Pyrazolyl derivatives useful as anticancer agents

Abstract

The present application relates to a compound of formula (I) [Formula 1] TIFF2023506841000215.tif43170 or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof; processes for preparing said compounds, and therapeutic uses thereof. The present application further provides pharmacologically active agent combinations and pharmaceutical compositions comprising said compounds.

Description

[Technical Field]

[0001] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in ASCII format, and is incorporated herein by reference in its entirety. The ASCII copy, created on December 1, 2020, is named PAT058632-WO-PCT02_SL.txt and is 7,192 bytes in size.

[0002] The present invention provides pyrazolyl derivative compounds, their use for inhibiting KRAS G12C, HRAS G12C or NRAS G12C, particularly KRAS G12C, methods of using said compounds to treat or prevent diseases, particularly cancer, and methods and intermediates for making these compounds. The present invention also provides these pyrazolyl derivative compounds for use in the treatment of cancer and certain cancers as defined herein. [Background technology]

[0003] RAS is a small GTPase that acts as a molecular on / off switch, adopting active and inactive states when bound to GTP or GDP, respectively. In response to growth factors, guanine exchange factors exchange GDP for GTP, turning on Ras. GTP-bound RAS adopts a conformation that recruits effector proteins to the cell membrane, thereby activating signaling cascades that lead to cell growth, proliferation, and survival. These pro-oncogenic signals are highly transient and tightly regulated. They are quickly turned off by the GTPase activity of RAS itself, primarily due to a 100,000-fold acceleration by GTPase-activating proteins (GAPs) (Bos JL et al., Cell, Volume 129, Issue 5, 1 June 2007, pp. 865-877). In contrast, RAS mutants are insensitive to these GAPs, so they exist longer in the GTP-bound state and switch the GTP / GDP cycle to the on state due to their intrinsic hydrolysis rate.

[0004] The three RAS genes constitute the most frequently mutated gene family in cancer, with RAS mutations occurring in approximately 25% of human tumors. Among the three paralogs, KRAS mutations are the most common (85% of all RAS-driven cancers), while NRAS and HRAS mutations are reported less frequently (12% and 3%, respectively). The majority of KRAS mutations occur at hotspot residues G12, G13, and Q61. The KRAS G12C mutation accounts for approximately 12% of all KRAS mutations and is commonly found in lung cancer patients (approximately 13% of lung adenomatous carcinomas [LUAC]), approximately 3-5% of colon adenocarcinomas, lesser proportions of other cancer types, and approximately 20% of MYH polyposis colorectal adenomas (COSMIC v80 database; A. Aime et al., Cancer Genet. 2015, 208:390-5).

[0005] Patients with KRAS G12C-positive solid tumors are inadequately treated with current therapies. Currently, there are no inhibitors of KRAS G12C, HRAS G12C, or NRAS G12C approved for therapeutic use.

[0006] Therefore, there remains a continuing need to develop new options for the treatment of cancer, particularly cancer tumors expressing G12C mutant Ras, and in particular for the treatment of KRAS, HRAS, or NRAS G12C-driven cancers. More particularly, there remains a need for the treatment of KRAS G12C mutant cancers.

[0007] Irreversible RAS G12C inhibitors have been previously described (e.g., WO2014152588, WO2017201161, WO2018 / 217651, and WO2018119183). Summary of the Invention

[0008] 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 the cysteine at position 12. This locks the RAS mutant proteins in an inactive state. The irreversible binding of these compounds prevents K-RAS downstream signaling. The compounds described in this invention can be used to treat cancer, particularly cancers characterized by KRAS, HRAS, or NRAS G12C mutations, more particularly cancers characterized by KRAS G12C mutations.

[0009] Thus, the present invention provides compounds, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and combinations thereof. The compounds can selectively bind to and inhibit G12C mutants of KRAS, HRAS, or NRAS, and may be useful in the treatment of cancer, particularly cancers characterized by KRAS, HRAS, or NRAS G12C mutations. The present invention also provides methods for making such compounds and intermediates useful in the synthesis of such compounds.

[0010] Various embodiments or aspects of the present invention are described herein.

[0011] A compound of formula (I) as defined herein [ka] or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof.

[0012] In another embodiment, the present invention provides a compound of formula (I) as defined herein, or an atropisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the atropisomer thereof.

[0013] In another embodiment, the present invention provides a compound of formula (I) (or sub-formula (Ia), (Ib) * ),(I C * ), (Id * ) or (Ie)), or an atropisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the atropisomer thereof.

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

[0015] In another embodiment, the present invention provides a compound of formula (I) (or sub-formula (Ia), (Ib) * ),(I C * ), (Id * ) or (Ie)), or a pharmaceutically acceptable salt thereof.

[0016] In another embodiment, the present invention provides a compound of formula (I) (or its subformulas (Ia), (Ib) * ),(I C * ), (Id * ) or (Ie)), or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof, and one or more pharmaceutically acceptable carriers.

[0017] In another embodiment, the present invention provides a compound of formula (I), (or its sub-formulas (Ia), (Ib) * ),(I C * ), (Id * ) or (Ie)), or a therapeutically effective amount of a compound of formula (I), (or its sub-formulas (Ia), (Ib * ),(I C * ), (Id *) or (Ie)), or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, and optionally one or more pharmaceutically acceptable carriers.

[0018] In another embodiment, the present invention provides a compound of formula (I), (or its sub-formulas (Ia), (Ib) * ),(I C * ), (Id * ) or (Ie)), or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, and one or more therapeutically active agents.

[0019] In another embodiment, the present invention provides a compound of formula (I), (or its sub-formulas (Ia), (Ib) * ),(I C * ), (Id * ) or (Ie)), or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, and one or more therapeutically active agents.

[0020] In a further embodiment, the present invention provides a method of inhibiting a G12C mutant KRAS, HRAS, or NRAS protein (e.g., a G12C mutant KRAS protein) in a subject in need thereof, comprising administering a therapeutically effective amount of a compound represented by formula (I) or sub-formulas (Ia), (Ib), or (Ic) thereof as defined herein. * ),(I C * ), (Id * or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the atropisomer, to a subject.

[0021] In yet another embodiment, the present invention provides a method of treating a disorder or disease in a subject in need thereof, wherein the disorder or disease is selected from cancer, for example, lung cancer (including lung adenocarcinoma and non-small cell lung cancer), colorectal cancer (including colorectal adenocarcinoma), pancreatic cancer (including pancreatic adenocarcinoma), uterine cancer (including endometrial cancer), rectal cancer (including rectal adenocarcinoma), and other solid tumors, comprising administering a therapeutically effective amount of a compound represented by formula (I) or sub-formulas (Ia), (Ib), or (Ic) as defined herein. * ),(I C * ), (Id * or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the atropisomer, to a subject.

[0022] In another embodiment, the present invention provides intermediate compounds useful for making the compounds of the present invention as well as compounds of formula (I) or sub-formulas (Ia), (Ib) and (Ic) as defined herein. * ),(I C * ), (Id * ) or (Ie), or a stereoisomer thereof, or an atropisomer thereof. [Brief explanation of the drawings]

[0023] [Figure 1] FIG. 1 shows the X-ray powder diffraction pattern of (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]heptan-2-yl)prop-2-en-1-one (Compound X) hydrate (modified HA). [Figure 2] FIG. 1 shows the X-ray powder diffraction pattern of the isopropyl alcohol (IPA) solvate of (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]heptan-2-yl)prop-2-en-1-one (Compound X). [Figure 3] FIG. 1 shows the X-ray powder diffraction pattern of the ethanol (EtOH) solvate of (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]heptan-2-yl)prop-2-en-1-one (Compound X). [Figure 4] FIG. 1 shows the X-ray powder diffraction pattern of the propylene glycol solvate of (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]heptan-2-yl)prop-2-en-1-one (Compound X). DETAILED DESCRIPTION OF THE INVENTION

[0024] In a first aspect, the present invention provides a compound of formula (I) [ka] (A, (a) C5-C alkyl, unsubstituted or substituted with one or more, preferably one, two or three, substituents independently selected from fluoro and C1-C4 alkyl. 7- cycloalkylene; (b) a 5- to 7-membered unsaturated heterocyclyl containing one carbon-carbon double bond and one oxygen atom as a ring member, said heterocyclyl being unsubstituted or substituted with one or more, preferably one, two or three, substituents independently selected from fluoro and C1-C4-alkyl, preferably one, two or three C1-C4-alkyl; (c) unsubstituted or 1, 2 or 3 R A2 C6~C substituted with 10 aryl; (da) a 5- to 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 at one or more (e.g., 1, 2, or 3) carbon atoms; A3 and the nitrogen atom, if present in the heteroaryl ring, is unsubstituted or C1-C4-alkyl, -(CH2) 1~2 -C 3~4 -cycloalkyl, C3-C6-cycloalkyl, hydroxy-C1-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 substituent is 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), heteroaryl ring; (e) an 8- to 10-membered heteroaryl ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or an 8- to 10-membered partially saturated heterobicyclic ring containing 1 to 3 heteroatoms or heteroatom groups 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 in the heterobicyclic ring, wherein the heteroaryl ring or heterobicyclic ring is unsubstituted or has 1, 2, 3, 4, or 5 R groups at the carbon atoms; A4the heterobicyclic ring is further optionally substituted at a carbon atom by oxo, and the nitrogen atom, if present, is unsubstituted or substituted by a substituent which is -(CO)-C1-C4-alkyl or C1-C4-alkyl, said C1-C4-alkyl being selected from the group consisting of cyano, hydroxy, oxo, fluoro, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 a heteroaryl or heterobicyclic ring optionally substituted with one or two substituents independently selected from selected from the group consisting of: Here, Het b is a 4-, 5- or 6-membered heterocyclic ring containing one or two heteroatoms or groups independently 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 to two nitrogen atoms), wherein said heterocyclic ring Het b is unsubstituted or substituted at a carbon atom with one or two substituents independently selected from C1-C4-alkyl, hydroxy, cyano, fluoro, C1-C4-alkoxy-hydroxy-C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy, fluoro-C1-C4-alkoxy and fluoro-C1-C4-alkyl, wherein the heterocycle Het b is further optionally substituted at a carbon atom with oxo, wherein the nitrogen atom is Het b when present, optionally further substituted with C1-C4-alkyl, optionally substituted with 1 to 3 substituents independently selected from fluoro, hydroxy and C1-C4-alkoxy; Here, A is sp 2 is attached to the remainder of the compound of formula (I) by a carbon atom in the hybridized A; where: B is B 1 and B 2 is selected from the group consisting of where B 1is unsubstituted or 1, 2, 3 or 4 R Ba C replaced by 6~10 is aryl; B 2 is a 6- to 13-membered heteroaryl containing 1, 2, or 3 nitrogen atoms, where B 2 is unsubstituted or 1, 2, 3 or 4 R Bb is replaced by; 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 halo; L, [ka] is selected from the group consisting of where n is 1, 2 or 3; R L is selected from hydrogen, methyl, ethyl, —CH—CN and —CH—OH, wherein G * represents the point of attachment to G; G, [ka] is selected from the group consisting of During the ceremony, R 2 is selected from hydrogen, C1-C3 alkyl, —C(O)—C1-C3-alkyl, and fluoro; R 3 is hydrogen; R 4 is selected from hydrogen, methyl, —CHF, —CH—OCH and —CH—N(CH); R 5 is selected from hydrogen and methyl; R 6 is hydrogen; R 7is selected from hydrogen and methyl; where R A2 But independently, NR 9 R 10 , cyano, -(CH2) p -CN, halo, OH, hydroxy-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-oxy, 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, NR 9 R 10 , cyano, C1-C4-alkyl, fluoro, fluoro-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 selected from the group consisting of; where R A3 However, independently, oxo, NR 9 R 10 , cyano, -(CH2) p -CN, halo, OH, hydroxy-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-oxy, 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, NR 9 R 10 , cyano, C1-C4-alkyl, fluoro, fluoro-C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Het py and -(CH2) p -Het py selected from the group consisting of; where R A4are independently selected from cyano, CO2H, halo, 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 selected from the group consisting of N-C1-C4-alkyl-oxy-(CO)-C1-C4-alkyl; where: p is 1, 2, or 3; R 9 is selected from hydrogen and C1-C4-alkyl; R 10 is 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 is a 4-, 5-, 6- or 7-membered saturated heterocycle containing 1 or 2 heteroatoms independently selected from O, N (such as pyrrolidin-1-yl, azetidin-1-yl, morpholin-1-yl) and S or containing an S-oxide (SO) or S-dioxide (SO2) group, wherein said heterocycle is optionally substituted at one carbon atom with oxo, wherein said heterocycle is optionally further substituted at one or more carbon atoms with 1, 2 or 3 substituents independently selected from C1-C4-alkoxy (preferably methoxy), halo (preferably fluoro), C1-C4-alkyl, hydroxy-C1-C4-alkyl and fluoro-C1-C4-alkyl, wherein if a nitrogen atom is present in said heterocycle, R 10 (preferably C1-C4-alkyl (such as methyl)); or Het py is a 5- or 6-membered heteroaryl ring containing 1, 2 or 3 nitrogen atoms (preferably 1,2,4-triazol-1-yl or pyrazol-1-yl), wherein the heteroaryl ring is NR 9 R 10 , -C(=O)-NR 9 R 10 , halo, C1-C4-alkyl, hydroxy-C1-C4-alkyl, fluoro-C1-C4-alkyl, cyano, OH, and C1-C4-alkoxy; Each R Ba are independently selected from the group consisting of hydroxy, NH2, C1-C4-alkyl and halo; Each R Bb are independently selected from the group consisting of C1-C4-alkyl (preferably methyl), cyclopropyl, fluoro-C1-C3-alkyl (preferably CHF2 or CF3), cyano, halo (preferably fluoro or chloro), NH2 and C1-C3-alkoxy (preferably methoxy), or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof.

[0025] In a second aspect, the present invention provides a compound of formula (I) [ka] (A, (a) C5-C alkyl, unsubstituted or substituted with one or more, preferably one, two or three, substituents independently selected from fluoro and C1-C4 alkyl. 7- cycloalkylene; (b) a 5- to 7-membered unsaturated heterocyclyl containing one carbon-carbon double bond and one oxygen atom as a ring member, said heterocyclyl being unsubstituted or substituted with one or more, preferably one, two or three, substituents independently selected from fluoro and C1-C4-alkyl, preferably one, two or three C1-C4-alkyl; (c) unsubstituted or 1, 2 or 3 R A2 C6~C substituted with 10 aryl; (d) A 5- to 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 at one or more (e.g., 1, 2, or 3) carbon atoms. A3 and the nitrogen atom, if present in the heteroaryl ring, is unsubstituted or C1-C4-alkyl, -(CH2) 1~2 -C 3~4 -cycloalkyl, C3-C6-cycloalkyl, hydroxy-C1-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 substituent is 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), heteroaryl ring; (e) an 8- to 10-membered heteroaryl ring containing 1, 2, or 3 nitrogen atoms, or an 8- to 10-membered partially saturated heterobicyclic ring containing 1 to 3 heteroatoms or heteroatom groups independently selected from 0 to 3 nitrogen atoms, 0 to 2 oxygen atoms, 0 to 1 sulfur atoms, and 0 to 1 S(═O)2 groups in the heterobicyclic ring, wherein the heteroaryl ring or heterobicyclic ring is unsubstituted or has 1, 2, 3, 4, or 5 R groups at the carbon atoms; A4 the heterobicyclic ring is further optionally substituted at a carbon atom by oxo, and the nitrogen atom, if present, is unsubstituted or substituted by a substituent which is -(CO)-C1-C4-alkyl or C1-C4-alkyl, said C1-C4-alkyl being selected from the group consisting of cyano, hydroxy, oxo, fluoro, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 a heteroaryl or heterobicyclic ring optionally substituted with one or two substituents independently selected from selected from the group consisting of: Here, Het b is a 4-, 5- or 6-membered heterocyclic ring containing one or two heteroatoms or groups independently 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 to two nitrogen atoms), wherein said heterocyclic ring Het b is unsubstituted or substituted at a carbon atom with one or two substituents independently selected from C1-C4-alkyl, hydroxy, cyano, fluoro, C1-C4-alkoxy-hydroxy-C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy, fluoro-C1-C4-alkoxy and fluoro-C1-C4-alkyl, wherein the heterocycle Het b is further optionally substituted at a carbon atom with oxo, wherein the nitrogen atom is Het bwhen present, optionally further substituted with C1-C4-alkyl, optionally substituted with 1 to 3 substituents independently selected from fluoro, hydroxy and C1-C4-alkoxy; Here, A is sp 2 is attached to the remainder of the compound of formula (I) by a carbon atom in the hybridized A; where: B is B 1 and B 2 is selected from the group consisting of where B 1 is unsubstituted or 1, 2, 3 or 4 R Ba C replaced by 6~10 is aryl; B 2 is a 6- to 13-membered heteroaryl containing 1, 2, or 3 nitrogen atoms, where B 2 is unsubstituted or 1, 2, 3 or 4 R Bb is replaced by; 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 halo; L, [ka] is selected from the group consisting of where n is 1, 2 or 3; R L is selected from hydrogen, methyl, ethyl, —CH—CN and —CH—OH, wherein G * represents the point of attachment to G; G, [ka] is selected from the group consisting of During the ceremony, R 2is selected from hydrogen, C1-C3 alkyl, —C(O)—C1-C3-alkyl, and fluoro; R 3 is hydrogen; R 4 is selected from hydrogen, methyl, —CHF, —CH—OCH and —CH—N(CH); R 5 is selected from hydrogen and methyl; R 6 is hydrogen; R 7 is selected from hydrogen and methyl; where R A2 But independently, NR 9 R 10 , cyano, -(CH2) p -CN, halo, OH, hydroxy-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-oxy, 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, NR9 R 10 , cyano, C1-C4-alkyl, fluoro, fluoro-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 selected from the group consisting of; where R A3 However, independently, oxo, NR 9 R 10 , cyano, -(CH2) p -CN, halo, OH, hydroxy-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-oxy, 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, NR 9 R 10 , cyano, C1-C4-alkyl, fluoro, fluoro-C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Het py and -(CH2) p -Het py selected from the group consisting of; where R A4 are independently selected from cyano, CO2H, halo, 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 selected from the group consisting of N-C1-C4-alkyl-oxy-(CO)-C1-C4-alkyl; where: p is 1, 2, or 3; R 9 is selected from hydrogen and C1-C4-alkyl; R 10 is 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 pyis a 4-, 5-, 6- or 7-membered saturated heterocycle containing 1 or 2 heteroatoms independently selected from O, N (such as pyrrolidin-1-yl, azetidin-1-yl, morpholin-1-yl) and S or containing an S-oxide (SO) or S-dioxide (SO2) group, wherein said heterocycle is optionally substituted at one carbon atom with oxo, wherein said heterocycle is optionally further substituted at one or more carbon atoms with 1, 2 or 3 substituents independently selected from C1-C4-alkoxy (preferably methoxy), halo (preferably fluoro), C1-C4-alkyl, hydroxy-C1-C4-alkyl and fluoro-C1-C4-alkyl, wherein if a nitrogen atom is present in said heterocycle, R 10 (preferably C1-C4-alkyl (such as methyl)); or Het py is a 5- or 6-membered heteroaryl ring containing 1, 2 or 3 nitrogen atoms (preferably 1,2,4-triazol-1-yl or pyrazol-1-yl), wherein the heteroaryl ring is NR 9 R 10 , -C(=O)-NR 9 R 10 , halo, C1-C4-alkyl, hydroxy-C1-C4-alkyl, fluoro-C1-C4-alkyl, cyano, OH, and C1-C4-alkoxy; Each R Ba are independently selected from the group consisting of hydroxy, NH2, C1-C4-alkyl and halo; Each R Bb are independently selected from the group consisting of C1-C4-alkyl (preferably methyl), cyclopropyl, fluoro-C1-C3-alkyl (preferably CHF2 or CF3), cyano, halo (preferably fluoro or chloro), NH2 and C1-C3-alkoxy (preferably methoxy), or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof.

[0026] When the term "preferably" is mentioned herein, another embodiment of the present invention relates in particular to compounds of formula (I), or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, in which all moieties or features specifically mentioned after the term "preferably" replace the more general term immediately preceding what they designate.

[0027] In a further aspect, there is provided a compound of formula (I), or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, for use as a medicament.

[0028] In a further aspect, there is provided a compound of formula (I), or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, for use in the treatment of a disorder or disease mediated by a KRAS, NRAS or HRAS G12C mutation, such as a KRAS G12C mutation (e.g., cancer).

[0029] In a further aspect, there is provided a compound of formula (I), or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, for the manufacture of a medicament for the treatment of cancer, for example cancer mediated by a KRAS, NRAS or HRAS G12C mutation.

[0030] In a further aspect, there is provided a method of treating a disorder or cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I), or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the atropisomer thereof.

[0031] In a further aspect, there is provided a method of treating a disorder or disease in a subject in need thereof, for example a cancer selected from lung cancer (including lung adenocarcinoma and non-small cell lung cancer), colorectal cancer (including colorectal adenocarcinoma), pancreatic cancer (including pancreatic adenocarcinoma), uterine cancer (including endometrial cancer), rectal cancer (including rectal adenocarcinoma) and solid tumors, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I), as defined herein, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof.

[0032] In a further aspect, there is provided a compound of formula (I), or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof, for use in the treatment of cancer, for example lung cancer (including lung adenocarcinoma and non-small cell lung cancer), colorectal cancer (including colorectal adenocarcinoma), pancreatic cancer (including pancreatic adenocarcinoma), uterine cancer (including endometrial cancer), rectal cancer (including rectal adenocarcinoma) and solid tumors.

[0033] In a further aspect, there is provided a compound of formula (I), or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof, for use in the treatment of cancer, such as lung cancer (including lung adenocarcinoma and non-small cell lung cancer), colorectal cancer (including colorectal adenocarcinoma), pancreatic cancer (including pancreatic adenocarcinoma), uterine cancer (including endometrial cancer), rectal cancer (including rectal adenocarcinoma) and solid tumours, wherein the cancer is KRAS-, NRAS- or HRAS-G12C mutant, typically wherein the cancer is KRAS-G12C mutant.

[0034] In a further aspect, there is provided a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, and a pharmaceutically acceptable carrier.

[0035] In a further aspect, there is provided a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, for use as a medicament.

[0036] In a further aspect, there is provided a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, for use in the treatment of cancer, such as lung cancer (including lung adenocarcinoma and non-small cell lung cancer), colorectal cancer (including colorectal adenocarcinoma), pancreatic cancer (including pancreatic adenocarcinoma), uterine cancer (including endometrial cancer), rectal cancer (including rectal adenocarcinoma) and solid tumors, optionally where the cancer is a KRAS-, NRAS- or HRAS-G12C mutant.

[0037] In a further aspect, there is provided a combination comprising a compound of formula (I), or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, and one or more therapeutically active agents.

[0038] In a further aspect, there is provided a process for the preparation of a compound of formula (I), or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof.

[0039] Unless otherwise specified and unless the context clearly indicates otherwise, the term "a compound of the invention" or "compounds of the invention" or "compounds of formula (I)" or "a compound of formula (I)" refers to compounds of formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij ... * ),(I C * ), (Id * ) and (Ie), and pharmaceutically acceptable salts thereof, as well as stereoisomers (including diastereoisomers and enantiomers), atropisomers, rotamers, tautomers, and isotopically labeled compounds (including deuterium substitutions), and inherently formed moieties.

[0040] It will be understood that compounds prepared as intermediates may also be considered compounds of the invention.

[0041] Therefore, Equation 2(a), (2b * ), (2c * ) and (2d * ), as well as salts thereof, are also considered compounds of the invention.

[0042] Therefore, unless otherwise specified and unless the context clearly indicates otherwise, the term "compound of formula (I)" or "compound of formula (I), or a pharmaceutically acceptable salt thereof" refers to a compound of formula (I), (Ia), (Ib), (Ic), (Id), (Ig), (Ih), (Ii), (Ij ... * ),(I C * ), (Id * ) and (Ie), or atropisomers thereof, or pharmaceutically acceptable salts thereof, or compounds of formula (I), (Ia), (Ib * ),(I C * ), (Id * ) and (Ie), or pharmaceutically acceptable salts of the stereoisomers of the compounds of formula (I), (Ia), (Ib * ),(I C * ), (Id * ) and (Ie) and the pharmaceutically acceptable salts of the atropisomers of the compounds of formula (Ie).

[0043] Formula (I), (Ia), (Ib * ),(I C * ), (Id * The compounds of formula 2(a), (2b) and (Ie) include all stereoisomers, including diastereoisomers, atropisomers, enantiomers, mixtures thereof, and racemic mixtures, including pharmaceutically acceptable salts thereof. * ), (2c * ) and (2d * ) also includes all stereoisomers, including diastereoisomers, atropisomers, enantiomers, mixtures thereof and racemic mixtures, including salts thereof.

[0044] When one isomer (e.g., enantiomer, diastereomer, atropisomer, or geometric isomer) has greater intrinsic activity as an inhibitor of a RAS G12C mutant protein than its opposite isomer, the more active isomer is typically preferred.

[0045] The presence of diastereoisomers can be identified by those skilled in the art using means such as NMR. Separation of diastereoisomers can be carried out 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 techniques. Separation of enantiomers can be carried out by those skilled in the art using means such as chiral HPLC, chiral SFC, chiral GC, etc.

[0046] The compounds of the present invention, particularly ortho-substituted biaryl compounds, can exhibit conformational and rotational isomerism, referred to herein as atropisomers (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 bi-aryl ring moiety, such biaryl compounds of the present invention exhibit atropisomerism.

[0047] Thus, the formula (I) and the sub-formulas (Ia), (Ib * ),(I C * ), (Id * ) and (Ie) and their isomeric mixtures (including diastereomeric mixtures, enantiomeric mixtures and racemic mixtures) are also part of the present invention. * ),(I C * ), (Id * "Diastereomerically enriched" or "enantiomerically enriched" mixtures of compounds of formula (Ie) and (Ie) are also part of the present invention.

[0048] The present invention also provides crystalline forms of Compound X as defined herein, such as a hydrate (modified HA) crystalline form of Compound X, or an isopropyl alcohol (IPA) solvate crystalline form, or an ethanol (EtOH) solvate crystalline form, or a propylene glycol solvate crystalline form.

[0049] The present invention also provides a crystalline form of Compound X as defined herein, having an X-ray powder diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in Figure 1, Figure 2, Figure 3 or Figure 4.

[0050] Unless otherwise indicated or clear from the context, the following definitions also apply: As used herein, the term "halogen" (or halo) refers to fluorine, bromine, chlorine, or iodine. Halogen-substituted groups and moieties, such as alkyl substituted with halogen (halo-alkyl), can be mono-, poly-, or perhalogenated. Chloro and fluoro are preferred halo substituents on alkyl or cycloalkyl groups, with fluoro being most preferred unless otherwise specified. Fluoro, chloro, and bromo are often preferred on aryl or heteroaryl groups, with fluoro being most preferred unless otherwise specified.

[0051] As used herein, unless otherwise indicated, the term "heteroatom" refers to a nitrogen (N), oxygen (O) or sulfur (S) atom, in particular nitrogen or oxygen.

[0052] When multiple substituents are present, the substituents are independently selected unless otherwise indicated; when two or three substituents are present, for example, the substituents can be the same or different.

[0053] As used herein, the term "C1-C4-alkyl" refers to a straight or branched hydrocarbon chain radical containing no unsaturation, having from 1 to 4 carbon atoms, and consisting solely of carbon and hydrogen atoms, attached to the remainder 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.

[0054] C1-C4-Alkyl groups when substituted by oxo include -C(O)-C1-C3-alkyl, in which the carbonyl moiety of the substituent is attached to the remainder of the molecule.

[0055] As used herein, the term "hydroxy-C1-C4-alkyl" refers to a C1-C4-alkyl group as defined above, in which one of the hydrogen atoms of the C1-C4-alkyl group has been replaced by OH. Examples of hydroxy-C1-C4-alkyl include, but are not limited to, hydroxy-methyl, 2-hydroxy-ethyl, 2-hydroxy-propyl, 3-hydroxy-propyl and 2-hydroxy-2-methyl-propyl.

[0056] As used herein, the term "C1-C4-alkoxy" refers to a group of the formula -OR a where R a is a C1-C4 alkyl group as generally defined above. Examples of C1-C4-alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy and butoxy.

[0057] As used herein, the term "hydroxy C1-C4-alkoxy" refers to a C1-C4-alkoxy group as defined above, wherein at least one of the hydrogen atoms of the C1-C4-alkoxy group is replaced by OH. 1~4 Examples of alkoxy include, but are not limited to, hydroxymethoxy, hydroxyethoxy, and 2-hydroxypropoxy.

[0058] As used herein, the term "C1-C4-alkyl-oxy" refers to a "C1-C4-alkyl" group as defined above, wherein said group is attached to the rest of the molecule by an oxygen atom.

[0059] As used herein, a "hydroxy-C1-C4-alkyl-oxy" substituent refers to a hydroxy-C1-C4-alkyl group as defined above that is attached to the remainder of the molecule by an oxygen atom. Examples of hydroxy-C1-C4-alkyl-oxy include, but are not limited to, hydroxymethoxy, hydroxyethoxy, 2-hydroxypropoxy.

[0060] As used herein, the term "C1-C4-alkoxy-C1-C4-alkyl" refers to a C1-C4-alkyl group as defined above, in which one of the hydrogen atoms of the C1-C4-alkyl group is replaced by a C1-C4-alkoxy.

[0061] 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 at least one of the hydrogen atoms of the C1-C4-alkyl group is replaced by OH.

[0062] As used herein, the term "C1-C4-alkoxy-C1-C4-alkyl-oxy" refers to "C1-C4-alkoxy-C1-C4-alkyl" as defined above, wherein said group is attached to the rest of the molecule via an oxygen atom.

[0063] As used herein, the term "C1-C4-alkyl-carbonyl-oxy-C1-C4-alkyl-oxy" refers to a group of formula C1-C4-alkyl-C(═O)—O—C1-C4-alkyl-O—, wherein said group is attached to the rest of the molecule by the last oxygen atom.

[0064] As used herein, the term "halo-alkyl" refers to an alkyl, as defined herein, substituted with one or more halo groups, as defined above. The halo-alkyl may be a monohalo-alkyl, a dihalo-alkyl, a trihalo-alkyl, or a polyhalo-alkyl, including a perhalo-alkyl. The monohalo-alkyl may have one iodo, bromo, chloro, or fluoro in the alkyl group. Chloro and fluoro are preferred in the alkyl or cycloalkyl group.

[0065] As used herein, the term "fluoro-alkyl" refers to an alkyl, as defined herein, substituted with one or more fluoro groups. Non-limiting examples of fluoro-C1-C4-alkyl include trifluoromethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-fluoropropyl, 3,3-difluoropropyl, and 1-fluoromethyl-2-fluoroethyl. Preferred fluoro-alkyl groups, unless otherwise specified, include monofluoro-, difluoro-, and trifluoro-substituted methyl and ethyl groups, such as CF3, CF2H, CFH2, and CH2CF3.

[0066] As used herein, the term "fluoro-alkoxy" refers to an alkoxy, as defined herein, substituted with one or more fluoro.

[0067] As used herein, the term "C1-C4-alkylamino" refers to a group of the formula -NH-R a where R a is a C1-C4-alkyl group as defined above.

[0068] As used herein, "di-C1-C 4- The term "alkylamino" refers to a group of the formula --N(R a )-R a where each R a are C1-C4-alkyl groups, which may be the same or different, as defined above.

[0069] As used herein, "NR 9 R 10 " or "N(R 9 )(R 10 )" substituent has the formula "-N(R 9 )(R 10 )" group, where the group is attached to the rest of the molecule by a nitrogen atom and has R 9 Groups and R 10 groups are also attached, where R 9 and R 10 may be the same or different and are as defined herein.

[0070] As used herein, "R 9 R 10 N-C1-C4-alkyl" or "N(R 9 )(R 10 The term "C1-C4-alkyl" refers to a group in which one of the hydrogen atoms of the C1-C4-alkyl group is replaced by an -N(R 9 )(R 10 ) is substituted with C1-C4 alkyl group as defined above.

[0071] As used herein, "R 9 R 10 N-C1-C4-alkyl-oxy" or "N(R 9 )(R 10 The term "C1-C4-alkyl-oxy" refers to an R radical as defined above attached to the rest of the molecule by an oxygen atom. 9 R 10 N-C1-C4-alkyl group (or N(R 9 )(R 10 )-C1 to C4-alkyl group).

[0072] As used herein, "N(R 9 )(R 10 The term "C1-C4-alkoxy" refers to a group in which one of the hydrogen atoms of the C1-C4-alkoxy group is replaced by -N(R 9 )(R 10) is a C1-C4 alkoxy group as defined above substituted with

[0073] As used herein, the term "-SO2-C1-C4-alkyl" refers to a C1-C4-alkyl group as defined above attached to the remainder of the molecule via a -S(=O)2- linker.

[0074] As used herein, the term "-SO2-C3-C4-cycloalkyl" refers to a C3-C4-cycloalkyl group as defined above attached to the remainder of the molecule via a -S(=O)2- linker.

[0075] As used herein, "hydroxy-C 1~4 The term "-alkoxy" refers to 1~4 - C as defined above, in which at least one of the hydrogen atoms of the alkoxy group is replaced by OH 1~4 -alkoxy groups. Examples of hydroxy C1-C6 alkoxy include, but are not limited to, hydroxymethoxy, hydroxyethoxy, and 2-hydroxypropoxy.

[0076] As used herein, the term "C1-C4 alkoxy-C1-C4 alkyl" refers to a C 1~4 C as defined above, in which one of the hydrogen atoms of the alkyl group is replaced by C1-C4-alkoxy. 1~4 Refers to an alkyl group.

[0077] As used herein, the term "C1-C4-alkoxy-C1-C4-alkyl-oxy" refers to "C1-C4 alkoxy-C1-C4 alkyl" as defined above, wherein said group is attached to the rest of the molecule by an oxygen atom.

[0078] As used herein, "C(O)-NR 9 R 10 The term "" refers to a compound of the formula -R a1 -NR 9 R 10where R a1 is a carbonyl group, and "NR 9 R 10 " is as defined above, and R 9 and R 10 may be the same or different and are as defined herein.

[0079] As used herein, the term "C(O)C1-C4-alkyl" refers to a group of the formula -R a1 -C1-C4-alkyl group, where R a1 is a carbonyl group and C1-C4-alkyl is as defined above.

[0080] As used herein, the term "cycloalkyl" refers to a saturated carbocyclic ring radical. C3-C7 cycloalkyl is any such ring radical containing from 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0081] As used herein, the term "cycloalkylene" refers to a non-aromatic carbocyclic ring radical containing at least one carbon-carbon double bond, preferably one. The term "monocyclic cycloalkylene" refers to a non-aromatic monocyclic carbocyclic ring radical containing at least one carbon-carbon double bond, preferably one carbon-carbon double bond. This term includes, but is not limited to, "C5-C7-cycloalkylene," a non-aromatic carbocyclic ring radical containing 5 to 7 carbon atoms and one C-C double bond. Examples of suitable cycloalkylene groups are non-aromatic carbocyclic rings 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).

[0082] As used herein, the term "aryl" refers to an aromatic hydrocarbon group having 6 to 14 carbon atoms in the ring portion. Typically, aryl is a monocyclic, bicyclic, or tricyclic aryl having 6 to 14 carbon atoms, often 6 to 10 carbon atoms, such as phenyl or naphthyl. Phenyl is sometimes preferred. Furthermore, as used herein, the term "aryl" refers to an aromatic substituent that can be a single aromatic ring or multiple aromatic rings fused together. Non-limiting examples include phenyl, naphthyl, and 1,2,3,4-tetrahydronaphthyl, where the tetrahydronaphthyl is attached to the depicted formula via a carbon of the aromatic ring of the tetrahydronaphthyl group.

[0083] "C6~C 10 The term "aryl" refers to a phenyl, 1,2,3,4-tetrahydronaphthyl, or naphthyl group. 10 An example of an aryl is a phenyl group. The term "phenyl" refers to a group of formula -CH. In a substituted phenyl, one or more of the hydrogen atoms in -CH are replaced with one or more substituents, particularly any one described herein.

[0084] As used herein, the term "heterocyclyl" or "heterocycle" refers to a heterocyclic group that may be saturated or partially unsaturated, but not aromatic, and may be monocyclic or polycyclic, including fused or bridged bicyclic ring systems. A heterocycle or heterocyclyl contains at least one non-carbon atom as a ring member, typically N, O, or S, unless otherwise specified. Unless otherwise specified, a heterocyclyl group has 3 to 10, preferably 4 to 7, ring atoms; wherein one or more, preferably 1 to 4, and particularly 1, 2, or 3, ring atoms are heteroatoms independently selected from O, S, and N (and therefore the remaining ring atoms are carbon). When a heterocycle contains S or N as a heteroatom, S may be present as an SO or SO group, and N may be present as an N-oxide, if valence permits.

[0085] Unsaturated heterocyclyls may have one or two double bonds but are not aromatic. Preferably, unless otherwise specified as unsaturated, heterocyclyl groups in the compounds of the present invention are saturated monocyclic rings. Preferably, heterocyclyl groups have one or two heteroatoms as ring atoms, and preferably the heteroatoms are not directly bonded to each other. Examples of heterocyclic rings include tetrahydrofuran (THF), dihydrofuran, 1,4-dioxane, morpholine, 1,4-dithiane, piperazine, piperidine, 1,3-dioxolane, imidazolidine, imidazoline, pyrroline, pyrrolidine, tetrahydropyran, dihydropyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane, oxathiane, thiomorpholine, and the like.

[0086] The term "5- to 7-membered unsaturated heterocyclyl" refers to a ring radical containing 5 to 7 ring atoms containing one, two, or three heteroatoms individually selected from nitrogen, oxygen, and sulfur (optionally further containing groups such as -S(=O)- and -S(=O)2-) and one or more C-C double bonds, preferably one C-C double bond. This term includes 5-, 6-, or 7-membered non-aromatic monocyclic ring radicals containing one or more C-C double bonds, preferably one C-C double bond, and one, two, or three heteroatoms individually selected from nitrogen, oxygen, and sulfur, preferably one oxygen. Examples of 5- to 7-membered unsaturated heterocyclyls include, but are not limited to, 6-membered non-aromatic monocyclic radicals containing one oxygen and a C-C double bond, such as 3,4-dihydro-2-H-pyranyl, 5,6-dihydro-2H-pyranyl, and 2H-pyranyl.

[0087] The term "heteroaryl" refers to a 5- to 14-membered, typically 5- to 10-membered, monocyclic or bicyclic aromatic ring radical containing 1, 2, 3, or 4 heteroatoms individually selected from nitrogen, oxygen, and sulfur in the ring radical. Typically, a heteroaryl is a 5- to 10-membered ring system, for example, a 5- to 6-membered monocyclic or an 8- to 10-membered bicyclic group. Typical heteroaryl groups include 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 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-isoxazolyl, 3- or 5-(1,2,4-triazolyl), 4- or 5-(1,2,3-triazolyl), 1-, 2-, or 3-tetrazolyl, 2-, 3-, or 4-pyridyl, 3- or 4-pyridazinyl, 2-pyrazinyl, and 2-, 4-, or 5-pyrimidinyl.

[0088] A substituted heteroaryl is a heteroaryl group having one or more substituents on the heteroaryl ring, typically 1, 2 or 3 substituents, replacing hydrogen atoms that might otherwise be on the unsubstituted heteroaryl.

[0089] The term "5- to 6-membered heteroaryl" refers to an aromatic monocyclic ring radical containing 1, 2, 3, or 4 heteroatoms individually selected from nitrogen, oxygen, and sulfur. The term includes 5- or 6-membered aromatic ring radicals containing 1, 2, or 3 heteroatoms selected from N, O, and S as ring members, preferably 1 to 2 nitrogen atoms, or 1 nitrogen atom and 1 sulfur atom. The term includes 6-membered rings in which aromatic tautomers exist, as in, for example, the 1H-pyridin-2-one system. Examples of suitable 5- to 6-membered heteroaryl groups include, but are not limited to, 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 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-isoxazolyl, 3- or 5-(1,2,4-triazolyl), 4- or 5-(1,2,3-triazolyl), 1-, 2-, or 3-tetrazolyl, 2-, 3-, or 4-pyridyl, 3- or 4-pyridazinyl, 2-pyrazinyl, and 2-, 4-, or 5-pyrimidinyl.

[0090] The term "8- to 10-membered heteroaryl" refers to an aromatic bicyclic ring radical containing 1, 2, 3, or 4 heteroatoms individually selected from nitrogen, oxygen, and sulfur. Non-limiting examples include 1-, 2-, 3-, 5-, 6-, 7-, or 8-indolizinyl, 1-, 3-, 4-, 5-, 6-, or 7-isoindolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, and 2-, 3-, 4-, 5-, 6-, or 7-indazolyl. Examples of 8-10 membered heteroaryl include, but are not limited to: pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[3,2-b]pyridinyl, benzofuranyl, benzothiophenyl, indolyl, isoindolyl, indolininyl, benzimidazolyl, and indazolyl.

[0091] The term "8- to 10-membered partially unsaturated heterobicyclyl" or "8- to 10-membered partially saturated heterobicyclic ring" includes (a) a 5- to 6-membered heteroaryl containing 1 to 3 or 1 to 2 nitrogen atoms fused to a second ring to form a 5,5-, 5,6-, 6,5-, or 6-6-ring system and (b) a phenyl ring fused to a second ring containing at least one heteroatom or heteroatom group to form a 6,5-, or 6-6-ring system.

[0092] The term "an 8-10 membered partially saturated heterobicyclic ring containing 1-3 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 in the heterobicyclic ring" means (i) a 5- to 6-membered heteroaryl ring containing 1, 2, or 3 nitrogen atoms fused to a 5- or 6-membered saturated or partially saturated carbocyclic ring optionally incorporating 1 or 2 atoms or groups independently selected from 1 to 2 oxygen atoms, 1 sulfur atom, and 0 to 1 S(=O)2 groups in the non-aromatic portion of the ring; or (ii) a phenyl ring fused to a 5- or 6-membered saturated or partially saturated carbocyclic ring incorporating 1 to 3 heteroatoms or heteroatom groups independently selected from 0 to 3 nitrogen atoms, 0 to 2 oxygen atoms, 0 to 1 sulfur atoms, and 0 to 1 S(=O)2 groups (e.g., 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) in the non-aromatic portion of the ring. is an 8- to 10-membered bicyclic radical consisting of provided that the point of attachment of the 8-10 membered partially saturated heterobicyclic ring to the remainder of the molecule is on the 5-6 membered heteroaryl or phenyl ring.

[0093] The 8-10 membered partially saturated heterobicyclic radical is unsubstituted or substituted with one or more substituents described herein and is further optionally substituted at a carbon atom (except on the aromatic ring) with oxo.

[0094] In one embodiment, the term "8- to 10-membered partially saturated heterobicyclic ring" refers to an 8- to 10-membered partially saturated heterobicyclic ring radical consisting of a 5- to 6-membered heteroaryl ring containing 1, 2, or 3 nitrogen atoms, or consisting of a phenyl ring, where the phenyl or heteroaryl ring is fused to a 5- or 6-membered saturated or partially saturated carbocyclic ring optionally incorporating, in the non-aromatic portion of the ring, one nitrogen atom and one oxygen atom; or one, two, or three nitrogen atoms; one oxygen atom; or one sulfur atom; or one group selected from -S(=O)- and -S(=O)2-, provided that the point of attachment of the 8- to 10-membered partially saturated heterobicyclic ring to the remainder of the molecule is on the 5- to 6-membered heteroaryl or phenyl ring. The bicyclic ring radical is unsubstituted or substituted with one or more substituents described herein and further optionally substituted at a carbon atom (except on the aromatic ring) with oxo. Thus, the term "8- to 10-membered partially unsaturated heterobicyclyl" includes (a) a 5- to 6-membered heteroaryl containing 1 to 2 nitrogen atoms fused to a second ring to form a 5,5-, 5,6-, 6,5-, or 6-6-ring system and (b) a phenyl ring fused to a second ring to form a 6,5-, or 6-6-ring system.

[0095] Examples of "8- to 10-membered partially saturated heterobicyclic rings" and "8- to 10-membered partially saturated heterobicyclic rings containing 1-3 heteroatoms or heteroatom groups independently selected from 0-3 nitrogen atoms, 0-2 oxygen atoms, 0-1 sulfur atoms, and 0-1 S(=O)2 groups in the heterobicyclic ring" include, but are not limited to: indolinyl (e.g., indolin-5-yl), isoindolinyl (e.g., isoindolin-5-yl), dihydrobenzofuranyl (e.g., 2,3-dihydrobenzofuran-6-yl), dihydroisobenzofuranyl (e.g., 1,3-dihydroisobenzofuran-5-yl), tetrahydroindazolyl, tetrahydrobenzimidazolyl (e.g., 4,5,6,7-tetrahydro-1H-benzimidazol-5-yl), tetrahydroisoquinolinyl, ... quinoxalinyl, dihydrobenzimidazolyl (e.g., 2,3-dihydro-1H-benzo[d]imidazol-5-yl), dihydrobenzothiophenyl (e.g., 1,3-dihydrobenzo[c]thiophen-5-yl), dihydrobenzothiophenyl dioxide (e.g., 1,3-dihydrobenzo[c]thiophen-5-yl 2,2-dioxide), dihydropyrrolopyrazolyl (e.g., 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl), isoindolinonyl (e.g., isoindolin-1-one-5-yl), indolinonyl (e.g., indolin-2-one-5-yl), benzofuranonyl (e.g., benzofuran-2(3H)-one-6-yl), isobenzofuranonyl (e.g., isobenzofuran-1(3H)-one-6-yl), and the like.Preferably, the 8- to 10-membered partially saturated heterobicyclic ring or "the 8- to 10-membered partially saturated heterobicyclic ring containing 1 to 3 heteroatoms or heteroatom groups independently selected from 0 to 3 nitrogen atoms, 0 to 2 oxygen atoms, 0 to 1 sulfur atoms, and 0 to 1 S(═O) groups in the heterobicyclic ring" is indolinyl (e.g., indolin-5-yl), isoindolinyl (e.g., isoindolin-5-yl), dihydrobenzofuranyl (e.g., 2,3-dihydrobenzofuran-6-yl), dihydroisobenzofuranyl (e.g., 1,3-dihydroisobenzofuran-5-yl), dihydrobenzimidazolyl (e.g., 2,3-dihydro-1H-benzo[d]imidazol-5-yl), dihydrobenzo thiophenyl (e.g., 1,3-dihydrobenzo[c]thiophen-5-yl, 2,3-dihydrobenzo[b]thiophen-6-yl), dihydrobenzothiophenyl dioxide (e.g., 1,3-dihydrobenzo[c]thiophen-5-yl 2,2-dioxide), dihydropyrrolopyrazolyl (e.g., 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl), isoindolinonyl (e.g., isoindolin-1-one-5-yl), indolinonyl (e.g., indolin-2-one-5-yl), benzofuranonyl (e.g., benzofuran-2(3H)-one-6-yl), isobenzofuranonyl (e.g., isobenzofuran-1(3H)-one-6-yl).

[0096] The term "cyano" refers to the group --CN.

[0097] The term "amino" refers to the group -NH2.

[0098] The term "hydroxy" refers to the group --OH.

[0099] The term "oxo" refers to the group =O.

[0100] Generally, for groups containing two or more subgroups, the last-named group is the radical point of attachment; for example, "alkylaryl" refers to a monovalent radical of the formula alkyl-aryl-, while "arylalkyl" refers to a monovalent radical of the formula aryl-alkyl-.

[0101] For a hyphen (-) or group beginning with (-), the group immediately following the hyphen is the point of attachment to the rest of the molecule. For example, -(CH2) 1~2 -C 3~4 -Cycloalkyl is attached to the rest of the molecule via a methylene or ethylene linker 3~4 -refers to a cycloalkyl group.

[0102] As used herein, the term "substituted with one or more substituents" includes substitution with two, three, four, five, or six substituents. Preferably, it includes one substituent or two or three substituents. For the avoidance of doubt, the term also includes the case where two or three substituents may be present on the same carbon atom, where valence permits.

[0103] The use of any examples or exemplary language (e.g., "etc.") presented herein is intended merely to further clarify the invention and does not impose limitations on the scope of the invention as otherwise claimed.

[0104] The term "substituted with 1, 2 or 3 substituents" should be construed accordingly.

[0105] The expression "A is sp 2 By "attached to the remainder of the compound of formula (I) by a carbon atom at the A hybrid," this means that the carbon atom is bonded to the remainder of the compound of formula (I) by a carbon atom at the A hybrid, as shown in the following diagram: [ka] It can be represented by:

[0106] When "heteroatom" or "heteroatoms" is referred to in reference to a ring, it refers to a ring heteroatom (where NH should also be considered a heteroatom that can substitute for "N").

[0107] As used herein, in the compounds described herein, the compounds of formula (2a), (2b * ), (2c * ) and (2d * The term "nitrogen-protecting group" (PG) in the compounds of formula (I) or in the schemes refers to a group that should protect the relevant functional group from undesired secondary reactions such as acylation, etherification, esterification, oxidation, solvolysis, and similar reactions. It can be removed under deprotection conditions. Depending on the protecting group used, one skilled in the art will know how to remove the protecting group to obtain the free amine NH group by reference to known procedures. These include references to organic chemistry texts and literature procedures such as J.F.W.M. Comie, "Protective Groups in Organic Chemistry," T.W. Greene and P.G.W.M. Buts, "Greene's Protective Groups in Organic Synthesis," and "Methoden der organischen Chemie" (Methods of Organic Chemistry).

[0108] Preferred nitrogen-protecting groups include C1-C6 alkyl (e.g., tert-butyl), preferably C1-C4 alkyl, more preferably C1-C2 alkyl, most preferably C1-alkyl mono-, di- or tri-substituted with trialkylsilyl-C1-C7 alkoxy (e.g., trimethylsilylethoxy); aryl, preferably phenyl, or heterocyclic groups (e.g., benzyl, cumyl, benzhydryl, pyrrolidinyl, trityl, pyrrolidinylmethyl, 1-methyl-1,1-dimethylbenzyl, (phenyl)methylbenzene), wherein the aryl ring or heterocyclic group is unsubstituted or substituted with one or more, for example two or three, residues selected from the group consisting of C1-C7 alkyl, hydroxy, C1-C7 alkoxy (e.g., para-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), pivaloyloxymethyl (POM))), C1-C 10 -alkenyloxycarbonyl, C1-C6 alkylcarbonyl (e.g., acetyl or pivaloyl), C6-C 10 -arylcarbonyl; C1-C6-alkoxycarbonyl (e.g., tert-butoxycarbonyl (Boc), methylcarbonyl, trichloroethoxycarbonyl (Troc), pivaloyl (Piv), allyloxycarbonyl), C6-C 10 -aryl C1-C6-alkoxycarbonyl (e.g., 9-fluorenylmethyloxycarbonyl (Fmoc)), allyl or cinnamyl, sulfonyl or sulfenyl, succinimidyl group, silyl group (e.g., triarylsilyl, trialkylsilyl, triethylsilyl (TES), trimethylsilylethoxymethyl (SEM), trimethylsilyl (TMS), triisopropylsilyl, or tertbutyldimethylsilyl).

[0109] In an embodiment of the present invention, the nitrogen-protecting group is C1-C6-alkoxycarbonyl (e.g., tert-butoxycarbonyl (Boc), methyloxycarbonyl, trichloroethoxycarbonyl (Troc), pivaloyl (Piv), allyloxycarbonyl). More preferably, the nitrogen-protecting group is tert-butoxycarbonyl.

[0110] In an embodiment of the invention, the nitrogen-protecting group is a C1-C6-alkoxycarbonyl (such as tert-butoxycarbonyl or t-butyl carbamate (Boc), methyloxycarbonyl or methyl carbamate, ethyl carbamate, 9-fluorophenylmethylcarbamate (Fmoc) and analogs thereof, 2,2,2-trichloroethylcarbamate trichloroethoxycarbonyl (Troc), 2-trimethylsilylethylcarbamate (Teoc), pivaloyl (Piv), allyloxycarbonyl or allyl carbamate (Alloc), benzyl carbamate (Cbz)) or an amide-protecting group, such as COCF3 (trifluoroacetamide), or N-allyl or N-benzyl and analogs thereof. More preferably, the nitrogen-protecting group is tert-butoxycarbonyl.

[0111] The terms "stereoisomer" or "stereoisomers" refer to compounds that have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

[0112] The terms "diastereoisomer" or "diastereomer" refer to stereoisomers that are not related as mirror images. Diastereoisomers are characterized by different physical properties and some differences in chemical behavior. Mixtures of diastereomers may separate under analytical procedures such as chromatography or crystallization.

[0113] The term "enantiomer" refers to one of a pair of molecular entities that are mirror images of each other and are not superimposable.

[0114] The term "enantiomeric mixture" refers to an enantiomerically enriched mixture, a composition that contains a greater proportion or percentage of one of the enantiomers of a compound of the invention relative to the other enantiomer, or a racemate.

[0115] The term "diastereomeric mixture" refers to a diastereomer-enriched mixture or a mixture of equal proportions of diastereoisomers.

[0116] The term "diastereomerically enriched" refers to a composition that contains a greater proportion or percentage of one of the diastereomers of a compound of the present invention relative to the other diastereoisomer.

[0117] The term "atropisomer" refers to a stereoisomer resulting from restricted rotation about a single bond, where the rotational barrier is high enough to allow separation of the isomeric species. Typically, rotation about a single bond in a molecule is hindered or greatly retarded as a result of steric interactions with other parts of the molecule, and the substituents on both ends of the single bond are asymmetric, resulting in a stereogenic unit called a "chiral axis."

[0118] For example, in exemplary compounds, the absolute configuration of the chiral axis is assigned using the Cahn-Ingold-Prelog (CIP) chirality rules with stereodescriptors (aR) or (aS), or the CIP helicity rules with stereodescriptors (P) or (M) (V. Prelog and G. Helmchen, Angewandte Chemie International Edition, 21(8):567-583, 1982, https: / / doi.org / 10.1002 / anie.198205671; P. Mata, A. L. Lobo, C. Marshall, and A. P. Johnson, Tetrahedron: Asymmetry, 4(4):657-688, 1993, https: / / doi.org / 10.1016 / S0957-4166(00)80173-1; both in H. A. Favre and W. H. Powell, Nomenclature of Organic Chemistry: IUPAC Cited in Recommendations and Preferred Names 2013 (the IUPAC “Blue Book”), Cambridge, UK: Royal Society of Chem., 2014, https: / / doi.org / 10.1039 / 9781849733069, Chapter P-9, “Specification of Configuration and Conformation”, https: / / doi.org / 10.1039 / 9781849733069-01156.

[0119] This is shown below for Example 12a (the more active atropisomer), which has a (R) or (M) configuration. Example 12b (the less active atropisomer), which has a (S) or (P) configuration. Their structures are shown below for comparison. [ka]

[0120] An alternative way to show the structures of Examples 12a and 12b is as follows. [ka]

[0121] In an embodiment of the invention, the compound of the invention adopts the same spatial orientation as shown in Example 12a.

[0122] Similarly, the compound of Example 1a can be described by the name "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]heptan-2-yl)prop-2-en-1-one." The compound of Example 1a can also be represented by the name "1-{6-[(4M)-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]heptan-2-yl}prop-2-en-1-one."

[0123] The structure of the compound of Example 1a (also referred to herein as Compound X) is as follows: [ka]

[0124] An alternative way of showing the structure of the compound of Example 1a (also referred to herein as Compound X) is as follows: [ka]

[0125] The term "substantially the same" in reference to X-ray diffraction peak positions means that typical peak position and intensity variations are taken into account. For example, those skilled in the art will understand that peak positions (2θ) typically exhibit some instrument-to-instrument variation of the order of 0.2°. Furthermore, those skilled in the art will understand that relative peak intensities exhibit instrument-to-instrument variation as well as variation due to crystallinity, preferred orientation, sample surface preparation, and other factors known to those skilled in the art, and should be interpreted solely as a qualitative measure.

[0126] Various embodiments or aspects of the present invention are described herein, particularly in the claims. It will be recognized that the features defined in each embodiment may be combined with other defined features to provide further embodiments of the present invention. In particular, it will be recognized that the features mentioned in a particular embodiment or aspect are preferred aspects of the present invention. The following listed embodiments are representative of the present invention.

[0127] Embodiment 1. Compound of Formula (I) [ka] (In the formula, A, (a) C5-C alkyl, unsubstituted or substituted with one or more, preferably one, two or three, substituents independently selected from fluoro and C1-C4 alkyl. 7- cycloalkylene; (b) a 5- to 7-membered unsaturated heterocyclyl containing one carbon-carbon double bond and one oxygen atom as a ring member, said heterocyclyl being unsubstituted or substituted with one or more, preferably one, two or three, substituents independently selected from fluoro and C1-C4-alkyl, preferably one, two or three C1-C4-alkyl; (c) unsubstituted or 1, 2 or 3 R A2 C6~C substituted with 10 aryl; (d) A 5- to 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 at one or more (e.g., 1, 2, or 3) carbon atoms. A3 and the nitrogen atom, if present in the heteroaryl ring, is unsubstituted or C1-C4-alkyl, -(CH2) 1~2 -C 3~4 -cycloalkyl, C3-C6-cycloalkyl, hydroxy-C1-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 substituent is 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), heteroaryl ring; (e) an 8- to 10-membered heteroaryl ring containing 1, 2, or 3 nitrogen atoms, or an 8- to 10-membered partially saturated heterobicyclic ring containing 1 to 3 heteroatoms or heteroatom groups independently selected from 0 to 3 nitrogen atoms, 0 to 2 oxygen atoms, 0 to 1 sulfur atoms, and 0 to 1 S(═O)2 groups in the heterobicyclic ring, wherein the heteroaryl ring or heterobicyclic ring is unsubstituted or has 1, 2, 3, 4, or 5 R groups at the carbon atoms; A4the heterobicyclic ring is further optionally substituted at a carbon atom by oxo, and the nitrogen atom, if present, is unsubstituted or substituted by a substituent which is -(CO)-C1-C4-alkyl or C1-C4-alkyl, said C1-C4-alkyl being selected from the group consisting of cyano, hydroxy, oxo, fluoro, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 a heteroaryl or heterobicyclic ring optionally substituted with one or two substituents independently selected from selected from the group consisting of: Here, Het b is a 4-, 5- or 6-membered heterocyclic ring containing one or two heteroatoms or groups independently 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 to two nitrogen atoms), wherein said heterocyclic ring Het b is unsubstituted or substituted at a carbon atom with one or two substituents independently selected from C1-C4-alkyl, hydroxy, cyano, fluoro, C1-C4-alkoxy-hydroxy-C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy, fluoro-C1-C4-alkoxy and fluoro-C1-C4-alkyl, wherein the heterocycle Het b is further optionally substituted at a carbon atom with oxo, wherein the nitrogen atom is Het b when present, optionally further substituted with C1-C4-alkyl, optionally substituted with 1 to 3 substituents independently selected from fluoro, hydroxy and C1-C4-alkoxy; Here, A is sp 2 is attached to the remainder of the compound of formula (I) by a carbon atom in the hybridized A; where: B is B 1 and B 2 is selected from the group consisting of where B 1is unsubstituted or 1, 2, 3 or 4 R Ba C replaced by 6~10 is aryl; B 2 is a 6- to 13-membered heteroaryl containing 1, 2, or 3 nitrogen atoms, where B 2 is unsubstituted or 1, 2, 3 or 4 R Bb is replaced by; 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 halo; L, [ka] is selected from the group consisting of where n is 1, 2 or 3; R L is selected from hydrogen, methyl, ethyl, —CH—CN and —CH—OH, wherein G * represents the point of attachment to G; G, [ka] selected from the group consisting of: During the ceremony, R 2 is selected from hydrogen, C1-C3 alkyl, —C(O)—C1-C3-alkyl, and fluoro; R 3 is hydrogen; R 4 is selected from hydrogen, methyl, —CHF, —CH—OCH and —CH—N(CH); R 5 is selected from hydrogen and methyl; R 6 is hydrogen; R 7is selected from hydrogen and methyl; where R A2 But independently, NR 9 R 10 , cyano, -(CH2) p -CN, halo, OH, hydroxy-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-oxy, 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, NR 9 R 10 , cyano, C1-C4-alkyl, fluoro, fluoro-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 selected from the group consisting of; where R A3 However, independently, oxo, NR 9 R 10 , cyano, -(CH2) p -CN, halo, OH, hydroxy-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-oxy, 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, NR 9 R 10 , cyano, C1-C4-alkyl, fluoro, fluoro-C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Het py and -(CH2) p -Het py selected from the group consisting of; where R A4are independently selected from cyano, CO2H, halo, 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 selected from the group consisting of N-C1-C4-alkyl-oxy-(CO)-C1-C4-alkyl; where: p is 1, 2, or 3; R 9 is selected from hydrogen and C1-C4-alkyl; R 10 is 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 is a 4-, 5-, 6- or 7-membered saturated heterocycle containing 1 or 2 heteroatoms independently selected from O, N (such as pyrrolidin-1-yl, azetidin-1-yl, morpholin-1-yl) and S or containing an S-oxide (SO) or S-dioxide (SO2) group, wherein said heterocycle is optionally substituted at one carbon atom with oxo, wherein said heterocycle is optionally further substituted at one or more carbon atoms with 1, 2 or 3 substituents independently selected from C1-C4-alkoxy (preferably methoxy), halo (preferably fluoro), C1-C4-alkyl, hydroxy-C1-C4-alkyl and fluoro-C1-C4-alkyl, wherein if a nitrogen atom is present in said heterocycle, R 10 (preferably C1-C4-alkyl (such as methyl)); or Het py is a 5- or 6-membered heteroaryl ring containing 1, 2 or 3 nitrogen atoms (preferably 1,2,4-triazol-1-yl or pyrazol-1-yl), wherein the heteroaryl ring is NR 9 R 10 , -C(=O)-NR 9 R 10 , halo, C1-C4-alkyl, hydroxy-C1-C4-alkyl, fluoro-C1-C4-alkyl, cyano, OH, and C1-C4-alkoxy; Each R Ba are independently selected from the group consisting of hydroxy, NH2, C1-C4-alkyl and halo; Each R Bb are independently selected from the group consisting of C1-C4-alkyl (preferably methyl), cyclopropyl, fluoro-C1-C3-alkyl (preferably CHF2 or CF3), cyano, halo (preferably fluoro or chloro), NH2 and C1-C3-alkoxy (preferably methoxy), or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the atropisomer.

[0128] Embodiment 2.A is (a) C5-C7-cycloalkylene that is unsubstituted or substituted with one or more, preferably one, two or three, substituents independently selected from fluoro and C1-C4-alkyl; (b) a 5- to 7-membered unsaturated heterocyclyl containing one carbon-carbon double bond and one oxygen atom as a ring member, said heterocyclyl being unsubstituted or substituted with one or more, preferably one, two or three, substituents independently selected from fluoro and C1-C4-alkyl, preferably one, two or three C1-C4-alkyl; (c) unsubstituted or 1, 2 or 3 RA2 C6~C substituted with 10 aryl; (d) A 5- to 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 at one or more (e.g., 1, 2, or 3) carbon atoms. A3 and the nitrogen atom, if present in the heteroaryl ring, is unsubstituted or C1-C4-alkyl, -(CH2) 1~2 -C 3~4 -cycloalkyl, C3-C6-cycloalkyl, hydroxy-C1-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 substituent is 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), heteroaryl ring; (e) 8-10 membered heteroaryl rings containing 1, 2 or 3 nitrogen atoms, each of which is unsubstituted or substituted by a substituent which is -(CO)-C1-C4-alkyl or C1-C4-alkyl, wherein the C1-C4-alkyl is selected from the group consisting of cyano, hydroxy, oxo, fluoro, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10and wherein the heteroaryl ring is unsubstituted or has 1, 2, 3, 4, or 5 R at carbon atoms. A4 is replaced by; Here, Het b is a 4-, 5- or 6-membered heterocyclic ring containing one or two heteroatoms or groups independently 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 to two nitrogen atoms), wherein said heterocyclic ring Het b is unsubstituted or substituted at a carbon atom with one or two substituents independently selected from C1-C4-alkyl, hydroxy, cyano, fluoro, C1-C4-alkoxy-hydroxy-C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy, fluoro-C1-C4-alkoxy and fluoro-C1-C4-alkyl, wherein the heterocycle Het b is further optionally substituted at a carbon atom with oxo, wherein the nitrogen atom is Het b when present in a heteroaryl ring, optionally further substituted with C1-C4-alkyl, optionally substituted with 1 to 3 substituents independently selected from fluoro, hydroxy and C1-C4-alkoxy; (f) an 8- to 10-membered partially saturated heterobicyclic ring containing 1 to 3 nitrogen atoms, or 1 to 2 oxygen atoms, or 1 sulfur atom, or 1 S(=O)2 group in the heterobicyclic ring, wherein the heterobicyclic ring is unsubstituted or contains 1, 2, 3, 4, or 5 R at the carbon atoms; A4 the heterobicyclic ring is further optionally substituted at a carbon atom by oxo, and the nitrogen atom, if present, is unsubstituted or substituted by a substituent which is -(CO)-C1-C4-alkyl or C1-C4-alkyl, said C1-C4-alkyl being selected from the group consisting of cyano, hydroxy, oxo, fluoro, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10optionally substituted with 1 or 2 substituents independently selected from Here, Het b is a 4-, 5- or 6-membered heterocyclic ring containing one or two heteroatoms or groups independently 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 to two nitrogen atoms), wherein said heterocyclic ring Het b is unsubstituted or substituted at a carbon atom with one or two substituents independently selected from C1-C4-alkyl, hydroxy, cyano, fluoro, C1-C4-alkoxy-hydroxy-C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy, fluoro-C1-C4-alkoxy and fluoro-C1-C4-alkyl, wherein the heterocycle Het b is further optionally substituted at a carbon atom with oxo, wherein the nitrogen atom is Het b When present in a heterobicyclic ring, the heterobicyclic ring is optionally further substituted with C1-C4-alkyl, which is optionally substituted with 1 to 3 substituents independently selected from fluoro, hydroxy and C1-C4-alkoxy. The compound of embodiment 1, selected from the group consisting of: or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the atropisomer.

[0129] Embodiment 3. Het b is a 4-, 5- or 6-membered heterocyclic ring containing one or two heteroatoms or groups independently 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 to two nitrogen atoms), wherein the heterocyclic ring Het bis unsubstituted or substituted at a carbon atom with one or two substituents independently selected from C1-C4-alkyl, hydroxy, cyano, fluoro, C1-C4-alkoxy-hydroxy-C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy and fluoro-C1-C4-alkyl, wherein the heterocycle Het b is further optionally substituted at a carbon atom with oxo, wherein the nitrogen atom is Het b when present, is optionally further substituted with C1-C4-alkyl, said C1-C4-alkyl optionally substituted with 1 to 3 substituents independently selected from fluoro, hydroxy and C1-C4-alkoxy; B is B 1 and B 2 selected from the group consisting of: B 1 is unsubstituted or 1, 2, 3 or 4 R Ba C replaced by 6~10 aryl, and each R Ba is independently selected from the group consisting of hydroxy, C1-C4-alkyl and halo; B 2 is a 6- to 10-membered (preferably 8- to 10-membered) heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein B 2 is unsubstituted or 1, 2, 3 or 4 R Bb is replaced by; Each R Bb are independently selected from the group consisting of C1-C4-alkyl (preferably methyl), fluoro-C1-C3-alkyl (preferably CHF2 or CF3), cyano, halo (preferably fluoro or chloro), NH2 and C1-C3-alkoxy (preferably methoxy), Het pyis a 4-, 5-, 6- or 7-membered saturated heterocycle containing 1 or 2 heteroatoms independently selected from O, N (such as pyrrolidin-1-yl, azetidin-1-yl, morpholin-1-yl) and S or containing an S-oxide (SO) or S-dioxide (SO2) group, wherein said heterocycle is optionally substituted at one carbon atom with oxo, and wherein said heterocycle is further substituted at one or more carbon atoms with 1, 2 or 3 substituents independently selected from C1-C4-alkoxy (preferably methoxy), halo (preferably fluoro), C1-C4-alkyl, hydroxy-C1-C4-alkyl and fluoro-C1-C4-alkyl, and wherein if a nitrogen atom is present in said heterocycle, R 10 (preferably C1-C4-alkyl (such as methyl)); or Het py is a 5- or 6-membered heteroaryl ring containing 1, 2 or 3 nitrogen atoms (preferably 1,2,4-triazol-1-yl or pyrazol-1-yl), wherein the heteroaryl ring is NR 9 R 10 optionally substituted with one or more (e.g., 1, 2, or 3) substituents independently selected from halo, C1-C4-alkyl, cyano, OH, and C1-C4-alkoxy; where R A4 are independently cyano, CO2H, halo, 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-oxy, -NR 9 R 10 , R 9 R 10 The compound according to embodiment 1 or 2, selected from the group consisting of N-C1-C4-alkyl-oxy, -(CO)-C1-C4-alkyl; or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the atropisomer.

[0130] Embodiment 4. Het b is a 4-, 5- or 6-membered heterocyclic ring containing one or two heteroatoms or groups independently 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 to two nitrogen atoms), wherein the heterocyclic ring Het b is unsubstituted or substituted at a carbon atom with one or two substituents independently selected from C1-C4-alkyl, hydroxy, cyano, fluoro, C1-C4-alkoxy-hydroxy-C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy and fluoro-C1-C4-alkyl, wherein the heterocycle Het b is further optionally substituted at a carbon atom with oxo, wherein the nitrogen atom is Het b when present, is optionally further substituted with C1-C4-alkyl, said C1-C4-alkyl optionally substituted with 1 to 3 substituents independently selected from fluoro, hydroxy and C1-C4-alkoxy; B 2 is a 6- to 10-membered (preferably 8- to 10-membered) heteroaryl containing 1, 2, or 3 nitrogen atoms, wherein B 2 is unsubstituted or 1, 2, 3 or 4 R Bb is replaced by; Het pyis a 4-, 5-, 6- or 7-membered saturated heterocycle containing 1 or 2 heteroatoms independently selected from O, N (such as pyrrolidin-1-yl, azetidin-1-yl, morpholin-1-yl) and S or containing an S-oxide (SO) or S-dioxide (SO2) group, wherein said heterocycle is optionally substituted at one carbon atom with oxo, and wherein said heterocycle is further substituted at one or more carbon atoms with 1, 2 or 3 substituents independently selected from C1-C4-alkoxy (preferably methoxy), halo (preferably fluoro), C1-C4-alkyl, hydroxy-C1-C4-alkyl and fluoro-C1-C4-alkyl, and wherein if a nitrogen atom is present in said heterocycle, R 10 (preferably C1-C4-alkyl (such as methyl)); or Het py is a 5- or 6-membered heteroaryl ring containing 1, 2 or 3 nitrogen atoms (preferably 1,2,4-triazol-1-yl or pyrazol-1-yl), wherein the heteroaryl ring is NR 9 R 10 , optionally substituted with one or more (e.g., 1, 2, or 3) substituents independently selected from halo, C1-C4-alkyl, cyano, OH, and C1-C4-alkoxy (preferably, the heteroaryl ring is substituted with one or more amino groups); R A4 are independently cyano, CO2H, halo, 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-oxy, -NR 9 R 10 and R 9 R 10 A compound according to any one of the above embodiments, selected from the group consisting of N-C1-C4-alkyl-oxy; or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the atropisomer.

[0131] Embodiment 5.G is [ka] or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the atropisomer thereof, according to any one of the preceding embodiments,

[0132] Embodiment 6.L is [ka] or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the atropisomer thereof, according to any one of the preceding embodiments,

[0133] Embodiment 7.R L is hydrogen, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the atropisomer thereof.

[0134] Embodiment 8. A compound according to any one of the above embodiments, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, wherein C is selected from C1-C3 alkyl (preferably methyl), fluoro-C1-C3 alkyl (preferably CHF2 or CF3), CH2-CN.

[0135] Embodiment 9.B is [ka] wherein B is unsubstituted or substituted with 1, 2 or 3 halo, or methyl groups, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the atropisomer, according to any one of the previous embodiments.

[0136] Embodiment 10.B is [ka] wherein X is N or CR B5 and; where R B1 are independently selected from hydrogen and C1-C4-alkyl (preferably methyl); R B2 is independently selected from hydrogen, halo (preferably chloro), C1-C4-alkyl (preferably methyl), cyclopropyl and NH2; R B3 are independently selected from hydrogen, halo (preferably chloro), cyclopropyl and C1-C4-alkyl (preferably methyl); R B4 are independently selected from hydrogen, halo (preferably chloro or fluoro) and C1-C4-alkyl (preferably methyl), or R B3 and R B4 together with the atoms to which they are attached form a 4- to 6-membered ring (preferably a 5- to 6-membered saturated or partially unsaturated carbocyclic ring) fused to the aromatic ring containing X; R B5 is independently selected from hydrogen, halo (preferably chloro) and C1-C4-alkyl (preferably methyl); or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the atropisomer.

[0137] Embodiment 11.R B2 is independently selected from the group consisting of hydrogen, NH2, and CH3, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of an atropisomer thereof.

[0138] Embodiment 12.R B4 is independently selected from hydrogen, halo (preferably chloro or fluoro) and C1-C4-alkyl (preferably methyl), or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the atropisomer.

[0139] Embodiment 13.R B1 is independently selected from hydrogen and methyl, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the atropisomer.

[0140] Embodiment 14.R B1 is hydrogen, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the atropisomer.

[0141] Embodiment 15.R B3 and R B4is each independently selected from halo (preferably chloro or fluoro) and C1-C4-alkyl (preferably methyl), or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the atropisomer.

[0142] Embodiment 16.R B3 is the halo, and R B4 is C1-C4-alkyl, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the atropisomer.

[0143] Embodiment 17.R B3 is chloro and R B4 is methyl, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the atropisomer.

[0144] Embodiment 18.R B3 is chloro and R B4 is chloro, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the atropisomer.

[0145] Embodiment 19. A compound according to any one of embodiments 10-18, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, wherein X is CH or N.

[0146] Embodiment 20. A compound according to any one of embodiments 10-19, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, wherein X is CH.

[0147] Embodiment 21. Compound of Formula (Ia) [ka] wherein A, B and C are as described in any one of the above embodiments, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the atropisomer.

[0148] Embodiment 22. A is a C5-C alkyl group which is unsubstituted or substituted with one or more, preferably one, two or three, substituents independently selected from fluoro and C1-C4-alkyl. 7- A compound of Formula (I) or Formula (Ia) according to any one of the above embodiments, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, which is cycloalkylene.

[0149] Embodiment 23.A is [ka] wherein W is O or C(R w )2, and each R w are independently selected from hydrogen and fluorine; R cis hydrogen or C1-C4-alkyl; and A is optionally further substituted with 1, 2 or 3 substituents independently selected from fluoro and C1-C4-alkyl; or a stereoisomer thereof; or an atropisomer thereof; or a pharmaceutically acceptable salt of the stereoisomer; or a pharmaceutically acceptable salt of the atropisomer; according to any one of the above embodiments.

[0150] Embodiment 24. A is unsubstituted or contains 1, 2 or 3 R A2 and preferably phenyl substituted with A2 are independently halo, OH, hydroxy-C1-C4-alkyl, -(COOH), C1-C4-alkyl, fluoro-C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkyl-carbonyl-oxy-C1-C4-alkyl-oxy, hydroxy-C1-C4-alkyl-oxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, -C(=O)-NR 9 R 10 , -NR 9 R 10 , Het py and -(CH2) p -Het py is selected from the group consisting of where: p is 1 or 2; R 9 is selected from hydrogen, C1-C4-alkyl and C1-C4-alkoxy-C1-C4-alkyl; R 10 is selected from hydrogen, C1-C4-alkyl, hydroxy-C1-C4-alkyl and C1-C4-alkoxy-C1-C4-alkyl; Het py But, -NR 9a R 10a and R 9a and R 10atogether with the nitrogen form a 4- or 5- or 6-membered heterocycle containing one or two further heteroatoms independently selected from O, N (such as pyrrolidin-1-yl, azetidin-1-yl or morpholin-1-yl) and S, or its N-oxide, or its S-oxide (SO) or S-dioxide, wherein said heterocycle is optionally substituted at one carbon atom by oxo, and wherein said heterocycle is further substituted by one or two substituents independently selected from C1-C4-alkoxy (preferably methoxy), halo (preferably fluoro), C1-C4-alkyl, hydroxy-C1-C4-alkyl and fluoro-C1-C4-alkyl; or R 9a and R 10a is taken together with the nitrogen to form 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 one amino group, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the atropisomer, as defined in any one of embodiments 1 to 21.

[0151] Embodiment 25. A is a 5-6 membered heteroaryl ring containing 1, 2 or 3 heteroatoms independently selected from N, O and S as ring members, and the heteroaryl ring is unsubstituted or has R at one or more (e.g., 1, 2 or 3) carbon atoms. A3 and the nitrogen atom, if present in the heteroaryl ring, is unsubstituted or C1-C4-alkyl, -(CH2) 1~2 -C 3~4 -cycloalkyl, hydroxy-C1-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 substituent is 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 a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the atropisomer.

[0152] Embodiment 26. A is unsubstituted or selected from the group consisting of NH2, cyano, halo, OH, hydroxy-C1-C4-alkyl, -COOH, C1-C4-alkyl, fluoro-C1-C4-alkyl, C1-C4-alkoxy, di-C1-C4-alkylamino-C1-C4-alkyl-oxy, 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, -C(=O)-NR 9 R 10 , N.R. 9 R 10 , Het py and -(CH2) p -Het py and where: p is 1 or 2; R 9 is selected from hydrogen and C1-C4-alkyl, R 10is selected from 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 But NR 9a R 10a and; R 9a and R 10a together with the nitrogen form a 4-, 5- or 6-membered saturated or unsaturated heterocycle containing 1 or 2 heteroatoms independently selected from O, N (pyrrolidin-1-yl, azetidin-1-yl, morpholin-1-yl) and S, or its N-oxide, or its S-oxide (SO) or S-dioxide, wherein said heterocycle is optionally substituted at one carbon atom in said heterocycle with oxo, and wherein said heterocycle is further substituted with 1, 2 or 3 substituents independently selected from C1-C4-alkoxy (preferably methoxy), halo (preferably fluoro), C1-C4-alkyl, hydroxy-C1-C4-alkyl and fluoro-C1-C4-alkyl; or R 9a and R 10a The compound of formula (I) or formula (Ia) according to any one of embodiments 1 to 21, wherein together with the nitrogen form a 4- or 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 one amino group; a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the atropisomer.

[0153] Embodiment 27.A is NH2, cyano, halo, C1-C4-alkyl, fluoro-C1-C4-alkyl, C1-C4-alkoxy, di-C1-C4-alkylamino-C1-C4-alkyl-oxy, -C(=O)-NR 9 R 10 , N.R. 9 R 10 , [ka] pyridinyl substituted with 1, 2 or 3 substituents independently selected from wherein p is 0, 1 or 2, preferably p is 0; R 22 is hydrogen or C1-C4-alkyl (preferably methyl), or amino; R 9 is selected from hydrogen and C1-C4-alkyl, R 10 is selected from hydrogen, C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, and di-C1-C4-alkyl-amino-C1-C4-alkyl; or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the atropisomer.

[0154] Embodiment 28.A is [ka] where R 23 Compounds of formula (I) or formula (Ia) according to any one of embodiments 1 to 21, wherein is hydrogen, C3-C6-cycloalkyl, C1-C4-alkyl (preferably methyl), and A is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from F, CH3, CH2F, CHF2 and CF3; or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the atropisomer.

[0155] Embodiment 29. A compound of formula (I) or formula (Ia) according to any one of embodiments 1 to 21, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, wherein A is pyrimidin-5-yl that is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from C1-C4-alkoxy (preferably methoxy) and CH3.

[0156] Embodiment 30.A is [ka] is selected from the group consisting of In the formula, R 24 is hydrogen, C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, -NR 9 R 10 C1~C4-Alkyl, -SO2-C1~C4-Alkyl, -SO2-C 3~4 -cycloalkyl or -(CH2) 1~2 -C 3~4 -cycloalkyl; R 4a , R 4b , R 4c and R 4d Compounds of formula (I) or formula (Ia) according to any one of embodiments 1 to 21, wherein each of is independently selected from hydrogen and C1-C4-alkyl (preferably methyl); or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the atropisomer.

[0157] Embodiment 31.A is [ka] [ka] [ka] is selected from the group consisting of During the ceremony, 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 But hydrogen, NR 9 R 10 , R 9 R 10 N—C1-C4-alkyl-oxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, hydroxy-C1-C4-alkyl-oxy and C1-C4-alkyl (preferably R O is hydrogen or NR 9 R 10 is selected from the group consisting of: R M is hydrogen, halo or C1-C4-alkyl, wherein said alkyl is OH, C1-C4-alkoxy or NR 9 R 10 (Preferably, R M is hydrogen); R N is hydrogen or C1-C4-alkyl, or halo- or fluoro-C1-C4-alkyl (preferably hydrogen); R q are independently C1-C4-alkyl, hydroxy, C1-C4-alkoxy and NR 9 R 10 selected from the group consisting of: R p is C1-C4-alkyl; Each R p1 are independently selected from hydrogen and C1-C4-alkyl; R v are independently selected from halogen, C1-C4-alkyl and fluoro-C1-C4-alkyl; R aeis selected from the group consisting of hydrogen and C1-C4-alkyl, where the alkyl is selected from cyano, hydroxy, fluoro, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 optionally substituted with one or two substituents selected from: R Ae is selected from the group consisting of hydrogen, -(CO)-C1-C4-alkyl and C1-C4-alkyl, where C1-C4-alkyl is in each case cyano, hydroxy, fluoro, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 optionally substituted with one or two substituents selected from: where: R 9 is selected from hydrogen and C1-C4-alkyl; R 10 is selected from hydrogen, C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl and di-C1-C4-alkyl-amino-C1-C4-alkyl; Here, Het b is a 4-, 5- or 6-membered heterocyclic ring containing one or two heteroatoms or groups independently 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 to two nitrogen atoms), wherein the heterocyclic ring Het b is unsubstituted or substituted at a carbon atom with one or two substituents independently selected from C1-C4-alkyl, hydroxy, cyano, fluoro, hydroxy-C1-C4-alkyl, C1-C4-alkoxy and fluoro-C1-C4-alkyl, wherein the heterocycle Het b is further optionally substituted at a carbon atom with oxo, wherein the nitrogen atom is Het bCompounds of formula (I) or formula (Ia) according to any one of the above embodiments 1-21, which, when present, are optionally further substituted with C1-C4-alkyl, which is optionally substituted with 1 to 3 substituents independently selected from fluoro, hydroxy and C1-C4-alkoxy; or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof.

[0158] Embodiment 32.A is [ka] is selected from the group consisting of wherein z is 0, 1 or 2; R v are independently selected from halogen, C1-C4-alkyl and fluoro-C1-C4-alkyl; R N is hydrogen or C1-C4-alkyl, or halo- or fluoro-C1-C4-alkyl (preferably hydrogen); R O But hydrogen, NR 9 R 10 , N(R 9 )(R 10 )-C1-C4-alkyl-oxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, hydroxy-C1-C4-alkyl-oxy and C1-C4-alkyl (preferably R O is hydrogen or NR 9 R 10 is selected from the group consisting of: R ae is selected from the group consisting of hydrogen and C1-C4-alkyl, where the alkyl is selected from cyano, hydroxy, fluoro, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 optionally substituted with one or two substituents selected from: R 9is selected from hydrogen and C1-C4-alkyl; R 10 is selected from hydrogen, C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl and di-C1-C4-alkyl-amino-C1-C4-alkyl; Here, Het b is a 4-, 5- or 6-membered heterocyclic ring containing one or two heteroatoms or groups independently 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 to two nitrogen atoms), wherein the heterocyclic ring Het b is unsubstituted or substituted at a carbon atom with one or two substituents independently selected from C1-C4-alkyl, hydroxy, cyano, fluoro, hydroxy-C1-C4-alkyl, C1-C4-alkoxy and fluoro-C1-C4-alkyl, wherein the heterocycle Het b is further optionally substituted at a carbon atom with oxo, wherein the nitrogen atom is Het b 22. Compounds of formula (I) or formula (Ia) according to any one of embodiments 1 to 21, wherein, when present, is further optionally substituted with C1-C4-alkyl, which is optionally substituted with 1 to 3 substituents independently selected from fluoro, hydroxy and C1-C4-alkoxy; or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the atropisomer.

[0159] Embodiment 33.A is [ka] or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof, as defined in any one of embodiments 1 to 21, or embodiment 31 or embodiment 32, selected from the group consisting of:

[0160] Embodiment 34. R N is hydrogen or C1-C4-alkyl (preferably hydrogen); R O is hydrogen or NR 9 R 10 and; R v is independently selected from fluoro, chloro, and C1-C4-alkyl (e.g., methyl); A compound of formula (I) or formula (Ia) as defined in embodiment 33, wherein z is 0 or 1; or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the atropisomer.

[0161] Embodiment 35.R ae is hydrogen, C1-C4-alkyl, -(CH2)2-Het b , -CH2-CN, -(CH2) 2- OH, -(CH2) 2- selected from the group consisting of O—C1-C4-alkyl, hydroxy-C1-C4-alkyl, —(CH2)2—O—(CH2)2—O—C1-C4-alkyl and —(CH2)2-diC1-C4-alkylamino, or R Ae is selected from the group consisting of hydrogen, fluoro-C1-C4-alkyl and C1-C4-alkyl; Het bis a 4-, 5- or 6-membered heterocycle containing one nitrogen atom and one oxygen atom, or one to two nitrogen atoms, wherein said heterocycle is unsubstituted or substituted on a carbon atom with one or two substituents independently selected from C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy and fluoro, and wherein the nitrogen atom, if present in the heterocycle, is optionally further substituted with C1-C4-alkyl; or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the atropisomer.

[0162] Embodiment 36.R ae is 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 selected from the group consisting of: Here, the Het b is a 4-, 5- or 6-membered heterocycle containing one nitrogen atom and one oxygen atom, or one to two nitrogen atoms, wherein said heterocycle is unsubstituted or substituted on a carbon atom with one or two substituents independently selected from C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy and fluoro, and wherein the nitrogen atom, if present in the heterocycle, is optionally further substituted with C1-C4-alkyl; or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the atropisomer.

[0163] Embodiment 37.R ae is 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 wherein Het b is selected from the group consisting of azetidin-1-yl, pyrrolidin-1-yl, pyrrolidin-3-yl, and morpholin-1-yl, wherein said heterocycle is optionally further substituted with one or two substituents independently selected from methyl, hydroxy-methyl, methoxy, and fluoro; or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt of said stereoisomer, or a pharmaceutically acceptable salt of said atropisomer, according to any one of embodiments 31-36.

[0164] Embodiment 38.R ae is hydrogen, fluoro-C1-C4-alkyl, C1-C4-alkyl, -(CH2)2-Het b , -(CH2) 2- 37. The compound of formula (I) or formula (Ia) according to any one of embodiments 31 to 36, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the atropisomer, selected from the group consisting of 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.

[0165] Embodiment 39. Formula (Ib * ) compounds [ka] (In the formula, A, C, R B2 , R B3 and R B4is as described in any one of the above embodiments, where A is unsubstituted or substituted as described in any one of the above embodiments), or a pharmaceutically acceptable salt thereof.

[0166] Embodiment 40. Formula (Ic * ) compounds [ka] (In the formula, C, R A2 , R B2 , R B3 and R B4 is as described in any one of the above embodiments, wherein a is 0, 1, 2 or 3 (preferably, a is 0 or 1 or 2), or a pharmaceutically acceptable salt thereof.

[0167] Embodiment 41. Formula (Id * ) compounds [ka] (In the formula, C, R B2 , R N , R B3 and R B4 is as described in any one of the above embodiments, wherein: [ka] Lines indicate single or double bonds; R ae as defined above).

[0168] Embodiment 42. A compound according to any one of the above embodiments, selected from the compounds of any one of the Examples, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof.

[0169] Embodiment 43. 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]heptan-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-fluoropyrrolidin-1-yl)ethyl)-1H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-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]heptan-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]heptan-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]heptan-2-yl)prop-2-en-1-one, a(R) 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-(2-methoxyethoxy)ethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-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]heptan-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]heptan-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]heptan-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]heptan-2-yl)prop-2-en-1-one a compound selected from or a pharmaceutically acceptable salt thereof.

[0170] Embodiment 44. 1-{6-[(4M)-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]heptan-2-yl}prop-2-en-1-one, 1-{6-[(4M)-4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(1-{2-[(3S)-3-fluoropyrrolidin-1-yl]ethyl}-1H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl}prop-2-en-1-one, 1-{6-[(4M)-4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-phenyl-1H-pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl}prop-2-en-1-one, 1-(6-{(4M)-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]heptan-2-yl)prop-2-en-1-one, 1-(6-{(4M)-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]heptan-2-yl)prop-2-en-1-one, 1-{6-[(4M)-4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-{2-[2-(2-methoxyethoxy)ethyl]-2H-indazol-5-yl}-5-methyl-1H-pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl}prop-2-en-1-one, 1-(6-{(4M)-4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-[4-(hydroxymethyl)phenyl]-5-methyl-1H-pyrazol-1-yl}-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, 1-(6-{(4M)-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]heptan-2-yl)prop-2-en-1-one, 1-(6-{(4M)-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]heptan-2-yl)prop-2-en-1-one, 1-{6-[(4M)-4-(3-amino-5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-phenyl-1H-pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl}prop-2-en-1-one a compound selected from or a pharmaceutically acceptable salt thereof.

[0171] Embodiment 45: A compound selected from the group of compounds having the following structure and name, or a pharmaceutically acceptable salt thereof.

[0172] [Table 1]

[0173] Embodiment 46. A compound selected from the compounds having the following structures and names, or a pharmaceutically acceptable salt thereof:

[0174] [Table 2]

[0175] Embodiment 47. A crystalline form of a compound according to any one of the above embodiments.

[0176] Embodiment 48. A compound according to any one of the above embodiments, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a crystalline form thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, for use as a medicament.

[0177] Embodiment 49. A compound according to any one of the above embodiments, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a crystalline form thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, for use in the treatment of cancer.

[0178] Embodiment 50. A pharmaceutical composition comprising a compound according to any one of the above embodiments, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a crystalline form thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, and at least one pharmaceutically acceptable excipient.

[0179] Embodiment 51. Compound of Formula (2a) [ka] wherein A, B, and C are as described in any one of the above embodiments, and R 25 is hydrogen or a nitrogen-protecting group), or a salt thereof.

[0180] Embodiment 52. Formula (2b * ) compounds [ka] (In the formula, A, C, R B2 , R B3 and R B4 is as described in any one of the above embodiments, and R 25 is hydrogen or a nitrogen-protecting group, where A is unsubstituted or substituted as described in any one of the above embodiments), or a salt thereof.

[0181] Embodiment 53. Formula (2c * ) compounds [ka] (In the formula, C, R A2 , R B2 , R B3 and R B4 is as described in any one of the above embodiments, and R 25is hydrogen or a nitrogen-protecting group, where a is 0, 1, 2 or 3 (preferably, a is 0 or 1 or 2), or a pharmaceutically acceptable salt thereof.

[0182] Embodiment 54. Formula (2d * ) compounds [ka] (In the formula, C, R ae , R B2 , R N , R B3 and R B4 is as described in any one of the above embodiments, and R 25 is hydrogen or a nitrogen-protecting group, where [ka] The lines indicate single or double bonds), or a salt thereof.

[0183] Embodiment 55. A crystalline form of Compound X, such as a hydrate (modified HA) crystalline form of Compound X, or an isopropyl alcohol (IPA) solvate crystalline form, or an ethanol (EtOH) solvate crystalline form, or a propylene glycol solvate crystalline form.

[0184] Embodiment 56. A crystalline form of compound X having an X-ray powder diffraction spectrum substantially the same as the X-ray powder diffraction spectrum shown in Figure 1, Figure 2, Figure 3 or Figure 4. The present invention includes the following aspects. <1> Compounds of formula (I) [ka] (In the formula, A, (a) unsubstituted or fluoro and C 1 ~C 4 -C substituted with one or more, preferably one, two or three, substituents independently selected from alkyl 5~C 7- cycloalkylene; (b) a 5- to 7-membered unsaturated heterocyclyl containing one carbon-carbon double bond and one oxygen atom as a ring member, wherein the heterocyclyl is unsubstituted or is selected from the group consisting of fluoro and C 1 ~C 4 - alkyl, preferably 1, 2 or 3 C 1 ~C 4 -5-7 membered unsaturated heterocyclyl substituted by one or more, preferably one, two or three, substituents independently selected from alkyl; (c) unsubstituted or 1, 2 or 3 R A2 C replaced by 6 ~C 10 aryl; (d) A 5- to 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 at one or more (e.g., 1, 2, or 3) carbon atoms. A3 and the nitrogen atom, if present in the heteroaryl ring, is unsubstituted or 1 ~C 4 -Alkyl, -(CH 2 ) 1~2 -C 3~4 -cycloalkyl, C 3 ~C 6 -cycloalkyl, hydroxy-C 1 ~C 4 -Alkyl, Fluoro-C 1 ~C 4 -Alkyl, C 1 ~C 4 -Alkoxy-C 1 ~C 4 -Alkyl, N(R 9 )(R 10 )-C 1 ~C 4 -Alkyl, -SO 2 -C 1 ~C 4 -Alkyl, -SO 2 -C 3~4 -cycloalkyl, -(CH 2 ) p -Het py , and -(CH 2 ) p -N(R 9 )(R 10 a heteroaryl ring substituted with a substituent selected from the group consisting of: (e) an 8- to 10-membered heteroaryl ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or a heterobicyclic ring containing 0 to 3 nitrogen atoms, 0 to 2 oxygen atoms, 0 to 1 sulfur atom, and 0 to 1 S(=O) 2 and an 8- to 10-membered partially saturated heterobicyclic ring containing 1 to 3 heteroatoms or heteroatom groups independently selected from the group R, ... A4 and said heterobicyclic ring is further optionally substituted at a carbon atom with oxo, and the nitrogen atom, if present, is unsubstituted or is —(CO)—C 1 ~C 4 -Alkyl or C 1 ~C 4 -substituted with a substituent which is alkyl; 1 ~C 4 -Alkyl is cyano, hydroxy, oxo, fluoro, C 1 ~C 4 -alkoxy, C 1~C 4 -Alkoxy-C 1 ~C 4 -Alkyl-oxy, Het b and NR 9 R 10 a heteroaryl or heterobicyclic ring optionally substituted with one or two substituents independently selected from selected from the group consisting of: Here, Het b But N, O, S, SO and SO 2 and wherein the heterocycle Het b is unsubstituted or at a carbon atom, C 1 ~C 4 -Alkyl, hydroxy, cyano, fluoro, C 1 ~C 4 -Alkoxy-hydroxy-C 1 ~C 4 -Alkyl, Hydroxy-C 1 ~C 4 -Alkyl, C 1 ~C 4 -Alkoxy, Fluoro-C 1 ~C 4 -alkoxy and fluoro-C 1 ~C 4 -alkyl, wherein the heterocycle Het b is further optionally substituted at a carbon atom with oxo, wherein the nitrogen atom is Het b Fluoro, hydroxy and C when present 1 ~C 4 -C optionally substituted with 1 to 3 substituents independently selected from alkoxy 1 ~C 4 -optionally further substituted with alkyl; Here, A is sp 2 is attached to the remainder of the compound of formula (I) by a carbon atom in the hybridized A; where: B is B 1 and B 2 is selected from the group consisting of where B 1 is unsubstituted or 1, 2, 3 or 4 R Ba C replaced by 6~10 is aryl; B 2 is a 6- to 13-membered heteroaryl containing 1, 2, or 3 nitrogen atoms, where B 2 is unsubstituted or 1, 2, 3 or 4 R Bb is replaced by; C is hydrogen, C 1 ~C 3 Alkyl, C 3 ~C 5 Cycloalkyl, Fluoro-C 1~C 3 Alkyl, cyano, -CH 2 -CN, -CH(CN)-CH 3 , -CH 2 -OH, -CH(OH)-CH 3 and halo; L,

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[0185] In an embodiment of the present invention, pyis a 4-, 5-, 6- or 7-membered saturated heterocycle containing 1 or 2 heteroatoms independently selected from O, N (such as pyrrolidin-1-yl, azetidin-1-yl, morpholin-1-yl) and S or containing an S-oxide (SO) or S-dioxide (SO2) group, wherein said heterocycle is unsubstituted or substituted at one carbon atom by oxo, and wherein said heterocycle is optionally further substituted at one or more carbon atoms by 1, 2 or 3 substituents independently selected from C1-C4-alkoxy (preferably methoxy), halo (preferably fluoro), C1-C4-alkyl, hydroxy-C1-C4-alkyl and fluoro-C1-C4-alkyl, and wherein if a nitrogen atom is present in said heterocycle, R 10 (preferably C1-C4 alkyl (such as methyl)).

[0186] In an embodiment of the present invention, py is a 5- or 6-membered heteroaryl ring containing 1, 2, or 3 nitrogen atoms (preferably 1,2,4-triazol-1-yl or pyrazol-1-yl), wherein the heteroaryl ring is unsubstituted or is NR 9 R 10 , -C(=O)-NR 9 R 10 , halo, C1-C4-alkyl, hydroxy-C1-C4-alkyl, fluoro-C1-C4-alkyl, cyano, OH, and C1-C4-alkoxy, or wherein the heteroaryl ring is unsubstituted or substituted by one or more (e.g., 1, 2, or 3) substituents independently selected from NR 9 R 10 , halo, C1-C4-alkyl, cyano, OH, and C1-C4-alkoxy; and in embodiments of the invention, the heteroaryl ring is substituted with one or more amino groups.

[0187] In an embodiment of the present invention, A is a C5-C alkyl group which is unsubstituted or substituted with one or more, preferably one, two or three, substituents independently selected from fluoro and C1-C4-alkyl. 7- A is a cycloalkylene. For example, A is [ka] wherein W is O or C(R w )2, where each R w are independently selected from H and fluorine; R c is hydrogen or C1-C4-alkyl, and A is optionally further substituted with 1, 2 or 3 substituents independently selected from fluoro and C1-C4-alkyl.

[0188] Representative examples of A include, but are not limited to: [ka] Examples include:

[0189] In an embodiment of the present invention, A is C6 to C 10 Aryl, e.g., unsubstituted or containing one or more R A2 It is a phenyl group which may be substituted with a substituent (eg, 1, 2 or 3 substituents).

[0190] When A is phenyl, the substituent on A, if present, is preferably para to the point of attachment of the phenyl to the pyrazolyl moiety of the compounds of formula (I) and (Ia).

[0191] A is fluoro A2 When R is phenyl substituted with A2 can be in the ortho, para or meta position relative to the point of attachment of the phenyl to the pyrazolyl moiety of the compounds of formula (I) and (Ia).

[0192] When A is phenyl, R A2is, if present, preferably halo, 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 , N.R. 9 R 10 , N.R. 9a R 10a , Het py , -(CH2) p -Het py and -NR 9a R 10a and -(CH2) p NR 9a R 10a is selected from the group consisting of where: p is 1 or 2; Het py is a 4-, 5- or 6-membered heterocycle 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 to two nitrogen atoms, wherein the heterocycle is unsubstituted or substituted on a carbon atom with one or two substituents independently selected from C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy, halo and fluoro-C1-C4-alkyl, and wherein the heterocycle is further optionally substituted on a carbon atom with oxo, and wherein the nitrogen atom, if present in the heterocycle, is further optionally substituted with C1-C4-alkyl; R 9 is selected from hydrogen and C1-C4-alkyl; R 10 is selected from hydrogen, C1-C4-alkyl, hydroxy-C1-C4-alkyl, and C1-C4-alkoxy-C1-C4-alkyl; R 9a and R 10atogether with the nitrogen form a 4- or 5- or 6-membered (saturated or unsaturated) heterocycle containing one or two further heteroatoms independently selected from O, N (preferably, where the heterocycle is pyrrolidin-1-yl, azetidin-1-yl or morpholin-1-yl) and S, or its N-oxide, or its S-oxide (SO) or S-dioxide, wherein the heterocycle is optionally substituted at one carbon atom in the heterocycle with oxo, and wherein the heterocycle is optionally further substituted with one or two substituents independently selected from C1-C4-alkoxy (methoxy), halo (fluoro), C1-C4-alkyl, hydroxy-C1-C4-alkyl and fluoro-C1-C4-alkyl; or R 9a and R 10a together with the nitrogen form a 5- or 6-membered heteroaryl ring containing 1, 2, or 3 nitrogen atoms (preferably, wherein said heteroaryl ring is 1,2,4-triazol-1-yl and pyrazol-1-yl), wherein said heteroaryl ring is optionally substituted with one or two amino groups; Two R on the phenyl ring A2 When substituents are present, they are preferably in the (a) ortho and para, or (b) meta and para, or (c) ortho and meta positions relative to the point of attachment of the phenyl to the pyrazolyl moiety of the compounds of Formula (I) and (Ia).

[0193] Representative R in phenyl 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-CH3, -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-OCH3, -C(O)-N(H)-CH2-CH2-N(CH3)2, -(CH2) p -Het py where Het py is a 4-, 5- or 6-membered saturated heterocycle containing one or two heteroatoms independently selected from O, N (such as pyrrolidin-1-yl, azetidin-1-yl, morpholin-1-yl) and S, or containing an S-oxide (SO) or S-dioxide (SO) group, or Het py is a 5- or 6-membered heteroaryl ring containing 1, 2, or 3 nitrogen atoms; wherein the 5- or 6-membered heterocycle may be further substituted with one or two substituents independently selected from oxo, C1-C4-alkoxy (preferably methoxy), halo (preferably fluoro), 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 C1-C4-alkoxy (preferably methoxy), halo (preferably fluoro), C1-C4-alkyl, hydroxy-C1-C4-alkyl, and fluoro-C1-C4-alkyl; wherein 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 amino, C1-C4-alkoxy (preferably methoxy), halo (preferably fluoro), 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 C1-C4-alkoxy (preferably methoxy), halo (preferably fluoro), C1-C4-alkyl, hydroxy-C1-C4-alkyl, and fluoro-C1-C4-alkyl; and p is 0, 1 or 2 (preferably 0 or 1).

[0194] For example, R A2 Representative examples include: [ka] are listed, In the formula, R 20 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).

[0195] For example, R A2 Representative examples include: [ka] are listed, In the formula, R 21 is hydrogen or C1-C4-alkyl (preferably methyl), or amino, Here, p is 0, 1 or 2, and preferably p is 0 or 1.

[0196] In an embodiment 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, and said heteroaryl ring is unsubstituted or has R at one or more (e.g., 1, 2 or 3) carbon atoms. A3 and the nitrogen atom, if present in the heteroaryl ring, is unsubstituted or C1-C4-alkyl, -(CH2) 1~2 -C 3~4 -cycloalkyl, hydroxy-C1-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 substituent is 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).

[0197] For example, A may be unsubstituted or may contain one or more substituents R A3 A may be a pyridin-2-yl or pyridin-3-yl or pyridin-4-yl group which may be substituted with A is preferably a pyridin-3-yl or pyridin-4-yl group.

[0198] When A is pyridin-3-yl, R in A A3 Substituents, such as C1-C4-alkyl, when present, are preferably in the 2- or 6-position on the pyridinyl ring of compounds of formula (I) and (Ia).

[0199] When there are two substituents on the pyridin-3-yl ring (eg, fluoro and amino), they are preferably at the 5- and 6-positions of the pyridin-3-yl ring of compounds of formula (I) and (Ia).

[0200] When A is pyridin-4-yl, R in A A3 Substituents, such as C1-C4-alkyl, when present, are preferably at the 2- or 3-position (preferably the 3-position) on the pyridinyl ring of compounds of formula (I) and (Ia).

[0201] When A is pyridin-4-yl, preferably the two R in A are independently selected from C1-C4-alkyl, fluoro and amino (more preferably C1-C4-alkyl). A3 Substituents, when present, are preferably at the 2 and 6 positions on the pyridinyl ring of compounds of formula (I) and (Ia).

[0202] Representative substituents on pyridinyl include, but are not limited to, NH2, 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-CH3, -SO2-CH3, -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-O CH3, -C(O)-N(H)-CH2-CH2-N(CH3)2, -(CH2) p -Het py where Het pyis a 4-, 5- or 6-membered saturated heterocycle containing 1 or 2 heteroatoms independently selected from O, N (such as pyrrolidin-1-yl, azetidin-1-yl, morpholin-1-yl) and S, or containing an S-oxide (SO) or S-dioxide (SO2) group, wherein said heterocycle can be further substituted with 1, 2 or 3 substituents independently selected from C1-C4-alkoxy (preferably methoxy), halo (preferably fluoro), C1-C4-alkyl, hydroxy-C1-C4-alkyl, fluoro-C1-C4-alkyl, and —C(O)—N(CH3)—(CH2—CH2—OCH3), or Het py is a 5- or 6-membered heteroaryl ring containing 1, 2 or 3 nitrogen atoms, wherein said heteroaryl ring can be further substituted with 1, 2 or 3 substituents independently selected from C1-C4-alkoxy (methoxy), halo (fluoro), C1-C4-alkyl, hydroxy-C1-C4-alkyl, and fluoro-C1-C4-alkyl.

[0203] For example, R A3 A representative example of is when A is pyridinyl: [ka] may be selected from In the formula, R 20 is hydrogen or C1-C4-alkyl (preferably methyl), Here, p is 0, 1 or 2, and preferably p is 0 or 1.

[0204] For example, R A3 A representative example in the formula (I) is when A is pyridinyl, e.g., pyridin-3-yl: [ka] may be selected from In the formula, R 21 is hydrogen or C1-C4-alkyl (preferably methyl), or amino, Here, p is 0, 1 or 2. Preferably, p is 0 or 1.

[0205] In embodiments of compounds of formula (I) and (Ia), representative substituents R A3 is NH2, F, -CH3, -CF3, -CH2OH, CN, -C(O)-N(H)-C(CH3)2-CH2-O-CH3, -C(O)-N(CH3)-(CH2-CH2-OCH3), -O-(CH2)3)-N(CH3)2, when A is a pyridinyl ring; [ka] wherein p is 0, 1 or 2, preferably p is 1 or 2; R 21 is hydrogen or C1-C4-alkyl (preferably methyl), R 22 is hydrogen or C1-C4-alkyl (preferably methyl), or amino, Preferably, p is 0 and R 22 is an amino.

[0206] In an embodiment of the invention, A is unsubstituted or contains one or more substituents R A3 A pyrimidin-3-yl or pyrimidin-5-yl group may be substituted with: Representative substituents on the pyrimidinyl group include -O-CH3.

[0207] In an embodiment of the present invention, A is [ka] wherein R 24 is hydrogen, C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, -NR 9 R 10 C1~C4-Alkyl, -SO2-C1~C4-Alkyl, -SO2-C 3~4-cycloalkyl or -(CH2) 1~2 -C 3~4 -cycloalkyl; or R 24 is hydrogen, C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, amino-C1-C4-alkyl, C1-C4-alkylamino-C1-C4-alkyl, di-C1-C4-alkylamino-C1-C4-alkyl, -SO2-C1-C4-alkyl, -SO2-C 3~4 -cycloalkyl or -(CH2) 1~2 -C 3~4 -cycloalkyl; R 4a , R 4b , R 4c and R 4d are each independently selected from hydrogen and C1-C4-alkyl (preferably methyl).

[0208] R 24 Preferably, di-C1-C4-alkylamino-C1-C4-alkyl (e.g., —CH2—CH2—N(CH3)2) or —SO2—C 3~4 -cycloalkyl (e.g., -SO2-cyclopropyl).

[0209] R 4c is preferably C1-C4-alkyl (e.g., methyl), and R 4a , R 4b and R 4d Each of is preferably hydrogen.

[0210] R 24 is di-C1-C4-alkylamino-C1-C4-alkyl, R 4c is preferably C1-C4-alkyl (e.g., methyl), and R 4a and R 4d is hydrogen.

[0211] In an embodiment of the present invention, A is (i) an 8- to 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 to 3 nitrogen atoms, 0 to 1 oxygen atoms, and 0 to 1 sulfur atoms); or (ii) an 8- to 10-membered partially saturated heterobicyclic ring containing 1-3 heteroatoms or heteroatom groups independently selected from 0-3 nitrogen atoms, 0-2 oxygen atoms, 0-1 sulfur atoms, and 0-1 S(═O) groups in the heterobicyclic ring, wherein the heteroaryl ring or heterobicyclic ring is unsubstituted or has 1, 2, 3, 4, or 5 R groups at the carbon atoms; A4 the heterobicyclic ring is further optionally substituted at a carbon atom by oxo, and the nitrogen atom, if present, is unsubstituted or substituted by a substituent which is -(CO)-C1-C4-alkyl or C1-C4-alkyl, said C1-C4-alkyl being selected from the group consisting of cyano, hydroxy, oxo, fluoro, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 is a heteroaryl or heterobicyclic ring optionally substituted with one or two substituents independently selected from:

[0212] In an embodiment of the present invention, A is an 8-10 membered heteroaryl ring containing 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. For example, A is an 8-10 membered heteroaryl containing 1-3 heteroatoms independently selected from 0-3 nitrogen atoms, 0-1 oxygen atoms, and 0-1 sulfur atoms. The heteroaryl ring is unsubstituted or contains 1, 2, 3, 4, or 5 R groups at the carbon atoms. A4 and the nitrogen atom, if present, is unsubstituted or substituted by a substituent which is -(CO)-C1-C4-alkyl or C1-C4-alkyl, said C1-C4-alkyl being selected from the group consisting of cyano, hydroxy, oxo, fluoro, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9R 10 is optionally substituted with one or two substituents independently selected from

[0213] Therefore, a typical example of A is: [ka] Also mentioned are: In the formula, wavy line [ka] indicates the point of attachment of A to the rest of the molecule.

[0214] In an embodiment 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 heterobicyclic ring containing 1-3 heteroatoms or heteroatom groups independently selected from 0-3 nitrogen atoms, 0-2 oxygen atoms, 0-1 sulfur atoms and 0-1 S(=O)2 groups in the heterobicyclic ring, and said heteroaryl ring or heterobicyclic ring is unsubstituted or has 1, 2, 3, 4 or 5 R at the carbon atoms. A4 the heterobicyclic ring is further optionally substituted at a carbon atom by oxo, and the nitrogen atom, if present, is unsubstituted or substituted by a substituent which is -(CO)-C1-C4-alkyl or C1-C4-alkyl, said C1-C4-alkyl being selected from the group consisting of cyano, hydroxy, oxo, fluoro, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 is optionally substituted with one or two substituents independently selected from

[0215] In an embodiment 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 heterobicyclic ring containing 1-3 nitrogen atoms or 1-2 oxygen atoms or 1 sulfur atom or 1 S(=O)2 group in the heterobicyclic ring, said heteroaryl ring or heterobicyclic ring being unsubstituted or containing 1, 2, 3, 4 or 5 R at the carbon atoms. A4 the heterobicyclic ring is further optionally substituted at a carbon atom by oxo, and the nitrogen atom, if present, is unsubstituted or substituted by a substituent which is -(CO)-C1-C4-alkyl or C1-C4-alkyl, said C1-C4-alkyl being selected from the group consisting of cyano, hydroxy, oxo, fluoro, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 is optionally substituted with one or two substituents independently selected from

[0216] In an embodiment of the present invention, the nitrogen atom, when present in the abovementioned 8-10 membered heteroaryl ring or the abovementioned 8-10 membered partially saturated heterobicyclic ring, is unsubstituted or substituted with cyano, hydroxy, oxo, fluoro, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 is substituted with C1-C4 alkyl optionally substituted with 1 or 2 substituents independently selected from:

[0217] In an embodiment of the present invention, b is a 4-, 5-, or 6-membered heterocyclic or heteroaryl ring containing one or two heteroatoms or groups independently 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 to two nitrogen atoms; more preferably one nitrogen atom and one oxygen atom, or one to two nitrogen atoms), wherein the heterocyclic ring Het bis unsubstituted or substituted on a carbon atom with one or two substituents independently selected from C1-C4-alkyl, hydroxy, cyano, fluoro, 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, fluoro, C1-C4-alkoxy-hydroxy-C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy and fluoro-C1-C4-alkyl), wherein the heterocycle Het b is further optionally substituted at a carbon atom with oxo, wherein the nitrogen atom is Het b When present in, it is optionally further substituted with C1-C4-alkyl, said C1-C4-alkyl being optionally substituted with 1 to 3 substituents independently selected from fluoro, hydroxy and C1-C4-alkoxy.

[0218] In an embodiment of the present invention, b is azetidin-1-yl, pyrrolidin-1-yl, pyrrolidin-3-yl or morpholin-1-yl, optionally substituted with fluoro, hydroxy and C1-C4-alkoxy (eg methyl, hydroxy-methyl, methoxy and fluoro).

[0219] In an embodiment 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 heterobicyclic ring containing 1-3 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 in the heterobicyclic ring, wherein when A contains nitrogen, the nitrogen is selected from R ae or R Ae is replaced by

[0220] In an embodiment 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 heterobicyclic ring containing 1-3 nitrogen atoms or 1-2 oxygen atoms or 1 sulfur atom or 0-1 S(=O)2 groups in the heterobicyclic ring, wherein when A contains nitrogen, the nitrogen is not selected from R ae or R Ae is replaced by

[0221] In an embodiment of the 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 is replaced by

[0222] In an embodiment of the invention, A is an 8-10 membered heteroaryl ring containing 1, 2 or 3 nitrogen atoms, where one of the nitrogen atoms is R ae or R Ae is replaced by

[0223] In an embodiment of the present invention, R Ae is selected from the group consisting of hydrogen, -(CO)-C1-C4-alkyl and C1-C4-alkyl, where C1-C4-alkyl is in each case cyano, hydroxy, fluoro, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 is optionally substituted with one or two substituents selected from:

[0224] In an embodiment of the present invention, R Ae is selected from the group consisting of hydrogen, fluoro-C1-C4-alkyl and C1-C4-alkyl (eg methyl).

[0225] In an embodiment of the present invention, R aeis selected from the group consisting of hydrogen and C1-C4-alkyl, where the alkyl is selected from cyano, hydroxy, fluoro, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 is optionally substituted with one or two substituents independently selected from

[0226] In an embodiment of the present invention, R ae is hydrogen, C1-C4-alkyl, -(CH2)2-Het b , -CH2-CN, -(CH2) 2- OH, -(CH2) 2- and selected from the group consisting of 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., Het b is selected from the group consisting of azetidin-1-yl, pyrrolidin-1-yl, pyrrolidin-3-yl and morpholin-1-yl), preferably R ae is selected from the group consisting of hydrogen, C1-C4-alkyl and -CH2-CN. ae is selected from the group consisting of hydrogen and C1-C4-alkyl.

[0227] In an embodiment of the present invention, y is 0, 1 or 2 (preferably 0 or 1).

[0228] In an embodiment of the present invention, x is 0, 1 or 2 (preferably 0 or 1).

[0229] In an embodiment of the present invention, z is 0, 1 or 2 (preferably 0 or 1).

[0230] In an embodiment of the present invention, R q is C1-C4-alkyl, hydroxy, C1-C4-alkoxy and NR 9 R 10 and y is 0 or 1.

[0231] Preferably, R q is selected from the group consisting of C1-C4-alkyl and hydroxy.

[0232] Typical examples of A as an 8-10 membered heteroaryl ring or heterobicyclic ring include: [ka] are listed, In the formula, wavy line [ka] indicates the point of attachment of A to the rest of the molecule, where A is unsubstituted or contains 1, 2, 3, 4 or 5 R A4 (Preferably, one or two R A4 ), where the nitrogen atom in the NH moiety in the above structure is also substituted with NR ae where R ae cyano, hydroxy, oxo, fluoro, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 Preferably, R is C1-C4-alkyl optionally substituted with one or two substituents independently selected from ae is hydrogen or C1-C4-alkyl such as methyl.

[0233] For example, a typical example of A is: [ka] are listed, where the wavy line indicates the point of attachment of A to the rest of the molecule, where A is unsubstituted or contains 1, 2, 3, 4, or 5 R A4 (Preferably, one or two R A4 ), where Rae is hydrogen or cyano, hydroxy, oxo, fluoro, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 Preferably, R is C1-C4-alkyl optionally substituted with one or two substituents independently selected from ae is hydrogen or C1-C4-alkyl such as methyl.

[0234] A typical example of A is: [ka] Also mentioned are: where the wavy line indicates the point of attachment of A to the rest of the molecule; where A is unsubstituted or contains 1, 2, 3, 4 or 5 R A4 (Preferably, one or two R A4 ), where the nitrogen atom in the NH moiety in the above structure is also substituted with NR Ae or NR ae where R Ae is selected from the group consisting of hydrogen, -(CO)-C1-C4-alkyl and C1-C4-alkyl, where C1-C4-alkyl is in each case cyano, hydroxy, fluoro, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 and R is optionally substituted with one or two substituents independently selected from ae cyano, hydroxy, oxo, fluoro, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 Preferably, R ae is hydrogen or C1-C4 alkyl such as methyl. Preferably, R aeis hydrogen or C1-C4-alkyl such as methyl.

[0235] Therefore, a typical example of A is: [ka] are listed, where the wavy line indicates the point of attachment of A to the rest of the molecule; where A is unsubstituted or contains 1, 2, 3, 4 or 5 R A4 (Preferably, one or two R A4 ), where R Ae is selected from the group consisting of hydrogen, -(CO)-C1-C4-alkyl and C1-C4-alkyl, where C1-C4-alkyl is in each case cyano, hydroxy, fluoro, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 and R is optionally substituted with one or two substituents independently selected from ae cyano, hydroxy, oxo, fluoro, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 Preferably, R is C1-C4-alkyl optionally substituted with one or two substituents independently selected from ae is hydrogen or C1-C4 alkyl such as methyl. Preferably, R ae is hydrogen or C1-C4-alkyl such as methyl.

[0236] Other representative examples of A are: [ka] are listed, In the formula, wavy line [ka] indicates the point of attachment of A to the rest of the molecule, where A is unsubstituted or has 1, 2, 3, 4, or 5 R A4 (Preferably, one or two R A4 ), where the nitrogen atom in the NH moiety in the above structure is also substituted with NR ae or NR Ae where R Ae is selected from the group consisting of hydrogen, -(CO)-C1-C4-alkyl and C1-C4-alkyl, where C1-C4-alkyl is in each case cyano, hydroxy, fluoro, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 and R is optionally substituted with one or two substituents independently selected from ae cyano, hydroxy, oxo, fluoro, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 Preferably, R ae is hydrogen or C1-C4 alkyl such as methyl. Preferably, R ae is hydrogen or C1-C4-alkyl such as methyl. As used herein and further in relation to the substituent B, "C 6~10 The term "aryl" refers to a phenyl or naphthyl group, where the phenyl or naphthyl is unsubstituted or contains one, two, three or four (preferably one or two) R Ba is replaced by

[0237] In an embodiment of the present invention, R Ba are independently selected from the group consisting of hydroxy, NH2, C1-C4-alkyl and halo, or preferably selected from the group consisting of hydroxy, C1-C4-alkyl and halo.

[0238] In an embodiment of the invention, B is 3-hydroxy-phenyl or 3-hydroxy-naphthyl, wherein B is unsubstituted or substituted with 1, 2 or 3 halo (preferably chloro) atoms. In a further embodiment of the invention, B is [ka] and In the formula, Hal represents a halogen atom.

[0239] In an embodiment of the present invention, B is [ka] wherein X is N or CR B5 and; R B1 are independently selected from hydrogen and C1-C4-alkyl (preferably methyl); R B2 is independently selected from hydrogen, halo (preferably chloro), C1-C4-alkyl (preferably methyl), cyclopropyl and NH2; R B3 are independently selected from hydrogen, halo (preferably chloro), cyclopropyl and C1-C4-alkyl (preferably methyl); R B4 are independently selected from hydrogen, halo (preferably chloro or fluoro) and C1-C4-alkyl (preferably methyl), or R B3 and R B4 together with the atoms to which they are attached form a 4- to 6-membered ring (preferably a 5- to 6-membered saturated or partially unsaturated carbocyclic ring) fused to the aromatic ring containing X; R B5 is independently selected from hydrogen, halo (preferably chloro) and C1-C4-alkyl (preferably methyl).

[0240] In an embodiment of the present invention, X is N or CR B5 and R B1 are independently selected from hydrogen and C1-C4-alkyl; R B2 is independently selected from hydrogen and NH; R B3 and R B4 are each independently selected from hydrogen, halo (preferably chloro) and C1-C4-alkyl (preferably methyl), or R B3 and R B4 together with the atoms to which they are attached, form a 4- to 6-membered ring (preferably a 5- to 6-membered saturated or partially unsaturated carbocyclic ring) fused to the aromatic ring containing X.

[0241] R B5 is independently selected from hydrogen, halo (preferably chloro) and C1-C4-alkyl (preferably methyl).

[0242] In an embodiment of the present invention, B is [ka] where R B1 are independently selected from hydrogen and C1-C4-alkyl; R B2 is independently selected from hydrogen, C1-C4-alkyl and NH2; R B3 and R B4 are each independently selected from hydrogen, halo (preferably fluoro or chloro, more preferably chloro) and C1-C4-alkyl (preferably methyl); R B5 is independently selected from hydrogen, halo (preferably chloro) and C1-C4-alkyl (preferably methyl).

[0243] In an embodiment of the present invention, X is N or CR B5 and where R B1 are independently selected from hydrogen and C1-C4-alkyl; R B2 is independently selected from hydrogen and NH; R B3 and R B4 are each independently selected from hydrogen, halo (preferably chloro) and C1-C4-alkyl (preferably methyl).

[0244] R B5 is independently selected from hydrogen, halo (preferably chloro) and C1-C4-alkyl (preferably methyl).

[0245] In an embodiment of the present invention, X is N or CH, preferably X is CH.

[0246] In an embodiment of the invention, X is CH and R B1 is hydrogen or C1-C4 alkyl (such as methyl).

[0247] In an embodiment of the present invention, R B1 is hydrogen or C1-C4-alkyl (such as methyl), preferably R B1 is hydrogen.

[0248] In an embodiment of the present invention, R B2 is hydrogen or amino, preferably R B2 is hydrogen.

[0249] In an embodiment of the present invention, R B3 and R B4 are each independently selected from halo (preferably chloro) and C1-C4-alkyl (preferably methyl).

[0250] The present invention provides compounds of formula (I) and (Ia), wherein R B1 are independently selected from hydrogen and C1-C4-alkyl; R B2 is amino and R B3 is halo (preferably chloro), and R B4 is methyl and X is CH, or R B2 is amino and R B3 is halo (preferably chloro) or methyl, and R B4 is hydrogen and X is CH, or R B2 is hydrogen and R B3 is halo (preferably chloro) or methyl, and R B4 is hydrogen, X is CH, In an embodiment of the present invention, R B2 is amino and R B3 and R B4 are both halo (preferably chloro) and X is CH.

[0251] In an embodiment of the present invention, R B1 is C1-C4-alkyl (preferably methyl), and R B2 , R B3 , R B4 and R B5 are all hydrogen.

[0252] In an embodiment of the invention, X is N and R B1 and R B2 is hydrogen and R B3 is independently selected from halo (preferably chloro) and C1-C4-alkyl (preferably methyl), and R B4 is halo (preferably chloro).

[0253] In a further aspect of the invention there is provided a compound selected from any one of the Examples, or a pharmaceutically acceptable salt thereof.

[0254] In a further aspect of the present invention, [ka] a compound selected from the group consisting of or a pharmaceutically acceptable salt thereof.

[0255] In a further aspect of the present invention, 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]heptan-2-yl)prop-2-en-1-one (Example 1a), [ka] ; a(R)(S)-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(1-(2-(3-fluoropyrrolidin-1-yl)ethyl)-1H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one (Example 18a), [ka] ; 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]heptan-2-yl)prop-2-en-1-one (Example 26a), [ka] ; 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]heptan-2-yl)prop-2-en-1-one (Example 41a), [ka] ; 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]heptan-2-yl)prop-2-en-1-one (Example 42a), [ka] ; a(R) 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-(2-methoxyethoxy)ethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one (Example 43a), [ka] ; 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]heptan-2-yl)prop-2-en-1-one (Example 47a), [ka] ; 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]heptan-2-yl)prop-2-en-1-one (Example 60a), [ka] ; 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]heptan-2-yl)prop-2-en-1-one (Example 69a), [ka] 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]heptan-2-yl)prop-2-en-1-one (Example 70a), [ka] a compound selected from the group consisting of or a pharmaceutically acceptable salt thereof.

[0256] The present invention provides [ka] a compound selected from the group consisting of or a pharmaceutically acceptable salt thereof.

[0257] Depending on the selection of starting materials and procedures, the compounds may exist in the form of one of the possible isomers or as a mixture thereof, e.g., as pure optical isomers or as isomeric mixtures, such as racemic and diastereomeric mixtures, depending on the number of asymmetric centers. The present invention is intended to include all such possible isomers, including racemic mixtures, enantiomerically enriched mixtures, diastereomeric mixtures, and optically pure forms. Optically active (R)- and (S)-isomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. When a compound contains a di- or trisubstituted cycloalkyl, the cycloalkyl substituent may have a cis- or trans-configuration. The present invention includes cis- and trans-configurations of substituted cycloalkyl groups and mixtures thereof. All tautomers are also intended to be included. In particular, when a heteroaryl ring containing N as a ring atom is a 2-pyridone, tautomers in which, for example, the carbonyl is shown as hydroxy (e.g., 2-hydroxypyridine) are included.

[0258] As used herein, the term "salt" or "salts" refers to acid addition salts or base addition salts of the compounds of the present invention. "Salt" specifically includes "pharmaceutically acceptable salts." The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds of the present invention, which are typically not biologically or otherwise undesirable. In many cases, the compounds of the present invention are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0259] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. 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, trifluoroacetic acid, etc.

[0260] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0261] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts.

[0262] 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, basic ion exchange resins, etc. Particular organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0263] In another aspect, the present invention provides an ester of benzoate, ascorbate, adipate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, caprate, chloride / hydrochloride, chlorotheophyllinate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, lauryl phosphate, lauric acid ... In some embodiments, the compound is provided in the form of a methylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, mucate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate, triphenate, trifluoroacetate or xinafoate salt.

[0264] Pharmaceutically acceptable salts are preferred.

[0265] Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures shown by the formulas given herein, except that one or more atoms are replaced with an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine (respectively, 2 H, 3 H, 11 C. 13 C. 14 C. 15 N, 17 O. 18 O. 18 F, 35 S, 36 The present invention includes various isotopically labeled compounds as defined herein, e.g., 3 H and 14 those containing radioactive isotopes such as C, or 3 H and 14 These isotope-labeled compounds include those containing non-radioactive isotopes such as C. These isotope-labeled compounds are useful for metabolic studies ( 14 C), reaction rate tests (e.g. 2 H and 13 C), detection or imaging techniques including drug or substrate tissue distribution assays (such as positron emission tomography (PET) or single photon emission computed tomography (SPECT)), or radiation treatment of patients. 18 F compounds may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of formula (I) may generally be prepared by conventional techniques known to those skilled in the art, or by methods similar to those described in the accompanying Examples, substituting an appropriate isotopically labeled reagent for the previously used non-labeled reagent.

[0266] Additionally, heavier isotopes, particularly deuterium (i.e., 2Substitution with H or D) may provide certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements or improved therapeutic index. It is understood that deuterium in this context is considered a substituent of the compounds of formula (I). The concentration of such heavier isotopes, specifically deuterium, can be defined by the isotopic enrichment factor. As used herein, the term "isotopic enrichment factor" refers to the ratio between the isotopic abundance and the natural abundance of a particular isotope. When a substituent in a compound of the invention is designated as deuterium, such compounds have an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0267] The invention also relates to compounds of any of the described embodiments, wherein one or more hydrogen atoms in one or more substituents are replaced with deuterium, e.g., all hydrogen atoms in one or more alkyl substituents are replaced with deuterium (and each one or more moieties are then perdeuterated).

[0268] In embodiments of the present invention, in particular 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 in A and / or B, when A or B is an indazolyl ring, C1-C3-alkyl (or methyl) can be deuterated or perdeuterated.

[0269] The present invention also relates to crystalline forms of the compound of formula (I).

[0270] The hydrate (modified HA) crystalline form of Compound X is obtained from an isopropyl (IPA) solvate, an ethanol (EtOH) solvate, a methanol solvate, and a propylene glycolate solvate of Compound X. The hydrate (modified HA) crystalline form of Compound X can be characterized by an X-ray powder diffraction pattern (XRPD) comprising at least one, two, three, or four peaks having refraction angle 2θ values selected from the group consisting of 8.2°, 11.6°, 12.9°, and 18.8° (CuKα λ=1.5418 Å), measured at a temperature of about 25°C and an X-ray wavelength, λ, of 1.5418 Å. The hydrate (modified HA) crystalline form may also be characterized by an X-ray powder diffraction pattern (XRPD) comprising at least one, two, three, or four or all peaks having refraction angle 2θ values selected from the group consisting of 8.2°, 11.6°, 12.1°, 12.9°, 14.6°, 16.2°, 18.8°, 20.4°, and 24.1° (CuKα λ=1.5418Å), measured at a temperature of about 25°C and an X-ray wavelength, λ, of 1.5418Å.

[0271] The isopropyl alcohol (IPA) solvate of Compound X may be characterized by an X-ray powder diffraction pattern (XRPD) comprising at least one, two, or three peaks having refraction angle 2θ values selected from the group consisting of 7.5°, 12.5°, and 17.6° (CuKα λ=1.5418 Å), measured at a temperature of about 25° C. and an X-ray wavelength, λ, of 1.5418 Å. The isopropyl alcohol solvate of Compound X may be characterized by an X-ray powder diffraction pattern (XRPD) comprising at least one, two, three, or four or more peaks, or all of the peaks, having refraction angle 2θ values selected from the group consisting of 7.5°, 12.5°, 15.5°, 16.4°, 17.6°, 21.4°, and 24.4° (CuKα λ=1.5418 Å), measured at a temperature of about 25° C. and an X-ray wavelength, λ, of 1.5418 Å.

[0272] The ethanol (EtOH) solvate of Compound X may be characterized by an X-ray powder diffraction pattern (XRPD) comprising at least one, two, or three or four peaks having refraction angle 2θ values selected from the group consisting of 7.9°, 12.7°, 18.2° and 23.1° (CuKα λ=1.5418 Å), measured at a temperature of about 25° C. and an X-ray wavelength, λ, of 1.5418 Å. The ethanol solvate of Compound X may be characterized by an X-ray powder diffraction pattern (XRPD) including at least one, two, three, or four or more, or all, peaks having refraction angle 2θ values selected from the group consisting of 7.9°, 12.7°, 13.1°, 15.5°, 15.9°, 16.9°, 18.2°, 18.6°, and 23.1° (CuKα λ=1.5418 Å) measured at a temperature of about 25° C. and an X-ray wavelength, λ, of 1.5418 Å.

[0273] The propylene glycol solvate of Compound X may be characterized by an X-ray powder diffraction pattern (XRPD) comprising at least one, two, or three, or four peaks having refraction angle 2θ values selected from the group consisting of 7.3°, 13.2°, 18.0°, and 22.5° (CuKα λ=1.5418 Å), 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 may be characterized by an X-ray powder diffraction pattern (XRPD) including at least one, two, three, or four or more, or all, peaks having refraction angle 2θ values selected from the group consisting of 7.3°, 13.2°, 15.6°, 16.2°, 18.0°, 22.5°, 22.8°, 23.2°, and 25.1° (CuKα λ=1.5418 Å) measured at a temperature of about 25° C. and an X-ray wavelength, λ, of 1.5418 Å.

[0274] As used herein, the term "pharmaceutically acceptable carrier" includes any one or more selected from all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavoring agents, dyes, and the like, and combinations thereof, as known to those skilled in the art (see, e.g., Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Use of any conventional carrier in a therapeutic or pharmaceutical composition is contemplated, unless such use is incompatible with the active ingredient.

[0275] The term "therapeutically effective amount" of a compound of the present invention refers to an amount of a compound of the present invention that causes a biological or medical response in a subject, such as a reduction or inhibition of enzyme or protein activity, or that improves symptoms, alleviates a pathology, slows or delays disease progression, or prevents a disease. In one non-limiting embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the present invention that, when administered to a subject, is effective to at least partially alleviate, inhibit, prevent, and / or ameliorate (1) a pathology, such as cancer, or a disorder or disease caused by a KRAS, HRAS, or NRAS G12C mutation.

[0276] In another non-limiting embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the invention that, when administered to a cell, or tissue, or noncellular biomaterial, or culture medium, is effective to at least partially reduce or inhibit the activity of a KRAS, HRAS, or NRAS G12C mutant protein.

[0277] As used herein, the term "subject" refers to an animal. Typically, an animal is a mammal. A subject also refers to, for example, a primate (e.g., a male or female human), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird, etc. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.

[0278] As used herein, the terms "inhibit," "inhibition," or "inhibiting" refer to the alleviation or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0279] As used herein, the terms "treat," "treating," or "treatment" of any disease or disorder refer, in one embodiment, to ameliorating the disease or disorder (i.e., slowing, halting, or reducing the onset of the disease or at least one of its clinical symptoms). In another embodiment, "treat," "treating," or "treatment" refers to alleviating or improving at least one physical parameter, including those that may not be discernible by the patient. In yet another embodiment, "treat," "treating," or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilization of discernible symptoms), physiologically (e.g., stabilization of physical parameters), or both. In yet another embodiment, "treat," "treating," or "treatment" refers to preventing or delaying the onset or development or progression of the disease or disorder.

[0280] As used herein, a subject is "in need of" a treatment if such subject would benefit biologically, medically, or in quality of life from such treatment.

[0281] As used herein, the terms "a," "an," "the," and similar terms used in the context of the present invention (particularly in the context of the claims) are to be construed as encompassing both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0282] All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context. The use of any examples or exemplary language (e.g., "etc.") provided herein is intended merely to further clarify the invention and does not impose limitations on the scope of the invention as otherwise claimed.

[0283] Any asymmetric center of the compounds of the present invention can be present in a racemic mixture, a mixture of enantiomers, or an enantiomerically enriched form. In certain embodiments, for example, as a mixture of enantiomers, each asymmetric center is present in at least 10% enantiomeric excess, at least 20% enantiomeric excess, at least 30% enantiomeric excess, at least 40% enantiomeric excess, at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess. In certain embodiments, for example, in the enantiomerically enriched form, each chiral center is present in at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.

[0284] Thus, as used herein, the compounds of the present invention may exist in the form of one of the possible isomers, enantiomers, atropisomers, diastereoisomers, tautomers or mixtures thereof, for example as substantially pure diastereoisomers, optical isomers (enantiomers), racemates or mixtures thereof.

[0285] Any resulting mixture of isomers can be separated on the basis of the physical chemical differences of the components into pure or substantially pure optical isomers, diastereoisomers, atropisomers, racemates, for example, by chromatography and / or fractional crystallization.

[0286] Any resulting racemic forms of the final products or intermediates can be resolved into their optical antipodes by known methods, for example, by separation of their diastereomeric salts obtained with optically active acids or bases and liberating the optically active acidic or basic compounds. Thus, in particular, basic moieties can be used to resolve the compounds of the present invention into their optical antipodes by fractional crystallization of salts formed with optically active acids, for example, tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'-p-toluoyltartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid. Racemic products can also be resolved by chiral chromatography, for example, high-performance liquid chromatography (HPLC), using a chiral adsorbent.

[0287] Typically, compounds of formula (I) can be prepared according to the schemes shown below: The examples outlining specific synthetic routes, and the general schemes below, provide guidance to those skilled in the art of synthetic chemistry, who will readily understand that adjustments can be made, as necessary, to solvents, concentrations, reagents, protecting groups, order of synthetic steps, times, temperatures, and the like.

[0288] The schemes shown below are intended to represent single diastereomers / enantiomers as well as isomeric mixtures thereof. Separation of diastereomers / enantiomers can be carried out according to the techniques described herein. Unless otherwise defined, in the general schemes shown below, the substituents Z, X1, X2, Ar 1 and Ar 2 is as defined herein. In the following general scheme, Ar 1 corresponds to the substituent A defined for compounds of formula (I), and Ar 2corresponds to the substituent B defined for compounds of formula (I). In particular, the substituents C, R 2 , R 3 , R 4 and R 5 is as defined herein and, in particular, in the claims. Amine protecting groups (also referred to herein as nitrogen-protecting groups) are referred to as "PG" in the following schemes. In the following schemes, compounds of formula (Iy) are compounds of formula RC(O)-X, and the RC(O) substituent attached to the nitrogen atom of the spiro linker in compounds of formula (Ie) should be interpreted accordingly. In the following schemes, Ar 1 corresponds, where appropriate, to substituent A in compounds of formula (I), and Ar 2 corresponds, where appropriate, to substituent B in compounds of formula (I).

[0289] [ka] Scheme-1 Synthesis: Compounds of formula (Ie) disclosed herein can be synthesized as outlined in Scheme-1. A suitable di-halogenated heteroaromatic ring (1) is reacted with an aryl or heteroaryl boronic acid / ester (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 ) is reacted with a coupling partner to give compound (2). 1is introduced by a palladium cross-coupling reaction using a suitably functionalized aryl or heteroaryl system, such as an arylboronic acid, in the presence of a palladium catalyst, such as RuPhos-Pd-G3 / RuPhos, in a solvent such as toluene with a base such as K3PO4 to give compound (3). In step C, the protecting group (PG) is removed under appropriate conditions, depending on the protecting group used. For example, the Boc group of compound (3) is removed using conditions known in the art, such as an organic acid, such as trifluoroacetic acid, in a solvent such as dichloromethane, or a mineral acid, such as sulfuric acid, in a solvent such as 1,4-dioxane, to give compound (4). Ar 2 may also contain a protecting group (e.g., THP), which is removed in the same reaction under the conditions described above to cleave the Boc group. In step D, compound (5) can be prepared by reacting compound (4) with a compound of formula (Iy) (wherein X is a leaving group, such as halo (e.g., chloro)) in the presence of a suitable base (e.g., Hunig's base); or when X is OH, the reaction is carried out under standard amide bond-forming conditions (e.g., in the presence of an amide coupling reagent such as HATU and a suitable base such as DIPEA). For example, acrylamide can be introduced by treating compound (4) with acrylic acid in a solvent such as methylene chloride in the presence of a coupling agent such as propylphosphonic anhydride and a base such as Hunig's base to give compound (5). 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 atropisomers is separated using SFC or HPLC conditions using an appropriate column and eluent.

[0290] Compounds (1), (2), (3) and (4) shown in Scheme-1 and described above are useful intermediates for preparing compounds of formula (Ie). [ka] Scheme 2 Synthesis: Scheme 2 provides an alternative method for preparing compounds of formula (Ie) disclosed herein. After a cross-coupling reaction such as Suzuki reaction between halogenated heteroaromatic (1) and an aryl or heteroaryl coupling partner such as a boronic acid / ester 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), compound (2) is treated with a halogenating agent such as N-iodosuccinimide or N-bromosuccinimide in a solvent such as THF or CH3CN. In step C, the substituent Ar 2 is introduced by a palladium-catalyzed coupling reaction with a suitably functionalized aryl or heteroaryl system, such as an arylboronic acid ester, in the presence of a palladium catalyst such as RuPhos-Pd-G3 / RuPhos in a solvent such as 1,4-dioxane with a base such as K3PO4 to give compound (4). The remaining steps D to F are similar to steps C to E in Scheme 1 above.

[0291] Compounds (1), (2), (3), (4) and (5) shown in Scheme-2 and described above are useful intermediates for preparing compounds of formula (Ie). [ka] Scheme 3 Synthesis: Scheme 3 provides an alternative method for preparing compounds of formula (Ie) disclosed herein. A halogenated heteroaromatic compound (1) is converted to a heteroaromatic boronate ester (2) using bis-(pinacolato)-diboron in the presence of a palladium catalyst such as PdCl(dppf).CHCl adduct in a solvent such as 1,4-dioxane with a base such as potassium acetate. In Step B, the substituent Ar 1is introduced by palladium coupling reaction with a suitably functionalized aryl or heteroaryl system, such as a heteroaryl halide, in the presence of a palladium catalyst, such as RuPhos-Pd-G3 / RuPhos, in a solvent such as toluene with a base, such as K3PO4, to give compound (3). The remaining steps C to G are the same as steps B to F in Scheme 2 above.

[0292] Compounds (1), (2), (3), (4), (5) and (6) shown in Scheme-3 and described above are useful intermediates for preparing compounds of formula (Ie). [ka] Scheme 4 Synthesis: A halogenated heteroaromatic compound of formula (I) or a di-halogenated heteroaromatic compound of formula (II) is obtained as outlined in Scheme 4. A suitable tri-halogenated heteroaromatic compound (1), such as 3,4,5-dibromo-1H-pyrazole, is reacted with a metal-halogen exchange agent, such as an alkyllithium agent, for example, n-butyllithium, in a solvent such as THF to obtain compound (2) after hydrolysis, for example, using methanol. In step B, an N-protected linker is introduced by reaction with a suitable functionalized N-protected linker, for example, functionalized with tosylate, in a solvent such as DMF in the presence of a base such as cesium carbonate to obtain compound (3). In step C, a halogen / metal exchange is carried out using a suitable reagent, such as n-butyllithium, in a solvent such as THF to obtain a halogenated heteroaromatic compound of formula (I) after reaction with a suitable alkylating agent, such as methyl iodide. Compounds of formula (I) are treated with a halogenating agent such as N-iodosuccinimide in a solvent such as CH3CN to provide di-halogenated heteroaromatic rings of formula (II).

[0293] [ka] Scheme-5 Synthesis: Scheme-5 provides an alternative method for the preparation of halogenated heteroaromatic compounds of formula (I). A suitable halogenated heteroaromatic compound (1), such as 3-iodo-5-methyl-1H-pyrazole, is alkylated with a suitably functionalized N-protected linker, for example, functionalized with a tosylate, in the presence of a base, such as cesium carbonate, in a solvent, such as DMF, to give the halogenated heteroaromatic compound of formula (I).

[0294] 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 a further embodiment, the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein. For purposes of the present invention, solvates and hydrates are generally considered compositions unless otherwise specified. Preferably, the pharmaceutically acceptable carrier is sterile. The pharmaceutical composition may be formulated for a specific route of administration, such as oral, parenteral, or rectal administration. Furthermore, the pharmaceutical composition of the present invention may be in solid form (including, but not limited to, capsules, tablets, pills, granules, powders, or suppositories) or liquid form (including, but not limited to, solutions, suspensions, or emulsions). The pharmaceutical composition may be subjected to conventional pharmaceutical processes, such as sterilization, and / or may contain conventional inert diluents, lubricants, or buffers, as well as auxiliary substances, such as preservatives, stabilizers, wetting agents, emulsifiers, and buffers.

[0295] Typically, the pharmaceutical composition is a tablet or gelatin capsule containing the active ingredient together with one or more of the following: a) diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricants, such as silica, talcum, stearic acid, its magnesium or calcium salts and / or polyethylene glycol; c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; d) disintegrants, such as starch, agar, alginic acid or its sodium salt, or effervescent mixtures; and e) Absorbents, colorants, flavors and sweeteners.

[0296] In one embodiment, the pharmaceutical composition is a capsule containing only the active ingredient.

[0297] Tablets may be film coated or enteric coated according to methods known in the art.

[0298] Compositions suitable for oral administration contain an effective amount of the compound 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 for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions can contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives to provide a pharmaceutically acceptable and palatable formulation. Tablets can contain the active ingredient in a mixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients include inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin, or acacia; and lubricants such as magnesium stearate, stearic acid, or talc. The tablets are uncoated, or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over a longer period of time. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate can be used. Formulations for oral use can be presented as hard gelatin capsules (in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin) or as soft gelatin capsules (in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil).

[0299] Certain injectable compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. The compositions may be sterilized and / or contain auxiliary substances such as preservatives, stabilizers, wetting agents or emulsifiers, solution enhancers, salts for regulating osmotic pressure, and / or buffers. In addition, they may also contain other therapeutically useful substances. The compositions are prepared according to conventional mixing, granulating, or coating methods, respectively, and contain about 0.1 to 75%, or about 1 to 50%, of the active ingredient.

[0300] The suitable composition for transdermal application comprises an effective amount of the compound of the present invention together with a suitable carrier.The suitable carrier for transdermal delivery comprises an absorbable pharmacologically acceptable solvent to assist the passage through the host's skin.For example, the transdermal device is in the form of a bandage, comprising a backing member, a reservoir containing the compound optionally containing a carrier, optionally a rate-controlling barrier for delivering the compound to the host's skin at a controlled and predetermined rate over a long period of time, and a means for fixing the device to the skin.

[0301] Suitable compositions for topical application, e.g., to the skin and eyes, include aqueous solutions, suspensions, ointments, creams, gels, or sprayable formulations, e.g., for delivery by aerosol, etc. Such topical delivery systems would be particularly suitable for dermal application, e.g., for the treatment of skin cancer, for prophylactic use, e.g., in sun creams, lotions, sprays, etc. They are therefore particularly suitable for use in topical (including cosmetic) formulations well known in the art, which may contain solubilizers, stabilizers, tonicity enhancing agents, buffers, and preservatives.

[0302] As used herein, topical application can also refer to inhalation or intranasal application, which can be conveniently delivered in the form of a dry powder from a dry powder inhaler (alone, in a mixture, e.g., a dry blend with lactose, or as mixed component particles, e.g., with phospholipids), or in the form of an aerosol spray from a pressurized container, pump, spray, atomizer, or nebulizer, with or without a suitable propellant.

[0303] Compounds of formula (I), in free form or in pharmaceutically acceptable salt form, exhibit beneficial pharmacological properties, such as RAS mutant inhibitory properties, as shown, for example, in the in vitro tests provided in the Examples, and are therefore indicated for use therapeutically or as research chemicals, e.g., as tool compounds.

[0304] Particularly interesting compounds of the present invention have good efficacy in the biological assays described herein, particularly in the covalent binding competition assays described herein. In another aspect, they should have a favorable safety profile. In another aspect, they should have favorable pharmacokinetic properties.

[0305] Compounds of the present invention preferably have an IC 50 of less than 0.5 μM, more preferably less than 0.1 μM.

[0306] In view of their activity as RAS mutant inhibitors, particularly KRAS, HRAS or NRAS G12C mutant inhibitors, the compounds of formula (I), in free form or in the form of a pharmaceutically acceptable salt, are useful in the treatment of conditions caused by KRAS, HRAS or NRAS G12C mutations, such as cancers that are responsive (meaning in particular in a therapeutically beneficial form) to the inhibition of RAS mutant proteins, particularly KRAS, HRAS or NRAS G12C mutant proteins, most particularly the diseases or disorders described herein below.

[0307] The compounds of the present invention may be useful in the treatment of cancer. In particular, the compounds of the present invention may be useful in the treatment of an indication selected from the group consisting of lung cancer (such as lung adenocarcinoma and non-small cell lung cancer), colorectal cancer (including colorectal adenocarcinoma), pancreatic cancer (including pancreatic adenocarcinoma), uterine cancer (including endometrial cancer), rectal cancer (including rectal adenocarcinoma) and solid tumors.

[0308] The compounds of the invention may also be useful in the treatment of solid malignancies characterized by mutations in RAS.

[0309] The compounds of the invention may also be useful in the treatment of solid malignancies characterized by one or more mutations in KRAS, particularly the G12C mutation in KRAS.

[0310] Thus, in a further embodiment, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in therapy. As a further embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in therapy. Thus, in a further embodiment, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament. In a preferred embodiment, the treatment, i.e., the treatment for which the medicament is useful, is selected from diseases that can be treated by inhibiting mutant RAS proteins, particularly KRAS, HRAS, or NRAS G12C mutant proteins. In another embodiment, the present invention provides a method for treating a disease that can be treated by inhibiting mutant RAS proteins, particularly the G12C mutant of any of KRAS, HRAS, or NRAS proteins, in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0311] In a more preferred embodiment, the disease is selected from the above list, preferably non-small cell lung cancer, colorectal cancer and pancreatic cancer.

[0312] In a preferred embodiment, the treatment is for a disease that can be treated by inhibiting mutant RAS proteins, particularly G12C mutants of either KRAS, HRAS or NRAS proteins. In a more preferred embodiment, the disease is selected from the list above, preferably non-small cell lung cancer, colorectal cancer and pancreatic cancer, which are characterized by G12C mutations of either KRAS, HRAS or NRAS.

[0313] In one embodiment of the present invention, optionally for use in the treatment of cancer or solid malignancies characterized by a KRAS, HRAS or NRAS G12C mutation: 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]heptan-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-fluoropyrrolidin-1-yl)ethyl)-1H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-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]heptan-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]heptan-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]heptan-2-yl)prop-2-en-1-one, a(R)-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-(2-methoxyethoxy)ethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-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]heptan-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]heptan-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]heptan-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]heptan-2-yl)prop-2-en-1-one or a pharmaceutically acceptable salt thereof.

[0314] In one embodiment of the invention, for use in the treatment of a cancer selected from lung cancer (such as lung adenocarcinoma and non-small cell lung cancer), colorectal cancer (including colorectal adenocarcinoma), pancreatic cancer (including pancreatic adenocarcinoma), uterine cancer (including endometrial cancer) and rectal cancer (including rectal adenocarcinoma); more preferably lung cancer, colorectal cancer or pancreatic cancer or a solid tumor, 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]heptan-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-fluoropyrrolidin-1-yl)ethyl)-1H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-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]heptan-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]heptan-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]heptan-2-yl)prop-2-en-1-one, a(R)-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-(2-methoxyethoxy)ethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-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]heptan-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]heptan-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]heptan-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]heptan-2-yl)prop-2-en-1-one or a pharmaceutically acceptable salt thereof.

[0315] In one embodiment of the invention, for use in the treatment of a cancer selected from lung cancer (such as lung adenocarcinoma and non-small cell lung cancer), colorectal cancer (including colorectal adenocarcinoma), pancreatic cancer (including pancreatic adenocarcinoma), uterine cancer (including endometrial cancer) and rectal cancer (including rectal adenocarcinoma); more preferably, lung cancer, colorectal cancer or pancreatic cancer or a solid tumor (wherein the cancer is KRAS G12C mutant), 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]heptan-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-fluoropyrrolidin-1-yl)ethyl)-1H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-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]heptan-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]heptan-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]heptan-2-yl)prop-2-en-1-one, a(R)-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-(2-methoxyethoxy)ethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-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]heptan-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]heptan-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]heptan-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]heptan-2-yl)prop-2-en-1-one or a pharmaceutically acceptable salt thereof. More preferably, the cancer treated by the compound of the present invention is KRAS G12C mutant lung cancer, including KRAS G12C mutant non-small cell lung cancer.

[0316] The compounds of the present invention can be administered simultaneously with, before, or after one or more other therapeutic agents. The compounds of the present invention can be administered separately, by the same or different administration route, or together with other agents in the same pharmaceutical composition. The therapeutic agent can be, for example, a chemical compound, peptide, antibody, antibody fragment, or nucleic acid, which has a therapeutic effect or enhances therapeutic activity when administered to a patient in combination with the compounds of the present invention. In an embodiment of the present invention, the other therapeutic agent can be an anti-cancer agent.

[0317] In one embodiment, the present invention provides a product comprising a compound of the present invention and at least one other therapeutic agent as a combined preparation for simultaneous, separate, or sequential use in therapy. In one embodiment, the therapy is treatment of a disease or condition characterized by a KRAS, HRAS, or NRAS G12C mutation. A product provided as a combined preparation may comprise a compound of the present invention and the other therapeutic agent together in the same pharmaceutical composition, or may comprise a composition comprising a compound of the present invention and the other therapeutic agent in separate forms, for example, in the form of a kit.

[0318] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and another therapeutic agent. Optionally, the pharmaceutical composition may include a pharmaceutically acceptable carrier, as described above.

[0319] In one embodiment, the present invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of the present invention. In one embodiment, the kit comprises a means for keeping the compositions separate, such as a container, a divided bottle, or a divided foil packet. An example of such a kit is a blister pack, such as those typically used for packaging tablets, capsules, and the like.

[0320] The kits of the invention can be used to administer different dosage forms (e.g., oral and parenteral), to administer the separate compositions at different dosage intervals, or to titrate the separate compositions relative to one another. To aid in compliance, the kits of the invention typically include directions for administration.

[0321] In the combination therapy of the present invention, the compound of the present invention and the other therapeutic agent may be manufactured and / or formulated by the same or different manufacturers. Furthermore, the compound of the present invention and the other therapeutic agent may be combined into a combination therapy: (i) prior to presentation of the combination product to the physician (e.g., in the case of a kit containing the compound of the present invention and the other therapeutic agent); (ii) by the physician (or under the physician's guidance) immediately prior to administration; or (iii) by the patient (e.g., during sequential administration of the compound of the present invention and the other therapeutic agent). [Example]

[0322] Preparation of compounds The compounds of the present invention can be prepared as described in the following examples, which are intended to illustrate the invention and should not be construed as limiting the invention.

[0323] General methods and conditions: Temperatures are given in ° C. Unless otherwise stated, all evaporations are carried out under reduced pressure, typically between about 15 mm Hg and 100 mm Hg (= 20 to 133 mbar).

[0324] Mass spectra were obtained on an LC-MS, SFC-MS, or GC-MS system using electrospray, chemical, and electron impact ionization methods on a Waters Acquity UPLC equipped with a Waters SQ detector, or mass spectra were obtained on an LCMS system using ESI methods on a Waters Acquity LCMS equipped with a PDA detector. [M+H] + refers to the protonated molecular ion of a chemical species.

[0325] NMR spectra were performed using Bruker Ultrashield™ 400 (400 MHz), Bruker Ultrashield™ 600 (600 MHz), and Bruker Ascend™ 400 (400 MHz) spectrometers, with and without tetramethylsilane as an internal standard. Chemical shifts (δ values) are reported in ppm downfield from tetramethylsilane, and spectral splitting patterns are indicated as singlet (s), doublet (d), triplet (t), quartet (q), multiplet, unsplit or more overlapping signals (m), or broad signal (br). Solvents are indicated in parentheses. Only proton signals observed and not overlapping with solvent peaks are reported.

[0326] Celite: Celite® (the Celite Corporation) = a diatomaceous earth-based filter aid Phase Separator: Biotage Isolute Phase Separator (Part Number: 120-1908-F for 70 mL and Part Number: 120-1909-J for 150 mL) SiliaMetS® Thiol: SiliCYCLE thiol metal scavenger (R51030B, particle size: 40-63 μm).

[0327] X-ray powder diffraction (XRPD) patterns described herein were obtained using a Bruker Advance D8 in reflection geometry. Powder samples were analyzed using a zero-background Si flat sample holder. The radiation was Cu Kα (λ=1.5418 Å). Patterns were measured from 2° to 40° 2θ.

[0328] Sample amount: 5–10 mg Sample holder: Zero background Si flat sample holder XRPD parameters:

[0329] [Table 3]

[0330] device Microwave: Unless otherwise stated, all microwave reactions were performed in a Biotage Initiator using a Robot Eight / Robot Sixty throughput, emitting 0-400 W from a magnetron at 2.45 GHz.

[0331] UPLC-MS and MS analytical methods: A Waters Acquity UPLC equipped with a Waters SQ detector is used.

[0332] UPLC-MS-1: Acquity HSS T3; particle size: 1.8 μm; column size: 2.1 × 50 mm; eluent A: HO + 0.05% HCOOH + 3.75 mM ammonium acetate; eluent B: CHCN + 0.04% HCOOH; gradient: 5 to 98% B in 1.40 min, then 98% B over 0.40 min; flow rate: 1 mL / min; column temperature: 60 °C.

[0333] UPLC-MS-2: Acquity HSS T3; particle size: 1.8 μm; column size: 2.1 × 100 mm; eluent A: HO + 0.05% HCOOH + 3.75 mM ammonium acetate; eluent B: CHCN + 0.04% HCOOH; gradient: 5 to 98% B in 9.4 min, then 98% B over 0.40 min; flow rate: 1.0 mL / min; column temperature: 60 °C.

[0334] UPLC-MS-3: Acquity BEH C18; particle size: 1.7 μm; column size: 2.1 × 50 mm; eluent A: HO + 4.76% isopropanol + 0.05% HCOOH + 3.75 mM ammonium acetate; eluent B: isopropanol + 0.05% HCOOH; gradient: 1 to 98% B in 1.7 min, then 98% B over 0.1 min; flow rate: 0.6 mL / min; column temperature: 80 °C.

[0335] UPLC-MS-4: Acquity BEH C18; particle size: 1.7 μm; column size: 2.1 × 100 mm; eluent A: HO + 4.76% isopropanol + 0.05% HCOOH + 3.75 mM ammonium acetate; eluent B: isopropanol + 0.05% HCOOH; gradient: 1–60% B in 8.4 min, then 60–98% B in 1 min; flow rate: 0.4 mL / min; column temperature: 80 °C.

[0336] UPLC-MS-5: Ascentis Express C18; particle size: 2.7 μm; column size: 2.1 × 50 mm; eluent A: HO + 4.76% isopropanol + 0.05% HCOOH + 3.75 mM ammonium acetate; eluent B: isopropanol + 0.05% HCOOH; gradient: 1–50% B in 1.4 min, 50–98% B in 0.30 min, then 98% over 0.10 min; flow rate: 1 mL / min; column temperature: 80 °C.

[0337] UPLC-MS-6: Acquity BEH C18; particle size: 1.7 μm; column size: 2.1 × 50 mm; eluent A: HO + 0.05% HCOOH + 3.75 mM ammonium acetate; eluent B: isopropanol + 0.05% HCOOH; gradient: 5 to 98% B in 1.7 min, then 98% B over 0.1 min; flow rate: 0.6 mL / min; column temperature: 80 °C.

[0338] UPLC-MS-7: Acquity BEH C18; particle size: 1.7 μm; column size: 2.1 × 50 mm; eluent A: HO + 0.05% HCOOH + 3.75 mM ammonium acetate; eluent B: isopropanol + 0.05% HCOOH; gradient: 5 to 98% B in 1.7 min, then 98% B over 0.1 min; flow rate: 0.7 mL / min; column temperature: 80 °C.

[0339] UPLC-MS-8: Acquity HSS T3; particle size: 1.8 μm; column size: 2.1 × 100 mm; eluent A: HO + 0.05% HCOOH + 3.75 mM ammonium acetate; eluent B: CHCN + 0.04% HCOOH; gradient: 5 to 98% B in 9.4 min, then 98% B over 0.40 min; flow rate: 0.8 mL / min; column temperature: 60 °C.

[0340] UPLC-MS-9: CORTECS C18+; particle size: 2.7 μm; column size: 2.1 × 50 mm; eluent A: HO + 4.76% isopropanol + 0.05% HCOOH + 3.75 mM ammonium acetate; eluent B: isopropanol + 0.05% HCOOH; gradient: 1–50% B in 1.4 min, 50–98% B in 0.30 min, then 98% over 0.10 min; flow rate: 1 mL / min; column temperature: 80 °C.

[0341] UPLC-MS-10: Acquity HSS T3; particle size: 1.8 μm; column size: 2.1 × 50 mm; eluent A: HO + 0.05% HCOOH + 3.75 mM ammonium acetate; eluent B: isopropanol + 0.05% HCOOH; gradient: 5 to 98% B in 1.7 min, then 98% B over 0.10 min; flow rate: 0.6 mL / min; column temperature: 80 °C.

[0342] UPLC-MS-11: Acquity BEH C18; particle size: 1.7 μm; column size: 2.1 × 50 mm; eluent A: HO + 0.2% HCOOH; eluent B: CH3CN; gradient: 5 to 98% B in 1.4 min, then 98% B over 0.4 min; flow rate: 1.0 mL / min; column temperature: 80 °C.

[0343] UPLC-MS-12: Acquity BEH C18; particle size: 1.7 μm; column size: 2.1 × 100 mm; eluent A: HO + 0.05% HCOOH + 3.75 mM ammonium acetate; eluent B: isopropanol + 0.05% HCOOH; gradient: 5–60% B in 8.4 min, then 60–98% B in 1 min; flow rate: 0.4 mL / min; column temperature: 80 °C.

[0344] UPLC-MS-13: Acquity HSS T3; particle size: 1.8 μm; column size: 2.1 × 100 mm; eluent A: HO + 0.05% HCOOH + 3.75 mM ammonium acetate; eluent B: isopropanol + 0.05% HCOOH; gradient: 5–60% B in 8.4 min, then 60–98% B in 1 min; flow rate: 0.4 mL / min; column temperature: 80 °C.

[0345] LCMS-1: Acquity BEH C18; particle size: 1.7 μm; column size: 2.1 × 50 mm; eluent A: HO + 0.10% HCOOH + 2.0 mM ammonium acetate; eluent B: CH3CN + 0.10% HCOOH; gradient: 98:2 from 0.01 to 0.3 min, 50:50 at 0.6 min, 25:75 at 1.1 min, flow rate: 0:100 from 2.0 to 2.70 min at 0.60 mL / min, flow rate: 98:2 from 2.71 to 3.0 min at 0.55 mL / min; column temperature: room temperature.

[0346] LCMS-2: Acquity BEH C18; particle size: 1.7 μm; column size: 2.1 × 50 mm; eluent A: HO + 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 to 4.50 min, 50:50 from 4.6 to 5.0 min; flow rate: 0.40 mL / min; column temperature: room temperature.

[0347] LCMS-3: X-Bridge C18; particle size: 3.5 μm; column size: 50 × 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 to 7.20 min, flow rate: 95:5 from 7.21 to 10.0 min at 1 mL / min; column temperature: room temperature.

[0348] LCMS-4: Acquity BEH C18; particle size: 1.7 μm; column size: 2.1 × 50 mm; eluent A: HO + 0.10% HCOOH + 2.0 mM ammonium acetate; eluent B: CH3CN + 0.10% HCOOH; gradient: 98:2 from 0.01 to 0.5 min, 10:90 at 5.0 min, 5:95 from 6.0 to 7.0 min, 98:2 from 7.01 to 8.0 min; flow rate: 0.45 mL / min; column temperature: room temperature.

[0349] LCMS-5: YMC-Pack ODS-AQ; particle size: 5.0 μm; column size: 4.6 × 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 to 33 min, 90:10 from 33.01 to 35.0 min; flow rate: 1.0 mL / min; column temperature: room temperature.

[0350] MS-1: MS flow injection; eluent A: HO + 4.76% isopropanol + 0.05% HCOOH + 3.75 mM ammonium acetate; eluent B: isopropanol + 0.04% HCOOH; gradient: isocratic 70% B over 0.8 min; flow rate: 0.4 mL / min.

[0351] Preparation method: Normal Phase Chromatography:Normal phase chromatography was carried out on silica gel using pre-packed columns or using glass columns as detailed below according to standard flash chromatography methods unless otherwise stated. System 1: Teledyne ISCO, CombiFlash® Rf System 2: Biotage Isolera Column: Pre-packed RediSep Rf cartridge or SNAP cartridge Sample adsorption: onto Isolute, or onto silica gel, or applied as a solution

[0352] Reversed-phase HPLC and SFC: RP-HPLC-1: Gilson PLC 2020, column: Maisch Reprosil C18 5 μm, 250 × 30 mm, detection UV 215 and 254 nM, mobile phase: A: water + 0.1% TFA, B: acetonitrile; gradient: 30–95% B in 25 min.

[0353] RP-HPLC-5: Agela-H1000GC500, column: Welch Ultimate XB C18 40 μm, 100 × 400 mm, detection: UV, mobile phase: A: water + 0.1% NH4HCO3, B: acetonitrile; gradient: 60–100% B in 50 min.

[0354] SFC-1: Column: Reprosphere PEI 100A 5 μm; 250 × 30 mm; Mobile phase; Flow rate: 30 mL / min; Column temperature: 40 °C; Back pressure: 120 bar.

[0355] Chiral HPLC / SFC Method: C-SFC-1: Column: Amylose-C NEO 5 μm; 250 × 30 mm; Mobile phase; Flow rate: 80 mL / min; Column temperature: 40 °C; Back pressure: 120 bar.

[0356] C-SFC-2: Column: Lux Amylose-1 5 μm; 250 × 30 mm; mobile phase; flow rate: 80 mL / min; column temperature: 40 °C; back pressure: 120 bar.

[0357] C-SFC-3: Column: Chiralpak AD-H 5μm; 100×4.6mm; Mobile phase; Flow rate: 3mL / min; Column temperature: 40°C; Back pressure: 1800psi.

[0358] C-SFC-4: Column: Chiralpak AD-H 5 μm; 250 × 30 mm; mobile phase; flow rate: 80 mL / min; column temperature: 40 °C; back pressure: 120 bar.

[0359] C-SFC-5: Column: Chiralpak IB-N 5μm; 250×30mm; Mobile phase; Flow rate: 80mL / min; Column temperature: 40°C; back pressure: 120 bar.

[0360] C-SFC-6: Column: Chiralpak IB-N 5μm; 100×4.6mm; Mobile phase; Flow rate: 3mL / min; Column temperature: 40°C; Back pressure: 1800psi.

[0361] C-SFC-7: Column: Chiralpak IG 5 μm; 250 × 30 mm; mobile phase; flow rate: 80 mL / min; column temperature: 40 °C; back pressure: 120 bar.

[0362] C-SFC-8: Column: Chiralpak IG 5μm; 100×4.6mm; Mobile phase; Flow rate: 3mL / min; Column temperature: 40°C; Back pressure: 1800psi.

[0363] C-SFC-9: Column: Chiralpak AD-YMC 5 μm; 250 × 30 mm; mobile phase; flow rate: 80 mL / min; column temperature: 40 °C; back pressure: 120 bar.

[0364] C-SFC-10: Column: Chiralpak IG 5 μm; 250 × 30 mm; Mobile phase; Flow rate: 100 mL / min; Column temperature: 40 °C; Back pressure: 120 bar.

[0365] C-SFC-11: Column: Lux cellulose 5 μm; 100 × 4.6 mm; mobile phase; flow rate: 3 mL / min; column temperature: 20 °C; back pressure: 120 bar.

[0366] C-SFC-12: Column: Chiralpak OD-H 5 μm; 250 × 30 mm; Mobile phase; Flow rate: 80 mL / min; Column temperature: 40 °C; Back pressure: 110 bar.

[0367] C-SFC-13: Column: Chiralpak OD-H 5 μm; 100 × 4.6 mm; mobile phase; flow rate: 3 mL / min; column temperature: 40 °C; back pressure: 120 bar.

[0368] C-SFC-14: Waters SFC 200 equipped with UV detector; column: Chiralpak AD-H 5 μm; 250 × 30 mm; mobile phase; flow rate: 80 mL / min; column temperature: 40 °C; back pressure: 100 bar.

[0369] C-SFC-15: Waters SFC investigator equipped with a PDA detector; column: Chiralpak AD-H 5 μm; 250 × 4.6 mm; mobile phase; flow rate: 4 mL / min; column temperature: 40 °C; back pressure: 100 bar.

[0370] C-SFC-16: Waters SFC 200 equipped with UV detector; column: Chiralpak IG 5 μm; 250 × 30 mm; mobile phase; flow rate: 80 mL / min; column temperature: 40 °C; back pressure: 100 bar.

[0371] C-SFC-17: Waters SFC 200 equipped with UV detector; column: Chiralpak IG 5 μm; 250 × 21 mm; mobile phase; flow rate: 80 mL / min; column temperature: 40 °C; back pressure: 100 bar.

[0372] C-SFC-18: Waters SFC investigator equipped with a PDA detector; column: Chiralpak IG 5 μm; 250 × 4.6 mm; mobile phase; flow rate: 4 mL / min; column temperature: 40 °C; back pressure: 100 bar.

[0373] C-SFC-19: Waters SFC investigator equipped with PDA detector; column: Chiralpak IC 5 μm; 250 × 4.6 mm; mobile phase; flow rate: 4 mL / min; column temperature: 40 °C; back pressure: 100 bar.

[0374] C-SFC-20: Column: Lux cellulose 5 μm; 250 × 30 mm; mobile phase; flow rate: 80 mL / min; column temperature: 40 °C; back pressure: 120 bar.

[0375] C-HPLC-1: Column: Chiralpak IC 5 μm; 250 × 20 mm; Mobile phase; Flow rate: 10 mL / min; Column temperature: Room temperature.

[0376] C-HPLC-2: Column: ChiralPak ID 5 μm; 250 × 25 mm; Mobile phase; Flow rate: 15 mL / min; Column temperature: Room temperature.

[0377] C-HPLC-3: Column: Chiralpak IC 3 μm; 100 × 4.6 mm; Mobile phase; Flow rate: 0.42 mL / min; Column temperature: RT; Back pressure: 1800 psi.

[0378] C-HPLC-4: Column: Chiralpak IC-3 3 μm; 100 × 3 mm; Mobile phase; Flow rate: 0.42 mL / min; Column temperature: Room temperature.

[0379] C-HPLC-5: Column: Chiralpak IA 5 μm; 250 × 4.6 mm; Mobile phase; Flow rate: 1 mL / min; Column temperature: RT; Back pressure: 49 bar.

[0380] C-HPLC-6: Column: Chiralpak IA 5 μm; 250 × 30 mm; Mobile phase; Flow rate: 20 mL / min; Column temperature: Room temperature.

[0381] C-HPLC-7: ChiralPak ID 5 μm; 250 × 4.6 mm; mobile phase; flow rate: 1 mL / min; instrument temperature: room temperature.

[0382] C-HPLC-8: Cell: ChiralPak AD 5 μm; 250 × 30 mm; mobile phase; flow rate: 20 mL / min; cell temperature: room temperature.

[0383] C-HPLC-9: Cell: ChiralPak AD 3 μm; 100 × 3.0 mm; mobile phase; flow rate: 0.42 mL / min; cell temperature: room temperature.

[0384] C-HPLC-10: Chiralpak IG-3; 3 μm; 100 × 3.0 mm; mobile phase; flow rate: 0.42 mL / min; instrument temperature: 25°C.

[0385] C-HPLC-11: Chiralpak IG 5 μm; 250 × 20 mm; mobile phase; flow rate: 10 mL / min; cell temperature: 25°C.

[0386] C-HPLC-12: Cell: Chiralpak IA-5; 5 μm; 250 × 3.0 mm; mobile phase; flow rate: 1 mL / min; cell temperature: 25°C.

[0387] C-HPLC-13: Cartridge: Chiralpak IG-3; 3 μm; 100 × 3.0 mm; mobile phase; flow rate: 0.42 mL / min; cartridge temperature: 25°C.

[0388] C-HPLC-14: Cell: Chiralcel OZ; 3 μm; 250 × 25 mm; mobile phase; flow rate: 15 mL / min; cell temperature: 25°C.

[0389] C-HPLC-15: Cell: Chiralcel OZ; 3 μm; 100 × 3.0 mm; mobile phase; flow rate: 0.42 mL / min; cell temperature: 25°C.

[0390] C-HPLC-16: cell: Chiralcel OZ; 5 μm; 250×4.6 mm; mobile phase; flow rate: 1.0 mL / min; cell temperature: 25°C.

[0391] C-HPLC-17: cartridge: Chiralpak IG 5 μm; 250 × 20 mm; mobile phase; flow rate: 12 mL / min; cartridge temperature: 25°C.

[0392] C-HPLC-18: カラム: Luxアミロース-1 5μm; 250×20mm; mobile phase; flow rate: 10mL / min; カラム temperature: 40℃; back pressure: 120バール.

[0393] C-HPLC-19: cartridge: ChiralPak AD 5 μm; 250 × 25 mm; mobile phase; flow rate: 15 mL / min; cartridge temperature: room temperature.

[0394] C-HPLC-20: cartridge: Chiralpak IC 5 μm; 250×4.6 mm; mobile phase; flow rate: 1 mL / min; cartridge temperature: room temperature.

[0395] C-HPLC-21: cartridge: Chiralpak AD-H 5 μm; 250 × 21 mm; mobile phase; flow rate: 18 mL / min; cartridge temperature: 40°C.

[0396] C-HPLC-22: cartridge: Chiralpak AD-H 5 μm; 250 × 4.6 mm; mobile phase; flow rate: 1 mL / min; cartridge temperature: 25°C.

[0397] C-HPLC-23: cell: Chiralcel OX-H 5 μm; 250 × 21 mm; mobile phase; flow rate: 18 mL / min; cell temperature: 40°C.

[0398] C-HPLC-24: cartridge: Chiralpak OX-H 5 μm; 250 × 4.6 mm; mobile phase; flow rate: 1 mL / min; cartridge temperature: 25°C.

[0399] C-HPLC-25: Column: Chiralpak IBN 5 μm; 250 x 21 mm; Mobile phase; Flow rate: 18 mL / min; Column temperature: 40°C.

[0400] C-HPLC-26: Column: Chiralpak IBN 5 μm; 250 x 4.6 mm; Mobile phase; Flow rate: 1 mL / min; Column temperature: 25°C.

[0401] C-HPLC-27: Column: Chiralpak IC 5 μm; 250 x 21 mm; Mobile phase; Flow rate: 18 mL / min; Column temperature: 40°C.

[0402] C-HPLC-28: Column: Chiralpak IG, 5 μm; 250 × 21 mm; mobile phase; flow rate: 18 mL / min; column temperature: 40 °C.

[0403] C-HPLC-29: Column: ChiralPak IG 5μm; 250×4.6mm; Mobile phase; Flow rate: 1mL / min; Column temperature: 25℃.

[0404] C-HPLC-30: Column: Chiralpak IC 5 μm; 250 × 30 mm; Mobile phase; Flow rate: 20 mL / min; Column temperature: Room temperature.

[0405] Abbreviations used are those conventional in the art.

[0406] [Table 4]

[0407] [Table 5]

[0408] [Table 6]

[0409] All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts used in preparing the compounds of the invention are either commercially available or can be prepared by organic synthesis methods known to those skilled in the art. Additionally, the compounds of the invention can be prepared by organic synthesis methods known to those skilled in the art, as shown in the examples below.

[0410] The structures of all final products, intermediates, and starting materials are confirmed by standard analytical spectroscopic properties, e.g., MS, IR, and NMR. The absolute stereochemistry of representative preferred (most active) atropisomers has been determined by analysis of the X-ray crystal structure of the complex of each compound bound to the KRASG12C mutant or by analysis of small molecule X-ray crystal structures. In all other cases where X-ray structures are not available, stereochemistry has been assigned by analogy, assuming that the atropisomer exhibiting the highest activity in the covalent competition assay for each pair has the same configuration as observed by X-ray crystallography for the representative example. Absolute stereochemistry is assigned according to the Cahn-Ingold-Prelog rules, as shown above for Example 12a (the more active atropisomer), which is representative of the other examples and has the a(R) configuration.

[0411] Preparation of final compounds Method-1: Synthesis scheme [ka] 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]heptan-2-yl)prop-2-en-1-one or 1-{6-[(4M)-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]heptan-2-yl}prop-2-en-1-one and 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]heptan-2-yl)prop-2-en-1-one or 1-{6-[(4P)-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]heptan-2-yl}prop-2-en-1-one 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 In a 500 mL flask, 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, 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) under argon. K3PO4 (2 M, 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 saturated aqueous NH4Cl and extracted with EtOAc (x3). The combined organic layers were washed with saturated aqueous NaHCO3, dried (phase separator), and concentrated under reduced pressure. The crude residue was diluted with THF (50 mL), SiliaMetS® thiol (15.9 mmol) was added, and the mixture was rotated 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: 0-2% MeOH in CHCl2). The purified fractions were re-purified by normal phase chromatography (eluent: 0-2% MeOH in CHCl2) to give the title compound as a beige foam. UPLC-MS-3: Rt = 1.23 min; MS m / z [M+H] + ;656.3 / 658.3.

[0412] Step 2: 5-chloro-6-methyl-4-(5-methyl-3-(1-methyl-1H-indazol-5-yl)-1-(2-azaspiro[3.3]heptan-6-yl)-1H-pyrazol-4-yl)-1H-indazole 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 CHCl (33 mL). The reaction mixture was stirred at room temperature under nitrogen for 1.5 h. The RM was concentrated under reduced pressure to give the title compound as a trifluoroacetic acid salt, which was used in the next step without purification. UPLC-MS-3: Rt=0.74 min; MS m / z [M+H] + ;472.3 / 474.3.

[0413] 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]heptan-2-yl)prop-2-en-1-one A mixture of acrylic acid (0.69 mL, 10.1 mmol), propylphosphonic anhydride (50% in EtOAc, 5.94 mL, 7.53 mmol), and DIPEA (21.6 mL, 126 mmol) in CHCl (80 mL) was stirred at room temperature 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]heptan-6-yl)-1H-pyrazol-4-yl)-1H-indazole trifluoroacetate (Step 2, 6.30 mmol) in CHCl (40 mL). The reaction mixture was stirred at room temperature under nitrogen for 15 min. The RM was poured into saturated aqueous NaHCO and extracted with CHCl (×3). 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 room temperature for 30 min until the disappearance of the by-product resulting from the reaction of acryloyl chloride with the free NH group of the indazole (UPLC), then poured into saturated aqueous NaHCO3 and extracted with CHCl2 (3x). The combined organic layers were dried (phase separator) and concentrated. The crude residue was purified by normal phase chromatography (eluent: 0-5% MeOH in CHCl2) to give the title compound. The isomers were separated by chiral SFC (C-SFC-1; mobile phase: CO / [IPA+0.1% EtN]: 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]heptan-2-yl)prop-2-en-1-one as the second eluting peak (white powder): 1H NMR (600 MHz, DMSO-d) 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,1 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 this specification, the compound of Example 1a is also referred to as "Compound X."

[0414] The other isomer 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]heptan-2-yl)prop-2-en-1-one was obtained as the first eluting peak: C-SFC-3 (mobile phase: CO2 / [IPA+0.1% Et3N]:67 / 33): Rt=1.55 min.

[0415] Method-1a: Same as Method-1, except that step 2 was performed as described below: To a stirred 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, 1.66 g, 2.10 mmol) in dioxane (40 mL), sulfuric acid (3.30 mL, 42.0 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was diluted with water, neutralized with saturated aqueous NaHCO (to pH 8-9), extracted with n-butanol (×2), and the combined organic extracts were washed with water (×2), 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]heptan-6-yl)-1H-pyrazol-4-yl)-1H-indazole, was dried under high vacuum overnight and used in the next step without purification.

[0416] Note: For some of the examples in Tables 1 and 2, CH2Cl2 may be used in place of n-butanol for extraction.

[0417] Method-1b: Same as Method-1, except that step 3 was performed as described below: 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]heptan-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) under argon was added NaHCO (516 mg, 6.14 mmol), HO (0.20 mL), and acryloyl chloride (0.026 mL, 0.32 mmol). The reaction mixture was stirred at 0 °C for 60 min. Next, LiOH (2 M in water, 4.91 mL, 9.83 mmol) was added, and the mixture was stirred at 0 °C for 1 h until the disappearance of the by-product resulting from the reaction of acryloyl chloride with the indazole NH (UPLC). Saturated aqueous NaHCO was added, the layers were separated, and the aqueous layer was extracted with CHCl (2×). The combined organic extracts were washed with saturated aqueous NaHCO, dried (NaSO), filtered, and evaporated. The crude residue was purified by normal phase chromatography (eluent: 0–9% MeOH in CHCl) 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]heptan-2-yl)prop-2-en-1-one.

[0418] Method-1c: Same as Method-1, except that in step 1, XPhos and XPhos-Pd-G2 were used instead of Ruphos and RuPhos-Pd-G3.

[0419] Method-1d: Same as Method-1, except that in step 1, dioxane was used instead of toluene.

[0420] Method-1e: Same as Method-1, except that in step 1, Na2CO3 (2M, 3 equiv.), Pd(PPh3)4 (0.1 equiv.) and dioxane were used instead of K3PO4, RuPhos, RuPhos-Pd-G3 and toluene.

[0421] Method-1f: Same as Method-1, except that in step 1 solid Na2CO3 (3 eq) was used instead of K3PO4 and H2O (10% v / v toluene) was also added.

[0422] Method-1j: Same as Method-1, except that step 3 was carried out using Et3N and acryloyl chloride in CH2Cl2 as described in Method-9 step 3.

[0423] Method-1k: Same as Method-1, except that step 3 was carried out using iPr2NEt and acryloyl chloride in CH2Cl2 as described in Method-9 step 3.

[0424] The following Examples 2-44 in Table 1 below were prepared from the intermediates described in the Intermediate Synthesis section (in Step 1) using methods similar to Method 1 or are commercially available.

[0425] [Table 7]

[0426] [Table 8]

[0427] [Table 9]

[0428] [Table 10]

[0429] [Table 11]

[0430] [Table 12]

[0431]

Table 13

[0432]

Table 14

[0433]

Table 15

[0434] Table 16

[0435]

Table 17

[0436]

Table 18

[0437]

Table 19

[0438] Table 20

[0439] Table 21

[0440] Table 22

[0441] [Table 23]

[0442] [ka] Example 45a / 45b: 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-2'-(cyclopropylmethyl)-5-methyl-1H,2'H-[3,3'-bipyrazol]-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one The title example was prepared from 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'-bipyrazol]-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (prepared as described below) using a method similar to Method-1b steps 2 and 3. The 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 eluting peak: 1 H NMR (400 MHz, DMSO-d) δ 13.12(s,1H), 7.54(s,1H), 7.46(s,1H), 7.15(d,1H), 6.32(m,1H), 6.1 0(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. The other isomer Example 45b was obtained as the first eluting peak: C-SFC-3 (mobile phase: CO2 / MeOH: 72 / 28): Rt = 1.19 min.

[0443] 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'-bipyrazol]-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate. 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, 300 mg, 0.47 mmol), 1-(cyclopropylmethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (175 mg, 0.71 mmol), and PdCl(dppf).CHCl 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 flushed with argon and subjected to microwave irradiation at 120 °C for 20 min. The reaction mixture was allowed to reach room temperature, diluted with EtOAc, saturated aqueous NaHCO3 was added, and the layers were separated. The aqueous layer was extracted with EtOAc (x2), and the combined organic extracts were washed with brine, dried (MgSO4), filtered, and concentrated to half the volume. SiliaMetS® thiol (100 mg) was added, and the mixture was stirred at room temperature for 15 min, filtered, and concentrated. The crude residue was purified by normal-phase flash column chromatography (eluent: 20-70% EtOAc in c-hexane) to give the title compound. UPLC-MS-3: Rt = 1.28 min; MS m / z [M+H] + ;646.3 / 648.2.

[0444] [ka] 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]heptan-2-yl)prop-2-en-1-one The title example was prepared from 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 (prepared as described below) using a method similar to Method-1b steps 2 and 3. The 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 eluting peak: 1 H NMR (400MHz, 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. The other isomer Example 46b was obtained as the second eluting peak: C-SFC-3 (mobile phase: CO2 / MeOH: 65 / 35): Rt = 3.28 min.

[0445] 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 To a solution of 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-t-butylphosphine)palladium (68 mg, 0.13 mmol) in THF (3 mL) placed under an argon atmosphere was added 2-pyridylzinc bromide (0.5 M in THF, 14.0 mL, 7.00 mmol). The reaction mixture was heated at 70 °C for 3 h. The RM was poured into a saturated aqueous solution of NaHCO and extracted with EtOAc (x2). The combined organic extracts were washed with brine, dried (NaSO), 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 room temperature for 1 hour, filtered, and concentrated. The crude residue was purified by normal phase chromatography (eluent: 0-5% MeOH in CH2Cl2) to give a mixture containing the desired material, which was purified again 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.

[0446] [ka] 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]heptan-2-yl)prop-2-en-1-one To a solution of 4-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1-(2-azaspiro[3.3]heptan-6-yl)-1H-pyrazol-3-yl)benzyl acetate trifluoroacetate (prepared as described below, 0.7 mmol) in THF (12 mL) and water (0.3 mL), NaHCO (588 mg, 7.0 mmol) and acryloyl chloride (70 μL, 0.84 mmol) were added sequentially, and the reaction mixture was stirred at room temperature for 2.5 h. LiOH (2 M, 3.50 mL, 7.00 mmol) was added, and the RM was stirred at room temperature for 45 min until the disappearance of the by-product resulting from the reaction of acryloyl chloride with the indazole NH (UPLC). The RM was diluted with water and extracted with EtOAc (×2). 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 room temperature for 2 hours. The 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 reverse-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. The isomers were separated by chiral SFC (C-SFC-2; mobile phase: CO2 / IPA: 70 / 30) to give the title compound Example 47a as the second eluting peak: 1 H NMR (400MHz, DMSO-d6)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. The other isomer Example 47b was obtained as the first eluting peak: C-SFC-3 (mobile phase: CO2 / IPA: 70 / 30): Rt = 2.85 min.

[0447] 4-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1-(2-azaspiro[3.3]heptan-6-yl)-1H-pyrazol-3-yl)benzyl acetate trifluoroacetate The title compound was prepared from 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) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate [562098-08-2] using a method similar to Method-1 steps 1 and 2; UPLC-MS-6: Rt=0.80 min; MS m / z [M+H] + 490.2 / 492.2.

[0448] [ka] Example 48: 1-(4-(1-(2-acryloyl-2-azaspiro[3.3]heptan-6-yl)-4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1H-pyrazol-3-yl)benzyl)pyrrolidin-2-one The title example was prepared from tert-butyl 6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-3-(4-((2-oxopyrrolidin-1-yl)methyl)phenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (prepared as described below) using a method similar to Method-1b steps 2 and 3. 1H NMR (400 MHz, DMSO-d) 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.

[0449] tert-Butyl 6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-3-(4-((2-oxopyrrolidin-1-yl)methyl)phenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate 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, 300 mg, 0.47 mmol) and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidin-2-one (Intermediate B2, 473 mg, 0.94 mmol) were suspended in DMF (3.95 mL). Aqueous KPO (1 M, 0.94 mL, 0.942 mmol) and Pd(PhP) (27.2 mg, 0.024 mmol) were added, and the suspension was flushed with argon and subjected to microwave irradiation at 120 °C for 45 min. The reaction mixture was allowed to reach room temperature, diluted with EtOAc, saturated aqueous NaHCO was added, and the layers were separated. The aqueous layer was extracted with EtOAc (x2), and the combined organic extracts were washed with brine, dried (MgSO), filtered, and concentrated. The crude residue was purified by normal-phase flash column chromatography (eluent: 0-50% (MeOH / CHCl 9 / 1) in CHCl) to give the title compound. UPLC-MS-3: Rt = 1.22 min; MS m / z [M+H] + ;699.4 / 701.4.

[0450] [ka] Example 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]heptan-2-yl)prop-2-en-1-one The title example was prepared from 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 (prepared as described below) using a method similar to Method-1b steps 2 and 3. 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 eluting peak: 1 H NMR (400MHz, 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: gradient of 0.1% DEA in hexane / IPA / ACN; UV: 262 nM): Rt = 10.3 min. The other isomer Example 49b was obtained as the first eluting peak: C-HPLC-24 (mobile phase: gradient of 0.1% DEA in hexane / IPA / ACN, UV: 262 nM): Rt = 8.98 min.

[0451] 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. 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-picoline-4-boronic acid (0.27 g, 1.98 mmol), and KPO (0.42 g, 1.98 mmol) were dissolved in t-BuOH:HO (5:1) (24 mL), and the mixture was degassed with argon for 15 min. XPhos (0.094 g, 0.19 mmol) and Pddba (0.06 g, 0.07 mmol) were added, and the reaction mixture was stirred at 120 °C for 4 h under sealed conditions. 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 reduced pressure. The crude residue was purified by C18 (15 μm) reverse-phase chromatography (eluent: 0-68% CHCN in H2O containing 0.1% HCOOH) to give the desired product. LCMS-1: Rt = 1.82 min; MS m / z [M+H] + ;617.7 / 620.6.

[0452] [ka] Example 50a / 50b: 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(4-(1,1-dioxidethiomorpholino)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one The title example was prepared starting from Intermediate C1 and 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)thiomorpholine 1,1-dioxide (Intermediate B15) using a protocol similar to that described for Examples 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 to elute: 1H NMR (400MHz, CDCl3)δ 10.12(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] + : 605.5 / 607.5; C-SFC-19 (mobile phase: CO2 / MeOH / ACN 55 / 22.5 / 22.5; UV: 270 nM): Rt = 6.77 min. The other isomer Example 50b was obtained as the second eluting peak: C-SFC-19 (mobile phase: CO2 / MeOH / ACN 55 / 22.5 / 22.5; UV: 270 nM): Rt = 10.8 min.

[0453] [ka] Example 51a / 51b: 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(thiazol-4-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one The title example was prepared from tert-butyl 6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-3-(thiazol-4-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (prepared as described below) using a method similar to Method-1b steps 2 and 3. The isomers were separated by chiral HPLC C-HPLC-23 (mobile phase: [hexane + 0.1% EtNH] / [IPA + 0.1% EtNH] / CHCN (60 / 28 / 12); flow rate: 20 mL / min; UV: 216 nM) to give the title compound Example 51a as the first eluting peak: 1H NMR (400MHz, 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: gradient of 0.1% DEA in hexane / IPA / CHCN): Rt = 10.0 min. The other isomer Example 51b was obtained as the second eluting peak: C-HPLC-24 (mobile phase: gradient of 0.1% DEA in hexane / IPA / CHCN): Rt = 12.3 min.

[0454] tert-Butyl 6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-3-(thiazol-4-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate. 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-(tributylstannyl)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 minutes. The reaction mixture was then heated to 100° C. under sealed tube conditions for 16 hours. The RM was filtered through a pad of Celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and the crude residue was purified by C18 (15 μm) reverse phase chromatography (eluent: 0-100% CH3CN in H2O containing 0.1% HCOOH) to give the title product. LCMS-1: Rt=2.06; 2.08 min; MS m / z [M+H] + :609.8 / 611.8.

[0455] [ka] Example 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]heptan-2-yl)prop-2-en-1-one Step 1: tert-Butyl 6-(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 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-dioxaborolan-2-yl)phenoxy)ethan-1-ol (0.22 g, 0.83 mmol), and KPO (0.52 g, 2.48 mmol) were added to 1,4-dioxane:HO (2:1) (12 mL), and the mixture was degassed with nitrogen for 10 minutes. 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 completion of the reaction, the RM was poured into water and extracted with EtOAc (x2). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude residue was purified by normal phase chromatography (eluent: 0-60% EtOAc in hexanes) to give the title product. LCMS-1: Rt = 2.05, 2.09 min; MS m / z [M+H] + :662.7.3 / 664.7.

[0456] 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 tert-Butyl 6-(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 CHCl (5 mL). EtN (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) in CHCl (0.5 mL) was added dropwise, and the reaction mixture was stirred at room temperature for 2 h. After completion of the reaction, the RM was diluted with CH2Cl2, washed with water, brine, dried (Na2SO4), filtered and concentrated under reduced pressure to give 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.

[0457] Process-3: 2-(4-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1-(2-azaspiro[3.3]heptan-6-yl)-1H-pyrazol-3-yl)phenoxy)ethyl acetate 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 (0.68 mmol) was dissolved in dry CHCl (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 completion of the reaction, the RM was concentrated under reduced pressure and co-distilled with CHCl several times to give a crude residue, which was purified by trituration with diethyl ether and filtration to give 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.

[0458] Process-4: 2-(4-(1-(2-acryloyl-2-azaspiro[3.3]heptan-6-yl)-4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1H-pyrazol-3-yl)phenoxy)ethyl acetate 2-(4-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1-(2-azaspiro[3.3]heptan-6-yl)-1H-pyrazol-3-yl)phenoxy)ethyl acetate (0.22 g, 0.42 mmol) was dissolved in THF (2 mL). NaHCO (0.35 g, 4.15 mmol) in water (2.5 mL) was added and the reaction mixture was stirred at room temperature for 10 minutes. 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 minutes. After completion of the reaction, the RM was diluted with water and extracted with EtOAc (×2). The combined organic layers were washed with water, brine, dried (NaSO), filtered and concentrated under reduced pressure. The crude residue was purified by C18 silica gel (15 μm) reverse-phase chromatography (eluent: 0-43% CH3CN in H2O containing 0.1% NH3) to give the desired product. The 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 eluting 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. The other isomer-II was obtained as the second eluting peak: LCMS-1: Rt=1.63 min; MS m / z [M+H] + : 574.8; C-HPLC-29 (mobile phase: hexane / IPA gradient): Rt = 13.8 min.

[0459] Process-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]heptan-2-yl)prop-2-en-1-one The title example was prepared using a method similar to that described for the preparation of 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]heptan-2-yl)prop-2-en-1-one (step 6) starting from 2-(4-(1-(2-acryloyl-2-azaspiro[3.3]heptan-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 H NMR(400MHz, 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,1 3H), 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% EtNH] / [IPA + 0.1% EtNH] gradient): Rt = 11.2 min.

[0460] Process-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]heptan-2-yl)prop-2-en-1-one 2-(4-(1-(2-Acryloyl-2-azaspiro[3.3]heptan-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) isomer-I was dissolved in MeOH (2.5 mL) and cooled to 0 °C. LiOH.HO (1 M in water, 0.08 mL, 0.08 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 1 h. After completion of the reaction, the RM was diluted with water and extracted with EtOAc (×2). The combined organic layers were washed with water, brine, dried (NaSO), filtered and concentrated under reduced pressure. The crude residue was purified by C18 silica gel (15 μm) reverse-phase chromatography (eluent: 0-40% CH3CN in H2O containing 0.025% NH3) to give the title product: C-HPLC-29 (mobile phase: [hexane + 0.1% Et2NH] / [IPA + 0.1% Et2NH] gradient): Rt = 9.37 min.

[0461] [ka] 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]heptan-2-yl)prop-2-en-1-one 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 two steps as described below) using a method similar to Method-1b steps 2 and 3. 1H NMR (400MHz, 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 MS m / z[M+H] + :554.8 / 556.8.

[0462] 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 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 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-(3-nitro-1H-pyrazol-1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Intermediate B16) (0.52 g, 1.65 mmol), and KPO (0.53 g, 2.48 mmol) were dissolved in 1,4-dioxane (4 mL) and HO (2 mL). The reaction mixture was degassed with N for 5 minutes. 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 completion of the reaction, the 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 reduced pressure. The crude residue was purified by normal phase chromatography (eluent: 30-40% EtOAc in hexanes) to give the desired product. LCMS-1: Rt = 2.24 min; MS m / z [M+H] + :714.6 / 716.5.

[0463] 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 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 under nitrogen atmosphere. 10% dry Pd / C (0.25 g) was added and the reaction mixture was stirred for 1 h at room temperature under an atmosphere of H2 (1 atm). The RM was filtered through a pad of Celite, filtered and concentrated under reduced pressure to give the desired product, which was used directly in the next step without further purification. LCMS-1: Rt=2.06, 2.09 min; MS m / z [M+H] + :684.5 / 686.5.

[0464] Method-2: Synthesis scheme [ka] 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]heptan-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]heptan-2-yl)prop-2-en-1-one

[0465] Alternatively, Examples 1a and 1b can be prepared according to the method described below: Step 1: tert-butyl 6-(5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2azaspiro[3.3]heptane-2-carboxylate To a stirred solution of 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-dioxaborolan-2-yl)-1H-indazole (1.59 g, 6.18 mmol), and KPO (3.57 g, 16.8 mmol) in dioxane (20 mL) and HO (4 mL) under an argon atmosphere, RuPhos (0.26 g, 0.56 mmol) and RuPhos-Pd-G (0.47 g, 0.56 mmol) were added. The reaction mixture was stirred at 100 °C for 1 h. The reaction mixture was quenched by the addition of saturated aqueous NaHCO3 and extracted with EtOAc (2x). The combined organic extracts were washed with saturated aqueous NaHCO3, dried (Na2SO4), and evaporated. The crude residue was purified by normal phase chromatography (eluent: 0-90% EtOAc in c-hexane) to give the title compound as a brown solid. UPLC-MS-3: Rt = 1.14 min; MS m / z [M+H] + :408.2.

[0466] Step 2: 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 To a stirred solution of 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) in THF (50 mL) under an argon atmosphere, NIS (1.53 g, 6.80 mmol) was added, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched by the addition of saturated aqueous NaHCO3 and extracted with EtOAc (2x). The combined organic extracts were washed with saturated aqueous NaHCO3, dried (Na2SO4), filtered, and evaporated. The crude residue was purified by normal phase chromatography (eluent: 0-80% EtOAc 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.

[0467] 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 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 (100 mg, 0.187 mmol), 5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-4 ...tetrahydro-2H To a stirred solution of -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (Intermediate D1, 85 mg, 0.225 mmol) and KPO (119 mg, 0.56 mmol) under an argon atmosphere was added RuPhos (8.75 mg, 0.019 mmol) and RuPhos-Pd-G (15.7 mg, 0.019 mmol). The reaction mixture was degassed with N and stirred at 100 °C for 1 h. The reaction mixture was quenched by the addition of saturated aqueous NaHCO and extracted with EtOAc (2x), and the combined organic extracts were washed with saturated aqueous NaHCO, dried (NaSO), 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 reaction mixtures) was added, and the mixture was rotated 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: 0-100% EtOAc in c-hexane) 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.

[0468] Steps 4 and 5 Chiral separation of the isomers was carried out as described in Method-1.

[0469] Method-2a: Similar to Method-2, except that step 4 was carried out using sulfuric acid in dioxane as described in step 2 of Method-1a.

[0470] Method-2b:Similar to Method-2, except that step 5 was carried out with acryloyl chloride and NaHCO3 in THF / water as described in step 3 of Method-1b.

[0471] Method-2c: Same as Method-2, except that NBS was used instead of NIS in step 2.

[0472] Method-2d: Similar to Method-2, except that step 3 was carried out using Et3N and acryloyl chloride in CH2Cl2 as described in Method-9 step 3.

[0473] The following Examples 54-58 in Table 2 below were prepared from the intermediates described in the intermediate synthesis section (in Step 1 or 3) using methods similar to Method-2, or are commercially available.

[0474] [Table 24]

[0475] [Table 25]

[0476] Example 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]heptan-2-yl)prop-2-en-1-one [ka] The title example was prepared from 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 (prepared as described below) using a method similar to Method-2a,b steps 3-5. The 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 eluting peak: 1H NMR (600MHz, DMSO-d6)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), 4.4...

Claims

1. Compounds of formula (Ia) 【Chemistry 8】 (In the formula, A is, an 8- to 10-membered heteroaryl ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or 0 to 3 nitrogen atoms, 0 to 2 oxygen atoms, 0 to 1 sulfur atom, and 0 to 1 S(═O) in a heterobicyclic ring; ２ and an 8- to 10-membered partially saturated heterobicyclic ring containing 1 to 3 heteroatoms or heteroatom groups independently selected from the group R, ... Ａ４ and said heterobicyclic ring is further optionally substituted at a carbon atom with oxo, and the nitrogen atom, if present, is unsubstituted or is —(CO)—C １ ~C ４ -Alkyl or C １ ~C ４ -substituted with a substituent which is alkyl, １ ~C ４ - alkyl is cyano, hydroxy, oxo, fluoro, C １ ~C ４ -alkoxy, C １ ~C ４ -alkoxy-C １ ~C ４ -Alkyl-oxy, Het ｂ and NR ９ R １０ a heteroaryl or heterobicyclic ring optionally substituted with one or two substituents independently selected from selected from the group consisting of: wherein A is attached to the remainder of the compound of formula (Ia) by a carbon atom at A; B, 【Chemistry 19】 wherein X is N or C—R Ｂ５ and Here, R Ｂ１ are independently hydrogen and C １ ~C ４ - selected from alkyl; R Ｂ２ are independently hydrogen, halo, C １ ~C ４ - alkyl, cyclopropyl and NH ２ Selected from: R Ｂ３ are independently selected from hydrogen, halo, cyclopropyl and C １ ~C ４ - selected from alkyl; R Ｂ４ are independently hydrogen, halo, and C １ ~C ４ -alkyl or R Ｂ３ and R Ｂ４ together with the atoms to which they are attached form a 4- to 6-membered ring fused to the aromatic ring containing X; R Ｂ５ are independently selected from hydrogen, halo, and C １ ~C ４ - selected from alkyl; C is hydrogen, C １ ~C ３ Alkyl, C ３ ~C ５ Cycloalkyl, fluoro-C １ ~C ３ Alkyl, cyano, -CH ２ -CN, -CH(CN)-CH ３ , -CH ２ -OH, -CH(OH)-CH ３ and halo; Each R Ａ４ However, independently, cyano, CO ２ H, halo, C １ ~C ４ -Alkyl, Fluoro-C １ ~C ４ -Alkyl, hydroxy, hydroxy-C １ ~C ４ -Alkyl, hydroxy-C １ ~C ４ -alkyl-oxy, C １ ~C ４ -alkoxy, C １ ~C ４ -alkoxy-C １ ~C ４ -Alkyl, C １ ~C ４ -alkoxy-C １ ~C ４ -alkyl-oxy, NR ９ R １０ , (N(R ９ ) (R １０ )-C １ ~C ４ -alkyl, (N(R ９ ) (R １０ )-C １ ~C ４ -Alkyl-oxy, -(CO)-C １ ~C ４ - alkyl, and R ９ R １０ N-C １ ~C ４ -Alkyl-oxy-(CO)-C １ ~C ４ - selected from the group consisting of alkyl; R ９ is hydrogen and C １ ~C ４ - selected from alkyl; R １０ But hydrogen, C １ ~C ４ -Alkyl, hydroxy-C １ ~C ４ -Alkyl, C １ ~C ４ -alkoxy-C １ ~C ４ -Alkyl and di-C １ ~C ４ -Alkyl-amino-C １ ~C ４ - selected from the group consisting of alkyl; Het ｂ N, O, S, SO and SO ２ wherein the heterocycle Het is a 4-, 5-, or 6-membered heterocycle containing 1 or 2 heteroatoms or groups independently selected from ｂ is unsubstituted or at a carbon atom, C １ ~C ４ - alkyl, hydroxy, cyano, fluoro, C １ ~C ４ -alkoxy-hydroxy-C １ ~C ４ -Alkyl, hydroxy-C １ ~C ４ -Alkyl, C １ ~C ４ -alkoxy, fluoro-C １ ~C ４ -alkoxy and fluoro-C １ ~C ４ -alkyl, wherein the heterocycle Het ｂ is further optionally substituted at a carbon atom with oxo, wherein the nitrogen atom is Het ｂ When present in １ ~C ４ -C optionally substituted with 1 to 3 substituents independently selected from -alkoxy １ ~C ４ -alkyl), or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the atropisomer.

2. A is, 【Chemistry 13】 【Chemistry 14】 【Chemistry 15-1】 is selected from the group consisting of During the ceremony, y is 0, 1 or 2; x is 0, 1 or 2; z is 0, 1 or 2; R Ｏ But hydrogen, NR ９ R １０ , R ９ R １０ N-C １ ~C ４ -alkyl-oxy, C １ ~C ４ -alkoxy-C １ ~C ４ -Alkyl-oxy, hydroxy-C １ ~C ４ -Alkyl-oxy and C １ ~C ４ - selected from the group consisting of alkyl; R Ｍ is hydrogen, halo or C １ ~C ４ -alkyl, wherein said alkyl is OH, C １ ~C ４ -alkoxy or NR ９ R １０ optionally substituted with; R Ｎ is hydrogen or C １ ~C ４ -alkyl, or halo or fluoro-C １ ~C ４ - alkyl; R ｑ But independently, C １ ~C ４ -Alkyl, hydroxy, C １ ~C ４ -alkoxy and NR ９ R １０ selected from the group consisting of: R ｐ is C １ ~C ４ - alkyl; Each R ｐ１ are independently hydrogen and C １ ~C ４ - selected from alkyl; R ｖ are independently halogen, C １ ~C ４ -Alkyl and fluoro-C １ ~C ４ - selected from alkyl; R ａｅ is hydrogen and C １ ~C ４ -alkyl, wherein said alkyl is selected from the group consisting of cyano, hydroxy, fluoro, C １ ~C ４ -alkoxy, C １ ~C ４ -alkoxy-C １ ~C ４ -Alkyl-oxy, Het ｂ and NR ９ R １０ optionally substituted with one or two substituents selected from R Ａｅ is hydrogen, -(CO)-C １ ~C ４ -Alkyl and C １ ~C ４ -alkyl, wherein said C １ ~C ４ Alkyl, in each case, is selected from the group consisting of cyano, hydroxy, fluoro, C １ ~C ４ -alkoxy, C １ ~C ４ -alkoxy-C １ ~C ４ -Alkyl-oxy, Het ｂ and NR ９ R １０ optionally substituted with one or two substituents selected from where: R ９ is hydrogen and C １ ~C ４ - selected from alkyl; R １０ But hydrogen, C １ ~C ４ -Alkyl, hydroxy-C １ ~C ４ -Alkyl, C １ ~C ４ -alkoxy-C １ ~C ４ -Alkyl and di-C １ ~C ４ -Alkyl-amino-C １ ~C ４ - selected from alkyl; Het ｂ N, O, S, SO and SO ２ wherein the heterocycle Het is a 4-, 5-, or 6-membered heterocycle containing 1 or 2 heteroatoms or groups independently selected from ｂ is unsubstituted or at a carbon atom, C １ ~C ４ -Alkyl, hydroxy, cyano, fluoro, hydroxy-C １ ~C ４ -Alkyl, C １ ~C ４ -alkoxy and fluoro-C １ ~C ４ -alkyl, wherein the heterocycle Het ｂ is further optionally substituted at a carbon atom with oxo, wherein the nitrogen atom is Het ｂ When present in １ ~C ４ -C optionally substituted with 1 to 3 substituents independently selected from -alkoxy １ ~C ４ - a compound of formula (Ia) according to claim 1, optionally further substituted with alkyl; or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the atropisomer.

3. A is, 【Chemistry 16】 is selected from the group consisting of wherein z is 0, 1 or 2; R ｖ are independently halogen, C １ ~C ４ -Alkyl and fluoro-C １ ~C ４ - selected from alkyl; R N is hydrogen or C １ ~C ４ -alkyl, or halo or fluoro-C １ ~C ４ - alkyl; R Ｏ But hydrogen, NR ９ R １０ , N(R ９ ) (R １０ )-C １ ~C ４ -alkyl-oxy, C １ ~C ４ -alkoxy-C １ ~C ４ -Alkyl-oxy, hydroxy-C １ ~C ４ -Alkyl-oxy and C １ ~C ４ - selected from the group consisting of alkyl; R ａｅ is hydrogen and C １ ~C ４ -alkyl, wherein said alkyl is selected from the group consisting of cyano, hydroxy, fluoro, C １ ~C ４ -alkoxy, C １ ~C ４ -alkoxy-C １ ~C ４ -Alkyl-oxy, Het ｂ and NR ９ R １０ optionally substituted with one or two substituents selected from R ９ is hydrogen and C １ ~C ４ - selected from alkyl; R １０ But hydrogen, C １ ~C ４ -Alkyl, hydroxy-C １ ~C ４ -Alkyl, C １ ~C ４ -alkoxy-C １ ~C ４ -Alkyl and di-C １ ~C ４ -Alkyl-amino-C １ ~C ４ - selected from alkyl; Het ｂ N, O, S, SO and SO ２ wherein the heterocycle Het is a 4-, 5-, or 6-membered heterocycle containing 1 or 2 heteroatoms or groups independently selected from ｂ is unsubstituted or at a carbon atom, C １ ~C ４ -Alkyl, hydroxy, cyano, fluoro, hydroxy-C １ ~C ４ -Alkyl, C １ ~C ４ -alkoxy and fluoro-C １ ~C ４ -alkyl, wherein the heterocycle Het ｂ is further optionally substituted at a carbon atom with oxo, wherein the nitrogen atom is Het ｂ When present in １ ~C ４ -C optionally substituted with 1 to 3 substituents independently selected from -alkoxy １ ~C ４ - a compound of formula (Ia) according to claim 1, which is optionally further substituted with alkyl; or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the atropisomer.

4. A is, 【Chemistry 17】 is selected from the group consisting of wherein z is 0, 1 or 2; R v is independently selected from halogen, C 1 -C 4 -alkyl and fluoro-C 1 -C 4 -alkyl; R N is hydrogen or C 1 -C 4 -alkyl or halo or fluoro-C 1 -C 4 -alkyl; R 0 is selected from the group consisting of hydrogen, NR 9 R 10 , N(R 9 )(R 10 )—C 1 -C 4 -alkyl-oxy, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl-oxy, hydroxy-C 1 -C 4 -alkyl-oxy and C 1 -C 4 -alkyl; R ae is selected from the group consisting of hydrogen and C 1 -C 4 -alkyl, wherein said alkyl is optionally substituted with 1 or 2 substituents selected from cyano, hydroxy, fluoro, C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl-oxy, Het b and NR 9 R 10 ; R 9 is selected from hydrogen and C 1 -C 4 -alkyl; R 10 is selected from hydrogen, C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl and di-C 1 -C 4 -alkyl-amino-C 1 -C 4 -alkyl; Het b is a 4- or 5- or 6-membered heterocycle containing 1 or 2 heteroatoms or groups independently selected from N, O, S, SO and SO 2 , wherein said heterocycle Het b is unsubstituted or substituted at a carbon atom with 1 or 2 substituents independently selected from C 1 -C 4 -alkyl, hydroxy, cyano, fluoro, hydroxy-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy and fluoro-C 1 -C 4 -alkyl, wherein said heterocycle Het b is further optionally substituted at a carbon atom with oxo, wherein the nitrogen atom, if present in Het b , is further optionally substituted with C 1 -C 4 -alkyl optionally substituted with 1 to 3 substituents independently selected from fluoro, hydroxy and C 1 -C 4 -alkoxy, A compound of formula (Ia) according to any one of claims 1 to 3, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the atropisomer.

5. R Ｎ is hydrogen or C １ ~C ４ - alkyl; R Ｏ is hydrogen or NR ９ R １０ and R ｖ are independently fluoro, chloro and C １ ~C ４ - selected from alkyl; A compound of formula (Ia) according to claim 4, wherein z is 0 or 1; or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the atropisomer.

6. R ａｅ But hydrogen, C １ ~C ４ -alkyl, -(CH ２ ) ２ -Het ｂ , -CH ２ -CN, -(CH ２ ) ２－ OH, -(CH ２ ) ２－ O-C １ ~C ４ -Alkyl, hydroxy-C １ ~C ４ -alkyl, -(CH ２ ) ２ -O-(CH ２ ) ２ -O-C １ ~C ４ -alkyl and -(CH ２ ) ２ -JiC １ ~C ４ - alkylamino, or R Ａｅ But hydrogen, fluoro-C １ ~C ４ -Alkyl and C １ ~C ４ - selected from the group consisting of alkyl; Het ｂ is a 4-, 5- or 6-membered heterocyclic ring containing one nitrogen atom and one oxygen atom, or one to two nitrogen atoms, wherein the heterocyclic ring is unsubstituted or has at a carbon atom １ ~C ４ -Alkyl, hydroxy-C １ ~C ４ -Alkyl, C １ ~C ４ -substituted with one or two substituents independently selected from alkoxy and fluoro, wherein a nitrogen atom, if present in said heterocycle, is C １ ~C ４ - a compound of formula (Ia) according to any one of claims 2 to 5, optionally further substituted with alkyl; or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the atropisomer.

7. R ａｅ is hydrogen, methyl, -CH ２ -CN, -(CH ２ ) ２ -OH, -(CH ２ ) ２ -OCH ３ , -(CH ２ )-C(CH ３ ) ２ -OH, -(CH ２ ) ２ -O-(CH ２ ) ２ -OCH ３ , -(CH ２ ) ２ -N(CH ３ ) ２ and -(CH ２ ) ２ -Het ｂ selected from the group consisting of: The Het ｂ is a 4-, 5- or 6-membered heterocyclic ring containing one nitrogen atom and one oxygen atom, or one to two nitrogen atoms, wherein the heterocyclic ring is unsubstituted or has at a carbon atom １ ~C ４ -Alkyl, hydroxy-C １ ~C ４ -Alkyl, C １ ~C ４ -substituted with one or two substituents independently selected from alkoxy and fluoro, wherein a nitrogen atom, if present in said heterocycle, is C １ ~C ４ - a compound of formula (Ia) according to any one of claims 2 to 6, optionally further substituted with alkyl; or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the atropisomer.

8. R ａｅ is hydrogen, methyl, -CH ２ -CN, -(CH ２ ) ２－ OH, -(CH ２ ) ２ -OCH ３ , -(CH ２ )-C(CH ３ ) ２ -OH, -(CH ２ ) ２ -O-(CH ２ ) ２ -OCH ３ , -(CH ２ ) ２ -N(CH ３ ) ２ , and -(CH ２ ) ２ -Het ｂ wherein Het is selected from the group consisting of ｂ is selected from the group consisting of azetidin-1-yl, pyrrolidin-1-yl, pyrrolidin-3-yl and morpholin-1-yl, wherein said heterocycle is optionally further substituted with one or two substituents independently selected from methyl, hydroxy-methyl, methoxy and fluoro; or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the atropisomer.

9. R ａｅ But hydrogen, fluoro-C １ ~C ４ -Alkyl, C １ ~C ４ -alkyl, -(CH ２ ) ２ -Het ｂ , -(CH ２ ) ２－ OH, -(CH ２ ) ２ -O-C １ ~C ４ -Alkyl, hydroxy-C １ ~C ４ -alkyl, -(CH ２ ) ２ -O-(CH ２ ) ２ -O-C １ ~C ４ -alkyl and -(CH ２ ) ２ -JiC １ ~C ４ - alkylamino, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the atropisomer.

10. The compound of formula (Ia) is a compound of formula (Ib ＊ ) compounds 【Chemistry 18】 (In the formula, R Ｂ２ But hydrogen, halo, C １ ~C ４ - alkyl, cyclopropyl and NH ２ Selected from: R Ｂ３ is hydrogen, halo, cyclopropyl and C １ ~C ４ - selected from alkyl; R Ｂ４ is hydrogen, halo and C １ ~C ４ -alkyl) 2. The compound of claim 1, wherein:

11. The compound of formula (Ia) is represented by the formula (Id ＊ ) compounds 【Chemistry 20】 (In the formula, R Ｂ２ But hydrogen, halo, C １ ~C ４ - alkyl, cyclopropyl and NH ２ Selected from: R Ｂ３ is hydrogen, halo, cyclopropyl and C １ ~C ４ - selected from alkyl; R Ｂ４ is hydrogen, halo and C １ ~C ４ - selected from alkyl; R N is hydrogen or C １ ~C ４ -alkyl, or halo or fluoro-C １ ~C ４ - alkyl; R ａｅ is hydrogen and C １ ~C ４ -alkyl, wherein said alkyl is selected from the group consisting of cyano, hydroxy, fluoro, C １ ~C ４ -alkoxy, C １ ~C ４ -alkoxy-C １ ~C ４ -Alkyl-oxy, Het ｂ and NR ９ R １０ optionally substituted with one or two substituents selected from R ９ is hydrogen and C １ ~C ４ - selected from alkyl; R １０ But hydrogen, C １ ~C ４ -Alkyl, hydroxy-C １ ~C ４ -Alkyl, C １ ~C ４ -alkoxy-C １ ~C ４ -Alkyl and di-C １ ~C ４ -Alkyl-amino-C １ ~C ４ - selected from alkyl; Het ｂ N, O, S, SO and SO ２ wherein the heterocycle Het is a 4-, 5-, or 6-membered heterocycle containing 1 or 2 heteroatoms or groups independently selected from ｂ is unsubstituted or at a carbon atom, C １ ~C ４ -Alkyl, hydroxy, cyano, fluoro, hydroxy-C １ ~C ４ -Alkyl, C １ ~C ４ -alkoxy and fluoro-C １ ~C ４ -alkyl, wherein the heterocycle Het ｂ is further optionally substituted at a carbon atom with oxo, wherein the nitrogen atom is Het ｂ When present in １ ~C ４ -C optionally substituted with 1 to 3 substituents independently selected from -alkoxy １ ~C ４ -optionally further substituted with alkyl, The aforementioned 【Chemical 21】 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the line represents a single or double bond.

12. (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]heptan-2-yl}prop-2-en-1-one, (R)(S)-1-{6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(1-{2-[3-fluoropyrrolidin-1-yl]ethyl}-1H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl}prop-2-en-1-one, (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]heptan-2-yl)prop-2-en-1-one, (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]heptan-2-yl)prop-2-en-1-one, (R)-1-{6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-{2-[2-(2-methoxyethoxy)ethyl]-2H-indazol-5-yl}-5-methyl-1H-pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl}prop-2-en-1-one, (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]heptan-2-yl)prop-2-en-1-one The compound of claim 1 selected from or a pharmaceutically acceptable salt thereof.

13. 1-{6-[(4M)-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]heptan-2-yl}prop-2-en-1-one, 1-{6-[(4M)-4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(1-{2-[(3S)-3-fluoropyrrolidin-1-yl]ethyl}-1H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl}prop-2-en-1-one, 1-(6-{(4M)-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]heptan-2-yl)prop-2-en-1-one, 1-(6-{(4M)-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]heptan-2-yl)prop-2-en-1-one, 1-{6-[(4M)-4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-{2-[2-(2-methoxyethoxy)ethyl]-2H-indazol-5-yl}-5-methyl-1H-pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl}prop-2-en-1-one, 1-(6-{(4M)-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]heptan-2-yl)prop-2-en-1-one, 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(1H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(1H-indazol-6-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(1-(2-(dimethylamino)ethyl)-1H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-(dimethylamino)ethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-(2-morpholinoethyl)-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, 1-(6-(3-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(isoquinolin-6-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol-4-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-benzo[d]imidazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(imidazo[1,2-a]pyridin-7-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-pyrazol o [3,4-b] pyridin-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(3-methyl-3H-imidazo[4,5-b]pyridin-6-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, and 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(2-(methylamino)quinazolin-6-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one a compound selected from or a pharmaceutically acceptable salt thereof.

14. C is C １ ~C ３ 11. The compound of claim 10, or a pharmaceutically acceptable salt thereof, wherein: R is alkyl;

15. C is C １ ~C ３ 12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein: R is alkyl;

16. A is an 8- to 10-membered heteroaryl ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the nitrogen atom, if present, is unsubstituted or C １ ~C ４ -substituted with alkyl; C is C １ ~C ３ is alkyl, The compound of claim 1 , or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the atropisomer.

17. 1. A pharmaceutical composition for use in a method of treating cancer characterized by one or more KRAS mutations in a patient in need thereof, comprising: The pharmaceutical composition comprises a compound according to any one of claims 1 to 16, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof; 17. The method of claim 1, wherein the method comprises administering to the patient a therapeutically effective amount of a compound of any one of claims 1 to 16, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof.

18. 17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, and at least one pharmaceutically acceptable excipient.

19. A compound which is 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]heptan-2-yl}prop-2-en-1-one, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the atropisomer.

20. The following structure: 【Chemical 22】 or a pharmaceutically acceptable salt thereof.

21. The following structure: 【Chemical 22】 A compound having the formula:

22. 22. A pharmaceutical composition comprising the compound according to any one of claims 19 to 21, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, and at least one pharmaceutically acceptable excipient.

23. 1. A pharmaceutical composition for use in a method of treating cancer characterized by one or more KRAS mutations in a patient in need thereof, comprising: The pharmaceutical composition comprises a compound according to any one of claims 19 to 21, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof; 22. The method of claim 19, wherein the method comprises administering to the patient a therapeutically effective amount of a compound of any one of claims 19 to 21, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof.

24. 24. The pharmaceutical composition of claim 23, wherein the cancer is lung cancer, colorectal cancer, pancreatic cancer, uterine cancer, or rectal cancer.

25. 24. The pharmaceutical composition of claim 23, wherein the cancer is a solid tumor.

26. 25. The pharmaceutical composition of claim 24, wherein the lung cancer is non-small cell lung cancer.

27. 27. The pharmaceutical composition of claim 26, wherein the non-small cell lung cancer is characterized by a G12C mutation of KRAS.

28. 25. The pharmaceutical composition of claim 24, wherein the colorectal cancer is characterized by a G12C mutation of KRAS.

29. 1. A pharmaceutical composition for use in a method of treating cancer characterized by a G12C mutation of KRAS in a patient in need thereof, comprising: the pharmaceutical composition comprises a compound which is 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]heptan-2-yl}prop-2-en-1-one, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the atropisomer; The method comprises administering to the patient a therapeutically effective amount of a compound which is 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]heptan-2-yl}prop-2-en-1-one, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer, or a pharmaceutically acceptable salt of the atropisomer.

30. 30. The pharmaceutical composition of claim 29, wherein the compound is 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]heptan-2-yl}prop-2-en-1-one, or a pharmaceutically acceptable salt thereof.

31. 30. The pharmaceutical composition of claim 29, wherein the cancer is non-small cell lung cancer.

32. 30. The pharmaceutical composition of claim 29, wherein the cancer is colorectal cancer.

33. 31. The pharmaceutical composition of claim 30, wherein the cancer is non-small cell lung cancer.

34. 31. The pharmaceutical composition of claim 30, wherein the cancer is colorectal cancer.

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