CN-122010905-A - Pyrazolyl derivatives as anticancer agents

Abstract

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

Inventors

• COTESTA SIMONA
• N. SCHNEIDER
• S. STUTZ
• VAUPEL ANDREA
• N. Varan
• R. Vicon
• M. Gershpach
• C. LeBron
• LIU BO
• LORTHIOIS EDWIGE LILIANE JEANNE
• R. Marshall
• R.MA
• C. Mulla
• RIGOLLIER PASCAL

Assignees

• 诺华股份有限公司

Dates

Publication Date

20260512

Application Date

20201217

Priority Date

20201030

Claims (20)

1. 1. A compound of formula (I), (I) Wherein the method comprises the steps of A is selected from the group consisting of: (a) A C 5 -C 7- cycloalkylene group which is unsubstituted or substituted with one or more, preferably 1, 2 or 3 substituents independently selected from fluorine and C 1 -C 4 -alkyl; (b) A 5-7 membered unsaturated heterocyclyl containing one carbon-carbon double bond and one oxygen atom as ring members, wherein said heterocyclyl is unsubstituted or substituted with one or more, preferably 1, 2 or 3 substituents independently selected from fluoro and C 1 -C 4 -alkyl, preferably 1, 2 or 3C 1 -C 4 -alkyl; (c) C 6 -C 10 aryl, which is unsubstituted or substituted with 1,2 or 3R A2 ; (d) A 5-6 membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from N, O and S as ring members, wherein the heteroaryl ring is unsubstituted or substituted on one or more (e.g., 1, 2, or 3) carbon atoms with R A3 , and wherein when a nitrogen atom is present in the heteroaryl ring, the nitrogen atom is unsubstituted or substituted with a substituent selected from the group consisting of C 1 -C 4 -alkyl, - (CH 2 ) 1-2 -C 3-4 -cycloalkyl, C 3- C 6 -cycloalkyl, hydroxy-C 1- C 4 -alkyl, fluoro-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, N (R 9 )(R 10 )-C 1 -C 4 -alkyl, -SO 2 -C 1 -C 4 -alkyl, -SO 2 -C 3-4 -cycloalkyl, - (CH 2 ) p -Het py , and- (CH 2 ) p -N(R 9 )(R 10 ); (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 heteroatoms independently selected from 0-3 nitrogen atoms, 0-2 oxygen atoms, 0-1 sulfur atoms and 0-1S (=o) 2 groups in the heterobicyclic ring, wherein the heteroaryl ring or heterobicyclic ring is unsubstituted or substituted on a carbon atom with 1, 2, 3, 4 or 5R A4 , and wherein the heterobicyclic ring is further optionally substituted on a carbon atom with oxo and wherein when a nitrogen atom is present, the nitrogen atom is unsubstituted or substituted with a substituent- (CO) -C 1 -C 4 -alkyl or C 1 -C 4 -alkyl, and wherein the C 1 -C 4 -alkyl is optionally substituted with 1 or 2 heteroatoms independently selected from cyano, hydroxy, oxo, fluoro, C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl-oxy, 3556 and NR 35 Wherein Het b is a 4-or 5-or 6-membered heterocycle comprising 1 or 2 heteroatoms or groups independently selected from N, O, S, SO and SO 2 , wherein the heterocycle Het b is unsubstituted or substituted on a carbon atom with one or two substituents independently selected from C 1 -C 4 -alkyl, hydroxy, cyano, fluoro, C 1 -C 4 -alkoxy-hydroxy-C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, fluoro-C 1 -C 4 -alkoxy and fluoro-C 1 -C 4 -alkyl, and wherein the heterocycle Het b is further optionally substituted on a carbon atom with oxo, and wherein when a nitrogen atom is present in Het b the nitrogen atom is optionally further substituted with C 1 -C 4 -alkyl, the C 1 -C 4 -alkyl is optionally substituted with 1 to 3 substituents independently selected from fluoro, hydroxy and C 1 -C 4 -alkoxy; Wherein a is attached to the remainder of the compound having formula (I) through an sp 2 hybridized carbon atom on a; Wherein the method comprises the steps of B is selected from the group consisting of B 1 and B 2 , Wherein B 1 is C 6-10 aryl, which is unsubstituted or substituted with 1,2, 3 or 4R Ba ; b 2 is a 6-13 membered heteroaryl group containing 1,2 or 3 nitrogen atoms, wherein B 2 is unsubstituted or substituted with 1,2, 3 or 4R Bb ; C is selected from the group consisting of hydrogen, C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl, fluoro-C 1 -C 3 alkyl, cyano, -CH 2 -CN、-CH(CN)-CH 3 、-CH 2 -OH、-CH(OH)-CH 3 , and halo; L is selected from the group consisting of: wherein n is 1,2 or 3, R L is selected from hydrogen, methyl, ethyl, -CH 2 -CN and-CH 2 -OH, wherein G Represents an attachment point to G; G is selected from the group consisting of: ; Wherein the method comprises the steps of R 2 is selected from hydrogen, C 1 -C 3 alkyl, -C (O) -C 1 -C 3 -alkyl, and fluoro; r 3 is hydrogen; R 4 is selected from hydrogen, methyl, -CH 2 F、-CH 2 -OCH 3 , and-CH 2 -N(CH 3 ) 2 ; r 5 is selected from hydrogen and methyl; r 6 is hydrogen; r 7 is selected from hydrogen and methyl; Wherein R A2 is independently selected from the group consisting of NR 9 R 10 , cyano, - (CH 2 ) p -CN, halo, OH, hydroxy-C 1 -C 4 -alkyl, - (COOH), - (CH 2 ) p -COOH、C 1 -C 4 -alkyl, fluoro-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl), N (R 9 )(R 10 )-C 1 -C 4 -alkyl, N (R 9 )(R 10 )-C 1 -C 4 -alkyl-oxy, N (R 9 )(R 10 )-C 1 -C 4 -alkoxy, C 1 -C 4 -alkyl-carbonyl-oxy-C 1 -C 4 -alkyl-oxy), hydroxy-C 1 -C 4 -alkyl-oxy, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl-oxy, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl-oxy-C 1 -C 4 -alkyl, -SO 2 -C 1 -C 4 -alkyl, -SO 2 -C 3-4 -cycloalkyl, - (CH 2 ) 1-2 -C 3-4 -cycloalkyl) 、Het py 、-(CH 2 ) p -Het py 、-C(=O)-NR 9 R 10 、-(CH 2 ) p -C(=O)NR 9 R 10 ; Wherein R A3 is independently selected from the group consisting of oxo, NR 9 R 10 , cyano, - (CH 2 ) p -CN, halo, OH, hydroxy-C 1 -C 4 -alkyl, - (COOH), - (CH 2 ) p -COOH、C 1 -C 4 -alkyl, fluoro-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl), N (R 9 )(R 10 )-C 1 -C 4 -alkyl, N (R 9 )(R 10 )-C 1 -C 4 -alkyl-oxy, N (R 9 )(R 10 )-C 1 -C 4 -alkoxy, C 1 -C 4 -alkyl-carbonyl-oxy-C 1 -C 4 -alkyl-oxy), hydroxy-C 1 -C 4 -alkyl-oxy, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl-oxy, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl-oxy-C 1 -C 4 -alkyl, -SO 2 -C 1 -C 4 -alkyl, -SO 2 -C 3-4 -cycloalkyl, - (CH 2 ) 1-2 -C 3-4 -cycloalkyl) 、Het py 、-(CH 2 ) p -Het py 、-C(=O)-NR 9 R 10 、-(CH 2 ) p -C(=O)NR 9 R 10 、(CH 2 ) p -NR 9 R 10 ; Wherein R A4 is independently selected from the group consisting of cyano, CO 2 H, halo, C 1 -C 4 -alkyl, fluoro-C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl-oxy, C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl-oxy, NR 9 R 10 、(N(R 9 )(R 10 )-C 1 -C 4 -alkyl, (N (R 9 )(R 10 )-C 1 -C 4 -alkyl-oxy, - (CO) -C 1 -C 4 -alkyl, and R 9 R 10 N-C 1 -C 4 -alkyl-oxy- (CO) -C 1 -C 4 -alkyl; Wherein the method comprises the steps of P is 1 or 2 or 3; R 9 is selected from hydrogen and C 1 -C 4 -alkyl; R 10 is selected from the group consisting of hydrogen, C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl and di-C 1 -C 4 -alkyl-amino-C 1 -C 4 -alkyl; Het py is a 4-, 5-, 6-, or 7-membered saturated heterocyclic ring comprising one or two heteroatoms independently selected from O, N and S, or comprising an S-oxide (SO) or S-dioxide (SO 2 ) group, and wherein the heterocyclic ring is optionally substituted on one carbon atom with oxo, and wherein the heterocyclic ring is optionally further substituted on one or more carbon atoms with 1, 2, or 3 substituents independently selected from C 1 -C 4 -alkoxy, halo, C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl, and fluoro-C 1 -C 4 -alkyl, and wherein if a nitrogen atom is present in the heterocyclic ring, the nitrogen atom is optionally further substituted with R 10 ; Or Het py is a 5-or 6-membered heteroaryl ring containing 1, 2, or 3 nitrogen atoms and wherein the heteroaryl ring is optionally substituted with one or more (e.g., 1, 2, or 3) substituents independently selected from NR 9 R 10 、-C(=O)-NR 9 R 10 , halo, C 1- C 4 -alkyl, hydroxy-C 1- C 4 -alkyl, fluoro-C 1- C 4 -alkyl, cyano, OH, and C 1- C 4 -alkoxy; each R Ba is independently selected from the group consisting of hydroxy, NH 2 、C 1 -C 4 -alkyl, and halo; Each R Bb is independently selected from the group consisting of C 1 -C 4 -alkyl, cyclopropyl, fluoro-C 1 -C 3 -alkyl, cyano, halo, NH 2 and C 1 -C 3 -alkoxy, Or a stereoisomer thereof, or a atropisomer thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of a atropisomer thereof.
2. 2. The compound of claim 1, wherein a is selected from the group consisting of (A) A C 5 -C 7- cycloalkylene group which is unsubstituted or substituted with one or more, preferably 1, 2 or 3 substituents independently selected from fluorine and C 1 -C 4 -alkyl; (b) A 5-7 membered unsaturated heterocyclyl containing one carbon-carbon double bond and one oxygen atom as ring members, wherein said heterocyclyl is unsubstituted or substituted with one or more, preferably 1, 2 or 3 substituents independently selected from fluoro and C 1 -C 4 -alkyl, preferably 1, 2 or 3C 1 -C 4 -alkyl; (c) C 6 -C 10 aryl, which is unsubstituted or substituted with 1,2 or 3R A2 ; (d) A 5-6 membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from N, O and S as ring members, wherein the heteroaryl ring is unsubstituted or substituted on one or more (e.g., 1, 2, or 3) carbon atoms with R A3 , and wherein when a nitrogen atom is present in the heteroaryl ring, the nitrogen atom is unsubstituted or substituted with a substituent selected from the group consisting of C 1 -C 4 -alkyl, - (CH 2 ) 1-2 -C 3-4 -cycloalkyl, C 3- C 6 -cycloalkyl, hydroxy-C 1- C 4 -alkyl, fluoro-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, N (R 9 )(R 10 )-C 1 -C 4 -alkyl, -SO 2 -C 1 -C 4 -alkyl, -SO 2 -C 3-4 -cycloalkyl, - (CH 2 ) p -Het py , and- (CH 2 ) p -N(R 9 )(R 10 ); (e) An 8-10 membered heteroaryl ring containing 1,2 or 3 nitrogen atoms, wherein each nitrogen atom is unsubstituted or substituted with a substituent- (CO) -C 1 -C 4 -alkyl or C 1 -C 4 -alkyl, and wherein the C 1 -C 4 -alkyl is optionally substituted with 1 or 2 substituents independently selected from cyano, hydroxy, oxo, fluoro, C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl-oxy, het b and NR 9 R 10 , wherein the heteroaryl ring is unsubstituted or substituted on a carbon atom with 1,2, 3, 4 or 5R A4 ; Wherein Het b is a 4-or 5-or 6-membered heterocycle comprising 1 or 2 heteroatoms or groups independently selected from N, O, S, SO and SO 2 , wherein the heterocycle Het b is unsubstituted or substituted on a carbon atom with one or two substituents independently selected from C 1 -C 4 -alkyl, hydroxy, cyano, fluoro, C 1 -C 4 -alkoxy-hydroxy-C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, fluoro-C 1 -C 4 -alkoxy and fluoro-C 1 -C 4 -alkyl, and wherein the heterocycle Het b is further optionally substituted on a carbon atom with oxo, and wherein when a nitrogen atom is present in Het b the nitrogen atom is optionally further substituted with C 1 -C 4 -alkyl, the C 1 -C 4 -alkyl is optionally substituted with 1 to 3 substituents independently selected from fluoro, hydroxy and C 1- C 4 -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 1S (=o) 2 groups in the heterobicyclic ring, wherein the heterobicyclic ring is unsubstituted or substituted on a carbon atom with 1, 2,3, 4 or 5R A4 , and wherein the heterobicyclic ring is further optionally substituted on a carbon atom with oxo and wherein when a nitrogen atom is present the nitrogen atom is unsubstituted or substituted with a substituent- (CO) -C 1 -C 4 -alkyl or C 1 -C 4 -alkyl, and wherein the C 1 -C 4 -alkyl is optionally substituted with 1 or 2 substituents independently selected from cyano, hydroxy, oxo, fluoro, C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl-oxy, het b and NR 9 R 10 , and Wherein Het b is a 4-or 5-or 6-membered heterocycle comprising 1 or 2 heteroatoms or groups independently selected from N, O, S, SO and SO 2 , wherein the heterocycle Het b is unsubstituted or substituted on a carbon atom with one or two substituents independently selected from C 1 -C 4 -alkyl, hydroxy, cyano, fluoro, C 1 -C 4 -alkoxy-hydroxy-C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, fluoro-C 1 -C 4 -alkoxy and fluoro-C 1 -C 4 -alkyl, and wherein the heterocycle Het b is further optionally substituted on a carbon atom with oxo, and wherein when a nitrogen atom is present in Het b the nitrogen atom is optionally further substituted with C 1 -C 4 -alkyl, the C 1 -C 4 -alkyl is optionally substituted with 1 to 3 substituents independently selected from fluoro, hydroxy and C 1 -C 4 -alkoxy, Or a stereoisomer thereof, or a atropisomer thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of a atropisomer thereof.
3. 3. The compound according to claim 1 or 2, wherein Het b is a 4-or 5-or 6-membered heterocycle comprising 1 or 2 heteroatoms or groups independently selected from N, O, S, SO and SO 2 , wherein the heterocycle Het b is unsubstituted or substituted on a carbon atom with one or two substituents independently selected from C 1 -C 4 -alkyl, hydroxy, cyano, fluoro, C 1 -C 4 -alkoxy-hydroxy-C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy and fluoro-C 1 -C 4 -alkyl, and wherein the heterocycle Het b is further optionally substituted on a carbon atom with oxo, and wherein when a nitrogen atom is present in Het b the nitrogen atom is optionally further substituted with C 1 -C 4 -alkyl, wherein the C 1 -C 4 -alkyl is optionally substituted with 1 to 3 substituents independently selected from fluoro, hydroxy and C 1 -C 4 -alkoxy; B is selected from the group consisting of B 1 and B 2 ; B 1 is C 6-10 aryl, which is unsubstituted or substituted with 1, 2,3 or 4R Ba and each R Ba is independently selected from the group consisting of hydroxy, C 1 -C 4 -alkyl and halo; B 2 is a 6-10 membered heteroaryl group containing 1,2 or 3 nitrogen atoms, wherein B 2 is unsubstituted or substituted with 1,2, 3 or 4R Bb ; Each R Bb is independently selected from the group consisting of C 1 -C 4 -alkyl (preferably methyl), fluoro-C 1 -C 3 -alkyl, cyano, halo, NH 2 and C 1 -C 3 -alkoxy, Het py is a 4-, 5-, 6-, or 7-membered saturated heterocyclic ring comprising one or two heteroatoms independently selected from O, N and S, or comprising an S-oxide (SO) or S-dioxide (SO 2 ) group, and wherein the heterocyclic ring is optionally substituted with oxo on one carbon atom, and wherein the heterocyclic ring is further substituted on one or more carbon atoms with 1, 2, or 3 substituents independently selected from C 1 -C 4 -alkoxy, halo, C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl, and fluoro-C 1 -C 4 -alkyl, and wherein the nitrogen atom, if present in the heterocyclic ring, is optionally further substituted with R 10 ; Or Het py is a 5-or 6-membered heteroaryl ring containing 1,2, or 3 nitrogen atoms and wherein the heteroaryl ring is optionally substituted with one or more (e.g., 1,2, or 3) substituents independently selected from NR 9 R 10 , halo, C 1- C 4 -alkyl, cyano, OH, and C 1- C 4 -alkoxy; Wherein R A4 is independently selected from the group consisting of cyano, CO 2 H, halo, C 1 -C 4 -alkyl, fluoro-C 1- C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl, hydroxy-C 1- C 4 -alkyl-oxy, C 1- C 4 -alkoxy, C 1- C 4 -alkoxy-C 1- C 4 -alkyl-oxy, -NR 9 R 10 、R 9 R 10 N-C 1- C 4 -alkyl-oxy, - (CO) -C 1 -C 4 -alkyl; Or a stereoisomer thereof, or a atropisomer thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of a atropisomer thereof.
4. 4. A compound according to any one of the preceding claims wherein Het b is a 4-or 5-or 6-membered heterocycle comprising 1 or 2 heteroatoms or groups independently selected from N, O, S, SO and SO 2 , wherein the heterocycle Het b is unsubstituted or substituted on a carbon atom with one or two substituents independently selected from C 1 -C 4 -alkyl, hydroxy, cyano, fluoro, C 1 -C 4 -alkoxy-hydroxy-C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy and fluoro-C 1 -C 4 -alkyl, and wherein the heterocycle Het b is further optionally substituted on a carbon atom with oxo, and wherein when a nitrogen atom is present in Het b the nitrogen atom is optionally further substituted with C 1 -C 4 -alkyl, wherein the C 1 -C 4 -alkyl is optionally substituted with 1 to 3 substituents independently selected from fluoro, hydroxy and C 1 -C 4 -alkoxy; B 2 is a 6-10 membered heteroaryl group containing 1,2 or 3 nitrogen atoms, wherein B 2 is unsubstituted or substituted with 1,2, 3 or 4R Bb ; Het py is a 4-, 5-, 6-, or 7-membered saturated heterocyclic ring comprising one or two heteroatoms independently selected from O, N and S, or comprising an S-oxide (SO) or S-dioxide (SO 2 ) group, and wherein the heterocyclic ring is optionally substituted with oxo on one carbon atom, and wherein the heterocyclic ring is further substituted on one or more carbon atoms with 1, 2, or 3 substituents independently selected from C 1 -C 4 -alkoxy, halo, C 1 -C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl, and fluoro-C 1 -C 4 -alkyl, and wherein the nitrogen atom, if present in the heterocyclic ring, is optionally further substituted with R 10 ; Or Het py is a 5-or 6-membered heteroaryl ring containing 1,2, or 3 nitrogen atoms and wherein the heteroaryl ring is optionally substituted with one or more (e.g., 1,2, or 3) substituents independently selected from NR 9 R 10 , halo, C 1- C 4 -alkyl, cyano, OH, and C 1- C 4 -alkoxy; r A4 is independently selected from the group consisting of cyano, CO 2 H, halo, C 1 -C 4 -alkyl, fluoro-C 1- C 4 -alkyl, hydroxy-C 1 -C 4 -alkyl, hydroxy-C 1- C 4 -alkyl-oxy, C 1- C 4 -alkoxy, C 1- C 4 -alkoxy-C 1- C 4 -alkyl-oxy, -NR 9 R 10 and R 9 R 10 N-C 1- C 4 -alkyl-oxy, Or a stereoisomer thereof, or a atropisomer thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of a atropisomer thereof.
5. 5. The compound of any one of the preceding claims, wherein G is Or a stereoisomer thereof, or a atropisomer thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of a atropisomer thereof.
6. 6. The compound of any one of the preceding claims, wherein L is , Or a stereoisomer thereof, or a atropisomer thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of a atropisomer thereof.
7. 7. The compound of claim 6, wherein R L is hydrogen, or a stereoisomer thereof, or a atropisomer thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of a atropisomer thereof.
8. 8. The compound of any one of the preceding claims, wherein C is selected from C 1 -C 3 alkyl, fluoro-C 1 -C 3 alkyl, CH 2 -CN, or a stereoisomer thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof.
9. 9. The compound of any one of the preceding claims, wherein B is Wherein B is unsubstituted or substituted with 1,2 or 3 halo, or methyl groups, or a stereoisomer thereof, or a atropisomer thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of a atropisomer thereof.
10. 10. The compound of any one of the preceding claims, wherein B is Wherein X is N or C-R B5 ; Wherein R B1 is independently selected from hydrogen and C 1 -C 4 -alkyl; r B2 is independently selected from hydrogen, halo, C 1 -C 4 -alkyl, cyclopropyl, and NH 2 ; r B3 is independently selected from hydrogen, halo, cyclopropyl, and C 1 -C 4 -alkyl; R B4 is independently selected from hydrogen, halo, and C 1 -C 4 -alkyl, or R B3 and R B4 together with the atoms to which they are attached form a 4-6 membered ring fused to an aromatic ring containing X; R B5 is independently selected from hydrogen, halo and C 1 -C 4 -alkyl, Or a stereoisomer thereof, or a atropisomer thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of a atropisomer thereof.
11. 11. The compound of claim 10, wherein R B2 is independently selected from the group consisting of hydrogen, NH 2 , and CH 3 , or a atropisomer thereof, or a pharmaceutically acceptable salt of a atropisomer thereof.
12. 12. The compound of claim 10 or 11, wherein R B4 is independently selected from hydrogen, halo, and C 1 -C 4 -alkyl, or a stereoisomer, or a atropisomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a stereoisomer, or a pharmaceutically acceptable salt of a atropisomer thereof.
13. 13. The compound according to any one of claims 10 to 12, wherein R B1 is independently selected from hydrogen and methyl, or a stereoisomer thereof, or a atropisomer thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of a atropisomer thereof.
14. 14. The compound according to any one of claims 10 to 13, wherein R B1 is hydrogen, or a stereoisomer thereof, or a atropisomer thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of a atropisomer thereof.
15. 15. The compound according to any one of claims 10 to 14, wherein R B3 and R B4 are each independently selected from halo and C 1 -C 4 -alkyl, or a stereoisomer thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of a atropisomer thereof.
16. 16. The compound of any one of claims 10 to 15, wherein R B3 is halo and R B4 is C 1 -C 4 -alkyl, or a stereoisomer thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of a atropisomer thereof.
17. 17. The compound according to any one of claims 10 to 16, wherein R B3 is chloro and R B4 is methyl, or a stereoisomer thereof, or a atropisomer thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of a atropisomer thereof.
18. 18. The compound according to any one of claims 10 to 16, wherein R B3 is chloro and R B4 is chloro, or a stereoisomer thereof, or a atropisomer thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of a atropisomer thereof.
19. 19. The compound according to any one of claims 10 to 18, wherein X is CH or N, or a stereoisomer thereof, or a atropisomer thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of a atropisomer thereof.
20. 20. The compound according to any one of claims 10 to 19, wherein X is CH, or a stereoisomer thereof, or a atropisomer thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of a atropisomer thereof.

Description

Pyrazolyl derivatives as anticancer agents The present application is a divisional application, and the parent application is application number 202080089867.2, application number 2020, 12-17, and entitled "pyrazolyl derivative used as anticancer agent". Sequence listing The present application contains a sequence listing that has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. The ASCII copy name created on month 1 of year 12 of 2020 is PAT058632-WO-PCT02_ sl. Txt and is 7,192 bytes in size. Technical Field The present invention provides pyrazolyl derivative compounds, their use for inhibiting KRAS G12C, HRAS G12C or NRAS G12C and in particular KRAS G12C, methods of using the compounds for the treatment or prophylaxis of diseases, in particular cancer, and methods and intermediates for preparing these compounds. The invention also provides these pyrazolyl derivative compounds for use in the treatment of cancer and specific cancers as defined herein. Background RAS is a small GTPase that acts as a molecular ON/OFF switch, assuming an active/inactive state when bound to GTP/GDP, respectively. In response to growth factors, guanine exchange factors exchange GDP for GTP, turning Ras into the ON state. RAS binding to GTP adopts a conformation that recruits effector proteins to the plasma membrane, activating the signaling cascade, leading to cell growth, proliferation and survival. These pro-cancerous signals are very short and tightly controlled. They are immediately turned off by the GTPase activity of the RAS itself, mainly due to 100000-fold acceleration by the GTPase Activating Protein (GAP) (Bos JL et al, cell [ Cell ], volume 129, 5, 6, 1, 2007, pages 865-877). In contrast, RAS mutants are insensitive to these GAPs, which results in longer residence times of the RAS mutants in the GTP-bound state and shift the GTP/GDP cycle to the ON state according to their inherent hydrolysis rate. These three RAS genes constitute the most common mutant gene family in cancer, with RAS mutations found in about 25% of human tumors. Of these three paralogs, KRAS mutations are most common (85% of all RAS-driven cancers), whereas NRAS and HRAS mutations are less reported (12% and 3%, respectively). Most KRAS mutations occur at hotspot residues G12, G13 and Q61. KRAS G12C mutations account for about 12% of all KRAS mutations, and are prevalent in lung cancer patients (about 13% lung adenoma carcinoma (LUAC)), about 3% -5% colon adenocarcinoma patients, a small proportion of other cancer types, and about 20% of MYH polyposis colorectal adenoma patients (COSIC v80 database; A.Aime' et al; CANCER GENET [ cancer genetics ] 2015, 208:390-5). Patients with KRAS G12C positive solid tumors are poorly treated with existing therapies alone. There are currently no inhibitors of KRAS G12C, HRAS G12C or NRAS G12C approved for therapeutic use. Thus, there remains a continuing need to develop new options for treating cancer, particularly cancer tumors expressing G12C mutant Ras, particularly KRAS, HRAS, or NRAS G12C-driven cancers. More particularly, there remains a need for the treatment of KRAS G12C mutated cancers. Irreversible RAS G12C inhibitors have been previously described (e.g. WO 2014152588, WO 2017201161, WO 2018/217651 and WO 2018119183). Disclosure of Invention The compounds described in the present invention selectively react with G12C mutated KRAS, HRAS or NRAS proteins and inhibit G12C mutated KRAS, HRAS or NRAS proteins by forming an irreversible covalent bond with the cysteine at position 12. This locks the RAS mutein in an inactive state. Irreversible binding of these compounds disrupts K-RAS downstream signaling. The compounds described in the present invention are useful for the treatment of cancer, in particular cancer characterized by KRAS, HRAS or NRAS G12C mutations, more particularly cancer characterized by KRAS G12C mutations. The present invention provides compounds, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and combinations thereof. The compounds are capable of selectively binding and inhibiting G12C mutants of KRAS, HRAS or NRAS and may be useful for the treatment of cancer, particularly cancer characterized by KRAS HRAS or NRAS G12C mutations. The invention also provides methods of preparing such compounds and intermediates useful in the synthesis of such compounds. Various embodiments or aspects of the invention are described herein. Provided herein are compounds having formula (I), or a stereoisomer thereof, or a atropisomer thereof, or a pharmaceutically acceptable salt of a stereoisomer thereof, or a pharmaceutically acceptable salt of a atropisomer thereof, as defined herein, (I)。 In another embodiment, the invention provides a compound having formula (I), or a atropisomer thereof, or a pharmaceutically acceptable salt of a atropisomer thereof, as defined herein. In another embodiment, the present invention provi