BR112022012128B1 - PYRAZOLYL DERIVATIVES USEFUL AS ANTICANCER AGENTS, THEIR USES, PHARMACEUTICAL COMPOSITION AND COMBINATION, AND KIT - Google Patents

Abstract

PYRAZOLYL DERIVATIVES USEFUL AS ANTICANCER AGENTS. The present invention 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 a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof; to a method for manufacturing said compound and therapeutic uses thereof. The present invention further relates to a combination of pharmacologically active agents and a pharmaceutical composition comprising said compound.

Description

Sequence Listing

[0001] This application contains a Sequence Listing, which was submitted electronically in ASCII format and is incorporated herein by reference in its entirety. Said ASCII copy, created on December 1, 2020, is named PAT058632-WO-PCT02_SL.txt and is 7192 bytes in size.

Field of Invention

[0002] The present invention relates to pyrazolyl derivative compounds; the use thereof for inhibiting KRAS G12C, HRAS G12C or NRAS G12C and in particular KRAS G12C; methods for treating or preventing diseases, in particular cancer, using said compounds; and processes and intermediates for producing these compounds. The invention also provides such pyrazolyl derivative compounds for use in the treatment of cancer and specific cancers as defined herein.

Background of the Invention

[0003] RAS are small GTPases that act as molecular on/off switches that adopt an active/inactive state when bound to GTP/GDP, respectively. In response to growth factors, guanine exchange factors exchange GDP for GTP, binding Ras. GTP-bound RAS adopts conformations that recruit effector proteins to the plasma membrane, thereby activating signaling cascades causing cell growth, proliferation, and survival. These cancer-promoting signals are very transient and tightly controlled. They are immediately turned off by the GTPase activity of RAS itself, largely due to 100,000-fold acceleration by GTPase-activating proteins (GAPs) (Bos JL et al., Cell, Volume 129, Issue 5, June 1, 2007, pages 865–877). In contrast, RAS mutants are insensitive to these GAPs, causing RAS mutants to remain in the GTP-bound state longer and shift the GTP/GDP cycle according to its intrinsic hydrolysis rate toward the bound state.

[0004] The three RAS genes constitute the gene family most frequently mutated in cancer, with RAS mutations found in ~25% of human tumors. Among the 3 paralogs, KRAS mutations are most frequent (85% of all RAS-driven cancers), while NRAS and HRAS mutations are less frequently reported (12% and 3%, respectively). The majority of KRAS mutations occur at the hotspot residues G12, G13, and Q61. KRAS G12C mutations represent about 12% of all KRAS mutations and are prevalent in patients with lung cancer (~13% lung adenocarcinoma (LUAC)), ~3-5% colon adenocarcinomas, smaller fractions of other cancers, and in about 20% of MYH-associated polyposis colorectal adenomas (COSMIC database v80; A. Aime' et al, Cancer genet. 2015, 208:390-5).

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

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

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

Summary of the Invention

[0008] The compounds described in the present invention selectively react with and inhibit the KRAS, HRAS or NRAS G12C mutant proteins by forming an irreversible covalent bond with the cysteine at position 12. This locks the RAS mutant protein in the inactive state. The irreversible binding of these compounds disrupts signaling downstream of K-RAS. The compounds described in the present invention can be used for the treatment of cancer, particularly, the treatment of a cancer characterized by a KRAS, HRAS or NRAS G12C mutation, more particularly, a cancer characterized by a KRAS G12C mutation.

[0009] The invention therefore provides compounds, their pharmaceutically acceptable salts thereof, pharmaceutical compositions and combinations thereof. The compounds have the ability to selectively bind to and inhibit the G12C mutant of KRAS, HRAS or NRAS, and may be useful for the treatment of cancer, particularly the treatment of cancer characterized by a KRAS HRAS or NRAS G12C mutation. The invention also provides processes for producing such compounds and intermediates useful in the synthesis of such compounds.

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

[0011] Provided herein is a compound of formula (I) as defined herein, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof,

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

[0013] In another embodiment, the invention provides a compound of formula (I) (or of subformula (Ia), (Ib*), (Ic*), (Id*) or (Ie)), as defined herein, or an atropisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of an atropisomer thereof.

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

[0015] In another embodiment, the invention provides a compound of formula (I) (or subformula (Ia), (Ib*), (Ic*), (Id*) or (Ie)), as defined herein, or a pharmaceutically acceptable salt thereof.

[0016] In another embodiment, the invention provides a pharmaceutical composition comprising a compound of formula (I) (or of the subformula thereof (Ia), (Ib*), (Ic*), (Id*) or (Ie)), or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, and one or more pharmaceutically acceptable carriers.

[0017] In another embodiment, the invention provides a pharmaceutical composition comprising a compound of formula (I), (or of the subformula thereof (Ia), (Ib*), (Ic*), (Id*) or (Ie)), or a therapeutically effective amount of a compound of formula (I), (or of the subformula thereof (Ia), (Ib*), (Ic*), (Id*) or (Ie)), or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, and optionally one or more pharmaceutically acceptable carriers.

[0018] In another embodiment, the invention provides a combination, in particular a pharmaceutical combination, comprising a compound of formula (I), (or of the subformula thereof (Ia), (Ib*), (Ic*), (Id*) or (Ie)), or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, and one or more therapeutically active agents.

[0019] In another embodiment, the invention provides a pharmaceutical combination, comprising a compound of formula (I), (or of the subformula thereof (Ia), (Ib*), (Ic*), (Id*) or (Ie)), or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, and one or more therapeutically active agents.

[0020] In another embodiment, the invention relates to a method for inhibiting a KRAS, HRAS or NRAS G12C mutant protein (e.g., a KRAS G12C mutant protein) in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of formula (I) or subformula thereof (Ia), (Ib*), (Ic*), (Id*) or (Ie), as defined herein, 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.

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

[0022] In another embodiment, the invention provides intermediate compounds useful for producing the compounds of the invention, as well as methods for producing a compound of formula (I), as defined herein, or of the subformula thereof (Ia), (Ib*), (Ic*), (Id*) or (Ie), or a stereoisomer thereof, or an atropisomer thereof.

BRIEF DESCRIPTION OF THE FIGURES

[0023] Figure 1 illustrates the powder X-ray diffraction pattern of the hydrate (HA Modification) of a(R)-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one (Compound X).

[0024] Figure 2 illustrates the powder X-ray diffraction pattern of a(R)-1-(6-(4-(5-chloro-6-methyl-1H-indazole) isopropyl alcohol (IPA) solvate -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).

[0025] Figure 3 illustrates the powder X-ray diffraction pattern of ethanol solvate (EtOH) of a(R)-1-(6-(4-(5-chloro-6-methyl-1H-indazole- 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).

[0026] Figure 4 illustrates the powder X-ray diffraction pattern of the propylene glycol solvate of a(R)-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one (Compound X).

DETAILED DESCRIPTION

[0027] The invention provides, in a first aspect, a compound of formula (I),

[0028] A is selected from the group consisting of (a) C5-C7-cycloalkylene that is unsubstituted or substituted by one or more, preferably 1, 2 or 3, substituents independently selected from fluorine and C1-C4-alkyl; (b) a 5-7 membered unsaturated heterocyclyl containing a carbon-carbon double bond and an oxygen atom as ring member, wherein said heterocyclyl is unsubstituted or substituted by one or more, preferably 1, 2 or 3, substituents independently selected from fluorine and C1-C4-alkyl, preferably 1, 2 or 3, C1-C4-alkyl; (c) C6-C10 aryl that is unsubstituted or substituted by 1, 2 or 3 RA2; (d) a 5-6 membered heteroaryl ring containing 1, 2 or 3 heteroatoms independently selected from N, O and S as ring members, wherein said heteroaryl ring is unsubstituted or substituted on one or more (e.g. 1, 2 or 3) carbon atoms by RA3, and wherein a nitrogen atom, when present in the heteroaryl ring, is unsubstituted or substituted by a substituent selected from the group consisting of: C1-C4-alkyl, -(CH2)i—2-C3-4-cycloalkyl, C3-C6-cycloalkyl, hydroxy-C1-C4-alkyl, fluoro-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, N(R9)(R10)-C1-C4-alkyl, -SO2-C1-C4-alkyl, -SO2-C3—4-cycloalkyl, -(CH2)p-Hetpy, and -(CH2)pN(R9)(R10), (preferably wherein said substituent is selected from the group consisting of fluoro-C1-C4-alkyl, N(R9)(R10)-C1-C4-alkyl, -SO2-C3-4-cycloalkyl, or -(CH2)i-2-C3—4-cycloalkyl); (e) an 8-10 membered heteroaryl ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur or an 8-10 membered partially saturated heterobicyclic ring containing 1 to 3 heteroatoms or heteroatom groups independently selected from 0-3 nitrogen atoms, 0-2 oxygen atoms, 0-1 sulfur atom and 0-1 S(=O)2 group in the heterobicyclic ring, wherein said heteroaryl ring or heterobicyclic ring is unsubstituted or substituted on a carbon atom by 1, 2, 3, 4 or 5 RA4, and wherein the heterobicyclic ring is further optionally substituted on a carbon atom by oxo and wherein a nitrogen atom, when present, is unsubstituted or substituted by a substituent that is -(CO)-C1-C4-alkyl or C1-C4-alkyl, and wherein said C1-C4-alkyl is optionally substituted by 1 or 2 substituents independently selected from cyano, hydroxy, oxo, fluorine, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyloxy, Hetb and NR9R10; and wherein Hetb is a 4- or 5- or 6-membered heterocyclic ring comprising 1 or 2 heteroatoms or groups independently selected from N, O, S, SO and SO2 (preferably 1 oxygen atom, or 1 sulfur atom, or an S(=O) or an S(=O)2 group, or 1 nitrogen atom and 1 oxygen atom, or 1-2 nitrogen atoms), wherein said Hetb heterocyclic ring is unsubstituted or substituted on a carbon atom by one or two substituents independently selected from C1-C4-alkyl, hydroxy, cyano, fluorine, C1-C4-alkoxy-hydroxy-C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy, fluorine-C1-C4-alkoxy and fluorine-C1-C4-alkyl, and wherein said heterocyclic ring Hetb is further optionally substituted on a carbon atom by oxo, and wherein the nitrogen atom when present in Hetb is further optionally substituted by C1-C4-alkyl that is optionally substituted by 1 to 3 substituents independently selected from fluorine, hydroxy and C1-C4-alkoxy; wherein A is bonded to the remainder of the compound of Formula (I) by a carbon atom in A that is sp2 hybridized; wherein B is selected from the group consisting of B1 and B2, wherein B1 is C6-10 aryl that is unsubstituted or substituted by 1, 2, 3 or 4 RBa; B2 is a 6-13 membered heteroaryl comprising 1, 2 or 3 nitrogen atoms, wherein B2 is unsubstituted or substituted by 1, 2, 3 or 4 RBb; C is selected from the group consisting of hydrogen, C1-C3 alkyl (preferably methyl), C3-C5 cycloalkyl (preferably cyclopropyl), fluoro-C1-C3 alkyl (preferably CHF2 or CF3), cyano, -CH2-CN, -CH(CN)-CH3, -CH2-OH, -CH(OH)-CH3 and halo; L is selected from the group consisting of: where n is 1, 2, or 3, RL is selected from hydrogen, methyl, ethyl, -CH2-CN, and -CH2-OH, where G* represents the point of attachment to G; G is selected from the group consisting of where R2 is selected from hydrogen, C1-C3 alkyl, -C(O)-C1-C3-alkyl and fluorine; R3 is hydrogen; R4 is selected from hydrogen, methyl, -CH2F, -CH2-OCH3 and -CH2-N(CH3)2; R5 is selected from hydrogen and methyl; R6 is hydrogen; R7 is selected from hydrogen and methyl; wherein RA2 is independently selected from the group consisting of: NR9R10, cyano, -(CH2)p-CN, halo, OH, hydroxy-C1-C4-alkyl, -(COOH), -(CH2)p-COOH, C1-C4-alkyl, fluorine-C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl, R9) C1-C4-alkoxy-C1-C4-alkyl-oxy-C1-C4-alkyl, -SO2-C1-C4-alkyl, -Sθ2-C3-4-cycloalkyl, -(CH2)i-2-C3—4-cycloalkyl, Hetpy, -(CH2)p- Hetpy, -C(=O)-NR9R10, -(CH2)pC(=O)NR9R1 0, (preferably from the group consisting of NR9R10, cyano, C1-C4-alkyl, fluorine, fluoro-C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyloxy, hydroxy-C1-C4-alkyl, hydroxy-C1-C4-alkyloxy, Hetpy, -(CH2)p-Hetpy and -C(=O)-NR9R10); wherein RA3 is independently selected from the group consisting of oxo, NR9R10, cyano, -(CH2)p-CN, halo, OH, hydroxy-C1-C4-alkyl, -(COOH), -(CH2)p-COOH, C1-C4-alkyl, fluoro-Cr C4-alkyl, C1-C4-alkoxy, , N(R9)(R10)-C1-C4-alkyl, N(R9)(R10)-C1-C4-alkyloxy, N(R9)(R10)-C1-C4-alkoxy, C1-C4-alkyl-carbonyl-oxy-C1-C4-alkyloxy, hydroxy-C1-C4-alkyloxy, C1-C4-alkoxy-C1-C4-alkyloxy, C1-C4-alkoxy-C1-C4-alkyl-oxy-C1-C4-alkyl, -SO2-C1-C4-alkyl, -SO2-C3-4-cycloalkyl, -(CH2)1-2-C3-4-cycloalkyl, Hetpy, -(CH2)p- Hetpy, -C(=O)-NR9R10, -(CH2)pC(=O)NR9R10, (CH2)p-NR9R10 (preferably from the group consisting of NR9R10, cyano, C1-C4-alkyl, fluorine, fluorine-C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyloxy, Hetpy and -(CH2)p-Hetpy); wherein RA4 is independently selected from the group consisting of cyano, CO2H, halo, C1-C4-alkyl, fluoro-C1-C4-alkyl, hydroxy, hydroxy-C1-C4-alkyl, hydroxy-C1-C4-alkyloxy, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyloxy, NR9R10, (N(R9)(R10)-C1-C4-alkyl, (N(R9)(R10)-C1-C4-alkyloxy, -(CO)-CI-C4-alkyl and R9R10N-C1-C4-alkyl-oxy-(CO)-C1-C4-alkyl; wherein p is 1 or 2 or 3; R9 is selected from hydrogen and C1-C4-alkyl; R10 is selected from the group consisting of hydrogen, C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, and di-C1-C4-alkyl-amino-C1-C4-alkyl; Hetpy is a 4-, 5-, 6-, or 7-membered saturated heterocyclic ring comprising one or two heteroatoms independently selected from O, N (such as, pyrrolidin-1-yl, azetidin-1-yl, morpholin-1-yl), and S, or comprising an S-oxide (SO) or S-dioxide (SO2) group, and wherein said heterocyclic ring is optionally substituted by oxo on a carbon atom, and wherein said heterocyclic ring is further optionally substituted on one or more carbon atoms by 1, 2, or 3 substituents independently selected from C1-C4-alkoxy (preferably methoxy), halo (preferably fluorine), C1-C4-alkyl, hydroxy-C1-C4-alkyl, and fluorine-C1-C4-alkyl, and wherein the nitrogen atom, if present in said heterocycle, is further optionally substituted by R10 (preferably C1-C4-alkyl (such as methyl)); or Hetpy is a 5- or 6-membered heteroaryl ring (preferably 1,2,4-triazol-1-yl or pyrazol-1-yl) comprising 1, 2 or 3 nitrogen atoms and wherein said heteroaryl ring is optionally substituted by one or more (e.g., 1, 2 or 3) substituents independently selected from NR9R10, -C(=O)-NR9R10, halo, C1-C4-alkyl, hydroxy-C1-C4-alkyl, fluoro-C1-C4-alkyl, cyano, OH and C1-C4-alkoxy; each RBa is independently selected from the group consisting of hydroxy, NH2, C1-C4-alkyl and halo; each RBb is independently selected from the group consisting of C1-C4-alkyl (preferably methyl), cyclopropyl, fluoro-C1-C3-alkyl (preferably CHF2 or CF3), cyano, halo (preferably fluoro or chloro), NH2, and C1-C3-alkoxy (preferably methoxy), or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof.

[0029] The invention provides, in a second aspect, a compound of formula (I),

[0030] A is selected from the group consisting of (a) C5-C7-cycloalkylene that is unsubstituted or substituted by one or more, preferably 1, 2 or 3, substituents independently selected from fluorine and C1-C4-alkyl; (b) 5-7 membered unsaturated heterocyclyl containing a carbon-carbon double bond and an oxygen atom as ring member, wherein said heterocyclyl is unsubstituted or substituted by one or more, preferably 1, 2 or 3, substituents independently selected from fluorine and C1-C4-alkyl, preferably 1, 2 or 3, C1-C4-alkyl; (c) C6-C10 aryl that is unsubstituted or substituted by 1, 2 or 3 RA2; (d) a 5-6 membered heteroaryl ring containing 1, 2 or 3 heteroatoms independently selected from N, O and S as ring members, wherein said heteroaryl ring is unsubstituted or substituted on one or more (e.g., 1, 2 or 3) carbon atoms by RA3, and wherein a nitrogen atom, when present in the heteroaryl ring, is unsubstituted or substituted by a substituent selected from the group consisting of: C1-C4-alkyl, -(CH2)i—2-C3-4-cycloalkyl, C3-C6-cycloalkyl, hydroxy-C1-C4-alkyl, fluoro-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, N(R9)(R10)-C1-C4-alkyl, -SO2-C1-C4-alkyl, -SO2-C3—4-cycloalkyl, -(CH2)p-Hetpy, and -(CH2)pN(R9)(R10), (preferably, wherein said substituent is selected from the group consisting of fluoro-C1-C4-alkyl, N(R9)(R10)-C1-C4-alkyl, -SO2-C3-4-cycloalkyl, or -(CH2)i-2-C3-4-cycloalkyl); (e) 8-10 membered heteroaryl ring containing 1, 2 or 3 nitrogen atoms, or 8-10 membered partially saturated heterobicyclic ring containing 1 to 3 heteroatoms or heteroatom groups independently selected from 0-3 nitrogen atoms, 0-2 oxygen atoms, 0-1 sulfur atom and 0-1 S(=O)2 group in the heterobicyclic ring, wherein said heteroaryl ring or heterobicyclic ring is unsubstituted or substituted on a carbon atom by 1, 2, 3, 4 or 5 RA4, and wherein the heterobicyclic ring is further optionally substituted on a carbon atom by oxo and wherein a nitrogen atom, when present, is unsubstituted or substituted by a substituent that is -(CO)-C1-C4-alkyl or C1-C4-alkyl, and wherein said C1-C4-alkyl is optionally substituted by 1 or 2 substituents independently selected from cyano, hydroxy, oxo, fluorine, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyloxy, Hetb and NR9R10; and wherein Hetb is a 4- or 5- or 6-membered heterocyclic ring comprising 1 or 2 heteroatoms or groups independently selected from N, O, S, SO and SO2 (preferably 1 oxygen atom, or 1 sulfur atom, or an S(=O) or an S(=O)2 group, or 1 nitrogen atom and 1 oxygen atom, or 1-2 nitrogen atoms), wherein said Hetb heterocyclic ring is unsubstituted or substituted on a carbon atom by one or two substituents independently selected from C1-C4-alkyl, hydroxy, cyano, fluorine, C1-C4-alkoxy-hydroxy-C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy, fluorine-C1-C4-alkoxy and fluorine-C1-C4-alkyl, and wherein said heterocyclic ring Hetb is further optionally substituted on a carbon atom by oxo, and wherein the nitrogen atom when present in Hetb is further optionally substituted by C1-C4-alkyl that is optionally substituted by 1 to 3 substituents independently selected from fluorine, hydroxy and C1-C4-alkoxy; wherein A is bonded to the remainder of the compound of Formula (I) by a carbon atom in A that is sp2 hybridized; wherein B is selected from the group consisting of B1 and B2, wherein B1 is C6-10 aryl that is unsubstituted or substituted by 1, 2, 3 or 4 RBa; B2 is a 6-13 membered heteroaryl comprising 1, 2 or 3 nitrogen atoms, wherein B2 is unsubstituted or substituted by 1, 2, 3 or 4 RBb; C is selected from the group consisting of hydrogen, C1-C3 alkyl (preferably methyl), C3-C5 cycloalkyl (preferably cyclopropyl), fluoro-C1-C3 alkyl (preferably CHF2 or CF3), cyano, -CH2-CN, -CH(CN)-CH3, -CH2-OH, -CH(OH)-CH3 and halo; L is selected from the group consisting of: where n is 1, 2, or 3, RL is selected from hydrogen, methyl, ethyl, -CH2-CN, and -CH2-OH, where G* represents the point of attachment to G; G is selected from the group consisting of where R2 is selected from hydrogen, C1-C3 alkyl, -C(O)-C1-C3-alkyl and fluorine; R3 is hydrogen; R4 is selected from hydrogen, methyl, -CH2F, -CH2-OCH3 and -CH2-N(CH3)2; R5 is selected from hydrogen and methyl; R6 is hydrogen; R7 is selected from hydrogen and methyl; wherein RA2 is independently selected from the group consisting of: NR9R10, cyano, -(CH2)p-CN, halo, OH, hydroxy-C1-C4-alkyl, -(COOH), -(CH2)p-COOH, C1-C4-alkyl, fluorine-C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl, R9) Ci-C4-alkoxy-Ci-C4-alkyl-oxy-Ci-C4-alkyl, -SO2-Ci-C4-alkyl, -SO2-C3-4-cycloalkyl, -(CH2)1-2-C3-4-cycloalkyl, Hetpy, -(CH2)p- Hetpy, -C(=O)-NR9R10, -(CH2)pC(=O)NR9R10, ( preferably from the group consisting of NR9Ri0, cyano, C1-C4-alkyl, fluorine, fluorine-C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyloxy, hydroxy-C1-C4-alkyl, hydroxy-C1-C4-alkyloxy, Hetpy, -(CH2)p-Hetpy and -C(=O)-NR9R10); wherein RA3 is independently selected from the group consisting of oxo, NR9Ri0, cyano, -(CH2)p-CN, halo, OH, hydroxy-C1-C4-alkyl, -(COOH), -(CH2)p-COOH, C1-C4-alkyl, fluorine-C1-C4-alkyl, Ci-C4-alkoxy, Ci-C4-alkoxy-Ci-C4-alkyl, N (R9) (Ri0)-Ci-C4- alkyl, N(R9) Ci-C4-alkoxy-Ci-C4-alkyl-oxy-Ci-C4-alkyl, -SO2-Ci-C4-alkyl, -SO2-C3-4-cycloalkyl, -(CH2)i-2-C3-4-cycloalkyl, Hetpy, -(CH2)p- Hetpy, -C(=O)-NR9Ri0, -(CH2)pC(=O)NR9Ri0, (CH2) )p-NR9Ri0 (preferably from the group consisting of NR9Ri0, cyano, Ci-C4-alkyl, fluorine, fluorine-Ci-C4-alkyl, Ci-C4-alkoxy, Ci-C4-alkoxy-Ci-C4-alkyloxy, Hetpy and -(CH2)p-Hetpy); wherein RA4 is independently selected from the group consisting of cyano, CO2H, halo, C1-C4-alkyl, fluoro-C1-C4-alkyl, hydroxy, hydroxy-C1-C4-alkyl, hydroxy-C1-C4-alkyloxy, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyloxy, NR9R10, (N(R9)(R10)-C1-C4-alkyl, (N(R9)(R10)-C1-C4-alkyloxy, -(CO)-C1-C4-alkyl and R9R10N-C1-C4-alkyl-oxy-(CO)-C1-C4-alkyl; wherein p is i or 2 or 3; R9 is selected from hydrogen and C1-C4-alkyl; R10 is selected from the group consisting of hydrogen, C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, and di-C1-C4-alkyl-amino-C1-C4-alkyl; Hetpy is a 4-, 5-, 6-, or 7-membered saturated heterocyclic ring comprising one or two heteroatoms independently selected from O, N (such as, pyrrolidin-yl, azetidin-yl, morpholin-yl), and S, or comprising an S-oxide (SO) or S-dioxide (SO2) group, and wherein said heterocyclic ring is optionally substituted by oxo on a carbon atom, and wherein said heterocyclic ring is further optionally substituted on one or more carbon atoms by 1, 2, or 3 substituents independently selected from C1-C4-alkoxy (preferably methoxy), halo (preferably fluorine), C1-C4-alkyl, hydroxy-C1-C4-alkyl, and fluorine-C1-C4-alkyl, and wherein the nitrogen atom, if present in said heterocycle, is further optionally substituted by R10 (preferably C1-C4-alkyl (such as methyl)); or Hetpy is a 5- or 6-membered heteroaryl ring (preferably 1,2,4-triazol-1-yl or pyrazol-1-yl) comprising 1, 2 or 3 nitrogen atoms and wherein said heteroaryl ring is optionally substituted by one or more (e.g., 1, 2 or 3) substituents independently selected from NR9R10, -C(=O)-NR9R10, halo, C1-C4-alkyl, hydroxy-C1-C4-alkyl, fluoro-C1-C4-alkyl, cyano, OH and C1-C4-alkoxy; each RBa is independently selected from the group consisting of hydroxy, NH2, C1-C4-alkyl and halo; each RBb is independently selected from the group consisting of C1-C4-alkyl (preferably methyl), cyclopropyl, fluoro-C1-C3-alkyl (preferably CHF2 or CF3), cyano, halo (preferably fluoro or chloro), NH2, and C1-C3-alkoxy (preferably methoxy), or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof.

[0031] When the term "preferably" is mentioned in the present specification, other embodiments of the invention relate especially 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 a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, in which all chemical moieties or characteristics specifically mentioned after the term "preferably" replace the more general term immediately preceding the one(s) they specify.

[0032] In another aspect, there is provided a compound of formula (I), or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, for use as a medicament.

[0033] In another aspect, there is provided a compound of formula (I), or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, for use in the treatment of a disorder or disease (e.g., a cancer) mediated by a KRAS, NRAS, or HRAS G12C mutation, e.g., a KRAS G12C mutation.

[0034] In another aspect, there is provided a compound of formula (I), or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof for the manufacture of a medicament for the treatment of cancer, e.g., a cancer mediated by a KRAS, NRAS or HRAS G12C mutation.

[0035] In another aspect, a method is provided for treating a disorder or a cancer in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of formula (I), or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof.

[0036] In another aspect, a method is provided for treating a disorder or disease, e.g., a cancer that is selected from lung cancer (including lung adenocarcinoma and non-small cell lung cancer), colorectal cancer (including colorectal adenocarcinoma), pancreatic cancer (including pancreatic adenocarcinoma), uterine cancer (including uterine endometrial cancer), rectal cancer (including rectal adenocarcinoma), and a solid tumor, in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of formula (I) as defined herein, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof.

[0037] In another aspect, there is provided a compound of formula (I), or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, for use in the treatment of cancer, for example, lung cancer (including lung adenocarcinoma and non-small cell lung cancer), colorectal cancer (including colorectal adenocarcinoma), pancreatic cancer (including pancreatic adenocarcinoma), uterine cancer (including uterine endometrial cancer), rectal cancer (including rectal adenocarcinoma), and a solid tumor.

[0038] In another aspect, there is provided a compound of formula (I), or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, for use in the treatment of cancer, for example, lung cancer (including lung adenocarcinoma and non-small cell lung cancer), colorectal cancer (including colorectal adenocarcinoma), pancreatic cancer (including pancreatic adenocarcinoma), uterine cancer (including uterine endometrial cancer), rectal cancer (including rectal adenocarcinoma), and a solid tumor, wherein the cancer is KRAS, NRAS, or HRAS G12C mutant, typically wherein the cancer is KRAS G12C mutant.

[0039] In another aspect, there is provided a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof and a pharmaceutically acceptable carrier.

[0040] In another aspect, there is provided a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, for use as a medicament.

[0041] In another aspect, there is provided a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, for use in the treatment of cancer, 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 uterine endometrial cancer), rectal cancer (including rectal adenocarcinoma), and a solid tumor, optionally wherein the cancer is KRAS, NRAS, or HRAS G12C mutant.

[0042] In another aspect, there is provided a combination comprising a compound of formula (I), or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, and one or more therapeutically active agents.

[0043] In another aspect, there is provided a method for manufacturing 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 a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof.

[0044] Unless otherwise specified, and unless the context clearly indicates otherwise, the terms "a compound of the present invention" or "compounds of the invention" or "compounds of formula (I)" or "a compound of formula (I)" include a compound or compounds of formula (I), (Ia), (Ib*), (Ic*), (Id*) and (Ie), and pharmaceutically acceptable salts thereof, as well as all stereoisomers (including diastereoisomers and enantiomers), atropisomers, rotamers, tautomers, and isotopically labeled compounds (including deuterium substitutions), as well as inherently formed chemical moieties.

[0045] It will be understood that compounds prepared as intermediates may also be considered as compounds of the invention.

[0046] Compounds of formula 2(a), (2b*), (2c*) and (2d*), and salts thereof, are therefore also considered as compounds of the invention.

[0047] Thus, unless otherwise specified, and unless the context clearly indicates otherwise, the terms "a compound of formula (I)" or "a compound of formula (I), or a pharmaceutically acceptable salt thereof" include a stereoisomer of a compound of formula (I), (Ia), (Ib*), (Ic*), (Id*) and (Ie), or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer of a compound of formula (I), (Ia), (Ib*), (Ic*), (Id*) and (Ie), or a pharmaceutically acceptable salt of an atropisomer of a compound of formula (I), (Ia), (Ib*), (Ic*), (Id*) and (Ie).

[0048] Compounds of formula (I), (Ia), (Ib*), (Ic*), (Id*) and (Ie) include all stereoisomers, including diastereoisomers, atropisomers, enantiomers, mixtures thereof and racemic mixtures, including pharmaceutically acceptable salts thereof. Compounds of formula 2(a), (2b*), (2c*) and (2d*) also include all stereoisomers, including diastereoisomers, atropisomers, enantiomers, mixtures thereof and racemic mixtures, including salts thereof.

[0049] When one isomer (e.g. enantiomer, diastereomer, atropisomer or geometric isomer) has higher intrinsic activity as an inhibitor of RAS G12C mutant protein than its opposite isomer, the more active isomer is typically preferred.

[0050] The presence of diastereoisomers can be identified by a person skilled in the art with tools such as NMR. Separation of diastereoisomers can be performed by a person skilled in the art using chromatographic methods such as tools such as HPLC (High Performance Liquid Chromatography), Thin Layer Chromatography, SFC (Supercritical Fluid Chromatography), GC (Gas Chromatography) or recrystallization techniques. Separation of enantiomers can be performed by a person skilled in the art with tools such as chiral HPLC, chiral SFC, chiral GC.

[0051] Compounds of the present invention, in particular orthosubstituted biaryl compounds may exhibit conformational, rotational isomerism, herein referred to as atropisomers (Eliel, E. and Wilen, S. (1994) Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., pages 1142-55). In some cases, depending on the substituents on the biaryl ring chemical moiety, such biaryl compounds of the present invention exhibit atropisomerism.

[0052] Thus, the compounds of formula (I) and subformulas (Ia), (Ib*), (Ic*), (Id*) and (Ie) and their isomeric mixtures (including diastereomeric mixtures, enantiomeric mixtures and racemic mixtures), also form part of the invention. Similarly, "diastereomerically enriched" mixtures or "enantiomerically enriched" mixtures of the compounds of formula (I), and subformulas (Ia), (Ib*), (Ic*), (Id*) and (Ie) also form part of the invention.

[0053] The present invention also provides a crystalline form of Compound X as defined herein, such as the hydrate crystalline form (HA Modification), or the isopropyl alcohol (IPA) solvate crystalline form, or the ethanol (EtOH) solvate crystalline form, or the propylene glycol solvate crystalline form of Compound X.

[0054] The present invention also provides a crystalline form of Compound X, as defined herein, which has a powder X-ray diffraction spectrum substantially the same as the powder X-ray diffraction spectrum shown in Figure 1, Figure 2, Figure 3 or Figure 4.

[0055] The following definitions also apply unless otherwise provided or evident from the context: As used herein, the term "halogen" (or halo) refers to fluorine, bromine, chlorine or iodine. Halogen-substituted groups and chemical moieties, such as halogen-substituted alkyl (haloalkyl) may be mono-, poly- or per-halogenated. Chlorine and fluorine are preferred halo substituents in alkyl or cycloalkyl groups, with fluorine being more preferred unless otherwise specified. Fluorine, chlorine and bromine are often preferred in aryl or heteroaryl groups, with fluorine being more preferred unless otherwise specified.

[0056] As used herein, the term "heteroatoms" refers to nitrogen (N), oxygen (O) or sulfur (S) atoms, in particular, nitrogen or oxygen, unless otherwise provided.

[0057] When multiple substituents are present, the substituents are independently selected unless otherwise indicated, thus when 2 or 3 substituents are present, for example, those substituents may be the same or different.

[0058] As used herein, the term "C1-C4-alkyl" refers to a straight or branched hydrocarbon chain radical consisting only of carbon and hydrogen atoms, containing no unsaturation, having from one to four carbon atoms, and linked to the remainder of the molecule by a single bond. Examples of C1-C4-alkyl include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), and n-butyl. A preferred example is methyl.

[0059] A C1-C4-alkyl radical when substituted by oxo includes a -C(O)-C1-C3-alkyl when the carbonyl portion of the substituent is bonded to the remainder of the molecule.

[0060] As used herein, the term "hydroxy-C1-C4-alkyl" refers to a C1-C4-alkyl radical, as defined above, in which one of the hydrogen atoms of the C1-C4-alkyl radical is replaced by OH. Examples of hydroxy-C1-C4-alkyl include, but are not limited to, hydroxy-methyl, 2-hydroxy-ethyl, 2-hydroxy-propyl, 3-hydroxy-propyl, and 2-hydroxy-2-methyl-propyl.

[0061] As used herein, the term "C1-C4alkoxy" refers to a radical of the formula -ORa where Ra is a C1-C4alkyl radical as generally defined above. Examples of C1-C4-alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, and butoxy.

[0062] As used herein, the term "hydroxy-C1-C4-alkoxy" refers to a C1-C4-alkoxy radical, as defined above, in which at least one of the hydrogen atoms of the C1-C4-alkoxy radical is replaced by OH. Examples of hydroxy-C1-4alkoxy include, but are not limited to, hydroxymethoxy, hydroxyethoxy, 2-hydroxypropoxy.

[0063] As used herein, the term "C1-C4-alkyloxy" refers to a "C1-C4-alkyl" radical, as defined above, wherein said radical is bonded by an oxygen atom to the remainder of the molecule.

[0064] As used herein, a "hydroxy-C1-C4-alkyloxy" substituent refers to a hydroxy-C1-C4-alkyl radical, as defined above, that is bonded by an oxygen atom to the remainder of the molecule. Examples of hydroxy-C1-C4-alkyloxy include, but are not limited to, hydroxymethoxy, hydroxyethoxy, 2-hydroxypropoxy.

[0065] As used herein, the term "C1-C4-alkoxy-C1-C4-alkyl" refers to a C1-C4-alkyl radical, as defined above, in which one of the hydrogen atoms of the C1-C4-alkyl radical is replaced by C1-C4-alkoxy.

[0066] As used herein, the term "C1-C4-alkoxy-hydroxy-C1-C4-alkyl" refers to a C1-C4-alkoxy-C1-C4-alkyl radical as defined above, wherein herein at least one of the hydrogen atoms of the C1-C4-alkyl radical is replaced by OH.

[0067] As used herein, the term "C1-C4-alkoxy-C1-C4-alkyloxy" refers to a "C1-C4-alkoxy-C1-C4-alkyl" radical as defined above, wherein said radical is bonded by an oxygen atom to the remainder of the molecule.

[0068] As used herein, the term "C1-C4-alkyl-carbonyl-oxy-C1-C4-alkyloxy" refers to a radical of the formula C1-C4-alkyl-C(=O)-O-C1-C4-alkyl-O-, wherein said radical is bonded by the last oxygen atom to the remainder of the molecule.

[0069] As used herein, the term "haloalkyl" refers to an alkyl, as defined herein, that is substituted by one or more halo radicals, as defined herein. The haloalkyl may be monohaloalkyl, dihaloalkyl, trihaloalkyl, or polyhaloalkyl including perhaloalkyl. A monohaloalkyl may have an iodine, bromine, chlorine, or fluorine within the alkyl group. Chlorine and fluorine are preferred in the alkyl or cycloalkyl groups.

[0070] As used herein, the term "fluoroalkyl" refers to an alkyl, as defined herein, that is substituted by one or more fluoros. Non-limiting examples of fluoro-C1-C4-alkyl include trifluoromethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 2-fluoropropyl, 3,3-difluoropropyl, and 1-fluoromethyl-2-fluoroethyl. Preferred fluoroalkyl groups, unless otherwise specified, include monofluoro, difluoro, and trifluoro substituted methyl and ethyl groups, for example CF3, CF2H, CFH2, and CH2CF3.

[0071] As used herein, the term "fluoroalkoxy" refers to an alkoxy, as defined herein, that is substituted by one or more fluoros.

[0072] As used herein, the term "C1-C4alkylamino" refers to a radical of the formula -NH-Ra where Ra is a C1-C4 alkyl radical as defined above.

[0073] As used herein, the term "di-C1-C4-alkylamino" refers to a radical of the formula --N(Ra)-Ra where each Ra is a C1-C4-alkyl radical, which may be the same or different as defined above.

[0074] As used herein, a substituent "NR9R10" or "N(R9)(R10)" refers to a radical of the formula "-N(R9)(R10)" wherein said radical is linked to the remainder of the molecule by the nitrogen atom to which an R9 group and an R10 group are also linked, and wherein R9 and R10 may be the same or different, and are as defined herein.

[0075] As used herein, the term "R9R10N-C1-C4-alkyl" or "N(R9)(R10)-C1-C4-alkyl" refers to a C1-C4 alkyl radical, as defined above, in which one of the hydrogen atoms of the C1-C4-alkyl radical is replaced by -N(R9)(R10).

[0076] As used herein, the term "R9R10N-C1-C4-alkyloxy" or "N(R9)(R10)-C1-C4-alkyloxy" refers to an R9R10N-C1-C4-alkyl radical (or N(R9)(R10)-C1-C4-alkyl radical), as defined above, which is bonded by an oxygen atom to the remainder of the molecule.

[0077] As used herein, the term "N(R9)(R10)-C1-C4-alkoxy" refers to a C1-C4-alkoxy radical, as defined above, in which one of the hydrogen atoms of the C1-C4-alkoxy radical is replaced by -N(R9)(R10).

[0078] As used herein, the term "-SO2-C1-C4-alkyl" refers to a C1-C4-alkyl radical, as defined above, which is linked to the remainder of the molecule via a -S(=O)2- linker.

[0079] As used herein, the term "-SO2-C3-C4-cycloalkyl" refers to a C3-C4-cycloalkyl radical, as defined below, which is attached to the remainder of the molecule via a -S(=O)2- linker.

[0080] As used herein, the term "hydroxy-C1-4-alkoxy" refers to a C1-4-alkoxy radical, as defined above, in which at least one of the hydrogen atoms of the C1-4-alkoxy radical is replaced by OH. Examples of hydroxy-C1-C6alkoxy include, but are not limited to, hydroxymethoxy, hydroxyethoxy, 2-hydroxypropoxy.

[0081] As used herein, the term "C1-C4 alkoxy-C1-C4 alkyl" refers to a C1-4alkyl radical, as defined above, in which one of the hydrogen atoms of the C1-4 alkyl radical is replaced by C1-C4-alkoxy.

[0082] As used herein, the term "C1-C4-alkoxy-C1-C4-alkyloxy" refers to a "C1-C4 alkoxy-C1-C4 alkyl" as defined above, wherein said radical is bonded to the remainder of the molecule by an oxygen atom.

[0083] As used herein, the term "C(O)-NR9R10" refers to a radical of the formula -Rai-NR9R10 where Rai is a carbonyl radical, "NR9R10" is as defined above, and R9 and R10 may be the same or different, and are as defined herein.

[0084] As used herein, the term "C(O)C1-C4-alkyl" refers to a radical of the formula -Rai-C1-C4-alkyl, where Ra1 is a carbonyl radical and C1-C4-alkyl is as defined above.

[0085] As used herein, the term "cycloalkyl" refers to a saturated carbocyclic ring radical. C3-C7 cycloalkyl is any such ring radical containing 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0086] As used herein, the term "cycloalkylene" refers to a non-aromatic carbocyclic ring radical containing at least one carbon-carbon double bond, preferably a carbon-carbon double bond. The term "monocyclic cycloalkylene" refers to a non-aromatic monocyclic carbocyclic ring radical containing at least one carbon-carbon double bond, preferably a carbon-carbon double bond. The term includes, but is not limited to, "C5-C7-cycloalkylene" which is a non-aromatic carbocyclic ring radical containing 5 to 7 carbon atoms and a C-C double bond. Examples of suitable cycloalkylene groups are non-aromatic carbocyclic ring containing 5 to 7 carbon atoms and one or more C-C double bonds, such as, cyclopentenyl, cyclohexenyl (e.g., cyclohex-1-en-1-yl, cyclohex-2-en-1-yl, cyclohex-3-en-1-yl).

[0087] As used herein, the term "aryl" refers to an aromatic hydrocarbon group having 6-14 carbon atoms in the ring portion. Typically, aryl is a monocyclic, bicyclic or tricyclic aryl having 6-14 carbon atoms, often 6-10 carbon atoms, e.g., phenyl or naphthyl. Phenyl is sometimes preferred. In addition, the term "aryl" as used herein refers to an aromatic substituent that may be a single aromatic ring or multiple aromatic rings that are fused together. Non-limiting examples include phenyl, naphthyl and 1,2,3,4-tetrahydronaphthyl, provided that tetrahydronaphthyl is connected to the formula as described through a carbon of the aromatic ring of the tetrahydronaphthyl group.

[0088] The term "C6-C10 aryl" refers to a phenyl, 1,2,3,4-tetrahydronaphthyl or naphthyl group. An example of a suitable C6-C10 aryl is a phenyl group. The term "phenyl" refers to a radical of the formula -C6H5. In substituted phenyl, one or more or the hydrogen atoms in -C6H5 are replaced by a substituent or substituents, especially any described herein.

[0089] As used herein, the term "heterocyclyl" or "heterocyclic ring" refers to a heterocyclic radical that is saturated or partially unsaturated, but non-aromatic, and may be a monocyclic or polycyclic ring, including a fused or bridged bicyclic ring system. A heterocycle or heterocyclyl contains at least one non-carbon atom as a ring member, typically N, O or S, unless otherwise specified. Unless otherwise specified, a heterocyclyl group has 3 to 10, and preferably 4 to 7, ring atoms; wherein one or more, preferably one to four, especially 1, 2 or 3 ring atoms are heteroatoms independently selected from O, S and N (the remaining ring atoms therefore being carbon). When the heterocycle contains S or N as heteroatoms, S may be present as SO or SO2 groups and N may be present as the N-oxide, when valency permits.

[0090] An unsaturated heterocyclyl may have one or two double bonds, but is not aromatic. Preferably, unless described as unsaturated, the heterocyclyl groups in the compounds of the invention are saturated single rings. Preferably, a heterocyclyl group has one or two heteroatoms as ring atoms, and preferably the heteroatoms are not directly connected to each other. Examples of heterocycles include tetrahydrofuran (THF), dihydrofuran, 1,4-dioxane, morpholine, 1,4-dithiane, piperazine, piperidine, 1,3-dioxolane, imidazolidine, imidazoline, pyrroline, pyrrolidine, tetrahydropyran, dihydropyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane, oxathiane, thiomorpholine, and the like.

[0091] The term "5-7 membered unsaturated heterocyclyl" refers to a ring radical containing 5 to 7 ring atoms comprising 1, 2, or 3 heteroatoms individually selected from nitrogen, oxygen and sulfur, (optionally further comprising groups such as -S(=O)- and -S(=O)2-) and containing one or more C-C double bonds, preferably a C-C double bond. The term includes a 5-, 6- or 7-membered non-aromatic monocyclic ring radical containing one or more C-C double bonds, preferably a C-C double bond, and 1, 2, or 3 heteroatoms individually selected from nitrogen, oxygen and sulfur, preferably an oxygen. Examples of 57-membered unsaturated heterocyclyls include, but are not limited to, 6-membered non-aromatic monocyclic radicals containing one oxygen and one C-C double bond, such as 3,4-dihydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl, and 2H-pyranyl.

[0092] The term "heteroaryl" is a 5-14 membered, typically 5-10 membered, monocyclic or bicyclic aromatic ring radical comprising 1, 2, 3 or 4 heteroatoms individually selected from nitrogen, oxygen and sulfur in the ring radical. Typically, the heteroaryl is a 5-10 membered ring system, e.g., a 5-6 membered monocyclic or 8-10 membered bicyclic group. Typical heteroaryl groups include 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4- or 5-imidazolyl, 1-, 3-, 4-, or 5-pyrazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 3- or 5-(1,2,4-triazolyl), 4- or 5-(1,2,3-triazolyl), 1- or 2- or 3-tetrazoyl, 2-, 3- or 4-pyridyl, 3- or 4-pyridazinyl, 2-pyrazinyl, and 2-, 4-, or 5-pyrimidinyl.

[0093] A heteroaryl is a heteroaryl group that has one or more substituents, typically 1, 2 or 3 substituents, on the heteroaryl ring that replaces a hydrogen atom that is located on the unsubstituted heteroaryl.

[0094] The term "5-6 membered heteroaryl" is an aromatic monocyclic ring radical comprising 1, 2, 3 or 4 heteroatoms individually selected from nitrogen, oxygen and sulfur. The term includes a 5- or 6-membered aromatic ring radical containing 1, 2 or 3 heteroatoms selected from N, O and S as ring members, preferably 1-2 nitrogen atoms or 1 nitrogen atom and 1 sulfur atom. The term includes 6-membered rings in which an aromatic tautomer exists as, for example, in the case for the 1H-pyridin-2-one system. Examples of suitable 5-6 membered heteroaryl groups include, but are not limited to, 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4- or 5-imidazolyl, 1-, 3-, 4-, or 5-pyrazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 3- or 5-(1,2,4-triazolyl), 4- or 5-(1,2,3-triazolyl), 1- or 2- or 3-tetrazoyl, 2-, 3- or 4-pyridyl, 3- or 4-pyridazinyl, 2-pyrazinyl and 2-, 4-, or 5-pyrimidinyl.

[0095] The term "8-10 membered heteroaryl" is an aromatic bicyclic ring radical comprising 1, 2, 3 or 4 heteroatoms individually selected from nitrogen, oxygen and sulfur. Non-limiting examples include 1-, 2-, 3-, 5-, 6-, 7- or 8-indolizinyl, 1, 3-, 4-, 5-, 6- or 7-isoindolyl, 2-, 3-, 4-, 5-, 6- or 7-indolyl and 2-, 3-, 4-, 5, 6- or 7-indazolyl. Examples of 8-10 membered heteroaryl include, but are not limited to: pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[3,2-b]pyridinyl, benzofuranyl, benzothiophenyl, indolyl, isoindolyl, indolininyl, benzimidazolyl, indazolyl.

[0096] The term "8-10 membered partially unsaturated heterobicyclyl" or "8-10 membered partially saturated heterobicyclic ring" includes (a) a 5-6 membered heteroaryl containing 1-3 or 1-2 nitrogen atoms fused to a second ring to form a 5,5-, 5,6-, 6,5- or 6-6 ring system and (b) a phenyl ring fused to a second ring containing at least one heteroatom or group of heteroatoms to form a 6,5- or 6-6 ring system.

[0097] The term "8-10 membered partially saturated heterobicyclic ring containing 1 to 3 heteroatoms or heteroatom groups independently selected from 0-3 nitrogen atoms, 0-2 oxygen atoms, 0-1 sulfur atom and 0-1 S(=O)2 group in the heterobicyclic ring" is an 8-10 membered bicyclic radical consisting of: (i) a 5-6 membered heteroaryl ring containing 1, 2 or 3 nitrogen atoms, wherein the heteroaryl ring is fused to a 5- or 6 membered saturated or partially saturated carbocyclic ring optionally incorporating one or two atoms or groups independently selected from 1-2 oxygen atoms, 1 sulfur atom and 0-1 S(=O)2 group in the non-aromatic portion of the ring, or (ii) a phenyl ring wherein the phenyl ring is fused to a 5- or 6-membered saturated or partially saturated carbocyclic ring that incorporates 1 to 3 heteroatoms or heteroatom groups independently selected from 0-3 nitrogen atoms, 0-2 oxygen atoms, 0-1 sulfur atom, and 0-1 S(=O)2 group (e.g., 1 nitrogen atom and 1 oxygen atom; or 1, 2, or 3 nitrogen atoms; 1 oxygen atom; or 1 sulfur atom; or 1-S(=O)2 group) on the non-aromatic portion of the ring, provided that the point of attachment of the partially saturated 8-10-membered heterobicyclic ring to the remainder of the molecule is on the 5-6-membered heteroaryl or phenyl ring.

[0098] The 8-10 membered partially saturated heterobicyclic radical is unsubstituted or substituted by one or more substituents as described herein and is further optionally substituted on a carbon atom by oxo (except in aromatic rings).

[0099] In one embodiment, the term "8-10 membered partially saturated heterobicyclic ring" is an 8-10 membered partially saturated heterobicyclic ring radical consisting of a 5-6 membered heteroaryl ring containing 1, 2 or 3 nitrogen atoms or consisting of a phenyl ring wherein the phenyl ring or the heteroaryl ring is fused to a 5- or 6 membered saturated or partially saturated carbocyclic ring optionally incorporating 1 nitrogen atom and 1 oxygen atom; or 1, 2 or 3 nitrogen atoms; 1 oxygen atom; or 1 sulfur atom; or 1 group selected from -S(=O)- and -S(=O)2-, in the non-aromatic portion of the ring, provided that the point of attachment of the partially saturated 8-10 membered heterobicyclic ring to the remainder of the molecule is on the 5-6 membered heteroaryl or phenyl ring. The bicyclic ring radical is unsubstituted or substituted by one or more substituents as described herein and is further optionally substituted on a carbon atom by oxo (except in aromatic rings). Thus, the term "partially unsaturated 8-10 membered heterobicyclyl" includes (a) a 5-6 membered heteroaryl containing 1-2 nitrogen atoms fused to a second ring to form a 5,5-, 5,6-, 6,5- or 6-6 ring system and (b) a phenyl ring fused to a second ring to form a 6,5- or 6-6 ring system.

[0100] Examples of "8-10 membered partially saturated heterobicyclic ring" and "8-10 membered partially saturated heterobicyclic ring containing 1 to 3 heteroatoms or heteroatom groups independently selected from 0-3 nitrogen atoms, 0-2 oxygen atoms, 0-1 sulfur atom, and 0-1 S(=O)2 group in the heterobicyclic ring" include, but are not limited to: indolinyl (e.g., indolin-5-yl), isoindolinyl (e.g., isoindolin-5-yl), dihydrobenzofuranyl (e.g., 2,3-dihydrobenzofuran-6-yl), dihydroisobenzofuranyl (e.g., 1,3-dihydroisobenzofuran-5-yl), tetrahydroindazolyl, tetrahydrobenzimidazolyl (e.g., 4,5,6,7- tetra-hidro-1H-benzimidazol-5-ila), tetra-hidroisoquinolinila, tetra- hidroquinoxalinila, di-hidrobenzimidazolila (por exemplo, 2,3-di-hidro- 1H-benzo[d]imidazol-5-ila), di-hidrobenzotiofenila (por exemplo, 1,3-di- hidrobenzo[c]tiofen-5-ila), dióxido de di-hidrobenzotiofenila (por exemplo, 2,2-dióxido de 1,3-di-hidrobenzo[c]tiofen-5-ila), di- hidropirrolopirazolila (por exemplo, 5,6-di-hidro-4H-pirrolo[1,2-b]pirazol- 3-ila), isoindolinonila (por exemplo, isoindolin-1-ona-5-ila), indolinonila (por exemplo, indolin-2-ona-5-ila), benzofuranonila (por exemplo, benzofuran-2(3H)-one-6-yl), isobenzofuranonyl (e.g., isobenzofuran-1(3H)-one-6-yl) and the like. Preferably, the 8-10 membered partially saturated heterobicyclic ring or the "8-10 membered partially saturated heterobicyclic ring containing 1 to 3 heteroatoms or heteroatom groups independently selected from 0-3 nitrogen atoms, 0-2 oxygen atoms, 0-1 sulfur atom and 0-1 S(=O)2 group in the heterobicyclic ring" is selected from indolinyl (e.g., indolin-5-yl), isoindolinyl (e.g., isoindolin-5-yl), dihydrobenzofuranyl (e.g., 2,3-dihydrobenzofuran-6-yl), dihydroisobenzofuranyl (e.g., 1,3-dihydroisobenzofuran-5-yl), dihydrobenzimidazolyl (e.g., 2,3-dihydro-1H-benzo[d]imidazol-5-yl), dihydrobenzothiophenyl (e.g. 1,3-dihydrobenzo[c]thiophen-5-yl, 2,3-dihydrobenzo[b]thiophen-6-yl), dihydrobenzothiophenyl dioxide (e.g. 1,3-dihydrobenzo[c]thiophen-5-yl 2,2-dioxide), dihydropyrrolopyrazolyl (e.g. 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl), isoindolinonyl (e.g. isoindolin-1-one-5-yl), indolinonyl (e.g. indolin-2-one-5-yl), benzofuranonyl (e.g. benzofuran-2(3H)-one-6-yl), isobenzofuranonyl (e.g. isobenzofuran-1(3H)-one-6-yl).

[0101] The term "cyano" refers to the radical -CN.

[0102] The term "amino" refers to the radical —NH2.

[0103] The term "hydroxy" refers to the radical —OH.

[0104] The term "oxo" refers to the radical =O.

[0105] In general, for groups comprising two or more subgroups, the last named group is the point of attachment of the radical, e.g., "alkylaryl" means a monovalent radical of the formula alkyl-aryl-, while "arylalkyl" means a monovalent radical of the formula aryl-alkyl-.

[0106] For groups beginning with a hyphen (-) or (-), it is the group immediately following the hyphen that is the point of attachment to the remainder of the molecule. For example, -(CH2)1-2-C3-4-cycloalkyl refers to a C3-4-cycloalkyl radical that is attached to the remainder of the molecule through a methylene or ethylene linker.

[0107] As used herein, the term "substituted by one or more substituents" includes substituted by 2, 3, 4, 5, or 6 substituents. Preferably, it includes 1 substituent or 2 or 3 substituents. For the avoidance of doubt, this term also includes cases where 2 or 3 substituents may be present on the same carbon atom as valency permits.

[0108] The use of any and all examples, or exemplary language (e.g., "how to"), provided herein is intended merely to further illuminate the invention and does not place a limitation on the scope of the invention otherwise claimed.

[0109] The term "substituted by 1, 2 or 3 substituents" should be interpreted accordingly.

[0110] By the expression "A is bonded to the remainder of the compound of Formula (I) by a carbon atom in A that is sp2 hybridized", this can be represented by the following diagram

[0111] When "heteroatom" or "heteroatoms" are mentioned for a ring, this refers to the ring heteroatoms (where NH should also be considered as a heteroatom that can stand in place of "N").

[0112] As used herein, the term "nitrogen protecting group" (PG) in a compound described herein, in a compound of formula (2a), (2b*), (2c*) and (2d*), or in the Schemes, refers to a group that is intended to protect related functional groups against undesired side reactions such as acylations, etherifications, esterifications, oxidations, solvolysis and similar reactions. The same can be removed under deprotection conditions. Depending on the protecting group used, the person skilled in the art knows how to remove the protecting group to obtain the free amine NH2 group with reference to known procedures. These include reference to organic chemistry textbooks and literature proceedings, such as J. F. W. McOmie, "Protective Groups in Organic Chemistry", T. W. Greene and P. G. M. Wuts, "Greene's Protective Groups in Organic Synthesis" and in "Methoden der organischen Chemie" (Methods of Organic Chemistry).

[0113] Preferred nitrogen protecting groups include: C1-C6alkyl (e.g., tert-butyl), preferably C1-C4alkyl, more preferably C1-C2alkyl, most preferably C1-alkyl that is mono-, di-, or tri-substituted by trialkylsilyl-C1-C7alkoxy (e.g., trimethylsiliethoxy), aryl, preferably phenyl, or a heterocyclic group (e.g., benzyl, cumyl, benzhydryl, pyrrolidinyl, trityl, pyrrolidinylmethyl, 1-methyl-1,1-dimethylbenzyl, (phenyl)methylbenzene), wherein the aryl ring or heterocyclic group is unsubstituted or substituted by one or more, e.g., two or three residues, e.g., selected from the group consisting of C1-C7alkyl, hydroxy, C1-C7alkoxy (e.g., para-methoxybenzyl (PMB)), C2-C8-alkanoyloxy, halogen, nitro, cyano and CF3, aryl-C1-C2-alkoxycarbonyl (preferably phenyl-C1-C2-alkoxycarbonyl (e.g. benzyloxycarbonyl (Cbz), benzyloxymethyl (BOM), pivaloyloxymethyl (POM)), C1-C10-alkenyloxycarbonyl, C1-C6alkylcarbonyl (e.g. acetyl or pivaloyl), C6-C10-arylcarbonyl; C1-C6-alkoxycarbonyl (e.g. tert-butoxycarbonyl (Boc), methylcarbonyl, trichloroethoxycarbonyl (Troc), pivaloyl (Piv), allyloxycarbonyl), C6-C10-arylC1-C6-alkoxycarbonyl (e.g. 9-fluorenylmethyloxycarbonyl (Fmoc)), allyl or cinnamyl, sulfonyl or sulphenyl, succinimidyl group, silyl groups la (e.g., triarylsilyl, trialkylsilyl, triethylsilyl (TES), trimethylsilylethoxymethyl (SEM), trimethylsilyl (TMS), triisopropylsilyl or tert-butyldimethylsilyl).

[0114] In embodiments of the invention, the nitrogen protecting group is C1-C6-alkoxycarbonyl (e.g., tert-butoxycarbonyl (Boc), methyloxycarbonyl, trichloroethoxycarbonyl (Troc), pivaloyl (Piv), allyloxycarbonyl). More preferably, the nitrogen protecting group is tert-butoxycarbonyl.

[0115] In embodiments of the invention, the nitrogen protecting group is a C1-C6-alkoxycarbonyl (e.g., tert-butoxycarbonyl or tert-butyl carbamate (Boc), methyloxycarbonyl or methyl carbamate, ethyl carbamate, 9-fluorophenylmethyl carbamate (Fmoc) and analogues thereof, 2,2,2-trichloroethyl trichloroethoxycarbonyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), pivaloyl (Piv), allyloxycarbonyl or allyl carbamate (Alloc), benzyl carbamate (Cbz)) or an amide protecting group, e.g., COCF3 (trifluoroacetamide), or N-allyl or N-benzyl and analogues thereof. More preferably, the nitrogen protecting group is tert-butoxycarbonyl.

[0116] The term "stereoisomer" or "stereoisomers" refers to compounds that have identical chemical constitution, but differ in relation to the arrangement of atoms or groups in space.

[0117] The term "diastereoisomer" or "diastereomer" refers to unrelated stereoisomers that are mirror images. Diastereoisomers are characterized by differences in physical properties and by some differences in chemical behavior. Mixtures of diastereomers can be separated under analytical procedures such as chromatography or crystallization.

[0118] The term "enantiomer" refers to one of a pair of molecular entities that are mirror images of each other and non-superimposable.

[0119] The term "enantiomeric mixture" refers to an enantiomerically enriched mixture, a composition comprising a greater proportion or percentage of one of the enantiomers of the compounds of the invention, in relation to another enantiomer or a racemate.

[0120] The term "diastereomeric mixture" refers to a diastereomerically enriched mixture or a mixture of diastereomers of equal proportion.

[0121] The term "diastereomerically enriched" refers to a composition comprising a greater proportion or percentage of one of the diastereomers of the compounds of the invention, relative to the other diastereomer (or diastereomers).

[0122] The term "atropisomer" refers to a stereoisomer that results from restricted rotation about single bonds where the rotation barrier is high enough to allow isolation of the isomeric species. Typically, rotation about the single bond in the molecule is prevented, or greatly reduced, as a result of steric interactions with other parts of the molecule, and the substituents at both ends of the single bond are asymmetric, resulting in a stereogenic unit referred to as a "chiral axis".

[0123] The absolute configuration of the chiral axes, for example in exemplary compounds, is assigned using the Cahn–Ingold–Prelog (CIP) chirality rule, with stereodescriptors (aR) or (aS), or the CIP helicity rule, with stereodescriptors (P) or (M) (V. Prelog and G. Helmchen, Angewandte Chemie International Edition, 21(8): 567–583, 1982, https://doi.org/10.1002/anie.198205671 ; P. Mata, A. M. Lobo, C. Marshall, and A. P. Johnson, Tetrahedron: Asymmetry, 4(4): 657–688, 1993, https://doi.org/10.1016/S0957-4166(00)80173-1 ; both cited in H. A. Favre and W. H. Powell, Nomenclature of Organic Chemistry: IUPAC Recommendations and Preferred Names 2013 (the IUPAC "Blue Book"), Cambridge, UK: Royal Soc. of Chem., 2014, https://doi.org/10.1039/9781849733069, Chapter P-9, "Specification of Configuration and Conformation", https://doi.org/10 .1039/9781849733069- 01156).

[0124] This is shown below for Example 12a (the more active atropisomer), which has the a(R) or (M) configuration. Example 12b (the less active atropisomer) has the a(S) or (P) configuration. Their

[0125] An alternative way of showing the structures of Examples 12a and 12b is as follows.

[0126] In embodiments of the invention, the compounds of the invention adopt the same spatial orientation as shown in Example 12a.

[0127] Similarly, the compound of Example 1a can be described by the name "a(R)-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5 - methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one" . The compound of Example 1a can also be designated by the name "1-{6-[(4M)-4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1 -methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl}prop-2-en-1-one".

[0128] The structure of the compound of Example 1a (also referred to herein as Compound X) is as follows.

[0129] An alternative way of showing the structure of the compound of Example 1a (also referred to herein as Compound X) is as follows.

[0130] The term "substantially equal" with reference to X-ray diffraction peak positions means that typical peak position and intensity variability are taken into account. For example, one skilled in the art will observe that peak positions (2θ) will show some variability between instruments, typically at most 0.2°. Additionally, one skilled in the art will observe that relative peak intensities will show variability between instruments, as well as variability due to degree of crystallinity, preferred orientation, prepared sample surface, and other factors known to those skilled in the art, and should be taken as qualitative measures only.

[0131] Various embodiments or aspects of the invention are described herein, and in particular in the claims. It will be recognized that the features specified in each embodiment may be combined with other specified features to provide other embodiments of the present invention. In particular, it will be recognized that the features recited in a particular embodiment or aspect are preferred aspects of the invention. The following enumerated embodiments are representative of the invention.

[0132] Embodiment 1. A compound of formula (I), wherein A is selected from the group consisting of (a) C5-C7-cycloalkylene that is unsubstituted or substituted by one or more, preferably 1, 2 or 3, substituents independently selected from fluorine and C1-C4-alkyl; (b) 5-7 membered unsaturated heterocyclyl containing a carbon-carbon double bond and an oxygen atom as ring member, wherein said heterocyclyl is unsubstituted or substituted by one or more, preferably 1, 2 or 3, substituents independently selected from fluorine and C1-C4-alkyl, preferably 1, 2 or 3, C1-C4-alkyl; (c) C6-C10 aryl that is unsubstituted or substituted by 1, 2 or 3 RA2; (d) a 5-6 membered heteroaryl ring containing 1, 2 or 3 heteroatoms independently selected from N, O and S as ring members, wherein said heteroaryl ring is unsubstituted or substituted on one or more (e.g., 1, 2 or 3) carbon atoms by RA3, and wherein a nitrogen atom, when present in the heteroaryl ring, is unsubstituted or substituted by a substituent selected from the group consisting of: C1-C4-alkyl, -(CH2)i—2-C3-4-cycloalkyl, C3-C6-cycloalkyl, hydroxy-C1-C4-alkyl, fluoro-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, N(R9)(R10)-C1-C4-alkyl, -SO2-C1-C4-alkyl, -SO2-C3—4-cycloalkyl, -(CH2)p-Hetpy, and -(CH2)pN(R9)(R10), (preferably wherein said substituent is selected from the group consisting of fluoro-C1-C4-alkyl, N(R9)(R10)-C1-C4-alkyl, -SO2-C3-4-cycloalkyl, or -(CH2)i-2-C3—4-cycloalkyl); (e) 8-10 membered heteroaryl ring containing 1, 2 or 3 nitrogen atoms, or 8-10 membered partially saturated heterobicyclic ring containing 1 to 3 heteroatoms or heteroatom groups independently selected from 0-3 nitrogen atoms, 0-2 oxygen atoms, 0-1 sulfur atom and 0-1 S(=O)2 group in the heterobicyclic ring, wherein said heteroaryl ring or heterobicyclic ring is unsubstituted or substituted on a carbon atom by 1, 2, 3, 4 or 5 RA4, and wherein the heterobicyclic ring is further optionally substituted on a carbon atom by oxo and wherein a nitrogen atom, when present, is unsubstituted or substituted by a substituent that is -(CO)-C1-C4-alkyl or C1-C4-alkyl, and wherein said C1-C4-alkyl is optionally substituted by 1 or 2 substituents independently selected from cyano, hydroxy, oxo, fluorine, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyloxy, Hetb and NR9R10; and wherein Hetb is a 4- or 5- or 6-membered heterocyclic ring comprising 1 or 2 heteroatoms or groups independently selected from N, O, S, SO and SO2 (preferably 1 oxygen atom, or 1 sulfur atom, or an S(=O) or an S(=O)2 group, or 1 nitrogen atom and 1 oxygen atom, or 1-2 nitrogen atoms), wherein said Hetb heterocyclic ring is unsubstituted or substituted on a carbon atom by one or two substituents independently selected from C1-C4-alkyl, hydroxy, cyano, fluorine, C1-C4-alkoxy-hydroxy-C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy, fluorine-C1-C4-alkoxy and fluorine-C1-C4-alkyl, and wherein said heterocyclic ring Hetb is further optionally substituted on a carbon atom by oxo, and wherein the nitrogen atom when present in Hetb is further optionally substituted by C1-C4-alkyl that is optionally substituted by 1 to 3 substituents independently selected from fluorine, hydroxy and C1-C4-alkoxy; wherein A is bonded to the remainder of the compound of Formula (I) by a carbon atom in A that is sp2 hybridized; wherein B is selected from the group consisting of B1 and B2, wherein B1 is C6-10 aryl that is unsubstituted or substituted by 1, 2, 3 or 4 RBa; B2 is a 6-13 membered heteroaryl comprising 1, 2 or 3 nitrogen atoms, wherein B2 is unsubstituted or substituted by 1, 2, 3 or 4 RBb; C is selected from the group consisting of hydrogen, C1-C3 alkyl (preferably methyl), C3-C5 cycloalkyl (preferably cyclopropyl), fluoro-C1-C3 alkyl (preferably CHF2 or CF3), cyano, -CH2-CN, -CH(CN)-CH3, -CH2-OH, -CH(OH)-CH3 and halo; L is selected from the group consisting of: where n is 1, 2, or 3, RL is selected from hydrogen, methyl, ethyl, -CH2-CN, and -CH2-OH, where G* represents the point of attachment to G; G is selected from the group consisting of where R2 is selected from hydrogen, C1-C3 alkyl, -C(O)-C1-C3-alkyl and fluorine; R3 is hydrogen; R4 is selected from hydrogen, methyl, -CH2F, -CH2-OCH3 and -CH2-N(CH3)2; R5 is selected from hydrogen and methyl; R6 is hydrogen; R7 is selected from hydrogen and methyl; wherein RA2 is independently selected from the group consisting of: NR9R10, cyano, -(CH2)p-CN, halo, OH, hydroxy-C1-C4-alkyl, -(COOH), -(CH2)p-COOH, C1-C4-alkyl, fluorine-C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl, R9) Ci-C4-alkoxy-Ci-C4-alkyl-oxy-Ci-C4-alkyl, -SO2-Ci-C4-alkyl, -Sθ2-C3-4-cycloalkyl, -(CH2)i-2-C3—4-cycloalkyl, Hetpy, -(CH2)p- Hetpy, -C(=O)-NR9R10, -(CH2)pC(=O)NR9R10 , (preferably from the group consisting of NR9R10, cyano, C1-C4-alkyl, fluorine, fluoro-C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyloxy, hydroxy-C1-C4-alkyl, hydroxy-C1-C4-alkyloxy, Hetpy, -(CH2)p-Hetpy and -C(=O)-NR9R10); wherein RA3 is independently selected from the group consisting of oxo, NR9R10, cyano, -(CH2)p-CN, halo, OH, hydroxy-C1-C4-alkyl, -(COOH), -(CH2)p-COOH, C1-C4-alkyl, fluoro-Cr C4-alkyl, C1-C4-alkoxy, , N(R9)(R10)-C1-C4-alkyl, N(R9)(R10)-C1-C4-alkyloxy, N(R9)(R10)-C1-C4-alkoxy, C1-C4-alkyl-carbonyl-oxy-C1-C4-alkyloxy, hydroxy-C1-C4-alkyloxy, C1-C4-alkoxy-C1-C4-alkyloxy, C1-C4-alkoxy-C1-C4-alkyl-oxy-C1-C4-alkyl, -SO2-C1-C4-alkyl, -SO2-C3-4-cycloalkyl, -(CH2)1-2-C3-4-cycloalkyl, Hetpy, -(CH2)p- Hetpy, -C(=O)-NR9R10, -(CH2)pC(=O)NR9R10, (CH2)p-NR9R10 (preferably from the group consisting of NR9R10, cyano, C1-C4-alkyl, fluorine, fluorine-C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyloxy, Hetpy and -(CH2)p-Hetpy); wherein RA4 is independently selected from the group consisting of cyano, CO2H, halo, C1-C4-alkyl, fluoro-C1-C4-alkyl, hydroxy, hydroxy-C1-C4-alkyl, hydroxy-C1-C4-alkyloxy, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyloxy, NR9R10, (N(R9)(R10)-C1-C4-alkyl, (N(R9)(R10)-C1-C4-alkyloxy, -(CO)-CI-C4-alkyl and R9R10N-C1-C4-alkyl-oxy-(CO)-C1-C4-alkyl; wherein p is 1 or 2 or 3; R9 is selected from hydrogen and C1-C4-alkyl; R10 is selected from the group consisting of hydrogen, C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, and di-C1-C4-alkyl-amino-C1-C4-alkyl; Hetpy is a 4-, 5-, 6-, or 7-membered saturated heterocyclic ring comprising one or two heteroatoms independently selected from O, N (such as, pyrrolidin-1-yl, azetidin-1-yl, morpholin-1-yl), and S, or comprising an S-oxide (SO) or S-dioxide (SO2) group, and wherein said heterocyclic ring is optionally substituted by oxo on a carbon atom, and wherein said heterocyclic ring is further optionally substituted on one or more carbon atoms by 1, 2, or 3 substituents independently selected from C1-C4-alkoxy (preferably methoxy), halo (preferably fluorine), C1-C4-alkyl, hydroxy-C1-C4-alkyl, and fluorine-C1-C4-alkyl, and wherein the nitrogen atom, if present in said heterocycle, is further optionally substituted by R10 (preferably C1-C4-alkyl (such as methyl)); or Hetpy is a 5- or 6-membered heteroaryl ring (preferably 1,2,4-triazol-1-yl or pyrazol-1-yl) comprising 1, 2 or 3 nitrogen atoms and wherein said heteroaryl ring is optionally substituted by one or more (e.g., 1, 2 or 3) substituents independently selected from NR9R10, -C(=O)-NR9R10, halo, C1-C4-alkyl, hydroxy-C1-C4-alkyl, fluoro-C1-C4-alkyl, cyano, OH and C1-C4-alkoxy; each RBa is independently selected from the group consisting of hydroxy, NH2, C1-C4-alkyl and halo; each RBb is independently selected from the group consisting of C1-C4-alkyl (preferably methyl), cyclopropyl, fluoro-C1-C3-alkyl (preferably CHF2 or CF3), cyano, halo (preferably fluoro or chloro), NH2, and C1-C3-alkoxy (preferably methoxy), or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof.

[0133] Embodiment 2. A compound according to embodiment 1 in A is selected from the group consisting of (a) C5-C7-cycloalkylene that is unsubstituted or substituted by one or more, preferably 1, 2 or 3, substituents independently selected from fluorine and C1-C4-alkyl; (b) 5-7 membered unsaturated heterocyclyl containing a carbon-carbon double bond and an oxygen atom as ring member, wherein said heterocyclyl is unsubstituted or substituted by one or more, preferably 1, 2 or 3, substituents independently selected from fluorine and C1-C4-alkyl, preferably 1, 2 or 3, C1-C4-alkyl; (c) C6-C10 aryl that is unsubstituted or substituted by 1, 2 or 3 RA2; (d) a 5-6 membered heteroaryl ring containing 1, 2 or 3 heteroatoms independently selected from N, O and S as ring members, wherein said heteroaryl ring is unsubstituted or substituted on one or more (e.g., 1, 2 or 3) carbon atoms by RA3, and wherein a nitrogen atom, when present in the heteroaryl ring, is unsubstituted or substituted by a substituent selected from the group consisting of: C1-C4-alkyl, -(CH2)i—2-C3-4-cycloalkyl, C3-C6-cycloalkyl, hydroxy-C1-C4-alkyl, fluoro-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, N(R9)(R10)-C1-C4-alkyl, -SO2-C1-C4-alkyl, -SO2-C3—4-cycloalkyl, -(CH2)p-Hetpy, and -(CH2)p-N(R9)(R10), (preferably wherein said substituent is selected from the group consisting of fluoro-C1-C4-alkyl, N(R9)(R10)-C1-C4-alkyl, -SO2-C3-4-cycloalkyl, or -(CH2)i-2-C3—4-cycloalkyl); (e) an 8-10 membered heteroaryl ring containing 1, 2 or 3 nitrogen atoms, wherein each nitrogen atom is unsubstituted or substituted by a substituent that is -(CO)-C1-C4-alkyl or C1-C4-alkyl, and wherein said C1-C4-alkyl is optionally substituted by 1 or 2 substituents independently selected from cyano, hydroxy, oxo, fluorine, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyloxy, Hetb and NR9R10, wherein said heteroaryl ring is unsubstituted or substituted on a carbon atom by 1, 2, 3, 4 or 5 RA4; wherein Hetb is a 4- or 5- or 6-membered heterocyclic ring comprising 1 or 2 heteroatoms or groups independently selected from N, O, S, SO and SO2 (preferably 1 oxygen atom, or 1 sulfur atom, or an S(=O) or an S(=O)2 group, or 1 nitrogen atom and 1 oxygen atom, or 1-2 nitrogen atoms), wherein said Hetb heterocyclic ring is unsubstituted or substituted on a carbon atom by one or two substituents independently selected from C1-C4-alkyl, hydroxy, cyano, fluorine, C1-C4-alkoxy-hydroxy-C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy, fluorine-C1-C4-alkoxy and fluorine-C1-C4-alkyl, and wherein said heterocyclic ring Hetb is further optionally substituted on a carbon atom by oxo, and wherein the nitrogen atom when present in Hetb is further optionally substituted by C1-C4-alkyl which is optionally substituted by 1 to 3 substituents independently selected from fluorine, hydroxy and C1-C4-alkoxy; and (f) an 8-10 membered partially saturated heterobicyclic ring containing 1-3 nitrogen atoms, or 1-2 oxygen atoms, or 1 sulfur atom or 1 S(=O)2 group in the heterobicyclic ring, wherein said heterobicyclic ring is unsubstituted or substituted on a carbon atom by 1, 2, 3, 4 or 5 RA4, and wherein the heterobicyclic ring is further optionally substituted on a carbon atom by oxo and wherein a nitrogen atom, when present, is unsubstituted or substituted by a substituent that is -(CO)-C1-C4-alkyl or C1-C4-alkyl, and wherein said C1-C4-alkyl is optionally substituted by 1 or 2 substituents independently selected from cyano, hydroxy, oxo, fluorine, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4- alkyloxy, Hetb and NR9R10; and wherein Hetb is a 4- or 5- or 6-membered heterocyclic ring comprising 1 or 2 heteroatoms or groups independently selected from N, O, S, SO and SO2 (preferably 1 oxygen atom, or 1 sulfur atom, or an S(=O) or an S(=O)2 group, or 1 nitrogen atom and 1 oxygen atom, or 1-2 nitrogen atoms), wherein said Hetb heterocyclic ring is unsubstituted or substituted on a carbon atom by one or two substituents independently selected from C1-C4-alkyl, hydroxy, cyano, fluorine, C1-C4-alkoxy-hydroxy-C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy, fluorine-C1-C4-alkoxy and fluorine-C1-C4-alkyl, and wherein said heterocyclic ring Hetb is further optionally substituted on a carbon atom by oxo, and wherein the nitrogen atom when present in Hetb is further optionally substituted by C1-C4-alkyl which is optionally substituted by 1 to 3 substituents independently selected from fluorine, hydroxy and C1-C4-alkoxy, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof.

[0134] Embodiment 3. A compound according to embodiment 1 or 2, wherein Hetb is a 4- or 5- or 6-membered heterocyclic ring comprising 1 or 2 heteroatoms or groups independently selected from N, O, S, SO and SO2 (preferably 1 oxygen atom, or 1 sulfur atom, or a S(=O) or a S(=O)2 group, or 1 nitrogen atom and 1 oxygen atom, or 1-2 nitrogen atoms), wherein said Hetb heterocyclic ring is unsubstituted or substituted on a carbon atom by one or two substituents independently selected from C1-C4-alkyl, hydroxy, cyano, fluorine, C1-C4-alkoxy-hydroxy-C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy and fluorine-C1-C4-alkyl, and wherein said heterocyclic ring Hetb is further optionally substituted on a carbon atom by oxo, and wherein the nitrogen atom when present in Hetb is further optionally substituted by C1-C4-alkyl, wherein said C1-C4-alkyl is optionally substituted by 1 to 3 substituents independently selected from fluorine, hydroxy and C1-C4-alkoxy; B is selected from the group consisting of B1 and B2, B1 is C6-10 aryl that is unsubstituted or substituted by 1, 2, 3 or 4 RBa and each RBa is independently selected from the group consisting of hydroxy, C1-C4-alkyl and halo; B2 is a 6-10 (preferably 8-10) membered heteroaryl comprising 1, 2 or 3 nitrogen atoms, wherein B2 is unsubstituted or substituted by 1, 2, 3 or 4 RBb; each RBb is independently selected from the group consisting of C1-C4-alkyl (preferably methyl), fluoro-C1-C3-alkyl (preferably CHF2 or CF3), cyano, halo (preferably fluoro or chloro), NH2, and C1-C3-alkoxy (preferably methoxy), Hetpy is a 4-, 5-, 6-, or 7-membered saturated heterocyclic ring comprising one or two heteroatoms independently selected from O, N (such as pyrrolidin-1-yl, azetidin-1-yl, morpholin-1-yl), and S, or comprising an S-oxide (SO) or S-dioxide (SO2) group, and wherein said heterocyclic ring is optionally substituted by oxo on a carbon atom, and wherein said heterocyclic ring is further substituted on one or more carbon atoms by 1, 2, or 3 substituents independently selected from C1-C4-alkoxy (preferably methoxy), halo (preferably fluorine), C1-C4-alkyl, hydroxy-C1-C4-alkyl, and fluorine-C1-C4-alkyl, and wherein the nitrogen atom, if present in said heterocycle, is further optionally substituted by R10 (preferably C1-C4-alkyl (such as methyl)); or Hetpy is a 5- or 6-membered heteroaryl ring (preferably 1,2,4-triazol-1-yl or pyrazol-1-yl) comprising 1, 2 or 3 nitrogen atoms and wherein said heteroaryl ring is optionally substituted by one or more (e.g., 1, 2 or 3) substituents independently selected from NR9R10, halo, C1-C4-alkyl, cyano, OH and C1-C4-alkoxy; wherein RA4 is independently selected from the group consisting of cyano, CO2H, halo, C1-C4-alkyl, fluoro-C1-C4-alkyl, hydroxy, hydroxy-C1-C4-alkyl, hydroxy-C1-C4-alkyloxy, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyloxy, -NR9R10, R9R10N-C1-C4-alkyloxy, -(CO)-C1-C4-alkyl; 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.

[0135] Embodiment 4. A compound according to any of the previous embodiments, wherein Hetb is a 4- or 5- or 6-membered heterocyclic ring comprising 1 or 2 heteroatoms or groups independently selected from N, O, S, SO and SO2 (preferably 1 oxygen atom, or 1 sulfur atom, or a S(=O) or a S(=O)2 group, or 1 nitrogen atom and 1 oxygen atom, or 1-2 nitrogen atoms), wherein said Hetb heterocyclic ring is unsubstituted or substituted on a carbon atom by one or two substituents independently selected from C1-C4-alkyl, hydroxy, cyano, fluorine, C1-C4-alkoxy-hydroxy-C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy and fluorine-C1-C4-alkyl, and wherein said heterocyclic ring Hetb is further optionally substituted on a carbon atom by oxo, and wherein the nitrogen atom when present in Hetb is further optionally substituted by C1-C4-alkyl, wherein said C1-C4-alkyl is optionally substituted by 1 to 3 substituents independently selected from fluorine, hydroxy and C1-C4-alkoxy; B2 is a 6-10 (preferably 8-10) membered heteroaryl comprising 1, 2 or 3 nitrogen atoms, wherein B2 is unsubstituted or substituted by 1, 2, 3 or 4 RBb; Hetpy is a 4-, 5-, 6-, or 7-membered saturated heterocyclic ring comprising one or two heteroatoms independently selected from O, N (such as pyrrolidin-1-yl, azetidin-1-yl, morpholin-1-yl), and S, or comprising an S-oxide (SO) or S-dioxide (SO2) group, and wherein said heterocyclic ring is optionally substituted by oxo on a carbon atom, and wherein said heterocyclic ring is further substituted on one or more carbon atoms by 1, 2, or 3 substituents independently selected from C1-C4-alkoxy (preferably methoxy), halo (preferably fluorine), C1-C4-alkyl, hydroxy-C1-C4-alkyl, and fluorine-C1-C4-alkyl, and wherein the nitrogen atom, if present in said heterocycle, is further optionally substituted by R10 (preferably C1-C4-alkyl (such as methyl)); or Hetpy is a 5- or 6-membered heteroaryl ring (preferably 1,2,4-triazol-1-yl or pyrazol-1-yl) comprising 1, 2 or 3 nitrogen atoms and wherein said heteroaryl ring is optionally substituted by one or more (e.g. 1, 2 or 3) substituents independently selected from NR9R10, halo, C1-C4-alkyl, cyano, OH and C1-C4-alkoxy (preferably said heteroaryl ring is substituted by one or more amino groups); RA4 is independently selected from the group consisting of cyano, CO2H, halo, C1-C4-alkyl, fluoro-C1-C4-alkyl, hydroxy, hydroxy-C1-C4-alkyl, hydroxy-C1-C4-alkyloxy, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyloxy, -NR9R10 and R9R10N-C1-C4-alkyloxy, 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.

[0136] Embodiment 5. A compound according to any of the preceding embodiments, wherein G is 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.

[0137] Embodiment 6. A compound according to any of the preceding embodiments, wherein L is 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.

[0138] Embodiment 7. A compound according to embodiment 6, wherein RL is hydrogen, 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.

[0139] Embodiment 8. A compound according to any of the previous embodiments, wherein C is selected from C1-C3 alkyl (preferably methyl), fluoro-C1-C3 alkyl (preferably CHF2 or CF3), CH2-CN, or a stereoisomer thereof, or 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.

[0140] Embodiment 9. A compound according to any of the preceding embodiments, wherein B is wherein B is unsubstituted or substituted by 1, 2 or 3 halo, or methyl groups 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.

[0141] Embodiment 10. A compound according to any of the preceding embodiments, wherein B is wherein X is N or C-RB5; wherein RB1 is independently selected from hydrogen and C1-C4-alkyl (preferably methyl); RB2 is independently selected from hydrogen, halo (preferably chlorine), C1-C4-alkyl (preferably methyl), cyclopropyl, and NH2; RB3 is independently selected from hydrogen, halo (preferably chlorine), cyclopropyl, and C1-C4-alkyl (preferably methyl); RB4 is independently selected from hydrogen, halo (preferably chlorine or fluorine), and C1-C4-alkyl (preferably methyl), or RB3 and RB4 together with the atoms to which they are attached form a 4-6 membered ring (preferably a 5-6 membered saturated or partially unsaturated carbocyclic ring) fused to the aromatic ring containing X; RB5 is independently selected from hydrogen, halo (preferably chlorine), and C1-C4-alkyl (preferably methyl), or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof.

[0142] Embodiment 11. A compound according to embodiment 10, wherein RB2 is independently selected from the group consisting of hydrogen, NH2, and CH3, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of an atropisomer thereof.

[0143] Embodiment 12. A compound according to embodiment 10 or 11, wherein RB4 is independently selected from hydrogen, halo (preferably chlorine or fluorine), and C1-C4-alkyl (preferably methyl), or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof.

[0144] Embodiment 13. A compound according to any one of embodiments 10 to 12, wherein RB1 is independently selected from hydrogen and methyl, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof.

[0145] Embodiment 14. A compound according to any one of embodiments 10 to 13, wherein RB1 is hydrogen, 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.

[0146] Embodiment 15. A compound according to any one of embodiments 10 to 14, wherein RB3 and RB4 are each independently selected from halo (preferably chloro or fluoro) and C1-C4-alkyl (preferably methyl), or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof.

[0147] Embodiment 16. A compound according to any one of embodiments 10 to 15, wherein RB3 is halo and RB4 is C1-C4-alkyl, 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.

[0148] Embodiment 17. A compound according to any one of embodiments 10 to 16, wherein RB3 is chloro and RB4 is methyl, 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.

[0149] Embodiment 18. A compound according to any one of embodiments 10 to 16, wherein RB3 is chloro and RB4 is chloro, 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.

[0150] Embodiment 19. A compound according to any one of embodiments 10 to 18, wherein X is CH or N, 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.

[0151] 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 a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof.

[0152] Embodiment 21. A compound of formula (Ia) wherein A, B and C are as defined in any of the previous embodiments, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof.

[0153] Embodiment 22. A compound of formula (I) or formula (Ia) according to any of the previous embodiments, wherein A is C5-C7-cycloalkylene that is unsubstituted or substituted by one or more, preferably 1, 2 or 3, substituents independently selected from fluorine and C1-C4-alkyl, 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.

[0154] Embodiment 23. A compound of formula (I) or of formula (Ia) according to any of the preceding embodiments, wherein A is wherein W is O or C(Rw)2, each Rw is independently selected from hydrogen and fluorine, Rc is hydrogen or C1-C4-alkyl, and A is further optionally substituted by 1, 2, or 3 substituents independently selected from fluorine and C1-C4-alkyl, 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.

[0155] Embodiment 24. A compound of formula (I) or formula (Ia) according to any one of embodiments 1 to 21, wherein A is phenyl that is unsubstituted or substituted by 1, 2, or 3 RA2, preferably wherein RA2 is independently selected from the group consisting of halo, OH, hydroxy-C1-C4-alkyl, -(COOH), C1-C4-alkyl, fluoro-C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkylcarbonyl-oxy-C1-C4-alkyloxy, hydroxy-C1-C4-alkyloxy, C1-C4-alkoxy-C1-C4-alkyloxy, -C(=O)-NR9R10, -NR9R10, Hetpy, and -(CH2)p-Hetpy, wherein p is 1 or 2; R9 is selected from hydrogen, C1-C4-alkyl and C1-C4-alkoxy-C1-C4-alkyl; R10 is selected from hydrogen, C1-C4-alkyl, hydroxy-C1-C4-alkyl and C1-C4-alkoxy-C1-C4-alkyl; Hetpy is -NR9aR10a and R9a and R10a together with nitrogen form a 4- or 5- or 6-membered heterocyclic ring comprising one or two additional heteroatoms independently selected from O, N (such as pyrrolidin-1-yl, azetidin-1-yl or morpholin-1-yl) and S, or an N-oxide thereof, or an S-oxide (SO) or S-dioxide thereof, and wherein said heterocyclic ring is optionally substituted by oxo on a carbon atom, and wherein said heterocyclic ring is further substituted by one or two substituents independently selected from C1-C4-alkoxy (preferably methoxy), halo (preferably fluorine), C1-C4-alkyl, hydroxy-C1-C4-alkyl and fluorine-C1-C4-alkyl; or R9a and R10a together with nitrogen form a 4- or 5- or 6-membered heteroaryl ring (preferably 1,2,4-triazol-1-yl or pyrazol-1-yl) comprising 1, 2 or 3 nitrogen atoms and wherein said heteroaryl ring is optionally substituted by an amino group, 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.

[0156] Embodiment 25. A compound of formula (I) or formula (Ia) according to any one of embodiments 1 to 21, wherein A is a 5-6 membered heteroaryl ring containing 1, 2 or 3 heteroatoms independently selected from N, O and S as ring members, wherein said heteroaryl ring is unsubstituted or substituted on one or more (e.g., 1, 2 or 3) carbon atoms by RA3, and wherein a nitrogen atom, when present in the heteroaryl ring, is unsubstituted or substituted by a substituent selected from the group consisting of: C1-C4-alkyl, -(CH2)i—2-C3-4-cycloalkyl, hydroxy-C1-C4-alkyl, fluoro-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, N(R9)(R10)-C1-C4-alkyl, -SO2-C1-C4-alkyl, -SO2-C3-4-cycloalkyl, -(CH2)p-Hetpy, and -(CH2)p-N(R9)(R10), (preferably wherein said substituent is selected from the group consisting of fluoro-C1-C4-alkyl, N(R9)(R10)-C1-C4-alkyl, -SO2-C3-4-cycloalkyl, or -(CH2)1-2-C3-4-cycloalkyl), 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.

[0157] Embodiment 26. A compound of formula (I) or formula (Ia) according to any one of embodiments 1 to 21, wherein A is pyridin-1-yl, pyridin-2-yl, or pyridin-3-yl, which is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from 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-alkyloxy, C1-C4-alkylcarbonyl-oxy-C1-C4-alkyloxy, hydroxy-C1-C4-alkyloxy, C1-C4-alkoxy-C1-C4-alkyloxy, C1-C4-alkoxy-C1-C4-alkyl-oxy-C1-C4-alkyl, -C(=O)-NR9R10, NR9R10, Hetpy and -(CH2)p-Hetpy, where p is 1 or 2;; R9 is selected from hydrogen and C1-C4-alkyl, R10 is selected from hydrogen, C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl and di-C1-C4-alkyl-amino-C1-C4-alkyl, Hetpy is NR9a R10a; R9a and R10a together with nitrogen form a 4- or 5- or 6-membered saturated or unsaturated heterocyclic ring comprising one or two heteroatoms independently selected from O, N (pyrrolidin-1-yl, azetidin-1-yl, morpholin-1-yl) and S, or an N-oxide thereof, or an S-oxide (SO) or S-dioxide thereof, and wherein said heterocyclic ring is optionally substituted by oxo on a carbon atom in said heterocyclic ring, and wherein said heterocyclic ring is further substituted by 1, 2 or 3 substituents independently selected from C1-C4-alkoxy (preferably methoxy), halo (preferably fluorine), C1-C4-alkyl, hydroxy-C1-C4-alkyl and fluorine-C1-C4-alkyl; or R9a and R10a together with nitrogen form a 4- or 5- or 6-membered heteroaryl ring (preferably 1,2,4-triazol-1-yl or pyrazol-1-yl) comprising 1, 2 or 3 nitrogen atoms and wherein said heteroaryl ring is optionally substituted by an amino group, 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.

[0158] Embodiment 27. A compound of formula (I) or (Ia) according to any one of embodiments 1 to 21, wherein A is pyridinyl substituted with 1, 2 or 3 substituents independently selected from NH2, cyano, halo, C1-C4-alkyl, fluoro-C1-C4-alkyl, C1-C4-alkoxy, di-C1-C4-alkylamino-C1-C4-alkyloxy, -C(=O)-NR9R10, NR9R10, wherein p is 0, 1 or 2, preferably p is 0; R22 is hydrogen or C1-C4-alkyl (preferably methyl), or amino; R9 is selected from hydrogen and C1-C4-alkyl, R10 is selected from hydrogen, C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl and di-C1-C4-alkyl-amino-C1-C4-alkyl, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof.

[0159] Embodiment 28. A compound of formula (I) or of formula (Ia) according to any one of embodiments 1 to 21, wherein A is wherein R23 is hydrogen, C3-C6-cycloalkyl, C1-C4-alkyl (preferably methyl), wherein A is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from F, CH3, CH2F, CHF2 and CF3; or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof.

[0160] Embodiment 29. A compound of formula (I) or formula (Ia) according to any one of embodiments 1 to 21, wherein A is pyrimidin-5-yl that is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from C1-C4-alkoxy (preferably methoxy) and CH3, 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.

[0161] Embodiment 30. A compound of formula (I) or of formula (Ia) according to any one of embodiments 1 to 21, wherein A is selected from the group consisting of wherein R24 is hydrogen, C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, -NR9R10C1-C4-alkyl, -SO2-C1-C4-alkyl, -Sθ2-C3-4-cycloalkyl or -(CH2)1-2-C3—4-cycloalkyl; each of R4a, R4b, R4c and R4d is independently selected from hydrogen and C1-C4-alkyl (preferably methyl), or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof.

[0162] Embodiment 31. A compound of formula (I) or of formula (Ia) according to any of the previous embodiments 1 to 21, wherein A is selected from the group consisting of: wherein 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; RO is selected from the group consisting of hydrogen, NR9R10, R9R10N-C1-C4-alkyloxy, C1-C4-alkoxy-C1-C4-alkyloxy, hydroxy-C1-C4-alkyloxy, and C1-C4-alkyl (preferably RO is hydrogen or NR9R10); RM is hydrogen, halo, or C1-C4-alkyl, wherein said alkyl is optionally substituted by OH, C1-C4-alkoxy, or NR9R10 (preferably RM is hydrogen); RN is hydrogen, or C1-C4-alkyl, or halo, or fluoro-C1-C4-alkyl (preferably hydrogen); Rq is independently selected from the group consisting of C1-C4-alkyl, hydroxy, C1-C4-alkoxy, and NR9R10; Rp is C1-C4-alkyl; each Rp1 is independently selected from hydrogen and C1-C4-alkyl; Rv is independently selected from halogen, C1-C4-alkyl, and fluoro-C1-C4-alkyl; Rae is selected from the group consisting of hydrogen and C1-C4-alkyl, wherein said alkyl is optionally substituted by 1 or 2 substituents selected from cyano, hydroxy, fluoro, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyloxy, Hetb, and NR9R10; RaeAe is selected from the group consisting of hydrogen, -(CO)-C1-C4-alkyl, and C1-C4-alkyl, wherein the C1-C4-alkyl in each case is optionally substituted by 1 or 2 substituents selected from cyano, hydroxy, fluorine, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyloxy, Hetb, and NR9R10; wherein R9 is selected from hydrogen and C1-C4-alkyl; R10 is selected from hydrogen, C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, and di-C1-C4-alkyl-amino-C1-C4-alkyl; wherein Hetb is a 4- or 5- or 6-membered heterocyclic ring comprising 1 or 2 heteroatoms or groups independently selected from N, O, S, SO and SO2 (preferably comprising 1 oxygen atom, or 1 sulfur atom, or an S(=O) or an S(=O)2 group, or 1 nitrogen atom and 1 oxygen atom, or 1-2 nitrogen atoms), wherein said Hetb heterocyclic ring is unsubstituted or substituted on a carbon atom by one or two substituents independently selected from C1-C4-alkyl, hydroxy, cyano, fluorine, hydroxy-C1-C4-alkyl, C1-C4-alkoxy and fluorine-C1-C4-alkyl, and wherein said Hetb heterocyclic ring is further optionally substituted on a carbon atom by oxo, and wherein the nitrogen atom when present in Hetb is further optionally substituted by C1-C4-alkyl which is optionally substituted by 1 to 3 substituents independently selected from fluoro, hydroxy and C1-C4-alkoxy; or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof.

[0163] Embodiment 32. A compound of formula (I) or formula (Ia) according to any one of embodiments 1 to 21, wherein A is selected from the group consisting of: wherein z is 0, 1, or 2; Rv is independently selected from halogen, C1-C4-alkyl, and fluoro-C1-C4-alkyl; RN is hydrogen or C1-C4-alkyl, or halo or fluoro-C1-C4-alkyl (preferably hydrogen); RO is selected from the group consisting of hydrogen, NR9R10, N(R9)(R10)-C1-C4-alkyloxy, C1-C4-alkoxy-C1-C4-alkyloxy, hydroxy-C1-C4-alkyloxy, and C1-C4-alkyl (preferably RO is hydrogen or NR9R10); Rae is selected from the group consisting of hydrogen and C1-C4-alkyl, wherein said alkyl is optionally substituted by 1 or 2 substituents selected from cyano, hydroxy, fluorine, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyloxy, Hetb and NR9R10; R9 is selected from hydrogen and C1-C4-alkyl; R10 is selected from hydrogen, C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl and di-C1-C4-alkyl-amino-C1-C4-alkyl; wherein Hetb is a 4- or 5- or 6-membered heterocyclic ring comprising 1 or 2 heteroatoms or groups independently selected from N, O, S, SO and SO2 (preferably comprising 1 oxygen atom, or 1 sulfur atom, or an S(=O) or an S(=O)2 group, or 1 nitrogen atom and 1 oxygen atom, or 1-2 nitrogen atoms), wherein said Hetb heterocyclic ring is unsubstituted or substituted on a carbon atom by one or two substituents independently selected from C1-C4-alkyl, hydroxy, cyano, fluorine, hydroxy-C1-C4-alkyl, C1-C4-alkoxy and fluorine-C1-C4-alkyl, and wherein said Hetb heterocyclic ring is further optionally substituted on a carbon atom by oxo, and wherein the nitrogen atom when present in Hetb is further optionally substituted by C1-C4-alkyl which is optionally substituted by 1 to 3 substituents independently selected from fluoro, hydroxy and C1-C4-alkoxy; or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof.

[0164] Embodiment 33. A compound of formula (I) or formula (Ia) according to any one of embodiments 1 to 21, or embodiment 31 or embodiment 32, wherein A is 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 a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof.

[0165] Embodiment 34. A compound of formula (I) or formula (Ia) according to embodiment 33, wherein RN is hydrogen or C1-C4-alkyl (preferably hydrogen); RO is hydrogen or NR9R10; Rv is independently selected from fluorine, chlorine, and C1-C4-alkyl (e.g., methyl); 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 a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof.

[0166] Embodiment 35. A compound of formula (I) or formula (Ia) according to any one of embodiments 31 to 34, wherein Rae is selected from the group consisting of hydrogen, C1-C4-alkyl, -(CH2)2-Hetb, -CH2-CN, -(CH2)2-OH, -(CH2)2-O-C1-C4-alkyl, hydroxy-C1-C4-alkyl, -(CH2)2-O-(CH2)2-O-C1-C4-alkyl, and -(CH2)2-diC1-C4-alkylamino, or wherein RAe is selected from the group consisting of hydrogen, fluoro-C1-C4-alkyl, and C1-C4-alkyl; Hetb is a 4-, 5- or 6-membered heterocyclic ring comprising 1 nitrogen atom and 1 oxygen atom, or 1-2 nitrogen atoms, wherein said heterocyclic ring is unsubstituted or substituted on a carbon atom by one or two substituents independently selected from C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy and fluorine, and wherein the nitrogen atom when present in the heterocycle is further optionally substituted by C1-C4-alkyl, 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.

[0167] Embodiment 36. A compound of formula (I) or formula (Ia) according to any one of embodiments 31 to 35, wherein Rae is selected from the group consisting of 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-Hetb; wherein said Hetb is a 4-, 5- or 6-membered heterocyclic ring comprising 1 nitrogen atom and 1 oxygen atom, or 1-2 nitrogen atoms, wherein said heterocyclic ring is unsubstituted or substituted on a carbon atom by one or two substituents independently selected from C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy and fluorine, and wherein the nitrogen atom when present in the heterocycle is further optionally substituted by C1-C4-alkyl, 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.

[0168] Embodiment 37. A compound of formula (I) or formula (Ia) according to any one of embodiments 31 to 36, wherein Rae is selected from the group consisting of 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-Hetb, wherein Hetb is selected from the group consisting of azetidin-1-yl, pyrrolidin-1-yl, pyrrolidin-3-yl, and morpholin-1-yl, and wherein said heterocyclic ring is further optionally substituted by one or two substituents independently selected from methyl, hydroxymethyl, methoxy, and fluorine, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof.

[0169] Embodiment 38. A compound of formula (I) or formula (Ia) according to any one of embodiments 31 to 36, wherein Rae is selected from the group consisting of hydrogen, fluoro-C1-C4-alkyl, C1-C4-alkyl, -(CH2)2-Hetb, -(CH2)2-OH, -(CH2)2-O-C1-C4-alkyl, hydroxy-C1-C4-alkyl, -(CH2)2-O-(CH2)2-O-C1-C4-alkyl, and -(CH2)2-diC1-C4-alkylamino, or 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.

[0170] Embodiment 39. A compound of the formula (Ib*), wherein A, C, RB2, RB3, and RB4 are as defined in any of the preceding embodiments, wherein A is unsubstituted or substituted as defined in any of the preceding embodiments, or a pharmaceutically acceptable salt thereof.

[0171] Embodiment 40. A compound of formula (Ic*), wherein C, RA2, RB2, RB3, and RB4 are as defined in any of the preceding embodiments, wherein a is 0, 1, 2, or 3 (preferably, a is 0 or 1 or 2), or a pharmaceutically acceptable salt thereof.

[0172] Embodiment 41. A compound of the formula (Id*), wherein C, RB2, RN, RB3, and RB4 are as defined in any of the preceding embodiments, wherein the lines indicate a single bond or a double bond; and Rae is as defined above.

[0173] Embodiment 42. A compound according to any of the previous embodiments, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, selected from the compound of any of the Examples.

[0174] Embodiment 43. A compound that is selected from: a(R)-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3- (1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, a(R)( S)-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(1-(2-(3-fluoropyrrolidin-1-yl)ethyl)-1H -indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, a(R)1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-phenyl-1H-pyrazol-1-yl)-2-azaspiro [3.3]heptan-2-yl)prop-2-en-1-one, a(R)1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3 -(2-(2-methoxyethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en- 1-one, a(R)1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-hydroxy- 2-methylpropyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, the (R)1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-(2-methoxyethoxy)ethyl)-2H-indazol-5 -yl)-5-methyl-1H-pyrazol-1-yl)-2- azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, a(R)1-(6-(4 -(5-chloro-6-methyl-1H-indazol-4-yl)-3-(4- (hydroxymethyl)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, a(R)1-(6- (4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-fluoro-4-(2-methoxyethoxy)phenyl)-5-methyl-1H-pyrazol-1-yl) -2-azaspiro[3.3]heptan-2- yl)prop-2-en-1-one, a(R)1-(6-(4-(3-amino-5-chloro-6-methyl-1H- indazol-4-yl)-3-(2- (2-methoxyethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2- azaspiro[3.3]heptan-2-yl)prop-2-en-1-one and a(R)1-(6-(4-(3-amino-5-chloro-6-methyl-1H-indazole-4 -yl)-5-methyl-3-phenyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, or a pharmaceutically acceptable salt thereof .

[0175] Embodiment 44. A compound that is selected from: 1-{6-[(4M)-4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-( 1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl}prop-2-en-1-one, 1-{6-[ (4M)-4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(1-{2-[(3S)-3-fluoropyrrolidin-1-yl]ethyl}-1H- indazol-5-yl)-5-methyl-1H-pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl}prop-2-en-1-one, 1-{6-[(4M)-4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-phenyl-1H-pyrazol-1-yl]-2-azaspiro [3.3]heptan-2-yl}prop-2-en-1-one, 1-(6-{(4M)-4-(5-chloro-6-methyl-1H-indazol-4-yl)-3 -[2-(2-methoxyethyl)-2H-indazol-5-yl]-5-methyl-1H-pyrazol-1-yl}-2-azaspiro[3.3]heptan-2-yl)prop-2-en- 1-one, 1-(6-{(4M)-4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-[2-(2-hydroxy- 2-methylpropyl)-2H-indazol-5-yl]-5-methyl-1H-pyrazol-1-yl}-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, 1 -{6-[(4M)-4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-{2-[2-(2-methoxyethoxy)ethyl]-2H-indazol-5 -yl}-5-methyl-1H-pyrazol-1-yl]-2- azaspiro[3.3]heptan-2-yl}prop-2-en-1-one, 1-(6-{(4M)-4 -(5-chloro-6-methyl-1H-indazol-4-yl)-3-[4- (hydroxymethyl)phenyl]-5-methyl-1H-pyrazol-1-yl}-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, 1-(6-{(4M) -4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-[2-fluoro-4-(2-methoxyethoxy)phenyl]-5-methyl-1H-pyrazol-1-yl} -2-azaspiro[3.3]heptan-2- yl)prop-2-en-1-one, 1-(6-{(4M)-4-(3-amino-5-chloro-6-methyl-1H- indazol-4-yl)-3-[2-(2-methoxyethyl)-2H-indazol-5-yl]-5-methyl-1H-pyrazol-1-yl}-2- azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, 1-{6-[(4M)-4-(3-amino-5-chloro-6-methyl-1H-indazol-4 -yl)-5-methyl-3-phenyl-1H-pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl}prop-2-en-1-one, or a pharmaceutically acceptable salt thereof .

[0176] Embodiment 45: A compound that is selected from the group of compounds with the following structure and name: or a pharmaceutically acceptable salt thereof.

[0177] Embodiment 46. A compound that is selected from a compound having the following structure and name: or a pharmaceutically acceptable salt thereof.

[0178] Embodiment 47. A crystalline form of a compound according to any of the preceding embodiments.

[0179] Embodiment 48. A compound according to any of the previous embodiments, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a crystalline form thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, for use as a medicament.

[0180] Embodiment 49. A compound according to any of the previous embodiments, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a crystalline form thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, for use in the treatment of cancer.

[0181] Embodiment 50. A pharmaceutical composition comprising a compound according to any of the previous 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.

[0182] Embodiment 51. A compound of formula (2a), wherein A, B and C are as defined in any of the preceding embodiments and R25 is hydrogen or a nitrogen protecting group, or a salt thereof.

[0183] Embodiment 52. A compound of formula (2b*), wherein A, C, RB2, RB3, and RB4 are as defined in any of the preceding embodiments, R25 is hydrogen or a nitrogen protecting group, wherein A is unsubstituted or substituted as defined in any of the preceding embodiments, or a salt thereof.

[0184] Embodiment 53. A compound of formula (2c*), wherein C, RA2, RB2, RB3 and RB4 are as defined in any of the previous embodiments, R25 is hydrogen or a nitrogen protecting group, wherein a is 0, 1, 2 or 3 (preferably, a is 0 or 1 or 2), or a pharmaceutically acceptable salt thereof.

[0185] Embodiment 54. A compound of formula (2d*), wherein C, Rae, RB2, RN, RB3, and RB4 are as defined in any of the preceding embodiments, R25 is hydrogen or a nitrogen protecting group, wherein the lines indicate a single bond or a double bond, or a salt thereof.

[0186] Embodiment 55. A crystalline form of Compound X, such as the hydrate crystalline form (HA Modification), or the isopropyl alcohol (IPA) solvate crystalline form, or the ethanol (EtOH) solvate crystalline form, or the propylene glycol solvate crystalline form of Compound X.

[0187] Embodiment 56. A crystalline form of Compound X having a powder X-ray diffraction spectrum substantially the same as the powder X-ray diffraction spectrum shown in Figure 1, Figure 2, Figure 3, or Figure 4.

[0188] In embodiments of the invention, Hetpy is a 4-, 5-, 6-, or 7-membered saturated heterocyclic ring comprising one or two heteroatoms independently selected from O, N (such as pyrrolidin-1-yl, azetidin-1-yl, morpholin-1-yl), and S, or comprising an S-oxide (SO) or S-dioxide (SO2) group, and wherein said heterocyclic ring is unsubstituted or substituted by oxo on a carbon atom, and wherein said heterocyclic ring is further optionally substituted on one or more carbon atoms by 1, 2, or 3 substituents independently selected from C1-C4-alkoxy (preferably methoxy), halo (preferably fluorine), C1-C4-alkyl, hydroxy-C1-C4-alkyl, and fluorine-C1-C4-alkyl, and wherein the nitrogen atom, if present in the ring, is a substituent of the nitrogen atom. said heterocycle is further optionally substituted by R10 (preferably C1-C4-alkyl (such as methyl)).

[0189] In embodiments of the invention, Hetpy is a 5- or 6-membered heteroaryl ring (preferably 1,2,4-triazol-1-yl or pyrazol-1-yl), comprising 1, 2 or 3 nitrogen atoms and wherein said heteroaryl ring is unsubstituted or substituted by one or more (e.g., 1, 2 or 3) substituents independently selected from NR9R10, -C(=O)-NR9R10, halo, C1-C4-alkyl, hydroxy-C1-C4-alkyl, fluoro-C1-C4-alkyl, cyano, OH and C1-C4-alkoxy, or wherein said heteroaryl ring is unsubstituted or substituted by one or more (e.g., 1, 2 or 3) substituents independently selected from NR9Ri0, halo, C1-C4-alkyl, cyano, OH and C1-C4-alkoxy. In embodiments of the invention, said heteroaryl ring is substituted by one or more amino groups.

[0190] In embodiments of the invention, A is C5-C7-cycloalkylene that is unsubstituted or substituted by one or more, preferably 1, 2 or 3, substituents independently selected from fluorine and C1-C4-alkyl. For example, A is wherein W is O or C(Rw)2, wherein each Rw is independently selected from H and fluorine, Rc is hydrogen or C1-C4-alkyl, and A is optionally further substituted by 1, 2, or 3 substituents independently selected from fluorine and C1-C4-alkyl.

[0191] Representative examples of A include, but are not limited to:

[0192] In embodiments of the invention, A is a C6-C10 aryl, e.g., a phenyl group, which may be unsubstituted or substituted by one or more RA2 substituents (e.g., by 1, 2 or 3 substituents).

[0193] When A is phenyl, a substituent on A, when present, is preferably located in the para position up to the point of attachment of the phenyl to the pyrazolyl moiety of the compound of Formula (I) and (Ia).

[0194] When A is phenyl, it is replaced by an RA2 which is fluorine, RA2 may be located in the ortho, para or meta position to the point of attachment of the phenyl to the pyrazolyl moiety of the compound of Formula (I) and (Ia).

[0195] When A is phenyl, RA2, when present, is preferably selected from the group consisting of halo, OH, hydroxy-Ci-C4-alkyl, -(COOH), Ci-C4-alkyl, fluorine-Ci-C4 -alkyl, C1-C4-alkoxy, fluorine-C1-C4-alkoxy, C1-C4-alkyl-carbonyl-oxy-C1-C4-alkyloxy, hydroxy-C1-C4-alkyloxy, C1-C4-alkoxy-Ci-C4 -alkyloxy, -SO2-Ci- C4-alkyl, -C(O)-NR9Ri0, NR9Ri0, NR9aRi0a , Hetpy, -(CH2)p-Hetpy and - NR9a Ri0a and -(CH2)pNR9a Ri0a, where p is i or 2; Hetpy is a 4- or 5- or 6-membered heterocyclic ring comprising i oxygen atom, or i sulfur atom, or an S(=O) or an S(=O)2 group, or i nitrogen atom and i sulfur atom. oxygen, or i-2 nitrogen atoms, wherein said heterocyclic ring is unsubstituted or substituted on a carbon atom by one or two substituents independently selected from C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1- C4-alkoxy, halo and fluoro-C1-C4-alkyl, and wherein said heterocyclic ring is further optionally substituted on a carbon atom by oxo and wherein the nitrogen atom when present in the heterocycle is further optionally substituted by Ci- C4-alkyl; R9 is selected from hydrogen and Ci-C4-alkyl; Ri0 is selected from hydrogen, Ci-C4-alkyl, hydroxy-Ci-C4-alkyl, and Ci-C4-alkoxy-Ci-C4-alkyl; R9a and Ri0a together with nitrogen form a 4- or 5- or 6-membered heterocyclic ring (saturated or unsaturated) comprising one or two additional heteroatoms independently selected from O, N (preferably wherein said heterocyclic ring is pyrrolidinyl) i-yl, azetidin-i-yl or morpholin-i-yl) and S, or an N-oxide thereof, or an S-oxide (SO) or S-dioxide thereof, and wherein said heterocyclic ring is optionally substituted by oxo on a carbon atom in said heterocyclic ring, and wherein said heterocyclic ring is further optionally substituted by one or two substituents independently selected from C1-C4-alkoxy (methoxy), halo (fluoro), C1-C4 -alkyl, hydroxy-C1-C4-alkyl, and fluoro-C1-C4-alkyl; or R9a and R10a together with nitrogen form a 5- or 6-membered heteroaryl ring (preferably wherein said heteroaryl ring is 1,2,4-triazol-1-yl and pyrazol-1-yl), which comprises 1, 2 or 3 nitrogen atoms, and wherein said heteroaryl ring is optionally substituted by one or two amino groups; When there are two RA2 substituents on the phenyl ring, they are preferably located in the (a) ortho and para positions, or (b) meta and para or (c) ortho and meta to the point of attachment of the phenyl to the pyrazolyl moiety of the compound of Formula (I) and (Ia).

[0196] Representative RA2 substituents on phenyl 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-CH2-OCH3), -C(O)-N(CH3)-(CH2-CH2-OCH3), -C(O)-NH-CH2-C(CH3)2OH, -C(O)-N(CH3)-CH2-C(CH3)2-OH, -C(O)-N(H)- C(CH3)2-CH2-OCH3, -C(O)-N(H)-CH2-CH2-N(CH3)2, -(CH2)p-Hetpy wherein Hetpy is a 4-, 5-, or 6-membered saturated heterocyclic ring comprising one or two heteroatoms independently selected from O, N (such as, pyrrolidin-1-yl, azetidin-1-yl, morpholin-1-yl), and S, or comprising an S-oxide (SO) or S-dioxide (SO2) group or Hetpy is a 5- or 6-membered heteroaryl ring comprising 1, 2, or 3 nitrogen atoms; wherein said 5- or 6-membered heterocyclic ring may be further substituted by one or two substituents independently selected from oxo, C1-C4-alkoxy (preferably methoxy), halo (preferably fluorine), C1-C4-alkyl, hydroxy-C1-C4-alkyl, and fluorine-C1-C4-alkyl; or wherein said 5- or 6-membered heterocyclic ring may be further substituted by one or two substituents independently selected from C1-C4-alkoxy (preferably methoxy), halo (preferably fluorine), C1-C4-alkyl, hydroxy-C1-C4-alkyl, and fluorine-C1-C4-alkyl; wherein said 5- or 6-membered heteroaryl ring comprising 1, 2 or 3 nitrogen atoms may be further substituted by 1, 2 or 3 substituents independently selected from amino, C1-C4-alkoxy (preferably methoxy), halo (preferably fluorine), C1-C4-alkyl, hydroxy-C1-C4-alkyl, and fluorine-C1-C4-alkyl; or wherein said 5- or 6-membered heteroaryl ring may be further substituted by 1, 2 or 3 substituents independently selected from C1-C4-alkoxy (preferably methoxy), halo (preferably fluorine), C1-C4-alkyl, hydroxy-C1-C4-alkyl, and fluorine-C1-C4-alkyl; and p is 0, 1 or 2 (preferably 0 or 1).

[0197] For example, representative examples of RA2 include: wherein R20 is hydrogen or C1-C4-alkyl (preferably methyl); wherein p is 0, 1 or 2 (preferably 0 or 1); q is 1, 2 or 3 (preferably 1 or 2).

[0198] For example, representative examples of RA2 include wherein R21 is hydrogen, or C1-C4-alkyl (preferably methyl), or amino, wherein p is 0, 1 or 2, preferably p is 0 or 1.

[0199] In embodiments of the invention, A is a 5-6 membered heteroaryl ring containing 1, 2 or 3 heteroatoms independently selected from N, O and S as ring members, wherein said heteroaryl ring is unsubstituted or substituted on one or more (e.g., 1, 2 or 3) carbon atoms by RA3, and wherein a nitrogen atom, when present in the heteroaryl ring, is unsubstituted or substituted by a substituent selected from the group consisting of: C1-C4-alkyl, -(CH2)1-2-C3—4-cycloalkyl, hydroxy-C1-C4-alkyl, fluoro-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, N(R9)(R10)-C1-C4-alkyl, -SO2-C1-C4-alkyl, -SO2-C3—4-cycloalkyl, -(CH2)p-Hetpy, and -(CH2)p—N(R9)(R10), (preferably wherein said substituent is selected from the group consisting of fluoro-C1-C4-alkyl, N(R9)(R10)-C1-C4-alkyl, -SO2-C3-4-cycloalkyl, or -(CH2)i-2-C3—4-cycloalkyl).

[0200] For example, A may be a pyridin-2-yl or pyridin-3-yl or pyridin-4-yl group, which may be unsubstituted or substituted by one or more substituents RA3. A is preferably a pyridin-3-yl or pyridin-4-yl group.

[0201] When A is pyridin-3-yl, a substituent RA3 on A, e.g. a C1-C4-alkyl, when present, is preferably located in the 2 or 6 positions on the pyridinyl ring of the compound of Formula (I) and (Ia).

[0202] When there are two substituents (e.g., fluorine and amino) on the pyridin-3-yl ring, they are preferably located at positions 5 and 6 of the pyridin-3-yl ring of the compound of Formula (I) and (Ia).

[0203] When A is pyridin-4-yl, a substituent RA3 on A, e.g. a C1-C4-alkyl, when present, is preferably located in the 2 or 3 position (preferably the 3 position) on the pyridinyl ring of the compound of Formula (I) and (Ia).

[0204] When A is pyridin-4-yl, two substituents RA3 on A, which are preferably independently selected from C1-C4-alkyl, fluorine and amino (most preferably C1-C4-alkyl) when present, are preferably located at positions 2 and 6 on the pyridinyl ring of the compound of Formula (I) and (Ia).

[0205] Representative substituents on pyridinyl include, but are not limited to, NH2, F, CN, OH, -CH2-OH, -COOH, -CH3, -O-CH2-CH2- OH, -O-(CH2)3)-N(CH3)2, -O-CH2-CH3, -O-CH2-CH2-O-(CO)-CH3, - N(CH3)(CH2-CH2-OCH3), -N(H)(CH2-CH2-OCH3), -CH2-O-CH2-CH2-O- CH3 , -SO2-CH3, -C(O)-NH-(CH2-CH2-OCH3), -C(O)-N(CH3)-(CH2-CH2- OCH3), -C(O)-NH-CH2-C(CH3)2OH , -C(O)-N(CH3)-CH2-C(CH3)2-OH, - C(O)-N(H)-C(CH3)2-CH2-OCH3 , -C(O)-N(H)-CH2-CH2-N(CH3)2, - (CH2)p-Hetpy, wherein Hetpy is a 4-, 5- or 6-membered saturated heterocyclic ring comprising one or two heteroatoms independently selected from O, N (such as pyrrolidin-1-yl, azetidin-1-yl, morpholin-1-yl), and S, or comprising an S-oxide (SO) or S-dioxide (SO2) group, wherein said heterocyclic ring may be further substituted by 1, 2 or 3 substituents independently selected from C1-C4-alkoxy (preferably methoxy), halo (preferably fluorine), C1-C4-alkyl, hydroxy-C1-C4-alkyl, fluoro-C1-C4-alkyl, and -C(O)-N(CH3)-(CH2-CH2-OCH3), or Hetpy is a 5- or 6-membered heteroaryl ring comprising 1, 2, or 3 nitrogen atoms, wherein said heteroaryl ring may be further substituted by 1, 2, or 3 substituents independently selected from C1-C4-alkoxy (methoxy), halo (fluorine), C1-C4-alkyl, hydroxy-C1-C4-alkyl, and fluoro-C1-C4-alkyl.

[0206] For example, representative examples of RA3 when A is pyridinyl may be selected from wherein R20 is hydrogen or C1-C4-alkyl (preferably methyl), wherein p is 0. 1 or 2, preferably p is 0 or 1.

[0207] For example, representative examples of RA3 when A is pyridinyl, e.g., pyridin-3-yl, may be selected from wherein R21 is hydrogen, or C1-C4-alkyl (preferably methyl), or amino, wherein p is 0, 1, or 2. Preferably, p is 0 or 1.

[0208] In embodiments of the compounds of Formula (I) and (Ia), representative substituents RA3 when A is a pyridinyl ring are 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, wherein p is 0, 1, or 2, preferably p is 1 or 2; R21 is hydrogen or C1-C4-alkyl (preferably methyl), R22 is hydrogen or C1-C4-alkyl (preferably methyl), or amino, Preferably p is 0, and R22 is amino.

[0209] In embodiments of the invention, A is a pyrimidin-3-yl group or a pyrimidin-5-yl group, which may be unsubstituted or substituted by one or more substituents RA3. Representative substituents on the pyrimidinyl group include -O-CH3.

[0210] In embodiments of the invention, A is selected from the group consisting of wherein R24 is hydrogen, C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, -NR9R10C1-C4-alkyl, -SO2-C1-C4-alkyl, -SO2-C3-4-cycloalkyl or -(CH2)i-2-C3—4-cycloalkyl; or wherein R24 is hydrogen, C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, amino-C1-C4-alkyl, C1-C4-alkylamino-C1-C4-alkyl, di-C1-C4-alkylamino-C1-C4-alkyl, -Sθ2-Ci—C4-alkyl, -Sθ2-C3-4-cycloalkyl or -(CH2)i-2-C3—4-cycloalkyl; each of R4a, R4b, R4c and R4d is independently selected from hydrogen and C1-C4-alkyl (preferably methyl).

[0211] R24 is preferably di-C1-C4-alkylamino-C1-C4-alkyl (e.g., -CH2-CH2-N(CH3)2) or -SO2-C3-4-cycloalkyl (e.g., -SO2-cyclopropyl).

[0212] R4c is preferably C1-C4-alkyl (e.g. methyl) and each of R4a, R4b and R4d is preferably hydrogen.

[0213] When R24 is di-C1-C4-alkylamino-C1-C4-alkyl, R4c is preferably C1-C4-alkyl (e.g., methyl) and each of R4a and R4d is hydrogen.

[0214] In embodiments of the invention, A is (i) an 8-10 membered heteroaryl ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur (e.g., 1 to 3 heteroatoms independently selected from 0-3 nitrogen atoms, 0-1 oxygen atom and 0-1 sulfur atom), or (ii) an 8-10 membered partially saturated heterobicyclic ring containing 1 to 3 heteroatoms or heteroatom groups independently selected from 0-3 nitrogen atoms, 0-2 oxygen atoms, 0-1 sulfur atom and 0-1 S(=O)2 group in the heterobicyclic ring, wherein said heteroaryl ring or heterobicyclic ring is unsubstituted or substituted on a carbon atom by 1, 2, 3, 4 or 5 RA4, and wherein the heterobicyclic ring is further optionally substituted on a carbon atom by oxo and wherein a nitrogen atom, when present, is unsubstituted or substituted by a substituent that is -(CO)- C1-C4-alkyl or C1-C4-alkyl, and wherein said C1-C4-alkyl is optionally substituted by 1 or 2 substituents independently selected from cyano, hydroxy, oxo, fluorine, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyloxy, Hetb and NR9R10.

[0215] In embodiments of the invention, A is an 8-10 membered heteroaryl ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. For example, A is an 8-10 membered heteroaryl containing 1-3 heteroatoms independently selected from 0-3 nitrogen atoms, 0-1 oxygen atom, and 0-1 sulfur atom. The heteroaryl ring is unsubstituted or substituted on a carbon atom by 1, 2, 3, 4 or 5 RA4, and a nitrogen atom, when present, is unsubstituted or substituted by a substituent that is -(CO)-C1-C4-alkyl or C1-C4-alkyl, and wherein said C1-C4-alkyl is optionally substituted by 1 or 2 substituents independently selected from cyano, hydroxy, oxo, fluorine, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyloxy, Hetb and NR9R10.

[0216] Representative examples of A thus also include in which the wavy line . denotes the point of attachment of A to the rest of the molecule.

[0217] In embodiments of the invention, A is an 8-10 membered heteroaryl ring containing 1, 2 or 3 nitrogen atoms, or a partially saturated 8-10 membered heterobicyclic ring containing 1 to 3 heteroatoms or heteroatom groups independently selected from 0-3 nitrogen atoms, 0-2 oxygen atoms, 0-1 sulfur atom and 01 S(=O)2 group in the heterobicyclic ring, wherein said heteroaryl ring or heterobicyclic ring is unsubstituted or substituted on a carbon atom by 1, 2, 3, 4 or 5 RA4, and wherein the heterobicyclic ring is optionally further substituted on a carbon atom by oxo and wherein a nitrogen atom, when present, is unsubstituted or substituted by a substituent that is -(CO)-C1-C4-alkyl or C1-C4-alkyl, and wherein said C1-C4-alkyl is optionally substituted by 1 or 2 substituents independently selected from cyano, hydroxy, oxo, fluorine, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyloxy, Hetb, and NR9R10.

[0218] In embodiments of the invention, A is an 8-10 membered heteroaryl ring containing 1, 2 or 3 nitrogen atoms, or 8-10 membered partially saturated heterobicyclic ring containing 1-3 nitrogen atoms or 1-2 oxygen atoms or 1 sulfur atom or 1 S(=O)2 group in the heterobicyclic ring, wherein said heteroaryl ring or heterobicyclic ring is unsubstituted or substituted on a carbon atom by 1, 2, 3, 4 or 5 RA4, and wherein the heterobicyclic ring is further optionally substituted on a carbon atom by oxo and wherein a nitrogen atom, when present, is unsubstituted or substituted by a substituent that is -(CO)-C1-C4-alkyl or C1-C4-alkyl, and wherein said C1-C4-alkyl is optionally substituted by 1 or 2 substituents independently selected from cyano, hydroxy, oxo, fluorine, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyloxy, Hetb and NR9R10.

[0219] In embodiments of the invention, the nitrogen atom, when present in the above-mentioned 8-10 membered heteroaryl ring or above-mentioned 8-10 membered partially saturated heterobicyclic ring, is unsubstituted or substituted by C1-C4-alkyl that is optionally substituted by 1 or 2 substituents independently selected from cyano, hydroxy, oxo, fluorine, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyloxy, Hetb, and NR9R10.

[0220] In embodiments of the invention, Hetb is a 4- or 5- or 6-membered heterocyclic ring or heteroaryl ring comprising 1 or 2 heteroatoms or groups independently selected from N, O, S, SO, and SO2 (preferably comprising 1 oxygen atom, or 1 sulfur atom, or a S(=O) or a S(=O)2 group, or 1 nitrogen atom and 1 oxygen atom, or 1-2 nitrogen atoms; more preferably comprising 1 nitrogen atom and 1 oxygen atom, or 1-2 nitrogen atoms), wherein said Hetb heterocyclic ring is unsubstituted or substituted on a carbon atom by one or two substituents independently selected from C1-C4-alkyl, hydroxy, cyano, fluorine, C1-C4-alkoxy-hydroxy-C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy, fluoro-C1-C4-alkoxy, and fluoro-C1-C4-alkyl (preferably selected from C1-C4-alkyl, hydroxy, cyano, fluoro, C1-C4-alkoxy-hydroxy-C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy, and fluoro-C1-C4-alkyl), and wherein said heterocyclic ring Hetb is further optionally substituted on a carbon atom by oxo, and wherein the nitrogen atom when present in Hetb is further optionally substituted by C1-C4-alkyl, wherein said C1-C4-alkyl is optionally substituted by 1 to 3 substituents independently selected from fluoro, hydroxy, and C1-C4-alkoxy.

[0221] In embodiments of the invention, Hetbé is azetidin-1-yl, pyrrolidin-1-yl, pyrrolidin-3-yl or morpholin-1-yl, and is optionally substituted by fluoro, hydroxy and C1-C4-alkoxy (e.g. by methyl, hydroxy-methyl, methoxy and fluoro).

[0222] In embodiments of the invention, A is an 8-10 membered heteroaryl ring containing 1, 2 or 3 nitrogen atoms, or an 8-10 membered partially saturated heterobicyclic ring containing 1 to 3 heteroatoms or heteroatom groups independently selected from 0-3 nitrogen atoms, 0-2 oxygen atoms, 0-1 sulfur atom and 0-1 S(=O)2 group in the heterobicyclic ring wherein when A contains a nitrogen, which nitrogen is replaced by Rae or RAe.

[0223] In embodiments of the invention, A is an 8-10 membered heteroaryl ring containing 1, 2 or 3 nitrogen atoms, or a partially saturated 8-10 membered heterobicyclic ring containing 1-3 nitrogen atoms or 1-2 oxygen atoms or 1 sulfur atom or 0-1 S(=O)2 group in the heterobicyclic ring wherein when A contains a nitrogen, which nitrogen is replaced by Rae or RAe.

[0224] In embodiments of the invention, A is an 8-10 membered heteroaryl ring containing 1, 2 or 3 nitrogen atoms, wherein at least one of the nitrogen atoms is replaced by Rae or RAe.

[0225] In embodiments of the invention, A is an 8-10 membered heteroaryl ring containing 1, 2 or 3 nitrogen atoms, wherein one of the nitrogen atoms is replaced by Rae or RAe.

[0226] In embodiments of the invention, RAe is selected from the group consisting of hydrogen, -(CO)-C1-C4-alkyl and C1-C4-alkyl, wherein the C1-C4-alkyl in each case is optionally substituted by 1 or 2 substituents selected from cyano, hydroxy, fluorine, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyloxy, Hetb and NR9R10.

[0227] In embodiments of the invention, RAe is selected from the group consisting of hydrogen, fluoro-C1-C4-alkyl, and C1-C4-alkyl (e.g., methyl).

[0228] In embodiments of the invention, Rae is selected from the group consisting of hydrogen and C1-C4-alkyl, wherein said alkyl is optionally substituted by 1 or 2 substituents independently selected from cyano, hydroxy, fluorine, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyloxy, Hetb, and NR9R10.

[0229] In embodiments of the invention, Rae is selected from the group consisting of hydrogen, C1-C4-alkyl, -(CH2)2-Hetb, -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-di-C1-C4-alkylamino, (e.g., when Hetb is selected from the group consisting of azetidin-1-yl, pyrrolidin-1-yl, pyrrolidin-3-yl, and morpholin-1-yl). Preferably, Rae is selected from the group consisting of hydrogen, C1-C4-alkyl, and -CH2-CN. Preferably Rae is selected from the group consisting of hydrogen and C1-C4-alkyl.

[0230] In embodiments of the invention, y is 0, 1, or 2 (preferably 0 or 1).

[0231] In embodiments of the invention, x is 0, 1, or 2 (preferably 0 or 1).

[0232] In embodiments of the invention, z is 0, 1, or 2 (preferably 0 or 1).

[0233] In embodiments of the invention, Rq is selected from the group consisting of C1-C4-alkyl, hydroxy, C1-C4-alkoxy, and NR9R10 and y is 0 or 1.

[0234] Preferably, Rq is selected from the group consisting of C1-C4-alkyl and hydroxy.

[0235] Typical examples of A as an 8-10 membered heteroaryl ring or heterobicyclic ring include in which the wavy line denotes the point of attachment of A to the remainder of the molecule, wherein A is unsubstituted or substituted by 1, 2, 3, 4, or 5 RA4 (preferably by 1 or 2 RA4), wherein the nitrogen atom in the NH moiety in the above structures may also be replaced by an N-Rae, wherein Rae is C1-C4-alkyl that is optionally substituted by 1 or 2 substituents independently selected from cyano, hydroxy, oxo, fluorine, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyloxy, Hetb, and NR9R10. Preferably, Rae is hydrogen or C1-C4-alkyl, such as methyl.

[0236] For example, typical examples of A include wherein the wavy line denotes the point of attachment of A to the remainder of the molecule, wherein A is unsubstituted or substituted by 1, 2, 3, 4 or 5 Ra4 (preferably by 1 or 2 Ra4), wherein Rae is hydrogen or C1-C4-alkyl that is optionally substituted by 1 or 2 substituents independently selected from cyano, hydroxy, oxo, fluorine, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyloxy, Hetb and NR9R10. Preferably, Rae is hydrogen or C1-C4-alkyl, such as methyl.

[0237] Representative examples of A also include: wherein the wavy line denotes the point of attachment of A to the remainder of the molecule, wherein A is unsubstituted or substituted by 1, 2, 3, 4, or 5 RA4 (preferably by 1 or 2 RA4), wherein the nitrogen atom in the NH moiety in the above structures may also be replaced by an N-RAe or N-Rae , wherein RAe is selected from the group consisting of hydrogen, -(CO)-C1-C4-alkyl, and C1-C4-alkyl, wherein the C1-C4alkyl in each case is optionally substituted by 1 or 2 substituents independently selected from cyano, hydroxy, fluorine, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyloxy, Hetb, and NR9R10, and Rae is C1-C4-alkyl that is optionally substituted by 1 or 2 substituents independently selected from cyano, hydroxy, oxo, fluorine, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyloxy, Hetb and NR9R10. Preferably, RAe is hydrogen or C1-C4-alkyl, such as methyl. Preferably, Rae is hydrogen or C1-C4-alkyl, such as methyl.

[0238] Thus, typical examples of A include: wherein the wavy line denotes the point of attachment of A to the remainder of the molecule, wherein A is unsubstituted or substituted by 1, 2, 3, 4, or 5 RA4 (preferably by 1 or 2 RA4), wherein RAe is selected from the group consisting of hydrogen, -(CO)-C1-C4-alkyl, and C1-C4-alkyl, wherein the C1-C4alkyl in each case is optionally substituted by 1 or 2 substituents independently selected from cyano, hydroxy, fluorine, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyloxy, Hetb, and NR9R10, and Rae is C1-C4-alkyl that is optionally substituted by 1 or 2 substituents independently selected from cyano, hydroxy, oxo, fluorine, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyloxy, Hetb and NR9R10. Preferably, Rae is hydrogen or C1-C4-alkyl, such as methyl. Preferably, Rae is hydrogen or C1-C4-alkyl, such as methyl.

[0239] Other representative examples of A include, wherein the wavy line denotes the point of attachment of A to the remainder of the molecule, wherein A is unsubstituted or substituted by 1, 2, 3, 4, or 5 RA4 (preferably by 1 or 2 RA4), wherein the nitrogen atom in the NH moiety in the above structures may also be replaced by an N-Rae or N-RAe, wherein RAe is selected from the group consisting of hydrogen, -(CO)-C1-C4-alkyl, and C1-C4-alkyl, wherein the C1-C4alkyl in each case is optionally substituted by 1 or 2 substituents independently selected from cyano, hydroxy, fluorine, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyloxy, Hetb, and NR9R10, and Rae is C1-C4-alkyl that is optionally substituted by 1 or 2 substituents independently selected from cyano, hydroxy, oxo, fluoro, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyloxy, Hetb and NR9R10. Preferably, RAe is hydrogen or C1-C4-alkyl, such as methyl. Preferably, Rae is hydrogen or C1-C4-alkyl, such as methyl. The term "C6-10 aryl", as used herein and also with reference to substituent B, refers to a phenyl or naphthyl group, wherein the phenyl or naphthyl is unsubstituted or substituted by 1,2, 3 or 4 (preferably 1 or 2) RBa.

[0240] In embodiments of the invention, RBa is independently selected from the group consisting of hydroxy, NH2, C1-C4-alkyl, and halo, or preferably selected from the group consisting of hydroxy, C1-C4-alkyl, and halo.

[0241] In embodiments of the invention, B is 3-hydroxy-phenyl or 3-hydroxy-naphthyl, wherein B is unsubstituted or substituted by 1, 2 or 3 halo atoms (preferably chlorine). In other embodiments of the invention, B is where Hal represents a halogen atom.

[0242] In embodiments of the invention, B is wherein X is N or C-RB5; RB1 is independently selected from hydrogen and C1-C4-alkyl (preferably methyl); RB2 is independently selected from hydrogen, halo (preferably chlorine), C1-C4-alkyl (preferably methyl), cyclopropyl, and NH2; RB3 is independently selected from hydrogen, halo (preferably chlorine), cyclopropyl, and C1-C4-alkyl (preferably methyl); RB4 is independently selected from hydrogen, halo (preferably chlorine or fluorine), and C1-C4-alkyl (preferably methyl), or RB3 and RB4 together with the atoms to which they are attached form a 4-6 membered ring (preferably a 5-6 membered saturated or partially unsaturated carbocyclic ring) fused to the aromatic ring containing X; RB5 is independently selected from hydrogen, halo (preferably chlorine) and C1-C4-alkyl (preferably methyl), In embodiments of the invention, X is N or C-RB5, RB1 is independently selected from hydrogen and C1-C4-alkyl, RB2 is independently selected from hydrogen and NH2, RB3 and RB4 are each independently selected from hydrogen, halo (preferably chlorine) and C1-C4-alkyl (preferably methyl), or RB3 and RB4 together with the atoms to which they are attached form a 4-6 membered ring (preferably a 5-6 membered saturated or partially unsaturated carbocyclic ring) used for the aromatic ring containing X.

[0243] RB5 is independently selected from hydrogen, halo (preferably chlorine) and C1-C4-alkyl (preferably methyl).

[0244] In embodiments of the invention, B is wherein RB1 is independently selected from hydrogen and C1-C4-alkyl, RB2 is independently selected from hydrogen, C1-C4-alkyl and NH2, RB3 and RB4 are each independently selected from hydrogen, halo (preferably fluorine or chlorine, more preferably chlorine) and C1-C4-alkyl (preferably methyl), RB5 is independently selected from hydrogen, halo (preferably chlorine) and C1-C4-alkyl (preferably methyl), In embodiments of the invention, X is N or C-RB5, wherein RB1 is independently selected from hydrogen and C1-C4-alkyl, RB2 is independently selected from hydrogen and NH2, RB3 and RB4 are each independently selected from hydrogen, halo (preferably chlorine) and C1-C4-alkyl (preferably methyl).

[0245] RB5 is independently selected from hydrogen, halo (preferably chlorine) and C1-C4-alkyl (preferably methyl).

[0246] In embodiments of the invention, X is N or CH, preferably, X is CH.

[0247] In embodiments of the invention, X is CH and RB1 is hydrogen or C1-C4-alkyl (such as, methyl).

[0248] In embodiments of the invention, RB1 is hydrogen or C1-C4-alkyl (such as methyl), preferably RB1 is hydrogen.

[0249] In embodiments of the invention, RB2 is hydrogen or amino, preferably, RB2 is hydrogen.

[0250] In embodiments of the invention, RB3 and RB4 are each independently selected from halo (preferably chloro) and C1-C4-alkyl (preferably methyl).

[0251] The present invention provides compounds of Formula (I) and (Ia), wherein RB1 is independently selected from hydrogen and C1-C4-alkyl, RB2 is amino, RB3 is halo (preferably chlorine) and RB4 is methyl, and X is CH, or RB2 is amino, RB3 is halo (preferably chlorine) or methyl, RB4 is hydrogen, X is CH, or RB2 is hydrogen, RB3 is halo (preferably chlorine) or methyl and RB4 is hydrogen, X is CH,

[0252] In embodiments of the invention, RB2 is amino, RB3 and RB4 are both halo (preferably chloro), and X is CH.

[0253] In embodiments of the invention, RB1 is C1-C4-alkyl (preferably methyl), RB2, RB3, RB4 and RB5 are all hydrogen.

[0254] In embodiments of the invention, X is N, RB1 and RB2 are hydrogen, RB3 is independently selected from halo (preferably chlorine) and C1-C4-alkyl (preferably methyl), RB4 is halo (preferably chlorine).

[0255] In another aspect of the invention there is provided a compound which is selected from any of those shown in the Examples, or a pharmaceutically acceptable salt thereof.

[0256] In another aspect of the invention, there is provided a compound that is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

[0257] In another aspect of the invention, there is provided a compound which is selected from the group consisting of: a(R)-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one (Example 1a), a(R) 18a), a(R)1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-phenyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one (Example 26a), a(R)1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-methoxyethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one (Example 41a), a(R)1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-hydroxy-2-methylpropyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one (Example 42a), a(R)1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-(2-methoxyethoxy)ethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one (Example 43a), a(R)1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(4-(hydroxymethyl)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one (Example 47a), a(R)1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-fluoro-4-(2-methoxyethoxy)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one (Example 60a), a(R)1-(6-(4-(3-amino-5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-methoxyethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one (Example 69a), a(R)1-(6-(4-(3-amino-5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-phenyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one (Example 70a), or a pharmaceutically acceptable salt thereof.

[0258] The present invention provides a compound that is selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

[0259] Depending on the choice of starting materials and procedures, the compounds may be present in the form of one of the possible isomers or as mixtures thereof, for example as pure optical isomers, or as mixtures of isomers, such as racemates and diastereomeric mixtures, depending on the number of asymmetric centers. The present invention is intended to include all such possible isomers, including racemic mixtures, enantiomerically enriched mixtures, diastereomeric mixtures and optically pure forms. Optically active (R) and (S) isomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques. If the compound contains a disubstituted or trisubstituted cycloalkyl, the cycloalkyl substituent(s) may have a cis or trans configuration. The present invention includes cis and trans configurations of substituted cycloalkyl groups, as well as mixtures thereof. All tautomeric forms are also intended to be included. In particular, when a heteroaryl ring containing N as a ring atom is 2-pyrodone, for example, tautomers where the carbonyl is shown as a hydroxy (e.g., 2-hydroxypyridine) are included.

[0260] As used herein, the terms "salt" or "salts" refer to an acid addition or base addition salt of a compound of the invention. "Salts" include, in particular, "pharmaceutically acceptable salts." The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds of the present invention and that are typically not biologically or otherwise undesirable. In many cases, the compounds of the present invention have the ability to form acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.

[0261] Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, trifluoroacetic acid, and the like.

[0262] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0263] Inorganic bases from which the salts may be derived include, for example, salts of ammonium and metals from columns I through XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include salts of ammonium, potassium, sodium, calcium, and magnesium.

[0264] Organic bases from which salts may be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, choline, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0265] In another aspect, the present invention provides compounds in acetate, ascorbate, adipate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, caprate, chloride/hydrochloride, chlortheophyllonate, citrate, etandisulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydrogen iodide/iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methyl sulfate, mucate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate trifenatate, trifluoroacetate or salt form of xinafoate.

[0266] Pharmaceutically acceptable salts are preferred.

[0267] Any formula set forth herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures represented by the formulas provided herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 2H, 3H, 11C, 13C, 14C, 15N, 17O, 18O, 18F, 35S, 36Cl, respectively. The invention includes various isotopically labeled compounds as defined herein, for example those in which radioactive isotopes such as 3H and 14C, or those in which non-radioactive isotopes such as 3H and 14C are present. Such isotopically labeled compounds are useful in metabolic studies (with 14C), reaction kinetic studies (with, for example, 2H and 13H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, a 18F compound may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of formula (I) may generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using suitable isotopically labeled reagents in place of the previously used unlabeled reagent.

[0268] Furthermore, substitution with heavier isotopes, particularly deuterium (i.e. 2H or D) may confer certain therapeutic advantages resulting from increased metabolic stability, e.g. increased in vivo half-life or reduced dosage requirements or an improvement in the therapeutic index. It is understood that deuterium in this context is considered to be a substituent of a compound of formula (I). The concentration of such a heavier isotope, specifically deuterium, may be defined by the isotopic enrichment factor. The term "isotopic enrichment factor" as used herein means the ratio of the isotopic abundance to the natural abundance of a specified isotope. If a substituent in a compound of the present invention is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation into each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0269] The invention also relates to compounds of any of the mentioned embodiments, in which one or more hydrogen atoms in one or more substituents are replaced by deuterium, for example, all hydrogens in one or more alkyl substituents are replaced by deuterium (the respective chemical moiety/chemical moieties are then percatered).

[0270] In embodiments of the invention, C1-C3-alkyl (or methyl) may be deuterated or percaterated, in particular, when the C1-C3-alkyl (or methyl) is present as substituent C in the compounds of the invention and/or when the C1-C3-alkyl (or methyl) is present as a substituent on A and/or B, when A or B is an indazolyl ring.

[0271] The invention also relates to crystalline forms of the compounds of formula (I).

[0272] The hydrate crystalline form (HA Modification) of Compound X can be obtained from isopropyl solvate (IPA), ethanol solvate (EtOH), methanol solvate, and propylene glycolate solvate of Compound X. The hydrate crystalline form (HA Modification) of Compound X can be characterized by an X-ray powder diffraction (XRPD) pattern comprising at least one, two, three, or four peaks having refraction angle 2θ values (CuKα À=1.5418 Â) selected from the group consisting of 8.2°, 11.6°, 12.9°, and 18.8°, measured at a temperature of about 25°C and an X-ray wavelength, À, of 1.5418 Â. The hydrate crystalline form (HA Modification) can also be characterized by an X-ray powder diffraction (XRPD) pattern comprising at least one, two, three, or four or all of the peaks having refraction angle values 2θ (CuKα À=1.5418 Â) selected from the group consisting of 8.2°, 11.6°, 12.1°, 12.9°, 14.6°, 16.2°, 18.8°, 20.4°, and 24.1°, measured at a temperature of about 25°C and an X-ray wavelength, À, of 1.5418 Â.

[0273] The isopropyl alcohol (IPA) solvate of Compound X can be characterized by an X-ray powder diffraction (XRPD) pattern comprising at least one, two, or three peaks having refraction angle values 2θ CuKα À=1.5418 Â) selected from the group consisting of 7.5°, 12.5°, and 17.6° measured at a temperature of about 25 □ C and an X-ray wavelength, À, of 1.5418 Â. The isopropyl alcohol solvate of Compound X can be characterized by an X-ray powder diffraction (XRPD) pattern comprising at least one, two, three, or four or more, or all of the peaks having refraction angle 2θ values (CuKα À=1.5418 Â) selected from the group consisting of 7.5°, 12.5°, 15.5°, 16.4°, 17.6°, 21.4°, and 24.4°, measured at a temperature of about 25°C and an X-ray wavelength, À, of 1.5418 Â.

[0274] The ethanol (EtOH) solvate of Compound X can be characterized by an X-ray powder diffraction (XRPD) pattern comprising at least one, two, three, or four peaks having refraction angle values 2θ (CuKα À=1.5418 Â) selected from the group consisting of 7.9°, 12.7°, 18.2°, and 23.1°, measured at a temperature of about 25 □ C and an X-ray wavelength, À, of 1.5418 Â. The ethanol solvate of Compound X can be characterized by an X-ray powder diffraction (XRPD) pattern comprising at least one, two, three, or four or more, or all of the peaks having refraction angle 2θ values (CuKα À=1.5418 Â) selected from the group consisting of 7.9°, 12.7°, 13.1°, 15.5°, 15.9°, 16.9°, 18.2°, 18.6°, and 23.1°, measured at a temperature of about 25°C and an X-ray wavelength, À, of 1.5418 Â.

[0275] The propylene glycol solvate of Compound X can be characterized by an X-ray powder diffraction (XRPD) pattern comprising at least one, two, three, or four peaks having refraction angle values 2θ (CuKα À=1.5418 Â) selected from the group consisting of 7.3°, 13.2°, 18.0°, and 22.5°, measured at a temperature of about 25 □ C and an X-ray wavelength, À, of 1.5418 Â. The propylene glycol solvate of Compound X can be characterized by an X-ray powder diffraction (XRPD) pattern comprising at least one, two, three, or four or more, or all of the peaks having refraction angle 2θ values (CuKα À=1.5418 Â) selected from the group consisting of 7.3°, 13.2°, 15.6°, 16.2°, 18.0°, 22.5°, 22.8°, 23.2°, and 25.1°, measured at a temperature of about 25 °C and an X-ray wavelength, À, of 1.5418 Â.

[0276] As used herein, the term "pharmaceutically acceptable carrier" includes any one or more selected from all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegrating agents, lubricants, sweetening agents, flavoring agents, colorants, and the like, and combinations thereof, as would be known to those skilled in the art (see, e.g., Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except to the extent that any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is contemplated.

[0277] The term "a therapeutically effective amount" of a compound of the present invention refers to an amount of the compound of the present invention that will induce a biological or medical response in a subject, e.g., reducing or inhibiting an enzyme or protein activity, or improving symptoms, alleviating conditions, delaying or retarding disease progression, or preventing a disease, etc. In a non-limiting embodiment, the term "a therapeutically effective amount" refers to the amount of the compound of the present invention that, when administered to a subject, is effective to (1) alleviate, inhibit, prevent, and/or ameliorate, at least partially, a condition or disorder or disease, such as a cancer driven by a KRAS, HRAS, or NRAS G12C mutation.

[0278] In another non-limiting embodiment, the term "a therapeutically effective amount" refers to the amount of the compound of the present invention that, when administered to a cell or a tissue or a non-cellular biological material or a medium, is effective in reducing or inhibiting, at least partially, the activity of KRAS, HRAS or NRAS G12C mutant protein.

[0279] As used herein, the term “subject” refers to an animal. Typically, the animal is a mammal. A subject also refers to, for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the subject is a primate. In still other embodiments, the subject is a human.

[0280] As used herein, the term "inhibit", "inhibition" or "inhibiting" refers to the reduction or suppression of a given condition, symptom or disorder, or disease, or a significant reduction in the baseline activity of a biological activity or process.

[0281] As used herein, the term “treating,” “treating,” or “treatment” of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., slowing or stopping or reducing the development of the disease or at least one of its clinical symptoms). In another embodiment, “treating,” “treating,” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those that may not be discernible to the patient. In yet another embodiment, “treating,” “treating,” or “treatment” refers to modulating the disease or disorder, whether physically (e.g., stabilizing a discernible symptom), physiologically (e.g., stabilizing a physical parameter), or both. In yet another embodiment, “treating,” “treating,” or “treatment” refers to preventing or delaying the onset or development or progression of the disease or disorder.

[0282] As used herein, an individual "needs" a treatment if such individual would benefit biologically, medically, or in terms of quality of life from such treatment.

[0283] As used herein, the terms "a", "an", "the", "the" and similar terms used in the context of the present invention (especially in the context of the claims) are to be construed as encompassing both the singular and the plural, unless otherwise indicated herein or clearly contradicted by the context.

[0284] All methods described herein may be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "how to"), provided herein is intended merely to further illuminate the invention and does not place a limitation on the scope of the invention otherwise claimed.

[0285] Any asymmetric center in the compounds of the present invention can be present in a racemic mixture or in a mixture of enantiomers or in enantiomerically enriched form. In certain embodiments, for example, as a mixture of enantiomers, each asymmetric center is present in at least 10% enantiomeric excess, at least 20% enantiomeric excess, at least 30% enantiomeric excess, at least 40% enantiomeric excess, at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess. In certain embodiments, for example, in the enantiomerically enriched form, each asymmetric center is present in at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.

[0286] Accordingly, as used herein, a compound of the present invention may be in the form of one of the possible isomers, enantiomers, atropisomers, diastereoisomers, tautomers or mixtures thereof, for example, as substantially pure diastereoisomers, optical isomers (enantiomers), racemates or mixtures thereof.

[0287] Any resulting mixtures of isomers may be separated on the basis of physicochemical differences of the constituents into pure or substantially pure geometric or optical isomers, diastereoisomers, atropisomers, racemates, for example by chromatography and/or fractional crystallization.

[0288] Any racemates resulting from the final products or intermediates may be resolved into the optical enantiomers by known methods, for example by separating the diastereoisomeric salts thereof obtained with an optically active acid or base and liberating the optically active acidic or basic compound. In particular, a basic chemical moiety may thus be used for the resolution of the compounds of the present invention into their optical enantiomers, for example by fractional crystallization of a salt formed with an optically active acid, for example tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-O,O'-p-toluyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. Racemic products may also be resolved by chiral chromatography, for example high pressure liquid chromatography (HPLC) using a chiral adsorbent.

[0289] Typically, compounds of formula (I) can be prepared according to the Schemes provided below. The examples describing specific synthetic routes, and the generic schemes below provide guidance to the synthetic chemist skilled in the art, who will readily appreciate that the solvent, concentration, reagent, protecting group, order of synthetic steps, time, temperature, and the like can be modified as needed.

[0290] The schemes provided below are intended to represent single diastereomers/enantiomers as well as their isomeric mixtures. Separation of diastereomers/enantiomers can be carried out according to techniques described herein. If not otherwise defined, in the general schemes described below, the substituents Z, X1, X2, Ar1 and Ar2 are as defined herein. In the general schemes below, Ar1 corresponds to a substituent A as defined for a compound of formula (I) and Ar2 corresponds to a substituent B as defined for a compound of formula (I). In particular, the substituents C, R2, R3, R4 and R5 are as defined herein and in particular in the claims. The amine protecting group (also referred to herein as nitrogen protecting group) is referred to as "PG" in the Schemes below. In the Schemes below, the compound of formula (Iy) is a compound of formula RC(O)-X and the substituent R-C(O) attached to the nitrogen atom of the spiro ligand in the compound of formula (Ie) should be interpreted accordingly. In the Schemes below, Ar1 corresponds to substituent A of the compound of formula (I) as appropriate and Ar2 corresponds to substituent B of the compound of formula (I) as appropriate. Scheme-1

[0291] Synthesis of Scheme-1: A compound of Formula (Ie) as disclosed herein can be synthesized as described in Scheme-1. A suitable dihalogenated heteroaromatic (1) is reacted with an aryl or heteroaryl coupling partner (Ar2) such as a boronic acid/ester in a Suzuki (or Stille) type cross-coupling reaction in the presence of a palladium catalyst such as RuPhos-Pd-G3/RuPhos in a solvent such as 1,4-dioxane (or toluene) with a base such as K3PO4 (or Na2CO3) to afford compound (2). In step B, the substituent Ar1 is introduced with a palladium cross-coupling reaction using a suitably functionalized aryl or heteroaryl system, e.g., an aryl boronic acid in the presence of a palladium catalyst such as RuPhos-Pd-G3/RuPhos in a solvent such as toluene with a base such as K3PO4 to afford compound (3). In step C, the protecting groups (PG) are removed under suitable conditions depending on the protecting group used. For example, the Boc group of compound (3) is removed using conditions known in the art with an organic acid such as trifluoroacetic acid in a solvent such as dichloromethane or with a mineral acid such as sulfuric acid in a solvent such as 1,4-dioxane to afford compound (4). Ar2 may also contain a protecting group (e.g., THP) which is removed in the same reaction under the aforementioned conditions to cleave the Boc group. In step D, compound (5) can be produced by reacting compound (4) with a compound of formula (Iy) wherein X is a leaving group, for example, halo (such as, chlorine) in the presence of a suitable base (such as, Hunig's base); or wherein X is OH and the reaction is carried out under standard amide bond forming conditions (for example, in the presence of an amide coupling reagent such as, HATU and a suitable base such as DIPEA). For example, acrylamide is introduced by treating compound (4) with acrylic acid in the presence of a coupling agent such as, propylphosphonic anhydride and a base such as, Hunig's base in a solvent such as, methylene chloride to afford compound (5). Alternatively, compound (4) can be treated with acryloyl chloride in the presence of a base such as, aqueous sodium bicarbonate in a solvent such as, THF. In step E, the atropisomer mixture is separated using SFC or HPLC conditions with the appropriate column and eluent.

[0292] Compounds (1), (2), (3) and (4) as shown and described above for Scheme-1 are useful intermediates for preparing compounds of Formula (Ie) Scheme-2

[0293] Synthesis of Scheme-2: Scheme-2 provides an alternative method for preparing compounds of Formula (Ie) as disclosed herein. Following a cross-coupling reaction such as a Suzuki reaction of a halogenated heteroaromatic (1) with an aryl or heteroaryl coupling partner such as a boronic acid/ester in the presence of a palladium catalyst such as RuPhos-Pd-G3/RuPhos in a solvent such as 1,4-dioxane (or toluene) with a base such as K3PO4 (or Na2CO3), compound (2) is treated with a halogenating agent such as N-iodosuccinimide or N-bromosuccinimide in a solvent such as THF or CH3CN. In step C, the Ar2 substituent is introduced with a palladium catalyzed coupling reaction using a suitably functionalized aryl or heteroaryl system, e.g., an aryl boronic ester in the presence of a palladium catalyst such as RuPhos-Pd-G3/RuPhos in a solvent such as 1,4-dioxane with a base such as K3PO4 to afford compound (4). The remaining steps D - F are analogous to steps C - E in Scheme-1 described above.

[0294] Compounds (1), (2), (3), (4) and (5) as shown and described above for Scheme-2 are useful intermediates for preparing compounds of Formula (Ie) Scheme-3

[0295] Synthesis of Scheme-3: Scheme-3 provides an alternative method for preparing compounds of Formula (Ie) as disclosed herein. The halogenated heteroaromatic (1) is converted to the heteroaromatic boronic ester (2) with bis-(pinacolato)-diboron in the presence of a palladium catalyst such as PdCl2(dppf).CH2Cl2 adduct in a solvent such as 1,4-dioxane with a base such as potassium acetate. In step B, the Ar1 substituent is introduced with a palladium coupling reaction using a suitably functionalized aryl or heteroaryl system, e.g., heteroaryl halide in the presence of a palladium catalyst such as RuPhos-Pd-G3/RuPhos in a solvent such as toluene with a base such as K3PO4 to afford compound (3). The remaining steps C - G are analogous to steps B - F in Scheme 2 described above.

[0296] Compounds (1), (2), (3), (4), (5) and (6) as shown and described above for Scheme-3 are useful intermediates for preparing compounds of Formula (Ie) Scheme-4

[0297] Synthesis of Scheme-4: A halogenated heteroaromatic compound of formula (I) or a dihalogenated heteroaromatic compound of formula (II) can be obtained as described in Scheme-4. A suitable trihalogenated heteroaromatic (1) such as 3,4,5-dibromo-1H-pyrazole is reacted with a metal-halogen exchange agent such as an alkyllithium agent, e.g. n-butyllithium, in a solvent such as THF to provide after hydrolysis, e.g. with methanol, compound (2). In step B, an N-protected ligand is introduced by reaction with a suitably functionalized N-protected ligand, e.g. functionalized with a tosylate in the presence of a base such as cesium carbonate in a solvent such as DMF to provide compound (3). In step C, a halogen/metal exchange is carried out using a suitable reagent such as n-butyllithium in a solvent such as THF to provide, upon reaction with a suitable alkylating agent such as methyl iodide, the halogenated heteroaromatic compound of formula (I). The compound of formula (I) is treated with a halogenating agent such as N-iodosuccinimide in a solvent such as CH3CN to provide a dihalogenated heteroaromatic ring of formula (II). Scheme-5

[0298] Synthesis of Scheme-5: Scheme-5 provides an alternative method for the preparation of a halogenated heteroaromatic compound of formula (I). A suitable halogenated heteroaromatic (1) such as, 3-iodo-5-methyl-1H-pyrazole is alkylated with a suitably functionalized N-protected linker, e.g., functionalized with a tosylate in the presence of a base such as, cesium carbonate in a solvent such as, DMF to provide the halogenated heteroaromatic compound of formula (I).

[0299] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In another embodiment, the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein. For purposes of the present invention, unless otherwise designated, solvates and hydrates are generally considered compositions. Preferably, pharmaceutically acceptable carriers are sterile. The pharmaceutical composition may be formulated for particular routes of administration, such as oral administration, parenteral administration, and rectal administration, etc. Furthermore, the pharmaceutical compositions of the present invention may be constituted in a solid form (including, without limitation, capsules, tablets, pills, granules, powders, or suppositories), or in a liquid form (including, without limitation, solutions, suspensions, or emulsions). The pharmaceutical compositions may be subjected to conventional pharmaceutical operations, such as sterilization, and/or may contain conventional inert diluents, lubricating agents or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers and buffers, etc.

[0300] Typically, the pharmaceutical compositions are gelatin tablets or capsules comprising the active ingredient together with one or more of: a) diluents, for example, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants, for example, silica, talc, stearic acid, its magnesium or calcium salt and/or polyethylene glycol; c) binders, for example, magnesium and aluminum silicate, starch paste, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose and/or polyvinylpyrrolidone; d) disintegrants, for example, starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and e) absorbents, colorants, flavors and sweeteners.

[0301] In one embodiment, the pharmaceutical compositions are capsules comprising only the active ingredient.

[0302] Tablets may be film coated or enteric coated according to methods known in the art.

[0303] Compositions suitable for oral administration include an effective amount of a compound of the invention in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules or syrups or elixirs, solutions or solid dispersion. Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents so as to provide pharmaceutically complete and palatable preparations. The tablets may contain the active ingredient in admixture by addition with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. Such excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, maize starch or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example, magnesium stearate, stearic acid or talc. Tablets are either uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thus provide a sustained action over a longer period. For example, a delay material such as glyceryl monostearate or glyceryl distearate may be used. Formulations for oral use may be presented as hard gelatin capsules, in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules, in which the active ingredient is mixed with water or an oily medium, for example, peanut oil, liquid paraffin or olive oil.

[0304] Certain injectable compositions are aqueous isotonic solutions or suspensions and suppositories are advantageously prepared from fatty emulsions or suspensions. Such compositions may be sterilized and/or contain adjuvants, such as preservatives, stabilizers, wetting or emulsifying agents, solution promoters, salts for regulating osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances. Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 to 75%, or contain about 1 to 50%, of the active ingredient.

[0305] Compositions suitable for transdermal application include an effective amount of a compound of the invention with a suitable carrier. Carriers suitable for transdermal delivery include absorbable pharmacologically acceptable solvents to aid passage through the skin of the host. For example, transdermal devices are in the form of a bandage comprising a reinforcing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier for delivering the compound to the skin of the host at a controlled and predetermined rate over an extended period of time, and means for securing the device to the skin.

[0306] Compositions suitable for topical application, e.g. to the skin and eyes, include aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations, e.g. for delivery by means of aerosol or the like. Such topical delivery systems will in particular be suitable for dermal application, e.g. for the treatment of skin cancer, e.g. for prophylactic use in sunscreens, lotions, sprays and the like. They are therefore particularly suitable for use in topical, including cosmetic, formulations well known in the art. These may contain solubilizers, stabilizers, tonicity agents, buffers and preservatives.

[0307] As used herein, a topical application may relate to an inhalation or an intranasal application. They may be conveniently administered in the form of a dry powder (alone, or as a mixture, e.g., a dry mixture with lactose or a mixed component particle, e.g., with phospholipids) from a dry powder inhaler or an aerosol spray presentation from a pressurized container, pump, sprayer, atomizer or nebulizer, with or without the use of an appropriate propellant.

[0308] The compounds of formula (I) in free form or in pharmaceutically acceptable salt form, exhibit valuable pharmacological properties, e.g. mutant RAS inhibition properties, e.g. as indicated in in vitro tests as given in the examples, and are therefore indicated for therapy or for use as research chemicals, e.g. as tool compounds.

[0309] Particularly interesting compounds of the invention have good potency in the biological assays described herein, in particular in the covalent competition assay as described herein. In another aspect, they should have a favorable safety profile. In another aspect, they should have favorable pharmacokinetic properties.

[0310] The compounds of the present invention preferably have an IC 50 of less than 0.5 μM, more preferably less than 0.1 μM.

[0311] Taking into account their activity as RAS mutant inhibitors, in particular KRAS, HRAS or NRAS G12C mutant inhibitors, compounds of formula (I) in the form of free or pharmaceutically acceptable salt, are useful in the treatment of conditions that are triggered by KRAS, HRAS or NRAS G12C mutations, such as a cancer that is responsive (meaning, especially in a therapeutically beneficial way) to the inhibition of RAS mutant proteins, in particular KRAS, HRAS or NRAS G12C, more especially a disease or disorder as mentioned herein below.

[0312] Compounds of the invention may be useful in the treatment of cancer. In particular, compounds of the invention may be useful in the treatment of an indication that is selected from the group consisting of lung cancer (such as lung adenocarcinoma and non-small cell lung cancer), colorectal cancer (including colorectal adenocarcinoma), pancreatic cancer (including pancreatic adenocarcinoma), uterine cancer (including uterine endometrial cancer), rectal cancer (including rectal adenocarcinoma) and a solid tumor.

[0313] The compounds of the invention may also be useful in the treatment of solid malignancies characterized by RAS mutations.

[0314] The compounds of the invention may also be useful in the treatment of solid malignancies characterized by one or more KRAS mutations, in particular, G12C mutations in KRAS.

[0315] Thus, as another embodiment, the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in therapy. As another embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in therapy. Thus, as another embodiment, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament. In a preferred embodiment, the therapy or therapy for which the medicament is useful is selected from a disease that can be treated by inhibiting RAS mutant proteins, in particular, KRAS, HRAS or NRAS G12C mutant proteins. In another embodiment, the invention provides a method of treating a disease, which is treated by inhibiting a mutant RAS protein, in particular, a G12C mutant protein of KRAS, HRAS or NRAS, in a subject in need thereof, wherein the method comprises administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, to the subject.

[0316] In a more preferred embodiment, the disease is selected from the list mentioned above, suitably non-small cell lung cancer, colorectal cancer and pancreatic cancer.

[0317] In a preferred embodiment, the therapy is for a disease, which can be treated by inhibiting a mutant RAS protein, in particular a G12C mutant of KRAS, HRAS or NRAS protein. In a more preferred embodiment, the disease is selected from the list mentioned above, suitably non-small cell lung cancer, colorectal cancer and pancreatic cancer, which is characterized by a G12C mutation in KRAS, HRAS or NRAS.

[0318] In one embodiment of the present invention, a compound is provided that is selected from the group consisting of: a(R)-1-(6-(4-(5-chloro-6-methyl-1H-indazole- 4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2- en-1-one, a(R)-(S)-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(1-(2-( 3-fluoropyrrolidin-1-yl)ethyl)-1H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2- azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, a(R)-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl) -5-methyl-3-phenyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, a(R)-1-(6- (4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-methoxyethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1 -il)-2- azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, a(R)-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-hydroxy-2-methylpropyl)-2H-indazol- 5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, a(R)-1-(6- (4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-(2-methoxyethoxy)ethyl)-2H-indazol-5-yl)-5-methyl- 1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, a(R)-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(4-(hydroxymethyl)phenyl)-5-methyl-1H-pyrazol- 1-yl)-2-azaspiro[3.3]heptan-2- yl)prop-2-en-1-one, a(R)-1-(6-(4-(5-chloro-6-methyl-1H -indazol-4-yl)-3-(2-fluoro-4-(2-methoxyethoxy)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl) prop-2-en-1-one, a(R)-1-(6-(4-(3-amino-5-chloro-6-methyl-1H-indazol-4-yl)-3-(2- (2-methoxyethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one and a(R)-1-(6-(4-(3-amino-5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-phenyl-1H-pyrazol-1-yl )-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, or a pharmaceutically acceptable salt thereof for use in the treatment of a cancer or a solid malignancy, optionally characterized by a KRAS mutation, HRAS or NRAS G12C.

[0319] In one embodiment of the present invention, a compound is provided that is selected from the group consisting of: a(R)-1-(6-(4-(5-chloro-6-methyl-1H-indazole- 4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2- en-1-one, a(R)-(S)-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(1-(2-( 3-fluoropyrrolidin-1-yl)ethyl)-1H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2- azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, a(R)-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl) -5-methyl-3-phenyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, a(R)-1-(6- (4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-methoxyethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1 -yl)-2- azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, a(R)-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-hydroxy-2-methylpropyl)-2H-indazol- 5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, a(R)-1-(6- (4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-(2-methoxyethoxy)ethyl)-2H-indazol-5-yl)-5-methyl- 1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, a(R)-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(4-(hydroxymethyl)phenyl)-5-methyl-1H-pyrazol- 1-yl)-2-azaspiro[3.3]heptan-2- yl)prop-2-en-1-one, a(R)--1-(6-(4-(5-chloro-6-methyl- 1H-indazol-4-yl)-3-(2-fluoro-4-(2-methoxyethoxy)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl )prop-2-en-1-one, a(R)1-(6-(4-(3-amino-5-chloro-6-methyl-1H-indazol-4-yl)-3-(2- (2-methoxyethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one and a(R)-1-(6-(4-(3-amino-5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-phenyl-1H-pyrazol-1-yl )-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of a cancer that is selected from lung cancer (such as, lung adenocarcinoma and non-small cell lung cancer), colorectal cancer (including colorectal adenocarcinoma), pancreatic cancer (including pancreatic adenocarcinoma), uterine cancer (including uterine endometrial cancer), and rectal cancer (including rectal adenocarcinoma); more appropriately, lung cancer, colorectal cancer, or pancreatic cancer or a solid tumor.

[0320] In one embodiment of the present invention, a compound is provided that is selected from the group consisting of: a-(R)-1-(6-(4-(5-chloro-6-methyl-1H-indazole -4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2 - en-1-one, a(R)-(S)-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(1-(2- (3-fluoropyrrolidin-1-yl)ethyl)-1H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2- azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, a(R)-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl) -5-methyl-3-phenyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, a(R)-1-(6- (4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-methoxyethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1 -il)-2- azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, a(R)-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-hydroxy-2-methylpropyl)-2H-indazol- 5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, a(R)-1-(6- (4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-(2-methoxyethoxy)ethyl)-2H-indazol-5-yl)-5-methyl- 1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, a(R)-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(4-(hydroxymethyl)phenyl)-5-methyl-1H-pyrazol- 1-yl)-2-azaspiro[3.3]heptan-2- yl)prop-2-en-1-one, a(R)-1-(6-(4-(5-chloro-6-methyl-1H -indazol-4-yl)-3-(2-fluoro-4-(2-methoxyethoxy)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl) prop-2-en-1-one, a(R)-1-(6-(4-(3-amino-5-chloro-6-methyl-1H-indazol-4-yl)-3-(2- (2-methoxyethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one and a(R)-1-(6-(4-(3-amino-5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-phenyl-1H-pyrazol-1-yl )-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, or a pharmaceutically acceptable salt thereof, for use in the treatment of a cancer that is selected from lung cancer (such as, lung adenocarcinoma and non-small cell lung cancer), colorectal cancer (including colorectal adenocarcinoma), pancreatic cancer (including pancreatic adenocarcinoma), uterine cancer (including uterine endometrial cancer), and rectal cancer (including rectal adenocarcinoma); more suitably, lung cancer, colorectal cancer or pancreatic cancer or a solid tumor, wherein the cancer is KRAS G12C mutant. More suitably, the cancer to be treated by the compound of the invention is KRAS G12C mutant lung cancer, including KRAS G12C mutant non-small cell lung cancer.

[0321] The compound of the present invention may be administered simultaneously with, or before or after, one or more other therapeutic agents. The compound of the present invention may be administered separately, by the same or a different route of administration, or together in the same pharmaceutical composition as the other agents. A therapeutic agent is, for example, a chemical compound, peptide, antibody, antibody fragment, or nucleic acid, which is therapeutically active or enhances therapeutic activity when administered to a patient in combination with a compound of the present invention. In embodiments of the invention, the other therapeutic agent may be an anticancer agent.

[0322] In one embodiment, the invention provides a product comprising a compound of the present invention and at least one other therapeutic agent as a combination preparation for simultaneous, separate or sequential use in therapy. In one embodiment, the therapy is the treatment of a disease or condition characterized by a KRAS, HRAS or NRAS G12C mutation. Products provided as a combination preparation include a composition comprising the compound of the present invention and the other therapeutic agent(s) together in the same pharmaceutical composition, or the compound of the present invention and the other therapeutic agent(s) in separate form, e.g., in the form of a kit.

[0323] In one embodiment, the invention provides a pharmaceutical composition comprising a compound of the present invention and another therapeutic agent(s). Optionally, the pharmaceutical composition may comprise a pharmaceutically acceptable carrier as described above.

[0324] In one embodiment, the invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of the present invention. In one embodiment, the kit comprises means for separately holding said compositions, such as a container, divided bottle, or divided foil packet. An example of such a kit is a blister pack, as typically used for packaging tablets, capsules, and the like.

[0325] The kit of the invention may be used for the administration of different dosage forms, e.g., oral and parenteral, for the administration of the separate compositions at different dosage intervals, or for the titration of the separate compositions relative to each other. To aid in adherence to treatment, the kit of the invention typically comprises instructions for administration.

[0326] In the combination therapies of the invention, the compound of the invention and the other therapeutic agent may be manufactured and/or formulated by the same or different manufacturers. Furthermore, the compound of the invention and the other therapeutic agent may be combined in a combination therapy: (i) prior to release of the combination product to physicians (e.g., in the case of a kit comprising the compound of the invention and the other therapeutic agent); (ii) by the physicians themselves (or under the direction of the physician) shortly before administration; (iii) in the patients themselves, for example during sequential administration of the compound of the invention and the other therapeutic agent.

Compound Preparation

[0327] The compounds of the present invention can be prepared as described in the following Examples. The Examples are intended to illustrate the invention and should not be construed as being limitations thereof.

Methods and General Conditions

[0328] Temperatures are given in degrees Celsius. Unless otherwise stated, all evaporations are carried out under reduced pressure, typically between about 15 mm Hg and 100 mm Hg (= 20-133 mbar).

[0329] Mass spectra were acquired on LC-MS, SFC-MS or GC-MS systems using electrospray, chemical impact ionization and electron methods with a range of instruments of the following configurations: Waters Acquity UPLC with Waters SQ detector or mass spectra were acquired on LCMS systems using the ESI method with a range of instruments of the following configurations: Waters Acquity LCMS with PDA detector. [M+H]+ refers to the protonated molecular ion of the chemical species.

[0330] NMR spectra were performed with Bruker Ultrashield™400 (400 MHz), Bruker Ultrashield™600 (600 MHz) and Bruker AscendTM400 (400 MHz) spectrometers, both with and without tetramethylsilane as an internal standard. Chemical shifts (δ values) are reported in ppm downfield of tetramethylsilane, the spectral splitting pattern is designated as singlet (s), doublet (d), triplet (t), quartet (q), multiplet, unresolved or most overlapping signals (m), broad signal (br). Solvents are indicated in parentheses. Only proton signals that are observed and not overlapping with solvent peaks are reported.

[0331] Celite: CeliteR (the Celite corporation) = diatomaceous earth based filtration aid

[0332] Phase Separator: Biotage - Isolute Phase Separator - (Part Number: 120-1908-F for 70 mL and Part Number: 120-1909-J for 150 mL)

[0333] SiliaMetS®Thiol: SiliCYCLE metal thiol scavenger - (R51030B, Particle Size: 40-63 μm).

[0334] The X-ray powder diffraction (XRPD) patterns described herein were obtained using a Bruker Advance D8 in reflection geometry. Powder samples were analyzed using a zero-base Si flat sample holder. The radiation was Cu Kα (À=1.5418 A). Patterns were measured between 2theta of 2° and 40°. Sample amount: 5-10 mg Sample holder: Zero-base Si flat sample holder XRPD parameters: Instrumentation

[0335] Microwave: All microwave reactions were conducted in a Biotage Initiator, irradiating at 0-400 W from a 2.45 GHz magnetron with Robot Eight/Robot Sixty processing capability, unless otherwise stated. UPLC-MS and MS analytical methods: Using Waters Acquity UPLC with Waters SQ detector.

[0336] UPLC-MS-1: Acquity HSS T3; particle size: 1.8 μm; column size: 2.1 x 50 mm; eluent A: H2O + 0.05% HCOOH + 3.75 mM ammonium acetate; eluent B: CH3CN + 0.04% HCOOH; gradient: 5 to 98% B in 1.40 min, then 98% B for 0.40 min; flow rate: 1 mL/min; column temperature: 60 °C.

[0337] UPLC-MS-2: Acquity HSS T3; particle size: 1.8 μm; column size: 2.1 x 100 mm; eluent A: H2O + 0.05% HCOOH + 3.75 mM ammonium acetate; eluent B: CH3CN + 0.04% HCOOH; gradient: 5 to 98% B in 9.4 min, then 98% B for 0.40 min; flow rate: 1.0 mL/min; column temperature: 60 °C.

[0338] UPLC-MS-3: Acquity BEH C18; particle size: 1.7 μm; column size: 2.1 x 50 mm; eluent A: H2O + 4.76% isopropanol + 0.05% HCOOH + 3.75 mM ammonium acetate; eluent B: isopropanol + 0.05% HCOOH; gradient: 1 to 98% B in 1.7 min, then 98% B for 0.1 min; flow rate: 0.6 mL/min; column temperature: 80 °C.

[0339] UPLC-MS-4: Acquity BEH C18; particle size: 1.7 μm; column size: 2.1 x 100 mm; eluent A: H2O + 4.76% isopropanol + 0.05% HCOOH + 3.75 mM ammonium acetate; eluent B: isopropanol + 0.05% HCOOH; gradient: 1 to 60% B in 8.4 min then 60 to 98% B in 1 min; flow rate: 0.4 mL/min; column temperature: 80 °C.

[0340] UPLC-MS-5: Ascentis Express C18; particle size: 2.7 μm; column size: 2.1 x 50 mm; eluent A: H2O + 4.76% isopropanol + 0.05% HCOOH + 3.75 mM ammonium acetate; eluent B: isopropanol + 0.05% HCOOH; gradient: 1 to 50% B in 1.4 min, 50 to 98% B in 0.30 min, then 98% for 0.10 min; flow rate: 1 mL/min; column temperature: 80 °C.

[0341] UPLC-MS-6: Acquity BEH C18; particle size: 1.7 μm; column size: 2.1 x 50 mm; eluent A: H2O + 0.05% HCOOH + 3.75 mM ammonium acetate; eluent B: isopropanol + 0.05% HCOOH; gradient: 5 to 98% B in 1.7 min then 98% B for 0.1 min; flow rate: 0.6 mL/min; column temperature: 80 °C.

[0342] UPLC-MS-7: Acquity BEH C18; particle size: 1.7 μm; column size: 2.1 x 50 mm; eluent A: H2O + 0.05% HCOOH + 3.75 mM ammonium acetate; eluent B: isopropanol + 0.05% HCOOH; gradient: 5 to 98% B in 1.7 min, then 98% B for 0.1 min; flow rate: 0.7 mL/min; column temperature: 80 °C.

[0343] UPLC-MS-8: Acquity HSS T3; particle size: 1.8 μm; column size: 2.1 x 100 mm; eluent A: H2O + 0.05% HCOOH + 3.75 mM ammonium acetate; eluent B: CH3CN + 0.04% HCOOH; gradient: 5 to 98% B in 9.4 min then 98% B for 0.40 min; flow rate: 0.8 mL/min; column temperature: 60 °C.

[0344] UPLC-MS-9: CORTECS C18+; particle size: 2.7 μm; column size: 2.1 x 50 mm; eluent A: H2O + 4.76% isopropanol + 0.05% HCOOH + 3.75 mM ammonium acetate; eluent B: isopropanol + 0.05% HCOOH; gradient: 1 to 50% B in 1.4 min, 50 to 98% B in 0.30 min, then 98% for 0.10 min; flow rate: 1 mL/min; column temperature: 80 °C.

[0345] UPLC-MS-10: Acquity HSS T3; particle size: 1.8 μm; column size: 2.1 x 50 mm; eluent A: H2O + 0.05% HCOOH + 3.75 mM ammonium acetate; eluent B: isopropanol + 0.05% HCOOH; gradient: 5 to 98% B in 1.7 min then 98% B for 0.10 min; flow rate: 0.6 mL/min; column temperature: 80 °C.

[0346] UPLC-MS-11: Acquity BEH C18; particle size: 1.7 μm; column size: 2.1 x 50 mm; eluent A: H2O + 0.2% HCOOH; eluent B: CH3CN; gradient: 5 to 98% B in 1.4 min, then 98% B for 0.4 min; flow rate: 1.0 mL/min; column temperature: 80 °C.

[0347] UPLC-MS-12: Acquity BEH C18; particle size: 1.7 μm; column size: 2.1 x 100 mm; eluent A: H2O + 0.05% HCOOH + 3.75 mM ammonium acetate; eluent B: isopropanol + 0.05% HCOOH; gradient: 5 to 60% B in 8.4 min then 60 to 98% B in 1 min; flow rate: 0.4 mL/min; column temperature: 80 °C.

[0348] UPLC-MS-13: Acquity HSS T3; particle size: 1.8 μm; column size: 2.1 x 100 mm; eluent A: H2O + 0.05% HCOOH + 3.75 mM ammonium acetate; eluent B: isopropanol + 0.05% HCOOH; gradient: 5 to 60% B in 8.4 min then 60 to 98% B in 1 min; flow rate: 0.4 mL/min; column temperature: 80 °C.

[0349] LCMS-1: Acquity BEH C18; particle size: 1.7 μm; column size: 2.1 x 50 mm; eluent A: H2O + 0.10% HCOOH + 2.0 mM ammonium acetate; eluent B: CH3CN + 0.10% HCOOH; gradient: 98:2 at 0.01 min to 0.3 min, 50:50 to 0.6 min, 25:75 to 1.1 min, 0:100 to 2.0 min to 2.70 min at flow rate: 0.60 mL/min, 98:2 at 2.71 min to 3.0 min at flow rate: 0.55 mL/min; column temperature: RT.

[0350] LCMS-2: Acquity BEH C18; particle size: 1.7 μm; column size: 2.1 x 50 mm; eluent A: H2O + 0.10% HCOOH + 2.0 mM ammonium acetate; eluent B: CH3CN + 0.10% HCOOH; gradient 50:50 at 0.01 min, 10:90 at 1.0 min, 0:100 at 1.5 min to 4.50 min, 50:50 at 4.6 min to 5.0 min; flow rate: 0.40 mL/min; column temperature: RT.

[0351] LCMS-3: X-Bridge C18; particle size: 3.5 μm; column size: 50 x 4.6 mm; Eluent A: 5.0 mM ammonium bicarbonate; eluent B: CH3CN; Gradient: 95:5 at 0.01 min, 10:90 at 5.0 min, 5:95 at 5.80 min up to 7.20 min, 95:5 at 7.21 min up to 10.0 min at flow rate: 1 mL/min; column temperature: RT.

[0352] LCMS-4: Acquity BEH C18; particle size: 1.7 μm; column size: 2.1 x 50 mm; eluent A: H2O + 0.10% HCOOH + 2.0 mM ammonium acetate; eluent B: CH3CN + 0.10% HCOOH; gradient 98:2 at 0.01 min to 0.5 min, 10:90 to 5.0 min, 5:95 to 6.0 min to 7.0 min, 98:2 at 7.01 min to 8.0 min; flow rate: 0.45 mL/min; column temperature: RT.

[0353] LCMS-5: YMC-Pack ODS-AQ; particle size: 5.0 μm; column size: 4.6 x 250 mm; Eluent A: 10 mM ammonium acetate + 0.10% HCOOH; Eluent B: CH3CN + 0.10% HCOOH; gradient 90:10 at 0.01 min, 70:30 at 10 min, 60:40 at 20 min, 0:100 at 30 min to 33 min, 90:10 at 33.01 min to 35.0 min; flow rate: 1.0 mL/min; column temperature: RT.

[0354] MS-1: MS flow injection; eluent A: H2O + 4.76% isopropanol + 0.05% HCOOH + 3.75 mM ammonium acetate; eluent B: isopropanol + 0.04% HCOOH; gradient: isocratic 70% B for 0.8 min; flow rate: 0.4 mL/min. Preparative methods:

[0355] Normal Phase Chromatography: Normal phase chromatography was performed on silica gel using pre-packed columns as detailed below, or using glass columns following standard flash chromatography methodology unless otherwise stated. System 1 Teledyne ISCO, CombiFlash Rf System 2 Biotage Isolera Column Pre-packed RediSep Rf cartridges or SNAP cartridges Sample adsorption onto Isolute, or onto silica gel, or applied as solutions Reversed Phase HPLC and SFC:

[0356] RP-HPLC-1: Gilson PLC 2020, column: Maisch Reprosil C18 5 μm, 250 x 30 mm, UV detection 215 & 254 nM, mobile phase: A: water + 0.1% TFA, B: acetonitrile; gradient: 30 to 95% B in 25 min.

[0357] RP-HPLC-5: Agela-H1000GC500, column: Welch Ultimate XB C18 40 μm, 100 x 400 mm, UV detection, mobile phase: A: water + 0.1% NH4HCO3, B: acetonitrile; gradient: 60 to 100% B in 50 min.

[0358] SFC-1: column: Reprosphere PEI 100A 5 μm; 250 x 30 mm; mobile phase; flow rate: 30 mL/min; column temperature: 40 °C; backpressure: 120 bar. Chiral HPLC/SFC methods:

[0359] C-SFC-1: column: Amylose-C NEO 5 μm; 250 x 30 mm; mobile phase; flow rate: 80 mL/min; column temperature: 40 °C; backpressure: 120 bar.

[0360] C-SFC-2: column: Lux Amylose-1 5 μm; 250 x 30 mm; mobile phase; flow rate: 80 mL/min; column temperature: 40 °C; backpressure: 120 bar.

[0361] C-SFC-3: column: Chiralpak AD-H 5 μm; 100 x 4.6 mm; mobile phase; flow rate: 3 mL/min; column temperature: 40 °C; backpressure: 1800 psi.

[0362] C-SFC-4: column: Chiralpak AD-H 5 μm; 250 x 30 mm; mobile phase; flow rate: 80 mL/min; column temperature: 40 °C; backpressure: 120 bar. C-SFC-5: column: Chiralpak IB-N 5 μm; 250 x 30 mm; mobile phase; flow rate: 80 mL/min;

[0363] column temperature: 40 °C; back pressure: 120 bar.

[0364] C-SFC-6: column: Chiralpak IB-N 5 μm; 100 x 4.6 mm; mobile phase; flow rate: 3 mL/min; column temperature: 40 °C; backpressure: 1800 psi.

[0365] C-SFC-7: column: Chiralpak IG 5 μm; 250 x 30 mm; mobile phase; flow rate: 80 mL/min; column temperature: 40 °C; backpressure: 120 bar.

[0366] C-SFC-8: column: Chiralpak IG 5 μm; 100 x 4.6 mm; mobile phase; flow rate: 3 mL/min; column temperature: 40 °C; backpressure: 1800 psi.

[0367] C-SFC-9: column: Chiralpak AD-YMC 5 μm; 250 x 30 mm; mobile phase; flow rate: 80 mL/min; column temperature: 40 °C; backpressure: 120 bar.

[0368] C-SFC-10: column: Chiralpak IG 5 μm; 250 x 30 mm; mobile phase; flow rate: 100 mL/min; column temperature: 40 °C; backpressure: 120 bar.

[0369] C-SFC-11: column: Lux Cellulose 5 μm; 100 x 4.6 mm; mobile phase; flow rate: 3 mL/min; column temperature: 20 °C; backpressure: 120 bar.

[0370] C-SFC-12: column: Chiralpak OD-H 5 μm; 250 x 30 mm; mobile phase; flow rate: 80 mL/min; column temperature: 40 °C; backpressure: 110 bar.

[0371] C-SFC-13: column: Chiralpak OD-H 5 μm; 100 x 4.6 mm; mobile phase; flow rate: 3 mL/min; column temperature: 40 °C; backpressure: 120 bar.

[0372] C-SFC-14: Waters SFC 200 with UV detector; column: Chiralpak AD-H 5 μm; 250 x 30 mm; mobile phase; flow rate: 80 mL/min; column temperature: 40 °C; backpressure: 100 bar.

[0373] C-SFC-15: Waters SFC investigator with PDA detector; column: Chiralpak AD-H 5 μm; 250 x 4.6 mm; mobile phase; flow rate: 4 mL/min; column temperature: 40 °C; backpressure: 100 bar.

[0374] C-SFC-16: Waters SFC 200 with UV detector; column: Chiralpak IG 5 μm; 250 x 30 mm; mobile phase; flow rate: 80 mL/min; column temperature: 40 °C; backpressure: 100 bar.

[0375] C-SFC-17: Waters SFC 200 with UV detector; column: Chiralpak IG 5 μm; 250 x 21 mm; mobile phase; flow rate: 80 mL/min; column temperature: 40 °C; backpressure: 100 bar.

[0376] C-SFC-18: Waters SFC investigator with PDA detector; column: Chiralpak IG 5 μm; 250 x 4.6 mm; mobile phase; flow rate: 4 mL/min; column temperature: 40 °C; backpressure: 100 bar. C-SFC-19: Waters SFC investigator with PDA detector; column: Chiralpak IC 5 μm; 250 x 4.6 mm; mobile phase; flow rate: 4 mL/min; column temperature: 40 °C; backpressure: 100 bar.

[0377] C-SFC-20: column: Lux Cellulose 5 μm; 250 x 30 mm; mobile phase; flow rate: 80 mL/min; column temperature: 40 °C; backpressure: 120 bar.

[0378] C-HPLC-1: column: Chiralpak IC 5 μm; 250 x 20 mm; mobile phase; flow rate: 10 mL/min; column temperature: RT.

[0379] C-HPLC-2: column: ChiralPak ID 5 μm; 250 x 25 mm; mobile phase; flow rate: 15 mL/min; column temperature: RT.

[0380] C-HPLC-3: column: Chiralpak IC 3 μm; 100 x 4.6 mm; mobile phase; flow rate: 0.42 mL/min; column temperature: RT; backpressure: 1800 psi.

[0381] C-HPLC-4: column: Chiralpak IC-3 3 μm; 100 x 3 mm; mobile phase; flow rate: 0.42 mL/min; column temperature: RT.

[0382] C-HPLC-5: column: Chiralpak IA 5 μm; 250 x 4.6 mm; mobile phase; flow rate: 1 mL/min; column temperature: RT; backpressure: 49 bar.

[0383] C-HPLC-6: column: Chiralpak IA 5 μm; 250 x 30 mm; mobile phase; flow rate: 20 mL/min; column temperature: RT.

[0384] C-HPLC-7: column: ChiralPak ID 5 μm; 250 x 4.6 mm; mobile phase; flow rate: 1 mL/min; column temperature: RT.

[0385] C-HPLC-8: column: ChiralPak AD 5 μm; 250 x 30 mm; mobile phase; flow rate: 20 mL/min; column temperature: RT.

[0386] C-HPLC-9: column: ChiralPak AD 3 μm; 100 x 3.0 mm; mobile phase; flow rate: 0.42 mL/min; column temperature: RT.

[0387] C-HPLC-10: column: Chiralpak IG-3; 3 μm; 100 x 3.0 mm; mobile phase; flow rate: 0.42 mL/min; column temperature: 25 °C.

[0388] C-HPLC-11: column: Chiralpak IG 5 μm; 250 x 20 mm; mobile phase; flow rate: 10 mL/min; column temperature: 25 °C.

[0389] C-HPLC-12: column: Chiralpak IA-5; 5 μm; 250 x 3.0 mm; mobile phase; flow rate: 1 mL/min; column temperature: 25 °C.

[0390] C-HPLC-13: column: Chiralpak IG-3; 3 μm; 100 x 3.0 mm; mobile phase; flow rate: 0.42 mL/min; column temperature: 25 °C.

[0391] C-HPLC-14: column: Chiralcel OZ; 3 μm; 250 x 25 mm; mobile phase; flow rate: 15 mL/min; column temperature: 25 °C.

[0392] C-HPLC-15: column: Chiralcel OZ; 3 μm; 100 x 3.0 mm; mobile phase; flow rate: 0.42 mL/min; column temperature: 25 °C.

[0393] C-HPLC-16: column: Chiralcel OZ; 5 μm; 250 x 4.6 mm; mobile phase; flow rate: 1.0 mL/min; column temperature: 25 °C.

[0394] C-HPLC-17: column: Chiralpak IG 5 μm; 250 x 20 mm; mobile phase; flow rate: 12 mL/min; column temperature: 25 °C.

[0395] C-HPLC-18: column: Lux Amylose-1 5 μm; 250 x 20 mm; mobile phase; flow rate: 10 mL/min; column temperature: 40 °C; backpressure: 120 bar.

[0396] C-HPLC-19: column: ChiralPak AD 5 μm; 250 x 25 mm; mobile phase; flow rate: 15 mL/min; column temperature: RT.

[0397] C-HPLC-20: column: Chiralpak IC 5 μm; 250 x 4.6 mm; mobile phase; flow rate: 1 mL/min; column temperature: RT.

[0398] C-HPLC-21: column: Chiralpak AD-H 5 μm; 250 x 21 mm; mobile phase; flow rate: 18 mL/min; column temperature: 40 °C.

[0399] C-HPLC-22: column: Chiralpak AD-H 5 μm; 250 x 4.6 mm; mobile phase; flow rate: 1 mL/min; column temperature: 25 °C.

[0400] C-HPLC-23: column: Chiralcel OX-H 5 μm; 250 x 21 mm; mobile phase; flow rate: 18 mL/min; column temperature: 40 °C.

[0401] C-HPLC-24: column: Chiralpak OX-H 5 μm; 250 x 4.6 mm; mobile phase; flow rate: 1 mL/min; column temperature: 25 °C.

[0402] C-HPLC-25: column: Chiralpak IBN 5 μm; 250 x 21 mm; mobile phase; flow rate: 18 mL/min; column temperature: 40 °C.

[0403] C-HPLC-26: column: Chiralpak IBN 5 μm; 250 x 4.6 mm; mobile phase; flow rate: 1 mL/min; column temperature: 25 °C.

[0404] C-HPLC-27: column: Chiralpak IC 5 μm; 250 x 21 mm; mobile phase; flow rate: 18 mL/min; column temperature: 40 °C.

[0405] C-HPLC-28: column: Chiralpak IG, 5 μm; 250 x 21 mm; mobile phase; flow rate: 18 mL/min; column temperature: 40 °C.

[0406] C-HPLC-29: column: ChiralPak IG 5 μm; 250 x 4.6 mm; mobile phase; flow rate: 1 mL/min; column temperature: 25 °C.

[0407] C-HPLC-30: column: Chiralpak IC 5 μm; 250 x 30 mm; mobile phase; flow rate: 20 mL/min; column temperature: RT.

[0408] The abbreviations used are those conventional in the art. Abbreviations:

[0409] All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts used to prepare the compounds of the present invention are commercially available or can be produced by organic synthesis methods known to one of ordinary skill in the art. In addition, the compounds of the present invention can be produced by organic synthesis methods known to one of ordinary skill in the art, as shown in the following examples.

[0410] The structures of all final products, intermediates and starting materials are confirmed by standard analytical spectroscopic characteristics, e.g., MS, IR, NMR. The absolute stereochemistry of representative examples of the preferred (most active) atropisomers was determined by analyses of X-ray crystal structures of complexes in which the respective compounds are bound to the KRASG12C mutant or by analyses of small molecule X-ray crystal structures. In all other cases where X-ray structures are not available, the stereochemistry was assigned by analogy, assuming that for each pair, the atropisomer exhibiting the highest activity in the covalent competition assay has the same configuration observed by X-ray crystallography for the representative examples mentioned above. The absolute stereochemistry is assigned according to the Cahn-Ingold-Prelog rule as described above for Example 12a (the most active atropisomer), which is representative for other examples and which has the a(R) configuration. Preparation of Final Compounds Method-1: Synthetic Scheme Example 1a: a( R )-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one or 1-{6-[(4M)-4-(5-chloro- 6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl}prop-2-en-1-one and Example 1b: a(S )-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one or 1-{6-[(4 P)-4-(5-chloro-6-methyl-1 dazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl}prop-2-en-1-one Step 1: 6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4- tert-butyl yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0411] In a 500 mL flask, tert-butyl 6-(3-bromo-4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate C1, 10 g, 16.5 mmol), (1-methyl-1H-indazol-5-yl)boronic acid (6.12 g, 33.1 mmol), RuPhos (1.16 g, 2.48 mmol), and RuPhos-Pd-G3 (1.66 g, 1.98 mmol) were suspended in toluene (165 mL) under argon. K3PO4 (2 M, 24.8 mL, 49.6 mmol) was added and the reaction mixture was placed in a preheated (95 °C) oil bath and stirred for 45 min. The reaction mixture was poured into a sat. aq. NH4Cl solution and extracted with EtOAc (x3). The combined organic layers were washed with a sat. aq. NaHCO3 solution, dried (phase separator), and concentrated under reduced pressure. The crude residue was diluted with THF (50 mL), SiliaMetS®Thiol (15.9 mmol) was added, and the mixture was vortexed for 1 h at 40 °C. The mixture was filtered, the filtrate was concentrated, and the crude residue was purified by normal phase chromatography (eluent: MeOH in CH2Cl2 0-2%), the purified fractions were further purified by normal phase chromatography (eluent: MeOH in CH2Cl2 0-2%) to give the title compound as a beige foam. UPLC-MS-3: Rt = 1.23 min; MS m/z [M+H]+; 656.3/658.3. Step 2: 5-chloro-6-methyl-4-(5-methyl-3-(1-methyl-1H-indazol-5-yl)-1-(2-azaspiro[3.3]heptan-6-yl)-1H-pyrazol-4-yl)-1H-indazole

[0412] TFA (19.4 mL, 251 mmol) was added to a solution of 6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane- tert-butyl 2-carboxylate (Step 1, 7.17 g, 10.0 mmol) in CH2Cl2 (33 mL). The reaction mixture was stirred at RT under nitrogen for 1.5 h. The RM was concentrated under reduced pressure to give the title compound as a trifluoroacetate salt, which was used without purification in the next step. UPLC-MS-3: Rt = 0.74 min; MS m/z [M+H]+; 472.3/474.3. Step 3: 1 -(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one

[0413] A mixture of acrylic acid (0.69 mL, 10.1 mmol), propylphosphonic anhydride (50% in EtOAc, 5.94 mL, 7.53 mmol), and DIPEA (21.6 mL, 126 mmol) in CH2Cl2 (80 mL) was stirred for 20 min at RT and then added (dropping funnel) to an ice-cooled solution of 5-chloro-6-methyl-4-(5-methyl-3-(1-methyl-1H-indazol-5-yl)-1-(2-azaspiro[3.3]heptan-6-yl)-1H-pyrazol-4-yl)-1H-indazole trifluoroacetate (Step 2, 6.30 mmol) in CH2Cl2 (40 mL). The reaction mixture was stirred at RT under nitrogen for 15 min. The RM was poured into a sat. aq. NaHCO3 solution and extracted with CH2Cl2 (x3). The combined organic layers were dried (phase separator) and concentrated. The crude residue was diluted with THF (60 mL) and LiOH (2 N, 15.7 mL, 31.5 mmol) was added. The mixture was stirred at RT for 30 min until the disappearance (UPLC) of the by-product resulting from the reaction of acryloyl chloride with the free NH group of indazole, then it was poured into a sat. aq. NaHCO3 solution and extracted with CH2Cl2 (3x). The combined organic layers were dried (phase separator) and concentrated. The crude residue was purified by normal phase chromatography (eluent: MeOH in CH2Cl2 0–5%) to give the title compound. The isomers were separated by chiral SFC (C-SFC-1; mobile phase: CO2/0.1% [IPA+Et3N]: 69/31) to give Example 1a: a(R)-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one as the second elution peak (white powder): 1H NMR (600 MHz, DMSO-d6) δ 13.1 (s, 1H), 7.89 (s, 1H), 7.59 (s, 1H), 7.55 (s, 1H), 7.42 (m, 2H), 7.30 (d, 1H), 6.33 (m, 1H), 6.12 (m, 1H), 5.68 (m, 1H), 4.91 (m, 1H), 4.40 (s, 1H), 4.33 (s, 1H), 4.11 (s, 1H), 4.04 (s, 1H), 3.95 (s, 3H), 2.96-2.86 (m, 2H), 2.83-2.78 (m, 2H), 2.49 (s, 3H), 2.04 (s, 3H); UPLC-MS-4: Rt = 4.22 min; MS m/z [M+H]+ 526.3/528.3; C-SFC-3 (mobile phase: CO2/0.1% [IPA+Et3N]: 67/33): Rt = 2.23 min. Throughout this description, the compound of Example 1a is also referred to as "Compound X".

[0414] The other isomer Example 1b; (S)-1-(6-(4-(5-chloro-6-methyl- 1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one was obtained as the first eluting peak: C-SFC-3 (mobile phase: CO2/[IPA+Et3N] 0.1%: 67/33): Rt = 1.55 min. Method-1a: Similar to Method-1 except that Step 2 was performed as described below:

[0415] To a stirred solution of tert-butyl -6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Step 1, 1.66 g, 2.10 mmol) in dioxane (40 mL) was added sulfuric acid (3.30 mL, 42.0 mmol), and the mixture was stirred at RT overnight. The mixture was diluted with water, neutralized with sat. aq. English: NaHCO3 (at pH 8-9), extracted with n-butanol (x2) and the combined organic extracts were washed with water (x2), dried (phase separator) and evaporated. The crude material 5-chloro-6-methyl-4-(5-methyl-3-(1-methyl-1H-indazol-5-yl)-1-(2-azaspiro[3.3]heptan-6-yl)-1H-pyrazol-4-yl)-1H-indazole was dried overnight under high vacuum and used without purification in the next step.

[0416] Note: For some of the examples in Table 1 and Table 2, CH2Cl2 may be used for the extraction instead of n-butanol. Method-1b: Similar to Method-1 except that Step 3 was performed as described below:

[0417] To an ice-cooled solution of 5-chloro-6-methyl-4-(5-methyl-3-(1-methyl-1H-indazol-5-yl)-1-(2-azaspiro[3.3]heptan-6-yl)-1H-pyrazol-4-yl)-1H-indazole (trifluoroacetate (Step 2) or free base (Step 2 Method-1a), 0.25 mmol) in THF (4 mL) was added under argon NaHCO3 (516 mg, 6.14 mmol), H2O (0.20 mL), and acryloyl chloride (0.026 mL, 0.32 mmol). The reaction mixture was stirred for 60 min at 0 °C. Then, LiOH (2 M in water, 4.91 mL, 9.83 mmol) was added and the mixture was stirred for 1 h at 0 °C until the disappearance (UPLC) of the side product resulting from the reaction of acryloyl chloride with NH indazole. A sat. aq. NaHCO3 solution was added, the layers were separated and the aqueous layer was extracted with CH2Cl2 (2x). The combined organic extracts were washed with a sat. aq. NaHCO3 solution, dried (Na2SO4), filtered and evaporated. The crude residue was purified by normal phase chromatography (eluent: MeOH in 0 to 9% CH2Cl2) to give 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en- 1-one.

[0418] Method-1c: Similar to Method-1 except that in Step-1 XPhos and XPhos-Pd-G2 were used instead of Ruphos and RuPhos-Pd-G3.

[0419] Method-1d: Similar to Method-1 except that in Step-1 dioxane was used instead of toluene.

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

[0421] Method-1f: Similar to Method-1 except that in Step-1 solid Na2CO3 (3 eq) was used instead of K3POh4 and H2O (10% v/v toluene) was also added.

[0422] Method-1j: Similar to Method-1 except that Step-3 was performed using Et3N and acryloyl chloride in CH2Cl2 in a similar manner as described in Method-9 Step-3.

[0423] Method-1k: Similar to Method-1 except that Step-3 was performed using iPr2NEt and acryloyl chloride in CH2Cl2 as described in Method-9 Step-3.

[0424] The following Examples 2 through 44 in Table 1 below were prepared using methods analogous to Method 1 from intermediates (in Step 1) described in the Synthesis of Intermediates section or commercially available. Table 1 Examples 45a/45b: 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-2'-(cyclopropylmethyl)-5-methyl-1H,2'H-[3,3'-bipyrazol]-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one

[0425] The title examples were prepared using the method similar to Method-1b steps 2 and 3 from tert-butyl 6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2'-(cyclopropylmethyl)-5-methyl- 1H,2'H-[3,3'-bipyrazol]-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (prepared as described below). The isomers were separated by chiral SFC (C-SFC-2; mobile phase: CO2/MeOH: 72/28) to give the title compound Example 45a as the second eluting peak: 1H NMR (400 MHz, 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, 1H), 4.36−4.21 (m, 3H), 4.09 (s, 1H), 4.00 (s, 1H), 2.90 - 2.78 (m, 4H), 2.47 (s, 3H), 2.04 (s, 3H), 1.32 - 1.22 (m, 1H), 0.49 - 0.29 (m, 4H); UPLC-MS-3: Rt = 0.97 min; MS m/z [M+H]+ 516.3/518.3; C-SFC-3 (mobile phase: CO2/MeOH: 72/28): Rt = 2.27 min. The other isomer Example 45b was obtained as the first eluting peak: C-SFC-3 (mobile phase: mobile phase: CO2/MeOH: 72/28): Rt = 1.19 min.

[0426] 6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-2'-(cyclopropylmethyl)-5 tert-butyl-methyl-1H,2'H-[3,3'-bipyrazol]-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate.

[0427] 6-(3-bromo-4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl- tert-butyl 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).CH2Cl2 adduct (38.5 mg, 0.047 mmol) were suspended in acetonitrile (2.25 mL). Aqueous Na2CO3 (2 M, 0.48 mL, 0.97 mmol) was added and the suspension was flushed with argon and subjected to microwave irradiations at 120 °C for 20 min. The reaction mixture was allowed to reach RT, diluted with EtOAc, a sat. aq. solution of NaHCO3 was added and the layers were separated. The aqueous layer was extracted with EtOAc (x2) and the combined organic extracts were washed with brine and dried (MgSO4), filtered and concentrated to half of the volume. SiliaMetS®Thiol (100 mg) was added and the mixture was stirred at RT for 15 min, filtered and concentrated. The crude residue was purified by normal flash column chromatography (eluent: EtOAc in c-hexane from 20 to 70 %) to generate the title compound. UPLC-MS-3: Rt = 1.28 min; MS m/z [M+H]+; 646.3/648.2. Examples 46a/46b: 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(pyridin-2-yl)-1H-pyrazol-1 -il)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one

[0428] The titled examples were prepared using the method similar to Method-1b steps 2 and 3 from 6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(pyridin-2-yl)-1H-pyrazol-1-yl)-2- tert-butyl azaspiro[3.3]heptane-2-carboxylate (prepared as described below). The isomers were separated by chiral SFC (C-SFC- 2; mobile phase: CO2/MeOH: 63/37) to give the title compound Example 46a as the first eluting peak: 1H NMR (400 MHz, DMSO-d6) δ 13.0 (s, 1H), 8.16 (d, 1H), 7.69 (t, 1H), 7.66 (d, 1H), 7.47 (s, 1H), 7.40 (s, 1H), 7.12 (t, 1H), 6.33 (m, 1H), 6.12 (m, 1H), 5.69 (m, 1H), 4.94 (m, 1H), 4.40 (s, 1H), 4.33 (s, 1H), 4.11 (s, 1H), 4.04 (s, 1H), 2.92 - 2.79 (m, 4H), 2.46 (s, 3H), 2.03 (s, 3H); UPLC-MS-3: Rt = 0.84 min; MS m/z [M+H]+ 473.2/475.2; C-SFC-3 (mobile phase: CO2/MeOH: 65/35): Rt = 0.97 min. The other isomer Example 46b was obtained as the second elution peak: C-SFC-3 (mobile phase: CO2/MeOH: 65/35): Rt = 3.28 min. tert-butyl 6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(pyridin-2-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0429] To a solution of 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- tert-butyl azaspiro[3.3]heptane-2-carboxylate (Intermediate C1, 1.35 g, 2.23 mmol) and bis(tri-t-butylphosphine)palladium (68 mg, 0.13 mmol) in THF (3 mL) placed under an argon atmosphere was added 2-pyridylzinc bromide (0.5 M in THF, 14.0 mL, 7.00 mmol). The reaction mixture was heated at 70 °C for 3 h. RM was poured into a sat. aq. solution of 1H 2O. NaHCO3 and extracted with EtOAc (x2). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. The crude residue was dissolved in THF (20 mL), SiliaMetS®Thiol (1.3 mmol) was added, and the mixture was stirred at RT for 1 h, filtered, and concentrated. The crude residue was purified by normal phase chromatography (eluent: MeOH in CH2Cl2 0–5%) to afford a mixture containing the desired material which was further purified by normal phase chromatography (eluent: EtOAc) to afford the title compound. UPLC-MS-3: Rt = 1.22 min; MS m/z [M+H]+; 603.3/605.2. Examples 47a /47b: 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(4-(hydroxymethyl)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one

[0430] To a solution of 4-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1-(2-azaspiro[3.3]heptan-6-yl)-1H-pyrazol-3-yl)benzyl acetate trifluoroacetate (prepared as described below, 0.7 mmol) in THF (12 mL) and water (0.3 mL) were successively added NaHCO3 (588 mg, 7.0 mmol) and acryloyl chloride (70 μL, 0.84 mmol), and the reaction mixture was stirred at RT for 2.5 h. LiOH was added (2 M, 3.50 mL, 7.00 mmol), and the RM was stirred at RT for 45 min until the disappearance (UPLC) of the by-product resulting from the reaction of acryloyl chloride with NH indazole. RM was diluted in water and extracted with EtOAc (x2). The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated. The crude residue was dissolved in THF (12 mL), LiOH (2 M, 3.50 mL, 7 mmol) was added and the reaction mixture was stirred at RT for 2 h. RM was diluted in water extracted with EtOAc (x2). The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated. The crude residue was purified by reversed-phase HPLC (RP-HPLC-1), the purified fractions were neutralized with a sat. aq. NaHCO3 solution and extracted with EtOAc. The organic extract was washed with brine, dried (Na2SO4), filtered and evaporated. The isomers were separated by chiral SFC (C-SFC-2; mobile phase: CO2/IPA: 70/30) to give the title compound Example 47a as the second eluting peak: 1H NMR (400 MHz, DMSO-d6) δ 13.12 (s, 1H), 7.54 (s, 1H), 7.40 (s, 1H), 7.19 (d, 2H), 7.08 (d, 2H), 6.32 (m, 1H), 6.11 (m, 1H), 5.68 (m, 1H), 5.08 (t, 1H), 4.89 (m, 1H), 4.39−4.37 (m, 3H), 4.32 (s, 1H), 4.10 (s, 1H), 4.02 (s, 1H), 2.91 - 2.76 (m, 4H), 2.48 (s, 3H), 2.01 (s, 3H); UPLC-MS- 3: Rt = 0.88 min; MS m/z [M+H]+ 502.1/504.1; C-SFC-3 (mobile phase: CO2/IPA: 70/30): Rt = 3.78 min. The other isomer Example 47b was obtained as the first eluting peak: C-SFC-3 (mobile phase: mobile phase: CO2/IPA: 70/30): Rt = 2.85 min. 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

[0431] The title compound was prepared using the similar method to Method-1 steps 1 and 2 from 6-(3-bromo-4-(5-chloro-6-methyl-1-(tetrahydro- 2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-1H-pyrazol-1-yl)-2- tert-butyl azaspiro[3.3]heptane-2-carboxylate (Intermediate C1) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate [56209808-2]; UPLC-MS-6: Rt = 0.80 min; MS m/z [M+H]+; 490.2/492.2. Example 48: 1-(4-(1-(2-acryloyl-2-azaspiro[3.3]heptan-6-yl)-4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1H-pyrazol-3-yl)benzyl)pyrrolidin-2-one

[0432] The title example was prepared using the method similar to Method-1b steps 2 and 3 from tert-butyl 6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-3-(4-((2-oxopyrrolidin-1-yl)methyl)phenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (prepared as described below). 1H NMR (400 MHz, DMSO-d) 9 (m, 1H), 4.37 (s, 1H), 4.31 (s, 1H), 4.25 (s, 2H), 4.09 (s, 1H), 4.02 (s, 1H), 3.14 (t, 2H), 2.93 - 2.73 (m, 4H), 2.47 (s, 3H), 2.24 (t, 2H), 2.00 (s, 3H), 1.87 (p, 2H); UPLC-MS-3: Rt = 0.92 min; MS m/z [M+H]+; 569.3/571.3. tert-butyl 6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-3-(4-((2-oxopyrrolidin-1-yl)methyl)phenyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0433] 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- tert-butyl carboxylate (Intermediate C1, 300 mg, 0.47 mmol) and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidin-2-one (Intermediate B2, 473 mg, 0.94 mmol) were suspended in DMF (3.95 mL). Aqueous K3PO4 (1 M, 0.94 mL, 0.942 mmol) and Pd(Ph3P)4 (27.2 mg, 0.024 mmol) were added, and the suspension was flushed with argon and subjected to microwave irradiations at 120 °C for 45 min. The reaction mixture was allowed to reach RT, diluted with EtOAc, a sat. aq. NaHCO3 solution was added, and the layers were separated. The aqueous layer was extracted with EtOAc (x2), and the combined organic extracts were washed with brine and dried (MgSO4), filtered, and concentrated. The crude residue was purified by normal flash column chromatography (eluent: (MeOH/CH2Cl2 9/1) in 0–50% CH2Cl2) to give the title compound. UPLC-MS-3: Rt = 1.22 min; MS m/z [M+H]+; 699.4/701.4. Examples 49a/49b: 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(3-methylpyridin-4-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one

[0434] The title examples were prepared using the method similar to Method-1b steps 2 and 3 from tert-butyl 6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-3-(3-methylpyridin-4-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (prepared as described below). The isomers were separated by chiral HPLC C-HPLC-23 (mobile phase: Hexane/IPA/ACN 60/28/12; flow rate: 20 mL/min; UV: 227 nM) to give the title compound Example 49a as the second elution peak: 1H NMR (400 MHz, DMSO-d6) δ 13.11 (s, 1H), 8.35 (s, 1H), 8.13 (d, 1H), 7.50 (s, 1H), 7.45 (s, 1H), 6.79 (d, 1H), 6.34 (m, 1H), 6.13 (m, 1H), 5.70 (m, 1H), 4.97 (m, 1H), 4.39 (s, 1H), 4.30 (s, 1H), 4.11 (s, 1H), 4.00 (s, 1H), 2.89 (m, 4H), 2.44 (s, 3H), 2.13 (s, 3H), 2.03 (s, 3H); LCMS-2: Rt = 1.39 min; MS m/z [M+H]+ = 487.9/490.0; C-HPLC-24 (mobile phase: 0.1% DEA in Hexane/IPA/ACN gradient; UV: 262 nM): Rt = 10.3 min. The other isomer Example 49b was obtained as the first elution peak: C-HPLC-24 (mobile phase: 0.1% DEA in Hexane/IPA/ACN gradient, UV: 262 nM): Rt = 8.98 min.

[0435] 6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-3-(3 tert-butyl-methylpyridin-4-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate.

[0436] 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-tert-butyl carboxylate (Intermediate C1, 0.40 g, 0.66 mmol), 3-picoline-4-boronic acid (0.27 g, 1.98 mmol), and K3PO4 (0.42 g, 1.98 mmol) were dissolved in t-BuOH:H2O (5:1) (24 mL) and the mixture was degassed with argon for 15 min. XPhos (0.094 g, 0.19 mmol) and Pd2dba3 (0.06 g, 0.07 mmol) were added and the reaction mixture was stirred at 120 °C for 4 h under sealed conditions. The reaction mixture was quenched with water and extracted with EtOAc (x3). The combined organic layers were washed with brine, dried (sodium sulfate), filtered, and concentrated in vacuo. The crude residue was purified by C18 reversed-phase chromatography (15 micron) (eluent: 0-68% CH3CN in H2O containing 0.1% HCOOH) to afford the desired product. LCMS-1: Rt = 1.82 min; MS m/z [M+H]+; 617.7/620.6. Examples 50a/50b: 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(4-(1,1-dioxidothiomorpholino)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one

[0437] The title examples were prepared using similar protocols as described for Examples 49a and 49b starting from Intermediate C1 and 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)thiomorpholine 1,1-dioxide (Intermediate B15). The isomers were separated by chiral HPLC C-HPLC-23 (mobile phase: MeOH:ACN (80:20); flow rate: 15 mL/min; UV: 270 nM) to give the title compound Example 50a as the first elution: 1H NMR (400 MHz, CDCl3) δ 10.12 (s, 1H), 7.55 (s, 1H), 7.42 (s, 1H), 7.34 (d, 2H), 6.73 (d, 2H), 6.42 (m, 1H), 6.29 (m, 1H), 5.75 (m, 1H), 4.79 (m, 1H), 4.41 (s, 1H), 4.38 (s, 1H), 4.27 (s, 2H), 3.80 (m, 4H), 3.15 (m, 2H), 3.05 (m, 4H), 2.86 (m, 2H), 2.60 (s, 3H), 2.09 (s, 3H); LCMS-2: Rt = 1.53 min; MS m/z [M+H]+: 605.5/607.5; C-SFC-19 (mobile phase: CO2/MeOH/ACN 55/22.5/22.5; UV: 270 nM): Rt = 6.77 min. The other isomer Example 50b was obtained as the second elution peak: C-SFC-19 (mobile phase: CO2/MeOH/ACN 55/22.5/22.5; UV: 270 nM): Rt = 10.8 min. Examples 51a/51b: 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(thiazol-4-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one

[0438] The title examples were prepared using the method similar to Method-1b steps 2 and 3 from tert-butyl 6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-3-(thiazol-4-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (prepared as described below). The isomers were separated by chiral HPLC C-HPLC-23 (mobile phase: [Hexane + 0.1% Et2NH]/[IPA + 0.1% Et2NH]/CH3CN (60/28/12); flow rate: 20 mL/min; UV: 216 nM) to give the title compound Example 51a as the first eluting peak: 1H NMR (400 MHz, DMSO-d6) δ 13.07 (s, 1H), 8.84 (s, 1H), 7.49 (s, 1H), 7.39 (s, 1H), 7.34 (s, 1H), 6.32 (m, 1H), 6.12 (m, 1H), 5.67 (m, 1H), 4.92 (m, 1H), 4.38 (s, 1H), 4.30 (s, 1H), 4.09 (s, 1H), 4.00 (s, 1H), 2.84 - 2.78 (m, 4H), 2.46 (s, 3H), 2.02 (s, 3H); LCMS-1: Rt = 1.49 min; MS m/z [M+H]+: 479.3/481.3; C-HPLC-24 (mobile phase: 0.1% DEA in Hexane/IPA/CH3CN gradient): Rt = 10.0 min. The other isomer Example 51b was obtained as the second elution peak: C-HPLC-24 (mobile phase: 0.1% DEA in Hexane/IPA/CH3CN gradient): Rt = 12.3 min.

[0439] 6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-3-(thiazole tert-butyl -4-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate.

[0440] 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-tert-butyl carboxylate (Intermediate C1, 0.30 g, 0.49 mmol), 4-(tributylstannyl)thiazole (0.28 g, 0.74 mmol), and anhydrous LiCl (0.03 g, 0.74 mmol) were suspended in dry toluene and the mixture was degassed with nitrogen for 10 min. The reaction mixture was then heated at 100 °C for 16 h under sealed tube conditions. The RM was filtered through a celite pad and washed with ethyl acetate. The filtrate was concentrated under vacuum and the crude residue was purified by C18 reverse phase chromatography (15 micron) (eluent: 0-100% CH3CN in H2O containing 0.1% HCOOH) to obtain the title product. LCMS-1: Rt = 2.06; 2.08 min; MS m/z [M+H]+: 609.8/611.8. Examples 52a/52b: 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(4-(2-hydroxyethoxy)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one Step 1: tert-butyl -(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-3-(4-(2-hydroxyethoxy)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0441] 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-tert-butyl carboxylate (Intermediate C1, 0.50 g, 0.83 mmol), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethan-1-ol (0.22 g, 0.83 mmol) and K3PO4 (0.52 g, 2.48 mmol) were added in 1,4-dioxane:H2O (2:1) (12 mL) and the mixture was degassed with nitrogen for 10 min. RuPhos (0.038 g, 0.08 mmol) and RuPhos-Pd-G3 (0.034 g, 0.08 mmol) were added, and the reaction mixture was stirred at 100 °C for 2 h. After completion of the reaction, RM was poured into water and extracted with EtOAc (x2). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by normal phase chromatography (eluent: 0–60% EtOAc in Hexane) to obtain the title product. LCMS-1: Rt = 2.05, 2.09 min; MS m/z [M+H]+: 662.7.3/664.7. Step 2: tert-butyl 6-(3-(4-(2-acetoxyethoxy)phenyl)-4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0442] 6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-3-(4-(2-hydroxyethoxy)phenyl)-5-methyl-1H-pyrazol-1-yl)-2- tert-butyl azaspiro[3.3]heptane-2-carboxylate (0.45 g, 0.68 mmol) was dissolved in CH2Cl2 (5 mL). Et3N (0.21 g, 2.03 mmol) was added, and the reaction mixture was cooled to 0 °C under a nitrogen atmosphere and stirred for 10 min. Acetyl chloride (0.08 g, 1.02 mmol) in CH2Cl2 (0.5 mL) was added dropwise, and the reaction mixture was stirred at RT for 2 h. After completion of the reaction, RM was diluted with CH2Cl2, washed with water, brine, dried (Na2SO4), filtered, and concentrated under vacuum to give the title product which was directly used in the next step without further purification. LCMS-1: Rt = 2.14, 2.16 min; MS m/z [M+H]+: 704.6/706.6. Step-3: 2-(4-(4-(5-Chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1-(2-azaspiro[3.3]heptan-6-yl)-1H-pyrazol-3-yl)phenoxy)ethyl acetate

[0443] 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- tert-butyl azaspiro[3.3]heptane-2-carboxylate (0.68 mmol) was dissolved in dry CH2Cl2 (5 mL) and cooled to 0 °C. TFA (6 mL) was added and the reaction mixture was stirred at room temperature for 5 h. After completion of the reaction, RM was concentrated under vacuum, co-distilled with CH2Cl2 several times to afford a crude residue which was purified by trituration with diethyl ether and filtration to obtain the desired product which was directly used in the next step without further purification. LCMS-1: Rt = 1.49 min; MS m/z [M+H]+: 520.4. Step-4: 2-(4-(1-(2-acryloyl-2-azaspiro[3.3]heptan-6-yl)-4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1H-pyrazol-3-yl)phenoxy)ethyl acetate

[0444] 2-(4-(4-(5-Chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1-(2-azaspiro[3.3]heptan-6-yl)-1H-pyrazol-3-yl)phenoxy)ethyl acetate (0.22 g, 0.42 mmol) was dissolved in THF (2 mL). NaHCO3 (0.35 g, 4.15 mmol) in water (2.5 mL) was added and the reaction mixture was stirred at RT for 10 min. The reaction mixture was cooled to 0 °C and a solution of acryloyl chloride (0.04 g, 0.46 mmol) in THF (0.5 mL) was added dropwise and stirred for 40 min. After completion of the reaction, RM was diluted with water and extracted with EtOAc (x2). The combined organic layers were washed with water, brine, dried (Na2SO4), filtered, and concentrated under vacuum. The crude residue was purified by reverse-phase chromatography on C18 silica gel (15 micron) (eluent: 0–43% CH3CN in H2O containing 0.1% NH3) to afford the desired product. The isomers were separated by chiral HPLC C-HPLC-23 (mobile phase: Hexane/IPA/ACN 70/21/9; flow rate: 18 mL/min; UV: 264 nM) to afford the title compound Isomer-I as the first eluting peak: LCMS-1: Rt = 1.63 min; MS m/z [M+H]+ 574.8; C-HPLC-29 (mobile phase: Hexane/IPA gradient): Rt = 11.8 min. The other isomer-II was obtained as the second elution peak: LCMS-1: Rt = 1.63 min; MS m/z [M+H]+: 574.8; C-HPLC-29 (mobile phase: Hexane/IPA gradient): Rt = 13.8 min. Step-5: Example 52a: 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(4-(2-hydroxyethoxy)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one

[0445] The title example was prepared using the similar method as described for the preparation of Example 52b 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-( 4-(2-hydroxyethoxy)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one (Step 6) starting to from 2-(4-(1-(2-acryloyl-2-azaspiro[3.3]heptan-6-yl)-4-(5-chloro-6-methyl-1H-indazol-4-yl)- acetate 5-methyl-1H-pyrazol-3-yl)phenoxy)ethyl Isomer-II instead of Isomer-I; LCMS-3: Rt = 3.30 min; MS m/z [M+H]+: 532/534; 1H NMR (400 MHz, CD3OD) δ 7.49 (s, 1H), 7.39 (s, 1H), 7.23 (d, 2H), 6.75 (d, 2H), 6.39 ( m, 1H), 6.28 (m, 1H), 5.77 (m, 1H), 5.01 (m, 1H), 4.48 (s, 1H), 4.42 (s, 1H), 4.24 (s, 1H), 4.19 (s, 1H), 3.96 (m, 2H), 3.82 (m, 2H), 3.05 (m, 2H), 2.88 (m , 2H), 2.55 (s, 3H), 2.09 (s, 3H); C-HPLC-29 (mobile phase: gradient [Hexane + 0.1% Et2NH]/[IPA + 0.1% Et2NH]): Rt = 11.2 min. Step-6: Example 52b: 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(4-(2-hydroxyethoxy)phenyl)-5-methyl- 1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one

[0446] 2-(4-(1-(2-Acryloyl-2-azaspiro[3.3]heptan-6-yl)-4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1H-pyrazol-3-yl)phenoxy)ethyl acetate (0.05 g, 0.08 mmol) Isomer-I was dissolved in MeOH (2.5 mL) and cooled to 0 °C. LiOH.H2O (1 M in water, 0.08 mL, 0.08 mmol) was added dropwise and the reaction mixture was stirred at RT for 1 h. After completion of the reaction, RM was diluted with water and extracted with EtOAc (x2). The combined organic layers were washed with water, brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by reverse-phase chromatography on C18 silica gel (15 microns) (eluent: 0-40% CH3CN in H2O containing 0.025% NH3) to afford the title product: C-HPLC-29 (mobile phase: gradient [Hexane + 0.1% Et2NH]/[IPA + 0.1% Et2NH]): Rt = 9.37 min. Example 53: 1-(6-(3-(6-(5-amino-1H-pyrazol-1-yl)pyridin-3-yl)-4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one

[0447] The title example was prepared using the method similar to Method-1b steps 2 and 3 from tert-butyl 6-(3-(6-(3-amino-1H-pyrazol-1-yl)pyridin-3-yl)-4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (prepared in 2 steps as described below). 1H NMR (400 MHz, DMSO-d) H); LCMS-1: Rt = 1.53 min; MS m/z [M+H]+: 554.8/556.8. tert-butyl 6-(3-(6-(3-amino-1H-pyrazol-1-yl)pyridin-3-yl)-4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate Step 1: tert-butyl 6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-3-(6-(3-nitro-1H-pyrazol-1-yl)pyridin-3-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0448] 6-(3-bromo-4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazol-4-yl)-5-methyl- tert-butyl 1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate C1, 0.50 g, 0.83 mmol), 2-(3-nitro-1H-pyrazol- 1-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Intermediate B16) (0.52 g, 1.65 mmol) and K3PO4 (0 .53 g, 2.48 mmol) were dissolved in 1,4-dioxane (4 mL) and H2O (2 mL). The reaction mixture was degassed with N2 for 5 min. Ruphos (0.04 g, 0.08 mmol) and Ruphos-Pd-G3 (0.035 g, 0.04 mmol) were added and the reaction mixture was stirred at 120 °C for 1 h. After completion of the reaction, RM was diluted with water and extracted with ethyl acetate (x2). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue The crude product was purified by normal phase chromatography (eluent: 30-40% EtOAc in Hexane) to obtain the desired product. LCMS-1: Rt = 2.24 min; MS m/z [M+H]+: 714. 6 /716.5. Step 2: 6-(3-(6-(3-amino-1H-pyrazol-1-yl)pyridin-3-yl)-4-(5-chloro-6-methyl-1-(tetrahydro-2H tert-butyl-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0449] 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- tert-butyl azaspiro[3.3]heptane-2-carboxylate (0.53 g, 0.7 mmol) was dissolved in dry IPA under a nitrogen atmosphere. Dry 10% Pd/C (0.25 g) was added and the reaction mixture was stirred under a H2 atmosphere (1 atm) at RT for 1 h. The RM was filtered through a celite pad, filtered and concentrated in vacuo to yield the desired product which was directly used in the next step without further purification. LCMS-1: Rt = 2.06, 2.09 min; MS m/z [M+H]+: 684.5/686.5. Method-2: Synthetic Scheme Examples 1a: a(R)-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one and 1b: a(S)-1-(6-(4-(5) -chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one

[0450] Alternatively, examples 1a and 1b can be prepared following the method described below: Step 1: tert-butyl 6-(5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2azaspiro[3.3]heptane-2-carboxylate

[0451] To a stirred solution of tert-butyl 6-(3-bromo-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate C3, 2.00 g, 5.61 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (1.59 g, 6.18 mmol) and K3PO4 (3.57 g, 16.8 mmol) in dioxane (20 mL) and H2O (4 mL) was added under argon atmosphere RuPhos (0.26 g, 0.56 mmol) and RuPhos-Pd-G3 (0.47 g, 0.56 mmol). The reaction mixture was stirred for 1 h at 100 °C. The reaction mixture was quenched by addition of sat. aq. NaHCO3 solution, extracted with EtOAc (2x), and the combined organic extracts were washed with sat. aq. NaHCO3 solution, dried (Na2SO4), and evaporated. The crude residue was purified by normal phase chromatography (eluent: 0–90% EtOAc in c-hexane) to give the title compound as a brown solid. UPLC-MS-3: Rt = 1.14 min; MS m/z [M+H]+: 408.2. Step 2: tert-butyl 6-(4-iodo-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0452] To a stirred solution of tert-butyl 6-(4-iodo-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (2.13 g, 5.23 mmol) in THF (50 mL) was added under argon atmosphere, NIS (1.53 g, 6.80 mmol) and the reaction mixture was stirred for 1 h at RT. The reaction mixture was quenched by addition of sat. aq. NaHCO3 solution, extracted with EtOAc (2x) and the combined organic extracts were washed with sat. aq. NaHCO3 solution, dried (Na2SO4), filtered and evaporated. The crude residue was purified by normal phase chromatography (eluent: 0-80% EtOAc in c-hexane) to give the title compound as a brown solid. UPLC-MS-3: Rt = 1.22 min; MS m/z [M+H]+: 534.1. Step 3: tert-butyl 6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0453] To a stirred solution of tert-butyl 6-(4-iodo-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (100 mg, 0.187 mmol), 5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (Intermediate D1, 85 mg, 0.225 mmol) and K3PO4 (119 mg, 0.56 mmol) in dioxane (2 mL) and H2O (0.50 mL) was added under an argon atmosphere RuPhos (8.75 mg, 0.019 mmol) mmol) and RuPhos-Pd-G3 (15.7 mg, 0.019 mmol). The reaction mixture was degassed with N2 and stirred for 1 h at 100 °C. The reaction mixture was quenched by addition of sat. aq. NaHCO3 solution, extracted with EtOAc (2x), and the combined organic extracts were washed with sat. aq. NaHCO3 solution, dried (Na2SO4), filtered, and evaporated. The crude residue was diluted in THF (3 mL), SiliaMetS®Thiol (0.076 mmol) (i.e., functionalized silica gel designed to remove metals from a reaction mixture) was added, and the mixture vortexed for 1 h at 40 °C. The mixture was filtered, the filtrate was concentrated, and the crude residue was purified by normal phase chromatography (eluent: EtOAc in c-hexane 0 to 100%) to give the title compound as a yellow solid. UPLC-MS-3: Rt = 1.25 min; MS m/z [M+H]+: 656.3/658.3.

[0454] Steps 4, 5 and chiral separation of isomers were performed as described in Method-1.

[0455] Method-2a: Similar to Method-2 except that Step-4 was performed using sulfuric acid in dioxane as described in Step-2 of Method-1a.

[0456] Method-2b: Similar to Method-2 except that Step-5 was performed using acryloyl chloride and NaHCO3 in THF/water as described in Step-3 of Method-1b.

[0457] Method-2c: Similar to Method-2 except that NBS was used instead of NIS in Step 2.

[0458] Method-2d: Similar to Method-2 except that Step-3 was performed using Et3N and acryloyl chloride in CH2Cl2 as described in Method-9 Step-3.

[0459] The following examples 54 to 58 in Table 2 below were prepared using methods analogous to Method-2 of intermediates (in Step 1 or 3) described in the synthesis of intermediates section or commercially available. Table 2 Examples 59a/59b: 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1H-pyrrolo[2,3-c]pyridin-2-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one

[0460] The title example was prepared using a method similar to Method-2a,b Steps 3-5 from tert-butyl 6-(4-bromo-5-methyl-3-(1H-pyrrolo[2,3-c]pyridin-2-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (prepared as described below). The isomers were separated by chiral SFC (C-SFC-7; mobile phase: CO2/[MeOH + 0.1% NEt3]: 50/50) to give the title compound Example 59a as the second eluting peak: 1H NMR (600 MHz, DMSO-d6) δ 13.20 (d, 1H), 11.68 (s, 1H), 8.71 (s, 1H), 7.92 (d, 1H), 7.63 (s, 1H), 7.50 (s, 1H), 7.20 (d, 1H), 6.52 (s, 1H), 6.41 − 6.28 (m, 1H), 6.17 − 6.02 (m, 1H), 5.74 − 5.61 (m, 1H), 5.06 - 4.87 (m, 1H), 4.42 (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 other 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. tert-Butyl 6-(4-bromo-5-methyl-3-(1H-pyrrolo[2,3-c]pyridin-2-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0461] To a stirred solution of tert-butyl 6-(4-bromo-3-iodo-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate C7, 400 mg, 0.83 mmol), (1H-pyrrolo[2,3-c]pyridin-2-yl)boronic acid (202 mg, 1.24 mmol) and potassium phosphate (2 M aq. solution, 1.24 mL, 2.48 mmol) in 1,4-dioxane (10 mL) was added tetrakis(triphenylphosphine)palladium (96 mg, 0.08 mmol). The reaction mixture was stirred at 90 °C for 1 h. Then, it was allowed to cool to RT, diluted with water (10 mL), and extracted twice with EtOAc. The combined organic layers were concentrated and the remaining crude material was purified by normal flash column chromatography (eluent: MeOH in CH2Cl2 0–5%) to give the title compound. UPLC-MS-4: Rt = 4.19 min; MS m/z [M+H]+: 472.0/474.0. Examples 60a/60b: 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-fluoro-4-(2-methoxyethoxy)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one

[0462] The title examples were prepared using a method similar to Method-2c starting from tert-butyl 6-(3-bromo-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate C3) and 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol with an additional alkylation step introduced between step 1 and step 2 (described below to prepare tert-butyl 6-(3-(2-fluoro-4-(2-methoxyethoxy)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate). 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 as the second eluting peak: 1H 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, 1H), 6.13–6.07 (m, 1H), 5.69–5.65 (m, 1H), 4.95–4.85 (m, 1H), 4.38 (s, 1H), 4.28 (s, 1H), 4.09 (s, 1H), 4.02 - 3.99 (m, 3H), 3.60 - 3.57 (m, 2H), 3.26 (s, 3H), 2.90 - 2.75 (m, 4H), 2.44 (s, 3H), 2.06 (s, 3H); UPLC-MS-3: Rt = 0.97 min; MS m/z [M+H]+ 564.5/566.5; C-SFC-3 (mobile phase: CO2/[IPA+NEt3 0.1%]: 70/30): Rt = 2.50 min. The other isomer Example 60b was obtained as the first eluting peak: C-SFC-3 (mobile phase: mobile phase: CO2/[IPA + 0.1% NEt3]: 70/30): Rt = 1.74 min. tert-Butyl 6-(3-(2-fluoro-4-(2-methoxyethoxy)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0463] A solution of tert-butyl 6-(3-(2-fluoro-4-hydroxyphenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Step 1, 710 mg, 1.65 mmol), 1-bromo-2-methoxyethane (0.310 mL, 3.30 mmol), and cesium carbonate (1075 mg, 3.30 mmol) in DMF (5 mL) was stirred at 60 °C for 2 h. The reaction mixture was diluted with EtOAc and water, extracted with EtOAc, the organic phase washed with brine, dried (phase separator), and concentrated under reduced pressure. The crude residue was purified by normal flash column chromatography (eluent: c-hexane/EtOAc 100/0 to 70/30 within 30 min) to give the title compound. UPLC-MS-3: Rt = 1.20 min; MS m/z [M+H]+ 446.3. Examples 61a/61b: 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-fluoro-4-((2-methoxyethyl)amino)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one

[0464] The title examples were prepared using a method similar to Method-2c starting from tert-butyl 6-(3-bromo-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate C3) and benzyl (3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate with an additional alkylation step introduced between Step 1 and Step 2, and an additional hydrogenation step introduced between Step 3 and Step 4, (described below to prepare 6-(3-(4-(((benzyloxy)carbonyl)(2-methoxyethyl)amino)-2- tert-butyl fluorophenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate and 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 tert-butyl-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate). 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 61a as the second eluting peak: 1H NMR (400 MHz, DMSO-d6) δ 12.96 (s, 1H), 7.42 (s, 1H), 7.34 (s, 1H), 6.94 (t, 1H), 6.35−6.25 (m, 2H), 6.15−6.07 (m, 2H), 5.86 (t, 1H), 5.69−5.64 (m, 1H), 4.91−4.81 (m, 1H), 4.37 (s, 1H), 4.28 (s, 1H); UPLC-MS-3: Rt = 0.94 min; MS m/z [M+H]+: 563.5/565.5; C-SFC-3 (mobile phase: CO2/[IPA + 0.025% NH3]: 70/30): Rt = 3.55 min. The other isomer Example 61b was obtained as the first eluting peak: C-SFC-3 (mobile phase: mobile phase: CO2/[IPA + 0.025% NH3]: 70/30): Rt = 2.55 min. tert-Butyl 6-(3-(4-(((benzyloxy)carbonyl)(2-methoxyethyl)amino)-2-fluorophenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0465] To a stirred solution of tert-butyl 6-(3-(4-(((benzyloxy)carbonyl)amino)-2-fluorophenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Step 1, 1.40 g, 2.55 mmol) in DMF (20 mL) was added sodium hydride (60% in mineral oil, 0.123 g, 3.07 mmol) under an inert atmosphere. After 15 min, 1-bromo-2-methoxyethane (1.20 mL, 12.8 mmol) was added and the reaction mixture was stirred at RT overnight. The reaction mixture was quenched with water, extracted with EtOAc, the organic phase was washed with brine, dried (phase separator) and concentrated under reduced pressure. The crude residue was purified by normal phase chromatography (eluent: c-hexane/EtOAc 100/0 to 70/30 within 30 min) to give the title compound. UPLC-MS-3: Rt = 1.30 min; MS m/z [M+H]+: 579.4. tert-butyl 6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-3-(2-fluoro-4-((2-methoxyethyl)amino)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0466] A solution of 6-(3-(4-(((benzyloxy)carbonyl)(2-methoxyethyl)amino)-2-fluorophenyl)-4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-1H-pyrazol-1-yl)-2- tert-butyl azaspiro[3.3]heptane-2-carboxylate (470 mg, 0.511 mmol) and palladium on carbon (5.44 mg, 0.051 mmol) in MeOH (10 mL) was stirred under a hydrogen atmosphere at RT for 0.5 h. The reaction mixture was filtered and concentrated under reduced pressure. The crude residue was purified by normal phase chromatography (eluent: c-hexane/EtOAc 100/0 to 0/100 within 30 min) to give the title compound. UPLC-MS-3: Rt = 1.25 min; MS m/z [M+H]+: 693.4/695.4. Method-3: Synthetic Scheme chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1H-pyrazol-3-yl)-N-(2-methoxyethyl)benzamide tert-butyl 2-carboxylate

[0467] A solution of 6-(3-bromo-4-(5-chloro-6-methyl-1-tosyl-1H-indazol-4-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2- tert-butyl carboxylate (Intermediate C6) (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), RuPhos (0.06 g, 0.13 mmol), RuPhos-Pd-G3 (0.10 g, 0.13 mmol), and potassium phosphate (2 N, 1.89 mL, 3.78 mmol) in dioxane (8 mL) was stirred at 80 °C for 1.5 h. The reaction mixture was cooled to RT, diluted with EtOAc and water, extracted with EtOAc, the combined organic phases washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude residue was purified by normal phase chromatography (eluent: c-hexane/EtOAc 100/0 to 50/50 within 30 min) to give the product with some impurity. A second purification was performed by normal phase chromatography (eluent: c-hexane/EtOAc 100/0 to 60/40 within 30 min) to yield the title compound (86% purity by UPLC) with some minor impurity. 1H NMR (600 MHz, DMSO-d) (m, 2H), 3.81 (s, 3H), 2.86 - 2.71 (m, 4H), 2.59 (s, 3H), 2.37 (s, 3H), 2.00 (s, 3H), 1.39 (s, 9H); UPLC-MS-10: Rt = 1.32 min; MS m/z [M+H]+: 730.2/732.2. Step 2: 4-(1-(2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptan-6-yl)-4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1H-pyrazol-3-yl)benzoic acid

[0468] A solution of 6-(4-(5-chloro-6-methyl-1-tosyl-1H-indazol-4-yl)-3-(4-(methoxycarbonyl)phenyl)-5-methyl-1H-pyrazol-1-yl)-2- tert-butyl azaspiro[3.3]heptane-2-carboxylate (Step 1, 100 mg, 0.14 mmol) and LiOH (2 N, 0.14 mL, 0.27 mmol) in THF (2 mL) was stirred at 20 °C for 2.5 h. The mixture was heated at 45 °C for 1.5 h, then at 70 °C for 2.5 h. After cooling to RT, the reaction mixture was lyophilized and the crude product used in the next reaction without further purification. UPLC-MS-10: Rt = 1.32 min; MS m/z [M+H]+: 562.2/564.2. Step 3: tert-butyl 6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(4-((2-methoxyethyl)carbamoyl)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0469] To a solution of 4-(1-(2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptan-6-yl)-4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1H-pyrazol-3-yl)benzoic acid (Step 2, 93 mg, 0.12 mmol) and DIPEA (0.10 mL, 0.59 mmol) in CH2Cl2/DMF (2.5 mL, 4/1 ratio) was added propylphosphonic anhydride (50% in EtOAc, 0.10 mL, 0.177 mmol) and the resulting solution was stirred at RT. After 10 min, 2-methoxyethan-1-amine (0.03 mL, 0.35 mmol) was added, and the reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated under reduced pressure, and the crude residue purified by normal phase chromatography (eluent: c-hexane/EtOAc 100/0 to 0/100 within 30 min) to give the title compound. 1H NMR (400MHz, DMSO-d6) .94 (br s, 2H), 3.42-3.36 (m, 4H), 3.23 (s, 3H), 2.86-2.75 (m, 4H), 2.49 (s, 3H), 2.02 (s, 3H), 1.40 (s, 9H); UPLC-MS-10: Rt = 1.09 min; MS m/z [M+H]+: 619.2/621.3. Step 4: 4-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1-(2-azaspiro[3.3]heptan-6-yl)-1H-pyrazol-3-yl)-N-(2-methoxyethyl)benzamide

[0470] To a solution of 6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(4-((2-methoxyethyl)carbamoyl)phenyl)-5-methyl-1H-pyrazol-1-yl)-2- tert-butyl azaspiro[3.3]heptane-2-carboxylate (Step 3, 109 mg, 0.14 mmol) in THF (2 mL) was added TFA (0.33 mL, 4.28 mmol) and the reaction mixture was stirred at RT for 3 h. The reaction mixture was concentrated under reduced pressure and the oily residue was dissolved in MeOH and placed in a Waters PoraPakTMRxn Cx cartridge previously washed with MeOH. After rinsing with MeOH the resin was rinsed with NH3 (7 N in MeOH), the basic MeOH solution was concentrated under reduced pressure to give the title compound which was used in the next reaction without further purification. UPLC-MS-6: Rt = 0.72 min; MS m/z [M+H]+: 519.2/521.2. Step 5: 4-(1-(2-acryloyl-2-azaspiro[3.3]heptan-6-yl)-4-(5-chloro-6-methyl- 1H-indazol-4-yl)-5-methyl-1H-pyrazol-3-yl)-N-(2-methoxyethyl)benzamide

[0471] To a solution of 4-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1-(2-azaspiro[3.3]heptan-6-yl)-1H-pyrazol-3-yl)-N-(2-methoxyethyl)benzamide (Step 4, 55 mg, 0.08 mmol) in THF (3 mL) was added sodium bicarbonate (0.80 mL, 0.40 mmol) followed directly by acryloyl chloride (6.54 μL, 0.08 mmol). The reaction mixture was stirred at 0 °C for 1 h. Excess acryloyl chloride was destroyed by addition of LiOH (2 N, 2 mL) and stirred at RT for 1 h. The reaction mixture was extracted with DCM, the organic phases dried (phase separator), concentrated under reduced pressure, and the crude residue purified by normal phase chromatography (eluent: DCM/MeOH 100/0 to 90/10 within 30 min) to give the title compound. The isomers were separated by chiral SFC (C-SFC-2; mobile phase: CO2/IPA: 65/35) to give the title compound Example 62a as the second eluting isomer (white powder): 1H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.35 (t, 1H), 7.63 (d, 2H), 7.57 (s, 1H), 7.44 (s, 1H), 7.31 (d, 2H), 6.37–6.30 (m, 1H), 6.15–6.09 (m, 1H), 5.71–5.67 (m, 1H), 4.98–4.88 (m, 1H), 4.40 (s, 1H), 4.34 (s, 1H), 4.11 (s, 1H), 4.04 (s, 1H), 3.35-3.32 (m, 4H), 3.22 (s, 3H), 2.94-2.78 (m, 4H), 2.04 (s, 3H); UPLC-MS-10: Rt = 0.88 min; MS m/z [M+H]+ 573.3/575.3; C-SFC-3: (mobile phase: CO2/IPA: 65/35): Rt = 2.14 min. The other isomer Example 62b was obtained as the first eluting peak: C-SFC-3: (mobile phase: CO2/IPA: 65/35): Rt = 1.28 min. Method-3a: Similar to Method-3 except that in Step-2 2N NaOH was used instead of 2N LiOH.

[0472] The following Examples 63 through 65 in Table 3 were prepared using methods analogous to Method-3, using the appropriate commercially available pinacol (Step 1) and amine reagents (Step 3). Table 3 Examples 66a/66b: 4-(1-(2-acryloyl-2-azaspiro[3.3]heptan-6-yl)-4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1H-pyrazol-3-yl)-N-(2-methoxyethyl)-N-methylbenzamide Step 1: 6-(3-(4-(methoxycarbonyl)phenyl tert-butyl )-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0473] A solution of 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-1,3,2-dioxaborolan-2-yl)benzoate (1.33 g, 5.09 mmol), RuPhos (0.198 g, 0.42 mmol), RuPhos-Pd-G3 (0.355 g, 0.42 mmol), and potassium phosphate (2 N, 6.36 mL, 12.7 mmol) in dioxane (20 mL) was stirred at 80 °C for 15 min. After cooling to RT, the reaction mixture was added to sat. NaHCO3 aq., extracted with EtOAc and the organic phase washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude residue was purified by normal phase chromatography (eluent: c-hexane/EtOAc 100/0 to 70/30 within 30 min) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 7.99 (d, 2H), 7.91 (d, 2H), 6.60 (s, 1H), 4.80–4.72 (m, 1H), 3.99 (s, 2H), 3.90 (s, 2H), 3.87 (s, 3H), 2.75–2.65 (m, 4H), 2.27 (s, 3H), 1.39 (s, 9H); UPLC-MS-6: Rt = 1.23 min; MS m/z [M+H]+: 412.3. Step 2: tert-butyl 6-(4-bromo-3-(4-(methoxycarbonyl)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0474] To a solution of tert-butyl 6-(3-(4-(methoxycarbonyl)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Step 1, 1.76 g, 4.15 mmol) in CH3CN (45 mL) was added NBS (0.724 g, 4.07 mmol) and the reaction mixture was stirred at RT for 0.5 h. The reaction mixture was concentrated under reduced pressure, and the crude residue was purified by normal phase chromatography (eluent: c-hexane/EtOAc 100/0 to 70/30 within 30 min) to obtain the title compound. 1H NMR (400 MHz, 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), (s, 9H); UPLC-MS-6: Rt = 1.31 min; MS m/z [M+H]+: 490.1/492.1. Step 3: 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-tert-butyl 2-carboxylate

[0475] A solution of tert 6-(4-bromo-3-(4-(methoxycarbonyl)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate -butyl (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-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 (2 N, 3.00 mL, 6.00 mmol) in dioxane (10 mL) was stirred at 80 °C for 15 min. After cooling to RT, the reaction mixture was added to sat. aq. NaHCO3, extracted with EtOAc and the organic phase washed with brine, dried (Na2SO4) filtered and concentrated under reduced pressure. The crude residue was dissolved in THF (20 mL), SiliaMetS®Thiol (0.60 mmol, 0.84 g) was added and the mixture was vortexed at 50 °C for 0.5 h on a rotavapor. The mixture was filtered, washed with MeOH and the filtrate was concentrated under reduced pressure to give crude product which was purified by normal phase chromatography (eluent: c-hexane/EtOAc 100/0 to 60 /40 within 30 min) to generate the title compound as a colorless foam. UPLC-MS-6: Rt = 1.31 min; MS m/z [M+H]+: 660.2/662.2. Step 4: 4-(1-(2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptan-6-yl)-4-(5-chloro-6-methyl-1-(tetrahydro-2H) acid -pyran-2-yl)-1H-indazol-4-yl)-5-methyl-1H-pyrazol-3-yl)benzoic acid

[0476] A solution of 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- tert-butyl azaspiro[3.3]heptane-2-carboxylate (Step 3, 1.42 g, 1.99 mmol) and NaOH (2 N, 1.00 mL, 2.00 mmol) in dioxane (10 mL) was stirred at 60 °C for 15 min. More NaOH (2 N, 1.00 mL, 2.00 mmol) was added and the reaction mixture was stirred at RT overnight, then the reaction mixture was heated at 60 °C for 3 h. The reaction mixture was lyophilized and the crude product used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.78 (br s, 1H), 7.64 - 7.60 (m, 2H), 7.47 (s, 0.5H), 7.45 (s, 0.5H), 7.16 - 7.13 (m, 2H), 5.85 - 5.80 (m, 1H), - 4.83 (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. Step 5: 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-tert-butyl carboxylate

[0477] To a solution of 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-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) in CH2Cl2 (3 mL) was added propylphosphonic anhydride (50% in EtOAc, 0.27 mL, 0.46 mmol). Then, DIPEA (0.27 mL, 1.53 mmol) was added and the mixture stirred at RT for 5 h. The reaction mixture was concentrated under reduced pressure and the crude residue purified by normal phase chromatography (eluent: c-hexane/EtOAc 100/0 to 0/100 within 30 min) to give the title compound. - 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 - 1.96 (m, 5H), 1.73 (m, 1H), 1.62 - 1.55 (m, 2H), 1.40 (s, 9H); UPLC-MS-11: Rt = 1.24 min; MS m/z [M+H]+: 717.5/719.5. Step 6: 4-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1-(2-azaspiro[3.3]heptan-6-yl)-1H-pyrazol-3-yl)-N-(2-methoxyethyl)-N-methylbenzamide

[0478] To a solution of 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 (Step 5, 168 mg, 0.23 mmol) in CH2Cl2 (2 mL) was added TFA (0.52 mL, 6.82 mmol) and the reaction mixture was stirred at RT for 4 h. The reaction mixture was concentrated under reduced pressure, the residue 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 = 0.73; MS m/z [M+H]+: 533.3/535.3. Step 7: 4-(1-(2-acryloyl-2-azaspiro[3.3]heptan-6-yl)-4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1H-pyrazol-3-yl)-N-(2-methoxyethyl)-N-methylbenzamide

[0479] To a solution of 4-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl- 1-(2-azaspiro[3.3]heptan-6-yl)-1H-pyrazol-3-yl)-N-(2-methoxyethyl)-N-methylbenzamide (0.23 mmol) and acrylic acid (0.016 mL, 0.23 mmol) in CH2Cl2 (3 mL) was added propylphosphonic anhydride (50% in EtOAc, 0.20 mL, 0.34 mmol). Then, DIPEA (0.198 mL, 1.13 mmol) was added and the reaction mixture stirred at RT for 1.25 h. The reaction was quenched by addition of MeOH, the reaction mixture was concentrated under reduced pressure, and the crude residue was purified by normal phase chromatography (eluent: DCM/MeOH 100/0 to 80/20 within 30 min) to give the title compound. The isomers were separated by chiral SFC (C-HPLC- 11: mobile phase: n-heptane/IPA + 0.1% NEt3: 55/45) to give the title compound Example 66a as the second eluting peak: 1H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 7.57 (s, 1H), 7.45 (s, 1H), 7.30 (d, 2H), 7.18 (d, 2H), 6.37−6.30 (m, 1H), 6.15−6.09 (m, 1H), 5.71−5.67 (m, 1H), 4.98−4.88 (m, 1H), 4.40 (s, 1H), 4.33 (s, 1H), 4.11 (s, 1H), 4.04 (s, 1H), 3.55 - 3.46 (m, 5H), 3.09 (br s, 2H), 2.91 - 2.81 (m, 6H), 2.03 (s, 3H); UPLC-MS-3: Rt = 0.89 min; MS m/z [M+H]+: 587.3/589.3; C-HPLC-13 (mobile phase: n-heptane/[IPA + 0.1% DEA]: 55/45): Rt = 10.39 min. The other isomer Example 66b was obtained as the first elution peak: C-HPLC- 13 (mobile phase: n-heptane/[IPA + 0.1% DEA]: 55/45): Rt = 6.83 min.

[0480] The following Examples 67 to 68 in Table 4 below were prepared by analogy to Method-4, using the suitable commercial amine (suitable 5) or proceeding with the acid. Table 4 Method-5: Synthetic scheme Examples 69a/69b: 1-(6-(4-(3-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-methoxyethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one Step 1: tert-butyl -(2-methoxyethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0481] A solution of 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-indazole (Intermediate B22, 2.09 g, 6.95 mmol), RuPhos (0.22 g, 0.46 mmol), RuPhos-Pd-G3 (0.39 g, 0.46 mmol) and potassium phosphate (2 N, 6.95 mL, 13.9 mmol) in dioxane (22 mL) was stirred at 80 °C for 15 min. After cooling to RT, the reaction mixture was extracted with EtOAc, the organic phase washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude residue was purified by normal phase chromatography (eluent: c-hexane/EtOAc 100/0 to 50/50 within 30 min) to afford the title compound. 1H NMR (400 MHz, DMSO-d) ), 3.91 (s, 2H), 3.83 (t, 2H), 3.24 (s, 3H), 2.76 - 2.63 (m, 4H), 2.25 (s, 3H), 1.39 (s, 9H); UPLC-MS-3: Rt = 1.07 min; MS m/z [M+H]+: 452.3. Step 2: tert-butyl 6-(4-bromo-3-(2-(2-methoxyethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0482] To a solution of tert-butyl 6-(3-(2-(2-methoxyethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Step 1, 2.02 g, 4.20 mmol) in THF (30 mL) was added NBS (0.73 g, 4.12 mmol) and the reaction mixture stirred at RT for 40 min. Additional NBS (75 mg, 0.42 mmol) was added and the mixture was stirred at RT for an additional 10 min. The reaction mixture was concentrated under reduced pressure and the crude residue purified by normal phase chromatography (eluent: c-hexane/EtOAc 100/0 to 20/80 within 30 min) to give the title compound. 1H NMR (400 MHz, DMSO-d) (t, 2H), 3.24 (s, 3H), 2.75 - 2.64 (m, 4H), 2.28 (s, 3H), 1.38 (s, 9H); UPLC-MS-3: Rt = 1.14 min; MS m/z [M+H]+: 530.2/532.2. 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-indazol-1-carboxylate

[0483] A solution of 6-(4-bromo-3-(2-(2-methoxyethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[ 3.3] tert-butyl heptane-2-carboxylate (Step 2, 0.77 g, 1.46 mmol), 3-amino-5-chloro-6-methyl-4-(4,4,5,5-tetramethyl tert-butyl -1,3,2-dioxaborolan-2-yl)-1H-indazol-1-carboxylate (Intermediate D6, 0.74 g, 1.82 mmol), RuPhos (0.085 g, 0.18 mmol) , RuPhos-Pd-G3 (0.152 g, 0.18 mmol) and potassium phosphate (2 N, 2.73 mL, 5.46 mmol) in dioxane (10 mL) was stirred at 80 °C for 2.25 h. The reaction mixture was extracted with EtOAc, the organic phase washed with sat. aq. NaHCO3 and brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was dissolved in THF (20 mL), SiliaMetS®Thiol (0.65 mmol) was added and the mixture was vortexed for 0.5 h at 50 °C. The The mixture was filtered, the resin was washed with MeOH, and the filtrate was concentrated under reduced pressure. The crude residue was purified by normal phase chromatography (eluent: c-hexane/EtOAc 100/0 to 0/100 within 30 min) to give the title compound. UPLC- MS-5: Rt = 1.37 min; MS m/z [M+H]+: 731.5/733.4. Step 4: 5-chloro-4-(3-(2-(2-methoxyethyl)-2H-indazol-5-yl)-5-methyl-1-(2-azaspiro[3.3]heptan-6-yl)- 1H-pyrazol-4-yl)-6-methyl-1H-indazol-3-amine

[0484] To a solution of 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 (Step 1, 181 mg, 0.25 mmol) in DCM (2 mL) was added TFA (0.38 mL, 4.95 mmol) and the reaction mixture was stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure and dried under high vacuum overnight to give the title compound as a trifluoroacetate salt which was used without purification in the next step. UPLC-MS-5: Rt = 0.58 min; MS m/z [M+H]+; 531.3/533.3. Step 5: 1 -(6-(4-(3-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-methoxyethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one

[0485] To a solution of acrylic acid (0.022 mL, 0.32 mmol) and propylphosphonic anhydride (50% in EtOAc, 0.19 mL, 0.32 mmol) in CH2Cl2 (1.5 mL) was added DIPEA (0.21 mL, 1.22 mmol). Then, this solution was added dropwise to a solution of 5-chloro-4-(3-(2-(2-methoxyethyl)-2H-indazol-5-yl)-5-methyl-1-(2-azaspiro[3.3]heptan-6-yl)-1H-pyrazol-4-yl)-6-methyl-1H-indazol-3-amine trifluoroacetic acid salt (0.24 mmol) in CH2Cl2 (2 mL). The reaction mixture was stirred at RT for 2.5 h. The RM was quenched with lithium hydroxide (2 N, 0.61 mL, 1.22 mmol), stirred for 30 min, diluted with DCM, washed with sat. aq. NaHCO3, the organic phase dried (phase separator), and concentrated under reduced pressure. The crude residue was purified by normal phase chromatography (eluent: DCM/MeOH 100/0 to 90/10 within 30 min) to give the title compound. The isomers were separated by chiral SFC (C-SFC-5; mobile phase: CO2/[MeOH + 0.1% NEt3]: 60/40) to give the title compound Example 69a as the first eluting peak: 1H NMR (400 MHz, DMSO-d6) δ 11.60 (s, 1H), 8.18 (s, 1H), 7.44−7.43 (m, 3H), 7.28 (d, 1H), 6.36−6.28 (m, 1H), 6.13−6.08 (m, 1H), 5.70−5.66 (m, 1H), 4.96−4.86 (m, 1H), 4.47 (t, 2H), 4.38 (s, 1H), 4.32 (s, 1H), 4.10 - 4.08 (m, 3H), 4.03 (s, 1H), 3.76 (t, 2H), 3.19 (s, 3H), 2.94 - 2.77 (m, 4H), 2.44 (s, 3H), 1.99 (s, 3H); UPLC-MS-5: Rt = 0.83 min; MS m/z [M+H]+: 585.4/587.4; C-SFC-6: (mobile phase: CO2/[MeOH + 0.1% NH3]: 60/40): Rt = 2.64 min. The other isomer Example 69b was obtained as the second elution peak: C-SFC-6: (mobile phase: CO2/[MeOH + 0.1% NH3]: 60/40): Rt = 3.50 min. Examples 70a/70b: 1-(6-(4-(3-amino-5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-phenyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one

[0486] The title examples were prepared using a method similar to Method-5 starting from phenylboronic acid instead of 2-(2-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole in Step 1. The isomers were separated by chiral SFC (C-SFC-5; mobile phase: CO2/IPA: 50/50) to give the title compound Example 70a as the first eluting peak: 1H NMR (400 MHz, DMSO-d6) δ 11.61 (s, 1H), 7.35-7.32 (m, 2H), 7.27 (d, 1H), 7.21-7.14 (m, 3H), 6.36-6.28 (m, 1H), 6.13 - 6.07 (m, 1H), 5.70 - 5.65 (m, 1H), 4.96 - 4.86 (m, 1H), 4.38 (s, 1H), 4.31 (s, 1H), 4.08 (s, 1H), 4.02 (s, 1H), 2.92 - 2.76 (m, 4H), 2.43 (s, 3H), 1.98 (s, 3H); UPLC-MS-9: Rt = 0.98 min; MS m/z [M+H]+: 487.3/489.3; C-SFC-6: (mobile phase: CO2/IPA: 50/50): Rt = 1.80 min. The other isomer Example 70b was obtained as the second elution peak: C-SFC-6: (mobile phase: CO2/IPA: 50/50): Rt = 2.55 min. Method-6: Synthetic scheme Examples 71a/71b: 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(cinolin-6-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one or 1-{6-[4-(5-chloro-6-methyl-1H-indazol- 4-yl)-3-(cinolin-6-yl)-5-methyl-1H- pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl}prop-2-en-1-one Step 1: 6-(5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- tert-butyl pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate, (1-(2-(tert-butoxycarbonyl)-2-azaspiro[3.3]heptan-6-yl)-5-methyl-1H-pyrazol-3-yl)boronic acid

[0487] In an ace tube, a solution of tert-butyl 6-(3-bromo-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate C3, 5 g, 14.0 mmol), bis-(pinacolato)-diboron (5.35 g, 21.0 mmol), PdCl2(dppf).CH2Cl2 adduct (1.15 g, 1.40 mmol), and potassium acetate (3.44 g, 35.1 mmol) in 1,4-dioxane (62.4 mL) was stirred at 100 °C overnight under a nitrogen atmosphere. The reaction mixture was poured into a sat. aq. solution of NaHCO 3.0. NaHCO3, extracted with EtOAc (3x) and the combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated to give the title compound as a dark solid which was used without purification in the next step. UPLC-MS-3: Rt = 0.91 min; MS m/z [M+H]+ 322.1 Step 2 tert-butyl 6-(3-(cynolin-6-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0488] In a microwave vial 6-(5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)-2- tert-butyl azaspiro[3.3]heptane-2-carboxylate (Step 1, 1.50 g, 1.86 mmol), 6-bromocinoline (0.53 g, 2.42 mmol), RuPhos-Pd-G3 (0.16 g, 0.19 mmol), and RuPhos (0.087 g, 0.19 mmol) were dissolved in toluene (16.3 mL) and potassium phosphate (2 M, 2.79 mL, 5.58 mmol) was added. The reaction mixture was placed under a nitrogen atmosphere and heated at 120 °C under microwave irradiations for 1 h. The reaction mixture was poured into a sat. aq. NaHCO3 solution, extracted with EtOAc (x3), and the combined organic extracts were dried (phase separator) and concentrated. The crude residue was diluted in THF (6 mL), SiliaMetS®Thiol (0.8 mmol) was added, and the mixture was vortexed for 1 h at 40 °C. The mixture was filtered, the filtrate was concentrated, and the crude residue was purified by normal phase chromatography (eluent: MeOH in CH2Cl2 0–10%), the purified fractions were further purified by normal phase chromatography (eluent: EtOAc in c-hexane 0–100%) to give the title compound as a brownish foam. UPLC-MS-3: Rt = 1.04 min; MS m/z [M+H]+ 406.3 Step 3: tert-butyl 6-(3-(cinolin-6-yl)-4-iodo-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0489] To an ice-cooled solution of tert-butyl 6-(3-(cynolin-6-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Step 2, 672 mg, 1.66 mmol) in THF (17.4 mL) was added NIS (1.49 g, 6.63 mmol) and the reaction mixture was stirred under nitrogen while allowed to slowly reach RT. After 19 h, NIS (746 mg, 3.31 mmol) was added and the reaction mixture was stirred again for 50 h. NIS (373 mg, 1.66 mmol) was added again and the reaction mixture was further stirred for 20 h. The reaction mixture was poured into 10% Na2S2O3 solution, extracted with CH2Cl2 (x2), and the combined organic extracts were washed with sat. aq. NaHCO3 solution, dried (phase separator), and concentrated. The crude residue was purified by normal-phase flash chromatography (eluent: MeOH in CH2Cl2 0–5%) to give the title compound as a brownish foam. UPLC-MS-3: Rt = 1.12 min; MS m/z [M+H]+ 532.2 Step 4: 6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-3-(cinolin-6-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-tert-butyl carboxylate

[0490] In an Ace tube were placed under a nitrogen atmosphere, 6-(3-(cynolin-6-yl)-4-iodo-5-methyl-1H-pyrazol-1-yl)-2- tert-butyl azaspiro[3.3]heptane-2-carboxylate (Step 3, 910 mg, 1.71 mmol), 5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (Intermediate D1, 774 mg, 2.05 mmol), RuPhos (80 mg, 0.17 mmol), RuPhos-Pd-G3 (143 mg, 0.17 mmol) in dioxane (15 mL). K3PO4 (1.5 M, 3.42 mL, 5.14 mmol) was added and the reaction mixture was heated at 80 °C for 2 h. The reaction mixture was poured into sat. aq. NaHCO3 solution, extracted with EtOAc (3x), and the combined organic extracts were dried (phase separator) and concentrated. The crude residue was diluted in THF (15 mL), SiliaMetS®Thiol (0.73 mmol) was added, and the mixture was vortexed for 1 h at 40 °C. The mixture was filtered, the filtrate was concentrated, and the crude residue was purified by normal phase chromatography (eluent: 0–100% EtOAc in c-hexane) to give the title compound as a pale yellow foam. UPLC-MS-3: Rt = 1.19 min; MS m/z [M+H]+; 654.3/656.3. Step 5 6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1-(2-azaspiro[3.3]heptan-6-yl)-1H-pyrazol-3-yl)cinoline

[0491] To a solution of 6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-3-(cynolin-6-yl)-5-methyl-1H-pyrazol-1-yl)-2- tert-butyl azaspiro[3.3]heptane-2-carboxylate (Step 4, 806 mg, 1.21 mmol) in CH2Cl2 (9 mL) was added TFA (2.79 mL, 36.2 mmol) and the reaction mixture was stirred at RT for 16 h. The reaction mixture was concentrated to give the title compound as a trifluoroacetate salt which was used without purification in the next step. UPLC-MS-3: Rt = 0.69 min; MS m/z [M+H]+; 470.2/472.2. Step 6: 1 -(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(cinolin-6-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one

[0492] A mixture of acrylic acid (0.11 mL, 1.61 mmol), propylphosphonic anhydride (50% in EtOAc, 0.95 mL, 1.61 mmol), and DIPEA (2.81 mL, 16.1 mmol) in CH2Cl2 (15 mL) was stirred at RT for 15 min. This solution was added to a solution of 6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1-(2-azaspiro[3.3]heptan-6-yl)-1H-pyrazol-3-yl)cinnoline trifluoroacetate (Step 5, 1.07 mmol) in CH2Cl2 (7.5 mL) and the reaction mixture was stirred at RT for 30 min. The reaction mixture was poured into a sat. aq. NaHCO3, extracted with CH2Cl2 (2x) and the combined organic layers were dried (phase separator) and concentrated. The crude residue was purified by normal phase chromatography (eluent: MeOH in CH2Cl2 0–10%) to give a mixture of the expected compound and a side product resulting from the addition of acrylamide in indazole. The mixture was diluted with THF (15 mL) and LiOH (2 M, 5.35 mL, 10.7 mmol) was added. The solution was stirred at RT for 30 min and poured into a sat. aq. NaHCO3 solution, then extracted with EtOAc (3x) and the combined organic extracts were dried (phase separator) and concentrated. The residue was purified by normal phase chromatography (eluent: MeOH in CH2Cl2 0–10%) to give the title compound. The isomers were separated by chiral SFC (C-SFC-1; mobile phase: CO2/[0.1% EtOH + Et3N]: 75/25) to give the title compound Example 71a as the second eluting peak (white powder): 1H NMR (600 MHz, DMSO-d6) δ 13.1 (s, 1H), 9.23 (d, 1H), 8.25 (d, 1H), 7.97 (d, 1H), 7.84 (s, 1H), 7.80 (d, 1H), 6.61 (s, 1H), 7.50 (s, 1H), 6.33 (m, 1H), 6.12 (m, 1H), 5.68 (m, 1H), 4.99 (m, 1H), 4.41 (s, 1H), 4.34 (s, 1H), 4.12 (s, 1H), 4.05 (s, 1H), 2.99-2.80 (m, 4H), 2.08 (s, 3H); UPLC-MS-4: Rt = 3.88 min; MS m/z [M+H]+ 524.3/526.3; C-SFC- 3 (mobile phase: CO2/[0.1% EtOH + Et3N]: 70/30): Rt = 2.29 min. The other isomer Example 71b was obtained as the first eluting peak: C-SFC- 3 (mobile phase: CO2/[0.1% EtOH + Et3N]: 70/30): Rt = 1.91 min.

[0493] Method-6a: Similar to Method-6 except that in Step-2 dioxane was used instead of toluene.

[0494] Method-6b: Similar to Method-6 except that in Step-3 NBS (1.1 eq.) in acetonitrile was used instead of NIS in THF to prepare the corresponding 4-bromo-pyrazole.

[0495] Method-6c: Similar to Method-6 except that Step-5 was performed using H2SO4 in dioxane as described in Method-1a Step-2.

[0496] Method-6d: Similar to Method-6 except that Step-6 was performed using NaHCO3, acryloyl chloride, H2O and THF as described in Method-1b Step-3.

[0497] The following examples 72 through 77 in Table 5 below were prepared using methods analogous to Method-6 from intermediates (in Step 2) described in the intermediate synthesis section or commercially available. Table 5 Example 78a: 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(6-methoxypyridin-3-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one Step 1: 6-(4-(5-chloro-6-methyl-1-tosyl-1H tert-butyl-indazol-4-yl)-3-(6-methoxypyridin-3-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0498] In a 20 mL microwave vial, under an argon atmosphere, was placed 6-(3-bromo-4-(5-chloro-6-methyl-1-tosyl-1H-indazol-4-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-tert-butyl carboxylate (Intermediate C6, 350 mg, 0.51 mmol), 2-methoxypyridine-5-boronic acid pinacol ester (373 mg, 1.54 mmol), and Na2CO3 (2 M, 0.80 mL, 1.60 mmol) in 1,4-dioxane (5 mL), Pd(PPh3)4 (59.3 mg, 0.05 mmol) was added. The vial was sealed and the reaction mixture was heated at 100 °C for 3.5 h. 2-Methoxypyridine-5-boronic acid pinacol ester (181 mg, 0.77 mmol) and Pd(PPh3)4 (59.3 mg, 0.05 mmol) were added again and the RM further stirred at 100 °C for 2 h. The reaction mixture was poured into water, extracted with EtOAc (2x) and the combined organic extracts were dried (phase separator) and concentrated. The crude residue was diluted in THF, SiliaMetS®Thiol (0.91 mmol) was added and the mixture vortexed for 1 h at 40 °C. The mixture was filtered, the filtrate was concentrated, and the crude residue was purified by normal phase chromatography (eluent: EtOAc in heptane 0-60%) to give the title compound as white foam. UPLC-MS-1: Rt = 1.51 min; MS m/z [M+H]+: 703.2/705.2. Step 2: tert-butyl 6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(6-methoxypyridin-3-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0499] To a solution of tert-butyl 6-(4-(5-chloro-6-methyl-1-tosyl-1H-indazol-4-yl)-3-(6-methoxypyridin-3-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Step 1, 295 mg, 0.37 mmol) in 1,4-dioxane (3.5 mL) was added NaOH (0.99 mL, 1.99 mmol) and the reaction mixture was stirred at 75 °C for 1.5 h. The RM was poured into water and extracted with EtOAc (2x). The combined organic extracts were washed with brine, dried (phase separator), and concentrated. The crude residue was purified by normal phase chromatography (eluent: (MeOH/CH2Cl2 (1/9)) in CH2Cl2 from 0 to 100%) to give the title compound as white solid. The isomers were separated by chiral HPLC (C-SFC-7; mobile phase: CO2/IPA 73/27) to give first eluting isomer 6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(6-methoxypyridin-3-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane- tert-butyl 2-carboxylate (white powder); C-SFC-8 (mobile phase: CO2/IPA 73/27): Rt = 2.21 min and second elution isomer 6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(6-methoxypyridin-3-yl)-5-methyl-1H-pyrazol-1-yl)-2- azaspiro[3.3]heptane-2-carboxylate c-butyl; C-SFC-8 (mobile phase: CO2/IPA 73/27): Rt = 3.21 min. UPLC-MS-1: Rt = 1.27 min; MS m/z [M+H]+; 549.2/551.2. Step 3: 5-chloro-4-(3-(6-methoxypyridin-3-yl)-5-methyl-1-(2-azaspiro[3.3]heptan-6-yl)-1H-pyrazol-4-yl)-6-methyl-1H-indazole

[0500] A solution of the second eluting isomer 6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(6-methoxypyridin-3-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl (Step 2, 68 mg, 0.12 mmol) and H2SO4 (0.03 mL, 0.60 mmol) in dioxane (2.5 mL) was stirred at RT overnight. The RM was diluted with sat. aq. NaHCO3 solution and extracted with EtOAc (2x). The combined organic extracts were washed with brine, dried (phase separator), and evaporated to give the title compound as a white foam which was used without purification in the next step. UPLC-MS-7: Rt = 0.71 min; MS m/z [M+H]+; 449.1/451.1. Step 4: 1 -(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(6-methoxypyridin-3-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one

[0501] To an ice-cooled solution of 5-chloro-4-(3-(6-methoxypyridin-3-yl)-5-methyl-1-(2-azaspiro[3.3]heptan-6-yl)-1H-pyrazol-4-yl)-6-methyl-1H-indazole (Step 3, 59 mg, 0.12 mmol) in THF (4.00 mL) and water (1.00 mL) were added at 0 °C under an argon atmosphere NaHCO3 (30.5 mg, 0.36 mmol) and acryloyl chloride (0.015 mL, 0.18 mmol). The reaction mixture was stirred at 0-5 °C for 1.5 h. After completion of the reaction, MeOH (1 mL) was added and the mixture was stirred for 2 h at RT. RM was diluted with EtOAc, a sat. aq. NaHCO3 solution was added and the layers were separated. The organic layer was extracted with EtOAc (2x) and the combined organic extracts were dried (phase separator) and evaporated. The crude residue was purified by normal phase chromatography (eluent: (MeOH/CH2Cl2 (1/4)) in 0-30% CH2Cl2) to give the title Example 78a as a white solid: 1H NMR (600 MHz, DMSO-d6) δ 13.2 (s, 1H), 7.83 (m, 1H), 7.66 (m, 1H), 7.58 (s, 1H), 7.47 (s, 1H), 6.71 (m, 1H), 6.33 (m, 1H), 6.11 (m, 1H), 5.68 (m, 1H), 4.91 (m, 1H), 4.39 (s, 1H), 4.32 (s, 1H), 4.10 (s, 1H), 4.07 (s, 1H), 3.74 (s, 3H), 2.91 - 2.75 (m, 4H), 2.53 (s, 3H), 2.02 (s, 3H). UPLC-MS-14: Rt = 0.90 min; MS m/z [M+H]+; 503.1/505.1. Example 79a: 1-(6-(3-(6-aminopyridin-3-yl)-4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one

[0502] The title example was prepared using the method similar to Method-7 Steps 3 and 4 of first eluting isomer 6-(3-(6-aminopyridin-3-yl)-4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate tert-butyl (prepared as described below). 1H NMR (600 MHz, DMSO-d) 5 (br, s, 2H), 5.68 (m, 1H), 4.87 (m, 1H), 4.38 (s, 1H), 4.31 (s, 1H), 4.09 (s, 1H), 4.02 (s, 1H), 2.90 - 2.82 (m, 2H), 2.79 - 2.75 (m, 2H), 2.49 (s, 3H), 2.00 (s, 3H); UPLC-MS-14: Rt = 0.67 min; MS m/z [M+H]+; 488.1/490.1. tert-butyl 6-(3-(6-aminopyridin-3-yl)-4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0503] The title compound was prepared using a method similar to Method-7 Steps 1 and 2 from (2-aminopyridin-5-yl)boronic acid pinacol ester [CAS 827614-64-2] and tert-butyl 6-(3-bromo-4-(5-chloro-6-methyl-1-tosyl-1H-indazol-4-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate C6). The isomers were separated by chiral SFC (C-SFC-4; mobile phase: CO2/[IPA+0.1% NH3]: 70/30) to give first eluting isomer 6-(3-(6-aminopyridin-3-yl)-4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate: C-SFC-3 (mobile phase: CO2/[IPA+0.1% NH3]: 70/30): Rt = 2.04 min; UPLC-MS-1: Rt = 0.90 min; MS m/z [M+H]+; 534.2/536.2. The other isomer was obtained as the second elution peak: C-SFC-3 (mobile phase: mobile phase: CO2/[IPA+0.1%NH3] 70/30): Rt = 2.83 min. Method-8: Synthetic Scheme Examples 80a/80b: (S)-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-(3-fluoropyrrolidin-1-yl)ethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1 -one Step 1: 6-(3-(2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2H-indazol-5-yl)-4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-1H- tert-butyl pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0504] 6-(3-bromo-4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)- 1H-indazol-4-yl)-5-methyl- tert-butyl 1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate C1, 1.50 g, 2.48 mmol), 2-(2-((tert-butyldimethylsilyl) oxy)ethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole (Intermediate B19, 1.20 g, 2.99 mmol) and K3PO4 (1.58 g, 7.44 mmol) were dissolved in 1,4-dioxane (20 mL) and H2O (10 mL). The reaction mixture was degassed with N2 for 10 min. Ruphos (0.17 g, 0.37 mmol) and Ruphos-Pd-G3 (0.10 g, 0.12 mmol) were added and the reaction mixture was stirred at 120 °C for 1 h. After completion of the reaction, RM was quenched with water and extracted with EtOAc (x2). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated under vacuum to give the crude residue which was purified by chromatography on neutral alumina (eluent: 0-20% EtOAc in Hexane) to obtain the desired product. LCMS-1: Rt: 2.62, 2.65 min ; MS m/z [M+H]+: 800.8 /802.8. Step 2: 6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-3-(2-(2- tert-butyl hydroxyethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0505] tert-Butyl 6-(3-(2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2H-indazol-5-yl)-4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Step 1, 1.50 g, 1.87 mmol) was dissolved in THF (12 mL) and cooled to 0 °C under a nitrogen atmosphere. TBAF (1.0 M in THF, 1.87 mL, 1.87 mmol) was added dropwise, and the reaction mixture was stirred at RT for 10 min. After completion of the reaction, the reaction mixture was diluted with water and extracted with EtOAc (x2). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to yield a crude product which was used in the next step without further purification. LCMS-1: Rt: 1.93, 1.98 min; MS m/z [M+H]+: 686.6/688.6. Step 3: tert-butyl 6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-3-(2-(2-(mesityloxy)ethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0506] To a solution of tert-butyl 6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-3-(2-(2-hydroxyethyl)-2H-indazol-5-yl)-5-methyl- 1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (1.40 g, 2.04 mmol) and triethylamine (Step 2, 1.22 mL, 8.16 mmol) in CH2Cl2 (15.5 mL) at 0 °C under a nitrogen atmosphere was added mesyl chloride (0.24 mL, 3.06 mmol) and the reaction mixture was stirred at RT for 30 min. After completion of the reaction, RM was quenched with water and extracted with EtOAc (x2). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by trituration in pentane and diethyl ether to afford the desired product. LCMS-1: Rt: 2.04, 2.09 min; MS m/z [M+H]+: 764.5/766.5. Step 4: 6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-3-(2-(2-((S)-3-fluoropyrrolidin-1-yl)ethyl)-2H-indazol-5-yl)-5-methyl-1H- tert-butyl -2-carboxylate

[0507] A solution of 6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-3-(2- tert-butyl (2-(mesityloxy)ethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Step 3, 0.75 g, 0.98 mmol), (S)-3-fluoropyrrolidine.HCl (0.31 g, 2.45 mmol) and Cs2CO3 (1.44 g, 4.41 mmol) in 1,4-dioxane (9 mL) was stirred at 80°C overnight. After completion of the reaction, the reaction mixture was diluted with water extracted with EtOAc (x2). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated under vacuum. The crude residue was purified by multiphase chromatography normal (eluent: 4% MeOH in CH2Cl2) to obtain the desired product. LCMS-1: Rt: 1.77, 1.80 min; MS m/z [M+H]+: 757.7/759.7 . Step 5: (S)-5-chloro-4-(3-(2-(2-(3-fluoropyrrolidin-1-yl)ethyl)-2H-indazol-5-yl)-5-methyl-1- (2-azaspiro[3.3]heptan-6-yl)-1H-pyrazol-4-yl)-6-methyl-1H-indazole

[0508] To a solution of 6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-3-(2-(2-((S)-3-fluoropyrrolidin-1-yl)ethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-tert-butyl carboxylate (Step 4, 0.48 g, 0.63 mmol) in CH2Cl2 (10 mL) at 0 °C was added TFA (5 mL) and the reaction mixture was stirred at RT for 2 h. The RM was concentrated in vacuo to give a crude residue that was purified by reverse-phase chromatography on C18 silica gel (15 micron) (eluent: 0-53% CH3CN in H2O containing 0.025% NH3) to give the desired product. LCMS-1: Rt: 1.28 min; MS m/z [M+H]+: 573.5/575.5. Step 6: (S)-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-(3-fluoropyrrolidin-1-yl)ethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one

[0509] To a solution of (S)-5-chloro-4-(3-(2-(2-(3-fluoropyrrolidin-1-yl)ethyl)-2H-indazol-5-yl)-5-methyl-1-(2-azaspiro[3.3]heptan-6-yl)-1H-pyrazol-4-yl)-6-methyl-1H-indazole (Step 5, 0.25 g, 0.44 mmol) in THF (2 mL) was added NaHCO3 (0.33 g, 3.93 mmol) in solution in H2O (3 mL) followed by acrylyl chloride (0.05 g, 0.52 mmol) as a solution in THF (1 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min, then was poured into water and extracted with EtOAc. The combined organic layers were washed with sat. aq. NaHCO3 solution, brine, dried (Na2SO4), filtered and concentrated under vacuum. The crude residue was purified by reversed-phase chromatography on C18 silica gel (15 micron) (eluent: 0-53% CH3CN in H2O containing 0.1% NH3) to give the title compound. The isomers were separated by chiral SFC (C-SFC-17; mobile phase: CO2/MeOH/CH3CN 65:18:7; UV: 242 nM) to give the title compound Example 80a as the second eluting peak: 1H NMR (400 MHz, CD3OD) δ 8.00 (s, 1H), 7.51 (m, 2H), 7.43 (m, 3H), 6.38 (m, 1H), 6.29 (m, 1H), 5.78 (m, 1H), 5.18−5.03 (m, 1H), 4.84 (m, 2H), 4.52 (m, 2H), 4.44 (s, 1H), 4.26 (s, 1H), 4.20 (s, 1H), 3.24 - 3.07 (m, 4H), 2.89 -2.67 (m, 5H), 2.56 (s, 3H), 2.46 (m, 1H), 2.17 (s, 3H), 2.08 - 2.00 (m, 2H); LCMS-1: Rt: 1.49 min; MS m/z [M+H]+: 627.6/629.6; C-SFC-18 (mobile phase: CO2/MeOH 60/40; UV: 242 nM): Rt: 14.37 min. The other isomer Example 80b was obtained as the first elution: C-SFC-18 (mobile phase: CO2/MeOH 60/40): UV: 242 nM): Rt: 7.31 min.

[0510] The following examples 81 through 82 in Table 6 below were prepared using methods analogous to Method-6 from intermediates (in Step 1) described in the intermediate synthesis section or commercially available. Table 6 Examples 83a/83b: 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(1-(2-hydroxyethyl)-1H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one

[0511] The titled examples were prepared using the method similar to Method-8 Steps 4 and 5 tert-butyl 6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-3-(2-(2-hydroxyethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0512] (Intermediate prepared in Step 2 Method-8). The isomers were separated by chiral SFC (C-SFC-2; mobile phase: CO2/IPA: 72/28) to give the title compound Example 83a as the second eluting peak: 1H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 1H), 7.89 (s, 1H), 7.55 (m, 2H), 7.45 (m, 2H), 7.31 (m, 1H), 6.35 (m, 1H), 6.13 (m, 1H), 5.69 (m, 1H), 4.93−4.82 (m, 2H), 4.39 (s, 1H), 4.32 (m, 2H), 4.10 (s, 1H), 4.03 (s, 1H), 3.74 (m, 2H), 2.90 - 2.78 (m, 4H), 2.04 (s, 3H); LCMS- 5: Rt = 19.3 min; MS m/z [M+H]+: 556.2/558.2; C-SFC-18 (mobile phase: MeOH, UV: 242 nM): Rt = 7.52 min. The other isomer Example 83b was obtained as the first eluting peak: C-SFC-18 (mobile phase: mobile phase: MeOH; UV: 242 nM): Rt = 6.85 min. Method-9: Synthetic Scheme Examples 84a/84b: 1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-(difluoromethyl)-3-(2-methylpyridin-3-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one Step 1: 6-(4-(5-chloro-6-methyl) tert-butyl -1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-(difluoromethyl)-3-(2-methylpyridin-3-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0513] To a solution of tert-butyl 6-(5-(difluoromethyl)-4-iodo-3-(2-methylpyridin-3-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate C9, 135 mg, 0.25 mmol) in dioxane (2 mL) were added 5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (Intermediate D1, 125 mg, 0.33 mmol), RuPhos (17.8 mg, 0.04 mmol), RuPhos-Pd-G3 (31.9 mg, 0.04 mmol) and K3PO4 (1.5 M, 0.51 mL, 0.77 mmol). The sealed vial was flushed with argon and heated at 80 °C for 1 h. The RM was poured into a sat. aq. NaHCO3 solution and extracted with EtOAc (2x). The combined organic extracts were washed with brine, dried (Na2SO4), and filtered. SiliaMetS®Thiol (0.16 mmol) was added and the mixture vortexed for 1 h at 40 °C, filtered, and concentrated. The crude product was purified by normal phase chromatography (eluent: 1–100% tBME in c-hexane) to give the title compound. UPLC-MS-1: Rt = 1.40 min; MS m/z [M+H]+: 653.7/655.7. Step 2: 5-Chloro-4-(5-(difluoromethyl)-3-(2-methylpyridin-3-yl)-1-(2-azaspiro[3.3]heptan-6-yl)-1H-pyrazol-4-yl)-6-methyl-1H-indazole trifluoroactate

[0514] To a solution of tert-butyl 6-(4-(5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-5-(difluoromethyl)-3-(2-methylpyridin-3-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Step 1, 119 mg, 0.18 mmol) in CH2Cl2 (2 mL) was added at 0 °C TFA (0.35 mL, 4.55 mmol) and the reaction mixture was stirred at RT until completion. Volatiles were removed by evaporation to give the title compound as a trifluoroacetate salt which was used without purification in the next step. UPLC-MS-1: Rt = 0.63 min; MS m/z [M+H]+: 469.5/471.5. Step 3: 1 -(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-(difluoromethyl)-3-(2-methylpyridin-3-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one

[0515] To a solution of 5-chloro-4-(5-(difluoromethyl)-3-(2-methylpyridin-3-yl)-1-(2-azaspiro[3.3]heptan-6-yl)-1H-pyrazol-4-yl)-6-methyl-1H-indazole trifluoroacetate salt (Step 2, 0.18 mmol) in CH2Cl2 (5 mL) at 0 °C under argon atmosphere were added DIPEA (0.47 mL, 2.69 mmol) and acryloyl chloride (0.022 mL, 0.27 mmol). The reaction mixture was stirred at 0 °C for 1.5 h. MeOH (10 mL) was added and the RM was stirred for 15 min while allowed to reach RT. The RM was poured into a sat. aq. solution. NaHCO3 and extracted with CH2Cl2 (2x). The combined organic extracts were dried (phase separator), filtered and evaporated. The crude residue was purified by normal phase chromatography (eluent: MeOH/ CH2Cl2 (10/90)) to give the title compound. The isomers were separated by chiral SFC (C-SFC-7; mobile phase: CO2/IPA 63/37) to give the title compound Example 84a as the second eluting peak (white powder): 1H NMR (600 MHz, DMSO- d6) δ 13.1 (s, 1H), 8.30 (d, 1H), 7.52 (d, 2H), 7.28 (m, 1H), 7.04–6.86 (m, 2H), 6.30 (m, 1H), 6.10 (m, 1H), 5.67 (m, 1H), 5.11 (m, 1H), 4.39 (s, 1H), 4.30 (s, 1H), 4.10 (s, 1H), 4.00 (s, 1H), 2.95 - 2.84 (m, 4H), 2.41 (s, 3H), 2.36 (s, 1.5H), 2.35 (s, 1.5H); UPLC-MS-1: Rt = 0.89 min; MS m/z [M+H]+: 523.3/525.3; C-SFC-8 (mobile phase: CO2/IPA 63/37): Rt = 2.66 min. The other isomer Example 84b was obtained as the first eluting peak: C-SFC-8 (mobile phase: CO2/IPA 63/37): Rt = 1.61 min.

[0516] Method-9a: Similar to Method-9 except that Step-2 was performed using H2SO4 in dioxane as described in Method-1a Step-2.

[0517] Method-9b: Similar to Method-9 except that Step-3 was performed using acryloyl chloride and NaHCO3 followed by a LiOH treatment as described in Method-1b Step-3.

[0518] Method-9c: Similar to Method-9 except that Step 3 was performed using acrylic acid, DIPEA and HATU in DMF.

[0519] The following examples 85 to 93 in Table 7 below were prepared using methods analogous to Method-9 from intermediates (in Step 1) described in the intermediate synthesis section or commercially available. Table 7 Method 10: Synthetic Scheme Example 94: 1-(6-(4-(2-chloro-5-hydroxyphenyl)-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one Step 1: 6-(4-bromo-5-methyl-3-(1-methyl-1H-indazol-5-yl) -1H-pyrazol-1-yl)- tert-butyl 2-azaspiro[3.3]heptane-2-carboxylate

[0520] To a suspension of (Intermediate C7, 3.00 g, 6.22 mmol), (1-methyl-1H-indazol-5-yl)boronic acid (1.09 g, 6.22 mmol), K3PO4 (3.96 g, 18.7 mmol) in 1,4-dioxane (20 mL) and water (5.00 mL), degassed with argon, were added tetrakis(triphenylphosphine)palladium (0.72 g, 0.62 mmol) and K3PO4 (3.96 g, 18.7 mmol). The reaction mixture was stirred at 75 °C for 8 h. The RM was quenched by addition of sat. aq. NaHCO3 solution. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with brine, dried (MgSO4), filtered, and evaporated. The crude residue was purified by normal phase chromatography (eluent: EtOAc in n-heptane 0–30%) to give the title compound. UPLC-MS-3: Rt = 1.20 min; MS m/z [M+H]+: 486.1/488.1. Step 2: 5-(4-bromo-5-methyl-1-(2-azaspiro[3.3]heptan-6-yl)-1H-pyrazol-3-yl)-1-methyl-1H-indazole

[0521] To a stirred solution of tert-butyl 6-(4-bromo-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Step 1, 460 mg, 0.95 mmol) in 1,4-dioxane (5 mL) was added H2SO4 (0.15 mL, 2.84 mmol) and the solution was stirred at RT for 8 h. The RM was quenched by addition of sat. aq. NaHCO3 solution. The mixture was extracted with DCM (x2) and the combined organic extracts were washed with brine, dried (MgSO4), filtered, and evaporated to dryness. UPLC-MS-3: Rt = 0.74 min; MS m/z [M+H]+: 387.2/389.2. Step 3: 1 -(6-(4-bromo-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

[0522] To a solution of 5-(4-bromo-5-methyl-1-(2-azaspiro[3.3]heptan-6-yl)-1H-pyrazol-3-yl)-1-methyl-1H-indazole (Step 2, 350 mg, 0.91 mmol) in THF (15 mL) at 0 °C were added a solution of NaHCO3 (0.5 M, 5.44 mL, 2.72 mmol) and acryloyl chloride (0.08 mL, 0.99 mmol). The reaction mixture was stirred at 0 °C and allowed to reach RT in 1 h. A sat. aq. solution of NaHCO3 and DCM was added. The layers were separated and the organic layer was washed with brine, dried (MgSO4), filtered, and evaporated. The crude residue was purified by normal phase chromatography (eluent: ((MeOH/DCM 10/90) in DCM) from 0 to 100%) again purified by normal phase chromatography (eluent: EtOAc in n-heptane from 0 to 100%, then, (MeOH/DCM 10/90) in DCM from 0 to 100%) to give the title compound. UPLC-MS-3: Rt = 0.95 min; MS m/z [M+H]+: 440.2/442.2. Step 4: 1-(6-(4-(2-chloro-5-hydroxyphenyl)-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

[0523] To a suspension of 1-(6-(4-bromo-5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one (Step 3, 220 mg, 0.50 mmol), (2-chloro-5-hydroxyphenyl)boronic acid (86 mg, 0.50 mmol), K3PO4 (318 mg, 1.50 mmol) in 1,4-dioxane (2 mL) and water (0.50 mL), degassed with argon, were added RuPhos (23.3 mg, 0.05 mmol) and RuPhos-Pd-G3 (41.8 mg, 0.05 mmol). The reaction mixture was stirred at 80 °C for 1 h. The RM was quenched by addition of sat. aq. NaHCO3 solution, extracted with EtOAc and the organic layer was washed with brine, dried (MgSO4), filtered and evaporated. The crude residue was purified by normal phase chromatography (eluent: (MeOH/DCM (10-90) in DCM) from 0 to 100%) to give the title Example 94. 1H NMR (600 MHz, DMSO-d6) δ 9.69 (s, 1H), 7.97 (s, 1H), 7.64 (s, 1H), 7.53 (d, 1H), 7.40 (d, 1H), 7.33 (d, 1H), 6.79 (dd, 1H), 6.60 (d, 1H), 6.33 (m, 1H), 6.11 (m, 1H), 5.68 (m, 1H), 4.86 (m, 1H), 4.38 (s, 1H), 4.31 (s, 1H), 4.10 (s, 1H), 4.02 (s, 1H), 4.01 (s, 3H), 2.89 - 2.82 (m, 2H), 2.79 - 2.73 (m, 2H), 2.09 (s, 3H); UPLC-MS- 3: Rt = 0.92 min; MS m/z [M+H]+: 488.1/490.1. Example 95: Crystalline isopropyl alcohol (IPA) solvate of Compound X and crystalline hydrate form (HA modification) of Compound X

[0524] 25 mg of Compound X (Example 1a) was added to 0.1 mL of 2-propanol. The resulting clear solution was stirred at 25 °C for 3 days, after which the crystalline solid precipitated. The solid was collected by centrifugal filtration and dried at ambient condition overnight. The wet cake was characterized as crystalline isopropyl solvate (IPA) of Compound X. Drying the cake at ambient condition overnight afforded the crystalline hydrate form (HA Modification).

[0525] The crystalline hydrate form (HA Modification) of Compound X was analyzed by XRPD and the most characteristic peaks are shown in the Table below (see also Figure 1).

[0526] In particular, the most characteristic peaks of the XRPD pattern of the crystalline hydrate form (HA Modification) can be selected from one, two, three or four peaks having refraction angle values 2θ (CuKα À=1.5418 Â) selected from the group consisting of 8.2°, 11.6°, 12.9° and 18.8°.

[0527] The IPA crystalline solvate form of Compound X was analyzed by XRPD and the most characteristic peaks are shown in the Table below (see also Figure 2).

[0528] In particular, the most characteristic peaks of the XRPD pattern of the crystalline solvate form IPA can be selected from one, two or three peaks having refraction angle values 2θ (CuKα À=1.5418 Â) selected from the group consisting of 7.5°, 12.5° and 17.6°. Example 96: Crystalline ethanol (EtOH) solvate of Compound X and crystalline hydrate form (HA Modification) of Compound X

[0529] 25 mg of Compound X (Example 1a) was added to 0.1 mL of ethanol. The resulting clear solution was stirred at 25 °C for 3 days. The crystalline hydrate form (HA Modification) of Compound X obtained in Example 1a was added as seeds to the resulting solution. The resulting suspension was equilibrated for an additional 1 day, after which a solid precipitated. The solid was collected by centrifugal filtration and dried at ambient condition overnight. The wet cake was characterized as crystalline ethanol solvate, which upon drying at ambient condition overnight, yielded crystalline hydrate (HA Modification).

[0530] Alternatively, 3.1 g of Compound X was added to 20 mL of ethanol, the resulting clear solution was stirred at 25 °C for 20 min. Approximately 50 mg of crystalline hydrate (HA Modification) (obtained above) was added as seeds, and the resulting mixture was equilibrated at 25 °C for 6 h. The resulting suspension was filtered and the wet cake was characterized as crystalline ethanol solvate. The solid was then dried at ambient condition (25 °C, 60-70% relative humidity) for 3 days, 2.8 g of Compound X HA Modification hydrate was obtained in 90% yield.

[0531] The crystalline ethanol solvate form of Compound X was analyzed by XRPD and the most characteristic peaks are shown in the Table below (see also Figure 3).

[0532] In particular, the most characteristic peaks of the XRPD pattern of the crystalline ethanol solvate form can be selected from one, two, three or four peaks having refraction angle values 2θ (CuKα À=1.5418 Â) selected from the group consisting of 7.9°, 12.7°, 18.2° and 23.1°. Example 97: Alternative preparation of crystalline hydrate preparation (HA modification)

[0533] 25 mg of Compound X (Example 1a) was added to 0.1 mL of methanol. The resulting clear solution was stirred at 25 °C for 3 days. The crystalline hydrate (HA Modification) obtained in Example 1A was added as seed to the resulting solution. The resulting suspension was equilibrated for an additional 1 day, after which a solid precipitated. The solid was collected by centrifugal filtration and dried at ambient condition overnight. After drying at ambient condition overnight, the wet cake yielded crystalline hydrate (HA Modification). Example 98: Preparation of Crystalline Propylene Glycol Solvate and Hydrate Preparation of (HA Modification)

[0534] 25 mg of Compound X (Example 1a) was added to 0.1 mL of propylene glycol. The resulting suspension was stirred at 50 °C for 1 week. The solid was collected by centrifugal filtration. The wet cake obtained after filtration was characterized as crystalline propylene glycol solvate. After drying the cake at ambient condition for 1 week, the crystalline hydrate (HA Modification) was obtained.

[0535] The crystalline propylene glycol solvate form of Compound X was analyzed by XRPD and the most characteristic peaks are shown in the Table below (see also Figure 4).

[0536] In particular, the most characteristic peaks of the XRPD pattern of the crystalline propylene glycol solvate form can be selected from one, two, three or four peaks having refraction angle values 2θ (CuKα À=1.5418 Â) selected from the group consisting of 7.3°, 13.2°, 18.0° and 25.5°. Synthesis of Intermediates Aryl Bromide Intermediates: Intermediates A Intermediate A1: tert-butyl (1-(5-bromopyridin-2-yl)-1H-pyrazol-5-yl)carbamate

[0537] 1-(5-Bromopyridin-2-yl)-1H-pyrazol-5-amine (0.80 g, 3.35 mmol) was dissolved in dry THF (7 mL) and cooled to -78 °C under a nitrogen atmosphere. NaHMDS (1 M in THF, 6.70 mL, 6.69 mmol) was added dropwise and stirred for 10 min. Boc anhydride (0.73 g, 3.35 mmol) in THF (1 mL) was added dropwise at -78 °C and stirred at RT for 30 min. After completion of the reaction, RM was diluted with water and extracted with EtOAc (x2). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by normal phase chromatography (eluent: 5-7% EtOAc in hexane) to obtain the title product as a pale white solid. LCMS-1: Rt = 2.10 min; MS m/z [M+H]+; 339.1/341.1. Intermediates A2 and A3: 2-(5-bromo-1H-indazol-1-yl)-N,N-dimethylethan-1-amine (A2) and 2-(5-bromo-2H-indazol-2-yl)-N,N-dimethylethan-1-amine (A3)

[0538] In a microwave vial, a solution of 5-bromoindazole (1 g, 5.02 mmol), dimethylaminoethyl chloride hydrochloride (0.40 g and 2.64 mmol), and potassium carbonate (3.47 g, 25.1 mmol) in DMF (10 mL) was heated at 80 °C for 18 h. Dimethylaminoethyl chloride hydrochloride (0.33 g and 2.2 mmol) was added, and the reaction mixture was further stirred at 80 °C for 6 h. Dimethylaminoethyl chloride hydrochloride (0.40 g and 2.64 mmol) was again added, and RM was further heated for 15 h. RM was poured into water and extracted with EtOAc (x2). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and evaporated. The crude residue was purified by normal phase chromatography (eluent: MeOH in CH2Cl2 0–8%) to give a mixture of both regioisomers. The regioisomers were separated by SFC-1 (mobile phase: MeOH in CO2 2–6%) to give 2-(5-bromo-1H-indazol-1-yl)-N,N-dimethylethan-1-amine as the first eluting isomer: UPLC-MS-1: Rt = 0.58 min; MS m/z [M+H]+ 268.1/270.1 and -(5-bromo-2H-indazol-2-yl)-N,N-dimethylethan-1-amine as the second eluting isomer: UPLC-MS-1: Rt = 0.57 min; MS m/z [M+H]+ 268.1/270.1. Intermediate A4: 4-(2-(5-bromo-1H-indazol-1-yl)ethyl)morpholine Step 1: ethyl 2-(5-bromo-1H-indazol-1-yl)acetate

[0539] To a solution of 5-bromoindazole ([53857-57-1], 6 g, 30.1 mmol) and cesium carbonate (19.65 g, 6.3 mmol) in DMF (80 mL) under argon was added ethyl chloroacetate (4.60 g, 36.8 mmol) and the reaction mixture was stirred at 60 °C for 2 h. The RM was poured into water and extracted with EtOAc (x2). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and evaporated. The crude residue was purified by normal phase chromatography (eluent: EtOAc in heptane 0 to 30%) to give the title compound. UPLC- MS-10: Rt = 1.02 min; MS m/z [M+H]+; 283.0/285.0. Step 2: 2-(5-bromo-1H-indazol-1-yl)ethan-1-ol

[0540] To a solution of ethyl 2-(5-bromo-1H-indazol-1-yl)acetate (4.86 g, 16.5 mmol) in THF (100 mL) was added under Ar at 0 °C DIBAL-H (25% in toluene, 54.9 mL, 82 mmol). The reaction mixture was stirred at 0 °C for 30 min, then at RT for 2 days. The reaction mixture was cooled to 0 °C, carefully poured into water, and extracted with EtOAc (x2). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and evaporated to give the title compound as an oil. UPLC-MS-10: Rt = 0.88 min; MS m/z [M+H]+ 241.0/243.0. Step 3: 2-(5-Bromo-1H-indazol-1-yl)ethyl methanesulfonate

[0541] To a solution of 2-(5-bromo-1H-indazol-1-yl)ethan-1-ol (4.10 g, 15.3 mmol) in CH2Cl2 (50 mL) cooled to 0 °C was added under argon Et3N (4.50 mL, 32.3 mmol) followed by methanesulfonyl chloride (1.45 mL, 18.4 mmol). The reaction mixture was stirred at 0 °C for 2.5 h. Then, RM was poured into a sat. aq. NaHCO3 solution and extracted with EtOAc (x2). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and evaporated to give the title compound as a yellow solid which was used without further purification in the next step. UPLC-MS-10: Rt = 0.88 min; MS m/z [M+H]+ 319.0/321.0. Step 4: 4-(2-(5-bromo-1H-indazol-1-yl)ethyl)morpholine

[0542] A solution of 2-(5-bromo-1H-indazol-1-yl)ethyl methanesulfonate (1.50 g, 4.23 mmol) and morpholine (5 mL, 56.8 mmol) in THF (20 mL) was heated at 60 °C under an argon atmosphere for 18 h. The mixture was diluted with sat. aq. NaHCO3 solution and extracted with EtOAc (x2). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and evaporated. The crude residue was purified by normal phase chromatography (eluent: MeOH in CH2Cl2 0 to 5%) to give the title compound. UPLC-MS-6: Rt = 0.73 min; MS m/z [M+H]+ 310.0/312.0. Intermediate A5: (S)-5-bromo-1-(2-(3-fluoropyrrolidin-1-yl)ethyl)-1H-indazole

[0543] The title compound was prepared using the similar method described for the synthesis of 4-(2-(5-bromo-1H-indazol-1-yl)ethyl)morpholine (Intermediate A4). UPLC-MS-3: Rt = 0.65 min; MS m/z [M+H]+; 312.0/314.0. o ( s=o .hL J Intermediate A6: 4-(4-bromophenyl)thiomorpholine 1,1-dioxide

[0544] Thiomorpholine dioxide (5.00 g, 37 mmol), 1,4-dibromobenzene (4.61, 40.7 mmol), and Cs2CO3 (36.2 g, 111 mmol) were suspended in dry 1,4-dioxane (150 mL) and the reaction mixture was degassed with nitrogen for 10 min. Pd(OAc)2 (0.83 g, 3.70 mmol) and BINAP (2.31 g, 3.70 mmol) were added and the reaction mixture was heated at 120 °C in a sealed tube for 12 h. The RM was filtered through a celite pad and washed with EtOAc. The filtrate was poured into water and extracted with EtOAc (x2). The combined organic extracts were washed with brine, dried (Na2SO4), and concentrated in vacuo. The crude residue was purified by normal phase chromatography (eluent: 0-50% EtOAc in Hexane) to obtain the desired product. LCMS-1: Rt = 1.57 min; MS m/z [M+H]+; 290.1/292.0. Intermediate A7: 5-Bromo-2-(3-nitro-1H-pyrazol-1-yl)pyridine

[0545] 5-Nitro-1H-pyrazole (0.50 g, 0.44 mmol), 2,5-dibromopyridine (1.05 g, 0.44 mmol), and Cs2CO3 (1.44 g, 0.44 mmol) were suspended in NMP (15 mL) and degassed with nitrogen for 5 min. CuI (0.084 g, 0.04 equiv) was added and the reaction mixture was stirred at 120 °C for 1 h. After completion of the reaction, the reaction mixture was diluted with EtOAc and filtered through a celite pad. The filtrate was washed with cold water, brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by normal phase chromatography (eluent: 0-7% EtOAc in Hexane) to afford the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.85 (d, 1H), 8.79 (s, 1H), 8.36 (d, 1H), 7.97 (d, 1H), 7.36 (d, 1H). Intermediate A8: ((5-bromo-2,3-dihydrobenzofuran-2-yl)methoxy)(tert-butyl)dimethylsilane

[0546] To a solution of (5-bromo-2,3-dihydrobenzofuran-2-yl)methanol (1.00 g, 4.15 mmol) in DCM (20 mL) was added 1H-imidazole (0.90 g, 13.3 mmol) and the reaction mixture was stirred for 5 min. Then, tert-butylchlorodimethylsilane (1.97 g, 12.4 mmol) was added and the RM was stirred for 2 h at RT. The reaction mixture was diluted with EtOAc (40 mL) and washed with sat. aq. NaHCO3 solution. The organic layer was washed with water, dried (Na2SO4), filtered and evaporated to dryness. UPLC-MS-3: Rt = 1.55 min; MS m/z [M+H]+: 343.1/345.0. Intermediate A9: 6-bromo-8-fluoro-2,2-dimethyl-2,3-dihydroimidazo[1,2- a ]pyridine Step 1: 2-((5-bromo-3-fluoropyridin-2-yl)amino)-2-methylpropan-1-ol

[0547] A mixture of 5-bromo-2,3-difluoropyridine [89402-44-8] (6.93 g, 35.0 mmol) and 2-amino-2-methylpropan-1-ol [124-68-5] (7.43 mL, 70.0 mmol) was stirred at 100 °C. After 22 h, the cooled reaction mixture was diluted with sat. aq. NaHCO3 and extracted with EtOAc (2x). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated. The crude residue was purified by normal phase chromatography (eluent: heptane/(20:1 EtOAc/MeOH) 0 to 90%) to give the title compound as a colorless oil. UPLC-MS-1: Rt = 1.00 min; MS m/z [M+H]+; 263.0/265.0. Step 2: 6-bromo-8-fluoro-2,2-dimethyl-2,3-dihydroimidazo[1,2-a]pyridine

[0548] Thionyl chloride (5.55 mL, 76.0 mmol) was added dropwise to a solution of 2-((5-bromo-3-fluoropyridin-2-yl)amino)-2-methylpropan-1-ol (5.05 g, 19.0 mmol) in xylene (38 mL) at RT. After stirring for 15 min, the mixture was heated to 100 °C. After 15 h, the cooled reaction mixture was diluted with sat. aq. NaHCO3 and extracted with EtOAc (2x). The combined aqueous layers were re-extracted with DCM (4x). The combined organic layers were dried (Na2SO4) and concentrated to give the title compound which was used without purification in the next step. NMR (400 MHz, DMSO-d6) δ 7.48 (s, 1H), 6.98 (dd, 1H), 3.73 (s, 2H), 1.18 (s, 6H). UPLC-MS-1: Rt = 0.34 min; MS m/z [M+H]+; 245.0/247.0. Intermediate A10: 5-bromo-2-methylisoindoline

[0549] To a solution of 5-bromoisoindoline [127168-84-7] (0.50 g, 2.52 mmol) in MeOH (31.9 mL)/H2O (3.19 mL) at RT was added CH3COOH to reach pH 5. To the reaction mixture was added formaldehyde (37% in water, 0.376 mL, 5.05 mmol) after 15 min followed by NaCNBH3 (0.24 g, 3.79 mmol). The reaction mixture was stirred at RT for 16 h under a nitrogen atmosphere. The RM was concentrated, diluted with EtOAc, and washed with NaOH (1 N) and brine. The organic layer was dried (Na2SO4), filtered, and evaporated to give the title compound which was used without purification in the next step. UPLC-MS-1: Rt = 0.39 min; MS m/z [M+H]+: 212/214. Intermediate A11: (S )-1-(5-bromoindolin-1-yl)-2-(3-fluoropyrrolidin-1-yl)ethan-1-one Step 1: 1 -(5-bromoindolin-1-yl)-2-chloroetan-1-one

[0550] To a solution of 5-bromoindoline [22190-33-6] (2.00 g, 10.1 mmol) in DCM (101 mL) at 0 °C under inert atmosphere were added dropwise Et3N (3.52 mL, 25.2 mmol) followed by a solution of 2-chloroacetyl chloride (1.71 g, 15.15 mmol) in DCM (100 μl). The reaction mixture was stirred at RT for 2 h. Then, the RM was washed with HCl (1 N) and a sat. aq. NaHCO3 solution. The organic layer was dried (Na2SO4), filtered, and evaporated to give the title compound which was used without purification in the next step. UPLC-MS-1: Rt = 0.99 min; MS m/z [M+H]+: 274/276/278. Step 2: (S)-1-(5-bromoindolin-1-yl)-2-(3-fluoropyrrolidin-1-yl)ethan-1-one

[0551] To a solution of 1-(5-bromoindolin-1-yl)-2-chloroethan-1-one (0.50 g, 1.82 mmol) in acetonitrile (11.3 mL)/H2O (0.81 mL) were added K2CO3 (0.75 g, 5.46 mmol) and (S)-3-fluoropyrrolidine (0.46 g, 3.64 mmol). The reaction mixture was stirred at 60 °C for 1 h. The RM was diluted with CH2Cl2 and washed with water. The organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude residue was purified by normal phase chromatography (eluent: 0-5% MeOH in CH2Cl2) to give the title compound. UPLC-MS-7: Rt = 0.61 min; MS m/z [M+H]+: 327/329. Intermediates A12 and A13: 5-Bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2H-indazole and 5-bromo-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-indazole and 5-bromo-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-indazole

[0552] (2-Bromoethoxy)(tert-butyl)dimethylsilane (4.85 g, 20.3 mmol) was added dropwise at 0 °C to a suspension of 5-bromo-1H-indazole (2.0 g, 10.2 mmol) and Cs2CO3 (9.93 g, 30.5 mmol) in DMF (30 mL), and then the reaction mixture was stirred at 60 °C for 5 h in a sealed tube. The RM was filtered through a celite pad and washed with EtOAc. The filtrate was poured into ice-cold water and extracted with EtOAc (x2). The combined organic layers were washed with cold water, brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by neutral alumina chromatography (eluent: 0–1% EtOAc in Hexane) to give 5-bromo-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-indazole A13 as a pale orange liquid as the first eluting isomer: 1H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.86 (s, 1H), 7.45 (m, 2H), 4.50 (t, 2H), 4.05 (t, 2H), 0.75 (s, 9H), 0.19 (s, 6H); LCMS-1: Rt = 2.27 min; MS m/z [M+H]+; 355.3/357.2 and 5-bromo-2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2H-indazole A12 as a pale orange as the second eluting isomer; 1H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.83 (s, 1H), 7.60 (d, 1H), 7. 36 (d, 1H), 4.53 (t, 2H), 4.10 (t, 2H), 0.85 (s, 9H), -0.12 (s, 6H); LCMS-1: Rt = 2.33 min; MS m/z [M+H]+ ; 355.4/357.4. Ester/boronic acid intermediates: Intermediates B Intermediate B1: 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)isothiazolidine 1,1-dioxide

[0553] To a solution of 1,3-propanesulfan (1.00 g, 8.25 mmol) in DMF (20 mL) at 0 °C under a nitrogen atmosphere was added NaH (60% in paraffin, 0.26 g, 10.7 mmol) and the mixture was stirred at 0 °C for 15 min. 2-(4-(bromomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.96 g, 6.60 mmol) was added and the reaction mixture was stirred at RT for 16 h. The mixture was quenched with cold water, extracted with EtOAc (x2). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo to afford the desired product which was directly used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.96 (d, 2H), 7.37 (d, 2H), 4.11 (s, 2H), 3.28 (m, 2H), 2.08 (m, 2H), 2.25 (m, 2H), 1.33 (s, 12H). Method-B1: Synthesis of Intermediate B2: Intermediate B2: 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)pyrrolidin-2-one

[0554] 1-[(4-Bromophenyl)methyl]-2-pyrrolidinone (400 mg, 1.57 mmol), bis(pinacolato)diboron (480 mg, 1.89 mmol), KOAc (340 mg, 3.46 mmol), and PdCl2(dppf).CH2Cl2 (70.7 mg, 0.087 mmol) were suspended in dioxane (6.05 mL) under argon in a 20 mL microwave vial. The suspension was subjected to microwave irradiations for 30 min at 120 °C. UPLC-MS after 30 min indicated completion of the reaction. The RM was concentrated in vacuo and diluted with CH2Cl2 (40 mL), washed with water (2x 15 mL), dried (MgSO4), filtered, and concentrated in vacuo to give the title compound which was used without purification in the next step. UPLC- MS-3: Rt = 1.04 min; MS m/z [M+H]+ 302.3. Method-B1a: Similar to Method-B1 except that the reaction mixture was heated to 100 °C instead of 120 °C.

[0555] The following intermediates B3 to B20 were prepared using methods analogous to Method-B1 from the corresponding intermediates A or commercially available reagents. Intermediate B21: (1-(Tetrahydro-2H-pyran-2-yl)-1H-indazol-6-yl)boronic acid

[0556] A solution of indazole-6-boronic acid pinacol ester (0.5 g, 1.95 mmol), p-toluenesulfonic acid monohydrate (37 mg, 0.195 mmol), and 3,4-dihydro-2H-pyran (0.45 mL, 4.46 mmol) in CH2Cl2 (10 mL) was stirred at RT overnight under an argon atmosphere. The reaction mixture was poured into sat. aq. NaHCO3 solution and extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and evaporated. The crude residue was purified by normal phase chromatography (0 to 25% EtOAc in heptane) to give the title compound.

[0557] UPLC-MS-1: Rt = 1.28 min; MS m/z [M+H]+: 329.3. Method-B2: Synthesis of Intermediate B22: Intermediate B22: 2-(2-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole Step 1: 5-bromo-2-(2-methoxyethyl)-2H-indazole

[0558] To a solution of 5-bromo-2-nitrobenzaldehyde (5.18 g, 22.5 mmol) in MeOH (55 mL) was added 2-methoxyethan-1-amine (1.98 mL, 22.75 mmol), and the reaction mixture was stirred at 70 °C for 1.15 h. Then, the reaction mixture was concentrated and dried under high vacuum. The residual white solid was dissolved with triethyl phosphite (39.4 mL, 225 mmol), and the solution was stirred at 140 °C overnight. After cooling to RT, the excess triethyl phosphite was evaporated under high vacuum (rotary evaporator) and the crude residue purified by normal phase chromatography (eluent: c-hexane/EtOAc 100/0 to 70/30 within 30 min) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.36 (d, 1H), 7.97 (dd, 1H), 7.59 (dt, 1H), 7.31 (dd, 1H), 4.59 (t, 2H), 3.82 (t, 2H), 3.22 (s, 3H); UPLC-MS-3: Rt = 0.97 min; MS m/z [M+H]+: 255.1/257.1. Step 2: 2-(2-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 2H-indazole

[0559] In a sealed tube, a solution of 5-bromo-2-(2-methoxyethyl)-2H-indazole (6.12 g, 17.75 mmol), bis-(pinacolato)-diboron (9.02 g, 35.5 mmol), PdCl2(dppf) (1.30 g, 1.77 mmol), and potassium acetate (4.36 g, 44.4 mmol) in dioxane (60 mL) was stirred at 90 °C for 1.5 h. The reaction mixture was cooled to RT, diluted with water, extracted with EtOAc, the organic phase washed with brine, dried with a phase separator, and concentrated under reduced pressure. The crude residue was purified by normal phase chromatography (eluent: c-hexane/EtOAc 100/0 to 40/60 within 30 min) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.42 (d, 1H), 8.15 (s, 1H), 7.55 (dt, 1H), 7.45 (dd, 1H), 4.59 (t, 2H), 3.83 (t, 2H), 3.22 (s, 3H), 1.31 (s, 12H); UPLC-MS-3: Rt = 1.02 min; MS m/z [M+H]+: 303.3.

[0560] The following intermediates B23 to B24 were prepared using methods analogous to Method-B2 from commercially available building blocks. Intermediate B25: 1-(2-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indoline Step 1: 5-bromo-1-(2-methoxyethyl)indoline

[0561] A solution of 5-bromoindoline (1 g, 5.05 mmol), 1-bromo-2-methoxyethane (0.95 mL, 10.1 mmol), and cesium carbonate (3.29 g, 10.1 mmol) in DMF (15 mL) was stirred at 60 °C for 5 h, then additional 1-bromo-2-methoxyethane (0.95 mL, 10.1 mmol) was added and the reaction mixture was stirred at 60 °C overnight. After cooling to RT, the reaction mixture was diluted with EtOAc and water, extracted with EtOAc, the organic phase washed with brine, dried with a phase separator, and concentrated under reduced pressure. The crude residue was purified by normal phase chromatography (eluent: c-hexane/EtOAc 100/0 to 70/30 within 30 min) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 7.14 (dd, 1H), 7.09 (dd, 1H), 6.43 (d, 1H), 3.51 (t, 2H), 3.40 (t, 2H), 3.27 (s, 3H), 3.20 (t, 2H), 2.89 (t, 2H); UPLC-MS-3: Rt = 1.17 min; MS m/z [M+H]+: 256.1/258.1. Step 2: 1-(2-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indoline

[0562] In a sealed tube, a solution of 5-bromo-1-(2-methoxyethyl)indoline (650 mg, 2.11 mmol), bis-(pinacolato)-diboron (1070 mg, 4.21 mmol), PdCl2(dppf) (154 mg, 0.21 mmol), and potassium acetate (517 mg, 5.27 mmol) in dioxane (8 mL) was stirred at 90 °C for 30 min. After cooling to RT, the reaction mixture was diluted with EtOAc and water, extracted with EtOAc, the organic phase washed with brine, dried with a phase separator, and concentrated under reduced pressure. The crude residue was purified by normal phase chromatography (eluent: c-hexane/EtOAc 100/0 to 70/30 within 30 min) to give the title compound. 1H NMR (400 MHz, DMSO-d) H); UPLC-MS-3: Rt = 1.18 min; MS m/z [M+H]+: 304.2. Pyrazole intermediates: Intermediates C Intermediate C1: 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- tert-butyl carboxylate Step 1: Intermediate C2: tert-butyl 6-(tosyloxy)-2-azaspiro[3.3]heptane-2-carboxylate

[0563] To a solution of tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate [1147557-97-8] (2.92 kg, 12.94 mmol) in DCM (16.5 L) were added DMAP (316.12 g, 2.59 mol) and TsCl (2.96 kg, 15.52 mol) at 20 °C-25 °C. To the reaction mixture was added dropwise EtβN (2.62 kg, 25.88 mol) at 10 °C-20 °C. The reaction mixture was stirred 0.5 h at 5 °C-15 °C and then stirred 1.5 h at 18 °C-28 °C. After completion of the reaction, the reaction mixture was concentrated in vacuo. To the residue was added NaCl (5% in water, 23 L) followed by extraction with EtOAc (23 L). The combined aqueous layers were extracted with EtOAc (10 L × 2). The combined organic layers were washed with NaHCO3 (3% in water, 10 L × 2) and concentrated in vacuo to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 7.81–7.70 (m, 2H), 7.53–7.36 (m, 2H), 4.79–4.62 (m, 1H), 3.84–3.68 (m, 4H), 2.46–2.38 (m, 5H), 2.26–2.16 (m, 2H), 1.33 (s, 9H). UPLC-MS-1: Rt = 1.18 min; MS m/z [M+H]+ 368.2 Step 2: 3,5-dibromo-1H-pyrazole

[0564] To a solution of 3,4,5-tribromo-1H-pyrazole [17635-44-8] (55.0 g, 182.2 mmol) in anhydrous THF (550 mL) was added at -78 °C n-BuLi (145.8 mL, 364.5 mmol) dropwise over 20 min while maintaining the internal temperature at -78 °C/-60 °C. The RM was stirred at this temperature for 45 min. Then, the reaction mixture was carefully quenched with MeOH (109 mL) at -78 °C and stirred at this temperature for 30 min. The mixture was allowed to reach 0 °C and stirred for 1 h. Then, the mixture was diluted with EtOAc (750 mL) and HCl (0.5 N, 300 mL) was added. The layers were concentrated in vacuo. The crude residue was dissolved in DCM (100 mL), cooled to −50 °C, and petroleum ether (400 mL) was added. The precipitated solid was filtered and washed with n-hexane (250 mL x2) and dried under vacuum to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 13.5 (br s, 1H), 6.58 (s, 1H). Step 3: tert-butyl 6-(3,5-dibromo-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0565] To a solution of tert-butyl 6-(tosyloxy)-2-azaspiro[3.3]heptane-2-carboxylate (Step 1, 900 g, 2.40 mol) in DMF (10.8 L) was added Cs2CO3 (1988 g, 6.10 mol) and 3,5-dibromo-1H-pyrazole (Step 2, 606 g, 2.68 mol) at 15 °C. The reaction mixture was stirred at 90 °C for 16 h. The reaction mixture was poured into ice-water/brine (80 L) and extracted with EtOAc (20 L). The aqueous layer was back-extracted with EtOAc (10 L x 2). The combined organic layers were washed with brine (10 L), dried (Na2SO4), filtered, and concentrated under vacuum. The residue was triturated with dioxane (1.8 L) and dissolved at 60 °C. To the clear yellow solution was slowly added water (2.2 L), and recrystallization began after the addition of 900 mL of water. The resulting suspension was cooled to 0 °C, filtered, and washed with cold water. The filter cake was triturated with n-heptane, filtered, then dried under vacuum at 40 °C to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 6.66 (s, 1H), 4.86 - 4.82 (m, 1H), 3.96 - 3.85 (m, 4H), 2.69 - 2.62 (m, 4H), 1.37 (s, 9H); UPLC-MS-3: Rt = 1.19 min; MS m/z [M+H]+; 420.0/422.0/424.0. Step 4: Intermediate C3: tert-butyl 6-(3-bromo-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0566] To a solution of tert-butyl 6-(3,5-dibromo-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Step 3, 960 g, 2.3 mol) in THF (9.6 L) was added n-BuLi (1.2 L, 2.5 mol) dropwise at -80 °C under an inert atmosphere. The reaction mixture was stirred 10 min at -80 °C. To the reaction mixture was then added dropwise iodomethane (1633 g, 11.5 mol) at -80 °C. After stirring for 5 min at -80 °C, the reaction mixture was allowed to warm to 18 °C. The reaction mixture was poured into sat. aq. of NH4Cl (4 L) and extracted with DCM (10 L). The separated aqueous layer was reextracted with DCM (5 L), and the combined organic layers were concentrated under vacuum. The crude product was dissolved in 1,4-dioxane (4.8 L) at 60 °C, then water (8.00 L) was added dropwise slowly. The resulting suspension was cooled to 17 °C and stirred for 30 min. The solid was filtered, washed with water, and dried under vacuum to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 6.14 (s, 1H), 4.74 - 4.66 (m, 1H), 3.95 - 3.84 (m, 4H), 2.61 - 2.58 (m, 4H), 2.20 (s, 3H), 1.37 (s, 9H); UPLC-MS-1: Rt = 1.18 min; MS m/z [M+H]+; 356.1/358.1. Step 5: Intermediate C4: tert-butyl 6-(3-bromo-4-iodo-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0567] To a solution of tert-butyl 6-(3-bromo-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Step 4, 350 g, 0.980 mol) in acetonitrile (3.5 L) was added NIS (332 g, 1.47 mol) at 15 °C. The reaction mixture was stirred at 40 °C for 6 h. After completion of the reaction, the reaction mixture was diluted with EtOAc (3 L) and washed with water (5 L x 2). The organic layer was washed with Na2SO3 (10% in water, 2 L), brine (2 L), dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 4.81 - 4.77 (m, 1H), 3.94 - 3.83 (m, 4H), 2.61 - 5.59 (m, 4H), 2.26 (s, 3H), 1.37 (s, 9H); UPLC-MS-1: Rt = 1.31 min; MS m/z [M+H]+; 482.0/484.0. Step 6: 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

[0568] To a stirred suspension of tert-butyl 6-(3-bromo-4-iodo-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Step 5, 136 g, 282 mmol) and 5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (Intermediate D1, 116 g, 310 mmol) in 1,4-dioxane (680 mL) was added aqueous K3PO4 (2 M, 467 mL, 934 mmol) followed by RuPhos (13.1 g, 28.2 mmol) and RuPhos-Pd-G3 (14.1 g, 16.9 mmol). The reaction mixture was stirred at 80 °C for 1 h under an inert atmosphere. After completion of the reaction, the reaction mixture was poured into 1 M aqueous NaHCO3 solution (1 L) and extracted with EtOAc (1 L × 3). The combined organic layers were washed with brine (1 L × 3), dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by normal phase chromatography (eluent: Petroleum ether/EtOAc 1/0 to 0/1) to give a yellow oil. The oil was dissolved in petroleum ether (1 L) and MTBE (500 mL), then concentrated in vacuo to give the title compound. 1H NMR (400 MHz, DMSO-d) 70 (m, 1H), 2.81 - 2.64 (m, 4H), 2.52 (s, 3H), 2.46 - 2.31 (m, 1H), 2.11 - 1.92 (m, 5H), 1.82 - 1.67 (m, 1H), 1.64 - 1.52 (m, 2H), 1.38 (s, 9H); UPLC-MS-3: Rt = 1.30 min; MS m/z [M+H]+; 604.1/606.1.

[0569] The following intermediates C5 and C6 were prepared using methods analogous to the method used in the preparation of Intermediate C1 from intermediates described in the intermediate synthesis section or commercially available (in Step 7). Intermediate C7: tert-butyl 6-(4-bromo-3-iodo-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate Step 1: tert-butyl 6-(3-iodo-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0570] To a solution of 3-iodo-5-methyl-1H-pyrazole (340 g, 925 mmol) in DMA (3.4 L) was added Cs2CO3 (754 g, 2.31 mol) followed by tert-butyl 6-(tosyloxy)-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate C2, 193 g, 925 mmol). The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was poured into water (3000 mL) and extracted with EtOAc (1000 mL × 3). The combined organic layers were washed with brine (1 L × 3), dried (Na2SO4), filtered, and concentrated in vacuo to give a crude product as a mixture of 2 regioisomers. The regioisomers were separated by normal phase chromatography (eluent: heptane/EtOAc 8/1 to 5/1) to give isomer-1 as a white solid: UPLC-MS-1: Rt = 1.23 min; MS m/z [M+H]+: 404.1, and the title compound isomer-2 as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 6.24–6.22 (m, 1H), 4.82–4.60 (m, 1H), 4.01–3.92 (m, 2H), 3.88–3.81 (m, 2H), 2.66–2.57 (m, 4H), 2.18 (s, 3H), 1.37 (s, 9H). UPLC-MS-1: Rt = 1.20 min; MS m/z [M+H]+: 404.1. Step 2: tert-butyl 6-(4-bromo-3-iodo-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0571] To a solution of tert-butyl 6-(3-iodo-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Step 1, 100 g, 248 mmol) in acetonitrile (1 L) was added NBS (53 g, 298 mmol) and the reaction mixture was stirred at RT for 3 h. The reaction mixture was diluted with EtOAc (1.5 L), washed with sat. aq. NaHCO3 solution (1 Lx 3), then with brine (1 L), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was triturated with MTBE (200 mL), the solid was filtered, and dried in vacuo to give the title compound as a white solid. 1H NMR (400 MHz, CDCl) .44 (s, 9H). UPLC-MS-1: Rt = 1.31 min; MS m/z [M+H]+: 482.1/484.1. Intermediate C8: 6-(4-bromo-3-(2-(((tert-butyldimethylsilyl)oxy)methyl)-2,3-dihydrobenzofuran-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-tert-butyl 2-carboxylate

[0572] To a stirred solution of tert-butyl 6-(4-bromo-3-iodo-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate C7, 800 mg, 1.66 mmol), 3-tert-butyldimethyl((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrobenzofuran-2-yl)methoxy)silane (Intermediate B18) (777 mg, 1.99 mmol) and potassium phosphate (2 M aq. solution; 2.50 mL, 5.00 mmol) in 1,4-dioxane (10 mL) was added tetrakis(triphenylphosphine)palladium (192 mg, 0.16 mmol) and the reaction mixture was stirred at 90 °C for 14 h. The reaction mixture was allowed to cool to RT, diluted with water (10 mL), and extracted with EtOAc (x2). The combined organic extracts were washed with water, dried, and concentrated. The crude residue was purified by normal phase chromatography (eluent: MeOH in CH2Cl2 0–10%) to give the title compound as a racemic mixture. The enantiomers were separated by chiral SFC separation using the C-SFC-20 method (mobile phase: CO2/[IPA/NH3a 0.025%] 85/15) to give the 2nd eluting isomer: 1H NMR (400 MHz, CDCl3) δ 7.60 (d, 1H), 7.53 (dd, 1H), 6.80 (d, 1H), 4.92 - 4.86 (m, 1H), 4.84 - 4.73 (m, 1H), 3.98 (br s, 2H), 3.88 (bs, s, 2H), 3.79 (ddd, 2H), 3.28 (dd, 1H), 3.03 (dd, 1H), 2.72 - 2.62 (m, 4H), 2.26 (s, 3H), 1.39 (s, 9H), 0.83 (s, 9H), 0.08 (s, 3H), 0.03 (s, 3H); UPLC-MS-3: Rt = 1.57 min, MS m/z [M+H]+ 618.3/620.3; C-SFC-11 (mobile phase: CO2/[IPA/NH3a 0.025%] 85/15); 2nd eluting isomer: Rt = 3.90 min. The other enantiomer was obtained as the first eluting isomer; C-SFC- 11 (mobile phase: CO2/[IPA + NH3a 0.025%] 85/15): 1st eluting isomer: Rt = 3.14 min. Intermediate C9: tert-butyl 6-(5-(difluoromethyl)-4-iodo-3-(2-methylpyridin-3-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate Step 1: 3,5-dibromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole

[0573] To a solution of 3,5-dibromo-1H-pyrazole (Intermediate C1, Step 2, 5.12 g, 20.4 mmol) in DCM (100 mL) were added 3,4-dihydro-2H-pyran (3.45 mL, 36.7 mmol) and PTSA (241 mg, 1.27 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction was quenched with sat. aq. NaHCO3 solution and extracted with DCM. The combined organic layers were dried (phase separator), and concentrated in vacuo. The residue was purified by normal phase chromatography (eluent: TBME in 0 to 50% n-heptane) to give the title compound as a white solid. UPLC-MS-1: Rt = 1.11 min; MS m/z [M+H]+: 309.0/311.0/312.9. Step 2: 3-Bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-carbaldehyde

[0574] To a solution of 3,5-dibromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (Step 1, 2.50 g, 7.98 mmol) in THF (80.0 mL) was added a solution of iPrMgCl (2 M in THF, 5.19 mL, 10.38 mmol) dropwise with stirring at -70 °C under an inert atmosphere. During the addition, the temperature was kept below -60 °C. The reaction mixture was stirred at -70 °C/-60 °C for 1 h. Then, to the reaction mixture was added DMF (6.18 mL, 80 mmol) dropwise with stirring, keeping the temperature below -60 °C. The reaction mixture was stirred for 5 min at the same temperature, then slowly warmed to room temperature over 1 h. The reaction mixture was stirred overnight at room temperature. The RM was quenched with sat. aq. NH4Cl solution and extracted with a mixture of tBME and EtOAc. The combined organic layers were washed with brine, dried (phase separator), and concentrated in vacuo to give the title compound as a yellow oil which was used without purification in the next step. UPLC-MS-1: Rt = 0.96 min; MS m/z [M+H]+: 259.2/261.1. Step 3: 3-Bromo-5-(difluoromethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole

[0575] To a solution of 3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-carbaldehyde (Step 2, 508 mg, 1.51 mmol) in DCM (15.0 mL) was added DAST (0.60 mL, 4.53 mmol) dropwise with stirring at 0 °C under inert atmosphere. The reaction mixture was stirred and allowed to warm to RT overnight. The reaction mixture was quenched with crushed ice then sat. aq. NaHCO3 solution and extracted with DCM (x2). The combined organic layers were washed with brine, dried (phase separator), and concentrated in vacuo to give the title compound as a yellow oil which was used without purification in the next step. 1H NMR (400 MHz, DMSO-d6) δ 7.30 (t, 1H), 6.87 (t, 1H), 5.60 - 5.48 (m, 1H), 3.90 - 3.78 (m, 1H), 3.68 - 3.60 (m, 1H), 2.20 - 2.07 (m, 1H), - 1.89 (m, 2H), 1.69 - 1.59 (m, 1H), 1.55 - 1.50 (m, 2H). Step 4: 3-(5-(difluoromethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)- 2-methylpyridine

[0576] To a solution of 3-bromo-5-(difluoromethyl)-1-(tetrahydro- 2H-pyran-2-yl)-1H-pyrazole (Step 3, 950 mg, 1.69 mmol) in 1,4-dioxane (10.0 mL) under inert atmosphere were added 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.11 g, 5.07 mmol), Pd(PPh3)4 (195 mg, 0.17 mmol), and 2 M aqueous Na2CO3 solution. The reaction mixture was stirred at 120 °C for 15 min. The reaction mixture was diluted with EtOAc and the aqueous layer was separated. The organic layer was washed with sat. aq. NaHCO3 and the combined aqueous layers were extracted with EtOAc. The combined organic layers were washed with brine, dried (phase separator), and concentrated in vacuo. The crude residue was purified by normal phase chromatography (eluent: [tBME/MeOH 9/1] in 0–40% tBME) to give the title compound as a white solid. UPLC- MS-1: Rt = 0.85 min; MS m/z [M+H]+ : 294.2. Step 5: 3-(5-(difluoromethyl)-1H-pyrazol-3-yl)-2-methylpyridine

[0577] To a solution of 3-(5-(difluoromethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-2-methylpyridine (Step 4, 420 mg, 1.35 mmol) in MeOH (10 mL) was added aqueous HCl solution (4 M, 3.36 mL, 13.5 mmol) and the reaction mixture was stirred for 1 h at RT. The reaction mixture was quenched with sat. aq. NaHCO3 solution and extracted with DCM (x3). The combined organic layers were dried (phase separator) and concentrated in vacuo to give the title compound which was used without further purification in the next step. UPLC-MS-1: Rt = 0.54 min; MS m/z [M+H]+: 210.2. Step 6: 3-(5-(difluoromethyl)-4-iodo-1H-pyrazol-3-yl)-2-methylpyridine

[0578] To a solution of 3-(5-(difluoromethyl)-1H-pyrazol-3-yl)-2-methylpyridine (Step 5, 280 mg, 1.03 mmol) in acetonitrile (7 mL) was added NIS (348 mg, 1.55 mmol) and the reaction mixture was stirred overnight at RT. The RM was quenched by addition of sat. aq. Na2S2O3 solution and extracted with EtOAc. The organic layer was washed with brine, then dried (phase separator) and concentrated in vacuo. The residue was purified by normal phase chromatography (eluent: [TBME/MeOH 9/1] in TBME 0 to 100%) to give the title compound as a white solid. UPLC-MS-1: Rt = 0.77 min; MS m/z [M+H]+ 336.1 Step 7: tert-butyl 6-(5-(difluoromethyl)-4-iodo-3-(2-methylpyridin-3-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0579] To a clear yellow solution of 3-(5-(difluoromethyl)-4-iodo-1H-pyrazol-3-yl)-2-methylpyridine (Step 6, 25 mg, 0.75 mmol) in dry DMF (5 mL) was added Cs2CO3 (736 mg, 2.26 mmol) and tert-butyl 6-(tosyloxy)-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate C2, 305 mg, 0.83 mmol). The reaction mixture was stirred at 120 °C under an inert atmosphere for 1.5 h. Additional tert-butyl 6-(tosyloxy)-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate C2, 83 mg, 0.23 mmol) was added and the reaction mixture was stirred at 120 °C for an additional 1 h. The reaction mixture was poured into a water/tBME mixture then extracted twice with tBME. The combined organic layers were washed with brine, dried (phase separator), and concentrated in vacuo. The crude residue was purified by normal phase chromatography (eluent: tBME in 0–90% heptane) to give the desired isomer tert-butyl 6-(5-(difluoromethyl)-4-iodo-3-(2-methylpyridin-3-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.59 - 8.49 (m, 1H), 7.74 - 7.62 (m, 1H), 7.41 - 7.28 (m, 1H), 7.24 (t, 1H), 5.13 - 4.95 (m, 1H), 4.02 - 3.91 (m, 2H ), 3.89 - 3.79 (m, 2H), 2.81 - 2.65 (m, 4H) 2.37 (s, 3H), 1.37 (s, 9H); UPLC-MS-1: Rt = 1.22 min; MS m/z [M+H]+: 531.5.

[0580] The following intermediate C10 was prepared using methods analogous to the method used in the preparation of Intermediate C9 from commercially available intermediates (in Step 1). Intermediate C11: tert-butyl 6-(5-(difluoromethyl)-4-iodo-3-(pyridin-3-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate Step 1: 4,4-difluoro-1-(pyridin-3-yl)butane-1,3-dione

[0581] To a solution of 3-acetylpyridine (24.2 g, 196 mmol) in THF (980 mL) under inert atmosphere was added tBuOK (24.9 g, 215 mmol) in portions. The reaction mixture was stirred for 1 h at RT. Then, ethyl 2,2-difluoroacetate (31.0 g, 245 mmol) was added and the reaction mixture was stirred at RT overnight. The RM was neutralized with citric acid (1 M), diluted in water and extracted with EtOAc (x2). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. UPLC-MS-7: Rt = 0.50 min; MS m/z [M+H]+: 200.1 Step 2: 3-(5-(difluoromethyl)-1H-pyrazol-3-yl)pyridine

[0582] To a solution of 4,4-difluoro-1-(pyridin-3-yl)butane-1,3-dione (Step 1, 39.9 g, 180 mmol) in THF (450 mL) and EtOH (450 mL) under inert atmosphere was added hydrazine hydrate (11.4 mL, 234 mmol). The reaction mixture was stirred at 70 °C for 17 h. The RM was partially concentrated in vacuo and the residue was taken up in EtOAc. The organic layer was separated and washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. UPLC-MS-7: Rt = 0.58 min; MS m/z [M+H]+ : 196.1. Step 3: 3-(5-(difluoromethyl)-4-iodo-1H-pyrazol-3-yl)pyridine

[0583] To a solution of 3-(5-(difluoromethyl)-1H-pyrazol-3-yl)pyridine (Step 2, 35.0 g, 126 mmol) in acetonitrile (630 mL) was added NIS (36.7 g, 163 mmol) and the reaction mixture was stirred at RT for 17 h. More NIS (8.50 g, 37.7 mmol) was added and the RM was stirred at RT for an additional 6 h. The RM was quenched by addition of sodium thiosulfate (1 M, 500 mL). The solvent was removed in vacuo and the solution was extracted twice with EtOAc. The organic layer was washed with water, brine, dried (Na2SO4), filtered, and evaporated. The crude product was purified by normal phase chromatography (eluent: [CH2Cl2/MeOH/NH4OH; 100/10/1] in 0-80% CH2Cl2) to give the title compound. UPLC-MS-7: Rt = 0.79 min; MS m/z [M+H]+: 322.0. Step 4: tert-butyl 6-(5-(difluoromethyl)-4-iodo-3-(pyridin-3-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0584] To a stirred solution of 3-(5-(difluoromethyl)-4-iodo-1H-pyrazol-3-yl)pyridine (Step 3, 5.20 g, 16.2 mmol) and tert-butyl 6-(tosyloxy)-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate C2, 8.93 g, 24.3 mmol) in DMF (81 mL) was added Cs2CO3 (13.2 g, 40.5 mmol) and the mixture was stirred at 80 °C overnight. The RM was poured into NaHCO3 (1 M, 25 mL) and extracted with EtOAc (x2). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by normal phase chromatography (eluent: [EtOAc/MeOH; 20/1] in n-heptane 0–100%) and repurified by normal phase chromatography (eluent: tBME in n-heptane 0–100%) to give the desired regioisomer tert-butyl 6-(5-(difluoromethyl)-4-iodo-3-(pyridin-3-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate: 1H NMR (400 MHz, DMSO-d6) δ 9.00–8.87 (m, 1H), 8.68–8.50 (m, 1H), 8.19–8.06 (m, 1H), 7.61– 7.47 (m, 1H), 7.24 (t, 1H), 5.13 - 4.93 (m, 1H), 4.04 - 3.90 (m, 2H), 3.92 - 3.79 (m, 2H), 2.85 - 2.60 (m, 4H), 1.37 (s, 9H); UPLC-MS-6: Rt = 1.17 min; MS m/z [M+H]+ 517.2, The other regioisomer tert-butyl 6-(4-iodo-3-methyl-5-(pyridin-3-yl)- 1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate was also isolated: UPLC-MS-6: Rt = 1.14 min; MS m/z [M+H]+ 517.2 Intermediate C12: tert-butyl 6-(5-(bromomethyl)-4-iodo-3-(pyridin-3-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate Step 1: (3-bromo-1H-pyrazol-5-yl)methanol

[0585] To a solution of 3-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-carbaldehyde (Intermediate C9, step 2) (980 mg, 3.78 mmol) in MeOH (20 mL) was added NaBH4 (572 mg, 15.1 mmol). The reaction mixture was stirred at RT overnight. After completion of the reduction, HCl (4 M in dioxane, 9.46 mL, 37.8 mmol) was added and the reaction mixture was stirred for 1 h at RT. The reaction mixture was neutralized with sat. aq. NaHCO3 solution and extracted with EtOAc (x2). The combined organic layers were dried (phase separator) and concentrated under reduced pressure to give the title compound which was used without purification in the next step. UPLC-MS-1: Rt = 0.42 min; MS m/z [M-H]-: 175.0/177.0. Step 2: 3-Bromo-5-(((tert-butyldimethylsilyl)oxy)methyl)-1H-pyrazole

[0586] To a solution of (3-bromo-1H-pyrazol-5-yl)methanol (Step 1, 1.00 g, 4.24 mmol) in DCM (20 mL) under inert atmosphere were added imidazole (822 mg, 12.1 mmol) and TBDMSCl (1.59 g, 10.6 mmol) and the reaction mixture was stirred overnight under inert atmosphere. The reaction mixture was quenched with sat. aq. NaHCO3 and extracted with EtOAc (x3). The combined organic extracts were concentrated under reduced pressure. The crude residue was purified by normal phase chromatography (eluent: EtOAc in n-heptane 0 to 100%) to give the title compound. UPLC-MS-1: Rt = 1.24 min; MS m/z [M+H]+: 289.2/291.1. Step 3: 3-(5-(((tert-butyldimethylsilyl)oxy)methyl)-1H-pyrazol-3-yl)pyridine

[0587] To a mixture of 3-bromo-5-(((tert-butyldimethylsilyl)oxy)methyl)-1H-pyrazole (Step 2, 800 mg, 2.06 mmol) and pyridin-3-ylboronic acid (506 mg, 4.12 mmol) in 1,4-dioxane (15 mL) under inert atmosphere were added PdCl2(dppf) (106 mg, 0.144 mmol) and Na2CO3 (2 M, 4.12 mL, 8.24 mmol). The reaction mixture was stirred at 100 °C for 1 h. Then, RM was partitioned between EtOAc and water. The organic layer was extracted with EtOAc (x2). The combined organic extracts were washed with water, brine, dried (MgSO4), filtered, and concentrated in vacuo. The crude residue was purified by normal phase chromatography (eluent: [tBME/iPrOH 8/2] in 0-25% tBME) to give the title compound. UPLC-MS-1: Rt = 1.10 min; MS m/z [M+H]+: 290.3. Step 4: 3-(5-(((tert-butyldimethylsilyl)oxy)methyl)-4-iodo-1H-pyrazol-3-yl)pyridine

[0588] To a solution of 3-(5-(((tert-butyldimethylsilyl)oxy)methyl)-1H-pyrazol-3-yl)pyridine (Step 3, 440 mg, 1.44 mmol) in acetonitrile (10 mL) under inert atmosphere was added NIS (406 mg, 1.80 mmol) and the reaction mixture was stirred overnight at RT. The RM was quenched by addition of Na2S2O3 (10% in water), extracted with EtOAc (x2). The combined organic extracts were washed with sat. aq. NaHCO3 solution, brine, dried (MgSO4), filtered and evaporated. The crude residue was purified by normal phase chromatography (eluent: EtOAc in n-heptane 0 to 100%) to give the title compound. UPLC-MS-1: Rt = 1.26 min; MS m/z [M+H]+: 416.2. Step 5: tert-butyl 6-(5-(hydroxymethyl)-4-iodo-3-(pyridin-3-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0589] To a solution of 3-(5-(((tert-butyldimethylsilyl)oxy)methyl)-4-iodo-1H-pyrazol-3-yl)pyridine (Step 4, 576 mg, 1.39 mmol) in DMF (15 mL) was added Cs2CO3 (1356 mg, 4.16 mmol) and tert-butyl 6-(tosyloxy)-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate C2, 561 mg, 1.52 mmol). The reaction mixture was stirred under an inert atmosphere at 80 °C for 16 h. The reaction mixture was partitioned between EtOAc and water. The organic layer was extracted with EtOAc (x2). The combined organic extracts were washed with water, brine, dried (MgSO4), filtered, and concentrated in vacuo. The crude residue was purified by normal phase chromatography (eluent: EtOAc in n-heptane 0–100%) to give the title compound as the desired isomer. UPLC- MS-1: Rt = 1.01 min; MS m/z [M+H]+: 497.5. Step 6: tert-butyl 6-(5-(cyanomethyl)-4-iodo-3-(pyridin-3-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0590] To an ice-cooled solution of tert-butyl 6-(5-(hydroxymethyl)-4-iodo-3-(pyridin-3-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Step 5, 170 mg, 0.31 mmol) in CH2Cl2 (5 mL) were added under inert atmosphere Ph3P (170 mg, 0.65 mmol) and CBr4 (215 mg, 0.65 mmol). The reaction mixture was stirred for 60 min at 0-5 °C. The formation of the bromo intermediate was confirmed by UPLC-MS. UPLC-MS-1: Rt = 1.27 min; MS m/z [M+H]+: 559/561. The above reaction mixture was slowly added under inert atmosphere to an ice-cooled solution of KCN (301 mg, 4.62 mmol) in DMF (5 mL). The reaction mixture was stirred overnight allowing the temperature to slowly rise to RT. The reaction mixture was partitioned between tBME and water. The organic layer was extracted twice with tBME. The combined organic extracts were washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The crude residue was purified by normal phase chromatography (eluent: [tBME/CH3OH 9/1] in n-heptane 0–100%) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 9.00 - 8.95 (m, 1H), 8.65 - 8.61 (m, 1H), 8.16 - 8.13 (m, 1H), 7.57 - 7.51 (m, 1H), 5.12 - 5.01 (m, 1H), 4.27 (s, 2H ), 4.02 -3.86 (m, 4H), 2.77 - 2.71 (m, 4H), 1.39 (s, 9H); UPLC-MS-1: Rt = 1.11 min; MS m/z [M+H]+: 506.1. Intermediate C13: tert-butyl 6-(4-bromo-5-methyl-3-(2-methylpyridin-3-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate Step 1: 2-methyl-3-(5-methyl-1H-pyrazol-3-yl)pyridine

[0591] 3-Iodo-5-methyl-1H-pyrazole (1.50 g, 7.21 mmol), 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.05 g, 9.30 mmol), and Na2CO3 (2.0 M in water, 10.8 mL, 21.6 mmol) were added in 1,4-dioxane (60 mL) and the reaction mixture was degassed for 5 min. Pd(PPh3)4 (0.42 g, 0.36 mmol) was added and the reaction mixture was stirred at 120 °C for 15 h. The reaction mixture was quenched with ice-water and extracted with EtOAc (x2). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by normal phase chromatography (eluent: 0-1.5% MeOH in CH2Cl2) to afford the desired product. LCMS-1: Rt = 1.19 min. MS m/z [M+H]+: 174.31. Step 2: 3-(4-bromo-5-methyl-1H-pyrazol-3-yl)-2-methylpyridine

[0592] To a solution of 2-methyl-3-(5-methyl-1H-pyrazol-3-yl)pyridine (Step 1, 0.50 g, 2.89 mmol) in CH3CN at 0 °C was added AIBN (0.047 g, 0.28 mmol). The mixture was stirred for 5 min, N-bromosuccinimide (0.62 g, 3.47 mmol) was added portionwise and RM was stirred at RT for 2 h. After completion of the reaction, RM was poured into ice-cold water extracted with EtOAc (x2). The combined organic layers were washed with sat. aq. NaHCO3 solution, brine, dried (Na2SO4), filtered and concentrated in vacuo to yield a desired product which was directly used in the next step without further purification. LCMS-1: Rt = 1.26 min. MS m/z [M+H]+: 252/254. Step 3: tert-butyl 6-(4-bromo-5-methyl-3-(2-methylpyridin-3-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0593] Cs2CO3 (1.93 g, 5.95 mmol) was added to a solution of 3-(4-bromo-5-methyl-1H-pyrazol-3-yl)-2-methylpyridine (Step 2, 0.60 g, 2.38 mmol) in DMF (6 mL) and stirred for 10 min. tert-Butyl 6-(tosyloxy)-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate C2, 0.87 g, 2.38 mmol) was added and the reaction mixture was stirred at 80 °C for 15 h. After completion of the reaction, the reaction mixture was poured into ice-water and extracted with EtOAc (x2). The combined organic layers were washed with water, brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by normal phase chromatography (eluent: 0-20% EtOAc in Hexane) to give the desired product tert-butyl 6-(4-bromo-5-methyl-3-(2-methylpyridin-3-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate: 1H NMR (400 MHz, CDCl3) δ 8.62 (m, 1H), 7.91 (m, 1H), 7.40 (m, 1H), 4.69 (m, 1H), 4.10 (s, 2H), 3.99 (s, 2H), 2.93 (m, 2H), 2.88-2.76 (m, 5H), 2.36 (s, 3H), 1.48 (s, 9H); LCMS-1: Rt = 1.62 min. MS m/z [M+H]+: 447.3/449.3 and tert-butyl 6-(4-bromo-3-methyl-5-(2-methylpyridin-3-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate: LCMS-1: Rt = 1.83 min. MS m/z [M+H]+: 447.3/449.3.

[0594] The following intermediate C14 was prepared using methods analogous to the method used in the preparation of Intermediate C13 from commercially available building blocks. Intermediate C15: tert-butyl 6-(4-bromo-5-methyl-3-(1-methyl-6-oxo-1,6-dihydropyridin-2-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate Step 1: 1-methyl-6-(5-methyl-1H-pyrazol-3-yl)pyridin-2(1H)-one

[0595] 3-Methyl-1H-pyrazole-5-boronic acid (1.00 g, 8.00 mmol), 6-bromo-1-methylpyridin-2(1H)-one (1.24 g, 6.60 mmol), Na2CO3 (2.0 M in water, 9.90 mL, 19.7 mmol) were taken up in 1,4-dioxane (30 mL) and the reaction mixture was degassed for 10 min. Pd(PPh3)4 (0.27 g, 0.24 mmol) was added and the reaction mixture was stirred at 110 °C for 20 h. RMN was diluted in ice-cold water and extracted with EtOAc (x2). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by normal phase chromatography (eluent: 0-8% MeOH in CH2Cl2) to give the desired product. 1H NMR (400 MHz, CDCl3) δ 11.0 (br, 1H), 7.40 (t, 1H), 6.67 (d, 1H), 6.39 (d, 1H), 6.24 (s, 1H), 3.64 (s, 3H), 2.41 (s, 3H). Step 2: 6-(4-Iodo-5-methyl-1H-pyrazol-3-yl)-1-methylpyridin-2(1H)-one

[0596] To a solution of 1-methyl-6-(5-methyl-1H-pyrazol-3-yl)pyridin-2(1H)-one (Step 1, 0.48 g, 2.52 mmol) in dry DMF (25 mL) cooled to -20 °C was added N-iodosuccinimide (0.57 g, 2.52 mmol) in portions and the reaction mixture was stirred for 4 h. The reaction mixture was poured into ice-cold water, extracted with EtOAc (x2). The combined organic layers were washed with sat. aq. Na2S2O3 solution, brine, dried (Na2SO4), filtered, and concentrated in vacuo to afford the desired product which was directly used in the next step without further purification. LCMS-1: Rt = 1.36 min. MS m/z [M+H]+: 316.1. Step 3: tert-butyl 6-(4-iodo-5-methyl-3-(1-methyl-6-oxo-1,6-dihydropyridin-2-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0597] To a solution of 6-(4-iodo-5-methyl-1H-pyrazol-3-yl)-1-methylpyridin-2(1H)-one (Step 2, 0.53 g, 1.68 mmol) and tert-butyl 6-(tosyloxy)-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate C2, 0.68 g, 1.85 mmol) in CH3CN (35 mL) was added Cs2CO3 (0.60 g, 1.85 mmol) and the reaction mixture was stirred at 70-75 °C for 16 h. The reaction mixture was poured into water and extracted with EtOAc (x2). The combined organic layers were washed with water, brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by normal phase chromatography (eluent: 0–7% MeOH in CH2Cl2) to give the desired product: 1H NMR (400 MHz, CDCl3) δ 7.41 (m, 1H), 6.70 (d, 1H), 6.26 (d, 1H), 4.72 (m, 1H), 4.09 (s, 2H), 3.98 (s, 2H), 3.43 (s, 3H), 2.9 (m 2H), 2.75 (m, 2H), 2.35 (s, 3H), 1.48 (s, 9H). LCMS-1: Rt = 1.71 min. MS m/z [M+H]+: 511.3. The other tert-butyl regioisomer 6-(4-bromo-3-methyl-5-(1-methyl-6-oxo-1,6-dihydropyridin-2-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate was also isolated; LCMS-Pir-1:Rt = 1.78 min, MS m/z [M+H]+: = 511.8. Intermediates C16 and C17: tert-butyl 6-(4-bromo-2'-(2-(dimethylamino)ethyl)-5,5'-dimethyl-1H,2'H-[3,3'-bipyrazol]-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (C16) and 6-(4-bromo-1'-(2-(dimethylamino)ethyl)-5 tert-butyl ,5'-dimethyl-1H,1'H-[3,3'-bipyrazol]-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (C17) Step 1: 1-(4-bromo-5-methyl-1H-pyrazol-3-yl)ethan-1-one

[0598] A solution of 1-(5-methyl-1H-pyrazol-3-yl)ethanone ([17357 74-3], 963 mg, 7.45 mmol) and N-bromosuccinimide (2.38 g, 13.4 mmol) in EtOAc (30 mL) was stirred at RT overnight under argon. The reaction mixture was poured into 10% aqueous sodium thiosulfate solution and extracted with EtOAc (x2). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and evaporated to give the title compound as a white solid. UPLC-MS-1: Rt = 0.64 min; MS m/z [M+H]+: 201.0/203.0. Step 21 tert-Butyl 6-(3-acetyl-4-bromo-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0599] To a solution of 1-(4-bromo-5-methyl-1H-pyrazol-3-yl)ethan-1-one (Step 1, 1.63 g, 7.79 mmol) in DMF (30 mL) was added cesium carbonate (6.34 g, 19.5 mmol), tert-butyl 6-(tosyloxy)-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate C2, 3.72 g, 10.1 mmol) and the reaction mixture was stirred at 80 °C under argon for 16 h. The RM was poured into water and extracted with EtOAc (x2), the combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated. The crude residue was purified by normal phase chromatography (eluent: EtOAc in n-heptane 0-30%) to give the title compound as a white solid. UPLC-MS-1: Rt = 1.17 min; MS m/z [M+H]+: 398.2/400.2. Step 3: tert-butyl 6-(4-bromo-3-(3-(dimethylamino)but-2-enoyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate and tert-butyl 6-(4-bromo-5-methyl-3-(3-oxobutanoyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0600] A solution of tert-butyl 6-(3-acetyl-4-bromo-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Step 2, 700 mg, 1.71 mmol) in N,N-dimethylacetamide dimethyl acetal (84 mL, 24.6 mmol) was flushed with argon and stirred at 120 °C under microwave irradiations for 1 h. The reaction mixture was concentrated, and the crude residue was purified by normal phase chromatography (eluent: 0 to 4% MeOH in CH2Cl2) to give a mixture of the title compounds. UPLC-MS- 1: Rt = 1.06 and 1.14 min; MS m/z [M+H]+; 467.3/469.3 and 440.2/442.2. Step 4: Intermediate C16: tert-butyl 6-(4-bromo-2'-(2-(dimethylamino)ethyl)-5,5'-dimethyl-1H,2'H-[3,3'-bipyrazol]-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate and Intermediate C17: tert-butyl 6-(4-bromo-1'-(2-(dimethylamino)ethyl)-5,5'-dimethyl-1H,1'H-[3,3'-bipyrazol]-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate

[0601] A mixture of tert-butyl 6-(4-bromo-3-(3-(dimethylamino)but-2-enoyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate and tert-butyl 6-(4-bromo-5-methyl-3-(3-oxobutanoyl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate (Step 3, 2.50 mmol), 2-(dimethylamino)ethylhydrazine dihydrochloride (330 mg, 1.87 mmol), and DIPEA (0.65 mL, 3.75 mmol) in EtOH (8 mL) was stirred at 80 °C for 45 min. The reaction mixture was poured into a sat. NaHCO 3.0 solution. aq. NaHCO3 and extracted with EtOAc (x2). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and evaporated. The crude residue was purified by normal phase chromatography (eluent: MeOH in CH2Cl2 0–10%) to give tert-butyl 6-(4-bromo-2'-(2-(dimethylamino)ethyl)-5,5'-dimethyl-1H,2'H-[3,3'-bipyrazol]-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate as the first eluting isomer: UPLC-MS-1: Rt = 0.98 min; MS m/z [M+H]+; 507.3/509.3. The column was further eluted to give a mixture of the title compounds which was further purified by SFC (SFC-1; mobile phase: 0 to 15% MeOH in CO2) to give tert-butyl 6-(4-bromo-1'-(2-(dimethylamino)ethyl)-5,5'-dimethyl-1H,1'H-[3,3'-bipyrazol]-1-yl)-2-azaspiro[3.3]heptane-2-carboxylate: UPLC-MS-1: Rt = 0.93 min; MS m/z [M+H]+; 507.3/509.3. Indazole Intermediates: Intermediates D Intermediate D1: 5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole Step 1: 1-chloro-2,5-dimethyl-4-nitrobenzene

[0602] To an ice-cooled solution of 2-chloro-1,4-dimethylbenzene (3.40 kg, 24.2 mol) in AcOH (20.0 L) was added H2SO4 (4.74 kg, 48.4 mol, 2.58 L) followed by a dropwise addition (dropping funnel) of a cold solution of HNO3 (3.41 kg, 36.3 mol, 2.44 L, 67.0% purity) in H2SO4 (19.0 kg, 193 mol, 10.3 L). The reaction mixture was then allowed to stir at 0-5 °C for 0.5 h. The reaction mixture was slowly poured onto crushed ice (35.0 L) and the yellow solid precipitated. The suspension was filtered and the cake was washed with water (5.00 L × 5) to give a yellow solid which was suspended in MTBE (2.00 L) for 1 h, filtered and dried to give the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.34 (s, 1H), 2.57 (s, 3H), 2.42 (s, 3H). Step 2: 3-Bromo-2-chloro-1,4-dimethyl-5-nitrobenzene

[0603] To a cooled solution of 1-chloro-2,5-dimethyl-4-nitrobenzene (Step 1, 2.00 kg, 10.8 mol) in TFA (10.5 L) was slowly added concentrated H2SO4 (4.23 kg, 43.1 mol, 2.30 L) and the reaction mixture was stirred at 20 °C. NBS (1.92 kg, 10.8 mol) was added in small portions and the reaction mixture was heated at 55 °C for 2 h. The reaction mixture was cooled to 25 °C then poured into crushed ice solution to obtain a pale white precipitate which was filtered through vacuum, washed with cold water and dried under vacuum to give the title compound as a yellow solid which was used without further purification in the next step. NMR (400 MHz, CDCl3) δ 7.65 (s, 1H), 2.60 (s, 3H), 2.49 (s, 3H). Step 3: 3-bromo-4-chloro-2,5-dimethylaniline

[0604] To an ice-cooled solution of 3-bromo-2-chloro-1,4-dimethyl-5-nitrobenzene (Step 2, 2.75 kg, 10.4 mol) in THF (27.5 L) was added HCl (4 M, 15.6 L) then Zn (2.72 kg, 41.6 mol) in small portions. The reaction mixture was allowed to stir at 25 °C for 2 h. The reaction mixture was basified by addition of sat. aq. NaHCO3 solution (to pH = 8). The mixture was diluted with EtOAc (2.50 L) and stirred vigorously for 10 min and then filtered through a pad of celite. The organic layer was separated and the aqueous layer was re-extracted with EtOAc (3.00 L x 4). The combined organic layers were washed with brine (10.0 L), dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound as a yellow solid that was used without further purification in the next step. 1H NMR (400 MHz, DMSO-d6) δ 6.59 (s, 1H), 5.23 (s, 2H), 2.22 (s, 3H), 2.18 (s, 3H). Step 4: 3-Bromo-4-chloro-2,5-dimethylbenzenediazonium tetrafluoroborate

[0605] BF3.Et2O (2.00 kg, 14.1 mol, 1.74 L) was dissolved in DCM (20.0 L) and cooled to -5 to -10 °C under a nitrogen atmosphere. A solution of 3-bromo-4-chloro-2,5-dimethylaniline (Step 3, 2.20 kg, 9.38 mol) in DCM (5.00 L) was added to the above reaction mixture and stirred for 0.5 h. tert-Butyl nitrite (1.16 kg, 11.3 mol, 1.34 L) was added dropwise, and the reaction mixture was stirred at the same temperature for 1.5 h. TLC (petroleum ether:EtOAc = 5:1) showed that the starting material (Rf = 0.45) was completely consumed. MTBE (3.00 L) was added to the reaction mixture to give a yellow precipitate, which was filtered through vacuum and washed with cold MTBE (1.50 L x 2) to give the title compound as a yellow solid that was used without further purification in the next step. Step 5: 4-Bromo-5-chloro-6-methyl-1H-indazole

[0606] To 18-crown-6 ether (744 g, 2.82 mol) in chloroform (20.0 L) was added KOAc (1.29 kg, 13.2 mol), and the reaction mixture was cooled to 20 °C. Then, 3-bromo-4-chloro-2,5-dimethylbenzenediazonium tetrafluoroborate (Step 4, 3.13 kg, 9.39 mol) was added slowly. The reaction mixture was then allowed to stir at 25 °C for 5 h. After completion of the reaction, the reaction mixture was poured into ice-cold water (10.0 L), and the aqueous layer was extracted with DCM (5.00 L × 3). The combined organic layers were washed with sat. aq. NaHCO3 (5.00 L), brine (5.00 L), dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound as a yellow solid. 1H NMR (600 MHz, CDCl3) δ 10.42 (br s, 1H), 8.04 (s, 1H), 7.35 (s, 1H), 2.58 (s, 3H). UPLC-MS-1: Rt = 1.02 min; MS m/z [M+H]+; 243/245/247. Step 6: 4-Bromo-5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0607] To a solution of PTSA (89.8 g, 521 mmol) and 4-bromo-5-chloro-6-methyl-1H-indazole (Step 5, 1.28 kg, 5.21 mol) in DCM (12.0 L) was added DHP (658 g, 7.82 mol, 715 mL) dropwise at 25 °C. The mixture was stirred at 25 °C for 1 h. After completion of the reaction, the reaction mixture was diluted with water (5.00 L) and the organic layer was separated. The aqueous layer was re-extracted with DCM (2.00 L). The combined organic layers were washed with sat. aq. NaHCO3 solution (1.50 L), brine (1.50 L), dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by normal phase chromatography (eluent: Petroleum ether/EtOAc 100/1 to 10/1) to give the title compound as a yellow solid. 1H NMR (600 MHz, DMSO-d6) δ 8.04 (s, 1H), 7.81 (s, 1H), 5.88 - 5.79 (m, 1H), 3.92 - 3.83 (m, 1H), 3.80 - 3.68 (m, 1H), 2.53 (s, 3H), 2.40 - (m, 1H), 2.06 - 1.99 (m, 1H), 1.99 - 1.93 (m, 1H), 1.77 - 1.69 (m, 1H), 1.60 - 1.56 (m, 2H). UPLC-MS-6: Rt = 1.32 min; MS m/z [M+H]+; 329.0/331.0/333.0. Step 7: 5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

[0608] A suspension of 4-bromo-5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Step 6, 450 g, 1.37 mol), KOAc (401 g, 4.10 mol), and B2Pin2 (520 g, 2.05 mol) in 1,4-dioxane (3.60 L) was degassed with nitrogen for 0.5 h. Pd(dppf)Cl2.CH2Cl2 (55.7 g, 68.3 mmol) was added, and the reaction mixture was stirred at 90 °C for 6 h. The reaction mixture was filtered through diatomite, and the filter cake was washed with EtOAc (1.50 Lx 3). The mixture was concentrated under vacuum to give a black oil which was purified by normal phase chromatography (eluent: Petroleum ether/EtOAc 100/1 to 10/1) to give the desired product as brown oil. The residue was suspended in petroleum ether (250 mL) for 1 h to obtain a white precipitate. The suspension was filtered, dried under vacuum to give the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.17 (d, 1H), 7.52 (s, 1H), 5.69 - 5.66 (m, 1H), 3.99 - 3.96 (m, 1H), 3.75 - 3.70 (m, 1H), 2.51 (d, 4H), 2.21 - 2.10 (m , 1H), 2.09 - 1.99 (m, 1H), 1.84 - 1.61 (m, 3H), 1.44 (s, 12H); UPLC-MS-6: Rt = 1.29 min; MS m/z [M+H]+; 377.1/379. Intermediate D2: 5-chloro-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indazole Step 1: 4-bromo-5-chloro-6-methyl-1-tosyl-1H-indazole

[0609] A stirred solution of 4-bromo-5-chloro-6-methyl-1H-indazole (Intermediate D1 Step 5, 240 g, 977 mmol) in THF (2.40 L) was treated with NaH (43.0 g, 1.08 mol, 60.0% purity) under a nitrogen atmosphere and the reaction mixture was stirred at 0 °C for 30 min. Then, the reaction mixture was treated with TsCl (195 g, 1.03 mol) and stirred at 0 °C for 1 h. The reaction was quenched with water (1.00 L), diluted, and extracted with EtOAc (1.00 L x 3). The combined organic layers were washed with water, brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was suspended in MTBE (200 mL) for 20 min to give the title compound as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.49 (s, 1H), 8.16 (s, 1H), 7.91−7.83 (m, 2H), 7.47−7.37 (m, 2H), 2.61 (s, 3H), 2.35 (s, 3H). UPLC-MS-1: Rt = 1.42 min; MS m/z [M+H]+; 399.1/401.1/403.1. Step 2: 5-chloro-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indazole.

[0610] A suspension of 4-bromo-5-chloro-6-methyl-1-tosyl-1H-indazole (Step 1, 370 g, 925 mmol), KOAc (272 g, 2.78 mol), and B2Pin2 (470 g, 1.85 mol) in 1,4-dioxane (3.00 L) was degassed with nitrogen for 30 min. Pd(dppf)Cl2.CH2Cl2 (75.6 g, 92.6 mmol) was added, and the reaction mixture was stirred at 100 °C for 4 h. The reaction mixture was filtered through diatomite, and the filter cake was washed with EtOAc (1.50 L). The filtrate was concentrated in vacuo to give a black oil that was filtered through silica gel, and then the residue was suspended in EtOAc (500 mL) at 60 °C for 1 h. The mixture was cooled to 25 °C, and the solid precipitated. The solid was filtered and concentrated in vacuo to give the title compound as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.36 (d, 1H), 8.15 (s, 1H), 7.83 (d, 2H), 7.24 (d, 2H), 2.56 (s, 3H), 2.36 (s, 3H), 1.41 (s, 12H); UPLC-MS-7: Rt = 1.27 min; MS m/z [M+H]+: 447.1/449.2. Intermediate D3: 5,6-dichloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole Step 1: 1,2-dichloro-4-methyl-5-nitrobenzene

[0611] The title compound was prepared by a method similar to Step 1 in the synthesis of Intermediate D1 by substituting 2-chloro-1,4-dimethylbenzene for 1,2-dichloro-4-methylbenzene. NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.43 (s, 1H), 2.56 (s, 3H). Step 2: 3-bromo-1,2-dichloro-4-methyl-5-nitrobenzene

[0612] The title compound was prepared by a method similar to Step 2 in the synthesis of Intermediate D1 by substituting 1-chloro-2,5-dimethyl-4-nitrobenzene for 1,2-dichloro-4-methyl-5-nitrobenzene. 1H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 2.62 (s, 3H). Step 3: 3-bromo-4,5-dichloro-2-methylaniline

[0613] To a solution of 3-bromo-1,2-dichloro-4-methyl-5-nitrobenzene (Step 2, 3.45 kg, 12.1 mol) in MeOH (27.0 L) was added SnCl2.2H2O (8.20 kg, 36.3 mol) and the reaction mixture was stirred at 65 °C for 10 h. TLC (petroleum ether:EtOAc = 5:1 (Rf (starting material) = 0.49, Rf (product) = 0.22) showed that the starting material was completely consumed and a new spot was formed. The pH of the mixture was adjusted to pH = 8 with 20.0% (w/w) aqueous NaOH solution (10.0 L) at 0–10 °C, and the mixture was extracted with EtOAc (5.00 L × 8). The combined organic layers were washed with brine (5.00 L × 2), dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was triturated with petroleum ether (2.00 L) at 25 °C for 12 h to give the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 6.77 (s, 1H), 3.61 - 3.89 (m, 2H), 2.30 (s, 3H). Step 4: 3-Bromo-4,5-dichloro-2-methylbenzenediazonium trifluoro(hydroxy)borate

[0614] To an ice-cooled solution of 3-bromo-4,5-dichloro-2-methylaniline (Step 3, 1.70 kg, 6.67 mol) in HCl (6 M, 17.4 L, 105 mmol) stirred for 30 min was added dropwise an ice-cooled solution of NaNO2 (506 g, 7.34 mol) in H2O (1.20 L) while maintaining a temperature of 0 °C. The resulting mixture was stirred for 1 h. HBF4 (9.22 kg, 42.0 mol, 6.54 L, 40.0% purity) was added dropwise, and the reaction mixture was stirred at 0 °C for 30 min. TLC (petroleum ether:EtOAc = 5:1) showed that the starting material (Rf = 0.39) was consumed completely, and a new spot (Rf = 0.00) formed. The resulting precipitate was filtered through vacuum, washed with cold water (2.00 L) and MTBE (2.00 L), and then dried under vacuum to obtain a pale yellow solid of the diazonium salt. The crude product was triturated with MTBE (1000 mL) at 25 °C for 30 min to give the title compound as a yellow solid that was used without further purification in the next step. Step 5: 4-Bromo-5,6-dichloro-1 H-indazole

[0615] The title compound was prepared by a method similar to that of Intermediate D1, Step 5 by substituting 3-bromo-4-chloro-2,5-dimethylbenzenediazonium tetrafluoroborate for 3-bromo-4,5-dichloro-2-methylbenzenediazonium trifluoro(hydroxy)borate. 1H NMR (400 MHz, DMSO-d6) δ 13.71 (br s, 1H), 8.10 (d, 1H), 7.94 (d, 1H); UPLC-MS-9: Rt = 1.18 min; MS m/z [M+H]-: 262.9/264.9/266.8/268.8. Step 6: 4-bromo-5,6-dichloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0616] The title compound was prepared by a method similar to Step 6 in the synthesis of Intermediate D1 by substituting 4-bromo-5-chloro-6-methyl-1H-indazole for 4-bromo-5,6-dichloro-1H-indazole. 1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 1H), 8.13 (s, 1H), 5.91 - 5.88 (m, 1H), 3.90 - 3.83 (m, 1H), 3.81 - 3.72 (m, 1H), 2.40 - 2.27 (m, 1H), - 1.92 (m, 2H), 1.78 - 1.65 (m, 1H), 1.62 - 1.52 (m, 2H); UPLC-MS-9: Rt = 1.55 min; MS m/z [M+H]+: 349.1/351.0/353.0. Step 7: 5,6-dichloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

[0617] The title compound was prepared by a method similar to Step 7 in the synthesis of Intermediate D1, Step 7 substituting 4-bromo-5-chloro-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole for 4-bromo-5,6-dichloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole. 1H NMR (400 MHz, DMSO-d6) δ 8.23 (s, 1H), 8.16 (s, 1H), 5.90 - 5.87 (m, 1H), 3.89 - 3.71 (m, 2H), 2.41 - 2.28 (m, 1H), 2.07 - 1.90 (m, 2H), - 1.65 (m, 1H), 1.62 - 1.52 (m, 2H), 1.38 (s, 12H); UPLC-MS-9: Rt = 1.53 min; MS m/z [M+H]+: 395.3/397.3/399.3. Intermediate D4: 5-chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole Step 1: 4-bromo-5-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0618] To a solution of 4-bromo-5-chloro-1H-indazole (250 g, 1.08 mol, 1.00 eq) in DCM (2.50 L) were added p-TSA (9.30 g, 54.0 mmol, 0.05 eq) followed by DHP (273 g, 3.24 mol, 296 mL, 3.00 eq). The resulting reaction mixture was stirred at 25 °C for 1 h. The mixture was poured into sat. aq. NaHCO3 solution (1 L), washed with brine and dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was triturated in petroleum ether (500 mL) and collected by filtration to give the title product. UPLC-MS-1: Rt = 1.28 min; MS m/z [M+H]+; 315/317/319. Step 2: 5-chloro-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole

[0619] A solution of 4-bromo-5-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (step 1) (320 g, 1.01 mol, 1.00 eq), B2Pin2 (283 g, 1.12 mol, 1.10 eq), and KOAc (299 g, 3.04 mol, 3.00 eq) in dioxane (1.39 L) was degassed with N2. Then, Pd(dppf)Cl2.CH2Cl2 (24.8 g, 30.4 mmol, 0.03 eq) was added, and the reaction mixture was stirred at 110 °C for 18 h. The mixture was filtered, the cake was washed with EtOAc (10 L), and the filtrate was concentrated in vacuo. The crude product was purified by normal phase chromatography (eluent: EtOAc in 0-50% petroleum ether) to give the title compound. UPLC-MS-1: Rt = 1.35 min, MS m/z [M+H]+ : 363/365. Intermediate D5: 5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indazole Step 1: 4-bromo-5-methyl-1-tosyl-1H-indazole

[0620] To an ice-cooled solution of 4-bromo-5-methyl-1H-indazole (5 g, 23.7 mmol) in THF (50 mL) under inert atmosphere was added NaH (1.90 g, 47.4 mmol), followed by toluene-4-sulfonyl chloride (4.97 g, 26.1 mmol) and the reaction mixture was stirred at RT for 1 h. The reaction mixture was carefully quenched to 0 °C with water and extracted with CH2Cl2. The organic phase was dried over Na2SO4, filtered and evaporated. The crude residue was triturated with Et2O and the white precipitate was filtered, washed with cold Et2O and dried under high vacuum to give the title compound as a white solid. UPLC-MS- 1: Rt = 1.34 min; MS m/z [M+H]+: 365/367. Step 2: 5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indazole

[0621] To a solution of 4-bromo-5-methyl-1-tosyl-1H-indazole (step 1) (7.94 g, 21.7 mmol) in 1,4-dioxane (80 mL) under inert atmosphere were added BISPIN (11.04 g, 43.5 mmol), PdCl2(dppf).CH2Cl2 adduct (0.89 g, 1.09 mmol), and KOAc (6.40 g, 65.2 mmol). The reaction mixture was degassed then stirred at 100 °C for 16 h. The reaction mixture was quenched with water and extracted with CH2Cl2. The organic phase was washed with brine, then dried over Na2SO4, filtered, and evaporated. The crude residue was triturated with Et2O, the white precipitate was filtered, washed with cold Et2O and dried under high vacuum. The crude product was purified by normal phase chromatography (eluent: 0 to 40% EtOAc in c-hexane) to give the title compound. UPLC-MS-1: Rt = 1.48 min; MS m/z [M+H]+: 413. Intermediate D6: tert-butyl 3-amino-5-chloro-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole-1-carboxylate Step 1: 4-bromo-5-chloro-6-methyl-2-nitro-2H-indazole

[0622] To a solution of fuming nitric acid (3.64 mL, 81 mmol) in acetic anhydride (100 mL) was added at 0 °C 4-bromo-5-chloro-6-methyl-1H-indazole (Intermediate D1, step 5, 5 g, 20.4 mmol) and the reaction mixture was stirred at 0 °C for 30 min. The reaction mixture was poured into an ice/water mixture and the precipitate was filtered, washed with water and dried under reduced pressure to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 9.35 (s, 1H), 7.78 (s, 1H); UPLC-MS-5: Rt = 1.36 min; MS m/z [M-H]-: 288.0/290.0. Step 2: 4-bromo-5-chloro-6-methyl-3-nitro-1H-indazole

[0623] A solution of 4-bromo-5-chloro-6-methyl-2-nitro-2H-indazole (Step 1, 5.55 g, 17.4 mmol) in toluene (100 mL) was heated to 120 °C and stirred for 1 h. The reaction mixture was cooled to RT and the solid was filtered, washed with toluene, and dried under reduced pressure to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 14.58 (br s, 1H), 7.79 (s, 1H), 2.57 (s, 3H); UPLC-MS-5: Rt = 1.13 min; MS m/z [M-H]-: 288.0/290.0. Step 3: 4-bromo-5-chloro-6-methyl-1H-indazol-3-amine

[0624] To a suspension of 4-bromo-5-chloro-6-methyl-3-nitro-1H-indazole (Step 2, 4.19 g, 14.3 mmol) in EtOH (160 mL) and hydrochloric acid (10.55 N, 27.1 mL, 286 mmol) was added tin(II) chloride (13.5 g, 71.4 mmol) and the reaction mixture was stirred at RT for 2 h. The reaction mixture was concentrated under reduced pressure, the white residue was diluted with DCM (150 mL) and water (200 mL), cooled to 0 °C, and basified with solid NaOH to pH 9. The cloudy mixture was extracted with DCM (3 × 500 mL), the organic phase dried (phase separator), and concentrated under reduced pressure to give the title compound as a light pink cotton wool. 1H NMR (400 MHz, DMSO-d6) δ 11.86 (s, 1H), 7.26 (s, 1H), 5.19 (s, 2H), 2.44 (s, 3H); UPLC-MS-5: Rt = 0.88 min; MS m/z [M+H]+: 260.1/262.0. Step 4: tert-butyl 3-amino-4-bromo-5-chloro-6-methyl-1H-indazol-1-carboxylate

[0625] To a suspension of 4-bromo-5-chloro-6-methyl-1H-indazol-3-amine (Step 3, 3.25 g, 12.5 mmol), triethylamine (3.48 mL, 24.95 mmol), and DMAP (0.38 g, 3.12 mmol) in DCM (70 mL) was added Boc-anhydride (3.13 g, 14.35 mmol) and the reaction mixture was stirred at RT for 2.33 h and a precipitate formed. The reaction mixture was filtered to give tert-butyl 3-amino-4-bromo-5-chloro-6-methyl-1H-indazole-1-carboxylate as the major product: 1H NMR (400 MHz, DMSO-d6) δ 8.03 (s, 1H), 6.10 (s, 2H), 2.52 (s, 3H), 1.59 (s, 9H); UPLC-MS-5: Rt = 1.30 min; MS m/z [M+H]+: 360.0/362.0. The filtrate was concentrated under reduced pressure, the residue dissolved in EtOAc, washed with sat. aq. NaHCO3 and brine, the organic phase dried with a phase separator and concentrated under reduced pressure. The crude residue was purified by normal phase chromatography (eluent: c-hexane/EtOAc 100/0 to 70/30 within 30 min) to give tert-butyl 3-amino-4-bromo-5-chloro-6-methyl-2H-indazole-2-carboxylate: 1H NMR (400 MHz, DMSO-d6) δ 7.21 (s, 1H), 7.03 (s, 2H), 2.36 (s, 3H), 1.60 (s, 9H); UPLC-MS-5: Rt = 1.31 min; MS m/z [M+H]+: 360.1/362.1. Step 5: tert-butyl 3-amino-5-chloro-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-carboxylate

[0626] In a sealed tube, a solution of tert-butyl 3-amino-4-bromo-5-chloro-6-methyl-1H-indazole-1-carboxylate (Step 4, 1.00 g, 2.77 mmol), bis-(pinacolato)-diboron (2.82 g, 11.1 mmol), PdCl2(dppf) (0.20 g, 0.28 mmol), and potassium acetate (0.68 g, 6.93 mmol) in 1,4-dioxane (24 mL) was stirred at 80 °C for 16 h. Additional bis-(pinacolato)-diboron (2.82 g, 11.1 mmol) and PdCl2(dppf) (0.20 g, 0.28 mmol) were added, and the reaction mixture was stirred for an additional 13.5 h. The reaction mixture was filtered, the filtrate concentrated under reduced pressure, and the crude residue purified by normal-phase chromatography (eluent: c-hexane/EtOAc 100/0 to 40/60 within 30 min) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 7.92 (s, 2H), 6.35 (s, 1H), 2.45 (s, 3H), 1.59 (s, 9H), 1.40 (s, 12H); UPLC-MS-5: Rt = 1.43 min; MS m/z [M+H]+: 408.3/410.3. Biological assays and biological data

[0627] The activity of a compound according to the present invention can be evaluated by the following in vitro methods. Purification of human KRasG12C 1-169, biotinylated at the N-terminus

[0628] Amino acids of human KRASG12C (UniProtKB: P01116) M1-K169 were expressed from plasmid pCZ239 (SEQ ID NO: 1) in E.coli BL21(DE3) in the presence of a plasmid encoding biotin-[acetyl-CoA-carboxylase] ligase BirA (NCBI Reference Sequence: NP_418404.1, aa 1-321, full length) in Luria-Bertani (LB)-medium supplemented with 25 μg/mL kanamycin, 34 μg/mL chloramphenicol, 135 μM biotin, and 1 mM isopropyl β-D-1-thiogalactopyranoside overnight at 18 °C. Cells were harvested by centrifugation and frozen at −80 °C until further processing. Cells were thawed and resuspended in buffer A (20 mM Tris-HCl pH8, 500 mM NaCl, 5 mM imidazole, 2 mM TCEP, 10% glycerol) supplemented with 1 protease inhibitor tablet/50 mL buffer (Complete EDTA free, Roche) and 15 μL Turbonuclease (90% purity, 50KUN, >200.00 units/mL, Sigma) and incubated for 20 min at 4 °C. Cells were lysed by 4 passages through an Avestin Emulsiflex at approximately 20,000 psi and insoluble debris removed by centrifugation and filtered through a 0.45 μm Durapore membrane (Millipore). Immobilized metal affinity chromatography was performed with a 5 mL HisTrap HP column (GE) with buffer A and eluted with a linear gradient in 10 column volumes of buffer A replaced by 200 mM imidazole. Eluted protein fractions were analyzed by Novex NuPage 4–12% PAGE. The affinity tag was removed by HRV3C protease cleavage (HRV3C protease produced in-house but also commercially available) during dialysis against buffer A for 18 h at 4 °C and captured by a reverse IMAC purification on a 5 mL HisTrap HP column. Protein in the flow-through was subjected to a final polishing step on a HiLoad 16/60 Superdex 200 prep-grade size exclusion column pre-equilibrated with SEC buffer (20 mM HEPES pH 7.4, 150 mM NaCl, 5 mM MgCl2, 1 μM GDP). Positive fractions were determined by PAGE analysis (Novex NuPage 4-12% BisTris). The correct mass was determined by LC-MS RP (Reverse Phase), and indicated complete biotinylation of the protein. SEQ ID No:1 - plasmid pCZ239 DNA sequence, underlined coding sequence ATGCGTCCGGCGTAGAGGATCGAGATCGATCTCGATCCCGCGAA ATTAATACGACTCACTATAGGGGAATTGTGAGCGGATAACAATTCC CCTCTAGAAATAATTTTGTTTAACTTTAAGAAGGAGATATACATATG AAAACACATCATCATCATCATCATGGTGGCGGCAGTGGCGGTGGC TCAGGCGGTGGTTCTCTCGAGGTTCTGTTCCAGGGTCCGGGTTTG AACGACATCTTCGAAGCTCAGAAGATCGAATGGCACGAGGGTG CGGTAGTGGTGGTGGCTCTATGACTGAATACAAGCTGGTTGTTGT TGGTGCTTGTGGCGTTGGTAAGAGCGCACTGACCATCCAGCTCAT TCAGAATCACTTCGTGGACGAGTACGACCCGACCATCGAAGATTC TTACCGTAAACAGGTGGTTATTGATGGCGAAACCTGTCTGCTGGA TATTCTGGACACTGCTGGTCAGGAAGAGTACTCCGCTATGCGTGA TCAGTACATGCGTACTGGTGAAGGTTTCCTCTGCGTGTTCGCTAT CAACAACACCAAGTCCTTCGAAGATATCCACCATTACCGTGAACA GATCAAACGTGTGAAGGACAGCGAAGACGTGCCAATGGTTCTGGT GGGCAACAAATGTGATCTCCCGA GCCGTACCGTTGACACCAAACA GGCACAAGACCTGGCACGTTCCTACGGCATCCCATTCATTGAAAC TAGCGCGAAGACTCGTCAGGGTGTGGACGACGCATTCTACACTCT GGTGCGTGAAATTCGCAAGCACAAAGAGAAATAATGGTACCGAAT TCGCGGCCGCCTGCAGCCTAGGCTGCTAAACAAAGCCCGAAAGG AAGCTGAGTTGGCTGCTGCCACCGCTGAGCAATAACTAGCATAAC CCCTTGGGGCCTCTAAACGGGTCTTGAGGGGTTTTTTGCTGAAAG GAGGAACTATATCCGGATTGGCGAATGGGACGCGCCCTGTAGCG GCGCATTAAGTGCAGCGTCAAAAGGGCGACACAAAATTTATTCTA AATGCATAATAAATACTGATAACATCTTATAGTTTGTATTATATTTTG TATTATCGTTGACATGTATAATTTTGATA TCAAAAACTGATTTTCCC TTTATTATTTTCGAGATTTATTTTCTTAATTCTCTTTAACAAACTAGA AATATTGTATATACAAAAAATCATAAATAATAGATGAATAGTTTAATT ATAGGTGTTCATCAATCGAAAAAGCAACGTATCTTATTTAAAGTGC GTTGCTTTTTTCTCATTTATAAGGTTAAATAATTCTCATATATCAAG CAAAGTGACAGGCGCCCTTAAATATTCTGACAAATGCTCTTTCCCT AAACTCCCCCCATAAAAAAACCCGCCGAAGCGGGTTTTTACGTTA TTTGCGGATTAACGATTACTCGTTATCAGAACCGCCCAGGGGGCC CGAGCTTAAGACTGGCCGTCGTTTTACAACACAGAAAGAGTTTGT AGAAACGCAAAAAGGCCATCCGTCAGGGGCCTTCTGCTTAGTTTG ATGCCTGGCAGTTCCCTACTCTCGCC TTCCGCTTCCCTCGCTCACT GACTCGCTGCGCTCGGTCGTTCGGCTGCGGCGAGCGGTATCAGC TCACTCAAAGGCGGTAATACGGTTATCCACAGAATCAGGGGATAA CGCAGGAAAGAACATGTGAGCAAAAGGCCAGCAAAAGGCCAGGA ACCGTAAAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCC CCCCTGACGAGCATCACAAAAATCGACGCTCAAGTCAGAGGTGG CGAAACCCGACAGGACTATAAAGATACCAGGCGTTTCCCCCTGGA AGCTCCCTCGTGCGCTCTCCTGTTCCGACCCTGCCGCTTACCGGA TACCTGTCCGCCTTTCTCCCTTCGGGAAGCGTGGCGCTTTCTCAT AGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTCGTTCGCTCC AAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGCTG CGCCTTATCCGGTAACTAT CGTCTTGAGTCCAACCCGGTAAGACA CGACTTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAG AGCGAGGTATGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGG CTAACTACGGCTACACTAGAAGAACAGTATTTGGTATCTGCGCTCT GCTGAAGCCAGTTACCTTCGGAAAAAGAGTTGGTAGCTCTTGATC CGGCAAACAAACCACCGCTGGTAGCGGTGGTTTTTTTGTTTGCAA GCAGCAGATTACGCGCAGAAAAAAAGGATCTCAAGAAGATCCTTT GATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGACGCGCGCG TAACTCACGTTAAGGGATTTTGGTCATGAGCTTGCGCCGTCCCGT CAAGTCAGCGTAATGCTCTGCTTTTAGAAAAACTCATCGAGCATCA AATGAAACTGCAATTTATTCATATCAGG ATTATCAATACCATATTTT TGAAAAAGCCGTTTCTGTAATGAAGGAGAAAACTCACCGAGGCAG TTCCATAGGATGGCAAGATCCTGGTATCGGTCTGCGATTCCGACT CGTCCAACATCAATACAACCTATTAATTTCCCCTCGTCAAAAATAA GGTTATCAAGTGAGAAATCACCATGAGTGACGACTGAATCCGGTG AGAATGGCAAAAGTTTATGCATTTCTTTCCAGACTTGTTCAACAGG CCAGCCATTACGCTCGTCATCAAAATCACTCGCATCAACCAAACC GTTATTCATTCGTGATTGCGCCTGAGCGAGGCGAAATACGCGATC GCTGTTAAAAGGACAATTACAAACAGGAATCGAGTGCAACCGGCG CAGGAACACTGCCAGCGCATCAACAATATTTTCACCTGAATCAGG ATATTCTTCTAATACCTGGAACGCTGTTTTTCCGGG GATCGCAGTG GTGAGTAACCATGCATCATCAGGAGTACGGATAAAATGCTTGATG GTCGGAAGTGGCATAAATTCCGTCAGCCAGTTTAGTCTGACCATC TCATCTGTAACATCATTGGCAACGCTACCTTTGCCATGTTTCAGAA ACAACTCTGGCGCATCGGGCTTCCCATACAAGCGATAGATTGTCG CACCTGATTGCCCGACATTATCGCGAGCCCATTTATACCCATATAA ATCAGCATCCATGTTGGAATTTAATCGCGGCCTCGACGTTTCCCG TTGAATATGGCTCATATTCTTCCTTTTTCAATATTATTGAAGCATTT ATCAGGGTTATTGTCTCATGAGCGGATACATATTTGAATGTATTTA GAAAAATAAACAAATAGGGGTCAGTGTTACAACCAATTAACCAATT CTGAACATTATCGCGAGCCCATTTATACCTGAATA TGGCTCATAAC ACCCCTTGTTTGCCTGGCGGCAGTAGCGCGGTGGTCCCACCTGA CCCCATGCCGAACTCAGAAGTGAAACGCCGTAGCGCCGATGGTA GTGTGGGGACTCCCCATGCGAGAGTAGGGAACTGCCAGGCATCA AATAAAACGAAAGGCTCAGTCGAAAGACTGGGCCTTTCGCCCGG GCTAATTAGGGGGTGTCGCCCTTCGCTGAAGAATTGATCCCGGTG CCTAATGAGTGAGCTAACTTACATTAATTGCGTTGCGCTCACTGCC CGCTTTCCAGTCGGGAAACCTGTCGTGCCAGCTGCATTAATGAAT CGGCCAACGCGGGGAGAGGCGGTTTGCGTATTGGGCGCCAG GGTGGTTTTTCTTTTCACCAGTGACACGGGCAACAGCTGATTGCC CTTCACCGCCTGGCCCTGAGAGAGTTGCAGCAAGCGGTCCACGC TGGTTTGCCCCAGCAGGCGAAAAT CCTGTTTGATGGTGGTTAACG GCGGGATATAACATGAGCTGTCTTCGGTATCGTCGTATCCCACTA CCGAGATGTCCGCACCAACGCGCAGCCCGGACTCGGTAATGGCG CGCATTGCGCCCAGCGCCATCTGATCGTTGGCAACCAGCATCGC AGTGGGAACGATGCCCTCATTCAGCATTTGCATGGTTTGTTGAAA ACCGGACATGGCACTCCAGTCGCCTTCCCGTTCCGCTATCGGCT GAATTTGATTGCGAGTGAGATATTTATGCCAGCCAGCCAGACGCA GACGCGCCGAGACAGAACTTAATGGGCCCGCTAACAGCGCGATT TGCTGGTGACCCAATGCGACCAGATGCTCCACGCCCAGTCGCGT ACCGTCTTCATGGGAGAAAATAATACTGTTGATGGGTGTCTGGTC AGAGACATCAAGAAATAACGCCGGAACATTAG TGCAGGCAGCTTC CACAGCAATGGCATCCTGGTCATCCAGCGGATAGTTAATGATCAG CCCACTGACGCGTTGCGCGAGAAGATTGTGCACCGCCGCTTTAC AGGCTTCGACGCCGCTTCGTTCTACCATCGACACCACCACGCTGG CACCCAGTTGATCGGCGCGAGATTTAATCGCCGCGACAATTTGCG ACGGCGCGTGCAGGGCCAGACTGGAGGTGGCAACGCCAATCAG CAACGACTGTTTGCCCGCCAGTTGTTGTGCCACGCGGTTGGGAAT GTAATTCAGCTCCGCCATCGCCGCTTCCACTTTTTCCCGCGTTTTC GCAGAAACGTGGCTGGCCTGGTTCACCACGCGGGAAACGGTCTG ATAAGAGACACCGGCATACTCTGCGACATCGTATAACGTTACTGG TTTCACATTCACCACCCTGAATTGACTCTCTTCCGGGCGCTATCAT GCCATACCGCGAAAGGTTTTGCGCCAT TCGATGGTGTCCGGGATC TCGACGCTCTCCCTTATGCGACTCCTGCATTAGGAAGCAGCCCAG TAGTAGGTTGAGGCCGTTGAGCACCGCCGCCGCAAGGAATGGTG CATGCAAGGAGATGGCGCCCAACAGTCCCCCGGCCACGGGGCCT GCCACCATACCCACGCCGAAACAAGCGCTCATGAGCCCGAAGTG GCGAGCCCGATCTTCCCCATCGGTGATGTCGGCGATATAGGCGC CAGCAACCGCACCTGTGGCGCCGGTGATGCCGGCCACG Preparation of: N-(3-fluoro-4-(2-methyl-3-(5-methyl-1H-indazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl)phenyl)acrylamide (Compound A) Step 1: 3-bromo-2-methyl-1H-pyrrolo[2,3-b]pyridine

[0629] To a solution of 2-methyl-1H-pyrrolo[2,3-b]pyridine (1.63 g, 12.3 mmol) in acetonitrile (50 mL) was added NBS (2.19 g, 12.33 mmol) at RT. The reaction mixture was stirred at RT for 1 h. The reaction was quenched by addition of 10% sodium thiosulfate solution (10 mL). The solution was then extracted with EtOAc (20 mL). The organic phase was washed with water (3x), brine, then dried (MgSO4), filtered, and evaporated. UPLC-MS-1: Rt = 0.88 min; MS m/z [M+H]+; 211/213. Step 2: 3-bromo-1-(2-fluoro-4-nitrophenyl)-2-methyl-1H-pyrrolo[2,3-b]pyridine

[0630] To a solution of 3-bromo-2-methyl-1H-pyrrolo[2,3-b]pyridine (Step 1, 2.4 g, 11.37 mmol) in dry DMSO (20 mL) was added under inert atmosphere potassium tert-butoxide (1.40 g, 12.5 mmol) and 1,2-difluoro-4-nitrobenzene (1.81 g, 11.4 mmol). The reaction mixture was stirred at 80 °C for 2 h. The reaction was quenched by addition of water. The solution was then extracted with EtOAc (3x). The organic phase was washed with brine, then dried (MgSO4), filtered, and evaporated. The crude product was purified by normal phase chromatography (eluent: 0 to 30% EtOAc in Heptane) to give the title compound. UPLC-MS-1: Rt = 1.24 min; MS m/z [M+H]+; 350.0/352.1. Step 3: 4-(1-(2-fluoro-4-nitrophenyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-methyl-1-tosyl-1H-indazole

[0631] To a solution of 3-bromo-1-(2-fluoro-4-nitrophenyl)-2-methyl- 1H-pyrrolo[2,3-b]pyridine (Step 2, 1.00 g, 2.86 mmol) in 1,4-dioxane (10 mL)/water (2.8 mL) was added under inert atmosphere 5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indazole (Intermediate D5) (1.41 g, 3.43 mmol) followed by K3PO4 (1.21 g, 5.71 mmol) and then Pd-XPhos-G3 (0.24 g, 0.29 mmol). The reaction mixture was stirred 3 h at 80 °C. The reaction was quenched by addition of saturated NaHCO3 solution. The solution was then extracted with EtOAc. The organic phase was washed with brine, then dried (MgSO4), filtered and evaporated. The crude product was purified by normal phase chromatography (eluent: EtOAc in n-heptane 0 to 50%) to give the title compound. UPLC-MS-1: Rt = 1.38 min; MS m/z [M+H]+ 556.2 Step 4: 4-(1-(2-fluoro-4-nitrophenyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-methyl-1H-indazole

[0632] To a stirred solution of 4-(1-(2-fluoro-4-nitrophenyl)-2-methyl- 1H-pyrrolo[2,3-b]pyridin-3-yl)-5-methyl-1-tosyl-1H-indazole (Step 3, 1.34 g, 2.41 mmol) in 1,4-dioxane (12 mL) was added NaOH (6.03 mL, 12.1 mmol) at RT. The mixture was stirred at 60 °C for 3 h. The reaction was quenched by addition of water. The solution was then extracted with EtOAc. The organic phase was washed with brine, then dried over MgSO4, filtered, and evaporated. The crude product was purified by normal phase chromatography (eluent: 0 to 100% EtOAc in Heptane) to give the title compound. UPLC-MS-1: Rt = 1.11 min; MS m/z [M+H]+ 402.2 Step 5: 3-fluoro-4-(2-methyl-3-(5-methyl-1H-indazol-4-yl)-1H-pyrrolo[2,3- b]pyridin-1-yl)aniline

[0633] To a solution of 4-(1-(2-fluoro-4-nitrophenyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-methyl-1H-indazole (Step 4, 780 mg, 1.94 mmol) in THF (10 mL) were added tin powder (807 mg, 6.80 mmol) and conc. HCl (0.59 mL, 19.43 mmol). The solution was stirred at 70 °C for 4 h. The reaction was quenched by addition of sodium hydroxide and water. The solution was then extracted with EtOAc. The organic phase was washed with brine, then dried over MgSO4, filtered, and evaporated to give the title compound. UPLC-MS-1: Rt = 0.93 min; MS m/z [M+H]+ 372.4 Step 6: 3-fluoro-4-(2-methyl-3-(5-methyl-1H-indazol-4-yl)-1H-pyrrolo[2,3- b]pyridin-1-yl)aniline

[0634] 3-Fluoro-4-(2-methyl-3-(5-methyl-1H-indazol-4-yl)-1H-pyrrolo[2,3- b ]pyridin-1-yl)aniline as isomer mixture (454 mg) in IPA (30 mg/mL) was separated by chiral SFC (column: Lux IC 5 μm; 250 x 21.2 mm; mobile phase: CO2/IPA 55/45; flow rate: 50 mL/min; column temperature: 40 °C; back pressure: 105 bar) to give 3-fluoro-4-(2-methyl- 3-(5-methyl-1H-indazol-4-yl)-1H-pyrrolo[2,3- b ]pyridin-1-yl)aniline as first eluting isomer (analytical chiral SFC; column: Chiralpak AD- H 5 μm; 250 x 4.6 mm; mobile phase: CO2/[IPA+1% isopropylamine]: 50/50; flow rate: 3 mL/min; column temperature: 40 °C; back pressure: 120 bar): Rt = 2.99 min and 3-fluoro-4-(2-methyl-3-(5-methyl-1H-indazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl)aniline as the second eluting isomer (analytical chiral SFC; column: Chiralpak AD-H 5 μm; 250 x 4.6 mm; mobile phase: CO2/[IPA+1% isopropylamine]: 50/50; flow rate: 3 mL/min; column temperature: 40 °C; back pressure: 120 bar bar): Rt = 5.79 min. UPLC-MS-1: Rt = 0.92 min; MS m/z [M+H]+ 372.2 Step 7: N-(3-fluoro-4-(2-methyl-3-(5-methyl-1H-indazol-4-yl)-1H-pyrrolo[2,3- b]pyridin-1-yl)phenyl)acrylamide

[0635] To a solution of 3-fluoro-4-(2-methyl-3-(5-methyl-1H-indazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl)aniline (Step 6, second elution peak, 19 mg, 0.05 mmol) in CH2Cl2 (1.5 mL) were added DIPEA (0.03 mL, 0.15 mmol) and acryloyl chloride (4.57 μL, 0.06 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 4 h. MeOH was added to the mixture and evaporated to dryness. The reaction was quenched by addition of saturated NaHCO3 solution. The solution was then extracted with CH2Cl2. The organic phase was washed with brine, then dried over MgSO4, filtered and evaporated. The crude product was purified by normal phase chromatography (eluent: EtOAc in n-heptane 0 to 100%) to give the title compound. 1H NMR (600 MHz, DMSO-d6) δ 13.12 - 13.03 (m, 1H), 10.63 (s, 1H), 8.21 - 8.16 (m, 1H), 8.03 - 7.96 (m, 1H), 7.79 - 7.45 (m, 5H), 7.43 - 7.37 (m, 1H), 7.18 - 7.10 (m, 1H), 6.54 - 6.45 (m, 1H), 6.40 - 6.32 (m, 1H), 5.90 - 5.83 (m, 1H), 2.29 - 2.22 (m, 3H), 2.09 (s, 3H); UPLC-MS-1: Rt = 0.98 min; MS m/z [M+H]+ 426.4 Preparation of [acrylamide-2,3-3H2]-N-(3-fluoro-4-(2-methyl-3-(5-methyl-1H-indazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl)phenyl)acrylamide (Compound B): Step 1: N-(3-fluoro-4-(2-methyl-3-(5-methyl-1H-indazol-4-yl)-1H-pyrrolo[2,3- b]pyridin-1-yl)phenyl)propiolamide

[0636] To an ice-cooled solution of 3-fluoro-4-(2-methyl-3-(5-methyl-1H-indazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl)aniline (Compound A, step 6 second elution peak) (50 mg, 0.14 mmol) in DMF (1.5 mL) was added a mixture of DIPEA (0.09 mL, 0.54 mmol), propionic acid (9.43 mg, 0.14 mmol), and propylphosphonic anhydride (50% in DMF, 0.16 mL, 0.27 mmol). The reaction mixture was stirred at RT under nitrogen for 15 min. The reaction mixture was poured into sat. aq. NaHCO3 solution and extracted with EtOAc (x3). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by achiral SFC (column: Princeton PPU 5 μm; 250 × 30 mm; mobile phase: CO2/MeOH: gradient with 24-29% MeOH in CO2 over 9.8 min; flow rate: 30 mL/min; column temperature: 36 °C; backpressure: 120 bar) and repurified by achiral SFC (column: Princeton PPU 5 μm; 250 × 30 mm; mobile phase: CO2/MeOH: gradient with 20-26% MeOH in CO2 over 9.8 min; flow rate: 30 mL/min; column temperature: 36 °C; backpressure: 120 bar) to afford the title compound. UPLC-MS-1: Rt = 0.97 min; MS m/z [M+H]+ 424.4 Step 2: [acrylamide-2,3-3H2]-N-(3-fluoro-4-(2-methyl-3-(5-methyl-1H-indazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl)phenyl)acrylamide

[0637] N-(3-fluoro-4-(2-methyl-3-(5-methyl-1H-indazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl)phenyl)propiolamide (step 1) (3.20 mg, 7.56 μmol), Lindlar catalyst (6.57 mg), quinoline (11.8 μL, 12.90 mg, 99.6 μmol) were suspended in DMF (0.60 mL). The suspension was degassed three times in the high vacuum manifold and stirred under a tritium gas atmosphere (355 GBq, 508 mbar initial pressure) for 80 min at room temperature (final pressure was 505 mbar, no further tritium gas consumption was observed). The solvent was removed in vacuo, and labile tritium was exchanged by adding methanol (0.70 mL), stirring the solution, and removing the solvent again in vacuo. This process was repeated twice. Finally, the well-dried solid was extracted with 5 mL of ethanol, and the suspension was filtered through a 0.2 μm nylon membrane to obtain a clear, colorless solution. The radiochemical purity was determined to be 86% by HPLC (Waters Sunfire HPLC with UV detector; column: C18 5 μm; 250 × 4.6 mm; mobile phase: A: water/B: acetonitrile, 0 min 10% B, 10 min 95% B, 14.5 min 95% B, 15 min 10% B; flow rate: 1 mL/min; column temperature: 30 °C). Purification of the crude product was performed by reversed-phase HPLC (Waters Sunfire; column: C18 5 μm; 250 × 10 mm; UV detection 254 nM; mobile phase: A: water/B: MeOH, isocratic 62% B; flow rate: 4.7 mL/min; column temperature: 25 °C). The target compound eluted at 19.1 min. The combined HPLC fractions were partially reduced on the rotary evaporator at 40 °C. Then, the product was extracted with a Phenomenex StrataX cartridge (reversed-phase polymeric 33 μm, 100 mg, 3 mL; 8B-S100-EB) that was eluted with 5 mL of ethanol. The extracted product contained the title compound with an activity of 2.61 GBq and a radiochemical purity >99%. The molar activity was determined to be 2.12 TBq/mmol.

In vitro biochemical quantification of covalent modification of KRASG12C

[0638] A scintillation proximity assay (SPA) was used to determine the potency of the compounds.

[0639] This assay measures the ability of the test compound to compete with the radiolabeled covalent probe for binding and covalently modifying KRASG12C.

[0640] The signal to be measured is generated by binding an isotopic dilution of the covalent radioligand [[acrylamide-2,3-3H2]-N-(3-fluoro-4-(2-methyl-3-(5-methyl-1H-indazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl)phenyl)acrylamide (Compound B) (2.12 TBq/mmol) and its unlabeled analogue [N-(3-fluoro-4-(2-methyl-3-(5-methyl-1H-indazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl)phenyl)acrylamide (Compound A) to KRasG12C (M1-K169, biotinylated at the N-terminus) which is attached to SPA microspheres via the coupling of biotin-streptavidin. (see below for synthesis of Compound A and Compound B). A serial dilution of the compounds to be tested is mixed with a fixed concentration of the radiolabeled covalent probe prior to incubation with KRASG12C:GDP as described below. KRASG12C can be bound by the radiolabeled covalent probe (Compound B), resulting in light being emitted from the microspheres, or bound by the covalent test compound which prevents signal generation.

[0641] Assays were performed using 384-well plates (781207/Greiner) in which one column was designated as the high signal control (no inhibition) and contained DMSO without test compound, and the other column was designated as the low signal control (maximal inhibition) and contained no protein. Serial dilutions of the compounds to be tested were added to the assay plate (resulting in a 11-point dose response in duplicate with half-log compound dilutions from 50 μM to 0.5 nM or from 5 μM to 0.05 nM for the most potent compounds). A 1/20 isotopic dilution of covalently labeled (Compound B) and unlabeled (Compound A) probe was prepared and added to all wells in the plate. The reaction was initiated by addition of KRasG12C (M1-K169, biotinylated at the N-terminus) to the compounds and incubated for 2 h with continuous shaking allowing full modification of KRasG12C with probe or test compounds. Final concentrations in a 40 μl assay volume were 10 nM KRasG12C, 25 nM radioligand, and 475 nM unlabeled ligand. The assay buffer contained 20 mM Tris-HCl pH 7.5 (Invitrogen), 150 mM NaCl (Sigma Aldrich), 0.1 mM MgCl2 (Sigma Aldrich), and 0.01% Tween-20 (Sigma Aldrich). After addition of 50 μl of a 400 μg/mL suspension of streptavidin-coated YSi microspheres (Perkin Elmer), the plates were incubated for an additional 30 min with continuous shaking before reading the plates in a scintillation counter (Topcount NXT 384 (Packard).

[0642] Evaluation was performed using assay data analysis software (such as the standard Novartis in-house Helios software application, Novartis Institutes for BioMedical Research, unpublished) using the methods described in Formenko et al., Robust Regression for high-throughput screening, Computer Methods and Programs in Biomedicine, 2006, 82, 31-37. After normalization of activity values for the wells to % inhibition (% inhibition = [(high control-sample)/(high control-low control)] x 100), IC50 adjustment was performed from the duplicate determinations present on each plate according to Formenko et al., 2006.

[0643] The assessment may also be performed using commercially available software that is designed to derive IC50 values using 4-parameter fits (e.g., GraphPad Prism, XL fit).

[0644] Titration of the unlabeled version of the probe, Compound A, in this assay resulted in an IC50 of 0.5 μM. IC50 values, e.g., 1 to 94, are tabulated in Table .2

[0645] Note: The IC50 test endpoint values generated in this manner can in principle be used to derive second-order rate constants for the covalent binders according to a method described by Miyahisa et al. 2015, Rapid Determination of the Specificity Constant of Irreversible Inhibitors (kinact/KI) by Means of an Endpoint Competition Assay, Angew. Chem, Int, Ed. Engl, 2015 Nov 16;54(47):14099-14102,).

[0646] After this, the rate constants can be derived by applying the equation (kinact/K)inhibitor=(kinact/KI)probe x [probe]/IC50 using 0.5 uM as [probe]. "(kinact/KI)probe", the second-order rate constant for modification of KRasG12C by this probe was internally determined to be ~5,000 M-1*s-1 for the unlabeled ligand [N-(3-fluoro-4-(2-methyl-3-(5-methyl-1H-indazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl)phenyl)acrylamide (Compound A) using an MS-based assay (assessing % modification for a range of compound concentrations and time points). Table 2: Tabulated in vitro KRASG12C activities

Claims (27)

1. Compound, characterized by the fact that it presents Formula (I), or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, wherein A is selected from the group consisting of: (a) C5-C7-cycloalkylene which is unsubstituted or substituted with one or more, preferably 1, 2 or 3, substituents independently selected from fluorine and C1-C4-alkyl; (b) an unsaturated 5-7 membered heterocyclyl containing a carbon-carbon double bond and an oxygen atom as a ring member, said heterocyclyl being unsubstituted or substituted with one or more, preferably 1, 2 or 3, substituents independently selected from fluorine and C1-C4-alkyl, preferably 1, 2 or 3, C1-C4-alkyl; (c) C6-C10 aryl, which is unsubstituted or substituted with 1, 2 or 3 RA2; (d) a 5-6 membered heteroaryl ring containing 1, 2 or 3 heteroatoms independently selected from N, O and S as ring members, wherein said heteroaryl ring is unsubstituted or substituted on one or more (e.g., 1, 2 or 3) carbon atoms with RA3, and wherein a nitrogen atom, when present in the heteroaryl ring, is unsubstituted or substituted with a substituent selected from the group consisting of: C1-C4-alkyl, -(CH2)1-2-C3-4-cycloalkyl, C3-C6-cycloalkyl, hydroxy-C1-C4-alkyl, fluoro-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, N(R9)(R10)-C1-C4-alkyl, -SO2-C1-C4-alkyl, -Sθ2-C3-4-cycloalkyl, -(CH2)p-Hetpy, and -(CH2)pN(R9)(R10); (e) an 8-10 membered heteroaryl ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or a partially saturated 8-10 membered heterobicyclic ring containing 1 to 3 heteroatoms or heteroatom groups independently selected from 0-3 nitrogen atoms, 0-2 oxygen atoms, 0-1 sulfur atom and 0-1 S(=O)2 group, in the heterobicyclic ring, wherein said heteroaryl ring or heterobicyclic ring is unsubstituted or substituted on one carbon atom with 1, 2, 3, 4 or 5 RA4, and wherein the heterobicyclic ring is further optionally substituted on one carbon atom by oxo and wherein a nitrogen atom, when present, is unsubstituted or substituted with a substituent which is -(CO)-C1-C4-alkyl or C1-C4-alkyl, and wherein said C1-C4-alkyl is optionally substituted with 1 or 2 substituents independently selected from cyano, hydroxy, oxo, fluorine, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Hetb and NR9R10; and wherein Hetb is a 4-, 5-, or 6-membered heterocyclic ring comprised of 1 or 2 heteroatoms or groups independently selected from N, O, S, SO, and SO2, wherein said Hetb heterocyclic ring is unsubstituted or substituted on a carbon atom with one or two substituents independently selected from C1-C4-alkyl, hydroxy, cyano, fluorine, C1-C4-alkoxy-hydroxy-C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy, fluorine-C1-C4-alkoxy, and fluorine-C1-C4-alkyl, and wherein said Hetb heterocyclic ring is further optionally substituted on a carbon atom with oxo, and wherein the nitrogen atom, when present in Hetb, is further optionally substituted with C1-C4-alkyl, which is optionally substituted with 1 to 3 substituents independently selected from fluorine, hydroxy and C1-C4-alkoxy; wherein A is bonded to the remainder of the compound of formula (I) through a carbon atom in A which is sp2 hybridized; wherein B is selected from the group consisting of B1 and B2, wherein B1 is a C6-10 aryl which is unsubstituted or substituted with 1, 2, 3 or 4 RBa; B2 is a 6-13 membered heteroaryl which comprises 1, 2 or 3 nitrogen atoms, wherein B2 is unsubstituted or substituted with 1, 2, 3 or 4 RBb; C is selected from the group consisting of hydrogen, C1-C3 alkyl, C3-C5 cycloalkyl, fluorine-C1-C3 alkyl, cyano, -CH2-CN, -CH(CN)-CH3, -CH2-OH, -CH(OH)-CH3 and halo; L represents: in which RL is selected from hydrogen, methyl, ethyl, -CH2-CN and -CH2-OH; G* represents the point of attachment to G; G represents: in which R2 is selected from hydrogen, C1-C3 alkyl, -C(O)-C1-C3-alkyl and fluorine; R3 is hydrogen; R4 is selected from hydrogen, methyl, -CH2F, -CH2-OCH3 and -CH2-N(CH3)2; wherein RA2 is independently selected from the group consisting of: NR9R10, cyano, -(CH2)p-CN, halo, OH, hydroxy-C1-C4-alkyl, -(COOH), -(CH2)p-COOH, C1-C4-alkyl, fluoro-C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl, N( R9) C1-C4-alkoxy-C1-C4-alkyl-oxy-C1-C4-alkyl, -SO2-Ci-C4-alkyl, -SO2-C3-4-cycloalkyl, -(CH2)1-2-C3-4-cycloalkyl, Hetpy, - (CH2)p-Hetpy, -C(=O)-NR9R10, -(CH2)pC(=O)NR9R10; wherein RA3 is independently selected from the group consisting of oxo, NR9Ri0, cyano, -(CH2)p-CN, halo, OH, hydroxy-C1-C4-alkyl, -(COOH), -(CH2)p-COOH, C1-C4-alkyl, fluorine-C1-C4-alkyl, Ci-C4-alkoxy, Ci-C4-alkoxy-C1-C4-alkyl, N( R9) Ci-C4-alkoxy-Ci-C4-alkyl-oxy-Ci-C4-alkyl, -SO2-Ci-C4-alkyl, -SO2-C3-4-cycloalkyl, -(CH2)i-2-C3-4-cycloalkyl, Hetpy, -(CH2)p- Hetpy, -C(=O)-NR9Ri0, -(CH2)pC(=O)NR9Ri0, (CH2) )p-NR9Ri0; where RA4 is independently selected from the group consisting of cyano, CO2H, halo, C1-C4-alkyl, fluoro-C1-C4-alkyl, hydroxy, hydroxy-C1-C4-alkyl, hydroxy-C1-C4-alkyl-oxy, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl-oxy, NR9R10, (N(R9)(R10)-C1-C4-alkyl, (N(R9)(R10)-C1-C4-alkyl-oxy, -(CO)-C1-C4-alkyl, and R9R10N-C1-C4-alkyl-oxy-(CO)-C1-C4-alkyl; where p is i or 2 or 3; R9 is selected from hydrogen and C1-C4-alkyl; R10 is selected from the group consisting of hydrogen, C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, and di-C1-C4-alkyl-amino-C1-C4-alkyl; Hetpy is a saturated 4-, 5-, 6-, or 7-membered heterocyclic ring comprising one or two heteroatoms independently selected from O, N, and S, or comprising an S-oxide (SO) or S-dioxide (SO2) group, and wherein said heterocyclic ring is optionally substituted with oxo at a carbon atom, and wherein said heterocyclic ring is optionally further substituted on one or more carbon atoms with 1, 2, or 3 substituents independently selected from C1-C4-alkoxy, halo, C1-C4-alkyl, hydroxy-C1-C4-alkyl, and fluoro-C1-C4-alkyl, and wherein the nitrogen atom, if present, in said heterocycle, is optionally further substituted with Ri0; or Hetpy is a 5- or 6-membered heteroaryl ring comprising i, 2 or 3 nitrogen atoms and wherein said heteroaryl ring is optionally substituted with one or more (e.g., i, 2 or 3) substituents independently selected from NR9Ri0, -C(=O)-NR9Ri0, halo, C1-C4-alkyl, hydroxy-C1-C4-alkyl, fluoro-C1-C4-alkyl, cyano, OH, and Ci-C4-alkoxy; each RBa is independently selected from the group consisting of hydroxy, NH2, C1-C4-alkyl and halo; and each RBb is independently selected from the group consisting of C1-C4-alkyl, cyclopropyl, fluoro-C1-C3-alkyl, cyano, halo, NH2, and C1-C3-alkoxy. 2. The compound of claim 1, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, wherein C is selected from C1-C3 alkyl, fluoro-C1-Cs alkyl, CH2-CN. 3. Compound according to claim 1 or 2, characterized in that B is: or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, wherein X is N or C-RB5; RBi is selected from hydrogen and C1-C4-alkyl; RB2 is selected from hydrogen, halo, C1-C4-alkyl, cyclopropyl, and NH2; RB3 is selected from hydrogen, halo, cyclopropyl, and C1-C4-alkyl; RB4 is independently selected from hydrogen, halo, and C1-C4-alkyl, or RB3 and RB4 together with the atoms to which they are attached, form a 4-6 membered ring fused to the aromatic ring containing X; RB5 is independently selected from hydrogen, halo, and C1-C4-alkyl. 4. The compound of claim 3, 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, characterized in that RB2 is independently selected from the group consisting of hydrogen, NH2, and CH3. 5. The compound of claim 3 or 4, 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, characterized in that RB4 is independently selected from hydrogen, halo and C1-C4-alkyl. 6. The compound of any one of claims 3 to 5, 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, characterized in that RB1 is independently selected from hydrogen and methyl. 7. The compound of any one of claims 3 to 6, 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, characterized in that RB3 is halo and RB4 is C1-C4-alkyl. 8. The compound of any one of claims 3 to 7, 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, characterized in that X is CH or N. 9. Compound, characterized by the fact that it presents Formula (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, wherein A, B and C are as defined in any one of claims 1 to 8. 10. 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 pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, characterized in that A is selected from the group consisting of: in which y is 0, 1 or 2; x is 0, 1 or 2; z is 0, 1 or 2; RO is selected from the group consisting of hydrogen, NR9R10, R9R10N-C1-C4-alkyl-oxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, hydroxy-C1-C4-alkyl-oxy and C1-C4-alkyl; RM is hydrogen, halo or C1-C4-alkyl, wherein said alkyl is optionally substituted by OH, C1-C4-alkoxy or NR9R10; RN is hydrogen or C1-C4-alkyl, or halo or fluoro-C1-C4-alkyl; Rq is independently selected from the group consisting of C1-C4-alkyl, hydroxy, C1-C4-alkoxy and NR9R10; Rp is C1-C4-alkyl; each Rp1 is independently selected from hydrogen and C1-C4-alkyl; Rv is independently selected from halogen, C1-C4-alkyl, and fluoro-C1-C4-alkyl; Rae is selected from the group consisting of hydrogen and C1-C4-alkyl, said alkyl being optionally substituted with 1 or 2 substituents selected from cyano, hydroxy, fluoro, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Hetb, and NR9R10; RAe is selected from the group consisting of hydrogen, -(CO)-C1-C4-alkyl, and C1-C4-alkyl wherein the C1-C4alkyl in each instance is optionally substituted with 1 or 2 substituents selected from cyano, hydroxy, fluorine, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Hetb, and NR9R10; wherein R9 is selected from hydrogen and C1-C4-alkyl; R10 is selected from hydrogen, C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl, and di-C1-C4-alkyl-amino-C1-C4-alkyl; wherein Hetb is a 4-, 5-, or 6-membered heterocyclic ring comprising 1 or 2 heteroatoms or groups independently selected from N, O, S, SO, and SO2, wherein said Hetb heterocyclic ring is unsubstituted or substituted on a carbon atom with one or two substituents independently selected from C1-C4-alkyl, hydroxy, cyano, fluorine, hydroxy-C1-C4-alkyl, C1-C4-alkoxy, and fluorine-C1-C4-alkyl, and wherein said Hetb heterocyclic ring is further optionally substituted on a carbon atom with oxo, and wherein the nitrogen atom, when present, in Hetb is optionally further substituted with C1-C4-alkyl which is optionally substituted with 1 to 3 substituents independently selected from fluorine, hydroxy, and C1-C4-alkoxy. 11. A compound of formula (I) or of 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 pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, characterized in that A is selected from the group consisting of: in which z is 0, 1 or 2; Rv is independently selected from halogen, C1-C4-alkyl and fluoro-C1-C4-alkyl; RN is hydrogen or C1-C4-alkyl, or halo or fluoro-C1-C4-alkyl; RO is selected from the group consisting of hydrogen, NR9R10, N(R9)(R10)-C1-C4-alkyl-oxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, hydroxy-C1-C4-alkyl-oxy and C1-C4-alkyl; Rae is selected from the group consisting of hydrogen and C1-C4-alkyl, said alkyl being optionally substituted with 1 or 2 substituents selected from cyano, hydroxy, fluorine, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkyl-oxy, Hetb and NR9R10; R9 is selected from hydrogen and C1-C4-alkyl; R10 is selected from hydrogen, C1-C4-alkyl, hydroxy-C1-C4-alkyl, C1-C4-alkoxy-C1-C4-alkyl and di-C1-C4-alkyl-amino-C1-C4-alkyl; wherein Hetb is a 4- or 5- or 6-membered heterocyclic ring comprising 1 or 2 heteroatoms or groups independently selected from N, O, S, SO and SO2, wherein said Hetb heterocyclic ring is unsubstituted or substituted at a carbon atom with one or two substituents independently selected from C1-C4-alkyl, hydroxy, cyano, fluorine, hydroxy-C1-C4-alkyl, C1-C4-alkoxy and fluorine-C1-C4-alkyl, and wherein said Hetb heterocyclic ring is further optionally substituted on a carbon atom with oxo, and wherein the nitrogen atom, when present in Hetb, is further optionally substituted with C1-C4-alkyl, which is optionally substituted with 1 to 3 substituents independently selected from fluorine, hydroxy and C1-C4-alkoxy. 12. A compound of formula (I) or formula (Ia) according to claim 10 or 11, 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, characterized in that A is selected from the group consisting of: 13. A compound of formula (I) or formula (Ia) according to claim 12, 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, characterized in that: RN is hydrogen or C1-C4-alkyl; RO is hydrogen or NR9R10; Rv is independently selected from fluorine, chlorine and C1-C4-alkyl; z is 0 or 1. 14. Compound, characterized by the fact that it presents the Formula (Ib*), wherein A, C, RB2, RB3 and RB4 are as defined in any one of claims 1 to 13, wherein A is unsubstituted or substituted as defined in any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof. 15. Compound, characterized by the fact that it presents the Formula (Id*), wherein C, RB2, RN, RB3 and RB4 are as defined in any one of claims 1 to 14, with the lines indicating a single bond or a double bond; and Rae is as defined in claim 10 or 11. 16. Compound, according to claim 1, characterized by the fact that it is selected from: or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof. 17. Compound according to claim 1, characterized in that it is selected from: a(R)-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl) -5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1- one, a(R)(S)-1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(1-(2-(3-fluoropyrrolidin-1 -yl)ethyl)-1H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, a(R)1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-phenyl-1H-pyrazol-1-yl)-2-azaspiro [3.3]heptan-2-yl)prop-2-en-1-one, a(R)1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3 -(2-(2- methoxyethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2- azaspiro[3.3]heptan-2-yl)prop-2-en- 1-one, a(R)1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-hydroxy- 2-methylpropyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, the (R)1-(6-(4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-(2-(2-methoxy-ethoxy)ethyl)-2H-indazole -5-yl)-5-methyl-1H-pyrazol-1-yl)-2- azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, a(R)1-(6- (4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(4- (hydroxymethyl)phenyl)-5-methyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, a(R)1-(6- (4-(5-chloro-6-methyl-1H-indazol-4-yl)-3-(2-fluoro-4-(2-methoxy-ethoxy)phenyl)-5-methyl-1H-pyrazol-1- il)-2-azaspiro[3.3]heptan-2- yl)prop-2-en-1-one, a(R)1-(6-(4-(3-amino-5-chloro-6-methyl- 1H-indazol-4-yl)-3-(2- (2-methoxyethyl)-2H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl)-2- azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, a(R)1-(6-(4-(3-amino-5-chloro-6-methyl-1H-indazole-4 -yl)-5-methyl-3-phenyl-1H-pyrazol-1-yl)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, or a pharmaceutically acceptable salt thereof . 18. Compound according to claim 1, characterized in that it is selected from: 1-{6-[(4M)-4-(5-Chloro-6-methyl-1H-indazol-4-yl)- 5-methyl-3-(1-methyl-1H-indazol-5-yl)-1H-pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl}prop-2-en-1-one , 1-{6-[(4M)-4-(5-Chloro-6-methyl-1H-indazol-4-yl)-3-(1-{2-[(3S)- 3-fluoropyrrolidin-1- yl]ethyl}-1H-indazol-5-yl)-5-methyl-1H-pyrazol-1-yl]-2- azaspiro[3.3]heptan-2-yl}prop-2-en-1-one, 1-{6-[(4M)-4-(5-Chloro-6-methyl-1H-indazol-4-yl)- 5-methyl-3-phenyl-1H-pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl}prop-2-en-1-one, 1-(6-{(4M)-4 -(5-Chloro-6-methyl-1H-indazol-4-yl)-3-[2-(2-methoxyethyl)-2H-indazol-5-yl]-5-methyl-1H-pyrazol-1-yl }-2- azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, 1-(6-{(4M)-4-(5-Chloro-6-methyl-1H-indazol-4-yl)-3-[2-(2-hydroxy-2-methylpropyl)-2H-indazol-5 -yl]-5-methyl-1H-pyrazol-1-yl}-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, 1-{6-[(4M)-4 -(5-Chloro-6-methyl-1H-indazol-4-yl)-3-{2-[2-(2-methoxy-ethoxy)ethyl]-2H-indazol-5-yl}-5-methyl- 1H-pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl}prop-2-en-1-one, 1-(6-{(4M)-4-(5-Chloro-6-methyl-1H-indazol-4-yl)-3-[4-(hydroxymethyl)phenyl]-5-methyl-1H-pyrazol-1 -yl}-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, 1-(6-{(4M)-4-(5-Chloro-6-methyl-1H-indazole -4-yl)-3-[2-fluoro-4-(2-methoxy-ethoxy)phenyl]-5-methyl-1H-pyrazol-1-yl}-2-azaspiro[3.3]heptan-2-yl) prop-2-en-1-one, 1-(6-{(4M)-4-(3-Amino-5-chloro-6-methyl-1H-indazol-4-yl)-3-[2-(2-methoxyethyl)-2H-indazol-5 -yl]-5-methyl-1H-pyrazol-1-yl}-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one, 1-{6-[(4M)-4 -(3-Amino-5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-phenyl-1H-pyrazol-1-yl]-2-azaspiro[3.3]heptan-2- yl}prop-2-en-1-one, or a pharmaceutically acceptable salt thereof. 19. Compound, according to claim 1, characterized by the fact that it presents the following structure: or a pharmaceutically acceptable salt thereof. 20. The compound of any one of claims 1 to 19, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, characterized in that it is for use as a medicament. 21. The compound of claim 20, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, for treating a cancer defined by one or more KRAS mutations. 22. The compound of claim 21, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, for treating a cancer selected from lung cancer, colorectal cancer, pancreatic cancer, uterine cancer, and rectal cancer. 23. The compound of claim 21 or 22, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, for treating: a cancer, wherein the cancer is a solid tumor; a lung cancer, wherein the cancer is non-small cell lung cancer; and/or a lung cancer, wherein the cancer is non-small cell lung cancer defined by a KRAS G12C mutation. 24. Pharmaceutical composition, characterized by the fact that it comprises a compound, as defined in any one of claims 1 to 19, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, and at least one pharmaceutically acceptable excipient. 25. Use of a compound as defined in any one of claims 1 to 19, or of 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, characterized in that it is for the manufacture of a medicament and/or pharmaceutical composition for treating a cancer, wherein the cancer is a solid tumor; and/or of a lung cancer, wherein the cancer is non-small cell lung cancer; and/or of a lung cancer, wherein the cancer is non-small cell lung cancer defined by a KRAS G12C mutation. 26. Pharmaceutical combination, characterized by the fact that it comprises a compound, as defined in any one of claims 1 to 19, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof, and one or more therapeutically active agents. 27. A kit comprising: (a) a compound as defined in any one of claims 1 to 19, or a stereoisomer thereof, or an atropisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of an atropisomer thereof; or (b) a pharmaceutical composition as defined in claim 24; or (c) a pharmaceutical combination as defined in claim 26; and (d) instructions for administration.