Pyrazolyl derivatives useful as Anti-cancer agents

Abstract

To provide pyrazolyl derivative compounds; their use for inhibiting KRAS G12C, HRAS G12C, or NRAS G12C, particularly KRAS G12C; methods for treating or preventing diseases, especially cancer, by using the compounds; and methods and intermediates for producing the compounds.SOLUTION: The present application relates to 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; a method for producing the compound; and its therapeutic use. The present application further provides a pharmaceutical composition comprising the compound and a combination of pharmacologically active substances.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Sequence Listing This application 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 a PAT Named 058632-WO-PCT02_SL.txt and 7,192 bytes in size is.

[0002] The present invention relates to a pyrazolyl derivative compound; KRAS G12C, HRAS G12C or N their use for inhibiting RAS G12C, in particular KRAS G12C; and methods for treating or preventing diseases, particularly cancer, using the compounds of the present invention; and methods for making these compounds. The present invention also provides methods and intermediates for treating cancer and certain conditions as defined herein. These pyrazolyl derivative compounds are provided for use in the treatment of cancer. [Background technology]

[0003] RAS is a molecule that assumes active and inactive states when bound to GTP and GDP, respectively. It is a small GTPase that acts as an on / off switch. It responds to growth factors and regulates guar The nin exchange factor exchanges GDP for GTP, turning Ras on. RAS recruits effector proteins to the plasma membrane, thereby initiating signal transduction cascades. These carcinogenic molecules activate the ATP-dependent ... Stimulatory signals are very transient and tightly regulated. They are primarily mediated by GTP. The G of RAS itself is accelerated by 100,000 times by Gase-activating proteins (GAPs). It is immediately turned off by TPase activity (Bos JL et al., Cell, Volume 129, Issue 5, 1 June 2007, pp 865-87 7) In contrast, RAS mutants are insensitive to these GAPs, and therefore R AS mutants exist longer in the GTP-bound state and are enhanced by their intrinsic hydrolysis rate. This switches the GTP / GDP cycle on.

[0004] The three RAS genes comprise the most frequently mutated gene family in cancer. Constitutive RAS mutations are found in approximately 25% of human tumors. Among the three paralogs, K While RAS mutations are the most frequent (85% of all RAS-driven cancers), NRAS and H RAS mutations are reported less frequently (12% and 3%, respectively). The majority of mutations occur at hotspot residues G12, G13, and Q61. The RAS G12C mutation accounts for approximately 12% of all KRAS mutations and is the most common mutation in lung cancer patients. It is most common in lung adenocarcinoma (LUAC) (approximately 13%), colon adenocarcinoma (approximately 3-5%), and less common in lung adenocarcinoma (approximately 13%). MYH polyposis is found in approximately 20% of colorectal adenomas and in a small proportion of other cancer types. (COSMIC v80 database; A. Aime et al., Cancer g enet.2015,208:390-5).

[0005] Patients with KRAS G12C-positive solid tumors are inadequately treated with current therapies Currently, only KRAS G12C and HRAS G1 are approved for therapeutic use. There are no inhibitors of NRAS G12C or NRAS G12C.

[0006] Therefore, for the treatment of cancer, particularly cancer tumors expressing G12C mutant Ras, In particular, new options for the treatment of KRAS, HRAS or NRAS G12C-driven cancers There is still a continuing need to develop new drugs. More specifically, KRAS G12 There remains a need for treatments for C-mutant cancers.

[0007] Irreversible RAS G12C inhibitors have been previously described (e.g., WO 2004 / 013994). Pamphlet No. 14152588, Pamphlet No. 2017201161, Country International Publication No. 2018 / 217651 and International Publication No. 2018119183 Brochure). Summary of the Invention

[0008] The compounds described in this invention have an irreversible covalent bond with cysteine ​​at position 12. By forming a G12C mutant KRAS, HRAS or NRAS protein It selectively reacts with and inhibits RAS mutant proteins, rendering them inactive. The irreversible binding of these compounds prevents downstream K-RAS signaling. The compounds described in this invention are useful in the treatment of cancer, particularly in the treatment of KRAS, HRAS or N Cancers characterized by RAS G12C mutations, more particularly KRAS G12 It may be used to treat cancers characterized by C mutations.

[0009] Accordingly, the present invention provides compounds, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof and methods for treating the same. The compound inhibits G12 of either KRAS, HRAS or NRAS. C mutants and inhibiting them, and are useful in the treatment of cancer, particularly For the treatment of cancers characterized by KRAS, HRAS, or NRAS G12C mutations The present invention also provides compounds useful in the synthesis of such compounds. Methods for making the intermediates are provided.

[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, or a pharmaceutically acceptable salt of the atropisomer. Salts are provided herein.

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

[0013] In another embodiment, the present invention provides a compound of formula (I) (or are subformulas (Ia), (Ib * ),(I C * ), (Id * ) or (Ie)), or an atropisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the atropisomer thereof and providing salts that are acceptable to the compounds of the present invention.

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

[0015] In another embodiment, the present invention provides a compound of formula (I) (or are subformulas (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 subformula (Ia), (I b * ),(I C * ), (Id * ) or (Ie)), or a stereoisomer thereof, or or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, of a stereoisomer thereof. a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, and one or more pharmaceutically acceptable salts thereof. and a pharmaceutical composition comprising a carrier acceptable thereto.

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

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

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

[0020] In a further embodiment, the present invention provides a method for treating a G12C mutant K RAS, HRAS, or NRAS proteins (e.g., G12C mutant KRAS proteins) 1. A method for inhibiting the activity of a compound of formula (I) or (II) as defined herein, comprising administering to a subject a therapeutically effective amount of a compound of formula (I) or (II) as defined herein. is the subformula (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, or a pharmaceutically acceptable salt of the atropisomer. The present invention relates to a method comprising administering a salt to a subject.

[0021] In yet another embodiment, the present invention provides a method for treating a disorder or disease in a subject in need thereof. The method of claim 1, wherein the disorder or disease is 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) a therapeutically effective amount of a compound selected from the group consisting of rectal cancer (including rectal adenocarcinoma), rectal cancer (including rectal adenocarcinoma), and other solid tumors; Formula (I) or its sub-formulas (Ia), (Ib) as defined in the specification * ),(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 The method comprises administering to a subject a pharmaceutically acceptable salt of the atropisomer.

[0022] In another embodiment, the present invention provides intermediate compounds and methods useful for making the compounds of the present invention. and formula (I) or its sub-formulas (Ia), (Ib) as defined herein. * ),(I C * ), (Id * ) or (Ie), or a stereoisomer thereof, or an atropisomer thereof A method for producing a genotype is provided. [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) unsubstituted or independently selected from fluoro and C1-C4-alkyl C5-C substituted with one or more, preferably one, two or three, substituents 7- Cycloal Killen; (b) 5- to 7-membered unsymmetrical ring structure containing one carbon-carbon double bond and one oxygen atom as a ring member saturated heterocyclyl, wherein the heterocyclyl is unsubstituted or substituted with fluoro and and C1-C4-alkyl, preferably 1, 2 or 3 C1-C4-alkyl independently 5- to 7-membered alkyl substituted with one or more, preferably one, two or three, substituents selected from the following: Unsaturated heterocyclyl; (c) unsubstituted or 1, 2 or 3 R A2 C6~C substituted with 10 a reel; (da) 1, 2 or 3 heteroatoms independently selected from N, O and S as ring members a 5- to 6-membered heteroaryl ring containing a substituted or unsubstituted heteroaryl group, or at one or more (e.g., 1, 2, or 3) carbon atoms A3 is replaced by If a nitrogen atom is present in a heteroaryl ring, it is unsubstituted or Rukill, -(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 a substituent selected from the group consisting of and substituted with a substituent (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), heteroaromatic Reel ring; (e) an 8-membered alkyl group containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 0-3 nitrogen atoms, 0-2 oxygen atoms in a 10-membered heteroaryl ring or heterobicyclic ring 1 to 3 independently selected from 0 to 1 sulfur atoms, 0 to 1 S(=O)2 groups, and 0 to 1 S(=O)2 groups. It is an 8-10 membered partially saturated heterobicyclic ring containing one heteroatom or heteroatom group. wherein the heteroaryl or heterobicyclic ring is unsubstituted or has a carbon atom 1, 2, 3, 4 or 5 R A4 and the heterobicyclic ring is further substituted at the carbon atom with and the nitrogen atom, if present, is unsubstituted or -(C O) substituted with a substituent that is —C1-C4-alkyl or C1-C4-alkyl, The C1-C4-alkyl may be cyano, hydroxy, oxo, fluoro, C1-C4-alkanol, Koxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 Heteroaryl optionally substituted with one or two substituents independently selected from ring or heterobicyclic ring selected from the group consisting of: Here, Het b is 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). a 4-, 5- or 6-membered heterocyclic ring containing a hetero atom or group, wherein said heterocyclic ring Het b is unsubstituted or is substituted at the carbon atom with C1-C4 alkyl, hydroxy, cyano, Fluoro, C1-C4-alkoxy-hydroxy-C1-C4-alkyl, hydroxy C1-C4-alkyl, C1-C4-alkoxy, fluoro-C1-C4-alkoxy one or two substituted alkyl groups independently selected from aryl and fluoro-C1-C4-alkyl; group, wherein the heterocycle Het b may further be optionally oxo at the carbon atom. where the nitrogen atom is substituted with Het b When present in and C1-C4-alkoxy, optionally further substituted with C1-C4-alkyl; Here, A is sp 2 The remainder of the compound of formula (I) is connected by a carbon atom in the hybrid A Combined into; 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, wherein B 2 is unsubstituted or 1, 2, 3 or 4 R Bb is replaced by; C is hydrogen, C1-C3 alkyl (preferably methyl), C3-C5 cycloalkyl (preferably cyclopropyl), fluoro-C1-C3 alkyl (preferably CHF 2 or CF3), cyano, -CH2-CN, -CH(CN)-CH3, -CH2-OH, selected from the group consisting of —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; So, G * represents the point of attachment to G; G, [ka] is selected from the group consisting of During the ceremony, R 2 is hydrogen, C1-C3 alkyl, -C(O)-C1-C3-alkyl, and fluoro Selected from B; R 3 is hydrogen; R 4 is hydrogen, methyl, -CH2F, -CH2-OCH3 and -CH2-N(CH3) Selected from 2; 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, O H, hydroxy-C1-C4-alkyl, -(COOH), -(CH2) p -COOH, C1-C4-alkyl, fluoro-C1-C4-alkyl, C1-C4-alkoxy, C 1-C4-alkoxy-C1-C4-alkyl, N(R 9)(R 10 )-C1~C4-A Rukill, 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)N R 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 oxy-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 -C OOH, C1-C4-alkyl, fluoro-C1-C4-alkyl, C1-C4-alkoxy oxy, 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-a Alkyl-oxy-C1~C4-alkyl, -SO2-C1~C4-alkyl, -SO2- C 3~4 -cycloalkyl, -(CH2) 1~2 -C 3~4 -cycloalkyl, Het p y , -(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, H et 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 hydroxy-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, N R 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 Selected; where: p is 1, 2, or 3; R 9 is selected from hydrogen and C1-C4-alkyl; R 10 is 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 O, N(pyrrolidin-1-yl, azetidin-1-yl, morpholine- 1-yl, etc.) and S; or or a 4-, 5-, or 6-membered alkyl group containing an S-oxide (SO) or S-dioxide (SO2) group or a 7-membered saturated heterocycle, wherein the heterocycle is optionally oxo at one carbon atom. and wherein the heterocycle is optionally substituted at one or more carbon atoms with a C1-C4 alkyl group. oxy (preferably methoxy), halo (preferably fluoro), C1-C4-alkyl Independently of alkyl, hydroxy-C1-C4-alkyl, and fluoro-C1-C4-alkyl wherein the nitrogen atom is optionally further substituted with one, two or three substituents selected from: When present in said heterocycle, R 10 (Preferably, C1-C4 alkyl (e.g., methyl) )) optionally further substituted; or Het py is a 5- or 6-membered heteroaryl containing 1, 2 or 3 nitrogen atoms; a 1,2,4-triazol-1-yl or pyrazol-1-yl ring (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-C one independently selected from 4-alkyl, cyano, OH, and C1-C4-alkoxy; optionally substituted with one or more (e.g., one, two, or three) substituents; Each R Ba are independently selected from hydroxy, NH2, C1-C4-alkyl and halo Selected from the group; Each R Bb are independently C1-C4 alkyl (preferably methyl), cyclopropyl fluoro-C1-C3-alkyl (preferably CHF2 or CF3), cyano, hal bro (preferably fluoro or chloro), NH2 and C1-C3-alkoxy (preferably is selected from the group consisting of methoxy), or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or or a pharmaceutically acceptable salt of an atropisomer thereof. to provide.

[0025] In a second aspect, the present invention provides a compound of formula (I) [ka] (A, (a) unsubstituted or independently selected from fluoro and C1-C4-alkyl C5-C substituted with one or more, preferably one, two or three, substituents 7- Cycloal Killen; (b) 5- to 7-membered unsymmetrical ring structure containing one carbon-carbon double bond and one oxygen atom as a ring member saturated heterocyclyl, wherein the heterocyclyl is unsubstituted or substituted with fluoro and and C1-C4-alkyl, preferably 1, 2 or 3 C1-C4-alkyl independently 5- to 7-membered alkyl substituted with one or more, preferably one, two or three, substituents selected from the following: Unsaturated heterocyclyl; (c) unsubstituted or 1, 2 or 3 R A2 C6~C substituted with 10 a reel; (d) 1, 2, or 3 heteroatoms independently selected from N, O, and S as ring members a 5- to 6-membered heteroaryl ring, wherein the heteroaryl ring is unsubstituted or or R at one or more (e.g., 1, 2, or 3) carbon atoms A3 is substituted with nitrogen If present in a heteroaryl ring, the atom is unsubstituted or C1-C4-alkyl. Le, -(CH2) 1~2 -C 3~4-cycloalkyl, C3-C6-cycloalkyl, Hydroxy-C1~C4-alkyl, fluoro-C1~C4-alkyl, C1~C4-al Koxy-C1-C4-alkyl, N(R 9 )(R 10 )-C1~C4-Alkyl, -SO 2-C1~C4-Alkyl, -SO2-C 3~4 -cycloalkyl, -(CH2) p -H et py , and -(CH2) p -N(R 9 )(R 10 a substituent selected from the group consisting of (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 Le ring; (e) an 8- to 10-membered heteroaryl ring containing 1, 2, or 3 nitrogen atoms, or In the heterobicyclic ring, 0-3 nitrogen atoms, 0-2 oxygen atoms, 0-1 sulfur atoms, and 0- 1 to 3 heteroatoms or heteroatoms independently selected from one S(=O)2 group 8-10 membered partially saturated heterobicyclic ring containing a group, The bicyclic ring is unsubstituted or has 1, 2, 3, 4 or 5 R at the carbon atoms. A 4 and the heterobicyclic ring is further optionally substituted at a carbon atom with oxo and at a nitrogen atom with Atoms, if present, are unsubstituted or -(CO)-C1-C4-alkyl or is substituted with a substituent which is C1-C4-alkyl, and said C1-C4-alkyl is cyano , hydroxy, oxo, fluoro, C1-C4-alkoxy, C1-C4-alkoxy- C1-C4-Alkyl-oxy, Het b and NR 9 R 10 one or more independently selected from is a heteroaryl or heterobicyclic ring optionally substituted with two substituents; selected from the group consisting of: Here, Het b is 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). a 4-, 5- or 6-membered heterocyclic ring containing a hetero atom or group, wherein said heterocyclic ring Het b is unsubstituted or is substituted at the carbon atom with C1-C4 alkyl, hydroxy, cyano, Fluoro, C1-C4-alkoxy-hydroxy-C1-C4-alkyl, hydroxy C1-C4-alkyl, C1-C4-alkoxy, fluoro-C1-C4-alkoxy one or two substituted alkyl groups independently selected from aryl and fluoro-C1-C4-alkyl; group, wherein the heterocycle Het b may further be optionally oxo at the carbon atom. where the nitrogen atom is substituted with Het b When present in and C1-C4-alkoxy, optionally further substituted with C1-C4-alkyl; Here, A is sp 2 The remainder of the compound of formula (I) is connected by a carbon atom in the hybrid A Combined into; 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, wherein B 2 is unsubstituted or 1, 2, 3 or 4 R Bb is replaced by; C is hydrogen, C1-C3 alkyl (preferably methyl), C3-C5 cycloalkyl (preferably cyclopropyl), fluoro-C1-C3 alkyl (preferably CHF 2 or CF3), cyano, -CH2-CN, -CH(CN)-CH3, -CH2-OH, selected from the group consisting of —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; So, G * represents the point of attachment to G; G, [ka] is selected from the group consisting of During the ceremony, R 2 is hydrogen, C1-C3 alkyl, -C(O)-C1-C3-alkyl, and fluoro Selected from B; R 3 is hydrogen; R 4 is hydrogen, methyl, -CH2F, -CH2-OCH3 and -CH2-N(CH3) Selected from 2; 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, O H, hydroxy-C1-C4-alkyl, -(COOH), -(CH2) p -COOH, C1-C4-alkyl, fluoro-C1-C4-alkyl, C1-C4-alkoxy, C 1-C4-alkoxy-C1-C4-alkyl, N(R 9 )(R 10 )-C1~C4-A Rukill, 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)-NR9 R 10 , -(CH2) p -C(=O)N R 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 oxy-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 -C OOH, C1-C4-alkyl, fluoro-C1-C4-alkyl, C1-C4-alkoxy oxy, 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-a Alkyl-oxy-C1~C4-alkyl, -SO2-C1~C4-alkyl, -SO2- C 3~4 -cycloalkyl, -(CH2) 1~2 -C 3~4 -cycloalkyl, Het p y , -(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, H et 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 hydroxy-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, N R 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 Selected; where: p is 1, 2, or 3; R 9 is selected from hydrogen and C1-C4-alkyl; R 10 is 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 O, N(pyrrolidin-1-yl, azetidin-1-yl, morpholine- 1-yl, etc.) and S; or or a 4-, 5-, or 6-membered alkyl group containing an S-oxide (SO) or S-dioxide (SO2) group or a 7-membered saturated heterocycle, wherein the heterocycle is optionally oxo at one carbon atom. and wherein the heterocycle is optionally substituted at one or more carbon atoms with a C1-C4 alkyl group. oxy (preferably methoxy), halo (preferably fluoro), C1-C4-alkyl Independently of alkyl, hydroxy-C1-C4-alkyl, and fluoro-C1-C4-alkyl wherein the nitrogen atom is optionally further substituted with one, two or three substituents selected from: When present in said heterocycle, R 10 (Preferably, C1-C4 alkyl (e.g., methyl) )) optionally further substituted; or Het py is a 5- or 6-membered heteroaryl containing 1, 2 or 3 nitrogen atoms; a 1,2,4-triazol-1-yl or pyrazol-1-yl ring (preferably 1,2,4-triazol-1-yl or pyrazol-1-yl) wherein the heteroaryl ring is NR 9 R10 , -C(=O)-NR 9 R 10 , Halo, C1-C4-alkyl, hydroxy-C1-C4-alkyl, fluoro-C1-C one independently selected from 4-alkyl, cyano, OH, and C1-C4-alkoxy; optionally substituted with one or more (e.g., one, two, or three) substituents; Each R Ba are independently selected from hydroxy, NH2, C1-C4-alkyl and halo Selected from the group; Each R Bb are independently C1-C4 alkyl (preferably methyl), cyclopropyl fluoro-C1-C3-alkyl (preferably CHF2 or CF3), cyano, hal bro (preferably fluoro or chloro), NH2 and C1-C3-alkoxy (preferably is selected from the group consisting of methoxy), or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or or a pharmaceutically acceptable salt of an atropisomer thereof. to provide.

[0026] The term "preferably" when referred to herein refers to other embodiments of the present invention. The embodiment is particularly intended to include all parts or features specifically mentioned after the term "preferably". , replacing the more general term immediately preceding what they designate, compounds of formula (I), or 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. Regarding.

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

[0028] In a further embodiment, a KRAS, NRAS or HRAS G12C mutation, e.g. For use in treating disorders or diseases (e.g., cancer) mediated by the KRAS G12C mutation a compound of formula (I), or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, for A salt, or a pharmaceutically acceptable salt of an atropisomer thereof, is provided.

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

[0030] In a further aspect, there is provided a method of treating a disorder or cancer in a subject in need thereof, comprising: 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 a stereoisomer thereof, or an attolytic acid thereof A method is provided that includes administering to a subject a pharmaceutically acceptable salt of the prop isomer.

[0031] In a further aspect, a disorder or disease in a subject in need thereof, such as lung cancer (lung adenocarcinoma), and non-small cell lung cancer), colorectal cancer (including colorectal adenocarcinoma), pancreatic cancer (including pancreatic adenocarcinoma) selected from the group consisting of uterine cancer (including endometrial cancer), rectal cancer (including rectal adenocarcinoma), and solid tumors 10. A method of treating cancer comprising administering a therapeutically effective amount of a compound of formula (I) as defined herein. Compound, 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 The method includes administering to a subject a salt comprising:

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

[0033] In a further embodiment, the cancer is a KRAS-, NRAS-, or HRAS-G12C mutation. Typically, the cancer is a KRAS-G12C mutant cancer, such as lung cancer ( lung adenocarcinoma and non-small cell lung cancer), colorectal cancer (including colorectal adenocarcinoma), pancreatic cancer (pancreatic adenocarcinoma) cancer), uterine cancer (including endometrial cancer), rectal cancer (including rectal adenocarcinoma), and solid tumors Compounds of formula (I), or stereoisomers thereof, or atropisomers thereof, for use in therapy or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or Pharmaceutically acceptable salts of the atropisomers of the formula:

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

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

[0036] In a further embodiment, optionally, the cancer is KRAS-, NRAS-, or HRAS-G12 C mutants, cancers such as lung cancer (including lung adenocarcinoma and non-small cell lung cancer), colorectal cancer ( colorectal adenocarcinoma), pancreatic cancer (including pancreatic adenocarcinoma), uterine cancer (including endometrial cancer), rectal A compound of formula (I) or a compound thereof for use in the treatment of cancer (including colorectal adenocarcinoma) and solid tumours. or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof Include pharmaceutically acceptable salts of the isomers, or pharmaceutically acceptable salts of the atropisomers thereof. Pharmaceutical compositions are provided.

[0037] In a further embodiment, a compound of formula (I), or a stereoisomer thereof, or an atropisomer thereof a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, and pharmaceutically acceptable salts of the atropisomers thereof, and one or more therapeutically active agents. Combinations are provided.

[0038] In a further embodiment, a compound of formula (I), or a stereoisomer thereof, or an atropisomer thereof a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, provides a process for the preparation of pharmaceutically acceptable salts of the atropisomers.

[0039] Unless otherwise specified and unless the context clearly indicates otherwise, "compounds of the present invention" shall mean "a compound of the invention" or "a compound of the invention" "compounds of the invention" or "compounds of formula (I)" "Compounds of the formula (I)" or "compounds of the formula (I)" The term "a compound of formula (I)" means a compound of formula (I) , (Ia), (Ib * ),(I C * ), (Id * ) and one or more compounds of (Ie) and pharmaceutically acceptable salts thereof, as well as stereoisomers (diastereoisomers and enantiomers) thereof. isomers), atropisomers, rotamers, tautomers, and isotopically labeled compounds (including deuterium isomers) This includes moieties formed from a substituted or unsubstituted group, as well as moieties formed inherently.

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

[0041] Therefore, Equation 2(a), (2b * ), (2c * ) and (2d * ) compounds, and Salts of 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" is used interchangeably with "compound of formula (I)" or "compound of formula (I), or a pharmaceutically acceptable salt thereof." The term refers to compounds of formula (I), (Ia), (Ib) * ),(I C * ), (Id * ) and compounds of (Ie) or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a compound of formula (I) , (Ia), (Ib * ),(I C * ), (Id * ) and (Ie) A pharmaceutically acceptable salt or a compound of formula (I), (Ia), (Ib) * ),(I C * ), (Id * ) and pharmaceutically acceptable salts of atropisomers of compounds of formula (Ie).

[0043] Formula (I), (Ia), (Ib * ),(I C * ), (Id * ) and (Ie) diastereoisomers, atropisomers, enantiomers, including pharmaceutically acceptable salts thereof; All stereoisomers are included, including mixtures thereof and racemic mixtures. * ), (2c * ) and (2d * The compounds of formula (I) are also useful in the form of diastereoisomers, astereoisomers, and salts thereof. All stereoisomers, including tropisomers, enantiomers, mixtures thereof and racemic mixtures. include.

[0044] One isomer (e.g., enantiomer, diastereomer, atropisomer, or geometric isomer) isomer) is more effective as an inhibitor of RAS G12C mutant protein than its opposite isomer. If it has high intrinsic activity, the more active isomer is typically preferred.

[0045] The presence of diastereoisomers can be identified by one skilled in the art using means such as NMR. Diastereoisomers can be separated by HPLC (high performance liquid chromatography), thin layer chromatography, etc. Chromatography, SFC (Supercritical Fluid Chromatography), GC (Gas Chromatography) Those skilled in the art can easily obtain the desired product by using chromatographic methods, such as by using recrystallization techniques, or by using other techniques. Separation of enantiomers can be performed by chiral HPLC, chiral SFC, chiral GC This can be done by a person skilled in the art using such means.

[0046] The compounds of the present invention, particularly ortho-substituted biaryl compounds, are referred to herein as atto-substituted biaryl compounds. They can exhibit conformational and rotational isomerism called prop isomerism (Eliel, E. and Wil en, S. (1994) Stereochemistry of Organic Co. mpounds,John Wiley & Sons,Inc.,pp.1142-5 5). In some cases, depending on the substituents on the bi-aryl ring moiety, such compounds of the present invention may be Biaryl compounds exhibit atropisomerism.

[0047] Thus, the formula (I) and the sub-formulas (Ia), (Ib * ),(I C * ), (Id * ) and (Ie) and their isomeric mixtures (diastereomeric mixtures, enantiomeric mixtures) Similarly, compounds of formula (I), and Subformula (Ia), (Ib * ),(I C * ), (Id * ) and (Ie) "Teleomer-enriched" or "enantiomer-enriched" mixtures also form part of the present invention.

[0048] The present invention also provides a hydrate (modified HA) crystalline form of Compound X, or a compound obtained by condensing the compound in isopropyl alcohol. (IPA) solvate crystalline form, or ethanol (EtOH) solvate crystalline form, or propionyl Crystalline forms of Compound X as defined herein, such as ethylene glycol solvate crystalline forms. Provide a positive attitude.

[0049] The present invention also provides a compound having an X-ray powder diffraction spectrum substantially identical to that shown in FIG. 1, FIG. 2, FIG. 3 or FIG. 4. A crystalline form of compound X as defined herein having the same X-ray powder diffraction spectrum as Provide a positive attitude.

[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. Halo-substituted alkyl, such as alkyl substituted with halogen (halo-alkyl). The halogen-substituted groups and moieties may be mono-, poly-, or perhalogenated. and fluoro are preferred halo substituents on alkyl or cycloalkyl groups, especially Unless otherwise specified, fluoro is most preferred. Fluoro, chloro and bromo are often preferred. In this case, it is preferred in the aryl or heteroaryl group, and unless otherwise specified, fluoro is most preferred.

[0051] As used herein, unless otherwise indicated, the term "heteroatom" means It 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. Or when three substituents are present, for example, the substituents can be the same or different.

[0053] As used herein, the term "C1-C4-alkyl" includes unsaturation. First, carbon atoms, which have 1 to 4 carbon atoms and are attached to the rest of the molecule by single bonds. and refers to a linear or branched hydrocarbon chain radical consisting only of hydrogen atoms. C1 to C4- Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, 1-methyl Ethyl (iso-propyl) and n-butyl are mentioned. A preferred example is methyl.

[0054] When substituted with oxo, the C1-C4 alkyl group has a carbonyl moiety that is It includes -C(O)-C1-C3-alkyl, which is bonded to the remainder of the molecule.

[0055] As used herein, the term "hydroxy-C1-C4-alkyl" , a C1-C4-alkyl group as defined above, in which one of the hydrogen atoms of the C1-C4-alkyl group is replaced by OH; Examples of hydroxy-C1-C4-alkyl include, but are not limited to, However, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 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 1-C4-alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, Examples include butyl, isopropoxy and butoxy.

[0057] As used herein, the term "hydroxy C1-C4-alkoxy" , wherein at least one hydrogen atom of the C1-C4-alkoxy group is substituted with OH; refers to a C1-C4 alkoxy group defined as a hydroxy group. 1~4 Examples of alkoxy are hydroxymethoxy, hydroxyethoxy, 2-hydroxypropionyl Kisi is one example.

[0058] As used herein, the term "C1-C4-alkyl-oxy" refers to the above "C1-C4-alkyl" refers to a "C1-C4-alkyl" group as defined in is bonded to by an oxygen atom.

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

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

[0061] As used herein, "C1-C4-alkoxy-hydroxy-C1-C4 The term "-alkyl" means that at least one of the hydrogen atoms of a C1-C4-alkyl group is O refers to a C1-C4-alkoxy-C1-C4-alkyl group as defined above, substituted with H. vinegar.

[0062] As used herein, "C1-C4-alkoxy-C1-C4-alkyl- The term "oxy" refers to "C1-C4-alkoxy-C1-C4-alkoxy" as defined above. "O-alkyl" refers to a "carbonyl" group, where the group is attached to the rest of the molecule by an oxygen atom.

[0063] As used herein, "C1-C4-alkyl-carbonyl-oxy-C1 The term "C4-alkyl-oxy" refers to a group of the formula C1-C4-alkyl-C(=O)-O- refers to a C1-C4-alkyl-O- group, where said group is attached to the rest of the molecule at the end It is bonded by an oxygen atom.

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

[0065] As used herein, the term "fluoro-alkyl" refers to one or more fluoroalkyl groups. Fluoro-C1-C4 refers to an alkyl as defined herein substituted with fluoro. Non-limiting examples of -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 include, unless otherwise specified, monofluoro-, difluoro-, Fluoro- and trifluoro-substituted methyl and ethyl groups, e.g., CF3, CF2H, CFH2, and CH2CF3.

[0066] As used herein, the term "fluoro-alkoxy" refers to one or more It refers to alkoxy as defined herein substituted with 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" means Formula--N(R a )-R a where each R a may be the same or different as defined above. C1-C4 alkyl groups which can be:

[0069] As used herein, "NR 9 R 10 " or "N(R 9 )(R 10 )” replacement The group has the formula "-N(R 9 )(R 10 )" group, wherein said group is bonded by a nitrogen atom. attached to the rest of the molecule and 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 C1-C4 alkyl group. One of the elementary atoms is -N(R 9 )(R 10 C1-C4 alkyl groups as defined above, substituted with Refers to the kill group.

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

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

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

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

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

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

[0077] As used herein, "C1-C4-alkoxy-C1-C4-alkyl- The term "oxy" refers to "C1-C4 alkoxy-C1-C4 alkyl" as defined above. where the 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 a 1-NR 9 R 10 where 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 As defined in

[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, C1-C4-alkyl is as defined above.

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

[0081] As used herein, the term "cycloalkylene" refers to at least one a carbon-carbon double bond, preferably a non-aromatic carbocyclic ring containing one carbon-carbon double bond; The term "monocyclic cycloalkylene" refers to a monocyclic cycloalkylene having at least one carbon-carbon bond. A non-aromatic monocyclic carbocyclic radical containing a double bond, preferably one carbon-carbon double bond. This term refers to, but is not limited to, alkylenes having 5 to 7 carbon atoms and one C—C double bond. and "C5-C7-cycloalkylene," a non-aromatic carbocyclic radical containing Examples of cycloalkylene groups are cyclopentenyl, cyclohexenyl (e.g., cyclohexyl) and the like. cyclohex-1-en-1-yl, cyclohex-2-en-1-yl, cyclohex-3-en non-aromatic containing 5 to 7 carbon atoms and one or more C—C double bonds, such as 1-1-yl It is a carbocyclic ring.

[0082] As used herein, the term "aryl" refers to a group having 6 to 14 ring atoms in the ring moiety. It refers to an aromatic hydrocarbon group having carbon atoms. Typically, aryl is a group having 6 to 14 carbon atoms. monocyclic, bicyclic or tricyclic aryl, often having 6 to 10 carbon atoms; For example, phenyl or naphthyl. Phenyl is sometimes preferred. The term "aryl" as used herein refers to a single aromatic ring or rings fused together. refers to an aromatic substituent which may be multiple aromatic rings connected together. Non-limiting examples include phenyl, naphthyl and 1,2,3,4-tetrahydronaphthyl, provided that tetrahydro The naphthyl is attached to the formula described above through a carbon atom in the aromatic ring of the tetrahydronaphthyl group. will be done.

[0083] "C6~C 10 The term "aryl" includes phenyl, 1,2,3,4-tetrahydronaphthalene, It refers to a butyl or naphthyl group. Preferred C6-C 10 An example of an aryl group is a phenyl group. The term "phenyl" refers to a group of formula -C6H5. In substituted phenyl, -C6 One or more of the hydrogen atoms in H5 may be substituted with one or more substituents, particularly those described herein. It will be replaced by one of them.

[0084] As used herein, the term "heterocyclyl" or "heterocycle" means a saturated Monocyclic or polycyclic rings containing fused or bridged bicyclic ring systems that are saturated or partially unsaturated but not aromatic Heterocycle or heterocyclyl refers to a heterocyclic group which may be a cyclic ring. Contains one non-carbon atom, 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, in particular 1, 2 or 3 ring atoms are O, and N are heteroatoms independently selected from S and N (thus the remaining ring atoms are carbon When the heterocycle contains S or N as a heteroatom, valence permits , S may be present as an SO or SO2 group, and N may be present as an N-oxide.

[0085] An unsaturated heterocyclyl may have one or two double bonds, but is not aromatic. Preferably, unless specified as unsaturated, heterocyclyl groups in the compounds of the invention are Preferably, the heterocyclyl group has one or two heterocyclic ring atoms. Preferably, the heteroatoms are not directly bonded to each other. Examples include tetrahydrofuran (THF), dihydrofuran, 1,4-dioxane, and morpholino. 1,4-dithiane, piperazine, piperidine, 1,3-dioxolane, imidazolidin imidazoline, pyrroline, pyrrolidine, tetrahydropyran, dihydropyran, oxalic acid Sathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane, oxathiane, thio Morpholine, etc.

[0086] The term "5- to 7-membered unsaturated heterocyclyl" refers to a heterocyclyl group consisting of nitrogen, oxygen, and sulfur (optionally, -S (=O)- and -S(=O)- groups are further included), or three heteroatoms and one or more C—C double bonds, preferably one C—C double bond This term refers to a ring radical containing 5 to 7 ring atoms, including a double bond. C—C double bonds, preferably one C—C double bond, and nitrogen, oxygen and sulfur, preferably or a 5-membered, 6-membered ring containing 1, 2, or 3 heteroatoms individually selected from one oxygen atom; Examples of 5- to 7-membered unsaturated heterocyclyl radicals include: includes, but is not limited to, 3,4-dihydro-2-H-pyranyl, 5,6-dihydro-2H six-membered non-aromatic alkyl groups containing one oxygen atom and a CC double bond, such as -pyranyl and 2H-pyranyl; aromatic monocyclic radicals.

[0087] The term "heteroaryl" refers to any heteroaryl independently selected from nitrogen, oxygen, and sulfur in a ring radical. 5-14 membered, typically 5-10 membered, monocyclic alkyl esters containing 1, 2, 3 or 4 heteroatoms. A cyclic or bicyclic aromatic ring radical. Typically, heteroaryl is a 5- to 10-membered ring system, For example, it is a 5- to 6-membered monocyclic or 8- to 10-membered bicyclic group. Typical heteroaryl groups include Examples 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- or 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 that replaces a hydrogen atom that would otherwise be present on an unsubstituted heteroaryl. Heteroaryl groups with one or more substituents on the aryl ring, typically 1, 2 or 3 substituents. It is an aryl group.

[0089] The term "5- to 6-membered heteroaryl" refers to any group individually selected from nitrogen, oxygen, and sulfur. An aromatic monocyclic ring radical containing 1, 2, 3 or 4 heteroatoms. 1, 2 or 3 heteroatoms selected from N, O and S as members, preferably 1 to 2 5- or 6-membered aromatic rings containing one nitrogen atom, or one nitrogen atom and one sulfur atom This term includes aromatic alkyls, as in the case of the 1H-pyridin-2-one system, for example. Examples of suitable 5- to 6-membered heteroaryl groups include: Examples include, but are not limited to, 2- or 3-thienyl, 2- or 3-furyl, and 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- or 2- or 3-tetrazolyl Tolazolyl, 2-, 3-, or 4-pyridyl, 3- or 4-pyridazinyl, 2-pyraziny and 2-, 4-, or 5-pyrimidinyl.

[0090] The term "8- to 10-membered heteroaryl" refers to any group individually selected from nitrogen, oxygen, and sulfur. Non-limiting examples include aromatic bicyclic ring radicals containing 1, 2, 3, or 4 heteroatoms. Examples of the indolizinyl compounds include 1-, 2-, 3-, 5-, 6-, 7-, and 8-indolizinyl, 1-, and 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]pyridyl Lysinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo [3,2-b]pyridinyl, benzofuranyl, benzothiophenyl, indolyl, isopropyl Indolyl, indolininyl, benzimidazolyl, indazoline Lil is an example.

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

[0092] "0-3 nitrogen atoms, 0-2 oxygen atoms, 0-1 sulfur atoms and and 0 to 1 S(=O)2 groups; The term "8-10 membered partially saturated heterobicyclic ring containing a cyclic group" means (i) 1 to 2 oxygen atoms, 1 sulfur atom, and 0 to 1 S( ═O)2 groups independently selected from the group consisting of a 5-membered alkyl group or a 5-membered saturated or partially saturated carbocyclic ring containing 1, 2 or 3 nitrogen atoms, fused to a 6-membered saturated or partially saturated carbocyclic ring ~6-membered heteroaryl ring, or (ii) 0 to 3 nitrogen atoms, 0 to 2 oxygen atoms, 0 to 1 1 to 3 heteroatoms or 1 to 3 heteroatoms independently selected from sulfur atoms and 0 to 1 S(=O)2 groups is a heteroatom group (e.g., one nitrogen atom and one oxygen atom; or one, two, or three nitrogen atoms) one oxygen atom; or one sulfur atom; or one -S(=O)2 group) A phenyl ring fused to a 5- or 6-membered saturated or partially saturated carbocyclic ring is an 8- to 10-membered bicyclic radical consisting of provided that the point of attachment of the 8- to 10-membered partially saturated heterobicyclic ring to the rest of the molecule shall be a 5- or 6-membered heterobicyclic ring. on the heteroaryl or on the phenyl ring.

[0093] The 8- to 10-membered partially saturated heterobicyclic radical may be unsubstituted or may be any of the 8- to 10-membered partially saturated heterobicyclic radicals described herein. and (except on aromatic rings) with one or more substituents selected from the group consisting of oxo and oxazolidinyl groups. is optionally replaced by

[0094] In one embodiment, the term "8-10 membered partially saturated heterobicyclic ring" refers to a 1, 2 or Consists of a 5- to 6-membered heteroaryl ring containing three nitrogen atoms or a phenyl ring an 8- to 10-membered partially saturated heterobicyclic ring radical, wherein the phenyl ring or heteroaryl ring is The aromatic ring may contain one nitrogen atom and one oxygen atom; or one, two or more aromatic rings in the non-aromatic portion of the ring. is three nitrogen atoms; one oxygen atom; or one sulfur atom; or -S(=O)- and -S a 5- or 6-membered saturated or partially saturated carbon atom optionally incorporating one group selected from (=O)2-; fused to a heterocyclic ring, but not to the attachment of an 8- to 10-membered partially saturated heterobicyclic ring to the rest of the molecule The dots are on the 5- to 6-membered heteroaryl or phenyl ring. Bicyclic ring radicals are unsubstituted or substituted with one or more substituents described herein, and further comprising (on the aromatic ring Optionally substituted with oxo at the carbon atom (except for 8-10 membered moiety). The term "unsaturated heterobicyclyl" means (a) a 5,5-, 5,6-, 6,5-, or 6 -5-6 containing 1-2 nitrogen atoms fused to a second ring to form a 6-ring system and (b) a 6,5-, or 6-6-ring system fused to a second ring. It contains a bonded phenyl ring.

[0095] "8-10 membered partially saturated heterobicyclic ring" and "0-3 nitrogen atoms, 0 Independently selected from: up to 2 oxygen atoms, 0-1 sulfur atoms, and 0-1 S(=O)2 groups 8-10 membered partially saturated heterobicyclic rings containing 1-3 heteroatoms or heteroatom groups Examples of "rings" 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, tetrahydro benzimidazolyl (e.g., 4,5,6,7-tetrahydro-1H-benzimidazolyl) quinolinyl, tetrahydroquinoxalinyl, dihydroiso ... Benzimidazolyl (e.g., 2,3-dihydro-1H-benzo[d]imidazole-5- yl), dihydrobenzothiophenyl (e.g., 1,3-dihydrobenzo[c]thiophene -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), isoindoli nonyl (e.g., isoindolin-1-on-5-yl), indolinonyl (e.g., indoline benzofuran-2(3H)-on-5-yl), benzofuranonyl (e.g., benzofuran-2(3H)-on-5-yl), isobenzofuran-1(3H)-one-6-yl), isobenzofuranonyl (e.g., isobenzofuran-1(3H)-one- 6-yl). Preferably, 8- to 10-membered partially saturated heterobicyclic ring or "heterocyclic 0-3 nitrogen atoms, 0-2 oxygen atoms, 0-1 sulfur atoms, and 0-1 and 1 to 3 heteroatoms or heteroatom groups independently selected from S(=O)2 groups. The 8-10 membered partially saturated heterobicyclic ring having the formula "indolinyl (e.g., indoline-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. For example, 2,3-dihydro-1H-benzo[d]imidazol-5-yl), dihydrobenzo Thiophenyl (e.g., 1,3-dihydrobenzo[c]thiophen-5-yl, 2,3-di Hydrobenzo[b]thiophen-6-yl), dihydrobenzothiophenyl dioxide ( For example, 1,3-dihydrobenzo[c]thiophen-5-yl 2,2-dioxide, dihydrobenzo[c]thiophen-5-yl 2,2-dioxide, Dropyrrolopyrazolyl (e.g., 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl) isoindolinyl (e.g., isoindolin-1-on-5-yl), indolinonyl (e.g., indolin-2-one-5-yl), benzofuranonyl (e.g., benzofuran-2(3H)-on-6-yl), isobenzofuranonyl (e.g., isoben zofran-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] In general, for groups containing two or more subgroups, the last named group is the radical bond. For example, "alkylaryl" refers to a monovalent radical of the formula alkyl-aryl-. while "arylalkyl" means a monovalent radical of the formula aryl-alkyl- do.

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

[0102] As used herein, the term "substituted with one or more substituents" means two Preferably, it is substituted with one, two, three, four, five, or six substituents. For the avoidance of doubt, this term refers to a group having a valence of 1 to 3. Where permitted, two or three substituents may be present on the same carbon atom.

[0103] Any use of examples or exemplary language (e.g., "such as") shown herein is to be construed as limiting the scope of the present invention. It is intended merely to clarify the invention and not to limit the scope of the invention as separately claimed. It does not impose any regulations.

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

[0105] The expression "A is sp 2 The remainder of the compound of formula (I) is connected by a carbon atom in the hybrid A By "bonded to" this is meant the following schematic diagram: [ka] It can be represented by:

[0106] "Heteroatom" or "heteroatoms" ) when referring to a ring, this refers to a ring heteroatom (where NH is also , should be considered as a heteroatom that can replace "N").

[0107] As used herein, in the compounds described herein, the compounds of formula (2a), (2b * ), (2c * ) and (2d * ) in the compound or in the scheme "nitrogen-protecting group" (PG ) refers to acylation, etherification, esterification, oxidation, solvolysis and similar reactions. It refers to a group that should protect the functional group in question from unwanted secondary reactions such as Depending on the protecting group used, those skilled in the art can refer to known procedures to remove the protecting group. In light of this, one will know how to remove the protecting group to obtain the free amine NH2 group. JFWMcOmie, “Protective Groups in Or ganic Chemistry”,TWGreene and PGMWu ts,“Greene's Protective Groups in Organi c Synthesis” and “Methoden der organischen Chemie” (Methods of Organic Chemistry), etc. , including references to organic chemistry texts and literature procedures.

[0108] Preferred nitrogen-protecting groups include C1-C6 alkyl (e.g., tert-butyl); Preferably, C1-C4 alkyl, more preferably C1-C2 alkyl, most preferably , trialkylsilyl-C1-C7 alkoxy (e.g., trimethylsilylethoxy) substituted, disubstituted or trisubstituted C1-alkyl; Aryl, preferably phenyl, or heterocyclic groups (e.g., benzyl, cumyl, benzyl, Hydryl, pyrrolidinyl, trityl, pyrrolidinylmethyl, 1-methyl-1,1-dimethyl benzyl, (phenyl)methylbenzene) (wherein the aryl ring or heterocyclic group is not It may be substituted or may be substituted with, for example, C1-C7 alkyl, hydroxy, C1-C7 alkoxy (e.g. For example, para-methoxybenzyl (PMB), C2-C8-alkanoyl-oxy, halogen one or more, for example two or less, selected from the group consisting of nitro, cyano, and CF3; is replaced by three residues), Aryl-C1-C2-alkoxycarbonyl (preferably phenyl-C1-C2-alkoxycarbonyl) Alkoxycarbonyl (e.g., benzyloxycarbonyl (Cbz), benzyloxymethyl (BOM), pivaloyloxymethyl (POM), C1-C 10 -Alkenyloxy carbonyl, C1-C6 alkylcarbonyl (e.g., acetyl or pivaloyl), C6- C 10 -arylcarbonyl; C1-C6-alkoxycarbonyl (e.g., tert-butyl) oxycarbonyl (Boc), methylcarbonyl, trichloroethoxycarbonyl (Tro c), pivaloyl (Piv), allyloxycarbonyl), C6-C 10 -aryl C1 ~C6-alkoxycarbonyl (e.g., 9-fluorenylmethyloxycarbonyl (Fm oc)), allyl or cinnamyl, sulfonyl or sulfenyl, succinimidyl group, Silyl groups (e.g., triarylsilyl, trialkylsilyl, triethylsilyl (TES ), trimethylsilylethoxymethyl (SEM), trimethylsilyl (TMS), trimethylsilyl isopropylsilyl or tertbutyldimethylsilyl).

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

[0110] In an embodiment of the invention, the nitrogen-protecting group is C1-C6-alkoxycarbonyl (e.g. For example, tert-butoxycarbonyl or t-butyl carbamate (Boc), methyloxy Carbonyl or methyl carbamate, ethyl carbamate, 9-fluorophenylcarbamate Methyl methylcarbamate (Fmoc) and its analogues, 2,2,2-trichloroethylcarbamate Trichloroethoxycarbonyl (Troc), 2-trimethylsilylethylcarbamate (Teoc), pivaloyl (Piv), allyloxycarbonyl or allyl carbamate (Alloc), benzyl carbamate (Cbz)) or amide protecting groups such as COCF 3 (trifluoroacetamide), or N-allyl or N-benzyl and their analogues. More preferably, the nitrogen-protecting group is tertbutoxycarbonyl.

[0111] "Stereoisomer" or "stereoisomeric The term "mers" refers to compounds that have the same chemical structure but differ in the arrangement of atoms or groups in space. refers to compounds that differ in terms of

[0112] The terms "diastereoisomers" or "diastereomers" refer to compounds related as mirror images. Diastereoisomers refer to stereoisomers that differ in physical properties and chemical behavior. The mixture of diastereomers is characterized by some difference. These compounds may be separated under analytical procedures such as filtration or crystallization.

[0113] The term "enantiomers" refers to a pair of non-superimposable isomers that are mirror images of each other. Refers to one side of a molecular entity.

[0114] The term "enantiomeric mixture" refers to a mixture enriched in one enantiomer, the other enantiomer. and containing a higher proportion or percentage of one of the enantiomers of the compound of the present invention. It refers to a composition, or a racemate.

[0115] The term "diastereomeric mixture" refers to a mixture enriched or equivalent to a diastereomer. It refers to a mixture of diastereoisomers in proportions.

[0116] The term "diastereomerically enriched" refers to the diastereomeric form of the compound of the present invention relative to the other diastereoisomer. A composition containing a higher proportion or percentage of one of the diastereomers of the compound of interest. Point to something.

[0117] The term "atropisomer" refers to a compound in which the rotational barrier is sufficient to allow separation of isomeric species. refers to stereoisomers resulting from restricted rotation around a single bond, typically in a molecule. Is rotation about the single bond of hindered as a result of steric interactions with the rest of the molecule? or greatly retarded, and the substituents on both ends of the single bond are asymmetric, called the "chiral axis" This results in a stereo unit that can be

[0118] For example, the absolute configuration of the chiral axis in exemplary compounds is represented by the stereodescriptor (aR) or (aS) Cahn-Ingold-Prelog (CIP) chirality rules, or stereochemistry Assigned using CIP helicity rules with descriptors (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, AM Lobo, C. Marshall, and AP Johns on,Tetrahedron:Asymmetry,4(4):657-688,19 93,https: / / doi.org / 10.1016 / S0957-4166(00 )80173-1; both by HA Favre and WH Powell, N omenclature of Organic Chemistry:IUPAC R ecommendations and Preferred Names 2013( the IUPAC “Blue Book”), Cambridge, UK:Roya l Soc.of Chem.,2014,https: / / doi.org / 10.1 039 / 9781849733069,Chapter P-9,“Specifica tion of Configuration and Conformation”, https: / / doi.org / 10.1039 / 9781849733069-01 156).

[0119] This is Example 12a (the more active atropisomer) having a (R) or (M) configuration. Example 12b (the less active atropisomer) is shown below: or (P) configuration, the structures of which 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 present invention, the compounds of the present invention are in the same spatial domain as shown in Example 12a. Get the orientation.

[0122] Similarly, the compound of Example 1a is "a(R)-1-(6-(4-(5-chloro-6-methyl)- 5-methyl-3-(1-methyl-1H-indazol-4-yl)- (1H-pyrazol-5-yl)-2-azaspiro[3.3]hepta It can be described by the name "(2-phenyl-2-yl)prop-2-en-1-one". Compound 1a is also known as "1-{6-[(4M)-4-(5-chloro-6-methyl-1H- Indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazole-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 shown below: It is. [ka]

[0124] 1 shows an alternative structure of the compound of Example 1a (also referred to herein as Compound X). The method is as follows. [ka]

[0125] The term "substantially the same" in relation to X-ray diffraction peak positions refers to typical peak positions and This means that the peak position (2θ) and intensity fluctuations are taken into account. It will be appreciated that typically exhibits some instrument-to-instrument variation of the order of 0.2°. Furthermore, one skilled in the art will appreciate that the relative peak intensities may vary depending on instrument-to-instrument variations, as well as crystallinity, preferred orientation, These values ​​reflect variations due to sample surface preparation and other factors known to those skilled in the art and are not intended to be definitive. It will be understood that this should be interpreted as a sexual scale.

[0126] Various embodiments or aspects of the present invention are set forth herein and particularly in the claims. The features defined in each embodiment may be combined with other embodiments to provide further embodiments of the present invention. It will be appreciated that certain features may be combined with other features of the invention. It will be appreciated that the features mentioned in the embodiments are preferred embodiments of the invention. The embodiments listed below are representative of the present invention.

[0127] Embodiment 1. Compound of Formula (I) [ka] (In the formula, A, (a) unsubstituted or independently selected from fluoro and C1-C4-alkyl C5-C substituted with one or more, preferably one, two or three, substituents 7- Cycloal Killen; (b) 5- to 7-membered unsymmetrical ring structure containing one carbon-carbon double bond and one oxygen atom as a ring member saturated heterocyclyl, wherein the heterocyclyl is unsubstituted or substituted with fluoro and and C1-C4-alkyl, preferably 1, 2 or 3 C1-C4-alkyl independently 5- to 7-membered alkyl substituted with one or more, preferably one, two or three, substituents selected from the following: Unsaturated heterocyclyl; (c) unsubstituted or 1, 2 or 3 R A2 C6~C substituted with 10 a reel; (d) 1, 2, or 3 heteroatoms independently selected from N, O, and S as ring members a 5- to 6-membered heteroaryl ring, wherein the heteroaryl ring is unsubstituted or or R at one or more (e.g., 1, 2, or 3) carbon atoms A3 is substituted with nitrogen If present in a heteroaryl ring, the atom is unsubstituted or C1-C4-alkyl. Le, -(CH2) 1~2 -C 3~4 -cycloalkyl, C3-C6-cycloalkyl, Hydroxy-C1~C4-alkyl, fluoro-C1~C4-alkyl, C1~C4-al Koxy-C1-C4-alkyl, N(R 9 )(R 10 )-C1~C4-Alkyl, -SO 2-C1~C4-Alkyl, -SO2-C 3~4 -cycloalkyl, -(CH2) p -H et py , and -(CH2) p -N(R 9 )(R 10 a substituent selected from the group consisting of (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 Le ring; (e) an 8- to 10-membered heteroaryl ring containing 1, 2, or 3 nitrogen atoms, or In the heterobicyclic ring, 0-3 nitrogen atoms, 0-2 oxygen atoms, 0-1 sulfur atoms, and 0- 1 to 3 heteroatoms or heteroatoms independently selected from one S(=O)2 group 8-10 membered partially saturated heterobicyclic ring containing a group, The bicyclic ring is unsubstituted or has 1, 2, 3, 4 or 5 R at the carbon atoms. A 4 and the heterobicyclic ring is further optionally substituted at a carbon atom with oxo and at a nitrogen atom with Atoms, if present, are unsubstituted or -(CO)-C1-C4-alkyl or is substituted with a substituent which is C1-C4-alkyl, and said C1-C4-alkyl is cyano , hydroxy, oxo, fluoro, C1-C4-alkoxy, C1-C4-alkoxy- C1-C4-Alkyl-oxy, Het b and NR 9 R 10 one or more independently selected from is a heteroaryl or heterobicyclic ring optionally substituted with two substituents; selected from the group consisting of: Here, Het b is 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). a 4-, 5- or 6-membered heterocyclic ring containing a hetero atom or group, wherein said heterocyclic ring Het b is unsubstituted or is substituted at the carbon atom with C1-C4 alkyl, hydroxy, cyano, Fluoro, C1-C4-alkoxy-hydroxy-C1-C4-alkyl, hydroxy C1-C4-alkyl, C1-C4-alkoxy, fluoro-C1-C4-alkoxy one or two substituted alkyl groups independently selected from aryl and fluoro-C1-C4-alkyl; group, wherein the heterocycle Het b may further be optionally oxo at the carbon atom. where the nitrogen atom is substituted with Het b When present in and C1-C4-alkoxy, optionally further substituted with C1-C4-alkyl; Here, A is sp 2 The remainder of the compound of formula (I) is connected by a carbon atom in the hybrid A Combined into; 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, wherein B 2 is unsubstituted or 1, 2, 3 or 4 R Bb is replaced by; C is hydrogen, C1-C3 alkyl (preferably methyl), C3-C5 cycloalkyl (preferably cyclopropyl), fluoro-C1-C3 alkyl (preferably CHF 2 or CF3), cyano, -CH2-CN, -CH(CN)-CH3, -CH2-OH, selected from the group consisting of —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; So, G *represents the point of attachment to G; G, [ka] selected from the group consisting of: During the ceremony, R 2 is hydrogen, C1-C3 alkyl, -C(O)-C1-C3-alkyl, and fluoro Selected from B; R 3 is hydrogen; R 4 is hydrogen, methyl, -CH2F, -CH2-OCH3 and -CH2-N(CH3) Selected from 2; 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, O H, hydroxy-C1-C4-alkyl, -(COOH), -(CH2) p -COOH, C1-C4-alkyl, fluoro-C1-C4-alkyl, C1-C4-alkoxy, C 1-C4-alkoxy-C1-C4-alkyl, N(R 9 )(R 10 )-C1~C4-A Rukill, 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)N R 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 oxy-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 -C OOH, C1-C4-alkyl, fluoro-C1-C4-alkyl, C1-C4-alkoxy oxy, 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-a Alkyl-oxy-C1~C4-alkyl, -SO2-C1~C4-alkyl, -SO2- C 3~4 -cycloalkyl, -(CH2) 1~2 -C 3~4 -cycloalkyl, Het p y , -(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, H et 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 hydroxy-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, N R 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 Selected; where: p is 1, 2, or 3; R 9 is selected from hydrogen and C1-C4-alkyl; R 10 is 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 O, N(pyrrolidin-1-yl, azetidin-1-yl, morpholine- 1-yl, etc.) and S; or or a 4-, 5-, or 6-membered alkyl group containing an S-oxide (SO) or S-dioxide (SO2) group or a 7-membered saturated heterocycle, wherein the heterocycle is optionally oxo at one carbon atom. and wherein the heterocycle is optionally substituted at one or more carbon atoms with a C1-C4 alkyl group. oxy (preferably methoxy), halo (preferably fluoro), C1-C4-alkyl Independently of alkyl, hydroxy-C1-C4-alkyl, and fluoro-C1-C4-alkyl wherein the nitrogen atom is optionally further substituted with one, two or three substituents selected from: When present in said heterocycle, R 10 (Preferably, C1-C4 alkyl (e.g., methyl) )) optionally further substituted; or Het py is a 5- or 6-membered heteroaryl containing 1, 2 or 3 nitrogen atoms; a 1,2,4-triazol-1-yl or pyrazol-1-yl ring (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-C one independently selected from 4-alkyl, cyano, OH, and C1-C4-alkoxy; optionally substituted with one or more (e.g., one, two, or three) substituents; Each R Ba are independently selected from hydroxy, NH2, C1-C4-alkyl and halo Selected from the group; Each R Bb are independently C1-C4 alkyl (preferably methyl), cyclopropyl fluoro-C1-C3-alkyl (preferably CHF2 or CF3), cyano, hal bro (preferably fluoro or chloro), NH2 and C1-C3-alkoxy (preferably is selected from the group consisting of methoxy), or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or or a pharmaceutically acceptable salt of an atropisomer thereof. .

[0128] Embodiment 2.A is (a) unsubstituted or independently selected from fluoro and C1-C4-alkyl C5-C7-cycloalkanes substituted with one or more, preferably one, two or three, substituents Killen; (b) 5- to 7-membered unsymmetrical ring structure containing one carbon-carbon double bond and one oxygen atom as a ring member saturated heterocyclyl, wherein the heterocyclyl is unsubstituted or substituted with fluoro and and C1-C4-alkyl, preferably 1, 2 or 3 C1-C4-alkyl independently 5- to 7-membered alkyl substituted with one or more, preferably one, two or three, substituents selected from the following: Unsaturated heterocyclyl; (c) unsubstituted or 1, 2 or 3 R A2 C6~C substituted with 10 a reel; (d) 1, 2, or 3 heteroatoms independently selected from N, O, and S as ring members a 5- to 6-membered heteroaryl ring, wherein the heteroaryl ring is unsubstituted or or R at one or more (e.g., 1, 2, or 3) carbon atoms A3 is substituted with nitrogen If present in a heteroaryl ring, the atom is unsubstituted or C1-C4-alkyl. Le, -(CH2) 1~2 -C 3~4 -cycloalkyl, C3-C6-cycloalkyl, Hydroxy-C1~C4-alkyl, fluoro-C1~C4-alkyl, C1~C4-al Koxy-C1-C4-alkyl, N(R 9 )(R 10 )-C1~C4-Alkyl, -SO 2-C1~C4-Alkyl, -SO2-C 3~4 -cycloalkyl, -(CH2) p -H et py , and -(CH2) p -N(R 9 )(R 10 a substituent selected from the group consisting of (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 Le ring; (e) an 8- to 10-membered heteroaryl ring containing 1, 2, or 3 nitrogen atoms; , each nitrogen atom is unsubstituted or is —(CO)—C1-C4-alkyl or C1 substituted with a substituent of C1-C4-alkyl, wherein the C1-C4-alkyl is cyano, hydroxyl, oxy, oxo, fluoro, C1-C4-alkoxy, C1-C4-alkoxy-C1- C4-Alkyl-oxy, Het b and NR 9 R 10 One or two independently selected from wherein the heteroaryl ring is unsubstituted or 1, 2, 3, 4 or 5 R in elementary atoms A4 is replaced by; Here, Het b is 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). a 4-, 5- or 6-membered heterocyclic ring containing a hetero atom or group, wherein said heterocyclic ring Het b is unsubstituted or is substituted at the carbon atom with C1-C4 alkyl, hydroxy, cyano, Fluoro, C1-C4-alkoxy-hydroxy-C1-C4-alkyl, hydroxy C1-C4-alkyl, C1-C4-alkoxy, fluoro-C1-C4-alkoxy one or two substituted alkyl groups independently selected from aryl and fluoro-C1-C4-alkyl; group, wherein the heterocycle Het b may further be optionally oxo at the carbon atom. where the nitrogen atom is substituted with Het b When present in and C1-C4-alkoxy, heteroaryl rings optionally further substituted with C1-C4-alkyl; (f) A heterobicyclic ring having 1 to 3 nitrogen atoms, 1 to 2 oxygen atoms, or 1 sulfur atom an 8-10 membered partially saturated heterobicyclic ring containing a Y atom or one S(=O)2 group, The heterobicyclic ring is unsubstituted or has 1, 2, 3, 4 or 5 carbon atoms. R A4 and the heterobicyclic ring is further optionally substituted at a carbon atom with oxo. and the nitrogen atom, if present, is unsubstituted or -(CO)-C1-C4-alkyl. substituted with a substituent which is aryl or C1-C4-alkyl, , cyano, hydroxy, oxo, fluoro, C1-C4-alkoxy, C1-C4-al Koxy-C1~C4-alkyl-oxy, Het b and NR 9 R 10 selected independently from optionally substituted with 1 or 2 substituents selected from the group consisting of methyl, ... Here, Het b is 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). a 4-, 5- or 6-membered heterocyclic ring containing a hetero atom or group, wherein said heterocyclic ring Het b is unsubstituted or is substituted at the carbon atom with C1-C4 alkyl, hydroxy, cyano, Fluoro, C1-C4-alkoxy-hydroxy-C1-C4-alkyl, hydroxy C1-C4-alkyl, C1-C4-alkoxy, fluoro-C1-C4-alkoxy one or two substituted alkyl groups independently selected from aryl and fluoro-C1-C4-alkyl; group, wherein the heterocycle Het b may further be optionally oxo at the carbon atom. where the nitrogen atom is substituted with Het b When present in and C1-C4-alkoxy, Heterobicyclic rings optionally further substituted with C1-C4-alkyl 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 or a pharmaceutically acceptable salt of an atropisomer thereof. .

[0129] Embodiment 3. Het b is one or two groups independently selected from N, O, S, SO and SO2 a hetero atom or group (preferably one oxygen atom, or one sulfur atom, or one S(= O) or one S(=O) group, or one nitrogen atom and one oxygen atom, or 1 to 2 a 4-, 5- or 6-membered heterocyclic ring containing a nitrogen atom of the formula Het b but , unsubstituted or substituted at the carbon atom with 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 He is substituted with one or two substituents independently selected from t b is further optionally substituted at a carbon atom with oxo, wherein the nitrogen atom is He t b optionally further substituted with C1-C4 alkyl, if present in - alkyl is independently selected from fluoro, hydroxy and C1-C4-alkoxy; optionally substituted with 1 to 3 substituents; 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 6~1 0 aryl, and each R Ba are independently selected from hydroxy, C1-C4-alkyl and halo selected from the group consisting of: B 2 is a 6- to 10-membered (preferably 8- to 10-membered) heterocyclic group containing 1, 2, or 3 nitrogen atoms. aryl, where B 2 is unsubstituted or 1, 2, 3 or 4 R B b is replaced by; Each R Bb are independently C1-C4 alkyl (preferably methyl), fluoro-C 1-C3-alkyl (preferably CHF2 or CF3), cyano, halo (preferably fluoro or chloro), NH2 and C1-C3-alkoxy (preferably methoxy) is selected from the group consisting of Het pyO, N(pyrrolidin-1-yl, azetidin-1-yl, morpholine- 1-yl, etc.) and S; or or a 4-, 5-, or 6-membered alkyl group containing an S-oxide (SO) or S-dioxide (SO2) group or a 7-membered saturated heterocycle, wherein the heterocycle is optionally oxo at one carbon atom. and wherein the heterocycle is optionally substituted at one or more carbon atoms with a C1-C4 alkyl group. oxy (preferably methoxy), halo (preferably fluoro), C1-C4-alkyl Independently of alkyl, hydroxy-C1-C4-alkyl, and fluoro-C1-C4-alkyl wherein the nitrogen atom is further substituted with one, two or three substituents selected from the group consisting of When present in a ring, R 10 (preferably C1-C4 alkyl (e.g., methyl)) optionally further substituted; or Het py is a 5- or 6-membered heteroaryl containing 1, 2 or 3 nitrogen atoms; a 1,2,4-triazol-1-yl or pyrazol-1-yl ring (preferably 1,2,4-triazol-1-yl or pyrazol-1-yl) wherein the heteroaryl ring is NR 9 R 10 , halo, C1-C4-alkyl, one or more independently selected from cyano, OH, and C1-C4-alkoxy (e.g., Optionally substituted with 1, 2 or 3) substituents; where R A4 are independently selected from cyano, CO2H, halo, C1-C4-alkyl, fluoro hydroxy-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 R10 , R 9 R 10 N-C1~C4-Alky Embodiment 1: The compound is selected from the group consisting of -(CO)-C1-C4-alkyl, ... or the compound according to 2; or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or or a pharmaceutically acceptable salt of an atropisomer thereof. .

[0130] Embodiment 4. Het b is one or two groups independently selected from N, O, S, SO and SO2 a hetero atom or group (preferably one oxygen atom, or one sulfur atom, or one S(= O) or one S(=O) group, or one nitrogen atom and one oxygen atom, or 1 to 2 a 4-, 5- or 6-membered heterocyclic ring containing a nitrogen atom of the formula Het b but , unsubstituted or substituted at the carbon atom with 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 He is substituted with one or two substituents independently selected from t b is further optionally substituted at a carbon atom with oxo, wherein the nitrogen atom is He t b optionally further substituted with C1-C4 alkyl, if present in - alkyl is independently selected from fluoro, hydroxy and C1-C4-alkoxy; optionally substituted with 1 to 3 substituents selected from the group consisting of methyl, ... B 2is a 6- to 10-membered (preferably 8- to 10-membered) heterocyclic group containing 1, 2, or 3 nitrogen atoms. aryl, where B 2 is unsubstituted or 1, 2, 3 or 4 R B b is replaced by; Het py O, N(pyrrolidin-1-yl, azetidin-1-yl, morpholine- 1-yl, etc.) and S; or or a 4-, 5-, or 6-membered alkyl group containing an S-oxide (SO) or S-dioxide (SO2) group or a 7-membered saturated heterocycle, wherein the heterocycle is optionally oxo at one carbon atom. and wherein the heterocycle is optionally substituted at one or more carbon atoms with a C1-C4 alkyl group. oxy (preferably methoxy), halo (preferably fluoro), C1-C4-alkyl Independently of alkyl, hydroxy-C1-C4-alkyl, and fluoro-C1-C4-alkyl wherein the nitrogen atom is further substituted with one, two or three substituents selected from the group consisting of When present in a ring, R 10 (preferably C1-C4 alkyl (e.g., methyl)) optionally further substituted; or Het py is a 5- or 6-membered heteroaryl containing 1, 2 or 3 nitrogen atoms; a 1,2,4-triazol-1-yl or pyrazol-1-yl ring (preferably 1,2,4-triazol-1-yl or pyrazol-1-yl) wherein the heteroaryl ring is NR 9 R 10 , halo, C1-C4-alkyl, one or more independently selected from cyano, OH, and C1-C4-alkoxy (e.g., 1, 2 or 3) substituents (preferably, the heteroaryl ring is , substituted with one or more amino groups); R A4 are independently selected from cyano, CO2H, halo, C1-C4-alkyl, fluoro-C 1-C4-Alkyl, Hydroxy, Hydroxy-C1-C4-Alkyl, Hydroxy-C 1-C4-Alkyl-oxy, C1-C4-alkoxy, C1-C4-alkoxy-C1 ~C4-Alkyl-oxy, -NR 9 R 10 and R 9 R 10 N-C1~C4-Alkyl- The compound of any one of the above embodiments is selected from the group consisting of oxy, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or or a pharmaceutically acceptable salt of an atropisomer thereof. .

[0131] Embodiment 5.G is [ka] or a stereoisomer thereof, or atropisomers, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of stereoisomers thereof or a pharmaceutically acceptable salt of an atropisomer thereof.

[0132] Embodiment 6.L is [ka] or a stereoisomer thereof, or atropisomers, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable salts of stereoisomers thereof or a pharmaceutically acceptable salt of an atropisomer thereof.

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

[0134] Embodiment 8. C is C1-C3 alkyl (preferably methyl), fluoro-C1-C 3 alkyl (preferably CHF2 or CF3), CH2-CN, A compound according to any one of the 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 of

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

[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). Selected from; RB2 are independently hydrogen, halo (preferably chloro), C1-C4 alkyl (preferably Preferably, selected from methyl, cyclopropyl and NH; R B3 are independently hydrogen, halo (preferably chloro), cyclopropyl and C1- C4-alkyl (preferably methyl); R B4 are independently hydrogen, halo (preferably chloro or fluoro) and C1-C4 - alkyl (preferably methyl) or R B3 and R B4 But those is bonded to an aromatic ring containing X, and together with the atom to which it is bonded, a 4- to 6-membered ring (preferably Forms a 5- to 6-membered saturated or partially unsaturated carbocyclic ring); R B5 are independently selected from hydrogen, halo (preferably chloro) and C1-C4-alkyl ( Preferably, the compound according to any one of the above embodiments is selected from: or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or or a pharmaceutically acceptable salt of an atropisomer thereof. .

[0137] Embodiment 11.R B2 are independently selected from the group consisting of hydrogen, NH2, and CH3 11. The compound of embodiment 10, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of an atropisomer thereof.

[0138] Embodiment 12.R B4 are independently hydrogen, halo (preferably chloro or fluoro), and C1-C4-alkyl (preferably methyl). 1 or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt of its stereoisomer, or a pharmaceutically acceptable salt of its atropisomer. A physiologically acceptable salt.

[0139] Embodiment 13.R B1 is independently selected from hydrogen and methyl. 12, or a stereoisomer thereof, or an atropisomer thereof, or or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or Pharmaceutically acceptable salts of tropisomers.

[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 its stereoisomer, or a pharmaceutically acceptable salt of its atropisomer. Salt.

[0141] Embodiment 15.R B3 and R B4 each independently represents halo (preferably chloro or is selected from fluoro) and C1-C4-alkyl (preferably methyl), A compound according to any one of Forms 10 to 14, or a stereoisomer thereof, or an atropisomer thereof. a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, is a pharmaceutically acceptable salt of the atropisomer.

[0142] Embodiment 16.R B3 is the halo, and R B4 is C1-C4-alkyl, 16. A compound according to any one of 10 to 15, or a stereoisomer thereof, or an atropisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or Pharmaceutically acceptable salts of the atropisomers thereof.

[0143] Embodiment 17.R B3 is chloro and R B4 is methyl. A compound according to any one of the preceding claims, or a stereoisomer thereof, or an atropisomer thereof, or A pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of a stereoisomer thereof, or an atropine thereof Pharmaceutically acceptable salts of the isomers.

[0144] Embodiment 18.R B3 is chloro and R B4 is chloro. A compound according to any one of the preceding claims, or a stereoisomer thereof, or an atropisomer thereof, or A pharmaceutically acceptable salt, or a pharmaceutically acceptable salt of a stereoisomer thereof, or an atropine thereof Pharmaceutically acceptable salts of the isomers.

[0145] Embodiment 19. Any one of embodiments 10 to 18, wherein X is CH or N. Compound, 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 Salt to be used.

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

[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 or a pharmaceutically acceptable salt of an atropisomer thereof. .

[0148] Embodiment 22. A is unsubstituted or independently selected from fluoro and C1-C4-alkyl C5-C substituted with one or more, preferably one, two or three, substituents independently selected from 7- cycloalkylene, A compound of formula (Ia), or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt of its stereoisomer, or an atropisomer thereof Pharmaceutically acceptable salts.

[0149] Embodiment 23.A is [ka] wherein W is O or C(R w )2, and each R w are independently hydrogen and fluorine Selected from R c is hydrogen or C1-C4-alkyl, A is fluoro and C1 1, 2, or 3 substituents independently selected from C1-C4-alkyl; 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, or a pharmaceutically acceptable salt of an atropisomer thereof.

[0150] Embodiment 24. A is unsubstituted or contains 1, 2 or 3 R A2 is replaced by phenyl, preferably wherein R 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-C 1~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 hydrogen, C1-C4-alkyl and C1-C4-alkoxy-C1-C4-alkenyl Selected from kill; R 10 is 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 10a However, together with the nitrogen, O, N(pyrrolidin-1-yl, azetidine- 1-yl or morpholin-1-yl, etc.) and S, or its N-oxide, or its S- one or two further independently selected from S-oxide (SO) or S-dioxide forming a 4-, 5-, or 6-membered heterocyclic ring containing a heteroatom, wherein the heterocyclic ring is and optionally substituted at the carbon atom of said heterocycle with oxo, wherein said heterocycle is oxy (preferably methoxy), halo (preferably fluoro), C1-C4-alkyl independently from alkyl, hydroxy-C1-C4-alkyl and fluoro-C1-C4-alkyl further substituted with one or two substituents selected from or R 9a and R 10a together with the nitrogen, a 4- or 5-membered ring containing 1, 2 or 3 nitrogen atoms 1- or 6-membered heteroaryl ring (preferably 1,2,4-triazol-1-yl or wherein the heteroaryl ring is optionally substituted with one amino group. Optionally substituted, 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 a salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof Acceptable salt.

[0151] Embodiment 25. A is a ring having 1, 2 or 3 ring members independently selected from N, O and S. and the heteroaryl ring is a 5- to 6-membered heteroaryl ring containing a heteroatom of the formula: is substituted or has R at one or more (e.g., 1, 2, or 3) carbon atoms A3 Place and the nitrogen atom, if present in the heteroaryl ring, is unsubstituted or C4-Alkyl, -(CH2) 1~2 -C 3~4 -Cycloalkyl, hydroxy-C1 C4-Alkyl, Fluoro-C1-C4-Alkyl, C1-C4-Alkoxy-C1-C 4-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 and (preferably) is substituted with a substituent selected from the group consisting of Preferably, the substituent is fluoro-C1-C4-alkyl, N(R 9 )(R 10 )-C 1~C4-Alkyl, -SO2-C 3~4 -cycloalkyl, or -(CH2) 1~2 - C 3~4 Any one of embodiments 1 to 21, wherein the aryl group is selected from the group consisting of cycloalkyl. or a stereoisomer thereof, or an atropisomer thereof. an isomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof; or a pharmaceutically acceptable salt of an atropisomer thereof.

[0152] Embodiment 26. A is unsubstituted or is 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 substituted with one, two or three substituents independently selected from pyridin-1-yl, pyridin-2-yl or pyridin-3-yl where: p is 1 or 2; R 9 is selected from hydrogen and C1-C4-alkyl, R 10 is 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 However, together with the nitrogen, O, N(pyrrolidin-1-yl, azetidine- 1-yl, morpholin-1-yl) and S, or its N-oxide, or its S-oxy one or two heteroatoms independently selected from S-oxide (SO) or S-dioxide; forming a 4-, 5-, or 6-membered saturated or unsaturated heterocyclic ring containing Optionally substituted at one carbon atom in the heterocycle with oxo, wherein said heterocycle is , C1-C4-alkoxy (preferably methoxy), halo (preferably fluoro), C1-C4-alkyl, hydroxy-C1-C4-alkyl and fluoro-C1-C4- further substituted with 1, 2, or 3 substituents independently selected from alkyl; or R 9a and R10a together with the nitrogen, a 4- or 5-membered ring containing 1, 2 or 3 nitrogen atoms 1- or 6-membered heteroaryl ring (preferably 1,2,4-triazol-1-yl or wherein the heteroaryl ring is optionally substituted with one amino group. Optionally substituted, Formula (I) or Formula (Ia) according to any one of embodiments 1 to 21. The compound its stereoisomer, or its atropisomer, or its pharmaceutically acceptable salt, or its isomer A pharmaceutically acceptable salt of the isomer, 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 hydrogen, C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1- C4-alkoxy-C1-C4-alkyl and di-C1-C4-alkyl-amino-C 1-C4-alkyl, or a compound of formula (Ia), or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or or a pharmaceutically acceptable salt of an atropisomer thereof. .

[0154] Embodiment 28.A is [ka] where R 23 is hydrogen, C3-C6-cycloalkyl, C1-C4-alkyl( Preferably, A is unsubstituted or is selected from the group consisting of F, CH3, CH2, substituted with 1, 2 or 3 substituents independently selected from F, CHF2 and CF3; 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 or a pharmaceutically acceptable salt of an atropisomer thereof. .

[0155] Embodiment 29. A is unsubstituted or C1-C4-alkoxy (preferably methyl). pyrimidinyl substituted with 1, 2 or 3 substituents independently selected from phenyl, ... 22. The compound of formula (I) or formula (I) according to any one of embodiments 1 to 21, wherein the compound is zinzyl-5-yl. Ia) 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. A commercially acceptable salt.

[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, C 1-C4-alkoxy-C1-C4-alkyl, -NR 9 R 10 C1-C4-alkyl, -SO2-C1~C4-Alkyl, -SO2-C 3~4 -cycloalkyl or -(CH ) 1~2 -C 3~4 -cycloalkyl; R 4a , R 4b , R 4c and R 4d each independently represents hydrogen and C1-C4 alkyl 22. The method of claim 1, wherein the aryl group is selected from alkyl (preferably methyl). a compound of formula (I) or formula (Ia) or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or or a pharmaceutically acceptable salt of an atropisomer thereof. .

[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 selected from the group consisting of OH , C1-C4-alkoxy or NR 9 R 10 (Preferably, R M is hydrogen) and Replaced; R N is hydrogen or C1-C4-alkyl, or halo- or fluoro-C1-C4-a 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-al Selected from kill; R ae is selected from the group consisting of hydrogen and C1-C4-alkyl, The alkyl is cyano, hydroxy, fluoro, C1-C4-alkoxy, C1-C4-alkoxy, Oxy-C1~C4-alkyl-oxy, Het b and NR 9 R 10 1 or optionally substituted with two substituents; R Ae consists of hydrogen, -(CO)-C1-C4-alkyl and C1-C4-alkyl wherein C1-C4 alkyl is selected from the group consisting of cyano, hydroxyl, Fluoro, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkoxy Ru-oxy, Het b and NR 9 R 10 optionally substituted with one or two substituents selected from be; where: R 9 is selected from hydrogen and C1-C4-alkyl; R 10 is 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 1 or 2 independently selected from N, O, S, SO and SO2 containing heteroatoms or groups (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 1 to 2 nitrogen atoms), wherein the heterocyclic ring is a 4-, 5-, or 6-membered heterocyclic ring. RingHet b is unsubstituted or is substituted at the carbon atom with C1-C4-alkyl, hydro Oxy, cyano, fluoro, hydroxy-C1-C4-alkyl, C1-C4-alkoxy and one or two substituents independently selected from fluoro-C1-C4-alkyl wherein the heterocycle Het b may further optionally be oxo at a carbon atom substituted, where the nitrogen atom is Het b When present in C optionally substituted with 1 to 3 substituents independently selected from C1-C4-alkoxy Any one of the above embodiments 1 to 21, optionally further substituted with 1-C4-alkyl a compound of formula (I) or formula (Ia) according to or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical preparation 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-al Selected from kill; R N is hydrogen or C1-C4-alkyl, or halo- or fluoro-C1-C4-a 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 1 0 is selected from the group consisting of: R ae is selected from the group consisting of hydrogen and C1-C4-alkyl, The alkyl is cyano, hydroxy, fluoro, C1-C4-alkoxy, C1-C4-alkoxy, Oxy-C1~C4-alkyl-oxy, Het b and NR 9 R 10 1 or optionally substituted with two substituents; R 9 is selected from hydrogen and C1-C4-alkyl; R 10 is 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 1 or 2 independently selected from N, O, S, SO and SO2 containing heteroatoms or groups (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 1 to 2 nitrogen atoms), wherein the heterocyclic ring is a 4-, 5-, or 6-membered heterocyclic ring. RingHet b is unsubstituted or is substituted at the carbon atom with C1-C4-alkyl, hydro Oxy, cyano, fluoro, hydroxy-C1-C4-alkyl, C1-C4-alkoxy and one or two substituents independently selected from fluoro-C1-C4-alkyl wherein the heterocycle Het b may further optionally be oxo at a carbon atom substituted, where the nitrogen atom is Het b When present in C optionally substituted with 1 to 3 substituents independently selected from C1-C4-alkoxy 22. Any one of embodiments 1 to 21, optionally further substituted with 1-C4-alkyl. a compound of formula (I) or formula (Ia); or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or or a pharmaceutically acceptable salt of an atropisomer thereof. .

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

[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 are independently selected from fluoro, chloro and C1-C4-alkyl (e.g., methyl). Selected from; 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 or a pharmaceutically acceptable salt of an atropisomer thereof. .

[0161] Embodiment 35.R ae is hydrogen, C1-C4-alkyl, -(CH2)2-Het b , -CH2-CN, -(CH2) 2- OH, -(CH2) 2- O-C1-C4-alkyl, Hydroxy-C1-C4-alkyl, -(CH2)2-O-(CH2)2-O-C1-C 4-alkyl and -(CH2)2-diC1-C4-alkylamino Re or R Ae is selected from hydrogen, fluoro-C1-C4-alkyl and C1-C4-alkyl selected from the group consisting of: Het b is a four-membered ring containing one nitrogen atom and one oxygen atom, or one to two nitrogen atoms , 5-membered or 6-membered heterocycle, wherein the heterocycle is unsubstituted or has a carbon atom In the above, C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkan substituted with one or two substituents independently selected from koxy and fluoro; and the nitrogen atom, if present in a heterocycle, is optionally further substituted with C1-C4-alkyl. A compound of formula (I) or formula (Ia) according to any one of embodiments 31 to 34, , or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or or a pharmaceutically acceptable salt of an atropisomer thereof. .

[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 one nitrogen atom and one oxygen atom, or one to two nitrogen atoms wherein the heterocycle is unsubstituted, or At the carbon atom, C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1- Substituted with one or two substituents independently selected from C4-alkoxy and fluoro wherein the nitrogen atom, if present in a heterocycle, is optionally C1-C4-alkyl. and the compound of formula (I) or formula (Ia) according to any one of embodiments 31 to 35, further substituted with ) compounds, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or or a pharmaceutically acceptable salt of an atropisomer thereof. .

[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-He t b wherein Het b Azetidin-1-yl, pyrrolidine -1-yl, pyrrolidin-3-yl, and morpholin-1-yl; wherein said heterocycle is independently methyl, hydroxy-methyl, methoxy and fluoro. Any of embodiments 31 to 36, optionally further substituted with one or two substituents selected from A compound of formula (I) or formula (Ia) according to any one of the preceding claims, or a stereoisomer thereof, or or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof or a pharmaceutically acceptable salt of an atropisomer thereof.

[0164] Embodiment 38.R ae is hydrogen, fluoro-C1-C4-alkyl, C1-C4-al Kill, -(CH2)2-Het b , -(CH2) 2- OH, -(CH2)2-O-C1~ C4-Alkyl, Hydroxy-C1~C4-Alkyl, -(CH2)2-O-(CH2) 2-O-C1-C4-alkyl and -(CH2)2-diC1-C4-alkylamino 37. The compound of formula (I) or (II) according to any one of embodiments 31 to 36, selected from the group consisting of: A compound of formula (Ia), or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt of its stereoisomer, or an atropisomer thereof Pharmaceutically acceptable salts.

[0165] Embodiment 39. Formula (Ib * ) compounds [ka] (In the formula, A, C, R B2 , R B3 and R B4 However, as described in any one of the above embodiments, wherein A is unsubstituted or any one of the above embodiments. substituted as described above), 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 However, the present invention is not limited to the above embodiments. wherein a is 0, 1, 2 or 3 (preferably, a is 0, 1, 2 or 3). 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 However, as described in any one of the above embodiments, where: [ka] Lines indicate single or double bonds; R ae as defined above).

[0168] Embodiment 42. Any of the above embodiments, selected from the compound of any one of the Examples. Any one of the compounds, or its stereoisomers, or its atropisomers, or its pharmaceutical compositions a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or an atropisomer thereof Pharmaceutically acceptable salts of the body.

[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-pyrazoline (2-azaspiro[3.3]heptan-2-yl)prop-2-ene-1 -on, a(R)(S)-1-(6-(4-(5-chloro-6-methyl-1H-indazole-4 -yl)-3-(1-(2-(3-fluoropyrrolidin-1-yl)ethyl)-1H-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)propan -2-en-1-on, 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]heptane- 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]heptane- 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 (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-on, a(R) 1-(6-(4-(3-amino-5-chloro-6-methyl-1H-indazole) -4-yl)-3-(2-(2-methoxyethyl)-2H-indazol-5-yl)- 5-Methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2- yl)prop-2-en-1-one and a(R) 1-(6-(4-(3-amino-5-chloro-6-methyl-1H-indazole) -4-yl)-5-methyl-3-phenyl-1H-pyrazol-1-yl)-2-azazol Pyrro[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-pyrazoline {2-azaspiro[3.3]heptan-2-yl}prop-2-ene-1 -on, 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-azazol pyro[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)propionate Pa-2-en-1-on, 1-(6-{(4M)-4-(5-chloro-6-methyl-1H-indazol-4-yl )-3-[2-(2-hydroxy-2-methylpropyl)-2H-indazole-5-yl {5-methyl-1H-pyrazol-1-yl}-2-azaspiro[3.3]heptane -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]heptane -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-pyrazole-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)propa-2 -en-1-on, 1-(6-{(4M)-4-(3-amino-5-chloro-6-methyl-1H-indazole (2-(2-methoxyethyl)-2H-indazol-5-yl)-3-[2-(2-methoxyethyl)-2H-indazol-5-yl] -5-methyl-1H-pyrazol-1-yl}-2-azaspiro[3.3]heptane-2 -yl)prop-2-en-1-one, 1-{6-[(4M)-4-(3-amino-5-chloro-6-methyl-1H-indazole [4-(4-yl)-5-methyl-3-phenyl-1H-pyrazol-1-yl]-2-aza Spiro[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 of

[0172] [Table 1]

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

[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 preceding embodiments for use as a medicament. a compound thereof, 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 an atropisomer thereof Pharmaceutically acceptable salts of the body.

[0177] Embodiment 49. A compound according to any one of the preceding embodiments for use in the treatment of cancer. a compound thereof, 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 an atropisomer thereof Pharmaceutically acceptable salts of the body.

[0178] Embodiment 50. 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 However, as described in any one of the above embodiments, As stated above, 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 However, the present invention is not limited to the above embodiments. As published in R 25 is hydrogen or a nitrogen-protecting group, where a is 0, 1 , 2 or 3 (preferably, a is 0, 1 or 2)), or a pharmaceutically acceptable salt thereof. Acceptable salt.

[0182] Embodiment 54. Formula (2d * ) compounds [ka] (In the formula, C, R ae , R B2 , R N , R B3 and R B4 However, any one of the above embodiments As described in 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 hydrate (modified HA) crystalline form of Compound X, or isopropyl alcohol (IPA) solvate crystalline form, or ethanol (EtOH) solvate crystalline form, or propionyl A crystalline form of Compound X, such as a ethylene glycol solvate crystalline form.

[0184] Embodiment 56. An X-ray powder diffraction spectrum substantially similar to that shown in FIG. 1, FIG. 2, FIG. 3 or FIG. 4. A crystalline form of compound X having the same X-ray powder diffraction spectrum as

[0185] In an embodiment of the present invention, py O, N(pyrrolidin-1-yl, azetidinyl) one or more independently selected from S; Contains two heteroatoms or is an S-oxide (SO) or S-dioxide (SO2 ) group, wherein the heterocycle is unsubstituted or substituted at one carbon atom with oxo, wherein the heterocycle is At the above carbon atoms, C1-C4-alkoxy (preferably methoxy), halo (preferably Preferably, fluoro), C1-C4-alkyl, hydroxy-C1-C4-alkyl, and and fluoro-C1-C4-alkyl; optionally further substituted, wherein a nitrogen atom, if present in said heterocycle, is 10 (Preferred or optionally further substituted with C1-C4 alkyl (such as methyl).

[0186] In an embodiment of the present invention, py 5-membered or or 6-membered heteroaryl rings (preferably 1,2,4-triazol-1-yl or pyrazol-1-yl) azol-1-yl), wherein the heteroaryl ring is unsubstituted or R 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-C and one or more (e.g., one, two, or three) substituents independently selected from 4-alkoxy. substituted, or wherein the heteroaryl ring is unsubstituted or NR 9 R 10 , Independently from halo, C1-C4-alkyl, cyano, OH, and C1-C4-alkoxy substituted with one or more (e.g., 1, 2, or 3) selected substituents, and wherein the heteroaryl ring is substituted with one or more amino groups.

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

[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, for example, unsubstituted or or one or more R A2 Phenyi, which may be substituted with substituents (e.g., 1, 2, or 3 substituents) It is a aryl group.

[0190] When A is phenyl, the substituents on A, if present, are preferably selected from the group consisting of: and in the para position relative to the point of attachment of the phenyl to the pyrazolyl moiety of compound (Ia).

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

[0192] When A is phenyl, R A2 When present, is preferably halo, OH, hydro Oxy-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 Si, -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 one oxygen atom, or one sulfur atom, or one S(=O) or 1 S(=O)2 group, or 1 nitrogen atom and 1 oxygen atom, or 1-2 nitrogen atoms a 4-, 5-, or 6-membered heterocyclic ring containing a ring atom, wherein the heterocyclic ring is unsubstituted or or at the carbon atom, C1-C4-alkyl, hydroxy-C1-C4-alkyl, C independently selected from C1-C4-alkoxy, halo, and fluoro-C1-C4-alkyl; wherein the heterocycle further comprises one or two substituents selected from the group consisting of oxy, oxy, oxy- ... and optionally substituted by cyclohexane, wherein the nitrogen atom, if present in the heterocycle, is a C1-C4-aromatic group. optionally further substituted with rutile; R 9 is selected from hydrogen and C1-C4-alkyl; R 10 is hydrogen, C1-C4-alkyl, hydroxy-C1-C4-alkyl, and C selected from 1-C4-alkoxy-C1-C4-alkyl; R 9a and R 10a together with the nitrogen, 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 4-, 5- or 6-membered (saturated) alkyl groups containing one or two additional heteroatoms selected from the group or unsaturated) heterocyclic ring, wherein the heterocyclic ring is a carbon atom in the heterocyclic ring. and optionally substituted at the heterocycle with oxo, wherein the heterocycle is C1-C4-alkoxy( methoxy), halo(fluoro), C1-C4-alkyl, hydroxy-C1-C4-al and one or two substituents independently selected from fluoro-C1-C4-alkyl, optionally further substituted with a group; or R 9a and R 10a together with the nitrogen, a five-membered or is a 6-membered heteroaryl ring (preferably wherein said heteroaryl ring is 1,2,4- triazol-1-yl and pyrazol-1-yl), wherein the aryl ring is optionally substituted with one or two amino groups; Two R on the phenyl ring A2 If there are substituents, they are preferably of formula (I) and (a) ortho and pa la, or (b) meta and para, or (c) ortho and meta positions.

[0193] Representative R in phenyl A2 Substituents 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-CH3, -C(O)-NH-(CH2-CH 2-OCH3), -C(O)-N(CH3)-(CH2-CH2-OCH3), -C(O )-NH-CH2-C(CH3)2OH, -C(O)-N(CH3)-CH2-C(CH 3)2-OH, -C(O)-N(H)-C(CH3)2-CH2-OCH3, -C(O) -N(H)-CH2-CH2-N(CH3)2, -(CH2) p -Het py The following are mentioned: , where Het py O, N(pyrrolidin-1-yl, azetidin-1-yl, mol folin-1-yl, etc.) and 1 or 2 heteroatoms independently selected from S or a 4-membered, 5-membered alkyl group containing an S-oxide (SO) or S-dioxide (SO2) group. a 1- or 6-membered saturated heterocyclic ring, or Het py contains 1, 2 or 3 nitrogen atoms a 5- or 6-membered heteroaryl ring; wherein the 5- or 6-membered heterocycle is oxo, C1-C4-alkoxy (preferably, methyl hydroxy), halo (preferably fluoro), C1-C4-alkyl, hydroxy-C1- one or more independently selected from C4-alkyl and fluoro-C1-C4-alkyl; or the 5- or 6-membered heterocycle may be a C1-C4-alkoxy group. oxy (preferably methoxy), halo (preferably fluoro), C1-C4-alkyl , hydroxy-C1-C4-alkyl, and fluoro-C1-C4-alkyl. may be further substituted with one or two substituents selected from wherein said 5- or 6-membered heteroaryl ring containing 1, 2 or 3 nitrogen atoms is selected from the group consisting of 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 is C1-C4-alkoxy (preferably methoxy). , halo (preferably fluoro), C1-C4-alkyl, hydroxy-C1-C4-a one, two or three independently selected from alkyl, fluoro-C1-C4-alkyl, and fluoro-C1-C4-alkyl; It may be further substituted with a substituent; 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; can be, Here, p is 0, 1 or 2, and preferably p is 0 or 1.

[0196] In an embodiment of the present invention, A is a ring member independently selected from N, O and S. a 5- to 6-membered heteroaryl ring containing 2 or 3 heteroatoms, The ring may be unsubstituted or may have one or more (e.g., 1, 2, or 3) carbon atoms substituted thereon. TeR A3 and the nitrogen atom, if present in a heteroaryl ring, is unsubstituted or , or C1-C4-alkyl, -(CH2) 1~2 -C 3~4 -cycloalkyl, hydro Oxy-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 and a substituent selected from the group consisting of (Preferably, the substituent is fluoro-C1-C4-alkyl, N(R 9 )( R 10 )-C1~C4-Alkyl, -SO2-C 3~4 -cycloalkyl, or -(CH 2) 1~2 -C 3~4 -cycloalkyl).

[0197] For example, A may be unsubstituted or may contain one or more substituents R A3 Pyridine, which may be substituted with A may be a pyridin-2-yl, pyridin-3-yl or pyridin-4-yl group. Typically, it is 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, is preferably attached to the pyridinyl ring of the compounds of formula (I) and (Ia). It is ranked 2nd or 6th in the

[0199] When there are two substituents on the pyridin-3-yl ring (e.g., fluoro and amino), They are preferably located at the 5-position and the 5-position of the pyridin-3-yl ring of the compounds of formula (I) and (Ia). and is ranked 6th.

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

[0201] When A is pyridin-4-yl, it is preferably C1-C4-alkyl, fluoro and and amino (more preferably, C1-C4-alkyl) in A The Two R's A3 Substituents, when present, are preferably present in the compounds of formula (I) and (Ia). It is at positions 2 and 6 on the lysinyl ring.

[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)-(CH 2-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 py However, O, N(pyrrolidine-1 -yl, azetidin-1-yl, morpholin-1-yl, etc.) and S or S-oxide (SO) or S-dioxide (SO). a 4-, 5-, or 6-membered saturated heterocyclic ring containing an oxide (SO2) group, wherein the heterocyclic ring is C1-C4-alkoxy (preferably methoxy), halo (preferably fluoro) , C1-C4-alkyl, hydroxy-C1-C4-alkyl, fluoro-C1-C4- Independently from alkyl, and -C(O)-N(CH3)-(CH2-CH2-OCH3) may be further substituted with one, two or three selected substituents; or Het py is a 5- or 6-membered heteroaryl containing 1, 2 or 3 nitrogen atoms; wherein the heteroaryl ring is a C1-C4-alkoxy(methoxy), Halo(fluoro), C1-C4-alkyl, hydroxy-C1-C4-alkyl, and fluoro further comprising one, two or three substituents independently selected from fluoro-C1-C4-alkyl; It can be substituted.

[0203] For example, R A3A 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 is where A is pyridinyl, e.g., pyridin-3-yl. If yes, [ka] may be selected from In the formula, R 21 is hydrogen or C1-C4-alkyl (preferably methyl), or amino; can be, 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 A is Pi When the ring is a lysinyl ring, 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, [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 22is 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 Place A pyrimidin-3-yl group or a pyrimidin-5-yl group which can be substituted with a pyrimidinyl group. Representative substituents in 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 1 0 C1~C4-Alkyl, -SO2-C1~C4-Alkyl, -SO2-C 3~4 -Sik alkyl or -(CH2) 1~2 -C 3~4 -cycloalkyl; or R 24 but, Hydrogen, C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy Oxy-C1~C4-alkyl, amino-C1~C4-alkyl, C1~C4-alkyla Amino-C1~C4-alkyl, di-C1~C4-alkylamino-C1~C4-alkyl , -SO2-C1~C4-alkyl, -SO2-C 3~4 -cycloalkyl or -(CH 2) 1~2 -C 3~4 -cycloalkyl; R4a , R 4b , R 4c and R 4d each independently represents hydrogen and C1-C4 alkyl alkyl (preferably methyl).

[0208] R 24 However, preferably, di-C1-C4-alkylamino-C1-C4-alkyl (e.g. For example, -CH2-CH2-N(CH3)2) or -SO2-C 3~4 -cycloalkyl( For example, -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 4 c 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 independently selected from: (i) nitrogen, oxygen, and sulfur. 1 to 3 heteroatoms (e.g., 0 to 3 nitrogen atoms, 0 to 1 oxygen atoms, and 0 to 1 8-10 membered heterocyclic group containing 1-3 heteroatoms independently selected from 1 to 3 sulfur atoms an aryl ring, or (ii) A heterobicyclic ring having 0 to 3 nitrogen atoms, 0 to 2 oxygen atoms, and 0 to 1 sulfur atom. and 0 to 1 S(=O)2 groups. 8-10 membered partially saturated heterobicyclic ring containing a b atom group, The heterobicyclic ring is unsubstituted or has 1, 2, 3, 4 or 5 carbon atoms. R A4 and the heterobicyclic ring is further optionally substituted at a carbon atom with oxo. , the nitrogen atom, if present, is unsubstituted or -(CO)-C1-C4-alkyl or a C1-C4-alkyl group, wherein the C1-C4-alkyl group is Cyano, hydroxy, oxo, fluoro, C1-C4-alkoxy, C1-C4-alkoxy Oxy-C1~C4-alkyl-oxy, Het b and NR 9 R 10 are selected independently from and optionally substituted with one or two substituents selected from the group consisting of: a heteroaryl ring and a heterobicyclic ring, optionally substituted with one or two substituents selected from the group consisting of:

[0212] In an embodiment of the present invention, A is 1 to 3 independently selected from nitrogen, oxygen and sulfur. A is an 8- to 10-membered heteroaryl ring containing 0 to 3 heteroatoms. 1 to 1 independently selected from nitrogen atoms, 0 to 1 oxygen atoms, and 0 to 1 sulfur atoms It is an 8-10 membered heteroaryl containing 3 heteroatoms. The heteroaryl ring is a non- substituted or having 1, 2, 3, 4 or 5 R at a carbon atom A4 is substituted with nitrogen The atom, if present, is unsubstituted or is -(CO)-C1-C4-alkyl or substituted with a C1-C4-alkyl substituent, wherein the C1-C4-alkyl is cyano, Hydroxy, oxo, fluoro, C1-C4-alkoxy, C1-C4-alkoxy-C 1~C4-Alkyl-oxy, Het b and NR 9 R 10or It is optionally substituted with two substituents.

[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 present invention, A is an 8-10 alkyl group containing 1, 2 or 3 nitrogen atoms. 0 to 3 nitrogen atoms, 0 to 2 oxygen atoms in the membered heteroaryl ring or heterobicyclic ring, 1 to 3 groups independently selected from 0 to 1 sulfur atoms and 0 to 1 S(=O)2 groups an 8- to 10-membered partially saturated heterobicyclic ring containing a heteroatom or heteroatom group, The heteroaryl or heterobicyclic ring is unsubstituted or has 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 39 3, 4 or 5 R's A4 and the heterobicyclic ring is further substituted at a carbon atom with oxy. and the nitrogen atom, if present, is unsubstituted or —(CO)—C substituted with a substituent which is C1-C4-alkyl or C1-C4-alkyl, C4-alkyl is cyano, hydroxy, oxo, fluoro, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Het b and NR 9 R 10 mosquito is optionally substituted with one or two substituents independently selected from:

[0215] In an embodiment of the present invention, A is an 8-10 alkyl group containing 1, 2 or 3 nitrogen atoms. 1 to 3 nitrogen atoms or 1 to 2 oxygen atoms in a membered heteroaryl ring or heterobicyclic ring or an 8-10 membered partially saturated heterobicyclic ring containing one sulfur atom or one S(=O)2 group ring, wherein the heteroaryl ring or heterobicyclic ring is unsubstituted or has a carbon atom 1, 2, 3, 4 or 5 R A4 and the heterobicyclic ring is further substituted with a carbon atom. optionally substituted at the nitrogen atom with oxo, and the nitrogen atom, if present, is unsubstituted, or -(CO)-C1-C4-alkyl or C1-C4-alkyl wherein the C1-C4 alkyl is 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 is an 8- to 10-membered heteroaryl ring as described above or When present in an 8- to 10-membered partially saturated heterobicyclic ring, it is unsubstituted or hydroxy, oxo, fluoro, C1-C4-alkoxy, C1-C4-alkoxy-C1 ~C4-Alkyl-oxy, Het b and NR 9 R 10 1 or more independently selected from is substituted with C1-C4-alkyl optionally substituted with two substituents.

[0217] In an embodiment of the present invention, b are independently selected from N, O, S, SO and SO2 and 1 or 2 heteroatoms or groups selected from the group consisting of 1 oxygen atom, 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 4-, 5-, or 6-membered heterocyclic ring containing one atom and one oxygen atom, or one or two nitrogen atoms or a heteroaryl ring, wherein the heterocyclic ring Het b is unsubstituted or In the element atom, 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 -one or two substituents independently selected from alkyl (preferably C1 to C4 -Alkyl, hydroxy, cyano, fluoro, C1-C4-alkoxy-hydroxy-C 1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy, and and fluoro-C1-C4-alkyl), wherein the heterocycle H et b is further optionally substituted at a carbon atom with oxo, wherein the nitrogen atom is H et b optionally further substituted with C1-C4-alkyl, if present in 4-alkyl is independently selected from fluoro, hydroxy and C1-C4-alkoxy; It is optionally substituted with 1 to 3 substituents.

[0218] In an embodiment of the present invention, b Azetidin-1-yl, pyrrolidin-1-yl fluoro, hydroxy and C1-C4-alkoxy (e.g., methyl, hydroxy-methyl, methoxy and fluoro) is optionally replaced by

[0219] In an embodiment of the present invention, A is an 8-10 alkyl group containing 1, 2 or 3 nitrogen atoms. 0 to 3 nitrogen atoms, 0 to 2 oxygen atoms in the membered heteroaryl ring or heterobicyclic ring, 1 to 3 groups independently selected from 0 to 1 sulfur atoms and 0 to 1 S(=O)2 groups an 8-10 membered partially saturated heterobicyclic ring containing a heteroatom or heteroatom group, wherein: If A contains nitrogen, the nitrogen may be ae or R Ae is replaced by

[0220] In an embodiment of the present invention, A is an 8-10 alkyl group containing 1, 2 or 3 nitrogen atoms. 1 to 3 nitrogen atoms or 1 to 2 oxygen atoms in a membered heteroaryl ring or heterobicyclic ring or 8-10 membered partially saturated heterodimer containing 1 sulfur atom or 0-1 S(=O)2 groups cyclic ring, where if A contains nitrogen, the nitrogen is ae or R Ae Replace with will be done.

[0221] In an embodiment of the present invention, A is an 8-10 alkyl group containing 1, 2 or 3 nitrogen atoms. a membered heteroaryl ring, wherein at least one of the nitrogen atoms is R ae or R Ae in will be replaced.

[0222] In an embodiment of the present invention, A is an 8-10 alkyl group containing 1, 2 or 3 nitrogen atoms. a membered heteroaryl ring, wherein 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 hydrogen, -(CO)-C1-C4-alkyl and C1-C4 alkyl, wherein C1-C4 alkyl is selected from the group consisting of In this case, cyano, hydroxy, fluoro, C1-C4-alkoxy, C1-C4-alkanol Koxy-C1~C4-alkyl-oxy, Het b and NR 9 R 10 Select one or is optionally substituted with two substituents.

[0224] In an embodiment of the present invention, R Ae is hydrogen, fluoro-C1-C4-alkyl and C It is selected from the group consisting of 1-C4-alkyl (eg methyl).

[0225] In an embodiment of the present invention, R ae is selected from the group consisting of hydrogen and C1-C4-alkyl wherein the alkyl is selected from cyano, hydroxy, fluoro, C1-C4-al Koxy, 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- O-C1~C4 -Alkyl, hydroxy-C1-C4-alkyl, -(CH2)2-O-(CH2)2- O-C1-C4-alkyl and -(CH2)2-diC1-C4-alkylamino selected from the group (e.g., Het b Azetidin-1-yl, pyrrolidin-1-yl, pyrrolidin-3-yl and morpholin-1-yl), preferably For more information, see R ae is selected from the group consisting of hydrogen, C1-C4-alkyl and -CH2-CN Preferably, R ae is selected from the group consisting of hydrogen and C1-C4-alkyl do.

[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 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 , 1 or 2 R A4 ) where the nitrogen in the NH moiety in the above structure The atom is also NR ae where R ae But cyano, hydroxy, oxo , fluoro, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl -Oxy, Het b and NR 9 R 10 and optionally one or two substituents independently selected from Preferably, R ae However, hydrogen or methyl etc. is a C1-C4 alkyl.

[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 , or 1, 2, 3, 4 or 5 R A4 (Preferably, one or two R A4 )in where R ae is hydrogen, or cyano, hydroxy, oxo, fluoro, C1 ~C4-alkoxy, C1~C4-alkoxy-C1~C4-alkyl-oxy, Het b and NR 9 R 10 C1 optionally substituted with 1 or 2 substituents independently selected from 1 to C4-alkyl. Preferably, R aeis hydrogen or C1-C4 alkyl such as methyl It's Rukiru.

[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 , 1 or 2 R A4 ) where the nitrogen in the NH moiety in the above structure The atom is also NR Ae or NR ae where R Ae But hydrogen, -(C O) is selected from the group consisting of -C1-C4-alkyl and C1-C4-alkyl, , 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 but, Cyano, hydroxy, oxo, fluoro, C1-C4-alkoxy, C1-C4-alkoxy Oxy-C1~C4-alkyl-oxy, Het b and NR 9 R 10 are selected independently from Preferably, the alkyl is C1-C4 optionally substituted with one or two substituents. Preferably, R ae is hydrogen or C1-C4 alkyl such as methyl. R ae is 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 , 1 or 2 R A4 ), where R Ae But hydrogen, -(CO)-C1~ Selected from the group consisting of C4-alkyl and C1-C4-alkyl, Alkyl, in each case, is 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 But, cyano, hyd oxy, oxo, fluoro, C1-C4-alkoxy, C1-C4-alkoxy-C1- C4-Alkyl-oxy, Het b and NR 9 R 10 One or two independently selected from Preferably, R ae But hydrogen or C1-C4 alkyl such as methyl. Preferably, R ae is hydrogen or methyl and the like are C1 to C4 alkyls.

[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 1, 2, 3, 4 or 5 R's A4 (Preferably, one or two R A4 ), where the nitrogen atom in the NH moiety in the above structure is also NR ae or NR Ae in may be substituted, where R Ae is hydrogen, -(CO)-C1-C4-alkyl and C1-C 4-alkyl, wherein C1-C4 alkyl is selected from the group consisting of , cyano, hydroxy, fluoro, C1-C4-alkoxy, C1-C4-alkoxy- C1-C4-Alkyl-oxy, Het b and NR 9 R 10 one or more independently selected from is optionally substituted with two substituents, and R ae However, cyano, hydroxy, oxo, fluoro, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, H et b and NR 9 R 10 and optionally substituted with one or two substituents independently selected from C1-C4 alkyl. Preferably, R ae However, hydrogen or methyl etc. Preferably, R ae is hydrogen or C1-C such as methyl As used herein and further in connection with the substituent B, "C 6~10The term "aryl" refers to a phenyl or naphthyl group, where phenyl or naphthyl is unsubstituted or has 1, 2, 3 or 4 (preferably 1 or 2) substituted groups. R Ba is replaced by

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

[0238] In an embodiment of the invention, B is 3-hydroxy-phenyl or 3-hydroxy-naphthalene. and n is 0, 1, 2, or 3 halo (preferably 1, 2, or 3). In a further embodiment of the invention, B is substituted with [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) be; R B2 are independently hydrogen, halo (preferably chloro), C1-C4 alkyl (preferably Preferably, selected from methyl, cyclopropyl and NH; R B3are independently hydrogen, halo (preferably chloro), cyclopropyl and C1- C4-alkyl (preferably methyl); R B4 are independently hydrogen, halo (preferably chloro or fluoro) and C1-C4 - alkyl (preferably methyl) or R B3 and R B4 But those is bonded to an aromatic ring containing X, and together with the atom to which it is bonded, a 4- to 6-membered ring (preferably Forms a 5- to 6-membered saturated or partially unsaturated carbocyclic ring); R B5 are independently selected from hydrogen, halo (preferably chloro) and C1-C4-alkyl ( Preferably, it is selected from 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 hydrogen, halo (preferably chloro) and C to C4-alkyl (preferably methyl), or R B3 and R B4 but, 4-6 membered rings (preferably fused together with the atoms to which they are attached) fused to the aromatic ring containing X It forms a 5- or 6-membered saturated or partially unsaturated carbocyclic ring).

[0241] R B5 are independently selected from hydrogen, halo (preferably chloro) and C1-C4-alkyl ( Preferably, it is selected from 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 hydrogen, halo (preferably fluoro or chloro). more preferably chloro) and C1-C4-alkyl (preferably methyl). Selected, R B5 are independently selected from hydrogen, halo (preferably chloro) and C1-C4-alkyl ( Preferably, it is selected from 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 hydrogen, halo (preferably chloro) and C to C4-alkyl (preferably methyl).

[0244] R B5 are independently selected from hydrogen, halo (preferably chloro) and C1-C4-alkyl ( Preferably, it is selected from 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 B1is hydrogen or C1-C4-alkyl (e.g., methyl).

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

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

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

[0250] The present invention provides compounds of formula (I) and (Ia), wherein R B1 But independently, hydrogen and C1-C4-alkyl, R B2 is amino and R B3 is halo (preferably chloro), and R B4 Gametchi 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 B 4 is hydrogen, X is CH, In an embodiment of the present invention, R B2 is amino and R B3 and R B4Both are 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 but , independently halo (preferably chloro) and C1-C4-alkyl (preferably methyl R B4 is halo (preferably chloro).

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

[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-pyrazoline (2-azaspiro[3.3]heptan-2-yl)prop-2-ene-1 -on (Example 1a), [ka] ; a(R)(S)-1-(6-(4-(5-chloro-6-methyl-1H-indazole-4 -yl)-3-(1-(2-(3-fluoropyrrolidin-1-yl)ethyl)-1H-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)propan -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]heptane- 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]heptane- 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 (actual 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- Ene-1-one (Example 60a), [ka] ; a(R) 1-(6-(4-(3-amino-5-chloro-6-methyl-1H-indazole) -4-yl)-3-(2-(2-methoxyethyl)-2H-indazol-5-yl)- 5-Methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2- (yl)prop-2-en-1-one (Example 69a), [ka] and a(R) 1-(6-(4-(3-amino-5-chloro-6-methyl-1H-indazole) -4-yl)-5-methyl-3-phenyl-1H-pyrazol-1-yl)-2-azazol Pyrro[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 choice of starting materials and procedures, the compounds may be in the form of one of the possible isomers; as mixtures, e.g. as pure enantiomers, or as racemates and phenanthrene depending on the number of asymmetric centers The present invention relates to isomers, such as racemic mixtures, diastereomeric mixtures, and the like. including enantiomerically enriched mixtures, diastereomeric mixtures and optically pure forms. All such possible isomers are intended to be included. Optically active (R)- and (S)- Isomers may be prepared using chiral synthons or chiral reagents, or may be prepared using conventional techniques. If the compound contains a di- or tri-substituted cycloalkyl, the cycloalkyl may be The alkyl substituents may have a cis- or trans-configuration. The present invention relates to substituted cycloalkyl groups. All tautomers are also included, including cis and trans configurations and mixtures thereof. In particular, the heteroaryl ring containing N as a ring atom is a 2-pyridone. For example, the carbonyl may be shown as a hydroxy (e.g., 2-hydroxypyridine). This includes tautomers that are

[0258] As used herein, the term "salt" or "salts" The term refers to acid addition or base addition salts of the compounds of the present invention. The term "pharmaceutically acceptable salts" typically refers to salts that are biologically or refers to salts that retain the biological effectiveness and properties of the compounds of this invention, which are not otherwise undesirable. In many cases, the compounds of the present invention will have the advantage that they contain amino and / or carboxyl groups or groups similar thereto. Depending on the presence of the compound, acid and / or base salts can be formed.

[0259] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Examples of inorganic acids that can be used include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, citric acid, and the like. Oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, Andric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicyl acid, trifluoroacetic acid, and the like.

[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 salts of I to XII of the periodic table. In certain embodiments, the salts include metals from the sodium, potassium, ammonium, Particularly preferred salts are derived from ammonium, calcium, magnesium, iron, silver, zinc, and copper. Examples include ammonium, potassium, sodium, calcium and magnesium salts. can be done.

[0262] Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, ammonium salts, and the like. Examples of suitable amines include naturally occurring substituted amines, cyclic amines, and basic ion exchange resins. Specific organic amines include isopropylamine, benzathine, and cholinate. inate), diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.

[0263] In another aspect, the present invention provides a method for producing a compound comprising the steps of: Phosphate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / Sulfate, camphorsulfonate, caprate, chloride / hydrochloride, chlorotheophylline nate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate Salt, glucuronate, glutamate, glutarate, glycolate, hippurate, iodide Hydrogen chloride / iodide, isethionate, lactate, lactobionate, lauryl sulfate, Malate, maleate, malonate, mandelate, mesylate, methyl sulfate, Salt, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate Inosinate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / diphosphate Hydrogen salt, polygalacturonate, propionate, sebacate, stearate, succinate Salt, sulfosalicylate, sulfate, tartrate, tosylate, trifenatate, tri The compounds are provided in fluoroacetate or xinafoate salt form.

[0264] Pharmaceutically acceptable salts are preferred.

[0265] Any formula given herein also represents unlabeled forms as well as isotopically labeled forms of the compounds. It is intended that isotopically labeled compounds are compounds in which one or more atoms have a selected atomic mass or molecular weight. The structures shown by the formulas shown herein are substituted with atoms having the desired number of atoms. Examples of isotopes that can be incorporated into compounds of the invention include hydrogen, carbon, nitrogen, Isotopes of 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 the use of , various isotopically labeled compounds as defined herein, e.g., 3 H and 14 C, etc. radioactive isotopes present in it, or 3 H and14 Non-radioactive isotopes such as C are present in Such isotope-labeled compounds may be used in metabolic studies ( 14 C), reaction rate Tests (e.g. 2 H and 13 C), detection or imaging assays, including drug or substrate tissue distribution assays Imaging techniques (Positron Emission Tomography (PET) or Single Photon Emission Tomography) In particular, they are useful in radiotherapy of patients. 18 F compounds may be particularly desirable for PET or SPECT studies. The labeled compounds may be prepared by conventional techniques known to those skilled in the art or by using previously used unlabeled reagents. Instead, suitable isotopically labeled reagents may be used in a manner similar to that described in the accompanying examples. It can be prepared generally by the method.

[0266] Additionally, heavier isotopes, particularly deuterium (i.e., 2 Substitution by H or D) is more High metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements or therapeutic index Deuterium in this context may provide certain therapeutic benefits resulting from the improvement of the formula (I It is understood that such heavier isotopes, particularly The concentration of deuterium can be defined by the isotopic enrichment factor. 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 present invention is indicated to be deuterium, this Such compounds have an isotopic enrichment factor (Eq. 1) for each designated deuterium atom of at least 3500. 52.5% deuterium incorporation at the designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5 000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation) ), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium uptake), at least 6466.7 (97% deuterium uptake), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) It has a basic uptake.

[0267] The present invention also relates to compounds of any of the described embodiments, wherein one or more substituents One or more hydrogen atoms in the substituent are replaced with deuterium, e.g., one or more alkyl substituents All hydrogen atoms in the molecule are replaced with deuterium atoms (then one or more portions of each molecule are replaced with deuterium atoms). (It will be converted into

[0268] In an embodiment of the present invention, in particular, C1-C3-alkyl (or methyl) is When present as a substituent C in a compound, and / or C1-C3-alkyl (or methyl) ) is present as a substituent on A and / or B, A or B is indazolyl When it is a ring, the C1-C3-alkyl (or methyl) can be deuterated or perdeuterated. do.

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

[0271] The isopropyl alcohol (IPA) solvate of Compound X is dissolved at a temperature of about 25° C. and 1.5 The group consisting of 7.5°, 12.5°, and 17.6°, measured at an X-ray wavelength, λ, of 418 Å At least one having a refraction angle 2θ value (CuKα λ=1.5418 Å) selected from characterized by an X-ray powder diffraction pattern (XRPD) containing one, two, or three peaks. The isopropyl alcohol solvate of Compound X can be obtained at a temperature of about 25° C. and a viscosity of 1.541 μg / cm 2 . Measured at an X-ray wavelength, λ, of 8 Å, the angles are 7.5°, 12.5°, 15.5°, 16.4°, and 1 Refraction angle 2θ value (CuKα) selected from the group consisting of 7.6°, 21.4°, and 24.4° At least one, two, three, or four or more having a wavelength of λ=1.5418 Å or can be characterized by an X-ray powder diffraction pattern (XRPD) that includes all peaks. .

[0272] The ethanol (EtOH) solvate of Compound X has a temperature of about 25°C and a viscosity of 1.5418 Å. Measured in X-ray wavelength, λ, the angles are 7.9°, 12.7°, 18.2°, and 23.1°. At least one having a refraction angle 2θ value (CuKα λ=1.5418 Å) selected from the group by an X-ray powder diffraction pattern (XRPD) containing one, two, three or four peaks The ethanol solvate of Compound X can be characterized at a temperature of about 25° C. and a viscosity of 1.5418 Measured at X-ray wavelengths, λ, of 7.9°, 12.7°, 13.1°, 15.5°, and 15 Å 0.9°, 16.9°, 18.2°, 18.6°, and 23.1° At least one, two, or three refracting angles 2θ (CuKα λ=1.5418Å) or an X-ray powder diffraction pattern (XRPD) including four or more or all of the peaks. It can be characterized by:

[0273] The propylene glycol solvate of compound X has a temperature of about 25° C. and an X The group consisting of 7.3°, 13.2°, 18.0°, and 22.5°, measured in linear wavelength, λ At least one having a refraction angle 2θ value (CuKα λ=1.5418 Å) selected from characterized by an X-ray powder diffraction pattern (XRPD) containing two, three, or four peaks. The propylene glycol solvate of Compound X can be characterized as follows: Measured at an X-ray wavelength of 5418 Å, λ, 7.3°, 13.2°, 15.6°, 16.2 18.0°, 22.5°, 22.8°, 23.2°, and 25.1° At least one or two specimens with the selected refraction angle 2θ value (CuKα λ=1.5418Å) , three or four or more, or all peaks in the X-ray powder diffraction pattern (XR PD).

[0274] As used herein, the term "pharmaceutically acceptable carrier" means a compound that is As is known (e.g., Remington's Pharmaceuticals Sciences,18th Ed.Mack Printing Company,1 990, pp. 1289-1329) All solvents, dispersion media, coatings, and surface active agents Antioxidants, antioxidants, preservatives (e.g., antibacterial, antifungal), isotonic agents, absorption delaying agents, salts, preservatives Preservatives, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavoring agents, dyes, etc. Any conventional carrier may be used to combine the active ingredient with the Unless incompatible, their use in therapeutic or pharmaceutical compositions is contemplated.

[0275] The term "therapeutically effective amount" of a compound of the present invention refers to a therapeutically effective amount of a compound that is effective to treat a biological or medical response in a subject, e.g., For example, they may cause a decrease or inhibition of enzyme or protein activity, or improve symptoms and reduce the pathology. The present invention provides a method for treating a variety of conditions, such as alleviating the symptoms of atopic dermatitis, slowing or delaying disease progression, or preventing disease. In one non-limiting embodiment, the term "therapeutically effective amount" refers to an amount of a compound When administered to animals, (1) KRAS, HRAS, or NRAS G12C mutations and at least partially alleviating or inhibiting a pathological condition, such as cancer, or a disorder or disease caused by the "Amount of compound of the present invention effective to prevent, prevent, and / or ameliorate" refers to the amount of compound of the present invention effective to prevent, prevent, and / or ameliorate

[0276] In another non-limiting embodiment, the term "therapeutically effective amount" refers to a therapeutically effective amount of a cell, tissue, or When administered to a non-cellular biomaterial or culture medium, KRAS, HRAS, or NRAS G1 2C mutant protein. "effective" refers to an amount of a compound of the present invention that is effective.

[0277] As used herein, the term "subject" refers to an animal. Typically, an animal The subject is also a mammal, e.g., a primate (e.g., a human, male or female), a rabbit, a guinea pig ... This refers to animals such as sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, and birds. In certain embodiments, the subject is a primate. is a human.

[0278] As used herein, the terms "inhibit," "inhibition," or "inhibiting" The term refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or the improvement or suppression of a biological A significant decrease in baseline activity of a biological activity or process.

[0279] As used herein, any disease or disorder can be "treated" or "treated" in any manner. The term "treatment" or "treatment" refers, in one embodiment, to ameliorating a disease or disorder (i.e., i.e., slowing or halting the onset of the disease or at least one of its clinical symptoms In another embodiment, "treat," "treating," or "Treatment" refers to the process of changing at least one physical parameter, including those not perceptible by the patient. In yet another embodiment, "treat" or "treat" refers to reducing or improving "Treatment" or "treatment" means the physical alleviation (e.g., stabilization of discernible symptoms) of a disease or disorder. , physiologically (e.g., stabilizing physical parameters), or both. In yet another embodiment, "treat," "treating," or "treatment" refers to " refers to preventing or delaying the onset or development or progression of a disease or disorder.

[0280] As used herein, a subject is defined as a person who has not yet recovered from such treatment. A person "needs" treatment if they would benefit psychologically, medically, or in quality of life. .

[0281] As used herein, the terms "a," "an," "the," and "the" refer to the present invention. Similar terms used in this context (especially in the context of the claims) are intended to be used in the present invention. Unless otherwise indicated in the specification or clearly contradicted by the context, both the singular and the plural are used. should be interpreted as inclusive.

[0282] All methods described herein are intended to be illustrative unless otherwise indicated herein or otherwise clear from the context. The steps may be performed in any suitable order unless otherwise inconsistent with the use of any example or the specification. The exemplary language shown (e.g., "etc.") is intended to further clarify the invention. It is intended merely to pose a limitation on the scope of the invention as otherwise claimed.

[0283] Any asymmetric centers of the compounds of the present invention may be present as a racemic mixture or a mixture of enantiomers or enantiomers. In certain embodiments, for example, mixtures of enantiomers may exist. As such, each asymmetric center has an enantiomeric excess of at least 10%, an enantiomeric excess of 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 enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess. In embodiments, for example, in enantiomerically enriched forms, each asymmetric center is at least 50% an enantiomeric excess of at least 60%, an enantiomeric excess of at least 70%, At least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% or an enantiomeric excess of at least 99%.

[0284] Thus, as used herein, the compounds of the present invention are intended to encompass all possible isomers, enantiomers, isomers, atropisomers, diastereoisomers, tautomers or mixtures thereof One form, e.g., substantially pure, diastereoisomers, optical isomers (enantiomers) , racemic or mixtures thereof.

[0285] Any resulting mixture of isomers can be purified, for example, by chromatography and / or fractional crystallization. Therefore, pure or substantially pure optical isomers, diastereoisomers, etc., based on the physicochemical differences of the components They can be separated into stereoisomers, atropisomers and racemates.

[0286] Any resulting racemates of the final product or intermediates may be purified by known methods, e.g., photocatalysis. Separation of the diastereomeric salts obtained with optically active acids or bases, and separation of the diastereomeric salts obtained with optically active acids or bases can be resolved into their optical antipodes by liberating the basic compound. In addition, the basic moiety may be, for example, an optically active acid, such as tartaric acid, dibenzoyltartaric acid, diacetone, or the like. Toluoyltartaric acid, di-O,O'-p-toluoyltartaric acid, mandelic acid, malic acid or camphor The compounds of the present invention can be obtained by fractional crystallization of the salts formed with 1,4-dihydro-1,4-trimethyl-2,4-trimethyl ... The racemic products can also be resolved into their optical antipodes using chiral adsorbents. and by chiral chromatography, e.g., high performance liquid chromatography (HPLC). It can be divided into

[0287] Typically, compounds of formula (I) can be prepared according to the scheme shown below. The examples outlining specific synthetic routes and the general schemes below will be readily apparent to those skilled in the art of synthetic chemistry. The guidelines provide a framework for synthetic chemistry to allow one skilled in the art to determine the solvents, concentrations, reagents, protecting groups, order of synthetic steps, duration, It will be readily apparent that temperatures, etc. may be adjusted as needed.

[0288] The schemes shown below show the single diastereomers / enantiomers as well as their isomers. The separation of diastereomers / enantiomers is not intended to be construed as limiting the scope of the present invention. Unless otherwise specified, the general method described below can be used. In the scheme, the substituents Z, X1, X2, Ar 1 and Ar 2 is defined in this specification. In the following general scheme, Ar 1 is a compound of formula (I) corresponds to the substituent A defined for Ar 2 is defined for compounds of formula (I) In particular, the substituents C and R 2 , R 3 , R 4 and R 5 However, as used herein and in particular as defined in the claims. Amine protecting groups (as used herein in the context of nitrogen The protecting group (also called a protecting group) is referred to as "PG" in the following schemes. In the formula (Iy), the compound of formula (Iy) is a compound of formula RC(O)-X, and the compound of formula (Ie) is a compound of formula (Ie) The RC(O) substituent attached to the nitrogen atom of the spiro linker in the compound is resolved accordingly. In the following scheme, Ar 1 where appropriate, compounds of formula (I) corresponds to the substituent A of the compound, 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 prepared as shown in Scheme-1. The appropriate di-halogenated heteroaromatic ring (1) can be synthesized as outlined in K3. 1,4-dioxane (or toluene) with a base such as PO4 (or Na2CO3) In the presence of palladium catalysts such as RuPhos-Pd-G3 / RuPhos in solvents such as In Suzuki (or Stille) type cross-coupling reactions, boronic acids / esters Any aryl or heteroaryl (Ar 2 ) reacts with a coupling partner to form compound (2 In step B, the substituent Ar 1 is dissolved in toluene with a base such as K3PO4. In solvents such as benzene, palladium catalysts such as RuPhos-Pd-G3 / RuPhos In the presence of a suitably functionalized aryl or heteroaryl system, such as an arylboronic acid is introduced by a palladium cross-coupling reaction 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) can be removed by trifluoromethane in a solvent such as dichloromethane. using an organic acid such as acetic acid or a mineral acid such as sulfuric acid in a solvent such as 1,4-dioxane This is removed using conditions known in the art to give compound (4). Ar 2 is a protecting group that is removed in the same reaction under the conditions described above to cleave the Boc group. In step D, compound (5) may also contain a suitable base (e.g., THP). In the presence of a hydroxyl group such as a hydroxyl group, compound (4) is reacted with a compound of formula (Iy) (wherein X is an ion-removing group, or when X is OH, and the reaction is carried out under standard amide bond forming conditions (e.g., amide capping such as HATU). In the presence of a coupling reagent and a suitable base such as DIPEA, for example, The amide is reacted with a coupling agent such as propylphosphonic anhydride in a solvent such as methylene chloride. Compound (4) is treated with acrylic acid in the presence of a blocking agent and a base such as Hunig's base. Alternatively, compound (4) can be introduced by a method such as THF. In any solvent, in the presence of a base such as aqueous sodium bicarbonate, acryloyl chloride is used. In step E, the mixture of atropisomers can be purified using a suitable column and eluent. and are separated using SFC or HPLC conditions.

[0290] Compounds (1), (2), (3) and (4) shown in Scheme 1 and described above can be prepared by the following reaction: It is a useful intermediate for preparing compounds of formula (Ie). [ka] Scheme-2 Synthesis: Scheme-2 illustrates the preparation of compounds of formula (Ie) disclosed herein. With a base such as K3PO4 (or Na2CO3), In a solvent such as 1,4-dioxane (or toluene), RuPhos-Pd-G3 / R In the presence of a palladium catalyst such as uPhos, a halogenated heteroaromatic compound (1) is reacted with a borohydride (2). Suzuki reactions with aryl or heteroaryl coupling partners such as carboxylic acids / esters After the cross-coupling reaction, compound (2) can be reacted with a solvent such as THF or CH3CN to Treated with a halogenating agent such as N-iodosuccinimide or N-bromosuccinimide In step C, the substituent Ar 2 is formed by the reaction of 1,4-dioxo- In solvents such as ethanol, palladium catalysts such as RuPhos-Pd-G3 / RuPhos In the presence of a suitably functionalized aryl or heteroaryl system, such as an arylboronic acid The ester is introduced by a palladium-catalyzed coupling reaction to give compound (4). The remaining steps D to F are the same as steps C to E in the above scheme 1.

[0291] Compounds (1), (2), (3), (4) and (5) shown in Scheme 2 and described above can be prepared by the following steps: 5) is a useful intermediate for preparing compounds of formula (Ie). [ka] Scheme-3 Synthesis: Scheme-3 illustrates the preparation of compounds of formula (Ie) disclosed herein. The halogenated heteroaromatic compounds (1) can be reacted with potassium acetate or other suitable catalysts to form the heteroaromatic compounds (1). With any base, in a solvent such as 1,4-dioxane, PdCl2(dppf).CH In the presence of a palladium catalyst such as the bis(pinacolato)-diboron adduct, In step B, the heterocyclic aromatic boronic acid ester (2) is converted to the heterocyclic aromatic boronic acid ester (3). r 1 is prepared by reacting RuPhos-Pd with a base such as K3PO4 in a solvent such as toluene. -G3 / In the presence of a palladium catalyst such as RuPhos, a suitably functionalized aryl or uses heteroaryl systems, e.g., heteroaryl halides, to couple palladium The remaining steps C to G are carried out in the same manner as above. This is the same as steps B to F in M-2.

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

[0293] [ka] Scheme 5 Synthesis: Scheme 5 shows the synthesis of halogenated heteroaromatic compounds of formula (I). The present invention provides an alternative method for the preparation of 3-iodo-5-methyl-1H-pyrazole and the like. Suitable halogenated heteroaromatic compounds (1) can be prepared by the addition of cesium carbonate or other suitable cations in a solvent such as DMF. In the presence of a base, a suitably functionalized N-protected alkylation with a linker to give a halogenated heteroaromatic compound of formula (I) do.

[0294] In another aspect, the present invention provides a method for treating a rheumatoid arthritis, comprising administering to a subject a compound of the present invention, or a pharmaceutically acceptable salt thereof, in a patient receiving the treatment of a rheumatoid arthritis. and a physiologically acceptable carrier. The article comprises at least two pharmaceutically acceptable carriers, such as those described herein. For purposes of this invention, unless otherwise indicated, solvates and hydrates are generally considered compositions. Preferably, the pharmaceutically acceptable carrier is sterile. The pharmaceutical composition is administered orally. The compositions may be formulated for specific routes of administration, such as oral, parenteral, and rectal administration. The pharmaceutical compositions of the present invention may be in solid form (including but not limited to capsules, tablets, pills, granules, etc.). , powder or suppository), or in 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 adjuvants, such as preservatives, stabilizers, Wetting agents, emulsifying agents, buffers, and the like may also be present.

[0295] Typically, the pharmaceutical composition is a tablet or gel containing the active ingredient together with one or more of the following: Latin capsules: a) diluents, such as lactose, dextrose, sucrose, mannitol, sol Vitol, cellulose and / or glycine; b) lubricants, such as silica, talcum, stearic acid, its magnesium or calcium calcium salts and / or polyethylene glycol; c) binders, such as magnesium aluminum silicate, starch paste, gelatin , tragacanth, methylcellulose, sodium carboxymethylcellulose and / or Polyvinylpyrrolidone; d) disintegrating agents, such as starch, agar, alginic acid or its sodium salt, or granules; foam mixture; 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. It can be melt coated.

[0298] Compositions suitable for oral administration include tablets, lozenges, aqueous or oily suspensions, dispersible powders, and the like. or granules, emulsion, hard or soft capsules, or syrup or elixir, solution Or a solid dispersion form of the compound of the present invention. Prepared according to any method known in the art for the manufacture of pharmaceutical compositions. Such compositions provide pharmaceutical formulations that are both aesthetically pleasing and palatable. In order to achieve this, one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives are added. Tablets may contain the compound in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may contain the active ingredient. inert diluents such as cereals, lactose, calcium phosphate or sodium phosphate; granulating agents and and disintegrants, e.g., corn starch or alginic acid; binders, e.g., starch , gelatin or acacia; and lubricants such as magnesium stearate, stearic acid The tablets are uncoated or coated to prevent disintegration and absorption in the gastrointestinal tract. To slow the onset of symptoms and thereby provide a longer-lasting effect It can be coated by known techniques, for example, glyceryl monostearate or distearate. A time delay material such as glyceryl tearate can be used. Formulations for oral use can be prepared as hard syrups or as ointments. Gelatin capsules (in which the active ingredient is dissolved in an inert solid diluent, e.g., calcium carbonate) mixed with calcium phosphate or kaolin) or in soft gelatin capsules ( The active ingredient is then dissolved in water or an oil medium, such as peanut oil, liquid paraffin, or olive oil. It may be indicated as (mixed with oil).

[0299] Certain injectable compositions are aqueous isotonic solutions or suspensions, and suppositories are fatty emulsions or suspensions. The compositions may be sterilized and / or may contain preservatives, stabilizers, moistening agents, etc. or auxiliary agents such as emulsifiers, dissolution promoters, salts and / or buffers for adjusting osmotic pressure. In addition, they may also contain other therapeutically valuable substances. It is prepared according to conventional mixing, granulation or coating methods, and has a concentration of about 0.1 to 7 Contains 5%, or approximately 1-50% of the active ingredient.

[0300] Suitable compositions for transdermal application include an effective amount of a compound of the invention with a suitable carrier. Carriers suitable for transdermal delivery include absorbable pharmacological agents to assist passage through the skin of the host. For example, the transdermal device may comprise a backing member, an optional carrier-containing chemical, a reservoir containing the compound, optionally for delivering the compound to the skin of the host in a controlled, predetermined manner over an extended period of time. a bandage comprising a rate-controlling barrier for delivering a rate of 100 rpm and a means for securing the device to the skin; It is in the form of:

[0301] Suitable compositions for topical application, for example to the skin and eyes, may be formulated as, for example, an aerosol or the like. and aqueous solutions, suspensions, ointments, creams, gels, or sprayable formulations for delivery by Such topical delivery systems include, for example, sunscreens for the treatment of skin cancer. Particularly suitable for dermal application, for preventative use in creams, lotions, sprays, etc. Therefore, they are suitable for topical (including cosmetic) applications well known in the art. These are particularly suitable for use in formulations such as solubilizers, stabilizers, tonicity enhancers, etc. May contain tonicity enhancing agents, buffers and preservatives. do.

[0302] As used herein, topical application may also refer to inhalation or intranasal application. These are dry powders from dry powder inhalers (alone or in mixtures, e.g., dry powder with lactose). or as mixed component particles, for example with phospholipids), or with a suitable propellant. With or without a pressurized container, pump, spray, atomizer, or nebulizer The composition may be conveniently delivered in the form of an aerosol spray from a dispenser.

[0303] Compounds of formula (I), in free form or in pharmaceutically acceptable salt form, are, for example, those listed in the Examples. As shown in the in vitro tests provided in For example, RAS mutants may exhibit inhibitory properties and therefore may be useful therapeutically or as research chemicals. and are indicated for use as tool compounds, for example. do.

[0304] Compounds of particular interest according to the invention are those which perform well in the biological assays described herein, particularly in the biological assays described herein. In another embodiment, the antibody has good efficacy in the covalent binding competition assay described herein. In another embodiment, they should have a favorable safety profile. They should have favorable pharmacokinetic properties.

[0305] The compounds of the present invention preferably have a concentration of less than 0.5 μM, more preferably less than 0.1 μM. It has an IC50.

[0306] RAS mutant inhibitors, in particular KRAS, HRAS or NRAS G12C mutations In view of its activity as a steroid inhibitor, the formula in free form or in the form of a pharmaceutically acceptable salt is The compounds of formula (I) are RAS mutant proteins, in particular KRAS, HRAS or NRA. S G12C mutant protein is responsive to inhibition (especially therapeutically beneficial cancer, most particularly the diseases or disorders described herein below Damage caused by KRAS, HRAS, or NRAS G12C mutations, such as It is useful in treating the condition.

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

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

[0309] The compounds of the present invention also inhibit one or more mutations in KRAS, particularly G1 in KRAS. It may be useful in the treatment of solid malignancies characterized by 2C mutations.

[0310] Thus, in a further embodiment, the present invention relates to the use of a compound of formula (I) or In a further embodiment, the present invention provides the use of a pharmaceutically acceptable salt thereof. The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of Thus, in a further embodiment, the present invention provides a compound of formula (I) or In a preferred embodiment, the present invention provides the use of pharmaceutically acceptable salts thereof. Therapies for which drugs are useful include those targeting mutant RAS proteins, particularly KRAS and HRAS. or a disease that can be treated by inhibiting the NRAS G12C mutant protein. In another embodiment, the present invention provides a method for detecting a RAS mutant in a subject in need thereof. Proteins, particularly G12C fragments of either KRAS, HRAS or NRAS proteins The present invention provides a method for treating a disease that is treated by the inhibition of a natural mutant of a compound, the method comprising administering to a subject The present invention relates to a method for treating a rheumatoid arthritis, comprising administering 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 one of those listed above, preferably non-small cell lung cancer, It is selected from colorectal cancer and pancreatic cancer.

[0312] In a preferred embodiment, the treatment involves the treatment of mutant RAS proteins, particularly KRAS, Treatment by inhibiting the G12C mutant of either the HRAS or NRAS protein In a more preferred embodiment, the disease is one of the diseases listed above. Preferably, the tumor is characterized by a G12C mutation in either KRAS, HRAS, or NRAS. The cancer is selected from non-small cell lung cancer, colorectal cancer and pancreatic cancer.

[0313] In one embodiment of the present invention, optionally, KRAS, HRAS, or NRAS G12C receptor for use in the treatment of cancer or solid malignant tumors characterized by spontaneous mutations, a(R)-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl )-5-Methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazoline (2-azaspiro[3.3]heptan-2-yl)prop-2-ene-1 -on, a(R)-(S)-1-(6-(4-(5-chloro-6-methyl-1H-indazole- 4-yl)-3-(1-(2-(3-fluoropyrrolidin-1-yl)ethyl)-1H- Indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspipri (b)(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)pro Pa-2-en-1-on, a(R)-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl )-3-(2-(2-hydroxy-2-methylpropyl)-2H-indazole-5-yl (1H-pyrazol-1-yl)-5-methyl-1H-pyrazol-1-yl-2-azaspiro[3.3]heptane -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 (1H-pyrazol-1-yl)-5-methyl-1H-pyrazol-1-yl-2-azaspiro[3.3]heptane -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-pyrazole-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)propa-2 -en-1-on, a(R)-1-(6-(4-(3-amino-5-chloro-6-methyl-1H-indazole) (2-(2-methoxyethyl)-2H-indazol-5-yl)-3-(2-(2-methoxyethyl)-2H-indazol-5-yl) -5-Methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2 -yl)prop-2-en-1-one and a(R)-1-(6-(4-(3-amino-5-chloro-6-methyl-1H-indazole) (4-yl)-5-methyl-3-phenyl-1H-pyrazol-1-yl)-2-aza Spiro[3.3]heptan-2-yl)prop-2-en-1-one or a pharmaceutically acceptable salt thereof.

[0314] In one embodiment of the present invention, the present invention is directed to the treatment of lung cancer (such as lung adenocarcinoma and non-small cell lung cancer), colorectal cancer (such as colon cancer), and the like. colorectal adenocarcinoma), pancreatic cancer (including pancreatic adenocarcinoma), uterine cancer (including endometrial cancer) and rectal cancer cancer (including colon adenocarcinoma); more preferably selected from lung cancer, colorectal cancer or pancreatic cancer or solid tumors for use in the treatment of selected cancers, a(R)-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl )-5-Methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazoline (2-azaspiro[3.3]heptan-2-yl)prop-2-ene-1 -on, a(R)-(S)-1-(6-(4-(5-chloro-6-methyl-1H-indazole- 4-yl)-3-(1-(2-(3-fluoropyrrolidin-1-yl)ethyl)-1H- Indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspipri (b)(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)pro Pa-2-en-1-on, a(R)-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl )-3-(2-(2-hydroxy-2-methylpropyl)-2H-indazole-5-yl (1H-pyrazol-1-yl)-5-methyl-1H-pyrazol-1-yl-2-azaspiro[3.3]heptane -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 (1H-pyrazol-1-yl)-5-methyl-1H-pyrazol-1-yl-2-azaspiro[3.3]heptane -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-pyrazole-1- (yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, a(R)--1-(6-(4-(5-chloro-6-methyl-1H-indazole-4-yl) (2-fluoro-4-(2-methoxyethoxy)phenyl)-5-methyl-1 H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)propan- 2-en-1-one, a(R) 1-(6-(4-(3-amino-5-chloro-6-methyl-1H-indazole) -4-yl)-3-(2-(2-methoxyethyl)-2H-indazol-5-yl)- 5-Methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2- yl)prop-2-en-1-one and a(R)-1-(6-(4-(3-amino-5-chloro-6-methyl-1H-indazole) (4-yl)-5-methyl-3-phenyl-1H-pyrazol-1-yl)-2-aza Spiro[3.3]heptan-2-yl)prop-2-en-1-one or a pharmaceutically acceptable salt thereof.

[0315] In one embodiment of the present invention, the present invention is directed to the treatment of lung cancer (such as lung adenocarcinoma and non-small cell lung cancer), colorectal cancer (such as colon cancer), and the like. colorectal adenocarcinoma), pancreatic cancer (including pancreatic adenocarcinoma), uterine cancer (including endometrial cancer) and rectal cancer cancer (including colon adenocarcinoma); more preferably lung cancer, colorectal cancer or pancreatic cancer or solid tumors (herein and wherein the cancer is a KRAS G12C mutant. Meno, a-(R)-1-(6-(4-(5-chloro-6-methyl-1H-indazole-4-yl) 1H-indazol-5-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazo (2-azaspiro[3.3]heptan-2-yl)prop-2-ene- 1-on, a(R)-(S)-1-(6-(4-(5-chloro-6-methyl-1H-indazole- 4-yl)-3-(1-(2-(3-fluoropyrrolidin-1-yl)ethyl)-1H- Indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspipri (b)(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)pro Pa-2-en-1-on, a(R)-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl )-3-(2-(2-hydroxy-2-methylpropyl)-2H-indazole-5-yl (1H-pyrazol-1-yl)-5-methyl-1H-pyrazol-1-yl-2-azaspiro[3.3]heptane -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 (1H-pyrazol-1-yl)-5-methyl-1H-pyrazol-1-yl-2-azaspiro[3.3]heptane -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-pyrazole-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)propa-2 -en-1-on, a(R)-1-(6-(4-(3-amino-5-chloro-6-methyl-1H-indazole) (2-(2-methoxyethyl)-2H-indazol-5-yl)-3-(2-(2-methoxyethyl)-2H-indazol-5-yl) -5-Methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2 -yl)prop-2-en-1-one and a(R)-1-(6-(4-(3-amino-5-chloro-6-methyl-1H-indazole) (4-yl)-5-methyl-3-phenyl-1H-pyrazol-1-yl)-2-aza Spiro[3.3]heptan-2-yl)prop-2-en-1-one or a pharmaceutically acceptable salt thereof. Suitably, the cancer treated by the compounds of the present invention is KRAS G12C mutant non-small cell lung cancer. KRAS G12C mutation lung cancer including lung cancer.

[0316] The compounds of the present invention may be administered simultaneously with, before, or after one or more other therapeutic agents. The compounds of the present invention may be administered separately, by the same or different routes, or in combination with other drugs. The therapeutic agent may be administered together with other agents in the same pharmaceutical composition. , antibodies, antibody fragments or nucleic acids, which have a therapeutic effect or which are useful in the preparation of compounds of the invention. When administered to a patient in combination with a compound, the therapeutic activity is enhanced. In this case, the other therapeutic agent may be an anti-cancer agent.

[0317] In one embodiment, the present invention provides a method for simultaneous, separate or sequential use in therapy. A product containing a compound of the present invention and at least one other therapeutic agent as a combined preparation is provided. In one embodiment, the treatment is a KRAS, HRAS, or NRAS G12C mutation. The treatment of diseases or conditions characterized by mutations in the The composition may comprise a compound of the present invention and another therapeutic agent together in the same pharmaceutical composition, or may be administered in separate doses. The present invention also includes compositions comprising a compound of the present invention and other therapeutic agents in the form of a kit, for example.

[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 pharmaceutical composition comprising two or more separate pharmaceutical compositions, at least one of which In one embodiment, a kit is provided that includes a compound of the present invention. The container may be a container, a divided bottle, or a divided foil packet, which holds the compositions separately. An example of such a kit is a package such as that typical of tablets, capsules and the like. It comes in a blister pack for convenient use.

[0320] The kits of the present invention can be used to administer different dosage forms (e.g., oral and parenteral), and therefore can be used to administer different dosage forms. for administering the separate compositions at regular intervals or for titrating the separate compositions against each other To aid in compliance, the kits of the invention typically include instructions for administration. Includes indications.

[0321] In the combination therapy of the present invention, the compound of the present invention and the other therapeutic agent may be of the same or different composition. Further, the compounds of the present invention and other therapeutic agents may be manufactured and / or formulated by other manufacturers. Agents may be combined into a combination therapy: (i) prior to presentation of the combination product to physicians ( For example, in the case of a kit containing a compound of the present invention and another therapeutic agent; (ii) immediately before administration (iii) by the patient themselves (e.g., by using the compound of the present invention); (during the continuous administration of compounds and other therapeutic agents). [Example]

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

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

[0324] Mass spectra were obtained using a series of instruments configured as follows: a Waters SQ detector; Electrospray, chemical and electron impact analysis were performed using the ters Acquity UPLC. Ionization methods were used to collect the data in LC-MS, SFC-MS, or GC-MS systems. Mass spectra were acquired using a series of instruments consisting of: a Wafer equipped with a PDA detector; Using the ters Acquity LCMS, ESI method was used for LCMS system Obtained at [M+H] + refers to the protonated molecular ion of a chemical species.

[0325] NMR spectra were obtained with and without tetramethylsilane as an internal standard. uker Ultrashield(TM) 400(400MHz), Bruker U Itrashield™ 600 (600MHz) and Bruker Ascend The measurements were carried out using a 400 MHz spectrometer. The spectral splitting pattern is reported in ppm downfield from tetramethylsilane. Single line (s), double line (d), triple line (t), quartet (q), multiple line, unsplit or overlapping The solvent is shown in parentheses. Only proton signals that are observed and do not overlap with solvent peaks are reported.

[0326] Celite: Celite® (the Celite Corporation) ion) = diatomaceous earth-based filter aid Phase separator: Biotage-Isolute Phase Separator - (Part Number: 1 for 70 mL) 20-1908-F and part number: 120-1909-J for 150 mL) SiliaMetS® Thiol: SiliCYCLE Thiol Metal Scavenging (R51030B, particle size: 40~63μm).

[0327] X-ray powder diffraction (XRPD) patterns described herein are analyzed using the Bru The powder samples were acquired using a zero background scanner Advance D8. The analysis was performed using a flat silicon sample holder. The radiation was Cu Kα (λ = 1.5 The pattern was 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 using a Robot Eight / Robot Sixty processing power: 0-40 from magnetron at 2.45GHz The experiment was carried out in a Biotage Initiator with 0 W irradiation.

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

[0332] UPLC-MS-1: Acquity HSS T3; particle size: 1.8 μm; column size: Size: 2.1 x 50 mm; Eluent A: H2O + 0.05% HCOOH + 3.75 mM vinegar Eluent B: CH3CN + 0.04% HCOOH; Gradient: 1.40 min 5 to 98% B for 0.40 min, then 98% B for 0.40 min; flow rate: 1 mL / min; Temperature: 60℃.

[0333] UPLC-MS-2: Acquity HSS T3; particle size: 1.8 μm; column size: Size: 2.1 x 100 mm; Eluent A: H2O + 0.05% HCOOH + 3.75 mM Ammonium acetate; Eluent B: CH3CN + 0.04% HCOOH; Gradient: 9.4 min 5 to 98% B, then 98% B for 0.40 min; flow rate: 1.0 mL / min; Column temperature: 60°C.

[0334] UPLC-MS-3: Acquity BEH C18; Particle size: 1.7μm; Column sensor Size: 2.1 x 50 mm; Eluent A: H2O + 4.76% isopropanol + 0.05 % HCOOH + 3.75 mM ammonium acetate; Eluent B: isopropanol + 0. 0.5% HCOOH; Gradient: 1 to 98% B in 1.7 min, then over 0.1 min 98% B; flow rate: 0.6 mL / min; column temperature: 80 °C.

[0335] UPLC-MS-4: Acquity BEH C18; Particle size: 1.7μm; Column sensor Size: 2.1 x 100 mm; Eluent A: H2O + 4.76% isopropanol + 0.0 Eluent A: 5% HCOOH + 3.75 mM ammonium acetate; Eluent B: isopropanol + 0 0.05% HCOOH; Gradient: 1 to 60% B in 8.4 min, then 60 to 98% B in 1 min % B; flow rate: 0.4 mL / min; column temperature: 80°C.

[0336] UPLC-MS-5: Ascentis Express C18; Particle size: 2.7μm Column size: 2.1 x 50 mm; Eluent A: H2O + 4.76% isopropanol + 0.05% HCOOH + 3.75 mM ammonium acetate; Eluent B: isopropanol B in 0.30 min; gradient: 1 to 50% B in 1.4 min, 5 to 50% B in 0.30 min 0 to 98% B, then 98% over 0.10 min; flow rate: 1 mL / min; column temperature :80℃.

[0337] UPLC-MS-6: Acquity BEH C18; Particle size: 1.7μm; Column sensor Size: 2.1 x 50 mm; Eluent A: H2O + 0.05% HCOOH + 3.75 mM Ammonium acetate; eluent B: isopropanol + 0.05% HCOOH; gradient: 1. 5–98% B for 7 min, then 98% B for 0.1 min; flow rate: 0.6 mL / min; column temperature: 80°C.

[0338] UPLC-MS-7: Acquity BEH C18; Particle size: 1.7μm; Column sensor Size: 2.1 x 50 mm; Eluent A: H2O + 0.05% HCOOH + 3.75 mM Ammonium acetate; eluent B: isopropanol + 0.05% HCOOH; gradient: 1. 5–98% B for 7 min, then 98% B for 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: Size: 2.1 x 100 mm; Eluent A: H2O + 0.05% HCOOH + 3.75 mM Ammonium acetate; Eluent B: CH3CN + 0.04% HCOOH; Gradient: 9.4 min 5 to 98% B, then 98% B for 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 dimensions: 2.1 x 50 mm; Eluent A: H2O + 4.76% isopropanol + 0.05% H COOH + 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 Size: 2.1 x 50 mm; Eluent A: H2O + 0.05% HCOOH + 3.75 mM Ammonium acetate; eluent B: isopropanol + 0.05% HCOOH; gradient: 1. 5–98% B for 7 min, then 98% B for 0.10 min; flow rate: 0.6 mL / min; column temperature: 80°C.

[0342] UPLC-MS-11: Acquity BEH C18; Particle size: 1.7μm; Column Size: 2.1×50mm; Eluent A: H2O+0.2% HCOOH; Eluent B: CH 3CN; 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: 1.7μm; Column Size: 2.1×100mm; Eluent A: H2O+0.05% HCOOH+3.75m M ammonium acetate; eluent B: isopropanol + 0.05% HCOOH; gradient: 8. 5–60% B in 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 Size: 2.1 x 100 mm; Eluent A: H2O + 0.05% HCOOH + 3.75 mM of ammonium acetate; Eluent B: isopropanol + 0.05% HCOOH; Gradient: 8 .5-60% B in 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 dimensions: 2.1 x 50 mm; Eluent A: H2O + 0.10% HCOOH + 2.0 mM acetic acid monium; Eluent B: CH3CN + 0.10% HCOOH; Gradient: 0.01 min to 0. 98:2 at 3 minutes, 50:50 at 0.6 minutes, 25:75 at 1.1 minutes , Flow rate: 0.60 mL / min, 0:100 from 2.0 to 2.70 minutes, Flow rate: 0 98:2 at 0.55 mL / min from 2.71 to 3.0 min; column temperature: room temperature.

[0346] LCMS-2: Acquity BEH C18; particle size: 1.7 μm; column dimensions: 2.1 x 50 mm; Eluent A: H2O + 0.10% HCOOH + 2.0 mM acetic acid monium; eluent B: CH3CN + 0.10% HCOOH; gradient 5 at 0.01 min 0:50, 10:90 at 1.0 minutes, 0:10 from 1.5 minutes to 4.50 minutes 0, 50:50 from 4.6 to 5.0 min; flow rate: 0.40 mL / min; column temperature: Degree: 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 minutes, 10:90 at 5.0 minutes, 5.80 to 7.20 5:95 at 10.0 min, 9 at 7.21 min to 10.0 min at 1 mL / min 5:5; column temperature: room temperature.

[0348] LCMS-4: Acquity BEH C18; particle size: 1.7 μm; column dimensions: 2.1 x 50 mm; Eluent A: H2O + 0.10% HCOOH + 2.0 mM acetic acid monium; eluent B: CH3CN + 0.10% HCOOH; gradient 0.01 min to 0.5 min 98:2 at 1 minute, 10:90 at 5.0 minutes, and 10:90 at 6.0 to 7.0 minutes. 5:95 at point 7.01 to 8.0 min, 98:2 at point 7.01; 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 x 250 mm; Eluent A: 10 mM ammonium acetate + 0.10% HCOOH Eluent B: CH3CN + 0.10% HCOOH; gradient 90:1 at 0.01 min 70:30 at 0 and 10 minutes, 60:40 at 20 minutes, and from 30 to 33 minutes 0:100 at point 33.01 min to 35.0 min, 90:10 at point 33.01 min to 35.0 min; flow rate: 1.0 mL / min; column temperature: room temperature.

[0350] MS-1: MS flow injection; Eluent A: H2O + 4.76% isopropanol Eluent B: Isopropyl alcohol + 0.05% HCOOH + 3.75 mM ammonium acetate; ... Propanol + 0.04% HCOOH; Gradient: Isocratic over 0.8 min 70% B; flow rate: 0.4 mL / min.

[0351] Preparation method: Normal Phase Chromatography: Normal phase chromatography was performed using standard According to the flash chromatography method, as detailed below, The separations were carried out on silica gel, using a glass column, or on a glass column. 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 Re prosil C18 5μm, 250×30mm, detection UV 215 and 254nM, Mobile phase: A: water + 0.1% TFA, B: acetonitrile; gradient: 30-95°C in 25 min %B.

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

[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; Transfer 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; 100×4.6m m; mobile phase; flow rate: 3 mL / min; column temperature: 40 °C; back pressure: 1800 psi.

[0358] C-SFC-4: Column: Chiralpak AD-H 5μm; 250×30mm ;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; 100×4.6m m; mobile phase; flow rate: 3 mL / min; column temperature: 40 °C; back pressure: 1800 psi.

[0361] C-SFC-7: Column: Chiralpak IG 5μm; 250×30mm; 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: 3 mL / min; column temperature: 40°C; back pressure: 1800 psi.

[0363] C-SFC-9: Column: Chiralpak AD-YMC 5μm; 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 5μm; 250×30mm; 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 5μm; 250×30m m; mobile phase; flow rate: 80 mL / min; column temperature: 40°C; back pressure: 110 bar.

[0367] C-SFC-13: Column: Chiralpak OD-H 5μm; 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 with UV detector; column: Ch iralpak AD-H 5μm; 250×30mm; mobile phase; flow rate: 80mL / min; Column temperature: 40°C; back pressure: 100 bar.

[0369] C-SFC-15: Waters SFC investiga with PDA detector tor;Column:Chiralpak AD-H 5μm;250×4.6mm;Mobile phase ; Flow rate: 4 mL / min; Column temperature: 40°C; Back pressure: 100 bar.

[0370] C-SFC-16: Waters SFC 200 with UV detector; column: Ch Iralpak 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 with UV detector; column: Ch Iralpak 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 investiga with PDA detector tor;Column:Chiralpak IG 5μm;250×4.6mm;Mobile phase;Flow Flow rate: 4 mL / min; column temperature: 40°C; back pressure: 100 bar.

[0373] C-SFC-19: Waters SFC investiga with PDA detector tor;Column:Chiralpak IC 5μm;250×4.6mm;Mobile phase;Flow 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 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 5μm; 250×25mm; Mobile phase; flow rate: 15 mL / min; column temperature: room temperature.

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

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

[0379] C-HPLC-5: カラム: Chiralpak IA 5μm; 250×4.6mm ; Mobile phase; flow rate: 1mL / min; temperature: RT; back pressure: 49 バール.

[0380] C-HPLC-6: カラム: Chiralpak IA 5μm; 250×30mm; Mobile phase; flow rate: 20 mL / min; temperature: room temperature.

[0381] C-HPLC-7: カラム: ChiralPak ID 5μm; 250×4.6mm ;Mobile phase;Flow rate: 1mL / min;Kura temperature: room temperature.

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

[0383] C-HPLC-9:カラム:ChiralPak AD 3μm;100×3.0mm ;Mobile phase;Flow rate: 0.42mL / min;Kura temperature: room temperature.

[0384] C-HPLC-10: カラム:Chiralpak IG-3; 3μm; 100×3. 0mm; mobile phase; flow rate: 0.42mL / min; temperature: 25℃.

[0385] C-HPLC-11: カラム: Chiralpak IG 5μm; 250×20mm ;Mobile phase;Flow rate:10mL / min;Kura temperature:25℃.

[0386] C-HPLC-12: カラム:Chiralpak IA-5; 5μm; 250×3. 0mm; mobile phase; flow rate: 1mL / min; temperature: 25℃.

[0387] C-HPLC-13: カラム: Chiralpak IG-3; 3μm; 100×3. 0mm; mobile phase; flow rate: 0.42mL / min; temperature: 25℃.

[0388] C-HPLC-14: カラム: Chiralcel OZ; 3μm; 250×25mm ;Mobile phase;Flow rate:15mL / min;Kura temperature:25℃.

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

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

[0391] C-HPLC-17: カラム: Chiralpak IG 5μm; 250×20mm ;Mobile phase;Flow rate:12mL / min;Kura temperature:25℃.

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

[0393] C-HPLC-19: カラム: ChiralPak AD 5μm; 250×25mm ;Mobile phase;Flow rate: 15mL / min;Kura temperature: room temperature.

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

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

[0396] C-HPLC-22: カラム: Chiralpak AD-H 5μm; 250×4. 6mm; mobile phase; flow rate: 1mL / min; KURAL temperature: 25℃.

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

[0398] C-HPLC-24: カラム: Chiralpak OX-H 5μm; 250×4. 6mm; mobile phase; flow rate: 1mL / min; KURAL temperature: 25℃.

[0399] C-HPLC-25:カラム:Chiralpak IBN 5μm;250×21m m; mobile phase; flow rate: 18mL / min; temperature: 40°C.

[0400] C-HPLC-26: カラム: Chiralpak IBN 5μm; 250×4.6 mm; mobile phase; flow rate: 1mL / min; temperature: 25°C.

[0401] C-HPLC-27: カラム: Chiralpak IC 5μm; 250×21mm ;Mobile phase;Flow rate: 18mL / min;Kura temperature: 40℃.

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

[0403] C-HPLC-29: Column: ChiralPak IG 5μm; 250×4.6m m; mobile phase; flow rate: 1 mL / min; column temperature: 25°C.

[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 used in preparing the compounds of this invention The dehydrating agents, solvents, and catalysts are commercially available or can be prepared by organic synthesis methods known to those skilled in the art. Additionally, the compounds of the present invention can be prepared by methods known to those skilled in the art, as shown in the examples below. These compounds can be prepared by well-known organic synthesis methods.

[0410] The structures of all final products, intermediates and starting materials are confirmed by standard analytical spectroscopic properties, e.g. This is confirmed by MS, IR, and NMR. The absolute stereochemistry of representative compounds was determined when each compound was bound to the KRASG12C mutant. Determined by analysis of the X-ray crystal structure of the complex or by analysis of the X-ray crystal structure of a small molecule In all other cases where no X-ray structure is available, the stereochemistry is determined by the covalent bond for each pair. The atropisomers showing the highest activity in the competitive assay were selected from the representative examples shown above. Divide by analogy, assuming that the nuclei have the same configuration as observed by X-ray crystallography. The absolute stereochemistry is given for Example 12a (the more active atropisomer). As shown above, they are assigned according to the Cahn-Ingold-Prelog rule, Example 12a is exemplary of 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-indazole) (1-methyl-1H-indazol-5-yl)-5-methyl-3-(1-methyl-1H-indazol-4-yl)-1 H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)propan- 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-pyrazoline {2-azaspiro[3.3]heptan-2-yl}prop-2-ene-1 -on and Example 1b: a(S)-1-(6-(4-(5-chloro-6-methyl-1H-indazole) (1-methyl-1H-indazol-5-yl)-5-methyl-3-(1-methyl-1H-indazol-4-yl)-1 H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)propan- 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-pyrazoline {2-azaspiro[3.3]heptan-2-yl}prop-2-ene-1 -on 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-azazol Pyro[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-indazole-4 -yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hept Benzene-2-carboxylate (Intermediate C1, 10 g, 16.5 mmol), (1-methyl -1H-indazol-5-yl)boronic acid (6.12 g, 33.1 mmol), RuP hos (1.16 g, 2.48 mmol) and RuPhos-Pd-G3 (1.66 g, K3P (1.98 mmol) was suspended in toluene (165 mL) under argon. O4 (2M, 24.8 mL, 49.6 mmol) was added and the reaction mixture was heated in a preheated The mixture was placed in an oil bath (95°C) and stirred for 45 minutes. The reaction mixture was poured into a saturated aqueous solution of NH4Cl. The combined organic layers were washed with saturated aqueous NaHCO3. The crude residue was diluted with THF (50 mL) and concentrated under reduced pressure. SiliaMetS® thiol (15.9 mmol) was added and the mixture was Rotated for 1 hour at 40° C. The mixture was filtered, the filtrate concentrated, and the crude residue purified by normal phase chromatography. The purified fractions were collected by column chromatography (eluent: 0-2% MeOH in CH2Cl2). , reconstituted by normal phase chromatography (eluent: 0-2% MeOH in CH2Cl2). After extensive purification, the title compound was obtained 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-indole) (2-azaspiro[3.3]heptan-6-yl)-1H-pyridin-5-yl (4-pyrazol-1H-indazole) TFA (19.4 mL, 251 mmol) was dissolved in tert-butyl ether in CH2Cl2 (33 mL). -butyl 6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2 -yl)-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol-4-yl) (1H-pyrazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-1 Add to a solution of butane-2-carboxylate (Step 1, 7.17 g, 10.0 mmol) The reaction mixture was stirred at room temperature under nitrogen for 1.5 hours. The RM was concentrated under reduced pressure. Condensation gave the title compound as the trifluoroacetate 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-pyrazole -1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-ene-1- on Acrylic acid (0.69 mL, 10.1 mmol) in CH2Cl2 (80 mL), pro Pyruphosphonic anhydride (50% in EtOAc, 5.94 mL, 7.53 mmol) and D A mixture of IPEA (21.6 mL, 126 mmol) was stirred at room temperature for 20 min, and then 5-chloro-6-methyl-4-(5-methyl-3-(1-chloro-6-methyl-4-(1-chloro-3 ... Methyl-1H-indazol-5-yl)-1-(2-azaspiro[3.3]heptane- 6-yl)-1H-pyrazol-4-yl)-1H-indazole trifluoroacetate The reaction mixture was added (dropping funnel) to an ice-cold solution of 1,2-dimethyl-3,4-trimethyl-2,5-dichloro-1,6 ... The RM was poured into saturated aqueous NaHCO3 and stirred at room temperature under nitrogen for 1 min. The combined organic layers were dried (phase separator) and concentrated. The crude residue was diluted with THF (60 mL) and treated with LiOH (2N, 15.7 mL, 31.5 mL). mol) was added. The reaction of acryloyl chloride with the free NH group of indazole gave The mixture was stirred at room temperature for 30 min until the disappearance of the by-product (UPLC), then washed with saturated NaHC The combined organic layers were dried and extracted with CH2Cl2 (3x). The crude residue was purified by normal phase chromatography (eluent: 0-5% CH The isomers were purified by chiral SFC (MeOH in HCl) to give the title compounds. (C-SFC-1; Mobile phase: CO2 / [IPA + 0.1% Et3N]: 69 / 31) Thus, Example 1a: a(R)-1-(6-(4-(5-chloro-6-methyl- 1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazole -5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2 -yl)prop-2-en-1-one was obtained as the second eluting peak (white powder): 1 H NMR (600MHz, DMSO-d6)δ 13.1(s,1H), 7.89( s,1H), 7.59(s,1H), 7.55(s,1H), 7.42(m,2H), 7 .30(d,1H), 6.33(m,1H), 6.12(m,1H), 5.68(m,1 H), 4.91(m,1H), 4.40(s,1H), 4.33(s,1H), 4.11 (s,1H), 4.04(s,1H), 3.95(s,3H), 2.96-2.86(m ,2H), 2.83-2.78(m,2H), 2.49(s,3H), 2.04(s,3 H);UPLC-MS-4:Rt=4.22 min;MS m / z[M+H] + 52 6.3 / 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 called "Compound X."

[0414] The other isomer, Example 1b; a(S)-1-(6-(4-(5-chloro-6-methyl-1 H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazole- 5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2- C-SFC- 3 (Mobile phase: CO2 / [IPA + 0.1% Et3N]: 67 / 33): Rt = 1.55 Minutes.

[0415] Method-1a: Same as Method-1, except that step 2 was performed as described below: 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-pyrazole-1 -yl)-2-azaspiro[3.3]heptane-2-carboxylate (Step 1, 1.6 To a stirred solution of 6 g of HCl (2.10 mmol), sulfuric acid (3.30 mL, 42.0 mmol) was added. The mixture was stirred at room temperature overnight. The mixture was diluted with water and diluted with saturated aqueous NaHCO3 (pH 8-9), extracted with n-butanol (×2), and the combined organic extracts were The crude material was washed with water (x2), dried (phase separator) and evaporated. 4-(5-methyl-3-(1-methyl-1H-indazol-5-yl)-1-( 2-Azaspiro[3.3]heptan-6-yl)-1H-pyrazol-4-yl)-1H The -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 was used instead of n-butanol. Alternatively, it can be used for extraction.

[0417] Method-1b: Same as Method-1, except that step 3 was performed as described below: 5-chloro-6-methyl-4-(5-methyl-3-(1-methyl)-2-(2-chloro-6-methyl-4-(5-methyl-3-(1-methyl)-2-methyl)-2-methyl)-2-methyl-4-chloro-6-methyl-4-(5-methyl-3-(1 ... -1H-indazol-5-yl)-1-(2-azaspiro[3.3]heptan-6-yl) (1H-pyrazol-4-yl)-1H-indazole (trifluoroacetate ( Step 2) or to an ice-cold solution of the free base (Step 2 Method-1a), 0.25 mmol), Under pressure, NaHCO3 (516 mg, 6.14 mmol), H2O (0.20 mL) and Acryloyl chloride (0.026 mL, 0.32 mmol) was added. The reaction mixture was stirred at 0°C. Stirred for 60 min. Then LiOH (2 M in water, 4.91 mL, 9.83 mmol) was added. The disappearance of the by-products obtained from the reaction of acryloyl chloride with indazole NH (UPL C), the mixture was stirred at 0°C for 1 hour. A saturated aqueous solution of NaHCO3 was added and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2x). The combined organic extracts were washed with saturated NaH The crude residue was washed with aqueous CO3, dried (Na2SO4), filtered and evaporated. Purification was performed by phase chromatography (eluent: 0-9% MeOH in CH2Cl2). 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5 -Methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazole-1 -yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one obtained.

[0418] Method-1c: In step 1, XPhos and XPhos-Pd-G2 were mixed with Ruphos and Same as method-1, except that HCl was used instead of RuPhos-Pd-G3.

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

[0420] Method-1e: In step 1, Na2CO3 (2M, 3 equivalents), Pd(PPh3)4 (0. 1 equivalent) and dioxane with K3PO4, RuPhos, RuPhos-Pd-G3 and Same as method-1 except that toluene was used instead.

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

[0422] Method-1j: Step 3 was carried out in the same manner as described in Method-9, Step 3, with Et Same as method-1 except performed with 3N and acryloyl chloride.

[0423] Method-1k: Step 3 was carried out using iPr2 in CH2Cl2 as described in Method-9 Step 3. Same as Method-1, except that NEt and acryloyl chloride were used.

[0424] The following Examples 2 to 44 in Table 1 below are examples of intermediates described in the Intermediate Synthesis section (Step 1 ) using a method similar to Method 1 or is 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-indazole) -4-yl)-2'-(cyclopropylmethyl)-5-methyl-1H,2'H-[3, 3'-bipyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)p ropa-2-en-1-one The title example was prepared by the reaction of tert-butyl 6-(4-(5-chloro-6-methyl-1-(tetrachloromethyl)-2-methyl-1-methyl ... Hydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2'-(cyclo Propylmethyl)-5-methyl-1H,2'H-[3,3'-bipyrazol]-1-yl )-2-azaspiro[3.3]heptane-2-carboxylate (prepared as described below) The isomers were prepared from chiral isomers (as described above) using the same method as in steps 2 and 3 of Method-1b. Separation was performed by SFC (C-SFC-2; mobile phase: CO2 / MeOH: 72 / 28). , affording the title compound Example 45a as the second eluting peak: 1 H NMR (400MH z, DMSO-d6)δ 13.12(s,1H), 7.54(s,1H), 7.46( s,1H), 7.15(d,1H), 6.32(m,1H), 6.10(m,1H), 5 .67(m,1H), 5.45(d,1H), 4.96(m,1H), 4.38(s,1 H), 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. 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-pyridinyl) (Iran-2-yl)-1H-indazol-4-yl)-2'-(cyclopropylmethyl) -5-methyl-1H,2'H-[3,3'-bipyrazol-1-yl]-2-azaspirillum b[3.3]heptane-2-carboxylate. tert-Butyl 6-(3-bromo-4-(5-chloro-6-methyl-1-(tetrahydrofuran) 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 PdCl2(dppf).CHCl The 2-adduct (38.5 mg, 0.047 mmol) was dissolved in acetonitrile (2.25 mL). Aqueous Na2CO3 solution (2 M, 0.48 mL, 0.97 mmol) was added, and the mixture was suspended in water. 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, and saturated aqueous NaHCO3 was added. 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. liaMetS® thiol (100 mg) was added and the mixture was stirred at room temperature for 15 minutes. The crude residue was purified by normal phase flash column chromatography (eluent Purification by elution with hexane (20-70% EtOAc in c-hexane) gave the title compound. UPLC-MS-3:Rt=1.28 min;MS m / z[M+H] + ;646.3 / 64 8.2.

[0444] [ka] Example 46a / 46b: 1-(6-(4-(5-chloro-6-methyl-1H-indazole) (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 by the reaction of tert-butyl 6-(4-(5-chloro-6-methyl-1H-indole) (4-yl)-5-methyl-3-(pyridin-2-yl)-1H-pyrazole-1 -yl)-2-azaspiro[3.3]heptane-2-carboxylate (as described below) The isomers were prepared from 1H-dimethyl-2H-pyridin-1H-one (prepared in step 1) using the same method as in steps 2 and 3 of Method-1b. , and analyzed by chiral SFC (C-SFC-2; mobile phase: CO2 / MeOH: 63 / 37). Upon separation, the title compound Example 46a was obtained as the first eluting peak: 1 H NMR (400 MHz, DMSO-d6)δ 13.0(s,1H), 8.16(d,1H), 7.69 (t,1H), 7.66(d,1H), 7.47(s,1H), 7.40(s,1H), 7.12(t,1H), 6.33(m,1H), 6.12(m,1H), 5.69(m, 1H), 4.94(m,1H), 4.40(s,1H), 4.33(s,1H), 4.1 1(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;M S 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 in the second solvent. The peak obtained was: C-SFC-3 (mobile phase: CO2 / MeOH: 65 / 35): Rt=3.28 minutes.

[0445] tert-Butyl 6-(4-(5-chloro-6-methyl-1H-indazol-4-yl) )-5-methyl-3-(pyridin-2-yl)-1H-pyrazol-1-yl)-2-a Zaspiro[3.3]heptane-2-carboxylate tert-Butyl 6-(3-bromo) -4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1 H-indazol-4-yl)-5-methyl-1H-pyrazol-1-yl)-2-aza Spiro[3.3]heptane-2-carboxylate (Intermediate C1, 1.35 g, 2.23 mmol) and bis(tri-t-butylphosphine)palladium (68 mg, 0.13 To a solution of 2-pyridylzinc bromide (0.5 M in THF, 14.0 mL, 7 mmol) 0.00 mmol) was added. The reaction mixture was heated at 70°C for 3 hours. The RM was dissolved in NaHCO The combined organic extracts were poured into a saturated aqueous solution of 3 and extracted with EtOAc (x2). The crude residue was washed with brine, dried (Na2SO4), filtered and concentrated. mL) and SiliaMetS (registered trademark) thiol (1.3 mmol) was added. 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 obtain the desired material. The resulting mixture was purified by normal phase chromatography (eluent: EtOAc). The title compound was obtained by further purification. 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-indazole) (4-hydroxymethyl)phenyl)-5-methyl-1H-pyrazol-4-yl (2-azaspiro[3.3]heptan-2-yl)prop-2-ene -1-on 4-(4-(5-chloro-6-methyl-)- 1H-indazol-4-yl)-5-methyl-1-(2-azaspiro[3.3]hepta (1H-pyrazol-6-yl)benzyl acetate trifluoroacetate To a solution of phosphate (prepared as described below, 0.7 mmol) was added NaHCO3 (588 mg, 7.0 mmol) and acryloyl chloride (70 μL, 0.84 mmol) were added successively. The reaction mixture was stirred at room temperature for 2.5 hours. LiOH (2M, 3.50 mL) was added. , 7.00 mmol), a by-product obtained from the reaction of acryloyl chloride with indazole NH The RM was stirred at room temperature for 45 min until the disappearance of the product (UPLC). The combined organic extracts were washed with brine, dried (N a2SO4), filtered and evaporated. The crude residue was dissolved in THF (12 mL) and treated with LiO H (2M, 3.50 mL, 7 mmol) was added and the reaction mixture was stirred at room temperature for 2 hours. M was diluted with water and extracted with EtOAc (x2). The combined organic extracts were washed with brine. The crude residue was purified by reverse phase HPLC (R The purified fraction was neutralized with a saturated aqueous solution of NaHCO3, Extraction with EtOAc was performed. The organic extract was washed with brine, dried (Na2SO4), and filtered. The isomers were separated by chiral SFC (C-SFC-2; mobile phase: CO2 / IPA:7 0 / 30) to give the title compound Example 47a as the second eluting peak. : 1 H NMR (400MHz, DMSO-d6)δ 13.12(s,1H), 7.5 4(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,1 H), 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(Move Phase: CO2 / IPA: 70 / 30): Rt = 3.78 min. The other isomer Example 47b was The first eluted peak was obtained: C-SFC-3 (mobile phase: CO2 / IPA: 70 / 30):Rt=2.85 minutes.

[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 synthesized by the reaction 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 Carboxylate (Intermediate C1) and 4-(4,4,5,5-tetramethyl-1,3,2- Dioxaborolan-2-yl)benzyl acetate [562098-08-2] Prepared using the same method as Method-1, steps 1 and 2; UPLC-MS-6: Rt=0.8 0 min;MS m / z[M+H] + 490.2 / 492.2.

[0448] [ka] Example 48: 1-(4-(1-(2-acryloyl-2-azaspiro[3.3]heptane -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 by the reaction of tert-butyl 6-(4-(5-chloro-6-methyl-1-(tetrachloromethyl)-2-methyl-1-methyl ... Hydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-3 -(4-((2-oxopyrrolidin-1-yl)methyl)phenyl)-1H-pyrazole -1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (described below) This was prepared from the above compound (prepared as described above) using the same method as in steps 2 and 3 of Method-1b. 1 H NMR (400MHz, DMSO-d6)δ 13.12(s,1H), 7.54(s ,1H), 7.41(s,1H), 7.23(d,2H), 6.99(d,2H), 6. 32(m,1H), 6.10(m,1H), 5.67(m,1H), 4.89(m,1H ), 4.37(s,1H), 4.31(s,1H), 4.25(s,2H), 4.09( s,1H), 4.02(s,1H), 3.14(t,2H), 2.93-2.73(m, 4H), 2.47(s,3H), 2.24(t,2H), 2.00(s,3H), 1.8 7(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-pyridinyl) lan-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-(tetrahydrofuran) 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-2-methyl-4- ... (tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidin-2-one (Intermediate B2, 473 mg, 0.94 mmol) was suspended in DMF (3.95 mL). Aqueous solution of K3PO4 (1 M, 0.94 mL, 0.942 mmol) and Pd(Ph P)4 (27.2 mg, 0.024 mmol) was added and the suspension was flushed with argon. The reaction mixture was then subjected to microwave irradiation at 120° C. for 45 minutes. The mixture was diluted with EtOAc, saturated aqueous NaHCO3 was added, and the layers were separated. Ac (x2) and the combined organic extracts were washed with brine, dried (MgS The crude residue was purified by normal phase flash column chromatography (elution Reagent: Purified by (MeOH / CH2Cl2 9 / 1) in 0-50% CH2Cl2 The title compound was obtained. 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-indazole) (3-methylpyridin-4-yl)-5-methyl-3-(3-methylpyridin-4-yl)-1H-pyrazoline (2-azaspiro[3.3]heptan-2-yl)prop-2-ene-1 -on The title example was prepared by the reaction of tert-butyl 6-(4-(5-chloro-6-methyl-1-(tetrachloromethyl)-2-methyl-1-methyl ... Hydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-3 -(3-methylpyridin-4-yl)-1H-pyrazol-1-yl)-2-azaspiro [3.3] From heptane-2-carboxylate (prepared as described below), The isomers were prepared using a method similar to that of steps 2 and 3 of .-1b. PLC-23 (mobile phase: hexane / IPA / ACN 60 / 28 / 12; flow rate: 20 mL) / min; UV: 227 nM) and the title compound Example 49a was the second eluting peak. As a result: 1H NMR (400MHz, DMSO-d6)δ 13.11(s, 1H), 8.35(s,1H), 8.13(d,1H), 7.50(s,1H), 7.4 5(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-HPL C-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: 262nM): Rt=8.98min.

[0451] tert-Butyl 6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyridinyl) Indazol-2-yl)-1H-indazol-4-yl)-5-methyl-3-(3-methylpiperidin-2-yl)- Lysin-4-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta Benzene-2-carboxylate. tert-Butyl 6-(3-bromo-4-(5-chloro-6-methyl-1-(tetrahydrofuran) 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 (0.2 7g, 1.98mmol) and K3PO4 (0.42g, 1.98mmol) were added to tB The mixture was dissolved in 24 mL of HClOH:HO (5:1) and heated under reduced pressure for 15 min. The mixture was degassed with argon. 0.06g, 0.07mmol) was added, and the reaction mixture was heated in a sealed condition at 120°C for 4 hours. The reaction mixture was quenched with water and extracted with EtOAc (x3). The combined organic layer was washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The crude residue was purified by C18 (15 μm) reversed-phase chromatography (eluent: 0.1% HCOOH Purification by elution with 0-68% CH3CN in H2O containing HCl gave 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-indazole) methyl-4-yl)-3-(4-(1,1-dioxidethiomorpholino)phenyl)-5-methyl (ethyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl) Prop-2-en-1-one The title example was prepared by the synthesis of intermediates C1 and 4-(4-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl)phenyl)thiomorpholine 1,1-dioxide (intermediate Starting from compound B15), a similar protocol as described for Examples 49a and 49b was used. The isomers were separated by chiral HPLC C-HPLC-23 (mobile phase: Me OH:ACN (80:20); flow rate: 15 mL / min; UV: 270 nM The title compound Example 50a was obtained as the first elution: 1H NMR (400 MHz, C DCl3)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] + :60 5.5 / 607.5;C-SFC-19 (Mobile phase: CO2 / MeOH / ACN 55 / 2 2.5 / 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:270nM):Rt=10.8 min.

[0453] [ka] Example 51a / 51b: 1-(6-(4-(5-chloro-6-methyl-1H-indazole) (thiazol-4-yl)-5-methyl-3-(thiazol-4-yl)-1H-pyrazole-1- (yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one The title example was prepared by the reaction of tert-butyl 6-(4-(5-chloro-6-methyl-1-(tetrachloromethyl)-2-methyl-1-methyl ... Hydro-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) in Method-1b The isomers were prepared using the same method as in steps 2 and 3. 23 (Mobile phase: [hexane + 0.1% EtNH] / [IPA + 0.1% EtNH ] / CH3CN (60 / 28 / 12); flow rate: 20 mL / min; UV: 216 nM) and separated to give the title compound Example 51a as the first eluting peak: 1 H NMR(4 00MHz, 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,1 H), 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);LC MS-1: Rt = 1.49 min; MS m / z [M+H] + :479.3 / 481. 3; C-HPLC-24 (mobile phase: hexane / IPA / CH3CN with 0.1% DEA) Gradient): Rt = 10.0 min. The other isomer, Example 51b, was obtained as the second eluting peak. C-HPLC-24 (mobile phase: hexane / IPA / CH3CN with 0.1% DE Gradient of A): Rt = 12.3 min.

[0454] tert-Butyl 6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyridinyl) thiazole-2-yl)-1H-indazol-4-yl)-5-methyl-3-(thiazole- 4-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2- Carboxylate. tert-Butyl 6-(3-bromo-4-(5-chloro-6-methyl-1-(tetrahydrofuran) 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)thiazo LiCl (0.28 g, 0.74 mmol) and anhydrous LiCl (0.03 g, 0.74 mmol) l) was 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 mixture was filtered through a pad of light and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give the crude residue. The resulting solution was purified by reversed-phase chromatography on a C18 (15 μm) column (eluent: 0.1% HCOOH Purification by LCMS (0-100% CHCN in H2O) gave the title product. S-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-indazole) (4-(2-hydroxyethoxy)phenyl)-5-methyl-1H -pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)propa-2 -en-1-on Step 1: tert-Butyl 6-(4-(5-chloro-6-methyl-1-(tetrahydro- 2H-pyran-2-yl)-1H-indazol-4-yl)-3-(4-(2-hydrogen (5-methyl-1H-pyrazol-1-yl)-2-azaspirillum b[3.3]heptane-2-carboxylate tert-Butyl 6-(3-bromo-4-(5-chloro-6-methyl-1-(tetrahydrofuran) 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-2-methyl-4- ... Methyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethan-1-ol ( 0.22g, 0.83mmol) and K3PO4 (0.52g, 2.48mmol), 1,4-Dioxane:H2O (2:1) (12 mL) was added, and the mixture was stirred for 10 min. The mixture was degassed with nitrogen. os-Pd-G3 (0.034 g, 0.08 mmol) was added, and the reaction mixture was heated to 100 °C. After stirring for 2 hours, the reaction mixture 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). Purification by c) gave 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-azaspipri b[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-hydroxyethyl)- (5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3 3]Heptane-2-carboxylate (0.45 g, 0.68 mmol) was added to CH The mixture was dissolved in 12 (5 mL). Et3N (0.21 g, 2.03 mmol) was added and the reaction The mixture was cooled to 0°C under a nitrogen atmosphere and stirred for 10 min. Acetyl chloride (0.08 g, 1.02 mmol) in 1 mL of acetic acid was added dropwise, and the reaction mixture was After stirring at room temperature for 2 hours, the RM was diluted with CH2Cl2 and washed with water and brine. The mixture was evaporated, 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-pyrazo (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-indole (4-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3 3]Heptane-2-carboxylate (0.68 mmol) was dissolved in dry CH2Cl2 (5 The mixture was dissolved in 1 mL of TFA and cooled to 0° C. TFA (6 mL) was added and the reaction mixture was stirred at room temperature for 5 hours. After completion of the reaction, the RM was concentrated under reduced pressure and co-evaporated with CH2Cl2 several times to give The crude residue was purified by trituration with diethyl ether and filtration to give the desired The product was obtained and 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]heptane- 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-pyrazole-3 -yl)phenoxy)ethyl acetate (0.22 g, 0.42 mmol) in THF( Dissolved in 2 mL of NaHCO3 (0.35 g, 4.15 mmHg) in water (2.5 mL). ol) was added and the reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was cooled to 0°C and TH A solution of acryloyl chloride (0.04 g, 0.46 mmol) in F (0.5 mL) was added dropwise. After completion of the reaction, the RM was diluted with water and The combined organic layers were washed with water, brine, dried (Na2SO4), The crude residue was purified by reverse phase chromatography on C18 silica gel (15 μm). (eluent: 0-43% CH3CN in H2O containing 0.1% NH3) The isomers were purified by chiral HPLC C-HPLC-23 (transfer Mobile phase: Hexane / IPA / ACN 70 / 21 / 9; Flow rate: 18 mL / min; UV: 264 The title compound isomer-I was obtained as the first eluting peak by LCM. S-1: Rt = 1.63 min; MS m / z [M+H] + 574.8; C-HPLC-2 9 (Mobile phase: Hexane / IPA gradient): Rt = 11.8 min. The other isomer II was The first elution peak was obtained: LCMS-1: Rt = 1.63 min; MS m / z [M+ H] + : 574.8; C-HPLC-29 (mobile phase: hexane / IPA gradient): Rt = 1 3.8 minutes.

[0459] Process-5: Example 52a: 1-(6-(4-(5-chloro-6-methyl-1H-indazoline) (4-(2-hydroxyethoxy)phenyl)-5-methyl-1 H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)propan- 2-en-1-one The title example was prepared by substituting 2-(4-(1-(2-acryloyl-2-azabicyclo[4.2.1.2.2.1])-4-(1-(2-acryloyl-2-azabicyclo[4.2.1.2.1])-4 ... Spiro[3.3]heptan-6-yl)-4-(5-chloro-6-methyl-1H-indane (4-yl)-5-methyl-1H-pyrazol-3-yl)phenoxy)ethyl Starting from acetate isomer-II, Example 52b 1-(6-(4-(5-chloro-6 -methyl-1H-indazol-4-yl)-3-(4-(2-hydroxyethoxy)furan) (phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hept as described for the preparation of (tan-2-yl)prop-2-en-1-one (step 6) Prepared using the same method; LCMS-3: Rt = 3.30 min; MS m / z [M+H ] + :532 / 534; 1H NMR(400MHz, CD3OD)δ 7.49(s, 1H), 7.39(s,1H), 7.23(d,2H), 6.75(d,2H), 6.3 9(m,1H), 6.28(m,1H), 5.77(m,1H), 5.01(m,1H) , 4.48(s,1H), 4.42(s,1H), 4.24(s,1H), 4.19(s ,1H), 3.96(m,2H), 3.82(m,2H), 3.05(m,2H), 2. 88(m,2H), 2.55(s,3H), 2.09(s,3H);C-HPLC-29 (Mobile phase: [hexane + 0.1% Et2NH] / [IPA + 0.1% Et2NH] gradient Delivery): Rt=11.2 minutes.

[0460] Process-6: Example 52b: 1-(6-(4-(5-chloro-6-methyl-1H-indazoline) (4-(2-hydroxyethoxy)phenyl)-5-methyl-1 H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)propan- 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-1 H-pyrazol-3-yl)phenoxy)ethyl acetate (0.05g, 0.08mm ol) 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 heated to room temperature. After completion of the reaction, the RM was diluted with water and extracted with EtOAc (x2). The combined organic layers were washed with water, brine, dried (Na2SO4), filtered, and The crude residue was purified by reversed-phase chromatography on C18 silica gel (15 μm). Eluent: 0-40% CH3CN in H2O containing 0.025% NH3 The title product was obtained by purification using C-HPLC-29 (mobile phase: [hexane + 0.1% Et 2NH] / [IPA+0.1% Et2NH] gradient): Rt = 9.37 min.

[0461] [ka] Example 53: 1-(6-(3-(6-(3-amino-1H-pyrazol-1-yl)pyridine) 5-chloro-6-methyl-1H-indazol-4-yl)- 5-Methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2- (I)prop-2-en-1-one The title example was prepared by the reaction of tert-butyl 6-(3-(6-(3-amino-1H-pyrazole- 1-yl)pyridin-3-yl)-4-(5-chloro-6-methyl-1-(tetrahydro) -2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-1H-pyran (isothiazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate ( (prepared in two steps as described in Method-1b) using a method similar to steps 2 and 3 of Method-1b. Prepared. 1 H 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,1 H), 5.69 (m 2H), 5.26 (s, 2H), 4.93 (m, 1H), 4.39 (s,1H), 4.32(s,1H), 4.1(s,1H), 4.03(s,1H), 2 .89-2.79(m,4H), 2.03(s,3H);LCMS-1:Rt=1.53 min; MS m / z [M+H] + :554.8 / 556.8.

[0462] tert-Butyl 6-(3-(6-(3-amino-1H-pyrazol-1-yl)pyridinyl) 4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-3-yl)- 2-yl)-1H-indazol-4-yl)-5-methyl-1H-pyrazol-1-yl (I)-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-pyrazole -1-yl)-2-azaspiro[3.3]heptane-2-carboxylate tert-Butyl 6-(3-bromo-4-(5-chloro-6-methyl-1-(tetrahydrofuran) 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-pyrazole -1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- 2-yl)pyridine (Intermediate B16) (0.52 g, 1.65 mmol) and K3PO4 (0.53 g, 2.48 mmol) in 1,4-dioxane (4 mL) and HO (2 m The reaction mixture was degassed with N2 for 5 minutes. 0.04g, 0.08mmol) and Ruphos-Pd-G3 (0.035g, 0.04 (mmol) was added and the reaction mixture was stirred at 120° C. for 1 hour. After completion of the reaction, the RM was The combined organic layers were washed with brine and dried. The crude residue was purified by normal phase chromatography. (eluent: 30-40% EtOAc in hexanes) to give the desired product. Got it. LCMS-1:Rt=2.24 min;MS m / z[M+H] + :714.6 / 71 6.5.

[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-pyrazole -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 a nitrogen atmosphere. 10% dry Pd / C (0. 25 g) was added and the reaction mixture was heated under an atmosphere of H2 (1 atm) at room temperature for 1 h. The RM was filtered through a pad of celite and concentrated under reduced pressure to give the desired The product was obtained, which was used directly in the next step without further purification. LCMS-1:R t = 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-indazole) (1-methyl-1H-indazol-5-yl)-5-methyl-3-(1-methyl-1H-indazol-4-yl)-1 H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)propan- 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-indazole -5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-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-indazole- 5-yl)-1H-pyrazol-1-yl)-2azaspiro[3.3]heptane-2-yl Ruboxylate tert-Butyl 6-(3-bromo)propanol in dioxane (20 mL) and HO (4 mL) -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 To a stirred solution of 0.26 g of RuPhos (0.56 mmol) was added under an argon atmosphere. mol) and RuPhos-Pd-G3 (0.47 g, 0.56 mmol) were added. The reaction mixture was stirred at 100° C. for 1 hour. The reaction mixture was added saturated aqueous NaHCO3 solution. The mixture was quenched with HCl, extracted with EtOAc (2x), and the combined organic extracts were washed with saturated The crude residue was washed with aqueous NaHCO3, dried (Na2SO4) and evaporated. Purified by chromatography (eluent: 0-90% EtOAc in c-hexane) The title compound was obtained as a brown solid. UPLC-MS-3: Rt=1.14 min; S m / z[M+H] + :408.2.

[0466] Step 2: tert-Butyl 6-(4-iodo-5-methyl-3-(1-methyl-1H-iodo) (1H-pyrazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-1 Butane-2-carboxylate tert-Butyl 6-(4-iodo-5-methyl-3-(1- Methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azazol Pyro[3.3]heptane-2-carboxylate (2.13 g, 5.23 mmol) was stirred. To the stirred solution, NIS (1.53 g, 6.80 mmol) was added under an argon atmosphere, and the reaction The mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to room temperature by adding saturated aqueous NaHCO3 solution. Quench and extract with EtOAc (2x) and wash the combined organic extracts with saturated NaHC The crude residue was washed with aqueous O3, dried (Na2SO4), filtered and evaporated. Purified by chromatography (eluent: 0-80% EtOAc in c-hexane) The title compound was obtained as a brown solid. UPLC-MS-3: Rt=1.22 min; S 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-azazol Pyro[3.3]heptane-2-carboxylate tert-Butyl 6-(4-iodomethyl)propanol in dioxane (2 mL) and HO (0.50 mL) 5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazoline (1-yl)-2-azaspiro[3.3]heptane-2-carboxylate(100 mg, 0.187 mmol), 5-chloro-6-methyl-1-(tetrahydro-2H-pyridinyl) 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborola-2-yl)- (2-phenyl-1H-indazole) (Intermediate D1, 85 mg, 0.225 mmol) and A stirred solution of KPO (119 mg, 0.56 mmol) was added under an argon atmosphere to uPhos (8.75 mg, 0.019 mmol) and RuPhos-Pd-G3 (15 The reaction mixture was degassed with N2 and heated at 100 °C for 1 hour. The reaction mixture was quenched by the addition of saturated aqueous NaHCO3 solution and Extract with Ac (2x) and wash the combined organic extracts with saturated aqueous NaHCO3 The crude residue was diluted in THF (3 mL) and evaporated. SiliaMetS® thiol (0.076 mmol) (i.e., Add a functionalized silica gel (designed to remove metals from reaction mixtures) and mix. The mixture was rotated for 1 hour at 40° C. The mixture was filtered, the filtrate was concentrated, and the crude residue was purified by normal phase chromatography. Purification was performed by chromatography (eluent: 0-100% EtOAc in c-hexane). The title compound was obtained 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 and chiral separation of the isomers was carried out as described in Method-1.

[0469] Method-2a: Step 4 was carried out using sulfuric acid in dioxane as described in step 2 of Method-1a. This is the same as Method 2, except that

[0470] Method-2b: Step 5 was carried out by adding acrylonitrile in THF / water as described in step 3 of Method-1b. Same as Method-2 except that it was carried out using thiazolinone and NaHCO3.

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

[0472] Method-2d: Step 3 was carried out using EtN and HCl in CH2Cl2 as described in Method-9, Step 3. Same as Method-2, except that the reaction was carried out using acryloyl chloride.

[0473] The following Examples 54-58 in Table 2 below are examples of intermediates described in the Intermediate Synthesis section (Step 1 or 3) using a method 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-indazole) (1H-pyrrolo[2,3-c]pyridin-2-yl)-5-methyl-3-(1H-pyrrolo[2,3-c]pyridin-2-yl) -1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)pro Pa-2-en-1-on [ka] The title example was prepared by the reaction of tert-butyl 6-(4-bromo-5-methyl-3-(1H-pyrrolomethyl)- [2,3-c]pyridin-2-yl)-1H-pyrazol-1-yl)-2-azaspiro [3.3] From heptane-2-carboxylate (prepared as described below), The isomers were prepared using the same method as in steps 3 to 5 of 2a and 2b. FC-7; Mobile phase: CO2 / [MeOH + 0.1% NEt3]: 50 / 50) Separation afforded the title compound Example 59a as the second eluting peak: 1 H NMR(60 0MHz, 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,1 H), 7.20(d,1H), 6.52(s,1H), 6.41-6.28(m,1H) , 6.17-6.02(m,1H), 5.74-5.61(m,1H), 5.06-4. 87(m,1H), 4.42(s,1H), 4.34(s,1H), 4.13(s,1H ), 4.05(s,1H), 3.04-2.91(m,2H), 2.84(s,2H), 2.53(s,3H), 2.04(s,3H);UPLC-MS-3:Rt=0.77 min; MS m / z [M+H] + 512.2 / 514.2;C-SFC-8 (mobile phase :CO2 / [MeOH+0.1% NEt3]:50 / 50): Rt = 2.43 min. The isomer Example 59b was obtained as the first eluting peak: C-SFC-8 (mobile phase: Mobile phase: CO2 / [MeOH + 0.1% NEt3]: 50 / 50): Rt = 1.28 min .

[0477] tert-Butyl 6-(4-bromo-5-methyl-3-(1H-pyrrolo[2,3-c]pyridinyl) Lysin-2-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta Benzene-2-carboxylate tert-Butyl 6-(4-bromo-3-iodo)acetate in 1,4-dioxane (10 mL) -5-Methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2 -carboxylate (intermediate C7, 400 mg, 0.83 mmol), (1H-pyrrolo[ 2,3-c]pyridin-2-yl)boronic acid (202 mg, 1.24 mmol) and phosphorus To a stirred solution of potassium carbonate (2 M aqueous solution, 1.24 mL, 2.48 mmol) was added tetrakis(III). Tris(triphenylphosphine)palladium (96 mg, 0.08 mmol) was added to the reaction mixture. The reaction mixture was stirred at 90°C for 1 hour. It was then cooled to room temperature and diluted with water (10 mL). The combined organic layers were concentrated and the remaining crude material was extracted twice with EtOAc. Normal-phase flash column chromatography (eluent: 0-5% MeO in CH2Cl2) H) to give the title compound. UPLC-MS-4: Rt=4.19 min; S m / z[M+H] + :472.0 / 474.0.

[0478] Example 60a / 60b: 1-(6-(4-(5-chloro-6-methyl-1H-indazole) -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 [ka] The title example is based on the additional alkylation step (tert- Butyl 6-(3-(2-fluoro-4-(2-methoxyethoxy)phenyl)-5-methyl (1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxamide tert-butyl 6-(3-bromo-2-methylpropanol) with 3-(2-methylpropanol)-2-methylpropanol (prepared below for the preparation of 3-bromo-2-methylpropanol). 5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane 2-carboxylate (intermediate C3) and 3-fluoro-4-(4,4,5,5-tetrafluoro- Method-2: Starting from methyl-1,3,2-dioxaborolan-2-ylphenol The isomers were prepared using a method similar to that of c. The isomers were separated by chiral SFC (C-SFC-1; mobile phase: CO2 / [IPA + 0.1% NEt3]:70 / 30) to give the title compound Example 60a was obtained as the second eluting peak: 1 H NMR (400 MHz, DMSO -d6)δ 12.99(s,1H), 7.44(s,1H), 7.37(s,1H), 7.18(t,1H), 6.68-6.60(m,2H), 6.35-6.26(m,1 H), 6.13-6.07(m,1H), 5.69-5.65(m,1H), 4.95- 4.85(m,1H), 4.38(s,1H), 4.28(s,1H), 4.09(s, 1H), 4.02-3.99(m,3H), 3.60-3.57(m,2H), 3.26 (s,3H), 2.90-2.75(m,4H), 2.44(s,3H), 2.06(s ,3H);UPLC-MS-3:Rt=0.97 min;MS m / z[M+H] + 564.5 / 566.5; C-SFC-3 (mobile phase: CO2 / [IPA + 0.1% NE t3]: 70 / 30): Rt = 2.50 min. The other isomer, Example 60b, was the first to elute. The sample obtained was C-SFC-3 (mobile phase: CO2 / [IPA + 0.1% NEt3]:70 / 30):Rt=1.74 min.

[0479] tert-Butyl 6-(3-(2-fluoro-4-(2-methoxyethoxy)phenyl) -5-Methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2 -carboxylate tert-Butyl 6-(3-(2-fluoro-4-hydroxybenzoate)) in DMF (5 mL) (phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hept Benzene-2-carboxylate (Step 1, 710 mg, 1.65 mmol), 1-bromo- 2-Methoxyethane (0.310 mL, 3.30 mmol) and cesium carbonate (1075 mg, 3.30 mmol) was stirred at 60° C. for 2 h. The reaction mixture was diluted with EtOAc and diluted with water, extracted with EtOAc, the organic phase washed with brine and dried (phase separator), The crude residue was purified by normal phase flash column chromatography (eluent: 30 The product was purified by hexane / EtOAc (100 / 0 to 70 / 30) within 1 minute. Compound was obtained. UPLC-MS-3: Rt=1.20 min; MS m / z [M+H] + 4 46.3.

[0480] [ka] Example 61a / 61b: 1-(6-(4-(5-chloro-6-methyl-1H-indazole) (2-fluoro-4-((2-methoxyethyl)amino)phenyl)-3-(2-fluoro-4-((2-methoxyethyl)amino)phenyl) )-5-Methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane- 2-yl)prop-2-en-1-one The title example is a simplified version of the additional alkylation step introduced between steps 1 and 2, as well as step An additional hydrogenation step (tert-butyl 6-(3-(4-( ((benzyloxy)carbonyl)(2-methoxyethyl)amino)-2-fluorophen (5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]hepta tert-butyl 6-(4-(5-chloro-6-methyl- 1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-3 -(2-fluoro-4-((2-methoxyethyl)amino)phenyl)-5-methyl-1 H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate tert-Butyl 6-(3-bromo-5-methyl-5-methyl-2 ... -methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate carboxylate (intermediate C3) and benzyl (3-fluoro-4-(4,4,5,5-tetracarboxylate) Derived from tetramethyl-1,3,2-dioxaborolan-2-ylphenyl carbamate The isomers were prepared using a method similar to Method-2c. C-1: Mobile phase: CO2 / [IPA + 0.1% NEt3]: 70 / 30 to give the title compound Example 61a as the second eluting peak: 1 H NMR (400 MHz, DMSO-d6)δ 12.96(s,1H), 7.42(s,1H), 7.3 4(s,1H), 6.94(t,1H), 6.35-6.25(m,2H), 6.15- 6.07(m,2H), 5.86(t,1H), 5.69-5.64(m,1H), 4. 91-4.81(m,1H), 4.37(s,1H), 4.28(s,1H), 4.09 (s,1H), 3.99(s,1H), 3.41(t,2H), 3.24(t,3H), 3.09(q,2H), 2.88-2.76(m,4H), 2.44(s,3H), 2. 04(s,3H);UPLC-MS-3:Rt=0.94 min;MS m / z[M+ H] + :563.5 / 565.5;C-SFC-3(Mobile phase: CO2 / [IPA+0.0 25% NH3]:70 / 30): Rt = 3.55 min. The other isomer, Example 61b, was the most The first elution peak was obtained: C-SFC-3 (mobile phase: CO2 / [IPA+ 0.025% NH3]:70 / 30):Rt=2.55 min.

[0481] tert-Butyl 6-(3-(4-((benzyloxy)carbonyl)(2-methoxy) Ethyl)amino)-2-fluorophenyl)-5-methyl-1H-pyrazol-1-yl )-2-Azaspiro[3.3]heptane-2-carboxylate tert-Butyl 6-(3-(4-((benzyloxy)carbonyl)-2-carboxylate in DMF (20 mL) (carbonyl)amino)-2-fluorophenyl)-5-methyl-1H-pyrazol-1-yl (3.3)-2-azaspiro[3.3]heptane-2-carboxylate (Step 1, 1.40 g To a stirred solution of sodium hydride (60% in mineral oil, 0.123 g, 3.07 mmol) was added under an inert atmosphere. After 15 minutes, 1-bromo-2-methoxyethane Methanol (1.20 mL, 12.8 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with water and extracted with EtOAc, and the organic phase was washed with brine and dried (phase The crude residue was purified by normal phase chromatography (eluent: 1000 mg / ml) and concentrated under reduced pressure. The title compound was obtained by purifying the compound with hexane / EtOAc (100 / 0 to 70 / 30). UPLC-MS-3: Rt = 1.30 min; MS m / z [M+H] + :579. 4.

[0482] tert-Butyl 6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyridinyl) lan-2-yl)-1H-indazol-4-yl)-3-(2-fluoro-4-((2 -Methoxyethyl)amino)phenyl)-5-methyl-1H-pyrazol-1-yl)- 2-Azaspiro[3.3]heptane-2-carboxylate tert-Butyl 6-(3-(4-((benzyloxy))) in MeOH (10 mL) Carbonyl)(2-methoxyethyl)amino)-2-fluorophenyl)-4-(5-chlorophenyl) 6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (4-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3 ]heptane-2-carboxylate (470 mg, 0.511 mmol) and palladium A solution of carbon (5.44 mg, 0.051 mmol) was added to water at room temperature for 0.5 h. The reaction mixture was filtered and concentrated under reduced pressure. The crude residue was purified by normal phase chromatography. HPLC (eluent: 100 / 0 to 10 / 10 c-hexane / EtOAc within 30 min) 0) to give the title compound. UPLC-MS-3: Rt=1.25 min; S m / z[M+H] + :693.4 / 695.4.

[0483] Method 3: Synthesis scheme [ka] Example 62a / 62b: 4-(1-(2-acryloyl-2-azaspiro[3.3]heptyl) 5-chloro-6-methyl-1H-indazol-4-yl)- 5-Methyl-1H-pyrazol-3-yl)-N-(2-methoxyethyl)benzamide Step 1: tert-Butyl 6-(4-(5-chloro-6-methyl-1-tosyl-1H-isothiazolinone) 3-(4-(methoxycarbonyl)phenyl)-5-methyl- 1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate Route tert-Butyl 6-(3-bromo-4-(5-chloro-6)-methyl-2-methyl-2-propanol) in dioxane (8 mL) -Methyl-1-tosyl-1H-indazol-4-yl)-5-methyl-1H-pyrazo (2-amino-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate C 6) (1.00 g, 1.26 mmol), methyl 4-(4,4,5,5-tetramethyl- 1,3,2-Dioxaborolan-2-yl)benzoate (0.40 g, 1.51 mmol) l), RuPhos(0.06g, 0.13mmol), RuPhos-Pd-G3(0 0.10g, 0.13mmol) and potassium phosphate (2N, 1.89mL, 3.78mmol) The solution of 1,2-diol) was stirred at 80° C. for 1.5 h. The reaction mixture was cooled to room temperature and The mixture was diluted with water and extracted with EtOAc, and the combined organic phases were washed with brine and dried. The crude residue was purified by normal phase chromatography ( Eluent: Purified within 30 min with c-hexane / EtOAc (100 / 0 to 50 / 50) The second purification was carried out by normal phase chromatography to give a product containing some impurities. (Eluent: c-hexane / EtOAc 100 / 0~60 / 40 within 30 minutes) The title compound (86% purity by UPLC) was purified with some minor impurities. Got it. 1 H NMR (600MHz, DMSO-d6)δ 8.19(s,1H), 7. 89(s,1H), 7.79(d,2H), 7.67(d,2H), 7.41(d,2H ), 7.22(d,2H), 4.88(m,1H), 4.01(m,2H), 3.91( m,2H), 3.81(s,3H), 2.86-2.71(m,4H), 2.59(s, 3H), 2.37(s,3H), 2.00(s,3H), 1.39(s,9H);UPL C-MS-10:Rt=1.32 min;MS m / z[M+H] + :730.2 / 7 32.2.

[0484] Step 2: 4-(1-(2-(tert-butoxycarbonyl)-2-azaspiro[3.3 ]heptan-6-yl)-4-(5-chloro-6-methyl-1H-indazol-4-yl (1H-pyrazol-3-yl)-5-methyl-1H-pyrazol-3-ylbenzoic acid tert-Butyl 6-(4-(5-chloro-6-methyl-1-thiazolinone)-2-yl)propanol in THF (2 mL) Sil-1H-indazol-4-yl)-3-(4-(methoxycarbonyl)phenyl) -5-Methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2 -carboxylate (Step 1, 100 mg, 0.14 mmol) and LiOH (2 N, 0 A solution of 1.14 mL, 0.27 mmol) was stirred at 20° C. for 2.5 hours. Warm to 45°C for 0.5 hours, then to 70°C for 2.5 hours. Cool to room temperature Afterwards, the reaction mixture was lyophilized and the crude product was used in the next reaction without further purification. UPLC-MS-10:Rt=1.32 min;MS m / z[M+H] + :562.2 / 5 64.2.

[0485] Step 3: tert-Butyl 6-(4-(5-chloro-6-methyl-1H-indazole- 4-yl)-3-(4-((2-methoxyethyl)carbamoyl)phenyl)-5-methyl (1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxamide Silate 4-(1-(2-(tert -butoxycarbonyl)-2-azaspiro[3.3]heptan-6-yl)-4-(5- Chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1H-pyrazole 1-3-yl)benzoic acid (Step 2, 93 mg, 0.12 mmol) and DIPEA (0.1 0 mL, 0.59 mmol) was added to a solution of propylphosphonic anhydride (50% in EtOAc) , 0.10 mL, 0.177 mmol) was added and the resulting solution was stirred at room temperature for 10 minutes. Then, 2-methoxyethan-1-amine (0.03 mL, 0.35 mmol) was added and the reaction The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and the crude residue was purified by normal phase chromatography. Graphy (eluent: 100 / 0 to 100 / 100 c-hexane / EtOAc within 30 min) ) to give the title compound. 1 H NMR (400 MHz, DMSO-d )δ 13.16(s,1H), 8.36(t,1H), 7.62(d,2H), 7.5 7(s,1H), 7.43(s,1H), 7.29(d,2H), 4.88(m,1H) , 4.02(br s,2H), 3.94(br s,2H), 3.42-3.36(m ,4H), 3.23(s,3H), 2.86-2.75(m,4H), 2.49(s,3 H), 2.02(s,3H), 1.40(s,9H);UPLC-MS-10:Rt=1 0.09 min; MS m / z [M+H] + :619.2 / 621.3.

[0486] Step 4: 4-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5- Methyl-1-(2-azaspiro[3.3]heptan-6-yl)-1H-pyrazole-3 -yl)-N-(2-methoxyethyl)benzamide tert-Butyl 6-(4-(5-chloro-6-methyl-1H- Indazol-4-yl)-3-(4-((2-methoxyethyl)carbamoyl)phenyl (1H-pyrazol-1-yl)-5-methyl-1H-pyrazol-1-yl-2-azaspiro[3.3]heptane To a solution of 1,2-dimethyl-2-carboxylate (Step 3, 109 mg, 0.14 mmol) was added TFA ( 0.33 mL, 4.28 mmol) was added and the reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure, and the oily residue was dissolved in MeOH and washed with Wa The cartridge was placed in a PoraPak® Rxn Cx. After rinsing with H, the resin was rinsed with NH3 (7N in MeOH) and the basic MeOH solution was Concentration under reduced pressure gave the title compound, which was used in the next reaction without further purification. C-MS-6: Rt = 0.72 min; MS m / z [M+H] + :519.2 / 521.2 .

[0487] Step 5:4-(1-(2-acryloyl-2-azaspiro[3.3]heptan-6-yl) )-4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1 H-pyrazol-3-yl)-N-(2-methoxyethyl)benzamide 4-(4-(5-chloro-6-methyl-1H-indazole-4)-yl)-2 ... -yl)-5-methyl-1-(2-azaspiro[3.3]heptan-6-yl)-1H- pyrazol-3-yl)-N-(2-methoxyethyl)benzamide (Step 4, 55 mg , 0.08 mmol) was added to a solution of sodium bicarbonate (0.80 mL, 0.40 mmol) ), followed directly by the addition of acryloyl chloride (6.54 μl, 0.08 mmol). The reaction mixture was stirred at 0° C. for 1 h. Excess acryloyl chloride was quenched with LiOH (2N, 2 mL The reaction mixture was then extracted with DCM and stirred at room temperature for 1 hour. The organic phase was dried (phase separator) and concentrated under reduced pressure, and the crude residue was purified by normal phase chromatography. (Eluent: DCM / MeOH 100 / 0 to 90 / 10 within 30 min) The isomers were purified by chiral SFC (C-SFC-2: mobile phase: CO2 / IP A: 65 / 35) to give the title compound Example 62a as the second eluting isomer (white powder): 1 H NMR (400 MHz, DMSO-d6) δ 13. 15(s,1H), 8.35(t,1H), 7.63(d,2H), 7.57(s,1H ), 7.44(s,1H), 7.31(d,2H), 6.37-6.30(m,1H), 6.15-6.09(m,1H), 5.71-5.67(m,1H), 4.98-4.8 8(m,1H), 4.40(s,1H), 4.34(s,1H), 4.11(s,1H) , 4.04(s,1H), 3.35-3.32(m,4H), 3.22(s,3H), 2 .94-2.78(m,4H), 2.04(s,3H);UPLC-MS-10:Rt= 0.88 min; MS m / z [M+H] + 573.3 / 575.3;C-SFC- 3: (Mobile phase: CO2 / IPA: 65 / 35): Rt = 2.14 min. Example of the other isomer 62b was obtained as the first eluting peak: C-SFC-3: (Mobile phase: CO2 / IP A:65 / 35):Rt=1.28 minutes.

[0488] Method-3a: Step 2 Except NaOH 2N was used instead of LiOH 2N Same as Method 3.

[0489] The following Examples 63-65 in Table 3 below are examples of suitable commercially available pinacol (Step 1 and Amino Prepared using a method similar to Method-3 using the Benzene reagent (Step 3).

[0490] [Table 26]

[0491] [Table 27]

[0492] Method-4: Synthesis scheme [ka] Example 66a / 66b: 4-(1-(2-acryloyl-2-azaspiro[3.3]heptyl) 5-chloro-6-methyl-1H-indazol-4-yl)- 5-Methyl-1H-pyrazol-3-yl)-N-(2-methoxyethyl)-N-methyl benzamide Step 1:tert-Butyl 6-(3-(4-(methoxycarbonyl)phenyl)-5-methyl) (1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carbo Xylates tert-Butyl 6-(3-bromo-5-methyl-1H- pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate ( Intermediate C3, 1.51 g, 4.24 mmol), methyl 4-(4,4,5,5-tetramethyl ethyl-1,3,2-dioxaborolan-2-yl)benzoate (1.33g, 5.09 mmol), RuPhos(0.198g, 0.42mmol), RuPhos-Pd- G3 (0.355 g, 0.42 mmol) and potassium phosphate (2 N, 6.36 mL, 1 A solution of 2.7 mmol) was stirred at 80° C. for 15 min. After cooling to room temperature, the reaction mixture was The mixture was added to saturated aqueous NaHCO3, extracted with EtOAc, and the organic phase was washed with brine and dried. The crude residue was purified by normal phase chromatography ( Eluent: Purified within 30 min with c-hexane / EtOAc (100 / 0 to 70 / 30) The title compound was obtained by purification. 1 H NMR (400 MHz, DMSO-d) δ 7.9 9(d,2H), 7.91(d,2H), 6.60(s,1H), 4.80-4.72( m,1H), 3.99(s,2H), 3.90(s,2H), 3.87(s,3H), 2 .75-2.65(m,4H), 2.27(s,3H), 1.39(s,9H);UPL C-MS-6:Rt=1.23 min;MS m / z[M+H] + :412.3.

[0493] Step 2:tert-Butyl 6-(4-bromo-3-(4-(methoxycarbonyl)phenyl) (1H-pyrazol-1-yl)-5-methyl-1H-pyrazol-1-yl-2-azaspiro[3.3]heptane -2-carboxylate tert-Butyl 6-(3-(4-(methoxycarbonyl) )phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3] To a solution of heptane-2-carboxylate (Step 1, 1.76 g, 4.15 mmol), NBS (0.724 g, 4.07 mmol) was added and the reaction mixture was stirred at room temperature for 0.5 h. The reaction mixture was concentrated under reduced pressure and the crude residue was purified by normal phase chromatography (eluent: 30 The product was purified by hexane / EtOAc (100 / 0 to 70 / 30) within 1 minute. The compound was obtained. 1 H NMR (400MHz, DMSO-d6)δ 8.06(d,2H ), 8.00(d,2H), 4.91-4.83(m,1H), 3.99(s,2H), 3.89(s,5H), 2.74-2.65(m,4H), 2.29(s,3H), 1. 39(s,9H);UPLC-MS-6:Rt=1.31 min;MS m / z[M+ H] + :490.1 / 492.1.

[0494] Step 3: tert-Butyl 6-(4-(5-chloro-6-methyl-1-(tetrahydro- 2H-pyran-2-yl)-1H-indazol-4-yl)-3-(4-(methoxycarbonyl) (carbonyl)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[ 3.3]heptane-2-carboxylate tert-Butyl 6-(4-bromo-3-(4-methoxyphenyl)methyl)propanol in dioxane (10 mL) (Dicarbonyl)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspirillum b[3.3]heptane-2-carboxylate (Step 2, 1.00 g, 2.00 mmol) ), 5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-isothiazolinone Indazole (Intermediate D1, 0.98 g, 2.60 mmol), RuPhos (0.093 g, 0.20 mmol), RuPhos-Pd-G3 (0.167 g, 0.20 mmol) ) and potassium phosphate (2N, 3.00 mL, 6.00 mmol) at 80 °C for 15 min. After cooling to room temperature, the reaction mixture was added to saturated aqueous NaHCO3 solution and OAc, and the organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude residue was dissolved in THF (20 mL) and treated with SiliaMetS® Thiol (0.60 mmol, 0.84 g) was added and the mixture was evaporated on a rotary evaporator. The mixture was vortexed in a rotavapor for 0.5 hours at 50°C. Filtration, washing with MeOH, and concentration of the filtrate under reduced pressure gave the crude product, which was purified by normal phase chromatography. Chromatography (eluent: 100% hexane / EtOAc 0-60% in 30 min) The title compound was purified by UPLC-MS / 40 to give a colorless foam. Rt = 1.31 min; MS m / z [M+H] + :660.2 / 662.2.

[0495] Step 4: 4-(1-(2-(tert-butoxycarbonyl)-2-azaspiro[3.3 ]heptan-6-yl)-4-(5-chloro-6-methyl-1-(tetrahydro-2H- Pyran-2-yl)-1H-indazol-4-yl)-5-methyl-1H-pyrazole -3-yl)benzoic acid tert-Butyl 6-(4-(5-chloro-6-methyl-)- 1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-3 -(4-(methoxycarbonyl)phenyl)-5-methyl-1H-pyrazol-1-yl )-2-azaspiro[3.3]heptane-2-carboxylate (Step 3, 1.42 g, 1.99 mmol) and NaOH (2 N, 1.00 mL, 2.00 mmol), Stirred at 60° C. for 15 min. Additional NaOH (2N, 1.00 mL, 2.00 mmol) ) was added and the reaction mixture was stirred at room temperature overnight, and then the reaction mixture was heated at 60 The reaction mixture was lyophilized and the crude product was used in the next step without further purification. did. 1 H NMR (400MHz, DMSO-d6)δ 7.78(br s,1H) , 7.64-7.60(m,2H), 7.47(s,0.5H), 7.45(s,0.5 H), 7.16-7.13(m,2H), 5.85-5.80(m,1H), 4.91- 4.83(m,1H), 4.02(br s,2H), 3.95-3.87(m,3H) , 3.79-3.72(m,1H), 2.91-2.68(m,4H), 2.39-2. 32(m,1H), 2.01-1.94(m,5H), 1.74-1.70(m,1H) , 1.61-1.56(m,2H), 1.40(s,9H);UPLC-MS-6:Rt = 1.23 min; MS m / z [M+H] + :646.2 / 648.2.

[0496] Step 5:tert-Butyl 6-(4-(5-chloro-6-methyl-1-(tetrahydro- 2H-pyran-2-yl)-1H-indazol-4-yl)-3-(4-((2-methan-2-yl) (methyl)carbamoyl)phenyl)-5-methyl-1H-pyrazole-1 -yl)-2-azaspiro[3.3]heptane-2-carboxylate 4-(1-(2-(tert-butoxycarbonyl)-2-yl)-2-methyl-2-propanol in CH2Cl2 (3 mL) -azaspiro[3.3]heptan-6-yl)-4-(5-chloro-6-methyl-1-( Tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl (1H-pyrazol-3-yl)benzoic acid (Step 4, 250 mg, 0.31 mmol) and 2-methoxy-N-methylethan-1-amine (0.067 ml, 0.61 mmol ) was added to a solution of propylphosphonic anhydride (50% in EtOAc, 0.27 mL, 0.46 Next, DIPEA (0.27 mL, 1.53 mmol) was added and mixed. The mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure and the crude residue was purified by normal phase chromatography. raffinate (eluent: c-hexane / EtOAc 100 / 0 to 0 / 100 within 30 min) Purification by HCl afforded the title compound. 1 H NMR (400 MHz, DMSO-d6) δ 7.79(s,1H), 7.51(s,0.5H), 7.49(s,0.5H), 7 .30-7.27(m,2H), 7.20-7.17(m,2H), 5.86-5.81 (m,1H), 4.92-4.85(m,1H), 4.02(s,2H), 3.94-3 .87(m,3H), 3.79-3.72(m,1H), 3.58-3.24(m,6H ), 3.09(br s,1H), 2.93-2.74(m,7H), 2.03-1.9 6(m,5H), 1.73(m,1H), 1.62-1.55(m,2H), 1.40( s,9H);UPLC-MS-11:Rt=1.24 min;MS m / z[M+H] + :717.5 / 719.5.

[0497] Step 6: 4-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5- Methyl-1-(2-azaspiro[3.3]heptan-6-yl)-1H-pyrazole-3 -yl)-N-(2-methoxyethyl)-N-methylbenzamide tert-Butyl 6-(4-(5-chloro-6-methyl-)- 1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-3 -(4-((2-methoxyethyl)(methyl)carbamoyl)phenyl)-5-methyl- 1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate To a solution of methylpropanol (Step 5, 168 mg, 0.23 mmol) was added TFA (0.52 mL, 6. 82 mmol) was added, and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in dioxane and lyophilized to give the title compound as a trifluoroacetate salt. which was used in the next reaction without further purification. UPLC-MS-6: Rt=0 0.73; MS m / z [M+H] + :533.3 / 535.3.

[0498] Step 7: 4-(1-(2-acryloyl-2-azaspiro[3.3]heptan-6-yl) )-4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1 H-pyrazol-3-yl)-N-(2-methoxyethyl)-N-methylbenzamide 4-(4-(5-chloro-6-methyl-1H-indazole)-2-methyl-1H-indazole) in CH2Cl2 (3 mL) -4-yl)-5-methyl-1-(2-azaspiro[3.3]heptan-6-yl)- 1H-pyrazol-3-yl)-N-(2-methoxyethyl)-N-methylbenzamide (0.23 mmol) and acrylic acid (0.016 ml, 0.23 mmol), Propylphosphonic anhydride (50% in EtOAc, 0.20 mL, 0.34 mmol) DIPEA (0.198 ml, 1.13 mmol) was then added and the reaction mixture was The reaction was quenched by the addition of MeOH and the reaction mixture was stirred at room temperature for 1.25 hours. The mixture was concentrated under reduced pressure and the crude residue was purified by normal phase chromatography (eluent: DCM within 30 min). / MeOH 100 / 0 to 80 / 20) to give the title compound. , Chiral SFC (C-HPLC-11: Mobile phase: n-heptane / IPA + 0.1% NE The title compound Example 66a was the second eluting peak. And got: 1 H NMR(400MHz, DMSO-d6)δ 13.15(s,1H) , 7.57(s,1H), 7.45(s,1H), 7.30(d,2H), 7.18(d ,2H), 6.37-6.30(m,1H), 6.15-6.09(m,1H), 5.7 1-5.67(m,1H), 4.98-4.88(m,1H), 4.40(s,1H), 4.33(s,1H), 4.11(s,1H), 4.04(s,1H), 3.55-3. 46(m,5H), 3.09(br s,2H), 2.91-2.81(m,6H), 2 .03(s,3H);UPLC-MS-3:Rt=0.89 min;MS m / z[M +H] +: 587.3 / 589.3; C-HPLC-13 (mobile phase: n-heptane / [I PA + 0.1% DEA]: 55 / 45): Rt = 10.39 min. Other isomer Example 6 6b was obtained as the first eluting peak: C-HPLC-13 (mobile phase: n-heptane / [IPA + 0.1% DEA]: 55 / 45): Rt = 6.83 min.

[0499] The following Examples 67-68 in Table 4 below were prepared using the appropriate commercially available amine (Step 5): Alternatively, it was prepared by a method similar to Method-4, proceeding with acid.

[0500] [Table 28]

[0501] Method-5: Synthesis scheme [ka] Example 69a / 69b: 1-(6-(4-(3-amino-5-chloro-6-methyl-1H -indazol-4-yl)-3-(2-(2-methoxyethyl)-2H-indazole -5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3] (Heptan-2-yl)prop-2-en-1-one Step 1: tert-Butyl 6-(3-(2-(2-methoxyethyl)-2H-indazole) (5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3 ]heptane-2-carboxylate tert-Butyl 6-(3-bromo-5-methyl-1H- pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate ( Intermediate C3, 1.65 g, 4.63 mmol), 2-(2-methoxyethyl)-5-(4 ,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-yne Dazole (Intermediate B22, 2.09g, 6.95mmol), RuPhos (0.22g , 0.46mmol), RuPhos-Pd-G3 (0.39g, 0.46mmol) and and potassium phosphate (2N, 6.95 mL, 13.9 mmol) at 80 °C for 15 min. After cooling to room temperature, the reaction mixture was extracted with EtOAc and the organic phase was washed with brine. The crude residue was purified by normal phase chromatography. (eluent: c-hexane / EtOAc 100 / 0 to 50 / 50 within 30 min) Purification thereto afforded the title compound. 1 H NMR (400 MHz, DMSO-d) δ 8.35(s,1H), 8.01(t,1H), 7.74(dd,1H), 7.60( d,1H), 6.46(s,1H), 4.76-4.68(m,1H), 4.57(t, 2H), 3.99(s,2H), 3.91(s,2H), 3.83(t,2H), 3.2 4(s,3H), 2.76-2.63(m,4H), 2.25(s,3H), 1.39( s,9H);UPLC-MS-3:Rt=1.07 min;MS m / z[M+H]+ :452.3.

[0502] Step 2: tert-Butyl 6-(4-bromo-3-(2-(2-methoxyethyl)-2H) -indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azazol Pyro[3.3]heptane-2-carboxylate tert-Butyl 6-(3-(2-(2-methoxyethyl)- 2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-a Zaspiro[3.3]heptane-2-carboxylate (Step 1, 2.02 g, 4.20 m To a solution of 0.73 g (4.12 mmol) of NBS was added, and the reaction mixture was heated at room temperature. The mixture was stirred at rt for 40 min. Additional NBS (75 mg, 0.42 mmol) was added and the mixture was The reaction mixture was stirred at room temperature for an additional 10 minutes. The reaction mixture was concentrated under reduced pressure and the crude residue was purified by normal phase chromatography. Graphy (eluent: 100 / 0 to 20 / 80 c-hexane / EtOAc within 30 min) ) to give the title compound. 1 H NMR (400 MHz, DMSO-d )δ 8.44(s,1H), 8.17(s,1H), 7.71-7.65(m,2H) , 4.87-4.79(m,1H), 4.59(t,2H), 3.98(s,2H), 3 .89(s,2H), 3.84(t,2H), 3.24(s,3H), 2.75-2.6 4(m,4H), 2.28(s,3H), 1.38(s,9H); UPLC-MS-3: Rt=1.14 min;MS m / z[M+H]+:530.2 / 532.2.

[0503] Step 3: tert-Butyl 3-amino-4-(1-(2-(tert-butoxycarbonyl) -2-azaspiro[3.3]heptan-6-yl)-3-(2-(2-methoxyethyl)- ... 2H-indazol-5-yl)-5-methyl-1H-pyrazol-4-yl)- 5-chloro-6-methyl-1H-indazole-1-carboxylate tert-Butyl 6-(4-bromo-3-(2-methyl-2-propanol)-2-one in dioxane (10 mL) (2H-indazol-5-yl)-5-methyl-1H-pyrazole-1 -yl)-2-azaspiro[3.3]heptane-2-carboxylate (Step 2, 0.7 7g, 1.46mmol), tert-butyl 3-amino-5-chloro-6-methyl-4 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H - indazole-1-carboxylate (intermediate D6, 074 g, 1.82 mmol), RuPhos (0.085g, 0.18mmol), RuPhos-Pd-G3 (0.1 52 g, 0.18 mmol) and potassium phosphate (2 N, 2.73 mL, 5.46 mmol) The solution of l) was stirred at 80° C. for 2.25 hours. The reaction mixture was extracted with EtOAc, and the organic layer was The phase was washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4), filtered, Concentration under reduced pressure was carried out. The crude residue was dissolved in THF (20 mL) and treated with SiliaMetS ( Thiol (0.65 mmol) was added and the mixture was rotated at 50°C for 0.5 h. The mixture was filtered, the resin was washed with MeOH, and the filtrate was concentrated under reduced pressure. Normal phase chromatography (eluent: c-hexane / EtOAc 100 / 0 within 30 min) ~0 / 100) to give the title compound. UPLC-MS-5: Rt=1. 37 minutes; MS m / z[M+H] + :731.5 / 733.4.

[0504] Step 4: 5-chloro-4-(3-(2-(2-methoxyethyl)-2H-indazole- 5-yl)-5-methyl-1-(2-azaspiro[3.3]heptan-6-yl)-1H -pyrazol-4-yl)-6-methyl-1H-indazol-3-amine tert-Butyl 3-amino-4-(1-(2-(tert-butyl)-2-amino-4-(1-(2- ... (2-(2-hydroxycarbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(2-(2 -Methoxyethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazole -4-yl)-5-chloro-6-methyl-1H-indazole-1-carboxylate( Step 1: To a solution of 181 mg, 0.25 mmol) was added TFA (0.38 mL, 4.95 m mol) was added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give a high Drying under vacuum overnight gave the title compound as the trifluoroacetate salt, which was then purified. Used in the next step without further purification. UPLC-MS-5: Rt = 0.58 min; MS m / z [M+ H] + ;531.3 / 533.3.

[0505] Step 5: 1-(6-(4-(3-amino-5-chloro-6-methyl-1H-indazole -4-yl)-3-(2-(2-methoxyethyl)-2H-indazol-5-yl)- 5-Methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2- (I)prop-2-en-1-one Acrylic acid (0.022 mL, 0....

Claims

1. Compounds of formula (I) 【Chemical 1】 (In the formula, A is, (a) unsubstituted or containing fluoro and C １ ~C ４ -alkyl C substituted with one or more, preferably one, two or three, substituents ５ ~C ７－ Cycloal Killen; (b) a 5- to 7-membered heterocyclic ring containing one carbon-carbon double bond and one oxygen atom as a ring member; saturated heterocyclyl, wherein the heterocyclyl is unsubstituted or substituted with fluoro and Bi C １ ~C ４ - alkyl, preferably 1, 2 or 3 C １ ~C ４ - Independent of alkyl 5- to 7-membered alkyl groups substituted with one or more, preferably one, two or three, substituents selected from unsaturated heterocyclyl; (c) is unsubstituted or contains 1, 2, or 3 R Ａ２ C substituted with ６ ~C １０ a reel; (d) 1, 2, or 3 heteroatoms independently selected from N, O, and S as ring members; a 5- to 6-membered heteroaryl ring containing or R at one or more (e.g., 1, 2, or 3) carbon atoms Ａ３ is substituted with nitrogen Atoms, if present in said heteroaryl ring, are unsubstituted or C １ ~C ４ -a Lukil, - (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 substituent selected from the group consisting of a heteroaryl ring substituted with a substituent; (e) an 8-membered alkyl group containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; 0 to 3 nitrogen atoms, 0 to 2 oxygen atoms in a 10-membered heteroaryl ring or heterobicyclic ring atom, 0-1 sulfur atoms and 0-1 S(=O) ２ 1 to 3 independently selected from the group an 8-10 membered partially saturated heterobicyclic ring containing heteroatoms or heteroatom groups, The heteroaryl or heterobicyclic ring is unsubstituted or has 1, 2 or 3 carbon atoms. 2, 3, 4 or 5 R Ａ４ and said heterobicyclic ring is further substituted at carbon atom with and the nitrogen atom, if present, is unsubstituted or -(C O)-C １ ~C ４ -Alkyl or C １ ~C ４ -substituted with a substituent that is alkyl, Record C １ ~C ４ - alkyl is cyano, hydroxy, oxo, fluoro, C １ ~C ４ -Al Kokisi, C. １ ~C ４ -alkoxy-C １ ~C ４ -Alkyl-oxy, Het ｂ and NR ９ R １０ Heteroaryl optionally substituted with one or two substituents independently selected from ring or heterobicyclic ring selected from the group consisting of: Here, Het ｂ N, O, S, SO and SO ２ or a 4-, 5-, or 6-membered heterocyclic ring containing two heteroatoms or groups, wherein said heterocyclic ring Het ｂ is unsubstituted or at a carbon atom, C １ ~C ４ -Alkyl, hydroxy Ci, 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 -one or two independently selected from alkyl and wherein the heterocycle Het is substituted by one or more substituents. ｂ Furthermore, at the carbon atom, wherein the nitrogen atom is optionally substituted with Het ｂ If present in Roxy and C １ ~C ４ -alkoxy; Replaced C １ ~C ４ -optionally further substituted with alkyl; Here, A is sp ２ The remainder of the compound of formula (I) is connected by a carbon atom in the hybrid A. Combined into minutes; where: B is B １ and B ２ is selected from the group consisting of Here, B １ is unsubstituted or 1, 2, 3 or 4 R Ｂａ is replaced by C ６～１０ is aryl; B ２ is a 6- to 13-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; 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, 【Chemistry 2】 is selected from the group consisting of where n is 1, 2 or 3; R Ｌ is hydrogen, methyl, ethyl, -CH ２ -CN and -CH ２ -OH, So, G ＊ represents the point of attachment to G; G, 【Chemistry 3】 selected from the group consisting of: During the ceremony, R ２ But hydrogen, C １ ~C ３ Alkyl, —C(O)—C １ ~C ３ -Alkyl and fluoro Selected from b; R ３ is hydrogen; R ４ is hydrogen, methyl, -CH ２ F, -CH ２ -OCH ３ and -CH ２ -N(CH ３ ) ２ Selected from: R ５ is selected from hydrogen and methyl; R ６ is hydrogen; R ７ is selected from hydrogen and methyl; Here, R Ａ２ But independently, NR ９ R １０ , cyano, -(CH ２ ) ｐ -CN, Haro, OH, hydroxy-C １ ~C ４ -Alkyl, -(COOH), -(CH ２ ) ｐ -COOH , C １ ~C ４ -Alkyl, Fluoro-C １ ~C ４ -Alkyl, C １ ~C ４ -alkoxy, C １ ~C ４ -alkoxy-C １ ~C ４ -alkyl, N(R ９ ) (R １０ )-C １ ~C ４ - Alkyl, N(R ９ ) (R １０ )-C １ ~C ４ -alkyl-oxy, N(R ９ ) (R １０ )-C １ ~C ４ -alkoxy, C １ ~C ４ -Alkyl-carbonyl-oxy-C １ ~C ４ -Alkyl-oxy, hydroxy-C １ ~C ４ -alkyl-oxy, C １ ~C ４ -Arco Kishi-C １ ~C ４ -alkyl-oxy, C １ ~C ４ -alkoxy-C １ ~C ４ -Alkyl -oxy-C １ ~C ４ -Alkyl, -SO ２ -C １ ~C ４ -Alkyl, -SO ２ -C ３～ ４ -cycloalkyl, -(CH ２ ) １～２ -C ３～４ -cycloalkyl, Het ｐｙ ,- (CH ２ ) ｐ -Het ｐｙ 、-C(=O)-NR ９ R １０ 、-(CH ２ ) ｐ -C(=O) NR ９ R １０ selected from the group consisting of: Here, R Ａ３ are independently oxo, NR ９ R １０ , cyano, -(CH ２ ) ｐ -CN , halo, OH, hydroxy-C １ ~C ４ -Alkyl, -(COOH), -(CH ２ ) ｐ - COOH, C １ ~C ４ -Alkyl, Fluoro-C １ ~C ４ -Alkyl, C １ ~C ４ -Al Kokisi, C. １ ~C ４ -alkoxy-C １ ~C ４ -alkyl, N(R ９ ) (R １０ )-C １ ~C ４ -alkyl, N(R ９ ) (R １０ )-C １ ~C ４ -alkyl-oxy, N(R ９ ) (R １０ )-C １ ~C ４ -alkoxy, C １ ~C ４ -Alkyl-carbonyl-oxy-C １ ~C ４ -Alkyl-oxy, hydroxy-C １ ~C ４ -alkyl-oxy, C １ ~C ４ -alkoxy-C １ ~C ４ -alkyl-oxy, C １ ~C ４ -alkoxy-C １ ~C ４ - Alkyl-oxy-C １ ~C ４ -Alkyl, -SO ２ -C １ ~C ４ -Alkyl, -SO ２ -C ３～４ -cycloalkyl, -(CH ２ ) １～２ -C ３～４ -cycloalkyl, Het ｐｙ 、-(CH ２ ) ｐ -Het ｐｙ 、-C(=O)-NR ９ R １０ 、-(CH ２ ) ｐ -C (=O)NR ９ R １０ , (CH ２ ) ｐ -NR ９ R １０ selected from the group consisting of: Here, R Ａ４ However, independently, cyano, CO ２ H, halo, C １ ~C ４ -Alkyl, full Oro-C １ ~C ４ -Alkyl, hydroxy, hydroxy-C １ ~C ４ -Alkyl, Hydro Kishi-C １ ~C ４ -alkyl-oxy, C １ ~C ４ -alkoxy, C １ ~C ４ -Alcoki Sea 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 １ ０ N-C １ ~C ４ -Alkyl-oxy-(CO)-C １ ~C ４ - alkyl Selected; where: p is 1, 2, or 3; 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 ｐｙ contains 1 or 2 heteroatoms independently selected from O, N and S; or S-oxide (SO) or S-dioxide (SO ２ ) groups, including 4-membered, 5-membered a 6-, 6- or 7-membered saturated heterocyclic ring, wherein the heterocyclic ring has an oxy group at one carbon atom. and optionally substituted with xo, wherein the heterocycle is optionally substituted at one or more carbon atoms with １ ~C ４ -alkoxy, halo, C １ ~C ４ -Alkyl, hydroxy-C １ ~C ４ -Alkyl, and and Fluoro-C １ ~C ４ - any one, two or three substituents independently selected from alkyl; optionally further substituted, wherein a nitrogen atom, if present in said heterocycle, is １０ Any further substituted with; or Het ｐｙ is a 5- or 6-membered heteroaryl containing 1, 2 or 3 nitrogen atoms; wherein the heteroaryl ring is an NR ９ R １０ , -C(=O)-NR ９ R １０ , Haro, C １ ~C ４ -Alkyl, hydroxy-C １ ~C ４ -Alkyl, Fluoro-C １ ~C ４ -Alkyl, cyano, OH, and C １ ~C ４ -alkoxy optionally substituted with one or more (e.g., 1, 2, or 3) substituents selected from the group consisting of: Each R Ｂａ are independently hydroxy, NH ２ , C １ ~C ４ - consisting of alkyl and halo selected from the group; Each R Ｂｂ But independently, C １ ~C ４ -Alkyl, cyclopropyl, fluoro-C １ ~C ３ -Alkyl, cyano, halo, NH ２ and C １ ~C ３ -alkoxy (can be) 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. salt.

2. A is, (a) unsubstituted or containing fluoro and C １ ~C ４ -alkyl C substituted with one or more, preferably one, two or three, substituents ５ ~C ７－ Cycloal Killen; (b) a 5- to 7-membered heterocyclic ring containing one carbon-carbon double bond and one oxygen atom as a ring member; saturated heterocyclyl, wherein said heterocyclyl is unsubstituted or substituted; Ruolo and C １ ~C ４ - alkyl, preferably 1, 2 or 3 C １ ~C ４ -Alkyl and heterocyclyl; (c) is unsubstituted or contains 1, 2, or 3 R Ａ２ C substituted with ６ ~C １０ a reel; (d) 1, 2, or 3 heteroatoms independently selected from N, O, and S as ring members; a 5- to 6-membered heteroaryl ring containing or R at one or more (e.g., 1, 2, or 3) carbon atoms Ａ３ is substituted with nitrogen Atoms, if present in said heteroaryl ring, are unsubstituted or C １ ~C ４ -a Lukil, - (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 substituent selected from the group consisting of a heteroaryl ring substituted with a substituent; (e) an 8- to 10-membered heteroaryl ring containing 1, 2, or 3 nitrogen atoms; , each nitrogen atom 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 Roxy, 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 One or two independently selected from wherein the heteroaryl ring is unsubstituted or 1, 2, 3, 4 or 5 R at the atom Ａ４ is replaced by; Here, Het ｂ N, O, S, SO and SO ２ or a 4-, 5-, or 6-membered heterocyclic ring containing two heteroatoms or groups, wherein said heterocyclic ring Het ｂ is unsubstituted or at a carbon atom, C １ ~C ４ -Alkyl, hydroxy Ci, 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 -one or two independently selected from alkyl and wherein the heterocycle Het is substituted by one or more substituents. ｂ Furthermore, at the carbon atom, wherein the nitrogen atom is optionally substituted with Het ｂ If present in Roxy and C １ ~C ４ -alkoxy; Replaced C １ ~C ４ - a heteroaryl ring optionally further substituted with alkyl; (f) 1 to 3 nitrogen atoms, or 1 to 2 oxygen atoms, or 1 sulfur atom in the heterobicyclic ring Yellow atom or one S(=O) ２ an 8-10 membered partially saturated heterobicyclic ring containing a group, The heterobicyclic ring is unsubstituted or has 1, 2, 3, 4 or 5 carbon atoms. 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 -a Rukill or C １ ~C ４ -substituted with a substituent which is alkyl, １ ~C ４ -Arki The group 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 Selected independently from optionally substituted with one or two substituents selected from the group consisting of: Here, Het ｂ N, O, S, SO and SO ２ or a 4-, 5-, or 6-membered heterocyclic ring containing two heteroatoms or groups, wherein said heterocyclic ring Het ｂ is unsubstituted or at a carbon atom, C １ ~C ４ -Alkyl, hydroxy Ci, 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 -one or two independently selected from alkyl and wherein the heterocycle Het is substituted by one or more substituents. ｂ Furthermore, at the carbon atom, wherein the nitrogen atom is optionally substituted with Het ｂ If present in Roxy and C １ ~C ４ -alkoxy; Replaced C １ ~C ４ -heterobicyclic ring optionally further substituted with alkyl The compound of claim 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. salt.

3. Het ｂ N, O, S, SO and SO ２ One or two independently selected from a 4-, 5- or 6-membered heterocyclic ring containing a hetero atom or group, wherein the heterocyclic ring Het ｂ is unsubstituted or at a carbon atom, C １ ~C ４ -Alkyl, hydroxy, cyano No, Fluoro, C １ ~C ４ -alkoxy-hydroxy-C １ ~C ４ -Alkyl, hydroxy Sea C １ ~C ４ -Alkyl, C １ ~C ４ -alkoxy and fluoro-C １ ~C ４ -Arki wherein the heterocycle H is substituted with one or two substituents independently selected from et ｂ is further optionally substituted at a carbon atom with oxo, wherein the nitrogen atom is H et ｂ If present in １ ~C ４ - is optionally further substituted with alkyl, １ ~C ４ - alkyl is fluoro, hydroxy and C １ ~C ４ -alkoxy optionally substituted with 1 to 3 substituents selected from the group consisting of methyl, ... 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 substituted with ６～１ ０ aryl, and each R Ｂａ are independently hydroxy, C １ ~C ４ - alkyl and halo selected from the group consisting of: B ２ is a 6-10 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 But independently, C １ ~C ４ -alkyl (preferably methyl), fluoro-C １ ~C ３ -Alkyl, cyano, halo, NH ２ and C １ ~C ３ - from the group consisting of alkoxy Selected, Het ｐｙ contains 1 or 2 heteroatoms independently selected from O, N and S; or S-oxide (SO) or S-dioxide (SO ２ ) groups, including 4-membered, 5-membered a 6-, 6- or 7-membered saturated heterocyclic ring, wherein the heterocyclic ring has an oxy group at one carbon atom. and optionally substituted with xo, wherein the heterocycle is optionally substituted at one or more carbon atoms with １ ~C ４ -alkoxy, halo, C １ ~C ４ -Alkyl, hydroxy-C １ ~C ４ -Alkyl, and and Fluoro-C １ ~C ４ - 1, 2 or 3 substituents independently selected from alkyl wherein when a nitrogen atom is present in said heterocycle, R １０ Optionally, is replaced by; or Het ｐｙ is a 5- or 6-membered heteroaryl containing 1, 2 or 3 nitrogen atoms; wherein the heteroaryl ring is an NR ９ R １０ , Haro, C １ ~C ４ -Al Kyl, Cyano, OH, and C １ ~C ４ - one or more independently selected from alkoxy (e.g. optionally substituted with at least one substituent (e.g., 1, 2, or 3); Here, R Ａ４ However, independently, cyano, CO ２ H, halo, C １ ~C ４ -Alkyl, full Oro-C １ ~C ４ -Alkyl, hydroxy, hydroxy-C １ ~C ４ -Alkyl, Hydro Kishi-C １ ~C ４ -alkyl-oxy, C １ ~C ４ -alkoxy, C １ ~C ４ -Alcoki Sea C １ ~C ４ -alkyl-oxy, -NR ９ R １０ , R ９ R １０ N-C １ ~C ４ -Al Kyl-oxy, -(CO)-C １ ~C ４ - alkyl, or the compound according to 2; 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. salt.

4. Het ｂ N, O, S, SO and SO ２ One or two he independently selected from a 4-, 5- or 6-membered heterocyclic ring containing a hetero atom or group, wherein the heterocyclic ring Het ｂ is unsubstituted or at a carbon atom, C １ ~C ４ -Alkyl, hydroxy, cyano No, Fluoro, C １ ~C ４ -alkoxy-hydroxy-C １ ~C ４ -Alkyl, hydroxy Sea C １ ~C ４ -Alkyl, C １ ~C ４ -alkoxy and fluoro-C １ ~C ４ -Arki wherein the heterocycle H is substituted with one or two substituents independently selected from et ｂ is further optionally substituted at a carbon atom with oxo, wherein the nitrogen atom is H et ｂ If present in １ ~C ４ - is optionally further substituted with alkyl, １ ~C ４ - alkyl is fluoro, hydroxy and C １ ~C ４ -alkoxy optionally substituted with 1 to 3 substituents selected from the group consisting of methyl, ... B ２ is a 6-10 membered heteroaryl containing 1, 2 or 3 nitrogen atoms, wherein B ２ is unsubstituted or has 1, 2, 3 or 4 R Ｂｂ is replaced by; Het ｐｙ contains one or two heteroatoms independently selected from O, N and S. or S-oxide (SO) or S-dioxide (SO ２ ) groups, including 4-membered, 5-membered a 6-, 6- or 7-membered saturated heterocyclic ring, wherein the heterocyclic ring has an oxy group at one carbon atom. and optionally substituted with xo, wherein the heterocycle is optionally substituted at one or more carbon atoms with １ ~C ４ -alkoxy, halo, C １ ~C ４ -Alkyl, hydroxy-C １ ~C ４ -Alkyl, and and Fluoro-C １ ~C ４ - 1, 2 or 3 substituents independently selected from alkyl wherein when a nitrogen atom is present in said heterocycle, R １０ Optionally, is replaced by; or Het ｐｙ is a 5- or 6-membered heteroaryl containing 1, 2 or 3 nitrogen atoms; wherein the heteroaryl ring is an NR ９ R １０ , Haro, C １ ~C ４ -Al Kyl, Cyano, OH, and C １ ~C ４ - one or more independently selected from alkoxy (e.g. optionally substituted with at least one substituent (e.g., 1, 2, or 3); 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-oxy, -NR ９ R １０ and R ９ R １０ N-C １ ~C ４ -Alkyl- The compound according to any one of claims 1 to 3, selected from the group consisting of 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. salt.

5. G, 【Chemistry 4】 The compound according to any one of claims 1 to 4, or a stereoisomer thereof, or an aryl group 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.

6. L, 【Chemistry 5】 The compound according to any one of claims 1 to 5, or a stereoisomer thereof, or an aryl group 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.

7. R Ｌ is hydrogen, or a stereoisomer thereof, or an atropisomer thereof. an isomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof; or a pharmaceutically acceptable salt of an atropisomer thereof.

8. C is C １ ~C ３ Alkyl, Fluoro-C １ ~C ３ Alkyl, CH ２ -Selected from CN The compound according to any one of claims 1 to 7, or a stereoisomer thereof, or an atomiZer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof a salt, or a pharmaceutically acceptable salt of an atropisomer thereof.

9. B, 【Chemistry 6】 wherein B is unsubstituted or is substituted with 1, 2 or 3 halo or methyl groups. A compound according to any one of claims 1 to 8, or a stereoisomer thereof, or or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof or a pharmaceutically acceptable salt of an atropisomer thereof.

10. B, 【Chemistry 7】 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 - Select from alkyl And; R Ｂ４ are independently selected from hydrogen, halo, and C １ ~C ４ - alkyl, or R Ｂ３ and R Ｂ４ together with the atoms to which they are attached, are fused to an aromatic ring containing X. forming a six-membered ring; R Ｂ５ are independently selected from hydrogen, halo, and C １ ~C ４ - alkyl, as claimed in claim 1 10. A compound according to any one of claims 1 to 9, 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. salt.

11. R Ｂ２ are independently hydrogen, NH ２ , and C.H. ３ 10. The compound according to claim 1, wherein the compound is selected from the group consisting of 0, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or Pharmaceutically acceptable salts of the atropisomers.

12. R Ｂ４ are independently selected from hydrogen, halo, and C １ ~C ４ - alkyl, as claimed in claim 1 10. A compound according to claim 0 or 11, or a stereoisomer thereof, or an atropisomer thereof, or a drug thereof. a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or an atropisomer thereof Pharmaceutically acceptable salts of the active form.

13. R Ｂ１ are independently selected from hydrogen and methyl. The compound according to any one of claims 1 to 5, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof. or a pharmaceutically acceptable salt of its stereoisomer, or a pharmaceutically acceptable salt of its atropisomer. A physiologically acceptable salt.

14. R Ｂ１ is hydrogen, or a steric compound thereof according to any one of claims 10 to 13 isomer, or atropisomer thereof, or a pharmaceutically acceptable salt thereof, or stereoisomer thereof or a pharmaceutically acceptable salt of an atropisomer thereof.

15. R Ｂ３ and R Ｂ４ each independently represents a halo and C １ ~C ４ - alkyl The compound according to any one of claims 10 to 14, or a stereoisomer thereof, or an aryl group 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.

16. R Ｂ３ is a halo, and R Ｂ４ is C １ ~C ４ -alkyl A compound according to any one of claims 1 to 4, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutical a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or an atropisomer thereof Pharmaceutically acceptable salts of the body.

17. R Ｂ３ is chloro and R Ｂ４ is methyl. The compound, 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. Acceptable salts.

18. R Ｂ３ is chloro and R Ｂ４ is chloro. The compound, 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. Acceptable salts.

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

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

21. Compounds of formula (Ia) 【Chemistry 8】 wherein A, B and C are as defined in any one of claims 1 to 20. 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. salt.

22. A is unsubstituted or is selected from the group consisting of fluoro and C １ ~C ４ -alkyl C substituted with one or more, preferably one, two or three, substituents ５ ~C ７－ Cycloal The compound of formula (I) or formula (Ia) according to any one of claims 1 to 21, which is alkylene. a compound thereof, 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. Salt that can be used.

23. A is, 【Chemistry 9】 wherein W is O or C(R ｗ ) ２ and each R ｗ are independently hydrogen and fluorine and R ｃ is hydrogen or C １ ~C ４ -alkyl, A is fluoro and C １ ~C ４ -alkyl, optionally further substituted with 1, 2 or 3 substituents independently selected from A compound of formula (I) or formula (Ia) according to any one of claims 1 to 22, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or A pharmaceutically acceptable salt of a stereoisomer, or a pharmaceutically acceptable salt of an atropisomer thereof.

24. A is unsubstituted or contains 1, 2 or 3 R Ａ２ is a phenyl substituted with 22. A compound of formula (I) or formula (Ia) according to any one of claims 1 to 21, or or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof A pharmaceutically acceptable salt of the isomer, or a pharmaceutically acceptable salt of the atropisomer.

25. A has 1, 2 or 3 heteroatoms independently selected from N, O and S as ring members; a 5- to 6-membered heteroaryl ring containing or R at one or more (e.g., 1, 2, or 3) carbon atoms Ａ３ is substituted with nitrogen atoms When present in the heteroaryl ring, it is unsubstituted or １ ~C ４ -Al Kill, -(CH ２ ) １～２ -C ３～４ -cycloalkyl, hydroxy-C １ ~C ４ -Al Kill, Fluoro-C １ ~C ４ -Alkyl, C １ ~C ４ -alkoxy-C １ ~C ４ -Arki Lu, 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 ) substituted with a substituent selected from the group consisting of:

1. A compound of formula (I) or formula (Ia) according to any one of claims 1 to 9, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical preparation of a stereoisomer thereof or a pharmaceutically acceptable salt of an atropisomer thereof.

26. A is unsubstituted or NH ２ , cyano, halo, OH, hydroxy-C １ ~C ４ - Alkyl, —COOH, C １ ~C ４ -Alkyl, Fluoro-C １ ~C ４ -Alkyl, C １ ~C ４ -alkoxy, di-C １ ~C ４ -Alkylamino-C １ ~C ４ -Alkyl-oxy , C １ ~C ４ -Alkyl-carbonyl-oxy-C １ ~C ４ -Alkyl-oxy, hydro Kishi-C １ ~C ４ -alkyl-oxy, C １ ~C ４ -alkoxy-C １ ~C ４ -Alkyl -oxy, C １ ~C ４ -alkoxy-C １ ~C ４ -Alkyl-oxy-C １ ~C ４ -Al Kill, -C(=O)-NR ９ R １０ , N.R. ９ R １０ , Het ｐｙ and -(CH ２ ) ｐ -H et ｐｙ pyridine-1 substituted with one, two or three substituents independently selected from -yl, pyridin-2-yl or pyridin-3-yl; where: p is 1 or 2; R ９ is hydrogen and C １ ~C ４ - 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 - alkyl, Het ｐｙ But NR ９ａ R １０ａ and R ９ａ and R １０ａ together with the nitrogen, O, N (pyrrolidin-1-yl, azetidine- 1-yl, morpholin-1-yl) and S, or its N-oxide, or its S-oxy one or two heteroatoms independently selected from S-oxide (SO) or S-dioxide; and forming a 4-, 5-, or 6-membered saturated or unsaturated heterocyclic ring containing Optionally substituted at one carbon atom in the heterocycle with oxo, wherein said heterocycle is , C １ ~C ４ -alkoxy, halo, C １ ~C ４ -Alkyl, hydroxy-C １ ~C ４ -a Alkyl and Fluoro-C １ ~C ４ - 1, 2 or 3 substituents independently selected from - alkyl further substituted with a substituent; or R ９ａ and R １０ａ together with the nitrogen, a 4- or 5-membered group containing 1, 2 or 3 nitrogen atoms forming a 1- or 6-membered heteroaryl ring, wherein said heteroaryl ring is 22. The compound of formula (I) or formula (I) according to any one of claims 1 to 21, optionally substituted with a group. a) the compound of formula (I), a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or A pharmaceutically acceptable salt of a stereoisomer, or a pharmaceutically acceptable salt of an atropisomer thereof.

27. A is NH ２ , Cyano, Halo, C １ ~C ４ -Alkyl, Fluoro-C １ ~C ４ -Arki Lu, C １ ~C ４ -alkoxy, di-C １ ~C ４ -Alkylamino-C １ ~C ４ -Alkyl -oxy, -C(=O)-NR ９ R １０ , N.R. ９ R １０ , 【Chemistry 10】 pyridinyl substituted with 1, 2 or 3 substituents independently selected from wherein p is 0, 1 or 2; R ２２ is hydrogen or C １ ~C ４ - alkyl or amino; R ９ is hydrogen and C １ ~C ４ - 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 -alkyl. or a compound of formula (Ia), 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. salt.

28. A is, 【Chemistry 11】 wherein R ２３ But hydrogen, C ３ ~C ６ -cycloalkyl, C １ ~C ４ -Alkyl where A is unsubstituted or is F, CH ３ , C.H. ２ F, CHF ２ and CF ３ 22. The compound according to claim 1, wherein the compound is substituted with one, two or three substituents independently selected from a compound of formula (I) or formula (Ia) according to any one of claims 1 to 5; 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. salt.

29. A is unsubstituted or C １ ~C ４ -alkoxy and CH ３ are selected independently from 1, 2 or 3 substituents, 1. A compound of formula (I) or formula (Ia) according to any one of claims 1 to 9, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical preparation of a stereoisomer thereof or a pharmaceutically acceptable salt of an atropisomer thereof.

30. A is, 【Chemistry 12】 is selected from the group consisting of In the formula, R ２４ But hydrogen, C １ ~C ４ -Alkyl, hydroxy-C １ ~C ４ - alkyl, C １ ~C ４ -alkoxy-C １ ~C ４ -alkyl, -NR ９ R １０ C １ ~C ４ -Alkyl , -SO ２ -C １ ~C ４ -Alkyl, -SO ２ -C ３～４ -cycloalkyl or -(CH ２ ) １～２ -C ３～４ -cycloalkyl; R ４ａ , R ４ｂ , R ４ｃ and R ４ｄ each independently selected from hydrogen and C １ ~C ４ -a 22. The compound of formula (I) or (I) according to any one of claims 1 to 21, selected from the group consisting of alkyl, aryl, methyl ... a) the 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. salt.

31. A is, 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 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 -a It is Lukil; 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 -Al Selected from kill; R ａｅ is hydrogen and C １ ~C ４ -alkyl, wherein said alkyl is selected from the group consisting of: Kill, cyano, hydroxy, fluoro, C １ ~C ４ -alkoxy, C １ ~C ４ -Arco Kishi-C １ ~C ４ -Alkyl-oxy, Het ｂ and NR ９ R １０ or optionally substituted with two substituents; R Ａｅ is hydrogen, -(CO)-C １ ~C ４ -Alkyl and C １ ~C ４ -From alkyl wherein said C １ ~C ４ In each case, alkyl is cyano, hydroxyl, Roxy, Fluoro, C １ ~C ４ -alkoxy, C １ ~C ４ -alkoxy-C １ ~C ４ -a Alkyl-oxy, Het ｂ and NR ９ R １０ optionally one or two substituents selected from Replaced; 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; Here, Het ｂ N, O, S, SO and SO ２ or a 4-, 5-, or 6-membered heterocyclic ring containing two heteroatoms or groups, wherein said heterocyclic ring Het ｂ is unsubstituted or at a carbon atom, C １ ~C ４ -Alkyl, hydroxy Ci, cyano, fluoro, hydroxy-C １ ~C ４ -Alkyl, C １ ~C ４ -Alkoxy and and Fluoro-C １ ~C ４ - one or two substituents independently selected from alkyl substituted, wherein the heterocycle Het ｂ is optionally substituted with oxo at a carbon atom; 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 optionally further substituted with (I) or a compound of formula (Ia); or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a pharmaceutically acceptable salt of an atropisomer thereof.

32. 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 -Al Selected from kill; R is hydrogen or C １ ~C ４ -alkyl, or halo or fluoro-C １ ~C ４ -Al It is a kill; 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: Kill, cyano, hydroxy, fluoro, C １ ~C ４ -alkoxy, C １ ~C ４ -Arco Kishi-C １ ~C ４ -Alkyl-oxy, Het ｂ and NR ９ R １０ or optionally substituted with two substituents; 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; Here, Het ｂ N, O, S, SO and SO ２ or a 4-, 5-, or 6-membered heterocyclic ring containing two heteroatoms or groups, wherein said heterocyclic ring Het ｂ is unsubstituted or at a carbon atom, C １ ~C ４ -Alkyl, hydroxy Ci, cyano, fluoro, hydroxy-C １ ~C ４ -Alkyl, C １ ~C ４ -Alkoxy and and Fluoro-C １ ~C ４ - one or two substituents independently selected from alkyl substituted, wherein the heterocycle Het ｂ is optionally substituted with oxo at a carbon atom; 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 substituted or unsubstituted, (I) or a compound of formula (Ia); 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. salt.

33. A is, 【Chemistry 17】 Any of claims 1 to 21, or claim 31 or claim 32 selected from the group consisting of a compound of formula (I) or formula (Ia) according to any one of claims 1 to 4, 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. salt.

34. 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 - alkyl (e.g., methyl) Selected from; 34. A compound of formula (I) or formula (Ia) according to claim 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. salt.

35. 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 Bi-(CH ２ ) ２ -JiC １ ~C ４ - alkylamino, or R Ａｅ But hydrogen, fluoro-C １ ~C ４ -Alkyl and C １ ~C ４ - alkyl Selected; Het ｂ is a four-membered ring containing one nitrogen atom and one oxygen atom, or one or two nitrogen atoms , 5-membered or 6-membered heterocycle, wherein the heterocycle is unsubstituted or has a carbon atom Leave it, C １ ~C ４ -Alkyl, hydroxy-C １ ~C ４ -Alkyl, C １ ~C ４ -Al substituted with one or two substituents independently selected from koxy and fluoro; and when a nitrogen atom is present in the heterocycle, C １ ~C ４ - alkyl optionally further substituted A compound of formula (I) or formula (Ia) according to any one of claims 31 to 34, thing, 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. salt.

36. R ａｅ is hydrogen, methyl, -CH ２ -CN, -(CH ２ ) ２ -OH, -(CH ２ ) ２ - OCH ３ ,-(EH ２ )-C(CH ３ ) ２ -OH、-(EH ２ ) ２ -O-(CH) ２ ) ２ - OCH ３ , -(CH ２ ) ２ -N(CH ３ ) ２ and -(CH ２ ) ２ -Het ｂ A group consisting of Selected from; Here, the Het ｂ is one nitrogen atom and one oxygen atom, or one to two nitrogen atoms a 4-, 5-, or 6-membered heterocyclic ring containing a heterocyclic ring, wherein the heterocyclic ring is unsubstituted or is a carbon atom, C 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 -Alkyl Optionally further substituted, formula (I) or formula (I) according to any one of claims 31 to 35 Ia) compound of formula 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. salt.

37. R ａｅ is hydrogen, methyl, -CH ２ -CN, -(CH ２ ) ２－ OH, -(CH ２ ) ２ - OCH ３ ,-(EH ２ )-C(CH ３ ) ２ -OH、-(EH ２ ) ２ -O-(CH) ２ ) ２ - OCH ３ , -(CH ２ ) ２ -N(CH ３ ) ２ , and -(CH ２ ) ２ -Het ｂ A group consisting of wherein Het ｂ Azetidin-1-yl, pyrrolidin-1-yl, pyrrolidin-1-yl, roridin-3-yl and morpholin-1-yl, wherein said compound is selected from the group consisting of wherein the ring is independently selected from methyl, hydroxymethyl, methoxy, and fluoro.

37. The compound according to claim 31, further optionally substituted with one or two substituents. or a stereoisomer or an atropisomer thereof of formula (I) or formula (Ia) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or A pharmaceutically acceptable salt of an atropisomer of

38. 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 - selected from the group consisting of alkylamino The compound of formula (I) or formula (Ia) according to any one of claims 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. salt.

39. Formula (Ib ＊ ) compounds 【Chemistry 18】 (In the formula, A, C, R Ｂ２ , R Ｂ３ and R Ｂ４ is described in any one of claims 1 to 38 wherein A is unsubstituted or is selected from the group consisting of aryl, ... substituted as described in paragraph (a) above), or a pharmaceutically acceptable salt thereof.

40. Formula (Ic ＊ ) compounds 【Chemistry 19】 (In the formula, C, R Ａ２ , R Ｂ２ , R Ｂ３ and R Ｂ４ is any one of claims 1 to 39 wherein a is 0, 1, 2 or 3), or a pharmaceutically Acceptable salts.

41. Formula (Id ＊ ) compounds 【Chemistry 20】 (In the formula, C, R Ｂ２ , R Ｎ , R Ｂ３ and R Ｂ４ is described in any one of claims 1 to 40. As described above, wherein 【Chemical formula 21】 The lines represent single or double bonds; R ａｅ as defined above).

42. 42. A compound according to any one of claims 1 to 41 selected from the compounds of any one of the Examples. or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof a salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof Acceptable salt.

43. a(R)-1-(6-(4-(5-chloro-6-methyl-1H-indazole-4-yl) 1H-indazol-5-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazo (2-azaspiro[3.3]heptan-2-yl)prop-2-ene- 1-on, a(R)(S)-1-(6-(4-(5-chloro-6-methyl-1H-indazole- 4-yl)-3-(1-(2-(3-fluoropyrrolidin-1-yl)ethyl)-1H- (indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspipri b)[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)pro Pa-2-en-1-on, a(R) 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl )-3-(2-(2-hydroxy-2-methylpropyl)-2H-indazole-5-yl (1H-pyrazol-1-yl)-5-methyl-1H-pyrazol-1-yl-2-azaspiro[3.3]heptane -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 (1H-pyrazol-1-yl)-5-methyl-1H-pyrazol-1-yl-2-azaspiro[3.3]heptane -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-pyrazole-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)propa-2 -en-1-one, a(R) 1-(6-(4-(3-amino-5-chloro-6-methyl-1H-indazole) (2-(2-methoxyethyl)-2H-indazol-5-yl) -5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2 -yl)prop-2-en-1-one, a(R) 1-(6-(4-(3-amino-5-chloro-6-methyl-1H-indazole) (4-yl)-5-methyl-3-phenyl-1H-pyrazol-1-yl)-2-aza Spiro[3.3]heptan-2-yl)prop-2-en-1-one a compound selected from or a pharmaceutically acceptable salt thereof.

44. 1-{6-[(4M)-4-(5-chloro-6-methyl-1H-indazole-4-yl] 1H-indazol-5-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazo -1-yl]-2-azaspiro[3.3]heptan-2-yl}prop-2-ene- 1-on, 1-{6-[(4M)-4-(5-chloro-6-methyl-1H-indazole-4-yl] (3S)-3-fluoropyrrolidin-1-yl]ethyl)-3-(1-{2-[(3S)-3-fluoropyrrolidin-1-yl]ethyl}-1 1H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl]-2-aza spiro[3.3]heptan-2-yl}prop-2-en-1-one, 1-{6-[(4M)-4-(5-chloro-6-methyl-1H-indazole-4-yl] 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-indazole-4-yl) 2-(2-methoxyethyl)-2H-indazol-5-yl]-5-methyl {2-azaspiro[3.3]heptan-2-yl}-1H-pyrazol-1-yl lopa-2-en-1-one, 1-(6-{(4M)-4-(5-chloro-6-methyl-1H-indazole-4-yl) 2-(2-hydroxy-2-methylpropyl)-2H-indazole-5- yl]-5-methyl-1H-pyrazol-1-yl}-2-azaspiro[3.3]hepta (2-en-2-yl)prop-2-en-1-one, 1-{6-[(4M)-4-(5-chloro-6-methyl-1H-indazole-4-yl] 2-[2-(2-methoxyethoxy)ethyl]-2H-indazole-5- {5-methyl-1H-pyrazol-1-yl}-2-azaspiro[3.3]hepta prop-2-en-1-one, 1-(6-{(4M)-4-(5-chloro-6-methyl-1H-indazole-4-yl) (phenyl)-3-[4-(hydroxymethyl)phenyl]-5-methyl-1H-pyrazole-1 -yl}-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one 、 1-(6-{(4M)-4-(5-chloro-6-methyl-1H-indazole-4-yl) (2-fluoro-4-(2-methoxyethoxy)phenyl)-3-[2-fluoro-4-(2-methoxyethoxy)phenyl]-5-methyl-1 H-pyrazol-1-yl}-2-azaspiro[3.3]heptan-2-yl)propan- 2-en-1-one, 1-(6-{(4M)-4-(3-amino-5-chloro-6-methyl-1H-indazoline 2-(2-methoxyethyl)-2H-indazol-5-yl ]-5-methyl-1H-pyrazol-1-yl}-2-azaspiro[3.3]heptane- 2-yl)prop-2-en-1-one, 1-{6-[(4M)-4-(3-amino-5-chloro-6-methyl-1H-indazoline [0044] [5-methyl-3-phenyl-1H-pyrazol-1-yl]-2-azoline Zaspiro[3.3]heptan-2-yl}prop-2-en-1-one a compound selected from or a pharmaceutically acceptable salt thereof.

45. A crystalline form of the compound of any one of claims 1 to 44.

46. A compound according to any one of claims 1 to 45, or a compound thereof, for use as a medicament. Stereoisomers, or atropisomers thereof, or pharmaceutically acceptable salts thereof, or crystalline forms thereof or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof. Acceptable salt.

47. A compound according to any one of claims 1 to 46 for use in treating cancer or solid tumors. or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof a salt thereof, or a crystalline form thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or an atropine thereof Pharmaceutically acceptable salts of the isomers.

48. A compound according to any one of claims 1 to 47, or a stereoisomer thereof, or an atron thereof. or a pharmaceutically acceptable salt thereof, or a crystalline form thereof, or a stereoisomer thereof or a pharmaceutically acceptable salt of an atropisomer thereof, and at least one and a pharmaceutically acceptable excipient.

49. Compound of formula (2a) 【Chemical 22】 wherein A, B and C are as defined in any one of claims 1 to 48; R ２５ is hydrogen or a nitrogen-protecting group), or a salt thereof.

50. Formula (2b ＊ ) compounds 【Chemical 23】 (In the formula, A, C, R Ｂ２ , R Ｂ３ and R Ｂ４ is described in any one of claims 1 to 49 As described above, R ２５ is hydrogen or a nitrogen-protecting group, where A is unsubstituted or substituted as claimed in any one of claims 1 to 49), or salt.

51. Formula (2c ＊ ) compounds 【Chemistry 24】 (In the formula, C, R Ａ２ , R Ｂ２ , R Ｂ３ and R Ｂ４ is any one of claims 1 to 50 As described, R ２５ is hydrogen or a nitrogen-protecting group, where a is 0, 1, 2 or 3), or a pharmaceutically acceptable salt thereof.

52. Formula (2d ＊ ) compounds 【Chemistry 25】 (In the formula, C, R ａｅ , R Ｂ２ , R Ｎ , R Ｂ３ and R Ｂ４ is any one of claims 1 to 51 as described in claim 1, ２５ is hydrogen or a nitrogen-protecting group, 【Chemical 26】 The line indicates a single or double bond), or a salt thereof.

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