Condensed ring KRAS inhibitors for treatment of disease

Abstract

The present disclosure relates to fused ring compounds targeting KRAS, pharmaceutical compositions containing the compounds and methods of using such compounds in the treatment of diseases, such as cancer.

Description

Related Applications

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 502,046, filed May 12, 2023, and U.S. Provisional Application No. 63 / 469,292, filed May 26, 2023, the entire disclosures of all of which are incorporated herein by reference. TECHNICAL FIELD

[0002] The present disclosure relates to fused ring compounds targeting KRAS, pharmaceutical compositions containing the compounds, and methods of using such compounds to treat diseases such as cancer. BACKGROUND

[0003] Ras is a GTP-binding protein and regulates many important physiological processes within the cell, such as cell cycle progression, survival, apoptosis, etc., H-Ras, K-Ras, and N-Ras are the major members of the Ras superfamily, which are tightly regulated by factors that turn on / off GTPase activity. Somatic mutations at codons 12, 13, and 61 in the RAS gene are associated with about 16% of all human cancers, and KRAS is the most frequently mutated RAS isoform, accounting for 85% of all RAS-associated cancers (Prior I. A. et al. A comprehensive survey of Ras mutations in cancer. Cancer Res. 2012, 72, 2457-2467), including 86-96% in pancreatic cancer, 40-50% in colorectal cancer, and 27-39% in lung adenocarcinoma (Kessler D. et al. Drugging an undruggable pocket on KRAS. Proc Natl Acad Sci U S A. 2019, 116(32): 15823-15829). Mutated RAS is locked in a constitutively activated GTP-bound state and promotes enhanced Ras signaling in cancer cells.

[0004] Direct targeting of mutant KRAS has previously been shown to be challenging due to the high affinity of mutant KRAS for nucleotides and the lack of an easily accessible binding pocket for small molecule inhibitors. Recent success in inhibiting the KRAS G12C mutant in lung cancer patients by the covalent chemical modifiers sotorasib and adagrasib (Stower K, KRAS inhibitors at last, Nature Medicine 2020, 26, 1804) provides an inspiration for targeting KRAS mutants for therapeutic inventions. However, inhibitors that target KRAS mutants at KRAS G12C without covalent formation are still not present. Increased understanding of the structural elements of the KRAS switch II pocket makes it possible to design KRAS inhibitors that are selective for different mutant variants. MRTX1133 has been reported to be a potent and highly selective non-covalent KRAS G12D inhibitor (Wang X. et al., Identification of MRTX1133, a noncovalent, potent, and selective KRAS inhibitor, J. Med. Chem. 2022, 65: 3123-3133). However, intraperitoneal injection of MRTX1133 was required to achieve sufficient plasma exposure and demonstrate drug efficacy in mice. This suggests that the bioavailability of MRTX1133 can be poor. G12D Identification of MRTX1133, a noncovalent, potent, and selective KRAS G12D inhibitor), J. Med. Chem. 2022, 65: 3123-3133). However, intraperitoneal injection of MRTX1133 was required to achieve sufficient plasma exposure and demonstrate drug efficacy in mice. This suggests that the bioavailability of MRTX1133 can be poor.

[0005] Therefore, the medical need for the development of new non-covalent KRAS inhibitors that can selectively target KRAS mutants (such as KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D) and have good in vivo efficacy, safety, and predictive human oral pharmacokinetic profiles for the treatment of patients with KRAS mutant cancers has not been met. SUMMARY

[0006] In one aspect, the disclosure relates to a compound of Formula I, or a pharmaceutically acceptable salt thereof,

[0007]

[0008] I

[0009] Where R 1 R 2 R 3 R 9 R 10 A, B, X, Y, Z 1 Z 2 Z 3 Z 4 m, n, p, and q are as described in this article.

[0010] On the other hand, this disclosure relates to a compound of formula II, III, IV, V, VI, VII, VIII or IX, or a pharmaceutically acceptable salt thereof.

[0011] (II),

[0012] (III), or

[0013] (IV),

[0014] (V),

[0015] (VI),

[0016] (VII),

[0017] (VIII), or

[0018] (IX),

[0019] Where R 1 R 2 R 3 R 9 R 10 A, B, X, X 1 Z 1 Z 2 Z 3 Z 4 m, n, p, q, q1, t, and v are as described in this article.

[0020] On the other hand, this disclosure relates to a compound of formula X, XI, XII, XIII, XIV, XV, XVI, or XVII, or a pharmaceutically acceptable salt thereof.

[0021] (X),

[0022] (XI),

[0023] (XII),

[0024] (XIII),

[0025] (XIV),

[0026] (XV),

[0027] (XVI), or

[0028] (XVII),

[0029] Where R 1 R 2 R 3 R 9 R 10 B, X, Z 1 Z 2 Z 3 Z 4 Z 5 Z 6 m, n, p, q, and q1 are as described in this article.

[0030] On the other hand, this disclosure relates to a compound of formula XVIII, XIX, XX, XXI, XXII, XXIII, XXIV or XXV, or a pharmaceutically acceptable salt thereof.

[0031] (XVIII),

[0032] (XIX),

[0033] (XX),

[0034] (XXI),

[0035] (XXII),

[0036] (XXIII), (XXIV), or

[0037] (XXV),

[0038] Where R 1 R 2 R 3 R 9 R 10X, X 1 Z 1 Z 2 Z 3 Z 4 Z 5 Z 6 m, n, p, q, q1, t, and v are as described in this article.

[0039] On the other hand, this disclosure relates to a compound of formula XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII or XXXIII or a pharmaceutically acceptable salt thereof.

[0040] (XXVI),

[0041] (XXVII),

[0042] (XXVIII),

[0043] (XXIX),

[0044] (XXX),

[0045] (XXXI),

[0046] (XXXII), or

[0047] (XXXIII),

[0048] Where R 1 R 2 R 3 R 9 R 10 B, X, X 1 Z 1 Z 2 Z 3 Z 4 m, n, p, q, q1, t, and v are as described in this article.

[0049] On the other hand, this disclosure relates to a compound of formula XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, XXXX or XXXXI, or a pharmaceutically acceptable salt thereof.

[0050] (XXXIV),

[0051] (XXV),

[0052] (XXXVI),

[0053] (XXXVII),

[0054] (XXXVIII),

[0055] (XXXIX),

[0056] (XXXX), or

[0057] (XXXXI),

[0058] Where R 1 R 2 R 3 R 9 R 10 B, X, X 1 Z 1 Z 2 Z 3 Z 4 m, n, p, q, q1, t, and v are as described in this article.

[0059] On the other hand, this disclosure relates to a compound of the formula XXXXII, XXXXIII, XXXXIV, XXXV, XXXVI, XXXXVII, XXXXVIII or XXXXIX, or a pharmaceutically acceptable salt thereof.

[0060] (XXXXII),

[0061] (XXXXIII),

[0062] (XXXXIV),

[0063] (XXXXV),

[0064] (XXXXVI),

[0065] (XXXXVII),

[0066] (XXXXVIII), or

[0067] (XXXXIX),

[0068] Where R 1 R 2 R 3 R 9 R 10 B, X, X 1 Z 1 Z 2 Z 3 Z 4 m, n, p, q, q1, t, and v are as described in this article.

[0069] On the other hand, this disclosure relates to a compound of the formula L, LI, LII, LIII, LIV, LV, LVI, or LVII, or a pharmaceutically acceptable salt thereof.

[0070] (L),

[0071] (LI),

[0072] (LII),

[0073] (LIII),

[0074] (LIV),

[0075] (LV),

[0076] (LVI), or

[0077] (LVII),

[0078] Where R 1 R 2 R 3 R 9 R 10 B, X, X 1 Z 1 Z 2 Z 3 Z 4 m, n, p, q, q1, t, and v are as described in this article.

[0079] On the other hand, this disclosure relates to a compound of the formula LVIII, LVIX, LX, LXI, LXII, LXIII, LXIV or LXV, or a pharmaceutically acceptable salt thereof.

[0080] (LVIII),

[0081] (LIX),

[0082] (LX),

[0083] (LXI),

[0084] (LXII),

[0085] (LXIII),

[0086] (LXIV), or

[0087] (LXV),

[0088] R 1 R 2 R 3 R 9 R 10 B, X, X 1 Z 1 Z 2 Z 3 Z 4 m, n, p, q, q1, t, and v are as described in this article.

[0089] On the other hand, this disclosure relates to a compound of the formula LXVI, LXVII, LXVIII, LXIX, LXX, LXXI, LXXII, LXXIII, LXXIV, LXXV, LXXVI, LXXVII, LXXVIII, LXXIX, LXXX or LXXXI, or a pharmaceutically acceptable salt thereof.

[0090] (LXVI),

[0091] (LXVII),

[0092] (LXVIII),

[0093] (LXIX),

[0094] (LXX),

[0095] (LXXI),

[0096] (LXXII),

[0097] (LXXIII),

[0098] (LXXIV),

[0099] (LXXV),

[0100] (LXXVI),

[0101] (LXXVII),

[0102] (LXXVIII),

[0103] (LXXIX),

[0104] (LXXX), or

[0105] (LXXXI),

[0106] R 1 R 2 R 3 R 9 R 10 B, X, X 1 Z 1 Z 2 Z 3 Z 4 m, n, p, q, q1, t, and v are as described in this article.

[0107] Further embodiments, features, and advantages of this disclosure will become apparent from the following detailed description and through practice of this disclosure. The compounds of this disclosure may be described as embodiments of any of the following enumerated terms. It should be understood that any embodiment described herein may be used in conjunction with any other embodiment described herein, provided that the embodiments do not contradict each other.

[0108] 1. A compound of formula I or a pharmaceutically acceptable salt thereof,

[0109]

[0110] I

[0111] in

[0112] X is -O-, -S-, or -NR 4 -;

[0113] Y is a bond, -O-, -S-, -S(O)- or -S(O)2-;

[0114] Z 1 Is it N or C(R)? 5 );

[0115] Z 2 Is it N or C(R)? 6 );

[0116] Z 3 Is it N or C(R)? 7 );

[0117] Z 4 Is it N or C(R)? 8 );

[0118] The condition is Z 1 -Z 4 At least two of them are N;

[0119] Ring A is C6-C 10 Aryl, 5- to 10-membered heteroaryl or 4- to 10-membered heterocyclic alkyl;

[0120] Ring B is a 4- to 9-membered heterocyclic alkyl group;

[0121] Each R 1 Independently, it is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OC(=NR) a )NR a R b -OS(O)R a -OS(O)2R a -OS(O)NR a R b -OS(O)2NR a R b -SR a -S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR a R b -NR a R b -NR a C(O)R b -N(C(O)R a )(C(O)R b-NR a C(O)OR b -NR a C(O)NR a R b -NR a C(=NR a )NR a R b -NR a S(O)R b -NR a S(O)2R b -NR a S(O)NR a R b -NR a S(O)2NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -C(=NR) a )NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN or -NO2; or two Rs 1 Together with one or more atoms to which it is attached, it forms a C3-C6 cycloalkyl or a 4- to 10-membered heterocyclic alkyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclic alkyl groups is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -R e -R f -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e-OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2; or R 1 R on the adjacent carbon of ring B 9 or R 10 Together with the carbon atoms it is attached to, they combine to form a carbon-carbon double bond;

[0122] Each R 2 Independently, it is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C10 Aryl, 5- to 10-membered heteroaryl, -OR c 、-OC(O)R c 、-OC(O)NR c R d 、-OC(=NR c )NR c R d 、-OS(O)R c 、-OS(O)2R c `、-OS(O)NR c R d 、-OS(O)2NR c R d 、-SR c 、-S(O)R c 、-S(O)2R c 、-S(O)NR c R d 、-S(O)2NR c R d 、-NR c R d 、-NR c C(O)R d 、-N(C(O)R c )(C(O)R d 、-NR c C(O)OR d 、-NR c C(O)NR c R d 、-NR c C(=NR c )NR c R d 、-NR c S(O)R d 、-NR c S(O)2R d 、-NR c S(O)NR c R d 、-NR c S(O)2NR c R d 、-C(O)R c 、-C(O)OR c 、-C(O)NR c R d 、-C(=NR c )NR c R d 、-PR c R d 、-P(O)R cR d -P(O)2R c R d -P(O)NR c R d -P(O)2NR c R d -P(O)OR c -P(O)2OR c -CN or -NO2, or two Rs 2 Together with the atoms to which they are attached, they form C3-C6 cycloalkyl or 4- to 10-membered heterocyclic alkyl groups, including C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, and C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclic alkyl groups is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -R e -R f -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e Rf -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2;

[0123] R 3 It is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, -C1-C6 alkylene- (4- to 10-membered heterocyclic alkyl), C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 Aryl), 5- to 10-membered heteroaryl or -C1-C6 alkylene- (4- to 10-membered heterocyclic alkyl), wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, -C1-C6 alkylene- (4- to 10-membered heterocyclic alkyl), C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 Each hydrogen atom in aryl, 5- to 10-membered heteroaryl, and -C1-C6 alkylene- (5- to 10-membered heteroaryl) is independently and optionally substituted with the following groups: deuterium, halogen, -R e -R f C1-C6 alkyl, -C1-C6 alkylene-O-C1-C6 alkyl, -C1-C6 alkylene-OR a C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkylene- (5- to 10-membered heterocycloalkyl), -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e Rf -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e C(=NR f )NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2;

[0124] R 4 It is H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10aryl or 5 to 10-membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4 to 10-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl and 5- to 10-membered heteroaryl groups is independently and optionally substituted with the following groups: deuterium, halogen, -R e -R f C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e Rf -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2;

[0125] R 5 R 6 R 7 and R 8 Each of these elements is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR g -OC(O)R g -OC(O)NR g R h -OS(O)R g -OS(O)2R g -SR g -S(O)R g -S(O)2R g -S(O)NR g R h -S(O)2NR g R h -OS(O)NR g R h -OS(O)2NR g R h -NR g R h -NR g C(O)R h -NR g C(O)OR h -NR g C(O)NR g R h -NR g S(O)R h -NR g S(O)2R h -NR g S(O)NR g R h -NR g S(O)2NR g R h -C(O)R g -C(O)OR g -C(O)NR g R h -PRg R h -P(O)R g R h -P(O)2R g R h -P(O)NR g R h -P(O)2NR g R h -P(O)OR g -P(O)2OR g -CN or -NO2;

[0126] R 9 and R 10 Each of these elements is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OC(=NR) a )NR a R b -OS(O)R a -OS(O)2R a -OS(O)NR a R b -OS(O)2NR a R b -SR a -S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR a R b -NR a R b -NR a C(O)R b -N(C(O)R a )(C(O)R b -NR a C(O)OR b -NR a C(O)NR a R b -NR a C(=NR a )NR a R b -NRa S(O)R b -NR a S(O)2R b -NR a S(O)NR a R b -NR a S(O)2NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -C(=NR) a )NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN or -NO2; or R 9 and R 10 Together with the carbon atoms they are attached to, they form C2-C6 alkenyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl or oxo groups, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclic alkyl groups is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -R e -R f -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NRe R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2; or R on adjacent carbon atoms 9 and R 10 Together with the carbon atoms it is attached to, they combine to form R 9 and R 10 Substituted carbon-carbon double bonds;

[0127] R a R b R c R d R e R f R g and R h Each is independently selected from the following groups: H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10Aryl, C1-C6 alkylene-C6-C 10 aryl and 5 to 10-membered heteroaryl; or R a and R b or R c and R d or R e and R f or R g and R h The two atoms in the compound, together with one or more atoms attached to them, combine to form C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 aryl or 5 to 10-membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4 to 10-membered heterocycloalkyl, C6-C 10 Aryl, C1-C6 alkylene-C6-C 10 Each hydrogen atom in the aryl and 5- to 10-membered heteroaryl groups is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OC1-C6 alkyl, -OC(O)C1-C6 alkyl, -OC(O)N(H or C1-C6 alkyl)2, -OS(O)C1-C6 alkyl, -OS(O)2C1-C6 alkyl, -OS(O)N(H or C1-C6 alkyl)2, -OS( O)2N(H or C1-C6 alkyl)2, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)N(H or C1-C6 alkyl)2, -S(O)2N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)C(O)C1-C6 alkyl, - N(C1-C6 alkyl)C(O)N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)C1-C6 alkyl, -N(C1-C6 alkyl)S(O)2C1-C6 alkyl, -N(C1-C6 alkyl)S(O)N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)2N(H or C1-C6 alkyl)2, -C(O)C1-C6 alkyl, -C(O)OC1- C6 alkyl, -C(O)N(H or C1-C6 alkyl)2, -P(H or C1-C6 alkyl)2, -P(O)(H or C1-C6 alkyl)2, -P(O)2(H or C1-C6 alkyl)2, -P(O)N(H or C1-C6 alkyl)2, -P(O)2N(H or C1-C6 alkyl)2, -P(O)OC1-C6 alkyl, -P(O)2OC1-C6 alkyl, -CN or -NO2, or -R e and -R fTogether with the carbon atom it is attached to, it forms an oxo group or a C2-C6 alkenyl group;

[0128] m is 0, 1, 2, 3, 4, 5, 6 or 7;

[0129] n is 0, 1, 2, 3, 4, 5, 6, or 7;

[0130] p is 0 or 1; and

[0131] q is 0, 1, or 2.

[0132] 2. A compound of formula I or a pharmaceutically acceptable salt thereof,

[0133]

[0134] I

[0135] in

[0136] X is -O-, -S-, or -NR 4 -;

[0137] Y is a bond, -O-, -S-, -S(O)- or -S(O)2-;

[0138] Z 1 Is it N or C(R)? 5 );

[0139] Z 2 Is it N or C(R)? 6 );

[0140] Z 3 Is it N or C(R)? 7 );

[0141] Z 4 Is it N or C(R)? 8 );

[0142] The condition is Z 1 -Z 4 At least two of them are N;

[0143] Ring A is C6-C 10 Aryl or 5 to 10-membered heteroaryl;

[0144] Ring B is a 4- to 9-membered heterocyclic alkyl group;

[0145] Each R 1 Independently, it is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a、-OC(O)NR a R b 、-OC(=NR a )NR a R b 、-OS(O)R a 、-OS(O)2R a 、-OS(O)NR a R b 、-OS(O)2NR a R b 、-SR a 、-S(O)R a 、-S(O)2R a 、-S(O)NR a R b 、-S(O)2NR a R b 、-NR a R b 、-NR a C(O)R b 、-N(C(O)R a )(C(O)R b )、-NR a C(O)OR b 、-NR a C(O)NR a R b 、-NR a C(=NR a )NR a R b 、-NR a S(O)R b 、-NR a S(O)2R b 、-NR a S(O)NR a R b 、-NR a S(O)2NR a R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-C(=NR a )NR a R b 、-PR a R b 、-P(O)R a R b 、-P(O)2R a R b 、-P(O)NRa R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN or -NO2, or two Rs 1 Together with one or more atoms to which it is attached, it forms a C3-C6 cycloalkyl or a 4- to 10-membered heterocyclic alkyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclic alkyl groups is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -R e -R f -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e-C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2;

[0146] Each R 2 Independently, it is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR c -OC(O)R c -OC(O)NR c R d -OC(=NR) c )NR c R d -OS(O)R c -OS(O)2R c -OS(O)NR c R d -OS(O)2NR c R d -SR c -S(O)R c -S(O)2R c -S(O)NR c R d -S(O)2NR c R d -NR c R d -NR c C(O)R d -N(C(O)R c )(C(O)R d -NR c C(O)OR d -NR c C(O)NR c R d -NR c C(=NR c )NR c Rd -NR c S(O)R d -NR c S(O)2R d -NR c S(O)NR c R d -NR c S(O)2NR c R d -C(O)R c -C(O)OR c -C(O)NR c R d -C(=NR) c )NR c R d -PR c R d -P(O)R c R d -P(O)2R c R d -P(O)NR c R d -P(O)2NR c R d -P(O)OR c -P(O)2OR c -CN or -NO2, or two Rs 2 Together with the atoms to which they are attached, they form C3-C6 cycloalkyl or 4- to 10-membered heterocyclic alkyl groups, including C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, and C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclic alkyl groups is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -R e -R f -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e Rf -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2;

[0147] R 3 It is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, -C1-C6 alkylene- (4- to 10-membered heterocyclic alkyl), C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 Aryl), 5- to 10-membered heteroaryl or -C1-C6 alkylene- (4- to 10-membered heterocyclic alkyl), wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, -C1-C6 alkylene- (4- to 10-membered heterocyclic alkyl), C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10Each hydrogen atom in aryl, 5- to 10-membered heteroaryl, and -C1-C6 alkylene- (5- to 10-membered heteroaryl) is independently and optionally substituted with the following groups: deuterium, halogen, -R e -R f C1-C6 alkyl, -C1-C6 alkylene-O-C1-C6 alkyl, -C1-C6 alkylene-OR a C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkylene- (5- to 10-membered heterocycloalkyl), -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e C(=NR f )NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NRe R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2;

[0148] R 4 It is H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 aryl or 5 to 10-membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4 to 10-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl and 5- to 10-membered heteroaryl groups is independently and optionally substituted with the following groups: deuterium, halogen, -R e -R f C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR eS(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2;

[0149] R 5 R 6 R 7 and R 8 Each of these elements is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR g -OC(O)R g -OC(O)NR g R h -OS(O)R g -OS(O)2R g -SR g -S(O)R g -S(O)2R g -S(O)NR g R h -S(O)2NR g R h -OS(O)NR g R h -OS(O)2NR g R h -NR g R h -NR g C(O)Rh -NR g C(O)OR h -NR g C(O)NR g R h -NR g S(O)R h -NR g S(O)2R h -NR g S(O)NR g R h -NR g S(O)2NR g R h -C(O)R g -C(O)OR g -C(O)NR g R h -PR g R h -P(O)R g R h -P(O)2R g R h -P(O)NR g R h -P(O)2NR g R h -P(O)OR g -P(O)2OR g -CN or -NO2;

[0150] R 9 and R 10 Each of these elements is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OC(=NR) a )NR a R b -OS(O)R a -OS(O)2R a -OS(O)NR a R b -OS(O)2NR a R b -SR a -S(O)R a -S(O)2Ra -S(O)NR a R b -S(O)2NR a R b -NR a R b -NR a C(O)R b -N(C(O)R a )(C(O)R b -NR a C(O)OR b -NR a C(O)NR a R b -NR a C(=NR a )NR a R b -NR a S(O)R b -NR a S(O)2R b -NR a S(O)NR a R b -NR a S(O)2NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -C(=NR) a )NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN or -NO2; or R 9 and R 10 Together with the carbon atoms they are attached to, they form C2-C6 alkenyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl or oxo groups, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C6-C 10Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclic alkyl groups is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -R e -R f -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)ORe -P(O)2OR e -CN or -NO2; or R on adjacent carbon atoms 9 and R 10 Together with the carbon atoms it is attached to, they combine to form R 9 and R 10 Substituted carbon-carbon double bonds;

[0151] R a R b R c R d R e R f R g and R h Each is independently selected from the following groups: H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, C1-C6 alkylene-C6-C 10 aryl and 5 to 10-membered heteroaryl; or R a and R b or R c and R d or R e and R f or R g and R h The two atoms in the compound, together with one or more atoms attached to them, combine to form C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 aryl or 5 to 10-membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4 to 10-membered heterocycloalkyl, C6-C 10 Aryl, C1-C6 alkylene-C6-C 10Each hydrogen atom in the aryl and 5- to 10-membered heteroaryl groups is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OC1-C6 alkyl, -OC(O)C1-C6 alkyl, -OC(O)N(H or C1-C6 alkyl)2, -OS(O)C1-C6 alkyl, -OS(O)2C1-C6 alkyl, -OS(O)N(H or C1-C6 alkyl)2, -OS( O)2N(H or C1-C6 alkyl)2, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)N(H or C1-C6 alkyl)2, -S(O)2N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)C(O)C1-C6 alkyl, - N(C1-C6 alkyl)C(O)N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)C1-C6 alkyl, -N(C1-C6 alkyl)S(O)2C1-C6 alkyl, -N(C1-C6 alkyl)S(O)N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)2N(H or C1-C6 alkyl)2, -C(O)C1-C6 alkyl, -C(O)OC1- C6 alkyl, -C(O)N(H or C1-C6 alkyl)2, -P(H or C1-C6 alkyl)2, -P(O)(H or C1-C6 alkyl)2, -P(O)2(H or C1-C6 alkyl)2, -P(O)N(H or C1-C6 alkyl)2, -P(O)2N(H or C1-C6 alkyl)2, -P(O)OC1-C6 alkyl, -P(O)2OC1-C6 alkyl, -CN or -NO2, or -R e and -R f Together with the carbon atom it is attached to, it forms an oxo group or a C2-C6 alkenyl group;

[0152] m is 0, 1, 2, 3, 4, 5, 6 or 7;

[0153] n is 0, 1, 2, 3, 4, 5, 6, or 7;

[0154] p is 0 or 1; and

[0155] q is 0, 1, or 2.

[0156] 3. A compound of formula I or a pharmaceutically acceptable salt thereof,

[0157]

[0158] I

[0159] in

[0160] X is -O-, -S-, or -NR 4 -;

[0161] Y is a bond, -O-, -S-, -S(O)- or -S(O)2-;

[0162] Z 1 Is it N or C(R)? 5 );

[0163] Z 2 Is it N or C(R)? 6 );

[0164] Z 3 Is it N or C(R)? 7 );

[0165] Z 4 Is it N or C(R)? 8 );

[0166] The condition is Z 1 -Z 4 At least two of them are N;

[0167] Ring A is C6-C 10 Aryl or 5 to 10-membered heteroaryl;

[0168] Ring B is a 4- to 9-membered heterocyclic alkyl ring having a nitrogen atom in it;

[0169] Each R 1 Independently, it is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OC(=NR) a )NR a R b -OS(O)R a -OS(O)2R a -OS(O)NR a R b -OS(O)2NR a R b -SR a -S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR a Rb -NR a R b -NR a C(O)R b -N(C(O)R a )(C(O)R b -NR a C(O)OR b -NR a C(O)NR a R b -NR a C(=NR a )NR a R b -NR a S(O)R b -NR a S(O)2R b -NR a S(O)NR a R b -NR a S(O)2NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -C(=NR) a )NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN or -NO2, or two Rs 1 Together with one or more atoms to which it is attached, it forms a C3-C6 cycloalkyl or a 4- to 10-membered heterocyclic alkyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclic alkyl groups is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -R e -R f -ORe 、 -OC(O)R e 、 -OC(O)NR e R f 、 -OS(O)R e 、 -OS(O)2R e 、 -OS(O)NR e R f 、 -OS(O)2NR e R f 、 -SR e 、 -S(O)R e 、 -S(O)2R e 、 -S(O)NR e R f 、 -S(O)2NR e R f 、 -NR e R f 、 -NR e C(O)R f 、 -NR e C(O)OR f 、 -NR e C(O)NR e R f 、 -NR e S(O)R f 、 -NR e S(O)2R f 、 -NR e S(O)NR e R f 、 -NR e S(O)2NR e R f 、 -C(O)R e 、 -C(O)OR<000...​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​Independently, it is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR c -OC(O)R c -OC(O)NR c R d -OC(=NR) c )NR c R d -OS(O)R c -OS(O)2R c -OS(O)NR c R d -OS(O)2NR c R d -SR c -S(O)R c -S(O)2R c -S(O)NR c R d -S(O)2NR c R d -NR c R d -NR c C(O)R d -N(C(O)R c )(C(O)R d -NR c C(O)OR d -NR c C(O)NR c R d -NR c C(=NR c )NR c R d -NR c S(O)R d -NR c S(O)2R d -NR c S(O)NR c R d -NR c S(O)2NR c R d -C(O)R c -C(O)OR c -C(O)NR c R d -C(=NR) c )NR c Rd -PR c R d -P(O)R c R d -P(O)2R c R d -P(O)NR c R d -P(O)2NR c R d -P(O)OR c -P(O)2OR c -CN or -NO2, or two Rs 2 Together with the atoms to which they are attached, they form C3-C6 cycloalkyl or 4- to 10-membered heterocyclic alkyl groups, including C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, and C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclic alkyl groups is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -R e -R f -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NRe R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2;

[0171] R 3 It is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, -C1-C6 alkylene- (4- to 10-membered heterocyclic alkyl), C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 Aryl), 5- to 10-membered heteroaryl or -C1-C6 alkylene- (4- to 10-membered heterocyclic alkyl), wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, -C1-C6 alkylene- (4- to 10-membered heterocyclic alkyl), C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 Each hydrogen atom in aryl, 5- to 10-membered heteroaryl, and -C1-C6 alkylene- (5- to 10-membered heteroaryl) is independently and optionally substituted with the following groups: deuterium, halogen, -R e -R f C1-C6 alkyl, -C1-C6 alkylene-O-C1-C6 alkyl, -C1-C6 alkylene-OR a C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkylene- (5- to 10-membered heterocycloalkyl), -OR e -OC(O)R e -OC(O)NR e R f, -OS(O)R e , -OS(O)2R e , -OS(O)NR e R f , -OS(O)2NR e R f , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR e R f , -S(O)2NR e R f , -NR e R f , -NR e , -NRC(O)R f , -NR e , -NRC(O)OR f , -NR e C(O)NR e R f , -NR e C(=NR f )NR e R f , -NR e , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)2NR e ​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​It is H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 aryl or 5 to 10-membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4 to 10-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl and 5- to 10-membered heteroaryl groups is independently and optionally substituted with the following groups: deuterium, halogen, -R e -R f C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e Rf -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2;

[0173] R 5 R 6 R 7 and R 8 Each of these elements is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR g -OC(O)R g -OC(O)NR g R h -OS(O)R g -OS(O)2R g -SR g -S(O)R g -S(O)2R g -S(O)NR g R h -S(O)2NR g R h -OS(O)NR g R h -OS(O)2NR g R h -NR g R h -NR g C(O)R h -NR g C(O)OR h -NR g C(O)NR g R h -NR g S(O)R h -NR g S(O)2R h -NR g S(O)NR g R h -NR g S(O)2NR g R h -C(O)Rg -C(O)OR g -C(O)NR g R h -PR g R h -P(O)R g R h -P(O)2R g R h -P(O)NR g R h -P(O)2NR g R h -P(O)OR g -P(O)2OR g -CN or -NO2;

[0174] R 9 and R 10 Each of these elements is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OC(=NR) a )NR a R b -OS(O)R a -OS(O)2R a -OS(O)NR a R b -OS(O)2NR a R b -SR a -S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR a R b -NR a R b -NR a C(O)R b -N(C(O)R a )(C(O)R b -NR a C(O)OR b -NR a C(O)NR a R b-NR a C(=NR a )NR a R b -NR a S(O)R b -NR a S(O)2R b -NR a S(O)NR a R b -NR a S(O)2NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -C(=NR) a )NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN or -NO2, or R 9 and R 10 Together with the carbon atoms to which they are attached, they form C3-C6 cycloalkyl or 4- to 10-membered heterocyclic alkyl groups, including C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, and C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclic alkyl groups is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -R e -R f -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SRe -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2; or R on adjacent carbon atoms 9 and R 10 Together with the carbon atoms it is attached to, they combine to form R 9 and R 10 Substituted carbon-carbon double bonds;

[0175] R a R b R c R d R e R f R g and R hEach is independently selected from the following groups: H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, C1-C6 alkylene-C6-C 10 aryl and 5 to 10-membered heteroaryl; or R a and R b or R c and R d or R e and R f or R g and R h The two atoms in the compound, together with one or more atoms attached to them, combine to form C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 aryl or 5 to 10-membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4 to 10-membered heterocycloalkyl, C6-C 10 Aryl, C1-C6 alkylene-C6-C 10Each hydrogen atom in the aryl and 5- to 10-membered heteroaryl groups is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OC1-C6 alkyl, -OC(O)C1-C6 alkyl, -OC(O)N(H or C1-C6 alkyl)2, -OS(O)C1-C6 alkyl, -OS(O)2C1-C6 alkyl, -OS(O)N(H or C1-C6 alkyl)2, -OS( O)2N(H or C1-C6 alkyl)2, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)N(H or C1-C6 alkyl)2, -S(O)2N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)C(O)C1-C6 alkyl, - N(C1-C6 alkyl)C(O)N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)C1-C6 alkyl, -N(C1-C6 alkyl)S(O)2C1-C6 alkyl, -N(C1-C6 alkyl)S(O)N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)2N(H or C1-C6 alkyl)2, -C(O)C1-C6 alkyl, -C(O)OC1- C6 alkyl, -C(O)N(H or C1-C6 alkyl)2, -P(H or C1-C6 alkyl)2, -P(O)(H or C1-C6 alkyl)2, -P(O)2(H or C1-C6 alkyl)2, -P(O)N(H or C1-C6 alkyl)2, -P(O)2N(H or C1-C6 alkyl)2, -P(O)OC1-C6 alkyl, -P(O)2OC1-C6 alkyl, -CN or -NO2, or -R e and -R f Together with the carbon atom it is attached to, it forms an oxo group or a C2-C6 alkenyl group;

[0176] m is 0, 1, 2, 3, 4, 5, 6 or 7;

[0177] n is 0, 1, 2, 3, 4, 5, 6, or 7;

[0178] p is 0 or 1; and

[0179] q is 0, 1, or 2.

[0180] 4. A compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein said compound has formula II, III, IV, V, VI, VII, VIII, or IX.

[0181] (II),

[0182] (III),

[0183] (IV),

[0184] (V),

[0185] (VI),

[0186] (VII),

[0187] (VIII), or

[0188] (IX),

[0189] in

[0190] X 1 It is -O-, -S-, -S(O)-, -S(O)2- or -C(R) 1 )2-;

[0191] q1 is 0 or 1;

[0192] t is 0, 1, 2, or 3; and

[0193] v is 0, 1, or 2.

[0194] 5. A compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein said compound has the formula X, XI, XII, XIII, XIV, XV, XVI, or XVII.

[0195] (X),

[0196] (XI),

[0197] (XII),

[0198] (XIII),

[0199] (XIV),

[0200] (XV),

[0201] (XVI), or

[0202] (XVII),

[0203] in

[0204] Z 5 Is it N or C(R)? 11 );

[0205] Z 6 Is it N or C(R)? 12 );

[0206] R 11 and R 12 Each of these elements, when present, is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR g -OC(O)R g -OC(O)NR g R h -OS(O)R g -OS(O)2R g -SR g -S(O)R g -S(O)2R g -S(O)NR g R h -S(O)2NR g R h -OS(O)NR g R h -OS(O)2NR g R h -NR g R h -NR g C(O)R h -NR g C(O)OR h -NR g C(O)NR g R h -NR g S(O)R h -NR g S(O)2R h -NR g S(O)NR g R h -NR g S(O)2NR g R h -C(O)R g -C(O)OR g -C(O)NR g R h -PR g R h-P(O)R g R h -P(O)2R g R h -P(O)NR g R h -P(O)2NR g R h -P(O)OR g -P(O)2OR g -CN or -NO2; and

[0207] q1 is 0 or 1.

[0208] 6. A compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein said compound has the formula XVIII, XIX, XX, XXI, XXII, XXIII, XXIV or XXV.

[0209] (XVIII),

[0210] (XIX),

[0211] (XX),

[0212] (XXI),

[0213] (XXII),

[0214] (XXIII), (XXIV), or

[0215] (XXV),

[0216] in

[0217] X 1 Is -O-, -S-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)- or -C(R 1 )2-;

[0218] Z 5 Is it N or C(R)? 11 );

[0219] Z 6 Is it N or C(R)? 12 );

[0220] R 11 and R 12Each of these elements, when present, is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR g -OC(O)R g -OC(O)NR g R h -OS(O)R g -OS(O)2R g -SR g -S(O)R g -S(O)2R g -S(O)NR g R h -S(O)2NR g R h -OS(O)NR g R h -OS(O)2NR g R h -NR g R h -NR g C(O)R h -NR g C(O)OR h -NR g C(O)NR g R h -NR g S(O)R h -NR g S(O)2R h -NR g S(O)NR g R h -NR g S(O)2NR g R h -C(O)R g -C(O)OR g -C(O)NR g R h -PR g R h -P(O)R g R h -P(O)2R g R h -P(O)NR g R h -P(O)2NR g R h -P(O)OR g-P(O)2OR g -CN or -NO2, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclic alkyl groups is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -R e -R f -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f-P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2;

[0221] q1 is 0 or 1; t is 0, 1, 2 or 3; and

[0222] v is 0, 1, or 2.

[0223] 7. A compound or a pharmaceutically acceptable salt thereof as described in any of clauses 1 to 4, wherein said compound has the formula XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, or XXXIII.

[0224] (XXVI),

[0225] (XXVII),

[0226] (XXVIII),

[0227] (XXIX),

[0228] (XXX),

[0229] (XXXI),

[0230] (XXXII), or

[0231] (XXXIII),

[0232] in

[0233] X 1 Is -O-, -S-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)- or -C(R 1 )2-;

[0234] q1 is 0 or 1;

[0235] t is 0, 1, 2, or 3; and

[0236] v is 0, 1, or 2.

[0237] 8. A compound or a pharmaceutically acceptable salt thereof as described in Clause 1 or 4, wherein said compound has the formula XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, XXXX, or XXXXI.

[0238] (XXXIV),

[0239] (XXV),

[0240] (XXXVI),

[0241] (XXXVII),

[0242] (XXXVIII),

[0243] (XXXIX),

[0244] (XXXX), or

[0245] (XXXXI),

[0246] in

[0247] X 1 Is -O-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)- or -C(R 1 )2-;

[0248] q1 is 0 or 1;

[0249] t is 0, 1, 2, or 3; and

[0250] v is 0, 1, or 2.

[0251] 9. A compound or a pharmaceutically acceptable salt thereof as described in any of clauses 1 to 4, wherein said compound has the formula XXXXII, XXXXIII, XXXXIV, XXXV, XXXVI, XXXXVII, XXXXVIII or XXXXIX.

[0252] (XXXXII),

[0253] (XXXXIII),

[0254] (XXXXIV),

[0255] (XXXXV),

[0256] (XXXXVI),

[0257] (XXXXVII),

[0258] (XXXXVIII), or

[0259] (XXXXIX),

[0260] in

[0261] X 1 Is -O-, -S-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)- or -C(R 1 )2-;

[0262] q1 is 0 or 1;

[0263] t is 0, 1, 2, or 3; and

[0264] v is 0, 1, or 2.

[0265] 10. A compound or a pharmaceutically acceptable salt thereof as described in any of clauses 1 to 4, wherein said compound has the formula L, LI, LII, LIII, LIV, LV, LVI, or LVII.

[0266] (L),

[0267] (LI),

[0268] (LII),

[0269] (LIII),

[0270] (LIV),

[0271] (LV),

[0272] (LVI), or

[0273] (LVII),

[0274] in

[0275] X 1Is -O-, -S-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)- or -C(R 1 )2-;

[0276] q1 is 0 or 1;

[0277] t is 0, 1, 2, or 3; and

[0278] v is 0, 1, or 2.

[0279] 11. A compound or a pharmaceutically acceptable salt thereof as described in any of clauses 1 to 4, wherein said compound has the formula LVIII, LVIX, LX, LXI, LXII, LXIII, LXIV, or LXV.

[0280] (LVIII),

[0281] (LIX),

[0282] (LX),

[0283] (LXI),

[0284] (LXII),

[0285] (LXIII),

[0286] (LXIV), or

[0287] (LXV),

[0288] in

[0289] X 1 Is -O-, -S-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)- or -C(R 1 )2-;

[0290] q1 is 0 or 1;

[0291] t is 0, 1, 2, or 3; and

[0292] v is 0, 1, or 2.

[0293] 12. A compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein q is 0 when present.

[0294] 13. A compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein q is 1 when present.

[0295] 14. A compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein q1 is 0 when present.

[0296] 15. A compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein q1 is 1 when present.

[0297] 16. A compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein R 1 It is deuterium, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl, wherein each hydrogen atom in the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl group is independently and optionally substituted by the following groups: deuterium, halogen, -R e -R f C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NRe R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2, or two hydrogen atoms on a single carbon atom of the 4- to 10-membered heterocyclic alkyl group combine to form an oxo group or a C2-C6 alkenyl group; or two R 1 Together with one or more atoms to which it is attached, it forms a C3-C6 cycloalkyl or a 4- to 10-membered heterocyclic alkyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclic alkyl groups is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -R e -R f -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NRe C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2.

[0298] 17. A compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein said compound comprises a core having the following formula

[0299] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ,

[0300] Each of these " "Is it related to ring A or -(X)?" p -R 3 Covalent connection points.

[0301] 18. The compound or a pharmaceutically acceptable salt thereof described in any of the preceding clauses, wherein m is 0, 1, 2 or 3.

[0302] 19. A compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein n is 0, 1, 2 or 3.

[0303] 20. A compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein Z 1 It is N.

[0304] 21. A compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein Z 2 It is N.

[0305] 22. A compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein Z 3 It is CR 7 And Z 4 It is N.

[0306] 23. A compound or a pharmaceutically acceptable salt thereof as described in any of clauses 1 to 21, wherein Z 3 It is CR 7 And Z 4 It is CR 8 .

[0307] 24. A compound or a pharmaceutically acceptable salt thereof as described in any of clauses 1 to 21, wherein Z 3 It is N, and Z 4 It is CR 8 .

[0308] 25. A compound or a pharmaceutically acceptable salt thereof as described in any of clauses 1 to 21, wherein Z 3 It is N, and Z 4 It is N.

[0309] 26. A compound or a pharmaceutically acceptable salt thereof as described in any of clauses 1 to 21, wherein Z 3 It is N, Z 4 It is CR 8 Z 5 It is CR 11 And Z 6 It is CR 12 .

[0310] 27. A compound or a pharmaceutically acceptable salt thereof as described in any of clauses 1 to 21, wherein Z 3 It is CR 7 Z 4 It is N, Z 5 It is CR 11 And Z 6 It is CR 12 .

[0311] 28. A compound or a pharmaceutically acceptable salt thereof as described in any of clauses 1 to 21, wherein Z 3 It is N, Z 4 It is N, Z 5 It is CR 11 And Z 5 It is CR 12 .

[0312] 29. A compound or a pharmaceutically acceptable salt thereof as described in any of clauses 1 to 22, wherein said compound comprises a core having the following formula

[0313] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ,

[0314] Each of these " "Is it related to ring A or -(X)?" p -R 3 Covalent connection points.

[0315] 30. A compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein p is 0.

[0316] 31. A compound or a pharmaceutically acceptable salt thereof as described in any of the clauses 1 to 29, wherein p is 1.

[0317] 32. A compound or a pharmaceutically acceptable salt thereof as described in any of the clauses 1 to 29 or 31, wherein X is O.

[0318] 33. A compound or a pharmaceutically acceptable salt thereof as described in any of clauses 1 to 29 or 31, wherein X is -NR 4 -

[0319] 34. A compound or a pharmaceutically acceptable salt thereof as described in any of the clauses 1 to 29 or 31, wherein X is -S-.

[0320] 35. A compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein R 3It is a -C1-C6 alkyl, a 4- to 10-membered heterocyclic alkyl, or a -C1-C6 alkylene-(4- to 10-membered heterocyclic alkyl), wherein each hydrogen atom in the -C1-C6 alkyl, 4- to 10-membered heterocyclic alkyl, or -C1-C6 alkylene-(4- to 10-membered heterocyclic alkyl) is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, -C1-C6 alkylene-O-C1-C6 alkyl, -OC1-C6 alkylene-O-C1-C6 alkyl, -C1-C6 alkylene-OR a C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkylene- (5- to 10-membered heterocycloalkyl), -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e C(=NR f )NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)Re -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2.

[0321] 36. A compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein R 3 It is a -C1-C6 alkylene- (4 to 10-membered heterocyclic alkyl), wherein each hydrogen atom in -C1-C6 alkylene- (4 to 10-membered heterocyclic alkyl) is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, -C1-C6 alkylene-O-C1-C6 alkyl, -OC1-C6 alkylene-O-C1-C6 alkyl, -C1-C6 alkylene-OR a C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkylene- (5- to 10-membered heterocycloalkyl), -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NRe C(O)OR f -NR e C(O)NR e R f -NR e C(=NR f )NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2.

[0322] 37. A compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein R 3 yes

[0323] ,

[0324] Each hydrogen atom is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, -C1-C6 alkylene-O-C1-C6 alkyl, -OC1-C6 alkylene-O-C1-C6 alkyl, -C1-C6 alkylene-OR a C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkylene- (5- to 10-membered heterocycloalkyl), -OR e -OC(O)R e-OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e C(=NR f )NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2, and " "It is a covalent connection point."

[0325] 38. A compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein R 3 yes

[0326] , , , , , , , , , , , , , , or ,

[0327] Among them W It is an inorganic counter ion or an organic counter ion.

[0328] 39. A compound or a pharmaceutically acceptable salt thereof as described in any of clauses 1 to 35, wherein R 3 It is a 4- to 10-membered heterocyclic alkyl group, wherein each hydrogen atom in the 4- to 10-membered heterocyclic alkyl group is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, optionally halogenated C2-C6 alkenyl, -C1-C6 alkylene-O-C1-C6 alkyl, -OC1-C6 alkylene-O-C1-C6 alkyl, -C1-C6 alkylene-OR a C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkylene- (5- to 10-membered heterocycloalkyl), -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e Rf -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e C(=NR f )NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2.

[0329] 40. A compound or a pharmaceutically acceptable salt thereof as described in any of clauses 1 to 35 or 39, wherein R 3 yes

[0330] , , , or ,

[0331] in" "It is a covalent connection point."

[0332] 41. A compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein each R 2Independently, it is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, -OR c -C(O)R C -NR c R d Or -CN, wherein each hydrogen atom in the C1-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl groups is independently and optionally substituted with deuterium or a halogen.

[0333] 42. A compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein ring A is

[0334] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ,

[0335] in" "It is a covalent connection point."

[0336] 43. A compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein R 4 When present, it is H or methyl.

[0337] 44. A compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein R 5When present, it is H or deuterium.

[0338] 45. A compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein R 6 When present, it is H or deuterium.

[0339] 46. ​​A compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein R 7 When present, it is H, deuterium, or F.

[0340] 47. A compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein R 8 When present, it is H or deuterium.

[0341] 48. A compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein Z 5 It is N when it exists.

[0342] 49. A compound or a pharmaceutically acceptable salt thereof as described in any of the preceding clauses, wherein Z 6 It is N when it exists.

[0343] 50. A compound or a pharmaceutically acceptable salt thereof as described in any of clauses 1 to 42, wherein Z 5 When it exists, it is CR. 11 .

[0344] 51. A compound or a pharmaceutically acceptable salt thereof as described in Clause 50, wherein R 11 When present, it is H or deuterium.

[0345] 52. A compound or a pharmaceutically acceptable salt thereof as described in clause 50 or 51, wherein Z 6 It is N when it exists.

[0346] 53. A compound or a pharmaceutically acceptable salt thereof as described in any of clauses 1 to 48, wherein Z 6 When it exists, it is CR. 12 .

[0347] 54. The compound or a pharmaceutically acceptable salt thereof as described in Clause 53, wherein R 12 When present, it is H or deuterium.

[0348] 55. The compounds described in Clause 1 are selected from the group consisting of:

[0349] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and ,

[0350] Or its pharmaceutically acceptable salt.

[0351] 56. A pharmaceutical composition comprising at least one compound described in any one of clauses 1 to 55 or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients.

[0352] 57. A method for treating a disease such as cancer, said method comprising administering to an individual in need of such treatment an effective amount of a compound or a pharmaceutically acceptable salt thereof as described in any one of clauses 1 to 55.

[0353] 58. A method of using a compound or a pharmaceutically acceptable salt thereof described in any of the provisions 1 to 55 for the treatment of cancer in an individual.

[0354] 59. A compound or a pharmaceutically acceptable salt thereof described in any of the provisions 1 to 55, used to treat an individual’s cancer.

[0355] 60. Use of a compound or a pharmaceutically acceptable salt thereof described in any one of clauses 1 to 55 for the preparation of a medicament for treating cancer in an individual. Detailed Implementation

[0356] Before further describing this disclosure, it should be understood that this disclosure is not limited to the specific embodiments described, as these embodiments can certainly vary. It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting, as the scope of this disclosure will be defined only by the appended terms.

[0357] For the sake of brevity, all publications, including patents, cited in this specification are incorporated herein by reference. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. All patents, applications, publications, and other publications mentioned herein are incorporated herein by reference in their entirety. If any definition set forth in this section contradicts or otherwise conflicts with the definitions set forth in a patent, application, or other publication incorporated herein by reference, the definitions set forth in this section shall prevail over those incorporated herein by reference.

[0358] As used herein and in the attached terms, the singular forms “a / an” and “the” include plural references unless the context clearly indicates otherwise. Additionally, it should be noted that the terms may be drafted to exclude any optional elements. Therefore, this statement is intended to serve as a precondition for the use of exclusive terms such as “solely” or “only”, or for the use of negative limiting terms, in conjunction with the elements of the terms.

[0359] As used herein, the terms “including,” “containing,” and “comprising” are used in their open, non-restrictive sense.

[0360] To provide a more concise description, some quantitative expressions given herein are not limited by the term "about". It should be understood that, whether or not the term "about" is explicitly used, each quantity given herein is intended to refer to an actual given value, and also to an approximation of such a given value based on what a person of ordinary skill in the art would reasonably infer, including equivalents and approximations resulting from the experimental and / or measurement conditions of such a given value. Whenever yield is given as a percentage, this yield refers to the yield given by the mass of the entity relative to the maximum amount of the same entity that can be obtained under specific stoichiometric conditions. Unless otherwise indicated, concentrations given as percentages refer to mass ratios.

[0361] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. While any methods and materials similar to or equivalent to those described herein may also be used in the practice or testing of this disclosure, preferred methods and materials are described hereafter. All publications referenced herein are incorporated by way of citation to disclose and describe the methods and / or materials in connection with the cited publications.

[0362] Unless otherwise stated, the methods and techniques of embodiments of the invention are generally carried out according to conventional methods well known in the art and as described in the various general and more specific references cited and discussed throughout this specification. See, for example, Loudon, Organic Chemistry, 4th Edition, New York: Oxford University Press, 2002, pp. 360-361, 1084-1085; Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th Edition, Wiley-Interscience, 2001.

[0363] The chemical nomenclature of the compounds described herein is generally derived using commercially available ACD / Name 2014 (ACD / Labs) or ChemBioDraw Ultra 13.0 (Perkin Elmer).

[0364] As used herein and in conjunction with the description of the chemical structures of the various embodiments described herein, "", "and" "Each represents a covalently bonded point of a chemical group or chemical structure, where the identifier is shown as an adjacent chemical group or chemical structure. For example, in the hypothetical chemical structure AB, where A and B are connected by a covalent bond, in some embodiments, the portion of AB defined by group or chemical structure A may be represented by..." "", "or" "This indicates that among them" "", "and" "Each represents a bond connection point with A and a covalent bond connection point with B. Alternatively, in some embodiments, the portion of AB defined by the group or chemical structure B can be represented by " "", "or" "This indicates that among them" "", "and" "Each represents the bond connection point with B and the covalent bond connection point with A."

[0365] It should be understood that certain features of this disclosure described in the context of individual embodiments for clarity may also be provided in combination in individual embodiments. Conversely, for brevity, various features of this disclosure described in the context of individual embodiments may also be provided individually or in any suitable sub-combination. All combinations of embodiments relating to chemical groups represented by variables are specifically covered and disclosed herein, as each combination is disclosed individually and explicitly, and to some extent, such combinations cover compounds as stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity). Additionally, all sub-combinations of chemical groups listed in embodiments describing such variables are also specifically covered and disclosed herein, as each such sub-combination of chemical groups is disclosed individually and explicitly herein.

[0366] Chemical definition

[0367] The term "alkyl" refers to a straight-chain or branched monovalent hydrocarbon group. The term "alkylene" refers to a straight-chain or branched divalent hydrocarbon group. In some embodiments, it may be advantageous to limit the number of atoms in "alkyl" or "alkylene" to a specific atomic range, such as C1-C. 20 Alkyl or C1-C 20 Alkylene, C1-C 12 Alkyl or C1-C 12 Alkylene or C1-C6 alkylene or C1-C6 alkylene. Examples of alkyl groups include methyl (Me), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups from the viewpoint of a person skilled in the art, and the teachings provided herein shall be considered equivalent to any of the foregoing examples. Examples of alkylene groups include methylene (-CH2-), ethylene ((-CH2-)2), n-propylene ((-CH2-)3), isopropylene ((-C(H)(CH3)CH2-)), n-butylene ((-CH2-)4), etc. It should be understood that, as described herein, alkyl or alkylene groups may be unsubstituted or substituted. Alkyl or alkylene groups may be substituted by any substituent in the substituents in the various embodiments described herein, including one or more such substituents.

[0368] The term "alkenyl" refers to a straight-chain or branched monovalent hydrocarbon group having one or more double bonds. In some embodiments, it may be advantageous to limit the number of atoms in the "alkenyl" group to a specific atomic range, such as C2-C. 20 alkenyl, C2-C 12Alkenyl or C2-C6 alkenyl. Examples of alkenyl include vinyl (ethenyl or vinyl), allyl, and but-3-en-1-yl. This term includes cis and trans isomers and mixtures thereof. It should be understood that, as described herein, alkenyl can be unsubstituted or substituted. Alkenyl can be substituted by any of the substituents in the various embodiments described herein, including one or more such substituents.

[0369] The term "alkynyl" refers to a straight-chain or branched monovalent hydrocarbon group having one or more triple bonds. In some embodiments, it may be advantageous to limit the number of atoms in the "alkynyl" group to a specific atomic range, such as C2-C. 20 alkynyl group, C2-C 12 The alkynyl group or C2-C6 alkynyl group. Examples of alkynyl groups include ethynyl (-C≡CH) and propynyl (-CH2C≡CH), but-3-yn-1,4-diyl (-C≡C-CH2CH2-), etc. It should be understood that, as described herein, the alkynyl group can be unsubstituted or substituted. The alkynyl group can be substituted by any substituent in the substituents in the various embodiments described herein, including one or more such substituents.

[0370] The term "cycloalkyl" refers to a saturated or partially saturated monocyclic or polycyclic monovalent carbon ring. In some embodiments, it may be advantageous to limit the number of atoms in "cycloalkyl" to a specific atomic range, such as having 3 to 12 ring atoms. Polycyclic carbon rings include fused, bridged, and spirocyclic systems. Illustrative examples of cycloalkyl include monovalent groups of the following entities:

[0371] .

[0372] Specifically, the cyclopropyl moiety can be derived from the structural formula Description. It should be understood that, as described herein, cycloalkyl groups may be unsubstituted or substituted. Cycloalkyl groups may be substituted by any of the substituents in the various embodiments described herein, including one or more such substituents.

[0373] The term "halogen" or "halogenated" refers to chlorine, fluorine, bromine, or iodine.

[0374] The term "haloalkyl" refers to an alkyl group having one or more halogenated substituents. Examples of haloalkyl groups include -CF3, -(CH2)F, -CHF2, -CH2Br, -CH2CF3, and -CH2CH2F.

[0375] In some embodiments, the alkenyl group may be substituted. For example, the alkenyl group may be halogenated (e.g., fluorinated). Illustratively, a halogenated alkenyl group may be =CHF.

[0376] The term "aryl" refers to a monovalent, all-carbon monocyclic or fused-ring polycyclic group having a fully conjugated π-electron system. In some embodiments, it may be advantageous to limit the number of atoms in the "aryl" group to a specific range, such as monovalent, all-carbon monocyclic or fused-ring polycyclic groups having 6 to 14 carbon atoms (C6-C4). 14 Aryl groups or monovalent all-carbon monocyclic or fused-ring polycyclic groups having 6 to 10 carbon atoms (C 6- C 10 Aryl groups. Examples of aryl groups are not limited to phenyl, naphthyl, and anthracene. It should be understood that, as described herein, aryl groups can be unsubstituted or substituted. Aryl groups can be substituted by any of the substituents in the various embodiments described herein, including one or more such substituents.

[0377] The term "heterocyclic alkyl" refers to a saturated or partially saturated monovalent monocyclic or polycyclic structure having one or more non-carbon ring atoms. In some embodiments, it may be advantageous to limit the number of atoms in the "heterocyclic alkyl" to a specific range of ring atoms, such as 3 to 12 ring atoms (3 to 12-membered), or 3 to 7 ring atoms (3 to 7-membered), or 3 to 6 ring atoms (3 to 6-membered), or 4 to 6 ring atoms (4 to 6-membered), 5 to 7 ring atoms (5 to 7-membered), or 4 to 10 ring atoms (4 to 10-membered). In some embodiments, it may be advantageous to limit the number and type of cyclic heteroatoms in the "heterocyclic alkyl" to a specific range or type of heteroatoms, such as 1 to 5 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. Examples of monocyclic heterocyclic alkyls are not limited to, but include, tetrahydrofuran, pyrrolidine, and morpholine. Polycyclic systems include fused, bridged, and spirocyclic systems. In some embodiments, it may be advantageous to limit the number of atoms in the bicyclic "heterocyclic alkyl" to a specific range of ring atoms, such as 5 to 10 ring atoms (5 to 10 cyclic) or 6 to 10 ring atoms (6 to 10 cyclic). The ring structure may optionally contain an oxo group or an imino group on the carbocyclic member or up to two oxo groups on the thiocyclic member. Examples of fused bicyclic, bridged bicyclic, and spirobicyclic heterocyclic alkyl groups are not limited to pyrrolazinyl, 2,5-diazabicyclo[2.2.2]octyl, 1-oxaspiro[4.5]decyl, and hexahydro-1H-pyrrolazinyl. Illustrative examples of heterocyclic alkyl groups include the following entities with monovalent groups:

[0378] .

[0379] Specifically, the hexahydro-1H-pyrrolazinyl moiety can be expressed through the structural formula To depict.

[0380] Three-membered heterocycles may contain at least one heteroatom ring atom, wherein the heteroatom ring atom is sulfur, oxygen, or nitrogen. Non-limiting examples of three-membered heterocyclic groups include monovalent and divalent groups of ethylene oxide, aziridine, and thiohexacyclic propane. Four-membered heterocycles may contain at least one heteroatom ring atom, wherein the heteroatom ring atom is sulfur, oxygen, or nitrogen. Non-limiting examples of four-membered heterocyclic groups include monovalent and divalent groups of aziridine, oxobutane, and thiohexacyclic butane. Five-membered heterocycles may contain up to four heteroatom ring atoms, wherein (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. Non-limiting examples of five-membered heterocyclic groups include monovalent and divalent groups of pyrrolidine, tetrahydrofuran, 2,5-dihydro-1H-pyrrole, pyrazolidine, thiazolidinyl, 4,5-dihydro-1H-imidazolium, dihydrothiophene-2(3H)-one, tetrahydrothiophene-1,1-dioxide, imidazolidin-2-one, pyrrolidine-2-one, dihydrofuran-2(3H)-one, 1,3-dioxolane-2-one, and oxazolidine-2-one. A six-membered heterocycle may contain up to four heteroatomic ring atoms, wherein (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. Non-limiting examples of six-membered heterocyclic groups include monovalent or divalent groups of piperidine, morpholine, 4H-1,4-thiazine, 1,2,3,4-tetrahydropyridine, piperazine, 1,3-oxazin-2-one, piperazin-2-one, thiomorpholine, and thiomorpholine 1,1-dioxide. A "heterobicyclic" is a fused bicyclic system comprising one heterocycle fused with a cycloalkyl group or another heterocycle.

[0381] It should be understood that, as described herein, heterocyclic alkyl groups may be unsubstituted or substituted. Heterocyclic alkyl groups may be substituted with any of the substituents in the various embodiments described herein, including one or more such substituents.

[0382] Heterocyclic alkyl groups can be combined with another group (such as an alkenyl group) to provide a portion that can be unsubstituted or substituted with one or more groups (such as one or more halogen atoms). Illustratively, the hexahydro-1H-pyrrolazinyl moiety can be combined with an alkenyl group to provide an exocyclic alkenyl group on the hexahydro-1H-pyrrolazinyl group, which can be further substituted with a halogen. For example, a haloalkenyl-substituted hexahydro-1H-pyrrolazinyl moiety can be depicted by the following structural formula:

[0383] .

[0384] The term "heteroaryl" refers to a fully unsaturated monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (having a ring structure with ring atoms or members selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) having 3 to 12 ring atoms per heterocycle. The term "heteroarylene" refers to a dicyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (having a ring structure with ring atoms or members selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) having 3 to 12 ring atoms per heterocycle. In some embodiments, it may be advantageous to limit the number of ring atoms in "heteroaryl" or "heteroarylene" to a specific range of atomic members, such as 5- to 10-membered heteroaryls. In some cases, 5- to 10-membered heteroaryls may be monocyclic or fused bicyclic with 5 to 10 ring atoms, wherein at least one ring atom is a heteroatom, such as N, O, or S. The ring structure may optionally contain an oxo group or an imino group on the carbocyclic member or up to two oxo groups on the thiocyclic member. Illustrative examples of 5- to 10-membered heteroaryl groups include monovalent groups of the following entities, while examples of 5- to 10-membered heteroarylene groups include divalent groups of the following entities, in the form of appropriately bonded portions:

[0385] .

[0386] In some embodiments, a “monocyclic” heteroaryl group may be an aromatic five- or six-membered heterocycle. A five-membered heteroaryl group may contain up to four heteroatom ring atoms, wherein (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. Non-limiting examples of five-membered heteroaryl groups include monovalent groups of furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole, or tetraazole. A six-membered heteroaryl group may contain up to four heteroatom ring atoms, wherein (a) at least one ring atom is oxygen and sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. Non-limiting examples of six-membered heteroaryl groups include monovalent groups of pyridine, pyrazine, pyrimidine, pyridazine, or triazine. "Bicyclic heteroaryl" is a fused bicyclic system comprising one heteroaryl ring fused to a phenyl or another heteroaryl ring. Non-limiting examples of bicyclic heteroaryl include monovalent groups of quinoline, isoquinoline, quinazoline, quinoxaline, 1,5-naphthidine, 1,8-naphthidine, isoquinoline-3(2H)-one, thieno[3,2-b]thiophene, 1H-pyrrolo[2,3-b]pyridine, indazole, 1H-benzo[d]imidazolium, benzo[d]oxazole, and benzo[d]thiazole.

[0387] Specifically, the isoquinoline-3(2H)-keto moiety can be described by the following structural formula:

[0388] .

[0389] Specifically, the divalent pyridine-pyrimidine moiety can be described by the following structural formula:

[0390] .

[0391] It should be understood that, as described herein, heteroaryl groups can be unsubstituted or substituted. Heteroaryl groups can be substituted by any of the substituents in the various embodiments described herein, including one or more such substituents.

[0392] It should be understood that, as described herein, heteroaryl or heteroarylene groups may be unsubstituted or substituted. Heteroaryl or heteroarylene groups may be substituted by any of the substituents in the various embodiments described herein, including one or more such substituents.

[0393] The term "oxo" refers to the carbonyl oxygen. For example, a cyclopentyl group substituted with an oxygen group is cyclopentanone.

[0394] The term "substituted" means that a specified group or portion contains one or more substituents. The term "unsubstituted" means that a specified group does not contain any substituents. When the term "substituted" is used to describe a structural system, substitution refers to occurring at any position in the system where the valence is permissible. In some embodiments, "substituted" means that a specified group or portion contains one, two, or three substituents. In other embodiments, "substituted" means that a specified group or portion contains one or two substituents. In still other embodiments, "substituted" means that a specified group or portion contains one substituent.

[0395] Any formula described herein is intended to represent a compound having the stated structural formula as well as certain variations or forms. For example, the formulas given herein are intended to include racemic mixtures or one or more enantiomers, diastereomers, or geometric isomers or mixtures thereof. Additionally, any formula given herein is also intended to refer to hydrates, solvates, or polymorphs of such compounds or mixtures thereof.

[0396] Any formulas given herein are also intended to represent the unlabeled form and isotopically labeled form of the compound. Isotopically labeled compounds have the structure described by the formulas given herein, except that one or more atoms are replaced by atoms having selected atomic masses or mass numbers. Examples of isotopes that may be incorporated into the compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, respectively, as follows: 2 H, 3 H, 11 C 13 C 14 C 15 N、 18 O、 17O、 31 P, 32 P, 35 S, 18 F, 36 Cl and 125 I. Compounds labeled with this type of isotope can be used for metabolic studies (preferably using...). 14 C) Reaction kinetic studies (using, for example) 2 H or 3 H) Detection or imaging techniques, including the determination of drug or substrate tissue distribution [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)], or radiation therapy to the patient. Additionally, the use of heavier isotopes such as deuterium (i.e., 2 H) Substitution can provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dose requirements. The isotopically labeled compounds and their prodrugs of this disclosure can generally be prepared by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents by performing the procedures disclosed in the protocols or examples and the preparations described below.

[0397] Certain chemical entities having formulas (I)-(LXXXI) can be described in two or more tautomer forms. Any and all alternative tautomers are included within the scope of these formulas, and it should not be inferred whether a chemical entity exists in its drawn tautomer form. It should be understood that the chemical entities described herein and their constituent rings A, B, etc., can exist in different tautomer forms. It will be readily understood by those skilled in the art that tautomers can generally be considered the same compound due to rapid tautomerization. Examples of tautomers include, but are not limited to, enol-keto tautomers, amine-imine tautomers, etc.

[0398]

[0399] Specifically, the ring selection of isoquinoline-3(2H)-imone can be performed as the following tautomers. exist.

[0400] When applied to a class of substituents in this paper, it is named "(atom)". i- (atom) j "(where j>i)" is intended to refer to an embodiment of this disclosure in which each of the plurality of atomic members from i to j (inclusive) is implemented independently. By way of example, the term C 1- C3 independently refers to embodiments having one carbon member (C1), embodiments having two carbon members (C2), and embodiments having three carbon members (C3).

[0401] This disclosure also includes pharmaceutically acceptable salts of compounds represented by formulas (I)-(LXXXI) (preferably pharmaceutically acceptable salts of the compounds described above) and pharmaceutically acceptable salts of the specific compounds illustrated herein, pharmaceutical compositions comprising such salts, and methods of using such salts.

[0402] "Pharmaceutically acceptable salt" is intended to mean a salt of the free acid or base of the compounds described herein that is non-toxic, biologically tolerable, or otherwise biologically suitable for administration to an individual. See also S.M. Berge et al., "Pharmaceutical Salts," Journal of Pharmaceutical Sciences, 1977, 66, 1-19. Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with an individual's tissues without excessive toxicity, irritation, or anaphylactic reactions. The compounds described herein may have sufficiently acidic groups, sufficiently basic groups, two types of functional groups, or more than one group of each type, and thus react with a variety of inorganic or organic bases and inorganic and organic acids to form pharmaceutically acceptable salts.

[0403] It should be understood that the chemical entities described herein may exist as salts of the free acid or base of the compounds represented herein with inorganic or organic counterions. Illustratively, salts may be formed during the preparation of the compound (e.g., a salt or a pharmaceutically acceptable salt) or may be substituted by salts for further preparation, formulation, or administration. As shown herein, some compounds include “W”. ”, where “W” "W" is an inorganic counter ion (e.g., an inorganic anion) or an organic counter ion (e.g., an organic anion). In some embodiments, W It is an anion that complexes with the cation of the compound disclosed herein to form a pharmaceutically acceptable salt.

[0404] The term "inorganic counterion" refers to an inorganic ion that accompanies another ion to maintain electroneutrality. Inorganic counterions can be anions or cations. Inorganic counterions can accompany the free acid or base of the compounds represented herein. Inorganic ions can be formed by the reaction of an inorganic base or inorganic acid with the compounds described herein, which have sufficiently acidic groups, sufficiently basic groups, two types of functional groups, or more than one group of each type.

[0405] The term "organic counterion" refers to an organic counterion that accompanies the type of ion in order to maintain electroneutrality. An organic ion can be an anion or a cation. An organic counterion can be accompanied by a free acid or base of the compound represented herein. Organic ions can be formed by the reaction of an organic base or organic acid with the compound described herein, the compound having a sufficiently acidic group, a sufficiently basic group, two types of functional groups, or more than one group of each type.

[0406] Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfites, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, hexanoates, heptarates, propynylates, oxalates, malonates, succinates, octanoates, sebacic acid, fumarates, maleates, and butynediol. ,4-Diosyl salt, hexyn-1,6-diosyl salt, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methanesulfonate, propylsulfonate, benzenesulfonate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, γ-hydroxybutyrate, glycolate, tartrate, and mandelate. A list of other suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, PA, 1985.

[0407] For compounds of formula (I)-(LXXXI) containing basic nitrogen, pharmaceutically acceptable salts can be prepared by any suitable method available in the art, for example, by treating the free base with acids such as: inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, aminosulfonic acid, nitric acid, boric acid, phosphoric acid, etc.; or organic acids, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, hydroxyethylsulfonic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, etc. Palmitic acid, lauric acid; pyranotropic acids, such as glucuronic acid or galacturonic acid; α-hydroxy acids, such as mandelic acid, citric acid or tartaric acid; amino acids, such as aspartic acid or glutamic acid; aromatic acids, such as benzoic acid, 2-acetoxybenzoic acid, naphtholic acid or cinnamic acid; sulfonic acids, such as laurylsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid or ethanesulfonic acid; or any compatible mixture of acids, such as the acids given herein by way of example; and any other acids and mixtures thereof considered equivalent or acceptable substitutes at the ordinary level of the present invention.

[0408] This disclosure also relates to pharmaceutically acceptable prodrugs of compounds of formula (I)-(LXXXI), and treatment methods using such pharmaceutically acceptable prodrugs. The term "prodrug" means a precursor of a specified compound that, upon administration to an individual, produces the compound in vivo through a chemical or physiological process (such as solvent degradation or enzymatic cleavage) or under physiological conditions (e.g., a prodrug reaching physiological pH would be converted into a compound of formula (I)-(LXXXI)). A "pharmaceutically acceptable prodrug" is a non-toxic, biologically tolerable, and otherwise biologically suitable for administration to an individual. Illustrative procedures for selecting and preparing suitable prodrug derivatives are described, for example, in "Design of Prodrugs," edited by H. Bundgaard, Elsevier, 1985.

[0409] This disclosure also relates to pharmaceutically active metabolites of compounds of formula (I)-(LXXXI) and the use of such metabolites in the methods of this disclosure. "Pharmacoactive metabolite" means a pharmacologically active product of the in vivo metabolism of a compound of formula (I)-(LXXXI) or a salt thereof. The prodrugs and active metabolites of the compounds can be determined using conventional techniques known or available in the art. See, for example, Bertolini et al., *Journal of Medicinal Chemistry*, 1997, 40, 2011-2016; Shan et al., *Journal of Pharmaceutical Science*, 1997, 86(7), 765-767; Bagshawe, *Drug Dev. Res.*, 1995, 34, 220-230; Bodor, *Advances in Drug Research*, 1984, 13, 255-331; Buengard, *Prodrug Design* (Elsevier, 1985); and Larsen, *Design and Application of Prodrugs*, *Drug Design and Development*. (Edited by Krogsgaard-Larsen et al., Harwood Academic Publishers, 1991).

[0410] As used herein, the term "KRAS inhibitor" includes, but is not limited to, compounds capable of inhibiting proteins (called K-Ras) encoded by the KRAS gene that are involved in the RAS / MAPK signaling pathway. The terms KRAS gene, K-Ras, and RAS / MAPK signaling pathway are known and understood by those skilled in the art. It should be understood that approximately one in seven human metastatic cancers are associated with KRAS mutations, and these mutations can occur at multiple locations in the KRAS gene coding sequence. KRAS mutations primarily occur at KRAS codons 12 and 13, and also occur at low frequencies at codons 18, 61, 117, and 146, and have different effects on codon-based and missense-based tumor cell signaling. Examples of KRAS mutations include, but are not limited to, KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G12S, KRAS G13C, KRASG13D, KRAS A18D, KRAS Q61H, and KRAS K117N. Those skilled in the art will understand that reference to suppressing a KRAS mutation, such as KRAS G12D, refers to suppressing the protein encoded by the KRAS G12D gene, which has a coding sequence that produces the K-Ras G12D protein (e.g., a guanine-to-adenine substitution at codon 35 of KRAS coding sequence), wherein glycine at position 12 of the protein sequence is replaced by aspartic acid.

[0411] Representative Examples

[0412] In some embodiments, this disclosure relates to a compound of formula I or a pharmaceutically acceptable salt thereof.

[0413]

[0414] I

[0415] in

[0416] X is -O-, -S-, or -NR 4 -;

[0417] Y is a bond, -O-, -S-, -S(O)- or -S(O)2-;

[0418] Z 1 Is it N or C(R)? 5 );

[0419] Z 2 Is it N or C(R)? 6 );

[0420] Z 3 Is it N or C(R)? 7 );

[0421] Z 4 Is it N or C(R)? 8 );

[0422] The condition is Z 1 -Z 4 At least two of them are N;

[0423] Ring A is C6-C 10 Aryl, 5- to 10-membered heteroaryl or 4- to 10-membered heterocyclic alkyl;

[0424] Ring B is a 4- to 9-membered heterocyclic alkyl group;

[0425] Each R 1 Independently, it is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OC(=NR) a )NR a R b -OS(O)R a -OS(O)2R a -OS(O)NR a R b -OS(O)2NR a R b -SR a -S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR a R b -NR a R b -NR a C(O)R b -N(C(O)R a )(C(O)R b -NR a C(O)OR b -NR a C(O)NR a R b -NR a C(=NR a )NR a R b -NR aS(O)R b -NR a S(O)2R b -NR a S(O)NR a R b -NR a S(O)2NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -C(=NR) a )NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN or -NO2; or two Rs 1 Together with one or more atoms to which it is attached, it forms a C3-C6 cycloalkyl or a 4- to 10-membered heterocyclic alkyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclic alkyl groups is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -R e -R f -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NRe R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2; or R 1 R on the adjacent carbon of ring B 9 or R 10 Together with the carbon atoms it is attached to, they combine to form a carbon-carbon double bond;

[0426] Each R 2 Independently, it is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR c -OC(O)R c -OC(O)NR c R d -OC(=NR) c )NR c R d -OS(O)R c、-OS(O)2R c 、-OS(O)NR c R d 、-OS(O)2NR c R d 、-SR c 、-S(O)R c 、-S(O)2R c 、-S(O)NR c R d 、-S(O)2NR c R d 、-NR c R d 、-NR c C(O)R d 、-N(C(O)R c )(C(O)R d )、-NR c C(O)OR d 、-NR c C(O)NR c R d 、-NR c C(=NR c )NR c R d 、-NR c S(O)R d 、-NR c S(O)2R d 、-NR c S(O)NR c R d 、-NR c S(O)2NR c R d 、-C(O)R c 、-C(O)OR c 、-C(O)NR c R d 、-C(=NR c )NR c R d 、-PR c R d 、-P(O)R c R d 、-P(O)2R c R d 、-P(O)NR c R d 、-P(O)2NR c R d 、-P(O)OR c 、-P(O)2OR c-CN or -NO2, or two Rs 2 Together with the atoms to which they are attached, they form C3-C6 cycloalkyl or 4- to 10-membered heterocyclic alkyl groups, including C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, and C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclic alkyl groups is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -R e -R f -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2Re R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2;

[0427] R 3 It is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, -C1-C6 alkylene- (4- to 10-membered heterocyclic alkyl), C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 Aryl), 5- to 10-membered heteroaryl or -C1-C6 alkylene- (4- to 10-membered heterocyclic alkyl), wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, -C1-C6 alkylene- (4- to 10-membered heterocyclic alkyl), C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 Each hydrogen atom in aryl, 5- to 10-membered heteroaryl, and -C1-C6 alkylene- (5- to 10-membered heteroaryl) is independently and optionally substituted with the following groups: deuterium, halogen, -R e -R f C1-C6 alkyl, -C1-C6 alkylene-O-C1-C6 alkyl, -C1-C6 alkylene-OR a C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkylene- (5- to 10-membered heterocycloalkyl), -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e Rf -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e C(=NR f )NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2;

[0428] R 4 It is H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 aryl or 5 to 10-membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4 to 10-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl and 5- to 10-membered heteroaryl groups is independently and optionally substituted with the following groups: deuterium, halogen, -R e -R f C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e, -OC(O)NR e R f , -OS(O)R e , -OS(O)₂R e , -OS(O)NR e R f , -OS(O)₂NR e R f , -SR e , -S(O)R e , -S(O)₂R e , -S(O)NR e R f , -S(O)₂NR e R f , -NR e R f , -NR e , -NRC(O)R f , -NRC(O)OR e C(O)OR f , -NRC(O)NR e C(O)NR e R f , -NRS(O)R e S(O)R f , -NRS(O)₂R e S(O)₂R f , -NRS(O)NR e S(O)NR e R f , -NRS(O)₂NR e S(O)₂NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O)₂R e R f , -P(O)NR e R f , -P(O)₂NR e R f , -P(O)OR e , -P(O)₂OR e , -CN or -NO₂;

[0429] R 5 , R 6 , R 7 and R 8Each of these elements is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR g -OC(O)R g -OC(O)NR g R h -OS(O)R g -OS(O)2R g -SR g -S(O)R g -S(O)2R g -S(O)NR g R h -S(O)2NR g R h -OS(O)NR g R h -OS(O)2NR g R h -NR g R h -NR g C(O)R h -NR g C(O)OR h -NR g C(O)NR g R h -NR g S(O)R h -NR g S(O)2R h -NR g S(O)NR g R h -NR g S(O)2NR g R h -C(O)R g -C(O)OR g -C(O)NR g R h -PR g R h -P(O)R g R h -P(O)2R g R h -P(O)NR g R h -P(O)2NR g R h -P(O)OR g-P(O)2OR g -CN or -NO2;

[0430] R 9 and R 10 Each of these elements is independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OC(=NR) a )NR a R b -OS(O)R a -OS(O)2R a -OS(O)NR a R b -OS(O)2NR a R b -SR a -S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR a R b -NR a R b -NR a C(O)R b -N(C(O)R a )(C(O)R b -NR a C(O)OR b -NR a C(O)NR a R b -NR a C(=NR a )NR a R b -NR a S(O)R b -NR a S(O)2R b -NR a S(O)NR a R b -NR a S(O)2NR a R b -C(O)R a-C(O)OR a -C(O)NR a R b -C(=NR) a )NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN or -NO2; or R 9 and R 10 Together with the carbon atoms they are attached to, they form C2-C6 alkenyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl or oxo groups, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclic alkyl groups is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -R e -R f -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NRe R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2; or R on adjacent carbon atoms 9 and R 10 Together with the carbon atoms it is attached to, they combine to form R 9 and R 10 Substituted carbon-carbon double bonds;

[0431] R a R b R c R d R e R f R g and R h Each is independently selected from the following groups: H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, C1-C6 alkylene-C6-C 10 aryl and 5 to 10-membered heteroaryl; or R a and R b or R c and R d or R e and R f or R g and R hThe two atoms in the compound, together with one or more atoms attached to them, combine to form C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 aryl or 5 to 10-membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4 to 10-membered heterocycloalkyl, C6-C 10 Aryl, C1-C6 alkylene-C6-C 10 Each hydrogen atom in the aryl and 5- to 10-membered heteroaryl groups is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OC1-C6 alkyl, -OC(O)C1-C6 alkyl, -OC(O)N(H or C1-C6 alkyl)2, -OS(O)C1-C6 alkyl, -OS(O)2C1-C6 alkyl, -OS(O)N(H or C1-C6 alkyl)2, -OS( O)2N(H or C1-C6 alkyl)2, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)N(H or C1-C6 alkyl)2, -S(O)2N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)C(O)C1-C6 alkyl, - N(C1-C6 alkyl)C(O)N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)C1-C6 alkyl, -N(C1-C6 alkyl)S(O)2C1-C6 alkyl, -N(C1-C6 alkyl)S(O)N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)2N(H or C1-C6 alkyl)2, -C(O)C1-C6 alkyl, -C(O)OC1- C6 alkyl, -C(O)N(H or C1-C6 alkyl)2, -P(H or C1-C6 alkyl)2, -P(O)(H or C1-C6 alkyl)2, -P(O)2(H or C1-C6 alkyl)2, -P(O)N(H or C1-C6 alkyl)2, -P(O)2N(H or C1-C6 alkyl)2, -P(O)OC1-C6 alkyl, -P(O)2OC1-C6 alkyl, -CN or -NO2, or -R e and -R f Together with the carbon atom it is attached to, it forms an oxo group or a C2-C6 alkenyl group;

[0432] m is 0, 1, 2, 3, 4, 5, 6 or 7;

[0433] n is 0, 1, 2, 3, 4, 5, 6, or 7;

[0434] p is 0 or 1; and

[0435] q is 0, 1, or 2.

[0436] In some embodiments, this disclosure relates to a compound of formula I or a pharmaceutically acceptable salt thereof.

[0437]

[0438] I

[0439] in

[0440] X is -O-, -S-, or -NR 4 -;

[0441] Y is a bond, -O-, -S-, -S(O)- or -S(O)2-;

[0442] Z 1 Is it N or C(R)? 5 );

[0443] Z 2 Is it N or C(R)? 6 );

[0444] Z 3 Is it N or C(R)? 7 );

[0445] Z 4 Is it N or C(R)? 8 );

[0446] The condition is Z 1 -Z 4 At least two of them are N;

[0447] Ring A is C6-C 10 Aryl or 5 to 10-membered heteroaryl;

[0448] Ring B is a 4- to 9-membered heterocyclic alkyl group;

[0449] Each R 1 Independently, it is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OC(=NR) a )NR a R b -OS(O)R a -OS(O)2R a -OS(O)NR a R b -OS(O)2NRa R b 、 -SR a 、 -S(O)R a 、 -S(O)₂R a 、 -S(O)NR a R b 、 -S(O)₂NR a R b 、 -NR a R b 、 -NR a 、 -NR(C(O)R b 、 -N(C(O)R a )(C(O)R b )、 -NR a 、 -NR(C(O)OR b 、 -NR a 、 -NR(C(O)NR a R b 、 -NR a 、 -NR(C(=NR a )NR a R b 、 -NR a 、 -NR(S(O)R b 、 -NR[[ID=?]] a 、 -NR(S(O)₂R b 、 -NR a 、 -NR(S(O)NR a R b 、 -NR a 、 -NR(S(O)₂NR a R b 、 -C(O)R a 、 -C(O)OR a 、 -C(O)NR a R b 、 -C(=NR a )NR a R b 、 -PR a R b 、 -P(O)R a R b 、 -P(O)₂R a R b 、 -P(O)NR a R b 、 -P(O)₂NR a R b 、 -P(O)OR a 、 -P(O)₂OR a 、 -CN or -NO₂; or two Rs 1 It seems there might be a small error in the original text where the "? " appears in the translation. You may want to double-check the original for accuracy.Together with one or more atoms to which it is attached, it forms a C3-C6 cycloalkyl or a 4- to 10-membered heterocyclic alkyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclic alkyl groups is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -R e -R f -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f-P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2;

[0450] Each R 2 Independently, it is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR c -OC(O)R c -OC(O)NR c R d -OC(=NR) c )NR c R d -OS(O)R c -OS(O)2R c -OS(O)NR c R d -OS(O)2NR c R d -SR c -S(O)R c -S(O)2R c -S(O)NR c R d -S(O)2NR c R d -NR c R d -NR c C(O)R d -N(C(O)R c )(C(O)R d -NR c C(O)OR d -NR c C(O)NR c R d -NR c C(=NR c )NR c R d -NR c S(O)R d -NR c S(O)2R d -NR c S(O)NR c R d -NRc S(O)2NR c R d -C(O)R c -C(O)OR c -C(O)NR c R d -C(=NR) c )NR c R d -PR c R d -P(O)R c R d -P(O)2R c R d -P(O)NR c R d -P(O)2NR c R d -P(O)OR c -P(O)2OR c -CN or -NO2, or two Rs 2 Together with the atoms to which they are attached, they form C3-C6 cycloalkyl or 4- to 10-membered heterocyclic alkyl groups, including C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, and C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclic alkyl groups is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -R e -R f -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)ORf -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2;

[0451] R 3 It is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, -C1-C6 alkylene- (4- to 10-membered heterocyclic alkyl), C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 Aryl), 5- to 10-membered heteroaryl or -C1-C6 alkylene- (4- to 10-membered heterocyclic alkyl), wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, -C1-C6 alkylene- (4- to 10-membered heterocyclic alkyl), C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 Each hydrogen atom in aryl, 5- to 10-membered heteroaryl, and -C1-C6 alkylene- (5- to 10-membered heteroaryl) is independently and optionally substituted with the following groups: deuterium, halogen, -R e -R f C1-C6 alkyl, -C1-C6 alkylene-O-C1-C6 alkyl, -C1-C6 alkylene-OR a C6-C 10Aryl, -C1-C6 alkylene-(C6-C 10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkylene- (5- to 10-membered heterocycloalkyl), -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e C(=NR f )NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f-P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2;

[0452] R 4 It is H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 aryl or 5 to 10-membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4 to 10-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl and 5- to 10-membered heteroaryl groups is independently and optionally substituted with the following groups: deuterium, halogen, -R e -R f C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f-C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2;

[0453] R 5 R 6 R 7 and R 8 Each of these elements is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR g -OC(O)R g -OC(O)NR g R h -OS(O)R g -OS(O)2R g -SR g -S(O)R g -S(O)2R g -S(O)NR g R h -S(O)2NR g R h -OS(O)NR g R h -OS(O)2NR g R h -NR g R h -NR g C(O)R h -NR g C(O)OR h -NR g C(O)NR g R h -NR g S(O)R h -NR g S(O)2Rh -NR g S(O)NR g R h -NR g S(O)2NR g R h -C(O)R g -C(O)OR g -C(O)NR g R h -PR g R h -P(O)R g R h -P(O)2R g R h -P(O)NR g R h -P(O)2NR g R h -P(O)OR g -P(O)2OR g -CN or -NO2;

[0454] R 9 and R 10 Each of these elements is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OC(=NR) a )NR a R b -OS(O)R a -OS(O)2R a -OS(O)NR a R b -OS(O)2NR a R b -SR a -S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR a R b -NR a R b -NR a C(O)R b -N(C(O)Ra )(C(O)R b -NR a C(O)OR b -NR a C(O)NR a R b -NR a C(=NR a )NR a R b -NR a S(O)R b -NR a S(O)2R b -NR a S(O)NR a R b -NR a S(O)2NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -C(=NR) a )NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN or -NO2; or R 9 and R 10 Together with the carbon atoms they are attached to, they form C2-C6 alkenyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl or oxo groups, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclic alkyl groups is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -R e -R f -OR e -OC(O)R e -OC(O)NR e Rf -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2; or R on adjacent carbon atoms 9 and R 10 Together with the carbon atoms it is attached to, they combine to form R 9 and R 10 Substituted carbon-carbon double bonds;

[0455] Ra R b R c R d R e R f R g and R h Each is independently selected from the following groups: H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, C1-C6 alkylene-C6-C 10 aryl and 5 to 10-membered heteroaryl; or R a and R b or R c and R d or R e and R f or R g and R h The two atoms in the compound, together with one or more atoms attached to them, combine to form C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 aryl or 5 to 10-membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4 to 10-membered heterocycloalkyl, C6-C 10 Aryl, C1-C6 alkylene-C6-C 10Each hydrogen atom in the aryl and 5- to 10-membered heteroaryl groups is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OC1-C6 alkyl, -OC(O)C1-C6 alkyl, -OC(O)N(H or C1-C6 alkyl)2, -OS(O)C1-C6 alkyl, -OS(O)2C1-C6 alkyl, -OS(O)N(H or C1-C6 alkyl)2, -OS( O)2N(H or C1-C6 alkyl)2, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)N(H or C1-C6 alkyl)2, -S(O)2N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)C(O)C1-C6 alkyl, - N(C1-C6 alkyl)C(O)N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)C1-C6 alkyl, -N(C1-C6 alkyl)S(O)2C1-C6 alkyl, -N(C1-C6 alkyl)S(O)N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)2N(H or C1-C6 alkyl)2, -C(O)C1-C6 alkyl, -C(O)OC1- C6 alkyl, -C(O)N(H or C1-C6 alkyl)2, -P(H or C1-C6 alkyl)2, -P(O)(H or C1-C6 alkyl)2, -P(O)2(H or C1-C6 alkyl)2, -P(O)N(H or C1-C6 alkyl)2, -P(O)2N(H or C1-C6 alkyl)2, -P(O)OC1-C6 alkyl, -P(O)2OC1-C6 alkyl, -CN or -NO2, or -R e and -R f Together with the carbon atom it is attached to, it forms an oxo group or a C2-C6 alkenyl group;

[0456] m is 0, 1, 2, 3, 4, 5, 6 or 7;

[0457] n is 0, 1, 2, 3, 4, 5, 6, or 7;

[0458] p is 0 or 1; and

[0459] q is 0, 1, or 2.

[0460] In some embodiments, this disclosure relates to a compound of formula I or a pharmaceutically acceptable salt thereof.

[0461]

[0462] I

[0463] in

[0464] X is -O-, -S-, or -NR 4 -;

[0465] Y is a bond, -O-, -S-, -S(O)- or -S(O)2-;

[0466] Z 1 Is it N or C(R)? 5 );

[0467] Z 2 Is it N or C(R)? 6 );

[0468] Z 3 Is it N or C(R)? 7 );

[0469] Z 4 Is it N or C(R)? 8 );

[0470] The condition is Z 1 -Z 4 At least two of them are N;

[0471] Ring A is C6-C 10 Aryl or 5 to 10-membered heteroaryl;

[0472] Ring B is a 4- to 9-membered heterocyclic alkyl ring having a nitrogen atom in it;

[0473] Each R 1 Independently, it is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OC(=NR) a )NR a R b -OS(O)R a -OS(O)2R a -OS(O)NR a R b -OS(O)2NR a R b -SR a -S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR aR b -NR a R b -NR a C(O)R b -N(C(O)R a )(C(O)R b -NR a C(O)OR b -NR a C(O)NR a R b -NR a C(=NR a )NR a R b -NR a S(O)R b -NR a S(O)2R b -NR a S(O)NR a R b -NR a S(O)2NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -C(=NR) a )NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN or -NO2; or two Rs 1 Together with one or more atoms to which it is attached, it forms a C3-C6 cycloalkyl or a 4- to 10-membered heterocyclic alkyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclic alkyl groups is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -R e -R f, -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O)2R e , -OS(O)NR e R f , -OS(O)2NR e R f , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR e R f , -S(O)2NR e R f , -NR e R f , -NR e , -NR f , -NR e , -C(O)OR f , -NR e , -C(O)NR e R f , -NR e , -NR f , -NR e , -S(O)2R f , -NR e , -S(O)NR e R f , -NR e , -S(O)2NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O)2R e R f , -P(O)NR e R f , -P(O)2NR e R f , -P(O)OR e , -P(O)2OR e , -CN or -NO2;

[0474] Each R 2Independently, it is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR c -OC(O)R c -OC(O)NR c R d -OC(=NR) c )NR c R d -OS(O)R c -OS(O)2R c -OS(O)NR c R d -OS(O)2NR c R d -SR c -S(O)R c -S(O)2R c -S(O)NR c R d -S(O)2NR c R d -NR c R d -NR c C(O)R d -N(C(O)R c )(C(O)R d -NR c C(O)OR d -NR c C(O)NR c R d -NR c C(=NR c )NR c R d -NR c S(O)R d -NR c S(O)2R d -NR c S(O)NR c R d -NR c S(O)2NR c R d -C(O)R c -C(O)OR c -C(O)NR c R d -C(=NR) c )NR c Rd -PR c R d -P(O)R c R d -P(O)2R c R d -P(O)NR c R d -P(O)2NR c R d -P(O)OR c -P(O)2OR c -CN or -NO2, or two Rs 2 Together with the atoms to which they are attached, they form C3-C6 cycloalkyl or 4- to 10-membered heterocyclic alkyl groups, including C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, and C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclic alkyl groups is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -R e -R f -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NRe R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2;

[0475] R 3 It is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, -C1-C6 alkylene- (4- to 10-membered heterocyclic alkyl), C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 Aryl), 5- to 10-membered heteroaryl or -C1-C6 alkylene- (4- to 10-membered heterocyclic alkyl), wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, -C1-C6 alkylene- (4- to 10-membered heterocyclic alkyl), C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 Each hydrogen atom in aryl, 5- to 10-membered heteroaryl, and -C1-C6 alkylene- (5- to 10-membered heteroaryl) is independently and optionally substituted with the following groups: deuterium, halogen, -R e -R f C1-C6 alkyl, -C1-C6 alkylene-O-C1-C6 alkyl, -C1-C6 alkylene-OR a C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkylene- (5- to 10-membered heterocycloalkyl), -OR e -OC(O)R e -OC(O)NR e R f, -OS(O)R e , -OS(O)₂R e , -OS(O)NR e R f , -OS(O)₂NR e R f , -SR e , -S(O)R e , -S(O)₂R e , -S(O)NR e R f , -S(O)₂NR e R f , -NR e R f , -NR e , -NRC(O)R f , -NRC(O)OR e , -NRC(O)NR f R e , -NRC(=NR e )NR f R e , -NRS(O)R f e R f , -NRS(O)₂R e f , -NRS(O)NR e R f , -NRS(O)₂NR e R e , -C(O)R f , -C(O)OR e , -C(O)NR e R f , -PR e R e , -P(O)R e R f , -P(O)₂R e R f , -P(O)NR e R f , -P(O)₂NR e R f , -P(O)OR e , -P(O)₂OR f , -CN or -NO₂;

[0476] R e f , -P(O)OR e , -P(O)₂OR e , -CN or -NO₂;

[0476] R 4It is H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 aryl or 5 to 10-membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4 to 10-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl and 5- to 10-membered heteroaryl groups is independently and optionally substituted with the following groups: deuterium, halogen, -R e -R f C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e Rf -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2;

[0477] R 5 R 6 R 7 and R 8 Each of these elements is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR g -OC(O)R g -OC(O)NR g R h -OS(O)R g -OS(O)2R g -SR g -S(O)R g -S(O)2R g -S(O)NR g R h -S(O)2NR g R h -OS(O)NR g R h -OS(O)2NR g R h -NR g R h -NR g C(O)R h -NR g C(O)OR h -NR g C(O)NR g R h -NR g S(O)R h -NR g S(O)2R h -NR g S(O)NR g R h -NR g S(O)2NR g R h -C(O)Rg -C(O)OR g -C(O)NR g R h -PR g R h -P(O)R g R h -P(O)2R g R h -P(O)NR g R h -P(O)2NR g R h -P(O)OR g -P(O)2OR g -CN or -NO2;

[0478] R 9 and R 10 Each of these elements is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OC(=NR) a )NR a R b -OS(O)R a -OS(O)2R a -OS(O)NR a R b -OS(O)2NR a R b -SR a -S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR a R b -NR a R b -NR a C(O)R b -N(C(O)R a )(C(O)R b -NR a C(O)OR b -NR a C(O)NR a R b-NR a C(=NR a )NR a R b -NR a S(O)R b -NR a S(O)2R b -NR a S(O)NR a R b -NR a S(O)2NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -C(=NR) a )NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN or -NO2, or R 9 and R 10 Together with the carbon atoms to which they are attached, they form C3-C6 cycloalkyl or 4- to 10-membered heterocyclic alkyl groups, including C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, and C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclic alkyl groups is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -R e -R f -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SRe -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2; or R on adjacent carbon atoms 9 and R 10 Together with the carbon atoms it is attached to, they combine to form R 9 and R 10 Substituted carbon-carbon double bonds;

[0479] R a R b R c R d R e R f R g and R hEach is independently selected from the following groups: H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, C1-C6 alkylene-C6-C 10 aryl and 5 to 10-membered heteroaryl; or R a and R b or R c and R d or R e and R f or R g and R h The two atoms in the compound, together with one or more atoms attached to them, combine to form C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 aryl or 5 to 10-membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4 to 10-membered heterocycloalkyl, C6-C 10 Aryl, C1-C6 alkylene-C6-C 10Each hydrogen atom in the aryl and 5- to 10-membered heteroaryl groups is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OC1-C6 alkyl, -OC(O)C1-C6 alkyl, -OC(O)N(H or C1-C6 alkyl)2, -OS(O)C1-C6 alkyl, -OS(O)2C1-C6 alkyl, -OS(O)N(H or C1-C6 alkyl)2, -OS( O)2N(H or C1-C6 alkyl)2, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)N(H or C1-C6 alkyl)2, -S(O)2N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)C(O)C1-C6 alkyl, - N(C1-C6 alkyl)C(O)N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)C1-C6 alkyl, -N(C1-C6 alkyl)S(O)2C1-C6 alkyl, -N(C1-C6 alkyl)S(O)N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)2N(H or C1-C6 alkyl)2, -C(O)C1-C6 alkyl, -C(O)OC1- C6 alkyl, -C(O)N(H or C1-C6 alkyl)2, -P(H or C1-C6 alkyl)2, -P(O)(H or C1-C6 alkyl)2, -P(O)2(H or C1-C6 alkyl)2, -P(O)N(H or C1-C6 alkyl)2, -P(O)2N(H or C1-C6 alkyl)2, -P(O)OC1-C6 alkyl, -P(O)2OC1-C6 alkyl, -CN or -NO2, or -R e and -R f Together with the carbon atom it is attached to, it forms an oxo group or a C2-C6 alkenyl group;

[0480] m is 0, 1, 2, 3, 4, 5, 6 or 7;

[0481] n is 0, 1, 2, 3, 4, 5, 6, or 7;

[0482] p is 0 or 1; and

[0483] q is 0, 1, or 2.

[0484] In some embodiments, this disclosure relates to a compound of formula I or a pharmaceutically acceptable salt thereof.

[0485]

[0486] I

[0487] in

[0488] X is -O-, -S-, or -NR 4 -;

[0489] Y is a bond, -O-, -S-, -S(O)- or -S(O)2-;

[0490] Z 1 Is it N or C(R)? 5 );

[0491] Z 2 Is it N or C(R)? 6 );

[0492] Z 3 Is it N or C(R)? 7 );

[0493] Z 4 Is it N or C(R)? 8 );

[0494] The condition is Z 1 -Z 4 At least two of them are N;

[0495] Ring A is C6-C 10 aryl, 5- to 10-membered heteroaryl or ;

[0496] Ring B is a 4- to 9-membered heterocyclic alkyl group;

[0497] Each R 1 Independently, it is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OC(=NR) a )NR a R b -OS(O)R a -OS(O)2R a -OS(O)NR a R b -OS(O)2NR a R b -SR a -S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR a Rb -NR a R b -NR a C(O)R b -N(C(O)R a )(C(O)R b -NR a C(O)OR b -NR a C(O)NR a R b -NR a C(=NR a )NR a R b -NR a S(O)R b -NR a S(O)2R b -NR a S(O)NR a R b -NR a S(O)2NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -C(=NR) a )NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN or -NO2; or two Rs 1 Together with one or more atoms to which it is attached, it forms a C3-C6 cycloalkyl or a 4- to 10-membered heterocyclic alkyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclic alkyl groups is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -R e -R f -ORe 、 -OC(O)R e 、 -OC(O)NR e R f 、 -OS(O)R e 、 -OS(O)2R e 、 -OS(O)NR e R f 、 -OS(O)2NR e R f 、 -SR e 、 -S(O)R e 、 -S(O)2R e 、 -S(O)NR e R f 、 -S(O)2NR e R f 、 -NR e R f 、 -NR e C(O)R f 、 -NR e C(O)OR f 、 -NR e C(O)NR e R f 、 -NR e S(O)R f 、 -NR e S(O)2R f [[ID=�9]]、 -NR e S(O)NR e R f 、 -NR e S(O)2NR e R f 、 -C(O)R e 、 -C(O)OR e 、 -C(O)NR e R f 、 -PR<\\ e R f 、 -P(O)R e R f 、 -P(O)2R e R f 、 -P(O)NR e R f 、 -P(O)\\2NR e R f 、 -P(O)OR e 、 -P(O)2OR e 、 -CN or -NO\\2;

[0498] Each R 2Independently, it is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR c -OC(O)R c -OC(O)NR c R d -OC(=NR) c )NR c R d -OS(O)R c -OS(O)2R c -OS(O)NR c R d -OS(O)2NR c R d -SR c -S(O)R c -S(O)2R c -S(O)NR c R d -S(O)2NR c R d -NR c R d -NR c C(O)R d -N(C(O)R c )(C(O)R d -NR c C(O)OR d -NR c C(O)NR c R d -NR c C(=NR c )NR c R d -NR c S(O)R d -NR c S(O)2R d -NR c S(O)NR c R d -NR c S(O)2NR c R d -C(O)R c -C(O)OR c -C(O)NR c R d -C(=NR) c )NR c Rd -PR c R d -P(O)R c R d -P(O)2R c R d -P(O)NR c R d -P(O)2NR c R d -P(O)OR c -P(O)2OR c -CN or -NO2, or two Rs 2 Together with the atoms to which they are attached, they form C3-C6 cycloalkyl or 4- to 10-membered heterocyclic alkyl groups, including C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, and C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclic alkyl groups is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -R e -R f -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NRe R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2;

[0499] R 3 It is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, -C1-C6 alkylene- (4- to 10-membered heterocyclic alkyl), C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 Aryl), 5- to 10-membered heteroaryl or -C1-C6 alkylene- (4- to 10-membered heterocyclic alkyl), wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, -C1-C6 alkylene- (4- to 10-membered heterocyclic alkyl), C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 Each hydrogen atom in aryl, 5- to 10-membered heteroaryl, and -C1-C6 alkylene- (5- to 10-membered heteroaryl) is independently and optionally substituted with the following groups: deuterium, halogen, -R e -R f C1-C6 alkyl, -C1-C6 alkylene-O-C1-C6 alkyl, -C1-C6 alkylene-OR a C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkylene- (5- to 10-membered heterocycloalkyl), -OR e -OC(O)R e -OC(O)NR e R f, -OS(O)R e , -OS(O)₂R e , -OS(O)NR e R f , -OS(O)₂NR e R f , -SR e , -S(O)R e , -S(O)₂R e , -S(O)NR e R f , -S(O)₂NR e R f , -NR e R f , -NR e , -NRC(O)R f , -NRC(O)OR e , -NRC(O)NR f , -NR e , -NRC(=NR e R f , -NR e , -NRS(O)R f )NR e R f , -NR e , -NRS(O)₂R f , -NR e , -NRS(O)NR f ​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​It is H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 aryl or 5 to 10-membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4 to 10-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl and 5- to 10-membered heteroaryl groups is independently and optionally substituted with the following groups: deuterium, halogen, -R e -R f C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e Rf -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2;

[0501] R 5 R 6 R 7 and R 8 Each of these elements is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR g -OC(O)R g -OC(O)NR g R h -OS(O)R g -OS(O)2R g -SR g -S(O)R g -S(O)2R g -S(O)NR g R h -S(O)2NR g R h -OS(O)NR g R h -OS(O)2NR g R h -NR g R h -NR g C(O)R h -NR g C(O)OR h -NR g C(O)NR g R h -NR g S(O)R h -NR g S(O)2R h -NR g S(O)NR g R h -NR g S(O)2NR g R h -C(O)Rg -C(O)OR g -C(O)NR g R h -PR g R h -P(O)R g R h -P(O)2R g R h -P(O)NR g R h -P(O)2NR g R h -P(O)OR g -P(O)2OR g -CN or -NO2;

[0502] R 9 and R 10 Each of these elements is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OC(=NR) a )NR a R b -OS(O)R a -OS(O)2R a -OS(O)NR a R b -OS(O)2NR a R b -SR a -S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR a R b -NR a R b -NR a C(O)R b -N(C(O)R a )(C(O)R b -NR a C(O)OR b -NR a C(O)NR a R b-NR a C(=NR a )NR a R b -NR a S(O)R b -NR a S(O)2R b -NR a S(O)NR a R b -NR a S(O)2NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -C(=NR) a )NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN or -NO2; or R 9 and R 10 Together with the carbon atoms they are attached to, they form C2-C6 alkenyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl or oxo groups, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclic alkyl groups is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -R e -R f -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e Rf -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2; or R on adjacent carbon atoms 9 and R 10 Together with the carbon atoms it is attached to, they combine to form R 9 and R 10 Substituted carbon-carbon double bonds;

[0503] R a R b R c R d R e R f R g and R hEach is independently selected from the following groups: H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, C1-C6 alkylene-C6-C 10 aryl and 5 to 10-membered heteroaryl; or R a and R b or R c and R d or R e and R f or R g and R h The two atoms in the compound, together with one or more atoms attached to them, combine to form C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 aryl or 5 to 10-membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4 to 10-membered heterocycloalkyl, C6-C 10 Aryl, C1-C6 alkylene-C6-C 10Each hydrogen atom in the aryl and 5- to 10-membered heteroaryl groups is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OC1-C6 alkyl, -OC(O)C1-C6 alkyl, -OC(O)N(H or C1-C6 alkyl)2, -OS(O)C1-C6 alkyl, -OS(O)2C1-C6 alkyl, -OS(O)N(H or C1-C6 alkyl)2, -OS( O)2N(H or C1-C6 alkyl)2, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)N(H or C1-C6 alkyl)2, -S(O)2N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)C(O)C1-C6 alkyl, - N(C1-C6 alkyl)C(O)N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)C1-C6 alkyl, -N(C1-C6 alkyl)S(O)2C1-C6 alkyl, -N(C1-C6 alkyl)S(O)N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)2N(H or C1-C6 alkyl)2, -C(O)C1-C6 alkyl, -C(O)OC1- C6 alkyl, -C(O)N(H or C1-C6 alkyl)2, -P(H or C1-C6 alkyl)2, -P(O)(H or C1-C6 alkyl)2, -P(O)2(H or C1-C6 alkyl)2, -P(O)N(H or C1-C6 alkyl)2, -P(O)2N(H or C1-C6 alkyl)2, -P(O)OC1-C6 alkyl, -P(O)2OC1-C6 alkyl, -CN or -NO2, or -R e and -R f Together with the carbon atom it is attached to, it forms an oxo group or a C2-C6 alkenyl group;

[0504] m is 0, 1, 2, 3, 4, 5, 6 or 7;

[0505] n is 0, 1, 2, 3, 4, 5, 6, or 7;

[0506] p is 0 or 1; and

[0507] q is 0, 1, or 2.

[0508] In some embodiments, this disclosure relates to a compound of formula II, III, IV, V, VI, VII, VIII, or IX, or a pharmaceutically acceptable salt thereof.

[0509] (II),

[0510] (III), or

[0511] (IV),

[0512] (V),

[0513] (VI),

[0514] (VII),

[0515] (VIII), or

[0516] (IX),

[0517] Where R 1 R 2 R 3 R 9 R 10 A, B, X, X 1 Y, Z 1 Z 2 Z 3 Z 4 m, n, p, q, q1, t, and v are as described in this article.

[0518] In some embodiments, this disclosure relates to a compound of formula X, XI, XII, XIII, XIV, XV, XVI, or XVII, or a pharmaceutically acceptable salt thereof.

[0519] (X),

[0520] (XI),

[0521] (XII),

[0522] (XIII),

[0523] (XIV),

[0524] (XV),

[0525] (XVI), or

[0526] (XVII),

[0527] Where R 1 R 2 R3 R 9 R 10 B, X, Z 1 Z 2 Z 3 Z 4 Z 5 Z 6 m, n, p, q, and q1 are as described in this article.

[0528] In some embodiments, this disclosure relates to a compound of formula XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, or XXV, or a pharmaceutically acceptable salt thereof.

[0529] (XVIII),

[0530] (XIX),

[0531] (XX),

[0532] (XXI),

[0533] (XXII),

[0534] (XXIII), (XXIV), or

[0535] (XXV),

[0536] Where R 1 R 2 R 3 R 9 R 10 X, X 1 Z 1 Z 2 Z 3 Z 4 Z 5 Z 6 m, n, p, q, q1, t, and v are as described in this article.

[0537] In some embodiments, this disclosure relates to a compound of formula XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, or XXXIII, or a pharmaceutically acceptable salt thereof.

[0538] (XXVI),

[0539] (XXVII),

[0540] (XXVIII),

[0541] (XXIX),

[0542] (XXX),

[0543] (XXXI),

[0544] (XXXII), or

[0545] (XXXIII),

[0546] Where R 1 R 2 R 3 R 9 R 10 B, X, X 1 Z 1 Z 2 Z 3 Z 4 m, n, p, q, q1, t, and v are as described in this article.

[0547] In some embodiments, this disclosure relates to a compound of formula XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, XXXX, or XXXXI, or a pharmaceutically acceptable salt thereof.

[0548] (XXXIV),

[0549] (XXV),

[0550] (XXXVI),

[0551] (XXXVII),

[0552] (XXXVIII),

[0553] (XXXIX),

[0554] (XXXX), or

[0555] (XXXXI),

[0556] Where R 1 R 2 R 3 R 9 R 10 B, X, X 1 Z 1 Z 2 Z 3 Z 4 m, n, p, q, q1, t, and v are as described in this article.

[0557] In some embodiments, this disclosure relates to a compound of the formula XXXXII, XXXXIII, XXXXIV, XXXV, XXXVI, XXXXVII, XXXXVIII or XXXXIX, or a pharmaceutically acceptable salt thereof.

[0558] (XXXXII),

[0559] (XXXXIII),

[0560] (XXXXIV),

[0561] (XXXXV),

[0562] (XXXXVI),

[0563] (XXXXVII),

[0564] (XXXXVIII), or

[0565] (XXXXIX),

[0566] Where R 1 R 2 R 3 R 9 R 10 B, X, X 1 Z 1 Z 2 Z 3 Z 4 m, n, p, q, q1, t, and v are as described in this article.

[0567] In some embodiments, this disclosure relates to a compound of the formula L, LI, LII, LIII, LIV, LV, LVI, or LVII, or a pharmaceutically acceptable salt thereof.

[0568] (L),

[0569] (LI),

[0570] (LII),

[0571] (LIII),

[0572] (LIV),

[0573] (LV),

[0574] (LVI), or

[0575] (LVII),

[0576] Where R 1 R 2 R 3 R 9 R 10 B, X, X 1 Z 1 Z 2 Z 3 Z 4 m, n, p, q, q1, t, and v are as described in this article.

[0577] In some embodiments, this disclosure relates to a compound of the formula LVIII, LVIX, LX, LXI, LXII, LXIII, LXIV, or LXV, or a pharmaceutically acceptable salt thereof.

[0578] (LVIII),

[0579] (LIX),

[0580] (LX),

[0581] (LXI),

[0582] (LXII),

[0583] (LXIII),

[0584] (LXIV), or

[0585] (LXV),

[0586] R 1 R 2 R 3 R 9 R 10 B, X, X 1 Z 1 Z 2 Z 3 Z 4 m, n, p, q, q1, t, and v are as described in this article.

[0587] In some embodiments, this disclosure relates to a compound of the formula LXVI, LXVII, LXVIII, LXIX, LXX, LXXI, LXXII, LXXIII, LXXIV, LXXV, LXXVI, LXXVII, LXXVIII, LXXIX, LXXX, or LXXXI, or a pharmaceutically acceptable salt thereof.

[0588] (LXVI),

[0589] (LXVII),

[0590] (LXVIII),

[0591] (LXIX),

[0592] (LXX),

[0593] (LXXI),

[0594] (LXXII),

[0595] (LXXIII),

[0596] (LXXIV),

[0597] (LXXV),

[0598] (LXXVI),

[0599] (LXXVII),

[0600] (LXXVIII),

[0601] (LXXIX),

[0602] (LXXX), or

[0603] (LXXXI),

[0604] R 1 R 2 R 3 R 9 R 10 B, X, X 1 Z 1 Z 2 Z 3 Z 4 m, n, p, q, q1, t, and v are as described in this article.

[0605] In some embodiments, ring A is C6-C 10 Aryl or 5 to 10 heteroaryl compounds.

[0606] In some embodiments, ring B is a 4- to 9-membered heterocyclic alkyl group. In some embodiments, ring B is a 4- to 7-membered heterocyclic alkyl group. In some embodiments, ring B is a 4- to 9-membered heterocyclic alkyl ring having a nitrogen atom in a 4- to 9-membered heterocyclic alkyl ring. In some embodiments, ring B is a 4- to 7-membered heterocyclic alkyl ring having a nitrogen atom in a 4- to 9-membered heterocyclic alkyl ring. For example, in some embodiments, ring B is a fused 4- to 9-membered heterocyclic alkyl group forming the core of a compound of formula I, the compound comprising a core having the following formula

[0607] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ,

[0608] Each of these " "Is it related to ring A or -(X)?" p -R 3 Covalent connection points.

[0609] In some embodiments, the compound comprises a core having the following formula

[0610] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ,

[0611] Each of these " "Is it related to ring A or -(X)?" p -R 3 Covalent connection points.

[0612] In some embodiments, the compound comprises a core having the following formula

[0613] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ,

[0614] Each of these " "Is it related to ring A or -(X)?" p -R 3 Covalent connection points.

[0615] In some embodiments, the compound comprises a core having the following formula

[0616] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ,

[0617] Each of these " "Is it related to ring A or -(X)?" p -R 3 Covalent connection points.

[0618] In some embodiments, the compound comprises a core having the following formula

[0619] , , , , , , , , , , , 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , or ,

[0620] Each of these " "Is it related to ring A or -(X)?" p -R 3 Covalent connection points.

[0621] In some embodiments, the compound comprises a core having the following formula

[0622] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ,

[0623] Each of these " "Is it related to ring A or -(X)?" p -R 3 Covalent connection points.

[0624] In some embodiments, ring A is C6-C 10 Aryl or 5- to 10-membered heteroaryl. In some embodiments, ring A is C6-C. 10 Aryl, 5- to 10-membered heteroaryl, or 4- to 10-membered heterocyclic alkyl. In some embodiments, ring A is C6-C. 10 aryl, 5- to 10-membered heteroaryl or .

[0625] In some embodiments, ring A is C6-C 10Aryl. In some embodiments, ring A is a 5- to 10-membered heteroaryl group. In some embodiments, ring A is...

[0626] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ,

[0627] in" "It is a covalent connection point."

[0628] In some embodiments, ring A is

[0629] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ,

[0630] in" "It is a covalent connection point."

[0631] In some embodiments, X is -O-, -S-, or -NR. 4 -; In some embodiments, X is -O-. In some embodiments, X is -NR. 4 - In some embodiments, X is -S-.

[0632] In some embodiments, Y is a bond, -O-, -S-, -S(O)-, or -S(O)2-.

[0633] In some embodiments, Z 1 Is it N or C(R)? 5 In some embodiments, Z 1 It is N.

[0634] In some embodiments, Z 2 Is it N or C(R)? 6 In some embodiments, Z 2 It is N.

[0635] In some embodiments, Z 3 Is it N or C(R)? 7 In some embodiments, Z 3 It is CR 7 .

[0636] In some embodiments, Z 4 Is it N or C(R)? 8 In some embodiments, Z 4 It is N.

[0637] In some embodiments, Z 3 It is CR 7 And Z 4 It is N. In some embodiments, Z 3 It is CR7 And Z 4 It is CR 8 In some embodiments, Z 3 It is N and Z 4 It is CR 8 In some embodiments, Z 3 It is N and Z 4 It is N. In some embodiments, Z 3 It is N, Z 4 It is CR 8 Z 5 It is CR 11 And Z 6 It is CR 12 In some embodiments, Z 3 It is CR 7 Z 4 It is N, Z 5 It is CR 11 And Z 6 It is CR 12 In some embodiments, Z 3 It is N, Z 4 It is N, Z 5 It is CR 11 And Z 6 It is CR 12 .

[0638] In some embodiments, Z 1 -Z 4 At least two of them are N, for example,

[0639] , or .

[0640] In some embodiments, Z 1 -Z 4 The three elements in the equation are N, for example, or In some embodiments, at least Z 4 It is N, for example, , , or .

[0641] In some embodiments, each R 1 Independently, it is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NRa R b 、-OC(=NR a )NR a R b 、-OS(O)R a 、-OS(O)2R a 、-OS(O)NR a R b 、-OS(O)2NR a R b 、-SR a 、-S(O)R a 、-S(O)2R a 、-S(O)NR a R b 、-S(O)2NR a R b 、-NR a R b 、-NR a C(O)R b 、-N(C(O)R a )(C(O)R b )、-NR a C(O)OR b 、-NR a C(O)NR a R b 、-NR a C(=NR a )NR a R b 、-NR a S(O)R b 、-NR a S(O)2R b 、-NR a S(O)NR a R b 、-NR a S(O)2NR a R b 、-C(O)R a 、-C(O)OR a 、-C(O)NR a R b 、-C(=NR a )NR a R b 、-PR a R b 、-P(O)R a R b 、-P(O)2R a R b 、-P(O)NR a Rb -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN or -NO2, or two Rs 1 Together with one or more atoms to which it is attached, it forms a C3-C6 cycloalkyl or a 4- to 10-membered heterocyclic alkyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclic alkyl groups is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -R e -R f -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e、 -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NRe R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2.

[0642] In some embodiments, each R 1 Independently, it is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OC(=NR) a )NR a R b -OS(O)R a -OS(O)2R a -OS(O)NR a R b -OS(O)2NR a R b -SR a -S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR a R b -NR a R b -NR a C(O)R b -N(C(O)R a )(C(O)R b -NR a C(O)OR b -NR a C(O)NR a R b -NR a C(=NR a )NR a Rb -NR a S(O)R b -NR a S(O)2R b -NR a S(O)NR a R b -NR a S(O)2NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -C(=NR) a )NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN or -NO2; or two Rs 1 Together with one or more atoms to which it is attached, it forms a C3-C6 cycloalkyl or a 4- to 10-membered heterocyclic alkyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclic alkyl groups is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -R e -R f -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NRe R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2; or R 1 R on the adjacent carbon of ring B 9 or R 10 Together with the carbon atoms it is attached to, they combine to form a carbon-carbon double bond.

[0643] In some embodiments, each R 2 Independently, it is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR c -OC(O)R c -OC(O)NR c R d -OC(=NR) c )NR cR d 、-OS(O)R c 、-OS(O)2R c 、-OS(O)NR c R d 、-OS(O)2NR c R d 、-SR c 、-S(O)R c 、-S(O)2R c 、-S(O)NR c R d 、-S(O)2NR c R d 、-NR c R d 、-NR c C(O)R d 、-N(C(O)R c )(C(O)R d )、-NR c C(O)OR d 、-NR c C(O)NR c R d 、-NR c C(=NR c )NR c R d 、-NR c S(O)R d 、-NR c S(O)2R d 、-NR c S(O)NR c R d 、-NR c S(O)2NR c R d 、-C(O)R c 、-C(O)OR c 、-C(O)NR c R d 、-C(=NR c )NR c R d 、-PR c R d 、-P(O)R c R d 、-P(O)2R c R d 、-P(O)NR c R d 、-P(O)2NR c R d 、-P(O)ORc -P(O)2OR c -CN or -NO2, or two Rs 2 Together with the atoms to which they are attached, they form C3-C6 cycloalkyl or 4- to 10-membered heterocyclic alkyl groups, including C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, and C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclic alkyl groups is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -R e -R f -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)Re R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2. In some embodiments, each R 2 Independently, it is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, -OR c -C(O)R C -NR c R d Or -CN, wherein each hydrogen atom in the C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl groups is independently and optionally substituted with deuterium or a halogen. In some embodiments, each R 2 It is independently a halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -OR c In some embodiments, each R 2 It is independently halogen, C1-C6 alkyl, C2-C6 alkynyl, or -OR c In some embodiments, R 2 It is fluorine. In some embodiments, R 2 It is ethyl. In some embodiments, R 2 It is an acetylene group. In some embodiments, R 2 It is -OH.

[0644] In some embodiments, R 3 It is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, -C1-C6 alkylene- (4- to 10-membered heterocyclic alkyl), C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 Aryl), 5- to 10-membered heteroaryl or -C1-C6 alkylene- (4- to 10-membered heterocyclic alkyl), wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, -C1-C6 alkylene- (4- to 10-membered heterocyclic alkyl), C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 Each hydrogen atom in aryl, 5- to 10-membered heteroaryl, and -C1-C6 alkylene- (5- to 10-membered heteroaryl) is independently and optionally substituted with the following groups: deuterium, halogen, -R e -R fC1-C6 alkyl, -C1-C6 alkylene-O-C1-C6 alkyl, -C1-C6 alkylene-OR a C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkylene- (5- to 10-membered heterocycloalkyl), -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e C(=NR f )NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f-P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2. In some embodiments, R 3 It is a -C1-C6 alkyl, a 4- to 10-membered heterocyclic alkyl, or a -C1-C6 alkylene-(4- to 10-membered heterocyclic alkyl), wherein each hydrogen atom in the -C1-C6 alkyl, 4- to 10-membered heterocyclic alkyl, or -C1-C6 alkylene-(4- to 10-membered heterocyclic alkyl) is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, -C1-C6 alkylene-O-C1-C6 alkyl, -OC1-C6 alkylene-O-C1-C6 alkyl, -C1-C6 alkylene-OR a C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkylene- (5- to 10-membered heterocycloalkyl), -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e C(=NR f )NR e R f-NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e' -CN or -NO2. In some embodiments, R 3 It is a -C1-C6 alkylene- (4 to 10-membered heterocyclic alkyl), wherein each hydrogen atom in the -C1-C6 alkylene- (4 to 10-membered heterocyclic alkyl) is independently and optionally substituted with the following groups: deuterium, halogen, -R e -R f C1-C6 alkyl, -C1-C6 alkylene-O-C1-C6 alkyl, -OC1-C6 alkylene-O-C1-C6 alkyl, -C1-C6 alkylene-OR a C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkylene- (5- to 10-membered heterocycloalkyl), -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e-S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e C(=NR f )NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e' -CN or -NO2. In some embodiments, R 3 It is -methylene-(4 to 10-membered heterocyclic alkyl), wherein each hydrogen atom in -methylene-(4 to 10-membered heterocyclic alkyl) is independently and optionally substituted with a halogen. In some embodiments, R 3 yes

[0645] ,

[0646] Each hydrogen atom is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, -C1-C6 alkylene-O-C1-C6 alkyl, -OC1-C6 alkylene-O-C1-C6 alkyl, -C1-C6 alkylene-OR a C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkylene- (5- to 10-membered heterocycloalkyl), -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e C(=NR f )NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e Rf -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e' -CN or -NO2, and " " is a covalent connection point. In some embodiments, R 3 yes

[0647] ,

[0648] Each hydrogen atom is independently and optionally replaced by a halogen, wherein " " is a covalent connection point. In some embodiments, R 3 yes

[0649] , , , , , , , , , , , , , , or ,

[0650] Among them W It is an inorganic counter ion or an organic counter ion.

[0651] In some embodiments, R 3 It is a 4- to 10-membered heterocyclic alkyl group, wherein each hydrogen atom in the 4- to 10-membered heterocyclic alkyl group is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, -C1-C6 alkylene-O-C1-C6 alkyl, -OC1-C6 alkylene-O-C1-C6 alkyl, -C1-C6 alkylene-OR a C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkylene-(5- to 10-membered heterocycloalkyl), -OR e -OC(O)R e-OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e C(=NR f )NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e ', -CN, or -NO2. In some embodiments, R 3 yes

[0652] , , , or ,

[0653] in" "It is a covalent connection point."

[0654] In some embodiments, R 4 It is H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 aryl or 5 to 10-membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4 to 10-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl and 5- to 10-membered heteroaryl groups is independently and optionally substituted with the following groups: deuterium, halogen, -R e -R f C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e Rf -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e' -CN or -NO2. In some embodiments, R 4 It is H or a C1-C6 alkyl group. In some embodiments, R 4 It is H or methyl. In some embodiments, R 4 It is H.

[0655] In some embodiments, R 5 R 6 R 7 and R 8 Each of these elements is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR g -OC(O)R g -OC(O)NR g R h -OS(O)R g -OS(O)2R g -SR g -S(O)R g -S(O)2R g -S(O)NR g R h -S(O)2NR g R h -OS(O)NR g R h -OS(O)2NR g R h -NR g R h -NR g C(O)Rh -NR g C(O)OR h -NR g C(O)NR g R h -NR g S(O)R h -NR g S(O)2R h -NR g S(O)NR g R h -NR g S(O)2NR g R h -C(O)R g -C(O)OR g -C(O)NR g R h -PR g R h -P(O)R g R h -P(O)2R g R h -P(O)NR g R h -P(O)2NR g R h -P(O)OR g -P(O)2OR g -CN or -NO2. In some embodiments, R 5 It is H or deuterium. In some embodiments, R 6 It is H or deuterium. In some embodiments, R 7 It is H, deuterium, or F. In some embodiments, R 8 It is H or deuterium.

[0656] In some embodiments, R 9 and R 10 Each of these elements is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OC(=NR) a )NR a R b -OS(O)R a -OS(O)2R a, -OS(O)NR a R b , -OS(O)2NR a R b , -SR a , -S(O)R a , -S(O)2R a , -S(O)NR a R b , -S(O)2NR a R b , -NR a R b , -NR a , -NR b , -N(C(O)R a )(C(O)R b , -NR a , -NR b , -NR a , -NR a R b , -NR a , -NR a )(C(O)R a R b , -NR a , -NR b , -NR a , -NR b , -NR a , -NR a R b , -NR a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -C(=NR a )(C(O)R a R b , -PR a R b , -P(O)R a R b , -P(O)2R a R b , -P(O)NR a R b , -P(O)2NR a R b , -P(O)OR a , -P(O)2OR a , -CN or -NO2, or R 9and R 10 Together with the carbon atoms to which they are attached, they form C3-C6 cycloalkyl or 4- to 10-membered heterocyclic alkyl groups, including C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, and C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclic alkyl groups is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -R e -R f -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R eR f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2; or R on adjacent carbon atoms 9 and R 10 Together with the carbon atoms it is attached to, they combine to form R 9 and R 10 Substituted carbon-carbon double bonds; in some embodiments, R 9 It is H, deuterium, or methyl. In some embodiments, R 10 It is H, deuterium, or methyl. In some embodiments, R 9 and R 10 It is H or deuterium. In some embodiments, R on adjacent carbon atoms 9 and R 10 Together with the carbon atoms it is attached to, they combine to form R 9 and R 10 Substituted carbon-carbon double bonds.

[0657] In some embodiments, R a R b R c R d R e R f R g and R h Each is independently selected from the following groups: H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, C1-C6 alkylene-C6-C 10 aryl and 5 to 10-membered heteroaryl; or R a and R b or R c and R d or R e and R f or R g and R h The two atoms in the compound, together with one or more atoms attached to them, combine to form C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 aryl or 5 to 10-membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4 to 10-membered heterocycloalkyl, C6-C 10 Aryl, C1-C6 alkylene-C6-C 10Each hydrogen atom in the aryl and 5- to 10-membered heteroaryl groups is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OC1-C6 alkyl, -OC(O)C1-C6 alkyl, -OC(O)N(H or C1-C6 alkyl)2, -OS(O)C1-C6 alkyl, -OS(O)2C1-C6 alkyl, -OS(O)N(H or C1-C6 alkyl)2, -OS( O)2N(H or C1-C6 alkyl)2, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)N(H or C1-C6 alkyl)2, -S(O)2N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)C(O)C1-C6 alkyl, - N(C1-C6 alkyl)C(O)N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)C1-C6 alkyl, -N(C1-C6 alkyl)S(O)2C1-C6 alkyl, -N(C1-C6 alkyl)S(O)N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)2N(H or C1-C6 alkyl)2, -C(O)C1-C6 alkyl, -C(O)OC1- C6 alkyl, -C(O)N(H or C1-C6 alkyl)2, -P(H or C1-C6 alkyl)2, -P(O)(H or C1-C6 alkyl)2, -P(O)2(H or C1-C6 alkyl)2, -P(O)N(H or C1-C6 alkyl)2, -P(O)2N(H or C1-C6 alkyl)2, -P(O)OC1-C6 alkyl, -P(O)2OC1-C6 alkyl, -CN or -NO2, or -R e and -R f Together with the carbon atom it is attached to, it forms an oxo group or a C2-C6 alkenyl group.

[0658] In some embodiments, m is 0, 1, 2, 3, 4, 5, 6, or 7. In some embodiments, m is 1, 2, 3, or 4. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0659] In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7. In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1, 2, or 3. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0660] In some embodiments, p is 0 or 1. In some embodiments, p is 0. In some embodiments, p is 1.

[0661] In some embodiments, q is 0, 1, or 2. In some embodiments, q is 0. In some embodiments, q is 1. In some embodiments, q is 2.

[0662] In some embodiments, q1 is 0 or 1. In some embodiments, q1 is 0. In some embodiments, q1 is 1.

[0663] In some embodiments, t is 0, 1, 2, or 3. In some embodiments, t is 0, 1, or 2. In some embodiments, t is 0 or 1. In some embodiments, t is 1 or 2. In some embodiments, t is 0. In some embodiments, t is 1. In some embodiments, t is 2.

[0664] In some embodiments, v is 0, 1, or 2. In some embodiments, v is 0. In some embodiments, v is 1. In some embodiments, v is 2. In some embodiments, v is 1 or 2. In some embodiments, v is 0 or 1.

[0665] In some embodiments, X 1 Is -O-, -S-, -S(O)-, -S(O)2-, -NR 13 -、-C(O)NR 13 -、-NR 13 C(O)-, -C(O)O-, -OC(O)- or -C(R 1 )2-. In some embodiments, X 1 Is -O-, -S-, -S(O)-, -S(O)2-, -NR 13 -、-C(O)NR 13 -、-NR 13 C(O)-, -C(O)O-, -OC(O)- or -C(R 1 )2-, q is 0 when it exists and q1 is 0 when it exists. In some embodiments, X 1 Is -O-, -S-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)- or -C(R 1)2-. In some embodiments, X 1 It is -O-, -S-, -S(O)-, -S(O)2- or -C(R) 1 )2-.

[0666] In some embodiments, R 11 It is H, deuterium, -C(O)R g -C(O)NR g R h C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 aryl or 5 to 10-membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4 to 10-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl and 5- to 10-membered heteroaryl groups is independently and optionally substituted with the following groups: deuterium, halogen, -R e -R f C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NRe S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e' -CN or -NO2; or two hydrogen atoms on a single carbon atom of a 4- to 10-membered heterocyclic alkyl group combine to form an oxo group or a C2-C6 alkenyl group. In some embodiments, R 11 It is H, deuterium, or methyl.

[0667] In some embodiments, Z 5 Is it N or C(R)? 11 In some embodiments, Z 5 It is N. In some embodiments, Z 5 It is CR 11 .

[0668] In some embodiments, Z 6 Is it N or C(R)? 12 In some embodiments, Z 6 It is N. In some embodiments, Z 6 It is CR 12 .

[0669] In some embodiments, R 11 and R 12 Each of these elements is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR g -OC(O)R g -OC(O)NR g R h -OS(O)R g -OS(O)2R g -SR g -S(O)R g -S(O)2Rg -S(O)NR g R h -S(O)2NR g R h -OS(O)NR g R h -OS(O)2NR g R h -NR g R h -NR g C(O)R h -NR g C(O)OR h -NR g C(O)NR g R h -NR g S(O)R h -NR g S(O)2R h -NR g S(O)NR g R h -NR g S(O)2NR g R h -C(O)R g -C(O)OR g -C(O)NR g R h -PR g R h -P(O)R g R h -P(O)2R g R h -P(O)NR g R h -P(O)2NR g R h -P(O)OR g -P(O)2OR g -CN or -NO2. In some embodiments, R 11 It is H or deuterium. In some embodiments, R 12 It is H or deuterium.

[0670] In some embodiments, R 13 It is H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10aryl or 5 to 10-membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4 to 10-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl and 5- to 10-membered heteroaryl groups is independently and optionally substituted with the following groups: deuterium, halogen, -R e -R f C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e Rf -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2.

[0671] In some embodiments, the compound is selected from the group consisting of:

[0672] , , , , , , , , , , , , , , , , , and ,

[0673] Or its pharmaceutically acceptable salt.

[0674] The following are illustrative examples of compounds representing formulas (I)-(LXXXI):

[0675]

[0676]

[0677]

[0678]

[0679]

[0680]

[0681] And its pharmaceutically acceptable salts.

[0682] Those skilled in the art will recognize that the types listed or shown herein are not exhaustive, and other types may be selected within the scope of the terms defined herein.

[0683] Pharmaceutical Composition

[0684] For therapeutic purposes, pharmaceutical compositions comprising the compounds described herein may further comprise one or more pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients are non-toxic substances that are otherwise biologically suitable for administration to an individual. Such excipients facilitate the administration of the compounds described herein and are compatible with the active ingredient. Examples of pharmaceutically acceptable excipients include stabilizers, lubricants, surfactants, diluents, antioxidants, binders, colorants, swelling agents, emulsifiers, or taste modifiers. In a preferred embodiment, the pharmaceutical composition according to this disclosure is a sterile composition. The pharmaceutical composition can be prepared using compounding techniques known to or becoming available to those skilled in the art.

[0685] This disclosure also considers sterile compositions, including those that comply with national and local regulations governing such compositions.

[0686] The pharmaceutical compositions and compounds described herein can be formulated into solutions, emulsions, suspensions, or dispersants in suitable pharmaceutical solvents or carriers, or into pills, tablets, lozenges, suppositories, capsules, sugar-coated pills, granules, powders, powders for reconstitution, or capsules with a solid carrier, according to conventional methods known in the art for preparing various dosage forms. The pharmaceutical compositions of this disclosure can be administered via suitable routes of delivery (e.g., oral, parenteral, rectal, nasal, topical, or ocular) or by inhalation. Preferably, the compositions are formulated for intravenous or oral administration.

[0687] For oral administration, the compounds of this disclosure may be provided in solid form (such as tablets or capsules) or as solutions, emulsions, or suspensions. To prepare oral compositions, the compounds of this disclosure may be formulated to produce doses, for example, from about 0.1 mg to 1 g daily, or about 1 mg to 50 mg daily, or about 50 mg to 250 mg daily, or about 250 mg to 1 g daily. Oral tablets may include the active ingredient mixed with compatible pharmaceutically acceptable excipients (such as diluents, disintegrants, binders, lubricants, sweeteners, flavorings, colorants, and preservatives). Suitable inert fillers include sodium carbonate and calcium carbonate, sodium phosphate and calcium phosphate, lactose, starch, sugar, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol, etc. Exemplary liquid oral excipients include ethanol, glycerin, water, etc. Starch, polyvinylpyrrolidone (PVP), sodium carboxyacetic acid starch, microcrystalline cellulose, and alginate are exemplary disintegrants. Binders may include starch and gelatin. The lubricant (if present) may be magnesium stearate, stearic acid, or talc. If desired, the tablets may be coated with materials such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or they may be coated with an enteric coating.

[0688] Capsules for oral administration include hard gelatin capsules and soft gelatin capsules. To prepare hard gelatin capsules, the active ingredient can be mixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsules can be prepared by mixing the active ingredient with water, oil (such as peanut oil or olive oil), liquid paraffin, a mixture of monoglycerides and diglycerides of short-chain fatty acids, polyethylene glycol 400, or propylene glycol.

[0689] Liquids intended for oral administration may be in the form of suspensions, solutions, emulsions, or syrups, or may be lyophilized or exist as a dried product to be reconstituted with water or other suitable media prior to use. Such liquid compositions may optionally contain: pharmaceutically acceptable excipients, such as suspending agents (e.g., sorbitol, methylcellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, etc.); non-aqueous media, such as oils (e.g., almond oil or fractionated coconut oil), propylene glycol, ethanol, or water; preservatives (e.g., methylparaben or propylparaben or sorbic acid); wetting agents, such as lecithin; and, if desired, flavoring or coloring agents.

[0690] For parenteral use, including intravenous, intramuscular, intraperitoneal, intranasal, or subcutaneous routes, the pharmaceutical preparations disclosed herein can be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or parenteral acceptable oil. Suitable aqueous media include Ringer's solution and isotonic sodium chloride. Such forms can be available in single-dose forms (e.g., ampoules or disposable injection devices), in multi-dose formulations (e.g., vials from which appropriate doses can be dispensed), or in solid forms or pre-concentrated forms suitable for preparing injectable formulations. The illustrative infusion dose ranges from about 1 to 1000 μg / kg / min mixed with a drug carrier over a period of several minutes to several days.

[0691] For nasal, inhalation, or oral administration, the pharmaceutical compositions of the present invention can be administered using, for example, a spray formulation further containing a suitable carrier. The compositions of the present invention can also be formulated as suppositories for rectal administration.

[0692] For topical application, the compounds of this disclosure are preferably formulated as creams or ointments or similar mediators suitable for topical application. For topical application, the compounds of the present invention can be mixed with a drug carrier at a concentration of about 0.1% to about 10% drug:mediator. Another mode of applying the agents of this disclosure can be achieved through transdermal delivery using patch formulations.

[0693] As used herein, the term "treat" encompasses both "preventive" and "curative" treatment. "Preventive" treatment refers to the slowing of disease progression, symptoms, or medical conditions; the suppression of potential symptoms; or the reduction of the risk of disease or symptom progression or recurrence. "Cure" treatment includes reducing the severity of existing disease, symptoms, or conditions or suppressing their worsening. Therefore, treatment includes improving or preventing the worsening of existing disease symptoms; preventing the occurrence of additional symptoms; improving or preventing the underlying systemic causes of symptoms; and suppressing the condition or disease, for example, stopping the progression of the condition or disease, alleviating the condition or disease, causing the condition or disease to regress, relieving the symptoms caused by the condition or disease, or stopping the symptoms of the condition or disease.

[0694] The term "individual" refers to a mammalian patient, such as a human, who requires this treatment.

[0695] Exemplary diseases include cancer, pain, neurological disorders, autoimmune diseases, and inflammation. As used herein, the term "cancer" includes, but is not limited to, ALCL, NSCLC, neuroblastoma, inflammatory myofibroblastic tumor, adult renal cell carcinoma, pediatric renal cell carcinoma, breast cancer, and ER. +Breast cancer, colon adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid carcinoma, cholangiocarcinoma, ovarian cancer, gastric adenocarcinoma, colorectal cancer, inflammatory myofibroblastic tumor, angiosarcoma, epithelioid angioendothelioma, intrahepatic cholangiocarcinoma, papillary thyroid carcinoma, spitzoid neoplasms, sarcoma, astrocytoma, low-grade glioma of the brain, secretory breast cancer, breast analogue carcinoma, acute myeloid leukemia, congenital mesodermal nephroma, congenital fibrosarcoma, Ph-like acute lymphoblastic leukemia, thyroid cancer, melanoma of the skin, squamous cell carcinoma of the head and neck, pediatric glioma (CML), prostate cancer, squamous cell carcinoma of the lung, serous cystadenocarcinoma of the ovary, melanoma of the skin, castration-resistant prostate cancer, Hodgkin's lymphoma, and serous clear cell endometrial carcinoma. In some embodiments, cancers include lung cancer, colon cancer, breast cancer, prostate cancer, hepatocellular carcinoma, renal cell carcinoma, gastric and esophageal cancer, glioblastoma, head and neck cancer, inflammatory myofibroblastic tumor, and anaplastic large cell lymphoma. Pain includes pain of any origin or etiology, including cancer pain, pain caused by chemotherapy, neuropathic pain, pain caused by injury, or pain from other sources. Autoimmune diseases include, for example, rheumatoid arthritis, Sjögren's syndrome, type 1 diabetes, and lupus. Exemplary neurological diseases include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), and Huntington's disease. Exemplary inflammatory diseases include atherosclerosis, allergies, and inflammation caused by infection or injury.

[0696] On the one hand, the compounds and pharmaceutical compositions disclosed herein specifically target Ras, particularly K-Ras. Therefore, these compounds and pharmaceutical compositions can be used to prevent, reverse, slow down, or inhibit the activity of one or more KRAS mutations (such as KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D, KRAS A18D, KRASQ61H, KRAS K117N, etc.). In a preferred embodiment, a method for treating a target cancer is described.

[0697] In the inhibition methods disclosed herein, "effective amount" means an amount sufficient to inhibit the target protein. This target regulation can be measured by conventional analytical methods (such as those described below). This regulation can be used in a variety of environments, including in vitro assays. In such methods, the cells are preferably cancer cells with aberrant signaling due to mutations in KRAS (such as KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D, KRAS A18D, KRAS Q61H, KRAS K117N, etc.).

[0698] In the treatment methods according to this disclosure, "effective amount" means an amount or dose sufficient to produce the desired therapeutic benefit in an individual requiring such treatment. The effective amount or dose of the compounds of this disclosure can be determined by conventional methods, such as modeling, dose escalation, or clinical trials; taking into account conventional factors, such as the manner or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the infection, the individual's health status, symptoms and weight, and the judgment of the treating physician. Exemplary doses range from about 0.1 mg to 1 g daily, or from about 1 mg to 50 mg daily, or from about 50 mg to 250 mg daily, or from about 250 mg to 1 g daily. The total dose can be administered in single or separate dose units (e.g., BID, TID, QID).

[0699] Once a patient's condition improves, the dosage can be adjusted for prevention or maintenance treatment. For example, the dosage or frequency, or both, can be reduced based on symptoms to maintain the desired therapeutic or preventative effect. Of course, treatment can be discontinued if symptoms have subsided to an appropriate level. However, in the event of any recurrence of symptoms, the patient may require intermittent treatment on a long-term basis. The patient may also require chronic treatment on a long-term basis.

[0700] Drug combination

[0701] The compounds of the present invention described herein can be combined with one or more additional active ingredients in pharmaceutical compositions or methods for treating the diseases and conditions described herein. Additionally, the additional active ingredients include other therapeutic agents or pharmaceuticals that mitigate the adverse effects of therapies targeting the intended disease target. Such combinations can be used to increase efficacy, improve other disease symptoms, reduce one or more side effects, or reduce the required dosage of the compounds of the present invention. The additional active ingredients can be administered in a pharmaceutical composition separate from the compounds disclosed herein or can be included together with the compounds disclosed herein in a single pharmaceutical composition. The additional active ingredients can be administered simultaneously with, before, or after the compounds disclosed herein.

[0702] Combination agents that include additional active ingredients are combination agents known or found to be effective in treating the diseases and conditions described herein, including combination agents active against another target associated with the disease. For example, the compositions and formulations and treatments disclosed herein may further include other medicines or pharmaceuticals, such as other active agents that can be used to treat or alleviate the target disease or related symptoms or conditions. For cancer indications, additional such agents include, but are not limited to, kinase inhibitors such as ALK inhibitors (e.g., crizotinib); Raf inhibitors (e.g., vemurafenib); VEGFR inhibitors (e.g., sunitinib); standard chemotherapeutic agents such as alkylating agents; antimetabolites; antitumor antibiotics; topoisomerase inhibitors; platinum drugs; mitotic inhibitors; antibodies; hormone therapy; or corticosteroids. For pain indications, suitable combination agents include anti-inflammatory drugs such as NSAIDs. The pharmaceutical compositions disclosed herein may additionally include one or more of these active agents, and treatments may additionally include administration of an effective amount of one or more of these active agents.

[0703] Chemical synthesis methods

[0704] The following examples are provided for illustration and not for limitation of this disclosure. Those skilled in the art will recognize that the following synthetic reactions and schemes can be modified by selecting suitable starting materials and reagents to obtain other compounds of formula (I)-(LXXXI).

[0705] Abbreviations: The examples and materials used herein include, but are not limited to, materials described by the following abbreviations known to those skilled in the art:

[0706]

[0707]

[0708]

[0709] The proposed target can be prepared using conventional chemical methods.

[0710] The proposed target can be prepared by conventional chemical methods or according to the general scheme shown below.

[0711] Option I

[0712]

[0713] General scheme I is used to prepare products having a general structural example X. The bicyclic aryl core I-1-1 and various amines I-2 are commercially available or prepared from commercially available materials. A: Under photochemical conditions (e.g., a 10 W blue LED lamp), in the presence of an Ir(III) catalyst, a Ni(II) co-catalyst, and a base (e.g., morpholine-containing DMF), at room temperature, compound I-1-1 and amine I-2 are converted to product I-3. B: Under acidic conditions (e.g., HCl-containing dioxane), at room temperature, compound I-3 is converted to product I-4. C: In the presence of phosphorus oxychloride and a base (e.g., diisopropylethylamine-containing THF), at room temperature, compound I-4 is converted to product I-5. D: Under palladium-catalyzed Suzuki coupling conditions, compound I-5 and borate ester I-6 are converted to product I-7. E: In the presence of an oxidizing agent (such as DCM containing m-CPBA), compound I-7 is converted to product I-8 at room temperature. F: Under alkaline conditions (such as toluene containing potassium tert-butoxide), at low temperature (such as 0°C), compound I-8 and alcohol I-9 are converted to the product, which is then deprotected if necessary to provide final product example X.

[0714] intermediate synthesis

[0715] Intermediate Table 1

[0716]

[0717] Preparation of tert-butyl 3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)ethyl)-1,4-oxazacycloheptane-4-carboxylate (I-2-1):

[0718]

[0719] Step 1. LiOH·H2O (178 mg, 4.24 mmol, 1.1 equivalent) was added to a solution of 4-(tert-butyl)-3-methyl 1,4-oxazacycloheptane-3,4-dicarboxylic acid (1.00 g, 3.86 mmol, 1 equivalent) in THF (2 mL) and H2O (1 mL). The mixture was stirred at 25 °C for 0.5 h. After completion, the mixture was concentrated to obtain a residue. The residue was purified by column chromatography (SiO2, DCM: MeOH = 20:1) to give 4-(tert-butoxycarbonyl)-1,4-oxazacycloheptane-3-carboxylic acid (940 mg, 3.83 mmol, 99% yield) as a yellow oil.

[0720] Step 2. Add the following to a 15 mL vial equipped with a stir bar: 4-(tert-butoxycarbonyl)-1,4-oxazacycloheptan-3-carboxylic acid (940 mg, 3.83 mmol, 1 equivalent), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborheptanyl (590 mg, 3.83 mmol, 0.65 mL, 1 equivalent), Ir[dF(CF3)ppy]2(dtbpy)(PF6) (43.0 mg, 0.038 mmol, 0.01 equivalent), NiCl2.dtbbpy (7.63 mg, 0.019 mmol, 0.005 equivalent), 2-tert-butyl-1,1,3,3-tetramethyl-guanidine (984 mg, 5.75 mmol, 1.2 mL, 1.5 equivalent), and phthalimide (563 mg, 1.5 equivalent). DMSO (10 mL) was added (mg, 3.83 mmol, 1 equivalent). The reaction mixture was stirred in air and irradiated with a 10 W blue LED lamp (3 cm away). The reaction temperature was maintained at 25 °C with cold water for 2 hours. After completion, the reaction mixture was diluted with water (30 mL) and extracted with EA (20 mL × 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 50 / 1) to give tert-butyl 3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)ethyl)-1,4-oxazacycloheptane-4-carboxylate (400 mg, 1.13 mmol, 29% yield) as a white solid.

[0721] Preparation of tert-butyl 5-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborheptan-2-yl)ethyl)-1,4-oxazacycloheptane-4-carboxylate (I-2-2):

[0722]

[0723] Step 1. To a solution of 1,4-oxazacycloheptan-5-one (10.0 g, 86.8 mmol, 1 equivalent) in DCM (150 mL), TEA (13.1 g, 130 mmol, 1.5 equivalent), DMAP (1.06 g, 8.69 mmol, 0.1 equivalent), and Boc₂O (24.6 g, 112 mmol, 1.3 equivalent) were added. The mixture was stirred at 25 °C for 12 hours. After completion, the reaction mixture was partitioned between ethyl acetate (200 mL × 3) and water (200 mL), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl 5-oxazacycloheptan-4-carboxylate (14.2 g, 65.9 mmol, 75% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ = 3.92 – 3.85 (m, 2H), 3.75 – 3.64 (m, 4H), 2.84 – 2.73 (m, 2H), 1.45 (s, 9H).

[0724] Step 2. A mixture of tert-butyl 5-oxaazacycloheptan-4-carboxylate (14.2 g, 65.9 mmol, 1 equivalent) in THF (200 mL) was degassed and purged three times with N2, followed by the addition of LiHMDS (1 M, 65.9 mL, 1 equivalent) at -70 °C for 0.5 h. Then, [chloro(phenoxy)phosphoryl]oxybenzene (17.7 g, 65.9 mmol, 1 equivalent) was added to the reaction mixture at -70 °C, and the mixture was stirred at -70 °C for 1.5 h under N2 atmosphere. After completion, the reaction mixture was partitioned between ethyl acetate (200 mL × 3) and water (200 mL), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1:0 to 0:1) to give tert-butyl 5-((diphenoxyphosphoryl)oxy)-2,3-dihydro-1,4-oxazazepine-4(7H)-carboxylate (23.0 g, 51.4 mmol, 77% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ = 7.47 – 7.16 (m, 10H), 5.52 (dt, J = 2.8, 6.4 Hz, 1H), 4.09 (dd, J= 1.2, 6.4 Hz, 2H), 3.77 (t, J = 4.4 Hz, 2H), 3.66 (s, 2H), 1.45 (s, 9H).

[0725] Step 3. Add tert-butyl 5-((diphenoxyphosphoryl)oxy)-2,3-dihydro-1,4-oxazapyro-4(7H)-carboxylate (13.0 g, 29.0 mmol, 1 equivalent), potassium vinyltrifluoroborate (4.67 g, 34.8 mmol, 1.2 equivalent), K3PO4 (18.0 g, 87.1 mmol, 3 equivalent), and Pd(dppf)Cl... 2. The mixture of CH2Cl2 (2.37 g, 2.91 mmol, 0.1 equivalent) in I (200 mL) and H2O (50 mL) was degassed and purged three times with N2, and then stirred at 75 °C for 4 hours under N2 atmosphere. After completion, the reaction mixture was partitioned between ethyl acetate (150 mL × 3) and water (150 mL), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1:0 to 0:1) to give tert-butyl 5-vinyl-2,3-dihydro-1,4-oxazapyro-4(7H)-carboxylate (4.60 g, 20.4 mmol, 70% yield) as a white oil. 1 H NMR (400 MHz, CDCl3) δ = 6.17 (dd, J = 10.4, 16.8 Hz, 1H), 5.66 (t, J = 5.6 Hz, 1H), 5.32 –4.96 (m, 2H), 4.05 (d, J = 6.0 Hz, 2H), 3.74 (t, J = 4.4 Hz, 2H), 3.45 (s, 2H), 1.51 – 1.27 (m, 9H).

[0726] Step 4. A mixture of tert-butyl 5-vinyl-3,7-dihydro-2H-1,4-oxazopyro-4-carboxylate (4.60 g, 20.4 mmol, 1 equivalent), 1,2-bis(diphenylphosphino)ethane (2.85 g, 7.15 mmol, 0.35 equivalent), and [Ir(COD)(Cl)]2 (2.06 g, 3.06 mmol, 0.15 equivalent) in DCM (60 mL) was degassed and purged three times with N2. The mixture was then stirred at 25 °C for 0.5 h under N2 atmosphere. Next, 4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentane (3.92 g, 30.6 mmol, 1.5 equivalent) was added to the mixture at 0 °C, and the mixture was stirred at 25 °C for 0.5 h. After completion, the mixture was filtered and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1:0 to 0:1) to give tert-butyl 5-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)ethyl)-2,3-dihydro-1,4-oxazazepine-4(7H)-carboxylate (900 mg, 2.55 mmol, 12% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ = 5.39 (s, 1H), 3.95 (d, J = 5.6 Hz,2H), 3.71 – 3.63 (m, 2H), 3.45 (s, 2H), 2.39 (s, 2H), 1.40 (s, 9H), 1.17 (s,12H), 0.83 (t, J = 8.0 Hz, 2H).

[0727] Step 5. A mixture of 5-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)ethyl]-3,7-dihydro-2H-1,4-oxazolane-4-carboxylic acid tert-butyl ester (860 mg, 2.43 mmol, 1 equivalent), Pd / C (1.50 g, 1.41 mmol, 10% purity) and Pd(OH)₂ (1.20 g, 0.854 mmol, 10% purity) in THF (5 mL) was degassed and purged three times with H₂, and then the mixture was stirred at 25 °C for 2 hours under H₂ atmosphere. After completion, the mixture was filtered and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1:0 to 0:1) to give tert-butyl 5-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)ethyl)-1,4-oxazacycloheptane-4-carboxylate (430 mg, 1.21 mmol, 49% yield) as a yellow oil.

[0728] Intermediate Method I-2A

[0729] Preparation of (S)-2-((1-(tert-butoxycarbonyl)piperidin-2-yl)methoxy)acetic acid (I-2-3):

[0730]

[0731] Step 1. The mixture of (S)-2-(hydroxymethyl)piperidin-1-carboxylic acid tert-butyl ester (8.00 g, 37.2 mmol, 1 equivalent) and rhodium diacetoxy (493 mg, 2.23 mmol, 0.06 equivalent) in DCM (70 mL) was degassed and purged three times with N2. DCM (10 mL) containing ethyl 2-diazolate (5.09 g, 44.6 mmol, 4.69 mL, 1.2 equivalent) was added under N2 at 0 °C. The mixture was stirred at 25 °C for 16 hours under N2 atmosphere. After completion, the reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give (S)-2-((2-ethoxy-2-oxoethoxy)methyl)piperidine-1-carboxylic acid tert-butyl ester (5.60 g, 18.6 mmol, 50% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ = 4.47 – 4.31 (m, 1H), 4.30 – 4.16 (m,2H), 4.13 – 4.05 (m, 2H), 4.03 – 3.92 (m, 1H), 3.69 – 3.55 (m, 2H), 2.86 –2.69 (m, 1H), 1.92 – 1.71 (m, 2H), 1.65 – 1.50 (m, 4H), 1.41 (d, J = 3.2 Hz,9H), 1.31 – 1.23 (m, 3H).

[0732] Step 2. LiOH·H2O (835 mg, 19.9 mmol, 3 equivalents) was added to a solution of (S)-2-((1-(tert-butoxycarbonyl)piperidin-2-yl)methoxy)carboxylic acid tert-butyl ester (2.00 g, 6.64 mmol, 1 equivalent) in THF (20 mL) and H2O (4 mL). The mixture was stirred at 25 °C for 2 hours. After completion, the reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give (S)-2-((1-(tert-butoxycarbonyl)piperidin-2-yl)methoxy)acetic acid (1.34 g, 4.90 mmol, 74% yield) as a yellow oil.

[0733] Intermediate Method I-2B

[0734] Preparation of tert-butyl 2-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborheptan-2-yl)ethyl)azacycloheptane-1-carboxylate (I-2-8):

[0735]

[0736] Add DMA (24 mL) containing 1-(tert-butoxycarbonyl)azacycloheptane-2-carboxylic acid (4.50 g, 18.5 mmol, 1 equivalent), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborhexacyclopentane (4.27 g, 27.7 mmol, 4.71 mL, 1.5 equivalent), Ir[F(Me)ppy]2(dtbpy)(PF6) (362 mg, 0.370 mmol, 0.02 equivalent), and Cs2CO3 (6.03 g, 18.5 mmol, 1 equivalent) to a 40 mL vial equipped with a stir bar. Seal the vial and place it under nitrogen. Stir the reaction mixture and irradiate it with a blue 4 × 50 W LED lamp (3 cm away). Maintain the reaction temperature at 25 °C with cold water for 14 hours. After completion, the reaction mixture was diluted with H2O (200 mL) and extracted with EA (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1:0 to 10:1) to give the compound tert-butyl 2-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)ethyl]azacycloheptane-1-carboxylate (1.22 g, 2.76 mmol, 15% yield, 80% purity) as an orange liquid.

[0737] Preparation of tert-butyl 2-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)ethyl)piperidine-1-carboxylic acid (I-2-12):

[0738]

[0739] DMA (50 mL) containing 1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid (5.00 g, 21.8 mmol, 1 equivalent), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxabortane (4.37 g, 28.4 mmol, 4.81 mL, 1.3 equivalent), Cs₂CO₃ (7.11 g, 21.8 mmol, 1 equivalent), and Ir[dF(Me)ppy]₂dtbpy(PF₆) (442 mg, 0.436 mmol, 0.02 equivalent) was added to a 40 mL vial equipped with a stir bar. The vial was sealed and placed under nitrogen. The reaction mixture was stirred and irradiated with a 4 × 50 W [455 nm] blue LED lamp (at a distance of 3 cm), and the reaction temperature was maintained at 25 °C with cold water for 14 hours. After completion, the reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by rapid silica gel chromatography (0-100% ethyl acetate / petroleum) to give tert-butyl 2-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)ethyl)piperidine-1-carboxylate (1.20 g, 3.18 mmol, 15% yield, 90% purity) as a yellow oil.

[0740] Table 2. Intermediates.

[0741]

[0742]

[0743] Intermediate Table 3

[0744]

[0745] General Method A

[0746] 5-Ethynyl-6-fluoro-4-[(8aR)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl]methoxy}-7,8,8a,9,12,13-hexahydro-11H-10-oxa-1,3,6,13a-tetraazanaphtho[1,8-ab]heptanronen-5-yl]naphth-2-ol (Example 1) and 5 Preparation of -ethynyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl]methoxy}-7,8,8a,9,12,13-hexahydro-11H-10-oxa-1,3,6,13a-tetraazanaphtho[1,8-ab]heptanronen-5-yl]naphth-2-ol (Example 2):

[0747]

[0748]

[0749] Step 1. Add the following to a 15 mL vial equipped with a stir bar: tert-butyl 3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)ethyl)-1,4-oxazacycloheptane-4-carboxylate (I-2-1, 480 mg, 1.35 mmol, 2 equivalents), 5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (189 mg, 0.675 mmol, 1 equivalent), Ir[dF(CF3)ppy]2(dtbpy)(PF6) (7.58 mg, 0.0068 mmol, 0.01 equivalents), NiCl2.dtbbpy (13.4 mg, 0.034 mmol, 0.05 equivalents), and morpholine (88.2 mg, 1.01 mmol, 0.09... 2 mL of DMF (1.5 equivalents) was added. The reaction mixture was stirred in air and irradiated with a 10 W blue LED lamp (3 cm away). The reaction temperature was maintained at 25 °C with cold water for 2 hours. After completion, the mixture was filtered and the filtrate was purified by preparative HPLC to give tert-butyl 3-(2-(7-chloro-8-fluoro-4-hydroxy-2-(methylthio)pyrido[4,3-d]pyrimidin-5-yl)ethyl)-1,4-oxazacycloheptane-4-carboxylate (105 mg, 0.206 mmol, 30% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6)δ = 13.12 (s, 1H), 4.21 - 4.09 (m, 1H), 4.08 - 3.89 (m, 2H), 3.89 - 3.78 (m,2H), 3.76 - 3.54 (m, 2H), 3.28 - 3.23 (m, 2H), 2.59 (s, 3H), 1.69 - 1.65 (m,2H), 1.60 - 1.51 (m, 2H), 1.34 (s, 9H); LCMS: (M+1:473.0).

[0750] Step 2. To a solution of 3-(2-(7-chloro-8-fluoro-4-hydroxy-2-(methylthio)pyrido[4,3-d]pyrimidin-5-yl)ethyl)-1,4-oxazacycloheptan-4-carboxylic acid tert-butyl ester (80.0 mg, 0.169 mmol, 1 equivalent) in DCM (0.5 mL), HCl / dioxane (2 M, 1 mL, 11.8 equivalents) was added. The mixture was stirred at 25 °C for 0.5 h. After completion, the reaction mixture was concentrated under reduced pressure to give 5-(2-(1,4-oxazacycloheptan-3-yl)ethyl)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (63.0 mg, 0.168 mmol, 99% yield) as a white solid. LCMS: (M+1:373.0).

[0751] Step 3. To a solution of 5-(2-(1,4-oxazacycloheptan-3-yl)ethyl)-7-chloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-ol (63.0 mg, 0.168 mmol, 1 equivalent) in THF (1 mL), POCl3 (0.506 mmol, 0.048 mL, 3 equivalents) and DIEA (1.52 mmol, 0.264 mL, 9 equivalents) were added. The mixture was stirred at 25 °C for 1 hour. After completion, the reaction mixture was quenched with H2O (0.1 mL) at 25 °C and then concentrated under reduced pressure to produce a residue. The residue was purified by preparative TLC (SiO2, PE: EA = 0:1) to give 2-chloro-1-fluoro-12-(methylthio)-4,5,5a,6,9,10-hexahydro-8H-7-oxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptanronne (50.0 mg, 0.140 mmol, 83% yield) as a white solid. LCMS: (M+1: 354.9).

[0752] Step 4. Dissolve ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)naphth-1-yl)ethynyl)triisopropylsilane (91.3 mg, 0.183 mmol, 1.3 equivalents), 2-chloro-1-fluoro-12-(methylthio)-4,5,5a,6,9,10-hexahydro-8H-7-oxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptanronne (50.0 mg, 0.140 mmol, 1 equivalent), Cs₂CO₃ (91.8 mg, 0.281 mmol, 2 equivalents), Pd(dtbpf)Cl₂ (9.18 mg, 0.014 mmol, 0.1 equivalents) in dioxane (1 mL) and H₂O. The mixture in (0.2 mL) was degassed and purged three times with N2, and then stirred at 80 °C for 2 hours under N2 atmosphere. After completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO2, PE: EA = 2:1) to give 1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthyl-1-yl)-12-(methylthio)-4,5,5a,6,9,10-hexahydro-8H-7-oxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptanronne (80.0 mg, 0.106 mmol, 76% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ = 8.12 - 8.05 (m, 1H), 7.74- 7.70 (m, 1H), 7.59 - 7.51 (m, 1H), 7.47 - 7.22 (m, 1H), 5.40 - 5.31 (m,2H), 4.45 - 4.28 (m, 1H), 3.92 - 3.79 (m, 4H), 3.68 - 3.61 (m, 1H), 3.61 -3.52 (m, 2H), 3.43 (s, 3H), 3.12 - 3.04 (m, 1H), 3.03 - 2.92 (m, 2H), 2.29 -2.07 (m, 3H), 2.04 - 1.79 (m, 3H), 0.85 - 0.77 (m, 18H); LCMS: (M+1:705.3).

[0753] Step 5. Add m-CPBA (57.6 mg, 0.283 mmol, 85% purity, 2.5 equivalents) to a solution of 1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthyl-1-yl)-12-(methylthio)-4,5,5a,6,9,10-hexahydro-8H-7-oxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptanronne (80.0 mg, 0.113 mmol, 1 equivalent) in DCM (1 mL). Stir the mixture at 25 °C for 1 hour. After completion, quench the reaction mixture at 0 °C with saturated Na₂S₂O₃ (1.5 mL), then dilute with saturated NaHCO₃ (5 mL) and extract with DCM (10 mL × 3). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give 1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-12-(methanesulfonyl)-4,5,5a,6,9,10-hexahydro-8H-7-oxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptanronne (83.0 mg, 0.112 mmol, 99% yield) as a white solid. LCMS: (M+1:737.3).

[0754] Step 6. At 0°C, after 30 minutes, t-BuOK (37.9 mg, 0.337 mmol, 3 equivalents) was added to a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (53.7 mg, 0.337 mmol, 3 equivalents) in toluene (2 mL), and then 1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-12-(methanesulfonyl)-4,5,5a,6,9,10-hexahydro-8H-7-oxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptanronne (83.0 mg, 0.112 mmol, 1 equivalent) was added. The mixture was stirred at 0°C for 1 hour. After completion, the reaction mixture was diluted with water (10 mL) and extracted with EA (5 mL × 3). The combined organic layers were washed with brine (5 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give the residue. The residue was purified by preparative TLC (SiO2, DCM: MeOH = 10:1) to give 1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4,5,5a,6,9,10-hexahydro-8H-7-oxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptanronne (30.0 mg, 0.03-3.0 mmol, 30% yield) as a white solid. LCMS: (M+1:816.4).

[0755] Step 7. Add HCl / dioxane (2 M, 0.5 mL, 27 equivalents) to a solution of 1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4,5,5a,6,9,10-hexahydro-8H-7-oxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptanronne (30.0 mg, 0.037 mmol, 1 equivalent) in DCM (0.5 mL). Stir the mixture at 25 °C for 1 hour. After completion, the mixture was concentrated under vacuum to give 6-fluoro-4-(1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4,5,5a,6,9,10-hexahydro-8H-7-oxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptan-2-yl)-5-((triisopropylsilyl)ethynyl)naphth-2-ol (28.0 mg, 0.036 mmol, 98% yield) as a white solid. LCMS: (M+1:772.3).

[0756] Step 8. Add CsF (25.9 mg, 0.170 mmol, 6 equivalents) to a solution of 6-fluoro-4-(1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4,5,5a,6,9,10-hexahydro-8H-7-oxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptanronen-2-yl)-5-((triisopropylsilyl)ethynyl)naphth-2-ol (22.0 mg, 0.028 mmol, 1 equivalent) in DMSO (2 mL). Stir the mixture at 25 °C for 16 hours. After completion, the mixture was filtered, and the filtrate was purified by preparative HPLC followed by SFC separation to provide two crude products, which were further purified by preparative HPLC to give 5-ethynyl-6-fluoro-4-[(8aR)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl]methoxy}-7,8,8a,9,12,13-hexahydro-11H-10-oxa-1,3,6,13a-tetraazanaphtho[1,8-ab]heptanronen-5-yl]naphth-2-ol (2.57 mg, 0.0039 mmol, 19.9% ​​yield, FA salt) as a yellow solid. (Example 1) and 5-ethynyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl]methoxy}-7,8,8a,9,12,13-hexahydro-11H-10-oxa-1,3,6,13a-tetraazanaphtho[1,8-ab]heptanronen-5-yl]naphth-2-ol (3.14 mg, 0.0048 mmol, 24.4% yield, FA salt) (Example 2). Analytical data for Examples 1 and 2 can be found in the table below.

[0757] 5-Ethyl-6-fluoro-4-[(8aR)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl]methoxy}-7,8,8a,9,12,13-hexahydro-11H-10-oxa-1,3,6,13a-tetraazanaphtho[1,8-ab]heptanronen-5-yl]naphth-2-ol (Example 3) and 5 Preparation of ethyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl]methoxy}-7,8,8a,9,12,13-hexahydro-11H-10-oxa-1,3,6,13a-tetraazanaphtho[1,8-ab]heptanronen-5-yl]naphth-2-ol (Example 4):

[0758]

[0759] Step 1. Dissolve 2-chloro-1-fluoro-12-(methylthio)-4,5,5a,6,9,10-hexahydro-8H-7-oxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptanronene (prepared according to the method described in General Method A) (160 mg, 0.451 mmol, 1 equivalent), 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane (211 mg, 0.586 mmol, 1.3 equivalent), Cs₂CO₃ (441 mg, 1.35 mmol, 3 equivalent), Pd(dtbpf)Cl₂ (29.4 mg, 0.045 mmol, 0.1 equivalent) in dioxane (2 mL) and H₂O (0.4 mL). The mixture in mL was degassed and purged three times with N2, and then stirred at 80 °C for 1 hour under N2 atmosphere. After completion, the mixture was concentrated to obtain a residue. The residue was purified by column chromatography (SiO2, PE / THF = 1:0 to 2:1) to give 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-1-fluoro-12-(methylthio)-4,5,5a,6,9,10-hexahydro-8H-7-oxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptanronne (190 mg, 0.344 mmol, 76% yield) as a white solid. LCMS: (M+1:553.2).

[0760] Step 2. At 0 °C, m-CPBA (156 mg, 0.769 mmol, 85% purity, 2.5 equivalents) was added to a solution of 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-1-fluoro-12-(methylthio)-4,5,5a,6,9,10-hexahydro-8H-7-oxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptanronne (170 mg, 0.308 mmol, 1 equivalent) in DCM (2 mL). The mixture was stirred at 25 °C for 1 hour. The mixture was quenched with saturated Na2SO3 (5 mL) and extracted with DCM (5 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, PE / THF = 1:0 to 1:1) to give 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-1-fluoro-12-(methanesulfonyl)-4,5,5a,6,9,10-hexahydro-8H-7-oxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptanronne (136 mg, 0.233 mmol, 76% yield) as a white solid. LCMS: (M+1:585.2).

[0761] Step 3. Add NaH (11.8 mg, 0.295 mmol, 60% purity, 1.5 equivalents) to a mixture of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (34.5 mg, 0.216 mmol, 1.1 equivalents) in THF (2 mL) and stir the mixture at 0 °C for 0.5 h. Then add THF (2 mL) containing 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthyl-1-yl)-1-fluoro-12-(methanesulfonyl)-4,5,5a,6,9,10-hexahydro-8H-7-oxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptanronne (115 mg, 0.197 mmol, 1 equivalent). Stir the resulting mixture at 25 °C for 1 h. After completion, the mixture was quenched with saturated NH4Cl (5 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, PE / THF = 1:0 to 1:3) to give 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4,5,5a,6,9,10-hexahydro-8H-7-oxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptanronne (90.0 mg, 0.136 mmol, 69% yield). LCMS: (M+1:664.3).

[0762] Step 4. HCl / dioxane (2 M, 0.301 mL, 5 equivalents) was added to a solution of 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphth-1-yl)-1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-4,5,5a,6,9,10-hexahydro-8H-7-oxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptanronne (80.0 mg, 0.120 mmol, 1 equivalent) in DCM (1 mL). The mixture was stirred at 25 °C for 1 hour. After completion, the mixture was concentrated to obtain a residue. The residue was purified by preparative HPLC to give a mixture of diastereomers as a white solid (50 mg, 0.081 mmol, 66.9% yield). The mixture was separated by SFC to obtain two crude products, which were further purified by preparative HPLC to give 5-ethyl-6-fluoro-4-[(8aR)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl]methoxy}-7,8,8a,9,12,13-hexahydro-11H-10-oxa-1,3,6,13a-tetraazanaphtho[1,8-ab]heptanronen-5-yl]naphth-2-ol as a white solid (3.95 mg, 0.0064 mmol, 6.58% yield). (Example 3) and 5-ethyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl]methoxy}-7,8,8a,9,12,13-hexahydro-11H-10-oxa-1,3,6,13a-tetraazanaphtho[1,8-ab]heptanronen-5-yl]naphth-2-ol (5.79 mg, 0.0093 mmol, 9.65% yield) as a white solid (Example 4). Analytical data for Examples 3 and 4 can be found in the table below.

[0763] 5-Ethynyl-6-fluoro-4-[(8aR)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl]methoxy}-8,8a,9,10,12,13-hexahydro-7H-11-oxa-1,3,6,13a-tetraazanaphtho[1,8-ab]heptanronen-5-yl]naphth-2-ol (Example 5) and 5- Preparation of ethynyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl]methoxy}-8,8a,9,10,12,13-hexahydro-7H-11-oxa-1,3,6,13a-tetraazanaphtho[1,8-ab]heptanronen-5-yl]naphth-2-ol (Example 25):

[0764]

[0765] I-5-2 was prepared using intermediate I-2-2 according to the procedure described in steps 1-3 for general method A.

[0766] Step 1. Dissolve 2-chloro-1-fluoro-12-(methylthio)-5,5a,6,7,9,10-hexahydro-4H-8-oxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptanronene (I-5-5, 54.0 mg, 0.152 mmol, 1 equivalent), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)naphth-1-yl)ethynyl)triisopropylsilane (85.8 mg, 0.167 mmol, 1.1 equivalent), cataCXium A Pd G3 (11.0 mg, 0.015 mmol, 0.1 equivalent), and K3PO4 (96.9 mg, 0.456 mmol, 3 equivalent) in THF (3 The mixture in 0.3 mL of H2O and 0.3 mL of water was degassed and purged three times with N2, and then stirred at 80 °C for 2 hours under N2 atmosphere. After completion, the mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1:0 to 0:1) to give 1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthyl-1-yl)-12-(methylthio)-5,5a,6,7,9,10-hexahydro-4H-8-oxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptanronne (94.0 mg, 0.133 mmol, 87% yield) as a yellow solid. LCMS: (M+1: 705.3).

[0767] Step 2. Add m-CPBA (115 mg, 0.400 mmol, 60% purity, 3 equivalents) to a solution of 1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthyl-1-yl)-12-(methylthio)-5,5a,6,7,9,10-hexahydro-4H-8-oxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptanronne (94.0 mg, 0.133 mmol, 1 equivalent) in DCM (3 mL). Stir the mixture at 25 °C for 1 hour. After completion, the mixture was quenched with saturated Na₂SO₃ solution (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give 1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-12-(methanesulfonyl)-5,5a,6,7,9,10-hexahydro-4H-8-oxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptanronne (98.0 mg, 0.132 mmol, 99% yield) as a yellow solid. LCMS: (M+1: 737.3).

[0768] Step 3. Add NaH (47.8 mg, 1.20 mmol, 60% purity, 9 equivalents) and 1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-12-(methanesulfonyl)-5,5a,6,7,9,10-hexahydro-4H-8-oxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptanronne (98.0 mg, 0.133 mmol, 1 equivalent) to a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methanol (63.5 mg, 0.398 mmol, 3 equivalents) in THF (3 mL). Stir the mixture at 0 °C for 1 hour. After completion, the mixture was quenched with water (1 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1:0 to 0:1) to give 1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,5a,6,7,9,10-hexahydro-4H-8-oxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptanronne (105 mg, 0.128 mmol, 96% yield). LCMS: (M+1:816.4).

[0769] Step 4. Add HCl / EtOAc (2 M, 0.5 mL) to a solution of 1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,5a,6,7,9,10-hexahydro-4H-8-oxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptanronne (105 mg, 0.128 mmol, 1 equivalent) in DCM (3 mL). Stir the mixture at 25 °C for 1 hour. After completion, the mixture was filtered and concentrated to give 6-fluoro-4-(1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,5a,6,7,9,10-hexahydro-4H-8-oxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptan-2-yl)-5-((triisopropylsilyl)ethynyl)naphth-2-ol (99.0 mg, 0.128 mmol, 99% yield) as a yellow solid.

[0770] Step 5. Add CsF (97.4 mg, 0.641 mmol, 5 equivalents) to a solution of 6-fluoro-4-(1-fluoro-12-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,5a,6,7,9,10-hexahydro-4H-8-oxa-3,10a,11,13-tetraazanaphtho[1,8-ab]heptanronen-2-yl)-5-((triisopropylsilyl)ethynyl)naphth-2-ol (99.0 mg, 0.128 mmol, 1 equivalent) in DMSO (1 mL). Stir the mixture at 25 °C for 1 hour. After completion, filter and concentrate the mixture to obtain the residue. The residue was purified by preparative HPLC to give 5-ethynyl-6-fluoro-4-(4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl]methoxy}-8,8a,9,10,12,13-hexahydro-7H-11-oxa-1,3,6,13a-tetraazanaphtho[1,8-ab]heptanen-5-yl)naphth-2-ol (40.0 mg, 0.059 mmol, 46.20% yield, FA salt) as a white solid. The mixture of diastereomers was purified by SFC to give 5-ethynyl-6-fluoro-4-[(8aR)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl]methoxy}-8,8a,9,10,12,13-hexahydro-7H-11-oxa-1,3,6,13a-tetraazanaphtho[1,8-ab]heptanronen-5-yl]naphth-2-ol as a white solid (15.4 mg, 0.0246 mmol, 43.34% yield). (Example 5) and 5-ethynyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl]methoxy}-8,8a,9,10,12,13-hexahydro-7H-11-oxa-1,3,6,13a-tetraazanaphtho[1,8-ab]heptanronen-5-yl]naphth-2-ol (14.9 mg, 0.0235 mmol, 41.49% yield) as a yellow solid (Example 25). Analytical data for Examples 5 and 25 can be found in the table below.

[0771] Using intermediate I-6-2 from step 1, Examples 6 and 26 were prepared according to the method used to prepare Example 5.

[0772] Example 9 was prepared using intermediate I-2-3 from step 1, following general method A.

[0773] Example 10 was prepared using intermediate I-2-4 from step 1 and XPhos Pd G4 from step 4 as a catalyst, according to general method A.

[0774] Example 13 was prepared using intermediate I-2-5 from step 1, following general method A.

[0775] Example 18 was prepared using intermediate I-2-6 from step 1 and Ad2nBuP-Pd-G3 / K3PO4 / dioxane from step 4, following general method A.

[0776] Examples 20 and 27 were prepared using intermediate I-2-7 from step 1 and Ad2nBuP-Pd-G3 / K3PO4 / THF from step 4, according to general method A.

[0777] General Method B

[0778] Preparation of 5-ethynyl-6-fluoro-4-(4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl]methoxy}-9,10,11,12-tetrahydro-8aH-1,3,6,12a-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphth-5-yl)naphth-2-ol (Example 21):

[0779]

[0780] Step 1. At 0 °C, DIPEA (3.44 g, 26.6 mmol, 4.63 mL) was slowly added to a solution of 4,5,7-trichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidine (2.27 g, 7.60 mmol) and 1-(piperidin-2-yl)ethyl-1-one (1.49 g, 9.12 mmol, HCl salt) in DCM (33.4 mL). The mixture was slowly heated to ambient temperature over 1.5 h, followed by stirring for another 2.5 h. The reaction was then quenched with saturated NaHCO3 solution (50 mL). The mixture was extracted with DCM (3 × 50 mL), and the combined extracts were dried over Na2SO4 and then concentrated under reduced pressure. Rapid chromatography (0–20% ethyl acetate / hexane) yielded 1-(1-(5,7-dichloro-8-fluoro-2-(methylthio)pyrido[4,3-d]pyrimidin-4-yl)piperidin-2-yl)ethyl-1-one (2.60 g, 6.67 mmol, 88% yield). LCMS: m / z 389.1 (M+1).

[0781] Step 2. At -23°C, after 100 minutes, 1-(1-(5,7-dichloro-8-fluoro-2-(methylthio)pyridino[4,3-d]pyrimidin-4-yl)piperidin-2-yl)ethyl-1-one (1.85 g, 4.75 mmol) in THF (10 mL) was added dropwise to a solution of LiHMDS (1 M, 12.4 mL) in THF (55.5 mL) using a syringe pump. The reaction mixture was stirred at -23°C for another 20 minutes, and then quenched by adding saturated NH4Cl (25 mL) solution. The reaction mixture was heated to ambient temperature and extracted with ethyl acetate (3 × 20 mL). The combined extracts were dried over brine (25 mL), then dried over Na2SO4 and concentrated under reduced pressure. Rapid chromatography (10-20% ethyl acetate / hexane) yielded 2-chloro-1-fluoro-11-(methylthio)-6,7,8,9-tetrahydro-4H-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthyl-5(5aH)-one as an orange solid (564 mg, 1.60 mmol, 34% yield). LCMS: m / z 353.1 (M+1).

[0782] Step 3. At 0 °C, LiBH4 (2 M, 1.80 mL) was added to a solution of 2-chloro-1-fluoro-11-(methylthio)-6,7,8,9-tetrahydro-4H-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphth-5(5aH)-one (564 mg, 1.60 mmol) in THF (8.86 mL). The mixture was stirred at 0 °C for 45 min, and then quenched by adding saturated NH4Cl solution (25 mL). The mixture was heated to ambient temperature and then extracted with ethyl acetate (3 × 15 mL), and the combined extracts were dried over Na2SO4 and concentrated under reduced pressure. The solid was ground with DCM, and the supernatant was purified by rapid chromatography (15-25% ethyl acetate / hexane) to provide 2-chloro-1-fluoro-11-(methylthio)-5,5a,6,7,8,9-hexahydro-4H-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthyl-5-ol (490.6 mg, 1.38 mmol, 86% yield) as a white crystalline solid (a mixture of cis and trans isomers). LCMS: m / z 355.2 (M+1); 1H NMR(499 MHz, DMSO-d6 ) δ ppm 5.65 (d, J=4.38 Hz, 1 H) 5.42 (d, J=5.48 Hz, 1 H)4.32 (td, J=8.76, 5.48 Hz, 1 H) 3.99 - 4.18 (m, 2 H) 3.85 - 3.93 (m, 1 H)3.65 (ddd, J=12.87, 8.49, 3.83 Hz, 1 H) 3.47 (dt, J=9.99, 4.04 Hz, 1 H) 3.17- 3.29 (m, 2 H) 3.08 (dd, J=14.24, 4.93 Hz, 1 H) 2.99 - 3.06 (m, 1 H) 2.54(s, 3 H) 2.53 (s, 1 H) 1.87 - 1.96 (m, 1 H) 1.72 - 1.87 (m, 4 H) 1.49 - 1.72(m, 3 H) 1.42 (ddt, J=12.59, 8.35, 4.31, 4.31 Hz, 1 H)。

[0783] Step 4. Add Pd(dtbpf)Cl2 (16 mg, 0.025 mmol) to a solution of 2-chloro-1-fluoro-11-(methylthio)-5,5a,6,7,8,9-hexahydro-4H-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphth-5-ol (88.42 mg, 0.249 mmol), ((2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)naphth-1-yl)ethynyl)triisopropylsilane (159.7 mg, 0.311 mmol), and K2CO3 (206.6 mg, 1.50 mmol) degassed with argon in dioxane (1.03 mL) and water (0.212 mL). The mixture was heated to 105 °C for 15 hours. The reaction was treated by cooling and dilution with DCM (15 mL) and water (15 mL). The mixture was extracted with DCM (3 × 15 mL). The combined extracts were dried over Na2SO4 and then concentrated under reduced pressure. The crude material was purified by rapid chromatography (0-50% ethyl acetate / dichloromethane) to give 1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-11-(methylthio)-5,5a,6,7,8,9-hexahydro-4H-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphth-5-ol (46.48 mg, 0.066 mmol, 26% yield). LCMS: m / z 705.1 (M+1).

[0784] Step 5. At 0°C, add m-CPBA (57 mg, 0.33 mmol) to a solution of 1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthyl-1-yl)-11-(methylthio)-5,5a,6,7,8,9-hexahydro-4H-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphth-5-ol (46.48 mg, 0.066 mmol) in DCM (0.5 mL). The reaction mixture was stirred at 0 °C for 5 hours and then purified by rapid chromatography (automated system, 12 g silica, 0-100% ethyl acetate / DCM) to give 1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-11-(methanesulfonyl)-5,5a,6,7,8,9-hexahydro-4H-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphth-5-ol (32.30 mg, 0.044 mmol, 66% yield) as a pale yellow glassy solid. LCMS: m / z 737.4 (M+1).

[0785] Step 6. At 0°C, potassium tert-butoxide (1 M, 0.18 mL) was added to a solution of ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methanol (28 mg, 0.175 mmol) in toluene (0.4 mL). The mixture was stirred at 0°C for 10 minutes, and then a solution of 1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-11-(methanesulfonyl)-5,5a,6,7,8,9-hexahydro-4H-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphth-5-ol (32.30 mg, 0.044 mmol) in toluene (0.25 mL). The mixture was stirred at 0°C for 1.5 hours. The mixture was then quenched by adding saturated NH4Cl solution (5 mL). The mixture was extracted with ethyl acetate (3 × 5 mL). The combined extracts were dried over Na2SO4 and then concentrated under reduced pressure. The material was purified by rapid chromatography (DCM + TEA (0.1 mL), (1.25–10% methanol / dichloromethane)) to give 1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,8,9-tetrahydro-7H-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene (3.35 mg, 0.004 mmol, 9.6% yield) as a glassy solid; LCMS: m / z 798.5 (M+1) and 1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,5a,6,7,8,9-hexahydro-4H-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphth-5-ol (12.42 mg, 0.015 mmol, 35% yield), as a white solid. LCMS: m / z 816.5 (M+1).

[0786] Step 7. At 0°C, add dioxane containing HCl (4 M, 0.2 mL) to a solution of 1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,8,9-tetrahydro-7H-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene (3.35 mg, 0.004 mmol) in DCM (1 mL). Stir the mixture at 0°C for 45 minutes. The mixture was concentrated under reduced pressure to give 6-fluoro-4-(1-fluoro-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,8,9-tetrahydro-7H-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphth-2-yl)-5-((triisopropylsilyl)ethynyl)naphth-2-ol (3.16 mg, 0.004 mmol, assumed quantification). LCMS: m / z 754.6 (M+1).

[0787] Then, CsF (9.6 mg, 0.063 mmol) was added to a solution of 6-fluoro-4-(1-fluoro-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5a,6,8,9-tetrahydro-7H-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphth-2-yl)-5-((triisopropylsilyl)ethynyl)naphth-2-ol (3.16 mg, 0.004 mmol) in DMSO (0.5 mL). The mixture was stirred at ambient temperature for 1 hour. The mixture was then diluted with ethyl acetate (15 mL), filtered through a syringe filter, washed with 10% saline (5 mL), and then concentrated under reduced pressure. 5-ethynyl-6-fluoro-4-(4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl]methoxy}-9,10,11,12-tetrahydro-8aH-1,3,6,12a-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphth-5-yl)naphth-2-ol (1.72 mg, 0.0024 mmol, 57% yield) as a TFA salt was obtained by HPLC purification (Example 21). Analytical data for Example 21 can be found in the table below.

[0788] Example 22 was prepared using intermediate I-2-8 from step 1, following general method A.

[0789] Preparation of 5-ethyl-6-fluoro-4-(4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl]methoxy}-7,8,8a,9,10,11,12,13-octahydro-1,3,6,13a-tetraazanaphtho[1,8-ab]heptanen-5-yl)naphth-2-ol (Example 23):

[0790]

[0791] Under argon atmosphere, Pd / C (26.0 mg, 0.024 mmol, 10% purity, 0.5 equivalents) was moistened with MeOH (1 mL). Then, a solution of 5-ethynyl-6-fluoro-4-(4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl]methoxy}-7,8,8a,9,10,11,12,13-octahydro-1,3,6,13a-tetraazanaphtho[1,8-ab]heptanronen-5-yl)naphth-2-ol (30.0 mg, 0.049 mmol, 1 equivalent) in MeOH (1 mL) was added. The suspension was degassed under vacuum and purged three times with H2 (15 Psi). The mixture was stirred under H2 (15 Psi) at 25 °C for 1 hour. After completion, the reaction solution was filtered to remove Pd / C. The residue was purified by preparative HPLC (min) to give 5-ethyl-6-fluoro-4-(4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl]methoxy}-7,8,8a,9,10,11,12,13-octahydro-1,3,6,13a-tetraazanaphtho[1,8-ab]heptanen-5-yl)naphth-2-ol as a grayish-white solid (9.62 mg, 0.015 mmol, 30.85% yield). Analytical data for Example 23 can be found in the table below.

[0792] Example 24 was prepared using intermediate I-2-7 from step 1 and intermediate I-9-2 from step 6, according to general method A.

[0793] 5-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7H-1,3,6,12a-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthyl-8-carboxynitrile (Example 28) and 5 Preparation of -(8-vinyl-7-fluoro-3-hydroxynaphth-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7H-1,3,6,12a-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthalene-8-carboxynitrile (Example 32):

[0794]

[0795] Step 1. At 0 °C, methanesulfonyl chloride (26 mg, 0.228 mmol, 0.018 mL) was added dropwise to a solution of 1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,5a,6,7,8,9-hexahydro-4H-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphth-5-ol (the preparation of which is described in Example 21) (37.19 mg, 0.045 mmol) and triethylamine (46.2 mg, 0.456 mmol, 0.064 mL) in THF (0.5 mL). The reaction mixture was stirred for 15 minutes and then quenched with water (3 mL). The mixture was extracted with DCM (3 × 5 mL). The combined extracts were dried over Na2SO4 and concentrated under reduced pressure. The material was purified by rapid chromatography (DCM + TEA (0.1 mL), 0-10% methanol / dichloromethane) to give 1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,5a,6,7,8,9-hexahydro-4H-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphth-5-ylmethanesulfonate (35.19 mg, 0.039 mmol, 86% yield) as a white solid. LCMS: m / z 894.6 (M+1).

[0796] Step 2. Add NaCN (96 mg, 1.97 mmol) to a solution of 1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,5a,6,7,8,9-hexahydro-4H-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphth-5-ylmethanesulfonate (35.19 mg, 0.039 mmol) in DMSO (0.5 mL). Heat the mixture to 40 °C and stir for 50 hours. Dilute the reaction solution with ethyl acetate (30 mL) and wash with water (20 mL) and 30% brine (20 mL). Dry the organic layer with Na2SO4 and concentrate under reduced pressure. Rapid chromatography (0.1 mL TEA loaded), (0-10% methanol / dichloromethane) yielded 1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,5a,6,7,8,9-hexahydro-4H-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthyl-5-carboxynitrile (30.15 mg, 0.036 mmol, 92% yield, product contamination eliminated). LCMS: m / z 825.6 (M+1).

[0797] Step 3. At 0°C, add dioxane containing HCl (4 M, 0.5 mL) to a solution of 1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,5a,6,7,8,9-hexahydro-4H-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthyl-5-carboxynitrile (30.15 mg, 0.036 mmol) in DCM (2 mL). Stir the mixture at 0°C for 1.5 hours. The mixture was concentrated under reduced pressure to give 1-fluoro-2-(7-fluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,5a,6,7,8,9-hexahydro-4H-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthyl-5-carboxynitrile (28.54 mg, 0.036 mmol, assumed quantification). LCMS: m / z 781.4 (M+1).

[0798] Then, CsF (139 mg, 0.915 mmol) was added to a solution of 1-fluoro-2-(7-fluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,5a,6,7,8,9-hexahydro-4H-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthyl-5-carboxynitrile (28.54 mg, 0.036 mmol) in DMSO (1 mL). The mixture was stirred at ambient temperature for 10 minutes. The mixture was diluted with ethyl acetate (25 mL), filtered, washed with 10% brine (15 mL), 50% brine (15 mL), dried over Na2SO4, and then concentrated under reduced pressure. 5-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7H-1,3,6,12a-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthyl-8-carboxynitrile (10.82 mg, 0.003 mmol, 7.7% yield), as a TFA salt, was obtained by HPLC purification (Example 28). Analytical data for Example 28 can be found in the table below.

[0799] Step 4. Add Pd / C (7.2 mg, 0.007 mmol, 10% purity) to a solution of 5-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7H-1,3,6,12a-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthyl-8-carboxynitrile (10 mg, 0.0013 mmol) as a TFA salt in methanol (4 mL) and DMSO (1.5 mL). Remove air from the mixture and place it under H2 (1 atm). Stir the mixture for 2 hours, then filter and concentrate under reduced pressure. HPLC yielded 5-(8-vinyl-7-fluoro-3-hydroxynaphth-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7H-1,3,6,12a-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphthyl-8-carboxynitrile (3.40 mg, 0.004 mmol, 34% yield, TFA salt) as a pale yellow solid (Example 32). Analytical data for Example 32 can be found in the table below.

[0800] Preparation of 5-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7H-1,3,6,12a-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphth-8-ol (Example 29):

[0801]

[0802] Step 1. At 0 °C, dioxane containing HCl (4 M, 0.250 mL) was added to a solution of 1-fluoro-2-(7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,5a,6,7,8,9-hexahydro-4H-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphth-5-ol (the preparation of which is described in Example 21) (12.42 mg, 0.015 mmol) in DCM (1 mL). The mixture was stirred at 0 °C for 1.25 h. The mixture was then concentrated under reduced pressure to give 1-fluoro-2-(7-fluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,5a,6,7,8,9-hexahydro-4H-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphth-5-ol (11.75 mg, 0.015 mmol, assumed quantification). LCMS: m / z 772.5 (M+1).

[0803] Then, CsF (35 mg, 0.228 mmol) was added to a solution of 1-fluoro-2-(7-fluoro-3-hydroxy-8-((triisopropylsilyl)ethynyl)naphth-1-yl)-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-5,5a,6,7,8,9-hexahydro-4H-3,9a,10,12-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphth-5-ol (11.75 mg, 0.015 mmol) in DMSO (0.5 mL). The mixture was stirred at ambient temperature for 10 minutes. The mixture was diluted with ethyl acetate (15 mL), filtered through a syringe filter, washed with 10% brine (5 mL), dried over Na2SO4, and then concentrated under reduced pressure. 5-(8-ethynyl-7-fluoro-3-hydroxynaphth-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7H-1,3,6,12a-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphth-8-ol (9.48 mg, 0.013 mmol, 85% yield) as a TFA salt was obtained by HPLC purification. Analytical data for Example 29 can be found in the table below.

[0804] Preparation of 5-ethynyl-6-fluoro-4-(4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl]methoxy}-7-methyl-8,9,10,11-tetrahydropyrido[1,2-g]pyrimido[4,5,6-de][1,6]naphthid-5-yl)naphth-2-ol (Example 30):

[0805]

[0806] Step 1. At 0 °C, KHMDS (1 M, 14.0 mL, 3 equivalents) was added to a solution of methyl(triphenyl)phosphonium bromide (5.02 g, 14.0 mmol, 3 equivalents) in THF (10 mL). The mixture was stirred at 25 °C for 0.5 h, and then a solution of 2-formylpiperidin-1-carboxylic acid tert-butyl ester (1.00 g, 4.69 mmol, 1 equivalent) in THF (5 mL) was added at -78 °C, and the mixture was stirred at 25 °C for 1.5 h. After completion, the mixture was quenched with water (50 mL) and extracted with ethyl acetate (40 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1:0 to 3:1) to give tert-butyl 2-vinylpiperidine-1-carboxylate (780 mg, 3.69 mmol, 79% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ= 5.87 - 5.68 (m, 1H), 5.24 - 5.12 (m, 1H), 5.07 - 4.99 (m, 1H), 4.88 - 4.67(m, 1H), 4.05 - 3.88 (m, 1H), 2.92 - 2.75 (m, 1H), 1.81 - 1.55 (m, 6H), 1.46 (s, 9H).

[0807] Step 2. Add HCl / EtOAc (4 M, 1 mL, 1.69 equivalents) to a solution of tert-butyl 2-vinylpiperidine-1-carboxylate (500 mg, 2.37 mmol, 1 equivalent) in DCM (5 mL). Stir the mixture at 25 °C for 1 hour. After completion, concentrate the mixture to give 2-vinylpiperidine (260 mg, crude product) as a yellow oil.

[0808] Step 3. Add DIEA (871 mg, 6.75 mmol, 1.17 mL, 3 equivalents) to a solution of 2-vinylpiperidine (250 mg, 2.25 mmol, 1 equivalent) in DCM (4 mL). Stir the mixture at 25 °C for 1 hour. Dilute the mixture with water (50 mL) and extract with ethyl acetate (40 mL × 3). Wash the combined organic phases with water (50 mL × 2) and dry over Na2SO4, filter, and concentrate the filtrate to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1:0 to 80:20) to give 5,7-dichloro-8-fluoro-2-(methylthio)-4-(2-vinylpiperidin-1-yl)pyrido[4,3-d]pyrimidine (550 mg, 1.47 mmol, 66% yield) as a yellow oil. LCMS: (M+1:373.1).

[0809] Step 4. A mixture of 5,7-dichloro-8-fluoro-2-(methylthio)-4-(2-vinylpiperidin-1-yl)pyrido[4,3-d]pyrimidine (400 mg, 1.07 mmol, 1 equivalent), TBAC (297 mg, 1.07 mmol, 1 equivalent), Pd(OAc)2 (48.1 mg, 0.214 mmol, 0.2 equivalent), and NaHCO3 (225 mg, 2.68 mmol, 2.5 equivalent) in DMF (4 mL) was degassed and purged three times with N2. The mixture was then stirred at 80 °C for 2 hours under N2 atmosphere. After completion, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with water (50 mL × 2) and dried over Na2SO4, filtered, and the filtrate was concentrated to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1:0 to 5:1) to give 5-chloro-4-fluoro-7-methyl-2-(methylthio)-8,9,10,11-tetrahydropyrido[1,2-g]pyrimido[4,5,6-de][1,6]naphthidine as a black solid (100 mg, 0.296 mmol, 28% yield). LCMS: (M+1:337.0).

[0810] Example 30 was synthesized using the above intermediate (5-chloro-4-fluoro-7-methyl-2-(methylthio)-8,9,10,11-tetrahydropyrido[1,2-g]pyrimidino[4,5,6-de][1,6]naphthidine) according to steps 4 to 7 of General Method B.

[0811] Preparation of 5-ethyl-6-fluoro-4-(4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl]methoxy}-9,10,11,12-tetrahydro-8aH-1,3,6,12a-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphth-5-yl)naphth-2-ol (Example 31):

[0812]

[0813] Pd / C (2.8 mg, 0.0028 mmol, 10% purity) was added to a solution of 5-ethynyl-6-fluoro-4-(4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl]methoxy}-9,10,11,12-tetrahydro-8aH-1,3,6,12a-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphth-5-yl)naphth-2-ol (Example 21, 1.90 mg, 0.0027 mmol) in ethanol (1.5 mL). Air was removed from the mixture, and it was placed under H2 (1 atm). The mixture was stirred for 2 hours, then filtered and concentrated under reduced pressure. HPLC yielded 5-ethyl-6-fluoro-4-(4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl]methoxy}-9,10,11,12-tetrahydro-8aH-1,3,6,12a-tetraazabenzo[4,5]cycloheptane[1,2,3-de]naphth-5-yl)naphth-2-ol (0.79 mg, 0.001 mmol, 39% yield, TFA salt) as a pale yellow solid (Example 31). Analytical data for Example 31 can be found in the table below.

[0814] Perform the following examples according to general method A or B as indicated in the table:

[0815]

[0816]

[0817]

[0818]

[0819]

[0820]

[0821]

[0822] Screening assay

[0823] Cell proliferation assay:

[0824] 2000 KRAS mutant cells / well were seeded in 384-well white plates and treated with the specified compound at 37°C and 5% CO2 for 72 h. Cell proliferation was measured using a CellTiter-Glo 2.0 luciferase-based ATP assay (Promega, Madison, WI) according to the manufacturer's protocol. IC50 was determined using Prism software (GraphPad Software, San Diego, CA). 50 value.

[0825]

[0826]

Claims

1. A salt that accepts a compound of formula I, I in X is -O-, -S-, or -NR 4 -; Y is a bond, -O-, -S-, -S(O)- or -S(O)2-; Z 1 Is it N or C(R)? 5 ); Z 2 Is it N or C(R)? 6 ); Z 3 Is it N or C(R)? 7 ); Z 4 Is it N or C(R)? 8 ); The condition is Z 1 -Z 4 At least two of them are N; Ring A is C6-C 10 Aryl, 5- to 10-membered heteroaryl or 4- to 10-membered heterocyclic alkyl; Ring B is a 4- to 9-membered heterocyclic alkyl group; Each R 1 Independently, it is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OC(=NR) a )NR a R b -OS(O)R a -OS(O)2R a -OS(O)NR a R b -OS(O)2NR a R b -SR a -S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR a R b -NR a R b -NR a C(O)R b -N(C(O)R a )(C(O)R b -NR a C(O)OR b -NR a C(O)NR a R b -NR a C(=NR a )NR a R b -NR a S(O)R b -NR a S(O)2R b -NR a S(O)NR a R b -NR a S(O)2NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -C(=NR) a )NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN or -NO2; or two Rs 1 Together with one or more atoms to which it is attached, it forms a C3-C6 cycloalkyl or a 4- to 10-membered heterocyclic alkyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclic alkyl groups is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -R e -R f -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2; or R 1 R on the adjacent carbon of ring B 9 or R 10 Together with the carbon atoms it is attached to, they combine to form a carbon-carbon double bond; Each R 2 Independently, it is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR c -OC(O)R c -OC(O)NR c R d -OC(=NR) c )NR c R d -OS(O)R c -OS(O)2R c -OS(O)NR c R d -OS(O)2NR c R d -SR c -S(O)R c -S(O)2R c -S(O)NR c R d -S(O)2NR c R d -NR c R d -NR c C(O)R d -N(C(O)R c )(C(O)R d -NR c C(O)OR d -NR c C(O)NR c R d -NR c C(=NR c )NR c R d -NR c S(O)R d -NR c S(O)2R d -NR c S(O)NR c R d -NR c S(O)2NR c R d -C(O)R c -C(O)OR c -C(O)NR c R d -C(=NR) c )NR c R d -PR c R d -P(O)R c R d -P(O)2R c R d -P(O)NR c R d -P(O)2NR c R d -P(O)OR c -P(O)2OR c -CN or -NO2, or two Rs 2 Together with the atoms to which they are attached, they form C3-C6 cycloalkyl or 4- to 10-membered heterocyclic alkyl groups, including C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, and C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclic alkyl groups is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -R e -R f -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f 、 -NR e S(O)2NR e R f 、 -C(O)R e 、 -C(O)OR e 、 -C(O)NR e R f 、 -PR e R f 、 -P(O)R e R f 、 -P(O)2R e R f 、 -P(O)NR e R f 、 -P(O)2NR e R f 、 -P(O)OR e 、 -P(O)2OR e 、 -CN or -NO2; R 3 It is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, -C1-C6 alkylene- (4- to 10-membered heterocyclic alkyl), C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 Aryl), 5- to 10-membered heteroaryl or -C1-C6 alkylene- (4- to 10-membered heterocyclic alkyl), wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, -C1-C6 alkylene- (4- to 10-membered heterocyclic alkyl), C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 Each hydrogen atom in aryl, 5- to 10-membered heteroaryl, and -C1-C6 alkylene- (5- to 10-membered heteroaryl) is independently and optionally substituted with the following groups: deuterium, halogen, -R e -R f C1-C6 alkyl, -C1-C6 alkylene-O-C1-C6 alkyl, -C1-C6 alkylene-OR a C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkylene- (5- to 10-membered heterocycloalkyl), -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e C(=NR f )NR e R f 、 -NR e S(O)R f 、 -NR e S(O)2R f 、 -NR e S(O)NR e R f 、 -NR e S(O)2NR e R f 、 -C(O)R e 、 -C(O)OR e 、 -C(O)NR e R f 、 -PR e R f 、 -P(O)R e R f 、 -P(O)2R e R f 、 -P(O)NR e R f 、 -P(O)2NR<0​​​​​​​ R 4 It is H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 aryl or 5 to 10-membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4 to 10-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl and 5- to 10-membered heteroaryl groups is independently and optionally substituted with the following groups: deuterium, halogen, -R e -R f C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f 、 -P(O)2R e R f 、 -P(O)NR e R f 、 -P(O)2NR e R f 、 -P(O)OR e 、 -P(O)2OR e 、 -CN or -NO2; R 5 R 6 R 7 and R 8 Each of these elements is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR g -OC(O)R g -OC(O)NR g R h -OS(O)R g -OS(O)2R g -SR g -S(O)R g -S(O)2R g -S(O)NR g R h -S(O)2NR g R h -OS(O)NR g R h -OS(O)2NR g R h -NR g R h -NR g C(O)R h -NR g C(O)OR h -NR g C(O)NR g R h -NR g S(O)R h -NR g S(O)2R h -NR g S(O)NR g R h -NR g S(O)2NR g R h -C(O)R g -C(O)OR g -C(O)NR g R h -PR g R h -P(O)R g R h -P(O)2R g R h -P(O)NR g R h -P(O)2NR g R h -P(O)OR g -P(O)2OR g -CN or -NO2; R 9 and R 10 Each of these elements is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OC(=NR) a )NR a R b -OS(O)R a -OS(O)2R a -OS(O)NR a R b -OS(O)2NR a R b -SR a -S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR a R b -NR a R b -NR a C(O)R b -N(C(O)R a )(C(O)R b -NR a C(O)OR b -NR a C(O)NR a R b -NR a C(=NR a )NR a R b -NR a S(O)R b -NR a S(O)2R b -NR a S(O)NR a R b -NR a S(O)2NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -C(=NR) a )NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN or -NO2; or R 9 and R 10 Together with the carbon atoms they are attached to, they form C2-C6 alkenyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl or oxo groups, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclic alkyl groups is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -R e -R f -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2; or R on adjacent carbon atoms 9 and R 10 Together with the carbon atoms it is attached to, they combine to form R 9 and R 10 Substituted carbon-carbon double bonds; R a R b R c R d R e R f R g and R h Each is independently selected from the following groups: H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, C1-C6 alkylene-C6-C 10 aryl and 5 to 10-membered heteroaryl; or R a and R b or R c and R d or R e and R f or R g and R h The two atoms in the compound, together with one or more atoms attached to them, combine to form C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 aryl or 5 to 10-membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4 to 10-membered heterocycloalkyl, C6-C 10 Aryl, C1-C6 alkylene-C6-C 10 Each hydrogen atom in the aryl and 5- to 10-membered heteroaryl groups is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OC1-C6 alkyl, -OC(O)C1-C6 alkyl, -OC(O)N(H or C1-C6 alkyl)2, -OS(O)C1-C6 alkyl, -OS(O)2C1-C6 alkyl, -OS(O)N(H or C1-C6 alkyl)2, -OS( O)2N(H or C1-C6 alkyl)2, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)N(H or C1-C6 alkyl)2, -S(O)2N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)C(O)C1-C6 alkyl, - N(C1-C6 alkyl)C(O)N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)C1-C6 alkyl, -N(C1-C6 alkyl)S(O)2C1-C6 alkyl, -N(C1-C6 alkyl)S(O)N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)2N(H or C1-C6 alkyl)2, -C(O)C1-C6 alkyl, -C(O)OC1- C6 alkyl, -C(O)N(H or C1-C6 alkyl)2, -P(H or C1-C6 alkyl)2, -P(O)(H or C1-C6 alkyl)2, -P(O)2(H or C1-C6 alkyl)2, -P(O)N(H or C1-C6 alkyl)2, -P(O)2N(H or C1-C6 alkyl)2, -P(O)OC1-C6 alkyl, -P(O)2OC1-C6 alkyl, -CN or -NO2, or -R e and -R f Together with the carbon atom it is attached to, it forms an oxo group or a C2-C6 alkenyl group; m is 0, 1, 2, 3, 4, 5, 6 or 7; n is 0, 1, 2, 3, 4, 5, 6, or 7; p is 0 or 1; and q is 0, 1, or 2.

2. A compound of formula I or a pharmaceutically acceptable salt thereof, I in X is -O-, -S-, or -NR 4 -; Y is a bond, -O-, -S-, -S(O)- or -S(O)2-; Z 1 Is it N or C(R)? 5 ); Z 2 Is it N or C(R)? 6 ); Z 3 Is it N or C(R)? 7 ); Z 4 Is it N or C(R)? 8 ); The condition is Z 1 -Z 4 At least two of them are N; Ring A is C6-C 10 Aryl or 5 to 10-membered heteroaryl; Ring B is a 4- to 9-membered heterocyclic alkyl group; Each R 1 Independently, it is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OC(=NR) a )NR a R b -OS(O)R a -OS(O)2R a -OS(O)NR a R b -OS(O)2NR a R b -SR a -S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR a R b -NR a R b -NR a C(O)R b -N(C(O)R a )(C(O)R b -NR a C(O)OR b -NR a C(O)NR a R b -NR a C(=NR a )NR a R b -NR a S(O)R b -NR a S(O)2R b -NR a S(O)NR a R b -NR a S(O)2NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -C(=NR) a )NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN or -NO2; or two Rs 1 Together with one or more atoms to which it is attached, it forms a C3-C6 cycloalkyl or a 4- to 10-membered heterocyclic alkyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclic alkyl groups is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -R e -R f -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f 、 -NR e S(O)2NR e R f 、 -C(O)R e 、 -C(O)OR e 、 -C(O)NR e R f 、 -PR e R f 、 -P(O)R e R f 、 -P(O)2R e R f 、 -P(O)NR e R f 、 -P(O)2NR e R f 、 -P(O)OR e 、 -P(O)2OR e 、 -CN or -NO2; Each R 2 Independently, it is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR c -OC(O)R c -OC(O)NR c R d -OC(=NR) c )NR c R d -OS(O)R c -OS(O)2R c -OS(O)NR c R d -OS(O)2NR c R d -SR c -S(O)R c -S(O)2R c -S(O)NR c R d -S(O)2NR c R d -NR c R d -NR c C(O)R d -N(C(O)R c )(C(O)R d -NR c C(O)OR d -NR c C(O)NR c R d -NR c C(=NR c )NR c R d -NR c S(O)R d -NR c S(O)2R d -NR c S(O)NR c R d -NR c S(O)2NR c R d -C(O)R c -C(O)OR c -C(O)NR c R d -C(=NR) c )NR c R d -PR c R d -P(O)R c R d -P(O)2R c R d -P(O)NR c R d -P(O)2NR c R d -P(O)OR c -P(O)2OR c -CN or -NO2, or two Rs 2 Together with the atoms to which they are attached, they form C3-C6 cycloalkyl or 4- to 10-membered heterocyclic alkyl groups, including C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, and C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclic alkyl groups is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -R e -R f -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f 、 -NR e S(O)2NR e R f 、 -C(O)R e 、 -C(O)OR e 、 -C(O)NR e R f 、 -PR e R f 、 -P(O)R e R f 、 -P(O)2R e R f 、 -P(O)NR e R f 、 -P(O)2NR e R f 、 -P(O)OR e 、 -P(O)2OR e 、 -CN or -NO2; R 3 It is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, -C1-C6 alkylene- (4- to 10-membered heterocyclic alkyl), C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 Aryl), 5- to 10-membered heteroaryl or -C1-C6 alkylene- (4- to 10-membered heterocyclic alkyl), wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, -C1-C6 alkylene- (4- to 10-membered heterocyclic alkyl), C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 Each hydrogen atom in aryl, 5- to 10-membered heteroaryl, and -C1-C6 alkylene- (5- to 10-membered heteroaryl) is independently and optionally substituted with the following groups: deuterium, halogen, -R e -R f C1-C6 alkyl, -C1-C6 alkylene-O-C1-C6 alkyl, -C1-C6 alkylene-OR a C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkylene- (5- to 10-membered heterocycloalkyl), -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e C(=NR f )NR e R f 、 -NR e S(O)R f 、 -NR e S(O)2R f 、 -NR e S(O)NR e R f 、 -NR e S(O)2NR e R f 、 -C(O)R e 、 -C(O)OR e 、 -C(O)NR e R f 、 -PR e R f 、 -P(O)R e [[ID=4l]]R f 、 -P(O)2R e R f 、 -P(O)NR e R f 、 -P(O)2NR e R f 、 -P(O)OR e 、 -P(O)2OR e 、 -CN or -NO2; R 4 It is H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 aryl or 5 to 10-membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4 to 10-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl and 5- to 10-membered heteroaryl groups is independently and optionally substituted with the following groups: deuterium, halogen, -R e -R f C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f ,-P(O)2R e R f ,-P(O)NR e R f ,-P(O)2NR e R f ,-P(O)OR e ,-P(O)2OR e ,-CN or -NO2; R 5 R 6 R 7 and R 8 Each of these elements is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR g -OC(O)R g -OC(O)NR g R h -OS(O)R g -OS(O)2R g -SR g -S(O)R g -S(O)2R g -S(O)NR g R h -S(O)2NR g R h -OS(O)NR g R h -OS(O)2NR g R h -NR g R h -NR g C(O)R h -NR g C(O)OR h -NR g C(O)NR g R h -NR g S(O)R h -NR g S(O)2R h -NR g S(O)NR g R h -NR g S(O)2NR g R h -C(O)R g -C(O)OR g -C(O)NR g R h -PR g R h -P(O)R g R h -P(O)2R g R h -P(O)NR g R h -P(O)2NR g R h -P(O)OR g -P(O)2OR g -CN or -NO2; R 9 and R 10 Each of these elements is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OC(=NR) a )NR a R b -OS(O)R a -OS(O)2R a -OS(O)NR a R b -OS(O)2NR a R b -SR a -S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR a R b -NR a R b -NR a C(O)R b -N(C(O)R a )(C(O)R b -NR a C(O)OR b -NR a C(O)NR a R b -NR a C(=NR a )NR a R b -NR a S(O)R b -NR a S(O)2R b -NR a S(O)NR a R b -NR a S(O)2NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -C(=NR) a )NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN or -NO2; or R 9 and R 10 Together with the carbon atoms they are attached to, they form C2-C6 alkenyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl or oxo groups, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclic alkyl groups is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -R e -R f -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2; or R on adjacent carbon atoms 9 and R 10 Together with the carbon atoms it is attached to, they combine to form R 9 and R 10 Substituted carbon-carbon double bonds; R a R b R c R d R e R f R g and R h Each is independently selected from the following groups: H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, C1-C6 alkylene-C6-C 10 aryl and 5 to 10-membered heteroaryl; or R a and R b or R c and R d or R e and R f or R g and R h The two atoms in the compound, together with one or more atoms attached to them, combine to form C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 aryl or 5 to 10-membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4 to 10-membered heterocycloalkyl, C6-C 10 Aryl, C1-C6 alkylene-C6-C 10 Each hydrogen atom in the aryl and 5- to 10-membered heteroaryl groups is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OC1-C6 alkyl, -OC(O)C1-C6 alkyl, -OC(O)N(H or C1-C6 alkyl)2, -OS(O)C1-C6 alkyl, -OS(O)2C1-C6 alkyl, -OS(O)N(H or C1-C6 alkyl)2, -OS( O)2N(H or C1-C6 alkyl)2, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)N(H or C1-C6 alkyl)2, -S(O)2N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)C(O)C1-C6 alkyl, - N(C1-C6 alkyl)C(O)N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)C1-C6 alkyl, -N(C1-C6 alkyl)S(O)2C1-C6 alkyl, -N(C1-C6 alkyl)S(O)N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)2N(H or C1-C6 alkyl)2, -C(O)C1-C6 alkyl, -C(O)OC1- C6 alkyl, -C(O)N(H or C1-C6 alkyl)2, -P(H or C1-C6 alkyl)2, -P(O)(H or C1-C6 alkyl)2, -P(O)2(H or C1-C6 alkyl)2, -P(O)N(H or C1-C6 alkyl)2, -P(O)2N(H or C1-C6 alkyl)2, -P(O)OC1-C6 alkyl, -P(O)2OC1-C6 alkyl, -CN or -NO2, or -R e and -R f Together with the carbon atom it is attached to, it forms an oxo group or a C2-C6 alkenyl group; m is 0, 1, 2, 3, 4, 5, 6 or 7; n is 0, 1, 2, 3, 4, 5, 6, or 7; p is 0 or 1; and q is 0, 1, or 2.

3. A compound of formula I or a pharmaceutically acceptable salt thereof, I in X is -O-, -S-, or -NR 4 -; Y is a bond, -O-, -S-, -S(O)- or -S(O)2-; Z 1 Is it N or C(R)? 5 ); Z 2 Is it N or C(R)? 6 ); Z 3 Is it N or C(R)? 7 ); Z 4 Is it N or C(R)? 8 ); The condition is Z 1 -Z 4 At least two of them are N; Ring A is C6-C 10 Aryl or 5 to 10-membered heteroaryl; Ring B is a 4- to 9-membered heterocyclic alkyl ring having a nitrogen atom in it; Each R 1 Independently, it is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OC(=NR) a )NR a R b -OS(O)R a -OS(O)2R a -OS(O)NR a R b -OS(O)2NR a R b -SR a -S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR a R b -NR a R b -NR a C(O)R b -N(C(O)R a )(C(O)R b -NR a C(O)OR b -NR a C(O)NR a R b -NR a C(=NR a )NR a R b -NR a S(O)R b -NR a S(O)2R b -NR a S(O)NR a R b -NR a S(O)2NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -C(=NR) a )NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN or -NO2; or two Rs 1 Together with one or more atoms to which it is attached, it forms a C3-C6 cycloalkyl or a 4- to 10-membered heterocyclic alkyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclic alkyl groups is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -R e -R f -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f 、 -NR e S(O)2NR e R f 、 -C(O)R e 、 -C(O)OR e 、 -C(O)NR e R f 、 -PR e R f 、 -P(O)R e R f 、 -P(O)2R e R f 、 -P(O)NR e R f 、 -P(O)2NR e R f 、 -P(O)OR e 、 -P(O)2OR e 、 -CN or -NO2; Each R 2 Independently, it is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR c -OC(O)R c -OC(O)NR c R d -OC(=NR) c )NR c R d -OS(O)R c -OS(O)2R c -OS(O)NR c R d -OS(O)2NR c R d -SR c -S(O)R c -S(O)2R c -S(O)NR c R d -S(O)2NR c R d -NR c R d -NR c C(O)R d -N(C(O)R c )(C(O)R d -NR c C(O)OR d -NR c C(O)NR c R d -NR c C(=NR c )NR c R d -NR c S(O)R d -NR c S(O)2R d -NR c S(O)NR c R d -NR c S(O)2NR c R d -C(O)R c -C(O)OR c -C(O)NR c R d -C(=NR) c )NR c R d -PR c R d -P(O)R c R d -P(O)2R c R d -P(O)NR c R d -P(O)2NR c R d -P(O)OR c -P(O)2OR c -CN or -NO2, or two Rs 2 Together with the atoms to which they are attached, they form C3-C6 cycloalkyl or 4- to 10-membered heterocyclic alkyl groups, including C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, and C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclic alkyl groups is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -R e -R f -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f 、 -NR e S(O)2NR e R f 、 -C(O)R e 、 -C(O)OR e 、 -C(O)NR e R f 、 -PR e R f 、 -P(O)R e R f 、 -P(O)2R e R f 、 -P(O)NR e R f 、 -P(O)2NR e R f 、 -P(O)OR e 、 -P(O)2OR e 、 -CN or -NO2; R 3 It is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, -C1-C6 alkylene- (4- to 10-membered heterocyclic alkyl), C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 Aryl), 5- to 10-membered heteroaryl or -C1-C6 alkylene- (4- to 10-membered heterocyclic alkyl), wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, -C1-C6 alkylene- (4- to 10-membered heterocyclic alkyl), C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 Each hydrogen atom in aryl, 5- to 10-membered heteroaryl, and -C1-C6 alkylene- (5- to 10-membered heteroaryl) is independently and optionally substituted with the following groups: deuterium, halogen, -R e -R f C1-C6 alkyl, -C1-C6 alkylene-O-C1-C6 alkyl, -C1-C6 alkylene-OR a C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkylene- (5- to 10-membered heterocycloalkyl), -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e C(=NR f )NR e R f 、 -NR e S(O)R f 、 -NR e S(O)2R f 、 -NR e S(O)NR e R f 、 -NR e S(O)2NR e R f 、 -C(O)R e 、 -C(O)OR e 、 -C(O)NR e R f 、 -PR e R f 、 -P(O)R e R f 、 -P(O)2R e R f 、 -P(O)NR e R f 、 -P(O)2NR e R f 、 -P(O)OR e 、 -P(O)2OR e 、 -CN or -NO2; R 4 It is H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 aryl or 5 to 10-membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4 to 10-membered heterocycloalkyl, C6-C 10 Each hydrogen atom in the aryl and 5- to 10-membered heteroaryl groups is independently and optionally substituted with the following groups: deuterium, halogen, -R e -R f C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f 、 -P(O)2R e R f 、 -P(O)NR e R f 、 -P(O)2NR e R f 、 -P(O)OR e 、 -P(O)2OR e 、 -CN or -NO2; R 5 R 6 R 7 and R 8 Each of these elements is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR g -OC(O)R g -OC(O)NR g R h -OS(O)R g -OS(O)2R g -SR g -S(O)R g -S(O)2R g -S(O)NR g R h -S(O)2NR g R h -OS(O)NR g R h -OS(O)2NR g R h -NR g R h -NR g C(O)R h -NR g C(O)OR h -NR g C(O)NR g R h -NR g S(O)R h -NR g S(O)2R h -NR g S(O)NR g R h -NR g S(O)2NR g R h -C(O)R g -C(O)OR g -C(O)NR g R h -PR g R h -P(O)R g R h -P(O)2R g R h -P(O)NR g R h -P(O)2NR g R h -P(O)OR g -P(O)2OR g -CN or -NO2; R 9 and R 10 Each of these elements is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a -OC(O)R a -OC(O)NR a R b -OC(=NR) a )NR a R b -OS(O)R a -OS(O)2R a -OS(O)NR a R b -OS(O)2NR a R b -SR a -S(O)R a -S(O)2R a -S(O)NR a R b -S(O)2NR a R b -NR a R b -NR a C(O)R b -N(C(O)R a )(C(O)R b -NR a C(O)OR b -NR a C(O)NR a R b -NR a C(=NR a )NR a R b -NR a S(O)R b -NR a S(O)2R b -NR a S(O)NR a R b -NR a S(O)2NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -C(=NR) a )NR a R b -PR a R b -P(O)R a R b -P(O)2R a R b -P(O)NR a R b -P(O)2NR a R b -P(O)OR a -P(O)2OR a -CN or -NO2, or R 9 and R 10 Together with the carbon atoms to which they are attached, they form C3-C6 cycloalkyl or 4- to 10-membered heterocyclic alkyl groups, including C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, and C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclic alkyl groups is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -R e -R f -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2; or R on adjacent carbon atoms 9 and R 10 Together with the carbon atoms it is attached to, they combine to form R 9 and R 10 Substituted carbon-carbon double bonds; R a R b R c R d R e R f R g and R h Each is independently selected from the following groups: H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, C1-C6 alkylene-C6-C 10 aryl and 5 to 10-membered heteroaryl; or R a and R b or R c and R d or R e and R f or R g and R h The two atoms in the compound, together with one or more atoms attached to them, combine to form C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 aryl or 5 to 10-membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4 to 10-membered heterocycloalkyl, C6-C 10 Aryl, C1-C6 alkylene-C6-C 10 Each hydrogen atom in the aryl and 5- to 10-membered heteroaryl groups is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, -OC1-C6 alkyl, -OC(O)C1-C6 alkyl, -OC(O)N(H or C1-C6 alkyl)2, -OS(O)C1-C6 alkyl, -OS(O)2C1-C6 alkyl, -OS(O)N(H or C1-C6 alkyl)2, -OS( O)2N(H or C1-C6 alkyl)2, -SC1-C6 alkyl, -S(O)C1-C6 alkyl, -S(O)2C1-C6 alkyl, -S(O)N(H or C1-C6 alkyl)2, -S(O)2N(H or C1-C6 alkyl)2, -N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)C(O)C1-C6 alkyl, - N(C1-C6 alkyl)C(O)N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)C1-C6 alkyl, -N(C1-C6 alkyl)S(O)2C1-C6 alkyl, -N(C1-C6 alkyl)S(O)N(H or C1-C6 alkyl)2, -N(C1-C6 alkyl)S(O)2N(H or C1-C6 alkyl)2, -C(O)C1-C6 alkyl, -C(O)OC1- C6 alkyl, -C(O)N(H or C1-C6 alkyl)2, -P(H or C1-C6 alkyl)2, -P(O)(H or C1-C6 alkyl)2, -P(O)2(H or C1-C6 alkyl)2, -P(O)N(H or C1-C6 alkyl)2, -P(O)2N(H or C1-C6 alkyl)2, -P(O)OC1-C6 alkyl, -P(O)2OC1-C6 alkyl, -CN or -NO2, or -R e and -R f Together with the carbon atom it is attached to, it forms an oxo group or a C2-C6 alkenyl group; m is 0, 1, 2, 3, 4, 5, 6 or 7; n is 0, 1, 2, 3, 4, 5, 6, or 7; p is 0 or 1; and q is 0, 1, or 2.

4. A compound according to any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein the compound has formula II, III, IV, V, VI, VII, VIII or IX. (II), (III), (IV), (V)， (WE), (VII), (VIII), or (IX), in X 1 It is -O-, -S-, -S(O)-, -S(O)2- or -C(R) 1 )2-; q1 is 0 or 1; t is 0, 1, 2, or 3; and v is 0, 1, or 2.

5. A compound according to any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein the compound has the formula X, XI, XII, XIII, XIV, XV, XVI, or XVII. (X)， (XI), (XII), (XIII), (XIV), (XV), (XVI), or (XVII), in Z 5 Is it N or C(R)? 11 ); Z 6 Is it N or C(R)? 12 ); R 11 and R 12 Each of these elements, when present, is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR g -OC(O)R g -OC(O)NR g R h -OS(O)R g -OS(O)2R g -SR g -S(O)R g -S(O)2R g -S(O)NR g R h -S(O)2NR g R h -OS(O)NR g R h -OS(O)2NR g R h -NR g R h -NR g C(O)R h -NR g C(O)OR h -NR g C(O)NR g R h -NR g S(O)R h -NR g S(O)2R h -NR g S(O)NR g R h -NR g S(O)2NR g R h -C(O)R g -C(O)OR g -C(O)NR g R h -PR g R h -P(O)R g R h -P(O)2R g R h -P(O)NR g R h -P(O)2NR g R h -P(O)OR g -P(O)2OR g -CN or -NO2; and q1 is 0 or 1.

6. A compound according to any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein the compound has the formula XVIII, XIX, XX, XXI, XXII, XXIII, XXIV or XXV. (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), or (XXV), in X 1 is -O-, -S-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)- or -C(R 1 )2-; Z 5 Is it N or C(R)? 11 ); Z 6 Is it N or C(R)? 12 ); R 11 and R 12 Each of these elements, when present, is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocyclic alkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR g -OC(O)R g -OC(O)NR g R h -OS(O)R g -OS(O)2R g -SR g -S(O)R g -S(O)2R g -S(O)NR g R h -S(O)2NR g R h -OS(O)NR g R h -OS(O)2NR g R h -NR g R h -NR g C(O)R h -NR g C(O)OR h -NR g C(O)NR g R h -NR g S(O)R h -NR g S(O)2R h -NR g S(O)NR g R h -NR g S(O)2NR g R h -C(O)R g -C(O)OR g -C(O)NR g R h -PR g R h -P(O)R g R h -P(O)2R g R h -P(O)NR g R h -P(O)2NR g R h -P(O)OR g -P(O)2OR g -CN or -NO2, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclic alkyl groups is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -R e -R f -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2; q1 is 0 or 1; t is 0, 1, 2, or 3; and v is 0, 1, or 2.

7. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein the compound has the formula XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, or XXXIII. (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), or (XXXIII), in X 1 is -O-, -S-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)- or -C(R 1 )2-; q1 is 0 or 1; t is 0, 1, 2, or 3; and v is 0, 1, or 2.

8. The compound according to claim 1 or 4, or a pharmaceutically acceptable salt thereof, wherein the compound has the formula XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, XXXX, or XXXXI. (XXXIV), (XXV), (XXXVI), (XXXVII), (XXXVIII), (XXXIX), (XXXX), or (XXXXI), in X 1 is -O-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)- or -C(R 1 )2-; q1 is 0 or 1; t is 0, 1, 2, or 3; and v is 0, 1, or 2.

9. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein the compound has the formula XXXXII, XXXXIII, XXXXIV, XXXV, XXXVI, XXXXVII, XXXXVIII, or XXXXIX. (XXXXII), (XXXIII), (XXXXIV), (XXXXV), (XXXXVI), (XXXXVII), (XXXXVIII), or (XXXXIX), in X 1 is -O-, -S-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)- or -C(R 1 )2-; q1 is 0 or 1; t is 0, 1, 2, or 3; and v is 0, 1, or 2.

10. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein the compound has the formula L, L1, L1I, LIII, LIV, LV, LV, LVI, or LVII. (L)， (LI), (LII), (LIII), (LIFE), (LV), (LVI), or (LVII), in X 1 is -O-, -S-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)- or -C(R 1 )2-; q1 is 0 or 1; t is 0, 1, 2, or 3; and v is 0, 1, or 2.

11. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein the compound has the formula LVIII, LVIX, LX, LXI, LXII, LXIII, LXIV, or LXV. (LVIII), (SIX), (LX), (LXI), (LXII), (LXIII), (LXIV), or (65), in X 1 is -O-, -S-, -S(O)-, -S(O)2-, -C(O)O-, -OC(O)- or -C(R 1 )2-; q1 is 0 or 1; t is 0, 1, 2, or 3; and v is 0, 1, or 2.

12. The compound or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein q is 0 when present.

13. The compound or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein q is 1 when present.

14. The compound or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein q1 is 0 when present.

15. The compound or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein q1 is 1 when present.

16. The compound or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein R 1 It is deuterium, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl, wherein each hydrogen atom in the C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 ynyl group is independently and optionally substituted by the following groups: deuterium, halogen, -R e -R f C1-C6 alkyl, C1-C6 haloalkyl, -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2, or two hydrogen atoms on a single carbon atom of the 4- to 10-membered heterocyclic alkyl group combine to form an oxo group or a C2-C6 alkenyl group; or two R 1 Together with one or more atoms to which it is attached, it forms a C3-C6 cycloalkyl or a 4- to 10-membered heterocyclic alkyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, C6-C 10 Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocyclic alkyl groups is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, -R e -R f -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f 、 -C(O)R e 、 -C(O)OR e 、 -C(O)NR e R f 、 -PR e R f 、 -P(O)R e R f 、 -P(O)2R e R f 、 -P(O)NR e R f 、 -P(O)2NR e R f 、 -P(O)OR e 、 -P(O)2OR e 、 -CN or -NO2.

17. A compound or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein the compound comprises a core having the following formula , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or , Each of them "Is it related to ring A or -(X)?" p -R 3 Covalent connection points.

18. The compound or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein m is 0, 1, 2 or 3.

19. The compound or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein n is 0, 1, 2 or 3.

20. The compound or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein Z 1 It is N.

21. The compound or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein Z 2 It is N.

22. The compound or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein Z 3 It is CR 7 And Z 4 It is N.

23. The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein Z 3 It is CR 7 And Z 4 It is CR 8 .

24. The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein Z 3 It is N, and Z 4 It is CR 8 .

25. The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein Z 3 It is N, and Z 4 It is N.

26. The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein Z 3 It is N, Z 4 It is CR 8 Z 5 It is CR 11 And Z 6 It is CR 12 .

27. The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein Z 3 It is CR 7 Z 4 It is N, Z 5 It is CR 11 And Z 6 It is CR 12 .

28. The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein Z 3 It is N, Z 4 It is N, Z 5 It is CR 11 And Z 5 It is CR 12 .

29. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein the compound comprises a core having the following formula 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , or , Each of them "Is it related to ring A or -(X)?" p -R 3 Covalent connection points.

30. The compound or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein p is 0.

31. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 29, wherein p is 1.

32. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 29 or 31, wherein X is O.

33. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 29 or 31, wherein X is -NR 4 - 34. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 29 or 31, wherein X is -S-.

35. The compound or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein R 3 It is a -C1-C6 alkyl, a 4- to 10-membered heterocyclic alkyl, or a -C1-C6 alkylene-(4- to 10-membered heterocyclic alkyl), wherein each hydrogen atom in the -C1-C6 alkyl, 4- to 10-membered heterocyclic alkyl, or -C1-C6 alkylene-(4- to 10-membered heterocyclic alkyl) is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, -C1-C6 alkylene-O-C1-C6 alkyl, -OC1-C6 alkylene-O-C1-C6 alkyl, -C1-C6 alkylene-OR a C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkylene- (5- to 10-membered heterocycloalkyl), -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e C(=NR f )NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f 、 -C(O)R e 、 -C(O)OR e 、 -C(O)NR e R f 、 -PR e R f 、 -P(O)R e R f 、 -P(O)2R e R f 、 -P(O)NR e R f 、 -P(O)2NR e R f 、 -P(O)OR e 、 -P(O)2OR e 、 -CN or -NO2.

36. The compound or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein R 3 It is a -C1-C6 alkylene- (4 to 10-membered heterocyclic alkyl), wherein each hydrogen atom in -C1-C6 alkylene- (4 to 10-membered heterocyclic alkyl) is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, -C1-C6 alkylene-O-C1-C6 alkyl, -OC1-C6 alkylene-O-C1-C6 alkyl, -C1-C6 alkylene-OR a C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkylene- (5- to 10-membered heterocycloalkyl), -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e C(=NR f )NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f 、 -C(O)R e 、 -C(O)OR e 、 -C(O)NR e R f 、 -PR e R f 、 -P(O)R e R f 、 -P(O)2R e R f 、 -P(O)NR e R f 、 -P(O)2NR e R f 、 -P(O)OR e 、 -P(O)2OR e 、 -CN or -NO2.

37. The compound or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein R 3 yes ， Each hydrogen atom is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, -C1-C6 alkylene-O-C1-C6 alkyl, -OC1-C6 alkylene-O-C1-C6 alkyl, -C1-C6 alkylene-OR a C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkylene- (5- to 10-membered heterocycloalkyl), -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e C(=NR f )NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f -C(O)R e -C(O)OR e -C(O)NR e R f -PR e R f -P(O)R e R f -P(O)2R e R f -P(O)NR e R f -P(O)2NR e R f -P(O)OR e -P(O)2OR e -CN or -NO2, and " "It is a covalent connection point." 38. The compound or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein R 3 yes 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ， Among them W It is an inorganic counter ion or an organic counter ion.

39. The compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein R 3 It is a 4- to 10-membered heterocyclic alkyl group, wherein each hydrogen atom in the 4- to 10-membered heterocyclic alkyl group is independently and optionally substituted with the following groups: deuterium, halogen, C1-C6 alkyl, optionally halogenated C2-C6 alkenyl, -C1-C6 alkylene-O-C1-C6 alkyl, -OC1-C6 alkylene-O-C1-C6 alkyl, -C1-C6 alkylene-OR a C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkylene- (5- to 10-membered heterocycloalkyl), -OR e -OC(O)R e -OC(O)NR e R f -OS(O)R e -OS(O)2R e -OS(O)NR e R f -OS(O)2NR e R f -SR e -S(O)R e -S(O)2R e -S(O)NR e R f -S(O)2NR e R f -NR e R f -NR e C(O)R f -NR e C(O)OR f -NR e C(O)NR e R f -NR e C(=NR f )NR e R f -NR e S(O)R f -NR e S(O)2R f -NR e S(O)NR e R f -NR e S(O)2NR e R f , -C(O)R e , -C(O)OR e , -C(O)NR e R f , -PR e R f , -P(O)R e R f , -P(O)2R e R f , -P(O)NR e R f , -P(O)2NR e R f , -P(O)OR e , -P(O)2OR e , -CN or -NO2.

40. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 35 or 39, wherein R 3 yes , , , or , in" "It is a covalent connection point." 41. The compound according to any one of the preceding claims or a pharmaceutically acceptable salt thereof, wherein each R 2 Independently, it is deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, -OR c -C(O)R C -NR c R d Or -CN, wherein each hydrogen atom in the C1-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl groups is independently and optionally substituted with deuterium or a halogen.

42. The compound according to any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein ring A is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or , in" "It is a covalent connection point." 43. The compound or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein R 4 When present, it is H or methyl.

44. The compound according to any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 5 When present, it is H or deuterium.

45. The compound according to any of the preceding claims or a pharmaceutically acceptable salt thereof, wherein R 6 When present, it is H or deuterium.

46. ​​The compound or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein R 7 When present, it is H, deuterium, or F.

47. The compound or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein R 8 When present, it is H or deuterium.

48. The compound or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein Z 5 It is N when it exists.

49. The compound or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein Z 6 It is N when it exists.

50. The compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein Z 5 When it exists, it is CR. 11 .

51. The compound of claim 50 or a pharmaceutically acceptable salt thereof, wherein R 11 When present, it is H or deuterium.

52. The compound according to claim 50 or 51, or a pharmaceutically acceptable salt thereof, wherein Z 6 It is N when it exists.

53. The compound according to any one of claims 1 to 48, or a pharmaceutically acceptable salt thereof, wherein Z 6 When it exists, it is CR. 12 .

54. The compound of claim 53 or a pharmaceutically acceptable salt thereof, wherein R 12 When present, it is H or deuterium.

55. The compound according to claim 1, wherein the compound is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and , Or its pharmaceutically acceptable salt.

56. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 55 or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients.

57. A method of treating a disease, such as cancer, the method comprising administering to an individual in need of such treatment an effective amount of the compound of any one of claims 1 to 55 or a pharmaceutically acceptable salt thereof.

58. A method of using the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 55 for treating cancer in an individual.

59. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 55, for the treatment of cancer in an individual.

60. Use of a compound according to any one of claims 1 to 55 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating cancer in an individual.

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