Sulfonamide derivatives as cyclin-dependent kinase 2 inhibitors

Abstract

The present disclosure provides certain sulfonamide derivatives that are CDK2 inhibitors of formula (I): for the treatment of diseases treatable by inhibition of cyclin-dependent kinase 2 (CDK2). Pharmaceutical compositions containing such compounds and processes for preparing such compounds are also provided. In a second aspect, there is provided a pharmaceutical composition comprising a compound of formula (I) as described in the first aspect (or any of embodiments 1-66 thereof as described herein) or a pharma-ceutically acceptable salt thereof, and a pharma-ceutically acceptable excipient. TIFF2025509886000393.tif36170

Description

[Technical field]

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 362,036, filed March 28, 2022, the entire contents of which are incorporated herein by reference.

[0002] The present invention provides certain sulfonamide derivatives that are cyclin-dependent kinase 2 (CDK2) inhibitors and are therefore useful in the treatment of diseases treatable by inhibition of CDK2. Pharmaceutical compositions containing such compounds and processes for preparing such compounds are also provided. [Background technology]

[0003] Cyclin-dependent kinases (CDKs) are cellular kinases important for coordinating signaling events such as DNA replication and protein synthesis to ensure the division and proliferation of eukaryotic cells. To achieve activation, the cyclin-dependent kinase catalytic unit of CDKs often requires binding to a regulatory subunit known as a cyclin. In addition, the activity of CDKs is also controlled by phosphorylation state and binding of inhibitory proteins.

[0004] Of the CDKs identified so far, at least the CDK1 / cyclin B, CDK2 / cyclin E, CDK2 / cyclin A, CDK4 / cyclin D and CDK6 / cyclin D complexes are known to be important regulators of cell cycle progression, while other CDKs are important in the regulation of gene transcription, DNA repair, differentiation and apoptosis (see Morgan, DO Annu. Rev. Cell. Dev. Biol. (1997) 13:261-291).

[0005] Due to their important role in regulating the cell cycle and other important cellular processes, increased activity or transient aberrant activation of CDKs has been shown to result in the development of various types of cancer. The CDK2 / cyclin E complex plays a key role in regulating the G1 / S transition, histone biosynthesis, and centrosome duplication. Following the initial phosphorylation of retinoblastoma (Rb) by CDK4 / 6 / cyclin D, CDK2 / cyclin E further hyperphosphorylates p-RB, releasing the G1 transcription factor E2F to transcribe genes required for the transition to S phase. During S phase, cyclin E is degraded and CDK2 forms a complex with cyclin A to promote the phosphorylation of substrates that enable DNA replication and the inactivation of E2F, completing S phase (see Asghar et al. Nat. Rev. Drug. Discov. (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, which represent an optimal environment for the cell cycle, p21 and p27 are phosphorylated and degraded, halting CDK2 / cyclin activation.

[0006] Cyclin E, a cyclin regulating CDK2, is frequently overexpressed in cancer, and its overexpression correlates with poor prognosis. For example, it has been shown that amplification or overexpression of cyclin E is associated with poor outcome in breast cancer (see Keyomarsi et al., N Engl J Med. (2002) 347: 1566-75). It has been reported that overexpression of cyclin E2 (CCNE2) is associated with endocrine resistance in breast cancer cells, and CDK2 inhibition restores sensitivity to tamoxifen or CDK4 / 6 inhibitors in tamoxifen-resistant and CCNE2-overexpressing cells (see Caldon et al., Mol Cancer Ther. (2012) 11: 1488-99; and Herrera-Abreu et al., Cancer Res. (2016) 76: 2301-2313). Cyclin E amplification has also been reported to contribute 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) and 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 seen in ovarian, gastric, endometrial, uterine, bladder, esophageal, prostate, lung and other types of cancer (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 Pathol. (2017) 61:58-67; and Noske et al. Oncotarget (2017) 8:14794-14805), and is often correlated with poor clinical outcomes.

[0008] Cyclin E1 turnover is regulated by SCF Fbxw7 It is regulated by the ubiquitin E3 ligase component FBXW7 and the deubiquitinase USP28, which are frequently 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. & Clurman, BE 2008 Nat. Rev. Cancer 8, 83; Diefenbacher, ME et al. (2014) J. Clin. Invest. 124, 3407-3418). Instead, certain cancer cells express hyperactive truncated forms of cyclin E (Caruso JA et al. Cancer Res. 2018 Oct 1; 78(19): 5481-5491). Furthermore, amplification and overexpression of cyclin A has 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, the inhibitory regulators CDK2, p21, and p27 are often aberrantly downregulated in cancer. SKP2, a component of the SKP1-CUL1-F-box (SCF) complex, has also been linked to 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 loss or reduction of p21 / p27 or overexpression of SKP2 leads to high and / or aberrant temporal activation of CDK2, thereby promoting tumor growth.

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

[0011] The retinoblastoma (Rb) protein functions as a transcriptional corepressor and is a key substrate for the CDK4 / 6 and CDK2 complexes that promote cell division. Consistent with this standard model, Rb-deficient tumors are CDK4 / 6 independent and uniformly resistant to CDK4 / 6 inhibitors. However, analysis of DepMAP (McFarland et al., 2018; Tsherniak et al., 2017), a database that uses CRISPR technology to evaluate the functional requirements of genes across 717 cancer cell lines, revealed that Rb deficiency and high CDKN2A are associated with increased vulnerability to CDK2 or cyclin E1 inhibition (Erik S. Knudsen et al. Cell Reports March 1, 2022, 38:110448). In this Rb-deficient CDK2 / cyclin E1-dependent setting, it was proposed that CDK2 / cyclin E1 promotes phosphorylation of p130 to allow cell cycle progression.

[0012] Furthermore, CDK2 / cyclin E phosphorylates oncogenic Myc to counter ras-induced senescence, highlighting the importance of CDK2 in myc / ras-induced tumorigenesis (Per Hydbring, PNAS January 5, 2010, 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 for cancer cells overexpressing myc (Jan J. Molenaar, PNAS August 4, 2009 106(31)12968-12973; Sara Bolin et al., Oncogene 37:2850-2862(2018)).

[0013] The centrosomal protein CP110 plays a key role in centrosome duplication / segregation and requires CDK2 phosphorylation to induce centrosome clustering (reviewed in M ​​Kawakami et al.,(2018)Mol Cancer Ther 17(4):724-731). Aneuploid cancer cells are genetically unstable and often have extra centrosomes. When centrosome clustering is blocked, aneuploid cells with extra centrosomes undergo multipolar divisions leading to apoptosis of daughter cells, a process called late catastrophe. Furthermore, CP110 is downregulated in KRAS mutant lung cancer, enhancing the sensitivity of this cancer to CDK2 inhibitors. In a model of KRAS mutant lung cancer, CDK2 inhibition caused late catastrophe and apoptosis and reduced the growth of lung cancer xenografts. Aneuploid cells with extra centrosomes occur in many cancers, so CDK2 inhibitors may be extended to situations other than KRAS mutant lung cancer.

[0014] CDK2 has also been shown to play a role in blocking myeloid differentiation in AML (Meidan Ying et al., Blood 2018 Jun 14;131(24):2698-2711). Inhibiting CDK2 effectively induced granulocytic differentiation in AML cell lines and suppressed tumor growth in AML mouse models. Synergistic effects were demonstrated both in vitro and in vivo for the combination of CDK2 inhibition and all-trans retinoic acid (ATRA) in AML (Xuejing Shao et al., Pharmacol Res,2020 151:104545). Pharmacological inhibition or genetic deletion of CDK2 has also been shown to preserve 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). Thus, in addition to antitumor therapy, CDK2 inhibition can also be used as a promising preventative treatment for noise-, cisplatin- or antibiotic-induced or age-related hearing loss, for which there are currently no Food and Drug Administration-approved drugs. [Prior art documents] [Non-patent literature]

[0015] [Non-Patent Document 1] Morgan,DOAnnu.Rev.Cell.Dev.Biol.(1997)13:261-291 [Non-Patent Document 2] Asghar et al.Nat.Rev.Drug.Discov.(2015)14:130-146 [Non-Patent Document 3] Keyomarsi et al.,N Engl J Med.(2002)347:1566-75 [Non-Patent Document 4] Caldon et al., Mol Cancer Ther. (2012)11:1488-99 [Non-Patent Document 5] Herrera-Abreu et al.,Cancer Res.(2016)76:2301-2313

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[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 meets this and related needs. [Means for solving the problem]

[0017] In a first aspect, the compound of formula (I): [ka] (In the formula, R 1 is hydrogen or halo; Ring R A is represented by formula (i), (ii), (iii) or (iv): [ka] where alk is alkyl, and R A Each ring is independently selected from hydrogen, alkyl, and halo. 4 and R 5 is replaced by; R 2 and R 3 is independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halo, haloalkyl, and haloalkoxy; Ring R B is cycloalkyl, bridged cycloalkyl, heterocyclyl or bridged heterocyclyl; (A) Ring R B R is a cycloalkyl or bridged cycloalkyl selected from hydrogen, halo, haloalkyl, and hydroxyalkyl. a is replaced by; (B) Ring R B The heterocyclyl of R b , Rc and R d is replaced by R b and R c is independently selected from hydrogen, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; and R d is hydrogen, alkyl, deuteroalkyl, cycloalkyl (optionally substituted with one or two substituents independently selected from alkyl, halo, hydroxy, and cyano), alkoxy, halo, haloalkyl, haloalkoxy, alkoxycarbonyl, amino, alkylamino, dialkylamino, aryl, aralkyl, heterocyclyl, or heteroaryl; and (C) Ring R B The heterocyclyl of R e , R f and R g is replaced by R e and R f is independently selected from hydrogen, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; and R g is hydrogen, alkyl, deuteroalkyl, cycloalkyl (optionally substituted with one or two substituents independently selected from alkyl, halo, hydroxy, or cyano), alkoxy, halo, haloalkyl, haloalkoxy, alkoxycarbonyl, oxo, amino, alkylamino, dialkylamino, aryl, aralkyl, heterocyclyl, or heteroaryl. or a pharma- ceutically acceptable salt thereof.

[0018] In a second aspect, there is provided a pharmaceutical composition comprising a compound of formula (I) as defined in the first aspect (or any of embodiments 1-66 thereof as described herein) or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0019] Generally, compounds of formula (I) selectively inhibit CDK2 over CDK1. Compounds of formula (I) generally selectively inhibit CDK2 over CDK4 and / or CDK6. Thus, in a third aspect, there is provided a method of treating a disease treatable by inhibition of CDK2 in a patient, preferably where the patient is in need of such treatment, comprising administering to the patient, preferably in need of such treatment, a therapeutically effective amount of a compound of formula (I) as defined in the first aspect (or any of the embodiments thereof described herein) or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition thereof as disclosed herein.

[0020] In a first embodiment of the third aspect, the disease is cancer. In a second embodiment of the third aspect, the disease is ovarian cancer (e.g., serous carcinoma, clear cell carcinoma, mucinous carcinoma and / or endometrioid carcinoma), endometrial carcinoma, breast cancer (e.g., hormone receptor positive breast cancer and / or triple negative breast cancer), lung cancer (e.g., adenocarcinoma, small cell lung cancer and / or non-small cell lung cancer, small cell and non-small cell carcinoma, bronchial 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, or The cancer is selected from bladder cancer, cervical cancer, colorectal cancer, cancer of the small intestine, colon cancer, rectal cancer, cancer of the anus, gastric cancer (e.g., tubular adenocarcinoma, papillary adenocarcinoma, mucinous adenocarcinoma, signet ring cell carcinoma and / or adenosquamous carcinoma), head and neck cancer (e.g., cancer of the larynx, hypopharynx, nasopharynx, oropharynx, lip and / or oral cavity), 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 and parathyroid cancer. In a third embodiment of the third aspect, the disease is a cancer that is resistant to CDK4 / 6 inhibitors via a CDK2-mediated mechanism.

[0021] In a fourth aspect, there is provided a method of treating noise-, cisplatin-, antibiotic-induced or age-related hearing loss, 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 described in the first aspect (or any of its embodiments described herein) or a pharma- ceutically acceptable salt thereof or a pharmaceutical composition thereof disclosed herein. In some embodiments, the extent of hearing loss is reduced when compared to age-matched controls. In some embodiments, hearing loss is prevented when compared to age-matched controls.

[0022] A fifth aspect is provided, which is a compound of formula (I) as described in the first aspect (or any of its embodiments described herein) or a pharma- ceutically acceptable salt thereof, for use as a medicament. In one embodiment of the fourth aspect, the compound of formula (I) (and any of its embodiments described herein) or a pharma- ceutically acceptable salt thereof is useful for the treatment of one or more diseases as disclosed in the third and / or fourth aspects above (including their embodiments).

[0023] A sixth aspect is provided, which is the use of a compound of formula (I) as defined in the first aspect (and any of the embodiments thereof disclosed herein) or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease in a patient in which activity of CDK2 contributes to the pathology and / or symptomology of the disease. In an embodiment of the sixth aspect, the disease is one or more of the diseases disclosed in the third and / or fourth aspects above (including their embodiments).

[0024] In a seventh aspect, there is provided a method of inhibiting CDK2, the method comprising contacting CDK2 with a compound of formula (I) (or any of its embodiments described herein) as described in the first aspect or a pharma- ceutically acceptable salt thereof; or contacting CDK2 with a pharmaceutical composition comprising a compound of formula (I) (or any of its embodiments described herein) or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient thereof. In one embodiment, CDK2 is contacted with a compound of formula (I) (or any of its embodiments described herein) or a pharma- ceutically 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 pharma- ceutically acceptable salt thereof in vivo.

[0025] In any of the foregoing aspects relating to the treatment of cancer, further embodiments include administering a compound of formula (I) as described in the first aspect (or any of its embodiments disclosed herein) or a pharma- ceutically acceptable salt thereof in combination with at least one additional anti-cancer agent. When a combination therapy is used, the agents may be administered simultaneously or sequentially.

[0026] In an eighth embodiment, the compound of formula (I): [ka] A process for preparing a compound of the formula: (1)R 1 , R 2 , R 3 , ring R A and ring R B is as defined in the first aspect (or any of its embodiments below), the process further comprises (i)(a): [ka] (Wherein, Z is S N R is a leaving group under Ar or metal catalyzed cross-coupling reaction conditions; 1 , R 2 , R 3 and ring RB is as defined in the first aspect (or any of its embodiments below). with a compound of formula (b): [ka] (In the formula, ring R A is as defined in the first aspect (or any of its embodiments below). or reacting with an amine of (ii)(c): [ka] (In the formula, R 1 , R A and ring R B is as defined in the first aspect (or any of its embodiments below). With a compound of formula (d): [ka] (In the formula, X 1 is a leaving group under nucleophilic substitution reaction conditions, and R 2 and R 3 is as defined in the first aspect (or any of its embodiments below). with a sulfonyl compound of the formula: (2)R 1 , R 2 , R 3 and ring R A is as defined in the first aspect (or any of its embodiments below), and ring R B But R b , R c and R d Heterocyclylaminyl substituted with R e , R f and R g and wherein the heterocyclylaminyl and the bridged heterocyclylaminyl are attached to the thiazolyl ring via a ring nitrogen atom, the process can be represented by the formula (e): [ka] (In the formula, X 2 is S N R is a leaving group under Ar or metal catalyzed cross-coupling reaction conditions; 1 , R 2 , R 3 and ring R A is as defined in the first aspect (or any of its embodiments below). With a compound of formula (f): [ka] (In the formula, ring R B is R b , R c and R d Heterocyclylaminyl substituted with R e , R f and R g and a bridged heterocyclylaminyl substituted with with an amine compound of (3) Optionally, R 2 , R 3 , R b , R c , R d , R e , R f and R g by modifying one or more of the following to provide a compound of formula (I); (4) optionally forming an acid addition salt of the compound of formula (I) obtained from steps (1), (2) and / or (3) above; and (5) Optionally, forming a free base of the acid addition salt of the compound of formula (I) obtained from steps (1), (2), (3) and / or (4).

[0027] In an embodiment of the eighth aspect, Z is halo or alkylsulfonyl (e.g., methylsulfonyl), and X 1 and X 2 is halo (such as chloro or bromo).

[0028] In a ninth embodiment, the compound of the formula: [ka] wherein X a is S N R is a leaving group under Ar or metal catalyzed cross-coupling reaction conditions; 1 is hydrogen or halo, R 2 and R 3 are independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halo, haloalkyl, and haloalkoxy (or any of the embodiments thereof disclosed below); 2 and R 3 When one of R is hydrogen or halo, 2 and R 3 and the other is alkyl, cycloalkyl, alkoxy, haloalkyl, and haloalkoxy (or any of the embodiments thereof disclosed below). In one embodiment of the ninth aspect, X a is halo (e.g., chloro, bromo) or alkylsulfonyl (e.g., methylsulfonyl).

[0029] In a tenth aspect, the compound of the formula: [ka] The intermediate X b is S N is a leaving group under Ar or metal catalyzed cross-coupling reaction conditions, X c is a leaving group under nucleophilic addition reaction conditions, and R 1 is hydrogen or halo, R 2 and R 3 are independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halo, haloalkyl, and haloalkoxy (or any of the embodiments thereof disclosed below); 1 If is a halo, then R 2 and R 3 In one embodiment of the tenth aspect, X is not simultaneously halo. b and X c is independently halo (e.g., chloro or bromo). In another embodiment of the tenth aspect, X bis chloro, and X c is bromo.

[0030] In an eleventh embodiment, the compound of formula: [ka] wherein X d is S N is a leaving group under Ar or metal catalyzed coupling conditions; R 1 is hydrogen or halo; R 2 and R 3 is independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halo, haloalkyl, and haloalkoxy; Ring R B is cycloalkyl, bridged cycloalkyl, heterocyclyl or bridged heterocyclyl; (A) cycloalkyl is an R selected from halo, haloalkyl, and hydroxyalkyl. a and the ring R B The bridged cycloalkyl in R is selected from hydrogen, halo, haloalkyl, and hydroxyalkyl. a is replaced by; (B) Ring R B The heterocyclyl of R b , R c and R d is replaced by R b and R c is independently selected from hydrogen, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy, and R d is hydrogen, alkyl, deuteroalkyl, alkoxy, halo, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, aryl, aralkyl, heterocyclyl or heteroaryl; and (C) Ring R B The heterocyclyl of R e , R f and R g is replaced by R e and Rf is independently selected from hydrogen, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy; and R g is hydrogen, alkyl, deuteroalkyl, cycloalkyl (optionally substituted with one or two substituents independently selected from alkyl, halo, hydroxy, or cyano), alkoxy, halo, haloalkyl, haloalkoxy, alkoxycarbonyl, oxo, amino, alkylamino, dialkylamino, aryl, aralkyl, heterocyclyl, or heteroaryl (or R as disclosed below). 1 , R 2 , R 3 , ring R A and ring R B (any one of the above embodiments).

[0031] In one embodiment of the eleventh aspect, X d is halo (eg, chloro or bromo) or alkylsulfonyl (eg, methylsulfonyl).

[0032] In a twelfth embodiment, the compound of formula: [ka] wherein X e is H or an amino protecting group, and R, R and R are as disclosed in the first aspect (or any embodiment disclosed herein below). In one embodiment of the twelfth aspect, X e is alkylcarbonyl (e.g., acetyl).

[0033] In a thirteenth embodiment, the compound of the formula: [ka] wherein X f is amino or halo, R 1 , R 2 , R 3 and R A as disclosed in the first aspect (or any one of the embodiments thereof disclosed below). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0034] Definition: Unless otherwise stated, the following terms used in the specification and claims are defined for purposes of this application and have the following meanings:

[0035] "Alkyl" means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl, pentyl, and the like.

[0036] "Alkylene", unless otherwise specified, means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, e.g., methylene, ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene, pentylene, and the like.

[0037] "Alkoxy" means an --OR radical where R is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert-butoxy, and the like.

[0038] "Amino" means --NH2.

[0039] "Alkylamino" means --NHR where R is alkyl as defined above, e.g., methylamino, ethylamino, propylamino, and the like.

[0040] "Alkoxycarbonyl" is R Z is alkyl as defined above. Z Radicals such as ethoxycarbonyl, ethoxycarbonyl, and the like.

[0041] "Aryl" means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of six to ten ring atoms, e.g., phenyl or naphthyl.

[0042] "Aralkyl" is -(alkylene)-R z R stands for radical. z is aryl as defined above. Examples include, but are not limited to, benzyl, phenethyl, and the like.

[0043] A "bridged cycloalkyl" is a saturated monovalent bicyclic or tricyclic hydrocarbon radical having five to ten ring carbon atoms in which one or two ring atoms are (CR z R z1 )n groups, where n is an integer selected from 1 to 3 (endpoints included), R z and R z1 are independently H or methyl) to non-adjacent ring atoms (which may also be referred to herein as "bridging" groups). For clarity, when a bridged cycloalkyl is a bicyclic ring, it has one bridging group, and when a bridged cycloalkyl is a tricyclic ring, 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.

[0044] A "bridged heterocyclyl" is a saturated monovalent bicyclic radical having five to nine ring carbon atoms in which two non-adjacent ring atoms are (CR z R z1 ) n groups, n is 1 to 3, R z and R z1 are independently H or methyl (also referred to herein as a "bridging" group), and further wherein one or two ring carbon atoms, including the atoms in the bridging group, are selected from N, O, and S(O) nand n is an integer selected from 0 to 2. When the bridged heterocyclyl group contains at least one nitrogen atom, it is also referred to herein as bridged heterocyclylaminyl and is a subset of the bridged heterocyclyl group. Examples include, but are not limited to, 2-azabicyclo[2.2.2]octyl, quinuclidinyl, 7-oxabicyclo[2.2.1]heptyl, and the like.

[0045] "Cycloalkyl" means a monocyclic saturated monovalent hydrocarbon radical of three to ten carbon atoms. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0046] "Dialkylamino" means --NRR', where R and R' are independently alkyl as defined above, e.g., dimethylamino, diethylamino, methylpropylamino, and the like.

[0047] "Deuteroalkyl" means an alkyl as defined above substituted with one, two or three deuteriums (eg, trideuteromethyl).

[0048] "Halo" means fluoro, chloro, bromo or iodo, preferably fluoro or chloro.

[0049] "Haloalkyl" means an alkyl radical as defined above that is substituted with one or more halogen atoms, such as fluorine or chlorine, including those substituted with different halogens, e.g., 1 to 5 halogen atoms, e.g., -CH2Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3, -CF(CH3)2, etc. When an alkyl is substituted with only fluoro, it may be referred to in this application as fluoroalkyl.

[0050] "Haloalkoxy" means an -OR radical where R is haloalkyl as defined above, e.g., -OCF, -OCHF, etc. When R is haloalkyl and the alkyl is substituted with only fluoro, it is referred to in this application as fluoroalkoxy.

[0051] "Hydroxyalkyl" means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one or two hydroxy groups, provided that if two hydroxy groups are present, they are not both 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.

[0052] "Heteroaryl" means, unless otherwise specified, a monovalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms, where 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, furanyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, and the like. As defined herein, the terms "heteroaryl" and "aryl" are mutually exclusive. When a heteroaryl ring contains 5 or 6 ring atoms and is a monocyclic ring, it is also referred to herein as a 5- or 6-membered monocyclic heteroaryl. When the heteroaryl ring contains 9 or 10 ring atoms and is a bicyclic ring, it is also referred to herein as a 9- or 10-membered fused bicyclic heteroaryl.

[0053] "Heterocyclyl" refers to a heterocyclic ring in which one or two ring atoms are N, O, and S(O). n where n is an integer from 0 to 2, and the remaining ring atoms are C, unless otherwise specified. Additionally, one or two ring carbon atoms of the heterocyclyl ring can be optionally substituted with a -C(=O)- group. More specifically, the term heterocyclyl includes, but is not limited to, pyrrolidinyl, piperidinyl, homopiperidinyl, 2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholinyl, piperazinyl, tetrahydro-pyranyl, thiomorpholinyl, and the like. When a heterocyclyl group contains at least one nitrogen atom, it is also referred to herein as heterocyclylaminyl, and is a subset of the heterocyclyl group.

[0054] The term "oxo" as used herein, alone or in combination, refers to =(O).

[0055] The present disclosure also includes protected derivatives of compounds of formula (I). For example, when compounds of formula (I) contain groups such as hydroxy, carboxy, or any group containing a nitrogen atom, these groups can be protected with a suitable protecting group. A comprehensive list of suitable protecting groups can be found in TW Greene, Protective Groups in Organic Synthesis, 5 th Ed., John Wiley & Sons, Inc. (2014), the disclosure of which is incorporated herein by reference in its entirety. Protected derivatives of the compounds of the present disclosure can be prepared by methods known in the art.

[0056] The present disclosure also includes polymorphs and deuterated forms of compounds of Formula (I) or pharma- ceutically acceptable salts thereof.

[0057] The term "prodrug" refers to a compound that is 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 (see Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003). Prodrugs of the compounds described herein are structurally modified forms of the compounds that readily undergo chemical changes under physiological conditions to provide the active compound. Prodrugs are often useful because in some situations they may be easier to administer than the compound or parent drug. They may be bioavailable, for example, by oral administration, whereas the parent drug is not bioavailable. A variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug. Examples of prodrugs include, but are not limited to, compounds that are administered as esters, but are subsequently metabolically hydrolyzed to the carboxylic acid, the active entity ("prodrug"). Further examples include peptidyl derivatives of the compounds.

[0058] A "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include: Acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with 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, acid, acid addition salts formed with organic acids such as benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or Salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., either an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordination with organic bases such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc. It is understood that pharma- ceutically acceptable salts are non-toxic. Additional information regarding suitable pharma- ceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, 1985, which is incorporated herein by reference in its entirety.

[0059] Compounds of formula (I) may have asymmetric centers. Compounds of formula (I) containing asymmetrically substituted atoms may be isolated in optically active or racemic form. Individual stereoisomers of the compounds may be synthesized from commercially available starting materials containing chiral centers, or may be prepared by preparing a mixture of enantiomeric products, followed by separation, such as conversion to a mixture of diastereomers, followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on a chiral chromatographic column, or other suitable methods known in the art. Unless a particular stereochemistry or isomeric form is specifically indicated, all chiral, diastereomeric, all mixtures of chiral or diastereomeric forms, and racemic forms are within the scope of this disclosure. It will also be understood by those skilled in the art that when a compound is indicated as an (R) stereoisomer, it may contain the corresponding (S) stereoisomer as an impurity, and vice versa.

[0060] Certain compounds of formula (I) may exist as tautomers and / or geometric isomers. All possible tautomers, both individual and mixtures thereof, as well as cis and trans isomers, are within the scope of this disclosure. Furthermore, as used herein, the term alkyl includes all possible isomeric forms of said alkyl groups, although only a few examples are shown. Furthermore, when a cyclic group, such as aryl, is substituted, it includes all positional isomers, although only a few examples are shown. Furthermore, all hydrates of compounds of formula (I) are within the scope of this disclosure.

[0061] Compounds of formula (I) may also contain unusual amounts of isotopes at one or more atoms that constitute such compounds. An unusual amount of isotope may be defined as ranging from the amount found in nature to 100% of the amount of the atom in question, differing only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into compounds of the invention, such as compounds of formula (I) (and any embodiment thereof disclosed herein, including specific compounds), include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine (respectively). 2 H, 3 H, 11 C. 13C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I, 125 Isotopically labeled compounds (e.g., 3 H and 14 C) can be useful in compound or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) isotopes can be useful for their ease of preparation and detectability. Additionally, deuterium (i.e. 2 Substitution with heavier isotopes, such as H, may provide certain therapeutic advantages (e.g., increased in vivo half-life or reduced required dosage) resulting from greater metabolic stability. In some embodiments, in the compounds of formula (I), including those in Table 1 below, one or more hydrogen atoms are 2 H or 3 H or one or more carbon atoms are replaced by 13 C or 14 Replaced by C-rich carbon. 15 O. 13 N, 11 C and 15 Positron emitting isotopes such as F are useful 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.

[0062] "Pharmaceutically acceptable carrier or excipient" means a carrier or excipient that is generally safe, non-toxic, and not biologically or otherwise undesirable and is useful in preparing pharmaceutical compositions, and includes carriers or excipients acceptable for veterinary and human medicine. As used in the specification and claims, "pharmaceutically acceptable carrier / excipient" includes both one and more than one such excipient.

[0063] The term "about" as used herein is intended to specify the numerical value it modifies and indicates such value as variable within a margin of error. When no particular margin of error is stated, such as a standard deviation to the average value stated in a chart or table of data, the term "about" should be understood to mean a range that includes the stated value and range, and that would encompass ±10%, preferably ±5%.

[0064] As used herein, the phrase "optionally" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes cases where the event or circumstance occurs and cases where it does not occur. For example, the phrase "cycloalkyl optionally substituted with alkyl" is intended to cover both cycloalkyl that is not substituted with alkyl and cycloalkyl that is substituted with alkyl.

[0065] The term "disease" as used herein is generally intended to be synonymous and is used interchangeably with the terms "disorder," "syndrome," and "condition" (as in medical condition), in that all reflect an abnormal condition of the human or animal body or one of its parts that impairs normal functioning, typically indicated by distinguishing signs and symptoms, and causing a decrease in the duration or quality of life of the human or animal.

[0066] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat a disease or disorder described in this disclosure. Such administration includes co-administration of these therapeutic agents in a substantially simultaneous manner, such as a single capsule having a fixed ratio of active ingredients or separate multiple capsules for each active ingredient. Furthermore, such administration also includes the use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen provides the beneficial effect of the drug combination in the treatment of the condition or disorder described herein.

[0067] The term "patient" is generally synonymous with the term "subject" and includes all mammals, including humans. Examples of patients include humans, domestic animals such as cows, goats, sheep, pigs and rabbits, and companion animals such as dogs, cats, rabbits and horses. Preferably, the patient is a human.

[0068] "Treating" a disease or "treatment" of a disease includes: (1) To prevent the disease, i.e., to prevent the development of clinical symptoms of the disease in a mammal that is exposed to or susceptible to the disease, but which may still not experience or exhibit symptoms of the disease; (2) inhibiting the disease, i.e., delaying, preventing (i.e., stabilizing), or reducing the onset or severity of the disease or its clinical symptoms; or (3) alleviating the disease, i.e., causing regression of the disease or its clinical symptoms; Includes:

[0069] In one embodiment, treating a disease or treatment of a disease includes inhibiting the disease, i.e., delaying, preventing or reducing the onset or severity of the disease or its clinical symptoms; or relieving the disease, i.e., causing regression of the disease or its clinical symptoms.

[0070] "Therapeutically effective amount" means the amount of a compound of the present disclosure, or a pharma- ceutically acceptable salt thereof, that, 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 being treated.

[0071] The terms "inhibit" and "reduce" or any variations of these terms relating to CDK2 include a measurable decrease or complete inhibition to achieve a desired result, such as 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, decrease in CDK2 activity compared to its normal activity.

[0072] Representative disclosed compounds are set forth in Table I below.

[0073] [Table 1]

[0074] [Table 2]

[0075] [Table 3]

[0076] [Table 4]

[0077] [Table 5]

[0078]

Table 6

[0079]

Table 7

[0080]

Table 8

[0081]

Table 9

[0082]

Table 10

[0083]

Table 11

[0084]

Table 12

[0085]

Table 13

[0086]

Table 14

[0087]

Table 15

[0088]

Table 16

[0089] [Table 17]

[0090] [Table 18]

[0091] [Table 19]

[0092] [Table 20]

[0093] [Table 21]

[0094] [Table 22]

[0095] [Table 23]

[0096] [Table 24]

[0097] Embodiments: In further embodiments 1-66 below, the disclosure includes the following:

[0098] 1. In embodiment 1, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is as provided in the first aspect of the summary above.

[0099] 2. In embodiment 2, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to embodiment 1 has a ring R B is cycloalkyl or bridged cycloalkyl, and cycloalkyl and bridged cycloalkyl are R a has been replaced with.

[0100] 3. In embodiment 3, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to embodiment 1 or 2 has a ring R B But R a is a cycloalkyl substituted with

[0101] 4. In embodiment 4, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to embodiment 1 or 2 has a ring R B But R a is a bridged cycloalkyl substituted with

[0102] 5. In embodiment 5, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to embodiment 1 has a ring R B is heterocyclyl or bridged heterocyclyl, and heterocyclyl is R b , R c and R d and the bridged heterocyclyl is R e , R f and R g has been replaced with.

[0103] 6. In embodiment 6, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to embodiment 1 or 5 has a ring R B But R b , R c and R d and heterocyclyl substituted with

[0104] 7. In embodiment 7, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to embodiment 1 or 5 has a ring R B But R e , R f and R g is a bridged heterocyclyl substituted with

[0105] 8. In embodiment 8, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to embodiment 1 has a ring R B Cycloalkyl and bridged cycloalkyl of the formula: [ka] and the ring R B Heterocyclyl and bridged heterocyclyl are [ka] each cycloalkyl and bridged cycloalkyl is selected from R a and each heterocyclyl is substituted with R b , R c and R d and each bridged heterocyclyl is substituted with R e , R f and R g has been replaced with.

[0106] 9. In embodiment 9, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to embodiment 1 or 8 has a ring R B Cycloalkyl and bridged cycloalkyl of the formula: [ka] and the ring R B Heterocyclyl and bridged heterocyclyl are [ka] each cycloalkyl and bridged cycloalkyl is selected from R a and each heterocyclyl ring is substituted with R b , R c and R d and each bridged heterocyclyl is substituted with R e , R f and R g has been replaced with.

[0107] 10. In embodiment 10, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to embodiment 1 or 2 has a ring R B Cycloalkyl and bridged cycloalkyl of the formula: [ka] each cycloalkyl and bridged cycloalkyl is selected from R a has been replaced with.

[0108] 11. In embodiment 11, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to embodiment 1, 2 or 10 has a ring R B Cycloalkyl and bridged cycloalkyl of the formula: [ka] each cycloalkyl and bridged cycloalkyl is selected from R a has been replaced with.

[0109] 12. In embodiment 12, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to embodiment 1 or 5 has a ring R B Heterocyclyl and bridged heterocyclyl are [ka] and each heterocyclyl is selected from R b , R c and R d and each bridged heterocyclyl is substituted with R e , R f and R g has been replaced with.

[0110] 13. In embodiment 13, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to embodiment 1 or 5 has a ring R B Heterocyclyl and bridged heterocyclyl are [ka] and each heterocyclyl is selected from R b , Rc and R d and each bridged heterocyclyl is substituted with R e , R f and R g has been replaced with.

[0111] 14. In embodiment 14, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to embodiment 1, 2 or 3 has a ring R B The cycloalkyl of [ka] and each cycloalkyl is selected from R a has been replaced with.

[0112] 15. In embodiment 15, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1 to 3, 8 to 11, and 14, is a compound having a ring R B The cycloalkyl of [ka] and each cycloalkyl is selected from R a has been replaced with.

[0113] 16. In embodiment 16, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to embodiment 1, 2 or 4 has a ring R B The bridged cycloalkyl of [ka] and each bridging cycloalkyl is selected from R a has been replaced with.

[0114] 17. In embodiment 17, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1, 2, 4, 8 to 11, and 16, is a compound having a ring R B The cycloalkyl of [ka] and each bridging cycloalkyl is selected from R a has been replaced with.

[0115] 18. In embodiment 18, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1, 2, 4, 8 to 11, 16 and 17, is a compound having a ring R B The cycloalkyl of [ka] and R a has been replaced with.

[0116] 19. In embodiment 19, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to embodiment 1, 5 or 6 has a ring R B The heterocyclyl of [ka] and each heterocyclyl is selected from R b , R c and R d has been replaced with.

[0117] 20. In embodiment 20, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to embodiment 1, 5 or 6 has a ring R B The heterocyclyl of [ka] and each heterocyclyl is selected from R b , R c and R d has been replaced with.

[0118] 21. In embodiment 21, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to embodiment 1, 5, 6, 8, 9, 12, 19 or 20 is a compound having a ring R B The heterocyclyl of [ka] and each heterocyclyl is selected from Rb , R c and R d has been replaced with.

[0119] 22. In embodiment 22, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to embodiment 1, 5 or 7 has a ring R B The bridged heterocyclyl is [ka] and each bridged heterocyclyl is selected from R e , R f and R g has been replaced with.

[0120] 23. In embodiment 23, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to embodiment 1, 5, 7 or 22, is a compound having a ring R B The bridged heterocyclyl is [ka] and each bridged heterocyclyl is selected from R e , R f and R g has been replaced with.

[0121] 24. In embodiment 24, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to embodiment 1, 5, 7, 8, 9, 12 or 23 has a ring R B The bridged heterocyclyl is [ka] and each bridged heterocyclyl is selected from R e , R f and R g has been replaced with.

[0122] 25. In embodiment 25, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1 to 4, 8 to 11, and 14 to 18, is R a is hydrogen, chloro, fluoro, difluoromethyl, trifluoromethyl or hydroxymethyl.

[0123] 26. In embodiment 26, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1 to 4, 8 to 11, 14 to 18, and 25, is R a is hydrogen.

[0124] 27. In embodiment 27, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1 to 4, 8 to 11, 14 to 18, and 25, is R a is fluoro or chloro.

[0125] 28. In embodiment 28, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1 to 4, 8 to 11, 14 to 18, and 25, is R a is difluoromethyl or trifluoromethyl.

[0126] 29. In embodiment 29, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1 to 4, 8 to 11, 14 to 18, and 25, is R a is hydrogen, chloro, fluoro, difluoromethyl or trifluoromethyl.

[0127] 30. In embodiment 30, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1 to 4, 8 to 11, and 14 to 18, is R a is hydrogen or haloalkyl.

[0128] 31. In embodiment 31, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1 to 4, 8 to 11, and 14 to 18, is R a is hydrogen or halo.

[0129] 32. In embodiment 32, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1 to 4, 8 to 11, and 14 to 18, is R a is halo or haloalkyl.

[0130] 33. In embodiment 33, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1 to 4, 8 to 11, 14 to 18, and 25 to 32, is a compound having a ring R B 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, cyclobutyl, cyclopropyl, 1-(difluoromethyl)cyclobutyl, 1-(trifluoromethyl)cyclobutyl, 1-(difluoromethyl)cyclopropyl or 1-(trifluoromethyl)cyclopropyl.

[0131] 34. In embodiment 34, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1, 2, 4, 8 to 11, 16 to 18, and 25 to 33, is a compound having a ring R B 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 or 3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl.

[0132] 35. In embodiment 35, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1, 2, 3, 8 to 11, 14, 15 and 25, 26, 28 to 30, 32 and 33, is a compound having a ring R B is cyclobutyl, cyclopropyl, 1-(difluoromethyl)-cyclobutyl, 1-(trifluoromethyl)cyclobutyl, 1-(difluoromethyl)-cyclopropyl or 1-(trifluoromethyl)-cyclopropyl.

[0133] 36. In embodiment 36, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1, 3, 8 to 11, 14, 15, 25, 26, 28 to 30, 32, 33, and 34, is a compound having a ring R B is 1-(difluoromethyl)cyclobutyl, 1-(trifluoromethyl)cyclobutyl, 1-(difluoromethyl)-cyclopropyl or 1-(trifluoromethyl)cyclopropyl.

[0134] 37. In embodiment 37, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1, 5 to 9, 12, 13, and 19 to 24, is R b and R c is independently selected from hydrogen, methyl, fluoro, chloro, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, hydroxy, and cyano; R d is selected from hydrogen, methyl, trideuteromethyl, 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-dioxidothietan-3-yl, 1,1-dioxidotetrahydro-2H-thiopyran-4-yl, benzyl, phenyl, pyridin-2-yl, pyridin-3-yl and pyridin-4-yl; and R e and R f is independently selected from hydrogen, methyl, fluoro, chloro, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, hydroxy, and cyano; R gis selected from hydrogen, methyl, trideuteromethyl, 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-dioxidothietan-3-yl, 1,1-dioxidotetrahydro-2H-thiopyran-4-yl, benzyl, phenyl, pyridin-2-yl, pyridin-3-yl and pyridin-4-yl.

[0135] 38. In embodiment 38, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1, 5 to 9, 12, 13, 19 to 24, and 37, is R b is hydrogen and R c is selected from hydrogen, methyl, fluoro, chloro, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, hydroxy, and cyano, and R d is selected from hydrogen, methyl, trideuteromethyl, 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-dioxidothietan-3-yl, 1,1-dioxidotetrahydro-2H-thiopyran-4-yl, benzyl, phenyl, pyridin-2-yl, pyridin-3-yl and pyridin-4-yl; and R e is hydrogen and R fis selected from hydrogen, methyl, fluoro, chloro, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, hydroxy, and cyano, and R g is selected from hydrogen, methyl, trideuteromethyl, 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-dioxidothietan-3-yl, 1,1-dioxidotetrahydro-2H-thiopyran-4-yl, benzyl, phenyl, pyridin-2-yl, pyridin-3-yl and pyridin-4-yl.

[0136] 39. In embodiment 39, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1, 5 to 9, 12, 13, 19 to 24, and 38, is R b and R c is hydrogen and R d is selected from hydrogen, methyl, trideuteromethyl, 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-dioxidothietan-3-yl, 1,1-dioxidotetrahydro-2H-thiopyran-4-yl, benzyl, phenyl, pyridin-2-yl, pyridin-3-yl and pyridin-4-yl; and R e and R f is hydrogen and R gis selected from hydrogen, methyl, trideuteromethyl, 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-dioxidothietan-3-yl, 1,1-dioxidotetrahydro-2H-thiopyran-4-yl, benzyl, phenyl, pyridin-2-yl, pyridin-3-yl and pyridin-4-yl.

[0137] 40. In embodiment 40, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1, 5 to 9, 12, 13, 19 to 24, and 37 to 39, further comprises: (i) a ring R B heterocyclyl 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 (ii) Ring R BThe bridged heterocyclyl is 2-oxabicyclo[2.1.1]hexan-1-yl, 7-azabicyclo[2.2.1]heptan-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]heptan-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-dioxidotetrahydro-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-dioxidothietan-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- Dioxido-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]heptan-7-yl, 4-(3,3-difluorocyclobutyl)-2,6-dimethylpiperazin-1-yl, 7-methyl-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl or 3-cyclopropyl-3,8-diazabicyclo[3.2.1]octan-8-yl.

[0138] 41. In embodiment 41, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1, 5 to 9, 12, 13, 19 to 24, and 37 to 40, is a compound having a ring R B wherein the bridged heterocyclyl is 3-(3,3-difluorocyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl.

[0139] 42. In embodiment 42, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1, 5 to 9, 12, 13, 19 to 24, and 37 to 40, is a compound having a ring R B wherein the bridged heterocyclyl is 3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl.

[0140] 43. In embodiment 43, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1 to 42, is a compound having a ring R A is represented by formula (i) or (ii): [ka] wherein alk is alkyl, and each ring R A R 4 and R 5 has been replaced with.

[0141] 44. In embodiment 44, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1 to 43, is a compound having a ring R A Formula (i): [ka] wherein alk is alkyl and the ring of formula (i) is R 4 and R 5 has been replaced with.

[0142] 45. In embodiment 45, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1 to 44, is a compound having a ring R A Formula (i): [ka] where alk is alkyl and R 4 is hydrogen and R 5 is fluoro or methyl bonded at a carbon that is meta to the carbon of ring (i) substituted with -SO2alk.

[0143] 46. ​​In embodiment 46, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1 to 44, is a compound having a ring R A Formula (i): [ka] where alk is alkyl and R 4 and R5 is hydrogen.

[0144] 47. In embodiment 46, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1 to 44 and 46, is a compound having a ring R A is the formula: [ka] It is a ring.

[0145] 48. In embodiment 48, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1 to 43, is a compound having a ring R A Is of formula (ii): [ka] and the ring of formula (ii) is R 4 and R 5 has been replaced with.

[0146] 49. In embodiment 49, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1 to 43 and 48, is a compound having a ring R A is the formula: [ka] It is a ring.

[0147] 50. In embodiment 50, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1 to 42, is a compound having a ring R A is represented by formula (iii) or (iv): [ka] where each ring is R 4 and R 5 has been replaced with.

[0148] 51. In embodiment 51, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1 to 42 and 50, is a compound having a ring R A is the formula: [ka] It is a ring.

[0149] 52. In embodiment 52, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1 to 42, is a compound having a ring R A is the formula: [ka] It is a ring.

[0150] 53. In embodiment 53, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1 to 52 is [ka] but [ka] It is.

[0151] 54. In embodiment 54, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1 to 53 is [ka] But(a1): [ka] It is.

[0152] 55. In embodiment 55, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1 to 54 is R 2 and R 3 are independently selected from hydrogen, fluoro, chloro, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, propoxy, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, difluoromethoxy, and trifluoromethoxy.

[0153] 56. In embodiment 56, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1 to 55, is R 2 and R 3 is independently selected from fluoro, chloro, cyclopropyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, and trifluoromethoxy.

[0154] 57. In embodiment 57, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1 to 54 is R 2 is halo, cycloalkyl or haloalkyl, and R 3 is halo, alkoxy or haloalkoxy.

[0155] 58. In embodiment 58, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1 to 56 is R 2 is fluoro, chloro, cyclopropyl, difluoromethyl or trifluoromethyl, and R 3 is fluoro, chloro, methoxy or difluoromethoxy.

[0156] 59. In embodiment 59, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1 to 52 is [ka] is 2,6-difluorophenyl, 2-fluoro-6-trifluoromethylphenyl, 2-chloro-6-trifluoromethylphenyl, 2-difluoromethoxy-6-fluorophenyl, 2-difluoromethoxy-6-trifluoromethylphenyl, 2-methoxy-6-trifluoromethylphenyl, 2-fluoro-6-methoxyphenyl, 2-difluoromethyl-6-fluorophenyl, 2-cyclopropyl-6-fluorophenyl or 2,6-dichlorophenyl.

[0157] 60. In embodiment 60, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1 to 52 is [ka] is 2,6-difluorophenyl or 2-fluoro-6-trifluoromethylphenyl.

[0158] 61. In embodiment 61, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1 to 52 is [ka] is 2,6-difluorophenyl.

[0159] 62. In embodiment 62, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1 to 52 is [ka] is 2-fluoro-6-trifluoromethylphenyl.

[0160] 63. In embodiment 63, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1 to 62, is R 1 is the halo.

[0161] 64. In embodiment 64, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1 to 62, R 1 is fluoro or chloro.

[0162] 65. In embodiment 65, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1 to 62, is R 1 is fluoro.

[0163] 66. In embodiment 66, the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to any one of embodiments 1 to 62, is R 1is hydrogen. It is understood that the above embodiments and subembodiments include all combinations of the embodiments and subembodiments described therein.

[0164] General synthesis scheme Compounds of formula (I) can be made by the methods depicted in the reaction scheme shown below.

[0165] The starting materials and reagents used in the preparation of these compounds are available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Bachem (Torrance, Calif.) or Sigma (St. Louis, Mo.), or are prepared by methods known to those skilled in the art according to procedures described in reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some of the methods by which compounds of formula (I) can be synthesized, and various modifications to these schemes can be made and will be suggested to those skilled in the art upon reading this disclosure. The starting materials and intermediates, as well as the end products of the reactions, can be isolated and purified, if necessary, using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data.

[0166] Unless specified to the contrary, reactions described herein are carried out at atmospheric pressure over a temperature range of about -78°C to about 150°C, such as about 0°C to about 125°C, and also about room temperature (or ambient temperature), e.g., about 20°C.

[0167] R 1 , R 2 , R 3 , R A , R B Compounds of formula (I) as defined generally or in any of the embodiments disclosed herein above may also be prepared as illustrated and described in Scheme 1 below. Scheme 1 [ka]

[0168] A benzenesulfonyl compound of formula 1-1, 2 and R 3 is as described in the Summary (or any of its embodiments herein above), and X 1 is a halogen) with an aniline of formula 1-2, 1 as described in the Summary (or any of its embodiments herein above) in the presence of a suitable base such as DIPEA, pyridine, etc., to provide sulfonamide compounds of formula 1-3. 3 Reaction with a halogen such as chlorine or bromine) in the presence of a base such as LiHMDS under conditions known in the art provides the sulfonamide compounds of formula 1-5.

[0169] Compound 1-5 is halogenated using a suitable halogenating reagent, such as NBS, under conditions known in the art, and the resulting compound 1-6 is subsequently converted to a thioamide of formula 1-7, where R Bis as defined in the Summary (or any of its embodiments herein above) to give compounds of formula 1-8. The reaction can be carried out in a suitable organic solvent such as DMA, DMF, etc. at elevated temperature, or alternatively in the presence of a suitable reagent such as TFAA, NaHCO3, etc. under conditions known in the art.

[0170] The compound of formula 1-8 is reacted with R A As defined in the summary (or any of its embodiments herein above), treatment with an amine of formula 1-9 gives compounds of formula (I). The reaction can be carried out in an organic solvent under basic conditions, such as in DMSO or under Buchwald-type cross-coupling conditions, in the presence of DIPEA, CsF, K2CO3. Typically, Buchwald-type cross-coupling conditions include a combination of a Pd catalyst, a ligand and a base, such as Pd-RuPhos G2 and Cs2CO3. Compounds of formula 1-1, 1-2, 1-4, 1-7 and 1-9 are commercially available or can be prepared by methods known in the art and / or the following synthetic examples.

[0171] Instead, R 1 , R 2 , R 3 , R A , R B Compounds of formula (I) as defined generally (or any of its embodiments herein above) may be prepared as depicted and described in Scheme 2 below. Scheme 2 [ka]

[0172] Treatment of compound 1-8 with an appropriate thiol or thiol salt, such as sodium thiomethoxide, under reaction conditions known in the art, affords the methylthio compounds of formula 2-1. Oxidation of compound 2-1 with an appropriate oxidizing agent, such as oxone, mCPBA, affords the methylsulfonyl compounds of formula 2-2. Compound 2-2 can be reacted with R AAs defined in the summary (or any of its embodiments herein above), treatment with an amine of formula 1-9 provides compounds of formula (I). The reaction can be carried out in an appropriate solvent such as DMF, DMSO, under basic conditions such as in the presence of DIPEA, K2CO3, in an organic solvent.

[0173] R 1 , R 2 , R 3 , R A , R B Compounds of formula (I) as defined in the summary (or any of its embodiments herein above) may also be prepared as illustrated and described in Scheme 3 below. Scheme 3 [ka]

[0174] Protection of the amino group of compound 1-5 with a suitable nitrogen protecting group (PG), such as acetyl, under conditions well known in the art, gives compounds of formula 3-1, which proceed in a similar manner to that described above in Scheme 1 to convert to compounds of formula 3-5. Removal of the amino protecting group PG in 3-5 by treatment of 3-5 with a suitable reagent, such as NaOH, HCl, under conditions well known in the art, gives compounds of formula 3-6, which are converted to compounds of formula (I) as described above in Scheme 1.

[0175] R 1 , R 2 , R 3 , R A is defined in the overview (or any of its embodiments herein above), and R B Compounds of formula (I) where is a substituted heterocyclyl or bridged heterocyclyl as defined in the Summary (or any of its embodiments above) and attached via a nitrogen ring atom may also be prepared as shown and described in Scheme 4 below. Scheme 4 [ka]

[0176] Cyclization of compounds of formula 1-6 with thiourea 4-1 under conditions similar to those described in Scheme 1 above provides compounds of formula 4-2, which are converted to compounds of formula 4-5 as described in Scheme 2 above. Compounds 4-5 can be converted to compounds of formula 4-6 by cyclization of X under conditions known in the art. 4 is a halogen, such as chlorine or bromine, to a compound of formula 4-6. For example, 4 Compounds 4-6, where R is bromine, can be prepared by treating compound 4-5 with tert-butyl nitrite and CuBr2. Compounds of formula 4-6 can be converted to amines of formula 4-7, where R B corresponds to a heterocyclyl or bridged heterocyclyl as defined for compounds of formula (I) in the summary, to give compounds of formula (I) B is heterocyclyl or bridged heterocyclyl as defined in the Summary. The reaction can be carried out in an organic solvent under basic conditions such as in the presence of DIPEA, K2CO3 in DMSO at elevated temperature.

[0177] Compounds of formula (I) can be converted to other compounds of formula (I) by methods well known in the art. For example, R B at the second nitrogen ring atom of the piperazin-1-yl ring. d A compound of formula (I) that is piperazin-1-yl substituted with (as defined in the Summary) may be as shown below: [ka]

[0178] The protecting group PG of compound 1 (prepared as described in Scheme 4 above) 2 (e.g., tert-butyloxycarbonyl) is removed to give R d is obtained, and then by well-known methods, R d can be converted to a compound of formula (I) where R is other than hydrogen. For example, dCompounds of formula (I) where R is hydrogen can be reacted with an alkyl or cycloalkyl ketone under reductive amination conditions to give R d is alkyl or cycloalkyl,

[0179] utility Increasing evidence suggests that overactivated CDK2 leads to abnormal cell cycle regulation and proliferation of cancer cells. The kinase activity of CDK2 / cyclin E or CDK2 / cyclin A complexes is elevated in human cancers by several mechanisms. Cyclin E has been found to be frequently amplified, for example, in uterine, ovarian, gastric and breast cancers. In some cancer types, loss-of-function mutations in FBXW7, which controls cyclin E turnover, or overexpression of USP28, lead to overexpression of cyclin E and activation of CDK2. Instead, certain cancer cells express overactive truncated forms of cyclin E or cyclin A. Furthermore, amplification and overexpression of cyclin A have also been reported in various cancers, such as hepatocellular carcinoma, colorectal cancer and breast cancer. In some tumors, the catalytic activity of CDK2 is increased following loss or altered expression of the endogenous CDK2 inhibitors p27 or p21, or overexpression of SKP2, a negative regulator of p27. Furthermore, the protein phosphatases responsible for the dephosphorylation that activates CDK2, CDC25A and CDC25B, are overexpressed in various tumors. These different mechanisms of CDK2 activation have been examined using cancer cells or mouse cancer models.

[0180] Furthermore, CDK2 / cyclin E phosphorylates oncogenic Myc to counter ras-induced senescence, highlighting the importance of CDK2 in myc / ras-induced tumorigenesis. CDK2 inactivation has been shown to be synthetic lethal to cancer cells overexpressing myc. In aneuploid cancer cells, e.g., KRAS-mutated lung cancer, CDK2 inhibition led to late catastrophe and apoptosis. Furthermore, CDK2 inhibition effectively induced granulocytic differentiation in AML cell lines and suppressed tumor growth in AML mouse models.

[0181] Activation of CDK2 as a result of amplification or overexpression of cyclin E has also been identified as a major primary or acquired resistance pathway for tumors treated with CDK4 / 6 inhibitors or trastuzumab. Thus, compounds of formula (I) can be used in combination with CDK4 / 6 inhibitors to treat cancers that become refractory to CDK4 / 6 inhibitors.

[0182] Thus, the compounds of formula (I) as described in the first aspect (or any of the above embodiments herein) or pharma- ceutically acceptable salts thereof may be useful for treating tumours characterised by one or more of CDK2 overexpression, CDK2 hyperphosphorylation (Thr160), cyclin E or cyclin A amplification / overexpression, RB deficiency, loss-of-function mutations of FBXW7 or USP28 overexpression, truncated cyclin E or cyclin A expression, p21 or p27 dysregulation or SKP2 overexpression, CDC25A or / and CDC25B amplification / overexpression, AMBRA1 depletion, MYC / RAS overactivity, aneuploid cancer, CDK4 and / or CDK6 inhibitor-resistant cancer.

[0183] 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 / or non-small cell lung cancer, small cell and / or non-small cell carcinoma, bronchial 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, cancer of the small intestine, colon cancer, rectal cancer, cancer of the anus, gastric cancer, head and neck cancer (e.g., cancer of the larynx, hypopharynx, nasopharynx, oropharynx, lip and / or oral cavity), 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), stomach 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.

[0184] 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 of the above embodiments, the breast cancer is characterized by amplification or overexpression of CCNE1, CCNE2, and / or CCNA2.

[0185] Furthermore, the compounds of formula (I) as described in the first aspect (or any of its embodiments herein above) may also be useful for the treatment of Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, neuroblastoma, medulloblastoma and AL in pediatric patients.

[0186] Besides cancer, upregulation of CDK2 has also been implicated in autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), primary Sjogren's syndrome (pSS), multiple sclerosis (MS), Crohn's disease (CD), gout, uveitis, pemphigus vulgaris and sepsis. Thus, the compounds of formula (I) as described in the Summary, as described in the first aspect (or any of its embodiments herein above), are useful for the treatment of the above autoimmune diseases.

[0187] test The CDK2 inhibitory activity of the compounds of formula (I) may be tested using the in vitro assay described in Biological Example 1 below.

[0188] Pharmaceutical Compositions In general, the compounds of formula (I) (unless otherwise indicated, references herein to compounds of formula (I) include the embodiments thereof described herein above or pharma- ceutically acceptable salts thereof) are administered in therapeutically effective amounts by any of the accepted modes of administration for agents providing similar utilities. The therapeutically effective amount of the compounds of formula (I) may range from about 0.01 to about 500 mg per kg of patient body weight per day, which may be administered in single or multiple doses. Suitable dosage levels may be from about 0.1 to about 250 mg / kg per day; from about 0.5 to about 100 mg / kg per day. Suitable dosage levels may be from about 0.01 to about 250 mg / kg per day, from about 0.05 to about 100 mg / kg per day, or from about 0.1 to about 50 mg / kg per day. Within this range, the dosage may be about 0.05 to about 0.5, about 0.5 to about 5, or about 5 to about 50 mg / kg per day. For oral administration, the composition may be provided in the form of a tablet containing about 1.0 to about 1000 milligrams 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 milligrams of active ingredient. The actual amount of the compound of formula (I), i.e., the active ingredient, will depend on many factors, such as the severity of the disease being treated, the age and relative health of the patient, the potency of the compound utilized, the route and form of administration, and other factors.

[0189] In general, the compounds of formula (I) are administered as pharmaceutical compositions by any of the following routes: oral, systemic (e.g., transdermal, intranasal or suppository) or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration. The preferred method of administration is oral, using a convenient daily dosage regimen that can be adjusted according to the degree of affliction. The compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols or other suitable compositions.

[0190] The choice of formulation depends on various factors, such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules, with pills or capsules containing enteric coatings or delayed release tablets being preferred) and the bioavailability of the drug substance.

[0191] The composition generally comprises a compound of formula (I) in combination with at least one pharma- ceutically acceptable excipient.Acceptable excipients are generally non-toxic, aid in administration, and do not adversely affect the therapeutic benefits of the compound of formula (I).Such excipients can be any solid, liquid, semi-solid, or, in the case of aerosol compositions, gaseous excipients that are generally available to those skilled in the art.

[0192] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, etc. Liquid and semi-solid excipients may be selected from glycerol, propylene glycol, water, ethanol, and various oils including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, preferably particularly for injectable solutions, include water, saline, aqueous dextrose and glycols.

[0193] The compound of formula (I) can be formulated for parenteral administration by injection, for example, bolus injection or continuous infusion. The formulation for injection can be provided in unit dosage form, for example, in ampoules or multi-dose containers, with the addition of a preservative. The composition can take the form of a suspension, solution or emulsion in an oily or aqueous vehicle, and can contain compounding agents, such as suspending, stabilizing and / or dispersing agents. The formulation can be provided in unit dosage or multi-dose containers, for example, sealed ampoules and vials, and can be stored in powder form or freeze-dried (lyophilized) condition, requiring only the addition of a sterile liquid carrier, for example, physiological saline or sterile pyrogen-free water immediately before use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets of the kind previously described.

[0194] Preparations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compound, which may contain antioxidants, buffers, bacteriostats, and solutes that render the preparation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may contain 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, allowing for the preparation of highly concentrated solutions.

[0195] In addition to the above-mentioned formulations, the compound of formula (I) can also be formulated as a depot preparation.Such long-acting preparations can be administered by implantation (for example, subcutaneous or intramuscular) or intramuscular injection.Thus, for example, the compound can be formulated with suitable polymer or hydrophobic material (for example, as an emulsion in acceptable oil) or ion exchange resin, or as sparingly soluble derivative, for example, as a sparingly soluble salt.

[0196] For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, pastilles, or gels formulated in a conventional manner.Such compositions may contain the active ingredient in a flavor base, such as sucrose and acacia or tragacanth.

[0197] 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.

[0198] Certain compounds of formula (I) can be administered by local administration, i.e., non-systemic administration. This includes application of a compound of formula (I) to the outside of the epidermis or buccal cavity, and instillation of such compounds into the ears, eyes, and nose, such that the compound does not significantly enter the bloodstream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

[0199] Formulations suitable for topical administration include liquid or semi-liquid formulations suitable for penetration through the skin to the site of inflammation, such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose. The active ingredient for topical administration may comprise, for example, 0.001% to 10% w / w (weight) of the formulation. In certain embodiments, the active ingredient may comprise up to 10% w / w. In other embodiments, this may comprise less than 5% w / w. In certain embodiments, the active ingredient may comprise 2% w / w to 5% w / w. In other embodiments, this may comprise 0.1% to 1% w / w of the formulation.

[0200] For administration by inhalation, the compound of formula (I) can be conveniently delivered from an insufflator, a nebulizer pressurized pack or other convenient means of delivering an aerosol spray. The pressurized pack can contain a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the unit of dosage can be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the compound of formula (I) can be in the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base, such as lactose or starch. The powder composition can be presented in unit dosage form, for example in capsules, cartridges, gelatin or blister packs, from which the powder can be administered with the aid of an inhaler or insufflator. Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by EW Martin (Mack Publishing Company, 20th ed., 2000).

[0201] The level of the compound of formula (I) in the formulation can vary within the full range used by those skilled in the art. Typically, the formulation contains, on a weight percent (wt%) basis, about 0.01-99.99% by weight 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% by weight.

[0202] Combinations and Combination Therapies The compound of formula (I) may be used in combination with one or more other drugs in the treatment of diseases or conditions for which the compound of formula (I) or other drugs may be useful. Such other drugs may be administered simultaneously or sequentially with the compound of formula (I) by a route and in an amount commonly used thereby. When the compound of formula (I) is used simultaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of formula (I) is preferred. However, combination therapy may also include therapy in which the compound of formula (I) and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compound of formula (I) and the other active ingredients may be used in lower doses than when each is used alone.

[0203] Thus, the pharmaceutical compositions of the disclosure include those that contain one or more other drugs, in addition to a compound of formula (I).

[0204] The above combinations include not only combinations of the compound of formula (I) with one other drug, but also combinations with two or more other active drugs. Similarly, the compound of formula (I) may be used in combination with other drugs used in the prevention, treatment, control, amelioration or reduction of the risk of a disease or condition for which the compound of formula (I) is useful. Such other drugs may be administered simultaneously or sequentially with the compound of formula (I) by a route and in an amount commonly used therefor. When the compound of formula (I) is used simultaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of formula (I) can be used. Thus, the pharmaceutical compositions of the present disclosure also include those that contain one or more other active ingredients in addition to the compound of formula (I). The weight ratio of the compound of the present disclosure to the second active ingredient may vary and depends on the effective dose of each ingredient. Generally, an effective dose of each is used.

[0205] If a subject in need has or is at risk of having cancer, the subject may be treated with a MAP kinase pathway (RAS / RAF / MEK / ERK) inhibitor, including, but not limited to, vemurafanib (PLX4032), dabrafenib, encorafenib (LGX818), TQ-B3233, XL-518 (Cas number 1029872-29-4, available from ACCCorp); trametinib, selumetinib (AZD624 4), TQ-B3234, PD184352, PD325901, TAK-733, pimasertinib, binimetinib, refametinib, cobimetinib (GDC-0973), AZD8330, BVD-523, LTT462, ulixertinib, AMG510, ARS853 and International Publication No. 2016049565, International Publication No. 2016164675, International Publication No. 2016168540 , International Publication No. 2017015562, International Publication No. 2017058728, International Publication No. 2017058768, International Publication No. 2017058792, International Publication No. 2017058805, International Publication No. 2017058807, International Publication No. 2017058902, International Publication No. 2017058915, International Publication No. 201 any RAS inhibitor disclosed in WO 7070256, WO 2017087528, WO 2017100546, WO 2017172979, WO 2017201161, WO 2018064510, WO 2018068017, WO 2018119183; CSF1R inhibitors (e.g. PLX3397, LY3022855) and CSF1R antibodies (IMC-054, RG7155); TGF beta receptor kinase inhibitors, such as LY2157299; BTK inhibitors such as ibrutinib; BCR-ABL inhibitors: imatinib (Gleevec®); inilotinib hydrochloride; nilotinib (Tasigna®); dasatinib (BMS-345825); bosutinib (SKI-606); ponatinib (AP24534); bafetinib (INNO406); danusertib (PHA-739358); AT9283 (CA S1133385-83-7; 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, CAS942487-16-3); ALK inhibitors: PF-2341066 (XALKOPJ®; crizotinib); 5-chloro-N4-(2-(isopropylsulfonyl)phenyl)-N2-(2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)pyrimidine-2,4-diamine; GSK1838705A; CH5424802; Ceritinib (ZYKADIA); TQ-B3139, TQ-B3101 PI3K inhibitors: 4-[2-(1H-indazol-4-yl)-6-[[4-(methylsulfonyl)-piperazin-1-yl]methyl]thieno[3,2-d]pyrimidin-4-yl]morpholine (also known as GDC0941, described in 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 BEZ235 or NVP-BEZ235, described in WO 06 / 122806); Vascular endothelial growth factor (VEGF) receptor inhibitors: bevacizumab (sold under the trade name Avastin® by Genentech / Roche), axitinib, (also known as N-methyl-2-[[3-[(E)-2-pyridin-2-ylethenyl]-1H-indazol-6-yl]sulfanyl]benzamide, AG013736, described in WO 01 / 002369), brivanib alaninate ((S)-((R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazine- 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-pyridinylmethyl)amino]-3-pyridinecarboxamide, described in WO 02 / 066470), pasireotide (also known as SOM230, described in WO 02 / 010192), sorafenib (sold under the trade name Nexavar®); AL-2846 MET inhibitors such as foretinib, carbozantinib, and crizotinib; FLT3 inhibitors - sunitinib malate (sold under the trade name Sutent® by Pfizer); PKC412 (midostaurin); tanutinib, sorafenib, lestaurtinib, KW-2449, quizartinib (AC220) and crenolanib; Epidermal growth factor receptor (EGFR) inhibitors: gefitonib (sold under the trade name Iressa®), N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4(dimethylamino)-2-butenamide (sold under the trade name Tovok® by Boehringer Ingelheim), cetuximab (sold under the trade name Erbitux® by Bristol-Myers Squibb), panitumumab (sold under the trade name Vectibix® by Amgen); HER2 receptor inhibitors: trastuzumab (marketed under the trade name Herceptin® by Genentech / Roche), 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, described in WO 05 / 028443), lapatinib or lapatinib ditosylate (marketed under the trade name Tykerb® by GlaxoSmithKline); trastuzumab emtansine (known in the US as ado-trastuzumab emtansine, trade name Kadcyla) - an antibody drug conjugate consisting of the monoclonal antibody trastuzumab (Herceptin) linked to the cytotoxic agent mertansine (DM1); HER dimerization inhibitors: pertuzumab (sold under the trade name Omnitarg® by Genentech); CD20 antibodies: rituximab (sold under the trade names Riuxan® and MabThera® by Genentech / Roche), tositumomab (sold under the trade name Bexxar® by GlaxoSmithKline), ofatumumab (sold under the trade name Arzerra® by GlaxoSmithKline); Tyrosine kinase inhibitors: erlotinib hydrochloride (sold under the trade name Tarceva® by Genentech / Roche), 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 (sold under the trade name Sutent® by Pfizer), 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. Pat. No. 6,780,996), dasatinib (sold under the trade name Sprycel® by GlaxoSmithKline), Almara (also known as pazopanib, sold under the trade name Votrient® by GlaxoSmithKline), imatinib and imatinib mesylate (sold under the trade names Gilvec® and Gleevec® by Novartis); DNA synthesis inhibitors: capecitabine (sold under the trade name Xeloda® by Roche), gemcitabine hydrochloride (sold under the trade name Gemzar® by Eli Lilly), nelarabine ((2R3S,4R,5R)-2-(2-amino-6-methoxypurin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol, sold under the trade names Arranon® and Atriance® by GlaxoSmithKline; Antitumor agents: oxaliplatin (sold under the trade name Eloxatin® by Sanofi-Aventis and described in U.S. Pat. No. 4,169,846); Human granulocyte colony-stimulating factor (G-CSF) modulators: filgrastim (sold under the trade name Neupogen® by Amgen); Immunomodulatory agents: afutuzumab (available from Roche), pegfilgrastim (sold under the trade name Neulasta® by Amgen), lenalidomide (also known as CC-5013, sold under the trade name Revlimid®), thalidomide (sold under the trade name Thalomid®); CD40 inhibitor: dacetuzumab (also known as SGN-40 or huS2C6, available from Seattle Genetics, Inc.); Pro-apoptotic receptor agonist (PARA): dulanermin (also known as AMG-951, available from Amgen / Genentech); Hedgehog antagonist: 2-chloro-N-[4-chloro-3-(2-pyridinyl)phenyl]-4-(methylsulfonyl)benzamide (also known as GDC-0449 and described in WO 06 / 028958); Phospholipase A2 inhibitors: anagrelide (sold under the brand name Agrylin®); BCL-2 inhibitors: 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, described in WO 09 / 155386); MCl-1 inhibitors: MIK665, S64315, AMG397 and AZD5991; Aromatase inhibitors: exemestane (sold under the brand name Aromasin® by Pfizer), letrozole (sold under the brand name Femara® by Novartis), anastrozole (sold under the brand name Arimidex®); Topoisomerase I inhibitors: irinotecan (sold under the trade name Camptosar® by Pfizer), topotecan hydrochloride (sold under the trade name Hycamtin® by GlaxoSmithKline); Topoisomerase II inhibitors: etoposide (also known as VP-16 and etoposide phosphate, sold under the trade names Toposar®, VePesid®, Etopophos®), teniposide (also known as VM-26, sold under the trade name Vumon®); mTOR inhibitors: temsirolimus (sold under the trade name Torisel® by Pfizer), ridaforolimus (formally 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[30.3.1.04'9]hexatriaconta-16,24,26,28-tetraen-12-yl]propyl]-2-methoxycyclohexyl dimethylphosphinate, also known as AP23573 and MK8669 and described in WO 03 / 064383), everolimus (sold under the trade name Afinitor® by Novartis); Proteasome inhibitors such as carfilzomib, MLN9708, delanzomib or bortezomib; BET inhibitors such as INCB054329, OTX015 and CPI-0610; LSD1 inhibitors such as GSK2979552, INCB059872; HIF-2α inhibitors such as PT2977 and PT2385; Osteoclastic bone resorption inhibitor: 1-hydroxy-2-imidazol-1-yl-phosphonoethyl)phosphonic acid monohydrate (sold under the trade name Zometa® by Novartis); CD33 antibody drug conjugate: gemtuzumab ozogamicin (sold under the trade name Mylotarg® by Pfizer / Wyeth); CD22 antibody-drug conjugate: inotuzumab·ozogamicin (also known as CMC-544 and WAY-207294, available from Hangzhou Sage Chemical Co., Ltd.); CD20 antibody-drug conjugate: ibritumomab tiuxetan (sold under the brand name Zevalin®); Somatostatin analogs: octreotide (also known as octreotide acetate, sold under the trade names Sandostatin® and Sandostatin LAR®); Synthetic interleukin-11 (IL-11): Oprelvekin (sold under the trade name Neumega® by Pfizer / Wyeth); Synthetic erythropoietin: darbepoetin alfa (sold under the trade name Aranesp® by Amgen); Receptor activator of nuclear factor kappa B (RANK) inhibitors: denosumab (sold under the brand name Prolia® by Amgen); Thrombopoietin mimetic peptibodies: romiplostim (sold under the trade name Nplate® by Amgen); Cell growth stimulators: Palifermin (sold under the trade name Kepivance® by Amgen); Anti-insulin-like growth factor 1 receptor (IGF-1R) antibodies: figitumumab (also known as CP-751,871, available from ACC Corp), lobatumumab (CAS number 934235-44-6); Anti-CSl antibody: elotuzumab (HuLuc63, CAS number 915296-00-3) CD52 antibodies: alemtuzumab (sold under the brand name Campath®); Histone deacetylase inhibitors (HDIs): boninostat (sold under the trade name Zolinza® by Merck); Alkylating agents: temozolomide (sold under the trade names Temodar® and Temodal® by Schering-Plough / Merck), dactinomycin (also known as actinomycin-D, sold under the trade name Cosmegen®), melphalan (also known as L-PAM, L-sarcolysin, and phenylalanine mustard, sold under the trade name Alkeran®), altretamine (also known as hexamethylmelamine (HMM), sold under the trade name H Exalen®), carmustine (sold under the trade name BiCNU®), bendamustine (sold under the trade name Treanda®), busulfan (sold under the trade names Busulfex® and Myleran®), carboplatin (sold under the trade name Paraplatin®), lomustine (also known as CCNU, sold under the trade name CeeNU®), cisplatin (also known as CDDP, sold under the trade name Platinum®), ol® and Platinol®-AQ), chlorambucil (sold under the trade names Leukeran®), cyclophosphamide (sold under the trade names Cytoxan® and Neosar®), dacarbazine (also known as DTIC, DIC, and imidazole carboxamide, sold under the trade name DTIC-Dome®), altretamine (also known as hexamethylmelamine (HMM), sold under the trade name Hexalen®), serotonin (sold under the trade name Ifosfamide (sold under the trade name Ifex®), procarbazine (sold under the trade name Matulane®), mechlorethamine (also known as nitrogen mustard, mustine and mechloroethamine hydrochloride, sold under the trade name Mustargen®), streptozocin (sold under the trade name Zanosar®), thiotepa (also known as thiophosphoamide, TESPA and TSPA, sold under the trade name Thioplex®); Biological response modifiers: Bacillus Calmette-Guerin (sold under the trade names theraCys® and TICE® BCG), denileukin diftitox (sold under the trade names Ontak®); Antitumor antibiotics: doxorubicin (sold under the trade names Adriamycin® and Rubex®), bleomycin (sold under the trade name Lenoxane®), daunorubicin (also known as dauorubicin hydrochloride, daunomycin, rubidomycin hydrochloride, sold under the trade name Cerubidine®), daunorubicin liposomal (daunorubicin citrate liposomal, sold under the trade name DaunoXome®), mitoxantrone (also known as DHAD, sold under the trade name Novantrone®), epirubicin (sold under the trade name Ellence®), idarubicin (sold under the trade names Idamycin®, Idamycin PFS®), mitomycin C (sold under the trade name Mutamycin®); Anti-microtubule agents: estramustine (sold under the trade name Emcyl®); Cathepsin K inhibitors: 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, available from Lanzhou Chon Chemicals, ACC Corp. and Chemie Tek, and described in WO 03 / 075836); Epothilone B analogues: ixabepilone (sold under the trade name Lxempra® by Bristol-Myers Squibb); Heat shock protein (HSP) inhibitors: tanespimycin (also known as 17-allylamino-17-demethoxygeldanamycin, 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; TpoR agonists: Eltrombopag (sold under the trade names Promacta® and Revolade® by GlaxoSmithKline); Antimitotic agents: docetaxel (sold under the brand name Taxotere® by Sanofi-Aventis); Adrenal steroid inhibitors: aminoglutethimide (sold under the brand name Cytadren®); Antiandrogens: nilutamide (sold under the brand names Nilandron® and Anandron®), bicalutamide (sold under the brand name Casodex®), flutamide (sold under the brand name Fulexin™); Androgens: Fluoxymesterone (sold under the brand name Halotestin®); 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 flavopirdol or HMR-1275, 2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-1-methyl-4-piperidinyl]-4-chromenone, described in U.S. Pat. No. 5,621,002); CDK4 / 6 inhibitors, including but not limited to pabociclib, ribociclib, abemaciclib, and trilaciclib; CDK9 inhibitors, including but not limited to AZD4573, P276-00, AT7519M, TP-1287; CDK2 / 4 / 6 inhibitors, such as PF-06873600; 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)thio-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 (IRC083864) or 2-methoxyestradiol or a pharma- ceutically acceptable salt thereof; SHP-2 inhibitors such as TNO155; MDM2 / MDMX, MDM2 / p53 and / or MDMX / p53 modulators; Gonadotropin-releasing hormone (GnRH) receptor agonists: leuprolide or leuprolide acetate (sold under the trade names Viadure® by Bayer AG, Eligard® by Sanofi-Aventis, and Lupron® by Abbott Lab); Taxane antitumor agents: cabazitaxel (1-hydroxy-7,10-dimethoxy-9-oxo-5,20-epoxytax-11-ene-2a,4,13a-triyl-4-acetate-2-benzoate-13-[(2R,3S)-3-{[(tert-butoxy)carbonyl]amino}-2-hydroxy-3-phenylpropanoate), larotaxel ((2α,3ξ,4α,5β,7α,10β,13α)-4,10-bis(acetyloxy)-13-({(2R,3S)-3-[(tert-butoxycarbonyl)amino]-2-hydroxy-3-phenylpropanoyl}-oxy)-1-hydroxy-9-oxo-5,20-epoxy-7,19-cyclotax-11-en-2-ylbenzoate); 5HT1a receptor agonist: xaliproden (also known as SR57746, 1-[2-(2-naphthyl)ethyl]-4-[3-(trifluoromethyl)phenyl]-1,2,3,6-tetrahydropyridine, described in U.S. Pat. No. 5,266,573); HPC vaccine: Cervarix® marketed by GlaxoSmithKline, Gardasil® marketed by Merck; iron chelator: deferasinox (marketed under the trade name Exjade® by Novartis); Antimetabolites: claribine (2-chlorodeoxyadenosine, sold under the trade name leustatin®), 5-fluorouracil (sold under the trade name Adrucil®), 6-thioguanine (sold under the trade name Purinethol®), pemetrexed (sold under the trade name Alimta®), cytarabine (also known as arabinosylcytosine (Ara-C), sold under the trade name Cytosar-U®), cytarabine liposomal (also known as liposomal Ara-C, sold under the trade name DepoCyt™), decitabine (sold under the trade name Dacogen®) , hydroxyurea (sold under the trade names Hydrea®, Droxia™, Mylocel™), fludarabine (sold under the trade name Fludara®), floxuridine (sold under the trade name FUDR®), cladribine (also known as 2-chlorodeoxyadenosine (2-CdA) and sold under the trade name Leusstatin™), methotrexate (also known as amethopterin, methotrexate sodium (MTX) and sold under the trade names Rheumatrex® and Trexall™), pentostatin (sold under the trade name Nipent®); Bisphosphonates: pamidronic acid (sold under the brand name Aredia®), zoledronic acid (sold under the brand name Zometa®); demethylating agents: 5-azacytidine (sold under the brand name Vidaza®), decitabine (sold under the brand name Dacogen®); Plant Alkaloids: protein-bound paclitaxel (sold under the trade name Abraxane®), vinblastine (also known as vinblastine sulfate, vincaleukoblastine and VLB, sold under the trade names Alkaban-AQ® and Velban®), vincristine (also known as vincristine sulfate, LCR and VCR, sold under the trade names Oncovin® and Vincasar Pfs®), vinorelbine (sold under the trade name Navelbine®), paclitaxel (sold under the trade names Taxol and Onxal™); Retinoids: Alitretinoin (sold under the trade name Panretin®), tretinoin (also known as all-trans retinoic acid, ATRA, sold under the trade name Vesanoid®), isotretinoin (13-cis-retinoic acid, sold under the trade names Accutane®, Amnesteem®, Claravis®, Clarus®, Decutan®, Isotane®, Izotech®, Oratane®, Isotret® and Sotret®), bexarotene (sold under the trade name Targretin®); Glucocorticosteroids: Hydrocortisone (also known as Cortisone, Hydrocortisone Sodium Succinate, Hydrocortisone Sodium Phosphate, Ala-Cort®, Hydrocortisone Phosphate, Solu-Cortef®, Hydrocort Acetate®, Lanacort®), 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]phenanthren-3-one), prednisolone (Delta-Cortel®, Orapred®, Pediapred®, and Prednisolone), lone®), prednisone (sold under the trade names Deltasone®, LiquidRed®, Meticorten® and Orasone®), methylprednisolone (also known as 6-methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, sold under the trade names Duralone®, Medralone®, Medrol®, M-Prednisol® and Solu-Medrol®); Cytokines: interleukin-2 (also known as aldesleukin and IL-2, sold under the trade name Proleukin®), interleukin-11 (also known as oplebukin, sold under the trade name Neumega®), alpha interferon alpha (also known as IFN-alpha, sold under the trade names Intron® A and Roferon-A®); estrogen receptor downregulators: fulvestrant (sold under the trade name Faslodex®); Antiestrogens: tamoxifen (sold under the brand name Novaldex®); toremifene (sold under the brand name Fareston®); Selective estrogen receptor modulators (SERMs): raloxifene (sold under the brand name Evista®); Luteinizing hormone-releasing hormone (LHRH) agonists: goserelin (sold under the brand name Zoladex®); Progesterone: megestrol (also known as megestrol acetate, sold under the brand name Megace®); Treatment with the compounds of formula (I) may be in any combination with one or more other anti-cancer agents, including, but not limited to, a variety of cytotoxic agents: arsenic trioxide (sold under the trade name Trisenox®), asparaginase (L-asparaginase, also known as Erwinia L-asparaginase, sold under the trade names Elspar® and Kidrolase®).

[0206] The one or more immune checkpoint inhibitors are 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 a KIR inhibitor, a TIGIT inhibitor, a LAIR1 inhibitor, a CD160 inhibitor, a 2B4 inhibitor, and a TGFR beta inhibitor.

[0207] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1, such as an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, or AMP-224. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab or PDR001. In some embodiments, the anti-PD1 antibody is pembrolizumab.

[0208] In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, such as an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments, the anti-PD-L1 monoclonal antibody is MPDL3280A (atezolizumab) or MEDI4736 (durvalumab).

[0209] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of CTLA-4, such as an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab or tremelimumab. In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of LAG3, such as an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016 or LAG525. In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of GITR, such as an anti-GITR antibody. In some embodiments, the anti-GITR antibody is TRX518 or MK-4166, INCAGN01876 or MK-1248. In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of OX40, such as an anti-OX40 antibody or an OX40L fusion protein. In some embodiments, the anti-OX40 antibody is MEDI0562 or INCAGN01949, GSK2831781, GSK-3174998, MOXR-0916, PF-04518600, or LAG 525. In some embodiments, the OX40L fusion protein is MEDI6383.

[0210] The compounds of formula (I) can also be used to increase or enhance immune responses, including increasing immune responses to antigens; improve immunization, including increasing vaccine efficacy; and increase inflammation. In some embodiments, the compounds of formula (I) can be sued to enhance immune responses to vaccines, including, but not limited to, Listeria vaccines, oncolytic virus vaccines, and cancer vaccines such as GVAX® (a tumor cell vaccine transfected with the granulocyte-macrophage colony-stimulating factor (GM-CF) gene). Anti-cancer vaccines include dendritic cells, synthetic peptides, DNA vaccines, and recombinant viruses. Other immunomodulatory agents include those that block immune cell migration, such as antagonists against chemokine receptors, including CCR2 and CCR4; Sting agonists, and Toll receptor agonists.

[0211] Other anti-cancer agents include those that enhance the immune system, such as adjuvants or adoptive T cell transfer. The compounds of the present application may be effective in combination with CAR (chimeric antigen receptor) T cell treatment as a booster of T cell activation.

[0212] The compounds of formula (I) may also be used in combination with the following adjunctive therapies: antiemetics: NK-1 receptor antagonists: casopitant (sold under the trade names Rezonic® and Zunrisa® by GlaxoSmithKline); and Cytoprotective agents: Amifostine (sold under the brand name Ethyol®), Leucovorin (also known as calcium leucovorin, citrovorum factor and folic acid). EXAMPLES

[0213] Synthesis Examples The following preparations of intermediates and compounds of formula (I) are given to enable those skilled in the art to more clearly understand and to practice the present disclosure, and they should not be considered as limiting the scope of the disclosure, but merely as illustrative and representative thereof.

[0214] Intermediate 1 Synthesis of (3aR,5s,6aS)-5-aminohexahydro-1H-cyclopenta[c]thiophene 2,2-dioxide [ka] Step 1: Dimethyl 4-oxocyclopentane-1,2-dicarboxylate [ka] 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 h and then concentrated. The residue was dissolved in EtOAc and washed with H2O and brine. The organic layer was dried over Na2SO4, filtered and concentrated to give the title compound as a colorless oil.

[0215] Step 2: Dimethyl 1,4-dioxaspiro[4.4]nonane-7,8-dicarboxylate [ka] 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, cat.) in toluene (100.0 mL) was heated to 140 °C for 16 h 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.

[0216] Step 3: 1,4-Dioxaspiro[4.4]nonane-7,8-diyldimethanol [ka] A solution of LiAlH4 (690 mg, 18.20 mmol, 1.20 equiv) in THF (20.0 mL) was cooled to 0 °C and a solution of dimethyl 1,4-dioxaspiro[4.4]nonane-7,8-dicarboxylate (3.70 g, 15.20 mmol, 1.00 equiv) in THF (30.0 mL) was added dropwise at 0 °C. The mixture was stirred at 0 °C for 1 h and then quenched with H2O. The mixture was filtered and the filter cake was washed with MeOH. The filtrates were combined and concentrated to give the title compound as a yellow oil.

[0217] Step 4: 1,4-Dioxaspiro[4.4]nonane-7,8-diylbis(methylene)dimethanesulfonate [ka] TEA (8.06 g, 79.80 mmol, 6.00 equiv) was added to a solution of 1,4-dioxaspiro[4.4]nonane-7,8-diyldimethanol (2.50 g, 13.30 mmol, 1.00 equiv) in DCM (30 mL) followed by dropwise addition of MsCl (4.55 g, 39.90 mmol, 3.00 equiv) at room temperature. The mixture was stirred at room temperature for 5 h and then poured onto ice. The mixture was extracted with DCM. The organic layers were combined and concentrated to give the title compound as a yellow oil.

[0218] Step 5: (3aR,6aS)-Tetrahydro-1H,3H-spiro[cyclopenta[c]thiophene-5,2'-[1,3]dioxolane] [ka] Na2S (907 mg, 11.60 mmol, 1.00 equiv) 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 equiv) in EtOH (30.0 mL) at room temperature. The mixture was heated to 60° C. under N2 atmosphere for 16 h and then poured into water. The mixture was extracted with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4, concentrated and purified by silica gel column chromatography (PE / EtOAc=10:1) to give the title compound as a white solid.

[0219] Step 6: (3aR,6aS)-Tetrahydro-1H-cyclopenta[c]thiophen-5(3H)-one [ka] 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 h and diluted with H2O. The mixture was extracted with EtOAc, and the organic layers were combined, washed with saturated aqueous NaHCO3 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.

[0220] Step 7: (3aR,5r,6aS)-Hexahydro-1H-cyclopenta[c]thiophen-5-ol [ka] To a solution of (3aR,6aS)-tetrahydro-1H-cyclopenta[c]thiophen-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) in portions. The mixture was stirred at room temperature for 3 h, 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.

[0221] Step 8: (3aR,5r,6aS)-Hexahydro-1H-cyclopenta[c]thiophen-5-yl methanesulfonate [ka] TEA (840 mg, 8.33 mmol, 3.00 equiv) was added to a solution of (3aR,5r,6aS)-hexahydro-1H-cyclopenta[c]thiophen-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 was stirred for 3 h, then poured into water (10.0 mL) and the mixture was extracted with DCM. The organic layers were combined, washed with brine, dried over Na2SO4, filtered and concentrated to give the title compound as a yellow oil.

[0222] Step 9: (3aR,5s,6aS)-Hexahydro-1H-cyclopenta[c]thiophene-5-amine [ka] NaN3 (350 mg, 5.40 mmol, 2.00 equiv) was added to a solution of (3aR,5r,6aS)-hexahydro-1H-cyclopenta[c]thiophen-5-yl methanesulfonate (600 mg, 2.70 mmol, 1.00 equiv) in DMF (6 mL). The mixture was heated to 60 °C under N2 atmosphere for 16 h, then diluted with EtOAc and H2O. The organic layers were combined and concentrated. The residue was diluted with NH3 in MeOH (7 M, 10 mL), followed by the addition of Pd / C (10%, 120 mg, 0.2 W / W). The mixture was stirred at room temperature under H2 atmosphere for 16 h, then filtered and concentrated. The residue was purified by silica gel column chromatography (DCM / MeOH=10:1) to give the title compound as a yellow oil.

[0223] Step 10: tert-Butyl ((3aR,5s,6aS)-2,2-dioxidehexahydro-1H-cyclopenta[c]thiophen-5-yl)carbamate [ka] (Boc)2O (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 h, then diluted with H2O and extracted with EtOAc. The organic layers were combined, washed with brine, and concentrated under reduced pressure. The residue was dissolved in THF / H2O (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 h, then diluted with H2O 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.

[0224] Step 11: (3aR,5s,6aS)-5-aminohexahydro-1H-cyclopenta[c]thiophene 2,2-dioxide [ka] HCl in MeOH (4 M, 5.0 mL) was added to tert-butyl ((3aR,5s,6aS)-2,2-dioxidohexahydro-1H-cyclopenta[c]thiophen-5-yl)carbamate (450 mg, 1.64 mmol, 1.00 equiv) at room temperature. After stirring for 3 h, the mixture was concentrated. The residue was suspended in DCM followed by the addition of aqueous NaHCO3. The mixture was stirred at room temperature for 1 h and then filtered. The layers were separated and the organic layer was concentrated to give the title compound.

[0225] Intermediate 2 Synthesis of (1R,5S,6s)-6-amino-3-thiabicyclo[3.1.0]hexane 3,3-dioxide [ka] 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 [ka] Diazoacetic acid ethyl ester (7.20 g, 63.48 mmol, 1.5 equiv) in DCM (50.0 mL) was added slowly to a stirred solution of 2,5-dihydrothiophene 1,1-dioxide (5.00 g, 42.32 mmol, 1.00 equiv) and rhodium(II) acetate (281 mg, 1.27 mmol, 0.03 equiv) in DCM (80.0 mL) at room temperature under N2 using a syringe pump over 5 h. The mixture was concentrated and the residue was purified by silica gel column chromatography (PE:EA=5:1) to isolate the title compound.

[0226] Step 2: (1R,5S,6r)-3-Thiabicyclo[3.1.0]hexane-6-carboxylic acid 3,3-dioxide [ka] A solution of LiOH.HO (740 mg, 17.63 mmol, 3.00 equiv) in HO (6.0 mL) was added to a mixture of ethyl (1R,5S,6r)-3-thiabicyclo[3.1.0]hexane-6-carboxylate 3,3-dioxide (1.2 g, 5.88 mmol, 1.00 equiv) in EtOH (12.0 mL). The mixture was stirred at room temperature for 3 h. 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 the crude product as a pale yellow solid.

[0227] Step 3: Benzyl ((1R,5S,6s)-3,3-dioxido-3-thiabicyclo[3.1.0]hexan-6-yl)carbamate [ka] 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). The mixture was stirred at room temperature under N2 for 2 h, then benzyl alcohol (614 mg, 5.68 mmol, 2.00 equiv) was added dropwise. The 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.

[0228] Step 4: (1R,5S,6s)-6-amino-3-thiabicyclo[3.1.0]hexane 3,3-dioxide [ka] To a mixture of benzyl ((1R,5S,6s)-3,3-dioxide-3-thiabicyclo[3.1.0]hexan-6-yl)carbamate (500 mg, 0.36 mmol, 1.00 equiv) in methanol (5.0 mL) was added Pd / C (50 mg). The mixture was stirred at room temperature under H2 for 5 h. The mixture was filtered and concentrated to give the title compound as a white solid.

[0229] Intermediate 3 Synthesis of (1R,5S,6r)-6-amino-3-thiabicyclo[3.1.0]hexane 3,3-dioxide [ka] The title compound was prepared by proceeding in a similar manner as described for Intermediate 2, replacing ethyl (1R,5S,6r)-3-thiabicyclo[3.1.0]hexane-6-carboxylate 3,3-dioxide with ethyl (1R,5S,6s)-3-thiabicyclo[3.1.0]hexane-6-carboxylate 3,3-dioxide in steps 2-4.

[0230] Intermediate 4 Synthesis of (1s,4s)-4-(methylsulfonyl)cyclohexan-1-amine trifluoroacetate [ka] Step 1: (1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl methanesulfonate [ka] TEA (4.20 g, 41.79 mmol, 3.00 equiv) was added to a mixture of tert-butyl ((1r,4r)-4-hydroxycyclohexyl)carbamate (3.00 g, 13.93 mmol, 1.00 equiv) in DCM (30.0 mL), followed by slow addition of MsCl (2.40 g, 20.90 mmol, 1.50 equiv) at 0 °C. The mixture was stirred under N2 at 0 °C for 1 h, then it was warmed to room temperature and stirred under N2 for 2 h. The mixture was diluted with H2O and it was 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.

[0231] Step 2: tert-Butyl ((1s,4s)-4-(methylthio)cyclohexyl)carbamate [ka] CH3SNa (1.10 g, 15.68 mmol, 2.00 equiv) was added to a mixture of (1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexylmethanesulfonate (2.30 g, 7.84 mmol, 1.00 equiv) in DMF (23.0 mL). The mixture was stirred at room temperature overnight, 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.

[0232] Step 3: tert-Butyl ((1s,4s)-4-(methylsulfonyl)cyclohexyl)carbamate [ka] 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). The 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 pale yellow solid.

[0233] Step 4: (1s,4s)-4-(Methylsulfonyl)cyclohexan-1-amine trifluoroacetate [ka] 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, after which it was concentrated to give the crude title compound as a yellow oil.

[0234] Intermediate 5 Synthesis of (1r,4r)-4-(methylsulfonyl)cyclohexane-1-amine trifluoroacetate [ka] The title compound was prepared by proceeding in an analogous manner as described for Intermediate 4, replacing tert-butyl ((1r,4r)-4-hydroxycyclohexyl)carbamate in step 1 with tert-butyl ((1s,4s)-4-hydroxycyclohexyl)carbamate.

[0235] Intermediate 6 Synthesis of 6-amino-2-thiaspiro[3.3]heptane 2,2-dioxide [ka] Step 1: Diisopropyl 3-oxocyclobutane-1,1-dicarboxylate [ka] To a mixture of diisopropyl 3,3-dimethoxycyclobutane-1,1-dicarboxylate (40.00 g, 139.00 mmol) in acetone (100.0 ml) was added 2N aqueous HCl (100.0 mL) and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with EA and washed with water, saturated aqueous NaHCO3, and brine. The organic layer was dried over Na2SO4 and concentrated to give the crude product as a yellow liquid.

[0236] Step 2: Diisopropyl 3-hydroxycyclobutane-1,1-dicarboxylate [ka] 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, extracted with EtOAc, and the combined organic phases were washed with water, brine, dried over Na2SO4, and concentrated to give the crude product as a yellow oil.

[0237] Step 3: Diisopropyl 3-((methylsulfonyl)oxy)cyclobutane-1,1-dicarboxylate [ka] To a mixture of diisopropyl 3-hydroxycyclobutane-1,1-dicarboxylate (28.0 g, 115.0 mmol, 1.00 equiv) in DCM (300.0 ml) was added TEA (34.80 g, 344.0 mmol, 3.0 equiv), followed by MsCl (15.8 g, 138.0 mmol, 1.2 equiv) and the mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with 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.

[0238] Step 4: Diisopropyl 3-azidocyclobutane-1,1-dicarboxylate [ka] NaN3 (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 under N2 at 90° C. overnight. The mixture was diluted with water and extracted with EtOAc, and the combined organic layers were washed with water, brine, dried over Na2SO4, concentrated and purified by silica gel column chromatography (PE:EA=20:1) to give the title compound as a yellow liquid.

[0239] Step 5: Diisopropyl 3-aminocyclobutane-1,1-dicarboxylate [ka] 10% Pd / C (3.00 g) was added to a mixture of diisopropyl 3-azidocyclobutane-1,1-dicarboxylate (15.00 g, 55.70 mmol, 1.00 equiv) in IPA / NH3 (150.0 mL) and the mixture was stirred at room temperature under H2 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.

[0240] Step 6: Diisopropyl 3-((tert-butoxycarbonyl)amino)cyclobutane-1,1-dicarboxylate [ka] Boc2O (10.8 g, 49.4 mmol, 1.20 equiv) was added to a mixture of diisopropyl 3-aminocyclobutane-1,1-dicarboxylate (10.0 g, 41.10 mmol, 1.00 equiv) in DCM (100.0 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was washed with 1N aqueous HCl, brine, and the organic layer was dried over Na2SO4 and concentrated to give the crude product as a yellow liquid.

[0241] Step 7: tert-Butyl (3,3-bis(hydroxymethyl)cyclobutyl)carbamate [ka] Diisopropyl 3-((tert-butoxycarbonyl)amino)cyclobutane-1,1-dicarboxylate (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 allowed to warm to room temperature and stirred for 3 h, then quenched with water. After stirring for 30 min, the mixture was filtered and the organic layer was concentrated to give the crude product as a yellow oil.

[0242] Step 8: (3-((tert-butoxycarbonyl)amino)cyclobutane-1,1-diyl)bis(methylene)dimethanesulfonate [ka] 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 h. 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.

[0243] Step 9: tert-Butyl 2-thiaspiro[3.3]heptan-6-ylcarbamate [ka] Na2S (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 stirred at 60° C. overnight under N2. The reaction mixture was poured into ice water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by silica gel column chromatography (PE:EA=10:1) to give the title compound as a yellow solid.

[0244] Step 10: tert-Butyl (2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)carbamate [ka] Oxone (22.50 g, 36.70 mmol, 3.00 equiv) was added to a mixture of tert-butyl 2-thiaspiro[3.3]heptan-6-ylcarbamate (2.80 g, 12.20 mmol, 1.00 equiv) in MeOH:THF:H2O=2:2:1 (100.0 mL) and the mixture was stirred at room temperature overnight. The mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated to give the crude product.

[0245] Step 11: 6-Amino-2-thiaspiro[3.3]heptane 2,2-dioxide [ka] To a mixture of tert-butyl (2,2-dioxide-2-thiaspiro[3.3]heptan-6-yl)carbamate (3.19 g, 12.20 mmol, 1.00 equiv) in MeOH (2.0 ml), MeOH / HCl (10.0 mL) was added and the mixture was stirred at room temperature for 2 h. 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.

[0246] Intermediate 7 Synthesis of 6-amino-1-methyl-2-thiaspiro[3.3]heptane 2,2-dioxide and 6-amino-1,3-dimethyl-2-thiaspiro[3.3]heptane 2,2-dioxide [ka] Step 1: 6-(dibenzylamino)-2-thiaspiro[3.3]heptane 2,2-dioxide [ka] To a solution of 6-amino-2-thiaspiro[3.3]heptane 2,2-dioxide (1.00 g, 5.08 mmol, 1.00 equiv) in MeCN (10.0 mL) was added (bromomethyl)benzene (1.71 g, 10.15 mmol, 2.00 equiv) and K2CO3 (3.50 g, 25.40 mmol, 5.00 equiv) and the mixture was stirred at room temperature overnight. The mixture was extracted with DCM and the organic layer was concentrated to give the title compound as a white solid.

[0247] Step 2: 6-(dibenzylamino)-1-methyl-2-thiaspiro[3.3]heptane 2,2-dioxide and 6-(dibenzylamino)-1,3-dimethyl-2-thiaspiro[3.3]heptane 2,2-dioxide [ka] n-BuLi (1.4 mL, 3.53 mmol, 1.50 equiv) was added to a solution of 6-(dibenzylamino)-2-thiaspiro[3.3]heptane 2,2-dioxide (800 mg, 2.35 mmol, 1.00 equiv) in THF (5.0 mL) at -78 °C and stirred for 0.5 h. MeI (1.67 g, 11.7 mmol, 5.00 equiv) was added and the mixture was allowed to warm to room temperature and stirred for 1 h. The mixture was diluted with aqueous NH4Cl and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by silica gel column chromatography eluting with PE / EtOAc (5:1) to give the title compound.

[0248] Step 3: 6-amino-1-methyl-2-thiaspiro[3.3]heptane 2,2-dioxide and 6-amino-1,3-dimethyl-2-thiaspiro[3.3]heptane 2,2-dioxide [ka] A mixture of 6-(dibenzylamino)-1-methyl-2-thiaspiro[3.3]heptane 2,2-dioxide and 6-(dibenzylamino)-1,3-dimethyl-2-thiaspiro[3.3]heptane 2,2-dioxide (800 mg) was dissolved in MeOH (30.0 mL) and Pd / C (80 mg) was added. The mixture was stirred at room temperature under H2 atmosphere overnight, filtered, and concentrated to give a mixture of the title compounds.

[0249] Intermediate 8 Synthesis of N-(3-(2-bromo-2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)-2-fluoro-6-(trifluoromethyl)benzenesulfonamide [ka] Step 1: Methyl 3-amino-2-fluorobenzoate [ka] A mixture of methyl 2-fluoro-3-nitrobenzoate (20.0 g, 100.0 mmol, 1.00 equiv) and Pd / C (2.00 g, 10%) in MeOH (200.0 mL) was stirred under H2 (50 Psi) at 40° C. overnight. The mixture was filtered and concentrated to give the crude product as a brown oil.

[0250] Step 2: Benzyl(2-fluoro-6-(trifluoromethyl)phenyl)sulfane [ka] A solution of phenylmethanethiol (21.45 g, 173.00 mmol, 1.05 equiv) in DMF (20.0 mL) was added dropwise to a mixture of 1,2-difluoro-3-(trifluoromethyl)benzene (30.00 g, 165.00 mmol, 1.00 equiv) and K2CO3 (34.16 g, 247.50 mmol, 1.50 equiv) in DMF (100.0 mL) at 0 °C over 3 h using a syringe pump, then at 50 °C under N2 for 3 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel (PE) column chromatography to give the title compound as a colorless oil.

[0251] Step 3: 2-Fluoro-6-(trifluoromethyl)benzene-1-sulfonyl chloride [ka] 1,3-Dichloro-5,5-dimethylimidazolidine-2,4-dione (13.80 g, 70.00 mmol, 2.00 equiv) was slowly added to a solution of benzyl(2-fluoro-6-(trifluoromethyl)phenyl)sulfane (10.00 g, 35.00 mmol, 1.00 equiv) in MeCN (200.0 mL) / H2O (30.0 mL) / AcOH (90.0 mL) at 0° C. under N2 and stirred for 3 h. The solution was poured into EtOAc and the organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE / EA=100:1) to give the title compound as a yellow oil.

[0252] Step 4: Methyl 2-fluoro-3-(2-fluoro-6-(trifluoromethyl)phenylsulfonamido)benzoate [ka] Methyl 3-amino-2-fluorobenzoate (12.80 g, 76.00 mmol, 1.00 equiv) was added to a solution of 2-fluoro-6-(trifluoromethyl)benzene-1-sulfonyl chloride (30.00 g, 114.00 mmol, 1.50 equiv) and pyridine (30.00 g, 380.00 mmol, 5.00 equiv) in DCM (300.0 mL). After the solution was stirred at room temperature overnight, it was poured into H2O and taken up with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE / EA=6:1) to give the title compound as a yellow solid.

[0253] Step 5: N-(3-(2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)-2-fluoro-6-(trifluoromethyl)benzenesulfonamide [ka] LiHMDS (1M in THF, 182.30 mL, 182.30 mmol, 3.00 equiv.) was added dropwise to a solution of methyl 2-fluoro-3-(2-fluoro-6-(trifluoromethyl)phenylsulfonamido)benzoate (24.00 g, 60.76 mmol, 1.00 equiv.) in THF (250.0 mL) under N2 at 0° C. and stirred at 0° C. for 1 h. A solution of 2-chloro-4-methylpyrimidine (11.72 g, 91.14 mmol, 1.50 equiv.) in THF (120.0 mL) was added dropwise to the mixture at 0° C. and the mixture was stirred for 1 h. The solution was poured into ice water and adjusted to pH=5 with 0.5 N HCl, then the mixture was taken up with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (PE / EA=3:1) to give the title product as a yellow solid.

[0254] Step 6: N-(3-(2-bromo-2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)-2-fluoro-6-(trifluoromethyl)benzenesulfonamide [ka] NBS (9.28 g, 52.14 mmol, 1.00 equiv) was added portionwise to a solution of N-(3-(2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)-2-fluoro-6-(trifluoromethyl)benzenesulfonamide (25.60 g, 52.14 mmol, 1.00 equiv) in DCM (400.0 mL) at 0° C., and the mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue was purified by silica gel column chromatography (PE / EA=3:1) to give the title compound as a yellow solid.

[0255] Intermediate 9 Synthesis of N-(3-(2-bromo-2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide [ka] The title compound was prepared by proceeding in an analogous manner as described in Step 4 of Intermediate 8, substituting 2-fluoro-6-(trifluoromethyl)benzene-1-sulfonyl chloride with 2,6-difluorobenzenesulfonyl chloride.

[0256] Intermediate 10 Synthesis of N-(3-(2-bromo-2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)acetamide [ka] Step 1: Methyl 3-acetamido-2-fluorobenzoate [ka] AcO (23.10 g, 0.23 mol, 1.50 equiv.) was added to a solution of methyl 3-amino-2-fluorobenzoate (25.50 g, 0.15 mol, 1.00 equiv.) in THF (250.0 mL), and the mixture was stirred at room temperature overnight under N. The mixture was concentrated and purified by silica gel column chromatography (PE:EA=5:1-3:1) to give the title compound as a pink solid.

[0257] Step 2: N-(3-(2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)acetamide [ka] LiHMDS (427.0 mL, 0.43 mol, 3.00 equiv) in THF was added to a solution of methyl 3-acetamido-2-fluorobenzoate (30.0 g, 0.14 mol, 1.00 equiv) in THF (300.0 mL) under N2 at 0 °C, followed by dropwise addition of 2-chloro-4-methylpyrimidine (23.70 g, 0.18 mol, 1.30 equiv) in THF (100.0 mL) at 0 °C. The mixture was stirred at room temperature for 2 h and then quenched with aqueous NH4Cl. The mixture was extracted with EtOAc and the combined organic phase was dried over Na2SO4, concentrated and purified by silica gel column chromatography (PE:EA=2:1 to 1:1) to give the title compound as a pink solid.

[0258] Step 3: N-(3-(2-bromo-2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)acetamide [ka] 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, concentrated, and purified by silica gel column chromatography (PE:EA=5:1) to give the title compound as a yellow oil.

[0259] Intermediate 11 Synthesis of 2-(difluoromethoxy)-6-(trifluoromethyl)benzenesulfonyl chloride [ka] Step 1: 2-Bromo-1-(difluoromethoxy)-3-(trifluoromethyl)benzene [ka] Chlorodifluoromethane was bubbled into a solution of 2-bromo-3-(trifluoromethyl)phenol (10.00 g, 41.49 mmol, 1.00 equiv) and K2CO3 (17.18 g, 124.48 mmol, 3.00 equiv) in DMF (100.0 mL). It was sealed and the mixture was stirred at 70 °C overnight. The mixture was diluted with DCM and washed with aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, concentrated and purified by silica gel column chromatography (PE / EA = 20:1) to give the title compound as a yellow oil.

[0260] Step 2: Benzyl(2-(difluoromethoxy)-6-(trifluoromethyl)phenyl)sulfane [ka] A mixture of 2-bromo-1-(difluoromethoxy)-3-(trifluoromethyl)benzene (1.20 g, 4.12 mmol, 1.00 equiv.), phenylmethanethiol (1.02 g, 8.24 mmol, 2.00 equiv.), Pd2(dba)3 (375 mg, 0.41 mmol, 0.10 equiv.), Xantphos (237 mg, 0.41 mmol, 0.10 equiv.) and Cs2CO3 (4.03 g, 12.36 mmol, 3.00 equiv.) in 1,4-dioxane (20.0 mL) was stirred overnight at 100° C. under N2 atmosphere. The mixture was concentrated and purified by silica gel column chromatography (PE / EA=20:1) to give the title compound as a yellow solid.

[0261] Step 3: 2-(Difluoromethoxy)-6-(trifluoromethyl)benzenesulfonyl chloride [ka] 1,3-Dichloro-5,5-dimethylhydantoin (177 mg, 0.90 mmol, 2.00 equiv) was added to a solution of benzyl(2-(difluoromethoxy)-6-(trifluoromethyl)phenyl)sulfane (150 mg, 0.45 mmol, 1.00 equiv) in HO / ACN / AcOH (1.0 mL / 7.5 mL / 3.0 mL) at 0° C. and the mixture was stirred for 3 h. The mixture was diluted with DCM and the organic layer was washed with aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4 and concentrated to give the title compound as a yellow oil.

[0262] Intermediate 12 Synthesis of 2-(difluoromethoxy)-6-fluorobenzene-1-sulfonyl chloride [ka] The title intermediate was synthesized by proceeding in an analogous manner as described in Step 1 of Intermediate 11, substituting 2-bromo-3-(trifluoromethyl)phenol with 2-bromo-3-fluorophenol.

[0263] Intermediate 13 Synthesis of 3-hydroxy-3-methylcyclobutan-1-one [ka] Step 1: 3-(benzyloxy)-1-methylcyclobutanol [ka] Methylmagnesium bromide (47.0 mL, 141.88 mmol, 10.00 equiv, 3 M) was added dropwise to a solution of 3-(benzyloxy)cyclobutanone (2.50 g, 14.19 mmol, 1.00 equiv) in THF (20.0 mL) at -78 °C, then warmed to room temperature and stirred for 2 h. The reaction mixture was quenched with aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by silica gel chromatography (DCM:MeOH = 20:1) to give the title compound as a yellow oil.

[0264] Step 2: 1-Methylcyclobutane-1,3-diol [ka] To a stirred solution of 3-(benzyloxy)-1-methylcyclobutanol (1.20 g, 6.25 mmol, 1.00 equiv) in MeOH (20.0 mL) was added Pd / C (1.00 g) and the resulting mixture was stirred under H2 (50 psi) at room temperature overnight. The reaction mixture was filtered and the filtrate was concentrated to give the title compound as a yellow oil.

[0265] Step 3: 3-Hydroxy-3-methylcyclobutanone [ka] Dess-Martin (3.60 g, 8.69 mmol, 1.10 equiv) was added to a solution of 1-methylcyclobutane-1,3-diol (800 mg, 7.90 mmol, 1.00 equiv) in DCM / THF (17.0:2.5 mL) and the mixture was stirred at room temperature overnight. The reaction mixture was filtered and the filtrate was concentrated and purified by flash chromatography (EA / PE (20%-40%)) to give the title compound.

[0266] Intermediate 14 Synthesis of 3-(((tert-butyldiphenylsilyl)oxy)methyl)bicyclo[1.1.1]pentane-1-carboxylic acid [ka] Step 1: Methyl 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate [ka] To a stirred solution of 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (10.00 g, 76.33 mmol, 1.00 equiv) in THF (100.0 mL) was added BH3 (7.80 g, 91.60 mmol, 1.20 equiv) under N2 at 0 °C. The resulting mixture was stirred at 0 °C for 16 h. The reaction mixture was concentrated to give the title compound.

[0267] Step 2: Methyl 3-(((tert-butyldiphenylsilyl)oxy)methyl)bicyclo[1.1.1]pentane-1-carboxylate [ka] TBDPSCl (15.78 g, 57.60 mmol, 1.50 equiv) and 1H-imidazole (15.25 g, 76.80 mmol, 2.00 equiv) were added to a solution of methyl 3-(hydroxymethyl)bicyclo[1.1.1]pentane-1-carboxylate (6.00 g, 38.40 mmol, 1.00 equiv) in DMF (10.0 mL) at 0° C. The resulting mixture was stirred at room temperature under N2 for 16 h. The reaction mixture was concentrated and purified by silica gel chromatography (EA:PE=1:5) to give the title compound as a white solid.

[0268] Step 3: 3-(((tert-butyldiphenylsilyl)oxy)methyl)bicyclo[1.1.1]pentane-1-carboxylic acid [ka] NaOH (1.98 g, 49.60 mmol, 4.00 equiv) was added to a stirred solution of methyl 3-(((tert-butyldiphenylsilyl)oxy)methyl)bicyclo[1.1.1]pentane-1-carboxylate (4.90 g, 12.40 mmol, 1.00 equiv) in MeOH (50.0 mL) at room temperature. The resulting mixture was stirred at 60° C. for 16 h. The pH of the reaction mixture was adjusted to pH=6 and extracted with DCM. The combined organic layers were concentrated to give the title compound as a white solid.

[0269] Intermediate 15 Synthesis of bicyclo[1.1.1]pentane-1-carboxylic acid [ka] Step 1: Tricyclo[1.1.1.01,3]pentane [ka] 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, then it was warmed to −5° C. and stirred for 2 h. The reaction mixture was warmed to 40° C. and vacuum distilled to give the title compound as a solution in diethyl ether.

[0270] Step 2: Bicyclo[1.1.1]pentan-1-yl(phenyl)sulfane [ka] A mixture of sodium benzenethiolate (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 METE (100.0 mL). A solution of benzenethiol in MBTE 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 h. The mixture was poured into 1M NaOH, extracted with MBTE, washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 20:1) to give the title compound as a colorless oil.

[0271] Step 3: Bicyclo[1.1.1]pentane-1-carboxylic acid [ka] n-BuLi (2.5 M in hexanes, 0.2 mL, 0.57 mmol, 0.10 equiv) was added to a mixture of 4,4'-di-tert-butylbiphenyl (3.00 g, 1.35 mmol, 2.00 equiv) and 1,10-phenanthroline (102 mg, 0.57 mmol, 0.10 equiv) in THF (10.0 mL) at -78 °C. The mixture was stirred at -78 °C for 30 min and then at -50 °C for 30 min. To the mixture was added a solution of bicyclo[1.1.1]pentan-1-yl(phenyl)sulfane (1.00 g, 5.67 mmol, 1.00 equiv) in THF (5.0 mL). Dry CO2 was bubbled into the solution and the mixture was allowed to warm slowly to room temperature before it was quenched with saturated Na2CO3. The mixture was extracted with MBTE, and the organic layer was washed with saturated Na2CO3. The aqueous layer was adjusted to pH=1-2 with 2N HCl aqueous solution, and extracted with DCM / MeOH. The combined organic layers were concentrated and purified by silica gel column chromatography (DCM / MeOH=50:1) to give the title compound as a brown oil.

[0272] Intermediate 16 Synthesis of 1-(difluoromethyl)cyclopropanecarboxylic acid [ka] Step 1: Ethyl 1-formylcyclopropanecarboxylate [ka] Dess-Martin reagent (110.0 g, 0.26 mol, 1.50 equiv.) was added to a stirred mixture of ethyl 1-(hydroxymethyl)cyclopropanecarboxylate (25.00 g, 0.17 mol, 1.00 equiv.) in DCM (500.0 mL), and the mixture was stirred at room temperature overnight under N2. The mixture was concentrated and purified by silica gel column chromatography (PE:EA=20:1) to give the title compound as a pale yellow oil.

[0273] Step 2: Ethyl 1-(difluoromethyl)cyclopropanecarboxylate [ka] To a stirred mixture of ethyl 1-formylcyclopropanecarboxylate (18.00 g, 0.13 mol, 1.00 equiv) in DCM (350.0 mL) was added DAST (41.00 g, 0.25 mol, 2.00 equiv) at 0° C. and the mixture was stirred at room temperature under N2 overnight. The reaction mixture was diluted with water and extracted with EtOAc, and the combined organic layers were washed with water, brine, dried over Na2SO4, concentrated and purified by silica gel column chromatography (PE:EA=10:1) to give the title compound as a pale yellow oil.

[0274] Step 3: 1-(Difluoromethyl)cyclopropanecarboxylic acid [ka] To a stirred mixture of ethyl 1-(difluoromethyl)cyclopropanecarboxylate (16.00 g, 97.56 mmol, 1.00 equiv) in MeOH (150.0 mL) and water (75.0 mL) was added NaOH (7.80 g, 195.12 mmol, 2.00 equiv) and the mixture was stirred at room temperature overnight. The mixture was diluted with water and the pH was adjusted to 1 by addition of 3N aqueous HCl. The mixture was extracted with EtOAc and the combined organic phases were washed with water, brine, dried over Na2SO4 and concentrated to give the title compound as a pale yellow oil.

[0275] Intermediate 17 Synthesis of 1-(difluoromethyl)cyclobutanecarboxylic acid [ka] The title compound was prepared proceeding in an analogous manner as described in Intermediate 16, Step 1 using ethyl 1-(hydroxymethyl)cyclobutanecarboxylate instead of ethyl 1-(hydroxymethyl)cyclopropanecarboxylate.

[0276] Intermediate 18 Synthesis of 3-chlorobicyclo[1.1.1]pentane-1-carboxylic acid [ka] Step 1: Methyl 3-chlorobicyclo[1.1.1]pentane-1-carboxylate [ka] A solution of 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (500 mg, 2.94 mmol, 1.00 equiv) in Et2O (12.0 mL) at 0 °C was treated with DMF (21 mg, 0.29 mmol, 0.10 equiv) and oxalyl chloride (821 mg, 6.47 mmol, 2.20 equiv) and the mixture was allowed to warm to room temperature. After 70 min, the solvent was removed and the crude product was dissolved in CCl4 (4.0 mL) in flask A. In a separate flask B, sodium 2-thioxopyridine-1(2H)-oleate (533 mg, 3.53 mmol, 1.20 equiv) and CCl4 (15.0 mL) were added and the mixture was heated to reflux. The solution of the crude acid chloride in CCl4 from flask A was then added dropwise to flask B over 15 min under illumination with a halogen work lamp. After 90 minutes, the reaction was cooled to room temperature. The reaction was diluted with 1M HCl. The mixture was extracted with DCM. The combined organic layers were washed with saturated NaHCO3, dried over Na2SO4, and concentrated to give the title compound as a pale yellow oil.

[0277] Step 2: 3-Chlorobicyclo[1.1.1]pentane-1-carboxylic acid [ka] To a mixture of methyl 3-chlorobicyclo[1.1.1]pentane-1-carboxylate (472 mg, 2.94 mmol, 1.00 equiv) in THF / H2O (8.0 mL / 2.0 mL) was added LiOH.H2O (617 mg, 14.70 mmol, 5.00 equiv). The mixture was stirred at room temperature overnight. The mixture was concentrated, diluted with H2O, and adjusted to pH=2-3 with 3N HCl. The mixture was extracted with DCM, and the combined organic layers were dried over Na2SO4 and concentrated to give the title compound as a pale yellow solid.

[0278] Intermediate 19 Synthesis of 1-methyl-3-oxocyclobutane-1-carbonitrile [ka] Step 1: 3,3-Dimethoxycyclobutanecarbonitrile [ka] To a stirred solution of 3-oxocyclobutanecarbonitrile (1.50 g, 15.79 mmol, 1.00 equiv) in MeOH (15.0 mL) was added CH(OCH3)3 (14.0 mL) and TsOH (150 mg, 0.79 mmol, 0.05 equiv) and the resulting mixture was stirred at 65° C. overnight. The mixture was concentrated and the residue was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give the title compound as a colorless oil.

[0279] Step 2: 3,3-Dimethoxy-1-methylcyclobutanecarbonitrile [ka] To a stirred solution of 3,3-dimethoxycyclobutanecarbonitrile (1.00 g, 7.09 mmol, 1.00 equiv) in THF (5.0 mL) was slowly added LDA (8.5 mL, 21.27 mmol, 3.00 equiv, 2.5 M) at -78 °C, and the mixture was stirred at -78 °C for 1 h. CH3I (2.01 g, 14.18 mmol, 2.00 equiv) was slowly added at -78 °C, and the mixture was stirred for 1 h, after which it was allowed to warm to room temperature. After 2 h, the reaction mixture was quenched with aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, concentrated, and purified by silica gel column chromatography (PE:EA=5:1) to give the title compound as a yellow oil.

[0280] Step 3: 1-Methyl-3-oxocyclobutanecarbonitrile [ka] To a stirred solution of 3,3-dimethoxy-1-methylcyclobutanecarbonitrile (100 mg, 0.64 mmol, 1.00 equiv) in acetone / water (1.0:1.0 mL) was added TsOH (122 mg, 0.64 mmol, 1.00 equiv) and the resulting mixture was stirred for 2 h at 65° C. The reaction mixture was extracted with EtOAc and the combined organic phases were washed with brine, dried over Na2SO4 and concentrated to give the title compound as a yellow oil.

[0281] Intermediate 20 Synthesis of (1R,5S)-3-thia-8-azabicyclo[3.2.1]octane 3,3-dioxide [ka] Step 1: Diethyl 1-benzylpyrrolidine-2,5-dicarboxylate [ka] A mixture of diethyl 2,5-dibromohexanedioate (25.00 g, 69.44 mmol, 1.00 equiv), phenylmethanamine (7.40 g, 69.44 mmol, 1.00 equiv) and K2CO3 (28.70 g, 208.33 mmol, 3.00 equiv) in toluene / H2O (250.0 mL / 25.0 mL) was stirred under reflux overnight. The mixture was concentrated, diluted with EtOAc, and the organic layer was washed with water and brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (PE / EA=8:1) to give the product as a yellow oil.

[0282] Step 2: (1-benzylpyrrolidine-2,5-diyl)dimethanol [ka] To a solution of diethyl 1-benzylpyrrolidine-2,5-dicarboxylate (11.00 g, 36.06 mmol, 1.00 equiv) in THF (150.0 mL) was added LAH (5.50 g, 144.24 mmol, 4.00 equiv) portionwise at 0 °C. The mixture was stirred at room temperature for 3 h. The mixture was quenched with Na2SO4·10H2O, filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (PE / EA=3:1) to give the product as a yellow oil.

[0283] Step 3: tert-Butyl 2,5-bis(hydroxymethyl)pyrrolidine-1-carboxylate [ka] A mixture of (1-benzylpyrrolidine-2,5-diyl)dimethanol (1.00 g, 4.52 mmol, 1.00 equiv), BocO (1.97 g, 9.05 mmol, 2.00 equiv) and Pd / C (10%, 200 mg, 20% wt) in MeOH (20.0 mL) was stirred under H at 50° C. overnight. The mixture was filtered and the filtrate was concentrated and purified by silica gel column chromatography (PE / EA=3:1) to give the crude title compound as a colorless oil.

[0284] Step 4: tert-Butyl 2,5-bis((tosyloxy)methyl)pyrrolidine-1-carboxylate [ka] TsCl (3.70 g, 19.48 mmol, 5.00 equiv) in DCM (10.0 mL) was added dropwise to a solution of tert-butyl 2,5-bis(hydroxymethyl)pyrrolidine-1-carboxylate (900 mg, 3.90 mmol, 1.00 equiv) and pyridine (3.10 g, 38.96 mmol, 10.00 equiv) in DCM (20.0 mL) at 0° C. The mixture was stirred at room temperature overnight, concentrated and purified by silica gel column chromatography (PE / EA=5:1) to give the title compound as a white solid.

[0285] Step 5: tert-Butyl (1R,5S)-3-thia-8-azabicyclo[3.2.1]octane-8-carboxylate [ka] To a solution of tert-butyl 2,5-bis((tosyloxy)methyl)pyrrolidine-1-carboxylate (2.00 g, 3.71 mmol, 1.00 equiv) in EtOH (20.0 mL) was added Na2S (60%, 482 mg, 3.71 mmol, 1.00 equiv) in water (4.0 mL). The mixture was stirred at 90° C. overnight, then concentrated, diluted with water, and extracted with EtOAc. The combined organic layers were dried over Na2SO4, concentrated, and purified by silica gel column chromatography (PE / EA=10:1) to give the title compound as a white solid.

[0286] Step 6: tert-Butyl (1R,5S)-3-thia-8-azabicyclo[3.2.1]octane-8-carboxylate 3,3-dioxide [ka] A mixture of tert-butyl (1R,5S)-3-thia-8-azabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.87 mmol, 1.00 equiv) and oxone (1.07 g, 1.75 mmol, 2.00 equiv) in THF / H2O (8.0 mL / 2.0 mL) was stirred at room temperature overnight. The mixture was diluted with water, extracted with EtOAc, and the combined organic phases were washed with brine, dried over Na2SO4, and concentrated to give the title compound as a yellow solid.

[0287] Step 7: (1R,5S)-3-Thia-8-azabicyclo[3.2.1]octane 3,3-dioxide [ka] A mixture of tert-butyl (1R,5S)-3-thia-8-azabicyclo[3.2.1]octane-8-carboxylate 3,3-dioxide (150 mg, 0.58 mmol, 1.00 equiv) in TFA / DCM (0.5 mL / 2.0 mL) was stirred at room temperature for 2 hours. The mixture was concentrated to give the title compound as a yellow oil.

[0288] Intermediate 21 Synthesis of (1R,5S)-3-methyl-8-azabicyclo[3.2.1]octane-3-carbonitrile [ka] Step 1: tert-Butyl (1R,5S)-3-cyano-3-methyl-8-azabicyclo[3.2.1]octane-8-carboxylate [ka] LDA (1.0M in THF, 3.2 mL, 3.20 mmol, 3.02 equiv) was added to a solution of tert-butyl (1R,5S)-3-cyano-8-azabicyclo[3.2.1]octane-8-carboxylate (250 mg, 1.06 mmol, 1.00 equiv) in THF (5.0 mL) at −78° C. under N2, and the mixture was stirred for 2 h. CHI (226 mg, 1.59 mmol, 1.50 equiv) in THF (1.0 mL) was added. The mixture was stirred at room temperature overnight and then diluted with aqueous NH4Cl. The mixture was extracted with EtOAc, and the combined organic phase was dried over Na2SO4, concentrated, and purified by silica gel column chromatography (PE / EA=3:1) to give the title compound as a brown solid.

[0289] Step 2: (1R,5S)-3-Methyl-8-azabicyclo[3.2.1]octane-3-carbonitrile [ka] A mixture of tert-butyl (1R,5S)-3-cyano-3-methyl-8-azabicyclo[3.2.1]octane-8-carboxylate (60 mg, 0.24 mmol, 1.00 equiv) in TFA / DCM (0.5 mL / 2.0 mL) was stirred at room temperature for 2 h. The mixture was concentrated to give the title compound as a yellow oil.

[0290] Intermediate 22 Synthesis of 3-(2,2,2-trifluoroethyl)-3,8-diazabicyclo[3.2.1]octane [ka] Step 1: tert-Butyl 3-(2,2,2-trifluoroethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] 2,2,2-Trifluoroethyl trifluoromethanesulfonate (7.87 g, 33.92 mmol, 1.2 equiv.) was added to a solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (6.00 g, 28.26 mmol, 1.00 equiv.) in THF (60.0 mL) and TEA (5.72 g, 56.52 mmol, 2.00 equiv.), and the mixture was stirred overnight at room temperature under N2. The mixture was concentrated and purified by flash column chromatography (EA:PE=0-100%) to give the title compound as a yellow oil.

[0291] Step 2: 3-(2,2,2-trifluoroethyl)-3,8-diazabicyclo[3.2.1]octane [ka] To a solution of tert-butyl 3-(2,2,2-trifluoroethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (7.00 g, 23.78 mmol, 1.00 equiv) in EtOAc (30.0 mL) was added EtOAc / HCl (30.0 mL, 2 M) and the mixture was stirred at room temperature under N2 for 2 h. The mixture was concentrated to give the title compound as a yellow solid.

[0292] Intermediate 23 Synthesis of 3-(2,2-difluoroethyl)-3,8-diazabicyclo[3.2.1]octane [ka] The title compound was prepared proceeding in a similar manner as described in the step of Intermediate 22 using 2,2-difluoroethyl trifluoromethanesulfonate instead of 2,2,2-trifluoroethyl trifluoromethanesulfonate.

[0293] Intermediate 24 Synthesis of 3-(3,3,3-trifluoropropyl)-3,8-diazabicyclo[3.2.1]octane [ka] Step 1: tert-Butyl 3-(3,3,3-trifluoropropyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] 1,1,1-Trifluoro-3-iodopropane (317 mg, 1.41 mmol, 1.50 equiv) was added to a solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (200 mg, 0.94 mmol, 1.00 equiv) and K2CO3 (260 mg, 1.89 mmol, 2.00 equiv) in DMF (5.0 mL), and the mixture was stirred at room temperature overnight and then at 40 °C for 20 h. The mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over Na2SO4, concentrated, and purified by flash column chromatography (EA:PE=0-100%) to give the title compound as a yellow oil.

[0294] Step 2: 3-(3,3,3-trifluoropropyl)-3,8-diazabicyclo[3.2.1]octane [ka] To a solution of tert-butyl 3-(3,3,3-trifluoropropyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (210 mg, 0.68 mmol, 1.0 equiv) in EtOAc (1 mL) was added EtOAc / HCl (2M, 1 mL) and the mixture was stirred at room temperature for 2 h. The mixture was concentrated to give the title compound as a yellow solid.

[0295] Intermediate 25 Synthesis of 3-benzyl-3,8-diazabicyclo[3.2.1]octane [ka] The title compound was prepared proceeding in a similar manner as described in Step 1 of Intermediate 24 using (bromomethyl)benzene instead of 1,1,1-trifluoro-3-iodopropane.

[0296] Intermediate 26 Synthesis of 3-cyclopropyl-3,8-diazabicyclo[3.2.1]octane [ka] Step 1: tert-Butyl 3-cyclopropyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (500 mg, 2.36 mmol, 1.00 equiv) in MeOH:THF=1:1 (10.0 mL), (1-ethoxycyclopropoxy)trimethylsilane (821 mg, 4.71 mmol, 2.00 equiv), NaBH3CN (223 mg, 3.54 mmol, 1.50 equiv), and AcOH (0.5 mL) were added and the mixture was stirred overnight at room temperature under N2. The mixture was concentrated and purified by flash column chromatography (PE:EA=50:1 to 10:1) to give the title compound as a yellow liquid.

[0297] Step 2: 3-Cyclopropyl-3,8-diazabicyclo[3.2.1]octane [ka] To a solution of tert-butyl 3-cyclopropyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (485 mg, 1.92 mmol, 1.00 equiv) in EtOAc (3.0 mL) was added EtOAc / HCl (2 M, 3.0 mL) and the mixture was stirred at room temperature under N2 for 2 h. The mixture was concentrated to give the title compound as a white solid.

[0298] Intermediate 27 Synthesis of 7-azabicyclo[2.2.1]heptane-1-carbonitrile [ka] Step 1: tert-Butyl 7-azabicyclo[2.2.1]heptane-7-carboxylate [ka] MsCl (9.58 g, 83.61 mmol, 1.50 equiv.) was added to a solution of tert-butyl ((1r,4r)-4-hydroxycyclohexyl)carbamate (12 g, 55.74 mmol, 1.00 equiv.) and TEA (8.46 g, 83.61 mmol, 1.50 equiv.) in DCM (200.0 mL) at 0° C., and the mixture was stirred for 1 h. The mixture was washed with water, brine, and the organic layer was dried over Na2SO4 and concentrated to give the product. The resulting product was dissolved in THF (200.0 mL), followed by the addition of t-BuOK (6.25 g, 55.74 mmol, 1.00 equiv.). After 2 h, additional t-BuOK (9.38 g, 83.61 mmol, 1.50 equiv.) was added, and the mixture was stirred at room temperature under N2 overnight. The mixture was quenched with 1N HCl aqueous solution, extracted with EtOAc, and the combined organic layers were washed with water, brine, dried over Na2SO4, and concentrated. The residue was purified by flash column chromatography (PE:EA=50:1-10:1) to give the title compound as a yellow liquid.

[0299] Step 2: tert-Butyl 1-formyl-7-azabicyclo[2.2.1]heptane-7-carboxylate [ka] s-BuLi (2.9 mL, 3.80 mmol, 1.50 equiv) was added to a solution of tert-butyl 7-azabicyclo[2.2.1]heptane-7-carboxylate (500 mg, 2.53 mmol, 1.00 equiv) and TMEDA (442 mg, 3.80 mmol, 1.50 equiv) in Et2O (5.0 mL) at 0 °C, and the mixture was stirred under N2 for 1 h. DMF (370 mg, 5.07 mmol, 2.00 equiv) was added, and the mixture was stirred under N2 at room temperature for 20 h. The mixture was quenched with saturated aqueous NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4, concentrated, and the residue was purified by flash column chromatography (EA:PE=0-100%) to give the title compound as a yellow liquid.

[0300] Step 3: tert-Butyl 1-((hydroxyimino)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate [ka] To a solution of tert-butyl 1-formyl-7-azabicyclo[2.2.1]heptane-7-carboxylate (1.30 g, 5.77 mmol, 1.00 equiv) in MeOH:H2O=1:1 (30.0 mL) was added NH2OH·HCl (0.48 g, 6.92 mmol, 1.20 equiv) and Na2CO3 (0.37 g, 3.46 mmol, 0.60 equiv) at room temperature and the mixture was stirred for 3 h. The mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated to give the title compound as a yellow oil.

[0301] Step 4: tert-Butyl 1-cyano-7-azabicyclo[2.2.1]heptane-7-carboxylate [ka] To a solution of tert-butyl 1-((hydroxyimino)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate (1.39 g, 5.78 mmol, 1.00 equiv) in MeCN (50.0 mL) was added Cu(OAc)2·H2O (23 mg, 0.12 mmol, 0.02 equiv) and the mixture was stirred at 80 °C under N2 for 20 h. The mixture was concentrated and purified by flash column chromatography (EA:PE=0-100%) to give the title compound as a white solid.

[0302] Step 5: 7-Azabicyclo[2.2.1]heptane-1-carbonitrile [ka] TFA (1.0 mL) was added to a solution of tert-butyl 1-cyano-7-azabicyclo[2.2.1]heptane-7-carboxylate (500 mg, 2.25 mmol, 1.00 equiv) in DCM (5.0 mL) and the mixture was stirred at room temperature for 2 h. The mixture was concentrated, the pH adjusted to 8-9 with THF / NH3, and then concentrated to give the title compound as a yellow solid.

[0303] Intermediate 28 Synthesis of 3-(methyl-d3)-3,8-diazabicyclo[3.2.1]octane [ka] The title compound was prepared proceeding in a similar manner as described in step 1 of Intermediate 24 using iodomethane-d3 instead of 1,1,1-trifluoro-3-iodopropane.

[0304] Intermediate 29 Synthesis of 2-(difluoromethyl)-6-fluorobenzenesulfonyl chloride [ka] Step 1: 2-(benzylthio)-3-fluorobenzaldehyde [ka] A mixture of 2-bromo-3-fluorobenzaldehyde (200 mg, 0.99 mmol, 1.00 equiv), phenylmethanethiol (245 mg, 1.97 mmol, 2.00 equiv), Pd2(dba)3 (180 mg, 0.20 mmol, 0.20 equiv), Xantphos (114 mg, 0.20 mmol, 0.20 equiv) and DIEA (381 mg, 2.96 mmol, 3.00 equiv) in 1,4-dioxane (4.0 mL) was stirred overnight at 90° C. under N2. The mixture was concentrated and purified by silica gel column chromatography (PE:EA=20:1) to give the title compound as a yellow oil.

[0305] Step 2: Benzyl(2-(difluoromethyl)-6-fluorophenyl)sulfane [ka] BAST (269 mg, 1.22 mmol, 1.50 equiv) was added portionwise to a mixture of 2-(benzylthio)-3-fluorobenzaldehyde (200 mg, 0.81 mmol, 1.00 equiv) in DCM (5.0 mL) at 0° C. The mixture was stirred overnight at room temperature under N2, then quenched with saturated NaHCO3 and diluted with DCM. The organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (PE:EA=20:1) to give the title compound as a colorless oil.

[0306] Step 3: 2-(Difluoromethyl)-6-fluorobenzenesulfonyl chloride [ka] To a mixture of benzyl(2-(difluoromethyl)-6-fluorophenyl)sulfane (50 mg, 0.19 mmol, 1.00 equiv) in AcOH / HO (1.0 mL / 0.4 mL) was added NCS (75 mg, 0.56 mmol, 3.00 equiv) at 0° C. The mixture was stirred at room temperature for 3 h, and then HO was added. The mixture was extracted with EtOAc and the combined organic phase was washed with brine, dried over NaSO and concentrated to give the crude product as a yellow oil.

[0307] Intermediate 30 Synthesis of 3-phenyl-3,8-diazabicyclo[3.2.1]octane [ka] Step 1: tert-Butyl 3-phenyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate [ka] To a stirred solution of bromobenzene (100 mg, 0.637 mmol, 1.00 equiv) in toluene (2.0 mL) was added Pd2(dba)3 (29 mg, 0.03 mmol, 0.05 equiv), t-BuOK (214 mg, 1.89 mmol, 3.00 equiv), BINAP (19.6 mg, 0.0637 mmol, 0.10 equiv) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (270 mg, 1.262 mmol, 2.00 equiv). The resulting mixture was stirred at 100 °C for 12 h, concentrated and purified by silica gel column chromatography eluting with PE / EtOAc (10:1) to give the title compound as a white solid.

[0308] Step 2: 3-Phenyl-3,8-diazabicyclo[3.2.1]octane [ka] A mixture of tert-butyl 3-phenyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (160 mg, 0.50 mmol, 1.00 equiv) in DCM / TFA=5:1 (2.0 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated to give the crude product as a white solid.

[0309] Intermediate 31 Synthesis of 8-(pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane [ka] The title compound was prepared proceeding in a similar manner as described in Intermediate 30, step 1, using tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate instead of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate and 2-iodopyridine instead of bromobenzene.

[0310] Intermediate 32 Synthesis of 3-(pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane [ka] The title compound was prepared proceeding in an analogous manner as described in Intermediate 30, Step 1, using 2-iodopyridine instead of bromobenzene.

[0311] Intermediate 33 Synthesis of N-(3-(2-bromo-2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)-2-chloro-6-(trifluoromethyl)benzenesulfonamide [ka] Step 1: 2-Chloro-6-(trifluoromethyl)benzene-1-sulfonyl chloride [ka] (Solution A): SOCl2 (12.20 g, 102.30 mmol, 4.00 equiv) was slowly added to water (50.0 ml) at 0 °C, and the mixture was stirred at room temperature under N2 for 18 h. CuCl (100 mg, 0.04 mmol, 0.04 equiv) was added, and the resulting mixture was stirred at 0 °C for 1.5 h.

[0312] (Solution B): To a mixture of 2-chloro-6-(trifluoromethyl)aniline (5.00 g, 25.60 mmol, 1.00 equiv) in HCl (8.0 ml) was added NaNO2 (1.98 g, 28.70 mmol, 1.12 equiv) in water and stirred at 0 °C for 15 min.

[0313] Solution A was added to solution B at 0° C., and the mixture was stirred at 0° C. for 1.5 h. The mixture was extracted with DCM, and the combined organic layers were washed with brine, dried over NaSO4, and concentrated. The residue was purified by silica gel column chromatography PE / EtOAc (3:1) to give the title compound as a yellow solid.

[0314] Step 2: Methyl 3-(2-chloro-6-(trifluoromethyl)phenylsulfonamido)-2-fluorobenzoate [ka] 2-Chloro-6-(trifluoromethyl)benzene-1-sulfonyl chloride (500 mg, 1.80 mmol, 1.20 equiv) in DCM was added dropwise to a stirred solution of methyl 3-amino-2-fluorobenzoate (254 mg, 1.50 mmol, 1.00 equiv) and pyridine (356 mg, 4.50 mmol, 3.00 equiv) in DCM under N2 at 0°C, and the resulting mixture was stirred overnight at room temperature under N2. The mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over NaSO4, concentrated, and purified by silica gel column chromatography PE / EtOAc (3:1) to give the title compound as a yellow solid.

[0315] Step 3: 2-Chloro-N-(3-(2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)-6-(trifluoromethyl)benzenesulfonamide [ka] LiHMDS (1M in THF, 16.5 mL, 16.51 mmol, 3.00 equiv.) was added to a stirred solution of methyl 3-(2-chloro-6-(trifluoromethyl)phenylsulfonamido)-2-fluorobenzoate (2.25 g, 5.47 mmol, 1.00 equiv.) in THF (10.0 ml) at 0° C. A solution of 2-chloro-4-methylpyrimidine (911 mg, 7.12 mmol, 1.30 equiv.) in THF (10.0 ml) was added dropwise to the mixture. After 1 h, the mixture was poured into aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO4, concentrated, and purified by silica gel column chromatography PE / EtOAc (1:1) to give the title compound as a yellow solid.

[0316] Step 4: N-(3-(2-bromo-2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)-2-chloro-6-(trifluoromethyl)benzenesulfonamide [ka] To a stirred solution of 2-chloro-N-(3-(2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)-6-(trifluoromethyl)benzenesulfonamide (1.78 g, 3.48 mmol, 1.00 equiv) in DCM was added NBS (411 mg, 3.48 mmol, 1.00 equiv). The mixture was stirred at room temperature under N2 for 3 h, then poured into water and extracted with DCM. The combined organic layers were dried over NaSO4, concentrated and purified by silica gel column chromatography PE / EtOAc (1:1) to give the title compound as a yellow solid.

[0317] Intermediate 34 Synthesis of 4-methyl-4-(methylsulfonyl)cyclohexan-1-amine hydrochloride [ka] Step 1: tert-Butyl (4-hydroxy-4-methylcyclohexyl)carbamate [ka] To a stirred solution of tert-butyl (4-oxocyclohexyl)carbamate (25.00 g, 0.12 mmol, 1.00 equiv) in THF (500.0 mL) was added CH3MgBr (117 mL, 0.35 mmol, 3.00 equiv) at -78 °C and the mixture was stirred at room temperature under N2 for 20 h. The mixture was poured into saturated aqueous NH4Cl solution and the mixture was extracted with EtOAc and washed with brine. The organic layer was concentrated and purified by silica gel column chromatography eluting with (EA:PE=0-100%) to give the title compound as a pale yellow solid.

[0318] Step 2: 4-((tert-butoxycarbonyl)amino)-1-methylcyclohexyl methanesulfonate [ka] To a stirred solution of tert-butyl (4-hydroxy-4-methylcyclohexyl)carbamate (8.20 g, 35.81 mmol, 1.00 equiv) in DCM (100.0 mL) was added TEA (15.0 mL, 107.42 mmol, 3.00 equiv), MsCl (3.3 mL, 42.97 mmol, 1.20 equiv) at 0° C. The resulting mixture was stirred at room temperature for 16 h and the mixture was washed with brine. The organic layer was dried over Na2SO4 and concentrated to give the title compound as a yellow solid.

[0319] Step 3: tert-Butyl (4-methyl-4-(methylthio)cyclohexyl)carbamate [ka] To a stirred solution of 4-((tert-butoxycarbonyl)amino)-1-methylcyclohexylmethanesulfonate (11.00 g, 35.83 mmol, 1.00 equiv) in DMF (100.0 mL) was added NaSCH3 (5.02 g, 71.66 mmol, 2.00 equiv). The reaction mixture was stirred at room temperature for 16 h, the mixture was quenched with H2O, and then extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, concentrated, and purified by reverse phase column chromatography to give the title compound as a white solid.

[0320] Step 4: tert-Butyl (4-methyl-4-(methylsulfonyl)cyclohexyl)carbamate [ka] To a stirred solution of tert-butyl (4-methyl-4-(methylthio)cyclohexyl)carbamate (500 mg, 1.93 mmol, 1.00 equiv) in MeOH:THF:H2O=2:2:1 (20.0 mL) was added oxone (2.37 g, 3.86 mmol, 2.00 equiv). The mixture was stirred at room temperature for 16 h, the mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine and dried over Na2SO4. The organic layer was concentrated to give the title compound as a pale yellow solid.

[0321] Step 5: 4-Methyl-4-(methylsulfonyl)cyclohexan-1-amine hydrochloride [ka] To a stirred solution of tert-butyl (4-methyl-4-(methylsulfonyl)cyclohexyl)carbamate (380 mg, 1.31 mmol, 1.00 equiv) in EA (2.0 mL) was added EA / HCl (2 M, 2.0 mL) and stirred at room temperature under nitrogen atmosphere for 2 h. The resulting mixture was concentrated to give the title compound as a white solid.

[0322] Example 1 Synthesis of N-(3-(2-(3-(3,3-difluorocyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-(2-(((1R,5S,6s)-3,3-dioxido-3-thiabicyclo[3.1.0]hexan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide [ka] Step 1: tert-Butyl (1R,5S)-8-(benzoylcarbamothioyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate [ka] Benzoyl isothiocyanate (169 mg, 1.03 mmol, 1.10 equiv) was added to a mixture of tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (200 mg, 0.94 mmol, 1.00 equiv) in THF (5.0 mL), and the mixture was stirred at room temperature under N2 overnight. The mixture was concentrated and purified by silica gel column chromatography (PE:EA=5:1) to give the title compound as a white solid.

[0323] Step 2: tert-Butyl (1R,5S)-8-carbamothioyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate [ka] A mixture of tert-butyl (1R,5S)-8-(benzoylcarbamothioyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (300 mg, 0.80 mmol, 1.00 equiv) and N2H4 (80%, 5.0 mL) was stirred overnight at room temperature under N2. Water was added and the mixture was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by silica gel column chromatography (PE:EA=1:1) to give the title compound as a white solid.

[0324] Step 3: tert-Butyl 8-(5-(2-chloropyrimidin-4-yl)-4-(3-((2,6-difluorophenyl)sulfonamido)-2-fluorophenyl)thiazol-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate [ka] A mixture of N-(3-(2-bromo-2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (Intermediate 9; 384 mg, 0.74 mmol, 1.00 equiv.) and tert-butyl (1R,5S)-8-carbamothioyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (200 mg, 0.74 mmol, 1.00 equiv.) in DMA (5.0 mL) was stirred at room temperature for 30 min, then at 65° C. overnight under N2. The mixture was concentrated and purified by silica gel column chromatography (PE:EA=2:1) ​​to give the title compound as a yellow solid.

[0325] Step 4: N-(3-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-(2-chloropyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide [ka] A mixture of tert-butyl 8-(5-(2-chloropyrimidin-4-yl)-4-(3-((2,6-difluorophenyl)sulfonamido)-2-fluorophenyl)thiazol-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (400 mg, 0.58 mmol, 1.00 equiv) in DCM (10.0 mL) and TFA (4.0 mL) was stirred at 0° C. for 2 h. The mixture was concentrated to give the crude product as a yellow oil.

[0326] Step 5: N-(3-(5-(2-chloropyrimidin-4-yl)-2-(3-(3,3-difluorocyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide [ka] 3,3-Difluorocyclobutan-1-one (162 mg, 1.53 mmol, 3.00 equiv) was added to a solution of N-(3-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-(2-chloropyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (300 mg, 0.51 mmol, 1.00 equiv) in DCE / MeOH (1:1, 6.0 mL) and the mixture was stirred at room temperature under N for 1 h. NaBH3CN (163 mg, 2.55 mmol, 5.00 equiv) was added at 0° C. and the mixture was stirred at room temperature overnight. The mixture was concentrated and purified by silica gel column chromatography (PE:EA=2:1) ​​to give the title compound as a yellow solid.

[0327] Step 6: N-(3-(2-(3-(3,3-difluorocyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-(2-(((1R,5S,6r)-3,3-dioxido-3-thiabicyclo[3.1.0]hexan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide [ka] A mixture of N-(3-(5-(2-chloropyrimidin-4-yl)-2-(3-(3,3-difluorocyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (60 mg, 0.09 mmol, 1.00 equiv), (1R,5S,6r)-6-amino-3-thiabicyclo[3.1.0]hexane 3,3-dioxide (Intermediate 3; 19 mg, 0.13 mmol, 1.50 equiv), RuPhos (20 mg), RuPhos Pd G2 (20 mg) and Cs2CO3 (86 mg, 0.26 mmol, 3.00 equiv) in t-BuOH (1.0 mL) was stirred at 90 °C under N2 overnight. The mixture was concentrated and purified by preparative HPLC to give the title compound as a yellow solid. LCMS (ES, m / z): [M+1] + =794.3.

[0328] Proceeding in a similar manner as described in Example 1, the following compounds were prepared:

[0329] [Table 25]

[0330] Example 5 Synthesis of N-(3-(2-((3R,5R)-3,5-dimethylmorpholino)-5-(2-((2,2-dioxido-2-thiaspiro[3.3]-heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide [ka] Step 1: N-((3R,5R)-3,5-dimethylmorpholine-4-carbonothioyl)benzamide [ka] To a stirred solution of (3R,5R)-3,5-dimethylmorpholine (500 mg, 4.34 mmol, 1.00 equiv) in THF (10.0 mL), benzoyl isothiocyanate (708 mg, 4.34 mmol, 1.00 equiv) was added and stirred at room temperature overnight. The reaction mixture was concentrated and purified by silica gel chromatography (EA:PE=1:5) to give the title compound as a white solid.

[0331] Step 2: (3R,5R)-3,5-Dimethylmorpholine-4-carbothioamide [ka] A mixture of N-((3R,5R)-3,5-dimethylmorpholine-4-carbonothioyl)benzamide (975 mg, 3.50 mmol, 1.00 equiv) and N2H4.H2O (15.0 mL) was stirred at room temperature overnight. The mixture was diluted with DCM and washed with 10% citric acid, and the organic layer was washed with brine, dried over Na2SO4, concentrated, and purified by silica gel chromatography (EA:PE=1:1) to give the title compound as a white solid.

[0332] Step 3: N-(3-(5-(2-chloropyrimidin-4-yl)-2-((3R,5R)-3,5-dimethylmorpholino)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide [ka] A mixture of N-(3-(2-bromo-2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (Intermediate 9; 449 mg, 0.86 mmol, 1.00 equiv.), (3R,5R)-3,5-dimethylmorpholine-4-carbothioamide (150 mg, 0.86 mmol, 1.00 equiv.) in DMA (10.0 mL) was stirred at 70° C. under N overnight. The reaction mixture was extracted with EtOAc and the combined organic phase was washed with brine, dried over NaSO, concentrated, and purified by flash chromatography to give the title compound as a yellow solid.

[0333] Step 4: N-(3-(2-((3R,5R)-3,5-dimethylmorpholino)-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide [ka] A mixture of N-(3-(5-(2-chloropyrimidin-4-yl)-2-((3R,5R)-3,5-dimethylmorpholino)-thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (200 mg, 0.34 mmol, 1.00 equiv), 6-amino-2-thiaspiro[3.3]heptane 2,2-dioxide hydrochloride (Intermediate 6, 79 mg, 0.40 mmol, 1.20 equiv), CsCO (552 mg, 1.70 mmol, 5.00 equiv), RuPhos (20 mg), RuPhos Pd G (20 mg) in t-BuOH (5.0 mL) was stirred at 90 °C overnight under N. The reaction mixture was extracted with EtOAc, and the combined organic phase was washed with brine, dried over Na2SO4, concentrated, and purified by silica gel chromatography (PE:EA=1:1) to give the title compound as a yellow solid. MS (ES, m / z): [M+1] + =721.3

[0334] Proceeding in a similar manner as described in Example 5, the following compounds were prepared:

[0335] [Table 26]

[0336] [Table 27]

[0337] [Table 28]

[0338] [Table 29]

[0339] Additional compounds that were prepared proceeding in a similar manner to that described in Example 5 are as follows:

[0340] [Table 30]

[0341] [Table 31]

[0342] Example 20 Synthesis of N-(3-(5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)-2-((2S,6S)-2,4,6-trimethylpiperazin-1-yl)thiazol-4-yl)-2-fluorophenyl)-2-fluoro-6-(trifluoromethyl)benzenesulfonamide [ka] Step 1: tert-Butyl (3S,5S)-4-carbamothioyl-3,5-dimethylpiperazine-1-carboxylate [ka] The title compound was synthesized proceeding in a similar manner as described in step 1 of Example 5 using tert-butyl (3S,5S)-3,5-dimethylpiperazine-1-carboxylate instead of (3R,5R)-3,5-dimethylmorpholine.

[0343] Step 2: tert-Butyl (3S,5S)-4-(4-(3-acetamido-2-fluorophenyl)-5-(2-chloropyrimidin-4-yl)thiazol-2-yl)-3,5-dimethylpiperazine-1-carboxylate [ka] A mixture of N-(3-(2-bromo-2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)acetamide (Intermediate 10; 462 mg, 1.20 mmol, 1.20 equiv) and (3S,5S)-tert-butyl 4-carbamothioyl-3,5-dimethylpiperazine-1-carboxylate (273 mg, 1.00 mmol, 1.00 equiv) in DMA (10.0 mL) was stirred at 70° C. under N overnight. The reaction mixture was extracted with EtOAc and the combined organic phase was washed with brine, dried over NaSO, concentrated and purified by flash chromatography to give the title compound as a yellow solid.

[0344] Step 3: tert-Butyl (3S,5S)-4-(4-(3-acetamido-2-fluorophenyl)-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-2-yl)-3,5-dimethylpiperazine-1-carboxylate [ka] (tert-Butyl (3S,5S)-4-(4-(3-acetamido-2-fluorophenyl)-5-(2-chloropyrimidin-4-yl)thiazol-2-yl)-3,5-dimethylpiperazine-1-carboxylate (180 mg, 0.32 mmol, 1.00 equiv.), 6-amino-2-thiaspiro[3.3]heptane 2,2-dioxide hydrochloride (70 mg, 0.36 mmol, 1.20 equiv.), Cs2CO3 (520 mg, 1.60 mmol, 5.00 equiv.), RuPhos (30 mg), RuPhos Pd in ​​t-BuOH (5.0 mL). A mixture of G2 (30 mg) was stirred under N2 at 90 °C overnight. The reaction mixture was extracted with EtOAc, and the combined organic phase was washed with brine, dried over Na2SO4, concentrated, and the residue was purified by silica gel chromatography (PE:EA = 1:1) to give the title compound as a yellow solid.

[0345] Step 4: tert-Butyl (3S,5S)-4-(4-(3-amino-2-fluorophenyl)-5-(2-((2,2-dioxido-2-thiaspiro[3.3]-heptan-6-yl)amino)pyrimidin-4-yl)thiazol-2-yl)-3,5-dimethylpiperazine-1-carboxylate [ka] To a stirred solution of tert-butyl (3S,5S)-4-(4-(3-acetamido-2-fluorophenyl)-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-2-yl)-3,5-dimethylpiperazine-1-carboxylate (130 mg, 0.19 mmol, 1.00 equiv) in EtOH (3.0 mL) was added NaOH (120 mg, 3.00 mmol, 1 M) and the resulting mixture was stirred at 80° C. under N overnight. The reaction mixture was extracted with EtOAc and the combined organic phase was washed with brine, dried over NaSO and concentrated to give the title compound as a brown oil.

[0346] Step 5: tert-Butyl (3S,5S)-4-(5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)-pyrimidin-4-yl)-4-(2-fluoro-3-((2-fluoro-6-(trifluoromethyl)phenyl)sulfonamido)-phenyl)thiazol-2-yl)-3,5-dimethylpiperazine-1-carboxylate [ka] 2-Fluoro-6-(trifluoromethyl)benzene-1-sulfonyl chloride (79 mg, 0.30 mmol, 1.50 equiv) was added to a stirred solution of tert-butyl (3S,5S)-4-(4-(3-amino-2-fluorophenyl)-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-2-yl)-3,5-dimethylpiperazine-1-carboxylate (122 mg, 0.19 mmol, 1.00 equiv) and pyridine (90 mg, 1.14 mmol, 6.00 equiv) in DCM (4.0 mL), and the resulting mixture was stirred overnight at 45° C. under N. The mixture was extracted with DCM, and the combined organic layers were washed with brine, dried over NaSO, concentrated, and purified by flash chromatography to give the title compound as a yellow solid.

[0347] Step 6: N-(3-(2-((2S,6S)-2,6-dimethylpiperazin-1-yl)-5-(2-((2,2-dioxido-2-thiaspiro[3.3]-heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2-fluoro-6-(trifluoromethyl)benzenesulfonamide [ka] To a stirred solution of tert-butyl (3S,5S)-4-(5-(2-((2,2-dioxido-2-thiaspiro[3.3]-heptan-6-yl)amino)pyrimidin-4-yl)-4-(2-fluoro-3-(2-fluoro-6-(trifluoromethyl)-phenylsulfonamido)phenyl)-thiazol-2-yl)-3,5-dimethylpiperazine-1-carboxylate (50 mg, 0.06 mmol, 1.00 equiv) in DCM (2.0 mL) was added TFA (0.5 mL) and the resulting mixture was stirred at room temperature for 2 h. The mixture was concentrated to provide the title compound as a yellow oil.

[0348] Step 7: N-(3-(5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)-2-((2S,6S)-2,4,6-trimethylpiperazin-1-yl)thiazol-4-yl)-2-fluorophenyl)-2-fluoro-6-(trifluoromethyl)benzenesulfonamide [ka] To a stirred solution of N-(3-(2-((2S,6S)-2,6-dimethylpiperazin-1-yl)-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2-fluoro-6-(trifluoromethyl)benzenesulfonamide (44 mg, 0.06 mmol, 1.00 equiv.) in MeOH (2.0 mL), HCHO (25 mg, 0.30 mmol, 5.00 equiv., 35%) and AcOH (1 drop) were added and the resulting mixture was stirred at room temperature for 30 min. NaBH3CN (8 mg, 0.12 mmol, 2.00 equiv.) was added and the mixture was stirred at room temperature overnight. The solution was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, concentrated and purified by preparative HPLC to give the title compound as a yellow solid. MS (ES, m / z): [M+1] + =784.3

[0349] Example 21 Synthesis of N-(3-(5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)-2-(2,4,6-trimethylpiperazin-1-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide [ka] Step 1: tert-Butyl 4-(benzoylcarbamothioyl)-3,5-dimethylpiperazine-1-carboxylate [ka] To a stirred solution of tert-butyl 3,5-dimethylpiperazine-1-carboxylate (2.00 g, 9.34 mmol, 1.00 equiv) in THF (30.0 mL) was added benzoyl isothiocyanate (1.67 g, 10.28 mmol, 1.10 equiv) and the mixture was stirred at room temperature overnight. The mixture was concentrated and purified by silica gel chromatography (EA:PE=1:5) to give the title compound as a yellow solid.

[0350] Step 2: tert-Butyl 4-carbamothioyl-3,5-dimethylpiperazine-1-carboxylate [ka] A mixture of tert-butyl 4-(benzoylcarbamothioyl)-3,5-dimethylpiperazine-1-carboxylate (2.80 g, 7.43 mmol, 1.00 equiv) and N2H4·H2O (30.0 mL) was stirred at room temperature overnight. The mixture was diluted with DCM and the organic layer was washed with 10% citric acid, brine, dried over Na2SO4, concentrated and purified by silica gel chromatography (EA:PE=1:3) to give the title compound as a white solid.

[0351] Step 3: tert-Butyl 4-(5-(2-chloropyrimidin-4-yl)-4-(3-(2,6-difluorophenylsulfonamido)-2-fluorophenyl)thiazol-2-yl)-3,5-dimethylpiperazine-1-carboxylate [ka] A mixture of N-(3-(2-bromo-2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (Intermediate 9; 1.14 g, 2.20 mmol, 1.00 equiv) and tert-butyl 4-carbamothioyl-3,5-dimethylpiperazine-1-carboxylate (600 mg, 2.20 mmol, 1.00 equiv) in DMA (12.0 mL) was stirred at 70° C. under N overnight. The reaction mixture was extracted with EtOAc and the combined organic phase was washed with brine, dried over NaSO, concentrated and purified by flash chromatography to give the title compound as a yellow solid.

[0352] Step 4: tert-Butyl 4-(4-(3-(2,6-difluorophenylsulfonamido)-2-fluorophenyl)-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-2-yl)-3,5-dimethylpiperazine-1-carboxylate [ka] A mixture of tert-butyl 4-(5-(2-chloropyrimidin-4-yl)-4-(3-(2,6-difluorophenylsulfonamido)-2-fluorophenyl)thiazol-2-yl)-3,5-dimethylpiperazine-1-carboxylate (200 mg, 0.29 mmol, 1.00 equiv), 6-amino-2-thiaspiro[3.3]heptane 2,2-dioxide hydrochloride (Intermediate 6; 68 mg, 0.35 mmol, 1.20 equiv), CsCO (471 mg, 1.45 mmol, 5.00 equiv), RuPhos (20 mg), RuPhos Pd G (20 mg) in t-BuOH (5.0 mL) was stirred at 90 °C overnight under N. The reaction mixture was extracted with EtOAc, and the combined organic phase was washed with brine, dried over Na.sub.2SO.sub.4, concentrated and purified by silica gel chromatography (PE:EA=1:1) to give the title compound as a yellow solid.

[0353] Step 5: N-(3-(2-(2,6-dimethylpiperazin-1-yl)-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide [ka] To a stirred solution of tert-butyl 4-(4-(3-(2,6-difluorophenylsulfonamido)-2-fluorophenyl)-5-(2-((2,2-dioxide-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-2-yl)-3,5-dimethylpiperazine-1-carboxylate (50 mg, 0.06 mmol, 1.00 equiv) in DCM (2.0 mL) was added TFA (0.5 mL). The resulting mixture was stirred at room temperature for 2 h and then concentrated to give the title compound as a yellow oil.

[0354] Step 6: N-(3-(5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)-2-(2,4,6-trimethylpiperazin-1-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide [ka] To a stirred solution of N-(3-(2-(2,6-dimethylpiperazin-1-yl)-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (44 mg, 0.06 mmol, 1.00 equiv.) in MeOH (2.0 mL), HCHO (25 mg, 0.30 mmol, 5.00 equiv., 35%) and AcOH (1 drop) were added, the resulting mixture was stirred at room temperature for 30 min, and NaBH3CN (8 mg, 0.12 mmol, 2.00 equiv.) was added. The mixture was stirred at room temperature overnight. The mixture was diluted with water, extracted with EtOAc, and the combined organic phase was washed with brine, dried over Na2SO4, concentrated, and purified by preparative HPLC to give the title compound as a yellow solid. MS(ES,m / z):[M+1] + =734.3

[0355] Proceeding in a similar manner as described in Example 21, the following compounds were prepared:

[0356] [Table 32]

[0357] [Table 33]

[0358] Example 30 Synthesis of 2-fluoro-N-(2-fluoro-3-(5-(2-(((1r,4r)-4-(methylsulfonyl)cyclohexyl)amino)pyrimidin-4-yl)-2-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)thiazol-4-yl)phenyl)-6-(trifluoromethyl)benzenesulfonamide [ka] Step 1: 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxamide [ka] Oxalyl chloride (641 mg, 5.05 mmol, 1.30 equiv) and DMF (1 drop) were added dropwise to a mixture of 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid (700 mg, 3.89 mmol, 1.00 equiv) in DCM (14.0 mL) at 0° C., and the mixture was stirred at room temperature under N2 for 2 h. Then, NH3 (gas) was bubbled into the reaction mixture at −10° C. After the mixture was stirred at room temperature overnight, it was filtered and the filtrate was concentrated to give the crude product as a white solid.

[0359] Step 2: 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carbothioamide [ka] Lawesson's reagent (1.57 g, 3.89 mmol, 1.00 equiv) was added to a mixture of (trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxamide (697 mg, 3.89 mmol, 1.00 equiv) in THF (28.0 mL), and the mixture was stirred overnight at 65° C. under N2. The mixture was concentrated and purified by silica gel column chromatography (PE:EA=5:1) to give the title compound as a white solid.

[0360] Step 3: N-(3-(5-(2-chloropyrimidin-4-yl)-2-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)thiazol-4-yl)-2-fluorophenyl)-2-fluoro-6-(trifluoromethyl)benzenesulfonamide [ka] A mixture of N-(3-(2-bromo-2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)-2-fluoro-6-(trifluoromethyl)benzenesulfonamide (Intermediate 8; 876 mg, 1.54 mmol, 1.00 equiv.) and 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carbothioamide (300 mg, 1.54 mmol, 1.00 equiv.) in DMA (36.0 mL) was stirred at room temperature under N2 for 30 min. The mixture was stirred at 65 °C under N2 overnight, 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=2:1) ​​to give the title product as a pale yellow solid.

[0361] Step 4: 2-Fluoro-N-(2-fluoro-3-(5-(2-(((1r,4r)-4-(methylsulfonyl)cyclohexyl)amino)-pyrimidin-4-yl)-2-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)thiazol-4-yl)phenyl)-6-(trifluoromethyl)benzenesulfonamide [ka] A mixture of N-(3-(5-(2-chloropyrimidin-4-yl)-2-(3-(trifluoromethyl)bicyclo[1.1.1]-pentan-1-yl)thiazol-4-yl)-2-fluorophenyl)-2-fluoro-6-(trifluoromethyl)benzenesulfonamide (200 mg, 0.30 mmol, 1.00 equiv.), (1r,4r)-4-(methylsulfonyl)cyclohexane-1-amine trifluoroacetate (Intermediate 5; 131 mg, 0.45 mmol, 1.50 equiv.), Ruphos (50 mg), RuPhos Pd G2 (50 mg) and Cs2CO3 (293 mg, 0.90 mmol, 3.00 equiv.) in NMP / t-BuOH (1.0 mL / 3.0 mL) was stirred overnight at 90 °C under N2. The mixture was diluted with HO 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 (DCM:MeOH=30:1) and preparative TLC (DCM:MeOH=30:1) to give the title compound. The title compound was triturated with ether / MeOH (20:1) for 1 h, the solid was filtered and the filter cake was washed with ether. The filtrate was lyophilized to give the title compound as a pale yellow solid. MS (ES, m / z): [M+1] + =808.1

[0362] Proceeding in a similar manner as described in Example 30, the following compounds were prepared:

[0363] [Table 34]

[0364] [Table 35]

[0365] Example 36 Synthesis of N-(3-(5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)-2-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)thiazol-4-yl)-2-fluorophenyl)-2-fluoro-6-(trifluoromethyl)benzenesulfonamide [ka] Step 1: 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxamide [ka] Oxalyl chloride (641 mg, 5.05 mmol, 1.30 equiv) and DMF (1 drop) were added dropwise to a mixture of 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxylic acid (700 mg, 3.89 mmol, 1.00 equiv) in DCM (14.0 mL) at 0° C., and the mixture was stirred at room temperature under N2 for 2 h. NH3 (gas) was bubbled into the reaction mixture at −10° C., and the mixture was allowed to warm to room temperature and stirred overnight. The mixture was filtered and the filtrate was concentrated to give the crude title compound as a white solid.

[0366] Step 2: 3-Trifluoromethyl)bicyclo[1.1.1]pentane-1-carbothioamide [ka] Lawesson's reagent (1.57 g, 3.89 mmol, 1.00 equiv) was added to a mixture of (trifluoromethyl)bicyclo[1.1.1]pentane-1-carboxamide (697 mg, 3.89 mmol, 1.00 equiv) in THF (28.0 mL), and the mixture was stirred overnight at 65° C. under N2. The mixture was concentrated and purified by silica gel column chromatography (PE:EA=5:1) to give the title compound as a white solid.

[0367] Step 3: N-(3-(5-(2-chloropyrimidin-4-yl)-2-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)-thiazol-4-yl)-2-fluorophenyl)-2-fluoro-6-(trifluoromethyl)benzenesulfonamide [ka] A mixture of N-(3-(2-bromo-2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)-2-fluoro-6-(trifluoromethyl)benzenesulfonamide (Intermediate 8, 876 mg, 1.54 mmol, 1.00 equiv.) and 3-(trifluoromethyl)bicyclo[1.1.1]pentane-1-carbothioamide (300 mg, 1.54 mmol, 1.00 equiv.) in DMA (36.0 mL) was stirred at room temperature under N2 for 30 min. The mixture was stirred at 65 °C under N2 overnight, 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=2:1) ​​to give the title compound as a pale yellow solid.

[0368] Step 4: N-(3-(5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)-2-(3-(trifluoromethyl)bicyclo[1.1.1]pentan-1-yl)thiazol-4-yl)-2-fluorophenyl)-2-fluoro-6-(trifluoromethyl)benzenesulfonamide [ka] A mixture of N-(3-(5-(2-chloropyrimidin-4-yl)-2-(3-(trifluoromethyl)bicyclo[1.1.1]-pentan-1-yl)thiazol-4-yl)-2-fluorophenyl)-2-fluoro-6-(trifluoromethyl)benzenesulfonamide (300 mg, 0.45 mmol, 1.00 equiv.), 6-amino-2-thiaspiro[3.3]heptane 2,2-dioxide (Intermediate 6; 133 mg, 0.68 mmol, 1.50 equiv.), RuPhos (60 mg), RuPhos Pd G2 (60 mg) and Cs2CO3 (440 mg, 1.35 mmol, 3.00 equiv.) in NMP / t-BuOH (1.5 mL / 6.0 mL) was stirred overnight at 90 °C under N2. The mixture was diluted with HO and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by preparative TLC (DCM:EtOAc=1:2) to give the title compound as a white solid. LCMS (ES, m / z): [M+1] + =792.1

[0369] Proceeding in a similar manner as described in Example 36, the following compounds were prepared:

[0370] [Table 36]

[0371] [Table 37]

[0372] Additional compounds that were prepared proceeding in a similar manner to that described in Example 36 are as follows:

[0373] [Table 38]

[0374] [Table 39]

[0375] Example 42 Synthesis of N-(3-(2-(bicyclo[1.1.1]pentan-1-yl)-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide [ka] Step 1: Bicyclo[1.1.1]pentane-1-carboxamide [ka] Oxalyl chloride (294 mg, 2.32 mmol, 1.30 equiv) and DMF (1 drop) were added to a mixture of bicyclo[1.1.1]pentane-1-carboxylic acid (Intermediate 15; 200 mg, 1.78 mmol, 1.00 equiv) in DCM (2.0 mL) at 0 °C. The mixture was allowed to warm to room temperature and stirred under N2 for 2 h. The mixture was added dropwise to a solution of NH3·H2O (1.90 g, 53.52 mmol, 30.00 equiv) in THF (3.0 mL) and stirred at room temperature overnight. The mixture was diluted with H2O and extracted with DCM. The combined organic layers were dried over Na2SO4 and concentrated to give the title compound as a yellow solid.

[0376] Step 2: Bicyclo[1.1.1]pentane-1-carbothioamide [ka] Lawesson's reagent (655 mg, 1.62 mmol, 1.00 equiv) was added to a mixture of bicyclo[1.1.1]pentane-1-carboxamide (180 mg, 1.62 mmol, 1.00 equiv) in THF (10.0 mL), and the mixture was stirred under N2 at 60° C. for 3 h. The mixture was concentrated and purified by silica gel column chromatography (PE:EA=2:1) ​​to give the title compound as a yellow solid.

[0377] Step 3: N-(3-(2-(bicyclo[1.1.1]pentan-1-yl)-5-(2-chloropyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide [ka] A mixture of N-(3-(2-bromo-2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (Intermediate 9; 260 mg, 0.50 mmol, 1.00 equiv.) and bicyclo[1.1.1]pentane-1-carbothioamide (64 mg, 0.50 mmol, 1.00 equiv.) in DMA (5.0 mL) was stirred at room temperature for 30 min. The mixture was stirred at 75° C. overnight and then concentrated. The residue was purified by silica gel column chromatography (PE:EA=2:1) ​​to give the title compound as a yellow solid.

[0378] Step 4: N-(3-(2-(bicyclo[1.1.1]pentan-1-yl)-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide [ka] A mixture of N-(3-(2-(bicyclo[1.1.1]pentan-1-yl)-5-(2-chloropyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (50 mg, 0.09 mmol, 1.00 equiv), 6-amino-2-thiaspiro[3.3]heptane 2,2-dioxide (Intermediate 6; 18 mg, 0.11 mmol, 1.20 equiv) and DIEA (35 mg, 0.27 mmol, 3.00 equiv) in t-BuOH (2.0 mL) was stirred at 130° C. overnight under N2. The mixture was cooled to room temperature and concentrated. The residue was purified by preparative HPLC to give the title compound as a white solid. LCMS (ES, m / z): [M+H] + =674.2.

[0379] Proceeding in a similar manner as described in Example 42, the following compounds were prepared:

[0380] [Table 40]

[0381] [Table 41]

[0382] [Table 42]

[0383] [Table 43]

[0384] [Table 44]

[0385] Additional compounds that were prepared proceeding in a similar manner to that described in Example 42 are as follows:

[0386] [Table 45]

[0387] Example 63 Synthesis of N-(3-(5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)-2-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide [ka] Step 1: N-(3-(2-(3-(((tert-butyldiphenylsilyl)oxy)methyl)bicyclo[1.1.1]pentan-1-yl)-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide [ka] The title compound was synthesized proceeding in an analogous manner as described in steps 1-4 of Example 42 using 3-(((tert-butyldiphenylsilyl)oxy)methyl)-bicyclo[1.1.1]pentane-1-carboxylic acid (Intermediate 14) instead of bicyclo[1.1.1]pentane-1-carboxylic acid.

[0388] Step 2: N-(3-(5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)-2-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide [ka] TBAF (5.0 mL of a 1M solution in THF) was added to a stirred solution of N-(3-(2-(3-(((tert-butyldiphenylsilyl)oxy)methyl)bicyclo[1.1.1]pentan-1-yl)-5-(2-((2,2-dioxido-2-thiaspiro-[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (310 mg, 0.33 mmol, 1.00 equiv) in THF (50.0 mL) at room temperature under N2. The resulting mixture was stirred at room temperature for 16 h, concentrated, and purified by silica gel chromatography (EA:PE=1:1) to give the title compound. MS (ES, m / z): [M+1] + =704.2

[0389] Example 67 Synthesis of N-(3-(5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)-2-(4-methylpiperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide [ka] To a solution of tert-butyl 4-(4-(3-(2,6-difluorophenylsulfonamido)-2-fluorophenyl)-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-2-yl)-4-methylpiperidine-1-carboxylate (150 mg, 0.19 mmol, 1.00 equiv) in DCM (4.0 mL) was added TFA (1.0 mL). The mixture was stirred at room temperature for 2 h and then concentrated to give the title compound. MS (ES, m / z): [M+1] + =705.1

[0390] Example 68 Synthesis of N-(3-(2-(1,4-dimethylpiperidin-4-yl)-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide [ka] To a solution of N-(3-(5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)-pyrimidin-4-yl)-2-(4-methylpiperidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (50 mg, 0.07 mmol, 1.00 equiv.) and NaBH(OAc)3 (45 mg, 0.21 mmol, 3.00 equiv.) was added HCHO (35% in HO, 24 mg, 0.28 mmol, 4.00 equiv.) at 0° C. The mixture was stirred at room temperature for 3 h, then concentrated and purified by preparative HPLC to give the title compound. MS (ES, m / z): [M+1] + =719.2.

[0391] Example 69 Synthesis of N-(3-(2-(bicyclo[1.1.1]pentan-1-yl)-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-dichlorobenzenesulfonamide [ka] Step 1: N-(3-(2-(bicyclo[1.1.1]pentan-1-yl)-5-(2-chloropyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)acetamide [ka] A mixture of bicyclo[1.1.1]pentane-1-carbothioamide (2.00 g, 15.70 mmol, 1.00 equiv) and N-(3-(2-bromo-2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)acetamide (Intermediate 10; 6.00 g, 15.70 mmol, 1.00 equiv) in DMA (100.0 mL) was stirred at room temperature for 1 h, then at 65° C. overnight under N2. The mixture was extracted with EtOAc and the combined organic phase was washed with water, brine, dried over Na2SO4, and concentrated to give the title compound as a yellow solid.

[0392] Step 2: N-(3-(2-(bicyclo[1.1.1]pentan-1-yl)-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)acetamide [ka] To a solution of N-(3-(2-(bicyclo[1.1.1]pentan-1-yl)-5-(2-chloropyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)acetamide (4.75 g, 11.47 mmol, 1.00 equiv.) in n-BuOH (100.0 mL), 2-thiaspiro[3.3]heptan-6-amine (Intermediate 6; 3.39 g, 17.21 mmol, 1.50 equiv.), DIEA (8.88 g, 68.84 mmol, 6.00 equiv.) were added and the mixture was stirred overnight at 130 °C under N2. The mixture was concentrated and purified by silica gel column chromatography (PE:EA=2:1 to 1:2) to give the title compound as a yellow solid.

[0393] Step 3: 6-((4-(4-(3-amino-2-fluorophenyl)-2-(bicyclo[1.1.1]pentan-1-yl)thiazol-5-yl)pyrimidin-2-yl)amino)-2-thiaspiro[3.3]heptane 2,2-dioxide [ka] To a solution of N-(3-(2-(bicyclo[1.1.1]pentan-1-yl)-5-(2-((2,2-dioxide-2-thiaspiro[3.3]-heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)acetamide (1.50 g, 2.78 mmol) in MeOH (15.0 mL) was added MeOH / HCl (2 M, 10.0 mL) and the mixture was stirred at 50° C. under N for 2 h. The mixture was concentrated and the pH was adjusted to 9 by addition of 1N aqueous NaOH. The mixture was extracted with EtOAc and the combined organic phase was washed with water, brine, dried over NaSO and concentrated to give the title compound as a yellow solid.

[0394] Step 4: N-(3-(2-(bicyclo[1.1.1]pentan-1-yl)-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-dichlorobenzenesulfonamide [ka] 2,6-Dichlorobenzenesulfonyl chloride (197 mg, 0.80 mmol, 2.00 equiv.) was added to a mixture of 6-((4-(4-(3-amino-2-fluorophenyl)-2-(bicyclo[1.1.1]pentan-1-yl)thiazol-5-yl)pyrimidin-2-yl)amino)-2-thiaspiro[3.3]heptane 2,2-dioxide (200 mg, 0.40 mmol, 1.00 equiv.) and pyridine (95 mg, 1.21 mmol, 3.00 equiv.) in DCM (4.0 mL) at 0° C. The mixture was slowly warmed to room temperature and stirred overnight. The mixture was concentrated and purified by silica gel column chromatography (DCM:MeOH=20:1) to give the title compound as a yellow solid. MS (ES, m / z): [M+1] + =706.1.

[0395] Proceeding in a similar manner as described in Example 69, the following compounds were prepared:

[0396] [Table 46]

[0397] [Table 47]

[0398] Example 78 Synthesis of N-(3-(2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-(2-((2,2-dioxido-2-thiaspiro-[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide [ka] Step 1: N-(3-(2-amino-5-(2-chloropyrimidin-4-yl)-2,3-dihydrothiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide [ka] A mixture of N-(3-(2-bromo-2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (Intermediate 9; 15.00 g, 28.85 mmol, 1.00 equiv) and thiourea (2.20 g, 3.72 mmol, 1.00 equiv) in DMA (150.0 mL) was stirred at room temperature for 30 min and then heated to 70° C. under N for 4 h. The mixture was poured into water and filtered to give the title compound as a yellow solid.

[0399] Step 2: N-(3-(2-amino-5-(2-(methylthio)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide [ka] Sodium methanethiolate (196 mg, 2.80 mmol, 2.00 equiv) was added to a mixture of N-(3-(2-amino-5-(2-chloropyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (700 mg, 1.40 mmol, 1.00 equiv) in DMSO (10.0 ml) at room temperature, 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 brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography (DCM / MeOH=20 / 1) to give the title compound as a yellow solid.

[0400] Step 3: N-(3-(2-bromo-5-(2-(methylthio)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide [ka] tert-Butyl nitrite (91 mg, 0.89 mmol, 1.50 equiv) was added to a mixture of N-(3-(2-amino-5-(2-(methylthio)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (300 mg, 0.59 mmol, 1.00 equiv) and CuBr2 (158 mg, 0.71 mmol, 1.20 equiv) in MeCN (6.0 ml) at 0° C. The mixture was stirred at room temperature overnight and extracted with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4. The residue was then purified by silica gel chromatography (DCM / MeOH=100 / 1) to give the title compound as a yellow solid.

[0401] Step 4: N-(3-(2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-(2-(methylthio)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide [ka] A mixture of N-(3-(2-bromo-5-(2-(methylthio)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (100 mg, 0.18 mol, 1.00 equiv.), 3-oxa-8-azabicyclo[3.2.1]octane (131 mg, 0.90 mmol, 5.00 equiv.) and TEA (111 mg, 1.10 mmol, 6.00 equiv.) in DMA (2.0 ml) was stirred at 120° C. for 3 h under microwave irradiation. The mixture was then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (DCM / MeOH=50 / 1) to give the title compound as a yellow solid.

[0402] Step 5: N-(3-(2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-(2-(methylsulfonyl)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide [ka] Oxone (246 mg, 0.40 mmol, 2.00 equiv) was added to a mixture of N-(3-(2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-(2-(methylthio)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (120 mg, 0.20 mmol, 1.00 equiv) in THF / H2O=4 / 1 (2.0 ml) at room temperature, and the mixture was stirred overnight. The mixture was extracted with EtOAc, and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by preparative HPLC to give the title compound as a yellow solid.

[0403] Step 6: N-(3-(2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide [ka] A mixture of N-(3-(2-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-(2-(methylsulfonyl)-pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (70 mg, 0.11 mmol, 1.00 equiv.), 6-amino-2-thiaspiro[3.3]heptane 2,2-dioxide (Intermediate 6; 27 mg, 0.17 mmol, 1.50 equiv.), DIEA (43 mg, 0.33 mmol, 3.00 equiv.) in DMSO (1 ml) was stirred at 70° C. overnight. The mixture was purified by silica gel chromatography to give the title compound as a yellow solid. LCMS (ES, m / z): [M+H] + =719.2

[0404] Proceeding in a similar manner as described in Example 78, the following compounds were prepared:

[0405] [Table 48]

[0406] Example 81 Synthesis of N-(3-(5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)-2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide [ka] Step 1: N-(3-(2-amino-5-(2-chloropyrimidin-4-yl)-2,3-dihydrothiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide [ka] A mixture of N-(3-(2-bromo-2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (Intermediate 9; 15.00 g, 28.85 mmol, 1.00 equiv) and thiourea (2.20 g, 3.72 mmol, 1.00 equiv) in DMA (150.0 mL) was stirred at room temperature for 30 min, then the mixture was heated to 70° C. under N for 4 h. The mixture was poured into water and filtered to give the title compound as a yellow solid.

[0407] Step 2: N-(3-(2-amino-5-(2-(methylthio)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide [ka] Sodium methanethiolate (196 mg, 2.80 mmol, 2.00 equiv) was added to a mixture of N-(3-(2-amino-5-(2-chloropyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (700 mg, 1.40 mmol, 1.00 equiv) in DMSO (10.0 ml) at room temperature, and the mixture was stirred overnight. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography (DCM / MeOH=20 / 1) to give the title compound as a yellow solid.

[0408] Step 3: N-(3-(2-bromo-5-(2-(methylthio)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide [ka] tert-Butyl nitrite (91 mg, 0.89 mmol, 1.50 equiv) was added to a mixture of N-(3-(2-amino-5-(2-(methylthio)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (300 mg, 0.59 mmol, 1.00 equiv) and CuBr2 (158 mg, 0.71 mmol, 1.20 equiv) in MeCN (6.0 ml) at 0° C., 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 brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography (DCM / MeOH=100 / 1) to give the title compound as a yellow solid.

[0409] Step 4: 2,6-difluoro-N-(2-fluoro-3-(2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-(2-(methylthio)pyrimidin-4-yl)thiazol-4-yl)phenyl)benzenesulfonamide [ka] A mixture of N-(3-(2-bromo-5-(2-(methylthio)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (500 mg, 0.87 mmol, 1.00 equiv.), 3-methyl-3,8-diazabicyclo[3.2.1]octane hydrochloride (425 mg, 2.62 mmol, 3.0 equiv.), TEA (796 mg, 7.87 mmol, 9.00 equiv.) in DMA (6.0 mL) was stirred at 120° C. for 3 h under microwave irradiation. The mixture was concentrated and the residue was purified by flash column chromatography (EA:PE=0-100%) to give the title compound as a yellow oil.

[0410] Step 5: 2,6-difluoro-N-(2-fluoro-3-(2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-(2-(methylsulfonyl)pyrimidin-4-yl)thiazol-4-yl)phenyl)benzenesulfonamide [ka] To a solution of 2,6-difluoro-N-(2-fluoro-3-(2-(3-methyl-3,8-diazabicyclo[3.2.1]-octan-8-yl)-5-(2-(methylthio)pyrimidin-4-yl)thiazol-4-yl)phenyl)benzenesulfonamide (513 mg, 0.83 mmol, 1.00 equiv) in MeOH:THF:H2O=2:2:1 (15.0 mL) was added oxone (1.50 g, 2.49 mmol, 3.00 equiv). The mixture was stirred at 35° C. overnight, then diluted with H2O and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated to give the title compound as a yellow oil, which was used directly in the next step without purification.

[0411] Step 6: N-(3-(5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)-2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide [ka] A mixture of 2,6-difluoro-N-(2-fluoro-3-(2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-(2-(methylsulfonyl)pyrimidin-4-yl)thiazol-4-yl)phenyl)benzenesulfonamide (520 mg, 0.80 mmol, 1.00 equiv), 6-amino-2-thiaspiro[3.3]heptane 2,2-dioxide (Intermediate 6; 237 mg, 1.20 mmol, 1.50 equiv), DIEA (620 mg, 4.80 mmol, 6.00 equiv) in DMSO (15.0 mL) was stirred at 65° C. under N overnight. The mixture was poured into water and the mixture was extracted with EtOAc. The combined organic layers were washed with water, brine, dried over NaSO and concentrated. The residue was purified by preparative HPLC to give the title compound as a pale yellow solid. MS(ES,m / z):[M+1] + =732.2.

[0412] Proceeding in a similar manner as described in Example 81, the following compounds were prepared:

[0413] [Table 49]

[0414] [Table 50]

[0415] [Table 51]

[0416] [Table 52]

[0417] Example 95 Synthesis of N-(3-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-(2-((2,2-dioxido-2-thiaspiro-[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide [ka] Step 1: N-(3-(2-amino-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)-2,3-dihydrothiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide [ka] A mixture of N-(3-(2-amino-5-(2-chloropyrimidin-4-yl)-2,3-dihydrothiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (10.00 g, 20.10 mmol, 1.00 equiv.), 6-amino-2-thiaspiro[3.3]heptane 2,2-dioxide (Intermediate 6; 4.40 g, 22.10 mmol, 1.10 equiv.) and DIEA (13.00 g, 100.50 mmol, 5.00 equiv.) in n-BuOH (100.0 mL) was stirred overnight at 130° C. under N2. The mixture was concentrated and the residue was purified by silica gel column chromatography (DCM / MeOH=40:1) to give the title compound as a yellow solid.

[0418] Step 2: N-(3-(2-bromo-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide [ka] tert-Butyl nitrite (2.20 g, 21.70 mmol, 1.50 equiv) was added to a mixture of N-(3-(2-amino-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)-2,3-dihydrothiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (9.00 g, 14.47 mmol, 1.00 equiv) and CuBr2 (4.20 g, 18.81 mmol, 1.30 equiv) in MeCN (100.0 mL) at 0 °C. The mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was diluted with EtOAc and the organic layer was washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (PE / EA=1:1) to give the tilted compound as a yellow solid.

[0419] Step 3: tert-Butyl 8-(4-(3-(2,6-difluorophenylsulfonamido)-2-fluorophenyl)-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate [ka] A mixture of N-(3-(2-bromo-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)-pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (5.00 g, 7.28 mmol, 1.00 equiv.) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (2.32 g, 10.92 mmol, 1.50 equiv.), TEA (4.42 g, 43.70 mmol, 6.00 equiv.) in DMA (30.0 mL) was stirred at 120° C. under N overnight. The mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (DCM:MeOH=50:1 to 10:1) to give the title compound as a yellow oil.

[0420] Step 4: N-(3-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide [ka] To a solution of tert-butyl 8-(4-(3-(2,6-difluorophenylsulfonamido)-2-fluorophenyl)-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-2-yl)-3,8-diazabicyclo-[3.2.1]octane-3-carboxylate (10 g, 12.20 mmol) in DCM (10.0 mL) was added TFA (4.0 mL) and the mixture was stirred at room temperature for 3 h. The mixture was concentrated to give the title compound as a yellow oil. MS (ES, m / z): [M+1] + =718.0.

[0421] Example 96 Synthesis of N-(3-(2-(3-(3,3-difluorocyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide [ka] To a solution of N-(3-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-(2-((2,2-dioxido-2-thiaspiro-[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (300 mg, 0.37 mmol, 1.00 equiv.) in MeOH:THF=1:1 (5 mL), 3,3-difluorocyclobutanone (117 mg, 1.10 mmol, 3.00 equiv.), AcOH (3 drops) were added and the mixture was stirred at room temperature for 15 min. NaBH3CN (116 mg, 1.84 mmol, 5.00 equiv.) was added and the mixture was stirred at room temperature under N2 overnight. The mixture was poured into water and the pH was adjusted to 7-8 with 1N NaOH. The mixture was extracted with EtOAc, washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (EA:PE=0-100%), then purified by reverse column to give the title compound as a yellow solid. MS (ES, m / z): [M+H] + =808.3.

[0422] Proceeding in a similar manner as described in Example 96, the following compounds were prepared:

[0423] [Table 53]

[0424] [Table 54]

[0425] [Table 55]

[0426] Example 105 Synthesis of N-(3-(2-(7-azabicyclo[2.2.1]heptan-7-yl)-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide [ka] A mixture of N-(3-(2-bromo-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)-pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (0.5 g, 0.73 mmol, 1.00 equiv.) and 7-azabicyclo[2.2.1]heptane (0.11 g, 1.1 mmol, 1.50 equiv.), TEA (0.44 g, 4.3 mmol, 6.00 equiv.) in DMA (3.0 mL) was stirred at 120° C. under N overnight. The mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (DCM:MeOH=50:1 to 10:1) to give the title compound as a yellow solid. LCMS (ES, m / z): [M+1] + =703.2

[0427] Proceeding in a similar manner as described in Example 105, the following compounds were prepared:

[0428] [Table 56]

[0429] [Table 57]

[0430] [Table 58]

[0431] Example 117 Synthesis of N-(3-(5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)-2-(3-(1,1-dioxidothietan-3-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide [ka] Step 1: 6N-(3-(5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)-2-(3-(thietan-3-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide [ka] To a solution of N-(3-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (100 mg, 0.14 mmol, 1.00 equiv) in MeOH / THF (2.0 mL, 1:1) was added thietan-3-one (61 mg, 0.70 mmol, 5.00 equiv) and AcOH (1 drop). The mixture was stirred at room temperature for 20 min. NaBH3CN (44 mg, 0.70 mmol, 5.00 equiv) was added and the mixture was stirred at room temperature overnight. The mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified on a silica flash column DCM / MeOH (20:1) to give the title compound as a yellow solid.

[0432] Step 2: N-(3-(5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)-2-(3-(1,1-dioxidothietan-3-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide [ka] Oxone (93 mg, 0.15 mmol, 3.00 equiv) was added to a mixture of 6N-(3-(5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)-2-(3-(thietan-3-yl)-3,8-diazabicyclo[3.2.1]-octan-8-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (40 mg, 0.05 mmol, 1.00 equiv) in MeOH:THF:HO (2.0 mL, 2:2:1) and the mixture was stirred at room temperature for 1 h. The mixture was extracted with DCM and the combined organic layers were washed with water, brine, dried over NaSO and concentrated. The residue was purified by preparative HPLC to give the title compound as a yellow solid. MS(ES,m / z):[M+H] + =822.1

[0433] Example 126 Synthesis of N-(3-(2-(3-(3,3-difluorocyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2-fluoro-6-(trifluoromethyl)benzenesulfonamide [ka] Step 1: N-(3-(2-amino-5-(2-chloropyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)acetamide [ka] A mixture of N-(3-(2-bromo-2-(2-chloropyrimidin-4-yl)acetyl)-2-fluorophenyl)acetamide (Intermediate 10; 6.32 g, 16.40 mmol, 1.00 equiv.), thiourea (1.25 g, 16.40 mmol, 1.00 equiv.) in DMA (70.0 mL) was stirred at 65° C. under N for 3 h. The mixture was poured into water and the mixture was extracted with EtOAc. The combined organic layers were washed with water, brine, dried over NaSO and concentrated to give the title compound as a yellow solid.

[0434] Step 2: N-(3-(2-amino-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)-thiazol-4-yl)-2-fluorophenyl)acetamide [ka] A mixture of N-(3-(2-amino-5-(2-chloropyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)acetamide (5.05 g, 13.90 mmol, 1.00 equiv), 2-thiaspiro[3.3]heptan-6-amine hydrochloride (Intermediate 6; 3.30 g, 16.70 mmol, 1.50 equiv), DIEA (8.90 g, 69.60 mmol, 5.00 equiv) in n-BuOH (100.0 mL) was stirred at 130 °C under N overnight. The mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over NaSO and concentrated. The residue was purified by silica gel column chromatography (PE:EA=1:1 to DCM:MeOH=20:1) to give the title compound as a yellow solid.

[0435] Step 3: N-(3-(2-bromo-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)acetamide [ka] tert-Butyl nitrite (1.15 g, 11.20 mmol, 1.50 equiv) in MeCN (50.0 mL) was added to a solution of N-(3-(2-amino-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)acetamide (3.63 g, 7.40 mmol, 1.00 equiv) and CuBr2 (2.16 g, 9.70 mmol, 1.30 equiv) at 0 °C, and the mixture was stirred at room temperature under N2 for 3 h. The mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4, concentrated, and the residue was purified by column chromatography (PE:EA=1:1 to DCM:MeOH=20:1) to give the title compound as a yellow solid.

[0436] Step 4: tert-Butyl 8-(4-(3-acetamido-2-fluorophenyl)-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate [ka] A mixture of N-(3-(2-bromo-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)-pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)acetamide (800 mg, 1.45 mmol, 1.00 equiv), tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (400 mg, 1.88 mmol, 1.30 equiv) and TEA (439 mg, 4.38 mmol, 3.00 equiv) in DMA (10.0 mL) was stirred at 120° C. 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. The residue was purified on a silica flash column PE / EtOAc (1:2) to give the title compound as a yellow solid.

[0437] Step 5: tert-Butyl 8-(4-(3-amino-2-fluorophenyl)-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate [ka] To a solution of tert-butyl 8-(4-(3-acetamido-2-fluorophenyl)-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (900 mg, 1.32 mmol, 1.00 equiv.) in EtOH (10.0 mL) was added NaOH (105 mg, 2.64 mmol, 2.00 equiv.) and the mixture was stirred at 80° C. overnight. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give the title compound as a yellow solid.

[0438] Step 6: tert-Butyl 8-(5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)-4-(2-fluoro-3-(2-fluoro-6-(trifluoromethyl)phenylsulfonamido)phenyl)thiazol-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate [ka] 2-Fluoro-6-(trifluoromethyl)benzene-1-sulfonyl chloride (536 mg, 2.05 mmol, 1.60 equiv) was added to a solution of tert-butyl 8-(4-(3-amino-2-fluorophenyl)-5-(2-((2,2-dioxide-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (820 mg, 1.28 mmol, 1.00 equiv) and pyridine (303 mg, 3.84 mmol, 3.00 equiv) in DCM (20.0 mL) and the mixture was stirred overnight at 40° C. The mixture was concentrated and the residue was purified on a silica flash column DCM / MeOH (20:1) to give the title compound as a yellow solid.

[0439] Step 7: N-(3-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2-fluoro-6-(trifluoromethyl)benzenesulfonamide [ka] To a solution of tert-butyl 8-(5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)-pyrimidin-4-yl)-4-(2-fluoro-3-(2-fluoro-6-(trifluoromethyl)phenylsulfonamido)-phenyl)thiazol-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (540 mg, 0.62 mmol, 1.00 equiv.) in DCM (4.0 mL) was added TFA (1.0 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.

[0440] Step 8: N-(3-(2-(3-(3,3-difluorocyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2-fluoro-6-(trifluoromethyl)benzenesulfonamide [ka] A mixture of N-(3-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2-fluoro-6-(trifluoromethyl)benzenesulfonamide (200 mg, 0.26 mmol, 1.00 equiv.), AcOH (2 drops) and 3,3-difluorocyclobutanone (138 mg, 1.30 mmol, 5.00 equiv.) in MeOH / THF (4.0 mL, 1:1) was stirred at room temperature for 0.5 h. NaBH3CN (82 mg, 1.30 mmol, 5.00 equiv.) was added and the mixture was stirred at room temperature overnight. The mixture was extracted with DCM and the combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica flash column to give the title compound as a yellow solid.

[0441] Proceeding in a similar manner as described in Example 126, the following compounds were prepared:

[0442] [Table 59]

[0443] Example 136 Synthesis of N-(3-(2-(3-(3,3-difluorocyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2-(difluoromethyl)-6-fluorobenzenesulfonamide [ka] Step 1: N-(3-(2-amino-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)acetamide [ka] A mixture of N-(3-(2-amino-5-(2-chloropyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)acetamide (5.05 g, 13.90 mmol, 1.00 equiv), 2-thiaspiro[3.3]heptan-6-amine hydrochloride (Intermediate 6; 3.30 g, 16.70 mmol, 1.50 equiv), DIEA (8.90 g, 69.60 mmol, 5.00 equiv) in n-BuOH (100.0 mL) was stirred at 130 °C under N overnight. The mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over NaSO and concentrated. The residue was purified by silica gel column chromatography (PE:EA=1:1 to DCM:MeOH=20:1) to give the title compound as a yellow solid.

[0444] Step 2: N-(3-(2-bromo-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)acetamide [ka] tert-Butyl nitrite (1.15 g, 11.20 mmol, 1.50 equiv) in MeCN (50.0 mL) was added to a solution of N-(3-(2-amino-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)acetamide (3.63 g, 7.40 mmol, 1.00 equiv) and CuBr2 (2.16 g, 9.70 mmol, 1.30 equiv) at 0 °C, and the mixture was stirred at room temperature under N2 for 3 h. The mixture was poured into water and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (PE:EA=1:1 to DCM:MeOH=20:1) to give the title compound as a yellow solid.

[0445] Step 3: tert-Butyl 8-(4-(3-acetamido-2-fluorophenyl)-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate [ka] A mixture of N-(3-(2-bromo-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)-pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)acetamide (800 mg, 1.45 mmol, 1.00 equiv), tert-butyl 3,8-diazabicyclo[3.2.1]octane-3-carboxylate (400 mg, 1.88 mmol, 1.30 equiv) and TEA (439 mg, 4.38 mmol, 3.00 equiv) in DMA (10.0 mL) was stirred at 120° C. 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. The residue was purified on a silica flash column PE / EtOAc (1:2) to give the title compound as a yellow solid.

[0446] Step 4: N-(3-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-(2-((2,2-dioxide-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)acetamide [ka] TFA (1.0 mL) was added to a mixture of tert-butyl 8-(4-(3-acetamido-2-fluorophenyl)-5-(2-((2,2-dioxide-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (450 mg, 0.66 mmol, 1.00 equiv) in DCM (5.0 mL) at 0° C. The mixture was stirred at room temperature under N for 2 h and then concentrated to give the crude product as a brown solid.

[0447] Step 5: N-(3-(2-(3-(3,3-difluorocyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)acetamide [ka] A mixture of N-(3-(2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)acetamide (350 mg, 0.50 mmol, 1.00 equiv) and 3,3-difluorocyclobutan-1-one (160 mg, 1.506 mmol, 3.00 equiv) in DCE / MeOH (1:1, 7.0 mL) was stirred at room temperature for 1 h. NaBH3CN (158 mg, 2.51 mmol, 5.00 equiv) was added and the mixture was stirred at room temperature under N2 overnight. The mixture was concentrated and the residue was purified by silica gel column chromatography (DCM:MeOH=20:1) to give the title compound as a yellow solid.

[0448] Step 6: 6-((4-(4-(3-amino-2-fluorophenyl)-2-(3-(3,3-difluorocyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)thiazol-5-yl)pyrimidin-2-yl)amino)-2-thiaspiro[3.3]heptane 2,2-dioxide [ka] A mixture of N-(3-(2-(3-(3,3-difluorocyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-(2-((2,2-dioxide-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)acetamide (325 mg, 0.48 mmol, 1.00 equiv) in HCl / MeOH (2M, 10.0 mL) was stirred at 50° C. under N for 3 h. The mixture was concentrated to give the crude title compound, which was used in the next step without further purification.

[0449] Step 7: N-(3-(2-(3-(3,3-difluorocyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2-(difluoromethyl)-6-fluorobenzenesulfonamide [ka] 2-(Difluoromethyl)-6-fluorobenzenesulfonyl chloride (Intermediate 29; 180 mg, 0.74 mmol, 3.00 equiv.) was added to a mixture of 6-((4-(4-(3-amino-2-fluorophenyl)-2-(3-(3,3-difluorocyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl)thiazol-5-yl)pyrimidin-2-yl)amino)-2-thiaspiro[3.3]heptane 2,2-dioxide (155 mg, 0.25 mmol, 1.00 equiv.), pyridine (97 mg, 1.23 mmol, 5.00 equiv.) in DCM (5.0 mL) and the mixture was stirred overnight at room temperature under N2. The mixture was concentrated and the residue was purified by preparative HPLC to give the title compound as a yellow solid. MS (ES, m / z): [M+1] + =840.3.

[0450] Proceeding in a similar manner as described in Example 136, the following compounds were prepared:

[0451] [Table 60]

[0452] Example 140 Synthesis of N-(3-(2-(bicyclo[1.1.1]pentan-1-yl)-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2-fluoro-6-methoxybenzenesulfonamide [ka] To a stirred solution of N-(3-(2-(bicyclo[1.1.1]pentan-1-yl)-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2,6-difluorobenzenesulfonamide (Example 42; 50 mg, 0.07 mmol, 1.00 equiv) in THF (2.0 mL) was added NaH (60%) (14.8 mg, 0.37 mmol, 5.00 equiv) at 0° C. The mixture was stirred at room temperature for 30 min. MeOH (9.6 mg, 0.30 mmol, 14.00 equiv) was added at room temperature and the mixture was stirred overnight. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by preparative HPLC to give the title compound as a white solid. LCMS (ES, m / z): [M+H] + =686.2

[0453] Proceeding in a similar manner as described in Example 140, the following compounds were prepared:

[0454] [Table 61]

[0455] Example 143 Synthesis of N-(3-(2-(bicyclo[1.1.1]pentan-1-yl)-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2-cyclopropyl-6-fluorobenzenesulfonamide [ka] Step 1: 2-Bromo-6-fluorobenzene-1-sulfonyl chloride [ka] (Solution A) SOCl2 (1.70 g, 14.47 mmol, 5.50 equiv) was added dropwise to H2O (7.5 mL) at 0 °C, then the reaction was stirred at room temperature overnight. CuCl (130 mg, 1.32 mmol, 0.50 equiv) was added to the reaction mixture.

[0456] (Solution B) To a 100 mL three-neck flask, HCl (6.0 mL) and 2-bromo-6-fluoroaniline (500 mg, 2.63 mmol, 1.00 equiv) were added at 0° C. Then, NaNO2 (272 mg, 3.95 mmol, 1.50 equiv) in H2O (5.0 mL) was added dropwise at 0° C. The mixture was stirred for 1 h.

[0457] Solution A was added dropwise to solution B at 0° C., and the mixture was stirred at room temperature for 1 h. The mixture was diluted with water and extracted with DCM. The combined organic layers were dried over Na2SO4 and concentrated to give the title compound as a yellow oil.

[0458] Step 2: N-(3-(2-(bicyclo[1.1.1]pentan-1-yl)-5-(2-((2,2-dioxide-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2-bromo-6-fluorobenzenesulfonamide [ka] 2-Bromo-6-fluorobenzene-1-sulfonyl chloride (165 mg, 0.60 mmol, 2.0 equiv) was added to a solution of 6-((4-(4-(3-amino-2-fluorophenyl)-2-(bicyclo[1.1.1]pentan-1-yl)thiazol-5-yl)pyrimidin-2-yl)amino)-2-thiaspiro[3.3]heptane 2,2-dioxide (150 mg, 0.30 mmol, 1.00 equiv) and pyridine (71 mg, 0.90 mmol, 3.00 equiv) in DCM (2.0 mL). The mixture was stirred at 40° C. overnight. The mixture was concentrated and the residue was purified on a silica gel flash column PE / EtOAc (1:2) to give the title compound as a white solid.

[0459] Step 3: N-(3-(2-(bicyclo[1.1.1]pentan-1-yl)-5-(2-((2,2-dioxide-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2-cyclopropyl-6-fluorobenzenesulfonamide [ka] A mixture of cyclopropylboronic acid (35 mg, 0.41 mmol, 3.00 equiv), CsCO (133 mg, 0.41 mmol, 3.00 equiv), Pd(dppf)Cl (30 mg), N-(3-(2-(bicyclo[1.1.1]pentan-1-yl)-5-(2-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)pyrimidin-4-yl)thiazol-4-yl)-2-fluorophenyl)-2-bromo-6-fluorobenzenesulfonamide (100 mg, 0.14 mmol, 1.00 equiv) in dioxane / HO (2.0 mL, 5:1) was stirred at 100° C. for 2 h under microwave irradiation. The mixture was extracted with DCM and the combined organic layers were dried over NaSO and concentrated. The residue was then purified by preparative HPLC to give the title compound as a white solid. MS (ES, m / z): [M+1] + =696.1

[0460] Biological Examples Example 1: Phospho-RB measurements in OVCAR3 cells The ability of compounds of formula (I) to inhibit CDK2 was determined in OVCAR3 cells. Phosphorylation of RB protein at S807 / 811 was measured using the HTRF Phospho-RB Cell Kit from Cisbio (Cat. No. 64RBS807PEG).

[0461] On day 1, OVCAR3 cells were seeded at 20,000 cells / well in 200 μL in a 96-well tissue culture treated plate and incubated overnight at 37 °C under a CO2 atmosphere. On day 2, cells were treated with test compounds at concentrations ranging from 0.3 to 10,000 nM using an HP D300 digital dispenser. 24 hours after compound treatment, cell culture medium was removed by flicking the plate and tapping it on a clean paper towel. Immediately replenished with 30 μL of 1X lysis buffer from the kit and the plate was incubated for 30 min at room temperature on a shaker. After homogenization by pipetting, 8 μL of cell lysate from the 96-well cell culture plate was transferred to a 384-well small volume white detection plate. 2 μL of premixed detection solution was added and the plate was covered with a sealer. To prepare the detection solution, d2-conjugated phospho-RB antibody and Eu-cryptate-conjugated phospho-RB antibody were diluted in detection buffer according to the manufacturer's instructions.

[0462] The detection plate was incubated at room temperature for 4 hours and read on a ClarioStar (BMG Labtech) in TR-FRET mode (665 nM and 620 nM). The TR-FRET ratio (665 nM / 620 nM) was plotted versus compound concentration and normalized to the DMSO control. The half maximal inhibitory concentration (IC 50 ) values ​​are calculated with a four-parameter logistic fit using GraphPad Prism (version 8; La Jolla, Calif.).

[0463] CDK2 IC of compounds in Table 1 50 The data is provided in Table 2 below.

[0464] [Table 62]

[0465] [Table 63]

[0466] Formulation examples The following are representative formulations containing the compounds of the present disclosure.

[0467] Tablet formulation The following ingredients are mixed and pressed into single scored tablets:

[0468] [Table 64]

[0469] Capsule formulation The following ingredients are blended and loaded into a hard shell gelatin capsule:

[0470] [Table 65]

[0471] Injectable preparations A compound of the disclosure (e.g., compound) up to at least 20 mg / mL in an appropriate amount of DI water containing 2% HPMC, 1% Tween® 80, pH 2·2 with MSA.

[0472] Inhalation composition To prepare a pharmaceutical composition for inhalation delivery, 20 mg of a compound disclosed herein is mixed with 50 mg of anhydrous citric acid and 100 mL of 0.9% sodium chloride solution. The mixture is incorporated into an inhalation delivery unit, such as a nebulizer, suitable for inhalation administration.

[0473] Topical gel compositions To prepare a pharmaceutical topical gel composition, 100 mg of a compound disclosed herein is mixed with 1.75 g of hydroxypropylcellulose, 10 mL of propylene glycol, 10 mL of isopropyl myristate, and 100 mL of purified alcohol USP. The resulting gel mixture is then incorporated into a container, such as a tube, suitable for topical administration.

[0474] Ophthalmic solution composition To prepare pharmaceutical eye drop composition, 100mg of compound disclosed herein is mixed with 0.9g of NaCl in 100mL of purified water, and filtered using a 0.2 micron filter.The resulting isotonic solution is then incorporated into an ophthalmic delivery unit, such as an eye dropper, suitable for ophthalmic administration.

[0475] Nasal spray solution To prepare a medicinal nasal spray solution, 10 g of a compound disclosed herein is mixed with 30 mL of 0.05 M phosphate buffer (pH 4.4). The solution is placed into a nasal applicator designed to deliver 100 ul of spray for each administration.

Claims

1. Formula (I): 【Chemistry 301】 (In the formula, R １ is hydrogen or halo; Ring R Ａ is represented by formula (i), (ii), (iii) or (iv): 【Chemistry 302】 where alk is alkyl and R Ａ Each ring is independently selected from hydrogen, alkyl, and halo. ４ and R ５ is substituted with; R ２ and R ３ is independently selected from hydrogen, alkyl, cycloalkyl, alkoxy, halo, haloalkyl, and haloalkoxy; Ring R Ｂ is cycloalkyl, bridged cycloalkyl, heterocyclyl or bridged heterocyclyl; (A) Ring R Ｂ Cycloalkyl and bridged cycloalkyl are selected from hydrogen, halo, haloalkyl, and hydroxyalkyl. ａ is substituted with; (B) Ring R Ｂ The heterocyclyl of R ｂ , R ｃ and R ｄ is substituted with R ｂ and R ｃ is independently selected from hydrogen, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy, and R ｄ is hydrogen, alkyl, deuteroalkyl, cycloalkyl (optionally substituted with 1 or 2 substituents independently selected from alkyl, halo, hydroxy, and cyano), alkoxy, halo, haloalkyl, haloalkoxy, alkoxycarbonyl, amino, alkylamino, dialkylamino, aryl, aralkyl, heterocyclyl, or heteroaryl; and (C) Ring R Ｂ The bridged heterocyclyl of R ｅ , R ｆ and R ｇ is substituted with R ｅ and R ｆ is independently selected from hydrogen, alkyl, alkoxy, hydroxy, cyano, halo, haloalkyl, and haloalkoxy, and R ｇ is hydrogen, alkyl, deuteroalkyl, cycloalkyl (optionally substituted with one or two substituents independently selected from alkyl, halo, hydroxy, or cyano), alkoxy, halo, haloalkyl, haloalkoxy, alkoxycarbonyl, oxo, amino, alkylamino, dialkylamino, aryl, aralkyl, heterocyclyl, or heteroaryl. or a pharma- ceutically acceptable salt thereof.

2. Ring R Ｂ is R ａ 2. The compound of claim 1, wherein R is a bridged cycloalkyl substituted with R, or a pharma- ceutically acceptable salt thereof.

3. Ring R Ｂ is R ａ 2. The compound of claim 1, wherein R is substituted cycloalkyl with R, or a pharma- ceutically acceptable salt thereof.

4. Ring R Ｂ is R ｅ , R ｆ and R ｇ 2. The compound of claim 1, which is a bridged heterocyclyl substituted with: or a pharma- ceutically acceptable salt thereof.

5. Ring R Ｂ is R ｂ , R ｃ and R ｄ 2. The compound of claim 1, wherein R is a heterocyclyl substituted with R, or a pharma- ceutically acceptable salt thereof.

6. R Ｂ The bridged cycloalkyl of 【Chemistry 303】 each bridged cycloalkyl is selected from R ａ 3. The compound of claim 1 or 2, or a pharma- ceutically acceptable salt thereof, substituted with:

7. Ring R Ｂ The bridged cycloalkyl of 【Chemistry 304】 and each bridged cycloalkyl is selected from R ａ 7. The compound of claim 1, 2 or 6, or a pharma- ceutically acceptable salt thereof, substituted with:

8. Ring R Ｂ The bridged cycloalkyl of 【Chemistry 305】 and R ａ 8. The compound of claim 1, 2, 6 or 7, or a pharma- ceutically acceptable salt thereof, substituted with:

9. Ring R Ｂ The cycloalkyl of 【Chemistry 306】 Each cycloalkyl ring is selected from R ａ 4. The compound of claim 1 or 3, or a pharma- ceutically acceptable salt thereof, substituted with:

10. Ring R Ｂ The cycloalkyl of 【Chemistry 307】 Each cycloalkyl is selected from R ａ 10. The compound of claim 1, 3 or 9, or a pharma- ceutically acceptable salt thereof, substituted with:

11. Ring R Ｂ The heterocyclyl of 【Chemistry 308】 Each heterocyclyl is selected from R ｂ , R ｃ and R ｄ 6. The compound of claim 1 or 5, or a pharma- ceutically acceptable salt thereof, substituted with:

12. Ring R Ｂ The heterocyclyl of 【Chemistry 309】 Each heterocyclyl is selected from R ｂ , R ｃ and R ｄ 12. The compound of claim 1, 5 or 11, or a pharma- ceutically acceptable salt thereof, substituted with:

13. Ring R Ｂ The bridged heterocyclyl of 【Chemistry 310】 and each bridged heterocyclyl is selected from R ｅ , R ｆ and R ｇ 5. The compound of claim 1 or 4, or a pharma- ceutically acceptable salt thereof, substituted with:

14. Ring R Ｂ The bridged heterocyclyl of 【Chemistry 311】 and each bridged heterocyclyl is selected from R ｅ , R ｆ and R ｇ 14. The compound of claim 1, 4 or 13, or a pharma- ceutically acceptable salt thereof, substituted with:

15. Ring R Ｂ The bridged heterocyclyl of 【Chemistry 312】 and each bridged heterocyclyl is selected from R ｅ , R ｆ and R ｇ 15. The compound of claim 1, 4 or 14, or a pharma- ceutically acceptable salt thereof, substituted with:

16. R ａ is hydrogen, chloro, fluoro, difluoromethyl, trifluoromethyl or hydroxymethyl, or a pharma- ceutically acceptable salt thereof.

17. R ａ 17. The compound according to any one of claims 1 to 3, 6 to 10, or 16, or a pharma- ceutically acceptable salt thereof, wherein:

18. R ａ is fluoro or chloro, or a pharma- ceutically acceptable salt thereof.

19. R ａ is difluoromethyl or trifluoromethyl, or a pharma- ceutically acceptable salt thereof.

20. R ａ The compound according to any one of claims 1 to 3 or 6 to 10, or a pharma- ceutically acceptable salt thereof, wherein: is hydrogen or haloalkyl.

21. R ａ The compound according to any one of claims 1 to 3 or 6 to 10, or a pharma- ceutically acceptable salt thereof, wherein: is hydrogen or halo.

22. R ａ is halo or haloalkyl, or a pharma- ceutically acceptable salt thereof.

23. Ring R Ｂ 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 or 3-(difluoromethyl)bicyclo[1.1.1]pentan-1-yl, or a pharma- ceutically acceptable salt thereof.

24. Ring R Ｂ is cyclobutyl, cyclopropyl, 1-(difluoromethyl)cyclobutyl, 1-(trifluoromethyl)cyclobutyl, 1-(difluoromethyl)-cyclopropyl, or 1-(trifluoromethyl)cyclopropyl, or a pharma- ceutically acceptable salt thereof.

25. Ring R Ｂ is 1-(difluoromethyl)-cyclobutyl, 1-(trifluoromethyl)cyclobutyl, 1-(difluoromethyl)cyclopropyl, or 1-(trifluoromethyl)-cyclopropyl, or a pharma- ceutically acceptable salt thereof.

26. R ｂ and R ｃ is independently selected from hydrogen, methyl, fluoro, chloro, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, hydroxy, and cyano, and R ｄ is selected from hydrogen, methyl, trideuteromethyl, 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-dioxidothietan-3-yl, 1,1-dioxidotetrahydro-2H-thiopyran-4-yl, benzyl, phenyl, pyridin-2-yl, pyridin-3-yl and pyridin-4-yl; and R ｅ and R ｆ is independently selected from hydrogen, methyl, fluoro, chloro, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, hydroxy, and cyano, and R ｇ is selected from hydrogen, methyl, trideuteromethyl, 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-dioxidothietan-3-yl, 1,1-dioxidotetrahydro-2H-thiopyran-4-yl, benzyl, phenyl, pyridin-2-yl, pyridin-3-yl and pyridin-4-yl, or a pharma- ceutically acceptable salt thereof.

27. R ｂ is hydrogen, R ｃ is selected from hydrogen, methyl, fluoro, chloro, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, hydroxy and cyano, and R ｄ is selected from hydrogen, methyl, trideuteromethyl, 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-dioxidothietan-3-yl, 1,1-dioxidotetrahydro-2H-thiopyran-4-yl, benzyl, phenyl, pyridin-2-yl, pyridin-3-yl and pyridin-4-yl; and R ｅ is hydrogen, R ｆ is selected from hydrogen, methyl, fluoro, chloro, difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, hydroxy and cyano, and R ｇ is selected from hydrogen, methyl, trideuteromethyl, 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-dioxidothietan-3-yl, 1,1-dioxidotetrahydro-2H-thiopyran-4-yl, benzyl, phenyl, pyridin-2-yl, pyridin-3-yl and pyridin-4-yl, or a pharma-ceutically acceptable salt thereof.

28. (i) Ring R Ｂ heterocyclyl 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 (ii) Ring R Ｂ The bridged heterocyclyl is 2-oxabicyclo[2.1.1]hexan-1-yl, 7-azabicyclo[2.2.1]heptan-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]heptan-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 3-(1,1-dioxidetetrahydro-2H-thiopyran-4-yl)-3,8-diazabicyclo[3.2.1]octan-3-yl, ...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-dioxidothietan-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-dioxido-3-thia-8-azabicyclo 27. The compound according to any one of claims 1, 4, 5, 11 to 15, or 26 to 28, which is selected from the group consisting of 3-cyclobutyl-3,8-diazabicyclo[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]heptan-7-yl, 4-(3,3-difluorocyclobutyl)-2,6-dimethylpiperazin-1-yl, 7-methyl-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl, and 3-cyclopropyl-3,8-diazabicyclo[3.2.1]octan-8-yl, or a pharma- ceutical acceptable salt thereof.

29. Ring R Ｂ or a pharma- ceutically acceptable salt thereof.

29. The compound of any one of claims 1, 4, 13, 14, 15, or 28, wherein the bridged heterocyclyl is 3-(3,3-difluorocyclobutyl)-3,8-diazabicyclo[3.2.1]octan-8-yl.

30. Ring R Ｂ 31. The compound of any one of claims 1, 4, 13, 14, 15 or 28, wherein the bridged heterocyclyl is 3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl.

31. Ring R Ａ is represented by formula (i) or (ii): 【Chemistry 313】 where alk is alkyl, and each ring R Ａ is R ４ and R ５ 31. The compound according to any one of claims 1 to 30, or a pharma- ceutically acceptable salt thereof, substituted with:

32. Ring R Ａ is represented by formula (i): 【Chemistry 314】 where alk is alkyl and R ４ is hydrogen, and R ５ is -SO ２ 32. The compound of any one of claims 1 to 31, or a pharma- ceutically acceptable salt thereof, which is fluoro or methyl attached at the carbon meta to the alk-substituted carbon.

33. Ring R Ａ is represented by formula (i): 【Chemistry 315】 where alk is alkyl and R ４ and R ５ The compound according to any one of claims 1 to 31, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

34. Ring R Ａ is the formula: 【Chemistry 316】 The compound according to any one of claims 1 to 33, wherein the ring is:

35. Ring R Ａ is represented by formula (ii): 【Chemistry 317】 The ring of formula (ii) is ４ and R ５ 32. The compound according to any one of claims 1 to 31, or a pharma- ceutically acceptable salt thereof, substituted with:

36. Ring R Ａ is represented by the formula (iii) or (iv): 【Chemistry 318】 and each ring is represented by R ４ and R ５ 31. The compound according to any one of claims 1 to 30, or a pharma- ceutically acceptable salt thereof, substituted with:

37. Ring R Ａ is the formula: 【Chemical 319】 37. The compound according to any one of claims 1 to 30 or 36, wherein the ring is: or a pharma- ceutically acceptable salt thereof.

38. Ring R Ａ is the formula: 【Chemistry 320】 The compound according to any one of claims 1 to 30, wherein the ring is:

39. 【Chemical 321】 teeth, 【Chemistry 322】 39. The compound according to any one of claims 1 to 38, wherein: 【Request 40】 【Chemical 323】 is (a1): 【Chemical 324】 40. The compound according to any one of claims 1 to 39, wherein:

41. R ２ and R ３ is independently selected from hydrogen, fluoro, chloro, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, propoxy, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, difluoromethoxy, and trifluoromethoxy; or a pharma- ceutically acceptable salt thereof.

42. R ２ and R ３ or a pharma- ceutically acceptable salt thereof. The compound of any one of claims 1 to 41, wherein: is independently selected from fluoro, chloro, cyclopropyl, methoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, and trifluoromethoxy.

43. R ２ is halo, cycloalkyl or haloalkyl, and R ３ is halo, alkoxy or haloalkoxy, or a pharma- ceutically acceptable salt thereof.

44. R ２ is fluoro, chloro, cyclopropyl, difluoromethyl or trifluoromethyl, and R ３ is fluoro, chloro, methoxy or difluoromethoxy, or a pharma- ceutically acceptable salt thereof. 【Request 45】 【Chemical 325】 is 2,6-difluorophenyl, 2-fluoro-6-trifluoromethylphenyl, 2-chloro-6-trifluoromethylphenyl, 2-difluoromethoxy-6-fluorophenyl, 2-difluoromethoxy-6-trifluoromethylphenyl, 2-methoxy-6-trifluoromethylphenyl, 2-fluoro-6-methoxyphenyl, 2-difluoromethyl-6-fluorophenyl, 2-cyclopropyl-6-fluorophenyl or 2,6-dichlorophenyl. The compound according to any one of claims 1 to 38, or a pharma- ceutically acceptable salt thereof. 【Request 46】 【Chemical 326】 The compound according to any one of claims 1 to 38, wherein is 2,6-difluorophenyl or 2-fluoro-6-trifluoromethylphenyl, or a pharma- ceutically acceptable salt thereof.

47. R １ or a pharma- ceutically acceptable salt thereof.

48. R １ or a pharma- ceutically acceptable salt thereof.

48. The compound of any one of claims 1 to 47, wherein:

49. 3. The compound of claim 2, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of: 【Table 71】 【Table 72】 【Table 73】 【Table 74】

50. 4. The compound of claim 3, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of: 【Table 75】 【Table 76】

51. 5. The compound of claim 4, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of: 【Table 77】 【Table 78】 【Table 79】 【Table 80】 【Table 81】 【Table 82】 【Table 83】

52. 6. The compound of claim 5, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of: 【Table 84】 【Table 85】 【Table 86】

53. 53. A pharmaceutical composition comprising a compound according to any one of claims 1 to 52, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

54. 54. A method of treating cancer in a patient comprising administering to said patient in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 53, or a pharma- ceutically acceptable salt thereof, in a pharmaceutical composition according to claim 53.

55. The method according to claim 54, wherein the compound according to any one of claims 1 to 53, or a pharma- ceutically acceptable salt thereof, in the pharmaceutical composition according to claim 53, is administered in combination with at least one other anticancer agent.

56. 56. The method of claim 54 or 55, 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, gastric 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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