EP4652154A1 - Neuartiger alsk1-hemmer - Google Patents

Neuartiger alsk1-hemmer

Info

Publication number: EP4652154A1
Authority: EP; European Patent Office
Prior art keywords: alkyl; haloalkyl; halo; connected form; compound
Prior art date: 2023-01-20
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Pending

Application number

EP24710011.8A

Other languages

English (en)

French (fr)

Inventor

Nana Du

Zhihong Li

Hexiang Wang

Zhenhua TIAN

Zhijiang JI

Yabin Chen

Counde O'yang

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Pyrotech Beijing Biotechnology Co Ltd

Original Assignee

Pyrotech Beijing Biotechnology Co Ltd

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

2023-01-20

Filing date

2024-01-19

Publication date

2025-11-26

2024-01-19 Application filed by Pyrotech Beijing Biotechnology Co Ltd filed Critical Pyrotech Beijing Biotechnology Co Ltd

2025-11-26 Publication of EP4652154A1 publication Critical patent/EP4652154A1/de

Status Pending legal-status Critical Current

Links

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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
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- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
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- C07C233/07—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/56—Ring systems containing bridged rings
- C07C2603/58—Ring systems containing bridged rings containing three rings
- C07C2603/60—Ring systems containing bridged rings containing three rings containing at least one ring with less than six members
- C07C2603/62—Ring systems containing bridged rings containing three rings containing at least one ring with less than six members containing three- or four-membered rings

Definitions

the disclosure is directed to novel ALPK1 inhibitors, or a pharmaceutical acceptable salt, a stereoisomer, a tautomer, a stable isotopic variant, a prodrug, or a crystal form thereof.
the disclosure is also directed to pharmaceutical composition comprising the novel ALPK1 inhibitors, and use thereof in treating inflammation related diseases, such as ROSAH syndrome, inflammatory bowel disease (IBD) , NASH, gout, diabetes, chronic kidney disease, pancreatitis, Kawasaki disease, inflammatory skin diseases and neurodegenerative diseases including the Alzheimer’s disease.
inflammation related diseases such as ROSAH syndrome, inflammatory bowel disease (IBD) , NASH, gout, diabetes, chronic kidney disease, pancreatitis, Kawasaki disease, inflammatory skin diseases and neurodegenerative diseases including the Alzheimer’s disease.
ALPK1 alpha-kinase 1
NTD N-terminal domain
KD C-terminal kinase domain
ADP-heptose can directly bind with the NTD and activates the KD to phosphorylate the substrate TIFA (TRAF-interacting protein with a forkhead-associated domain) .
the phosphorylated TIFA then oligomerizes to bind and activate TRAF6 for downstream NF- ⁇ B activation and innate immune responses eventually.
ALPK1 Deregulated activation of ALPK1 correlates with lots of diseases and disorders.
Gain-of-function mutations in ALPK1 cause an NF- ⁇ B mediated-autoinflammatory diseases named ROSAH (retinal dystrophy, optic nerve oedema, splenomegaly, anhidrosis and headache) syndrome (Genet. Med. 2019, 21 (9) : 2103-2115; J. Clin. Immunol. 2020, 40 (2) : 350-358; Ann. Rheum. Dis. 2022, 81 (10) : 1453-1464) .
ROSAH NF- ⁇ B mediated-autoinflammatory diseases
Another ALPK1 gain-of-function mutation is connected to a rare skin adnexal tumor, spiradenoma or spiradenocarcinoma (Nat. Commun.
ALPK1 Rare missense variants in the ALPK1 gene were also reported as a predisposing factor for the PFAPA (periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis) syndrome (Eur. J. Hum. Genet. 2019, 27 (9) : 1361-1368) .
PFAPA peripheral fever, aphthous stomatitis, pharyngitis, cervical adenitis
ALPK1 is implicated in lots of other inflammation related diseases, such as inflammatory bowel disease (IBD) , NASH, gout, diabetes, chronic kidney disease, pancreatitis, Kawasaki disease, inflammatory skin diseases and neurodegenerative diseases including the Alzheimer’s disease (Nat. Commun. 2018, 9 (1) : 3797; J. Mol.
the disclosure provides compounds of Formula (I) and sub-Formulae (II) , (II-1) , (II-2) , (III-1) , (III-2) , (III-3) , and (IV) as described herein, that are inhibitors of ALPK1 activity, and compositions and methods thereof in treating inflammation related diseases.
the disclosure provides a compound of Formula (I) :
M 1 is selected from CR 1 and N;
M 2 is selected from CR 2 and N;
M 3 is selected from CR 3 and N;
M 4 is selected from CR 4 and N;
L is selected from a chemical bond, -O-, -S-, and -NH-;
Y is selected from -C (O) -, -C (S) -, -C (N-OH) -, -S (O) -, -S (O) 2 -, and
Z is -C (R 2s ) (R 3s ) -or -N (R 2s ) -;
Ring A is selected from C 3-6 cycloalkyl, 4-to 6-membered heterocyclyl, phenyl and 5-to 10-membered heteroaryl, preferably phenyl or 5-to 9-membered heteroaryl;
R a is selected from H, D, halo, oxo, CN, NO 2 , NH 2 , -C 0-6 alkylene-OH, -C (O) OR x , -C (O) NR y R z , -S (O) NR y R z , -S (O) 2 NR y R z , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl, C 3-6 cycloalkyl, 4-to 6-membered heterocyclyl, phenyl, 5-to 6-membered heteroaryl, and amino protecting group, which is optionally substituted with 1, 2, or 3 halo, oxo, OR x , NR y R z , C 1-6 alkyl, or C 1-6 haloalkyl, and amino protecting group
R 1 is selected from H, D, halo, CN, OR x , NR y R z , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxyl, C 1-6 haloalkoxyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl, C 3-8 cycloalkyl, and 4-to 10-membered heterocyclyl;
R 2 is selected from H, D, halo, CN, -C 0-6 alkylene-OH, -C 0-6 alkylene-NH 2 , -C (O) C 1-6 alkyl, -C (O) C 1-6 haloalkyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxyl, C 1-6 haloalkoxyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl, -T-C 3-8 cycloalkyl, -T-4-to 10-membered heterocyclyl, -T-C 6-10 aryl, and -T-5-to 10-membered heteroaryl, which is optionally substituted with 1, 2, 3, 4 or 5 CN, halo, oxo, -C 1-6 alkylene-OH, C 1-6 alkyl, C 1-6 haloalkyl
T is a chemical bond, -O-, -S-or -NH-;
R 3 is selected from H, D, halo, CN, -C 0-6 alkylene-OH, -C 0-6 alkylene-NH 2 , C 1-6 alkyl, and C 1-6 haloalkyl;
R 4 is selected from H, D, halo, C 1-6 alkyl, and C 1-6 haloalkyl;
R 1 and R 2 together with the carbon atoms to which they connected form C 5-6 cycloalkyl, 5-to 6-membered heterocyclyl, phenyl or 5-to 6-membered heteroaryl, which is optionally substituted with 1, 2, or 3 halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, -C (O) H, -C (O) C 1-6 alkyl, -C (O) C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl, or C 2-6 alkynyl-substituted phenyl, preferably 1, 2, or 3 halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, -C (O) C 1-6 alkyl, -C (O) C 1-6 haloalkyl, C 2-6 alkenyl, C
R 2 and R 3 together with the carbon atoms to which they connected form C 5-6 cycloalkyl, 5-to 7-membered heterocyclyl, phenyl, or 5-to 6-membered heteroaryl, which is optionally substituted with 1, 2, 3, or 4 halo, C 1-6 alkyl, C 1-6 haloalkyl, -C 1-6 alkylene-C 1-6 alkoxyl, -C 1-6 alkylene-C 1-6 haloalkoxyl, -C (O) C 1-6 alkyl, or -C (O) C 1-6 haloalkyl;
R 1s is selected from H, D, -C 0-6 alkylene-OR x , -C 0-6 alkylene-NR y R z , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl, C 3-6 cycloalkyl and phenyl;
R 2s is selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, and C (R 2s1 ) (R 2s2 ) (R 2s3 ) ;
R 2s1 is selected from H, D, -C 0-6 alkylene-OR x , -C 0-6 alkylene-NR y R z , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl, and C 3-6 cycloalkyl;
R 2s2 is selected from H, D, -C 0-6 alkylene-OH, C 1-6 alkyl, and C 1-6 haloalkyl;
R 2s3 is C 1-6 alkyl, or C 1-6 haloalkyl
R 2s1 and R 2s2 together with the carbon atom to which they connected form C 3-6 cycloalkyl
R 2s2 and R 2s3 together with the atom to which they connected form C 3-6 cycloalkyl or 4-to 6-membered heterocyclyl, which is optionally substituted with 1 or 2 halo;
R 2s1 , R 2s2 and R 2s3 together with the atom to which they connected form C 4-8 bridged bicycloalkyl, which is optionally substituted with 1 or 2 halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, and C 2-6 haloalkynyl, or form 4-to 8-membered bridged heterocyclyl;
R 1s and R 2s3 connect to form C 2-6 alkylene, which is optionally substituted with 1, 2, or 3 halo, OR x , NR y R z , C 1-6 alkyl, or C 1-6 haloalkyl;
R 3s is selected from H, D, C 1-6 alkyl, and C 1-6 haloalkyl;
R 2s and R 3s together with the carbon atom to which they connected form C 3-6 cycloalkyl or 4-to 6-membered heterocyclyl, which is optionally substituted with 1 or 2 halo, C 1-6 alkyl or C 1-6 haloalkyl;
R 1s and R 2s together with the nitrogen atom to which they connected form 4-to 6-membered heterocyclyl, which is optionally substituted with 1 or 2 halo, C 1-6 alkyl or C 1-6 haloalkyl;
R 1s , R 2s and R 3s together with the carbon atom to which they connected form C 4-8 bridged bicycloalkyl, which is optionally substituted with 1 or 2 halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, and C 2-6 haloalkynyl, or form
Y 1 is CR 11 or N
Y 2 is CR 12 or N
R 11 , and R 13 are independently selected from H, D, C 1-6 alkyl, and C 1-6 haloalkyl;
R 12 is selected from H, and D;
R x , R y , and R z are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl, C 3-8 cycloalkyl, and 4-to 6-membered heterocyclyl; or R y and R z together with the nitrogen atom to which they connected form 4-to 6-membered heterocyclyl;
the disclosure provides a compound of Formula (I) :
M 1 is selected from CR 1 and N;
M 2 is selected from CR 2 and N;
M 3 is selected from CR 3 and N;
M 4 is selected from CR 4 and N;
L is selected from a chemical bond, -O-, -S-, and -NH-;
Y is selected from -C (O) -, -C (S) -, -C (N-OH) -, -S (O) -, -S (O) 2 -, and
Z is -C (R 2s ) (R 3s ) -or -N (R 2s ) -;
Ring A is selected from phenyl and 5-to 9-membered heteroaryl
R 1 is selected from H, D, halo, OR x , NR y R z , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxyl, C 1-6 haloalkoxyl, C 2- 6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl, C 3-8 cycloalkyl, and 4-to 10-membered heterocyclyl;
R 2 is selected from H, D, halo, CN, -C 0-6 alkylene-OH, -C 0-6 alkylene-NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1- 6 alkoxyl, C 1-6 haloalkoxyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl, -T-C 3-8 cycloalkyl, -T-4-to 10-membered heterocyclyl, -T-C 6-10 aryl, and -T-5-to 10-membered heteroaryl, which is optionally substituted with 1, 2, 3, 4 or 5 CN, halo, oxo, -C 1-6 alkylene-OH, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, or 5-to 6-membered heterocyclyl;
T is a chemical bond, -O-, -S-or -NH-;
R 3 is selected from H, D, halo, CN, -C 0-6 alkylene-OH, -C 0-6 alkylene-NH 2 , C 1-6 alkyl, and C 1-6 haloalkyl;
R 4 is selected from H, D, halo, C 1-6 alkyl, and C 1-6 haloalkyl;
R 1 and R 2 together with the carbon atoms to which they connected form C 5-6 cycloalkyl, 5-to 6-membered heterocyclyl, phenyl or 5-to 6-membered heteroaryl, which is optionally substituted with 1, 2, or 3 halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl, or C 2-6 alkynyl-substituted phenyl;
R 2 and R 3 together with the carbon atoms to which they connected form C 5-6 cycloalkyl, or 5-to 7-membered heterocyclyl, which is optionally substituted with 1, 2, 3, or 4 halo, C 1-6 alkyl, C 1-6 haloalkyl, -C 1-6 alkylene-C 1-6 alkoxyl, -C 1-6 alkylene-C 1-6 haloalkoxyl, -C (O) C 1-6 alkyl, or -C (O) C 1-6 haloalkyl;
R 1s is selected from H, D, -C 0-6 alkylene-OR x , -C 0-6 alkylene-NR y R z , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl, C 3-6 cycloalkyl and phenyl;
R 2s is selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, and C (R 2s1 ) (R 2s2 ) (R 2s3 ) ;
R 2s1 is selected from H, D, -C 0-6 alkylene-OR x , -C 0-6 alkylene-NR y R z , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl, and C 3-6 cycloalkyl;
R 2s2 is selected from H, D, -C 0-6 alkylene-OH, C 1-6 alkyl, and C 1-6 haloalkyl;
R 2s3 is C 1-6 alkyl, or C 1-6 haloalkyl
R 2s2 and R 2s3 together with the atom to which they connected form C 3-6 cycloalkyl or 4-to 6-membered heterocyclyl, which is optionally substituted with 1 or 2 halo;
R 2s1 , R 2s2 and R 2s3 together with the atom to which they connected form C 4-8 bridged bicycloalkyl or 4-to 8-membered bridged heterocyclyl;
R 1s and R 2s3 connect to form C 2-6 alkylene, which is optionally substituted with 1, 2, or 3 halo, OR x , NR y R z , C 1-6 alkyl, or C 1-6 haloalkyl;
R 3s is selected from C 1-6 alkyl, and C 1-6 haloalkyl
R 2s and R 3s together with the carbon atom to which they connected form C 3-6 cycloalkyl or 4-to 6-membered heterocyclyl, which is optionally substituted with 1 or 2 halo, C 1-6 alkyl or C 1-6 haloalkyl;
R 1s and R 2s together with the nitrogen atom to which they connected form 4-to 6-membered heterocyclyl, which is optionally substituted with 1 or 2 halo, C 1-6 alkyl or C 1-6 haloalkyl;
R 1s , R 2s and R 3s together with the carbon atom to which they connected form C 4-8 bridged bicycloalkyl or
Y 1 is CR 11 or N
Y 2 is CR 12 or N
R 11 , and R 13 are independently selected from H, D, C 1-6 alkyl, and C 1-6 haloalkyl;
R 12 is selected from H, and D;
R x , R y , and R z are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl, C 3-8 cycloalkyl, and 4-to 6-membered heterocyclyl; or R y and R z together with the nitrogen atom to which they connected form 4-to 6-membered heterocyclyl;
the disclosure provides a pharmaceutical composition, comprising: the compound, or the pharmaceutical acceptable salt, the stereoisomer, the tautomer, the stable isotopic variant, the prodrug, or the crystal form thereof described herein; pharmaceutically acceptable excipient (s) ; and optionally, one or more other therapeutic agents.
the disclosure provides a kit, comprising: a first container which contains the compound, or the pharmaceutical acceptable salt, the stereoisomer, the tautomer, the stable isotopic variant, the prodrug, or the crystal form thereof described herein; and optionally, a second container which contains one or more other therapeutic agents; and optionally, a third container which contains pharmaceutically acceptable excipient (s) for diluting or suspending the said compound and/or other therapeutic agent (s) .
the disclosure provides use of a compound, or a pharmaceutical acceptable salt, a stereoisomer, a tautomer, a stable isotopic variant, a prodrug, or a crystal form thereof described herein, in the manufacture of a medicament for treating an immune and/or inflammatory disease, disorder, or condition related by excessive or inappropriate ALPK1-dependent proinflammatory signaling
the disclosure provides the compound, or a pharmaceutical acceptable salt, a stereoisomer, a tautomer, a stable isotopic variant, a prodrug, or a crystal form thereof described herein, for use in treating an immune and/or inflammatory disease, disorder, or condition related by excessive or inappropriate ALPK1-dependent proinflammatory signaling
the disclosure provides a method of treating an immune and/or inflammatory related disease, disorder, or condition by excessive or inappropriate ALPK1-dependent proinflammatory signaling in a subject in need thereof, comprising administering to the subject a compound, or a pharmaceutical acceptable salt, a stereoisomer, a tautomer, a stable isotopic variant, a prodrug, or a crystal form thereof described herein.
the disease, disorder, or condition is selected from sepsis, cancer (including lung cancer, colon cancer, and oral squamous cancer) , systemic lupus erythematosus, spiroandenoma, spiroandenocarcinoma, Kawasaki disease, ROSAH (Retinal dystrophy, Optic nerve edema, Splenomegaly, Anhidrosis and migraine Headache) syndrome, and PFAPA (Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis) syndrome.
cancer including lung cancer, colon cancer, and oral squamous cancer
systemic lupus erythematosus e.g., spiroandenoma
spiroandenocarcinoma Kawasaki disease
ROSAH Retinal dystrophy
Optic nerve edema Optic nerve edema
Splenomegaly Splenomegaly
C 1-6 alkyl is intended to include C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2- 4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 and C 5-6 alkyl.
C 1-6 alkyl refers to a radical of a straight or branched, saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, C 1-4 alkyl is preferred. Examples of C 1-6 alkyl include methyl (C 1 ) , ethyl (C 2 ) , n-propyl (C 3 ) , iso-propyl (C 3 ) , n-butyl (C 4 ) , tert-butyl (C 4 ) , sec-butyl (C 4 ) , iso-butyl (C 4 ) , n-pentyl (C 5 ) , 3-pentyl (C 5 ) , pentyl (C 5 ) , neopentyl (C 5 ) , 3-methyl-2-butyl (C 5 ) , tert-pentyl (C 5 ) and n-hexyl (C 6 ) .
C 1-6 alkyl also includes heteroalkyl, wherein one or more (e.g., 1, 2, 3 or 4) carbon atoms are subsituted with heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) .
Alkyl groups can be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents or 1 substituent.
alkyl examples include Me (-CH 3 ) , Et (-CH 2 CH 3 ) , iPr (-CH (CH 3 ) 2 ) , nPr (-CH 2 CH 2 CH 3 ) , n-Bu (-CH 2 CH 2 CH 2 CH 3 ) or i-Bu (-CH 2 CH (CH 3 ) 2 ) .
C 2-6 alkenyl refers to a radical of a straight or branched hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 2-4 alkenyl is preferred. Examples of C 2- 6 alkenyl include vinyl (C 2 ) , 1-propenyl (C 3 ) , 2-propenyl (C 3 ) , 1-butenyl (C 4 ) , 2-butenyl (C 4 ) , butadienyl (C 4 ) , pentenyl (C 5 ) , pentadienyl (C 5 ) , hexenyl (C 6 ) , etc.
C 2-6 alkenyl also includes heteroalkenyl, wherein one or more (e.g., 1, 2, 3 or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) .
the alkenyl groups can be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents or 1 substituent.
C 2-6 alkynyl refers to a radical of a straight or branched hydrocarbon group having 2 to 6 carbon atoms, at least one carbon-carbon triple bond and optionally one or more carbon-carbon double bonds. In some embodiments, C 2-4 alkynyl is preferred. Examples of C 2-6 alkynyl include, but are not limited to, ethynyl (C 2 ) , 1-propynyl (C 3 ) , 2-propynyl (C 3 ) , 1-butynyl (C 4 ) , 2-butynyl (C 4 ) , pentynyl (C 5 ) , hexynyl (C 6 ) , etc.
C 2-6 alkynyl also includes heteroalkynyl, wherein one or more (e.g., 1, 2, 3 or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) .
the alkynyl groups can be substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents or 1 substituent.
C 1-6 alkylene refers to a divalent group of the “C 1-6 alkyl” as defined above. Particularly, “C 1-6 alkylene” refers to a divalent group formed by removing another hydrogen of the C 1-6 alkyl, and can be a substituted or unsubstituted alkylene. In some embodiments, C 2-6 alkylene, C 1-4 alkylene, and C 2-3 alkylene are particularly preferred.
the unsubstituted alkylene groups include, but are not limited to, methylene (-CH 2 -) , ethylene (-CH 2 CH 2 -) , propylene (-CH 2 CH 2 CH 2 -) , butylene (-CH 2 CH 2 CH 2 CH 2 -) , pentylene (-CH 2 CH 2 CH 2 CH 2 CH 2 -) , hexylene (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -) , etc.
substituted alkylene groups such as those substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted methylene (-CH (CH 3 ) -, -C (CH 3 ) 2 -) , substituted ethylene (-CH (CH 3 ) CH 2 -, -CH 2 CH (CH 3 ) -, -C (CH 3 ) 2 CH 2 -, -CH 2 C (CH 3 ) 2 -) , substituted propylene (-CH (CH 3 ) CH 2 CH 2 -, -CH 2 CH (CH 3 ) CH 2 -, -CH 2 CH 2 CH (CH 3 ) -, -C (CH 3 ) 2 CH 2 CH 2 -, -CH 2 C (CH 3 ) 2 CH 2 -, -CH 2 CH 2 C (CH 3 ) 2 -) , etc.
C 0-6 alkylene includes chemical bond and “C 1-6 alkylene” .
C 0-4 alkylene includes chemical bond and “C 1-4 alkylene” .
Halo or "halogen” refers to fluorine (F) , chlorine (Cl) , bromine (Br) and iodine (I) .
C 1-6 haloalkyl represents the “C 1-6 alkyl” described above, which is substituted with one or more halogen groups. Examples include the mono-, di-, poly-halogenated, including perhalogenated, alkyl. A monohalogen substituent may have one iodine, bromine, chlorine or fluorine atom in the group; a dihalogen substituent and a polyhalogen substituent may have two or more identical halogen atoms or a combination of different halogens. In some embodiments, C 1-4 haloalkyl is particularly preferred.
haloalkyl groups examples include monofluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.
the haloalkyl groups can be substituted at any available point of attachment, for example, with 1 to 5 substituents, 1 to 3 substituents or 1 substituent.
C 2-6 haloalkenyl and “C 2-4 haloalkenyl” represents the “C 2-6 alkenyl” and “C 2-4 alkenyl” described above, which is substituted with one or more halogen groups.
C 2-6 haloalkynyl and “C 2-4 haloalkynyl” represents the “C 2-6 alkynyl” and “C 2-4 alkynyl” described above, which is substituted with one or more halogen groups.
C 1-6 alkoxy refers to an -O-C 1-6 alkyl radical
C 1-4 alkoxy refers to an -O-C 1-4 alkyl radical, (e.g., -OCH 3 )
C 1-6 haloalkoxy refers to an -O-C 1-6 haloalkyl radical
C 1-4 haloalkoxy refers to an -O-C 1-4 haloalkyl radical, (e.g., -OCF 3 ) .
C 3-8 cycloalkyl refers to a radical of non-aromatic cyclic hydrocarbon group having 3 to 8 ring carbon atoms and zero heteroatoms.
the term cycloalkyl may include one or more double or triple bonds, as long as it is non-aromatic.
C 3-6 cycloalkyl is particularly preferred.
C 5- 6 cycloalkyl is particularly preferred.
C 4-6 cycloalkyl is particularly preferred.
C 3-5 cycloalkyl is particularly preferred.
C 3-4 cycloalkyl is particularly preferred.
the cycloalkyl also includes a ring system in which the cycloalkyl described herein is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring, and in such case, the number of carbon atoms continues to represent the number of carbon atoms in the cycloalkyl system.
the cycloalkyl can be substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents or 1 substituent.
Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl (C 3 ) , cyclopropenyl (C 3 ) , cyclobutyl (C 4 ) , cyclobutenyl (C 4 ) , cyclopentyl (C 5 ) , cyclopentenyl (C 5 ) , cyclohexyl (C 6 ) , cyclohexenyl (C 6 ) , cyclohexadienyl (C 6 ) , cycloheptyl (C 7 ) , cycloheptenyl (C 7 ) , cycloheptadienyl (C 7 ) , cycloheptatrienyl (C 7 ) , etc.
cycloalkyl groups further include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
Cycloalkyl may include multiple fused and/or bridged rings.
Non-limiting examples of fused/bridged cycloalkyl includes C 4-8 bridged bicycloalkyl, for example bicyclo [1.1.0] butanyl, bicyclo [2.1.0] pentanyl, bicyclo [1.1.1] pentanyl, bicyclo [3.1.0] hexanyl, bicyclo [2.1.1] hexanyl, bicyclo [3.2.0] heptanyl, bicyclo [4.1.0] heptanyl, bicyclo [2.2.1] heptanyl, bicyclo [3.1.1] heptanyl, bicyclo [4.2.0] octanyl, bicyclo [3.2.1] octanyl, bicyclo [2.2.2] octanyl, and the like.
Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom) .
spirocyclic cycloalkyls include spiro [2.2] pentanyl, spiro [2.5] octanyl, spiro [3.5] nonanyl, spiro [3.5] nonanyl, spiro [3.5] nonanyl, spiro [4.4] nonanyl, spiro [2.6] nonanyl, spiro [4.5] decanyl, spiro [3.6] decanyl, spiro [5.5] undecanyl, and the like.
4-to 10-membered heterocyclyl refers to a radical of 4-to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms, wherein each of the heteroatoms is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon.
the point of attachment can be a carbon or nitrogen atom as long as the valence permits.
the term heterocyclyl may include one or more double or triple bonds, as long as it is non-aromatic.
5-to 10-membered heterocyclyl is preferred, which is a radical of 5-to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms.
5-to 7-membered heterocyclyl is preferred, which is a radical of 5-to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms.
5-to 6-membered heterocyclyl is more preferred, which is a radical of 5-to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms.
4-to 6-membered heterocyclyl is preferred, which is a radical of 4-to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms.
the heterocyclyl also includes a ring system wherein the heterocyclyl described above is fused with one or more cycloalkyl groups, wherein the point of attachment is on the cycloalkyl ring, or the heterocyclyl described above is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring; and in such cases, the number of ring members continues to represent the number of ring members in the heterocyclyl ring system.
Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl and thiorenyl.
Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl and thietanyl.
Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2, 5-dione.
Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one.
Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidyl, tetrahydropyranyl, dihydropyridyl and thianyl.
Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl and dioxanyl.
Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazinanyl.
Exemplary 7-membered heterocycly groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl and thiepanyl.
Exemplary 5-membered heterocyclyl groups fused with a C 6 aryl include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinonyl, etc.
Exemplary 6-membered heterocyclyl groups fused with a C 6 aryl include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.
the heterocyclyl can be substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents or 1 substituent.
heterocyclyl groups include, pyrrolinyl, imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, dihydropyranyl, dihydrofuranyl, thiazolidinyl, dihydrothiazolyl, 2, 3-dihydro-benzo [l, 4] dioxol, indolinyl, isoindolinyl, dihydrobenzothiophene, dihydrobenzofuranyl, isodihydrobenzopyranyl, dihydrobenzopyranyl, 1, 2-dihydroisoquinoline, 1, 2, 3, 4-tetrahydroisoquinoline, 1, 2, 3, 4-tetrahydroquinoline, 2, 3, 4, 4a, 9, 9a-hexahydro-1H-3-azafluorene, 5, 6, 7-trihydro-1, 2, 4-triazolo [3, 4-a] isoquinolyl, 3, 4-dihydro-2H-benzo [l, 4] oxol,
heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like.
Heterocyclyl may include multiple fused and bridged rings.
Non-limiting examples of fused/bridged heteorocyclyl includes: 2-azabicyclo [1.1.0] butanyl, 2-azabicyclo [2.1.0] pentanyl, 2-azabicyclo [1.1.1] pentanyl, 3-azabicyclo [3.1.0] hexanyl, 5-azabicyclo [2.1.1] hexanyl, 3-azabicyclo [3.2.0] heptanyl, octahydrocyclopenta [c] pyrrolyl, 3-azabicyclo [4.1.0] heptanyl, 7-azabicyclo [2.2.1] heptanyl, 6-azabicyclo [3.1.1] heptanyl, 7-azabicyclo [4.2.0] octanyl, 2-azabicyclo [2.2.2] octanyl, 3-azabicyclo [3.2.1] octanyl, 2-oxabicyclo [1.1.0] butanyl, 2-oxabicyclo [2.1.0] pentanyl, 2-ox
Heterocyclyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom) .
spirocyclic heterocyclyls include 2-azaspiro [2.2] pentanyl, 4-azaspiro [2.5] octanyl, 1-azaspiro [3.5] nonanyl, 2-azaspiro [3.5] nonanyl, 7-azaspiro [3.5] nonanyl, 2-azaspiro [4.4] nonanyl, 6-azaspiro [2.6] nonanyl, 1, 7-diazaspiro [4.5] decanyl, 7-azaspiro [4.5] decanyl, 2, 5-diazaspiro [3.6] decanyl, 3-azaspiro [5.5] undecanyl, 2-oxaspiro [2.2] pentanyl, 4-oxaspiro [2.5] octanyl, 1-oxaspiro [3.5] nonanyl, 2-ox
C 6-10 aryl refers to a radical of monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system having 6-10 ring carbon atoms and zero heteroatoms (e.g., having 6 or 10 shared ⁇ electrons in a cyclic array) .
the aryl group has six ring carbon atoms ( “C 6 aryl” ; for example, phenyl) .
the aryl group has ten ring carbon atoms ( "C 10 aryl” ; for example, naphthyl, e.g., 1-naphthyl and 2-naphthyl) .
the aryl group also includes a ring system in which the aryl ring described above is fused with one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system.
the aryl can be substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents or 1 substituent.
5-to 10-membered heteroaryl refers to a radical of 5-to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 shared ⁇ electrons in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur.
the point of attachment can be a carbon or nitrogen atom as long as the valence permits.
Heteroaryl bicyclic systems may include one or more heteroatoms in one or two rings.
Heteroaryl also includes ring systems wherein the heteroaryl ring described above is fused with one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring. In such case, the number the carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system.
5-to 9-membered heteroaryl groups are particularly preferred, which are radicals of 5-to 9-membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms.
5-to 6-membered heteroaryl groups are particularly preferred, which are radicals of 5-to 6-membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms.
5-membered heteroaryl group is particularly preferred, which is a radical of 5-membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms.
Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furyl and thienyl.
Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl (such as, 1, 2, 4-oxadiazoly) , and thiadiazolyl.
Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl.
Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridyl.
Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl.
Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively.
Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl.
Exemplary 5, 6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl , benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolizinyl and purinyl.
Exemplary 6, 6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolyl, isoquinolyl, cinnolinyl, quinoxalinyl, phthalazinyl and quinazolinyl.
the heteroaryl can be substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents or 1 substituent.
heteroaryl groups include: pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (4H-l, 2, 4-triazolyl, 1H-1, 2, 3-triazolyl, 2H-1, 2, 3-triazolyl, pyranyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, oxazolyl, isoxazolyl, oxazolyl (1, 2, 4-oxazolyl, 1, 3, 4-oxazolyl, 1, 2, 5-oxazolyl, thiazolyl, thiadiazolyl (1, 2, 4-thiadiazolyl, 1, 3, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl) .
heteroaryl examples include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido [2, 3-d] pyrimidinyl, pyrrolo [2, 3-b] pyridinyl, quinazolinyl
the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl.
a ring when a ring is described as being “aromatic” , it means said ring has a continuous, delocalized ⁇ -electron system. Typically, the number of out of plane ⁇ -electrons corresponds to the Hückel rule (4n+2) .
rings and cyclic groups e.g., aryl, heteroaryl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, cycloalkyl, and the like described herein
rings and cyclic groups encompass those having fused rings, including those in which the points of fusion are located (i) on adjacent ring atoms (e.g., [x. x.
0 ring systems, in which 0 represents a zero atom bridge (e.g., ) ) ; (ii) a single ring atom (spiro-fused ring systems) (e.g., ) , or (iii) a contiguous array of ring atoms (bridged ring systems having all bridge lengths > 0) (e.g., ) .
atoms making up the compounds of the present embodiments are intended to include all isotopic forms of such atoms.
Isotopes include those atoms having the same atomic number but different mass numbers.
isotopes of hydrogen include tritium and deuterium
isotopes of carbon include 13 C and 14 C.
a compound containing the moiety encompasses the tautomeric form containing the moiety:
a pyridinyl or pyrimidinyl moiety that is described to be optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms.
amino protecting groups are used to prevent amino groups from undergoing undesired reactions.
suitable protecting groups for specific functional groups as well as suitable conditions for protecting and deprotecting are well known in the art. For example, numerous protecting groups and their introduction and removal are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991 and references cited therein.
Exemplary amino protecting agent is selected from Cbz, Boc, Fmoc, Alloc, and Teoc.
Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl as defined herein are optionally substituted groups.
each of the R aa is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two of the R aa groups are combined to form a heterocyclyl or heteroaryl ring, wherein each of the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R dd groups;
each of the R cc is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R cc groups are combined to form a heterocyclyl or a heteroaryl ring, wherein each of the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R dd groups;
each of the R ee is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl, and heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R gg groups;
each of the R ff is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl, or two R ff groups are combined to form a heterocyclyl or a heteroaryl ring, wherein each of the alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R gg groups;
the disclosure provides compounds that are the inhibitors of ALPK1, compositions comprising same, and methods for their use in therapy.
APK1 is used herein to refer interchangeably to isoform 1 (Q96QP1-1) or the alternative splice variant isoform 2 (Q96QP1-2) of the human sequence identified by UniProtKB-Q96QP1 (ALPK1_HUMAN) .
the “immunotherapy agent” or “immune modulator” refers to a small molecule drug, antibody, or other biologic molecules.
the modulator is used to inhibit an inhibitory immune receptor signal on T-cells, and/or other immune cells, such as dendritic cells.
the modulator is used to enhance and/or stimulate a co-stimulatory immune receptor signal on T-cells, and/or other immune cells, such as dendritic cells.
the biologic immune modulator includes, but is not limited to, cancer vaccines, antibodies, and cytokines.
the antibody is a monoclonal antibody. In another aspect, the monoclonal antibody is humanized.
treat, ” “treating, ” and “treatment, ” in the context of treating a disease, disorder, or condition are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or slowing the progression, spread or worsening of a disease, disorder or condition or of one or more symptoms thereof.
beneficial effects that a subject derives from a therapeutic agent do not result in a complete cure of the disease, disorder or condition.
the terms “treat, ” “treating, ” and “treatment, ” include virologically curing a viral disorder, disease, or condition; reducing viral shedding; decreasing viral RNA load (e.g., a measured by PCR) ; reducing the length of stay in a hospital; reducing the length of stay in an infectious disease unit and/or intensive care unit; or slowing (including stopping) the progression/development of respiratory (or other serious) symptoms.
the “treatment of cancer” refers to one or more of the following effects: (1) inhibition, to some extent, of tumor growth, including, (i) slowing down and (ii) complete growth arrest; (2) reduction in the number of tumor cells; (3) maintaining tumor size; (4) reduction in tumor size; (5) inhibition, including (i) reduction, (ii) slowing down or (iii) complete prevention, of tumor cell infiltration into peripheral organs; (6) inhibition, including (i) reduction, (ii) slowing down or (iii) complete prevention, of metastasis; (7) enhancement of anti-tumor immune response, which may result in (i) maintaining tumor size, (ii) reducing tumor size, (iii) slowing the growth of a tumor, (iv) reducing, slowing or preventing invasion and/or (8) relief, to some extent, of the severity or number of one or more symptoms associated with the disorder.
therapeutically effective amount refers to the amount of a drug or other pharmaceutical agent (e.g., a compound disclosed herein) , that will elicit the biological and/or medical response of a tissue, system, animal or human (e.g., subject or patient) that is being sought, for instance, by a researcher or clinician.
therapeutically effective amount means any amount, as compared to a corresponding subject (e.g., patient) who has not received such amount, which is sufficient to decrease the rate of advancement of, prevent development of, or alleviate to some extent, one or more of the symptoms of the condition or disorder being treated.
the therapeutically effective amount will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
the therapeutically effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route.
the term “subject or patient” used interchangeably herein refers to an animal, including, but not limited to, a primate (e.g., human) , monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse.
the subject is a human to be treated by the methods and compositions of the present disclosure.
the methods described herein further include the step of identifying a subject (e.g., a patient) in need of such treatment (e.g., by way of biopsy, endoscopy, or other conventional method known in the art) .
the chemical entities, methods, and compositions described herein can be administered to certain treatment-resistant patient populations (e.g., patients resistant to checkpoint inhibitors; e.g., patients having one or more cold tumors, e.g., tumors lacking T-cells or exhausted T-cells) .
certain treatment-resistant patient populations e.g., patients resistant to checkpoint inhibitors; e.g., patients having one or more cold tumors, e.g., tumors lacking T-cells or exhausted T-cells.
the term “vaccine” refers to a biological preparation administered to a human or animal in order to elicit or enhance a specific immune response and/or protection against one or more antigens in that human or animal.
the vaccine is a cancer vaccine against one or more antigens of cancer cell.
adjuvant refers to a secondary therapeutic substance that is administered together (either sequentially in any order, or concurrently) with a primary therapeutic substance to achieve some kind of complimentary, synergic or otherwise beneficial effect that could not be achieved through use of the primary therapeutic substance alone.
An adjuvant can be used together with a vaccine, chemotherapy, or some other therapeutic substance.
Adjuvants can enhance the efficacy of the primary therapeutic substance, reduce the toxicity or side effects of the primary therapeutic substance, or provide some kind of protection to the subject that receives the primary therapeutic substance, such as, but not limited to, improved functioning of the immune system.
cancer refers to the physiological condition in subjects that is characterized by unregulated or dysregulated cell growth or death.
cancer includes solid tumors and blood-born tumors, whether malignant or benign.
API refers to an active pharmaceutical ingredient.
excipient or “pharmaceutically acceptable excipient” means a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material.
each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
pharmaceutically acceptable salt refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound.
pharmaceutically acceptable salts are obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
pharmaceutically acceptable salts are obtained by reacting a compound having acidic group described herein with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris (hydroxymethyl) methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined.
a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris (hydroxymethyl) methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously
Examples of a salt that the compounds described hereinform with a base include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts thereof with organic bases such as methylamine, ethylamine and ethanolamine; salts thereof with basic amino acids such as lysine and ornithine; and ammonium salt.
the salts may be acid addition salts, which are specifically exemplified by acid addition salts with the following: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid: organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid.
mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid
organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric
Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers.
the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer (such as cis-and trans-isomer) , or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses.
HPLC high pressure liquid chromatography
prodrugs are also included within the context of the present disclosure.
the term "prodrug” as used herein refers to a compound which is converted in vivo to an active form thereof having a medical effect by, for example, hydrolysis in blood.
Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, A.C.S. Symposium Series, Vol. 14, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon and H. Barbra “Improved oral drug delivery: solubility limitations overcome by the use of prodrugs” , Advanced Drug Delivery Reviews (1996) 19 (2) 115-130, each is incorporated herein by reference.
a prodrug is any covalently bonded carrier which, when administered to a patient, releases the compound of formula (I) in vivo.
Prodrugs are typically prepared by modifying functional groups in such a way that the modifications can be cleaved by routine manipulation or in vivo to yield the parent compound.
Prodrugs include, for example, compounds disclosed herein wherein a hydroxy, amine or sulfhydryl group is bonded to any group which, when administered to a patient, can be cleaved to form a hydroxy, amine or sulfhydryl group.
prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol, mercapto and amine functional groups of the compounds of formula (I) .
an ester such as a methyl ester, an ethyl ester or the like can be used.
the ester itself may be active and/or may hydrolyze under conditions in human bodies.
Suitable pharmaceutically acceptable hydrolysable in vivo ester groups include those groups which readily decompose in the human body to release the parent acid or a salt thereof.
An isotope derivative of a compound disclosed herein is defined as wherein at least one atom is replaced by an atom having the same atomic number but differing in atomic mass from the atomic mass typically found in nature.
isotopes that can be listed as compounds disclosed herein include hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine isotopes, such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 18 F, 31 P, 32 P, 35 S and 36 Cl, respectively.
isotopical derivertives of the compounds disclosed herein are also among them and are useful in the tissue distribution experiments of drugs and substrates.
Tritium, i.e., 3 H, and carbon-14, i.e., 14 C are easier to prepare and detect and are the first choice for isotopes.
substitution with isotopes such as deuterium, i.e., 2 H has advantages in some therapies due to its good metabolic stability, for example, increased half-life in vivo or reduced dosage, and thus priority may be given in some cases.
Isotopical derivertives of the compounds disclosed herein can be prepared by conventional procedures, for example by descriptive methods or by the preparations described in the Examples below, using appropriate isotopic derivatives of the appropriate reagents.
stable isotope refers to those exist stably in nature.
composition refers to a mixture of a compound described herein with other chemical components (referred to collectively herein as “excipients” ) , such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and/or thickening agents.
excipients such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and/or thickening agents.
the pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to: rectal, oral, intravenous, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.
the disclosure provides compounds represented by formula (I) and a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a stable isotopic variant, a prodrug, or a crystal form thereof:
M 1 is selected from CR 1 and N;
M 2 is selected from CR 2 and N;
M 3 is selected from CR 3 and N;
M 4 is selected from CR 4 and N;
L is selected from a chemical bond, -O-, -S-, and -NH-;
Y is selected from -C (O) -, -C (S) -, -C (N-OH) -, -S (O) -, -S (O) 2 -, and
Z is -C (R 2s ) (R 3s ) -or -N (R 2s ) -;
Ring A is selected from C 3-6 cycloalkyl, 4-to 6-membered heterocyclyl, phenyl and 5-to 10-membered heteroaryl, preferably phenyl or 5-to 9-membered heteroaryl;
R a is selected from H, D, halo, oxo, CN, NO 2 , NH 2 , -C 0-6 alkylene-OH, -C (O) OR x , -C (O) NR y R z , -S (O) NR y R z , -S (O) 2 NR y R z , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl, C 3-6 cycloalkyl, 4-to 6-membered heterocyclyl, phenyl, 5-to 6-membered heteroaryl, and amino protecting group, which is optionally substituted with 1, 2, or 3 halo, oxo, OR x , NR y R z , C 1-6 alkyl, or C 1-6 haloalkyl, and amino protecting group
R 1 is selected from H, D, halo, CN, OR x , NR y R z , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxyl, C 1-6 haloalkoxyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl, C 3-8 cycloalkyl, and 4-to 10-membered heterocyclyl;
R 2 is selected from H, D, halo, CN, -C 0-6 alkylene-OH, -C 0-6 alkylene-NH 2 , -C (O) C 1-6 alkyl, -C (O) C 1-6 haloalkyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxyl, C 1-6 haloalkoxyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl, -T-C 3-8 cycloalkyl, -T-4-to 10-membered heterocyclyl, -T-C 6-10 aryl, and -T-5-to 10-membered heteroaryl, which is optionally substituted with 1, 2, 3, 4 or 5 CN, halo, oxo, -C 1-6 alkylene-OH, C 1-6 alkyl, C 1-6 haloalkyl
T is a chemical bond, -O-, -S-or -NH-;
R 3 is selected from H, D, halo, CN, -C 0-6 alkylene-OH, -C 0-6 alkylene-NH 2 , C 1-6 alkyl, and C 1-6 haloalkyl;
R 4 is selected from H, D, halo, C 1-6 alkyl, and C 1-6 haloalkyl;
R 1 and R 2 together with the carbon atoms to which they connected form C 5-6 cycloalkyl, 5-to 6-membered heterocyclyl, phenyl or 5-to 6-membered heteroaryl, which is optionally substituted with 1, 2, or 3 halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, -C (O) H, -C (O) C 1-6 alkyl, -C (O) C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl, or C 2-6 alkynyl-substituted phenyl, preferably 1, 2, or 3 halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, -C (O) C 1-6 alkyl, -C (O) C 1-6 haloalkyl, C 2-6 alkenyl, C
R 2 and R 3 together with the carbon atoms to which they connected form C 5-6 cycloalkyl, 5-to 7-membered heterocyclyl, phenyl, or 5-to 6-membered heteroaryl, which is optionally substituted with 1, 2, 3, or 4 halo, C 1-6 alkyl, C 1-6 haloalkyl, -C 1-6 alkylene-C 1-6 alkoxyl, -C 1-6 alkylene-C 1-6 haloalkoxyl, -C (O) C 1-6 alkyl, or -C (O) C 1-6 haloalkyl;
R 1s is selected from H, D, -C 0-6 alkylene-OR x , -C 0-6 alkylene-NR y R z , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl, C 3-6 cycloalkyl and phenyl;
R 2s is selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, and C (R 2s1 ) (R 2s2 ) (R 2s3 ) ;
R 2s1 is selected from H, D, -C 0-6 alkylene-OR x , -C 0-6 alkylene-NR y R z , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl, and C 3-6 cycloalkyl;
R 2s2 is selected from H, D, -C 0-6 alkylene-OH, C 1-6 alkyl, and C 1-6 haloalkyl;
R 2s3 is C 1-6 alkyl, or C 1-6 haloalkyl
R 2s1 and R 2s2 together with the carbon atom to which they connected form C 3-6 cycloalkyl
R 2s2 and R 2s3 together with the atom to which they connected form C 3-6 cycloalkyl or 4-to 6-membered heterocyclyl, which is optionally substituted with 1 or 2 halo;
R 2s1 , R 2s2 and R 2s3 together with the atom to which they connected form C 4-8 bridged bicycloalkyl, which is optionally substituted with 1 or 2 halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, and C 2-6 haloalkynyl, or form 4-to 8-membered bridged heterocyclyl;
R 1s and R 2s3 connect to form C 2-6 alkylene, which is optionally substituted with 1, 2, or 3 halo, OR x , NR y R z , C 1-6 alkyl, or C 1-6 haloalkyl;
R 3s is selected from H, D, C 1-6 alkyl, and C 1-6 haloalkyl;
R 2s and R 3s together with the carbon atom to which they connected form C 3-6 cycloalkyl or 4-to 6-membered heterocyclyl, which is optionally substituted with 1 or 2 halo, C 1-6 alkyl or C 1-6 haloalkyl;
R 1s and R 2s together with the nitrogen atom to which they connected form 4-to 6-membered heterocyclyl, which is optionally substituted with 1 or 2 halo, C 1-6 alkyl or C 1-6 haloalkyl;
R 1s , R 2s and R 3s together with the carbon atom to which they connected form C 4-8 bridged bicycloalkyl, which is optionally substituted with 1 or 2 halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, and C 2-6 haloalkynyl, or form
Y 1 is CR 11 or N
Y 2 is CR 12 or N
R 11 , and R 13 are independently selected from H, D, C 1-6 alkyl, and C 1-6 haloalkyl;
R 12 is selected from H, and D;
R x , R y , and R z are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl, C 3-8 cycloalkyl, and 4-to 6-membered heterocyclyl; or R y and R z together with the nitrogen atom to which they connected form 4-to 6-membered heterocyclyl;
the disclosure further provides compounds represented by formula (I) and a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a stable isotopic variant, a prodrug, or a crystal form thereof:
M 1 is selected from CR 1 and N;
M 2 is selected from CR 2 and N;
M 3 is selected from CR 3 and N;
M 4 is selected from CR 4 and N;
L is selected from a chemical bond, -O-, -S-, and -NH-;
Y is selected from -C (O) -, -C (S) -, -C (N-OH) -, -S (O) -, -S (O) 2 -, and
Z is -C (R 2s ) (R 3s ) -or -N (R 2s ) -;
Ring A is selected from phenyl and 5-to 9-membered heteroaryl
R 1 is selected from H, D, halo, OR x , NR y R z , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxyl, C 1-6 haloalkoxyl, C 2- 6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl, C 3-8 cycloalkyl, and 4-to 10-membered heterocyclyl;
R 2 is selected from H, D, halo, CN, -C 0-6 alkylene-OH, -C 0-6 alkylene-NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1- 6 alkoxyl, C 1-6 haloalkoxyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl, -T-C 3-8 cycloalkyl, -T-4-to 10-membered heterocyclyl, -T-C 6-10 aryl, and -T-5-to 10-membered heteroaryl, which is optionally substituted with 1, 2, 3, 4 or 5 CN, halo, oxo, -C 1-6 alkylene-OH, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, or 5-to 6-membered heterocyclyl;
T is a chemical bond, -O-, -S-or -NH-;
R 3 is selected from H, D, halo, CN, -C 0-6 alkylene-OH, -C 0-6 alkylene-NH 2 , C 1-6 alkyl, and C 1-6 haloalkyl;
R 4 is selected from H, D, halo, C 1-6 alkyl, and C 1-6 haloalkyl;
R 1 and R 2 together with the carbon atoms to which they connected form C 5-6 cycloalkyl, 5-to 6-membered heterocyclyl, phenyl or 5-to 6-membered heteroaryl, which is optionally substituted with 1, 2, or 3 halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl, or C 2-6 alkynyl-substituted phenyl;
R 2 and R 3 together with the carbon atoms to which they connected form C 5-6 cycloalkyl, or 5-to 7-membered heterocyclyl, which is optionally substituted with 1, 2, 3, or 4 halo, C 1-6 alkyl, C 1-6 haloalkyl, -C 1-6 alkylene-C 1-6 alkoxyl, -C 1-6 alkylene-C 1-6 haloalkoxyl, -C (O) C 1-6 alkyl, or -C (O) C 1-6 haloalkyl;
R 1s is selected from H, D, -C 0-6 alkylene-OR x , -C 0-6 alkylene-NR y R z , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl, C 3-6 cycloalkyl and phenyl;
R 2s is selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, and C (R 2s1 ) (R 2s2 ) (R 2s3 ) ;
R 2s1 is selected from H, D, -C 0-6 alkylene-OR x , -C 0-6 alkylene-NR y R z , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl, and C 3-6 cycloalkyl;
R 2s2 is selected from H, D, -C 0-6 alkylene-OH, C 1-6 alkyl, and C 1-6 haloalkyl;
R 2s3 is C 1-6 alkyl, or C 1-6 haloalkyl
R 2s2 and R 2s3 together with the atom to which they connected form C 3-6 cycloalkyl or 4-to 6- membered heterocyclyl, which is optionally substituted with 1 or 2 halo;
R 2s1 , R 2s2 and R 2s3 together with the atom to which they connected form C 4-8 bridged bicycloalkyl or 4-to 8-membered bridged heterocyclyl;
R 1s and R 2s3 connect to form C 2-6 alkylene, which is optionally substituted with 1, 2, or 3 halo, OR x , NR y R z , C 1-6 alkyl, or C 1-6 haloalkyl;
R 3s is selected from C 1-6 alkyl, and C 1-6 haloalkyl
R 2s and R 3s together with the carbon atom to which they connected form C 3-6 cycloalkyl or 4-to 6-membered heterocyclyl, which is optionally substituted with 1 or 2 halo, C 1-6 alkyl or C 1-6 haloalkyl;
R 1s and R 2s together with the nitrogen atom to which they connected form 4-to 6-membered heterocyclyl, which is optionally substituted with 1 or 2 halo, C 1-6 alkyl or C 1-6 haloalkyl;
R 1s , R 2s and R 3s together with the carbon atom to which they connected form C 4-8 bridged bicycloalkyl or
Y 1 is CR 11 or N
Y 2 is CR 12 or N
R 11 , and R 13 are independently selected from H, D, C 1-6 alkyl, and C 1-6 haloalkyl;
R 12 is selected from H, and D;
R x , R y , and R z are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl, C 3-8 cycloalkyl, and 4-to 6-membered heterocyclyl; or R y and R z together with the nitrogen atom to which they connected form 4-to 6-membered heterocyclyl;
M 1 is CR 1 ; and in some embodiments, M 1 is N.
M 2 is CR 2 ; and in some embodiments, M 2 is N.
M 3 is CR 3 ; and in some embodiments, M 3 is N.
M 4 is CR 4 ; and in some embodiments, M 4 is N.
L is a chemical bond; in some embodiments, L is -O-; in some embodiments, L is -S-; and in some embodiments, L is -NH-.
Y is -C (O) -; in some embodiments, Y is -C (S) -; in some embodiments, Y is -C (N-OH) -; in some embodiments, Y is -S (O) -; in some embodiments, Y is -S (O) 2 -; and in some embodiments, Y is
Z is -C (R 2s ) (R 3s ) -; and in some embodiments, Z is -N (R 2s ) -.
Ring A is C 3-6 cycloalkyl; in some embodiments, Ring A is 4-to 6-membered heterocyclyl; in some embodiments, Ring A is 5-to 10-membered heteroaryl; in some embodiments, Ring A is phenyl; and in some embodiments, Ring A is 5-to 9-membered heteroaryl.
R a is H; in some embodiments, R a is D; in some embodiments, R a is halo; in some embodiments, R a is oxo; in some embodiments, R a is CN; in some embodiments, R a is NO 2 ; in some embodiments, R a is OH; in some embodiments, R a is NH 2 ; in some embodiments, R a is -C 1-6 alkylene-OH; in some embodiments, R a is -C (O) OR x ; in some embodiments, R a is -C (O) NR y R z ; in some embodiments, R a is -S (O) NR y R z ; in some embodiments, R a is -S (O) 2 NR y R z ; in some embodiments, R a is C 1-6 alkyl; in some embodiments, R a is C 1-6 haloalkyl; in some embodiments, R a is C
R 1 is H; in some embodiments, R 1 is D; in some embodiments, R 1 is halo; in some embodiments, R 1 is CN; in some embodiments, R 1 is OR x ; in some embodiments, R 1 is NR y R z ; in some embodiments, R 1 is C 1-6 alkyl; in some embodiments, R 1 is C 1-6 haloalkyl; in some embodiments, R 1 is C 1-6 alkoxyl; in some embodiments, R 1 is C 1-6 haloalkoxyl; in some embodiments, R 1 is C 2-6 alkenyl; in some embodiments, R 1 is C 2-6 haloalkenyl; in some embodiments, R 1 is C 2-6 alkynyl; in some embodiments, R 1 is C 2-6 haloalkynyl; in some embodiments, R 1 is C 3-8 cycloalkyl; and in some embodiments, R 1 is 4-to 10-membered heterocyclyl.
R 2 is H; in some embodiments, R 2 is D; in some embodiments, R 2 is halo; in some embodiments, R 2 is CN; in some embodiments, R 2 is -C 0-6 alkylene-OH; in some embodiments, R 2 is -C (O) C 1- 6 alkyl; in some embodiments, R 2 is -C (O) C 1-6 haloalkyl; in some embodiments, R 2 is -C 0-6 alkylene-NH 2 ; in some embodiments, R 2 is C 1-6 alkyl; in some embodiments, R 2 is C 1-6 haloalkyl; in some embodiments, R 2 is C 1-6 alkoxyl; in some embodiments, R 2 is C 1-6 haloalkoxyl; in some embodiments, R 2 is C 2-6 alkenyl; in some embodiments, R 2 is C 2-6 haloalkenyl; in some embodiments, R 2 is C 2-6 alkynyl; in some embodiments,
T is a chemical bond; in some embodiments, T is -O-; in some embodiments, T is -S-; and in some embodiments, T is -NH-.
R 3 is H; in some embodiments, R 3 is D; in some embodiments, R 3 is halo; in some embodiments, R 3 is CN; in some embodiments, R 3 is -C 0-6 alkylene-OH; in some embodiments, R 3 is -C 0-6 alkylene-NH 2 ; in some embodiments, R 3 is C 1-6 alkyl; and in some embodiments, R 3 is C 1-6 haloalkyl.
R 4 is H; in some embodiments, R 4 is D; in some embodiments, R 4 is halo; in some embodiments, R 4 is C 1-6 alkyl; and in some embodiments, R 4 is C 1-6 haloalkyl.
R 1 and R 2 together with the carbon atoms to which they connected form C 5-6 cycloalkyl; in some embodiments, R 1 and R 2 together with the carbon atoms to which they connected form 5-to 6-membered heterocyclyl; in some embodiments, R 1 and R 2 together with the carbon atoms to which they connected form phenyl; and in some embodiments, R 1 and R 2 together with the carbon atoms to which they connected form 5-to 6-membered heteroaryl.
R 2 and R 3 together with the carbon atoms to which they connected form C 5-6 cycloalkyl; and in some embodiments, R 2 and R 3 together with the carbon atoms to which they connected form 5-to 7-membered heterocyclyl.
R 1s is H; in some embodiments, R 1s is D; in some embodiments, R 1s is -C 0-6 alkylene-OR x ; in some embodiments, R 1s is -C 0-6 alkylene-NR y R z ; in some embodiments, R 1s is C 1-6 alkyl; in some embodiments, R 1s is C 1-6 haloalkyl; in some embodiments, R 1s is C 2-6 alkenyl; in some embodiments, R 1s is C 2-6 haloalkenyl; in some embodiments, R 1s is C 2-6 alkynyl; in some embodiments, R 1s is C 2-6 haloalkynyl; in some embodiments, R 1s is C 3-6 cycloalkyl; and in some embodiments, R 1s is phenyl.
R 2s is H; in some embodiments, R 2s is D; in some embodiments, R 2s is C 1-6 alkyl; in some embodiments, R 2s is C 1-6 haloalkyl; and in some embodiments, R 2s is C (R 2s1 ) (R 2s2 ) (R 2s3 ) .
R 2s1 is H; in some embodiments, R 2s1 is D; in some embodiments, R 2s1 is -C 0-6 alkylene-OR x ; in some embodiments, R 2s1 is -C 0-6 alkylene-NR y R z ; in some embodiments, R 2s1 is C 1-6 alkyl; in some embodiments, R 2s1 is C 1-6 haloalkyl; in some embodiments, R 2s1 is C 2-6 alkenyl; in some embodiments, R 2s1 is C 2-6 haloalkenyl; in some embodiments, R 2s1 is C 2-6 alkynyl; in some embodiments, R 2s1 is C 2-6 haloalkynyl; and in some embodiments, R 2s1 is C 3-6 cycloalkyl.
R 2s2 is H; in some embodiments, R 2s2 is D; in some embodiments, R 2s2 is C 1-6 alkyl; and in some embodiments, R 2s2 is C 1-6 haloalkyl.
R 2s3 is C 1-6 alkyl; and in some embodiments, R 2s3 is C 1-6 haloalkyl.
R 2s2 and R 2s3 together with the atom to which they connected form C 3-6 cycloalkyl; and in some embodiments, R 2s2 and R 2s3 together with the atom to which they connected form 4-to 6-membered heterocyclyl.
R 2s1 and R 2s2 together with the carbon atom to which they connected form C 3-6 cycloalkyl.
R 2s1 , R 2s2 and R 2s3 together with the atom to which they connected form C 4-8 bridged bicycloalkyl, which is optionally substituted with 1 or 2 halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, and C 2-6 haloalkynyl; and in some embodiments, R 2s1 , R 2s2 and R 2s3 together with the atom to which they connected form 4-to 8-membered bridged heterocyclyl.
R 1s and R 2s3 connect to form C 2-6 alkylene.
R 3s is H; in some embodiments, R 3s is D; in some embodiments, R 3s is C 1-6 alkyl; and in some embodiments, R 3s is C 1-6 haloalkyl.
R 2s and R 3s together with the carbon atom to which they connected form C 3-6 cycloalkyl; and in some embodiments, R 2s and R 3s together with the carbon atom to which they connected form 4-to 6-membered heterocyclyl.
R 1s and R 2s together with the nitrogen atom to which they connected form 4-to 6-membered heterocyclyl.
R 1s , R 2s and R 3s together with the carbon atom to which they connected form C 4-8 bridged bicycloalkyl, which is optionally substituted with 1 or 2 halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, and C 2-6 haloalkynyl; and in some embodiments, R 1s , R 2s and R 3s together with the carbon atom to which they connected form
Y 1 is CR 11 ; and in some embodiments, Y 1 is N.
Y 2 is CR 12 ; and in some embodiments, Y 2 is N.
R 11 , and R 13 are H; in some embodiments, R 11 , and R 13 are D; in some embodiments, R 11 , and R 13 are C 1-6 alkyl; and in some embodiments, R 11 , and R 13 are C 1-6 haloalkyl.
R 12 is H; and in some embodiments, R 12 is D.
the present disclosure specifically relates to the following technical solutions:
M 1 is selected from CR 1 and N;
M 2 is selected from CR 2 and N;
M 3 is selected from CR 3 and N;
M 4 is selected from CR 4 and N;
L is selected from a chemical bond, -O-, -S-, and -NH-;
Y is selected from -C (O) -, -C (S) -, -C (N-OH) -, -S (O) -, -S (O) 2 -, and
Z is -C (R 2s ) (R 3s ) -or -N (R 2s ) -;
Ring A is selected from C 3-6 cycloalkyl, 4-to 6-membered heterocyclyl, phenyl and 5-to 10-membered heteroaryl, preferably phenyl or 5-to 9-membered heteroaryl;
R a is selected from H, D, halo, oxo, CN, NO 2 , NH 2 , -C 0-6 alkylene-OH, -C (O) OR x , -C (O) NR y R z , -S (O) NR y R z , -S (O) 2 NR y R z , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl, C 3-6 cycloalkyl, 4-to 6-membered heterocyclyl, phenyl, 5-to 6-membered heteroaryl, and amino protecting group, which is optionally substituted with 1, 2, or 3 halo, oxo, OR x , NR y R z , C 1-6 alkyl, or C 1-6 haloalkyl, and amino protecting group
R 1 is selected from H, D, halo, CN, OR x , NR y R z , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxyl, C 1-6 haloalkoxyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl, C 3-8 cycloalkyl, and 4-to 10-membered heterocyclyl;
R 2 is selected from H, D, halo, CN, -C 0-6 alkylene-OH, -C 0-6 alkylene-NH 2 , -C (O) C 1-6 alkyl, -C (O) C 1-6 haloalkyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxyl, C 1-6 haloalkoxyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl, -T-C 3-8 cycloalkyl, -T-4-to 10-membered heterocyclyl, -T-C 6-10 aryl, and -T-5-to 10-membered heteroaryl, which is optionally substituted with 1, 2, 3, 4 or 5 CN, halo, oxo, -C 1-6 alkylene-OH, C 1-6 alkyl, C 1-6 haloalkyl
T is a chemical bond, -O-, -S-or -NH-;
R 3 is selected from H, D, halo, CN, -C 0-6 alkylene-OH, -C 0-6 alkylene-NH 2 , C 1-6 alkyl, and C 1-6 haloalkyl;
R 4 is selected from H, D, halo, C 1-6 alkyl, and C 1-6 haloalkyl;
R 1 and R 2 together with the carbon atoms to which they connected form C 5-6 cycloalkyl, 5-to 6-membered heterocyclyl, phenyl or 5-to 6-membered heteroaryl, which is optionally substituted with 1, 2, or 3 halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, -C (O) H, -C (O) C 1-6 alkyl, -C (O) C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl, or C 2-6 alkynyl-substituted phenyl, preferably 1, 2, or 3 halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, -C (O) C 1-6 alkyl, -C (O) C 1-6 haloalkyl, C 2-6 alkenyl, C
R 2 and R 3 together with the carbon atoms to which they connected form C 5-6 cycloalkyl, 5-to 7-membered heterocyclyl, phenyl, or 5-to 6-membered heteroaryl, which is optionally substituted with 1, 2, 3, or 4 halo, C 1-6 alkyl, C 1-6 haloalkyl, -C 1-6 alkylene-C 1-6 alkoxyl, -C 1-6 alkylene-C 1-6 haloalkoxyl, -C (O) C 1-6 alkyl, or -C (O) C 1-6 haloalkyl;
R 1s is selected from H, D, -C 0-6 alkylene-OR x , -C 0-6 alkylene-NR y R z , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl, C 3-6 cycloalkyl and phenyl;
R 2s is selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, and C (R 2s1 ) (R 2s2 ) (R 2s3 ) ;
R 2s1 is selected from H, D, -C 0-6 alkylene-OR x , -C 0-6 alkylene-NR y R z , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl, and C 3-6 cycloalkyl;
R 2s2 is selected from H, D, -C 0-6 alkylene-OH, C 1-6 alkyl, and C 1-6 haloalkyl;
R 2s3 is C 1-6 alkyl, or C 1-6 haloalkyl
R 2s1 and R 2s2 together with the carbon atom to which they connected form C 3-6 cycloalkyl
R 2s2 and R 2s3 together with the atom to which they connected form C 3-6 cycloalkyl or 4-to 6-membered heterocyclyl, which is optionally substituted with 1 or 2 halo;
R 2s1 , R 2s2 and R 2s3 together with the atom to which they connected form C 4-8 bridged bicycloalkyl, which is optionally substituted with 1 or 2 halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, and C 2-6 haloalkynyl, or form 4-to 8-membered bridged heterocyclyl;
R 1s and R 2s3 connect to form C 2-6 alkylene, which is optionally substituted with 1, 2, or 3 halo, OR x , NR y R z , C 1-6 alkyl, or C 1-6 haloalkyl;
R 3s is selected from H, D, C 1-6 alkyl, and C 1-6 haloalkyl;
R 2s and R 3s together with the carbon atom to which they connected form C 3-6 cycloalkyl or 4-to 6-membered heterocyclyl, which is optionally substituted with 1 or 2 halo, C 1-6 alkyl or C 1-6 haloalkyl;
R 1s and R 2s together with the nitrogen atom to which they connected form 4-to 6-membered heterocyclyl, which is optionally substituted with 1 or 2 halo, C 1-6 alkyl or C 1-6 haloalkyl;
R 1s , R 2s and R 3s together with the carbon atom to which they connected form C 4-8 bridged bicycloalkyl, which is optionally substituted with 1 or 2 halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, and C 2-6 haloalkynyl, or form
Y 1 is CR 11 or N
Y 2 is CR 12 or N
R 11 , and R 13 are independently selected from H, D, C 1-6 alkyl, and C 1-6 haloalkyl;
R 12 is selected from H, and D;
R x , R y , and R z are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl, C 3-8 cycloalkyl, and 4-to 6-membered heterocyclyl; or R y and R z together with the nitrogen atom to which they connected form 4-to 6-membered heterocyclyl;
Ring A is selected from
Ring A is selected from
Ring A is selected from
Ring A is selected from
Ring A is selected from
Ring A is selected from
Ring A is selected from
Ring A is selected from
Ring A is selected from
Ring A is selected from
Ring A is selected from
Ring A is selected from
Ring A is selected from
Ring A is selected from
Ring A is selected from
Ring A is selected from
Ring A is selected from
Ring A is selected from
Ring A is selected from
Ring A is selected from
Ring A is selected from
Ring A is selected from
Ring A is selected from
Ring A is
Ring A is
Ring A is selected from
Ring A is
R 1 is selected from H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxyl, C 1-6 haloalkoxyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl, C 3-8 cycloalkyl, and 4-to 10-membered heterocyclyl;
R 1 is selected from H, D, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl, C 1-6 alkoxyl, C 1-6 haloalkoxyl, and C 3-6 cycloalkyl;
R 1 is selected from H, D, halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 haloalkenyl, C 2-4 alkynyl, C 2-4 haloalkynyl, C 1-4 alkoxyl, C 1-4 haloalkoxyl, and C 3-6 cycloalkyl;
R 1 is selected from H, D, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, and C 2-6 haloalkynyl;
R 1 is selected from H, D, halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, and C 2-6 haloalkynyl;
R 1 is selected from H, D, halo, C 1-6 alkyl, and C 1-6 haloalkyl;
R 1 is selected from halo, C 1-6 alkyl, and C 1-6 haloalkyl;
R 1 is selected from H, D, halo, C 1-4 alkyl, and C 1-4 haloalkyl;
R 1 is selected from H, D, and halo
R 1 is halo
R 1 is selected from H, D, F, Cl, Me, and CF 3 ;
R 1 is selected from H, D, F, Cl, and Me;
R 1 is selected from H, D, F, Me, and OMe;
R 1 is selected from H, D, F, and Me;
R 1 is selected from H, D, Cl, and Me;
R 1 is selected from H, D, F, and Cl;
R 1 is selected from H, D, and F;
R 1 is selected from Cl, and Me;
R 1 is selected from F, and Cl;
R 1 is selected from H, and D.
R 2 is selected from H, D, halo, -C 0-6 alkylene-OH, NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxyl, C 1-6 haloalkoxyl, -T-C 5-6 cycloalkyl, -T-5-to 10-membered heterocyclyl, -T-C 6-10 aryl, and -T-5-to 10-membered heteroaryl, which is optionally substituted with 1, 2, 3, 4 or 5 CN, halo, oxo, -C 1-6 alkylene-OH, C 1-6 alkyl, C 1- 6 haloalkyl, C 3-6 cycloalkyl, or 5-to 6-membered heterocycly
R 2 is selected from H, D, halo, -C 0-6 alkylene-OH, NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxyl, C 5-6 cycloalkyl, 5-to 10-membered heterocyclyl, C 6-10 aryl, 5-to 10-membered heteroaryl, -O-5-to 6-membered heteroaryl, -NH-5-to 6-membered heteroaryl, -OC (O) -5-to 6-membered heteroaryl, or -NHC (O) -5-to 6-membered heteroaryl, which is optionally substituted with 1, 2, 3, 4 or 5 CN, halo, oxo, -C 1- 6 alkylene-OH, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, or 5-to 6-membered heterocyclyl;
R 2 is selected from H, D, halo, NH 2 , -C 0-6 alkylene-OH, -O-C 1-6 alkylene-OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxyl, and C 1-6 haloalkoxyl, and 5-membered heteroaryl, which is optionally substituted with 1, 2, or 3 halo;
R 2 is selected from H, D, halo, NH 2 , -C 0-4 alkylene-OH, -O-C 1-4 alkylene-OH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxyl, C 1-4 haloalkoxyl, and 5-membered heteroaryl, which is optionally substituted with 1, or 2 halo;
R 2 is selected from H, D, halo, NH 2 , -C 0-6 alkylene-OH, -O-C 1-6 alkylene-OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxyl, and C 1-6 haloalkoxyl;
R 2 is selected from H, D, halo, NH 2 , -C 0-4 alkylene-OH, -O-C 1-4 alkylene-OH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxyl, and C 1-4 haloalkoxyl;
R 2 is selected from H, D, halo, -C 0-6 alkylene-OH, -O-C 1-6 alkylene-OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxyl, and C 1-6 haloalkoxyl;
R 2 is selected from H, D, halo, -C 0-4 alkylene-OH, -O-C 1-4 alkylene-OH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxyl, and C 1-4 haloalkoxyl;
R 2 is selected from H, D, halo, -C 0-6 alkylene-OH, NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxyl, C 5-6 cycloalkyl, 5-to 10-membered heterocyclyl, C 6-10 aryl, 5-to 10-membered heteroaryl, -O-5-to 6-membered heteroaryl, -NH-5-to 6-membered heteroaryl, -OC (O) -5-to 6-membered heteroaryl, or -NHC (O) -5-to 6-membered heteroaryl; which is optionally substituted with 1, 2, 3, 4 or 5 CN, halo, oxo, -C 1- 6 alkylene-OH, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, or 5-to 6-membered heterocyclyl;
R 2 is selected from H, D, halo, C 1-4 alkyl, and C 1-4 haloalkyl;
R 2 is selected from H, D, halo, -C 0-6 alkylene-OH, NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxyl, C 1-6 haloalkoxyl, -T-C 5-6 cycloalkyl, -T-5-to 6-membered heterocyclyl, -T-C 6-10 aryl, and -T-5-to 6-membered heteroaryl, which is optionally substituted with 1, 2, 3, 4 or 5 halo, oxo, C 1-6 alkyl or C 1-6 haloalkyl;
R 2 is selected from H, D, halo, -C 0-6 alkylene-OH, NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxyl, C 5-6 cycloalkyl, 5-to 6-membered heterocyclyl, C 6-10 aryl, 5-to 6-membered heteroaryl, -O-5-to 6-membered heteroaryl, and -NH-5-to 6-membered heteroaryl, which is optionally substituted with 1, 2, 3, 4 or 5 oxo, C 1-6 alkyl or C 1-6 haloalkyl;
R 2 is selected from H, D, halo, NH 2 , -C 0-6 alkylene-OH, -O-C 1-6 alkylene-OH, -C (O) C 1-6 alkyl, -C (O) C 1-6 haloalkyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxyl, C 1-6 haloalkoxyl, and 5-membered heteroaryl, which is optionally substituted with 1, 2, or 3 halo;
R 2 is selected from H, D, halo, NH 2 , -C 0-4 alkylene-OH, -O-C 1-4 alkylene-OH, -C (O) C 1-4 alkyl, -C (O) C 1-4 haloalkyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxyl, C 1-4 haloalkoxyl, and 5-membered heteroaryl, which is optionally substituted with 1, or 2 halo;
R 2 is selected from H, D, halo, NH 2 , -C 0-6 alkylene-OH, -O-C 1-6 alkylene-OH, -C (O) C 1-6 alkyl, -C (O) C 1-6 haloalkyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxyl, and C 1-6 haloalkoxyl;
R 2 is selected from H, D, halo, NH 2 , -C 0-4 alkylene-OH, -O-C 1-4 alkylene-OH, -C (O) C 1-4 alkyl, -C (O) C 1-4 haloalkyl, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxyl, and C 1-4 haloalkoxyl;
R 2 is selected from H, D, halo, OH, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxyl, C 1-6 haloalkoxyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, and C 2-6 haloalkynyl;
R 2 is selected from H, D, halo, OH, C 1-6 alkoxyl, and C 1-6 haloalkoxyl;
R 2 is selected from H, D, halo, -C 0-6 alkylene-OH, NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxyl, C 1-6 haloalkoxyl,
R 2 is selected from H, D, Cl, OH, Me, CH 2 F, CHF 2 , CF 3 , OMe, CH 2 OH, NH 2 , which is optionally substituted with 1, 2, 3, 4 or 5 CN, halo, -C 1-6 alkylene-OH, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, or 5-to 6-membered heterocyclyl;
R 2 is selected from H, D, halo, -C 0-6 alkylene-OH, NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxyl, C 1-6 haloalkoxyl, which is optionally substituted with 1, 2, 3, 4 or 5 CN, halo, C 1-6 alkyl, C 1-6 haloalkyl, or C 3-6 cycloalkyl;
R 2 is selected from H, D, halo, -C 0-6 alkylene-OH, NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxyl, C 1-6 haloalkoxyl,
R 2 is selected from H, D, Cl, OH, NH 2 , Me, CH 2 F, CHF 2 , CF 3 , OMe, CH 2 OH,
R 2 is selected from H, D, Cl, OH, Me, CH 2 F, CHF 2 , CF 3 , OMe, CH 2 OH, NH 2 , which is optionally substituted with 1, 2, 3, 4 or 5 C 1-6 alkyl or C 1-6 haloalkyl;
R 2 is selected from H, D, halo, -C 0-6 alkylene-OH, NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxyl, C 1-6 haloalkoxyl, which is optionally substituted with 1, 2, 3, 4 or 5 C 1-6 alkyl or C 1-6 haloalkyl;
R 2 is selected from H, D, halo, -C 0-6 alkylene-OH, NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxyl, C 1-6 haloalkoxyl,
R 2 is selected from H, D, Cl, OH, NH 2 , Me, CH 2 F, CHF 2 , CF 3 , OMe, CH 2 OH,
R 2 is selected from H, D, Cl, Br, OH, Me, CH 2 F, CHF 2 , CF 3 , OMe, OCH 2 CH 2 OH, CH 2 OH, NH 2
R 2 is selected from H, D, Cl, Br, OH, Me, CH 2 F, CHF 2 , CF 3 , OMe, OCH 2 CH 2 OH, CH 2 OH, NH 2
R 2 is selected from H, D, Cl, Br, OH, Me, CH 2 F, CHF 2 , CF 3 , OMe, OCH 2 CH 2 OH, CH 2 OH, NH 2
R 2 is selected from H, D, Cl, Br, OH, Me, CH 2 F, CHF 2 , CF 3 , OMe, OCH 2 CH 2 OH, CH 2 OH, -C (O) Me, NH 2 ,
R 2 is selected from H, D, Cl, Br, OH, Me, CH 2 F, CHF 2 , CF 3 , OMe, OCH 2 CH 2 OH, CH 2 OH, -C (O) Me, and NH 2 ;
R 2 is selected from H, D, Cl, Br, OH, Me, CH 2 F, CHF 2 , CF 3 , OMe, OCH 2 CH 2 OH, CH 2 OH, and NH 2 ;
R 2 is selected from H, D, Cl, Br, OH, Me, CH 2 F, CHF 2 , CF 3 , OMe, OCH 2 CH 2 OH, and CH 2 OH;
R 2 is selected from H, D, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxyl, C 1-6 haloalkoxyl, C 2-4 alkenyl, C 2-4 haloalkenyl, C 2-4 alkynyl, C 2-4 haloalkynyl, C 4-6 cycloalkyl, and 5-to 6-membered heterocyclyl;
R 2 is selected from H, D, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxyl, C 1-6 haloalkoxyl, C 2-4 alkenyl, C 2-4 haloalkenyl, C 2-4 alkynyl, C 2-4 haloalkynyl, and C 3-8 cycloalkyl;
R 2 is selected from H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl;
R 2 is selected from H, D, halo, OH, C 1-6 alkyl, and C 1-6 haloalkyl;
R 2 is selected from H, D, halo, OH, C 1-4 alkyl, and C 1-4 haloalkyl;
R 2 is selected from H, D, C 1-6 alkyl, and C 1-6 haloalkyl;
R 2 is selected from C 1-6 alkyl, and C 1-6 haloalkyl
R 2 is selected from H, D, Cl, OH, Me, CH 2 F, CHF 2 , and CF 3 ;
R 2 is selected from H, D, Cl, OH, OMe, and OCHF 2 ;
R 2 is selected from H, D, Cl, Me, and cyclopropyl
R 2 is selected from H, D, Me, and CF 3 ;
R 2 is selected from H, D, and Me
R 2 is selected from H, and D;
R 2 is Me
R 3 is selected from H, D, halo, C 1-6 alkyl, and C 1-6 haloalkyl;
R 3 is selected from H, D, halo, and OH;
R 3 is selected from H, D, and halo
R 3 is selected from H, D, halo, OH, C 1-6 alkoxyl, and C 1-6 haloalkoxyl;
R 3 is selected from H, D, halo, OH, C 1-4 alkoxyl, and C 1-4 haloalkoxyl;
R 3 is selected from H, D, F, Br, OH, and OMe;
R 3 is selected from H, D, F, Br, and OH;
R 3 is selected from H, D, F, and OH;
R 3 is selected from H, D, and OH;
R 3 is selected from H, D, and F;
R 3 is selected from H, and D.
R 4 is selected from H, D, and halo
R 4 is selected from H, D, F, and Me;
R 4 is selected from H, D, and F;
R 4 is selected from H, and D.
R 1 and R 2 together with the carbon atoms to which they connected form phenyl or 5-to 6-membered heteroaryl;
R 1 and R 2 together with the carbon atoms to which they connected form C 5-6 cycloalkyl, or phenyl;
R 1 and R 2 together with the carbon atoms to which they connected form which is optionally substituted with 1, 2, or 3 halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl, or C 2-6 alkynyl-substituted phenyl;
R 1 and R 2 together with the carbon atoms to which they connected form which is optionally substituted with 1, 2, or 3 halo, CN, or C 2-6 alkynyl-substituted phenyl;
R 1 and R 2 together with the carbon atoms to which they connected form which is optionally substituted with 1 or 2 Br, or C 2-6 alkynyl-substituted phenyl;
R 1 and R 2 together with the carbon atoms to which they connected form which is optionally substituted with 1, 2, or 3 halo, or C 2-6 alkynyl-substituted phenyl;
R 1 and R 2 together with the carbon atoms to which they connected form which is optionally substituted with 1 or 2 Br, or C 2-6 alkynyl-substituted phenyl;
R 1 and R 2 together with the carbon atoms to which they connected form which is optionally substituted with Br, or C 2-6 alkynyl-substituted phenyl;
R 1 and R 2 together with the carbon atoms to which they connected form which is optionally substituted with 1, 2, or 3 halo, C 1-6 alkyl, or C 1-6 haloalkyl;
R 1 and R 2 together with the carbon atoms to which they connected form which is optionally substituted with 1, 2, or 3 halo, C 1-6 alkyl, or C 1-6 haloalkyl;
R 1 and R 2 together with the carbon atoms to which they connected form which is optionally substituted with 1, 2, or 3 halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, -C (O) C 1-6 alkyl, or -C (O) C 1-6 haloalkyl;
R 1 and R 2 together with the carbon atoms to which they connected form which is optionally substituted with 1, 2, or 3 halo, CN, C 1-6 alkyl, or C 1-6 haloalkyl;
R 1 and R 2 together with the carbon atoms to which they connected form
R 1 and R 2 together with the carbon atoms to which they connected form
R 1 and R 2 together with the carbon atoms to which they connected form
R 1 and R 2 together with the carbon atoms to which they connected form
R 1 and R 2 together with the carbon atoms to which they connected form
R 1 and R 2 together with the carbon atoms to which they connected form
R 1 and R 2 together with the carbon atoms to which they connected form
R 1 and R 2 together with the carbon atoms to which they connected form
R 1 and R 2 together with the carbon atoms to which they connected form
R 1 and R 2 together with the carbon atoms to which they connected form
R 1 and R 2 together with the carbon atoms to which they connected form
R 1 and R 2 together with the carbon atoms to which they connected form
R 1 and R 2 together with the carbon atoms to which they connected form
R 1 and R 2 together with the carbon atoms to which they connected form
R 2 and R 3 together with the carbon atoms to which they connected form C 5-6 cycloalkyl, or 5-to 7-membered heterocyclyl;
R 2 and R 3 together with the carbon atoms to which they connected form 5-to 7-membered heterocyclyl, which is optionally substituted with 1, 2, 3, or 4 halo, C 1-6 alkyl, or C 1-6 haloalkyl;
R 2 and R 3 together with the carbon atoms to which they connected form 5-to 6-membered heterocyclyl, which is optionally substituted with 1, 2, 3, or 4 halo, C 1-6 alkyl, C 1-6 haloalkyl, -C (O) C 1-6 alkyl, or -C (O) C 1-6 haloalkyl;
R 2 and R 3 together with the carbon atoms to which they connected form 5-to 6-membered heterocyclyl, which is optionally substituted with 1, 2, 3, or 4 halo;
R 2 and R 3 together with the carbon atoms to which they connected form C 5-6 cycloalkyl or 5-to 6-membered heterocyclyl;
R 1s is selected from H, D, -C 0-6 alkylene-OH, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 haloalkenyl, C 2-4 alkynyl, and C 2-4 haloalkynyl;
R 1s is selected from H, D, OH, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 haloalkenyl, C 2- 4 alkynyl, and C 2-4 haloalkynyl;
R 1s is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl and phenyl;
R 1s is selected from C 1-6 alkyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl;
R 1s is selected from C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, and C 2-4 haloalkenyl;
R 1s is selected from C 1-4 alkyl, C 1-4 haloalkyl, and C 2-4 alkenyl;
R 1s is selected from C 1-6 alkyl, and C 1-6 haloalkyl
R 1s is selected from C 1-4 alkyl, and C 1-4 haloalkyl
R 1s is selected from H, D, C 1-6 alkyl, and C 1-6 haloalkyl;
R 1s is selected from H, C 1-6 alkyl, C 1-6 haloalkyl
R 1s is selected from H, D, Me, CHF 2 , and CF 3 ;
R 1s is selected from H, D, Me, and CHF 2 ;
R 1s is selected from H, Me, and Et;
R 1s is selected from H, and Me;
R 1s is selected from Me, cyclopropyl and phenyl
R 1s is selected from Me and cyclopropyl
R 1s is selected from Me, and CHF 2 ;
R 1s is Me
R 1s is H.
R 2s is selected from H, D, C 1-4 alkyl, and C 1-4 haloalkyl;
R 2s is selected from C 1-6 alkyl, and C 1-6 haloalkyl
R 2s is selected from C 1-4 alkyl, and C 1-4 haloalkyl
R 2s is selected from H, D, and Me;
R 2s is selected from H, and D;
R 2s is Me.
R 2s is C (R 2s1 ) (R 2s2 ) (R 2s3 )
R 2s1 is selected from H, D, -C 0-6 alkylene-OH, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl, and C 3-6 cycloalkyl;
R 2s1 is selected from H, D, -C 0-6 alkylene-OR x , -C 0-6 alkylene-NR y R z , C 1-6 alkyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl;
R 2s1 is selected from H, D, -C 0-6 alkylene-OR x , -C 0-6 alkylene-NR y R z , C 1-6 alkyl, and C 1-6 haloalkyl;
R 2s1 is selected from -C 0-6 alkylene-OR x , C 1-6 alkyl, C 1-6 haloalkyl, and C 3-6 cycloalkyl;
R 2s1 is selected from -C 0-6 alkylene-OH, C 1-6 alkyl, and C 1-6 haloalkyl;
R 2s1 is selected from H, D, -C 0-4 alkylene-OH, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 haloalkenyl, C 2-4 alkynyl, C 2-4 haloalkynyl, and C 3-6 cycloalkyl;
R 2s1 is selected from H, D, -C 0-6 alkylene-OH, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, and C 2-6 haloalkynyl;
R 2s1 is selected from H, D, -C 0-4 alkylene-OH, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 haloalkenyl, C 2-4 alkynyl, and C 2-4 haloalkynyl;
R 2s1 is selected from H, D, C 1-6 alkyl, and C 1-6 haloalkyl;
R 2s1 is selected from H, D, C 1-4 alkyl, and C 1-4 haloalkyl;
R 2s1 is selected from -C 0-6 alkylene-OR x , -C 0-6 alkylene-NR y R z , C 1-6 alkyl, and C 1-6 haloalkyl;
R 2s1 is selected from -C 0-6 alkylene-OR x , C 1-6 alkyl, and C 1-6 haloalkyl;
R 2s1 is selected from C 1-6 alkyl, and C 1-6 haloalkyl
R 2s1 is selected from H, D, OH, Me, Et, CH 2 F, CHF 2 , CF 3 , CH 2 OH, CH 2 CH 2 OH, C ⁇ CH, and cyclopropyl;
R 2s1 is selected from H, D, OH, Me, Et, CH 2 F, CHF 2 , CF 3 , CH 2 OH, CH 2 CH 2 OH, and C ⁇ CH;
R 2s1 is selected from H, D, and Me;
R 2s1 is selected from Me, CH 2 F, CH 2 OH, CH 2 OCH 3 , and cyclopropyl;
R 2s1 is selected from Me, CH 2 F, CH 2 OH, and cyclopropyl
R 2s1 is selected from Me, Et, iPr, CH 2 F, CHF 2 , and CH 2 OH;
R 2s1 is selected from Me, Et, iPr, CH 2 F, and CHF 2 ;
R 2s1 is selected from Me, and CH 2 OH;
R 2s1 is Me.
R 2s2 is H, D, C 1-6 alkyl, or C 1-6 haloalkyl
R 2s2 is H, D, C 1-4 alkyl, or C 1-4 haloalkyl
R 2s2 is selected from C 1-6 alkyl, and C 1-6 haloalkyl
R 2s2 is selected from H, D, and Me,
R 2s2 is Me.
R 2s3 is selected from C 1-6 alkyl, and C 1-6 haloalkyl
R 2s3 is C 1-4 alkyl, or C 1-4 haloalkyl
R 2s3 is Me.
R 2s2 and R 2s3 together with the carbon atom to which they connected form cyclopropyl.
R 2s1 and R 2s2 together with the carbon atom to which they connected form C 3-5 cycloalkyl
R 2s1 and R 2s2 together with the carbon atom to which they connected form cyclopropyl.
R 1s and R 2s3 together with the atoms to which they connected form 5-to 7-membered heterocyclyl, which is optionally substituted with 1 or 2 halo;
R 1s and R 2s3 together with the atoms to which they connected form 5-membered heterocyclyl, which is optionally substituted with 1 or 2 halo;
R 1s and R 2s3 together with the atoms to which they connected form 4-to 6-membered heterocyclyl
R 1s and R 2s3 together with the atoms to which they connected form 4-to 5-membered heterocyclyl, which is optionally substituted with OH;
R 1s and R 2s3 together with the atoms to which they connected form 4-to 5-membered heterocyclyl.
R 3s is selected from C 1-4 alkyl, and C 1-4 haloalkyl
R 3s is selected from H, and D;
R 3s is Me.
R 2s and R 3s together with the carbon atom to which they connected form C 3-5 cycloalkyl, which is optionally substituted with 1 or 2 halo;
R 2s and R 3s together with the carbon atom to which they connected form C 3-4 cycloalkyl, which is optionally substituted with 1 or 2 halo;
R 2s and R 3s together with the carbon atom to which they connected form C 3-4 cycloalkyl
R 2s and R 3s together with the carbon atom to which they connected form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, which is optionally substituted with 1 or 2 F or Me;
R 2s and R 3s together with the carbon atom to which they connected form cyclopropyl, cyclobutyl or cyclopentyl, which is optionally substituted with 1 or 2 F;
R 2s and R 3s together with the carbon atom to which they connected form cyclopropyl or cyclobutyl, which is optionally substituted with 1 or 2 F;
R 2s and R 3s together with the carbon atom to which they connected form cyclopropyl.
R 2s1 , R 2s2 and R 2s3 together with the carbon atom to which they connected form C 4-8 bridged bicycloalkyl, which is optionally substituted with 1, 2, or 3 halo, C 1-6 alkyl, or C 1-6 haloalkyl;
R 2s1 , R 2s2 and R 2s3 together with the carbon atom to which they connected form C 4-8 bridged bicycloalkyl
R 2s1 , R 2s2 and R 2s3 together with the carbon atom to which they connected form
R 2s1 , R 2s2 and R 2s3 together with the carbon atom to which they connected form
R 2s1 , R 2s2 and R 2s3 together with the carbon atom to which they connected form
R 1s , R 2s and R 3s together with the carbon atom to which they connected form
R 1s , R 2s and R 3s together with the carbon atom to which they connected form wherein Y 1 is CR 11 or N; Y 2 is CR 12 or N; R 11 , and R 13 are independently selected from H, D, C 1-6 alkyl, and C 1-6 haloalkyl; and R 12 is selected from H, and D;
R 1s , R 2s and R 3s together with the carbon atom to which they connected form wherein Y 1 is CR 11 ; Y 2 is CR 12 ; R 11 , and R 13 are independently selected from H, D, C 1-6 alkyl, and C 1-6 haloalkyl; and R 12 is selected from H, and D;
R 1s , R 2s and R 3s together with the carbon atom to which they connected form wherein Y 1 is CR 11 ; Y 2 is CR 12 ; R 11 is selected from H, D, C 1-6 alkyl, and C 1-6 haloalkyl; and R 12 , and R 13 are independently selected from H, and D;
M 1 is selected from CR 1 and N, preferably CR 1 ;
M 2 is selected from CR 2 and N, preferably CR 2 ;
M 3 is selected from CR 3 and N, preferably CR 3 ;
M 4 is selected from CR 4 and N, preferably CR 4 ;
Y is selected from -C (O) -, -C (S) -, -C (N-OH) -, -S (O) -, and -S (O) 2 -;
Ring A is selected from phenyl and 5-to 9-membered heteroaryl
R 1 and R 4 are independently selected from H, D, and halo
R 2 is selected from H, D, halo, -C 0-6 alkylene-OH, NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxyl, C 1-6 haloalkoxyl, -T-C 5-6 cycloalkyl, -T-5-to 10-membered heterocyclyl, -T-C 6-10 aryl, and -T-5-to 10-membered heteroaryl, which is optionally substituted with 1, 2, 3, 4 or 5 CN, halo, oxo, -C 1-6 alkylene-OH, C 1-6 alkyl, C 1- 6 haloalkyl, C 3-6 cycloalkyl, or 5-to 6-membered heterocyclyl;
T is a chemical bond, -O-, -S-or -NH-;
R 3 is selected from H, D, halo, CN, -C 0-6 alkylene-OH, -C 0-6 alkylene-NH 2 , C 1-6 alkyl, and C 1-6 haloalkyl;
R 1 and R 2 together with the carbon atoms to which they connected form 5-to 6-membered heterocyclyl, phenyl or 5-to 6-membered heteroaryl;
R 2 and R 3 together with the carbon atoms to which they connected form 5-to 6-membered heterocyclyl, which is optionally substituted with 1, 2, 3, or 4 halo, C 1-6 alkyl, C 1-6 haloalkyl, -C (O) C 1-6 alkyl, or -C (O) C 1-6 haloalkyl;
R 1s is selected from H, D, -C 0-6 alkylene-OH, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2- 6 alkynyl, and C 2-6 haloalkynyl;
R 2s is selected from H, D, C 1-6 alkyl, and C 1-6 haloalkyl;
R 3s is selected from C 1-6 alkyl, and C 1-6 haloalkyl
R 2s and R 3s together with the carbon atom to which they connected form C 3-6 cycloalkyl, which is optionally substituted with 1 or 2 halo, C 1-6 alkyl or C 1-6 haloalkyl;
R 1s , R 2s and R 3s together with the carbon atom to which they connected form C 4-8 bridged bicycloalkyl
M 1 is selected from CR 1 and N, preferably CR 1 ;
M 2 is selected from CR 2 and N, preferably CR 2 ;
M 3 is selected from CR 3 and N, preferably CR 3 ;
M 4 is selected from CR 4 and N, preferably CR 4 ;
Y is selected from -C (O) -, -C (S) -, -C (N-OH) -, -S (O) -, and -S (O) 2 -;
Ring A is selected from
R 1 and R 4 are independently selected from H, D, and halo
R 2 is selected from H, D, halo, -C 0-6 alkylene-OH, NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxyl, C 5-6 cycloalkyl, 5-to 10-membered heterocyclyl, C 6-10 aryl, 5-to 10-membered heteroaryl, -O-5-to 6-membered heteroaryl, -NH-5-to 6-membered heteroaryl, -OC (O) -5-to 6-membered heteroaryl, or -NHC (O) -5-to 6-membered heteroaryl, which is optionally substituted with 1, 2, 3, 4 or 5 CN, halo, oxo, -C 1-6 alkylene-OH, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, or 5-to 6-membered heterocyclyl;
R 3 is selected from H, D, halo, OH, C 1-6 alkyl, and C 1-6 haloalkyl;
R 1 and R 2 together with the carbon atoms to which they connected form 5-to 6-membered heterocyclyl, phenyl or 5-to 6-membered heteroaryl;
R 2 and R 3 together with the carbon atoms to which they connected form 5-to 6-membered heterocyclyl, which is optionally substituted with 1, 2, 3, or 4 halo, C 1-6 alkyl, C 1-6 haloalkyl, -C (O) C 1-6 alkyl, or -C (O) C 1-6 haloalkyl;
R 1s is selected from H, D, -C 0-6 alkylene-OH, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2- 6 alkynyl, and C 2-6 haloalkynyl;
R 2s is selected from H, D, C 1-6 alkyl, and C 1-6 haloalkyl;
R 3s is selected from C 1-6 alkyl, and C 1-6 haloalkyl
R 2s and R 3s together with the carbon atom to which they connected form C 3-6 cycloalkyl, which is optionally substituted with 1 or 2 halo, C 1-6 alkyl or C 1-6 haloalkyl;
R 1s , R 2s and R 3s together with the carbon atom to which they connected form C 4-8 bridged bicycloalkyl
M 1 is selected from CR 1 and N, preferably CR 1 ;
M 2 is selected from CR 2 and N, preferably CR 2 ;
M 3 is selected from CR 3 and N, preferably CR 3 ;
M 4 is selected from CR 4 and N, preferably CR 4 ;
X is selected from O, S, and N-OH
Ring A is selected from
R 1 is selected from H, D, F, and Cl;
R 2 is selected from H, D, Cl, OH, Me, CH 2 F, CHF 2 , CF 3 , OMe, CH 2 OH, NH 2 , which is optionally substituted with 1, 2, 3, 4 or 5 CN, halo, -C 1-6 alkylene-OH, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, or 5-to 6-membered heterocyclyl;
R 3 is selected from H, D, F, Br, and OH;
R 4 is selected from H, D, and F;
R 2s is selected from H, D, and Me
R 3s is Me
R 2s and R 3s together with the carbon atom to which they connected form cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, which is optionally substituted with 1 or 2 F or Me;
M 1 is selected from CR 1 and N, preferably CR 1 ;
M 2 is selected from CR 2 and N, preferably CR 2 ;
M 3 is selected from CR 3 and N, preferably CR 3 ;
M 4 is selected from CR 4 and N, preferably CR 4 ;
X is selected from O, S, and N-OH
Ring A is selected from
R 1 and R 4 are independently selected from H, D, and halo
R 2 is selected from H, D, halo, -C 0-6 alkylene-OH, NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxyl, C 1-6 haloalkoxyl, which is optionally substituted with 1, 2, 3, 4 or 5 CN, halo, C 1-6 alkyl, C 1-6 haloalkyl, or C 3-6 cycloalkyl;
R 3 is selected from H, D, halo, OH, C 1-6 alkyl, and C 1-6 haloalkyl;
R 1 and R 2 together with the carbon atoms to which they connected form phenyl or 5-to 6-membered heteroaryl;
R 2 and R 3 together with the carbon atoms to which they connected form 5-to 6-membered heterocyclyl, which is optionally substituted with 1, 2, 3, or 4 halo, C 1-6 alkyl, C 1-6 haloalkyl, -C (O) C 1-6 alkyl, or -C (O) C 1-6 haloalkyl;
R 1s is selected from H, D, -C 0-6 alkylene-OH, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 haloalkenyl, C 2- 4 alkynyl, and C 2-4 haloalkynyl;
R 2s is selected from H, D, C 1-4 alkyl, and C 1-4 haloalkyl;
R 3s is selected from C 1-4 alkyl, and C 1-4 haloalkyl
R 2s and R 3s together with the carbon atom to which they connected form C 3-5 cycloalkyl, which is optionally substituted with 1 or 2 halo;
R 1s , R 2s and R 3s together with the carbon atom to which they connected form C 4-8 bridged bicycloalkyl
M 1 is selected from CR 1 and N, preferably CR 1 ;
M 2 is selected from CR 2 and N, preferably CR 2 ;
M 3 is selected from CR 3 and N, preferably CR 3 ;
M 4 is selected from CR 4 and N, preferably CR 4 ;
Ring A is selected from phenyl and 5-to 6-membered heteroaryl
R 1 is selected from H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxyl, C 1-6 haloalkoxyl, C 2-6 alkenyl, C 2- 6 haloalkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl, C 3-8 cycloalkyl, and 4-to 10-membered heterocyclyl;
R 2 is selected from H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxyl, C 1-6 haloalkoxyl, C 2-6 alkenyl, C 2- 6 haloalkenyl, C 2-6 alkynyl, and C 2-6 haloalkynyl;
R 3 and R 4 are independently selected from H, D, halo, C 1-6 alkyl, and C 1-6 haloalkyl;
R 1 and R 2 together with the carbon atoms to which they connected form which is optionally substituted with 1, 2, or 3 halo, C 1-6 alkyl, or C 1-6 haloalkyl;
R 1s , R 2s and R 3s are independently selected from H, D, C 1-6 alkyl, and C 1-6 haloalkyl;
R 2s1 , R 2s2 and R 2s3 together with the carbon atom to which they connected form C 4-8 bridged bicycloalkyl, which is optionally substituted with 1 or 2 halo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 haloalkenyl, C 2-6 alkynyl, and C 2-6 haloalkynyl;
M 1 is selected from CR 1 and N, preferably CR 1 ;
M 2 is selected from CR 2 and N, preferably CR 2 ;
M 3 is selected from CR 3 and N, preferably CR 3 ;
M 4 is selected from CR 4 and N, preferably CR 4 ;
R 1 is selected from H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxyl, C 1-6 haloalkoxyl, C 2-6 alkenyl, C 2- 6 haloalkenyl, C 2-6 alkynyl, C 2-6 haloalkynyl, C 3-8 cycloalkyl, and 4-to 10-membered heterocyclyl;
R 2 is selected from H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxyl, C 1-6 haloalkoxyl, C 2-6 alkenyl, C 2- 6 haloalkenyl, C 2-6 alkynyl, and C 2-6 haloalkynyl;
R 3 and R 4 are independently selected from H, D, halo, C 1-6 alkyl, and C 1-6 haloalkyl;
R 1s , R 2s and R 3s are independently selected from H, D, C 1-6 alkyl, and C 1-6 haloalkyl;
R 2s1 , R 2s2 and R 2s3 together with the carbon atom to which they connected form C 4-8 bridged bicycloalkyl
M 1 is selected from CR 1 and N, preferably CR 1 ;
M 2 is selected from CR 2 and N, preferably CR 2 ;
M 3 is selected from CR 3 and N, preferably CR 3 ;
M 4 is selected from CR 4 and N, preferably CR 4 ;
R 1 , R 2 , R 3 and R 4 are independently selected from H, D, and halo;
R 1s is selected from H, D, C 1-6 alkyl, and C 1-6 haloalkyl;
R 2s and R 3s are independently selected from H, and D;
M 1 is selected from CR 1 and N, preferably CR 1 ;
M 2 is selected from CR 2 and N, preferably CR 2 ;
M 3 is selected from CR 3 and N, preferably CR 3 ;
M 4 is selected from CR 4 and N, preferably CR 4 ;
R 1 , R 2 , R 3 and R 4 are independently selected from H, D, and halo;
R 1s is selected from H, D, Me, and CHF 2 ;
R 2s and R 3s are independently selected from H, and D;
M 1 is selected from CR 1 and N, preferably CR 1 ;
M 2 is selected from CR 2 and N, preferably CR 2 ;
M 3 is selected from CR 3 and N, preferably CR 3 ;
M 4 is selected from CR 4 and N, preferably CR 4 ;
Ring A is selected from
R 1 and R 2 together with the carbon atoms to which they connected form which is optionally substituted with 1, 2, or 3 halo, C 1-6 alkyl, or C 1-6 haloalkyl;
R 3 and R 4 are independently selected from H, D, halo, C 1-6 alkyl, and C 1-6 haloalkyl;
R 1s is selected from H, D, C 1-6 alkyl, and C 1-6 haloalkyl;
R 2s and R 3s together with the carbon atom to which they connected form C 3-6 cycloalkyl
M 1 is selected from CR 1 and N, preferably CR 1 ;
M 2 is selected from CR 2 and N, preferably CR 2 ;
M 3 is selected from CR 3 and N, preferably CR 3 ;
M 4 is selected from CR 4 and N, preferably CR 4 ;
Ring A is selected from
R 3 is selected from H, and D;
R 4 is selected from H, D, and halo
R 1s is selected from H, D, C 1-6 alkyl, and C 1-6 haloalkyl;
R 2s and R 3s together with the carbon atom to which they connected form C 3-5 cycloalkyl
M 1 is selected from CR 1 and N, preferably CR 1 ;
M 2 is selected from CR 2 and N, preferably CR 2 ;
M 3 is selected from CR 3 and N, preferably CR 3 ;
M 4 is selected from CR 4 and N, preferably CR 4 ;
Ring A is selected from
R 3 is selected from H, and D;
R 4 is selected from H, D, and F;
R 1s is selected from H, D, Me, CHF 2 , and CF 3 ;
R 2s and R 3s together with the carbon atom to which they connected form cyclopropyl
M 1 is selected from CR 1 and N, preferably CR 1 ;
M 2 is selected from CR 2 and N, preferably CR 2 ;
M 3 is selected from CR 3 and N, preferably CR 3 ;
M 4 is selected from CR 4 and N, preferably CR 4 ;
R 1 and R 2 together with the carbon atoms to which they connected form which is optionally substituted with 1, 2, or 3 halo, C 1-6 alkyl, or C 1-6 haloalkyl;
R 3 and R 4 are independently selected from H, D, halo, C 1-6 alkyl, and C 1-6 haloalkyl;
R 1s is selected from H, D, C 1-6 alkyl, and C 1-6 haloalkyl;
R 2s and R 3s together with the carbon atom to which they connected form C 3-6 cycloalkyl
M 1 is selected from CR 1 and N, preferably CR 1 ;
M 2 is selected from CR 2 and N, preferably CR 2 ;
M 3 is selected from CR 3 and N, preferably CR 3 ;
M 4 is selected from CR 4 and N, preferably CR 4 ;
R 3 is selected from H, and D;
R 4 is selected from H, D, and halo
R 1s is selected from H, D, C 1-6 alkyl, and C 1-6 haloalkyl;
R 2s and R 3s together with the carbon atom to which they connected form C 3-5 cycloalkyl
M 1 is selected from CR 1 and N, preferably CR 1 ;
M 2 is selected from CR 2 and N, preferably CR 2 ;
M 3 is selected from CR 3 and N, preferably CR 3 ;
M 4 is selected from CR 4 and N, preferably CR 4 ;
R 3 is selected from H, and D;
R 4 is selected from H, D, and F;
R 1s is selected from H, D, Me, CHF 2 , and CF 3 ;
R 2s and R 3s together with the carbon atom to which they connected form cyclopropyl
M 1 is selected from CR 1 and N, preferably CR 1 ;
M 2 is selected from CR 2 and N, preferably CR 2 ;
M 3 is selected from CR 3 and N, preferably CR 3 ;
M 4 is selected from CR 4 and N, preferably CR 4 ;
Ring A is selected from
R 1 and R 4 are independently selected from H, D, and halo
R 1s is selected from C 1-6 alkyl, and C 1-6 haloalkyl
R 2s and R 3s together with the carbon atom to which they connected form C 3-6 cycloalkyl
M 1 is selected from CR 1 and N, preferably CR 1 ;
M 2 is selected from CR 2 and N, preferably CR 2 ;
M 3 is selected from CR 3 and N, preferably CR 3 ;
M 4 is selected from CR 4 and N, preferably CR 4 ;
Ring A is selected from
R 1 is halo
R 4 is selected from H, and D;
R 1s is selected from C 1-6 alkyl, and C 1-6 haloalkyl
R 2s and R 3s together with the carbon atom to which they connected form C 3-5 cycloalkyl
M 1 is selected from CR 1 and N, preferably CR 1 ;
M 2 is selected from CR 2 and N, preferably CR 2 ;
M 3 is selected from CR 3 and N, preferably CR 3 ;
M 4 is selected from CR 4 and N, preferably CR 4 ;
Ring A is selected from
R 1 is selected from F, and Cl
R 4 is selected from H, and D;
R 1s is selected from Me, and CHF 2 ;
R 2s and R 3s together with the carbon atom to which they connected form cyclopropyl
M 1 is selected from CR 1 and N, preferably CR 1 ;
M 2 is selected from CR 2 and N, preferably CR 2 ;
M 3 is selected from CR 3 and N, preferably CR 3 ;
M 4 is selected from CR 4 and N, preferably CR 4 ;
Ring A is selected from
R 1 and R 4 are independently selected from H, D, and halo
R 1s is selected from C 1-6 alkyl, and C 1-6 haloalkyl
R 2s and R 3s together with the carbon atom to which they connected form C 3-6 cycloalkyl
M 1 is selected from CR 1 and N, preferably CR 1 ;
M 2 is selected from CR 2 and N, preferably CR 2 ;
M 3 is selected from CR 3 and N, preferably CR 3 ;
M 4 is selected from CR 4 and N, preferably CR 4 ;
Ring A is selected from
R 1 is halo
R 4 is selected from H, and D;
R 1s is selected from C 1-6 alkyl, and C 1-6 haloalkyl
R 2s and R 3s together with the carbon atom to which they connected form C 3-5 cycloalkyl
M 1 is selected from CR 1 and N, preferably CR 1 ;
M 2 is selected from CR 2 and N, preferably CR 2 ;
M 3 is selected from CR 3 and N, preferably CR 3 ;
M 4 is selected from CR 4 and N, preferably CR 4 ;
Ring A is selected from
R 1 is selected from F, and Cl
R 4 is selected from H, and D;
R 1s is selected from Me, and CHF 2 ;
R 2s and R 3s together with the carbon atom to which they connected form cyclopropyl
M 1 is selected from CR 1 and N, preferably CR 1 ;
M 2 is selected from CR 2 and N, preferably CR 2 ;
M 3 is selected from CR 3 and N, preferably CR 3 ;
M 4 is selected from CR 4 and N, preferably CR 4 ;
Ring A is selected from
R 1 and R 4 are independently selected from H, D, and halo
R 2 is selected from H, D, halo, -C 0-6 alkylene-OH, NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxyl, C 1-6 haloalkoxyl,
R 3 is selected from H, D, halo, OH, C 1-6 alkyl, and C 1-6 haloalkyl;
R 1 and R 2 together with the carbon atoms to which they connected form phenyl or 5-to 6-membered heteroaryl;
R 2 and R 3 together with the carbon atoms to which they connected form 5-to 6-membered heterocyclyl, which is optionally substituted with 1, 2, 3, or 4 halo, C 1-6 alkyl, C 1-6 haloalkyl, -C (O) C 1-6 alkyl, or -C (O) C 1-6 haloalkyl;
R 1s is selected from H, D, OH, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, C 2-4 haloalkenyl, C 2-4 alkynyl, and C 2-4 haloalkynyl;
R 2s is selected from H, D, C 1-4 alkyl, and C 1-4 haloalkyl;
R 3s is selected from C 1-4 alkyl, and C 1-4 haloalkyl
R 2s and R 3s together with the carbon atom to which they connected form C 3-5 cycloalkyl, which is optionally substituted with 1 or 2 halo;
R 1s , R 2s and R 3s together with the carbon atom to which they connected form C 4-8 bridged bicycloalkyl
M 1 is selected from CR 1 and N, preferably CR 1 ;
M 2 is selected from CR 2 and N, preferably CR 2 ;
M 3 is selected from CR 3 and N, preferably CR 3 ;
M 4 is selected from CR 4 and N, preferably CR 4 ;
Ring A is selected from
R 1 is selected from H, D, F, and Cl;
R 2 is selected from H, D, Cl, OH, NH 2 , Me, CH 2 F, CHF 2 , CF 3 , OMe, CH 2 OH,
R 3 is selected from H, D, F, Br, and OH;
R 4 is selected from H, D, and F;
R 2s is selected from H, D, and Me
R 3s is Me
R 2s and R 3s together with the carbon atom to which they connected form cyclopropyl, cyclobutyl or cyclopentyl, which is optionally substituted with 1 or 2 F;
M 1 is selected from CR 1 and N, preferably CR 1 ;
M 2 is selected from CR 2 and N, preferably CR 2 ;
M 3 is selected from CR 3 and N, preferably CR 3 ;
M 4 is selected from CR 4 and N, preferably CR 4 ;
Ring A is selected from
R 1 and R 4 are independently selected from H, D, and halo
R 2 and R 3 are independently selected from H, D, halo, OH, C 1-6 alkyl, and C 1-6 haloalkyl;
R 2 and R 3 together with the carbon atoms to which they connected form 5-to 6-membered heterocyclyl, which is optionally substituted with 1, 2, 3, or 4 halo;
R 1s is selected from C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, and C 2-4 haloalkenyl;
R 2s and R 3s together with the carbon atom to which they connected form C 3-4 cycloalkyl, which is optionally substituted with 1 or 2 halo;
M 1 is selected from CR 1 and N, preferably CR 1 ;
M 2 is selected from CR 2 and N, preferably CR 2 ;
M 3 is selected from CR 3 and N, preferably CR 3 ;
M 4 is selected from CR 4 and N, preferably CR 4 ;
Ring A is selected from
R 1 and R 4 are independently selected from H, D, and halo
R 2 is selected from H, D, halo, OH, C 1-4 alkyl, and C 1-4 haloalkyl;
R 3 is selected from H, D, halo, and OH;
R 1s is selected from C 1-4 alkyl, C 1-4 haloalkyl, and C 2-4 alkenyl;
R 2s and R 3s together with the carbon atom to which they connected form C 3-4 cycloalkyl, which is optionally substituted with 1 or 2 halo;
M 1 is selected from CR 1 and N, preferably CR 1 ;
M 2 is selected from CR 2 and N, preferably CR 2 ;
M 3 is selected from CR 3 and N, preferably CR 3 ;
M 4 is selected from CR 4 and N, preferably CR 4 ;
Ring A is selected from
R 1 is selected from H, D, F, and Cl;
R 2 is selected from H, D, Cl, OH, Me, CH 2 F, CHF 2 , and CF 3 ;
R 3 is selected from H, D, F, and OH
R 4 is selected from H, D, and F;
R 2s and R 3s together with the carbon atom to which they connected form cyclopropyl or cyclobutyl, which is optionally substituted with 1 or 2 F;
M 1 is selected from CR 1 and N, preferably CR 1 ;
M 2 is selected from CR 2 and N, preferably CR 2 ;
M 3 is selected from CR 3 and N, preferably CR 3 ;
M 4 is selected from CR 4 and N, preferably CR 4 ;
Ring A is selected from
R 1 is selected from H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxyl, and C 1-6 haloalkoxyl;
R 2 is selected from H, D, halo, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxyl, C 1-6 haloalkoxyl, C 2-4 alkenyl, C 2-4 haloalkenyl, C 2-4 alkynyl, C 2-4 haloalkynyl, C 4-6 cycloalkyl, and 5-to 6-membered heterocyclyl;
R 3 is selected from H, D, halo, C 1-6 alkyl, and C 1-6 haloalkyl;
R 4 is selected from H, D, halo, C 1-6 alkyl, and C 1-6 haloalkyl;
R 1 and R 2 together with the carbon atoms to which they connected form C 5-6 cycloalkyl, 5-to 6-membered heterocyclyl, phenyl and 5-to 6-membered heteroaryl;

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