Fused-ring KRAS inhibitors for treating diseases
Fused ring compounds provide a solution to the challenge of developing non-covalent KRAS inhibitors, achieving selective inhibition and improved bioavailability for treating KRAS mutant cancers.
Patent Information
- Application Number
- JP2024576508
- Authority / Receiving Office
- JP · JP
- Patent Type
- Applications
- Current Assignee / Owner
- Priority Date
- 2023-06-16
- Filing Date
- 2023-07-07
- Publication Date
- 2025-08-05
AI Technical Summary
Current therapies face challenges in developing non-covalent KRAS inhibitors that can effectively 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 predictable human oral pharmacokinetic properties to treat KRAS mutant cancers.
Development of fused ring compounds, represented by formula I, which selectively target KRAS mutants by incorporating specific heterocyclic and aromatic rings with various functional groups, allowing for non-covalent binding and potential oral administration.
The fused ring compounds demonstrate selective inhibition of KRAS mutants, offering potential therapeutic benefits for treating KRAS mutant cancers with improved bioavailability and safety profiles.
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Abstract
Description
[Technical Field]
[0001] (Related Applications) This application claims the benefit of U.S. Provisional Patent Application No. 63 / 359,817, filed July 9, 2022, U.S. Provisional Patent Application No. 63 / 417,684, filed October 19, 2022, U.S. Provisional Patent Application No. 63 / 502,047, filed May 12, 2023, U.S. Provisional Patent Application No. 63 / 469,290, filed May 26, 2023, and U.S. Provisional Patent Application No. 63 / 521,487, filed June 16, 2023, the disclosures of all of which are incorporated herein by reference in their entireties.
[0002] FIELD OF THE INVENTION FIELD OF THE DISCLOSURE The present disclosure relates to fused ring compounds that target KRAS, to pharmaceutical compositions containing the compounds, and to methods of using such compounds to treat diseases such as cancer. [Background technology]
[0003] Ras is a GTP-binding protein that regulates many important physiological processes in cells, such as cell cycle progression, survival, apoptosis, etc. H-Ras, K-Ras, and N-Ras are major members of the Ras superfamily and are tightly regulated by factors that switch on and off their GTPase activity. Somatic mutations at codons 12, 13, and 61 of 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-related cancers (Prior IA et al., A comprehensive survey of Ras mutations in cancer. Cancer Res. 2012, 72, 2457-2467), including 86-96% of pancreatic cancers, 40-50% of colorectal cancers, and 27-39% of lung adenocarcinomas (Kessler D. et al., Drugging an undruggable pocket on KRAS. Proc Natl Acad Sci USA. 2019, 116(32):15823-15829). Mutated RAS is constitutively locked in an activated, GTP-bound state, promoting enhanced Ras signaling in cancer cells.
[0004] Direct targeting of mutant KRAS has proven challenging due to its high affinity for nucleotides and lack of a binding pocket amenable to small-molecule inhibitors. Recently, successful inhibition of KRAS G12C mutants with the covalent chemical modifiers sotorasib and adagrasib in patients with lung cancer carrying the KRAS G12C mutation (Stower K, KRAS inhibitors at last, Nature Medicine 2020, 26, 1804) sheds light on targeting KRAS mutants for therapeutic intervention. However, inhibitors targeting KRAS mutants that do not form covalent bonds at KRAS G12C are yet to be discovered. Increased understanding of the structural elements of the KRAS switch II pocket has enabled the design of KRAS inhibitors selective for different mutant variants. MRTX1133 has been reported as a potent and highly selective non-covalent KRAS G12D inhibitor (Wang X. et al., Identification of MRTX1133, a noncovalent, potent, and selective KRASG12D inhibitor, J. Med. Chem. 2022, 65: 3123-3133). However, intraperitoneal injection of MRTX1133 was required to achieve sufficient plasma exposure and demonstrate efficacy in mice, suggesting that MRTX1133 may have low bioavailability.
[0005] 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 predictable human oral pharmacokinetic properties to treat patients with KRAS mutant cancers. Summary of the Invention
[0006] In one embodiment, the present disclosure provides a compound of formula I: [ka] [In formula: X is -O-, -S-, or -NR 4 - and; Z 1 is N or C(R 5 ) and; Z 2 is N or C(R 6 ) and; Z 3 is N or C(R 7 ) and; Z 4 is N or C(R 8 ) is; However, Z 1 -Z 4 at least two of which are N; Ring A is a 5- to 8-membered heterocycloalkyl or C5-C8 cycloalkyl; Ring B is a 5- to 10-membered heterocycloalkyl, C-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- 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)NRa R b , -S(O)NR 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)NR 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 atom to which they are attached form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is 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 R f , -S(O)NR 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)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 Rf , -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- to 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)NR 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)NRc 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 atom to which they are attached form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, 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 is 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 R f , -S(O)NR 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)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 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), where 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 10Each hydrogen atom in -C-C alkylene-(5- to 10-membered heteroaryl), -C-C alkylene-(5- to 10-membered heteroaryl), and -C-C alkylene-(5- to 10-membered heteroaryl) is independently selected from 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)NR 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 eS(O)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 4 is H, deuterium, 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, where 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 may be independently selected from 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)NR 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)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 5 , R 6 , R 7 , and R 8 are each 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 SOUTH h 、-NR g S(O)2R h 、-NR g S(O)NR g R h 、-NR g S(O)2NR g R h 、-C(O)R g 、-C(O)OR g 、-C(O)NR g R h 、-PR g R h 、-P(O)R g R h 、-P(O)2R g R h 、-P(O)NR g R h 、-P(O)2NR g R h 、-P(O)OR g 、-P(O)2OR g 、-CN、or—NO2; R a 、R b 、R c 、R d 、R e 、R f 、R g 、and R hare each independently H, deuterium, 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 aryl, and 5- to 10-membered heteroaryl; or R a and R b , or R c and R d , or R e and R f , or R g and R h two of these, together with the atoms to which they are attached, combine to form a C3-C6 cycloalkyl, a 4- to 10-membered heterocycloalkyl, 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 an aryl and a 5- to 10-membered heteroaryl is independently selected from deuterium, halogen, C-C alkyl, C-C haloalkyl, —OH, —OC-C alkyl, —OC(O)C-C alkyl, —OC(O)N(H or C-C alkyl), —OS(O)C-C alkyl, —OS(O)C-C alkyl, —OS(O)N(H or C-C alkyl), —OS(O)N (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 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 is optionally substituted by -C1-C6 alkyl), -P(H or C1-C6 alkyl), -P(O)(H or C1-C6 alkyl), -P(O)2(H or C1-C6 alkyl), -P(O)N(H or C1-C6 alkyl), -P(O)2N(H or C1-C6 alkyl), -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 they are attached form an oxo group or an alkenyl; m is 0, 1, 2, 3, 4, 5, 6, or 7; n is 0, 1, 2, 3, 4, 5, 6, or 7; p is 0 or 1] or a pharmaceutically acceptable salt thereof.
[0007] In another aspect, the present disclosure provides a compound of formula I: [ka] [In formula: X is -O-, -S-, or -NR 4 - and; Z 1 is N or C(R 5 ) and; Z 2 is N or C(R 6 ) and; Z 3 is N or C(R 7 ) and; Z 4 is N or C(R 8 ) is; However, Z 1 -Z 4 at least two of which are N; Ring A is a 5- to 8-membered heterocycloalkyl or C5-C8 cycloalkyl; Ring B is C6-C 10 aryl or 5- to 10-membered heteroaryl; R 1 are each independently 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)NR 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)NR 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 atom to which they are attached form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is 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 R f , -S(O)NR 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)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 Rf , -P(O)OR e , -P(O)2OR e , -CN, or -NO2; R 2 are each independently 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 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)NR 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 cS(O)NR 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 atom to which they are attached form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, 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 is 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 R f , -S(O)NR 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)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 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), where 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-C10 Each hydrogen atom in -C-C alkylene-(5- to 10-membered heteroaryl), -C-C alkylene-(5- to 10-membered heteroaryl), and -C-C alkylene-(5- to 10-membered heteroaryl) is independently selected from 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)NR 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 , -NRe S(O)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 4 is H, deuterium, 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, where 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 may be independently selected from 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)NR e Rf , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)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 -NO; or R 1 and R 10and together with the atoms to which they are attached, combine 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 selected from deuterium, halogen, C-C alkyl, C-C haloalkyl, —OH, —OC -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-C 6 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 )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)O-C1-C6 alkyl, -P(O)2O-C1-C6 alkyl, -CN, or -NO2, or a monocyclic 4 to 10 membered heterocycloalkyl, a fused bicyclic 5 to 10 membered heterocycloalkyl,or two hydrogen atoms on a single carbon atom of a bridged bicyclic 6- to 10-membered heterocycloalkyl combine to form an oxo group or an alkenyl group; R 5 , R 6 , R 7 , and R 8 are each 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)NR 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)NR g R h , -C(O)R g , -C(O)OR g , -C(O)NR g R h , -PRg R h , -P(O)R g R h , -P(O)2R g R h , -P(O)NR g R h , -P(O)2NR g R h , -P(O)OR g , -P(O)2OR g , -CN, or -NO2; R a , R b , R c , R d , R e , R f , R g , and R h are each independently H, deuterium, 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 aryl, and 5- to 10-membered heteroaryl; or R a and R b , or R c and R d , or R e and R f , or R g and R h two of these, together with the atom to which they are attached, combine to form a C3-C6 cycloalkyl, a 4- to 10-membered heterocycloalkyl, 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 is independently selected from deuterium, halogen, C-C alkyl, C-C haloalkyl, —OH, —OC-C alkyl, —OC(O)C-C alkyl, —OC(O)N(H or C-C alkyl), —OS(O)C-C alkyl, —OS(O)C-C alkyl, —OS(O)N(H or C-C alkyl), —OS(O)N(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 is optionally substituted by -C1-C6 alkyl), -P(H or C1-C6 alkyl), -P(O)(H or C1-C6 alkyl), -P(O)2(H or C1-C6 alkyl), -P(O)N(H or C1-C6 alkyl), -P(O)2N(H or C1-C6 alkyl), -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 they are attached form an oxo group or an alkenyl; m is 0, 1, 2, 3, 4, 5, 6, or 7; n is 0, 1, 2, 3, 4, 5, 6, or 7; p is 0 or 1] or a pharmaceutically acceptable salt thereof.
[0008] In some embodiments, at least one hydrogen atom in the compound of formula I is replaced with deuterium. 1 , R 2 , or R 3 At least one hydrogen atom in is replaced with deuterium.
[0009] In another aspect, the present disclosure provides a compound of formula II: [ka] [In formula: X is -O-, -S-, or -NR 4 - and; Y 1 are -O-, -S-, -S(O)-, -S(O)2-, -NR 9 -or-CR 11 R 12 - and; Y 2 are -O-, -S-, -S(O)-, -S(O)2-, -NR 10 - or -CR 13 R 14 - and; Z 1 is N or C(R 5 ) and; Z 2 is N or C(R 6 ) and; Z 3 is N or C(R 7 ) and; Z 4 is N or C(R 8 ) is; However, Z 1 -Z 4 at least two of which are N; Ring A is a 5- to 8-membered heterocycloalkyl or C5-C8 cycloalkyl; Ring B is a 5- to 10-membered heterocycloalkyl, C-C 10 aryl or 5- to 10-membered heteroaryl; Each R 1are independently 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)NR 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)NR 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 atom to which they are attached form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, 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 is 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 R f , -S(O)NR 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)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; Each R 2 are independently 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 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)NRc 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)NR 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 atom to which they are attached form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is 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 R f , -S(O)NR 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)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 Rf , -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), where 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 -C-C alkylene-(5- to 10-membered heteroaryl), -C-C alkylene-(5- to 10-membered heteroaryl), and -C-C alkylene-(5- to 10-membered heteroaryl) is independently selected from 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 , -SRe , -S(O)R e , -S(O)2R e , -S(O)NR e R f , -S(O)NR 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)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 4 is H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C 10aryl, or 5- to 10-membered heteroaryl, where 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 may be independently selected from 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)NR 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)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 -NO; or R 1 and R 10and together with the atoms to which they are attached, combine 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 selected from deuterium, halogen, C-C alkyl, C-C haloalkyl, —OH, —OC -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-C 6 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 )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)O-C1-C6 alkyl, -P(O)2O-C1-C6 alkyl, -CN, or -NO2, or a monocyclic 4 to 10 membered heterocycloalkyl, a fused bicyclic 5 to 10 membered heterocycloalkyl,or two hydrogen atoms on a single carbon atom of a bridged bicyclic 6- to 10-membered heterocycloalkyl combine to form an oxo group or an alkenyl group; R 5 , R 6 , R 7 , and R 8 are each 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)NR 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)NR g R h , -C(O)R g , -C(O)OR g , -C(O)NR g R h , -PRg R h , -P(O)R g R h , -P(O)2R g R h , -P(O)NR g R h , -P(O)2NR g R h , -P(O)OR g , -P(O)2OR g , -CN, or -NO2; 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, where 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 may be independently selected from 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)NR 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)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 -NO; or R 9 and R 1 , or R 10 and R 1together with the atom to which they are attached, combine to form a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in the 4- to 10-membered heterocycloalkyl is independently selected from deuterium, halogen, C-C alkyl, C-C haloalkyl, —OH, —OC-C alkyl, —OC(O)C-C alkyl, —OC(O)N(H or C-C alkyl), —OS(O)C-C alkyl, —OS(O)C-C alkyl, —OS(O)N(H or C -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)O C1-C6 alkyl, -C(O)N(H or C1-C6 alkyl)2, -P(H or C1-C6 alkyl)2, optionally substituted by -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 combine to form an oxo group or an alkenyl group; R 11 , R 12 , R 13 , and R 14are each 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)NR 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)NR 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 , R 11 and R 12 Two of these, or R 13 and R 14 two of these, together with the carbons to which they are attached, combine to form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, 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 is independently selected from 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)NR 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)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, or R 11 and R 12 or R 13 and R 14 two of these together with the carbon atoms to which they are attached form an oxo group or a C2-C6 alkenyl group; R a , R b , R c , R d , R e , R f , R g , and R hare each independently H, deuterium, 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 aryl, and 5- to 10-membered heteroaryl; or R a and R b , or R c and R d , or R e and R f , or R g and R h two of these, together with the atom to which they are attached, combine to form a C3-C6 cycloalkyl, a 4- to 10-membered heterocycloalkyl, 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 is independently selected from deuterium, halogen, C-C alkyl, C-C haloalkyl, —OH, —OC-C alkyl, —OC(O)C-C alkyl, —OC(O)N(H or C-C alkyl), —OS(O)C-C alkyl, —OS(O)C-C alkyl, —OS(O)N(H or C-C alkyl), —OS(O)N(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 is optionally substituted by -C1-C6 alkyl), -P(H or C1-C6 alkyl), -P(O)(H or C1-C6 alkyl), -P(O)2(H or C1-C6 alkyl), -P(O)N(H or C1-C6 alkyl), -P(O)2N(H or C1-C6 alkyl), -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 they are attached form an oxo group or an alkenyl; m is 0, 1, 2, 3, 4, 5, 6, or 7; n is 0, 1, 2, 3, 4, 5, 6, or 7; p is 0 or 1] or a pharmaceutically acceptable salt thereof.
[0010] In another aspect, the present disclosure provides a compound of formula II: [ka] [In formula: X is -O-, -S-, or -NR 4 - and; Y 1 are -O-, -S-, -S(O)-, -S(O)2-, -NR 9 -or-CR 11 R 12 - and; Y 2 are -O-, -S-, -S(O)-, -S(O)2-, -NR 10 - or -CR 13 R 14 - and; Z 1 is N or C(R 5 ) and; Z 2 is N or C(R 6 ) and; Z 3 is N or C(R 7 ) and; Z 4 is N or C(R 8 ) is; However, Z 1 -Z 4 at least two of which are N; Ring A is a 5- to 8-membered heterocycloalkyl or C5-C8 cycloalkyl; Ring B is C6-C 10 aryl or 5- to 10-membered heteroaryl; R 1 are each independently 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 Rb , -P(O)OR a , -P(O)2OR a , -CN, or -NO2, or two R 1 together with the atom to which they are attached form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, 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 is 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 R f , -S(O)NR 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)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 2 are each independently 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 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)NR 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 Rd , -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)NR 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 atom to which they are attached form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, 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 is 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)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)NR 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)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 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 10Aryl, -C1-C6 alkylene-(C6-C 10 aryl), 5- to 10-membered heteroaryl, or -C1-C6 alkylene-(4- to 10-membered heterocycloalkyl), where 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 -C-C alkylene-(5- to 10-membered heteroaryl), -C-C alkylene-(5- to 10-membered heteroaryl), and -C-C alkylene-(5- to 10-membered heteroaryl) is independently selected from 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)NR 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)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 4 is H, deuterium, 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, where 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 may be independently selected from 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)NR 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)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 -NO; or R 1 and R 10and together with the atoms to which they are attached, combine 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 selected from deuterium, halogen, C-C alkyl, C-C haloalkyl, —OH, —OC -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-C 6 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 )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)O-C1-C6 alkyl, -P(O)2O-C1-C6 alkyl, -CN, or -NO2, or a monocyclic 4 to 10 membered heterocycloalkyl, a fused bicyclic 5 to 10 membered heterocycloalkyl,or two hydrogen atoms on a single carbon atom of a bridged bicyclic 6- to 10-membered heterocycloalkyl combine to form an oxo group or an alkenyl group; R 5 , R 6 , R 7 , and R 8 are each 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)NR 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)NR g R h , -C(O)R g , -C(O)OR g , -C(O)NR g R h , -PRg R h , -P(O)R g R h , -P(O)2R g R h , -P(O)NR g R h , -P(O)2NR g R h , -P(O)OR g , -P(O)2OR g , -CN, or -NO2; 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, where 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 may be independently selected from 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)NR 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)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 -NO; or R 9 and R 1 or R 10 and R 1together with the atom to which they are attached, combine to form a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in the 4- to 10-membered heterocycloalkyl is independently selected from deuterium, halogen, C-C alkyl, C-C haloalkyl, —OH, —OC-C alkyl, —OC(O)C-C alkyl, —OC(O)N(H or C-C alkyl), —OS(O)C-C alkyl, —OS(O)C-C alkyl, —OS(O)N(H or C 1-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)O C1-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 combine to form an oxo group or an alkenyl group; R 11 , R 12 , R 13 , and R 14are each 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)NR 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)NR 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 , R 11 and R 12 Two of these, or R 13 and R 14 two of these, together with the carbons to which they are attached, combine to form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, 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 is independently selected from 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)NR 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)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, or R 11 and R 12 or R 13 and R 14 two of these together with the carbon atoms to which they are attached form an oxo group or a C2-C6 alkenyl group; R a , R b , R c , R d , R e , R f , R g , and R hare each independently H, deuterium, 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 aryl, and 5- to 10-membered heteroaryl; or R a and R b , or R c and R d , or R e and R f , or R g and R h two of these, together with the atom to which they are attached, combine to form a C3-C6 cycloalkyl, a 4- to 10-membered heterocycloalkyl, 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 is independently selected from deuterium, halogen, C-C alkyl, C-C haloalkyl, —OH, —OC-C alkyl, —OC(O)C-C alkyl, —OC(O)N(H or C-C alkyl), —OS(O)C-C alkyl, —OS(O)C-C alkyl, —OS(O)N(H or C-C alkyl), —OS(O)N(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 is optionally substituted by -C1-C6 alkyl), -P(H or C1-C6 alkyl), -P(O)(H or C1-C6 alkyl), -P(O)2(H or C1-C6 alkyl), -P(O)N(H or C1-C6 alkyl), -P(O)2N(H or C1-C6 alkyl), -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 they are attached form an oxo group or an alkenyl; m is 0, 1, 2, 3, 4, 5, 6, or 7; n is 0, 1, 2, 3, 4, 5, 6, or 7; p is 0 or 1] or a pharmaceutically acceptable salt thereof.
[0011] In some embodiments, at least one hydrogen atom in the compound of formula II is replaced with deuterium. 1 , R 2 , or R 3 At least one hydrogen atom in is replaced with deuterium.
[0012] In some embodiments, the present disclosure provides a compound of formula III: [ka] [In the formula: 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. or a pharmaceutically acceptable salt thereof.
[0013] In some embodiments, the present disclosure provides compounds of formula IV: [ka] [In the formula: 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. or a pharmaceutically acceptable salt thereof.
[0014] In some embodiments, the present disclosure provides compounds of formula IV: [ka] [In the formula: 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; Z 5 is N or C(R 15 ) and Z 6 is N or C(R 16 ) is] or a pharmaceutically acceptable salt thereof.
[0015] In some embodiments, the present disclosure provides a compound of formula V: [ka] [In the formula: 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. or a pharmaceutically acceptable salt thereof.
[0016] In some embodiments, the present disclosure provides a compound of formula VI: [ka] [In the formula: 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. or a pharmaceutically acceptable salt thereof.
[0017] In some embodiments, the present disclosure provides a compound of formula VII: [ka] [In the formula: 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. or a pharmaceutically acceptable salt thereof.
[0018] In some embodiments, the present disclosure provides a compound of formula VII: [ka] [In the formula: 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; Z 5 is N or C(R 15 ) and Z 6 is N or C(R 16 ) is] or a pharmaceutically acceptable salt thereof.
[0019] In some embodiments, the present disclosure provides a compound of formula VIII: [ka] [In the formula: 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. or a pharmaceutically acceptable salt thereof.
[0020] In some embodiments, the present disclosure provides a compound of formula IX: [ka] [In the formula: 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. or a pharmaceutically acceptable salt thereof.
[0021] In some embodiments, the present disclosure provides compounds of formula X: [ka] [In the formula: 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. or a pharmaceutically acceptable salt thereof.
[0022] In some embodiments, the present disclosure provides a compound of formula XI: [ka] [In the formula: 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. or a pharmaceutically acceptable salt thereof.
[0023] In some embodiments, the present disclosure provides a compound of formula XII: [ka] [In the formula: 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. or a pharmaceutically acceptable salt thereof.
[0024] In some embodiments, the present disclosure provides a compound of formula XIII: [ka] [In the formula: 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. or a pharmaceutically acceptable salt thereof.
[0025] In some embodiments, the present disclosure provides a compound of formula XIV: [ka] [In the formula: R 1 , R 2 , R 3 , R 9 , A, X, Y 2 , Z 1 , Z2 , Z 3 , Z 4 , Z 5 , Z 6 , m, n, and p are as described herein. or a pharmaceutically acceptable salt thereof.
[0026] In some embodiments, the present disclosure provides a compound of formula XIV: [ka] [In the formula: 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; Z 5 is N or C(R 15 ) and;Z 6 is N or C(R 16 ) is] or a pharmaceutically acceptable salt thereof.
[0027] In some embodiments, the present disclosure provides a compound of formula XV: [ka] [In the formula: 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. or a pharmaceutically acceptable salt thereof.
[0028] In some embodiments, the present disclosure provides a compound of formula XV: [ka] [In the formula: 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; Z 5 is N or C(R 15 ) and;Z 6 is N or C(R 16 ) is] or a pharmaceutically acceptable salt thereof.
[0029] In some embodiments, the present disclosure provides a compound of formula XVI: [ka] [In the formula: 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, Ring C is a 4- to 8-membered heterocycloalkyl, and q is 0, 1, or 2. or a pharmaceutically acceptable salt thereof.
[0030] In some embodiments, the present disclosure provides a compound of formula XVII: [ka] [In the formula: R 1 , R 2 , R 3 , A, X, Y 2 , Z 1 , Z2 , Z 3 , Z 4 , Z 5 , Z 6 , m, n, and p are as described herein, Ring C is a 4- to 8-membered heterocycloalkyl, and q is 0, 1, or 2. or a pharmaceutically acceptable salt thereof.
[0031] In some embodiments, the present disclosure provides a compound of formula XVII: [ka] [In the formula: 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 is N or C(R 15 ) and;Z 6 is N or C(R 16 ) is] or a pharmaceutically acceptable salt thereof.
[0032] In some embodiments, the present disclosure provides a compound of formula XVIII: [ka] [In the formula: 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, and q is 0, 1, or 2. or a pharmaceutically acceptable salt thereof.
[0033] In some embodiments, the present disclosure provides a compound of formula XIX: [ka] [In the formula: 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, and q is 0, 1, or 2. or a pharmaceutically acceptable salt thereof.
[0034] In some embodiments, the present disclosure provides compounds of formula XX: [ka] [In the formula: 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, and q is 0, 1, or 2. or a pharmaceutically acceptable salt thereof.
[0035] In some embodiments, the present disclosure provides compounds of formula XXI: [ka] [In the formula: 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, and q is 0, 1, or 2. or a pharmaceutically acceptable salt thereof.
[0036] In some embodiments, the present disclosure provides compounds of formula XXII: [ka] [In the formula: 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, Ring C is a 4- to 8-membered heterocycloalkyl, and q is 0, 1, or 2. or a pharmaceutically acceptable salt thereof.
[0037] In some embodiments, the present disclosure provides compounds of formula XXII: [ka] [In the formula: 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 is N or C(R 15 ) and;Z 6 is N or C(R 16 ) is] or a pharmaceutically acceptable salt thereof.
[0038] In some embodiments, the present disclosure provides a compound of formula XXIII: [ka] [In the formula: 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, Ring C is a 4- to 8-membered heterocycloalkyl, and q is 0, 1, or 2. or a pharmaceutically acceptable salt thereof.
[0039] In some embodiments, the present disclosure provides compounds of formula XXIV: [ka] [In the formula: 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, Ring C is a 4- to 8-membered heterocycloalkyl, and q is 0, 1, or 2. or a pharmaceutically acceptable salt thereof.
[0040] In some embodiments, the present disclosure provides compounds of formula XXIV: [ka] [In the formula: 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 is N or C(R 15 ) and;Z 6 is N or C(R 16 ) is] or a pharmaceutically acceptable salt thereof.
[0041] In some embodiments, the present disclosure provides a compound of formula XXV: [ka] [In the formula: 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, and q is 0, 1, or 2. or a pharmaceutically acceptable salt thereof.
[0042] In some embodiments, the present disclosure provides a compound of formula XXVI: [ka] [In the formula: 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, and q is 0, 1, or 2. or a pharmaceutically acceptable salt thereof.
[0043] In some embodiments, the present disclosure provides a compound of formula XXVII: [ka] [In the formula: 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, and q is 0, 1, or 2. or a pharmaceutically acceptable salt thereof.
[0044] In some embodiments, the present disclosure provides a compound of formula XXVIII: [ka] [In the formula: 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, and q is 0, 1, or 2. or a pharmaceutically acceptable salt thereof.
[0045] In some embodiments, the present disclosure provides compounds of formula XXIX: [ka] [In the formula: 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, Ring C is a 4- to 8-membered heterocycloalkyl, and q is 0, 1, or 2. or a pharmaceutically acceptable salt thereof.
[0046] In some embodiments, the present disclosure provides compounds of formula XXIX: [ka] [In the formula: 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 is N or C(R 15 ) and;Z 6 is N or C(R 16 ) is] or a pharmaceutically acceptable salt thereof.
[0047] In some embodiments, the present disclosure provides compounds of formula XXX: [ka] [In the formula: 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 X 1 is -O-, -NH-, or -CH2-, q is 0, 1, or 2, t is 1 or 2, and v is 1 or 2. or a pharmaceutically acceptable salt thereof.
[0048] In some embodiments, the present disclosure provides compounds of formula XXXI: [ka] [In the formula: 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. or a pharmaceutically acceptable salt thereof.
[0049] In some embodiments, the present disclosure provides compounds of formula XXXI: [ka] [In the formula: 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, and Z 5 is N or C(R 15 ) and Z 6 is N or C(R 16 ) is] or a pharmaceutically acceptable salt thereof.
[0050] In some embodiments, the present disclosure provides compounds of formula XXXII: [ka] [In the formula: 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. or a pharmaceutically acceptable salt thereof.
[0051] In some embodiments, the present disclosure provides compounds of formula XXXIII: [ka] [In the formula: 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. or a pharmaceutically acceptable salt thereof.
[0052] In some embodiments, the present disclosure provides compounds of formula XXXIV: [ka] [In the formula: 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. or a pharmaceutically acceptable salt thereof.
[0053] In some embodiments, the present disclosure provides compounds of formula XXXV: [ka] [In the formula: 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. or a pharmaceutically acceptable salt thereof.
[0054] In some embodiments, the present disclosure provides compounds of formula XXXVI: [ka] [In the formula: 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. or a pharmaceutically acceptable salt thereof.
[0055] In some embodiments, the present disclosure provides compounds of formula XXXVI: [ka] [In the formula: 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, and Z 5 is N or C(R 15 ) and Z 6 is N or C(R 16 ) is] or a pharmaceutically acceptable salt thereof.
[0056] In some embodiments, the present disclosure provides compounds of formula XXXVII: [ka] [In the formula: R 1 , R 2 , R 3 , A, B, 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. or a pharmaceutically acceptable salt thereof.
[0057] In some embodiments, the present disclosure provides compounds of formula XXXVIII: [ka] [In the formula: R 1 , R 2 , R3 , 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. or a pharmaceutically acceptable salt thereof.
[0058] In some embodiments, the present disclosure provides compounds of formula XXXVIII: [ka] [In the formula: 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; Ring D is C3-C6 cycloalkyl or 4- to 8-membered heterocycloalkyl; Z 5 is N or C(R 15 ) and Z 6 is N or C(R 16 ) is] or a pharmaceutically acceptable salt thereof.
[0059] In some embodiments, the present disclosure provides compounds of formula XXXIX: [ka] [In the formula: 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. or a pharmaceutically acceptable salt thereof.
[0060] In some embodiments, the present disclosure provides compounds of formula XXXX: [ka] [In the formula: 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. or a pharmaceutically acceptable salt thereof.
[0061] In some embodiments, the present disclosure provides compounds of formula XXXXI: [ka] [In the formula: 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. or a pharmaceutically acceptable salt thereof.
[0062] In some embodiments, the present disclosure provides compounds of formula XXXXII: [ka] [In the formula: 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. or a pharmaceutically acceptable salt thereof.
[0063] In some embodiments, the present disclosure provides compounds of formula XXXXIII: [ka] [In the formula: 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. or a pharmaceutically acceptable salt thereof.
[0064] In some embodiments, the present disclosure provides compounds of formula XXXXIII: [ka] [In the formula: 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; Ring D is C3-C6 cycloalkyl or 4- to 8-membered heterocycloalkyl; Z 5 is N or C(R 15 ) and Z 6 is N or C(R 16 ) is] or a pharmaceutically acceptable salt thereof.
[0065] In some embodiments, the present disclosure provides compounds of formula XXXXIV: [ka] [In the formula: 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, and q is 0, 1, or 2. or a pharmaceutically acceptable salt thereof.
[0066] In some embodiments, the present disclosure provides compounds of formula XXXXV: [ka] [In the formula: 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, and q is 0, 1, or 2. or a pharmaceutically acceptable salt thereof.
[0067] In some embodiments, the present disclosure provides compounds of formula XXXXVI: [ka] [In the formula: 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; X 1 is -O-, -NH-, or -CH2-; q is 0, 1, or 2; t is 1 or 2, and v is 1 or 2. or a pharmaceutically acceptable salt thereof.
[0068] In certain embodiments of the above aspects, the compound of Formulae (I)-(XXXXVI) is a compound selected from those classes described or specifically illustrated in the detailed description below. In a further aspect, the present disclosure relates to a pharmaceutical composition comprising at least one compound of Formula (I)-(XXXXVI) or a pharmaceutically acceptable salt thereof. The pharmaceutical composition according to the present disclosure may further comprise a pharmaceutically acceptable excipient.
[0069] In a further aspect, the present disclosure relates to a compound of Formula (I)-(XXXXVI) or a pharmaceutically acceptable salt thereof for use as a pharmaceutical. In a further aspect, 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)-(XXXXVI) or a pharmaceutically acceptable salt thereof.
[0070] In a further aspect, the disclosure relates to the use of compounds of Formulas (I)-(XXXXVI) or pharmaceutically acceptable salts thereof in the manufacture of a medicament for treating diseases such as cancer, and to the use of such compounds and salts for treating such diseases. In a further aspect, the present disclosure relates to a method of inhibiting Ras, such as K-Ras, comprising contacting a cell containing one or more Ras with an effective amount of at least one compound of Formula (I)-(XXXXVI) or a pharmaceutically acceptable salt thereof, and / or with at least one pharmaceutical composition of the present disclosure, wherein the contacting is effected in vitro, ex vivo, or in vivo.
[0071] Further embodiments, features, and advantages of the present disclosure will become apparent from the following detailed description and through the practice of the present disclosure. The compounds of the present disclosure can be described as embodiments of any of the clauses listed below. It will be understood that any of the embodiments described herein can be used in conjunction with other embodiments described herein to the extent that the embodiments are not mutually inconsistent.
[0072] 1. Formula I: [ka] [In formula: X is -O-, -S-, or -NR 4 - and; Z 1 is N or C(R 5 ) and; Z 2 is N or C(R 6 ) and; Z 3 is N or C(R 7 ) and; Z 4 is N or C(R 8 ) is; However, Z 1 -Z 4 at least two of which are N; Ring A is a 5- to 8-membered heterocycloalkyl or C5-C8 cycloalkyl; Ring B is C6-C 10 aryl or 5- to 10-membered heteroaryl; R 1are each independently 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)NR 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)NR 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 atom to which they are attached form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, 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 is 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 R f , -S(O)NR 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)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; Each R 2 are independently 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 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)NRc 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)NR 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 atom to which they are attached form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, wherein C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C6-C 10Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is 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 R f , -S(O)NR 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)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 Rf , -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), where 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 -C-C alkylene-(5- to 10-membered heteroaryl), -C-C alkylene-(5- to 10-membered heteroaryl), and -C-C alkylene-(5- to 10-membered heteroaryl) is independently selected from 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 , -SRe , -S(O)R e , -S(O)2R e , -S(O)NR e R f , -S(O)NR 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)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 4 is H, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, C6-C 10aryl, or 5- to 10-membered heteroaryl, where 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 may be independently selected from 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)NR 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)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 5 , R 6 , R 7 , and R 8 are each 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)NR 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)NRg R h , -C(O)R g , -C(O)OR g , -C(O)NR g R h , -PR g R h , -P(O)R g R h , -P(O)2R g R h , -P(O)NR g R h , -P(O)2NR g R h , -P(O)OR g , -P(O)2OR g , -CN, or -NO2; R a , R b , R c , R d , R e , R f , R g , and R h are each independently H, deuterium, 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 aryl, and 5- to 10-membered heteroaryl; or R a and R b , or R c and R d , or R e and R f , or R g and R h two of these, together with the atom to which they are attached, combine to form a C3-C6 cycloalkyl, a 4- to 10-membered heterocycloalkyl, 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 is independently selected from deuterium, halogen, C-C alkyl, C-C haloalkyl, —OH, —OC-C alkyl, —OC(O)C-C alkyl, —OC(O)N(H or C-C alkyl), —OS(O)C-C alkyl, —OS(O)C-C alkyl, —OS(O)N(H or C-C alkyl), —OS(O)N(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 is optionally substituted by -C1-C6 alkyl), -P(H or C1-C6 alkyl), -P(O)(H or C1-C6 alkyl), -P(O)2(H or C1-C6 alkyl), -P(O)N(H or C1-C6 alkyl), -P(O)2N(H or C1-C6 alkyl), -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 they are attached form an oxo group or an alkenyl; m is 0, 1, 2, 3, 4, 5, 6, or 7; n is 0, 1, 2, 3, 4, 5, 6, or 7; p is 0 or 1] or a pharmaceutically acceptable salt thereof.
[0073] 2. Formula II: [ka] [In formula: Y 1 are -O-, -S-, -S(O)-, -S(O)2-, -NR 9 - or -CR 11 R 12 - and; Y 2 are -O-, -S-, -S(O)-, -S(O)2-, -NR 10 - or -CR 13 R 14 - and; 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, where 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 may be independently selected from 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)NR 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)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 optionally substituted by -, -CN, or -NO; or R 9 and R 1 , or R 10 and R 1together with the atom to which they are attached, combine to form a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in the 4- to 10-membered heterocycloalkyl is independently selected from deuterium, halogen, C-C alkyl, C-C haloalkyl, —OH, —OC-C alkyl, —OC(O)C-C alkyl, —OC(O)N(H or C-C alkyl), —OS(O)C-C alkyl, —OS(O)C-C alkyl, —OS(O)N(H or C -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)O C1-C6 alkyl, -C(O)N(H or C1-C6 alkyl)2, -P(H or C1-C6 alkyl)2, -P optionally substituted by (O)(H or C-C alkyl), -P(O)(H or C-C alkyl), -P(O)N(H or C-C alkyl), -P(O)N(H or C-C alkyl), -P(O)OC-C alkyl, -P(O)OC-C alkyl, -CN, or -NO, or two hydrogen atoms on a single carbon atom of a 4- to 10-membered heterocycloalkyl combine to form an oxo or alkenyl group; and R 11 , R 12 , R 13 , and R 14are each 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)NR 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)NR 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 , R 11 and R 12 Two of these, or R 13 and R 14 two of these, together with the carbons to which they are attached, combine to form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, 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 is independently selected from 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)NR 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)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, or R 11 and R 12 or R 13 and R 14 two of these together with the carbon atoms to which they are attached form an oxo group or a C2-C6 alkenyl group. Item 2. The compound according to item 1, which is a compound represented by the following formula: or a pharmaceutically acceptable salt thereof.
[0074] 3. Formula XXXVII, XXXVIII, XXXIX, XXXX, XXXXI, XXXXII, or XXXXIII: [ka] [ka] or [ka] [In formula: Y 1 are -O-, -S-, -S(O)-, -S(O)2-, -NR 9 - or -CR 11 R 12 - and; Y 2 are -O-, -S-, -S(O)-, -S(O)2-, -NR 10 - or -CR 13 R 14 - and; Z 5 is N or C(R 15 ) and; Z 6 is N or C(R 16 ) and; 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, where 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 may be independently selected from 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)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)NR 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)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 -NO; or R 9 and R 1 or R 10 and R 1together with the atom to which they are attached, combine to form a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in the 4- to 10-membered heterocycloalkyl is independently selected from deuterium, halogen, C-C alkyl, C-C haloalkyl, —OH, —OC-C alkyl, —OC(O)C-C alkyl, —OC(O)N(H or C-C alkyl), —OS(O)C-C alkyl, —OS(O)C-C alkyl, —OS(O)N(H or C- 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)O C1-C6 alkyl, -C(O)N(H or C1-C6 alkyl)2, -P(H or C1-C6 alkyl)2, -P( optionally substituted by -P(O)(H or C-C alkyl), -P(O)N(H or C-C alkyl), -P(O)N(H or C-C alkyl), -P(O)OC-C alkyl, -P(O)OC-C alkyl, -CN, or -NO, or two hydrogen atoms on a single carbon atom of a 4- to 10-membered heterocycloalkyl combine to form an oxo group or a C-C alkenyl group; R 11 , R 12 , R 13 , and R 14are each 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)NR 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)NR 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 , R 11 and R 12 Two of these, or R 13 and R 14 two of these, together with the carbons to which they are attached, combine to form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, 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 is independently selected from 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)NR 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)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, or R 11 and R 12 or R 13 and R 14 two of these together with the carbon atoms to which they are attached form an oxo group or a C2-C6 alkenyl group; and R 15 and R 16 are each 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)NR 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)NR 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] Item 2. The compound according to item 1, which is a compound represented by the following formula: or a pharmaceutically acceptable salt thereof.
[0075] 4. Formula III: [ka] Item 3. The compound according to item 1 or 2, which is a compound represented by the formula: or a pharmaceutically acceptable salt thereof.
[0076] 5. Formula XVI, XXIII, or XXX: [ka] wherein ring C is a 4- to 8-membered heterocycloalkyl; and X 1 is -NH-, -O- or -CH2-, q is 0, 1 or 2, t is 1 or 2, and v is 1 or 2. Item 3. The compound according to item 1 or 2, which is a compound represented by the formula: or a pharmaceutically acceptable salt thereof.
[0077] 6. Formula IV, XIV, XVII, XXII, XXIV, XXIX, XXXI, or XXXVI: [ka] [ka] [ka] [In formula: Z 5 is N or C(R 15 ) and; Z 6 is N or C(R 16 ) and; R 15 and R 16 are each 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 Rh , -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)NR 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)NR 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, v is 1 or 2] Item 6. The compound according to any one of Items 1 to 5, which is a compound represented by the following formula: or a pharmaceutically acceptable salt thereof.
[0078] 7. Formula V, XI, XVIII, XXI, XXV, XXVIII, XXXII, or XXXV: [ka] [ka] [ka] wherein ring C is a 4- to 8-membered heterocycloalkyl; 1 is -O-, -NH-, or -CH2-; q is 0, 1, or 2; t is 1 or 2; and v is 1 or 2. Item 6. The compound according to any one of Items 1 to 5, which is a compound represented by the following formula: or a pharmaceutically acceptable salt thereof.
[0079] 8. Formula VI, X, XIX, XX, XXVI, XXVII, XXXIII, XXXIV, XXXXIII, XXXXIV, XXXXV, or XXXXVI: [ka] [ka] [ka] [ka] wherein ring C is a 4- to 8-membered heterocycloalkyl; 1 is -O-, -NH-, or -CH2-; q is 0, 1, or 2; t is 1 or 2; and v is 1 or 2. Item 6. The compound according to any one of Items 1 to 5, which is a compound represented by the following formula: or a pharmaceutically acceptable salt thereof.
[0080] Formula VII or XV: [ka] [In formula: Z 5 is N or C(R 15 ) and; Z 6 is N or C(R 16 ) and; R 15 and R 16 are each 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)NR 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 gS(O)NR g R h , -NR g S(O)NR 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] Item 6. The compound according to any one of Items 1 to 5, which is a compound represented by the following formula: or a pharmaceutically acceptable salt thereof.
[0081] Formula VIII or XIII: [ka] Item 6. The compound according to any one of Items 1 to 5, which is a compound represented by the following formula: or a pharmaceutically acceptable salt thereof.
[0082] 11. Formula IX or XII: [ka] Item 6. The compound according to any one of Items 1 to 5, which is a compound represented by the following formula: or a pharmaceutically acceptable salt thereof.
[0083] 12. 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 selected from deuterium, halogen, -R e , -R f , C1-C6 alkyl, C1-C6 haloalkyl, -ORe , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O)2R e , -OS(O)NR e R f , -OS(O)2NR e R f , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR e R f , -S(O)NR 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)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 1 or R 10and R 1 together with the atom to which they are attached, combine to form a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in the 4- to 10-membered heterocycloalkyl is independently selected from deuterium, halogen, C-C alkyl, C-C haloalkyl, —OH, —OC-C alkyl, —OC(O)C-C alkyl, —OC(O)N(H or C-C alkyl), —OS(O)C-C alkyl, —OS(O)C-C alkyl, —OS(O)N(H or C-C 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 C 1-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 or two hydrogen atoms on a single carbon atom of a 4- to 10-membered heterocycloalkyl combine to form an oxo group or a C-C alkenyl group; or two R 1together with the atom to which they are attached form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, 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 is 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 R f , -S(O)NR 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)NR 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, A compound according to any one of the above items or a pharmaceutically acceptable salt thereof.
[0084] 13. Ring A, optionally together with ring C or ring D, may form the core of a compound of formula I, which core has the formula: [ka] [ka] is shown by where: [ka] are each ring B or -(X) p -R 3 and each hydrogen atom in ring A, ring C, and ring D, if present, is 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 R f, -S(O)NR 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)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; 1 optionally substituted with A compound according to any one of the above items or a pharmaceutically acceptable salt thereof.
[0085] 14. Ring A, optionally together with ring C or ring D, may form the core of a compound of formula I, which core has the formula: [ka] [ka] [ka] is shown by where: [ka] are each ring B or -(X) p -R 3 is a point of covalent bonding to one of A compound according to any one of the above items or a pharmaceutically acceptable salt thereof.
[0086] 15. Ring A is a fused 5- to 8-membered heterocycloalkyl that forms the core of a compound of formula I, and the core has the formula: [ka] [ka] [ka] is shown by where: [ka] are each ring B or -(X) p -R 3 is a point of covalent bonding to one of Item 14. The compound according to any one of Items 1 to 13, or a pharmaceutically acceptable salt thereof.
[0087] 16. Y 2 The compound according to any one of the preceding clauses, wherein is -O-, or a pharmaceutically acceptable salt thereof. 17. Y 2 The compound according to any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein is -CH2-.
[0088] 18. R 3is —C1-C6 alkyl, a 4- to 10-membered heterocycloalkyl, or —C1-C6 alkylene-(4- to 10-membered heterocycloalkyl), wherein each hydrogen atom in —C1-C6 alkyl, a 4- to 10-membered heterocycloalkyl, or —C1-C6 alkylene-(4- to 10-membered heterocycloalkyl) is independently selected from deuterium, halogen, C1-C6 alkyl, —C1-C6 alkylene-O—C1-C6 alkyl, —O—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)NR 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 eS(O)NR e R f , -NR e S(O)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, The compound according to any one of the above items or a pharmaceutically acceptable salt thereof.
[0089] 19. R 3 is —C1-C6 alkylene-(4- to 10-membered heterocycloalkyl), wherein each hydrogen atom in —C1-C6 alkylene-(4- to 10-membered heterocycloalkyl) is independently selected from deuterium, halogen, C1-C6 alkyl, —C1-C6 alkylene-O—C1-C6 alkyl, —O—C1-C6 alkylene-O—C1-C6 alkyl, —C1-C6 alkylene-OR a , C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkylene-(5- to 10-membered heterocycloalkyl), -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O)2R e , -OS(O)NR e R f , -OS(O)2NR e Rf , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR e R f , -S(O)NR 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)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, The compound according to any one of the above items or a pharmaceutically acceptable salt thereof.
[0090] R 3 but [ka] wherein each hydrogen atom is independently selected from deuterium, halogen, C1-C6 alkyl, —C1-C6 alkylene-O—C1-C6 alkyl, —O—C1-C6 alkylene-O—C1-C6 alkyl, —C1-C6 alkylene-OR a , C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkylene-(5- to 10-membered heterocycloalkyl), -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O)2R e , -OS(O)NR e R f , -OS(O)2NR e R f , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR e R f , -S(O)NR 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)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, [ka] is the point of covalent bonding, The compound according to any one of the above items or a pharmaceutically acceptable salt thereof.
[0091] 21. R 3 but, [ka] where W is an inorganic or organic counterion; The compound according to any one of the above items or a pharmaceutically acceptable salt thereof.
[0092] 22. R 3 is a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in the 4- to 10-membered heterocycloalkyl is independently selected from deuterium, halogen, C-C alkyl, —C-C alkylene-O—C-C alkyl, —O—C alkylene-O—C-C alkyl, —C-C 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)Re , -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)NR 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)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, 19. The compound according to any one of items 1 to 18, or a pharmaceutically acceptable salt thereof.
[0093] 23. R 3 but [ka] where [ka] 23. The compound according to any one of items 1 to 18 or 22, or a pharmaceutically acceptable salt thereof, wherein: is the point of covalent attachment.
[0094] 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. 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. 26. Z 1 is N, or a pharmaceutically acceptable salt thereof. 27. Z 2 is N, or a pharmaceutically acceptable salt thereof.
[0095] 28. Z 3 is CR 7 and Z 4 The compound according to any one of the above items, wherein is N, or a pharmaceutically acceptable salt thereof. 29. Z 3 is CR 7 and Z 4 is CR 8 28. The compound according to any one of items 1 to 27, wherein: 30. Z 3 is N and Z 4 is CR 8 28. The compound according to any one of items 1 to 27, wherein: 31. Z 3is N and Z 4 28. The compound according to any one of items 1 to 27, wherein is N, or a pharmaceutically acceptable salt thereof.
[0096] 32. Z 3 is N and Z 4 is CR 8 and Z 5 is CR 15 And Z 6 is CR 16 28. The compound according to any one of items 1 to 27, wherein: 33. Z 3 is CR 7 and Z 4 is N and Z 5 is CR 15 And Z 6 is CR 16 28. The compound according to any one of items 1 to 27, wherein: 34. Z 3 is N and Z 4 is N and Z 5 is CR 15 And Z 6 is CR 16 28. The compound according to any one of items 1 to 27, wherein: 35. A compound according to any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein p is 0.
[0097] 36. The compound according to any one of items 1 to 34, wherein p is 1, or a pharmaceutically acceptable salt thereof. 37. The compound according to any one of items 1 to 34 or 36, or a pharmaceutically acceptable salt thereof, wherein X is —O—. 38. X is -NR 4 Item 37. The compound according to any one of items 1 to 34 or 36, or a pharmaceutically acceptable salt thereof, wherein 39. The compound according to any one of items 1 to 34 or 36, or a pharmaceutically acceptable salt thereof, wherein X is -S-.
[0098] 40. R2 each independently represents deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OR c , -C(O)RC, -NR c R d or -CN, wherein each hydrogen atom in the C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl may be independently replaced with deuterium or halogen, as desired, or a pharmaceutically acceptable salt thereof.
[0099] 41. Ring B [ka] [ka] where
[0100] [ka] is the point of covalent attachment, or a pharmaceutically acceptable salt thereof. 42. R 4 A compound according to any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein, if present, is H or methyl. 43. R 5 A compound according to any one of the preceding clauses, wherein, if present, is H, or a pharmaceutically acceptable salt thereof.
[0101] 44. R 6 A compound according to any one of the preceding clauses, wherein, if present, is H, or a pharmaceutically acceptable salt thereof. 45. R 7 A compound according to any one of the preceding clauses, wherein, if present, is H or F, or a pharmaceutically acceptable salt thereof. 46. R 8 A compound according to any one of the preceding clauses, wherein, if present, is H, or a pharmaceutically acceptable salt thereof. 47. R 9 A compound according to any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein, if present, is H or methyl.
[0102] 48. R 10 A compound according to any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, wherein, if present, is H or methyl. 49. R 11 A compound according to any one of the preceding clauses, wherein, if present, is H, or a pharmaceutically acceptable salt thereof. 50. R 12 A compound according to any one of the preceding clauses, wherein, if present, is H, or a pharmaceutically acceptable salt thereof. 51. R 13 A compound according to any one of the preceding clauses, wherein, if present, is H, or a pharmaceutically acceptable salt thereof. 52. R 14 A compound according to any one of the preceding clauses, wherein, if present, is H, or a pharmaceutically acceptable salt thereof.
[0103] 53. Z 5 A compound according to any one of the preceding clauses, wherein, if present, is N, or a pharmaceutically acceptable salt thereof. 54. Z 6 A compound according to any one of the preceding clauses, wherein, if present, is N, or a pharmaceutically acceptable salt thereof. 55. Z 5 If exists, CR 15 52. The compound according to any one of items 1 to 51, wherein:
[0104] 56. R 15 A compound according to any one of the preceding clauses, wherein, if present, is H, or a pharmaceutically acceptable salt thereof. 57. Z 6 If exists, CR 1654. The compound according to any one of items 1 to 53, wherein: 58. R 16 A compound according to any one of the preceding clauses, wherein, if present, is H, or a pharmaceutically acceptable salt thereof.
[0105] 59. 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-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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]-1,3-benzothiazol-2-amine;
[0106] 5-ethyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2Z,7aS)-2-(fluoromethylidene)tetrahydro-1H-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-methyl-5-(trifluoromethyl)pyridin-2-amine; 3-chloro-5-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydropyrido[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-5-yl]naphthalen-2-ol; 5-ethynyl-6-fluoro-4-[(9S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-(fluoromethylidene)tetrahydro-1H-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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; 5-ethynyl-6-fluoro-4-[(7aS,9aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl]methoxy}-10-methyl-8,9,9a,10-tetrahydro-7aH-7-oxa-1,3,6,10-tetraazacyclobuta[5,6]cyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol;
[0107] 5-ethynyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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;
[0108] (8aS,12R)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-(fluoromethylidene)tetrahydro-1H-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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;
[0109] 2-amino-7-fluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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; (8aS)-5-(8-ethynyl-3,7-difluoronaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-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-pyrrolidin-2-ol; 5-ethynyl-6-fluoro-4-[(8aS)-4,11,11-trifluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-2-ol; 5-ethynyl-6-fluoro-4-[(7aR,10aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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;
[0110] (8aS,9S)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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;
[0111] (8aS)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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 Item 1. The compound according to item 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.
[0112] 60. 5-ethynyl-6-fluoro-4-[(9S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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;
[0113] 5-ethyl-6-fluoro-4-{(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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;
[0114] 5,6-difluoro-4-{(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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;
[0115] 5-ethynyl-6-fluoro-4-[(9S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-4-ium;
[0116] 4-[(9S)-10-benzyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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;
[0117] 4-(10-ethyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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;
[0118] 4-(9-cyclopropyl-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-7a(5H)-yl)methoxy)-10-((R)-2-hydroxypropyl)-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)naphthalen-2-ol; 4-((S)-10-(2,2-difluoroethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 5-ethyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-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; Item 1. The compound according to item 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.
[0119] 61. A pharmaceutical composition comprising at least one compound according to any one of paragraphs 1 to 60, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients. 62. A method for treating a disease such as cancer, comprising administering an effective amount of a compound described in any one of paragraphs 1 to 60, or a pharmaceutically acceptable salt thereof, to a subject in need of such treatment. 63. A compound according to any one of paragraphs 1 to 60, or a pharmaceutically acceptable salt thereof, for use in a method for treating cancer in a subject. 64. A compound according to any one of paragraphs 1 to 60, or a pharmaceutically acceptable salt thereof, for treating cancer in a subject. 65. Use of a compound according to any one of paragraphs 1 to 60, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a subject. DETAILED DESCRIPTION OF THE INVENTION
[0120] Before describing the present disclosure in further detail, it is to be understood that the disclosure is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims.
[0121] For the sake of brevity, the disclosures of the publications (including patents) cited herein are incorporated herein by reference. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents, applications, published applications, and other publications mentioned herein are incorporated by reference in their entirety. To the extent that a definition set forth in this section contradicts or otherwise conflicts with a definition set forth in a patent, application, or other publication incorporated herein by reference, the definition set forth in this section shall take precedence over the definition incorporated herein by reference.
[0122] As used herein in the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. Accordingly, this application serves as a predicate for using exclusive language such as "solely," "only," and the like in connection with the recitation of claim elements, or for using a "negative" limitation. As used herein, the terms "comprise," "contain," and "include" are used in their open, non-limiting sense.
[0123] In order to provide a more concise description, some of the quantitative expressions set forth herein are not modified with the word "about." Whether the word "about" is explicitly used or not, it is understood that all quantities set forth herein refer to the actual given value and to values approximating such given value that would be reasonably inferred based on ordinary skill in the art, including equivalents or similarities resulting from experimental and / or measurement conditions for such given value. Whenever a yield is expressed as a percentage, such yield refers to the mass of an entity given relative to the maximum amount of the same entity that the yield can be obtained under specific stoichiometric conditions. Concentrations expressed as percentages refer to mass ratios unless otherwise indicated.
[0124] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used to practice or test the present disclosure, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference as if fully set forth to disclose or describe the methods and / or materials in connection with which the publications are cited.
[0125] Unless otherwise specified, the methods and techniques of the present embodiment are generally carried out according to conventional methods well known in the art and as described in various general and more specific references cited and discussed throughout this specification. See, for example, Loudon, Organic Chemistry, Fourth Edition, New York: Oxford University Press, 2002, pp. 360-361, 1084-1085; Smith and March, March's Advanced-Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley-Interscience, 2001. Chemical naming of compounds described herein has generally been done using commercially available ACD / Name 2014 (ACD / Labs) or ChemBioDraw Ultra 13.0 (Perkin Elmer).
[0126] As used herein and in conjunction with the chemical structures illustrating the various embodiments described herein, [ka] represents a point at which the chemical group or chemical structure indicated by the identifier is covalently bonded to an adjacent chemical group or chemical structure. For example, in a hypothetical chemical structure in which A and B are covalently bonded, in some embodiments, the portion of AB defined by group or chemical structure A is: [ka] can be expressed as, where [ka] respectively represent a bond to A and a point of attachment covalently to B. Alternatively, in some embodiments, the portion of AB defined by group or chemical structure B is [ka] can be expressed as, where [ka] represent the bond to B and the point of attachment covalently to A, respectively.
[0127] It is understood that certain features of the present disclosure that are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the present disclosure that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. All combinations of embodiments relating to chemical groups represented by variables are specifically embraced by the present disclosure, and to the extent such combinations encompass stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity), each and every combination is herein disclosed as if individually and explicitly disclosed. In addition, all subcombinations of chemical groups listed in embodiments describing such variables are also specifically embraced by the present disclosure, and each and every such subcombination of chemical groups is herein disclosed as if individually and explicitly disclosed herein.
[0128] chemical definition The term "alkyl" refers to a straight or branched chain monovalent hydrocarbon group. The term "alkylene" refers to a straight or branched chain divalent hydrocarbon group. In some embodiments, the number of atoms in an "alkyl" or "alkylene" is C-C 20 Alkyl or C1-C 20 Alkylene, C1-C 12 Alkyl or C1-C 12It may be advantageous to limit the atom range to a specific range, such as 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 one of the above examples in light 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 will be understood that the alkyl or alkylene groups can be unsubstituted or substituted as described herein. The alkyl or alkylene groups can be substituted with any of the substituents described herein in various embodiments, for example, with one or more such substituents.
[0129] The term "alkenyl" refers to a straight or branched chain monovalent hydrocarbon group having one or more double bonds. In some embodiments, the number of atoms in an "alkenyl" is C-C 20 Alkenyl, C2-C 12 It may be advantageous to limit the term to a particular range of atoms, such as alkenyl, or C2-C6 alkenyl. Examples of alkenyl groups include ethenyl (or vinyl), allyl, and but-3-en-1-yl. Cis and trans isomers, as well as mixtures thereof, are also included in this term. It is understood that alkenyl can be unsubstituted or substituted as described herein. Alkenyl groups can be substituted with any of the substituents in various embodiments described herein, for example, with one or more such substituents.
[0130] The term "alkynyl" refers to a straight or branched chain monovalent hydrocarbon group having one or more triple bonds. In some embodiments, the number of atoms in an "alkynyl" is C-C20 Alkynyl, C2-C 12 It may be advantageous to limit the alkynyl group to a particular range of atoms, such as alkynyl, or C2-C6 alkynyl. Examples of alkynyl groups include acetylenyl (-C≡CH) and propargyl (-CH2C≡CH), but-3-yn-1,4-diyl (-C≡C-CH2CH2-), and the like. It is understood that alkynyl groups can be unsubstituted or substituted as described herein. Alkynyl groups can be substituted with any of the substituents in various embodiments described herein, for example, with one or more such substituents.
[0131] 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 a "cycloalkyl" to a specific range of atoms, such as 3 to 12 ring atoms. Polycyclic carbocycles include fused, bridged, and spiropolycyclic systems. Exemplary cycloalkyl groups include monovalent groups of the following entities: [ka]
[0132] In particular, the cyclopropyl moiety has the structural formula: [ka] It is also 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, for example, with one or more such substituents.
[0133] The term "halogen" or "halo" refers to chlorine, fluorine, bromine or iodine. The term "haloalkyl" refers to an alkyl group having one or more halo substituents. Examples of haloalkyl groups include -CF, -(CH)F, -CHF, -CHBr, -CHCF, and -CHCHF.
[0134] In certain embodiments, the alkenyl may be substituted. For example, the alkenyl may be substituted with halo (e.g., fluoro). Illustratively, the alkenyl substituted with halo may be =CHF. Illustratively, the hexahydro-1H-pyrrolidinyl moiety may be substituted with a halo-substituted alkenyl, for example, the substituted hexahydro-1H-pyrrolidinyl moiety has the structural formula: [ka] It can be expressed as:
[0135] The term "aryl" refers to a monovalent all-carbon monocyclic or fused-ring polycyclic group having a fully conjugated pi-electron system. In some embodiments, the number of atoms in "aryl" refers to a monovalent all-carbon monocyclic or fused-ring polycyclic group of 6 to 14 carbon atoms (C6-C6). 14 aryl), or a monovalent all-carbon monocyclic or fused-ring polycyclic group of 6 to 10 carbon atoms (C6-C 10 It may be advantageous to limit the aryl group to a particular range of atoms, such as aryl (aryl). Examples of aryl groups include, but are not limited to, phenyl, naphthalenyl, and anthracenyl. It is understood that aryl groups can be unsubstituted or substituted as described herein. Aryl groups can be substituted with any of the substituents in various embodiments described herein, for example, with one or more such substituents.
[0136] The term "heterocycloalkyl" refers to a saturated or partially saturated, monovalent, monocyclic or polycyclic ring system having one or more non-carbon ring atoms. In some embodiments, it may be advantageous to limit the number of atoms in a "heterocycloalkyl" to a particular 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 a "heterocycloalkyl" to a particular range or type, such as 1 to 5 ring heteroatoms selected from nitrogen, oxygen, and sulfur. Examples of monocyclic heterocycloalkyl groups 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 particular 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 oxo or imino groups on the carbon ring members and up to two oxo groups on the sulfur ring members. Examples of fused bicyclic, bridged bicyclic, and spiro bicyclic heterocycloalkyl groups include, but are not limited to, pyrrolidine, 2,5-diazabicyclo[2.2.2]octane, and 1-oxaspiro[4.5]decane. Illustrative heterocycloalkyl groups include monovalent groups of the following entities: [ka] Examples include:
[0137] A three-membered heterocycle may contain at least one heteroatom ring atom, where the heteroatom ring atom is sulfur, oxygen, or nitrogen. Non-limiting examples of three-membered heterocyclic groups include the monovalent and divalent groups oxirane, azetidine, and thiirane. A four-membered heterocycle may contain at least one heteroatom ring atom, where the heteroatom ring atom is sulfur, oxygen, or nitrogen. Non-limiting examples of four-membered heterocyclic groups include the divalent groups azitidine, oxtenane, and thietane. A five-membered heterocycle may contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen or 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 5-membered heterocyclic groups include monovalent and divalent groups such as pyrrolidine, tetrahydrofuran, 2,5-dihydro-1H-pyrrole, pyrazolidine, thiazolidine, 4,5-dihydro-1H-imidazole, dihydrothiophen-2(3H)-one, tetrahydrothiophene 1,1-dioxide, imidazolidin-2-one, pyrrolidin-2-one, dihydrofuran-2(3H)-one, 1,3-dioxolan-2-one, and oxazolidin-2-one. A 6-membered heterocycle can contain up to four heteroatom ring atoms, where (a) at least one ring atom is oxygen or sulfur and zero, one, two, or three ring atoms are nitrogen, or (b) zero ring atoms are oxygen or sulfur and up to four ring atoms are nitrogen. Non-limiting examples of six-membered heterocyclic groups include monovalent or divalent groups of piperidine, morpholine, 4H-1,4-thiazine, 1,2,3,4-tetrahydropyridine, piperazine, 1,3-oxazinan-2-one, piperazin-2-one, thiomorpholine, and thiomorpholine 1,1-dioxide. A "heterobicycle" is a fused bicyclic ring system in which one heterocyclic ring is fused to a cycloalkyl or to another heterocyclic ring.
[0138] In particular, the hexahydro-1H-pyrrolidinyl moiety has the structural formula: [ka] It can be expressed as: It is understood that heterocycloalkyl groups can be unsubstituted or substituted as described herein. Heterocycloalkyl groups can be substituted with any of the substituents in the various embodiments described herein, for example, with one or more such substituents.
[0139] The term "heteroaryl" refers to a monovalent, monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (the ring structure has ring atoms or members selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) that is fully unsaturated and has 3 to 12 ring atoms per heterocycle. The term "heteroarylene" refers to a divalent, monocyclic, fused bicyclic, or fused polycyclic aromatic heterocycle (the ring structure has ring atoms or members selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen, and sulfur) that has 3 to 12 ring atoms per heterocycle. In some embodiments, it may be advantageous to limit the number of ring atoms in a "heteroaryl" or "heteroarylene" to a specific range of atom members, such as a 5- to 10-membered heteroaryl. In some embodiments, a 5- to 10-membered heteroaryl can be a monocyclic or fused bicyclic ring having 5 to 10 ring atoms, in which at least one ring atom is a heteroatom such as N, O, or S. The ring structure may optionally contain oxo or imino groups on carbon ring members or up to two oxo groups on sulfur ring members. Illustrative examples of 5- to 10-membered heteroaryl groups include monovalent radicals of the following entities, in the form of appropriately linked moieties, while illustrative examples of 5- to 10-membered heteroarylene groups include divalent radicals of the following entities: [ka]
[0140] In some embodiments, a "monocyclic" heteroaryl can be an aromatic 5- or 6-membered heterocycle. A 5-membered heteroaryl can contain up to four heteroatom ring atoms, where (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 5-membered heteroaryl groups include monovalent groups of furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, pyrazole, imidazole, oxadiazole, thiadiazole, triazole, or tetrazole. A 6-membered heteroaryl can contain up to four heteroatom ring atoms, where (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 6-membered heteroaryl groups include monovalent radicals of pyridine, pyrazine, pyrimidine, pyridazine, or triazine. A "bicyclic heteroaryl" is a fused bicyclic ring system in which one heteroaryl ring is fused to a phenyl or another heteroaryl ring. Non-limiting examples of bicyclic heteroaryl groups include monovalent radicals of 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.
[0141] In particular, the isoquinolin-3(2H)-onyl moiety has the structural formula: [ka] It can be expressed as: In particular, the divalent pyridopyrimidine moiety has the structural formula: [ka] It can be expressed as:
[0142] It is understood that heteroaryl groups can be unsubstituted or substituted as described herein. Heteroaryl groups can be substituted with any of the substituents of the various embodiments described herein, for example, with one or more such substituents.
[0143] It will be understood that a heteroaryl or heteroarylene group can be unsubstituted or substituted as described herein. A heteroaryl or heteroarylene group can be substituted with any of the substituents in various embodiments described herein, for example, with one or more such substituents. The term "oxo" refers to a carbonyl oxygen. For example, cyclopentyl substituted with oxo is cyclopentanone.
[0144] The term "substituted" means that a particular group or moiety has one or more substituents. The term "unsubstituted" means that a particular group has no substituents. When the term "unsubstituted" is used to describe a structural system, it means that substitution occurs at any valence-allowed position on the system. In some embodiments, "substituted" means that a particular group or moiety has one, two, or three substituents. In other embodiments, "substituted" means that a particular group or moiety has one or two substituents. In yet other embodiments, "substituted" means that a particular group or moiety has one substituent.
[0145] Any formula shown herein is intended to represent the compound of that structural formula, as well as specific modifications or forms.For example, any formula shown herein is intended to encompass a racemate, or one or more enantiomers, diastereomers, or geometric isomers, or mixtures thereof.In addition, any formula shown herein is also intended to refer to the hydrate, solvate, or polymorph of such compound, or mixtures thereof.
[0146] Any formula shown herein is also intended to represent the unlabeled form as well as the isotopically labeled form of the compound.Isotopically labeled compounds have the structure shown in the formula shown herein, except that one or more atoms are replaced with atoms of selected atomic mass or mass number.Examples of isotopes that can be incorporated into the compounds of the present disclosure include: 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 These include isotopes of each of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as I. Such isotopically labeled compounds are useful in metabolic studies (preferably 14 C), reaction kinetic studies (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 assays, or in radiotherapy in patients. 2 Substitution with a heavy isotope, such as H, can offer certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced required dosage. Isotopically labeled compounds of the present disclosure and prodrugs thereof can generally be prepared according to the procedures disclosed in the following schemes or in the Examples and Preparations by replacing non-isotopically labeled reagents with readily available isotopically labeled reagents.
[0147] Certain chemical entities of formulas (I)-(XXXXVI) may be represented in more than one tautomeric form. Any and all alternative tautomers are included within the scope of these formulas, and no inference should be made as to whether a chemical entity exists in the tautomeric form it is depicted in. It is understood that 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, due to rapid interconversion, tautomers can generally be considered to be the same compound. Examples of tautomers include enol-keto tautomers, amine-imine tautomers: [ka] These include, but are not limited to:
[0148] In particular, the ring options of isoquinoline-3(2H)-oneylene are the following tautomers: [ka] It can exist as.
[0149] As used herein, when applied to a set of substituents, the term "(ATOM) i -(ATOM) j " (j>i) refers to an embodiment of this disclosure in which each and every number of atomic members from i to j, inclusive, is understood independently. As an 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).
[0150] The present disclosure also includes pharmaceutically acceptable salts of the compounds of Formulas (I)-(XXXXVI), preferably salts of the compounds described above and salts of the specific compounds exemplified herein, as well as compositions containing such salts and methods of using such salts.
[0151] "Pharmaceutically acceptable salt" is intended to mean a free acid or base salt of a compound provided herein that is non-toxic, biologically acceptable, and otherwise biologically suitable for administration to a subject. See generally S. M. 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. Compounds acceptable herein may have sufficient acidic groups, sufficient basic groups, both types of functional groups, or one or more functional groups of each type, and thus may react with many inorganic or organic bases, and inorganic and organic acids, to form pharmaceutically acceptable salts. Compounds include: [ka] where [ka] is an inorganic counterion (e.g., an inorganic anion) or an organic counterion (e.g., an organic anion). In certain embodiments, [ka] is an anion that complexes with the cation of a compound of the present disclosure to form a pharmaceutically acceptable salt.
[0152] It will be understood that the chemical entities described herein may exist as salts of the free acid or base of the compounds described herein with inorganic or organic counterions. Illustratively, salts may be formed during the preparation of the compounds (e.g., salts or pharmaceutically acceptable salts), or may be replaced by salts for further preparation, formulation, or administration. As described herein, certain compounds include: [ka] is included, where [ka] is an inorganic counterion (e.g., an inorganic anion) or an organic counterion (e.g., an organic anion). In certain embodiments, [ka] is an anion that complexes with the cation of a compound of the present disclosure to form a pharmaceutically acceptable salt.
[0153] The term "inorganic counterion" refers to an inorganic ion associated with an ionic species to maintain electrical neutrality. An inorganic counterion may represent an anion or a cation. An inorganic counterion may be associated with the free acid or base of a compound described herein. Inorganic ions can be formed by reaction of an inorganic base or an inorganic acid with a compound described herein having sufficient acidic groups, sufficient basic groups, both types of functional groups, or more than one type of each type.
[0154] The term "organic counterion" refers to an organic counterion associated with an ionic species to maintain electrical neutrality. The organic ion may represent an anion or a cation. The organic counterion may be associated with the free acid or base of a compound described herein. The organic ion may be formed by reaction of an organic base or an organic acid with a compound described herein having sufficient acidic groups, sufficient basic groups, both types of functional groups, or more than one type of each type.
[0155] Examples of pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen sulfate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propionate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyrate-1,4-dioate, hexyne-1,6-diol ... -dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, methylsulfonate, propylsulfonate, besylate, 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 can be found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa., 1985.
[0156] For compounds of formula (I)-(XXXXVI) containing a basic nitrogen, pharmaceutically acceptable salts may be prepared by any suitable method available in the art, for example, by reaction of the free base with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like, or with a pyranosidic 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, lauric acid, glucuronic acid, or galacturonic acid. The hydroxy acids may be prepared by treatment with an organic acid such as alpha-hydroxy acids such as carboxylic acid, mandelic acid, citric acid, or tartaric acid; amino acids such as aspartic acid or glutamic acid; aromatic acids such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid; sulfonic acids such as laurylsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, or ethanesulfonic acid; or a compatible mixture of any of the acids exemplified herein, and any other acids and mixtures thereof that are considered equivalents or acceptable substitutes in light of the ordinary skill in the art.
[0157] The present disclosure also relates to pharmaceutically acceptable prodrugs of compounds of Formulas (I)-(XXXXVI) and methods of treatment utilizing such pharmaceutically acceptable prodrugs. The term "prodrug" refers to a precursor of a specified compound that, after administration to a subject, generates the compound in vivo through a chemical or physiological process, such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g., when the prodrug is placed in physiological pH conditions, it is converted to a compound of Formulas (I)-(XXXXVI)). A "pharmaceutically acceptable prodrug" is a prodrug that is nontoxic, biologically acceptable, and otherwise biologically suitable for administration to a subject. Exemplary procedures for selecting and preparing suitable prodrug derivatives are described, for example, in "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985.
[0158] The present disclosure also relates to pharmaceutically active metabolites of compounds of Formula (I)-(XXXXVI) and the use of such compounds in the disclosed methods. "Pharmaceutically active metabolite" means a pharmacologically active product of metabolism in the body of a compound of Formula (I)-(XXXXVI) or a salt thereof. Prodrugs and active metabolites of a compound may be determined using conventional techniques known or available in the art. See, for example, Bertolini et al., J. Med. Chem. 1997, 40, 2011-2016; Shan et al., J. Pharm. Sci. 1997, 86(7), 765-767; Bagshawe, Drug Dev. Res. 1995, 34, 220-230; Bodor, Adv. Drug Res. 1984, 13, 255-331; Bundgaard, Design of Prodrugs (Elsevier Press, 1985); and Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen et al., eds., Harwood Academic Publishers, 1991).
[0159] As used herein, the term "KRAS inhibitor" includes, but is not limited to, compounds capable of inhibiting the protein encoded by the KRAS gene, referred to as K-Ras, which is involved in the RAS / MARK signaling pathway. The terms KRAS gene, K-Ras, and RAS / MARK signaling pathway are known and understood by those skilled in the art. It is understood that KRAS mutations occur in approximately one in seven human metastatic cancers, and that these mutations can occur at various positions in the KRAS gene coding sequence. KRAS mutations occur primarily at KRAS codons 12 and 13, with lower frequencies at codons 18, 61, 117, and 146, and have different effects on tumor cell signaling based on the codon and missense mutation. 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. Those skilled in the art will understand that reference to inhibiting a KRAS mutation, such as KRAS G12D, refers to inhibiting the protein encoded by the KRAS G12D gene, which has a coding sequence that produces a K-Ras G12D protein in which the glycine at position 12 of the protein sequence is replaced with aspartic acid (e.g., a substitution of guanine for adenine at position 35 of codon 12 of the KRAS coding sequence).
[0160] Representative Embodiments In some embodiments, the present disclosure provides a compound of formula I: [ka] [In the formula: 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. or a pharmaceutically acceptable salt thereof.
[0161] In some embodiments, the present disclosure provides a compound of formula II: [ka] [In the formula: R 1 , R 2 , R 3 , A, B, X, Y 1 , Y 2 , Z 1 , Z 2 , Z 3 , Z 4 , m, n, and p are as described herein. or a pharmaceutically acceptable salt thereof.
[0162] In some embodiments, the present disclosure provides a compound of formula III: [ka] [In the formula: 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. or a pharmaceutically acceptable salt thereof.
[0163] In some embodiments, the present disclosure provides compounds of formula IV: [ka] [In the formula: R 1 , R 2 , R 3 , R 9 , A, X, Y 2 , Z 1 , Z 2 , Z3 , Z 4 , Z 5 , Z 6 , m, n, and p are as described herein. or a pharmaceutically acceptable salt thereof.
[0164] In some embodiments, the present disclosure provides compounds of formula IV: [ka] [In the formula: 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; Z 5 is N or C(R 15 ) and Z 6 is N or C(R 16 ) is] or a pharmaceutically acceptable salt thereof.
[0165] In some embodiments, the present disclosure provides a compound of formula V: [ka] [In the formula: 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. or a pharmaceutically acceptable salt thereof.
[0166] In some embodiments, the present disclosure provides a compound of formula VI: [ka] [In the formula: 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. or a pharmaceutically acceptable salt thereof.
[0167] In some embodiments, the present disclosure provides a compound of formula VII: [ka] [In the formula: 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. or a pharmaceutically acceptable salt thereof.
[0168] In some embodiments, the present disclosure provides a compound of formula VII: [ka] [In the formula: 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; Z 5 is N or C(R 15 ) and Z 6 is N or C(R 16 ) is] or a pharmaceutically acceptable salt thereof.
[0169] In some embodiments, the present disclosure provides a compound of formula VIII: [ka] [In the formula: 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. or a pharmaceutically acceptable salt thereof.
[0170] In some embodiments, the present disclosure provides a compound of formula IX: [ka] [In the formula: 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. or a pharmaceutically acceptable salt thereof.
[0171] In some embodiments, the present disclosure provides compounds of formula X: [ka] [In the formula: 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. or a pharmaceutically acceptable salt thereof.
[0172] In some embodiments, the present disclosure provides a compound of formula XI: [ka] [In the formula: 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. or a pharmaceutically acceptable salt thereof.
[0173] In some embodiments, the present disclosure provides a compound of formula XII: [ka] [In the formula: 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. or a pharmaceutically acceptable salt thereof.
[0174] In some embodiments, the present disclosure provides a compound of formula XIII: [ka] [In the formula: 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. or a pharmaceutically acceptable salt thereof.
[0175] In some embodiments, the present disclosure provides a compound of formula XIV: [ka] [In the formula: 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. or a pharmaceutically acceptable salt thereof.
[0176] In some embodiments, the present disclosure provides a compound of formula XIV: [ka] [In the formula: 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; Z 5 is N or C(R 15 ) and;Z 6 is N or C(R 16 ) is] or a pharmaceutically acceptable salt thereof.
[0177] In some embodiments, the present disclosure provides a compound of formula XV: [ka] [In the formula: R 1 , R 2 , R 3 , R 9 , A, X, Y2 , Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , m, n, and p are as described herein. or a pharmaceutically acceptable salt thereof.
[0178] In some embodiments, the present disclosure provides a compound of formula XV: [ka] [In the formula: 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; Z 5 is N or C(R 15 ) and;Z 6 is N or C(R 16 ) is] or a pharmaceutically acceptable salt thereof.
[0179] In some embodiments, the present disclosure provides a compound of formula XVI: [ka] [In the formula: 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, Ring C is a 4- to 8-membered heterocycloalkyl, and q is 0, 1, or 2. or a pharmaceutically acceptable salt thereof.
[0180] In some embodiments, the present disclosure provides a compound of formula XVII: [ka] [In the formula: 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, Ring C is a 4- to 8-membered heterocycloalkyl, and q is 0, 1, or 2. or a pharmaceutically acceptable salt thereof.
[0181] In some embodiments, the present disclosure provides a compound of formula XVII: [ka] [In the formula: 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 is N or C(R 15 ) and;Z 6 is N or C(R 16 ) is] or a pharmaceutically acceptable salt thereof.
[0182] In some embodiments, the present disclosure provides a compound of formula XVIII: [ka] [In the formula: R 1 , R 2 , R3 , 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, and q is 0, 1, or 2. or a pharmaceutically acceptable salt thereof.
[0183] In some embodiments, the present disclosure provides a compound of formula XIX: [ka] [In the formula: 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, and q is 0, 1, or 2. or a pharmaceutically acceptable salt thereof.
[0184] In some embodiments, the present disclosure provides compounds of formula XX: [ka] [In the formula: 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, and q is 0, 1, or 2. or a pharmaceutically acceptable salt thereof.
[0185] In some embodiments, the present disclosure provides compounds of formula XXI: [ka] [In the formula: 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, and q is 0, 1, or 2. or a pharmaceutically acceptable salt thereof.
[0186] In some embodiments, the present disclosure provides compounds of formula XXII: [ka] [In the formula: 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, Ring C is a 4- to 8-membered heterocycloalkyl, and q is 0, 1, or 2. or a pharmaceutically acceptable salt thereof.
[0187] In some embodiments, the present disclosure provides compounds of formula XXII: [ka] [In the formula: 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 is N or C(R 15 ) and;Z 6 is N or C(R 16 ) is] or a pharmaceutically acceptable salt thereof.
[0188] In some embodiments, the present disclosure provides a compound of formula XXIII: [ka] [In the formula: 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, Ring C is a 4- to 8-membered heterocycloalkyl, and q is 0, 1, or 2. or a pharmaceutically acceptable salt thereof.
[0189] In some embodiments, the present disclosure provides compounds of formula XXIV: [ka] [In the formula: 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, Ring C is a 4- to 8-membered heterocycloalkyl, and q is 0, 1, or 2. or a pharmaceutically acceptable salt thereof.
[0190] In some embodiments, the present disclosure provides compounds of formula XXIV: [ka] [In the formula: 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 is N or C(R 15 ) and;Z 6 is N or C(R 16 ) is] or a pharmaceutically acceptable salt thereof.
[0191] In some embodiments, the present disclosure provides a compound of formula XXV: [ka] [In the formula: 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, and q is 0, 1, or 2. or a pharmaceutically acceptable salt thereof.
[0192] In some embodiments, the present disclosure provides a compound of formula XXVI: [ka] [In the formula: R 1 , R 2 , R 3 , A, X, Y 2 , Z1 , Z 2 , Z 3 , Z 4 , m, n, and p are as described herein, Ring C is a 4- to 8-membered heterocycloalkyl, and q is 0, 1, or 2. or a pharmaceutically acceptable salt thereof.
[0193] In some embodiments, the present disclosure provides a compound of formula XXVII: [ka] [In the formula: 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, and q is 0, 1, or 2. or a pharmaceutically acceptable salt thereof.
[0194] In some embodiments, the present disclosure provides a compound of formula XXVIII: [ka] [In the formula: 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, and q is 0, 1, or 2. or a pharmaceutically acceptable salt thereof.
[0195] In some embodiments, the present disclosure provides compounds of formula XXIX: [ka] [In the formula: 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, Ring C is a 4- to 8-membered heterocycloalkyl, and q is 0, 1, or 2. or a pharmaceutically acceptable salt thereof.
[0196] In some embodiments, the present disclosure provides compounds of formula XXIX: [ka] [In the formula: 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 is N or C(R 15 ) and;Z 6 is N or C(R 16 ) is] or a pharmaceutically acceptable salt thereof.
[0197] In some embodiments, the present disclosure provides compounds of formula XXX: [ka] [In the formula: R 1 , R 2 , R 3 , A, B, X, Y 2 , Z 1 , Z 2 , Z 3 , Z4 , 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. or a pharmaceutically acceptable salt thereof.
[0198] In some embodiments, the present disclosure provides compounds of formula XXXI: [ka] [In the formula: 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. or a pharmaceutically acceptable salt thereof.
[0199] In some embodiments, the present disclosure provides compounds of formula XXXI: [ka] [In the formula: 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, and Z 5 is N or C(R 15) and Z 6 is N or C(R 16 ) is] or a pharmaceutically acceptable salt thereof.
[0200] In some embodiments, the present disclosure provides compounds of formula XXXII: [ka] [In the formula: 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. or a pharmaceutically acceptable salt thereof.
[0201] In some embodiments, the present disclosure provides compounds of formula XXXIII: [ka] [In the formula: 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. or a pharmaceutically acceptable salt thereof.
[0202] In some embodiments, the present disclosure provides compounds of formula XXXIV: [ka] [In the formula: 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. or a pharmaceutically acceptable salt thereof.
[0203] In some embodiments, the present disclosure provides compounds of formula XXXV: [ka] [In the formula: 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. or a pharmaceutically acceptable salt thereof.
[0204] In some embodiments, the present disclosure provides compounds of formula XXXVI: [ka] [In the formula: 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 X1 is -O- or -CH2-, q is 0, 1, or 2, t is 1 or 2, and v is 1 or 2. or a pharmaceutically acceptable salt thereof.
[0205] In some embodiments, the present disclosure provides compounds of formula XXXVI: [ka] [In the formula: 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, and Z 5 is N or C(R 15 ) and Z 6 is N or C(R 16 ) is] or a pharmaceutically acceptable salt thereof.
[0206] In some embodiments, the present disclosure provides compounds of formula XXXVII: [ka] [In the formula: R 1 , R 2 , R 3 , A, B, 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. or a pharmaceutically acceptable salt thereof.
[0207] In some embodiments, the present disclosure provides compounds of formula XXXVIII: [ka] [In the formula: 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. or a pharmaceutically acceptable salt thereof.
[0208] In some embodiments, the present disclosure provides compounds of formula XXXVIII: [ka] [In the formula: 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; Ring D is C3-C6 cycloalkyl or 4- to 8-membered heterocycloalkyl; Z 5 is N or C(R 15 ) and Z 6 is N or C(R 16 ) is] or a pharmaceutically acceptable salt thereof.
[0209] In some embodiments, the present disclosure provides compounds of formula XXXIX: [ka] [In the formula: 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. or a pharmaceutically acceptable salt thereof.
[0210] In some embodiments, the present disclosure provides compounds of formula XXXX: [ka] [In the formula: 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. or a pharmaceutically acceptable salt thereof.
[0211] In some embodiments, the present disclosure provides compounds of formula XXXXI: [ka] [In the formula: 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. or a pharmaceutically acceptable salt thereof.
[0212] In some embodiments, the present disclosure provides compounds of formula XXXXII: [ka] [In the formula: 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. or a pharmaceutically acceptable salt thereof.
[0213] In some embodiments, the present disclosure provides compounds of formula XXXXIII: [ka] [In the formula: 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. or a pharmaceutically acceptable salt thereof.
[0214] In some embodiments, the present disclosure provides compounds of formula XXXXIII: [ka] [In the formula: R 1 , R2 , 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; Ring D is C3-C6 cycloalkyl or 4- to 8-membered heterocycloalkyl; Z 5 is N or C(R 15 ) and Z 6 is N or C(R 16 ) is] or a pharmaceutically acceptable salt thereof.
[0215] In some embodiments, the present disclosure provides compounds of formula XXXXIV: [ka] [In the formula: 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, and q is 0, 1, or 2. or a pharmaceutically acceptable salt thereof.
[0216] In some embodiments, the present disclosure provides compounds of formula XXXXV: [ka] [In the formula: 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, and q is 0, 1, or 2. or a pharmaceutically acceptable salt thereof.
[0217] In some embodiments, the present disclosure provides compounds of formula XXXXVI: [ka] [In the formula: 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; X 1 is -O-, -NH-, or -CH2-; q is 0, 1, or 2; t is 1 or 2, and v is 1 or 2. or a pharmaceutically acceptable salt thereof.
[0218] In some embodiments, at least one hydrogen atom in the compound of formula I is replaced with deuterium. 1 , R 2 , or R 3 At least one hydrogen atom in is replaced with deuterium.
[0219] In some embodiments, Y 1 are -O-, -S-, -S(O)-, -S(O)2-, -NR 9 - or -CR 11 R 12 In some embodiments, Y 1 is —O—. In some embodiments, Y 1 is -S-. In some embodiments, Y 1 is -S(O)-. In some embodiments, Y 1is -S(O)-. In some embodiments, Y 1 Ha-NR 9 In some embodiments, Y 2 Ha-CR 11 R 12 In some embodiments, Y 2 are -O-, -S-, -S(O)-, -S(O)2-, -NR 10 - or -CR 13 R 14 In some embodiments, Y 2 is —O—. In some embodiments, Y 2 is -S-. In some embodiments, Y 2 is -S(O)-. In some embodiments, Y 2 is -S(O)-. In some embodiments, Y 1 Ha-NR 10 In some embodiments, Y 2 Ha-CR 13 R 14 -It is.
[0220] In some embodiments, ring A is a C5-C8 cycloalkyl or a 5- to 8-membered heterocycloalkyl, wherein each of the C5-C8 cycloalkyl or 5- to 8-membered heterocycloalkyl is unsubstituted or is substituted with one or more R 1 In some embodiments, ring A is unsubstituted C5-C8 cycloalkyl or is substituted with one or more R 1 In some embodiments, ring A is an unsubstituted 5- to 8-membered heterocycloalkyl or is a C5-C8 cycloalkyl substituted with one or more R 1 and 5- to 8-membered heterocycloalkyl substituted with
[0221] In some embodiments, ring A is a C5-C8 cycloalkyl or a 5- to 8-membered heterocycloalkyl, wherein each of the C5-C8 cycloalkyl or 5- to 8-membered heterocycloalkyl is unsubstituted or contains 1, 2, 3, 4, 5, or 6 R 1 In some embodiments, ring A is unsubstituted C5-C8 cycloalkyl or is 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 is a C5-C8 cycloalkyl substituted with 1, 2, 3, 4, 5, or 6 R 1 is a 5- to 8-membered heterocycloalkyl substituted with
[0222] In some embodiments, ring A is a 5- to 8-membered heterocycloalkyl, wherein the 5- to 8-membered heterocycloalkyl is unsubstituted or has one or more R 1 and / or two R on ring A 1 together with the atoms to which they are attached are combined and unsubstituted or are one or more R 1 In some embodiments, ring A optionally forms a 4- to 8-membered heterocycloalkyl (ring C) substituted with one or more R 1 and / or two R on ring A are optionally substituted with 1 together with the atoms to which they are attached are unsubstituted or one or more R 1 In some embodiments, ring A optionally forms a 4-8 membered heterocycloalkyl having no more than one nitrogen atom in the 4-8 membered heterocycloalkyl (ring C), substituted with one or more R 1 and / or two R on ring A are optionally substituted with 1 together with the atoms to which they are attached are unsubstituted or one or more R 1and forming a 4- to 8-membered heterocycloalkyl having one or more -O- and / or -S- in the 4- to 8-membered heterocycloalkyl (ring C), wherein the 4- to 8-membered heterocycloalkyl has not more than one nitrogen atom in the 4- to 8-membered heterocycloalkyl substituted with
[0223] In some embodiments, ring A is a 5- to 7-membered heterocycloalkyl, wherein the 5- to 7-membered heterocycloalkyl is unsubstituted or has one or more R 1 and / or two R on ring A 1 together with the atoms to which they are attached are combined and unsubstituted or are one or more R 1 In some embodiments, Ring A forms a 4- to 8-membered heterocycloalkyl (Ring C) substituted with one or more R 1 and / or two R on ring A are optionally substituted with 1 together with the atoms to which they are attached are unsubstituted or one or more R 1 In some embodiments, ring A is substituted with one or more R 1 and / or two R on ring A are optionally substituted with 1 together with the atoms to which they are attached are unsubstituted or one or more R 1 and forming a 4- to 8-membered heterocycloalkyl having one or more -O- and / or -S- in the 4- to 8-membered heterocycloalkyl (ring C), wherein the 4- to 8-membered heterocycloalkyl has not more than one nitrogen atom in the 4- to 8-membered heterocycloalkyl substituted with
[0224] In some embodiments, ring A is a 5- to 8-membered heterocycloalkyl, wherein the 5- to 8-membered heterocycloalkyl is unsubstituted or has one or more R1 and / or two R on ring A 1 together with the atoms to which they are attached are unsubstituted or one or more R 1 In some embodiments, ring A optionally forms a C4-C8 cycloalkyl or 4- to 8-membered heterocycloalkyl (ring D) substituted with one or more R 1 and / or two R on ring A are optionally substituted with 1 together with the atoms to which they are attached are unsubstituted or one or more R 1 In some embodiments, Ring A optionally forms a C4-C8 cycloalkyl (Ring D) substituted with one or more R 1 and / or two R on ring A are optionally substituted with 1 together with the atoms to which they are attached are unsubstituted or one or more R 1 In some embodiments, Ring A optionally forms a C4-C8 cycloalkyl (Ring D) substituted with one or more R 1 and / or two R on ring A are optionally substituted with 1 together with the atoms to which they are attached are unsubstituted or one or more R 1 In some embodiments, ring A optionally forms a 4-8 membered heterocycloalkyl (ring D) substituted with one or more R 1 and / or two R on ring A are optionally substituted with 1 together with the atoms to which they are attached are unsubstituted or one or more R 1 and forming a 4- to 8-membered heterocycloalkyl (ring D) substituted with
[0225] In some embodiments, ring A is a 5- to 8-membered heterocycloalkyl, wherein the 5- to 8-membered heterocycloalkyl is unsubstituted or has 1, 2, 3, 4, 5, or 6 R 1 and / or two R on ring A 1 together with the atoms to which they are attached are unsubstituted or are 1, 2, 3 R 1 In some embodiments, ring A is substituted with 1, 2, 3, 4, 5, or 6 R 1 and / or two R on ring A are 5- to 8-membered heterocycloalkyl substituted with 1 together with the atoms to which they are attached are unsubstituted or are 1, 2, 3 R 1 In some embodiments, Ring A is substituted with 1, 2, 3, 4, 5, or 6 R 1 and / or two R on ring A are 5- to 8-membered heterocycloalkyl substituted with 1 together with the atoms to which they are attached are unsubstituted or are 1, 2, 3 R 1 and forming a 4- to 8-membered heterocycloalkyl having not more than one nitrogen atom in the 4- to 8-membered heterocycloalkyl (ring C) substituted with one or more -O- and / or -S- in the 4- to 8-membered heterocycloalkyl.
[0226] In some embodiments, ring A is a 5- to 8-membered heterocycloalkyl, wherein the 5- to 7-membered heterocycloalkyl is unsubstituted or has 1, 2, 3, 4, 5, or 6 R 1 and / or two R on ring A 1 together with the atoms to which they are attached are unsubstituted or are 1, 2, 3 R 1In some embodiments, ring A is substituted with 1, 2, 3, 4, 5, or 6 R 1 and / or two R on ring A are substituted with 1 together with the atoms to which they are attached are unsubstituted or are 1, 2, 3 R 1 In some embodiments, Ring A is substituted with 1, 2, 3, 4, 5, or 6 R 1 and / or two R on ring A are substituted with 1 together with the atoms to which they are attached are unsubstituted or are 1, 2, 3 R 1 and forming a 4- to 8-membered heterocycloalkyl having not more than one nitrogen atom in the 4- to 8-membered heterocycloalkyl (ring C) substituted with one or more -O- and / or -S- in the 4- to 8-membered heterocycloalkyl.
[0227] In some embodiments, ring A is a 5- to 8-membered heterocycloalkyl group having a nitrogen atom in ring A, and R 9 is attached to a 5- to 8-membered heterocycloalkyl, wherein the 5- to 8-membered heterocycloalkyl is unsubstituted or has one or more R 1 and / or on ring A is substituted with R 9 and R 1 and together with the atoms to which they are attached are combined and unsubstituted or are substituted with one or more R 1 In some embodiments, ring A is substituted with R 9 is attached to a 5- to 8-membered heterocycloalkyl, wherein the 5- to 8-membered heterocycloalkyl is unsubstituted or has one or more R 1and / or R 9 and R 1 and together with the atom to which they are attached on ring A are either unsubstituted or are substituted with one or more R 1 In some embodiments, ring A is substituted with R to a nitrogen atom in the 5- to 8-membered heterocycloalkyl (ring A). 9 is attached to a 5- to 8-membered heterocycloalkyl, wherein the 5- to 8-membered heterocycloalkyl is unsubstituted or has one or more R 1 and / or R 9 and R 1 and together with the atom to which they are attached on ring A are either unsubstituted or are substituted with one or more R 1 and forming a 4- to 8-membered heterocycloalkyl having one or more -O- and / or -S- in the 4- to 8-membered heterocycloalkyl (ring C), wherein the 4- to 8-membered heterocycloalkyl has not more than one nitrogen atom in the 4- to 8-membered heterocycloalkyl substituted with
[0228] In some embodiments, ring A is R 9 is a 5- to 7-membered heterocycloalkyl attached to a nitrogen atom in a 5- to 7-membered heterocycloalkyl (ring A), wherein the 5- to 7-membered heterocycloalkyl is unsubstituted or is substituted with one or more R 1 and / or R 9 and R 1 and together with the atom to which they are attached on ring A are either unsubstituted in combination or are substituted by one or more R 1 In some embodiments, ring A forms a 4- to 8-membered heterocycloalkyl (ring C) substituted with R 9 is a 5- to 7-membered heterocycloalkyl attached to a nitrogen atom in a 5- to 7-membered heterocycloalkyl (ring A), wherein the 5- to 7-membered heterocycloalkyl is unsubstituted or is substituted with one or more R1 and / or R 9 and R 1 and together with the atom to which they are attached on ring A are either unsubstituted or are substituted with one or more R 1 In some embodiments, ring A is substituted with R 9 is a 5- to 7-membered heterocycloalkyl attached to a nitrogen atom in a 5- to 7-membered heterocycloalkyl (ring A), wherein the 5- to 7-membered heterocycloalkyl is unsubstituted or is substituted with one or more R 1 and / or R 9 and R 1 and together with the atom to which they are attached on ring A are either unsubstituted or are substituted with one or more R 1 and forming a 4- to 8-membered heterocycloalkyl having one or more -O- and / or -S- in the 4- to 8-membered heterocycloalkyl (ring C), wherein the 4- to 8-membered heterocycloalkyl has not more than one nitrogen atom in the 4- to 8-membered heterocycloalkyl substituted with
[0229] In some embodiments, ring A is a 5- to 8-membered heterocycloalkyl ring having a nitrogen atom in the ring A, and R 9 is attached to a 5- to 8-membered heterocycloalkyl, wherein the 5- to 8-membered heterocycloalkyl is unsubstituted or has one or more R 1 and / or R 9 and R 9 R on the carbon adjacent to 1 and together with the atom to which they are attached on ring A are either unsubstituted or are substituted with one or more R 1 In some embodiments, ring A is substituted with R 9is attached to a 5- to 8-membered heterocycloalkyl, wherein the 5- to 8-membered heterocycloalkyl is unsubstituted or has one or more R 1 and / or R 9 and R 9 R on the carbon adjacent to 1 and on ring A, together with the atoms to which they are attached, are unsubstituted or one or more R 1 In some embodiments, ring A is substituted with R 9 is attached to a 5- to 8-membered heterocycloalkyl, wherein the 5- to 8-membered heterocycloalkyl is unsubstituted or has one or more R 1 and / or R 9 and R 9 R on the carbon atom adjacent to 1 and together with the atom to which they are attached on ring A are either unsubstituted in combination or are substituted by one or more R 1 and forming a fused 4- to 8-membered heterocycloalkyl having not more than one nitrogen atom in the fused 4- to 8-membered heterocycloalkyl (ring C) substituted with one or more -O- and / or -S- in the fused 4- to 8-membered heterocycloalkyl.
[0230] In some embodiments, ring A is R 9 is attached to a nitrogen atom in a 5- to 7-membered heterocycloalkyl (ring A), wherein the 5- to 7-membered heterocycloalkyl is unsubstituted or is substituted with one or more R 1 and / or R 9 and R 9 R on the carbon atom adjacent to 1 and together with the atom to which they are attached on ring A are either unsubstituted or are substituted with one or more R1 In some embodiments, ring A forms a fused 4- to 8-membered heterocycloalkyl (ring C) substituted with R 9 is attached to a nitrogen atom in a 5- to 7-membered heterocycloalkyl (ring A), wherein the 5- to 7-membered heterocycloalkyl is unsubstituted or is substituted with one or more R 1 and / or R 9 and R 9 R on the carbon atom adjacent to 1 and together with the atom to which they are attached on ring A are either unsubstituted or are substituted with one or more R 1 In some embodiments, ring A is substituted with R to a nitrogen atom in the fused 4-8 membered heterocycloalkyl (ring C). 9 is attached to a 5- to 7-membered heterocycloalkyl, wherein the 5- to 7-membered heterocycloalkyl is unsubstituted or has one or more R 1 and / or R 9 and R 9 R on the carbon atom adjacent to 1 and together with the atom to which they are attached on ring A are either unsubstituted in combination or are substituted by one or more R 1 and forming a fused 4- to 8-membered heterocycloalkyl having not more than one nitrogen atom in the fused 4- to 8-membered heterocycloalkyl (ring C) substituted with one or more -O- and / or -S- in the fused 4- to 8-membered heterocycloalkyl.
[0231] In some embodiments, ring A is a 5- to 8-membered heterocycloalkyl group having a nitrogen atom in ring A, and R 9 is attached to a 5- to 8-membered heterocycloalkyl, wherein the 5- to 8-membered heterocycloalkyl is unsubstituted or has one or more R 1 and / or R9 and R 9 R on a carbon atom not adjacent to 1 and together with the atom to which they are attached on ring A are either unsubstituted or are substituted with one or more R 1 In some embodiments, ring A is substituted with R 9 is attached to a 5- to 8-membered heterocycloalkyl, wherein the 5- to 8-membered heterocycloalkyl is unsubstituted or has one or more R 1 and / or R 9 and R 9 R on a carbon atom not adjacent to 1 and together with the atom to which they are attached on ring A are either unsubstituted in combination or are substituted by one or more R 1 In some embodiments, Ring A forms a bridged 5-8 membered heterocycloalkyl having no more than one nitrogen atom in the 5-8 membered heterocycloalkyl (Ring C) substituted with R 9 is attached to a 5- to 8-membered heterocycloalkyl, wherein the 5- to 8-membered heterocycloalkyl is unsubstituted or has one or more R 1 and / or R 9 and R 9 R on a carbon atom not adjacent to 1 and together with the atom to which they are attached on ring A are either unsubstituted in combination or are substituted by one or more R 1 and forming a bridged 5- to 8-membered heterocycloalkyl having one or more -O- and / or -S- in the 5- to 8-membered heterocycloalkyl.
[0232] In some embodiments, ring A is a 5- to 7-membered heterocycloalkyl ring having a nitrogen atom in the ring A, and R 9is attached to a 5- to 7-membered heterocycloalkyl, wherein the 5- to 7-membered heterocycloalkyl is unsubstituted; R 9 is 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, where 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 may be independently selected from 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)NR 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 eR f , -NR e S(O)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.
[0233] In some embodiments, ring A is R 9 is attached to a nitrogen atom in a 5- to 7-membered heterocycloalkyl (ring A), wherein the 5- to 7-membered heterocycloalkyl is selected from the group consisting of C-C alkyl, C-C alkenyl, C-C alkynyl, C-C cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and C-C 10 one or more R selected from the group consisting of aryl 1 (For example, one R 1 or two R 1 ), wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, and C6-C 10 Each hydrogen atom in an aryl may be independently selected from deuterium, halogen, -R e , -R f , -OR e or -CN, or -NO2, optionally substituted by R 9 is H, deuterium, -C(O)R g , -C(O)NR g Rh , 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 said 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 may be independently selected from 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)NR 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)NR 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.
[0234] In some embodiments, ring A is R 9 is a 5- to 8-membered heterocycloalkyl or a 5- to 7-membered heterocycloalkyl attached to a nitrogen atom in a 5- to 8-membered heterocycloalkyl or a 5- to 7-membered heterocycloalkyl (ring A), wherein R 9 is H, deuterium, unsubstituted C1-C6 alkyl, or C1-C6 haloalkyl.
[0235] In some embodiments, Ring A is a fused 5-8 membered heterocycloalkyl that may optionally be taken together with Ring C or Ring D to form the core of a compound of Formula I, the core having the formula: [ka] [In formula: [ka] are ring B or -(X) p -R 3 and Ring C and Ring D are as defined herein. It is shown as follows.
[0236] In some embodiments, ring A, optionally together with ring C or ring D, has the formula: [ka] [In formula: [ka] are the covalent bonding points] wherein each hydrogen atom in the piperidinyl group is 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 R f , -S(O)NR 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)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.
[0237] In some embodiments, ring A, optionally together with ring C or ring D, has the formula: [ka] [In formula: [ka] are the covalent bonding points] wherein each hydrogen atom in the piperidinyl group is 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 R f , -S(O)NR 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)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.
[0238] In some embodiments, ring A, optionally together with ring C or ring D, may form a core of a compound of formula I, wherein the core has the formula: [ka] [ka] [In formula: [ka] are ring B or -(X) p -R 3 ] and each hydrogen atom in ring A, ring C, and ring D, if present, is independently selected from deuterium, halogen, C-C alkyl, C-C 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)NR 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)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)ORe , -P(O)2OR e , -CN, or NO2; 1 may be optionally substituted with
[0239] In some embodiments, ring A, optionally together with ring C or ring D, may form a core of a compound of formula I, wherein the core has the formula: [ka] [ka] [In formula: [ka] are ring B or -(X) p -R 3 ] and each hydrogen atom in the piperidinyl group is 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 R f , -S(O)NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)OR f , -NR e C(O)NR eR 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)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.
[0240] In some embodiments, each R in ring C 1 are independently 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)NR 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)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.
[0241] In some embodiments, each R in ring D 1 are independently 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)NR 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)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.
[0242] In some embodiments, ring A, optionally together with ring C or ring D, has the formula: [ka] [ka] [ka] [In formula: [ka] are the covalent bonding points] and a fused 5- to 8-membered heterocycloalkyl which may form the core of compounds of formula I,
[0243] In some embodiments, ring A, optionally together with ring C or ring D, may form the core of a compound of formula I, wherein the core is: [ka] [ka] [ka] [In formula: [ka] are ring B or -(X) p -R 3 ] It is shown as follows.
[0244] In some embodiments, Ring A is a fused 5- to 8-membered heterocycloalkyl that forms the core of the compound of Formula I, wherein the core is: [ka] [ka] [In formula: [ka] Each of the rings B or -(X) p -R 3 ] It is shown as follows.
[0245] In some embodiments, ring A, optionally together with ring C or ring D, may form the core of a compound of formula I, wherein the core is: [ka] [ka] [ka] [In formula: [ka] is ring B or -(X) p -R 3 ] It is shown as follows.
[0246] In some embodiments, ring A, optionally together with ring C or ring D, may form the core of a compound of formula I, wherein the core is: [ka] [ka] [ka] [In formula: [ka] is ring B or -(X) p -R 3 ] It is shown as follows.
[0247] In some embodiments, m is 0. In some embodiments, m is a number of 1 or more. 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.
[0248] In some embodiments, ring B is selected from the group consisting of one or more R 2 C-C optionally substituted 10 In some embodiments, ring B is selected from the group consisting of one or more R 2 C-C cycloalkyl, 4- to 10-membered heterocycloalkyl, C-C 10 In some embodiments, ring B is selected from the group consisting of one or more R 2 C-C optionally substituted 10 In some embodiments, ring B is one or more R 2 is a 5- to 10-membered heteroaryl optionally substituted with
[0249] In some embodiments, ring B is [ka] where * is [ka] and n is a number equal to or greater than 0. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7.
[0250] In some embodiments, ring B is [ka] where * is [ka] and n is a number 0 or greater. In some embodiments, n is 0, 1, 2, 3, or 4.
[0251] In some embodiments, ring B is [ka] where * is [ka] and n is a number 0 or greater. In some embodiments, n is 0, 1, 2, 3, or 4.
[0252] In some embodiments, ring B is [ka] where * is [ka] and n is a number 0 or greater. In some embodiments, n is 0, 1, 2, 3, or 4.
[0253] In some embodiments, ring B is [ka] where * is [ka] and n is a number 0 or greater. In some embodiments, n is 0, 1, 2, 3, or 4.
[0254] In some embodiments, ring B is [ka] where * is [ka] and n is a number 0 or greater. In some embodiments, n is 0, 1, 2, 3, or 4.
[0255] In some embodiments, Ring B is naphthyl, wherein each hydrogen atom in the naphthyl is independently selected from R 2 In some embodiments, Ring B is phenyl, wherein each hydrogen atom in the phenyl is independently substituted with R 2 In some embodiments, Ring B is pyridyl, wherein each hydrogen atom in the pyridyl is independently substituted with R 2 In some embodiments, Ring B is indolyl, wherein each hydrogen atom in the indolyl is independently substituted with R 2 In some embodiments, Ring B is indazolyl, wherein each hydrogen atom in the indazolyl is independently substituted with R 2 In some embodiments, Ring B is benzothiazolyl, wherein each hydrogen atom in the benzothiazolyl is independently substituted with R 2 may be optionally substituted by:
[0256] In some embodiments, ring B is [ka] where * is [ka] and n is a number 0 or greater. In some embodiments, n is 0, 1, 2, 3, 4, 5, 6, or 7.
[0257] In some embodiments, R 1 are each independently 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)NR 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)NR 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 atom to which they are attached form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, 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 is independently selected from deuterium, halogen, C1C6 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)NR 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)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 —NO. 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 selected from deuterium, halogen, -R e , -R f , C1-C6 alkyl, C1-C6 haloalkyl, -OR e , -OC(O)R e , -OC(O)NR eR 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)NR 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)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 —NO. In some embodiments, R 9 and R 1 or R 10 and R 1together with the atom to which they are attached, combine to form a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in the 4- to 10-membered heterocycloalkyl is independently selected from deuterium, halogen, C-C alkyl, C-C haloalkyl, —OH, —OC-C alkyl, —OC(O)C-C alkyl, —OC(O)N(H or C-C alkyl), —OS(O)C-C alkyl, —OS(O)C-C 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-C In some embodiments, two hydrogen atoms on a single carbon atom of a 4- to 10-membered heterocycloalkyl combine to form an oxo group or a C-C alkenyl group; or two R 1together with the atom to which they are attached form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, 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 is independently selected from deuterium, halogen, C1C6 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)NR 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)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 —NO. In some embodiments, each R 1 represents 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)NR 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)NR 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 —NO. In some embodiments, R 1 and R 10and together with the atoms to which they are attached, combine 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 selected from deuterium, halogen, C-C alkyl, C-C haloalkyl, —OH, —OC -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-C 6 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 )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)O-C1-C6 alkyl, -P(O)2O-C1-C6 alkyl, -CN, or -NO2, or a monocyclic 4 to 10 membered heterocycloalkyl, a fused bicyclic 5 to 10 membered heterocycloalkyl,or two hydrogen atoms on a single carbon atom of a bridged bicyclic 6- to 10-membered heterocycloalkyl combine to form an oxo group or an alkenyl group.
[0258] In some embodiments, R 2 are each independently 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 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)NR 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 Rd , -NR c S(O)NR 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 atom to which they are attached form a C3-C6 cycloalkyl or a 4- to 10-membered heterocycloalkyl, 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 is independently selected from deuterium, halogen, C1C6 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)NR 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)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 —NO. In some embodiments, R 2 are each independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OR c , -C(O)RC, or -NR c R d In some embodiments, R 2 are each independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OR c or -CN. In some embodiments, R 2 are each independently deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -OR c , -C(O)Rc , -NR c R d or —CN, wherein each hydrogen atom in the C-C alkyl, C-C alkenyl, and C-C alkynyl is independently optionally substituted with deuterium or halogen. 2 When present, R is independently selected from the group consisting of fluoro, chloro, C-C alkyl, —OH, and —CN. 2 are each independently selected from the group consisting of fluoro, chloro, methyl, ethyl, isopropyl, —NH, —C≡CH, —CN, —CF, and —OH. 2 When present, is independently selected from the group consisting of fluoro, chloro, methyl, ethyl, isopropyl, —C≡CH, —CN, and —OH.
[0259] In some embodiments, n is 0. In some embodiments, n is a number of 1 or more. 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.
[0260] In some embodiments, ring B is [ka] where [ka] is the point of covalent bonding.
[0261] In some embodiments, ring B has the formula: [ka] [In formula: [ka] is the point of covalent bonding] It is a group represented by the following formula:
[0262] In some embodiments, ring B is [ka] [ka] [In formula: [ka] is the point of covalent bonding] It is shown as follows.
[0263] In some embodiments, p is 0. In some embodiments, p is 1. 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 -It is.
[0264] In some embodiments, R4 is H, deuterium, 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, where 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 may be independently selected from 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)NR 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 , N.R. e S(O)NR 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 —NO. In some embodiments, R 4 is H, deuterium, or C1-C6 alkyl. In some embodiments, R 4 is H, deuterium, or methyl.
[0265] In some embodiments, 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), where 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 -C-C alkylene-(5- to 10-membered heteroaryl), -C-C alkylene-(5- to 10-membered heteroaryl), and -C-C alkylene-(5- to 10-membered heteroaryl) is independently selected from 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)NR 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)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 Rf , -P(O)NR e R f , -P(O)2NR e R f , -P(O)OR e , -P(O)2OR e , -CN, or -NO2.
[0266] In some embodiments, 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 selected from deuterium, halogen, C1-C6 alkyl, -C1-C6 alkylene-O-C1-C6 alkyl, -O-C1-C6 alkylene-O-C1-C6 alkyl, -C1-C6 alkylene-OR a , C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkylene-(5- to 10-membered heterocycloalkyl), -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O)2R e , -OS(O)NR e R f , -OS(O)2NR e R f , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR e R f , -S(O)NR 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 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)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.
[0267] In some embodiments, R 3 is a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in the 4- to 10-membered heterocycloalkyl is independently selected from deuterium, halogen, C-C alkyl, —C-C alkylene-O—C-C alkyl, —O—C alkylene-O—C-C alkyl, —C-C 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)Re , -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)NR 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)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.
[0268] In some embodiments, R 3 teeth [ka] [In formula: [ka] is the point of covalent bonding] It is shown as follows.
[0269] In some embodiments, R 3 teeth [ka] [In formula: [ka] is the point of covalent bonding] is.
[0270] In some embodiments, R 3 teeth [ka] [In formula: [ka] is the point of covalent bonding] It is shown as follows.
[0271] 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 selected from deuterium, halogen, C1-C6 alkyl, —C1-C6 alkylene-O—C1-C6 alkyl, —O—C1-C6 alkylene-O—C1-C6 alkyl, —C1-C6 alkylene-OR a , C6-C 10Aryl, -C1-C6 alkylene-(C6-C 10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkylene-(5- to 10-membered heterocycloalkyl), -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O)2R e , -OS(O)NR e R f , -OS(O)2NR e R f , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR e R f , -S(O)NR 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)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)NRe R f , -P(O)2NR e R f , -P(O)OR e , -P(O)2OR e , -CN, or -NO2.
[0272] In some embodiments, R 3 is —C1-C6 alkylene-(4- to 10-membered heterocycloalkyl), wherein each hydrogen atom in —C1-C6 alkylene-(4- to 10-membered heterocycloalkyl) is independently selected from deuterium, halogen, C1-C6 alkyl, —C1-C6 alkylene-O—C1-C6 alkyl, —O—C1-C6 alkylene-O—C1-C6 alkyl, —C1-C6 alkylene-OR a , C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkylene-(5- to 10-membered heterocycloalkyl), -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O)2R e , -OS(O)NR e R f , -OS(O)2NR e R f , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR e R f , -S(O)NR 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 eC(=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)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.
[0273] In some embodiments, R 3 is the expression: [ka] [In formula: [ka] is the point of covalent bonding] and each hydrogen atom is independently selected from deuterium, halogen, C1-C6 alkyl, -C1-C6 alkylene-O-C1-C6 alkyl, -O-C1-C6 alkylene-O-C1-C6 alkyl, -C1-C6 alkylene-OR a , C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10aryl), 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)NR 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)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.
[0274] In some embodiments, R 3 is the expression: [ka] [In formula: [ka] is the point of covalent bonding] and each hydrogen atom is independently selected from deuterium, halogen, C1-C6 alkyl, -C1-C6 alkylene-O-C1-C6 alkyl, -O-C1-C6 alkylene-O-C1-C6 alkyl, -C1-C6 alkylene-OR a , C6-C 10 Aryl, -C1-C6 alkylene-(C6-C 10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkylene-(5- to 10-membered heterocycloalkyl), -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O)2R e , -OS(O)NR e R f , -OS(O)2NR e R f , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR e R f , -S(O)NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)ORf , -NR e C(O)NR e R f , -NR e 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)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.
[0275] In some embodiments, R 3 is the expression: [ka] [In formula: [ka] is the point of covalent bonding] and each hydrogen atom is independently selected from deuterium, halogen, C1-C6 alkyl, -C1-C6 alkylene-O-C1-C6 alkyl, -O-C1-C6 alkylene-O-C1-C6 alkyl, -C1-C6 alkylene-OR a , C6-C 10Aryl, -C1-C6 alkylene-(C6-C 10 aryl), haloalkyl, C3-C6 cycloalkyl, 5- to 10-membered heteroaryl, -C1-C6 alkylene-(5- to 10-membered heterocycloalkyl), -OR e , -OC(O)R e , -OC(O)NR e R f , -OS(O)R e , -OS(O)2R e , -OS(O)NR e R f , -OS(O)2NR e R f , -SR e , -S(O)R e , -S(O)2R e , -S(O)NR e R f , -S(O)NR 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)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)NRe R f , -P(O)2NR e R f , -P(O)OR e , -P(O)2OR e , -CN, or -NO2.
[0276] In some embodiments, R 3 is the expression: [ka] [In formula: [ka] is the point of covalent bonding] and each hydrogen atom is independently selected from deuterium, halogen, C1-C6 alkyl, haloalkyl, -OR e , -CN, or -NO2.
[0277] In some embodiments, R 3 is the expression: [ka] [In formula: [ka] is the point of covalent bonding] and each hydrogen atom is independently selected from deuterium, halogen, C1-C6 alkyl, -OR e , -CN, or -NO2.
[0278] In some embodiments, R 3 is the expression: [ka] [In formula: [ka] is the point of covalent bonding] It is shown as follows.
[0279] In some embodiments, R 3 is the expression: [ka] [In formula: [ka] is an inorganic or organic counterion] It is shown as follows.
[0280] In some embodiments, R 3 is the expression: [ka] [In formula: [ka] is an inorganic or organic counterion] It is shown as follows.
[0281] In some embodiments, R a , R b , R c , R d , R e , R f , R g , and R h are each independently H, deuterium, 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 aryl, and 5- to 10-membered heteroaryl; or R a and R b , or R c and R d , or R e and R f , or R g and Rh two of these, together with the atom to which they are attached, combine to form a C3-C6 cycloalkyl, a 4- to 10-membered heterocycloalkyl, 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 is independently selected from deuterium, halogen, C-C alkyl, C-C haloalkyl, —OH, —OC-C alkyl, —OC(O)C-C alkyl, —OC(O)N(H or C-C alkyl), —OS(O)C-C alkyl, —OS(O)C-C alkyl, —OS(O)N(H or C-C alkyl), —OS(O)N(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 is optionally substituted by -C1-C6 alkyl), -P(H or C1-C6 alkyl), -P(O)(H or C1-C6 alkyl), -P(O)(H or C1-C6 alkyl), -P(O)N(H or C1-C6 alkyl), -P(O)N(H or C1-C6 alkyl), -P(O)OC1-C6 alkyl, -P(O)OC1-C6 alkyl, -CN, or -NO, or Re and R f together with the carbon atom to which they are attached form an oxo group or an alkenyl.
[0282] In some embodiments, R a , R b , R c , R d , R e , R f , R g , and R h are each independently H, deuterium, 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 aryl, and 5- to 10-membered heteroaryl.
[0283] In some embodiments, Z 1 is 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 is C(R 5 In some embodiments, Z 2 is C(R 6 In some embodiments, Z 3 is C(R 7 In some embodiments, Z 3 is CH. In some embodiments, Z 3 is CF. In some embodiments, Z 4 is C(R 8 In some embodiments, Z 5 is C(R 15 In some embodiments, Z 6is C(R 16 In some embodiments, Z 5 is CH. In some embodiments, Z 6 is CH. In some embodiments, Z 1 -Z 7 Any possible combination of Z may be combined in an embodiment. 5 is N or C(R 15 In some embodiments, Z 6 is N or C(R 16 In some embodiments, Z 1 is N and Z 2 is N. In some embodiments, Z 1 is N and Z 2 is N and Z 3 is C(R 7 ) and Z 4 is N. In some embodiments, Z 1 is N and Z 2 is N and Z 3 is C(R 7 ) and Z 4 is C(R 8 In some embodiments, Z 1 is N and Z 2 is N and Z 3 is N and Z 4 is N. In some embodiments, Z 1 is N and Z 2 is N and Z 3 is N and Z 4 is C(R 8 In some embodiments, Z 1 is N and Z 2 is N and Z 3 is C(R 7 ) and Z 4 is C(R 8 In some embodiments, Z 1 is N and Z 2 is N and Z 3 is CH and Z 4is N. In some embodiments, Z 1 is N and Z 2 is N and Z 3 is CF and Z 4 is N.
[0284] In some embodiments, R 5 , R 6 , R 7 , R 8 , R 15 , and R 16 are each 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)NR 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)NR g Rh , -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 —NO. In some embodiments, R 5 , R 6 , R 7 , R 8 , R 15 , and R 16 are each independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR g , —CN, or —NO. In some embodiments, R 5 , R 6 , R 7 , R 8 , R 15 and R 16 are each independently H, deuterium, halogen, C1-C6 alkyl, -OR g , -CN or -NO2.
[0285] In some embodiments, R 5 , R 6 , R 7 , and R 8 are each independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR g , -CN, or -NO2.
[0286] In some embodiments, R 15 and R 16are each 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)NR 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)NR 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 Rh , -P(O)OR g , -P(O)2OR g , —CN, or —NO. In some embodiments, R 15 and R 16 are each independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -OR g , -CN, or -NO2.
[0287] In some embodiments, R 5 When present, R is H. In some embodiments, R 6 When present, R is H. In some embodiments, R 7 When present, R is H or F. In some embodiments, R 8 When present, R is H. In some embodiments, R 15 When present, R is H. In some embodiments, R 16 is H, if present.
[0288] In some embodiments, the present disclosure provides a compound of the formula: [ka] [In formula: * represents the point of covalent attachment to Ring B, as described herein; ** denotes -(X) as described herein. p -R 3 represents the point of covalent bonding with; R 1 , R 7 , R 9 and m is as described herein. The present invention provides a compound represented by the formula:
[0289] In some embodiments, the present disclosure provides a compound of the formula: [ka] [In formula: * represents the point of covalent attachment to Ring B, as described herein; ** denotes -(X) as described herein. p -R 3 represents the point of covalent bonding with; R 1 are each independently 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)NR 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 aS(O)NR a R b , -NR a S(O)NR 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, where 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 is 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 R f , -S(O)NR 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)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 7 is 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)NR g R h , -OS(O)NR g Rh , -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)NR g R h , -C(O)R g , -C(O)OR g , -C(O)NR g R h , -PR g R h , -P(O)R g R h , -P(O)2R g R h , -P(O)NR g R h , -P(O)2NR g R h , -P(O)OR g , -P(O)2OR g , -CN, or -NO2; R 9 is 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, where 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 may be independently selected from 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)NR 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)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)ORe , -P(O)2OR e , -CN, or -NO2; and m is 0, 1, or 2] The present invention provides a compound represented by the formula:
[0290] In some embodiments, the present disclosure provides a compound of the formula: [ka] [In formula: * represents the point of covalent attachment to Ring B, as described herein; ** denotes -(X) as described herein. p -R 3 represents the point of covalent bonding with; Each R 1 is independently deuterium, halogen, C1-C6 alkyl, C3-C6 cycloalkyl, or 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in the C1-C6 alkyl, C3-C6 cycloalkyl, and 4- to 10-membered heterocycloalkyl is independently 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)NR e R f , -NR e R f , -NR e C(O)R f , -NR e C(O)ORf , -NR e C(O)NR e R f , -NR e S(O)R f , -NR e S(O)2R f , -NR e S(O)NR e R f , -NR e S(O)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 7 is H, deuterium, or a halogen; R 9 is H, -C(O)R g , -C(O)NR g R h , C1-C6 alkyl, or C3-C6 cycloalkyl, wherein each hydrogen atom in the C1-C6 alkyl and C3-C6 cycloalkyl is independently selected from deuterium, halogen, -R e , or -OR e may be optionally substituted by; and m is 0, 1, or 2] The present invention provides a compound represented by the formula:
[0291] In some embodiments, the present disclosure provides: 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-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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; 5-ethynyl-6-fluoro-4-[(9S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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;
[0292] 5-ethyl-6-fluoro-4-[(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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;
[0293] 5-ethyl-6-fluoro-4-{(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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; (8aR,9R)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-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-[(9S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-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; (8aS,11R)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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;
[0294] (8aS,11R)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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; 4-[(9S)-9-cyclopropyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-{(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-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-ethyl-6-fluoro-4-[(8S,8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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;
[0295] 7-fluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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]-1,3-benzothiazol-2-amine; 5-ethyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2Z,7aS)-2-(fluoromethylidene)tetrahydro-1H-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-methyl-5-(trifluoromethyl)pyridin-2-amine; 3-chloro-5-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydropyrido[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-5-yl]naphthalen-2-ol; 5-ethynyl-6-fluoro-4-[(9S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-[(9S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-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; 4-(9-cyclopropyl-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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;
[0296] 5-ethynyl-6-fluoro-4-[(9S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-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; 5-ethynyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2Z,7aS)-2-(fluoromethylidene)tetrahydro-1H-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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; 5-ethynyl-6-fluoro-4-[(7aS,9aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl]methoxy}-10-methyl-8,9,9a,10-tetrahydro-7aH-7-oxa-1,3,6,10-tetraazacyclobuta[5,6]cyclohepta[1,2,3-de]naphthalen-5-yl]naphthalen-2-ol; 5-ethynyl-6-fluoro-4-[(9S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-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-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-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;
[0297] (8aS,12S)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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;
[0298] (8aS,12R)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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 5-ethynyl-6-fluoro-4-[(8aS,13S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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; The present invention provides a compound selected from the group consisting of:
[0299] In some embodiments, the present disclosure provides: 4-[(9S)-10-benzyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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; 5-ethynyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2Z,7aS)-2-(fluoromethylidene)tetrahydro-1H-pyrrolidin-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; (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-pyrrolidin-4-ium; (8aS)-5-(5-chloro-1H-indazol-4-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-(fluoromethylidene)tetrahydro-1H-pyrrolidin-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; 4-[(9S)-10-benzyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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; (5P,8aS)-5-(3,5-dichloro-1H-indazol-4-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-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;
[0300] 2-amino-7-fluoro-4-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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; (8aS)-5-(8-ethynyl-3,7-difluoronaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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; 4-[(9S)-9-ethyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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; (8aR,11S)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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;
[0301] 5-ethynyl-6-fluoro-4-(4'-fluoro-2'-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-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; (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-pyrrolidin-2-ol; 5-ethynyl-6-fluoro-4-[(8aS)-4,11,11-trifluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-4-[(9S)-9-ethyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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; 5-ethyl-6-fluoro-4-[(9R)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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; (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-pyrrolidin-2-ol; 5-ethynyl-6-fluoro-4-[(7aR,10aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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;
[0302] 4-[(8aS)-4,11-difluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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; 4-(10-ethyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-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; 5-chloro-4-[(9S)-9-ethyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-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; (8aS,9S)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-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;
[0303] 4-[(9S)-9-ethyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-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-pyrrolidin-7a(5H)-yl]methoxy}-7,8,9,10-tetrahydro-1,3,6,10-tetraazacyclohepta[1,2,3-de]naphthalen-5-yl)naphthalen-2-ol; (8aS)-5-(8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-ethynyl-6-fluoro-4-(4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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; 5-ethynyl-6-fluoro-4-(4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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;
[0304] 1-[8-(10-cyclopropyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-7a(5H)-yl)methoxy)-10-((R)-2-hydroxypropyl)-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)naphthalen-2-ol; 4-((S)-10-(2,2-difluoroethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 5-ethyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-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; The present invention provides a compound selected from the group consisting of:
[0305] In some embodiments, the compound has the formula: [ka] [ka] [ka] [ka]
[0306] [ka] [ka] [ka]
[0307] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.
[0308] Next, exemplary embodiments of compounds of formula (I): [Table 1] [Table 2] [Table 3] [Table 4] [Table 5]
[0309]
Table 6
Table 7
Table 8
Table 9
[0310]
Table 10
Table 11
Table 12
Table 13
Table 14
Table 15
[0311] Table 16 Table 17 Table 18
Table 19
[0312] Table 21 [Table 22] [Table 23] [Table 24] [Table 25]
[0313] [Table 26] [Table 27] [Table 28] [Table 29] and pharmaceutically acceptable salts thereof.
[0314] Those skilled in the art will recognize that the species listed or exemplified herein are not exhaustive and that additional species may also be selected that fall within the scope of these defined terms.
[0315] Pharmaceutical Composition For therapeutic purposes, pharmaceutical compositions containing the compounds described herein may further contain one or more pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients are non-toxic and otherwise biologically suitable substances for administration to a subject. Such excipients facilitate administration of the compounds described herein and are compatible with the active ingredients. Examples of pharmaceutically acceptable excipients include stabilizers, lubricants, surfactants, diluents, antioxidants, binders, colorants, bulking agents, emulsifiers, or flavoring agents. In a preferred embodiment, the pharmaceutical compositions disclosed herein are sterile compositions. Pharmaceutical compositions can be prepared using known or available formulation techniques to those skilled in the art.
[0316] Sterile compositions are also contemplated by this disclosure and include compositions that comply with national and local regulations governing such compositions. The pharmaceutical compositions and compounds described herein can be formulated as solutions, emulsions, suspensions, or dispersions in suitable pharmaceutical solvents or carriers, or as pills, tablets, lozenges, suppositories, sachets, dragees, granules, powders, powders for reconstitution, or capsules with solid carriers according to conventional methods known in the art for preparing various dosage forms. The pharmaceutical compositions of the present disclosure can be administered by a suitable route of delivery, such as oral, parenteral, rectal, nasal, topical, or ocular routes, or by inhalation. Preferably, the compositions are formulated for intravenous or oral administration.
[0317] For oral administration, the compounds of the present disclosure may be provided in solid form, such as tablets or capsules, or as solutions, emulsions, or suspensions. To prepare oral compositions, the compounds of the present disclosure may be formulated to provide a dosage of, for example, about 0.1 mg to 1 g per day, or about 1 mg to 50 mg per day, or about 50 mg to 250 mg per day, or about 250 mg to 1 g per day. Oral tablets may contain the active ingredient mixed with compatible pharmaceutically acceptable excipients, such as diluents, disintegrants, binders, lubricants, sweeteners, flavoring agents, coloring agents, and preservatives. Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol, and the like. Exemplary liquid oral excipients include ethanol, glycerol, water, and the like. Starch, polyvinylpyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are exemplary disintegrants. Binders include starch and gelatin. Lubricants, if present, may be magnesium stearate, stearic acid, or talc. If necessary, tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.
[0318] Oral capsules include hard and soft gelatin capsules. To produce hard gelatin capsules, the active ingredient may be mixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsules can be produced by mixing the active ingredient with water, oil such as peanut oil or olive oil, liquid paraffin, a mixture of monoglycerides and diglycerides of short-chain fatty acids, polyethylene glycol 400, or propylene glycol.
[0319] Oral liquids may be in the form of suspensions, solutions, emulsions, or syrups, or may be freeze-dried or provided as a dry product for reconstitution with water or other suitable vehicles before use. Such liquid compositions may optionally contain 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, ethyl alcohol, or water; preservatives (e.g., methyl or propyl p-hydroxybenzoate, or sorbic acid); wetting agents such as lecithin; and, if desired, pharmaceutically acceptable excipients such as flavorings or coloring agents.
[0320] For parenteral use, including intravenous, intramuscular, intraperitoneal, intranasal, or subcutaneous routes, the agents of the present disclosure may be provided in a sterile aqueous solution or suspension buffered to an appropriate pH and isotonicity, or in a parenterally acceptable oil. Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride. Such forms may be provided in unit-dose form, such as an ampule or disposable syringe, in multi-dose form, such as a vial from which an appropriate amount can be withdrawn, or in solid form or pre-concentrate that can be used to prepare injectable formulations. Exemplary infusion doses range from about 1 to 1,000 μg / kg / min of the agent, admixed with a pharmaceutical carrier, over a period ranging from several minutes to several days.
[0321] For nasal, inhaled, or oral administration, the pharmaceutical compositions of the present invention may be administered, for example, using a spray formulation also containing a suitable carrier. The compositions of the present invention may be formulated for rectal administration as suppositories. For topical application, the compounds of the present disclosure are preferably formulated into creams or ointments, or similar vehicles 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 to the vehicle. Another mode of administering the drugs of the present disclosure may be transdermal delivery using a patch formulation.
[0322] As used herein, the term "treating" or "treatment" encompasses both "prophylactic" and "curative" treatment. "Prophylactic" treatment means delaying the onset of a disease, symptom of a disease, or medical condition, suppressing symptoms that may develop, or reducing the risk of the onset or recurrence of a disease or symptom. "Curative" treatment includes reducing the severity of, or inhibiting the worsening of, an existing disease, sign, or symptom. Thus, treatment includes ameliorating or preventing the worsening of an existing symptom of a disease, preventing further symptoms from occurring, ameliorating or preventing the underlying systemic cause of a symptom, inhibiting a disorder or disease, for example, arresting the onset of a disorder or disease, relieving a disorder or disease, causing regression of a disorder or disease, alleviating symptoms caused by a disease or disorder, or arresting the symptoms of a disease or disorder. The term "subject" refers to a mammalian patient, such as a human, in need of such treatment.
[0323] Exemplary diseases include cancer, pain, neurological disorders, autoimmune disorders, and inflammation. As used herein, the term "cancer" refers to, 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, cholangiocarcinoma, ovarian cancer, gastric adenocarcinoma, colorectal cancer, inflammatory myofibroblastoma, angiosarcoma, hemangioendothelioma in epithelioid form, intrahepatic cholangiocarcinoma, papillary thyroid carcinoma, spitzoid tumor, sarcoma ... Cancers include tumors, astrocytoma, brain low-grade glioma, secretory breast cancer, breast analog carcinoma, acute myeloid leukemia, congenital methemoblastic nephroma, congenital fibrosarcoma, Ph-like acute lymphoblastic leukemia, thyroid cancer, cutaneous melanoma, head and neck squamous cell carcinoma, childhood glioma CML, prostate cancer, lung squamous cell carcinoma, ovarian serous cystadenocarcinoma, cutaneous melanoma, castration-resistant prostate cancer, Hodgkin's lymphoma, and serous and clear cell endometrial cancer. In some embodiments, cancers include lung cancer, colon cancer, breast cancer, prostate cancer, hepatocellular carcinoma, renal cell carcinoma, gastric cancer and esophagogastric cancer, glioblastoma, head and neck cancer, inflammatory myofibroblastic tumor, and anaplastic large cell lymphoma. Pain includes pain from any cause or etiology, including, for example, cancer pain, pain from chemotherapy, neuralgia, pain from trauma, or pain from other sources. Autoimmune diseases include, for example, rheumatoid arthritis, Sjogren's syndrome, type I 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 from infection or injury.
[0324] In one aspect, the compounds and pharmaceutical compositions of the present disclosure specifically target Ras, particularly K-Ras. Thus, these compounds and pharmaceutical compositions can be used to prevent, reverse, slow down, or inhibit the activity of one or more KRAS mutations, such as KRAS G12C, KRAS G12D, KRAS G12V, KRAS G12R, KRAS G12S, KRAS G13C, KRAS G13D, KRAS A18D, KRAS Q61H, KRAS K117N, etc. In a preferred embodiment, a method for treating targeted cancer is described.
[0325] In the inhibitory methods of the present disclosure, an "effective amount" refers to an amount sufficient to inhibit a target protein. Such target modulation can be measured by conventional analytical methods, such as those described below. Such modulation is useful in a variety of settings, including in vitro assays. In such methods, the cells are preferably cancer cells with aberrant 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, KRAS K117N, etc.
[0326] In the therapeutic methods of the present disclosure, an "effective amount" generally refers to an amount or dosage sufficient to provide the desired therapeutic benefit in a subject in need of such treatment. Effective amounts or dosages of compounds of the present disclosure can be ascertained by conventional methods, such as dose escalation or modeling clinical trials, taking into account conventional factors, such as the mode or route of administration or drug delivery, the pharmacokinetics of the drug, the severity and course of the infection, the subject's health, condition, and weight, and the judgment of the attending physician. Exemplary dosages are 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 mg to 250 mg per day, or about 250 mg to 1 g per day. The total dosage may be administered in single or divided dose units (e.g., BID, TID, QID).
[0327] Once the improvement of the target disease is observed, the dosage can be adjusted for prevention or maintenance treatment.For example, the dosage or administration frequency, or both, can be reduced according to the symptom function to the level that maintains the desired treatment or prevention effect.Of course, once the symptom is alleviated to an appropriate level, treatment can be stopped.However, if the symptom recurs, the patient may need to continue treatment on a long-term basis.The patient may also need chronic treatment on a long-term basis.
[0328] Drug combinations The compounds of the present invention described herein can be used in pharmaceutical compositions or methods in combination with one or more additional active ingredients in the treatment of the diseases and disorders described herein. Further additional active ingredients include other therapeutic agents or agents that alleviate the side effects of the intended targeted disease therapy. Such combinations can serve to increase the efficacy, ameliorate other disease symptoms, reduce one or more side effects, or reduce the required dosage of the compounds of the present invention. The additional active ingredients can be administered in a pharmaceutical composition separate from the compounds of the present disclosure, or can be formulated together with the compounds of the present disclosure in a single pharmaceutical composition. The additional active ingredients can be administered simultaneously with, before, or after the administration of the compounds of the present disclosure.
[0329] Combination drugs containing additional active ingredients are drugs known or found to be effective in treating the diseases and disorders described herein, including drugs active against another target associated with the disease. For example, the compositions and formulations and treatment methods of the present disclosure may further include other drugs or pharmaceuticals, such as other active agents useful in treating or alleviating the targeted disease or associated signs or symptoms. For cancer indications, such additional drugs include, but are not limited to, ALK inhibitors (e.g., crizotinib), R aExamples of suitable anti-inflammatory drugs include standard chemotherapeutic agents such as kinase inhibitors, such as NF-κB inhibitors (e.g., vemurafenib), VEGFR inhibitors (e.g., sunitinib), alkylating agents, antimetabolites, antitumor antibiotics, topoisomerase inhibitors, platinum drugs, cytostatics, antibodies, hormonal therapy agents, or corticosteroids. For pain indications, suitable concomitant medications include anti-inflammatory agents, such as NSAIDs. The pharmaceutical compositions of the present disclosure may additionally contain one or more such active agents, and the treatment methods may additionally include administering an effective amount of one or more such active agents.
[0330] Chemical synthesis method The following examples are offered to illustrate, but not limit, the present disclosure. Those s...
Claims
1. Formula I: 【Chemical 1】 [In the formula: X is —O—, —S—, or —NR ４ - and; Z １ is N or C(R ５ ) and Z ２ is N or C(R ６ ) and Z ３ is N or C(R ７ ) and Z ４ is N or C(R ８ ) is: However, Z １ -Z ４ at least two of are N; Ring A is a 5- to 8-membered heterocycloalkyl or C ５ -C ８ is cycloalkyl; Ring B is C ６ -C １０ aryl or 5- to 10-membered heteroaryl; R １ are each independently deuterium, halogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６ -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) ２ R ａ , -OS(O)NR ａ R ｂ , -OS(O) ２ NR ａ R ｂ , -SR ａ , -S(O)R ａ , -S(O) ２ R ａ , -S(O)NR ａ R ｂ , -S(O) ２ NR 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) ２ R ｂ , -NR ａ S(O)NR ａ R ｂ , -NR ａ S (O) ２ NR 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) ２ R ａ R ｂ , -P(O)NR ａ R ｂ , -P(O) ２ NR ａ R ｂ , -P(O)OR ａ , -P(O) ２ OR ａ , -CN, or -NO ２ or two R １ together with their bonding atoms, C ３ -C ６ cycloalkyl or 4 to 10 membered heterocycloalkyl, wherein C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ Cycloalkyl, C ６ -C １０ Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently selected from deuterium, halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -R ｅ , -R ｆ , -OR ｅ , -OC(O)R ｅ 、-OC(O)NR ｅ R ｆ 、-OS(O)R ｅ 、-OS(O) ２ R ｅ 、-OS(O)NR ｅ R ｆ 、-OS(O) ２ NR ｅ R ｆ 、-SR ｅ 、-S(O)R ｅ 、-S(O) ２ R ｅ 、-S(O)NR ｅ R ｆ 、-S(O) ２ NR 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) ２ R ｆ 、-NR ｅ S(O)NR ｅ R ｆ 、-NR ｅ S(O) ２ 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) ２ R ｅ R ｆ 、-P(O)NR ｅ R ｆ 、-P(O) ２ NR ｅ R ｆ 、-P(O)OR ｅ 、-P(O) ２ OR ｅ , -CN, or -NO ２ may be replaced by R ２ are each independently deuterium, halogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６ -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) ２ R ｃ , -OS(O)NR ｃ R ｄ , -OS(O) ２ NR ｃ R ｄ , -SR ｃ , -S(O)R ｃ , -S(O) ２ R ｃ , -S(O)NR ｃ R ｄ , -S(O) ２ NR 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) ２ R ｄ , -NR ｃ S(O)NR ｃ R ｄ , -NR ｃ S (O) ２ NR 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) ２ R ｃ R ｄ , -P(O)NR ｃ R ｄ , -P(O) ２ NR ｃ R ｄ , -P(O)OR ｃ , -P(O) ２ OR ｃ , -CN, or -NO ２ or two R ２ together with their bonding atoms, C ３ -C ６ cycloalkyl or 4 to 10 membered heterocycloalkyl, wherein C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ Cycloalkyl, C ６ -C １０ Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently selected from deuterium, halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -R ｅ , -R ｆ , -OR ｅ , -OC(O)R ｅ 、-OC(O)NR ｅ R ｆ 、-OS(O)R ｅ 、-OS(O) ２ R ｅ 、-OS(O)NR ｅ R ｆ 、-OS(O) ２ NR ｅ R ｆ 、-SR ｅ 、-S(O)R ｅ 、-S(O) ２ R ｅ 、-S(O)NR ｅ R ｆ 、-S(O) ２ NR 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) ２ R ｆ 、-NR ｅ S(O)NR ｅ R ｆ 、-NR ｅ S(O) ２ 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) ２ R ｅ R ｆ 、-P(O)NR ｅ R ｆ 、-P(O) ２ NR ｅ R ｆ 、-P(O)OR ｅ 、-P(O) ２ OR ｅ , -CN, or -NO ２ may be replaced by R ３ is -C １ -C ６ Alkyl, -C ２ -C ６ Alkenyl, -C ２ -C ６ Alkynyl, —C ３ -C ６ cycloalkyl, 4- to 10-membered heterocycloalkyl, —C １ -C ６ alkylene-(4 to 10 membered heterocycloalkyl), C ６ -C １０ Aryl, —C １ -C ６ Alkylene-(C ６ -C １０ aryl), 5- to 10-membered heteroaryl, or —C １ -C ６ alkylene-(4- to 10-membered heterocycloalkyl), where C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ cycloalkyl, 4- to 10-membered heterocycloalkyl, —C １ -C ６ alkylene-(4 to 10 membered heterocycloalkyl), C ６ -C １０ Aryl, —C １ -C ６ Alkylene-(C ６ -C １０ aryl), 5- to 10-membered heteroaryl, and —C １ -C ６ Each hydrogen atom in alkylene-(5- to 10-membered heteroaryl) can be independently selected from deuterium, halogen, —R ｅ , -R ｆ , C １ -C ６ Alkyl, -C １ -C ６ Alkylene -O-C １ -C ６ Alkyl, —OC １ -C ６ Alkylene -O-C １ -C ６ Alkyl, -C １ -C ６ Alkylene-O-R ａ , C ６ -C １０ Aryl, —C １ -C ６ Alkylene-(C ６ -C １０ aryl), haloalkyl, C ３ -C ６ cycloalkyl, 5- to 10-membered heteroaryl, —C １ -C ６ alkylene-(5- to 10-membered heterocycloalkyl), —OR ｅ , -OC(O)R ｅ , —OC(O)NR ｅ R ｆ , -OS(O)R ｅ , -OS(O) ２ R ｅ , -OS(O)NR ｅ R ｆ , -OS(O) ２ NR ｅ R ｆ , -SR ｅ , -S(O)R ｅ , -S(O) ２ R ｅ , -S(O)NR ｅ R ｆ , -S(O) ２ NR 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) ２ R ｆ , -NR ｅ S(O)NR ｅ R ｆ , -NR ｅ S (O) ２ 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) ２ R ｅ R ｆ , -P(O)NR ｅ R ｆ , -P(O) ２ NR ｅ R ｆ , -P(O)OR ｅ , -P(O) ２ OR ｅ , -CN, or -NO ２ may be replaced by R ４ is H, deuterium, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６ -C １０ aryl, or 5- to 10-membered heteroaryl, wherein C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６ -C １０ Each hydrogen atom in the aryl and 5- to 10-membered heteroaryl is independently selected from deuterium, halogen, -R ｅ , -R ｆ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -OR ｅ , -OC(O)R ｅ , —OC(O)NR ｅ R ｆ , -OS(O)R ｅ , -OS(O) ２ R ｅ , -OS(O)NR ｅ R ｆ , -OS(O) ２ NR ｅ R ｆ , -SR ｅ , -S(O)R ｅ , -S(O) ２ R ｅ , -S(O)NR ｅ R ｆ , -S(O) ２ NR 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) ２ R ｆ , -NR ｅ S(O)NR ｅ R ｆ , -NR ｅ S (O) ２ 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) ２ R ｅ R ｆ , -P(O)NR ｅ R ｆ , -P(O) ２ NR ｅ R ｆ , -P(O)OR ｅ , -P(O) ２ OR ｅ , -CN, or -NO ２ may be replaced by R ５ , R ６ , R ７ , and R ８ are each independently H, deuterium, halogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６ -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) ２ R ｇ , -SR ｇ , -S(O)R ｇ , -S(O) ２ R ｇ , -S(O)NR ｇ R ｈ , -S(O) ２ NR ｇ R ｈ , -OS(O)NR ｇ R ｈ , -OS(O) ２ NR 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) ２ R ｈ , -NR ｇ S(O)NR ｇ R ｈ , -NR ｇ S (O) ２ NR 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) ２ R ｇ R ｈ , -P(O)NR ｇ R ｈ , -P(O) ２ NR ｇ R ｈ , -P(O)OR ｇ , -P(O) ２ OR ｇ , -CN, or -NO ２ and R ａ , R ｂ , R ｃ , R ｄ , R ｅ , R ｆ , R ｇ , and R ｈ are each independently H, deuterium, or C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６ -C １０ Aryl, C １ -C ６ Alkylene-C ６ -C １０ aryl, and 5- to 10-membered heteroaryl; or R ａ and R ｂ , or R ｃ and R ｄ , or R ｅ and R ｆ , or R ｇ and R ｈ The two, together with their bonding atoms, combine to form C ３ -C ６ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６ -C １０ aryl, or 5- to 10-membered heteroaryl, wherein C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６ -C １０ Aryl, C １ -C ６ Alkylene-C ６ -C １０ Each hydrogen atom in the aryl and 5- to 10-membered heteroaryl is independently selected from deuterium, halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, —OH, —OC １ -C ６ Alkyl, —OC(O)C １ -C ６ Alkyl, —OC(O)N(H or C １ -C ６ alkyl) ２ , -OS(O)C １ -C ６ Alkyl, —OS(O) ２ C １ -C ６ Alkyl, —OS(O)N(H or C １ -C ６ alkyl) ２ , -OS(O) ２ N (H or C １ -C ６ alkyl) ２ , -SC １ -C ６ Alkyl, —S(O)C １ -C ６ Alkyl, —S(O) ２ C １ -C ６ Alkyl, —S(O)N(H or C １ -C ６ alkyl) ２ , -S(O) ２ N (H or C １ -C ６ alkyl) ２ , -N(H or C １ -C ６ alkyl) ２ , -N(C １ -C ６ alkyl)C(O)-C １ -C ６ Alkyl, —N(C １ -C ６ alkyl)C(O)OC １ -C ６ Alkyl, —N(C １ -C ６ alkyl)C(O)N(H or C １ -C ６ alkyl) ２ , -N(C １ -C ６ alkyl)S(O)C １ -C ６ Alkyl, —N(C １ -C ６ alkyl)S(O) ２ C １ -C ６ Alkyl, —N(C １ -C ６ alkyl)S(O)N(H or C １ -C ６ alkyl) ２ , -N(C １ -C ６ alkyl)S(O) ２ N (H or C １ -C ６ alkyl) ２ , -C(O)C １ -C ６ Alkyl, —C(O)OC １ -C ６ Alkyl, —C(O)N(H or C １ -C ６ alkyl) ２ , -P(H or C １ -C ６ alkyl) ２ , -P(O)(H or C １ -C ６ alkyl) ２ , -P(O) ２ (H or C １ -C ６ alkyl) ２ , -P(O)N(H or C １ -C ６ alkyl) ２ , -P(O) ２ N (H or C １ -C ６ alkyl) ２ , -P(O)OC １ -C ６ Alkyl, -P(O) ２ O.C. １ -C ６ Alkyl, —CN, or —NO ２ or may be substituted by —R ｅ and-R ｆ together with the carbon atom to which they are attached form an oxo group or an alkenyl; m is 0, 1, 2, 3, 4, 5, 6, or 7; n is 0, 1, 2, 3, 4, 5, 6, or 7; p is 0 or 1. or a pharmaceutically acceptable salt thereof.
2. Formula II: 【Chemistry 2】 [In the formula: Y １ -O-, -S-, -S(O)-, -S(O) ２ -,-NR ９ -or-CR １１ R １２ - and; Y ２ -O-, -S-, -S(O)-, -S(O) ２ -, -NR １０ - or -CR １３ R １４ - and; Each R ９ and R １０ are independently H, deuterium, or —C(O)R ｇ , —C(O)NR ｇ R ｈ , C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６ -C １０ aryl, or 5- to 10-membered heteroaryl, wherein C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６ -C １０ Each hydrogen atom in the aryl and 5- to 10-membered heteroaryl is independently selected from deuterium, halogen, -R ｅ , -R ｆ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -OR ｅ , -OC(O)R ｅ , —OC(O)NR ｅ R ｆ , -OS(O)R ｅ , -OS(O) ２ R ｅ , -OS(O)NR ｅ R ｆ , -OS(O) ２ NR ｅ R ｆ , -SR ｅ , -S(O)R ｅ , -S(O) ２ R ｅ , -S(O)NR ｅ R ｆ , -S(O) ２ NR 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) ２ R ｆ , -NR ｅ S(O)NR ｅ R ｆ , -NR ｅ S (O) ２ 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) ２ R ｅ R ｆ , -P(O)NR ｅ R ｆ , -P(O) ２ NR ｅ R ｆ , -P(O)OR ｅ , -P(O) ２ OR ｅ ', -CN, or -NO ２ or R ９ and R １ or R １０ and R １ together with the atom to which they are attached, combine to form a 4- to 10-membered heterocycloalkyl, where each hydrogen atom in the 4- to 10-membered heterocycloalkyl is independently selected from deuterium, halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, —OH, —OC １ -C ６ Alkyl, —OC(O)C １ -C ６ Alkyl, —OC(O)N(H or C １ -C ６ alkyl) ２ , -OS(O)C １ -C ６ Alkyl, —OS(O) ２ C １ -C ６ Alkyl, —OS(O)N(H or C １ -C ６ alkyl) ２ , -OS(O) ２ N (H or C １ -C ６ alkyl) ２ , -SC １ -C ６ Alkyl, —S(O)C １ -C ６ Alkyl, —S(O) ２ C １ -C ６ Alkyl, —S(O)N(H or C １ -C ６ alkyl) ２ , -S(O) ２ N (H or C １ -C ６ alkyl) ２ , -N(H or C １ -C ６ alkyl) ２ , -N(C １ -C ６ alkyl)C(O)-C １ -C ６ Alkyl, —N(C １ -C ６ alkyl)C(O)OC １ -C ６ Alkyl, —N(C １ -C ６ alkyl)C(O)N(H or C １ -C ６ alkyl) ２ , -N(C １ -C ６ alkyl)S(O)C １ -C ６ Alkyl, —N(C １ -C ６ alkyl)S(O) ２ C １ -C ６ Alkyl, —N(C １ -C ６ alkyl)S(O)N(H or C １ -C ６ alkyl) ２ , -N(C １ -C ６ alkyl)S(O) ２ N (H or C １ -C ６ alkyl) ２ , -C(O)C １ -C ６ Alkyl, —C(O)OC １ -C ６ Alkyl, —C(O)N(H or C １ -C ６ alkyl) ２ , -P(H or C １ -C ６ alkyl) ２ , -P(O)(H or C １ -C ６ alkyl) ２ , -P(O) ２ (H or C １ -C ６ alkyl) ２ , -P(O)N(H or C １ -C ６ alkyl) ２ , -P(O) ２ N (H or C １ -C ６ alkyl) ２ , -P(O)OC １ -C ６ Alkyl, -P(O) ２ O.C. １ -C ６ Alkyl, —CN, or —NO ２ or two hydrogen atoms on a single carbon atom of a 4- to 10-membered heterocycloalkyl combine to form an oxo group or an alkenyl group; and R １１ , R １２ , R １３ , and R １４ are each independently H, deuterium, halogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６ -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) ２ R ａ , -OS(O)NR ａ R ｂ , -OS(O) ２ NR ａ R ｂ , -SR ａ , -S(O)R ａ , -S(O) ２ R ａ , -S(O)NR ａ R ｂ , -S(O) ２ NR 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) ２ R ｂ , -NR ａ S(O)NR ａ R ｂ , -NR ａ S (O) ２ NR 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) ２ R ａ R ｂ , -P(O)NR ａ R ｂ , -P(O) ２ NR ａ R ｂ , -P(O)OR ａ , -P(O) ２ OR ａ , -CN, or -NO ２ or R １ and R １１ , R １ and R １２ , R １ and R １３ , R １ and R １４ , R １１ and R １２ Two of these, or R １３ and R １４ Two of these, together with the carbons to which they are attached, combine to form C ３ -C ６ cycloalkyl or 4 to 10 membered heterocycloalkyl, wherein C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ Cycloalkyl, C ６ -C １０ Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently selected from deuterium, halogen, —R ｅ , -R ｆ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -OR ｅ , -OC(O)R ｅ , —OC(O)NR ｅ R ｆ , -OS(O)R ｅ , -OS(O) ２ R ｅ , -OS(O)NR ｅ R ｆ , -OS(O) ２ NR ｅ R ｆ , -SR ｅ , -S(O)R ｅ , -S(O) ２ R ｅ , -S(O)NR ｅ R ｆ , -S(O) ２ NR 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) ２ R ｆ , -NR ｅ S(O)NR ｅ R ｆ , -NR ｅ S (O) ２ 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) ２ R ｅ R ｆ , -P(O)NR ｅ R ｆ , -P(O) ２ NR ｅ R ｆ , -P(O)OR ｅ , -P(O) ２ OR ｅ , -CN, or -NO ２ or may be substituted by R １１ and R １２ or R １３ and R １４ two of these together with the carbon atoms to which they are attached form an oxo group or C ２ -C ６ forming an alkenyl group] 2. The compound of claim 1, wherein:
3. Formula XXXVII, XXXVIII, XXXIX, XXXX, XXXXI, XXXXII, or XXXXIII: 【Chemistry 3】 【Chemistry 4】 【Chemistry 5】 [In the formula: Y １ -O-, -S-, -S(O)-, -S(O) ２ -, -NR ９ -or-CR １１ R １２ - and; Y ２ -O-, -S-, -S(O)-, -S(O) ２ -, -NR １０ -or-CR １３ R １４ - and; Z ５ is N or C(R １５ ) and Z ６ is N or C(R １６ ) and Ring D is C ３ -C ６ cycloalkyl or 4- to 8-membered heterocycloalkyl; Each R ９ and R １０ are independently H, deuterium, or —C(O)R ｇ , —C(O)NR ｇ R ｈ , C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６ -C １０ aryl, or 5- to 10-membered heteroaryl, wherein C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６ -C １０ Each hydrogen atom in the aryl and 5- to 10-membered heteroaryl is independently selected from deuterium, halogen, -R ｅ , -R ｆ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -OR ｅ , -OC(O)R ｅ , —OC(O)NR ｅ R ｆ , -OS(O)R ｅ , -OS(O) ２ R ｅ , -OS(O)NR ｅ R ｆ , -OS(O) ２ NR ｅ R ｆ , -SR ｅ , -S(O)R ｅ , -S(O) ２ R ｅ , -S(O)NR ｅ R ｆ , -S(O) ２ NR 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) ２ R ｆ , -NR ｅ S(O)NR ｅ R ｆ , -NR ｅ S (O) ２ 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) ２ R ｅ R ｆ , -P(O)NR ｅ R ｆ , -P(O) ２ NR ｅ R ｆ , -P(O)OR ｅ , -P(O) ２ OR ｅ , -CN, or -NO ２ or R ９ and R １ or R １０ and R １ together with the atom to which they are attached, combine to form a 4- to 10-membered heterocycloalkyl, where each hydrogen atom in the 4- to 10-membered heterocycloalkyl is independently selected from deuterium, halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, —OH, —OC １ -C ６ Alkyl, —OC(O)C １ -C ６ Alkyl, —OC(O)N(H or C １ -C ６ alkyl) ２ , -OS(O)C １ -C ６ Alkyl, —OS(O) ２ C １ -C ６ Alkyl, —OS(O)N(H or C １ -C ６ alkyl) ２ , -OS(O) ２ N (H or C １ -C ６ alkyl) ２ , -SC １ -C ６ Alkyl, —S(O)C １ -C ６ Alkyl, —S(O) ２ C １ -C ６ Alkyl, —S(O)N(H or C １ -C ６ alkyl) ２ , -S(O) ２ N (H or C １ -C ６ alkyl) ２ , -N(H or C １ -C ６ alkyl) ２ , -N(C １ -C ６ alkyl)C(O)-C １ -C ６ Alkyl, —N(C １ -C ６ alkyl)C(O)OC １ -C ６ Alkyl, —N(C １ -C ６ alkyl)C(O)N(H or C １ -C ６ alkyl) ２ , -N(C １ -C ６ alkyl)S(O)C １ -C ６ Alkyl, —N(C １ -C ６ alkyl)S(O) ２ C １ -C ６ Alkyl, —N(C １ -C ６ alkyl)S(O)N(H or C １ -C ６ alkyl) ２ , -N(C １ -C ６ alkyl)S(O) ２ N (H or C １ -C ６ alkyl) ２ , -C(O)C １ -C ６ Alkyl, —C(O)OC １ -C ６ Alkyl, —C(O)N(H or C １ -C ６ alkyl) ２ , -P(H or C １ -C ６ alkyl) ２ , -P(O)(H or C １ -C ６ alkyl) ２ , -P(O) ２ (H or C １ -C ６ alkyl) ２ , -P(O)N(H or C １ -C ６ alkyl) ２ , -P(O) ２ N (H or C １ -C ６ alkyl) ２ , -P(O)OC １ -C ６ Alkyl, -P(O) ２ O.C. １ -C ６ Alkyl, —CN, or —NO ２ or two hydrogen atoms on a single carbon atom of the 4- to 10-membered heterocycloalkyl may combine to form an oxo group or C ２ -C ６ Forming an alkenyl group; R １１ , R １２ , R １３ , and R １４ are each independently H, deuterium, halogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６ -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) ２ R ａ , -OS(O)NR ａ R ｂ , -OS(O) ２ NR ａ R ｂ , -SR ａ , -S(O)R ａ , -S(O) ２ R ａ , -S(O)NR ａ R ｂ , -S(O) ２ NR 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) ２ R ｂ , -NR ａ S(O)NR ａ R ｂ , -NR ａ S (O) ２ NR 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) ２ R ａ R ｂ , -P(O)NR ａ R ｂ , -P(O) ２ NR ａ R ｂ , -P(O)OR ａ , -P(O) ２ OR ａ , -CN, or -NO ２ or R １ and R １１ , R １ and R １２ , R １ and R １３ , R １ and R １４ , R １１ and R １２ Two of these, or R １３ and R １４ Two of them, together with the carbons to which they are attached, combine to form C ３ -C ６ cycloalkyl or 4 to 10 membered heterocycloalkyl, wherein C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ Cycloalkyl, C ６ -C １０ Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently selected from deuterium, halogen, —R ｅ , -R ｆ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -OR ｅ , -OC(O)R ｅ , —OC(O)NR ｅ R ｆ , -OS(O)R ｅ , -OS(O) ２ R ｅ , -OS(O)NR ｅ R ｆ , -OS(O) ２ NR ｅ R ｆ , -SR ｅ , -S(O)R ｅ , -S(O) ２ R ｅ , -S(O)NR ｅ R ｆ , -S(O) ２ NR 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) ２ R ｆ , -NR ｅ S(O)NR ｅ R ｆ , -NR ｅ S (O) ２ 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) ２ R ｅ R ｆ , -P(O)NR ｅ R ｆ , -P(O) ２ NR ｅ R ｆ , -P(O)OR ｅ , -P(O) ２ OR ｅ , -CN, or -NO ２ or may be substituted by R １１ and R １２ or R １３ and R １４ two of these together with the carbon atoms to which they are attached form an oxo group or C ２ -C ６ forming an alkenyl group; and R １５ and R １６ are each independently H, deuterium, halogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６ -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) ２ R ｇ , -SR ｇ , -S(O)R ｇ , -S(O) ２ R ｇ , -S(O)NR ｇ R ｈ , -S(O) ２ NR ｇ R ｈ , -OS(O)NR ｇ R ｈ , -OS(O) ２ NR 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) ２ R ｈ , -NR ｇ S(O)NR ｇ R ｈ , -NR ｇ S (O) ２ NR 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) ２ R ｇ R ｈ , -P(O)NR ｇ R ｈ , -P(O) ２ NR ｇ R ｈ , -P(O)OR ｇ , -P(O) ２ OR ｇ , -CN, or -NO ２ is] 2. The compound of claim 1, wherein:
4. Formula III: 【Chemistry 6】 3. The compound of claim 1 or 2, wherein:
5. Formula XVI, XXIII or XXX: 【Chemistry 7】 wherein ring C is a 4- to 8-membered heterocycloalkyl; and X １ is -NH-, -O- or -CH ２ -, q is 0, 1 or 2, t is 1 or 2, and v is 1 or 2.
3. The compound of claim 1 or 2, wherein:
6. Formula IV, XIV, XVII, XXII, XXIV, XXIX, XXXI or XXXVI: 【Chemistry 8】 【Chemistry 9】 【Chemistry 10】 [In the formula: Z ５ is N or C(R １５ ) and Z ６ is N or C(R １６ ) and R １５ and R １６ are each independently H, deuterium, halogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６ -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) ２ R ｇ , -SR ｇ , -S(O)R ｇ , -S(O) ２ R ｇ , -S(O)NR ｇ R ｈ , -S(O) ２ NR ｇ R ｈ , -OS(O)NR ｇ R ｈ , -OS(O) ２ NR 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) ２ R ｈ , -NR ｇ S(O)NR ｇ R ｈ , -NR ｇ S (O) ２ NR 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) ２ R ｇ R ｈ , -P(O)NR ｇ R ｈ , -P(O) ２ NR ｇ R ｈ , -P(O)OR ｇ , -P(O) ２ OR ｇ , -CN, or -NO ２ and Ring C is a 4- to 8-membered heterocycloalkyl; X １ is —O—, —NH— or —CH ２ - and; q is 0, 1 or 2; t is 1 or 2, v is 1 or 2.
6. The compound according to any one of claims 1 to 5, wherein: or a pharmaceutically acceptable salt thereof.
7. Formula V, XI, XVIII, XXI, XXV, XXVIII, XXXII or XXXV: 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 wherein ring C is a 4- to 8-membered heterocycloalkyl; １ is —O—, —NH—, or —CH ２ -; q is 0, 1 or 2; t is 1 or 2; and v is 1 or 2] 6. The compound according to any one of claims 1 to 5, wherein: or a pharmaceutically acceptable salt thereof.
8. Formula VI, X, XIX, XX, XXVI, XXXVII, XXXIII, XXXIV, XXXXIII, XXXXIV, XXXXV or XXXXVI: 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 wherein ring C is a 4- to 8-membered heterocycloalkyl; １ is —O—, —NH— or —CH ２ -; q is 0, 1 or 2; t is 1 or 2; and v is 1 or 2] 6. The compound according to any one of claims 1 to 5, wherein: or a pharmaceutically acceptable salt thereof.
9. Formula VII or XV: 【Chemistry 18】 [In the formula: Z ５ is N or C(R １５ ) and Z ６ is N or C(R １６ ) wherein: R １５ and R １６ are each independently H, deuterium, halogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ cycloalkyl, 4- to 10-membered heterocycloalkyl, C ６ -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) ２ R ｇ , -SR ｇ , -S(O)R ｇ , -S(O) ２ R ｇ , -S(O)NR ｇ R ｈ , -S(O) ２ NR ｇ R ｈ , -OS(O)NR ｇ R ｈ , -OS(O) ２ NR 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) ２ R ｈ , -NR ｇ S(O)NR ｇ R ｈ , -NR ｇ S (O) ２ NR 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) ２ R ｇ R ｈ , -P(O)NR ｇ R ｈ , -P(O) ２ NR ｇ R ｈ , -P(O)OR ｇ , -P(O) ２ OR ｇ , -CN, or -NO ２ is] 6. The compound according to any one of claims 1 to 5, wherein: or a pharmaceutically acceptable salt thereof.
10. Formula VIII or XIII 【Chemistry 19】 6. The compound according to any one of claims 1 to 5, wherein: or a pharmaceutically acceptable salt thereof.
11. Formula IX or XII: 【Chemistry 20】 6. The compound according to any one of claims 1 to 5, wherein: or a pharmaceutically acceptable salt thereof.
12. R １ But deuterium, C １ -C ６ Alkyl, C ２ -C ６ alkenyl, or C ２ -C ６ alkynyl, where C １ -C ６ Alkyl, C ２ -C ６ alkenyl, or C ２ -C ６ Each hydrogen atom in an alkynyl can be independently selected from deuterium, halogen, -R ｅ , -R ｆ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -OR ｅ , -OC(O)R ｅ , —OC(O)NR ｅ R ｆ , -OS(O)R ｅ , -OS(O) ２ R ｅ , -OS(O)NR ｅ R ｆ , -OS(O) ２ NR ｅ R ｆ , -SR ｅ , -S(O)R ｅ , -S(O) ２ R ｅ , -S(O)NR ｅ R ｆ , -S(O) ２ NR 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) ２ R ｆ , -NR ｅ S(O)NR ｅ R ｆ , -NR ｅ S (O) ２ 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) ２ R ｅ R ｆ , -P(O)NR ｅ R ｆ , -P(O) ２ NR ｅ R ｆ , -P(O)OR ｅ , -P(O) ２ OR ｅ , -CN, or -NO ２ may be substituted by R ９ and R １ or R １０ and R １ together with the atom to which they are attached, combine to form a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in the 4- to 10-membered heterocycloalkyl is independently selected from deuterium, halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, —OH, —OC １ -C ６ Alkyl, —OC(O)C １ -C ６ Alkyl, —OC(O)N(H or C １ -C ６ alkyl) ２ , -OS(O)C １ -C ６ Alkyl, —OS(O) ２ C １ -C ６ Alkyl, —OS(O)N(H or C １ -C ６ alkyl) ２ , -OS(O) ２ N (H or C １ -C ６ alkyl) ２ , -SC １ -C ６ Alkyl, —S(O)C １ -C ６ Alkyl, —S(O) ２ C １ -C ６ Alkyl, —S(O)N(H or C １ -C ６ alkyl) ２ , -S(O) ２ N (H or C １ -C ６ alkyl) ２ , -N(H or C １ -C ６ alkyl) ２ , -N(C １ -C ６ alkyl)C(O)-C １ -C ６ Alkyl, —N(C １ -C ６ alkyl)C(O)OC １ -C ６ Alkyl, —N(C １ -C ６ alkyl)C(O)N(H or C １ -C ６ alkyl) ２ , -N(C １ -C ６ alkyl)S(O)C １ -C ６ Alkyl, —N(C １ -C ６ alkyl)S(O) ２ C １ -C ６ Alkyl, —N(C １ -C ６ alkyl)S(O)N(H or C １ -C ６ alkyl) ２ , -N(C １ -C ６ alkyl)S(O) ２ N (H or C １ -C ６ alkyl) ２ , -C(O)C １ -C ６ Alkyl, —C(O)OC １ -C ６ Alkyl, —C(O)N(H or C １ -C ６ alkyl) ２ , -P(H or C １ -C ６ alkyl) ２ , -P(O)(H or C １ -C ６ alkyl) ２ , -P(O) ２ (H or C １ -C ６ alkyl) ２ , -P(O)N(H or C １ -C ６ alkyl) ２ , -P(O) ２ N (H or C １ -C ６ alkyl) ２ , -P(O)OC １ -C ６ Alkyl, -P(O) ２ O.C. １ -C ６ Alkyl, —CN, or —NO ２ or two hydrogen atoms taken together on a single carbon atom of a 4- to 10-membered heterocycloalkyl form an oxo group or C ２ -C ６ form an alkenyl group; or two R １ together with their bonding atoms, C ３ -C ６ cycloalkyl or 4 to 10 membered heterocycloalkyl, wherein C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, C ３ -C ６ Cycloalkyl, C ６ -C １０ Each hydrogen atom in the aryl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl is independently selected from deuterium, halogen, C １ -C ６ アルキル、C １ -C ６ ハロアルキル、-R ｅ 、-R ｆ 、-OR ｅ 、-OC(O)R ｅ 、-OC(O)NR ｅ R ｆ 、-OS(O)R ｅ 、-OS(O) ２ R ｅ 、-OS(O)NR ｅ R ｆ 、-OS(O) ２ NR ｅ R ｆ 、-SR ｅ 、-S(O)R ｅ 、-S(O) ２ R ｅ 、-S(O)NR ｅ R ｆ 、-S(O) ２ NR 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) ２ R ｆ 、-NR ｅ S(O)NR ｅ R ｆ 、-NR ｅ S(O) ２ 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) ２ R ｅ R ｆ 、-P(O)NR ｅ R ｆ , -P(O) ２ NR ｅ R ｆ , -P(O)OR ｅ , -P(O) ２ OR ｅ , -CN, or -NO ２ 10. A compound according to any one of the preceding claims, optionally substituted by: or a pharmaceutically acceptable salt thereof.
13. Ring A together with ring C or ring D may form the core of a compound of formula I, which core has the formula: 【Chemical 21】 [In the formula: 【Chemical 23】 is ring B or -(X) ｐ -R ３ and each hydrogen atom in ring A, ring C, and ring D, if present, is independently selected from deuterium, halogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, -R ｅ , -R ｆ , -OR ｅ , -OC(O)R ｅ , —OC(O)NR ｅ R ｆ , -OS(O)R ｅ , -OS(O) ２ R ｅ , -OS(O)NR ｅ R ｆ , -OS(O) ２ NR ｅ R ｆ , -SR ｅ , -S(O)R ｅ , -S(O) ２ R ｅ , -S(O)NR ｅ R ｆ , -S(O) ２ NR 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) ２ R ｆ , -NR ｅ S(O)NR ｅ R ｆ , -NR ｅ S (O) ２ 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) ２ R ｅ R ｆ , -P(O)NR ｅ R ｆ , -P(O) ２ NR ｅ R ｆ , -P(O)OR ｅ , -P(O) ２ OR ｅ , -CN, or -NO ２ R selected from the group consisting of １ may be replaced by] 10. The compound of claim 9, wherein R is an integer from 1 to 2; or a pharmaceutically acceptable salt thereof.
14. Ring A together with ring C or ring D may form the core of a compound of formula I, which core has the formula: 【Chemistry 24】 【Chemistry 25】 【Chemical 26】 [In the formula: 【Chemical 27】 are each ring B or -(X) ｐ -R ３ ] 10. The compound of claim 9, wherein R is an integer from 1 to 2; or a pharmaceutically acceptable salt thereof.
15. Ring A is a fused 5- to 8-membered heterocycloalkyl that forms the core of the compound of formula I, said core having the formula: 【Chemical 28】 【Chemical 29】 【Chemistry 30】 [In the formula: 【Chemical 31】 Each of the groups is ring B or -(X) ｐ -R ３ ] 14. The compound according to any one of claims 1 to 13, wherein:
16. Y ２ 10. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein is -O-.
17. Y ２ Ga-CH ２ 10. The compound of claim 9, wherein R is - or a pharmaceutically acceptable salt thereof.
18. R ３ Ga-C １ -C ６ alkyl, 4- to 10-membered heterocycloalkyl, or —C １ -C ６ alkylene-(4- to 10-membered heterocycloalkyl), where —C １ -C ６ alkyl, 4- to 10-membered heterocycloalkyl, or —C １ -C ６ Each hydrogen atom in the alkylene-(4- to 10-membered heterocycloalkyl) is independently selected from deuterium, halogen, C １ -C ６ Alkyl, -C １ -C ６ Alkylene -O-C １ -C ６ Alkyl, —OC １ -C ６ Alkylene -O-C １ -C ６ Alkyl, -C １ -C ６ Alkylene-O-R ａ , C ６ -C １０ Aryl, —C １ -C ６ Alkylene-(C ６ -C １０ aryl), haloalkyl, C ３ -C ６ cycloalkyl, 5- to 10-membered heteroaryl, —C １ -C ６ alkylene-(5- to 10-membered heterocycloalkyl), —OR ｅ , -OC(O)R ｅ , —OC(O)NR ｅ R ｆ , -OS(O)R ｅ , -OS(O) ２ R ｅ , -OS(O)NR ｅ R ｆ , -OS(O) ２ NR ｅ R ｆ , -SR ｅ , -S(O)R ｅ , -S(O) ２ R ｅ , -S(O)NR ｅ R ｆ , -S(O) ２ NR 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) ２ R ｆ , -NR ｅ S(O)NR ｅ R ｆ , -NR ｅ S (O) ２ 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) ２ R ｅ R ｆ , -P(O)NR ｅ R ｆ , -P(O) ２ NR ｅ R ｆ , -P(O)OR ｅ , -P(O) ２ OR ｅ , -CN, or -NO ２ 10. A compound according to any one of the preceding claims, optionally substituted by: or a pharmaceutically acceptable salt thereof.
19. R ３ Ga-C １ -C ６ alkylene-(4- to 10-membered heterocycloalkyl), where —C １ -C ６ Each hydrogen atom in the alkylene-(4- to 10-membered heterocycloalkyl) is independently selected from deuterium, halogen, C １ -C ６ Alkyl, -C １ -C ６ Alkylene -O-C １ -C ６ Alkyl, —OC １ -C ６ Alkylene -O-C １ -C ６ Alkyl, -C １ -C ６ Alkylene-O-R ａ , C ６ -C １０ Aryl, —C １ -C ６ Alkylene-(C ６ -C １０ aryl), haloalkyl, C ３ -C ６ cycloalkyl, 5- to 10-membered heteroaryl, —C １ -C ６ alkylene-(5- to 10-membered heterocycloalkyl), —OR ｅ , -OC(O)R ｅ , —OC(O)NR ｅ R ｆ , -OS(O)R ｅ , -OS(O) ２ R ｅ , -OS(O)NR ｅ R ｆ , -OS(O) ２ NR ｅ R ｆ , -SR ｅ , -S(O)R ｅ , -S(O) ２ R ｅ , -S(O)NR ｅ R ｆ , -S(O) ２ NR 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) ２ R ｆ , -NR ｅ S(O)NR ｅ R ｆ , -NR ｅ S (O) ２ 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) ２ R ｅ R ｆ , -P(O)NR ｅ R ｆ , -P(O) ２ NR ｅ R ｆ , -P(O)OR ｅ , -P(O) ２ OR ｅ , -CN, or -NO ２ 10. A compound according to any one of the preceding claims, optionally substituted by: or a pharmaceutically acceptable salt thereof.
20. R ３ but 【Chemical 32】 wherein each hydrogen atom is independently selected from deuterium, halogen, C １ -C ６ Alkyl, -C １ -C ６ Alkylene -O-C １ -C ６ Alkyl, —OC １ -C ６ Alkylene -O-C １ -C ６ Alkyl, -C １ -C ６ Alkylene-O-R ａ , C ６ -C １０ Aryl, —C １ -C ６ Alkylene-(C ６ -C １０ aryl), haloalkyl, C ３ -C ６ cycloalkyl, 5- to 10-membered heteroaryl, —C １ -C ６ alkylene-(5- to 10-membered heterocycloalkyl), —OR ｅ , -OC(O)R ｅ , —OC(O)NR ｅ R ｆ , -OS(O)R ｅ , -OS(O) ２ R ｅ , -OS(O)NR ｅ R ｆ , -OS(O) ２ NR ｅ R ｆ , -SR ｅ , -S(O)R ｅ , -S(O) ２ R ｅ , -S(O)NR ｅ R ｆ , -S(O) ２ NR 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) ２ R ｆ , -NR ｅ S(O)NR ｅ R ｆ , -NR ｅ S (O) ２ 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) ２ R ｅ R ｆ , -P(O)NR ｅ R ｆ , -P(O) ２ NR ｅ R ｆ , -P(O)OR ｅ , -P(O) ２ OR ｅ , -CN, or -NO ２ may be replaced by 【Chemical 33】 10. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: is the point of covalent attachment.
21. R ３ but 【Chemical 34】 where 【Chemical Formula 35】 10. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein is an inorganic counterion or an organic counterion.
22. R ３ is a 4- to 10-membered heterocycloalkyl, wherein each hydrogen atom in the 4- to 10-membered heterocycloalkyl is independently selected from deuterium, halogen, C １ -C ６ Alkyl, -C １ -C ６ Alkylene -O-C １ -C ６ Alkyl, —OC １ -C ６ Alkylene -O-C １ -C ６ Alkyl, -C １ -C ６ Alkylene-O-R ａ , C ６ -C １０ Aryl, —C １ -C ６ Alkylene-(C ６ -C １０ aryl), haloalkyl, C ３ -C ６ cycloalkyl, 5- to 10-membered heteroaryl, —C １ -C ６ alkylene-(5- to 10-membered heterocycloalkyl), —OR ｅ , -OC(O)R ｅ , —OC(O)NR ｅ R ｆ , -OS(O)R ｅ , -OS(O) ２ R ｅ , -OS(O)NR ｅ R ｆ , -OS(O) ２ NR ｅ R ｆ , -SR ｅ , -S(O)R ｅ , -S(O) ２ R ｅ , -S(O)NR ｅ R ｆ , -S(O) ２ NR 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) ２ R ｆ , -NR ｅ S(O)NR ｅ R ｆ , -NR ｅ S (O) ２ 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) ２ R ｅ R ｆ , -P(O)NR ｅ R ｆ , -P(O) ２ NR ｅ R ｆ , -P(O)OR ｅ , -P(O) ２ OR ｅ , -CN, or -NO ２ 23. The compound of any one of claims 1 to 18 or 22, or a pharmaceutically acceptable salt thereof, optionally substituted by
23. R ３ but 【Chemical 36】 where 【Chemical 37】 23. The compound of any one of claims 1 to 18 or 22, or a pharmaceutically acceptable salt thereof, wherein is the point of covalent attachment.
24. 10. 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. 10. A compound according to any one of the preceding claims, wherein n is 0, 1, 2 or 3, or a pharmaceutically acceptable salt thereof.
26. Z １ 10. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein is N.
27. Z ２ 10. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein is N.
28. Z ３ is CR ７ And Z ４ 10. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein is N.
29. Z ３ is CR ７ And Z ４ is CR ８ 28. The compound according to any one of claims 1 to 27, wherein:
30. Z ３ is N and Z ４ is CR ８ 28. The compound according to any one of claims 1 to 27, wherein:
31. Z ３ is N and Z ４ The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein
32. Z ３ is N and Z ４ is CR ８ and Z ５ is CR １５ And Z ６ is CR １６ 28. The compound according to any one of claims 1 to 27, wherein:
33. Z ３ is CR ７ and Z ４ is N and Z ５ is CR １５ And Z ６ is CR １６ 28. The compound according to any one of claims 1 to 27, wherein:
34. Z ３ is N and Z ４ is N and Z ５ is CR １５ And Z ６ is CR １６ 28. The compound according to any one of claims 1 to 27, wherein:
35. 10. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein p is 0.
36. 35. The compound of any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein p is 1.
37. 37. The compound of any one of claims 1 to 34, or 36, or a pharmaceutically acceptable salt thereof, wherein X is -O-.
38. X is -NR ４ 37. The compound of any one of claims 1 to 34, or 36, wherein R is -, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof.
39. 37. The compound of any one of claims 1 to 34, or 36, or a pharmaceutically acceptable salt thereof, wherein X is -S-.
40. R ２ are each independently deuterium, halogen, C １ -C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, -OR ｃ , -C(O)RC, -NR ｃ R ｄ or -CN, where C １ -C ６ Alkyl, C ２ -C ６ alkenyl, and C ２ -C ６ 10. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein each hydrogen atom in the alkynyl may each independently be substituted with deuterium or halogen.
41. Ring B is 【Chemical Formula 38】 【Chemical Formula 39】 where 【Chemistry 40】 10. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: is the point of covalent attachment.
42. R ４ 10. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein, if present, is H or methyl.
43. R ５ 10. A compound according to any one of the preceding claims, wherein, if present, is H, or a pharmaceutically acceptable salt thereof.
44. R ６ 10. A compound according to any one of the preceding claims, wherein, if present, is H, or a pharmaceutically acceptable salt thereof.
45. R ７ 10. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein, if present, is H or F.
46. R ８ 10. A compound according to any one of the preceding claims, wherein, if present, is H, or a pharmaceutically acceptable salt thereof.
47. R ９ 10. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein, if present, is H or methyl.
48. R １０ 10. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein, if present, is H or methyl.
49. R １１ 10. A compound according to any one of the preceding claims, wherein, if present, is H, or a pharmaceutically acceptable salt thereof.
50. R １２ 10. A compound according to any one of the preceding claims, wherein, if present, is H, or a pharmaceutically acceptable salt thereof.
51. R １３ 10. A compound according to any one of the preceding claims, wherein, if present, is H, or a pharmaceutically acceptable salt thereof.
52. R １４ 10. A compound according to any one of the preceding claims, wherein, if present, is H, or a pharmaceutically acceptable salt thereof.
53. Z ５ 10. A compound according to any one of the preceding claims, wherein, if present, is N, or a pharmaceutically acceptable salt thereof.
54. Z ６ 10. A compound according to any one of the preceding claims, wherein, if present, is N, or a pharmaceutically acceptable salt thereof.
55. Z ５ If it exists, CR １５ 52. The compound of any one of claims 1 to 51, wherein:
56. R １５ 10. A compound or pharmaceutically acceptable salt according to any one of the preceding claims, wherein, if present, is H.
57. Z ６ If it exists, CR １６ 54. The compound of any one of claims 1 to 53, wherein:
58. R １６ 10. A compound or pharmaceutically acceptable salt according to any one of the preceding claims, wherein, if present, is H.
59. 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-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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]-1,3-benzothiazol-2-amine; 5-ethyl-6-fluoro-4-[(8aS)-4-fluoro-2-{[(2Z,7aS)-2-(fluoromethylidene)tetrahydro-1H-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-methyl-5-(trifluoromethyl)pyridin-2-amine; 3-chloro-5-[(8aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-7a(5H)-yl]methoxy}-8,8a,9,10,11,12-hexahydropyrido[2',1':3,4][1,4]oxazepino[5,6,7-de]quinazolin-5-yl]naphthalen-2-ol; 5-ethynyl-6-fluoro-4-[(9S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-(fluoromethylidene)tetrahydro-1H-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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; 5-ethynyl-6-fluoro-4-[(7aS,9aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl]methoxy}-10-methyl-8,9,9a,10-tetrahydro-7aH-7-oxa-1,3,6,10-tetraazacyclobuta[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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-(fluoromethylidene)tetrahydro-1H-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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; (8aS)-5-(8-ethynyl-3,7-difluoronaphthalen-1-yl)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-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-pyrrolidin-2-ol; 5-ethynyl-6-fluoro-4-[(8aS)-4,11,11-trifluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-2-ol; 5-ethynyl-6-fluoro-4-[(7aR,10aS)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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; 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
60. 5-ethynyl-6-fluoro-4-[(9S)-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-4-ium; 4-[(9S)-10-benzyl-4-fluoro-2-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-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-pyrrolidin-7a(5H)-yl)methoxy)-10-((R)-2-hydroxypropyl)-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)naphthalen-2-ol; 4-((S)-10-(2,2-difluoroethyl)-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)-9-methyl-9,10-dihydro-8H-7-oxa-1,3,6,10-tetraazacyclohepta[de]naphthalen-5-yl)-5-ethyl-6-fluoronaphthalen-2-ol; 5-ethyl-6-fluoro-4-(4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-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-pyrrolidin-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; 2. The compound of claim 1 selected from the group consisting of: or a pharmaceutically acceptable salt thereof.
61. 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. 61. 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 of any one of claims 1 to 60, or a pharmaceutically acceptable salt thereof.
63. 61. A compound according to any one of claims 1 to 60, or a pharmaceutically acceptable salt thereof, for use in a method for treating cancer in a subject.
64. 61. A compound according to any one of claims 1 to 60, or a pharmaceutically acceptable salt thereof, for treating cancer in a subject.
65. 61. Use of a compound according to any one of claims 1 to 60, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer in a subject.