Fused ring KRAS inhibitors for treatment of disease
By designing specific compounds of formula I, using multi-compartmented ring systems and variable group structures, the problem of lack of effective inhibitors for KRAS mutants in the prior art is solved, and selective inhibition and good pharmacokinetic properties of KRAS mutants are achieved.
Patent Information
- Application Number
- CN202380062484.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Priority Date
- 2023-06-16
- Filing Date
- 2023-07-07
- Publication Date
- 2025-04-08
AI Technical Summary
It is difficult to develop non-covalent KRAS inhibitors in the prior art, especially for targeted KRAS mutants that are not covalently formed at KRAS G12C, and there are poor bioavailability of inhibitors such as MRTX1133.
A compound of formula I or a pharmaceutically acceptable salt thereof is designed to achieve selective inhibition of the KRAS mutant by specific heterocyclic structures and groups substitutions. The structure of the compound includes a variety of variable groups (such as -O-, -S-, -NR4-) and multi-compartmented ring systems, which can be flexibly adjusted to accommodate different KRAS mutation forms.
This compound can effectively and selectively inhibit KRAS mutants, such as KRAS G12C, KRAS G12D, etc., has good in vivo efficacy and safety, and predicts good oral motility in humans.
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Figure BDA0005288821930000021 
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Figure BDA0005288821930000091
Abstract
Description
[0001] Related applications
[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 359,817, filed on July 9, 2022, U.S. Provisional Application No. 63 / 417,684, filed on October 19, 2022, U.S. Provisional Application No. 63 / 502,047, filed on May 12, 2023, U.S. Provisional Application No. 63 / 469,290, filed on May 26, 2023, and U.S. Provisional Application No. 63 / 521,487, filed on June 16, 2023, the entire disclosures of which are incorporated herein by reference. Technical Field
[0003] The present disclosure relates to fused-ring compounds that target KRAS, pharmaceutical compositions containing the compounds, and methods of using the compounds to treat diseases such as cancer. Background Art
[0004] Ras is a GTP-binding protein that regulates many important physiological processes within cells, such as cell cycle progression, survival, and apoptosis. H-Ras, K-Ras, and N-Ras are key 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 approximately 16% of all human cancers, and KRAS is the most frequently mutated RAS isoform, accounting for 85% of all RAS-associated cancers (Prior IA, et al., A comprehensive survey of Ras mutations in cancer. Cancer Res. 2012, 72, 2457-2467), including 86 to 96% in pancreatic cancer, 40 to 50% in colorectal cancer, and 27 to 39% in lung adenocarcinoma (Kessler D, et al., Drugging an undruggable pocket on KRAS. Proc Natl Acad Sci US A. 2019, 116(32): 15823-15829). Mutated RAS is locked in a constitutively active GTP-bound state and promotes enhanced Ras signaling in cancer cells.
[0005] It has been previously demonstrated that directly targeting mutant KRAS is challenging because of its high affinity for nucleotides and the lack of an easily tractable small molecule inhibitor binding pocket. KRASG12C mutants have recently been successfully inhibited by covalent chemical modulators sotorasib and adagrasib (Stower K, KRAS inhibitors at last, Nature Medicine 2020, 26, 1804) in lung cancer patients with KRAS G12C mutations, illustrating KRAS mutant targeting for therapeutic inventions. However, there are still no inhibitors targeting KRAS mutants without covalent formation at KRAS G12C. A deeper understanding of the structural elements of the KRAS switch II pocket makes it possible to design KRAS inhibitors that are selective for different mutation variants. MRTX1133 has been reported to be a potent and highly selective non-covalent KRAS G12D inhibitor (Wang X. et al., 2014). G12D Identification of MRTX1133, a noncovalent, potent, and selective KRAS inhibitor G12D Inhibitor), Journal of Medicinal Chemistry (J. Med. Chem.) 2022, 65: 3123-3133. However, intraperitoneal injection of MRTX1133 was required to achieve sufficient plasma exposure and demonstrate efficacy in mice. This suggests that the bioavailability of MRTX1133 may be poor.
[0006] Therefore, there is an unmet medical need to develop 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, and KRAS G13D, with good in vivo efficacy, safety, and predicted oral pharmacokinetic profiles in humans for the treatment of patients with KRAS mutant cancers. Summary of the Invention
[0007] In one aspect, the present disclosure relates to a compound of formula I or a pharmaceutically acceptable salt thereof,
[0008]
[0009] in
[0010] X is -O-, -S- or -NR 4 -;
[0011] Z 1 N or C(R 5 );
[0012] Z 2 N or C(R 6 );
[0013] Z 3 N or C(R 7 );
[0014] Z 4 N or C(R 8 );
[0015] The premise is Z 1 to Z 4 At least two of them are N;
[0016] Ring A is a 5- to 8-membered heterocycloalkyl group or a C5-C8 cycloalkyl group;
[0017] Ring B is a 5- to 10-membered heterocycloalkyl group, a C6-C 10 aryl or 5- to 10-membered heteroaryl;
[0018] Each R 1 are independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-10 membered heterocycloalkyl, 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 R 1 Together with the one or more atoms to which it is attached, it forms a C3-C6 cycloalkyl group or a 4- to 10-membered heterocycloalkyl group, 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 heterocycloalkyl groups is independently optionally substituted with 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)2Re 、-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;
[0019] Each R 2 are independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-10 membered heterocycloalkyl, 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)NRc R d 、-P(O)2NR c R d 、-P(O)OR c 、-P(O)2OR c , -CN or -NO2, or two R 2 Together with the atoms to which they are attached, they form a C3-C6 cycloalkyl group or a 4- to 10-membered heterocycloalkyl group, 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 heterocycloalkyl groups is independently optionally substituted with 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;
[0020] R 3 -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl), -C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 aryl), 5- to 10-membered heteroaryl or -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl), wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl), C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 Each hydrogen atom in -C1-C6 alkylene-(5-10 membered heteroaryl) is independently optionally substituted with 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 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 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;
[0021] R 4 is H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl or 5 to 10 membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4 to 10 membered heterocycloalkyl, C6-C10 Each hydrogen atom in the aryl and 5- to 10-membered heteroaryl groups is independently optionally substituted with 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)ORe 、-P(O)2OR e , -CN or -NO2;
[0022] Each R 5 、R 6 、R 7 and R 8 are independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-10 membered heterocycloalkyl, 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;
[0023] Each R a 、R b 、R c 、R d 、R e 、R f 、R g and R h independently selected from the group consisting of: H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, C1-C6 alkylene-C6-C 10 Aryl and 5- to 10-membered heteroaryl; or two R a and R b , or R c and R d , or R e and R f , or R g and R h Together with the one or more atoms to which it is attached, it forms a C3-C6 cycloalkyl group, a 4- to 10-membered heterocycloalkyl group, a C6-C 10 Aryl or 5 to 10 membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 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 optionally substituted with 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)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)OC1-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 to which it is attached, form an oxo or alkenyl group;
[0024] m is 0, 1, 2, 3, 4, 5, 6 or 7;
[0025] n is 0, 1, 2, 3, 4, 5, 6 or 7; and
[0026] p is 0 or 1.
[0027] In another aspect, the present disclosure relates to a compound of formula I or a pharmaceutically acceptable salt thereof,
[0028]
[0029] in
[0030] X is -O-, -S- or -NR 4 -;
[0031] Z1 N or C(R 5 );
[0032] Z 2 N or C(R 6 );
[0033] Z 3 N or C(R 7 );
[0034] Z 4 N or C(R 8 );
[0035] The premise is Z 1 to Z 4 At least two of them are N;
[0036] Ring A is a 5- to 8-membered heterocycloalkyl group or a C5-C8 cycloalkyl group;
[0037] Ring B is C6-C 10 aryl or 5- to 10-membered heteroaryl;
[0038] Each R 1 are independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-10 membered heterocycloalkyl, 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 ),-NRa 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 R 1 Together with the one or more atoms to which it is attached, it forms a C3-C6 cycloalkyl group or a 4- to 10-membered heterocycloalkyl group, 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 heterocycloalkyl groups is independently optionally substituted with 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)NRe 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;
[0039] Each R 2 are independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR c 、-OC(O)R c 、-OC(O)NR c Rd 、-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 R 2 Together with the atoms to which they are attached, they form a C3-C6 cycloalkyl group or a 4- to 10-membered heterocycloalkyl group, 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 heterocycloalkyl groups is independently optionally substituted with 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;
[0040] R 3 -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl), -C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 aryl), 5- to 10-membered heteroaryl or -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl), wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl), C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 Each hydrogen atom in -C1-C6 alkylene-(5-10 membered heteroaryl) is independently optionally substituted with 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;
[0041] R 4 is H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl or 5 to 10 membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4 to 10 membered heterocycloalkyl, C6-C 10Each hydrogen atom in the aryl and 5- to 10-membered heteroaryl groups is independently optionally substituted with 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 R 1 and R 10 and the one or more atoms to which they are attached are combined to form a monocyclic 4- to 10-membered heterocycloalkyl, a fused bicyclic 5- to 10-membered heterocycloalkyl, or a bridged bicyclic 6- to 10-membered heterocycloalkyl, wherein each hydrogen atom in the monocyclic 4- to 10-membered heterocycloalkyl, the fused bicyclic 5- to 10-membered heterocycloalkyl, or the bridged bicyclic 6- to 10-membered heterocycloalkyl is independently optionally substituted with 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( 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)OC1-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)2(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 two hydrogen atoms on a single carbon atom of a monocyclic 4- to 10-membered heterocycloalkyl group, a fused bicyclic 5- to 10-membered heterocycloalkyl group, or a bridged bicyclic 6- to 10-membered heterocycloalkyl group are combined to form an oxo or alkenyl group;
[0042] Each R 5 、R 6 、R 7 and R 8 are independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10Aryl, 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;
[0043] Each R a 、Rb 、R c 、R d 、R e 、R f 、R g and R h independently selected from the group consisting of: H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, C1-C6 alkylene-C6-C 10 Aryl and 5- to 10-membered heteroaryl; or two R a and R b , or R c and R d , or R e and R f , or R g and R h Together with the one or more atoms to which it is attached, it forms a C3-C6 cycloalkyl group, a 4- to 10-membered heterocycloalkyl group, a C6-C 10 Aryl or 5 to 10 membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 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 optionally substituted with 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)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)OC1-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 to which it is attached, form an oxo or alkenyl group;
[0044] m is 0, 1, 2, 3, 4, 5, 6 or 7;
[0045] n is 0, 1, 2, 3, 4, 5, 6 or 7; and
[0046] p is 0 or 1.
[0047] In some embodiments, at least one hydrogen atom in the compound of Formula I is substituted with deuterium. In some embodiments, R 1 、R 2 or R 3 At least one hydrogen atom in the molecule is substituted with deuterium.
[0048] In another aspect, the present disclosure provides a compound of formula II or a pharmaceutically acceptable salt thereof,
[0049]
[0050] in
[0051] X is -O-, -S- or -NR 4 -;
[0052] Y 1 -O-, -S-, -S(O)-, -S(O)2- or -NR 9 -or-CR 11 R 12 -;
[0053] Y 2 for -O-, -S-, -S(O)-, -S(O)2-, -NR 10 -or-CR 13 R 14 -;
[0054] Z 1 N or C(R 5 );
[0055] Z 2 N or C(R 6 );
[0056] Z 3 N or C(R 7 );
[0057] Z 4 N or C(R 8 );
[0058] The premise is Z 1 to Z 4 At least two of them are N;
[0059] Ring A is a 5- to 8-membered heterocycloalkyl group or a C5-C8 cycloalkyl group;
[0060] Ring B is a 5- to 10-membered heterocycloalkyl group, a C6-C 10 aryl or 5- to 10-membered heteroaryl;
[0061] Each R 1 are independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-10 membered heterocycloalkyl, 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)Ra 、-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)2ORa , -CN or -NO2, or two R 1 Together with the one or more atoms to which it is attached, it forms a C3-C6 cycloalkyl group or a 4- to 10-membered heterocycloalkyl group, 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 heterocycloalkyl groups is independently optionally substituted with 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;
[0062] Each R 2 are independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-10 membered heterocycloalkyl, 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 cS(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 R 2 Together with the atoms to which they are attached, they form a C3-C6 cycloalkyl group or a 4- to 10-membered heterocycloalkyl group, 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 heterocycloalkyl groups is independently optionally substituted with 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)Rf 、-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;
[0063] R 3 -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl), -C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 aryl), 5- to 10-membered heteroaryl or -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl), wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl), C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 Each hydrogen atom in -C1-C6 alkylene-(5-10 membered heteroaryl) is independently optionally substituted with 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)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;
[0064] R 4 is H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl or 5 to 10 membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 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 optionally substituted with 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 、-NRe 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 and R 10and the one or more atoms to which they are attached are combined to form a monocyclic 4- to 10-membered heterocycloalkyl, a fused bicyclic 5- to 10-membered heterocycloalkyl, or a bridged bicyclic 6- to 10-membered heterocycloalkyl, wherein each hydrogen atom in the monocyclic 4- to 10-membered heterocycloalkyl, the fused bicyclic 5- to 10-membered heterocycloalkyl, or the bridged bicyclic 6- to 10-membered heterocycloalkyl is independently optionally substituted with 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( 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)OC1-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)2(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 two hydrogen atoms on a single carbon atom of a monocyclic 4- to 10-membered heterocycloalkyl group, a fused bicyclic 5- to 10-membered heterocycloalkyl group, or a bridged bicyclic 6- to 10-membered heterocycloalkyl group are combined to form an oxo or alkenyl group;
[0065] Each R 5 、R 6 、R 7 and R 8 are independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR g 、-OC(O)R g 、-OC(O)NR gR 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;
[0066] Each R 9 and R 10 are independently H, deuterium, -C(O)R g 、-C(O)NR g R h, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4 to 10 membered heterocycloalkyl, C6-C 10 Aryl or 5 to 10 membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 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 optionally substituted with 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 R 9 and R 1 or R 10 and R 1 and the atoms to which they are attached are combined to form a 4- to 10-membered heterocycloalkyl group, wherein each hydrogen atom in the 4- to 10-membered heterocycloalkyl group is independently optionally substituted with 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 -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)OC1-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-C -P(O)2(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 two hydrogen atoms on a single carbon atom of a 4- to 10-membered heterocycloalkyl group are combined to form an oxo or alkenyl group;
[0067] Each R 11 、R 12 、R 13 and R 14are independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-10 membered heterocycloalkyl, 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 Rb 、-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 1 and R 11 、R 1 and R 12 、R 1 and R 13 、R 1 and R 14 , two R 11 and R 12 or two R 13 and R 14 and one or more carbon atoms to which they are attached are combined to form a C3-C6 cycloalkyl group or a 4-10 membered heterocycloalkyl group, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10 Each hydrogen atom in aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted with 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 eC(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 R 11 and R 12 or R 13 and R 14 Together with the carbon atom to which it is attached, it forms an oxo or C2-C6 alkenyl group;
[0068] Each R a 、R b 、R c 、R d 、R e 、R f 、R g and R h independently selected from the group consisting of: H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, C1-C6 alkylene-C6-C 10 Aryl and 5- to 10-membered heteroaryl; or two R a and R b , or R c and R d , or R e and R f , or Rg and R h Together with the one or more atoms to which it is attached, it forms a C3-C6 cycloalkyl group, a 4- to 10-membered heterocycloalkyl group, a C6-C 10 Aryl or 5 to 10 membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 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 optionally substituted with 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)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)OC1-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 to which it is attached, form an oxo or alkenyl group;
[0069] m is 0, 1, 2, 3, 4, 5, 6 or 7;
[0070] n is 0, 1, 2, 3, 4, 5, 6 or 7; and
[0071] p is 0 or 1.
[0072] In another aspect, the present disclosure provides a compound of formula II or a pharmaceutically acceptable salt thereof,
[0073]
[0074] in
[0075] X is -O-, -S- or -NR 4 -;
[0076] Y 1 for -O-, -S-, -S(O)-, -S(O)2-, -NR 9 -or-CR 11 R 12 -;
[0077] Y 2 for -O-, -S-, -S(O)-, -S(O)2-, -NR 10 -or-CR 13 R 14 -;
[0078] Z 1 N or C(R 5 );
[0079] Z 2 N or C(R 6 );
[0080] Z 3 N or C(R 7 );
[0081] Z 4 N or C(R 8 );
[0082] The premise is Z 1 to Z 4 At least two of them are N;
[0083] Ring A is a 5- to 8-membered heterocycloalkyl group or a C5-C8 cycloalkyl group;
[0084] Ring B is C6-C 10 aryl or 5- to 10-membered heteroaryl;
[0085] Each R 1 are independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR a 、-OC(O)R a 、-OC(O)NR a R b 、-OC(=NRa )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 aR b 、-P(O)OR a 、-P(O)2OR a , -CN or -NO2, or two R 1 Together with the one or more atoms to which it is attached, it forms a C3-C6 cycloalkyl group or a 4- to 10-membered heterocycloalkyl group, 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 heterocycloalkyl groups is independently optionally substituted with 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 eR 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;
[0086] Each R 2 are independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-10 membered heterocycloalkyl, 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 、-NRc 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 R 2 Together with the atoms to which they are attached, they form a C3-C6 cycloalkyl group or a 4- to 10-membered heterocycloalkyl group, 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 heterocycloalkyl groups is independently optionally substituted with 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 、-NRe 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;
[0087] R 3 -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl), -C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 aryl), 5- to 10-membered heteroaryl or -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl), wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl), C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 Each hydrogen atom in -C1-C6 alkylene-(5-10 membered heteroaryl) is independently optionally substituted with 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;
[0088] R 4 is H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl or 5 to 10 membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 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 optionally substituted with 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 R 1 and R 10and the one or more atoms to which they are attached are combined to form a monocyclic 4- to 10-membered heterocycloalkyl, a fused bicyclic 5- to 10-membered heterocycloalkyl, or a bridged bicyclic 6- to 10-membered heterocycloalkyl, wherein each hydrogen atom in the monocyclic 4- to 10-membered heterocycloalkyl, the fused bicyclic 5- to 10-membered heterocycloalkyl, or the bridged bicyclic 6- to 10-membered heterocycloalkyl is independently optionally substituted with 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( 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)OC1-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)2(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 two hydrogen atoms on a single carbon atom of a monocyclic 4- to 10-membered heterocycloalkyl group, a fused bicyclic 5- to 10-membered heterocycloalkyl group, or a bridged bicyclic 6- to 10-membered heterocycloalkyl group are combined to form an oxo or alkenyl group;
[0089] Each R 5 、R 6 、R 7 and R 8 are independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR g 、-OC(O)R g 、-OC(O)NR gR 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;
[0090] Each R 9 and R 10 are independently H, deuterium, -C(O)R g 、-C(O)NR g R h, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4 to 10 membered heterocycloalkyl, C6-C 10 Aryl or 5 to 10 membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 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 optionally substituted with 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 R 9 and R 1 or R 10 and R 1 and the atoms to which they are attached are combined to form a 4- to 10-membered heterocycloalkyl group, wherein each hydrogen atom in the 4- to 10-membered heterocycloalkyl group is independently optionally substituted with 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 -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)OC1-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-C -P(O)2(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 two hydrogen atoms on a single carbon atom of a 4- to 10-membered heterocycloalkyl group are combined to form an oxo or alkenyl group;
[0091] Each R 11 、R 12 、R 13 and R 14are independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-10 membered heterocycloalkyl, 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 Rb 、-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 1 and R 11 、R 1 and R 12 、R 1 and R 13 、R 1 and R 14 , two R 11 and R 12 or two R 13 and R 14 and one or more carbon atoms to which they are attached are combined to form a C3-C6 cycloalkyl group or a 4-10 membered heterocycloalkyl group, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10 Each hydrogen atom in aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted with 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 eC(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 R 11 and R 12 or R 13 and R 14 Together with the carbon atom to which it is attached, it forms an oxo or C2-C6 alkenyl group;
[0092] Each R a 、R b 、R c 、R d 、R e 、R f 、R g and R h independently selected from the group consisting of: H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, C1-C6 alkylene-C6-C 10 Aryl and 5- to 10-membered heteroaryl; or two R a and R b , or R c and R d , or R e and R f , or Rg and R h Together with the one or more atoms to which it is attached, it forms a C3-C6 cycloalkyl group, a 4- to 10-membered heterocycloalkyl group, a C6-C 10 Aryl or 5 to 10 membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 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 optionally substituted with 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)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)OC1-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 to which it is attached, form an oxo or alkenyl group;
[0093] m is 0, 1, 2, 3, 4, 5, 6 or 7;
[0094] n is 0, 1, 2, 3, 4, 5, 6 or 7; and
[0095] p is 0 or 1.
[0096] In some embodiments, at least one hydrogen atom in the compound of formula II is substituted with deuterium. In some embodiments, R 1 、R 2 or R 3 At least one hydrogen atom in the molecule is substituted with deuterium.
[0097] In some embodiments, the present disclosure provides a compound of formula III or a pharmaceutically acceptable salt thereof,
[0098]
[0099] where R 1 、R 2 、R 3 、R 9 , A, B, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein.
[0100] In some embodiments, the present disclosure provides a compound of formula IV or a pharmaceutically acceptable salt thereof,
[0101]
[0102] where R 1 、R 2 、R 3 、R 9 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , m, n and p are as described herein.
[0103] In some embodiments, the present disclosure provides a compound of formula IV or a pharmaceutically acceptable salt thereof,
[0104]
[0105] where R 1 、R 2 、R 3 、R 9 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n, and p are as described herein, and Z 5 N or C(R 15 ), and Z6 N or C(R 16 ).
[0106] In some embodiments, the present disclosure provides a compound of formula V or a pharmaceutically acceptable salt thereof,
[0107]
[0108] where R 1 、R 2 、R 3 、R 9 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein.
[0109] In some embodiments, the present disclosure provides a compound of Formula VI or a pharmaceutically acceptable salt thereof,
[0110]
[0111] where R 1 、R 2 、R 3 、R 9 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein.
[0112] In some embodiments, the present disclosure provides a compound of Formula VII or a pharmaceutically acceptable salt thereof,
[0113]
[0114] where R 1 、R 2 、R 3 、R 9 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein.
[0115] In some embodiments, the present disclosure provides a compound of Formula VII or a pharmaceutically acceptable salt thereof,
[0116]
[0117] where R 1、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n, and p are as described herein, and Z 5 N or C(R 15 ), and Z 6 N or C(R 16 ).
[0118] In some embodiments, the present disclosure provides a compound of Formula VIII or a pharmaceutically acceptable salt thereof,
[0119]
[0120] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein.
[0121] In some embodiments, the present disclosure provides a compound of Formula IX or a pharmaceutically acceptable salt thereof,
[0122]
[0123] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein.
[0124] In some embodiments, the present disclosure provides a compound of formula X or a pharmaceutically acceptable salt thereof,
[0125]
[0126] where R 1 、R 2 、R 3 、R 9 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein.
[0127] In some embodiments, the present disclosure provides a compound of Formula XI or a pharmaceutically acceptable salt thereof,
[0128]
[0129] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein.
[0130] In some embodiments, the present disclosure provides a compound of Formula XII or a pharmaceutically acceptable salt thereof,
[0131]
[0132] where R 1 、R 2 、R 3 、R 9 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein.
[0133] In some embodiments, the present disclosure provides a compound of Formula XIII or a pharmaceutically acceptable salt thereof,
[0134]
[0135] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein.
[0136] In some embodiments, the present disclosure provides a compound of Formula XIV or a pharmaceutically acceptable salt thereof,
[0137]
[0138] where R 1 、R 2 、R 3 、R 9 , A, X, Y 2, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , m, n and p are as described herein.
[0139] In some embodiments, the present disclosure provides a compound of Formula XIV or a pharmaceutically acceptable salt thereof,
[0140]
[0141] where R 1 、R 2 、R 3 、R 9 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n, and p are as described herein; and Z 5 N or C(R 15 ); and Z 6 N or C(R 16 ).
[0142] In some embodiments, the present disclosure provides a compound of Formula XV or a pharmaceutically acceptable salt thereof,
[0143]
[0144] where R 1 、R 2 、R 3 、R 9 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , m, n and p are as described herein.
[0145] In some embodiments, the present disclosure provides a compound of Formula XV or a pharmaceutically acceptable salt thereof,
[0146]
[0147] where R 1 、R 2 、R 3 、R 9 , A, X, Y 2 , Z 1 , Z 2 , Z3 , Z 4 , m, n, and p are as described herein; and Z 5 N or C(R 15 ); and Z 6 N or C(R 16 ).
[0148] In some embodiments, the present disclosure provides a compound of Formula XVI or a pharmaceutically acceptable salt thereof,
[0149]
[0150] where R 1 、R 2 、R 3 , A, B, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , m, n and p are as described herein, and Ring C is a 4- to 8-membered heterocycloalkyl, and q is 0, 1 or 2.
[0151] In some embodiments, the present disclosure provides a compound of Formula XVII or a pharmaceutically acceptable salt thereof,
[0152]
[0153] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , m, n and p are as described herein, and Ring C is a 4- to 8-membered heterocycloalkyl, and q is 0, 1 or 2.
[0154] In some embodiments, the present disclosure provides a compound of Formula XVII or a pharmaceutically acceptable salt thereof,
[0155]
[0156] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4, m, n and p are as described herein; Ring C is a 4- to 8-membered heterocycloalkyl; q is 0, 1 or 2; Z 5 N or C(R 15 ); and Z 6 N or C(R 16 ).
[0157] In some embodiments, the present disclosure provides a compound of Formula XVIII or a pharmaceutically acceptable salt thereof,
[0158]
[0159] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein, and Ring C is a 4- to 8-membered heterocycloalkyl, and q is 0, 1 or 2.
[0160] In some embodiments, the present disclosure provides a compound of Formula XIX or a pharmaceutically acceptable salt thereof,
[0161]
[0162] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein, and Ring C is a 4- to 8-membered heterocycloalkyl, and q is 0, 1 or 2.
[0163] In some embodiments, the present disclosure provides a compound of formula XX or a pharmaceutically acceptable salt thereof,
[0164]
[0165] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein, and Ring C is a 4- to 8-membered heterocycloalkyl, and q is 0, 1 or 2.
[0166] In some embodiments, the present disclosure provides a compound of formula XXI or a pharmaceutically acceptable salt thereof,
[0167]
[0168] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein, and Ring C is a 4- to 8-membered heterocycloalkyl, and q is 0, 1 or 2.
[0169] In some embodiments, the present disclosure provides a compound of formula XXII or a pharmaceutically acceptable salt thereof,
[0170]
[0171] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , m, n and p are as described herein, and Ring C is a 4- to 8-membered heterocycloalkyl, and q is 0, 1 or 2.
[0172] In some embodiments, the present disclosure provides a compound of formula XXII or a pharmaceutically acceptable salt thereof,
[0173]
[0174] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein; Ring C is a 4- to 8-membered heterocycloalkyl; q is 0, 1 or 2; Z 5 N or C(R 15 ); and Z 6 N or C(R 16 ).
[0175] In some embodiments, the present disclosure provides a compound of formula XXIII or a pharmaceutically acceptable salt thereof,
[0176]
[0177] where R 1 、R 2 、R 3 , A, B, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , m, n and p are as described herein, and Ring C is a 4- to 8-membered heterocycloalkyl, and q is 0, 1 or 2.
[0178] In some embodiments, the present disclosure provides a compound of Formula XXIV or a pharmaceutically acceptable salt thereof,
[0179]
[0180] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , m, n and p are as described herein, and Ring C is a 4- to 8-membered heterocycloalkyl, and q is 0, 1 or 2.
[0181] In some embodiments, the present disclosure provides a compound of Formula XXIV or a pharmaceutically acceptable salt thereof,
[0182]
[0183] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein; Ring C is a 4- to 8-membered heterocycloalkyl; q is 0, 1 or 2; Z 5 N or C(R 15 ); and Z 6 N or C(R 16 ).
[0184] In some embodiments, the present disclosure provides a compound of Formula XXV or a pharmaceutically acceptable salt thereof,
[0185]
[0186] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein, and Ring C is a 4- to 8-membered heterocycloalkyl, and q is 0, 1 or 2.
[0187] In some embodiments, the present disclosure provides a compound of formula XXVI or a pharmaceutically acceptable salt thereof,
[0188]
[0189] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein, and Ring C is a 4- to 8-membered heterocycloalkyl, and q is 0, 1 or 2.
[0190] In some embodiments, the present disclosure provides a compound of Formula XXVII or a pharmaceutically acceptable salt thereof,
[0191]
[0192] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein, and Ring C is a 4- to 8-membered heterocycloalkyl, and q is 0, 1 or 2.
[0193] In some embodiments, the present disclosure provides a compound of Formula XXVIII or a pharmaceutically acceptable salt thereof,
[0194]
[0195] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z3 , Z 4 , m, n and p are as described herein, and Ring C is a 4- to 8-membered heterocycloalkyl, and q is 0, 1 or 2.
[0196] In some embodiments, the present disclosure provides a compound of Formula XXIX or a pharmaceutically acceptable salt thereof,
[0197]
[0198] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , m, n and p are as described herein, and Ring C is a 4- to 8-membered heterocycloalkyl, and q is 0, 1 or 2.
[0199] In some embodiments, the present disclosure provides a compound of Formula XXIX or a pharmaceutically acceptable salt thereof,
[0200]
[0201] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein; Ring C is a 4- to 8-membered heterocycloalkyl; q is 0, 1 or 2; Z 5 N or C(R 15 ); and Z 6 N or C(R 16 ).
[0202] In some embodiments, the present disclosure provides a compound of formula XXX or a pharmaceutically acceptable salt thereof,
[0203]
[0204] where R 1 、R 2 、R 3 , A, B, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z6 , m, n, and p are as described herein, and X 1 is -O-, -NH- or -CH2-, q is 0, 1 or 2, t is 1 or 2, and v is 1 or 2.
[0205] In some embodiments, the present disclosure provides a compound of Formula XXXI or a pharmaceutically acceptable salt thereof,
[0206]
[0207] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , m, n, and p are as described herein, and X 1 is -O- or -CH2-, q is 0, 1 or 2, t is 1 or 2, and v is 1 or 2.
[0208] In some embodiments, the present disclosure provides a compound of Formula XXXI or a pharmaceutically acceptable salt thereof,
[0209]
[0210] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n, and p are as described herein, and X 1 is -O- or -CH2-, q is 0, 1 or 2, t is 1 or 2, v is 1 or 2, Z 5 N or C(R 15 ), and Z 6 N or C(R 16 ).
[0211] In some embodiments, the present disclosure provides a compound of Formula XXXII or a pharmaceutically acceptable salt thereof,
[0212]
[0213] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1, Z 2 , Z 3 , Z 4 , m, n, and p are as described herein, and X 1 is -O- or -CH2-, q is 0, 1 or 2, t is 1 or 2, and v is 1 or 2.
[0214] In some embodiments, the present disclosure provides a compound of formula XXXIII or a pharmaceutically acceptable salt thereof,
[0215]
[0216] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n, and p are as described herein, and X 1 is -O-, -NH- or -CH2-, q is 0, 1 or 2, t is 1 or 2, and v is 1 or 2.
[0217] In some embodiments, the present disclosure provides a compound of Formula XXXIV or a pharmaceutically acceptable salt thereof,
[0218]
[0219] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n, and p are as described herein, and X 1 is -O- or -CH2-, q is 0, 1 or 2, t is 1 or 2, and v is 1 or 2.
[0220] In some embodiments, the present disclosure provides a compound of Formula XXXV or a pharmaceutically acceptable salt thereof,
[0221]
[0222] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n, and p are as described herein, and X1 is -O- or -CH2-, q is 0, 1 or 2, t is 1 or 2, and v is 1 or 2.
[0223] In some embodiments, the present disclosure provides a compound of Formula XXXVI or a pharmaceutically acceptable salt thereof,
[0224]
[0225] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , m, n, and p are as described herein, and X 1 is -O- or -CH2-, q is 0, 1 or 2, t is 1 or 2, and v is 1 or 2.
[0226] In some embodiments, the present disclosure provides a compound of Formula XXXVI or a pharmaceutically acceptable salt thereof,
[0227]
[0228] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n, and p are as described herein, and X 1 is -O- or -CH2-, q is 0, 1 or 2, t is 1 or 2, v is 1 or 2, Z 5 N or C(R 15 ), and Z 6 N or C(R 16 ).
[0229] In some embodiments, the present disclosure provides a compound of Formula XXXVII or a pharmaceutically acceptable salt thereof,
[0230]
[0231] where R 1 、R 2 、R 3 , A, B, X, Y 2 、Y 2 , Z 1 , Z2 , Z 3 , Z 4 , Z 5 , Z 6 , m, n and p are as described herein, and Ring D is C3-C6 cycloalkyl or 4- to 8-membered heterocycloalkyl.
[0232] In some embodiments, the present disclosure provides a compound of Formula XXXVIII or a pharmaceutically acceptable salt thereof,
[0233]
[0234] where R 1 、R 2 、R 3 , A, X, Y 1 、Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , m, n and p are as described herein, and Ring D is C3-C6 cycloalkyl or 4- to 8-membered heterocycloalkyl.
[0235] In some embodiments, the present disclosure provides a compound of Formula XXXVIII or a pharmaceutically acceptable salt thereof,
[0236]
[0237] where R 1 、R 2 、R 3 , A, X, Y 1 、Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein, and Ring D is C3-C6 cycloalkyl or 4- to 8-membered heterocycloalkyl, Z 5 N or C(R 15 ), and Z 6 N or C(R 16 ).
[0238] In some embodiments, the present disclosure provides a compound of formula XXXIX or a pharmaceutically acceptable salt thereof,
[0239]
[0240] where R 1 、R 2 、R 3 , A, X, Y1 、Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein, and Ring D is C3-C6 cycloalkyl or 4- to 8-membered heterocycloalkyl.
[0241] In some embodiments, the present disclosure provides a compound of formula XXXX or a pharmaceutically acceptable salt thereof,
[0242]
[0243] Its R 1 、R 2 、R 3 , A, X, Y 1 、Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein, and Ring D is C3-C6 cycloalkyl or 4- to 8-membered heterocycloalkyl.
[0244] In some embodiments, the present disclosure provides a compound of Formula XXXXI or a pharmaceutically acceptable salt thereof,
[0245]
[0246] Its R 1 、R 2 、R 3 , A, X, Y 1 、Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein, and Ring D is C3-C6 cycloalkyl or 4- to 8-membered heterocycloalkyl.
[0247] In some embodiments, the present disclosure provides a compound of formula XXXXII or a pharmaceutically acceptable salt thereof,
[0248]
[0249] Its R 1 、R 2 、R 3 , A, X, Y 1 、Y 2 , Z 1 , Z 2 , Z 3 , Z 4, m, n and p are as described herein, and Ring D is C3-C6 cycloalkyl or 4- to 8-membered heterocycloalkyl.
[0250] In some embodiments, the present disclosure provides a compound of formula XXXXIII or a pharmaceutically acceptable salt thereof,
[0251]
[0252] where R 1 、R 2 、R 3 、R 9 , A, X, Y 1 、Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , m, n and p are as described herein, and Ring D is C3-C6 cycloalkyl or 4- to 8-membered heterocycloalkyl.
[0253] In some embodiments, the present disclosure provides a compound of formula XXXXIII or a pharmaceutically acceptable salt thereof,
[0254]
[0255] where R 1 、R 2 、R 3 、R 9 , A, X, Y 1 、Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein, and Ring D is C3-C6 cycloalkyl or 4- to 8-membered heterocycloalkyl, Z 5 N or C(R 15 ), and Z 6 N or C(R 16 ).
[0256] In some embodiments, the present disclosure provides a compound of formula XXXXIV or a pharmaceutically acceptable salt thereof,
[0257]
[0258] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z3 , Z 4 , m, n, and p are as described herein, and wherein Ring C is a 4- to 8-membered heterocycloalkyl; and q is 0, 1, or 2.
[0259] In some embodiments, the present disclosure provides a compound of formula XXXXV or a pharmaceutically acceptable salt thereof,
[0260]
[0261] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n, and p are as described herein, and wherein Ring C is a 4- to 8-membered heterocycloalkyl; and q is 0, 1, or 2.
[0262] In some embodiments, the present disclosure provides a compound of formula XXXXVI or a pharmaceutically acceptable salt thereof,
[0263]
[0264] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein, and wherein Ring C is a 4- to 8-membered heterocycloalkyl; X 1 is -O-, -NH- or -CH2-; q is 0, 1 or 2; t is 1 or 2, and v is 1 or 2.
[0265] In certain embodiments of the above aspects, the compound of formula (I) to (XXXXVI) is a compound selected from those described or exemplified in the detailed description below.
[0266] In other aspects, the present disclosure relates to a pharmaceutical composition comprising at least one compound of formula (I) to (XXXXVI) or a pharmaceutically acceptable salt thereof. The pharmaceutical composition according to the present disclosure may further comprise a pharmaceutically acceptable excipient.
[0267] In other aspects, the present disclosure relates to a compound of Formula (I) to (XXXXVI) or a pharmaceutically acceptable salt thereof, which is suitable for use as a medicament.
[0268] In other aspects, the present disclosure relates to a method of treating a disease such as cancer, comprising administering to a subject in need of such treatment an effective amount of at least one compound of Formula (I) to (XXXXVI) or a pharmaceutically acceptable salt thereof.
[0269] In other aspects, the present disclosure relates to the use of compounds of formula (I) to (XXXXVI), or pharmaceutically acceptable salts thereof, for the preparation of medicaments for treating diseases such as cancer, and the use of these compounds and salts for treating these diseases.
[0270] In other aspects, the present disclosure relates to a method of inhibiting Ras (such as K-Ras), comprising: contacting a cell comprising one or more of Ras with an effective amount of at least one compound of Formula (I) to (XXXXVI) or a pharmaceutically acceptable salt thereof and / or with at least one pharmaceutical composition of the present disclosure, wherein the contacting is in vitro, ex vivo, or in vivo.
[0271] Other embodiments, features and advantages of the present disclosure will be apparent from the following embodiments and through practice of the present disclosure. The disclosed compounds may be described as embodiments in any of the following enumerated clauses. It should be understood that any embodiment described herein may be used in combination with any other embodiment described herein to the extent that the embodiments do not contradict each other.
[0272] 1. A compound of formula I or a pharmaceutically acceptable salt thereof,
[0273]
[0274] in
[0275] X is -O-, -S- or -NR 4 -;
[0276] Z 1 N or C(R 5 );
[0277] Z 2 N or C(R 6 );
[0278] Z 3 N or C(R 7 );
[0279] Z 4 N or C(R 8 );
[0280] The premise is Z 1 to Z 4 At least two of them are N;
[0281] Ring A is a 5- to 8-membered heterocycloalkyl group or a C5-C8 cycloalkyl group;
[0282] Ring B is C6-C 10 aryl or 5- to 10-membered heteroaryl;
[0283] Each R 1 are independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-10 membered heterocycloalkyl, 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 R 1 Together with the one or more atoms to which it is attached, it forms a C3-C6 cycloalkyl group or a 4- to 10-membered heterocycloalkyl group, 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 heterocycloalkyl groups is independently optionally substituted with 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;
[0284] Each R 2 are independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-10 membered heterocycloalkyl, 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 、-NRc 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 R 2 Together with the atoms to which they are attached, they form a C3-C6 cycloalkyl group or a 4- to 10-membered heterocycloalkyl group, 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 heterocycloalkyl groups is independently optionally substituted with 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;
[0285] R 3 -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl), C6-C10 Aryl, -C1-C6 alkylene-(C6-C 10 aryl), 5- to 10-membered heteroaryl or -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl), wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl), C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 Each hydrogen atom in -C1-C6 alkylene-(5-10 membered heteroaryl) is independently optionally substituted with 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 、-NRe 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;
[0286] R 4 is H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl or 5 to 10 membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 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 optionally substituted with 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 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;
[0287] Each R 5 、R 6 、R 7 and R 8 are independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-10 membered heterocycloalkyl, 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;
[0288] Each R a 、R b 、R c 、R d 、R e 、R f 、R g and R h independently selected from the group consisting of: H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10Aryl, C1-C6 alkylene-C6-C 10 Aryl and 5- to 10-membered heteroaryl; or two R a and R b , or R c and R d , or R e and R f , or R g and R h Together with the one or more atoms to which it is attached, it forms a C3-C6 cycloalkyl group, a 4- to 10-membered heterocycloalkyl group, a C6-C 10 Aryl or 5 to 10 membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 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 optionally substituted with 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)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)OC1-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 to which it is attached, form an oxo or alkenyl group;
[0289] m is 0, 1, 2, 3, 4, 5, 6 or 7;
[0290] n is 0, 1, 2, 3, 4, 5, 6 or 7; and
[0291] p is 0 or 1.
[0292] 2. The compound according to clause 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula II,
[0293]
[0294] in
[0295] Y 1 for -O-, -S-, -S(O)-, -S(O)2-, -NR 9 -or-CR 11 R 12 -;
[0296] Y 2 for -O-, -S-, -S(O)-, -S(O)2-, -NR 10 -or-CR 13 R 14 -;
[0297] Each R 9 and R 10 are independently H, deuterium, -C(O)R g 、-C(O)NR g R h , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4 to 10 membered heterocycloalkyl, C6-C 10 Aryl or 5 to 10 membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 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 optionally substituted with 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 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 9 及R 1 或R 10 及R 1and the atoms to which they are attached are combined to form a 4- to 10-membered heterocycloalkyl group, wherein each hydrogen atom in the 4- to 10-membered heterocycloalkyl group is independently optionally substituted with 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) -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)OC1-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 -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 two hydrogen atoms on a single carbon atom of a 4- to 10-membered heterocycloalkyl group are combined to form an oxo or alkenyl group; and
[0298] Each R 11 、R 12 、R 13 and R 14 are independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-10 membered heterocycloalkyl, 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 1 and R 11 、R 1 and R 12 、R 1 and R 13 、R 1 and R 14 , two R 11 and R 12 or two R 13 and R 14 and one or more carbon atoms to which they are attached are combined to form a C3-C6 cycloalkyl group or a 4-10 membered heterocycloalkyl group, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10 Each hydrogen atom in aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted with 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 R 11 and R 12 or R 13 and R 14 Together with the carbon atom to which it is attached, it forms an oxo or C2-C6 alkenyl group.
[0299] 3. The compound according to clause 1 or a pharmaceutically acceptable salt thereof, wherein the compound has Formula XXXVII, XXXVIII, XXXIX, XXXX, XXXXI, XXXXII or XXXXIII:
[0300]
[0301]
[0302]
[0303] in
[0304] Y 1 for -O-, -S-, -S(O)-, -S(O)2-, -NR 9 -or-CR 11 R 12 -;
[0305] Y 2 for -O-, -S-, -S(O)-, -S(O)2-, -NR 10 -or-CR 13 R 14 -;
[0306] Z 5 N or C(R 15 );
[0307] Z 6 N or C(R16 );
[0308] Ring D is a C3-C6 cycloalkyl group or a 4- to 8-membered heterocycloalkyl group;
[0309] Each R 9 and R 10 are independently H, deuterium, -C(O)R g 、-C(O)NR g R h , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4 to 10 membered heterocycloalkyl, C6-C 10 Aryl or 5 to 10 membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 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 optionally substituted with 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 R 9 and R 1 or R 10 and R 1and the atoms to which they are attached are combined to form a 4- to 10-membered heterocycloalkyl group, wherein each hydrogen atom in the 4- to 10-membered heterocycloalkyl group is independently optionally substituted with 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)OC1-C6 alkyl、-N(C1-C6 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 two hydrogen atoms on a single carbon atom of a 4- to 10-membered heterocycloalkyl group are combined to form an oxo or C2-C6 alkenyl group;
[0310] Each R 11 、R 12 、R 13 and R 14 are independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-10 membered heterocycloalkyl, 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 1 and R 11 、R 1 and R 12 、R 1 and R 13 、R 1 and R 14 , two R 11 and R 12 or two R 13 and R 14 and one or more carbon atoms to which they are attached are combined to form a C3-C6 cycloalkyl group or a 4-10 membered heterocycloalkyl group, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10 Each hydrogen atom in aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently optionally substituted with 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 R 11 and R 12 or R 13 and R 14 Together with the carbon atom to which it is attached, it forms an oxo or C2-C6 alkenyl group; and
[0311] Each R 15 and R 16 are independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-10 membered heterocycloalkyl, 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)NRg 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.
[0312] 4. The compound according to clause 1 or 2, wherein the compound has formula III
[0313]
[0314] or a pharmaceutically acceptable salt thereof.
[0315] 5. The compound according to clause 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound has formula XVI, XXIII or XXX,
[0316]
[0317]
[0318] wherein ring C is a 4- to 8-membered heterocycloalkyl group, X 1 is -NH-, -O- or -CH2-, q is 0, 1 or 2, t is 1 or 2, and v is 1 or 2.
[0319] 6. A compound according to any one of clauses 1 to 5, or a pharmaceutically acceptable salt thereof, wherein the compound has Formula IV, XIV, XVII, XXII, XXIV, XXIX, XXXI or XXXVI,
[0320]
[0321]
[0322]
[0323] Z 5 N or C(R 15 );
[0324] Z 6 N or C(R 16 );
[0325] Each R 15 and R 16 are independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-10 membered heterocycloalkyl, 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;
[0326] Ring C is a 4- to 8-membered heterocycloalkyl group;
[0327] X 1 is -O-, -NH- or -CH2-;
[0328] q is 0, 1, or 2;
[0329] t is 1 or 2, and
[0330] v is 1 or 2.
[0331] 7. A compound according to any one of clauses 1 to 5, or a pharmaceutically acceptable salt thereof, wherein the compound has Formula V, XI, XVIII, XXI, XXV, XXVIII, XXXII or XXXV,
[0332]
[0333]
[0334]
[0335] wherein ring C is a 4- to 8-membered heterocycloalkyl group; 1 is -O-, -NH-, or -CH2-; q is 0, 1, or 2; t is 1 or 2; and v is 1 or 2.
[0336] 8. A compound according to any one of clauses 1 to 5, or a pharmaceutically acceptable salt thereof, wherein the compound has Formula VI, X, XIX, XX, XXVI, XXVII, XXXIII, XXXIV, XXXXIII, XXXXIV, XXXXV or XXXXVI,
[0337]
[0338]
[0339]
[0340]
[0341] wherein ring C is a 4- to 8-membered heterocycloalkyl group; 1 is -O-, -NH-, or -CH2-; q is 0, 1, or 2; t is 1 or 2; and v is 1 or 2.
[0342] 9. A compound according to any one of clauses 1 to 5, or a pharmaceutically acceptable salt thereof, wherein the compound has Formula VII or XV,
[0343]
[0344] Z 5 N or C(R 15 );
[0345] Z 6 N or C(R 16 );and
[0346] Each R 15 and R 16 are independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-10 membered heterocycloalkyl, 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 Rh 、-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.
[0347] 10. A compound according to any one of clauses 1 to 5, or a pharmaceutically acceptable salt thereof, wherein the compound has formula VIII or XIII
[0348]
[0349] or a pharmaceutically acceptable salt thereof.
[0350] 11. A compound according to any one of clauses 1 to 5, or a pharmaceutically acceptable salt thereof, wherein the compound has Formula IX or Formula XII
[0351]
[0352]
[0353] or a pharmaceutically acceptable salt thereof.
[0354] 12. A compound according to any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R 1 is deuterium, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, wherein each hydrogen atom in the C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is independently optionally substituted with deuterium, halogen, -R e 、-Rf , 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 , -NR f , -NR e , -NR f , -NR e , -NR e R f , -NR e , -NR f , -NR e , -NR f , -NR e , -NR e R f , -NR e , -NR 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 9 and R 1or R 10 and R 1 and the atoms to which they are attached are combined to form a 4- to 10-membered heterocycloalkyl group, wherein each hydrogen atom in the 4- to 10-membered heterocycloalkyl group is independently optionally substituted with 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)OC1-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 two hydrogen atoms on a single carbon atom of a 4- to 10-membered heterocycloalkyl group are combined to form an oxo or C2-C6 alkenyl group; or two R 1 Together with the one or more atoms to which it is attached, it forms a C3-C6 cycloalkyl group or a 4- to 10-membered heterocycloalkyl group, 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 heterocycloalkyl groups is independently optionally substituted with 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)Re 、-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.
[0355] 13. A compound according to any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein Ring A optionally together with Ring C or Ring D forms a core of a compound of Formula I, said core having the following formula:
[0356]
[0357]
[0358] Among them Is with ring B or -(X) p -R 3 and each hydrogen atom in Ring A, Ring C if present, and Ring D if present is independently optionally substituted with R 1 Substitution: 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 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.
[0359] 14. A compound according to any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein Ring A optionally forms together with Ring C or Ring D a core of a compound of Formula I, said core having the following formula:
[0360]
[0361]
[0362] Among them Is with ring B or -(X) p -R 3 covalent attachment point.
[0363] 15. A compound according to any one of clauses 1 to 13, or a pharmaceutically acceptable salt thereof, wherein Ring A is a fused 5- to 8-membered heterocycloalkyl group forming the core of a compound of Formula I, said core having the formula:
[0364]
[0365]
[0366] Among them Is with ring B or -(X) p -R 3 covalent attachment point.
[0367] 16. A compound according to any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein Y 2 It is -O-.
[0368] 17. A compound according to any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein Y 2 It is -CH2-.
[0369] 18. A compound according to any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R 3is -C1-C6 alkyl, 4- to 10-membered heterocycloalkyl, or -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl), wherein each hydrogen atom in -C1-C6 alkyl, 4- to 10-membered heterocycloalkyl, or -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl) is independently optionally substituted with 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.
[0370] 19. A compound according to any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R 3 -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl), wherein each hydrogen atom in -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl) is independently optionally substituted with 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.
[0371] 20. A compound according to any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R 3 for
[0372]
[0373] wherein each hydrogen atom is independently optionally substituted by 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)NRe 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 is the point of covalent attachment.
[0374] 21. A compound according to any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R 3 for
[0375]
[0376] in It is an inorganic counter ion or an organic counter ion.
[0377] 22. A compound according to any one of clauses 1 to 18, or a pharmaceutically acceptable salt thereof, wherein R 3 is a 4- to 10-membered heterocycloalkyl group, wherein each hydrogen atom in the 4- to 10-membered heterocycloalkyl group is independently optionally substituted with 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 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.
[0378] 23. A compound according to any one of clauses 1 to 18 or 22, or a pharmaceutically acceptable salt thereof, wherein R 3 for
[0379]
[0380] in is the point of covalent attachment.
[0381] 24. A compound according to any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein m is 1, 2, 3 or 4.
[0382] 25. A compound according to any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2 or 3.
[0383] 26. A compound according to any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein Z 1 is N.
[0384] 27. A compound according to any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein Z 2 is N.
[0385] 28. A compound according to any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein Z 3 CR 7 And Z4 is N.
[0386] 29. A compound according to any one of clauses 1 to 27, or a pharmaceutically acceptable salt thereof, wherein Z 3 CR 7 And Z 4 CR 8 .
[0387] 30. A compound according to any one of clauses 1 to 27, or a pharmaceutically acceptable salt thereof, wherein Z 3 N and Z 4 CR 8 .
[0388] 31. A compound according to any one of clauses 1 to 27, or a pharmaceutically acceptable salt thereof, wherein Z 3 N and Z 4 is N.
[0389] 32. A compound according to any one of clauses 1 to 27, or a pharmaceutically acceptable salt thereof, wherein Z 3 N, Z 4 CR 8 , Z 5 CR 15 , and Z 6 CR 16 .
[0390] 33. A compound according to any one of clauses 1 to 27, or a pharmaceutically acceptable salt thereof, wherein Z 3 CR 7 , Z 4 N, Z 5 CR 15 , and Z 6 CR 16 .
[0391] 34. A compound according to any one of clauses 1 to 27, or a pharmaceutically acceptable salt thereof, wherein Z 3 N, Z 4 N, Z 5 CR 15 , and Z 6 CR 16 .
[0392] 35. A compound according to any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein p is 0.
[0393] 36. The compound according to any one of clauses 1 to 34, or a pharmaceutically acceptable salt thereof, wherein p is 1.
[0394] 37. A compound according to any one of clauses 1 to 34 or 36, or a pharmaceutically acceptable salt thereof, wherein X is -O-.
[0395] 38. A compound according to any one of clauses 1 to 34 or 36, or a pharmaceutically acceptable salt thereof, wherein X is -NR 4 -.
[0396] 39. A compound according to any one of clauses 1 to 34 or 36, or a pharmaceutically acceptable salt thereof, wherein X is -S-.
[0397] 40. A compound according to any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein each R 2 are independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -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 optionally substituted independently with deuterium or halogen.
[0398] 41. A compound according to any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein Ring B is
[0399]
[0400]
[0401] in is the point of covalent attachment.
[0402] 42. A compound according to any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R 4 is H or methyl.
[0403] 43. A compound according to any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R 5 For H.
[0404] 44. A compound according to any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R 6 For H.
[0405] 45. A compound according to any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R 7 H or F.
[0406] 46. A compound according to any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R8 For H.
[0407] 47. A compound according to any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R 9 is H or methyl.
[0408] 48. A compound according to any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R 10 is H or methyl.
[0409] 49. A compound according to any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R 11 For H.
[0410] 50. A compound according to any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R 12 For H.
[0411] 51. A compound according to any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R 13 For H.
[0412] 52. A compound according to any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R 14 For H.
[0413] 53. A compound according to any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein Z may be present 5 is N.
[0414] 54. A compound according to any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein Z may be present 6 is N.
[0415] 55. A compound according to any one of clauses 1 to 51, or a pharmaceutically acceptable salt thereof, wherein Z may be present 5 CR 15 .
[0416] 56. A compound according to any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R 15 For H.
[0417] 57. A compound according to any one of clauses 1 to 53, or a pharmaceutically acceptable salt thereof, wherein Z may be present 6 CR 16 .
[0418] 58. A compound according to any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein R16 For H.
[0419] 59. The compound of clause 1 selected from the group consisting of 5-ethynyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[0420] 5-Ethyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[0421] (8aR,9R)-5-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-methyl-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-9-ol;
[0422] (8aR,9R)-5-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-methyl-8,8a,9,10,11,12-hexahydro-7H-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-9-ol;
[0423] (8aR,9R)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-9-ol;
[0424] (8aR,9R)-5-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-9-ol;
[0425] (8aS,11R)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-11-ol;
[0426] (8aS,11R)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-11-methyl-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-11-ol;
[0427] 5-Ethyl-6-fluoro-4-[(8S,8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8-methyl-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[0428] 7-Fluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphth-5-yl]-1,3-benzothiazol-2-amine;
[0429] 5-Ethyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2Z,7aS)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[0430] (3S)-7-Chloro-1-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl]-2,3-dihydro-1H-indol-3-ol;
[0431] 6-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphth-5-yl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine;
[0432] 3-Chloro-5-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl]-4-(trifluoromethyl)aniline;
[0433] 5-Ethynyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydropyrido[2',1':3,4][1,4]oxazaquino[5,6,7-de]quinazolin-5-yl]naphthalen-2-ol;
[0434] 5-Ethynyl-6-fluoro-4-[(9S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(propan-2-yl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[0435] 5-Ethynyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2Z,7aS)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[0436] (8aR,9R)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-methyl-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-9-ol;
[0437] 5-Ethynyl-6-fluoro-4-[(7aR,10aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-11-methyl-7a,8,10a,11-tetrahydro-10H-7,9-dioxa-1,3,6,11-tetraazanaphtho[1,8-fg]azulen-5-yl]naphthalen-2-ol;
[0438] 5-Ethynyl-6-fluoro-4-[(7aS,9aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-10-methyl-8,9,9a,10-tetrahydro-7aH-7-oxa-1,3,6,10-tetraazacyclotidino[5,6]cyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[0439] 5-Ethynyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8a,9,11,12-tetrahydro-8H-7,10-dioxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[0440] 5-Ethynyl-6-fluoro-4-[(8aS,12S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-12-methyl-8a,9,11,12-tetrahydro-8H-7,10-dioxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[0441] (8aS,12S)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8a,9,11,12-tetrahydro-8H-7,10-dioxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-12-carbonitrile;
[0442] (8aS,11R)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8a,9,11,12-tetrahydro-8H-7,10-dioxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11-carbonitrile;
[0443] (8aS,12R)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-12-carbonitrile;
[0444] (8aS,11R)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11-carbonitrile;
[0445] 5-Ethynyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8a,9,12,13-tetrahydro-8H,11H-7,10-dioxa-1,3,6,13a-tetraazanaphtho[1,8-ab]heptalen-5-yl]naphthalen-2-ol;
[0446] 5-Ethynyl-6-fluoro-4-[(8aS,13S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-13-methyl-8a,9,12,13-tetrahydro-8H,11H-7,10-dioxa-1,3,6,13a-tetraazanaphtho[1,8-ab]heptalen-5-yl]naphthalen-2-ol;
[0447] (8aS,13R)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8a,9,12,13-tetrahydro-8H,11H-7,10-dioxa-1,3,6,13a-tetraazanaphtho[1,8-ab]heptalene-13-carbonitrile;
[0448] 5-Ethynyl-6-fluoro-4-[(8aS,12S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-12-methyl-8a,9,12,13-tetrahydro-8H,11H-7,10-dioxa-1,3,6,13a-tetraazanaphtho[1,8-ab]heptalen-5-yl]naphthalen-2-ol;
[0449] (8aS,12R)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8a,9,12,13-tetrahydro-8H,11H-7,10-dioxa-1,3,6,13a-tetraazanaphtho[1,8-ab]heptalene-12-carbonitrile;
[0450] 5-Ethynyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,12,13-hexahydro-7,11-dioxa-1,3,6,13a-tetraazanaphtho[1,8-ab]heptalen-5-yl]naphthalen-2-ol;
[0451] 5-Ethynyl-6-fluoro-4-[(8aS,9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-methyl-8,8a,9,10,12,13-hexahydro-7,11-dioxa-1,3,6,13a-tetraazanaphtho[1,8-ab]heptalen-5-yl]naphthalen-2-ol;
[0452] 5-Ethynyl-6-fluoro-4-[(8aS,13S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-13-methyl-8,8a,9,10,12,13-hexahydro-7,11-dioxa-1,3,6,13a-tetraazanaphtho[1,8-ab]heptalen-5-yl]naphthalen-2-ol;
[0453] (8aS,13S)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,12,13-hexahydro-7,11-dioxa-1,3,6,13a-tetraazanaphtho[1,8-ab]heptalene-13-carbonitrile;
[0454] (8aS,12R)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,12,13-hexahydro-7,11-dioxa-1,3,6,13a-tetraazanaphtho[1,8-ab]heptalene-12-carbonitrile;
[0455] (8aS)-5-(5-chloro-1H-indazol-4-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene;
[0456] 5-Ethynyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2E)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[0457] (5P,8aS)-5-(3,5-dichloro-1H-indazol-4-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene;
[0458] (5M,8aS)-5-(3,5-dichloro-1H-indazol-4-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene;
[0459] 2-amino-7-fluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphth-5-yl]-1-benzothiophene-3-carbonitrile;
[0460] (8aS,11S)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-11-ol;
[0461] (8aR,11R)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-11-ol;
[0462] 6-((S)-1-Fluoro-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,5a,6,7,8,9-hexahydro-4-oxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-2-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine;
[0463] (8aS)-5-(8-ethynyl-3,7-difluoronaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene;
[0464] (8aR,11S)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-11-ol;
[0465] (2R,7aS)-7a-({[(8aS)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-2-yl]oxy}methyl)hexahydro-1H-pyrrolizin-2-ol;
[0466] 5-Ethynyl-6-fluoro-4-[(8aS)-4,11,11-trifluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[0467] (2S,7aS)-7a-({[(8aS)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-2-yl]oxy}methyl)hexahydro-1H-pyrrolizin-2-ol;
[0468] 5-Ethynyl-6-fluoro-4-[(7aR,10aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-7a,8,9,10,10a,11-hexahydro-7-oxa-1,3,6,11-tetraazanaphtho[1,8-fg]azulen-5-yl]naphthalen-2-ol;
[0469] (8aS,9S)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-9-ol;
[0470] 5-Ethynyl-6-fluoro-4-[4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-13-(hydroxymethyl)-8,9,10,11-tetrahydro-8,12-methano-7-oxa-1,3,6,12-tetraazacyclonona[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[0471] 4-[(8aS)-4,11-difluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl]-5-ethynyl-6-fluoronaphthalen-2-ol;
[0472] 5-Ethynyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,12-tetrahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[0473] 5-Ethynyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10-tetrahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[0474] 5-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11-carbonitrile;
[0475] 5-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11-carboxamide;
[0476] (8aS,9S)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-methyl-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-9-ol;
[0477] (8aS,9S)-5-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-methyl-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-9-ol;
[0478] (8aS)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11-carbonitrile;
[0479] 5-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-9-ol;
[0480] (8aS,11S)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-11-methyl-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-11-ol; and
[0481] 5-Ethynyl-6-fluoro-4-(4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7H-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl)naphthalen-2-ol;
[0482] or a pharmaceutically acceptable salt thereof.
[0483] 60. The compound of clause 1 selected from the group consisting of 5-ethynyl-6-fluoro-4-[(9S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(hydroxymethyl)-9,10-dimethyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[0484] 5-Ethynyl-6-fluoro-4-[(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(hydroxymethyl)-9,10-dimethyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[0485] 5-Ethyl-6-fluoro-4-[(9S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(hydroxymethyl)-9,10-dimethyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[0486] 5-Ethynyl-6-fluoro-4-[(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(hydroxymethyl)-9,10-dimethyl-7,8,9,10-tetrahydro-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[0487] 5-Ethyl-6-fluoro-4-[(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(hydroxymethyl)-9,10-dimethyl-7,8,9,10-tetrahydro-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[0488] 5-Ethynyl-6-fluoro-4-[(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(2-hydroxypropan-2-yl)-8,9-dihydro-7H-10-oxa-1,3,6-triazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[0489] 5-Ethyl-6-fluoro-4-[(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(2-hydroxypropan-2-yl)-8,9-dihydro-7H-10-oxa-1,3,6-triazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[0490] 5-Ethynyl-6-fluoro-4-{(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-[(1S)-1-hydroxyethyl]-8,9-dihydro-7H-10-oxa-1,3,6-triazacyclohepta[1,2,3-de]naphthalen-5-yl}naphthalen-2-ol;
[0491] 5-Ethyl-6-fluoro-4-{(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-[(1S)-1-hydroxyethyl]-8,9-dihydro-7H-10-oxa-1,3,6-triazacyclohepta[1,2,3-de]naphthalen-5-yl}naphthalen-2-ol;
[0492] 5-Ethynyl-6-fluoro-4-{(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-[(1R)-1-hydroxyethyl]-8,9-dihydro-7H-10-oxa-1,3,6-triazacyclohepta[1,2,3-de]naphthalen-5-yl}naphthalen-2-ol;
[0493] 5-Ethyl-6-fluoro-4-{(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-[(1R)-1-hydroxyethyl]-8,9-dihydro-7H-10-oxa-1,3,6-triazacyclohepta[1,2,3-de]naphthalen-5-yl}naphthalen-2-ol;
[0494] 5-Ethynyl-6-fluoro-4-{(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-[(1R)-1-hydroxyethyl]-10-methyl-7,8,9,10-tetrahydro-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl}naphthalen-2-ol;
[0495] 5-Ethyl-6-fluoro-4-{(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-[(1R)-1-hydroxyethyl]-10-methyl-7,8,9,10-tetrahydro-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl}naphthalen-2-ol;
[0496] 5-Ethynyl-6-fluoro-4-{(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-[(1R)-1-hydroxyethyl]-7,8,9,10-tetrahydro-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl}naphthalen-2-ol;
[0497] 5-Ethyl-6-fluoro-4-{(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-[(1R)-1-hydroxyethyl]-7,8,9,10-tetrahydro-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl}naphthalen-2-ol;
[0498] 5-Ethynyl-6-fluoro-4-{(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-[(1R)-1-hydroxyethyl]-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl}naphthalen-2-ol;
[0499] 5-Ethyl-6-fluoro-4-{(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-[(1R)-1-hydroxyethyl]-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl}naphthalen-2-ol;
[0500] 5-Ethynyl-6-fluoro-4-[(5R)-9-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-5-(2-hydroxypropan-2-yl)-4-methyl-5,6-dihydro-4H-pyrimido[4,5,6-de][1,6]naphthyridin-8-yl]naphthalen-2-ol;
[0501] 5-Ethyl-6-fluoro-4-[(5R)-9-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-5-(2-hydroxypropan-2-yl)-4-methyl-5,6-dihydro-4H-pyrimido[4,5,6-de][1,6]naphthyridin-8-yl]naphthalen-2-ol;
[0502] 5-Chloro-6-fluoro-4-{(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-[(1R)-1-hydroxyethyl]-7,8,9,10-tetrahydro-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl}naphthalen-2-ol;
[0503] 5,6-difluoro-4-{(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-[(1R)-1-hydroxyethyl]-7,8,9,10-tetrahydro-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl}naphthalen-2-ol;
[0504] 5-Ethynyl-6-fluoro-4-[(9S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(hydroxymethyl)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[0505] 5-Ethyl-6-fluoro-4-[(9S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(hydroxymethyl)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[0506] 4-[(9S)-9-Cyclopropyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]-5-ethynyl-6-fluoronaphthalen-2-ol;
[0507] 4-[(9S)-9-Cyclopropyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]-5-ethynyl-6-fluoronaphthalen-2-ol;
[0508] 4-[(9S)-9-Cyclopropyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]-5-ethyl-6-fluoronaphthalen-2-ol;
[0509] 4-[(9S)-9-Cyclopropyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]-5-ethyl-6-fluoronaphthalen-2-ol;
[0510] 4-[(9S)-9-cyclobutyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]-5-ethynyl-6-fluoronaphthalen-2-ol;
[0511] 5-Ethynyl-6-fluoro-4-{(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-[(2R)-oxolan-2-yl]-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl}naphthalen-2-ol;
[0512] 5-Ethynyl-6-fluoro-4-{(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-[(2R)-oxan-2-yl]-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl}naphthalen-2-ol;
[0513] 5-Ethynyl-6-fluoro-4-[(9S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[0514] 5-Ethynyl-6-fluoro-4-{(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-[(2R)-oxetan-2-yl]-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl}naphthalen-2-ol;
[0515] 5-Ethynyl-6-fluoro-4-[(9S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-methyl-10-(propan-2-yl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[0516] 5-Ethynyl-6-fluoro-4-[(9S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-methyl-10-(oxetan-3-yl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[0517] 5-Ethynyl-6-fluoro-4-[(9S)-4-fluoro-2-{[(2R)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(propan-2-yl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[0518] 5-Ethynyl-6-fluoro-4-[(9S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(2-methoxyethyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[0519] 5-Ethynyl-6-fluoro-4-[(9S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9,10-dimethyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[0520] 5-Ethynyl-6-fluoro-4-[(9S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-10-methyl-9-(propan-2-yl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[0521] 4-[(9S)-10-Benzyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]-5-ethynyl-6-fluoronaphthalen-2-ol;
[0522] (2R,7aS)-7a-({[(9S)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-2-yl]oxy}methyl)-2-fluoro-4-methylhexahydro-1H-pyrrolizin-4-ium;
[0523] 4-[(9S)-10-Benzyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(hydroxymethyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]-5-ethynyl-6-fluoronaphthalen-2-ol;
[0524] 4-[(9R)-10-Benzyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(hydroxymethyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]-5-ethynyl-6-fluoronaphthalen-2-ol;
[0525] 5-Ethynyl-6-fluoro-4-(4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl)naphthalen-2-ol;
[0526] 4-[(9S)-9-ethyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]-5-ethynyl-6-fluoronaphthalen-2-ol;
[0527] 5-Ethynyl-6-fluoro-4-[(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(hydroxymethyl)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[0528] 5-Ethyl-6-fluoro-4-[(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(hydroxymethyl)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[0529] 5-Ethynyl-6-fluoro-4-(4'-fluoro-2'-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-10'-methyl-8'H,10'H-spiro[cyclopropane-1,9'-[7]oxa[1,3,6,10]tetraazacyclohepta[1,2,3-de]naphthyl]-5'-yl)naphthalen-2-ol;
[0530] 5-Ethynyl-6-fluoro-4-(4'-fluoro-2'-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8'H,10'H-spiro[cyclopropane-1,9'-[7]oxa[1,3,6,10]tetraazacyclohepta[1,2,3-de]naphthyl]-5'-yl)naphthalen-2-ol;
[0531] 4-[(9S)-9-ethyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]-5-ethynyl-6-fluoronaphthalen-2-ol;
[0532] 5-Ethyl-4-[(9S)-9-ethyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]-6-fluoronaphthalen-2-ol;
[0533] 4-(10-ethyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
[0534] 5-Chloro-4-[(9S)-9-ethyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]-6-fluoronaphthalen-2-ol;
[0535] 4-(10-Benzyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-7,8,9,10-tetrahydro-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
[0536] 4-[(9S)-9-ethyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]-5,6-difluoronaphthalen-2-ol;
[0537] 2-amino-4-[(9S)-9-ethyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]-1-benzothiophene-3-carbonitrile;
[0538] 5-ethyl-6-fluoro-4-(4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-7,8,9,10-tetrahydro-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl)naphthalen-2-ol;
[0539] 5-Ethynyl-6-fluoro-4-(4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-7,8,9,10-tetrahydro-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl)naphthalen-2-ol;
[0540] 5-Ethyl-6-fluoro-4-[(9S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9,10-dimethyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[0541] 5-Ethyl-6-fluoro-4-[(9S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(hydroxymethyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[0542] 1-[8-(10-cyclopropyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl)-2-fluoro-6-hydroxynaphthalen-1-yl]ethan-1-one;
[0543] 4-(9-cyclopropyl-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
[0544] 4-(9-cyclopropyl-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
[0545] 5-ethyl-6-fluoro-4-((5aS)-1-fluoro-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methyl-5,5a,6,7,8,9-hexahydro-4-oxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-2-yl)naphthalen-2-ol;
[0546] 4-((S)-10-ethyl-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
[0547] 4-((S)-10-(2,2-difluoroethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
[0548] 5-Ethynyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10-methyl-4',5'-dihydro-2'H,8H,10H-7-oxa-1,3,6,10-tetraazaspiro[cyclohepta[de]naphthalene-9,3'-furan]-1(10a),2,3a,3a1(6a),5-pentaen-5-yl)naphthalen-2-ol;
[0549] 5-Ethynyl-6-fluoro-4-((S)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10-((R)-2-hydroxypropyl)-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphth-5-yl)naphthalen-2-ol;
[0550] 4-((S)-10-(2,2-difluoroethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol;
[0551] 5-ethyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10-methyl-4',5'-dihydro-2'H,8H,10H-7-oxa-1,3,6,10-tetraazaspiro[cyclohepta[de]naphthalene-9,3'-furan]-1(10a),2,3a,3a1(6a),5-pentaen-5-yl)naphthalen-2-ol; and
[0552] 5-Ethynyl-6-fluoro-4-((S)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-methyl-10-(2,2,2-trifluoroethyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphth-5-yl)naphthalen-2-ol;
[0553] or a pharmaceutically acceptable salt thereof.
[0554] 61. A pharmaceutical composition comprising at least one compound according to any one of clauses 1 to 60, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients.
[0555] 62. A method of treating a disease such as cancer, comprising administering to a subject in need of such treatment an effective amount of a compound according to any one of clauses 1 to 60, or a pharmaceutically acceptable salt thereof.
[0556] 63. A compound according to any one of clauses 1 to 60, or a pharmaceutically acceptable salt thereof, for use in a method of treating cancer in a subject.
[0557] 64. A compound according to any one of clauses 1 to 60, or a pharmaceutically acceptable salt thereof, for use in treating cancer in a subject.
[0558] 65. Use of a compound according to any one of clauses 1 to 60, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a subject. DETAILED DESCRIPTION
[0559] Before further describing the present disclosure, it should be understood that this disclosure is not limited to the particular embodiments described, as such may, of course, 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 the present disclosure will be limited only by the appended terms.
[0560] For the sake of brevity, the disclosures of the 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 meanings as those generally understood by those skilled in the art to which this disclosure pertains. All patents, applications, disclosed applications, and other publications mentioned herein are incorporated herein by reference in their entirety. If the definitions set forth in this section are contrary to or otherwise inconsistent with the definitions set forth in the patents, applications, or other publications incorporated herein by reference, the definitions set forth in this section shall prevail relative to the definitions incorporated herein by reference.
[0561] As used herein and in the appended clauses, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should be further noted that clauses can be drafted to exclude any optional elements. Thus, this statement is intended to serve as an antecedent basis for the use of exclusive terminology such as "solely," "only," and the like with respect to the recitation of clause elements, or the use of a "negative" limitation.
[0562] As used herein, the terms "including," "containing," and "comprising" are used in their open, non-limiting sense.
[0563] To provide a more concise description, some quantitative expressions given herein are not qualified with the term "about". It should be understood that, regardless of whether the term "about" is explicitly used, each quantity given herein is intended to refer to the actual given value, and it also means an approximate value of the given value reasonably inferred by a person of ordinary skill in the art, including equivalent values and approximate values obtained due to the experimental and / or measurement conditions of the given value. Whenever the yield is given in percentage form, such yield means that the yield is the mass of the same entity given relative to the maximum amount of the entity that can be obtained under specific stoichiometric conditions. Unless otherwise indicated, concentrations given in percentage form refer to mass ratios.
[0564] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to the methods and materials described herein can also be used to practice or test this disclosure, preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials listed in conjunction with the publications.
[0565] Unless otherwise indicated, the methods and techniques of the presently disclosed embodiments are generally performed according to conventional methods well known in the art and as described in various general and more specific references cited and discussed throughout this disclosure. See, for example, Loudon, Organic Chemistry, 4th ed., New York: Oxford University Press, 2002, pp. 360-361, 1084-1085; Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th ed., Wiley-Interscience, 2001.
[0566] Chemical nomenclature of compounds described herein was generally generated using the commercially available ACD / Name 2014 (ACD / Labs) or ChemBioDraw Ultra 13.0 (Perkin Elmer).
[0567] As used herein and in connection with depicting the chemical structures of the various embodiments described herein, "*", "**" and Indicates the point of covalent attachment of the chemical group or chemical structure in which the identifier is displayed to an adjacent chemical group or chemical structure. For example, in a hypothetical chemical structure AB, where A and B are joined by a covalent bond, in some embodiments, the portion of AB defined by the group or chemical structure A may be represented by "A-*," "A-**," or Indicates that "-*", "-**" and Each of the 's represents the bond of A and the point of covalent attachment to B. Alternatively, in some embodiments, the portion of AB defined by a group or chemical structure B may be represented by "*-B", "**-B" or Indicates that "-*", "-**" and Each of the represents a bond to B and a point of covalent attachment to A.
[0568] It will be appreciated that certain features of the disclosure described for clarity in the context of respective embodiments may also be provided in combination in a single embodiment. Conversely, various features of the disclosure described for brevity in the context of a single embodiment may also be provided separately or in any suitable subcombination. All combinations of embodiments for chemical groups represented by variables are particularly encompassed by the disclosure and disclosed herein to the extent that such combinations encompass compounds that are stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity), just as each combination is disclosed individually and explicitly herein. Additionally, all subcombinations of chemical groups listed in embodiments describing such variables are also particularly encompassed by the disclosure and disclosed herein, just as each such subcombination of chemical groups and each such subcombination is disclosed individually and explicitly herein.
[0569] Chemical definition
[0570] The term "alkyl" refers to a straight or branched monovalent hydrocarbon group. The term "alkylene" refers to a straight or branched divalent hydrocarbon group. In some embodiments, it may be advantageous to limit the number of atoms in an "alkyl" or "alkylene" group 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 alkyl 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 that would be considered equivalent to any of the foregoing examples given those of ordinary skill in the art and the teachings provided herein. Examples of alkylene groups include methylene (-CH2-), ethylene ((-CH2-)2), n-propylene ((-CH2-)3), isopropylene ((-C(H)(CH3)CH2-)), n-butylene ((-CH2-)4), and the like. It should be understood that an alkyl or alkylene group may be unsubstituted or substituted as described herein. An alkyl or alkylene group may be substituted with any substituent in the various embodiments described herein, including one or more of such substituents.
[0571] The term "alkenyl" refers to a straight or branched monovalent hydrocarbon radical having one or more double bonds. In some embodiments, it may be advantageous to limit the number of atoms in the "alkenyl" radical to a specific atomic range, such as C2-C 20 Alkenyl, C2-C 12Examples of alkenyl groups include ethenyl, allyl, and but-3-en-1-yl. This term encompasses cis- and trans-isomers, and mixtures thereof. It should be understood that alkenyl groups may be unsubstituted or substituted as described herein. Alkenyl groups may be substituted with any of the substituents described herein, including one or more of such substituents.
[0572] The term "alkynyl" refers to a straight or branched monovalent hydrocarbon radical having one or more triple bonds. In some embodiments, it may be advantageous to limit the number of atoms in the "alkynyl" radical to a specific atomic range, such as C2-C 20 Alkynyl, C2-C 12 Alkynyl, or C2-C6 alkynyl. Examples of alkynyl groups include ethynyl (-C≡CH) and propargyl (-CH2C≡CH), but-3-yn-1,4-diyl (-C≡C-CH2CH2-), etc. It should be understood that alkynyl groups can be unsubstituted or substituted as described herein. Alkynyl groups can be substituted with any substituent in the various embodiments described herein, including one or more of such substituents.
[0573] The term "cycloalkyl" refers to a saturated or partially saturated monocyclic or polycyclic monovalent carbocyclic ring. In some embodiments, it may be advantageous to limit the number of atoms in the "cycloalkyl" to a specific atomic range, such as having 3 to 12 ring atoms. Polycyclic carbocyclic rings include fused, bridged, and spiro polycyclic ring systems. Illustrative examples of cycloalkyl groups include monovalent groups of the following entities:
[0574]
[0575] In particular, the cyclopropyl moiety may be represented by the formula It is understood that the cycloalkyl group can be unsubstituted or substituted as described herein. The cycloalkyl group can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.
[0576] The term "halogen" or "halo" refers to chlorine, fluorine, bromine or iodine.
[0577] The term "haloalkyl" refers to an alkyl group having one or more halo substituents. Examples of haloalkyl groups include -CF3, -(CH2)F, -CHF2, -CH2Br, -CH2CF3, and -CH2CH2F.
[0578] In certain embodiments, the alkenyl group may be substituted. For example, the alkenyl group may be substituted with a halo group (e.g., a fluoro group). Exemplarily, the halo-substituted alkenyl group may be =CHF. Exemplarily, the hexahydro-1H-pyrrolazinyl moiety may be substituted with a halo-substituted alkenyl group, for example, the substituted hexahydro-1H-pyrrolazinyl moiety may be depicted by the following structural formula:
[0579]
[0580] The term "aryl" refers to a monovalent all-carbon monocyclic or fused-ring polycyclic group having a completely conjugated π electron system. In some embodiments, it may be advantageous to limit the number of atoms in the "aryl" group to a specific atomic range, such as a monovalent all-carbon monocyclic or fused-ring polycyclic group having 6 to 14 carbon atoms (C6-C 14 aryl), or a monovalent all-carbon monocyclic or condensed-ring polycyclic group having 6 to 10 carbon atoms (C6-C 10 Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl. It should be understood that aryl groups may be unsubstituted or substituted as described herein. Aryl groups may be substituted with any of the substituents described herein, including one or more of such substituents.
[0581] The term "heterocycloalkyl" refers to a saturated or partially saturated monovalent monocyclic or polycyclic ring structure having one or more non-carbon ring atoms. In some embodiments, it may be advantageous to limit the number of atoms in "heterocycloalkyl" to a specific range of ring atoms, such as 3 to 12 ring atoms (3 to 12 members), or 3 to 7 ring atoms (3 to 7 members), or 3 to 6 ring atoms (3 to 6 members), or 4 to 6 ring atoms (4 to 6 members), 5 to 7 ring atoms (5 to 7 members), or 4 to 10 ring atoms (4 to 10 members). In some embodiments, it may be advantageous to limit the number and type of ring heteroatoms in "heterocycloalkyl" to a specific range or type of heteroatoms, such as 1 to 5 ring heteroatoms selected from nitrogen, oxygen, and sulfur. Examples of monocyclic heterocycloalkyls include, but are not limited to, tetrahydrofuran, pyrrolidine, and morpholine. Polycyclic ring systems include fused, bridged, and spiro systems. In some embodiments, it may be advantageous to limit the number of atoms in a bicyclic "heterocycloalkyl" to a specific range of ring atoms, such as 5 to 10 ring atoms (5-10 members) or 6 to 10 ring atoms (6-10 members). The ring structure may optionally contain an oxo or imino group on a carbon ring member or up to two oxo groups on a sulfur ring member. Examples of fused bicyclic, bridged bicyclic, and spiro bicyclic heterocycloalkyl groups include, but are not limited to, pyrrolazine, 2,5-diazabicyclo[2.2.2]octane, and 1-oxaspiro[4.5]decane. Illustrative examples of heterocycloalkyl groups include monovalent radicals of the following entities:
[0582]
[0583] A three-membered heterocyclic ring 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 oxirane, azetidine, and thiirane. A four-membered heterocyclic ring 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 azetidine, oxtenane, and thietane. A five-membered heterocyclic ring 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 the following monovalent and divalent groups: pyrrolidine, tetrahydrofuran, 2,5-dihydro-1H-pyrrole, pyrazolidine, thiazolidine, 4,5-dihydro-1H-imidazole, dihydrothiophen-2(3H)-one, 1,1-dioxotetrahydrothiophene, imidazolidin-2-one, pyrrolidin-2-one, dihydrofuran-2(3H)-one, 1,3-dioxolane-2-one, and oxazolidin-2-one. Six-membered heterocyclic rings 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 heterocyclic groups include the following monovalent or divalent groups: piperidine, morpholine, 4H-1,4-thiazine, 1,2,3,4-tetrahydropyridine, piperazine, 1,3-oxazacyclohexan-2-one, piperazin-2-one, thiomorpholine, and 1,1-dioxothiomorpholine. "Heterobicyclic" is a fused bicyclic ring system comprising a heterocycle fused to a cycloalkyl group or another heterocycle.
[0584] In particular, the hexahydro-1H-pyrrolizinyl moiety can be represented by the structural formula Describe.
[0585] It should be understood that heterocycloalkyl groups can be unsubstituted or substituted as described herein.Heterocycloalkyl groups can be substituted with any substituent in the various embodiments described herein, including one or more of such substituents.
[0586] The term "heteroaryl" refers to a monovalent monocyclic, fused bicyclic, or fused polycyclic aromatic heterocyclic ring (a ring structure having ring atoms or members selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) that is fully unsaturated and each heterocyclic ring has 3 to 12 ring atoms. The term "heteroarylene" refers to a divalent monocyclic, fused bicyclic, or fused polycyclic aromatic heterocyclic ring (a ring structure having ring atoms or members selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) that each heterocyclic ring has 3 to 12 ring atoms. In some embodiments, it may be advantageous to limit the number of ring atoms in "heteroaryl" or "heteroarylene" to a specific atomic number range, such as a 5- to 10-membered heteroaryl group. In some cases, a 5- to 10-membered heteroaryl group may be a monocyclic or fused bicyclic ring having 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 or imino group on a carbon ring member or up to two oxo groups on a sulfur ring member. Illustrative examples of 5- to 10-membered heteroaryl groups include monovalent radicals of the following entities, while examples of 5- to 10-membered heteroarylene groups include divalent radicals of the following entities, in the form of appropriately bonded moieties:
[0587]
[0588] 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 the following monovalent groups: furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole, or tetrazole. 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 the following monovalent groups: pyridine, pyrazine, pyrimidine, pyridazine, or triazine. "Bicyclic heteroaryl" is a fused bicyclic ring system comprising a heteroaryl ring fused to a phenyl or another heteroaryl ring. Non-limiting examples of bicyclic heteroaryl groups include the following monovalent radicals: quinoline, isoquinoline, quinazoline, quinoxaline, 1,5-naphthyridine, 1,8-naphthyridine, isoquinolin-3(2H)-one, thieno[3,2-b]thiophene, 1H-pyrrolo[2,3-b]pyridine, indazole, 1H-benzo[d]imidazole, benzo[d]oxazole, and benzo[d]thiazole.
[0589] In particular, the isoquinolin-3(2H)-one moiety can be depicted by the following structural formula:
[0590]
[0591] In particular, the divalent pyridopyrimidine moiety can be depicted by the following structural formula:
[0592]
[0593] It should be understood that heteroaryl groups can be unsubstituted or substituted as described herein. Heteroaryl groups can be substituted with any of the substituents in the various embodiments described herein, including one or more of such substituents.
[0594] It should be understood that the heteroaryl or heteroarylene group can be unsubstituted or substituted as described herein. The heteroaryl or heteroarylene group can be substituted with any substituent in the various embodiments described herein, including one or more of such substituents.
[0595] The term "oxo" represents a carbonyl oxygen. For example, an oxo-substituted cyclopentyl is cyclopentanone.
[0596] The term "substituted" means that the specified group or moiety carries one or more substituents. The term "unsubstituted" means that the specified group carries no substituents. When the term "substituted" is used to describe a structural system, substitution is intended to occur at any valence-allowed position on the system. In some embodiments, "substituted" means that the specified group or moiety carries one, two, or three substituents. In other embodiments, "substituted" means that the specified group or moiety carries one or two substituents. In other embodiments, "substituted" means that the specified group or moiety carries one substituent.
[0597] Any chemical formula depicted herein is intended to represent the compounds of the formula as well as certain variations or forms. For example, the chemical formulas given herein are intended to encompass racemic forms or one or more enantiomers, diastereomers, or geometric isomers, or mixtures thereof. Additionally, any chemical formula given herein is intended to also refer to hydrates, solvates, or polymorphs, or mixtures thereof, of the compounds.
[0598] Any chemical formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the chemical formulas given herein, but where one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 15 N. 18 O. 17 O. 31 P.32 P. 35 S. 18 F. 36 Cl and 125 I. Such isotopically labeled compounds are suitable for metabolic studies (preferably using 14 C); reaction kinetic studies (using e.g. 2 H or 3 H); detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)], including drug or substrate tissue distribution analysis; or radiotherapy applied to the patient. In addition, the use of deuterium (i.e. 2 H) can afford certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds and prodrugs thereof disclosed herein can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
[0599] Certain chemical entities of formula (I) to (XXXXVI) may be depicted in two or more tautomeric forms. Any and all alternative tautomers are included within the scope of these chemical formulas, and no inference should be made as to whether the chemical entity exists in the drawn tautomeric form. It should be understood that the chemical entities described herein and their constituent rings A, B, etc. may exist in different tautomeric forms. Those skilled in the art will readily appreciate that tautomers can generally be considered to be the same compound due to rapid interconversion. Examples of tautomers include, but are not limited to, enol-keto tautomers, amine-imine tautomers, etc.
[0600]
[0601] In particular, the ring options of the isoquinolin-3(2H)-one group may exist as the following tautomers:
[0602] Where j>i, the specialized term "(ATOM) i- (ATOM) j" " when applied herein to a class of substituents refers to embodiments of the present disclosure in which each of the numbers of atom members from i to j (inclusive) is independently realized. For example, the terms C1-C3 independently refer to an embodiment with one carbon member (C1), an embodiment with two carbon members (C2), and an embodiment with three carbon members (C3).
[0603] The present disclosure also encompasses pharmaceutically acceptable salts of compounds represented by Formulas (I) to (XXXXVI), preferably those described above and specific compounds exemplified herein, and pharmaceutical compositions comprising such salts, and methods of using such salts.
[0604] "Pharmaceutically acceptable salts" means salts of the free acids or bases of the compounds represented herein that are non-toxic, biotolerable, or otherwise biologically suitable for administration to a subject. See generally SM Berge et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977, 66, 1-19. Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of a subject without undue toxicity, irritation, or allergic reaction. The compounds described herein may have sufficiently acidic groups, sufficiently basic groups, both types of functional groups, or more than one of each type, and thus react with a variety of inorganic or organic bases and inorganic and organic acids to form pharmaceutically acceptable salts. in is an inorganic counterion (e.g., an inorganic anion) or an organic counterion (e.g., an organic anion). is an anion that complexes with the cation of the disclosed compound to form a pharmaceutically acceptable salt.
[0605] It is understood that the chemical entities described herein may exist in the form of salts of the free acids or bases of the compounds represented herein with inorganic or organic counterions. For example, salts may be formed during the manufacture of the compounds (e.g., salts or pharmaceutically acceptable salts) or may be replaced with salts for further manufacturing, formulation, or administration reasons. As described herein, certain compounds comprise in is an inorganic counterion (e.g., an inorganic anion) or an organic counterion (e.g., an organic anion). is an anion that complexes with the cation of the disclosed compound to form a pharmaceutically acceptable salt.
[0606] The term "inorganic counterion" refers to an inorganic ion that is accompanied by an ionic species to maintain electrical neutrality. The inorganic counterion can represent an anion or a cation. The inorganic counterion can be accompanied by a free acid or base of a compound represented herein. Inorganic ions can be formed by the reaction of an inorganic base or an inorganic acid with a compound described herein that has a sufficiently acidic group, a sufficiently basic group, both types of functional groups, or more than one of each type of group.
[0607] The term "organic counterion" refers to an organic ion that is accompanied by an ionic species to maintain electrical neutrality. The organic ion can represent an anion or a cation. The organic counterion can be accompanied by a free acid or base of a compound represented herein. The organic ion can be formed by the reaction of an organic base or an organic acid with a compound described herein that has a sufficiently acidic group, a sufficiently basic group, both types of functional groups, or more than one of each type of group.
[0608] Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, octanoates, acrylates, formates, isobutyrates, hexanoates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyrates, butylates ... Suitable pharmaceutically acceptable salts include, but are not limited to, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methylsulfonate, propylsulfonate, benzenesulfonate, xylenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, and mandelate. A list of other suitable pharmaceutically acceptable salts is found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985.
[0609] For compounds of formula (I) to (XXXXVI) containing a basic nitrogen, pharmaceutically acceptable salts can be prepared by any suitable method available in the art, for example, by treating the free base with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, or the like; or an organic acid such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, or the like. Acid, lauric acid, a pyranosonic acid (such as glucuronic acid or galacturonic acid), an α-hydroxy acid (such as mandelic acid, citric acid or tartaric acid), an amino acid (such as aspartic acid or glutamic acid), an aromatic acid (such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid or cinnamic acid), a sulfonic acid (such as laurylsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid or ethanesulfonic acid); or any compatible mixture of acids, such as those given as examples herein; and any other acids and mixtures thereof that are considered equivalents or acceptable substitutes in view of the general level of skill in the art.
[0610] The present disclosure further relates to pharmaceutically acceptable prodrugs of formula (I) to (XXXXVI) compounds, and methods of treating using such pharmaceutically acceptable prodrugs. The term "prodrug" means that a given compound produces a precursor of a compound in vivo via a chemical or physiological process (such as solvolysis or enzymatic cleavage) or under physiological conditions (for example, a prodrug is converted into a formula (I) to (XXXXVI) compound when physiological pH is reached) after being administered to an individual. "Pharmaceutically acceptable prodrug" is a prodrug that is non-toxic, biologically tolerable, and otherwise biocompatible for administration to an individual. Illustrative procedures for selecting and preparing suitable prodrug derivatives are described in, for example, "Prodrug Design (Design of Prodrugs)", edited by H. Bundgaard (H.Bundgaard), Elsevier (Elsevier), 1985.
[0611] The present disclosure also relates to pharmaceutically active metabolites of compounds of Formulas (I) to (XXXXVI), and the use of such metabolites in the methods of the present disclosure. "Pharmaceutically active metabolite" means a pharmacologically active product of in vivo metabolism of a compound of Formulas (I) to (XXXXVI) or a salt thereof. Prodrugs and active metabolites of a compound can be determined using conventional techniques known or available in the art. See, e.g., Bertolini et al., 1997, 40, 2011-2016; Shan et al., Journal of Pharmaceutical Sciences 1997, 86(7), 765-767; Bagshawe, Drug Dev. Res. 1995, 34, 220-230; Bodor, Adv. Drug Res. 1984, 13, 255-331; Bongard, Prodrug Design (Elsevier Press, 1985); and Larsen, Design and Application of Prodrugs, in Drug Design and Development (Krogsgaard-Larsen et al., eds., Harwood Academic Publishers, 1991).
[0612] As used herein, the term "KRAS inhibitor" includes, but is not limited to, compounds that can inhibit a protein encoded by the KRAS gene, called K-Ras, involved in the RAS / MAPK signaling pathway. The terms KRAS gene, K-Ras, and RAS / MAPK signaling pathway will be known and understood by those skilled in the art. It will be understood that KRAS mutations occur in approximately one-seventh of all human metastatic cancers, and those mutations can occur at multiple positions in the KRAS gene coding sequence. KRAS mutations occur primarily in KRAS codons 12 and 13, and also occur at low frequencies in codons 18, 61, 117, and 146, and have significant effects on tumor cell signaling based on codon and missense mutations. Examples of KRAS mutations include, but are not limited to, KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D, KRAS A18D, KRAS Q61H, KRAS K117N, etc. One of ordinary skill in the art will understand that reference to inhibition of a KRAS mutation, such as KRAS G12D, refers to inhibition of a protein encoded by a KRAS G12D gene having a coding sequence that produces a K-Ras G12D protein (e.g., a guanine to adenine substitution at position 35 on codon 12 of the KRAS coding sequence), wherein the glycine at position 12 of the protein sequence is substituted with aspartic acid.
[0613] Representative Examples
[0614] In some embodiments, the present disclosure relates to a compound of Formula I or a pharmaceutically acceptable salt thereof,
[0615]
[0616] where R 1 、R 2 、R 3 、R 9 , A, B, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein.
[0617] In some embodiments, the present disclosure provides a compound of Formula II or a pharmaceutically acceptable salt thereof,
[0618]
[0619] where R 1 、R 2 、R3 , A, B, X, Y 1 、Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein.
[0620] In some embodiments, the present disclosure provides a compound of formula III or a pharmaceutically acceptable salt thereof,
[0621]
[0622] where R 1 、R 2 、R 3 、R 9 , A, B, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein.
[0623] In some embodiments, the present disclosure provides a compound of formula IV or a pharmaceutically acceptable salt thereof,
[0624]
[0625] where R 1 、R 2 、R 3 、R 9 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , m, n and p are as described herein.
[0626] In some embodiments, the present disclosure provides a compound of formula IV or a pharmaceutically acceptable salt thereof,
[0627]
[0628] where R 1 、R 2 、R 3 、R 9 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n, and p are as described herein, and Z 5N or C(R 15 ), and Z 6 N or C(R 16 ).
[0629] In some embodiments, the present disclosure provides a compound of formula V or a pharmaceutically acceptable salt thereof,
[0630]
[0631] where R 1 、R 2 、R 3 、R 9 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein.
[0632] In some embodiments, the present disclosure provides a compound of Formula VI or a pharmaceutically acceptable salt thereof,
[0633]
[0634] where R 1 、R 2 、R 3 、R 9 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein.
[0635] In some embodiments, the present disclosure provides a compound of Formula VII or a pharmaceutically acceptable salt thereof,
[0636]
[0637] where R 1 、R 2 、R 3 、R 9 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein.
[0638] In some embodiments, the present disclosure provides a compound of Formula VII or a pharmaceutically acceptable salt thereof,
[0639]
[0640] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n, and p are as described herein, and Z 5 N or C(R 15 ), and Z 6 N or C(R 16 ).
[0641] In some embodiments, the present disclosure provides a compound of Formula VIII or a pharmaceutically acceptable salt thereof,
[0642]
[0643] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein.
[0644] In some embodiments, the present disclosure provides a compound of Formula IX or a pharmaceutically acceptable salt thereof,
[0645]
[0646] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein.
[0647] In some embodiments, the present disclosure provides a compound of formula X or a pharmaceutically acceptable salt thereof,
[0648]
[0649] where R 1 、R 2 、R 3 、R 9 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z4 , m, n and p are as described herein.
[0650] In some embodiments, the present disclosure provides a compound of Formula XI or a pharmaceutically acceptable salt thereof,
[0651]
[0652] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein.
[0653] In some embodiments, the present disclosure provides a compound of Formula XII or a pharmaceutically acceptable salt thereof,
[0654]
[0655] where R 1 、R 2 、R 3 、R 9 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein.
[0656] In some embodiments, the present disclosure provides a compound of Formula XIII or a pharmaceutically acceptable salt thereof,
[0657]
[0658] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein.
[0659] In some embodiments, the present disclosure provides a compound of Formula XIV or a pharmaceutically acceptable salt thereof,
[0660]
[0661] where R 1 、R 2 、R 3 、R9 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , m, n and p are as described herein.
[0662] In some embodiments, the present disclosure provides a compound of Formula XIV or a pharmaceutically acceptable salt thereof,
[0663]
[0664] where R 1 、R 2 、R 3 、R 9 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n, and p are as described herein; and Z 5 N or C(R 15 ); and Z 6 N or C(R 16 ).
[0665] In some embodiments, the present disclosure provides a compound of Formula XV or a pharmaceutically acceptable salt thereof,
[0666]
[0667] where R 1 、R 2 、R 3 、R 9 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , m, n and p are as described herein.
[0668] In some embodiments, the present disclosure provides a compound of Formula XV or a pharmaceutically acceptable salt thereof,
[0669]
[0670] where R 1 、R 2 、R 3 、R 9 , A, X, Y 2 , Z1 , Z 2 , Z 3 , Z 4 , m, n, and p are as described herein; and Z 5 N or C(R 15 ); and Z 6 N or C(R 16 ).
[0671] In some embodiments, the present disclosure provides a compound of Formula XVI or a pharmaceutically acceptable salt thereof,
[0672]
[0673] where R 1 、R 2 、R 3 , A, B, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , m, n and p are as described herein, and Ring C is a 4- to 8-membered heterocycloalkyl, and q is 0, 1 or 2.
[0674] In some embodiments, the present disclosure provides a compound of Formula XVII or a pharmaceutically acceptable salt thereof,
[0675]
[0676] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , m, n and p are as described herein, and Ring C is a 4- to 8-membered heterocycloalkyl, and q is 0, 1 or 2.
[0677] In some embodiments, the present disclosure provides a compound of Formula XVII or a pharmaceutically acceptable salt thereof,
[0678]
[0679] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z3 , Z 4 , m, n and p are as described herein; Ring C is a 4- to 8-membered heterocycloalkyl; q is 0, 1 or 2; Z 5 N or C(R 15 ); and Z 6 N or C(R 16 ).
[0680] In some embodiments, the present disclosure provides a compound of Formula XVIII or a pharmaceutically acceptable salt thereof,
[0681]
[0682] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein, and Ring C is a 4- to 8-membered heterocycloalkyl, and q is 0, 1 or 2.
[0683] In some embodiments, the present disclosure provides a compound of Formula XIX or a pharmaceutically acceptable salt thereof,
[0684]
[0685] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein, and Ring C is a 4- to 8-membered heterocycloalkyl, and q is 0, 1 or 2.
[0686] In some embodiments, the present disclosure provides a compound of formula XX or a pharmaceutically acceptable salt thereof,
[0687]
[0688] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein, and Ring C is a 4- to 8-membered heterocycloalkyl, and q is 0, 1 or 2.
[0689] In some embodiments, the present disclosure provides a compound of formula XXI or a pharmaceutically acceptable salt thereof,
[0690]
[0691] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein, and Ring C is a 4- to 8-membered heterocycloalkyl, and q is 0, 1 or 2.
[0692] In some embodiments, the present disclosure provides a compound of formula XXII or a pharmaceutically acceptable salt thereof,
[0693]
[0694] where R 1 、R 2 、R 3 、R 9 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , m, n and p are as described herein, and Ring C is a 4- to 8-membered heterocycloalkyl, and q is 0, 1 or 2.
[0695] In some embodiments, the present disclosure provides a compound of formula XXII or a pharmaceutically acceptable salt thereof,
[0696]
[0697] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein; Ring C is a 4- to 8-membered heterocycloalkyl; q is 0, 1 or 2; Z 5 N or C(R 15 ); and Z 6 N or C(R 16 ).
[0698] In some embodiments, the present disclosure provides a compound of formula XXIII or a pharmaceutically acceptable salt thereof,
[0699]
[0700] where R 1 、R 2 、R 3 , A, B, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , m, n and p are as described herein, and Ring C is a 4- to 8-membered heterocycloalkyl, and q is 0, 1 or 2.
[0701] In some embodiments, the present disclosure provides a compound of Formula XXIV or a pharmaceutically acceptable salt thereof,
[0702]
[0703] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , m, n and p are as described herein, and Ring C is a 4- to 8-membered heterocycloalkyl, and q is 0, 1 or 2.
[0704] In some embodiments, the present disclosure provides a compound of Formula XXIV or a pharmaceutically acceptable salt thereof,
[0705]
[0706] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein; Ring C is a 4- to 8-membered heterocycloalkyl; q is 0, 1 or 2; Z 5 N or C(R 15 ); and Z 6 N or C(R 16 ).
[0707] In some embodiments, the present disclosure provides a compound of Formula XXV or a pharmaceutically acceptable salt thereof,
[0708]
[0709] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein, and Ring C is a 4- to 8-membered heterocycloalkyl, and q is 0, 1 or 2.
[0710] In some embodiments, the present disclosure provides a compound of formula XXVI or a pharmaceutically acceptable salt thereof,
[0711]
[0712] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein, and Ring C is a 4- to 8-membered heterocycloalkyl, and q is 0, 1 or 2.
[0713] In some embodiments, the present disclosure provides a compound of Formula XXVII or a pharmaceutically acceptable salt thereof,
[0714]
[0715] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein, and Ring C is a 4- to 8-membered heterocycloalkyl, and q is 0, 1 or 2.
[0716] In some embodiments, the present disclosure provides a compound of Formula XXVIII or a pharmaceutically acceptable salt thereof,
[0717]
[0718] where R 1 、R 2 、R 3, A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein, and Ring C is a 4- to 8-membered heterocycloalkyl, and q is 0, 1 or 2.
[0719] In some embodiments, the present disclosure provides a compound of Formula XXIX or a pharmaceutically acceptable salt thereof,
[0720]
[0721] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , m, n and p are as described herein, and Ring C is a 4- to 8-membered heterocycloalkyl, and q is 0, 1 or 2.
[0722] In some embodiments, the present disclosure provides a compound of Formula XXIX or a pharmaceutically acceptable salt thereof,
[0723]
[0724] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein; Ring C is a 4- to 8-membered heterocycloalkyl; q is 0, 1 or 2; Z 5 N or C(R 15 ); and Z 6 N or C(R 16 ).
[0725] In some embodiments, the present disclosure provides a compound of formula XXX or a pharmaceutically acceptable salt thereof,
[0726]
[0727] where R 1 、R 2 、R 3 , A, B, X, Y 2 , Z 1 , Z2 , Z 3 , Z 4 , Z 5 , Z 6 , m, n, and p are as described herein, and X 1 is -O-, -NH- or -CH2-, q is 0, 1 or 2, t is 1 or 2, and v is 1 or 2.
[0728] In some embodiments, the present disclosure provides a compound of Formula XXXI or a pharmaceutically acceptable salt thereof,
[0729]
[0730] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , m, n, and p are as described herein, and X 1 is -O- or -CH2-, q is 0, 1 or 2, t is 1 or 2, and v is 1 or 2.
[0731] In some embodiments, the present disclosure provides a compound of Formula XXXI or a pharmaceutically acceptable salt thereof,
[0732]
[0733] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n, and p are as described herein, and X 1 is -O- or -CH2-, q is 0, 1 or 2, t is 1 or 2, v is 1 or 2, Z 5 N or C(R 15 ), and Z 6 N or C(R 16 ).
[0734] In some embodiments, the present disclosure provides a compound of Formula XXXII or a pharmaceutically acceptable salt thereof,
[0735]
[0736] where R 1 、R2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n, and p are as described herein, and X 1 is -O- or -CH2-, q is 0, 1 or 2, t is 1 or 2, and v is 1 or 2.
[0737] In some embodiments, the present disclosure provides a compound of formula XXXIII or a pharmaceutically acceptable salt thereof,
[0738]
[0739] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n, and p are as described herein, and X 1 is -O-, -NH- or -CH2-, q is 0, 1 or 2, t is 1 or 2, and v is 1 or 2.
[0740] In some embodiments, the present disclosure provides a compound of Formula XXXIV or a pharmaceutically acceptable salt thereof,
[0741]
[0742] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n, and p are as described herein, and X 1 is -O- or -CH2-, q is 0, 1 or 2, t is 1 or 2, and v is 1 or 2.
[0743] In some embodiments, the present disclosure provides a compound of Formula XXXV or a pharmaceutically acceptable salt thereof,
[0744]
[0745] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z2 , Z 3 , Z 4 , m, n, and p are as described herein, and X 1 is -O- or -CH2-, q is 0, 1 or 2, t is 1 or 2, and v is 1 or 2.
[0746] In some embodiments, the present disclosure provides a compound of Formula XXXVI or a pharmaceutically acceptable salt thereof,
[0747]
[0748] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , m, n, and p are as described herein, and X 1 is -O- or -CH2-, q is 0, 1 or 2, t is 1 or 2, and v is 1 or 2.
[0749] In some embodiments, the present disclosure provides a compound of Formula XXXVI or a pharmaceutically acceptable salt thereof,
[0750]
[0751] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n, and p are as described herein, and X 1 is -O- or -CH2-, q is 0, 1 or 2, t is 1 or 2, v is 1 or 2, Z 5 N or C(R 15 ), and Z 6 N or C(R 16 ).
[0752] In some embodiments, the present disclosure provides a compound of Formula XXXVII or a pharmaceutically acceptable salt thereof,
[0753]
[0754] where R 1 、R 2 、R 3, A, B, X, Y 2 、Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , m, n and p are as described herein, and Ring D is C3-C6 cycloalkyl or 4- to 8-membered heterocycloalkyl.
[0755] In some embodiments, the present disclosure provides a compound of Formula XXXVIII or a pharmaceutically acceptable salt thereof,
[0756]
[0757] where R 1 、R 2 、R 3 , A, X, Y 1 、Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , m, n and p are as described herein, and Ring D is C3-C6 cycloalkyl or 4- to 8-membered heterocycloalkyl.
[0758] In some embodiments, the present disclosure provides a compound of Formula XXXVIII or a pharmaceutically acceptable salt thereof,
[0759]
[0760] where R 1 、R 2 、R 3 , A, X, Y 1 、Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein, and Ring D is C3-C6 cycloalkyl or 4- to 8-membered heterocycloalkyl, Z 5 N or C(R 15 ), and Z 6 N or C(R 16 ).
[0761] In some embodiments, the present disclosure provides a compound of formula XXXIX or a pharmaceutically acceptable salt thereof,
[0762]
[0763] Its R1 、R 2 、R 3 , A, X, Y 1 、Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein, and Ring D is C3-C6 cycloalkyl or 4- to 8-membered heterocycloalkyl.
[0764] In some embodiments, the present disclosure provides a compound of formula XXXX or a pharmaceutically acceptable salt thereof,
[0765]
[0766] Its R 1 、R 2 、R 3 , A, X, Y 1 、Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein, and Ring D is C3-C6 cycloalkyl or 4- to 8-membered heterocycloalkyl.
[0767] In some embodiments, the present disclosure provides a compound of Formula XXXXI or a pharmaceutically acceptable salt thereof,
[0768]
[0769] Its R 1 、R 2 、R 3 , A, X, Y 1 、Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein, and Ring D is C3-C6 cycloalkyl or 4- to 8-membered heterocycloalkyl.
[0770] In some embodiments, the present disclosure provides a compound of formula XXXXII or a pharmaceutically acceptable salt thereof,
[0771]
[0772] Its R 1 、R 2 、R 3 , A, X, Y 1 、Y 2 , Z 1 , Z2 , Z 3 , Z 4 , m, n and p are as described herein, and Ring D is C3-C6 cycloalkyl or 4- to 8-membered heterocycloalkyl.
[0773] In some embodiments, the present disclosure provides a compound of formula XXXXIII or a pharmaceutically acceptable salt thereof,
[0774]
[0775] where R 1 、R 2 、R 3 、R 9 , A, X, Y 1 、Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , m, n and p are as described herein, and Ring D is C3-C6 cycloalkyl or 4- to 8-membered heterocycloalkyl.
[0776] In some embodiments, the present disclosure provides a compound of formula XXXXIII or a pharmaceutically acceptable salt thereof,
[0777]
[0778] where R 1 、R 2 、R 3 、R 9 , A, X, Y 1 、Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein, and Ring D is C3-C6 cycloalkyl or 4- to 8-membered heterocycloalkyl, Z 5 N or C(R 15 ), and Z 6 N or C(R 16 ).
[0779] In some embodiments, the present disclosure provides a compound of formula XXXXIV or a pharmaceutically acceptable salt thereof,
[0780]
[0781] where R 1 、R 2 、R 3 , A, X, Y2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n, and p are as described herein, and wherein Ring C is a 4- to 8-membered heterocycloalkyl; and q is 0, 1, or 2.
[0782] In some embodiments, the present disclosure provides a compound of formula XXXXV or a pharmaceutically acceptable salt thereof,
[0783]
[0784] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n, and p are as described herein, and wherein Ring C is a 4- to 8-membered heterocycloalkyl; and q is 0, 1, or 2.
[0785] In some embodiments, the present disclosure provides a compound of formula XXXXVI or a pharmaceutically acceptable salt thereof,
[0786]
[0787] where R 1 、R 2 、R 3 , A, X, Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n and p are as described herein, and wherein Ring C is a 4- to 8-membered heterocycloalkyl; X 1 is -O-, -NH- or -CH2-; q is 0, 1 or 2; t is 1 or 2, and v is 1 or 2.
[0788] In some embodiments, at least one hydrogen atom in the compound of Formula I is substituted with deuterium. In some embodiments, R 1 、R 2 or R 3 At least one hydrogen atom in the molecule is substituted with deuterium.
[0789] In some embodiments, Y 1 for -O-, -S-, -S(O)-, -S(O)2-, -NR 9 -or-CR 11 R 12 -. In some embodiments, Y 1In some embodiments, Y 1 In some embodiments, Y 1 In some embodiments, Y 1 In some embodiments, Y 1 -NR 9 -. In some embodiments, Y 2 -CR 11 R 12 -. In some embodiments, Y 2 for -O-, -S-, -S(O)-, -S(O)2-, -NR 10 -or-CR 13 R 14 -. In some embodiments, Y 2 In some embodiments, Y 2 In some embodiments, Y 2 In some embodiments, Y 2 In some embodiments, Y 1 -NR 10 -. In some embodiments, Y 2 -CR 13 R 14 -.
[0790] In some embodiments, Ring A is a C5-C8 cycloalkyl or a 5- to 8-membered heterocycloalkyl, wherein each C5-C8 cycloalkyl or 5- to 8-membered heterocycloalkyl is unsubstituted or substituted with one or more R 1 In some embodiments, ring A is unsubstituted C5-C8 cycloalkyl or substituted with one or more R 1 In some embodiments, Ring A is an unsubstituted 5- to 8-membered heterocycloalkyl or substituted with one or more R 1 Substituted 5- to 8-membered heterocycloalkyl.
[0791] In some embodiments, Ring A is C5-C8 cycloalkyl or 5-8 membered heterocycloalkyl, wherein each C5-C8 cycloalkyl or 5-8 membered heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 R 1 In some embodiments, Ring A is unsubstituted C5-C8 cycloalkyl or substituted with 1, 2, 3, 4, 5, or 6 R 1 In some embodiments, Ring A is an unsubstituted 5- to 8-membered heterocycloalkyl or substituted with 1, 2, 3, 4, 5, or 6 R 1 Substituted 5- to 8-membered heterocycloalkyl.
[0792] In some embodiments, Ring A is a 5- to 8-membered heterocycloalkyl, wherein the 5- to 8-membered heterocycloalkyl is unsubstituted or substituted with one or more R 1 Substitution, and / or two R on ring A 1 Together with the one or more atoms to which it is attached, it forms an unsubstituted or substituted R 1 In some embodiments, Ring A is optionally substituted with one or more R 1 substituted 5- to 8-membered heterocycloalkyl, and / or two R on ring A 1 Together with the one or more atoms to which it is attached, it forms a 4- to 8-membered heterocycloalkyl group, which is unsubstituted or substituted with one or more R 1 The substituted 4- to 8-membered heterocycloalkyl (ring C) has no more than one nitrogen atom. In some embodiments, ring A is optionally substituted with one or more R 1 substituted 5- to 8-membered heterocycloalkyl, and / or two R on ring A 1 and the one or more atoms to which they are attached are combined to form a 4- to 8-membered heterocycloalkyl group having no more than one nitrogen atom in the 4- to 8-membered heterocycloalkyl group and being unsubstituted or substituted with one or more R 1 The substituted 4- to 8-membered heterocycloalkyl group (ring C) has one or more -O- and / or -S- groups.
[0793] In some embodiments, Ring A is a 5- to 7-membered heterocycloalkyl, wherein the 5- to 7-membered heterocycloalkyl is unsubstituted or substituted with one or more R 1 Substitution, and / or two R on ring A 1 Together with the one or more atoms to which it is attached, it forms an unsubstituted or substituted R 1 In some embodiments, Ring A is optionally substituted with one or more R 1 substituted 5- to 7-membered heterocycloalkyl, and / or two R on ring A 1 Together with the one or more atoms to which it is attached, it forms a 4- to 8-membered heterocycloalkyl group, which is unsubstituted or substituted with one or more R 1 The substituted 4- to 8-membered heterocycloalkyl (ring C) has no more than one nitrogen atom. In some embodiments, ring A is optionally substituted with one or more R 1 substituted 5- to 7-membered heterocycloalkyl, and / or two R on ring A 1 and the one or more atoms to which they are attached are combined to form a 4- to 8-membered heterocycloalkyl group having no more than one nitrogen atom in the 4- to 8-membered heterocycloalkyl group and being unsubstituted or substituted with one or more R 1 The substituted 4- to 8-membered heterocycloalkyl group (ring C) has one or more -O- and / or -S- groups.
[0794] In some embodiments, Ring A is a 5- to 8-membered heterocycloalkyl group, wherein the 5- to 8-membered heterocycloalkyl group is unsubstituted or substituted with one or more R 1 Substitution, and / or two R on ring A 1 Together with the one or more atoms to which it is attached, it forms an unsubstituted or substituted R 1 In some embodiments, ring A is optionally substituted with one or more R 1 substituted 5- to 8-membered heterocycloalkyl, and / or two R on ring A 1 Together with the one or more atoms to which it is attached, it forms an unsubstituted or substituted R 1 In some embodiments, ring A is optionally substituted with one or more R 1 substituted 5- to 8-membered heterocycloalkyl, and / or two R on ring A 1 Together with the one or more atoms to which it is attached, it forms an unsubstituted or substituted R 1 In some embodiments, ring A is optionally substituted with one or more R 1 substituted 5- to 8-membered heterocycloalkyl, and / or two R on ring A 1 Together with the one or more atoms to which it is attached, it forms an unsubstituted or substituted R 1 In some embodiments, Ring A is optionally substituted with one or more R 1 substituted 5- to 8-membered heterocycloalkyl, and / or two R on ring A 1 Together with the one or more atoms to which it is attached, it forms an unsubstituted or substituted R 1 Substituted 4- to 8-membered heterocycloalkyl (Ring D).
[0795] In some embodiments, Ring A is a 5- to 8-membered heterocycloalkyl, wherein the 5- to 8-membered heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 R 1 Substitution, and / or two R on ring A 1 Together with the one or more atoms to which it is attached, it forms an unsubstituted or substituted 1, 2, or 3 R 1 In some embodiments, Ring A is substituted with 1, 2, 3, 4, 5, or 6 R 1 substituted 5- to 8-membered heterocycloalkyl, and / or two R on ring A 1 Together with the one or more atoms to which it is attached, it forms a 4- to 8-membered heterocycloalkyl group, which is unsubstituted or substituted with 1, 2, or 3 R 1The substituted 4- to 8-membered heterocycloalkyl (ring C) has no more than one nitrogen atom. In some embodiments, ring A is substituted with 1, 2, 3, 4, 5, or 6 R 1 substituted 5- to 8-membered heterocycloalkyl; and / or two R on ring A 1 and the one or more atoms to which they are attached are combined to form a 4- to 8-membered heterocycloalkyl group having no more than one nitrogen atom in the 4- to 8-membered heterocycloalkyl group and in the case of unsubstituted or substituted 1, 2, or 3 R 1 The substituted 4- to 8-membered heterocycloalkyl group (ring C) has one or more -O- and / or -S- groups.
[0796] In some embodiments, Ring A is a 5- to 8-membered heterocycloalkyl, wherein the 5- to 7-membered heterocycloalkyl is unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 R 1 Substitution, and / or two R on ring A 1 Together with the one or more atoms to which it is attached, it forms an unsubstituted or substituted 1, 2, or 3 R 1 In some embodiments, Ring A is substituted with 1, 2, 3, 4, 5, or 6 R 1 substituted 5- to 7-membered heterocycloalkyl, and / or two R on ring A 1 Together with the one or more atoms to which it is attached, it forms a 4- to 8-membered heterocycloalkyl group, which is unsubstituted or substituted with 1, 2, or 3 R 1 The substituted 4- to 8-membered heterocycloalkyl (ring C) has no more than one nitrogen atom. In some embodiments, ring A is substituted with 1, 2, 3, 4, 5, or 6 R 1 substituted 5- to 7-membered heterocycloalkyl; and / or two R on ring A 1 and the one or more atoms to which they are attached are combined to form a 4- to 8-membered heterocycloalkyl group having no more than one nitrogen atom in the 4- to 8-membered heterocycloalkyl group and being unsubstituted or substituted with 1, 2, or 3 R 1 The substituted 4- to 8-membered heterocycloalkyl group (ring C) has one or more -O- and / or -S- groups.
[0797] In some embodiments, Ring A is 9 A 5- to 8-membered heterocycloalkyl group attached to a nitrogen atom in a 5- to 8-membered heterocycloalkyl group (ring A), wherein the 5- to 8-membered heterocycloalkyl group is unsubstituted or substituted with one or more R 1 Substituted, and / or R 9 and R on ring A 1 Together with the atoms to which they are attached, they form an unsubstituted or substituted 1 In some embodiments, Ring A is a 4- to 8-membered heterocycloalkyl group. 9A 5- to 8-membered heterocycloalkyl group attached to a nitrogen atom in a 5- to 8-membered heterocycloalkyl group (ring A), wherein the 5- to 8-membered heterocycloalkyl group is unsubstituted or substituted with one or more R 1 Substituted, and / or R 9 and R on ring A 1 Together with the atoms to which they are attached, they form a 4- to 8-membered heterocycloalkyl group, which is unsubstituted or substituted with one or more R 1 The substituted 4- to 8-membered heterocycloalkyl (ring C) has no more than one nitrogen atom. In some embodiments, ring A is 9 A 5- to 8-membered heterocycloalkyl group attached to a nitrogen atom in a 5- to 8-membered heterocycloalkyl group (ring A), wherein the 5- to 8-membered heterocycloalkyl group is unsubstituted or substituted with one or more R 1 Substituted, and / or R 9 and R on ring A 1 and the atoms to which they are attached are combined to form a 4- to 8-membered heterocycloalkyl group having no more than one nitrogen atom in the 4- to 8-membered heterocycloalkyl group and being unsubstituted or substituted with one or more R 1 The substituted 4- to 8-membered heterocycloalkyl group (ring C) has one or more -O- and / or -S- groups.
[0798] In some embodiments, Ring A is 9 A 5- to 7-membered heterocycloalkyl group attached to a nitrogen atom in a 5- to 7-membered heterocycloalkyl group (ring A), wherein the 5- to 7-membered heterocycloalkyl group is unsubstituted or substituted with one or more R 1 Substituted, and / or R 9 and R on ring A 1 Together with the atoms to which they are attached, they form an unsubstituted or substituted 1 In some embodiments, Ring A is a 4- to 8-membered heterocycloalkyl group. 9 A 5- to 7-membered heterocycloalkyl group attached to a nitrogen atom in a 5- to 7-membered heterocycloalkyl group (ring A), wherein the 5- to 7-membered heterocycloalkyl group is unsubstituted or substituted with one or more R 1 Substituted, and / or R 9 and R on ring A 1 Together with the atoms to which they are attached, they form a 4- to 8-membered heterocycloalkyl group, which is unsubstituted or substituted with one or more R 1 The substituted 4- to 8-membered heterocycloalkyl (ring C) has no more than one nitrogen atom. In some embodiments, ring A is 9 A 5- to 7-membered heterocycloalkyl group attached to a nitrogen atom in a 5- to 7-membered heterocycloalkyl group (ring A), wherein the 5- to 7-membered heterocycloalkyl group is unsubstituted or substituted with one or more R 1 Substituted, and / or R 9 and R on ring A 1and the atoms to which they are attached are combined to form a 4- to 8-membered heterocycloalkyl group having no more than one nitrogen atom in the 4- to 8-membered heterocycloalkyl group and being unsubstituted or substituted with one or more R 1 The substituted 4- to 8-membered heterocycloalkyl group (ring C) has one or more -O- and / or -S- groups.
[0799] In some embodiments, Ring A is 9 A 5- to 8-membered heterocycloalkyl group attached to a nitrogen atom in a 5- to 8-membered heterocycloalkyl group (ring A), wherein the 5- to 8-membered heterocycloalkyl group is unsubstituted or substituted with one or more R 1 Substituted, and / or R 9 and on Ring A near R 9 R on the carbon atom 1 Together with the atoms to which they are attached, they form an unsubstituted or substituted 1 Substituted fused 4- to 8-membered heterocycloalkyl (ring C). In some embodiments, ring A is R 9 A 5- to 8-membered heterocycloalkyl group attached to a nitrogen atom in a 5- to 8-membered heterocycloalkyl group (ring A), wherein the 5- to 8-membered heterocycloalkyl group is unsubstituted or substituted with one or more R 1 Substituted, and / or R 9 and on Ring A near R 9 R on the carbon atom 1 Together with the atoms to which they are attached, they form a fused 4- to 8-membered heterocycloalkyl group, which is unsubstituted or substituted with one or more R 1 The substituted fused 4- to 8-membered heterocycloalkyl (ring C) has no more than one nitrogen atom. In some embodiments, ring A is R 9 A 5- to 8-membered heterocycloalkyl group attached to a nitrogen atom in a 5- to 8-membered heterocycloalkyl group (ring A), wherein the 5- to 8-membered heterocycloalkyl group is unsubstituted or substituted with one or more R 1 Substituted, and / or R 9 and on Ring A near R 9 R on the carbon atom 1 and the atoms to which they are attached are combined to form a fused 4- to 8-membered heterocycloalkyl having no more than one nitrogen atom in the fused 4- to 8-membered heterocycloalkyl and being unsubstituted or substituted with one or more R 1 The substituted fused 4- to 8-membered heterocycloalkyl (ring C) has one or more -O- and / or -S- groups.
[0800] In some embodiments, Ring A is 9 A 5- to 7-membered heterocycloalkyl group attached to a nitrogen atom in a 5- to 7-membered heterocycloalkyl group (ring A), wherein the 5- to 7-membered heterocycloalkyl group is unsubstituted or substituted with one or more R 1 Substituted, and / or R 9 and on Ring A near R 9 R on the carbon atom1 Together with the atoms to which they are attached, they form an unsubstituted or substituted 1 Substituted fused 4- to 8-membered heterocycloalkyl (ring C). In some embodiments, ring A is R 9 A 5- to 7-membered heterocycloalkyl group attached to a nitrogen atom in a 5- to 7-membered heterocycloalkyl group (ring A), wherein the 5- to 7-membered heterocycloalkyl group is unsubstituted or substituted with one or more R 1 Substituted, and / or R 9 and on Ring A near R 9 R on the carbon atom 1 Together with the atoms to which they are attached, they form a fused 4- to 8-membered heterocycloalkyl group, which is unsubstituted or substituted with one or more R 1 The substituted fused 4- to 8-membered heterocycloalkyl (ring C) has no more than one nitrogen atom. In some embodiments, ring A is R 9 A 5- to 7-membered heterocycloalkyl group attached to a nitrogen atom in a 5- to 7-membered heterocycloalkyl group (ring A), wherein the 5- to 7-membered heterocycloalkyl group is unsubstituted or substituted with one or more R 1 Substituted, and / or R 9 and on Ring A near R 9 R on the carbon atom 1 and the atoms to which they are attached are combined to form a fused 4- to 8-membered heterocycloalkyl having no more than one nitrogen atom in the fused 4- to 8-membered heterocycloalkyl and being unsubstituted or substituted with one or more R 1 The substituted fused 4- to 8-membered heterocycloalkyl (ring C) has one or more -O- and / or -S- groups.
[0801] In some embodiments, Ring A is 9 A 5- to 8-membered heterocycloalkyl group attached to a nitrogen atom in a 5- to 8-membered heterocycloalkyl group (ring A), wherein the 5- to 8-membered heterocycloalkyl group is unsubstituted or substituted with one or more R 1 Substituted, and / or R 9 and on Ring A near R 9 R on the carbon atom 1 Together with the atoms to which they are attached, they form an unsubstituted or substituted 1 In some embodiments, Ring A is a substituted bridged 5- to 8-membered heterocycloalkyl group (Ring C). 9 A 5- to 8-membered heterocycloalkyl group attached to a nitrogen atom in a 5- to 8-membered heterocycloalkyl group (ring A), wherein the 5- to 8-membered heterocycloalkyl group is unsubstituted or substituted with one or more R 1 Substituted, and / or R 9 and on Ring A near R 9 R on the carbon atom 1 Together with the atoms to which they are attached, they form a bridged 5- to 8-membered heterocycloalkyl group, which is unsubstituted or substituted with one or more R 1The substituted 5- to 8-membered heterocycloalkyl (ring C) has no more than one nitrogen atom. In some embodiments, ring A is 9 A 5- to 8-membered heterocycloalkyl group attached to a nitrogen atom in a 5- to 8-membered heterocycloalkyl group (ring A), wherein the 5- to 8-membered heterocycloalkyl group is unsubstituted or substituted with one or more R 1 Substituted, and / or R 9 and on Ring A near R 9 R on the carbon atom 1 and the atoms to which they are attached are combined to form a bridged 5- to 8-membered heterocycloalkyl having no more than one nitrogen atom in the 5- to 8-membered heterocycloalkyl and being unsubstituted or substituted with one or more R 1 The substituted 5- to 8-membered heterocycloalkyl group (ring C) has one or more -O- and / or -S- groups.
[0802] In some embodiments, Ring A is 9 A 5- to 7-membered heterocycloalkyl group attached to a nitrogen atom in a 5- to 7-membered heterocycloalkyl group (ring A), wherein the 5- to 7-membered heterocycloalkyl group is unsubstituted and R 9 H, deuterium, -C(O)R g 、-C(O)NR g R h , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4 to 10 membered heterocycloalkyl, C6-C 10 Aryl or 5 to 10 membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 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 optionally substituted with 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 、-NRe 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.
[0803] In some embodiments, Ring A is 9 A 5- to 7-membered heterocycloalkyl group attached to a nitrogen atom in a 5- to 7-membered heterocycloalkyl group (ring A), wherein the 5- to 7-membered heterocycloalkyl group is selected from one or more R 1 (For example, an R 1 or two R 1 ) substituted: C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl and C6-C 10 Aryl, among which C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-10 membered heterocycloalkyl, 5-10 membered heteroaryl and C6-C 10 Each hydrogen atom in the aryl group is independently optionally substituted with deuterium, halogen, -R e 、-R f 、-OR eor -CN or -NO2, and R 9 H, deuterium, -C(O)R g 、-C(O)NR g R h , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4 to 10 membered heterocycloalkyl, C6-C 10 Aryl or 5 to 10 membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 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 optionally substituted with 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)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.
[0804] In some embodiments, Ring A is 9 A 5- to 8-membered heterocycloalkyl or 5- to 7-membered heterocycloalkyl group attached to a nitrogen atom in a 5- to 8-membered heterocycloalkyl or 5- to 7-membered heterocycloalkyl group (ring A), wherein R 9 is H, deuterium, unsubstituted C1-C6 alkyl or C1-C6 haloalkyl.
[0805] In some embodiments, Ring A is a fused 5- to 8-membered heterocycloalkyl, which optionally together with Ring C or Ring D forms a core of a compound of Formula I having the following formula:
[0806]
[0807] Among them Is with ring B or -(X) p -R 3 The point of covalent attachment of , and Ring C and Ring D are as defined herein.
[0808] In some embodiments, Ring A is a fused 5- to 8-membered heterocycloalkyl, which optionally together with Ring C or Ring D forms a core of a compound of Formula I having the following formula:
[0809]
[0810]
[0811] Among them is a covalent attachment point, and each hydrogen atom in the piperidinyl group is independently optionally substituted with 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)2Re 、-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.
[0812] In some embodiments, Ring A is a fused 5- to 8-membered heterocycloalkyl, which optionally together with Ring C or Ring D forms a core of a compound of Formula I having the following formula:
[0813]
[0814]
[0815] Among them is a covalent attachment point, and each hydrogen atom in the piperidinyl group is independently optionally substituted with 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 Rf 、-P(O)OR e 、-P(O)2OR e , -CN or -NO2.
[0816] In some embodiments, Ring A optionally together with Ring C or Ring D forms a core of a compound of Formula I having the following formula:
[0817]
[0818]
[0819] Among them Is with ring B or -(X) p -R 3 and each hydrogen atom in Ring A, Ring C if present, and Ring D if present is independently optionally substituted with R 1 Substitution: 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.
[0820] In some embodiments, Ring A is a fused 5- to 8-membered heterocycloalkyl, which optionally together with Ring C or Ring D forms a core of a compound of Formula I having the following formula:
[0821]
[0822]
[0823] Among them Is with ring B or -(X) p -R 3 The covalent attachment point of the piperidinyl group is substituted with 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 、-NRe 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.
[0824] In some embodiments, each R on ring C 1 independently selected from 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.
[0825] In some embodiments, each R on ring D 1 independently selected from 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)Re 、-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.
[0826] In some embodiments, Ring A is a fused 5- to 8-membered heterocycloalkyl, which optionally together with Ring C or Ring D forms a core of a compound of Formula I having the following formula:
[0827]
[0828]
[0829]
[0830] Among them is the point of covalent attachment.
[0831] In some embodiments, Ring A is a fused 5- to 8-membered heterocycloalkyl, which optionally together with Ring C or Ring D forms a core of a compound of Formula I having the following formula:
[0832]
[0833]
[0834]
[0835] Among them Is with ring B or -(X) p -R 3 covalent attachment point.
[0836] In some embodiments, Ring A is a fused 5- to 8-membered heterocycloalkyl group that forms the core of a compound of Formula I, said core having the formula:
[0837]
[0838]
[0839]
[0840] Among them Is with ring B or -(X) p -R 3 covalent attachment point.
[0841] In some embodiments, Ring A optionally together with Ring C or Ring D forms a core of a compound of Formula I having the following formula:
[0842]
[0843]
[0844]
[0845] Among them Is with ring B or -(X) p -R 3 covalent attachment point.
[0846] In some embodiments, Ring A optionally together with Ring C or Ring D forms a core of a compound of Formula I having the following formula:
[0847]
[0848]
[0849]
[0850] Among them Is with ring B or -(X) p -R 3 covalent attachment point.
[0851] In some embodiments, m is 0. In some embodiments, m is one or greater than one. In some embodiments, m is 0, 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, m is 0, 1, 2, 3, 4, 5, 6, or 7. In some embodiments, m is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, m is 0, 1, 2, 3, 4, or 5. In some embodiments, m is 0, 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 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.
[0852] In some embodiments, Ring B is optionally substituted with one or more R 2 Substituted C6-C 10 In some embodiments, ring B is optionally substituted with one or more R 2 Substituted C3-C6 cycloalkyl, 4 to 10 membered heterocycloalkyl, C6-C 10 In some embodiments, ring B is optionally substituted with one or more R 2 Substituted C6-C 10 In some embodiments, ring B is optionally substituted with one or more R 2 Substituted 5- to 10-membered heteroaryl.
[0853] In some embodiments, Ring B is
[0854]
[0855] Among them, * is wherein n is 0, 1, 2, 3, 4, 5, 6, or 7.
[0856] In some embodiments, Ring B is
[0857]
[0858] Among them, * is wherein n is 0, 1, 2, 3, or 4.
[0859] In some embodiments, Ring B is
[0860]
[0861] Among them, * is wherein n is 0, 1, 2, 3, or 4.
[0862] In some embodiments, Ring B is
[0863]
[0864] Among them, * is wherein n is 0, 1, 2, 3, or 4.
[0865] In some embodiments, Ring B is
[0866]
[0867] Among them, * is wherein n is 0, 1, 2, 3, or 4.
[0868] In some embodiments, Ring B is
[0869]
[0870] Among them, * is wherein n is 0, 1, 2, 3, or 4.
[0871] In some embodiments, Ring B is naphthyl, wherein each hydrogen atom in the naphthyl group is independently optionally replaced by R 2 In some embodiments, ring B is phenyl, wherein each hydrogen atom in the phenyl group is independently optionally substituted by R 2 In some embodiments, Ring B is pyridyl, wherein each hydrogen atom in the pyridyl group is independently optionally replaced by R 2 In some embodiments, Ring B is an indolyl group, wherein each hydrogen atom in the indolyl group is independently replaced by R 2 In some embodiments, Ring B is indazolyl, wherein each hydrogen atom in the indazolyl group is independently optionally replaced by R 2 In some embodiments, Ring B is benzothiazolyl, wherein each hydrogen atom in the benzothiazolyl is independently optionally substituted by R 2 replace.
[0872] In some embodiments, Ring B is
[0873]
[0874] Among them, * is wherein n is 0, 1, 2, 3, 4, 5, 6, or 7.
[0875] In some embodiments, each R 1 are independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-10 membered heterocycloalkyl, 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)Ra 、-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 R 1 Together with the one or more atoms to which it is attached, it forms a C3-C6 cycloalkyl group or a 4- to 10-membered heterocycloalkyl group, 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 heterocycloalkyl groups is independently optionally substituted with 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 Rf 、-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, each R 1 is deuterium, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, wherein each hydrogen atom in the C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is independently optionally substituted with 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 eC(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. In some embodiments, R 9 and R 1 or R 10 and R 1and the atoms to which they are attached are combined to form a 4- to 10-membered heterocycloalkyl group, wherein each hydrogen atom in the 4- to 10-membered heterocycloalkyl group is independently optionally substituted with 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 -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)OC1-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. In some embodiments, two hydrogen atoms on a single carbon atom of a 4- to 10-membered heterocycloalkyl group combine to form an oxo or C2-C6 alkenyl group; or two R 1 Together with the one or more atoms to which it is attached, it forms a C3-C6 cycloalkyl group or a 4- to 10-membered heterocycloalkyl group, 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 heterocycloalkyl groups is independently optionally substituted with 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)2Re 、-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. In some embodiments, each R 1 Selected from the group consisting of: 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. In some embodiments, R 1 and R 10and the one or more atoms to which they are attached are combined to form a monocyclic 4- to 10-membered heterocycloalkyl, a fused bicyclic 5- to 10-membered heterocycloalkyl, or a bridged bicyclic 6- to 10-membered heterocycloalkyl, wherein each hydrogen atom in the monocyclic 4- to 10-membered heterocycloalkyl, the fused bicyclic 5- to 10-membered heterocycloalkyl, or the bridged bicyclic 6- to 10-membered heterocycloalkyl is independently optionally substituted with 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( 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)OC1-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 two hydrogen atoms on a single carbon atom of a monocyclic 4 to 10-membered heterocycloalkyl, a fused bicyclic 5 to 10-membered heterocycloalkyl or a bridged bicyclic 6 to 10-membered heterocycloalkyl are combined to form an oxo or alkenyl group.
[0876] In some embodiments, each R 2 are independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, -OR c 、-OC(O)R c 、-OC(O)NR c R d 、-OC(=NR c )NRc 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 R 2 Together with the atoms to which they are attached, they form a C3-C6 cycloalkyl group or a 4- to 10-membered heterocycloalkyl group, 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 heterocycloalkyl groups is independently optionally substituted with 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. In some embodiments, each R 2 are independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OR c 、-C(O)R c or -NR c R d In some embodiments, each R 2 are independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OR c In some embodiments, each R 2 are independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OR c 、-C(O)R c 、-NR c R d or -CN, wherein each hydrogen atom in C1-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl is independently optionally substituted with deuterium or halogen. In some embodiments, each R 2 In some embodiments, each R 2 is independently selected from the group consisting of fluorine, chlorine, methyl, ethyl, isopropyl, -NH2, -C≡CH, -CN, -CF3 and -OH. In some embodiments, each R 2 are independently selected from the group consisting of fluoro, chloro, methyl, ethyl, isopropyl, -C≡CH, -CN, and -OH.
[0877] In some embodiments, n is 0. In some embodiments, n is one or greater than one. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7. In some embodiments, n is 0, 1, 2, 3, 4, 5, or 6. In some embodiments, n is 0, 1, 2, 3, 4, or 5. In some embodiments, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 1, 2, 3, 4, or 5. In some embodiments, n is 2, 3, 4, or 5. In some embodiments, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 2 or 3. In some embodiments, n is 0 or 1. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.
[0878] In some embodiments, Ring B is
[0879]
[0880] in is the point of covalent attachment.
[0881] In some embodiments, Ring B has the formula:
[0882]
[0883] in is the point of covalent attachment.
[0884] In some embodiments, Ring B is
[0885]
[0886]
[0887] in is the point of covalent attachment.
[0888] In some embodiments, p is 0. In some embodiments, p is 1.
[0889] In some embodiments, -X- is -O-, -S-, or -NR 4 -. In some embodiments, -X- is -O-. In some embodiments, -X- is -S-. In some embodiments, -X- is -NR 4 -.
[0890] In some embodiments, R 4is H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl or 5 to 10 membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 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 optionally substituted with 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. In some embodiments, R 4 is H, deuterium or C1-C6 alkyl. In some embodiments, R 4 is H, deuterium or methyl.
[0891] In some embodiments, R 3 -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl), -C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 aryl), 5- to 10-membered heteroaryl or -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl), wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl), C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 Each hydrogen atom in -C1-C6 alkylene-(5-10 membered heteroaryl) is independently optionally substituted with 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.
[0892] In some embodiments, R 3is -C1-C6 alkyl, 4- to 10-membered heterocycloalkyl, or -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl), wherein each hydrogen atom in -C1-C6 alkyl, 4- to 10-membered heterocycloalkyl, or -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl) is independently optionally substituted with 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.
[0893] In some embodiments, R 3 is a 4- to 10-membered heterocycloalkyl group, wherein each hydrogen atom in the 4- to 10-membered heterocycloalkyl group is independently optionally substituted with 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)NRe 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.
[0894] In some embodiments, R 3 for
[0895]
[0896] in is the point of covalent attachment.
[0897] In some embodiments, R 3 for
[0898]
[0899] in is the point of covalent attachment.
[0900] In some embodiments, R 3 for
[0901]
[0902] in is the point of covalent attachment.
[0903] In some embodiments, R 3 is -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl), wherein each hydrogen atom in methyl, ethyl, propyl or -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl) is independently optionally substituted with 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.
[0904] In some embodiments, R 3 -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl), wherein each hydrogen atom in -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl) is independently optionally substituted with 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 、-NRe 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.
[0905] In some embodiments, R 3 Has the following formula:
[0906]
[0907] in is a covalent attachment point, and each hydrogen atom is independently optionally substituted with 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)Re 、-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.
[0908] In some embodiments, R 3 Has the following formula:
[0909]
[0910] in is a covalent attachment point, and each hydrogen atom is independently optionally substituted with 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)ORe 、-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.
[0911] In some embodiments, R 3 Has the following formula:
[0912]
[0913] in is a covalent attachment point, and each hydrogen atom is independently optionally substituted with 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.
[0914] In some embodiments, R 3 Has the following formula:
[0915]
[0916] in is a covalent attachment point, and each hydrogen atom is independently optionally substituted with deuterium, halogen, C1-C6 alkyl, haloalkyl, -OR e , -CN or -NO2.
[0917] In some embodiments, R 3 Has the following formula:
[0918]
[0919] in is a covalent attachment point, and each hydrogen atom is independently optionally substituted with deuterium, halogen, C1-C6 alkyl, -ORe , -CN or -NO2.
[0920] In some embodiments, R 3 Has the following formula:
[0921]
[0922] in is the point of covalent attachment.
[0923] In some embodiments, R 3 Has the following formula:
[0924]
[0925] in It is an inorganic counter ion or an organic counter ion.
[0926] In some embodiments, R 3 Has the following formula:
[0927]
[0928] in It is an inorganic counter ion or an organic counter ion.
[0929] In some embodiments, each R a 、R b 、R c 、R d 、R e 、R f 、R g and R h independently selected from the group consisting of: H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, C1-C6 alkylene-C6-C 10 Aryl and 5- to 10-membered heteroaryl; or two R a and R b , or R c and R d , or R e and R f , or R g and R h Together with the one or more atoms to which it is attached, it forms a C3-C6 cycloalkyl group, a 4- to 10-membered heterocycloalkyl group, a C6-C 10 Aryl or 5 to 10 membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4 to 10 membered heterocycloalkyl, C6-C 10 Aryl, C1-C6 alkylene-C6-C10 Each hydrogen atom in the aryl and 5- to 10-membered heteroaryl groups is independently optionally substituted with 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)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)OC1-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 to which it is attached, it forms an oxo or alkenyl group.
[0930] In some embodiments, each R a 、R b 、R c 、R d 、R e 、R f 、R g and R h independently selected from the group consisting of: H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, C1-C6 alkylene-C6-C 10 aryl and 5- to 10-membered heteroaryl.
[0931] In some embodiments, Z 1is N. In some embodiments, Z 2 is N. In some embodiments, Z 3 is N. In some embodiments, Z 4 is N. In some embodiments, Z 5 is N. In some embodiments, Z 6 is N. In some embodiments, Z 1 C(R 5 In some embodiments, Z 2 C(R 6 In some embodiments, Z 3 C(R 7 In some embodiments, Z 3 In some embodiments, Z 3 In some embodiments, Z 4 C(R 8 In some embodiments, Z 5 C(R 15 ). In some embodiments, Z 6 C(R 16 In some embodiments, Z 5 In some embodiments, Z 6 In some embodiments, Z 1 to Z 7 Any of the possible combinations of can be combined into an embodiment. In some embodiments, Z 5 N or C(R 15 In some embodiments, Z 6 N or C(R 16 In some embodiments, Z 1 is N, and Z 2 is N. In some embodiments, Z 1 N, Z 2 N, Z 3 C(R 7 ), and Z 4 is N. In some embodiments, Z 1 N, Z 2 N, Z 3 C(R 7 ), and Z 4 C(R 8 ). In some embodiments, Z 1 N, Z 2 N, Z 3 is N, and Z 4 is N. In some embodiments, Z 1 N, Z 2 N, Z 3is N, and Z 4 C(R 8 ). In some embodiments, Z 1 N, Z 2 N, Z 3 C(R 7 ), and Z 4 C(R 8 ). In some embodiments, Z 1 N, Z 2 N, Z 3 is CH, and Z 4 is N. In some embodiments, Z 1 N, Z 2 N, Z 3 is CF, and Z 4 is N.
[0932] In some embodiments, each R 5 、R 6 、R 7 、R 8 、R 15 and R 16 are independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-10 membered heterocycloalkyl, 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)Rh 、-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, each R 5 、R 6 、R 7 、R 8 、R 15 and R 16 are independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR g , -CN or -NO2. In some embodiments, each R 5 、R 6 、R 7 、R 8 、R 15 and R 16 are independently H, deuterium, halogen, C1-C6 alkyl, -OR g , -CN or -NO2.
[0933] In some embodiments, each R 5 、R 6 、R 7 and R 8 are independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR g , -CN or -NO2.
[0934] In some embodiments, each R 15 and R 16are independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-10 membered heterocycloalkyl, 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. In some embodiments, each R 15 and R 16 are independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR g , -CN or -NO2.
[0935] In some embodiments, there may be R 5 is H. In some embodiments, R 6 is H. In some embodiments, R 7 is H or F. In some embodiments, R 8 is H. In some embodiments, R 15 is H. In some embodiments, R 16 For H.
[0936] In some embodiments, the present disclosure provides compounds of the formula:
[0937]
[0938] in
[0939] * indicates the point of covalent attachment to Ring B as described herein;
[0940] ** indicates the same as described herein -(X) p -R 3 a point of covalent attachment of
[0941] R 1 、R 7 , R and m are as described herein.
[0942] In some embodiments, the present disclosure provides compounds of the formula:
[0943]
[0944] in
[0945] * indicates the point of covalent attachment to Ring B as described herein;
[0946] ** indicates the same as described herein -(X) p -R 3 covalent attachment point;
[0947] Each R 1 are independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10Aryl, 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 [[ID=�6]]、-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 Rb 、-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, 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 heterocycloalkyl groups is independently optionally substituted with 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;
[0948] R 7 is H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-10 membered heterocycloalkyl, 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)2NRg 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;
[0949] R 9 H, deuterium, -C(O)R g 、-C(O)NR g R h , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4 to 10 membered heterocycloalkyl, C6-C 10 Aryl or 5 to 10 membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 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 optionally substituted with 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 、-NRe 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; and
[0950] m is 0, 1 or 2.
[0951] In some embodiments, the present disclosure provides compounds of the formula:
[0952]
[0953] in
[0954] * indicates the point of covalent attachment to Ring B as described herein;
[0955] ** indicates the same as described herein -(X) p -R 3 covalent attachment point;
[0956] Each R 1is independently deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl or 4-10 membered heterocycloalkyl, wherein each hydrogen atom in C1-C6 alkyl, C3-C6 cycloalkyl and 4-10 membered heterocycloalkyl is independently optionally substituted with 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)2NRe R f 、-P(O)OR e 、-P(O)2OR e , -CN or -NO2;
[0957] R 7 is H, deuterium or halogen; and
[0958] R 9 H, -C(O)R g 、-C(O)NR g R h , C1-C6 alkyl or C3-C6 cycloalkyl, wherein each hydrogen atom in C1-C6 alkyl and C3-C6 cycloalkyl is independently optionally substituted by the following groups: deuterium, halogen, -R e OR e ;and
[0959] Where m is 0, 1, or 2.
[0960] In some embodiments, the present disclosure provides a compound selected from the group consisting of: 5-ethynyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[0961] 5-Ethyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[0962] (8aR,9R)-5-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-methyl-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-9-ol;
[0963] (8aR,9R)-5-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-methyl-8,8a,9,10,11,12-hexahydro-7H-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-9-ol;
[0964] 5-Ethynyl-6-fluoro-4-[(9S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(hydroxymethyl)-9,10-dimethyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[0965] 5-Ethynyl-6-fluoro-4-[(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(hydroxymethyl)-9,10-dimethyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[0966] 5-Ethyl-6-fluoro-4-[(9S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(hydroxymethyl)-9,10-dimethyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[0967] 5-Ethynyl-6-fluoro-4-[(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(hydroxymethyl)-9,10-dimethyl-7,8,9,10-tetrahydro-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[0968] 5-Ethyl-6-fluoro-4-[(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(hydroxymethyl)-9,10-dimethyl-7,8,9,10-tetrahydro-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[0969] 5-Ethynyl-6-fluoro-4-[(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(2-hydroxypropan-2-yl)-8,9-dihydro-7H-10-oxa-1,3,6-triazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[0970] 5-Ethyl-6-fluoro-4-[(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(2-hydroxypropan-2-yl)-8,9-dihydro-7H-10-oxa-1,3,6-triazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[0971] 5-Ethynyl-6-fluoro-4-{(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-[(1S)-1-hydroxyethyl]-8,9-dihydro-7H-10-oxa-1,3,6-triazacyclohepta[1,2,3-de]naphthalen-5-yl}naphthalen-2-ol;
[0972] 5-Ethyl-6-fluoro-4-{(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-[(1S)-1-hydroxyethyl]-8,9-dihydro-7H-10-oxa-1,3,6-triazacyclohepta[1,2,3-de]naphthalen-5-yl}naphthalen-2-ol;
[0973] 5-Ethynyl-6-fluoro-4-{(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-[(1R)-1-hydroxyethyl]-8,9-dihydro-7H-10-oxa-1,3,6-triazacyclohepta[1,2,3-de]naphthalen-5-yl}naphthalen-2-ol;
[0974] 5-Ethyl-6-fluoro-4-{(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-[(1R)-1-hydroxyethyl]-8,9-dihydro-7H-10-oxa-1,3,6-triazacyclohepta[1,2,3-de]naphthalen-5-yl}naphthalen-2-ol;
[0975] 5-Ethynyl-6-fluoro-4-{(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-[(1R)-1-hydroxyethyl]-10-methyl-7,8,9,10-tetrahydro-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl}naphthalen-2-ol;
[0976] 5-Ethyl-6-fluoro-4-{(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-[(1R)-1-hydroxyethyl]-10-methyl-7,8,9,10-tetrahydro-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl}naphthalen-2-ol;
[0977] 5-Ethynyl-6-fluoro-4-{(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-[(1R)-1-hydroxyethyl]-7,8,9,10-tetrahydro-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl}naphthalen-2-ol;
[0978] 5-Ethyl-6-fluoro-4-{(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-[(1R)-1-hydroxyethyl]-7,8,9,10-tetrahydro-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl}naphthalen-2-ol;
[0979] 5-Ethynyl-6-fluoro-4-{(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-[(1R)-1-hydroxyethyl]-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl}naphthalen-2-ol;
[0980] 5-Ethyl-6-fluoro-4-{(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-[(1R)-1-hydroxyethyl]-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl}naphthalen-2-ol;
[0981] 5-Ethynyl-6-fluoro-4-[(5R)-9-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-5-(2-hydroxypropan-2-yl)-4-methyl-5,6-dihydro-4H-pyrimido[4,5,6-de][1,6]naphthyridin-8-yl]naphthalen-2-ol;
[0982] 5-Ethyl-6-fluoro-4-[(5R)-9-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-5-(2-hydroxypropan-2-yl)-4-methyl-5,6-dihydro-4H-pyrimido[4,5,6-de][1,6]naphthyridin-8-yl]naphthalen-2-ol;
[0983] 5-Chloro-6-fluoro-4-{(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-[(1R)-1-hydroxyethyl]-7,8,9,10-tetrahydro-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl}naphthalen-2-ol;
[0984] 5,6-difluoro-4-{(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-[(1R)-1-hydroxyethyl]-7,8,9,10-tetrahydro-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl}naphthalen-2-ol;
[0985] (8aR,9R)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-9-ol;
[0986] (8aR,9R)-5-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-9-ol;
[0987] 5-Ethynyl-6-fluoro-4-[(9S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(hydroxymethyl)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[0988] 5-Ethyl-6-fluoro-4-[(9S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(hydroxymethyl)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[0989] (8aS,11R)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-11-ol;
[0990] (8aS,11R)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-11-methyl-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-11-ol;
[0991] 4-[(9S)-9-Cyclopropyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]-5-ethynyl-6-fluoronaphthalen-2-ol;
[0992] 4-[(9S)-9-Cyclopropyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]-5-ethynyl-6-fluoronaphthalen-2-ol;
[0993] 4-[(9S)-9-Cyclopropyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]-5-ethyl-6-fluoronaphthalen-2-ol;
[0994] 4-[(9S)-9-Cyclopropyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]-5-ethyl-6-fluoronaphthalen-2-ol;
[0995] 4-[(9S)-9-cyclobutyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]-5-ethynyl-6-fluoronaphthalen-2-ol;
[0996] 5-Ethynyl-6-fluoro-4-{(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-[(2R)-oxetan-2-yl]-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl}naphthalen-2-ol;
[0997] 5-Ethynyl-6-fluoro-4-{(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-[(2R)-oxolan-2-yl]-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl}naphthalen-2-ol;
[0998] 5-Ethynyl-6-fluoro-4-{(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-[(2R)-oxan-2-yl]-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl}naphthalen-2-ol;
[0999] 5-Ethyl-6-fluoro-4-[(8S,8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8-methyl-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[1000] 7-Fluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphth-5-yl]-1,3-benzothiazol-2-amine;
[1001] 5-Ethyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2Z,7aS)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[1002] (3S)-7-Chloro-1-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl]-2,3-dihydro-1H-indol-3-ol;
[1003] 6-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphth-5-yl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine;
[1004] 3-Chloro-5-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl]-4-(trifluoromethyl)aniline;
[1005] 5-Ethynyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydropyrido[2',1':3,4][1,4]oxazaquino[5,6,7-de]quinazolin-5-yl]naphthalen-2-ol;
[1006] 5-Ethynyl-6-fluoro-4-[(9S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[1007] 5-Ethynyl-6-fluoro-4-[(9S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(propan-2-yl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[1008] 5-Ethynyl-6-fluoro-4-[(9S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(2-methoxyethyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[1009] 4-(9-cyclopropyl-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
[1010] 5-Ethynyl-6-fluoro-4-[(9S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9,10-dimethyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[1011] 5-Ethynyl-6-fluoro-4-[(9S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-10-methyl-9-(propan-2-yl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[1012] 5-Ethynyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2Z,7aS)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[1013] (8aR,9R)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-methyl-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-9-ol;
[1014] 5-Ethynyl-6-fluoro-4-[(7aR,10aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-11-methyl-7a,8,10a,11-tetrahydro-10H-7,9-dioxa-1,3,6,11-tetraazanaphtho[1,8-fg]azulen-5-yl]naphthalen-2-ol;
[1015] 5-Ethynyl-6-fluoro-4-[(7aS,9aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-10-methyl-8,9,9a,10-tetrahydro-7aH-7-oxa-1,3,6,10-tetraazacyclotidino[5,6]cyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[1016] 5-Ethynyl-6-fluoro-4-[(9S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-methyl-10-(propan-2-yl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[1017] 5-Ethynyl-6-fluoro-4-[(9S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-methyl-10-(oxetan-3-yl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[1018] 5-Ethynyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8a,9,11,12-tetrahydro-8H-7,10-dioxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[1019] 5-Ethynyl-6-fluoro-4-[(8aS,12S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-12-methyl-8a,9,11,12-tetrahydro-8H-7,10-dioxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[1020] (8aS,12S)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8a,9,11,12-tetrahydro-8H-7,10-dioxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-12-carbonitrile;
[1021] (8aS,11R)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8a,9,11,12-tetrahydro-8H-7,10-dioxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11-carbonitrile;
[1022] (8aS,12R)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-12-carbonitrile;
[1023] (8aS,11R)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11-carbonitrile;
[1024] 5-Ethynyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8a,9,12,13-tetrahydro-8H,11H-7,10-dioxa-1,3,6,13a-tetraazanaphtho[1,8-ab]heptalen-5-yl]naphthalen-2-ol;
[1025] 5-Ethynyl-6-fluoro-4-[(8aS,13S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-13-methyl-8a,9,12,13-tetrahydro-8H,11H-7,10-dioxa-1,3,6,13a-tetraazanaphtho[1,8-ab]heptalen-5-yl]naphthalen-2-ol;
[1026] (8aS,13R)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8a,9,12,13-tetrahydro-8H,11H-7,10-dioxa-1,3,6,13a-tetraazanaphtho[1,8-ab]heptalene-13-carbonitrile;
[1027] 5-Ethynyl-6-fluoro-4-[(8aS,12S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-12-methyl-8a,9,12,13-tetrahydro-8H,11H-7,10-dioxa-1,3,6,13a-tetraazanaphtho[1,8-ab]heptalen-5-yl]naphthalen-2-ol;
[1028] (8aS,12R)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8a,9,12,13-tetrahydro-8H,11H-7,10-dioxa-1,3,6,13a-tetraazanaphtho[1,8-ab]heptalene-12-carbonitrile;
[1029] 5-Ethynyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,12,13-hexahydro-7,11-dioxa-1,3,6,13a-tetraazanaphtho[1,8-ab]heptalen-5-yl]naphthalen-2-ol;
[1030] 5-Ethynyl-6-fluoro-4-[(8aS,9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-methyl-8,8a,9,10,12,13-hexahydro-7,11-dioxa-1,3,6,13a-tetraazanaphtho[1,8-ab]heptalen-5-yl]naphthalen-2-ol; and
[1031] 5-Ethynyl-6-fluoro-4-[(8aS,13S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-13-methyl-8,8a,9,10,12,13-hexahydro-7,11-dioxa-1,3,6,13a-tetraazanaphtho[1,8-ab]heptalen-5-yl]naphthalen-2-ol;
[1032] or a pharmaceutically acceptable salt thereof.
[1033] In some embodiments, the present disclosure provides a compound selected from the group consisting of:
[1034] 4-[(9S)-10-Benzyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]-5-ethynyl-6-fluoronaphthalen-2-ol;
[1035] 5-Ethynyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2Z,7aS)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[1036] (2R,7aS)-7a-({[(9S)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-2-yl]oxy}methyl)-2-fluoro-4-methylhexahydro-1H-pyrrolizin-4-ium;
[1037] (8aS)-5-(5-chloro-1H-indazol-4-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene;
[1038] 5-Ethynyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2E)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[1039] 4-[(9S)-10-Benzyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(hydroxymethyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]-5-ethynyl-6-fluoronaphthalen-2-ol;
[1040] 4-[(9R)-10-Benzyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(hydroxymethyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]-5-ethynyl-6-fluoronaphthalen-2-ol;
[1041] 5-Ethynyl-6-fluoro-4-(4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl)naphthalen-2-ol;
[1042] (5P,8aS)-5-(3,5-dichloro-1H-indazol-4-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene;
[1043] (5M,8aS)-5-(3,5-dichloro-1H-indazol-4-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene;
[1044] 2-amino-7-fluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphth-5-yl]-1-benzothiophene-3-carbonitrile;
[1045] (8aS,11S)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-11-ol;
[1046] (8aR,11R)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-11-ol;
[1047] 6-((S)-1-Fluoro-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,5a,6,7,8,9-hexahydro-4-oxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-2-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine;
[1048] (8aS)-5-(8-ethynyl-3,7-difluoronaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene;
[1049] 4-[(9S)-9-ethyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]-5-ethynyl-6-fluoronaphthalen-2-ol;
[1050] 5-Ethynyl-6-fluoro-4-[(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(hydroxymethyl)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[1051] 5-Ethyl-6-fluoro-4-[(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(hydroxymethyl)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[1052] 5-Ethynyl-6-fluoro-4-(4'-fluoro-2'-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-10'-methyl-8'H,10'H-spiro[cyclopropane-1,9'-[7]oxa[1,3,6,10]tetraazacyclohepta[1,2,3-de]naphthyl]-5'-yl)naphthalen-2-ol;
[1053] (8aR,11S)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-11-ol;
[1054] 5-Ethynyl-6-fluoro-4-(4'-fluoro-2'-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8'H,10'H-spiro[cyclopropane-1,9'-[7]oxa[1,3,6,10]tetraazacyclohepta[1,2,3-de]naphthyl]-5'-yl)naphthalen-2-ol;
[1055] 4-[(9S)-9-ethyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]-5-ethynyl-6-fluoronaphthalen-2-ol;
[1056] (2R,7aS)-7a-({[(8aS)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-2-yl]oxy}methyl)hexahydro-1H-pyrrolizin-2-ol;
[1057] 5-Ethynyl-6-fluoro-4-[(8aS)-4,11,11-trifluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[1058] 5-Ethyl-4-[(9S)-9-ethyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]-6-fluoronaphthalen-2-ol;
[1059] 5-Ethyl-6-fluoro-4-[(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(hydroxymethyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[1060] (2S,7aS)-7a-({[(8aS)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-2-yl]oxy}methyl)hexahydro-1H-pyrrolizin-2-ol;
[1061] 5-Ethynyl-6-fluoro-4-[(7aR,10aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-7a,8,9,10,10a,11-hexahydro-7-oxa-1,3,6,11-tetraazanaphtho[1,8-fg]azulen-5-yl]naphthalen-2-ol;
[1062] (8aS,9S)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-9-ol;
[1063] 5-Ethynyl-6-fluoro-4-[4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-13-(hydroxymethyl)-8,9,10,11-tetrahydro-8,12-methano-7-oxa-1,3,6,12-tetraazacyclonona[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[1064] 4-[(8aS)-4,11-difluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl]-5-ethynyl-6-fluoronaphthalen-2-ol;
[1065] 5-Ethynyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,12-tetrahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[1066] 5-Ethynyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10-tetrahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[1067] 4-(10-ethyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
[1068] 5-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11-carbonitrile;
[1069] 5-(8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11-carboxamide;
[1070] 5-Chloro-4-[(9S)-9-ethyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]-6-fluoronaphthalen-2-ol;
[1071] 4-(10-Benzyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-7,8,9,10-tetrahydro-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
[1072] (8aS,9S)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-methyl-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-9-ol;
[1073] (8aS,9S)-5-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-methyl-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-9-ol;
[1074] 4-[(9S)-9-ethyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]-5,6-difluoronaphthalen-2-ol;
[1075] 2-amino-4-[(9S)-9-ethyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]-1-benzothiophene-3-carbonitrile;
[1076] 5-ethyl-6-fluoro-4-(4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-7,8,9,10-tetrahydro-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl)naphthalen-2-ol;
[1077] (8aS)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11-carbonitrile;
[1078] 5-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-9-ol;
[1079] (8aS,11S)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-11-methyl-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-11-ol;
[1080] 5-Ethynyl-6-fluoro-4-(4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7H-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl)naphthalen-2-ol;
[1081] 5-Ethynyl-6-fluoro-4-(4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-7,8,9,10-tetrahydro-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl)naphthalen-2-ol;
[1082] 5-Ethyl-6-fluoro-4-[(9S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9,10-dimethyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[1083] 5-Ethyl-6-fluoro-4-[(9S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(hydroxymethyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[1084] 1-[8-(10-cyclopropyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl)-2-fluoro-6-hydroxynaphthalen-1-yl]ethan-1-one;
[1085] 4-(9-cyclopropyl-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
[1086] 4-(9-cyclopropyl-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
[1087] 5-ethyl-6-fluoro-4-((5aS)-1-fluoro-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methyl-5,5a,6,7,8,9-hexahydro-4-oxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-2-yl)naphthalen-2-ol;
[1088] 4-((S)-10-ethyl-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
[1089] 4-((S)-10-(2,2-difluoroethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol;
[1090] 5-Ethynyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10-methyl-4',5'-dihydro-2'H,8H,10H-7-oxa-1,3,6,10-tetraazaspiro[cyclohepta[de]naphthalene-9,3'-furan]-1(10a),2,3a,3a1(6a),5-pentaen-5-yl)naphthalen-2-ol;
[1091] 5-Ethynyl-6-fluoro-4-((S)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10-((R)-2-hydroxypropyl)-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphth-5-yl)naphthalen-2-ol;
[1092] 4-((S)-10-(2,2-difluoroethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol;
[1093] 5-ethyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10-methyl-4',5'-dihydro-2'H,8H,10H-7-oxa-1,3,6,10-tetraazaspiro[cyclohepta[de]naphthalene-9,3'-furan]-1(10a),2,3a,3a1(6a),5-pentaen-5-yl)naphthalen-2-ol; and
[1094] 5-Ethynyl-6-fluoro-4-((S)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-methyl-10-(2,2,2-trifluoroethyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphth-5-yl)naphthalen-2-ol;
[1095] or a pharmaceutically acceptable salt thereof.
[1096] In some embodiments, the compound does not have the formula:
[1097]
[1098]
[1099]
[1100]
[1101]
[1102]
[1103]
[1104]
[1105]
[1106]
[1107]
[1108]
[1109]
[1110]
[1111]
[1112]
[1113]
[1114] or a pharmaceutically acceptable salt thereof.
[1115] The following represent illustrative examples of compounds of formula (I):
[1116]
[1117]
[1118]
[1119]
[1120]
[1121]
[1122]
[1123]
[1124]
[1125]
[1126]
[1127]
[1128]
[1129]
[1130]
[1131]
[1132]
[1133]
[1134]
[1135]
[1136]
[1137]
[1138]
[1139]
[1140]
[1141]
[1142]
[1143]
[1144]
[1145]
[1146]
[1147]
[1148]
[1149]
[1150] and pharmaceutically acceptable salts thereof.
[1151] Those skilled in the art will recognize that the species listed or described herein are not exhaustive and that other species within the scope of these defined terms may also be selected.
[1152] Pharmaceutical composition
[1153] For therapeutic purposes, pharmaceutical compositions comprising the compounds described herein may further include one or more pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients are non-toxic and otherwise biologically suitable substances for administration to an individual. Such excipients facilitate administration of the compounds described herein and are compatible with the active ingredient. Examples of pharmaceutically acceptable excipients include stabilizers, lubricants, surfactants, diluents, antioxidants, adhesives, colorants, bulking agents, emulsifiers, or flavor modifiers. In a preferred embodiment, the pharmaceutical compositions of the present disclosure are sterile compositions. Pharmaceutical compositions can be prepared using compounding techniques known or available to those skilled in the art.
[1154] The present disclosure also contemplates sterile compositions, including compositions that comply with national and regional regulations governing such compositions.
[1155] The pharmaceutical compositions and compounds described herein can be formulated into solutions, emulsions, suspensions, or dispersions in suitable pharmaceutical solvents or carriers according to conventional methods known in the art for preparing various dosage forms, or formulated into pills, tablets, buccal tablets, suppositories, sachets, dragees, granules, powders, powders for reconstitution, or capsules together with solid carriers. The pharmaceutical compositions of the present disclosure can be administered by a suitable delivery route (such as oral, parenteral, rectal, nasal, topical, or ocular routes) or by inhalation. Preferably, the composition is formulated for intravenous or oral administration.
[1156] For oral administration, the compounds of the present disclosure can be provided in solid form (such as tablets or capsules) or in the form of solutions, emulsions or suspensions. To prepare oral compositions, the compounds of the present disclosure can be formulated to produce, for example, a dose of about 0.1 mg to 1 g per day, or about 1 mg to 50 mg per day, or about 50 to 250 mg per day, or about 250 mg to 1 g per day. Oral tablets can include active ingredients 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, glycerol, water, etc. Exemplary disintegrants are starch, polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose and alginic acid. Binders can include starch and gelatin. If present, the lubricant may be magnesium stearate, stearic acid or talc.If desired, tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be given an enteric coating.
[1157] 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, semisolid or liquid diluent. Soft gelatin capsules can be prepared by mixing the active ingredient with water, an 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.
[1158] Liquids for oral administration may be in the form of suspensions, solutions, emulsions or syrups or may be lyophilized or presented as dry products for reconstitution with water or other suitable vehicles before 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 vehicles, 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 necessary, flavoring or coloring agents.
[1159] For parenteral use, including intravenous, intramuscular, intraperitoneal, intranasal or subcutaneous routes, the medicaments of the present disclosure can be provided in the form of a sterile aqueous solution or suspension buffered to an appropriate pH and isotonicity or in the form of a parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms can be provided in unit dosage form (such as an ampoule or a disposable injection device), multiple dose form (such as a vial from which an appropriate dose can be taken out), or a solid form or preconcentrate form that can be used to prepare an injectable formulation. Illustrative infusion doses are in the range of about 1 to 1000 μg / kg of the mixture of the medicament and the pharmaceutical carrier per minute over a period ranging from a few minutes to a few days.
[1160] For nasal, inhaled, or oral administration, the pharmaceutical compositions of the present disclosure can be administered using, for example, a spray formulation also containing a suitable carrier. The compositions of the present disclosure can be formulated for rectal administration in the form of a suppository.
[1161] For topical administration, the compounds of the present disclosure are preferably formulated as a cream or ointment or a similar vehicle suitable for topical administration. For topical administration, the compounds of the present disclosure may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of the drug relative to the vehicle. Another mode of administration of the disclosed agents may utilize patch formulations to achieve transdermal delivery.
[1162] As used herein, the terms "treat" or "treatment" encompass both "prophylactic" and "curative" treatments. "Prophylactic" treatment is intended to indicate delaying the development of a disease, disease symptom, or medical condition, inhibiting symptoms that may develop, or reducing the risk of the disease or symptom developing or recurring. "Curative" treatment includes reducing the severity of an existing disease, symptom, or condition or inhibiting its worsening. Thus, treatment includes improving existing disease symptoms or preventing their worsening; preventing additional symptoms from occurring; improving or preventing potential systemic causes of symptoms; inhibiting the condition or disease, such as curbing its development; relieving the condition or disease; causing the condition or disease to regress; relieving the condition caused by the disease or disease; or stopping the symptoms of the disease or disease.
[1163] The term "subject" refers to a mammalian patient, such as a human, in need of such treatment.
[1164] Exemplary diseases include cancer, pain, neurological diseases, 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, ER +Breast cancer, colon adenocarcinoma, glioblastoma, glioblastoma multiforme, anaplastic thyroid cancer, bile duct cancer, ovarian cancer, gastric adenocarcinoma, colorectal cancer, inflammatory myofibroblastic tumor, angiosarcoma, epithelioid hemangioendothelioma, intrahepatic bile duct cancer, papillary thyroid carcinoma, spitzoid neoplasms, sarcoma, astrocytoma, low-grade glioma of the brain, secretory breast cancer, mammary analogue carcinoma, acute myeloid leukemia, congenital mesoblastic nephroma, congenital fibrosarcoma, Ph-like acute lymphoblastic leukemia, thyroid cancer, skin melanoma, head and neck squamous cell carcinoma, pediatric glioma CML, prostate cancer, lung squamous cell carcinoma, ovarian serous cystadenocarcinoma In some embodiments, the present invention includes but is not limited to: cystadenocarcinoma, melanoma of the skin, castration-resistant prostate cancer, Hodgkin lymphoma, and serous and clear cell endometrial cancer. In some embodiments, the cancer includes lung cancer, colon cancer, breast cancer, prostate cancer, hepatocellular carcinoma, renal cell carcinoma, gastric and esophago-gastric cancer, glioblastoma, head and neck cancer, inflammatory myofibroblastic tumor, and anaplastic large cell lymphoma. Pain includes, for example, pain from any source or etiology, including cancer pain, chemotherapy pain, nerve pain, injury pain, or pain from other sources. Autoimmune diseases include, for example, rheumatoid arthritis, Sjogren's syndrome, type 1 diabetes, and lupus. Exemplary neurological diseases include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Exemplary inflammatory diseases include atherosclerosis, allergies, and inflammation caused by infection or injury.
[1165] In one aspect, the compounds and pharmaceutical compositions disclosed herein specifically target Ras, particularly K-Ras. Thus, these compounds and pharmaceutical compositions can be used to prevent, reverse, slow, or inhibit the activity of one or more KRAS mutations, such as KRASG12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D, KRAS A18D, KRAS Q61H, KRAS K117N, and the like. In a preferred embodiment, methods of treating a target cancer are described.
[1166] In the inhibition methods disclosed herein, "effective amount" means an amount sufficient to inhibit the target protein. Measuring such target regulation can be performed by conventional analytical methods (such as those described below). Such regulation is applicable to various situations, including in vitro analysis. In such methods, the cells are preferably cancer cells with abnormal signaling due to KRAS mutations, such as KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D, KRAS A18D, KRAS Q61H, KRASK117N, etc.
[1167] In the treatment methods disclosed herein, "effective amount" means an amount or dosage that is generally sufficient to produce the desired therapeutic benefit in an individual in need of such treatment. The effective amount or dosage of the disclosed compounds can be determined by conventional methods (such as modeling, dose escalation or clinical trials) considering conventional factors (such as the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of infection, the health status of the individual, the condition and weight and the judgment of the treating physician). An exemplary dosage is approximately in the range of about 0.1 mg to 1 g per day, or about 1 mg to 50 mg per day, or about 50 to 250 mg per day, or about 250 mg to 1 g per day. The total dose can be given in single or divided dose units (e.g., BID, TID, QID).
[1168] Once the patient's disease improves, the dosage can be adjusted for preventive or maintenance treatment. For example, the dosage or frequency of administration, or both, can be reduced to a level that maintains the desired therapeutic or preventive effect as the symptoms change. Of course, treatment can be discontinued if symptoms have been alleviated to an appropriate level. However, patients may require long-term intermittent treatment upon any recurrence of symptoms. Patients may also require long-term continuous treatment.
[1169] Drug combinations ...
Claims
1. A compound of formula I or a pharmaceutically acceptable salt thereof, in X is -O-, -S- or -NR 4 -; Z 1 N or C (R 5 ); Z 2 N or C (R 6 ); Z 3 N or C (R 7 ); Z 4 N or C (R 8 ); The premise is Z 1 To Z 4 At least two of them are N; Ring A is a 5- to 8-membered heterocycloalkyl group or a C5-C8 cycloalkyl group; Ring B is C6-C 10 Aryl or 5- to 10-membered heteroaryl; Each R 1 are independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-10 membered heterocycloalkyl, 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 R 1 Together with the one or more atoms to which it is attached, it forms a C3-C6 cycloalkyl group or a 4-10 membered heterocycloalkyl group, 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 heterocycloalkyl group is independently optionally substituted with 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 are independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-10 membered heterocycloalkyl, 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 R 2 Together with the atoms to which they are attached, they form a C3-C6 cycloalkyl group or a 4- to 10-membered heterocycloalkyl group, 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 heterocycloalkyl group is independently optionally substituted with 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 is -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl), C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 aryl), 5- to 10-membered heteroaryl or -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl), wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl), C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 Each hydrogen atom in -C1-C6 alkylene-(5- to 10-membered heteroaryl) is independently optionally substituted with 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; R 4 is H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 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 optionally substituted with 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; Each R 5 , R 6 , R 7 and R 8 are independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, 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; Each R a , R b , R c , R d , R e , R f , R g and R h independently selected from the group consisting of: H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C 10 Aryl, C1-C6 alkylene-C6-C 10 Aryl and 5- to 10-membered heteroaryl; or two R a and R b , or R c and R d , or R e and R f , or R g and R h Together with the one or more atoms to which it is attached, it forms a C3-C6 cycloalkyl group, a 4- to 10-membered heterocycloalkyl group, a C6-C 10 aryl or 5- to 10-membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 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 optionally substituted with 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)OC1-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 to which it is attached, it forms an oxo or alkenyl group; m is 0, 1, 2, 3, 4, 5, 6 or 7; n is 0, 1, 2, 3, 4, 5, 6 or 7; and p is 0 or 1.
2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula II, in Y 1 is -O-, -S-, -S(O)-, -S(O)2-, -NR 9 -, or -CR 11 R 12 -; Y 2 is -O-, -S-, -S(O)-, -S(O)2-, -NR 10 -, or -CR 13 R 14 -; Each R 9 and R 10 are independently H, deuterium, -C(O)R g 、-C(O)NR g R h , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 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 optionally substituted with 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 R 9 and R 1 or R 10 and R 1 The 4- to 10-membered heterocycloalkyl radicals are combined together with the atoms to which they are attached to form a 4- to 10-membered heterocycloalkyl radical, wherein each hydrogen atom in the 4- to 10-membered heterocycloalkyl radical is independently optionally substituted with 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 -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)OC1-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) -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 two hydrogen atoms on a single carbon atom of the 4- to 10-membered heterocycloalkyl group are combined to form an oxo or alkenyl group; and Each R 11 , R 12 , R 13 and R 14 are independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, 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 1 and R 11 , R 1 and R 12 , R 1 and R 13 , R 1 and R 14 , two R 11 and R 12 or two R 13 and R 14 The one or more carbon atoms to which they are attached are combined to form a C3-C6 cycloalkyl group or a 4-10 membered heterocycloalkyl group, 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 heterocycloalkyl groups is independently optionally substituted with 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 R 11 and R 12 or R 13 and R 14 Together with the carbon atom to which it is attached, it forms an oxo or C2-C6 alkenyl group.
3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula XXXVII, XXXVIII, XXXIX, XXXX, XXXXI, XXXXII or XXXXIII in Y 1 is -O-, -S-, -S(O)-, -S(O)2-, -NR 9 -, or -CR 11 R 12 -; Y 2 is -O-, -S-, -S(O)-, -S(O)2-, -NR 10 -, or -CR 13 R 14 -; Z 5 N or C (R 15 ); Z 6 N or C (R 16 ); Ring D is C3-C6 cycloalkyl or 4- to 8-membered heterocycloalkyl; Each R 9 and R 10 are independently H, deuterium, -C(O)R g 、-C(O)NR g R h , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 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 optionally substituted with 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 R 9 and R 1 or R 10 and R 1 The 4- to 10-membered heterocycloalkyl is combined with the atoms to which it is attached to form a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in the 4- to 10-membered heterocycloalkyl is independently optionally substituted with 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)OC1-C6 alkyl, -N(C1-C6 -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 two hydrogen atoms on a single carbon atom of the 4- to 10-membered heterocycloalkyl group are combined to form an oxo or C2-C6 alkenyl group; Each R 11 , R 12 , R 13 and R 14 are independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, 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 1 and R 11 , R 1 and R 12 , R 1 and R 13 , R 1 and R 14 , two R 11 and R 12 or two R 13 and R 14 The one or more carbon atoms to which they are attached are combined to form a C3-C6 cycloalkyl group or a 4-10 membered heterocycloalkyl group, 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 heterocycloalkyl groups is independently optionally substituted with 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 R 11 and R 12 or R 13 and R 14 Together with the carbon atom to which it is attached, it forms an oxo or C2-C6 alkenyl group; and Each R 15 and R 16 are independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, 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.
4. The compound according to claim 1 or 2, wherein the compound has formula III or a pharmaceutically acceptable salt thereof.
5. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the compound has formula XVI, XXIII or XXX, Wherein ring C is a 4- to 8-membered heterocycloalkyl group, X 1 is -NH-, -O- or -CH2-, q is 0, 1 or 2, t is 1 or 2, and v is 1 or 2.
6. A compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein the compound has formula IV, XIV, XVII, XXII, XXIV, XXIX, XXXI or XXXVI, Z 5 N or C (R 15 ); Z 6 N or C (R 16 ); Each R 15 and R 16 are independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, 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; Ring C is a 4- to 8-membered heterocycloalkyl; X 1 is -O-, -NH- or -CH2-; q is 0, 1, or 2; t is 1 or 2, and v is 1 or 2.
7. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein the compound has formula V, XI, XVIII, XXI, XXV, XXVIII, XXXII or XXXV, wherein ring C is a 4- to 8-membered heterocycloalkyl group; 1 is -O-, -NH- or -CH2-; q is 0, 1 or 2; t is 1 or 2; and v is 1 or 2.
8. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein the compound has formula VI, X, XIX, XX, XXVI, XXVII, XXXIII, XXXIV, XXXXIII, XXXXIV, XXXXV or XXXXVI, wherein ring C is a 4- to 8-membered heterocycloalkyl group; 1 is -O-, -NH- or -CH2-; q is 0, 1 or 2; t is 1 or 2; and v is 1 or 2.
9. The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein the compound has formula VII or XV, Z 5 N or C (R 15 ); Z 6 N or C (R 16 );and Each R 15 and R 16 are independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, 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.
10. The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein the compound has formula VIII or XIII or a pharmaceutically acceptable salt thereof.
11. The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein the compound has Formula IX or Formula XII or a pharmaceutically acceptable salt thereof.
12. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 1 is deuterium, C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, wherein each hydrogen atom in the C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is independently optionally substituted by: 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 9 and R 1 or R 10 and R 1 The 4- to 10-membered heterocycloalkyl radicals are combined together with the atoms to which they are attached to form a 4- to 10-membered heterocycloalkyl radical, wherein each hydrogen atom in the 4- to 10-membered heterocycloalkyl radical is independently optionally substituted with 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)OC1-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 or two hydrogen atoms on a single carbon atom of the 4- to 10-membered heterocycloalkyl group are combined to form an oxo or C2-C6 alkenyl group; or two R 1 Together with the one or more atoms to which it is attached, it forms a C3-C6 cycloalkyl group or a 4-10 membered heterocycloalkyl group, 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 heterocycloalkyl group is independently optionally substituted with 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.
13. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Ring A optionally together with Ring C or Ring D forms the core of the compound of Formula I, the core having the following formula: Among them Is with ring B or -(X) p -R 3 and each hydrogen atom in Ring A, Ring C if present, and Ring D if present is independently optionally substituted by R selected from the group consisting of 1 Substitution: 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.
14. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Ring A optionally together with Ring C or Ring D forms the core of the compound of Formula I, the core having the following formula: Among them Is with ring B or -(X) p -R 3 covalent attachment point.
15. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein Ring A is a fused 5- to 8-membered heterocycloalkyl group forming the core of the compound of Formula I, the core having the following formula: Among them Is with ring B or -(X) p -R 3 covalent attachment point.
16. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Y 2 For -O-.
17. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Y 2 It is -CH2-.
18. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 3 is -C1-C6 alkyl, 4- to 10-membered heterocycloalkyl, or -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl), wherein each hydrogen atom in -C1-C6 alkyl, 4- to 10-membered heterocycloalkyl, or -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl) is independently optionally substituted with 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.
19. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 3 -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl), wherein each hydrogen atom in -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl) is independently optionally substituted with 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.
20. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 3 for wherein each hydrogen atom is independently optionally substituted by 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 is the point of covalent attachment.
21. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 3 for in It is an inorganic counter ion or an organic counter ion.
22. The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein R 3 is a 4- to 10-membered heterocycloalkyl group, wherein each hydrogen atom in the 4- to 10-membered heterocycloalkyl group is independently optionally substituted by a deuterium, a halogen, a C1-C6 alkyl group, a -C1-C6 alkylene group-O-C1-C6 alkyl group, a -OC1-C6 alkylene group-O-C1-C6 alkyl group, a -C1-C6 alkylene group-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.
23. A compound according to any one of claims 1 to 18 or 22, or a pharmaceutically acceptable salt thereof, wherein R 3 for in is the point of covalent attachment.
24. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein m is 1, 2, 3 or 4.
25. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2 or 3.
26. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Z 1 is N.
27. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Z 2 is N.
28. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Z 3 CR 7 And Z 4 is N.
29. The compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein Z 3 CR 7 And Z 4 CR 8 .
30. The compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein Z 3 N and Z 4 CR 8 .
31. A compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein Z 3 N and Z 4 is N.
32. A compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein Z 3 N, Z 4 CR 8 , Z 5 CR 15 , and Z 6 CR 16 .
33. A compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein Z 3 CR 7 , Z 4 N, Z 5 CR 15 , and Z 6 CR 16 .
34. A compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein Z 3 N, Z 4 N, Z 5 CR 15 , and Z 6 CR 16 .
35. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein p is 0.
36. The compound according to any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein p is 1.
37. The compound according to any one of claims 1 to 34 or 36, or a pharmaceutically acceptable salt thereof, wherein X is -O-.
38. A compound according to any one of claims 1 to 34 or 36, or a pharmaceutically acceptable salt thereof, wherein X is -NR 4 -.
39. The compound according to any one of claims 1 to 34 or 36, or a pharmaceutically acceptable salt thereof, wherein X is -S-.
40. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein each R 2 are independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -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 is optionally substituted independently with deuterium or halogen.
41. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Ring B is in is the point of covalent attachment.
42. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 4 It is H or methyl.
43. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 5 For H.
44. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 6 For H.
45. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 7 It is H or F.
46. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 8 For H.
47. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 9 It is H or methyl.
48. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 10 It is H or methyl.
49. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 11 For H.
50. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 12 For H.
51. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 13 For H.
52. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 14 For H.
53. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Z may be present 5 is N.
54. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Z may be present 6 is N.
55. A compound according to any one of claims 1 to 51, or a pharmaceutically acceptable salt thereof, wherein Z may be present 5 CR 15 .
56. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 15 For H.
57. A compound according to any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, wherein Z may be present 6 CR 16 .
58. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 16 For H.
59. The compound of claim 1 selected from the group consisting of: 5-ethynyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol; 5-ethyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol; (8aR,9R)-5-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-methyl-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-9-ol; (8aR,9R)-5-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-methyl-8,8a,9,10,11,12-hexahydro-7H-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-9-ol; (8aR,9R)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-9-ol; (8aR,9R)-5-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-9-ol; (8aS,11R)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-11-ol; (8aS,11R)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-11-methyl-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-11-ol; 5-ethyl-6-fluoro-4-[(8S,8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8-methyl-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol; 7-Fluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphth-5-yl]-1,3-benzothiazol-2-amine; 5-ethyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2Z,7aS)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol; (3S)-7-Chloro-1-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl]-2,3-dihydro-1H-indol-3-ol; 6-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cycloheptano[1,2,3-de]naphth-5-yl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine; 3-Chloro-5-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl]-4-(trifluoromethyl)aniline; 5-Ethynyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydropyrido[2',1':3,4][1,4]oxaza-1-[5,6,7-de]quinazolin-5-yl]naphthalen-2-ol; 5-Ethynyl-6-fluoro-4-[(9S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(propan-2-yl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol; 5-ethynyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2Z,7aS)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol; (8aR,9R)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-methyl-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-9-ol; 5-Ethynyl-6-fluoro-4-[(7aR,10aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-11-methyl-7a,8,10a,11-tetrahydro-10H-7,9-dioxa-1,3,6,11-tetraazanaphtho[1,8-fg]azulene-5-yl]naphthalen-2-ol; 5-Ethynyl-6-fluoro-4-[(7aS,9aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-10-methyl-8,9,9a,10-tetrahydro-7aH-7-oxa-1,3,6,10-tetraazacyclotidin[5,6]cyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol; 5-Ethynyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8a,9,11,12-tetrahydro-8H-7,10-dioxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol; 5-Ethynyl-6-fluoro-4-[(8aS,12S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-12-methyl-8a,9,11,12-tetrahydro-8H-7,10-dioxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol; (8aS,12S)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8a,9,11,12-tetrahydro-8H-7,10-dioxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-12-carbonitrile; (8aS,11R)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl]methoxy}-8a,9,11,12-tetrahydro-8H-7,10-dioxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11-carbonitrile; (8aS,12R)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-12-carbonitrile; (8aS,11R)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11-carbonitrile; 5-Ethynyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8a,9,12,13-tetrahydro-8H,11H-7,10-dioxa-1,3,6,13a-tetraazanaphtho[1,8-ab]heptalen-5-yl]naphthalen-2-ol; 5-Ethynyl-6-fluoro-4-[(8aS,13S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-13-methyl-8a,9,12,13-tetrahydro-8H,11H-7,10-dioxa-1,3,6,13a-tetraazanaphtho[1,8-ab]heptalen-5-yl]naphthalen-2-ol; (8aS,13R)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl]methoxy}-8a,9,12,13-tetrahydro-8H,11H-7,10-dioxa-1,3,6,13a-tetraazanaphtho[1,8-ab]heptalene-13-carbonitrile; 5-Ethynyl-6-fluoro-4-[(8aS,12S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-12-methyl-8a,9,12,13-tetrahydro-8H,11H-7,10-dioxa-1,3,6,13a-tetraazanaphtho[1,8-ab]heptalen-5-yl]naphthalen-2-ol; (8aS,12R)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl]methoxy}-8a,9,12,13-tetrahydro-8H,11H-7,10-dioxa-1,3,6,13a-tetraazanaphtho[1,8-ab]heptalene-12-carbonitrile; 5-Ethynyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,12,13-hexahydro-7,11-dioxa-1,3,6,13a-tetraazanaphtho[1,8-ab]heptalen-5-yl]naphthalen-2-ol; 5-Ethynyl-6-fluoro-4-[(8aS,9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-methyl-8,8a,9,10,12,13-hexahydro-7,11-dioxa-1,3,6,13a-tetraazanaphtho[1,8-ab]heptalen-5-yl]naphthalen-2-ol; 5-Ethynyl-6-fluoro-4-[(8aS,13S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-13-methyl-8,8a,9,10,12,13-hexahydro-7,11-dioxa-1,3,6,13a-tetraazanaphtho[1,8-ab]heptalen-5-yl]naphthalen-2-ol; (8aS,13S)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl]methoxy}-8,8a,9,10,12,13-hexahydro-7,11-dioxa-1,3,6,13a-tetraazanaphtho[1,8-ab]heptalene-13-carbonitrile; (8aS,12R)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl]methoxy}-8,8a,9,10,12,13-hexahydro-7,11-dioxa-1,3,6,13a-tetraazanaphtho[1,8-ab]heptalene-12-carbonitrile; (8aS)-5-(5-chloro-1H-indazol-4-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene; 5-Ethynyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2E)-2-(fluoromethylene)tetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol; (5P,8aS)-5-(3,5-dichloro-1H-indazol-4-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene; (5M,8aS)-5-(3,5-dichloro-1H-indazol-4-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene; 2-amino-7-fluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl]-1-benzothiophene-3-carbonitrile; (8aS,11S)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-11-ol; (8aR,11R)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-11-ol; 6-((S)-1-fluoro-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5,5a,6,7,8,9-hexahydro-4-oxa-3,9a,10,12-tetraazabenzo[4,5]cycloheptano[1,2,3-de]naphthalen-2-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine; (8aS)-5-(8-ethynyl-3,7-difluoronaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene; (8aR,11S)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-11-ol; (2R,7aS)-7a-({[(8aS)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-2-yl]oxy}methyl)hexahydro-1H-pyrrolizin-2-ol; 5-ethynyl-6-fluoro-4-[(8aS)-4,11,11-trifluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol; (2S,7aS)-7a-({[(8aS)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-2-yl]oxy}methyl)hexahydro-1H-pyrrolizin-2-ol; 5-Ethynyl-6-fluoro-4-[(7aR,10aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl]methoxy}-7a,8,9,10,10a,11-hexahydro-7-oxa-1,3,6,11-tetraazanaphtho[1,8-fg]azulen-5-yl]naphthalen-2-ol; (8aS,9S)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-9-ol; 5-Ethynyl-6-fluoro-4-[4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-13-(hydroxymethyl)-8,9,10,11-tetrahydro-8,12-methano-7-oxa-1,3,6,12-tetraazacyclonona[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol; 4-[(8aS)-4,11-difluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; 5-ethynyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,12-tetrahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol; 5-ethynyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10-tetrahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol; 5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11-carbonitrile; 5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11-carboxamide; (8aS,9S)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-methyl-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-9-ol; (8aS,9S)-5-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-methyl-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-9-ol; (8aS)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11-carbonitrile; 5-(8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-9-ol; (8aS,11S)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-11-methyl-8,8a,9,10,11,12-hexahydro-7-oxa-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-11-ol; and 5-ethynyl-6-fluoro-4-(4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydro-7H-1,3,6,12a-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-5-yl)naphthalen-2-ol; or a pharmaceutically acceptable salt thereof.
60. The compound of claim 1 selected from the group consisting of: 5-Ethynyl-6-fluoro-4-[(9S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(hydroxymethyl)-9,10-dimethyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol; 5-Ethynyl-6-fluoro-4-[(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(hydroxymethyl)-9,10-dimethyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol; 5-ethyl-6-fluoro-4-[(9S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(hydroxymethyl)-9,10-dimethyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol; 5-ethynyl-6-fluoro-4-[(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(hydroxymethyl)-9,10-dimethyl-7,8,9,10-tetrahydro-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol; 5-ethyl-6-fluoro-4-[(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(hydroxymethyl)-9,10-dimethyl-7,8,9,10-tetrahydro-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol; 5-Ethynyl-6-fluoro-4-[(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(2-hydroxypropan-2-yl)-8,9-dihydro-7H-10-oxa-1,3,6-triazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol; 5-ethyl-6-fluoro-4-[(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(2-hydroxypropan-2-yl)-8,9-dihydro-7H-10-oxa-1,3,6-triazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol; 5-ethynyl-6-fluoro-4-{(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-[(1S)-1-hydroxyethyl]-8,9-dihydro-7H-10-oxa-1,3,6-triazacyclohepta[1,2,3-de]naphthalen-5-yl}naphthalen-2-ol; 5-ethyl-6-fluoro-4-{(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-[(1S)-1-hydroxyethyl]-8,9-dihydro-7H-10-oxa-1,3,6-triazacyclohepta[1,2,3-de]naphthalen-5-yl}naphthalen-2-ol; 5-ethynyl-6-fluoro-4-{(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-[(1R)-1-hydroxyethyl]-8,9-dihydro-7H-10-oxa-1,3,6-triazacyclohepta[1,2,3-de]naphthalen-5-yl}naphthalen-2-ol; 5-ethyl-6-fluoro-4-{(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-[(1R)-1-hydroxyethyl]-8,9-dihydro-7H-10-oxa-1,3,6-triazacyclohepta[1,2,3-de]naphthalen-5-yl}naphthalen-2-ol; 5-ethynyl-6-fluoro-4-{(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-[(1R)-1-hydroxyethyl]-10-methyl-7,8,9,10-tetrahydro-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl}naphthalen-2-ol; 5-ethyl-6-fluoro-4-{(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-[(1R)-1-hydroxyethyl]-10-methyl-7,8,9,10-tetrahydro-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl}naphthalen-2-ol; 5-ethynyl-6-fluoro-4-{(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-[(1R)-1-hydroxyethyl]-7,8,9,10-tetrahydro-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl}naphthalen-2-ol; 5-ethyl-6-fluoro-4-{(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-[(1R)-1-hydroxyethyl]-7,8,9,10-tetrahydro-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl}naphthalen-2-ol; 5-ethynyl-6-fluoro-4-{(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-[(1R)-1-hydroxyethyl]-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl}naphthalen-2-ol; 5-ethyl-6-fluoro-4-{(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-[(1R)-1-hydroxyethyl]-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl}naphthalen-2-ol; 5-Ethynyl-6-fluoro-4-[(5R)-9-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-5-(2-hydroxypropan-2-yl)-4-methyl-5,6-dihydro-4H-pyrimido[4,5,6-de][1,6]naphthyridin-8-yl]naphthalen-2-ol; 5-ethyl-6-fluoro-4-[(5R)-9-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-5-(2-hydroxypropan-2-yl)-4-methyl-5,6-dihydro-4H-pyrimido[4,5,6-de][1,6]naphthyridin-8-yl]naphthalen-2-ol; 5-Chloro-6-fluoro-4-{(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-[(1R)-1-hydroxyethyl]-7,8,9,10-tetrahydro-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl}naphthalen-2-ol; 5,6-difluoro-4-{(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-[(1R)-1-hydroxyethyl]-7,8,9,10-tetrahydro-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl}naphthalen-2-ol; 5-Ethynyl-6-fluoro-4-[(9S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(hydroxymethyl)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol; 5-ethyl-6-fluoro-4-[(9S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(hydroxymethyl)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol; 4-[(9S)-9-cyclopropyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; 4-[(9S)-9-Cyclopropyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; 4-[(9S)-9-Cyclopropyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]-5-ethyl-6-fluoronaphthalen-2-ol; 4-[(9S)-9-Cyclopropyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]-5-ethyl-6-fluoronaphthalen-2-ol; 4-[(9S)-9-cyclobutyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; 5-ethynyl-6-fluoro-4-{(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-[(2R)-oxolan-2-yl]-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl}naphthalen-2-ol; 5-Ethynyl-6-fluoro-4-{(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-[(2R)-oxan-2-yl]-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl}naphthalen-2-ol; 5-Ethynyl-6-fluoro-4-[(9S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol; 5-ethynyl-6-fluoro-4-{(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-[(2R)-oxetan-2-yl]-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl}naphthalen-2-ol; 5-Ethynyl-6-fluoro-4-[(9S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-methyl-10-(propan-2-yl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol; 5-Ethynyl-6-fluoro-4-[(9S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-methyl-10-(oxetan-3-yl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol; 5-Ethynyl-6-fluoro-4-[(9S)-4-fluoro-2-{[(2R)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(propan-2-yl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol; 5-Ethynyl-6-fluoro-4-[(9S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(2-methoxyethyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol; 5-Ethynyl-6-fluoro-4-[(9S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9,10-dimethyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol; 5-Ethynyl-6-fluoro-4-[(9S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-10-methyl-9-(propan-2-yl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol; 4-[(9S)-10-Benzyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; (2R,7aS)-7a-({[(9S)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-2-yl]oxy}methyl)-2-fluoro-4-methylhexahydro-1H-pyrrolizin-4-ium; 4-[(9S)-10-Benzyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(hydroxymethyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; 4-[(9R)-10-benzyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(hydroxymethyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; 5-ethynyl-6-fluoro-4-(4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl)naphthalen-2-ol; 4-[(9S)-9-ethyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; 5-Ethynyl-6-fluoro-4-[(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(hydroxymethyl)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol; 5-ethyl-6-fluoro-4-[(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(hydroxymethyl)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol; 5-ethynyl-6-fluoro-4-(4'-fluoro-2'-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl]methoxy}-10'-methyl-8'H,10'H-spiro[cyclopropane-1,9'-[7]oxa[1,3,6,10]tetraazacyclohepta[1,2,3-de]naphthalen]-5'-yl)naphthalen-2-ol; 5-ethynyl-6-fluoro-4-(4'-fluoro-2'-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-8'H,10'H-spiro[cyclopropane-1,9'-[7]oxa[1,3,6,10]tetraazacyclohepta[1,2,3-de]naphthalen]-5'-yl)naphthalen-2-ol; 4-[(9S)-9-ethyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]-5-ethynyl-6-fluoronaphthalen-2-ol; 5-ethyl-4-[(9S)-9-ethyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]-6-fluoronaphthalen-2-ol; 4-(10-ethyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 5-Chloro-4-[(9S)-9-ethyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]-6-fluoronaphthalen-2-ol; 4-(10-Benzyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-7,8,9,10-tetrahydro-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-[(9S)-9-ethyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]-5,6-difluoronaphthalen-2-ol; 2-amino-4-[(9S)-9-ethyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]-1-benzothiophene-3-carbonitrile; 5-ethyl-6-fluoro-4-(4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-7,8,9,10-tetrahydro-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl)naphthalen-2-ol; 5-ethynyl-6-fluoro-4-(4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-7,8,9,10-tetrahydro-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl)naphthalen-2-ol; 5-ethyl-6-fluoro-4-[(9S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9,10-dimethyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol; 5-ethyl-6-fluoro-4-[(9S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-(hydroxymethyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol; 1-[8-(10-cyclopropyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl)-2-fluoro-6-hydroxynaphthalen-1-yl]ethan-1-one; 4-(9-cyclopropyl-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-(9-cyclopropyl-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 5-ethyl-6-fluoro-4-((5aS)-1-fluoro-11-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-methyl-5,5a,6,7,8,9-hexahydro-4-oxa-3,9a,10,12-tetraazabenzo[4,5]cyclohepta[1,2,3-de]naphthalen-2-yl)naphthalen-2-ol; 4-((S)-10-ethyl-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 4-((S)-10-(2,2-difluoroethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethynyl-6-fluoronaphthalen-2-ol; 5-ethynyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10-methyl-4',5'-dihydro-2'H,8H,10H-7-oxa-1,3,6,10-tetraazaspiro[cyclohepta[de]naphthalene-9,3'-furan]-1(10a),2,3a,3a1(6a),5-pentaen-5-yl)naphthalen-2-ol; 5-ethynyl-6-fluoro-4-((S)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10-((R)-2-hydroxypropyl)-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphth-5-yl)naphthalen-2-ol; 4-((S)-10-(2,2-difluoroethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphth-5-yl)-5-ethyl-6-fluoronaphth-2-ol; 5-ethyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-10-methyl-4',5'-dihydro-2'H,8H,10H-7-oxa-1,3,6,10-tetraazaspiro[cyclohepta[de]naphthalene-9,3'-furan]-1(10a),2,3a,3a1(6a),5-pentaen-5-yl)naphthalen-2-ol; and 5-ethynyl-6-fluoro-4-((S)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9-methyl-10-(2,2,2-trifluoroethyl)-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)naphthalen-2-ol; or a pharmaceutically acceptable salt thereof.
61. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 60 or a pharmaceutically acceptable salt thereof and optionally one or more pharmaceutically acceptable excipients.
62. A method of treating a disease such as cancer comprising administering to a subject in need of such treatment an effective amount of a compound according to any one of claims 1 to 60, or a pharmaceutically acceptable salt thereof.
63. A compound according to any one of claims 1 to 60, or a pharmaceutically acceptable salt thereof, for use in a method of treating cancer in a subject.
64. A compound according to any one of claims 1 to 60, or a pharmaceutically acceptable salt thereof, for use in treating cancer in a subject.
65. Use of a compound according to any one of claims 1 to 60, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating cancer in a subject.