Nitrogen-containing compound, pharmaceutical composition and application thereof

Abstract

The invention discloses a nitrogen-containing compound, a pharmaceutical composition and application of the nitrogen-containing compound. The present invention provides a compound represented by formula (I) or formula (II), a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof. The compound disclosed by the invention shows a good inhibition effect on KIF18A, and can be used as a KIF18A inhibitor for treating cancers. # imgabs0 #

Description

[0001] The present invention claims priority to PCT / CN2022 / 1393732 filed on December 16, 2022 and PCT / CN2023 / 085427 filed on March 31, 2023, the contents of which are incorporated herein in their entirety. Field of the Invention

[0002] The present invention relates to nitrogen-containing compounds, pharmaceutical compositions and uses thereof. Existing technology

[0003] Mitosis, or cell division, is an effective intervention point for treating cancer.

[0004] Approved antimitotic drugs are anticancer agents that inhibit microtubule function. Microtubules are protein aggregates formed by heterodimers of α-tubulin and β-tubulin and play a crucial role in the formation of the mitotic spindle and cytokinesis at the end of mitosis. Anticancer drugs targeting microtubules represent a proven approach to intervene in cancer cell proliferation. Taxanes are the most prominent class of antimitotic drugs and include paclitaxel (Taxol) and docetaxel (Taxotere). Vinca alkaloids are a class of microtubule-destabilizing agents and include vincristine, vinblastine, and vinorelbine. Other new anticancer drugs that bind to tubulin include ixabepilone and eribulin. These antimitotic agents prevent cancer cell proliferation by stabilizing or eliminating microtubules. This direct inhibition of microtubules leads to cell arrest and death through apoptosis, mitotic catastrophe, and lethal multipolar division. Paclitaxel (Paditaxel) is the first compound in the taxane class to be discovered. Later, a structural analog of paclitaxel, docetaxel, was discovered. Paclitaxel and docetaxel are commonly used to treat a variety of human malignancies, including ovarian cancer, breast cancer, head and neck cancer, lung cancer, gastric cancer, esophageal cancer, prostate cancer, and AIDS-related Kaposi's sarcoma. The primary side effect of taxanes is myelosuppression, primarily neutropenia, while other side effects include peripheral edema and neurotoxicity (peripheral neuropathy).

[0005] Consistent with this view, microtubule-targeting agents are effective therapeutic agents for a variety of tumors. Paclitaxel, a microtubule-stabilizing drug commonly used to treat solid tumors, was initially shown to induce cytotoxicity by preventing cells from completing mitosis. However, due to the adverse side effects associated with widespread inhibition of microtubule function, significant efforts have been expended to identify less toxic mitotic regulators in cancer patients. Although drugs targeting mitotic proteins required for the completion of cell division have shown promise in preclinical models, they have been largely unsuccessful in clinical trials. One possible explanation for the apparent paradox between the failure of mitosis-targeting strategies and the effective therapeutic effects of paclitaxel is that studies have shown that clinically relevant paclitaxel doses induce aberrant multipolar divisions in tumors rather than completely arresting mitosis. Therefore, efforts to mimic the effects of paclitaxel on mitotic cells need to refocus on identifying proteins that can be targeted to disrupt normal bipolar division, ideally in a tumor cell-specific manner.

[0006] KIF18A is thought to influence the dynamics of kinetochore microtubule plus ends, thereby controlling proper chromosome positioning and spindle tension. Depletion of human KIF18A leads to increased spindle length, increased metaphase chromosome swing frequency, and activation of the mitotic spindle assembly checkpoint in HeLa cervical cancer cells. KIF18A is a viable target for cancer therapy. KIF18A is overexpressed in various cancer types, including but not limited to colon, breast, lung, pancreatic, prostate, bladder, head, neck, cervix, and ovarian cancers. Furthermore, genetic deletion, knockout, or inhibition of KIF18A affects mitotic spindles in cancer cell lines. In particular, KIF18A inhibition has been found to induce mitotic cell arrest, a known vulnerability that can promote cell death in mitosis through apoptosis, mitotic catastrophe, or multipolarization-driven lethality, or death following interphase mitotic slippage. Consequently, there has been significant interest in identifying inhibitors of the KIF18A protein. Summary of the Invention

[0007] The present invention relates to a nitrogen-containing compound, a pharmaceutical composition and uses thereof. The compound of the present invention exhibits a good inhibitory effect on KIF18A and can be used as a KIF18A inhibitor for treating cancer.

[0008] The present disclosure provides a compound represented by formula (I) or formula (II), a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof;

[0009]

[0010] in,

[0011] Ring A is

[0012] Ring C is a pyridone ring, a pyridazin-3(2H)-one ring or a pyrazin-2(1H)-one ring;

[0013] m is 0, 1, 2, or 3;

[0014] R 1 are independently F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 deuterated alkyl;

[0015] Y is a bond, -C 1-4 Alkyl-, -C 0-4 Alkyl-NR 4a -C 0-4 Alkyl-, -C 0-4 Alkyl-OC 0-4 Alkyl-, -C 0-4 Alkyl-SC 0-4 Alkyl-, -C 0-4 Alkyl-(C=O)-C 0-4 Alkyl-, -C 0-4 Alkyl-(C=O)-OC 0-4 Alkyl-, -C 0-4 Alkyl-C(=O)NR 4a -C 0-4 Alkyl-, -C 0-4 Alkyl-NR 4a -C(=O)-C 0-4 Alkyl-, -C 0-4 Alkyl-S(=O)-C 0-4 Alkyl-, -C 0-4 Alkyl-S(=O)2-C 0-4 Alkyl-, -C 0-4 Alkyl-SO2NR 4a -C 0-4 Alkyl-, -C 0-4 Alkyl-NR 4a -SO2-C 0-4 Alkyl-, -C 0-4 Alkyl-NR 4a -S(=O)(=NH)-, or -C 0-4 Alkyl-S(=O)(=NH)-;

[0016] R 4a Is H or C 1-6 alkyl;

[0017] R 4 It is R 4-1 or R 4-2 ;

[0018] R 4-1 Selected from the group consisting of a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered polycyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, which is surrounded by 0, 1, 2 or 3 R 4-3 group substitution;

[0019] R 4-2 Selected from the group consisting of 0, 1, 2, 3, 4 or 5 selected from F, Cl, Br, -OR a 、-OC 1-4 Haloalkyl, CN, and C=CR 4 -3a R 4-3b C 1-6 alkyl;

[0020] X 1 N, O, S, CR X1 or NR X1 ;

[0021] X 2 N, O, S, CR X2 or NR X2 ;

[0022] R X2 It is H, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl, -YR 4 or -N=S(=O)-(R 5 )2;

[0023] 2R 5 to form a saturated or partially saturated 3-, 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms, 0, 1, 2 or 3 O atoms and 1, 2 or 3 S atoms in combination with the sulfur atom to which they are attached;

[0024] X 3 N, O, S, CR X3 or NR X3 ;

[0025] X 4 N, O, S, CR X4 or NR X4 ;

[0026] R X1 It is H, CN, F, Cl, Br, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl, OC1-6 Haloalkyl, -C(=O)-C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -S(=O)2-C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, or C 1-6 deuterated alkyl;

[0027] R X3 It is H, CN, F, Cl, Br, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl, OC 1-6 Haloalkyl, -C(=O)-C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -S(=O)2-C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, or C 1-6 deuterated alkyl;

[0028] R X4 It is H, CN, F, Cl, Br, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl, OC 1-6 Haloalkyl, -C(=O)-C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -S(=O)2-C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, or C 1-6 deuterated alkyl;

[0029] Or, R X1 and R X2 Yes, R X2 and R X3 Yes, or R X3 and R X4 Each independently combines with the atoms to which they are attached to form a saturated, partially saturated or unsaturated 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, which is surrounded by 0, 1, 2 or 3 R 4-3 group substitution;

[0030] L is -NR c C(=O)- or -C(=O)NR c -;

[0031] Rc It is H, C 1-4 Alkyl, or C 1-4 alkyl halide;

[0032] Ring B is Ring D, a 6-, 9- or 10-membered heteroaromatic ring containing 1, 2 or 3 atoms selected from N, O and S, a benzene ring or a naphthalene ring;

[0033] Ring D is a 5-membered heteroaromatic ring containing 1, 2 or 3 atoms selected from N, O and S, or a pyridone ring;

[0034] R 2 yes

[0035] Z 1 Is N or CR 2c ;

[0036] Z 2 It's CR 2d R 2e NR 2c , or -O-;

[0037] Each R 2a and R 2b are independently H, OH, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-4 Alkyl-OC 1-6 Alkyl, -C 0-4 Alkyl-OC 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, or C 3-6 Halogenated cycloalkyl;

[0038] Or, two adjacent R 2a The groups together with the carbon atoms to which they are attached form a saturated 3-, 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2, or 3 N atoms and 0, 1, or 2 atoms selected from O and S; which is surrounded by 0, 1, 2 or 3 R 2a-1 group substitution;

[0039] Alternatively, R on two non-adjacent carbon atoms 2a The groups, together with the carbon atoms to which they are attached, form a bridging moiety;

[0040] Or, R 2a and R 2b Together with the carbon atom to which they are attached, they form C=CR 2f R 2g ;

[0041] R 2c It is H, C 1-6Alkyl or C 3-6 Cycloalkyl;

[0042] Each R 2d and R 2e are independently H, OH, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-4 Alkyl-OC 1-6 Alkyl, -C 0-4 Alkyl-OC 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or C 3-6 Halogenated cycloalkyl;

[0043] Or, R 2d and R 2e Together with the carbon atoms to which they are attached, they form a saturated 3-, 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S; which is surrounded by 0, 1, 2 or 3 R 2a-1 group substitution;

[0044] Or, R 2d and R 2e Together with the carbon atom to which they are attached, they form C=CR 2f R 2g ;

[0045] Each R 2a-1 are independently OH, CN, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-4 Alkyl-OC 1-6 Alkyl, -C 0-4 Alkyl-OC 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, or C 3-6 Halogenated cycloalkyl;

[0046] R 2f and R 2 g is independently F, Cl, or Br;

[0047] R 3 It is F, Cl, Br, CN, -ZR 6 , or -N=S(=O)-(R 5 )2;

[0048] Z is a bond, -C 1-4 Alkyl-, -C 0-4 Alkyl-NR 7 -、-C 0-4 Alkyl-NR 7 -SO2-, -C0-4 Alkyl-SO2NR 7 -、-C 0-4 Alkyl-NR 7 -S(=O)(=NR a )-、-C 0-4 Alkyl-S-, -C 0-4 Alkyl-S(=O)-, -C 0-4 Alkyl-S(=O)2-, -C 0-4 Alkyl-S(=O)(=NR a )-、-C 0-4 Alkyl-O-, -C 0-4 Alkyl-C(=O)-, -C 0-4 Alkyl-C(=O)NR 7 -、-C 0-4 Alkyl-C=N(OH)-, -C 0-4 Alkyl-NR 7 C(=O)-, -C 0-4 Alkyl-P-, -C 0-4 Alkyl-P(=O)R a -, or -C 0-4 Alkyl-P(=O)2R a -;

[0049] R 7 Is H or C 1-6 alkyl;

[0050] R 6 It is R 6a or R 6b ;

[0051] R 6a Selected from the group consisting of a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered polycyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, which is surrounded by 0, 1, 2 or 3 R 6a-1 group substitution;

[0052] R 6b Selected from the group consisting of 0, 1, 2, 3, 4 or 5 selected from F, Cl, Br, -OR a 、-OC 1-4 Halogenated alkyl, NR a R a and CN groups substituted C 1-6 alkyl;

[0053] R 0 are independently F, Cl, Br, C 1-6 Alkyl, C 1-6Haloalkyl, or C 1-6 deuterated alkyl;

[0054] n is 0, 1, or 2;

[0055] Each R 4-3 and R 6a-1 are independently F, Cl, Br, CN, C 1-6 Alkyl, C 1-6 Alkyl-C=CR 2f R 2g 、C 1-6 Haloalkyl, -C 0-6 Alkyl-C 3-6 Cycloalkyl, -C 0-6 Alkyl-C 3-6 Cycloalkyl-C 1-6 Haloalkyl, -C 0-6 Alkyl-C 3-6 Halogenated cycloalkyl, -C 0-6 Alkyl-C 3-6 Cycloalkyl-CN, -C 0-6 Alkyl-C 3-6 Cycloalkyl-C 3-6 Cycloalkyl, -OR a 、-C 0-6 Alkyl-OC 1-6 Haloalkyl, -C(=O)R b 、-C(=O)OR a 、-C(=O)NR a R a 、-C(=NR a )NR a R a 、-OC(=O)OR a 、-OC(=O)NR a R a 、-OC 2-6 Alkyl NR a R a 、-OC 2-6 Alkyl OR a 、-SR a 、-S(=O)R b 、-S(=O)2R b 、-S(=O)2NR a R a 、-NR a R a 、-N(R a )C(=O)R b 、-N(R a )C(=O)OR b 、-N(R a)C(=O)NR a R a 、-N(R a )C(=NR a )NR a R a 、-N(R a )S(=O)2R b 、-N(R a )S(=O)2NR a R a 、-N(R a )C 2-6 Alkyl NR a R a 、-N(R a )C 2-6 Alkyl OR a 、-C 1-6 Alkyl NR a R a 、-C 1-6 Alkyl OR a 、-C 1-6 Alkyl N(R a )C(=O)R b 、-C 1-6 Alkyl OC(=O)R b 、-C 1-6 Alkyl C(=O)NR a R a 、-C 1-6 Alkyl C(=O)OR a , or oxo;

[0056] Or, two R 4-3 Together with the carbon atoms to which they are attached, they form C=CR 4-3a R 4-3b ;

[0057] R 4-3a and R 4-3b are independently F, Cl, or Br;

[0058] At each occurrence, R a are independently H or R b ;

[0059] R b Independently C 1-6 alkyl, phenyl or benzyl, wherein the C 1-6 The alkyl group is replaced by 0, 1, 2 or 3 groups selected from F, Cl, Br, -OH, -OC 1-4 Alkyl, -NH2, NHC 1-4 Alkyl, -OC(=O)C 1-4 Alkyl and -N(C 1-4Alkyl)C 1-4 and the phenyl or benzyl group is substituted by 0, 1, 2 or 3 groups selected from F, Cl, Br, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -OH, -OC 1-6 Alkyl, -NH2, -NHC 1-4 Alkyl, -OC(=O)C 1-6 Alkyl, and -N(C 1-6 Alkyl)C 1-6 Substitution of alkyl groups;

[0060] Ring E is

[0061] Y 1 N, CR Y1 , or NR Y1 ;

[0062] Y 2 N, CR Y2 , or NR Y2 ;

[0063] Y 3 N, CR Y3 , or NR Y3 ;

[0064] Y 4 N or CR Y4 ;

[0065] Y 5 N or CR Y5 ;

[0066] R Y1 and R Y2 to form a saturated, partially saturated or unsaturated 4-, 5- or 6-membered monocyclic ring or a 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered polycyclic ring containing 0, 1, 2, 3 or 4 nitrogen atoms and 0, 1 or 2 atoms selected from O and S, which is surrounded by 0, 1, 2 or 3 R 6a-1 Group substitution; R Y3 It is H, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 deuterated alkyl;

[0067] Or, R Y2 and R Y3The atoms to which they are attached are combined to form a saturated, partially saturated or unsaturated 4-, 5- or 6-membered monocyclic ring or a 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered polycyclic ring containing 0, 1, 2, 3 or 4 N atoms and 0, 1 or 2 atoms selected from O and S, and which is surrounded by 0, 1, 2 or 3 R 6a-1 Group substitution; R Y1 It is H, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 deuterated alkyl;

[0068] R Y4 It is H, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 deuterated alkyl;

[0069] R Y5 It is H, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 deuterated alkyl;

[0070] Ring F is selected from:

[0071] a) Ring F is Ring D;

[0072] b) Ring F is a pyridazine ring, a pyrazine ring or a pyrimidine ring;

[0073] c) Ring F is a benzene ring, and R Y2 and R Y3 The atoms to which they are attached are combined to form a saturated, partially saturated or unsaturated 4-, 5- or 6-membered monocyclic ring or a 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered polycyclic ring containing 0, 1, 2, 3 or 4 N atoms and 0, 1 or 2 atoms selected from O and S, and which is surrounded by 0, 1, 2 or 3 R 6a-1 Group substitution; R Y1 It is H, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 deuterated alkyl;

[0074] d) Ring F is a benzene ring, and for R Y1 and R Y2The atoms to which they are attached are combined to form a saturated, partially saturated or unsaturated 4-, 5- or 6-membered monocyclic ring or a 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered polycyclic ring containing 0, 1, 2, 3 or 4 N atoms and 2 atoms selected from O and S, and which is surrounded by 0, 1, 2 or 3 R 6a-1 Group substitution; R Y3 It is H, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 deuterated alkyl;

[0075] e) Ring F is a benzene ring, and no R Y1 and R Y2 The atoms to which they are attached are combined to form a saturated, partially saturated or unsaturated 4-, 5- or 6-membered monocyclic ring or a 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered polycyclic ring containing 0, 1, 2, 3 or 4 N atoms and 0, 1 or 2 atoms selected from O and S, and which is surrounded by 0, 1, 2 or 3 R 6a-1 Group substitution; R Y3 It is H, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 deuterated alkyl;

[0076] f) Ring F is a pyridine ring, and R Y1 and R Y2 The atoms to which they are attached are combined to form a saturated, partially saturated or unsaturated 4-, 5- or 6-membered monocyclic ring or a 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered polycyclic ring containing 0, 1, 2, 3 or 4 N atoms and 0, 1 or 2 atoms selected from O and S, and which is surrounded by 0, 1, 2 or 3 R 6a-1 Group substitution; R Y3 It is H, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 deuterated alkyl;

[0077] g) Ring F is a pyridine ring, and yes R Y2 and R Y3 The atoms to which they are attached are combined to form a saturated, partially saturated or unsaturated 4-, 5- or 6-membered monocyclic ring or a 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered polycyclic ring containing 0, 1, 2, 3 or 4 N atoms and 2 atoms selected from O and S, and which is surrounded by 0, 1, 2 or 3 R 6a-1Group substitution; R Y1 It is H, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 deuterated alkyl groups; and

[0078] h) Ring F is a pyridine ring, and no R Y2 and R Y3 The atoms to which they are attached are combined to form a saturated, partially saturated or unsaturated 4-, 5- or 6-membered monocyclic ring or a 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered polycyclic ring containing 0, 1, 2, 3 or 4 N atoms and 0, 1 or 2 atoms selected from O and S, and which is surrounded by 0, 1, 2 or 3 R 6a-1 Group substitution; R Y1 It is H, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Deuterated alkyl.

[0079] The present disclosure provides a compound represented by formula (I) or formula (II), a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof;

[0080]

[0081] in,

[0082] Ring A is

[0083] Ring C is a pyridone ring, a pyridazin-3(2H)-one ring or a pyrazin-2(1H)-one ring;

[0084] m is 0, 1, 2, or 3;

[0085] R 1 are independently F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 deuterated alkyl;

[0086] Y is a bond, -C 1-4 Alkyl-, -C 0-4 Alkyl-NR 4a -C 0-4 Alkyl-, -C 0-4 Alkyl-OC 0-4 Alkyl-, -C 0-4 Alkyl-SC 0-4 Alkyl-, -C 0-4 Alkyl-(C=O)-C 0-4Alkyl-, -C 0-4 Alkyl-(C=O)-OC 0-4 Alkyl-, -C 0-4 Alkyl-C(=O)NR 4a -C 0-4 Alkyl-, -C 0-4 Alkyl-NR 4a -C(=O)-C 0-4 Alkyl-, -C 0-4 Alkyl-S(=O)-C 0-4 Alkyl-, -C 0-4 Alkyl-S(=O)2-C 0-4 Alkyl-, -C 0-4 Alkyl-SO2NR 4a -C 0-4 Alkyl-, -C 0-4 Alkyl-NR 4a -SO2-C 0-4 Alkyl-, -C 0-4 Alkyl-NR 4a -S(=O)(=NH)-, or -C 0-4 Alkyl-S(=O)(=NH)-;

[0087] R 4a Is H or C 1-6 alkyl;

[0088] R 4 It is R 4-1 or R 4-2 ;

[0089] R 4-1 is selected from the group consisting of a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered polycyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, and which is surrounded by 0, 1, 2 or 3 R 4-3 group substitution;

[0090] R 4-2 Selected from the group consisting of 0, 1, 2, 3, 4 or 5 selected from F, Cl, Br, -OR a 、-OC 1-4 C substituted with haloalkyl and CN groups 1-6 alkyl;

[0091] X 1 N, O, S, CR X1 or NR X1 ;

[0092] X 2 N, O, S, CRX2 or NR X2 ;

[0093] R X2 It is H, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl, -YR 4 or -N=S(=O)-(R 5 )2;

[0094] 2R 5 to form a saturated or partially saturated 3-, 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms, 0, 1, 2 or 3 O atoms and 1, 2 or 3 S atoms in combination with the sulfur atom to which they are attached;

[0095] X 3 N, O, S, CR X3 or NR X3 ;

[0096] X 4 N, O, S, CR X4 or NR X4 ;

[0097] R X1 It is H, CN, F, Cl, Br, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl, OC 1-6 Haloalkyl, -C(=O)-C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -S(=O)2-C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, or C 1-6 deuterated alkyl;

[0098] R X3 It is H, CN, F, Cl, Br, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl, OC 1-6 Haloalkyl, -C(=O)-C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -S(=O)2-C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, or C 1-6 deuterated alkyl;

[0099] R X4It is H, CN, F, Cl, Br, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl, OC 1-6 Haloalkyl, -C(=O)-C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -S(=O)2-C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, or C 1-6 deuterated alkyl;

[0100] Or, R X1 and R X2 Yes, R X2 and R X3 Yes, or R X3 and R X4 The pairs are each independently combined with the atoms to which they are attached to form a saturated, partially saturated or unsaturated 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, and which is surrounded by 0, 1, 2 or 3 R 4-3 group substitution;

[0101] L is -NR c C(=O)- or -C(=O)NR c -;

[0102] R c It is H, C 1-4 Alkyl, or C 1-4 alkyl halide;

[0103] Ring B is Ring D, a 6-, 9- or 10-membered heteroaromatic ring containing 1, 2 or 3 atoms selected from N, O and S, a benzene ring or a naphthalene ring;

[0104] Ring D is a 5-membered heteroaromatic ring containing 1, 2 or 3 atoms selected from N, O and S, or a pyridone ring;

[0105] R 2 yes

[0106] Z 1 Is N or CR 2c ;

[0107] Z 2 It's CR 2d R 2e NR 2c , or -O-;

[0108] Each R 2a and R2b are independently H, OH, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-4 Alkyl-OC 1-6 Alkyl, -C 0-4 Alkyl-OC 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, or C 3-6 Halogenated cycloalkyl;

[0109] Or, two adjacent R 2a The groups together with the carbon atoms to which they are attached form a saturated 3-, 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S; and which is surrounded by 0, 1, 2 or 3 R 2a-1 group substitution;

[0110] Alternatively, R on two non-adjacent carbon atoms 2a The groups, together with the carbon atoms to which they are attached, form a bridging moiety;

[0111] R 2c It is H, C 1-6 Alkyl or C 3-6 Cycloalkyl;

[0112] Each R 2d and R 2e are independently H, OH, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-4 Alkyl-OC 1-6 Alkyl, -C 0-4 Alkyl-OC 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or C 3-6 Halogenated cycloalkyl;

[0113] Or, R 2d and R 2e Together with the carbon atoms to which they are attached, they form a saturated 3-, 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S; and which is surrounded by 0, 1, 2 or 3 R 2a-1 group substitution;

[0114] Each R 2a-1 are independently OH, CN, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-4 Alkyl-OC 1-6 Alkyl, -C 0-4 Alkyl-OC1-6 Halogenated alkyl, C 3-6 Cycloalkyl, or C 3-6 Halogenated cycloalkyl;

[0115] R 3 It is F, Cl, Br, CN, -ZR 6 , or -N=S(=O)-(R 5 )2;

[0116] Z is a bond, -C 1-4 Alkyl-, -C 0-4 Alkyl-NR 7 -、-C 0-4 Alkyl-NR 7 -SO2-, -C 0-4 Alkyl-SO2NR 7 -、-C 0-4 Alkyl-NR 7 -S(=O)(=NR a )-、-C 0-4 Alkyl-S-, -C 0-4 Alkyl-S(=O)-, -C 0-4 Alkyl-S(=O)2-, -C 0-4 Alkyl-S(=O)(=NR a )-、-C 0-4 Alkyl-O-, -C 0-4 Alkyl-C(=O)-, -C 0-4 Alkyl-C(=O)NR 7 -、-C 0-4 Alkyl-C=N(OH)-, -C 0-4 Alkyl-NR 7 C(=O)-, -C 0-4 Alkyl-P-, -C 0-4 Alkyl-P(=O)R a -, or -C 0-4 Alkyl-P(=O)2R a -;

[0117] R 7 Is H or C 1-6 alkyl;

[0118] R 6 It is R 6a or R 6b ;

[0119] R 6ais selected from the group consisting of a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered polycyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, and which is surrounded by 0, 1, 2 or 3 R 6a-1 group substitution;

[0120] R 6b Selected from the group consisting of 0, 1, 2, 3, 4 or 5 selected from F, Cl, Br, -OR a 、-OC 1-4 Halogenated alkyl, NR a R a and CN groups substituted C 1-6 alkyl;

[0121] R 0 are independently F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 deuterated alkyl;

[0122] n is 0, 1, or 2;

[0123] Each R 4-3 and R 6a-1 are independently F, Cl, Br, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkyl-C 3-6 Cycloalkyl, -C 0-6 Alkyl-C 3-6 Cycloalkyl-C 1-6 Haloalkyl, -C 0-6 Alkyl-C 3-6 Halogenated cycloalkyl, -OR a 、-C 0-6 Alkyl-OC 1-6 Haloalkyl, -C(=O)R b 、-C(=O)OR a 、-C(=O)NR a R a 、-C(=NR a )NR a R a 、-OC(=O)OR a 、-OC(=O)NR a R a 、-OC 2-6 Alkyl NR a R a 、-OC 2-6 Alkyl OR a 、-SRa 、-S(=O)R b 、-S(=O)2R b 、-S(=O)2NR a R a 、-NR a R a 、-N(R a )C(=O)R b 、-N(R a )C(=O)OR b 、-N(R a )C(=O)NR a R a 、-N(R a )C(=NR a )NR a R a 、-N(R a )S(=O)2R b 、-N(R a )S(=O)2NR a R a 、-N(R a )C 2-6 Alkyl NR a R a 、-N(R a )C 2-6 Alkyl OR a 、-C 1-6 Alkyl NR a R a 、-C 1-6 Alkyl OR a 、-C 1-6 Alkyl N(R a )C(=O)R b 、-C 1-6 Alkyl OC(=O)R b 、-C 1-6 Alkyl C(=O)NR a R a 、-C 1-6 Alkyl C(=O)OR a , or oxo;

[0124] At each occurrence, R a are independently H or R b ;

[0125] R b Independently C 1-6 alkyl, phenyl or benzyl, wherein the C 1-6 The alkyl group is replaced by 0, 1, 2 or 3 groups selected from F, Cl, Br, -OH, -OC 1-4 Alkyl, -NH2, NHC1-4 Alkyl, -OC(=O)C 1-4 Alkyl and -N(C 1-4 Alkyl)C 1-4 and the phenyl or benzyl group is substituted by 0, 1, 2 or 3 groups selected from F, Cl, Br, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -OH, -OC 1-6 Alkyl, -NH2, -NHC 1-4 Alkyl, -OC(=O)C 1-6 Alkyl, and -N(C 1-6 Alkyl)C 1-6 Substitution of alkyl groups;

[0126] Ring E is

[0127] Y 1 N, CR Y1 , or NR Y1 ;

[0128] Y 2 N, CR Y2 , or NR Y2 ;

[0129] Y 3 N, CR Y3 , or NR Y3 ;

[0130] Y 4 N or CR Y4 ;

[0131] Y 5 N or CR Y5 ;

[0132] R Y1 and R Y2 The atoms to which they are attached are combined to form a saturated, partially saturated or unsaturated 4-, 5- or 6-membered monocyclic ring or a 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered polycyclic ring containing 0, 1, 2, 3 or 4 N atoms and 0, 1 or 2 atoms selected from O and S, and which is surrounded by 0, 1, 2 or 3 R 6a-1 Group substitution; R Y3 It is H, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 deuterated alkyl;

[0133] Or, R Y2 and R Y3The atoms to which they are attached are combined to form a saturated, partially saturated or unsaturated 4-, 5- or 6-membered monocyclic ring or a 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered polycyclic ring containing 0, 1, 2, 3 or 4 N atoms and 0, 1 or 2 atoms selected from O and S, and which is surrounded by 0, 1, 2 or 3 R 6a-1 Group substitution; R Y1 It is H, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 deuterated alkyl;

[0134] R Y4 It is H, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 deuterated alkyl;

[0135] R Y5 It is H, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 deuterated alkyl;

[0136] Ring F is selected from:

[0137] a) Ring F is Ring D;

[0138] b) Ring F is a pyridazine ring, a pyrazine ring or a pyrimidine ring;

[0139] c) Ring F is a benzene ring, and R Y2 and R Y3 The atoms to which they are attached are combined to form a saturated, partially saturated or unsaturated 4-, 5- or 6-membered monocyclic ring or a 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered polycyclic ring containing 0, 1, 2, 3 or 4 N atoms and 0, 1 or 2 atoms selected from O and S, and which is surrounded by 0, 1, 2 or 3 R 6a-1 Group substitution; R Y1 It is H, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 deuterated alkyl;

[0140] d) Ring F is a benzene ring, and for R Y1 and R Y2The atoms to which they are attached are combined to form a saturated, partially saturated or unsaturated 4-, 5- or 6-membered monocyclic ring or a 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered polycyclic ring containing 0, 1, 2, 3 or 4 N atoms and 2 atoms selected from O and S, and which is surrounded by 0, 1, 2 or 3 R 6a-1 Group substitution; R Y3 It is H, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 deuterated alkyl;

[0141] e) Ring F is a benzene ring, and no R Y1 and R Y2 The atoms to which they are attached are combined to form a saturated, partially saturated or unsaturated 4-, 5- or 6-membered monocyclic ring or a 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered polycyclic ring containing 0, 1, 2, 3 or 4 N atoms and 0, 1 or 2 atoms selected from O and S, and which is surrounded by 0, 1, 2 or 3 R 6a-1 Group substitution; R Y3 It is H, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 deuterated alkyl;

[0142] f) Ring F is a pyridine ring, and R Y1 and R Y2 The atoms to which they are attached are combined to form a saturated, partially saturated or unsaturated 4-, 5- or 6-membered monocyclic ring or a 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered polycyclic ring containing 0, 1, 2, 3 or 4 N atoms and 0, 1 or 2 atoms selected from O and S, and which is surrounded by 0, 1, 2 or 3 R 6a-1 Group substitution; R Y3 It is H, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 deuterated alkyl;

[0143] g) Ring F is a pyridine ring, and yes R Y2 and R Y3 The atoms to which they are attached are combined to form a saturated, partially saturated or unsaturated 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2, 3 or 4 N atoms and 2 atoms selected from O and S, or a 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered polycyclic ring, which is surrounded by 0, 1, 2 or 3 R 6a-1Group substitution; R Y1 It is H, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 deuterated alkyl groups; and

[0144] h) Ring F is a pyridine ring, and no R Y2 and R Y3 The atoms to which they are attached are combined to form a saturated, partially saturated or unsaturated 4-, 5- or 6-membered monocyclic ring or a 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered polycyclic ring containing 0, 1, 2, 3 or 4 N atoms and 0, 1 or 2 atoms selected from O and S, and which is surrounded by 0, 1, 2 or 3 R 6a-1 Group substitution; R Y1 It is H, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Deuterated alkyl.

[0145] In a preferred embodiment, some groups in the compound represented by formula (I) or formula (II), its solvate, its pharmaceutically acceptable salt, or its pharmaceutically acceptable salt solvate can be defined as follows, and the unmentioned groups are as described in any one of the other embodiments (referred to as "in one embodiment") (), in R 1 、R 4a 、R 4-2 、R X1 、R X2 、R X3 、R X4 、R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 2a-1 、R 7 、R 6b 、R 0 、R 4-3 、R 6a-1 、R b 、R Y1 、R Y3 、R Y4 and R Y5 In each C 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl, ethyl, n-propyl or tert-butyl.

[0146] In one embodiment, in R 1 、RX1 、R X2 、R X3 、R X4 、R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 2a-1 、R 0 、R 4-3 、R 6a-1 、R b 、R Y1 、R Y3 、R Y4 and R Y5 In each C 1-6 The alkyl halide is independently CH2F, CHF2, CF3, CH2CF3, CH2CH2Cl, CH2CH2CF3, CH2CH2CHF2, CH2CF2CF3, C(CH3)2CH2CF3 or C(CH3)2CF3.

[0147] In a preferred embodiment, some groups in the compound represented by formula (I) or formula (II), its solvate, its pharmaceutically acceptable salt, or its pharmaceutically acceptable salt solvate can be defined as follows, and the unmentioned groups are as described in any one of the other embodiments (referred to as "in one embodiment"), (), in R 1 、R 4a 、R 4-2 、R X1 、R X2 、R X3 、R X4 、R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 2a-1 、R 7 、R 6b 、R 0 、R 4-3 、R 6a-1 、R b 、R Y1 、R Y3 、R Y4 and R Y5 In each C 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl, ethyl, n-propyl or tert-butyl.

[0148] In one embodiment, in R 1 、R X1 、RX2 、R X3 、R X4 、R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 2a-1 、R 0 、R 4-3 、R 6a-1 、R b 、R Y1 、R Y3 、R Y4 and R Y5 In each C 1-6 Haloalkyl is independently CH2F, CHF2, CF3, CH2CF3, CH2CH2Cl, CH2CH2CF3, CH2CH2CHF2, CH2CF2CF3, C(CH3)2CH2CF3 or C(CH3)2CF3.

[0149] In one embodiment, in R 1 、R X1 、R X2 、R X3 、R X4 、R 0 、R Y1 、R Y3 、R Y4 and R Y5 wherein each C1-6 deuterated alkyl group is independently CH2D, CHD2, CD3, CH2CD3, CH2CH2CD3 and CH2CH2CHD2, for example CD3.

[0150] In one embodiment, in Y and Z, each -C 1-4 Alkyl- is independently -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)2-.

[0151] In one embodiment, Y, R 2a 、R 2b 、R 2d 、R 2e 、R 2a-1 and Z, each -C 0-4 Alkyl is independently a bond, -CH2- or -CH2CH2-.

[0152] In one embodiment, in R X1 、R X3 、R X4 、R 2a 、R 2b 、R 2d 、R2e 、R 2a-1 and R b OC 1-6 Alkyl is independently OCH3, OCH2CH3 or OCH2CH2CH3.

[0153] In one embodiment, in R X1 、R X3 、R X4 、R 2a 、R 2b 、R 2d 、R 2e 、R 2a-1 、R b 、R 4-3 and R 6a-1 OC 1-6 Haloalkyl is independently OCHF2, OCH2F, OCF3, OCH2CF3, OCH2CHF2, OCH2CH2F or OCH2CH2CF3. In one embodiment, in R X1 、R X3 、R X4 、R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 2a-1 、R 4-3 and R 6a-1 C 3-6 Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, For example, cyclopropyl.

[0154] In one embodiment, for

[0155] In one embodiment, m is 0 or 1.

[0156] In one embodiment, R 1 Independently C 1-6 alkyl.

[0157] In one embodiment, Y is a bond, -C 1-4 Alkyl- or -C 0-4 Alkyl-S(=O)2-C 0-4 alkyl-.

[0158] In one embodiment, R 4-1is a saturated 3-, 4-, 5-, 6-membered monocyclic ring or a 5-, 6-, 7-, 8-, 9-, 10-membered polycyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, and which is replaced by 0, 1, 2 or 3 R 4-3 Group substitution.

[0159] In one embodiment, R 4-2 Selected from the group consisting of C substituted with 0, 1, 2, 3, 4 or 5 groups selected from F, Cl and Br 1-6 alkyl.

[0160] In one embodiment, R 4-2 Selected from the group consisting of 0, 1, 2, 3, 4 or 5 selected from C=CR 4-3a R 4-3b C 1-6 alkyl.

[0161] In one embodiment, R 4-2 Selected from the group consisting of 0, 1, 2, 3, 4 or 5 selected from F, Cl, Br and C=CR 4-3a R 4-3b C 1-6 alkyl.

[0162] In one embodiment, R 4 It is R 4-1 .

[0163] In one embodiment, R X1 It is H, CN, F, Cl, Br, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl, OC 1-6 Halogenated alkyl, -S(=O)2-C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 deuterated alkyl;

[0164] R X2 YR 4 ;

[0165] R X3 It is H, CN, F, Cl, Br, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl, OC 1-6 Halogenated alkyl, -S(=O)2-C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 deuterated alkyl;

[0166] RX4 It is H, CN, F, Cl, Br, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl, OC 1-6 Halogenated alkyl, -S(=O)2-C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 deuterated alkyl;

[0167] Or, alternatively, R X1 and R X2 Yes, R X2 and R X3 Right or R X3 and R X4 Each independently combines with the atom to which they are attached to form a saturated, partially saturated or unsaturated 5- or 6-membered monocyclic ring containing 0 or 1 N atom, which is surrounded by 0, 1, 2 or 3 R 4-3 Group substitution.

[0168] In one embodiment, each R 4-3 are independently F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkyl-C 3-6 Cycloalkyl, -C 0-6 Alkyl-C 3-6 Cycloalkyl-C 1-6 Haloalkyl, -C 0-6 Alkyl-C 3-6 Halogenated cycloalkyl or -OR a .

[0169] In one embodiment, two R 4-3 The pairs combine with the carbon atoms to which they are attached to form C=CR 4-3a R 4 -3b .

[0170] In one embodiment, each R 4-3 are independently F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkyl-C 3-6 Cycloalkyl, -C 0-6 Alkyl-C 3-6 Cycloalkyl-C 1-6 Haloalkyl, -C 0-6 Alkyl-C 3-6 Halogenated cycloalkyl or -OR a ; or two R 4-3The pairs combine with the carbon atoms to which they are attached to form C=CR 4-3a R 4-3b .

[0171] In one embodiment, by The 5-membered cyclic group composed of the ring atoms in is a 5-membered heteroaromatic ring. Preferably, the 5-membered heteroaromatic ring contains 1, 2 or 3 N atoms, 0 or 1 O atoms and 0 or 1 S atoms.

[0172] In one embodiment, yes

[0173] In one embodiment, R X1 It is H, CN, F, Cl, Br, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl, OC 1-6 Halogenated alkyl, -S(=O)2-C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 Deuterated alkyl.

[0174] In one embodiment, R X3 It is H, CN, F, Cl, Br, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl, OC 1-6 Halogenated alkyl, -S(=O)2-C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 Deuterated alkyl.

[0175] In one embodiment, R X4 It is H, CN, F, Cl, Br, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl, OC 1-6 Halogenated alkyl, -S(=O)2-C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 Deuterated alkyl.

[0176] In one embodiment, It is a 5-membered aromatic ring containing 1, 2 or 3 N atoms, 0 or 1 O atom, and 0 or 1 S atom.

[0177] In one embodiment, R c It’s H.

[0178] In one embodiment, Ring B is Ring D, a 6-membered heteroaryl ring containing 1, 2, or 3 N atoms, or a benzene ring.

[0179] In one embodiment, ring D is a 5-membered heteroaromatic ring containing 1, 2 or 3 atoms selected from N, or a pyridone ring; preferably, ring D is

[0180] In one embodiment, Ring B is

[0181] In one embodiment, Ring F is

[0182] In one embodiment, R 2 yes

[0183] In one embodiment, R 2a It is H, or two adjacent R 2a The groups together with the carbon atoms to which they are attached form a saturated 3-, 4-, 5- or 6-membered monocyclic carbocyclic ring; which is surrounded by 0, 1, 2 or 3 R 2a-1 Group substitution, or, R on two non-adjacent carbon atoms 2a The groups, together with the carbon atoms to which they are attached, form a bridging moiety.

[0184] In one embodiment, R 2a It is H, or two adjacent R 2a The groups together with the carbon atoms to which they are attached form a saturated 3-, 4-, 5- or 6-membered monocyclic carbocyclic ring; which is surrounded by 0, 1, 2 or 3 R 2a-1 Group substitution, or, R on two non-adjacent carbon atoms 2a The groups together with the carbon atoms to which they are attached form a bridging moiety; or, R 2a and R 2b Together with the same carbon atom to which they are attached, they form C=CR 2f R 2 g.

[0185] In one embodiment, R 2b It’s H.

[0186] In one embodiment, R 2c It’s H.

[0187] In one embodiment, R 2d and R 2e Each independently is F, Cl, or Br, or R 2d and R 2eTogether with the carbon atoms to which they are attached, they form a saturated 3-, 4-, 5- or 6-membered monocyclic carbocyclic ring; which is supported by 0, 1, 2 or 3 R 2a-1 Group substitution.

[0188] In one embodiment, R 2d and R 2e Together with the carbon atom to which they are attached, they form C=CR 2f R 2 g.

[0189] In one embodiment, R 2d and R 2e Each independently is F, Cl, or Br, or R 2d and R 2e Together with the carbon atoms to which they are attached, they form a saturated 3-, 4-, 5- or 6-membered monocyclic carbocyclic ring; which is supported by 0, 1, 2 or 3 R 2a-1 Group substitution, or R 2d and R 2e Together with the carbon atom to which they are attached, they form C=CR 2f R 2 g.

[0190] In one embodiment, each R 2a-1 are independently F, Cl, Br or C 1-6 alkyl.

[0191] In one embodiment, R 2 yes R 2d and R 2e Together with the carbon atoms to which they are attached, they form a saturated 3-, 4-, 5- or 6-membered monocyclic carbocyclic ring; which is surrounded by 0, 1 or 2 R 2a-1 Group substitution, two adjacent R 2a The groups together with the carbon atoms to which they are attached form a saturated 3-, 4-, 5- or 6-membered monocyclic carbocyclic ring; which is surrounded by 0, 1 or 2 R 2a-1 Group substitution.

[0192] In one embodiment, R 2 yes R 2d and R 2e Together with the carbon atoms to which they are attached, they form a saturated 3-, 4-, 5- or 6-membered monocyclic carbocyclic ring; which is surrounded by 0, 1 or 2 R 2a-1 Group substitution, or R 2d and R 2e Together with the carbon atom to which they are attached, they form C=CR 2f R 2g ; Two adjacent R 2aThe groups together with the carbon atoms to which they are attached form a saturated 3-, 4-, 5- or 6-membered monocyclic carbocyclic ring; which is surrounded by 0, 1 or 2 R 2a-1 Group substitution.

[0193] In one embodiment, R 3 Yes-ZR 6 .

[0194] In one embodiment, Z is -C 0-4 Alkyl-NR 7 -SO2-, -C 0-4 Alkyl-SO2NR 7 -、-C 0-4 Alkyl-S(=O)2-, or -C 0-4 Alkyl-S(=O)(=NR a )-; preferably, Z is -NR 7 -SO2-, -SO2NR 7 -、-C 0-1 Alkyl-S(=O)2- or -C 0-1 Alkyl-S(=O)(=NR a )-.

[0195] In one embodiment, R 7 It’s H.

[0196] In one embodiment, R 6a is a saturated 3-, 4-, 5- or 6-membered monocyclic ring containing 0 or 1 N atoms and 0 or 1 O atoms, which is surrounded by 0, 1, 2 or 3 R 6a-1 Group substitution.

[0197] In one embodiment, R 6b Selected from the following group: 0 or 1 selected from -OR a and NR a R a C 1-6 alkyl.

[0198] In one embodiment, n is 0.

[0199] In one embodiment, each R 6a-1 Each independently is C 1-6 Alkyl or -OR a .

[0200] In one embodiment, each R 6a-1 Each independently is C 1-6 Alkyl-C=CR 2f R 2g 、C 1-6 Haloalkyl, -C 0-6Alkyl-C 3-6 Cycloalkyl, -C 0-6 Alkyl-C 3-6 Cycloalkyl-C 1-6 Haloalkyl, -C 0-6 Alkyl-C 3-6 Halogenated cycloalkyl, -C 0-6 Alkyl-C 3-6 Cycloalkyl-CN, -C 0-6 Alkyl-C 3-6 Cycloalkyl-C 3-6 Cycloalkyl or In one embodiment, each R 6a-1 Independently C 1-6 Alkyl, C 1-6 Alkyl-C=CR 2f R 2g 、C 1-6 Haloalkyl, -C 0-6 Alkyl-C 3-6 Cycloalkyl, -C 0-6 Alkyl-C 3-6 Cycloalkyl-C 1-6 Haloalkyl, -C 0-6 Alkyl-C 3-6 Halogenated cycloalkyl, -C 0-6 Alkyl-C 3-6 Cycloalkyl-CN, -C 0-6 Alkyl-C 3-6 Cycloalkyl-C 3-6 Cycloalkyl, OR a .

[0201] In one embodiment, R b Independently C 1-6 alkyl.

[0202] In one embodiment, R Y3 It is H; R Y4 is H, F, Cl, or C 1-6 Alkyl; R Y5 It is H; R Y1 and R Y2 The atoms to which they are attached are combined to form a saturated, partially saturated or unsaturated 5-membered monocyclic or 8-membered polycyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 O atoms, which is surrounded by 0, 1, 2 or 3 R 6a-1 group substitution;

[0203] or R Y1 It is H; R Y4 is H, F, Cl, or C 1-6 Alkyl; R Y5 It is H; R Y2and R Y3 The atoms to which they are attached are combined to form a saturated, partially saturated or unsaturated 5-membered monocyclic or 8-membered polycyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 O atoms, which is surrounded by 0, 1, 2 or 3 R 6a-1 Group substitution.

[0204] In one embodiment, by The 6-membered cyclic group composed of the ring atoms in is a 6-membered aromatic ring; preferably, the 6-membered aromatic ring contains 0, 1 or 2 N atoms.

[0205] In one embodiment, yes

[0206] In one embodiment, yes

[0207] In one embodiment, yes

[0208] In one embodiment, R Y1 、R Y3 、R Y4 and R Y5 are each independently H, F or C 1-6 Preferably, R Y1 、R Y3 and R Y5 is H, and R Y4 Is H, F or C 1-6 alkyl.

[0209] In one embodiment, Ring E is

[0210]

[0211] In one embodiment, Ring E is

[0212] In one embodiment, Ring E is

[0213]

[0214]

[0215]

[0216] In one embodiment, -YR 4 yes

[0217] In one embodiment, -YR 4 yes

[0218] In one embodiment, -YR 4 yes

[0219] In one embodiment, Ring A is

[0220]

[0221] In one embodiment, Ring A is

[0222] In one embodiment, Ring A is

[0223]

[0224]

[0225] In one embodiment, R 2 yes

[0226] In one embodiment, R 2 yes In one embodiment, R 2 yes

[0227] In one embodiment, R 3 yes

[0228] In one embodiment, R 3 yes

[0229] In one embodiment, R 3 yes

[0230] In one embodiment, the compound represented by formula (I) is preferably a compound represented by formula (Ia):

[0231]

[0232] Among them, ring A, ring B, R c 、R 0 、R 2 , Z, R 6 and n are as defined in any one of the present invention.

[0233] In one embodiment, the compound represented by formula (I) is preferably a compound represented by formula (I-1), formula (I-2), formula (I-3), formula (I-4), formula (I-5) or formula (I-6):

[0234]

[0235]

[0236] Among them, X 4 、R X3 , Y, R 4 , Ring B and R 1 The definition of is as defined in any one of the present invention.

[0237] In one embodiment, the compound represented by formula (II) is preferably a compound represented by formula (II-A):

[0238]

[0239] Among them, ring E, ring F, R c 、R 0 、R 2 , Z, R 6 and n are as defined in any one of the present invention.

[0240] In one embodiment, the compound represented by formula (II) is preferably a compound represented by formula (II-1) or formula (II-3):

[0241]

[0242] Among them, Y 4 、R 6a-1 、R Y5 and Ring F The definition of is as defined in any one of the present invention. Preferably, Y 4 Is N or CRY4 In one embodiment, the compound represented by formula (II) is preferably a compound represented by formula (II-2) or formula (II-4):

[0243]

[0244] Among them, R 6a-1 、R Y1 、R Y4 and R Y5 The definition of is as defined in any one of the present invention, and ring F is not a pyridine ring.

[0245] In one embodiment, the compound of formula (I) is:

[0246]

[0247]

[0248]

[0249]

[0250]

[0251] In one embodiment, the compound of formula (II) is:

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258] The present invention also provides a pharmaceutical composition comprising a compound represented by formula (I) or formula (II), a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0259] The present disclosure also provides use of a compound represented by formula (I) or formula (II), a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof in the preparation of a KIF18A inhibitor.

[0260] The present disclosure also provides use of a compound represented by formula (I) or formula (II), a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing cancer.

[0261] The present disclosure also provides a method for treating and / or preventing cancer in a subject in need thereof, comprising: administering to the subject an effective amount of a compound represented by formula (I) or formula (II), a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof.

[0262] Preferably, the cancer is breast cancer, bladder cancer, colorectal cancer, prostate cancer, cervical cancer, endometrial cancer, lung cancer, liver cancer, hyperdiploid acute lymphoblastic leukemia cells, ovarian cancer and glioblastoma cells.

[0263] The present invention also provides a compound represented by formula (III) or formula (IV);

[0264]

[0265] Among them, ring A, ring B, ring E, ring F, L, R 0 、R 2 and n are as defined in any one of the present invention.

[0266] In one embodiment, the compound of formula (III) is:

[0267]

[0268] In one embodiment, the compound of formula (IV) is:

[0269]

[0270]

[0271] Unless otherwise specified, the terms used in this application are defined as follows.

[0272] The term "pharmaceutically acceptable" means relatively non-toxic, safe, and suitable for patients.

[0273] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base. When the compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When the compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. For more information, please refer to the Handbook of Pharmaceutical Salts: Properties, Selection and Use (P. Heinrich Stahl, Camille, G. Wermuth, 2011, second revised edition).

[0274] The term "solvate" refers to a substance formed by the combination of a compound and a solvent. Solvents can be divided into stoichiometric solvents and non-stoichiometric solvents.

[0275] The term "pharmaceutically acceptable salt solvate" refers to a substance formed by combining a compound containing a pharmaceutically acceptable acid or base and a solvent. The amount of solvent can be stoichiometric or non-stoichiometric.

[0276] “C a-b "Alkyl" refers to an alkyl group containing a minimum of a and a maximum of b carbon atoms in a branched or straight chain relationship or any combination of the three, where a and b represent integers. C0 alkyl represents a direct bond. C 1-6 Examples of alkyl groups include, but are not limited to, the following:

[0277]

[0278] “C a-b "Haloalkyl" refers to an alkyl group as described above wherein any number (at least one) of the hydrogen atoms attached to the alkyl chain are replaced by F, Cl, Br or I.

[0279] "Carbocycle" or "carbocyclic" refers to a ring by itself or in combination with other terms and, unless otherwise indicated, means "Carbocycle". a-b Examples of "carbocycle" or "carbocyclic" include cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, cyclobutene, cyclohexene, etc.

[0280] "Heteroaryl" refers to an unsaturated monovalent group having the specified number of heteroatoms (e.g., 1, 2, or 3), the specified number of ring atoms (e.g., 5-, 6-, 9-, or 10-membered), and the specified types of heteroatoms (one or more independently selected from N, O, and S), which is monocyclic or polycyclic, the polycyclic rings sharing two atoms and one bond between the monocyclic rings, and is aromatic in each ring.

[0281] The term "treat" refers to eliminating the cause or alleviating the symptoms of a disease.

[0282] The term "prevention" refers to reducing the risk of developing a disease.

[0283] The term "pharmaceutically acceptable carrier" refers to all substances contained in a pharmaceutical preparation other than the active pharmaceutical ingredient, and is generally divided into excipients and additives. For details, see the "Handbook of Pharmaceutical Excipients" in the Pharmacopoeia of the People's Republic of China (2020 edition) (Paul Jsheskey, Bruno C Hancock, Gary Pmoss, David J Goldfarb, 2020, 9th edition).

[0284] The term "effective amount" refers to an amount sufficient to be taken by a patient to effectively treat a disease. The effective amount will vary depending on the type of compound, the type of disease, the severity of the disease, the age of the patient, etc., but can be appropriately adjusted by those skilled in the art.

[0285] Detailed Description of the Preferred Embodiments

[0286] Example 1: N-(1-(4,4-difluorocyclohexyl)-5-methyl-1H-pyrazol-3-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0287]

[0288]

[0289] Step 1: At 0 ° C, MsCl (2.5 g, 22.0 mmol) was added to a DCM (30 mL) solution of compound 4,4-difluorocyclohexan-1-ol (2 g, 14.7 mmol) and TEA (4.45 g, 44.1 mmol). The reaction mixture was stirred at 25 ° C for 2 hours. The solvent was evaporated and diluted with water (50 mL). The mixture was extracted with DCM (50 mL * 3). The organic layer was washed with saturated NH4Cl aqueous solution (30 mL), brine (30 mL), dried over anhydrous Na2SO4 and concentrated under vacuum to give a crude product 4,4-difluorocyclohexyl methanesulfonate (3 g) as a yellow oil. The crude product was used directly without further purification.

[0290] 1 H NMR (400MHz, CDCl3) δppm 4.91 (d, J = 2.4Hz, 1H), 3.05 (s, 3H), 2.16–1.94 (m, 8H).

[0291] Step 2: To a solution of 2-fluoro-4-iodobenzoic acid (5 g, 18.8 mmol) in DMSO (50 mL) was added 6-azaspiro[2.5]octane hydrochloride (3.05 g, 20.6 mmol) and K2CO3 (3.89 g, 28.2 mmol). The reaction mixture was stirred at 140°C for 10 hours. The reaction mixture was cooled to room temperature, poured into water (150 mL), and extracted with hexane (50 mL*3). The aqueous layer was acidified to pH = 4 with 1N HCl. The precipitate was collected by filtration and then washed with water (100 mL) and then with cold MeCN (30 mL). The solid was dried under vacuum to give 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (5 g, 14 mmol, yield: 74.5%) as a gray solid.

[0292] 1 H NMR (400MHz, DMSO-d6): δppm 8.09(s,1H),7.77–7.75(m,1H),7.71–7.69(m,1H),3.12–3.09(m,4H),1.56–1.54(m,4H),0.43(s,4H).

[0293] MS: (ESI) m / z = 358.1 [M+H] + .

[0294] Step 3: At 0 ° C, oxalyl chloride (350 mg, 2.80 mmol) was added to a solution of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (500 mg, 1.40 mmol) and 1 drop of DMF in DCM (10 mL). The reaction mixture was stirred at room temperature under N2 for 1 hour. The mixture was concentrated under reduced pressure to give 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride (510 mg, crude product) as a yellow solid. The crude product was used directly without further purification.

[0295] Step 4: To a mixture solution of 5-methyl-3-nitro-1H-pyrazole (1.5 g, 11.8 mmol) and 4,4-difluorocyclohexylmethanesulfonate (2.5 g, 11.8 mmol) in DMF (30 mL) was added K2CO3 (4.9 g, 35.4 mmol). The mixture was stirred at 80 ° C for 16 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL * 3). The organic layer was washed with water (30 mL) and brine (30 ml), dried over anhydrous Na2SO4, and concentrated under vacuum to obtain a crude product. It was purified by flash chromatography (elution gradient: PE EA = 5: 1) to give a white solid compound 1- (4,4-difluorocyclohexyl) -5-methyl-3-nitro-1H-pyrazole (1.2 g, crude product).

[0296] MS (ESI) m / z = 246.0 [M+H] + .

[0297] Step 5: To a solution of 1-(4,4-difluorocyclohexyl)-5-methyl-3-nitro-1H-pyrazole (1.2 g, crude) in THF (30 mL) was added Pd / C (300 mg). The reaction mixture was stirred at 25 ° C for 2 hours. The mixture was filtered and the filtrate was concentrated in vacuo to afford 1-(4,4-difluorocyclohexyl)-5-methyl-1H-pyrazol-3-amine (0.85 g, crude) as a yellow solid.

[0298] MS (ESI) m / z = 216.3 [M+H] + .

[0299] Step 6: To a solution of 1-(4,4-difluorocyclohexyl)-5-methyl-1H-pyrazol-3-amine (800 mg, crude) in DCE (30 mL) was added 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride (664 mg, 1.86 mmol), T3P (1418 mg, 4.46 mmol, 50% w / w in EtOAc), and DIEA (1438 mg, 11.2 mmol). The reaction mixture was stirred at 85° C. for 16 hours. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL*3). The organic layer was washed with water (30 mL), brine (30 ml), dried over anhydrous Na2SO4, and concentrated under vacuum to give the crude product, which was purified by silica gel chromatography (elution gradient: PE:EA=5:1) to give a yellow oily compound N-(1-(4,4-difluorocyclohexyl)-5-methyl-1H-pyrazol-3-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (800 mg, crude).

[0300] MS (ESI) m / z = 555.0 [M+H] + .

[0301] Step 7: To a solution of 2-hydroxyethane-1-sulfonamide (180.6 mg, 1.44 mmol) in DMF (10 mL) was added CuI (68.5 mg, 0.36 mmol), K3PO4 (765 mg, 3.61 mmol), and sarcosine (64 mg, 0.72 mmol). The reaction mixture was stirred at 50°C for 10 minutes. Then, N-(1-(4,4-difluorocyclohexyl)-5-methyl-1H-pyrazol-3-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (400 mg, crude) was added. The reaction mixture was stirred at 110°C for 16 hours. The reaction mixture was stirred at 25°C for 16 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL*3). The organic layer was washed with water (15 mL), brine (15 ml), dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product, which was purified by preparative HPLC (Gemini-C18 column, 5 μm silica, 21 mm diameter, 150 mm length) using decreasingly polar mixtures of water (containing 0.05% FA) and MeCN as eluents (45%-60%) to give the title compound N-(1-(4,4-difluorocyclohexyl)-5-methyl-1H-pyrazol-3-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (45.9 mg, 0.083 mmol) as an off-white solid.

[0302] 1 H NMR(400MHz,DMSO-d6)δppm 12.78(s,1H),7.97(d,J=8.6Hz,1H),7.21(d,J=1.6Hz,1H),7.08(dd,J=8.6,1.8Hz,1H),6.40(s,1H),4.36(s,1H),3.75(t,J=6.4H z,2H),3.33(t,J=6.4Hz,2H),2.93(d,J=4.8Hz,4H),2.34–2.14(m,5H),2.17–1.92(m,5H),1.91(s,2H),1.66(s,4H),0.36(s,4H).

[0303] MS (ESI) m / z = 552.2 [M+H] + .

[0304] Example 2:

[0305] N-(1-(3,3-Difluorocyclobutyl)-5-methyl-1H-pyrazol-3-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0306]

[0307] Step 1: To a solution of 3,3-difluorocyclobutan-1-ol (1.0 g, 9.25 mmol) in DCM (20 mL) was added TsCl (2.11 g, 11.10 mmol), DMAP (225.7 mg, 1.85 mmol), and DIEA (3.58 g, 27.76 mmol). The reaction mixture was stirred at 25°C for 16 hours. The mixture was diluted with water (20 mL) and extracted with dichloromethane (20 mL*3). The organic layers were combined, washed with 1N HCl (20 mL*3) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product, 3,3-difluorocyclobutyl-4-methylbenzenesulfonate (1.5 g, 5.73 mmol, yield: 61.95%), as a yellow oil.

[0308] Step 2: To a solution of 5-methyl-3-nitro-1H-pyrazole (500 mg, 3.93 mmol) in DMF (30 mL) was added 3,3-difluorocyclobutyl-4-methylbenzenesulfonate (1.03 g, 3.93 mol) and K2CO3 (1.63 g, 11.80 mmol). The reaction mixture was stirred at 80 ° C for 16 hours. The mixture was diluted with ethyl acetate (20 mL), washed with water (20 mL * 3) and brine (20 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (elution gradient: petroleum ether / ethyl acetate 5 / 1, v / v) to give 1-(3,3-difluorocyclobutyl)-5-methyl-3-nitro-1H-pyrazole (300 mg, 1.38 mmol, yield: 35.11%) as a yellow oil.

[0309] MS (ESI) m / z = 218.1 [M+H] + .

[0310] Step 3: To a solution of 1-(3,3-difluorocyclobutyl)-5-methyl-3-nitro-1H-pyrazole (300 mg, 1.38 mmol) in THF (10 mL) was added 10% Pd / C (50 mg). The reaction mixture was stirred at 25°C under an atmosphere of H2 for 4 hours. The mixture was filtered and the filtrate was concentrated in vacuo to give the crude product, 1-(3,3-difluorocyclobutyl)-5-methyl-1H-pyrazol-3-amine (220 mg, 1.18 mmol, yield: 85.5%), as a yellow oil.

[0311] MS (ESI) m / z = 188.1 [M+H] + .

[0312] Step 4: To a solution of 2-fluoro-4-iodobenzoic acid (5 g, 18.8 mmol) in DMSO (50 mL) was added 6-azaspiro[2.5]octane hydrochloride (3.05 g, 20.6 mmol) and K2CO3 (3.89 g, 28.2 mmol). The reaction mixture was stirred at 140 ° C for 10 hours. The reaction mixture was cooled to room temperature, poured into water (150 mL), and extracted with hexane (50 mL*3). The aqueous layer was acidified to pH = 4 with 1N HCl. The precipitate was collected by filtration, washed with water (100 mL), and then washed with cold MeCN (30 mL) to give 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (5 g, 14 mmol, 74.5% yield) as a gray solid.

[0313] 1 H NMR (400MHz, DMSO-d6): δppm 8.09(s,1H),7.77–7.75(m,1H),7.71–7.69(m,1H),3.12–3.09(m,4H),1.56–1.54(m,4H),0.43(s,4H).

[0314] MS: (ESI) m / z = 358.1 [M+H] + .

[0315] Step 5: To a solution of 1-(3,3-difluorocyclobutyl)-5-methyl-1H-pyrazol-3-amine (220 mg, 1.18 mmol) in DMF (10 mL) was added 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (251.7 mg, 0.71 mmol), HATU (446.9 mg, 1.18 mmol), and DIEA (455.7 mg, 3.53 mmol). The reaction mixture was stirred at 25°C for 16 hours. The mixture was diluted with ethyl acetate (20 mL) and washed with water (20 mL*3) and brine (20 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (elution gradient: elution gradient: petroleum ether / ethyl acetate 5 / 1, v / v) to give the product N-(1-(3,3-difluorocyclobutyl)-5-methyl-1H-pyrazol-3-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (180 mg, 0.34 mmol, yield: 28.81%) as a yellow oil.

[0316] MS (ESI) m / z = 527.1 [M+H] + .

[0317] Step 6: To a solution of 2-hydroxyethane-1-sulfonamide (85.6 mg, 0.68 mmol) in DMF (10 mL) was added CuI (32.7 mg, 0.17 mmol), KPO (362.5 mg, 1.71 mmol), and sarcosine (30.4 mg, 0.34 mmol). Under a nitrogen atmosphere, the reaction mixture was stirred at 50°C for 10 minutes. N-(1-(3,3-difluorocyclobutyl)-5-methyl-1H-pyrazol-3-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (180 mg, 0.34 mmol) was added, and the reaction mixture was stirred at 110°C for 2 hours. The mixture was diluted with ethyl acetate (10 mL) and washed with water (10 mL x 2) and brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by preparative HPLC (Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length) using decreasingly polar mixtures of water (containing 0.1% FA) and MeCN as eluents (30-65) to give the title compound N-(1-(3,3-difluorocyclobutyl)-5-methyl-1H-pyrazol-3-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (41.8 mg, 0.08 mmol, 23.53% yield) as a white solid.

[0318] 1 H NMR(400MHz,DMSO-d6)δppm 12.88(s,1H),7.94(d,J=8.6Hz,1H),7.18(d,J=1.6Hz,1H),7.05(dd,J=8.6,1.6Hz,1H),6.39(s,1H),4.87–4.78(m,1H),3 .71(t,J=6.4Hz,2H),3.35–3.30(m,4H),3.21–3.05(m,4H),2.91(t,J=5.0Hz,4H),2.23(s,3H),1.65(s,4H),0.33(s,4H).

[0319] MS (ESI) m / z = 524.2 [M+H] + .

[0320] Example 3:

[0321] 4-((2-Hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(1-(3,3,3-trifluoropropyl)-1H-indazol-6-yl)benzamide

[0322]

[0323] Step 1: To a solution of 6-nitro-1H-indazole (1 g, 6.13 mmol) in DMF (30 mL) was added 3,3,3-trifluoropropyl-4-methylbenzenesulfonate (2.5 g, 9.33 mmol) and Cs2CO3 (3 g, 9.33 mmol). The mixture was stirred at 80°C for 3 hours. The mixture was diluted with ethyl acetate (200 mL), washed with water (50 mL*2) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 3 / 1, v / v) to give 6-nitro-1-(3,3,3-trifluoropropyl)-1H-indazole (1.5 g, crude) as a yellow solid.

[0324] MS (ESI) m / z = 260.0 [M+H] + .

[0325] Step 2: Iron powder (1.06 g, 19.3 mmol) and NH4Cl (1.02 g, 19.3 mmol) were added to a mixture of 6-nitro-1-(3,3,3-trifluoropropyl)-1H-indazole (1 g, crude product) in ethanol (20 mL) / H2O (4 mL). The mixture was stirred at 70 ° C for 3 hours. The mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was diluted with water (20 mL) and extracted with dichloromethane (50 mL*3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 10 / 1, v / v) to obtain a yellow solid compound 1-(3,3,3-trifluoropropyl)-1H-indazole-6-amine (280 mg).

[0326] MS (ESI) m / z = 230.2 [M+H] + .

[0327] Step 3: To a solution of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (521 mg, 1.23 mmol, prepared in Example 1), DIEA (315 mg, 2.44 mmol), and HATU (555 mg, 1.46 mmol) in DMF (10 mL) was added 1-(3,3,3-trifluoropropyl)-1H-indazol-6-amine (280 mg, 1.22 mmol). The mixture was stirred at room temperature for 4 hours. The residue was diluted with ethyl acetate (100 mL) and washed with water (50 mL x 2) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 3 / 1, v / v) to give 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)-N-(1-(3,3,3-trifluoropropyl)-1H-indazol-6-yl)benzamide (450 mg, yield: 64.8%) as an off-white solid.

[0328] MS (ESI) m / z = 569.1 [M+H] + .

[0329] Step 4: To a solution of 2-hydroxyethane-1-sulfonamide (66 mg, 0.53 mmol) in DMF (10 mL) was added CuI (25 mg, 0.13 mmol), KPO (280 mg, 1.32 mmol), and sarcosine (24 mg, 0.26 mmol). The reaction mixture was stirred at 50°C for 10 minutes, followed by the addition of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)-N-(1-(3,3,3-trifluoropropyl)-1H-indazol-6-yl)benzamide (150 mg, 0.26 mmol). The reaction mixture was stirred at 110°C for 16 hours. The residue was diluted with ethyl acetate (100 mL) and washed with water (50 mL x 2) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by preparative HPLC (Gemini-C18 column, 5 μm silica, 21.2 mm diameter, 150 mm length) using decreasingly polar mixtures of water (containing 0.05% FA) and MeCN as eluents (45-70%) to give the title compound 4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(1-(3,3,3-trifluoropropyl)-1H-indazol-6-yl)benzamide (32.9 mg, yield: 22.1%) as a white solid.

[0330] 1H NMR (400MHz, DMSO-d6): δppm 11.77(s,1H),8.34(s,1H),8.05(s,1H),7.86(d,J=8.4Hz,1H),7.77(d,J=8.8Hz,1H),7.31–7.29(m,1H),7.18(d,J=1.6Hz,1H), 7.06–7.03(m,1H),4.60(t,J=6.4Hz,2H),3.77(t,J=6.4Hz,2H),3.35–3.34(m,2H),3.01–2.88(m,6H),1.54(s,4H),0.34(s,4H).

[0331] MS (ESI) m / z = 566.2 [M+H] + .

[0332] Example 4:

[0333] N-(1-(4,4-difluorocyclohexyl)-5-methyl-2-oxo-1,2-dihydropyridin-3-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0334]

[0335] Step 1: To a solution of 5-methyl-3-nitropyridin-2(1H)-one (600 mg, 3.89 mmol) and 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (950 mg, 3.89 mol) in MeCN / EtOH (18 / 2 mL) was added TEA (1180 mg, 11.7 mmol), Cu(OAc) (708 mg, 3.89 kmol) and 4A MS (100 mg) under O2. The mixture was stirred at 80°C for 16 hours. The mixture was filtered and the filtrate was concentrated in vacuo to give the crude product. Purification by preparative TLC (elution gradient: petroleum ether / EtOAc, 1 / 1, v / v) gave compound 1-(4,4-difluorocyclohex-1-en-1-yl)-5-methyl-3-nitropyridin-2(1H)-one (380 m, yield: 38.0%) as a yellow oil.

[0336] MS (ESI) m / z = 271.1 [M+H] + .

[0337] Step 2: Pd / C (100 mg) was added to a solution of 1-(4,4-difluorocyclohex-1-en-1-yl)-5-methyl-3-nitropyridin-2(1H)-one (380 mg, 1.41 mmol) in THF (10 mL) under H2. The mixture was stirred at 25°C for 48 hours. The mixture was filtered and the filtrate was concentrated in vacuo to give 3-amino-1-(4,4-difluorocyclohexyl)-5-methylpyridin-2(1H)-one (220 mg, crude) as a yellow oil.

[0338] MS (ESI) m / z = 243.2 [M+H] + .

[0339] Step 3: To a solution of 3-amino-1-(4,4-difluorocyclohexyl)-5-methylpyridin-2(1H)-one (220 mg, 0.91 mmol) in pyridine (10 mL) was added 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride (205 mg, 0.54 mmol, prepared in Example 1). The reaction mixture was stirred at 25°C for 16 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (25 mL x 3). The organic layer was washed with water (25 mL) and brine (25 mL), dried over anhydrous NaSO, and concentrated in vacuo to give a crude product, which was purified by silica gel chromatography (elution gradient: PE:EA = 5:1) to afford N-(1-(4,4-difluorocyclohexyl)-5-methyl-2-oxo-1,2-dihydropyridin-3-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (200 mg) as a yellow solid in a 37.9% yield.

[0340] MS (ESI) m / z = 582.0 [M+H] + .

[0341] Step 4: To a solution of 2-hydroxyethane-1-sulfonamide (86.1 mg, 0.69 mmol) in DMF (10 mL) were added CuI (32.7 mg, 0.17 mmol), KPO (364.6 mg, 1.72 mmol), and sarcosine (30.6 mg, 0.34 mmol). The reaction mixture was stirred at 50°C for 10 minutes. Then, N-(1-(4,4-difluorocyclohexyl)-5-methyl-2-oxo-1,2-dihydropyridin-3-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (200 mg, 0.34 mmol) was added. The reaction mixture was stirred at 110°C for 16 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 3). The organic layer was washed with water (15 mL) and brine (15 ml), dried over anhydrous Na2SO4 and concentrated under vacuum to give the crude product, which was purified by preparative HPLC (Gemini-C18 column, 5u silica, 21 mm diameter, 150 mm length) using decreasingly polar mixtures of water (containing 0.05% FA) and MeCN as eluents 50-60% to give the title compound N-(1-(4,4-difluorocyclohexyl)-5-methyl-2-oxo-1,2-dihydropyridin-3-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (19 mg, yield: 40.0%) as a white solid.

[0342] 1 H NMR(400MHz,DMSO-d6)δppm 11.83(s,1H),8.39(d,J=2.0Hz,1H),7.87(d,J=8.4Hz,1H),7.28(d,J=0. 8Hz,1H),7.16(s,1H),7.01(d,J=8.4Hz,1H),4.94(t,J=12.0Hz,1H),3.74 (t,J=6.4Hz,2H),3.30(d,J=6.4Hz,2H),2.92(t,J=5.2Hz,4H),2.22–2.0 7(m,7H),1.99–1.93(m,2H),1.76–1.71(m,2H),1.63(s,4H),0.32(s,4H).

[0343] MS (ESI) m / z = 579.2 [M+H] + .

[0344] Example 5:

[0345] N-(2,2-Dimethylbenzo[d][1,3]dioxol-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0346]

[0347] Step 1: To a solution of methyl 2,3-dihydroxybenzoate (6 g, 35.7 mmol) and acetone (3.11 g, 53.5 mmol) in toluene (200 mL) was added PCl3 (5.9 g, 42.8 mmol). The mixture was stirred at 50 ° C for 16 hours. The mixture was extracted with ethyl acetate (100 mL * 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 10 / 1, v / v) to obtain compound methyl 2,2-dimethylbenzo[d][1,3]dioxole-4-carboxylate (5 g, yield: 47.6%) as a white solid.

[0348] MS (ESI) m / z = 209.1 [M+H] + .

[0349] Step 2: To a solution of methyl 2,2-dimethylbenzo[d][1,3]dioxole-4-carboxylate (2 g, 9.6 mmol) in MeOH (5 ml) was added a solution of LiOH (2.01 g, 47.9 mmol) in H2O (10 ml). The mixture was stirred at 25°C for 16 hours. The reaction was diluted with water (100 mL). The mixture was adjusted to pH = 4 with 1N HCl and extracted with ethyl acetate (100 mL*3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 2 / 1, v / v) to give compound 2,2-dimethylbenzo[d][1,3]dioxole-4-carboxylic acid (1.5 g, yield: 74.1%) as a white solid.

[0350] MS (ESI) m / z = 195.1 [M+H] + .

[0351] Step 3: To a solution of 2,2-dimethylbenzo[d][1,3]dioxole-4-carboxylic acid (1 g, 5.1 mmol) in dioxane (50 ml) was added DPPA (2.11 g, 7.6 mmol) and TEA (1.55 g, 15.3 mmol). Under a nitrogen atmosphere, the mixture was stirred at 25°C for 2 hours. Phenylmethanol (1.1 g, 10.2 mmol) was added. Under a nitrogen atmosphere, the mixture was stirred at 80°C for 2 hours. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 10 / 1, v / v) to give compound (2,2-dimethylbenzo[d][1,3]dioxol-4-yl)benzylcarbamate (1 g, yield: 62.7%) as a yellow oil.

[0352] MS (ESI) m / z = 300.1 [M+H] + .

[0353] Step 4: To a solution of benzyl (2,2-dimethylbenzo[d][1,3]dioxol-4-yl)carbamate (1 g, 3.3 mmol) in MeOH (50 ml) was added Pd / C (1.05 g, 9.9 mmol). The mixture was stirred at 25°C under a hydrogen atmosphere for 16 hours. The solution was filtered and the filtrate was concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 3 / 1, v / v) to give 2,2-dimethylbenzo[d][1,3]dioxol-4-amine (500 mg, yield: 87.9%) as a yellow oil.

[0354] MS (ESI) m / z = 166.1 [M+H] + .

[0355] Step 5: To a solution of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (324.4 mg, 0.91 mmol, prepared in Example 1) in DMF (20 ml) was added HATU (414 mg, 1.09 mmol) and DIEA (176 mg, 1.36 mmol). The mixture was stirred at 25°C for 30 minutes. 2,2-dimethylbenzo[d][1,3]dioxol-4-amine (150 mg, 0.91 mmol) was then added. The mixture was stirred at 25°C for 16 hours. The mixture was diluted with water (40 mL) and extracted with ethyl acetate (30 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 5 / 1, v / v) to give compound N-(2,2-dimethylbenzo[d][1,3]dioxol-4-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (400 mg, yield: 82.9%) as a white solid.

[0356] 1 H NMR(400MHz,DMSO-d6)δppm 12.20(s,1H),7.99(dd,J=8.5,0.8Hz,1H),7.81(dd,J=11.9,4.9Hz,2H),7.71(dd,J=8.3,1.6Hz,1H),6.81(t, J=8.2Hz,1H),6.64(dd,J=7.8,0.9Hz,1H),2.99(t,J=5.2Hz,4H),1.72(s,6H),1.63–1.60(m,4H),0.37(s,4H).

[0357] MS (ESI) m / z = 505.0 [M+H] + .

[0358] Step 6: To a solution of 2-hydroxyethane-1-sulfonamide (74.4 mg, 0.59 mmol) in DMF (10 ml) were added CuI (28.3 mg, 0.15 mmol), sarcosine (53.0 mg, 0.59 mol), and K3PO4 (315.7 mg, 1.49 mmol). Under a nitrogen atmosphere, the mixture was stirred at 50°C for 10 minutes. Then, N-(2,2-dimethylbenzo[d][1,3]dioxol-4-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (150 mg, 0.30 mmol) was added. Under a nitrogen atmosphere, the mixture was stirred at 110°C for 2 hours. The mixture was diluted with water (40 mL) and extracted with ethyl acetate (30 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by preparative HPLC (Gemini-C18 column, 5 μm silica, 21 mm diameter, 150 mm length) using decreasingly polar mixtures of water (containing 0.05% FA) and MeCN as eluents (30-70) to give the title compound N-(2,2-dimethylbenzo[d][1,3]dioxol-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (40 mg, yield: 26.5%) as a white solid.

[0359] 1 H NMR(400MHz,DMSO-d6)δppm 12.18(s,1H),10.19(s,1H),8.03(dd,J=11.6,8.2Hz,2H),7.28(d,J=2.0Hz,1H),7.11(dd,J=8.6,2.1Hz,1H),6.80(t,J=8.2Hz,1H),6.62(dd ,J=7.8,0.9Hz,1H),4.96–4.92(m,1H),3.77–3.73(m,2H),3.37–3.33( m,2H),2.97–2.93(m,4H),1.73(s,6H),1.65–1.55(m,4H),0.38(s,4H).

[0360] MS (ESI) m / z = 502.2 [M+H] + .

[0361] Example 6:

[0362] 4-((2-Hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(5-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide

[0363]

[0364]

[0365] Step 1: To a solution of tert-butyl 3-bromo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (350 mg, 1.15 mmol) in dioxane (30 mL) were added diphenylcarbamate (251.2 mg, 1.38 mmol), t-BuONa (166.4 mg, 1.73 mmol), Pd2(dba)3 (105.7 mg, 0.12 mmol), and Xantphos (66.8 mg, 0.12 mmol). Under a nitrogen atmosphere, the mixture was stirred at 90°C for 16 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 1 / 1, v / v) to give compound 3-((benzhydryl)amino)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (450 mg, yield: 91.7%) as a white solid.

[0366] MS (ESI) m / z = 403.1 [M+H] + .

[0367] Step 2: To a solution of tert-butyl 3-((benzhydryl)amino)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (400 mg, 0.99 mmol) in MeOH (30 mL) was added AcONa (243.9 mg, 2.97 mmol) and NH2OH-HCl (137.8 mg, 1.98 mmol). Under a nitrogen atmosphere, the mixture was stirred at 25°C for 2 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: dichloromethane / methanol, 10 / 1, v / v) to give compound 3-amino-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (230 mg, yield: 92.1%) as a white solid.

[0368] MS (ESI) m / z = 239.1 [M+H] + .

[0369] Step 3: To a solution of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (328.4 mg, 0.92 mmol, prepared in Example 1) in DMF (20 mL) were added HATU (419.5 mg, 1.10 mmol) and DIEA (178.2 mg, 1.38 mmol). The mixture was stirred at 25°C for 30 minutes. Then, tert-butyl 3-amino-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (220 mg, 0.92 mmol) was added. The mixture was stirred at 25°C for 1 hour. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (40 mL*3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 10 / 1, v / v) to give compound 3-(4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamido)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (450 mg, yield: 80.3%) as a white solid.

[0370] MS (ESI) m / z = 578.0 [M+H] + .

[0371] Step 4: To a solution of compound 3-(4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamido)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylic acid tert-butyl ester (400 mg, 0.69 mmol) in DCM (10 mL) was added 4M HCl in dioxane (5 mL). The mixture was stirred at 25 ° C for 16 hours. The mixture was concentrated under vacuum. The residue was washed with DCM (15 mL) and filtered, and the filter cake was collected to give compound 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)-N-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-yl)benzamide (320 mg, yield: 92.1%) as a white solid.

[0372] MS (ESI) m / z = 478.0 [M+H] + .

[0373] Step 5: To a solution of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)-N-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (300 mg, 0.63 mmol) in dioxane (50 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (219.8 mg, 0.94 mmol) and DIEA (162.4 mg, 1.26 mmol). The mixture was stirred at 70°C for 16 hours. The mixture was diluted with ethyl acetate (100 mL) and washed with water (50 mL*2) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 5 / 1, v / v) to give compound 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)-N-(5-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (300 mg, yield: 81.0%) as a white solid.

[0374] 1 H NMR(400MHz,DMSO-d6)δppm 10.62(s,1H),7.69(s,1H),7.54(d,J=1.4Hz,1H),7.52(dd,J=8.1,1.5Hz,1H),7.44(d,J=8.0Hz,1H),4.10(t,J=5. 4Hz,2H),3.95(s,2H),3.46–3.42(m,2H),3.18(t,J=5.4Hz,2H),3.06–2.92(m,4H),1.52–1.40(m,4H),0.31(s,4H).

[0375] MS (ESI) m / z = 560.0 [M+H] + .

[0376] Step 6: To a solution of 2-hydroxyethane-1-sulfonamide (67.1 mg, 0.54 mmol) in DMF (15 mL) were added CuI (25.5 mg, 0.13 mmol), sarcosine (47.8 mg, 0.54 mmol), and KPO (284.7 mg, 1.34 mmol). Under a nitrogen atmosphere, the mixture was stirred at 50°C for 10 minutes. Then, 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)-N-(5-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (150 mg, 0.27 mmol) was added. Under a nitrogen atmosphere, the mixture was stirred at 110°C for 2 hours. The mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL x 2) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by preparative HPLC (Gemini-C18 column, 5μ silica, 21.2 mm diameter, 150 mm length) using decreasingly polar mixtures of water (containing 0.1% FA) and MeCN as eluents (30-60) to give the title compound 4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(5-(2,2,2-trifluoroethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl)benzamide (40 mg, yield: 24.5%) as a white solid.

[0377] 1 H NMR(400MHz,DMSO-d6)δppm 10.85(s,1H),7.75(d,J=8.5Hz,1H),7.70(s,1H),7.11(d,J=2.0Hz,1H),6.98(dd,J=8.5,2.0Hz,1H),4.10(t,J=5.4Hz,2H),3.96(s,2H),3. 75(t,J=6.6Hz,2H),3.45(q,J=10.0Hz,2H),3.29(d,J=6.6Hz,2H),3.18(t,J=5.4Hz,2H),3.00–2.90(m,4H),1.50–1.48(m,4H),0.34(s,4H).

[0378] MS (ESI) m / z = 557.1 [M+H] + .

[0379] Example 7:

[0380] N-(1-(4,4-difluorocyclohexyl)-5-methyl-1H-pyrazol-3-yl)-6-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide

[0381]

[0382] Step 1: To a solution of 6-bromo-2-fluoronicotinic acid (300 mg, 1.36 mmol) in MeCN (20 mL) was added 6-azaspiro[2.5]octane hydrochloride (241.6 mg, 1.64 mmol) and DIEA (352.5 mg, 2.73 mmol). The mixture was stirred at 50°C for 16 hours. The reaction mixture was diluted with H2O (60 mL) and extracted with ethyl acetate (30 mL*3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 2 / 1, v / v) to give 6-bromo-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid (400 mg, 1.22 mmol, yield: 89.7%) as a white solid.

[0383] MS (ESI) m / z = 311.1, 313.1 [M+H] + .

[0384] Step 2: To a solution of 6-bromo-2-(6-azaspiro[2.5]octan-6-yl)nicotinic acid (144.6 mg, 0.47 mmol) in DMF (5 mL) was added HATU (212.0 mg, 0.56 mmol) and DIEA (90.1 mg, 0.70 mmol). The mixture was stirred at 25°C for 5 minutes. 1-(4,4-difluorocyclohexyl)-5-methyl-1H-pyrazol-3-amine (100 mg, 0.47 mmol) (prepared in Example 1) was added. The mixture was stirred at 25°C for 1 hour. The reaction mixture was diluted with H2O (30 mL) and extracted with ethyl acetate (30 mL*3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 3 / 2, v / v) to give 6-bromo-N-(1-(4,4-difluorocyclohexyl)-5-methyl-1H-pyrazol-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (100 mg, 0.18 mmol, yield: 38.30%) as a white solid.

[0385] MS (ESI) m / z = 508.0, 510.0 [M+H] + .

[0386] Step 3: To a solution of 2-hydroxyethane-1-sulfonamide (74.4 mg, 0.59 mmol) in DMF (10 mL) were added CuI (28.3 mg, 0.15 mmol), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (53.0 mg, 0.60 mmol), and K3PO4 (315.7 mg, 1.49 mmol). Under a nitrogen atmosphere, the mixture was stirred at 50°C for 10 minutes. Then, 6-bromo-N-(1-(4,4-difluorocyclohexyl)-5-methyl-1H-pyrazol-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (150 mg, 0.30 mmol) was added to the mixture. The mixture was stirred at 110°C for 2 hours. The reaction mixture was diluted with H2O (30 mL) and extracted with ethyl acetate (50 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by preparative HPLC (Gemini-C18 column, 5 μm silica, 21 mm diameter, 150 mm length) using decreasingly polar mixtures of water (containing 0.1% FA) and MeCN as eluents (20-60) to afford the title compound, N-(1-(4,4-difluorocyclohexyl)-5-methyl-1H-pyrazol-3-yl)-6-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)nicotinamide (40 mg, 0.07 mmol, 23.33% yield) as an off-white solid.

[0387] 1 H NMR(400MHz,DMSO-d6)δppm 11.00(s,1H),10.65(s,1H),7.83(d,J=8.1Hz,1H),6.41(d,J=8.2Hz,1H),6.38(s,1H),4.34(s,1H),3.83–3.68(m,4H ),3.32–3.19(m,4H),2.27(s,3H),2.09(dd,J=33.0,18.9Hz,4H),2.02–1.85(m,4H),1.56–1.41(m,4H),0.32(s,4H).

[0388] MS (ESI) m / z = 553.2 [M+H] + .

[0389] Example 8:

[0390] N-(2-(4,4-difluorocyclohexyl)-2H-1,2,3-triazol-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0391]

[0392] Step 1: To a solution of 4-nitro-2H-1,2,3-triazole (500 mg, 4.38 mmol) and 4,4-difluorocyclohexyl-4-methylbenzenesulfonate (1.91 g, 6.57 mmol) in DMF (20 mL) was added cesium carbonate (2.14 g, 6.57 mol) under nitrogen. The reaction mixture was stirred at 90°C for 16 hours. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL*3). The organic layer was washed with brine (50 mL*2), dried over anhydrous Na2SO4, and concentrated in vacuo to obtain the crude product. The crude product was purified by flash silica gel chromatography (10 g, elution gradient: 0 to 30% EtOAc in hexanes) to afford compound 2-(4,4-difluorocyclohexyl)-4-nitro-2H-1,2,3-triazole (140 mg, 0.54 mmol, yield: 12.33%) as a yellow gum.

[0393] 1 H NMR (400MHz, DMSO-d6): δppm 9.50 (s, 1H), 4.89–4.86 (m, 1H), 2.23–2.07 (m, 8H).

[0394] MS (ESI) m / z = 233.0 [M+H] + .

[0395] Step 2: 10% Pd / C (60 mg) was added to a solution of 2-(4,4-difluorocyclohexyl)-4-nitro-2H-1,2,3-triazole (140 mg, 0.54 mmol) in MeOH (20 mL) stirred under a hydrogen atmosphere. The reaction mixture was stirred at room temperature for 4 hours. The mixture was filtered through a celite pad and the filtrate was concentrated under vacuum to give a crude product. The crude product was purified by flash silica gel chromatography (4 g, elution gradient: 0 to 100% EtOAc in hexane) to give compound 2-(4,4-difluorocyclohexyl)-2H-1,2,3-triazole-4-amine (100 mg, 0.445 mmol, yield: 82.4%) as a yellow gum.

[0396] 1 H NMR (400MHz, CDCl3): δppm 6.92 (s, 1H), 4.48–4.42 (m, 1H), 2.23–1.90 (m, 8H).

[0397] MS (ESI) m / z = 203.2 [M+H] + .

[0398] Step 3: A solution of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (140 mg, 0.39 mmol, prepared in Example 1), DIEA (102 mg, 0.79 mmol) and HATU (225 mg, 0.59 mmol) in DMF (10 mL) was placed in a round-bottom flask. The mixture was stirred at room temperature for 30 minutes. 2-(4,4-difluorocyclohexyl)-2H-1,2,3-triazole-4-amine (80 mg, 0.39 mmol) was then added to the reaction mixture. The resulting mixture was stirred at room temperature for 4 hours. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL*3). The organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated in vacuo to give the crude product, which was purified by flash silica gel chromatography (elution gradient: 0 to 50% EtOAc in PE) to give compound N-(2-(4,4-difluorocyclohexyl)-2H-1,2,3-triazol-4-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (110 mg, 0.18 mmol, yield: 46.15%) as a yellow solid.

[0399] 1 H NMR(400MHz,DMSO-d6)δppm 13.01(s,1H),8.36(s,1H),7.79–7.68(m,3H),4.77–4.76(m,1H),3.02–2.99(m,4H),2.12–2.10(m,8H),1.62–1.61(m,4H),0.39(s,4H).

[0400] MS: (ESI) m / z = 542.1 [M+H] + .

[0401] Step 4: A suspension of 2-hydroxyethanesulfonamide (36.8 mg, 0.29 mmol), CuI (14 mg, 0.07 mmol), sarcosine (13 mg, 0.15 mmol), and K 3 PO 4 (156 mg, 0.73 mmol) in DMF (10 mL) was preheated to 50° C. for 10 minutes. A solution of N-(2-(4,4-difluorocyclohexyl)-2H-1,2,3-triazol-4-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (80 mg, 0.15 mmol) in DMF (2 mL) was then added. The resulting mixture was stirred at 110° C. under nitrogen for 16 hours. The mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL*3). The organic layer was washed with brine (20 mL*2), dried over Na2SO4 and concentrated in vacuo to give the crude product, which was purified by preparative HPLC (Gemini-C18 column, 5 μm silica, 21 mm diameter, 150 mm length) using mixtures of water (containing 0.1% FA) and MeCN with decreasing polarity as eluents (40-80) to give the title compound N-(2-(4,4-difluorocyclohexyl)-2H-1,2,3-triazol-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (25 mg, 0.046 mmol, 30.67%) as a white solid.

[0402] 1 H NMR (400MHz, DMSO-d6): δppm 13.07(s,1H),8.32(s,1H),8.01–7.98(m,1H),7.24(s,1H),7.10–7.08(m,1H),4.77(s,1H),3.77 –3.74(m,2H),3.34–3.31(m,2H),2.98–2.97(m,4H),2.16–2.09(m,8H),1.65(s,4H),0.41(s,4H).

[0403] MS: (ESI) m / z = 539.2 [M+H] + .

[0404] Example 9:

[0405] N-(1-(4,4-difluorocyclohexyl)-5-methyl-1H-pyrazol-3-yl)-4-(3-hydroxypropylsulfonylimino)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0406]

[0407] Step 1: To a solution of N-(1-(4,4-difluorocyclohexyl)-5-methyl-1H-pyrazol-3-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (350 mg, 0.63 mmol, prepared in Example 1) in 1,4-dioxane (10 mL) was added methyl 3-mercaptopropionate (151.7 mg, 1.26 mmol), Pd2(dba)3 (57.8 mg, 0.063 mmol), Xantphos (73.1 mg, 0.123 mmol) and DIEA (244.3 mg, 1.89 mmol). The reaction mixture was stirred at 90 ° C under N2 for 16 hours. The mixture was concentrated under vacuum to give the crude product, which was purified by silica gel chromatography (elution gradient: petroleum ether / ethyl acetate 10 / 1, v / v) to give methyl 3-((4-((1-(4,4-difluorocyclohexyl)-5-methyl-1H-pyrazol-3-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)thio)propanoate (300 mg, 0.55 mmol, yield: 87.3%) as a yellow oil.

[0408] MS (ESI) m / z = 547.3 [M+H] + .

[0409] Step 2: To a solution of methyl 3-((4-(1-(4,4-difluorocyclohexyl)-5-methyl-1H-pyrazol-3-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)thio)propanoate (300 mg, 0.55 mmol) in MeOH (10 mL) was added ammonium carbonate (210.7 mg, 2.20 mmol) and PhI(OAc)2 (942.4 mg, 2.93 mmol) at 0° C. The reaction mixture was stirred at 25° C. for 2 h. The reaction was concentrated under vacuum to give a crude product, which was purified by silica gel chromatography (elution gradient: petroleum ether / ethyl acetate 1 / 1, v / v) to give compound 3-(4-((1-(4,4-difluorocyclohexyl)-5-methyl-1H-pyrazol-3-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenylsulfonylimino)propanoic acid methyl ester (260 mg, 0.45 mmol, yield: 81.82%) as a yellow oil.

[0410] MS (ESI) m / z = 578.2 [M+H] + .

[0411] Step 3: To a solution of methyl 3-(4-((1-(4,4-difluorocyclohexyl)-5-methyl-1H-pyrazol-3-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenylsulfonylimino)propanoate (260 mg, 0.45 mmol) in THF (10 mL) at 0°C was added LiBH4 (29.71 mg, 1.35 mmol). The reaction mixture was stirred at 25°C for 2 hours. The mixture was diluted with ethyl acetate (10 mL) and washed with water (10 mL*2) and brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by preparative HPLC (Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length) using decreasingly polar mixtures of water (containing 0.1% FA) and MeCN as eluents (45-95) to give the title compound N-(1-(4,4-difluorocyclohexyl)-5-methyl-1H-pyrazol-3-yl)-4-(3-hydroxypropylsulfonylimino)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (48.9 mg, 0.089 mmol, yield: 19.79%) as a white solid.

[0412] 1 H NMR(400MHz,DMSO-d6)δppm 12.42(s,1H),8.04(d,J=8.2Hz,1H),7.74(d,J=1.6Hz,1H),7.66(dd,J=8.2,1.6Hz,1H),6.39(s,1H),4.57–4.55(m,1H),4.36–4.20(m,2H), 3.38–3.34(m,2H),3.18–3.14(m,2H),3.07–2.95(m,4H),2.26(s,3H), 2.22–2.15(m,2H),2.07–1.84(m,6H),1.70–1.55(m,6H),0.32(s,4H).

[0413] MS (ESI) m / z = 550.2 [M+H] + .

[0414] Example 10:

[0415] N-(1-(4,4-difluorocyclohexyl)-5-methyl-1H-pyrazol-3-yl)-6-((2-hydroxyethyl)sulfonamido)-4-(6-azaspiro[2.5]octan-6-yl)nicotinamide

[0416]

[0417] Step 1: DIEA (941 mg, 7.28 mmol) was added to a solution of 4,6-dichloropyridine-3-carboxylic acid methyl ester (500 mg, 2.43 mmol) and 6-azaspiro [2.5] octane hydrochloride (430 mg, 2.91 mmol) in MeCN (15 mL). The reaction mixture was stirred at 40 ° C for 16 hours. The reaction mixture was concentrated in vacuo to give a crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 5 / 1, v / v) to give compound 6-chloro-4- (6-azaspiro [2.5] octan-6-yl) nicotinate (450 mg, 1.6 mmol, yield: 65.84%) as a colorless oil.

[0418] MS (ESI) m / z = 281.1 [M+H] + .

[0419] Step 2: To a solution of methyl 6-chloro-4-(6-azaspiro[2.5]octan-6-yl)nicotinate (450 mg, 1.6 mmol) in THF (5 mL) and H₂O (5 mL) was added LiOH·H₂O (840 mg, 20 mmol). The reaction mixture was stirred at 25°C for 16 hours. The mixture was diluted with water (30 mL) and acidified with 1N HCl. The precipitate was collected by filtration, washed with water and dried under vacuum to give 6-chloro-4-(6-azaspiro[2.5]octan-6-yl)nicotinic acid (210 mg, 0.71 mmol, 44.37% yield) as a white solid.

[0420] MS (ESI) m / z = 267.0 [M+H] + .

[0421] Step 3: To a solution of 6-chloro-4-(6-azaspiro[2.5]octan-6-yl)nicotinic acid (190 mg, 0.71 mmol), HATU (406 mg, 1.07 mmol), and DIEA (184 mg, 1.4 mmol) in DMF (10 mL) was added 1-(4,4-difluorocyclohexyl)-5-methyl-1H-pyrazol-3-amine (153 mg, 0.71 mmol, prepared in Example 1). The reaction mixture was stirred at 25°C for 3 hours. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (30 mL x 3). The organic layer was washed with brine (30 mL*3), dried over anhydrous Na2SO4, and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 3 / 1, v / v) to give compound 6-chloro-N-(1-(4,4-difluorocyclohexyl)-5-methyl-1H-pyrazol-3-yl)-4-(6-azaspiro[2.5]octan-6-yl)nicotinamide (300 mg, 0.58 mmol, yield: 81.69%) as a white solid.

[0422] MS (ESI) m / z = 464.2 [M+H] + .

[0423] Step 4: To a solution of 6-chloro-N-(1-(4,4-difluorocyclohexyl)-5-methyl-1H-pyrazol-3-yl)-4-(6-azaspiro[2.5]octan-6-yl)nicotinamide (250 mg, 0.54 mmol) and 2-hydroxyethanesulfonamide (337 mg, 2.69 mmol) in MeCN (15 mL) was added palladium acetate (36 mg, 0.16 mmol), Josiphos J-009 (90 mg, 0.16 mmol), DBU (164 mg, 1.08 mmol), and potassium carbonate (223 mg, 1.62 mmol). The mixture was stirred at 75°C under N2 for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with EtOAc (30 mL*3). The organic layer was washed with brine (30 mL*2), dried over anhydrous Na2SO4, and concentrated in vacuo to give the crude product. The crude product was purified by preparative HPLC (Gemini-C18 column, 5um silica, 21 mm diameter, 150 mm length) using decreasingly polar mixtures of water (containing 0.1% FA) and MeCN as eluents to give the title compound N-(1-(4,4-difluorocyclohexyl)-5-methyl-1H-pyrazol-3-yl)-6-((2-hydroxyethyl)sulfonamido)-4-(6-azaspiro[2.5]octan-6-yl) (53.5 mg, 0.09 mmol, 16.67% yield) as a white solid.

[0424] 1 H NMR(400MHz,DMSO-d6)δppm 10.78(s,1H),7.91(br.s,1H),6.54(s,1H),6.37(s,1H),4.80(br.s,1H),4.34(br.s,1H),3.75(t,J=6.6Hz,2H),3 .35–3.33(m,2H),3.16–3.14(m,4H),2.27(s,3H),2.20–1.95(m,6H),1.89(s,2H),1.45–1.43(m,4H),0.32(s,4H).

[0425] MS (ESI) m / z = 553.2 [M+H] + .

[0426] Example 11:

[0427] N-(1-(4,4-difluorocyclohex-1-en-1-yl)-5-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0428]

[0429]

[0430] Step 1: To a solution of 3-methyl-5-nitropyridin-2(1H)-one (1 g, 6.5 mmol) and 2-(4,4-difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.59 g, 6.5 mmol) in MeCN / EtOH (27 / 3 mL) was added TEA (1.97 g, 19.5 mmol), Cu(OAc)2 (1.18 g, 6.5 mmol) and 4A MS (200 mg). The reaction mixture was stirred at 80 ° C under an O2 atmosphere for 16 hours. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL*3). The organic layer was washed with water (30 mL) and brine (30 ml), dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (elution gradient: petroleum ether / ethyl acetate, 1 / 1, v / v) to give 1-(4,4-difluorocyclohex-1-en-1-yl)-3-methyl-5-nitropyridine-2(1H)-one (0.7 g, 2.6 mmol, yield: 40.00%) as a yellow oil.

[0431] MS (ESI) m / z = 271.0 [M+H] + .

[0432] Step 2: Under a hydrogen atmosphere, nickel (70 mg) was added to a stirred THF (20 mL) solution of 1- (4,4-difluorocyclohex-1-ene-1-yl) -3-methyl-5-nitropyridine -2 (1H) -one (140 mg, 0.52 mmol). The reaction mixture was stirred at room temperature for 16 hours. The mixture was filtered through a celite pad and the filtrate was concentrated under vacuum to give a crude product. The crude product was purified by flash silica gel chromatography (elution gradient: DCM / MeOH, 10 / 1, v / v) to give 5-amino-1- (4,4-difluorocyclohex-1-ene-1-yl) -3-methylpyridine -2 (1H) -one (90 mg, 0.37 mmol, yield: 71.2%) as a brown oil.

[0433] MS (ESI) m / z = 241.1 [M+H] + .

[0434] Step 3: To a solution of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (74.3 mg, 0.21 mmol, prepared in Example 1) and HATU (95 mg, 0.95 mmol) in DMF (3 mL) was added DIEA (80.7 mg, 0.62 mmol). The mixture was stirred at room temperature for 15 minutes. 5-amino-1-(4,4-difluorocyclohex-1-en-1-yl)-3-methylpyridin-2(1H)-one (50 mg, 0.21 mmol) was added thereto. The resulting mixture was stirred at room temperature for 6 hours. The mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL*3). The organic layer was washed with brine (20 mL*2), dried over Na2SO4, and concentrated in vacuo to give the crude product. The crude product was purified by flash silica gel chromatography (elution gradient: petroleum ether / ethyl acetate, 5 / 1, v / v) to give N-(1-(4,4-difluorocyclohex-1-en-1-yl)-5-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (90 mg, 0.155 mmol, yield: 73.8%) as a grey solid.

[0435] MS: (ESI) m / z = 580.1 [M+H] + .

[0436] Step 4: A suspension of 2-hydroxyethanesulfonamide (38.9 mg, 0.31 mmol), CuI (14.8 mg, 0.08 mmol), sarcosine (13.8 mg, 0.15 mmol), and K PO 4 (164.8 mg, 0.78 mmol) in DMF (3 mL) was preheated to 50° C. for 10 minutes. A solution of N-(1-(4,4-difluorocyclohex-1-en-1-yl)-5-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (90 mg, 0.155 mmol) in DMF (1 mL) was added. The resulting mixture was stirred at 110° C. under nitrogen for 6 hours. The mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL*3). The organic layer was washed with brine (20 mL*2), dried over Na2SO4 and concentrated in vacuo to give the crude product, which was purified by preparative HPLC (Gemini-C18 column, 5 μm silica, 21 mm diameter, 150 mm length) using decreasingly polar mixtures of water (containing 0.1% FA) and MeCN as eluents (30-70) to give the title compound N-(1-(4,4-difluorocyclohex-1-en-1-yl)-5-methyl-6-oxo-1,6-dihydropyridin-3-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (20 mg, 0.03 mmol 19.35%) as a white solid.

[0437] 1 H NMR (400 MHz, DMSO-d6): δ ppm 11.07(s,1H),8.16(d,J=2.6Hz,1H),7.70(d,J=8.5Hz,1H),7.43(s,1H),7.1 1(d,J=1.9Hz,1H),6.98(dd,J=8.5,1.9Hz,1H),5.73(s,1H),3.75(t,J=6.6Hz ,2H),3.31(t,J=6.6Hz,2H),2.99–2.90(m,4H),2.81–2.74(m,2H),2.59(t,J =6.1Hz,2H),2.26–2.16(m,2H),2.04(s,3H),1.52–1.48(m,4H),0.35(s,4H).

[0438] MS: (ESI) m / z = 577.2 [M+H] + .

[0439] Example 12: N-(1-(4,4-difluorocyclohexyl)-5-methyl-1H-pyrazol-3-yl)-4-((S-methylsulfonylimino)methyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0440]

[0441] Step 1: to 2-fluoro-4-methylbenzoic acid methyl ester (1g, 5.9mmol) and N-bromosuccinimide (1.06g, 5.9mmol) in CCl4 (20ml) in solution, add AIBN (0.1g, 0.59mmol).Reaction mixture is stirred at 70 ℃ for 16 hours.The mixture is concentrated under reduced pressure to obtain a crude product, which is purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 5 / 1, v / v) to obtain 4-(bromomethyl)-2-fluorobenzoic acid methyl ester (900mg, 3.64mmol, yield: 61.69%) as a white solid.

[0442] MS (ESI) m / z = 246.9, 248.9 [M+H] + .

[0443] Step 2: To a solution of methyl 4-(bromomethyl)-2-fluorobenzoate (900 mg, 3.64 mmol) in DMF (20 mL) was added sodium thiomethoxide (255.3 mg, 3.64 mmol). The reaction mixture was stirred at 25°C for 10 hours. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (20 mL*3). The organic layer was washed with brine (20 mL*2), dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 5 / 1, v / v) to give methyl 2-fluoro-4-((methylthio)methyl)benzoate (520 mg, 2.18 mmol, yield: 59.89%) as a yellow oil.

[0444] MS (ESI) m / z = 215.1 [M+H] + .

[0445] Step 3: To a solution of methyl 2-fluoro-4-((methylthio)methyl)benzoate (520 mg, 2.43 mmol) in dioxane (15 mL) was added 6-azaspiro[2.5]octane hydrochloride (716.7 mg, 4.85 mmol) and DIEA (941 mg, 7.28 mmol). The reaction mixture was stirred at 140°C for 10 hours. The reaction mixture was cooled to room temperature, poured into water (30 mL), and extracted with EtOAc (30 mL*3). The organic layer was washed with brine (30 mL*2), dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 5 / 1, v / v) to give methyl 4-((methylthio)methyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoate (150 mg, 0.49 mmol, yield: 20.16%) as a yellow oil.

[0446] MS (ESI) m / z = 306.1 [M+H] + .

[0447] Step 4: To a solution of methyl 4-((methylthio)methyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoate (150 mg, 0.49 mmol) in THF (10 mL) was added dropwise a solution of LiOH·H2O (41.2 mg, 0.98 mmol) in water (2 mL). The reaction mixture was stirred at 50°C for 3 hours. The reaction mixture was cooled to room temperature and the pH was adjusted to 4 with 2M HCl. The mixture was diluted into water (30 mL) and extracted with EtOAc (30 mL*3). The organic layer was washed with brine (30 mL*2), dried over anhydrous Na2SO4, and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 1 / 5, v / v) to give 4-((methylthio)methyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (100 mg, 0.34 mmol, yield: 69.39%) as a yellow solid.

[0448] MS (ESI) m / z = 292.1 [M+H] + .

[0449] Step 5: To a solution of 4-((methylthio)methyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (100 mg, 0.34 mmol), HATU (195.7 mg, 0.51 mmol), and DIEA (88.7 mg, 0.69 mmol) in DMF (7 mL) was added dropwise a solution of 1-(4,4-difluorocyclohexyl)-5-methyl-1H-pyrazol-3-amine (73.1 mg, 0.34 mmol, prepared in Example 1) in DMF (2 mL). The reaction mixture was stirred at 25°C for 10 hours. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (20 mL*3). The organic layer was washed with brine (20 mL*2), dried over anhydrous Na2SO4, and concentrated in vacuo to give the crude product. The crude product was purified by preparative HPLC (Gemini-C18 column, 5um silica, 21mm diameter, 150mm length) using decreasingly polar mixtures of water (containing 0.1% FA) and MeCN as eluents (30%-70%) to give compound N-(1-(4,4-difluorocyclohexyl)-5-methyl-1H-pyrazol-3-yl)-4-(methylthio)methyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (150mg, 0.31mmol, yield: 91.17%) as a white solid.

[0450] 1 H NMR(400MHz,DMSO-d6)δppm 13.12(s,1H),7.99(d,J=8.0Hz,1H),7.39(s,1H),7.22(d,J=8.0Hz,1H),6.41(s,1H),4.37(s,1H),3.74(s,2H),2.97(t,J =4.0Hz,4H),2.29(s,3H),2.26–2.22(m,2H),2.07–2.02(m,4H),1.92(s,3H),1.94–1.90(m,2H),1.66(s,4H),0.36(s,4H).

[0451] MS (ESI) m / z = 489.2 [M+H] + .

[0452] Step 6: To a solution of N-(1-(4,4-difluorocyclohexyl)-5-methyl-1H-pyrazol-3-yl)-4-((methylthio)methyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (40 mg, 0.082 mmol) in MeOH (3 mL) was added ammonium carbonate (23.6 mg, 0.25 mmol) and PhI(OAc)2 (105.5 mg, 0.33 mmol). The reaction mixture was stirred at 25 ° C for 5 hours. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (20 mL * 3). The organic layer was washed with brine (20 mL * 2), dried over anhydrous Na2SO4, and concentrated in vacuo to give the crude product. The crude product was purified by preparative HPLC (Gemini-C18 column, 5um silica, 21mm diameter, 150mm length) using decreasingly polar mixtures of water (containing 0.1% FA) and MeCN as eluents (20%-60%) to give the title compound N-(1-(4,4-difluorocyclohexyl)-5-methyl-1H-pyrazol-3-yl)-4-((S-methylsulfonylimino)methyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (3.2mg, 0.01mmol, 12.2% yield) as a white solid.

[0453] 1 H NMR(400MHz,DMSO-d6)δppm 13.07(s,1H),8.01(d,J=8.0Hz,1H),7.54(s,1H),7.33(d,J=8.0Hz,1H),6.42(s,1H),4.49–4.36(m,3H),3.74(s,1H),2.9 8(t,J=8.0Hz,4H),2.79(s,3H),2.29(s,3H),2.25–2.19(m,2H),2.05–2.01(m,4H),1.92(s,2H),1.66(s,4H),0.36(s,4H).

[0454] MS (ESI) m / z = 520.2 [M+H] + .

[0455] Example 13:

[0456] N-(1-(4,4-difluorocyclohexyl)-6-oxo-1,6-dihydropyridazin-3-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0457]

[0458]

[0459] Step 1: To a stirred solution of 4,4-difluorocyclohexan-1-ol (5 g, 36.7 mmol), triethylamine (7.43 g, 73.4 mmol), and 4-dimethylaminopyridine (2.24 g, 18.3 mmol) in DCM (200 mL) at 0°C under nitrogen was added a solution of 4-methylbenzenesulfonyl chloride (9.1 g, 47.7 mmol) in DCM (100 mL) dropwise. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was poured into 1N HCl (200 mL) and extracted with DCM (200 ml). The organic layer was washed with aqueous sodium bicarbonate (300 mL) and brine (200 mL*2), dried over anhydrous Na2SO4, and concentrated in vacuo to afford 4,4-difluorocyclohexyl-4-methylbenzenesulfonate (9.2 g, 28.5 mmol, yield: 77.66%) as a gray solid. The product was used directly without further purification.

[0460] 1 H NMR (400MHz, CDCl3) δppm 7.78 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 4.67–4.66 (m, 1H), 2.44 (s, 3H), 2.07–1.75 (m, 8H).

[0461] Step 2: To a solution of 6-chloropyridazin-3(2H)-one (500 mg, 3.83 mmol) in DMF (20 mL) was added 4,4-difluorocyclohexyl-4-methylbenzenesulfonate (1.67 g, 5.75 mmol) and K2CO3 (3.75 g, 11.49 mmol). The reaction mixture was stirred at 80°C for 16 hours. The reaction mixture was cooled to room temperature, poured into water (30 mL), and extracted with EtOAc (30 mL*3). The organic layer was washed with brine (30 mL*2), dried over anhydrous Na2SO4, and concentrated in vacuo to obtain the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 5 / 1, v / v) to give 6-chloro-2-(4,4-difluorocyclohexyl)pyridazin-3(2H)-one (600 mg, 2.17 mmol, yield: 56.66%) as a yellow oil.

[0462] 1 H NMR(400MHz, DMSO-d6)δppm 7.55(d,J=9.7Hz,1H),7.06(d,J=9.7Hz,1H),4.97–4.85(m,1H),2.21–2.03(m,4H),1.88–1.85(m,4H).

[0463] MS (ESI) m / z = 249.1 [M+H] + .

[0464] Step 3: To a solution of 6-chloro-2-(4,4-difluorocyclohexyl)pyridazin-3(2H)-one (550 mg, 2.2 mmol) and diphenylmethaneimine (401 mg, 2.2 mmol) in dioxane (30 mL) was added tris(dibenzylideneacetone)dipalladium (203 mg, 0.22 mmol), Xantphos (384 mg, 0.66 mmol), and Cs2CO3 (2.16 g, 6.64 mmol). The reaction mixture was stirred at 100°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with EtOAc (50 mL*3). The organic layer was washed with brine (50 mL*2), dried over anhydrous Na2SO4, and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 1 / 1, v / v) to give 2-(4,4-difluorocyclohexyl)-6-((benzhydryl)amino)pyridazine-3(2H)-one (610 mg, 1.39 mmol, yield: 63.18%) as a yellow solid.

[0465] MS (ESI) m / z = 394.1 [M+H] + .

[0466] Step 4: To a solution of 2-(4,4-difluorocyclohexyl)-6-((benzhydryl)amino)pyridazin-3(2H)-one (550 mg, 1.4 mmol) in 1,4-dioxane (10 mL) was added HCl (4N in dioxane, 10 mL). The reaction mixture was stirred at 25 ° C for 16 hours. The mixture was concentrated under reduced pressure to give the crude product, which was purified by flash chromatography (elution gradient: ethyl acetate) to give 6-amino-2-(4,4-difluorocyclohexyl)pyridazin-3(2H)-one (260 mg, 1.02 mmol, yield: 72.86%) as a yellow solid.

[0467] MS (ESI) m / z = 230.2 [M+H] + .

[0468] Step 5: To a solution of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (327 mg, 0.92 mmol, prepared in Example 1), HATU (522 mg, 1.37 mmol), and DIEA (237 mg, 1.83 mmol) in DMF (5 mL) was added 6-amino-2-(4,4-difluorocyclohexyl)pyridazin-3(2H)-one (210 mg, 0.92 mmol). The reaction mixture was stirred at 25° C. for 16 hours. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (30 mL*3). The organic layer was washed with brine (30 mL*2), dried over anhydrous Na2SO4, and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 1 / 1, v / v) to give a white solid compound N-(1-(4,4-difluorocyclohexyl)-6-oxo-1,6-dihydropyridazin-3-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (300 mg, 0.47 mmol, yield: 51.09%).

[0469] MS (ESI) m / z = 569.1 [M+H] + .

[0470] Step 6: A suspension of 2-hydroxyethanesulfonamide (25 mg, 0.2 mmol), CuI (10 mg, 0.05 mmol), sarcosine (9 mg, 0.1 mmol), and K3PO4 (106 mg, 0.5 mmol) in DMF (4 mL) was preheated to 50°C for 10 minutes. A solution of N-(1-(4,4-difluorocyclohexyl)-6-oxo-1,6-dihydropyridazin-3-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (57 mg, 0.1 mmol) in DMF (1 mL) was added. The resulting mixture was stirred at 110°C under nitrogen for 16 hours. The reaction mixture was cooled to room temperature, poured into water (30 mL), and extracted with EtOAc (20 mL*3). The organic layer was washed with brine (20 mL*2), dried over anhydrous Na2SO4, and concentrated in vacuo to obtain the crude product. The crude product was purified by preparative HPLC (Gemini-C18 column, 5um silica, 21mm diameter, 150mm length) using decreasingly polar mixtures of water (containing 0.05% FA) and MeCN as eluents (30%-70%) to give the title compound N-(1-(4,4-difluorocyclohexyl)-6-oxo-1,6-dihydropyridazin-3-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (3.5mg, 0.006mmol, 6.0% yield) as a white solid.

[0471] 1 H NMR(400MHz,DMSO-d6)δppm 13.60(s,1H),10.26(s,1H),8.37(d,J=10.0Hz,1H),8.05(d,J=8.6Hz,1H),7.29(d,J=1.7Hz,1H),7.14(dd,J=8.6,1.8Hz,1H),7.07(d,J=9.9Hz, 1H),5.03–4.97(m,2H),3.77–3.74(m,2H),3.38–3.35(m,2H),2.99–2.97 (m,4H),2.15–1.95(m,6H),1.87–1.85(m,2H),1.67(s,4H),0.39(s,4H).

[0472] MS (ESI) m / z = 566.2 [M+H] + .

[0473] Example 14:

[0474] 4-((2-Hydroxyethyl)sulfonamido)-N-(5-methyl-1-(4-methyl-4-azaspiro[2.5]octan-7-yl)-1H-pyrazol-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0475]

[0476] Step 1: To a solution of tert-butyl 7-oxo-4-azaspiro[2.5]octane-4-carboxylate (225 mg, 1 mmol) in methanol (10 mL) was added NaBH4 (41.56 mg, 1 mmol) at 0°C. The reaction was quenched with ice water and extracted with EA (20 mL*3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and then concentrated under vacuum to give tert-butyl 7-hydroxy-4-azaspiro[2.5]octane-4-carboxylate (227 mg, crude) as a pale yellow oil.

[0477] MS (ESI) m / z = 250.1 [M + Na] + .

[0478] Step 2: To a solution of tert-butyl 7-hydroxy-4-azaspiro[2.5]octan-4-carboxylate (235 mg, 1 mmol) in DCM (10 mL) was added TEA (209 mg, 2 mmol), DMAP (63 mg, 0.5 mmol), and TosCl (236 mg, 1.2 mmol). The reaction mixture was stirred at room temperature for 4 hours. The mixture was diluted with DCM (10 mL) and washed with 1N HCl (10 mL*2) and aqueous sodium bicarbonate (10 mL*2). The organic layer was dried over Na2SO4 and concentrated in vacuo to afford tert-butyl 7-(tosyloxy)-4-azaspiro[2.5]octan-4-carboxylate (350 mg, 0.92 mmol, 88.7% yield) as a colorless oil.

[0479] MS (ESI) m / z = 404.0 [M + Na] + .

[0480] Step 3: To a solution of tert-butyl 7-(tosyloxy)-4-azaspiro[2.5]octan-4-carboxylate (350 mg, 0.91 mmol) in DMF (10 mL) was added 3-methyl-5-nitro-2H-pyrazole (116.62 mg, 0.9 mmol) and Cs2CO3 (896.82 mg, 2.75 mmol). The mixture was stirred at 80°C overnight. The mixture was diluted with water (20 mL) and extracted with EA (20 mL*3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, concentrated in vacuo, and purified by flash chromatography (PE / EtOAc = 0-16%) to give tert-butyl 7-(5-methyl-3-nitro-1H-pyrazol-1-yl)-4-azaspiro[2.5]octane-4-carboxylate (127 mg, 0.38 mmol, yield: 41.1%) as a yellow oil.

[0481] 1 HNMR (400MHz, CDCl3) δ6.65(d,J=0.6Hz,1H),4.54-4.38(m,1H),4.25(d,J=12.6Hz,1H),2.99(dd,J=18.5,7.6Hz,1H),2.76–2.60(m,1H),2.36( d,J=0.7Hz,3H),2.18-2.11(m,1H),1.99–1.90(m,1H),1.49(s,9H),1.2 8–1.19(m,2H),0.99-0.90(m,1H),0.69-0.60(m,1H),0.53-0.43(m,1H).

[0482] MS (ESI) m / z = 359.1 [M + Na] +.

[0483] Step 4: To a solution of tert-butyl 7-(5-methyl-3-nitro-1H-pyrazol-1-yl)-4-azaspiro[2.5]octane-4-carboxylate (127 mg, 0.37 mol) in DCM (5 mL) was added TFA (0.5 mL). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under vacuum to remove DCM and TFA, diluted with water, basified to pH=9 with NaHCO 3 , and concentrated under vacuum to give 7-(5-methyl-3-nitro-1H-pyrazol-1-yl)-4-azaspiro[2.5]octane (81 mg, 0.34 mmol, yield: 91.8%) as a yellow solid.

[0484] MS (ESI) m / z = 237.1 [M+H] + .

[0485] Step 5: To a solution of 7-(5-methyl-3-nitropyrazol-1-yl)-4-azaspiro[2.5]octane (81 mg, 0.34 mmol) in methanol (5 mL) was added formaldehyde (83.46 mg, 1 mmol, 37%). The mixture was stirred at room temperature for 20 minutes, and then NaBH3CN (64.62 mg, 1 mmol) was added to the mixture. The mixture was diluted with water (20 mL) and extracted with EA (20 mL*3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4 and concentrated in vacuo, and purified by flash chromatography (CH2Cl2 / MeOH = 0-10%) to give 4-methyl-7-(5-methyl-3-nitro-1H-pyrazol-1-yl)-4-azaspiro[2.5]octane (72 mg, 0.29 mmol, yield: 83.9%) as a white solid.

[0486] MS (ESI) m / z = 251.1 [M+H] + .

[0487] Step 6: To a solution of 4-methyl-7-(5-methyl-3-nitro-1H-pyrazol-1-yl)-4-azaspiro[2.5]octane (72 mg, 0.28 mmol) in ethanol (5 mL) was added Raney nickel (1 mL) followed by hydrazine hydrate (1 mL). The mixture was filtered and the filtrate was concentrated in vacuo to afford 5-methyl-1-(4-methyl-4-azaspiro[2.5]octan-7-yl)-1H-pyrazol-3-amine (55 mg, 0.25 mmol, 86.8% yield) as a colorless oil.

[0488] MS (ESI) m / z = 221.2 [M+H] + .

[0489] Step 7: A mixture of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (89 mg, 0.25 mmol, prepared in Example 1), HATU (142 mg, 0.37 mmol) and DIPEA (96.77 mg, 0.74 mmol) in DMF (10 mL) was stirred at 25° C. for 20 minutes. 5-methyl-1-(4-methyl-4-azaspiro[2.5]octan-7-yl)-1H-pyrazol-3-amine (55 mg, 0.25 mmol) was then added and stirred at room temperature for 5 hours. The mixture was diluted with water (20 mL) and extracted with EA (20 mL*3). The combined organic layers were washed with water (20 mL) and brine (20 ml), dried over Na2SO4, concentrated in vacuo, and purified by flash chromatography (DCM / MeOH = 0-5%) to give 4-iodo-N-(5-methyl-1-(4-methyl-4-azaspiro[2.5]octan-7-yl)-1H-pyrazol-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (132 mg, 0.24 mmol, yield: 94.5%) as a yellow oil.

[0490] MS (ESI) m / z = 560.2 [M+H] + .

[0491] Step 8: A mixture of 2-hydroxyethanesulfonamide (59 mg, 0.472 mmol), CuI (22 mg, 0.118 mmol), K 3 PO 4 (250 mg, 1.18 mmol) and sarcosine (21 mg, 0.236 mmol) in DMF (6 mL) was stirred at 50° C. for 10 minutes, and then a solution of 4-iodo-N-(5-methyl-1-(4-methyl-4-azaspiro[2.5]octan-7-yl)-1H-pyrazol-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (132 mg, 0.236 mmol) in DMF (1 mL) was added to the solution and stirred at 110° C. under nitrogen for 5 hours. The mixture was diluted with water (20 mL) and extracted with DCM (20 mL*3). The combined organic layers were washed with water (20 mL) and brine (20 ml), dried over Na2SO4, concentrated in vacuo, and purified by preparative TLC (DCM / MeOH=13 / 1) to give the title compound 4-((2-hydroxyethyl)sulfonamido)-N-(5-methyl-1-(4-methyl-4-azaspiro[2.5]octan-7-yl)-1H-pyrazol-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (16.2 mg, 0.03 mmol, yield: 12.3%) as an off-white solid.

[0492] MS (ESI) m / z = 557.2 [M+H]+ .

[0493] 1 H NMR (400MHz, CD3OD) δ8.08(d,J=8.6Hz,1H),7.31(d,J=2.1Hz,1H),7.15(dd,J=8.6,2.2Hz,1 H),6.43(s,1H),4.44–4.33(m,1H),3.96(t,J=6.2Hz,2H),3.38(t,J=6.3Hz,2H),3.20-3.31( m,1H),3.11–2.96(m,5H),2.79(t,J=12.6Hz,1H),2.56(s,3H),2.52-2.42(m,1H),2.33(s,3 H),1.97–1.62(m,5H),1.04-1.00(m,1H),0.80–0.70(m,2H),0.67–0.48(m,2H),0.44(s,4H).

[0494] Example 15:

[0495] N-(1-(4,4-difluorocyclohexyl)-5-methyl-1H-pyrazol-3-yl)-4-(methylsulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0496]

[0497] Step 1: To a stirred solution of 4,4-difluorocyclohexan-1-ol (5 g, 36.7 mmol), triethylamine (7.43 g, 73.4 mmol), and 4-dimethylaminopyridine (2.24 g, 18.3 mmol) in DCM (200 mL) at 0°C under nitrogen was added a solution of 4-methylbenzenesulfonyl chloride (9.1 g, 47.7 mmol) in DCM (100 mL) dropwise. The reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was poured into 1N HCl (200 mL) and extracted with DCM (200 ml). The organic layer was washed with aqueous sodium bicarbonate (300 mL) and brine (200 mL*2), dried over anhydrous Na2SO4, and concentrated in vacuo to afford 4,4-difluorocyclohexyl-4-methylbenzenesulfonate (9.2 g, 28.5 mmol, 77.66% yield) as a gray solid. The product was used directly without further purification.

[0498] 1H NMR (400MHz, CDCl3) δppm 7.78 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 4.67–4.66 (m, 1H), 2.44 (s, 3H), 2.07–1.75 (m, 8H).

[0499] Step 2: To a solution of 5-methyl-3-nitro-1H-pyrazole (2 g, 15.7 mmol) and 4,4-difluorocyclohexyl-4-methylbenzenesulfonate (4.6 g, 15.7 mmol) in DMF (30 mL) was added KCO (4.9 g, 35.4 mmol). The mixture was stirred at 80°C for 16 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL*3). The organic layer was washed with water (30 mL), brine (30 ml), dried over anhydrous NaSO and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (elution gradient: PE EA = 5:1) to give 1-(4,4-difluorocyclohexyl)-5-methyl-3-nitro-1H-pyrazole (1.2 g, 4.9 mmol, yield: 31.2%) as a white solid.

[0500] MS (ESI) m / z = 246.1 [M+H] + .

[0501] Step 3: 10% Pd / C (100 mg) was added to a solution of 1-(4,4-difluorocyclohexyl)-5-methyl-3-nitro-1H-pyrazole (1.2 g, 4.9 mmol) in THF (30 mL). The reaction mixture was stirred at 25 ° C for 2 hours. The mixture was filtered through a celite pad and the filtrate was concentrated under vacuum to give a crude product, which was purified by silica gel chromatography (elution gradient: PE EA = 1: 1) to give 1-(4,4-difluorocyclohexyl)-5-methyl-1H-pyrazole-3-amine (0.8 g, 3.72 mmol, yield: 75.92%) as a yellow solid.

[0502] MS (ESI) m / z = 216.2 [M+H] + .

[0503] Step 4: To a solution of 1-(4,4-difluorocyclohexyl)-5-methyl-1H-pyrazol-3-amine (800 mg, 3.72 mmol) in DCE (30 mL) was added 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (664 mg, 1.86 mmol, prepared in Example 1), T3P (1.42 g, 4.46 mmol, 50% w / w in EtOAc) and DIEA (1.44 g, 11.2 mmol). The reaction mixture was stirred at 85 ° C for 16 hours. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL * 3). The organic layer was washed with water (30 mL) and brine (30 ml), dried over anhydrous Na2SO4, and concentrated under vacuum to give the crude product, which was purified by silica gel chromatography (elution gradient: PE:EA=5:1) to give N-(1-(4,4-difluorocyclohexyl)-5-methyl-1H-pyrazol-3-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (400 mg, 0.72 mmol, yield: 38.71%) as a white solid.

[0504] MS (ESI) m / z = 555.0 [M+H] + .

[0505] Step 5: To a solution of N-(1-(4,4-difluorocyclohexyl)-5-methyl-1H-pyrazol-3-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (400 mg, 0.72 mmol) in 1,4-dioxane (5 mL) was added sodium thiomethoxide (101.14 mg, 1.44 mmol), Pd2(dba)3 (66.1 mg, 0.072 mmol), Xantphos (83.5 mg, 0.14 mmol) and DIEA (279.2 mg, 2.16 mmol). The reaction mixture was stirred at 90 ° C under a nitrogen atmosphere for 16 hours. The mixture was diluted with ethyl acetate (20 mL) and washed with water (20 mL * 3) and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (elution gradient: petroleum ether / ethyl acetate 5 / 1, v / v) to give N-(1-(4,4-difluorocyclohexyl)-5-methyl-1H-pyrazol-3-yl)-4-(methylthio)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (200 mg, 0.42 mmol, yield: 58.33%) as a yellow solid.

[0506] MS (ESI) m / z = 475.2 [M+H] + .

[0507] Step 6: To a solution of N-(1-(4,4-difluorocyclohexyl)-5-methyl-1H-pyrazol-3-yl)-4-(methylthio)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (80 mg, 0.17 mmol) in DCE (5 mL) was added mCPBA (87.29 mg, 0.51 mmol) and the reaction mixture was stirred at 60° C. for 6 hours. The mixture was diluted with ethyl acetate (20 mL) and washed with water (20 mL*3) and sodium bicarbonate (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by preparative HPLC (Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length) using decreasingly polar mixtures of water (containing 0.05% FA) and MeCN as eluents 58-70% to give the title compound N-(1-(4,4-difluorocyclohexyl)-5-methyl-1H-pyrazol-3-yl)-4-(methylsulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (24.8 mg, 0.049 mmol, 29.06% yield) as a white solid.

[0508] 1 H NMR(400MHz,DMSO-d6)δppm 12.29(s,1H),8.07(d,J=8.2Hz,1H),7.80(d,J=1.6Hz,1H),7.72(dd,J=8.2,1.6Hz,1H),6.43(s,1H),4.38(br.s,1H),3.29(s, 3H),3.13–2.95(m,4H),2.30(s,3H),2.25–2.17(m,2H),2.10–1.98(m,4H),1.95–1.88(m,2H),1.62–1.59(m,4H),0.35(s,4H).

[0509] MS (ESI) m / z = 507.2 [M+H] + .

[0510] Example 16:

[0511] N-(1-(4,4-difluorocyclohexyl)-5-methyl-1H-pyrazol-3-yl)-4-(S-methylsulfonylimino)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0512]

[0513] Step 1: To a solution of N-(1-(4,4-difluorocyclohexyl)-5-methyl-1H-pyrazol-3-yl)-4-(methylthio)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (100 mg, 0.21 mmol, prepared in Example 15) in MeOH (10 mL) was added ammonium carbonate (60.7 mg, 0.63 mmol) and (diacetoxyiodo)benzene (271.4 mg, 0.84 mmol) at 0° C. The reaction mixture was stirred at 25° C. for 2 h. The reaction was concentrated under vacuum to give the crude product, which was purified by preparative HPLC (Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length, using decreasingly polar mixtures of water and MeCN as eluents 30%-45%) to give racemic N-(1-(4,4-difluorocyclohexyl)-5-methyl-1H-pyrazol-3-yl)-4-(S-methylsulfonylimino)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (30 mg).

[0514] Step 2: Racemic N-(1-(4,4-difluorocyclohexyl)-5-methyl-1H-pyrazol-3-yl)-4-(S-methylsulfonylimino)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (30 mg) was separated by SFC (Thar Preparation 80, column: CHIRALPAK WHELK-01 250 mm x 21.1 mm, 5 μm, modifier: 40% IPROH (NH4OH 0.2%) / 60% CO2, total flow rate: 50 g / min, temperature: 40°C) to give the title compound.

[0515] The first peak (RT = 7.07 min, 16-1): (R or S)-N-(1-(4,4-difluorocyclohexyl)-5-methyl-1H-pyrazol-3-yl)-4-(S-methylsulfonylimino)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (7.2 mg, 0.014 mmol, yield: 6.67%), as a white solid.

[0516] 1H NMR(400MHz,DMSO-d6)δppm 12.52(s,1H),8.09(d,J=8.2Hz,1H),7.85(d,J=1.4Hz,1H),7.75(dd,J=8.2,1.4Hz,1H),6.43(s,1H),4.38(s,2H),3.12(s,3 H),3.09–3.02(m,4H),2.30(s,3H),2.23–2.16(m,2H),2.12–1.97(m,4H),1.95–1.87(m,2H),1.66–1.62(m,4H),0.36(s,4H).

[0517] MS (ESI) m / z = 506.2 [M+H] + .

[0518] The second peak (RT = 7.88 min, 16-2): (S or R) -N- (1- (4,4-difluorocyclohexyl) -5-methyl-1H-pyrazol-3-yl) -4- (S-methylsulfonylimino) -2- (6-azaspiro [2.5] oct-6-yl) benzamide (4.9 mg, 0.097 mmol, yield: 4.62%), as a white solid.

[0519] 1 H NMR(400MHz,DMSO-d6)δppm 12.52(s,1H),8.09(d,J=8.2Hz,1H),7.85(d,J=1.4Hz,1H),7.75(dd,J=8.2,1.4Hz,1H),6.43(s,1H),4.38(s,2H),3.12(s,3 H),3.09–3.02(m,4H),2.30(s,3H),2.23–2.16(m,2H),2.12–1.97(m,4H),1.95–1.87(m,2H),1.66–1.62(m,4H),0.36(s,4H).

[0520] MS (ESI) m / z = 506.2 [M+H] + .

[0521] Example 17:

[0522] 4-((2-Hydroxyethyl)sulfonamido)-N-(5-methyl-1-((1s,3s)-3-(trifluoromethyl)cyclobutyl)-1H-pyrazol-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0523]

[0524] Step 1: To a solution of 3-(trifluoromethyl)cyclobutan-1-ol (500 mg, 3.57 mmol), triethylamine (722 mg, 7.13 mol), and 4-DMAP (218 mg, 1.78 mol) in DCM (30 mL) stirred at 25°C was added a solution of 4-methylbenzenesulfonyl chloride (816 mg, 4.28 mol) in DCM (5 mL) dropwise. The reaction mixture was stirred at 25°C for 16 hours. The mixture was washed with 1N HCl (50 mL*3), saturated aqueous NaHCO3 (50 mL*2), and brine (50 mL*2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford 3-(trifluoromethyl)cyclobutyl 4-methylbenzenesulfonate (750 mg, 2.55 mmol, 71.42% yield) as a yellow solid.

[0525] 1 H NMR (400MHz, CDCl3) δppm 7.79 (d, J = 2.0Hz, 2H), 7.36 (dd, J = 8.0Hz, 0.8Hz, 2H), 4.95–4.72 (m, 1H), 2.90–2.27 (m, 8H).

[0526] Step 2: To a solution of 5-methyl-3-nitro-1H-pyrazole (250 mg, 1.97 mmol) and 3-(trifluoromethyl)cyclobutyl-4-methylbenzenesulfonate (750 mg, 2.55 mmol) in DMF (15 mL) was added CsCO (1.28 g, 3.93 mol). The reaction mixture was stirred at 90°C for 10 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL*3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 4 / 1, v / v) to give 5-methyl-3-nitro-1-((1s,3s)-3-(trifluoromethyl)cyclobutyl)-1H-pyrazole (140 mg, 0.56 mmol, yield: 28.4%) as a yellow solid.

[0527] MS (ESI) m / z = 250.1 [M+H] + .

[0528] Step 3: Pd / C (60 mg, 0.56 mol) was added to a solution of compound 5-methyl-3-nitro-1-((1s, 3s)-3-(trifluoromethyl)cyclobutyl)-1H-pyrazole (140 mg, 0.56 mmol) in THF (20 mL). The mixture was stirred at 25 ° C under a hydrogen atmosphere for 3 hours. The mixture was filtered and concentrated in vacuo to give a crude product which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 1 / 2, v / v) to give 5-methyl-1-((1s, 3s)-3-(trifluoromethyl)cyclobutyl)-1H-pyrazole-3-amine (90 mg, 0.41 mmol, yield: 73.21%) as a yellow solid.

[0529] 1 H NMR (400MHz, DMSO-d6): δppm 5.21(s,1H),4.59(s,2H),4.55–4.52(m,1H),2.96–2.89(m,1H),2.52–2.46(m,2H),2.44–2.42(m,2H),2.08(s,3H).

[0530] MS (ESI) m / z = 220.1 [M+H] + .

[0531] Step 4: To a solution of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (147 mg, 0.41 mmol, prepared in Example 1), HATU (234 mg, 0.62 mmol) and DIEA (106 mg, 0.82 mmol) in DMF (10 mL) was added dropwise a solution of 5-methyl-1-((1s,3s)-3-(trifluoromethyl)cyclobutyl)-1H-pyrazol-3-amine (90 mg, 0.41 mmol) in DMF (2 mL). The reaction mixture was stirred at 25° C. for 4 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL*3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 3 / 1, v / v) to give 4-iodo-N-(5-methyl-1-((1s,3s)-3-(trifluoromethyl)cyclobutyl)-1H-pyrazol-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (100 mg, 0.179 mmol, yield: 43.62%) as a yellow solid.

[0532] MS (ESI) m / z = 559.1 [M+H] + .

[0533] Step 5: To a suspension of 2-hydroxyethanesulfonamide (22.4 mg, 0.18 mmol), CuI (8.5 mg, 0.045 mmol), sarcosine (8.0 mg, 0.089 mmol) and K 3 PO 4 (57 mg, 0.26 mmol) in DMF (10 mL) stirred at 50° C. under nitrogen was added a solution of 4-iodo-N-(5-methyl-1-((1s, 3s))-3-(trifluoromethyl)cyclobutyl)-1H-pyrazol-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (50 mg, 0.089 mmol) in DMF (2 mL). The reaction mixture was stirred at 110° C. for 2 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (40 mL*3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by preparative HPLC (Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length) using decreasingly polar mixtures of water (containing 0.1% FA) and MeCN as eluents (20%-40%) to give the title compound 4-((2-hydroxyethyl)sulfonamido)-N-(5-methyl-1-((1s,3s)-3-(trifluoromethyl)cyclobutyl)-1H-pyrazol-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (18 mg, 0.0324 mmol, 36.2% yield) as a white solid.

[0534] 1 H NMR (400MHz, DMSO-d6): δppm 12.98(s,1H),10.17(s,1H),8.01(d,J=8.4Hz,1H),7.24(d,J=2.0Hz,1H),7.12–7.09(m,1H),6.41(s,1H),4.80–4.76(m,1H),3.75(t, J=6.4Hz,2H),3.35(t,J=6.4Hz,2H),3.01–2.97(m,1H),2.96–2.95(m,4H),2.59–2.50(m,4H),2.24(s,3H),1.71(s,4H),0.37(s,4H).

[0535] MS (ESI) m / z = 556.2 [M+H] + .

[0536] Example 18:

[0537] 4-((2-Hydroxyethyl)sulfonamido)-N-(5-methyl-1-((1r,3r)-3-(trifluoromethyl)cyclobutyl)-1H-pyrazol-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0538]

[0539] Step 1: To a solution of 5-methyl-3-nitro-1H-pyrazole (250 mg, 1.97 mmol) and 3-(trifluoromethyl)cyclobutyl-4-methylbenzenesulfonate (750 mg, 2.55 mmol) in DMF (15 mL) was added CsCO (1.28 g, 3.93 mol). The reaction mixture was stirred at 90°C for 10 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL*3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 4 / 1, v / v) to give 5-methyl-3-nitro-1-((1r,3r)-3-(trifluoromethyl)cyclobutyl)-1H-pyrazole (150 mg, 0.6 mmol, yield: 30.45%) as a yellow solid.

[0540] MS (ESI) m / z = 250.1 [M+H] + .

[0541] Step 2: Pd / C (60 mg, 0.56 mmol) is added to a solution of 5-methyl-3-nitro-1-((1r, 3r)-3-(trifluoromethyl) cyclobutyl)-1H-pyrazole (150 mg, 0.6 mmol) in THF (20 mL). The mixture is stirred for 3 hours at 25 ° C under a hydrogen atmosphere. The mixture is filtered and concentrated in vacuo to give a crude product which is purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 1 / 2, v / v) to give compound 5-methyl-1-((1r, 3r)-3-(trifluoromethyl) cyclobutyl)-1H-pyrazole-3-amine (110 mg, 0.41 mmol, yield: 73.21%) as a yellow solid.

[0542] 1 H NMR (400MHz, DMSO-d6): δppm 5.22(s,1H),4.69–4.65(m,1H),4.58(s,2H),3.14–3.12(m,1H),2.75–2.71(m,2H),2.46–2.44(m,2H),2.06(s,3H).

[0543] MS (ESI) m / z = 220.1 [M+H] + .

[0544] Step 3: To a solution of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (179 mg, 0.50 mmol, prepared in Example 1), HATU (286 mg, 0.75 mmol) and DIEA (130 mg, 1.0 mmol) in DMF (10 ml) stirred under nitrogen was added dropwise a solution of 5-methyl-1-((1r,3r)-3-(trifluoromethyl)cyclobutyl)-1H-pyrazol-3-amine (110 mg, 0.50 mmol) in DMF (2 mL). The reaction mixture was stirred at 25° C. for 4 hours. The mixture was quenched with water (50 mL) and extracted with ethyl acetate (30 mL*3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 3 / 1, v / v) to give 4-iodo-N-(5-methyl-1-((1r,3r)-3-(trifluoromethyl)cyclobutyl)-1H-pyrazol-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (120 mg, 0.21 mmol, yield: 42.83%) as a yellow solid.

[0545] MS (ESI) m / z = 559.1 [M+H] + .

[0546] Step 4: To a suspension of 2-hydroxyethanesulfonamide (22.4 mg, 0.18 mmol), CuI (8.5 mg, 0.045 mmol), sarcosine (8.0 mg, 0.089 mmol) and K PO 4 (57 mg, 0.26 mmol) in DMF (10 mL) stirred at 50° C. under nitrogen was added a solution of 4-iodo-N-(5-methyl-1-((1r,3r))-3-(trifluoromethyl)cyclobutyl)-1H-pyrazol-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (50 mg, 0.088 mmol) in DMF (2 mL). The reaction mixture was stirred at 110° C. for 2 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (40 mL*3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by preparative HPLC (Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length) using decreasingly polar mixtures of water (containing 0.1% FA) and MeCN as eluents (20-40 purification) to give the title compound 4-((2-hydroxyethyl)sulfonamido)-N-(5-methyl-1-((1r,3r)-3-(trifluoromethyl)cyclobutyl)-1H-pyrazol-3-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (22 mg, 0.04 mmol, 44.25% yield) as a white solid.

[0547] 1 H NMR (400MHz, DMSO-d6): δppm 12.87(s,1H),10.17(s,1H),7.97(d,J=8.8Hz,1H),7.23(d,J=2.0Hz,1H),7.1–7.08(m,1H),6.42(s,1H),4.90–4.86(m,1H ),3.76(t,J=6.4Hz,2H),3.35–3.27(m,3H),2.99–2.96(m,4H),2.68–2.65(m,4H),2.23(s,3H),1.71(s,4H),0.38(s,4H).

[0548] MS (ESI) m / z = 556.2 [M+H] + .

[0549] Example 19: N-(1-cyclopropyl-1H-indazol-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0550]

[0551] Step 1: To a suspension of 5-nitro-1H-indazole (500 mg, 3.06 mmol), cyclopropylboronic acid (527 mg, 6.13 mmol), and Na2CO3 (650 mg, 6.13 mol) in dichloroethane (20 mL) was added copper (II) acetate (557 mg, 3.06 mol) and pyridine (242 mg, 3.06 mmol). The resulting mixture was stirred at 70°C under O2 for 4 hours. The reaction mixture was cooled to room temperature, poured into 2N HCl solution (50 mL), and the organic layer was separated. The aqueous layer was extracted with DCM (20 mL*3). The organic layers were combined, washed with brine (50 mL*2), dried over anhydrous Na2SO4, and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 2 / 1, v / v) to give 1-cyclopropyl-6-nitro-1H-indazole (300 mg, 1.48 mmol, yield: 48.17%) as a yellow solid.

[0552] 1 H NMR (400MHz, DMSO-d6) δppm 8.63(s,1H),8.27(s,1H),8.03–7.99(m,2H),3.99(s,1H),1.23–1.12(m,4H).

[0553] MS (ESI) m / z = 204.2 [M+H]+ .

[0554] Step 2: To a solution of 1-cyclopropyl-6-nitro-1H-indazole (300 mg, 1.48 mmol) in EtOH (10 mL) and H₂O (2 mL) were added iron powder (412 mg, 7.38 mmol) and NH₄Cl (395 mg, 7.38 mm mol). The reaction mixture was stirred at 70°C for 16 hours. The reaction mixture was cooled to room temperature and then filtered through a celite pad. The filtrate was poured into water (50 mL) and extracted with EtOAc (30 mL*3). The organic layer was washed with brine (30 mL*2), dried over anhydrous Na₂SO₄ and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 1 / 1, v / v) to give 1-cyclopropyl-1H-indazole-6-amine (160 mg, 0.92 mmol, yield: 62.56%) as a yellow gum.

[0555] MS (ESI) m / z = 174.1 [M+H] + .

[0556] Step 3: To a solution of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (165 mg, 0.46 mmol, prepared in Example 1), HATU (263 mg, 0.69 mmol) and DIEA (119 mg, 0.92 mmol) in DMF (5 mL) stirred at 25° C. under nitrogen was added a solution of 1-cyclopropyl-1H-indazol-6-amine (80 mg, 0.46 mmol) in DMF (1 mL). The reaction mixture was stirred at 25° C. for 16 hours. The reaction mixture was poured into water (40 mL) and extracted with EtOAc (30 mL*3). The organic layer was washed with brine (30 mL*2), dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 1 / 1, v / v) to give N-(1-cyclopropyl-1H-indazol-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (52 mg, 0.10 mmol, yield: 21.97%) as a yellow solid.

[0557] MS (ESI) m / z = 513.1 [M+H] + .

[0558] Step 4: A suspension of 2-hydroxyethanesulfonamide (24 mg, 0.20 mmol), CuI (9 mg, 0.05 mmol), sarcosine (9 mg, 0.10 mmol), and K3PO4 (104 mg, 0.49 mmol) in DMF (4 mL) was preheated to 50°C for 10 minutes. To this mixture was added a solution of N-(1-cyclopropyl-1H-indazol-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (50 mg, 0.10 mmol) in DMF (1 mL). The resulting mixture was stirred at 110°C under nitrogen for 16 hours. The reaction mixture was cooled to room temperature, poured into water (40 mL), and extracted with EtOAc (30 mL*3). The organic layer was washed with brine (30 mL*2), dried over anhydrous Na2SO4, and concentrated in vacuo to obtain the crude product. The crude product was purified by preparative HPLC (Gemini-C18 column, 5 um silica, 21 mm diameter, 150 mm length) using decreasingly polar mixtures of water (containing 0.1% FA) and MeCN as eluents (20%-60%) to give the title compound N-(1-cyclopropyl-1H-indazol-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (8.8 mg, 0.02 mmol, yield: 17.73%) as a white solid.

[0559] 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.80(s,1H),10.12(s,1H),8.48(s,1H),7.93(s,1H),7.87(d,J=8.5Hz,1H),7 .75(d,J=8.6Hz,1H),7.27(dd,J=8.7,1.4Hz,1H),7.19(d,J=1.8Hz,1H),7.06( dd,J=8.5,1.9Hz,1H),4.97(s,1H),3.79–3.75(m,2H),3.69–3.65(m,1H),3.36 –3.33(m,2H),3.08–2.92(m,4H),1.55(s,4H),1.15–1.09(m,4H),0.36(s,4H).

[0560] MS (ESI) m / z = 510.3 [M+H] + .

[0561] Example 20: 4-((2-Hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(1-(3,3,3-trifluoropropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)benzamide

[0562]

[0563] Step 1: To a solution of 3,3,3-trifluoropropyl 4-methylbenzenesulfonate (3 g, 11.2 mmol) in DMF (10 mL) was added 6-chloro-1H-pyrazolo[3,4-b]pyridine (2.1 mg, 13.4 mmol) and CsCO (7.3 g, 22.4 mmol). The mixture was stirred at 80°C for 16 hours. The mixture was diluted with EA (30 mL) and washed with water (30 mL*2) and brine (20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 5 / 1, v / v) to afford 6-chloro-1-(3,3,3-trifluoropropyl)-1H-pyrazolo[3,4-b]pyridine (1.2 g, 4.1 mmol, yield: 36.4%) as a yellow oil.

[0564] MS (ESI) m / z = 250.1 [M+H] + .

[0565] Step 2: To a solution of 6-chloro-1-(3,3,3-trifluoropropyl)-1H-pyrazolo[3,4-b]pyridine (1.2 g, 4.1 mmol) in dioxane (5 mL) was added tert-butyl carbamate (0.6 g, 4.8 mmol), Cs2CO3 (3.1 g, 9.6 mmol), Pd2(dba)3 (0.4 g, 0.5 mmol), and Xantphos (0.3 g, 0.5 mmol). The mixture was stirred at 110°C for 16 hours. The mixture was extracted with ethyl acetate (30 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 10 / 1, v / v) to give tert-butyl (1-(3,3,3-trifluoropropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)carbamate (1.0 g, 2.6 mmol, yield: 53.6%) as a white solid.

[0566] MS (ESI) m / z = 275.1 [M+H-56] + .

[0567] Step 3: A solution of tert-butyl (1-(3,3,3-trifluoropropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)carbamate (1.0 g, 2.6 mmol) in HCl / dioxane (4 M, 5 mL) was stirred at 40° C. for 16 hours. The mixture was concentrated under vacuum to give the crude product 1-(3,3,3-trifluoropropyl)-1H-pyrido[3,4b]pyridin-6-amine (0.6 g, 2.2 mmol, 73.1% yield) as a white solid.

[0568] MS (ESI) m / z = 231.1 [M+H] + .

[0569] Step 4: To a solution of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (154 mg, 0.4 mmol, prepared in Example 1) in MeCN (3 mL) was added 1-(3,3,3-trifluoropropyl)-1H-pyrazolo[3,4-b]pyridin-6-amine (100 mg, 0.4 mmol), T3P (1376 mg, 4.3 mmol), and pyridine (342 mg, 4.3 mmol). The mixture was stirred at 20° C. for 16 hours. The mixture was extracted with ethyl acetate (20 mL*3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 6 / 1, v / v) to give 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)-N-(1-(3,3,3-trifluoropropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)benzamide (70 mg, 0.1 mmol, yield: 24.2%) as a yellow solid.

[0570] MS (ESI) m / z = 570.0 [M+H] + .

[0571] Step 5: To a solution of 2-hydroxyethane-1-sulfonamide (31 mg, 0.2 mmol) in DMF (3 mL) were added CuI (12 mg, 0.06 mmol), sarcosine (11 mg, 0.1 mmol), and KPO (130 mg, 0.6 mmol). Under an argon atmosphere, the mixture was stirred at 50°C for 10 minutes. Then, 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)-N-(1-(3,3,3-trifluoropropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)benzamide (70 mg, 0.1 mmol) was added. The mixture was stirred at 110°C for 5 hours. The mixture was diluted with ethyl acetate (20 mL) and washed with water (20 mL*2) and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by preparative TLC (elution gradient: dichloromethane / methanol, 20 / 1, v / v) to give the title compound 4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(1-(3,3,3-trifluoropropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)benzamide (17.3 mg, 0.03 mmol, yield: 30.0%) as a white solid.

[0572] 1 H NMR (400MHz, CD3OD) δ8.29(d,J=8.8Hz,1H),8.17–8.13(m,2H),8.01(s,1H),7.33(d,J=2.1Hz,1H),7.16–7.13(dd,J=8.7,2.1Hz,1H),4.7 0(t,J=7.0Hz,2H),3.93(t,J=6.2Hz,2H),3.36(t,J=6.2Hz,2H),3.09(t,J=5.3Hz,4H),2.91–2.83(m,2H),2.05-1.83(m,4H),0.43(s,4H).

[0573] MS (ESI) m / z = 567.1 [M+H] + .

[0574] Example 99: N-(5-cyano-1-(4,4-difluorocyclohexyl)-1H-pyrazol-3-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0575]

[0576]

[0577] Step 1: To a solution of compound 5-bromo-1H-pyrazol-3-amine (500 mg, 3.1 mmol) in DMF (10 mL) was added Cs2CO3 (2011 mg, 6.2 mmol) and 4-methylbenzenesulfonic acid 4,4-difluorocyclohexyl ester (1075 mg, 3.7 mmol). The mixture was stirred at 90 ° C for 2 hours. The mixture was diluted with EtOAc (30 mL) and washed with water (30 mL * 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 5 / 1, v / v) to give 5-bromo-1-(4,4-difluorocyclohexyl)-1H-pyrazol-3-amine (530 mg, 1.6 mmol, yield: 61.3%) as a yellow solid.

[0578] MS: (ESI) m / z = 280.0 [M+H] + .

[0579] Step 2: To a solution of 5-bromo-1-(4,4-difluorocyclohexyl)-1H-pyrazol-3-amine (210 mg, 0.7 mmol) in DMA (15 mL) was added Zn(CN)2 (123 mg, 1.0 mmol), DPPF (42 mg, 0.07 mmol), Pd2(dba)3 (34 mg, 0.04 mmol), and Zn (20 mg, 0.3 mmol). Under a nitrogen atmosphere, the mixture was stirred at 120°C for 16 hours. The mixture was extracted with ethyl acetate (30 mL*3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 2 / 1, v / v) to give 3-amino-1-(4,4-difluorocyclohexyl)-1H-pyrazole-5-carbonitrile (100 mg, 0.4 mmol, yield: 50.1%) as a white solid.

[0580] MS: (ESI) m / z = 227.2 [M+H] + .

[0581] Step 3: A mixture of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (131 mg, 0.4 mmol), HATU (209 mg, 0.6 mmol), and DIEA (142 mg, 1.1 mmol) in DMF (2 mL) was stirred at room temperature for 0.5 h. This solution was then added to a solution of 3-amino-1-(4,4-difluorocyclohexyl)-1H-pyrazole-5-carbonitrile (83 mg, 0.4 mmol) and NaH (61 mg, 0.9 mmol, 60%) in DMF (3 mL), and stirred at room temperature under N for 16 h. The mixture was diluted with water (20 mL) and extracted with EA (20 mL*3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, concentrated in vacuo, and purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 2 / 1, v / v) to give compound N-(5-cyano-1-(4,4-difluorocyclohexyl)-1H-pyrazol-3-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (130 mg, 0.2 mmol, yield: 53.3%) as a yellow solid.

[0582] MS (ESI) m / z = 566.1 [M+H] + .

[0583] Step 4: To a solution of 2-hydroxyethane-1-sulfonamide (35 mg, 0.3 mmol) in DMF (3 mL) were added CuI (13 mg, 0.07 mmol), sarcosine (13 mg, 0.1 mmol), and KPO (150 mg, 0.7 mmol). Under an argon atmosphere, the mixture was stirred at 50°C for 10 minutes. Then, N-(5-cyano-1-(4,4-difluorocyclohexyl)-1H-pyrazol-3-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (80 mg, 0.1 mmol) was added. The mixture was stirred at 110°C for 5 hours. The mixture was diluted with ethyl acetate (20 mL) and washed with water (20 mL*2) and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by preparative TLC (elution gradient: dichloromethane / methanol, 20 / 1, v / v) to give the title compound N-(5-cyano-1-(4,4-difluorocyclohexyl)-1H-pyrazol-3-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (12.5 mg, 0.02 mmol, yield: 15.2%) as a white solid.

[0584] 1H NMR (400MHz, CD3OD) δ8.12(d,J=8.6Hz,1H),7.34(d,J=2.1Hz,1H),7.30(s,1H),7.18(dd,J=8.6,2.1Hz,1H),4.69(d,J=4.2Hz,1H), 3.96(t,J=6.2Hz,2H),3.38(t,J=6.2Hz,2H),3.08(t,J=5.3Hz,4H),2.42-2.19(m,4H),2.15-2.11(m,4H),1.76(s,4H),0.45(s,4H).

[0585] MS (ESI) m / z = 563.2 [M+H] + .

[0586] Example 131: 4-((2-Hydroxyethyl)sulfonamido)-N-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0587]

[0588] Step 1: To a solution of 6-chloro-1H-pyrazolo[3,4-b]pyridine (11.3 g, 73.5 mmol) in DMF (30 mL) was added 2,2,3,3,3-pentafluoropropyl trifluoromethanesulfonate (24.9 g, 88.3 mmol) and Cs2CO3 (47.9 g, 147.1 mmol). The mixture was stirred at 80°C for 4 hours. The mixture was diluted with EtOAc (300 mL) and washed with water (300 mL*2) and brine (200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 5 / 1, v / v) to afford 6-chloro-1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazolo[3,4-b]pyridine (7.8 g, 27.3 mmol, yield: 37.1%) as a yellow oil.

[0589] MS (ESI) m / z = 286.0 [M+H] + .

[0590] Step 2: To a solution of 6-chloro-1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazolo[3,4-b]pyridine (7.8 g, 27.3 mmol) in dioxane (20 mL) was added tert-butyl carbamate (3.2 g, 27.3 mmol), Cs2CO3 (17.8 mg, 54.6 mmol), Pd2(dba)3 (2.5 g, 2.7 mmol), and Xantphos (1.6 g, 2.7 mmol). The mixture was stirred at 110°C for 16 hours. The mixture was extracted with ethyl acetate (30 mL*3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 10 / 1, v / v) to give tert-butyl (1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)carbamate (6 g, 16.4 mmol, yield: 59.9%) as a colorless oil.

[0591] MS (ESI) m / z = 311.0 [M+H-56] + .

[0592] Step 3: To a solution of tert-butyl (1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)carbamate (6 g, 16.4 mmol) in DCM (30 mL) was added TFA (5 mL). The mixture was stirred at room temperature for 4 hours. The mixture was adjusted to pH = 7 with NaOH (10 wt%). The mixture was diluted with DCM (300 mL) and washed with water (30 mL * 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (elution gradient: DCM / MeOH, 10 / 1, v / v) to give 1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazolo[3,4-b]pyridin-6-amine (3.1 g, 11.6 mmol, 71.1% yield) as a white solid.

[0593] MS (ESI) m / z = 267.1 [M+H] + .

[0594] Step 4: To a solution of 1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazolo[3,4-b]pyridin-6-amine (2.7 g, 10.1 mmol) in MeCN (20 mL) was added 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (3.6 g, 10.1 mmol), T3P (32.3 g, 101.4 mmol), and pyridine (8.0 g, 101.4 mmol). The mixture was stirred at 50°C for 16 hours. The mixture was extracted with ethyl acetate (100 mL*3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 3 / 1, v / v) to give 4-iodo-N-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (4.3 g, 7.1 mmol, yield: 70.0%) as a yellow solid.

[0595] MS (ESI) m / z = 605.9 [M+H] + .

[0596] Step 5: To a solution of 2-hydroxyethane-1-sulfonamide (1.8 g, 14.2 mmol) in DMF (10 mL) were added CuI (0.7 g, 3.6 mmol), N,N-dimethylglycine (0.7 mg, 7.2 mmol), and KPO (7.5 g, 35.5 mmol). Under an argon atmosphere, the mixture was stirred at 50°C for 10 minutes. Then, 4-iodo-N-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (4.3 g, 7.1 mmol) was added. The mixture was stirred at 110°C for 5 hours. The mixture was diluted with ethyl acetate (100 mL) and washed with water (100 mL*2) and brine (100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: dichloromethane / methanol, 15 / 1, v / v) to give the title compound 4-((2-hydroxyethyl)sulfonamido)-N-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (1.29 g, 2.1 mmol, yield: 30.1%) as a white solid.

[0597] 1H NMR (400MHz, CD3OD) δ8.37(d,J=8.8Hz,1H),8.21(d,J=8.8Hz,1H),8.15(d,J=8.6Hz,1H),8.10(s,1H),7.33(d,J=2.1Hz,1H),7.15(dd,J =8.6, 2.2Hz, 1H), 5.17 (t, J = 14.6Hz, 2H), 3.93 (t, J = 6.2Hz, 2H), 3.36 (t, J = 6.2Hz, 2H), 3.09 (t, J = 5.2Hz, 4H), 2.01 (s, 4H), 0.41 (s, 4H).

[0598] MS (ESI) m / z = 603.0 [M+H] + .

[0599] Example 132: 4-((2-Hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(1-((1-(trifluoromethyl)cyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)benzamide

[0600]

[0601] Step 1: To a solution of compound (1-(trifluoromethyl)cyclopropyl)methanol (800 mg, 5.7 mmol) in DCM (5 mL) was added 4-DMAP (70 mg, 0.6 mmol) and TEA (11556 mg, 11.4 mmol). Under an argon atmosphere, the mixture was stirred at 0°C for 10 minutes. TsCl (1197 mg, 6.3 mmol) was then added. The mixture was stirred at room temperature for 2 hours. The mixture was adjusted to pH = 7 with HCl. The mixture was diluted with DCM (30 mL) and washed with water (30 mL*3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 3 / 1, v / v) to give (1-(trifluoromethyl)cyclopropyl)4-methylbenzenesulfonic acid methyl ester (1000 mg, 2.9 mmol, yield: 50.6%) as a colorless oil.

[0602] 1 H NMR (400MHz, CDCl3) δ7.79(d,J=8.3Hz,2H),7.36(d,J=8.1Hz,2H),4.09(s,2H),2.46(s,3H),1.22–1.03(m,2H),0.84(d,J=1.3Hz,2H).

[0603] Step 2: To a solution of methyl (1-(trifluoromethyl)cyclopropyl)-4-methylbenzenesulfonate (1000 mg, 4.7 mmol) in DMF (10 mL) was added 6-chloro-1H-pyrazolo[3,4-b]pyridine (600 mg, 3.9 mmol) and CsCO (2546 mg, 7.8 mmol). The mixture was stirred at 80°C for 16 hours. The mixture was diluted with EA (30 mL) and washed with water (30 mL*2) and brine (20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 5 / 1, v / v) to afford 6-chloro-1-((1-(trifluoromethyl)cyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyridine (675 mg, 2.2 mmol, yield: 56.4%) as a yellow oil.

[0604] MS (ESI) m / z = 276.1 [M+H] + .

[0605] Step 3: To a solution of 6-chloro-1-((1-(trifluoromethyl)cyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyridine (675 mg, 2.7 mmol) in dioxane (5 mL) was added tert-butyl carbamate (631 mg, 5.4 mmol), Cs2CO3 (1755 mg, 5.4 mmol), Pd2(dba)3 (247 mg, 0.3 mmol), and Xantphos (156 mg, 0.3 mmol). The mixture was stirred at 110°C for 16 hours. The mixture was extracted with ethyl acetate (30 mL*3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 10 / 1, v / v) to give tert-butyl (1-((1-(trifluoromethyl)cyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)carbamate (490 mg, 1.3 mmol, 49.4% yield) as a colorless oil.

[0606] MS (ESI) m / z = 301.2 [M+H-56] + .

[0607] Step 4: A solution of tert-butyl (1-((1-(trifluoromethyl)cyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)carbamate (490 mg, 1.3 mmol) in HCl / dioxane (4 M, 5 mL) was stirred at 40 ° C for 16 hours. The mixture was adjusted to pH = 7 with HCl. The mixture was diluted with DCM (30 mL) and washed with water (30 mL*3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (elution gradient: DCM / MeOH, 10 / 1, v / v) to give 1-((1-(trifluoromethyl)cyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyridin-6-amine (249 mg, 1.0 mmol, 70.7% yield) as a white solid.

[0608] MS (ESI) m / z = 257.1 [M+H] + .

[0609] Step 5: A mixture of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (195 mg, 0.5 mmol), HATU (249 mg, 0.6 mmol), and DIEA (141 mg, 1.1 mmol) in DMF (2 mL) was stirred at room temperature for 0.5 h. This solution was then added to a solution of 1-((1-(trifluoromethyl)cyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyridin-6-amine (140 mg, 0.5 mmol) and NaH (53 mg, 1.4 mmol, 60%) in DMF (3 mL), and stirred at room temperature under N for 16 h. The mixture was diluted with water (20 mL) and extracted with EA (20 mL*3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, concentrated in vacuo, and purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 5 / 1, v / v) to give compound 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)-N-(1-((1-(trifluoromethyl)cyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)benzamide (174 mg, 0.3 mmol, yield: 53.5%) as a yellow solid.

[0610] MS (ESI) m / z = 596.0 [M+H] + .

[0611] Step 6: To a solution of 2-hydroxyethane-1-sulfonamide (73 mg, 0.6 mmol) in DMF (3 mL) were added CuI (28 mg, 0.1 mmol), sarcosine (26 mg, 0.3 mmol), and KPO (210 mg, 1.5 mmol). Under an argon atmosphere, the mixture was stirred at 50°C for 10 minutes. Then, 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)-N-(1-((1-(trifluoromethyl)cyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)benzamide (174 mg, 0.3 mmol) was added. The mixture was stirred at 110°C for 5 hours. The mixture was diluted with ethyl acetate (20 mL) and washed with water (20 mL*2) and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by preparative TLC (elution gradient: dichloromethane / methanol, 15 / 1, v / v) to give the title compound 4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(1-((1-(trifluoromethyl)cyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)benzamide (28.3 mg, 0.05 mmol, yield: 16.3%) as a white solid.

[0612] 1 H NMR (400MHz, DMSO) δ13.43(s,1H),10.26(s,1H),8.28(s,2H),8.13(s,1H),8.11(d,J=8.6Hz,1H),7.32(d,J=1.8Hz,1H),7.15(dd,J=8.6,2.0Hz,1 H),4.96(s,1H),4.69(s,2H),3.76(d,J=6.2Hz,2H),3.37(t,J=6.5Hz,2H ),3.03(s,4H),1.79(s,4H),1.10(dd,J=16.6,12.4Hz,4H),0.42(s,4H).

[0613] MS (ESI) m / z = 593.2 [M+H] + .

[0614] Example 135: N-(1-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0615]

[0616]

[0617] Step 1: To a solution of 6-chloro-1H-pyrazolo[3,4-b]pyridine (500 mg, 3.25 mmol) and potassium trifluoro(vinyl)borate (1.31 g, 9.77 mmol) in DCE (30 mL) was added Cu(OAc)2 (591.4 mg, 3.25 mol), pyridine (515.1 mg, 6.51 mmol) and Na2CO3 (690 mg, 6.51 mmol). The reaction mixture was stirred at 70°C under O2 for 16 hours. The reaction mixture was cooled to room temperature and diluted with DCM (100 mL). The organic layer was washed with water (50 mL*2) and brine (50 mL*2), dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 2 / 1, v / v) to give 6-chloro-1-vinyl-1H-pyrazolo[3,4-b]pyridine (150 mg, 0.84 mmol, yield: 25.65%) as a yellow solid.

[0618] MS (ESI) m / z = 180.1 [M+H] + .

[0619] Step 2: To a solution of 6-chloro-1-vinyl-1H-pyrazolo[3,4-b]pyridine (150 mg, 0.84 mmol) and NaI (44 mg, 0.29 mmol) in THF (20 mL) was added trimethyl(trifluoromethyl)silane (416 mg, 2.92 mmol). The reaction mixture was stirred at 65 ° C for 16 hours. The mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 2 / 1, v / v) to obtain 6-chloro-1-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridine (110 mg, 0.48 mmol, yield: 57.36%) as an off-white solid.

[0620] MS (ESI) m / z = 230.1 [M+H] + .

[0621] Step 3: To a solution of 6-chloro-1-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridine (110 mg, 0.48 mmol) and tert-butyl carbamate (225 mg, 1.92 mmol) in dioxane (10 mL) was added Xantphos (83 mg, 0.14 mmol), Cs2CO3 (468 mg, 1.44 mmol), and Pd2(dba)3 (44 mg, 0.05 mmol). The reaction mixture was stirred at 110°C for 16 hours. The reaction mixture was cooled to room temperature, poured into water (50 mL), and extracted with EtOAc (30 mL*3). The organic layer was washed with brine (30 mL*3), dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 1 / 1, v / v) to give tert-butyl (1-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)carbamate (100 mg, 0.32 mmol, yield: 67.27%) as a colorless oil.

[0622] MS (ESI) m / z = 255.2 [M+H] + .

[0623] Step 4: To a solution of tert-butyl (1-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)carbamate (100 mg, 0.32 mmol) in DCM (8 mL) was added TFA (1 mL). The reaction mixture was stirred at 25 ° C for 16 hours. The mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 1 / 3, v / v) to give 1-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-6-amine (60 mg, 0.29 mmol, yield: 88.58%) as an off-white solid.

[0624] MS (ESI) m / z = 211.1 [M+H] + .

[0625] Step 5: To a solution of 1-(2,2-difluorocyclopropyl)pyrazolo[3,4-b]pyridin-6-amine (60 mg, 0.29 mmol) in DMF (2 mL) was added NaH (29 mg, 0.71 mmol). The mixture was stirred at room temperature under nitrogen for 10 minutes to form mixture A. DIEA (74 mg, 0.57 mmol) was added to a solution of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (102 mg, 0.29 mmol) and HATU (130 mg, 0.34 mmol) in DMF (2 mL). The mixture was stirred at room temperature under nitrogen for 15 minutes to form mixture B. Reaction mixture B was added dropwise to reaction mixture A. The resulting mixture was stirred at 25 ° C for 16 hours. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (30 mL * 3). The organic layer was washed with brine (30 mL*2), dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 1 / 1, v / v) to give N-(1-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (70 mg, 0.13 mmol, yield: 44.62%) as an off-white solid.

[0626] MS (ESI) m / z = 550.1 [M+H] + .

[0627] Step 6: A suspension of 2-hydroxyethanesulfonamide (64 mg, 0.51 mmol), CuI (12 mg, 0.06 mmol), sarcosine (11 mg, 0.13 mmol), and KPO (135 mg, 0.64 mmol) in DMF (6 mL) was preheated to 50°C for 10 minutes. To this mixture was added a solution of N-(1-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (70 mg, 0.13 mmol) in DMF (2 mL). The resulting mixture was stirred at 110°C under nitrogen for 16 hours. The reaction mixture was cooled to room temperature, poured into water (50 mL), and extracted with EtOAc (30 mL*3). The organic layer was washed with brine (30 mL x 2), dried over anhydrous Na2SO4, and concentrated in vacuo to afford the crude product. The crude product was purified by preparative HPLC (Gemini-C18 column, 5 μm silica, 21 mm diameter, 150 mm length) using decreasingly polar mixtures of water (containing 0.1% FA) and MeCN as eluents (30-60) to afford N-(1-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (10 mg, 0.02 mmol, 14.36% yield) as a white solid.

[0628] 1 H NMR(400MHz,DMSO-d6)δppm 13.43(s,1H),10.23(s,1H),8.32–8.24(m,2H),8.13(s,1H),8.07(d,J=8.6Hz,1H),7.28(d,J=2.1Hz,1H),7.13–7.11(m,1H),4 .44–4.38(m,1H),3.75–3.71(m,2H),3.35–3.32(m,2H),2.98(s,4H),2.51–2.49(m,1H),2.42(s,1H),1.73(s,4H),0.35(s,4H).

[0629] MS (ESI) m / z = 547.2 [M+H] + .

[0630] Example 138: N-(1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0631]

[0632] Step 1: To a THF (5 mL) solution of 6-chloro-1H-pyrazolo[3,4-b]pyridine (500 mg, 3.26 mmol), 3,3-difluorocyclobutan-1-ol (527.9 mg, 4.88 mmol) and PPh3 (1.03 g, 3.91 mmol) was added DIAD (790.1 mg, 3.91 mmol). The mixture was stirred at room temperature under N2 for 16 hours. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (30 mL*3). The organic layer was washed with brine (20 mL*2), dried over anhydrous Na2SO4, and concentrated in vacuo to give the crude product. Purification by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 3 / 1, v / v) gave 6-chloro-1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyridine (600 mg, 1.97 mmol, yield: 60.51%) as a yellow solid.

[0633] MS (ESI) m / z = 244.1 [M+H] + .

[0634] Step 2: To a solution of 6-chloro-1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyridine (600 mg, 2.46 mmol) and tert-butyl carbamate (346.2 mg, 2.96 mmol) in dioxane (10 mL) was added Xantphos (284.98 mg, 0.49 mmol), Cs2CO3 (2.4 g, 7.39 mmol) and Pd2(dba)3 (225.5 mg, 0.25 mmol). The mixture was stirred at 110°C under nitrogen for 16 hours. The reaction mixture was cooled to room temperature and then filtered. The filtrate was poured into water (30 mL) and extracted with EtOAc (30 mL*3). The organic layer was washed with brine (30 mL*2), dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 3 / 1, v / v) to give tert-butyl (1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)carbamate (600 mg, 1.57 mmol, yield: 63.86%) as a yellow oil.

[0635] MS (ESI) m / z = 269.2 [M+H] + .

[0636] Step 3: To a solution of tert-butyl (1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)carbamate (600 mg, 1.85 mmol) in DCM (10 mL) was added TFA (2 mL). The reaction mixture was stirred at 25 ° C for 3 hours. The reaction solution was concentrated under vacuum. The residue was diluted with EtOAc (30 mL), washed with saturated NaHCO3 aqueous solution (20 mL * 2) and brine (30 mL * 2), dried over anhydrous Na2SO4, and concentrated in vacuo to give a crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 3 / 1, v / v) to give 1- (3,3-difluorocyclobutyl) -1H-pyrazolo [3,4-b] pyridine -6-amine (230 mg, 0.92 mmol, yield: 49.90%) as a white solid.

[0637] 1 H NMR (400MHz, CDCl3) δppm 7.81(s,1H),7.74(d,J=8.0Hz,1H),6.37(d,J=8.0Hz,1H),5.30–5.21(m,1H),4.75(s,2H),3.45–3.31(m,2H),3.15–3.05(m,2H).

[0638] MS (ESI) m / z = 225.2 [M+H] + .

[0639] Step 4: To a solution of 1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyridin-6-amine (220 mg, 0.98 mmol) in DMF (2 mL) was added NaH (94.2 mg, 3.92 mmol). The mixture was stirred at room temperature under nitrogen for 10 minutes to form mixture A. To a solution of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (420.57 mg, 1.18 mmol) and HATU (410 mg, 1.08 mmol) in DMF (2 mL) was added DIEA (253.6 mg, 1.96 mmol). The mixture was stirred at room temperature under nitrogen for 15 minutes to form mixture B. Reaction mixture B was added dropwise to reaction mixture A. The resulting mixture was stirred at 25 ° C for 16 hours. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (30 mL * 3). The organic layer was washed with brine (30 mL * 2), dried over anhydrous Na2SO4, and concentrated in vacuo to give the crude product. Purification by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 3 / 1, v / v) gave N-(1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (240 mg, 0.38 mmol, yield: 39.07%) as a white solid.

[0640] MS (ESI) m / z = 564.2 [M+H] + .

[0641] Step 5: A solution of 2-hydroxyethane-1-sulfonamide (120 mg, 0.98 mmol), CuI (37.2 mg, 0.19 mmol), sarcosine (35 mg, 0.39 mmol), and K3PO4 (415 mg, 1.95 mmol) in DMF (2 mL) was stirred at 50°C under N2 for 15 minutes, followed by the addition of a solution of N-(1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (220 mg, 0.39 mmol) in DMF (2 mL). The mixture was stirred at 110°C under nitrogen for 16 hours. The reaction mixture was cooled to room temperature, poured into water (20 mL), and extracted with hexane (20 mL*3). The organic layer was washed with brine (30 mL x 2), dried over anhydrous Na2SO4, and concentrated in vacuo to afford the crude product. The crude product was purified by preparative HPLC (Gemini-C18 column, 5 μm silica, 21 mm diameter, 150 mm length) using decreasingly polar mixtures of water (containing 0.1% FA) and MeCN as eluents (20-60) to afford the title compound, N-(1-(3,3-difluorocyclobutyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (16.8 mg, 0.03 mmol, 7.3% yield) as a white solid.

[0642] 1 H NMR (400MHz, DMSO-d6): δppm 13.88(s,1H),8.31-8.25(m,2H),8.20(s,1H),8.12(d,J=8.0Hz,1H),7.32(s,1H),7.16(d,J=8.0Hz,1H),5.28 -5.25(m,1H),3.78-3.75(m,2H),3.37-3.33(m,2H),3.27-3.26(m,4H),3.03(s,4H),1.84(s,4H),0.44(s,4H).

[0643] MS: (ESI) m / z = 561.2 [M+H] + .

[0644] The following compounds were synthesized using methods similar to the above procedures or references. Starting materials were either commercially available or prepared in-house.

[0645]

[0646]

[0647]

[0648]

[0649]

[0650]

[0651]

[0652]

[0653]

[0654]

[0655]

[0656]

[0657]

[0658]

[0659]

[0660]

[0661]

[0662]

[0663]

[0664]

[0665]

[0666]

[0667] Example 159 and Example 160: (R)-N-(1-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]oct-6-yl)benzamide and (S)-N-(1-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]oct-6-yl)benzamide

[0668]

[0669] Step 1: To a solution of 6-chloro-1H-pyrazolo[3,4-b]pyridine (1000 mg, 6.5 mmol) and potassium trifluoro(vinyl)borate (2.62 g, 19.54 mmol) in DCE (50 mL) was added Cu(OAc)2 (1182.8 mg, 6.5 mmol), pyridine (1030.2 mg, 13.2 mmol) and Na2CO3 (1380 mg, 13.2 mmol). The reaction mixture was stirred at 70°C under O2 for 16 hours. The reaction mixture was cooled to room temperature and diluted with DCM (100 mL). The organic layer was washed with water (50 mL*2) and brine (50 mL*2), dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 2 / 1, v / v) to give 6-chloro-1-vinyl-1H-pyrazolo[3,4-b]pyridine (300 mg, 1.68 mmol, yield: 25.65%) as a yellow solid.

[0670] MS (ESI) m / z = 180.1 [M+H] + .

[0671] Step 2: To a THF (20 mL) solution of 6-chloro-1-vinyl-1H-pyrazolo[3,4-b]pyridine (300 mg, 1.68 mmol) and NaI (88 mg, 0.58 mmol) was added trimethyl(trifluoromethyl)silane (832 mg, 5.84 mmol). The reaction mixture was stirred at 65 ° C for 16 hours. The mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 2 / 1, v / v) to obtain 6-chloro-1-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridine (330 mg, 1.44 mmol, yield: 85.7%) as an off-white solid.

[0672] MS (ESI) m / z = 230.1 [M+H] + .

[0673] Step 3: To a solution of 6-chloro-1-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridine (330 mg, 1.44 mmol) and tert-butyl carbamate (675 mg, 5.76 mmol) in dioxane (10 mL) was added Xantphos (249 mg, 0.42 mmol), Cs2CO3 (1404 mg, 4.32 mmol), and Pd2(dba)3 (132 mg, 0.15 mmol). The reaction mixture was stirred at 110°C for 16 hours. The reaction mixture was cooled to room temperature, poured into water (50 mL), and extracted with EtOAc (30 mL*3). The organic layer was washed with brine (30 mL*3), dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 1 / 1, v / v) to give tert-butyl (1-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)carbamate (400 mg, 1.29 mmol, yield: 89.6%) as a colorless oil.

[0674] MS (ESI) m / z = 255.2 [M+H] + .

[0675] Step 4: To a solution of tert-butyl (1- (2,2-difluorocyclopropyl) -1H- pyrazolo [3,4-b] pyridin-6-yl) carbamate (400 mg, 1.29 mmol) in DCM (10 mL) was added TFA (2 mL). The reaction mixture was stirred at 25 ° C for 16 hours. The mixture was concentrated under reduced pressure to give a crude product. The crude product was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 1 / 3, v / v) to give 1- (2,2-difluorocyclopropyl) -1H- pyrazolo [3,4-b] pyridin-6-amine (350 mg, crude product) as an off-white solid. The crude product was purified by SFC (Thar prep 80, column: CHIRALPAK AD-H 250 mm x 20 mm x 5μm, modifier: IPA (NH4OH) / CO2, total flow rate: 40g / min, temperature: 40℃), to obtain two isomers: (R)-1-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridine-6-amine or (S)-1-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridine-6-amino (the first peak of SFC, 120mg) and (S)-1-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridine-6-amino or (R)-1-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridine-6-amino (the second peak of SFC, 110mg).

[0676] MS (ESI) m / z = 211.1 [M+H] + .

[0677] Step 5: To a solution A of (R)-1-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-6-amine or (S)-1-(2,2-difluorocyclopropyl)-1-pyrazolo[3,4-b]pyridin-6-amine (the first peak of SFC, 120 mg, 0.57 mmol) in DMF (3 mL) was added NaH (57 mg, 1.43 mmol). The mixture was stirred at room temperature under nitrogen for 10 minutes. To a solution B of 2-(6-azaspiro[2.5]octan-6-yl)-4-iodobenzoic acid (204 mg, 0.57 mmol) in DMF (3 mL) was added HATU (260 mg, 0.69 mmol) and DIEA (148 mg, 1.14 mmol). The mixture was stirred at 25 ° C under nitrogen for 15 minutes. Solution B was added to solution A. The resulting mixture was stirred at 25° C. for 16 hours. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (30 mL*3). The organic layer was washed with brine (30 mL*2), dried over anhydrous Na2SO4, and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 4 / 1, v / v) to give (R)-N-(1-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide or (S)-N-(1-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (160 mg, 0.29 mmol, yield: 51.02%) as a white solid.

[0678] MS (ESI) m / z = 550.1 [M+H] + .

[0679] Step 6: A suspension of 2-hydroxyethanesulfonamide (146 mg, 1.17 mmol), CuI (44 mg, 0.23 mmol), sarcosine (26 mg, 0.29 mmol) and K3PO4 (309 mg, 1.46 mmol) in DMF (5 mL) was preheated to 50°C for 10 minutes. Then, a solution of (R)-N-(1-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide or (S)-N-(1-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide in DMF (3 mL) was added. The resulting mixture was stirred at 110 ° C for 16 hours under nitrogen. The reaction mixture was cooled to room temperature, poured into water (50 mL), and extracted with EtOAc (30 mL * 3). The organic layer was washed with brine (30 mL * 3), dried over anhydrous Na2SO4, and concentrated in vacuo to give a crude product. The crude product was purified by preparative HPLC (Gemini-C18 column, 5um silica, 21 mm diameter, 150 mm length) using a mixture of water (containing 0.1% FA) and MeCN with gradually decreasing polarity as an eluent (20-40) to give the title compound Example 159 (R) -N- (1- (2,2-difluorocyclopropyl) -1H- pyrazolo [3,4-b] pyridin-6-yl) -4- ((2

[0268] 1-Hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]oct-6-yl)benzamide or (S)-N-(-1-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]oct-6-yl)benzamide (79.5 mg, 0.15 mmol, yield: 49.91%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δppm 13.47(s,1H),10.28(s,1H),8.31–8.24(m,2H),8.17(s,1H),8.11(d,J=8.7Hz,1H),7.32(d,J=2.1Hz,1H),7.17–7.15(m,1H),4.48 –4.42(m,1H),3.79–3.75(m,2H),3.40–3.36(m,2H),3.03(s,4H),2.57–2.54(m,1H),2.50–2.46(m,1H),1.78(s,4H),0.40(s,4H).

[0680] MS (ESI) m / z = 547.1 [M+H] + .

[0681] Example 160 was synthesized from (S)-1-(2,2-difluorocyclopropyl)pyrazolo[3,4-b]pyridin-6-amine or (R)-1-(2,2-difluorocyclopropyl)pyrazolo[3,4-b]pyridin-6-amine (second peak by SFC, 110 mg, 0.52 mmol) using a similar method to the above procedure.

[0682] 1 H NMR(400MHz,DMSO-d6)δppm 13.47(s,1H),10.28(s,1H),8.36–8.24(m,2H),8.17(s,1H),8.11(d,J=8.7Hz,1H),7.32(d,J=2.1Hz,1H),7.17–7.15(m,1H),4.48 –4.42(m,1H),3.79–3.75(m,2H),3.40–3.36(m,2H),3.03(s,4H),2.56–2.54(m,1H),2.50–2.43(m,1H),1.77(s,4H),0.40(s,4H).

[0683] MS (ESI) m / z = 547.2 [M+H] + .

[0684] Example 161: 2-(4-(difluoromethylene)piperidin-1-yl)-4-((2-hydroxyethyl)sulfonamido)-N-(1-(3,3,3-trifluoropropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)benzamide

[0685]

[0686]

[0687] Step 1: At -40 ° C, to a solution of tert-butyl 4-oxopiperidine-1-carboxylate (1.25 g, 6.2 mmol) and 2-(difluoromethane)sulfonylpyridine (1 g, 5.2 mmol) in DMF (30 mL) was added dropwise a solution of t-BuOK (1.05 g, 9.3 mmol) in DMF (10 mL). The mixture was then stirred at -40 ° C for 2 hours under nitrogen. The reaction mixture was warmed to room temperature, poured into water (50 mL), the pH value was adjusted to 3 with 2N HCl, and then extracted with EtOAc (50 mL * 3). The organic layer was washed with brine (50 mL * 2), dried over anhydrous Na2SO4, and concentrated in vacuo to obtain the crude product. The crude product was purified by flash silica gel chromatography (elution gradient: 0 to 20% EtOAc in hexanes, v / v) to give tert-butyl 4-(difluoromethylene)piperidine-1-carboxylate (1.1 g, 4.7 mmol, yield: 90.4%) as a colorless oil.

[0688] 1 H NMR (400MHz, CDCl3) δppm 3.38–3.37(m,4H),2.12–2.10(m,4H),1.42(s,9H).

[0689] MS (ESI) m / z = 178.2 [M-56] + .

[0690] Step 2: To a solution of tert-butyl 4-(difluoromethylene)piperidine-1-carboxylate (1.1 g, 4.7 mmol) in DCM (10 mL) stirred under nitrogen was added a 4M HCl solution in dioxane (10 mL, 40 mmol). The reaction mixture was stirred at 25 ° C for 2 hours. The mixture was concentrated under reduced pressure to give 4-(difluoromethylene)piperidine hydrochloride (0.6 g, 3.5 mmol, yield: 74.47%) as a white solid. The product was used directly without further purification.

[0691] 1 H NMR (400MHz, DMSO-d6) δppm 9.31–9.17(m,2H),3.06–3.05(m,4H),2.38–2.37(m,4H).

[0692] MS (ESI) m / z = 134.2 [M+H] + .

[0693] Step 3: To a solution of 4-(difluoromethylene)piperidine hydrochloride (500 mg, 2.93 mmol) and 2-fluoro-4-iodobenzoic acid (500 mg, 1.88 mmol) in DMSO (15 mL) was added potassium carbonate (779 mg, 5.63 mmol). The reaction mixture was stirred at 130°C for 16 hours. The reaction mixture was cooled to room temperature, poured into water (30 mL), and extracted with EtOAc (50 mL*3). The organic layer was washed with brine (50 mL*2), dried over anhydrous Na2SO4, and concentrated in vacuo to obtain the crude product. The crude product was purified by flash silica gel chromatography (10 g, elution gradient: 0 to 70% EtOAc in hexanes) to afford 2-(4-(difluoromethylene)piperidin-1-yl)-4-iodobenzoic acid (270 mg, crude) as a yellow solid.

[0694] MS (ESI) m / z = 380.1 [M+H] + .

[0695] Step 4: To a solution A of 1-(3,3,3-trifluoropropyl)pyrazolo[3,4-b]pyridin-6-amine (261 mg, 1.13 mmol, prepared in Example 20) in DMF (6 mL) was added NaH (227 mg, 1.13 mmol). The mixture was stirred at room temperature under nitrogen for 10 minutes. To a solution B of 2-(4-(difluoromethylene)piperidin-1-yl)-4-iodobenzoic acid (430 mg, 1.13 mmol) in DMF (6 mL) was added HATU (517 mg, 1.36 mmol) and DIEA (293 mg, 2.27 mmol). The mixture was stirred at 25°C under nitrogen for 15 minutes. Mixture B was then added to mixture A. The resulting mixture was stirred at 25°C for 16 hours. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (30 mL*3). The organic layer was washed with brine (30 mL*2), dried over anhydrous Na2SO4, and concentrated in vacuo to give a crude product. The crude product was purified by flash silica gel chromatography (elution gradient: 0 to 25% EtOAc in PE) to give 2-(4-(difluoromethylene)piperidin-1-yl)-4-iodo-N-(1-(3,3,3-trifluoropropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)benzamide (150 mg, 0.25 mmol, yield: 25.37%) as a yellow solid.

[0696] MS (ESI) m / z = 592.0 [M+H] + .

[0697] Step 5: To a solution of 2-hydroxyethanesulfonamide (79.4 mg, 0.63 mmol) in DMF (10 mL) was added K3PO4 (161 mg, 0.76 mmol), copper(I) iodide (24 mg, 0.13 mmol), and sarcosine (22.6 mg, 0.25 mmol). The mixture was stirred at 50°C under nitrogen for 10 minutes. A solution of 2-(4-(difluoromethylene)piperidin-1-yl)-4-iodo-N-(1-(3,3,3-trifluoropropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)benzamide (150 mg, 0.25 mmol) in DMF (2 mL) was added dropwise. The reaction mixture was stirred at 110°C for 16 hours. The reaction mixture was cooled to room temperature, poured into water (30 mL), and extracted with EtOAc (50 mL*3). The organic layer was washed with brine (50 mL x 3), dried over anhydrous Na2SO4, and concentrated in vacuo to afford the crude product, which was purified by preparative HPLC (Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length) using decreasingly polar mixtures of water (containing 0.1% FA) and MeCN as eluents (20-40). Fractions containing the desired compound were evaporated to dryness to afford 2-(4-(difluoromethylene)piperidin-1-yl)-4-((2-hydroxyethyl)sulfonamido)-N-(1-(3,3,3-trifluoropropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)benzamide (45 mg, 0.076 mmol, 30.15% yield) as a white solid.

[0698] 1 H NMR (400MHz, DMSO-d6): δppm 11.37(s,1H),8.31–8.26(m,2H),8.14–8.09(m,2H),7.23–7.22(m,1H),7.17–7.14(m,1H),4.57(t,J=7.2 Hz,2H),3.77(t,J=6.4Hz,2H),3.38(t,J=6.4Hz,2H),3.05–3.03(m,4H),2.92–2.86(m,2H),2.59(s,4H).

[0699] MS (ESI) m / z = 589.1 [M+H] + .

[0700] Example 162: N-(5-cyano-1-((1s,3s)-3-(trifluoromethyl)cyclobutyl)-1H-pyrazol-3-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0701]

[0702] Step 1: To a solution of 5-bromo-1H-pyrazol-3-amine (8 g, 0.04 mol) in DMF (100 mL) was added (1r,3r)-1-bromo-3-(trifluoromethyl)cyclobutane (10 g, 0.04 mol) and Cs2CO3 (32.13 g, 0.09 mol). The resulting mixture was stirred at 80°C under N2 for 2 hours. The reaction mixture was cooled to room temperature, diluted with water (200 mL), and extracted with EtOAc (50 mL*3). The organic layer was washed with saturated NH4Cl aqueous solution (50 mL*3), dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 3 / 1, v / v) to give 5-bromo-1-((1s, 3s)-3-(trifluoromethyl)cyclobutyl)-1H-pyrazole-3-amine (5 g, 0.01 mmol, yield: 35.50%) as a yellow solid.

[0703] 1 H NMR (400MHz, DMSO-d6) δppm 5.57(s,1H),5.02(s,2H),4.78–4.69(m,1H),3.07–2.96(m,1H),2.59–2.44(m,4H).

[0704] Step 2: To a solution of 5-bromo-1-((1s, 3s)-3-(trifluoromethyl)cyclobutyl)-1H-pyrazole-3-amine (5.0 g, 0.017 mol) in DMA (50 mL) was added Zn(CN) (6.2 g, 0.052 mol), DPPF (2.91 g, 0.005 mol), Zn powder (1.1 g, 0.017 mol) and Pd(dba) (1.6 g, 0.001 mol). The mixture was stirred at 120 ° C under nitrogen for 16 hours. The reaction mixture was cooled to room temperature, filtered through a celite pad, and concentrated under reduced pressure. The residue was diluted with water (100 mL) and extracted with EtOAc (100 mL*3). The organic layer was washed with brine (100 mL*2), dried over anhydrous Na2SO4, and concentrated in vacuo to give the crude product, which was purified by flash silica gel chromatography (elution gradient: petroleum ether / ethyl acetate, 5 / 1, v / v) to give 3-amino-1-((1s, 3s)-3-(trifluoromethyl)cyclobutyl)-1H-pyrazole-5-carbonitrile (3.2 g, 0.013 mol, yield: 78.86%) as a yellow solid.

[0705] 1H NMR (400MHz, DMSO-d6) δppm 6.15(s,1H),5.33(s,2H),4.84–4.79(m,1H),3.11–3.02(m,1H),2.61–2.50(m,4H).

[0706] Step 3: To a solution of 3-amino-1-((1s,3s)-3-(trifluoromethyl)cyclobutyl)-1H-pyrazole-5-carbonitrile (3.2 g, 0.013 mol) and 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (4.93 g, 0.013 mol) in DMF (50 mL) was added HATU (6.3 g, 0.016 mol) and DIEA (3.57 g, 0.027 mol). The mixture was stirred at room temperature under nitrogen for 16 hours. The reaction mixture was poured into water (200 mL). The precipitate was collected by filtration, washed with water (50 mL) and cold MeCN (50 ml), and dried in vacuo to give N-(5-cyano-1-((1s,3s)-3-(trifluoromethyl)cyclobutyl)-1H-pyrazol-3-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (4.0 g, 0.007 mol, yield: 53.97%) as a white solid.

[0707] MS (ESI) m / z = 570.1 [M+H] + .

[0708] Step 4: A suspension of 2-hydroxyethane-1-sulfonamide (1.99 g, 0.015 mol), CuI (0.5 g, 0.002 mol), sarcosine (0.47 g, 0.005 mol) and K PO (5.63 g, 0.026 mol) in DMF (20 mL) was preheated at 50° C. under N 2 for 20 minutes. To this mixture was added a solution of N-(5-cyano-1-((1s,3s)-3-(trifluoromethyl)cyclobutyl)-1H-pyrazol-3-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (3.0 g, 0.005 mmol) in DMF (30 mL). The reaction mixture was stirred at 110° C. for 5 hours. The mixture was cooled to room temperature, poured into water (100 mL), and extracted with EtOAc (100 mL*3). The organic layer was washed with saturated aqueous NH4Cl solution (100 mL*2), dried over anhydrous Na2SO4, and concentrated in vacuo to give a crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 1 / 3, v / v) to obtain the desired product. The product was further purified by recrystallization (MeCN) to obtain the title compound N-(5-cyano-1-((1s,3s)-3-(trifluoromethyl)cyclobutyl)-1H-pyrazol-3-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (1.2 g, 0.002 mol, yield: 39.61%) as a white solid.

[0709] 1 H NMR (400MHz, DMSO-d6): δppm 13.65(s,1H),10.23(s,1H),8.04–8.02(d,J=8.0Hz,1H),7.31–7.28(m,2H),7.15–7.12(m,1H),5.11–5.03(m,1H),4.97–4.94(m ,1H),3.78–3.74(m,2H),3.37–3.34(m,2H),3.20–3.09(m,1H),2.98–2.96(m,4H),2.74–2.67(m,4H),1.68(s,4H),0.38(s,4H).

[0710] MS: (ESI) m / z = 567.2 [M+H] + .

[0711] Example 163: N-(5-cyano-1-((1s,3s)-3-(trifluoromethyl)cyclobutyl)-1H-pyrazol-3-yl)-4-((2-hydroxy-1-methylethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0712]

[0713] Step 1: A solution of 1-hydroxypropane-2-sulfonamide (293.3 mg, 2.11 mmol), CuI (66.9 mg, 0.35 mmol), sarcosine (62.6 mg, 0.70 mmol), and KPO (745.6 mg, 3.51 mmol) in DMF (3 mL) was preheated at 50° C. under N₂ for 20 minutes. A solution of N-(5-cyano-1-((1s,3s)-3-(trifluoromethyl)cyclobutyl)-1H-pyrazol-3-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (400 mg, 0.70 mmol, prepared in Example 162) in DMF (3 mL) was added. The reaction mixture was stirred at 110° C. for 5 hours. The mixture was cooled to room temperature, poured into water (30 mL), and extracted with EtOAc (30 mL x 3). The organic layer was washed with saturated aqueous NH4Cl solution (30 mL*2), dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product, which was purified by flash silica gel chromatography (elution gradient: 0 to 30% EtOAc in hexane) to give the title compound N-(5-cyano-1-((1s, 3s)-3-(trifluoromethyl)cyclobutyl)-1H-pyrazol-3-yl)-4-((2-hydroxy-1-methylethyl)sulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (140 mg, 0.24 mmol, yield: 34.59%) as a white solid.

[0714] 1 H NMR (400MHz, DMSO-d6): δppm 13.65(s,1H),8.00(d,J=8.8Hz,1H),7.32–7.28(m,2H),7.12(d,J=8.4Hz,1H),5.11–5.03(m,1H),3.85–3.81(m,1H),3.49–3.46(m ,1H),3.28–3.23(m,1H),3.18–3.12(m,1H),2.98–2.95(m,4H),2.74–2.68(m,4H),1.68(s,4H),1.28(d,J=6.8Hz,3H),0.38(s,4H).

[0715] MS: (ESI) m / z = 581.2 [M+H] + .

[0716] Example 164: N-(5-cyano-1-(4,4-difluorocyclohexyl)-1H-pyrazol-3-yl)-2-(4-(difluoromethylene)piperidin-1-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide

[0717]

[0718] Step 1: To a solution of 3-amino-1-(4,4-difluorocyclohexyl)-1H-pyrazole-5-carbonitrile (50 mg, 0.22 mmol, prepared in Example 99) in DMF (5 mL) was added 2-(4-(difluoromethylene)piperidin-1-yl)-4-iodobenzoic acid (84 mg, 0.22 mmol, prepared in Example 161), HATU (101 mg, 0.27 mmol), and DIEA (57 mg, 0.44 mmol). The mixture was stirred at 25° C. for 3 hours. The mixture was extracted with ethyl acetate (30 mL*3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 15 / 1, v / v) to give N-(5-cyano-1-(4,4-difluorocyclohexyl)-1H-pyrazol-3-yl)-2-(4-(difluoromethylene)piperidin-1-yl)-4-iodobenzamide (100 mg, 0.17 mmol, yield: 77%) as a yellow solid.

[0719] MS: (ESI) m / z = 588.0 [M+H] + .

[0720] Step 2: To a solution of 2-hydroxyethane-1-sulfonamide (43 mg, 0.34 mmol) in DMF (2 mL) were added CuI (16 mg, 0.09 mmol), sarcosine (15 mg, 0.17 mmol), and KPO (181 mg, 0.85 mmol). Under an argon atmosphere, the mixture was stirred at 50°C for 10 minutes. Then, N-(5-cyano-1-(4,4-difluorocyclohexyl)-1H-pyrazol-3-yl)-2-(4-(difluoromethylene)piperidin-1-yl)-4-iodobenzamide (100 mg, 0.17 mmol) was added. The mixture was stirred at 110°C for 5 hours. The mixture was diluted with ethyl acetate (20 mL) and washed with water (20 mL*2) and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: elution gradient: petroleum ether / ethyl acetate, 4 / 1, v / v) to give the title compound N-(5-cyano-1-(4,4-difluorocyclohexyl)-1H-pyrazol-3-yl)-2-(4-(difluoromethylene)piperidin-1-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide (26.7 mg, 0.04 mmol, yield: 26.8%) as a white solid.

[0721] MS: (ESI) m / z = 585.2 [M+H] + .

[0722] 1 H NMR (400MHz, CD3OD) δ8.05(d,J=8.6Hz,1H),7.26(s,1H),7.21(d,J=2.1Hz,1H),7.14(dd,J=8.6,2.2Hz,1H),4.62(dd,J=8. 7,4.4Hz,1H),3.91(t,J=6.2Hz,2H),3.33(t,J=6.2Hz,2H),3.02(t,J=5.5Hz,4H),2.51(t,J=5.5Hz,4H),2.32–2.02(m,8H).

[0723] Example 165: N-(1-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0724]

[0725]

[0726] Step 1: LiAlH4(1M THF solution, 12.2mL, 12.2mmol) was added dropwise to a solution of 3-fluorobicyclo[1.1.1]pentane-1-carboxylic acid (800mg, 6.1mmol) in THF (30mL) stirred at 0°C under nitrogen. The reaction mixture was stirred for 1 hour at 0°C. The mixture was quenched with water (10mL) and filtered through a celite pad. The filtrate was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give (3-fluorobicyclo[1.1.1]pentane-1-yl)methanol (710mg, 6.1mmol, yield: 99.44%), which was a yellow jelly that could be used in the next step without further purification.

[0727] Step 2: To a solution of (3-fluorobicyclo[1.1.1]pentan-1-yl)methanol (0.71 g, 6.1 mmol), 4-DMAP (373 mg, 3.0 mmol) and triethylamine (1.23 g, 12.2 mmol) in DCM (20 mL) was added dropwise a solution of TsCl (1.51 g, 7.94 mmol) in DCM (10 mL). The reaction mixture was stirred at 25 ° C for 16 hours. The mixture was washed with 1N HCl (50 mL * 3), NaHCO3 (50 mL) aqueous solution and brine (50 mL * 2), dried over anhydrous sodium sulfate, and concentrated in vacuo to give (3-fluorobicyclo[1.1.1]pentan-1-yl)methyl 4-methylbenzenesulfonate (1.3 g, 4.81 mmol, 76.51% yield) as a yellow solid.

[0728] 1 H NMR (400MHz, DMSO-d6) δppm 7.80–7.78(m,2H),7.50–7.48(m,2H),4.30(s,2H),2.43(s,3H),1.94–1.93(m,6H).

[0729] MS (ESI) m / z = 293.1 [M + Na] + .

[0730] Step 3: A solution of (3-fluorobicyclo[1.1.1]pentan-1-yl)methyl 4-methylbenzenesulfonate (1.3 g, 4.7 mmol) and 6-chloro-1H-pyrazolo[3,4-b]pyridine (500 mg, 3.2 mmol) in DMF (20 mL) was stirred under nitrogen and cesium carbonate (1.85 g, 4.9 mmol) was added. The reaction mixture was stirred at 80°C for 4 hours. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL*3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain the crude product. The crude product was purified by flash silica gel chromatography (elution gradient: 0 to 30% EtOAc in PE) to afford 6-chloro-1-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-1H-pyrazolo[3,4-b]pyridine (450 mg, 1.78 mmol, 55.6% yield) as a yellow solid.

[0731] MS (ESI) m / z = 252.1 [M+H] + .

[0732] Step 4: To a solution of 6-chloro-1-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-1H-pyrazolo[3,4-b]pyridine (450 mg, 1.78 mmol), tert-butyl carbamate (628 mg, 5.36 mmol), Pd2(dba)3 (163 mg, 0.18 mmol) and Xantphos (207 mg, 0.35 mmol) in dioxane (20 mL) was added Cs2CO3 (1.47 g, 5.36 mmol). The reaction mixture was stirred at 110°C for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, poured into water (50 mL), and extracted with EtOAc (50 mL*3). The organic layer was washed with brine (50 mL*2), dried over anhydrous Na2SO4, and concentrated in vacuo to obtain the crude product. The crude product was purified by flash silica gel chromatography (elution gradient: 0-30% EtOAc in hexanes) to give tert-butyl (1-(((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)carbamate (360 mg, 1.07 mmol, 63.2% yield) as a yellow gum.

[0733] MS (ESI) m / z = 333.2 [M + Na] + .

[0734] Step 5: To a solution of tert-butyl (1-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)carbamate (360 mg, 1.07 mmol) in DCM (10 mL) was added trifluoroacetic acid (2 mL). The reaction mixture was stirred at 25 ° C for 2 hours. The mixture was concentrated under reduced pressure. The residue was basified with saturated aqueous NaHCO 3 solution. The mixture was extracted with EtOAc (50 mL * 3). The combined organic layers were dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to give a crude product. The crude product was purified by flash silica gel chromatography (elution gradient: 0 to 40% EtOAc in hexanes) to afford 1-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-6-amine (150 mg, 0.64 mmol, yield: 50.07%) as a yellow solid.

[0735] 1 H NMR (400MHz, DMSO-d6) δppm 7.72–7.69(m,2H),6.43(s,2H),6.35–6.33(m,1H),4.51(s,2H),1.92–1.91(m,6H).

[0736] MS (ESI) m / z = 233.2 [M+H] + .

[0737] Step 6: To a solution of 1-(((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-6-amine (150 mg, 0.65 mmol) and NaH (77.5 mg, 1.94 mmol) in DMF (5 mL) was added dropwise a solution of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (230 mg, 0.65 mmol), HATU (319 mg, 0.84 mmol) and DIEA (125 mg, 0.97 mmol) in DMF (5 mL). The reaction mixture was stirred at 25° C. for 16 h. The mixture was poured into water (50 mL) and extracted with EtOAc (50 mL * 3). The organic layer was washed with brine (50 mL * 2), dried over anhydrous Na2SO4, and concentrated in vacuo to obtain the crude product. The crude product was purified by flash silica gel chromatography (elution gradient: 0 to 30% EtOAc in hexanes) to obtain N-(1-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (100 mg, 0.175 mmol, yield: 27.1%) as a yellow solid.

[0738] MS (ESI) m / z = 572.1 [M+H] + .

[0739] Step 7: To a solution of 2-hydroxyethanesulfonamide (55 mg, 0.43 mmol), K3PO4 (111 mg, 0.52 mmol), CuI (17 mg, 0.087 mmol) and sarcosine (16 mg, 0.17 mmol) in DMF (10 mL) was added N-(1-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (100 mg, 0.175 mmol) at 50°C. The reaction mixture was stirred at 110°C for 16 hours. The reaction mixture was cooled to room temperature, poured into water (50 mL), and extracted with EtOAc (50 mL*3). The organic layer was washed with brine (50 mL*2), dried over anhydrous Na2SO4, and concentrated in vacuo to give the crude product. The crude product was purified by preparative HPLC (Gemini-C18 column, 5u silica, 21 mm diameter, 150 mm length) using decreasingly polar mixtures of water (containing 0.1% FA) and MeCN as eluents (20-40) to give N-(1-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (26 mg, 0.045 mmol, 26.1% yield) as a white solid.

[0740] 1 H NMR (400MHz, DMSO-d6): δppm 13.65(s,1H),10.25(br.s,1H),8.29–8.24(m,2H),8.13–8.11(m,2H),7.32(d,J=2.0Hz,1H),7.16(dd,J=8.8Hz,2.0Hz,1H ),4.97(br.s,1H),4.72(s,2H),3.76–3.74(m,2H),3.39–3.33(m,2H),3.04(s,4H),1.95(s,6H),1.82(s,4H),0.45(s,4H).

[0741] MS (ESI) m / z = 569.2 [M+H] + .

[0742] Example 166 and Example 167: (S)-N-(1-((3-Fluorobicyclo[1.1.1]pentan-1-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-((2-hydroxy-1-methylethyl)sulfonamido-2-(6-azaspiro[2.5]oct-6-yl)benzamide and (R)-N-(1-((3-Fluorobicyclo[1.1.1]pentan-1-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-((2-hydroxy-1-methylethyl)sulfonamido-2-(6-azaspiro[2.5]oct-6-yl)benzamide

[0743]

[0744] Step 1: To a solution of 2-hydroxyethanesulfonamide (241.1 mg, 1.73 mmol), K3PO4 (367.7 mg, 1.71 mmol), CuI (54.9 mg, 0.29 mmol) and sarcosine (36.0 mg, 0.40 mmol) in DMF (5 mL) stirred at 50°C for 20 minutes under nitrogen was added N-(1-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (330 mg, 0.57 mmol, prepared in Example 165). The reaction mixture was stirred at 110°C for 16 hours. The reaction mixture was cooled to room temperature, poured into water (50 mL), and extracted with EtOAc (50 mL*3). The organic layer was washed with brine (50 mL * 2), dried over anhydrous sodium sulfate, and concentrated in vacuo to give a crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 3 / 1, v / v) to give N-(1-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-((2-hydroxy-1-methylethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (220 mg) as an off-white solid. The compound was further purified by SFC (Thar prep 80, column: CHIRALPAK AD-H 250 mm x 20 mm x 5 μm, modifier: EtOH(DEA) / CO2, total flow rate: 40 g / min, temperature: 40°C) to give two compounds.

[0745] Example 166:

[0746] (R)-N-(1-((3-Fluorobicyclo[1.1.1]pentan-1-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-((2-hydroxy-1-methylethyl)sulfonamido)-2-(6-azaspiro[2.5]oct-6-yl)benzamide or (S)-N-(1-((3-Fluorobicyclo[1.1.1]pentan-1-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-((2-hydroxy-1-methylethyl)sulfonamido)-2-(6-azaspiro[2.5]oct-6-yl)benzamide (SFC first peak, 81 mg, 0.013 mmol, yield: 19.86%), as a white solid.

[0747] 1 H NMR(400MHz,MeOD)δppm 13.64(s,1H),8.26(s,2H),8.11(s,2H),7.35(d,J=1.6Hz,1H),7.24–7.10(m,1H),4.72(s,2H),3.90–3.80(m,1 H),3.52–3.48(m,1H),3.29–3.25(m,1H),3.03(s,4H),1.99–1.85(m,10H),1.30(d,J=6.8Hz,3H),0.45(s,4H).

[0748] MS (ESI) m / z = 583.2 [M+H] + .

[0749] Example 167:

[0750] (S)-N-(1-((3-Fluorobicyclo[1.1.1]pentan-1-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-((2-hydroxy-1-methylethyl)sulfonamido)-2-(6-azaspiro[2.5]oct-6-yl)benzamide or (R)-N-(1-((3-Fluorobicyclo[1.1.1]pentan-1-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-((2-hydroxy-1-methylethyl)sulfonamido)-2-(6-azaspiro[2.5]oct-6-yl)benzamide (SFC second peak, 99 mg, 0.017 mmol, yield: 24.27%), as a white solid.

[0751] 1H NMR(400MHz,MeOD)δppm 13.64(s,1H),8.26(s,2H),8.10(s,2H),7.34(d,J=1.6Hz,1H),7.23–7.10(m,1H),4.72(s,2H),3.90–3.80(m,1 H),3.52–3.48(m,1H),3.29–3.25(m,1H),3.03(s,4H),1.99–1.85(m,10H),1.30(d,J=6.8Hz,3H),0.45(s,4H).

[0752] MS (ESI) m / z = 583.2 [M+H] + .

[0753] Example 168: 2-(4-(Difluoromethylene)piperidin-1-yl)-N-(1-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide

[0754]

[0755] Step 1: To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (1.25 g, 6.2 mmol) and 2-(difluoromethane)sulfonylpyridine (1 g, 5.2 mmol) in DMF (30 mL) stirred at -40°C under nitrogen was added a solution of t-BuOK (1.05 g, 9.3 mmol) in DMSO (10 mL). The reaction mixture was stirred at -40°C for 2 hours. The reaction mixture was warmed to room temperature, poured into water (50 mL), and the pH was adjusted to 3 with 2N HCl, then extracted with EtOAc (50 mL*3). The organic layer was washed with brine (50 mL*2), dried over anhydrous Na2SO4, and concentrated in vacuo to obtain the crude product. The crude product was purified by flash silica gel chromatography (elution gradient: 0 to 20% EtOAc in hexanes, v / v) to give tert-butyl 4-(difluoromethylene)piperidine-1-carboxylate (1.1 g, 4.7 mmol, yield: 90.4%) as a colorless oil.

[0756] 1 H NMR (400MHz, CDCl3) δppm 3.38–3.37(m,4H),2.12–2.10(m,4H),1.42(s,9H).

[0757] MS (ESI) m / z = 178.2 [M-56] + .

[0758] Step 2: To a solution of tert-butyl 4-(difluoromethylene)piperidine-1-carboxylate (1.1 g, 4.7 mmol) in DCM (10 mL) stirred under nitrogen was added a 4M HCl solution in dioxane (10 mL, 40 mmol). The reaction mixture was stirred at 25 ° C for 2 hours. The mixture was concentrated under reduced pressure to give 4-(difluoromethylene)piperidine hydrochloride (0.6 g, 3.5 mmol, yield: 74.47%) as a white solid. The product was used directly without further purification.

[0759] 1 H NMR (400MHz, DMSO-d6) δppm 9.31–9.17(m,2H),3.06–3.05(m,4H),2.38–2.37(m,4H).

[0760] MS (ESI) m / z = 134.2 [M+H] + .

[0761] Step 3: To a solution of 4-(difluoromethylene)piperidine hydrochloride (500 mg, 2.93 mmol) and 2-fluoro-4-iodobenzoic acid (500 mg, 1.88 mmol) in DMSO (15 mL) was added potassium carbonate (779 mg, 5.63 mmol). The reaction mixture was stirred at 130°C for 16 hours. The reaction mixture was cooled to room temperature, poured into water (30 mL), and extracted with EtOAc (50 mL*3). The organic layer was washed with brine (50 mL*2), dried over anhydrous Na2SO4, and concentrated in vacuo to obtain the crude product. The crude product was purified by flash silica gel chromatography (10 g, elution gradient: 0 to 70% EtOAc in hexanes) to afford 2-(4-(difluoromethylene)piperidin-1-yl)-4-iodobenzoic acid (270 mg, crude) as a yellow solid.

[0762] MS (ESI) m / z = 380.1 [M+H] + .

[0763] Step 4: To a solution A of 1-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-6-amine (120 mg, 0.52 mmol, prepared in Example 165) in DMF (2 mL) was added NaH (82.67 mg, 2.06 mmol). The mixture was stirred at room temperature under nitrogen for 10 minutes. To a solution B of 2-(4-(difluoromethylene)piperidin-1-yl)-4-iodobenzoic acid (196 mg, 0.52 mmol) in DMF (3 mL) was added HATU (255.4 mg, 0.67 mmol) and DIEA (100.2 mg, 0.77 mmol). The mixture was stirred at 25 ° C under nitrogen for 15 minutes. Then, mixture B was added to mixture A. The resulting mixture was stirred at 25 ° C for 16 hours. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (30 mL * 3). The organic layer was washed with brine (30 mL * 2), dried over anhydrous Na2SO4, and concentrated in vacuo to obtain the crude product. The crude product was purified by flash silica gel chromatography (elution gradient: 0 to 25% EtOAc in PE) to afford 2-(4-(difluoromethylene)piperidin-1-yl)-N-(1-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-iodobenzamide (70 mg, 0.11 mmol, yield: 22.84%) as a yellow solid.

[0764] MS (ESI) m / z = 593.6 [M+H] + .

[0765] Step 5: To a solution of 2-hydroxyethanesulfonamide (44.3 mg, 0.35 mmol) in DMF (2 mL) was added K3PO4 (125.25 mg, 0.59 mmol), copper (I) iodide (11.24 mg, 0.06 mmol), and sarcosine (10.51 mg, 0.12 mmol). The mixture was stirred at 50°C under nitrogen for 10 minutes. A solution of 2-(4-(difluoromethylene)piperidin-1-yl)-N-(1-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-iodobenzamide (70 mg, 0.11 mmol) in DMF (2 mL) was then added dropwise. The reaction mixture was stirred at 110°C for 16 hours. The reaction mixture was cooled to room temperature, poured into water (30 mL), and extracted with EtOAc (50 mL * 3). The organic layer was washed with brine (50 mL * 3), dried over anhydrous Na2SO4, and concentrated in vacuo to give a crude product, which was purified by preparative HPLC (Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length) using decreasingly polar mixtures of water (containing 0.1% FA) and MeCN as eluents (20-40) to give the title compound, 2-(4-(difluoromethylene)piperidin-1-yl)-N-(1-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide (20 mg, 0.03 mmol, yield: 28.73%), as a white solid.

[0766] 1 H NMR (400MHz, DMSO-d6): δppm 13.41(s,1H),10.29(br.s,1H),8.29–8.22(m,2H),8.12–8.09(m,2H),7.22(d,J=2.0Hz,1H),7.18–7.15(m,1H),4.95(br.s ,1H),4.63(s,1H),3.77(t,J=6.4Hz,2H),3.60(t,J=6.4Hz,2H),3.06(t,J=5.2Hz,4H),2.64(s,4H),1.87(d,J=2.4Hz,6H).

[0767] MS: (ESI) m / z = 591.2 [M+H] + .

[0768] Example 169: 2-(4-(difluoromethylene)piperidin-1-yl)-4-((2-hydroxyethyl)sulfonamido)-N-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)benzamide

[0769]

[0770] Step 1: To a solution of 6-chloro-1H-pyrazolo[3,4-b]pyridine (11.3 g, 73.5 mmol) in DMF (30 mL) was added 2,2,3,3,3-pentafluoropropyl trifluoromethanesulfonate (24.9 g, 88.3 mmol) and Cs2CO3 (47.9 g, 147.1 mmol). The mixture was stirred at 80°C for 4 hours. The mixture was diluted with EtOAc (300 mL) and washed with water (300 mL*2) and brine (200 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 5 / 1, v / v) to afford 6-chloro-1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazolo[3,4-b]pyridine (7.8 g, 27.3 mmol, yield: 37.1%) as a yellow oil.

[0771] MS (ESI) m / z = 286.0 [M+H] + .

[0772] Step 2: To a solution of 6-chloro-1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazolo[3,4-b]pyridine (7.8 g, 27.3 mmol) in dioxane (20 mL) was added tert-butyl carbamate (3.2 g, 27.3 mmol), Cs2CO3 (17.8 mg, 54.6 mmol), Pd2(dba)3 (2.5 g, 2.7 mmol), and Xantphos (1.6 g, 2.7 mmol). The mixture was stirred at 110°C for 16 hours. The mixture was extracted with ethyl acetate (30 mL*3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 10 / 1, v / v) to give tert-butyl (1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)carbamate (6 g, 16.4 mmol, yield: 59.9%) as a colorless oil.

[0773] MS (ESI) m / z = 311.0 [M+H-56] + .

[0774] Step 3: To a solution of tert-butyl (1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)carbamate (6 g, 16.4 mmol) in DCM (30 mL) was added TFA (5 mL). The mixture was stirred at room temperature for 4 hours. The mixture was adjusted to pH = 7 with NaOH (10 wt%). The mixture was diluted with DCM (300 mL) and washed with water (30 mL * 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (elution gradient: DCM / MeOH, 10 / 1, v / v) to give 1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazolo[3,4-b]pyridin-6-amine (3.1 g, 11.6 mmol, 71.1% yield) as a white solid.

[0775] MS (ESI) m / z = 267.1 [M+H] + .

[0776] Step 4: To a solution of 1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazolo[3,4-b]pyridin-6-amine (390 mg, 1.46 mmol) in MeCN (10 mL) was added 2-(4-(difluoromethylene)piperidin-1-yl)-4-iodobenzoic acid (555.52 mg, 1.46 mol, prepared in Example 168), T3P (4.66 g, 14.60 mmol, 50% wt in EtOAc), and pyridine (1.16 g, 14.65 mmol). The mixture was stirred at 50° C. for 16 hours. The mixture was extracted with ethyl acetate (100 mL*3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 3 / 1, v / v) to give 2-(4-(difluoromethylene)piperidin-1-yl)-4-iodo-N-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)benzamide (240 mg, 0.34 mmol, yield: 23.50%) as a white solid.

[0777] MS (ESI) m / z = 628.0 [M+H] + .

[0778] Step 5: To a solution of 2-hydroxyethanesulfonamide (143.6 mg, 1.14 mmol) in DMF (2 mL) was added K3PO4 (406.07 mg, 1.91 mmol), copper(I) iodide (36.43 mg, 0.19 mmol), and sarcosine (34.09 mg, 0.38 mmol). The mixture was stirred at 50°C under nitrogen for 10 minutes. A solution of 2-(4-(difluoromethylene)piperidin-1-yl)-4-iodo-N-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)benzamide (240 mg, 0.38 mmol) in DMF (2 mL) was then added dropwise. The reaction mixture was stirred at 110°C for 16 hours. The reaction mixture was cooled to room temperature, poured into water (30 mL), and extracted with EtOAc (50 mL*3). The organic layer was washed with brine (50 mL*3), dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product, which was purified by preparative HPLC (Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length) using gradually decreasing polarity mixtures of water (containing 0.1% FA) and MeCN as eluents (20-60) to give the title compound 2-(4-(difluoromethylene)piperidin-1-yl)-4-((2-hydroxyethyl)sulfonamido)-N-(1-(2,2,3,3,3-pentafluoropropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)benzamide (13 mg, 0.02 mmol, yield: 5.28%) as a white solid.

[0779] 1 H NMR (400MHz, CD3OD): δppm 8.41(d,J=8.8Hz,1H),8.26(d,J=8.4Hz,1H),8.20(d,J=8.8Hz,1H),8.14(s,1H),7.29(s,1H),7.22(d,J=8.8 Hz,1H),5.17–5.10(m,2H),3.97(t,J=6.0Hz,2H),3.39(t,J=6.0Hz,2H),3.11(t,J=5.2Hz,4H),2.69(s,4H).

[0780] MS: (ESI) m / z = 625.2 [M+H] + .

[0781] Example 170 and Example 171: (R)-N-(1-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-(4-(difluoromethylene)piperidin-1-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide and (S)-N-(1-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-(4-(difluoromethylene)piperidin-1-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide

[0782]

[0783] Step 1: To a solution A of (R)-1-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-6-amine or (S)-1-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-6-amine (90 mg, 0.42 mmol, prepared in Examples 159 and 160, first peak by SFC) in DMF (2 mL) was added NaH (41.1 mg, 1.71 mmol). The mixture was stirred at room temperature under nitrogen for 10 minutes. To a solution B of 2-(4-(difluoromethylene)piperidin-1-yl)-4-iodobenzoic acid (162.4 mg, 0.42 mmol, prepared in Example 168) in DMF (3 mL) was added HATU (195.3 mg, 0.51 mmol) and DIEA (110.7 mg, 0.85 mmol). The mixture was stirred at 25°C under nitrogen for 15 minutes. Mixture B was then added to mixture A. The resulting mixture was stirred at 25°C for 16 hours. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (30 mL*3). The organic layer was washed with brine (30 mL*2), dried over anhydrous Na2SO4, and concentrated in vacuo to obtain a crude product. The crude product was purified by flash silica gel chromatography (elution gradient: 0 to 25% EtOAc in PE) to give (R)-N-(1-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-(4-(difluoromethylene)piperidin-1-yl)-4-iodobenzamide or (S)-N-(1-(2,2-difluorocyclopropyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-(4-(difluoromethylene)piperidin-1-yl)-4-iodobenzamide (180 mg, 0.28 mmol, yield: 66.23%) as a white solid.

[0784] MS (ESI) m / z = 572.1 [M+H] + .

[0785] Step 2: To a solution of 2-hydroxyethanesulfonamide (118.3 mg, 0.94 mmol) in DMF (2 mL) were added K3PO4 (334.4 mg, 1.57 mmol), copper (I) iodide (30.0 mg, 0.15 mmol) and sarcosine (28.1 mg, 0.31 mmol). The mixture was stirred at 50°C under nitrogen for 10 min. To this mixture, a solution of (R)-N-(1-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-(4-(difluoromethylene)piperidin-1-yl)-4-iodobenzamide or (S)-N-(1-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-(4-(difluoromethylene)piperidin-1-yl)-4-iodobenzamide in DMF (2 mL) was added dropwise. The reaction mixture was stirred at 110°C for 16 hours. The reaction mixture was cooled to room temperature, poured into water (30 mL), and extracted with EtOAc (50 mL x 3). The organic layer was washed with brine (50 mL*3), dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product, which was purified by preparative HPLC (Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length) using decreasingly polar mixtures of water (containing 0.1% FA) and MeCN as eluents (20-40). The fractions containing the desired compound were evaporated to dryness to give the title compound Example 170 (R)-N-(1-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-(4-(difluoromethylene)piperidin-1-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide or (S)-N-(1-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-(4-(difluoromethylene)piperidin-1-yl)-4-((2-hydroxyethyl)sulfonamido)benzamide (60 mg, 0.11 mmol, yield: 33.48%) as a white solid.

[0786] 1 H NMR (400MHz, DMSO-d6): δppm 13.43(s,1H),10.29(s,1H),8.34–8.29(m,2H),8.16(s,1H),8.11(d,J=8.8Hz,1H),7.23(d,J=2.0Hz,1H),7.17–7.14(m,1H ),4.42–4.37(m,1H),3.77(t,J=6.4Hz,2H),3.37(t,J=6.4Hz,2H),3.06–3.01(m,4H),2.63–2.60(m,4H),2.45–2.40(m,2H).

[0787] MS: (ESI) m / z = 568.7 [M+H] + .

[0788] Example 171 was synthesized using the same method from (R)-1-(2,2-difluorocyclopropyl)-1H-pyrazolo[3,4-b]pyridin-6-amine or (S)-1-(2,2-difluorocyclopropyl)-1H-pyrido[3,4-b]pyridin-6-amine (prepared in Example 159 and Example 160, the second peak by SFC)

[0789] MS: (ESI) m / z = 568.7 [M+H] + .

[0790] Example 172: N-(1-(3,3-difluoropropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0791]

[0792] Step 1: To a solution of 3,3-difluoropropan-1-ol (900 mg, 9.4 mmol) and 4-DMAP (1.4 g, 11.2 mmol) in DCM (10 mL) at 0°C was added 4-methylbenzenesulfonyl chloride (2.1 g, 11 mmol) and stirred at room temperature for 2 hours. The mixture was adjusted to pH 7 with HCl, diluted with water (20 mL), extracted with DCM (40 mL*3), and washed with brine (40 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford crude 3,3-difluoropropyl 4-methylbenzenesulfonate (2 g, 6.4 mmol, 68% yield) as a yellow oil.

[0793] 1 H NMR (400MHz, CDCl3) δ7.83–7.74(m,2H),7.40–7.32(m,2H),5.88(tt,J=56. 0,4.6Hz,1H),4.21–4.11(m,2H),2.46(d,J=12.1Hz,3H),2.20-2.03(m,2H).

[0794] MS (ESI) m / z = 251.1 [M+H] + .

[0795] Step 2: A mixture of 6-chloro-1H-pyrazolo[3,4-b]pyridine (300 mg, 2 mmol), 3,3-difluoropropyl-4-methylbenzenesulfonate (587 mg, 2.3 mmol), and Cs2CO3 (1.9 g, 5.9 mmol) in DMF (10 mL) was stirred at 80°C for 2 hours. The mixture was diluted with water (20 mL), extracted with EtOAc (40 mL*3), washed with water (40 mL*3) and brine (40 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 5 / 1, v / v) to give 6-chloro-1-(3,3-difluoropropyl)-1H-pyrazolo[3,4-b]pyridine (370 mg, 1.4 mmol, yield: 70%) as a yellow oil.

[0796] 1 H NMR (400MHz, CDCl3) δ8.04–7.91(m,2H),7.15(d,J=8.3Hz,1H),5.97(tt,J=56.1,4.5Hz,1H),4.67(t,J=6.9Hz,2H),2.58–2.42(m,2H).

[0797] MS (ESI) m / z = 232.2 [M+H] + .

[0798] Step 3: To a solution of 6-chloro-1-(3,3-difluoropropyl)-1H-pyrazolo[3,4-b]pyridine (370 mg, 1.6 mmol) in dioxane (10 mL) was added tert-butyl carbamate (281 mg, 2.4 mmol), Cs2CO3 (1 g, 3.2 mmol), Pd2(dba)3 (146 mg, 0.16 mmol) and Xantphos (92 mg, 0.16 mmol). The mixture was stirred at 110 ° C for 16 hours. The mixture was concentrated under vacuum to give a crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 10 / 1, v / v) to give tert-butyl (1-(3,3-difluoropropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)carbamate (180 mg, 0.5 mmol, yield: 31%) as a yellow oil.

[0799] MS (ESI) m / z = 313.1 [M+H] + .

[0800] Step 4: To a solution of tert-butyl (1-(3,3-difluoropropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)carbamate (180 mg, 0.58 mmol) in DCM (3 mL) was added a solution of HCl in dioxane (3 mL) and stirred at 40 ° C for 16 hours. NaOH was added to the mixture to adjust the pH to 9 and extracted with DCM (20 mL * 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: dichloromethane / methanol, 15 / 1, v / v) to give 1-(3,3-difluoropropyl)-1H-pyrazolo[3,4-b]pyridin-6-amine (90 mg, 0.38 mmol, yield: 65%) as a yellow oil.

[0801] MS (ESI) m / z = 213.1 [M+H] + .

[0802] Step 5: To a solution of 1-(3,3-difluoropropyl)-1H-pyrazolo[3,4-b]pyridin-6-amine (90 mg, 0.4 mmol) in DMF (2 mL) was added NaH (42 mg, 1 mmol) and stirred at 25°C for 1 hour. To another solution of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (151 mg, 0.4 mmol) in DMF (2 mL) was added HATU (194 mg, 0.5 mmol) and DIEA (110 mg, 0.8 mmol). The mixture was stirred at 25°C for 1 hour. The mixture was then added to the above reaction solution. The mixture was stirred at 25°C for 16 hours. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (40 mL*3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 20 / 1, v / v) to give compound N-(1-(3,3-difluoropropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (90 mg, 0.15 mmol, yield: 37%) as a yellow oil.

[0803] MS (ESI) m / z = 552.0 [M+H] + .

[0804] Step 6: To a solution of 2-hydroxyethane-1-sulfonamide (41 mg, 0.33 mmol) in DMF (2 mL) were added CuI (16 mg, 0.08 mmol), sarcosine (15 mg, 0.16 mmol), and KPO (173 mg, 0.8 mmol). Under an argon atmosphere, the mixture was stirred at 50°C for 10 minutes. Then, the compound N-(1-(3,3-difluoropropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (90 mg, 0.16 mmol) was added. The mixture was stirred at 110°C for 5 hours. The mixture was diluted with ethyl acetate (20 mL) and washed with water (20 mL*2) and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 3 / 1, v / v) to give the title compound N-(1-(3,3-difluoropropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (21.7 mg, 0.04 mmol, yield: 25%) as a white solid.

[0805] 1 H NMR (400MHz, CD3OD) δ8.29(d,J=8.8Hz,1H),8.19–8.12(m,2H),8.01(s,1H),7.33(d,J=1.9Hz,1H),7.16(dd,J=8.6,1.9Hz,1H),6.15–5.80(m,1H), 4.63(t,J=6.9Hz,2H),3.93(t,J=6.2Hz,2H),3.36(t,J=6.2Hz,2H),3.10 (t,J=5.2Hz,4H),2.61–2.41(m,2H),1.93(d,J=61.8Hz,4H),0.44(s,4H).

[0806] MS (ESI) m / z = 549.1 [M+H] + .

[0807] Example 173 and Example 174: (S)-N-(1-(2,2-difluorocyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]oct-6-yl)benzamide and (R)-N-(1-N-(1-(2,2-difluorocyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]oct-6-yl)benzamide

[0808]

[0809] Step 1: To a solution of 6-chloro-1H-pyrazolo[3,4-b]pyridine (500 mg, 3.2 mmol) in DMF (3 mL) was added 2-(bromomethyl)-1,1-difluorocyclopropane (668 mg, 3.9 mmol) and Cs2CO3 (2121 mg, 6.5 mmol). The mixture was stirred at 80°C for 2 hours. The mixture was diluted with EtOAc (30 mL) and washed with water (30 mL*2) and brine (30 ml). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 5 / 1, v / v) to afford 6-chloro-1-((2,2-difluorocyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyridine (400 mg, 1.6 mmol, yield: 42.8%) as a colorless oil.

[0810] MS (ESI) m / z = 244.1 [M+H] + .

[0811] Step 2: To a solution of 6-chloro-1-((2,2-difluorocyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyridine (400 mg, 1.6 mmol) in dioxane (3 mL) was added tert-butyl carbamate (192 mg, 1.6 mmol), Cs2CO3 (1069 mg, 3.3 mmol), Pd2(dba)3 (15 mg, 0.2 mmol), and Xantphos (95 mg, 0.2 mmol). The mixture was stirred at 110°C for 16 hours. The mixture was extracted with ethyl acetate (30 mL*3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 5 / 1, v / v) to give tert-butyl (1-((2,2-difluorocyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)carbamate (300 mg, 0.9 mmol, yield: 47.8%) as a white solid.

[0812] MS (ESI) m / z = 269.1 [M+H-56] + .

[0813] Step 3: To a solution of tert-butyl (1-((2,2-difluorocyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)carbamate (300 mg, 0.9 mmol) in DCM (3 mL) was added TFA (1 mL) and stirred at room temperature for 2 hours. The mixture was concentrated under vacuum to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 1 / 1, v / v), SFC (chiralpak-OJ, 5μ silica, 21 mm diameter, 150 mm length), using HEXA with decreasing polarity. Purification with EtOH(DEA) mixture as eluent (40-70) gave two isomers (S)-1-((2,2-difluorocyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyridin-6-amine or (R)-1-((2,2-difluorocyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyrazol-6-amine (80 mg, 0.36 mmol, 39.6% yield) and (R)-1-((2,2-difluorocyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyridin-6-amine or (S)-1-((2,2-difluorocyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyrazol-6-amine (80 mg, 0.36 mmol, 39.6% yield) as white solids.

[0814] MS (ESI) m / z = 225.2 [M+H] + .

[0815] Step 4: To a solution of chiral (S)-1-((2,2-difluorocyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyridin-6-amine or (R)-1-((2,-2-difluorocyclopropyl)methyl)-1-pyrazolo[3,4-b]pyridin-6-amine (80 mg, 0.36 mmol) in DMF (2 mL) was added NaH (36 mg, 0.9 mmol) and stirred at 25 ° C for 1 hour. To a solution of additional 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (127 mg, 0.36 mmol) in DMF (2 mL) was added HATU (163 mg, 0.43 mmol) and DIEA (92 mg, 0.7 mmol). The mixture was stirred at 25 ° C for 1 hour. The mixture was then added to the above reaction solution. The mixture was stirred at 25 ° C for 16 hours. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (40 mL * 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 10 / 1, v / v) to give chiral (S)-N-(1-((2,2-difluorocyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide or (R)-N-(-1-((2,2-difluorocyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (100 mg, 0.17 mmol, yield: 49%) as a white solid.

[0816] MS (ESI) m / z = 564.0 [M+H] + .

[0817] Step 5: To a solution of 2-hydroxyethane-1-sulfonamide (44 mg, 0.3 mmol) in DMF (2 mL) were added CuI (17 mg, 0.08 mmol), sarcosine (16 mg, 0.18 mmol) and K3PO4 (188 mg, 0.8 mmol) and the mixture was stirred at 50°C for 10 minutes under argon atmosphere. Then, (S)-N-(1-((2,2-difluorocyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide or (R)-N-(1-((2,2-difluorocyclopropyl)methyl)-1H-pyrido[3,4-b]pyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (100 mg, 0.17 mmol) was added. The mixture was stirred at 110°C for 5 hours. The mixture was diluted with ethyl acetate (20 mL) and washed with water (20 mL*2) and brine (20 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: dichloromethane / methanol, 20 / 1, v / v) to give the title compound (S)-N-(1-((2,2-difluorocyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide or (R)-N-(1-((2,2-difluorocyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (43.6 mg, 0.07 mmol, yield: 38%) as a white solid.

[0818] Example 173:

[0819] 1 H NMR(400MHz,CD3OD)δ8.29(d,J=8.8Hz,1H),8.16(dd,J=11.0,8.7Hz,2H),8.01 (s,1H),7.33(d,J=2.2Hz,1H),7.15(dd,J=8.7,2.2Hz,1H),4.64(dd,J=14.9,6. 7Hz,1H),4.47(dd,J=14.8,8.4Hz,1H),3.93(t,J=6.2Hz,2H),3.36(t,J=6.2Hz ,2H),3.09(t,J=5.3Hz,4H),2.38–2.22(m,1H),2.20–1.28(m,6H),0.43(s,4H).

[0820] MS (ESI) m / z = 561.1 [M+H] + .

[0821] Example 174:

[0822] 1 H NMR (400MHz, CD3OD) δ8.27(d,J=8.8Hz,1H),8.16–8.12(m,2H),8.00(s,1H),7.32(d,J=2.2Hz,1H),7.15(dd,J=8.6,2.2Hz,1H),4.65–4.60(m, 1H),4.48–4.43(m,1H),3.93(t,J=6.2Hz,2H),3.36(t,J=6.2Hz,2H),3. 08(t,J=5.3Hz,4H),2.37–2.21(m,1H),2.16–1.27(m,6H),0.43(s,4H).

[0823] MS (ESI) m / z = 561.1 [M+H] + .

[0824] Example 175: N-(1-((1-fluorocyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0825]

[0826]

[0827] Step 1: To a solution of (1-fluorocyclopropyl)methanol (200 mg, 2.21 mmol) in DCM (10 mL) was added TEA (673 mg, 6.65 mmol), DMAP (271 mg, 2.21 mol) and TosCl (508 mg, 2.66 mmol). The reaction mixture was stirred at room temperature for 4 hours. The mixture was acidified to pH = 6 with HCl (1 N) and extracted with DCM (20 mL * 3). The combined organic layers were washed with NaHCO solution (20 mL), dried over NaSO, and concentrated in vacuo to give the crude product (1-fluorocyclopropyl)methyl 4-methylbenzenesulfonate (410 mg, 1.7 mmol, yield: 75%) as a yellow oil.

[0828] 1H NMR (400MHz, CDCl3) δ7.82(d,J=8.3Hz,2H),7.36(d,J=8.0Hz,2H),4.28(d,J =21.5Hz,2H),2.46(s,3H),1.13(dt,J=18.1,7.3Hz,2H),0.79–0.71(m,2H).

[0829] Step 2: To a solution of 6-chloro-1H-pyrazolo[3,4-b]pyridine (257.79 mg, 1.67 mmol) in DMF (10 mL) was added CsCO (1.09 g, 3.35 mmol) and (1-fluorocyclopropyl)methyl 4-methylbenzenesulfonate (410 mg, 1.67 mol). The mixture was stirred at 80°C for 2 hours. The mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL*3). The combined organic layers were washed with brine (20 mL), dried over NaSO, concentrated in vacuo, and purified by flash chromatography (PE / EtOAc = 0-10%) to give the product, 6-chloro-1-((1-fluorocyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyridine (216 mg, 1.0 mmol, yield: 57%), as a colorless oil.

[0830] MS (ESI) m / z = 226.0 [M+H] + .

[0831] Step 3: A mixture of 6-chloro-1-((1-fluorocyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyridine (216 mg, 0.95 mmol), BocNH2 (168.2 mg, 1.43 mmol), Xantphos (55.33 mg, 0.09 mmol), Pd2(dba)3 (43.83 mg, 0.04 mmol) and Cs2CO3 (623.75 mg, 1.91 mmol) in dioxane (20 mL) was stirred at 110°C for 16 hours under nitrogen. The reaction mixture was concentrated under vacuum and purified by flash chromatography (PE / EtOAc=0-15%) to give the product tert-butyl (1-((1-fluorocyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)carbamate (220 mg, 0.7 mmol, yield: 75%) as a yellow oil.

[0832] MS (ESI) m / z = 307.1 [M+H] + .

[0833] Step 4: To a solution of tert-butyl (1-((1-fluorocyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)carbamate (220 mg, 0.7 mmol) in DCM (3 mL) was added TFA (1.5 mL). The mixture was stirred at room temperature for 2 hours. The mixture was adjusted to pH = 7 with NaOH (10w%). The mixture was diluted with DCM (30 mL) and washed with water (30 mL*3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (elution gradient: DCM / MeOH, 10 / 1, v / v) to give 1-((1-fluorocyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyridin-6-amine (120 mg, 0.6 mmol, 68.9% yield) as a white solid.

[0834] MS (ESI) m / z = 207.1 [M+H] + .

[0835] Step 5: A mixture of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (207 mg, 0.6 mmol), HATU (265 mg, 0.7 mmol), and DIEA (150 mg, 1.2 mmol) in DMF (2 mL) was stirred at room temperature for 0.5 h. This solution was then added to a solution of 1-((1-fluorocyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyridin-6-amine (120 mg, 0.6 mmol) and NaH (58 mg, 1.5 mmol, 60%) in DMF (3 mL) and stirred at room temperature under Ar2 for 16 h. The mixture was diluted with water (20 mL) and extracted with EA (20 mL*3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, concentrated in vacuo, and purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 1 / 1, v / v) to give compound N-(1-((1-fluorocyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (140 mg, 0.3 mmol, yield: 37.5%) as a yellow solid.

[0836] MS (ESI) m / z = 546.0 [M+H] + .

[0837] Step 6: To a solution of 2-hydroxyethane-1-sulfonamide (64 mg, 0.5 mmol) in DMF (3 mL) were added CuI (24 mg, 0.1 mmol), sarcosine (23 mg, 0.2 mmol), and KPO (272 mg, 1.2 mmol). Under an argon atmosphere, the mixture was stirred at 50°C for 10 minutes. N-(1-((1-fluorocyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (140 mg, 0.3 mmol) was then added. The mixture was stirred at 110°C for 5 hours. The mixture was diluted with ethyl acetate (20 mL) and washed with water (20 mL*2) and brine (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 4 / 1, v / v) to give the title compound N-(1-((1-fluorocyclopropyl)methyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (17.7 mg, 0.03 mmol, yield: 12.5%) as a white solid.

[0838] 1 H NMR (400MHz, CD3OD) δ8.27(d,J=8.7Hz,1H),8.19-8.12(m,2H),8.01(s,1H),7.33(d,J=2.1Hz,1H),7.15(dd,J=8.6,2.2Hz,1H),4.79 (d,J=19.6Hz,2H),3.93(t,J=6.2Hz,2H),3.36(t,J=6.2Hz,2H),3.07(t,J=5.2Hz,4H),1.69(s,4H),1.06-0.89(m,4H),0.43(s,4H).

[0839] MS (ESI) m / z = 543.2 [M+H] + .

[0840] Example 176: 4-((2-Hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(1-(3,3,3-trifluoro-2,2-dimethylpropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)benzamide

[0841]

[0842] Step 1: To a stirred solution of 3,3,3-trifluoro-2,2-dimethylpropan-1-ol (900 mg, 6.3 mmol) and N,N-diisopropylethylamine (1.23 g, 9.5 mmol) in DCM (15 mL) at 0°C under nitrogen was added a solution of trifluoromethanesulfonic anhydride (2.32 g, 8.23 ​​mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with 1N HCl (50 mL) and extracted with DCM (50 mL*3). The organic layer was washed with brine (50 mL*2), dried over anhydrous Na2SO4, and concentrated in vacuo to afford 3,3,3-trifluoro-2,2-dimethylpropyl trifluoromethanesulfonate (1.5 g, 5.47 mmol, 86.39% yield) as a yellow gum.

[0843] 1 H NMR (400MHz, DMSO-d6) δppm 3.65 -3.58(m,1H),3.15-3.10(m,1H),1.27–1.21(m,6H).

[0844] Step 2: To a stirred solution of 3,3,3-trifluoro-2,2-dimethylpropyl trifluoromethanesulfonate (1.5 g, 5.52 mmol) and Cs2CO3 (2.25 g, 6.9 mmol) in DMF (20 mL) under nitrogen was added dropwise a solution of 6-chloro-1H-pyrazolo[3,4-b]pyridine (0.7 g, 4.6 mmol) in DMF (2 mL). The reaction mixture was stirred at 80°C for 4 hours. The reaction mixture was cooled to room temperature, poured into water (100 mL), and extracted with EtOAc (50 mL x 3). The organic layer was washed with brine (50 mL*2), dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 3 / 1, v / v) to give 6-chloro-1-(3,3,3-trifluoro-2,2-dimethylpropyl)-1H-pyrazolo[3,4-b]pyridine (600 mg, 2.20 mmol, yield: 40.00%) as a yellow gum.

[0845] MS (ESI) m / z = 278.0 [M+H] + .

[0846] Step 3: To a solution of 6-chloro-1-(3,3,3-trifluoro-2,2-dimethylpropyl)-1H-pyrazolo[3,4-b]pyridine (600 mg, 2.16 mmol), tert-butyl carbamate (759 mg, 6.48 mmol), and Pd2(dba)3 (198 mg, 0.22 mmol) in dioxane (25 mL) was added Xantphos (250 mg, 0.43 mmol) and Cs2CO3 (2112 mg, 6.48 mm mol). The reaction mixture was stirred at 110°C for 16 hours. The reaction mixture was cooled to room temperature, poured into water (100 mL), and extracted with EtOAc (50 mL*3). The organic layer was washed with brine (50 mL*2), dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 3 / 1, v / v) to give tert-butyl (1-(3,3,3-trifluoro-2,2-dimethylpropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)carbamate (650 mg, 1.81 mmol, yield: 83.71%) as a yellow gum.

[0847] MS (ESI) m / z = 359.1 [M+H] + .

[0848] Step 4: To a solution of tert-butyl (1-(3,3,3-trifluoro-2,2-dimethylpropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)carbamate (650 mg, 1.81 mmol) in DCM (10 mL) was added TFA (2.5 mL). The reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure. The reaction mixture was diluted with DCM (50 mL) and washed with saturated aqueous NaHCO3 solution (30 mL*3) and brine (30 mL*2), dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 2 / 1, v / v) to give 1-(3,3,3-trifluoro-2,2-dimethylpropyl)-1H-pyrazolo[3,4-b]pyridin-6-amine (300 mg, 1.16 mmol, yield: 64.23%) as a yellow solid.

[0849] MS (ESI) m / z = 259.2 [M+H] + .

[0850] Step 5: To a solution A of 1-(3,3,3-trifluoro-2,2-dimethylpropyl)-1H-pyrazolo[3,4-b]pyridin-6-amine (220 mg, 0.85 mmol) in DMF (5 mL) was added NaH (170 mg, 4.26 mmol). The mixture was stirred at room temperature under nitrogen for 15 minutes. To a solution B of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (304 mg, 0.85 mmol) in DMF (5 mL) was added HATU (389 mg, 1.02 mmol) and DIEA (220 mg, 1.70 mmol). The mixture was stirred at 25 ° C for 15 minutes under nitrogen. Solution B was added to solution A. The resulting mixture was stirred at 25 ° C for 16 hours. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (30 mL * 3). The organic layer was washed with brine (30 mL*2), dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 3 / 1, v / v) to give 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)-N-(1-(3,3,3-trifluoro-2,2-dimethylpropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)benzamide (220 mg, 0.37 mmol, yield: 43.24%) as a white solid.

[0851] MS (ESI) m / z = 598.1 [M+H] + .

[0852] Step 6: To a solution of 2-hydroxyethane-1-sulfonamide (138 mg, 1.10 mmol), K3PO4 (391 mg, 1.84 mmol), CuI (35 mg, 0.18 mmol), and sarcosine (33 mg, 0.37 mmol) in DMF (3 mL) was added dropwise a solution of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)-N-(1-(3,3,3-trifluoro-2,2-dimethylpropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)benzamide (220 mg, 0.37 mmol) in DMF (2 mL) under nitrogen at 50°C. The reaction mixture was stirred at 110°C for 16 hours. The reaction mixture was cooled to room temperature, poured into water (50 mL), and extracted with EtOAc (30 mL*3). The organic layer was washed with brine (30 mL x 2), dried over anhydrous Na2SO4, and concentrated in vacuo to afford the crude product. The crude product was purified by preparative HPLC (Gemini-C18 column, 5 μm silica, 21 mm diameter, 150 mm length) using decreasingly polar mixtures of water (containing 0.1% FA) and MeCN as eluents (30-60) to afford the title compound, 4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(1-(3,3,3-trifluoro-2,2-dimethylpropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)benzamide (107 mg, 0.18 mmol, 48.36% yield) as a white solid.

[0853] 1 H NMR(400MHz,DMSO-d6)δppm 13.31(s,1H),10.25(br.s,1H),8.33–8.28(m,2H),8.17(s,1H),8.10(d,J=8.4Hz,1H),7.31(d,J=2.0Hz,1H),7.16–7.14(m,1H) ,4.94(br.s,1H),4.54(s,2H),3.77(t,J=6.4Hz,2H),3.37(t,J=6.4Hz,2H),3.03(s,4H),1.75(s,4H),1.21(s,6H),0.40(s,4H).

[0854] MS (ESI) m / z = 595.2 [M+H] + .

[0855] Example 177 and Example 178: (R)-4-((2-Hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(1-(4,4,4-trifluorobutan-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)benzamide and (S)-4-((2-Hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(1-(4,4,4-trifluorobutan-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)benzamide

[0856]

[0857]

[0858] Step 1: To a solution of 6-chloro-1H-pyrazolo[3,4-b]pyridine (400 mg, 2.61 mmol) in THF (20 mL) was added 4,4,4-trifluorobutan-2-ol (369.90 mg, 2.89 mmol), PPh3 (1024.78 mg, 3.91 mmol), and DIAD (790.04 mg, 3.91 mmmol). Under a nitrogen atmosphere, the mixture was stirred at 60°C for 16 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (30 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 10 / 1, v / v) to give tert-butyl 6-chloro-1-(4,4,4-trifluorobutan-2-yl)-1H-pyrazolo[3,4-b]pyridine (100 mg, 0.38 mmol, yield: 14.6%) as a solid.

[0859] MS (ESI) m / z = 263.9 [M+H] + .

[0860] Step 2: To a solution of 6-chloro-1-(4,4,4-trifluorobutan-2-yl)-1H-pyrazolo[3,4-b]pyridine (100 mg, 0.38 mmol) in dioxane (10 mL) was added tert-butyl carbamate (222.43 mg, 1.90 mmol), Pd2(dba)3 (36.63 mg, 0.04 mmol), Xantphos (63.65 mg, 0.11 mmol), and Cs2CO3 (136.13 mg, 0.42 mmol). The mixture was stirred at 110°C under a nitrogen atmosphere for 16 hours. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL*3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 10 / 1, v / v) to give tert-butyl (1-(4,4,4-trifluorobutan-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)carbamate (100 mg, 0.29 mmol, yield: 76.5%) as a colorless oil.

[0861] MS (ESI) m / z = 344.9 [M+H] + .

[0862] Step 3: Tert-butyl (1-(4,4,4-trifluorobutan-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)carbamate (100 mg, 0.29 mmol) was dissolved in DCM (2 mL) and TFA (2 ml) was added. The mixture was stirred at room temperature for 16 hours. The mixture was diluted with DCM (10 mL) and washed with saturated sodium bicarbonate solution (5 mL*3) and brine (5 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: DCM / MeOH, 10 / 1, v / v) to give 1-(4,4,4-trifluorobutan-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-amine (70 mg, 0.29 mmol, yield: 98.9%) as a yellow solid.

[0863] MS (ESI) m / z = 244.9 [M+H] + .

[0864] Step 4: To a solution of 1-(4,4,4-trifluorobutan-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-amine (70 mg, 0.29 mmol) in DMF (2 ml) was added NaH (34.26 mg, 1.43 mmol). The mixture was stirred at 25°C for 30 minutes under a nitrogen atmosphere. To a solution of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (103.53 mg, 0.29 mmol) in DMF (1 ml) was added HATU (133.08 mg, 0.35 mmol) and DIEA (56.22 mg, 0.43 mmol). The mixture was stirred at 25°C for 30 minutes under a nitrogen atmosphere. This mixture was added to the above mixture and then stirred at 25°C for 16 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL*3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 5 / 1, v / v) to give 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)-N-(1-(4,4,4-trifluorobutan-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)benzamide (50 mg, 0.09 mmol, yield: 29.6%) as an off-white solid.

[0865] MS (ESI) m / z = 583.7 [M+H] + .

[0866] Step 5: To a solution of 2-hydroxyethane-1-sulfonamide (22.50 mg, 0.18 mmol) in DMF (5 ml) was added CuI (8.57 mg, 0.045 mmol), sarcosine (16.04 mg, 0.18 mmol), and KPO (90.85 mg, 0.45 mmol). Under a nitrogen atmosphere, the mixture was stirred at 50°C for 10 minutes. 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)-N-(1-(4,4,4-trifluorobutan-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)benzamide (50 mg, 0.09 mmol) was then added. The mixture was stirred at 110°C for 2 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL*3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by SFC (Thar prep 80, column: CHIRALPAK AD-H 250 mm x 20 mm x 5 μm, modifier: EtOH (DEA) / CO 2 , total flow rate: 40 g / min, temperature: 40 ° C) to give the title compound.

[0867] Example 177:

[0868] (S)-4-((2-Hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(1-(4,4,4-trifluorobutan-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)benzamide or (R)-4-((2-Hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(1-(4,4,4-trifluorobutan-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)benzamide (first peak, 5 mg, 0.009 mmol, yield: 4.8%), as a white solid.

[0869] 1 H NMR(400MHz,MeOD)δppm 8.29–8.27(m,1H),8.17–8.15(m,2H),8.01(s,1H),7.34(d,J=2.2Hz,1H),7.18–7.15(m,1H),5.43–5.37(m,1H),3.93(t,J=6. 2Hz,2H),3.36(t,J=6.2Hz,2H),3.26–3.15(m,1H),3.10(t,J=5.3Hz,4H),2.83–2.75(m,1H),1.95–1.61(m,7H),0.44(s,4H).

[0870] MS (ESI) m / z = 581.1 [M+H] + .

[0871] Example 178:

[0872] (R)-4-((2-Hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(1-(4,4,4-trifluorobutan-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)benzamidebenzamide or (S)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(1-(4,4,4-trifluorobutan-2-yl)-1H-pyrazolo[3,4-b]pyridin-6-yl)benzamidebenzamide (second peak, 5 mg, 0.009 mmol, yield: 4.8%) as a white solid.

[0873] 1H NMR(400MHz,MeOD)δppm 8.29–8.27(m,1H),8.15–8.08(m,2H),7.99(s,1H),7.27(d,J=2.0Hz,1H),7.10–7.07(m,1H),5.42–5.37(m,1H),3.93(t,J=6. 4Hz,2H),3.31(t,J=6.5Hz,2H),3.24–3.14(m,1H),3.09(t,J=5.3Hz,4H),2.81–2.72(m,1H),1.99–1.55(m,7H),0.43(s,4H).

[0874] MS (ESI) m / z = 581.1 [M+H] + .

[0875] Example 179: 4-((2-Hydroxyethyl)sulfonamido)-N-(3-methyl-1-(3,3,3-trifluoropropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0876]

[0877] Step 1: To a solution of 6-chloro-3-methyl-1H-pyrazolo[3,4-b]pyridine (400 mg, 2.38 mmol) in DMF (10 mL) was added 3,3,3-trifluoropropyl-4-methylbenzenesulfonate (711.17 mg, 2.86 mmol) and Cs2CO3 (2334.2 mg, 7.16 mmol). The reaction mixture was stirred at 80°C for 16 hours. The mixture was diluted with water (10 mL) and extracted with dichloromethane (10 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (elution gradient: petroleum ether / ethyl acetate 5 / 1, v / v) to give 6-chloro-3-methyl-1-(3,3,3-trifluoropropyl)-1H-pyrazolo[3,4-b]pyridine (300 mg, 1.14 mmol, yield: 47.63%) as a yellow oil.

[0878] MS (ESI) m / z = 264.1 [M+H] + .

[0879] Step 2: To a solution of 6-chloro-3-methyl-1-(3,3,3-trifluoropropyl)-1H-pyrazolo[3,4-b]pyridine (300 mg, 1.13 mmol) and tert-butyl carbamate (159.36 mg, 1.36 mmol) in 1,4-dioxane (10 mL) was added CsCO (1108.7 mg, 3.40 mmol), Xantphos (131.18 mg, 0.23 mmol), and Pd(dba) (103.81 mg, 0.11 mmol) under nitrogen. The reaction mixture was stirred at 110°C for 16 hours. The mixture was diluted with ethyl acetate (20 mL) and washed with water (20 mL*3) and brine (20 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (elution gradient: petroleum ether / ethyl acetate 1 / 1, v / v) to give tert-butyl (3-methyl-1-(3,3,3-trifluoropropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)carbamate (300 mg, 0.87 mmol, yield: 76.43%) as a yellow oil.

[0880] MS (ESI) m / z = 345.2 [M+H] + .

[0881] Step 3: To a solution of tert-butyl (3-methyl-1-(3,3,3-trifluoropropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)carbamate (300 mg, 0.87 mmol) in DCM (3 mL) was added TFA (1 mL). The reaction mixture was stirred at 25°C for 2 hours. The mixture was diluted with NaHCO3 (10 mL) and extracted with DCM (15 mL*3). The organic layer was washed with water (15 mL) and brine (15 ml), dried over anhydrous Na2SO4, and concentrated under vacuum to give the crude product, which was purified by silica gel chromatography (elution gradient: petroleum ether / ethyl acetate 1 / 2, v / v) to give 3-methyl-1-(3,3,3-trifluoropropyl)-1H-pyrazolo[3,4-b]pyridin-6-amine (160 mg, 1.69 mmol, yield: 75.20%) as a yellow oil.

[0882] MS (ESI) m / z = 245.2 [M+H] + .

[0883] Step 4: To a DMF (5 mL) solution B of 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (230 mg, 0.64 mmol) was added HATU (244.68 mg, 0.64 mol) and DIEA (249.19 mg, 1.93 mmol). The mixture was stirred at 25 ° C for 15 minutes under nitrogen. To a DMF (5 mL) solution A of 3-methyl-1-(3,3,3-trifluoropropyl)-1H-pyrazolo[3,4-b]pyridin-6-amine (157.9 mg, 0.64 mmol) was added NaH (128.78 mg, 3.22 mmol). The mixture was stirred at room temperature under nitrogen for 10 minutes. Solution B was then added dropwise to solution A. The resulting mixture was stirred at 25 ° C for 16 hours. The mixture was diluted with ethyl acetate (10 mL), washed with water (10 mL * 3) and brine (10 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a crude product, which was purified by silica gel chromatography (elution gradient: elution gradient: petroleum ether / ethyl acetate 5 / 1, v / v) to give the product 4-iodo-N-(3-methyl-1-(3,3,3-trifluoropropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (200 mg, 0.34 mmol, yield: 53.24%) as a yellow oil.

[0884] MS (ESI) m / z = 584.2 [M+H] + .

[0885] Step 5: To a solution of 2-hydroxyethane-1-sulfonamide (85.65 mg, 0.68 mmol) in DMF (10 mL) was added CuI (52.14 mg, 0.27 mmol), K3PO4 (363.19 mg, 1.71 mmol), and sarcosine (30.49 mg, 0.34 mmol). The reaction mixture was stirred at 50°C for 10 minutes. 4-Iodo-N-(3-methyl-1-(3,3,3-trifluoropropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (200 mg, 0.34 mmol) was added. The reaction mixture was stirred at 110°C for 16 hours. The mixture was diluted with ethyl acetate (10 mL) and washed with water (10 mL*2) and brine (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product, which was purified by preparative HPLC (Gemini-C18 column, 5μ silica, 21 mm diameter, 150 mm length) using decreasingly polar mixtures of water (containing 0.1% FA) and MeCN as eluents (55-80%) to give the title compound 4-((2-hydroxyethyl)sulfonamido)-N-(3-methyl-1-(3,3,3-trifluoropropyl)-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (43.1 mg, 0.074 mmol, 21.66% yield) as a white solid.

[0886] 1 H NMR(400MHz,DMSO-d6)δppm 13.58(s,1H),8.32–8.18(m,2H),8.10(d,J=8.6Hz,1H),7.31(d,J=1.6Hz,1H),7.15(dd,J=8.6,1.6Hz,1H),4.57(t,J=6.8H z,2H),3.77(t,J=6.4Hz,2H),3.37(t,J=6.4Hz,2H),3.02(s,4H),2.93–2.88(m,2H),2.48(s,3H),1.78(s,4H),0.40(s,4H).

[0887] MS (ESI) m / z = 581.2 [M+H] + .

[0888] Example 180: N-(5-cyano-1-(4-(difluoromethylene)cyclohexyl)-1H-pyrazol-3-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0889]

[0890]

[0891] Step 1: To a solution of 4-hydroxycyclohexan-1-one (5 g, 0.04 mol) in DMF (50 mL) was added 2-((difluoromethyl)sulfonyl)pyridine (10 g, 0.05 mol). The mixture was stirred at -40 ° C for 10 minutes under nitrogen. A solution of t-BuOK (8.85 g, 0.07 mol) in DMF (10 mL) was then added dropwise. The reaction mixture was stirred at -40 ° C for 1 hour and at room temperature for another 3 hours. The reaction mixture was quenched with water (50 mL), the pH value was adjusted to 5 with 1N HCl, and then extracted with EtOAc (50 mL * 3). The organic layer was washed with brine (50 mL*2), dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product, which was purified by flash silica gel chromatography (elution gradient: petroleum ether / ethyl acetate, 10 / 1, v / v) to give 4-(difluoromethylene)cyclohexan-1-ol (5 g, 0.03 mol, yield: 61.64%) as a yellow oil.

[0892] 1 H NMR (400MHz, DMSO-d6) δppm 4.64 (d, J = 4.0 Hz, 1H), 3.66–3.48 (m, 1H), 2.31–2.25 (m, 2H), 1.92–1.85 (m, 2H), 1.76–1.70 (m, 2H), 1.36–1.18 (m, 2H).

[0893] Step 2: To a solution of 4-(difluoromethylene)cyclohexan-1-ol (5 g, 0.03 mol) in DCM (50 mL) was added DIEA (8.71 g, 0.07 mol) and 4-DMAP (2.06 g, 0.02 mol). The mixture was stirred at 0°C under nitrogen for 5 minutes. A solution of 4-methylbenzenesulfonyl chloride (7.71 g, 0.040 mol) in DCM (70 mL) was added dropwise. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with DCM (100 mL), washed with 1N HCl (50 mL*2) and brine (50 mL*2), dried over anhydrous Na2SO4, and concentrated under vacuum to give 4-(difluoromethylene)cyclohexyl-4-methylbenzenesulfonate (6.5 g, 0.02 mol, yield: 51.04%) as a yellow oil.

[0894] 1H NMR(400MHz,DMSO-d6)δppm 7.83(d,J=8.4Hz,2H),7.49(d,J=8.0Hz,2H),4.67–4.64(m,1H),2.43(s,3H) ,2.22–2.15(m,2H),2.05–1.99(m,2H),1.75–1.69(m,2H),1.61-1.53(m,2H).

[0895] Step 3: To a solution of 5-bromo-1H-pyrazol-3-amine (1.9 g, 11.7 mmol) in DMF (10 mL) was added 4-(difluoromethylene)cyclohexyl-4-methylbenzenesulfonate (3.5 g, 11.7 mmol) and Cs2CO3 (7.62 g, 23.3 mmol). The resulting mixture was stirred at 80°C under N2 for 16 hours. The reaction mixture was cooled to room temperature, diluted with water (50 mL), and extracted with EtOAc (50 mL*3). The organic layer was washed with saturated NH4Cl aqueous solution (50 mL*3), dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product, which was purified by flash chromatography (elution gradient: petroleum ether / ethyl acetate, 3 / 1, v / v) to give 5-bromo-1-(4-(difluoromethylene)cyclohexyl)-1H-pyrazole-3-amine (660 mg, 2.26 mmol, yield: 30.81%) as a yellow solid.

[0896] MS (ESI) m / z = 292.0 / 294.0 [M+H] + .

[0897] Step 4: To a solution of 5-bromo-1-(4-(difluoromethylene)cyclohexyl)-1H-pyrazol-3-amine (660 mg, 6.77 mmol) in DMA (10 mL) was added Zn(CN)2 (795.9 mg, 6.77 mmol), DPPF (375.75 mg, 0.67 mmol), Zn powder (147.8 mg, 2.26 mmol) and Pd2(dba)3 (206.9 g, 0.26 mmol). The mixture was stirred at 120 ° C under nitrogen for 16 hours. The reaction mixture was cooled to room temperature, filtered through a celite pad, and concentrated under reduced pressure. The residue was diluted with water (50 mL) and extracted with EtOAc (50 mL*3). The organic layer was washed with brine (50 mL*2), dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product, which was purified by flash silica gel chromatography (elution gradient: petroleum ether / ethyl acetate, 5 / 1, v / v) to give 3-amino-1-(4-(difluoromethylene)cyclohexyl)-1H-pyrazole-5-carbonitrile (208 mg, 0.78 mmol, yield: 34.78%) as a white solid.

[0898] MS: (ESI) m / z = 239.2 [M+H] + .

[0899] Step 5: To a solution of 3-amino-1-(4-(difluoromethylene)cyclohexyl)-1H-pyrazole-5-carbonitrile (200 mg, 0.84 mmol) and 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid (200 mg, 0.84 mmol) in DMF (5 mL) was added HATU (383 mg, 1.01 mmol) and DIEA (217 mg, 1.68 mmol). The mixture was stirred at room temperature under nitrogen for 16 hours. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (50 mL*3). The organic layer was washed with brine (50 mL*2), dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product, which was purified by flash silica gel chromatography (elution gradient: petroleum ether / ethyl acetate, 3 / 1, v / v) to give N-(5-cyano-1-(4-(difluoromethylene)cyclohexyl)-1H-pyrazol-3-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide (230 mg, 0.32 mmol, yield: 37.96%) as a yellow solid.

[0900] MS (ESI) m / z = 578.1 [M+H] + .

[0901] Step 6: A suspension of 2-hydroxyethane-1-sulfonamide (149 mg, 1.19 mmol), CuI (38 mg, 0.19 mmol), sarcosine (35.5 mg, 0.39 mmol), and KPO (422.7 mg, 1.99 mmol) in DMF (5 mL) was preheated at 50° C. under N₂ for 20 minutes. A solution of N-(5-cyano-1-(4-(difluoromethylene)cyclohexyl)-1H-pyrazol-3-yl)-4-iodo-2-(6-azaspiro[2.5]-octan-6-yl)benzamide (230 mg, 0.32 mmol) in DMF (3 mL) was added. The reaction mixture was stirred at 110° C. for 5 hours. The mixture was cooled to room temperature, poured into water (30 mL), and extracted with EtOAc (30 mL*3). The organic layer was washed with saturated aqueous NH4Cl solution (30 mL*2), dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product, which was purified by preparative HPLC (Gemini-C18 column, 5u silica, 21 mm diameter, 150 mm length) using decreasingly polar mixtures of water (containing 0.1% TFA) and MeCN as eluents (20-50) to give the title compound N-(5-cyano-1-(4-(difluoromethylene)cyclohexyl)-1H-pyrazol-3-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (91 mg, 0.15 mmol, yield: 39.62%) as a white solid.

[0902] 1 H NMR (400MHz, DMSO-d6): δppm 13.34(s,1H),10.21(s,1H),7.99(d,J=8.4Hz,1H),7.32(s,1H),7.24(d, J=1.6Hz,1H),7.12–7.09(m,1H),4.90(br.s,1H),4.63–4.58(m,1H),3.75 (t,J=6.4Hz,2H),3.35(t,J=6.4Hz,2H),2.95(t,J=4.8Hz,4H),2.55–2.5 3(m,2H),2.17–2.08(m,4H),1.87–1.81(m,2H),1.63(s,4H),0.37(s,4H).

[0903] MS: (ESI) m / z = 575.2 [M+H] + .

[0904] The following compounds were synthesized using methods similar to those described above or in references. Starting materials were either commercially available or prepared in-house.

[0905]

[0906]

[0907]

[0908]

[0909]

[0910]

[0911]

[0912]

[0913]

[0914]

[0915]

[0916]

[0917]

[0918]

[0919]

[0920] Biological assays

[0921] Mitotic index determination

[0922] OVCAR-3 cells were seeded at a density of 30,000 cells per well in a 96-well imaging microplate (Corning, 3599). The next day, cells were treated with DMSO or compound over an 8-point concentration range (maximum concentration: 10.0 μM) using an Echo(R) 650, and the cell plates were incubated at 37°C, 5% CO2 for 24 hours. Cells were then fixed with 4% formaldehyde for 30 minutes at room temperature. The cell plates were washed three times with 100 μl / well PBST (0.1% Tween 20, 1% BSA in PBS) for 5 minutes each. After washing, the cells were permeabilized in PBS containing 0.1% Triton X-100 and incubated at room temperature for 10 minutes. The cell plates were then washed three times with 100 μl / well PBST for 5 minutes each. Cells were stained with 0.2 μg / mL anti-phosphohistone H3Ser10 (pH3) mouse antibody (Sigma-Aldrich, 05-806) in 30 μl PBST and incubated for 2 hours at room temperature. Cells were washed three times with PBST and incubated with 0.8 μg / mL secondary antibody (donkey anti-mouse IgG (H+L) highly cross-adsorbed secondary antibody, AlexaFluor TM 568; Thermo, A10037) and 2μg / mL Hoechst 33342 DNA dye (Invitrogen, H3570) were used for staining at room temperature in the dark for 15 minutes. The cells were washed with PBST and then 1× PBS was added. The cell plate was sealed and imaging data was collected using an OperettaCLS with a 63x objective lens, with 21 fields of view per well. The percentage of pH3-positive cells at DMSO and each compound concentration was determined. Concentration-response curves were fitted using a 4-parameter logistic model in XLfit software. The average pH3 EC50 value was determined from two independent experiments, each repeated twice. Histone H3-positive objects were collected based on the above-mentioned OperettaCLS imaging analysis module.

[0923] (1) Find the cell nucleus population: This represents the total number of valid nuclear objects per well and outputs the total number as N.

[0924] (2) Calculate the pH3 intensity of the object: This represents the number of positive mitotic arrest objects per well based on the fluorescence intensity threshold set using alexa-568. The total number of pH3 positives is output as M.

[0925] (3) Mitotic arrest index: This represents the percentage of p-histone H3-positive objects [index of selected image area: (M / N) x 100%].

[0926] (4) Integrate and export all data sets from the Operetta analysis module.

[0927] The biological data are shown in Table 1 below:

[0928] Table 1: Biological data

[0929]

[0930]

[0931] A: <500nM; B: 500nM-1000nM; C: 1μM<C≤5μM;D:> 5μM. The biological data are shown in Table 2 below:

[0932] Table 2: Biological data

[0933]

[0934] A: <500nM; B: 500nM-1000nM; C: 1μM<C≤5μM;D:> 5μM.

Claims

1. A compound represented by formula (I) or formula (II), a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof; in, Ring A is Ring C is a pyridone ring, a pyridazin-3(2H)-one ring or a pyrazin-2(1H)-one ring; m is 0, 1, 2, or 3; R 1 are independently F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 deuterated alkyl; Y is a bond, -C 1-4 Alkyl-, -C 0-4 Alkyl-NR 4a -C 0-4 Alkyl-, -C 0-4 Alkyl-OC 0-4 Alkyl-, -C 0-4 Alkyl-SC 0-4 Alkyl-, -C 0-4 Alkyl-(C=O)-C 0-4 Alkyl-, -C 0-4 Alkyl-(C=O)-OC 0-4 Alkyl-, -C 0-4 Alkyl-C(=O)NR 4a -C 0-4 Alkyl-, -C 0-4 Alkyl-NR 4a -C(=O)-C 0-4 Alkyl-, -C 0-4 Alkyl-S(=O)-C 0-4 Alkyl-, -C 0-4 Alkyl-S(=O)2-C 0-4 Alkyl-, -C 0-4 Alkyl-SO2NR 4a -C 0-4 Alkyl-, -C 0-4 Alkyl-NR 4a -SO2-C 0-4 Alkyl-, -C 0-4 Alkyl-NR 4a -S(=O)(=NH)-, or -C 0-4 Alkyl-S(=O)(=NH)-; R 4a Is H or C 1-6 alkyl; R 4 It is R 4-1 or R 4-2 ; R 4-1 Selected from the group consisting of a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered polycyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, which is surrounded by 0, 1, 2 or 3 R 4-3 group substitution; R 4-2 Selected from the group consisting of 0, 1, 2, 3, 4 or 5 selected from F, Cl, Br, -OR a 、-OC 1-4 Haloalkyl, CN, and C=CR 4-3a R 4 -3b C 1-6 alkyl; X 1 N, O, S, CR X1 or NR X1 ; X 2 N, O, S, CR X2 or NR X2 ; R X2 It is H, F, Cl, Br, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -YR 4 or -N=S(=O)-(R 5 )2; 2R 5 to form a saturated or partially saturated 3-, 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms, 0, 1, 2 or 3 O atoms and 1, 2 or 3 S atoms in combination with the sulfur atom to which they are attached; X 3 N, O, S, CR X3 or NR X3 ; X 4 N, O, S, CR X4 or NR X4 ; R X1 It is H, CN, F, Cl, Br, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl, OC 1-6 Haloalkyl, -C(=O)-C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -S(=O)2-C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, or C 1-6 deuterated alkyl; R X3 It is H, CN, F, Cl, Br, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl, OC 1-6 Haloalkyl, -C(=O)-C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -S(=O)2-C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, or C 1-6 deuterated alkyl; R X4 It is H, CN, F, Cl, Br, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl, OC 1-6 Haloalkyl, -C(=O)-C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -S(=O)2-C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, or C 1-6 deuterated alkyl; Or, R X1 and R X2 Yes, R X2 and R X3 Yes, or R X3 and R X4 Each independently combines with the atoms to which they are attached to form a saturated, partially saturated or unsaturated 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, which is surrounded by 0, 1, 2 or 3 R 4-3 group substitution; L is -NR c C(=O)- or -C(=O)NR c -; R c It is H, C 1-4 Alkyl, or C 1-4 alkyl halide; Ring B is Ring D, a 6-, 9- or 10-membered heteroaromatic ring containing 1, 2 or 3 atoms selected from N, O and S, a benzene ring or a naphthalene ring; Ring D is a 5-membered heteroaromatic ring containing 1, 2 or 3 atoms selected from N, O and S, or a pyridone ring; R 2 yes Z 1 Is N or CR 2c ; Z 2 It's CR 2d R 2e NR 2c , or -O-; Each R 2a and R 2b are independently H, OH, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-4 Alkyl-OC 1-6 Alkyl, -C 0-4 Alkyl-OC 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, or C 3-6 Halogenated cycloalkyl; Or, two adjacent R 2a The groups together with the carbon atoms to which they are attached form a saturated 3-, 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S; which is surrounded by 0, 1, 2 or 3 R 2a-1 group substitution; Alternatively, R on two non-adjacent carbon atoms 2a The groups, together with the carbon atoms to which they are attached, form a bridging moiety; Or, R 2a and R 2b Together with the carbon atom to which they are attached, they form C=CR 2f R 2g ; R 2c It is H, C 1-6 Alkyl or C 3-6 Cycloalkyl; R 2d and R 2e Each independently represents H, OH, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-4 Alkyl-OC 1-6 Alkyl, -C 0-4 Alkyl-OC 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or C 3-6 Halogenated cycloalkyl; Or, R 2d and R 2e Together with the carbon atoms to which they are attached, they form a saturated 3-, 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S; which is surrounded by 0, 1, 2 or 3 R 2a-1 group substitution; Or, R 2d and R 2e Together with the carbon atom to which they are attached, they form C=CR 2f R 2g ; Each R 2a-1 are independently OH, CN, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-4 Alkyl-OC 1-6 Alkyl, -C 0-4 Alkyl-OC 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, or C 3-6 Halogenated cycloalkyl; R 2f and R 2 g is independently F, Cl, or Br; R 3 It is F, Cl, Br, CN, -ZR 6 , or -N=S(=O)-(R 5 )2; Z is a bond, -C 1-4 Alkyl-, -C 0-4 Alkyl-NR 7 -、-C 0-4 Alkyl-NR 7 -SO2-, -C 0-4 Alkyl-SO2NR 7 -、-C 0-4 Alkyl-NR 7 -S(=O)(=NR a )-、-C 0-4 Alkyl-S-, -C 0-4 Alkyl-S(=O)-, -C 0-4 Alkyl-S(=O)2-, -C 0-4 Alkyl-S(=O)(=NR a )-、-C 0-4 Alkyl-O-,-C 0-4 Alkyl-C(=O)-, -C 0-4 Alkyl-C(=O)NR 7 -、-C 0-4 Alkyl-C=N(OH)-, -C 0-4 Alkyl-NR 7 C(=O)-, -C 0-4 Alkyl-P-, -C 0-4 Alkyl-P(=O)R a -, or -C 0-4 Alkyl-P(=O)2R a -; R 7 Is H or C 1-6 alkyl; R 6 It is R 6a or R 6b ; R 6a is selected from the group consisting of a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered polycyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, and which is surrounded by 0, 1, 2 or 3 R 6a-1 group substitution; R 6b Selected from the group consisting of 0, 1, 2, 3, 4 or 5 selected from F, Cl, Br, -OR a 、-OC 1-4 Halogenated alkyl, NR a R a and CN groups substituted C 1-6 alkyl; R 0 are independently F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 deuterated alkyl; n is 0, 1, or 2; Each R 4-3 and R 6a-1 are independently F, Cl, Br, CN, C 1-6 Alkyl, C 1-6 Alkyl-C=CR 2f R 2g 、C 1-6 Haloalkyl, -C 0-6 Alkyl-C 3-6 Cycloalkyl, -C 0-6 Alkyl-C 3-6 Cycloalkyl-C 1-6 Haloalkyl, -C 0-6 Alkyl-C 3-6 Halogenated cycloalkyl, -C 0-6 Alkyl-C 3-6 Cycloalkyl-CN, -C 0-6 Alkyl-C 3-6 Cycloalkyl-C 3-6 Cycloalkyl, -OR a 、-C 0-6 Alkyl-OC 1-6 Haloalkyl, -C(=O)R b 、-C(=O)OR a 、-C(=O)NR a R a 、-C(=NR a )NR a R a 、-OC(=O)OR a 、-OC(=O)NR a R a 、-OC 2-6 Alkyl NR a R a 、-OC 2-6 Alkyl OR a 、-SR a ,-S(=O)R b 、-S(=O)2R b 、-S(=O)2NR a R a 、-NR a R a 、-N(R a )C(=O)R b 、-N(R a )C(=O)OR b 、-N(R a )C(=O)NR a R a 、-N(R a )C(=NR a )NR a R a 、-N(R a )S(=O)2R b 、-N(R a )S(=O)2NR a R a 、-N(R a )C 2-6 Alkyl NR a R a 、-N(R a )C 2-6 Alkyl OR a 、-C 1-6 Alkyl NR a R a 、-C 1-6 Alkyl OR a ,-C 1-6 Alkyl N(R a )C(=O)R b 、-C 1-6 Alkyl OC(=O)R b 、-C 1-6 Alkyl C(=O)NR a R a 、-C 1-6 Alkyl C(=O)OR a , or oxo; Or, two R 4-3 Together with the carbon atoms to which they are attached, they form C=CR 4-3a R 4-3b ; R 4-3a and R 4-3b independently F, Cl, Br; At each occurrence, R a are independently H or R b ; R b Independently C 1-6 alkyl, phenyl or benzyl, wherein the C 1-6 The alkyl group is replaced by 0, 1, 2 or 3 groups selected from F, Cl, Br, -OH, -OC 1-4 Alkyl, -NH2, NHC 1-4 Alkyl, -OC(=O)C 1-4 Alkyl and -N(C 1-4 Alkyl)C 1-4 and the phenyl or benzyl group is substituted by 0, 1, 2 or 3 groups selected from F, Cl, Br, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -OH, -OC 1-6 Alkyl, -NH2, -NHC 1-4 Alkyl, -OC(=O)C 1-6 Alkyl, and -N(C 1-6 Alkyl)C 1-6 Substitution of alkyl groups; Ring E is Y 1 N, CR Y1 , or NR Y1 ; Y 2 N, CR Y2 , or NR Y2 ; Y 3 N, CR Y3 , or NR Y3 ; Y 4 N or CR Y4 ; Y 5 N or CR Y5 ; R Y1 and R Y2 The atoms to which they are attached are combined to form a saturated, partially saturated or unsaturated 4-, 5- or 6-membered monocyclic ring or a 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered polycyclic ring containing 0, 1, 2, 3 or 4 N atoms and 0, 1 or 2 atoms selected from O and S, and which is surrounded by 0, 1, 2 or 3 R 6a-1 Group substitution; R Y3 It is H, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 deuterated alkyl; Or, R Y2 and R Y3 The atoms to which they are attached are combined to form a saturated, partially saturated or unsaturated 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2, 3 or 4 N atoms and 0, 1 or 2 atoms selected from O and S, or a 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered polycyclic ring, which is surrounded by 0, 1, 2 or 3 R 6a-1 Group substitution; R Y1 It is H, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 deuterated alkyl; R Y4 It is H, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 deuterated alkyl; R Y5 It is H, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 deuterated alkyl; Ring F is selected from: a) Ring F is Ring D; b) Ring F is a pyridazine ring, a pyrazine ring or a pyrimidine ring; c) Ring F is a benzene ring, and R Y2 and R Y3 The atoms to which they are attached are combined to form a saturated, partially saturated or unsaturated 4-, 5- or 6-membered monocyclic ring or a 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered polycyclic ring containing 0, 1, 2, 3 or 4 N atoms and 0, 1 or 2 atoms selected from O and S, and which is surrounded by 0, 1, 2 or 3 R 6a-1 Group substitution; R Y1 It is H, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 deuterated alkyl; d) Ring F is a benzene ring, and for R Y1 and R Y2 The atoms to which they are attached are combined to form a saturated, partially saturated or unsaturated 4-, 5- or 6-membered monocyclic ring or a 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered polycyclic ring containing 0, 1, 2, 3 or 4 N atoms and 2 atoms selected from O and S, and which is surrounded by 0, 1, 2 or 3 R 6a-1 Group substitution; R Y3 It is H, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 deuterated alkyl; e) Ring F is a benzene ring, and no R Y1 and R Y2 The atoms to which they are attached are combined to form a saturated, partially saturated or unsaturated 4-, 5- or 6-membered monocyclic ring or a 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered polycyclic ring containing 0, 1, 2, 3 or 4 N atoms and 0, 1 or 2 atoms selected from O and S, and which is surrounded by 0, 1, 2 or 3 R 6a-1 Group substitution; R Y3 It is H, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 deuterated alkyl; f) Ring F is a pyridine ring, and R Y1 and R Y2 The atoms to which they are attached are combined to form a saturated, partially saturated or unsaturated 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2, 3 or 4 N atoms and 0, 1 or 2 atoms selected from O and S, or a 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered polycyclic ring, which is surrounded by 0, 1, 2 or 3 R 6a-1 Group substitution; R Y3 It is H, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 deuterated alkyl; g) Ring F is a pyridine ring, and yes R Y2 and R Y3 The atoms to which they are attached are combined to form a saturated, partially saturated or unsaturated 4-, 5- or 6-membered monocyclic ring or a 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered polycyclic ring containing 0, 1, 2, 3 or 4 N atoms and 2 atoms selected from O and S, and which is surrounded by 0, 1, 2 or 3 R 6a-1 Group substitution; R Y1 It is H, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 deuterated alkyl groups; and h) Ring F is a pyridine ring, and no R Y2 and R Y3 The atoms to which they are attached are combined to form a saturated, partially saturated or unsaturated 4-, 5- or 6-membered monocyclic ring or a 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered polycyclic ring containing 0, 1, 2, 3 or 4 N atoms and 0, 1 or 2 atoms selected from O and S, and which is surrounded by 0, 1, 2 or 3 R 6a-1 Group substitution; R Y1 It is H, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Deuterated alkyl.

2. The compound represented by formula (I) or formula (II) according to claim 1, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that: Ring A is Ring C is a pyridone ring, a pyridazin-3(2H)-one ring or a pyrazin-2(1H)-one ring; m is 0, 1, 2, or 3; R 1 are independently F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 deuterated alkyl; Y is a bond, -C 1-4 Alkyl-, -C 0-4 Alkyl-NR 4a -C 0-4 Alkyl-, -C 0-4 Alkyl-OC 0-4 Alkyl-, -C 0-4 Alkyl-SC 0-4 Alkyl-, -C 0-4 Alkyl-(C=O)-C 0-4 Alkyl-, -C 0-4 Alkyl-(C=O)-OC 0-4 Alkyl-, -C 0-4 Alkyl-C(=O)NR 4a -C 0-4 Alkyl-, -C 0-4 Alkyl-NR 4a -C(=O)-C 0-4 Alkyl-, -C 0-4 Alkyl-S(=O)-C 0-4 Alkyl-, -C 0-4 Alkyl-S(=O)2-C 0-4 Alkyl-, -C 0-4 Alkyl-SO2NR 4a -C 0-4 Alkyl-, -C 0-4 Alkyl-NR 4a -SO2-C 0-4 Alkyl-, -C 0-4 Alkyl-NR 4a -S(=O)(=NH)-, or -C 0-4 Alkyl-S(=O)(=NH)-; R 4a Is H or C 1-6 alkyl; R 4 It is R 4-1 or R 4-2 ; R 4-1 Selected from the group consisting of a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered polycyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, which is surrounded by 0, 1, 2 or 3 R 4-3 group substitution; R 4-2 Selected from the group consisting of 0, 1, 2, 3, 4 or 5 selected from F, Cl, Br, -OR a 、-OC 1-4 C substituted with haloalkyl and CN groups 1-6 alkyl; X 1 N, O, S, CR X1 or NR X1 ; X 2 N, O, S, CR X2 or NR X2 ; R X2 It is H, F, Cl, Br, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -YR 4 or -N=S(=O)-(R 5 )2; 2R 5 the sulphur atoms to which they are attached form a saturated or partially saturated 3-, 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms, 0, 1, 2 or 3 O atoms and 1, 2 or 3 S atoms; X 3 N, O, S, CR X3 or NR X3 ; X 4 N, O, S, CR X4 or NR X4 ; R X1 It is H, CN, F, Cl, Br, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl, OC 1-6 Haloalkyl, -C(=O)-C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -S(=O)2-C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, or C 1-6 deuterated alkyl; R X3 It is H, CN, F, Cl, Br, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl, OC 1-6 Haloalkyl, -C(=O)-C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -S(=O)2-C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, or C 1-6 deuterated alkyl; R X4 It is H, CN, F, Cl, Br, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl, OC 1-6 Haloalkyl, -C(=O)-C 1-6 Alkyl, -C(=O)OC 1-6 Alkyl, -S(=O)2-C 1-6 Alkyl, C 3-6 Cycloalkyl, C 3-6 Halogenated cycloalkyl, or C 1-6 deuterated alkyl; Or, alternatively, R X1 and R X2 Yes, R. X2 and R X3 Right or R X3 and R X4 The pairs are each independently combined with the atoms to which they are attached to form a saturated, partially saturated or unsaturated 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, and which is surrounded by 0, 1, 2 or 3 R 4-3 group substitution; L is -NR c C(=O)- or -C(=0)NR c -; R c It is H, C 1-4 Alkyl or C 1-4 alkyl halide; Ring B is Ring D, a 6-, 9- or 10-membered heteroaromatic ring containing 1, 2 or 3 atoms selected from N, O and S, a benzene ring or a naphthalene ring; Ring D is a 5-membered heteroaromatic ring containing 1, 2 or 3 atoms selected from N, O and S, or a pyridone ring; R 2 yes Z 1 N or CR 2c ; Z 2 CR 2d R 2e NR 2c , or -O-; R 2a and R 2b Each independently represents H, OH, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-4 Alkyl-OC 1-6 Alkyl, -C 0-4 Alkyl-OC 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, or C 3-6 Halogenated cycloalkyl; Or, two adjacent R 2a The groups together with the carbon atoms to which they are attached form a saturated 3-, 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S; which is surrounded by 0, 1, 2 or 3 R 2a-1 group substitution; Alternatively, R on two non-adjacent carbon atoms 2a The groups, together with the carbon atoms to which they are attached, form a bridging moiety; R 2c It is H, C 1-6 Alkyl or C 3-6 Cycloalkyl; R 2d and R 2e Each independently represents H, OH, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-4 Alkyl-OC 1-6 Alkyl, -C 0-4 Alkyl-OC 1-6 Halogenated alkyl, C 3-6 Cycloalkyl or C 3-6 Halogenated cycloalkyl; Or, R 2d and R 2e Together with the carbon atoms to which they are attached, they form a saturated 3-, 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S; which is surrounded by 0, 1, 2 or 3 R 2a-1 group substitution; Each R 2a-1 are independently OH, CN, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-4 Alkyl-OC 1-6 Alkyl, -C 0-4 Alkyl-OC 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, or C 3-6 Halogenated cycloalkyl; R 3 It is F, Cl, Br, CN, -ZR 6 , or -N=S(=O)-(R 5 )2; Z is a bond, -C 1-4 Alkyl-, -C 0-4 Alkyl-NR 7 -、-C 0-4 Alkyl-NR 7 -SO2-, -C 0-4 Alkyl-SO2NR 7 -、-C 0-4 Alkyl-NR 7 -S(=O)(=NR a )-、-C 0-4 Alkyl-S-, -C 0-4 Alkyl-S(=O)-, -C 0-4 Alkyl-S(=O)2-, -C 0-4 Alkyl-S(=O)(=NR a )-、-C 0-4 Alkyl-O-, -C 0-4 Alkyl-(C=O)-, -C 0-4 Alkyl-(C=O)NR 7 、-C 0-4 Alkyl-C=N(OH)-, -C 0-4 Alkyl-NR 7 (C=O), -C 0-4 Alkyl-P-, -C 0-4 Alkyl-P(=O)R a -, or -C 0-4 Alkyl-P(=O)2R a -; R 7 Is H or C 1-6 alkyl; R 6 It is R 6a or R 6b ; R 6a Selected from the group consisting of a saturated, partially saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring or a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered polycyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, and surrounded by 0, 1, 2 or 3 R 6a-1 group substitution; R 6b Selected from the group consisting of 0, 1, 2, 3, 4 or 5 selected from F, Cl, Br, -OR a 、-OC 1-4 Halogenated alkyl, NR a R a and CN groups substituted C 1-6 alkyl; R 0 are independently F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl, or C 1-6 deuterated alkyl; n is 0, 1, or 2; Each R 4-3 and R 6a-1 are independently F, Cl, Br, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkyl-C 3-6 Cycloalkyl, -C 0-6 Alkyl-C 3-6 Cycloalkyl-C 1-6 Haloalkyl, -C 0-6 Alkyl-C 3-6 Halogenated cycloalkyl, -OR a 、-C 0-6 Alkyl-OC 1-6 Haloalkyl, -C(=O)R b 、-C(=O)OR a 、-C(=O)NR a R a 、-C(=NR a )NR a R a 、-OC(=O)OR a 、-OC(=O)NR a R a 、-OC 2-6 Alkyl NR a R a 、-OC 2-6 Alkyl OR a 、-SR a ,-S(=O)R b 、-S(=O)2R b 、-S(=O)2NR a R a 、-NR a R a 、-N(R a )C(=O)R b 、-N(R a )C(=O)OR b 、-N(R a )C(=O)NR a R a 、-N(R a )C(=NR a )NR a R a 、-N(R a )S(=O)2R b 、-N(R a )S(=O)2NR a R a 、-N(R a )C 2-6 Alkyl NR a R a 、-N(R a )C 2-6 Alkyl OR a 、-C 1-6 Alkyl NR a R a 、-C 1-6 Alkyl OR a 、-C 1-6 Alkyl N(R a )C(=O)R b 、-C 1-6 Alkyl OC(=O)R b 、-C 1-6 Alkyl C(=O)NR a R a 、-C 1-6 Alkyl C(=O)OR a , or oxo; At each occurrence, R a are independently H or R b ; R b Independently C 1-6 alkyl, phenyl or benzyl, wherein the C 1-6 The alkyl group is replaced by 0, 1, 2 or 3 groups selected from F, Cl, Br, -OH, -OC 1-4 Alkyl, -NH2, NHC 1-4 Alkyl, -OC(=O)C 1-4 Alkyl and -N(C 1-4 Alkyl)C 1-4 and the phenyl or benzyl group is substituted by 0, 1, 2 or 3 groups selected from F, Cl, Br, C 1-6 Alkyl, C 1-6 Halogenated alkyl, -OH, -OC 1-6 Alkyl, -NH2, -NHC 1-4 Alkyl, -OC(=O)C 1-6 Alkyl, and -N(C 1-6 Alkyl)C 1-6 Substitution of alkyl groups; Ring E is Y 1 N, CR Y1 , or NR Y1 ; Y 2 N, CR Y2 , or NR Y2 ; Y 3 N, CR Y3 , or NR Y3 ; Y 4 N or CR Y4 ; Y 5 N or CR Y5 ; R Y1 and R Y2 The atoms to which they are attached are combined to form a saturated, partially saturated or unsaturated 4-, 5- or 6-membered monocyclic ring or a 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered polycyclic ring containing 0, 1, 2, 3 or 4 N atoms and 0, 1 or 2 atoms selected from O and S, and which is surrounded by 0, 1, 2 or 3 R 6a-1 Group substitution; R Y3 It is H, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 deuterated alkyl; Or, R Y2 and R Y3 The atoms to which they are attached are combined to form a saturated, partially saturated or unsaturated 4-, 5- or 6-membered monocyclic ring or a 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered polycyclic ring containing 0, 1, 2, 3 or 4 N atoms and 0, 1 or 2 atoms selected from O and S, and which is surrounded by 0, 1, 2 or 3 R 6a-1 Group substitution; R Y1 It is H, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 deuterated alkyl; R Y4 It is H, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 deuterated alkyl; R Y5 It is H, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 deuterated alkyl; Ring F is selected from: a) Ring F is Ring D; b) Ring F is a pyridazine ring, a pyrazine ring or a pyrimidine ring; c) Ring F is a benzene ring, and R Y2 and R Y3 The atoms to which they are attached are combined to form a saturated, partially saturated or unsaturated 4-, 5- or 6-membered monocyclic ring or a 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered polycyclic ring containing 0, 1, 2, 3 or 4 N atoms and 0, 1 or 2 atoms selected from O and S, and which is surrounded by 0, 1, 2 or 3 R 6a-1 Group substitution; R Y1 It is H, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 deuterated alkyl; d) Ring F is a benzene ring, and for R Y1 and R Y2 The atoms to which they are attached are combined to form a saturated, partially saturated or unsaturated 4-, 5- or 6-membered monocyclic ring or a 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered polycyclic ring containing 0, 1, 2, 3 or 4 N atoms and 2 atoms selected from O and S, and which is surrounded by 0, 1, 2 or 3 R 6a-1 Group substitution; R Y3 It is H, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 deuterated alkyl; e) Ring F is a benzene ring, and Not for R Y1 and R Y2 to form a saturated, partially saturated or unsaturated 4-, 5- or 6-membered monocyclic ring or a 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered polycyclic ring containing 0, 1, 2, 3 or 4 nitrogen atoms and 0, 1 or 2 atoms selected from O and S, which is surrounded by 0, 1, 2 or 3 R 6a-1 Group substitution; R Y3 It is H, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 deuterated alkyl; f) Ring f is a pyridine ring, and R Y1 and R Y2 The atoms to which they are attached are combined to form a saturated, partially saturated or unsaturated 4-, 5- or 6-membered monocyclic ring or a 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered polycyclic ring containing 0, 1, 2, 3 or 4 N atoms and 0, 1 or 2 atoms selected from O and S, and which is surrounded by 0, 1, 2 or 3 R 6a-1 Group substitution; R Y3 It is H, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 deuterated alkyl; g) Ring F is a pyridine ring, and yes R Y2 and R Y3 The atoms to which they are attached are combined to form a saturated, partially saturated or unsaturated 4-, 5- or 6-membered monocyclic ring or a 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered polycyclic ring containing 0, 1, 2, 3 or 4 nitrogen atoms and 2 atoms selected from O and S, and are surrounded by 0, 1, 2 or 3 R 6a-1 Group substitution; R Y1 It is H, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 deuterated alkyl groups; and h) Ring F is a pyridine ring, and no R Y2 and R Y3 The atoms to which they are attached are combined to form a saturated, partially saturated or unsaturated 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2, 3 or 4 N atoms and 0, 1 or 2 atoms selected from O and S, or a 5-, 6-, 7-, 8-, 9-, 10-, 11- or 12-membered polycyclic ring, which is surrounded by 0, 1, 2 or 3 R 6a-1 Group substitution; R Y1 It is H, F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl or C 1-6 Deuterated alkyl.

3. The compound represented by formula (I) or formula (II) according to claim 1 or 2, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (I) or formula (II) is any one of the following: 1) In R 1 、R 4a 、R 4-2 、R X1 、R X2 、R X3 、R X4 、R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 2a-1 、R 7 、R 6b 、 R 0 、R 4-3 、R 6a-1 、R b 、R Y1 、R Y3 、R Y4 and R Y5 In each C 1-6 Alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example, methyl, ethyl, n-propyl or tert-butyl; 2) at R 1 、R X1 、R X2 、R X3 、R X4 、R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 2a-1 、R 0 、R 4-3 、R 6a-1 、 R b 、R Y1 、R Y3 、R Y4 and R Y5 In each C 1-6 The haloalkyl groups are independently CH2F, CHF2, CF3, CH2CF3, CH2CH2Cl, CH2CH2CF3, CH2CH2CHF2, CH2CF2CF3, C(CH3)2CH2CF3 or C(CH3)2CF3; 3) In R 1 、R X1 、R X2 、R X3 、R X4 、R 0 、R Y1 、R Y3 、R Y4 and R Y5 In each C 1-6 Deuterated alkyl is independently CH2D, CHD2, CD3, CH2CD3, CH2CH2CD3 and CH2CH2CHD2, for example CD3; 4) In Y and Z, each -C 1-4 Alkyl- is independently -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)2-; 5) In Y, R 2a 、R 2b 、R 2d 、R 2e 、R 2a-1 and Z, each -C 0-4 Alkyl is independently a bond, -CH2- or -CH2CH2-; 6) In R X1 、R X3 、R X4 、R 2a 、R 2b 、R 2d 、R 2e 、R 2a-1 and R b OC 1-6 Alkyl is independently OCH3, OCH2CH3 or OCH2CH2CH3; 7) In R X1 、R X3 、R X4 、R 2a 、R 2b 、R 2d 、R 2e 、R 2a-1 、R b 、R 4-3 and R 6a-1 OC 1-6 Haloalkyl is independently OCHF2, OCH2F, OCF3, OCH2CF3, OCH2CHF2, OCH2CH2F or OCH2CH2CF3; and 8) In R X1 、R X3 、R X4 、R 2a 、R 2b 、R 2c 、R 2d 、R 2e 、R 2a-1 、R 4-3 and R 6a-1 C 3-6 Cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, For example, cyclopropyl.

4. The compound represented by formula (I) or formula (II) according to claim 1 or 2, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (I) or formula (II) is any one of the following: 1) yes 2) m is 0 or 1; 3) R 1 Independently C 1-6 alkyl; 4) Y is a bond, -C 1-4 Alkyl- or -C 0-4 Alkyl-S(=O)2-C 0-4 alkyl-; 5)R 4-1 is a saturated 3-, 4-, 5-, 6-membered monocyclic ring or a 5-, 6-, 7-, 8-, 9-, 10-membered polycyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 atoms selected from O and S, which is surrounded by 0, 1, 2 or 3 R 4-3 group substitution; 6)R 4-2 Selected from the group consisting of C substituted with 0, 1, 2, 3, 4 or 5 groups selected from F, Cl and Br 1-6 alkyl; 7) R 4 It is R 4-1 ; 8)R X1 It is H, CN, F, Cl, Br, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl, OC 1-6 Halogenated alkyl, -S(=O)2-C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 Deuterated alkyl; R X2 YR 4 ; R X3 It is H, CN, F, Cl, Br, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl, OC 1-6 Halogenated alkyl, -S(=O)2-C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 Deuterated alkyl; R X4 It is H, CN, F, Cl, Br, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl, OC 1-6 Halogenated alkyl, -S(=O)2-C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 deuterated alkyl; or, alternatively, R X1 and R X2 Yes, R X2 and R X3 Right or R X3 and R X4 Each independently combines with the atom to which they are attached to form a saturated, partially saturated or unsaturated 5- or 6-membered monocyclic ring containing 0 or 1 N atom, which is surrounded by 0, 1, 2 or 3 R 4-3 Group substitution; preferably, is a 5-membered aromatic ring containing 1, 2 or 3 N atoms, 0 or 1 O atoms and 0 or 1 S atoms; 9) Each R 4-3 are independently F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkyl-C 3-6 Cycloalkyl, -C 0-6 Alkyl-C 3-6 Cycloalkyl-C 1-6 Haloalkyl, -C 0-6 Alkyl-C 3-6 Halogenated cycloalkyl or -OR a ; 10) By The 5-membered cyclic group composed of ring atoms is a 5-membered heteroaromatic ring, preferably, a 5-membered heteroaromatic ring containing 1, 2 or 3 N atoms, 0 or 1 O atoms, and 0 or 1 S atoms; 11)R c It is H; 12) Ring B is Ring D, a 6-membered heteroaromatic ring containing 1, 2 or 3 N atoms, or a benzene ring; 13) Ring D is a 5-membered heteroaromatic ring containing 1, 2 or 3 atoms selected from N, or a pyridone ring; preferably, Ring D is 14)R 2 yes 15)R 2a It is H, or two adjacent R 2a The groups together with the carbon atoms to which they are attached form a saturated 3-, 4-, 5- or 6-membered monocyclic carbocyclic ring; which is surrounded by 0, 1, 2 or 3 R 2a-1 Group substitution, or, R on two non-adjacent carbon atoms 2a The groups, together with the carbon atoms to which they are attached, form a bridging moiety; 16)R 2b It is H; 17)R 2c It is H; 18)R 2d and R 2e are each independently F, Cl, Br, or R 2d and R 2e Together with the carbon atoms to which they are attached, they form a saturated 3-, 4-, 5- or 6-membered monocyclic carbocyclic ring; which is supported by 0, 1, 2 or 3 R 2a-1 group substitution; 19)R 2a-1 Each independently is F, Cl, Br or C 1-6 alkyl; 20)R 3 Yes-ZR 6 ; 21) Z is -C 0-4 Alkyl-NR 7 -SO2-, -C 0-4 Alkyl-SO2NR 7 -、-C 0-4 -alkyl-S(=O)2-, or -C 0-4 Alkyl-S(=O)(=NR a )-; preferably, Z is -NR 7 -SO2-, -SO2NR 7 -、-C 0-1 Alkyl-S(=O)2-, or -C 0-1 Alkyl-S(=O)(=NR a )-; 22)R 7 It is H; 23)R 6a is a saturated 3-, 4-, 5- or 6-membered monocyclic ring containing 0 or 1 N atom and 0 or 1 O atom, and it is surrounded by 0, 1, 2 or 3 R 6a-1 group substitution; 24)R 6b Selected from 0, 1, 2 or 3 selected from -OR a and NR a R a C 1-6 alkyl; 25) n is 0; 26)R 6a-1 Each independently is C 1-6 Alkyl or -OR a ; 27)R b Independently C 1-6 alkyl; 28)R Y3 It is H; R Y4 It is H, F, Cl, C 1-6 Alkyl; R Y5 It is H; R Y1 and R Y2 The atoms to which they are attached are combined to form a saturated, partially saturated or unsaturated 5-membered monocyclic or 8-membered polycyclic ring containing 0, 1, 2 or 3 N atoms and 0, 1 or 2 O atoms, which is surrounded by 0, 1, 2 or 3 R 6a-1 group substitution; or R Y1 It is H; R Y4 It is H, F, Cl, C 1-6 Alkyl; R Y5 It is H; R Y2 and R Y3 Contains 0, 1, 2 or 3 nitrogen atoms which are combined with the atoms to which they are attached to form saturated, partially saturated or unsaturated groups, and 0, 1 or 2 O atoms of 5-membered monocyclic or 8-membered polycyclic ring, which is surrounded by 0, 1, 2 or 3 R 6a-1 group substitution; and 29) By The 6-membered cyclic group composed of the ring atoms in is a 6-membered aromatic ring, preferably containing 0, A 6-membered aromatic ring containing 1 or 2 nitrogen atoms.

5. The compound represented by formula (I) or formula (II) according to claim 1 or 2, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (I) or formula (II) is any one of the following: 1) yes 2) R X1 It is H, CN, F, Cl, Br, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl, OC 1-6 Halogenated alkyl, -S(=O)2-C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 deuterated alkyl; 3) R X3 It is H, CN, F, Cl, Br, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl, OC 1-6 Halogenated alkyl, -S(=O)2-C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 deuterated alkyl; 4) R X4 It is H, CN, F, Cl, Br, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl, OC 1-6 Halogenated alkyl, -S(=O)2-C 1-6 Alkyl, C 3-6 Cycloalkyl or C 1-6 deuterated alkyl; 5) yes 6)R Y1 、R Y3 、R Y4 and R Y5 are each independently H, F or C 1-6 Alkyl; preferably, R Y1 、R Y3 and R Y5 for H, and R Y4 H, F, or C 1-6 alkyl; 7) Ring B is 8) Ring F is 9)-YR 4 yes and 10)R 2 yes R 2d and R 2e Together with the carbon atoms to which they are attached, they form a saturated 3-, 4-, 5- or 6-membered monocyclic carbocyclic ring; which is surrounded by 0, 1 or 2 R 2a-1 group substitution; Two adjacent R 2a The groups together with the carbon atoms to which they are attached form a saturated 3-, 4-, 5- or 6-membered monocyclic carbocyclic ring; which is surrounded by 0, 1 or 2 R 2a-1 Group substitution.

6. The compound represented by formula (I) or formula (II), a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound represented by formula (I) or formula (II) is any one of the following: 1) R 4-2 Selected from the group consisting of 0, 1, 2, 3, 4 or 5 selected from C=CR 4-3a R 4-3b C 1-6 alkyl; 2) Two R 4-3 The pairs combine with the carbon atoms to which they are attached to form C=CR 4-3a R 4-3b ; 3) R 2d and R 2e Together with the carbon atom to which they are attached, they form C=CR 2f R 2g ; 4) Each R 6a-1 Independently C 1-6 Alkyl-C=CR 2f R 2g 、C 1-6 Haloalkyl, -C 0-6 Alkyl-C 3-6 Cycloalkyl, -C 0-6 Alkyl-C 3-6 Cycloalkyl-C 1-6 Haloalkyl, -C 0-6 Alkyl-C 3-6 Halogenated cycloalkyl, -C O-6 Alkyl-C 3-6 Cycloalkyl-CN, -C 0-6 -alkyl-C 3-6 Cycloalkyl-C 3-6 -cycloalkyl, or and 5) yes 7. The compound represented by formula (I) or formula (II), a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound represented by formula (I) or formula (II) is any one of the following: 1) R 4-2 Selected from the group consisting of 0, 1, 2, 3, 4 or 5 selected from F, Cl, Br, and C=CR 4-3a R 4-3b C 1-6 alkyl; 2) Each R 4-3 are independently F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkyl, -C 0-6 Alkyl-C 3-6 Cycloalkyl, -C 0-6 Alkyl-C 3-6 Cycloalkyl-C 1-6 Haloalkyl, -C 0-6 Alkyl-C 3-6 Halogenated cycloalkyl or -OR a ; or, 2R 4-3 The pairs combine with the carbon atoms to which they are attached to form C=CR 4-3a R 4-3b ; 3) R 2a It is H, or two adjacent R 2a The groups together with the carbon atoms to which they are attached form a saturated 3-, 4-, 5- or 6-membered monocyclic carbocyclic ring; which is surrounded by 0, 1, 2 or 3 R 2a-1 Group substitution, or, R on two non-adjacent carbon atoms 2a The groups together with the carbon atoms to which they are attached form a bridging moiety; or R 2a and R 2b Together with the carbon atom to which they are attached, they form C=CR 2f R 2g ; 4) R 2d and R 2e are each independently F, Cl, Br, or R 2d and R 2e Together with the carbon atoms to which they are attached, they form a saturated 3-, 4-, 5- or 6-membered monocyclic carbocyclic ring; which is supported by 0, 1, 2 or 3 R 2a-1 Group substitution; or R 2d and R 2e Together with the carbon atom to which they are attached, they form C=CR 2f R 2g ; 5) Each R 6a-1 Independently C 1-6 Alkyl, C 1-6 Alkyl-C=CR 2f R 2g 、C 1-6 Haloalkyl, -C 0-6 Alkyl-C 3-6 Cycloalkyl, -C 0-6 Alkyl-C 3-6 Cycloalkyl-C 1-6 Haloalkyl, -C 0-6 Alkyl-C 3-6 Halogenated cycloalkyl, -C 0-6 Alkyl-C 3-6 Cycloalkyl-CN, -C 0-6 -alkyl-C 3-6 Cycloalkyl-C 3-6 -cycloalkyl, OR a ;;and 6) yes 8. The compound represented by formula (I) or formula (II), a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound represented by formula (I) or formula (II) is any one of the following: 1) R 2 yes R 2d and R 2e Together with the carbon atoms to which they are attached, they form a saturated 3-, 4-, 5- or 6-membered monocyclic carbocyclic ring; which is surrounded by 0, 1 or 2 R 2a-1 Group substitution, or R 2d and R 2e Together with the carbon atom to which they are attached, they form C=CR 2f R 2g ; Two adjacent R 2a The groups together with the carbon atoms to which they are attached form a saturated 3-, 4-, 5- or 6-membered monocyclic carbocyclic ring; which is surrounded by 0, 1 or 2 R 2a-1 group substitution; 2) Ring E is For example, ring E is 3)-YR 4 yes For example, -YR 4 yes 9. The compound represented by formula (I) or formula (II) according to claim 1 or 2, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (I) or formula (II) is any one of the following: 1) Ring A is 2) R 2 yes 3) R 3 yes 4) Ring E is 10. The compound represented by formula (I) or formula (II), a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound represented by formula (I) or formula (II) is any one of the following: 1) Ring A is For example, ring A is 2) R 2 yes For example, R 2 yes 3) R 3 yes For example, R 3 yes 11. The compound of formula (I) or formula (II), a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof according to at least one of claims 1 to 10, characterized in that: The compound represented by formula (I) is a compound represented by formula (IA): In formula (IA), ring A, ring B, and R c 、R 0 、R 2 , Z, R 6 and n is as defined in at least one of claims 1 to 10; And / or, the compound represented by formula (II) is a compound represented by formula (II-A): In formula (II-A), ring E, ring F, and R c 、R 0 、R 2 , Z, R 6 and n are as defined in at least one of claims 1 to 10.

12. The compound of formula (I) or formula (II), a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof according to at least one of claims 1 to 10, characterized in that: The compound represented by the formula (I) is preferably a compound represented by the formula (I-1), formula (I-2), formula (I-3), formula (I-4), formula (I-5) or formula (I-6): In formula (I-1), formula (I-2) and formula (I-3), X 4 、R X3 , Y, R 4 , Ring B and R 1 is independently defined as in at least one of claims 1 to 10; And / or, the compound represented by formula (II) is a compound represented by formula (II-1) or formula (II-2), formula (II-3) or formula (II-4); In formula (II-1) and formula (II-3), Y 4 、R 6a-1 、R Y5 and ring F are as defined in at least one of claims 1 to 10; preferably, Y 4 N or CR Y4 ; In formula (II-2) and formula (II-4), R 6a-1 、R Y1 、R Y4 and R Y5 As defined in at least one of claims 1 to 10, ring F is not a pyridine ring.

13. The compound represented by formula (I) or formula (II), a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound represented by formula (I) is: The compound represented by formula (II) is:

14. A pharmaceutical composition comprising a compound of formula (I) or (II) according to at least one of claims 1 to 13, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

15. Use of a compound of formula (I) or (II) according to at least one of claims 1 to 13, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof in the preparation of a KIF18A inhibitor.

16. Use of a compound represented by formula (I) or formula (II) according to at least one of claims 1 to 13, a solvate thereof, a pharmaceutically acceptable salt thereof, or a solvate of a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing cancer, preferably, the cancer is breast cancer, bladder cancer, colorectal cancer, prostate cancer, cervical cancer, endometrial cancer, lung cancer, liver cancer, hyperdiploid acute lymphoblastic leukemia cells, ovarian cancer, and glioblastoma cells.

17. A compound represented by formula (III) or formula (IV); It is characterized by: Ring A, Ring B, Ring E, Ring F, L, R 0 、R 2 and n are as defined in any one of claims 1 to 13.

18. The compound of formula (III) or formula (IV) according to claim 17, characterized in that The compound represented by formula (III) is: And / or, the compound represented by formula (IV) is:

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