Pyrazolyl derivatives useful as anticancer agents

Abstract

The present invention relates to pyrazolyl derivatives useful as anticancer agents. More specifically, the present invention provides pyrazolyl derivative compounds; the use thereof for inhibiting KRAS G12C, HRAS G12C or NRAS G12C, and in particular KRAS G12C; methods of treating or preventing diseases, particularly cancer, using the compounds; and processes and intermediates for preparing these compounds. The invention also provides these pyrazolyl derivative compounds for use in the treatment of cancer and specific cancers as defined herein.

Description

[0001] This application is a divisional application. The parent application is the application filed on December 17, 2020, with application number 202080089867.2 and invention title "Pyrazolyl Derivatives Used as Anticancer Agents".

[0002] sequence list

[0003] This application contains a sequence list that has been electronically filed in ASCII format, and the entire sequence list is hereby incorporated by reference. The ASCII copy created on December 1, 2020, is named PAT058632-WO-PCT02_SL.txt and is 7,192 bytes in size. Technical Field

[0004] This invention provides pyrazolyl derivative compounds; their use in inhibiting KRAS G12C, HRAS G12C, or NRAS G12C, and particularly KRAS G12C; methods of using said compounds to treat or prevent diseases, particularly cancer; and methods and intermediates for preparing these compounds. This invention also provides these pyrazolyl derivative compounds for use in the treatment of cancer and specific cancers as defined herein. Background Technology

[0005] RAS is a small GTPase that acts as a molecular ON / OFF switch, assuming an active / inactive state when bound to GTP / GDP. In response to growth factors, guanine exchange factors exchange GDP for GTP, putting Ras into the ON state. GTP-bound RAS adopts a conformation that recruits effector proteins to the plasma membrane, thereby activating a signaling cascade that leads to cell growth, proliferation, and survival. These pro-cancer signals are very transient and tightly controlled. They are immediately shut down by the GTPase activity of RAS itself, primarily due to a 100,000-fold acceleration by GTPase-activated proteins (GAPs) (Bos JL et al., Cell, Vol. 129, No. 5, June 1, 2007, pp. 865-877). Conversely, RAS mutants are insensitive to these GAPs, resulting in a longer residence time in the GTP-bound state and a cycling shift of the GTP / GDP to the ON state according to their inherent hydrolysis rate.

[0006] These three RAS genes constitute the most common family of mutated genes in cancer, with RAS mutations found in approximately 25% of human tumors. Among these three paralogs, KRAS mutations are the most common (accounting for 85% of all RAS-driven cancers), while NRAS and HRAS mutations are less frequently reported (12% and 3%, respectively). Most KRAS mutations occur at hotspot residues G12, G13, and Q61. KRAS G12C mutations account for approximately 12% of all KRAS mutations and are prevalent in lung cancer patients (approximately 13% of lung adenocarcinoma (LUAC)), approximately 3%–5% of colorectal adenocarcinoma patients, a smaller proportion of patients with other cancer types, and approximately 20% of patients with MYH polyposis colorectal adenomas (COSMIC v80 database; A. Aime et al.; Cancer Genet [Cancer Genetics] 2015, 208:390-5).

[0007] Patients with KRAS G12C-positive solid tumors do not respond well to existing therapies alone. There are currently no approved inhibitors of KRAS G12C, HRAS G12C, or NRAS G12C for therapeutic use.

[0008] Therefore, there remains a need to develop new options for treating cancers, particularly cancers expressing the G12C mutant Ras, especially those driven by KRAS, HRAS, or NRAS G12C. More specifically, there is still a need to treat cancers with KRAS G12C mutations.

[0009] Irreversible RAS G12C inhibitors have been previously described (e.g., WO 2014152588, WO 2017201161, WO 2018 / 217651 and WO 2018119183). Summary of the Invention

[0010] The compounds described in this invention selectively react with and inhibit G12C-mutant KRAS, HRAS, or NRAS proteins by forming an irreversible covalent bond with a cysteine ​​residue at position 12. This locks the RAS mutant protein into an inactive state. The irreversible binding of these compounds disrupts downstream K-RAS signaling. The compounds described in this invention can be used to treat cancers, particularly cancers characterized by KRAS, HRAS, or NRAS G12C mutations, and more particularly cancers characterized by KRAS G12C mutations.

[0011] This invention provides compounds, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and combinations thereof. The compounds are capable of selectively binding to and inhibiting G12C mutants of KRAS, HRAS, or NRAS, and can be used to treat cancers, particularly cancers characterized by KRAS, HRAS, or NRAS G12C mutations. This invention also provides methods for preparing such compounds and intermediates useful in the synthesis of such compounds.

[0012] This document describes various embodiments or aspects of the present invention.

[0013] This document provides compounds having formula (I) as defined herein, or their stereoisomers, their transisomers, their pharmaceutically acceptable salts, their stereoisomers, or their transisomers that are pharmaceutically acceptable salts. (I).

[0014] In another embodiment, the present invention provides a compound having formula (I) as defined herein, or a transisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

[0015] In another embodiment, the present invention provides compounds having formula (I) as defined herein (or having sub-formulas (Ia), (Ib) ), (Ic ), (Id (or (Ie) compounds), or their transisomers, or their pharmaceutically acceptable salts, or their pharmaceutically acceptable salts.

[0016] In another embodiment, the present invention provides a compound having formula (I) as defined herein, or a pharmaceutically acceptable salt thereof.

[0017] In another embodiment, the present invention provides compounds having formula (I) as defined herein (or having sub-formulas (Ia), (Ib) ), (Ic ), (Id (or (Ie) compounds), or their pharmaceutically acceptable salts.

[0018] In another embodiment, the present invention provides a compound having formula (I) (or having sub-formulas (Ia), (Ib) thereof). ), (Ic ), (Id A pharmaceutical composition comprising a compound of (Ie) or (Ie), or a stereoisomer thereof, or a transisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a transisomer thereof, and one or more pharmaceutically acceptable carriers.

[0019] In another embodiment, the present invention provides a compound having formula (I) (or having sub-formulas (Ia), (Ib) thereof). ), (Ic ), (Id (I) or (Ie) compounds), or therapeutically effective amounts of compounds having formula (I) (or having its sub-formulas (Ia), (Ib) ), (Ic ), (Id A pharmaceutical composition comprising a compound of (Ie) or (Ie), or a stereoisomer thereof, or a transisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a transisomer thereof, and optionally one or more pharmaceutically acceptable carriers.

[0020] In another embodiment, the invention provides combinations, particularly pharmaceutical combinations, comprising compounds having formula (I) (or having sub-formulas (Ia), (Ib) thereof). ), (Ic ), (Id (or (Ie) compounds), or their stereoisomers, or their transisomers, or their pharmaceutically acceptable salts, or their pharmaceutically acceptable salts, or their transisomers, and one or more therapeutic agents.

[0021] In another embodiment, the present invention provides a pharmaceutical composition comprising a compound having formula (I) (or having sub-formulas (Ia), (Ib) thereof). ), (Ic ), (Id (or (Ie) compounds), or their transisomers, or their pharmaceutically acceptable salts, or their pharmaceutically acceptable salts, and one or more therapeutically active agents.

[0022] In another embodiment, the present invention relates to a method for inhibiting G12C-mutated KRAS, HRAS, or NRAS proteins (e.g., G12C-mutated KRAS proteins) in a subject with this need, wherein the method comprises administering to the subject a therapeutically effective amount of a compound having formula (I) or having a sub-formula (Ia), (Ib) as defined herein. ), (Ic ), (Id (Ie) or (Ie) compounds, or their stereoisomers, or their transisomers, or their pharmaceutically acceptable salts, or their stereoisomers, or their transisomers, or their transisomers, or their pharmaceutically acceptable salts.

[0023] In yet another embodiment, the present invention relates to a method of treating a disorder or disease in a subject in need, wherein the disorder or disease is selected from cancers, such as lung cancer (including lung adenocarcinoma and non-small cell lung cancer), colorectal cancer (including colorectal adenocarcinoma), pancreatic cancer (including pancreatic cancer), uterine cancer (including endometrial cancer), rectal cancer (including rectal adenocarcinoma), and other solid tumors, and wherein the method comprises administering to the patient a therapeutically effective amount of a compound having formula (I) as defined herein or having sub-formulas (Ia), (Ib), etc. ), (Ic ), (Id (Ie) or (Ie) compounds, or their stereoisomers, or their transisomers, or their pharmaceutically acceptable salts, or their stereoisomers, or their transisomers, or their transisomers, or their pharmaceutically acceptable salts.

[0024] In another embodiment, the present invention provides intermediate compounds for preparing compounds of the present invention, as well as compounds having formula (I) as defined herein, or having sub-formulas (Ia), (Ib). ), (Ic ), (Id Methods for the production of compounds of (Ie) or (Ie), or their stereoisomers or their transtransisomers. Attached Figure Description

[0025] Figure 1 This explains a( R X-ray powder diffraction pattern of the hydrate (variant HA) of compound X (compound X) 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepten-2-yl)prop-2-en-1-one.

[0026] Figure 2 This explains a( R X-ray powder diffraction pattern of the isopropanol (IPA) solvate of 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepten-2-yl)prop-2-en-1-one (compound X).

[0027] Figure 3 This explains a( RX-ray powder diffraction pattern of the ethanol (EtOH) solvate of 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta-2-yl)prop-2-en-1-one (compound X).

[0028] Figure 4 This explains a( R X-ray powder diffraction pattern of the propylene glycol solvate of 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]hept-2-yl)prop-2-en-1-one (compound X). Detailed Implementation

[0029] In a first aspect, the present invention provides compounds having formula (I), (I) A. Choose from the following groups (a) C5-C 7- Cycloalkylene groups, which are unsubstituted or substituted by one or more, preferably one, two or three, substituents independently selected from fluorine and C1-C4-alkyl groups; (b) 5-7 membered unsaturated heterocyclic groups containing a carbon-carbon double bond and an oxygen atom as ring members, wherein the heterocyclic group is unsubstituted or substituted by one or more, preferably 1, 2 or 3, substituents independently selected from fluorine and C1-C4-alkyl, preferably substituted by 1, 2 or 3 C1-C4-alkyl groups. (c) C6-C 10 Aryl groups, which are unsubstituted or composed of 1, 2, or 3 R groups. A2 replace; (d) A 5-6 membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S as ring members, wherein the heteroaryl ring is unsubstituted or has R atoms on one or more (e.g., 1, 2, or 3) carbon atoms. A3 Substitution, wherein when a nitrogen atom is present in the heteroaryl ring, the nitrogen atom is either unsubstituted or substituted with a substituent selected from the group consisting of: C1-C4-alkyl, -(CH2). 1-2 -C 3-4 -cycloalkyl, C 3- C6-cycloalkyl, hydroxy-C 1- C4-alkyl, fluoro-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, N(R) 9 (R) 10-C1-C4-alkyl, -SO2-C1-C4-alkyl, -SO2-C 3-4 -cycloalkyl, -(CH2) p -Het py and -(CH2) p -N(R 9 (R) 10 (Preferably, the substituents are selected from the group consisting of: fluoro-C1-C4-alkyl, N(R) 9 (R) 10 -C1-C4-alkyl, -SO2-C 3-4 -cycloalkyl, or -(CH2) 1-2 -C 3-4 -cycloalkyl); (e) An 8-10 membered heteroaryl ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10 membered partially saturated heterobicycle containing 1 to 3 heteroatoms or heterogroups independently selected from 0 to 3 nitrogen atoms, 0 to 2 oxygen atoms, 0 to 1 sulfur atom, and 0 to 1 S(=O)2 group, wherein the heteroaryl ring or heterobicycle is unsubstituted or has 1, 2, 3, 4, or 5 R atoms on the carbon atom. A4 Substitution, wherein the heterobicycle is further optionally oxidized at a carbon atom and wherein, when a nitrogen atom is present, the nitrogen atom is unsubstituted or substituted with a substituent -(CO)-C1-C4-alkyl or C1-C4-alkyl, and wherein the C1-C4-alkyl is optionally substituted with one or two independently selected from cyano, hydroxy, oxo, fluorine, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 Substituents; and Among them Het b It is a 4-, 5-, or 6-membered heterocycle containing one or two independent heteroatoms or groups selected from N, O, S, SO, and SO2 (preferably one oxygen atom, or one sulfur atom, or one S(=O) or one S(=O)2 group, or one nitrogen atom and one oxygen atom, or one or two nitrogen atoms), wherein the heterocycle Het b It is either unsubstituted or has one or two independent substituents selected from the following: C1-C4-alkyl, hydroxy, cyano, fluorine, C1-C4-alkoxy-hydroxy-C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy, fluoro-C1-C4-alkoxy, and fluoro-C1-C4-alkyl, and wherein the heterocyclic Het b Further, optionally, the carbon atom is substituted with oxygen, and wherein when the nitrogen atom is present in Hetb In this case, the nitrogen atom is optionally further substituted with a C1-C4-alkyl group, which is optionally substituted with one to three substituents independently selected from fluorine, hydroxyl and C1-C4-alkoxy groups; Where A passes through A on sp 2 The hybrid carbon atom is attached to the rest of the compound having formula (I); in Choose B freely. 1 and B 2 The group formed Among them B 1 It is C 6-10 Aryl groups, which are unsubstituted or composed of 1, 2, 3, or 4 R groups. Ba replace; B 2 It is a 6-13 membered heteroaryl group, which contains 1, 2 or 3 nitrogen atoms, wherein B 2 It is either unreplaced or replaced by 1, 2, 3, or 4 Rs. Bb replace; C is selected from the group consisting of: hydrogen, C1-C3 alkyl (preferably methyl), C3-C5 cycloalkyl (preferably cyclopropyl), fluoro-C1-C3 alkyl (preferably CHF2 or CF3), cyano, -CH2-CN, -CH(CN)-CH3, -CH2-OH, -CH(OH)-CH3 and halogen; L can choose from the following groups:

[0030] Where n is 1, 2, or 3. R L Selected from hydrogen, methyl, ethyl, -CH2-CN and -CH2-OH, wherein G Represents the attachment point to G; G can choose from the following groups:

[0031] in

[0032] R 2 Selected from hydrogen, C1-C3 alkyl, -C(O)-C1-C3-alkyl, and fluorine; R 3 It is hydrogen; R 4 Selected from hydrogen, methyl, -CH2F, -CH2-OCH3 and -CH2-N(CH3)2; R 5 Selected from hydrogen and methyl; R 6 It is hydrogen; R 7 Selected from hydrogen and methyl; Where R A2 Independently select from the following groups: NR 9 R 10 , cyano, -(CH2) p -CN, halogenated, OH, hydroxyl, -C1-C4-alkyl, -(COOH), -(CH2) p -COOH, C1-C4-alkyl, fluoro-C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl, N(R 9 (R) 10 )-C1-C4-alkyl, N(R 9 (R) 10 )-C1-C4-alkyl-oxygen, N(R 9 (R) 10 -C1-C4-alkoxy, C1-C4-alkyl-carbonyl-oxy-C1-C4-alkyl-oxy, hydroxy-C1-C4-alkyl-oxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, C1-C4-alkoxy-C1-C4-alkyl-oxy-C1-C4-alkyl, -SO2-C1-C4-alkyl, -SO2-C 3-4 -cycloalkyl, -(CH2) 1-2 -C 3-4 -cycloalkyl, Het py -(CH2) p -Het py -C(=O)-NR 9 R 10 -(CH2) p -C(=O)NR 9 R 10 (Preferably selected from the group consisting of: NR) 9 R 10 , cyano, C1-C4-alkyl, fluorine, fluorine-C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, hydroxy-C1-C4-alkyl, hydroxy-C1-C4-alkyl-oxy, Het py -(CH2) p -Het py and -C(=O)-NR 9 R 10 ); Where R A3 Independently select from the following groups: oxidative, NR 9 R 10 , cyano, -(CH2) p-CN, halogenated, OH, hydroxyl, -C1-C4-alkyl, -(COOH), -(CH2) p -COOH, C1-C4-alkyl, fluoro-C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl, N(R 9 (R) 10 )-C1-C4-alkyl, N(R 9 (R) 10 )-C1-C4-alkyl-oxygen, N(R 9 (R) 10 -C1-C4-alkoxy, C1-C4-alkyl-carbonyl-oxy-C1-C4-alkyl-oxy, hydroxy-C1-C4-alkyl-oxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, C1-C4-alkoxy-C1-C4-alkyl-oxy-C1-C4-alkyl, -SO2-C1-C4-alkyl, -SO2-C 3-4 -cycloalkyl, -(CH2) 1-2 -C 3-4 -cycloalkyl, Het py -(CH2) p -Het py -C(=O)-NR 9 R 10 -(CH2) p -C(=O)NR 9 R 10 (CH2) p -NR 9 R 10 (Preferably selected from the group consisting of: NR) 9 R 10 , cyano, C1-C4-alkyl, fluorine, fluorine-C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Het py and -(CH2) p -Het py ); Where R A4 Independently selected from the group consisting of: cyano, CO2H, halogen, C1-C4-alkyl, fluoro-C1-C4-alkyl, hydroxy, hydroxy-C1-C4-alkyl, hydroxy-C1-C4-alkyl-oxy, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl-oxy, NR 9 R 10 、(N(R 9 (R) 10 )-C1-C4-alkyl, (N(R)9 (R) 10 -C1-C4-alkyl-oxy, -(CO)-C1-C4-alkyl, and R 9 R 10 N-C1-C4-alkyl-oxy-(CO)-C1-C4-alkyl; in p is 1, 2, or 3; R 9 Selected from hydrogen and C1-C4-alkyl; R 10 Selected from the group consisting of: hydrogen, C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl and di-C1-C4-alkyl-amino-C1-C4-alkyl; Het py It is a 4-, 5-, 6-, or 7-membered saturated heterocycle containing one or two heteroatoms independently selected from O, N (e.g., pyrrolidin-1-yl, cyclobutane-1-yl, morpholin-1-yl), and S, or containing an S-oxide (SO) or S-dioxide (SO2) group, wherein the heterocycle is optionally substituted with an oxygen atom on one carbon atom, and wherein the heterocycle is optionally further substituted with one, two, or three substituents independently selected from C1-C4-alkoxy (preferably methoxy), halogen (preferably fluorine), C1-C4-alkyl, hydroxy-C1-C4-alkyl, and fluoro-C1-C4-alkyl on one or more carbon atoms, and wherein if a nitrogen atom is present in the heterocycle, the nitrogen atom is optionally further substituted with an R 10 (Preferred option C) 1- C4-alkyl (e.g., methyl) substitution; Or Het py It is a 5- or 6-membered heteroaryl ring (preferably 1,2,4-triazol-1-yl or pyrazol-1-yl) containing 1, 2 or 3 nitrogen atoms and wherein said heteroaryl ring is optionally substituted by one or more (e.g., 1, 2 or 3) substituents independently selected from the following: NR 9 R 10 -C(=O)-NR 9 R 10 Halogenated, C 1- C4-alkyl, hydroxy-C 1- C4-alkyl, fluorine-C 1- C4-alkyl, cyano, OH, and C 1- C4-alkoxy group; Each R Ba Independently selected from the group consisting of: hydroxyl, NH2, C1-C4-alkyl, and halogen; Each R BbIndependently selected from the group consisting of: C1-C4-alkyl (preferably methyl), cyclopropyl, fluoro-C1-C3-alkyl (preferably CHF2 or CF3), cyano, halogen (preferably fluorine or chlorine), NH2, and C1-C3-alkoxy (preferably methoxy). Or its stereoisomer, or its transisomer, or its pharmaceutically acceptable salt, or its pharmaceutically acceptable salt, or its transisomer.

[0033] In a second aspect, the present invention provides a compound having formula (I), (I) A. Choose from the following groups (a) C5-C 7- Cycloalkylene groups, which are unsubstituted or substituted by one or more, preferably one, two or three, substituents independently selected from fluorine and C1-C4-alkyl groups; (b) 5-7 membered unsaturated heterocyclic groups containing a carbon-carbon double bond and an oxygen atom as ring members, wherein the heterocyclic group is unsubstituted or substituted by one or more, preferably 1, 2 or 3, substituents independently selected from fluorine and C1-C4-alkyl, preferably substituted by 1, 2 or 3 C1-C4-alkyl groups. (c) C6-C 10 Aryl groups, which are unsubstituted or composed of 1, 2, or 3 R groups. A2 replace; (d) A 5-6 membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S as ring members, wherein the heteroaryl ring is unsubstituted or has R atoms on one or more (e.g., 1, 2, or 3) carbon atoms. A3 Substitution, wherein when a nitrogen atom is present in the heteroaryl ring, the nitrogen atom is either unsubstituted or substituted with a substituent selected from the group consisting of: C1-C4-alkyl, -(CH2). 1-2 -C 3-4 -cycloalkyl, C 3- C6-cycloalkyl, hydroxy-C 1- C4-alkyl, fluoro-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, N(R) 9 (R) 10 -C1-C4-alkyl, -SO2-C1-C4-alkyl, -SO2-C 3-4 -cycloalkyl, -(CH2) p -Het py and -(CH2) p -N(R 9 (R) 10(Preferably, the substituents are selected from the group consisting of: fluoro-C1-C4-alkyl, N(R) 9 (R) 10 -C1-C4-alkyl, -SO2-C 3-4 -cycloalkyl, or -(CH2) 1-2 -C 3-4 -cycloalkyl); (e) An 8-10 membered heteroaryl ring containing 1, 2, or 3 nitrogen atoms, or an 8-10 membered partially saturated heterobicycle containing 1 to 3 heteroatoms or heterogroups independently selected from 0-3 nitrogen atoms, 0-2 oxygen atoms, 0-1 sulfur atoms, and 0-1 S(=O)2 groups, wherein the heteroaryl ring or heterobicycle is unsubstituted or has 1, 2, 3, 4, or 5 R atoms on the carbon atom. A4 Substitution, wherein the heterobicycle is further optionally oxidized at a carbon atom and wherein, when a nitrogen atom is present, the nitrogen atom is unsubstituted or substituted with a substituent -(CO)-C1-C4-alkyl or C1-C4-alkyl, and wherein the C1-C4-alkyl is optionally substituted with one or two independently selected from cyano, hydroxy, oxo, fluorine, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 Substituents; and Among them Het b It is a 4-, 5-, or 6-membered heterocycle containing one or two independent heteroatoms or groups selected from N, O, S, SO, and SO2 (preferably one oxygen atom, or one sulfur atom, or one S(=O) or one S(=O)2 group, or one nitrogen atom and one oxygen atom, or one or two nitrogen atoms), wherein the heterocycle Het b It is either unsubstituted or has one or two independent substituents selected from the following: C1-C4-alkyl, hydroxy, cyano, fluorine, C1-C4-alkoxy-hydroxy-C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy, fluoro-C1-C4-alkoxy, and fluoro-C1-C4-alkyl, and wherein the heterocyclic Het b Further, optionally, the carbon atom is substituted with oxygen, and wherein when the nitrogen atom is present in Het b In this case, the nitrogen atom is optionally further substituted with a C1-C4-alkyl group, which is optionally substituted with one to three substituents independently selected from fluorine, hydroxyl and C1-C4-alkoxy groups; Where A passes through A on sp 2 The hybrid carbon atom is attached to the rest of the compound having formula (I); in Choose B freely. 1 and B 2 The group formed Among them B 1 It is C 6-10 Aryl groups, which are unsubstituted or composed of 1, 2, 3, or 4 R groups. Ba replace; B 2 It is a 6-13 membered heteroaryl group, which contains 1, 2 or 3 nitrogen atoms, wherein B 2 It is either unreplaced or replaced by 1, 2, 3, or 4 Rs. Bb replace; C is selected from the group consisting of: hydrogen, C1-C3 alkyl (preferably methyl), C3-C5 cycloalkyl (preferably cyclopropyl), fluoro-C1-C3 alkyl (preferably CHF2 or CF3), cyano, -CH2-CN, -CH(CN)-CH3, -CH2-OH, -CH(OH)-CH3 and halogen; L can choose from the following groups:

[0034] Where n is 1, 2, or 3. R L Selected from hydrogen, methyl, ethyl, -CH2-CN and -CH2-OH, wherein G Represents the attachment point to G; G can choose from the following groups:

[0035] in

[0036] R 2 Selected from hydrogen, C1-C3 alkyl, -C(O)-C1-C3-alkyl, and fluorine; R 3 It is hydrogen; R 4 Selected from hydrogen, methyl, -CH2F, -CH2-OCH3 and -CH2-N(CH3)2; R 5 Selected from hydrogen and methyl; R 6 It is hydrogen; R 7 Selected from hydrogen and methyl; Where R A2 Independently select from the following groups: NR 9 R 10 , cyano, -(CH2) p-CN, halogenated, OH, hydroxyl, -C1-C4-alkyl, -(COOH), -(CH2) p -COOH, C1-C4-alkyl, fluoro-C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl, N(R 9 (R) 10 )-C1-C4-alkyl, N(R 9 (R) 10 )-C1-C4-alkyl-oxygen, N(R 9 (R) 10 -C1-C4-alkoxy, C1-C4-alkyl-carbonyl-oxy-C1-C4-alkyl-oxy, hydroxy-C1-C4-alkyl-oxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, C1-C4-alkoxy-C1-C4-alkyl-oxy-C1-C4-alkyl, -SO2-C1-C4-alkyl, -SO2-C 3-4 -cycloalkyl, -(CH2) 1-2 -C 3-4 -cycloalkyl, Het py -(CH2) p -Het py -C(=O)-NR 9 R 10 -(CH2) p -C(=O)NR 9 R 10 (Preferably selected from the group consisting of: NR) 9 R 10 , cyano, C1-C4-alkyl, fluorine, fluorine-C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, hydroxy-C1-C4-alkyl, hydroxy-C1-C4-alkyl-oxy, Het py -(CH2) p -Het py and -C(=O)-NR 9 R 10 ); Where R A3 Independently select from the following groups: oxidative, NR 9 R 10 , cyano, -(CH2) p -CN, halogenated, OH, hydroxyl, -C1-C4-alkyl, -(COOH), -(CH2) p -COOH, C1-C4-alkyl, fluoro-C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl, N(R 9 (R)10 )-C1-C4-alkyl, N(R 9 (R) 10 )-C1-C4-alkyl-oxygen, N(R 9 (R) 10 -C1-C4-alkoxy, C1-C4-alkyl-carbonyl-oxy-C1-C4-alkyl-oxy, hydroxy-C1-C4-alkyl-oxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, C1-C4-alkoxy-C1-C4-alkyl-oxy-C1-C4-alkyl, -SO2-C1-C4-alkyl, -SO2-C 3-4 -cycloalkyl, -(CH2) 1-2 -C 3-4 -cycloalkyl, Het py -(CH2) p -Het py -C(=O)-NR 9 R 10 -(CH2) p -C(=O)NR 9 R 10 (CH2) p -NR 9 R 10 (Preferably selected from the group consisting of: NR) 9 R 10 , cyano, C1-C4-alkyl, fluorine, fluorine-C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Het py and -(CH2) p -Het py ); Where R A4 Independently selected from the group consisting of: cyano, CO2H, halogen, C1-C4-alkyl, fluoro-C1-C4-alkyl, hydroxy, hydroxy-C1-C4-alkyl, hydroxy-C1-C4-alkyl-oxy, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl-oxy, NR 9 R 10 、(N(R 9 (R) 10 )-C1-C4-alkyl, (N(R) 9 (R) 10 -C1-C4-alkyl-oxy, -(CO)-C1-C4-alkyl, and R 9 R 10 N-C1-C4-alkyl-oxy-(CO)-C1-C4-alkyl; in p is 1, 2, or 3; R 9 Selected from hydrogen and C1-C4-alkyl; R 10 Selected from the group consisting of: hydrogen, C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl and di-C1-C4-alkyl-amino-C1-C4-alkyl; Het py It is a 4-, 5-, 6-, or 7-membered saturated heterocycle containing one or two heteroatoms independently selected from O, N (e.g., pyrrolidin-1-yl, cyclobutane-1-yl, morpholin-1-yl), and S, or containing an S-oxide (SO) or S-dioxide (SO2) group, wherein the heterocycle is optionally substituted with an oxygen atom on one carbon atom, and wherein the heterocycle is optionally further substituted with one, two, or three substituents independently selected from C1-C4-alkoxy (preferably methoxy), halogen (preferably fluorine), C1-C4-alkyl, hydroxy-C1-C4-alkyl, and fluoro-C1-C4-alkyl on one or more carbon atoms, and wherein if a nitrogen atom is present in the heterocycle, the nitrogen atom is optionally further substituted with an R 10 (Preferred option C) 1- C4-alkyl (e.g., methyl) substitution; Or Het py It is a 5- or 6-membered heteroaryl ring (preferably 1,2,4-triazol-1-yl or pyrazol-1-yl) containing 1, 2 or 3 nitrogen atoms and wherein said heteroaryl ring is optionally substituted by one or more (e.g., 1, 2 or 3) substituents independently selected from the following: NR 9 R 10 -C(=O)-NR 9 R 10 Halogenated, C 1- C4-alkyl, hydroxy-C 1- C4-alkyl, fluorine-C 1- C4-alkyl, cyano, OH, and C 1- C4-alkoxy group; Each R Ba Independently selected from the group consisting of: hydroxyl, NH2, C1-C4-alkyl, and halogen; Each R Bb Independently selected from the group consisting of: C1-C4-alkyl (preferably methyl), cyclopropyl, fluoro-C1-C3-alkyl (preferably CHF2 or CF3), cyano, halogen (preferably fluorine or chlorine), NH2, and C1-C3-alkoxy (preferably methoxy). Or its stereoisomer, or its transisomer, or its pharmaceutically acceptable salt, or its pharmaceutically acceptable salt, or its transisomer.

[0037] When the term "preferred" is used in this specification, other embodiments of the invention particularly relate to compounds having formula (I), or stereoisomers thereof, or transisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof, or transisomers thereof, wherein all parts or features specifically mentioned after the term "preferred" replace the more general term that precedes one or more of the terms specifically described therein.

[0038] In another aspect, a compound having formula (I), or a transisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, is provided for use as a medicine.

[0039] In another aspect, a compound having formula (I), or a transisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, is provided for use in the treatment of disorders or diseases (e.g., cancer) mediated by KRAS, NRAS, or HRAS G12C mutations (e.g., KRAS G12C mutations).

[0040] In another aspect, a compound having formula (I), or a transisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a transisomer thereof, is provided for manufacturing a medicament for treating cancer, such as cancer mediated by KRAS, NRAS, or HRAS G12C mutations.

[0041] In another aspect, a method for treating a disorder or cancer in a subject with such need is provided, wherein the method comprises administering to the subject a therapeutically effective amount of a compound having formula (I), or a stereoisomer thereof, or a transisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a transisomer thereof.

[0042] In another aspect, methods are provided for treating disorders or diseases in subjects in need, such as those selected from cancers including lung cancer (including lung adenocarcinoma and non-small cell lung cancer), colorectal cancer (including colorectal adenocarcinoma), pancreatic cancer (including pancreatic cancer), uterine cancer (including endometrial cancer), rectal cancer (including rectal adenocarcinoma), and solid tumors, wherein said methods include administering to the subject a therapeutically effective amount of a compound having formula (I) as defined herein, or a stereoisomer thereof, or a transisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a transisomer thereof, or a pharmaceutically acceptable salt thereof.

[0043] In another aspect, a compound having formula (I), or a stereoisomer thereof, or a transisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a transisomer thereof, is provided for use in the treatment of cancers such as lung cancer (including lung adenocarcinoma and non-small cell lung cancer), colorectal cancer (including colorectal adenocarcinoma), pancreatic cancer (including pancreatic cancer), uterine cancer (including endometrial cancer), rectal cancer (including rectal adenocarcinoma), and solid tumors.

[0044] In another aspect, a compound having formula (I), or a stereoisomer thereof, or a transisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a transisomer thereof, is provided for use in the treatment of cancers, such as lung cancer (including lung adenocarcinoma and non-small cell lung cancer), colorectal cancer (including colorectal adenocarcinoma), pancreatic cancer (including pancreatic cancer), uterine cancer (including endometrial cancer), rectal cancer (including rectal adenocarcinoma), and solid tumors, wherein said cancer is a KRAS-, NRAS-, or HRAS-G12C mutant, typically said cancer is a KRAS-G12C mutant.

[0045] In another aspect, a pharmaceutical composition is provided comprising a compound having formula (I), a stereoisomer thereof, a transisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0046] In another aspect, a pharmaceutical composition is provided comprising a compound having formula (I), or a stereoisomer thereof, or a transisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a transisomer thereof, for use as a medicine.

[0047] In another aspect, a pharmaceutical composition is provided comprising a compound having formula (I), or a stereoisomer thereof, or a transisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a transisomer thereof, for use in the treatment of cancers such as lung cancer (including lung adenocarcinoma and non-small cell lung cancer), colorectal cancer (including colorectal adenocarcinoma), pancreatic cancer (including pancreatic cancer), uterine cancer (including endometrial cancer), rectal cancer (including rectal adenocarcinoma), and solid tumors, optionally wherein said cancer is a KRAS-, NRAS-, or HRAS-G12C mutant.

[0048] In another aspect, a combination is provided comprising a compound having formula (I), a stereoisomer thereof, a transisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt thereof, a transisomer thereof, and one or more therapeutically active agents.

[0049] In another aspect, methods are provided for manufacturing compounds having formula (I), or stereoisomers thereof, or transisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof, or transisomers thereof.

[0050] Unless otherwise stated herein, and unless the context clearly indicates otherwise, the terms "a compound of the present invention" or "compounds of the invention" include compounds having formula (I), (Ia), (Ib) formulas (Ia), (Ib), ... ), (Ic ), (Id One or more compounds of (Ie) and (Ie) and their pharmaceutically acceptable salts, as well as all stereoisomers (including diastereomers and enantiomers), steatoisomers, rotational isomers, tautomers and isotopically labeled compounds (including deuterium-substituted compounds), and intrinsically formed moieties.

[0051] It should be understood that compounds prepared as intermediates can also be considered as compounds of the present invention.

[0052] Therefore, having equations 2(a) and (2b) (2c) ) and (2d Compounds thereof and their salts are also considered to be compounds of the present invention.

[0053] Therefore, unless otherwise stated in the text and unless the context clearly indicates otherwise, the terms "compound having formula (I)" or "compound having formula (I), or a pharmaceutically acceptable salt thereof" include compounds having formulas (I), (Ia), (Ib). ), (Ic ), (Id Stereoisomers of compounds of formulas (I) and (Ie), or their transisomers, or pharmaceutically acceptable salts thereof, or compounds having formulas (I), (Ia), and (Ib). ), (Ic ), (Id Pharmaceutically acceptable salts of stereoisomers of compounds (I) and (Ie), or having formulas (I), (Ia), (Ib). ), (Ic ), (Id Pharmaceutically acceptable salts of the transisomers of compounds (Ie) and (Ie).

[0054] Having equations (I), (Ia), (Ib) ), (Ic ), (Id Compounds of formulas 2(a) and (Ie) include all stereoisomers, including diastereomers, transisomers, enantiomers, mixtures thereof, and racemic mixtures thereof, including their pharmaceutically acceptable salts. Compounds having formulas 2(a) and (2b) (2c) ) and (2d The compounds of ) include all stereoisomers, including diastereomers, transisomers, enantiomers, mixtures thereof and racemic mixtures thereof, including their salts.

[0055] When an isomer (e.g., enantiomer, diastereomer, transisomer, or geometric isomer) has a higher intrinsic activity as an inhibitor of the RAS G12C mutant protein than its opposite isomer, the isomer with higher activity is generally preferred.

[0056] The presence of diastereomers can be identified by those skilled in the art using tools such as NMR. The separation of diastereomers can be performed by those skilled in the art using chromatographic methods such as HPLC (High Performance Liquid Chromatography), thin-layer chromatography, SFC (Supercritical Fluid Chromatography), GC (Gas Chromatography), or recrystallization. The separation of enantiomers can be performed by those skilled in the art using tools such as chiral HPLC, chiral SFC, and chiral GC.

[0057] The compounds of the present invention, particularly ortho-substituted biaryl compounds, can exhibit rotational isomerism, referred to herein as transisomers (Eliel, E. and Wilen, S. (1994) Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., pp. 1142-55). In some cases, depending on the substituents on the biaryl ring moiety, such biaryl compounds of the present invention exhibit transisomerism.

[0058] Therefore, compounds having formula (I) and compounds having sub-formulas (Ia) and (Ib) ), (Ic ), (Id Compounds of formula (I) and (Ie) and mixtures of their isomers (including diastereomer mixtures, enantiomer mixtures, and racemic mixtures) also constitute a part of this invention. Similarly, compounds having formula (I) and those having sub-formulas (Ia), (Ib) are also included in this invention. ), (Ic ), (Id Mixtures of diastereomeric or enantiomerically enriched compounds of (Ie) are also part of this invention.

[0059] The present invention also provides crystalline forms of compound X as defined herein, such as hydrate (variant HA) crystalline form of compound X, or isopropanol (IPA) solvate crystalline form, or ethanol (EtOH) solvate crystalline form, or propylene glycol solvate crystalline form.

[0060] This invention also provides a crystalline form of compound X as defined herein, whose X-ray powder diffraction spectrum is consistent with... Figure 1 , Figure 2 , Figure 3 or Figure 4 The X-ray powder diffraction spectra shown are basically the same.

[0061] Unless otherwise provided or obvious from the context, the following definitions also apply: As used herein, the term "halogen" (or halogenated) refers to fluorine, bromine, chlorine, or iodine. Halogen-substituted groups and moieties, such as halogenated alkyl groups (halogenated alkyl groups), can be mono-, poly-, or per-halogenated. Unless otherwise stated, chlorine and fluorine are preferred halogenated substituents on alkyl or cycloalkyl groups, with fluorine being the most preferred. Unless otherwise stated, fluorine, chlorine, and bromine are generally preferred on aryl or heteroaryl groups, with fluorine being the most preferred.

[0062] Unless otherwise indicated, as used herein, the term “heteroatom” refers to a nitrogen (N), oxygen (O) or sulfur (S) atom, especially nitrogen or oxygen.

[0063] When multiple substituents are present, the substituents are selected independently unless otherwise specified, so that, for example, in the case of 2 or 3 substituents, those substituents may be the same or different.

[0064] As used herein, the term "C1-C4 alkyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, wherein the group is unsaturated, has one to four carbon atoms, and is attached to the rest of the molecule by a single bond. Examples of C1-C4 alkyl include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), and n-butyl. A preferred example is methyl.

[0065] When oxidized, C1-C4-alkyl groups include -C(O)-C1-C3-alkyl groups, wherein the carbonyl portion of the substituent is attached to the rest of the molecule.

[0066] As used herein, the term "hydroxy-C1-C4-alkyl" refers to C as defined above. 1- C4-alkyl group, wherein C 1- One hydrogen atom in the C4-alkyl group is replaced by an OH atom. (Hydroxy-C) 1- Examples of C4-alkyl groups include, but are not limited to: hydroxy-methyl, 2-hydroxy-ethyl, 2-hydroxy-propyl, 3-hydroxy-propyl, and 2-hydroxy-2-methyl-propyl.

[0067] As used herein, the term "C1-C4-alkoxy" refers to the formula -OR a The group, wherein R a It is as C is generally defined above. 1- C4 alkyl group. C 1- Examples of C4-alkoxy groups include, but are not limited to: methoxy, ethoxy, propoxy, isopropoxy, and butoxy.

[0068] As used herein, the term "hydroxy C1-C4-alkoxy" refers to the C1-C4-alkoxy group as defined above, where C 1- At least one hydrogen atom of the C4-alkoxy group is replaced by OH. (Hydroxy group C) 1-4 Examples of alkoxy groups include, but are not limited to, hydroxymethoxy, hydroxyethoxy, and 2-hydroxypropoxy.

[0069] As used herein, the term “C1-C4-alkyl-oxygen” refers to a “C1-C4-alkyl” group as defined above, wherein the group is attached to the remainder of the molecule by an oxygen atom.

[0070] As used herein, a “hydroxy-C1-C4-alkyl-oxy” substituent refers to a hydroxy-C1-C4-alkyl group as defined above, which is attached to the remainder of the molecule by an oxygen atom. Examples of hydroxy-C1-C4-alkyl-oxy groups include, but are not limited to, hydroxymethoxy, hydroxyethoxy, and 2-hydroxypropoxy.

[0071] As used herein, the term “C1-C4-alkoxy-C1-C4 alkyl” refers to a C1-C4-alkyl group as defined above, wherein one hydrogen atom of the C1-C4-alkyl group is replaced by a C1-C4-alkoxy group.

[0072] As used herein, the term "C1-C4-alkoxy-hydroxy-C1-C4-alkyl" refers to a C1-C4-alkoxy-C1-C4-alkyl group as defined above, wherein C... 1- At least one hydrogen atom of the C4 alkyl group is replaced by OH.

[0073] As used herein, the term “C1-C4-alkoxy-C1-C4-alkyl-oxy” means “C1-C4-alkoxy-C1-C4-alkyl” as defined above, wherein the group is attached to the remainder of the molecule by an oxygen atom.

[0074] As used herein, the term “C1-C4-alkyl-carbonyl-oxy-C1-C4-alkyl-oxy” refers to a group having the formula C1-C4-alkyl-C(=O)-O-C1-C4-alkyl-O-, wherein the group is attached to the remainder of the molecule by the last oxygen atom.

[0075] As used herein, the term "halo-alkyl" refers to an alkyl group as defined herein, which is substituted with one or more halogen groups as defined herein. A halo-alkyl group can be a monohalo-alkyl, dihalo-alkyl, trihalo-alkyl, or polyhalo-alkyl group, including perhalo-alkyl. A monohalo-alkyl group may have an iodine, bromine, chlorine, or fluorine group within the alkyl group. Chlorine and fluorine are preferred on the alkyl or cycloalkyl group.

[0076] As used herein, the term "fluoro-alkyl" refers to an alkyl group as defined herein, which is substituted with one or more fluorine molecules. Non-limiting examples of fluoro-C1-C4-alkyl groups include trifluoromethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-fluoropropyl, 3,3-difluoropropyl, and 1-fluoromethyl-2-fluoroethyl. Unless otherwise stated herein, preferred fluoro-alkyl groups include monofluoro-, difluoro-, and trifluoro-substituted methyl and ethyl groups, such as CF3, CF2H, CFH2, and CH2CF3.

[0077] As used herein, the term "fluoro-alkoxy" refers to an alkoxy group as defined herein, which is substituted with one or more fluorine molecules.

[0078] As used herein, the term "C1-C4-alkylamino" refers to an amino group having the formula -NH-R a The group, wherein R a It is a C1-C4-alkyl group as defined above.

[0079] As used in this article, the term "bi-C1-C" 4- "alkylamino" refers to a compound with the formula --N(R a )-R a The groups, wherein each R a It is a C1-C4 alkyl group, which may be the same or different, as defined above.

[0080] As used in this article, "NR" 9 R 10 "or "N(R 9 (R) 10 Substituents refer to those with the formula "-N(R)". 9 (R) 10 The group ")" wherein the group is transmitted through R 9 Groups and R 10 The nitrogen atom of the group is also attached to the rest of the molecule, and R is... 9 and R 10 They can be the same or different, as defined in this article.

[0081] As used in this article, the term "R" 9 R 10 "N-C1-C4-alkyl" or "N(R)" 9 (R) 10 "-C1-C4-alkyl" refers to a C1-C4 alkyl group as defined above, wherein one hydrogen atom of the C1-C4-alkyl group is surrounded by -N(R) 9 (R) 10 (replace)

[0082] As used in this article, the term "R" 9 R 10 "N-C1-C4-alkyl-oxygen" or "N(R" 9 (R) 10 "-C1-C4-alkyl-oxy" refers to R as defined above. 9 R 10 N-C1-C4-alkyl group (or N(R) 9 (R) 10 (-C1-C4-alkyl group), which is attached to the rest of the molecule by an oxygen atom.

[0083] As used in this article, the term "N(R)" 9 (R) 10 "-C1-C4-alkoxy" refers to the C1-C4 alkoxy group as defined above, wherein one hydrogen atom of the C1-C4-alkoxy group is surrounded by -N(R) 9 (R) 10 (replace)

[0084] As used herein, the term "-SO2-C1-C4-alkyl" refers to a C1-C4-alkyl group as defined above, which is attached to the remainder of the molecule via a -S(=O)2- linker.

[0085] As used herein, the term "-SO2-C3-C4-cycloalkyl" refers to a C3-C4-cycloalkyl group as defined below, which is attached to the remainder of the molecule via a -S(=O)2- linker.

[0086] As used herein, the term "hydroxy-C" 1-4 "-alkoxy" refers to C as defined above. 1-4 -alkoxy group, where C 1-4 At least one hydrogen atom of the alkoxy group is replaced by OH. Examples of hydroxy C1-C6 alkoxy groups include, but are not limited to, hydroxymethoxy, hydroxyethoxy, and 2-hydroxypropoxy.

[0087] As used in this article, the term "C" 1- C4 alkoxy-C 1- "C4 alkyl" refers to C4 as defined above. 1-4 alkyl groups, wherein C 1-4 One hydrogen atom of the alkyl group is C 1- C4-alkoxy substitution.

[0088] As used in this article, the term "C" 1- C4-alkoxy-C 1- "C4-alkyl-oxygen" refers to "C" as defined above. 1- C4 alkoxy-C 1- "C4 alkyl", where the group is attached to the rest of the molecule by an oxygen atom.

[0089] As used in this article, the term "C(O)-NR" 9 R 10 " refers to having the formula -R a1 -NR 9 R 10 The group, wherein R a1 It is a carbonyl group, "NR" 9 R 10 "As defined above, and R" 9and R 10 They can be the same or different, and as defined in this article.

[0090] As used herein, the term "C(O)C1-C4-alkyl" refers to an alkyl group having the formula -R a1 -C1-C4-alkyl groups, wherein R a1 It is a carbonyl group and C1-C4-alkyl is as defined above.

[0091] As used herein, the term "cycloalkyl" refers to a saturated carbocyclic group. C3-C7 cycloalkyl is any such cyclic group containing 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0092] As used herein, the term "cycloalkylene" refers to a non-aromatic carbocyclic group containing at least one carbon-carbon double bond, preferably one carbon-carbon double bond. The term "monocyclic cycloalkylene" refers to a non-aromatic monocyclic carbocyclic group containing at least one carbon-carbon double bond, preferably one carbon-carbon double bond. The term includes, but is not limited to, "C5-C7-cycloalkylene," which is a non-aromatic carbocyclic group containing 5 to 7 carbon atoms and one C-C double bond. Examples of suitable cycloalkylene groups are non-aromatic carbocyclic groups containing 5 to 7 carbon atoms and one or more C-C double bonds, such as cyclopentenyl and cyclohexenyl (e.g., cyclohex-1-en-1-yl, cyclohex-2-en-1-yl, cyclohex-3-en-1-yl).

[0093] As used herein, the term "aryl" refers to an aromatic hydrocarbon group having 6-14 carbon atoms in the ring moiety. Typically, an aryl is a monocyclic, bicyclic, or tricyclic aryl having 6-14 carbon atoms, often 6-10 carbon atoms, such as phenyl or naphthyl. Phenyl is sometimes preferred. Furthermore, as used herein, the term "aryl" refers to an aromatic substituent, which can be a monoaromatic ring or a polyaromatic ring fused together. Non-limiting examples include phenyl, naphthyl, and 1,2,3,4-tetrahydronaphthyl, provided that the tetrahydronaphthyl is attached to the formula described herein via a carbon atom of the aromatic ring of the tetrahydronaphthyl group.

[0094] Term "C" 6- C 10 "Aryl" refers to phenyl, 1,2,3,4-tetrahydronaphthyl, or naphthyl groups. A suitable C 6- C 10 An example of an aryl group is the phenyl group. The term "phenyl" refers to a group having the formula -C6H5. In a substituted phenyl group, one or more hydrogen atoms in -C6H5 are replaced by one or more substituents, especially any of those described herein.

[0095] As used herein, the term "heterocyclic group" or "heterocycle" refers to a saturated or partially unsaturated but not aromatic heterocyclic group, and can be monocyclic or polycyclic, including fused or bridged bicyclic systems. Unless otherwise stated, a heterocycle or heterocyclic group contains at least one non-carbon atom as a ring member, typically N, O, or S. Unless otherwise stated, a heterocyclic group has 3 to 10, preferably 4 to 7 ring atoms; wherein one or more, preferably one to four, particularly 1, 2, or 3 ring atoms are heteroatoms independently selected from O, S, and N (thus the remaining ring atoms are carbon). In the case where the heterocycle contains S or N as a heteroatom, S can exist as an SO or SO2 group and N can exist as an N-oxide, where the valence allows.

[0096] Unsaturated heterocyclic groups may have one or two double bonds, but are not aromatic. Preferably, unless described as unsaturated, the heterocyclic group in the compounds of the present invention is a saturated monocyclic ring. Preferably, the heterocyclic group has one or two heteroatoms as ring atoms, and preferably, the heteroatoms are not directly connected to each other. Examples of heterocycles include tetrahydrofuran (THF), dihydrofuran, 1,4-dioxane, morpholine, 1,4-dithiane, piperazine, piperidine, 1,3-dioxolane, imidazoline, imidazoline, pyrrolidine, pyrrolidine, tetrahydropyran, dihydropyran, oxothiocyclopentane, dithiocyclopentane, 1,3-dioxane, 1,3-dithiane, oxothiocyclohexane, thiomorpholine, etc.

[0097] The term "5-7 membered unsaturated heterocyclic group" refers to a cyclic group containing 5 to 7 ring atoms and one or more CC double bonds (preferably one CC double bond), wherein the ring atoms comprise 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur (optionally further comprising, for example, groups of -S(=O)- and -S(=O)2-). The term includes 5-, 6-, or 7-membered non-aromatic monocyclic groups containing one or more CC double bonds (preferably one CC double bond) and 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur (preferably one oxygen atom). Examples of 5-7 membered unsaturated heterocyclic groups include, but are not limited to, 6-membered non-aromatic monocyclic groups containing one oxygen atom and a CC double bond, such as 3,4-dihydro-2-H-pyranyl, 5,6-dihydro-2H-pyranyl, and 2H-pyranyl.

[0098] The term "heteroaryl" refers to a 5-14 membered, typically 5-10 membered, monocyclic or bicyclic aromatic ring group containing one, two, three, or four heteroatoms independently selected from nitrogen, oxygen, and sulfur. Typically, heteroaryls are 5-10 membered ring systems, such as 5-6 membered monocyclic or 8-10 membered bicyclic groups. Typical heteroaryl groups include 2- or 3-thienyl, 2- or 3-furanyl, 2- or 3-pyrroleyl, 2-, 4-, or 5-imidazolyl, 1-, 3-, 4-, or 5-pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isooxazolyl, 3- or 5-(1,2,4-triazolyl), 4- or 5-(1,2,3-triazolyl), 1- or 2- or 3-tetrazolyl, 2-, 3-, or 4-pyridinyl, 3- or 4-pyridazinyl, 2-pyrazinyl, and 2-, 4-, or 5-pyrimidinyl.

[0099] A substituted heteroaryl group is a heteroaryl group having one or more substituents (usually 1, 2 or 3 substituents) on the heteroaryl ring, which replace the hydrogen atom on the unsubstituted heteroaryl group.

[0100] The term "5-6-membered heteroaryl" refers to an aromatic monocyclic ring group containing 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term includes 5- or 6-membered aromatic ring groups containing 1, 2, or 3 heteroatoms selected from N, O, and S as ring members (preferably 1-2 nitrogen atoms or 1 nitrogen atom and 1 sulfur atom). The term includes 6-membered rings in which aromatic tautomers are present, for example, in the case of the 1H-pyridin-2-one system. Examples of suitable 5- or 6-membered heteroaryl groups include, but are not limited to: 2- or 3-thienyl, 2- or 3-furanyl, 2- or 3-pyrroleyl, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isooxazolyl, 3- or 5-(1,2,4-triazolyl), 4- or 5-(1,2,3-triazolyl), 1- or 2- or 3-tetrazolyl, 2-, 3- or 4-pyridinyl, 3- or 4-pyridazinyl, 2-pyrazinyl, and 2-, 4- or 5-pyrimidinyl.

[0101] The term "8-10-membered heteroaryl" refers to an aromatic bicyclic group comprising 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Non-limiting examples include 1-, 2-, 3-, 5-, 6-, 7-, or 8-indazinyl; 1-, 3-, 4-, 5-, 6-, or 7-isoindolyl; 2-, 3-, 4-, 5-, 6-, or 7-indolyl; and 2-, 3-, 4-, 5-, 6-, or 7-inzolyl. Examples of 8-10-membered heteroaryl groups include, but are not limited to: pyrrolo[2,3-b]pyridyl, pyrrolo[2,3-c]pyridyl, pyrrolo[3,2-c]pyridyl, pyrrolo[3,2-b]pyridyl, benzofuranyl, benzothiophenyl, indolyl, isoindolyl, indololinyl, benzimidazolyl, and inzolyl.

[0102] The terms “8-10-membered partially unsaturated heterobicyclic group” or “8-10-membered partially saturated heterobicycle” include (a) a 5-6-membered heteroaryl group containing 1-3 or 1-2 nitrogen atoms fused with a second ring to form a 5,5-, 5,6-, 6,5- or 6-6-ring system, and (b) a benzene ring fused with a second ring containing at least one heteroatom or heterogroup to form a 6,5- or 6-6-ring system.

[0103] The term "8-10 membered partially saturated heterobicycle, wherein the heterobicycle contains 1 to 3 heteroatoms or heterogroups independently selected from 0-3 nitrogen atoms, 0-2 oxygen atoms, 0-1 sulfur atoms and 0-1 S(=O)2 groups" refers to an 8-10 membered bicyclic group composed of the following: (i) A 5-6 membered heteroaryl ring containing 1, 2, or 3 nitrogen atoms, wherein the heteroaryl ring is fused to a 5- or 6-membered saturated or partially saturated carbon ring, wherein the carbon ring optionally incorporates one or two atoms or groups independently selected from 1-2 oxygen atoms, 1 sulfur atom, and 0-1 S(=O)2 groups in the non-aromatic portion of the ring, or (ii) A benzene ring, wherein the benzene ring is fused to a 5- or 6-membered saturated or partially saturated carbon ring, wherein the carbon ring incorporates 1 to 3 heteroatoms or heterogroups independently selected from 0-3 nitrogen atoms, 0-2 oxygen atoms, 0-1 sulfur atoms, and 0-1 S(=O)2 groups in the non-aromatic portion of the ring. (For example, 1 nitrogen atom and 1 oxygen atom; or 1, 2 or 3 nitrogen atoms; 1 oxygen atom; or 1 sulfur atom; or 1 -S(=O)2 group). The condition is that the attachment point between the 8-10 member partially saturated heterobicycle and the rest of the molecule is on the 5-6 member heteroaryl group or on the benzene ring.

[0104] The 8-10 quintile partially saturated heterobicyclic groups are either unsubstituted or substituted with one or more substituents as described herein, and are further optionally oxysubstituted on the carbon atom (except on the aromatic ring).

[0105] In one embodiment, the term "8-10-membered partially saturated heterobicycle" refers to an 8-10-membered partially saturated heterobicycle group consisting of a 5-6-membered heteroaryl ring containing 1, 2, or 3 nitrogen atoms or a benzene ring, wherein the phenyl or heteroaryl ring is fused to a 5- or 6-membered saturated or partially saturated carbon ring, said carbon ring optionally incorporating 1 nitrogen atom and 1 oxygen atom in the non-aromatic portion of the ring; or 1, 2, or 3 nitrogen atoms; 1 oxygen atom; or 1 sulfur atom; or 1 group selected from -S(=O)- and -S(=O)2-, provided that the attachment point of the 8-10-membered partially saturated heterobicycle to the remainder of the molecule is on the 5-6-membered heteroaryl group or the phenyl ring. The bicyclic group is unsubstituted or substituted with one or more substituents described herein, and further optionally oxysubstituted at the carbon atom (except on the aromatic ring). Therefore, the term "8-10-membered partially unsaturated heterobicyclic group" includes (a) a 5-6-membered heteroaryl group containing 1-2 nitrogen atoms fused to a second ring to form a 5,5-, 5,6-, 6,5-, or 6-6-cyclic system, and (b) a phenyl ring fused to a second ring to form a 6,5-, or 6-6-cyclic system.

[0106] Examples of “8-10 quintile partially saturated heterobicycles” and “8-10 quintile partially saturated heterobicycles containing 1 to 3 heteroatoms or heteroatomic groups independently selected from 0-3 nitrogen atoms, 0-2 oxygen atoms, 0-1 sulfur atoms, and 0-1 S(=O)2 groups” include, but are not limited to: indololinyl (e.g., indololin-5-yl), isoindololinyl (e.g., isoindololin-5-yl), dihydrobenzofuranyl (e.g., 2,3-dihydrobenzofuran-6-yl), dihydroisobenzofuranyl (e.g., 1,3-dihydroisobenzofuran-5-yl), tetrahydroindazoleyl, and tetrahydrobenzimidazolyl (e.g., 4,5,6,7-tetrahydro-1-yl). H -benzimidazol-5-yl), tetrahydroisoquinolinyl, tetrahydroquinoxalinyl, dihydrobenzimidazolyl (e.g., 2,3-dihydro-1-yl) H -benzo[ d Imidazol-5-yl), dihydrobenzothiophene (e.g., 1,3-dihydrobenzo[ c Thiophene-5-yl), dihydrobenzothiophene dioxide (e.g., 1,3-dihydrobenzo[ c Thiophene-5-yl 2,2-dioxide), dihydropyrrolopyrazolyl (e.g., 5,6-dihydro-4-yl pyrrolopyrazolyl) H -pyrrolo[1,2- b]pyrazol-3-yl), isoindoline ketone (e.g., isoindoline-1-one-5-yl), indoline ketone (e.g., indoline-2-one-5-yl), benzofuran ketone (e.g., benzofuran-2(3-yl) H )-keto-6-yl), isobenzofuran ketone (e.g., isobenzofuran-1(3) H (e.g., ketone-6-yl). Preferably, it is an 8-10 quinone partially saturated heterobicycle or "an 8-10 quinone partially saturated heterobicycle containing 1 to 3 heteroatoms or heteroatomic groups independently selected from 0-3 nitrogen atoms, 0-2 oxygen atoms, 0-1 sulfur atoms and 0-1 S(=O)2 groups" selected from indololinyl (e.g., indololin-5-yl), isoindololinyl (e.g., isoindololin-5-yl), dihydrobenzofuranyl (e.g., 2,3-dihydrobenzofuran-6-yl), dihydroisobenzofuranyl (e.g., 1,3-dihydroisobenzofuran-5-yl), dihydrobenzimidazolyl (e.g., 2,3-dihydro-1-yl), etc. H -benzo[ d Imidazol-5-yl), dihydrobenzothiophene (e.g., 1,3-dihydrobenzo[ c Thiophene-5-yl, 2,3-dihydrobenzo[b]thiophene-6-yl), dihydrobenzothiophene dioxides (e.g., 1,3-dihydrobenzo[b]thiophene-6-yl), and dihydrobenzothiophene dioxides (e.g., 1,3-dihydrobenzo[b]thiophene-6-yl). c Thiophene-5-yl 2,2-dioxide), dihydropyrrolopyrazolyl (e.g., 5,6-dihydro-4-yl pyrrolopyrazolyl) H -pyrrolo[1,2- b ]pyrazol-3-yl), isoindoline ketone (e.g., isoindoline-1-one-5-yl), indoline ketone (e.g., indoline-2-one-5-yl), benzofuran ketone (e.g., benzofuran-2(3-yl) H )-keto-6-yl), isobenzofuran ketone (e.g., isobenzofuran-1(3) H )-keto-6-yl).

[0107] The term "cyano" refers to the -CN group.

[0108] The term "amino" refers to the -NH2 group.

[0109] The term "hydroxyl group" refers to the -OH group.

[0110] The term "oxo" refers to the =O group.

[0111] Generally speaking, for groups containing two or more subgroups, the last group mentioned is the group connection point. For example, "alkylaryl" refers to a monovalent group of the formula alkyl-aryl-, while "arylalkyl" refers to a monovalent group of the formula aryl-alkyl-.

[0112] For groups beginning with a hyphen (-), the group immediately following the hyphen is the attachment point to the rest of the molecule. For example, -(CH2). 1-2 -C 3-4 -Cycloalkyl refers to a C-molecule attached to the rest of the molecule via a methylene or ethylene linker. 3-4 - Cycloalkyl groups.

[0113] As used herein, the term "substituted with one or more substituents" includes substitution with 2, 3, 4, 5, or 6 substituents. Preferably, it includes 1 substituent or 2 or 3 substituents. For the avoidance of doubt, the term also includes the possibility of 2 or 3 substituents being present on the same carbon atom, where the valence allows.

[0114] Any and all instances or exemplary language (e.g., "as") used herein are intended only to better illustrate the invention and not to limit the scope of the invention as otherwise claimed.

[0115] The term "substituted by 1, 2 or 3 substituents" should be interpreted accordingly.

[0116] The expression "where A passes through sp on A" is used to express the meaning of the expression "where A passes through sp on A". 2 "The hybrid carbon atom is attached to the rest of the compound having formula (I)," which can be represented by the following diagram. .

[0117] When referring to "heteroatoms" in a ring, this refers to cyclic heteroatoms (where NH is also considered a heteroatom and can be used in place of "N").

[0118] As used herein, in the compounds described herein, in compounds having formulas (2a) and (2b) (2c) ) and (2d In compounds, or in the aforementioned schemes, the term "nitrogen protecting group" (PG) refers to a group that should protect the relevant functional group from unwanted secondary reactions, such as acylation, etherification, esterification, oxidation, solvation, and similar reactions. It can be removed under deprotection conditions. Depending on the protecting group used, a person skilled in the art will know how to remove the protecting group to obtain the free amine NH2 group by referring to known methods. These include methods referenced in organic chemistry textbooks and literature, such as JFW McOmie, "Protective Groups in Organic Chemistry", TW Greene and PGM Wuts, "Greene's Protective Groups in Organic Synthesis", and in "Methoden der organischen Chemie" (Methods of Organic Chemistry).

[0119] Preferably, the nitrogen protecting group includes: C1-C6 alkyl (e.g., tert-butyl) mono, di, or trisubstituted with trialkylsilyl-C1-C7 alkoxy, preferably C1-C4 alkyl, more preferably C1-C2 alkyl, and most preferably C1-alkyl (e.g., trimethylsilylethoxy). The aryl (preferably phenyl) or heterocyclic group (e.g., benzyl, isopropylphenyl, diphenylmethyl, pyrrolyl, triphenylmethyl, pyrrolylmethyl, 1-methyl-1,1-dimethylbenzyl, (phenyl)methylbenzene), wherein the aryl ring or heterocyclic group is unsubstituted or substituted by one or more, for example, two or three residues selected from the group consisting of: C1-C7 alkyl, hydroxyl, C1-C7 alkoxy (e.g., p-methoxybenzyl (PMB)), C2-C8-alkanoyl-oxy, halogen, nitro, cyano, and CF3, aryl-C1-C2-alkoxycarbonyl (preferably phenyl-C1-C2-alkoxycarbonyl (e.g., benzyloxycarbonyl (Cbz), benzyloxymethyl (BOM), neopentyloxymethyl (POM)), C1-C 10 -Alkenyloxycarbonyl, C1-C6 alkylcarbonyl (e.g., acetyl or neopentyl), C6-C 10 -Arylcarbonyl; C1-C6-alkoxycarbonyl (e.g., tert-butoxycarbonyl (Boc), methylcarbonyl, trichloroethoxycarbonyl (Troc), neopentanoyl (Piv), allyloxycarbonyl), C6-C 10-aryl C1-C6-alkoxycarbonyl (e.g., 9-fluorenylmethyloxycarbonyl (Fmoc)), allyl or phenylallyl, sulfonyl or sulfinyl, succinimide group, silyl group (e.g., triarylsilyl, trialkylsilyl, triethylsilyl (TES), trimethylsilylethoxymethyl (SEM), trimethylsilyl (TMS), triisopropylsilyl or tert-butyldimethylsilyl).

[0120] In embodiments of the present invention, the nitrogen protecting group is a C1-C6-alkoxycarbonyl group (e.g., tert-butoxycarbonyl (Boc), methyloxycarbonyl, trichloroethoxycarbonyl (Troc), neopentanoyl (Piv), allyloxycarbonyl). More preferably, the nitrogen protecting group is tert-butoxycarbonyl.

[0121] In embodiments of the present invention, the nitrogen protecting group is a C1-C6-alkoxycarbonyl (e.g., tert-butoxycarbonyl or tert-butylcarbamate (Boc), methyloxycarbonyl or methylcarbamate, ethylcarbamate, 9-fluorophenylmethylcarbamate (Fmoc) and its analogues, 2,2,2-trichloroethylcarbamate trichloroethoxycarbonyl (Troc), 2-trimethylsilylethylcarbamate (Teoc), neopentanoyl (Piv), allyloxycarbonyl or allylcarbamate (Alloc), benzylcarbamate (Cbz)) or an amide protecting group such as COCF3 (trifluoroacetamide), or N-allyl or N-benzyl and its analogues. More preferably, the nitrogen protecting group is tert-butoxycarbonyl.

[0122] The term "stereoisomer" refers to compounds that have the same chemical composition but whose atoms or groups are arranged differently in space.

[0123] The term "diastereomer" or "diastereomer" refers to a stereoisomer that is independent of its mirror image. Diastereomers are characterized by differences in physical properties and some differences in chemical behavior. Mixtures of diastereomers can be separated using analytical procedures such as chromatography or crystallization.

[0124] The term "enantiomer" refers to one of a pair of molecular entities that are mirror images of each other and cannot be overlapped.

[0125] The term "enantiomer mixture" refers to an enantiomer-enriched mixture, a composition of an enantiomer of the present invention comprising a larger proportion or percentage of one enantiomer or racemate than another enantiomer or racemate.

[0126] The term "diastereomer mixture" refers to a mixture enriched with diastereomers or a mixture of diastereomers in equal proportions.

[0127] The term "diastereomer-enriched" refers to a composition containing a larger proportion or percentage of the diastereomer of the compound of the present invention relative to one or more other diastereomers.

[0128] The term "restricted rotation isomer" refers to a stereoisomer resulting from restricted rotation around a single bond, where the rotational barrier is high enough to allow for the separation of the isomers. Typically, rotation around the single bond in the molecule is prevented or significantly slowed down due to spatial interactions with other parts of the molecule and the asymmetry of the substituents at both ends of the single bond, resulting in the formation of a stereo unit called a "chiral axis".

[0129] Using stereotypes (a) R ) / (a( S The Cahn-Ingold-Prelog (CIP) chirality rule, or the stereotype ( P )or( M The CIP helical rule specifies the absolute configuration of the chiral axis, as seen in exemplary compounds (V. Prelog and G. Helmchen). Angewandte Chemie International Edition [Applied Chemistry International Edition], 21(8): 567-583, 1982, https: / / doi.org / 10.1002 / anie.198205671 P. Mata, AMLobo, C. Marshall, and A.P. Johnson, Tetrahedron: Asymmetry [Tetrahedron: Asymmetric], 4(4): 657-688, 1993, https: / / doi.org / 10.1016 / S0957-4166(00)80173-1 Both are cited in HAFarve and WHPowell. Nomenclature of Organic Chemistry: IUPAC Recommendations and Preferred Names [Organic Chemistry Nomenclature: IUPAC Recommendations and Preferred Names] 2013 (IUPAC "Blue Book"), Cambridge, UK: Royal Soc. Of Chem., 2014. https: / / doi.org / 10.1039 / 9781849733069 Chapter 9, “Specification of Configuration and Conformation”, https: / / doi.org / 10 / 1039 / 9781849733069-01156.

[0130] The following shows Example 12a (a more active transisomer), which has a( R )or( M Configuration. Example 12b (the less active transisomer) has a( S )or(P Configuration. For comparison, their structures are described below.

[0131]

[0132] The alternative ways to depict the structures of examples 12a and 12b are as follows.

[0133] , In embodiments of the present invention, the compounds of the present invention adopt the same spatial orientation as shown in Example 12a.

[0134] Similarly, the compound of Example 1a can be named "a( R )-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]hept-2-yl)prop-2-en-1-one”. The compound of Example 1a can also be described by the name “1-{6-[(4 M The designation is given as "(5-chloro-6-methyl-1H-indazole-4-yl)-5-methyl-3-(1-methyl-1H-indazole-5-yl)-1H-pyrazol-1-yl]-2-azaspiro[3.3]hept-2-yl}prop-2-en-1-one".

[0135] The structure of the compound in Example 1a (also referred to as compound X in this paper) is as follows.

[0136] (Compound X).

[0137] An alternative way to describe the structure of the compound of Example 1a (also referred to herein as compound X) is as follows.

[0138] (Compound X).

[0139] The term "substantially similar" regarding X-ray diffraction peak positions means taking into account typical peak position and intensity variability. For example, those skilled in the art will understand that peak positions (2... The relative peak intensity can show variability between certain devices, typically up to 0.2°. Furthermore, those skilled in the art should understand that the relative peak intensity will show variability between devices as well as variability due to crystallinity, preferred orientation, the surface of the prepared sample, and other factors known to those skilled in the art, and should be used only as a qualitative measurement.

[0140] Various embodiments or aspects of the invention are described herein and particularly in the claims. It should be recognized that the features specified in each embodiment may be combined with other specified features to provide further embodiments of the invention. In particular, it will be appreciated that features mentioned in particular embodiments or aspects are preferred aspects of the invention. The embodiments listed below are representative of the invention.

[0141] Example 1. A compound having formula (I), (I) in A. Choose from the following groups (a) C5-C 7- Cycloalkylene groups, which are unsubstituted or substituted by one or more, preferably one, two or three, substituents independently selected from fluorine and C1-C4-alkyl groups; (b) 5-7 membered unsaturated heterocyclic groups containing a carbon-carbon double bond and an oxygen atom as ring members, wherein the heterocyclic group is unsubstituted or substituted by one or more, preferably 1, 2 or 3, substituents independently selected from fluorine and C1-C4-alkyl, preferably substituted by 1, 2 or 3 C1-C4-alkyl groups. (c) C6-C 10 Aryl groups, which are unsubstituted or composed of 1, 2, or 3 R groups. A2 replace; (d) A 5-6 membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S as ring members, wherein the heteroaryl ring is unsubstituted or has R atoms on one or more (e.g., 1, 2, or 3) carbon atoms. A3 Substitution, wherein when a nitrogen atom is present in the heteroaryl ring, the nitrogen atom is either unsubstituted or substituted with a substituent selected from the group consisting of: C1-C4-alkyl, -(CH2). 1-2 -C 3-4 -cycloalkyl, C 3- C6-cycloalkyl, hydroxy-C 1- C4-alkyl, fluoro-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, N(R) 9 (R) 10 -C1-C4-alkyl, -SO2-C1-C4-alkyl, -SO2-C 3-4 -cycloalkyl, -(CH2) p -Het py and -(CH2) p -N(R 9 (R) 10 (Preferably, the substituents are selected from the group consisting of: fluoro-C1-C4-alkyl, N(R)9 (R) 10 -C1-C4-alkyl, -SO2-C 3-4 -cycloalkyl, or -(CH2) 1-2 -C 3-4 -cycloalkyl); (e) An 8-10 membered heteroaryl ring containing 1, 2, or 3 nitrogen atoms, or an 8-10 membered partially saturated heterobicycle containing 1 to 3 heteroatoms or heterogroups independently selected from 0-3 nitrogen atoms, 0-2 oxygen atoms, 0-1 sulfur atoms, and 0-1 S(=O)2 groups, wherein the heteroaryl ring or heterobicycle is unsubstituted or has 1, 2, 3, 4, or 5 R atoms on the carbon atom. A4 Substitution, wherein the heterobicycle is further optionally oxidized at a carbon atom and wherein, when a nitrogen atom is present, the nitrogen atom is unsubstituted or substituted with a substituent -(CO)-C1-C4-alkyl or C1-C4-alkyl, and wherein the C1-C4-alkyl is optionally substituted with one or two independently selected from cyano, hydroxy, oxo, fluorine, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 Substituents; and Among them Het b It is a 4-, 5-, or 6-membered heterocycle containing one or two independent heteroatoms or groups selected from N, O, S, SO, and SO2 (preferably one oxygen atom, or one sulfur atom, or one S(=O) or one S(=O)2 group, or one nitrogen atom and one oxygen atom, or one or two nitrogen atoms), wherein the heterocycle Het b It is either unsubstituted or has one or two independent substituents selected from the following: C1-C4-alkyl, hydroxy, cyano, fluorine, C1-C4-alkoxy-hydroxy-C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy, fluoro-C1-C4-alkoxy, and fluoro-C1-C4-alkyl, and wherein the heterocyclic Het b Further, optionally, the carbon atom is substituted with oxygen, and wherein when the nitrogen atom is present in Het b In this case, the nitrogen atom is optionally further substituted with a C1-C4-alkyl group, which is optionally substituted with one to three substituents independently selected from fluorine, hydroxyl and C1-C4-alkoxy groups; Where A passes through A on sp 2 The hybrid carbon atom is attached to the rest of the compound having formula (I); in Choose B freely. 1 and B2 The group formed Among them B 1 It is C 6-10 Aryl groups, which are unsubstituted or composed of 1, 2, 3, or 4 R groups. Ba replace; B 2 It is a 6-13 membered heteroaryl group, which contains 1, 2 or 3 nitrogen atoms, wherein B 2 It is either unreplaced or replaced by 1, 2, 3, or 4 Rs. Bb replace; C is selected from the group consisting of: hydrogen, C1-C3 alkyl (preferably methyl), C3-C5 cycloalkyl (preferably cyclopropyl), fluoro-C1-C3 alkyl (preferably CHF2 or CF3), cyano, -CH2-CN, -CH(CN)-CH3, -CH2-OH, -CH(OH)-CH3 and halogen; L can choose from the following groups:

[0142] Where n is 1, 2, or 3. R L Selected from hydrogen, methyl, ethyl, -CH2-CN and -CH2-OH, wherein G Represents the attachment point to G; G can choose from the following groups: ; in R 2 Selected from hydrogen, C1-C3 alkyl, -C(O)-C1-C3-alkyl, and fluorine; R 3 It is hydrogen; R 4 Selected from hydrogen, methyl, -CH2F, -CH2-OCH3 and -CH2-N(CH3)2; R 5 Selected from hydrogen and methyl; R 6 It is hydrogen; R 7 Selected from hydrogen and methyl; Where R A2 Independently select from the following groups: NR 9 R 10 , cyano, -(CH2) p -CN, halogenated, OH, hydroxyl, -C1-C4-alkyl, -(COOH), -(CH2) p-COOH, C1-C4-alkyl, fluoro-C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl, N(R 9 (R) 10 )-C1-C4-alkyl, N(R 9 (R) 10 )-C1-C4-alkyl-oxygen, N(R 9 (R) 10 -C1-C4-alkoxy, C1-C4-alkyl-carbonyl-oxy-C1-C4-alkyl-oxy, hydroxy-C1-C4-alkyl-oxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, C1-C4-alkoxy-C1-C4-alkyl-oxy-C1-C4-alkyl, -SO2-C1-C4-alkyl, -SO2-C 3-4 -cycloalkyl, -(CH2) 1-2 -C 3-4 -cycloalkyl, Het py -(CH2) p -Het py -C(=O)-NR 9 R 10 -(CH2) p -C(=O)NR 9 R 10 (Preferably selected from the group consisting of: NR) 9 R 10 , cyano, C1-C4-alkyl, fluorine, fluorine-C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, hydroxy-C1-C4-alkyl, hydroxy-C1-C4-alkyl-oxy, Het py -(CH2) p -Het py and -C(=O)-NR 9 R 10 ); Where R A3 Independently select from the following groups: oxidative, NR 9 R 10 , cyano, -(CH2) p -CN, halogenated, OH, hydroxyl, -C1-C4-alkyl, -(COOH), -(CH2) p -COOH, C1-C4-alkyl, fluoro-C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl, N(R 9 (R) 10 )-C1-C4-alkyl, N(R 9 (R) 10)-C1-C4-alkyl-oxygen, N(R 9 (R) 10 -C1-C4-alkoxy, C1-C4-alkyl-carbonyl-oxy-C1-C4-alkyl-oxy, hydroxy-C1-C4-alkyl-oxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, C1-C4-alkoxy-C1-C4-alkyl-oxy-C1-C4-alkyl, -SO2-C1-C4-alkyl, -SO2-C 3-4 -cycloalkyl, -(CH2) 1-2 -C 3-4 -cycloalkyl, Het py -(CH2) p -Het py -C(=O)-NR 9 R 10 -(CH2) p -C(=O)NR 9 R 10 (CH2) p -NR 9 R 10 (Preferably selected from the group consisting of: NR) 9 R 10 , cyano, C1-C4-alkyl, fluorine, fluorine-C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Het py and -(CH2) p -Het py ); Where R A4 Independently selected from the group consisting of: cyano, CO2H, halogen, C1-C4-alkyl, fluoro-C1-C4-alkyl, hydroxy, hydroxy-C1-C4-alkyl, hydroxy-C1-C4-alkyl-oxy, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl-oxy, NR 9 R 10 、(N(R 9 (R) 10 )-C1-C4-alkyl, (N(R) 9 (R) 10 -C1-C4-alkyl-oxy, -(CO)-C1-C4-alkyl, and R 9 R 10 N-C1-C4-alkyl-oxy-(CO)-C1-C4-alkyl; in p is 1, 2, or 3; R 9Selected from hydrogen and C1-C4-alkyl; R 10 Selected from the group consisting of: hydrogen, C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl and di-C1-C4-alkyl-amino-C1-C4-alkyl; Het py It is a 4-, 5-, 6-, or 7-membered saturated heterocycle containing one or two heteroatoms independently selected from O, N (e.g., pyrrolidin-1-yl, cyclobutane-1-yl, morpholin-1-yl), and S, or containing an S-oxide (SO) or S-dioxide (SO2) group, wherein the heterocycle is optionally substituted with an oxygen atom on one carbon atom, and wherein the heterocycle is optionally further substituted with one, two, or three substituents independently selected from C1-C4-alkoxy (preferably methoxy), halogen (preferably fluorine), C1-C4-alkyl, hydroxy-C1-C4-alkyl, and fluoro-C1-C4-alkyl on one or more carbon atoms, and wherein if a nitrogen atom is present in the heterocycle, the nitrogen atom is optionally further substituted with an R 10 (Preferred option C) 1- C4-alkyl (e.g., methyl) substitution; Or Het py It is a 5- or 6-membered heteroaryl ring (preferably 1,2,4-triazol-1-yl or pyrazol-1-yl) containing 1, 2 or 3 nitrogen atoms and wherein said heteroaryl ring is optionally substituted by one or more (e.g., 1, 2 or 3) substituents independently selected from the following: NR 9 R 10 -C(=O)-NR 9 R 10 Halogenated, C 1- C4-alkyl, hydroxy-C 1- C4-alkyl, fluorine-C 1- C4-alkyl, cyano, OH, and C 1- C4-alkoxy group; Each R Ba Independently selected from the group consisting of: hydroxyl, NH2, C1-C4-alkyl, and halogen; Each R Bb Independently selected from the group consisting of: C1-C4-alkyl (preferably methyl), cyclopropyl, fluoro-C1-C3-alkyl (preferably CHF2 or CF3), cyano, halogen (preferably fluorine or chlorine), NH2, and C1-C3-alkoxy (preferably methoxy). Or its stereoisomer, or its transisomer, or its pharmaceutically acceptable salt, or its pharmaceutically acceptable salt, or its transisomer.

[0143] Example 2. The compound according to Example 1, wherein A is selected from the group consisting of: (a) C5-C 7- Cycloalkylene groups, which are unsubstituted or substituted by one or more, preferably one, two or three, substituents independently selected from fluorine and C1-C4-alkyl groups; (b) 5-7 membered unsaturated heterocyclic groups containing a carbon-carbon double bond and an oxygen atom as ring members, wherein the heterocyclic group is unsubstituted or substituted by one or more, preferably 1, 2 or 3, substituents independently selected from fluorine and C1-C4-alkyl, preferably substituted by 1, 2 or 3 C1-C4-alkyl groups. (c) C6-C 10 Aryl groups, which are unsubstituted or composed of 1, 2, or 3 R groups. A2 replace; (d) A 5-6 membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S as ring members, wherein the heteroaryl ring is unsubstituted or has R atoms on one or more (e.g., 1, 2, or 3) carbon atoms. A3 Substitution, wherein when a nitrogen atom is present in the heteroaryl ring, the nitrogen atom is either unsubstituted or substituted with a substituent selected from the group consisting of: C1-C4-alkyl, -(CH2). 1-2 -C 3-4 -cycloalkyl, C 3- C6-cycloalkyl, hydroxy-C 1- C4-alkyl, fluoro-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, N(R) 9 (R) 10 -C1-C4-alkyl, -SO2-C1-C4-alkyl, -SO2-C 3-4 -cycloalkyl, -(CH2) p -Het py and -(CH2) p -N(R 9 (R) 10 (Preferably, the substituents are selected from the group consisting of: fluoro-C1-C4-alkyl, N(R) 9 (R) 10 -C1-C4-alkyl, -SO2-C 3-4 -cycloalkyl, or -(CH2) 1-2 -C 3-4 -cycloalkyl); (e) An 8- to 10-membered heteroaryl ring containing 1, 2, or 3 nitrogen atoms, wherein each nitrogen atom is unsubstituted or substituted with a substituent -(CO)-C1-C4-alkyl or C1-C4-alkyl, and wherein said C1-C4-alkyl is optionally replaced by 1 or 2 atoms independently selected from cyano, hydroxy, oxo, fluorine, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 The substituents are substituted, wherein the heteroaryl ring is unsubstituted or has 1, 2, 3, 4 or 5 R atoms on the carbon atom. A4 replace; Among them Het b It is a 4-, 5-, or 6-membered heterocycle containing one or two independent heteroatoms or groups selected from N, O, S, SO, and SO2 (preferably one oxygen atom, or one sulfur atom, or one S(=O) or one S(=O)2 group, or one nitrogen atom and one oxygen atom, or one or two nitrogen atoms), wherein the heterocycle Het b It is either unsubstituted or has one or two independent substituents selected from the following: C1-C4-alkyl, hydroxy, cyano, fluorine, C1-C4-alkoxy-hydroxy-C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy, fluoro-C1-C4-alkoxy, and fluoro-C1-C4-alkyl, and wherein the heterocyclic Het b Further, optionally, the carbon atom is substituted with oxygen, and wherein when the nitrogen atom is present in Het b In the latter case, the nitrogen atom is optionally further substituted with a C1-C4-alkyl group, which is optionally substituted with one to three substituents independently selected from fluorine, hydroxyl, and C1-C4-alkoxy groups; and (f) An 8-10 quintile partially saturated heterobicycle containing 1-3 nitrogen atoms, 1-2 oxygen atoms, 1 sulfur atom, or 1 S(=O)2 group, wherein the heterobicycle is unsubstituted or has 1, 2, 3, 4, or 5 R atoms on its carbon atom. A4 Substitution, wherein the heterobicycle is further optionally oxidized at a carbon atom and wherein, when a nitrogen atom is present, the nitrogen atom is unsubstituted or substituted with a substituent -(CO)-C1-C4-alkyl or C1-C4-alkyl, and wherein the C1-C4-alkyl is optionally substituted with one or two independently selected from cyano, hydroxy, oxo, fluorine, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 Substituents; and Among them Hetb It is a 4-, 5-, or 6-membered heterocycle containing one or two independent heteroatoms or groups selected from N, O, S, SO, and SO2 (preferably one oxygen atom, or one sulfur atom, or one S(=O) or one S(=O)2 group, or one nitrogen atom and one oxygen atom, or one or two nitrogen atoms), wherein the heterocycle Het b It is either unsubstituted or has one or two independent substituents selected from the following: C1-C4-alkyl, hydroxy, cyano, fluorine, C1-C4-alkoxy-hydroxy-C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy, fluoro-C1-C4-alkoxy, and fluoro-C1-C4-alkyl, and wherein the heterocyclic Het b Further, optionally, the carbon atom is substituted with oxygen, and wherein when the nitrogen atom is present in Het b In this embodiment, the nitrogen atom is optionally further substituted with a C1-C4-alkyl group, which is optionally substituted with one to three substituents independently selected from fluorine, hydroxyl, and C1-C4-alkoxy groups. Or its stereoisomer, or its transisomer, or its pharmaceutically acceptable salt, or its pharmaceutically acceptable salt, or its transisomer.

[0144] Example 3. The compound according to Example 1 or 2, wherein

[0145] Het b It is a 4-, 5-, or 6-membered heterocycle containing one or two independent heteroatoms or groups selected from N, O, S, SO, and SO2 (preferably one oxygen atom, or one sulfur atom, or one S(=O) or one S(=O)2 group, or one nitrogen atom and one oxygen atom, or one or two nitrogen atoms), wherein the heterocycle Het b It is either unsubstituted or has one or two independent substituents selected from the following: C1-C4-alkyl, hydroxy, cyano, fluorine, C1-C4-alkoxy-hydroxy-C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy, and fluoro-C1-C4-alkyl, and wherein said heterocyclic Het b Further, optionally, the carbon atom is substituted with oxygen, and wherein when the nitrogen atom is present in Het b In this case, the nitrogen atom is optionally further substituted with a C1-C4-alkyl group, wherein the C1-C4-alkyl group is optionally replaced by one to three atoms independently selected from fluorine, hydroxyl, and C. 1- Substituents of C4-alkoxy groups; Choose B freely. 1 and B 2 The group formed; B1 It is C 6-10 Aryl groups, which are unsubstituted or composed of 1, 2, 3, or 4 R groups. Ba Replace and each R Ba Independently selected from the group consisting of: hydroxyl, C1-C4-alkyl, and halogen; B 2 It is a 6-10 (preferably 8-10) heteroaryl group, which contains 1, 2 or 3 nitrogen atoms, wherein B 2 It is either unreplaced or replaced by 1, 2, 3, or 4 Rs. Bb replace; Each R Bb Independently selected from the group consisting of: C1-C4-alkyl (preferably methyl), fluoro-C1-C3-alkyl (preferably CHF2 or CF3), cyano, halogen (preferably fluorine or chlorine), NH2 and C1-C3-alkoxy (preferably methoxy). Het py It is a 4-, 5-, 6-, or 7-membered saturated heterocycle containing one or two heteroatoms independently selected from O, N (e.g., pyrrolidin-1-yl, cyclobutane-1-yl, morpholin-1-yl), and S, or containing an S-oxide (SO) or S-dioxide (SO2) group, wherein the heterocycle is optionally oxidized on one carbon atom, and wherein the heterocycle is further substituted on one or more carbon atoms with one, two, or three substituents independently selected from: C1-C4-alkoxy (preferably methoxy), halogen (preferably fluorine), C1-C4-alkyl, hydroxy-C1-C4-alkyl, and fluoro-C1-C4-alkyl, and wherein if a nitrogen atom is present in the heterocycle, the nitrogen atom is optionally further substituted with R. 10 (Preferred option C) 1- C4-alkyl (e.g., methyl) substitution; Or Het py It is a 5- or 6-membered heteroaryl ring (preferably 1,2,4-triazol-1-yl or pyrazol-1-yl) containing 1, 2 or 3 nitrogen atoms and wherein said heteroaryl ring is optionally substituted by one or more (e.g., 1, 2 or 3) substituents independently selected from the following: NR 9 R 10 Halogenated, C 1- C4-alkyl, cyano, OH, and C 1- C4-alkoxy group; Where R A4 Independently selected from the group consisting of: cyano, CO2H, halogen, C1-C4-alkyl, fluorine-C 1- C4-alkyl, hydroxy, hydroxy-C1-C4-alkyl, hydroxy-C 1- C4-alkyl-oxygen, C1- C4-alkoxy group, C 1- C4-alkoxy-C 1- C4-alkyl-oxygen, -NR 9 R 10 R 9 R 10 NC 1- C4-alkyl-oxygen, -(CO)-C1-C4-alkyl; Or its stereoisomer, or its transisomer, or its pharmaceutically acceptable salt, or its pharmaceutically acceptable salt, or its transisomer.

[0146] Example 4. The compound according to any one of the foregoing examples, wherein

[0147] Het b It is a 4-, 5-, or 6-membered heterocycle containing one or two independent heteroatoms or groups selected from N, O, S, SO, and SO2 (preferably one oxygen atom, or one sulfur atom, or one S(=O) or one S(=O)2 group, or one nitrogen atom and one oxygen atom, or one or two nitrogen atoms), wherein the heterocycle Het b It is either unsubstituted or has one or two independent substituents selected from the following: C1-C4-alkyl, hydroxy, cyano, fluorine, C1-C4-alkoxy-hydroxy-C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy, and fluoro-C1-C4-alkyl, and wherein said heterocyclic Het b Further, optionally, the carbon atom is substituted with oxygen, and wherein when the nitrogen atom is present in Het b In this case, the nitrogen atom is optionally further substituted with a C1-C4-alkyl group, wherein the C1-C4-alkyl group is optionally replaced by one to three atoms independently selected from fluorine, hydroxyl, and C. 1- Substituents of C4-alkoxy groups; B 2 It is a 6-10 (preferably 8-10) heteroaryl group, which contains 1, 2 or 3 nitrogen atoms, wherein B 2 It is either unreplaced or replaced by 1, 2, 3, or 4 Rs. Bb replace; Het pyIt is a 4-, 5-, 6-, or 7-membered saturated heterocycle containing one or two heteroatoms independently selected from O, N (e.g., pyrrolidin-1-yl, cyclobutane-1-yl, morpholin-1-yl), and S, or containing an S-oxide (SO) or S-dioxide (SO2) group, wherein the heterocycle is optionally oxidized on one carbon atom, and wherein the heterocycle is further substituted on one or more carbon atoms with one, two, or three substituents independently selected from: C1-C4-alkoxy (preferably methoxy), halogen (preferably fluorine), C1-C4-alkyl, hydroxy-C1-C4-alkyl, and fluoro-C1-C4-alkyl, and wherein if a nitrogen atom is present in the heterocycle, the nitrogen atom is optionally further substituted with R. 10 (Preferred option C) 1- C4-alkyl (e.g., methyl) substitution; Or Het py It is a 5- or 6-membered heteroaryl ring (preferably 1,2,4-triazol-1-yl or pyrazol-1-yl) containing 1, 2 or 3 nitrogen atoms and wherein said heteroaryl ring is optionally substituted by one or more (e.g., 1, 2 or 3) substituents independently selected from the following: NR 9 R 10 Halogenated, C 1- C4-alkyl, cyano, OH, and C 1- C4-alkoxy (preferably the heteroaryl ring is substituted by one or more amino groups); R A4 Independently selected from the group consisting of: cyano, CO2H, halogen, C1-C4-alkyl, fluorine-C 1- C4-alkyl, hydroxy, hydroxy-C1-C4-alkyl, hydroxy-C 1- C4-alkyl-oxygen, C 1- C4-alkoxy group, C 1- C4-alkoxy-C 1- C4-alkyl-oxygen, -NR 9 R 10 and R 9 R 10 NC 1- C4-alkyl-oxygen, Or its stereoisomer, or its transisomer, or its pharmaceutically acceptable salt, or its pharmaceutically acceptable salt, or its transisomer.

[0148] Example 5. The compound according to any one of the foregoing examples, wherein G is

[0149] Or its stereoisomer, or its transisomer, or its pharmaceutically acceptable salt, or its pharmaceutically acceptable salt, or its transisomer.

[0150] Example 6. The compound according to any one of the foregoing examples, wherein L is , Or its stereoisomer, or its transisomer, or its pharmaceutically acceptable salt, or its pharmaceutically acceptable salt, or its transisomer.

[0151] Example 7. The compound according to Example 6, wherein R L It is hydrogen, or its stereoisomer, or its transisomer, or its pharmaceutically acceptable salt, or its stereoisomer, or its transisomer, or its transisomer, or its pharmaceutically acceptable salt.

[0152] Example 8. A compound according to any one of the preceding examples, wherein C is selected from C1-C3 alkyl (preferably methyl), fluoro-C1-C3 alkyl (preferably CHF2 or CF3), CH2-CN, or a stereoisomer thereof, or a transisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a transisomer thereof.

[0153] Example 9. The compound according to any one of the foregoing examples, wherein B is

[0154] Wherein B is unsubstituted or substituted with 1, 2 or 3 halogenated or methyl groups, or a stereoisomer of the same, or a transisomer of the same, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a transisomer of the same.

[0155] Example 10. The compound according to any one of the foregoing examples, wherein B is

[0156] Where X is N or CR B5 ; Where R B1 Independently selected from hydrogen and C1-C4-alkyl (preferably methyl); R B2 Independently selected from hydrogen, halogen (preferably chlorine), C1-C4-alkyl (preferably methyl), cyclopropyl and NH2; R B3Independently selected from hydrogen, halogen (preferably chlorine), cyclopropyl and C1-C4-alkyl (preferably methyl); R B4 Independently selected from hydrogen, halogenated (preferably chlorine or fluorine), and C1-C4-alkyl (preferably methyl), or R B3 and R B4 Together with the atoms to which they are attached, they form 4-6 membered rings (preferably 5-6 membered saturated or partially unsaturated carbon rings) that are fused with an aromatic ring containing X. R B5 It is independently selected from hydrogen, halogen (preferably chlorine) and C1-C4-alkyl (preferably methyl). Or its stereoisomer, or its transisomer, or its pharmaceutically acceptable salt, or its pharmaceutically acceptable salt, or its transisomer.

[0157] Example 11. The compound according to Example 10, wherein R B2 Independently selected from the group consisting of: hydrogen, NH2, and CH3 or their transisomers, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of their transisomers.

[0158] Example 12. The compound according to Example 10 or 11, wherein R B4 It is independently selected from hydrogen, halogen (preferably chlorine or fluorine) and C1-C4-alkyl (preferably methyl), or stereoisomers thereof, or transisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof, or transisomers thereof.

[0159] Example 13. The compound according to any one of Examples 10 to 12, wherein R B1 It is independently selected from hydrogen and methyl, or their stereoisomers, their transisomers, their pharmaceutically acceptable salts, their stereoisomers, or their transisomers.

[0160] Example 14. The compound according to any one of Examples 10 to 13, wherein R B1 It is hydrogen, or its stereoisomer, its transisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of its stereoisomer, or its pharmaceutically acceptable salt of its transisomer.

[0161] Example 15. The compound according to any one of Examples 10 to 14, wherein R B3 and R B4Each is independently selected from halogenated (preferably chlorinated or fluorinated) and C1-C4-alkyl (preferably methyl), or their stereoisomers, their transisomers, their pharmaceutically acceptable salts, their pharmaceutically acceptable salts, or their transisomers.

[0162] Example 16. The compound according to any one of Examples 10 to 15, wherein R B3 It is halogenated and R B4 It is a C1-C4-alkyl group, or a stereoisomer thereof, or a transisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a transisomer thereof.

[0163] Example 17. The compound according to any one of Examples 10 to 16, wherein R B3 It is chlorine and R B4 It is methyl, or its stereoisomer, its transisomer, its pharmaceutically acceptable salt, its stereoisomer, or its transisomer.

[0164] Example 18. The compound according to any one of Examples 10 to 16, wherein R B3 It is chlorine and R B4 It is chlorine, or its stereoisomer, or its transisomer, or its pharmaceutically acceptable salt, or its stereoisomer, or its transisomer, or its transisomer, or its pharmaceutically acceptable salt.

[0165] Example 19. A compound according to any one of Examples 10 to 18, wherein X is CH or N, or a stereoisomer thereof, or a transisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a transisomer thereof.

[0166] Example 20. A compound according to any one of Examples 10 to 19, wherein X is CH, or a stereoisomer thereof, or a transisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a transisomer thereof.

[0167] Example 21. A compound having formula (Ia) (Ia) Wherein A, B and C are as defined in any of the foregoing embodiments, or their stereoisomers, their transisomers, their pharmaceutically acceptable salts, their stereoisomers, or their transisomers.

[0168] Example 22. A compound having formula (I) or formula (Ia) according to any one of the foregoing examples, wherein A is C5-C 7- Cycloalkylene, which is unsubstituted or substituted by one or more, preferably one, two or three, independently selected from the following substituents: fluorine and C1-C4-alkyl, or stereoisomers thereof, or transisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof, or transisomers thereof.

[0169] Example 23. A compound having formula (I) or formula (Ia) according to any one of the foregoing examples, wherein A is Where W is O or C(R) w )2, each R w Independently selected from hydrogen and fluorine, R c It is hydrogen or C1-C4-alkyl and A is optionally further substituted by 1, 2 or 3 substituents independently selected from: fluorine and C1-C4-alkyl, or a stereoisomer thereof, or a transisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a transisomer thereof.

[0170] Example 24. A compound having formula (I) or formula (Ia) according to any one of Examples 1 to 21, wherein A is a phenyl group that is unsubstituted or converted by 1, 2 or 3 R groups. A2 Replacement, preferably wherein R A2 Independently selected from the following groups: halogenated, OH, hydroxyl-C 1- C4-alkyl, -(COOH), C 1- C4-alkyl, fluorine-C 1- C4-alkyl, C 1- C4-alkoxy group, C 1- C4-alkyl-carbonyl-oxy-C 1- C4-alkyl-oxygen, hydroxy-C 1- C4-alkyl-oxygen, C 1- C4-alkoxy-C 1- C4-alkyl-oxygen, -C(=O)-NR 9 R 10 -NR 9 R 10 Het py and -(CH2) p -Het py , in p is 1 or 2; R 9 Selected from hydrogen, C 1-C4-alkyl and C 1- C4-alkoxy-C 1- C4-alkyl; R 10 Selected from hydrogen, C 1- C4-alkyl, hydroxy-C 1- C4-alkyl and C 1- C4-alkoxy-C 1- C4-alkyl; Het py Yes -NR 9a R 10a and R 9a and R 10a Together with nitrogen, it forms a 4-, 5-, or 6-membered heterocycle containing one or two additional heteroatoms independently selected from O, N (e.g., pyrrolidin-1-yl, azirrobutane-1-yl, or morpholino-1-yl) and S, or their N-oxides, or their S-oxides (SO) or S-dioxides, wherein the heterocycle is optionally substituted with an oxygen atom on one carbon atom, and wherein the heterocycle is further substituted with one or two substituents independently selected from the following: C1-C4-alkoxy (preferably methoxy), halogen (preferably fluorine), C1-C4-alkyl, hydroxy-C1-C4-alkyl, and fluoro-C1-C4-alkyl; Or R 9a and R 10a It forms a 4-, 5-, or 6-membered heteroaryl ring (preferably 1,2,4-triazol-1-yl or pyrazol-1-yl) with nitrogen, comprising 1, 2, or 3 nitrogen atoms, wherein the heteroaryl ring is optionally substituted with an amino group, or a stereoisomer thereof, a transisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.

[0171] Example 25. A compound having formula (I) or formula (Ia) according to any one of Examples 1 to 21, wherein A is a 5-6 membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S as ring members, wherein the heteroaryl ring is unsubstituted or R is present on one or more (e.g., 1, 2, or 3) carbon atoms. A3 Substitution, wherein when the nitrogen atom is present in the heteroaryl ring, the nitrogen atom is unsubstituted or substituted by a substituent selected from the group consisting of: C1-C4-alkyl, -(CH2). 1-2 -C 3-4 -cycloalkyl, hydroxy-C 1- C4-alkyl, fluoro-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, N(R) 9 (R)10 -C1-C4-alkyl, -SO2-C1-C4-alkyl, -SO2-C 3-4 -cycloalkyl, -(CH2) p -Het py and -(CH2) p -N(R 9 (R) 10 (Preferably, the substituents are selected from the group consisting of: fluoro-C1-C4-alkyl, N(R) 9 (R) 10 -C1-C4-alkyl, -SO2-C 3-4 -cycloalkyl, or -(CH2) 1-2 -C 3-4 -cycloalkyl), or its stereoisomer, or its transisomer, or its pharmaceutically acceptable salt, or its stereoisomer, or its transisomer, or its transisomer, or its pharmaceutically acceptable salt.

[0172] Example 26. A compound having formula (I) or formula (Ia) according to any one of Examples 1 to 21, wherein A is pyridin-1-yl, pyridin-2-yl, or pyridin-3-yl, which is unsubstituted or substituted by one, two, or three substituents independently selected from: NH2, cyano, halogen, OH, hydroxy-C 1- C4-alkyl, -COOH, C 1- C4-alkyl, fluorine-C 1- C4-alkyl, C 1- C4-alkoxy, di-C 1- C4-alkylamino-C 1- C4-alkyl-oxygen, C 1- C4-alkyl-carbonyl-oxy-C 1- C4-alkyl-oxygen, hydroxy-C 1- C4-alkyl-oxygen, C 1- C4-alkoxy-C 1- C4-alkyl-oxygen, C 1- C4-alkoxy-C 1- C4-alkyl-oxy-C 1- C4-alkyl, -C(=O)-NR 9 R 10 NR 9 R 10 Het py and -(CH2) p -Het py , in p is 1 or 2; R 9 Selected from hydrogen and C1- C4-alkyl, R 10 Selected from hydrogen, C 1- C4-alkyl, hydroxy-C 1- C4-alkyl, C 1- C4-alkoxy-C 1- C4-alkyl and di-C 1- C4-alkyl-amino-C 1- C4-alkyl, Het py It is NR 9a R 10a ; R 9a and R 10a Together with nitrogen, it forms a 4-, 5-, or 6-membered saturated or unsaturated heterocycle comprising one or two heteroatoms independently selected from O, N (pyrrolidin-1-yl, azirrobutane-1-yl, morpholino-1-yl) and S, or their N-oxides, or their S-oxides (SO) or S-dioxides, wherein the heterocycle is optionally substituted with an oxygen atom on one carbon atom, and wherein the heterocycle is further substituted with one, two, or three substituents independently selected from the following: C1-C4-alkoxy (preferably methoxy), halogen (preferably fluorine), C1-C4-alkyl, hydroxy-C1-C4-alkyl, and fluoro-C1-C4-alkyl; Or R 9a and R 10a Together with nitrogen, it forms a 4-, 5-, or 6-membered heteroaryl ring (preferably 1,2,4-triazol-1-yl or pyrazol-1-yl) containing 1, 2, or 3 nitrogen atoms, wherein said heteroaryl ring is optionally substituted with an amino group. Its stereoisomer, or its transisomer, or its pharmaceutically acceptable salt, or its pharmaceutically acceptable salt, or its transisomer.

[0173] Example 27. A compound having formula (I) or formula (Ia) according to any one of Examples 1 to 21, wherein A is a pyridyl group substituted by one, two, or three substituents independently selected from: NH2, cyano, halogenated, C 1- C4-alkyl, fluorine-C 1- C4-alkyl, C 1- C4-alkoxy, di-C 1- C4-alkylamino-C 1- C4-alkyl-oxygen, -C(=O)-NR 9 R 10 NR 9 R 10 ,

[0174] Where p is 0, 1 or 2, preferably p is 0; R 22 It is hydrogen or a C1-C4-alkyl (preferably methyl), or amino; R 9 Selected from hydrogen and C 1- C4-alkyl, R 10 Selected from hydrogen, C 1- C4-alkyl, hydroxy-C 1- C4-alkyl, C 1- C4-alkoxy-C 1- C4-alkyl and di-C 1- C4-alkyl-amino-C 1- C4-alkyl, Or its stereoisomer, or its transisomer, or its pharmaceutically acceptable salt, or its pharmaceutically acceptable salt, or its transisomer.

[0175] Example 28. A compound having formula (I) or formula (Ia) according to any one of Examples 1 to 21, wherein A is , Where R 23 It is hydrogen, C 3- C6-cycloalkyl, C 1- C4-alkyl (preferably methyl), wherein A is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the following: F, CH3, CH2F, CHF2 and CF3; Or its stereoisomer, or its transisomer, or its pharmaceutically acceptable salt, or its pharmaceutically acceptable salt, or its transisomer.

[0176] Example 29. A compound having formula (I) or formula (Ia) according to any one of Examples 1 to 21, wherein A is a pyrimidin-5-yl group, which is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from: C 1- C4-alkoxy (preferably methoxy) and CH3, or their stereoisomers, their transisomers, their pharmaceutically acceptable salts, their stereoisomers, or their transisomers.

[0177] Example 30. A compound having formula (I) or formula (Ia) according to any one of Examples 1 to 21, wherein A is selected from the group consisting of:

[0178] Where R 24 It is hydrogen, C 1- C4-alkyl, hydroxy-C 1- C4-alkyl, C 1- C4-alkoxy-C 1- C4-alkyl, -NR 9 R 10 C 1- C4-alkyl, -SO2-C 1- C4-alkyl, -SO2-C 3-4 -cycloalkyl or -(CH2) 1-2 -C 3-4 -cycloalkyl; R 4a R 4b R 4c and R 4d Each is independently selected from hydrogen and C. 1- C4-alkyl (preferably methyl) Or its stereoisomer, or its transisomer, or its pharmaceutically acceptable salt, or its pharmaceutically acceptable salt, or its transisomer.

[0179] Example 31. A compound having formula (I) or formula (Ia) according to any one of Examples 1 to 21 above, wherein A is selected from the group consisting of:

[0180] in

[0181] y is 0, 1, or 2 (preferably 0 or 1); x is 0, 1, or 2 (preferably 0 or 1); z is 0, 1, or 2; R O Choose from the following groups: hydrogen, NR 9 R 10 R 9 R 10 NC 1- C4-alkyl-oxygen, C 1- C4-alkoxy-C 1- C4-alkyl-oxygen, hydroxy-C 1- C4-alkyl-oxygen and C1-C4-alkyl (preferably R) O Is it hydrogen or NR? 9 R 10 ); R M It is hydrogen, halogenated, or C1-C4-alkyl, wherein the alkyl group is optionally converted to OH, C1-C4-alkoxy, or NR. 9 R 10 Replacement (preferably R) M It is hydrogen); R N It is hydrogen or C1-C4-alkyl, or halogenated or fluorinated-C1-C4-alkyl (preferably hydrogen); R q Independently selected from the group consisting of: C1-C4-alkyl, hydroxyl, C1-C4-alkoxy, and NR. 9 R 10 ; R p It is a C1-C4-alkyl group; Each R p1 Independently selected from hydrogen and C1-C4-alkyl; R v Independently selected from halogens, C1-C4-alkyl groups, and fluoro-C1-C4-alkyl groups; R ae The group selected is from the group consisting of hydrogen and C1-C4-alkyl, wherein the alkyl group is optionally substituted by one or two substituents selected from the group consisting of cyano, hydroxyl, fluorine, C 1- C4-alkoxy group, C 1- C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 ; R Ae The group selected is from the group consisting of: hydrogen, -(CO)-C1-C4-alkyl, and C1-C4-alkyl, wherein the C1-C4 alkyl group is optionally substituted by one or two substituents selected from: cyano, hydroxyl, fluorine, C 1- C4-alkoxy group, C 1- C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 ; in R 9 Selected from hydrogen and C 1- C4-alkyl; R 10 Selected from hydrogen, C 1- C4-alkyl, hydroxy-C 1- C4-alkyl, C 1- C4-alkoxy-C 1- C4-alkyl and di-C 1-C4-alkyl-amino-C 1- C4-alkyl; Among them Het b It is a 4-, 5-, or 6-membered heterocycle containing one or two heteroatoms or groups independently selected from N, O, S, SO, and SO2 (preferably containing one oxygen atom, or one sulfur atom, or one S(=O) or one S(=O)2 group, or one nitrogen atom and one oxygen atom, or one or two nitrogen atoms), wherein the heterocycle Het b It is either unsubstituted or has one or two independent substituents selected from the following: C1-C4-alkyl, hydroxy, cyano, fluorine, hydroxy-C1-C4-alkyl, C1-C4-alkoxy, and fluoro-C1-C4-alkyl, and wherein the heterocyclic Het b Further, optionally, the carbon atom is substituted with oxygen, and wherein when the nitrogen atom is present in Het b In this case, the nitrogen atom is optionally further substituted with a C1-C4-alkyl group, which is optionally substituted with one to three substituents independently selected from fluorine, hydroxyl and C1-C4-alkoxy groups; Or its transisomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a transisomer thereof.

[0182] Example 32. A compound having formula (I) or formula (Ia) according to any one of Examples 1 to 21, wherein A is selected from the group consisting of:

[0183] Where z is 0, 1, or 2; R v Independently selected from halogens, C1-C4-alkyl groups, and fluoro-C1-C4-alkyl groups; R N It is hydrogen or C1-C4-alkyl, or halogenated or fluorinated-C1-C4-alkyl (preferably hydrogen); R O Choose from the following groups: hydrogen, NR 9 R 10 、N(R 9 (R) 10 )-C 1- C4-alkyl-oxygen, C 1- C4-alkoxy-C 1- C4-alkyl-oxygen, hydroxy-C 1- C4-alkyl-oxygen and C1-C4-alkyl (preferably R) O Is it hydrogen or NR? 9R 10 ); R ae The group selected is from the group consisting of hydrogen and C1-C4-alkyl, wherein the alkyl group is optionally substituted by one or two substituents selected from the group consisting of cyano, hydroxyl, fluorine, C 1- C4-alkoxy group, C 1- C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 ; R 9 Selected from hydrogen and C 1- C4-alkyl; R 10 Selected from hydrogen, C 1- C4-alkyl, hydroxy-C 1- C4-alkyl, C 1- C4-alkoxy-C 1- C4-alkyl and di-C 1- C4-alkyl-amino-C 1- C4-alkyl; Among them Het b It is a 4-, 5-, or 6-membered heterocycle containing one or two heteroatoms or groups independently selected from N, O, S, SO, and SO2 (preferably containing one oxygen atom, or one sulfur atom, or one S(=O) or one S(=O)2 group, or one nitrogen atom and one oxygen atom, or one or two nitrogen atoms), wherein the heterocycle Het b It is either unsubstituted or has one or two independent substituents selected from the following: C1-C4-alkyl, hydroxy, cyano, fluorine, hydroxy-C1-C4-alkyl, C1-C4-alkoxy, and fluoro-C1-C4-alkyl, and wherein the heterocyclic Het b Further, optionally, the carbon atom is substituted with oxygen, and wherein when the nitrogen atom is present in Het b In this case, the nitrogen atom is optionally further substituted with a C1-C4-alkyl group, which is optionally substituted with one to three substituents independently selected from fluorine, hydroxyl and C1-C4-alkoxy groups; Or its stereoisomer, or its transisomer, or its pharmaceutically acceptable salt, or its pharmaceutically acceptable salt, or its transisomer.

[0184] Example 33. A compound having formula (I) or formula (Ia) according to any one of Examples 1 to 21, or Example 31 or Example 32, wherein A is selected from the group consisting of:

[0185] Or its stereoisomer, or its transisomer, or its pharmaceutically acceptable salt, or its pharmaceutically acceptable salt, or its transisomer.

[0186] Example 34. A compound having formula (I) or formula (Ia) according to Example 33, wherein

[0187] R N It is hydrogen or C1-C4-alkyl (preferably hydrogen); R O Is it hydrogen or NR? 9 R 10 ; R v Independently selected from fluorine, chlorine, and C1-C4-alkyl (e.g., methyl); z is 0 or 1; Or its stereoisomer, or its transisomer, or its pharmaceutically acceptable salt, or its pharmaceutically acceptable salt, or its transisomer.

[0188] Example 35. A compound having formula (I) or formula (Ia) according to any one of Examples 31 to 34, wherein R ae Choose from the following groups: hydrogen, C1-C4-alkyl, -(CH2)2-Het b -CH2-CN, -(CH2) 2- OH, -(CH2) 2- O-C1-C4-alkyl, hydroxy-C1-C4-alkyl, -(CH2)2-O-(CH2)2-O-C1-C4-alkyl and -(CH2)2-diC1-C4-alkylamino, or wherein R Ae Choose from the group consisting of: hydrogen, fluorine-C1-C4-alkyl, and C1-C4-alkyl; Het b It is a 4-, 5-, or 6-membered heterocycle comprising one nitrogen atom and one oxygen atom, or one or two nitrogen atoms, wherein the heterocycle is unsubstituted or has one or two independent substituents selected from the group consisting of C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy, and fluorine, and wherein when a nitrogen atom is present in the heterocycle, the nitrogen atom is optionally further substituted with a C1-C4-alkyl group. Or its stereoisomer, or its transisomer, or its pharmaceutically acceptable salt, or its pharmaceutically acceptable salt, or its transisomer.

[0189] Example 36. A compound having formula (I) or formula (Ia) according to any one of Examples 31 to 35, wherein R ae Choose from the following groups: hydrogen, methyl, -CH2-CN, -(CH2)2-OH, -(CH2)2-OCH3, -(CH2)-C(CH3)2-OH, -(CH2)2-O-(CH2)2-OCH3, -(CH2)2-N(CH3)2, and -(CH2)2-Het b ; The Het b It is a 4-, 5-, or 6-membered heterocycle containing one nitrogen atom and one oxygen atom, or one or two nitrogen atoms, wherein the heterocycle is unsubstituted or has one or two independent substituents selected from the group consisting of C1-C4-alkyl, hydroxy-C1-C4-alkyl-C1-C4-alkoxy, and fluorine, and wherein when a nitrogen atom is present in the heterocycle, the nitrogen atom is optionally further substituted with a C1-C4-alkyl group. Or its stereoisomer, or its transisomer, or its pharmaceutically acceptable salt, or its pharmaceutically acceptable salt, or its transisomer.

[0190] Example 37. A compound having formula (I) or formula (Ia) according to any one of Examples 31 to 36, wherein R ae Choose from the following groups: hydrogen, methyl, -CH2-CN, -(CH2) 2- OH, -(CH2)2-OCH3, -(CH2)-C(CH3)2-OH, -(CH2)2-O-(CH2)2-OCH3, -(CH2)2-N(CH3)2, and -(CH2)2-Het b Het b The heterocycle is selected from the group consisting of: azirmonobutan-1-yl, pyrrolidan-1-yl, pyrrolidan-3-yl, and morpholino-1-yl, wherein the heterocycle is optionally further substituted by one or two substituents independently selected from: methyl, hydroxy-methyl, methoxy, and fluorine, or stereoisomers thereof, or transisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof, or transisomers thereof.

[0191] Example 38. A compound having formula (I) or formula (Ia) according to any one of Examples 31 to 36, wherein R ae Choose from the group consisting of: hydrogen, fluorine, -C1-C4-alkyl, C1-C4-alkyl, -(CH2)2-Het b -(CH2) 2-OH, -(CH2)2-O-C1-C4-alkyl, hydroxy-C1-C4-alkyl, -(CH2)2-O-(CH2)2-O-C1-C4-alkyl and -(CH2)2-diC1-C4-alkylamino, or their stereoisomers, their transisomers, their pharmaceutically acceptable salts, their pharmaceutically acceptable salts, or their transisomers.

[0192] Example 39. A method having formula (Ib) ) compounds, (Ib ), Among them, A, C, R B2 R B3 and R B4 It is as defined in any of the foregoing embodiments, wherein A is unsubstituted or substituted as defined in any of the foregoing embodiments, or a pharmaceutically acceptable salt thereof.

[0193] Example 40. A method having formula (Ic) ) compounds, (Ic ), Among them, C and R A2 R B2 R B3 and R B4 It is as defined in any of the foregoing embodiments, wherein a is 0, 1, 2 or 3 (preferably a is 0 or 1 or 2), or a pharmaceutically acceptable salt thereof.

[0194] Example 41. A method having formula (Id) ) compounds, (Id ), Among them, C and R B2 R N R B3 and R B4 It is as defined in any of the foregoing embodiments, wherein ---- lines represent single or double bonds; And R ae It is as defined above.

[0195] Example 42. The compound according to any one of the preceding examples, or a stereoisomer thereof, or a transisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a transisomer thereof, selected from the compounds of any example.

[0196] Example 43. A compound selected from: a( R )-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta-2-yl)prop-2-en-1-one, a( R ()( S )-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(1-(2-(3-fluoropyrrolidine-1-yl)ethyl)-1H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepten-2-yl)prop-2-en-1-one, a( R )1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-phenyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepten-2-yl)prop-2-en-1-one, a( R )1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-methoxyethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta-2-yl)prop-2-en-1-one, a( R )1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-hydroxy-2-methylpropyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta-2-yl)prop-2-en-1-one, a( R )1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-(2-(2-methoxyethoxy)ethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta-2-yl)prop-2-en-1-one, a( R )1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(4-(hydroxymethyl)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta-2-yl)prop-2-en-1-one, a( R)1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-fluoro-4-(2-methoxyethoxy)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepten-2-yl)prop-2-en-1-one, a( R )1-(6-(4-(3-amino-5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-methoxyethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta-2-yl)prop-2-en-1-one and a( R )1-(6-(4-(3-amino-5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-phenyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta-2-yl)prop-2-en-1-one, Or its pharmaceutically acceptable salt.

[0197] Example 44. A compound selected from: 1-{6-[(4 M )-4-(5-chloro-6-methyl-1 H -Indazol-4-yl)-5-methyl-3-(1-methyl-1 H -indazole-5-yl)-1 H [-pyrazol-1-yl]-2-azaspiro[3.3]hept-2-yl}prop-2-en-1-one, 1-{6-[(4 M )-4-(5-chloro-6-methyl-1 H -indazole-4-yl)-3-(1-{2-[(3 S )-3-Fluoropyrrolidine-1-yl]ethyl}-1 H -Indazole-5-yl)-5-methyl-1 H [-pyrazol-1-yl]-2-azaspiro[3.3]hept-2-yl}prop-2-en-1-one, 1-{6-[(4 M )-4-(5-chloro-6-methyl-1 H -Indazole-4-yl)-5-methyl-3-phenyl-1 H [-pyrazol-1-yl]-2-azaspiro[3.3]hept-2-yl}prop-2-en-1-one, 1-(6-{(4 M )-4-(5-chloro-6-methyl-1 H -Indazole-4-yl)-3-[2-(2-methoxyethyl)-2 H [-indazole-5-yl]-5-methyl-1H -pyrazol-1-yl}-2-azaspiro[3.3]hept-2-yl)prop-2-en-1-one, 1-(6-{(4 M )-4-(5-chloro-6-methyl-1 H -Indazole-4-yl)-3-[2-(2-hydroxy-2-methylpropyl)-2 H [-indazole-5-yl]-5-methyl-1 H -pyrazol-1-yl}-2-azaspiro[3.3]hept-2-yl)prop-2-en-1-one, 1-{6-[(4 M )-4-(5-chloro-6-methyl-1 H -Indazole-4-yl)-3-{2-[2-(2-methoxyethoxy)ethyl]-2 H -Indazole-5-yl}-5-methyl-1 H [-pyrazol-1-yl]-2-azaspiro[3.3]hept-2-yl}prop-2-en-1-one, 1-(6-{(4 M )-4-(5-chloro-6-methyl-1 H -Indazole-4-yl)-3-[4-(hydroxymethyl)phenyl]-5-methyl-1 H -pyrazol-1-yl}-2-azaspiro[3.3]hept-2-yl)prop-2-en-1-one, 1-(6-{(4 M )-4-(5-chloro-6-methyl-1 H -Indazol-4-yl)-3-[2-fluoro-4-(2-methoxyethoxy)phenyl]-5-methyl-1 H -pyrazol-1-yl}-2-azaspiro[3.3]hept-2-yl)prop-2-en-1-one, 1-(6-{(4 M )-4-(3-amino-5-chloro-6-methyl-1 H -Indazole-4-yl)-3-[2-(2-methoxyethyl)-2 H [-indazole-5-yl]-5-methyl-1 H -pyrazol-1-yl}-2-azaspiro[3.3]hept-2-yl)prop-2-en-1-one, 1-{6-[(4 M )-4-(3-amino-5-chloro-6-methyl-1 H -Indazole-4-yl)-5-methyl-3-phenyl-1 H [-pyrazol-1-yl]-2-azaspiro[3.3]hept-2-yl}prop-2-en-1-one, Or its pharmaceutically acceptable salt.

[0198] Example 45: A compound selected from the group consisting of compounds having the following structures and names:

[0199] Or its pharmaceutically acceptable salt.

[0200] Example 46. A compound selected from compounds having the following structure and name:

[0201] Or its pharmaceutically acceptable salt.

[0202] Example 47. A crystalline form of a compound according to any one of the foregoing examples.

[0203] Example 48. The compound according to any one of the preceding examples, or its stereoisomer, its transisomer, its pharmaceutically acceptable salt, its crystalline form, its stereoisomer, or its transisomer, is used as a medicine.

[0204] Example 49. The compound according to any one of the preceding examples, or its stereoisomer, its transisomer, its pharmaceutically acceptable salt, its crystalline form, its stereoisomer, or its transisomer, is used for use in the treatment of cancer.

[0205] Example 50. A pharmaceutical composition comprising a compound according to any one of the preceding examples, or a stereoisomer thereof, or a transisomer thereof, or a pharmaceutically acceptable salt thereof, or a crystalline form thereof, or a pharmaceutically acceptable salt thereof, or a transisomer thereof, and at least one pharmaceutically acceptable excipient.

[0206] Example 51. A compound having formula (2a), (2a) Where A, B, and C are defined as in any of the foregoing embodiments and R 25 It is a hydrogen or nitrogen protecting group, or a salt thereof.

[0207] Example 52. A method having formula (2b) ) compounds, (2b ) Among them, A, C, R B2 R B3 and R B4R is as defined in any of the foregoing embodiments. 25 It is a hydrogen or nitrogen protecting group, wherein A is unsubstituted or substituted as defined in any of the foregoing examples, or a salt thereof.

[0208] Example 53. A method having formula (2c) ) compounds, (2c ). Among them, C and R A2 R B2 R B3 and R B4 R is as defined in any of the foregoing embodiments. 25 It is a hydrogen or nitrogen protecting group, wherein a is 0, 1, 2 or 3 (preferably a is 0, 1 or 2), or a pharmaceutically acceptable salt thereof.

[0209] Example 54. A method having formula (2d ) compounds, (2d ), Among them, C and R ae R B2 R N R B3 and R B4 R is as defined in any of the foregoing embodiments. 25 It is a hydrogen or nitrogen protecting group, where the ---- line indicates a single or double bond, or a salt thereof.

[0210] Example 55. Crystallization form of compound X, such as hydrate (variant HA) crystallization form of compound X, or isopropanol (IPA) solvate crystallization form, or ethanol (EtOH) solvate crystallization form, or propylene glycol solvate crystallization form.

[0211] Example 56. A crystalline form of compound X, having the same properties as... Figure 1 , Figure 2 , Figure 3 or Figure 4 The X-ray powder diffraction spectra shown are basically the same.

[0212] In an embodiment of the present invention, Het pyIt is a 4-, 5-, 6-, or 7-membered saturated heterocycle containing one or two heteroatoms independently selected from O, N (e.g., pyrrolidin-1-yl, cyclobutan-1-yl, morpholin-1-yl), and S, or containing an S-oxide (SO) or S-dioxide (SO2) group, and wherein said heterocycle is unsubstituted or optionally oxysubstituted on one carbon atom, and wherein said heterocycle is optionally further substituted on one or more carbon atoms by 1, 2, or 3 substituents independently selected from: C1-C4-alkoxy (preferably methoxy), halogen (preferably fluorine), C1-C4-alkyl, hydroxy-C1-C4-alkyl, and fluoro-C1-C4-alkyl, and wherein if a nitrogen atom is present in said heterocycle, said nitrogen atom is optionally further substituted with R 10 (Preferred option C) 1- C4-alkyl (e.g., methyl) substitution.

[0213] In an embodiment of the present invention, Het py It is a 5- or 6-membered heteroaryl ring (preferably 1,2,4-triazol-1-yl or pyrazol-1-yl) containing 1, 2, or 3 nitrogen atoms, and said heteroaryl ring is unsubstituted or substituted by one or more (e.g., 1, 2, or 3) independently selected from the following substituents: NR 9 R 10 -C(=O)-NR 9 R 10 Halogenated, C 1- C4-alkyl, hydroxy-C 1- C4-alkyl, fluorine-C 1- C4-alkyl, cyano, OH, and C 1- C4-alkoxy, or the heteroaryl ring therein is unsubstituted or substituted by one or more (e.g., 1, 2 or 3) substituents independently selected from the following: NR 9 R 10 Halogenated, C 1- C4-alkyl, cyano, OH, and C 1- In embodiments of the invention, the C4-alkoxy group is substituted with one or more amino groups.

[0214] In an embodiment of the present invention, A is C5-C. 7- Cycloalkylene groups, which are unsubstituted or substituted by one or more, preferably one, two or three, independently selected from fluorine and C1-C4-alkyl groups. For example, A is... Where W is O or C(R) w )2, where each R w Independently selected from H and fluorine, R cIt is hydrogen or C1-C4-alkyl, and A is optionally further substituted by 1, 2 or 3 substituents independently selected from fluorine and C1-C4-alkyl.

[0215] Exemplary instances of A include, but are not limited to:

[0216] In an embodiment of the present invention, A is C6-C. 10 Aryl groups, such as phenyl groups, can be unsubstituted or substituted with one or more R groups. A2 Substituents (e.g., replaced by 1, 2, or 3 substituents).

[0217] When A is phenyl, and when a substituent is present on A, the substituent is preferably at the para position of the phenyl group of the pyrazolyl moiety in compounds having formulas (I) and (Ia).

[0218] When A is R A2 When it is a fluorine-substituted phenyl group, R A2 The attachment site of the phenyl group of the pyrazolyl moiety in compounds having formulas (I) and (Ia) can be at the ortho, para, or meta position.

[0219] When A is a phenyl group, R A2 When present, preferably selected from the group consisting of: halogen, OH, hydroxy-C1-C4-alkyl, -(COOH), C1-C4-alkyl, fluoro-C1-C4-alkyl, C1-C4-alkoxy, fluoro-C1-C4-alkoxy, C1-C4-alkyl-carbonyl-oxy-C1-C4-alkyl-oxy, hydroxy-C1-C4-alkyl-oxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, -SO2-C1-C4-alkyl, -C(O)-NR 9 R 10 NR 9 R 10 NR 9a R 10a Het py -(CH2) p -Het py and -NR 9a R 10a and -(CH2) p NR 9a R 10a , in p is 1 or 2; Het pyIt is a 4-, 5-, or 6-membered heterocycle comprising one oxygen atom, or one sulfur atom, or one S(=O) or one S(=O)2 group, or one nitrogen atom and one oxygen atom, or one or two nitrogen atoms, wherein the heterocycle is unsubstituted or substituted on a carbon atom by one or two substituents independently selected from the following: C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy, halogenated, and fluoro-C1-C4-alkyl, and wherein the heterocycle is further optionally substituted on a carbon atom by an oxy-substituent and wherein when a nitrogen atom is present in the heterocycle, the nitrogen atom is optionally further substituted by a C1-C4-alkyl. R 9 Selected from hydrogen and C1-C4-alkyl; R 10 Selected from hydrogen, C1-C4-alkyl, hydroxy-C1-C4-alkyl, and C1-C4-alkoxy-C1-C4-alkyl; R 9a and R 10a Together with nitrogen, it forms a 4-, 5-, or 6-membered (saturated or unsaturated) heterocycle comprising one or two additional heteroatoms independently selected from O, N (preferably said heterocycle is pyrrolidin-1-yl, azirrobutane-1-yl, or morpholino-1-yl) and S, or their N-oxide, or their S-oxide (SO) or S-dioxide, and said heterocycle is optionally substituted with an oxygen atom on said heterocycle, and said heterocycle is optionally further substituted with one or two substituents independently selected from: C1-C4-alkoxy (methoxy), halo (fluorine), C1-C4-alkyl, hydroxy-C1-C4-alkyl, and fluoro-C1-C4-alkyl; Or R 9a and R 10a Together with nitrogen, it forms a 5- or 6-membered heteroaryl ring (preferably said heteroaryl ring is 1,2,4-triazol-1-yl and pyrazol-1-yl), which contains 1, 2 or 3 nitrogen atoms, and said heteroaryl ring is optionally substituted with one or two amino groups; When there are two R on the benzene ring A2 When substituents are used, the two Rs A2 The substituents are preferably located at (a) ortho and para positions, or (b) meta and para positions, or (c) ortho and meta positions, relative to the attachment site of the phenyl group of the pyrazolyl moiety of the compound having formula (I) and (Ia).

[0220] Representative R on the phenyl group A2Substituents include, but are not limited to: NH2, CN, F, OH, -CH2-OH, (COOH), -CH3, -O-CH2-CH2-OH, -O-CH2-CH3, -O-CH2-CH2-O-(CO)-CH3, -N(CH3)(CH2-CH2-OCH3) 、 -N(H)(CH2-CH2-OCH3) 、 -CH2-O-CH2-CH2-O-CH 3、 -SO2-CH 3、 -C(O)-NH-(CH2-CH2-OCH3) 、 -C(O)-N(CH3)-(CH2-CH2-OCH3) 、 -C(O)-NH-CH2-C(CH3)2OH 、 -C(O)-N(CH3)-CH2-C(CH3)2-OH 、 -C(O)-N(H)-C(CH3)2-CH2-OCH 3、 -C(O)-N(H)-CH2-CH2-N(CH3)2、-(CH2) p -Het py Het py It is a 4-, 5-, or 6-membered saturated heterocycle containing one or two heteroatoms independently selected from O, N (e.g., pyrrolidin-1-yl, azirrobutan-1-yl, morpholino-1-yl) S, or containing an S-oxide (SO) or S-dioxide (SO2) group or Het py It is a 5- or 6-membered heteroaryl ring containing 1, 2, or 3 nitrogen atoms; The 5- or 6-membered heterocycle may be further substituted with one or two substituents independently selected from the following: oxo, C1-C4-alkoxy (preferably methoxy), halo (preferably fluorine), C1-C4-alkyl, hydroxy-C1-C4-alkyl, and fluoro-C1-C4-alkyl; or the 5- or 6-membered heterocycle may be further substituted with one or two substituents independently selected from the following: C1-C4-alkoxy (preferably methoxy), halo (preferably fluorine), C1-C4-alkyl, hydroxy-C1-C4-alkyl, and fluoro-C1-C4-alkyl; The 5- or 6-membered heteroaryl ring containing 1, 2, or 3 nitrogen atoms may be further substituted with 1, 2, or 3 substituents independently selected from the following: amino, C1-C4-alkoxy (preferably methoxy), halogen (preferably fluorine), C1-C4-alkyl, hydroxy-C1-C4-alkyl, and fluoro-C1-C4-alkyl; or the 5- or 6-membered heteroaryl ring may be further substituted with 1, 2, or 3 substituents independently selected from the following: C1-C4-alkoxy (preferably methoxy), halogen (preferably fluorine), C1-C4-alkyl, hydroxy-C1-C4-alkyl, and fluoro-C1-C4-alkyl; and p is 0, 1, or 2 (preferably 0 or 1).

[0221] For example, R A2 Representative examples include:

[0222] Where R 20 It is hydrogen or C1-C4-alkyl (preferably methyl); Where p is 0, 1 or 2 (preferably 0 or 1); q is 1, 2 or 3 (preferably 1 or 2).

[0223] For example, R A2 Representative examples include

[0224] Where R 21 It is hydrogen or C1-C4-alkyl (preferably methyl), or amino. Where p is 0, 1 or 2, preferably p is 0 or 1.

[0225] In embodiments of the invention, A is a 5-6 membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S as ring members, wherein the heteroaryl ring is unsubstituted or has R on one or more (e.g., 1, 2, or 3) carbon atoms. A3 Substitution, wherein when the nitrogen atom is present in the heteroaryl ring, the nitrogen atom is unsubstituted or substituted by a substituent selected from the group consisting of: C1-C4-alkyl, -(CH2). 1-2 -C 3-4 -cycloalkyl, hydroxy-C 1- C4-alkyl, fluoro-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, N(R) 9 (R) 10 -C1-C4-alkyl, -SO2-C1-C4-alkyl, -SO2-C 3-4 -cycloalkyl, -(CH2) p -Hetpy and -(CH2) p -N(R 9 (R) 10 (Preferably, the substituents are selected from the group consisting of: fluoro-C1-C4-alkyl, N(R) 9 (R) 10 -C1-C4-alkyl, -SO2-C 3-4 -cycloalkyl, or -(CH2) 1-2 -C 3-4 -cycloalkyl).

[0226] For example, A can be a pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl group, which can be unsubstituted or substituted with one or more substituents R. A3 Substitution. A is preferably a pyridin-3-yl or pyridin-4-yl group.

[0227] When A is pyridin-3-yl, R on A A3 Substituents, such as C1-C4-alkyl groups, are preferably located at position 2- or 6- on the pyridyl ring of compounds having formulas (I) and (Ia).

[0228] When two substituents (e.g., fluorine and amino) are present on the pyridine-3-yl ring, the two substituents are preferably at positions 5- and 6- of the pyridine-3-yl ring of compounds having formulas (I) and (Ia).

[0229] When A is pyridin-4-yl, R on A A3 Substituents, such as C1-C4-alkyl groups, are preferably located at position 2- or 3- (preferably position 3-) on the pyridyl ring of compounds having formulas (I) and (Ia).

[0230] When A is pyridin-4-yl, the two R groups on A are preferably independently selected from C1-C4-alkyl, fluorine, and amino (more preferably C1-C4-alkyl). A3 When the substituents are present, they are preferably located at positions 2- and 6- of the pyridyl ring in compounds having formulas (I) and (Ia).

[0231] Representative substituents on the pyridyl group include, but are not limited to: NH 2、 F, CN, OH, -CH2-OH, -COOH, -CH3, -O-CH2-CH2-OH, -O-(CH2)3)-N(CH3)2, -O-CH2-CH3, -O-CH2-CH2-O-(CO)-CH3, -N(CH3)(CH2-CH2-OCH3) 、 -N(H)(CH2-CH2-OCH3) 、-CH2-O-CH2-CH2-O-CH 3、 -SO2-CH 3、 -C(O)-NH-(CH2-CH2-OCH3) 、 -C(O)-N(CH3)-(CH2-CH2-OCH3) 、 -C(O)-NH-CH2-C(CH3)2OH 、 -C(O)-N(CH3)-CH2-C(CH3)2-OH 、 -C(O)-N(H)-C(CH3)2-CH2-OCH 3、 -C(O)-N(H)-CH2-CH2-N(CH3)2、-(CH2) p -Het py Het py It is a 4-, 5-, or 6-membered saturated heterocycle containing one or two heteroatoms independently selected from O, N (e.g., pyrrolidin-1-yl, azirrobutan-1-yl, morpholino-1-yl) and S, or containing an S-oxide (SO) or S-dioxide (SO2) group, wherein the heterocycle may be further substituted by one, two, or three substituents independently selected from: C1-C4-alkoxy (preferably methoxy), halogen (preferably fluorine), C1-C4-alkyl, hydroxy-C1-C4-alkyl, fluoro-C1-C4-alkyl, and -C(O)-N(CH3)-(CH2-CH2-OCH3). ，

[0232] Or Het py It is a 5- or 6-membered heteroaryl ring containing 1, 2 or 3 nitrogen atoms, wherein the heteroaryl ring is further substituted by 1, 2 or 3 substituents independently selected from the following: C1-C4-alkoxy (methoxy), halogen (fluorine), C1-C4-alkyl, hydroxy-C1-C4-alkyl, and fluoro-C1-C4-alkyl.

[0233] For example, when A is pyridyl, R A3 Representative examples can be selected from

[0234] Where R 20 It is hydrogen or C1-C4-alkyl (preferably methyl). Where p is 0, 1 or 2, preferably p is 0 or 1.

[0235] For example, when A is a pyridinyl group, such as pyridin-3-yl, R A3 Representative examples can be selected from

[0236] Where R 21 It is hydrogen or C1-C4-alkyl (preferably methyl), or amino. Where p is 0, 1, or 2. Preferably, p is 0 or 1.

[0237] In examples of compounds having formulas (I) and (Ia), when A is a pyridyl ring, the representative substituent R A3 It is NH 2、 F, -CH3, -CF3, -CH2OH 、 CN, -C(O)-N(H)-C(CH3)2-CH2-O-CH 3、 -C(O)-N(CH3)-(CH2-CH2-OCH3) 、 -O-(CH2)3)-N(CH3) 2，

[0238] Where p is 0, 1 or 2, preferably p is 1 or 2; R 21 It is hydrogen or C1-C4-alkyl (preferably methyl). R 22 It is hydrogen or C1-C4-alkyl (preferably methyl), or amino. Preferably, p is 0, and R 22 It is an amino group.

[0239] In embodiments of the present invention, A is a pyrimidin-3-yl group or a pyrimidin-5-yl group, which may be unsubstituted or substituted with one or more substituents R. A3 Substitution. Representative substituents on the pyrimidinyl group include -O-CH. 3。

[0240] In an embodiment of the present invention, A is selected from the group consisting of the following.

[0241] Where R 24 It is hydrogen, C 1- C4-alkyl, hydroxy-C 1- C4-alkyl, C 1- C4-alkoxy-C 1- C4-alkyl, -NR 9 R 10 C 1- C4-alkyl, -SO2-C 1- C4-alkyl, -SO2-C 3-4 -cycloalkyl or -(CH2) 1-2 -C 3-4 -cycloalkyl; or wherein R24 It is hydrogen, C 1- C4-alkyl, hydroxy-C 1- C4-alkyl, C 1- C4-alkoxy-C 1- C4-alkyl, amino-C 1- C4-alkyl, C 1- C4-alkylamino-C 1- C4-alkyl, di-C 1- C4-alkylamino-C 1- C4-alkyl, -SO2-C 1- C4-alkyl, -SO2-C 3-4 -cycloalkyl or -(CH2) 1-2 -C 3-4 -cycloalkyl; R 4a R 4b R 4c and R 4d Each is independently selected from hydrogen and C. 1- C4-alkyl (preferably methyl).

[0242] R 24 Preferably, it is di-C 1- C4-alkylamino-C 1- C4-alkyl (e.g., -CH2-CH2-N(CH3)2) or -SO2-C 3-4 -Cycloalkyl (e.g., -SO2-cyclopropyl).

[0243] R 4c Preferably, it is C 1- C4-alkyl (e.g., methyl) and R 4a R 4b and R 4d Preferably, it is hydrogen.

[0244] When R 24 It is 2-C 1- C4-alkylamino-C 1- In C4-alkyl form, R 4c Preferably, it is C 1- C4-alkyl (e.g., methyl) and R 4a and R 4d Each is hydrogen.

[0245] In embodiments of the present invention, A is (i) an 8-10 membered heteroaryl ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., 1 to 3 heteroatoms independently selected from 0-3 nitrogen atoms, 0-1 oxygen atoms, and 0-1 sulfur atoms), or

[0246] (ii) An 8-10 quintile partially saturated heterobicycle, wherein the heterobicycle contains 1 to 3 heteroatoms or heterogroups independently selected from 0-3 nitrogen atoms, 0-2 oxygen atoms, 0-1 sulfur atoms, and 0-1 S(=O)2 groups, wherein the heteroaryl ring or heterobicycle is unsubstituted or has 1, 2, 3, 4, or 5 R atoms on the carbon atom. A4 Substitution, wherein the heterobicycle is further optionally oxidized at a carbon atom and wherein, when a nitrogen atom is present, the nitrogen atom is unsubstituted or substituted with a substituent -(CO)-C1-C4-alkyl or C1-C4-alkyl, and wherein the C1-C4-alkyl is optionally substituted with one or two independently selected from cyano, hydroxy, oxo, fluorine, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 Substituents are substituted.

[0247] In embodiments of the invention, A is an 8-10 membered heteroaryl ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. For example, A is an 8-10 membered heteroaryl ring containing 1 to 3 heteroatoms independently selected from 0 to 3 nitrogen atoms, 0 to 1 oxygen atom, and 0 to 1 sulfur atom. The heteroaryl ring is unsubstituted or has 1, 2, 3, 4, or 5 R atoms on the carbon atom. A4 The nitrogen atom, when present, is either unsubstituted or substituted with a substituent -(CO)-C1-C4-alkyl or C1-C4-alkyl, and said C1-C4-alkyl is optionally replaced by one or two independently selected from cyano, hydroxy, oxo, fluorine, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 Substituents are substituted.

[0248] Therefore, representative examples of A also include: , Among the curves This represents the attachment point between A and the rest of the molecule.

[0249] In embodiments of the present invention, A is an 8-10 membered heteroaryl ring containing 1, 2, or 3 nitrogen atoms, or an 8-10 membered partially saturated heterobicycle containing 1 to 3 heteroatoms or heterogroups independently selected from 0-3 nitrogen atoms, 0-2 oxygen atoms, 0-1 sulfur atoms, and 0-1 S(=O)2 groups, wherein the heteroaryl ring or heterobicycle is unsubstituted or has 1, 2, 3, 4, or 5 R atoms on the carbon atom. A4Substitution, wherein the heterobicycle is further optionally oxidized at a carbon atom and wherein, when a nitrogen atom is present, the nitrogen atom is unsubstituted or substituted with a substituent -(CO)-C1-C4-alkyl or C1-C4-alkyl, and wherein the C1-C4-alkyl is optionally substituted with one or two independently selected from cyano, hydroxy, oxo, fluorine, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 Substituents are substituted.

[0250] In embodiments of the present invention, A is an 8-10 membered heteroaryl ring containing 1, 2, or 3 nitrogen atoms; or an 8-10 membered partially saturated heterobicycle (containing 1-3 nitrogen atoms, or 1-2 oxygen atoms, or 1 sulfur atom, or 1 S(=O)2 group in the heterobicycle, wherein the heteroaryl ring or heterobicycle is unsubstituted or has 1, 2, 3, 4, or 5 R atoms on the carbon atom). A4 Substitution, wherein the heterobicycle is further optionally oxidized at a carbon atom and wherein, when a nitrogen atom is present, the nitrogen atom is unsubstituted or substituted with a substituent -(CO)-C1-C4-alkyl or C1-C4-alkyl, and wherein the C1-C4-alkyl is optionally substituted with one or two independently selected from cyano, hydroxy, oxo, fluorine, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 Substituents are substituted.

[0251] In embodiments of the present invention, when a nitrogen atom is present on the aforementioned 8-10 member heteroaryl ring or the aforementioned 8-10 member partially saturated hetero-bicycle, the nitrogen atom is unsubstituted or substituted with a C1-C4-alkyl group, wherein the C1-C4-alkyl group is optionally substituted by one or two substituents independently selected from the following: cyano, hydroxyl, oxo, fluorine, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 .

[0252] In an embodiment of the present invention, Het b It is a 4-, 5-, or 6-membered heterocyclic or heteroaryl ring, comprising one or two heteroatoms or groups independently selected from N, O, S, SO, and SO2 (preferably comprising one oxygen atom, or one sulfur atom, or one S(=O) or one S(=O)2 group, or one nitrogen atom and one oxygen atom, or one to two nitrogen atoms; more preferably comprising one nitrogen atom and one oxygen atom, or one to two nitrogen atoms), wherein the heterocyclic Hetb It is either unsubstituted or has one or two independent substituents selected from the following: C1-C4-alkyl, hydroxy, cyano, fluorine, C1-C4-alkoxy-hydroxy-C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy, fluoro-C1-C4-alkoxy, and fluoro-C1-C4-alkyl (preferably selected from C1-C4-alkyl, hydroxy, cyano, fluorine, C1-C4-alkoxy-hydroxy-C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy, and fluoro-C1-C4-alkyl), and wherein the heterocyclic Het b The carbon atom is optionally further substituted with oxygen, and wherein the nitrogen atom is present in Het b In this case, the nitrogen atom is optionally further substituted with a C1-C4-alkyl group, wherein the C1-C4-alkyl group is optionally substituted with one to three substituents independently selected from the group consisting of fluorine, hydroxyl, and C. 1- C4-alkoxy group.

[0253] In an embodiment of the present invention, Het b It is aza-butane-1-yl, pyrrolidine-1-yl, pyrrolidine-3-yl, or morpholino-1-yl, and optionally dilated by fluorine, hydroxyl, and C. 1- C4-alkoxy groups (e.g., substituted with methyl, hydroxy-methyl, methoxy, and fluorine).

[0254] In embodiments of the invention, A is an 8-10 membered heteroaryl ring containing 1, 2, or 3 nitrogen atoms; or an 8-10 membered partially saturated heterobicycle containing 1 to 3 heteroatoms or heterogroups independently selected from 0-3 nitrogen atoms, 0-2 oxygen atoms, 0-1 sulfur atoms, and 0-1 S(=O)2 groups, wherein when A contains nitrogen atoms, that nitrogen atom is R ae Or R Ae replace.

[0255] In embodiments of the present invention, A is an 8-10 membered heteroaryl ring containing 1, 2, or 3 nitrogen atoms; or an 8-10 membered partially saturated heterobicycle containing 1-3 nitrogen atoms, or 1-2 oxygen atoms, or 1 sulfur atom, or 0-1 S(=O)2 group, wherein when A contains nitrogen, that nitrogen is converted by R. ae Or R Ae replace.

[0256] In embodiments of the present invention, A is an 8-10 membered heteroaryl ring containing 1, 2, or 3 nitrogen atoms, wherein at least one of the nitrogen atoms is R ae Or R Ae replace.

[0257] In embodiments of the present invention, A is an 8-10 membered heteroaryl ring containing 1, 2, or 3 nitrogen atoms, wherein one of the nitrogen atoms is R ae Or R Ae replace.

[0258] In an embodiment of the present invention, R Ae The group selected is from the group consisting of: hydrogen, -(CO)-C1-C4-alkyl, and C1-C4-alkyl, wherein the C1-C4 alkyl group is optionally substituted by one or two substituents selected from: cyano, hydroxyl, fluorine, C 1- C4-alkoxy group, C 1- C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 .

[0259] In an embodiment of the present invention, R Ae Choose from the group consisting of: hydrogen, fluorine-C1-C4-alkyl, and C1-C4-alkyl (e.g., methyl).

[0260] In an embodiment of the present invention, R ae The group consisting of hydrogen and C1-C4-alkyl groups, wherein the alkyl group is optionally substituted by one or two substituents independently selected from the group consisting of cyano, hydroxyl, fluorine, C4, and C6. 1- C4-alkoxy group, C 1- C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 .

[0261] In an embodiment of the present invention, R ae Choose from the following groups: hydrogen, C1-C4-alkyl, -(CH2)2-Het b -CH2-CN, -(CH2) 2- OH, -(CH2) 2- O-C1-C4-alkyl, hydroxy-C1-C4-alkyl, -(CH2)2-O-(CH2)2-O-C1-C4-alkyl and -(CH2)2-diC1-C4-alkylamino, (e.g., when Het b When selected from the group consisting of: azirmonobutan-1-yl, pyrrolidine-1-yl, pyrrolidine-3-yl, and morpholino-1-yl, R is preferred. ae The group consisting of hydrogen, C1-C4-alkyl, and -CH2-CN is preferred. ae Choose from the group consisting of hydrogen and C1-C4-alkyl.

[0262] In embodiments of the present invention, y is 0, 1, or 2 (preferably 0 or 1).

[0263] In embodiments of the present invention, x is 0, 1, or 2 (preferably 0 or 1).

[0264] In embodiments of the present invention, z is 0, 1, or 2 (preferably 0 or 1).

[0265] In an embodiment of the present invention, R q Choose from the group consisting of: C1-C4-alkyl, hydroxy, C1-C4-alkoxy, and NR. 9 R 10 And y is 0 or 1.

[0266] Preferably R q Choose from the following groups: C1-C4-alkyl and hydroxyl.

[0267] Typical examples of A as an 8-10 member heteroaryl ring or heterodicyclic ring include

[0268] Among the curves This represents the attachment point between A and the rest of the molecule. Where A is unsubstituted or is replaced by 1, 2, 3, 4 or 5 Rs. A4 (Preferably by 1 or 2 R) A4 ) can be replaced, wherein the nitrogen atom in the NH moiety in the above structure can also be replaced by NR. ae Replacement, where R ae It is a C1-C4-alkyl group, wherein the C1-C4-alkyl group is optionally substituted by one or two substituents independently selected from the following: cyano, hydroxy, oxo, fluorine, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 Preferably, R ae It is hydrogen or C1-C4-alkyl, such as methyl.

[0269] For example, typical instances of A include

[0270] The curves represent the attachment points of A to the rest of the molecule, where A is unsubstituted or modified by 1, 2, 3, 4, or 5 R's. A4 (Preferably by 1 or 2 R) A4 ) replace, where R aeIt is hydrogen or C1-C4-alkyl, optionally substituted by one or two independent substituents selected from: cyano, hydroxy, oxo, fluorine, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 Preferably, R ae It is hydrogen or C1-C4-alkyl, such as methyl.

[0271] Representative examples of A also include:

[0272] The curves represent the attachment points of A to the rest of the molecule. Where A is unsubstituted or is replaced by 1, 2, 3, 4, or 5 Rs. A4 (Preferably by 1 or 2 R) A4 ) can be replaced, wherein the nitrogen atom in the NH moiety in the above structure can also be replaced by NR. Ae or NR ae Replacement, where R Ae The group consisting of hydrogen, -(CO)-C1-C4-alkyl, and C1-C4-alkyl, wherein in each case the C1-C4 alkyl group is optionally substituted by one or two independent substituents selected from: cyano, hydroxyl, fluorine, C 1- C4-alkoxy group, C 1- C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 And R ae It is a C1-C4-alkyl group optionally substituted with one or two independent substituents selected from the following: cyano, hydroxy, oxo, fluorine, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 Preferably, preferably, R Ae It is hydrogen or a C1-C4-alkyl group, such as methyl. Preferably, R ae It is hydrogen or C1-C4-alkyl, such as methyl.

[0273] Therefore, typical examples of A include:

[0274] The curves represent the attachment points of A to the rest of the molecule. Where A is unsubstituted or is replaced by 1, 2, 3, 4, or 5 Rs. A4 (Preferably by 1 or 2 R) A4 ) replace, where RAe The group consisting of hydrogen, -(CO)-C1-C4-alkyl, and C1-C4-alkyl, wherein in each case the C1-C4 alkyl group is optionally substituted by one or two independent substituents selected from: cyano, hydroxyl, fluorine, C 1- C4-alkoxy group, C 1- C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 And R ae It is a C1-C4-alkyl group optionally substituted with one or two independent substituents selected from the following: cyano, hydroxy, oxo, fluorine, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 Preferably, R Ae It is hydrogen or a C1-C4-alkyl group, such as methyl. Preferably, R ae It is hydrogen or C1-C4-alkyl, such as methyl.

[0275] Other representative examples of A include,

[0276] Among the curves The attachment point of A to the rest of the molecule, where A is unsubstituted or bound by 1, 2, 3, 4, or 5 R groups. A4 (Preferably by 1 or 2 R) A4 ) can be replaced, wherein the nitrogen atom in the NH moiety in the above structure can also be replaced by NR. ae or NR Ae Replacement, where R Ae The group consisting of hydrogen, -(CO)-C1-C4-alkyl, and C1-C4-alkyl, wherein in each case the C1-C4 alkyl group is optionally substituted by one or two independent substituents selected from: cyano, hydroxyl, fluorine, C 1- C4-alkoxy group, C 1- C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 And R ae It is a C1-C4-alkyl group optionally substituted with one or two independent substituents selected from the following: cyano, hydroxy, oxo, fluorine, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 Preferably, preferably, R AeIt is hydrogen or a C1-C4-alkyl group, such as methyl. Preferably, R ae It is hydrogen or a C1-C4 alkyl group, such as methyl. The term "C" is used to indicate hydrogen or C1-C4 alkyl groups. 6-10 "Aryl", as used herein and also referred to by substituent B, means a phenyl or naphthyl group, wherein the phenyl or naphthyl group is unsubstituted or has 1, 2, 3, or 4 (preferably 1 or 2) R groups. Ba replace.

[0277] In an embodiment of the present invention, R Ba It is independently selected from the group consisting of hydroxyl, NH2, C1-C4-alkyl and halogen, or preferably selected from the group consisting of hydroxyl, C1-C4-alkyl and halogen.

[0278] In embodiments of the invention, B is 3-hydroxy-phenyl or 3-hydroxy-naphthyl, wherein B is unsubstituted or substituted with 1, 2, or 3 halogenated (preferably chlorine) atoms. In further embodiments of the invention, B is

[0279] Hal represents a halogen atom.

[0280] In an embodiment of the present invention, B is

[0281] Where X is N or CR B5 ; R B1 Independently selected from hydrogen and C1-C4-alkyl (preferably methyl); R B2 Independently selected from hydrogen, halogen (preferably chlorine), C1-C4-alkyl (preferably methyl), cyclopropyl and NH2; R B3 Independently selected from hydrogen, halogen (preferably chlorine), cyclopropyl and C1-C4-alkyl (preferably methyl); R B4 Independently selected from hydrogen, halogenated (preferably chlorine or fluorine), and C1-C4-alkyl (preferably methyl), or R B3 and R B4 Together with the atoms to which they are attached, they form 4-6 membered rings (preferably 5-6 membered saturated or partially unsaturated carbon rings) that are fused with an aromatic ring containing X. R B5 It is independently selected from hydrogen, halogen (preferably chlorine) and C1-C4-alkyl (preferably methyl).

[0282] In embodiments of the present invention, X is N or CR. B5 , R B1Independently selected from hydrogen and C1-C4-alkyl groups, R B2 Independently selected from hydrogen and NH2, R B3 and R B4 Each is independently selected from hydrogen, halogenated (preferably chlorinated), and C1-C4-alkyl (preferably methyl), or R B3 and R B4 Together with the atoms to which they are attached, they form 4-6 membered rings (preferably 5-6 membered saturated or partially unsaturated carbon rings) that are fused with an aromatic ring containing X.

[0283] R B5 It is independently selected from hydrogen, halogen (preferably chlorine) and C1-C4-alkyl (preferably methyl).

[0284] In an embodiment of the present invention, B is

[0285] Where R B1 Independently selected from hydrogen and C1-C4-alkyl groups, R B2 Independently selected from hydrogen, C1-C4-alkyl groups, and NH2. R B3 and R B4 Each is independently selected from hydrogen, halogenated (preferably fluorine or chlorine, more preferably chlorine) and C1-C4-alkyl (preferably methyl). R B5 It is independently selected from hydrogen, halogen (preferably chlorine) and C1-C4-alkyl (preferably methyl).

[0286] In embodiments of the present invention, X is N or CR. B5 , Where R B1 Independently selected from hydrogen and C1-C4-alkyl groups, R B2 Independently selected from hydrogen and NH2, R B3 and R B4 Each is independently selected from hydrogen, halogen (preferably chlorine), and C1-C4-alkyl (preferably methyl).

[0287] R B5 It is independently selected from hydrogen, halogen (preferably chlorine) and C1-C4-alkyl (preferably methyl).

[0288] In embodiments of the present invention, X is N or CH, preferably X is CH.

[0289] In an embodiment of the present invention, X is CH and R B1It is hydrogen or C1-C4-alkyl (e.g., methyl).

[0290] In an embodiment of the present invention, R B1 It is hydrogen or C1-C4-alkyl (e.g., methyl), preferably R B1 It is hydrogen.

[0291] In an embodiment of the present invention, R B2 It is hydrogen or amino, preferably R B2 It is hydrogen.

[0292] In an embodiment of the present invention, R B3 and R B4 Each is independently selected from halogenated (preferably chlorinated) and C1-C4-alkyl (preferably methyl).

[0293] This invention provides compounds having formulas (I) and (Ia), wherein R B1 Independently selected from hydrogen and C1-C4-alkyl groups, R B2 It is an amino group, R B3 It is halogenated (preferably chlorinated) and R B4 It is a methyl group, and X is CH, or R B2 It is an amino group, R B3 It is halogenated (preferably chlorinated) or methyl, R B4 It is hydrogen, X is CH, or R B2 It is hydrogen, R B3 It is halogenated (preferably chlorinated) or methyl, and R B4 It is hydrogen, X is CH. In an embodiment of the present invention, R B2 It is an amino group, R B3 and R B4 All are halogenated (preferably chlorinated), and X is CH.

[0294] In an embodiment of the present invention, R B1 It is a C1-C4-alkyl (preferably methyl), R B2 R B3 R B4 and R B5 Both are hydrogen.

[0295] In embodiments of the present invention, X is N, R B1 and R B2 It is hydrogen, R B3 Independently selected from halogenated (preferably chlorinated) and C1-C4-alkyl (preferably methyl), R B4 It is halogenated (preferably chlorinated).

[0296] In a further aspect of the invention, compounds selected from any of the examples described are provided, or pharmaceutically acceptable salts thereof.

[0297] In a further aspect of the invention, compounds selected from the group consisting of: , , , , , , , and , Or its pharmaceutically acceptable salt.

[0298] In a further aspect of the invention, compounds selected from the group consisting of: a( R )-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]hept-2-yl)prop-2-en-1-one (Example 1a). ; a( R ()( S )-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(1-(2-(3-fluoropyrrolidine-1-yl)ethyl)-1H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepten-2-yl)prop-2-en-1-one (Example 18a). ; a( R )1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-phenyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hept-2-yl)prop-2-en-1-one (Example 26a). ; a( R )1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-methoxyethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta-2-yl)prop-2-en-1-one (Example 41a). ; a( R )1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-hydroxy-2-methylpropyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta-2-yl)prop-2-en-1-one (Example 42a). ; a( R )1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-(2-(2-methoxyethoxy)ethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta-2-yl)prop-2-en-1-one (Example 43a). ; a( R )1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(4-(hydroxymethyl)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hept-2-yl)prop-2-en-1-one (Example 47a). ; a( R )1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-fluoro-4-(2-methoxyethoxy)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepten-2-yl)prop-2-en-1-one (Example 60a). ; a( R )1-(6-(4-(3-amino-5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-methoxyethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta-2-yl)prop-2-en-1-one (Example 69a). ;as well as a( R )1-(6-(4-(3-amino-5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-phenyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hept-2-yl)prop-2-en-1-one (Example 70a). , Or its pharmaceutically acceptable salt.

[0299] This invention provides compounds selected from the group consisting of:

[0300] Or its pharmaceutically acceptable salt.

[0301] Depending on the choice of starting materials and procedures, the compound may exist in possible isomeric forms or as mixtures thereof (e.g., as pure optical isomers or as mixtures of isomers, such as racemic and diastereomeric mixtures), depending on the number of asymmetric centers. This invention aims to include all such possible isomers, including racemic mixtures, enantiomer-enriched mixtures, diastereomeric mixtures, and optically pure forms. Optically active (R)- and (S)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a disubstituted or trisubstituted cycloalkyl group, one or more cycloalkyl substituents may have cis or trans configurations. This invention includes cis and trans configurations of substituted cycloalkyl groups and mixtures thereof. All tautomeric forms are also included. In particular, when the heteroaryl ring containing N as a ring atom is a 2-pyridinone, for example, tautomers in which the carbonyl group is depicted as a hydroxyl group are included (e.g., 2-hydroxypyridine).

[0302] As used herein, the term "salt" (or salts) refers to an acid addition salt or a base addition salt of the compounds of the present invention. "Salt" specifically includes "pharmaceutically acceptable salts." The term "pharmaceutically acceptable salt" means that the compounds of the present invention retain their biological efficacy and properties and are typically not biologically or otherwise undesirable. In many cases, the compounds of the present invention are capable of forming acid salts and / or base salts due to the presence of amino and / or carboxyl groups or similar groups.

[0303] Pharmaceutically acceptable acid addition salts can be formed from inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and trifluoroacetic acid.

[0304] Pharmaceutically acceptable base addition salts can be formed using inorganic and organic bases.

[0305] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I through XII of the periodic table. In some embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

[0306] Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines; substituted amines (including naturally occurring substituted amines); cyclic amines; and basic ion exchange resins. Some organic amines include isopropylamine, benzylamine, choline salts, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0307] In another aspect, the present invention provides compounds in the form of: acetates, ascorbic acid salts, adipates, aspartates, benzoates, benzenesulfonates, bromides / hydrobromates, bicarbonates / carbonates, bisulfates / sulfates, camphorsulfonates, decanoates, chlorides / hydrochlorides, chlortheophyllonates, citrates, ethanedisulfonates, fumarates, glucoheponicates, glucuronates, glucuronates, glutamates, glutamates, glycolic acid, hippurate, hydroiodates / iodides. Hydroxyethyl sulfonate, lactate, lacturonate, dodecyl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methyl sulfate, mucilage, naphthate, naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, dihydroxynaphthalate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, sebate, stearate, succinate, sulfosalicylate, sulfate, tartrate, toluenesulfonate, trifluoromethanesulfonate, trifluoroacetate, or sine in the form of naphthate.

[0308] Pharmaceutically acceptable salts are preferred.

[0309] Any formulas given herein are intended to represent both the unlabeled and isotopically labeled forms of the compounds. Isotopically labeled compounds have the structures described by the formulas given herein, except that one or more atoms are replaced by atoms having a chosen atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, respectively. 2 H, 3 H, 11 C 13 C 14 C 15 N、 17 O、 18 O、 18 F, 35 S, 36 Cl. This invention includes various isotope-labeled compounds as defined herein, such as those containing radioactive isotopes (e.g., 3 H and 14 Those compounds in (C), or those containing non-radioactive isotopes (such as...) 3 H and 14 C). Compounds labeled with this type of isotope can be used for metabolic studies (using...)14 C) Reaction kinetic studies (e.g., using...) 2 H and 13 C) Detection or imaging techniques (e.g., positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays), or for use in the patient's radiation therapy. Specifically, 18 Compound F may be particularly ideal for PET or SPECT studies. Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by methods similar to those described in the appended examples, using an appropriate isotopically labeled reagent instead of an unlabeled previously used reagent.

[0310] In addition, heavier isotopes, especially deuterium (i.e., 2 Substitution with H or D can provide certain therapeutic advantages arising from greater metabolic stability, such as prolonged in vivo half-life, reduced dose requirement, or improved therapeutic index. It should be understood that, in this context, deuterium is considered a substituent in compounds having formula (I). The concentration of such heavier isotopes (particularly deuterium) can be defined by an isotope enrichment factor. As used herein, the term "isotope enrichment factor" refers to the ratio between the isotope abundance and the natural abundance of a given isotope. If the substituent in the compound of the present invention specifies deuterium, such a compound has an isotopic enrichment factor for each specified deuterium atom of at least 3500 (52.5% deuterium doping on each specified deuterium atom), at least 4000 (60% deuterium doping), at least 4500 (67.5% deuterium doping), at least 5000 (75% deuterium doping), at least 5500 (82.5% deuterium doping), at least 6000 (90% deuterium doping), at least 6333.3 (95% deuterium doping), at least 6466.7 (97% deuterium doping), at least 6600 (99% deuterium doping), or at least 6633.3 (99.5% deuterium doping).

[0311] The present invention also relates to any of the compounds described in the above embodiments, wherein one or more hydrogen atoms in one or more substituents are replaced by deuterium, for example, all hydrogen atoms in one or more alkyl substituents are replaced by deuterium (and then the corresponding one or more portions are fully deuterated).

[0312] In embodiments of the present invention, C1-C3-alkyl (or methyl) may be deuterated or fully deuterated, particularly when C1-C3-alkyl (or methyl) is present as a substituent C in the compounds of the present invention and / or when C1-C3-alkyl (or methyl) is present as a substituent on A and / or B, when A or B is an indazole ring.

[0313] The present invention also relates to the crystalline form of a compound having formula (I).

[0314] The hydrate (variant HA) crystalline form of compound X can be obtained from its isopropyl (IPA) solvate, ethanol (EtOH) solvate, methanol solvate, and propylene glycol ester solvate. The hydrate (variant HA) crystalline form of compound X can be characterized by X-ray powder diffraction (XRPD) patterns containing at least one, two, three, or four peaks with refractive 2θ values ​​(CuKα λ = 1.5418 Å) selected from the group consisting of 8.2°, 11.6°, 12.9°, and 18.8° (measured at a temperature of approximately 25°C and an X-ray wavelength λ of 1.5418 Å). The hydrate (variant HA) crystal form can be characterized by X-ray powder diffraction (XRPD) patterns containing at least one, two, three, four, or all of the following peaks with refractive 2θ values ​​(CuKα λ = 1.5418 Å): 8.2°, 11.6°, 12.1°, 12.9°, 14.6°, 16.2°, 18.8°, 20.4°, and 24.1° (measured at a temperature of about 25°C and an X-ray wavelength λ of 1.5418 Å).

[0315] The isopropanol (IPA) solvate of compound X can be characterized by X-ray powder diffraction (XRPD) patterns containing at least one, two, or three peaks with refractive 2θ values ​​(CuKα λ = 1.5418 Å) selected from the group consisting of 7.5°, 12.5°, and 17.6° (measured at a temperature of about 25°C and an X-ray wavelength λ of 1.5418 Å). The isopropanol solvate of compound X can be characterized by X-ray powder diffraction (XRPD) patterns containing at least one, two, three, four or more, or all of the following peaks with refractive 2θ values ​​(CuKα λ = 1.5418 Å): 7.5°, 12.5°, 15.5°, 16.4°, 17.6°, 21.4°, and 24.4° (measured at a temperature of about 25°C and an X-ray wavelength λ of 1.5418 Å).

[0316] The ethanol (EtOH) solvate of compound X can be characterized by X-ray powder diffraction (XRPD) patterns containing at least one, two, three, or four peaks with refractive 2θ values ​​(CuKα λ = 1.5418 Å) selected from the group consisting of 7.9°, 12.7°, 18.2°, and 23.1° (measured at a temperature of about 25°C and an X-ray wavelength λ of 1.5418 Å). The ethanol solvate of compound X can be characterized by X-ray powder diffraction (XRPD) containing at least one, two, three, four or more, or all of the following peaks with refractive 2θ values ​​(CuKα λ = 1.5418 Å): 7.9°, 12.7°, 13.1°, 15.5°, 15.9°, 16.9°, 18.2°, 18.6°, and 23.1° (measured at a temperature of about 25°C and an X-ray wavelength λ of 1.5418 Å).

[0317] The propylene glycol solvate of compound X can be characterized by X-ray powder diffraction (XRPD) patterns containing at least one, two, three, or four peaks with refractive 2θ values ​​(CuKα λ = 1.5418 Å) selected from the group consisting of 7.3°, 13.2°, 18.0°, and 22.5° (measured at a temperature of about 25°C and an X-ray wavelength λ of 1.5418 Å). The propylene glycol solvate of compound X can be characterized by X-ray powder diffraction (XRPD) patterns containing at least one, two, three, four or more, or all of the following peaks with refractive 2θ values ​​(CuKα λ = 1.5418 Å): 7.3°, 13.2°, 15.6°, 16.2°, 18.0°, 22.5°, 22.8°, 23.2°, and 25.1° (measured at a temperature of about 25°C and an X-ray wavelength λ of 1.5418 Å).

[0318] As used herein, the term "pharmaceutically acceptable carrier" includes any one or more of the following: all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antimicrobial agents, antifungal agents), isotonic agents, absorption delay agents, salts, preservatives, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavorings, dyes, and combinations thereof, as known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Printing Company, 1990, pp. 1289-1329). Except where any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions should be considered.

[0319] The term "therapeuticly effective amount" for compounds of the present invention refers to an amount of the compound of the present invention that will elicit a biological or medical response in a subject (e.g., a reduction or inhibition of enzyme or protein activity) or improve symptoms, alleviate symptoms, slow or delay disease progression, or prevent disease, etc. In one non-limiting embodiment, the term "therapeuticly effective amount" refers to an amount of the compound of the present invention that, when administered to a subject, is effective (1) in at least partially alleviating, inhibiting, preventing, and / or improving symptoms, or disorders or diseases, such as cancers driven by KRAS, HRAS, or NRAS G12C mutations.

[0320] In another non-limiting embodiment, the term "therapeuticly effective amount" refers to an amount of the compound of the present invention that, when applied to cells, tissues, noncellular biological materials, or media, effectively at least partially reduces or inhibits the activity of KRAS, HRAS, or NRAS G12C mutant proteins.

[0321] As used herein, the term "subject" refers to an animal. Typically, the animal is a mammal. "Subject" also refers to, for example, primates (e.g., humans, males or females), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In some embodiments, the subject is a primate. In still other embodiments, the subject is a human.

[0322] As used herein, the term “inhibit (inhibition or inhibiting)” means the reduction or suppression of a given condition, symptom or disorder, or disease, or a significant reduction in baseline activity of a biological activity or process.

[0323] As used herein, the term "treat, treating, or treatment" for any disease or disorder, in one embodiment, means improving the disease or disorder (i.e., slowing down or stopping or reducing the development of the disease or at least one of its clinical symptoms). In another embodiment, "treat, treating, or treatment" means reducing or improving at least one bodily parameter, including those that cannot be identified by the patient. In yet another embodiment, "treat, treating, or treatment" means regulating the disease or disorder physically (e.g., stabilization of identifiable symptoms), physiologically (e.g., stabilization of bodily parameters), or both. In yet another embodiment, "treat, treating, or treatment" means preventing or delaying the onset, development, or progression of the disease or disorder.

[0324] As used in this article, a subject is considered "needing" the treatment if the subject will benefit from it biologically, medically, or in terms of quality of life.

[0325] As used herein, the terms “a”, “the”, and similar terms used in the context of this invention (particularly in the context of the claims) should be interpreted to cover both the singular and the plural, unless otherwise stated or explicitly contradicted by the context.

[0326] All methods described herein can be performed in any suitable order unless otherwise stated herein or otherwise obviously contradicted by the context. The use of any and all instances or exemplary language (e.g., "as") provided herein is intended only to better illustrate the invention and not to limit the scope of the invention as otherwise claimed.

[0327] Any asymmetric center in the compounds of the present invention may exist in the form of a racemic mixture or a mixture of enantiomers or an enantiomer enrichment. In some embodiments, for example, as a mixture of enantiomers, each asymmetric center exists in an enantiomer excess of at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99%. In some embodiments, for example, in the form of enantiomer enrichment, each asymmetric center is present with an enantiomer excess of at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99%.

[0328] Therefore, as used herein, the compounds of the present invention may be in the form of one of the possible isomers, enantiomers, transisomers, diastereomers, tautomers or mixtures thereof, for example as substantially pure diastereomers, optical isomers (enantiomers), racemates or mixtures thereof.

[0329] Any resulting mixture of isomers can be separated into pure or substantially pure optical isomers, diastereomers, throttling isomers, and racemates based on the physicochemical differences of the components, for example by chromatography and / or fractional crystallization.

[0330] Racemic derivatives of any resulting end product or intermediate can be resolved into optical enantiomers by known methods, for example, by separating their diastereomer salts obtained with optically active acids or bases, releasing optically active acidic or basic compounds. In particular, the basic moiety can therefore be used to resolve the compounds of the present invention into their optically active enantiomers, for example, by fractional crystallization with salts formed from optically active acids such as tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'-p-toluyltartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid. Racemic products can also be resolved by chiral chromatography (e.g., high-performance liquid chromatography (HPLC) using chiral adsorbents).

[0331] Typically, compounds having formula (I) can be prepared according to the schemes provided below. The examples of specific synthetic routes outlined below, along with the general schemes, provide guidance for those skilled in the art, who will readily understand that solvents, concentrations, reagents, protecting groups, the order of synthetic steps, time, temperature, etc., can be modified as needed.

[0332] The schemes provided below are intended to represent single diastereomeric stereoisomers / enantiomers and mixtures thereof. Separation of diastereomeric stereoisomers / enantiomers can be performed according to the techniques described herein. Unless otherwise defined, in the general schemes described below, substituents Z, X1, X2, Ar... 1 and Ar 2 As defined in this article. In the general scheme below, Ar 1 Corresponding to substituent A as defined for compounds having formula (I), and Ar 2 This corresponds to substituent B as defined for compounds having formula (I). Specifically, substituents C and R... 2 R 3 R 4 and R 5 As defined herein and particularly in the claims. In the following schemes, the amine protecting group (also referred to herein as the nitrogen protecting group) is called "PG". In the following schemes, a compound having formula (Iy) is a compound having formula RC(O)-X, and the RC(O) substituents attached to the nitrogen atom of the screw thread attached to a compound having formula (Ie) should be understood accordingly. In the following schemes, Ar 1 Appropriately corresponding to the substituent A of a compound having formula (I), and Ar 2 Substituent B appropriately corresponds to the compound having formula (I).

[0333] Option-1

[0334] Scheme-1 Synthesis: Compounds having formula (Ie) as disclosed herein can be synthesized as outlined in Scheme-1. A suitable dihalogenated heteroaromatic compound (1) is reacted with an aryl or heteroaryl group (Ar) in a Suzuki (or Stille) type cross-coupling reaction in the presence of a palladium catalyst such as RuPhos-Pd-G3 / RuPhos, in a solvent such as 1,4-dioxane (or toluene), with a base such as K3PO4 (or Na2CO3). 2 (2) The coupling coupler, such as a boric acid / ester reaction, is used to provide compound (2). In step B, in the presence of a palladium catalyst, such as RuPhos-Pd-G3 / RuPhos, a suitable functionalized aryl or heteroaryl system, such as an arylboronic acid, is introduced via a palladium cross-coupling reaction in a solvent, such as toluene, with a base, such as K3PO4, to introduce the substituent Ar. 1To provide compound (3). In step C, depending on the protecting group used, the protecting group (PG) is removed under appropriate conditions. For example, using conditions known in the art, the Boc group of compound (3) is removed with an organic acid such as trifluoroacetic acid in a solvent such as dichloromethane, or with an inorganic acid such as sulfuric acid in a solvent such as 1,4-dioxane to provide compound (4). 2 It may also contain a protecting group (e.g., THP), which is removed in the same reaction under the conditions described above for cleaving the Boc group. In step D, compound (5) can be prepared by reacting compound (4) with a compound having formula (Iy) (where X is a leaving group, such as a halogen (e.g., chlorine)) in the presence of a suitable base (e.g., as a Hunig base); or where X is OH and the reaction is carried out under standard amide bond formation conditions (e.g., in the presence of an amide coupling agent such as HATU and a suitable base such as DIPEA). For example, compound (5) is provided by treating compound (4) with acrylic acid in a solvent such as dichloromethane in the presence of a coupling agent such as propylphosphonic anhydride and a base such as a Hunig base, thereby introducing acrylamide. Alternatively, compound (4) can be treated with acryloyl chloride in a solvent such as THF in the presence of a base such as aqueous sodium bicarbonate. In step E, the mixture of transisomers is separated using SFC or HPLC conditions with a suitable column and eluent.

[0335] As shown above for Scheme 1, compounds (1), (2), (3), and (4) are useful intermediates for preparing compounds having formula (Ie).

[0336] Option 2

[0337] Scheme-2 Synthesis: Scheme-2 provides an alternative method for preparing the compound having formula (Ie) disclosed herein. In the presence of a palladium catalyst such as RuPhos-Pd-G3 / RuPhos, in a solvent of 1,4-dioxane (or toluene), the halo-heteroaromatic compound (1) is treated with a base such as K3PO4 (or Na2CO3) via a cross-coupling reaction, for example a Suzuki reaction, with an aryl or heteroaryl coupling partner such as borate / ester, using a halogenating agent such as N-iodosuccinimide or N-bromosuccinimide in a solvent such as THF or CH3CN, followed by treatment of compound (2) with a halogenating agent such as N-iodosuccinimide or N-bromosuccinimide. In step C, in the presence of a palladium catalyst such as RuPhos-Pd-G3 / RuPhos, using a suitably functionalized aryl or heteroaryl system such as arylboronic esters, in a solvent such as 1,4-dioxane, with a base such as K3PO4, the substituent Ar is introduced via a palladium-catalyzed coupling reaction. 2To provide compound (4). The remaining steps DF are similar to step CE in scheme-1 above.

[0338] As shown above for Scheme-2, compounds (1), (2), (3), (4), and (5) are useful intermediates for preparing compounds having formula (Ie).

[0339] Option 3

[0340] Synthesis of Scheme-3: Scheme-3 provides an alternative method for preparing the compound of formula (Ie) disclosed herein. In the presence of a palladium catalyst such as PdCl2(dppf).CH2Cl2 adduct, in a solvent such as 1,4-dioxane, the halo-heteroaromatic compound (1) is converted to a heteroaromatic boronic ester (2) using a base such as potassium acetate and bis-(pinacol)-diboron. In step B, in the presence of a palladium catalyst such as RuPhos-Pd-G3 / RuPhos, using a suitably functionalized aryl or heteroaryl system such as halo-heteroaryl, in a solvent such as toluene, the substituent Ar is introduced via palladium coupling reaction using a base such as K3PO4. 1 To provide compound (3). The remaining steps CG are similar to step BF in scheme-2 above.

[0341] As shown above for Scheme-3, compounds (1), (2), (3), (4), (5), and (6) are useful intermediates for preparing compounds having formula (Ie).

[0342] Option 4

[0343] Scheme-4 Synthesis: A heteroaromatic compound having formula (I) or a dihaloheteroaromatic compound having formula (II) can be obtained as described in Scheme-4. A suitable trihaloheteroaromatic compound (1) (e.g., 3,4,5-dibromo-1-dimethylamine) is prepared. H(-pyrazole) reacts with a metal-halogen exchanger (e.g., an alkyllithium reagent, such as n-butyllithium) in a solvent such as THF, and provides compound (2) after hydrolysis with, for example, methanol. In step B, an N-protected linker is introduced by reacting with a suitable functionalized N-protected linker, such as a linker functionalized with toluenesulfonate, in a solvent such as DMF in the presence of a base such as cesium carbonate, to provide compound (3). In step C, halogen / metal exchange is performed in a solvent such as THF using a suitable reagent such as n-butyllithium to provide a halogenated heteroaromatic compound having formula (I) after reaction with a suitable alkylating agent such as iodomethane. In a solvent such as CH3CN, a halogenating agent such as N - Iodosuccinimide treatment of compounds having formula (I) to provide a dihalogenated heteroaromatic ring having formula (II).

[0344] Option 5

[0345] Scheme 5 Synthesis: Scheme 5 provides an alternative method for preparing haloheteroaromatic compounds having formula (I). Suitable haloheteroaromatic compounds (1), such as 3-iodo-5-methyl-1-yl-2 ... H -Pyrazole, in the presence of a base such as cesium carbonate, in a solvent such as DMF, is alkylated with a suitable functionalized N-protected linker, such as a toluenesulfonate-functionalized linker, to provide a halo-heteroaromatic compound having formula (I).

[0346] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In further embodiments, the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein. For the purposes of this invention, solvates and hydrates are generally considered to be part of the composition unless otherwise specified. Preferably, the pharmaceutically acceptable carrier is sterile. The pharmaceutical composition can be formulated for a specific route of administration, such as oral, parenteral, and rectal administration. Furthermore, the pharmaceutical compositions of the present invention can be formulated in solid form (including but not limited to capsules, tablets, pills, granules, powders, or suppositories) or in liquid form (including but not limited to solutions, suspensions, or emulsions). The pharmaceutical composition can be subjected to conventional pharmaceutical processes, such as sterilization, and / or can contain conventional inert diluents, lubricants, or buffers, as well as adjuvants (such as preservatives, stabilizers, wetting agents, emulsifiers, and buffers).

[0347] Typically, a pharmaceutical composition is a tablet or gelatin capsule containing an active ingredient and one or more of the following: a) Diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) Lubricants, such as silica, talc, stearic acid, its magnesium or calcium salts and / or polyethylene glycol; c) Adhesives, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth gum, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; d) Disintegrants, such as starch, agar, alginate, or their sodium salts or effervescent mixtures; and e) Adsorbents, colorants, flavoring agents, and sweeteners.

[0348] In one embodiment, the pharmaceutical composition is a capsule containing only the active ingredient.

[0349] Tablets may be coated with film or enteric coating according to methods known in the art.

[0350] Suitable compositions for oral administration include effective amounts of the compounds of the present invention in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs, solutions, or solid dispersions. Compositions intended for oral use are prepared according to any method known in the art for manufacturing pharmaceutical compositions, and in order to provide a pharmaceutically refined and palatable formulation, such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives. Tablets may contain an active ingredient mixed with a non-toxic, pharmaceutically acceptable excipient suitable for tablet production. These excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrants such as corn starch or alginic acid; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets are either uncoated or coated using known techniques to delay breakdown and absorption in the gastrointestinal tract, thereby providing a prolonged duration of action. For example, time-delaying materials such as glyceryl monostearate or glyceryl distearate may be used. Formulations for oral use may be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate, or kaolin), or as soft gelatin capsules in which the active ingredient is mixed with an aqueous or oily medium (e.g., peanut oil, liquid paraffin, or olive oil).

[0351] Some injectable compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fat emulsions or suspensions. The compositions may be sterile and / or contain adjuvants, such as preservatives, stabilizers, wetting agents or emulsifiers, solution promoters, salts and / or buffers for adjusting osmotic pressure. Furthermore, the compositions may contain other substances of therapeutic value. The compositions are prepared according to conventional mixing, granulation, or coating methods and contain about 0.1%–75%, or about 1%–50%, of the active ingredient.

[0352] Suitable compositions for transdermal applications include an effective amount of the compound of the present invention and a suitable carrier. Suitable carriers for transdermal delivery include absorbable, pharmacologically acceptable solvents to facilitate passage through the host's skin. For example, a transdermal device may take the form of a bandage comprising a backing member, a reservoir containing the compound (optionally with a carrier), a barrier optionally controlling the rate of delivery to the host skin at a controlled and predetermined rate over a prolonged period, and means for securing the device to the skin.

[0353] Compositions suitable for topical application (e.g., application to skin and eyes) include aqueous solutions, suspensions, ointments, creams, gels, or aerosol formulations, for example, for delivery by aerosol or the like. These topical delivery systems will be particularly suitable for dermal application, for example, for the treatment of skin cancer, and for preventative use in sunscreens, lotions, sprays, and the like. Therefore, it is particularly suitable for topical applications, including cosmetics and formulations well known in the art. Such systems may contain solubilizers, stabilizers, tension enhancers, buffers, and preservatives.

[0354] As used herein, local application may also involve inhalation or intranasal administration. They can be conveniently delivered, with or without a suitable propellant, from a dry powder inhaler in the form of dry powder (alone as a mixture, such as a dry blend with lactose, or mixed component particles, such as component particles mixed with phospholipids) or from a pressurized container, pump, spray, nebulizer, or nebulizer in the form of an aerosol spray.

[0355] Compounds of formula (I) in free form or in pharmaceutically acceptable salt form exhibit valuable pharmacological properties, such as RAS-mutant inhibitory properties, as shown by in vitro tests provided in the examples, and thus indicate their use in therapeutics or as research chemicals, such as as tool compounds.

[0356] The compounds of particular interest in this invention exhibit good potency in the bioassays described herein, particularly in the covalent competition assays described herein. On the other hand, they should have favorable safety profiles. On the other hand, they should have favorable pharmacokinetic properties.

[0357] The compounds of the present invention preferably have an IC50 of less than 0.5 μM, more preferably less than 0.1 μM.

[0358] Given their activity as inhibitors of RAS mutants, particularly KRAS, HRAS, or NRAS G12C mutants, compounds of formula (I) in free or pharmaceutically acceptable salt form may be used to treat diseases driven by KRAS, HRAS, or NRAS G12C mutations, such as cancers that respond to (meaning particularly therapeutically beneficial) inhibition of RAS mutant proteins (especially KRAS, HRAS, or NRAS G12C mutant proteins), particularly the diseases or disorders described herein as mentioned below.

[0359] The compounds of the present invention can be used in the treatment of cancer. In particular, the compounds of the present invention are useful in the treatment of indications selected from the group consisting of: lung cancer (e.g., lung adenocarcinoma and non-small cell lung cancer), colorectal cancer (including colorectal adenocarcinoma), pancreatic cancer (including pancreatic cancer), uterine cancer (including endometrial cancer), rectal cancer (including rectal adenocarcinoma), and solid tumors.

[0360] The compounds of this invention can also be used to treat solid malignancies characterized by RAS mutations.

[0361] The compounds of the present invention can also be used to treat solid malignancies characterized by one or more mutations in KRAS, particularly the G12C mutation in KRAS.

[0362] Therefore, as another embodiment, the present invention provides the use of a compound having formula (I) or a pharmaceutically acceptable salt thereof in a therapy. As another embodiment, the present invention provides a compound having formula (I) or a pharmaceutically acceptable salt thereof for use in a therapy. Therefore, as another embodiment, the present invention provides the use of a compound having formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament. In a preferred embodiment, the therapy or the medicament is useful for a disease selected from those treatable by inhibiting a RAS mutant protein, particularly a KRAS, HRAS, or NRAS G12C mutant protein. In another embodiment, the present invention provides a method of treating a disease in a subject in need by inhibiting a RAS mutant protein, particularly inhibiting a G12C mutant of a KRAS, HRAS, or NRAS protein, wherein the method comprises administering to the subject a therapeutically effective amount of a compound having formula (I) or a pharmaceutically acceptable salt thereof.

[0363] In a more preferred embodiment, the disease is selected from the above list, appropriately including non-small cell lung cancer, colorectal cancer, and pancreatic cancer.

[0364] In a preferred embodiment, the therapy is used for a disease that can be treated by inhibiting a mutant RAS protein, particularly by inhibiting a G12C mutant of the KRAS, HRAS, or NRAS protein. In a more preferred embodiment, the disease is selected from the above list, suitably non-small cell lung cancer, colorectal cancer, and pancreatic cancer, characterized by a G12C mutation in the KRAS, HRAS, or NRAS.

[0365] In one embodiment of the invention, compounds selected from the group consisting of: a( R )-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta-2-yl)prop-2-en-1-one, a( R )-( S )-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(1-(2-(3-fluoropyrrolidine-1-yl)ethyl)-1H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepten-2-yl)prop-2-en-1-one, a( R )-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-phenyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hept-2-yl)prop-2-en-1-one, a( R )-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-methoxyethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta-2-yl)prop-2-en-1-one, a( R )-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-hydroxy-2-methylpropyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta-2-yl)prop-2-en-1-one, a( R )-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-(2-(2-methoxyethoxy)ethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta-2-yl)prop-2-en-1-one, a( R )-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(4-(hydroxymethyl)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepten-2-yl)prop-2-en-1-one, a( R )-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-fluoro-4-(2-methoxyethoxy)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta-2-yl)prop-2-en-1-one, a( R )-1-(6-(4-(3-amino-5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-methoxyethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta-2-yl)prop-2-en-1-one and a( R )-1-(6-(4-(3-amino-5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-phenyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hept-2-yl)prop-2-en-1-one, or a pharmaceutically acceptable salt thereof, for the treatment of cancer or solid malignancies, optionally said cancer or solid malignancies characterized by KRAS, HRAS or NRAS G12C mutations.

[0366] In one embodiment of the invention, compounds selected from the group consisting of: a( R )-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta-2-yl)prop-2-en-1-one, a( R )-(S)-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(1-(2-(3-fluoropyrrolidine-1-yl)ethyl)-1H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepten-2-yl)prop-2-en-1-one, a( R )-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-phenyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hept-2-yl)prop-2-en-1-one, a( R)-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-methoxyethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta-2-yl)prop-2-en-1-one, a( R )-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-hydroxy-2-methylpropyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta-2-yl)prop-2-en-1-one, a( R )-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-(2-(2-methoxyethoxy)ethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta-2-yl)prop-2-en-1-one, a( R )-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(4-(hydroxymethyl)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepten-2-yl)prop-2-en-1-one, a( R )--1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-fluoro-4-(2-methoxyethoxy)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta-2-yl)prop-2-en-1-one, a( R )1-(6-(4-(3-amino-5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-methoxyethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta-2-yl)prop-2-en-1-one and a( R )-1-(6-(4-(3-amino-5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-phenyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hept-2-yl)prop-2-en-1-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancers selected from: lung cancer (e.g., lung adenocarcinoma and non-small cell lung cancer), colorectal cancer (including colorectal adenocarcinoma), pancreatic cancer (including pancreatic cancer), uterine cancer (including endometrial cancer), and rectal cancer (including rectal adenocarcinoma); more preferably, lung cancer, colorectal cancer, or pancreatic cancer or solid tumors.

[0367] In one embodiment of the invention, compounds selected from the group consisting of: a-( R )-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta-2-yl)prop-2-en-1-one, a( R )-( S )-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(1-(2-(3-fluoropyrrolidine-1-yl)ethyl)-1H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepten-2-yl)prop-2-en-1-one, a( R )-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-phenyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hept-2-yl)prop-2-en-1-one, a( R )-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-methoxyethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta-2-yl)prop-2-en-1-one, a( R )-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-hydroxy-2-methylpropyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta-2-yl)prop-2-en-1-one, a( R )-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-(2-(2-methoxyethoxy)ethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta-2-yl)prop-2-en-1-one, a( R )-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(4-(hydroxymethyl)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepten-2-yl)prop-2-en-1-one, a( R)-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-fluoro-4-(2-methoxyethoxy)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta-2-yl)prop-2-en-1-one, a( R )-1-(6-(4-(3-amino-5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-methoxyethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta-2-yl)prop-2-en-1-one and a( R )-1-(6-(4-(3-amino-5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-phenyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hept-2-yl)prop-2-en-1-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of cancers selected from: lung cancer (e.g., lung adenocarcinoma and non-small cell lung cancer), colorectal cancer (including colorectal adenocarcinoma), pancreatic cancer (including pancreatic cancer), uterine cancer (including endometrial cancer), and rectal cancer (including rectal adenocarcinoma); more preferably, lung cancer, colorectal cancer, or pancreatic cancer or solid tumor, wherein said cancer is a KRAS G12C-mutant. More preferably, the cancer treated with the compounds of the present invention is KRAS G12C-mutant lung cancer, including KRAS G12C-mutant non-small cell lung cancer.

[0368] The compounds of this invention can be administered simultaneously with, before, or after one or more other therapeutic agents. The compounds of this invention can be administered separately via the same or different routes of administration as other pharmaceutical agents, or together in the same pharmaceutical composition. The therapeutic agent is, for example, a chemical compound, peptide, antibody, antibody fragment, or nucleic acid, which, when administered to a patient in combination with the compounds of this invention, has therapeutic activity or enhances therapeutic activity. In embodiments of this invention, another therapeutic agent may be an anticancer agent.

[0369] In one embodiment, the present invention provides a product comprising the compound of the present invention and at least one other therapeutic agent, as a combination formulation for simultaneous, separate, or sequential use in a therapy. In one embodiment, the therapy is for treating a disease or condition characterized by a KRAS, HRAS, or NRAS G12C mutation. Products provided as combination formulations include compositions comprising the compound of the present invention and one or more other therapeutic agents together in the same pharmaceutical composition, or the compound of the present invention and one or more other therapeutic agents in separate forms (e.g., in kit form).

[0370] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and one or more other therapeutic agents. Optionally, the pharmaceutical composition may comprise a pharmaceutically acceptable carrier as described above.

[0371] In one embodiment, the present invention provides a kit comprising two or more separate pharmaceutical compositions, wherein at least one pharmaceutical composition contains a compound of the present invention. In one embodiment, the kit includes means for separately retaining the compositions (e.g., containers, separate bottles, or separate foil packets). An example of such a kit is blister packaging, as typically used for packaging tablets, capsules, and the like.

[0372] The kits of the present invention can be used to administer different dosage forms (e.g., oral and parenteral), to administer individual compositions at different dose intervals, or to titrate individual compositions relative to each other. To aid in compliance, the kits of the present invention typically include instructions for use.

[0373] In the combination therapies of the present invention, the compounds of the present invention and other therapeutic agents may be manufactured and / or formulated by the same or different manufacturers. Furthermore, the compounds of the present invention may be combined with another therapeutic agent to form a combination therapy: (i) before the combination product is released to a physician (e.g., in the case of a kit containing the compounds of the present invention and other therapeutic agents); (ii) shortly before administration, by the physician himself (or under the guidance of a physician); (iii) in the patient himself, for example during the sequential administration of the compounds of the present invention and other therapeutic agents.

[0374] Preparation of compounds

[0375] The compounds of the present invention can be prepared as described in the following examples. These examples are intended to illustrate the invention and should not be construed as limiting it.

[0376] General methods and conditions: Temperatures are given in degrees Celsius. Unless otherwise specified, all evaporation is carried out under reduced pressure, typically between approximately 15 mm Hg and 100 mm Hg (= 20-133 mbar).

[0377] Mass spectra were acquired on LC-MS, SFC-MS, or GC-MS systems using a range of instruments with the following configurations: electrospray ionization, chemical methods, and electron impact ionization; ESI methods were used on LCMS systems using a range of instruments with the following configurations: Waters Acquity UPLC or mass spectrometer with a Waters SQ detector; and Waters Acquity LCMS with a PDA detector. [M+H] +It refers to the protonated molecular ion of a chemical species.

[0378] NMR spectroscopy was performed using Bruker Ultrashield™ 400 (400 MHz), Bruker Ultrashield™ 600 (600 MHz), and Ascend. TM Spectrometer operation was performed at 400 MHz, with or without tetramethylsilane as an internal standard. Chemical shifts (δ values) were reported in low-field ppm for tetramethylsilane. Spectral splitting modes were specified as single signal (s), double signal (d), triple signal (t), quartet signal (q), multiple signal, unresolved or more overlapping signals (m), and broad signal (br). Solvents were given in parentheses. Only proton signals observed and not overlapping with solvent peaks were reported.

[0379] Celite: Celite R (Celite) = Diatomaceous earth-based filter aid

[0380] Phase separator: Biotage - Solute phase separator - (Part No.: 120-1908-F, 70 mL, Part No.: 120-1909-J, 150 mL)

[0381] SiliaMetS®Thiol: SiliCYCLE thiol metal purifier - (R51030B, particle size: 40-63 µm).

[0382] The X-ray powder diffraction (XRPD) patterns described herein were obtained using Bruker Advance D8 in reflection geometry. The powder sample was analyzed using a zero-background Si flat plate sample holder. The radiation was Cu Kα (λ = 1.5418 Å). The pattern was measured between 2° and 40°2θ.

[0383] Sample quantity: 5-10 mg

[0384] Sample rack: Zero-background Si flat plate sample holder

[0385] XRPD parameters:

[0386] instrument

[0387] Microwave: Unless otherwise stated, all microwave reactions were carried out in a Biotage initiator, irradiated at 0-400 W from a magnetron at 2.45 GHz with the processing power of Robot Eight / Robot Sixty.

[0388] UPLC-MS and MS analysis methods: Waters Acquity UPLC with Waters SQ detector.

[0389] UPLC-MS-1: Acquity HSS T3; Particle size: 1.8 µm; Column size: 2.1 x 50 mm; Eluent A: H2O + 0.05% HCOOH + 3.75 mM ammonium acetate; Eluent B: CH3CN + 0.04% HCOOH; Gradient: 5% to 98% B over 1.40 min, then 98% B for 0.40 min; Flow rate: 1 mL / min; Column temperature: 60°C.

[0390] UPLC-MS-2: Acquity HSS T3; Particle size: 1.8 µm; Column size: 2.1 x 100 mm; Eluent A: H2O + 0.05% HCOOH + 3.75 mM ammonium acetate; Eluent B: CH3CN + 0.04% HCOOH; Gradient: 5% to 98% B over 9.4 min, then 98% B for 0.40 min; Flow rate: 1.0 mL / min; Column temperature: 60°C.

[0391] UPLC-MS-3: Acquity BEH C18; Particle size: 1.7 µm; Column size: 2.1 x 50 mm; Eluent A: H2O + 4.76% isopropanol + 0.05% HCOOH + 3.75 mM ammonium acetate; Eluent B: Isopropanol + 0.05% HCOOH; Gradient: 1% to 98% B over 1.7 min, then 98% B for 0.1 min; Flow rate: 0.6 mL / min; Column temperature: 80°C.

[0392] UPLC-MS-4: Acquity BEH C18; Particle size: 1.7 µm; Column size: 2.1 x 100 mm; Eluent A: H2O + 4.76% isopropanol + 0.05% HCOOH + 3.75 mM ammonium acetate; Eluent B: Isopropanol + 0.05% HCOOH; Gradient: 1% to 60% B in 8.4 min, then 60% to 98% B in 1 min; Flow rate: 0.4 mL / min; Column temperature: 80°C.

[0393] UPLC-MS-5: Ascentis Express C18; Particle size: 2.7 µm; Column size: 2.1 x 50 mm; Eluent A: H2O + 4.76% isopropanol + 0.05% HCOOH + 3.75 mM ammonium acetate; Eluent B: Isopropanol + 0.05% HCOOH; Gradient: 1% to 50% B in 1.4 min, 50% to 98% B in 0.30 min, then 98% for 0.10 min; Flow rate: 1 mL / min; Column temperature: 80°C.

[0394] UPLC-MS-6: Acquity BEH C18; Particle size: 1.7 µm; Column size: 2.1 x 50 mm; Eluent A: H2O + 0.05% HCOOH + 3.75 mM ammonium acetate; Eluent B: Isopropanol + 0.05% HCOOH; Gradient: 5% to 98% B over 1.7 min, then 98% B for 0.1 min; Flow rate: 0.6 mL / min; Column temperature: 80°C.

[0395] UPLC-MS-7: Acquity BEH C18; Particle size: 1.7 µm; Column size: 2.1 x 50 mm; Eluent A: H2O + 0.05% HCOOH + 3.75 mM ammonium acetate; Eluent B: Isopropanol + 0.05% HCOOH; Gradient: 5% to 98% B over 1.7 min, then 98% B for 0.1 min; Flow rate: 0.7 mL / min; Column temperature: 80°C.

[0396] UPLC-MS-8: Acquity HSS T3; Particle size: 1.8 µm; Column size: 2.1 x 100 mm; Eluent A: H2O + 0.05% HCOOH + 3.75 mM ammonium acetate; Eluent B: CH3CN + 0.04% HCOOH; Gradient: 5% to 98% B over 9.4 min, then 98% B for 0.40 min; Flow rate: 0.8 mL / min; Column temperature: 60°C.

[0397] UPLC-MS-9: CORTECS C18+; Particle size: 2.7 µm; Column size: 2.1 x 50 mm; Eluent A: H2O + 4.76% isopropanol + 0.05% HCOOH + 3.75 mM ammonium acetate; Eluent B: Isopropanol + 0.05% HCOOH; Gradient: 1% to 50% B in 1.4 min, 50% to 98% B in 0.30 min, then 98% for 0.10 min; Flow rate: 1 mL / min; Column temperature: 80°C.

[0398] UPLC-MS-10: Acquity HSS T3; Particle size: 1.8 µm; Column size: 2.1 x 50 mm; Eluent A: H2O + 0.05% HCOOH + 3.75 mM ammonium acetate; Eluent B: Isopropanol + 0.05% HCOOH; Gradient: 5% to 98% B over 1.7 min, then 98% B for 0.10 min; Flow rate: 0.6 mL / min; Column temperature: 80°C.

[0399] UPLC-MS-11: Acquity BEH C18; Particle size: 1.7 µm; Column size: 2.1 x 50 mm; Eluent A: H2O + 0.2% HCOOH; Eluent B: CH3CN; Gradient: 5% to 98% B over 1.4 min, then 98% B for 0.4 min; Flow rate: 1.0 mL / min; Column temperature: 80°C.

[0400] UPLC-MS-12: Acquity BEH C18; Particle size: 1.7 µm; Column size: 2.1 x 100 mm; Eluent A: H2O + 0.05% HCOOH + 3.75 mM ammonium acetate; Eluent B: Isopropanol + 0.05% HCOOH; Gradient: 5% to 60% B in 8.4 min, then 60% to 98% B in 1 min; Flow rate: 0.4 mL / min; Column temperature: 80°C.

[0401] UPLC-MS-13: Acquity HSS T3; Particle size: 1.8 µm; Column size: 2.1 x 100 mm; Eluent A: H2O + 0.05% HCOOH + 3.75 mM ammonium acetate; Eluent B: Isopropanol + 0.05% HCOOH; Gradient: 5% to 60% B in 8.4 min, then 60% to 98% B in 1 min; Flow rate: 0.4 mL / min; Column temperature: 80°C.

[0402] LCMS-1: Acquity BEH C18; Particle size: 1.7 µm; Column size: 2.1 x 50 mm; Eluent A: H2O + 0.10% HCOOH + 2.0 mM ammonium acetate; Eluent B: CH3CN + 0.10% HCOOH; Gradient: 98:2 from 0.01 min to 0.3 min, 50:50 from 0.6 min, 25:75 from 1.1 min, 0:100 from 2.0 min to 2.70 min, Flow rate: 0.60 mL / min, 98:2 from 2.71 min to 3.0 min, Flow rate: 0.55 mL / min; Column temperature: RT.

[0403] LCMS-2: Acquity BEH C18; Particle size: 1.7 µm; Column size: 2.1 x 50 mm; Eluent A: H2O + 0.10% HCOOH + 2.0 mM ammonium acetate; Eluent B: CH3CN + 0.10% HCOOH; Gradient: 50:50 at 0.01 min, 10:90 at 1.0 min, 0:100 from 1.5 min to 4.50 min, and 50:50 from 4.6 min to 5.0 min; Flow rate: 0.40 mL / min; Column temperature: RT.

[0404] LCMS-3: X-Bridge C18; Particle size: 3.5 µm; Column size: 50 x 4.6 mm; Eluent A: 5.0 mM ammonium bicarbonate; Eluent B: CH3CN; Gradient: 95:5 at 0.01 min, 10:90 at 5.0 min, 5:95 from 5.80 min to 7.20 min, and 95:5 from 7.21 min to 10.0 min; Flow rate: 1 mL / min; Column temperature: RT.

[0405] LCMS-4: Acquity BEH C18; Particle size: 1.7 µm; Column size: 2.1 x 50 mm; Eluent A: H2O + 0.10% HCOOH + 2.0 mM ammonium acetate; Eluent B: CH3CN + 0.10% HCOOH; Gradient: 98:2 from 0.01 min to 0.5 min, 10:90 from 5.0 min, 5:95 from 6.0 min to 7.0 min, and 98:2 from 7.01 min to 8.0 min; Flow rate: 0.45 mL / min; Column temperature: RT.

[0406] LCMS-5: YMC-Pack ODS-AQ; Particle size: 5.0 µm; Column size: 4.6 x 250 mm; Eluent A: 10 mM ammonium acetate + 0.10% HCOOH; Eluent B: CH3CN + 0.10% HCOOH; Gradient: 90:10 at 0.01 min, 70:30 at 10 min, 60:40 at 20 min, 0:100 from 30 min to 33 min, and 90:10 from 33.01 min to 35.0 min; Flow rate: 1.0 mL / min; Column temperature: RT.

[0407] MS-1: MS flow injection; Eluent A: H2O + 4.76% isopropanol + 0.05% HCOOH + 3.75 mM ammonium acetate; Eluent B: isopropanol + 0.04% HCOOH; Gradient: 70% isocratic B for 0.8 min; Flow rate: 0.4 mL / min.

[0408] Preparation method: Normal phase chromatography: Unless otherwise stated, normal phase chromatography is performed on a pre-packed column using silica gel (described below) or on a glass column according to standard rapid chromatography.

[0409] System 1 Teledyne ISCO, CombiFlash Rf

[0410] System 2 Biotage Isolera

[0411] Prefilled RediSep Rf columns, or SNAP columns

[0412] The sample is adsorbed onto Isolute, or onto silica gel, or used as a solution.

[0413] Reversed-phase HPLC and SFC: RP-HPLC-1: Gilson PLC 2020, column: Maisch Reprosil C18 5 μm, 250 x 30 mm, detection UV 215 & 254 nM, mobile phase: A: water + 0.1% TFA, B: acetonitrile; gradient: 30% to 95% B over 25 min.

[0414] RP-HPLC-5: Agela-H1000GC500, column: Welch Ultimate XB C18 40 μm, 100 x 400 mm, detection UV, mobile phase: A: water + 0.1% NH4HCO3, B: acetonitrile; gradient: 60% to 100% B over 50 min.

[0415] SFC-1: Column: Reprosphere PEI 100A 5 µm; 250 x 30 mm; mobile phase; flow rate: 30 mL / min; column temperature: 40°C; back pressure: 120 bar.

[0416] Chiral HPLC / SFC methods: C-SFC-1: Column: Amylose-C NEO 5 µm; 250 x 30 mm; Mobile phase; Flow rate: 80 mL / min; Column temperature: 40°C; Back pressure: 120 bar.

[0417] C-SFC-2: Column: Lux amylose-1 5 µm; 250 x 30 mm; mobile phase; flow rate: 80 mL / min; column temperature: 40°C; back pressure: 120 bar.

[0418] C-SFC-3: Column: Chiralpak AD-H 5 µm; 100 x 4.6 mm; Mobile phase; Flow rate: 3 mL / min; Column temperature: 40°C; Back pressure: 1800 psi.

[0419] C-SFC-4: Column: Chiralpak AD-H 5 µm; 250 x 30 mm; Mobile phase; Flow rate: 80 mL / min; Column temperature: 40°C; Back pressure: 120 bar.

[0420] C-SFC-5: Column: Chiralpak IB-N 5 µm; 250 x 30 mm; mobile phase; flow rate: 80 mL / min; column temperature: 40°C; back pressure: 120 bar.

[0421] C-SFC-6: Column: Chiralpak IB-N 5 µm; 100 x 4.6 mm; Mobile phase; Flow rate: 3 mL / min; Column temperature: 40°C; Back pressure: 1800 psi.

[0422] C-SFC-7: Column: Chiralpak IG 5 µm; 250 x 30 mm; mobile phase; flow rate: 80 mL / min; column temperature: 40°C; back pressure: 120 bar.

[0423] C-SFC-8: Column: Chiralpak IG 5 µm; 100 x 4.6 mm; Mobile phase; Flow rate: 3 mL / min; Column temperature: 40°C; Back pressure: 1800 psi.

[0424] C-SFC-9: Column: Chiralpak AD-YMC 5 µm; 250 x 30 mm; mobile phase; flow rate: 80 mL / min; column temperature: 40°C; back pressure: 120 bar.

[0425] C-SFC-10: Column: Chiralpak IG 5 µm; 250 x 30 mm; mobile phase; flow rate: 100 mL / min; column temperature: 40°C; back pressure: 120 bar.

[0426] C-SFC-11: Column: Lux cellulose 5 µm; 100 x 4.6 mm; mobile phase; flow rate: 3 mL / min; column temperature: 20°C; back pressure: 120 bar.

[0427] C-SFC-12: Column: Chiralpak OD-H 5 µm; 250 x 30 mm; Mobile phase; Flow rate: 80 mL / min; Column temperature: 40°C; Back pressure: 110 bar.

[0428] C-SFC-13: Column: Chiralpak OD-H 5 µm; 100 x 4.6 mm; Mobile phase; Flow rate: 3 mL / min; Column temperature: 40°C; Back pressure: 120 bar.

[0429] C-SFC-14: Waters SFC 200 with UV detector; column: Chiralpak AD-H 5 µm; 250 x 30 mm; mobile phase; flow rate: 80 mL / min; column temperature: 40°C; back pressure: 100 bar.

[0430] C-SFC-15: Waters SFC investigator with PDA detector; column: Chiralpak AD-H 5 µm; 250 x 4.6 mm; mobile phase; flow rate: 4 mL / min; column temperature: 40°C; back pressure: 100 bar.

[0431] C-SFC-16: Waters SFC 200 with UV detector; column: Chiralpak IG 5 µm; 250 x 30 mm; mobile phase; flow rate: 80 mL / min; column temperature: 40°C; back pressure: 100 bar.

[0432] C-SFC-17: Waters SFC 200 with UV detector; column: Chiralpak IG 5 µm; 250 x 21 mm; mobile phase; flow rate: 80 mL / min; column temperature: 40°C; back pressure: 100 bar.

[0433] C-SFC-18: Waters SFC investigator with PDA detector; column: Chiralpak IG 5 µm; 250 x 4.6 mm; mobile phase; flow rate: 4 mL / min; column temperature: 40°C; back pressure: 100 bar.

[0434] C-SFC-19: Waters SFC investigator with PDA detector; column: Chiralpak IC 5 µm; 250 x 4.6 mm; mobile phase; flow rate: 4 mL / min; column temperature: 40°C; back pressure: 100 bar.

[0435] C-SFC-20: Column: Lux cellulose 5 µm; 250 x 30 mm; mobile phase; flow rate: 80 mL / min; column temperature: 40°C; back pressure: 120 bar.

[0436] C-HPLC-1: Column: Chiralpak IC 5 µm; 250 x 20 mm; Mobile phase; Flow rate: 10 mL / min; Column temperature: RT.

[0437] C-HPLC-2: Column: ChiralPak ID 5 µm; 250 x 25 mm; Mobile phase; Flow rate: 15 mL / min; Column temperature: RT.

[0438] C-HPLC-3: Column: Chiralpak IC 3 µm; 100 x 4.6 mm; Mobile phase; Flow rate: 0.42 mL / min; Column temperature: RT; Back pressure: 1800 psi.

[0439] C-HPLC-4: Column: Chiralpak IC-3 3 µm; 100 x 3 mm; Mobile phase; Flow rate: 0.42 mL / min; Column temperature: RT.

[0440] C-HPLC-5: Column: Chiralpak IA 5 µm; 250 x 4.6 mm; Mobile phase; Flow rate: 1 mL / min; Column temperature: RT; Back pressure: 49 bar.

[0441] C-HPLC-6: Column: Chiralpak IA 5 µm; 250 x 30 mm; Mobile phase; Flow rate: 20 mL / min; Column temperature: RT.

[0442] C-HPLC-7: Column: ChiralPak ID 5 µm; 250 x 4.6 mm; Mobile phase; Flow rate: 1 mL / min; Column temperature: RT.

[0443] C-HPLC-8: Column: ChiralPak AD 5 µm; 250 x 30 mm; Mobile phase; Flow rate: 20 mL / min; Column temperature: RT.

[0444] C-HPLC-9: Column: ChiralPak AD 3 µm; 100 x 3.0 mm; Mobile phase; Flow rate: 0.42 mL / min; Column temperature: RT.

[0445] C-HPLC-10: Column: Chiralpak IG-3; 3 µm; 100 x 3.0 mm; Mobile phase; Flow rate: 0.42 mL / min; Column temperature: 25°C.

[0446] C-HPLC-11: Column: Chiralpak IG 5 µm; 250 x 20 mm; Mobile phase; Flow rate: 10 mL / min; Column temperature: 25°C.

[0447] C-HPLC-12: Column: Chiralpak IA-5; 5 µm; 250 x 3.0 mm; Mobile phase; Flow rate: 1 mL / min; Column temperature: 25°C.

[0448] C-HPLC-13: Column: Chiralpak IG-3; 3 µm; 100 x 3.0 mm; Mobile phase; Flow rate: 0.42 mL / min; Column temperature: 25°C.

[0449] C-HPLC-14: Column: Chiralcel OZ; 3 µm; 250 x 25 mm; Mobile phase; Flow rate: 15 mL / min; Column temperature: 25°C.

[0450] C-HPLC-15: Column: Chiralcel OZ; 3 µm; 100 x 3.0 mm; Mobile phase; Flow rate: 0.42 mL / min; Column temperature: 25°C.

[0451] C-HPLC-16: Column: Chiralcel OZ; 5 µm; 250 x 4.6 mm; Mobile phase; Flow rate: 1.0 mL / min; Column temperature: 25°C.

[0452] C-HPLC-17: Column: Chiralpak IG 5 µm; 250 x 20 mm; Mobile phase; Flow rate: 12 mL / min; Column temperature: 25°C.

[0453] C-HPLC-18: Column: Lux amylose-1 5 µm; 250 x 20 mm; mobile phase; flow rate: 10 mL / min; column temperature: 40°C; back pressure: 120 bar.

[0454] C-HPLC-19: Column: ChiralPak AD 5 µm; 250 x 25 mm; Mobile phase; Flow rate: 15 mL / min; Column temperature: RT.

[0455] C-HPLC-20: Column: Chiralpak IC 5 µm; 250 x 4.6 mm; Mobile phase; Flow rate: 1 mL / min; Column temperature: RT.

[0456] C-HPLC-21: Column: Chiralpak AD-H 5 µm; 250 x 21 mm; Mobile phase; Flow rate: 18 mL / min; Column temperature: 40°C.

[0457] C-HPLC-22: Column: Chiralpak AD-H 5 µm; 250 x 4.6 mm; Mobile phase; Flow rate: 1 mL / min; Column temperature: 25°C.

[0458] C-HPLC-23: Column: Chiralcel OX-H 5 µm; 250 x 21 mm; Mobile phase; Flow rate: 18 mL / min; Column temperature: 40°C.

[0459] C-HPLC-24: Column: Chiralpak OX-H 5 µm; 250 x 4.6 mm; Mobile phase; Flow rate: 1 mL / min; Column temperature: 25°C.

[0460] C-HPLC-25: Column: Chiralpak IBN 5 µm; 250 x 21 mm; Mobile phase; Flow rate: 18 mL / min; Column temperature: 40°C.

[0461] C-HPLC-26: Column: Chiralpak IBN 5 µm; 250 x 4.6 mm; Mobile phase; Flow rate: 1 mL / min; Column temperature: 25°C.

[0462] C-HPLC-27: Column: Chiralpak IC 5 µm; 250 x 21 mm; Mobile phase; Flow rate: 18 mL / min; Column temperature: 40°C.

[0463] C-HPLC-28: Column: Chiralpak IG, 5 µm; 250 x 21 mm; Mobile phase; Flow rate: 18 mL / min; Column temperature: 40°C.

[0464] C-HPLC-29: Column: ChiralPak IG 5 µm; 250 x 4.6 mm; Mobile phase; Flow rate: 1 mL / min; Column temperature: 25°C.

[0465] C-HPLC-30: Column: Chiralpak IC 5 µm; 250 x 30 mm; Mobile phase; Flow rate: 20 mL / min; Column temperature: RT.

[0466] The abbreviations used are those that are common in this field.

[0467] abbreviation:

[0468] All starting materials, structural units, reagents, acids, bases, dehydrating agents, solvents, and catalysts used to prepare the compounds of the present invention are commercially available or can be prepared by organic synthesis methods known to those skilled in the art. Furthermore, the compounds of the present invention can be produced by organic synthesis methods known to those skilled in the art, as illustrated in the following examples.

[0469] The structures of all end products, intermediates, and starting materials were confirmed by standard analytical spectroscopic features (e.g., MS, IR, NMR). The absolute stereochemistry of representative examples of preferred (most active) transisomers has been determined by analysis of the X-ray crystal structure of the complex or by analysis of the X-ray crystal structure of the small molecule in which each compound is bound to the KRASG12C mutant. In all other cases where X-ray structures are not available, the stereochemistry is specified in a similar manner, assuming that for each pair, the transisomer exhibiting the highest activity in the covalent competition experiment has the same configuration as the representative example observed by X-ray crystallography. As shown in Example 12a above (a more active transisomer), the absolute stereochemistry is specified according to the Cahn-Ingold-Prelog rule, which is representative of the other examples and has a( R ) configuration.

[0470] Preparation of the final compound

[0471] Method 1: Synthesis scheme

[0472] Example 1a: a( R )-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol) (-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]hept-2-yl)prop-2-en-1-one or

[0473] 1-{6-[(4 M )-4-(5-chloro-6-methyl-1 H -Indazol-4-yl)-5-methyl-3-(1-methyl-1 H -Indazole-5- (base)-1 H [-pyrazol-1-yl]-2-azaspiro[3.3]hept-2-yl}prop-2-en-1-one and

[0474] Example 1b: a( S )-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol) (-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]hept-2-yl)prop-2-en-1-one or

[0475] 1-{6-[(4 P )-4-(5-chloro-6-methyl-1 H -Indazol-4-yl)-5-methyl-3-(1-methyl-1 H -Indazole-5- (base)-1 H [-pyrazol-1-yl]-2-azaspiro[3.3]hept-2-yl}prop-2-en-1-one

[0476] Step 1: tert-Butyl 6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0477] In a 500 mL flask, under argon atmosphere, tert-butyl6-(3-bromo-4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (intermediate C1, 10 g, 16.5 mmol), (1-methyl-1H-indazol-5-yl)boronic acid (6.12 g, 33.1 mmol), RuPhos (1.16 g, 2.48 mmol) and RuPhos-Pd-G3 (1.66 g, 1.98 mmol) were suspended in toluene (165 mL). K3PO4 (2M, 24.8 mL, 49.6 mmol) was added and the reaction mixture was placed in a preheated oil bath (95°C) and stirred for 45 min. The reaction mixture was poured into a saturated aqueous NH4Cl solution and extracted with EtOAc (x3). The combined organic layers were washed with a saturated aqueous solution of NaHCO3, dried (using a phase separator), and concentrated under reduced pressure. The crude residue was diluted with THF (50 mL), SiliaMetS® thiols (15.9 mmol) were added, and the mixture was vortexed at 40°C for 1 h. The mixture was filtered, the filtrate was concentrated, and the crude residue was purified by normal-phase chromatography (eluent: MeOH in CH2Cl2 from 0% to 2%). The purified fraction was further purified by normal-phase chromatography (eluent: MeOH in CH2Cl2 from 0% to 2%) to give the title compound as a pale yellow foam. UPLC-MS-3: Rt = 1.23 min; MS m / z [M+H] + ;656.3 / 658.3.

[0478] Step 2: 5-Chloro-6-methyl-4-(5-methyl-3-(1-methyl-1H-indazol-5-yl)-1-(2-azaspiro[3.3]hept-6-yl)-1H-pyrazol-4-yl)-1H-indazol

[0479] TFA (19.4 mL, 251 mmol) was added to a solution of tert-butyl-6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (step 1, 7.17 g, 10.0 mmol) in CH2Cl2 (33 mL). The reaction mixture was stirred under nitrogen at RT for 1.5 h. RM was concentrated under reduced pressure to give the title compound as a trifluoroacetate salt, which was used unpurified for the next step. UPLC-MS-3: Rt = 0.74 min; MS m / z [M+H] + ;472.3 / 474.3.

[0480] Step 3: 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepten-2-yl)prop-2-en-1-one

[0481] A mixture of acrylic acid (0.69 mL, 10.1 mmol), propylphosphonic anhydride (5.94 mL, 7.53 mmol in EtOAc, 50%), and DIPEA (21.6 mL, 126 mmol) in CH2Cl2 (80 mL) was stirred at RT for 20 min, and then added (dropping funnel) to an ice-cold solution of 5-chloro-6-methyl-4-(5-methyl-3-(1-methyl-1H-indazol-5-yl)-1-(2-azaspiro[3.3]hept-6-yl)-1H-pyrazol-4-yl)-1H-indazol trifluoroacetate (step 2, 6.30 mmol) in CH2Cl2 (40 mL). The reaction mixture was stirred at RT under nitrogen for 15 min. The RM was poured into a saturated aqueous solution of NaHCO3 and extracted with CH2Cl2 (x3). The combined organic layers were dried (phase separator) and concentrated. The crude residue was diluted with THF (60 mL) and LiOH (2N, 15.7 mL, 31.5 mmol) was added. The mixture was stirred at RT for 30 min until the byproducts generated by the reaction of acryloyl chloride with the free NH group of indazole disappeared (UPLC), then poured into a saturated aqueous solution of NaHCO3 and extracted with CH2Cl2 (3x). The combined organic layers were dried (phase separator) and concentrated. The crude residue was purified by normal phase chromatography (elution buffer: MeOH in CH2Cl2 from 0% to 5%) to give the title compound. The isomers were separated by chiral SFC (C-SFC-1; mobile phase: CO2 / [IPA+0.1% Et3N]: 69 / 31) to give Example 1a: a( R )-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta-2-yl)prop-2-en-1-one (white powder): 1 H NMR (600 MHz, DMSO- d6) δ 13.1 (s,1H), 7.89 (s, 1H), 7.59 (s, 1H), 7.55 (s, 1H), 7.42 (m, 2H), 7.30 (d, 1H), 6.33 (m, 1H), 6.12 (m, 1H), 5.68 (m, 1H), 4.91 (m, 1H), 4.40 (s, 1H), 4.33(s, 1H), 4.11 (s, 1H), 4.04 (s, 1H), 3.95 (s, 3H), 2.96-2.86 (m, 2H), 2.83-2.78 (m, 2H), 2.49 (s, 3H), 2.04 (s, 3H); UPLC-MS-4: Rt = 4.22 min; MS m / z [M+H] + 526.3 / 528.3; C-SFC-3 (mobile phase: CO2 / [IPA+0.1% Et3N]: 67 / 33): Rt = 2.23 min. Throughout the specification, the compound of Example 1a is also referred to as "Compound X".

[0482] Another isomer example 1b; obtain a( ) as the first elution peak S )-1-(6-(4-(5-chloro-6-methyl-1H-indazole-4-yl)-5-methyl-3-(1-methyl-1H-indazole-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta-2-yl)prop-2-en-1-one: C-SFC-3 (mobile phase: CO2 / [IPA+0.1% Et3N]: 67 / 33): Rt = 1.55 min.

[0483] Method-1a Similar to method-1, the difference is that step 2 is performed as follows: Towards tert-butyl6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (step 1, 1.66 g, 2.10 mmol) was added to a stirred solution of dioxane (40 mL) with sulfuric acid (3.30 mL, 42.0 mmol) and the mixture was stirred overnight at RT. The mixture was diluted with water, neutralized with a saturated aqueous solution of NaHCO3 (to pH 8-9), extracted with n-butanol (x2), and the combined organic extracts were washed with water (x2), dried (phase separator), and evaporated. The crude material 5-chloro-6-methyl-4-(5-methyl-3-(1-methyl-1H-indazol-5-yl)-1-(2-azaspiro[3.3]hept-6-yl)-1H-pyrazol-4-yl)-1H-indazole was dried overnight under high vacuum and used for the next step without purification.

[0484] Note: For some instances in Tables 1 and 2, CH can be used. 2 Cl 2 It can be used as a substitute for n-butanol in extraction.

[0485] Method-1b Similar to Method-1, the difference is that step 3 is performed as follows: Under argon atmosphere, NaHCO3 (516 mg, 6.14 mmol), H2O (0.20 mL), and acryloyl chloride (0.026 mL, 0.32 mmol) were added to an ice-cold solution of 5-chloro-6-methyl-4-(5-methyl-3-(1-methyl-1H-indazol-5-yl)-1-(2-azaspiro[3.3]hept-6-yl)-1H-pyrazol-4-yl)-1H-indazole (trifluoroacetate (step 2) or free base (step 2 method-1a), 0.25 mmol) in THF (4 mL). The reaction mixture was stirred at 0°C for 60 min. Then, LiOH (2M in water, 4.91 mL, 9.83 mmol) was added and the mixture was stirred at 0°C for 1 h until the byproducts generated by the reaction of acryloyl chloride with indazole NH disappeared (UPLC). Add saturated NaHCO3 aqueous solution, separate the layers and extract the aqueous layer with CH2Cl2 (2x). Wash the combined organic extracts with saturated NaHCO3 aqueous solution, dry (Na2SO4), filter and evaporate. Purify the crude residue by normal phase chromatography (eluent: MeOH in CH2Cl2 from 0% to 9%) to give 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]hept-2-yl)prop-2-en-1-one.

[0486] Method-1c Similar to Method-1, except that XPhos and XPhos-Pd-G2 are used instead of Ruphos and RuPhos-Pd-G3 in step 1.

[0487] Method-1d Similar to Method-1, except that dioxane is used instead of toluene in step 1.

[0488] Method-1e Similar to Method-1, except that in step 1, Na2CO3 (2 M, 3 equivalents), Pd(PPh3)4 (0.1 equivalents) and dioxane are used instead of K3PO4, RuPhos, RuPhos-Pd-G3 and toluene.

[0489] Method-1f Similar to Method-1, except that in step 1, solid Na2CO3 (3 equivalents) is used instead of K3PO4 and H2O (10% v / v toluene) is also added.

[0490] Method-1j Similar to Method-1, except that step 3 is performed in a similar manner as described in step 3 of Method-9, using Et3N and acryloyl chloride in CH2Cl2.

[0491] Method-1k Similar to Method-1, except that step 3 is performed using iPr2NEt and acryloyl chloride in CH2Cl2 as described in step 3 of Method-9.

[0492] Examples 2 to 44 in Table 1 below were prepared using a method similar to Method 1, from intermediates described in the intermediate synthesis section or commercially available intermediates (in step 1).

[0493] Table 1

[0494] Example 45a / 45b: 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-2'-(cyclopropylmethyl)-5-methyl-1H,2'H-[3,3'-dipyrazol]-1-yl)-2-azaspiro[3.3]hept-2-yl)prop-2-en-1-one

[0495] Using a method similar to steps 2 and 3 of Method-1b, by tert-butylThe title example was prepared by 6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2'-(cyclopropylmethyl)-5-methyl-1H,2'H-[3,3'-dipyrazol]-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (prepared as described below). Isomers were separated by chiral SFC (C-SFC-2; mobile phase: CO2 / MeOH: 72 / 28) to give the title compound example 45a as the second elution peak: 1 H NMR (400 MHz, DMSO-) d 6) δ 13.12 (s, 1H), 7.54 (s, 1H), 7.46 (s, 1H), 7.15 (d, 1H), 6.32 (m, 1H), 6.10 (m, 1H), 5.67 (m, 1H), 5.45 (d, 1H), 4.96 (m, 1H), 4.38(s, 1H), 4.36 - 4.21 (m, 3H), 4.09 (s, 1H), 4.00 (s, 1H), 2.90 - 2.78 (m,4H), 2.47 (s, 3H), 2.04 (s, 3H), 1.32 - 1.22 (m, 1H), 0.49 - 0.29 (m, 4H); UPLC-MS-3: Rt = 0.97 min; MS m / z [M+H] + 516.3 / 518.3; C-SFC-3 (mobile phase: CO2 / MeOH: 72 / 28): Rt = 2.27 min. Another isomer, example 45b, was obtained as the first elution peak: C-SFC-3 (mobile phase: CO2 / MeOH: 72 / 28): Rt = 1.19 min.

[0496] tert-butyl 6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2'-(cyclopropylmethyl)-5-methyl-1H,2'H-[3,3'-dipyrazole]-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate.

[0497] Will tert-butyl6-(3-bromo-4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (intermediate C1, 300 mg, 0.47 mmol), 1-(cyclopropylmethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1H-pyrazole (175 mg, 0.71 mmol), and PdCl2(dppf).CH2Cl2 adduct (38.5 mg, 0.047 mmol) were suspended in acetonitrile (2.25 mL). Aqueous Na₂CO₃ (2 M, 0.48 mL, 0.97 mmol) was added, and the suspension was washed with argon and subjected to microwave irradiation at 120°C for 20 min. The reaction mixture was allowed to reach RT, diluted with EtOAc, and saturated aqueous NaHCO₃ solution was added to separate the layers. The aqueous layer was extracted with EtOAc (x2), and the combined organic extracts were washed with brine and dried (MgSO₄), filtered, and concentrated to half volume. SiliaMetS® Thiol (100 mg) was added, and the mixture was stirred at RT for 15 min, filtered, and concentrated. The crude residue was purified by normal-phase rapid column chromatography (elution: EtOAc from 20% to 70% in c-hexane) to give the title compound. UPLC-MS-3: Rt = 1.28 min; MS m / z [M+H] + ;646.3 / 648.2.

[0498]

[0499] Example 46a / 46b: 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(pyridin-2-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]hept-2-yl)prop-2-en-1-one

[0500] Using a method similar to steps 2 and 3 of Method-1b, by tert-butyl The title example was prepared from 6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(pyridin-2-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (prepared as described below). Isomers were separated by chiral SFC (C-SFC-2; mobile phase: CO2 / MeOH: 63 / 37) to give the title compound example 46a as the first elution peak: 1 H NMR (400 MHz, DMSO- d6) δ 13.0 (s, 1H), 8.16(d, 1H), 7.69 (t, 1H), 7.66 (d, 1H), 7.47 (s, 1H), 7.40 (s, 1H), 7.12 (t, 1H), 6.33 (m, 1H), 6.12 (m, 1H), 5.69 (m, 1H), 4.94 (m, 1H), 4.40 (s, 1H), 4.33 (s, 1H), 4.11 (s, 1H), 4.04 (s, 1H), 2.92 - 2.79 (m, 4H), 2.46 (s, 3H), 2.03 (s, 3H); UPLC-MS-3: Rt = 0.84 min; MS m / z [M+H] + 473.2 / 475.2; C-SFC-3 (mobile phase: CO2 / MeOH: 65 / 35): Rt = 0.97 min. Another isomer example 46b was obtained as the second elution peak: C-SFC-3 (mobile phase: CO2 / MeOH: 65 / 35): Rt = 3.28 min.

[0501] tert-butyl 6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(pyridin-2-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0502] Towards tert-butyl 6-(3-bromo-4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (intermediate C1, 1.35 g, 2.23 mmol) and bis(tri-tert-butylphosphine)palladium (68 mg, 0.13 mmol) in THF (3 mL) were placed under argon atmosphere. of2-Pyridyl zinc bromide (0.5 M in THF, 14.0 mL, 7.00 mmol) was added to the solution. The reaction mixture was heated at 70°C for 3 h. The RM was poured into a saturated aqueous solution of NaHCO3 and extracted with EtOAc (x2). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. The crude residue was dissolved in THF (20 mL), SiliaMetS® Thiol (1.3 mmol) was added, and the mixture was stirred at RT for 1 h, filtered, and concentrated. The crude residue was purified by normal-phase chromatography (eluent: MeOH in CH2Cl2 from 0% to 5%) to give a mixture containing the desired material, which was further purified by normal-phase chromatography (eluent: EtOAc) to give the title compound. UPLC-MS-3: Rt = 1.22 min; MS m / z [M+H] + ;603.3 / 605.2.

[0503]

[0504] Example 47a / 47b: 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(4-(hydroxymethyl)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hept-2-yl)prop-2-en-1-one

[0505] To a solution of 4-(4-(5-chloro-6-methyl-1H-indazole-4-yl)-5-methyl-1-(2-azaspiro[3.3]hept-6-yl)-1H-pyrazol-3-yl)benzylacetate trifluoroacetate (prepared as described below, 0.7 mmol) in THF (12 mL) and water (0.3 mL), NaHCO3 (588 mg, 7.0 mmol) and acryloyl chloride (70 μL, 0.84 mmol) were added sequentially, and the reaction mixture was stirred at RT for 2.5 h. LiOH (2 M, 3.50 mL, 7.00 mmol) was added, and the mixture was stirred at RT for RM for 45 min until the byproducts generated by the reaction of acryloyl chloride with indazole NH disappeared (UPLC). RM was diluted with water and extracted with EtOAc (x2). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and evaporated. The crude residue was dissolved in THF (12 mL), LiOH (2 M, 3.50 mL, 7 mmol) was added, and the reaction mixture was stirred at RT for 2 h. RM was diluted with water and extracted with EtOAc (x2). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and evaporated. The crude residue was purified by reversed-phase HPLC (RP-HPLC-1), and the purified fraction was neutralized with a saturated aqueous solution of NaHCO3 and extracted with EtOAc. The organic extracts were washed with brine, dried (Na2SO4), filtered, and evaporated. Isomers were separated by chiral SFC (C-SFC-2; mobile phase: CO2 / IPA: 70 / 30) to give the title compound as the second elution peak. Example 47a: 1 H NMR (400 MHz, DMSO- d 6) δ 13.12 (s, 1H), 7.54 (s, 1H), 7.40 (s, 1H), 7.19 (d, 2H), 7.08 (d,2H), 6.32 (m, 1H), 6.11 (m, 1H), 5.68 (m, 1H), 5.08 (t, 1H), 4.89 (m, 1H), 4.39 - 4.37 (m, 3H), 4.32 (s, 1H), 4.10 (s, 1H), 4.02 (s, 1H), 2.91 - 2.76(m, 4H), 2.48 (s, 3H), 2.01 (s, 3H); UPLC-MS-3: Rt = 0.88 min; MS m / z [M+H] +502.1 / 504.1; C-SFC-3 (mobile phase: CO2 / IPA: 70 / 30): Rt = 3.78 min. Another isomer example 47b was obtained as the first elution peak: C-SFC-3 (mobile phase: CO2 / IPA: 70 / 30): Rt = 2.85 min.

[0506] 4-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1-(2-azaspiro[3.3]hept-6-yl)-1H-pyrazol-3-yl)benzyl acetate trifluoroacetate

[0507] Using a method similar to steps 1 and 2 of Method-1, by tert-butyl The title compound was prepared from 6-(3-bromo-4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (intermediate C1) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)benzylacetate [562098-08-2]; UPLC-MS-6: Rt = 0.80 min; MS m / z [M+H] + 490.2 / 492.2.

[0508]

[0509] Example 48: 1-(4-(1-(2-acryloyl-2-azaspiro[3.3]hept-6-yl)-4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1H-pyrazol-3-yl)benzyl)pyrrolidine-2-one

[0510] Using a method similar to steps 2 and 3 of Method-1b, by tert-butyl Preparation of title example of 6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-3-(4-((2-oxopyrrolidine-1-yl)methyl)phenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (prepared as described below). 1 H NMR (400 MHz, DMSO- d6) δ 13.12 (s, 1H), 7.54 (s, 1H), 7.41 (s, 1H), 7.23 (d, 2H), 6.99 (d,2H), 6.32 (m, 1H), 6.10 (m, 1H), 5.67 (m, 1H), 4.89 (m, 1H), 4.37 (s, 1H), 4.31 (s, 1H), 4.25 (s, 2H), 4.09 (s, 1H), 4.02 (s, 1H), 3.14 (t, 2H), 2.93 -2.73 (m, 4H), 2.47 (s, 3H), 2.24 (t, 2H), 2.00 (s, 3H), 1.87 (p, 2H); UPLC-MS-3: Rt = 0.92 min; MS m / z [M+H] + 569.3 / 571.3.

[0511] tert-butyl 6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-3-(4-((2-oxopyrrolidone-1-yl)methyl)phenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0512] Will tert-butyl6-(3-bromo-4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (intermediate C1, 300 mg, 0.47 mmol) and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)benzyl)pyrrolidine-2-one (intermediate B2, 473 mg, 0.94 mmol) were suspended in DMF (3.95 mL). Aqueous K₃PO₄ (1 M, 0.94 mL, 0.942 mmol) and Pd(Ph₃P)₄ (27.2 mg, 0.024 mmol) were added, and the suspension was washed with argon and subjected to microwave irradiation at 120°C for 45 min. The reaction mixture was allowed to reach RT, diluted with EtOAc, and saturated aqueous NaHCO₃ solution was added to separate the layers. The aqueous layer was extracted with EtOAc (x2), and the combined organic extracts were washed with brine and dried (MgSO₄), filtered, and concentrated. The crude residue was purified by normal-phase rapid column chromatography (elution buffer: (MeOH / CH₂Cl₂ 9 / 1) from 0% to 50% in CH₂Cl₂) to give the title compound. UPLC-MS-3: Rt = 1.22 min; MS m / z [M+H] + ;699.4 / 701.4.

[0513]

[0514] Examples 49a / 49b: 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(3-methylpyridin-4-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]hept-2-yl)prop-2-en-1-one

[0515] Using a method similar to steps 2 and 3 of Method-1b, by tert-butyl The title example was prepared by 6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-3-(3-methylpyridin-4-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (prepared as described below). The isomers were separated by chiral HPLC C-HPLC-23 (mobile phase: hexane / IPA / ACN 60 / 28 / 12; flow rate: 20 mL / min; UV: 227 nM) to give the title compound example 49a as the second elution peak: 1 H NMR (400 MHz, DMSO- d6) δ 13.11 (s, 1H), 8.35 (s, 1H), 8.13 (d, 1H), 7.50 (s, 1H), 7.45 (s, 1H), 6.79 (d, 1H), 6.34 (m, 1H), 6.13(m, 1H), 5.70 (m, 1H), 4.97 (m, 1H), 4.39 (s, 1H), 4.30 (s, 1H), 4.11 (s,1H), 4.00 (s, 1H), 2.89 (m, 4H), 2.44 (s, 3H), 2.13 (s, 3H), 2.03 (s, 3H); LCMS-2: Rt = 1.39 min; MS m / z [M+H] + = 487.9 / 490.0; C-HPLC-24 (mobile phase: 0.1% DEA gradient in hexane / IPA / ACN; UV: 262 nM): Rt = 10.3 min. Another isomer example 49b was obtained as the first elution peak: C-HPLC-24 (mobile phase: 0.1% DEA gradient in hexane / IPA / ACN, UV: 262 nM): Rt = 8.98 min.

[0516] tert-butyl 6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-3-(3-methylpyridin-4-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate.

[0517] Will tert-butyl 6-(3-bromo-4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (intermediate C1, 0.40 g, 0.66 mmol), 3-methylpyridin-4-boronic acid (0.27 g, 1.98 mmol) and K3PO4 (0.42 g, 1.98 mmol) were dissolved in t-BuOH : H2O (5:1) (24 mL) and degassed the mixture with argon for 15 min. XPhos (0.094 g, 0.19 mmol) and Pd2dba3 (0.06 g, 0.07 mmol) were added, and the reaction mixture was stirred at 120°C under sealed conditions for 4 h. The reaction mixture was quenched with water and extracted with EtOAc (x3). The combined organic layers were washed with brine, dried (sodium sulfate), filtered, and concentrated under vacuum. The crude residue was purified by C18 (15 μm) reversed-phase chromatography (eluent: 0-68% CH3CN in H2O containing 0.1% HCOOH) to obtain the desired product. LCMS-1: Rt = 1.82 min; MS m / z [M+H] + ;617.7 / 620.6.

[0518]

[0519] Example 50a / 50b: 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(4-(1,1-thiomorpholino)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta-2-yl)prop-2-en-1-one

[0520] The title examples were prepared from intermediate C1 and 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxane-2-yl)phenyl)thiomorpholine 1,1-dioxide (intermediate B15) using a similar scheme as described, for example, in 49a and 49b. The isomers were separated by chiral HPLC C-HPLC-23 (mobile phase: MeOH : ACN (80 : 20); flow rate: 15 mL / min; UV: 270 nM) to give the title compound example 50a as the first elution: 1 H NMR (400 MHz, CDCl3) δ10.12 (s, 1H), 7.55 (s, 1H), 7.42 (s, 1H), 7.34 (d, 2H), 6.73 (d, 2H), 6.42(m, 1H), 6.29 (m, 1H), 5.75 (m, 1H), 4.79 (m, 1H), 4.41 (s, 1H), 4.38 (s,1H), 4.27 (s, 2H), 3.80 (m, 4H), 3.15 (m, 2H), 3.05 (m, 4H), 2.86 (m, 2H),2.60 (s, 3H), 2.09 (s, 3H); LCMS-2: Rt = 1.53 min; MS m / z [M+H]+ Example 50b, another isomer obtained as the second elution peak: C-SFC-19 (mobile phase: CO2 / MeOH / ACN 55 / 22.5 / 22.5; UV: 270 nM): Rt = 6.77 min. The mobile phase was CO2 / MeOH / ACN 55 / 22.5 / 22.5; UV: 270 nM: Rt = 10.8 min.

[0521]

[0522] Example 51a / 51b: 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(thiazolyl-4-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]hept-2-yl)prop-2-en-1-one

[0523] Using a method similar to steps 2 and 3 of Method-1b, by tert-butyl The title example was prepared by 6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-3-(thiazolyl-4-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (prepared as described below). The isomers were separated by chiral HPLC C-HPLC-23 (mobile phase: [hexane + 0.1% Et2NH] / [IPA + 0.1% Et2NH] / CH3CN (60 / 28 / 12); flow rate: 20 mL / min; UV: 216 nM) to give the title compound example 51a as the first elution peak: 1 H NMR (400 MHz, DMSO-d6) δ 13.07(s, 1H), 8.84 (s, 1H), 7.49 (s, 1H), 7.39 (s, 1H), 7.34 (s, 1H), 6.32 (m,1H), 6.12 (m, 1H), 5.67 (m, 1H), 4.92 (m, 1H), 4.38 (s, 1H), 4.30 (s, 1H), 4.09 (s, 1H), 4.00 (s, 1H), 2.84 - 2.78 (m, 4H), 2.46 (s, 3H), 2.02 (s, 3H); LCMS-1: Rt = 1.49 min; MS m / z [M+H] +: 479.3 / 481.3; C-HPLC-24 (mobile phase: 0.1% DEA gradient in hexane / IPA / CH3CN): Rt = 10.0 min. Another isomer, example 51b, was obtained as the second elution peak: C-HPLC-24 (mobile phase: 0.1% DEA gradient in hexane / IPA / CH3CN): Rt = 12.3 min.

[0524] tert-butyl 6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-3-(thiazolyl-4-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate.

[0525] Will tert-butyl 6-(3-bromo-4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (intermediate C1, 0.30 g, 0.49 mmol), 4-(tributylmethyltinyl)thiazole (0.28 g, 0.74 mmol) and anhydrous LiCl (0.03 g, 0.74 mmol) were suspended in dry toluene and the mixture was degassed with nitrogen for 10 min. The reaction mixture was then heated to 100°C for 16 h in a sealed tube. The RM was filtered through a diatomaceous earth pad and washed with ethyl acetate. The filtrate was concentrated under vacuum, and the crude residue was purified by C18 (15 μm) reversed-phase chromatography (eluent: 0-100% CH3CN in H2O containing 0.1% HCOOH) to obtain the title product. LCMS-1: Rt = 2.06; 2.08 min; MS m / z [M+H] + : 609.8 / 611.8.

[0526]

[0527] Examples 52a / 52b: 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(4-(2-hydroxyethoxy)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hept-2-yl)prop-2-en-1-one

[0528] Step 1: tert-butyl6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-3-(4-(2-hydroxyethoxy)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0529] Will tert-butyl 6-(3-bromo-4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (intermediate C1, 0.50 g, 0.83 mmol), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenoxy)ethanol-1-ol (0.22 g, 0.83 mmol) and K3PO4 (0.52 g, 2.48 mmol) were added to 1,4-dioxane:H2O (2:1) (12 mL) and the mixture was degassed with nitrogen for 10 min. RuPhos (0.038 g, 0.08 mmol) and RuPhos-Pd-G3 (0.034 g, 0.08 mmol) were added, and the reaction mixture was stirred at 100°C for 2 h. After the reaction was complete, RM was poured into water and extracted with EtOAc (x2). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated under vacuum. The crude residue was purified by normal-phase chromatography (elution: 0-60% EtOAc in hexane) to obtain the title product. LCMS-1: Rt = 2.05, 2.09 min; MS m / z [M+H] + : 662.7.3 / 664.7.

[0530] Step 2: tert-butyl 6-(3-(4-(2-acetoxyethoxy)phenyl)-4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0531] Will tert-butyl6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-3-(4-(2-hydroxyethoxy)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (0.45 g, 0.68 mmol) was dissolved in CH2Cl2 (5 mL). Et3N (0.21 g, 2.03 mmol) was added and the reaction mixture was cooled to 0°C under a nitrogen atmosphere and stirred for 10 min. Acetyl chloride (0.08 g, 1.02 mmol) was added dropwise to CH2Cl2 (0.5 mL) and the reaction mixture was stirred at RT for 2 h. After the reaction was complete, RM was diluted with CH2Cl2, washed with water and brine, dried (Na2SO4), filtered, and concentrated under vacuum to provide the title product, which was used directly in the next step without further purification. LCMS-1: Rt = 2.14, 2.16 min; MS m / z [M+H] + : 704.6 / 706.6.

[0532] Step 3: 2-(4-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1-(2-azaspiro[3.3]hept-6-yl)-1H-pyrazol-3-yl)phenoxy)ethyl acetate

[0533] Will tert-butyl 0.68 mmol of 6-(3-(4-(2-acetoxyethoxy)phenyl)-4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate was dissolved in dry CH2Cl2 (5 mL) and cooled to 0°C. TFA (6 mL) was added and the reaction mixture was stirred at room temperature for 5 h. After the reaction was complete, RM was concentrated under vacuum and co-distilled several times with CH2Cl2 to provide a crude residue. This crude residue was purified by grinding with diethyl ether and filtered to obtain the desired product, which was used directly in the next step without further purification. LCMS-1: Rt = 1.49 min; MS m / z [M+H] + :520.4.

[0534] Step 4: 2-(4-(1-(2-Acryloyl-2-azaspiro[3.3]hept-6-yl)-4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1H-pyrazole-3-yl)phenoxy)ethyl acetate

[0535] Ethyl 2-(4-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1-(2-azaspiro[3.3]hept-6-yl)-1H-pyrazol-3-yl)phenoxy)ethyl acetate (0.22 g, 0.42 mmol) was dissolved in THF (2 mL). NaHCO3 (0.35 g, 4.15 mmol) in water (2.5 mL) was added and the reaction mixture was stirred at RT for 10 min. The reaction mixture was cooled to 0°C and a solution of acryloyl chloride (0.04 g, 0.46 mmol) in THF (0.5 mL) was added dropwise and stirred for 40 min. After the reaction was complete, RM was diluted with water and extracted with EtOAc (x2). The combined organic layers were washed with water and brine, dried (Na2SO4), filtered, and concentrated under vacuum. The crude residue was purified by reversed-phase chromatography on C18 silica gel (15 μm) (elution buffer: 0-43% CH3CN in H2O containing 0.1% NH3) to provide the desired product. Isomers were separated by chiral HPLC C-HPLC-23 (mobile phase: hexane / IPA / ACN 70 / 21 / 9; flow rate: 18 mL / min; UV: 264 nM) to give the title compound isomer-I as the first elution peak: LCMS-1: Rt = 1.63 min; MS m / z [M+H] + 574.8; C-HPLC-29 (mobile phase: hexane / IPA gradient): Rt = 11.8 min. Another isomer, -II, was obtained as the second elution peak: LCMS-1: Rt = 1.63 min; MS m / z [M+H] + Rt = 574.8; C-HPLC-29 (mobile phase: hexane / IPA gradient): Rt = 13.8 min.

[0536] Step 5: Example 52a: 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(4-(2-hydroxyethoxy)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hept-2-yl)prop-2-en-1-one

[0537] The title example was prepared using a similar method as described in Example 52b for the preparation of 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(4-(2-hydroxyethoxy)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hept-2-yl)prop-2-en-1-one (step 6), starting with 2-(4-(1-(2-acryloyl-2-azaspiro[3.3]hept-6-yl)-4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1H-pyrazol-3-yl)phenoxy)ethyl acetate isomer-II instead of isomer-I; LCMS-3: Rt = 3.30 min; MS m / z [M+H] + : 532 / 534; 1 ¹H NMR (400 MHz, CD₃OD) δ 7.49 (s, 1H), 7.39 (s, 1H), 7.23 (d, 2H), 6.75 (d, 2H), 6.39 (m, 1H), 6.28 (m, 1H), 5.77 (m, 1H), 5.01 (m, 1H), 4.48 (s, 1H), 4.42 (s, 1H), 4.24 (s, 1H), 4.19 (s, 1H), 3.96 (m, 2H), 3.82 (m, 2H), 3.05 (m, 2H), 2.88 (m, 2H), 2.55 (s, 3H), 2.09 (s, 3H); C-HPLC-29 (mobile phase: [hexane + [0.1% Et2NH] / [IPA + 0.1% Et2NH] gradient): Rt = 11.2 min.

[0538] Step 6: Example 52b: 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(4-(2-hydroxyethoxy)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hept-2-yl)prop-2-en-1-one

[0539] The isomer-I of 2-(4-(1-(2-acryloyl-2-azaspiro[3.3]hept-6-yl)-4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1H-pyrazol-3-yl)phenoxy)ethyl acetate (0.05 g, 0.08 mmol) was dissolved in MeOH (2.5 mL) and cooled to 0°C. LiOH·H2O (1 M in water, 0.08 mL, 0.08 mmol) was added dropwise and the reaction mixture was stirred at RT for 1 h. After the reaction was complete, RM was diluted with water and extracted with EtOAc (x2). The combined organic layers were washed with water and brine, dried (Na2SO4), filtered, and concentrated under vacuum. The crude residue was purified by reversed-phase chromatography on C18 silica gel (15 μm) (eluent: 0-40% CH3CN in H2O containing 0.025% NH3) to provide the title product: C-HPLC-29 (mobile phase: [hexane + 0.1% Et2NH] / [IPA + 0.1% Et2NH] gradient): Rt = 9.37 min.

[0540]

[0541] Example 53: 1-(6-(3-(6-(3-amino-1H-pyrazol-1-yl)pyridin-3-yl)-4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta-2-yl)prop-2-en-1-one

[0542] The title example was prepared from tert-butyl 6-(3-(6-(3-amino-1H-pyrazol-1-yl)pyridin-3-yl)-4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (prepared in step 2 as described below) using a method similar to steps 2 and 3 of Method-1b. 1 H NMR (400 MHz, DMSO-) d6) δ 13.23 (s, 1H), 8.12 (s, 1H), 7.90 - 7.86 (m, 2H), 7.59(s, 1H), 7.49 (m, 2H), 6.36 (m, 1H), 6.13 (m, 1H), 5.73 (s, 1H), 5.69 (m 2H),5.26 (s, 2H), 4.93 (m, 1H), 4.39 (s, 1H), 4.32 (s, 1H), 4.1 (s, 1H), 4.03 (s,1H), 2.89 - 2.79 (m, 4H), 2.03 (s, 3H); LCMS-1: Rt = 1.53 min; MS m / z [M+H] + : 554.8 / 556.8.

[0543] tert-butyl 6-(3-(6-(3-amino-1H-pyrazol-1-yl)pyridin-3-yl)-4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0544] Step 1: tert-butyl 6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-3-(6-(3-nitro-1H-pyrazol-1-yl)pyridin-3-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0545] Will tert-butyl6-(3-bromo-4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (intermediate C1, 0.50 g, 0.83 mmol), 2-(3-nitro-1H-pyrazol-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyridine (intermediate B16) (0.52 g, 1.65 mmol) and K3PO4 (0.53 g, 2.48 mmol) were dissolved in 1,4-dioxane (4 mL) and H2O (2 mL). The reaction mixture was degassed with N2 for 5 min. Ruphos (0.04 g, 0.08 mmol) and Ruphos-Pd-G3 (0.035 g, 0.04 mmol) were added, and the reaction mixture was stirred at 120°C for 1 h. After the reaction was complete, RM was diluted with water and extracted with ethyl acetate (x2). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated under vacuum. The crude residue was purified by normal-phase chromatography (elution: 30%–40% EtOAc in hexane) to obtain the desired product. LCMS-1: Rt = 2.24 min; MS m / z [M+H] + : 714.6 / 716.5.

[0546] Step 2: tert-butyl 6-(3-(6-(3-amino-1H-pyrazol-1-yl)pyridin-3-yl)-4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0547] Under a nitrogen atmosphere, tert-butyl 6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-3-(6-(3-nitro-1H-pyrazol-1-yl)pyridin-3-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (0.53 g, 0.7 mmol) was dissolved in dry IPA. 10% dry Pd / C (0.25 g) was added and the reaction mixture was stirred at RT for 1 h under H2 (1 atm) atmosphere. RM was filtered through a diatomaceous earth pad and the filtrate was concentrated under vacuum to provide the desired product, which was used directly for the next step without further purification. LCMS-1: Rt = 2.06, 2.09 min; MS m / z [M+H] + : 684.5 / 686.5.

[0548] Method-2 Synthesis scheme

[0549] Example 1a: a( R )-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta-2-yl)prop-2-en-1-one and 1b:a( S )-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta-2-yl)prop-2-en-1-one

[0550] Alternatively, Examples 1a and 1b can be prepared according to the following method: Step 1: tert-butyl 6-(5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate Under an argon atmosphere, towards tert-butyl 6-(3-bromo-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (intermediate C3, 2.00 g, 5.61 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxanepentoboron-2-yl)-1H-indazole (1.59 g, 6.18 mmol), and K3PO4 (3.57 g, 16.8 mmol) were added to a stirred solution of dioxane (20 mL) and H2O (4 mL) along with RuPhos (0.26 g, 0.56 mmol) and RuPhos-Pd-G3 (0.47 g, 0.56 mmol). The reaction mixture was stirred at 100°C for 1 h. The reaction mixture was quenched by adding saturated aqueous NaHCO3 solution, extracted with EtOAc (2x), and the combined organic extracts were washed with saturated aqueous NaHCO3 solution, dried (Na2SO4), and evaporated. The crude residue was purified by normal-phase chromatography (elution: EtOAc in C-hexane from 0 to 90%) to give the title compound as a brown solid. UPLC-MS-3: Rt = 1.14 min; MS m / z [M+H] + :408.2.

[0551] Step 2: tert-butyl6-(4-iodo-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0552] Under an argon atmosphere, towards tert-butyl 6-(4-iodo-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (2.13 g, 5.23 mmol) was added to a stirred solution of NIS (1.53 g, 6.80 mmol) in THF (50 mL), and the reaction mixture was stirred at RT for 1 h. The reaction mixture was quenched by adding saturated NaHCO3 aqueous solution, extracted with EtOAc (2x), and the combined organic extracts were washed with saturated NaHCO3 aqueous solution, dried (Na2SO4), filtered, and evaporated. The crude residue was purified by normal phase chromatography (elution: EtOAc from 0 to 80% in c-hexane) to give the title compound as a brown solid. UPLC-MS-3: Rt = 1.22 min; MS m / z [M+H] + :534.1.

[0553] Step 3: tert-Butyl 6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0554] Under an argon atmosphere, towards tert-butyl6-(4-iodo-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (100 mg, 0.187 mmol), 5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxanepentoborane-2-yl)-1H-indazole (intermediate D1, 85 mg, 0.225 mmol) and K3PO4 (119 mg, 0.56 mmol) were added to a stirred solution of dioxane (2 mL) and H2O (0.50 mL) with RuPhos (8.75 mg, 0.019 mmol) and RuPhos-Pd-G3 (15.7 mg, 0.019 mmol). The reaction mixture was degassed with N2 and stirred at 100°C for 1 h. The reaction mixture was quenched by adding saturated NaHCO3 aqueous solution, extracted with EtOAc (2x), and the combined organic extracts were washed with saturated NaHCO3 aqueous solution, dried (Na2SO4), filtered, and evaporated. The crude residue was diluted in THF (3 mL), SiliaMetS® thiol (0.076 mmol) (i.e., functionalized silica gel designed to remove metals from the reaction mixture), and the mixture was vortexed at 40°C for 1 h. The mixture was filtered, the filtrate was concentrated, and the crude residue was purified by normal-phase chromatography (elution: EtOAc in c-hexane 0 to 100%) to give the title compound as a yellow solid. UPLC-MS-3: Rt = 1.25 min; MS m / z [M+H] + : 656.3 / 658.3.

[0555] Perform as described in Method-1 Steps 4 and 5 Chiral separation from isomers.

[0556] Method-2a Similar to Method-2, except that step 4 is performed using sulfuric acid in dioxane as described in step 2 of Method-1a.

[0557] Method-2b Similar to Method-2, except that step 5 is performed using acryloyl chloride and NaHCO3 in THF / water as described in step 3 of Method-1b.

[0558] Method-2c Similar to Method-2, except that NBS is used instead of NIS in step 2.

[0559] Method-2d Similar to Method-2, except that step 3 is performed using Et3N and acryloyl chloride in CH2Cl2 as described in step 3 of Method-9.

[0560] Examples 54 to 58 in Table 2 below were prepared using a method similar to that of Method-2, from intermediates described in the intermediate synthesis section or commercially available intermediates (in step 1 or 3).

[0561] Table 2

[0562] Examples 59a / 59b: 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1H-pyrrolo[2,3-c]pyridin-2-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]hept-2-yl)prop-2-en-1-one

[0563] Using a method similar to steps 3 to 5 of methods-2a and b, by tert-butyl The title example was prepared from 6-(4-bromo-5-methyl-3-(1H-pyrrolo[2,3-c]pyridin-2-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (prepared as described below). Isomers were separated by chiral SFC (C-SFC-7; mobile phase: CO2 / [MeOH + 0.1% NEt3]: 50 / 50) to give the title compound example 59a as the second elution peak: 1 H NMR (600 MHz, DMSO- d 6) δ 13.20 (d,1H), 11.68 (s, 1H), 8.71 (s, 1H), 7.92 (d, 1H), 7.63 (s, 1H), 7.50 (s, 1H),7.20 (d, 1H), 6.52 (s, 1H), 6.41 - 6.28 (m, 1H), 6.17 - 6.02 (m, 1H), 5.74 -5.61 (m, 1H), 5.06 - 4.87 (m, 1H), 4.42 (s, 1H), 4.34 (s, 1H), 4.13 (s, 1H), 4.05 (s, 1H), 3.04 - 2.91 (m, 2H), 2.84 (s, 2H), 2.53 (s, 3H), 2.04 (s, 3H); UPLC-MS-3: Rt = 0.77 min; MS m / z [M+H] +512.2 / 514.2; C-SFC-8 (mobile phase: CO2 / [MeOH + 0.1% NEt3]: 50 / 50): Rt = 2.43 min. Another isomer example 59b was obtained as the first elution peak: C-SFC-8 (mobile phase: CO2 / [MeOH + 0.1% NEt3]: 50 / 50): Rt = 1.28 min.

[0564] tert-butyl 6-(4-bromo-5-methyl-3-(1H-pyrrolo[2,3-c]pyridin-2-yl)-1H-pyrazol-1-yl)-2-azaspiro[3,3]heptane-2-carboxylate

[0565] Towards tert-butyl 6-(4-bromo-3-iodo-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (intermediate C7, 400 mg, 0.83 mmol), (1H-pyrrolo[2,3-c]pyridin-2-yl)boronic acid (202 mg, 1.24 mmol), and potassium phosphate (2M aqueous solution, 1.24 mL, 2.48 mmol) were added to a stirred solution of 1,4-dioxane (10 mL) with tetrakis(triphenylphosphine)palladium (96 mg, 0.08 mmol). The reaction mixture was stirred at 90°C for 1 h. Then, it was allowed to cool to RT, diluted with water (10 mL), and extracted twice with EtOAc. The combined organic layers were concentrated, and the residual crude material was purified by normal-phase rapid column chromatography (elution: MeOH in CH2Cl2 from 0 to 5%) to give the title compound. UPLC-MS-4: Rt= 4.19 min; MS m / z [M+H] + :472.0 / 474.0.

[0566] Example 60a / 60b: 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-fluoro-4-(2-methoxyethoxy)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hept-2-yl)prop-2-en-1-one

[0567] Using a method similar to method-2c from tert-butyl The preparation of the title example (described below) begins with an additional alkylation step introduced between steps 1 and 2 using 6-(3-bromo-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (intermediate C3) and 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenol to prepare the product. tert-butyl 6-(3-(2-fluoro-4-(2-methoxyethoxy)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate). Isomers were separated by chiral SFC (C-SFC-1; mobile phase: CO2 / [IPA + 0.1% NEt3]: 70 / 30) to give example 60a of the title compound as the second elution peak: 1 H NMR (400 MHz, DMSO- d 6) δ 12.99(s, 1H), 7.44 (s, 1H), 7.37 (s, 1H), 7.18 (t, 1H), 6.68 - 6.60 (m, 2H), 6.35- 6.26 (m, 1H), 6.13 - 6.07 (m, 1H), 5.69 - 5.65 (m, 1H), 4.95 - 4.85 (m,1H), 4.38 (s, 1H), 4.28 (s, 1H), 4.09 (s, 1H), 4.02 - 3.99 (m, 3H), 3.60 -3.57 (m, 2H), 3.26 (s, 3H), 2.90 - 2.75 (m, 4H), 2.44 (s, 3H), 2.06 (s, 3H); UPLC-MS-3: Rt = 0.97 min; MS m / z [M+H] + 564.5 / 566.5; C-SFC-3 (mobile phase: CO2 / [IPA + 0.1% NEt3]: 70 / 30): Rt = 2.50 min. Another isomer example 60b was obtained as the first elution peak: C-SFC-3 (mobile phase: CO2 / [IPA + 0.1% NEt3]: 70 / 30): Rt = 1.74 min.

[0568] tert-butyl 6-(3-(2-fluoro-4-(2-methoxyethoxy)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0569] Will tert-butylA solution of 6-(3-(2-fluoro-4-hydroxyphenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (step 1, 710 mg, 1.65 mmol), 1-bromo-2-methoxyethane (0.310 mL, 3.30 mmol), and cesium carbonate (1075 mg, 3.30 mmol) in DMF (5 mL) was stirred at 60°C for 2 h. The reaction mixture was diluted with EtOAc and water, extracted with EtOAc, and the organic phase was washed with brine, dried (phase separator), and concentrated under reduced pressure. The crude residue was purified by normal-phase rapid column chromatography (elution buffer: c-hexane / EtOAc 100 / 0 to 70 / 30 within 30 min) to give the title compound. UPLC-MS-3: Rt = 1.20 min; MS m / z [M+H] + 446.3.

[0570]

[0571] Example 61a / 61b: 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-fluoro-4-((2-methoxyethyl)amino)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta-2-yl)prop-2-en-1-one

[0572] Using a method similar to method-2c from tert-butyl 6-(3-bromo-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carbamate (intermediate C3) and benzyl (3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl)carbamate are prepared by introducing an additional alkylation step between steps 1 and 2 and an additional hydrogenation step between steps 3 and 4. The title example (described below) is prepared to prepare tert-butyl 6-(3-(4-(((benzyloxy)carbonyl)(2-methoxyethyl)amino)-2-fluorophenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate and tert-butyl 6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-3-(2-fluoro-4-((2-methoxyethyl)amino)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate). Isomers were separated by chiral SFC (C-SFC-1; mobile phase: CO2 / [IPA + 0.1% NEt3]: 70 / 30) to give example 61a of the title compound as the second elution peak: 1H NMR (400 MHz, DMSO- d 6) δ 12.96 (s, 1H), 7.42 (s, 1H), 7.34 (s, 1H), 6.94 (t, 1H), 6.35 - 6.25 (m, 2H), 6.15 - 6.07(m, 2H), 5.86 (t, 1H), 5.69 - 5.64 (m, 1H), 4.91 - 4.81 (m, 1H), 4.37 (s,1H), 4.28 (s, 1H), 4.09 (s, 1H), 3.99 (s, 1H), 3.41 (t, 2H), 3.24 (t, 3H), 3.09 (q, 2H), 2.88 - 2.76 (m, 4H), 2.44 (s, 3H), 2.04 (s, 3H); UPLC-MS-3: Rt =0.94 min; MS m / z [M+H] + Example 61b, another isomer obtained as the first elution peak: C-SFC-3 (mobile phase: CO2 / [IPA + 0.025% NH3]: 70 / 30): Rt = 3.55 min. 563.5 / 565.5; C-SFC-3 (mobile phase: CO2 / [IPA + 0.025% NH3]: 70 / 30): Rt = 2.55 min.

[0573] tert-butyl 6-(3-(4-(((benzyloxy)carbonyl)(2-methoxyethyl)amino)-2-fluorophenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0574] In an inert atmosphere, towards tert-butyl6-(3-(4-(((benzyloxy)carbonyl)amino)-2-fluorophenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (step 1, 1.40 g, 2.55 mmol) was added to a stirred solution in DMF (20 mL) with sodium hydride (60% in mineral oil, 0.123 g, 3.07 mmol). After 15 min, 1-bromo-2-methoxyethane (1.20 mL, 12.8 mmol) was added and the reaction mixture was stirred overnight at RT. The reaction mixture was quenched with water, extracted with EtOAc, and the organic phase was washed with brine, dried (phase separator), and concentrated under reduced pressure. The crude residue was purified by normal-phase chromatography (eluent: c-hexane / EtOAc 100 / 0 to 70 / 30 over 30 min) to give the title compound. UPLC-MS-3: Rt = 1.30 min; MS m / z [M+H] + : 579.4.

[0575] tert-butyl 6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-3-(2-fluoro-4-((2-methoxyethyl)amino)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0576] Will tert-butyl A solution of 6-(3-(4-(((benzyloxy)carbonyl)(2-methoxyethyl)amino)-2-fluorophenyl)-4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (470 mg, 0.511 mmol) and palladium on carbon (5.44 mg, 0.051 mmol) in MeOH (10 mL) was stirred at RT for 0.5 h under a hydrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure. The crude residue was purified by normal-phase chromatography (elution: c-hexane / EtOAc 100 / 0 to 0 / 100 within 30 min) to give the title compound. UPLC-MS-3: Rt = 1.25 min; MS m / z [M+H] + : 693.4 / 695.4.

[0577] Method-3 Synthesis scheme

[0578] Example 62a / 62b: 4-(1-(2-acryloyl-2-azaspiro[3.3]hept-6-yl)-4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1H-pyrazol-3-yl)-N-(2-methoxyethyl)benzamide

[0579] Step 1: tert-butyl 6-(4-(5-chloro-6-methyl-1-toluenesulfonyl-1H-indazol-4-yl)-3-(4-(methoxycarbonyl)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0580] Will tert-butyl A solution of 6-(3-bromo-4-(5-chloro-6-methyl-1-toluenesulfonyl-1H-indazol-4-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (intermediate C6) (1.00 g, 1.26 mmol), methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)benzoate (0.40 g, 1.51 mmol), RuPhos (0.06 g, 0.13 mmol), RuPhos-Pd-G3 (0.10 g, 0.13 mmol) and potassium phosphate (2N, 1.89 mL, 3.78 mmol) in dioxane (8 mL) was stirred at 80°C for 1.5 h. The reaction mixture was cooled to RT, diluted with EtOAc and water, extracted with EtOAc, and the combined organic phases were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude residue was purified by normal-phase chromatography (eluent: c-hexane / EtOAc 100 / 0 to 50 / 50 over 30 min) to give the product containing some impurities. A second purification was performed by normal-phase chromatography (eluent: c-hexane / EtOAc 100 / 0 to 60 / 40 over 30 min) to yield the title compound (86% purity as measured by UPLC), containing some minor impurities. 1 H NMR (600 MHz, DMSO- d6) δ 8.19 (s, 1H), 7.89 (s, 1H), 7.79 (d, 2H), 7.67 (d, 2H), 7.41 (d,2H), 7.22 (d, 2H), 4.88 (m, 1H), 4.01 (m, 2H), 3.91 (m, 2H), 3.81 (s, 3H), 2.86 - 2.71 (m, 4H), 2.59 (s, 3H), 2.37 (s, 3H), 2.00 (s, 3H), 1.39 (s, 9H); UPLC-MS-10: Rt = 1.32 min; MS m / z [M+H] + : 730.2 / 732.2.

[0581] Step 2: 4-(1-(2-( Uncle (butoxycarbonyl)-2-azaspiro[3.3]hept-6-yl)-4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1H-pyrazole-3-yl)benzoic acid

[0582] Will tert-butyl A solution of 6-(4-(5-chloro-6-methyl-1-toluenesulfonyl-1H-indazol-4-yl)-3-(4-(methoxycarbonyl)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (step 1, 100 mg, 0.14 mmol) and LiOH (2N, 0.14 mL, 0.27 mmol) in THF (2 mL) was stirred at 20°C for 2.5 h. The mixture was heated to 45°C for 1.5 h, then to 70°C for 2.5 h. After cooling to RT, the reaction mixture was lyophilized, and the crude product was used for the next reaction without further purification. UPLC-MS-10: Rt = 1.32 min; MS m / z [M+H] + : 562.2 / 564.2.

[0583] Step 3: tert-butyl 6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(4-((2-methoxyethyl)carbamoyl)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0584] To 4-(1-(2-( Uncle(-Butoxycarbonyl)-2-azaspiro[3.3]hept-6-yl)-4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1H-pyrazol-3-yl)benzoic acid (step 2, 93 mg, 0.12 mmol) and DIPEA (0.10 mL, 0.59 mmol) in CH2Cl2 / DMF (2.5 mL, 4 / 1 ratio) were added to propylphosphonic anhydride (50% in EtOAc, 0.10 mL, 0.177 mmol) and the resulting solution was stirred at RT. After 10 min, 2-methoxyethyl-1-amine (0.03 mL, 0.35 mmol) was added and the reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated under reduced pressure and the crude residue was purified by normal-phase chromatography (eluent: c-hexane / EtOAc 100 / 0 to 0 / 100 over 30 min) to give the title compound. 1 H NMR (400 MHz, DMSO- d 6) δ 13.16 (s, 1H), 8.36 (t, 1H), 7.62 (d, 2H),7.57 (s, 1H), 7.43 (s, 1H), 7.29 (d, 2H), 4.88 (m, 1H), 4.02 (br s, 2H), 3.94(br s, 2H), 3.42-3.36 (m, 4H), 3.23 (s, 3H), 2.86-2.75 (m, 4H), 2.49 (s, 3H), 2.02 (s, 3H), 1.40 (s, 9H); UPLC-MS-10: Rt = 1.09 min;MS m / z [M+H] + :619.2 / 621.3.

[0585] Step 4: 4-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1-(2-azaspiro[3.3]hept-6-yl)-1H-pyrazol-3-yl)-N-(2-methoxyethyl)benzamide

[0586] Towards tert-butyl6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(4-((2-methoxyethyl)carbamoyl)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (step 3, 109 mg, 0.14 mmol) was added to a solution of TFA (0.33 mL, 4.28 mmol) in THF (2 mL) and the reaction mixture was stirred at RT for 3 h. The reaction mixture was concentrated under reduced pressure and the oily residue was dissolved in MeOH and placed in a Waters column pre-washed with MeOH (PoraPak). TM Rxn Cx. After rinsing with MeOH, the resin was washed with NH3 (7N in MeOH), and the alkaline MeOH solution was concentrated under reduced pressure to give the title compound, which was used for the next reaction without further purification. UPLC-MS-6: Rt = 0.72 min; MS m / z [M+H] + : 519.2 / 521.2.

[0587] Step 5: 4-(1-(2-Acryloyl-2-azaspiro[3.3]hept-6-yl)-4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1H-pyrazol-3-yl)-N-(2-methoxyethyl)benzamide

[0588] Sodium bicarbonate (0.80 mL, 0.40 mmol) was added to a solution of 4-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1-(2-azaspiro[3.3]hept-6-yl)-1H-pyrazol-3-yl)-N-(2-methoxyethyl)benzamide (step 4, 55 mg, 0.08 mmol) in THF (3 mL), followed by the direct addition of acryloyl chloride (6.54 µl, 0.08 mmol). The reaction mixture was stirred at 0 °C for 1 h. Excess acryloyl chloride was destroyed by adding LiOH (2N, 2 mL) and stirring at RT for 1 h. The reaction mixture was extracted with DCM, the organic phase was dried (phase separator), concentrated under reduced pressure, and the crude residue was purified by normal-phase chromatography (eluent: DCM / MeOH 100 / 0 to 90 / 10 over 30 min) to give the title compound. Isomers were separated by chiral SFC (C-SFC-2: mobile phase: CO2 / IPA: 65 / 35) to give example 62a (white powder) of the title compound as the second eluted isomer: 1 H NMR (400 MHz, DMSO- d6) δ 13.15 (s, 1H), 8.35 (t, 1H), 7.63 (d, 2H), 7.57 (s, 1H), 7.44 (s, 1H), 7.31 (d, 2H), 6.37-6.30 (m, 1H), 6.15-6.09 (m, 1H), 5.71-5.67 (m, 1H), 4.98-4.88 (m, 1H), 4.40(s, 1H), 4.34 (s, 1H), 4.11 (s, 1H), 4.04 (s, 1H), 3.35-3.32 (m, 4H), 3.22(s, 3H), 2.94-2.78 (m, 4H), 2.04 (s, 3H); UPLC-MS-10: Rt = 0.88 min; MS m / z [M+H] + 573.3 / 575.3; C-SFC-3: (mobile phase: CO2 / IPA: 65 / 35): Rt = 2.14 min. Another isomer example 62b was obtained as the first elution peak: C-SFC-3: (mobile phase: CO2 / IPA: 65 / 35): Rt = 1.28 min.

[0589] Method-3a Similar to Method-3, except that NaOH 2N is used instead of LiOH 2N in step 2.

[0590] Examples 63 to 65 in Table 3 below were prepared using a method similar to that of Method-3, employing appropriate commercially available pinacol (step 1) and amine reagent (step 3).

[0591] Table 3

[0592] Method 4 Synthesis scheme

[0593] Example 66a / 66b: 4-(1-(2-acryloyl-2-azaspiro[3.3]hept-6-yl)-4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1H-pyrazol-3-yl)-N-(2-methoxyethyl)-N-methylbenzamide

[0594] Step 1: tert-butyl 6-(3-(4-(methoxycarbonyl)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0595] Will tert-butyl A solution of 6-(3-bromo-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (intermediate C3, 1.51 g, 4.24 mmol), methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)benzoate (1.33 g, 5.09 mmol), RuPhos (0.198 g, 0.42 mmol), RuPhos-Pd-G3 (0.355 g, 0.42 mmol), and potassium phosphate (2N, 6.36 mL, 12.7 mmol) in dioxane (20 mL) was stirred at 80°C for 15 min. After cooling to RT, the reaction mixture was added to saturated aqueous NaHCO3, extracted with EtOAc, and the organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude residue was purified by normal-phase chromatography (elution buffer: c-hexane / EtOAc 100 / 0 to 70 / 30 over 30 min) to give the title compound. 1 H NMR (400 MHz, DMSO- d 6) δ7.99 (d, 2H), 7.91 (d, 2H), 6.60 (s, 1H), 4.80 -4.72 (m, 1H), 3.99 (s, 2H), 3.90 (s, 2H), 3.87 (s, 3H), 2.75 - 2.65 (m, 4H), 2.27 (s, 3H), 1.39 (s, 9H); UPLC-MS-6: Rt = 1.23 min; MS m / z [M+H] + :412.3.

[0596] Step 2: tert-butyl 6-(4-bromo-3-(4-(methoxycarbonyl)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0597] Towards tert-butyl6-(3-(4-(methoxycarbonyl)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (step 1, 1.76 g, 4.15 mmol) was added to a solution of NBS (0.724 g, 4.07 mmol) in CH3CN (45 mL), and the reaction mixture was stirred at RT for 0.5 h. The reaction mixture was concentrated under reduced pressure, and the crude residue was purified by normal-phase chromatography (elution: c-hexane / EtOAc 100 / 0 to 70 / 30 within 30 min) to obtain the title compound. 1 H NMR (400 MHz, DMSO- d 6) δ 8.06 (d, 2H), 8.00 (d, 2H), 4.91 - 4.83 (m,1H), 3.99 (s, 2H), 3.89 (s, 5H), 2.74 - 2.65 (m, 4H), 2.29 (s, 3H), 1.39 (s,9H); UPLC-MS-6: Rt = 1.31 min; MS m / z [M+H] + :490.1 / 492.1.

[0598] Step 3: tert-butyl 6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-3-(4-(methoxycarbonyl)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0599] Will tert-butylA solution of 6-(4-bromo-3-(4-(methoxycarbonyl)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (step 2, 1.00 g, 2.00 mmol), 5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1H-indazole (intermediate D1, 0.98 g, 2.60 mmol), RuPhos (0.093 g, 0.20 mmol), RuPhos-Pd-G3 (0.167 g, 0.20 mmol) and potassium phosphate (2N, 3.00 mL, 6.00 mmol) in dioxane (10 mL) was stirred at 80°C for 15 min. After cooling to RT, the reaction mixture was added to saturated aqueous NaHCO3, extracted with EtOAc, and the organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude residue was dissolved in THF (20 mL), SiliaMetS® thiol (0.60 mmol, 0.84 g) was added, and the mixture was vortexed at 50°C for 0.5 h on a rotary evaporator. The mixture was filtered, washed with MeOH, and the filtrate was concentrated under reduced pressure to give the crude product, which was purified by normal-phase chromatography (eluent: c-hexane / EtOAc 100 / 0 to 60 / 40 within 30 min) to give the title compound as a colorless foam. UPLC-MS-6: Rt = 1.31 min; MS m / z [M+H] + : 660.2 / 662.2.

[0600] Step 4: 4-(1-(2-( tert-butoxy Carbonyl)-2-azaspiro[3.3]hept-6-yl)-4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-1H-pyrazol-3-yl)benzoic acid

[0601] Will tert-butyl6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-3-(4-(methoxycarbonyl)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (step 3, 1.42 g, 1.99 mmol) and NaOH (2N, 1.00 mL, 2.00 mmol) in dioxane (10 mL) solution were stirred at 60°C for 15 min. More NaOH (2N, 1.00 mL, 2.00 mmol) was added and the reaction mixture was stirred overnight at RT, then the reaction mixture was warmed to 60°C for 3 h. The reaction mixture was lyophilized, and the crude product was used for the next step without further purification. 1 H NMR (400 MHz, DMSO- d 6) δ 7.78 (br s, 1H), 7.64 - 7.60 (m, 2H), 7.47 (s,0.5H), 7.45 (s, 0.5H), 7.16 - 7.13 (m, 2H), 5.85 - 5.80 (m, 1H), 4.91 - 4.83(m, 1H), 4.02 (br s, 2H), 3.95 -3.87 (m, 3H), 3.79 - 3.72 (m, 1H), 2.91 -2.68 (m, 4H), 2.39 - 2.32 (m, 1H), 2.01 - 1.94 (m, 5H), 1.74 - 1.70 (m, 1H),1.61 - 1.56 (m, 2H), 1.40 (s, 9H); UPLC-MS-6: Rt = 1.23 min; MS m / z [M+H] + : 646.2 / 648.2.

[0602] Step 5: tert-Butyl 6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-3-(4-((2-methoxyethyl)(methyl)carbamoyl)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0603] Propylphosphonic anhydride (0.27 mL, 0.46 mmol in EtOAc 50%) was added to a solution of 4-(1-(2-(tert-butoxycarbonyl)-2-azaspiro[3.3]hept-6-yl)-4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-1H-pyrazol-3-yl)benzoic acid (step 4, 250 mg, 0.31 mmol) and 2-methoxy-N-methylethyl-1-amine (0.067 mL, 0.61 mmol) in CH2Cl2 (3 mL). Then DIPEA (0.27 mL, 1.53 mmol) was added and the mixture was stirred at RT for 5 h. The reaction mixture was concentrated under reduced pressure and the crude residue was purified by normal-phase chromatography (eluent: c-hexane / EtOAc 100 / 0 to 0 / 100 over 30 min) to give the title compound. 1 H NMR (400MHz, DMSO- d 6) δ 7.79 (s, 1H), 7.51 (s, 0.5H), 7.49 (s, 0.5H), 7.30 - 7.27 (m,2H), 7.20 - 7.17 (m, 2H), 5.86 - 5.81 (m, 1H), 4.92 - 4.85 (m, 1H), 4.02 (s,2H), 3.94 - 3.87 (m, 3H), 3.79 - 3.72 (m, 1H), 3.58 - 3.24 (m, 6H), 3.09 (brs, 1H), 2.93 - 2.74 (m, 7H), 2.03 - 1.96 (m, 5H), 1.73 (m, 1H), 1.62 - 1.55(m, 2H), 1.40 (s, 9H); UPLC-MS-11: Rt = 1.24 min; MS m / z [M+H] + : 717.5 / 719.5.

[0604] Step 6: 4-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1-(2-azaspiro[3.3]hept-6-yl)-1H-pyrazol-3-yl)-N-(2-methoxyethyl)-N-methylbenzamide

[0605] Towards tert-butyl6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-3-(4-((2-methoxyethyl)(methyl)carbamoyl)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (step 5, 168 mg, 0.23 mmol) was added to a solution of TFA (0.52 mL, 6.82 mmol) in CH2Cl2 (2 mL) and the reaction mixture was stirred at RT for 4 h. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in dioxane and lyophilized to give the title compound as a trifluoroacetate salt, which was used for the next reaction without further purification. UPLC-MS-6: Rt = 0.73; MS m / z [M+H] + : 533.3 / 535.3.

[0606] Step 7: 4-(1-(2-Acryloyl-2-azaspiro[3.3]hept-6-yl)-4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1H-pyrazol-3-yl)-N-(2-methoxyethyl)-N-methylbenzamide

[0607] Propylphosphonic anhydride (0.20 mL, 0.34 mmol in EtOAc 50%) was added to a solution of 4-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1-(2-azaspiro[3.3]hept-6-yl)-1H-pyrazol-3-yl)-N-(2-methoxyethyl)-N-methylbenzamide (0.23 mmol) and acrylic acid (0.016 mL, 0.23 mmol) in CH2Cl2 (3 mL). Then DIPEA (0.198 mL, 1.13 mmol) was added and the reaction mixture was stirred at RT for 1.25 h. The reactants were quenched by the addition of MeOH, the reaction mixture was concentrated under reduced pressure, and the crude residue was purified by normal-phase chromatography (elution: DCM / MeOH 100 / 0 to 80 / 20 over 30 min) to give the title compound. Isomers were separated by chiral SFC (C-HPLC-11: mobile phase: n-heptane / IPA + 0.1% NEt3: 55 / 45) to give the title compound as the second elution peak. Example 66a: 1 H NMR (400 MHz, DMSO- d6) δ 13.15 (s, 1H), 7.57 (s, 1H), 7.45 (s, 1H), 7.30 (d, 2H), 7.18 (d, 2H), 6.37 - 6.30 (m, 1H), 6.15 - 6.09 (m, 1H), 5.71 -5.67 (m, 1H), 4.98 - 4.88 (m, 1H), 4.40 (s, 1H), 4.33 (s, 1H), 4.11 (s, 1H), 4.04 (s, 1H), 3.55 - 3.46 (m, 5H), 3.09 (br s, 2H), 2.91 - 2.81 (m, 6H), 2.03(s, 3H); UPLC-MS-3: Rt = 0.89 min; MS m / z [M+H] + Example 66b, another isomer, was obtained as the first elution peak: C-HPLC-13 (mobile phase: n-heptane / [IPA + 0.1% DEA]: 55 / 45): Rt = 10.39 min. Example 66b, another isomer, was obtained as the first elution peak: C-HPLC-13 (mobile phase: n-heptane / [IPA + 0.1% DEA]: 55 / 45): Rt = 6.83 min.

[0608] Examples 67 to 68 in Table 4 below are processed using a method similar to that of Method 4, employing a suitable commercially available amine (step 5) or acid.

[0609] Table 4

[0610] Method 5 Synthesis scheme

[0611] Examples 69a / 69b: 1-(6-(4-(3-amino-5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-methoxyethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta-2-yl)prop-2-en-1-one

[0612] Step 1: tert-butyl 6-(3-(2-(2-methoxyethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0613] Will tert-butylA solution of 6-(3-bromo-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (intermediate C3, 1.65 g, 4.63 mmol), 2-(2-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)-2H-indazole (intermediate B22, 2.09 g, 6.95 mmol), RuPhos (0.22 g, 0.46 mmol), RuPhos-Pd-G3 (0.39 g, 0.46 mmol), and potassium phosphate (2N, 6.95 mL, 13.9 mmol) in dioxane (22 mL) was stirred at 80°C for 15 min. After cooling to RT, the reaction mixture was extracted with EtOAc, the organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude residue was purified by normal-phase chromatography (elution buffer: c-hexane / EtOAc 100 / 0 to 50 / 50 within 30 min) to give the title compound. 1 H NMR (400 MHz, DMSO- d 6) δ 8.35 (s,1H), 8.01 (t, 1H), 7.74 (dd, 1H), 7.60 (d, 1H), 6.46 (s, 1H), 4.76 - 4.68 (m,1H), 4.57 (t, 2H), 3.99 (s, 2H), 3.91 (s, 2H), 3.83 (t, 2H), 3.24 (s, 3H), 2.76 - 2.63 (m, 4H), 2.25 (s, 3H), 1.39 (s, 9H); UPLC-MS-3: Rt = 1.07 min; MS m / z [M+H]+: 452.3.

[0614] Step 2: tert-butyl 6-(4-bromo-3-(2-(2-methoxyethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0615] Towards tert-butyl6-(3-(2-(2-methoxyethyl)-2H-indazole-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (step 1, 2.02 g, 4.20 mmol) was added to a solution of NBS (0.73 g, 4.12 mmol) in THF (30 mL), and the reaction mixture was stirred at RT for 40 min. More NBS (75 mg, 0.42 mmol) was added, and the mixture was stirred at RT for another 10 min. The reaction mixture was concentrated under reduced pressure, and the crude residue was purified by normal-phase chromatography (elution: c-hexane / EtOAc 100 / 0 to 20 / 80 within 30 min) to give the title compound. 1 HNMR (400 MHz, DMSO- d 6) δ 8.44 (s, 1H), 8.17 (s, 1H), 7.71 - 7.65 (m, 2H), 4.87 - 4.79 (m, 1H), 4.59 (t, 2H), 3.98 (s, 2H), 3.89 (s, 2H), 3.84 (t, 2H), 3.24 (s, 3H), 2.75 - 2.64 (m, 4H), 2.28 (s, 3H), 1.38 (s, 9H); UPLC-MS-3: Rt =1.14 min; MS m / z [M+H]+: 530.2 / 532.2.

[0616] Step 3: tert-butyl 3-Amino-4-(1-(2-(tert-butoxycarbonyl)-2-azaspiro[3.3]hept-6-yl)-3-(2-(2-methoxyethyl)-2H-indazole-5-yl)-5-methyl-1H-pyrazol-4-yl)-5-chloro-6-methyl-1H-indazole-1-carboxylate

[0617] Will tert-butyl 6-(4-bromo-3-(2-(2-methoxyethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (step 2, 0.77 g, 1.46 mmol), tert-butylA solution of 3-amino-5-chloro-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)-1H-indazole-1-carboxylate (intermediate D6, 074 g, 1.82 mmol), RuPhos (0.085 g, 0.18 mmol), RuPhos-Pd-G3 (0.152 g, 0.18 mmol), and potassium phosphate (2N, 2.73 mL, 5.46 mmol) in dioxane (10 mL) was stirred at 80°C for 2.25 h. The reaction mixture was extracted with EtOAc, and the organic phase was washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude residue was dissolved in THF (20 mL), SiliaMetS® thiol (0.65 mmol) was added, and the mixture was vortexed at 50°C for 0.5 h. The mixture was filtered, the resin was washed with MeOH, and the filtrate was concentrated under reduced pressure. The crude residue was purified by normal-phase chromatography (elution buffer: c-hexane / EtOAc 100 / 0 to 0 / 100 over 30 min) to give the title compound. UPLC-MS-5: Rt = 1.37 min; MS m / z [M+H] + : 731.5 / 733.4.

[0618] Step 4: 5-Chloro-4-(3-(2-(2-methoxyethyl)-2H-indazol-5-yl)-5-methyl-1-(2-azaspiro[3.3]hept-6-yl)-1H-pyrazol-4-yl)-6-methyl-1H-indazol-3-amine

[0619] Towards tert-butyl 3-Amino-4-(1-(2-(tert-butoxycarbonyl)-2-azaspiro[3.3]hept-6-yl)-3-(2-(2-methoxyethyl)-2H-indazole-5-yl)-5-methyl-1H-pyrazol-4-yl)-5-chloro-6-methyl-1H-indazole-1-carboxylate (step 1, 181 mg, 0.25 mmol) was added to a solution of TFA (0.38 mL, 4.95 mmol) in DCM (2 mL) and the reaction mixture was stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure and dried under high vacuum overnight to give the title compound as a trifluoroacetate, which was used for the next step without purification. UPLC-MS-5: Rt = 0.58 min; MS m / z [M+H] + ;531.3 / 533.3.

[0620] Step 5:1-(6-(4-(3-amino-5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-methoxyethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta-2-yl)prop-2-en-1-one

[0621] DIPEA (0.21 mL, 1.22 mmol) was added to a solution of acrylic acid (0.022 mL, 0.32 mmol) and propylphosphonic anhydride (50% in EtOAc, 0.19 mL, 0.32 mmol) in CH2Cl2 (1.5 mL). This solution was then added dropwise to a solution of 5-chloro-4-(3-(2-(2-methoxyethyl)-2H-indazol-5-yl)-5-methyl-1-(2-azaspiro[3.3]hept-6-yl)-1H-pyrazol-4-yl)-6-methyl-1H-indazol-3-amine trifluoroacetate (0.24 mmol) in CH2Cl2 (2 mL). The reaction mixture was stirred at RT for 2.5 h. RM was quenched with lithium hydroxide (2N, 0.61 mL, 1.22 mmol) with stirring for 30 min, diluted with DCM, washed with saturated aqueous NaHCO3, and the organic phase was dried (phase separator) and concentrated under reduced pressure. The crude residue was purified by normal-phase chromatography (eluent: DCM / MeOH 100 / 0 to 90 / 10 over 30 min) to give the title compound. Isomers were separated by chiral SFC (C-SFC-5: mobile phase: CO2 / [MeOH + 0.1% NEt3]: 60 / 40) to give the title compound as the first elution peak. Example 69a: 1 H NMR (400 MHz, DMSO- d 6) δ 11.60 (s,1H), 8.18 (s, 1H), 7.44 - 7.43 (m, 3H), 7.28 (d, 1H), 6.36-6.28 (m, 1H), 6.13- 6.08 (m, 1H), 5.70 -5.66 (m, 1H), 4.96 - 4.86 (m, 1H), 4.47 (t, 2H), 4.38(s, 1H), 4.32 (s, 1H), 4.10 - 4.08 (m, 3H), 4.03 (s, 1H), 3.76 (t, 2H), 3.19(s, 3H), 2.94 - 2.77 (m, 4H), 2.44 (s, 3H), 1.99 (s, 3H); UPLC-MS-5: Rt = 0.83min; MS m / z [M+H] +585.4 / 587.4; C-SFC-6: (mobile phase: CO2 / [MeOH + 0.1% NH3]: 60 / 40): Rt = 2.64 min. Another isomer, 69b, was obtained as the second elution peak: C-SFC-6: (mobile phase: CO2 / [MeOH + 0.1% NH3]: 60 / 40): Rt = 3.50 min.

[0622]

[0623] Example 70a / 70b: 1-(6-(4-(3-amino-5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-phenyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hept-2-yl)prop-2-en-1-one

[0624] The title example was prepared from phenylboronic acid instead of 2-(2-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2H-indazole in step 1 using a method similar to that of Method-5. Isomers were separated by chiral SFC (C-SFC-5: mobile phase: CO2 / IPA: 50 / 50) to give the title compound example 70a as the first elution peak: 1 H NMR (400 MHz, DMSO- d 6) δ 11.61 (s, 1H), 7.35 - 7.32 (m, 2H), 7.27 (d,1H), 7.21 - 7.14 (m, 3H), 6.36 - 6.28 (m, 1H), 6.13 - 6.07 (m, 1H), 5.70 -5.65 (m, 1H), 4.96 - 4.86 (m, 1H), 4.38 (s, 1H), 4.31 (s, 1H), 4.08 (s, 1H), 4.02 (s, 1H), 2.92 - 2.76 (m, 4H), 2.43 (s, 3H), 1.98 (s, 3H); UPLC-MS-9: Rt =0.98 min; MS m / z [M+H] + : 487.3 / 489.3; C-SFC-6: (mobile phase: CO2 / IPA: 50 / 50): Rt = 1.80 min. Another isomer, 70b, was obtained as the second elution peak: C-SFC-6: (mobile phase: CO2 / IPA: 50 / 50): Rt = 2.55 min.

[0625] Method 6 Synthesis scheme

[0626] Examples 71a / 71b: 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(cenolin-6-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepten-2-yl)prop-2-en-1-one or

[0627] 1-{6-[4-(5-chloro-6-methyl-1-] H -Indazol-4-yl)-3-(Cenolin-6-yl)-5-methyl-1 H [-pyrazol-1-yl]-2-azaspiro[3.3]hept-2-yl}prop-2-en-1-one

[0628] Step 1: tert-butyl 6-(5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate, (1-(2-(tert-butoxycarbonyl)-2-azaspiro[3.3]hept-6-yl)-5-methyl-1H-pyrazol-3-yl)boronic acid

[0629] In the ace tube, tert-butyl A solution of 6-(3-bromo-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (intermediate C3, 5 g, 14.0 mmol), bis-(pinacol)-diboron (5.35 g, 21.0 mmol), PdCl2(dppf).CH2Cl2 adduct (1.15 g, 1.40 mmol), and potassium acetate (3.44 g, 35.1 mmol) in 1,4-dioxane (62.4 mL) was stirred overnight at 100°C under a nitrogen atmosphere. The reaction mixture was poured into a saturated aqueous NaHCO3 solution, extracted with EtOAc (3x), and the combined organic extracts were washed with brine, dried (Na2SO4), filtered, and evaporated to give the title compound as a dark solid, which was used unpurified for the next step. UPLC-MS-3: Rt = 0.91 min; MS m / z [M+H] + ;322.1.

[0630] Step 2: tert-butyl 6-(3-(trinolin-6-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0631] In a microwave-safe vial, tert-butyl6-(5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (step 1, 1.50 g, 1.86 mmol), 6-bromo-borane (0.53 g, 2.42 mmol), RuPhos-Pd-G3 (0.16 g, 0.19 mmol), and RuPhos (0.087 g, 0.19 mmol) were dissolved in toluene (16.3 mL) and potassium phosphate (2 M, 2.79 mL, 5.58 mmol) was added. The reaction mixture was placed under a nitrogen atmosphere and heated at 120°C under microwave irradiation for 1 h. The reaction mixture was poured into a saturated aqueous NaHCO3 solution, extracted with EtOAc (x3), and the combined organic extracts were dried (phase separator) and concentrated. The crude residue was diluted in THF (6 mL), SiliaMetS® thiols (0.8 mmol) were added, and the mixture was vortexed at 40°C for 1 h. The mixture was filtered, the filtrate was concentrated, and the crude residue was purified by normal-phase chromatography (eluent: MeOH in CH2Cl2 from 0 to 10%). The purified fraction was further purified by normal-phase chromatography (eluent: EtOAc in C-hexane from 0 to 100%) to give the title compound as a brown foam. UPLC-MS-3: Rt = 1.04 min; MS m / z [M+H] + ;406.3.

[0632] Step 3: tert-butyl 6-(3-(trinolin-6-yl)-4-iodo-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0633] Towards tert-butyl6-(3-(trinolin-6-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (step 2, 672 mg, 1.66 mmol) was added to an ice-cold solution in THF (17.4 mL) with NIS (1.49 g, 6.63 mmol) and the reaction mixture was stirred under nitrogen while allowing slow RT to be reached. After 19 h, NIS (746 mg, 3.31 mmol) was added and the reaction mixture was stirred again for 50 h. NIS (373 mg, 1.66 mmol) was added again and the reaction mixture was stirred further for 20 h. The reaction mixture was poured into a 10% Na2S2O3 solution, extracted with CH2Cl2 (x2), and the combined organic extracts were washed with a saturated NaHCO3 aqueous solution, dried (phase separator), and concentrated. The crude residue was purified by normal-phase rapid chromatography (elution buffer: MeOH in CH2Cl2 from 0% to 5%) to give the title compound as a brown foam. UPLC-MS-3: Rt = 1.12 min; MS m / z [M+H] + ;532.2.

[0634] Step 4: tert-butyl 6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-3-(cenolin-6-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0635] Under a nitrogen atmosphere, place 15 mL of dioxane into an Ace tube. tert-butyl6-(3-(cylin-6-yl)-4-iodo-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (step 3, 910 mg, 1.71 mmol), 5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1H-indazole (intermediate D1, 774 mg, 2.05 mmol), RuPhos (80 mg, 0.17 mmol), RuPhos-Pd-G3 (143 mg, 0.17 mmol). K3PO4 (1.5 M, 3.42 mL, 5.14 mmol) was added and the reaction mixture was heated at 80°C for 2 h. The reaction mixture was poured into a saturated aqueous NaHCO3 solution, extracted with EtOAc (3x), and the combined organic extracts were dried (phase separator) and concentrated. The crude residue was diluted in THF (15 mL), SiliaMetS® thiol (0.73 mmol) was added, and the mixture was vortexed at 40°C for 1 h. The mixture was filtered, the filtrate was concentrated, and the crude residue was purified by normal-phase chromatography (elution: EtOAc in c-hexane from 0 to 100%) to give the title compound as a pale yellow foam. UPLC-MS-3: Rt = 1.19 min; MS m / z [M+H] + ;654.3 / 656.3.

[0636] Step 5: 6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1-(2-azaspiro[3.3]hept-6-yl)-1H-pyrazol-3-yl) cinnamoline

[0637] Towards tert-butyl 6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-3-(cenolin-6-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (step 4, 806 mg, 1.21 mmol) was added to a solution of CH2Cl2 (9 mL) with TFA (2.79 mL, 36.2 mmol) and the reaction mixture was stirred at RT for 16 h. The reaction mixture was concentrated to give the title compound as a trifluoroacetate salt, which was used for the next step without purification. UPLC-MS-3: Rt = 0.69 min; MS m / z [M+H] + ;470.2 / 472.2.

[0638] Step 6:1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(cenolin-6-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta-2-yl)prop-2-en-1-one

[0639] A mixture of acrylic acid (0.11 mL, 1.61 mmol), propylphosphonic anhydride (50% in EtOAc, 0.95 mL, 1.61 mmol), and DIPEA (2.81 mL, 16.1 mmol) in CH2Cl2 (15 mL) was stirred at RT for 15 min. This solution was added to a solution of 6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1-(2-azaspiro[3.3]hept-6-yl)-1H-pyrazol-3-yl) oxolin trifluoroacetate (step 5, 1.07 mmol) in CH2Cl2 (7.5 mL), and the reaction mixture was stirred at RT for 30 min. The reaction mixture was poured into a saturated aqueous NaHCO3 solution, extracted with CH2Cl2 (2x), and the combined organic layers were dried (phase separator) and concentrated. The crude residue was purified by normal-phase chromatography (eluent: MeOH in CH2Cl2 from 0 to 10%) to give a mixture of the expected compound and the byproducts generated by the addition of acrylamide to indazole. The mixture was diluted in THF (15 mL) and LiOH (2 M, 5.35 mL, 10.7 mmol) was added. The solution was stirred at RT for 30 min and poured into a saturated aqueous NaHCO3 solution, then extracted with EtOAc (3x), and the combined organic extracts were dried (phase separator) and concentrated. The residue was purified by normal-phase chromatography (eluent: MeOH in CH2Cl2 from 0 to 10%) to give the title compound. The isomers were separated by chiral SFC (C-SFC-1; mobile phase: CO2 / [EtOH + 0.1% Et3N]: 75 / 25) to give the title compound as the second elution peak. Example 71a: 1 H NMR (600 MHz, DMSO- d6) δ 13.1 (s, 1H), 9.23 (d, 1H), 8.25 (d, 1H), 7.97 (d, 1H), 7.84 (s, 1H), 7.80 (d, 1H), 6.61 (s, 1H), 7.50 (s, 1H), 6.33 (m, 1H), 6.12 (m, 1H), 5.68 (m, 1H), 4.99(m, 1H), 4.41 (s, 1H), 4.34 (s, 1H), 4.12 (s, 1H), 4.05 (s, 1H), 2.99-2.80(m, 4H), 2.08 (s, 3H); UPLC-MS-4: Rt = 3.88 min; MS m / z [M+H] + 524.3 / 526.3; C-SFC-3 (mobile phase: CO2 / [EtOH + 0.1% Et3N]: 70 / 30): Rt = 2.29 min. Another isomer, example 71b, was obtained as the first elution peak: C-SFC-3 (mobile phase: CO2 / [EtOH + 0.1% Et3N]: 70 / 30): Rt = 1.91 min.

[0640] Method-6a Similar to Method-6, except that dioxane is used instead of toluene in step 2.

[0641] Method-6b Similar to Method-6, except that in step 3, NBS (1.1 equivalents) in acetonitrile is used instead of NIS in THF to prepare the corresponding 4-bromopyrazole.

[0642] Method-6c Similar to Method-6, except that step 5 is performed using H2SO4 in dioxane as described in step 2 of Method-1a.

[0643] Method-6d Similar to Method-6, except that step 6 is performed using NaHCO3, acryloyl chloride, H2O and THF as described in step 3 of Method-1b.

[0644] Examples 72 to 77 in Table 5 below were prepared using a method similar to that of Method-6, from intermediates described in the intermediate synthesis section or commercially available intermediates (in step 2).

[0645] Table 5

[0646] Method 7 Synthesis scheme

[0647] Example 78a: 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(6-methoxypyridin-3-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta-2-yl)prop-2-en-1-one

[0648] Step 1: tert-butyl 6-(4-(5-chloro-6-methyl-1-toluenesulfonyl-1H-indazol-4-yl)-3-(6-methoxypyridin-3-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0649] Add 1,4-dioxane (5 mL) to a 20 mL microwave-safe vial under an argon atmosphere. tert-butyl 6-(3-bromo-4-(5-chloro-6-methyl-1-toluenesulfonyl-1H-indazol-4-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (intermediate C6, 350 mg, 0.51 mmol), 2-methoxypyridine-5-boronic acid pinacol ester (373 mg, 1.54 mmol), and Na2CO3 (2 M, 0.80 mL, 1.60 mmol) were added, along with Pd(PPh3)4 (59.3 mg, 0.05 mmol). The vials were sealed, and the reaction mixture was heated at 100°C for 3.5 min. 2-Methoxypyridine-5-boronic acid pinacol ester (181 mg, 0.77 mmol) and Pd(PPh3)4 (59.3 mg, 0.05 mmol) were added again, and RM was further stirred at 100°C for 2 h. The reaction mixture was poured into water, extracted with EtOAc (2x), and the combined organic extracts were dried (phase separator) and concentrated. The crude residue was diluted in THF, SiliaMetS® thiol (0.91 mmol) was added, and the mixture was vortexed at 40°C for 1 h. The mixture was filtered, the filtrate was concentrated, and the crude residue was purified by normal-phase chromatography (elution: EtOAc in heptane from 0 to 60%) to give the title compound as a white foam. UPLC-MS-1: Rt = 1.51 min; MS m / z [M+H] + : 703.2 / 705.2.

[0650] Step 2: tert-butyl6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(6-methoxypyridin-3-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0651] Towards tert-butyl 6-(4-(5-chloro-6-methyl-1-toluenesulfonyl-1H-indazole-4-yl)-3-(6-methoxypyridin-3-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (step 1, 295 mg, 0.37 mmol) was added to a solution of 1,4-dioxane (3.5 mL) with NaOH (0.99 mL, 1.99 mmol) and the reaction mixture was stirred at 75°C for 1.5 h. The RM was poured into water and extracted with EtOAc (2x). The combined organic extracts were washed with brine, dried (phase separator) and concentrated. The crude residue was purified by normal phase chromatography (eluent: (MeOH / CH2Cl2 (1 / 9)) from 0% to 100% in CH2Cl2) to give the title compound as a white soli...

Claims

1. A compound having formula (I), (I) in A. Choose from the following groups: (a) C5-C 7- Cycloalkylene groups, which are unsubstituted or substituted by one or more, preferably one, two or three, substituents independently selected from fluorine and C1-C4-alkyl groups; (b) 5-7 membered unsaturated heterocyclic groups containing a carbon-carbon double bond and an oxygen atom as ring members, wherein the heterocyclic group is unsubstituted or substituted by one or more, preferably 1, 2 or 3, substituents independently selected from fluorine and C1-C4-alkyl, preferably substituted by 1, 2 or 3 C1-C4-alkyl groups. (c) C6-C 10 Aryl groups, which are unsubstituted or composed of 1, 2, or 3 R groups. A2 replace; (d) A 5-6 membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S as ring members, wherein the heteroaryl ring is unsubstituted or has R atoms on one or more (e.g., 1, 2, or 3) carbon atoms. A3 Substitution, wherein when a nitrogen atom is present in the heteroaryl ring, the nitrogen atom is either unsubstituted or substituted with a substituent selected from the group consisting of: C1-C4-alkyl, -(CH2). 1-2 -C 3-4 -cycloalkyl, C 3- C6-cycloalkyl, hydroxy-C 1- C4-alkyl, fluoro-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, N(R) 9 (R) 10 -C1-C4-alkyl, -SO2-C1-C4-alkyl, -SO2-C 3-4 -cycloalkyl, -(CH2) p -Het py and -(CH2) p -N(R 9 (R) 10 ); (e) An 8-10 membered heteroaryl ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or an 8-10 membered partially saturated heterobicycle containing 1 to 3 heteroatoms or heterogroups independently selected from 0 to 3 nitrogen atoms, 0 to 2 oxygen atoms, 0 to 1 sulfur atom, and 0 to 1 S(=O)2 group, wherein the heteroaryl ring or heterobicycle is unsubstituted or has 1, 2, 3, 4, or 5 R atoms on the carbon atom. A4 Substitution, wherein the heterobicycle is further optionally oxidized at a carbon atom and wherein, when a nitrogen atom is present, the nitrogen atom is unsubstituted or substituted with a substituent -(CO)-C1-C4-alkyl or C1-C4-alkyl, and wherein the C1-C4-alkyl is optionally substituted with one or two independently selected from cyano, hydroxy, oxo, fluorine, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 Substituents; and Among them Het b It is a 4-, 5-, or 6-membered heterocycle containing one or two independent heteroatoms or groups selected from N, O, S, SO, and SO2, wherein the heterocycle Het b It is either unsubstituted or has one or two independent substituents selected from the following: C1-C4-alkyl, hydroxy, cyano, fluorine, C1-C4-alkoxy-hydroxy-C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy, fluoro-C1-C4-alkoxy, and fluoro-C1-C4-alkyl, and wherein the heterocyclic Het b Further, optionally, the carbon atom is substituted with oxygen, and wherein when the nitrogen atom is present in Het b In this case, the nitrogen atom is optionally further substituted with a C1-C4-alkyl group, which is optionally substituted with one to three substituents independently selected from fluorine, hydroxyl and C1-C4-alkoxy groups; Where A passes through A on sp 2 The hybrid carbon atom is attached to the rest of the compound having formula (I); in Choose B freely. 1 and B 2 The group formed Among them B 1 It is C 6-10 Aryl groups, which are unsubstituted or composed of 1, 2, 3, or 4 R groups. Ba replace; B 2 It is a 6-13 membered heteroaryl group, which contains 1, 2 or 3 nitrogen atoms, wherein B 2 It is either unreplaced or replaced by 1, 2, 3, or 4 Rs. Bb replace; C is selected from the group consisting of: hydrogen, C1-C3 alkyl, C3-C5 cycloalkyl, fluorine-C1-C3 alkyl, cyano, -CH2-CN, -CH(CN)-CH3, -CH2-OH, -CH(OH)-CH3, and halogen; L can choose from the following groups: Where n is 1, 2, or 3. R L Selected from hydrogen, methyl, ethyl, -CH2-CN and -CH2-OH, wherein G Represents the attachment point to G; G can choose from the following groups: ； in R 2 Selected from hydrogen, C1-C3 alkyl, -C(O)-C1-C3-alkyl, and fluorine; R 3 It is hydrogen; R 4 Selected from hydrogen, methyl, -CH2F, -CH2-OCH3 and -CH2-N(CH3)2; R 5 Selected from hydrogen and methyl; R 6 It is hydrogen; R 7 Selected from hydrogen and methyl; Where R A2 Independently select from the following groups: NR 9 R 10 , cyano, -(CH2) p -CN, halogenated, OH, hydroxyl, -C1-C4-alkyl, -(COOH), -(CH2) p -COOH, C1-C4-alkyl, fluoro-C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl, N(R 9 (R) 10 )-C1-C4-alkyl, N(R 9 (R) 10 )-C1-C4-alkyl-oxygen, N(R 9 (R) 10 -C1-C4-alkoxy, C1-C4-alkyl-carbonyl-oxy-C1-C4-alkyl-oxy, hydroxy-C1-C4-alkyl-oxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, C1-C4-alkoxy-C1-C4-alkyl-oxy-C1-C4-alkyl, -SO2-C1-C4-alkyl, -SO2-C 3-4 -cycloalkyl, -(CH2) 1-2 -C 3-4 -cycloalkyl, Het py -(CH2) p -Het py -C(=O)-NR 9 R 10 -(CH2) p -C(=O)NR 9 R 10 ; Where R A3 Independently select from the following groups: oxidative, NR 9 R 10 , cyano, -(CH2) p -CN, halogenated, OH, hydroxyl, -C1-C4-alkyl, -(COOH), -(CH2) p -COOH, C1-C4-alkyl, fluoro-C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl, N(R 9 (R) 10 )-C1-C4-alkyl, N(R 9 (R) 10 )-C1-C4-alkyl-oxygen, N(R 9 (R) 10 -C1-C4-alkoxy, C1-C4-alkyl-carbonyl-oxy-C1-C4-alkyl-oxy, hydroxy-C1-C4-alkyl-oxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, C1-C4-alkoxy-C1-C4-alkyl-oxy-C1-C4-alkyl, -SO2-C1-C4-alkyl, -SO2-C 3-4 -cycloalkyl, -(CH2) 1-2 -C 3-4 -cycloalkyl, Het py -(CH2) p -Het py -C(=O)-NR 9 R 10 -(CH2) p -C(=O)NR 9 R 10 (CH2) p -NR 9 R 10 ; Where R A4 Independently selected from the group consisting of: cyano, CO2H, halogen, C1-C4-alkyl, fluoro-C1-C4-alkyl, hydroxy, hydroxy-C1-C4-alkyl, hydroxy-C1-C4-alkyl-oxy, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl-oxy, NR 9 R 10 、(N(R 9 (R) 10 )-C1-C4-alkyl, (N(R) 9 (R) 10 -C1-C4-alkyl-oxy, -(CO)-C1-C4-alkyl, and R 9 R 10 N-C1-C4-alkyl-oxy-(CO)-C1-C4-alkyl; in p is 1, 2, or 3; R 9 Selected from hydrogen and C1-C4-alkyl; R 10 Selected from the group consisting of: hydrogen, C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl and di-C1-C4-alkyl-amino-C1-C4-alkyl; Het py It is a 4-, 5-, 6-, or 7-membered saturated heterocycle containing one or two heteroatoms independently selected from O, N, and S, or containing an S-oxide (SO) or S-dioxide (SO2) group, wherein the heterocycle is optionally substituted with an oxygen atom on one carbon atom, and wherein the heterocycle is optionally further substituted with one, two, or three substituents independently selected from C1-C4-alkoxy, halogen, C1-C4-alkyl, hydroxy-C1-C4-alkyl, and fluoro-C1-C4-alkyl on one or more carbon atoms, and wherein if a nitrogen atom is present in the heterocycle, the nitrogen atom is optionally further substituted with an R 10 replace; Or Het py It is a 5- or 6-membered heteroaryl ring containing 1, 2, or 3 nitrogen atoms, and said heteroaryl ring is optionally substituted by one or more (e.g., 1, 2, or 3) substituents independently selected from the following: NR 9 R 10 -C(=O)-NR 9 R 10 Halogenated, C 1- C4-alkyl, hydroxy-C 1- C4-alkyl, fluorine-C 1- C4-alkyl, cyano, OH, and C 1- C4-alkoxy group; Each R Ba Independently selected from the group consisting of: hydroxyl, NH2, C1-C4-alkyl, and halogen; Each R Bb Independently selected from the group consisting of: C1-C4-alkyl, cyclopropyl, fluoro-C1-C3-alkyl, cyano, halogen, NH2, and C1-C3-alkoxy. Or its stereoisomer, or its transisomer, or its pharmaceutically acceptable salt, or its pharmaceutically acceptable salt, or its transisomer.

2. The compound according to claim 1, wherein A is selected from the group consisting of... (a) C5-C 7- Cycloalkylene groups, which are unsubstituted or substituted by one or more, preferably one, two or three, substituents independently selected from fluorine and C1-C4-alkyl groups; (b) 5-7 membered unsaturated heterocyclic groups containing a carbon-carbon double bond and an oxygen atom as ring members, wherein the heterocyclic group is unsubstituted or substituted by one or more, preferably 1, 2 or 3, substituents independently selected from fluorine and C1-C4-alkyl, preferably substituted by 1, 2 or 3 C1-C4-alkyl groups. (c) C6-C 10 Aryl groups, which are unsubstituted or composed of 1, 2, or 3 R groups. A2 replace; (d) A 5-6 membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S as ring members, wherein the heteroaryl ring is unsubstituted or has R atoms on one or more (e.g., 1, 2, or 3) carbon atoms. A3 Substitution, wherein when a nitrogen atom is present in the heteroaryl ring, the nitrogen atom is either unsubstituted or substituted with a substituent selected from the group consisting of: C1-C4-alkyl, -(CH2). 1-2 -C 3-4 -cycloalkyl, C 3- C6-cycloalkyl, hydroxy-C 1- C4-alkyl, fluoro-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, N(R) 9 (R) 10 -C1-C4-alkyl, -SO2-C1-C4-alkyl, -SO2-C 3-4 -cycloalkyl, -(CH2) p -Het py and -(CH2) p -N(R 9 (R) 10 ); (e) An 8- to 10-membered heteroaryl ring containing 1, 2, or 3 nitrogen atoms, wherein each nitrogen atom is unsubstituted or substituted with a substituent -(CO)-C1-C4-alkyl or C1-C4-alkyl, and wherein said C1-C4-alkyl is optionally replaced by 1 or 2 atoms independently selected from cyano, hydroxy, oxo, fluorine, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 The substituents are substituted, wherein the heteroaryl ring is unsubstituted or has 1, 2, 3, 4 or 5 R atoms on the carbon atom. A4 replace; Among them Het b It is a 4-, 5-, or 6-membered heterocycle containing one or two independent heteroatoms or groups selected from N, O, S, SO, and SO2, wherein the heterocycle Het b It is either unsubstituted or has one or two independent substituents selected from the following: C1-C4-alkyl, hydroxy, cyano, fluorine, C1-C4-alkoxy-hydroxy-C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy, fluoro-C1-C4-alkoxy, and fluoro-C1-C4-alkyl, and wherein the heterocyclic Het b Further, optionally, the carbon atom is substituted with oxygen, and wherein when the nitrogen atom is present in Het b In this case, the nitrogen atom is optionally further substituted with a C1-C4-alkyl group, wherein the C1-C4-alkyl group is optionally replaced by one to three atoms independently selected from fluorine, hydroxyl, and C. 1- Substitution of C4-alkoxy groups; and (f) An 8-10 quintile partially saturated heterobicycle containing 1-3 nitrogen atoms, 1-2 oxygen atoms, 1 sulfur atom, or 1 S(=O)2 group, wherein the heterobicycle is unsubstituted or has 1, 2, 3, 4, or 5 R atoms on its carbon atom. A4 Substitution, wherein the heterobicycle is further optionally oxidized at a carbon atom and wherein, when a nitrogen atom is present, the nitrogen atom is unsubstituted or substituted with a substituent -(CO)-C1-C4-alkyl or C1-C4-alkyl, and wherein the C1-C4-alkyl is optionally substituted with one or two independently selected from cyano, hydroxy, oxo, fluorine, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 Substituents; and Among them Het b It is a 4-, 5-, or 6-membered heterocycle containing one or two independent heteroatoms or groups selected from N, O, S, SO, and SO2, wherein the heterocycle Het b It is either unsubstituted or has one or two independent substituents selected from the following: C1-C4-alkyl, hydroxy, cyano, fluorine, C1-C4-alkoxy-hydroxy-C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy, fluoro-C1-C4-alkoxy, and fluoro-C1-C4-alkyl, and wherein the heterocyclic Het b Further, optionally, the carbon atom is substituted with oxygen, and wherein when the nitrogen atom is present in Het b In this embodiment, the nitrogen atom is optionally further substituted with a C1-C4-alkyl group, which is optionally substituted with one to three substituents independently selected from fluorine, hydroxyl, and C1-C4-alkoxy groups. Or its stereoisomer, or its transisomer, or its pharmaceutically acceptable salt, or its pharmaceutically acceptable salt, or its transisomer.

3. The compound according to claim 1 or 2, wherein... Het b It is a 4-, 5-, or 6-membered heterocycle containing one or two independent heteroatoms or groups selected from N, O, S, SO, and SO2, wherein the heterocycle Het b It is either unsubstituted or has one or two independent substituents selected from the following: C1-C4-alkyl, hydroxy, cyano, fluorine, C1-C4-alkoxy-hydroxy-C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy, and fluoro-C1-C4-alkyl, and wherein said heterocyclic Het b Further, optionally, the carbon atom is substituted with oxygen, and wherein when the nitrogen atom is present in Het b In the case of nitrogen atom, the nitrogen atom is optionally further substituted with C1-C4-alkyl, wherein the C1-C4-alkyl is optionally substituted with 1 to 3 substituents independently selected from fluorine, hydroxyl and C1-C4-alkoxy; Choose B freely. 1 and B 2 The group formed; B 1 It is C 6-10 Aryl groups, which are unsubstituted or composed of 1, 2, 3, or 4 R groups. Ba Replace and each R Ba Independently selected from the group consisting of: hydroxyl, C1-C4-alkyl, and halogen; B 2 It is a 6-10 membered heteroaryl group, which contains 1, 2 or 3 nitrogen atoms, wherein B 2 It is either unreplaced or replaced by 1, 2, 3, or 4 Rs. Bb replace; Each R Bb Independently selected from the group consisting of: C1-C4-alkyl (preferably methyl), fluoro-C1-C3-alkyl, cyano, halogen, NH2, and C1-C3-alkoxy. Het py It is a 4-, 5-, 6-, or 7-membered saturated heterocycle containing one or two heteroatoms independently selected from O, N, and S, or containing an S-oxide (SO) or S-dioxide (SO2) group, wherein the heterocycle is optionally oxidized on one carbon atom, and wherein the heterocycle is further substituted on one or more carbon atoms with one, two, or three substituents independently selected from: C1-C4-alkoxy, halogenated, C1-C4-alkyl, hydroxy-C1-C4-alkyl, and fluoro-C1-C4-alkyl, and wherein if a nitrogen atom is present in the heterocycle, the nitrogen atom is optionally further substituted with R. 10 replace; Or Het py It is a 5- or 6-membered heteroaryl ring containing 1, 2, or 3 nitrogen atoms, and said heteroaryl ring is optionally substituted by one or more (e.g., 1, 2, or 3) substituents independently selected from the following: NR 9 R 10 Halogenated, C 1- C4-alkyl, cyano, OH, and C 1- C4-alkoxy group; Where R A4 Independently selected from the group consisting of: cyano, CO2H, halogen, C1-C4-alkyl, fluorine-C 1- C4-alkyl, hydroxy, hydroxy-C1-C4-alkyl, hydroxy-C 1- C4-alkyl-oxygen, C 1- C4-alkoxy group, C 1- C4-alkoxy-C 1- C4-alkyl-oxygen, -NR 9 R 10 R 9 R 10 NC 1- C4-alkyl-oxygen, -(CO)-C1-C4-alkyl; Or its stereoisomer, or its transisomer, or its pharmaceutically acceptable salt, or its pharmaceutically acceptable salt, or its transisomer.

4. The compound according to any one of the preceding claims, wherein Het b It is a 4-, 5-, or 6-membered heterocycle containing one or two independent heteroatoms or groups selected from N, O, S, SO, and SO2, wherein the heterocycle Het b It is either unsubstituted or has one or two independent substituents selected from the following: C1-C4-alkyl, hydroxy, cyano, fluorine, C1-C4-alkoxy-hydroxy-C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy, and fluoro-C1-C4-alkyl, and wherein said heterocyclic Het b Further, optionally, the carbon atom is substituted with oxygen, and wherein when the nitrogen atom is present in Het b In the case of nitrogen atom, the nitrogen atom is optionally further substituted with C1-C4-alkyl, wherein the C1-C4-alkyl is optionally substituted with 1 to 3 substituents independently selected from fluorine, hydroxyl and C1-C4-alkoxy; B 2 It is a 6-10 membered heteroaryl group, which contains 1, 2 or 3 nitrogen atoms, wherein B 2 It is either unreplaced or replaced by 1, 2, 3, or 4 Rs. Bb replace; Het py It is a 4-, 5-, 6-, or 7-membered saturated heterocycle containing one or two heteroatoms independently selected from O, N, and S, or containing an S-oxide (SO) or S-dioxide (SO2) group, wherein the heterocycle is optionally oxidized on one carbon atom, and wherein the heterocycle is further substituted on one or more carbon atoms with one, two, or three substituents independently selected from: C1-C4-alkoxy, halogenated, C1-C4-alkyl, hydroxy-C1-C4-alkyl, and fluoro-C1-C4-alkyl, and wherein if a nitrogen atom is present in the heterocycle, the nitrogen atom is optionally further substituted with R. 10 replace; Or Het py It is a 5- or 6-membered heteroaryl ring containing 1, 2, or 3 nitrogen atoms, and said heteroaryl ring is optionally substituted by one or more (e.g., 1, 2, or 3) substituents independently selected from the following: NR 9 R 10 Halogenated, C 1- C4-alkyl, cyano, OH, and C 1- C4-alkoxy group; R A4 Independently selected from the group consisting of: cyano, CO2H, halogen, C1-C4-alkyl, fluorine-C 1- C4-alkyl, hydroxy, hydroxy-C1-C4-alkyl, hydroxy-C 1- C4-alkyl-oxygen, C 1- C4-alkoxy group, C 1- C4-alkoxy-C 1- C4-alkyl-oxygen, -NR 9 R 10 and R 9 R 10 NC 1- C4-alkyl-oxygen, Or its stereoisomer, or its transisomer, or its pharmaceutically acceptable salt, or its pharmaceutically acceptable salt, or its transisomer.

5. The compound according to any one of the preceding claims, wherein G is Or its stereoisomer, or its transisomer, or its pharmaceutically acceptable salt, or its pharmaceutically acceptable salt, or its transisomer.

6. The compound according to any one of the preceding claims, wherein L is ， Or its stereoisomer, or its transisomer, or its pharmaceutically acceptable salt, or its pharmaceutically acceptable salt, or its transisomer.

7. The compound according to claim 6, wherein R L It is hydrogen, or its stereoisomer, its transisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of its stereoisomer, or its pharmaceutically acceptable salt of its transisomer.

8. The compound according to any one of the preceding claims, wherein C is selected from C1-C3 alkyl, fluoro-C1-C3 alkyl, CH2-CN, or a stereoisomer thereof, or a transisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a transisomer thereof.

9. The compound according to any one of the preceding claims, wherein B is Wherein B is unsubstituted or substituted with 1, 2 or 3 halogenated or methyl groups, or a stereoisomer of the same, or a transisomer of the same, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a transisomer of the same.

10. The compound according to any one of the preceding claims, wherein B is Where X is N or CR B5 ; Where R B1 Independently selected from hydrogen and C1-C4-alkyl; R B2 Independently selected from hydrogen, halogen, C1-C4-alkyl, cyclopropyl and NH2; R B3 Independently selected from hydrogen, halogenated, cyclopropyl, and C1-C4-alkyl; R B4 Independently selected from hydrogen, halogenated and C1-C4-alkyl, or R B3 and R B4 Together with the atoms to which they are attached, they form 4-6 membered rings that fused with an aromatic ring containing X; R B5 Independently selected from hydrogen, halogenated, and C1-C4-alkyl groups, Or its stereoisomer, or its transisomer, or its pharmaceutically acceptable salt, or its pharmaceutically acceptable salt, or its transisomer.

11. The compound according to claim 10, wherein R B2 The following are independently selected from the group consisting of hydrogen, NH2, and CH3, or their transisomers, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of their transisomers.

12. The compound according to claim 10 or 11, wherein R B4 It is independently selected from hydrogen, halogenated and C1-C4-alkyl, or stereoisomers thereof, or transisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof, or transisomers thereof.

13. The compound according to any one of claims 10 to 12, wherein R B1 It is independently selected from hydrogen and methyl, or their stereoisomers, their transisomers, their pharmaceutically acceptable salts, their stereoisomers, or their transisomers.

14. The compound according to any one of claims 10 to 13, wherein R B1 It is hydrogen, or its stereoisomer, its transisomer, its pharmaceutically acceptable salt, its pharmaceutically acceptable salt of its stereoisomer, or its pharmaceutically acceptable salt of its transisomer.

15. The compound according to any one of claims 10 to 14, wherein R B3 and R B4 Each is independently selected from halogenated and C1-C4-alkyl, or their stereoisomers, their transisomers, their pharmaceutically acceptable salts, their stereoisomers, or their transisomers.

16. The compound according to any one of claims 10 to 15, wherein R B3 It is halogenated and R B4 It is a C1-C4-alkyl group, or a stereoisomer thereof, or a transisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a transisomer thereof.

17. The compound according to any one of claims 10 to 16, wherein R B3 It is chlorine and R B4 It is methyl, or its stereoisomer, its transisomer, its pharmaceutically acceptable salt, its stereoisomer, or its transisomer.

18. The compound according to any one of claims 10 to 16, wherein R B3 It is chlorine and R B4 It is chlorine, or its stereoisomer, or its transisomer, or its pharmaceutically acceptable salt, or its stereoisomer, or its transisomer, or its transisomer, or its pharmaceutically acceptable salt.

19. The compound according to any one of claims 10 to 18, wherein X is CH or N, or a stereoisomer thereof, or a transisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a transisomer thereof.

20. The compound according to any one of claims 10 to 19, wherein X is CH, or a stereoisomer thereof, or a transisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a transisomer thereof.

21. A compound having formula (Ia) (him) Wherein A, B and C are as defined in any of the preceding claims, or their stereoisomers, their transisomers, their pharmaceutically acceptable salts, their stereoisomers, or their transisomers.

22. A compound having formula (I) or formula (Ia) according to any one of the preceding claims, wherein A is C5-C. 7- Cycloalkylene, which is unsubstituted or substituted by one or more, preferably one, two or three, independently selected from the following substituents: fluorine and C1-C4-alkyl, or stereoisomers thereof, or transisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof, or transisomers thereof.

23. A compound having formula (I) or formula (Ia) according to any one of the preceding claims, wherein A is Where W is O or C(R) w )2, each R w Independently selected from hydrogen and fluorine, R c It is hydrogen or C1-C4-alkyl and A is optionally further substituted by 1, 2 or 3 substituents independently selected from: fluorine and C1-C4-alkyl, or a stereoisomer thereof, or a transisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a transisomer thereof.

24. A compound having formula (I) or formula (Ia) according to any one of claims 1 to 21, wherein A is unsubstituted or is formed by 1, 2 or 3 Rs. A2 A substituted phenyl group, or its stereoisomer, its transisomer, its pharmaceutically acceptable salt, its stereoisomer, or its transisomer.

25. A compound having formula (I) or formula (Ia) according to any one of claims 1 to 21, wherein A is a 5-6 membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S as ring members, wherein the heteroaryl ring is unsubstituted or has R on one or more (e.g., 1, 2, or 3) carbon atoms. A3 Substitution, wherein when a nitrogen atom is present in the heteroaryl ring, the nitrogen atom is either unsubstituted or substituted with a substituent selected from the group consisting of: C1-C4-alkyl, -(CH2). 1-2 -C 3-4 -cycloalkyl, hydroxy-C 1- C4-alkyl, fluoro-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, N(R) 9 (R) 10 -C1-C4-alkyl, -SO2-C1-C4-alkyl, -SO2-C 3-4 -cycloalkyl, -(CH2) p -Het py and -(CH2) p -N(R 9 (R) 10 ), or its stereoisomer, or its transisomer, or its pharmaceutically acceptable salt, or its stereoisomer, or its transisomer, or its transisomer, or its pharmaceutically acceptable salt.

26. A compound having formula (I) or formula (Ia) according to any one of claims 1 to 21, wherein A is pyridin-1-yl, pyridin-2-yl, or pyridin-3-yl, which is unsubstituted or substituted by one, two, or three substituents independently selected from: NH2, cyano, halogen, OH, hydroxy-C 1- C4-alkyl, -COOH, C 1- C4-alkyl, fluorine-C 1- C4-alkyl, C 1- C4-alkoxy, di-C 1- C4-alkylamino-C 1- C4-alkyl-oxygen, C 1- C4-alkyl-carbonyl-oxy-C 1- C4-alkyl-oxygen, hydroxy-C 1- C4-alkyl-oxygen, C 1- C4-alkoxy-C 1- C4-alkyl-oxygen, C 1- C4-alkoxy-C 1- C4-alkyl-oxy-C 1- C4-alkyl, -C(=O)-NR 9 R 10 NR 9 R 10 Het py and -(CH2) p -Het py , in p is 1 or 2; R 9 Selected from hydrogen and C 1- C4-alkyl, R 10 Selected from hydrogen, C 1- C4-alkyl, hydroxy-C 1- C4-alkyl, C 1- C4-alkoxy-C 1- C4-alkyl and di-C 1- C4-alkyl-amino-C 1- C4-alkyl, Het py It is NR 9a R 10a ; R 9a and R 10a Together with nitrogen, it forms a 4-, 5-, or 6-membered saturated or unsaturated heterocycle comprising one or two heteroatoms independently selected from O, N (pyrrolidin-1-yl, azirrobutane-1-yl, morpholino-1-yl) and S, or their N-oxides, or their S-oxides (SO) or S-dioxides, wherein the heterocycle is optionally substituted with an oxygen atom on one carbon atom of the heterocycle, and wherein the heterocycle is further substituted with one, two, or three substituents independently selected from the following: C1-C4-alkoxy, halogen, C1-C4-alkyl, hydroxy-C1-C4-alkyl, and fluoro-C1-C4-alkyl; Or R 9a and R 10a Together with nitrogen, it forms a 4-, 5-, or 6-membered heteroaryl ring containing 1, 2, or 3 nitrogen atoms, wherein said heteroaryl ring is optionally substituted with an amino group. Its stereoisomer, or its transisomer, or its pharmaceutically acceptable salt, or its pharmaceutically acceptable salt, or its transisomer.

27. A compound having formula (I) or (Ia) according to any one of claims 1 to 21, wherein A is a pyridyl group substituted with one, two, or three substituents independently selected from: NH2, cyano, halogenated, C 1- C4-alkyl, fluorine-C 1- C4-alkyl, C 1- C4-alkoxy, di-C 1- C4-alkylamino-C 1- C4-alkyl-oxygen, -C(=O)-NR 9 R 10 NR 9 R 10 , Where p is 0, 1, or 2; R 22 It is hydrogen or C1-C4-alkyl or amino; R 9 Selected from hydrogen and C 1- C4-alkyl, R 10 Selected from hydrogen, C 1- C4-alkyl, hydroxy-C 1- C4-alkyl, C 1- C4-alkoxy-C 1- C4-alkyl and di-C 1- C4-alkyl-amino-C 1- C4-alkyl, Or its stereoisomer, or its transisomer, or its pharmaceutically acceptable salt, or its pharmaceutically acceptable salt, or its transisomer.

28. The compound having formula (I) or formula (Ia) according to any one of claims 1 to 21, wherein A is ， Where R 23 It is hydrogen, C 3- C6-cycloalkyl, C 1- C4-alkyl, wherein A is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the following: F, CH3, CH2F, CHF2 and CF3; Or its stereoisomer, or its transisomer, or its pharmaceutically acceptable salt, or its pharmaceutically acceptable salt, or its transisomer.

29. A compound having formula (I) or formula (Ia) according to any one of claims 1 to 21, wherein A is a pyrimidin-5-yl group, which is unsubstituted or substituted by one, two, or three substituents independently selected from: C 1- C4-alkoxy and CH3, or their stereoisomers, their transisomers, their pharmaceutically acceptable salts, their stereoisomers, or their transisomers.

30. A compound having formula (I) or formula (Ia) according to any one of claims 1 to 21, wherein A is selected from the group consisting of... Where R 24 It is hydrogen, C 1- C4-alkyl, hydroxy-C 1- C4-alkyl, C 1- C4-alkoxy-C 1- C4-alkyl, -NR 9 R 10 C 1- C4-alkyl, -SO2-C 1- C4-alkyl, -SO2-C 3-4 -cycloalkyl or -(CH2) 1-2 -C 3-4 -cycloalkyl; R 4a R 4b R 4c and R 4d Each is independently selected from hydrogen and C. 1- C4-alkyl, Or its stereoisomer, or its transisomer, or its pharmaceutically acceptable salt, or its pharmaceutically acceptable salt, or its transisomer.

31. A compound having formula (I) or formula (Ia) according to any one of claims 1 to 21, wherein A is selected from the group consisting of: in y is 0, 1, or 2; x is 0, 1, or 2; z is 0, 1, or 2; R O Choose from the following groups: hydrogen, NR 9 R 10 R 9 R 10 NC 1- C4-alkyl-oxygen, C 1- C4-alkoxy-C 1- C4-alkyl-oxygen, hydroxy-C 1- C4-alkyl-oxygen and C 1- C4-alkyl; R M It is hydrogen, halogenated, or C1-C4-alkyl, wherein the alkyl group is optionally converted to OH, C1-C4-alkoxy, or NR. 9 R 10 replace; R N It is hydrogen or C1-C4-alkyl, or halo- or fluoro-C1-C4-alkyl; R q Independently selected from the group consisting of: C1-C4-alkyl, hydroxyl, C1-C4-alkoxy, and NR. 9 R 10 ; R p It is a C1-C4-alkyl group; Each R p1 Independently selected from hydrogen and C1-C4-alkyl; R v Independently selected from halogens, C1-C4-alkyl groups, and fluoro-C1-C4-alkyl groups; R ae The group selected is from the group consisting of hydrogen and C1-C4-alkyl, wherein the alkyl group is optionally substituted by one or two substituents selected from the group consisting of cyano, hydroxyl, fluorine, C 1- C4-alkoxy group, C 1- C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 ; R Ae The group selected is from the group consisting of: hydrogen, -(CO)-C1-C4-alkyl, and C1-C4-alkyl, wherein the C1-C4 alkyl group is optionally substituted by one or two substituents selected from: cyano, hydroxyl, fluorine, C 1- C4-alkoxy group, C 1- C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 ; in R 9 Selected from hydrogen and C 1- C4-alkyl; R 10 Selected from hydrogen, C 1- C4-alkyl, hydroxy-C 1- C4-alkyl, C 1- C4-alkoxy-C 1- C4-alkyl and di-C 1- C4-alkyl-amino-C 1- C4-alkyl; Among them Het b It is a 4-, 5-, or 6-membered heterocycle containing one or two independent heteroatoms or groups selected from N, O, S, SO, and SO2, wherein the heterocycle Het b It is either unsubstituted or has one or two independent substituents selected from the following: C1-C4-alkyl, hydroxy, cyano, fluorine, hydroxy-C1-C4-alkyl, C1-C4-alkoxy, and fluoro-C1-C4-alkyl, and wherein the heterocyclic Het b Further, optionally, the carbon atom is substituted with oxygen, and wherein when the nitrogen atom is present in Het b In this case, the nitrogen atom is optionally further substituted with a C1-C4-alkyl group, which is optionally substituted with one to three substituents independently selected from fluorine, hydroxyl and C1-C4-alkoxy groups; Or its transisomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a transisomer thereof.

32. The compound having formula (I) or formula (Ia) according to any one of claims 1 to 21, wherein A is selected from the group consisting of: Where z is 0, 1, or 2; R v Independently selected from halogens, C1-C4-alkyl groups, and fluoro-C1-C4-alkyl groups; R is hydrogen or C1-C4-alkyl, or halo- or fluoro-C1-C4-alkyl; R O Choose from the following groups: hydrogen, NR 9 R 10 、N(R 9 (R) 10 )-C 1- C4-alkyl-oxygen, C 1- C4-alkoxy-C 1- C4-alkyl-oxygen, hydroxy-C 1- C4-alkyl-oxygen and C1-C4-alkyl; R ae The group selected is from the group consisting of hydrogen and C1-C4-alkyl, wherein the alkyl group is optionally substituted by one or two substituents selected from the group consisting of cyano, hydroxyl, fluorine, C 1- C4-alkoxy group, C 1- C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 ; R 9 Selected from hydrogen and C 1- C4-alkyl; R 10 Selected from hydrogen, C 1- C4-alkyl, hydroxy-C 1- C4-alkyl, C 1- C4-alkoxy-C 1- C4-alkyl and di-C 1- C4-alkyl-amino-C 1- C4-alkyl; Among them Het b It is a 4-, 5-, or 6-membered heterocycle containing one or two independent heteroatoms or groups selected from N, O, S, SO, and SO2, wherein the heterocycle Het b It is either unsubstituted or has one or two independent substituents selected from the following: C1-C4-alkyl, hydroxy, cyano, fluorine, hydroxy-C1-C4-alkyl, C1-C4-alkoxy, and fluoro-C1-C4-alkyl, and wherein the heterocyclic Het b Further, optionally, the carbon atom is substituted with oxygen, and wherein when the nitrogen atom is present in Het b In this case, the nitrogen atom is further optionally substituted with a C1-C4-alkyl group, which is optionally substituted with one to three substituents independently selected from fluorine, hydroxyl and C1-C4-alkoxy groups; Or its stereoisomer, or its transisomer, or its pharmaceutically acceptable salt, or its pharmaceutically acceptable salt, or its transisomer.

33. A compound having formula (I) or formula (Ia) according to any one of claims 1 to 21, or claims 31 or 32, wherein A is selected from the group consisting of: Or its stereoisomer, or its transisomer, or its pharmaceutically acceptable salt, or its pharmaceutically acceptable salt, or its transisomer.

34. The compound having formula (I) or formula (Ia) according to claim 33, wherein... R N It is hydrogen or C1-C4-alkyl; R O Is it hydrogen or NR? 9 R 10 ; R v Independently selected from fluorine, chlorine, and C1-C4-alkyl (e.g., methyl); z is 0 or 1; Or its stereoisomer, or its transisomer, or its pharmaceutically acceptable salt, or its pharmaceutically acceptable salt, or its transisomer.

35. The compound having formula (I) or formula (Ia) according to any one of claims 31 to 34, wherein R ae Choose from the following groups: hydrogen, C1-C4-alkyl, -(CH2)2-Het b -CH2-CN, -(CH2) 2- OH, -(CH2) 2- O-C1-C4-alkyl, hydroxy-C1-C4-alkyl, -(CH2)2-O-(CH2)2-O-C1-C4-alkyl and -(CH2)2-diC1-C4-alkylamino, or wherein R Ae Choose from the group consisting of: hydrogen, fluorine-C1-C4-alkyl, and C1-C4-alkyl; Het b It is a 4-, 5-, or 6-membered heterocycle comprising one nitrogen atom and one oxygen atom, or one or two nitrogen atoms, wherein the heterocycle is unsubstituted or has one or two independent substituents selected from the group consisting of C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy, and fluorine, and wherein when a nitrogen atom is present in the heterocycle, the nitrogen atom is optionally further substituted with a C1-C4-alkyl group. Or its stereoisomer, or its transisomer, or its pharmaceutically acceptable salt, or its pharmaceutically acceptable salt, or its transisomer.

36. The compound having formula (I) or having formula (Ia) according to any one of claims 31 to 35, wherein R ae Choose from the following groups: hydrogen, methyl, -CH2-CN, -(CH2)2-OH, -(CH2)2-OCH3, -(CH2)-C(CH3)2-OH, -(CH2)2-O-(CH2)2-OCH3, -(CH2)2-N(CH3)2, and -(CH2)2-Het b ; The Het b It is a 4-, 5-, or 6-membered heterocycle containing one nitrogen atom and one oxygen atom, or one or two nitrogen atoms, wherein the heterocycle is unsubstituted or has one or two independent substituents selected from the group consisting of C1-C4-alkyl, hydroxy-C1-C4-alkyl-C1-C4-alkoxy, and fluorine, and wherein when a nitrogen atom is present in the heterocycle, the nitrogen atom is optionally further substituted with a C1-C4-alkyl group. Or its stereoisomer, or its transisomer, or its pharmaceutically acceptable salt, or its pharmaceutically acceptable salt, or its transisomer.

37. The compound having formula (I) or having formula (Ia) according to any one of claims 31 to 36, wherein R ae Choose from the following groups: hydrogen, methyl, -CH2-CN, -(CH2) 2- OH, -(CH2)2-OCH3, -(CH2)-C(CH3)2-OH, -(CH2)2-O-(CH2)2-OCH3, -(CH2)2-N(CH3)2, and -(CH2)2-Het b Het b The heterocycle is selected from the group consisting of: azirmonobutan-1-yl, pyrrolidan-1-yl, pyrrolidan-3-yl, and morpholino-1-yl, wherein the heterocycle is optionally further substituted by one or two substituents independently selected from: methyl, hydroxy-methyl, methoxy, and fluorine, or stereoisomers thereof, or transisomers thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts thereof, or transisomers thereof.

38. The compound having formula (I) or having formula (Ia) according to any one of claims 31 to 36, wherein R ae Choose from the group consisting of: hydrogen, fluorine, -C1-C4-alkyl, C1-C4-alkyl, -(CH2)2-Het b -(CH2) 2- OH, -(CH2)2-O-C1-C4-alkyl, hydroxy-C1-C4-alkyl, -(CH2)2-O-(CH2)2-O-C1-C4-alkyl and -(CH2)2-diC1-C4-alkylamino, or their stereoisomers, their transisomers, their pharmaceutically acceptable salts, their pharmaceutically acceptable salts, or their transisomers.

39. A kind of formula (Ib) ) compounds, (One ), Among them, A, C, R B2 R B3 and R B4 It is as defined in any of the preceding claims, wherein A is unsubstituted or substituted as defined in any of the preceding claims, or a pharmaceutically acceptable salt thereof.

40. A kind of formula (Ic) ) compounds, (Ic ), Among them, C and R A2 R B2 R B3 and R B4 It is as defined in any of the preceding claims, wherein a is 0, 1, 2 or 3, or a pharmaceutically acceptable salt thereof.

41. A kind of formula (Id) ) compounds, (Id ), Among them, C and R B2 R N R B3 and R B4 It is as defined in any of the preceding claims, wherein the line represents a single bond or a double bond; And R ae It is as defined above.

42. The compound according to any one of the preceding claims, or a stereoisomer thereof, or a transisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a transisomer thereof, selected from any of the examples of compounds.

43. A compound selected from: a( R )-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta-2-yl)prop-2-en-1-one, a( R ()( S )-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(1-(2-(3-fluoropyrrolidine-1-yl)ethyl)-1H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepten-2-yl)prop-2-en-1-one, a( R )1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-phenyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepten-2-yl)prop-2-en-1-one, a( R )1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-methoxyethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta-2-yl)prop-2-en-1-one, a( R )1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-hydroxy-2-methylpropyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta-2-yl)prop-2-en-1-one, a( R )1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-(2-(2-methoxyethoxy)ethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta-2-yl)prop-2-en-1-one, a( R )1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(4-(hydroxymethyl)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta-2-yl)prop-2-en-1-one, a( R )1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-fluoro-4-(2-methoxyethoxy)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepten-2-yl)prop-2-en-1-one, a( R )1-(6-(4-(3-amino-5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-methoxyethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta-2-yl)prop-2-en-1-one, a( R )1-(6-(4-(3-amino-5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-phenyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta-2-yl)prop-2-en-1-one, Or its pharmaceutically acceptable salt.

44. A compound selected from: 1-{6-[(4 M )-4-(5-chloro-6-methyl-1 H -Indazol-4-yl)-5-methyl-3-(1-methyl-1 H -indazole-5-yl)-1 H [-pyrazol-1-yl]-2-azaspiro[3.3]hept-2-yl}prop-2-en-1-one, 1-{6-[(4 M )-4-(5-chloro-6-methyl-1 H -indazole-4-yl)-3-(1-{2-[(3 S )-3-Fluoropyrrolidine-1-yl]ethyl}-1 H -Indazole-5-yl)-5-methyl-1 H [-pyrazol-1-yl]-2-azaspiro[3.3]hept-2-yl}prop-2-en-1-one, 1-{6-[(4 M )-4-(5-chloro-6-methyl-1 H -Indazole-4-yl)-5-methyl-3-phenyl-1 H [-pyrazol-1-yl]-2-azaspiro[3.3]hept-2-yl}prop-2-en-1-one, 1-(6-{(4 M )-4-(5-chloro-6-methyl-1 H -Indazole-4-yl)-3-[2-(2-methoxyethyl)-2 H [-indazole-5-yl]-5-methyl-1 H -pyrazol-1-yl}-2-azaspiro[3.3]hept-2-yl)prop-2-en-1-one, 1-(6-{(4 M )-4-(5-chloro-6-methyl-1 H -Indazole-4-yl)-3-[2-(2-hydroxy-2-methylpropyl)-2 H [-indazole-5-yl]-5-methyl-1 H -pyrazol-1-yl}-2-azaspiro[3.3]hept-2-yl)prop-2-en-1-one, 1-{6-[(4 M )-4-(5-chloro-6-methyl-1 H -Indazole-4-yl)-3-{2-[2-(2-methoxyethoxy)ethyl]-2 H -Indazole-5-yl}-5-methyl-1 H [-pyrazol-1-yl]-2-azaspiro[3.3]hept-2-yl}prop-2-en-1-one, 1-(6-{(4 M )-4-(5-chloro-6-methyl-1 H -Indazole-4-yl)-3-[4-(hydroxymethyl)phenyl]-5-methyl-1 H -pyrazol-1-yl}-2-azaspiro[3.3]hept-2-yl)prop-2-en-1-one, 1-(6-{(4 M )-4-(5-chloro-6-methyl-1 H -Indazol-4-yl)-3-[2-fluoro-4-(2-methoxyethoxy)phenyl]-5-methyl-1 H -pyrazol-1-yl}-2-azaspiro[3.3]hept-2-yl)prop-2-en-1-one, 1-(6-{(4 M )-4-(3-amino-5-chloro-6-methyl-1 H -Indazole-4-yl)-3-[2-(2-methoxyethyl)-2 H [-indazole-5-yl]-5-methyl-1 H -pyrazol-1-yl}-2-azaspiro[3.3]hept-2-yl)prop-2-en-1-one, 1-{6-[(4 M )-4-(3-amino-5-chloro-6-methyl-1 H -Indazole-4-yl)-5-methyl-3-phenyl-1 H [-pyrazol-1-yl]-2-azaspiro[3.3]hept-2-yl}prop-2-en-1-one, Or its pharmaceutically acceptable salt.

45. A crystalline form of a compound according to any one of the preceding claims.

46. ​​The compound according to any one of the preceding claims, or its stereoisomer, its transisomer, its pharmaceutically acceptable salt, its crystalline form, its stereoisomer, or its transisomer, for use as a medicament.

47. The compound according to any one of the preceding claims, or a stereoisomer thereof, or a transisomer thereof, or a pharmaceutically acceptable salt thereof, or a crystalline form thereof, or a pharmaceutically acceptable salt thereof, or a transisomer thereof, for use in the treatment of cancer or solid tumors.

48. A pharmaceutical composition comprising a compound according to any one of the preceding claims, or a stereoisomer thereof, or a transisomer thereof, or a pharmaceutically acceptable salt thereof, or a crystalline form thereof, or a pharmaceutically acceptable salt thereof, or a transisomer thereof, and at least one pharmaceutically acceptable excipient.

49. A compound having formula (2a), (2a) Where A, B, and C are as defined in any of the preceding claims and R 25 It is a hydrogen or nitrogen protecting group, or a salt thereof.

50. A kind of formula (2b) ) compounds, (2b ) Among them, A, C, R B2 R B3 and R B4 R is as defined in any of the preceding claims. 25 It is a hydrogen or nitrogen protecting group, wherein A is unsubstituted or substituted as defined in any of the preceding claims, or a salt thereof.

51. A kind of formula (2c) ) compounds, (2c ). Among them, C and R A2 R B2 R B3 and R B4 R is as defined in any of the preceding claims. 25 It is a hydrogen or nitrogen protecting group, wherein a is 0, 1, 2 or 3, or a pharmaceutically acceptable salt thereof.

52. A kind of formula (2d) ) compounds, (2d )， Among them, C and R ae R B2 R N R B3 and R B4 R is as defined in any of the preceding claims. 25 It is a hydrogen or nitrogen protecting group, where the ---- line indicates a single or double bond, or a salt thereof.

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