Methods of modulating cell proliferation

Abstract

This disclosure provides compounds and pharmaceutically acceptable salts thereof. This disclosure further provides methods for using the compounds and pharmaceutically acceptable salts thereof, for example, in combinations of two or more compounds. The compounds and methods have a range of uses as therapeutic, diagnostic, and research tools. In particular, the subject compositions and methods can be used to reduce the signaling output of oncogenic proteins.

Claims

1. A method for reducing the proliferation of cancer cells containing a KRAS mutant protein or overexpressing a KRAS protein, the method comprising administering (a) an SOS1 inhibitor and (b) a KRAS inhibitor of formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV-1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H) to the cells, wherein (a) is administered before, simultaneously with, or after (b).

2. The method according to claim 1, wherein the cancer cells are non-small cell lung cancer cells, colorectal cancer cells, or pancreatic cancer cells.

3. A method for downregulating KRAS signal transduction output in multiple cancer cells, comprising: (i) Assess the KRAS mutation status in biological samples containing nucleic acids from the subject; and (ii) If a KRAS mutation is detected in the sample, an effective dose of (a) an SOS1 inhibitor and an effective dose of (b) a KRAS inhibitor of formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV-1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H) are administered, wherein (a) is administered before, simultaneously with, or after (b).

4. A method of treating a cancer in a subject, comprising administering to the subject (a) an SOS1 inhibitor and (b) a KRAS inhibitor of formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV-1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H), wherein (a) is administered before, simultaneously with, or after (b).

5. The method of claim 4, wherein the cancer is a mutant KRAS-mediated cancer.

6. The method according to any one of claims 1 to 5, wherein the KRAS inhibitor is a compound of formula (I), (I-1), (I-2), (II), (II-1), (II-2), or (II-3) or a pharmaceutically acceptable salt or solvate thereof.

7. The method according to any one of the preceding claims, wherein the application of (a) and (b) synergistically reduces the proliferation of the cancer cells, with a synergistic value of at least 0.05 as determined by the Bliss Independent Criterion.

8. A method of treating a subject with mutant KRAS-mediated cancer, comprising administering to the subject (a) an SOS1 inhibitor and (b) a KRAS inhibitor of formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV-1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H), wherein (a) is administered before, simultaneously with, or after (b), and wherein the administration of (a) and (b) synergistically reduces the proliferation of cancer cells, with a synergy value of at least 0.05 as determined by the Bliss Independent Criterion.

9. The method according to claim 7 or 8, wherein the synergy value is determined by the Bliss independence criterion according to the following formula: Y AB,O - Y AB,P in: Y AB,O is the percent growth inhibition of said cancer cells observed by applying (a) at dose A and (b) at dose B; Y AB,P is the percentage growth inhibition of the cancer cells predicted by applying (a) and (b) comprising (a) at dose A and (b) at dose B, wherein Y AB,P = Y A + Y B - Y A Y B ; Y A is the percentage of growth inhibition of the cancer cells observed with (a) alone at dose A; Y B is the percentage of growth inhibition of the cancer cells observed using (b) at dose B alone; and Y A Y B It is Y A and Y B The product of.

10. The method according to any one of claims 7 to 9, wherein the synergy value is at least 0.

1.

11. The method according to any one of claims 7 to 9, wherein the synergy value is at least 0.

4.

12. The method according to any one of claims 7 to 9, wherein the synergy value is at least 1.

13. The method according to any one of claims 7 to 9, wherein the synergy value is at least 5.

14. The method according to any one of claims 1 to 13, wherein the SOS1 inhibitor is a compound of formula (SI-1): (SI-1), Or a pharmaceutically acceptable salt or solvate thereof, wherein: Selected from C 5-7 Carbon rings and 5- to 7-membered heterocycles, each of which is optionally bounded by one or more R s11 replace; Does not exist or selected from C 3-8 Carbon rings and 3 to 8-membered heterocycles, each of which is optionally bounded by one or more R s11a replace; L s1 Selected from key, C 1-6 Alkylene and C 1-6 Halogenated alkylene; L s2 Selected from C 5-25 Alkylene, C 5-25 imidene group, C 5-25 5- to 25-membered heteroalkyl and 5- to 25-membered heteroenyl, each of which is optionally divided by one or more R s11b Replace, where L s2 Covalent bonding to W s3 W s4 W s5 W s6 or W s7 one of; W s3 Selected from N(R) s3b ), N, C(R) s3 ) and C(O); W s4 Selected from N(R) s4b ), N, C(R) s4 ) and C(O); W s5 Selected from N(R) s5b ), N and C(R) s5 ); W s6 Selected from C(R) s6 ) and C(O); W s7 It is C(R) s7 ); R s1 It is optionally controlled by one or more R s11c Replacement C 1-3 alkyl; R s8 Selected from hydrogen, halogens, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR s12 -SR s12 -N(R) s12 (R) s13 -C(O)OR s12 -OC(O)N(R) s12 (R) s13 ), -N(R s14 )C(O)N(R s12 (R) s13 ), -N(R s14 )C(O)OR s15 -N(R) s14 )S(O)2R s15 -C(O)R s15 -S(O)R s15 -OC(O)R s15 -C(O)N(R) s12 (R) s13 -C(O)C(O)N(R) s12 (R) s13 ), -N(R s14 )C(O)R s15 -S(O)2R s15 -S(O)2N(R) s12 (R) s13 -S(=O)(=NH)N(R) s12 (R) s13 -CH2C(O)N(R) s12 (R) s13 ), -CH2N(R s14 )C(O)R s15 -CH2S(O)2R s15 and -CH2S(O)2N(R s12 (R) s13 ), where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are independently and optionally separated by one, two, or three R... s20 replace; R s3 R s4 R s5 R s6 and R s7 Each independently selected from L s2 bonds, hydrogen, halogens, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR s12 -SR s12 -N(R) s12 (R) s13 -C(O)OR s12 -OC(O)N(R) s12 (R) s13 ), -N(R s14 )C(O)N(R s12 (R) s13 ), -N(R s14 )C(O)OR s15 -N(R) s14 )S(O)2R s15 -C(O)R s15 -S(O)R s15 -OC(O)R s15 -C(O)N(R) s12 (R) s13 -C(O)C(O)N(R) s12 (R) s13 ), -N(R s14 )C(O)R s15 -S(O)2R s15 -S(O)2N(R) s12 (R) s13 -S(=O)(=NH)N(R) s12 (R) s13 -CH2C(O)N(R) s12 (R) s13 ), -CH2N(R s14 )C(O)R s15 -CH2S(O)2R s15 and -CH2S(O)2N(R s12 (R) s13 ), where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are independently and optionally separated by one, two, or three R... s20 replace; R s3b R s4b and R s5b Each independently selected from L s2 bonds, hydrogen, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR s12 -SR s12 -C(O)OR s12 -OC(O)N(R) s12 (R) s13 -C(O)R s15 -S(O)R s15 -OC(O)R s15 -C(O)N(R) s12 (R) s13 -C(O)C(O)N(R) s12 (R) s13 -S(O)2R s15 -S(O)2N(R) s12 (R) s13 -S(=O)(=NH)N(R) s12 (R) s13 -CH2C(O)N(R) s12 (R) s13 ), -CH2N(R s14 )C(O)R s15 -CH2S(O)2R s15 and -CH2S(O)2N(R s12 (R) s13 ), where each C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are independently and optionally separated by one, two, or three R... s20 replace; R s11 and R s11a Each time it appears, it is independently selected from halogen, -CN, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR s12 -SR s12 -N(R) s12 (R) s13 -C(O)OR s12 -OC(O)N(R) s12 (R) s13 ), -N(R s14 )C(O)N(R s12 (R) s13 ), -N(R s14 )C(O)OR s15 -N(R) s14 )S(O)2R s15 -C(O)R s15 -S(O)R s15 -OC(O)R s15 -C(O)N(R) s12 (R) s13 -C(O)C(O)N(R) s12 (R) s13 ), -N(R s14 )C(O)R s15 -S(O)2R s15 -S(O)2N(R) s12 (R) s13 -S(=O)(=NH)N(R) s12 (R) s13 -CH2C(O)N(R) s12 (R) s13 ), -CH2N(R s14 )C(O)R s15 -CH2S(O)2R s15 -CH2S(O)2N(R) s12 (R) s13 ), -CH2N(R s12 )S(O)2(R s13 ) and -P(O)(R s17 (R) s17a ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. s20 replace; R s11b Each time it appears, it is independently selected from halogen, oxo, -CN, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings, 3- to 10-membered heterocycles, -OR s12 -SR s12 -N(R) s12 (R) s13 -C(O)OR s12 -OC(O)N(R) s12 (R) s13 ), -N(R s14 )C(O)N(R s12 (R) s13 ), -N(R s14 )C(O)OR s15 -N(R) s14 )S(O)2R s15 -C(O)R s15 -S(O)R s15 -OC(O)R s15 -C(O)N(R) s12 (R) s13 -C(O)C(O)N(R) s12 (R) s13 ), -N(R s14 )C(O)R s15 -S(O)2R s15 -S(O)2N(R) s12 (R) s13 -S(=O)(=NH)N(R) s12 (R) s13 -CH2C(O)N(R) s12 (R) s13 ), -CH2N(R s14 )C(O)R s15 -CH2S(O)2R s15 -CH2S(O)2N(R) s12 (R) s13 ), -CH2N(R s12 )S(O)2(R s13 ) and -P(O)(R s17 (R) s17a ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. s20 replace; R s11c Each time it appears, it is independently selected from halogen, -OR s12 and -N(R) s12 (R) s13 ); R s12 Each time it appears, it is independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. s20 replace; R s13 Each time it appears, it is independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl; or R s12 and R s13 Together with the nitrogen atoms they are attached to, they form a structure optionally bounded by one, two, or three R atoms. s20 Replaced 3- to 10-membered heterocycles; R s14 Each time it appears, it is independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; R s15 Each time it appears, it is independently selected from C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 The carbon ring and 3 to 10-membered heterocycles are optionally separated by one, two or three Rs. s20 replace; R s17 and R s17a Each time it appears, it is independently selected from C. 1-6 Alkyl and C 3-6 cycloalkyl, wherein C 1-6 Alkyl and C 3-6 Cycloalkyl groups are optionally surrounded by one, two, or three R groups. s20 Replace; or R s17 and R s17a Together with the phosphorus atoms they are attached to, they form 3 to 10-membered heterocycles; R s20 Each time it appears, it is independently selected from halogen, oxo, =NH, -CN, C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon ring, -CH2-(C 3-10 Carbon rings), 3- to 10-membered heterocycles, -CH2- (3- to 10-membered heterocycles), -OR s21 -SR s21 -N(R) s22 (R) s23 -C(O)OR s22 -C(O)N(R) s22 (R) s23 -C(O)C(O)N(R) s22 (R) s23 ), -OC(O)N(R s22 (R) s23 ), -N(R s24 )C(O)N(R s22 (R) s23 ), -N(R s24 )C(O)OR s25 -N(R) s24 )C(O)R s25 -N(R) s24 )S(O)2R s25 -C(O)R s25 -S(O)2R s25 -S(O)2N(R) s22 (R) s23 -OCH2C(O)OR s22 and -OC(O)R s25 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon ring, -CH2-(C 3-10 The carbocyclic ring (3 to 10-membered heterocycle) and -CH2- (3 to 10-membered heterocycle) are optionally substituted by one, two, or three independent groups selected from the following: halogen, oxo, =NH, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -OR s21 -SR s21 -N(R) s22 (R) s23 -C(O)OR s22 -C(O)N(R) s22 )(R s23 )、 -C(O)C(O)N(R s22 )(R s23 )、 -OC(O)N(R s22 )(R s23 )、 -N(R s24 )C(O)N(R s22 )(R s23 )、 -N(R s24 )C(O)OR s25 、 -N(R s24 )C(O)R s25 、 -N(R s24 )S(O)2R s25 、 -C(O)R s25 、 -S(O)2R s25 、 -S(O)2N(R s22 )(R s23 ) and -OC(O)R s25 ; R s21 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 3-10 The carbide ring and the 3 to 10-membered heterocycle are optionally substituted by one, two, or three independent groups selected from the following: halogen and C. 1-6 alkyl; R s22 Each time it appears, it is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 3-10 The carbide ring and the 3 to 10-membered heterocycle are optionally substituted by one, two, or three independent groups selected from the following: halogen and C. 1-6 alkyl; R s23 Each time it appears, it is independently selected from H and C. 1-6 alkyl; R s24 Each time it appears, it is independently selected from H and C. 1-6 alkyl; R s25 Each time it appears, it is independently selected from C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbon rings and 3 to 10-membered heterocycles, of which C 1-6 Alkyl, C 3-10 The carbide ring and the 3 to 10-membered heterocycle are optionally substituted by one, two, or three independent groups selected from the following: halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-10 Carbon rings and 3 to 10-membered heterocycles; and This indicates a single or double bond, such that all valences are satisfied.

15. The method according to any one of claims 1 to 14, wherein the SOS1 inhibitor is selected from BI-3406, MRTX0902, BAY 293, RMC-5845 and BI-1701963.

16. The method according to any one of claims 1 to 14, wherein the SOS1 inhibitor is .

17. The method according to any one of claims 1 to 14, wherein the SOS1 inhibitor is .

18. The method according to any one of claims 1 to 13, wherein the SOS1 inhibitor is a compound of formula (SIV-1): (SIV-1), Or its pharmaceutically acceptable salts or stereoisomers. in: L s1 It is a key; R s1 It is a 6- to 10-membered aryl group, wherein the 6- to 10-membered aryl group is optionally composed of one or more independently selected R groups. s10 Substituent substitution; R s2 Is it halogen or OR s2a ; R s2a It is C 1-6 Alkyl, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl or C 1-9 heteroaryl, wherein the C 1-6 Alkyl, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl or C 1-9 The heteroaryl group is optionally selected by one, two, or three independently chosen R groups. s20a Substituent substitution; R s3 It is halogen, C 1-6 Alkyl, C 3-14 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl or C 1-9 heteroaryl, wherein the C 1-6 Alkyl, C 3-14 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl or C 1-9 The heteroaryl group is optionally selected by one, two, or three independently chosen R groups. s20b Substituent substitution; R s4 It is H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R s5 It is H, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups; R s6 It is H, halogen, CN or C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally selected by one, two or three independently chosen R. s20c Substituent substitution; Each R s10 Halogen, CN, C independently 1-6 Alkyl, C 3-7 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl or C 1-9 Heteroaryl, wherein each C 1-6 Alkyl, C 3-7 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally and independently selected by one, two or three independently chosen R. s20d Substituent substitution; Each R s20a Halogen, CN, C independently 1-6 Alkyl, CH2C 3-10 cycloalkyl, CH2C 2-9 Heterocyclic alkyl, CH2C 6-10 Aryl, C 2-6 alkenyl, C 2-6 alkynyl group, C(O)R s25 C(O)C(O)NR s22 R s23 C(O)NR s22 R s23 C(O)OR s22 NR s22 R s23 NR s24 C(O)R s25 NR s24 C(O)NR s22 R s23 NR s24 C(O)OR s25 NR s24 S(O)2R s25 =NH, OR s21 OCH2C(O)OR s22 OC(O)R s25 OC(O)NR s22 R s23 =O,SR s21 S(O)2R s25 S(O)2NR s22 R s23 C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl or C 1-9 Mixed aromatics; Each C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group is optionally and independently substituted by one, two or three independently selected from the following substituents: halogen, CN, C(O)R. s25 C(O)C(O)NR s22 R s23 C(O)NR s22 R s23 C(O)OR s22 NR s22 R s23 NR s24 C(O)R s25 NR s24 C(O)NR s22 R s23 NR s24 C(O)OR s25 NR s24 S(O)2R s25 =NH, OR s21 OC(O)R s25 OC(O)NR s22 R s23 =O,SR s21 S(O)2R s25 and S(O)2NR s22 R s23 ;and Each CH2C 3-10 cycloalkyl, CH2C 2-9 Heterocyclic alkyl, CH2C 6-10 Aryl, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally and independently substituted by one, two, or three independently selected substituents from the following: halogen, CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C(O)R s25 C(O)C(O)NR s22 R s23 C(O)NR s22 R s23 C(O)OR s22 NR s22 R s23 NR s24 C(O)R s25 NR s24 C(O)NR s22 R s23 NR s24 C(O)OR s25 NR s24 S(O)2R s25 =NH, OR s21 OC(O)R s25 OC(O)NR s22 R s23 =O,SR s21 S(O)2R s25 and S(O)2NR s22 R s23 ; Each R s20b Halogen, CN, C independently 1-6 Alkyl, CH2C 3-10 cycloalkyl, CH2C 2-9 Heterocyclic alkyl, CH2C 6-10 Aryl, C 2-6 alkenyl, C 2-6 alkynyl group, C(O)R s25 C(O)C(O)NR s22 R s23 C(O)NR s22 R s23 C(O)OR s22 NR s22 R s23 NR s24 C(O)R s25 NR s24 C(O)NR s22 R s23 NR s24 C(O)OR s25 NR s24 S(O)2R s25 =NH, OR s21 OCH2C(O)OR s22 OC(O)R s25 OC(O)NR s22 R s23 =O,SR s21 S(O)2R s25 S(O)2NR s22 R s23 C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl or C 1-9 Mixed aromatics; Each C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group is optionally and independently substituted by one, two or three independently selected from the following substituents: halogen, CN, C(O)R. s25 C(O)C(O)NR s22 R s23 C(O)NR s22 R s23 C(O)OR s22 NR s22 R s23 NR s24 C(O)R s25 NR s24 C(O)NR s22 R s23 NR s24 C(O)OR s25 NR s24 S(O)2R s25 =NH, OR s21 OC(O)R s25 OC(O)NR s22 R s23 =O,SR s21 S(O)2R s25 and S(O)2NR s22 R s23 ;and Each CH2C 3-10 cycloalkyl, CH2C 2-9 Heterocyclic alkyl, CH2C 6-10 Aryl, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally and independently substituted by one, two, or three independently selected substituents from the following: halogen, CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C(O)R s25 C(O)C(O)NR s22 R s23 C(O)NR s22 R s23 C(O)OR s22 NR s22 R s23 NR s24 C(O)R s25 NR s24 C(O)NR s22 R s23 NR s24 C(O)OR s25 NR s24 S(O)2R s25 =NH, OR s21 OC(O)R s25 OC(O)NR s22 R s23 =O,SR s21 S(O)2R s25 and S(O)2NR s22 R s23 ; Each R s20c Halogen, CN, C independently 1-6 Alkyl, CH2C 3-10 cycloalkyl, CH2C 2-9 Heterocyclic alkyl, CH2C 6-10 Aryl, C 2-6 alkenyl, C 2-6 alkynyl group, C(O)R s25 C(O)C(O)NR s22 R s23 C(O)NR s22 R s23 C(O)OR s22 NR s22 R s23 NR s24 C(O)R s25 NR s24 C(O)NR s22 R s23 NR s24 C(O)OR s25 NR s24 S(O)2R s25 =NH, OR s21 OCH2C(O)OR s22 OC(O)R s25 OC(O)NR s22 R s23 =O,SR s21 S(O)2R s25 S(O)2NR s22 R s23 C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl or C 1-9 Mixed aromatics; Each C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group is optionally and independently substituted by one, two or three independently selected from the following substituents: halogen, CN, C(O)R. s25 C(O)C(O)NR s22 R s23 C(O)NR s22 R s23 C(O)OR s22 NR s22 R s23 NR s24 C(O)R s25 NR s24 C(O)NR s22 R s23 NR s24 C(O)OR s25 NR s24 S(O)2R s25 =NH, OR s21 OC(O)R s25 OC(O)NR s22 R s23 =O,SR s21 S(O)2R s25 and S(O)2NR s22 R s23 ;and Each CH2C 3-10 cycloalkyl, CH2C 2-9 Heterocyclic alkyl, CH2C 6-10 Aryl, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally and independently substituted by one, two, or three independently selected substituents from the following: halogen, CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C(O)R s25 C(O)C(O)NR s22 R s23 C(O)NR s22 R s23 C(O)OR s22 NR s22 R s23 NR s24 C(O)R s25 NR s24 C(O)NR s22 R s23 NR s24 C(O)OR s25 NR s24 S(O)2R s25 =NH, OR s21 OC(O)R s25 OC(O)NR s22 R s23 =O,SR s21 S(O)2R s25 and S(O)2NR s22 R s23 ; Each R s20d Halogen, CN, C independently 1-6 Alkyl, CH2C 3-10 cycloalkyl, CH2C 2-9 Heterocyclic alkyl, CH2C 6-10 Aryl, C 2-6 alkenyl, C 2-6 alkynyl group, C(O)R s25 C(O)C(O)NR s22 R s23 C(O)NR s22 R s23 C(O)OR s22 NR s22 R s23 NR s24 C(O)R s25 NR s24 C(O)NR s22 R s23 NR s24 C(O)OR s25 NR s24 S(O)2R s25 =NH, OR s21 OCH2C(O)OR s22 OC(O)R s25 OC(O)NR s22 R s23 =O,SR s21 S(O)2R s25 S(O)2NR s22 R s23 C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl or C 1-9 Mixed aromatics; Each C 1-6 Alkyl, C 2-6 alkenyl and C 2-6 The alkynyl group is optionally and independently substituted by one, two or three independently selected from the following substituents: halogen, CN, C(O)R. s25 C(O)C(O)NR s22 R s23 C(O)NR s22 R s23 C(O)OR s22 NR s22 R s23 NR s24 C(O)R s25 NR s24 C(O)NR s22 R s23 NR s24 C(O)OR s25 NR s24 S(O)2R s25 =NH, OR s21 OC(O)R s25 OC(O)NR s22 R s23 =O,SR s21 S(O)2R s25 and S(O)2NR s22 R s23 ;and Each CH2C 3-10 cycloalkyl, CH2C 2-9 Heterocyclic alkyl, CH2C 6-10 Aryl, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally and independently substituted by one, two, or three independently selected substituents from the following: halogen, CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C(O)R s25 C(O)C(O)NR s22 R s23 C(O)NR s22 R s23 C(O)OR s22 NR s22 R s23 NR s24 C(O)R s25 NR s24 C(O)NR s22 R s23 NR s24 C(O)OR s25 NR s24 S(O)2R s25 =NH, OR s21 OC(O)R s25 OC(O)NR s22 R s23 =O,SR s21 S(O)2R s25 and S(O)2NR s22 R s23 ; Each R s21 H and C independently 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl or C 1-9 Heteroaryl, wherein each C 3-7 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally and independently substituted by one, two, or three substituents independently selected from the following: halogens and C. 1-6 alkyl; Each R s22 H and C independently 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl or C 1-9 Heteroaryl, wherein each C 3-7 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally and independently substituted by one, two, or three substituents independently selected from the following: halogens and C. 1-6 alkyl; Each R s23 Independently, it is H or C 1-6 alkyl; Each R s24 Independently, it is H or C 1-6 Alkyl; and Each R s25 C is independent 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-7 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl or C 1-9 Heteroaryl, wherein each C 1-6 Alkyl, C 3-7 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally and independently substituted by one, two, or three substituents independently selected from the following: halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, OC 1-6 Alkyl, C 3-7 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Mixed aromatic compounds.

19. The method of claim 18, wherein R s3 It is C 2-9 Heterocyclic alkyl groups, wherein the C 2-9 Heterocyclic alkyl groups are optionally represented by one, two, or three independently selected R groups. s20b Substituent substitution.

20. The method of claim 18, wherein R s3 It is C 3-10 cycloalkyl, wherein the C 3-10 The cycloalkyl group is optionally represented by one, two, or three independently selected R. s20b Substituent substitution.

21. The method according to any one of claims 18 to 20, wherein R s1 yes: , , , , or .

22. The method according to any one of claims 1 to 13, wherein the SOS1 inhibitor is a compound selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

23. The method according to any one of claims 1 to 22, wherein the KRAS inhibitor is a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof: Equation (I); in W is N, C(R) 18 ), N(R 18b ), C(R 18 (R) 18a ), C(O), S(O) or S(O)2; Z is N, C(R) 8 ), N(R 8b ), C(R 8 (R) 8a W, Z, C(O), S(O) or S(O)2; where W and Z are not both selected from C(O), S(O) and S(O)2; V and J are each independently selected from C(R) 17 ), C(R 17 (R) 16a ), C(R 16 ), C(R 16 (R) 16a ), N, N(R) 17b ) and N(R 16b ); where exactly one of V and J is C(R) 17 ), C(R 17 (R) 16a ) or N(R 17b ); Y is N, C(R) 2 ), C(R 2 (R) 2c ), N(R 2b ), S(O) or S(O)2; U is N, C(R) 2c ), C(R 2c (R) 2c ), N(R 2b ), S(O), S(O)2 or C(O); R 10 Yes -L 7 -R 7 ; L 7 It is a key, -O-, -N(R) 14 )-, -C(O)-, -S-, -S(O)2-, -S(O)-, C 1-4 Alkyl or 2-4 heteroalkyl connectors, wherein the C 1-4 The alkyl and 2-4 heteroalkyl links are each optionally connected by one, two, or three Rs. 20a replace; R 7 yes ; W 1 and W 3 Independently selected from N(R) 1 ), N(R 4 ), C(R 1 (R) 1 ), C(R 1 (R) 4 ), C(R 4 (R) 4 ), C(O), S, O, S(O) and S(O)2; W 2 Independently selected from N(R) 1 ), N(R 4 ), C(R 1 (R) 1 ), C(R 1 (R) 4 ), C(R 4 (R) 4 ), C(O), S, O, S(O) and S(O)2; W 4 Selected from C(R) 1 (R) 1 ), C(R 1 (R) 4 ), C(R 4 (R) 4 ), S(O) and S(O)2; W 5 Selected from N, C(R) 1 ) and C(R 4 ); s1 is 1, and s2 is 0, 2, or 3; s1 is 2, and s2 is 0, 1, or 3; s1 is 3, and s2 is 0 to 3; s1 is 4, and s2 is 0 to 3; s1 is 5, and s2 is 0 to 3; or s1 is 6, and s2 is 0 to 3; or s3 is an integer from 1 to 3; Each R 1 Independently selected from hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-12 cycloalkyl, -CH2-C 3-12 cycloalkyl, C 1-11 Heterocyclic alkyl, -CH2-C 1-11 Heterocyclic alkyl, C 6-12 Aryl, -CH2-C 6-12 Aryl, -CH2-C 1-11 heteroaryl and C 1-11 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 3-12 cycloalkyl, -CH2-C 3-12 cycloalkyl, C 1-11 Heterocyclic alkyl, -CH2-C 1-11 Heterocyclic alkyl, C 6-12 Aryl, -CH2-C 6-12 Aryl, -CH2-C 1-11 heteroaryl and C 1-11 The heteroaryl group is optionally surrounded by one, two or three R 20a replace; Each R 4 Independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 12 -SR 12 -N(R) 12 (R) 13 =C(R) 21b )2、-C(O)OR 12 -OC(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)N(R 12 (R) 13 ), -N(R 14 )C(O)OR 15 -N(R) 14 )S(O)2R 15 -C(O)R 12 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)R 12 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 )-、S(=O)(=NH)N(R 12 (R) 13 ), -(C 1-6 alkyl)-C(O)N(R 12 (R) 13 ), -(C 1-6 alkyl)-N(R 14 )C(O)R 12 -(C 1-6 alkyl)-S(O)2R 15 -(C 1-6 alkyl)-N(R 12 (R) 13 ) and -(C 1-6 alkyl)-S(O)2N(R 12 (R) 13 ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two or three R 20a replace; R 6 Yes -L 2 -R 5 , where R 6 Optionally, it can form a covalent bond with Ras amino acids; L 2 is a bond, -O-, -N(R 4d )-, -C(O)-, -S-, -S(O)2-, -S(O)-, -P(O)R 4d -, CR 4c R 4c , -OCR 4c R 4c -, -N(R 4d )CR 4c R 4c , -C(O)CR 4c R 4c , -SCR 4c R 4c , -S(O)2CR 4c R 4c , -S(O)CR 4c R 4c , -P(O)R 4d CR 4c R 4c , -CR 4c R 4c CR 4c R 4c [[ID=I50]], -CR 4c R 4c , -CR 4c R 4c N(R 4d ), -CR 4c R 4c , -CR 4c R 4c , -CR 4c R 4c , -CR 4c R 4c , -CR 4c R 4c P(O)R 4d , -N(R 4d ), -N(R 4d ), -N(R 4d ), -N(R 4d ), -N(R 4d , -C(O)N(R 4d ), -S(O)2N(R 4d ), -S(O)N(R 4d ), -P(O)R 4d N(R 4d ), -OC(O)-, -OS(O)2-, -OS(O)-, -OP(O)R 4d -、-C(O)O-、-S(O)2O-、-S(O)O-、-P(O)R 4d O-、-CR 4c R 4c CR 4c R 4c CR 4c R 4c -、-OCR 4c R 4c CR 4c R 4c -、-N(R 4d )CR 4c R 4c CR 4c R 4c -、-C(O)CR 4c R 4c CR 4c R 4c -、-SCR 4c R 4c CR 4c R 4c -、-S(O)2CR 4c R 4c CR 4c R 4c -、-S(O)CR 4c R 4c CR 4c R 4c -、-P(O)R 4d CR 4c R 4c CR 4c R 4c -、-CR 4c R 4c CR 4c R 4c O-、-CR 4c R 4c CR 4c R 4c N(R 4d )-、-CR 4c R 4c CR 4c R 4c C(O)-、-CR 4c R 4c CR 4c R 4c S-、-CR 4c R 4c CR 4c R 4c S(O)2-、-CR 4c R 4c CR 4c R 4c S(O)- or -CR 4c R 4c CR 4c R 4c P(O)R 4d -; Each R 4c Independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-10 cycloalkyl, -CH2-C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, -CH2-C 2-9 Heterocyclic alkyl, -OR 14 -SR 14 -C(O)OR 14 -C(O)N(R) 14 (R) 14 -C(O)C(O)N(R) 14 (R) 14 ), -OC(O)N(R 14 (R) 14 -C(O)R 14a -S(O)2R 14 -S(O)2N(R) 14 (R) 14 -OCH2C(O)OR 14 -OC(O)R 14a -N(R) 14 (R) 14 ), -N(R 14 )C(O)N(R 14 (R) 14 ), -N(R 14 )C(O)OR 14 -N(R) 14 )C(O)R 14a and -N(R) 14 )S(O)2R 14 ; where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, -CH2-C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl groups and -CH2-C 2-9 The heterocyclic alkyl group is optionally substituted by one, two, or three independent substituents selected from the following: halogen, oxo, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -OR 14 -SR 14 , -N(R 14 )(R 14 ), -C(O)OR 14 , -C(O)N(R 14 )(R 14 ), -C(O)C(O)N(R 14 )(R 14 ), -OC(O)N(R 14 )(R 14 ), -N(R 14 )(R 14 )(R 14 ), -N(R 14 )(R 14 ), -N(R 14 )(R 14 ), -N(R 14 )(R 14 ), -C(O)R 14a ), -S(O)2R 14 ), -S(O)2N(R 14 )(R 14 ), and -OC(O)R 14a ; Each R 4d Independently selected from hydrogen, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-10 cycloalkyl, -CH2-C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, -CH2-C 2-9 Heterocyclic alkyl, -OR 14 -SR 14 -C(O)OR 14 -C(O)N(R) 14 (R) 14 -C(O)C(O)N(R) 14 (R) 14 ), -OC(O)N(R 14 (R) 14 -C(O)R 14a -S(O)2R 14 -S(O)2N(R) 14 (R) 14 -OCH2C(O)OR 14 and -OC(O)R 14a ; where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, -CH2-C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl groups and -CH2-C 2-9 The heterocyclic alkyl group is optionally substituted by one, two, or three independent substituents selected from the following: halogen, oxo, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -OR 14 -SR 14 -N(R) 14 (R) 14 -C(O)OR 14 -C(O)N(R) 14 (R) 14 -C(O)C(O)N(R) 14 (R) 14 ), -OC(O)N(R 14 (R) 14 ), -N(R 14 )C(O)N(R 14 )(R 14 )、-N(R 14 )C(O)OR 14 、-N(R 14 )C(O)R 14 、-N(R 14 )S(O)2R 14 、-C(O)R 14a 、-S(O)2R 14 、-S(O)2N(R 14 )(R 14 )和-OC(O)R 14a ; R 5 Each is chosen to be either one, two, or three Rs. 20k The substituted 5- or 6-membered partially unsaturated heterocyclic alkyl or 5- or 6-membered heteroaryl group comprises one, two, or three cyclic nitrogen atoms; and each of the 5- or 6-membered partially unsaturated heterocyclic alkyl or 5- or 6-membered heteroaryl group is bonded to L via a cyclic nitrogen bond. 2 ; R 8 and R 8a Independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)N(R 12 (R) 13 ), -N(R 14 )C(O)OR 15 -N(R) 14 )S(O)2R 15 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)R 15 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 )-、S(=O)(=NH)N(R 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 and -CH2S(O)2N(R 12 (R) 13 ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two or three R 20c replace; R 8b Independently selected from hydrogen, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 12 -SR 12 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 )-、S(=O)(=NH)N(R 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 and -CH2S(O)2N(R 12 (R) 13 ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two or three R 20c replace; R 17 Yes -L 1 -R 19 ; R 17b Yes -L 1b -R 19 ; L 1 Selected from bonds, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, -O-, -N(R) 14 -, -C(O)-, -N(R) 14 )C(O)-、-C(O)N(R 14 )-, -S-, -S(O)2-, -S(O)-, -S(O)2N(R 14 )-、-S(O)N(R 14 )-、-N(R 14 )S(O)-、-N(R 14 )S(O)2-、-OCON(R 14 )-、-N(R 14 )C(O)O-、N(R 1e ), C(O)N(R 1c ), S(O)2N(R 1c ), S(O)N(R 1c ), C(R 1f (R) 1g O、C(R) 1f (R) 1g )N(R 1c ) and C(R 1f (R) 1g ); wherein the C1-C4 alkyl, C2-C4 alkenyl and C2-C4 alkynyl groups are optionally represented by one, two or three R groups. 20i replace; L 1b Selected from bonds, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, -C(O)-, -C(O)N(R) 14 )-、C(O)N(R 1c ), C(R 1f (R) 1g O、C(R) 1f (R) 1g )N(R 1c ) and C(R 1f (R) 1g ); wherein the C1-C4 alkyl, C2-C4 alkenyl and C2-C4 alkynyl groups are optionally represented by one, two or three R groups. 20i replace; R 1e R 1f and R 1g Independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)N(R 12 (R) 13 ), -N(R 14 )C(O)OR 15 -N(R) 14 )S(O)2R 15 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)R 15 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 )-、S(=O)(=NH)N(R 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 and -CH2S(O)2N(R 12 (R) 13 ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two or three R 20i Replace; or R 1f and R 1g Combined to form a 4-7 membered heterocyclic alkyl ring or a 4-7 membered cycloalkyl ring, wherein the 4-7 membered heterocyclic alkyl ring or the 4-7 membered cycloalkyl ring is optionally connected by one, two or three R 20i replace; R 1c Selected from hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two or three R 20i replace; R 19 Selected from C 3-12 cycloalkyl, C 2-11 Heterocyclic alkyl, C 6-12 Aryl and C 2-12 heteroaryl, wherein the C 3-12 cycloalkyl, C 2-11 Heterocyclic alkyl, C 6-12 Aryl and C 2-12 The heteroaryl group is optionally surrounded by one, two, three, four, five, six, or seven R groups. 1i replace; Each R 1i Independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)N(R 12 (R) 13 ), -N(R 14 )C(O)OR 15 -N(R) 14 )S(O)2R 15 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)R 15 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 )-、S(=O)(=NH)N(R 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 and -CH2S(O)2N(R 12 (R) 13 ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two or three R 20i replace; R 16 and R 16a Independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)N(R 12 (R) 13 ), -N(R 14 )C(O)OR 15 -N(R) 14 )S(O)2R 15 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)R 15 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 )-、S(=O)(=NH)N(R 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 and -CH2S(O)2N(R 12 (R) 13 ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two or three R 20g replace; R 16b Independently selected from hydrogen, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 12 -SR 12 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 )-、S(=O)(=NH)N(R 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 and -CH2S(O)2N(R 12 (R) 13 ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two or three R 20g replace; R 2 Selected from halogens, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 12’ -SR 12’ -N(R) 12’’ (R) 13 ), -N=(R 15 -C(O)OR 12’ -OC(O)N(R) 12’ (R) 13 ), -N(R 14 )C(O)N(R 12’ (R) 13 ), -N(R 14 )C(O)OR 15 -N(R) 14 )S(O)2R 15 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12’ (R) 13 -C(O)C(O)N(R) 12’ (R) 13 ), -N(R 14 )C(O)R 15 -S(O)2R 15 -S(O)2N(R) 12’ (R) 13 )-、S(=O)(=NH)N(R 12’ (R) 13 -CH2C(O)N(R) 12’ (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 -CH2S(O)2N(R) 12’ (R) 13 -(C1-C6 alkyl)-R 12b -(C 2-6 alkenyl)-R 12b -(C 2-6 (alkynyl)-R 12b -(C 3-10 (cycloalkyl)-R 12b -(C 4-9 (heterocyclic alkyl)-R 12b -(C 6-10 (aryl)-R 12b and -(C 1-9 (heteroaryl)-R 12b Wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 4-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two or three R 20d replace; R 2c Independently, it is hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)N(R 12 (R) 13 ), -N(R 14 )C(O)OR 15 -N(R) 14 )S(O)2R 15 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)R 15 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 )-、S(=O)(=NH)N(R 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 -CH2S(O)2N(R) 12 (R) 13 -(C1-C6 alkyl)-R 12b -(C 2-6 alkenyl)-R 12b -(C 2-6 (alkynyl)-R 12b -(C 3-10 (cycloalkyl)-R 12b -(C 2-9 (heterocyclic alkyl)-R 12b -(C 6-10 (aryl)-R 12b or -(C 1-9 (heteroaryl)-R 12b Wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two or three R 20d replace; R 2b Independently, it is hydrogen, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 12’ -SR 12’ -C(O)OR 12’ -OC(O)N(R) 12’ (R) 13 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12’ (R) 13 -C(O)C(O)N(R) 12’ (R) 13 -S(O)2R 15 -S(O)2N(R) 12’ (R) 13 )-、S(=O)(=NH)N(R 12’ (R) 13 -CH2C(O)N(R) 12’ (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 -CH2S(O)2N(R) 12’ (R) 13 -(C1-C6 alkyl)-R 12b -(C 2-6 alkenyl)-R 12b -(C 2-6 (alkynyl)-R 12b -(C 3-10 (cycloalkyl)-R 12b -(C 2-9 (heterocyclic alkyl)-R 12b -(C 6-10 (aryl)-R 12b or -(C 1-9 (heteroaryl)-R 12b Wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two or three R 20d replace; R 12b Selected from hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, -CH2-C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, -CH2-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, -CH2-C 1-9 heteroaryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, -CH2-C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, -CH2-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, -CH2-C 1-9 heteroaryl and C 1-9 The heteroaryl group is optionally surrounded by one, two or three R 20d replace; X is C(R) 3 ), C(R 3 (R) 3 ), N(R 3 ) or N; Each R 3 Independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)N(R 12 (R) 13 ), -N(R 14 )C(O)OR 15 -N(R) 14 )S(O)2R 15 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)R 15 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 )-、S(=O)(=NH)N(R 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 and -CH2S(O)2N(R 12 (R) 13 ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two or three R 20b replace; Each R 12 Independently selected from hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, -CH2-C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, -CH2-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, -CH2-C 1-9 heteroaryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, -CH2-C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, -CH2-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, -CH2-C 1-9 heteroaryl and C 1-9 The heteroaryl group is optionally surrounded by one, two or three R 20d replace; Each R 12’ Independently selected from hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, -C(R) 12c )2-C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, -C(R) 12c )2-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, -C(R) 12c )2-C 6-10 Aryl, -C(R) 12c )2-C 1-9 heteroaryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, -C(R) 12c )2-C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, -C(R) 12c )2-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, -C(R) 12c )2-C 6-10 Aryl, -C(R) 12c )2-C 1-9 heteroaryl and C 1-9 The heteroaryl group is optionally surrounded by one, two or three R 20d replace; Each R 12’’ Selected independently from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, -C(R) 12c )2-C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, -C(R) 12c )2-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, -C(R) 12c )2-C 6-10 Aryl, -C(R) 12c )2-C 1-9 heteroaryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, -C(R) 12c )2-C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, -C(R) 12c )2-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, -C(R) 12c )2-C 6-10 Aryl, -C(R) 12c )2-C 1-9 heteroaryl and C 1-9 The heteroaryl group is optionally surrounded by one, two or three R 20d replace; Each R 12c Independently selected from hydrogen and R 20m ; Each R 13 Independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl; or R 12 and R 13 Together with the nitrogen atoms they are attached to, they form a mixture optionally bounded by one, two, or three R atoms. 20e Replacement C 2-9 Heterocyclic alkyl rings; Each R 14 Independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 14a Selected independently from C 1-6 Alkyl and C 1-6 Halogenated alkyl groups; Each R 15 Selected independently from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two or three R 20f replace; R 18 and R 18a Independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)N(R 12 (R) 13 ), -N(R 14 )C(O)OR 15 -N(R) 14 )S(O)2R 15 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)R 15 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 )-、S(=O)(=NH)N(R 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 and -CH2S(O)2N(R 12 (R) 13 ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two or three R 20h replace; R 18b Independently selected from hydrogen, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 12 -SR 12 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 )-、S(=O)(=NH)N(R 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 and -CH2S(O)2N(R 12 (R) 13 ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two or three R 20h replace; Each R 20a R 20b R 20c R 20d R 20e R 20f R 20g R 20h R 20i R 20k and R 20m Independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, -CH2-C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, -CH2-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, -CH2-C 1-9 heteroaryl, C 1-9 Mixed aromatics, -OR 21 -SR 21 -N(R) 22 (R) 23 =C(R) 21b )2、-C(O)OR 22 -C(O)N(R) 22 (R) 23 -C(O)C(O)N(R) 22 (R) 23 ), -OC(O)N(R 22 (R) 23 ), -N(R 24 )C(O)N(R 22 (R) 23 ), -N(R 24 )C(O)OR 25 -N(R) 24 )C(O)R 21 -N(R) 24 )S(O)2R 25 -C(O)R 21 -S(O)2R 25 -S(O)2N(R) 22 (R) 23 -OCH2C(O)OR 22 and -OC(O)R 25 Among them, two R atoms bonded to the same or adjacent atoms 20k They can be combined arbitrarily to form C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl or C 1-9 heteroaryl; of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, -CH2-C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, -CH2-C 2-9 Heterocyclic alkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, -CH2-C 1-9 heteroaryl and C 1-9 The heteroaryl group may optionally be substituted by one, two, or three independently selected groups from the following: halogen, oxo, -CN, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -OR 21 -SR 21 -N(R) 22 (R) 23 -C(O)OR 22 -C(O)N(R) 22 (R) 23 -C(O)C(O)N(R) 22 (R) 23 ), -OC(O)N(R 22 (R) 23 ), -N(R 24 )C(O)N(R 22 (R) 23 ), -N(R 24 )C(O)OR 25 -N(R) 24 )C(O)R 25 -N(R) 24 )S(O)2R 25 -C(O)R 25 -S(O)2R 25 -S(O)2N(R) 22 (R) 23 ) and -OC(O)R 25 ; Each R 21 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Mixed aromatics; R 21b Each time it appears, it is independently selected from hydrogen, halogen, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, or two R 21b Together with the carbon atoms they are attached to, they form C 3-10 cycloalkyl or C 2-9 Heterocyclic alkyl groups; each of which may optionally be substituted by one, two, or three independent substituents selected from the following: halogen, C 1-3 Alkyl, C 1-3 Halogenated alkyl groups and -OH; Each R 22 Independently selected from H and C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Mixed aromatics; Each R 23 Independently selected from H and C 1-6 alkyl; Each R 24 Independently selected from H and C 1-6 alkyl; Each R 25 Selected independently from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 Mixed aromatics; This indicates the connection positions of the depicted chemical formula or atoms with substituents, other components of the molecule, or atoms; and This indicates a single or double bond, such that all valences are satisfied.

24. The method of claim 23, wherein R 5 It can be arbitrarily determined by one, two, or three Rs. 20k Substituted 5-membered heteroaryl groups, wherein the 5-membered heteroaryl group comprises one, two, or three cyclic nitrogen atoms; and the 5-membered heteroaryl group is bonded to L via a cyclic nitrogen bond. 2 .

25. The method of claim 23, wherein L 2 It is -C(O)-; and R 5 It can be arbitrarily determined by one, two, or three Rs. 20k Substituted 5-membered heteroaryl groups, wherein the 5-membered heteroaryl group comprises one, two, or three cyclic nitrogen atoms; and L 2 Direct bonding to R 5 N-ring atoms.

26. The method according to any one of claims 23 to 25, wherein L 7 It is a key.

27. The method according to any one of claims 23 to 26, wherein s1 is 2 and s2 is 0, 1 or 3.

28. The method according to any one of claims 23 to 26, wherein R 7 Selected from , , , , , , , , , , , , and ;where R 1 and R 4 Substituents can be bonded to any spiroring.

29. The method according to any one of claims 23 to 28, wherein R 17 Yes -L 1 -R 19 or -L 1b -R 19 L 1 It is a key, and L 1b It is a key.

30. The method according to any one of claims 23 to 29, wherein R 19 yes: , , , , , , , , or ; Q 1 Q 3 and Q 5 Independently selected from N and C(R) 1d ); Q 4 and Q 6 Independently selected from O, S, C(R) 1a (R) 1b ) and N(R 1c ); X 4 X 5 X 6 X 9 X 10 Independently selected from C(R) 1a ) and N; X 13 Selected from key, C(R) 1a ), N, C(O), C(R) 1a (R) 1b ), C(O)C(R) 1a (R) 1b ), C(R 1a (R) 1b )C(R 1a (R) 1b ), C(R 1a (R) 1b )N(R 1c ) and N(R 1c ); X 14 X 15 X 17 X 18 Independently selected from C(O) and C(R) 1a ), N, C(R) 1a (R) 1b ) and N(R 1c ); X 16 Independently selected from C, N, and C(R) 1a ); Each R 1a R 1b R 1d and R 1h Each is independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl, C 1-9 Mixed aromatics, -OR 12 -SR 12 -N(R) 12 (R) 13 -C(O)OR 12 -OC(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)N(R 12 (R) 13 ), -N(R 14 )C(O)OR 15 -N(R) 14 )S(O)2R 15 -C(O)R 15 -S(O)R 15 -OC(O)R 15 -C(O)N(R) 12 (R) 13 -C(O)C(O)N(R) 12 (R) 13 ), -N(R 14 )C(O)R 15 -S(O)2R 15 -S(O)2N(R) 12 (R) 13 )-、S(=O)(=NH)N(R 12 (R) 13 -CH2C(O)N(R) 12 (R) 13 ), -CH2N(R 14 )C(O)R 15 -CH2S(O)2R 15 and -CH2S(O)2N(R 12 (R) 13 ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two or three R 20i Substitution; or bonding to the same carbon atom R 1a and R 1b Combined to form 3-10 membered heterocyclic alkyl rings or C 3-10 Cycloalkyl rings, wherein the 3-10 membered heterocyclic alkyl rings or C 3-10 The cycloalkyl ring is optionally surrounded by one, two, or three R... 20i Substitution; or bonding to two adjacent R atoms 1a Combined to form 3-10 membered heterocyclic alkyl rings, C 6-10 Aryl ring, 5-12 membered heteroaryl ring or C 3-10 Cycloalkyl rings, wherein the 3-10 membered heterocyclic alkyl rings, C 6-10 Aryl ring, 5-12 membered heteroaryl ring or C 3-10 The cycloalkyl ring is optionally surrounded by one, two, or three R... 20i Substitution; or R bonded to adjacent atoms 1h With R 1a R 1b R 1c and R 1d One of them combines to form a 3-10 membered heterocyclic alkyl ring, C 6-10 Aryl ring, 5-12 membered heteroaryl ring or C 3-10 Cycloalkyl rings, wherein the 3-10 membered heterocyclic alkyl rings, C 6-10 Aryl rings, 5-12 membered heteroaryl rings and C 3-10 The cycloalkyl ring is optionally surrounded by one, two, or three R... 20i Replace; and Each R 1c Independently selected from hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 heteroaryl, of which C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally surrounded by one, two or three R 20i replace.

31. The method according to any one of claims 23 to 29, wherein R 19 Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

32. The method according to any one of claims 23 to 31, wherein R 2 Yes - OR 12’ .

33. The method according to any one of claims 23 to 31, wherein R 2 Selected from , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , and .

34. The method of claim 23, wherein W is C(R) 18 Z is N, C(R) or C(O); 8 ) or N(R 8b V is C(R) 17 J is C(R) 16 ); Y is C(R) 2 ); U is N; X is N; L 1 It is a key; L 7 It is a key; W 1 W 2 and W 3 Independently selected from C(R) 1 (R) 1 ), C(R 1 (R) 4 ), C(R 4 (R) 4 ) and O; W 4 Selected from C(R) 1 (R) 1 ), C(R 1 (R) 4 ) and C(R 4 (R) 4 );W 5 Selected from N and CH; L 2 It is -C(O)-; R 5 It can be arbitrarily determined by one, two, or three Rs. 20k Substituted 5-membered heteroaryl groups, wherein the 5-membered heteroaryl group comprises one, two, or three cyclic nitrogen atoms, and further wherein when R 5 Direct bonding to L 2 When C(O) is present, L 2 Direct bonding to R 5 N-ring atoms; R 2 Selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, -OR 12’ -SR 12’ and -N(R) 12’’ (R) 13 ), wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl and C 2-9 Heterocyclic alkyl groups are optionally surrounded by one, two, or three R groups. 20d replace; R 8 Independently selected from hydrogen, halogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, -OR 12 -SR 12 and -N(R) 12 (R) 13 ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl and C 2-9 Heterocyclic alkyl groups are optionally surrounded by one, two, or three R groups. 20c replace; R 8b Selected from hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl and C 2-9 Heterocyclic alkyl groups, wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl and C 2-9 Heterocyclic alkyl groups are optionally surrounded by one, two, or three R groups. 20c replace; R 16 Independently selected from hydrogen, halogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 2-9 Heterocyclic alkyl, -OR 12 -SR 12 and -N(R) 12 (R) 13 ), where C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl and C 2-9 Heterocyclic alkyl groups are optionally surrounded by one, two, or three R groups. 20g Replace; and R 18 It is hydrogen.

35. The method of claim 34, wherein W 1 W 2 and W 3 Independently selected from CH2 and O; W 4 It is CH2; W 5 Selected from N and CH; R 2 is - OR 12’ ; R 8 The halogen and C are independently selected. 1-6 Halogenated alkyl groups; R 8b Selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl and C 2-9 Heterocyclic alkyl groups, wherein C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl and C 2-9 Heterocyclic alkyl groups are optionally surrounded by one, two, or three R groups. 20c Replace; and R 16 It is halogen.

36. The method according to any one of claims 4 to 35, wherein the cancer is lung cancer.

37. The method according to any one of claims 4 to 35, wherein the cancer is non-small cell lung cancer.

38. The method according to any one of claims 4 to 35, wherein the cancer is colorectal cancer.

39. The method according to any one of claims 4 to 35, wherein the cancer is pancreatic cancer.

40. The method according to any one of claims 4 to 35, wherein the cancer is a solid cancer.

41. The method according to any one of claims 4 to 40, wherein the cancer cells of said object contain the KRAS G12C mutant protein.

42. The method according to any one of claims 4 to 40, wherein the cancer cells of said object are refractory to at least one KRASG12C inhibitor.

43. The method according to any one of claims 4 to 40, wherein the cancer cells of said object contain the KRAS G12S mutant protein.

44. The method according to any one of claims 1 to 43, wherein the cancer cells of the object contain KRAS overexpression.

45. The method according to any one of the preceding claims, wherein the object exhibits recurrence of the cancer.

46. ​​The method according to any one of the preceding claims, wherein the subject has previously been treated with a KRAS G12C inhibitor.

47. The method according to any one of the preceding claims further includes (c) administering an additional agent or additional therapy.

48. The method of claim 47, wherein the additional agent is selected from immunomodulators, antinausea agents, antiemetics, analgesics, chemotherapeutic agents, SHP2 inhibitors, PI3K inhibitors, CDK4 / 6 inhibitors, RAF inhibitors, MEK inhibitors, ERK inhibitors, EGFR inhibitors, and AKT inhibitors.

49. The method of claim 47, wherein the additional agent is selected from immunomodulators, cytokine blockers, and checkpoint immunomodulators.

50. The method of claim 47, wherein the additional agent is selected from anti-PD-L1 antibody, anti-CTLA-4 antibody, anti-PD-1 antibody, anti-LAG3 antibody, anti-TIM3 antibody, and combinations thereof.

51. The method of claim 47, wherein the additional therapy is selected from surgery, cell therapy, chemotherapy, and radiation.

52. The method according to any one of the preceding claims, wherein the administration of (a) and (b) reduces the incidence of one or more adverse events associated with the SOS1 inhibitor or the KRAS inhibitor.

53. The method of claim 52, wherein the adverse event is selected from diarrhea, rash, nausea, vomiting, loss of appetite, fatigue, musculoskeletal pain, dyspnea, and acute kidney injury.

54. The method of claim 52, wherein the adverse event is selected from diarrhea, rash, and nausea.

55. The method according to any one of the preceding claims, wherein the application of (a) and (b) exhibits a synergistic effect.

56. The method of claim 54, wherein the synergy is characterized by a synergy value determined by the Bliss independence criterion of at least 0.

05.

57. The method according to any one of the preceding claims, wherein one or both of (a) and (b) are administered at a subtherapeutic dose, but achieve a therapeutic effect at least equivalent to that of administering (a) or (b) alone at its therapeutically effective dose.

58. The method according to any one of the preceding claims, wherein the KRAS inhibitor is administered at a dose less than about 25% of the standard monotherapy dose.

59. The method according to any one of the preceding claims, wherein (a) and (b) are administered in the same formulation.

60. The method according to any one of the preceding claims, wherein (a) and (b) are administered in separate formulations.

61. A kit for reducing the proliferation of cancer cells containing a KRAS mutant protein or KRAS overexpression, the kit comprising: (1) A composition containing an SOS1 inhibitor of formula (SI-1); (2) A composition comprising a KRAS inhibitor of formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV-1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H); and (3) Instructions for use of the compositions described in (1) and (2).

62. A kit for reducing the proliferation of cancer cells containing a KRAS mutant protein or KRAS overexpression, the kit comprising: (1) A composition containing an SOS1 inhibitor of formula (SIV-1); (2) A composition comprising a KRAS inhibitor of formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV-1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H); and (3) Instructions for use of the compositions described in (1) and (2).

63. The kit according to any one of claims 61 to 62, wherein the SOS1 inhibitor and the KRAS inhibitor are formulated in the same unit dosage form.

64. The kit according to any one of claims 61 to 62, wherein the SOS1 inhibitor and the KRAS inhibitor are formulated in different unit dosage forms.

65. A pharmaceutical composition comprising (i) an SOS1 inhibitor of formula (SI-1), or a pharmaceutically acceptable salt or solvation thereof, (ii) a KRAS inhibitor of formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV-1), (IV-2), (A), (B), (C), (D), (E), (F), (G) or (H), or a pharmaceutically acceptable salt or solvation thereof, and (iii) a pharmaceutically acceptable excipient.

66. A method of treating a subject with mutant KRAS-mediated cancer, comprising administering a pharmaceutical composition to the subject, the pharmaceutical composition comprising (i) an SOS1 inhibitor of formula (SI-1), or a pharmaceutically acceptable salt or solvation thereof, (ii) a KRAS inhibitor of formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV-1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H), or a pharmaceutically acceptable salt or solvation thereof, and (iii) a pharmaceutically acceptable excipient.

67. A pharmaceutical composition comprising (i) an SOS1 inhibitor of formula (SIV-1), or a pharmaceutically acceptable salt or solvation thereof; (ii) a KRAS inhibitor of formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV-1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H), or a pharmaceutically acceptable salt or solvation thereof; and (iii) a pharmaceutically acceptable excipient.

68. A method of treating a subject with mutant KRAS-mediated cancer, comprising administering a pharmaceutical composition to the subject, the pharmaceutical composition comprising (i) an SOS1 inhibitor of formula (SIV-1), or a pharmaceutically acceptable salt or solvation thereof, (ii) a KRAS inhibitor of formula (I), (I-1), (I-2), (II), (II-1), (II-2), (II-3), (IV), (IV-1), (IV-2), (A), (B), (C), (D), (E), (F), (G), or (H), or a pharmaceutically acceptable salt or solvation thereof, and (iii) a pharmaceutically acceptable excipient.

69. The method according to claim 1, 3, 4, 8, 66 or 68, wherein the subject is a treatment-naïve subject who has not been treated with a KRAS inhibitor prior to the administration of (a) and (b).

70. The method, kit, or pharmaceutical composition according to any one of claims 1-69, wherein the SOS1 inhibitor is a compound of Table 2a or a pharmaceutically acceptable salt or solvation thereof.

71. The method, kit, or pharmaceutical composition according to any one of claims 1-69, wherein the SOS1 inhibitor is a compound of Table 2b or a pharmaceutically acceptable salt or solvation thereof.

72. The method, kit, or pharmaceutical composition according to any one of claims 1-71, wherein the KRAS inhibitor is a compound of Table 1a or a pharmaceutically acceptable salt or solvation thereof.

73. The method, kit, or pharmaceutical composition according to any one of claims 1-71, wherein the KRAS inhibitor is a compound of Table 1b or a pharmaceutically acceptable salt or solvation thereof.

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