Bifunctional compounds containing pyrido[2,3-d]pyrimidin-7(8h)-one derivatives for degradation of cyclin-dependent kinases 2, 4 and 6 via the ubiquitin proteasome pathway

Abstract

The present disclosure provides certain bifunctional compounds that cause the degradation of cyclin-dependent kinase 2 (CDK2), cyclin-dependent kinase 4 (CDK4), and cyclin-dependent kinase 6 (CDK6) via the ubiquitin proteasome pathway, and are thus useful in the treatment of diseases mediated by CDK2 and / or CDK4 and / or CDK6. Also provided are pharmaceutical compositions containing such compounds and methods for making such compounds.

Description

Cross-references to related applications

[0001] This PCT international patent application claims the benefit of U.S. Provisional Application No. 63 / 613,023, filed on December 20, 2023; the entire contents of which are hereby incorporated by reference. Technical Field

[0002] This disclosure provides certain bifunctional compounds containing pyrido[2,3-d]-pyrimidine-7(8h)-one derivatives that induce the degradation of cyclin-dependent kinases 2, 4, and 6 (CDK 2 / 4 / 6) via the ubiquitin-proteasome pathway, and thus can be used to treat diseases mediated by these kinases. Pharmaceutical compositions containing such compounds and methods for preparing such compounds are also provided. Background Technology

[0003] Cyclin-dependent kinases (CDKs) are essential cellular serine / threonine kinases that play a crucial role in coordinating signaling events such as DNA replication and protein synthesis to ensure accurate division and proliferation of eukaryotic cells. The regulation of CDK activity is tightly controlled by fluctuations in the levels of various cyclins that form heterodimeric complexes with CDKs to activate them. Of the 21 identified CDKs, the CDK1 / cyclin B, CDK2 / cyclin E, CDK2 / cyclin A, CDK4 / cyclin D, and CDK6 / cyclin D complexes are well-known important regulators of cell cycle progression. Other CDKs are involved in regulating gene transcription, DNA repair, differentiation, and apoptosis (see Morgan, DO Annu. Rev. Cell. Dev. Biol. [Annual Review of Cell and Developmental Biology] (1997) 13: 261-291). In a typical model of the cell cycle, mitogenic signaling upregulates D-type cyclins, which directly bind to and activate CDK4 / 6. The active CDK4 / 6-cyclin D complex partially phosphorylates Rb, thereby disrupting the Rb / E2F interaction and relieving the inhibition of E2F activity, leading to the upregulation of cyclin E (a CDK2 activator). Cdk2-cyclin E further hyperphosphorylates Rb, thereby releasing E2F to transcribe genes required for entry into S phase. During S phase, cyclin E is degraded, and CDK2 forms a complex with cyclin A to promote phosphorylation of substrates essential for DNA replication and inactivation of E2F, thus completing S phase (Asghar et al. Nat. Rev. Drug. Discov. [Nature Reviews: Drug Discovery] (2015) 14: 130-146). The CDK1-cyclin A and CDK1-cyclin B complexes are activated in late S phase and G2 phase, respectively, to drive the transition to mitosis and the completion of mitosis (Katsuno et al., 2009; Lindqvist et al., 2009; Lohka et al., 1988).

[0004] Because CDKs play a crucial role in regulating the cell cycle and other essential cellular processes, increased or transiently abnormal CDK activity has been shown to promote tumorigenesis and disease progression (Cordon-Cardo C. Am. J. Pathol. [American Journal of Pathology] (1995) 147:545-560; Karp JE, Broder S. Nat. Med. [Nature Medicine] (1995) 1:309-320; Hall M, Peters G. Adv. Cancer Res. [Advances in Cancer Research] (1996) 68:67-108). Genetic alterations in the CDK-cyclin complex and the proteins that regulate them are widespread in various cancers and are often associated with poor clinical outcomes. Common alterations include amplification / overexpression of cyclin D, cyclin E, CDK4, and CDK6; loss of Rb; deficiency of CDK inhibitory regulators (such as p16, p21, p27); and FBXW7 (the SCF responsible for cyclin E degradation). Fbw7 Loss-of-function mutations in components of ubiquitin E3 ligase (Smalley et al. Cancer Res. (2008) 68: 5743-52).

[0005] Over the past two decades, there has been considerable interest in developing CDK inhibitors for therapeutic purposes. Selective and reversible inhibitors of CDK4 and CDK6 (such as palbociclib, ribociclib, and abeciclib), when combined with endocrine therapy, have revolutionized the management of hormone receptor-positive (HR+) metastatic breast cancer (MBC). Ongoing clinical trials are also investigating these CDK4 / 6 inhibitors as monotherapy or in combination with other therapeutic agents for various cancers. (O'Leary et al., Nature Reviews (2016) 13:417-430).

[0006] Despite the significant clinical efficacy of CDK4 / 6 inhibitors in ER-positive metastatic breast cancer, limitations exist. A major drawback is the development of primary or acquired resistance over time. A key mechanism of resistance involves aberrant activation of CDK2. This may be due to overactivation of the CDK2 / cyclin E complex caused by elevated cyclin E expression (Asghar, U. et al. Clin. Cancer Res. (2017) 23:5561), or due to the formation of an atypical CDK2 / cyclin D1 complex in response to CDK4 / 6 inhibition (Herrera-Abreu MT et al., Cancer Res. (2006) 15: 2301), thus bypassing the need for CDK4 / 6 for cell cycle reentry. In addition, it has been found that acquired CDK6 amplification can promote resistance to CDK4 / 6 inhibitors in breast cancer and lead to loss of ER dependence (Yang, C. et al., Oncogene (2017) 36, 2255-2264).

[0007] Taking these factors into account, developing a small molecule inhibitor or a proteolytic chimeric molecule (PROTAC) targeting CDK2 / 4 / 6 could offer therapeutic opportunities to improve overall treatment efficacy.

[0008] PROTAC is a bifunctional molecule consisting of a target protein recruitment moiety and an E3 ligase ligand (linked by a biocompatible linker). PROTAC brings the target protein and the E3 ligase into close proximity, inducing ubiquitination of the target protein and subsequent degradation of the target protein by the proteasome.

[0009] Compared to small molecule drugs that typically bind to disease-associated proteins and inhibit their function, PROTACs exhibit several unique and attractive features, making them ideal drug candidates. For example, PROTACs have been shown to be more selective than their inhibitor counterparts, which may reduce off-target toxicity. Furthermore, PROTACs can undergo multiple rounds of target ubiquitination and degradation. Due to this catalytic mode of action, PROTACs can function at substoichiometric receptor occupancy rates. The E3 ligases used in PROTACs primarily include cereblon (CRBN), Von Hippel-Lindau-containing complexes (VHL), inhibitors of apoptosis proteins (IAP), and mouse two-microsome 2 (MDM2).

[0010] Therefore, there is a need for PROTACs capable of recruiting CDK2 / 4 / 6 to ubiquitin ligases, thereby inducing ubiquitination and proteasome degradation of these kinases. This disclosure addresses this and related needs. Summary of the Invention

[0011] In the first aspect, compounds having formula (I) or pharmaceutically acceptable salts thereof are provided:

[0012]

[0013] (I)

[0014] in:

[0015] R 1 It is a branched alkyl, a branched haloalkyl, a branched cyanoalkyl, a branched hydroxyalkyl, a branched alkoxyalkyl, a branched haloalkoxyalkyl, a cycloalkyl, or a bridged cycloalkyl; wherein the cycloalkyl and the bridged cycloalkyl are substituted by 0, 1, 2 or 3 groups independently selected from halogen, cyano, hydroxy, alkoxy and haloalkoxy.

[0016] R 2 It is hydrogen, alkyl, halogenated, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, or heterocyclic alkyl;

[0017] R 2a It is hydrogen or deuterium;

[0018] Hy is a cycloalkylene, arylene, heteroarylene, heterocyclic, bicyclic, spirocyclic, bridged, or fused heterocyclic ring, wherein each of the above rings is independently selected from hydrogen, deuterium, alkyl, halogen, haloalkyl, alkoxy, hydroxy, and cyano. a R b and R c replace;

[0019] The degradation determinant is selected from the following E3 ubiquitin ligase ligands:

[0020] (a) Groups having formula (i):

[0021]

[0022] (i); and

[0023] (b) Having a group of formula (ii):

[0024]

[0025] (ii);

[0026] Ya It is CH or N;

[0027] Z a It is a bond, -CH2-, -NH-, -O-, or -NHC(O)-, where the NH in -NHC(O)- is attached to Y. a ;

[0028] Ring A is a group having formula (a) or (b):

[0029] ;

[0030] in:

[0031] R aa R bb R cc and R dd It is independently selected from hydrogen, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy and cyano;

[0032] R 4 and R 5 It is independently hydrogen or alkyl; or R 4 and R 5 Together with the carbon attached to them, they form >C=O;

[0033] M is -O- or -NR 6 -;and

[0034] R 6 It is hydrogen or alkyl;

[0035] Ring B is a phenylene, a cycloimino, a 5- or 6-membered monocyclic heteroarylene, or a 9- or 10-membered fused bicyclic heteroarylene, wherein one to three ring atoms of each heteroarylene ring are independently selected from nitrogen, oxygen, or sulfur heteroatoms, and further wherein the phenylene, cycloimino, and each heteroarylene are independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halogen, haloalkyl, haloalkoxy, and cyano groups. ee and R ff Replace; and

[0036] Z is -O-, -NR 3 - (where R) 3 The R group is composed of hydrogen or alkyl, cycloalkylene, phenylene, monocyclic heteroarylene, unsaturated heterocyclic, heterocyclic, bridged heterocyclic, or spirocyclic, and each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, and cyano. d and R e replace;

[0037] alk is an R group selected from hydrogen, fluorine, and cyano groups. fSubstituted C3 to C6 alkenyl group; C3 to C6 alkylene group or C3 to C6 heteroalkylene group, wherein the C3 to C6 alkylene group and the C3 to C6 heteroalkylene group are R g R h and R i Replace, where R g Is it hydrogen, deuterium, or halogenated, R h It is a group consisting of hydrogen, deuterium, cycloalkyl, cycloalkyloxy, bridged cycloalkyl, halogen, haloalkoxy, alkoxy, hydroxyl, cyano, cyanoalkyl, cyanoalkyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, phenyl, heteroaryl, heterocyclic, heterocyclicoxy, heterocyclic carbonyl, or bridged heterocyclic (wherein the cycloalkyl group—either itself or as part of the cycloalkyloxy group, the bridged cycloalkyl, phenyl, heteroaryl, heterocyclic group—either itself or as part of the heterocyclicoxy or heterocyclic carbonyl group, and the bridged heterocyclic group are independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxyl, alkylcarbonyl, alkyloxycarbonyl, amino, alkylamino, dialkylamino, and cyano). 7 and R 8 Replace); or when R g and R h When R is attached to the same or adjacent carbon atom of the straight-chain portion of the C3 to C6 alkylene or C3 to C6 heteroalkylene, g and R h They can form cycloalkylene or heterocyclic alkylene groups together with the carbon atoms to which they are attached (where R is the carbon atom of the cycloalkylene group). g and R h The resulting cycloalkylene and heterocyclic groups are independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxyl, alkylcarbonyl, alkyloxycarbonyl, amino, alkylamino, dialkylamino, and cyano groups. 9 and R 10 (replace), and R i It is hydrogen or halogenated; and the straight-chain portion of the C3 to C6 alkenyl group, C3 to C6 alkylene group and C3 to C6 heteroalkylene group attached with Ar and Z contains at least three atoms;

[0038] Ar is a phenylene, monocyclic heteroarylene, heterocyclic, bridged heterocyclic, or spirocyclic ring, wherein each of the above rings is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, and cyano. j R k and R m Replace; or

[0039] Its pharmaceutically acceptable salt.

[0040] In a second aspect, a pharmaceutical composition is provided comprising a compound having formula (I) (or any of the embodiments described herein) or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

[0041] In a third aspect, a method is provided for treating a patient (preferably a patient requiring such treatment) with a disease mediated by CDK2 and / or CDK4 and / or CDK6, the method comprising administering to the patient (preferably a patient requiring such treatment) a therapeutically effective amount of a compound having formula (I) (or any of the embodiments described below) or a pharmaceutically acceptable salt thereof; or the pharmaceutical compositions thereof disclosed herein. In a first embodiment of the third aspect, the disease is cancer. In a second sub-embodiment of the third aspect, the disease is cancer selected from: lung cancer (e.g., adenocarcinoma, small cell lung cancer, non-small cell lung cancer, small cell carcinoma and non-small cell carcinoma, bronchial carcinoma, bronchial adenoma and / or pleural blastoma), skin cancer (e.g., melanoma, squamous cell carcinoma, Kaposi's sarcoma and / or Merkel cell skin cancer), bladder cancer, breast cancer, cervical cancer, colorectal cancer, small bowel cancer, colon cancer, rectal cancer, anal cancer, uterine cancer, etc. Endometrial cancer, gastric cancer, head and neck cancer (e.g., laryngeal cancer, hypopharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, lip cancer, and / or oral cancer), liver cancer (e.g., hepatocellular carcinoma and / or cholangiocarcinoma), ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gallbladder cancer, pancreatic cancer (e.g., pancreatic exocrine carcinoma), gastric cancer, thyroid cancer, parathyroid cancer, bone cancer, biliary tract cancer, vaginal cancer, astrocytoma, liposarcoma, glioblastoma, neuroblastoma, and / or renal cancer. In a third embodiment of the third aspect, the cancer is one that is resistant to CDK4 / 6 inhibitors via a CDK2-mediated mechanism, such as breast cancer. In a fourth embodiment of the third aspect, the disease is an autoimmune disease or a condition associated with an autoimmune disease, and the method comprises administering to the patient (preferably a patient requiring such treatment) a therapeutically effective amount of a compound having formula (I) (or any of its embodiments described below) or a pharmaceutically acceptable salt thereof. In some embodiments, the autoimmune disease or condition associated with an autoimmune disease is selected from rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), primary Sjögren's syndrome (pSS), multiple sclerosis (MS), Crohn's disease (CD), uveitis, pemphigus vulgaris, and sepsis. In a fifth embodiment of the third aspect, the disease is gout.

[0042] In a fourth aspect, a method is provided for treating noise-induced, chemotherapy-induced (cisplatin-induced), antibiotic-induced, or age-related hearing loss, the method comprising administering to a patient (preferably a patient requiring such treatment) a therapeutically effective amount of a compound having formula (I) (or any of the embodiments described herein) or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition thereof disclosed herein. In some embodiments, the amount of hearing loss is reduced compared to an age-matched control. In some embodiments, hearing loss is prevented compared to an age-matched control.

[0043] In the fifth aspect, a compound having formula (I) (or any of the embodiments thereof described herein) or a pharmaceutically acceptable salt thereof is provided for use in a therapeutic manner. In one embodiment of the fifth aspect, a compound having formula (I) (or any of the embodiments thereof disclosed herein) or a pharmaceutically acceptable salt thereof is used for use in the treatment of one or more diseases disclosed in the third and / or fourth aspects above.

[0044] In a sixth aspect, the use of a compound having formula (I) (or any of the embodiments thereof described herein) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a patient’s disease in which the activity of CDK2 and / or CDK4 and / or CDK6 contributes to the pathology and / or symptoms of the disease is provided. In one embodiment of the seventh aspect, the disease is one or more of the diseases disclosed in the third and / or fourth aspects above.

[0045] In a seventh aspect, a method is provided for degrading CDK2 / 4 / 6 in cells via the ubiquitin-proteasome pathway, the method comprising contacting the cells with a compound having formula (I) (or as disclosed herein in embodiments thereof). In one embodiment of the seventh aspect, CDK2 / 4 / 6 is degraded in cells in vitro. In another embodiment of the seventh aspect, CDK2 / 4 / 6 is degraded in cells in vivo. In yet another embodiment of the seventh aspect, CDK2 / 4 / 6 is degraded in cells of a patient.

[0046] Surprisingly, PROTAC with formula (I) containing the -Z-alk-Ar-linker was found to selectively degrade CDK2 / 4 / 6, but not CDK1.

[0047] In the foregoing aspects relating to cancer treatment, further embodiments are provided, including the administration of a compound of the first aspect and a compound having formula (I) or a pharmaceutically acceptable salt thereof (or any of the embodiments disclosed herein) or a pharmaceutical composition of the third aspect in combination with at least one additional anticancer agent. When using combination therapy, these agents may be administered simultaneously or sequentially. Detailed Implementation

[0048] definition:

[0049] Unless otherwise stated, the following terms used in this specification and claims are defined for the purposes of this application and have the following meanings:

[0050] "Alkyl" refers to a straight-chain or branched saturated monovalent hydrocarbon group having one to six carbon atoms, such as methyl, ethyl, propyl, 2-propyl, butyl, pentyl, etc.

[0051] "Alkenyl" refers to a straight-chain or branched monovalent hydrocarbon group containing two to six carbon atoms with a double bond, such as vinyl, propenyl, 2-propenyl, butenyl, pentenyl, etc.

[0052] "Alynyl" refers to a straight-chain or branched monovalent hydrocarbon group containing two to six carbon atoms with a triple bond, such as ethynyl, propynyl, 2-propynyl, butynyl, etc.

[0053] Unless otherwise stated, "alkylene" means a straight-chain or branched saturated divalent hydrocarbon group having one to six carbon atoms. When an alkylene contains three to six carbon atoms, it is also referred to herein as a C3 to C6 alkylene. Examples include, but are not limited to, methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, etc.

[0054] "Alkenyl" refers to a straight-chain or branched divalent hydrocarbon group containing two to six carbon atoms and a double bond, such as vinylidene and propenide. For clarity, when alkenyl contains three to six carbon atoms, it is also referred to herein as C3 to C6 alkenyl.

[0055] "Alkoxy" refers to -OR p Group (where R) p (These are alkyl groups as defined above), such as methoxy, ethoxy, propoxy, or 2-propoxy, n-butoxy, isobutoxy, or tert-butoxy.

[0056] "Alkoxyalkyl" refers to a straight-chain or branched monovalent hydrocarbon group having one to six carbon atoms that is substituted with an alkoxy group (as defined above). Representative examples include, but are not limited to, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, and methoxypropyl.

[0057] "Branched alkoxyalkyl" refers to a branched monovalent hydrocarbon group with three to six carbon atoms that has been replaced by an alkoxy group (as defined above). Representative examples include, but are not limited to, 3-methoxybut-2-yl and 1-(methoxymethyl)-2-methylpropyl.

[0058] "Alkoxycarbonyl" or "alkyloxycarbonyl" refers to -C(O)OR p Group (where R) pAlkyl groups as defined above, such as methoxycarbonyl, ethoxycarbonyl, etc.

[0059] "alkylcarbonylamino" refers to -NR p 'C(O)R p Group (where R) p It is an alkyl group, and R p ' is H or alkyl, as defined above), such as methyl carbonylamino, ethyl carbonylamino, etc.

[0060] "alkyl carbonyl" refers to -C(O)R p Group (where R) p (as defined in this article), such as methyl carbonyl, ethyl carbonyl, etc.

[0061] "Amino" refers to -NH2.

[0062] "Amino carbonyl" refers to -C(O)NH2.

[0063] "alkylaminocarbonyl" refers to -C(O)NHR p Group (where R) p Alkyl groups as defined above, such as methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, etc.

[0064] "alkylcarbonylamino" refers to -NHC(O)R p Group (where R) p Alkyl groups as defined above, such as methyl carbonylamino, ethyl carbonylamino, propyl carbonylamino, etc.

[0065] "alkylsulfonyl" refers to -S(O)2R p Group (where R) p It is an alkyl group as defined above, such as methylsulfonyl, ethylsulfonyl, etc.

[0066] "Dialkylaminocarbonyl" refers to -C(O)NR p1 R p Group (where R) p and R p1 Independently, it is an alkyl group as defined above, such as dimethylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, etc.

[0067] "alkylamino" refers to -NHR p Group (where R) p Alkyl groups as defined above, such as methylamino, ethylamino, propylamino, etc.

[0068] "Aryl" refers to a monovalent monocyclic or bicyclic aromatic hydrocarbon group with 6 to 10 ring atoms, such as phenyl or naphthyl.

[0069] "Arylalkyl" or "arylalkyl" refers to -(alkylene)-R p Group (where R) p (These are aryl groups as defined above), such as benzyl, phenethyl, etc.

[0070] "Arylene" refers to a divalent aryl group (as defined above), such as phenylene or naphthylene.

[0071] "Aryloxy group" refers to -OR p Group (where R) p (It is an aryl group as defined above). For example Phenyloxy (or phenoxy) or naphthyloxy.

[0072] "Aryloxyalkyl" refers to -(alkylene)-R p Group (where R) p These are aryloxy groups as defined above, such as benzyloxy, phenethyloxy, etc.

[0073] Unless otherwise stated, "bicyclic heterocyclic group" means a saturated divalent fused bicyclic group having 8 to 12 ring atoms, one, two, or three of which are independently selected from N, NH, O, and S(O). n (where n is an integer selected from 0 to 2) heteroatoms, with the remaining ring atoms being carbon. Additionally, one or both ring carbon atoms in the bicyclic heterocyclic group may optionally be replaced by a -CO- group. More specifically, the term bicyclic heterocyclic group includes, but is not limited to, isoindoline-diyl, decahydro-2,6-naphthidine-diyl, octahydrocyclopentane[c]pyrrole-diyl, octahydro-1H-pyrrolo[3,4-c]pyridine-diyl, hexahydrofurano[3,2-b]furan-3,6-diyl, etc. When the heterocyclic group is unsaturated, it may contain one or two cyclic double bonds, provided that the ring is not aromatic.

[0074] "Bridged cycloalkyl" refers to a saturated monovalent bicyclic ring with 5 to 8 carbon atoms, where two non-adjacent ring atoms are connected by a (CR) ring. p R p ') n Groups (also referred to as "bridging groups" in this text) are connected, where n is an integer selected from 1 to 3 and R p and R p 'Independently H or methyl. Examples include, but are not limited to, bicyclo[1.1.1]pent-1-yl, bicyclo[2.2.1]heptyl, preferably bicyclo[2.2.1]hept-2-yl, etc.

[0075] "Bridging heterocyclic group" refers to a saturated monovalent bicyclic ring with 5 to 9 ring carbon atoms, where two non-adjacent ring atoms are connected by a (CR) linker. p R p ') nGroups (also referred to as "bridging groups" in this text) are connected, where n is an integer selected from 1 to 3 and R p and R p It is independently H or methyl, and further, one or both ring carbon atoms (including atoms in bridging groups) are selected from N, NH, O, and S(O). n (where n is an integer selected from 0 to 2) heteroatom substitutions. Unless otherwise stated, the bridging heterocyclic group is optionally substituted with one or two substituents independently selected from alkyl, halogen, alkoxy, hydroxy, and cyano groups. Examples include, but are not limited to, 3,8-diazabicyclo[3.2.1]octyl, 7-oxabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 3,6-diazabicyclo[3.1.1]heptyl, 2,5-diazabicyclo[2.2.2]octyl, 3,8-diazabicyclo[3.2.1]octyl, 6-azabicyclo[3.1.1]heptyl, 8-azabicyclo[3.2.1]octyl, etc.

[0076] "Bridging heterocyclic group" refers to a saturated divalent bicycle with 5 to 9 ring carbon atoms, where two non-adjacent ring atoms are connected by a (CR) ring. p R p ') n Groups (also referred to as "bridging groups" in this text) are connected, where n is an integer selected from 1 to 3 and R p and R p It is independently H or methyl, and further, one or both ring carbon atoms (including atoms in bridging groups) are selected from N, NH, O, and S(O). n (where n is an integer selected from 0 to 2) heteroatom substitution. Unless otherwise stated, the bridging heterocyclic group is optionally substituted with one or two independent substituents selected from alkyl, halogen, alkoxy, hydroxy, and cyano groups. Examples include, but are not limited to, 3,8-diazabicyclo[3.2.1]octane-3,8-diyl, 7-oxabicyclo[2.2.1]heptane-diyl, 2,5-diazabicyclo[2.2.1]heptane-diyl, 3,6-diazabicyclo[3.1.1]heptane-diyl, 2,5-diazabicyclo[2.2.2]octane-diyl, 3,8-diazabicyclo[3.2.1]octane-diyl, 6-azabicyclo[3.1.1]heptane-diyl, 8-azabicyclo[3.2.1]octane-diyl, etc.

[0077] "Cycloalkyl" refers to a monocyclic saturated monovalent hydrocarbon group having three to ten carbon atoms. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0078] "Cycloalkyloxy or cycloalkoxy" means -OR pa group in which R p is a cycloalkyl group as defined above). Examples include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc.

[0079] "cycloalkylene" means a divalent saturated hydrocarbon group having three to six carbon atoms, and for example, 1,1-cyclopropylene, 1,1-cyclobutylene, 1,4-cyclohexylene, etc.

[0080] "carbonyl" means -C(O)-.

[0081] "carboxyl" means -COOH.

[0082] "cycloimino" means a saturated divalent monocyclic ring having 4 to 8 ring atoms, where one or two ring atoms are nitrogen and the remaining ring atoms are carbon. More specifically, the term cycloimino includes, but is not limited to, pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, etc.

[0083] "cyanoalkyl" means an alkyl group as defined above substituted with a cyano group, such as cyanomethyl, cyanoethyl, etc.

[0084] "branched cyanoalkyl" means a branched monovalent hydrocarbon group having three to six carbons substituted with a cyano group. Representative examples include cyano-isopropyl and cyano-isobutyl, etc.

[0085] "cyanoalkyloxy" means -OR p a group in which R p is a cyanoalkyl group as defined above), such as cyanomethyloxy, cyanoethyloxy, etc.

[0086] "deuterium" means 2 H or D.

[0087] "dialkylamino" means -NR p R p a group in which each R p is an alkyl group as defined above and is independently selected), such as dimethylamino, methylethylamino, n-propylmethylamino, 2-propylmethylamino, n-butylmethylamino, isobutylmethylamino or tert-butylmethylamino, etc.

[0088] Unless otherwise stated, “fused heterocyclic group” means a monovalent bicyclic ring having 4 to 7 ring atoms, having one or two heteroatoms independently selected from N, NH, O, and S(O)n (where n is 0, 1, or 2), and the remaining ring atoms being carbon. Two adjacent ring atoms of the saturated monocyclic ring are fused with two adjacent ring members of a phenyl or a five- or six-membered heteroaryl group (each as defined herein). The nitrogen atom is optionally oxidized, and further, one of the carbon ring atoms of the saturated monocyclic ring is optionally replaced by a -C(=O)- group. Representative examples include, but are not limited to, 1,2,3,4-tetrahydroquinolinyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazinyl, etc.

[0089] Unless otherwise stated, "fused heterocyclic group" means a divalent bicycle having 4 to 7 ring atoms, one or two independent heteroatoms selected from N, NH, O, and S(O)n (where n is 0, 1, or 2), and the remaining ring atoms being two adjacent ring atoms of a saturated monocyclic ring fused with two adjacent ring members of a phenyl or a five- or six-membered heteroaryl group (each as defined herein). The nitrogen atom is optionally oxidized, and further, one of the carbon ring atoms of the saturated monocyclic ring is optionally replaced by a -C(=O)- group. The fused heterocyclic group can be attached to any two atoms of the ring. Representative examples include, but are not limited to, 1,2,3,4-tetrahydroquinoline-1,4-diyl, 3,4-dihydro-2H-benzo[b][1,4]oxazine-5,8-diyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-diyl, and 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-diyl.

[0090] "Halogenated" means fluorine, chlorine, bromine, or iodine, such as fluorine or chlorine.

[0091] "Haloalkyl" means an alkyl group as defined above, which is substituted with one or more halogen atoms (e.g., one to five halogen atoms, such as fluorine or chlorine), including those substituted with different halogens, such as -CH2Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3, -CF(CH3)2, etc. When an alkyl group is substituted only with fluorine, it may be referred to as fluoroalkyl in this application.

[0092] "Branched haloalkyl" means a branched monovalent hydrocarbon group having three to six carbon atoms that is substituted with one or more halogen atoms (e.g., one to five halogen atoms, such as fluorine or chlorine), including those substituted with different halogens. Representative examples include CF(CH3)2, etc. When a branched haloalkyl is substituted only with fluorine, it may be referred to as a branched fluoroalkyl in this application.

[0093] "Haloalkoxy" refers to -OR p Group (where R) p These are alkyl halides as defined above, such as -OCF3, -OCHF2, etc. When R p When it is a haloalkyl (where the alkyl group is substituted only by fluorine (in some instances, one or more fluorines)), it is referred to in this application as a fluoroalkoxy.

[0094] "Branched haloalkoxyalkyl" refers to a branched monovalent hydrocarbon group with three to six carbons that has been substituted with a haloalkoxy group (as defined above). Representative examples include, but are not limited to, 3-trifluoromethoxybut-2-yl and 1-(trifluoromethoxymethyl)-2-methylpropyl.

[0095] "Hydroxyalkyl" refers to a straight-chain or branched monovalent hydrocarbon group with one to six carbon atoms that has been replaced by a hydroxyl group. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, etc.

[0096] "Branched hydroxyalkyl" refers to a branched monovalent hydrocarbon group with three to six carbons that has been replaced by a hydroxyl group. Representative examples include, but are not limited to, hydroxy-isopropyl, 1-(hydroxymethyl)-2-methylpropyl, and hydroxy-isobutyl.

[0097] Unless otherwise stated, “heteroaryl” means a monovalent monocyclic or fused bicyclic aromatic group having 5 to 10 ring atoms, wherein one or more (in one embodiment, one, two, or three) of the ring atoms are heteroatoms selected from N, NH, O, and S, and the remaining ring atoms are carbon. Representative examples include, but are not limited to, pyrrole, thiophene, thiazolyl, imidazolyl, furanyl, indolyl, isoyindolyl, indolyl, imidazo[1,2-a]pyridyl, imidazo[1,2-a]pyrazinyl, oxazolyl, isoxazolyl, oxadiazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, etc. As defined herein, the terms “heteroaryl” and “aryl” are mutually exclusive. When a heteroaryl ring contains 5 or 6 ring atoms and is a monocyclic ring, it is also referred to herein as a "five- or six-membered" or "five- or six-membered" monocyclic heteroaryl. When a heteroaryl ring contains 9 or 10 ring atoms, it is also referred to herein as a 9- or 10-membered fused bicyclic heteroaryl.

[0098] "Heteroaryloxy" refers to -OR p Group (where R) p These are heteroaryl groups as defined above, such as pyridyloxy, pyrazolyloxy, imidazolyloxy, etc.

[0099] "Heteroarylalkyl" refers to -(alkylene)-R p Group (where R) p These are heteroaryl groups as defined above, such as pyridylmethyl, pyrazolylmethyl, etc.

[0100] "Heteroaryloxyalkyl" refers to -(alkylene)-R p Group (where R) p These are heteroaryloxy groups as defined above, such as pyridyloxymethyl, pyrazolyloxymethyl, imidazolyloxymethyl, etc.

[0101] Unless otherwise stated, “heteroaryl” means a divalent heteroaryl group as defined above. Representative examples include, but are not limited to, benzimidazole dimethyl groups, such as benzimidazole-1,5-dimethyl. When a heteroaryl ring contains 5 or 6 ring atoms and is monocyclic, it is also referred to herein as a monocyclic heteroaryl or a 5- or 6-membered monocyclic heteroaryl, such as pyrazolyl-dimethyl (pyrazolyl-1,3-dimethyl, pyrazolyl-1,4-dimethyl, pyrazolyl-1,5-dimethyl, etc.) and imidazole-dimethyl (imidazole-1,2-dimethyl, imidazole-1,4-dimethyl, imidazole-1,5-dimethyl). When a heteroaryl ring contains 9 or 10 ring atoms and is a fused bicyclic ring, it is also referred to herein as a 9- or 10-membered fused bicyclic heteroaryl.

[0102] Unless otherwise stated, "heterocyclic group" means a saturated monovalent monocyclic group having 4 to 8 ring atoms, one or two of which are independently selected from N, NH, O and S(O). n (where n is an integer selected from 0 to 2) heteroatoms, with the remaining ring atoms being carbon. Additionally, one or both ring carbon atoms in the heterocyclic ring may optionally be replaced by a -C(=O)- group. More specifically, the term heterocyclic group includes, but is not limited to, oxobutyl, piperidinyl, piperazine, pyrrolyl, aziryl, etc.

[0103] "Heterocyclic alkyl" refers to -(alkylene)-R p Group (where R) p These are heterocyclic groups as defined above, such as piperidinylmethyl, pyrrolidinylmethyl, etc.

[0104] "Heterocyclic carbonyl" means -C(O)R group (where R is a heterocyclic group as defined herein). More specifically, the term heterocyclic includes, but is not limited to, piperidinyl carbonyl, piperazine carbonyl, pyrrolidinyl carbonyl, and nitrogen-heterocyclic butyl carbonyl.

[0105] "Heterocyclic oxy group" means -OR group (where R is a heterocyclic group as defined herein). More specifically, the term heterocyclic group includes, but is not limited to, piperidinyloxy, piperazinyloxy, pyrrolidinyloxy, and azacyclic butyloxy.

[0106] Unless otherwise stated, "heterocyclic group" means a saturated divalent monocyclic group having 4 to 8 ring atoms, one or two of which are independently selected from N, NH, O, and S(O). n (where n is an integer selected from 0 to 2) heteroatoms, with the remaining ring atoms being carbon. Additionally, one or two ring carbon atoms in the heterocyclic group may optionally be replaced by a -C(=O)- group. More specifically, the term heterocyclic group includes, but is not limited to, […]. Piperidine-1,4-diyl, aziridine-1,3-diyl, etc.

[0107] "C3 to C6 heteroalkylene" refers to a straight-chain or branched saturated divalent hydrocarbon group having three to six carbon atoms, wherein (a) one carbon atom of the straight-chain portion of the divalent hydrocarbon group is X a (where X) a It is -O-, -S-, -SO-, -SO2-, -CO-, or -NR q -) substitution, or (b) two adjacent carbon atoms of the straight-chain portion of the divalent hydrocarbon group are replaced by X. a1 (where X) a1 Yes -NR q CO-、-CONR q -、-NR q SO-、-SONR q -、-NR q SO2- or -SO2NR q - (where each R) q (It is replaced by hydrogen, alkyl, alkyl carbonyl or alkyl sulfonyl) and, furthermore, the straight-chain portion of the divalent hydrocarbon group in (a) and (b) above does not interact with X. a and X a1 The adjacent carbon atom can be X y (where X) y Is it -O- or -NR? q1 - (where R) q1 (This can be replaced by hydrogen, alkyl, alkyl carbonyl, or alkyl sulfonyl) provided that the straight-chain portion of the C3 to C6 heteroalkylene group attached to Z and Ar contains at least three atoms. For clarity, as used in this definition, the straight-chain portion of the C3 to C6 heteroalkylene group means the consecutive atoms of the C3 to C6 heteroalkylene group connecting Z and Ar, for example, in the structure In the middle, with The atoms form the straight-chain portion of the C5 heteroalkylene group. When the C3 to C6 heteroalkylene group contains only one or two -O- atoms, it may be referred to herein as an "oxoalkylene group". When the C3 to C6 heteroalkylene group contains only one or two -NR atoms... q -and / or -NR q1When -S- is present, it may be referred to herein as "aminoalkylene". When C3 to C6 heteroalkylene contains only -S-, it may be referred to herein as "thioalkylalkylene". When C3 to C6 heteroalkylene contains only -SO-, it may be referred to herein as "sulfinylalkylene". When C3 to C6 heteroalkylene contains only -SO2-, it may be referred to herein as "sulfonylalkylene". Representative examples of C3 to C6 heteroalkylene include, for example wait.

[0108] "Phenylidene" refers to a divalent phenyl group.

[0109] As used herein, the phrases “optionally” or “optionally” mean that the event or situation described below may, but does not necessarily, occur, and that the description includes both cases in which the event or situation occurs and cases in which the event or situation does not occur. For example, the phrase “optionally halogenated alkylene” is intended to cover both unhalogenated and halogenated alkylene.

[0110] "Spirocyclone" refers to a saturated monovalent bicyclic ring with 6 to 10 ring atoms, one, two, or three of which are selected from N, O, and S(O). n (where n is an integer selected from 0 to 2) heteroatoms, the remaining ring atoms are C, and these rings are connected by only one atom, also called a spiro atom, most commonly a quaternary carbon (“spirocarbon”). Unless otherwise stated, the spiroheterocyclic group is optionally substituted by one or two independent substituents selected from alkyl, halogen, alkoxy, hydroxy, and cyano groups. Representative examples include, but are not limited to, 2-azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 1,7-diazaspiro[3.5]nonyl, 2,7-diazaspiro[3.5]nonyl, 3,9-diazaspiro[5.5]undecyl, etc.

[0111] "Spirohexacyclic subcyclic group" refers to a saturated divalent bicyclic ring with 6 to 10 ring atoms, one, two, or three of which are selected from N, O, and S(O). n (where n is an integer selected from 0 to 2) heteroatoms, the remaining ring atoms are C, and these rings are connected by only one atom, also called a spiro atom, most commonly a quaternary carbon (“spirocarbon”). Unless otherwise stated, the spiroheterocyclic group is optionally substituted by one or two independent substituents selected from alkyl, halogen, alkoxy, hydroxy, and cyano groups. Representative examples include, but are not limited to, 2-azaspiro[3.3]heptane-diyl, 2,6-diazaspiro[3.3]heptane-diyl, 1,7-diazaspiro[3.5]nonane-diyl, 2,7-diazaspiro[3.5]nonane-diyl, 3,9-diazaspiro[5.5]undecane-diyl, etc.

[0112] Unless otherwise stated, "unsaturated heterocyclic group" means a divalent monocyclic nonaromatic group having one or two double bonds and six to eight ring atoms, wherein one or two ring atoms are independently selected from N, O, and S(O). n (where n is an integer selected from 0 to 2) heteroatoms, and the remaining ring atoms are C. In addition, one or two ring carbon atoms in the heterocyclic base ring may optionally be replaced by -C(=O)- groups.

[0113] This disclosure also includes protected derivatives of compounds having formula (I) (or any of the embodiments disclosed herein) or pharmaceutically acceptable salts thereof. For example, when a compound having formula (I) contains a group such as a hydroxyl, carboxyl, or any group containing a nitrogen atom, these groups may be protected by suitable protecting groups. A complete list of suitable protecting groups can be found in TW Greene, Protective Groups in Organic Synthesis, 5th Edition, John Wiley & Sons, Inc. (2014), the disclosure of which is incorporated herein by reference in its entirety. Protected derivatives of the compounds disclosed herein may be prepared by methods well known in the art.

[0114] This disclosure also includes compounds having formula (I) (or any of the embodiments disclosed herein) or pharmaceutically acceptable salts thereof in polymorphic and deuterated forms.

[0115] Certain compounds disclosed herein may exist as tautomers and / or geometric isomers. All possible tautomers, as well as cis and trans isomers (as separate forms and mixtures thereof), are within the scope of this disclosure. For example, compounds having (I) with a hydroxyl-substituted pyridyl ring may exist as tautomers, as follows:

[0116]

[0117] The term "prodrug" refers to a compound that becomes more active in vivo. Certain compounds having formula (I) (and any examples thereof disclosed herein, including specific compounds) may also exist as prodrugs, as described in the following literature: Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003). Prodrugs of the compounds described herein are structurally modified forms of compounds that readily undergo chemical changes under physiological conditions to provide the active compound. Prodrugs are often useful because they may be more readily administered than the compound or parent drug in some cases. For example, they may be bioavailable through oral administration, whereas the parent drug may not. Various prodrug derivatives, such as those dependent on the hydrolytic cleavage or oxidative activation of the prodrug, are known in the art. Examples of prodrugs (but not limited to) are compounds that are administered as esters (“prodrugs”) but are then metabolized and hydrolyzed into carboxylic acids (the active entity). Other examples include peptide derivatives of compounds.

[0118] A "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. Such salts include:

[0119] Acid addition salts formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.); or acid addition salts formed with organic acids (such as formic acid, acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucono-2-carboxylic acid, 4,4'-methylenebis-(3-hydroxy-2-en-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muco-2-carboxylic acid, etc.); or

[0120] Salts formed when an acidic proton present in the parent compound is replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion); or when coordinated with an organic base (e.g., ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucosamine, etc.). It should be understood that pharmaceutically acceptable salts are non-toxic. Further information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pennsylvania, 1985, which is incorporated herein by reference in its entirety.

[0121] Compounds having formula (I) (and any of the embodiments disclosed herein, including specific compounds) may have an asymmetric center. Compounds having formula (I) containing asymmetrically substituted atoms (and any of the embodiments disclosed herein, including specific compounds) may be isolated in optically active or racemic form. Individual stereoisomers of a compound may be prepared by synthesis from commercially available starting materials containing a chiral center, or by preparing a mixture of enantiomeric products followed by separation (e.g., conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on a chiral column, or any other suitable method known in the art). Unless a specific stereochemical form or isomeric form is explicitly indicated, all chiral forms, diastereomeric forms, mixtures of chiral or diastereomeric forms, and racemic forms are within the scope of this disclosure. Those skilled in the art will also understand that when a compound is represented as an (R) stereoisomer, it may contain a corresponding (S) stereoisomer as an impurity, and vice versa.

[0122] Certain compounds having formula (I) (and any examples thereof disclosed herein, including specific compounds) may exist as tautomers and / or geometric isomers. All possible tautomers, as well as cis and trans isomers (as separate forms and mixtures thereof), are within the scope of this disclosure. Additionally, as used herein, although only a few examples are listed, the term alkyl includes all possible isomeric forms of the alkyl group. Furthermore, when these cyclic groups (such as aryl) are substituted, although only a few examples are listed, it includes isomers at all positions. Moreover, all hydrates of compounds having formula (I) (and any examples thereof disclosed herein, including specific compounds) are within the scope of this disclosure.

[0123] Compounds having formula (I) (and any embodiments thereof disclosed herein, including specific compounds) may also contain non-natural amounts of isotopes on one or more atoms constituting such compounds. Non-natural amounts of isotopes can be defined as ranging from amounts found in nature to 100% of the atoms in question, differing only in the presence of one or more isotope-enriched atoms. Exemplary isotopes that may be incorporated into compounds of this disclosure (such as compounds having formula (I) (and any embodiments thereof disclosed herein, including specific compounds)) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, respectively, such as... 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 32 P, 33 P, 35 S, 18 F, 36 Cl、 123 I and 125 1. Isotope-labeled compounds (e.g., those labeled with...) 3 H and 14 C-labeled compounds can be used in the determination of compound or substrate tissue distribution. Tritium-labeled compounds (i.e., 3 H) and carbon-14 (i.e., ... 14 C) Isotopes can be useful due to their ease of preparation and detectability. Furthermore, heavier isotopes such as deuterium (i.e., 2 H) substitution (or isotopic enrichment) may provide certain therapeutic advantages due to increased metabolic stability (e.g., increased in vivo half-life or reduced dose requirements). In some embodiments, in compounds having formula (I) (and any embodiments thereof disclosed herein, including specific compounds included in Table 1 below), one or more hydrogen atoms are... 2 H or 3 H substitution, or one or more carbon atoms being replaced 13 C- or 14 C-enriched carbon substitution. Positron-emitting isotopes (such as...) 15 O、 13 N、 11 C and 15 F) It can be used in positron emission tomography (PET) studies to examine the occupancy of matrix receptors. Isotope-labeled compounds can typically be prepared by replacing non-isotope-labeled reagents with isotope-labeled reagents through procedures similar to those disclosed in the protocols or examples herein.

[0124] "Pharmaceutical-acceptable carriers or excipients" means carriers or excipients that are useful in the preparation of pharmaceutical compositions, are generally safe, non-toxic and not biologically or otherwise undesirable, and include carriers or excipients that are acceptable for veterinary use as well as for human use.

[0125] As used herein and in the claims, "pharmaceuticalally acceptable carrier / excipient" includes both one and more such excipients. As used herein, the term "about" is intended to define the numerical value it modifies, indicating that the value is a variable within an error limit. When no specific error range is listed (e.g., the standard deviation of the average given in a data plot or table), the term "about" should be understood to mean a range covering ±10%, preferably ±5%, including the listed values ​​and ranges.

[0126] Some of the structures presented herein are drawn with one or more floating substituents. Unless otherwise provided or clearly apparent from the context, substituents may be present on any atom of the ring to which they are attached, provided that it is chemically feasible and the rules of valence permit. For example, in the structure: In the middle, R aa Substituents and similarly R bb The substituent can replace any hydrogen atom in CH, where CH is not yet replaced by R. bb (in R) aa In the case of) and similarly by R aa (in R) bb (in the case of) a portion of the benzo[a] portion of a bicyclic substituted benzo[a] portion.

[0127] Additionally, as used throughout the application (including in the embodiments), when a group is derived as divalent, the left bond of the divalent group is attached to a group located to its left in the remainder of the molecule, and the right bond of the divalent group is attached to a group located to its right in the remainder of the molecule. For example,

[0128]

[0129] In the following divalent groups of the E3 ubiquitin ligand group of formula (i), (a) and (b) on the left side Keys are attached to the following rings:

[0130] ,

[0131] And the right side of (a) and (b) Attached to structure (I) Z:

[0132] Similarly, for -Z-alk-Ar-, the left-hand bond (i.e., Z) is attached to the group to its left, i.e., ring A of formula (i) or ring B of formula (ii), while the right-hand bond (i.e., Ar) is attached to -SO2- (attached to the atom of Hy). For example, when -Z-alk-Ar- is a group having the following formula:

[0133] ,

[0134] Furthermore, the ring A of the degradation determinant of formula (i) is a ring with the following characteristics: When the group is piperidinyl, The bond is attached to the benzo[a] moiety of ring (a), while the phenyl group... The key is attached to -SO2- (attached to Hy).

[0135] As used herein, the term “disease” is intended to be broadly synonymous with and interchangeable with the terms “disorder,” “syndrome,” and “symptom” (as in medical conditions), all of which reflect an abnormality in a human or animal body or in one of its parts that impairs normal function, typically manifested as distinguishable signs and symptoms, and resulting in a reduced lifespan or quality of life for the human or animal.

[0136] The term "combination therapy" means the administration of two or more therapeutic agents to treat the disease or disorder described in this disclosure. Such administration encompasses the combined administration of these therapeutic agents in a substantially simultaneous manner, such as administration as a single capsule containing the active ingredients in a fixed ratio or as multiple separate capsules containing each active ingredient. Furthermore, such administration also encompasses the sequential use of each type of therapeutic agent. In either case, the treatment regimen will provide the beneficial effects of the combination of drugs in treating the condition or disorder described herein.

[0137] The term "patient" is broadly synonymous with the term "subject" and includes all mammals, including humans. Examples of patients include humans, livestock (such as cattle, goats, sheep, pigs, and rabbits), and companion animals (such as dogs, cats, rabbits, and horses). Preferably, the patient is a human.

[0138] "Treatment" of diseases includes:

[0139] (1) To prevent the disease, that is, to prevent the development of clinical symptoms of the disease in mammals that may be exposed to or susceptible to the disease but have not yet experienced or shown symptoms of the disease;

[0140] (2) To suppress the disease, that is, to delay, block (stabilize) or reduce the development or severity of the disease or its clinical symptoms; or

[0141] (3) To alleviate the disease, that is, to make the disease or its clinical symptoms disappear.

[0142] In one embodiment, treating a disease includes suppressing the disease, i.e., delaying, blocking, or reducing the development or severity of the disease or its clinical symptoms; or alleviating the disease, i.e., causing the disease or its clinical symptoms to subside.

[0143] "Therapeutic effective amount" means the amount of the disclosed compound and / or its pharmaceutically acceptable salt that, when administered to a patient for the treatment of a disease, is sufficient to affect that treatment. "Therapeutic effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal to be treated.

[0144] "Symptoms associated with autoimmune diseases" refers to conditions that patients with autoimmune diseases are susceptible to (such as sepsis) or conditions caused by autoimmune diseases (such as uveitis).

[0145] The terms “degrading” or any variations thereof, used in connection with CDK2, CDK4, CDK6, and CDK1, refer to a measurable decrease in the concentrations of CDK2, CDK4, CDK6, and CDK1 in a sample over time. For example, compared to an equivalent sample containing CDK2, CDK4, or CDK6, respectively, in the absence of the compounds disclosed herein, the examples, and the compounds listed in Table 1, the concentrations of CDK2, CDK4, and CDK6 may be reduced by approximately 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or any range thereof. The percentage of degradation can be determined as described in Biological Example 2 below.

[0146] If the given degrader has an inhibitory activity IC against CDK2, CDK4, and CDK6, 50 It is its inhibitory activity IC against CDKs other than CDK2, CDK4, and CDK6 (such as CDK1). 50 If the degradation agent is at least 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100 times stronger than the degradation agent, then the degradation agent is considered selective for CDK2, CDK4, and CDK6. Compounds having formula (I) have an IC50 value for CDK1, CDK2, CDK4, and CDK6. 50 Activity was measured using KYSE520, OVCAR3, T47D, and THP1 cell lines, as described in Biological Example 1 below.

[0147] E3 ubiquitin ligases are a family of proteins that work in conjunction with E1 ubiquitin activators and E2 ubiquitin conjugates to assist or directly catalyze the covalent linkage of ubiquitin to lysine residues of substrate proteins. E3 ubiquitin ligases bind directly to substrate proteins, thereby conferring substrate specificity for the ubiquitination process. Ubiquitination can serve as a universal signaling marker for substrate proteins that are targeted for degradation via proteasome or other regulation ranging from translocation to transcription. Cerebellar proteins (CRBN) and von Hippel-Lindau (VHL) are two universally expressed and biologically important substrate recognition subunits of the Cullin-RING E3 ubiquitin ligase complex. CRBN forms the E3 ubiquitin ligase complex with damaged DNA-binding protein 1 (DDB1), Cullin-4A (CUL4A), and cullins 1 regulator (ROC1). VHL is part of the E3 ligase complex VCB, which also consists of extension proteins B and C, Cul2, and Rbx1.

[0148] Example:

[0149] Example A

[0150] In embodiments A1 to A207, this disclosure includes:

[0151] A1. In Example A1, a compound having formula (I) or a pharmaceutically acceptable salt thereof as described in the second aspect of the invention is provided.

[0152] A2. In Example A2, the compound or a pharmaceutically acceptable salt thereof as described in Example A1 is wherein R 1 It is a branched alkyl group.

[0153] A3. In Example A3, the compound or its pharmaceutically acceptable salt as described in Examples A1 or A2 is wherein R 1 It is isopropyl, sec-butyl, or tert-butyl.

[0154] A4. In Example A4, the compound or a pharmaceutically acceptable salt thereof as described in Examples A1, A2 or A3 is wherein R 1 It is isopropyl or cyclopropyl. In the sub-example of A4, the compound or a pharmaceutically acceptable salt thereof is wherein R 1 It is isopropyl.

[0155] A5. In Example A5, the compound or a pharmaceutically acceptable salt thereof as described in Example A1 is wherein R 1It is a cycloalkyl group independently selected from halogen, cyano, hydroxy, alkoxy and haloalkoxy, preferably selected from 0, 1, 2 or 3 groups substituted with halogen and hydroxyl.

[0156] A5a. In Example A5a, the compound or its pharmaceutically acceptable salt as described in Examples A1 or A5 is wherein R 1 It is an unsubstituted cycloalkyl group.

[0157] A6. In Example A6, the compound or a pharmaceutically acceptable salt thereof as described in Examples A1, A5, or A5a is wherein R 1 It is unsubstituted cyclopropyl, unsubstituted cyclobutyl, or unsubstituted cyclopentyl.

[0158] A6b. In Example A6b, the compound or a pharmaceutically acceptable salt thereof as described in Example A1 is wherein R 1 It is a bridged cycloalkyl group substituted by 0, 1, 2 or 3 groups independently selected from halogen, cyano, hydroxy, alkoxy and haloalkoxy, preferably independently selected from 0, 1, 2 or 3 groups selected from halogen and hydroxy.

[0159] A7-1. In Example A7-1, the compound or a pharmaceutically acceptable salt thereof as described in A1 is wherein R 1 It is a branched haloalkyl, a branched cyanoalkyl, a branched hydroxyalkyl, a branched alkoxyalkyl, or a branched haloalkoxyalkyl.

[0160] A7-2. In Example A7-1, the compound or a pharmaceutically acceptable salt thereof as described in A1 is wherein R 1 It is a branched haloalkyl group.

[0161] A7-3. In Example A7-1, the compound or a pharmaceutically acceptable salt thereof as described in A1 is wherein R 1 It is a branched hydroxyalkyl group.

[0162] A7. In Example A7, the compound or a pharmaceutically acceptable salt thereof as described in Examples A1 to A7-3 is wherein R 2 It is hydrogen, halogenated, haloalkyl, alkyl, hydroxyalkyl, or alkoxyalkyl.

[0163] A8. In Example A8, the compound or a pharmaceutically acceptable salt thereof as described in Examples A1 to A7-3 is wherein R 2 It is hydrogen, methyl, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, hydroxymethyl, methoxymethyl, or ethoxymethyl. In the sub-example of A8, the compound or a pharmaceutically acceptable salt thereof is wherein R 2 It is methoxymethyl or ethoxymethyl.

[0164] A9. In Example A9, the compound or a pharmaceutically acceptable salt thereof as described in Examples A1 to A7-3 is wherein R 2 It is difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, hydroxymethyl, methoxymethyl, or ethoxymethyl. In the sub-example of A9, the compound or a pharmaceutically acceptable salt thereof is wherein R 2 It is difluoromethyl, trifluoromethyl, or 2,2-difluoroethyl.

[0165] A10. In Example A10, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A8 is wherein R 2 It is hydrogen.

[0166] A11. In Example A11, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A7 is wherein R 2 It is an alkyl group.

[0167] A12. In Example A12, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A7 and A11 is wherein R 2 It is methyl or ethyl.

[0168] A13. In Example A13, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A8, A11 and A12 is wherein R 2 It is a methyl group.

[0169] A14. In Example A14, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A7-3 is wherein R 2 It is a cyanoalkyl, hydroxyalkyl, or alkoxyalkyl.

[0170] A15. In Example A15, the compound or a pharmaceutically acceptable salt thereof as described in Examples A1 to A7-3 and A14 is wherein R 2 It is a cyanoalkyl group.

[0171] A16. In Example A16, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A7 and A14 is wherein R 2 It is a hydroxyalkyl group.

[0172] A17. In Example A17, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A7 and A14 is wherein R 2 It is an alkoxyalkyl group.

[0173] A18. In Example A18, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A9 and A14 to A17 is wherein R 2 It is cyanomethyl, hydroxymethyl, methoxymethyl, methoxyethyl, methoxypropyl, or ethoxymethyl, unless otherwise stated.

[0174] A19. In Example A19, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A9 and A14 to A18 is wherein R 2 It is cyanomethyl, hydroxymethyl, methoxymethyl, 2-methoxyethyl, or ethoxymethyl, unless otherwise stated.

[0175] A20. In Example A20, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A7 is wherein R 2 It is a halogenated or halogenated alkyl group.

[0176] A21. In Example A21, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A7 and A20 is wherein R 2 It is halogenated.

[0177] A22. In Example A22, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A7 and A20 is wherein R 2 It is a haloalkyl group.

[0178] A22a. In Example A22a, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A9, A21 and A22 is wherein R 2 It is fluorine, chlorine, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, or 2,2,2-trifluoroethyl, unless otherwise stated.

[0179] A22b. In Example A22b, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A9 and A21 to A22a is wherein R 2 It is fluorine, difluoromethyl, trifluoromethyl, or 2,2-difluoroethyl, unless otherwise stated.

[0180] A23. In Example A23, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A22b is wherein R 2a It is hydrogen.

[0181] A24. In Example A24, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A22b is wherein R 2a It is deuterium.

[0182] A25. In Example A25, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A24 is wherein Hy is a heterocyclic group, phenylene, spirocyclic, bridged heterocyclic group, or cycloalkylene group, wherein each of the above rings is R a R b and R c Replace, where R a and R b Independently selected from hydrogen, deuterium, alkyl, halogen, haloalkyl, alkoxy, hydroxyl, and cyano, and R c It is hydrogen.

[0183] A26. In Example A26, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A25 is wherein Hy is R a R b and R c Substituted heterocyclic groups, where R a and R b Independently selected from hydrogen, deuterium, alkyl, halogen, haloalkyl, alkoxy, hydroxyl, and cyano, and R c It is hydrogen.

[0184] A27. In Example A27, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A26 is wherein the heterocyclic group of Hy is pyrrolidine-1,3-diyl or piperidine-1,4-diyl, wherein each ring is R a R b and R c Replace, where R a and R b Independently, it is hydrogen, deuterium, methyl, fluorine, methoxy, or hydroxyl, R c It is hydrogen, and -SO2- is attached to the nitrogen atom of the piperidine-1,4-diyl or pyrrolidine-1,3-diyl ring of Hy.

[0185] A28. In Example A28, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A27 is wherein the heterocyclic subgroup of Hy is:

[0186]

[0187] The N atom of either pyrrolidine-1,3-diyl or piperidine-1,4-diyl ring is attached to -SO2-.

[0188] A29. In Example A29, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A28 is wherein the heterocyclic subgroup of Hy is:

[0189]

[0190] The N atom of either pyrrolidine-1,3-diyl or piperidine-1,4-diyl ring is attached to -SO2-.

[0191] A29a. In Example A29a, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A29 is wherein the heterocyclic subgroup of Hy is:

[0192]

[0193] The N atom of the piperidine-1,4-dicyclic ring is attached to -SO2-.

[0194] A30. In Example A30, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A25 is wherein Hy is R a R b and R c Replaced bridging heterocyclic groups, where R c It is hydrogen.

[0195] A31. In Example A31, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A25 and A30 is wherein the bridging heterocyclic group of Hy is a ring having the following formula:

[0196]

[0197] Each ring is R a R b and R c Replace, where R c It is hydrogen, and the nitrogen atom in each ring is attached to -SO2-.

[0198] A32. In Example A32, the compound or a pharmaceutically acceptable salt thereof as described in Examples A30 or A31 is wherein R a and R b It is independently hydrogen, deuterium, methyl, fluorine, methoxy, or hydroxyl.

[0199] A33. In Example A33, the compound or a pharmaceutically acceptable salt thereof as described in Examples A30, A31 or A32 is wherein R b It is hydrogen.

[0200] A34. In Example A34, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A25 is wherein Hy is R a R b and R c Substituted cycloalkylene, wherein R aIt is deuterium, methyl, fluorine, methoxy, or hydroxyl, and R b and R c It is hydrogen.

[0201] A35. In Example A35, the compound or a pharmaceutically acceptable salt thereof, as described in any one of Examples A1 to A25 and A34, is wherein the cycloalkylene group of Hy is cyclohexene.

[0202] A36. In Example A36, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A25, A34 and A35 is wherein the cycloalkylene group of Hy is ,in Indicates the bond to NH and The bond represents -SO2-.

[0203] A37. In Example A37, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A25 is wherein Hy is an arylene, wherein the arylene is R a R b and R c Substituted phenylene, wherein R a and R b Independently selected from hydrogen, deuterium, alkyl, halogen, haloalkyl, alkoxy, hydroxyl, and cyano, and R c It is hydrogen.

[0204] A38. In Example A38, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A25 is wherein Hy is R a R b and R c Substituted spirohexacyclic group (preferably 2-azaspiro[3.3]heptane-2-yl), wherein R a and R b Independently selected from hydrogen, deuterium, alkyl, halogen, haloalkyl, alkoxy, hydroxyl, and cyano, and R c It is hydrogen.

[0205] A39. In Example A39, the compound or its pharmaceutically acceptable salt as described in Example A37 is wherein the phenylene oxide of Hy is based on the structure 1,4-phenylene, wherein Indicates the bond to NH and This represents a bond to -SO2-, where R a It is hydrogen, fluorine, methyl, or methoxy, and R b It is hydrogen.

[0206] A39a. In Example A39a, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A24 is wherein Hy is R a R b and R c Substituted fused heterocyclic subcyclic groups, wherein R a and R b Independently selected from hydrogen, deuterium, alkyl, halogen, haloalkyl, alkoxy, hydroxyl, and cyano, and R c It is hydrogen.

[0207] A39b. In Example A39b, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A24 is wherein Hy is R a R b and R c Substituted bicyclic heterocyclic groups, wherein R a and R b Independently selected from hydrogen, deuterium, alkyl, halogen, haloalkyl, alkoxy, hydroxyl, and cyano, and R c It is hydrogen.

[0208] A40. In Example A40, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A39b is wherein the degradation determinant is an E3 ubiquitin ligase ligand having formula (i):

[0209] .

[0210] (i).

[0211] A41. In Example A41, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A40 is wherein the ring A of the E3 ubiquitin ligand having formula (i) is a group having formula (a):

[0212] .

[0213] A42. In Example A42, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A41 is wherein R 4 and R 5 It is either hydrogen or alkyl.

[0214] A43. In Example A43, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A42 is wherein R 4 and R 5 It is hydrogen.

[0215] A44. In Example A44, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A42 is wherein R 4 It is hydrogen and R 5 It is a methyl group.

[0216] A45. In Example A45, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A41 is wherein R 4 and R 5 Together with the carbon attached to them, they form >C=O.

[0217] A46a. In Example A46a, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A40 is wherein the ring A of the E3 ubiquitin ligand having formula (i) is a group having formula (b):

[0218] .

[0219] A46. In Example A46, the compound or a pharmaceutically acceptable salt thereof, as described in any one of Examples A1 to A40 and 46a, is wherein the ring A of the E3 ubiquitin ligand having formula (i) is a group having formula (b):

[0220] .

[0221] A47. In Example A47, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A40, A46a and A46 is wherein R 6 It is hydrogen.

[0222] A48. In Example A48, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A40, A46a and A46, wherein R 6 It is an alkyl group, preferably methyl.

[0223] A49. In Example A49, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A48 is wherein the ring A of the E3 ubiquitin ligase ligand having formula (i) is:

[0224] .

[0225] A50. In Example A50, the compound or a pharmaceutically acceptable salt thereof, as described in any one of Examples A1 to A49, is wherein the ring A of the E3 ubiquitin ligand having formula (i) is:

[0226] .

[0227] A51. In Example A51, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A50 is wherein the ring A of the E3 ubiquitin ligase ligand having formula (i) is:

[0228] .

[0229] A52. In Example A52, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A51 is wherein the ring A of the E3 ubiquitin ligase ligand having formula (i) is:

[0230] ;

[0231] That is, where R bb It is hydrogen.

[0232] A52a. In Example A52a, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A52 is wherein the ring A of the E3 ubiquitin ligase ligand having formula (i) is:

[0233]

[0234] That is, where R bb It is hydrogen.

[0235] A53. In Example A53, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A52 is wherein the ring A of the E3 ubiquitin ligase ligand having formula (i) is:

[0236]

[0237] That is, where R bb It is hydrogen.

[0238] A54. In Example A54, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A52 is wherein the ring A of the E3 ubiquitin ligase ligand having formula (i) is:

[0239]

[0240] That is, where R bb It is hydrogen.

[0241] A55. In Example A55, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A52 is wherein the ring A of the E3 ubiquitin ligase ligand having formula (i) is:

[0242]

[0243] That is, where R aa and R bb It is hydrogen.

[0244] A56. In Example A56, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A52 is wherein the ring A of the E3 ubiquitin ligand having formula (i) is:

[0245]

[0246] That is, where R cc and R dd It is hydrogen.

[0247] A57. In Example A57, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A52 is wherein the ring A of the E3 ubiquitin ligase ligand having formula (i) is:

[0248]

[0249] That is, where R cc and R dd It is hydrogen.

[0250] A58. In Example A58, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A54 is wherein R aa R bb R cc and R dd Independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, and haloalkoxy, unless otherwise stated, i.e., in Examples A52 to A54, R bb R cc and R dd It is hydrogen.

[0251] A59. In Example A59, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A54 is wherein R aa R bb R cc and R dd The radical is independently selected from hydrogen, alkyl, alkoxy, halogen, haloalkyl, and cyano, unless otherwise stated.

[0252] A60. In Example A60, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A54, A58 and A59 is wherein R aa R bb R cc and R ddThe ingredients are independently selected from hydrogen, methyl, methoxy, ethoxy, fluorine, trifluoromethyl, difluoromethyl, and trifluoromethoxy, unless otherwise stated.

[0253] A61. In Example A61, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A54 and A58 to A60 is wherein R aa R bb R cc and R dd Selected independently from hydrogen and methyl, unless otherwise stated.

[0254] A62. In Example A62, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A54 and A58 to A60 is wherein R aa R bb R cc and R dd The components are independently selected from hydrogen and methoxy, unless otherwise stated.

[0255] A63. In Example A63, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A54 and A58 to A60 is wherein R aa R bb R cc and R dd Selected independently from hydrogen and fluorine, unless otherwise stated.

[0256] A64. In Example A64, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A54 and A58 to A60 is wherein R aa R bb R cc and R dd The components are independently selected from hydrogen, trifluoromethyl, and difluoromethyl, unless otherwise stated.

[0257] A65. In Example A65, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A54, A58 and A60 is wherein R aa R bb R cc and R dd Selected independently from hydrogen and trifluoromethoxy, unless otherwise stated.

[0258] A66. In Example A66, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A54 and A58 to A60 is wherein R aa R bb R cc and R dd Selected independently from hydrogen, fluorine, and trifluoromethyl, unless otherwise stated.

[0259] A67. In Example A67, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A39b is wherein the degradation determinant is an E3 ubiquitin ligase ligand having formula (ii):

[0260]

[0261] (ii).

[0262] A68. In Example A68, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A39b and A41 to A67 is wherein Y a It is CH.

[0263] A69. In Example A69, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A39b and A41 to A67 is wherein Y a It is N.

[0264] A70. In Example A70, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A39b and A41 to A69 is wherein Z a It is a bond, -NH-, -O- or -NHC(O)-.

[0265] A71. In Example A71, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A39b and A41 to A70 is wherein Z a It is a bond, -NH- or -NHC(O)-.

[0266] A72. In Example A72, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A39b and A41 to A71 is wherein Z a It is a key.

[0267] A73. In Example A73, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A39b and A41 to A71 is wherein Z a It is -NH- or -NHC(O)-.

[0268] A74. In Example A74, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A39b, A41 to A71 and A73 is wherein Z a It is -NH-.

[0269] A74a. In Example A74a, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A39b, A41 to A71 and A73 is wherein Z a It is -NHC(O)-.

[0270] A75. In Example A75, the compound or a pharmaceutically acceptable salt thereof, as described in any one of Examples A1 to A39b and A41 to A74a, is wherein ring B is R ee and R ff Substituted phenylene.

[0271] A76. In Example A76, the compound or a pharmaceutically acceptable salt thereof, as described in any one of Examples A1 to A39b and A41 to A74a, is wherein ring B is R ee and R ff Substituted cyclic imine group.

[0272] A77. In Example A77, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A39b and A41 to A74a is wherein ring B is a 5- or 6-membered monocyclic heteroarylene or a 9- or 10-membered fused bicyclic heteroarylene, wherein each heteroarylene ring contains one to three nitrogen ring atoms, and each ring is divided by R. ee and R ff replace.

[0273] A78. In Example A78, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A39b, A41 to A74a and A77 is wherein ring B is a 5- or 6-membered monocyclic heteroarylene containing one or two nitrogen ring atoms, and is surrounded by R. ee and R ff replace.

[0274] A79. In Example A79, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A39b, A41 to A74a and A77 is wherein ring B is a 9- or 10-membered fused bicyclic heteroarylene containing one to three nitrogen ring atoms and R ee and R ff replace.

[0275] A80. In Example A80, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A39b, A41 to A74a, A77 and A79 is wherein ring B is a 9- or 10-membered fused bicyclic heteroarylene containing one or two nitrogen ring atoms and R ee and R ff replace.

[0276] A81. In Example A81, the compound or a pharmaceutically acceptable salt thereof, as described in any one of Examples A1 to A39b and A41 to A80, is wherein the E3 ubiquitin ligase ligand having formula (ii) is:

[0277] , , or .

[0278] A82-1. In Example A82-1, the compound or a pharmaceutically acceptable salt thereof, as described in any one of Examples A1 to A39b and A41 to A81, is wherein the E3 ubiquitin ligase ligand having formula (ii) is:

[0279] , , , , , , , , , , , , , or

[0280] Where ring B is a cyclic imine group. For clarity, it should be understood that when R... ee and / or R ff When not drawn out in the structure, they are hydrogen.

[0281] A82. In Example A82, the compound or a pharmaceutically acceptable salt thereof, as described in any one of Examples A1 to A39b and A41 to A82-1, is wherein the E3 ubiquitin ligase ligand having formula (ii) is:

[0282] , , , , , , , , , , or

[0283] Cycle B is a cyclic imine group.

[0284] A82A. In Example A82A, the compound or a pharmaceutically acceptable salt thereof, as described in any one of Examples A1 to A39b and A41 to A82, is wherein the E3 ubiquitin ligase ligand having formula (ii) is .

[0285] A83. In Example A83, the compound or a pharmaceutically acceptable salt thereof, as described in any one of Examples A1 to A39b and A41 to A82, is wherein the E3 ubiquitin ligase ligand having formula (ii) is:

[0286] , , , , , , , , , , or .

[0287] A83A. In Example A83A, the compound or a pharmaceutically acceptable salt thereof, as described in any one of Examples A1 to A39b and A41 to A83, is wherein the E3 ubiquitin ligase ligand having formula (ii) is or .

[0288] A84. In Example A84, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A39b and A41 to A83A is wherein each R ee and R ff The radical is independently selected from hydrogen, alkyl, alkoxy, halogen, cyano, haloalkyl, and haloalkoxy, unless otherwise stated.

[0289] A85. In Example A85, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A39b and A41 to A84 is wherein R ee and R ff The radical is independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halogen, haloalkyl, and cyano, unless otherwise stated.

[0290] A86. In Example A86, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A39b and A41 to A85 is wherein R ee and R ffThe radical is independently selected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, methoxy, ethoxy, fluorine, chlorine, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethyl, difluoromethoxy, trifluoromethoxy, and cyano, unless otherwise stated.

[0291] A87. In Example A87, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A39b and A41 to A86 is wherein R ee and R ff The radical is independently selected from hydrogen, methyl, ethyl and isopropyl, unless otherwise stated.

[0292] A88. In Example A88, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A39b and A41 to A86 is wherein R ee and R ff The components are independently selected from hydrogen and methoxy, unless otherwise stated.

[0293] A89. In Example A89, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A39b and A41 to A86 is wherein R ee and R ff The ingredients are independently selected from hydrogen, methyl, ethyl, isopropyl, chlorine, and fluorine, unless otherwise stated.

[0294] A90. In Example A90, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A39b and A41 to A86 is wherein R ee and R ff One of them is hydrogen or fluorine and R ee and R ff The other one is selected from hydrogen, trifluoromethyl, 2,2,2-trifluoroethyl and difluoromethyl, unless otherwise stated.

[0295] A91. In Example A91, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A39b and A41 to A86 is wherein R ee and R ff The components are independently selected from hydrogen, difluoromethoxy, and trifluoromethoxy, unless otherwise stated.

[0296] A92. In Example A92, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A39b and A41 to A86 is wherein R ee and R ff The components are independently selected from hydrogen, chlorine, fluorine, and trifluoromethyl, unless otherwise stated.

[0297] A93. In Example A93, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A39b and A41 to A86 is wherein R ee and R ff It is hydrogen.

[0298] A94. In Example A94, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A39b and A41 to A86 is wherein R ee and R ff It is chlorine, unless otherwise stated.

[0299] A95. In Example A95, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A39b and A41 to A86 is wherein R ee and R ff It is fluorine, unless otherwise stated.

[0300] A96. In Example A96, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A39b and A41 to A86 is wherein R ee and R ff It is trifluoromethyl or 2,2,2-trifluoroethyl, unless otherwise stated.

[0301] A97. In Example A97, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A96 is wherein Ar is a phenylene, a monocyclic heteroarylene, a bridged heterocyclic group, or a heterocyclic group, wherein each ring is determinated by R. j R k and R m Replace, where R m It is hydrogen.

[0302] A98. In Example A98, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A97 is wherein Ar is R j R k and R m The replacement has a formula or The phenylene (i.e., Ar is a phenylene in which alk and SO2 are attached to the meta or para position of the phenylene ring), wherein R j and R k Independently selected from hydrogen, alkyl, alkoxy, halogen, cyano, haloalkyl, and haloalkoxy, and R m It is hydrogen.

[0303] A99. In Example A99, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A98 is wherein the phenylene oxide of Ar is formed by R.j R k and R m Replacement or , where R j and R k Independently selected from hydrogen, deuterium, methyl, methoxy, fluorine, chlorine, cyano, difluoromethyl, trifluoromethyl, difluoromethoxy, and trifluoromethoxy, and R m It is hydrogen.

[0304] A100. In Example A100, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A99 is wherein the phenylene oxide of Ar is formed by R. j R k and R m Replacement or , where R j and R k Independently selected from hydrogen, fluorine, cyano, or trifluoromethyl, and R m It is hydrogen.

[0305] A101-1. In Example A101-1, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A100 is wherein the phenylene oxide of Ar is .

[0306] A101. In Example A101, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A100 is wherein the phenylene oxide of Ar is .

[0307] A102. In Example A102, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A97 is wherein Ar is R j R k and R m Substituted monocyclic heteroaryl groups (such as imidazole-1,5-diyl, pyridine-2,4-diyl, pyridine-2,6-diyl, pyridine-2,5-diyl, or pyridine-3,5-diyl), wherein R j and R k Independently selected from hydrogen, alkyl, alkoxy, halogen, haloalkyl, cyano, and haloalkoxy, and R m It is hydrogen.

[0308] A103. In Example A103, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A97 and A99 to A102 is wherein the monocyclic heteroarylene group of Ar is imidazole-2,5-diyl, pyridine-2,4-diyl, pyridine-2,6-diyl, pyridine-2,5-diyl, or pyridine-3,5-diyl, wherein each ring is determinated by R. j R k and R m Replace, where R j and R k Independently selected from hydrogen, methyl, methoxy, fluorine, chlorine, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethoxy, and trifluoromethoxy, and R m It is hydrogen.

[0309] A104. In Example A104, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A97 and A99 to A103 is wherein the monocyclic heteroarylene group of Ar is imidazole-2,5-diyl, pyridine-2,4-diyl, pyridine-2,6-diyl, or pyridine-3,5-diyl, wherein each ring is determinated by R. j R k and R m Replace, where R j and R k Independently selected from hydrogen, methyl, methoxy, fluorine, chlorine, difluoromethyl, trifluoromethyl, difluoromethoxy, and trifluoromethoxy, and R m It is hydrogen.

[0310] A105. In Example A105, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A97 is wherein Ar is R j R k and R m Substituted heterocyclic groups, where R j and R k Independently selected from hydrogen, methyl, methoxy, fluorine, chlorine, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, difluoromethoxy, and trifluoromethoxy, and R m It is hydrogen.

[0311] A106. In Example A106, the compound or a pharmaceutically acceptable salt thereof, as described in any one of Examples A1 to A97, A99 to A101 and A103 to A105, is wherein the heterocyclic group of Ar is a divalent nitrogen heterocyclic butyl, pyrrolidinyl, piperazine, or piperidinyl.

[0312] A107. In Example A107, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A97 is wherein Ar is a bridging heterocyclic group.

[0313] A108. In Example A108, the compound or a pharmaceutically acceptable salt thereof, as described in any one of Examples A1 to A97, A99 to A101, A103, A104, A106, and A107, is wherein the bridging heterocyclic group of Ar is selected from:

[0314] A109. In Example A109, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A108 is wherein Z is a cycloalkylene group selected from cyclopropylene, cyclobutylene, cyclopentylene, and cyclohexylene and substituted as defined therein.

[0315] A110. In Example A110, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A109 is wherein the cycloalkylene group of Z is independently selected from 1,3-cyclopentane, 1,3-cyclohexane, and 1,4-cyclohexane.

[0316] A111. In Example A111, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A108 and A110 is wherein Z is a phenylene or monocyclic heteroarylene (such as imidazolediyl, pyridinyl, and pyrimidinediyl) and is defined as R as described therein. d and R e replace.

[0317] A112. In Example A112, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A108 and A111 is wherein Z is a monocyclic heteroarylene selected from imidazole-2,5-diyl, pyridine-2,4-diyl, pyridine-2,6-diyl, and pyridine-3,5-diyl.

[0318] A113. In Example A113, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A108 and A111 is wherein Z is 1,3-phenylene or 1,4-phenylene.

[0319] A114. In Example A114, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A108 is wherein Z is a heterocyclic group, a bridged heterocyclic group, or a spirocyclic group, wherein each ring is defined by R as therein. d and R e replace.

[0320] A115. In Example A115, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A108 and A114 is wherein the heterocyclic group, bridging heterocyclic group, and spirocyclic group of Z are respectively selected from:

[0321]

[0322] Each ring is independently selected from hydrogen, deuterium, alkyl, and halogenated R. d and R e replace.

[0323] A116. In Example A116, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A108, A114 and A115, wherein the heterocyclic group, bridging heterocyclic group and spirocyclic group of Z are each independently selected from:

[0324] .

[0325] A117. In Example A117, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A108 and A114 to A116 is wherein Z is a heterocyclic group selected from:

[0326]

[0327] A118. In Example A118, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A108 and A114 to A117 is wherein Z is a heterocyclic group. .

[0328] A119. In Example A119, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A108 is wherein Z is -O-, -NH- or -NCH3-.

[0329] A120. In Example A120, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A98 and A114 is wherein -Z-alk-Ar-SO2- is:

[0330]

[0331] Each R d R e and R k Independently selected from hydrogen, alkyl, halogen, haloalkyl, haloalkoxy, alkoxy, and cyano, and R j It is hydrogen.

[0332] A121. In Example A121, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A98, A114 and A120 is wherein -Z-alk-Ar-SO2- is:

[0333]

[0334] Each R d R e and R k Independently selected from hydrogen, alkyl, halogen, haloalkyl, haloalkoxy, alkoxy, and cyano, and R j It is hydrogen.

[0335] A122. In Example A122, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A98, A114 and A120 is wherein -Z-alk-Ar-SO2- is:

[0336]

[0337] Each R d R e and R k Independently selected from hydrogen, alkyl, halogen, haloalkyl, haloalkoxy, alkoxy, and cyano, and R j It is hydrogen.

[0338] A123. In Example A123, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A98, A114, A120 and A121 is wherein -Z-alk-Ar-SO2- is:

[0339]

[0340] Where R d R e and R k It is as defined therein.

[0341] A124. In Example A124, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A98, A114, A120 and A121 is wherein -Z-alk-Ar-SO2- is:

[0342]

[0343] Where R d R e and R k It is as defined therein.

[0344] A125. In Example A125, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A98, A114, A120 and A121 is wherein -Z-alk-Ar-SO2- is:

[0345]

[0346] Where R d R e and R k It is as defined therein.

[0347] A126. In Example A126, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A98, A114, A120 and A121 is wherein -Z-alk-Ar-SO2- is:

[0348]

[0349] Where R d R e and R k It is as defined therein.

[0350] A127. In Example A127, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A98, A114, A120 and A121 is wherein -Z-alk-Ar-SO2- is:

[0351]

[0352] Where R d R e and R k It is as defined therein.

[0353] A128. In Example A128, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A98, A114, A120 and A122 is wherein -Z-alk-Ar-SO2- is:

[0354]

[0355] Where R d R e and R k It is as defined therein.

[0356] A129. In Example A129, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A98, A114, A120 and A122 is wherein -Z-alk-Ar-SO2- is:

[0357]

[0358] Where R d R e and R k It is as defined therein.

[0359] A130. In Example A130, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A98, A114, A120 and A122 is wherein -Z-alk-Ar-SO2- is:

[0360]

[0361] Where R d R e and R k It is as defined therein.

[0362] A131. In Example A131, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A98, A114, A120 and A122 is wherein -Z-alk-Ar-SO2- is:

[0363]

[0364] Where R d R e and R k It is as defined therein.

[0365] A132. In Example A132, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A98, A114, A120 and A122 is wherein -Z-alk-Ar-SO2- is:

[0366]

[0367] Where R d R e and R k It is as defined therein.

[0368] A133. In Example A133, the compound or a pharmaceutically acceptable salt thereof, as described in any one of Examples A1 to A98, A114, A120, A121, and A123 to A127, is wherein... (That is, Ar) is:

[0369] .

[0370] A134. In Example A134, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A98, A114, A120, A121, A123 to A127 and A133 is, wherein... (That is, Ar) is , or .

[0371] A135. In Example A135, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A134 is wherein alk is R f Substituted C3 to C6 alkenyl groups, wherein R f It is hydrogen.

[0372] A136. In Example A136, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A134 is wherein alk is R f Substituted C3 to C6 alkenyl groups, wherein R f It is either fluorine or cyanide.

[0373] A137. In Example A137, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A134 is wherein alk is R g R h and R i Substituted C3 to C6 alkylene groups, wherein R g R h and R i It is hydrogen.

[0374] A138. In Example A138, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A134 is wherein alk is R g R h and R i Substituted C3 to C6 alkylene groups, wherein R g R h and R i It is hydrogenated or halogenated, provided that R is hydrogenated. g R h and R i At least one of them is halogenated.

[0375] A139. In Example A139, the compound or a pharmaceutically acceptable salt thereof as described in Example A138 is wherein R g R h and R i At least one of them is halogenated as fluorine.

[0376] A140. In Example A140, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A134 is wherein alk is R g R h and R i Substituted C3 to C6 alkylene groups, wherein R h It is not hydrogen and R i It is hydrogen, or when R g and Rh When R is attached to the same or adjacent carbon atom of the straight-chain portion of the C3 to C6 alkylene group, g and R h They can form cycloalkylene or heterocyclic groups together with the carbon atoms to which they are attached, wherein R g and R h The formed cycloalkylene and heterocycloalkylene groups are R 9 and R 10 replace.

[0377] A141. In Example A141, the compound or its pharmaceutically acceptable salt as described in any one of Examples A140 is wherein alk is R g R h and R i Substituted C3 to C6 alkylene groups, wherein R h It is not hydrogen and R i It is hydrogen.

[0378] A142. In Example A142, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A141 is wherein the C3 to C6 alkenyl group and the C3 to C6 alkyl group of alk are respectively a straight-chain alkenyl group and an alkyl group and are substituted as defined therein.

[0379] A143. In Example A143, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A136 and A140 to A142 is wherein the straight-chain C3 to C6 imene group of alk is -CH=C(R f )CH2-, and the straight-chain C3 to C6 alkylene group of alk is -CH2CH(R h )CH2-、-CH2CH2CH(R h )-、-CH2C(R g (R) h CH2-, -CH2CH2C(R) g (R) h )-, where R h It is not hydrogen and R i It is hydrogen.

[0380] A144. In Example A144, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A134 and A140 to A143 is wherein the straight-chain C3 to C6 alkylene group of alk is -CH2CH(R) h CH2-, where R h It is not hydrogen and R i It is hydrogen.

[0381] A145. In Example A145, the compound or a pharmaceutically acceptable salt thereof, as described in any one of Examples A1 to A134 and A140 to A144, is an R-type compound with a straight-chain C3 to C6 alkylene group of alk. g It is hydrogen, deuterium, or halogenated, and the R of the straight-chain C3 to C6 alkylene group of alk is... h It is a halogenated, halogenated alkoxy, cycloalkyl, cycloalkyloxy, alkoxy, hydroxyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, cyanoalkyloxy, phenyl, heteroaryl, heterocyclic or bridging heterocyclic, wherein each ring is substituted as defined herein, unless otherwise stated.

[0382] A146. In Example A146, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A134 and A140 to A145 is an R-type compound with a straight-chain C3 to C6 alkylene group of alk. g It is hydrogen, and R is a straight-chain C3 to C6 alkylene group of alk. h It is a halogenated, haloalkoxy, cycloalkyl, cycloalkyloxy, alkoxy, hydroxyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, phenyl, heteroaryl, heterocyclic or bridging heterocyclic, wherein each ring is substituted as defined herein.

[0383] A147. In Example A147, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A134 and A140 to A146 is an R-type straight-chain C3 to C6 alkylene group of alk. g It is hydrogen, and R is a straight-chain C3 to C6 alkylene group of alk. h It is a halogenated, haloalkoxy, alkoxy, hydroxyl, dialkylaminocarbonyl, cyano, heterocyclic or heteroaryl, wherein each ring is substituted as defined herein.

[0384] A148. In Example A148, the compound or a pharmaceutically acceptable salt thereof, as described in any one of Examples A1 to A134 and A140 to A147, is an R-type compound with a straight-chain C3 to C6 alkylene group of alk. h The heteroaryl, heterocyclic, and bridging heterocyclic groups, when present, are five- or six-membered rings, and each ring is substituted as defined therein.

[0385] A149. In Example A149, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A134 and A140 to A148 is an R-type straight-chain C3 to C6 alkylene group of alk. g It is hydrogen, deuterium, or fluorine, unless otherwise stated, and the R of the straight-chain C3 to C6 alkylene group of alk is... hIt is fluorine, cyclopropyl, cyclobutyl, cyclopropyloxy, cyclobutyloxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, hydroxyl, cyano, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, methylcarbonylamino, ethylcarbonylamino, phenyl, pyrazolyl, furanyl, thiazolyl, pyridyl, pyrrolyl, 2-oxopyrrolyl, piperidinyl, piperazine, or tetrahydrofuranyl, wherein R h Each ring is independently selected from the R groups of hydrogen, deuterium, methyl, methoxy, fluorine, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethyl, hydroxyl, amino, methylamino, dimethylamino, and cyano. 7 and R 8 Replace, unless otherwise stated.

[0386] A149A. In Example A149A, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A134 and A140 to A149 is an R-type straight-chain C3 to C6 alkylene group of alk. g It is hydrogen, deuterium, or fluorine, unless otherwise stated, and the R of the straight-chain C3 to C6 alkylene group of alk is... h It is fluorine, cyclopropyl, cyclopropyloxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, hydroxyl, cyano, methylaminocarbonyl, dimethylaminocarbonyl, methylcarbonylamino, phenyl, pyrazol-1-yl, pyrazol-4-yl, pyridin-4-yl, pyrrolidine-1-yl, 2-oxopyrrolidine-1-yl, wherein R h Each ring is independently selected from hydrogen, deuterium, methyl, or fluorine R. 7 and R 8 Replace, unless otherwise stated.

[0387] A150. In Example A150, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A134, wherein alk is R g R h and R i Substituted branched C4 to C6 alkylene groups.

[0388] A151. In Example A151, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A138 and A150 is wherein the C3 to C6 alkenyl and C3 to C6 alkylene groups of alk are respectively branched C4 to C6 alkenyl and C4 to C6 alkylene groups, wherein the C4 to C6 alkylene group is defined as R as described therein. g R h and R i replace.

[0389] A152. In Example A152, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A138, A150 and A151 is wherein the C4 to C6 imene group of the alk branch is -CH2CH2C(CH3)=C(R) f )-、-CH2C(CH3)=C(R f )- or -CH2C(=CH2)CH2-, and the C4 to C6 alkylene group of alk is -CH2C(CH3)(R h CH2-、-CH2C(C2H5)(R h CH2-, -CH2CH(CH2R) h CH2-, -CH2CH(CH2CH2R) h CH2-, -CH2C(CH3)(CH2R) h CH2-、-CH2C(C2H5)(CH2R h CH2-, -CH2C(CH3)(CH2CH2R h CH2-, -CH2CH(CH3)CH(CH2R) h )-、-CH2CH2C(CH3)(CH2R h )-、-CH2CH(CH3)C(R g (R) h )-、-CH2CH(C2H5)C(R g (R) h )-、-CH2CH(C(R g (R) h (R) i ))CH(CH3)-、-CH2C(CH3)(C(R g (R) h (R) i ))CH(CH3)-、-CH2CH(C(R g (R) h (R) i ))CH2-、-CH2CH2CH(C(R g (R) h (R) i ))-、-CH2CH2CH(C(R g (R) h (R) i ))CH2- or -CH2CH2CH2CH(C(R g (R) h (R) i ))-, where R g R h and R iIt is as defined therein.

[0390] A153. In Example A153, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A138 and A150 to A152 is wherein the C4 to C6 imene group of the alk branch is -CH2C(CH3)=C(R) f )- or -CH2C(=)CH2-, and the C4 to C6 alkylene group of alk is -CH2C(CH3)(R h CH2-, -CH2CH(CH2R) h CH2-, -CH2CH(CH2CH2R) h CH2-, -CH2CH(C(R) g (R) h (R) i ))CH2-、-CH2CH2CH(C(R g (R) h (R) i ))CH2- or -CH2CH2CH2CH(C(R g (R) h (R) i ))-, where R g R h and R i It is as defined therein.

[0391] A154. In Example A154, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A138 and A150 to A153 is an R-terminated branched C4 to C6 alkylene group of alk. g and R i Independently hydrogenated or halogenated (unless otherwise stated), and the R of the branched C4 to C6 alkylene group of alk h It is hydrogen, halogenated, haloalkoxy, cycloalkyl, cycloalkyloxy, alkoxy, hydroxyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, cyanoalkyloxy, phenyl, heteroaryl, heterocyclic, heterocyclicoxy, heterocyclic carbonyl, or bridging heterocyclic (unless otherwise specified), wherein R h Each ring, as defined therein, is replaced.

[0392] A155. In Example A155, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A138 and A150 to A154 is an R-terminated branched C4 to C6 alkylene group of alk. g and R i It is hydrogen or fluorine (unless otherwise stated), and the R of the branched C4 to C6 alkylene group of alk is... hIt is hydrogen, halogenated, cycloalkyl, cycloalkyloxy, alkoxy, hydroxyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, phenyl, heteroaryl, heterocyclic, heterocyclicoxy, heterocyclic carbonyl, or bridging heterocyclic (unless otherwise specified), wherein R h Each ring, as defined therein, is replaced.

[0393] A156. In Example A156, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A138 and A150 to A155 is an R-terminated branched C4 to C6 alkylene group of alk. g and R i It is hydrogen or fluorine (unless otherwise stated), and the R of the branched C4 to C6 alkylene group of alk is... h It is hydrogen, halogenated, alkoxy, hydroxyl, dialkylaminocarbonyl, cyano or heteroaryl, as defined therein and substituted.

[0394] A157. In Example A157, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A138 and A150 to A155 is wherein alk is a substituted branched C4 to C6 alkylene group as defined therein, and the R of the branched C4 to C6 alkylene group of alk is... h The heteroaryl, heterocyclic group—either itself or as part of a heterocyclic oxygen group, a heterocyclic carbonyl group, or a bridging heterocyclic group—when present, is a five- or six-membered ring, and R h Each ring, as defined therein, is replaced.

[0395] A158. In Example A158, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A138 and A150 to A157 is an alk-branched C4 to C6 alkylene group. g and R i Independently hydrogen, deuterium, or fluorine (unless otherwise stated), and R of the branched C4 to C6 alkylene group of alk. h Unless otherwise specified, it is hydrogen, deuterium, fluorine, cyclopropyl, cyclobutyl, cyclopropyloxy, cyclobutyloxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, hydroxyl, cyano, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, methylcarbonylamino, ethylcarbonylamino, phenyl, pyrazolyl, thiazolyl, furanyl, pyridyl, pyrrolyl, 2-oxopyrrolyl, piperidinyl, piperazine, or tetrahydrofuranyl, wherein R h Each ring is independently selected from the R groups of hydrogen, deuterium, methyl, methoxy, fluorine, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethyl, hydroxyl, amino, methylamino, dimethylamino, and cyano. 7 and R 8 Replace, unless otherwise stated.

[0396] A158A. In Example A158A, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A138 and A150 to A158 is an R-terminated branched C4 to C6 alkylene group of alk. g and R i Unless otherwise stated, it is hydrogen or fluorine, and the R of the branched C4 to C6 alkylene group of alk is... h When present and unless otherwise stated, it is hydrogen, fluorine, hydroxyl, methoxy, cyano, pyrazol-1-yl or methylaminocarbonyl.

[0397] A159. In Example A159, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A134 and A140 is wherein alk is R g R h and R i Substituted C3 to C6 alkylene groups, wherein R g and R h The same or adjacent carbon atoms attached to the straight-chain portion of the C3 to C6 alkylene group, and R g and R h They can form cycloalkylene or heterocyclic groups together with the carbon atoms to which they are attached, wherein R g and R h The formed cycloalkylene and heterocycloalkylene groups are R 9 and R 10 replace.

[0398] A160. In Example A160, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A134, A140 and A159 is wherein alk is R g R h and R i Substituted C3 to C6 alkylene groups, wherein R g and R h The same carbon atom attached to the straight-chain portion of the C3 to C6 alkylene group and can form an R-shaped structure together with the carbon atoms to which they are attached. 9 and R 10 Substituted cycloalkylene groups.

[0399] A161. In Example A161, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A134, A140 and A159 is wherein alk is R g R h and R i Substituted C3 to C6 alkylene groups, wherein R g and R hThe same carbon atoms attached to the straight-chain portion of the C3 to C6 alkylene group and together with the carbon atoms to which they are attached can form R 9 and R 10 Substituted heterocyclic groups.

[0400] A162. In Example A162, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A134, A140 and A159 is wherein alk is R g R h and R i Substituted C3 to C6 alkylene groups, wherein R g and R h The adjacent carbon atoms of the straight-chain portion of the C3 to C6 alkylene group are attached and can form an R-shaped structure together with the carbon atoms to which they are attached. 9 and R 10 Substituted cycloalkylene groups.

[0401] A163. In Example A163, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A134, A140 and A159 is wherein alk is R g R h and R i Substituted C3 to C6 alkylene groups, wherein R g and R h The adjacent identical carbon atoms attached to the straight-chain portion of the C3 to C6 alkylene group and together with the carbon atoms to which they are attached form an R-shaped structure. 9 and R 10 Substituted heterocyclic groups.

[0402] A164. In Example A164, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A134, A140 and A159 to A161 is wherein R g and R h The same carbon atoms attached to the straight-chain portion of the C3 to C6 alkylene group and together with the carbon atoms to which they are attached can form cycloalkylene groups having the following formula:

[0403]

[0404] Or have a heterocyclic sub-cyclone group with the following formula:

[0405]

[0406] Each ring is R 9 and R 10 Replacement, preferably R 9 It is hydrogen, halo, methyl, or ethyl, and R 10 It is hydrogen.

[0407] A165. In Example A165, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A134, A140, A159, A162, and A163 is wherein R g and R h The adjacent carbon atoms of the straight-chain portion of the C3 to C6 alkylene group are attached and can together with the attached carbon atoms to form a cycloalkylene group having the following formula:

[0408]

[0409] Or have a heterocyclic sub-cyclone group with the following formula:

[0410]

[0411] Each ring is R 9 and R 10 Replacement, preferably R 9 It is hydrogen, halo, methyl, or ethyl, and R 10 It is hydrogen.

[0412] A166. In Example A166, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A134 is wherein the alk is R g R h and R i Substituted C3 to C6 heteroalkylene compounds.

[0413] A167. In Example A167, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A134 and A166 is wherein the alk is R g R h and R i Substituted C3 to C6 heteroalkylene groups, wherein R g R h and R i It is hydrogen.

[0414] A168. In Example A168, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A134 and A166 is wherein the alk is R g R h and R i Substituted C3 to C6 heteroalkylene groups, wherein R g R h and R i It is hydrogenated or halogenated, provided that R is hydrogenated. g R h and R i At least one of them is halogenated.

[0415] A169. In Example A169, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A134 and A166 is wherein alk is R g R h and R i Substituted C3 to C6 heteroalkylene groups, wherein R h It is not hydrogen and R i It is hydrogen, or when R g and R h When R is attached to the same or adjacent carbon atom of the straight-chain portion of the C3 to C6 heteroalkylene group, g and R h They can form cycloalkylene or heterocyclic groups together with the carbon atoms to which they are attached, wherein the cycloalkylene and heterocyclic groups are R 9 and R 10 replace.

[0416] A169a. In Example A169a, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A134 and A169 is wherein R g and R h The same carbon atoms attached to the straight-chain portion of the C3 to C6 heteroalkylene group and together with the carbon atoms to which they are attached can form cycloalkylene groups having the following formula:

[0417]

[0418] Or have a heterocyclic sub-cyclone group with the following formula:

[0419]

[0420] Each ring is R 9 and R 10 Replacement, preferably R 9 It is hydrogen, halo, methyl, or ethyl, and R 10 It is hydrogen.

[0421] A169b. In Example A169b, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A134 and A169 is wherein R g and R h The adjacent carbon atoms of the straight-chain portion of the C3 to C6 heteroalkylene group are attached and can together with the attached carbon atoms to form a cycloalkylene group having the following formula:

[0422]

[0423] Or have a heterocyclic sub-cyclone group with the following formula:

[0424]

[0425] Each ring is R 9 and R 10 Replacement, preferably R 9 It is hydrogen, halo, methyl, or ethyl, and R 10 It is hydrogen.

[0426] A170. In Example A170, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A134, A166 and A169 is wherein alk is R g R h and R i Substituted C3 to C6 heteroalkylene groups, wherein R h It is not hydrogen and R i It is hydrogen.

[0427] A171. In Example A171, the compound or a pharmaceutically acceptable salt thereof, as described in any one of Examples A1 to 134, A142 to A149A, A151 to A156, A158, A158A and A166 to A170, is wherein the C3 to C6 heteroalkylene group of alk is a straight-chain C3 to C6 heteroalkylene group.

[0428] A172. In Example A172, the compound or a pharmaceutically acceptable salt thereof, as described in any one of Examples A1 to A134, A142 to A149A, A151 to A156, A158, A158A, A166 to A169, A170, and A171, is wherein the straight-chain C3 to C6 heteroalkylene group of alk is R as defined therein. g R h and R i Replacement -CH2CH2X a CH2-、-CH2X a CH2CH2-、-CH2CH2CH2X a -、-X a CH2CH2CH2-、-X y CH2CH2X a -、-X y CH2CH2X a CH2-、-CH2CH2CH2X a CH2-、-CH2X a CH2-, -X a CH2CH2-、-CH2CH2X a -, -CH2CONR q CH2-、-CH2SO2NR q CH2-、-CH2NR q COCH2-、-CH2NRq SO2CH2-、-CH2CH2CH2NR q CO-, -CH2CONR q -、-CH2SO2NR q -、-CH2NR q CO-、-CH2NR q SO2-, -CONR q CH2-, -SO2NR q CH2-, -NR q COCH2- or -NR q SO2CH2-, and X a Yes -NR q -, -O-, -S-, -SO-, -SO2- or -CO-.

[0429] A173. In Example A173, the compound or a pharmaceutically acceptable salt thereof, as described in any one of Examples A1 to A134, A142 to A149A, A151 to A156, A158, A158A, A166 to A172, is wherein R q It is hydrogen, methyl, ethyl, methyl carbonyl, or methyl sulfonyl.

[0430] A174. In Example A174, the compound or a pharmaceutically acceptable salt thereof, as described in any one of Examples A1 to A134, A142 to A149A, A151 to A156, A158, A158A, A166 to A169, and A170 to A173, is wherein the straight-chain C3 to C6 heteroalkylene group of alk is -CH2X. a CH2-, -X a CH2CH2-、-CH2CH2X a -, -CH2CH(R) h )X a -、-X a CH(R h CH2-, -CH2CONR q -、-CH2SO2NR q -、-CH2NR q CO-、-CH2NR q SO2-, -CONR q CH2-, -SO2NR q CH2-, -NR q COCH2- or -NR q SO2CH2-, where X a Is it -S-, -SO2-, -O-, or -NR? q -

[0431] A175. In Example A175, the compound or a pharmaceutically acceptable salt thereof, as described in any one of Examples A1 to A134, A142 to A149A, A151 to A156, A158, A158A, A166 to A169, and A170 to A174, is wherein the straight-chain C3 to C6 heteroalkylene group of alk is -CH2CH2CH2X. a -or-CH2CH2X a .

[0432] A176. In Example A176, the compound or a pharmaceutically acceptable salt thereof, as described in any one of Examples A1 to A134, A142 to A149A, A151 to A156, A158, A158A, A166 to A169, and A170 to A175, is an R-type straight-chain C3 to C6 heteroalkylene group of alk. g It is hydrogenated or halogenated (unless otherwise stated), and the R of the straight-chain C3 to C6 heteroalkylene group of alk is... h It is (unless otherwise stated) hydrogen, halogenated, haloalkoxy, cycloalkyl, cycloalkyloxy, alkoxy, hydroxyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, cyanoalkyloxy, phenyl, heteroaryl, heterocyclic or bridging heterocyclic, wherein each ring is substituted as defined herein and R i It is hydrogen.

[0433] A177. In Example A177, the compound or a pharmaceutically acceptable salt thereof, as described in any one of Examples A1 to A134, A142 to A149A, A151 to A156, A158, A158A, A166 to A169, and A170 to A176, is an R-type compound of a straight-chain C3 to C6 heteroalkylene group of alk. g It is hydrogen or fluorine (unless otherwise stated), and R is a straight-chain C3 to C6 heteroalkylene group of alk. h (Unless otherwise stated) is hydrogen, halo, haloalkoxy, alkoxy, hydroxy, dialkylaminocarbonyl, cyano or heteroaryl, substituted as defined therein.

[0434] A178. In Example A178, the compound or a pharmaceutically acceptable salt thereof, as described in any one of Examples A1 to A134, A142 to A149A, A151 to A156, A158, A158A, A166 to A169, and A170 to A177, is an R-type straight-chain C3 to C6 heteroalkylene group of alk. h The heteroaryl, heterocyclic, and bridging heterocyclic groups, when present, are five- or six-membered rings, and each ring is substituted as defined therein.

[0435] A179. In Example A179, the compound or a pharmaceutically acceptable salt thereof, as described in any one of Examples A1 to A134, A142 to A149A, A151 to A156, A158, A158A, A166 to A169, and A170 to A176, is an R-type straight-chain C3 to C6 heteroalkylene group of alk. g When present and unless otherwise stated, is hydrogen, deuterium, or fluorine, and is an R of a straight-chain C3 to C6 heteroalkylene group of alk. h When present and unless otherwise stated, it is hydrogen, deuterium, fluorine, cyclopropyl, cyclobutyl, cyclopropyloxy, cyclobutyloxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, hydroxyl, cyano, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, methylcarbonylamino, ethylcarbonylamino, phenyl, pyrazolyl, thiazolyl, furanyl, pyridyl, pyrrolyl, 2-oxopyrrolyl, piperidinyl, piperazine, or tetrahydrofuranyl, wherein each ring is independently selected from the R group of hydrogen, deuterium, methyl, methoxy, fluorine, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethyl, hydroxyl, amino, methylamino, dimethylamino, and cyano. 7 and R 8 replace.

[0436] A180. In Example A180, the compound or a pharmaceutically acceptable salt thereof, as described in any one of Examples A1 to A134, A142 to A149A, A151 to A156, A158, A158A, A166 to A169, and A170 to A179, is an R-type straight-chain C3 to C6 heteroalkylene group of alk. g It is hydrogen, and R is a straight-chain C3 to C6 heteroalkylene group of alk. h It is fluorine, cyclopropyl, cyclopropyloxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, hydroxyl, cyano, methylaminocarbonyl, dimethylaminocarbonyl, methylcarbonylamino, phenyl, pyrazol-1-yl, pyrazol-4-yl, pyridin-4-yl, pyrrolidine-1-yl, or 2-oxopyrrolidine-1-yl, wherein each ring is independently selected from the R of hydrogen, deuterium, methyl, or fluorine. 7 and R 8 replace.

[0437] A181. In Example A181, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A172 to A180 is wherein X a Yes -NR q -, -O-, -S- or -SO2-, preferably -NR q -、-O- or -S-.

[0438] A182. In Example A182, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A172 to A181 is wherein X a Yes -NR q -, where R q It is either hydrogen or methyl.

[0439] A183. In Example A183, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A172 to A181 is wherein X a Yes -O-.

[0440] A184. In Example A184, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A172 to A181 is wherein X a Yes -S-.

[0441] A185. In Example A185, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A172 to A184 is wherein X y Yes -O-.

[0442] A186. In Example A186, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A172 to A184 is wherein X y It is -NH- or -NCH3-.

[0443] A187. In Example A187, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to 134, A166 to A169 and A170 is wherein the C3 to C6 heteroalkylene group of alk is a branched C4 to C6 heteroalkylene group.

[0444] A188. In Example A188, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A134, A166 to A169, A170 and A187 is wherein the C4 to C6 heteroalkylene branch of alk is -CH2X. a CH(CH3)CH2-、-CH2X y CH2CH(CH3)X a -, -CH2CH2CH(CH3)X a -、-X a CH(CH3)CH2CH2-、-X y CH2CH(CH3)X a -、-X y CH(CH3)CH2X a -, -CH2CH2CH2CH(CH3)X a -、-X aCH(CH2R h CH2-, -CH2CH(CH2R) h )X a -、-X a CH(CH2CH2R h CH2-, -CH2CH(CH2CH2R) h )X a -, -CH2C(CH3)(CH3)X a -、-X a C(CH3)(CH3)CH2-, -CH(CH3)CH(CH3)X a -、-CONR q CH2CH(CH3)X a -、-CH2NR q COCH(CH3)CH2- or -NR q COCH(CH3)CH2-, where X a Yes -NR q -, -O-, -S-, -SO-, -SO2-, or -CO-.

[0445] A189. In Example A189, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to 134, A166 to A169, A170, A187, and A188, is wherein the C4 to C6 heteroalkyl group of the alk branch is -CH2C(CH3)(CH3)X a -、-CH(CH3)(CHCH3)X a -、-X a CH(CH2CH2R h CH2-, -CH2CH(CH2CH2R) h )X a -、-X a CH(CH2R h CH2- or -CH2CH(CH2R) h )X a -

[0446] A190. In Example A190, the compound or a pharmaceutically acceptable salt thereof, as described in any one of Examples A1 to 134, A166 to A169, A170, A173, and A187 to A189, is an R-terminated branched C4 to C6 heteroalkylene group of alk. g and R i It is hydrogenated or halogenated (unless otherwise stated), and the R of the branched C4 to C6 heteroalkylene group of alk is... hIt is hydrogen, halogenated, haloalkoxy, cycloalkyl, cycloalkyloxy, alkoxy, hydroxyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, cyanoalkyloxy, phenyl, heteroaryl, heterocyclic, heterocyclicoxy, heterocyclic carbonyl, or bridging heterocyclic, as defined herein, and is substituted.

[0447] A191. In Example A191, the compound or a pharmaceutically acceptable salt thereof, as described in any one of Examples A1 to 134, A166 to A169, A170, A173, and A187 to A190, is an R-terminated branched C4 to C6 heteroalkylene group of alk. g and R i It is hydrogen or fluorine (unless otherwise stated), and R h (Unless otherwise stated) is hydrogen, halogenated, cycloalkyl, cycloalkyloxy, alkoxy, hydroxyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, phenyl, heteroaryl, heterocyclic, heterocyclicoxy, heterocyclic carbonyl, or bridging heterocyclic, as defined herein, and is substituted.

[0448] A192. In Example A192, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A134, A166 to A169, A170, A173, and A187 to A191 is wherein R g and R i It is hydrogen, and R h It is hydrogen, heteroaryl, alkylaminocarbonyl, or cyano.

[0449] A193. In Example A193, the compound or a pharmaceutically acceptable salt thereof, as described in any one of Examples A1 to 134, A166 to A169, A170, A173 and A187 to A192, is a heteroaryl and heterocyclic group of a branched C4 to C6 heteroalkylene group of alk—either as part of a heterocyclic oxygen group, a heterocyclic carbonyl group, and a bridging heterocyclic group, which, when present, is a five- or six-membered ring, and each ring is substituted as defined therein.

[0450] A194. In Example A194, the compound or a pharmaceutically acceptable salt thereof, as described in any one of Examples A1 to 134, A166 to A169, A170, A173, and A187 to A193, is an R-terminated compound of a branched C4 to C6 heteroalkylene group of alk. hUnless otherwise stated, it is hydrogen, deuterium, fluorine, cyclopropyl, cyclobutyl, cyclopropyloxy, cyclobutyloxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, hydroxyl, cyano, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, methylcarbonylamino, ethylcarbonylamino, phenyl, pyrazolyl, thiazolyl, furanyl, pyrrolylyl, pyridyl, piperidinyl, piperazine, or tetrahydrofuranyl, wherein each ring is independently selected from the R group of hydrogen, deuterium, methyl, methoxy, fluorine, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethyl, hydroxyl, amino, methylamino, dimethylamino, and cyano. 7 and R 8 replace.

[0451] A195. In Example A195, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A188 to A194 is wherein X a Yes -NR q -, -O-, -S- or -SO2-, preferably -NR q - or -O-.

[0452] A196. In Example A196, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A188 to A195 is wherein X a Yes -NR q -, where R q It is either hydrogen or methyl.

[0453] A197. In Example A197, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A188 to A195 is wherein X a Yes -O-.

[0454] A198. In Example A198, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A188 to A195 is wherein X a Yes -S-.

[0455] A199. In Example A199, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A188 to A198 is wherein X y Yes -O-.

[0456] A200. In Example A200, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A188 to A198 is wherein X y It is -NH- or -NCH3-.

[0457] A201. In Example A201, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A200 is wherein alk is:

[0458]

[0459] A202. In Example A202, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A201 is wherein alk is:

[0460]

[0461] A203. In Example A203, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A202 is wherein alk is:

[0462]

[0463] A204. In Example A204, the compound or its pharmaceutically acceptable salt as described in any one of Examples A1 to A203 is wherein the degradation determinant is an E3 ubiquitin ligase ligand selected from:

[0464] , , , , , , , , , , , and ;

[0465] Where R ee It is hydrogen, methyl, ethyl, cyclopropyl, or 2,2,2-trifluoroethyl, and R ff It is hydrogen, methyl, cyclopropyl, fluorine, cyano, methoxy, difluoromethoxy, trifluoromethoxy, or trifluoromethyl.

[0466] A205. In Example A205, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A204 is wherein the degradation determinant is an E3 ubiquitin ligase ligand selected from:

[0467] , , , , , , , , , and ;

[0468] Where R ee It is hydrogen, methyl, ethyl, cyclopropyl, or 2,2,2-trifluoroethyl, and R ff It is hydrogen, methyl, cyclopropyl, fluorine, cyano, methoxy, difluoromethoxy, trifluoromethoxy, or trifluoromethyl.

[0469] A206. In Example A206, the compound or a pharmaceutically acceptable salt thereof as described in any one of Examples A1 to A205 is wherein the degradation determinant is an E3 ligase ligand selected from:

[0470]

[0471] A207. In Example A207, the compound or a pharmaceutically acceptable salt thereof, as described in any one of Examples A1 to A39b, A67, A69 to A72, A77, A79 to A82, and A83 to A205, is wherein the degradation determinant is an E3 ubiquitin ligase ligand. , where each R ee It is hydrogen, methyl, ethyl, cyclopropyl or 2,2,2-trifluoroethyl, preferably methyl, and optionally wherein R ff It is hydrogen, methyl, cyclopropyl, fluorine, cyano, methoxy, difluoromethoxy, trifluoromethoxy, or trifluoromethyl.

[0472] The phrase "unless otherwise stated" as used in the embodiments means that when an embodiment involves more than one of the foregoing embodiments with different scopes, only those groups falling within the scope of the groups listed in the foregoing embodiments should be selected from the embodiments to which they relate. For example, R listed in embodiment A18 2 In the group, although Example A1 should select all R listed in A18 2 The group, however, for Example A16, since the scope of A16 is limited to hydroxyalkyl, can only be selected as R for hydroxymethyl from the group list listed in Example A18. 2 .

[0473] Representative compounds of the first aspect and compounds having formula (I) are shown in the following compound table 1:

[0474]

[0475] General synthesis scheme

[0476] Compounds having formula (I) (and any of the embodiments disclosed herein, including specific compounds) can be prepared by the methods described in the reaction schemes shown below.

[0477] The starting materials and reagents used to prepare these compounds were available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin), Bachem (Torrance, California), or Sigma (St. Louis, Missouri), or were prepared by methods known to those skilled in the art, according to procedures described in the following references: Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1–17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1–5 and Supplements (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1–40 (John Wiley and Sons). (1991); March's Advanced Organic Chemistry (John Wiley and Sons, 4th edition) and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some methods for synthesizing compounds having formula (I) (and any of the embodiments disclosed herein, including specific compounds), and various modifications can be made to these schemes as will be apparent to those skilled in the art upon reading this disclosure. If desired, these starting materials and intermediates, as well as the final products of the reactions, can be separated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, etc. Such materials can be characterized using conventional means, including physical constants and spectroscopic data.

[0478] Unless otherwise indicated, the reactions described herein occur at atmospheric pressure, in a temperature range from about -78°C to about 150°C, such as from about 0°C to about 125°C, and further as at about room temperature (or ambient temperature), such as about 20°C.

[0479] Compounds having formula (I) (where the degradation determinant is an E3 ligase ligand having formulas (i) and (ii), and Hy, R 1 R 2 R 2a Ar, Alk, and Z (as defined in the above description of the invention or in its embodiments) can be prepared as described in Scheme 1.

[0480] Option 1

[0481]

[0482] Under suitable conditions (such as acidic, basic, or transition metal-catalyzed reaction conditions well known in the art), using an amine having formula 1-1 (wherein the degradation determinant, Hy, R...) 1 R 2 R 2a Ar, alk, and Z (as defined in the above description of the invention or in its embodiments) are used to treat compounds having formulas 1-2 (wherein A 1 The leaving group, such as halogen (e.g., chlorine or bromine) or methylsulfonyl, provides a compound having formula (I).

[0483] Alternatively, compounds having formula (I) (e.g., where R) 1 R 2 Ar and alk are as defined in the invention description or its embodiments, R 2a (I is hydrogen, Hy is 1,4-piperidinediyl, the degradation determinant is a group having formula (i), and Z is a heterocyclic subcyclic group, a bridged heterocyclic subcyclic group, or a spirocyclic subcyclic group, each ring containing at least one nitrogen atom) can be synthesized as shown and described in Scheme 2.

[0484] Option 2

[0485]

[0486] Under conditions well known in the art, such as in the presence of DIPEA (in tert-butanol), at elevated temperatures, a compound having formula 2-1 (where A) is treated with piperidineamine having formula 2-2. 1 It is a halogen (such as chlorine or bromine), and R 1 and R 2Compounds having formulas 2-3 are provided as defined in the above description of the invention or in its embodiments. Amine compounds having formulas 2-4, prepared by removing the Boc protecting group of formulas 2-3 in the presence of an acid (such as TFA), are converted into sulfonamide compounds having formulas 2-6 by using a sulfonyl halide having formulas 2-5 (wherein A...). 2 It is a halogen (such as chlorine), and LG is a suitable leaving group (such as halo or methanesulfonyl), and Ar and alk are as defined in the above description of the invention or in its embodiments) to treat it. Under alkaline conditions, for example in the presence of DIPEA, it is treated with an amine compound having formula 2-7 (wherein It is a heterocyclic group, a bridged heterocyclic group or a spiroheterocyclic group, each ring containing at least one nitrogen atom, and ring A (as defined in the above description of the invention or in the embodiments thereof) treats compounds having formulas 2-6 to provide compounds having formula (I) (wherein the degradation determinant is a group having formula (i)).

[0487] Proceed as described in Scheme 2 above, but using compounds having formulas 2-8. (where Y) a Z a Ring B is as defined in the invention description and As defined above for compounds 2-7, in lieu of compounds having formulas 2-7, compounds having formula (I) (wherein the degradation determinant is a group having formula (ii)) or any embodiment thereof will be provided.

[0488] Compounds having formulas 2-1, 2-5, 2-7 and 2-8 are commercially available, or they can be prepared by methods known in the art.

[0489] Alternatively, compounds having formula (I) (e.g., where R) 1 R 2 Ar and alk are as defined in the invention description or its embodiments, R 2a The hydrogen is the degradation determinant, which is a group having formula (i), and Z is a heterocyclic subcyclic group containing at least one nitrogen atom (such as 4-piperidin-1-yl), which can be synthesized as shown and described in Scheme 3.

[0490] Option 3

[0491]

[0492] Make a compound having formula 3-1 (where A) 1The halogen, and ring A (as defined in the above description of the invention or in its embodiments) are cross-coupled with a tetrahydropiperidinyl group having formula 3-2 (where M is a metal, such as a borate ester or zinc), to provide a compound having formula 3-3. This reaction is typically carried out in the presence of a palladium catalyst; for example, when M is a borate ester, the Suzuki reaction is carried out in 1,4-dioxane and water in the presence of Pd(dppf)Cl2 and Na2CO3.

[0493] Reduction of the double bond in compound 3-3 under conditions well known in the art, such as in the presence of a palladium catalyst and under a hydrogen atmosphere, yields a compound having formula 3-4. Removal of the Boc protecting group from 3-4 under acidic conditions yields an amine compound having formula 3-5. Under conditions well known in the art, in the presence of a reducing agent such as NaBH(OAc)3 and in a suitable solvent such as DCM, 3-5 is reacted with an aldehyde having formula 3-6 (wherein Ar and -CH2-[alk] 1 ] n-1 It is alk, each as defined in the above description of the invention or its embodiments, wherein Hy is as defined in the above description of the invention or its embodiments, and -CH2-(alk) 1 ) n-1 The reaction is carried out as defined in the above description of the invention or in the embodiments thereof, providing compounds having formulas 3-7. The Boc protecting group in compounds 3-7 is removed using an acid (such as TFA), providing amine compounds having formulas 3-8. Compounds 3-8 are treated with compounds having formulas 2-1 under suitable conditions (such as acidic, basic, or transition metal-catalyzed reaction conditions well known in the art), providing compounds having formula (I) (wherein the degradation determinant is a group having formula (i)).

[0494] Proceeding as described in Scheme 3 above, but replacing the compounds having formulas 3-5 with the compounds having formulas 2-8, will provide compounds having formulas 3-5. The compound can then be converted into a compound having formula (I) (where the degradation determinant is a group having formula (ii)) or any embodiment thereof.

[0495] utility

[0496] Compounds having formula (I) (and any of the embodiments disclosed herein, including specific compounds) can cause degradation of CDK2 / 4 / 6 proteins and are therefore used to treat diseases mediated by CDK2, CDK4 and / or CDK6.

[0497] Mounting evidence suggests that aberrant activation of G1 cyclin kinases, including CDK2 and / or CDK4 and / or CDK6, leads to abnormal cell cycle regulation and proliferation in cancer cells. While mutations in CDK2 and / or CDK4 and / or CDK6 are rarely found, kinase activity in the CDK4 / cyclin D, CDK2 / cyclin E, or CDK2 / cyclin A complexes is elevated in human cancers via several mechanisms. Aberrant regulation of CDK4 and / or CDK6 and / or cyclin D has been identified in many human cancers. For example, cyclin D1 amplification or overexpression has been found in many cancers, including invasive ductal carcinoma of the breast, invasive breast cancer, urothelial carcinoma of the bladder, invasive lobular carcinoma of the breast, and lung adenocarcinoma. Cyclin D1 translocation and / or CDK4 amplification are common in liposarcoma. Lower frequencies of CDK4 amplification have also been observed in other solid tumors and hematologic malignancies. Loss of the CDK4 / 6 inhibitor p16 (CDKN2A) is also a common event in many cancers, including glioblastoma multiforme, squamous cell carcinoma of the head and neck, pancreatic adenocarcinoma, esophageal adenocarcinoma, mesothelioma, squamous cell carcinoma of the lung, urothelial carcinoma of the bladder, melanoma of the skin, diffuse large B-cell lymphoma, cholangiocarcinoma, lung adenocarcinoma, and gastric adenocarcinoma.

[0498] Cyclin E has been found to be frequently amplified in cancers such as uterine, ovarian, gastric, and breast cancer. In some cancer types, loss-of-function mutations in FBXW7, which controls cyclin E turnover, or overexpression of USP28 lead to cyclin E overexpression and CDK2 activation. Alternatively, some cancer cells express overactive truncated forms of cyclin E or cyclin A. Furthermore, amplification and overexpression of cyclin A have been reported in various cancers such as hepatocellular carcinoma, colorectal cancer, and breast cancer. In some tumors, the catalytic activity of CDK2 increases following loss of expression or positional alteration of the endogenous CDK2 inhibitors p27 or p21, or overexpression of SKP2, a negative regulator of p27. Additionally, CDC25A and CDC25B (protein phosphatases responsible for activating CDK2 dephosphorylation) are overexpressed in various tumors. These different mechanisms of CDK2 activation have been validated using cancer cells or mouse cancer models. Furthermore, CDK2 / cyclin E phosphorylates oncogenic Myc to counteract ras-induced senescence, highlighting the importance of CDK2 in myc / ras-induced tumorigenesis. CDK2 inactivation has been shown to be synthetically lethal to myc-overexpressing cancer cells. In aneuploid cancer cells (e.g., KRAS-mutant lung cancer), CDK2 inhibition leads to late catastrophe and apoptosis. Moreover, CDK2 inhibition effectively induces granulocyte differentiation in AML cell lines and arrests tumor growth in AML mouse models.

[0499] CDK2 activation due to cyclin E amplification or overexpression has also been identified as a key primary or acquired resistance pathway in HR+ or HER2+ breast cancer treated with CDK4 / 6 inhibitors or trastuzumab. Therefore, compounds having formula (I) can be used in combination with CDK4 / 6 inhibitors or anti-HER2 therapies for the treatment of cancers refractory to CDK4 / 6 inhibitors or anti-HER2 therapy.

[0500] Therefore, the compounds disclosed herein can be used to treat tumors characterized by: 1) overexpression of CDK2 and / or CDK4 and / or CDK6; 2) amplification / overexpression of cyclin D, cyclin E, or cyclin A; 3) hyperphosphorylation of CDK2 (Thr160) or CDK4 (Thr172); 4) loss-of-function mutations in FBXW7, depletion of AMBRA1, overexpression of USP28, or amplification / overexpression of CDC25A or / and CDC25B; 5) truncated expression of cyclin E or cyclin A; 6) dysregulation of p16, p21, or p27, or overexpression of SKP2; and 7) hyperactive MYC / RAS; 8) aneuploid cancers; and 9) cancers refractory to CDK4 and / or CDK6 inhibitors.

[0501] In some embodiments, the cancer is ovarian cancer (e.g., serous, clear cell, endometrioid, and mucinous ovarian cancer), uterine cancer (e.g., endometrial cancer and uterine sarcoma), gastric cancer (i.e., stomach cancer), lung cancer (e.g., adenocarcinoma, small cell lung cancer and non-small cell lung cancer, small cell and non-small cell carcinoma, bronchial carcinoma, bronchial adenoma, pleural pulmonary blastoma), kidney cancer (e.g., clear cell renal cell carcinoma, papillary renal cell carcinoma, and chromophobe renal cell carcinoma), brain cancer (including astrocytoma, meningioma, and glioblastoma), neuroblastoma, paraganglioma, pheochromocytoma, pancreatic neuroendocrine tumor, somatostatinoma, hemangioblastoma, gastrointestinal stromal tumor, pituitary adenoma, leiomyoma, leiomyosarcoma, polycythemia vera, retinal carcinoma, hereditary leiomyomatosis, renal cell carcinoma, astrocytoma, skin cancer (e.g., melanoma, squamous cell carcinoma, Kaposi's sarcoma, Merck's sarcoma). This includes cancers such as skin cancer (including urothelial carcinoma of the bladder), bladder cancer (including urothelial carcinoma of the bladder), cervical cancer, colorectal cancer (e.g., small bowel cancer, colon cancer, rectal cancer, anal cancer), head and neck cancer (e.g., laryngeal cancer, hypopharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, lip cancer, tongue cancer, and oral cancer), liver cancer (e.g., hepatocellular carcinoma and cholangiocarcinoma), prostate cancer, testicular cancer, gallbladder cancer, pancreatic cancer (e.g., exocrine pancreatic carcinoma and neuroendocrine pancreatic cancer), thyroid cancer and parathyroid cancer, and vas deferens cancer. Fallopian tube cancer, peritoneal cancer, vaginal cancer, bile duct cancer, esophageal cancer (e.g., esophageal squamous cell carcinoma and esophageal adenocarcinoma), sarcoma (e.g., liposarcoma and osteosarcoma), bone cancer, chondrosarcoma, leukemia (including acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, and chronic lymphocytic leukemia), lymphoma (e.g., non-Hodgkin lymphoma (NHL) (including mantle cell lymphoma MCL) and Hodgkin lymphoma), and multiple myeloma.

[0502] In other embodiments, the cancer is breast cancer, including, for example, ER-positive / HR-positive, HER2-negative breast cancer; ER-positive / HR-positive, HER2-positive breast cancer; ER-negative / HR-negative, HER2-positive breast cancer; triple-negative breast cancer (TNBC); or inflammatory breast cancer. In some embodiments, the breast cancer is endocrine-resistant breast cancer, anti-HER2 therapy (e.g., trastuzumab)-resistant breast cancer, or breast cancer exhibiting primary or acquired resistance to CDK4 / CDK6 inhibition. In some embodiments, the breast cancer is advanced or metastatic breast cancer. In some embodiments of each of the above, the breast cancer is characterized by amplification or overexpression of CCND1 and / or CCNE1 and / or CCNE2.

[0503] In addition to cancer, compounds having formula (I) as described in the first aspect of the invention (or any of the embodiments described above) can be used to treat autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), primary Sjögren's syndrome (pSS), multiple sclerosis (MS), Crohn's disease (CD), gout, uveitis, pemphigus vulgaris, and sepsis, and can also be used as a promising preventive treatment for noise-induced, cisplatin-induced, antibiotic-induced, or age-related hearing loss.

[0504] test

[0505] The CDK2 / 4 / 6 degradation activity of the disclosed compounds can be tested using an in vitro assay described in the biological examples below.

[0506] Pharmaceutical Composition

[0507] Generally, compounds having formula (I) (unless otherwise stated, references to compounds having formula (I) include any of the embodiments described herein and / or pharmaceutically acceptable salts thereof) will be administered in a therapeutically effective amount via any of the acceptable administration modes for an agent of similar efficacy. A therapeutically effective amount of a compound having formula (I) (and any of the embodiments disclosed herein, including specific compounds) may range from about 0.01 to about 500 mg / kg patient body weight / day, and may be administered in a single dose or multiple doses. Suitable dose levels may be from about 0.1 to about 250 mg / kg / day, about 0.5 to about 100 mg / kg / day. Suitable dose levels may be from about 0.01 to about 250 mg / kg / day, about 0.05 to about 100 mg / kg / day, or about 0.1 to about 50 mg / kg / day. Within this range, the dose may be from about 0.05 to about 0.5, about 0.5 to about 5, or about 5 to about 50 mg / kg / day. For oral administration, these compositions may be provided in tablet form containing about 1.0 to about 1000 mg of the active ingredient, particularly about 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 mg of the active ingredient. The actual amount of the compound having formula (I) (or any of the embodiments disclosed herein, including specific compounds) (i.e., the active ingredient) will depend on many factors, such as the severity of the disease to be treated, the patient's age and relative health, the potency of the compound being used, the route and form of administration, and other factors.

[0508] Typically, compounds having formula (I) (and any of the embodiments disclosed herein, including specific compounds) are administered as pharmaceutical compositions via any of the following routes: oral, systemic (e.g., transdermal, intranasal, or via suppository), or parenteral (e.g., intramuscular, intravenous, or subcutaneous). Preferred administration is oral administration using a convenient daily dosing regimen that can be adjusted according to the severity of the disease. The compositions may be in the form of tablets, pills, capsules, semi-solids, powders, sustained-release formulations, solutions, suspensions, elixirs, aerosols, or any other suitable composition.

[0509] The choice of formulation depends on a variety of factors, such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules are preferred, including enteric-coated or delayed-release tablets, pills or capsules) and the bioavailability of the active pharmaceutical ingredient.

[0510] The composition typically consists of a compound having formula (I) (or any of the embodiments disclosed herein, including specific compounds) combined with at least one pharmaceutically acceptable excipient. The acceptable excipient is generally non-toxic, facilitates administration, and does not adversely affect the therapeutic benefit of the compound having formula (I) (or any of the embodiments disclosed herein, including specific compounds). Such excipient can be any solid, liquid, semi-solid, or, in the case of an aerosol composition, a gaseous excipient that is generally available to those skilled in the art.

[0511] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice flour, flour, chalk, silica gel, magnesium stearate, sodium stearate, glyceryl monostearate, sodium chloride, and skim milk powder. Liquid and semi-solid excipients can be selected from glycerol, propylene glycol, water, ethanol, and various oils, including those of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, and sesame oil. Preferred liquid carriers, especially for injectable solutions, include water, saline, aqueous dextran, and glycols.

[0512] Compounds having formula (I) (and any of the embodiments disclosed herein, including specific compounds) can be formulated for parenteral administration by injection (e.g., by bolus or continuous infusion). Injectable formulations can be provided in unit dosage forms, such as in ampoules with added preservatives or in multi-dose containers. Compositions can take the form of suspensions, solutions, or emulsions, for example, in oily or aqueous media, and may contain formulations such as suspensions, stabilizers, and / or dispersants. Formulations can be present in unit-dose or multi-dose containers (e.g., sealed ampoules and vials) and can be stored in powder form or under lyophilized (freeze-dried) conditions requiring immediate addition of a sterile liquid carrier (e.g., saline or sterile pyrogen-free water) prior to use. Temporary injectable solutions and suspensions can be prepared from sterile powders, granules, and tablets of the aforementioned types.

[0513] Formulations for parenteral administration include aqueous and non-aqueous (oil-based) sterile injectable solutions of the active compound, which may contain antioxidants, buffers, antibacterial agents, and solutes that make the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickeners. Suitable lipophilic solvents or mediators include fatty oils (such as sesame oil) or synthetic fatty acid esters (such as ethyl oleate or triglycerides) or liposomes. Aqueous injectable suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound to allow for the preparation of highly concentrated solutions.

[0514] In addition to the formulations previously described, compounds having formula (I) (and any of the embodiments disclosed herein, including specific compounds) can also be formulated as reservoir formulations. Such long-acting formulations can be administered by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. Thus, for example, these compounds can be formulated with suitable polymers or hydrophobic materials (e.g., as emulsions in acceptable oils) or ion exchange resins, or formulated as slightly soluble derivatives, such as slightly soluble salts.

[0515] For buccal or sublingual administration, these compositions can be taken in the conventional form of tablets, lozenges, soft lozenges, or gels. Such compositions may contain flavoring bases such as sucrose and active ingredients from gum arabic or astragalus gum.

[0516] Compounds having formula (I) (and any of the embodiments disclosed herein, including specific compounds) may also be formulated into rectal compositions (such as suppositories or retention enemas), for example containing conventional suppository bases (such as cocoa butter, polyethylene glycol or other glycerides).

[0517] Certain compounds having formula (I) (and any embodiments thereof disclosed herein, including specific compounds) can be administered topically, i.e., by non-systemic administration. This includes external application of a compound having formula (I) (or any embodiments thereof disclosed herein, including specific compounds) to the epidermis or oral cavity, and instillation of such a compound into the ear, eye, and nose, such that the compound does not significantly enter the bloodstream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

[0518] Formulations suitable for topical application include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation, such as gels, liniments, lotions, creams, ointments, or pastes, and drops suitable for application to the eyes, ears, or nose. The active ingredient for topical application may constitute, for example, from 0.001% to 10% w / w (by weight) of the formulation. In some embodiments, the active ingredient may constitute up to 10% w / w. In other embodiments, it may constitute less than 5% w / w. In some embodiments, the active ingredient may constitute from 2% w / w to 5% w / w. In other embodiments, it may constitute from 0.1% to 1% w / w of the formulation.

[0519] For administration by inhalation, compounds having formula (I) (and any embodiments thereof disclosed herein, including specific compounds) can be conveniently delivered from an inhaler, a pressurized nebulizer pack, or other convenient method of delivering an aerosol spray. The pressurized pack may contain a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve for delivering a measured amount. Alternatively, for administration by inhalation or inhalation, compounds having formula (I) (and any embodiments thereof disclosed herein, including specific compounds) can be in the form of a dry powder composition, such as a powder mixture of the compound with a suitable powder matrix (e.g., lactose or starch). The powder composition can be presented in unit dosage forms, such as capsules, cartridges, gelatin, or blister packs, from which the powder can be administered by means of an inhaler or inhaler. Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by EW Martin (Mack Publishing Company, 20th edition, 2000).

[0520] The level of a compound having formula (I) (or any of the embodiments disclosed herein, including specific compounds) in the formulation can vary within the full range applicable to those skilled in the art. Typically, the formulation will contain (based on weight percentage (wt.%)) from about 0.01 to 99.99 wt.% of a compound having formula (I) (or any of the embodiments disclosed herein, including specific compounds), with the remainder being one or more suitable pharmaceutical excipients. For example, the compound may be present at a level of about 1-80 wt.%.

[0521] Combination and combination therapy

[0522] A compound having formula (I) (and any embodiments thereof disclosed herein, including specific compounds) may be combined with one or more other drugs for the treatment of diseases or conditions for which the compound having formula (I) (and any embodiments thereof disclosed herein, including specific compounds) or other drugs may be effective. Such other drugs may be administered concurrently or sequentially with a compound having formula (I) (or any embodiments thereof disclosed herein, including specific compounds) via a route and in their usual amounts. When a compound having formula (I) (or any embodiments thereof disclosed herein, including specific compounds) is used concurrently with one or more other drugs, a pharmaceutical composition comprising a unit dosage form of such other drugs and a compound having formula (I) (or any embodiments thereof disclosed herein, including specific compounds) is preferred. However, combination therapy may also include a therapy in which a compound having formula (I) (or any embodiments thereof disclosed herein, including specific compounds) and one or more other drugs are administered at different overlapping schedules. It is also considered that, when used in combination with one or more other active ingredients, compounds having formula (I) (and any embodiments thereof disclosed herein, including specific compounds) and other active ingredients may be used at lower doses than when used individually.

[0523] Therefore, the pharmaceutical compositions disclosed herein also include those containing one or more other drugs in addition to compounds having formula (I) (or any of the embodiments disclosed herein, including specific compounds).

[0524] The aforementioned combinations include not only combinations of compounds having formula (I) (or any of the embodiments disclosed herein, including specific compounds) with one other pharmaceutical agent, but also combinations with two or more other active pharmaceutical agents. Similarly, compounds having formula (I) (or any of the embodiments disclosed herein, including specific compounds) may be used in combination with other pharmaceutical agents for the prevention, treatment, control, improvement of a disease or condition, or reduction of the risk of a disease or condition for which compounds having formula (I) (or any of the embodiments disclosed herein, including specific compounds) are useful. Such other pharmaceutical agents may be administered simultaneously or sequentially with compounds having formula (I) (or any of the embodiments disclosed herein, including specific compounds) via a route and in their usual amounts. When compounds having formula (I) (or any of the embodiments disclosed herein, including specific compounds) are used concurrently with one or more other pharmaceutical agents, pharmaceutical compositions containing such other pharmaceutical agents and compounds having formula (I) (or any of the embodiments disclosed herein, including specific compounds) may be used. Therefore, the pharmaceutical compositions disclosed herein also include those containing one or more other active ingredients in addition to compounds having formula (I) (or any of the embodiments disclosed herein, including specific compounds). The weight ratio of the disclosed compounds to the second active ingredient may vary and will depend on the effective dose of each ingredient. Typically, the respective effective doses will be used.

[0525] In cases where a subject in need has cancer or is at risk of developing cancer, the subject may be treated with any combination of a compound having formula (I) (or any of the embodiments disclosed herein, including specific compounds) and one or more other anticancer agents, including but not limited to: MAP kinase pathway (RAS / RAF / MEK / ERK) inhibitors, including but not limited to: vemurafenib (PLX4032), dabrafenib, enrafenib (LGX818), TQ-B3233, XL-518 (CAS No. 1029872-29-4, available from ACC Inc. (ACC) (obtained by Corp); Trametinib, Selmetinib (AZD6244), TQ-B3234, PD184352, PD325901, TAK-733, Pimaserinib, Bimetinib, Remetinib, Cometinib (GDC-0973), AZD8330, BVD-523, LTT462, Uritinib, AMG510, ARS853 and disclosed in patents WO 2016049565, WO 2016164675, WO 2016168540, WO 2017015562, WO2017058728, WO 2017058768, WO 2017058792, WO 2017058805, WO Any RAS inhibitors listed in WO2017058807, WO2017058902, WO2017058915, WO2017070256, WO2017087528, WO2017100546, WO2017172979, WO2017201161, WO2018064510, WO2018068017, and WO2018119183;

[0526] CSF1R inhibitors (PLX3397, LY3022855, etc.) and CSF1R antibodies (IMC-054, RG7155) and TGFβ receptor kinase inhibitors such as LY2157299;

[0527] BTK inhibitors, such as ibrutinib; BCR-ABL inhibitors: imatinib (Gleevec®); nilotinib hydrochloride; nilotinib (Tasigna®); dasatinib (BMS-345825); bosutinib (SKI-606); ponatinib (AP24534); baffitinib (INNO406); darusertinib (Danusertib) (PHA-739358), AT9283 (CAS 1133385-83-7); cicatinib (AZD0530); and N-[2-[(1S,4R)-6-[[4-cyclobutylamino)-5-(trifluoromethyl)-2-pyrimidinyl]amino]-1,2,3,4-tetrahydronaphthyl-1,4-imino-9-yl]-2-oxoethyl]acetamide (PF-03814735, CAS 942487-16-3);

[0528] ALK inhibitors: PF-2341066 (XALKOPJ®; Crizotinib); 5-chloro-N4-(2-(isopropyl-sulfonyl)phenyl)-N2-(2-methoxy-4-(4-(4-methylpiperazin-l-yl)piperidin-l-yl)phenyl)pyrimidin-2,4-diamine; GSK1838705 A; CH5424802; Ceritinib (ZYKADIA); TQ-B3139, TQ-B3101 PI3K inhibitors: 4-[2-(lH-indazol-4-yl)-6-[[4-(methylsulfonyl)piperazin-l-yl]methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine (also known as GDC 0941 and described in PCT publications WO 09 / 036082 and WO 09 / 055730), 2-methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-l-yl]phenyl]propionitrile (also known as BEZ 235 or NVP-BEZ 235, and described in PCT Publication No. WO 06 / 122806);

[0529] Vascular endothelial growth factor (VEGF) receptor inhibitors: bevacizumab (marketed by Genentech / Roche under the trademark Avastin®), axitinib (N-methyl-2-[[3-[(E)-2-pyridin-2-ylvinyl]-lH-indazole-6-yl]thioalkyl]benzamide, also known as AG013736 and described in PCT Publication No. WO 01 / 002369), alanine brinib ((S)-((R)-l-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,lf][l,2,4]triazin-6-yloxy)propyl-2-yl)2-aminopropionate, also known as BMS-582664), motracene (N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridylmethyl)amino]-3-pyridinecarboxamide, and described in PCT Publication WO 02 / 066470), paretaide (also known as SOM230, and described in PCT Publication WO 02 / 010192), sorafenib (marketed under the brand name Nexavar®); AL-2846 MET inhibitors, such as furitinib, cabozantinib, or crizotinib;

[0530] FLT3 inhibitors - sunitinib malate (marketed by Pfizer under the brand name Sutent®); PKC412 (midotutolin); tanutinib, sorafenib, retalitinib, KW-2449, quezatinib (AC220), and clilanib;

[0531] Epidermal growth factor receptor (EGFR) inhibitors: Gefitnib (marketed under the brand name Iressa®), N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3"S")-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butyramide (marketed by Boehringer Ingelheim under the brand name Tovok®), cetuximab (marketed by Bristol-Myers Squibb under the brand name Erbitux®), panitumumab (marketed by Amgen under the brand name Vectibix®);

[0532] HER2 receptor inhibitors: trastuzumab (marketed by Genentech / Roche under the trademark Herceptin®), neratinib (also known as HKI-272, (2E)-N-[4-[[3-chloro-4-[(pyridin-2-yl)methoxy]phenyl]amino]-3-cyano-7-ethoxyquinoline-6-yl]-4-(dimethylamino)but-2-enamide, and described in PCT Publication No. WO 05 / 028443 (Chinese), lapatinib or lapatinib dimethylbenzenesulfate (marketed by GlaxoSmithKline under the trademark Tykerb®); trastuzumab entazoline (in the United States, ad-trastuzumab entazoline, trademark Kadcyla) - an antibody-drug conjugate consisting of trastuzumab (Herceptin), a monoclonal antibody linked to the cytotoxic agent mertansine (DM1); trastuzumab deruxtecan (trademark Enhertu);

[0533] HER dimer inhibitor: pertuzumab (marketed by Genentech under the trademark Omnitarg®).

[0534] TROP2 ADC: Sertolizumab-glavotecan; Dedabrotuzumab;

[0535] CD20 antibodies: Rituximab (marketed by Genentech / Roche under the trademarks Riuxan® and MabThera®), Tosimomab (marketed by GlaxoSmithKline under the trademark Bexxar®), and Ophamumab (marketed by GlaxoSmithKline under the trademark Arzerra®).

[0536] Tyrosine kinase inhibitors: Erlotinib hydrochloride (marketed by Genentech / Roche under the trademark Tarceva®), Linifanib (N-[4-(3-amino-1H-indazole-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea, also known as ABT) 869, available from Genentech, sunitinib malate (marketed by Pfizer under the brand name Sutent®), bosutinib (4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-carboxynitrile, also known as SKI-606 and described in U.S. Patent No. 6,780,996), dasatinib (marketed by Bristol-Myers Squibb under the brand name Sprycel®), armala (also known as pazopanib, marketed by GlaxoSmithKline under the brand name Votrient®), imatinib, and imatinib mesylate (marketed by Novartis under the brand names Gilvec® and Gleevec®).

[0537] DNA synthesis inhibitors: capecitabine (marketed by Roche under the trademark Xeloda®), gemcitabine hydrochloride (marketed by Eli Lilly and Company under the trademark Gemzar®), nelarabine ((2R3S,4R,5R)-2-(2-amino-6-methoxy-purine-9-yl)-5-(hydroxymethyl)oxopentane-3,4-diol, marketed by GlaxoSmithKline under the trademarks Arranon® and Atriance®);

[0538] Antitumor agent: Oxaliplatin (marketed by Sanofi-Aventis under the brand name Eloxatin® and described in U.S. Patent No. 4,169,846);

[0539] Human granulocyte colony-stimulating factor (G-CSF) regulator: filgrastim (marketed by Amgen under the brand name Neupogen®).

[0540] Immunomodulators: Atorizumab (available from Roche®), pegfilgrastim (marketed by Amgen under the brand name Neulasta®), lenalidomide (also known as CC-5013, marketed under the brand name Revlimid®), thalidomide (marketed under the brand name Thalomid®).

[0541] CD40 inhibitors: dasizumab (also known as SGN-40 or huS2C6, available from Seattle Genetics, Inc.); pro-apoptotic receptor agonists (PARA): dularemine (also known as AMG-951, available from Amgen / Genentech).

[0542] Hedgehog antagonist: 2-chloro-N-[4-chloro-3-(2-pyridyl)phenyl]-4-(methanesulfonyl)-benzamide (also known as GDC-0449 and described in PCT Publication No. WO 06 / 028958);

[0543] Phospholipase A2 inhibitor: Anagrelene (marketed under the brand name Agrylin®);

[0544] BCL-2 inhibitor: 4-[4-[[2-(4-chlorophenyl)-5,5-dimethyl-l-cyclohexen-l-yl]methyl]-l-piperazinyl]-N-[[4-[[(1R)-3-(4-morpholinyl)-l-[(phenylthio)methyl]propyl]amino]-3-[(trifluoromethyl)sulfonyl]phenyl]sulfonyl]benzamide (also known as ABT-263 and described in PCT Publication No. WO 09 / 155386);

[0545] MCl-1 inhibitors: MIK665, S64315, AMG 397 and AZD5991;

[0546] Aromatase inhibitors: exemestane (marketed by Pfizer under the trademark Aromasin®), letrozole (marketed by Novartis under the trademark Femara®); anastrozole (marketed under the trademark Arimidex®).

[0547] Topoisomerase I inhibitors: Irinotecan (marketed by Pfizer under the trademark Camptosar®) and topoisomercan hydrochloride (marketed by GlaxoSmithKline under the trademark Hycamtin®).

[0548] Topoisomerase II inhibitors: etoposide (also known as VP-16 and etoposide phosphate, marketed under the brand names Toposar®, VePesid® and Etopophos®), teniposide (also known as VM-26, marketed under the brand name Vumon®);

[0549] mTOR inhibitors: Tamsulolimus (marketed by Pfizer under the brand name Torisel®), Litrolimus (formerly known as deferolimus, (lR,2R,4S)-4-[(2R)-2[(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28Z,30S,32S,35R)-l,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentoxo-11,36-dioxa-4-azatricyclic[30.3.1.0 4') 9] Hexadecyl-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyl dimethyl phosphonate, also known as AP23573 and MK8669 and described in PCT Publication No. WO 03 / 064383, irolimus (marketed by Novartis under the trademark Afinitor®);

[0550] Proteasome inhibitors, such as carfilzomib, MLN9708, delaminine, or bortezomib;

[0551] BET inhibitors, such as INCB054329, OTX015 and CPI-0610;

[0552] LSD1 inhibitors, such as GSK2979552 and INCB059872;

[0553] HIF-2α inhibitors, such as PT2977 and PT2385;

[0554] Osteoclast inhibitors: L-hydroxy-2-imidazol-L-yl-phosphonoethyl)phosphonic acid monohydrate (marketed by Novartis under the brand name Zometa®); CD33 antibody-drug conjugates: gemtuzumab-orzomicin (marketed by Pfizer / Wyeth under the brand name Mylotarg®).

[0555] CD22 antibody drug conjugate: Ointtocilizumab (also known as CMC-544 and WAY-207294, available from Hangzhou Sage Chemical Co., Ltd.);

[0556] CD20 antibody drug conjugate: Tiimomab (marketed under the brand name Zevalin®);

[0557] Somatostatin analogue: Octreotide (also known as octreotide acetate, marketed under the brand names Sandostatin® and Sandostatin LAR®).

[0558] Synthetic interleukin-11 (IL-11): Oprelvekin (marketed by Pfizer / Wyeth under the brand name Neumega®).

[0559] Synthetic erythropoietin: Dapoxetine Al (marketed by Amgen under the trademark Aranesp®).

[0560] Nuclear factor κ B receptor activator (RANK) inhibitor: denosumab (marketed by Amgen under the brand name Prolia®).

[0561] Thrombopoietin mimic peptide: Romilastine (marketed by Amgen under the brand name Nplate®);

[0562] Cell growth stimulant: Palifamine (marketed by Amgen under the brand name Kepivance®).

[0563] Anti-insulin-like growth factor-1 receptor (IGF-1R) antibodies: Figitumumab (also known as CP-751,871, available from ACC), robatumumab (CAS No. 934235-44-6).

[0564] Anti-CS1 antibody: Elotuzumab (HuLuc63, CAS No. 915296-00-3);

[0565] CD52 antibody: alemtuzumab (marketed under the brand name Camppath®);

[0566] Histone deacetylase inhibitors (HDI): Voninostat (marketed by Merck under the brand name Zolinza®);

[0567] Alkylating agents: Temozolomide (marketed by Schering-Plough / Merck under the trademarks Temodar® and Temodal®), styromycin (also known as actinomycin D and marketed under the trademark Cosmegen®), melphalan (also known as L-PAM, L-sarcomain, and phenylalanine mustard, marketed under the trademark Alkeran®), hexamethylmelamine (also known as hexamethylpyrimidine (HMM), marketed under the trademark Hexalen®), carmustine (marketed under the trademark BiCNU®), bendamustine (marketed under the trademark Treanda®), busulfan (marketed under the trademarks Busulfex® and Myleran®), carboplatin (marketed under the trademark Paraplatin®). ), romaine mustard (also known as CCNU, sold under the brand name CeeNU®), cisplatin (also known as CDDP, sold under the brand names Platinol® and Platinol®-AQ), chlorambucil (sold under the brand name Leukeran®), cyclophosphamide (sold under the brand names Cytoxan® and Neosar®), dacarbazine (also known as DTIC, DIC, and imidazole carboxamide, sold under the brand name DTIC-Dome®), hexamethylmelamine (also known as hexamethylpyrimidine (HMM), sold under the brand name Hexalen®), ifosfamide (sold under the brand name Ifex®), procarbazine (sold under the brand name Matulane®), dichloromethyldiethylamine (also known as nitrogen) Mustard, nitrogen mustard and mechloroethamine hydrochloride (marketed under the brand name Mustargen®), streptozotocin (marketed under the brand name Zanosar®), thioplex (also known as thiophosphoramide, TESPA and TSPA, marketed under the brand name Thioplex®; biological response modulators: BCG (marketed under the brand names theraCys® and TICE® BCG), and dine-1 interleukin (marketed under the brand name Ontak®).

[0568] Antitumor antibiotics: Doxorubicin (marketed under the brand names Adriamycin® and Rubex®), Bleomycin (marketed under the brand name lenoxane®), Daunoxicin (also known as Daunoxicin Hydrochloride, Daunoxicin Hydrochloride, and Daunoxicin Hydrochloride, marketed under the brand name Cerubidine®), Daunoxicin Liposome (Daunoxicin Liposome Citrate, marketed under the brand name DaunoXome®), Mitoxantrone (also known as DHAD, marketed under the brand name Novantrone®), Epirubicin (marketed under the brand name Ellence™), Idamycin (marketed under the brand names Idamycin® and Idamycin PFS®), Mitomycin C (marketed under the brand name Mustamycin®).

[0569] Antimicrotubule agent: Estrogenus estradiol (marketed under the brand name Emcyl®);

[0570] Cathepsin K inhibitor: Odanacatib (also known as MK-0822, N-(l-cyanocyclopropyl)-4-fluoro-N-2-{(1S)-2,2,2-trifluoro-l-[4'-(methanesulfonyl)biphenyl-4-yl]ethyl}-L-leucamide, available from Lanzhou Chon Chemicals, ACC and ChemieTek, and described in PCT Publication No. WO 03 / 075836); Epothilone B analog: Ixaspirone (marketed by Bristol-Myers Squibb under the brand name Lxempra®).

[0571] Heat shock protein (HSP) inhibitors: Tanespimycin (17-allylamino-17-demethoxygeldmycin, also known as KOS-953 and 17-AAG, available from SIGMA and described in U.S. Patent No. 4,261,989), NVP-HSP990, AUY922, AT13387, STA-9090, Debio 0932, KW-2478, XL888, CNF2024, TAS-116

[0572] TpoR agonist: Eltrombopag (marketed by GlaxoSmithKline under the brand names Promacta® and Revolade®).

[0573] Antimitotic agents: Docetaxel (marketed by Sanofi-Aventis under the brand name Taxotere®); Adrenocorticosteroid inhibitors: Aminoglutate (marketed under the brand name Cytadren®).

[0574] Anti-androgens: Nilumet (marketed under the brand names Nilandron® and Anandron®), Bicalutamide (marketed under the brand name Casodex®), Flutamide (marketed under the brand name Fulexin™).

[0575] Androgens: Fluoromethyltestosterone (marketed under the brand name Halotestin®);

[0576] CDK (CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK11 / 12, or CDK16) inhibitors, including but not limited to avocidib (a pan-CDK inhibitor, also known as flavopirdol or HMR-1275, 2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-1-methyl-4-piperidinyl]-4-benzopyranone (chromenone), and described in U.S. Patent No. 5,621,002).

[0577] CDK4 / 6 inhibitors palbociclib, ribociclib, abeciclib, and trilacib; CDK9 inhibitors AZD 4573, P276-00, AT7519M, and TP-1287; CDK2 / 4 / 6 inhibitors, such as PF-06873600;

[0578] SHP-2 inhibitors, such as TNO155;

[0579] MDM2 / MDMX, MDM2 / p53 and / or MDMX / p53 modifiers;

[0580] Gonadotropin-releasing hormone (GnRH) receptor agonists: leuprorelin or leuprorelin acetate (marketed by Bayer AG under the brand name Viadure®, by Sanofi-Aventis under the brand name Eligard®, and by Abbott Labs under the brand name Lupron®).

[0581] Taxane antitumor agents: Cabazitaxel (l-hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytaxyl-2a,4,13a-triyl-4-acetate-2-benzoate-13-[(2R,3S)-3-{[(tert-butoxy)carbonyl]amino}-2-hydroxy-3-phenylpropionate), Lalotaxel ((2α,3ξ,4α,5β,7α,10β,13α)-4,10-bis(acetoxy)-13-({(2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-3-phenylpropionyl}oxy)-l-hydroxy-9-oxo-5,20-epoxy-7,19-cyclotaxyl-2-ene-2-ylbenzoate);

[0582] 5HT1a receptor agonist: zaliroden (also known as SR57746, l-[2-(2-naphthyl)ethyl]-4-[3-(trifluoromethyl)phenyl]-1,2,3,6-tetrahydropyridine, and described in U.S. Patent No. 5,266,573); HPC vaccine: Cervarix® marketed by GlaxoSmithKline and Gardasil® marketed by Merck; iron chelator: derafloxacin (marketed by Novartis under the brand name Exjade®);

[0583] Antimetabolites: Cladribine (2-chlorodeoxyadenosine, marketed under the brand name leustatin®), 5-fluorouracil (marketed under the brand name Adrucil®), 6-thioguanine (marketed under the brand name Purinethol®), pemetrexed (marketed under the brand name Alimta®), vidarabine (also known as vidarabine (Ara-C), marketed under the brand name Cytosar-U®), cytarabine liposomes (also known as liposome Ara-C, marketed under the brand name DepoCyt™), decitabine (marketed under the brand name Dacog) (Sold under the brand names Hydrea®, Droxia™, and Mylocel™), hydroxyurea (sold under the brand names Hydrea®, Droxia™, and Mylocel™), fludarabine (sold under the brand name Fludara®), fluorouracil (sold under the brand name FUDR®), cladribine (also known as 2-chlorodeoxyadenosine (2-CdA), sold under the brand name Leustatin™), methotrexate (also known as methotrexate, methotrexate sodium (MTX), sold under the brand names Rheumatrex® and Trexall™), pentostatin (sold under the brand name Nipent®);

[0584] Bisphosphonates: pamidronate (marketed under the brand name Aredia®), zoledronic acid (marketed under the brand name Zometa®); Demethylating agents: 5-azacitidine (marketed under the brand name Vidaza®), decitabine (marketed under the brand name Dacogen®);

[0585] Plant alkaloids: Paclitaxel protein-bound (marketed under the brand name Abraxane®), vinca alkaloid (also known as vinca sulfate, vinca alkaloid, and VLB, marketed under the brand names Alkaban-AQ® and Velban®), vincristine (also known as vinca alkaloid sulfate, LCR, and VCR, marketed under the brand names Oncovin® and Vincasar Pfs®), vinorelbine (marketed under the brand name Navelbine®), and paclitaxel (marketed under the brand names Taxol and Onxal™).

[0586] Retinoids: Alvitamin A (marketed under the brand name Panretin®), Retinoic acid (all-trans retinoic acid, also known as ATRA, marketed under the brand name Vesanoid®), Isotane (13-cis-retinoic acid, marketed under the brand names Accutane®, Amnesteem®, Claravis®, Clarus®, Decutan®, Isotane®, Izotech®, Oratane®, Isotret®, and Sotret®), Besalodin (marketed under the brand name Targretin®);

[0587] Glucocorticoids: Hydrocortisone (also known as cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate, and marketed under the brand names Ala-Cort®, hydrocortisone phosphate, Solu-Cortef®, Hydrocort Acetate®, and Lanacort®), dexamethasone ((8S,9R,10S,l) (lS,13S,14S,16R,17R)-9-fluoro-ll,17-dihydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-6,7,8,9,10,ll,12,13,14,15,16,17-dodecano-3H-cyclopentadien[a]phenanthrene-3-one), prednisolone (marketed under the brand names Delta-Cortel®, Orapred®, Pediapred® and Prelone®), prednisolone (marketed under the brand names Deltasone®, Liquid Red®, Meticorten® and Orasone®), methylprednisolone (also known as 6-methylprednisolone, methylprednisolone acetate, sodium methylprednisolone succinate, marketed under the brand names Duralone®, Medralone®, Medrol®, M-Prednisol® and Solu-Medrol®);

[0588] Cytokines: Interleukin-2 (also known as aleukin and IL-2, marketed under the brand name Proleukin®), Interleukin-11 (also known as olpreleukin, marketed under the brand name Neumega®), Interferon-α (also known as IFN-α, marketed under the brand names Intron® A and Roferon-A®);

[00209] Estrogen receptor downregulator: Fulvestrant (marketed under the brand name Faslodex®);

[0589] Anti-estrogens: Tamoxifen (marketed under the brand name Novaldex®); Toremifene (marketed under the brand name Fareston®);

[0590] Selective estrogen receptor modulator (SERM): Raloxifen (marketed under the brand name Evista®).

[0591] Luteinizing hormone-releasing hormone (LHRH) agonist: Goserelin (marketed under the brand name Zoladex®); Progesterone: Megestrol acetate (also known as medroxyprogesterone acetate, marketed under the brand name Megace®).

[0592] Miscellaneous cytotoxic agents: Arsenic trioxide (marketed under the brand name Trisenox®), asparaginase (also known as L-asparaginase, Erwinia L-asparaginase, marketed under the brand names Elspar® and Kidrolase®);

[0593] One or more immune checkpoint inhibitors: CD27, CD28, CD40, CD122, CD96, CD73, CD39, CD47, OX40, GITR, CSF1R, JAK, PI3Kδ, PI3Kγ, TAM kinase, arginase, CD137 (also known as 4-1BB), ICOS, A2AR, A2BR, HIF-2α, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, CD96, TIGIT, PD-1, PD-L1, and PD-L2. In some embodiments, the immune checkpoint molecule is a stimulating checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40, GITR, CD137, and STING. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint molecule selected from B7-H3, B7-H4, BTLA, CTLA-4, IDO, TDO, arginase, KIR, LAG3, PD-1, TIM3, CD96, TIGIT, and VISTA. In some embodiments, the compounds provided herein may be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors, and TGFRβ inhibitors.

[0594] In some embodiments, the inhibitor of the immune checkpoint molecule is a PD-1 inhibitor, such as an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, or AMP-224. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab, or PDR001. In some embodiments, the anti-PD1 antibody is pembrolizumab.

[0595] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of PD-L1, such as an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments, the anti-PD-L1 monoclonal antibody is MPDL3280A (atelizumab) or MEDI4736 (dulvarubb).

[0596] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of CTLA-4, such as an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab or trimemumab. In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of LAG3, such as an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016 or LAG525. In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of GITR, such as an anti-GITR antibody. In some embodiments, the anti-GITR antibody is TRX518 or MK-4166, INCAGN01876 or MK-1248. In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of OX40, such as an anti-OX40 antibody or OX40L fusion protein. In some embodiments, the anti-OX40 antibody is MEDI0562 or INCAGN01949, GSK2831781, GSK-3174998, MOXR-0916, PF-04518600, or LAG525. In some embodiments, the OX40L fusion protein is MEDI6383.

[0597] Compounds having formula (I) (and any of the embodiments disclosed herein, including specific compounds) can also be used to increase or enhance immune responses, including increasing immune responses to antigens; improving immunization, including increasing vaccine efficacy; and increasing inflammation. In some embodiments, the compounds of the present invention can be used to enhance immune responses to vaccines, including but not limited to Listeria vaccines, oncolytic cell virus vaccines, and cancer vaccines such as GVAX® (a tumor cell vaccine transfected with the granulocyte-macrophage colony-stimulating factor (GM-CF) gene). Anticancer vaccines include dendritic cells, synthetic peptides, DNA vaccines, and recombinant viruses. Other immunomodulators include those that block the migration of immune cells, such as antagonists of chemokine receptors (including CCR2 and CCR4); Sting agonists; and Toll receptor agonists.

[0598] Other anticancer agents include those that enhance the immune system, such as adjuvants or adoptive T-cell transfers. The compounds of this application may be effective as enhancers of T-cell activation when combined with CAR (chimeric antigen receptor) T-cell therapy.

[0599] Compounds having formula (I) (or any of the embodiments disclosed herein, including specific compounds) may also be used in combination with the following adjunctive therapies: antinausea agents: NK-1 receptor antagonists: cassopithin (marketed by GlaxoSmithKline under the brand names Rezonic® and Zunrisa®); and

[0600] Cell protectants: Amifostine (sold under the brand name Ethyol®), leucovorin (also known as calcium leucovorin, leucine factor, and folinic acid). Example

[0601] The following preparation methods for intermediates (reference materials) and compounds having formula (I) (examples) are given to enable those skilled in the art to more clearly understand and practice this disclosure. They should not be considered as limiting the scope of this disclosure, but merely as illustrations and representations.

[0602] Reference 1

[0603] Synthesis of 2,2,2-trifluoroacetate of 3-(5-(azacyclobutane-3-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione

[0604]

[0605] Step 1: (1-(tert-butoxycarbonyl)azacyclobutane-3-yl)zinc(II) iodide

[0606]

[0607] Add 1,2-dibromoethylene (66 mg, 0.35 mmol, 0.10 equivalent) to a mixture of Zn powder (300 mg, 4.59 mmol, 1.30 equivalent) in DMA (3.0 mL) and stir the mixture at 65°C under N2 for 30 min. Cool the mixture to room temperature and add TMSCl (38 mg, 0.35 mmol, 0.10 equivalent). After stirring the mixture for 30 min, add dropwise a solution of tert-butyl 3-iodozacyclobutane-1-carboxylate (1.00 g, 3.53 mmol, 1.00 equivalent) in DMA (1.0 mL). Stir the mixture at 65°C under N2 for 2 h, then cool to room temperature. Use the solution for the next step without further purification.

[0608] Step 2: 3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)azacyclobutane-1-carboxylic acid tert-butyl ester

[0609]

[0610] A solution of (1-(tert-butoxycarbonyl)azacyclobutane-3-yl)zinc(II) iodide (600 mg, 1.72 mmol, 3.00 equivalents) in DMA was slowly added to a mixture of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidin-2,6-dione (185 mg, 0.57 mmol, 1.00 equivalents), CuI (12 mg, 0.06 mmol, 0.10 equivalents), and Pd(dppf)Cl2 (44 mg, 0.06 mmol, 0.10 equivalents) in DMA (2.0 mL). The mixture was stirred overnight at 90°C under N2. The mixture was concentrated and purified by silica gel column chromatography (EtOAc) to give the title compound as a brown solid.

[0611] Step 3: 3-(5-(azacyclobutane-3-yl)-1-oxoisoindoline-2-yl)piperidine-2,6-dione 2,2,2-trifluoroacetate

[0612]

[0613] TFA (0.2 mL) was added dropwise to a solution of 3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)azacyclobutane-1-carboxylic acid tert-butyl ester (44 mg, 0.11 mmol, 1.00 equivalent) in DCM (1.0 mL), and the solution was stirred for 3 h. The resulting mixture was concentrated to give the title product as a brown oil.

[0614] Reference Item 2

[0615] Synthesis of 2,2,2-trifluoroacetate of 3-(4-(azacyclobutane-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione

[0616]

[0617] Step 1: 3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]-imidazol-4-yl)azacyclobutane-1-carboxylic acid tert-butyl ester

[0618]

[0619] A solution of (1-(tert-butoxycarbonyl)azacyclobutan-3-yl)zinc(II) iodide (600 mg, 1.72 mmol, 3.00 equivalents) in DMA was slowly added to a mixture of 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione (193 mg, 0.57 mmol, 1.00 equivalents), CuI (12 mg, 0.06 mmol, 0.10 equivalents), and Pd(dppf)Cl2 (44 mg, 0.06 mmol, 0.10 equivalents) in DMA (2.0 mL). The mixture was stirred overnight at 90°C under N2. The mixture was concentrated and purified by silica gel column chromatography (EtOAc) to give the title compound as a yellow solid.

[0620] Step 2: 3-(4-(azacyclobutane-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-2,6-dione 2,2,2-trifluoroacetate

[0621]

[0622] TFA (0.2 mL) was added dropwise to a solution of tert-butyl 3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)azacyclobutane-1-carboxylate (23 mg, 0.055 mmol, 1.00 equivalent) in DCM (1.0 mL), and the solution was stirred at room temperature for 3 h. The resulting mixture was concentrated to give the title compound as a brown oil.

[0623] Reference object 3

[0624] Synthesis of 2,2,2-trifluoroacetate of 3-(1-oxo-5-(piperazin-1-yl)isoindoline-2-yl)piperidine-2,6-dione

[0625]

[0626] Step 1: 4-(3-cyano-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester

[0627]

[0628] To a stirred solution of methyl 2-cyano-4-fluorobenzoate (10.00 g, 55.80 mmol, 1.00 equivalent) in DMSO (150.0 mL), tert-butyl piperazine-1-carboxylate (11.40 g, 61.38 mmol, 1.10 equivalent) and DIEA (34.70 g, 268.96 mmol, 4.80 equivalent) were added, and the resulting mixture was stirred at 110°C for 12 h. The mixture was diluted with water and extracted with EtOAc, and the combined organic layers were washed with brine and dried over Na2SO4. After filtration, the filtrate was concentrated and purified by silica gel column chromatography (eluting with PE / EtOAc (3:1)) to give the title compound as a yellow solid.

[0629] Step 2: 4-(3-formyl-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester

[0630]

[0631] A mixture of tert-butyl 4-(3-cyano-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate (8.00 g, 23.20 mmol, 1.00 equivalent), NaH₂PO₂·H₂O (5.20 g, 48.70 mmol, 2.10 equivalent), and Raney nickel (5.10 g) in pyridine:H₂O:AcOH = 2:1:1 (80.0 mL) was stirred at 70°C for 12 h. The mixture was adjusted to pH 7–8 with NaHCO₃ (aqueous), filtered, and extracted with EtOAc. The organic layer was washed with brine and dried over Na₂SO₄. After filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluting with PE / EtOAc (3:1)) to give the title compound as a yellow solid.

[0632] Step 3: 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindoline-5-yl)piperazine-1-carboxylic acid tert-butyl ester

[0633]

[0634] A mixture of 3-aminopiperidine-2,6-dione hydrochloride (2.60 g, 15.50 mmol, 1.20 equivalents), DIEA (4.03 g, 31.22 mmol, 2.42 equivalents), AcOH (10.63 g, 188.76 mmol, 13.78 equivalents) and 4-(3-formyl-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylic acid tert-butyl ester (4.50 g, 12.90 mmol, 1.00 equivalents) in DCM (50.0 mL) was stirred at 35°C for 4 h. Then, NaBH(OAc)3 (8.20 g, 38.70 mmol, 3.00 equivalents) was added to the mixture, and the mixture was stirred at 40°C for 12 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine and dried over Na2SO4. After filtration, the filtrate was concentrated and the residue was purified by silica gel column chromatography (eluting with PE / EtOAc (1:2)) to give the title compound as a white solid.

[0635] Step 4: 3-(1-oxo-5-(piperazin-1-yl)isoindololin-2-yl)piperidine-2,6-dione 2,2,2-trifluoroacetate

[0636]

[0637] TFA (1.0 mL) was added to a solution of tert-butyl piperazine-1-carboxylate (72 mg, 0.17 mmol, 1.00 equivalent) in DCM (4.0 mL). The resulting mixture was stirred at room temperature for 2 h and then concentrated to give the title compound as a yellow oil.

[0638] The following reference compounds were synthesized in a manner similar to that described in Reference 3.

[0639]

[0640] Reference Item 5

[0641] Synthesis of 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 2,2,2-2,2,2-trifluoroacetate

[0642]

[0643] Step 1: 6-Bromo-1-methyl-1H-indazole-3-amine

[0644]

[0645] Methylhydrazine (57 g, 0.50 mol, 10.00 equivalent) was added to a stirred solution of 4-bromo-2-fluorobenzonitrile (10 g, 0.05 mol, 1.00 equivalent) in EtOH (50.0 mL), and the mixture was stirred in a sealed tube at 100°C for 30 h. The mixture was then concentrated and diluted with water. The mixture was filtered to give the title compound as a pale yellow solid.

[0646] Step 2: Methyl 3-((6-bromo-1-methyl-1H-indazol-3-yl)amino)propionate

[0647]

[0648] Methyl acrylate (209.00 g, 2.43 mol, 10.00 equivalent) was added to a solution of 6-bromo-1-methyl-1H-indazole-3-amine (55.00 g, 0.24 mol, 1.00 equivalent), DBU (55.00 g, 0.36 mol, 1.50 equivalent), and lactic acid (33.00 g, 0.36 mol, 1.50 equivalent) at 0°C, and the mixture was stirred at 90°C under N2 for 20 h. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EtOAc: PE = 0 to 100%) to give the title compound as a yellow solid.

[0649] Step 3: Methyl 3-(1-(6-bromo-1-methyl-1H-indazol-3-yl)ureo)propionate

[0650]

[0651] NaOCN (26.00 g, 0.32 mol, 2.00 equivalents) was added to a solution of methyl 3-((6-bromo-1-methyl-1H-indazol-3-yl)amino)propionate (50.00 g, 0.16 mol, 1.00 equivalents) in AcOH (500.0 mL), and the mixture was stirred at 80°C under N2 for 20 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine and dried over Na2SO4. After filtration, the filtrate was concentrated to give the title compound as a yellow solid.

[0652] Step 4: 1-(6-bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0653]

[0654] Tirton-B (7.90 g, 0.05 mol, 0.30 equivalent) was added to a solution of methyl 3-(1-(6-bromo-1-methyl-1H-indazol-3-yl)ureido)propionate (56.00 g, 0.16 mol, 1.00 equivalent) in MeCN (500.0 mL) and stirred at room temperature under N2 for 20 h. The mixture was concentrated and then diluted with water. The mixture was filtered, and the solid was washed with water and air-dried to give the title compound as a pale yellow solid.

[0655] Step 5: 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-5,6-dihydropyridine-1(2H)-formate tert-butyl ester

[0656]

[0657] To a mixture of 1-(6-bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (1.10 g, 3.41 mmol, 1.00 equivalent) in 1,4-dioxane / H2O (10 mL / 1 mL), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.60 g, 5.11 mmol, 1.50 equivalent), K3PO4 (2.20 g, 10.22 mmol, 3.00 equivalent), and X-Phos-Pd G3 (289 mg, 0.34 mmol, 0.10 equivalent) were added, and the mixture was stirred at 60°C under N2 for 3 h. The mixture was diluted with DCM, and the organic layer was washed with brine and dried over Na2SO4. After filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (DCM: MeOH = 20:1) to give the title compound as a yellow solid.

[0658] Step 6: 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidine-1-carboxylic acid tert-butyl ester

[0659]

[0660] A mixture of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (300 mg, 0.71 mmol, 1.00 equivalent), Pd / C (150 mg, 50% wt), and Pd(OH)₂ (150 mg, 50% wt) in THF (20.0 mL) was stirred overnight at 50°C and 50 psi under H₂. The mixture was filtered, and the filtrate was concentrated and purified by silica gel column chromatography (PE:EtOAc = 1:1) to give the title compound as a yellow solid.

[0661] Step 7: 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 2,2,2-2,2,2-trifluoroacetate

[0662]

[0663] A mixture of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-carboxylate (100 mg, 0.25 mmol, 1.00 equivalent) in TFA / DCM (0.5 mL / 2.0 mL) was stirred at room temperature for 2 h. The mixture was concentrated to give the title compound as a brown oil.

[0664] The following reference compounds were synthesized in a manner similar to that described in Reference 5.

[0665]

[0666] Reference 8

[0667] Synthesis of 2,2,2-trifluoroacetate of 3-((4-(piperidin-4-yl)phenyl)amino)piperidin-2,6-dione

[0668]

[0669] Step 1: tert-butyl 4-(4-nitrophenyl)-5,6-dihydropyridine-1(2H)-carboxylate

[0670]

[0671] A mixture of 1-bromo-4-nitrobenzene (1.0 g, 4.95 mmol, 1.00 equivalent), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)-5,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (2.30 g, 7.43 mmol, 1.50 equivalent), K₂CO₃ (1.37 g, 9.90 mmol, 2.00 equivalent), and Pd(dppf)Cl₂ (724 mg, 0.99 mmol, 0.20 equivalent) in dioxane / H₂O (15 mL, 5 / 1) was stirred at 100°C for 4 h. The mixture was filtered and extracted with EtOAc. The combined organic layers were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated. The residue was purified by a silica fast column PE / EtOAc (10:1) to give the title compound as a yellow solid.

[0672] Step 2: tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate

[0673]

[0674] A mixture of tert-butyl 4-(4-nitrophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (1.20 g, 3.95 mmol, 1.00 equivalent) and Pd / C (360 mg, 10% w / w) in MeOH / THF (30 mL, 1:1) was stirred overnight at 45°C under H2. The mixture was filtered, and the filtrate was concentrated. The residue was purified by passing it through a silica rapid column PE / EtOAc (3:1) to give the title compound as a yellow solid.

[0675] Step 3: 4-(4-((2,6-dioxopiperidin-3-yl)amino)phenyl)piperidin-1-carboxylic acid tert-butyl ester

[0676]

[0677] A mixture of tert-butyl 4-(4-aminophenyl)piperidin-1-carboxylate (332 mg, 1.20 mmol, 1.00 equivalent), 3-bromopiperidin-2,6-dione (242 mg, 1.26 mmol, 1.05 equivalent), and NaHCO3 (302 mg, 3.60 mmol, 3.00 equivalent) in DMF (4.0 mL) was stirred overnight at 70°C. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and then concentrated. The residue was purified by passing it through a silica rapid column PE / EtOAc (1:1) to give the title compound as a yellow solid.

[0678] Step 4: 3-((4-(piperidin-4-yl)phenyl)amino)piperidin-2,6-dione 2,2,2-trifluoroacetate

[0679]

[0680] TFA (0.5 mL) was added to a mixture of tert-butyl 4-(4-((2,6-dioxopiridine-3-yl)amino)phenyl)piperidine-1-carboxylate (100 mg, 0.26 mmol, 1.00 equivalent) in DCM (2.0 mL), and the mixture was stirred at room temperature for 2 h. The mixture was concentrated to give the title compound as a yellow solid.

[0681] Reference Item 9

[0682] Synthesis of 2,2,2-trifluoroacetate of 3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione

[0683]

[0684] Step 1: 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyridine

[0685]

[0686] A mixture of 2,6-bis(benzyloxy)-3-bromopyridine (19.00 g, 0.05 mol, 1.00 equivalent), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxane) (19.60 g, 0.08 mol, 1.50 equivalent), KOAc (10.00 g, 0.10 mol, 2.00 equivalent), and Pd(dppf)Cl2 (3.7 g, 5.00 mmol, 0.10 equivalent) in 1,4-dioxane (200.0 mL) was stirred at 100°C under N2 for 25 h. The mixture was diluted with water and extracted with EtOAc, and the combined organic layers were washed with brine and dried over Na2SO4. After filtration, the filtrate was concentrated and the residue was purified by silica gel column chromatography (eluting with EtOAc : PE = 0 to 100%) to give the title compound as a yellow solid.

[0687] Step 4: 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine

[0688]

[0689] A mixture of 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyridine (4.42 g, 10.60 mmol, 1.20 equivalent), 1-bromo-4-iodobenzene (2.50 g, 8.83 mol, 1.00 equivalent), K3PO4 (5.63 g, 26.50 mmol, 3.00 equivalent), and Pd(PPh3)4 (510 mg, 0.44 mmol, 0.05 equivalent) in 1,4-dioxane / H2O = 10:1 (40.0 mL) was stirred at 100°C under N2 for 16 h. The mixture was diluted with water and extracted with EtOAc, and the combined organic layers were washed with brine and dried over Na2SO4. After filtration, the filtrate was concentrated and the residue was purified by silica gel column chromatography (eluting with EtOAc : PE = 0 to 100%) to give the title compound as a yellow solid.

[0690] Step 5: 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester

[0691]

[0692] A mixture of 2,6-bis(benzyloxy)-3-(4-bromophenyl)pyridine (500 mg, 1.12 mmol, 1.00 equivalent), tert-butyl piperazine-1-carboxylate (417 mg, 2.24 mmol, 2.00 equivalent), Cs₂CO₃ (730 mg, 2.24 mmol, 2.00 equivalent), Pd₂(dba)₃ (51 mg, 0.06 mmol, 0.05 equivalent), and RuPhos (52 mg, 0.11 mmol, 0.10 equivalent) in toluene (15.0 mL) was stirred at 110°C under N₂ for 20 h. The mixture was diluted with water and extracted with EtOAc, and the combined organic layers were washed with brine and dried over Na₂SO₄. After filtration, the filtrate was concentrated and the residue was purified by silica gel column chromatography (eluting with EtOAc : PE = 0 to 100%) to give the title compound as a yellow solid.

[0693] Step 6: 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazine-1-carboxylic acid tert-butyl ester

[0694]

[0695] A mixture of tert-butyl 4-(4-(2,6-bis(benzyloxy)pyridin-3-yl)phenyl)piperazine-1-carboxylate (260 mg, 0.47 mmol, 1.00 equivalent), 10% Pd / C (260 mg) in EtOAc (5.0 mL) and 1,4-dioxane (5.0 mL) was stirred at room temperature under H2 for 20 h. The mixture was filtered and the filtrate was concentrated to give the title compound as a yellow oil.

[0696] Step 7: 3-(4-(piperazin-1-yl)phenyl)piperidine-2,6-dione 2,2,2-trifluoroacetate

[0697]

[0698] TFA (0.5 mL) was added to a stirred solution of tert-butyl 4-(4-(2,6-dioxopiperidin-3-yl)phenyl)piperazine-1-carboxylate (160 mg, 0.43 mmol, 1.00 equivalent) in DCM (2.0 mL), and the mixture was stirred at room temperature under N2 for 2 h. The mixture was concentrated to give the title compound as a yellow oil.

[0699] Reference Item 10

[0700] Synthesis of 1-(6-(piperidin-4-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 2,2,2-trifluoroacetate

[0701]

[0702] Step 1: 6-Bromo-1-(2,2,2-trifluoroethyl)-1H-indazole-3-amine

[0703]

[0704] NaH (2.10 g, 52.83 mmol, 2.00 equivalent) was added to a stirred solution of 6-bromo-1H-indazole-3-amine (5.60 g, 26.42 mmol, 1.00 equivalent) in DMF (20.0 mL), and the mixture was stirred at 0°C for 1 h. 2,2,2-trifluoroethyl trifluoromethanesulfonate (6.7 g, 29.06 mmol, 1.10 equivalent) was added, and the mixture was stirred at room temperature under N2 for 3 h. The mixture was poured into cold water and filtered. The solid was washed with water and dried to give the title compound as a yellow solid.

[0705] Step 2: 1-(6-(piperidin-4-yl)-1-(2,2,2-trifluoroethyl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 2,2,2-trifluoroacetate

[0706]

[0707] The title compound was synthesized in a manner similar to that described in steps 2-7 of reference 5.

[0708] Reference Item 11

[0709] Synthesis of 1-(1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0710]

[0711] Step 1: Benzyl 4-(4-cyano-3-fluorophenyl)piperazine-1-carboxylate

[0712]

[0713] A mixture of 2,4-difluorobenzonitrile (18.95 g, 136.20 mmol, 1.50 equivalent), benzyl piperazine-1-carboxylate (20 g, 90.80 mmol, 1.00 equivalent), and potassium carbonate (25.10 g, 181.6 mmol, 2.00 equivalent) in ACN (200.0 mL) was stirred at 80°C under N2 for 16 h. The mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluting with PE / EtOAc (3:1)) to give the title compound as a white solid.

[0714] Step 2: Benzyl 4-(3-amino-1H-indazole-6-yl)piperazine-1-carboxylate

[0715]

[0716] A mixture of 4-(4-cyano-3-fluorophenyl)piperazine-1-carboxylate (11.00 g, 32.40 mmol, 1.00 equivalent) and N2H4 / H2O (10.14 g, 161.99 mmol, 5.00 equivalent) in BuOH (100.0 mL) was stirred at 100°C under N2 for 16 h. The mixture was concentrated and purified by rapid chromatography to give the title compound as a yellow solid.

[0717] Step 3: 4-(3-amino-1-methyl-1H-indazole-6-yl)piperazine-1-carboxylic acid benzyl ester

[0718]

[0719] NaH (0.91 g, 22.80 mmol, 1.00 equivalent) was added to a solution of 4-(3-amino-1H-indazole-6-yl)piperazine-1-carboxylic acid benzyl ester (4.00 g, 11.40 mmol, 1.00 equivalent) in dry DMF (50.0 mL) at 0°C under N2, and the mixture was stirred at room temperature for 30 min. The mixture was cooled to 0°C, and CH3I (1.78 g, 12.54 mmol, 1.10 equivalent) was added dropwise to dry DMF (10.0 mL), and the mixture was stirred for 3 h. The mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4. After filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluting with DCM / MeOH = (50:1)) to give the title compound as a yellow solid.

[0720] Step 4: 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-piperazine-1-carboxylic acid benzyl ester

[0721]

[0722] The title compound was synthesized in a manner similar to that described in steps 2-4 of reference 5.

[0723] Step 5: 1-(1-methyl-6-(piperazin-1-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0724]

[0725] A mixture of 4-[3-(2,4-dioxo-1,3-diazinan-1-yl)-1-methylindazole-6-yl]piperazine-1-carboxylate (500 mg, 1.08 mmol, 1.00 equivalent), 10% Pd / C (400 mg), and ammonium formate (682 mg, 10.81 mmol, 10.00 equivalent) in MeOH (20.0 mL) was stirred at 60°C under N2 for 16 h. The mixture was filtered and the filtrate was concentrated to give the title compound as a white solid.

[0726] The following reference compounds were synthesized in a manner similar to that described in Reference 11.

[0727]

[0728] Reference Item 13

[0729] Synthesis of 1-(6-(3,3-difluoropiperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 2,2,2-2,2,2-trifluoroacetate

[0730]

[0731] Step 1: 1-(1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione

[0732]

[0733] A mixture of 1-(6-bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (626 mg, 2.00 mmol, 1.00 equivalent), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxane) (762 mg, 3.00 mmol, 1.50 equivalent), KOAc (589 mg, 6.00 mmol, 3.00 equivalent), and Pd(dppf)Cl2 (146 mg, 0.20 mmol, 0.10 equivalent) in 1,4-dioxane (10 mL) was stirred overnight at 85°C under N2. The mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (DCM: MeOH = 100: 1) to give the title compound as a yellow solid.

[0734] Step 2: 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-3,3-difluoro-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

[0735]

[0736] A mixture of 1-(1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (800 mg, 2.00 mmol, 1.00 equivalent), tert-butyl 3,3-difluoro-4-(((trifluoromethyl)sulfonyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate (1.10 g, 3.00 mmol, 1.50 equivalent), Na2CO3 (636 mg, 6.00 mmol, 3.00 equivalent), Pd(dppf)Cl2 (146 mg, 0.20 mmol, 0.1 equivalent) and H2O (2.5 mL) in 1,4-dioxane (10.0 mL) was stirred overnight at 55°C under N2. The mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (DCM: MeOH = 120: 1) to give the title compound as a yellow solid.

[0737] Step 3: 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-3,3-difluoropiperidine-1-carboxylic acid tert-butyl ester

[0738]

[0739] A mixture of tert-butyl 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-3,3-difluoro-3,6-dihydropyridine-1(2H)-carboxylate (940 mg, 2.00 mmol, 1.00 equivalent), 10% Pd / C (900 mg), and Pd(OH)2 (900 mg) in MeOH (10.0 mL) was stirred overnight at 50°C in H2 (50 PSI). The mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (DCM:MeOH = 1:1) to give a title as a yellow solid.

[0740] Step 4: 1-(6-(3,3-difluoropiperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 2,2,2-2,2,2-trifluoroacetate

[0741]

[0742] A mixture of 4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-3,3-difluoropiperidin-1-carboxylic acid tert-butyl ester (102 mg, 0.22 mmol, 1.00 equivalent) in TFA / DCM (0.5 mL / 2.0 mL) was stirred at room temperature for 2 h. The mixture was concentrated to give the title compound as a brown oil.

[0743] Reference Item 14

[0744] Synthesis of 2,2,2-trifluoroacetate tert-butyl 6-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0745]

[0746] Step 1: 6-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

[0747]

[0748] A mixture of 1-(6-bromo-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione (300 mg, 0.93 mmol, 1.00 equivalent), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (570 mg, 2.32 mmol, 2.50 equivalent), t-BuOK (627 mg, 5.6 mmol, 6.00 equivalent), t-BuBrettphos Pd G3 (81 mg, 0.093 mmol, 0.10 equivalent), and t-BuXphos (76 mg, 0.186 mmol, 0.20 equivalent) in 1,4-dioxane (6 mL) was stirred at 100°C under N2 for 3 h. The mixture was diluted with DCM, and the organic layer was washed with water and brine and dried over Na2SO4. After filtration, the filtrate was concentrated and the residue was purified by silica gel column chromatography (DCM: MeOH = 20: 1) to give the title compound as a yellow solid.

[0749] Step 2: 1-(1-methyl-6-(2,6-diazaspiro[3.3]heptane-2-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione 2,2,2-2,2,2-trifluoroacetate

[0750]

[0751] A mixture of 6-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester (90 mg, 0.204 mmol, 1.00 equivalent) in TFA / DCM (0.5 mL / 2 mL) was stirred at room temperature for 2 h. The mixture was concentrated to give the title compound as a brown oil.

[0752] Reference Item 15

[0753] Synthesis of 1-(6-(1-(3-(3-(((4-aminopiperidin-1-yl)sulfonyl)phenyl)-2,2-dimethylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride

[0754]

[0755] Step 1: (1-((3-(2,2-dimethyl-3-oxopropyl)phenyl)sulfonyl)piperidin-4-yl)tert-butyl carbamate

[0756]

[0757] A mixture of N-[1-[3-(bromomethyl)phenyl]sulfonyl-4-piperidinyl]carbamate tert-butyl ester (1.0 g, 2.31 mmol), 2-methylpropionaldehyde (416 mg, 5.77 mmol), tetrabutylammonium iodide (85.24 mg, 0.23 mmol), and sodium hydroxide (323.06 mg, 8.08 mmol) in 1,4-dioxane (10 mL) was heated to 70°C and stirred for 3 h under an argon atmosphere. After cooling, the mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated, and the residue was purified by silica gel chromatography (eluting with ethyl acetate / petroleum ether (0-20%, with 5% dichloromethane)) to give the title compound as a white solid.

[0758] Step 2: (1-((3-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2,2-dimethylpropyl)phenyl)sulfonyl)piperidin-4-yl)tert-butyl carbamate

[0759]

[0760] Tetraisopropyl titanate (1.24 g, 4.37 mmol) was added to a mixture of (1-((3-(2,2-dimethyl-3-oxopropyl)phenyl)sulfonyl)piperidin-4-yl)tert-butyl carbamate (530 mg, 1.25 mmol) and 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-diketone hydrochloride (408.7 mg, 1.25 mmol) in anhydrous N-methyl-2-pyrrolidone (5.3 mL), and the mixture was heated to 90°C for 3 h under an argon atmosphere. The mixture was cooled to room temperature and sodium cyanoborohydride (274.56 mg, 4.37 mmol) was added, and the mixture was stirred at 25°C for 1 h. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated and the residue was purified by silica gel chromatography (eluting with methanol / dichloromethane (0-5%)) to give the title compound as a white solid.

[0761] Step 3: 1-(6-(1-(3-(3-((4-aminopiperidin-1-yl)sulfonyl)phenyl)-2,2-dimethylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride

[0762]

[0763] At 0°C, 4 M hydrogen chloride (1.5 mL) in dioxane was added to a stirred solution of (280 mg, 0.38 mmol) tert-butyl carbamate in dichloromethane (3 mL) and stirred for 1 h. The mixture was concentrated under reduced pressure to give the title compound as a white solid.

[0764] Reference Item 16

[0765] Synthesis of 1-(6-(1-(2-(3-(((4-aminopiperidin-1-yl)sulfonyl)benzyl)butyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride

[0766]

[0767] Step 1: (E)-2-(3-((4-((tert-butoxycarbonyl)amino)piperidin-1-yl)sulfonyl)benzylidene)-ethyl butyrate

[0768]

[0769] Ethyl 2-(diethoxyphosphoryl)butyrate (412 mg, 1.63 mmol, 1.20 equivalent) was added to a stirred solution of NaH (60% in mineral oil, 82 mg, 2.04 mmol, 1.50 equivalent) in THF (10.0 mL), and the mixture was stirred at 0°C for 30 min. Tert-butyl 1-(1-((3-formylphenyl)-sulfonyl)piperidin-4-yl)carbamate (500 mg, 1.36 mmol, 1.00 equivalent) was added to THF (10.0 mL). The mixture was stirred at 0°C for 30 min, then slowly heated to room temperature and stirred for 12 h. The mixture was quenched with H₂O at 0°C and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluting with DCM: MeOH (0-5%)) to give the title compound as a white solid.

[0770] Step 2: 2-(3-((4-((tert-butoxycarbonyl)amino)piperidin-1-yl)sulfonyl)benzyl)ethyl butyrate

[0771]

[0772] A mixture of (E)-2-(3-((4-((tert-butoxycarbonyl)amino)piperidin-1-yl)-sulfonyl)benzyl)butyrate (400 mg, 0.86 mmol, 1.00 equivalent) and 10% Pd / C (200 mg) in MeOH (10.0 mL) was stirred at 1 atm H2 for 12 h at room temperature. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with DCM: MeOH (0-5%)) to give the title compound as a pale yellow oil.

[0773] Step 3: (1-((3-(2-(hydroxymethyl)butyl)phenyl)sulfonyl)piperidin-4-yl)tert-butyl carbamate

[0774]

[0775] LiAlH4 (2.5 M in THF, 1.15 mL, 2.88 mmol, 3.00 equivalent) was added at -10°C to a stirred solution of ethyl 2-(3-((4-((tert-butoxycarbonyl)amino)piperidin-1-yl)sulfonyl)benzyl)-butyrate (450 mg, 0.96 mmol, 1.00 equivalent) in 20.0 mL of THF, and the mixture was stirred for 3 h. The mixture was diluted with DCM, quenched with H2O, and the resulting mixture was stirred at room temperature for 30 min. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with DCM: MeOH (0-5%)) to give the title compound as a pale yellow solid.

[0776] Step 4: (1-((3-(2-formylbutyl)phenyl)sulfonyl)piperidin-4-yl)tert-butyl carbamate

[0777]

[0778] Des Martin periodane (223 mg, 0.53 mmol, 1.50 equivalent) was added to a stirred solution of (1-((3-(2-(hydroxymethyl)butyl)phenyl)sulfonyl)piperidin-4-yl)carbamate (150 mg, 0.35 mmol, 1.00 equivalent) in DCM (7.0 mL) at 0°C, and the mixture was stirred under N2 for 2 h. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with DCM: MeOH (0-2%)) to give the title compound as a pale yellow solid.

[0779] Step 5: (1-((3-(2-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)butyl)phenyl)sulfonyl)piperidin-4-yl)tert-butyl carbamate

[0780]

[0781] NaBH(OAc)3 (180 mg, 0.85 mmol, 2.5 equivalence) in DMA (2.0 mL) was added to a mixture of 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (127 mg, 0.35 mmol, 1.00 equivalence), TEA (106 mg, 1.05 mmol, 3.00 equivalence), and (1-((3-(2-formylbutyl)phenyl)sulfonyl)piperidin-4-yl)tert-butyl carbamate (149 mg, 0.35 mmol, 1.00 equivalence) in DMA (6.0 mL) at 0°C, and the mixture was stirred at room temperature for 12 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluting with DCM: MeOH (0-5%)) to give the title compound as a pale yellow solid.

[0782] Step 6: 1-(6-(1-(2-(3-(((4-aminopiperidin-1-yl)sulfonyl)benzyl)butyl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride

[0783]

[0784] HCl (2 M, 5.0 mL) from EtOAc was added to (1-((3-(2-((4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)methyl)butyl)phenyl)sulfonyl)piperidin-4-yl)tert-butyl carbamate (170 mg, 0.23 mmol, 1.00 equivalent) at room temperature and stirred for 3 h. The mixture was concentrated under reduced pressure to give the title compound as a pale yellow solid.

[0785] Reference Item 17

[0786] Synthesis of 4-((4-aminopiperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile hydrochloride

[0787]

[0788] Step 1: 3-Bromo-4-cyanobenzenesulfonyl chloride

[0789]

[0790] A mixture of 4-amino-2-bromobenzonitrile (5.0 g, 25.38 mmol, 1.00 equivalent) in concentrated HCl / H₂O (60.0 mL / 225.0 mL) was heated to 90°C until completely dissolved. The mixture was cooled to 0°C–5°C. A solution of NaNO₂ (1.9 g, 27.54 mmol, 1.08 equivalent) in H₂O (5 mL) was added dropwise to the mixture, followed by dropwise addition of CuCl (0.2 g, 2.02 mmol, 0.08 equivalent) in SOCl₂ / H₂O (8.0 mL / 50.0 mL) at 0°C–5°C. The resulting mixture was stirred at 0°C–5°C for 1 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over anhydrous Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluting with PE: EtOAc = 4:1) to give the title compound as a white oil.

[0791] Step 2: (1-((3-bromo-4-cyanophenyl)sulfonyl)piperidin-4-yl)tert-butyl carbamate

[0792]

[0793] 3-Bromo-4-cyanobenzenesulfonyl chloride (500 mg, 1.79 mmol, 1.00 equivalent) in DCM (5.0 mL) was added dropwise to a stirred solution of piperidine-4-ylcarbamate tert-butyl ester (359.2 mg, 1.79 mmol, 1.00 equivalent) and TEA (542.4 mg, 5.37 mmol, 3.00 equivalent) in DCM (5.0 mL). The mixture was stirred at room temperature for 2 h. The mixture was poured into water and extracted with DCM. The combined organic layers were washed with water and brine and dried over Na2SO4. After filtration, the filtrate was concentrated and the residue was purified by rapid chromatography to give the title compound as a brown solid.

[0794] Step 3: (1-((4-cyano-3-(2-methyl-3-oxopropyl)phenyl)sulfonyl)piperidin-4-yl)-tert-butyl carbamate

[0795]

[0796] To a stirred solution of (1-((3-bromo-4-cyanophenyl)sulfonyl)piperidin-4-yl)-tert-butyl carbamate (400 mg, 0.90 mmol, 1.00 equivalent) in DMF (8.0 mL), 2-(di-tert-butyl-phosphono)-1-phenyl-1H-indole (20 mg, 0.06 mmol, 0.06 equivalent), N-cyclohexyl-N-methylcyclohexylamine (194.4 mg, 1.17 mmol, 1.1 equivalent), 2-methylprop-2-en-1-ol (130 mg, 1.8 mmol, 2.00 equivalent), and Pd2(dba)3 (16.8 mg, 0.02 mmol, 0.02 equivalent) were added. The mixture was purged with N2 and stirred at 100°C for 5 h. The mixture was poured into water, extracted with EtOAc, and the combined organic layers were washed with water and brine and dried over Na2SO4. After filtration, the filtrate was concentrated and the residue was purified by rapid chromatography to give the title compound as a white solid.

[0797] Step 4: 4-((4-aminopiperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile hydrochloride

[0798]

[0799] The title compound is synthesized in a manner similar to that described in steps 5-6 of reference 16.

[0800] Reference Item 18

[0801] Synthesis of (S)-1-(6-(1-(2-(3-(((4-aminopiperidin-1-yl)sulfonyl)phenoxy)propyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride

[0802]

[0803] Step 1: (1-((3-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)phenyl)sulfonyl)piperidin-4-yl)tert-butyl carbamate

[0804]

[0805] Pd(dppf)Cl2 (0.87 g, 1.19 mmol, 0.1 equivalent) and AcOK (3.51 g, 35.77 mmol, 3 equivalent) were added to a stirred solution of (1-((3-bromophenyl)sulfonyl)piperidin-4-yl)carbamate (5 g, 11.92 mmol, 1 equivalent) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxane-4-dioxane) (3.03 g, 11.92 mmol, 1 equivalent) in 1,4-dioxane (50 mL) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at 80°C for 2 h. The mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with water and brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain the title compound as a yellow solid.

[0806] Step 2: (1-((3-hydroxyphenyl)sulfonyl)piperidin-4-yl)tert-butyl carbamate

[0807]

[0808] H₂O₂ (30%, 45 mL) was added to a stirred solution of (1-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)-phenyl)sulfonyl)piperidin-4-yl) tert-butyl carbamate (9 g, 19.3 mmol, 1 equivalent) in ACN (90 mL). The resulting mixture was stirred at room temperature for 10 min. The mixture was quenched at 0°C with saturated Na₂SO₃ solution, and the resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and brine and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with EtOAc / PE (0-50%)) to give the title compound as a white solid.

[0809] Step 3: Methyl (S)-2-(3-((4-((tert-butoxycarbonyl)amino)piperidin-1-yl)sulfonyl)phenoxy)-propionate

[0810]

[0811] DIAD (1.36 g, 6.73 mmol, 1.20 equivalent) was added dropwise to a stirred mixture of (1-((3-hydroxyphenyl)sulfonyl)piperidin-4-yl)carbamate (2 g, 5.6 mmol, 1.0 equivalent), PPh3 (2.2 g, 8.4 mmol, 1.5 equivalent), and (2S)-2-hydroxypropionate (600 mg, 5.78 mmol, 1.03 equivalent) in THF (20 mL) under a nitrogen atmosphere at 0°C. The mixture was stirred at room temperature for 2 h. The mixture was quenched with water, and the resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with EtOAc / PE (0-25%)) to give the title compound as a white solid.

[0812] Step 4: (S)-(1-((3-((1-hydroxypropyl-2-yl)oxy)phenyl)sulfonyl)piperidin-4-yl)-tert-butyl carbamate

[0813]

[0814] 2 M LiAlH4 (3.6 mL, 7.2 mmol, 2 equivalents) in THF was added dropwise to a stirred solution of (S)-2-(3-((4-((tert-butoxycarbonyl)amino)piperidin-1-yl)sulfonyl)phenoxy)propionate (1.6 g, 3.62 mmol, 1.0 equivalent) in THF (16 mL). The resulting mixture was stirred at 0°C for 2 h. The mixture was quenched with water and 15% NaOH (aqueous), and the resulting mixture was diluted with EtOAc and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a yellow solid.

[0815] Step 5: (S)-1-(6-(1-(2-(3-((4-aminopiperidin-1-yl)sulfonyl)phenoxy)propyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride

[0816]

[0817] The title compound is synthesized in a manner similar to that described in steps 4-6 of reference 16.

[0818] Reference Item 19

[0819] Synthesis of 1-(6-(1-(3-(3-(((4-aminopiperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)-piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride

[0820]

[0821] Step 1: (1-((3-(2-methyl-3-oxopropyl)phenyl)sulfonyl)piperidin-4-yl)tert-butyl carbamate

[0822]

[0823] A solution of (1-((3-bromophenyl)sulfonyl)piperidin-4-yl)carbamate tert-butyl ester (5.1 g, 12.2 mmol, 1.0 equivalent), Pd(AcO)₂ (0.27 g, 1.2 mmol, 0.1 equivalent), 2-methylprop-2-en-1-ol (2.6 g, 36.5 mmol, 3.0 equivalent), NaHCO₃ (2 g, 24.3 mmol, 2.0 equivalent), and tetrabutylammonium bromide (19.6 g, 60.8 mmol, 5.0 equivalent) in DMF (51 mL) was stirred for 3 h at 100°C under a nitrogen atmosphere. The resulting mixture was diluted with EtOAc, and the organic layer was washed with water and brine and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with EtOAc / PE (0-25%)) to give the title compound as a pale yellow solid.

[0824] Step 2: (1-((3-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)phenyl)sulfonyl)piperidin-4-yl)tert-butyl carbamate

[0825]

[0826] TEA (5.7 g, 56 mmol, 5.0 equivalent) was added to a stirred solution of 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (4.06 g, 11.2 mmol, 1.0 equivalent) in DMAc (46 mL). The resulting mixture was stirred at room temperature for 5 min. (1-((3-(2-methyl-3-oxopropyl)phenyl)sulfonyl)piperidin-4-yl)tert-butyl carbamate (4.6 g, 11.2 mmol, 1.0 equivalent) was then added to the above mixture in portions at 0°C and stirred at room temperature for 2 h. The mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with EtOAc / PE (0-100%)) to give the title compound as a white solid.

[0827] Step 3: 1-(6-(1-(3-(3-(((4-aminopiperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride

[0828]

[0829] 4M HCl (18 mL) in 1,4-dioxane was added dropwise to a stirred solution of (1-((3-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)phenyl)sulfonyl)piperidin-4-yl)-carbamate (3.7 g, 5.1 mmol, 1.0 equivalent) in DCM (37 mL). The resulting mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure to give the title compound as a pale yellow solid.

[0830] The following reference compounds were synthesized in a manner similar to that described in Reference 19.

[0831]

[0832] Reference Item 20

[0833] Synthesis of 1-(6-(1-(3-(3-(((4-aminopiperidin-1-yl)sulfonyl)phenyl)-2-hydroxy-2-methylpropyl)-piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride

[0834]

[0835] Step 1: (1-((3-(2-methylallyl)phenyl)sulfonyl)piperidin-4-yl)tert-butyl carbamate

[0836]

[0837] A mixture of (1-((3-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenyl)sulfonyl)piperidin-4-yl)carbamate (3.3 g, 7.1 mmol, 1.0 equivalent), 3-bromo-2-methylprop-1-ene (1.91 g, 14.2 mmol, 2.0 equivalent), Pd(PPh3)2Cl2 (497 mg, 0.7 mmol, 0.1 equivalent), and Na2CO3 (2.25 g, 21.2 mmol, 3.0 equivalent) in THF (30 mL) and H2O (3 mL) was stirred for 4 h at 65°C under a nitrogen atmosphere. The resulting mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water and brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluting with EtOAc / PE (0-30%)) to give the title compound as a yellow solid.

[0838] Step 2: (1-((3-((2-methyloxapropane-2-yl)methyl)phenyl)sulfonyl)piperidin-4-yl)tert-butyl carbamate

[0839]

[0840] m-CPBA (834 mg, 4.1 mmol, 2.0 equivalent, 85%) was added fractionally to a stirred solution of (1-((3-(2-methylallyl)phenyl)sulfonyl)piperidin-4-yl)carbamate (810 mg, 2.1 mmol, 1.0 equivalent) in 10 mL of DCM at 0°C. The resulting mixture was stirred at room temperature for 4 h. The reaction was quenched with aqueous NaHCO3 at 0°C, and the resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with EtOAc / PE (0-100%)) to give the title compound as a pale yellow solid.

[0841] Step 3: (1-((3-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-hydroxy-2-methylpropyl)phenyl)sulfonyl)piperidin-4-yl)tert-butyl carbamate

[0842]

[0843] TEA (240 mg, 2.4 mmol, 1.5 equivalents) was added to a stirred solution of (1-((3-((2-methyloxapropane-2-yl)methyl)phenyl)sulfonyl)piperidin-4-yl)carbamate (650 mg, 1.6 mmol, 1.0 equivalent) and 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (634 mg, 1.76 mmol, 1.1 equivalent) in EtOH (6 mL), and the mixture was stirred at 80°C for 24 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water and brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by grinding with EtOAc / PE (1:3) to give the title compound as a white solid.

[0844] Step 4: 1-(6-(1-(3-(3-(((4-aminopiperidin-1-yl)sulfonyl)phenyl)-2-hydroxy-2-methylpropyl)-piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride

[0845]

[0846] 4 M HCl (3 mL) in 1,4-dioxane was added dropwise to a stirred solution of (700 mg, 1 mmol, 1.0 equivalent) of (1-((3-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-hydroxy-2-methylpropyl)phenyl)sulfonyl)piperidin-4-yl)carbamate in DCM (3 mL), and the mixture was stirred for 2 h. The resulting mixture was concentrated under vacuum to give the title compound as a pale yellow solid.

[0847] Reference Item 21

[0848] Synthesis of 1-(6-(1-(3-(4-((4-aminopiperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride

[0849]

[0850] Step 1: (1-((4-bromophenyl)sulfonyl)piperidin-4-yl)tert-butyl carbamate

[0851]

[0852] Piperidin-4-ylcarbamate tert-butyl ester (9.41 g, 46.96 mmol, 1.20 equivalent) and TEA (7.92 g, 78.27 mmol, 2.00 equivalent) were added to a stirred solution of 4-bromobenzenesulfonyl chloride (10.0 g, 39.14 mmol, 1.00 equivalent) in DCM (20.0 mL) at 0°C, and the mixture was stirred at room temperature for 2 h. The mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water and brine, and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluting with PE:EtOAc = 4:1) to give the title compound as a white solid.

[0853] Step 2: (1-((4-(2-methyl-3-oxopropyl)phenyl)sulfonyl)piperidin-4-yl)tert-butyl carbamate

[0854]

[0855] A mixture of (1-((4-bromophenyl)sulfonyl)piperidin-4-yl)tert-butyl carbamate (500 mg, 1.20 mmol, 1.00 equivalent), NaHCO3 (201 mg, 2.39 mmol, 2.00 equivalent), tetrabutylammonium bromide (77.1 mg, 0.239 mmol, 0.2 equivalent), 2-methylprop-2-en-1-ol (172.4 mg, 2.39 mmol, 2.00 equivalent), and Pd(OAc)2 (6 mg, 0.0239 mmol, 0.02 equivalent) in DMF (10.0 mL) was stirred at 100°C under N2 for 12 h. The mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with water and brine and dried over Na2SO4. After filtration, the filtrate was concentrated and the residue was purified by rapid chromatography to give the title compound as a white solid.

[0856] Step 3: (1-((4-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)phenyl)sulfonyl)piperidin-4-yl)tert-butyl carbamate

[0857]

[0858] NaBH(OAc)3 (187.7 mg, 0.886 mmol, 2.5 equivalents) was added to a stirred solution of (1-((4-(2-methyl-3-oxopropyl)phenyl)sulfonyl)piperidin-4-yl)carbamate tert-butyl (150 mg, 0.366 mmol, 1.00 equivalent), 1-(1-methyl-6-(piperidin-4-yl)-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (133 mg, 0.366 mmol, 1.00 equivalent) and TEA (110.9 mg, 1.1 mmol, 3.00 equivalent) in DMA (2.0 ml) at 0°C, and the mixture was stirred at 0°C for 2 h. The mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with water and brine and dried over Na2SO4. After filtration, the filtrate was concentrated and the residue was purified by rapid chromatography to give the title compound as a white solid.

[0859] Step 4: 1-(6-(1-(3-(4-((4-aminopiperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride

[0860]

[0861] HCl (2 M, 2.0 mL) from EtOAc was added to (1-((4-(3-(4-(3-(2,4-dioxotetrahydro-pyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)phenyl)sulfonyl)piperidin-4-yl)tert-butyl carbamate (110 mg, 0.15 mmol, 1.00 equivalent), and the mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure to give the title compound as a brown oil.

[0862] Reference Item 22

[0863] Synthesis of 8-isopropyl-2-(methanesulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one

[0864]

[0865] Step 1: 8-Isopropyl-2-(methylthio)pyrido[2,3-d]pyrimidine-7(8H)-one

[0866]

[0867] 2-Iodopropane (660 mg, 3.88 mmol, 1.50 equivalent) and Cs₂CO₃ (1.68 g, 5.18 mmol, 2.00 equivalent) were added to a stirred mixture of 2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (500 mg, 2.59 mmol, 1.00 equivalent) in DMF (5.0 mL) at room temperature, and the resulting mixture was stirred at 70°C for 16 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water and brine, and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with EtOAc: PE (0 to 100%)) to give the title compound as a white solid.

[0868] Step 2: 8-Isopropyl-2-(Methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one

[0869]

[0870] m-CPBA (276 mg, 1.36 mmol, 1.60 equivalent) was added to a stirred solution of 8-isopropyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (200 mg, 0.85 mmol, 1.00 equivalent) in DCM (3.0 mL) at room temperature, and the resulting mixture was stirred for 3 h. The mixture was diluted with water and extracted with DCM. The combined organic layers were washed with NH4Cl (aqueous) and brine, and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the title compound as a white solid.

[0871] Reference Item 23

[0872] Synthesis of 6-chloro-8-isopropyl-2-(methanesulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one

[0873]

[0874] Step 1: 6-Chloro-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one

[0875]

[0876] At 0°C, ethyl 2-chloro-2-(diethoxyphosphoryl)acetate (1.15 g, 4.44 mmol, 1.50 equivalent) was added dropwise to a solution of NaH (213 mg, 5.33 mmol, 1.80 equivalent) in THF (10.0 mL). After 1 h, 4-amino-2-(methylthio)pyrimidine-5-carboxaldehyde (500 mg, 2.96 mmol, 1.00 equivalent) was added dropwise to the mixture at 0°C. The mixture was stirred at room temperature for 16 h. The mixture was quenched with saturated NH4Cl and extracted with EtOAc. The combined organic layers were dried over Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 3:1) to give the title compound as a grayish-white solid.

[0877] Step 2: 6-Chloro-8-isopropyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one

[0878]

[0879] Cs₂CO₃ (287 mg, 0.88 mmol, 2.00 equivalent) and 2-iodopropane (112 mg, 0.66 mmol, 1.50 equivalent) were added to a solution of 6-chloro-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (100 mg, 0.44 mmol, 1.00 equivalent) in DMF (5.0 mL), and the resulting mixture was stirred at 100°C under N₂ for 12 h. The mixture was poured into water and extracted with EtOAc. The combined organic layers were dried over Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was concentrated and purified by silica gel column chromatography (PE:EtOAc = 3:1) to give the title compound as a yellow solid.

[0880] Step 3: 6-Chloro-8-isopropyl-2-(methanesulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one

[0881]

[0882] m-CPBA (151 mg, 0.74 mmol, 2.00 equivalent) was added to a solution of 6-chloro-8-isopropyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (100 mg, 0.37 mmol, 1.00 equivalent) in DCM (5.0 mL). The mixture was stirred at room temperature for 16 h. The mixture was concentrated and purified by preparative TLC (PE:EtOAc = 3:1) to give the title compound as a grayish-white solid.

[0883] The following reference compounds were synthesized in a manner similar to that described in reference 23.

[0884] Reference Item 24

[0885] Synthesis of 8-cyclopropyl-2-(methanesulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one

[0886]

[0887] Step 1: Ethyl 4-(cyclopropylamino)-2-(methylthio)pyrimidine-5-carboxylate

[0888]

[0889] Cyclopropylamine (589 mg, 10.32 mmol, 1.20 equivalent), DIEA (6.55 g, 43.00 mmol, 5.00 equivalent), and CsF (5.56 g, 43.0 mmol, 5.00 equivalent) were added to a stirred mixture of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (2.0 g, 8.60 mmol, 1.00 equivalent) in DMSO (20.0 mL), and the resulting mixture was stirred at 65°C for 16 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water and brine, and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with EtOAc: PE (0 to 100%)) to give the title compound as a white solid.

[0890] Step 2: (4-(cyclopropylamino)-2-(methylthio)pyrimidin-5-yl)methanol

[0891]

[0892] 2.5 M LiAlH4 (5.80 mL, 14.51 mmol, 1.50 equivalent) in THF was added to a stirred solution of ethyl 4-(cyclopropylamino)-2-(methylthio)pyrimidine-5-carboxylate (2.45 g, 9.67 mmol, 1.00 equivalent) in THF (20.0 mL), and the resulting mixture was stirred at room temperature for 2 h. The mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water and brine, and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with (PE:EtOAc = 1:1)) to give the title compound as a yellow solid.

[0893] Step 3: 4-(cyclopropylamino)-2-(methylthio)pyrimidine-5-carboxaldehyde

[0894]

[0895] MnO2 (16.48 g, 189.60 mmol, 20.00 equivalent) was added to a stirred solution of (4-(cyclopropylamino)-2-(methylthio)pyrimidin-5-yl)methanol (2.0 g, 9.48 mmol, 1.00 equivalent) in CHCl3 (20.0 mL) at room temperature, and the mixture was stirred at 70°C for 16 h. The mixture was filtered, and the filtrate was diluted with water and extracted with DCM. The combined organic layers were washed with water and brine, and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with (PE:EtOAc = 3:1)) to give the title compound as a white solid.

[0896] Step 4: 8-Cyclopropyl-2-(methylthio)pyrido[2,3-d]pyrimidine-7(8H)-one

[0897]

[0898] Ethyl acetate (1.26 g, 14.34 mmol, 3.00 equivalent) was added to a stirred mixture of 4-(cyclopropylamino)-2-(methylthio)pyrimidine-5-carboxaldehyde (1.00 g, 4.78 mmol, 1.00 equivalent) in THF (10.0 mL) at -75°C and stirred for 15 min. Then, 1 M LiHMDS (9.56 mL, 9.56 mmol, 2.00 equivalent) in THF was added to the mixture at -75°C, and the mixture was heated to room temperature and stirred for 3 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water and brine, and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with EtOAc: PE (0 to 100%)) to give the title compound as a white solid.

[0899] Step 5: 8-Cyclopropyl-2-(Methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one

[0900]

[0901] m-CPBA (139 mg, 0.69 mmol, 1.60 equivalent) was added to a stirred solution of 8-cyclopropyl-2-(methylthio)pyrido[2,3-d]pyrimidin-7(8H)-one (100 mg, 0.43 mmol, 1.00 equivalent) in DCM (3.0 mL) at 25°C, and the resulting mixture was stirred for 3 h. The mixture was diluted with water and extracted with DCM. The combined organic layers were washed with NH4Cl (aqueous) and brine, and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give the title compound as a white solid.

[0902] Reference Item 25

[0903] Synthesis of 8-isopropyl-2-(methanesulfonyl)-6-(difluoromethyl)pyrido[2,3-d]pyrimidin-7(8H)-one

[0904]

[0905] Step 1: 8-Isopropyl-2-(Methylsulfonyl)-6-(Difluoromethyl)pyrido[2,3-d]pyrimidin-7(8H)-one

[0906]

[0907] TFA (114 mg, 1.00 mmol, 1.00 equivalent), FeCl2 (63 mg, 0.50 mmol, 0.50 equivalent), zinc difluoromethanesulfinate (444 mg, 1.50 mmol, 1.50 equivalent), and TBHP (70% in H2O, 129 mg, 1.00 mmol, 1.00 equivalent) were added to a stirred solution of 8-isopropyl-2-(methanesulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (267 mg, 1.00 mmol, 1.00 equivalent) in DMSO (4.0 mL) at 0°C, and the mixture was stirred at room temperature for 16 h. The mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water and brine, and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with (PE: EtOAc = 2: 1)) to give the title compound as a yellow solid.

[0908] Example 1

[0909] Synthesis of 1-(6-(1-(3-(3-((4-((8-isopropyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidin-2,4(1H,3H)-dione

[0910]

[0911] Step 1: 1-(6-(1-(3-(3-((4-((8-isopropyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazole-3-yl)dihydropyrimidin-2,4(1H,3H)-dione

[0912]

[0913] To a stirred solution of 1-(6-(1-(3-(3-(((4-aminopiperidin-1-yl)sulfonyl)phenyl)-2-methylpropyl)piperidin-4-yl)-1-methyl-1H-indazol-3-yl)dihydropyrimidine-2,4(1H,3H)-dione hydrochloride (86 mg, 0.14 mmol, 1.00 equivalent) in DMSO (3.0 mL), 8-isopropyl-2-(methanesulfonyl)pyrido[2,3-d]pyrimidine-7(8H)-one (55 mg, 0.21 mmol, 1.50 equivalent) and DIEA (36 mg, 0.28 mmol, 2.00 equivalent) were added, and the resulting mixture was stirred at 65°C for 16 h. The mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water and brine, and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with DCM: MeOH (0 to 10%)) to give the title compound as a yellow solid. MS (ES, m / z): [M+1] + = 809.3.

[0914] Example 2

[0915] Synthesis of 4-((4-((6-chloro-8-isopropyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile

[0916]

[0917] Step 1: 4-((4-((6-chloro-8-isopropyl-7-oxo-7,8-dihydropyridino[2,3-d]pyrimidin-2-yl)amino)piperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile

[0918]

[0919] To a stirred solution of 4-((4-aminopiperidin-1-yl)sulfonyl)-2-(3-(4-(3-(2,4-dioxotetrahydropyrimidin-1(2H)-yl)-1-methyl-1H-indazol-6-yl)piperidin-1-yl)-2-methylpropyl)benzonitrile hydrochloride (120 mg, 0.19 mmol, 1.00 equivalent) in DMSO (3.0 mL), 6-chloro-8-isopropyl-2-(methanesulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (56 mg, 0.19 mmol, 1.00 equivalent) and DIEA (72 mg, 0.57 mmol, 3.00 equivalent) were added, and the resulting mixture was stirred at 65°C for 12 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water and brine, and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound as a white solid. MS (ES, m / z): [M+1] + = 867.9.

[0920] The following compounds were prepared in a manner similar to that described in Example 2.

[0921]

[0922] Biological examples

[0923] Biological Example 1

[0924] Measurement of phosphorylated Rb in cells

[0925] Phosphorylation of RB protein at S807 / 811 was measured using the HTRF phosphorylation RB cell kit (catalog number 64RBS807PEG) from Cisbio / Revvity.

[0926] On Day 1, adherent cells (such as OVCAR3 (CDK2-dependent cell line) and T47D (CDK4-dependent cell line)) were seeded at 20,000 cells / well in 96-well tissue culture-treated plates with 200 µL of medium, and suspension cells THP1 were seeded at 20,000 cells / well in sterile 384-well plates with 50 µL of medium. The cells were then incubated overnight at 37°C in a CO2 atmosphere. On Day 2, cells were treated with test compounds at concentrations from 0.3 to 3,000 nM using a Tecan D300e digital dispenser (HP Inc., California, USA). Twenty-four hours after compound treatment, the cell culture medium for adherent cells was removed by tapping the plate and patting it with a clean paper towel. 30 µL of 1X lysis buffer was added from the kit to each well containing adherent cells. For suspension cells, 16.7 µL of 4X lysis buffer was added directly to 50 µL of cells in a 384-well plate. The plate was then incubated on a shaker at room temperature for 30 min. After homogenization by pipetting, 8 µL of cell lysate was transferred from the cell culture plate to a small-volume white 384-well detection plate. 2 µL of premixed detection solution was added, and the plate was covered with blocking agent. To prepare the detection solution, d2-conjugated phosphorylated RB antibody and Eu-caecin-conjugated phosphorylated RB antibody were diluted in detection buffer according to the manufacturer's instructions. The detection plate was incubated at room temperature for 4 h, and readings were taken in TR-FRET mode (665 nM and 620 nM) on a ClarioStar (BMG Labtech). The TR-FRET ratio (665 nM / 620 nM) was plotted relative to the compound concentrations and normalized relative to the DMSO control. Half-maximum inhibitory concentration (IC50) was calculated. 50 The values ​​were calculated using a four-parameter logistic fit with GraphPad Prism (version 9; La Jolla, CA).

[0927] In the table below, AA represents ICs less than 1 nM. 50 A represents IC 50 Greater than or equal to 1 nM but less than or equal to 100 nM; B represents IC 50 Greater than 100 nM but less than or equal to 500 nM; C represents IC 50 Greater than 500 nM but less than or equal to 2.5 µM; D indicates IC 50 Greater than 2.5 µM but less than or equal to 5 µM.

[0928]

[0929] Biological Example 2

[0930] High-throughput measurement of endogenous CDK1 / 2 / 4 / 6 in cells

[0931] The effects of compounds on cellular CDK levels were monitored using high-throughput HTRF assays.

[0932] To determine the half-maximum degradation concentration (DC) of the compound 50 Cellular CDK levels were measured in 96-well format using the HTRF Total CDK Cell Kit (CDK1, catalog number 64CDK1TPEG; CDK2, catalog number 64CDK2TPEG; CDK4, catalog number 64CDK4TPEG; CDK6, catalog number 64CDK6TPEG) from Xisi / Refidi.

[0933] On Day 1, adherent cells were seeded at 20,000 cells / well into 96-well tissue culture-treated plates with 200 µL of culture medium and incubated overnight at 37°C in a CO2 atmosphere. On Day 2, cells were treated with compounds ranging from 0.1 to 1,000 nM using a Tecan D300e digital dispenser (HP, CA, USA). Six or 24 hours after compound treatment, the cell culture medium was removed by tapping the plate and patting it with a clean paper towel. Immediately, 30 µL of 1X lysis buffer was added to each well from the kit, and the plates were incubated on a shaker at room temperature for 30 min. After homogenization by pipetting, 8 µL of cell lysate was transferred from the 96-well cell culture plate to 384-well small-volume white detection plates. 2 µL of premixed detection solution was added, and the plates were covered with blocking agent. To prepare the assay solution, the d2-conjugated CDK antibody and the Eu-caecin-conjugated CDK antibody were diluted in the assay buffer according to the manufacturer's instructions. The assay plate was incubated overnight at room temperature and read on a ClarioStar (BMG Laboratory Technologies) in TR-FRET mode (665 nM and 620 nM). The TR-FRET ratio (665 nM / 620 nM) was normalized against the DMSO control (100% CDK) and the lysis buffer control (0% CDK) to calculate the relative CDK level (%CDK relative to DMSO), and this index was then plotted against compound concentration. Half-maximum degradation concentration (DC) was calculated. 50 The maximum degradation (Dmax) value was calculated using a four-parameter logistic fit with GraphPad Prism (version 9; La Jolla, CA).

[0934] Examples of preparations

[0935] The following are representative pharmaceutical formulations containing the compounds disclosed herein.

[0936] Tablet formulations

[0937] Mix the following ingredients tightly and compress them into single-cell tablets.

[0938]

[0939] Capsule formulations

[0940] Mix the following ingredients tightly and encapsulate them into hard-shelled gelatin capsules.

[0941]

[0942] Injectable formulations

[0943] Compounds of formula (I) in 2% HPMC, 1% Tween 80 in DI water, with MSA to make pH 2.2, are added in appropriate amounts to at least 20 mg / mL.

[0944] Inhalation Composition

[0945] To prepare a pharmaceutical composition for inhalation delivery, 20 mg of a compound having formula (I) was mixed with 50 mg of anhydrous citric acid and 100 mL of 0.9% sodium chloride solution. The mixture was then incorporated into an inhalation delivery unit (such as a nebulizer) suitable for inhalation administration.

[0946] Topical gel composition

[0947] To prepare a pharmaceutically acceptable topical gel composition, 100 mg of a compound having formula (I) was mixed with 1.75 g of hydroxypropyl cellulose, 10 mL of propylene glycol, 10 mL of isopropyl myristate, and 100 mL of purified alcohol (USP). The resulting gel mixture was then incorporated into a container (e.g., a tube) suitable for topical application.

[0948] Ophthalmic solution composition

[0949] To prepare a pharmaceutical ophthalmic solution composition, 100 mg of a compound having formula (I) was mixed with 0.9 g of NaCl in 100 mL of purified water and filtered using a 0.2-micron filter. The resulting isotonic solution was then incorporated into an ophthalmic delivery unit (such as an eye drop container) suitable for ophthalmic administration.

[0950] Nasal spray solution

[0951] To prepare the medicated nasal spray solution, 10 g of the compound having formula (I) was mixed with 30 mL of 0.05 M phosphate buffer solution (pH 4.4). The solution was placed in a nasal applicator designed to deliver 100 µL of spray for each dose.

Claims

1. A compound having formula (I): (I) in: R 1 It is a branched alkyl, a branched haloalkyl, a branched cyanoalkyl, a branched hydroxyalkyl, a branched alkoxyalkyl, a branched haloalkoxyalkyl, a cycloalkyl, or a bridged cycloalkyl; wherein the cycloalkyl and the bridged cycloalkyl are substituted by 0, 1, 2 or 3 groups independently selected from halogen, cyano, hydroxy, alkoxy and haloalkoxy. R 2 It is hydrogen, alkyl, halogenated, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, or heterocyclic alkyl; R 2a It is either hydrogen or deuterium; Hy is a cycloalkylene, arylene, heteroarylene, heterocyclic, bicyclic, spirocyclic, bridged, or fused heterocyclic ring, wherein each of the above rings is independently selected from hydrogen, deuterium, alkyl, halogen, haloalkyl, alkoxy, hydroxy, and cyano. a R b and R c replace; The degradation determinant is selected from the following E3 ubiquitin ligase ligands: (a) Groups having formula (i): (i); or (b) Having a group of formula (ii): (ii); Y a It is CH or N; Z a It is a bond, -CH2-, -NH-, -O-, or -NHC(O)-, where the NH in -NHC(O)- is attached to Y. a ; Ring A is a group having formula (a) or (b): ； in: R aa R bb R cc and R dd It is independently selected from hydrogen, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy and cyano; R 4 and R 5 It is independently hydrogen or alkyl; or R 4 and R 5 Together with the carbon attached to them, they form >C=O; M is -O- or -NR 6 -;and R 6 It is hydrogen or alkyl; Ring B is a phenylene, a cycloimino, a 5- or 6-membered monocyclic heteroarylene, or a 9- or 10-membered fused bicyclic heteroarylene, wherein one to three ring atoms of each heteroarylene ring are independently selected from nitrogen, oxygen, or sulfur heteroatoms, and further wherein the phenylene, cycloimino, and each heteroarylene are independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halogen, haloalkyl, haloalkoxy, and cyano groups. ee and R ff Replace; and Z is -O-, -NR 3 - (where R) 3 The R group is composed of hydrogen or alkyl, cycloalkylene, phenylene, monocyclic heteroarylene, unsaturated heterocyclic, heterocyclic, bridged heterocyclic, or spirocyclic, and each ring is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, and cyano. d and R e replace; alk is an R group selected from hydrogen, fluorine, and cyano groups. f Substituted C3 to C6 alkenyl group; C3 to C6 alkylene group or C3 to C6 heteroalkylene group, wherein the C3 to C6 alkylene group and the C3 to C6 heteroalkylene group are R g R h and R i Replace, where R g Is it hydrogen, deuterium, or halogenated, R h It is a group consisting of hydrogen, deuterium, cycloalkyl, cycloalkyloxy, bridged cycloalkyl, halogen, haloalkoxy, alkoxy, hydroxyl, cyano, cyanoalkyl, cyanoalkyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, phenyl, heteroaryl, heterocyclic, heterocyclicoxy, heterocyclic carbonyl, or bridged heterocyclic (wherein the cycloalkyl group—either itself or as part of the cycloalkyloxy group, the bridged cycloalkyl, phenyl, heteroaryl, heterocyclic group—either itself or as part of the heterocyclicoxy or heterocyclic carbonyl group, and the bridged heterocyclic group are independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxyl, alkylcarbonyl, alkyloxycarbonyl, amino, alkylamino, dialkylamino, and cyano). 7 and R 8 Replace); or when R g and R h When R is attached to the same or adjacent carbon atom of the straight-chain portion of the C3 to C6 alkylene or C3 to C6 heteroalkylene, g and R h They can form cycloalkylene or heterocyclic alkylene groups together with the carbon atoms to which they are attached (where R is the carbon atom of the cycloalkylene group). g and R h The resulting cycloalkylene and heterocyclic groups are independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, hydroxyl, alkylcarbonyl, alkyloxycarbonyl, amino, alkylamino, dialkylamino, and cyano groups. 9 and R 10 (replace), and R i It is hydrogen or halogenated; and the straight-chain portion of the C3 to C6 alkenyl group, C3 to C6 alkylene group and C3 to C6 heteroalkylene group attached with Ar and Z contains at least three atoms; Ar is a phenylene, monocyclic heteroarylene, heterocyclic, bridged heterocyclic, or spirocyclic ring, wherein each of the above rings is independently selected from hydrogen, deuterium, alkyl, alkoxy, halogen, haloalkyl, haloalkoxy, and cyano. j R k and R m Replace; or Its pharmaceutically acceptable salt.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 It is a branched alkyl group.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 It is R 1 It is a cycloalkyl group that is substituted by 0, 1, 2 or 3 groups independently selected from halogen, cyano, hydroxy, alkoxy and haloalkoxy.

4. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R 1 It is isopropyl, sec-butyl, tert-butyl, 2,2,2-trifluoroethyl, unsubstituted cyclopropyl, unsubstituted cyclobutyl, or unsubstituted cyclopentyl.

5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 2 It is hydrogen, halogenated, haloalkyl, alkyl, hydroxyalkyl, or alkoxyalkyl.

6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R 2a It is hydrogen.

7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein Hy is R a R b and R c Substituted heterocyclic groups, where R a and R b Independently selected from hydrogen, deuterium, alkyl, halogen, haloalkyl, alkoxy, hydroxyl, and cyano, and R c It is hydrogen.

8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein the heterocyclic group of Hy is: The N atom of the piperidine-1,4-dicyclic ring is attached to -SO2-.

9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein the degradation determinant is an E3 ubiquitin ligase ligand having formula (i): (i)。 10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein ring A of the E3 ubiquitin ligand having formula (i) is: 。 11. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein the degradation determinant is an E3 ubiquitin ligase ligand having formula (ii): (ii).

12. The compound of any one of claims 1 to 8 and 11, or a pharmaceutically acceptable salt thereof, wherein the E3 ubiquitin ligase ligand having formula (ii) is: , , , , , , , , , , , , , or Cycle B is a cyclic imine group.

13. The compound of any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, wherein Ar is a phenylene, a monocyclic heteroarylene, a bridged heterocyclic alkylene group, or a heterocyclic alkylene group, wherein each ring of Ar is determinated by R. j R k and R m Replace, where R m It is hydrogen.

14. The compound of any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, wherein Ar is a derivative of R. j R k and R m The replacement has a formula or phenylene, of which R j and R k Independently selected from hydrogen, alkyl, alkoxy, halogen, cyano, haloalkyl, and haloalkoxy, and R m It is hydrogen.

15. The compound of any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein Z is a heterocyclic group, a bridged heterocyclic group, or a spirocyclic group, wherein each ring of Z is divided by R d and R e replace.

16. The compound of any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, wherein the heterocyclic group, bridging heterocyclic group, and spirocyclic group of Z are each selected from: Furthermore, each of the aforementioned rings is independently selected from hydrogen, deuterium, alkyl, and halogenated R. d and R e replace.

17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein -Z-alk-Ar-SO2- is: Each R d R e and R k Independently selected from hydrogen, alkyl, halogen, haloalkyl, haloalkoxy, alkoxy, and cyano, and R j It is hydrogen.

18. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein alk is R f Substituted C3 to C6 alkenyl groups, wherein R f It is hydrogen.

19. The compound of any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, wherein alk is R g R h and R i Substituted C3 to C6 alkylene groups, wherein R g R h and R i It is hydrogen.

20. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein alk is R g R h and R i Substituted C3 to C6 alkylene groups, wherein R h It is not hydrogen and R i It is hydrogen.

21. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein the C3 to C6 alkenyl group and the C3 to C6 alkylene group of alk are respectively a straight-chain C3 to C6 alkenyl group and a straight-chain C3 to C6 alkylene group, wherein alk is R g R h and R i replace.

22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein the straight-chain C3 to C6 imene group of alk is -CH=C(R f )CH2-, and the straight-chain alkylene of the C3 to C6 alkylene of alk is -CH2CH(R h )CH2-、-CH2CH2CH(R h )-、-CH2C(R g (R) h CH2-, -CH2CH2C(R) g (R) h )-, where R h It is not hydrogen and R i It is hydrogen.

23. The compound of any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, wherein the C3 to C6 alkenyl group and the C3 to C6 alkyl group of alk are respectively branched C4 to C6 alkenyl group and C4 to C6 alkyl group.

24. The compound of any one of claims 1 to 20 and 23, or a pharmaceutically acceptable salt thereof, wherein the C4 to C6 imene group of the alk branch is -CH2CH2C(CH3)=C(R) f )-、-CH2C(CH3)=C(R f )- or -CH2C(=CH2)CH2-, and the C4 to C6 alkylene group of alk is -CH2C(CH3)(R h CH2-、-CH2C(C2H5)(R h CH2-, -CH2CH(CH2R) h CH2-, -CH2CH(CH2CH2R) h CH2-, -CH2C(CH3)(CH2R) h CH2-、-CH2C(C2H5)(CH2R h CH2-, -CH2C(CH3)(CH2CH2R h CH2-, -CH2CH(CH3)CH(CH2R) h )-、-CH2CH2C(CH3)(CH2R h )-、-CH2CH(CH3)C(R g (R) h )-、-CH2CH(C2H5)C(R g (R) h )-、-CH2CH(C(R g (R) h (R) i ))CH(CH3)-、-CH2C(CH3)(C(R g (R) h (R) i ))CH(CH3)-、-CH2CH(C(R g (R) h (R) i ))CH2-、-CH2CH2CH(C(R g (R) h (R) i ))-、-CH2CH2CH(C(R g (R) h (R) i CH2- or -CH2CH2CH2CH(C(R) g (R) h (R) i ))-.

25. The compound of any one of claims 1 to 20, 23 and 24, or a pharmaceutically acceptable salt thereof, wherein the R of the branched C4 to C6 alkylene group of alk is... g and R i It is (unless otherwise stated) hydrogen, deuterium, or fluorine, and the R of the branched C4 to C6 C6 alkylene group of alk is... h Unless otherwise specified, it is hydrogen, deuterium, fluorine, cyclopropyl, cyclobutyl, cyclopropyloxy, cyclobutyloxy, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, hydroxyl, cyano, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, methylcarbonylamino, ethylcarbonylamino, phenyl, pyrazolyl, thiazolyl, furanyl, pyridyl, pyrrolylyl, 2-oxopyrrolylyl, piperidinyl, piperazine, or tetrahydrofuranyl, wherein R h Each ring is independently selected from the R groups of hydrogen, deuterium, methyl, methoxy, fluorine, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethyl, hydroxyl, amino, methylamino, dimethylamino, and cyano. 7 and R 8 Replace, unless otherwise stated.

26. The compound of any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, wherein the alk is R g R h and R i Substituted C3 to C6 heteroalkylene compounds.

27. The compound of any one of claims 1 to 17 and 26, or a pharmaceutically acceptable salt thereof, wherein the C3 to C6 heteroalkylene group of alk is a straight-chain C3 to C6 heteroalkylene group.

28. The compound of any one of claims 1 to 17, 26 and 27, or a pharmaceutically acceptable salt thereof, wherein the straight-chain C3 to C6 heteroalkylene group of alk is R g R h and R i Replacement -CH2CH2X a CH2-、-CH2X a CH2CH2-、-CH2CH2CH2X a -、-X a CH2CH2CH2-、-X y CH2CH2X a -、-X y CH2CH2X a CH2-、-CH2CH2CH2X a CH2-、-CH2X a CH2-, -X a CH2CH2-、-CH2CH2X a -, -CH2CONR q CH2-、-CH2SO2NR q CH2-、-CH2NR q COCH2-、-CH2NR q SO2CH2-、-CH2CH2CH2NR q CO-, -CH2CONR q -、-CH2SO2NR q -、-CH2NR q CO-、-CH2NR q SO2-, -CONR q CH2-, -SO2NR q CH2-, -NR q COCH2- or -NR q SO2CH2, and X a Yes -NR q -, -O-, -S-, -SO-, -SO2-, or -CO-.

29. The compound of any one of claims 1 to 17 and 26, or a pharmaceutically acceptable salt thereof, wherein the C3 to C6 heteroalkylene group of alk is a branched C4 to C6 heteroalkylene group.

30. The compound of any one of claims 1 to 17, 26 and 29, or a pharmaceutically acceptable salt thereof, wherein the C4 to C6 heteroalkylene branch of alk is -CH2X. a CH(CH3)CH2-、-CH2X y CH2CH(CH3)X a -, -CH2CH2CH(CH3)X a -、-X a CH(CH3)CH2CH2-、-X y CH2CH(CH3)X a -、-X y CH(CH3)CH2X a -, -CH2CH2CH2CH(CH3)X a -、-X a CH(CH2R h CH2-, -CH2CH(CH2R) h )X a -、-X a CH(CH2CH2R h CH2-, -CH2CH(CH2CH2R) h )X a -, -CH2C(CH3)(CH3)X a -、-X a C(CH3)(CH3)CH2-, -CH(CH3)CH(CH3)X a -、-CONR z CH2CH(CH3)X a -、-CH2NR q COCH(CH3)CH2- or -NR q COCH(CH3)CH2-, where X a Yes -NR q -, -O-, -S-, -SO-, -SO2-, or -CO-.

31. The compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 17, 26, 29 and 30, wherein the R of the branched C4 to C6 heteroalkylene group of alk is... g and R i It is hydrogenated or halogenated (unless otherwise stated), and the R of the branched C4 to C6 heteroalkylene group of alk is... h It is hydrogen, halogenated, haloalkoxy, cycloalkyl, cycloalkyloxy, alkoxy, hydroxyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonylamino, cyano, cyanoalkyloxy, phenyl, heteroaryl, heterocyclic, heterocyclicoxy, heterocyclic carbonyl, or bridging heterocyclic, wherein R h Each ring is R 7 and R 8 replace.

32. The compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein alk is: 。 33. The compound of any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein the degradation determinant is an E3 ubiquitin ligase ligand selected from: , , , , , , , , , , , and ; Where R ee It is hydrogen, methyl, ethyl, cyclopropyl, or 2,2,2-trifluoroethyl, and R ff It is hydrogen, methyl, cyclopropyl, fluorine, cyano, methoxy, difluoromethoxy, trifluoromethoxy, or trifluoromethyl.

34. A pharmaceutical composition comprising a compound as described in any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

35. A method of treating a patient with cancer, the method comprising administering to a patient in need a therapeutically effective amount of a compound as described in any one of claims 1 to 33 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 34.

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