (br s, 1H), 8.69 (br s, 1H), 7.75 (s, 1H), 7.58 (s, 1H), 7.26 (t, 1H), 5.99 (s, 1H), 5.35-5.29 (m, 1H), 3.18-3.14 (m, 1H), 3.10-3.05 (m, 1H), -3.03-2.97 (m, 1H), 2.71-2.67 (m, 1H), 2.22-2.00 (m, 4H), 1.86-1.81 (m, 1H), 0.91 (d, 3H).

[0553] Example 69, N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(((4S,6S)-6-methylazepan-4-yl)oxy)pyrazine-2-amine or N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(((4R,6S)-6-methylazepan-4-yl)oxy)pyrazine-2-amine or N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(((4R,6R)-6-methylazepan-4-yl)oxy)pyrazine-2-amine or N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(((4S,6R)-6-methylazepan-4-yl)oxy)pyrazine-2-amine and

[0554] Example 70, N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(((4R,6S)-6-methylazepan-4-yl)oxy)pyrazine-2-amine or N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(((4S,6S)-6-methylazepan-4-yl)oxy)pyrazine-2-amine or N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(((4R,6R)-6-methylazepan-4-yl)oxy)pyrazine-2-amine or N-(5-(difluoromethoxy)-1H-pyrazole-3-yl)-6-(((4S,6R)-6-methylazepan-4-yl)oxy)pyrazine-2-amine [ka]

[0555] Step 1: Synthesis of (3S,5S)-5-((6-chloropyrazine-2-yl)oxy)-3-methylazepane-1-carboxylate tert-butyl and (3S,5R)-5-((6-chloropyrazine-2-yl)oxy)-3-methylazepane-1-carboxylate tert-butyl, or (3R,5S)-5-((6-chloropyrazine-2-yl)oxy)-3-methylazepane-1-carboxylate tert-butyl and (3R,5R)-5-((6-chloropyrazine-2-yl)oxy)-3-methylazepane-1-carboxylate tert-butyl

[0556] Following the procedure described in Step 1 of Example 39, (3S)-5-((6-chloropyrazine-2-yl)oxy)-3-methylazepan-1-carboxylate tert-butyl or (3R)-5-((6-chloropyrazine-2-yl)oxy)-3-methylazepan-1-carboxylate tert-butyl was obtained as a yellow oily substance in a concentration of 340 mg, 65%. This was then subjected to chiral SFC (column: OJ). Further purification was performed using a 20×250mm, 10μm (Daicel) column, with a column temperature of 35℃, mobile phase: CO2 / IPA [0.5% NH3 (7M in MeOH)] = 95 / 5, flow rate: 90g / min, and back pressure: 100 bar to obtain peak 1 (3S,5S)-5-((6-chloropyrazine-2-yl)oxy)-3-methylazepan-1-carboxylate tert-butyl or (3S,5R)-5-((6-chloropyrazine-2-yl)oxy)-3-methylazepan-1-carboxylate tert-butyl or (3R,5R)-5-((6-chloropyrazine- 150 mg of 2-yl)oxy)-3-methylazepane-1-carboxylate tert-butyl was obtained, along with peak 2 (3S,5R)-5-((6-chloropyrazine-2-yl)oxy)-3-methylazepane-1-carboxylate tert-butyl or (3S,5S)-5-((6-chloropyrazine-2-yl)oxy)-3-methylylazepane-1-carboxylate tert-butyl or (3R,5S)-5-((6-chloropyrazine-2-yl)oxy)-3-methylazepane-1-carboxylate tert-butyl or (3R,5R)-5-((6-chloropyrazine-2-yl)oxy)-3-methylazepane-1-carboxylate tert-butyl (130 mg). LCMS m / z = 286 [M + H] + .

[0557] Step 2: Synthesis of (3S,5S)-5-((6-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-3-methylazepan-1-carboxylate tert-butyl or (3S,5R)-5-((6-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-3-azepan-1-carboxylate tert-butyl or (3R,5S)-5-((6-((5-((difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine-2-yl)oxy)-3-azepan-1-carboxylate tert-butyl or (3R,5R)-5-((6-((5-((5-(difluoromethoxy)-1H-pyrazole-3-yl)amino)pyrazine...

Claims

1. Compound of formula (I), 【Chemistry 226】 or a pharmaceutically acceptable salt thereof During the ceremony, R １ is CN, C １ -C ４ alkyl, C １ -C ４ alkoxy, -(C(R ｄ )) ２ )) ｐ -C ３ -C １０ cycloalkyl, O(C(R ｄ )) ２ )) ｐ -C ３ -C １０ cycloalkyl, -(C(R ｄ )) ２ )) ｐ -4- to 12-membered heterocyclyl, -O(C(R ｄ )) ２ )) ｐ -4- to 12-membered heterocyclyl, -(C(R ｄ )) ２ )) ｐ -6- to 12-membered aryl, and -(C(R ｄ )) ２ )) ｐ -4- to 12-membered heteroaryl, selected from the group consisting of, said C １ -C ４ alkyl, C １ -C ４ alkoxy, C ３ -C １０ cycloalkyl, C ３ -C １０ cycloalkoxy, and 6- to 12-membered aryl may each be substituted with 1 to 4 R ａ , said 4- to 12-membered heterocyclyl and 4- to 12-membered heteroaryl each independently have 1 to 4 ring heteroatoms selected from the group consisting of O, S, N, and NR ｂ and may further be substituted with 1 to 4 R ａ on the ring carbon, X ２ However, -O-, -(C(R ｄ ) ２ ) ｎ -, -NR ｂ -, -NR ｂ - (C(R ｃ ) ２ ) ｍ -, -O(C(R ｃ ) ２ ) ｍ -, and -(C(R ｄ ) ２ ) ｎ Selected from the group consisting of -O-, R ２ However, C １ ~C ４ Selected from alkyl and ring A, and C １ ~C ４ The alkyl group consists of 1 to 4 groups independently selected from the group consisting of D, halo, CN, and OH, and / or O, S, N, and NR ｂ They may be substituted with one group of a 5-6 membered heteroaryl having 1-3 ring heteroatoms, each independently selected from the group consisting of the above, or X ２ and R ２ Together, they form a ring B bonded to pyrazine, and ring B is C ３ ~C １０ The C is a cycloalkyl or a 4-12 membered heterocycline. ３ ~C １０ Cycloalkyl groups with 1 to 4 R ａ The 4-12 member heterocyclyl may be substituted with O, S, N, and NR ｂ Each of the following groups independently selects 1 to 4 ring heteroatoms, and further has 1 to 4 R on the ring carbon ａ It may be replaced with, Ring A is C ３ ~C １０ Selected from the group consisting of cycloalkyl, 4-12 membered heterocyclyl, 6-12 membered aryl, and 4-12 membered heteroaryl, the C ３ ~C １０ Cycloalkyl groups and 6-12 membered aryl groups each have 1-4 R ａ They may be substituted with, and the 4-12 member heterocyclyl and 4-12 member heteroaryl are O, S, N, and NR ｂ Each of the following groups independently selects 1 to 4 ring heteroatoms, and further has 1 to 4 R on the ring carbon ａ It may be replaced with, R ３ However, H, D, Halo, OH, CN, C １ ~C ４ Alkyl, -SO ２ C １ ~C ４ Alkyl and -S(O)NR ｂ -C １ ~C ４ Selected from the group consisting of alkyl groups, R ４ However, H, D, C １ ~C ４ Alkyl and C ３ -C １０ Selected from the group consisting of cycloalkyl groups, R ５ is selected from the group consisting of H, D, and C １ -C ４ alkyl Each R ａ is independently selected from the group consisting of D, halo, OH, CN, N(R ｂ ), ２ C １ -C ４ alkyl, and C １ -C ４ alkoxy, or two Rs bonded to the same atom form =O, and the C ａ -C １ -C ４ alkyl and C １ -C ４ alkoxy may each be substituted with 1 to 4 groups independently selected from the group consisting of D, halo, OH, and CN, Each R ｂ However, H, D, and C １ ~C ４ Independently selected from the group consisting of alkyls, the C １ ~C ４ The alkyl group may be substituted with 1 to 4 D atoms. Each R ｃ However, H, D, C １ ~C ４ Alkyl, C １ ~C ４ Alkoxy, C ３ ~C １０ Independently selected from the group consisting of cycloalkyl and 4- to 12-membered heterocyclyl, the C １ ~C ４ Alkyl, C １ ~C ４ Alkoxy, and C ３ ~C １０ Each cycloalkyl group may be substituted with 1 to 4 groups independently selected from the group consisting of halo, OH, and CN, and the 4 to 12-membered heterocyclyl may be O, S, N, and NR ｂ It has 1 to 4 ring heteroatoms independently selected from the group consisting of , and may further be substituted on the ring carbon with 1 to 4 groups independently selected from the group consisting of halo, OH, and CN. Each R ｄ However, H, D, and C １ ~C ４ Independently selected from the group consisting of alkyls, m is 1 to 4, n is between 1 and 4, A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein p is between 0 and 3.

2. The aforementioned compound is a compound of formula (II): 【Chemistry 227】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. In the formula, X ２ However, -O-, -(CHR ｄ ) ｎ -, -NR ｂ -, -NR ｂ - (CHR ｃ ) ｍ -, and -O-(CHR) ｃ ) ｍ A compound according to claim 1 or 2, selected from the group consisting of -.

4. The aforementioned compound is a compound of formula (III): 【Chemistry 228】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

5. In the formula, ring B is C ４ ~C ６ The C is a cycloalkyl or a 4- to 8-membered heterocycline. ４ ~C ６ Cycloalkyl groups with 1 to 4 R ａ The 4-8 member heterocyclyl may be substituted with O, S, N, and NR ｂ Each of the following groups independently selects 1 to 4 ring heteroatoms, and further has 1 to 4 R on the ring carbon ａ The compound according to any one of claims 1, 3, and 4, which may be substituted with

6. In the formula, R ３ However, H, C １ ~C ４ Alkyl, CN, -SO ２ C １ ~C ４ Alkyl and -S(O)NH-C １ ~C ４ A compound according to any one of claims 1 to 5, selected from the group consisting of alkyl groups.

7. In the formula, R ４ However, H, C １ ~C ４ Alkyl and C ３ ~C ６ A compound according to any one of claims 1 to 6, selected from the group consisting of cycloalkyl groups.

8. In the formula, R ５ The compound according to any one of claims 1 to 7, wherein H is present.

9. The aforementioned compound is a compound of formula (IVa): 【Chemistry 229】 or a pharmaceutically acceptable salt thereof, During the ceremony, R １ However, C １ ~C ４ Alkyl, C １ ~C ４ Alkoxy, C ３ ~C ８ Selected from the group consisting of cycloalkyl and 4- to 10-membered heterocyclines, the C １ ~C ４ Alkyl, C １ ~C ４ Alkoxy, and C ３ ~C ８ Each cycloalkyl group has 1 to 3 R ａ The 4-10 member heterocyclyl may be substituted with O, S, N, and NR ｂ Each of the following groups independently selects 1 to 3 ring heteroatoms, and further has 1 to 3 R on the ring carbon ａ It may be replaced with, X ２ However, -O-, -O(C(R ｃ ) ２ ) ｍ -, and -(C(R ｄ ) ２ ) ｎ Selected from the group consisting of -O-, R ２ However, C １ ~C ４ Selected from alkyl and ring A, and C １ ~C ４ The alkyl group may be substituted with 1 to 3 groups independently selected from the group consisting of halo, CN, and OH. Ring A is C ３ ~C ８ Selected from the group consisting of cycloalkyl, 4-10 membered heterocyclyl, 6-10 membered aryl, and 4-10 membered heteroaryl, the C ３ ~C ８ Cycloalkyl and 6-10 membered aryl groups each have 1-3 R ａ They may be substituted with, and the 4-10 member heterocyclyl and 4-10 member heteroaryl are O, S, N, and NR ｂ Each of the following groups independently selects 1 to 3 ring heteroatoms, and further has 1 to 3 R on the ring carbon ａ It may be replaced with, R ３ However, H or C １ ~C ４ It is alkyl, Each R ａ However, halo, OH, CN, C １ ~C ４ Alkyl and C １ ~C ４ R is independently selected from the group consisting of alkoxys, or two R atoms bonded to the same atom. ａ ga = O, and the C １ ~C ４ Alkyl and C １ ~C ４ The alkoxy may be substituted with one to three groups independently selected from the group consisting of halo, OH, and CN. Each R ｂ However, independently H or C １ ~C ４ Alkyl, and the C １ ~C ４ The alkyl group may be substituted with 1 to 4 D atoms. Each R ｃ However, independently H or C １ ~C ４ It is alkyl, Each R ｄ However, independently H or C １ ~C ４ It is alkyl, m is 1 or 2, The compound according to claim 1, wherein n is 1 or 2.

10. The aforementioned compound is a compound of formula (IVb): 【Chemistry 230】 or a pharmaceutically acceptable salt thereof, During the ceremony, R １ However, C １ ~C ４ Alkyl, C １ ~C ４ Alkoxy, C ３ ~C ８ Selected from the group consisting of cycloalkyl and 4- to 10-membered heterocyclines, the C １ ~C ４ Alkyl, C １ ~C ４ Alkoxy, and C ３ ~C ８ Each cycloalkyl group has 1 to 3 R ａ The 4-10 member heterocyclyl may be substituted with O, S, N, and NR ｂ Each of the following groups independently selects 1 to 3 ring heteroatoms, and further has 1 to 3 R on the ring carbon ａ It may be replaced with, X ２ However, -NR ｂ - or - NR ｂ - (C(R ｃ ) ２ ) ｍ - and R ２ However, C １ ~C ４ Selected from alkyl and ring A, and C １ ~C ４ The alkyl group may be substituted with 1 to 3 groups independently selected from the group consisting of halo, CN, and OH. Ring A is C ３ ~C ８ Selected from the group consisting of cycloalkyl, 4-10 membered heterocyclyl, 6-10 membered aryl, and 4-10 membered heteroaryl, the C ３ ~C ８ Cycloalkyl and 6-10 membered aryl groups each have 1-3 R ａ They may be substituted with, and the 4-10 member heterocyclyl and 4-10 member heteroaryl are O, S, N, and NR ｂ Each of the following groups independently selects 1 to 3 ring heteroatoms, and further has 1 to 3 R on the ring carbon ａ It may be replaced with, R ３ However, H or C １ ~C ４ It is alkyl, Each R ａ However, halo, OH, CN, C １ ~C ４ Alkyl and C １ ~C ４ R is independently selected from the group consisting of alkoxys, or two R atoms bonded to the same atom. ａ ga = O, and the C １ ~C ４ Alkyl and C １ ~C ４ The alkoxy may be substituted with one to three groups independently selected from the group consisting of halo, OH, and CN. Each R ｂ However, independently H or C １ ~C ４ Alkyl, and the C １ ~C ４ The alkyl group may be substituted with 1 to 4 D atoms. Each R ｃ However, independently H or C １ ~C ４ It is alkyl, m is 1 or 2, The compound according to claim 1, wherein n is 1 or 2.

11. In the formula, R １ However, CN, C １ -C ４ Alkyl, C １ -C ４ Alkoxy, -C ３ -C ６ Cycloalkyl, -(CH ２ )-C ３ -C ６ Cycloalkyl, -O(CH ２ )-C ３ -C ６ Cycloalkyl, 4-6 membered heterocyclyl, -O- (4-6 membered heterocyclyl), -O (CH ２ )-(4-6 member heterocyclyl), and-(CH ２ ) Selected from the group consisting of -phenyl, the C １ -C ４ Alkyl, C １ -C ４ Alkoxy, C ３ -C ６ Cycloalkyl and phenyl groups have 1 to 3 R groups. ａ They may be substituted with, and the 4-6 member heterocyclyl may be O, S, N, and NR ｂ Each ring has 1 to 4 ring heteroatoms independently selected from the group consisting of and further has 1 to 3 R on the ring carbon ａ The compound according to any one of claims 1 to 10, which may be substituted with

12. In the formula, R ２ However, C may be substituted with 1 to 4 OH groups. １ ~C ４ The compound according to any one of claims 1 and 9 to 11, wherein it is alkyl.

13. In the formula, ring A is O, S, N, and NR ｂ A 4-10 membered heterocyclil having 1-3 ring heteroatoms independently selected from the group consisting of, and further having 1-3 R on the ring carbon ａ The compound according to any one of claims 1 to 3 and 9 to 12, which may be substituted with

14. In the formula, R ａ However, halo, OH, CN, N(R) ｂ ) ２ , C １ ~C ４ Alkyl and C １ ~C ４ Selected from the group consisting of alkoxys, or two R atoms bonded to the same atom. ａ The compound according to any one of claims 1 to 13, wherein it forms =O.

15. The aforementioned compound is a compound of formula (Va): 【Chemistry 231】 or a pharmaceutically acceptable salt thereof, During the ceremony, R １ However, C １ ~C ４ Alkyl or C １ ~C ４ It is an alkoxy with 1 to 3 R ａ It may be replaced with, or O, S, N, and NR ｂ A 4-10 membered heterocyclil having 1-3 ring heteroatoms independently selected from the group consisting of, and further having 1-3 R on the ring carbon ａ It may be replaced with, R ２ However, ring A is selected from the group consisting of phenyl, 4-6 membered heterocyclyl, and 6 membered heteroaryl, and the phenyl is 1-3 R ａ It may be substituted with, and the 4-6 member heterocyclyl is O, S, N, and NR ｂ Each of the following groups independently selects 1 to 3 ring heteroatoms, and further has 1 to 4 R on the ring atom ａ It may be substituted with, and the six-membered heteroaryl has 1 to 3 ring heteroatoms independently selected from the group consisting of O, S, and N, and further has 1 to 3 R on the ring carbon ａ It may be replaced with, R ３ However, H or C １ ~C ４ It is alkyl, Each R ａ However, halo, OH, CN, C １ ~C ４ Alkyl and C １ ~C ４ R is independently selected from the group consisting of alkoxys, or two R atoms bonded to the same atom. ａ However, it forms =O, Each R ｂ However, independently H or C １ ~C ４ The compound according to any one of claims 1, 2, and 9, wherein it is alkyl.

16. The compound is a compound of formula (VIa) or (VIb): 【Chemistry 232】 The compound according to any one of claims 1, 2, 9, and 15, or a pharmaceutically acceptable salt thereof.

17. The aforementioned compound is a compound of formula (Vb): 【Chemical 233】 or a pharmaceutically acceptable salt thereof, During the ceremony, R １ However, C １ ~C ４ Alkyl or C １ ~C ４ It is an alkoxy with 1 to 3 R ａ It may be replaced with, or O, S, N, and NR ｂ A 4-10 membered heterocyclil having 1-3 ring heteroatoms independently selected from the group consisting of, and further having 1-3 R on the ring carbon ａ It may be replaced with, R ２ However, ring A is selected from the group consisting of phenyl, 4-6 membered heterocyclyl, and 6 membered heteroaryl, and the phenyl is 1-3 R ａ It may be substituted with, and the 4-6 member heterocyclyl is O, S, N, and NR ｂ Each ring has 1 to 3 ring heteroatoms independently selected from the group consisting of and further has 1 to 4 R on the ring carbon. ａ It may be substituted with, and the six-membered heteroaryl has 1 to 3 ring heteroatoms independently selected from the group consisting of O, S, and N, and further has 1 to 3 R on the ring carbon ａ It may be replaced with, R ３ However, H or C １ ~C ４ It is alkyl, Each R ａ However, halo, OH, CN, C １ ~C ４ Alkyl and C １ ~C ４ R is independently selected from the group consisting of alkoxys, or two R atoms bonded to the same atom. ａ However, it forms =O, Each R ｂ However, independently H or C １ ~C ４ A compound according to any one of claims 1, 2, and 10, wherein the compound is alkyl.

18. The compound is a compound of formula (VIc) or (VId): 【Chemistry 234】 The compound according to any one of claims 1, 2, 10, and 17, or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof.

20. A method for treating cancer, comprising administering an effective amount of a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 19, to a subject in need of cancer treatment.

21. The method according to claim 20, wherein the cancer is breast cancer.

22. The method according to claim 21, wherein the breast cancer is progressing despite treatment with a CDK4 / 6 inhibitor.

23. The method according to claim 21 or 22, further comprising administering an effective amount of a CDK4 / 6 inhibitor.

24. The method according to claim 20, wherein the cancer is selected from the group consisting of ovarian cancer, endometrial cancer, gastric cancer, esophageal cancer, breast cancer, pancreatic cancer, and prostate cancer.

25. The method according to claim 24, wherein the cancer has CCNE1 overexpression and / or amplification.

26. The method according to claim 24 or 25, wherein the cancer is progressing despite platinum-based drug therapy.

27. The method according to any one of claims 20 to 22 and 24 to 26, further comprising administering to the subject an effective amount of carboplatin, ribociclib, fulvestrant, or a combination thereof.

28. The method according to any one of claims 20 to 22 and 24 to 26, wherein a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 19, is administered to the subject in combination with an effective amount of carboplatin, ribociclib, fulvestrant, or a combination thereof.

29. A method for treating a patient in whom the expression level of CCNE1 is amplified and who has solid tumor cancer or is at risk of developing solid tumor cancer, the method comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 19.

30. The method according to claim 29, wherein the solid tumor cancer is at least one of the following: uterine cancer (including uterine carcinosarcoma and endometrial carcinoma of the uterine body), endometrial cancer, breast cancer (including invasive breast carcinoma, TNBC (triple-negative breast cancer), ER (estrogen receptor) + HER2 (human epidermal growth factor 2)-breast cancer, and HER2+ breast cancer), ovarian cancer (e.g., ovarian serous cystadenocarcinoma), gastric cancer (including gastric adenocarcinoma), gastric cancer (including gastrointestinal stromal tumor), colorectal cancer, pancreatic cancer, kidney cancer, head and neck cancer, liver cancer, prostate cancer, skin cancer, lymphoma (including B-cell lymphoma), sarcoma, esophageal cancer (including esophageal carcinoma), bladder cancer (including urothelial carcinoma of the bladder), lung cancer (including squamous cell carcinoma of the lung and non-small cell lung cancer, e.g., EGFRm (epidermal growth factor receptor variant) + non-small cell lung cancer), cholangiocarcinoma, adrenocortical carcinoma, or mesothelioma.

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