Sulfonamide derivatives as cyclin-dependent kinase 2 inhibitors

Abstract

The present disclosure provides certain sulfonamide derivatives that are cyclin dependent kinase 2 (CDK2) inhibitors of formula (I) for the treatment of diseases treatable by inhibition of CDK2. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds. # imgabs0 #

Description

[0001] This application claims priority to U.S. Provisional Application No. 63 / 366,033, filed on June 8, 2022, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0002] The present disclosure provides certain sulfonamide derivatives that are inhibitors of cyclin-dependent kinase 2 (CDK2) and are useful for treating diseases mediated by inhibition of CDK2. Also provided herein are pharmaceutical compositions containing such compounds and methods for preparing such compounds. Background Art

[0003] Cyclin-dependent kinases (CDKs) are cellular kinases that are crucial for orchestrating signaling events such as DNA replication and protein synthesis to ensure reliable eukaryotic cell division and proliferation. To achieve activation, the cyclin-dependent kinase catalytic unit of a CDK typically binds to a regulatory subunit called a cyclin. In addition, the activity of a CDK is also controlled by its phosphorylation state and the binding of inhibitory proteins.

[0004] Of the CDKs identified to date, at least the CDK1 / cyclin B, CDK2 / cyclin E, CDK2 / cyclin A, CDK4 / cyclin D, and CDK6 / cyclin D complexes are considered important regulators of cell cycle progression; while other CDKs are important 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).

[0005] Due to their key role in regulating the cell cycle and other essential cellular processes, it has been shown that increased activity or transient abnormalities in CDK activation contribute to the development of various types of cancer. The CDK2 / cyclin E complex plays an important role in regulating the G1 / S transition, histone biosynthesis, and centrosome duplication. After initial phosphorylation of retinoblastoma (Rb) by CDK 4 / 6 / cyclin D, CDK2 / cyclin E further hyperphosphorylates p-RB, releasing the G1 transcription factor E2F to transcribe genes required for entry into the S phase. During the S phase, cyclin E is degraded, and CDK2 forms a complex with cyclin A to promote substrate phosphorylation, thereby allowing DNA replication and inactivation of E2F to complete the S phase (see Asghar et al. Nat. Rev. Drug. Discov. [Nature Reviews: Drug Discovery] (2015) 14: 130-146). In addition to cyclin binding, CDK2 activity is also tightly regulated through its interaction with negative regulators such as p21 and p27. In response to mitogenic stimuli that signal an optimal environment for the cell cycle, p21 and p27 are phosphorylated and degraded, thereby unblocking CDK2 / cyclin activation.

[0006] Cyclin E (regulatory cyclin of CDK2) is usually overexpressed in cancer, and its overexpression is associated with poor prognosis. For example, it has been shown that amplification or overexpression of cyclin E is associated with poor outcomes in breast cancer (see Keyomarsi et al., N Engl J Med. [New England Journal of Medicine] (2002) 347: 1566-75). Cyclin E2 (CCNE2) overexpression is associated with endocrine resistance in breast cancer cells, and it has been reported that CDK2 inhibition restores sensitivity to tamoxifen or CDK4 / 6 inhibitors in tamoxifen-resistant and CCNE2-overexpressing cells. (see Caldon et al., Mol Cancer Ther. [molecular cancer therapeutics] (2012) 11: 1488-99; and Herrera-Abreu et al., Cancer Res. [cancer research] (2016) 76: 2301-2313). It is reported that cyclin E amplification also contributes to trastuzumab resistance in HER2+ breast cancer. (See Scaltriti et al. Proc Natl Acad Sci. (2011) 108:3761-6.) Cyclin E overexpression has also been reported to play a role in basal-like and triple-negative breast cancer (TNBC), as well as inflammatory breast cancer (see Elsawaf Z. et al. Breast Care (2011) 6:273-278; and Alexander A. et al. Oncotarget (2017) 8:14897-14911).

[0007] Amplification or overexpression of cyclin E1 (CCNE1) is also frequently found in ovarian, gastric, endometrial, uterine, bladder, esophageal, prostate, lung, and other types of cancer (see Nakayama et al. Cancer (2010) 116:2621-34; Etemadmoghadam et al. Clin Cancer Res (2013) 19:5960-71; Au-Yeung et al. Clin. Cancer Res. (2017) 23:1862-1874; Ayhan et al. Modern Pathology (2017) 30:297-303; Ooi et al. Hum Cancer Res (2013) 19:5960-71). Pathol. [Human Pathology] (2017) 61:58-67; and Noske et al. Oncotarget [Tumor Target] (2017) 8:14794-14805) and is often associated with poor clinical outcomes.

[0008] Cyclin E1 turnover is regulated by SCF Fbxw7 The ubiquitin E3 ligase component FBXW7 and the deubiquitinase USP28 are regulated, which are often dysregulated in cancer. Loss-of-function mutations in FBXW7 or overexpression of USP28 lead to overexpression of cyclin E and activation of CDK2 (Welcker, M. and Clurman, BE 2008 Nat. Rev. Cancer [Nature Review - Cancer] 8, 83; Diefenbacher, ME et al. (2014) J. Clin. Invest. [Clinical Investigation Journal] 124, 3407-3418). Alternatively, some cancer cells express an overactive truncated form of cyclin E (Caruso JA et al. Cancer Res. [Cancer Research] 2018 Oct 1; 78(19): 5481-5491). In addition, cyclin A amplification and overexpression have also been reported in various cancers such as hepatocellular carcinoma (Bayard, Q. et al. Nat Commun 9, 5235 (2018)), colorectal cancer, and breast cancer.

[0009] In contrast to the frequent upregulation of cyclin E, inhibitory regulators of CDK2, p21, and p27 are often abnormally downregulated in cancer. SKP2, a component of the SKP1-CUL1-F-box (SCF) complex, has also been implicated in tumorigenesis due to its ability to degrade p27 (Zhen Cai et al., (2020) Seminars in Cancer Biology 67(2):16-33). It is hypothesized that the loss or reduction of p21 / p27 or the overexpression of SKP2 leads to high and / or abnormal transient activation of CDK2, thereby promoting oncogenic growth.

[0010] Furthermore, CDC25A and CDC25B, the protein phosphatases responsible for dephosphorylation that activates CDK2, are overexpressed in various tumors. These different mechanisms of CDK2 activation have been validated using mouse cancer models.

[0011] Retinoblastoma (Rb) protein is used as a transcriptional co-repressor and represents a key substrate for the CDK4 / 6 and CDK2 complexes that drive cell division. Consistent with this typical model, Rb-deficient tumors are independent of CDK4 / 6 and have consistent resistance to CDK4 / 6 inhibitors. However, analysis of DepMAP (McFarland et al., 2018; Tsherniak et al., 2017) (a database that uses CRISPR technology to assess the functional requirements of genes in 717 cancer cell lines) found that Rb deficiency and high CDKN2A are associated with a higher susceptibility to CDK2 or cyclin E1 inhibition (Erik S. Knudsen et al. Cell Reports [Cell Reports] March 1, 2022, 38: 110448). It has been proposed that CDK2 / cyclin E1 drives the phosphorylation of p130, enabling the cell cycle progression in this Rb-deficient CDK2 / cyclin E1-dependent environment to be achieved.

[0012] Furthermore, CDK2 / cyclin E phosphorylates oncogenic Myc to counteract ras-induced senescence, highlighting the importance of CDK2 in myc / ras-induced tumorigenesis (Per Hydbring, PNAS 2010 Jan 5, 107(1):58-63; Campaner, S., Doni, M., Hydbring, P. et al. Nat Cell Biol 12, 54-59 (2010). Inactivation of CDK2 has been shown to be synthetically lethal to myc-overexpressing cancer cells (Jan J. Molenaar, PNAS 2009 Aug 4, 106(31):12968-12973; Sara Bolin et al. Oncogene 37:2850-2862 (2018)).

[0013] The centrosomal protein CP110 plays an important role in centrosome duplication / separation and requires CDK2 phosphorylation to induce centrosome clustering (reviewed in M ​​Kawakami et al. (2018) Mol Cancer Ther [Molecular Cancer Therapeutics] 17(4):724-731). Aneuploid cancer cells are genetically unstable and often have supernumerary centrosomes. If centrosome clustering is blocked, aneuploid cells with supernumerary centrosomes undergo multipolar divisions, leading to apoptosis of progeny cells, a process known as late catastrophe. In addition, CP110 is downregulated in KRAS mutant lung cancer, thereby enhancing the sensitivity of this cancer to CDK2 inhibitors. In a model of KRAS mutant lung cancer, CDK2 inhibition led to late catastrophe and apoptosis and reduced the growth of lung cancer xenografts. Because aneuploid cells with supernumerary centrosomes appear in many cancers, it may be possible to extend CDK2 inhibitors to other environments beyond KRAS mutant lung cancer.

[0014] It has also been shown that CDK2 plays a role in blocking myeloid differentiation in AML (Meidan Ying et al., Blood [blood] June 14, 2018; 131 (24): 2698-2711). Inhibition of CDK2 effectively induces granulocyte differentiation in AML cell lines and blocks tumor growth in AML mouse models. The synergistic effect of CDK2 inhibition and all-trans retinoic acid (ATRA) combination in AML has been confirmed both in vitro and in vivo (Xuejing Shao et al., Pharmacol Res [Pharmacology Research], 2020 151: 104545).

[0015] It has also been shown that pharmacological inhibition or genetic deletion of CDK2 preserves hearing function in animal models treated with cisplatin or noise (see Teitz T et al. J Exp Med. 2018 Apr 2;215(4):1187-1203). Therefore, in addition to anti-tumor therapy, CDK2 inhibition may also be used as a promising preventive treatment for noise-, cisplatin-, or antibiotic-induced or age-related hearing loss, for which no Food and Drug Administration-approved drugs are currently available.

[0016] Given the role of CDK2 in human malignancies, there is a need for CDK2 inhibitors for the treatment of cancer and related diseases. The present disclosure satisfies this need and related needs. Summary of the Invention

[0017] In a first aspect, there is provided a compound having formula (I), or a pharmaceutically acceptable salt thereof;

[0018]

[0019] in:

[0020] W is N or CH (or C, when attached to R 6 hour);

[0021] X and Z are independently CR 8 NR 8A , N, O, or S; and Y is CR 9 NR 10 , or N; provided that both X and Z are not O or S; and at least one of X, Y and Z is not carbon;

[0022] R 8 is hydrogen, alkyl, halo, hydroxyalkyl, or cyano;

[0023] R 8A is hydrogen or an alkyl group;

[0024] R 9 and R 10 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, alkylsulfonyl, alkylsulfonylalkyl, amino, alkylamino, dialkylamino, substituted amino, aminoalkyl, cycloalkyl, bicyclic cycloalkyl, bridged cycloalkyl, spirocycloalkyl, heterocyclyl, bicyclic heterocyclyl, bridged heterocyclyl, spiroheterocyclyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, wherein:

[0025] (A)R 9 and R 10 The cycloalkyl, bicyclic cycloalkyl, bridged cycloalkyl, and spirocycloalkyl groups are each independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, cycloalkyl, halo, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, alkylamino, and dialkylamino groups. a replace;

[0026] (B)R 9 and R 10wherein the heterocyclyl, bicyclic heterocyclyl, bridged heterocyclyl, and spiroheterocyclyl are independently selected from hydrogen, alkyl, deuterated alkyl, cycloalkyl, bridged cycloalkyl, spirocycloalkyl (wherein the cycloalkyl, bridged cycloalkyl, and spirocycloalkyl are substituted with one or two substituents independently selected from hydrogen, alkyl, halo, hydroxy, and cyano), alkoxy, halo, haloalkyl, haloalkoxy, alkoxycarbonyl, hydroxy, cyano, amino, alkylamino, dialkylamino, aryl, aralkyl, heterocyclyl, bridged heterocyclyl, spiroheterocyclyl, heteroaryl, or heteroaralkyl (wherein aryl by itself or as part of aralkyl, heteroaryl by itself or as part of heteroaralkyl, heterocyclyl, bridged heterocyclyl, and spiroheterocyclyl are independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, cyano, amino, alkylamino, and dialkylamino) e 、R f and R g R b 、R c and R d Replacement; and

[0027] (C)R 9 and R 10 wherein the aryl radical by itself or as part of the aralkyl radical and the heteroaryl radical by itself or as part of the heteroaralkyl radical are independently selected from hydrogen, alkyl, deuterated alkyl, cycloalkyl (wherein the cycloalkyl radical is optionally substituted with one or two substituents independently selected from alkyl, halo, hydroxy, and cyano), alkoxy, halo, haloalkyl, haloalkoxy, alkoxycarbonyl, hydroxy, cyano, amino, alkylamino, dialkylamino, aryl, aralkyl, heterocyclyl, bridged heterocyclyl, spiroheterocyclyl, heteroaryl, or heteroaralkyl (wherein the aryl radical by itself or as part of the aralkyl radical, the heteroaryl radical by itself or as part of the heteroaralkyl radical, heterocyclyl, bridged heterocyclyl, and spiroheterocyclyl radical are independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, cyano, amino, alkylamino, and dialkylamino radicals; and wherein the R m 、R n and R o R h 、R j and R k replace;

[0028] Ring R A is phenyl or heteroaryl;

[0029] R 1 、R 2 and R 3 is independently hydrogen, deuterium, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, or cyano;

[0030] R4 and R 5 are independently hydrogen, alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, fused cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, bicyclic heterocyclyl, bicyclic heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, fused heterocyclyl, fused heterocyclylalkyl, spiroheterocyclyl, and spiroheterocyclylalkyl (wherein cycloalkyl by itself or as part of cycloalkylalkyl, fused cycloalkyl, aryl by itself or as part of aralkyl, heteroaryl by itself or as part of heteroaralkyl, heterocyclyl by itself or as part of heterocyclylalkyl, bicyclic heterocyclyl by itself or as part of bicyclic heterocyclylalkyl, bridged heterocyclyl by itself or as part of bridged heterocyclylalkyl, fused heterocyclyl by itself or as part of fused heterocyclylalkyl, and spiroheterocyclyl by itself or as part of spiroheterocyclylalkyl are independently selected from hydrogen, alkyl, alkoxy, alkylsulfonyl, alkyloxycarbonyl, R is hydroxy, acyl, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, substituted amino, alkoxycarbonylamino, alkoxycarbonylaminoalkyl, aminocarbonyl, aminocarbonylalkyl, cyano, hydroxyalkyl, hydroxyalkoxy, alkoxyalkyl, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, aminoalkylamino, cyanoalkyl, cyanoalkoxy, cycloalkyl, cycloalkoxy, aryl, aryloxy, aralkyl, heteroaryl, heteroaryloxy, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxy and heterocyclylalkyloxy (wherein aryl by itself or as part of aralkyl and aryloxy, heteroaryl by itself or as part of heteroaryloxy and heteroaralkyl, and heterocyclyl by itself or as part of heterocyclylalkyl, heterocyclyloxy and heterocyclylalkyloxy are substituted with one, two or three substituents independently selected from hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy and cyano) p 、R q and R r replaced); or

[0031] R 4 and R 5Together with the nitrogen atom to which they are attached, they form a ring selected from the group consisting of cyclic amine, bicyclic amine, fused cyclic amine, bridged cyclic amine, fused bridged cyclic amine, spiroamine, and fused spiroamine, wherein each of the above rings is independently selected from hydrogen, deuterium, alkyl, alkoxy, alkylsulfonyl, alkoxycarbonyl, hydroxy, acyl, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, substituted amino, alkoxycarbonylamino, alkoxycarbonylaminoalkyl, aminocarbonyl, aminocarbonylalkyl, cyano, hydroxyalkyl, hydroxyalkoxy, alkoxyalkyl, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, aminoalkylamino R is alkyl, cyanoalkyl, cyanoalkoxy, cycloalkyl, cycloalkoxy, aryl, aryloxy, aralkyl, heteroaryl, heteroaryloxy, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy and unsubstituted heterocyclyl (wherein aryl by itself or as part of aryloxy and aralkyl, heteroaryl by itself or as part of heteroaryloxy and heteroaralkyl, heterocyclyl by itself or as part of heterocyclylalkyl, heterocyclyloxy and heterocyclylalkyloxy, and unsubstituted heterocyclyl are substituted with one to three substituents independently selected from hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy and cyano) s 、R t and R u replace;

[0032] R 6 is hydrogen, alkyl, cycloalkyl, cyano, halo, or haloalkyl;

[0033] R 7 Yes-Q-(alk 1 ) n1 -SO2R 11 、-Q 1 -(alk 2 ) n2 -SO(=NR 12 )R 13 、-Q 2 -(alk 3 ) n3 -SO2NR 14 R 15 、-Q 3 -(alk 4 ) n4 -COR 16 、-Q 4 -(alk 5 ) n5 -CONR 17 R 18 、-Q 5 -(alk 6 ) n6 -NR 19COR 20 、-Q 6 -(alk 7 ) n7 -NR 21 SO2R 22 , heterocyclyl, bicyclic heterocyclyl, fused heterocyclyl, spiro heterocyclyl, bridged heterocyclyl, cyclic sulfoximino, bicyclic sulfoximino, spiro sulfoximino, aryl, heteroaryl, or fused heteroaryl, wherein:

[0034] Q, Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , and Q 6 Each of the is a bond, a cycloalkyl, a bridged cycloalkyl, a spiroalkyl, a heterocyclyl A , bicyclic heterocyclic group A , bridged heterocyclic group A , fused heterocyclic group A , spiro heterocyclic group A , aryl, or heteroaryl, wherein each of the above rings is independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, and cyano. v and R w replace;

[0035] n 1 、n 2 、n 3 、n 4 、n 5 、n 6 , and n 7 Each of is 0 or 1, provided that when Q is a bond, then n 1 、n 2 、n 3 、n 4 、n 5 、n 6 , and n 7 Each of is 1;

[0036] alk 1 alk 2 alk 3 alk 4 alk 5 alk 6 and alk 7 each is an alkylene group;

[0037] R 12 、R 19 and R 21 is hydrogen or an alkyl group;

[0038] R 11 、R 13 、R 16 、R 20 and R 22 independently selected from hydrogen, alkyl, fluorine, chlorine, bromine, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, bicyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl, spiroheterocyclyl, heterocyclylalkyl, or -CR 23 =CR 24 R 25 [where R 23 is hydrogen, alkyl, or cyano, R 24 is hydrogen or alkyl, and R 25 is hydrogen, alkyl, halo, haloalkyl, alkoxyalkyl, hydroxyalkyl, amino, alkylamino, dialkylamino, or -(alkylene)-NR 26 R 27 (where R 26 and R 27 are independently hydrogen or alkyl) or heterocyclylalkyl], wherein R 11 、R 13 、R 16 、R 20 and R 22 wherein the cycloalkyl radical is by itself or as part of a cycloalkylalkyl radical, the aryl radical is by itself or as part of an aralkyl radical, the heteroaryl radical is by itself or as part of a heteroaralkyl radical, the heterocyclyl radical is by itself or as part of a heterocyclylalkyl radical, the bicyclic heterocyclyl radical, the bridged heterocyclyl radical, the fused heterocyclyl radical, and the spiroheterocyclyl radical, and R 25 wherein the heterocyclylalkyl group is substituted with one to three substituents independently selected from hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cyano, and heterocyclyl; provided that R 11 、R 16 、R 20 , and R 22 It is not hydrogen;

[0039] R 14 、R 15 、R 17 and R 18independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl, wherein cycloalkyl by itself or as part of cycloalkylalkyl, aryl by itself or as part of aralkyl, heteroaryl by itself or as part of heteroaralkyl, and heterocyclyl by itself or as part of heterocyclylalkyl are substituted with one to three substituents independently selected from hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, and cyano; and

[0040] R 7 The heterocyclic, bicyclic, fused, spiroheterocyclic, bridged heterocyclic, cyclic sulfoximino, spirocyclic sulfoximino, aryl, heteroaryl, and fused heteroaryl groups are independently selected from hydrogen, deuterium, alkyl, alkoxy, alkoxycarbonyl, hydroxy, acyl, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, substituted amino, alkoxycarbonylamino, alkoxycarbonylaminoalkyl, aminocarbonyl, aminocarbonylalkyl, cyano, hydroxyalkyl, hydroxyalkoxy, alkoxyalkyl, alkoxyalkyloxy, alkoxyalkyloxyalkyl, aminoalkyl, aminoalkoxy, aminoalkylamino, cyanoalkyl, cyanoalkoxy R is alkyl, cycloalkyl, cycloalkyloxy, aryl, aryloxy, aralkyl, heteroaryl, heteroaryloxy, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, or heterocyclylalkyloxy (wherein aryl by itself or as part of aralkyl and aryloxy, heteroaryl by itself or as part of heteroaryloxy and heteroaralkyl, and heterocyclyl by itself or as part of heterocyclylalkyl, heterocyclyloxy, and heterocyclylalkyloxy are substituted with one to three substituents independently selected from hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, alkoxycarbonyloxy, alkoxyalkyl, alkoxyalkyloxyalkyl, cyano, and heterocyclyl) x 、R y , and R y1 replace;

[0041] This is provided that the compound of formula (I) is not:

[0042] N-(3-(2-Isopropyl-5-(2-((2-(methylsulfonyl)ethyl)amino)pyrimidin-4-yl)thiazol-4-yl)phenyl)-morpholine-4-sulfonamide; or a pharmaceutically acceptable salt thereof.

[0043] In a second aspect, a pharmaceutical composition is provided comprising a compound having formula (I) (or any embodiment thereof described herein) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0044] Generally, compounds of formula (I) selectively inhibit CDK2 relative to CDK1 and may also be selective relative to CDK4 and / or CDK6. Thus, in a third aspect, a method of treating a disease treatable by inhibiting CDK2 in a patient (preferably a patient in need of such treatment) is provided, the method comprising administering to the patient (preferably a patient in need of such treatment) a therapeutically effective amount of a compound of formula (I) as disclosed herein (or any embodiment thereof as described herein) or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition thereof.

[0045] In a first embodiment of the third aspect, the disease is cancer. In a second embodiment of the third aspect, the disease is a cancer selected from the group consisting of ovarian cancer, endometrial cancer, breast cancer (e.g., hormone receptor positive breast cancer and triple negative breast cancer), lung cancer (e.g., adenocarcinoma, small cell lung cancer, non-small cell lung cancer, small cell carcinoma, and non-small cell carcinoma, bronchogenic carcinoma, bronchial adenoma, and / or pleuropulmonary blastoma), skin cancer (e.g., melanoma, squamous cell carcinoma, Kaposi's sarcoma, and / or Merkel cell skin cancer), bladder cancer, cervical cancer, colorectal cancer, small intestine cancer, colon cancer, rectal cancer, anal cancer, stomach 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, cholangiocarcinoma), prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gallbladder cancer, pancreatic cancer (e.g., exocrine pancreatic cancer), gastric cancer, thyroid cancer, and parathyroid cancer. In a third embodiment of the third aspect the disease is cancer resistant to CDK4 / 6 inhibitors through a CDK2-mediated mechanism.

[0046] In a fourth aspect, a method of treating noise-, cisplatin-, or antibiotic-induced or age-related hearing loss is provided, the method comprising administering to a patient (preferably, a patient in need of such treatment) a therapeutically effective amount of a compound of formula (I) as disclosed herein (or any embodiment thereof as described herein) or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition thereof. In some embodiments, the amount of hearing loss is reduced when compared to an age-matched control. In some embodiments, hearing loss is prevented when compared to an age-matched control.

[0047] In a fifth aspect, there is provided a compound of formula (I) (or any embodiment thereof as described herein) or a pharmaceutically acceptable salt thereof for use as a medicine. In one embodiment of the fifth aspect, the compound of formula (I) (and any embodiment thereof as described herein) or a pharmaceutically acceptable salt thereof can be used to treat one or more of the diseases disclosed in the third and / or fourth aspects (including the embodiments therein).

[0048] In a sixth aspect, there is provided a use of a compound of formula (I) (and any embodiments thereof disclosed herein) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a disease treatable by inhibiting CDK2 in a patient. In an embodiment of the sixth aspect, the disease is one or more of the diseases disclosed in the third and / or fourth aspects (including embodiments therein).

[0049] In a seventh aspect, a method of inhibiting CDK2 is provided, comprising contacting CDK2 with a compound of formula (I) (and any of its embodiments described herein) or a pharmaceutically acceptable salt thereof; or contacting CDK2 with a pharmaceutical composition comprising a compound of formula (I) (and any of its embodiments described herein) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. In one embodiment, CDK2 is contacted with a compound of formula (I) (or any of its embodiments described herein) or a pharmaceutically acceptable salt thereof in vitro. In another embodiment, CDK2 is contacted with a compound of formula (I) (or any of its embodiments described herein) or a pharmaceutically acceptable salt thereof in vivo.

[0050] In any of the above aspects relating to the treatment of cancer, further embodiments include administering a compound of formula (I) (or any embodiment thereof disclosed herein) or a pharmaceutically acceptable salt thereof in combination with at least one additional anticancer agent. When combination therapy is used, these agents may be administered simultaneously or sequentially.

[0051] Detailed description

[0052] Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this application and have the following meanings:

[0053] "Alkyl" means a straight-chain saturated monovalent hydrocarbon group having one to six carbon atoms or a branched-chain saturated monovalent hydrocarbon group having three to six carbon atoms, for example, methyl, ethyl, propyl, 2-propyl, butyl, pentyl, and the like.

[0054] "Alkylene" means a straight-chain saturated divalent hydrocarbon radical having one to six carbon atoms or a branched-chain saturated divalent hydrocarbon radical having three to six carbon atoms, unless otherwise specified; for example, methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.

[0055] "Alkoxy" means a -OR radical (wherein R is alkyl as defined above), for example, methoxy, ethoxy, propoxy or 2-propoxy, n-butoxy, isobutoxy or tert-butoxy, and the like.

[0056] "Alkoxyalkyl" means a straight chain monovalent hydrocarbon radical having one to six carbon atoms or a branched chain monovalent hydrocarbon radical having three to six carbon atoms substituted with an alkoxy radical as defined above, for example, 2-methoxyethyl, 1-, 2-, or 3-methoxypropyl, 2-ethoxyethyl, and the like.

[0057] "Alkoxyalkyloxy" means -OR z Base, where R z is an alkoxyalkyl group as defined above. Representative examples include, but are not limited to, 2-methoxyethyloxy, 1-, 2- or 3-methoxypropyloxy, 2-ethoxyethyloxy, and the like.

[0058] "Alkoxyalkyloxyalkyl" refers to an -(alkylene)-R z , where R z is alkoxyalkyloxy as defined above. Representative examples include, but are not limited to, 2-methoxyethyloxymethyl, 1-, 2- or 3-methoxypropyloxymethyl, 2-ethoxyethyloxyethyl and the like.

[0059] "Alkoxycarbonyl" or "alkyloxycarbonyl" refers to -C(O)OR z Base (where R z is alkyl as defined above), for example, methoxycarbonyl, ethoxycarbonyl, and the like.

[0060] "Alkoxycarbonylamino" refers to -NHC(O)OR z Base, where R z is an alkyl group as defined above, for example, methoxycarbonylamino, ethoxycarbonylamino, and the like.

[0061] "Alkoxycarbonylaminoalkyl" refers to an -(alkylene)-R z Base, where R z is an alkoxycarbonylamino group as defined above, for example, methoxycarbonylaminomethyl, ethoxycarbonylaminoethyl and the like.

[0062] "Alkylsulfonyl" means -SO2R z Base (where R z is alkyl as defined above), for example, methylsulfonyl, ethylsulfonyl, etc.

[0063] "Alkylsulfonylalkyl" means a straight-chain monovalent hydrocarbon radical having one to six carbon atoms or a branched-chain monovalent hydrocarbon radical having three to six carbon atoms substituted with one alkylsulfonyl radical as defined above, for example, 2-methylsulfonylmethyl, methylsulfonylethyl, 2-ethylsulfonylethyl, and the like.

[0064] "Amino" means -NH2.

[0065] "Alkylamino" means -NHR (wherein R is alkyl as defined above), for example, methylamino, ethylamino, propylamino, and the like.

[0066] "Aminoalkyl" refers to an aminoalkyl group z 'R z "substituted linear monovalent hydrocarbon radicals having one to six carbon atoms or branched monovalent hydrocarbon radicals having three to six carbon atoms, wherein R z ' and R z " is independently hydrogen, alkyl, deuterated alkyl, cycloalkyl, cycloalkylalkyl (wherein the cycloalkyl and cycloalkyl rings in the cycloalkylalkyl are optionally substituted with one, two or three substituents independently selected from alkyl, haloalkyl, halo, hydroxy, alkoxy and cyano), haloalkyl, hydroxyalkyl, alkoxyalkyl, aminocarbonylalkyl, alkylsulfonylalkyl, alkylcarbonyl, alkoxycarbonyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl or optionally substituted heterocyclylalkyl, each as defined herein. Representative examples include, but are not limited to, aminomethyl, aminoethyl, methylaminomethyl and the like.

[0067] "Aminoalkyloxy" or "aminoalkoxy" means -OR z , where R z is aminoalkyl as defined above. Representative examples include, but are not limited to, aminomethyloxy, aminoethyloxy, methylaminomethyloxy, dimethylaminoethyloxy, and the like.

[0068] "Aminoalkylamino" refers to -NR-(alkylene)-NR z 'R z ”, where R z ' and R z " is independently hydrogen, alkyl, deuterated alkyl, cycloalkyl, cycloalkylalkyl (wherein the cycloalkyl and cycloalkyl rings in the cycloalkylalkyl are optionally substituted with one, two, or three substituents independently selected from alkyl, haloalkyl, halo, hydroxy, alkoxy, and cyano), haloalkyl, hydroxyalkyl, alkoxyalkyl, aminocarbonylalkyl, alkylsulfonylalkyl, alkylcarbonyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, each as defined herein. Representative examples include, but are not limited to, aminoethylamino, methylaminoethylamino, diethylaminoethylamino, and the like.

[0069] "Aminocarbonyl" means -CONR z 'R z " base, where R z ' and R z" is independently hydrogen, alkyl, cycloalkyl (optionally substituted with one, two or three substituents independently selected from alkyl, halo, hydroxy, alkoxy or cyano), haloalkyl, hydroxyalkyl, alkoxyalkyl and alkylcarbonyl, each as defined herein, for example, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl and the like.

[0070] "Aminocarbonylalkyl" refers to an -(alkylene)-CONR z 'R z " base, where R z ' and R z " is independently hydrogen, alkyl, cycloalkyl (optionally substituted with one, two or three substituents independently selected from alkyl, halo, hydroxy, alkoxy or cyano), haloalkyl, hydroxyalkyl, alkoxyalkyl and alkylcarbonyl, each as defined herein.

[0071] "Acyl" means -C(O)R z Base, where R z is an alkyl, haloalkyl, cycloalkyl, optionally substituted phenyl, optionally substituted heteroaryl, or optionally substituted heterocyclyl as defined herein. Representative examples include, but are not limited to, methylcarbonyl, ethylcarbonyl, benzoyl, trifluoromethylcarbonyl, cyclopropylcarbonyl, and the like. When R z When an alkyl group, an acyl group is also referred to herein as an alkylcarbonyl group.

[0072] "Aryl" means a monovalent monocyclic or bicyclic aromatic hydrocarbon group of 6 to 10 ring atoms, for example, phenyl or naphthyl.

[0073] "Aryloxy" means -OR z Base, where R z is an aryl group as defined above. Representative examples include phenoxy and naphthoxy.

[0074] "Aralkyl" refers to -(alkylene)-R z Base, where R z is an aryl group as defined above. Examples include, but are not limited to, benzyl, phenethyl, and the like.

[0075] "Bicyclic cycloalkyl" means a saturated monovalent bicyclic hydrocarbon radical having 5 to 10 carbon atoms, wherein the two rings are fused at two adjacent carbon ring atoms. Unless otherwise indicated, the bicyclic cycloalkyl radical is optionally substituted with one or two substituents independently selected from deuterium, alkyl, halo, haloalkyl, alkoxy, hydroxyl, and cyano. Examples include, but are not limited to, bicyclo[3.1.0]hex-6-yl, etc.

[0076] "Bicyclic amino" means a saturated monovalent bicyclic ring having 5 to 10 ring atoms, wherein the two rings are fused at two adjacent ring atoms, and wherein one of the ring atoms is nitrogen and the other ring atom is independently selected from N, O and S(O). n (wherein n is an integer from 0 to 2) heteroatom, the remaining ring atoms are C. In addition, one or two ring carbon atoms of the bicyclic amino group can be optionally replaced by a -CO- group. Representative examples include, but are not limited to, 3-azabicyclo[3.1.0]hexane-3-yl, 3-azabicyclo[4.1.0]heptane-3-yl, etc.

[0077] "Bicyclic heterocyclyl" means a saturated monovalent bicyclic radical having 5 to 10 ring atoms, wherein the two rings are fused at two adjacent ring atoms, and wherein one or two ring atoms are independently selected from N, O and S(O). n (wherein n is an integer selected from 0 to 2) heteroatoms, remaining annular atoms are C, unless otherwise indicated.In addition, one or two ring carbon atoms of bicyclic heterocyclic radical can be alternatively replaced by-CO-group.When bicyclic heterocyclic radical only contains S (O) 2, it can be referred to as bicyclic sulfonyl in this article.More particularly, term bicyclic heterocyclic radical includes but is not limited to, hexahydrofuran simultaneously [3,2-b] furyl, hexahydro -1H- pyrrolizinyl, 3,3- dioxo -3- thiabicyclo [3.1.0] hexane -6- base etc..When bicyclic heterocyclic radical ring as defined above only contains-SO in ring 2-, it is also referred to as " bicyclic sulfonyl " in this article and is the subset of bicyclic heterocyclic radical ring.

[0078] "Bicyclic heterocyclylalkyl" means a -(alkylene)-R radical where R is a bicyclic heterocyclyl as defined above.

[0079] "Bicyclic heterocyclic group A " means a saturated monovalent bicyclic radical having 5 to 10 ring atoms, wherein the two rings are fused at two adjacent ring atoms and wherein one or two of the ring atoms are heteroatoms independently selected from N and O and the remaining ring atoms are C, unless otherwise stated. In addition, one or two ring carbon atoms of the bicyclic heterocyclyl may be optionally replaced by a -CO- group. The term bicyclic heterocyclyl A Including but not limited to, 3-azabicyclo[3.1.0]hexan-6-yl and the like.

[0080] "Bicyclic sulfoximino" means a saturated monovalent bicyclic ring having 4 to 8 ring atoms, wherein the two rings are fused at two adjacent ring atoms and one of the ring atoms is >S(=O)(NR z ), where R z is hydrogen or alkyl as defined herein, and the remaining ring atoms are C. Representative examples of bicyclic sulfoximino groups include, but are not limited to, 1-imino-3-oxohexahydro-3λ6 -thiobicyclo[3.1.0]hexane-6-yl, octahydrocyclopenta[c]pyrrol-5-yl, and the like.

[0081] "Bridged cycloalkyl" means a saturated monovalent bicyclic or tricyclic hydrocarbon radical having from 5 to 10 ring carbon atoms, one or two of which are connected by (CR z R z1 )n group (wherein n is an integer selected from 1 to 3 and R z and R z1 is independently H or methyl) connected to non-adjacent ring atoms (which may also be referred to herein as "bridging" groups). For clarity, when the bridged cycloalkyl is bicyclic, it has one bridging group, and when the bridged cycloalkyl is tricyclic, it has two bridging groups. Examples include, but are not limited to, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.2]-octyl, adamantyl, and the like.

[0082] "Bridged cyclic amine" means a saturated monovalent bicyclic ring having 5 to 10 ring atoms, wherein one of the ring atoms is nitrogen, and two non-adjacent ring atoms are connected by a (CRR')m1 group (wherein m1 is an integer from 1 to 3, and R and R' are independently H or methyl) (which may also be referred to herein as a "bridging" group), and further, wherein the other ring atom, including the atom in the bridging group, may be independently selected from N, O and S(O) n (wherein n is an integer from 0 to 2) heteroatom, and the remaining ring atoms are C. Representative examples of bridged cyclic amino groups include, but are not limited to, 2-azabicyclo[2.2.1]heptan-2-yl, 3-azabicyclo[3.1.1]heptan-3-yl, 3-azabicyclo[3.2.1]octan-3-yl, and the like.

[0083] "Bridged heterocyclyl" means a saturated monovalent bicyclic radical having from 5 to 9 ring carbon atoms in which two non-adjacent ring atoms are joined by (CR z R z1 )n group (wherein n is 1 to 3 and R z and R z1 independently H or methyl) link (also referred to herein as a "bridging" group), and further, one or two of the ring carbon atoms (including the atoms in the bridging group) are selected from N, O and S(O) n (wherein n is an integer selected from 0 to 2). Examples include, but are not limited to, 2-azabicyclo[2.2.2]octyl, quinuclidinyl, 7-oxabicyclo[2.2.1]heptyl, and the like. When a bridged heterocyclyl ring as defined above contains only -SO2- in the ring, it is also referred to herein as a "bridged ring sulfonyl" and is a subset of bridged heterocyclyl rings.

[0084] "Bridged heterocyclylalkyl" means a -(alkylene)-R group where R is a bridged heterocyclyl as defined above.

[0085] "Bridged heterocyclic group A " means a saturated monovalent bicyclic radical having 5 to 9 ring carbon atoms, wherein two non-adjacent ring atoms are separated by (CR z R z1 )n group (wherein n is 1 to 3 and R z and R z1 The alkyl groups are independently H or methyl) (which may also be referred to herein as "bridging" groups), and further, one or two ring carbon atoms (including atoms in the bridging group) are replaced by heteroatoms selected from N and O. Examples include, but are not limited to, 2-azabicyclo[2.2.2]octyl, quinuclidinyl, 7-oxabicyclo[2.2.1]heptyl, 6-azabicyclo[3.1.1]heptan-3-yl, 8-azabicyclo[3.2.1]octan-3-yl, and the like.

[0086] "Cycloalkyl" means a monocyclic saturated monovalent hydrocarbon radical having three to ten carbon atoms. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0087] "Cycloalkoxy" means a -OR radical, where R is a cycloalkyl radical as defined above. Representative examples include, but are not limited to, cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

[0088] "Cycloalkylalkyl" refers to an -(alkylene)-R z Group, where R z is a cycloalkyl group as defined above. Examples include, but are not limited to, cyclopropylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclohexylmethyl, and the like.

[0089] "Cyanoalkyl" means a linear monovalent hydrocarbon group having one to six carbon atoms or a branched monovalent hydrocarbon group having three to six carbon atoms substituted with a cyano group, for example, cyanomethyl, cyanoethyl, and the like.

[0090] "Cyanoalkoxy" means a -OR radical, where R is a cyanoalkyl radical as defined above. Representative examples include, but are not limited to, cyanomethoxy, cyanoethoxy, and the like.

[0091] "Cyclic amino" means a saturated monovalent monocyclic group having 4 to 8 ring atoms, wherein one ring atom is nitrogen and another ring atom is selected from N, O and S(O). n(wherein n is an integer from 0 to 2) heteroatoms, and the remaining ring atoms are C, unless otherwise indicated. In addition, one or two ring carbon atoms in the cyclic amine group can be replaced by -C(=O)-groups alternatively. Representative examples include but are not limited to pyrrolidinyl, piperidinyl, homopiperidinyl, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholinyl, piperazinyl, thiomorpholinyl etc.

[0092] "Cyclic sulfoximino" means a saturated monovalent monocyclic ring having 4 to 8 ring atoms, one of which is >S(=O)(NR z ), where R z is hydrogen or alkyl as defined herein, and the remaining ring atoms are C. Representative examples of cyclic sulfoximino groups include, but are not limited to, 1-imino-1-oxohexahydro-1λ 6 -thiopyran-4-yl, etc.

[0093] Deuterium means 2 H or D.

[0094] "Dialkylamino" means -NRR', where R and R' are independently alkyl as defined above, for example, dimethylamino, diethylamino, methylpropylamino, and the like.

[0095] "Deuterated alkyl" means an alkyl group as defined above that is substituted with one, two, or three deuterium groups, such as trideuterated methyl.

[0096] As used herein, "fused bridged cyclic amino group" means a bridged cyclic amino group as defined above, wherein two adjacent ring atoms of the bridged cyclic amino group are fused to two adjacent ring atoms of a phenyl group or a five- or six-membered heteroaryl group (each as defined herein), unless otherwise indicated. The fused bridged cyclic amino group may be attached to any atom where the ring valence permits. Non-limiting examples of fused bridged cyclic amino groups include 1,2,3,4-tetrahydro-1,3-cycloiminonaphthalene-9-yl and the like.

[0097] "Fused cycloalkyl" means a three to six membered cycloalkyl as defined above, wherein two adjacent carbon atoms of the cycloalkyl are fused to two adjacent ring atoms of a phenyl or five or six membered heteroaryl (as defined herein), unless otherwise indicated. The fused cycloalkyl may be attached to any atom where the ring valence permits. Non-limiting examples of fused cycloalkyls include 4,5,6,7-tetrahydroindazol-5-yl and the like.

[0098] As used herein, "fused cyclic amino" means a cyclic amino group as defined above, wherein two adjacent ring atoms of the cyclic amino group are fused to two adjacent ring atoms of a phenyl group or a five- or six-membered heteroaryl group (each as defined herein), unless otherwise indicated. The fused cyclic amino group may be attached to any atom of the ring. Non-limiting examples of fused cyclic amino groups include 2,3-dihydrobenzo[b][1,4]-dioxinyl, 2-oxabicyclo[3.1.0]hexanyl, indolin-2-one-1-yl, indolinyl, isoindolyl, and the like.

[0099] As used herein, "fused heteroaryl" means a 5- or 6-membered heteroaryl as defined below, wherein two adjacent ring atoms of the 5- or 6-membered heteroaryl are fused to two adjacent ring atoms of a 5- to 7-membered cycloalkyl as defined herein, unless otherwise indicated. The fused heteroaryl may be attached to any atom of the ring. Non-limiting examples of fused heteroaryl include 4,5,6,7-tetrahydro-1H-indole, 4,5,6,7-tetrahydro-1H-pyrazole, and the like.

[0100] As used herein, "fused heterocyclic group" means a heterocyclic group as defined below, wherein two adjacent ring atoms of the heterocyclic group are fused to two adjacent ring atoms of a phenyl group or a five- or six-membered heteroaryl group (each as defined herein), unless otherwise indicated. A fused heterocyclic group may be attached to any atom of the ring. Non-limiting examples of fused heterocyclic groups include 2,3-dihydrobenzo[b][1,4]-dioxinyl, 2-oxabicyclo[3.1.0]hexane, indolin-2-one-1-yl, indolinyl, isoindolyl, etc.

[0101] "Fused heterocyclylalkyl" means a -(alkylene)-R radical where R is a fused heterocyclyl as defined above.

[0102] As used herein, "fused heterocyclic group A " means a heterocyclic group as defined below A , wherein the heterocyclic group A Unless otherwise indicated, two adjacent ring atoms of a phenyl group or a five- or six-membered heteroaryl group are fused to two adjacent ring atoms of a phenyl group or a five- or six-membered heteroaryl group (each as defined herein). A Attachment may be at any atom of the ring. A Non-limiting examples of include 2,3-dihydrobenzo[b][1,4]-dioxinyl, 2-oxabicyclo[3.1.0]hexanyl, indolin-2-on-1-yl, indolinyl, isoindolyl, and the like.

[0103] As used herein, "fused spiroamino" means a spiroamino group as defined above, wherein two adjacent ring atoms of the spiroamino group are fused to two adjacent ring atoms of a phenyl group or a five- or six-membered heteroaryl group (each as defined herein), unless otherwise indicated. Non-limiting examples of fused spiroamino groups include wait.

[0104] "Halo" means fluorine, chlorine, bromine, or iodine, preferably fluorine or chlorine.

[0105] "Haloalkyl" means an alkyl group as defined above, 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, for example, -CH2Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3, -CF(CH3)2, etc. When an alkyl group is substituted only with fluorine, it may be referred to herein as a fluoroalkyl group.

[0106] "Haloalkoxy" means a -OR group (wherein R is a haloalkyl group as defined above), for example, -OCF3, -OCHF2, etc. When R is a haloalkyl group (wherein the alkyl group is substituted only with fluorine), it may be referred to herein as a fluoroalkoxy group.

[0107] "Hydroxyalkyl" means a linear monovalent hydrocarbon radical having one to six carbon atoms or a branched monovalent hydrocarbon radical having three to six carbon atoms substituted with one or two hydroxy groups, provided that if two hydroxy groups are present, they are not on the same carbon atom. Representative examples include, but are not limited to, hydroxymethyl, 2-hydroxy-ethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl, and 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl, and 1-(hydroxymethyl)-2-hydroxyethyl.

[0108] "Hydroxyalkyloxy" means -OR z Base, where R z is hydroxyalkyl as defined above. Representative examples include, but are not limited to, 2-hydroxyethyloxy, 1-, 2- or 3-hydroxypropyloxy, 2-hydroxyethyloxy, and the like.

[0109] Unless otherwise indicated, " heteroaryl " means a monovalent monocyclic or fused bicyclic aromatic group with 5 to 10 ring atoms, wherein one or more (in one embodiment, one, two or three) ring atoms are heteroatoms selected from N, O and S, and the remaining ring atoms are carbon. Representative examples include but are not limited to pyrrolyl, thienyl, thiazolyl, imidazolyl, furyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, quinolyl, isoquinolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl etc. As defined herein, the terms " heteroaryl " and " aryl " are mutually exclusive. When the heteroaryl ring contains 5 or 6 ring atoms and is a monocycle, it is also referred to as a 5 yuan or 6 yuan monocyclic heteroaryl in this article. When the heteroaryl ring contains 9 or 10 ring atoms and is a bicycle, it is also referred to as a 9 yuan or 10 yuan bicyclic heteroaryl in this article.

[0110] "Heteroaryloxy" means -OR z Base, where R z is a heteroaryl group as defined above. Representative examples include, but are not limited to, pyridyloxy, imidazolyloxy, pyrimidinyloxy, furanyloxy, benzimidazolyloxy, and the like.

[0111] "Heteroaralkyl" refers to an -(alkylene)-R z Base, where R z is a heteroaryl group as defined above, for example, pyridylmethyl, etc. When the heteroaryl ring in the heteroarylalkyl group contains 5 or 6 ring atoms, it is also referred to herein as a 5-membered or 6-membered heteroarylalkyl group.

[0112] "Heterocyclyl" means a saturated monovalent monocyclic group having 4 to 8 ring atoms, wherein one or two ring atoms are independently selected from N, O and S(O) n (wherein n is an integer from 0 to 2) heteroatoms, remaining annular atoms are C, unless otherwise indicated. In addition, one or two annular carbon atoms in the heterocyclic ring can be alternatively replaced by -C (=O) -groups. Heterocyclic radical can be attached to any atom that the ring valence allows. More particularly, the term heterocyclic radical includes but is not limited to oxetanes, pyrrolidinyl, piperidinyl, homopiperidinyl, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, thiomorpholinyl etc. When the heterocyclic ring as defined above only contains -SO in the ring -, it is also referred to as " cyclic sulfonyl " in this article and is the subset of heterocyclic radical.

[0113] "Heterocyclyloxy" means -OR z Base, where R z is a heterocyclic group as defined above. Representative examples include, but are not limited to, oxetanyloxy, piperidinyloxy, pyrrolidinyloxy, tetrahydrofuranyloxy, and the like.

[0114] "Heterocyclylalkyl" refers to an -(alkylene)-R z Base, where R z is a heterocyclyl group as defined above. Representative examples include, but are not limited to, oxetanylmethyl, piperidinylmethyl, pyrrolidinylethyl, tetrahydrofuranylmethyl, and the like.

[0115] "Heterocyclylalkyloxy" means -OR z Base, where R z is heterocyclylalkyl as defined above. Representative examples include, but are not limited to, oxetanylmethyloxy, piperidinylmethyloxy, pyrrolidinylethyloxy, tetrahydrofuranylmethyloxy, and the like.

[0116] "Heterocyclic A " refers to a saturated monovalent monocyclic group having 4 to 8 ring atoms, wherein one or two ring atoms are heteroatoms independently selected from N and O, and the remaining ring atoms are C, unless otherwise stated. In addition, one or two ring carbon atoms in the heterocyclyl ring may be optionally replaced by a -C(=O)- group. More specifically, the term heterocyclyl includes, but is not limited to, pyrrolidinyl, piperidinyl, homopiperidinyl, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, and the like.

[0117] The term "oxo," as used herein, alone or in combination, refers to =(O).

[0118] "Optionally substituted aryl" means an aryl group as defined above optionally substituted with one, two, or three substituents independently selected from the group consisting of alkyl, hydroxy, cycloalkyl, carboxyl, alkoxycarbonyl, hydroxy, alkoxy, alkylthio, alkylsulfonyl, amino, alkylamino, dialkylamino, halo, haloalkyl, haloalkoxy, and cyano.

[0119] "Optionally substituted aralkyl" refers to -(alkylene)-R z , where R z is an optionally substituted aryl group as defined above.

[0120] "Optionally substituted heteroaryl" means a heteroaryl group as defined above optionally substituted with one, two, or three substituents independently selected from the group consisting of alkyl, alkylthio, alkylsulfonyl, hydroxy, cycloalkyl, carboxyl, alkoxycarbonyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, and cyano.

[0121] "Optionally substituted heteroaralkyl" refers to an -(alkylene)-R z , where R z is an optionally substituted heteroaryl group as defined above.

[0122] "Optionally substituted heterocyclyl" means a heterocyclyl as defined above optionally substituted by one, two, or three substituents independently selected from the group consisting of alkyl, alkylthio, alkylsulfonyl, alkylcarbonyl, hydroxy, cycloalkyl, cycloalkylalkyl, carboxyl, alkoxycarbonyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, aminoalkyl, cyanoalkyl, halo, haloalkyl, haloalkoxy, and cyano, unless otherwise indicated.

[0123] "Optionally substituted heterocyclylalkyl" refers to -(alkylene)-R z , where R z is an optionally substituted heterocyclyl as defined above.

[0124] "Substituted amino" means -NR z 'R z " base, where R z ' is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, or alkylcarbonyl, and R z " is cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylcarbonyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl, or optionally substituted heterocyclylalkyl, each as defined herein. Representative examples include, but are not limited to, cyclopropylmethylamino, 2-(methylamino)ethylamino, hydroxyethylamino, and the like. When R z ' is H and R z When " is not hydrogen, the amino group may also be referred to herein as a monosubstituted amino group. When R z When R' and Rz" are both not hydrogen, the term substituted amino may also be referred to herein as a disubstituted amino group.

[0125] "Spiroamino" means a saturated monovalent bicyclic ring having 6 to 12 ring atoms, wherein one ring atom is nitrogen and the other ring atoms are independently selected from N, O and S(O). n (wherein n is an integer from 0 to 2) heteroatoms, the remaining ring atoms are C, and further, wherein the two rings are connected by only one atom, the connecting atom is also referred to as a spiral atom, most commonly a quaternary carbon ("spiro carbon"). Representative examples of spirocyclic amido include but are not limited to 2-azaspiro[3.3]heptane-2-yl, 5-azaspiro[2.4]heptane-5-yl, 3-azaspiro[5.5]undecane-3-yl, 8-azaspiro[4.5]decane-8-yl, 6-azaspiro[3.4]octane-6-yl, 2-azaspiro[4.4]nonane-2-yl etc.

[0126] "Spiroalkyl" means a saturated bicyclic monovalent hydrocarbon ring with 7 to 11 ring atoms, wherein these rings are connected by only one carbon atom, and the connecting atom is also referred to as a spiro atom, most commonly a quaternary carbon ("spiro carbon"). Spiroalkyl is optionally substituted by one or two substituents independently selected from alkyl, halo, alkoxy, hydroxyl and cyano, unless otherwise indicated. Representative examples include, but are not limited to, spiro [3,3] heptane -2- base, spiro [3,5] nonane -2- base etc.

[0127] "Spiro heterocyclyl" means a saturated monovalent bicyclic ring with 6 to 10 ring atoms, wherein one, two or three of the ring atoms are heteroatoms selected from N, O and S(O)n (wherein n is an integer selected from 0 to 2 (inclusive)), the remaining ring atoms are C, and the rings are connected by only one atom, the connecting atom also called a spiro atom, most commonly a quaternary carbon ("spiro carbon"). Spiro heterocyclyl is optionally substituted by one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy and cyano, unless otherwise stated. When the spiro heterocyclyl contains only S(O) n When , it can be referred to as spirocyclic sulfonyl in this article. Representative examples include, but are not limited to, 2,6-diazaspiro-[3.3]heptyl, 2,2-dioxo-2-thiaspiro[3.3]hept-6-yl, 2,6-diazaspiro[3.4]octyl, 2-azaspiro[3.4]octyl, 2-azaspiro[3.5]-nonyl, 2,7-diazaspiro[4.4]nonyl, etc.

[0128] When a spiroheterocyclyl ring as defined above contains only -SO2- in the ring, it is also referred to herein as "spirosulfonyl" and is a subset of heterocyclyl.

[0129] "Spiroheterocyclylalkyl" means a -(alkylene)-R radical where R is a spiroheterocyclyl as defined above.

[0130] Spiroheterocyclic group A "" means a saturated monovalent bicyclic ring having 6 to 10 ring atoms, wherein one or two of the ring atoms are heteroatoms selected from N and O, the remaining ring atoms are C, and the rings are connected by only one atom, the connecting atom also called a spiro atom, most commonly a quaternary carbon ("spiro carbon"). Spiroheterocyclyl A and optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxyl, and cyano, unless otherwise indicated. Representative examples include, but are not limited to, 2,6-diazaspiro-[3.3]heptyl, 2,6-diazaspiro[3.4]octyl, 2-azaspiro[3.4]octyl, 2-azaspiro[3.5]-nonyl, 2,7-diazaspiro[4.4]nonyl, and the like.

[0131] "Spirosulfoximino" means a saturated monovalent bicyclic ring having 6 to 12 ring atoms, one of which is >S(=O)(NR z ), where R z is hydrogen or alkyl as defined herein, the remaining ring atoms are C, and further, wherein the two rings are connected by only one atom, the connecting atom is also called a spiro atom, most commonly a quaternary carbon ("spiro carbon"). Representative examples of spirosulfoximino groups include, but are not limited to, 2-imino-2-oxo- -thiaspiro[3.3]heptane-6-yl, 2-(2-methylimino)-2-oxo-2λ 6 -thiaspiro[3.3]heptane-6-yl, etc.

[0132] "Unsubstituted heterocyclyl" means a non-aromatic monovalent monocyclic ring having 5 to 8 ring atoms, containing one or two double bonds and wherein one or two ring atoms are independently selected from N, O and S(O). n (wherein n is an integer from 0 to 2) heteroatoms, the remaining ring atoms being C, unless otherwise stated. In addition, one or two ring carbon atoms in the heterocyclyl ring can be optionally replaced by a -C(=O)- group. The heterocyclyl group can be attached to any atom where the ring valence allows. More particularly, the term heterocyclyl includes, but is not limited to, dihydropyrrolidinyl, 1,2,3,6-tetrahydropyridine, 1,2-dihydropyridyl, pyridine-2(1H)-one, etc.

[0133] The present disclosure also includes protected derivatives of compounds with formula (I). For example, when compounds with formula (I) contain groups (such as hydroxyl, carboxyl or any group containing one or more nitrogen atoms), these groups can be protected by suitable protecting groups. A complete list of suitable protecting groups can be found in the following literature: TW Greene, Protective Groups in Organic Synthesis [protective groups in organic synthesis], 5th edition, John Wiley & Sons, Inc. [John Wiley & Sons Publishing Company] (2014), the disclosure of which is incorporated herein by reference in its entirety. The protected derivatives of compounds of the present disclosure can be prepared by methods well known in the art.

[0134] The present disclosure also encompasses polymorphic and deuterated forms of the compounds of Formula (I) or pharmaceutically acceptable salts thereof.

[0135] The term "prodrug" refers to a compound that becomes more active in vivo. Certain compounds of Formula (I) may also exist as prodrugs, as described in: 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 the compound that readily undergo chemical changes under physiological conditions to provide the active compound. Prodrugs are often useful because, in some cases, they are easier to administer than the compound or parent drug. For example, they may be bioavailable by oral administration, whereas the parent drug is not. Various prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug. An example, without limitation, of a prodrug would be a compound that is administered as an ester ("prodrug") but then metabolically hydrolyzes to the carboxylic acid (the active entity). Additional examples include peptidyl derivatives of the compounds.

[0136] 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:

[0137] 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, glucoheptanoic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc.); or

[0138] 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 salts formed by coordination with an organic base (e.g., ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc.). It is understood that pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pennsylvania, 1985, which is incorporated herein by reference in its entirety.

[0139] Compounds with formula (I) can have asymmetric centers. Compounds with formula (I) containing asymmetrically substituted atoms can be separated in optically active forms or racemic forms. The independent stereoisomers of the compound can be synthesized from commercially available starting materials containing chiral centers, or separated subsequently (as converted into a mixture of diastereomers and then separated or recrystallized, chromatographic techniques, directly separating enantiomers on a chiral chromatographic column, or any other appropriate method known in the art) by preparing a mixture of enantiomeric products. Unless specifically indicated as specific stereochemical form or isomeric form, all chiral forms, diastereomeric forms, all mixtures of chiral forms or diastereomeric forms and racemic forms are within the scope of the present disclosure. It will also be understood by those skilled in the art that when a compound is represented as a (R) stereoisomer, it can contain a corresponding (S) stereoisomer as an impurity, and vice versa.

[0140] Some compounds with formula (I) can exist as tautomers and / or geometric isomers.All possible tautomers and cis and trans isomers (as separate forms and mixtures thereof) are within the scope of the present disclosure. In addition, as used herein, although only a few examples have been listed, the term alkyl includes all possible isomeric forms of the alkyl group. In addition, when these cyclic groups (such as aryl) are substituted, although only a few examples have been listed, all positional isomers are included. In addition, all hydrates of compounds with formula (I) are within the scope of the present disclosure.

[0141] Compounds of formula (I) may also contain unnatural amounts of isotopes at one or more atoms that constitute such compounds. An unnatural amount of an isotope can be defined as an amount ranging from the amount found in nature to 100% of the atom in question, differing only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that may be incorporated into compounds of the invention, such as compounds of formula (I) (and any embodiments thereof disclosed herein, including specific compounds), include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as, respectively. 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., 3 H and 14 C-labeled compounds) can be used in compound or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes can be useful because of their ease of preparation and detectability. Further, heavier isotopes such as deuterium (i.e., 2 H) can confer certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In some embodiments, in compounds of formula (I) (including those listed in Table 1 below), one or more hydrogen atoms are replaced by 2 H or 3 H is replaced, or one or more carbon atoms are replaced 13 C- or 14 C-enriched carbon substitution. Positron-emitting isotopes (such as 15 O. 13 N. 11 C and 15 F) can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed in the Schemes or Examples herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0142] Certain structures provided herein, including Formula (I), are drawn with one or more floating substituents, i.e., in the following structures, R 1 、R 2 、R 3 and R 6 is a floating substituent. Unless otherwise provided or otherwise clear from the context, one or more substituents may be present on any atom of the ring to which they are attached, including any ring atom represented as CH of such ring, if chemically feasible and permitted by valence rules, unless otherwise stated. For example, in the structure: In, R 6 Substituents may replace any hydrogen on the azabenzo ring, including the hydrogen of CH (when W is CH).

[0143] "Pharmaceutically acceptable carrier or excipient" means a carrier or excipient useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and not biologically or otherwise undesirable, and includes carriers or excipients that are acceptable for veterinary as well as human pharmaceutical use. "Pharmaceutically acceptable carrier / excipient" as used in this specification and claims includes both one and more than one such excipient.

[0144] As used herein, the term "about" is intended to qualify the numerical value it modifies, indicating that the value is a variable within the margin of error. When no specific error range is listed (e.g., the standard deviation of the mean value given in a data graph or table), the term "about" should be understood to mean a range covering ±10%, preferably ±5%, including the listed values ​​and ranges.

[0145] As used herein, the phrase "optionally" or "optional" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, the phrase "cycloalkyl optionally substituted with alkyl" is intended to encompass both cycloalkyl groups that are not substituted with alkyl and cycloalkyl groups that are substituted with alkyl.

[0146] As used herein, the term "disease" is intended to be generally synonymous and may be used interchangeably with the terms "disorder," "syndrome," and "condition" (as in medical conditions), all of which reflect an abnormal condition of one of the parts of the human or animal body or of the body that impairs its normal function, typically manifests itself by distinctive signs and symptoms, and causes the human or animal to have a reduced life span or quality of life.

[0147] The term "combination therapy" means the administration of two or more therapeutic agents to treat the diseases or disorders described in this disclosure. Such administration encompasses the co-administration of these therapeutic agents in a substantially simultaneous manner, such as administration in a single capsule having a fixed ratio of active ingredients or administration in multiple separate capsules of each active ingredient. In addition, such administration also encompasses the use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide the beneficial effects of the drug combination in treating the conditions or disorders described herein.

[0148] The term "patient" is generally 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.

[0149] "Treating" or "treatment" diseases include:

[0150] (1) preventing the disease, that is, causing clinical symptoms of the disease to not develop in a mammal that may be exposed to or susceptible to the disease but does not yet experience or display symptoms of the disease;

[0151] (2) inhibit the disease, i.e., delay, arrest (i.e., stabilize), or reduce the development or severity of the disease or its clinical symptoms; or

[0152] (3) Alleviate the disease, that is, cause the disease or its clinical symptoms to subside.

[0153] In one embodiment, treating or treating a disease includes inhibiting the disease, i.e., delaying, arresting, or reducing the development or severity of the disease or its clinical symptoms; or alleviating the disease, i.e., causing regression of the disease or its clinical symptoms.

[0154] "Therapeutically effective amount" means the amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, which, when administered to a patient for treating a disease, is sufficient to affect such treatment of the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the mammal to be treated.

[0155] The terms "inhibit" and "reduce" or any variations of these terms with respect to CDK2 include any measurable reduction or complete inhibition to achieve the desired result. For example, reduction can be a decrease in CDK2 activity by about, up to about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more, or any range derivable therein, compared to normal activity.

[0156] Representative compounds of the present disclosure that were prepared are disclosed in Table 1 below:

[0157] Table 1

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

[0180]

[0181]

[0182]

[0183]

[0184]

[0185]

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196]

[0197]

[0198]

[0199]

[0200]

[0201]

[0202]

[0203]

[0204]

[0205]

[0206]

[0207]

[0208]

[0209]

[0210]

[0211]

[0212]

[0213]

[0214]

[0215]

[0216] Implementation plan:

[0217] In the following additional embodiments 1-203, the present disclosure includes:

[0218] 1. In embodiment 1, the compound of formula (I) or a pharmaceutically acceptable salt thereof is as provided in the first aspect of the present invention.

[0219] 2. In embodiment 2, the compound, or a pharmaceutically acceptable salt thereof, is as provided in embodiment 1, wherein:

[0220] yes:

[0221]

[0222] 3. In embodiment 3, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is as provided in embodiment 1 or 2, wherein:

[0223] yes

[0224] 4. In embodiment 4, the compound, or a pharmaceutically acceptable salt thereof, is as provided in embodiment 1 or 2, wherein:

[0225] yes

[0226] 4a. In embodiment 4a, the compound, or a pharmaceutically acceptable salt thereof, is as provided in embodiment 4, wherein R 8 is hydrogen, halo, or cyano.

[0227] 5. In embodiment 5, the compound, or a pharmaceutically acceptable salt thereof, is as provided in embodiment 1, 2 or 4, wherein:

[0228] yes

[0229] 6. In embodiment 6, the compound, or a pharmaceutically acceptable salt thereof, is as provided in embodiment 1, 2 or 4, wherein:

[0230] yes

[0231] 7. In embodiment 7, the compound, or a pharmaceutically acceptable salt thereof, is as provided in embodiment 1, 2 or 4, wherein:

[0232] yes

[0233] 8. In embodiment 8, the compound, or a pharmaceutically acceptable salt thereof, is as provided in embodiment 1, 2, 4 or 4a, wherein:

[0234] yes

[0235] 9. In embodiment 9, the compound, or a pharmaceutically acceptable salt thereof, is as provided in embodiment 1 or 2, wherein:

[0236] yes

[0237] 9a. In embodiment 9a, the compound, or a pharmaceutically acceptable salt thereof, is as provided in embodiment 9, wherein R 8 is hydrogen, halo, or cyano.

[0238] 10. In embodiment 10, the compound, or a pharmaceutically acceptable salt thereof, is as provided in embodiment 1 or 2, wherein:

[0239] yes

[0240] 11. In embodiment 11, the compound of any one of embodiments 1 to 10, or a pharmaceutically acceptable salt thereof, has a structure according to formula (Ia):

[0241]

[0242] 12. In embodiment 12, the compound of any one of embodiments 1 to 11, or a pharmaceutically acceptable salt thereof, has a structure according to formula (Ib):

[0243]

[0244] 13. In embodiment 13, the compound of any one of embodiments 1 to 11, or a pharmaceutically acceptable salt thereof, has a structure according to formula (Ic):

[0245]

[0246] 14. In embodiment 14, the compound of any one of embodiments 1 to 13, or a pharmaceutically acceptable salt thereof, has a structure according to formula (Id):

[0247]

[0248] 15. In embodiment 15, the compound of any one of embodiments 1 to 14, or a pharmaceutically acceptable salt thereof, has a structure according to formula (Ie):

[0249]

[0250] 16. In embodiment 16, the compound, or a pharmaceutically acceptable salt thereof, is provided as any one of embodiments 1 to 10, wherein ring R A It is a heteroaryl group.

[0251] 17. In embodiment 17, the compound, or a pharmaceutically acceptable salt thereof, is provided as any one of embodiments 1 to 10 and 16, wherein ring R A It is a six-membered heteroaryl group containing one or two nitrogen atoms.

[0252] 17a. In embodiment 17a, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 10, 16 and 17, wherein ring R A is pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl.

[0253] 17b. In embodiment 17b, the compound of any one of embodiments 1 to 10, 16 and 17, or a pharmaceutically acceptable salt thereof, has a structure according to Formula (If), (Ig), (Ih), (Ii), (Ij) or (Ik):

[0254]

[0255] 18. In embodiment 18, the compound as described in any one of embodiments 1 to 10 and 16, or a pharmaceutically acceptable salt thereof, is wherein ring R A It is a bicyclic heteroaryl group.

[0256] 18a. In embodiment 18a, the compound of any one of embodiments 1 to 10 and 18, or a pharmaceutically acceptable salt thereof, has a structure according to Formula (Im), (In), (Io), (Ip), or (Iq):

[0257]

[0258] 19. In embodiment 19, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 18a, wherein R 1 、R 2 , and R 3 and R is independently hydrogen, deuterium, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, or cyano.

[0259] 20. In embodiment 20, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 18a, wherein R 1 、R 2 , and R 3 are independently selected from hydrogen, deuterium, methyl, ethyl, propyl, fluorine, chlorine, bromine, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, methoxy, ethoxy, hydroxy, hydroxymethyl, methoxymethyl, cyano, and -CH2NH2.

[0260] 21. In embodiment 21, the compound, or a pharmaceutically acceptable salt thereof, is provided as any one of embodiments 1 to 20, wherein R 1 、R 2 , and R 3 and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34

[0261] 22. In embodiment 22, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 21, wherein R 1 and R 2 are independently hydrogen, deuterium, fluorine, chlorine, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, methoxy, hydroxyl or cyano, and R 3 It's hydrogen.

[0262] 23. In embodiment 23, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 22, wherein R 1 is fluorine, R 2 is hydrogen, deuterium, fluorine, chlorine, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, methoxy, hydroxyl or cyano, and R 3 It's hydrogen.

[0263] 23a. In embodiment 23a, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 23, wherein R 1 is fluorine, R 2 is hydrogen, deuterium, fluorine, chlorine, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy or cyano, and R 3 It's hydrogen.

[0264] 24. In embodiment 24, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 23, wherein R 1 is fluorine, and R 2 and R 3 It's hydrogen.

[0265] 25. In embodiment 25, the compound of any one of embodiments 1 to 24, or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 Together with the nitrogen atom to which they are attached, they form a ring selected from the group consisting of a cyclic amine group, a bicyclic amine group, a fused cyclic amine group, a bridged cyclic amine group, or a spiroamine group, wherein each of the above rings is represented by R s 、R t , and R u replace.

[0266] 26. In embodiment 26, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 24, wherein R 4 and R 5 Together with the nitrogen atom to which they are attached, they form a ring selected from the group consisting of: a fused bridged cyclic amine group and a fused spiroamine group, wherein each of the above rings is replaced by R s 、R t , and R u replace.

[0267] 27. In embodiment 27, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 25, wherein R 4 and R 5 Together with the nitrogen atom to which they are attached, they form a ring selected from the group consisting of a cyclic amine group, a bicyclic amine group, and a fused cyclic amine group, wherein each of the above rings is replaced by R s 、R t , and R u replace.

[0268] 28. In embodiment 28, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 25, wherein R 4 and R 5 Together with the nitrogen atom to which they are attached, they form a ring selected from the group consisting of: bridged cyclic amine groups and spiroamine groups, wherein each of the above rings is represented by R s、R t , and R u replace.

[0269] 29. In embodiment 29, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 25 and 27, wherein R 4 and R 5 Together with the nitrogen atom to which they are attached, they form the s 、R t , and R u Substituted fused cyclic amine group.

[0270] 30. In embodiment 30, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 25 and 27, wherein R 4 and R 5 Together with the nitrogen atom to which they are attached, they form a cyclic amine group or a bicyclic amine group, wherein each of the above rings is represented by R s 、R t , and R u replace.

[0271] 31. In embodiment 31, the compound, or a pharmaceutically acceptable salt thereof, is provided as any one of embodiments 1 to 25, 27 and 29, wherein R 4 and R 5 A fused cyclic amine group, formed together with the nitrogen atom to which they are attached, is one in which two adjacent ring atoms of the cyclic amine group are fused to two adjacent atoms of the phenyl group and are surrounded by R s 、R t , and R u replace.

[0272] 32. In embodiment 32, the compound, or a pharmaceutically acceptable salt thereof, is provided as any one of embodiments 1 to 25, 27 and 29, wherein R 4 and R 5 A fused cyclic amine group, formed together with the nitrogen atom to which they are attached, is one in which two adjacent ring atoms of a cyclic amine group are fused to two adjacent atoms of a five- or six-membered heteroaryl group and are surrounded by R s 、R t , and R u replace.

[0273] 33. In embodiment 33, the compound, or a pharmaceutically acceptable salt thereof, is provided as any one of embodiments 1 to 25, 27, 29 and 31, wherein R 4 and R 5 The fused cyclic amine groups formed together with the nitrogen atom to which they are attached have a structure according to formula (a):

[0274]

[0275] in:

[0276] p is 0, 1 or 2, and q is 0, 1, 2, 3 or 4, provided that p + q is at least 2 and p + q is not greater than 5; and when p or q is 3 or 4, then one of such p or q -CH2- may be replaced by NH, N (when attached to R s 、R t , and R u ), O or S(O) n substitution; wherein n is 0, 1 or 2; and

[0277] Ring (a) is R s 、R t , and R u replace.

[0278] 34. In embodiment 34, the compound, or a pharmaceutically acceptable salt thereof, is provided as any one of embodiments 1 to 25, 27, 29 and 32, wherein R 4 and R 5 The fused cyclic amine groups formed together with the nitrogen atom to which they are attached have a structure according to formula (b):

[0279]

[0280] in:

[0281] p1 is 0, 1 or 2, and q1 is 0, 1, 2, 3 or 4, provided that p+q is at least 2 and p+q is not greater than 5; and when p or q is 3 or 4, then one of such p or q -CH2- may be replaced by NH, N (when attached to R s 、R t , and R u ), O or S(O) n Substitution; wherein n is 0, 1 or 2;

[0282] Het is a 5-membered or 6-membered heteroaryl; and

[0283] Ring (b) is R s 、R t , and R u replace.

[0284] 35. In embodiment 35, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 34, wherein R 4 and R 5 Together with the nitrogen atom to which they are attached, they form a ring selected from:

[0285]

[0286] Each ring is R s 、R t , and R u replace.

[0287] 36. In embodiment 36, the compound, or a pharmaceutically acceptable salt thereof, is provided as any one of embodiments 1 to 25, 27, 29 and 31 to 35, wherein R 4 and R 5 The fused cyclic amine groups formed together with the nitrogen atom to which they are attached are selected from:

[0288]

[0289] Each ring is R s 、R t , and R u replace.

[0290] 37. In embodiment 37, the compound, or a pharmaceutically acceptable salt thereof, is provided as any one of embodiments 1 to 25, 27, 29, 31, 33, 35 and 36, wherein R 4 and R 5 The fused cyclic amine groups formed together with the nitrogen atom to which they are attached are selected from:

[0291]

[0292] Each ring is R s 、R t , and R u replace.

[0293] 38. In embodiment 38, the compound, or a pharmaceutically acceptable salt thereof, is provided as any one of embodiments 1 to 25, 27, 29, 32, and 34 to 36, wherein R 4 and R 5 The fused cyclic amine groups formed together with the nitrogen atom to which they are attached are selected from:

[0294]

[0295] Each ring is R s 、R t , and R u replace.

[0296] 39. In embodiment 39, the compound, or a pharmaceutically acceptable salt thereof, is provided as any one of embodiments 1 to 25, 27, 29, 31, 33, and 35 to 37, wherein R 4 and R 5 The fused cyclic amine groups formed together with the nitrogen atom to which they are attached are selected from:

[0297] Each ring is R s 、R t , and R u replace.

[0298] 40. In embodiment 40, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 39, wherein R u It's hydrogen.

[0299] 41. In embodiment 41, the compound, or a pharmaceutically acceptable salt thereof, is provided as any one of embodiments 1 to 25, 27, 29 and 31 to 40, wherein R 4 and R 5 The phenyl and 5-membered or 6-membered heteroaryl moieties of the fused cyclic amine group formed together with the nitrogen atom to which they are attached are R s and R t replace.

[0300] 42. In embodiment 42, the compound, or a pharmaceutically acceptable salt thereof, is provided as any one of embodiments 1 to 25, 27, 29, 31, 33, and 35 to 37, wherein R 4 and R 5 The fused cyclic amine groups formed together with the nitrogen atom to which they are attached are rings having the formula (a1) or (a2):

[0301]

[0302] 43. In embodiment 43, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 39 and 42, wherein R s 、R t , and R u independently selected from hydrogen, deuterium, alkyl, alkoxy, alkylsulfonyl, hydroxy, acyl, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, substituted amino, alkoxycarbonylaminoalkyl, aminocarbonyl, aminocarbonylalkyl, cyano, hydroxyalkyl, hydroxyalkoxy, alkoxyalkyl, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, cyanoalkyl, cyanoalkoxy, cycloalkyl, cycloalkoxy, aryl, aryloxy, aralkyl, heteroaryl, heteroaryloxy, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, and unsubstituted heterocyclyl (wherein aryl by itself or as part of aryloxy and aralkyl, heteroaryl by itself or as part of heteroaryloxy and heteroaralkyl, heterocyclyl by itself or as part of heterocyclylalkyl and heterocyclyloxy, and unsubstituted heterocyclyl are substituted with one to three substituents independently selected from hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, and cyano).

[0303] 44. In embodiment 44, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 39, 42 and 43, wherein R s is hydrogen, deuterium, alkyl, alkoxy, alkylsulfonyl, hydroxy, acyl, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, substituted amino, alkoxycarbonylaminoalkyl, aminocarbonyl, aminocarbonylalkyl, cyano, hydroxyalkyl, hydroxyalkoxy, alkoxyalkyl, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, cyanoalkyl, cyanoalkoxy, cycloalkyl, cycloalkoxy, aryl, aryloxy, aralkyl, heteroaryl, heteroaryloxy, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, or unsubstituted heterocyclyl (wherein aryl by itself or as part of aryloxy and aralkyl, heteroaryl by itself or as part of heteroaryloxy and heteroaralkyl, heterocyclyl by itself or as part of heterocyclylalkyl and heterocyclyloxy, and unsubstituted heterocyclyl are substituted with one to three substituents independently selected from hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, and cyano), and R t and R u Independently selected from hydrogen, alkyl, alkoxy, alkylsulfonyl, hydroxy, acyl, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, and cyano.

[0304] 45. In embodiment 45, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 39 and 42 to 44, wherein R s is hydrogen, deuterium, alkyl, alkoxy, alkylsulfonyl, hydroxy, acyl, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, substituted amino, alkoxycarbonylaminoalkyl, aminocarbonyl, aminocarbonylalkyl, cyano, hydroxyalkyl, hydroxyalkoxy, alkoxyalkyl, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, cyanoalkyl, cyanoalkoxy, cycloalkyl, cycloalkoxy, aryl, aryloxy, aralkyl, heteroaryl, heteroaryloxy, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, or unsubstituted heterocyclyl (wherein aryl by itself or as part of aryloxy and aralkyl, heteroaryl by itself or as part of heteroaryloxy and heteroaralkyl, heterocyclyl by itself or as part of heterocyclylalkyl and heterocyclyloxy, and unsubstituted heterocyclyl are substituted with one to three substituents independently selected from hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, and cyano), t is hydrogen, alkyl, alkoxy, alkylsulfonyl, hydroxy, acyl, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, and cyano, and R u It's hydrogen.

[0305] 46. ​​In embodiment 46, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 45, wherein R s is hydrogen, deuterium, alkyl, alkoxy, alkylsulfonyl, hydroxy, acyl, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, alkoxycarbonylaminoalkyl, aminocarbonyl, cyano, hydroxyalkyl, hydroxyalkoxy, aminoalkyl, aminoalkoxy, cyanoalkyl, cyanoalkoxy, cycloalkyl, aryl, aryloxy, aralkyl, heteroaryl, heterocyclylalkyl, or unsubstituted heterocyclyl (wherein aryl by itself or as part of aryloxy and aralkyl, heteroaryl, heterocyclyl as part of heterocyclylalkyl, and unsubstituted heterocyclyl are substituted with one to three substituents independently selected from hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, and cyano), R t is hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, or haloalkoxy, and R u It's hydrogen.

[0306] 47. In embodiment 47, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 46, wherein R s selected from hydrogen, deuterium, methyl, ethyl, isopropyl, cyclopropyl, cyclohexyl, methoxy, ethoxy, isopropoxy, methylsulfonyl, ethylsulfonyl, hydroxy, methylcarbonyl, fluorine, chlorine, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, amino, methylamino, dimethylamino, cyano, cyanomethyl, 2-cyanopropan-2-yl, cyanomethyloxy, hydroxymethyl, 1-hydroxyethyl, 1-hydroxy-1-methylethyl, methoxymethyl, methylaminomethyl 1-methyl-2-oxo-1,6-dihydropyridinyl, and morpholin-4-ylmethyl, R t is hydrogen, fluorine, chlorine, methoxy, difluoromethyl, difluoromethoxy, trifluoromethyl, trifluoromethoxy or cyano, and R u It's hydrogen.

[0307] 48. In embodiment 48, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 47, wherein R sselected from hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclohexyl, methoxy, ethoxy, isopropoxy, methylsulfonyl, ethylsulfonyl, hydroxy, methylcarbonyl, fluorine, chlorine, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, amino, methylamino, dimethylamino, cyano, cyanomethyl, 2-cyanoprop-2-yl, cyanomethyloxy, hydroxymethyl, 1-hydroxyethyl, 1-hydroxy-1-methylethyl, methoxymethyl, methylaminomethyl , dimethylaminomethyl, methoxycarbonylaminomethyl, -CONH2, methylaminocarbonyl, dimethylaminocarbonyl, 2-hydroxyethoxy, -O-(CH2)2NH2, 2-methylaminoethyloxy, 2-dimethylaminoethyloxy, phenyl, phenoxy, 3-fluorophenoxy, 4-fluorophenoxy, 2-cyanophenoxy, 3-cyanophenyl, benzyl, 1-methyl-2-oxo-1,6-dihydropyridinyl, and morpholin-4-ylmethyl, and R t and R u It's hydrogen.

[0308] 49. In embodiment 49, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 48, wherein R 4 and R 5Together with the nitrogen atom to which they are attached, they form a ring selected from the group consisting of morpholin-4-yl, piperidin-1-yl, 2-methylpiperidin-1-yl, 3-methylpiperidin-1-yl, 4-methylpiperidin-1-yl, 4-phenoxypiperidin-1-yl, 2-phenylpiperidin-1-yl, 2-phenylpyrrolidin-1-yl, 3,3-difluoropyrrolidin-1-yl, 4-phenylpiperazin-1-yl, 4-acetylpiperazin-1-yl, 4-Methyl-3-oxo-piperazin-1-yl, 4-methylsulfonylpiperazin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, azaspiro[2.4]heptane-5-yl, 2-azaspiro[4.4]nonan-2-yl, 6-azaspiro[3.4]octan-6-yl, 5-azaspiro[2.4]heptane-5-yl, 7-azabicyclo[2.2.1]heptane-7-yl, 8-aza Bicyclo[3.2.1]octan-8-yl, 2-azabicyclo[2.2.2]octan-2-yl, 3-azabicyclo[3.2.2]nonan-3-yl, isoindolin-2-yl, 4-cyanoisoindolin-2-yl, 5-cyanoisoindolin-2-yl, 4-methoxyisoindolin-2-yl, 5-methoxyisoindolin-2-yl, 4-ethoxyisoindolin-2-yl, 4-isopropoxyisoindolin-2-yl isoindolyl, 5,6-dimethoxyisoindolyl, 5-hydroxymethylisoindolyl, 4-difluoromethylisoindolyl, 5-difluoromethylisoindolyl, 4-difluoromethoxyisoindolyl, 4-trifluoromethylisoindolyl, 5-trifluoromethylisoindolyl, 4-fluoroisoindolyl, 5-fluoroisoindolyl, 5,6-difluoroisoindolin-2-yl, 1-methylisoindolin-2-yl, 4-methylamino-carbonylisoindolin-2-yl, 4-dimethylaminocarbonylisoindolin-2-yl, 5-dimethylaminocarbonylisoindolin-2-yl, 4-(2-(dimethylamino)ethoxy)isoindolin-2-yl, 4-(2-(methylamino)ethoxy)isoindolin-2-yl, 4-dimethylaminomethylisoindolin-2-yl, 5-dimethylaminomethylisoindolin-2-yl, 4-methylaminomethylisoindolin-2-yl, 4-dimethylaminoisoindolin-2-yl, 4-methylaminoisoindolin-2-yl, 3-phenylisoindolin-2-yl, 4-phenylisoindolin-2-yl, 4-phenoxyisoindolin indolin-2-yl, 1-benzylisoindolin-2-yl, 4-benzylisoindolin-2-yl, 4-(3-fluorophenoxy)isoindolin-2-yl, 4-(4-fluorophenoxy)isoindolin-2-yl, 4-(2-cyanophenoxy)-isoindolin-2-yl, 4-(3-cyanophenoxy)-isoindolin-2-yl, 4-cyclohexylisoindolin-2-yl, 5-(hydroxymethyl)isoindolin-2-yl, 4-(2-hydroxyethoxy)isoindolin-2-yl, 4-(2-aminoethoxy)-isoindolin-2-yl, 5-(cyanomethyl)isoindolin-2-yl, 4-(cyanomethyl)isoindolin-2-yl, indolin-1-yl, 2-methylindolin-1-yl, 4-cyanoindolin-1-yl Indolin-1-yl, 5-cyanoindolin-1-yl, 6-cyanoindolin-1-yl, 4-hydroxy-methylindolin-1-yl, 6-difluoromethylindolin-1-yl, 4-trifluoromethylindolin-1-yl, 5-trifluoromethylindolin-1-yl, 6-trifluoromethylindolin-1-yl, 6-methoxyindolin-1-yl, 5-chloro-indolin-1-yl, 6-chloroindolin-1-yl, 6-dimethylaminoindolin-1-yl, 6-fluoroindolin-1-yl, 5,6-difluoroindolin-1-yl, 4,6-difluoroindolin-1-yl, 4,5-difluoroindolin-1-yl, 6-difluoromethoxyindolin-1-yl, 6-trifluoromethoxyindolin-1-yl, 4-((dimethylamino)methyl)-indolin-1-yl 1-yl, 5-((dimethyl-amino)methyl)indolin-1-yl, 6-((dimethylamino)methyl)indolin-1-yl, 4-((methylamino)-methyl)indolin-1-yl, 5-((methylamino)methyl)indolin-1-yl, 6-((methylamino)-methyl)indolin-1-yl, 6-methylaminocarbonylindolin-1-yl, 6-aminocarbonyl-indolin-1-yl, 6-dimethylamino-carbonylindolin-1-yl, 4-(2-(methylamino)ethoxy)indolin-1-yl, 6-(2-(dimethylamino)ethoxy)-indolin-1-yl, 4-(hydroxymethyl)indolin-1-yl, 5-phenylindolin-1-yl, 6-(1-methyl-6-oxo-1,6-dihydropyridin-2-yl)indolin-1-yl, 4-(1-hydroxyethyl)indolin-1-yl, 4-(2-hydroxypropan-2-yl)-indolin-1-yl, 6-(2-hydroxypropan-2-yl)indolin-1-yl, 4-(cyanomethyl)indolin-1-yl, 6-(2-cyanopropan-2-yl)indolin-1-yl, 4-(morpholinomethyl)indolin-1-yl, 4-methoxycarbonyl-aminomethylindolin-1-yl, 7-(methylamino)indolin-1-yl, 6-(methylsulfonyl)indolin-1-yl, 6-chloroindolin-1-yl, 3,4-dihydroisoquinolin-2(1H)-yl, 1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl, 2,3 ,4,5-tetrahydro-1H-benzo[b]azepin-1-yl, 2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl, 4-methyl-3,4-dihydroquinoxalin-1(2H)-yl, 1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl, 3,4-dihydroquinoxalin-1(2H)-yl, 2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl, 1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl, 1-methyl-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl, and 2,3-dihydro-benzo[e][1,4]oxazepin-1(5H)-yl. ,

[0309] 50. In embodiment 50, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 49, wherein R 4 and R 5 Together with the nitrogen atom to which they are attached, they form a ring selected from the group consisting of: morpholin-4-yl, piperidin-1-yl, 2-methyl-piperidin-1-yl, 3-methylpiperidin-1-yl, 4-methylpiperidin-1-yl, 4-phenoxypiperidin-1-yl, 2-phenylpiperidin-1-yl, 2-phenylpyrrolidin-1-yl, 3,3-difluoropyrrolidin-1-yl, 4-phenylpiperazin-1-yl, 4-acetylpiperazin-1-yl, 4-methyl-3-oxo-piperazin-1-yl, 4-methylsulfonylpiperazin-1-yl. -yl, 3-azabicyclo[3.1.0]hexan-3-yl, azaspiro[2.4]heptan-5-yl, 2-azaspiro[4.4]nonan-2-yl, 6-azaspiro[3.4]octan-6-yl, 5-azaspiro[2.4]heptan-5-yl, 7-azabicyclo[2.2.1]heptan-7-yl, 8-azabicyclo[3.2.1]octan-8-yl, 2-azabicyclo[2.2.2]octan-2-yl, and 3-azabicyclo[3.2.2]nonan-3-yl.

[0310] 51. In embodiment 51, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 49, wherein R 4 and R 5Together with the nitrogen atom to which they are attached, they form a ring selected from the group consisting of isoindolin-2-yl, 4-cyanoisoindolin-2-yl, 5-cyanoisoindolin-2-yl, 4-methoxyisoindolin-2-yl, 5-methoxyisoindolin-2-yl, 4-ethoxyisoindolin-2-yl, 4-isopropoxyisoindolin-2-yl, 5,6-dimethoxyisoindolin-2-yl, 5-hydroxymethylisoindolin-2-yl, 4-difluoromethylisoindolin-2-yl, 5-difluoromethylisoindolin-2-yl, 4-difluoromethoxyisoindolin-2-yl, 4-trifluoromethylisoindolin-2-yl, 5-trifluoromethylisoindolin-2-yl, 4-fluoroisoindolin-2-yl, 5 -fluoroisoindolin-2-yl, 5,6-difluoroisoindolin-2-yl, 1-methylisoindolin-2-yl, 4-methylamino-carbonylisoindolin-2-yl, 4-dimethylaminocarbonylisoindolin-2-yl, 5-dimethylaminocarbonylisoindolin-2-yl, 4-(2-(dimethylamino)ethoxy)-isoindolin-2-yl, 4-(2-(methylamino)ethoxy)-isoindolin-2-yl, 4-dimethylaminomethylisoindolin-2-yl, 5-dimethylaminomethylisoindolin-2-yl, 4-methylaminomethylisoindolin-2-yl, 4-dimethyl-aminoisoindolin-2-yl, 4-methylaminoisoindolin-2-yl, 3- Phenylisoindolin-2-yl, 4-phenylisoindolin-2-yl, 4-phenoxyisoindolin-2-yl, 1-benzylisoindolin-2-yl, 4-benzylisoindolin-2-yl, 4-(3-fluorophenoxy)isoindolin-2-yl, 4-(4-fluorophenoxy)isoindolin-2-yl, 4-(2-cyanophenoxy)isoindolin-2-yl, 4-(3-cyanophenoxy)isoindolin-2-yl, 4-cyclohexylisoindolin-2-yl, 5-(hydroxymethyl)isoindolin-2-yl, 4-(2-hydroxyethoxy)isoindolin-2-yl, 4-(2-aminoethoxy)isoindolin-2-yl, 5-(cyanomethyl)isoindolin-2-yl, 4-(Cyanomethyl)isoindolin-2-yl, indolin-1-yl, 2-methylindolin-1-yl, 4-cyanoindolin-1-yl, 5-cyanoindolin-1-yl, 6-cyanoindolin-1-yl, 4-hydroxymethylindolin-1-yl, 6-difluoromethylindolin-1-yl, 4-trifluoromethylindolin-1-yl, 5-trifluoromethylindolin-1-yl, 6-trifluoromethylindolin-1-yl, 6-methoxyindolin-1-yl, 5-chloroindolin-1-yl, 6-chloroindolin-1-yl, 6-dimethylaminoindolin-1-yl, 6-fluoroindolin-1-yl, 5,6-difluoroindolin-1-yl, 4,6-difluoroindolin-1-yl, 4,5-difluoroindolin-1-yl, 6-difluoromethoxyindolin-1-yl, 6-trifluoromethoxyindolin-1-yl, 4-((dimethylamino)methyl)indolin-1-yl, 5-((dimethylamino)methyl)indolin-1-yl, 6-((dimethyl-amino)methyl)indolin-1-yl, 4-((methylamino)methyl)indolin-1-yl, 5-((methylamino)methyl)-indolin-1-yl, 6-((methylamino)-methyl)indolin-1-yl, 6-methylaminocarbonylindolin-1-yl, 6-aminocarbonyl-indolin-1-yl, -dimethylaminocarbonylindolin-1-yl, 4-(2-(methylamino)ethoxy)indolin-1-yl, 6-(2-(dimethylamino)ethoxy)indolin-1-yl, 4-(hydroxymethyl)indolin-1-yl, 5-phenylindolin-1-yl, 6-(1-methyl-6-oxo-1,6-dihydropyridin-2-yl)indolin-1-yl, 4-(1-hydroxyethyl)indolin-1-yl, 4-(2-hydroxypropan-2-yl)indolin-1-yl, 6-(2-hydroxypropan-2-yl)indolin-1-yl, 4-(cyanomethyl)indolin -1-yl, 6-(2-cyanopropan-2-yl)indolin-1-yl, 4-(morpholinomethyl)indolin-1-yl, 4-methoxycarbonyl-aminomethylindolin-1-yl, 7-(methylamino)indolin-1-yl, 6-(methylsulfonyl)indolin-1-yl, 6-chloroindolin-1-yl, 3,4-dihydroisoquinolin-2-yl, 1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl, 2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl, 2,3-dihydro-4H-benzo[b][1,4]oxazine-4 -yl, 4-methyl-3,4-dihydroquinoxalin-1(2H)-yl, 1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl, 3,4-dihydroquinoxalin-1(2H)-yl, 2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl, 1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl, and 1-methyl-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl, 2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)-yl. ,

[0311] 52. In embodiment 52, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 49 and 51, wherein R 4 and R 5Together with the nitrogen atom to which they are attached, they form a ring selected from the group consisting of isoindolin-2-yl, 4-cyanoisoindolin-2-yl, 5-cyanoisoindolin-2-yl, 4-methoxyisoindolin-2-yl, 5-methoxyisoindolin-2-yl, 4-ethoxyisoindolin-2-yl, 4-isopropoxyisoindolin-2-yl, 5,6-dimethoxyisoindolin-2-yl, 5-hydroxymethylisoindolin-2-yl, 4-difluoromethylisoindolin-2-yl, 5-difluoromethylisoindolin-2-yl, 4-difluoroisoindolin-2-yl. methoxyisoindolin-2-yl, 4-trifluoromethylisoindolin-2-yl, 5-trifluoromethylisoindolin-2-yl, 4-fluoroisoindolin-2-yl, 5-fluoroisoindolin-2-yl, 5,6-difluoroisoindolin-2-yl, 1-methyl-isoindolin-2-yl, 4-methylamino-carbonylisoindolin-2-yl, 4-dimethylaminocarbonylisoindolin-2-yl, 5-dimethylaminocarbonylisoindolin-2-yl, 4-(2-(dimethylamino)ethoxy)isoindolin-2-yl, 4-(2 -(methylamino)ethoxy)-isoindolin-2-yl, 4-dimethylaminomethylisoindolin-2-yl, 5-dimethylamino-methylisoindolin-2-yl, 4-methylaminomethylisoindolin-2-yl, 4-dimethylaminoisoindolin-2-yl, 4-methylaminoisoindolin-2-yl, 3-phenylisoindolin-2-yl, 4-phenylisoindolin-2-yl, 4-phenoxy-isoindolin-2-yl, 1-benzylisoindolin-2-yl, 4-benzylisoindolin-2-yl, 4-(3-fluoro)isoindolin-2-yl In some embodiments, 4-(4-fluorophenoxy)isoindolin-2-yl, 4-(2-cyanophenoxy)isoindolin-2-yl, 4-(3-cyano-phenoxy)isoindolin-2-yl, 4-cyclohexylisoindolin-2-yl, 5-(hydroxymethyl)isoindolin-2-yl, 4-(2-hydroxyethoxy)isoindolin-2-yl, 4-(2-aminoethoxy)isoindolin-2-yl, 5-(cyanomethyl)isoindolin-2-yl, and 4-(cyanomethyl)isoindolin-2-yl are also included.

[0312] 53. In embodiment 53, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 49 and 51, wherein R 4 and R 5Together with the nitrogen atom to which they are attached, they form a ring selected from the group consisting of indolin-1-yl, 2-methylindolin-1-yl, 4-cyanoindolin-1-yl, 5-cyanoindolin-1-yl, 6-cyanoindolin-1-yl, 4-hydroxy-methylindolin-1-yl, 6-difluoromethylindolin-1-yl, 4-trifluoromethylindolin-1-yl, 5-trifluoromethylindolin-1-yl, 6-trifluoromethylindolin-1-yl, 6-methoxyindolin-1-yl, 5-chloro-indolin-1-yl, 6-chloro-indolin-1-yl, 6-difluoromethylindolin-1-yl, methylaminoindolin-1-yl, 6-fluoroindolin-1-yl, 5,6-difluoroindolin-1-yl, 4,6-difluoroindolin-1-yl, 4,5-difluoroindolin-1-yl, 6-difluoromethoxyindolin-1-yl, 6-trifluoromethoxyindolin-1-yl, 4-((dimethylamino)methyl)indolin-1-yl, 5-((dimethyl-amino)methyl)indolin-1-yl, 6-((dimethyl-amino)methyl)indolin-1-yl, 4-((methylamino)methyl)-indolin-1-yl, 5-((methylamino)methyl)-indolin-1-yl indolin-1-yl, 6-((methylamino)-methyl)indolin-1-yl, 6-methylaminocarbonylindolin-1-yl, 6-aminocarbonyl-indolin-1-yl, 6-dimethylaminocarbonyl-indolin-1-yl, 4-(2-(methylamino)-ethoxy)indolin-1-yl, 6-(2-(dimethylamino)ethoxy)indolin-1-yl, 4-(hydroxymethyl)indolin-1-yl, 5-phenylindolin-1-yl, 6-(1-methyl-6-oxo-1,6-dihydropyridin-2-yl)indolin-1-yl In some embodiments, the present invention includes but is not limited to indolin-1-yl, 4-(1-hydroxyethyl)indolin-1-yl, 4-(2-hydroxypropan-2-yl)indolin-1-yl, 6-(2-hydroxypropan-2-yl)indolin-1-yl, 4-(cyanomethyl)indolin-1-yl, 6-(2-cyanopropan-2-yl)indolin-1-yl, 4-(morpholinomethyl)indolin-1-yl, 4-methoxycarbonyl-aminomethylindolin-1-yl, 7-(methylamino)indolin-1-yl, 6-(methylsulfonyl)indolin-1-yl, and 6-chloroindolin-1-yl.

[0313] 54. In embodiment 54, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 49 and 51, wherein R 4 and R 5Together with the nitrogen atom to which they are attached, they form a ring selected from the group consisting of: 3,4-dihydroisoquinolin-2(1H)-yl, 1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl, 2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl, 2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl, 4-methyl-3,4-dihydroquinoxalin-1(2H)-yl, 1,2,3,5-tetrahydro-4H-benzo[d]azepin-3-yl, [e][1,4]diazepin-4-yl, 3,4-dihydroquinoxalin-1(2H)-yl, 2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl, 1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl, 1-methyl-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl, and 2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)-yl.

[0314] 55. In embodiment 55, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 24, wherein R 4 and R 5 R is independently hydrogen, alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, fused cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, bicyclic heterocyclyl, bicyclic heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, fused heterocyclyl, fused heterocyclylalkyl, spiroheterocyclyl, or spiroheterocyclylalkyl, wherein each of the foregoing rings, alone or as part of another group, is replaced by R p 、R q , and R r replace.

[0315] 56. In embodiment 56, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 24 and 55, wherein R 4 is hydrogen, alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, fused cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, bicyclic heterocyclyl, bicyclic heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, fused heterocyclyl, fused heterocyclylalkyl, spiroheterocyclyl, and spiroheterocyclylalkyl, and R 5 is alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, fused cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, bicyclic heterocyclyl, bicyclic heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, fused heterocyclyl, fused heterocyclylalkyl, spiroheterocyclyl, or spiroheterocyclylalkyl, wherein each of the foregoing rings, alone or as part of another group, is replaced by Rp 、R q , and R r replace.

[0316] 57. In embodiment 57, the compound, or a pharmaceutically acceptable salt thereof, is as provided in any one of embodiments 1 to 56, wherein W is N.

[0317] 58. In embodiment 58, the compound, or a pharmaceutically acceptable salt thereof, is provided as any one of embodiments 1 to 56, wherein W is CH or C (when attached to R 6 hour).

[0318] 59. In embodiment 59, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 58, wherein R 6 is hydrogen, fluorine, methyl, cyclopropyl, cyano, difluoromethyl or trifluoromethyl.

[0319] 59a. In embodiment 59a, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 58, wherein R 6 is hydrogen, fluorine, cyano, difluoromethyl or trifluoromethyl.

[0320] 59b. In embodiment 59b, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 58, wherein R 6 It's hydrogen.

[0321] 60. In embodiment 60, the compound, or a pharmaceutically acceptable salt thereof, is as provided in any one of embodiments 1, 2, and 10 to 59b, wherein R 8A It's hydrogen.

[0322] 61. In embodiment 61, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1, 2, and 10 to 59b, wherein R 8A It is an alkyl group.

[0323] 62. In embodiment 62, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1, 2, 10 to 59b and 61, wherein R 8A is methyl, ethyl, or propyl.

[0324] 63. In embodiment 63, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1, 2, 8, 9, and 11 to 62, wherein R 8 is hydrogen, methyl, ethyl, propyl, fluorine, hydroxymethyl or cyano.

[0325] 64. In embodiment 58, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1, 2, 9, and 11 to 59b, wherein R 8 is hydrogen, fluorine or cyano.

[0326] 65. In embodiment 65, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 64, wherein R 9 and R 10 are independently alkyl, cycloalkyl, bridged cycloalkyl, spirocycloalkyl, heterocyclyl, bridged heterocyclyl, or spiroheterocyclyl, wherein:

[0327] (A)R 9 and R 10 The cycloalkyl, bridged cycloalkyl, and spirocycloalkyl groups are replaced by one or two R a Replacement; and

[0328] (B)R 9 and R 10 The heterocyclic group, bridged heterocyclic group, and spiro heterocyclic group in R b 、R c , and R d replace.

[0329] 66. In embodiment 66, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65, wherein R 9 and R 10 It is an alkyl group.

[0330] 67. In embodiment 67, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 66, wherein R 9 and R 10 is methyl, ethyl, propyl or butyl.

[0331] 68. In embodiment 68, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 67, wherein R 9 and R 10 It is a methyl or ethyl group.

[0332] 69. In embodiment 69, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 67, wherein R 9 and R 10 It is propyl or butyl.

[0333] 70. In embodiment 70, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 67 and 69, wherein R 9 and R 10 is isopropyl, isobutyl, sec-butyl or tert-butyl.

[0334] 71. In embodiment 71, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 67 and 69, wherein R 9 and R 10 is isopropyl or tert-butyl.

[0335] 72. In embodiment 72, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65, wherein R 9 and R 10 are independently cycloalkyl, bridged cycloalkyl, or spirocycloalkyl, wherein R 9 and R 10 The cycloalkyl, bridged cycloalkyl, and spirocycloalkyl groups are replaced by one or two R a replace.

[0336] 73. In embodiment 73, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65 and 72, wherein R 9 and R 10 are independently cycloalkyl, bridged cycloalkyl, or spirocycloalkyl, wherein R 9 and R 10 The cycloalkyl, bridged cycloalkyl, and spirocycloalkyl groups are replaced by an R a replace.

[0337] 74. In embodiment 74, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65, 72 and 73, wherein one or both R a are independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, halo, haloalkyl, and cyano.

[0338] 75. In embodiment 75, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65 and 72 to 74, wherein one or both R a Independently selected from hydrogen, deuterium, methyl, trideuterated methyl, cyclopropyl, fluorine, chlorine, difluoromethyl, trifluoromethyl, hydroxymethyl, cyano, amino, methylamino, diethylamino, and dimethylamino.

[0339] 76. In embodiment 76, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65 and 72 to 75, wherein one or both R a are independently selected from hydrogen, deuterium, methyl, trideuterated methyl, fluorine, chlorine, difluoromethyl, trifluoromethyl, and cyano.

[0340] 77. In embodiment 77, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65 and 72 to 76, wherein R 9 and R10 are independently cycloalkyl and bridged cycloalkyl, each ring being surrounded by R as defined therein a replace.

[0341] 78. In embodiment 78, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65 and 72 to 76, wherein R 9 and R 10 is defined as R a Substituted spirocycloalkyl.

[0342] 79. In embodiment 79, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65 and 72 to 77, wherein R 9 and R 10 is defined as R a Substituted cycloalkyl.

[0343] 80. In embodiment 80, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65 and 72 to 77, wherein R 9 and R 10 is defined as R a Substituted bridged cycloalkyl.

[0344] 81. In embodiment 81, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65, wherein R 9 and R 10 are independently heterocyclic, bridged heterocyclic, or spiroheterocyclic, wherein R 9 and R 10 The heterocyclic group, bridged heterocyclic group, and spiro heterocyclic group in R b 、R c , and R d replace.

[0345] 82. In embodiment 82, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65 and 81, wherein R 9 and R 10 are independently heterocyclic or bridged heterocyclic, each ring being b 、R c , and R d replace.

[0346] 83. In embodiment 83, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65 and 81, wherein R 9 and R 10 Is R b 、R c , and R dSubstituted spiroheterocyclyl.

[0347] 84. In embodiment 84, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65, 81 and 82, wherein R 9 and R 10 Is R b 、R c , and R d substituted heterocyclic group.

[0348] 85. In embodiment 85, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65, 81 and 82, wherein R 9 and R 10 Is R b 、R c , and R d Substituted bridged heterocyclyl.

[0349] 86. In embodiment 86, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65, 72 to 77, 79 to 82, 84 and 85, wherein R 9 and R 10 The cycloalkyl group and the bridged cycloalkyl group are selected from the group consisting of:

[0350]

[0351] And R 9 and R 10 The heterocyclic group and bridged heterocyclic group in are selected from:

[0352]

[0353] wherein each cycloalkyl group and bridged cycloalkyl group is represented by R as defined therein a and each heterocyclic group and bridged heterocyclic group is replaced by R b 、R c and R d replace.

[0354] 87. In embodiment 87, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65, 72 to 77, 79 to 82, and 84 to 85, wherein R 9 and R 10 The cycloalkyl group and the bridged cycloalkyl group are selected from the group consisting of:

[0355]

[0356] And R 9 and R 10 The heterocyclic group and bridged heterocyclic group in are selected from:

[0357]

[0358] wherein each cycloalkyl group and bridged cycloalkyl group is represented by R as defined therein a substituted; and heterocyclic groups and bridged heterocyclic groups are as defined therein R b 、R c and R d replace.

[0359] 88. In embodiment 88, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65, 72 to 77, 79 and 80, wherein R 9 and R 10 The cycloalkyl group and the bridged cycloalkyl group are selected from the group consisting of:

[0360]

[0361] wherein each cycloalkyl group and bridged cycloalkyl group is represented by R as defined therein a replace.

[0362] 89. In embodiment 89, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65, 72 to 77, 79 and 80, wherein R 9 and R 10 The cycloalkyl group and the bridged cycloalkyl group are selected from:

[0363]

[0364] wherein each cycloalkyl group and bridged cycloalkyl group is represented by R as defined therein a replace.

[0365] 90. In embodiment 90, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65, 74 to 76, 81, 82, 84 and 85, wherein R 9 and R 10 The heterocyclic group and bridged heterocyclic group in are selected from:

[0366]

[0367] wherein each ring is defined as R b 、R c and R d replace.

[0368] 91. In embodiment 91, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65, 74 to 76, 81, 82, 84 and 85, wherein R 9 and R 10 The heterocyclic group and bridged heterocyclic group in are selected from:

[0369]

[0370] Each ring is defined as R b 、R c and R d replace.

[0371] 92. In embodiment 92, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65, 72 to 77, 79, 86 and 87, wherein ring R 9 and R 10 The cycloalkyl group is selected from:

[0372]

[0373] wherein each cycloalkyl group is represented by R as defined therein a replace.

[0374] 93. In embodiment 93, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65, 72 to 77, 79, 86, 87, and 92, wherein ring R 9 and R 10 The cycloalkyl group is selected from:

[0375]

[0376] wherein each cycloalkyl group is replaced by one or two R a replace.

[0377] 94. In embodiment 94, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65, 72 to 77, and 80, wherein R 9 and R 10 The bridged cycloalkyl group in is selected from:

[0378]

[0379] wherein each bridged cycloalkyl group is replaced by R as defined therein a replace.

[0380] 95. In embodiment 95, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65, 72 to 77, and 80, wherein R 9 and R 10 The bridged cycloalkyl group in is selected from:

[0381] Selected from:

[0382] wherein each bridged cycloalkyl group is replaced by R as defined thereina replace.

[0383] 96. In embodiment 96, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65, 72 to 77, 80 and 95, wherein R 9 and R 10 The bridged cycloalkyl group in is:

[0384] And R a As defined therein.

[0385] 97. In embodiment 97, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65, 74 to 76, 81, 82, 84, and 92 to 96, wherein R 9 and R 10 The heterocyclic group is selected from:

[0386]

[0387] wherein each heterocyclic group is represented by R as defined therein b 、R c and R d replace.

[0388] 98. In embodiment 98, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65, 74 to 76, 81, 82, 84, and 92 to 97, wherein R 9 and R 10 The heterocyclic group is selected from:

[0389]

[0390] wherein each heterocyclic group is represented by R as defined therein b 、R c and R d replace.

[0391] 99. In embodiment 99, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65, 74 to 76, 81, 82, 84, 92 to 96, and 98, wherein R 9 and R 10 The heterocyclic group is selected from:

[0392]

[0393] wherein each heterocyclic group is represented by R as defined therein b 、R c and R d replace.

[0394] 100. In embodiment 100, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65, 74 to 76, 81, 82, 85, and 92 to 96, wherein R 9 and R 10 The bridged heterocyclic group in is selected from:

[0395]

[0396] wherein each bridged heterocyclic group is R b 、R c and R d replace.

[0397] 101 In embodiment 101, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65, 74 to 76, 81, 82, 85, and 92 to 96, wherein R 9 and R 10 The bridged heterocyclic group in is selected from:

[0398]

[0399] wherein each bridged heterocyclic group is R as defined therein b 、R c and R d replace.

[0400] 102. In embodiment 102, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65, 74 to 76, 81, 82, 85, 92 to 96, and 101, wherein R 9 and R 10 The bridged heterocyclic group in is selected from:

[0401]

[0402] wherein each bridged heterocyclic group is R as defined therein b 、R c and R d replace.

[0403] 103. In embodiment 103, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65, 72 to 80, and 86 to 102, wherein R a is hydrogen, deuterium, chlorine, fluorine, difluoromethyl or trifluoromethyl.

[0404] 104. In embodiment 104, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65, 72 to 80, and 86 to 103, wherein R a It's hydrogen.

[0405] 105. In embodiment 105, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65, 72 to 80, and 86 to 103, wherein R a It is fluorine or chlorine.

[0406] 106. In embodiment 106, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65, 72 to 80, and 86 to 103, wherein R a It is difluoromethyl or trifluoromethyl.

[0407] 107. In embodiment 107, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65, 72 to 74, 77 to 80, and 86 to 102, wherein R a is hydrogen or a haloalkyl group.

[0408] 108. In embodiment 108, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65, 72 to 74, 77 to 80, and 86 to 102, wherein R a is hydrogen or a halo.

[0409] 109. In embodiment 109, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65, 72, 73, 77 to 80, and 86 to 102, wherein R a It is a halo group or a haloalkyl group.

[0410] 110. In embodiment 110, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65, 72 to 77, 79, 80, 86, 87, 88, 90, 91, and 97 to 102, wherein R 9 and R 10 The bridged cycloalkyl group in which R is bicyclo[1.1.1]pentan-1-yl, 3-fluorobicyclo[1.1.1]pentan-1-yl, 3-chlorobicyclo-[1.1.1]pentan-1-yl, 3-(hydroxymethyl)-bicyclo[1.1.1]pentan-1-yl, 3-(trifluoromethyl)-bicyclo[1.1.1]pentan-1-yl, 3-(difluoromethyl)-bicyclo[1.1.1]pentan-1-yl, and R 9 and R 10 The cycloalkyl group in is cyclobutyl, cyclopropyl, 1-(difluoromethyl)cyclobutyl, 1-(trifluoromethyl)cyclobutyl, 1-(difluoromethyl)cyclopropyl or 1-(trifluoromethyl)cyclopropyl.

[0411] 111. In embodiment 111, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65, 72, 73, 77, 80, 86, 87, 88, 90, 91, 97 to 102, and 110, wherein R 9 and R 10 The bridged cycloalkyl group in which is bicyclo[1.1.1]pentan-1-yl, 3-fluoro-bicyclo[1.1.1]pentan-1-yl, 3-chlorobicyclo[1.1.1]pentan-1-yl, 3-(hydroxymethyl)-bicyclo[1.1.1]pentan-1-yl, 3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl or 3-(difluoromethyl)-bicyclo[1.1.1]pentan-1-yl.

[0412] 112. In embodiment 112, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65, 72, 73, 79, 86, 87, 88, 90, 91, 97 to 102, and 110, wherein R 9 and R 10 The cycloalkyl group in is cyclobutyl, cyclopropyl, 1-(difluoromethyl)cyclobutyl, 1-(trifluoromethyl)-cyclobutyl, 1-(difluoromethyl)-cyclopropyl or 1-(trifluoromethyl)cyclopropyl.

[0413] 113. In embodiment 113, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65, 72, 73, 79, 86, 87, 88, 90, 91, 97 to 102, 110, and 112, wherein R 9 and R 10 The cycloalkyl group in is 1-(difluoromethyl)cyclobutyl, 1-(trifluoromethyl)cyclobutyl, 1-(difluoromethyl)cyclopropyl or 1-(trifluoromethyl)cyclopropyl.

[0414] 114a. In embodiment 114a, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65, 74 to 76, 81 to 113, wherein R b and R c are independently selected from hydrogen, alkyl, halo, haloalkyl, hydroxy, and cyano, and R d is selected from hydrogen, alkyl, deuterated alkyl, cycloalkyl (as defined in the first aspect), haloalkyl, amino, alkylamino, dialkylamino, heterocyclyl, phenyl, phenylalkyl, and heteroaryl, wherein phenyl, phenylalkyl, heteroaryl, and heterocyclyl are replaced by R e 、R f , and R g replace.

[0415] 114. In embodiment 114, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65, 74 to 76, 81 to 113, wherein R b and R c are independently selected from hydrogen, methyl, fluorine, chlorine, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, hydroxyl, and cyano, and R d Selected from hydrogen, methyl, trideuterated methyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, amino, dimethylamino, diethylamino, 3,3-difluorocyclobutyl, 4,4-difluorocyclohexyl, 3-hydroxy-3-methylcyclobutyl, 3-cyano-3-methylcyclobutyl, oxetan-3-yl, tetrahydrofuran-2-yl, tetrahydropyran-4-yl, 1,1-dioxosulfurized cyclopropane-3-yl, 1,1-dioxotetrahydro-2H-thiopyran-4-yl, benzyl, phenyl, pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl.

[0416] 115. In embodiment 115, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65, 74 to 76, 81 to 113 and 114, wherein R b is hydrogen, R c is selected from hydrogen, methyl, fluorine, chlorine, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, hydroxyl, and cyano, and R d Selected from hydrogen, methyl, trideuterated methyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, amino, dimethylamino, diethylamino, 3,3-difluorocyclobutyl, 4,4-difluorocyclohexyl, 3-hydroxy-3-methylcyclobutyl, 3-cyano-3-methylcyclobutyl, oxetan-3-yl, tetrahydrofuran-2-yl, tetrahydropyran-4-yl, 1,1-dioxosulfurized cyclopropane-3-yl, 1,1-dioxotetrahydro-2H-thiopyran-4-yl, benzyl, phenyl, pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl.

[0417] 116. In embodiment 116, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65, 74 to 76, 81, 82, 84 to 90 to 97, 100, and 103 to 113, wherein (I) R 9 and R 10wherein the heterocyclyl group is 3,5-dimethylmorpholino, 4-methyltetrahydro-2H-pyran-4-yl, 2,2,4-trimethylpiperazin-1-yl, 4-methylpiperidin-4-yl, 1,4-dimethylpiperidin-4-yl, 3-oxo-8-azabicyclo[3.2.1]octan-8-yl, 2,2-dimethylpyrrolidin-1-yl, 2,2-dimethylazetidin-1-yl, 2,4-dimethylazetidin-1-yl, 2,4,6-trimethylpiperazin-1-yl, 2,6-dimethylpiperazin-1-yl or 2,5-dimethylpyrrolidin-1-yl; and

[0418] (ii)R 9 and R 10The bridged heterocyclic group is 2-oxabicyclo[2.1.1]hexan-1-yl, 7-azabicyclo[2.2.1]hept-7-yl, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, 3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl, 3,3-difluoro-8-azabicyclo[3.2.1]octan-8-yl, 3-(methyl-d3)-3,8-diazabicyclo[3.2.1]octan-8-yl, 3-cyclopropyl-3,8-diazabicyclo[3.2.1]octan-8-yl, 3-(2,2,2-trifluoroethyl)-3,8-diazabicyclo[3.2.1]octan-8-yl, 3-(2,2-difluoroethyl)-3,8-diazabicyclo [3.2.1]octan-8-yl, 3,8-diazabicyclo[3.2.1]octan-8-yl, 2-azabicyclo[2.2.2]octan-2-yl, 8-azabicyclo[3.2.1]octan-8-yl, 3-(3,3,3-trifluoropropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl, 3-azabicyclo[3.2.2]nonan-3-yl, 3-methyl-3,6-diazabicyclo[3.1.1]heptane-6-yl, 8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl, 3-(dimethylamino)-8-azabicyclo[3.2.1]octan-8-yl, 3-(3,3-difluorocyclobutyl)-3,8-diazabicyclo[3. 2.1]octan-8-yl, 3-(oxetan-3-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl, 5-methyl-2,5-diazabicyclo[2.2.2]octan-2-yl, 3-hydroxy-3-methyl-8-azabicyclo[3.2.1]octan-8-yl, 3-cyano-3-methyl-8-azabicyclo[3.2.1]octan-8-yl, 3-(4,4-difluorocyclohexyl)-3,8-diazabicyclo[3.2.1]octan-8-yl, 3-(tetrahydro-2H-pyran-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl, 8-(pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl, 3-(1,1-dioxotetrahydro-2H-thiopyran-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl, 3-benzyl-3,8-diazabicyclo[3.2.1]octan-8-yl, 3-phenyl-3,8-diazabicyclo[3.2.1]octan-8-yl, 3-(pyridin-2-yl)-3,8-diazabicyclo[ 3.2.1]octan-8-yl, 3-(tetrahydrofuran-3-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl, 3-(1,1-dioxosulfide cyclopropane-3-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl, 3-(3-hydroxy-3-methylcyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl, 3,3-dioxo-3-thia-8-azabicyclo[3.2.1]octan-8-yl, 3-(3-cyano-3-methylcyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl, 3-cyclobutyl-3,8-diazabicyclo[3.2.1]octan-8-yl, 2-(1-cyano-7-azabicyclo[2.2.1]heptane-7-yl, 4-(3,3-difluorocyclobutyl)-2,6-dimethylpiperazin-1-yl, 7-methyl-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-yl, or 3-cyclopropyl-3,8-diazabicyclo[3.2.1]octan-8-yl.

[0419] 117. In embodiment 117, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65, 74 to 76, 81, 82, 85 to 90, 92 to 100, 103 to 113, and 117, wherein R 9 and R 10 The bridged heterocyclic group in is 3-(3,3-difluorocyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl.

[0420] 118. In embodiment 118, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65, 74 to 76, 81, 82, 85 to 90, 92 to 100, and 103 to 113, wherein R 9 and R 10 The bridged heterocyclic group in is 3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl.

[0421] 119. In embodiment 119, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65, wherein R 9 and R 10 are independently hydrogen, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, alkylsulfonyl, alkylsulfonylalkyl, amino, alkylamino, dialkylamino, substituted amino, aminoalkyl, bicyclic cycloalkyl, bicyclic heterocyclyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, wherein R 9 and R 10 The bicyclic cycloalkyl group in the a Replacement; R 9 and R 10 The bicyclic heterocyclic group in R b 、R c , and R d Replace, and R 9 and R 10 The aryl group itself or as part of the arylalkyl group and the heteroaryl group itself or as part of the heteroarylalkyl group are Rh 、R j , and R k replace.

[0422] 120. In embodiment 120, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65 and 119, wherein R 9 and R 10 is a haloalkyl group, a hydroxyalkyl group, an alkoxyalkyl group, a cyanoalkyl group, a phenyl group or a heteroaryl group, wherein R 9 and R 10 The phenyl and heteroaryl groups in h 、R j , and R k replace.

[0423] 121. In embodiment 121, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 65, 119 and 120, wherein R 9 and R 10 is 3-hydroxy-1,1-dimethylethyl, difluoromethyl, 1-fluoro-1-methylethyl, 1-methoxy-1-methylethyl, 1-cyano-1-methylethyl, 1-cyano-1-methylethyl, 2-cyano-1,1-dimethylethyl, 1-fluoro-1-methylethyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 2-methylphenyl, 2-chloro-6-fluorophenyl, 2-chlorophenyl, 2-fluorophenyl, 2-methylphenyl, 2-fluoro-6-methylphenyl, pyridin-4-yl, 1,1-dimethyl-2-methylsulfonylethyl, 1-methyl-1-pyridin-3-ylethyl, N-methyl-N-phenylamino, N-methyl-N-(2-fluorophenyl)amino, N,N-bicyclopropylamino or bicyclo[3.1.0]hexyl.

[0424] 122. In embodiment 122, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 121, wherein R 7 Yes-Q-(alk 1 ) n1 -SO2R 11 、-Q 1 -(alk 2 ) n2 -SO(=NR 12 )R 13 、-Q 2 -(alk 3 ) n3 -SO2NR 14 R 15 、-Q 3 -(alk 4 ) n4 -COR 16、-Q 4 -(alk 5 ) n5 -CONR 17 R 18 、-Q 5 -(alk 6 ) n6 -NR 19 COR 20 、-Q 6 -(alk 7 ) n7 -NR 21 SO2R 22 , heterocyclic group, bicyclic heterocyclic group, fused heterocyclic group, spiro heterocyclic group, bridged heterocyclic group, cyclic sulfoximino group, bicyclic sulfoximino group, spiro sulfoximino group, aryl group, or heteroaryl group, wherein heterocyclic group, bicyclic heterocyclic group, fused heterocyclic group, spiro heterocyclic group, bridged heterocyclic group, cyclic sulfoximino group, bicyclic sulfoximino group, spiro sulfoximino group, aryl group, and heteroaryl group are R x 、R y , and R y1 replace.

[0425] 123. In embodiment 123, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 122, wherein R 7 Yes-Q-(alk 1 ) n1 -SO2R 11 、-Q 2 -(alk 3 ) n3 -SO2NR 14 R 15 , heterocyclic group, bicyclic heterocyclic group, spiro heterocyclic group, or spiro sulfoximino group, wherein the heterocyclic group, bicyclic heterocyclic group, spiro heterocyclic group, and spiro sulfoximino group are R x 、R y , and R y1 replace.

[0426] 124. In embodiment 124, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 122, wherein R 7 Yes-Q-(alk 1 ) n1 -SO2R 11 、-Q 1 -(alk 2 ) n2 -SO(=NR 12 )R 13 、-Q 2 -(alk 3 ) n3-SO2NR 14 R 15 、-Q 3 -(alk 4 ) n4 -COR 16 、-Q 4 -(alk 5 ) n5 -CONR 17 R 18 、-Q 5 -(alk 6 ) n6 -NR 19 COR 20 , or -Q 6 -(alk 6 ) n7 -NR 21 SO2R 22 .

[0427] 125. In embodiment 125, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 122, wherein R 7 is a heterocyclic group, a bicyclic heterocyclic group, a fused heterocyclic group, a spiro heterocyclic group, a bridged heterocyclic group, a cyclic sulfoximino group, a bicyclic sulfoximino group or a spiro sulfoximino group, wherein the heterocyclic group, the bicyclic heterocyclic group, the fused heterocyclic group, the spiro heterocyclic group, the bridged heterocyclic group, the cyclic sulfoximino group, the bicyclic sulfoximino group or the spiro sulfoximino group is replaced by R x 、R y , and R y1 replace.

[0428] 126. In embodiment 126, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 121, wherein R 7 is an aryl, heteroaryl, or fused heteroaryl group, wherein each of the above rings is replaced by R x 、R y , and R y1 replace.

[0429] 127. In embodiment 127, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 124, wherein R 7 Yes-Q-(alk 1 ) n1 -SO2R 11 .

[0430] 128. In embodiment 128, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 124, wherein R 7 Yes-Q 2 -(alk3 ) n3 -SO2NR 14 R 15 .

[0431] 129. In embodiment 129, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 123 and 125, wherein R 7 Is R x 、R y , and R y1 substituted heterocyclic group.

[0432] 130. In embodiment 130, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 123 and 125, wherein R 7 Is R x 、R y , and R y1 Substituted bicyclic heterocyclyl.

[0433] 131. In embodiment 131, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 123 and 125, wherein R 7 Is R x 、R y , and R y1 Substituted spiroheterocyclyl.

[0434] 132. In embodiment 132, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 123 and 125, wherein R 7 Is R x 、R y , and R y1 Substituted spirosulfoximino groups.

[0435] 133. In embodiment 133, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 122 and 124, wherein R 7 Yes-Q 1 -(alk 2 ) n2 -SO(=NR 12 )R 13 .

[0436] 134. In embodiment 134, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 122 and 124, wherein R 7 Yes-Q 3 -(alk 4 ) n4 -COR 16 .

[0437] 135. In embodiment 135, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 122 and 124, wherein R 7 Yes-Q 4 -(alk 5 ) n5 -CONR 17 R 18 .

[0438] 136. In embodiment 136, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 122 and 124, wherein R 7 Yes-Q 5 -(alk 6 ) n6 - NR 19 COR 20 .

[0439] 137. In embodiment 137, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 122 and 124, wherein R 7 Yes-Q 6 -(alk 7 ) n7 -NR 21 SO2R 22 .

[0440] 138. In embodiment 138, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 122 and 126, wherein R 7 Is R x 、R y , and R y1 Substituted phenyl.

[0441] 139. In embodiment 139, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 122 and 126, wherein R 7 Is R x 、R y , and R y1 Substituted 6-membered heteroaryl.

[0442] 140. In embodiment 140, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 124, 127, 128, and 133 to 137, wherein Q, Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , and Q 6Each of the cycloalkyl, bridged cycloalkyl, spirocycloalkyl, heterocyclyl A , bicyclic heterocyclic group A , bridged heterocyclic group A , spiro heterocyclic group A , aryl, or heteroaryl, wherein each of the above rings is replaced by R v and R w replace.

[0443] 141. In embodiment 141, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 124, 127, 128, 133 to 137, and 140, wherein Q, Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , and Q 6 Each of is a cycloalkyl, a bridged cycloalkyl, or a spirocycloalkyl, wherein each of the above rings is replaced by R v and R w replace.

[0444] 142. In embodiment 142, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 124, 127, 128, 133 to 137, 140, and 141, wherein Q, Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , and Q 6 Each of them is R v and R w Substituted cycloalkyl.

[0445] 143. In embodiment 143, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 124, 127, 128, 133 to 137, 140 and 141, wherein Q, Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , and Q 6 Each of them is R v and R w Substituted bridged cycloalkyl.

[0446] 144. In embodiment 144, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 124, 127, 128, 133 to 137, 140, and 141, wherein Q, Q 1 , Q 2 , Q3 , Q 4 , Q 5 , and Q 6 Each of them is R v and R w Substituted spirocycloalkyl.

[0447] 145. In embodiment 145, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 124, 127, 128, 133 to 137, and 140, wherein Q, Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , and Q 6 Each of which is a heterocyclic group A , bicyclic heterocyclic group A , bridged heterocyclic group A or spiroheterocyclic group A , where each of the above rings is R v and R w replace.

[0448] 146. In embodiment 146, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 124, 127, 128, 133 to 137, 140, and 145, wherein Q, Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , and Q 6 Each of which is a heterocyclic group A or bicyclic heterocyclic group A , where each of the above rings is R v and R w replace.

[0449] 147. In embodiment 147, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 124, 127, 128, 133 to 137, 140, 145, and 146, wherein Q, Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , and Q 6 Each of them is R v and R w Substituted heterocyclic group A .

[0450] 148. In embodiment 148, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 124, 127, 128, 133 to 137, 140, 145, and 146, wherein Q, Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , and Q 6 Each of them is R v and R w Substituted bicyclic heterocyclyl A .

[0451] 149. In embodiment 149, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 124, 127, 128, 133 to 137, 140 and 145, wherein Q, Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , and Q 6 Each of which is a bridged heterocyclic group A or spiroheterocyclic group A , where each of the above rings is R v and R w replace.

[0452] 150. In embodiment 150, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 124, 127, 128, 133 to 137, 140, 145, and 149, wherein Q, Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , and Q 6 Each of them is R v and R w Substituted spiro heterocyclyl A .

[0453] 151. In embodiment 151, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 124, 127, 128, 133 to 137, and 140, wherein Q, Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , and Q 6 Each of the above rings is an aryl or heteroaryl group, wherein each of the above rings is replaced by R v and R w replace.

[0454] 152. In embodiment 152, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 124, 127, 128, 133 to 137, 140 and 151, wherein Q, Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , and Q 6 Each of the phenyl group or the 6-membered heteroaryl group, wherein each of the above rings is replaced by R v and R w replace.

[0455] 153. In embodiment 153, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 124, 127, 128, 133 to 137, 140, 151 and 152, wherein Q, Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , and Q 6 Each of them is R v and R w Substituted phenyl.

[0456] 154. In embodiment 154, the compound, or a pharmaceutically acceptable salt thereof as provided in any one of embodiments 1 to 124, 127, 128, 133 to 137, and 140 to 153, wherein n 1 、n 2 、n 3 、n 4 、n 5 、n 6 , and n 7 Each of is 0.

[0457] 155. In embodiment 155, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 124, 127, 128, 133 to 137, and 140 to 153, wherein n 1 、n 2 、n 3 、n 4 、n 5 、n 6 , and n 7 Each of is 1.

[0458] 156. In embodiment 156, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 124, 127, 128, 133 to 137, 140 to 153 and 155, wherein alk 1 alk 2 alk 3 alk 4 alk 5 alk 6 , and alk 7 Each of is a methylene group or an ethylene group.

[0459] 157. In embodiment 157, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 124, 127, 128, 133 to 137, 140 to 153 and 155, wherein alk 1 alk 2 alk 3 alk 4 alk 5 alk 6 , and alk 7 Each of them is a methylene group.

[0460] 158. In embodiment 158, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 124, 127, 128, 133 to 137, 140 to 153 and 155, wherein alk 1 alk 2 alk 3 alk 4 alk 5 alk 6 , and alk 7 Each of is ethylene, propylene, butylene or pentylene.

[0461] 159. In embodiment 159, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 124, 127, 128, 133 to 137, 140 to 153, 155 and 158, wherein alk 1 alk 2 alk 3 alk 4 alk 5 alk 6 , and alk 7 Each of is an ethylene group or a butylene group.

[0462] 160. In embodiment 160, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 159, wherein R7 Among them:

[0463] (1).Q,Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , and Q 6 Each of these is:

[0464]

[0465] Among them, Q, Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , and Q 6 each of is substituted as defined therein; and

[0466] (2).R 7 The heterocyclic, bicyclic, spiro heterocyclic, bridged heterocyclic, cyclic sulfoximino, spiro sulfoximino, aryl, heteroaryl and fused heteroaryl groups in are wherein:

[0467] A bridged heterocyclic group is:

[0468]

[0469] Bicyclic heterocyclyl is:

[0470]

[0471] Spiroheterocyclyl is:

[0472]

[0473] Heterocyclic groups are:

[0474]

[0475] The spirosulfoximino group is:

[0476]

[0477] The cyclic sulfoximine group is:

[0478]

[0479]

[0480] wherein each ring in (2) is substituted as defined therein; and

[0481] In each of the loops (1) and (2) above, In the compound of formula (I) -NHR 7 The NH bond of the part; and in each ring in (1) Expressed to -Q-(alk 1 ) n1 -SO2R 11 、-Q 1 -(alk 2 ) n2 -SO(=NR 12 )R 13 、-Q 2 -(alk 3 ) n3 -SO2NR 14 R 15 、-Q 3 -(alk 4 ) n4 -COR 16 、-Q 4 -(alk 5 ) n5 -CONR 17 R 18 、-Q 5 -(alk 6 ) n6 - NR 19 COR 20 , or -Q 6 -(alk 6 ) n7 -NR 21 SO2R 22 The rest of the keys.

[0482] 161. In embodiment 161, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 160, wherein R 7 Among them:

[0483] (1).Q,Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , and Q 6 Each of these is:

[0484]

[0485] Among them, Q, Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , and Q 6each of is substituted as defined therein; and

[0486] (2).R 7 The heterocyclic, bicyclic, spiro heterocyclic, bridged heterocyclic, cyclic sulfoximino, spiro sulfoximino, aryl, heteroaryl and fused heteroaryl groups in are wherein:

[0487] Heterocyclyl is:

[0488]

[0489] Spiroheterocyclyl is:

[0490]

[0491] A bridged heterocyclic group is:

[0492]

[0493] Bicyclic heterocyclyl is:

[0494]

[0495] The spirosulfoximino group is:

[0496]

[0497] The cyclic sulfoximine group is:

[0498]

[0499] A fused heteroaryl group is:

[0500]

[0501] wherein each ring in (2) is substituted as defined therein; and

[0502] In each ring of (1) and (2) And in each ring in (1) Has the same meaning as in Embodiment 160.

[0503] 162. In embodiment 162, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 159 and 161, wherein R 7 Among them:

[0504] (1).Q,Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , and Q 6 Each of these is:

[0505]

[0506] Among them, Q, Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , and Q 6 each of is substituted as defined therein; and

[0507] (2).R 7 The heterocyclic, bicyclic heterocyclic, spiroheterocyclic, spirosulfoximino, aryl, and heteroaryl groups are wherein:

[0508]

[0509] wherein each ring in (2) is substituted as defined therein; and

[0510] In each ring of (1) and (2) and

[0511] In each ring in (1) has the same meaning as in embodiment 160, and in each ring in (2) Indicates attachment to R x 、R y , and R y1 one of the.

[0512] 163. In embodiment 163, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 124, 127, 128, 133 to 137, and 140 to 159, wherein Q, Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , and Q 6 Each of these is:

[0513]

[0514] wherein each ring is substituted as defined therein, and wherein each ring Has the same meaning as in Embodiment 160.

[0515] 164. In embodiment 164, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 124, 127, 128, 133 to 137, 140 to 160, or 163, wherein Q, Q 1 , Q 2 , Q 3 , Q4 , Q 5 , and Q 6 Each of these is:

[0516]

[0517] wherein each ring is substituted as defined therein; and

[0518] Each of the rings Has the same meaning as in Embodiment 160.

[0519] 165. In embodiment 165, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 124, 127, 128, 133 to 137, 140 to 143, 145 to 148, 151 to 159 and 164, wherein Q, Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , and Q 6 Each of these is:

[0520]

[0521] wherein each ring is substituted as defined therein; and

[0522] Each of the rings Has the same meaning as in Embodiment 160.

[0523] 166. In embodiment 166, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 124, 127, 128, 133 to 137, 140 to 143, 154 to 159, 164 and 165, wherein Q, Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , and Q 6 Each of these is: and each ring is substituted as defined therein; and

[0524] Each of the rings Has the same meaning as in Embodiment 160.

[0525] 167. In embodiment 167, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 124, 127, 128, 133 to 137, 140, 145 to 147, 154 to 159, 164 and 165, wherein Q, Q 1 , Q2 , Q 3 , Q 4 , Q 5 , and Q 6 Each of these is: and is substituted as defined therein; and

[0526] Each of the rings Has the same meaning as in Embodiment 160.

[0527] 168. In embodiment 168, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 124, 127, 128, 133 to 137, 140, 145, 146, 148, 154 to 159, 164, and 165, wherein Q, Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , and Q 6 Each of these is: and

[0528] Each ring is substituted as defined therein; and

[0529] Each of the rings Has the same meaning as in Embodiment 160.

[0530] 169. In embodiment 169, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 124, 127, 128, 133 to 137, 140, 151 to 159, 164, and 165, wherein Q, Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , and Q 6 Each of these is: and is substituted as defined therein; and

[0531] in Has the same meaning as in Embodiment 160.

[0532] 169a. In embodiment 169a, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 124, 127, 128, 133 to 137, 140, 143, 154 to 159, and 164 to 166, wherein Q, Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , and Q6 Each of these is: and is substituted as defined therein; and

[0533] in Has the same meaning as in Embodiment 160.

[0534] 170. In embodiment 170, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 123, 125, 126, 129 to 132, 138, 139, and 154 to 169a, wherein R 7 The heterocyclic, bicyclic, spiroheterocyclic, bridged, cyclic, sulfoximino, spirosulfoximino, aryl, heteroaryl, and fused heteroaryl groups are wherein:

[0535]

[0536] wherein each ring is substituted as defined therein; and

[0537] Each of the rings Has the same meaning as in Embodiment 160.

[0538] 171. In embodiment 171, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 123, 125, 126, 129 to 132, 138, 139, and 154 to 170, wherein R 7 The heterocyclic, bicyclic, spiroheterocyclic, bridged, cyclic, sulfoximino, spirosulfoximino, aryl, heteroaryl, and fused heteroaryl groups are wherein:

[0539]

[0540] and each ring is substituted as defined therein; and

[0541] Each of the rings Has the same meaning as in Embodiment 160.

[0542] 172. In embodiment 172, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 123, 125, 126, 129 to 132, 138, 139, 154 to 169a and 171, wherein R 7 The heterocyclic, bicyclic heterocyclic, spiroheterocyclic, spirosulfoximino, aryl, and heteroaryl groups are wherein:

[0543]

[0544] wherein each ring is substituted as defined therein; and

[0545] Each of the rings Has the same meaning as in Embodiment 160.

[0546] 173. In embodiment 173, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 123, 125, 126, 129 to 132, 138, 139, 154 to 169a, 171 and 172, wherein R 7 The heterocyclic group in is: and is substituted as defined therein, and wherein and Has the same meaning as in Implementation 162.

[0547] 174. In embodiment 174, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 123, 125, 126, 129 to 132, 138, 139, 154 to 169a, 171 and 172, wherein R 7 The spiroheterocyclyl group in is: and is substituted as defined therein; and

[0548] in Has the same meaning as in Embodiment 160.

[0549] 175. In embodiment 175, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 123, 125, 126, 129 to 132, 138, 139, 154 to 169a, 171 and 172, wherein R 7 The bicyclic heterocyclic group in is: and

[0550] Each ring is substituted as defined therein; and

[0551] Each of the rings Has the same meaning as in Implementation 162.

[0552] 175a. In embodiment 175a, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 123, 125, 126, 129 to 132, 138, 139, 154 to 169a, 171, and 172, wherein R 7 The aryl group in is: and is substituted as defined therein; and

[0553] in Has the same meaning as in Implementation 162.

[0554] 176. In embodiment 176, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 123, 125, 126, 129 to 132, 138, 139, 154 to 169a, 171 and 172, wherein R 7 The bicyclic heterocyclic group in And each ring is R x 、R y , and R y1 replace; and

[0555] Each of the rings Has the same meaning as in Embodiment 160.

[0556] 177. In embodiment 177, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 124, 127, 128, and 133 to 137, and 170 to 176, wherein Q, Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , and Q 6 Each of is a key.

[0557] 178. In embodiment 178, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 124, 127, 128, 133 to 137, and 170 to 177, wherein alk 2 alk 3 alk 4 alk 5 alk 6 , and alk 7 Each of is ethylene, propylene, butylene or pentylene.

[0558] 179. In embodiment 179, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 124, 127, 128, 133 to 137, and 170 to 178, wherein alk 2 alk 3 alk 4 alk 5 alk 6 , and alk 7 Each of is an ethylene group or a butylene group.

[0559] 180. In embodiment 180, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 122, 124, 133, 136, 137, and 140 to 179, wherein R 12 、R19 and R 21 is hydrogen, methyl, ethyl or propyl.

[0560] 181. In embodiment 181, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 122, 124, 133, 136, 137, and 140 to 180, wherein R 12 、R 19 and R 21 It's hydrogen.

[0561] 182. In embodiment 182, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 122, 124, 133, 136, 137, and 140 to 180, wherein R 12 、R 19 and R 21 is methyl, ethyl or propyl.

[0562] 183. In embodiment 183, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 124, 127, 128, 133 to 137, and 140 to 182, wherein

[0563] R 11 、R 16 、R 20 , and R 22 independently selected from alkyl, fluoro, chloro, -CR 23 =CR 24 R 25 or heterocyclyl substituted with one to three substituents independently selected from hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cyano, and heterocyclyl;

[0564] R 13 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, or cycloalkyl; and

[0565] R 14 、R 15 、R 17 , and R 18 independently selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, or heterocyclyl, substituted with one to three substituents independently selected from hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, and cyano.

[0566] 184. In embodiment 184, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 124, 127, 128, and 140 to 183, wherein R 11is methyl, ethyl, piperazinyl, 4-methylpiperazinyl or 4-ethylpiperazin-1-yl; R 14 is hydrogen, methyl or ethyl, R 15 is hydrogen, methyl, ethyl, aminoethyl, methylaminoethyl, dimethylaminoethyl, diethylaminoethyl, azetidin-3-yl, 1-methylazetidin-3-yl, 1-ethylazetidin-2-yl, 1-methylpyrrolidin-3-yl, 1-ethylpyrrolidin-3-yl, 1-methylpiperidinyl or 1-ethylpiperidinyl.

[0567] 185. In embodiment 185, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 124, 127, 128, and 140 to 184, wherein R 11 It's methyl.

[0568] 186. In embodiment 186, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 123, 125, 126, 129 to 132, and 138 to 186, wherein R x 、R y , and R y1 where R x and R y are independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, and cyano, and R y1 is hydrogen, deuterium, alkyl, alkoxy, hydroxy, acyl, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, substituted amino, alkoxycarbonylamino, alkoxycarbonylaminoalkyl, aminocarbonyl, aminocarbonylalkyl, cyano, hydroxyalkyl, hydroxyalkoxy, alkoxyalkyl, alkoxyalkyloxy, alkoxyalkyloxyalkyl, aminoalkyl, aminoalkoxy, aminoalkylamino, cyanoalkyl, cyanoalkoxy, cycloalkyl, cycloalkoxy, aryl, aryloxy, aralkyl, heteroaryl, heteroaryloxy, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy (wherein aryl by itself or as part of an aralkyl or aryloxy group, heteroaryl by itself or as part of both a heteroaryloxy and a heteroaralkyl group, and heterocyclyl by itself or as part of a heterocyclylalkyl, heterocyclyloxy or heterocyclylalkyloxy group are substituted with one to three substituents independently selected from the group consisting of hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, alkoxycarbonyloxy, alkoxyalkyl, alkoxyalkyloxyalkyl, cyano, and heterocyclyl).

[0569] 187. In embodiment 187, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 123, 125, 126, 129 to 133, and 138 to 186, wherein Rx and R y are independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, haloalkoxy, and cyano, and R y1 is hydrogen, deuterium, alkyl, alkoxy, hydroxy, acyl, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, substituted amino, alkoxycarbonylamino, alkoxycarbonylaminoalkyl, aminocarbonyl, aminocarbonylalkyl, cyano, hydroxyalkyl, hydroxyalkoxy, alkoxyalkyl, alkoxyalkyloxy, alkoxyalkyloxyalkyl, aminoalkyl, aminoalkoxy, aminoalkylamino, cyanoalkyl, cyanoalkoxy, cycloalkyl, cycloalkoxy, aryl, aryloxy, aralkyl, heteroaryl, heteroaryloxy, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy (wherein aryl by itself or as part of an aralkyl or aryloxy group, heteroaryl by itself or as part of both a heteroaryloxy and a heteroaralkyl group, and heterocyclyl by itself or as part of a heterocyclylalkyl, heterocyclyloxy or heterocyclylalkyloxy group are substituted with one to three substituents independently selected from the group consisting of hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, alkoxycarbonyloxy, alkoxyalkyl, alkoxyalkyloxyalkyl, cyano, and heterocyclyl).

[0570] 188. In embodiment 188, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 123, 125, 126, 129 to 132, and 138 to 187, wherein R x and R y are independently selected from hydrogen, deuterium, and alkyl, and R y1 is hydrogen, deuterium, alkyl, alkoxy, hydroxy, acyl, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, substituted amino, alkoxycarbonylamino, alkoxycarbonylaminoalkyl, aminocarbonyl, aminocarbonylalkyl, cyano, hydroxyalkyl, hydroxyalkoxy, alkoxyalkyl, alkoxyalkyloxy, alkoxyalkyloxyalkyl, aminoalkyl, aminoalkoxy, aminoalkylamino, cyanoalkyl, cyanoalkoxy, cycloalkyl, cycloalkoxy, aryl, aryloxy, aralkyl, heteroaryl, heteroaryloxy, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, or heterocyclylalkyloxy (wherein aryl by itself or as part of an aralkyl or aryloxy group, heteroaryl by itself or as part of both a heteroaryloxy and a heteroaralkyl group, and heterocyclyl by itself or as part of a heterocyclylalkyl, heterocyclyloxy, or heterocyclylalkyloxy group are substituted with one to three substituents independently selected from the group consisting of hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, alkoxycarbonyloxy, alkoxyalkyl, alkoxyalkyloxyalkyl, cyano, and heterocyclyl).

[0571] 189. In embodiment 189, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 123, 125, 126, 129 to 132, and 138 to 188, wherein R x and R y are independently selected from hydrogen or methyl, and R y1 is hydrogen, deuterium, acyl, aminocarbonyl, aminocarbonylalkyl, aminoalkyl, or heterocyclyl, wherein the heterocyclyl is substituted with one to three substituents independently selected from hydrogen, alkyl, alkoxycarbonyloxy, alkoxyalkyl, alkoxyalkyloxyalkyl, and heterocyclyl.

[0572] 190. In embodiment 190, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 121, wherein R 7 2,2-dioxo-2-thiaspiro[3.3]heptane-6-yl, 3,3-dioxo-3-thiabicyclo[3.1.0]hexane-6-yl, 4-(methylsulfonyl)-cyclohexyl, 2,2-dioxohexahydro-1H-cyclopenta[c]thien-5-yl, 1-(methylsulfonyl)piperidin-4-yl, 1-(methylaminosulfonyl)piperidin-4-yl, 1-(aminosulfonyl)piperidin-4-yl, 4-(piperazin-1-yl)phenyl , 4-(piperazin-1-ylsulfonyl)piperidin-4-yl, 1-(N-(2-dimethylaminoethyl)-N-methylaminosulfonyl)piperidin-4-yl, 4-(4-methylpiperazin-1-ylsulfonyl)piperidin-4-yl, 5-(piperazin-1-yl)pyridin-2-yl, 4-(piperazin-1-yl)phenyl, 1-(N-(azetidin-3-yl)-N-methylamino-sulfonyl)piperidin-4-yl, 1-(N-(1-methylazetidin-3-yl)-N-methylamino-sulfonyl)piperidin-4-yl, phenyl, 4-(4-(2-methoxyethoxy)ethyl)piperazin-1-yl)phenyl, 4-(4-(2-methoxyethoxy)ethyl)piperazin-1-yl)phenyl, 3-dimethylaminomethylphenyl, 4-methylsulfonylphenyl, 4-dimethylaminomethyl ... methylaminomethyl-phenyl, 4-(4-methylpiperazin-1-yl)phenyl, 4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl, 1-(piperazin-1-ylsulfonyl)piperidin-4-yl, 3-((methylsulfonyl)methyl)bicyclo[1.1.1]pentan-1-yl, or 2-imino-2-oxo-N-(3-(2-(bicyclo[1.1.1]pentan-1-yl)-5-(2-(2-imino-2-oxo-λ 6 -thiaspiro[3.3]hept-6-yl.

[0573] 191. In embodiment 191, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 121 and 190, wherein R 7 4-(methylsulfonyl)-cyclohexyl, 1-(methylsulfonyl)piperidin-4-yl, 1-(methylaminosulfonyl)piperidin-4-yl, 1-(aminosulfonyl)piperidin-4-yl, 4-(piperazin-1-ylsulfonyl)piperidin-4-yl, 1-(N-(2-dimethylaminoethyl)-N-methylaminosulfonyl)piperidin-4-yl, 4-(4-methylpiperazin-1-ylsulfonyl)piperidin-4-yl, 1-(N-(nitrogen)-1-yl)-1-yl)-1-yl)-1-yl .3]heptan-6-yl, 4-methylsulfonylphenyl, 1-(piperazin-1-ylsulfonyl)piperidin-4-yl, or 3-((methylsulfonyl)methyl)bicyclo[1.1.1]pentan-1-yl.

[0574] 192. In embodiment 192, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 121 and 190, wherein R 7 2,2-dioxo-2-thiaspiro[3.3]heptane-6-yl, 3,3-dioxo-3-thiabicyclo[3.1.0]hexane-6-yl, 2,2-dioxohexahydro-1H-cyclopenta[c]thiophene-5-yl, 4-(piperazin-1-yl)phenyl, 5-(piperazin-1-yl)pyridin-2-yl, 4-(piperazin-1-yl)phenyl, 4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl, 1-yl)phenyl, 4-(2-(2-methoxyethoxy)ethyl)piperazin-1-yl)phenyl, 4-(4-(2-(2-methoxyethoxy)ethyl)piperazin-1-yl)phenyl, 3-dimethylaminomethyl-phenyl, 4-dimethylaminomethylphenyl, 4-(4-methylpiperazin-1-yl)phenyl, 4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl or 2-imino-2-oxo-λ 6 -thiaspiro[3.3]hept-6-yl.

[0575] 193. In embodiment 193, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 121 and 190, wherein R 7 is 2,2-dioxo-2-thiaspiro[3.3]heptane-6-yl, 3,3-dioxo-3-thiabicyclo[3.1.0]hexane-6-yl, 2,2-dioxohexahydro-1H-cyclopenta[c]thiophen-5-yl or 2-imino-2-oxo-λ 6 -thiaspiro[3.3]hept-6-yl.

[0576] 194. In embodiment 194, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 121, wherein R 7 is a ring having formula (I) or (ii):

[0577]

[0578] Where alk is an alkyl group and each ring is R v and R w replace.

[0579] 195. In embodiment 195, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 121 and 195, wherein R 7 is a ring having formula (I):

[0580]

[0581] wherein alk is an alkyl group and the ring of formula (I) is replaced by R v and R w replace.

[0582] 196. In embodiment 196, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 121 and 196, wherein R 7 is a ring having formula (I):

[0583]

[0584] Where alk is an alkyl group, R v is hydrogen, and R w is fluoro or methyl attached to the carbon in the meta position to the carbon substituted by -SO2alk.

[0585] 197. In embodiment 197, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 121 and 194, wherein R 7 is a ring having formula (I):

[0586]

[0587] Where alk is an alkyl group, and R 4 and R 5 It's hydrogen.

[0588] 198. In embodiment 198, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 121 and 194, wherein R 7 is a ring with the formula:

[0589]

[0590] 199. In embodiment 199, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 121 and 194, wherein R 7 is a ring having formula (ii):

[0591]

[0592] wherein the ring of formula (ii) is R v and R w replace.

[0593] 200. In embodiment 200, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 121 and 194, wherein R 7 is a ring with the formula:

[0594]

[0595] 201. In embodiment 201, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 121, wherein R 7 is a ring having formula (iii) or (iv):

[0596]

[0597] Each ring is R v and R w replace.

[0598] 202. In embodiment 202, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 121 and 201, wherein R 7 is a ring with the formula:

[0599]

[0600] 203. In embodiment 203, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 121, wherein R 7 is a ring with the formula:

[0601]

[0602] 204. In embodiment 204, a compound disclosed in Table 1.

[0603] It is to be understood that the embodiments set forth above include all combinations of the embodiments listed therein.

[0604] Additional embodiments include embodiments 1A to 84A:

[0605] 1A. In embodiment 1A, there is provided a compound of formula (I) as defined in the first aspect.

[0606] 2A. In embodiment 2A, the compound, or a pharmaceutically acceptable salt thereof, is as provided in embodiment 1A, wherein:

[0607] yes

[0608] 3A. In Embodiment 3A, the compound, or a pharmaceutically acceptable salt thereof, as provided in Embodiments 1A or 2A, has a structure according to Formula (Ia) and (Ia'), respectively:

[0609]

[0610] 4A. In Embodiment 4A, the compound, or a pharmaceutically acceptable salt thereof, as provided in any one of Embodiments 1A to 3A, has a structure according to Formula (Id) and (Id'), respectively:

[0611]

[0612]

[0613] 5A. In embodiment 5A, the compound, or a pharmaceutically acceptable salt thereof, is as provided in any one of embodiments 1A to 4A, wherein R 1 、R 2 and R 3 and R is independently hydrogen, deuterium, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, or cyano.

[0614] 6A. In embodiment 6A, the compound, or a pharmaceutically acceptable salt thereof, is as provided in any one of embodiments 1A to 5A, wherein R 1 、R 2 and R 3 and 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34

[0615] 7A. In embodiment 7A, the compound, or a pharmaceutically acceptable salt thereof, is as provided in any one of embodiments 1A to 6A, wherein R 1 and R 2 are independently hydrogen, deuterium, fluorine, chlorine, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, methoxy, hydroxyl or cyano, and R 3 It's hydrogen.

[0616] 8A. In embodiment 8A, the compound, or a pharmaceutically acceptable salt thereof, is as provided in any one of embodiments 1A to 7A, wherein R 1 is fluorine, R 2 is hydrogen, deuterium, fluorine, chlorine, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy or cyano, and R 3 It's hydrogen.

[0617] 9A. In embodiment 9A, the compound, or a pharmaceutically acceptable salt thereof, is as provided in any one of embodiments 1A to 8A, wherein R 1 is fluorine, and R 2 and R 3 It's hydrogen.

[0618] 10A. In embodiment 10A, the compound, or a pharmaceutically acceptable salt thereof, is as provided in any one of embodiments 1A to 9A, wherein R 4 and R 5 Together with the nitrogen atom to which they are attached, they form a cyclic amine group, a bicyclic amine group, a fused cyclic amine group, a bridged cyclic amine group, or a spiroamine group, wherein the cyclic amine group, the bicyclic amine group, the fused cyclic amine group, the bridged cyclic amine group, and the spiroamine group are R s 、R t , and R u replace.

[0619] 11A. In embodiment 11A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 10A, wherein R 4 and R 5 Together with the nitrogen atom to which they are attached, they form the s 、R t , and R u Substituted fused cyclic amine group.

[0620] 12A. In embodiment 12A, the compound, or a pharmaceutically acceptable salt thereof, is provided as any one of embodiments 1A to 11A, wherein R 4 and R 5 The fused cyclic amine groups formed together with the nitrogen atom to which they are attached have a structure according to formula (a):

[0621]

[0622] in:

[0623] p is 0, 1 or 2; and q is 0, 1, 2, 3 or 4; provided that p + q is at least 2 and p + q is not greater than 5; and when p or q is 3 or 4, then one of such p or q -CH2- may be replaced by NH, N (when attached to R s 、R t , and Ru ), O or S(O)n; wherein n is 0, 1 or 2; and

[0624] The structure of formula (a) is R s 、R t , and R u replace.

[0625] 13A. In embodiment 13A, the compound, or a pharmaceutically acceptable salt thereof, is provided as any one of embodiments 1A to 11A, wherein R 4 and R 5 The fused cyclic amine groups formed together with the nitrogen atom to which they are attached have a structure according to formula (b):

[0626]

[0627] in:

[0628] p1 is 0, 1 or 2; and q1 is 0, 1, 2, 3 or 4; provided that p+q is at least 2 and p+q is not greater than 5; and when p or q is 3 or 4, then one of such p or q -CH2- may be replaced by NH, N (when attached to R s 、R t , and R u ), O or S(O) n Substitution; wherein n is 0, 1 or 2;

[0629] Het is a 5-membered or 6-membered heteroaryl; and

[0630] The structure of formula (b) is R s 、R t , and R u replace.

[0631] 14A. In embodiment 14A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 13A, wherein R 4 and R 5 Together with the nitrogen atom to which they are attached, they form a ring selected from:

[0632]

[0633] Each ring is R s 、R t , and R u replace.

[0634] 15A. In embodiment 15A, the compound, or a pharmaceutically acceptable salt thereof, is provided as any one of embodiments 1A to 14A, wherein R 4 and R 5The fused cyclic amine groups formed together with the nitrogen atom to which they are attached are selected from:

[0635]

[0636] Each ring is R s 、R t , and R u replace.

[0637] 16A. In embodiment 16A, the compound, or a pharmaceutically acceptable salt thereof, is provided as any one of embodiments 1A to 15A, wherein R 4 and R 5 The fused cyclic amine groups formed together with the nitrogen atom to which they are attached are selected from:

[0638]

[0639] Each ring is R s 、R t , and R u replace.

[0640] 17A. In embodiment 17A, the compound, or a pharmaceutically acceptable salt thereof, is provided as any one of embodiments 1A to 15A, wherein R 4 and R 5 The fused cyclic amine groups formed together with the nitrogen atom to which they are attached are selected from:

[0641]

[0642] Each ring is R s 、R t , and R u replace.

[0643] 18A. In embodiment 18A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 12A and 14A to 16A, wherein R 4 and R 5 The fused cyclic amine groups formed together with the nitrogen atom to which they are attached are rings having the formula (a1) or (a2):

[0644]

[0645] 19A. In embodiment 19A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 18A, wherein R sis hydrogen, deuterium, alkyl, alkoxy, alkylsulfonyl, hydroxy, acyl, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, substituted amino, alkoxycarbonylaminoalkyl, aminocarbonyl, aminocarbonylalkyl, cyano, hydroxyalkyl, hydroxyalkoxy, alkoxyalkyl, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, cyanoalkyl, cyanoalkoxy, cycloalkyl, cycloalkoxy, aryl, aryloxy, aralkyl, heteroaryl, heteroaryloxy, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, or unsubstituted heterocyclyl (wherein aryl by itself or as part of aryloxy and aralkyl, heteroaryl by itself or as part of heteroaryloxy and heteroaralkyl, heterocyclyl by itself or as part of heterocyclylalkyl and heterocyclyloxy, and unsubstituted heterocyclyl are substituted with one to three substituents independently selected from hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, and cyano), t is hydrogen, alkyl, alkoxy, alkylsulfonyl, hydroxy, acyl, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, and cyano, and R u It's hydrogen.

[0646] 20A. In embodiment 20A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 19A, wherein R s selected from hydrogen, deuterium, methyl, ethyl, isopropyl, cyclopropyl, cyclohexyl, methoxy, ethoxy, isopropoxy, methylsulfonyl, ethylsulfonyl, hydroxy, methylcarbonyl, fluorine, chlorine, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, amino, methylamino, dimethylamino, cyano, cyanomethyl, 2-cyanopropan-2-yl, cyanomethyloxy, hydroxymethyl, 1-hydroxyethyl, 1-hydroxy-1-methylethyl, methoxymethyl, methylaminomethyl 1-methyl-2-oxo-1,6-dihydropyridinyl, and morpholin-4-ylmethyl, R t is hydrogen, fluorine, chlorine, methoxy, difluoromethyl, difluoromethoxy, trifluoromethyl, trifluoromethoxy or cyano, and R u It's hydrogen.

[0647] 21A. In embodiment 21A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 20A, wherein R 4 and R 5Together with the nitrogen atom to which they are attached, they form a ring selected from the group consisting of morpholin-4-yl, piperidin-1-yl, 2-methylpiperidin-1-yl, 3-methylpiperidin-1-yl, 4-methylpiperidin-1-yl, 4-phenoxypiperidin-1-yl, 2-phenylpiperidin-1-yl, 2-phenylpyrrolidin-1-yl, 3,3-difluoropyrrolidin-1-yl, 4-phenylpiperazin-1-yl, 4-acetylpiperazin-1-yl, 4-Methyl-3-oxo-piperazin-1-yl, 4-methylsulfonylpiperazin-1-yl, 3-azabicyclo[3.1.0]hexan-3-yl, azaspiro[2.4]heptane-5-yl, 2-azaspiro[4.4]nonan-2-yl, 6-azaspiro[3.4]octan-6-yl, 5-azaspiro[2.4]heptane-5-yl, 7-azabicyclo[2.2.1]heptane-7-yl, 8-aza Bicyclo[3.2.1]octan-8-yl, 2-azabicyclo[2.2.2]octan-2-yl, 3-azabicyclo[3.2.2]nonan-3-yl, isoindolin-2-yl, 4-cyanoisoindolin-2-yl, 5-cyanoisoindolin-2-yl, 4-methoxyisoindolin-2-yl, 5-methoxyisoindolin-2-yl, 4-ethoxyisoindolin-2-yl, 4-isopropoxyisoindolin-2-yl isoindolyl, 5,6-dimethoxyisoindolyl, 5-hydroxymethylisoindolyl, 4-difluoromethylisoindolyl, 5-difluoromethylisoindolyl, 4-difluoromethoxyisoindolyl, 4-trifluoromethylisoindolyl, 5-trifluoromethylisoindolyl, 4-fluoroisoindolyl, 5-fluoroisoindolyl, 5,6-difluoroisoindolin-2-yl, 1-methylisoindolin-2-yl, 4-methylaminocarbonylisoindolin-2-yl, 4-dimethylaminocarbonylisoindolin-2-yl, 5-dimethylaminocarbonylisoindolin-2-yl, 4-(2-(dimethylamino)ethoxy)isoindolin-2-yl, 4-(2-(methylamino)ethoxy)isoindolin-2-yl, 4-dimethylaminomethylisoindolin-2-yl, 5-dimethylaminomethylisoindolin-2-yl, 4-methylaminomethylisoindolin-2-yl, 4-dimethylaminoisoindolin-2-yl, 4-methylaminoisoindolin-2-yl, 3-phenylisoindolin-2-yl, 4-phenylisoindolin-2-yl, 4-phenoxyisoindolin -2-yl, 1-benzylisoindolin-2-yl, 4-benzylisoindolin-2-yl, 4-(3-fluorophenoxy)isoindolin-2-yl, 4-(4-fluorophenoxy)isoindolin-2-yl, 4-(2-cyanophenoxy)-isoindolin-2-yl, 4-(3-cyanophenoxy)-isoindolin-2-yl, 4-cyclohexylisoindolin-2-yl, 5-(hydroxymethyl)isoindolin-2-yl, 4-(2-hydroxy-ethoxy)isoindolin-2-yl, 4-(2-aminoethoxy)-isoindolin-2-yl, 5-(cyanomethyl)isoindolin-2-yl, 4-(cyanomethyl)isoindolin-2-yl, indolin-1-yl, 2-methylindolin-1-yl, 4-cyanoindolin-1-yl , 5-cyanoindolyl, 6-cyanoindolyl, 4-hydroxy-methylindolyl, 6-difluoromethylindolyl, 4-trifluoromethylindolyl, 5-trifluoromethylindolyl, 6-trifluoromethylindolyl, 6-methoxyindolyl, 5-chloro-indolyl, 6-chloro-indolyl, 6-dimethylaminoindolyl, 6-fluoroindolyl, 5,6-difluoroindolyl, 4,6-difluoroindolyl, 4,5-difluoroindolyl, 6-difluoromethoxy-indolyl, 6-trifluoromethoxyindolyl, 4-((dimethylamino)-methyl)indolyl- 1-yl, 5-((dimethyl-amino)methyl)indolin-1-yl, 6-((dimethylamino)methyl)indolin-1-yl, 4-((methylamino)-methyl)indolin-1-yl, 5-((methylamino)methyl)indolin-1-yl, 6-((methylamino)-methyl)indolin-1-yl, 6-methylaminocarbonylindolin-1-yl, 6-aminocarbonyl-indolin-1-yl, 6-dimethylamino-carbonylindolin-1-yl, 4-(2-(methylamino)ethoxy)indolin-1-yl, 6-(2-(dimethylamino)ethoxy)-indolin-1-yl, 4-(hydroxymethyl)indolin-1-yl, 5-phenylindolin-1-yl, 6-(1-methyl-6-oxo-1,6-dihydropyridin-2-yl)indolin-1-yl, 4-(1-hydroxyethyl)indolin-1-yl, 4-(2-hydroxypropan-2-yl)-indolin-1-yl, 6-(2-hydroxypropan-2-yl)indolin-1-yl, 4-(cyanomethyl)indolin-1-yl, 6-(2-cyanopropan-2-yl)indolin-1-yl, 4-(morpholinomethyl)indolin-1-yl, 4-methoxycarbonyl-aminomethylindolin-1-yl, 7-(methylamino)indolin-1-yl, 6-(methylsulfonyl)indolin-1-yl, 6-chloroindolin-1-yl, 3,4-dihydroisoquinolin-2(1H)-yl, 1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl, 2,3 ,4,5-tetrahydro-1H-benzo[b]azepin-1-yl, 2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl, 4-methyl-3,4-dihydroquinoxalin-1(2H)-yl, 1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl, 3,4-dihydroquinoxalin-1(2H)-yl, 2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl, 1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl, 1-methyl-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl, and 2,3-dihydro-benzo[e][1,4]oxazepin-1(5H)-yl. ,

[0648] 22A. In embodiment 22A, the compound, or a pharmaceutically acceptable salt thereof, is as provided in any one of embodiments 1A to 21A, wherein R 4 and R 5Together with the nitrogen atom to which they are attached, they form a ring selected from the group consisting of isoindolin-2-yl, 4-cyanoisoindolin-2-yl, 5-cyanoisoindolin-2-yl, 4-methoxyisoindolin-2-yl, 5-methoxyisoindolin-2-yl, 4-ethoxyisoindolin-2-yl, 4-isopropoxyisoindolin-2-yl, 5,6-dimethoxyisoindolin-2-yl, 5-hydroxymethylisoindolin-2-yl, 4-difluoromethylisoindolin-2-yl, 5-difluoromethylisoindolin-2-yl, 4-difluoromethoxyisoindolin-2-yl, 4-trifluoromethylisoindolin-2-yl, 5-trifluoromethylisoindolin-2-yl, 4-fluoroisoindolin-2-yl, 5 -Fluoroisoindolin-2-yl, 5,6-difluoroisoindolin-2-yl, 1-methylisoindolin-2-yl, 4-methylamino-carbonylisoindolin-2-yl, 4-dimethylaminocarbonylisoindolin-2-yl, 5-dimethylaminocarbonylisoindolin-2-yl, 4-(2-(dimethylamino)ethoxy)-isoindolin-2-yl, 4-(2-(methylamino)ethoxy)-isoindolin-2-yl, 4-dimethylaminomethylisoindolin-2-yl, 5-dimethylaminomethylisoindolin-2-yl, 4-methylaminomethylisoindolin-2-yl, 4-dimethyl-aminoisoindolin-2-yl, 4-methylaminoisoindolin-2-yl, 3-phenylbenzene 1-Benzylisoindolin-2-yl, 4-phenylisoindolin-2-yl, 4-phenoxyisoindolin-2-yl, 1-benzylisoindolin-2-yl, 4-benzylisoindolin-2-yl, 4-(3-fluorophenoxy)isoindolin-2-yl, 4-(4-fluorophenoxy)-isoindolin-2-yl, 4-(2-cyanophenoxy)isoindolin-2-yl, 4-(3-cyanophenoxy)-isoindolin-2-yl, 4-cyclohexylisoindolin-2-yl, 5-(hydroxymethyl)isoindolin-2-yl, 4-(2-hydroxyethoxy)isoindolin-2-yl, 4-(2-aminoethoxy)isoindolin-2-yl, 5-(cyanomethyl)-isoindolin-2-yl, 4-(Cyanomethyl)isoindolin-2-yl, indolin-1-yl, 2-methylindolin-1-yl, 4-cyanoindolin-1-yl, 5-cyanoindolin-1-yl, 6-cyanoindolin-1-yl, 4-hydroxymethylindolin-1-yl, 6-difluoromethylindolin-1-yl, 4-trifluoromethylindolin-1-yl, 5-trifluoromethylindolin-1-yl, 6-trifluoromethylindolin-1-yl, 6-methoxyindolin-1-yl, 5-chloroindolin-1-yl, 6-chloroindolin-1-yl, 6-dimethylaminoindolin-1-yl, 6-fluoroindolin-1-yl, 5,6-difluoroindolin-1-yl, 4,6-difluoroindolin-1-yl, 4,5-difluoroindolin-1-yl, 6-difluoromethoxyindolin-1-yl, 6-trifluoromethoxyindolin-1-yl, 4-((dimethylamino)methyl)-indolin-1-yl, 5-((dimethyl-amino)methyl)indolin-1-yl, 6-((dimethyl-amino)methyl)indolin-1-yl, 4-((methylamino)-methyl)indolin-1-yl, 5-((methylamino)methyl)-indolin-1-yl, 6-((methylamino)-methyl)indolin-1-yl, 6-methylaminocarbonylindolin-1-yl, 6-aminocarbonyl-indolin-1-yl , 6-dimethylamino-carbonylindolin-1-yl, 4-(2-(methylamino)ethoxy)-indolin-1-yl, 6-(2-(dimethylamino)ethoxy)-indolin-1-yl, 4-(hydroxymethyl)indolin-1-yl, 5-phenylindolin-1-yl, 6-(1-methyl-6-oxo-1,6-dihydropyridin-2-yl)indolin-1-yl, 4-(1-hydroxyethyl)-indolin-1-yl, 4-(2-hydroxypropan-2-yl)indolin-1-yl, 6-(2-hydroxypropan-2-yl)indolin-1-yl, 4-(cyanomethyl)- Indolin-1-yl, 6-(2-cyanopropan-2-yl)indolin-1-yl, 4-(morpholinomethyl)indolin-1-yl, 4-methoxycarbonyl-aminomethylindolin-1-yl, 7-(methylamino)indolin-1-yl, 6-(methylsulfonyl)indolin-1-yl, 6-chloroindolin-1-yl, 3,4-dihydroisoquinolin-2-yl, 1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl, 2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl, 2,3-dihydro-4H-benzo[b][1,4]oxazine- 4-yl, 4-methyl-3,4-dihydroquinoxalin-1(2H)-yl, 1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl, 3,4-dihydroquinoxalin-1(2H)-yl, 2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl, 1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl, 1-methyl-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl, and 2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)-yl.

[0649] 23A. In embodiment 23A, the compound, or a pharmaceutically acceptable salt thereof, is as provided in any one of embodiments 1A to 22A, wherein W is N.

[0650] 24A. In embodiment 24A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 23A, wherein R 9 and R 10are independently alkyl, cycloalkyl, bridged cycloalkyl, spirocycloalkyl, heterocyclyl, bridged heterocyclyl, or spiroheterocyclyl, wherein:

[0651] (A)R 9 and R 10 The cycloalkyl, bridged cycloalkyl, and spirocycloalkyl groups are replaced by one or two R a Replacement; and

[0652] (B)R 9 and R 10 The heterocyclic group, bridged heterocyclic group, and spiro heterocyclic group in R b 、R c , and R d replace.

[0653] 25A. In embodiment 25A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 24A, wherein R 9 and R 10 It is an alkyl group.

[0654] 26A. In embodiment 26A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 25A, wherein R 9 and R 10 is methyl, ethyl, propyl or butyl.

[0655] 27A. In embodiment 27A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 26A, wherein R 9 and R 10 is isopropyl, isobutyl, sec-butyl or tert-butyl.

[0656] 28A. In embodiment 28A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 24A, wherein R 9 and R 10 are independently cycloalkyl, bridged cycloalkyl, or spirocycloalkyl, wherein R 9 and R 10 The cycloalkyl, bridged cycloalkyl, and spirocycloalkyl groups are replaced by one or two R a replace.

[0657] 29A. In embodiment 29A, the compound, or a pharmaceutically acceptable salt thereof, is as provided in any one of embodiments 1A to 24A and 27A to 28A, wherein one or both R a are independently selected from hydrogen, deuterium, methyl, trideuterated methyl, fluorine, chlorine, difluoromethyl, trifluoromethyl, and cyano.

[0658] 30A. In embodiment 30A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 24A and 27A to 29A, wherein R 9 and R 10 are independently cycloalkyl and bridged cycloalkyl, each ring being surrounded by one or two R a replace.

[0659] 31A. In embodiment 31A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 24A and 27A to 30A, wherein R 9 and R 10 Is one or two R a Substituted cycloalkyl.

[0660] 32A. In embodiment 32A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 24A and 27A to 30A, wherein R 9 and R 10 Is one or two R a Substituted bridged cycloalkyl.

[0661] 33A. In embodiment 33A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 24A, wherein R 9 and R 10 are independently heterocyclic, bridged heterocyclic, or spiroheterocyclic, wherein R 9 and R 10 The heterocyclic group, bridged heterocyclic group, and spiro heterocyclic group in R b 、R c , and R d replace.

[0662] 34A. In embodiment 34A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 24A and 33A, wherein R 9 and R 10 are independently heterocyclic or bridged heterocyclic, each of which is replaced by R b 、R c , and R d replace.

[0663] 35A. In embodiment 35A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 24A, 33A, and 34A, wherein R 9 and R 10 Is R b 、R c , and R d substituted heterocyclic group.

[0664] 36A. In embodiment 36A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 24A, 33A, and 34A, wherein R 9 and R 10 Is R b 、R c , and R d Substituted bridged heterocyclyl.

[0665] 37A. In embodiment 37A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 24A, 28A to 35A, wherein R 9 and R 10 The cycloalkyl group and the bridged cycloalkyl group are selected from the group consisting of:

[0666]

[0667] And R 9 and R 10 The heterocyclic group and bridged heterocyclic group in are selected from:

[0668]

[0669] wherein each cycloalkyl group and bridged cycloalkyl group is replaced by R a and each heterocyclic group and bridged heterocyclic group is replaced by R b 、R c and R d replace.

[0670] 38A. In embodiment 38A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 24A, 28A to 31A, and 37A, wherein ring R 9 and R 10 The cycloalkyl group is selected from:

[0671]

[0672] Each cycloalkyl group is replaced by one or two R a replace.

[0673] 39A. In embodiment 39A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 24A, 28A to 30A, 32A, and 37A, wherein R 9 and R 10 The bridged cycloalkyl group in is selected from:

[0674]

[0675] wherein each bridged cycloalkyl group is R a replace.

[0676] 40A. In embodiment 40A, the compound, or a pharmaceutically acceptable salt thereof, is provided as any one of embodiments 1A to 24A, 29A, 33A, 34A, 35A, and 37A, wherein R 9 and R 10 The heterocyclic group is selected from:

[0677]

[0678] Each heterocyclic group is R b 、R c and R d replace.

[0679] 41A. In embodiment 41A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 24A, 29A, 33A, 34A, 36A, and 37A, wherein R 9 and R 10 The bridged heterocyclic group in is selected from:

[0680]

[0681] wherein each bridged heterocyclic group is R b 、R c and R d replace.

[0682] 42A. In embodiment 42A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 24A, 28A to 32A, and 37A to 39A, wherein R a is hydrogen, deuterium, chlorine, fluorine, difluoromethyl or trifluoromethyl.

[0683] 43A. In embodiment 43A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 24A, 28A to 32A, 37A to 39A, and 42A, wherein R 9 and R 10 The bridged cycloalkyl group in which R is bicyclo[1.1.1]pentan-1-yl, 3-fluorobicyclo[1.1.1]pentan-1-yl, 3-chlorobicyclo-[1.1.1]pentan-1-yl, 3-(hydroxymethyl)-bicyclo[1.1.1]pentan-1-yl, 3-(trifluoromethyl)-bicyclo[1.1.1]pentan-1-yl, 3-(difluoromethyl)-bicyclo[1.1.1]pentan-1-yl, and R 9 and R 10 The cycloalkyl group in is cyclobutyl, cyclopropyl, 1-(difluoromethyl)cyclobutyl, 1-(trifluoromethyl)cyclobutyl, 1-(difluoromethyl)cyclopropyl or 1-(trifluoromethyl)cyclopropyl.

[0684] 44A. In embodiment 44A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 24A, 29A, and 33A to 43A, wherein R b and R c are independently selected from hydrogen, methyl, fluorine, chlorine, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, hydroxyl, and cyano, and R d Selected from hydrogen, methyl, trideuterated methyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, amino, dimethylamino, diethylamino, 3,3-difluorocyclobutyl, 4,4-difluorocyclohexyl, 3-hydroxy-3-methylcyclobutyl, 3-cyano-3-methylcyclobutyl, oxetan-3-yl, tetrahydrofuran-2-yl, tetrahydropyran-4-yl, 1,1-dioxosulfurized cyclopropane-3-yl, 1,1-dioxotetrahydro-2H-thiopyran-4-yl, benzyl, phenyl, pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl.

[0685] 45A. In embodiment 45A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 24A, 29A, 33A to 44A, wherein R b is hydrogen, R c is selected from hydrogen, methyl, fluorine, chlorine, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, hydroxyl, and cyano, and R d Selected from hydrogen, methyl, trideuterated methyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, amino, dimethylamino, diethylamino, 3,3-difluorocyclobutyl, 4,4-difluorocyclohexyl, 3-hydroxy-3-methylcyclobutyl, 3-cyano-3-methylcyclobutyl, oxetan-3-yl, tetrahydrofuran-2-yl, tetrahydropyran-4-yl, 1,1-dioxosulfurized cyclopropane-3-yl, 1,1-dioxotetrahydro-2H-thiopyran-4-yl, benzyl, phenyl, pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl.

[0686] 46A. In embodiment 46A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 45A, wherein R 7 Yes-Q-(alk 1 ) n1 -SO2R 11 、-Q 2 -(alk 3 ) n3 -SO2NR 14 R15 , heterocyclic group, bicyclic heterocyclic group, spiro heterocyclic group, or spiro sulfoximino group, wherein the heterocyclic group, bicyclic heterocyclic group, spiro heterocyclic group, and spiro sulfoximino group are R x 、R y , and R y1 replace.

[0687] 47A. In embodiment 47A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 45A, wherein R 7 is an aryl, heteroaryl, or fused heteroaryl group, wherein each of the above rings is replaced by R x 、R y , and R y1 replace.

[0688] 48A. In embodiment 48A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 46A, wherein R 7 Yes-Q-(alk 1 ) n1 -SO2R 11 .

[0689] 49A. In embodiment 49A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 46A, wherein R 7 Yes-Q 2 -(alk 3 ) n3 -SO2NR 14 R 15 .

[0690] 49B. In embodiment 49B, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1 to 46, wherein R 7 Is R x 、R y , and R y1 substituted heterocyclic group.

[0691] 50A. In embodiment 50A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 46A, wherein R 7 Is R x 、R y , and R y1 Substituted bicyclic heterocyclyl.

[0692] 51A. In embodiment 51A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 46A, wherein R 7 Is R x 、R y , and Ry1 Substituted spiroheterocyclyl.

[0693] 52A. In embodiment 52A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 46A, 48A, and 49A, wherein Q, Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , and Q 6 Each of the cycloalkyl, bridged cycloalkyl, spirocycloalkyl, heterocyclyl A , bicyclic heterocyclic group A , bridged heterocyclic group A , spiro heterocyclic group A , aryl, or heteroaryl, wherein each of the above rings is replaced by R v and R w replace.

[0694] 53A. In embodiment 53A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 46A, 48A, 49A, and 52A, wherein Q, Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , and Q 6 Each of them is R v and R w Substituted cycloalkyl.

[0695] 54A. In embodiment 54A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 46A, 48A, 49A, and 52A, wherein Q, Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , and Q 6 Each of them is R v and R w Substituted bridged cycloalkyl.

[0696] 55A. In embodiment 55A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 46A, 48A, 49A, and 52A, wherein Q, Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , and Q 6 Each of them is R v and R wSubstituted heterocyclic group A .

[0697] 56.A In embodiment 56A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 46A, 48A, 49A, and 52A, wherein Q, Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , and Q 6 Each of them is R v and R w Substituted bicyclic heterocyclyl A .

[0698] 57A. In embodiment 57A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 46A, 48A, 49A, and 52A, wherein Q, Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , and Q 6 Each of the above rings is an aryl or heteroaryl group, wherein each of the above rings is replaced by R v and R w replace.

[0699] 58A. In embodiment 58A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 46A, 48A, 49A, and 52A to 57A, wherein n 1 、n 2 、n 3 、n 4 、n 5 、n 6 , and n 7 Each of is 0.

[0700] 59A. In embodiment 59A, the compound, or a pharmaceutically acceptable salt thereof, is as provided in any one of embodiments 1A to 58A, wherein

[0701] (1) Q, Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , and Q 6 Each of which is independently selected from:

[0702]

[0703]

[0704] Each ring in (1) is R v and R w replace;

[0705] and

[0706] (2).R 7 The heterocyclic, bicyclic, spiro heterocyclic, bridged heterocyclic, cyclic sulfoximino, spiro sulfoximino, aryl, heteroaryl and fused heteroaryl groups in are wherein:

[0707] A bridged heterocyclic group is:

[0708]

[0709] Bicyclic heterocyclyl is:

[0710]

[0711] Spiroheterocyclyl is:

[0712]

[0713] Heterocyclyl is:

[0714]

[0715] The spirosulfoximino group is:

[0716]

[0717] The cyclic sulfoximine group is:

[0718]

[0719] A fused heteroaryl group is:

[0720]

[0721] Each ring in (2) is R x 、R y and R y1 replace; and wherein In the compound of formula (I) -NHR 7 part of the NH bond; and Expressed to -Q-(alk 1 ) n1 -SO2R 11 、-Q 1 -(alk 2 ) n2 -SO(=NR 12 )R 13 、-Q 2 -(alk3 ) n3 -SO2NR 14 R 15 、-Q 3 -(alk 4 ) n4 -COR 16 、-Q 4 -(alk 5 ) n5 -CONR 17 R 18 、-Q 5 -(alk 6 ) n6 - NR 19 COR 20 , or -Q 6 -(alk 6 ) n7 -NR 21 SO2R 22 The rest of the keys.

[0722] 60A. In embodiment 60A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 59A, wherein R 7 Among them:

[0723] (1).Q,Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , and Q 6 Each of these is:

[0724]

[0725] Each ring in (1) is R v and R w Replacement; and

[0726] (2).R 7 The heterocyclic, bicyclic, spiro heterocyclic, bridged heterocyclic, cyclic sulfoximino, spiro sulfoximino, aryl, heteroaryl and fused heteroaryl groups in are wherein:

[0727] Heterocyclyl is:

[0728] Spiroheterocyclyl is:

[0729]

[0730] A bridged heterocyclic group is:

[0731]

[0732] Bicyclic heterocyclyl is:

[0733]

[0734] The spirosulfoximino group is:

[0735]

[0736] The cyclic sulfoximine group is:

[0737]

[0738] A fused heteroaryl group is:

[0739]

[0740] Each ring in (2) is R x 、R y and R y1 replace; and

[0741] in represents a bond to the NH of the -NHR7 moiety in the compound of formula (I) and Expressed to -Q-(alk 1 ) n1 -SO2R 11 、-Q 1 -(alk 2 ) n2 -SO(=NR 12 )R 13 、-Q 2 -(alk 3 ) n3 -SO2NR 14 R 15 、-Q 3 -(alk 4 ) n4 -COR 16 、-Q 4 -(alk 5 ) n5 -CONR 17 R 18 、-Q 5 -(alk 6 ) n6 - NR 19 COR 20 , or -Q 6 -(alk 6 ) n7 -NR 21 SO2R 22The rest of the keys.

[0742] 61A. In embodiment 61A, the compound, or a pharmaceutically acceptable salt thereof, is as provided in any one of embodiments 1A to 60A, wherein:

[0743] (1).Q,Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , and Q 6 Each of these is:

[0744]

[0745] Each ring in (1) is R v and R w Replace, and In the compound of formula (I) -NHR 7 Part of the NH bond and Expressed to -Q-(alk 1 ) n1 -SO2R 11 、-Q 1 -(alk 2 ) n2 -SO(=NR 12 )R 13 、-Q 2 -(alk 3 ) n3 -SO2NR 14 R 15 、-Q 3 -(alk 4 ) n4 -COR 16 、-Q 4 -(alk 5 ) n5 CONR 17 R 18 、-Q 5 -(alk 6 ) n6 - NR 19 COR 20 , or -Q 6 -(alk 6 ) n7 -NR 21 SO2R 22 the remainder of the key; and

[0746] (2).R 7The heterocyclic, bicyclic heterocyclic, spiroheterocyclic, spirosulfoximino, aryl, and heteroaryl groups are wherein:

[0747]

[0748] Each ring in (2) is R x 、R y and R y1 Replace, and In the compound of formula (I) -NHR 7 Part of the NH bond and Indicates attachment to R x 、R y and R y1 one of the.

[0749] 62A. In embodiment 62A, the compound, or a pharmaceutically acceptable salt thereof, is as provided in any one of embodiments 1A to 61A, wherein Q, Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , and Q 6 Each of these is:

[0750]

[0751] Each ring in (1) is R v and R w replace.

[0752] 63A. In embodiment 63A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 46A, 47A, 49B to 51A, and 58A to 62A, wherein R 7 The heterocyclic, bicyclic, spiroheterocyclic, bridged, cyclic, sulfoximino, spirosulfoximino, aryl, heteroaryl, and fused heteroaryl groups are wherein:

[0753]

[0754] Each ring in (2) is R x 、R y and R y1 replace.

[0755] 64A. In embodiment 64A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 46A, 47A, 49B to 51A, and 58A to 63A, wherein R 7The heterocyclic, bicyclic, spiroheterocyclic, bridged, cyclic, sulfoximino, spirosulfoximino, aryl, heteroaryl, and fused heteroaryl groups are wherein:

[0756]

[0757] Each ring is R x 、R y and R y1 replace.

[0758] 65A. In embodiment 65A, the compound, or a pharmaceutically acceptable salt thereof, is provided as any one of embodiments 1A to 46A, 47A, 49B to 51A, and 58A to 64A wherein R 7 The heterocyclic group in is: And R x 、R y and R y1 replace.

[0759] 66A. In embodiment 66A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 46A, 47A, 49B to 51A, and 58A to 62A, wherein R 7 The spiro heterocyclic group in And R x 、R y and R y1 replace.

[0760] 67A. In embodiment 67A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 46A, 47A, 49B to 51A, and 58A to 62A, wherein R 7 The bicyclic heterocyclic group in is:

[0761] And each ring is R x 、R y and R y1 replace.

[0762] 68A. In embodiment 68A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 46A, 47A, 49B to 51A, and 58A to 62A, wherein R 7 The aryl group in is: And R x 、R y and R y1 replace.

[0763] 69A. In embodiment 69A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 46A, 47A, 49B to 51A, and 58A to 62A, wherein R 7 The bicyclic heterocyclic group in is: And each ring is R x 、R y and R y1 replace.

[0764] 70A. In embodiment 70A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 45A and 52A to 69A, wherein R 12 、R 19 and R 21 It's hydrogen.

[0765] 71A. In embodiment 71A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 45A and 52A to 69A, wherein R 12 、R 19 and R 21 is methyl, ethyl or propyl.

[0766] 72A. In embodiment 72A, the compound, or a pharmaceutically acceptable salt thereof, is as provided in any one of embodiments 1A to 46A, 48A, 49A, and 52A to 71A, wherein

[0767] R 11 、R 16 、R 20 , and R 22 independently selected from alkyl, fluoro, chloro, -CR 23 =CR 24 R 25 or heterocyclyl substituted with one to three substituents independently selected from hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cyano, and heterocyclyl;

[0768] R 13 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl; and

[0769] R 14 、R 15 、R 17 , and R 18 independently selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, or heterocyclyl, substituted with one to three substituents independently selected from hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, and cyano.

[0770] 73A. In embodiment 73A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 46A, 48A, 49A, and 52A to 73A, wherein R 11 is methyl, ethyl, piperazinyl, 4-methylpiperazinyl or 4-ethylpiperazin-1-yl; R 14 is hydrogen, methyl or ethyl, R 15 is hydrogen, methyl, ethyl, aminoethyl, methylaminoethyl, dimethylaminoethyl, diethylaminoethyl, azetidin-3-yl, 1-methylazetidin-3-yl, 1-ethylazetidin-2-yl, 1-methylpyrrolidin-3-yl, 1-ethylpyrrolidin-3-yl, 1-methylpiperidinyl or 1-ethylpiperidinyl.

[0771] 74A. In embodiment 74A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 46A, 47A, 49B to 51A, and 52A to 73A, wherein R x 、R y , and R y1 where R x and R y are independently selected from hydrogen, deuterium, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, and cyano, and R y1 is hydrogen, deuterium, alkyl, alkoxy, hydroxy, acyl, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, substituted amino, alkoxycarbonylamino, alkoxycarbonylaminoalkyl, aminocarbonyl, aminocarbonylalkyl, cyano, hydroxyalkyl, hydroxyalkoxy, alkoxyalkyl, alkoxyalkyloxy, alkoxyalkyloxyalkyl, aminoalkyl, aminoalkoxy, aminoalkylamino, cyanoalkyl, cyanoalkoxy, cycloalkyl, cycloalkoxy, aryl, aryloxy, aralkyl, heteroaryl, heteroaryloxy, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy (wherein aryl by itself or as part of an aralkyl or aryloxy group, heteroaryl by itself or as part of both a heteroaryloxy and a heteroaralkyl group, and heterocyclyl by itself or as part of a heterocyclylalkyl, heterocyclyloxy or heterocyclylalkyloxy group are substituted with one to three substituents independently selected from the group consisting of hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, alkoxycarbonyloxy, alkoxyalkyl, alkoxyalkyloxyalkyl, cyano, and heterocyclyl).

[0772] 75A. In embodiment 75A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 46A, 47A, 49A to 51A, and 52A to 74A, wherein R x and R yare independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, haloalkoxy, and cyano, and R y1 is hydrogen, deuterium, alkyl, alkoxy, hydroxy, acyl, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, substituted amino, alkoxycarbonylamino, alkoxycarbonylaminoalkyl, aminocarbonyl, aminocarbonylalkyl, cyano, hydroxyalkyl, hydroxyalkoxy, alkoxyalkyl, alkoxyalkyloxy, alkoxyalkyloxyalkyl, aminoalkyl, aminoalkoxy, aminoalkylamino, cyanoalkyl, cyanoalkoxy, cycloalkyl, cycloalkoxy, aryl, aryloxy, aralkyl, heteroaryl, heteroaryloxy, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy (wherein aryl by itself or as part of an aralkyl or aryloxy group, heteroaryl by itself or as part of both a heteroaryloxy and a heteroaralkyl group, and heterocyclyl by itself or as part of a heterocyclylalkyl, heterocyclyloxy or heterocyclylalkyloxy group are substituted with one to three substituents independently selected from the group consisting of hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, alkoxycarbonyloxy, alkoxyalkyl, alkoxyalkyloxyalkyl, cyano, and heterocyclyl).

[0773] 76A. In embodiment 76A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 45A, wherein R 72,2-dioxo-2-thiaspiro[3.3]heptane-6-yl, 3,3-dioxo-3-thiabicyclo[3.1.0]hexane-6-yl, 4-(methylsulfonyl)-cyclohexyl, 2,2-dioxohexahydro-1H-cyclopenta[c]thien-5-yl, 1-(methylsulfonyl)piperidin-4-yl, 1-(methylaminosulfonyl)piperidin-4-yl, 1-(aminosulfonyl)piperidin-4-yl, 4-(piperazine -1-yl)phenyl, 4-(piperazin-1-ylsulfonyl)piperidin-4-yl, 1-(N-(2-dimethylaminoethyl)-N-methylaminosulfonyl)piperidin-4-yl, 4-(4-methylpiperazin-1-ylsulfonyl)piperidin-4-yl, 5-(piperazin-1-yl)pyridin-2-yl, 4-(piperazin-1-yl)phenyl, 1-(N-(azetidin-3-yl)-N-methylaminosulfonyl)piperidin-4-yl, 1- (N-(1-methylazetidin-3-yl)-N-methylaminosulfonyl)-piperidin-4-yl, 2-(methylsulfonyl)-2-azaspiro[3.3]heptan-6-yl, 4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl, 4-(2-(2-methoxyethoxy)ethyl)piperazin-1-yl)phenyl, 4-(4-(2-(2-methoxyethoxy)ethyl)piperazin-1-yl)phenyl, 3-dimethoxy- methylaminomethylphenyl, 4-methylsulfonylphenyl, 4-dimethylaminomethylphenyl, 4-(4-methylpiperazin-1-yl)phenyl, 4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl, 1-(piperazin-1-ylsulfonyl)piperidin-4-yl, 3-((methylsulfonyl)methyl)bicyclo[1.1.1]-pentan-1-yl, or 2-imino-2-oxo-2-thiaspiro[3.3]heptan-6-yl.

[0774] 77A. In embodiment 77A, the compound, or a pharmaceutically acceptable salt thereof, is provided as in any one of embodiments 1A to 45A, wherein R 7 is a ring with the formula:

[0775]

[0776] 78A. In embodiment 78A, a compound is provided, which is provided in Table 1.

[0777] 79A. In embodiment 79A, a pharmaceutical composition is provided, comprising a compound as provided in any one of embodiments 1A to 78A, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0778] 80A. In embodiment 80A, a method of inhibiting CDK2 is provided, comprising contacting CDK2 with a compound or a pharmaceutically acceptable salt thereof as provided in any one of embodiments 1A-78A, or with a pharmaceutical composition as provided in embodiment 79A.

[0779] 81A. In embodiment 81A, a method of treating a disease mediated by CDK2 in a patient is provided, comprising administering to a patient in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof as provided in any one of embodiments 1A-78A, or a pharmaceutical composition as provided in embodiment 79A.

[0780] 82A. In embodiment 82A, a method of treating cancer in a patient is provided, comprising administering to a patient in need thereof a therapeutically effective amount of a compound as provided in any one of embodiments 1A-78A or a pharmaceutically acceptable salt thereof in a pharmaceutical composition as provided in embodiment 79A.

[0781] 83A. In embodiment 83A, the method is as provided in embodiment 82A, wherein the compound provided in any one of embodiments 1A to 78A, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition provided in embodiment 79A is administered in combination with at least one other anticancer agent.

[0782] 84A. In embodiment 84A, the compound is provided as in embodiment 82A or 83A, wherein the cancer is lung cancer, skin cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, small intestine cancer, colon cancer, rectal cancer, anal cancer, endometrial cancer, stomach cancer, head and neck cancer, liver cancer, ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gallbladder cancer, pancreatic cancer, stomach cancer, thyroid cancer, or parathyroid cancer.

[0783] General synthetic scheme

[0784] Compounds having formula (I) can be prepared by the methods depicted in the reaction schemes shown below.

[0785] Starting materials and reagents used to prepare these compounds are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin), Bachem (Torrance, California), or Sigma (St. Louis, Missouri), or are prepared by methods known to those skilled in the art according to the procedures described in, for example, Fieser and Fieser's Reagents for Organic Synthesis, Vols. 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Vols. 1-5 and Supplements (Elsevier Science Publishers, 1989); Organic Reactions, Vols. 1-40 (John Wiley & Sons, 1991); and and Sons [John Wiley and Sons, 1991]); March's Advanced Organic Chemistry [John Wiley and Sons, 4th Edition] and Larock's Comprehensive Organic Transformations [Larock's Comprehensive Organic Transformations] (VCH Publishers Inc. [VCH Publishing Company], 1989]. These schemes are merely illustrative of some of the methods by which compounds of formula (I) may be synthesized, and various modifications may be made to these schemes and will be enlightening to those skilled in the art upon reading this disclosure. If desired, the starting materials and intermediates, as well as the final products of the reactions, may be separated and purified using conventional techniques (including, but not limited to, filtration, distillation, crystallization, chromatography, and the like). Such materials may be characterized using conventional means, including physical constants and spectral data.

[0786] Unless indicated to the contrary, the reactions described herein occur at atmospheric pressure, at a temperature range from about -78°C to about 150°C, such as from about 0°C to about 125°C, and further such as at about room temperature (or ambient temperature), such as about 20°C.

[0787] A compound of formula (I) wherein

[0788] yes W is N and R1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 9 and R A as defined in the Summary of the Invention (or any embodiment thereof disclosed above) can be prepared as illustrated and described in Scheme 1 below.

[0789] Solution 1

[0790]

[0791] Under conditions well known in the art, the nitrogen protecting group (PG 1 ) such as acetyl protected compound 1-1 (wherein R is an alkyl group such as methyl, and R 1 、R 2 , and R 3 As defined in the Summary of the Invention (or any embodiment thereof above) or its precursor group), an amino group is provided, providing a compound of formula 1-2. In the presence of a base (such as LiHMDS) under conditions known in the art with a pyrimidine compound of formula 1-3 (wherein X 1 Compound 1-2 is treated with a halogen (e.g., chlorine, bromine) to provide a ketone compound of formula 1-4. Compounds of formulas 1-1 and 1-3 are commercially available or can be prepared by methods well known in the art. For example, methyl 3-amino-2-fluorobenzoate, methyl 3-amino-4-fluorobenzoate, and ethyl 3-amino-2-fluorobenzoate are commercially available.

[0792] Compound 1-4 is halogenated with a suitable halogenating agent (such as NBS) under conditions known in the art, followed by reaction with a thioamide of formula 1-6 (wherein R 9 As defined in the Summary of the Invention (or any embodiment thereof above) or its precursor group (ie, can be converted to R as defined in the Summary of the Invention) 9 The obtained compound 1-5 (wherein X 2 Is halogen, such as chlorine, bromine) cyclization, providing a compound with formula 1-7. The reaction can be carried out in a suitable organic solvent (such as DMA, DMF) at high temperature. Compounds with formula 1-6 are commercially available, or they can be prepared by methods known in the art. For example, 2,2-dimethylthiopropionamide, 3-(trifluoromethyl)-bicyclo[1.1.1]pentane-1-thiocarboxamide, (1R, 5S)-3-methyl-3,8-diazabicyclo[3.2.1]octane-8-thiocarboxamide, thiourea are commercially available.

[0793] With an amine of formula 1-8 (wherein R 7 As defined in the Summary of the Invention (or any embodiment thereof above) or its precursor group) treatment of a compound of formula 1-7 provides a compound of formula 1-9. The reaction can be carried out in an organic solvent under alkaline conditions, such as in the presence of DIPEA, CsF, K2CO3, in DMSO or under Buchwald-type cross-coupling conditions. Typically, Buchwald-type cross-coupling conditions include a Pd catalyst, a ligand and a base, such as a combination of Pd-RuPhos G2 and Cs2CO3. Under conditions well known in the art, the amino protecting group PG in 1-9 is removed by treating the compound of formula 1-9 with a suitable reagent such as NaOH or HCl. 1 , providing an amine compound having formula 1-10. Amines having formula 1-8 are commercially available, or they can be prepared by methods known in the art. For example, tert-butyl 4-(4-aminophenyl)piperazine-1-carboxylate, 1-(methylsulfonyl)piperidin-4-amine, (1r,4r)-4-(methylsulfonyl)cyclohexane-1-amine, and 6-amino-2-thiaspiro[3.3]heptane 2,2-dioxide are commercially available.

[0794] Sulfonylamino compounds of formula 1-11 (wherein LG is a suitable leaving group, such as chlorine, oxazolidin-2-one) can be prepared from amino compounds of formula 1-10 under conditions known in the art. In an organic solvent, under basic conditions, such as in the presence of DIPEA, TEA, amine 1-12 (wherein R 4 and R 5 Compounds of formula 1-11 are treated as defined in the Summary of the Invention (or any embodiment thereof above) to provide compounds of formula (I). Amines of formula 1-12 are commercially available, or they can be prepared by methods known in the art. For example, indoline, isoindoline, dimethylamine, and piperidine are commercially available.

[0795] Alternatively, a compound of formula (I) wherein

[0796] yes W is N and R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 9 and R A as defined in the Summary of the Invention (or in any embodiment thereof above) can be prepared as illustrated and described in Scheme 2.

[0797] Option 2

[0798]

[0799] Treatment of compound 1-7 with a suitable thiol or thiolate (e.g., sodium thiomethoxide) under reaction conditions known in the art provides a methylthio compound of formula 2-1, which is converted to a compound of formula 2-4 by proceeding similarly to that described in Scheme 1 above. Oxidation of compound 2-4 with a suitable oxidizing agent (e.g., Oxone, mCPBA, etc.) provides a methylsulfonyl compound of formula 2-5. Compound 2-8 (wherein R 7 Compound 2-5 is treated as defined in the Summary of the Invention (or any embodiment thereof above) to provide a compound of formula (I). The reaction can be carried out in an organic solvent under basic conditions, such as in the presence of DIPEA, K2CO3, etc., in a suitable solvent (such as DMF, DMSO, etc.).

[0800] Alternatively, a compound of formula (I) wherein

[0801] yes W is N and R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 9 and R A as defined in the Summary of the Invention (or in any embodiment thereof above) can be prepared as illustrated and described in Scheme 3 below.

[0802] Option 3

[0803]

[0804] In an organic solvent, under alkaline conditions, such as in the presence of DIPEA, TEA, etc., an aminosulfonyl compound of formula 3-1 (wherein R 4 and R 5 Amine 1-10 is treated as defined in the Summary of the Invention (or any embodiment thereof above), or a precursor thereof, and LG is a leaving group such as chloro, bromo, etc., to provide a compound of formula (I). Compounds of formula 3-1 are commercially available, or they can be prepared by methods known in the art and / or the methods described in the following synthetic examples.

[0805] Alternatively, a compound of formula (I) wherein

[0806] yes W is N and R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 9 and R A as defined in the Summary of the Invention (or in any embodiment thereof above) can be prepared as illustrated and described in Scheme 4 below.

[0807] Option 4

[0808]

[0809] By proceeding similarly to that described in Scheme 1 above, a compound of formula 4-1 (wherein X 3 is a halogen, such as iodine or bromine, R is an alkyl, such as methyl, and R 1 、R 2 and R 3 As defined in the Summary of the Invention (or any embodiment thereof above) or its precursor group) is converted into a compound of formula 4-9. Under coupling reaction conditions, an aminosulfonamide compound (R 4 and R 5 Compound 4-9 is treated as defined in the Summary of the Invention (or any embodiment thereof) to provide a compound of formula (I). The reaction can be carried out in an organic solvent in the presence of a metal catalyst, such as CuI, K2CO3, N 1 ,N 2 The reaction is carried out in the presence of 1,2-dimethylcyclohexane-1,2-diamine in DMF or under Buchwald-type cross-coupling conditions. Typically, Buchwald-type cross-coupling conditions include a Pd catalyst, a ligand, and a base, such as a combination of Pd2(dba)3, XantPhos, Cs2CO3 in dioxane. Compounds of formula 4-10 are commercially available, or they can be prepared by methods known in the art and / or the methods described in the following synthesis examples. For example, N,N-dimethylsulfonamide, morpholine-4-sulfonamide, and indoline-1-sulfonamide are commercially available.

[0810] A compound of formula (I) wherein

[0811] yes

[0812] where R 9 is a heterocyclyl, a bicyclic heterocyclyl, a bridged heterocyclyl, and a spiroheterocyclyl (each ring is referred to as Het in Scheme 5), attached to the thiazolyl ring via a ring nitrogen atom, W is N and R1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 9 and R A as defined in the Summary of the Invention (or in any embodiment thereof above) can be prepared as illustrated and described in Scheme 5 below.

[0813] Option 5

[0814]

[0815] Compounds of formula 1-5 as defined in Scheme 1 above are cyclized with thiourea under similar conditions as described in Scheme 1 above to provide compounds of formula 5-2, which are converted to compounds of formula 5-3 under similar conditions as described in Scheme 2 above. Compound 5-3 is then converted to a compound of formula 5-4 under reaction conditions known in the art, wherein X 4 Is a halogen, such as chlorine or bromine. For example, compound 5-4 (wherein X 4 Is bromine) can be prepared by treating compound 5-3 with tert-butyl nitrite and CuBr2. A compound of formula 5-4 is treated with an amine of formula 5-5 (wherein Het is a heterocyclic radical, a bicyclic heterocyclic radical, a bridged heterocyclic radical, and a spiro heterocyclic radical containing at least one ring nitrogen atom) to provide a compound of formula 5-6. The reaction can be carried out in an organic solvent under alkaline conditions, such as in the presence of DIPEA, K2CO3, etc., in DMSO at high temperature. By proceeding similarly to that described in Scheme 2, the thioether compound of formula 5-6 is converted into a compound of formula 5-8, and then compound 5-8 is a compound of formula (I) as described in Scheme 1 above.

[0816] A compound of formula (I) wherein

[0817] yes W is N and R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 10 and R A as defined in the Summary of the Invention (or in any embodiment thereof above) can be prepared as illustrated and described in Scheme 6 below.

[0818] Option 6

[0819]

[0820] Under cross-coupling reaction conditions known in the art, such as the Suzuki reaction (when M is boron), a compound of formula 6-2 (wherein PG 1 is a suitable amine protecting group (such as acetyl) and M is a metal (such as boron or zinc)) to treat the bromo compound 6-1 (wherein R 10 As defined in the Summary of the Invention (or in any embodiment thereof above), there is provided a compound of formula 6-3. Compounds of formula 6-1 can be prepared by methods known in the art, such as PCT Application Publication No. WO 2012125981. Compounds of formula 6-2 are commercially available (for example, (N-[2-fluoro-3-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetamide)), or they can be prepared by methods known in the art. The thioether compound 6-3 can be converted into a compound of formula (I) under conditions similar to those of Scheme 2.

[0821] A compound of formula (I) wherein

[0822] yes Where W is N, R A is phenyl and R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 and R 10 as defined in the Summary of the Invention (or in any embodiment thereof above) can be prepared as illustrated and described in Scheme 7 below.

[0823] Option 7

[0824]

[0825] Imidazoles of formula 7-1 can be converted to compounds of formula (I) by proceeding as described above in Scheme 6. Compounds of formula 7-1 can be prepared by the methods described in US Patent Application Publication No. US20110052578A1.

[0826] A compound of formula (I) wherein

[0827] yes where R 9is a heterocyclyl, bicyclic heterocyclyl, bridged heterocyclyl, or spiroheterocyclyl group attached to the thienyl ring via a ring nitrogen atom (referred to herein as Het), W is N, R A is phenyl, and R 1 、R 2 、R 3 、R 4 、R 5 、R 6 , and R 7 as defined in the Summary of the Invention (or in any embodiment thereof above) can be prepared as illustrated and described in Scheme 8 below.

[0828] Option 8

[0829]

[0830] Thiophenes of formula 8-3 can be prepared by reacting a compound of formula 8-1, wherein Het is a heterocyclyl, a bicyclic heterocyclyl, a bridged heterocyclyl, or a spiroheterocyclyl (or any embodiment thereof), with a compound of formula 8-2, wherein R 1 and R 2 As defined in the Summary of the Invention (or any of its embodiments above), the reaction is synthesized by performing similarly to that described in Korean Patent Application Publication No. KR20180024945 A. Treatment of compound 8-3 with a brominating agent (such as NBS) provides a compound of formula 8-4. The cross-coupling reaction between 8-4 and a pyrimidine of formula 8-5 (wherein M is a metal, such as trialkyltin or borate) gives a compound of formula 8-6. The cross-coupling reaction typically includes a Pd catalyst, a ligand, and a base, such as a combination of Pd2(dba)3, PPh3, and CsF in dioxane when M is tri-n-butyltin. The nitro group in compound 8-6 is reduced with a palladium catalyst under an H2 atmosphere, for example, to provide an amine compound of formula 8-7, which can be converted into a compound of formula (I) by performing as described in Scheme 6 above, wherein Het is a heterocyclic group, a bicyclic heterocyclic group, a bridged heterocyclic group, or a spiroheterocyclic group attached to a thiazolyl ring via a ring nitrogen atom.

[0831] Compounds of formula (I) can be converted into other compounds of formula (I) by methods known in the art. For example, compounds of formula (I) (wherein R 9 For example, the second nitrogen ring atom of the piperazin-1-yl ring is replaced by R b Substituted piperazin-1-yl, wherein R b is H) can be converted to the corresponding compound of formula (I) (wherein R b is alkyl or cycloalkyl), giving the corresponding compound of formula (I) (wherein Rb is an alkyl group or a cycloalkyl group).

[0832] A compound of formula (I) wherein R 7 is piperidin-4-yl) can be combined with a compound having the formula R 16 The carboxylic acid of COOH is reacted under amide coupling reaction conditions or with a 11 Sulfonylating agent of SO2X (wherein X is a halide ion and R 11 and R 16 as defined in the Summary of the Invention) to give the corresponding compound of formula (I), wherein R 7 They are 1-(R 16 CO-)piperidin-4-yl and 1-(R 11 SO2-)piperidin-4-yl.

[0833] utility

[0834] Accumulating evidence suggests that overactivated CDK2 leads to aberrant cell cycle regulation and proliferation in cancer cells. In human cancers, the kinase activity of the CDK2 / cyclin E or CDK2 / cyclin A complexes is elevated through several mechanisms. Cyclin E has been found to be frequently amplified in, for example, uterine, ovarian, gastric, and breast cancers. In some cancer types, loss-of-function mutations in FBXW7 or overexpression of USP28, which control cyclin E turnover, lead to cyclin E overexpression and CDK2 activation. Alternatively, certain cancer cells express overactive, truncated forms of cyclin E or cyclin A. Furthermore, cyclin A amplification and overexpression have been reported in various cancers, such as hepatocellular carcinoma, colorectal cancer, and breast cancer. In some tumors, CDK2 catalytic activity is increased following loss or alteration of expression of the endogenous CDK2 inhibitors p27 or p21, or overexpression of SKP2, a negative regulator of p27. In addition, CDC25A and CDC25B (protein phosphatases responsible for activating the dephosphorylation of CDK2) are overexpressed in various tumors. These different mechanisms of CDK2 activation have been verified using cancer cells or mouse cancer models. In addition, CDK2 / cyclin E phosphorylates oncogenic Myc to counteract ras-induced senescence, highlighting the importance of CDK2 in myc / ras-induced tumorigenesis. It has been shown that inactivation of CDK2 is synthetically lethal to cancer cells overexpressing myc. In aneuploid cancer cells (such as KRAS mutant lung cancer), CDK2 inhibition leads to late catastrophe and apoptosis. In addition, inhibition of CDK2 effectively induces granulocyte differentiation in AML cell lines and blocks tumor growth in AML mouse models.

[0835] CDK2 activation due to cyclin E amplification or overexpression has also been identified as a key primary or acquired resistance pathway in tumors treated with CDK4 / 6 inhibitors or trastuzumab. Therefore, compounds of formula (I) can be used in combination with CDK4 / 6 inhibitors to treat cancers that have become refractory to CDK4 / 6 inhibitors.

[0836] Therefore, the compound of formula (I) or a pharmaceutically acceptable salt thereof can be used to treat tumors characterized by one or more of the following: overexpression of CDK2, hyperphosphorylation of CDK2 (Thr160), amplification / overexpression of cyclin E or cyclin A, RB deletion, loss of function of mutations in FBXW7 or overexpression of USP28, expression of truncated cyclin E or cyclin A, deregulation of p21 or p27 or overexpression of SKP2, amplification / overexpression of CDC25A or / and CDC25B, depletion of AMBRA1, MYC / RAS overactivity, aneuploid cancers, cancers refractory to CDK4 and / or CDK6 inhibitors.

[0837] In some embodiments, the cancer is ovarian cancer, endometrial cancer, breast cancer (e.g., triple-negative breast cancer), lung cancer (e.g., adenocarcinoma, small cell lung cancer and non-small cell lung cancer, small cell carcinoma and non-small cell carcinoma, bronchogenic carcinoma, bronchial adenoma and / or pleuropulmonary blastoma), skin cancer (e.g., melanoma, squamous cell carcinoma, Kaposi's sarcoma and / or Merkel cell skin cancer), bladder cancer, cervical cancer, colorectal cancer, small intestine cancer, colon cancer, rectal cancer, anal cancer, stomach 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), prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gallbladder cancer, pancreatic cancer (e.g., exocrine pancreatic cancer), gastric cancer, thyroid cancer, brain cancer, fallopian tube cancer, peritoneal cancer, AML, and parathyroid cancer. In some embodiments, the cancer is ovarian cancer. In some such embodiments, the ovarian cancer is characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0838] In other embodiments, the cancer is breast cancer, including, for example, ER-positive / HR-positive breast cancer, HER2-negative breast cancer; ER-positive / HR-positive breast cancer, HER2-positive breast cancer; triple-negative breast cancer (TNBC); or inflammatory breast cancer. In some embodiments, the breast cancer is endocrine-resistant breast cancer, trastuzumab-resistant breast cancer, or breast cancer that exhibits primary or acquired resistance to CDK4 / CDK6 inhibition. In some embodiments, the breast cancer is advanced or metastatic breast cancer. In some embodiments of each of the above, the breast cancer is characterized by amplification or overexpression of CCNE1, CCNE2, and / or CCNA2.

[0839] In addition to cancer, CDK2 upregulation has also been implicated in autoimmune diseases (e.g., rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), primary Sjögren's syndrome (pSS), multiple sclerosis (MS), Crohn's disease (CD), gout, uveitis, and pemphigus vulgaris) and sepsis.

[0840] test

[0841] Compounds of the present disclosure can be tested for CDK2 inhibitory activity using the in vitro assay described in Biological Example 1 below.

[0842] Pharmaceutical composition

[0843] Typically, a compound of formula (I) (unless otherwise indicated, reference to a compound herein / a compound of formula (I) includes any embodiment thereof as described herein or a pharmaceutically acceptable salt thereof) will be administered in a therapeutically effective amount by any of the acceptable modes of administration for a medicament for similar efficacy. The therapeutically effective amount of a compound of formula (I) can range from about 0.01 to about 500 mg / kg patient weight / day, which can be administered in a single dose or multiple doses. Suitable dosage levels can be from about 0.1 to about 250 mg / kg / day; from about 0.5 to about 100 mg / kg / day. Suitable dosage levels can be from about 0.01 to about 250 mg / kg / day, from about 0.05 to about 100 mg / kg / day, or from about 0.1 to about 50 mg / kg / day. Within this range, dosage can be from about 0.05 to about 0.5, from about 0.5 to about 5, or from about 5 to about 50 mg / kg / day. For oral administration, the compositions can be provided in the form of tablets containing from about 1.0 to about 1000 mg of 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 active ingredient. The actual amount of compound of formula (I) (i.e., active ingredient) will depend on many factors, such as the severity of the disease to be treated, the age and relative health of the patient, the potency of the compound being used, the route and form of administration, and other factors.

[0844] Typically, the compound of formula (I) will be administered in the form of a pharmaceutical composition by any of the following routes: oral, systemic (e.g., transdermal, intranasal, or by suppository), or parenteral (e.g., intramuscular, intravenous, or subcutaneous) administration. A preferred mode of administration is oral administration using a convenient daily dosage regimen that can be adjusted based on the severity of the disease. The composition can take the form of a tablet, pill, capsule, semisolid, powder, sustained-release formulation, solution, suspension, elixir, aerosol, or any other suitable composition.

[0845] The choice of formulation depends on 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 sustained-release tablets, pills or capsules) and the bioavailability of the drug substance.

[0846] These compositions are usually made up of a combination of a compound with formula (I) and at least one pharmaceutically acceptable excipient. Acceptable excipients are normally nontoxic, contribute to administration, and do not adversely affect the therapeutic benefit of the compound with formula (I). Such excipients can be any solid, liquid, semisolid or, in the case of aerosol compositions, are the conventionally available gaseous excipients of those of ordinary skill in the art.

[0847] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glyceryl monostearate, sodium chloride, skim milk powder, etc. Liquid and semisolid excipients can be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, for example, peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.

[0848] The compound with formula (I) can be formulated for parenteral administration by injection (for example, by bolus injection or continuous infusion). Injectable preparations can be provided in unit dosage form, for example, in an ampoule added with a preservative or in a multi-dose container. Compositions can take the form of a suspension, solution or emulsion, for example, in an oily or aqueous vehicle, and can contain a preparaton (such as a suspending agent, a stabilizer and / or a dispersant). Preparations can be present in unit dose or multi-dose containers (for example, sealed ampoule and vial), and can be stored in powder form or stored under freeze-drying (lyophilization) conditions, requiring only the immediate addition of a sterile liquid carrier (for example, saline or sterile pyrogen-free water) before use. Temporary injection solutions and suspensions can be prepared by sterile powders, granules and tablets of the aforementioned types.

[0849] Preparations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compound, which may contain antioxidants, buffers, antibacterial agents, and solutes that make the preparation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils (such as sesame oil), or synthetic fatty acid esters (such as ethyl oleate or triglycerides), or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound to allow the preparation of highly concentrated solutions.

[0850] In addition to the aforementioned preparations, the compound with formula (I) can also be mixed with depot preparations. Such long-acting preparations can be used by implanting (for example, subcutaneously or intramuscularly) or by intramuscular injection. Therefore, for example, these compounds can be prepared together with suitable polymer or hydrophobic material (for example, as an emulsion in an acceptable oil) or ion exchange resin, or be mixed with slightly soluble derivatives, for example, be mixed with slightly soluble salts.

[0851] For buccal or sublingual administration, these compositions may take the form of tablets, lozenges, pastilles or gels in conventional manner. Such compositions may contain the active ingredient in a flavored base such as sucrose and acacia or tragacanth.

[0852] The compounds of formula (I) may also be formulated in rectal compositions such as suppositories or retention enemas, eg, containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.

[0853] Certain compounds of formula (I) can be administered topically, i.e., by non-systemic administration. This includes applying compounds of formula (I) topically to the epidermis or oral cavity, as well as instilling such compounds into the ears, eyes, and nose, so that the compound does not significantly enter the bloodstream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

[0854] Preparations 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 eyes, ears or noses. The active ingredient of topical application can constitute, for example, from 0.001% to 10% w / w (by weight) of the preparation. In certain embodiments, the active ingredient can constitute up to 10% w / w. In other embodiments, it can constitute less than 5% w / w. In certain embodiments, the active ingredient can constitute from 2% w / w to 5% w / w. In other embodiments, it can constitute from 0.1% to 1% w / w of the preparation.

[0855] For administration by inhalation, compounds of formula (I) can be conveniently delivered from an insufflator, nebulizer pressurized packs, or other convenient methods of delivering an aerosol spray. The pressurized packs can contain suitable propellants, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gases. In the case of pressurized aerosols, the dosage unit can be determined by providing a valve for delivering a metered amount. Alternatively, for administration by inhalation or insufflation, compounds of formula (I) can be in the form of dry powder compositions, such as a powder mixture of the compound and a suitable powder base (such as lactose or starch). Powder compositions can be presented in unit dosage form, such as capsules, cartridges, gelatin, or blister packs, from which the powder can be administered by means of an insufflator or insufflator. Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences (Mack Publishing Company, 20th edition, 2000), edited by E.W. Martin.

[0856] The level of the compound of formula (I) can vary within the full range employed by those skilled in the art. Typically, the formulation will contain (on a weight percentage (wt.%) basis) from about 0.01 wt.% to 99.99 wt.% of the compound of formula (I) based on the total formulation, with the remainder being one or more suitable pharmaceutical excipients. For example, the compound is present at a level of about 1-80 wt.%.

[0857] Combination and combination therapies

[0858] The compound with formula (I) can be used for treating disease or illness in combination with one or more other drugs, and for these diseases or illnesses, the compound with formula (I) or other drugs can have effectiveness.Such one or more other drugs can be used simultaneously or sequentially with the compound with formula (I) by a kind of approach and its usual amount.When the compound with formula (I) is used simultaneously with one or more other drugs, the pharmaceutical composition of the unit dosage form containing such other drugs and the compound with formula (I) is preferred.However, combination therapy can also include the therapy that wherein there is the compound with formula (I) and one or more other drugs are used with different overlapping schedules.It is also expected that, when used in combination with one or more other active ingredients, there is the compound with formula (I) and other active ingredients can be used with a lower dosage than when each is used alone.

[0859] Thus, the pharmaceutical compositions of the present disclosure also include those containing one or more additional drugs in addition to the compound of formula (I).

[0860] The above combination not only includes the combination of the compound with formula (I) and a kind of other drugs, but also includes the combination with two or more other active drugs. Similarly, the compound with formula (I) can be used in combination with other drugs for preventing, treating, controlling, improving disease or illness (for which, the compound with formula (I) is useful) or reducing its risk. Such other drugs can be used simultaneously or sequentially with the compound with formula (I) by a kind of approach and its usual amount. When the compound with formula (I) is used simultaneously with one or more other drugs, the pharmaceutical composition containing these other drugs except the compound with formula (I) can be used. Therefore, pharmaceutical composition of the present disclosure also includes those containing one or more other active ingredients except the compound with formula (I). The weight ratio of compound of the present disclosure and the second active ingredient can vary, and will depend on the effective dose of each composition. Usually, respective effective dose will be used.

[0861] Where a subject in need thereof has cancer or is at risk of developing cancer, the subject may be treated with any combination of a compound of formula (I) 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 Biosciences, Inc. Corp); trametinib, selumetinib (AZD6244), TQ-B3234, PD184352, PD325901, TAK-733, pimasertinib, bimetinib, rameltinib, cometinib (GDC-0973), AZD8330, BVD-523, LTT462, neratinib, AMG510, ARS853, adagrasib, opnurasib, divarasib, LY3537982 (2-amino-4-[(4aS)-8-chloro-10-fluoro-2,3,4,4a,5,6-hexahydro-12-oxo-

[0015] RAS inhibitors include 4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)pyrido[4,3-d]pyrimidin-7-yl)-5-ethynyl-6-fluoronaphthalen-2-ol), RMC-6291, RMC-9805, RMC0708, RMC-8839, and any RAS inhibitor disclosed in the following PCT Publication Nos. WO2011 / 010666. 2016049565、WO 2016164675、WO 2016168540、WO 2017015562、WO2017058728、WO 2017058768、WO 2017058792、WO 2017058805、WO 2017058807、WO2017058902、WO 2017058915、WO 2017070256、WO 2017087528、WO 2017100546、WO2017172979、WO 2017201161、WO 2018064510、WO 2018068017, and WO 2018119183;

[0862] CSF1R inhibitors (PLX3397, LY3022855, etc.) and CSF1R antibodies (IMC-054, RG7155);

[0863] TGFβ receptor kinase inhibitors (such as LY2157299);

[0864] BTK inhibitors, such as ibrutinib; BCR-ABL inhibitors: imatinib Inilotinib hydrochloride; Nilotinib Dasatinib (BMS-345825); Bosutinib (SKI-606); Ponatinib (AP24534); Bafitinib (INNO406); Danusertib (PHA-739358), AT9283 (CAS1133385-83-7); Saracatinib (AZD0530); and N-[2-[(15,4R)-6-[[4-(cyclobutylamino)-5-(trifluoromethyl)-2-pyrimidinyl]amino]-1,2,3,4-tetrahydronaphthalen-1,4-imin-9-yl]-2-oxoethyl]-acetamide (PF-03814735, CAS 942487-16-3);

[0865] ALK inhibitor: PF-2341066 ( Crizotinib); 5-chloro-N4-(2-(isopropylsulfonyl)phenyl)-N2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine; GSK1838705 A; CH5424802; Ceritinib (ZYKADIA); TQ-B3139, TQ-B3101 PI3K inhibitor: 4-[2-(1H-indazol-4-yl)-6-[[4-(methylsulfonyl)-piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine (also known as GDC 0941 and described in PCT Publication Nos. 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-1-yl]phenyl]propionitrile (also known as BEZ 235 or NVP-BEZ 235, and described in PCT Publication No. WO 06 / 122806);

[0866] Vascular endothelial growth factor (VEGF) receptor inhibitors: Bevacizumab (marketed by Genentech / Roche under the trademark and commercially available), axitinib (N-methyl-2-[[3-[(E)-2-pyridin-2-ylvinyl]-1H-indazol-6-yl]sulfanyl]benzamide, also known as AG013736 and described in PCT Publication No. WO 01 / 002369), brivanib alanine ((S)-((R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-yl)-2-aminopropanoate, also known as BMS-582664), motesanib (N-(2,3-dihydro-3,3-dimethyl-1H-indol-6-yl)-2-[(4-pyridylmethyl)amino]-3-pyridinecarboxamide, and described in PCT Publication No. WO 02 / 066470), pasireotide (also known as SOM230 and described in PCT Publication No. WO 02 / 010192), sorafenib (trademarked under the trademark (sold); AL-2846 MET inhibitors, such as foretinib, cabozantinib, or crizotinib;

[0867] FLT3 inhibitor - sunitinib malate (trademarked by Pfizer (sold); PKC412 (midostaurin); tanutinib, sorafenib, lestaurinib, KW-2449, quizartinib (AC220), and crelanib;

[0868] Epidermal growth factor receptor (EGFR) inhibitors: gefitinib (trade name: N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butyramide (sold by Boehringer Ingelheim under the trademark Cetuximab (sold by Bristol-Myers Squibb under the trademark Panitumumab (sold by Amgen under the trademark Sale);

[0869] HER2 receptor inhibitors: Trastuzumab (manufactured by Genentech / Roche under the trademark

[0014] Neratinib (also known as HKI-272, (2E)-N-[4-[[3-chloro-4-[(pyridin-2-yl)methoxy]phenyl]amino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide, and described in PCT Publication No. WO 05 / 028443), lapatinib or lapatinib ditosylate (available from GlaxoSmithKline under the trademark Trastuzumab emtansine (marketed in the United States as Ado-Trastuzumab emtansine, brand name Kadcyla) - an antibody-drug conjugate consisting of the monoclonal antibody trastuzumab (Herceptin) linked to the cytotoxic agent mertansine (DM1);

[0870] HER dimerization inhibitor: Pertuzumab (developed by Genentech under the trademark Sale);

[0871] CD20 antibody: Rituximab (developed by Genentech / Roche under the trademark and Tositumomab (sold by GlaxoSmithKline under the trademark ofatumumab (sold by GlaxoSmithKline under the trademark Sale);

[0872] Tyrosine kinase inhibitors: Erlotinib hydrochloride (manufactured by Genentech / Roche under the trademark Linifanib (N-[4-(3-amino-1H-indazol-4-yl)phenyl]-N'-(2-fluoro-5-methylphenyl)urea, also known as ABT-869, available from Genentech), sunitinib malate (available from Pfizer under the trademark ), bosutinib (4-[(2,4-dichloro-5-methoxyphenyl)amino]-6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinoline-3-carbonitrile, also known as SKI-606 and described in U.S. Patent No. 6,780,996), dasatinib (Bristol-Myers Squibb Company sold under the trademark ), Armala (also known as Pazopanib, sold by GlaxoSmithKline under the trademark ), imatinib, and imatinib mesylate (sold by Novartis under the trademark and Sale);

[0873] DNA synthesis inhibitors: Capecitabine (manufactured by Roche under the trademark Gemcitabine hydrochloride (sold by Eli Lilly and Company under the trademark Nelarabine ((2R3S,4R,5R)-2-(2-amino-6-methoxy-purin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol) is sold by GlaxoSmithKline under the trademark and Sale);

[0874] Antineoplastic agent: Oxaliplatin (manufactured by Sanofi-Aventis under the trademark sold and described in U.S. Patent No. 4,169,846);

[0875] Human granulocyte colony-stimulating factor (G-CSF) regulator: Filgrastim (available from Amgen under the trademark Sale).

[0876] Immunomodulator: Afutuzumab (available from Pegfilgrastim (available from Amgen under the trademark Sold under the trademark Sold under the trademark Sale);

[0877] CD40 inhibitor: daclizumab (also known as SGN-40 or huS2C6, available from Seattle Genetics, Inc.); Pro-apoptotic receptor agonist (PARA): duralamine (also known as AMG-951, available from Amgen / Genentech);

[0878] Hedgehog antagonist: 2-chloro-N-[4-chloro-3-(2-pyridinyl)phenyl]-4-(methylsulfonyl)-benzamide (also known as GDC-0449 and described in PCT Publication No. WO 06 / 028958);

[0879] Phospholipase A2 inhibitors: anagrelide (known under the trademark Sale);

[0880] BCL-2 inhibitor: 4-[4-[[2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexen-1-yl]methyl]-1-piperazinyl]-N-[[4-[[(1R)-3-(4-morpholinyl)-1-[(phenylthio)methyl]propyl]amino]-3-[(trifluoromethyl)sulfonyl]phenyl]sulfonyl]benzamide (also known as ABT-263 and described in PCT Publication No. WO 09 / 155386);

[0881] MCl-1 inhibitors: MIK665, S64315, AMG 397, and AZD5991;

[0882] Aromatase inhibitors: Exemestane (brand name of Letrozole (sold by Novartis under the trademark Anastrozole (sold under the trademark Sale);

[0883] Topoisomerase I inhibitors: irinotecan (marketed by Pfizer under the trademark Topotecan hydrochloride (sold by GlaxoSmithKline under the trademark Sale);

[0884] Topoisomerase II inhibitors: Etoposide (also known as VP-16 and etoposide phosphate, sold under the trademark and Teniposide (also known as VM-26, sold under the trademark Sale);

[0885] mTOR inhibitors: Temsirolimus (trademarked by Pfizer (marketed as lirolimus), lirolimus (formerly known as deferolimus), (1R,2R,4S)-4-[(2R)-2-[(1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28Z,30S,32S,35R)-1,18-dihydroxy-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-2,3,10,14,20-pentaoxo-11,36-dioxa-4-azatricyclo[30.3.1.0 [4'9]hexatricarborate-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyldimethylphosphinate, also known as AP23573 and MK8669 and described in PCT Publication No. WO 03 / 064383), irolimus (available from Novartis under the trademark Sale);

[0886] Proteasome inhibitors, such as carfilzomib, MLN9708, dextromethorphan, or bortezomib;

[0887] BET inhibitors, such as INCB054329, OTX015, and CPI-0610;

[0888] LSD1 inhibitors, such as GSK2979552 and INCB059872;

[0889] HIF-2α inhibitors, such as PT2977 and PT2385;

[0890] Osteoclast bone resorption inhibitor: 1-Hydroxy-2-imidazol-1-yl-phosphonoethyl)phosphonic acid monohydrate (available from Novartis under the trademark CD33 antibody drug conjugate: gemtuzumab ozogamicin (sold by Pfizer / Wyeth under the trademark Sale);

[0891] CD22 antibody-drug conjugate: inotuzumab (also known as CMC-544 and WAY-207294, available from Hangzhou Sage Chemical Co., Ltd.);

[0892] CD20 antibody drug conjugate: Ibritumomab (trademark Sale);

[0893] Somatostatin analogs: Octreotide (also known as octreotide acetate, under the trademark and Sandostatin down sales);

[0894] Synthetic interleukin-11 (IL-11): oprelvekin (developed by Pfizer / Wyeth under the trademark Sale);

[0895] Synthetic erythropoietin: Darbepoetin alfa (produced by Amgen under the trademark Sale);

[0896] Receptor activator of nuclear factor kappa B (RANK) inhibitor: Denosumab (available from Amgen under the trademark Sale);

[0897] Thrombopoietin mimetic peptide: Romiplostim (trademarked by Amgen Sale);

[0898] Cell growth stimulator: Parifelmin (produced by Amgen under the trademark Sale);

[0899] 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);

[0900] Anti-CS1 antibody: Elotuzumab (HuLuc63, CAS No. 915296-00-3);

[0901] CD52 antibody: Alemtuzumab (trade name Sale);

[0902] Histone deacetylase inhibitors (HDIs): Voninostat (marketed by Merck under the trademark Sale);

[0903] Alkylating agents: Temozolomide (marketed by Schering-Plough / Merck under the trademark and Dactinomycin (also known as actinomycin D and marketed under the trademark Melphalan (also known as L-PAM, L-sarcolysin, and phenylalanine mustard, sold under the trademark Hexamethylmelamine (also known as hexamethylmelamine (HMM), sold under the trademark Carmustine (sold under the trademark Bendamustine (sold under the trademark Sales), Busulfan (under the trademark and Carboplatin (sold under the trademark Sold), Lomustine (also known as CCNU, sold under the trademark Cisplatin (also known as CDDP, sold under the trademark and -AQ), chlorambucil (sold under the trademark Cyclophosphamide (sold under the trademark and ), dacarbazine (also known as DTIC, DIC, and imidazole carboxamide, sold under the trademark DTIC- Hexamethylmelamine (also known as hexamethylmelamine (HMM), sold under the trademark Ifosfamide (sold under the trademark Procarbazine (sold under the trademark Sold under the trademarks), dichloromethyldiethylamine (also known as nitrogen mustard, mustine, and mechloroethamine hydrochloride), Sold), Streptozotocin (trademark Thiotepa (also known as phosphorothioate amide, TESPA, and TSPA, sold under the trademark Sale);

[0904] Biological response modifier: BCG (trademark and BCG), denileukin (sold under the trademark Sale);

[0905] Antitumor antibiotics: Adriamycin (trademark and Bleomycin (sold under the trademark Daunomycin (also known as daunomycin hydrochloride, daunomycin, and daunorubicin hydrochloride, sold under the trademark daunomycin liposomes (daunomycin citrate liposomes, sold under the trademark Mitoxantrone (also known as DHAD, sold under the trademark Sold), Epirubicin (sold under the trademark Ellence TM Sales), Idabixin (trademark Idamycin Mitomycin C (sold under the trademark Sale);

[0906] Antimicrotubule agents: Estramustine (trade name Sale);

[0907] Cathepsin K inhibitor: Odanacatib (also known as MK-0822, N-(1-cyanocyclopropyl)-4-fluoro-N2-{(1S)-2,2,2-trifluoro-1-[4'-(methylsulfonyl)biphenyl-4-yl]ethyl}-L-leucinamide, obtained from Lanzhou Chon Chemicals, ACC, and ChemieTek, and described in PCT Publication No. WO 03 / 075836);

[0908] Epothilone B analogues: Ixabepilone (developed by Bristol-Myers Squibb under the trademark Sale);

[0909] Heat shock protein (HSP) inhibitors: Tanespimycin (17-allylamino-17-demethoxygeldanamycin, also known as KOS-953 and 17-AAG, available from Sigma and described in U.S. Pat. No. 4,261,989), NVP-HSP990, AUY922, AT13387, STA-9090, Debio 0932, KW-2478, XL888, CNF2024, TAS-116;

[0910] TpoR agonist: Eltrombopag (manufactured by GlaxoSmithKline under the trademark and Sale);

[0911] Antimitotic agents: docetaxel (available from Sanofi under the trademark Sale);

[0912] Adrenal steroid inhibitors: aminoglutethimide (trade name Sale);

[0913] Antiandrogen: Nilutamide (trade name and Bicalutamide (sold under the trademark Flutamide (sold under the trademark Fulexin TM Sale);

[0914] Androgens: Fluoxymesterone (trade name Sale);

[0915] CDK (CDK1, CDK2, CDK3, CDK5, CDK7, CDK8, CDK9, CDK11 / 12, or CDK16) inhibitors, including but not limited to Alvocidib (a pan-CDK inhibitor also known as flovopirdol or HMR-1275, 2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-1-methyl-4-piperidinyl]-4-chromenone, and described in U.S. Pat. No. 5,621,002);

[0916] CDK4 / 6 inhibitors, including but not limited to palbociclib, ribociclib, abemaciclib, and trilaciclib;

[0917] CDK9 inhibitors, including but not limited to AZD 4573, P276-00, AT7519M, and TP-1287; CDK2 / 4 / 6 inhibitors, such as PF-06873600;

[0918] Cell division cycle 25A (CDC25A) inhibitors, such as 2-(2-mercaptoethanol)-3-methyl-1,4-naphthoquinone, 1-([1,1'-biphenyl]-4-yl)-3,4-bis((2-hydroxyethyl)thioxo-1H-pyrrole-2,5-dione (PM-20), 2-(2,5-difluorophenyl)-6-((3-(methyl(3-((2-methyl-4,7-dioxo-4,7-dihydrobenzo[d]-thiazol-5-yl)amino)propyl)amino)propyl)amino)benzo[d]oxazole-4,7-dione (IRC 083864), or 2-methoxyestradiol, or a pharmaceutically acceptable salt thereof;

[0919] SHP-2 inhibitors, such as TNO155;

[0920] MDM2 / MDMX, MDM2 / p53, and / or MDMX / p53 modulators;

[0921] Gonadotropin-releasing hormone (GnRH) receptor agonists: leuprolide or leuprolide acetate (marketed by Bayer AG under the trademark Sanofi-Aventis and by Abbott Lab Sale);

[0922] Taxane antitumor agents: Cabazitaxel (1-hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytax-ll-ene-2a,4,13a-triyl-4-acetate-2-benzoate-13-[(2R,3S)-3-{[(tert-butoxy)carbonyl]-amino}-2-hydroxy-3-phenylpropionate), larotaxel ((2α,3ξ,4α,5β,7α,10β,13α)-4,10-bis(acetyloxy)-13-({(2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-3-phenylpropionyl}-oxy)-1-hydroxy-9-oxo-5,20-epoxy-7,19-cyclotax-ll-en-2-yl benzoate);

[0923] 5HT1a receptor agonist: Xaliroden (also known as SR57746, 1-[2-(2-naphthyl)ethyl]-4-[3-(trifluoromethyl)phenyl]-1,2,3,6-tetrahydropyridine, and described in U.S. Pat. No. 5,266,573); HPC vaccine: marketed by GlaxoSmithKline Marketed by Merck Iron chelators: Deferasirox (available from Novartis under the trademark Sale);

[0924] Antimetabolite: Cladribine (2-chlorodeoxyadenosine, sold under the trademark Sold under the trademark Sold under the trademark Pemetrexed (sold under the trademark Spore arabinoside (also known as cytosine arabinoside (Ara-C), sold under the trademark cytarabine liposomes (also known as liposome Ara-C, sold under the trademark DepoCyt TM Sold under the trademark Sold under the trademark Droxia TM and Mylocel TM Sold under the trademark Sold under the trademark Cladribine (also known as 2-chlorodeoxyadenosine (2-CdA), sold under the trademark Leustatin TM Sold under the trademarks and Trexall TM Sold under the trademark Sale);

[0925] Bisphosphonates: Pamidronate (known under the trademark Zoledronic acid (sold under the trademark demethylating agent: 5-azacitidine (sold under the trademark Sold under the trademark Sale);

[0926] Plant alkaloids: Taxol protein-bound (trademark ), vinblastine (also known as vinblastine sulfate, vinblastine, and VLB, sold under the trademark Alkaban- and Sold under the trademarks), vincristine (also known as vincristine sulfate, LCR, and VCR and Sales), Changchunorelbine (trademark Taxol and Onxal TM Sale);

[0927] Retinoids: alitretinoin (known under the trademark Retinoic acid (all-trans retinoic acid, also known as ATRA, sold under the trademark Isotretinoin (13-cis-retinoic acid, sold under the trademark

[0928] and Bexarotene (sold under the trademark Sale);

[0929] Glucocorticoids: Hydrocortisone (also known as cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate, and sold under the trademark Hydrocortisone phosphate, Hydrocort and Dexamethasone ((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-3-one), prednisolone (trademark and Sold under the trademark and Sold), methylprednisolone (also known as 6-methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, and under the trademark and Sale);

[0930] Cytokines: Interleukin-2 (also known as aldesleukin and IL-2, tradenames Interleukin-11 (also known as Oprelukin, marketed under the trademark Interferon alpha (also known as IFN-α, marketed under the trademark and

[00209] Estrogen receptor down-regulator: Fulvestrant (trademark Sale);

[0931] Antiestrogens: Tamoxifen (known under the brand name Toremifene (sold under the trademark Sale);

[0932] Selective estrogen receptor modulators (SERMs): raloxifene (trade name Sale);

[0933] Leukocyte stimulating hormone-releasing hormone (LHRH) agonists: Goserelin (trade name Progesterone: megestrol acetate (also known as megestrol acetate, sold under the trademark Sale);

[0934] Miscellaneous cytotoxic agents: Arsenic trioxide (trademark Asparaginase (also known as L-asparaginase, Erwinia L-asparaginase, sold under the trademark and Sale);

[0935] 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 stimulatory 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 can be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFRβ inhibitors.

[0936] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of PD-1, for example, 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.

[0937] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, for example, 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 (durvalumab).

[0938] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CTLA-4, for example, an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab or tremelimumab. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of LAG3, for example, an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016 or LAG525. In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of GITR, for example, 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 an immune checkpoint molecule is an inhibitor of OX40, for example, an anti-OX40 antibody or an 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.

[0939] The compounds of the present invention may 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 may be used to enhance immune responses to vaccines, including but not limited to Listeria vaccines, oncolytic virus vaccines, and cancer vaccines, such as (Granulocyte-macrophage colony-stimulating factor (GM-CF) gene-transfected tumor cell vaccines). Anticancer vaccines include dendritic cells, synthetic peptides, DNA vaccines, and recombinant viruses. Other immunomodulators include those that block immune cell migration, such as chemokine receptor antagonists (including CCR2 and CCR4); Sting agonists; and Toll receptor agonists.

[0940] Other anticancer agents also include those that enhance the immune system, such as adjuvants or adoptive T cell transfer. The compounds of the present application can be effective in combination with CAR (chimeric antigen receptor) T cell therapy as a booster for T cell activation.

[0941] The compounds of formula (I) may also be used in combination with the following adjunctive treatments: Antinausea drugs: NK-1 receptor antagonists: Casopitant (available from GlaxoSmithKline under the trademark and and cytoprotectants: Amifostine (marketed under the trademark (sold), leucovorin (also known as calcium folinate, leucovorin factor, and folinic acid). Example

[0942] The following preparations of intermediates and compounds of formula (I) are given to enable those skilled in the art to more clearly understand and practice the present disclosure. They should not be considered to limit the scope of the present disclosure, but merely serve as illustration and representation thereof.

[0943] Intermediate 1:

[0944] Synthesis of (3aR,5s,6aS)-5-aminohexahydro-1H-cyclopenta[c]thiophene 2,2-dioxide

[0945]

[0946] Step 1: Dimethyl 4-oxocyclopentane-1,2-dicarboxylate

[0947]

[0948] SOCl2 (7.14 g, 60.00 mmol, 2.00 equiv) was added dropwise to a solution of 4-oxocyclopentane-1,2-dicarboxylic acid (5.16 g, 30.00 mmol, 1.00 equiv) in MeOH (100.0 mL) at room temperature. The mixture was heated to 70 ° C for 16 hours and then concentrated. The residue was dissolved in EtOAc, washed with H2O and brine. The organic layer was dried over Na2SO4, filtered and concentrated to give the title compound as a colorless oil.

[0949] Step 2: Dimethyl 1,4-dioxaspiro[4.4]nonane-7,8-dicarboxylate

[0950]

[0951] A solution of dimethyl 4-oxocyclopentane-1,2-dicarboxylate (4.70 g, 23.50 mmol, 1.00 equiv), ethane-1,2-diol (1.75 g, 28.20 mmol, 1.20 equiv) and TsOH.HO (200 mg, catalyst) in toluene (100.0 mL) was heated to 140 ° C. for 16 hours using a Dean-Stark apparatus. The mixture was then concentrated and purified by silica gel column chromatography (PE / EtOAc=5:1) to give the title compound as a colorless oil.

[0952] Step 3: 1,4-Dioxaspiro[4.4]nonane-7,8-diyldimethanol

[0953]

[0954] A solution of LiAlH4 (690 mg, 18.20 mmol, 1.20 equivalents) in THF (20.0 mL) was cooled to 0 ° C, and 1,4-dioxaspiro [4.4] nonane -7,8- dimethyl dicarboxylate (3.70 g, 15.20 mmol, 1.00 equivalents) in THF (30.0 mL) was added dropwise at 0 ° C. The mixture was allowed to stir for 1 hour at 0 ° C, and then quenched with H2O. The mixture was filtered, and the filter cake was washed with MeOH. The filtrate was combined and concentrated to give the title compound as a yellow oil.

[0955] Step 4: 1,4-dioxaspiro[4.4]nonane-7,8-diylbis(methylene)dimethylsulfonate

[0956]

[0957] TEA (8.06 g, 79.80 mmol, 6.00 equivalents) is added to a solution of 1,4-dioxaspiro [4.4] nonane -7,8- diyldimethanol (2.50 g, 13.30 mmol, 1.00 equivalents) in DCM (30 mL), followed by dropwise addition of MsCl (4.55 g, 39.90 mmol, 3.00 equivalents) at room temperature. The mixture is stirred at room temperature for 5 hours and then poured onto ice. The mixture is extracted with DCM. The organic layers are combined and concentrated to give the title compound as a yellow oil.

[0958] Step 5: (3aR,6aS)-tetrahydro-1H,3H-spiro[cyclopenta[c]thiophene-5,2'-[1,3]dioxolane]

[0959]

[0960] Na2S (907 mg, 11.60 mmol, 1.00 equivalent) was added to a solution of 1,4-dioxaspiro-[4.4]nonane-7,8-diylbis(methylene) dimethanesulfonate (4.00 g, 11.60 mmol, 1.00 equivalent) in EtOH (30.0 mL) at room temperature. The mixture was heated to 60 ° C for 16 hours under an N2 atmosphere and then poured into water. The mixture was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4, concentrated, and the residue was purified by silica gel column chromatography (PE / EtOAc=10: 1) to give the title compound as a white solid.

[0961] Step 6: (3aR,6aS)-tetrahydro-1H-cyclopenta[c]thiophen-5(3H)-one

[0962]

[0963] 2M HCl aqueous solution (5.0 mL) was added to a mixture of (3aR, 6aS)-tetrahydro-1H, 3H-spiro[cyclopenta[c]thiophene-5,2'-[1,3]dioxolane] (750 mg, 4.03 mmol, 1.00 equiv) in acetone (5.0 mL). The mixture was stirred at room temperature for 16 hours and diluted with H2O. The mixture was extracted with EtOAc, and the organic layers were combined, washed with saturated NaHCO3 aqueous solution and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE / EtOAc=10:1) to give the title compound as a yellow solid.

[0964] Step 7: (3aR,5r,6aS)-Hexahydro-1H-cyclopenta[c]thiophen-5-ol

[0965]

[0966] To a solution of (3aR,6aS)-tetrahydro-1H-cyclopenta[c]thiophene-5(3H)-one (400 mg, 2.81 mmol, 1.00 equiv) in MeOH (10.0 mL) was added NaBH4 (321 mg, 8.45 mmol, 3.00 equiv) portionwise. The mixture was stirred at room temperature for 3 hours, diluted with H2O, and extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated to give the title compound as a yellow oil.

[0967] Step 8: (3aR,5r,6aS)-hexahydro-1H-cyclopenta[c]thiophen-5-yl methanesulfonate

[0968]

[0969] TEA (840 mg, 8.33 mmol, 3.00 equiv) is added to a solution of (3aR, 5r, 6aS)-hexahydro-1H-cyclopenta[c]thiophene-5-ol (400 mg, 2.78 mmol, 1.00 equiv) in DCM (10.0 mL), followed by dropwise addition of MsCl (380 mg, 3.33 mmol, 1.20 equiv) at room temperature. The mixture is stirred for 3 hours, then poured into water (10.0 mL), and the mixture is extracted with DCM. The organic layers are combined, washed with salt water, dried over Na2SO4, filtered and concentrated to give the title compound as a yellow oil.

[0970] Step 9: (3aR,5s,6aS)-Hexahydro-1H-cyclopenta[c]thiophene-5-amine

[0971]

[0972] NaN (350 mg, 5.40 mmol, 2.00 equiv) is added to a solution of (3aR, 5r, 6aS)-hexahydro-1H-cyclopenta[c]thiophene-5-yl methanesulfonate (600 mg, 2.70 mmol, 1.00 equiv) in DMF (6 mL). The mixture is heated to 60 ° C for 16 hours under N2 atmosphere, and then diluted with EtOAc and H2O. The organic layers are combined and concentrated. The residue is diluted with NH3 in MeOH (7 M, 10 mL), and Pd / C (10%, 120 mg, 0.2 W / W) is subsequently added. The mixture is stirred at room temperature under H2 atmosphere for 16 hours, and then filtered and concentrated. The residue is purified by silica gel column chromatography (DCM / MeOH=10: 1) to give the title compound as a yellow oil.

[0973] Step 10: ((3aR,5s,6aS)-2,2-dioxohexahydro-1H-cyclopenta[c]thiophen-5-yl)-carbamic acid tert-butyl ester

[0974]

[0975] (Boc) O (685 mg, 3.15 mmol, 1.50 equiv) was added dropwise to a solution of (3aR, 5s, 6aS)-hexahydro-1H-cyclopenta[c]thiophene-5-amine (300 mg, 2.10 mmol, 1.00 equiv) in THF (10.0 mL). The mixture was stirred at room temperature for 2 hours, then diluted with H o and extracted with EtOAc. The organic layers were combined, washed with brine, and concentrated under reduced pressure. The residue was dissolved in THF / H o (4: 1, 10 mL), followed by the addition of oxone (2.58 g, 4.20 mmol, 2.00 equiv). The mixture was stirred at room temperature for 16 hours, then diluted with H o and extracted with EtOAc. The organic layers were combined, concentrated, and purified by silica gel column chromatography (PE / EtOAc=10: 1) to give the title compound as a yellow solid.

[0976] Step 11: (3aR,5s,6aS)-5-aminohexahydro-1H-cyclopenta[c]thiophene 2,2-dioxide

[0977]

[0978] HCl in MeOH (4M, 5.0 mL) was added to tert-butyl ((3aR, 5s, 6aS)-2,2-dioxohexahydro-1H-cyclopenta[c]thiophene-5-yl)carbamate (450 mg, 1.64 mmol, 1.00 equiv) at room temperature. After stirring for 3 hours, the mixture was concentrated. The residue was suspended in DCM and then a NaHCO3 aqueous solution was added. The mixture was stirred at room temperature for 1 hour and then filtered. The layers were separated and the organic layer was concentrated to give the title compound.

[0979] Intermediate 2:

[0980] Synthesis of (1R,5S,6s)-6-amino-3-thiabicyclo[3.1.0]hexane 3,3-dioxide

[0981]

[0982] Step 1: Ethyl (1R,5S,6r)-3-thiabicyclo[3.1.0]hexane-6-carboxylate 3,3-dioxide and Ethyl (1R,5S,6s)-3-thiabicyclo[3.1.0]hexane-6-carboxylate 3,3-dioxide

[0983]

[0984] Ethyl diazepine (7.20 g, 63.48 mmol, 1.5 eq) in DCM (50.0 mL) was slowly added to a stirred solution of 2,5-dihydro-thiophene 1,1-dioxide (5.00 g, 42.32 mmol, 1.00 eq) and rhodium (II) acetate (281 mg, 1.27 mmol, 0.03 eq) in DCM (80.0 mL) at room temperature under N2. The mixture was concentrated and the residue was purified by silica gel column chromatography (PE:EA=5:1) to isolate the title compound.

[0985] Step 2: (1R,5S,6r)-3-thiabicyclo[3.1.0]hexane-6-carboxylic acid 3,3-dioxide

[0986]

[0987] A solution of LiOH.HO (740 mg, 17.63 mmol, 3.00 equivalents) in HO (6.0 mL) was added to a mixture of (1R, 5S, 6r) -3- thiabicyclo [3.1.0] hexane -6- ethyl carboxylate 3,3- dioxide (1.2 g, 5.88 mmol, 1.00 equivalents) in EtOH (12.0 mL). This mixture was stirred at room temperature for 3 hours. The pH of the mixture was adjusted to 2-3 with 1N HCl, and the mixture was extracted with DCM. The combined organic layers were concentrated to give a crude product as a light yellow solid.

[0988] Step 3: Benzyl ((1R,5S,6s)-3,3-dioxo-3-thiabicyclo[3.1.0]hexan-6-yl)carbamate

[0989]

[0990] To a mixture of (1R, 5S, 6r) -3-thiabicyclo [3.1.0] hexane -6- carboxylic acid 3,3- dioxide (500 mg, 2.84 mmol, 1.00 equiv) in toluene (15.0 mL) was added TEA (459 mg, 4.54 mmol, 1.60 equiv) and DPPA (937 mg, 3.41 mmol, 1.20 equiv). This mixture was stirred at room temperature under N2 for 2 hours and then benzyl alcohol (614 mg, 5.68 mmol, 2.00 equiv) was added dropwise. This mixture was stirred at 100 ° C under N2 overnight, then concentrated and purified by silica gel column chromatography (PE: EA = 2: 1) to give the title compound as a white solid.

[0991] Step 4: (1R,5S,6s)-6-amino-3-thiabicyclo[3.1.0]hexane 3,3-dioxide

[0992]

[0993] To a mixture of benzyl ((1R,5S,6s)-3,3-dioxo-3-thiabicyclo[3.1.0]hexan-6-yl)carbamate (500 mg, 0.36 mmol, 1.00 equiv) in MeOH (5.0 mL) was added Pd / C (50 mg). This mixture was stirred at room temperature under H for 5 hours. The mixture was filtered and concentrated to give the title compound as a white solid.

[0994] Intermediate 3:

[0995] Synthesis of (1R,5S,6r)-6-amino-3-thiabicyclo[3.1.0]hexane 3,3-dioxide

[0996]

[0997] The title compound was prepared by proceeding analogously to that described for Intermediate 2, substituting (1R,5S,6r)-3-thiabicyclo[3.1.0]hexane-6-carboxylic acid ethyl ester 3,3-dioxide for (1R,5S,6r)-3-thiabicyclo[3.1.0]hexane-6-carboxylic acid ethyl ester 3,3-dioxide in steps 2-4.

[0998] Intermediate 4:

[0999] Synthesis of (1s,4s)-4-(methylsulfonyl)cyclohexan-1-amine trifluoroacetate

[1000]

[1001] Step 1: (1r,4r)-4-((tert-Butoxycarbonyl)amino)cyclohexyl methanesulfonate

[1002]

[1003] TEA (4.20 g, 41.79 mmol, 3.00 equiv) was added to a solution of tert-butyl ((1r, 4r)-4-hydroxycyclohexyl)carbamate (3.00 g, 13.93 mmol, 1.00 equiv) in DCM (30.0 mL), followed by the slow addition of MsCl (2.40 g, 20.90 mmol, 1.50 equiv) at 0 ° C. This mixture was stirred at 0 ° C under N2 for 1 hour, and then warmed to room temperature and stirred under N2 for 2 hours. The mixture was diluted with H2O and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (PE: EA = 5: 1) to give the title compound as a white solid.

[1004] Step 2: tert-Butyl ((1s,4s)-4-(methylthio)cyclohexyl)carbamate

[1005]

[1006] CH3SNa (1.10 g, 15.68 mmol, 2.00 equiv) was added to a mixture of (1r, 4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl methanesulfonate (2.30 g, 7.84 mmol, 1.00 equiv) in DMF (23.0 mL). The mixture was stirred at room temperature overnight and then diluted with H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (PE:EA=10:1) to give the title compound as a white solid.

[1007] Step 3: tert-Butyl ((1s,4s)-4-(methylsulfonyl)cyclohexyl)carbamate

[1008]

[1009] To a mixture of tert-butyl ((1s,4s)-4-(methylthio)cyclohexyl)carbamate (202 mg, 0.82 mmol, 1.00 equiv) in THF / MeOH / H2O (2:2:1, 4.0 mL) was added oxone (504 mg, 1.64 mmol, 2.00 equiv), and the resulting mixture was stirred at room temperature under N2 overnight. H2O was added, and the mixture was extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated to give the crude product as a light yellow solid.

[1010] Step 4: (1s,4s)-4-(methylsulfonyl)cyclohexan-1-amine trifluoroacetate

[1011]

[1012] TFA (0.5 mL) was added to a mixture of tert-butyl ((1s,4s)-4-(methylsulfonyl)-cyclohexyl)carbamate (100 mg, 0.36 mmol, 1.00 equiv) in DCM (2.0 mL). The mixture was stirred at room temperature for 2 h, then concentrated to give the crude title compound as a yellow oil.

[1013] Intermediate 5:

[1014] Synthesis of (1r,4r)-4-(methylsulfonyl)cyclohexan-1-amine trifluoroacetate

[1015]

[1016] The title compound was prepared by proceeding analogously to that described in Intermediate 4, substituting tert-butyl ((1s,4s)-4-hydroxycyclohexyl)carbamate for tert-butyl ((1r,4r)-4-hydroxycyclohexyl)carbamate in Step 1.

[1017] Intermediate 6:

[1018] Synthesis of 6-amino-2-thiaspiro[3.3]heptane 2,2-dioxide

[1019]

[1020] Step 1: Diisopropyl 3-oxocyclobutane-1,1-dicarboxylate

[1021]

[1022] To a mixture of 3,3-dimethoxycyclobutane-1,1-diisopropyl dicarboxylate (40.00 g, 139.00 mmol) in acetone (100.0 ml) was added 2N HCl aqueous solution (100.0 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with EA, washed with water, saturated NaHCO aqueous solution and brine. The organic layer was dried over NaSO, filtered and concentrated to give a crude product as a yellow liquid.

[1023] Step 2: Diisopropyl 3-hydroxycyclobutane-1,1-dicarboxylate

[1024]

[1025] NaBH4 (15.70 g, 416.10 mmol, 3.00 equiv) was added to a mixture of diisopropyl 3-oxocyclobutane-1,1-dicarboxylate (33.60 g, 138.70 mmol, 1.00 equiv) in IPA (300.0 ml), and the mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4, and concentrated to give a crude product as a yellow oil.

[1026] Step 3: Diisopropyl 3-((methylsulfonyl)oxy)cyclobutane-1,1-dicarboxylate

[1027]

[1028] To a mixture of 3-hydroxycyclobutane-1,1-diisopropyl dicarboxylate (28.0 g, 115.0 mmol, 1.00 equivalent) in DCM (300.0 ml) was added TEA (34.80 g, 344.0 mmol, 3.0 equivalents), followed by addition of MsCl (15.8 g, 138.0 mmol, 1.2 equivalents), and the mixture was stirred at room temperature for 3 hours. The mixture was diluted with water and extracted with DCM. The combined organic layer was washed with salt water, dried over Na2SO4, filtered and concentrated to give a crude product in the form of a yellow oil.

[1029] Step 4: Diisopropyl 3-azidocyclobutane-1,1-dicarboxylate

[1030]

[1031] NaN (14.90 g, 229.00 mmol, 2.00 equiv) was added to a mixture of diisopropyl 3-((methylsulfonyl)oxy)cyclobutane-1,1-dicarboxylate (36.95 g, 115.0 mmol, 1.00 equiv) in DMF (200.0 ml), and the mixture was stirred at 90 ° C under N overnight. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over Na SO, filtered, concentrated, and the residue was purified by silica gel column chromatography (PE: EA = 20: 1) to give the title compound as a yellow liquid.

[1032] Step 5: Diisopropyl 3-aminocyclobutane-1,1-dicarboxylate

[1033]

[1034] 10% Pd / C (3.00g) was added to a mixture of diisopropyl 3-azidocyclobutane-1,1-dicarboxylate (15.00g, 55.70mmol, 1.00 equivalent) in IPA / NH (150.0mL), and the mixture was allowed to stir at room temperature under H overnight. The mixture was filtered, and the filtrate was concentrated and purified by silica gel column chromatography (PE: EA = 1: 1 to DCM: MeOH = 20: 1) to give the title compound as a yellow oil.

[1035] Step 6: Diisopropyl 3-((tert-Butoxycarbonyl)amino)cyclobutane-1,1-dicarboxylate

[1036]

[1037] Boc O (10.8 g, 49.4 mmol, 1.20 equivalents) was added to a mixture of 3-aminocyclobutane-1,1-dicarboxylic acid diisopropyl ester (10.0 g, 41.10 mmol, 1.00 equivalents) in DCM (100.0 ml), and the mixture was stirred at room temperature overnight. The reaction mixture was washed with 1N HCl aqueous solution and brine. The organic layer was dried over Na SO , filtered and concentrated to give a crude product as a yellow liquid.

[1038] Step 7: tert-Butyl (3,3-bis(hydroxymethyl)cyclobutyl)carbamate

[1039]

[1040] 3-((tert-butoxycarbonyl)amino)cyclobutane-1,1-dicarboxylic acid diisopropyl ester (14.00 g, 40.80 mmol, 1.00 equiv) in THF (50.0 ml) was added dropwise to LiAlH4 (1.70 g, 44.90 mmol, 1.10 equiv) in THF (150.0 ml) at 0 ° C. The resulting mixture was warmed to room temperature and stirred for 3 hours, and then quenched by water. After stirring for 30 minutes, the mixture was filtered, and the organic layer was concentrated to give the crude product as a yellow oil.

[1041] Step 8: (3-((tert-Butoxycarbonyl)amino)cyclobutane-1,1-diyl)bis(methylene) dimethanesulfonate

[1042]

[1043] To a mixture of tert-butyl (3,3-bis(hydroxymethyl)cyclobutyl)carbamate (9.40 g, 40.60 mmol, 1.00 equiv) and TEA (24.7 g, 243.8 mmol, 6.0 equiv) in DCM (120.0 ml) was added MsCl (14.0 g, 121.9 mmol, 3.00 equiv) and the mixture was stirred at room temperature for 3 hours. The mixture was poured into ice-cold water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the crude product as a yellow oil.

[1044] Step 9: tert-Butyl 2-thiaspiro[3.3]hept-6-ylcarbamate

[1045]

[1046] NaS (3.20 g, 40.50 mmol, 1.00 equiv) was added to a mixture of (3-((tert-butoxycarbonyl)-amino)cyclobutane-1,1-diyl)bis(methylene) dimethanesulfonate (15.70 g, 40.50 mmol, 1.00 equiv) in EtOH (100.0 ml), and the mixture was stirred at 60 ° C under N overnight. The mixture was poured into ice-cold water and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, concentrated, and the residue was purified by silica gel column chromatography (PE:EA=10:1) to give the title compound as a yellow solid.

[1047] Step 10: tert-Butyl (2,2-dioxo-2-thiaspiro[3.3]heptane-6-yl)carbamate

[1048]

[1049] Oxone (22.50 g, 36.70 mmol, 3.00 equiv) is added to a mixture of tert-butyl 2-thiaspiro-[3.3]heptane-6-ylcarbamate (2.80 g, 12.20 mmol, 1.00 equiv) in MeOH:THF:H2O=2:2:1 (100.0 mL), and the mixture is stirred at room temperature overnight. The mixture is diluted with H2O and extracted with EtOAc. The combined organic layers are washed with water, brine, dried over Na2SO4, filtered and concentrated to give a crude product.

[1050] Step 11: 6-Amino-2-thiaspiro[3.3]heptane 2,2-dioxide

[1051]

[1052] To a mixture of tert-butyl (2,2-dioxo-2-thiaspiro[3.3]heptane-6-yl)carbamate (3.19 g, 12.20 mmol, 1.00 equivalent) in MeOH (2.0 ml) was added MeOH / HCl (10.0 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (PE:EA=1:1 to DCM:MeOH=10:1) to give the title compound.

[1053] Intermediate 7:

[1054] Synthesis of N-(3-(2-bromo-2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)acetamide

[1055]

[1056] Step 1: Methyl 3-acetamido-2-fluorobenzoate

[1057]

[1058] AcO (23.10 g, 0.23 mol, 1.50 eq) is added to a solution of 3-amino-2-fluoro-benzoic acid methyl ester (25.50 g, 0.15 mol, 1.00 eq) in THF (250.0 mL), and the mixture is stirred at room temperature under N overnight. The mixture is concentrated, and the residue is purified by silica gel column chromatography (PE:EA=5:1 to 3:1) to give the title compound as a pink solid.

[1059] Step 2: N-(3-(2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)acetamide

[1060]

[1061] At 0 DEG C under N2, LiHMDS (427.0mL, 0.43mol, 3.00 equivalents) in THF is added to a solution of methyl 3-acetamido-2-fluorobenzoate (30.0g, 0.14mol, 1.00 equivalents) in THF (300.0mL), followed by dropwise addition of 2-chloro-4-methylpyrimidine (23.70g, 0.18mol, 1.30 equivalents) in THF (100.0mL) at 0 DEG C. The mixture is stirred at room temperature for 2 hours, which is then quenched by NH4Cl aqueous solution. The mixture is extracted with EtOAc, and the combined organic layer is dried over Na2SO4, filtered, concentrated, and the residue is purified by silica gel column chromatography (PE:EA=2:1 to 1:1) to give the title compound as a pink solid.

[1062] Step 3: N-(3-(2-bromo-2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)acetamide

[1063]

[1064] NBS (19.70 g, 0.11 mmol, 1.00 equiv) was added portionwise to a solution of N-(3-(2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)acetamide (34.0 g, 0.11 mol, 1.00 equiv) in DCM (350.0 mL), and the mixture was stirred at room temperature overnight. The mixture was washed with water, and the organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA=5:1) to give the title compound as a yellow oil.

[1065] Intermediate 8:

[1066] Synthesis of 4-(Difluoromethyl)isoindoline

[1067]

[1068] Step 1: tert-Butyl 4-bromoisoindoline-2-carboxylate

[1069]

[1070] BocO (5.60 g, 25.64 mmol, 1.50 eq) is added to a solution of 4-bromoisoindoline hydrochloride (4.00 g, 17.09 mmol, 1.00 eq) and TEA (5.20 g, 51.28 mmol, 3.00 eq) in DCM (40.0 mL), and the mixture is stirred at room temperature overnight. The mixture is concentrated, and the residue is purified by silica gel column chromatography (PE / EA=20:1) to give the title compound as a white solid.

[1071] Step 2: tert-Butyl 4-formylisoindoline-2-carboxylate

[1072]

[1073] At -78 DEG C under N2, n-BuLi (2.5M in hexane, 3.0mL, 7.55mmol, 1.50 equivalents) is added to a solution of tert-butyl 4-bromoisoindoline-2-carboxylate (1.50g, 5.03mmol, 1.00 equivalents) in THF (15.0mL). The mixture is stirred at -78 DEG C for 30 minutes, then the DMF (735mg, 10.07mmol, 2.00 equivalents) in THF (2.0mL) is added dropwise. The mixture is stirred at -78 DEG C for 2 hours, and then quenched with NH4Cl aqueous solution, and then diluted with EtOAc. The organic layer is washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue is purified by silica gel column chromatography (PE / EA=10:1) to give the title compound as a yellow oil.

[1074] Step 3: tert-Butyl 4-(difluoromethyl)isoindoline-2-carboxylate

[1075]

[1076] A solution of DAST (587 mg, 0.64 mmol, 5.00 equiv) in DCM (1.0 mL) was added to a solution of tert-butyl 4-formylisoindoline-2-carboxylate (180 mg, 0.73 mmol, 1.00 equiv) in DCM (4.0 mL). The mixture was stirred at room temperature overnight and then concentrated. The residue was purified by silica gel column chromatography (PE / EA=10:1) to give the title compound as a yellow solid.

[1077] Step 4: 4-(Difluoromethyl)isoindoline

[1078]

[1079] TFA (1.0 mL) was added to a solution of tert-butyl 4-(difluoromethyl)isoindoline-2-carboxylate (150 mg, 0.36 mmol, 1.00 equiv) in DCM (4.0 mL). The mixture was stirred at room temperature for 3 hours and then concentrated to give the title compound as a yellow solid.

[1080] Intermediate 9:

[1081] Synthesis of 6-(Difluoromethyl)indoline

[1082]

[1083] Step 1: tert-Butyl 6-formyl-1H-indole-1-carboxylate

[1084]

[1085] Boc O (2.20 g, 10.34 mmol, 1.50 equiv) is added to a mixture of 1H-indole-6-carbaldehyde (1.00 g, 6.90 mmol, 1.00 equiv), DMAP (84 mg, 10.69 mmol, 0.10 equiv) and TEA (2.10 g, 20.69 mmol, 3.00 equiv) in DCM (15.0 mL). The mixture is stirred at room temperature overnight. The organic layer is washed with 1N HCl and brine, dried over Na SO, filtered, and concentrated to give the title compound as a white solid.

[1086] Step 2: tert-Butyl 6-(difluoromethyl)-1H-indole-1-carboxylate

[1087]

[1088] To a solution of tert-butyl 6-formyl-1H-indole-1-carboxylate (1.10 g, 4.49 mmol, 1.00 equiv) in DCM (15.0 mL) was added dropwise DAST (3.60 g, 22.45 mmol, 5.00 equiv) in DCM (5.0 mL) at 0 ° C. and stirred overnight. The mixture was diluted with DCM, washed with aqueous NaHCO solution and brine, dried over Na SO, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE / EA=4:1) to give the title compound as a yellow oil.

[1089] Step 3: tert-Butyl 6-(difluoromethyl)indoline-1-carboxylate

[1090]

[1091] A mixture of tert-butyl 6-(difluoromethyl)-1H-indole-1-carboxylate (500 mg, 1.87 mmol, 1.00 equivalent) and Pd / C (10%, 100 mg, 20% wt) in MeOH (15.0 mL) was stirred at 50 ° C for 3 hours. The mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (PE / EtOAc (3: 1)) to give the title compound as a yellow solid.

[1092] Step 4: 6-(Difluoromethyl)indoline

[1093]

[1094] TFA (1.0 mL) was added to a mixture of tert-butyl 6-(difluoromethyl)indoline-1-carboxylate (350 mg, 1.30 mmol, 1.00 equiv) in DCM (4.0 mL), and the mixture was stirred at room temperature for 2 h. The mixture was concentrated to give the title compound as a yellow oil.

[1095] Intermediate 10:

[1096] Synthesis of 5-Isoindoline-1-ylmethanol

[1097]

[1098] Step 1: Methyl 3,4-bis(bromomethyl)benzoate

[1099]

[1100] NBS (21.70 g, 121.80 mmol, 2.00 equiv) and AIBN (0.30 g, 1.83 mmol, 0.03 equiv) were added to a solution of methyl 3,4-dimethylbenzoate (10.00 g, 60.90 mmol, 1.00 equiv) in CCl4 (80.0 mL), and the mixture was stirred at 80° C. for 16 h. The mixture was filtered and the filtrate was concentrated to give the title compound as a yellow oil.

[1101] Step 2: Methyl 2-benzylisoindoline-5-carboxylate

[1102]

[1103] Phenylmethylamine (2.50 g, 23.30 mmol, 1.00 equivalent) in THF (50.0 mL) is added to a stirred mixture of 3,4-bis(bromomethyl)benzoic acid methyl esters (7.50 g, 23.30 mmol, 1.00 equivalent) and TEA (5.20 g, 51.30 mmol, 2.20 equivalent) in THF (100.0 mL). The mixture is stirred at room temperature for 3 hours and then concentrated. The residue is purified by silica gel column chromatography eluting with PE / EtOAc (10: 1) to give the title compound as a yellow solid.

[1104] Step 3: (2-Benzylisoindolin-5-yl)methanol

[1105]

[1106] A solution of methyl 2-benzylisoindoline-5-carboxylate (2.00 g, 7.48 mmol, 1.00 equiv) in THF (20.0 mL) was added dropwise to a stirred suspension of LAH (426 mg, 11.22 mmol, 1.50 equiv) in THF (20.0 mL). The resulting mixture was stirred at room temperature for 3 hours. 1M NaSO aqueous solution (2.0 mL) was slowly added and the solid was removed by filtration. The filtrate was concentrated to give the title compound as a yellow solid.

[1107] Step 4: Isoindolin-5-ylmethanol

[1108]

[1109] Pd / C (10% w / w, 40 mg) was added to a solution of (2-benzylisoindolin-5-yl) methanol (200 mg, 0.84 mmol, 1.00 equiv) in EtOH (10.0 mL), and the mixture was stirred at 50 ° C. under H 2 (50 psi) overnight. The mixture was filtered and purified by silica gel column chromatography eluting with DCM / MeOH (10: 1) to give the title compound as a yellow solid.

[1110] Intermediate 11:

[1111] Synthesis of 4-(Difluoromethoxy)isoindoline

[1112]

[1113] Step 1: tert-Butyl 4-bromoisoindoline-2-carboxylate

[1114]

[1115] TEA (10.36 g, 102.34 mmol, 3.00 equiv) and Boc O (8.93 g, 40.93 mmol, 1.20 equiv) are added to a solution of 4-bromoisoindoline hydrochloride (8.00 g, 34.11 mmol, 1.00 equiv) in DCM (80.0 mL), and the mixture is stirred at room temperature for 2 hours. The mixture is diluted with H O and extracted with DCM. The combined organic layers are washed with brine, dried over Na SO , filtered and concentrated. The residue is slurried in PE (50.0 mL), and the mixture is filtered and the solid is washed with PE and dried under vacuum to give the title compound as an off-white solid.

[1116] Step 2: tert-Butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-2-carboxylate

[1117]

[1118] A mixture of tert-butyl 4-bromoisoindoline-2-carboxylate (1.00 g, 3.35 mmol, 1.00 equiv), Pd(dppf)Cl2 (0.25 g, 0.34 mmol, 0.10 equiv), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (1.02 g, 4.02 mmol, 1.20 equiv) and KOAc (0.66 g, 6.71 mmol, 2.00 equiv) in 1,4-dioxane (10.0 mL) was stirred at 100 ° C under N2 for 8 hours. The mixture was diluted with H2O and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was dissolved in DCM, passed through a pad of silica, and the filtrate was concentrated to give the title compound as a yellow solid.

[1119] Step 3: tert-Butyl 4-hydroxyisoindoline-2-carboxylate

[1120]

[1121] NH4Cl (0.18 g, 3.36 mmol, 0.10 equiv), H2O (10.0 mL) and H2O2 (10%, 20.0 mL) were added to a solution of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-2-carboxylate (1.16 g, 3.36 mmol, 1.00 equiv) in THF (20.0 mL), and the mixture was stirred at room temperature under N2 overnight. The mixture was extracted with EA, and the combined organic phases were washed with saturated aqueous Na2S2O3 solution, water, and brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (PE:EA=5:1) to give the title compound as an off-white solid.

[1122] Step 4: tert-Butyl 4-(difluoromethoxy)isoindoline-2-carboxylate

[1123]

[1124] NaH (61 mg, 1.53 mmol, 1.20 equiv) is added to a solution of tert-butyl 4-hydroxy-isoindoline-2-carboxylate (300 mg, 1.28 mmol, 1.00 equiv) in DMF (5.0 mL), and the mixture is stirred at 80 ° C for 15 minutes. CHClF2 is bubbled into the mixture, and the mixture is stirred at 80 ° C for 2 hours. The mixture is diluted with NH4Cl aqueous solution and extracted with EA. The combined organic phases are washed with water, brine, dried over Na2SO4, filtered and concentrated. The residue is purified by silica gel column chromatography (PE: EA = 10: 1) to give the title compound as a yellow solid.

[1125] Step 5: 4-(Difluoromethoxy)isoindoline

[1126]

[1127] MeOH / HCl (2M, 2.0 mL) was added to a solution of tert-butyl 4-(difluoromethoxy)-isoindoline-2-carboxylate (165 mg, 0.58 mmol, 1.00 equiv) in MeOH (1.0 mL), and the mixture was stirred at room temperature under N for 2 h. The mixture was concentrated to give the title compound as a yellow solid.

[1128] Intermediate 12:

[1129] Synthesis of Bicyclo[1.1.1]pentane-1-carboxylic Acid

[1130]

[1131] Step 1: Tricyclo[1.1.1.01,3]pentane

[1132]

[1133] MeLi (1.6 M in diethyl ether, 126.3 mL, 202.14 mmol, 2.40 equiv) was added dropwise to a mixture of 1,1-dibromo-2,2-bis(chloromethyl)cyclopropane (25.0 g, 84.23 mmol, 1.00 equiv) in diethyl ether (40.0 mL) at -78 ° C. The mixture was stirred at -78 ° C for 15 min and then warmed to -5 ° C and stirred for 2 hours. The reaction mixture was warmed to 40 ° C and the title compound was obtained as an ether solution by vacuum distillation.

[1134] Step 2: Bicyclo[1.1.1]pentan-1-yl(phenyl)sulfane

[1135]

[1136] A mixture of sodium thiophenolate (11.1 g, 84.23 mmol, 1.00 equiv) in H2O (60.0 mL) was adjusted to pH = 2-3 with 3M HCl and extracted with MTBE (100.0 mL). A solution of thiophenol in MTBE was added to a solution of tricyclo[1.1.1.01,3]pentane (5.70 g, 84.23 mmol, 1.00 equiv) in diethyl ether, and the mixture was stirred at room temperature under N2 for 1 hour. The mixture was poured into 1M NaOH, extracted with MBTE, and the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE:EA=20:1) to give the title compound as a colorless oil.

[1137] Step 3: Bicyclo[1.1.1]pentane-1-carboxylic acid

[1138]

[1139] At -78 DEG C, n-BuLi (2.5M in hexane, 0.2mL, 0.57mmol, 0.10 equivalent) is added to a mixture of 4,4'-di-tert-butylbiphenyl (3.00g, 1.35mmol, 2.00 equivalent) and 1,10-phenanthroline (102mg, 0.57mmol, 0.10 equivalent) in THF (10.0mL). The mixture is stirred at -78 DEG C for 30 minutes, and then at -50 DEG C for 30 minutes. A solution of bicyclo [1.1.1] pentane -1- base (phenyl) sulfane (1.00g, 5.67mmol, 1.00 equivalent) in THF (5.0mL) is added to the mixture. Anhydrous CO is bubbled into the solution, and the mixture is slowly warmed to room temperature, which is then quenched with saturated NaCOaqueous solution. The mixture is extracted with MTBE, and the organic layer is washed with saturated NaCO. The aqueous layer pH was adjusted to pH=1-2 with 2N HCl aqueous solution and extracted with DCM / MeOH. The combined organic layers were concentrated, and the residue was purified by silica gel column chromatography (DCM / MeOH=50:1) to give the title compound as a brown oil.

[1140] Intermediate 13:

[1141] Synthesis of 1-(Difluoromethyl)cyclopropanecarboxylic acid

[1142]

[1143] Step 1: Ethyl 1-formylcyclopropanecarboxylate

[1144]

[1145] Dess-Martin reagent (110.0 g, 0.26 mol, 1.50 eq) was added to a stirred solution of ethyl 1-(hydroxymethyl)cyclopropanecarboxylate (25.00 g, 0.17 mol, 1.00 eq) in DCM (500.0 mL), and the mixture was stirred at room temperature under N overnight. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (PE:EA=20:1) to give the title compound as a pale yellow oil.

[1146] Step 2: Ethyl 1-(difluoromethyl)cyclopropanecarboxylate

[1147]

[1148] DAST (41.00 g, 0.25 mol, 2.00 equivalents) was added to a stirred mixture of 1-formyl-cyclopropanecarboxylic acid ethyl ester (18.00 g, 0.13 mol, 1.00 equivalents) in DCM (350.0 mL) at 0 ° C, and the mixture was stirred at room temperature under N2 overnight. The reaction mixture was diluted with water and then extracted with EtOAc. The combined organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE: EA = 10: 1) to give the title compound as a light yellow oil.

[1149] Step 3: 1-(Difluoromethyl)cyclopropanecarboxylic acid

[1150]

[1151] NaOH (7.80 g, 195.12 mmol, 2.00 equiv) is added to a stirred mixture of ethyl 1-(difluoro-methyl)cyclopropanecarboxylate (16.00 g, 97.56 mmol, 1.00 equiv) in MeOH (150.0 mL) and water (75.0 mL), and the mixture is stirred at room temperature overnight. The mixture is diluted with water and adjusted to pH 1 by adding 3N HCl aqueous solution. The mixture is extracted with Et...

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof; in: W is N, CH or C - when W is attached to R 6 hour; X and Z are independently CR 8 NR 8A , N, O, or S; and Y is CR 9 NR 10 , or N; provided that both X and Z are not O or S at the same time; and at least one of X, Y and Z is not carbon; R 8 is hydrogen, alkyl, halo, hydroxyalkyl, or cyano; R 8A is hydrogen or alkyl; R 9 and R 10 are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cyanoalkyl, alkylsulfonyl, alkylsulfonylalkyl, amino, alkylamino, dialkylamino, substituted amino, aminoalkyl, cycloalkyl, bicyclic cycloalkyl, bridged cycloalkyl, spirocycloalkyl, heterocyclyl, bicyclic heterocyclyl, bridged heterocyclyl, spiroheterocyclyl, aryl, aralkyl, heteroaryl or heteroaralkyl, wherein: (A)R 9 and R 10 The cycloalkyl, bicyclic cycloalkyl, bridged cycloalkyl, and spirocycloalkyl in the present invention are substituted by one or two R independently selected from hydrogen, deuterium, alkyl, deuterated alkyl, cycloalkyl, halo, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, alkylamino, and dialkylamino. a replace; (B)R 9 and R 10 wherein the heterocyclyl, bicyclic heterocyclyl, bridged heterocyclyl, and spiro heterocyclyl are independently selected from hydrogen, alkyl, deuterated alkyl, cycloalkyl, bridged cycloalkyl, spiro cycloalkyl (wherein the cycloalkyl, bridged cycloalkyl, and spiro cycloalkyl are substituted with one or two substituents independently selected from hydrogen, alkyl, halo, hydroxy, and cyano), alkoxy, halo, haloalkyl, haloalkoxy, alkoxycarbonyl, hydroxy, cyano, amino, alkylamino, dialkylamino, aryl, aralkyl, heterocyclyl, bridged heterocyclyl, spiroheterocyclyl, heteroaryl, or heteroaralkyl (wherein the aryl itself or as part of the aralkyl, the heteroaryl itself or as part of the heteroaralkyl, the heterocyclyl, bridged heterocyclyl, and spiroheterocyclyl are independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, cyano, amino, alkylamino, and dialkylamino R e , R f and R g Replace) b , R c and R d Replacement; and (C)R 9 and R 10 wherein the aryl radical by itself or as part of the aralkyl radical and the heteroaryl radical by itself or as part of the heteroaralkyl radical are independently selected from hydrogen, alkyl, deuterated alkyl, cycloalkyl (wherein the cycloalkyl radical is optionally substituted with one or two substituents independently selected from alkyl, halo, hydroxy and cyano), alkoxy, halo, haloalkyl, haloalkoxy, alkoxycarbonyl, hydroxy, cyano, amino, alkylamino, dialkylamino, aryl, aralkyl, heterocyclyl, bridged heterocyclyl, spiroheterocyclyl, heteroaryl, or heteroaralkyl (wherein the R of the aryl radical by itself or as part of the aralkyl radical, the heteroaryl radical by itself or as part of the heteroaralkyl radical, heterocyclyl, bridged heterocyclyl and spiroheterocyclyl are independently selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, cyano, amino, alkylamino and dialkylamino radicals m , R n and R o Replace) h , R j and R k replace; Ring R A is phenyl or heteroaryl; R 1 , R 2 and R 3 are independently hydrogen, deuterium, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, or cyano; R 4 and R 5 are independently hydrogen, alkyl, haloalkyl, alkoxyalkyl, hydroxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, fused cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, bicyclic heterocyclyl, bicyclic heterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl, fused heterocyclyl, fused heterocyclylalkyl, spiroheterocyclyl, and spiroheterocyclylalkyl (wherein cycloalkyl itself or as part of cycloalkylalkyl, fused cycloalkyl, aryl itself or as part of aralkyl, heteroaryl itself or as part of heteroaralkyl, heterocyclyl itself or as part of heterocyclylalkyl, bicyclic heterocyclyl itself or as part of bicyclic heterocyclylalkyl, bridged heterocyclyl itself or as part of bridged heterocyclylalkyl, fused heterocyclyl itself or as part of fused heterocyclylalkyl, and spiroheterocyclyl itself or as part of spiroheterocyclylalkyl are independently selected from hydrogen, alkyl, alkoxy, alkylsulfonyl, alkyloxycarbonyl, R is hydroxy, acyl, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, substituted amino, alkoxycarbonylamino, alkoxycarbonylaminoalkyl, aminocarbonyl, aminocarbonylalkyl, cyano, hydroxyalkyl, hydroxyalkoxy, alkoxyalkyl, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, aminoalkylamino, cyanoalkyl, cyanoalkoxy, cycloalkyl, cycloalkyloxy, aryl, aryloxy, aralkyl, heteroaryl, heteroaryloxy, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxy and heterocyclylalkyloxy (wherein aryl by itself or as part of aralkyl and aryloxy, heteroaryl by itself or as part of heteroaryloxy and heteroaralkyl, and heterocyclyl by itself or as part of heterocyclylalkyl, heterocyclyloxy and heterocyclylalkyloxy are substituted with one, two or three substituents independently selected from hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy and cyano) p , R q and R r or R 4 and R 5 Together with the nitrogen atom to which they are attached, they form a cyclic amine, a bicyclic amine, a fused cyclic amine, a bridged cyclic amine, a fused bridged cyclic amine, a spiroamine, or a fused spiroamine, wherein each of the above rings is independently selected from hydrogen, deuterium, alkyl, alkoxy, alkylsulfonyl, alkoxycarbonyl, hydroxy, acyl, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, substituted amino, alkoxycarbonylamino, alkoxycarbonylaminoalkyl, aminocarbonyl, aminocarbonylalkyl, cyano, hydroxyalkyl, hydroxyalkoxy, alkoxyalkyl, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, aminoalkylamino, cyano R is substituted with one to three substituents independently selected from hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy and cyano. s , R t and R u replace; R 6 is hydrogen, alkyl, cycloalkyl, cyano, halo, or haloalkyl; R 7 Yes-Q-(alk 1 ) n1 -SO2R 11 , -Q 1 -(alk 2 ) n2 -SO(=NR 12 )R 13 , -Q 2 -(alk 3 ) n3 -SO2NR 14 R 15 , -Q 3 -(alk 4 ) n4 -COR 16 , -Q 4 -(alk 5 ) n5 -CONR 17 R 18 , -Q 5 -(alk 6 ) n6 -NR 19 COR 20 , -Q 6 -(alk 7 ) n7 -NR 21 S02R 22 , heterocyclic group, bicyclic heterocyclic group, fused heterocyclic group, spiro heterocyclic group, bridged heterocyclic group, cyclic sulfoximino group, bicyclic sulfoximino group, spiro sulfoximino group, aryl group, heteroaryl group, or fused heteroaryl group, wherein: Q, Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , and Q 6 Each of is a bond, a cycloalkyl, a bridged cycloalkyl, a spirocycloalkyl, a heterocyclyl A , bicyclic heterocyclic group A , bridged heterocyclic group A , fused heterocyclic group A , spiro heterocyclic group A , aryl, or heteroaryl, wherein each of the above rings is independently selected from hydrogen, deuterium, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, and cyano. v and R w replace; n 1 、n 2 、n 3 、n 4 、n 5 、n 6 , and n 7 Each of is 0 or 1, provided that when Q is a bond, then n 1 、n 2 、n 3 、n 4 、n 5 、n 6 , and n 7 Each of is 1; alk 1 alk 2 alk 3 alk 4 alk 5 alk 6 and alk 7 each is an alkylene group; R 12 , R 19 and R 21 is hydrogen or alkyl; R 11 , R 13 , R 16 , R 20 and R 22 are independently selected from hydrogen, alkyl, fluorine, chlorine, bromine, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, bicyclic heterocyclyl, bridged heterocyclyl, fused heterocyclyl, spiroheterocyclyl, heterocyclylalkyl, or -CR 23 =CR 24 R 25 [Where R 23 is hydrogen, alkyl, or cyano, R 24 is hydrogen or alkyl, and R 25 is hydrogen, alkyl, halo, haloalkyl, alkoxyalkyl, hydroxyalkyl, amino, alkylamino, dialkylamino, or -(alkylene)-NR 26 R 27 (where R 26 and R 27 are independently hydrogen or alkyl) or heterocyclylalkyl], wherein R 11 , R 13 , R 16 , R 20 and R 22 The cycloalkyl radicals in the formula (a) are cycloalkyl radicals by themselves or as part of cycloalkylalkyl radicals, aryl radicals by themselves or as part of arylalkyl radicals, heteroaryl radicals by themselves or as part of heteroarylalkyl radicals, heterocyclyl radicals by themselves or as part of heterocyclylalkyl radicals, bicyclic heterocyclyl radicals, bridged heterocyclyl radicals, fused heterocyclyl radicals, and spiroheterocyclyl radicals, and R 25 The heterocyclylalkyl in the heterocyclyl is substituted with one to three substituents independently selected from hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cyano, and heterocyclyl; provided that R 11 , R 16 , R 20 , and R 22 It is not hydrogen; R 14 , R 15 , R 17 and R 18 independently selected from hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl, wherein cycloalkyl by itself or as part of cycloalkylalkyl, aryl by itself or as part of aralkyl, heteroaryl by itself or as part of heteroaralkyl, and heterocyclyl by itself or as part of heterocyclylalkyl are substituted with one to three substituents independently selected from hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, and cyano; and R 7 The heterocyclic radical, bicyclic heterocyclic radical, fused heterocyclic radical, spiro heterocyclic radical, bridged heterocyclic radical, cyclic sulfoximino radical, spirocyclic sulfoximino radical, aryl, heteroaryl, and fused heteroaryl radical are independently selected from hydrogen, deuterium, alkyl, alkoxy, alkoxycarbonyl, hydroxy, acyl, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, substituted amino, alkoxycarbonylamino, alkoxycarbonylaminoalkyl, aminocarbonyl, aminocarbonylalkyl, cyano, hydroxyalkyl, hydroxyalkoxy, alkoxyalkyl, alkoxyalkyloxy, alkoxyalkyloxyalkyl, aminoalkyl, aminoalkoxy, aminoalkylamino, cyanoalkyl, cyanoalkoxy R is alkyl, cycloalkyl, cycloalkyloxy, aryl, aryloxy, aralkyl, heteroaryl, heteroaryloxy, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylalkyloxy (wherein aryl by itself or as a part of aralkyl and aryloxy, heteroaryl by itself or as a part of heteroaryloxy and heteroaralkyl, and heterocyclyl by itself or as a part of heterocyclylalkyl, heterocyclyloxy, and heterocyclylalkyloxy are substituted with one to three substituents independently selected from hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, alkoxycarbonyloxy, alkoxyalkyl, alkoxyalkyloxyalkyl, cyano, and heterocyclyl) x , R y , and R y1 replace; The prerequisite is that the compound having formula (I) is not: N-(3-(2-isopropyl-5-(2-((2-(methylsulfonyl)ethyl)amino)pyrimidin-4-yl)thiazol-4-yl)phenyl)morpholine-4-sulfonamide.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein:

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, having a structure according to formula (Ia):

4. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, having a structure according to formula (Id'):

5. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein: R 1 , R 2 , and R 3 and R is independently hydrogen, deuterium, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, or cyano.

6. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein: R 1 is fluorine, R 2 is hydrogen, deuterium, fluorine, chlorine, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy or cyano, and R 3 It's hydrogen.

7. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein: R 1 is fluorine, and R 2 and R 3 It's hydrogen.

8. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein R 4 and R 5 Together with the nitrogen atom to which they are attached, they form a cyclic amine group, a bicyclic amine group, a fused cyclic amine group, a bridged cyclic amine group, or a spiroamine group, wherein the cyclic amine group, the bicyclic amine group, the fused cyclic amine group, the bridged cyclic amine group, and the spiroamine group are R s , R t , and R u replace.

9. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein: R 4 and R 5 Together with the nitrogen atom to which they are attached, they form the s , R t , and R u A substituted fused cyclic amine group.

10. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein By R 4 and R 5 The fused cyclic amine groups formed together with the nitrogen atom to which they are attached have a structure according to formula (a): in: p is 0, 1 or 2; and q is 0, 1, 2, 3 or 4; provided that p+q is at least 2 and p+q is not greater than 5; and when p or q is 3 or 4, then one of such p or q -CH2- may be NH, N (when attached to R s , R t , and R u ), O or S(O) n substitution; wherein n is 0, 1 or 2; and The structure of formula (a) is R s , R t , and R u replace.

11. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, wherein: Said by R 4 and R 5 The fused cyclic amine groups formed together with the nitrogen atom to which they are attached have a structure according to formula (b): in: p1 is 0, 1 or 2; and q1 is 0, 1, 2, 3 or 4; provided that p+q is at least 2 and p+q is not greater than 5; and when p or q is 3 or 4, then one of such p or q -CH2- may be NH, N (when attached to R s , R t , and R u ), O or S(O) n substitution; wherein n is 0, 1 or 2; Het is a 5-membered or 6-membered heteroaryl; and The structure of formula (b) is R s , R t , and R u replace.

12. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein: R 4 and R 5 Together with the carbon atoms to which they are attached, they form a ring selected from: Each ring is R s , R t , and R u replace.

13. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein: R s is hydrogen, deuterium, alkyl, alkoxy, alkylsulfonyl, hydroxy, acyl, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, substituted amino, alkoxycarbonylaminoalkyl, aminocarbonyl, aminocarbonylalkyl, cyano, hydroxyalkyl, hydroxyalkoxy, alkoxyalkyl, alkoxyalkyloxy, aminoalkyl, aminoalkoxy, cyanoalkyl, cyanoalkoxy, cycloalkyl, cycloalkoxy, aryl, aryloxy, aralkyl, heteroaryl, heteroaryloxy, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, or unsubstituted heterocyclyl (wherein aryl by itself or as part of aryloxy and aralkyl, heteroaryl by itself or as part of heteroaryloxy and heteroaralkyl, heterocyclyl by itself or as part of heterocyclylalkyl and heterocyclyloxy, and unsubstituted heterocyclyl are substituted with one to three substituents independently selected from hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, and cyano), R t is hydrogen, alkyl, alkoxy, alkylsulfonyl, hydroxy, acyl, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, and cyano, and R u It's hydrogen.

14. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein: R s is selected from the group consisting of hydrogen, deuterium, methyl, ethyl, isopropyl, cyclopropyl, cyclohexyl, methoxy, ethoxy, isopropoxy, methylsulfonyl, ethylsulfonyl, hydroxy, methylcarbonyl, fluorine, chlorine, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, amino, methylamino, dimethylamino, cyano, cyanomethyl, 2-cyanopropan-2-yl, cyanomethyloxy, hydroxymethyl, 1-hydroxyethyl, 1-hydroxy-1-methylethyl, methoxymethyl, methylaminomethyl , 1-methyl-2-oxo-1,6-dihydropyridinyl ... t is hydrogen, fluorine, chlorine, methoxy, difluoromethyl, difluoromethoxy, trifluoromethyl, trifluoromethoxy or cyano, and R u It's hydrogen.

15. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 14, wherein: R 4 and R 5 Together with the nitrogen atom to which they are attached, they form a ring selected from the group consisting of isoindolyl, 4-cyanoisoindolyl, 5-cyanoisoindolyl, 4-methoxyisoindolyl, 5-methoxyisoindolyl, 4-ethoxyisoindolyl, 4-isopropoxyisoindolyl, 5,6-dimethoxyisoindolyl, 5-hydroxymethylisoindolyl, 4-difluoromethylisoindolyl, 5-difluoromethylisoindolyl, 4-difluoromethoxyisoindolyl, 4-trifluoromethylisoindolyl, 5-trifluoromethylisoindolyl, 4-fluoroisoindolyl, 5 -fluoroisoindolin-2-yl, 5,6-difluoroisoindolin-2-yl, 1-methylisoindolin-2-yl, 4-methylamino-carbonylisoindolin-2-yl, 4-dimethylaminocarbonylisoindolin-2-yl, 5-dimethylaminocarbonylisoindolin-2-yl, 4-(2-(dimethylamino)ethoxy)-isoindolin-2-yl, 4-(2-(methylamino)ethoxy)-isoindolin-2-yl, 4-dimethylaminomethylisoindolin-2-yl, 5-dimethylaminomethylisoindolin-2-yl, 4-methylaminomethylisoindolin-2-yl, 4-dimethyl-aminoisoindolin-2-yl, 4-methylaminoisoindolin-2-yl, 3- phenylisoindolin-2-yl, 4-phenylisoindolin-2-yl, 4-phenoxyisoindolin-2-yl, 1-benzylisoindolin-2-yl, 4-benzylisoindolin-2-yl, 4-(3-fluoro-phenoxy)isoindolin-2-yl, 4-(4-fluorophenoxy)isoindolin-2-yl, 4-(2-cyanophenoxy)isoindolin-2-yl, 4-(3-cyanophenoxy)-isoindolin-2-yl, 4-cyclohexylisoindolin-2-yl, 5-(hydroxymethyl)isoindolin-2-yl, 4-(2-hydroxyethoxy)isoindolin-2-yl, 4-(2-aminoethoxy)isoindolin-2-yl, 5-(cyanomethyl)-isoindolin-2-yl, 4-(Cyanomethyl)isoindolyl, indolyl-1-yl, 2-methylindolyl-1-yl, 4-cyanoindolyl-1-yl, 5-cyanoindolyl-1-yl, 6-cyanoindolyl-1-yl, 4-hydroxymethylindolyl-1-yl, 6-difluoromethylindolyl-1-yl, 4-trifluoromethylindolyl-1-yl, 5-trifluoromethylindolyl-1-yl, 6-trifluoromethylindolyl-1-yl, 6-methoxyindolyl-1-yl, 5-chloroindolyl-1-yl, 6-chloroindolyl-1-yl, 6-dimethylaminoindolyl-1-yl, 6-fluoroindolyl-1-yl, 5,6-difluoroindolyl-1-yl, 4,6-difluoroindolyl-1-yl, 4,5-difluoroindolyl, 6-difluoromethoxyindolyl, 6-trifluoromethoxyindolyl, 4-((dimethylamino)methyl)indolyl, 5-((dimethylamino)methyl)indolyl, 6-((dimethyl-amino)methyl)indolyl, 4-((methylamino)methyl)indolyl, 5-((methylamino)methyl)-indolyl, 6-((methylamino)methyl)indolyl, 6-methylaminocarbonylindolyl, 6-aminocarbonyl-indolyl, -dimethylaminocarbonyl indolin-1-yl, 4-(2-(methylamino)ethoxy)-indolin-1-yl, 6-(2-(dimethylamino)ethoxy)indolin-1-yl, 4-(hydroxymethyl)indolin-1-yl, 5-phenylindolin-1-yl, 6-(1-methyl-6-oxo-1,6-dihydropyridin-2-yl)indolin-1-yl, 4-(1-hydroxyethyl)-indolin-1-yl, 4-(2-hydroxypropane-2-yl)indolin-1-yl, 6-(2-hydroxypropane-2-yl)indolin-1-yl, 4-(cyanomethyl)indolin -1-yl, 6-(2-cyanopropane-2-yl)indol-1-yl, 4-(morpholinomethyl)indol-1-yl, 4-methoxycarbonyl-aminomethylindol-1-yl, 7-(methylamino)indol-1-yl, 6-(methylsulfonyl)indol-1-yl, 6-chloroindol-1-yl, 3,4-dihydroisoquinolin-2-yl, 1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl, 2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl, 2,3-dihydro-4H-benzo[b][1,4]oxazine-4 -yl, 4-methyl-3,4-dihydroquinoxalin-1(2H)-yl, 1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl, 3,4-dihydroquinoxalin-1(2H)-yl, 2,3-dihydrobenzo[f][1,4]oxazepin-4(5H)-yl, 1,3,4,5-tetrahydro-2H-benzo[c]azepin-2-yl, and 1-methyl-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepin-4-yl, 2,3-dihydrobenzo[e][1,4]oxazepin-1(5H)-yl. , 16. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, wherein: W is N.

17. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, wherein: R 9 and R 10 are independently alkyl, cycloalkyl, bridged cycloalkyl, spirocycloalkyl, heterocyclyl, bridged heterocyclyl, or spiroheterocyclyl, wherein: (A)R 9 and R 10 The cycloalkyl, bridged cycloalkyl, and spirocycloalkyl in the a Replacement; and (B)R 9 and R 10 The heterocyclic group, bridged heterocyclic group, and spiro heterocyclic group in R b , R c , and R d replace.

18. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 17, wherein: R 9 and R 10 It is an alkyl group.

19. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 17, wherein: R 9 and R 10 are independently cycloalkyl, bridged cycloalkyl, or spirocycloalkyl, wherein R 9 and R 10 The cycloalkyl, bridged cycloalkyl, and spirocycloalkyl in a replace.

20. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 17 and 19, wherein One or both R a are independently selected from hydrogen, deuterium, methyl, trideuterated methyl, fluorine, chlorine, difluoromethyl, trifluoromethyl, and cyano.

21. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 17, wherein: R 9 and R 10 are independently heterocyclyl, bridged heterocyclyl, or spiro heterocyclyl, wherein R 9 and R 10 The heterocyclic group, bridged heterocyclic group, and spiro heterocyclic group in R b , R c , and R d replace.

22. A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 17 and 19 to 21, wherein: R 9 and R 10 The cycloalkyl group and the bridged cycloalkyl group are selected from: And R 9 and R 10 The heterocyclic group and the bridged heterocyclic group are selected from: Where each cycloalkyl group and bridged cycloalkyl group is R a and each heterocyclic group and bridged heterocyclic group is replaced by R b , R c and R d replace.

23. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 17, 19, 20 and 22, wherein: Where R 9 and R 10 The bridged cycloalkyl group is selected from: Each bridging cycloalkyl group is R a replace.

24. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 17, 19, 20, 22, and 23, wherein: R a is hydrogen, deuterium, chlorine, fluorine, difluoromethyl or trifluoromethyl.

25. A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 17, 19, 20 and 22 to 24, wherein: R 9 and R 10 The bridged cycloalkyl in is bicyclo[1.1.1]pentan-1-yl, 3-fluorobicyclo[ 1.1.1]pentan-1-yl, 3-chlorobicyclo-[1.1.1]pentan-1-yl, 3-(hydroxymethyl)-bicyclo[1.1.1]pentan-1-yl, 3-(trifluoromethyl)-bicyclo[1.1.1]pentan-1-yl, 3-(difluoromethyl)-bicyclo[ 1.1.1] pentane-1-yl, and R 9 and R 10 The cycloalkyl group in is cyclobutyl, cyclopropyl, 1-(difluoromethyl)cyclobutyl, 1-(trifluoromethyl)cyclobutyl, 1-(difluoromethyl)cyclopropyl or 1-(trifluoromethyl)cyclopropyl.

26. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 17, 21 and 22, wherein: R b and R c are independently selected from hydrogen, methyl, fluorine, chlorine, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, hydroxyl, and cyano, and R d Selected from hydrogen, methyl, trideuterated methyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, amino, dimethylamino, diethylamino, 3,3-difluorocyclobutyl, 4,4-difluorocyclohexyl, 3-hydroxy-3-methylcyclobutyl, 3-cyano-3-methylcyclobutyl, oxetan-3-yl, tetrahydrofuran-2-yl, tetrahydropyran-4-yl, 1,1-dioxosulfurized cyclopropane-3-yl, 1,1-dioxotetrahydro-2H-thiopyran-4-yl, benzyl, phenyl, pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl.

27. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 26, wherein: R 7 Yes-Q-(alk 1 ) n1 -SO2R 11 , -Q 2 -(alk 3 ) n3 -SO2NR 14 R 15 , heterocyclic group, bicyclic heterocyclic group, spiro heterocyclic group, or spiro sulfoximino group, wherein the heterocyclic group, bicyclic heterocyclic group, spiro heterocyclic group, and spiro sulfoximino group are R x , R y , and R y1 replace.

28. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 27, wherein: R 7 Yes-Q-(alk 1 ) n1 -SO2R 11 .

29. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 27, wherein: R 7 Yes-Q 2 -(alk 3 ) n3 -SO2NR 14 R 15 .

30. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 29, wherein: Q, Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , and Q 6 Each of the following is a cycloalkyl group, a bridged cycloalkyl group, a spirocycloalkyl group, a heterocyclic group A , bicyclic heterocyclic group A , bridged heterocyclic group A , spiro heterocyclic group A , aryl, or heteroaryl, wherein each of the above rings is replaced by R v and R w replace.

31. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 30, wherein: n 1 、n 2 、n 3 、n 4 、n 5 、n 6 , and n 7 Each of is 0.

32. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 31, wherein: R 7 Among them: (1) Q, Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , and Q 6 Each of these is: Each ring in (1) is R v and R w Replacement; and (2)R 7 The heterocyclic group, bicyclic heterocyclic group, spiro heterocyclic group, bridged heterocyclic group, cyclic sulfoximino group, spiro sulfoximino group, aryl group, heteroaryl group and fused heteroaryl group in are wherein: Heterocyclic groups are: Spiroheterocyclyl is: The bridged heterocyclic group is: Bicyclic heterocyclyl is: The spirosulfoximine group is: The cyclic sulfoximine group is: The fused heteroaryl group is: Each ring in (2) is R x , R y and R y1 replace; and Among them, (1) and (2) In the compound of formula (I), -NHR 7 The NH bond of part; and (1) Expressed to -Q-(alk 1 ) n1 -SO2R 11 , -Q 1 -(alk 2 ) n2 -SO(=NR 12 )R 13 , -Q 2 -(alk 3 ) n3 -SO2NR 14 R 15 , -Q 3 -(alk 4 ) n4 -COR 16 , -Q 4 -(alk 5 ) n5 -CONR 17 R 18 , -Q 5 -(alk 6 ) n6 - NR 19 COR 20 , or -Q 6 -(alk 6 ) n7 -NR 21 S02R 22 The rest of the keys.

33. A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 32, wherein: (1) Q, Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , and Q 6 Each of these is: Each ring in (1) is R v and R w Replace, and In the compound having the formula (I), -NHR 7 Part of the NH bond and Expressed to -Q-(alk 1 ) n1 -SO2R 11 , -Q 1 -(alk 2 ) n2 -SO(=NR 12 )R 13 , -Q 2 -(alk 3 ) n3 -SO2NR 14 R 15 , -Q 3 -(alk 4 ) n4 -COR 16 , -Q 4 -(alk 5 ) n5 CONR 17 R 18 , -Q 5 -(alk 6 ) n6 - NR 19 COR 20 , or -Q 6 -(alk 6 ) n7 -NR 21 S02R 22 the remainder of the key; and (2)R 7 The heterocyclic group, bicyclic heterocyclic group, spiro heterocyclic group, spiro sulfoximino group, aryl group, and heteroaryl group in are wherein: Each ring in (2) is R x , R y and R y1 Replace, and In the compound having the formula (I), -NHR 7 Part of the NH bond and Indicates attachment to R x , R y and R y1 one of the.

34. A compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 33, wherein: R 11 , R 16 , R 20 , and R 22 independently selected from alkyl, fluorine, chlorine, -CR 23 =CR 24 R 25 or heterocyclyl substituted with one to three substituents independently selected from hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cyano, and heterocyclyl; R 13 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, cycloalkyl; and R 14 , R 15 , R 17 , and R 18 independently selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, or heterocyclyl, substituted with one to three substituents independently selected from hydrogen, alkyl, alkoxy, hydroxy, halo, haloalkyl, haloalkoxy, and cyano.

35. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 34, wherein: R 7 is a ring with the formula:

36. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 35, wherein: R 6 It's hydrogen.

37. A pharmaceutical composition comprising the compound according to any one of claims 1 to 36 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

38. A method of treating cancer in a patient, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1-36 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 37.

39. The method of claim 37, wherein: The compound of any one of claims 1 to 36 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 37 is administered in combination with at least one other anticancer agent.

40. The method of claim 38 or 39, wherein: The cancer is lung cancer, skin cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, small intestine cancer, colon cancer, rectal cancer, anal cancer, endometrial cancer, stomach cancer, head and neck cancer, liver cancer, ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gallbladder cancer, pancreatic cancer, stomach cancer, thyroid cancer or parathyroid cancer.

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