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CN117177972A - PARP1 inhibitors and uses thereof - Google Patents

PARP1 inhibitors and uses thereof Download PDF

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Publication number
CN117177972A
CN117177972A CN202280029124.5A CN202280029124A CN117177972A CN 117177972 A CN117177972 A CN 117177972A CN 202280029124 A CN202280029124 A CN 202280029124A CN 117177972 A CN117177972 A CN 117177972A
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alkyl
cycloalkyl
heterocycloalkyl
pharmaceutically acceptable
compound
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Chinese (zh)
Inventor
L·特佐斯
Q·董
S·W·卡尔多
R·L·霍夫曼
P·J·瓦
J·R·平克曼
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Xintra Co ltd
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Xintra Co ltd
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Priority claimed from PCT/US2022/025357 external-priority patent/WO2022225934A1/en
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Abstract

PARP1 inhibitors and pharmaceutical compositions comprising the inhibitors are described herein. The subject compounds and compositions are useful for treating cancer.

Description

PARP1 inhibitors and uses thereof
Cross reference
The present application claims the benefit of U.S. provisional application Ser. No. 63/176,610, filed on Ser. No. 63/183,563, filed on Ser. No. 3,5, 2021, and U.S. provisional application Ser. No. 63/254,832, filed on Ser. No. 63/254,832, 10, 2021, filed on Ser. No. 19, 4, 2021, which are hereby incorporated by reference in their entirety.
Background
Poly (ADP-ribose) polymerase (PARP) or poly (ADP-ribose) synthase (PARS) plays an important role in promoting DNA repair, controlling RNA transcription, mediating cell death, and regulating immune responses. These effects make PARP inhibitors targeted drugs for a wide variety of diseases. PARP inhibitors have demonstrated efficacy in many disease models, particularly models of ischemia reperfusion injury, inflammatory diseases, degenerative diseases, demonstrate protection against adverse effects of cytotoxic compounds and potentiation of cytotoxic cancer therapies. PARP is also useful for retroviral infections, and thus inhibitors are useful in antiretroviral therapy. PARP inhibitors are effective in preventing ischemia reperfusion injury in myocardial infarction, stroke, other neural trauma, organ transplantation, and reperfusion models of eye, kidney, intestine and skeletal muscle. Inhibitors are effective in inflammatory diseases such as arthritis, gout, inflammatory bowel disease, CNS inflammation such as MS and allergic encephalitis, sepsis, septic shock, hemorrhagic shock, pulmonary fibrosis and uveitis. PARP inhibitors have also shown benefit in several models of degenerative diseases including diabetes (and complications) and parkinson's disease. PARP inhibitors can ameliorate hepatotoxicity following acetaminophen overdose, cardiac and renal toxicity from doxorubicin and platinum-based antineoplastic agents, and skin damage secondary to sulfur mustard. In various cancer models, PARP inhibitors have been shown to potentiate radiation and chemotherapy by increasing cell death of cancer cells, limiting tumor growth, reducing metastasis, and prolonging survival of tumor-bearing animals.
PARP1 and PARP2 are the most widely studied PARPs because of their role in DNA damage repair. PARP1 is activated by DNA damage fragmentation and serves to catalyze the addition of poly (ADP-ribose) (PAR) chains to target proteins. This post-translational modification (called PAR formation) mediates the recruitment of additional DNA repair factors to the DNA lesion.
After this recruitment is completed, PARP auto-PAR-actuation triggers release of bound PARP from DNA to allow access to other DNA repair proteins to complete repair. Thus, binding of PARP to the site of injury, its catalytic activity and its final release from DNA are all important steps in cancer cells responding to DNA damage caused by chemotherapeutic agents and radiation therapy.
Inhibition of PARP family enzymes has been developed as a strategy to selectively kill cancer cells by inactivating complementary DNA repair pathways. Many preclinical and clinical studies have demonstrated that tumor cells harboring deleterious alterations of BRCA1 or BRCA2, key tumor suppressor proteins involved in double-stranded DNA break (DSB) repair by Homologous Recombination (HR), are selectively sensitive to small molecule inhibitors of the PARP family of DNA repair enzymes. Such tumors have defective Homologous Recombination Repair (HRR) pathways and rely on functional survival of the PARP enzyme. Although PARP inhibitor therapy targets mainly SRCA mutant cancers, clinical trials of PARP inhibitors have been conducted in non-SRCA mutant tumors that exhibit Homologous Recombination Defects (HRD).
PARP inhibitors with improved selectivity for PARP1 are believed to have improved efficacy and reduced toxicity compared to other clinical PARP1/2 inhibitors. It is also believed that the selective strong inhibition of PARP1 will lead to the capture of PARP1 on DNA, resulting in DNA Double Strand Breaks (DSBs) caused by collapse of the S-phase replication fork. PARP1-DNA capture is also believed to be an effective mechanism for selectively killing tumor cells with HRDs. Thus, there is an unmet medical need for effective and safe PARP inhibitors. In particular PARP inhibitors selective for PARP 1.
Disclosure of Invention
Disclosed herein is a compound of formula (III') or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:
wherein:
R C1 is hydrogen, deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally and independently substituted with one or more R Ca Substitution;
each R Ca Is independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl compoundsRadical, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
or two R's on the same atom Ca Together forming oxo;
R C2 is hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl or heterocycloalkyl;
R C3 is hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl or heterocycloalkyl;
each R 7 Independently hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl or heterocycloalkyl;
or two R 7 Together forming cycloalkyl or heterocycloalkyl; each of which is optionally substituted with deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
each R 8 Is independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
or two R's on the same carbon 8 Together forming oxo;
or two R's on the same carbon, adjacent carbon, or opposite carbon 8 Together forming cycloalkyl or heterocycloalkyl; each of which is optionally substituted with one OR more deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
n is 0-6;
R 12 is C 1 -C 6 Alkyl, C 1 -C 6 Deuterated alkyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
each R 11 Is independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl or heterocycloalkyl;
q is 0-3;
each R a Independently C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl group(heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 Alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
each R b Independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 Alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl、C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution; and
each R c And R is d Independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 Alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
or R is c And R is d Together with the atoms to which they are attached form a moiety optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl-substituted heterocycloalkyl.
Also disclosed herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.
Also disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising administering a compound disclosed herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. In some embodiments, the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, hematologic cancer, gastrointestinal cancer, or lung cancer.
Also disclosed herein is a method of treating cancer comprising BRCA1 and/or BRCA2 mutations in a subject in need thereof, the method comprising administering a compound according to any one of claims 1-70, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof. In some embodiments, the cancer is bladder, brain, and CNS cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, hodgkin's lymphoma, non-hodgkin's lymphoma, renal cancer, leukemia, lung cancer, melanoma, myeloma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, gastric cancer, thyroid cancer, or uterine cancer.
Incorporated by reference
All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.
Detailed Description
Definition of the definition
In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, it will be understood by those skilled in the art that the present invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Throughout the specification and the claims which follow, unless the context requires otherwise, the word "comprise" and variations such as "comprises" and "comprising" will be interpreted in an open, inclusive sense, i.e. as "including but not limited to. Furthermore, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.
Reference throughout this specification to "some embodiments" or "one embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrase "in one embodiment" or "in an embodiment" appearing in various places throughout the specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Furthermore, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. It should also be noted that the term "or" is generally employed in its sense including "and/or" unless the content clearly dictates otherwise.
As used herein, the following terms have the following meanings, unless otherwise indicated:
"oxo" means =o.
"carboxy" refers to-COOH.
"cyano" refers to-CN.
"alkyl" refers to a straight or branched saturated hydrocarbon monovalent radical having from one to about ten carbon atoms, more preferably from one to six carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2-dimethyl-1-butyl, 3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl and hexyl, and longer alkyl groups such as heptyl, octyl and the like. Whenever appearing herein, a numerical range such as "C 1 -C 6 Alkyl "or" C 1-6 Alkyl "means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but the present definition also covers the occurrence of the term" alkyl "where no numerical range is specified. In some embodiments, alkyl is C 1-10 An alkyl group. In some embodiments, alkyl is C 1-6 An alkyl group. In some embodiments, alkyl is C 1-5 An alkyl group. In some embodiments, alkyl is C 1-4 An alkyl group. In some embodiments, alkyl is C 1-3 An alkyl group. Unless specifically indicated otherwise in the specification, alkyl groups may be optionally substituted, for example by oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 or-NO 2 And (3) substitution. In some embodiments, alkyl is optionally substituted with halogen, -CN, -OH, or-OMe. In some embodiments, the alkyl group is optionally substituted with halo.
"alkenyl" refers to a straight or branched hydrocarbon monovalent radical having one or more carbon-carbon double bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. The group may be in cis or trans conformation with respect to the double bond and should be understood to include both isomers. Examples include, but are not limited to, vinyl (-ch=ch) 2 ) 1-propenyl (-CH) 2 CH＝CH 2 ) Isopropenyl [ -C (CH) 3 )＝CH 2 ]Butenyl, 1, 3-butadienyl, and the like. Whenever appearing herein, a numerical range such as "C 2 -C 6 Alkenyl "or" C 2-6 Alkenyl "means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4A composition of carbon atoms, 5 carbon atoms, or 6 carbon atoms, but the present definition also covers the occurrence of the term "alkenyl" in which no numerical range is specified. Unless specifically indicated otherwise in the specification, alkenyl groups may be optionally substituted, for example by oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkenyl is optionally oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 or-NO 2 And (3) substitution. In some embodiments, alkenyl is optionally substituted with halogen, -CN, -OH, or-OMe. In some embodiments, alkenyl is optionally substituted with halo.
"alkynyl" refers to a straight or branched hydrocarbon monovalent radical having one or more carbon-carbon triple bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1, 3-butadiynyl, and the like. Whenever appearing herein, a numerical range such as "C 2 -C 6 Alkynyl "or" C 2-6 Alkynyl "means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but the present definition also covers the occurrence of the term" alkynyl "where no numerical range is specified. Unless specifically indicated otherwise in the specification, alkynyl groups may be optionally substituted, for example by oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 or-NO 2 And (3) substitution. In some embodiments, alkynyl is optionally substituted with halogen, -CN, -OH, or-OMe. In some embodiments, alkynyl is optionally substituted with halo.
"alkylene" means a straight or branched divalent hydrocarbon chain. Unless otherwise specifically indicated in the specification, alkylene groups may be optionally substituted, e.g., by oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkylSubstituted heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkylene is optionally oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 or-NO 2 And (3) substitution. In some embodiments, the alkylene is optionally substituted with halogen, -CN, -OH, or-OMe. In some embodiments, the alkylene is optionally substituted with halo.
"alkoxy" means-OR a Wherein R is a group of a Is an alkyl group as defined. Unless specifically indicated otherwise in the specification, alkoxy groups may be optionally substituted, for example by oxo, halogen, amino, nitrile, nitro, hydroxy, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the alkoxy is optionally substituted with halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH 2 or-NO 2 And (3) substitution. In some embodiments, the alkoxy group is optionally substituted with halogen, -CN, -OH, or-OMe. In some embodiments, the alkoxy group is optionally substituted with halogen.
"aryl" refers to a group derived from a hydrocarbon ring system containing 6 to 30 carbon atoms and at least one aromatic ring. Aryl groups may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may include fused ring systems (when fused to a cycloalkyl or heterocycloalkyl ring, aryl groups are bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6 to 10 membered aryl. In some embodiments, the aryl is a 6 membered aryl (phenyl). Aryl groups include, but are not limited to, those derived from anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene,Aryl groups of hydrocarbon ring systems of fluoranthene, fluorene, asymmetric bisindene, symmetric bisindene, indane, indene, naphthalene, phenalene, phenanthrene, pyrene, and triphenylene. Unless specifically indicated otherwise in the specification, aryl groups may be optionally substituted, for example by halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodimentsAryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF 3 、-OH、-OMe、-NH 2 or-NO 2 And (3) substitution. In some embodiments, aryl is optionally substituted with halo, methyl, ethyl, -CN, -CF 3 -OH or-OMe substitution. In some embodiments, aryl is optionally substituted with halo.
"cycloalkyl" refers to a partially or fully saturated monocyclic or polycyclic carbocycle which may include a fused ring system (cycloalkyl being bonded through a non-aromatic ring atom when fused to an aryl or heteroaryl ring) or a bridged ring system. In some embodiments, cycloalkyl groups are fully saturated. Representative cycloalkyl groups include, but are not limited to, cycloalkyl groups having from three to fifteen carbon atoms (C 3 -C 15 Cycloalkyl or C 3 -C 15 Cycloalkenyl), cycloalkyl having three to ten carbon atoms (C 3 -C 10 Cycloalkyl or C 3 -C 10 Cycloalkenyl), cycloalkyl having three to eight carbon atoms (C 3 -C 8 Cycloalkyl or C 3 -C 8 Cycloalkenyl), cycloalkyl having three to six carbon atoms (C 3 -C 6 Cycloalkyl or C 3 -C 6 Cycloalkenyl), cycloalkyl having three to five carbon atoms (C 3 -C 5 Cycloalkyl or C 3 -C 5 Cycloalkenyl) or cycloalkyl having three to four carbon atoms (C) 3 -C 4 Cycloalkyl or C 3 -C 4 Cycloalkenyl group). In some embodiments, cycloalkyl is 3-to 10-membered cycloalkyl or 3-to 10-membered cycloalkenyl. In some embodiments, cycloalkyl is 3-to 6-membered cycloalkyl or 3-to 6-membered cycloalkenyl. In some embodiments, cycloalkyl is 5-to 6-membered cycloalkyl or 5-to 6-membered cycloalkenyl. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornyl, decalinyl, bicyclo [3.3.0 ] ]Octane, bicyclo [4.3.0 ]]Nonane, cis-decalin, trans-decalin, bicyclo [2.1.1]Hexane, bicyclo [2.2.1]Heptane, bicyclo [2.2.2]Octane, bicyclo [3.2.2]Nonane and bicyclo [3.3.2]Decane, and 7, 7-dimethyl-bicyclo [2.2.1]A heptyl group. The partially saturated cycloalkyl group includesSuch as cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless specifically indicated otherwise in the specification, cycloalkyl groups may be optionally substituted, for example, by oxo, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF 3 、-OH、-OMe、-NH 2 or-NO 2 And (3) substitution. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF 3 -OH or-OMe substitution. In some embodiments, cycloalkyl is optionally substituted with halo.
"halo" or "halogen" refers to bromine, chlorine, fluorine, or iodine. In some embodiments, the halogen is fluorine or chlorine. In some embodiments, the halogen is fluorine.
"haloalkyl" refers to an alkyl group as defined above substituted with one or more halo groups as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2-trifluoroethyl, 1, 2-difluoroethyl, 3-bromo-2-fluoropropyl, 1, 2-dibromoethyl and the like.
"hydroxyalkyl" refers to an alkyl group as defined above substituted with one or more hydroxyl groups. In some embodiments, the alkyl group is substituted with one hydroxy group. In some embodiments, the alkyl group is substituted with one, two, or three hydroxyl groups. Hydroxyalkyl groups include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl or hydroxypentyl. In some embodiments, the hydroxyalkyl group is hydroxymethyl.
"aminoalkyl" refers to an alkyl group as defined above substituted with one or more amines. In some embodiments, the alkyl group is substituted with one amine. In some embodiments, the alkyl group is substituted with one, two, or three amines. Aminoalkyl groups include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl or aminopentyl. In some embodiments, the aminoalkyl group is an aminomethyl group.
"cyanoalkyl" refers to an alkyl group as defined above substituted with one or more cyano groups. In some embodiments, the alkyl group is substituted with one cyano group. In some embodiments, the alkyl group is substituted with one or two cyano groups. Cyanoalkyl groups include, for example, cyanomethyl.
"deuterated alkyl" refers to an alkyl group as defined above substituted with one or more deuterium. In some embodiments, the alkyl group is substituted with one deuterium. In some embodiments, the alkyl group is substituted with one, two, or three deuterium. In some embodiments, the alkyl group is substituted with one, two, three, four, five, or six deuterium. Deuterated alkyl groups include, for example, CD 3 、CH 2 D、CHD 2 、CH 2 CD 3 、CD 2 CD 3 、CHDCD 3 、CH 2 CH 2 D or CH 2 CHD 2 . In some embodiments, the deuterated alkyl is CD 3 。
"heteroalkyl" refers to an alkyl group in which one or more backbone atoms of the alkyl group are selected from atoms other than carbon (e.g., oxygen, nitrogen (e.g., -NH-, -N (alkyl) -), sulfur, phosphorus, or a combination thereof). The heteroalkyl group is attached to the remainder of the molecule at a carbon atom of the heteroalkyl group. In one aspect, the heteroalkyl is C 1 -C 6 A heteroalkyl group, wherein the heteroalkyl group consists of 1 to 6 carbon atoms and one or more atoms other than carbon (e.g., oxygen, nitrogen (e.g., -NH-, -N (alkyl) -), sulfur, phosphorus, or a combination thereof), wherein the heteroalkyl group is attached to the remainder of the molecule at a carbon atom of the heteroalkyl group. Examples of such heteroalkyl groups are, for example, -CH 2 OCH 3 、-CH 2 CH 2 OCH 3 、-CH 2 CH 2 OCH 2 CH 2 OCH 3 、-CH(CH 3 )OCH 3 、-CH 2 NHCH 3 、-CH 2 N(CH 3 ) 2 、-CH 2 CH 2 NHCH 3 or-CH 2 CH 2 N(CH 3 ) 2 . Unless specifically indicated otherwise in the specification, heteroalkyl groups may be optionally substituted, e.g., with oxo, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some cases In embodiments, heteroalkyl is optionally substituted with oxo, halo, methyl, ethyl, -CN, -CF 3 、-OH、-OMe、-NH 2 or-NO 2 And (3) substitution. In some embodiments, heteroalkyl is optionally substituted with oxo, halo, methyl, ethyl, -CN, -CF 3 -OH or-OMe substitution. In some embodiments, the heteroalkyl is optionally substituted with halo.
"heterocycloalkyl" means a 3 to 24 membered partially or fully saturated cyclic group containing 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus and sulfur. In some embodiments, the heterocycloalkyl group is fully saturated. In some embodiments, the heterocycloalkyl group comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl group comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl group comprises one to three nitrogens. In some embodiments, the heterocycloalkyl group comprises one or two nitrogens. In some embodiments, the heterocycloalkyl group comprises one nitrogen. In some embodiments, the heterocycloalkyl group comprises one nitrogen and one oxygen. Unless specifically stated otherwise in the specification, heterocycloalkyl may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include a fused ring system (when fused to an aryl or heteroaryl ring, heterocycloalkyl is bonded through a non-aromatic ring atom) or a bridged ring system; and the nitrogen, carbon or sulfur atom in the heterocycloalkyl group may be optionally oxidized; the nitrogen atom may optionally be quaternized. Representative heterocycloalkyl groups include, but are not limited to, heterocycloalkyl groups having from two to fifteen carbon atoms (C 2 -C 15 Heterocycloalkyl or C 2 -C 15 Heterocycloalkenyl), heterocycloalkyl having two to ten carbon atoms (C) 2 -C 10 Heterocycloalkyl or C 2 -C 10 Heterocycloalkenyl), heterocycloalkyl having two to eight carbon atoms (C) 2 -C 8 Heterocycloalkyl or C 2 -C 8 Heterocycloalkenyl), heterocycloalkyl having two to seven carbon atoms (C) 2 -C 7 Heterocycloalkyl or C 2 -C 7 Heterocycloalkenyl), heterocycloalkyl having two to six carbon atoms (C) 2 -C 6 Heterocycloalkyl or C 2 -C 7 Heterocycloalkenyl), heterocycloalkyl having two to five carbon atoms (C) 2 -C 5 Heterocycloalkyl or C 2 -C 5 Heterocycloalkenyl) or heterocycloalkyl having two to four carbon atoms (C) 2 -C 4 Heterocycloalkyl or C 2 -C 4 Heterocycloalkenyl). Examples of such heterocycloalkyl groups include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl [1,3 ]]Dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidinyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1-dioxo-thiomorpholinyl, 1, 3-dihydroisobenzofuran-1-yl, 3-oxo-1, 3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1, 3-dioxol-4-yl and 2-oxo-1, 3-dioxol-4-yl. The term heterocycloalkyl also includes all cyclic forms of carbohydrates including, but not limited to, monosaccharides, disaccharides, and oligosaccharides. Unless otherwise indicated, heterocycloalkyl groups have 2 to 10 carbons in the ring. It is to be understood that when referring to the number of carbon atoms in the heterocycloalkyl group, the number of carbon atoms in the heterocycloalkyl group is different from the total number of atoms (including heteroatoms) constituting the heterocycloalkyl group (i.e., the backbone atoms of the heterocycloalkyl ring). In some embodiments, the heterocycloalkyl is a 3 to 8 membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3 to 7 membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3 to 6 membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4 to 6 membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5-to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3 to 7 membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4-to 6-membered heterocycloalkenyl. In some embodiments, the heterocycle Alkyl is a 5-to 6-membered heterocycloalkenyl. Unless specifically indicated otherwise in the specification, heterocycloalkyl groups may be optionally substituted as described below, for example by oxo, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF 3 、-OH、-OMe、-NH 2 or-NO 2 And (3) substitution. In some embodiments, heterocycloalkyl is optionally substituted with halo, methyl, ethyl, -CN, -CF 3 -OH or-OMe substitution. In some embodiments, the heterocycloalkyl group is optionally substituted with halo.
"heteroaryl" means a 5 to 14 membered ring system group comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl group comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl group comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, heteroaryl groups comprise one to three nitrogens. In some embodiments, heteroaryl groups comprise one or two nitrogens. In some embodiments, the heteroaryl group comprises one nitrogen. Heteroaryl groups may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may include fused ring systems (heteroaryl groups are bonded through an aromatic ring atom when fused to a cycloalkyl or heterocycloalkyl ring) or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl group may optionally be oxidized; the nitrogen atom may optionally be quaternized. In some embodiments, the heteroaryl is a 5-to 10-membered heteroaryl. In some embodiments, the heteroaryl is a 5-to 6-membered heteroaryl. In some embodiments, the heteroaryl is a 6 membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl. Examples include, but are not limited to, aza A radical, an acridinyl radical, a benzimidazolyl radical, a benzothiazolyl radical benzoindolyl group benzodioxolyl,Benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo [ b ]][1,4]Dioxepinyl, 1, 4-benzodioxanyl, benzonaphtofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothienyl), benzotriazole, benzo [4,6 ]]Imidazo [1,2-a]Pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxo-aza->A group, oxazolyl, oxiranyl, 1-oxopyridinyl, 1-oxopyrimidinyl, 1-oxopyrazinyl, 1-oxopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless specifically indicated otherwise in the specification, heteroaryl groups may be optionally substituted, for example by halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, heteroaryl is optionally substituted with halo, methyl, ethyl, -CN, -COOH, -COOMe, -CF 3 、-OH、-OMe、-NH 2 or-NO 2 And (3) substitution. In some embodiments, heteroaryl is optionally substituted with halo, methyl, ethyl, -CN, -CF 3 -OH or-OMe substitution. In some embodiments, heteroaryl is optionally substituted with halo.
The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occurThe description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted alkyl" refers to "alkyl" or "substituted alkyl" as defined above. In addition, the optionally substituted group may be unsubstituted (e.g., -CH 2 CH 3 ) Fully substituted (e.g. -CF) 2 CF 3 ) Monosubstituted (e.g. -CH 2 CH 2 F) Or substituted at any level between full substitution and single substitution (e.g., -CH 2 CHF 2 、-CH 2 CF 3 、-CF 2 CH 3 、-CFHCHF 2 Etc.). It will be understood by those skilled in the art that with respect to any group containing one or more substituents, such groups are not intended to introduce any substitution or pattern of substitution that is sterically impractical and/or synthetically infeasible (e.g., substituted alkyl groups include optionally substituted cycloalkyl groups, which in turn are defined to include optionally substituted alkyl groups, possibly unlimited). Thus, any substituent described is generally understood to have a maximum molecular weight of about 1,000 daltons, and more typically up to about 500 daltons.
An "effective amount" or "therapeutically effective amount" refers to the amount of a compound administered to a mammalian subject as a single dose or as part of a series of doses, which is effective to produce the desired therapeutic effect.
"treatment" of an individual (e.g., a mammal, such as a human) or cell is any type of intervention that is used to attempt to alter the natural course of the individual or cell. In some embodiments, the treatment comprises administering the pharmaceutical composition after initiating a pathological event or contacting with a pathogen, and comprises stabilizing the condition (e.g., the condition does not worsen) or alleviating the condition.
"synergistic" or "synergistically" means that the effect of the combination is greater than the sum of the effects of each component alone at the same dosage.
As used herein, "PARP-related disease or disorder" or alternatively "PARP-mediated disease or disorder" means any disease or other deleterious condition in which PARP or a mutant thereof is known or suspected to play a role.
As used herein, "PARP 1-related disease or disorder" or alternatively "PARP 1-mediated disease or disorder" means any disease or other deleterious condition in which PARP or a mutant thereof is known or suspected to play a role.
Compounds of formula (I)
Described herein are compounds of formula (I), (I '), (II), (III'), (III "), (IV) and (V), or pharmaceutically acceptable salts, solvates or stereoisomers thereof, useful in the treatment of cancer.
Disclosed herein is a compound of formula (I'), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:
wherein:
R 1 is hydrogen, deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Cyanoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl or heterocycloalkyl;
x is N or CR 2 ；
R 2 Is hydrogen, deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Cyanoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl or heterocycloalkyl;
z is N or CR 4 ；
R 4 Is hydrogen, deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Cyanoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl or heterocycleAn alkyl group;
y is N or CR 5 ；
R 5 Is hydrogen, deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Cyanoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl or heterocycloalkyl;
R 6 is hydrogen, deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Cyanoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl groups、C 2 -C 6 Alkynyl, cycloalkyl or heterocycloalkyl;
each R 7 Independently hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl or heterocycloalkyl;
or two R 7 Together forming cycloalkyl or heterocycloalkyl; each of which is optionally substituted with deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
each R 8 Is independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
or two R's on the same carbon 8 Together forming oxo;
or two R's on the same carbon, adjacent carbon, or opposite carbon 8 Together forming cycloalkyl or heterocycloalkyl; each of which is optionally substituted with one OR more deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
n is 0-6;
R 12 is cycloalkyl or heterocycloalkyl; wherein the cycloalkyl and heterocycloalkyl are optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
each R 11 Is independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl or heterocycloalkyl;
q is 0-3;
each R a Independently C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 Alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
Each R b Independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (Ring)Alkyl group, C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 Alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution; and
each R c And R is d Independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 Alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
or R is c And R is d Together with the atoms to which they are attached form a moiety optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl-substituted heterocycloalkyl.
Disclosed herein is a compound of formula (I) or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:
wherein:
R 1 is hydrogen, deuterium, halogen, -CN, -NO 2 、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Cyanoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl or heterocycloalkyl;
x is N or CR 2 ；
R 2 Is hydrogen, deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Cyanoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl or heterocycloalkyl;
or R is 1 And R is 2 Together forming cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each of which is optionally substituted with deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl or heterocycloalkyl substitution;
z is N or CR 4 ；
R 4 Is hydrogen, deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Cyanoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl or heterocycloalkyl;
y is N or CR 5 ；
R 5 Is hydrogen, deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Cyanoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkaneA group or heterocycloalkyl;
R 6 is hydrogen, deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Cyanoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl or heterocycloalkyl;
each R 7 Independently hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl or heterocycloalkyl;
or two R 7 Together forming cycloalkyl or heterocycloalkyl; each of which is optionally substituted with deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
each R 8 Is independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
or two R's on the same carbon 8 Together forming oxo;
or two R's on the same carbon, adjacent carbon, or opposite carbon 8 Together forming cycloalkyl or heterocycloalkyl; each of which is optionally substituted with one OR more deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
n is 0-6;
ring a is a 3 to 16-membered monocyclic, bicyclic or tricyclic ring optionally containing 1 to 5 heteroatoms selected from the group consisting of O, N, S, P or B;
each R A Is independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally and independently substituted with one or more R Aa Substitution;
or two R's on the same atom A Together forming oxo;
each R Aa Is independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
or two R's on the same atom Aa Together forming oxo;
m is 0-6;
each R a Independently C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 Alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
each R b Independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 Alkyl (heteroaryl); wherein each of alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl The radicals are independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution; and
each R c And R is d Independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 Alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl extractionSubstitution;
or R is c And R is d Together with the atoms to which they are attached form a moiety optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl-substituted heterocycloalkyl;
provided that at least one of X or Y is N; and
provided that when n is 0, thenNot be- >
In some embodiments of the compounds of formula (I) or (I'), R 1 Is C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Cyanoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkynyl or cycloalkyl.
In some embodiments of the compounds of formula (I) or (I'), R 1 Is halogen or cycloalkyl.
In some embodiments of the compounds of formula (I) or (I'), R 1 Is cycloalkyl.
In some embodiments of the compounds of formula (I) or (I'), R 1 Is C 1 -C 6 An alkyl group.
In some embodiments of the compounds of formula (I) or (I'), X is N and Y is CR 5 。
In some embodiments of the compounds of formula (I) or (I'), R 5 Is hydrogen, deuterium, halogen, C 1 -C 6 Alkyl, C1-C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Cyanoalkyl, C 1 -C 6 Heteroalkyl or cycloalkyl. In some embodiments of the compounds of formula (I) or (I'), R 5 Is hydrogen, deuterium, halogen or C 1 -C 6 An alkyl group. In some embodiments of the compounds of formula (I) or (I'), R 5 Is hydrogen.
In some embodiments of the compounds of formula (I) or (I'), X is CR 2 And Y is N.
In some embodiments of the compounds of formula (I) or (I'), R 2 Is hydrogen, deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Cyanoalkyl, C 1 -C 6 Heteroalkyl or cycloalkyl. In some embodiments of the compounds of formula (I) or (I'), R 2 Is hydrogen, deuterium, halogen or C 1 -C 6 An alkyl group. In some embodiments of the compounds of formula (I) or (I'), R 2 Is hydrogen. In some embodiments of the compounds of formula (I) or (I'), R 2 Is hydrogen or C 1 -C 6 An alkyl group. In some embodiments of the compounds of formula (I) or (I'), R 2 Is C 1 -C 6 An alkyl group.
In some embodiments of the compounds of formula (I) or (I'), X is N and Y is N.
In the course ofI) Or a compound of formula (I'), Z is N. In some embodiments of the compounds of formula (I) or (I'), Z is CR 4 。
In some embodiments of the compounds of formula (I) or (I'), R 4 Is hydrogen, deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Cyanoalkyl, C 1 -C 6 Heteroalkyl or cycloalkyl. In some embodiments of the compounds of formula (I) or (I'), R 4 Is hydrogen, deuterium, halogen or C 1 -C 6 An alkyl group. In some embodiments of the compounds of formula (I) or (I'), R 4 Is hydrogen.
In some embodiments of the compounds of formula (I) or (I'), R 6 Is hydrogen, deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Cyanoalkyl, C 1 -C 6 Heteroalkyl or cycloalkyl. In some embodiments of the compounds of formula (I) or (I'), R 6 Is hydrogen, deuterium, halogen or C 1 -C 6 An alkyl group. In some embodiments of the compounds of formula (I) or (I'), R 6 Is hydrogen.
In some embodiments of the compounds of formula (I) or formula (I'), each R 7 Independently hydrogen, deuterium, halogen, C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group. In some embodiments of the compounds of formula (I) or formula (I'), each R 7 Is hydrogen. In some embodiments of the compounds of formula (I) or (I'), two R 7 Together forming a cycloalkyl group.
In some embodiments of the compounds of formula (I) or formula (I'), each R 8 Is C 1 -C 6 An alkyl group; or two R's on the same carbon 8 Together form oxo. In some embodiments of the compounds of formula (I) or (I '), two R's on opposite carbons 8 Together forming a cycloalkyl group. In some embodiments of the compounds of formula (I) or (I '), two R's on the same carbon 8 Together forming a cycloalkyl group. In some embodiments of the compounds of formula (I) or (I '), two R's on adjacent carbons 8 Together forming a cycloalkyl group.
In some embodiments of the compounds of formula (I) or formula (I'), n is 0. In some embodiments of the compounds of formula (I) or formula (I'), n is 1. In some embodiments of the compounds of formula (I) or formula (I'), n is 2. In some embodiments of the compounds of formula (I) or formula (I'), n is 3. In some embodiments of the compounds of formula (I) or formula (I'), n is 4. In some embodiments of the compounds of formula (I) or formula (I'), n is 5. In some embodiments of the compounds of formula (I) or formula (I'), n is 6. In some embodiments of the compounds of formula (I) or formula (I'), n is 0-3. In some embodiments of the compounds of formula (I) or formula (I'), n is 1-3. In some embodiments of the compounds of formula (I) or (I'), n is 1 or 2. In some embodiments of the compounds of formula (I) or formula (I'), n is 1-4. In some embodiments of the compounds of formula (I) or formula (I'), n is 2-4.
In some embodiments of the compounds of formula (I), ring a is a 3 to 7 membered monocyclic ring, optionally comprising 1 to 3 heteroatoms selected from the group consisting of O, N or S.
In some embodiments of the compounds of formula (I), ring a is phenyl.
In some embodiments of the compounds of formula (I), ring a is a 5 to 6 membered heteroaryl group comprising 1 to 3 heteroatoms selected from the group consisting of O, N or S.
In some embodiments of the compounds of formula (I), ring a is a 5 membered heteroaryl comprising 1 to 3 heteroatoms selected from the group consisting of O, N or S.
In some embodiments of the compounds of formula (I), ring a is a 6 membered heteroaryl group comprising 1 to 3 heteroatoms which are N.
In some embodiments of the compounds of formula (I), ring a is pyridinyl.
In some embodiments of the compounds of formula (I), ring a is not pyridinyl.
The compound of any one of claims 1-26, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring a is a 3-to 7-membered cycloalkyl.
In some embodiments of the compounds of formula (I), ring a is a 3 to 7 membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from the group consisting of O, N or S.
In some embodiments of the compounds of formula (I), ring a is a 6 to 12 membered bicyclic ring, optionally comprising 1 to 3 heteroatoms selected from the group consisting of O, N or S.
In some embodiments of the compounds of formula (I), ring a is a 6 to 12 membered bicyclic heterocycloalkyl comprising 1 to 3 heteroatoms selected from the group consisting of O, N or S.
In some embodiments of the compounds of formula (I), ring a is a 6 to 12 membered bicyclic heteroaryl comprising 1 to 3 heteroatoms selected from the group consisting of O, N or S.
In some embodiments of the compounds of formula (I), ring a is a 6 to 12 membered bicyclic partially saturated ring, optionally comprising 1 to 3 heteroatoms selected from the group consisting of O, N or S.
In some embodiments of the compounds of formula (I), each R A Is independently deuterium, halogen, -CN, -OH, -OR a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally and independently substituted with one or more R Aa Substitution; or two R's on the same atom A Together forming oxo. Compounds of formula (I)In some embodiments of (2), each R A Independently deuterium, halogen, -S (=o) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally and independently substituted with one or more R Aa Substitution; or two R's on the same atom A Together forming oxo. In some embodiments of the compounds of formula (I), each R A Independently halogen, -C (=o) NR c R d Or C 1 -C 6 An alkyl group. In some embodiments of the compounds of formula (I), each R A Independently is-C (=O) NR c R d . In some embodiments of the compounds of formula (I), R A not-C (=O) NR c R d . In some embodiments of the compounds of formula (I), each R A Independently optionally and independently substituted with one or more R Aa Substituted heteroaryl groups.
In some embodiments of the compounds of formula (I), each R Aa Is independently deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R's on the same atom Aa Together forming oxo. In some embodiments of the compounds of formula (I), each R Aa Is independently deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 A heteroalkyl group; or two R's on the same atom Aa Together forming oxo.
In some embodiments of the compounds of formula (I), m is 0 to 4. In some embodiments of the compounds of formula (I), m is 0 or 1. In some embodiments of the compounds of formula (I), m is 2 or 3. In some embodiments of the compounds of formula (I), m is 1 or 2. In some embodiments of the compounds of formula (I), m is 0. In some embodiments of the compounds of formula (I), m is 1. In some embodiments of the compounds of formula (I), m is 2. In some embodiments of the compounds of formula (I), m is 3. In some embodiments of the compounds of formula (I), m is 4. In some embodiments of the compounds of formula (I), m is 5. In some embodiments of the compounds of formula (I), m is 6.
In some embodiments of the compounds of formula (I),is->
In some embodiments of the compounds of formula (I),is->
In some embodiments of the compounds of formula (I),is-> In some embodiments of the compounds of formula (I), the amino acid sequence of formula (I)>Is->In some embodiments of the compounds of formula (I), the amino acid sequence of formula (I)>Is that
In some embodiments of the compounds of formula (I'), each R 11 Is independently deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of formula (I'), each R 11 Is independently deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 Deuterated alkyl. In some embodiments of the compounds of formula (I'), each R 11 Independently halogen or C 1 -C 6 An alkyl group. At the position ofIn some embodiments of the compounds of formula (I'), each R 11 Independently halogen.
In some embodiments of the compounds of formula (I'), q is 0 or 1. In some embodiments of the compounds of formula (I'), q is 1 or 2. In some embodiments of the compounds of formula (I'), q is 0. In some embodiments of the compounds of formula (I'), q is 1. In some embodiments of the compounds of formula (I'), q is 2. In some embodiments of the compounds of formula (I'), q is 3.
In some embodiments of the compounds of formula (I'), R 12 Is cycloalkyl. In some embodiments of the compounds of formula (I'), R 12 Is cycloalkyl.
In some embodiments of the compounds of formula (I), the compound is a compound of the formula:wherein R is 1 Is C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 Deuterated alkyl; y is N, CH or CF; each A 1 CH, CD, CMe, CCF independently 3 Cci, CF or N; each R A Independently hydrogen, deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, NHMe or NHCD 3 。
In some embodiments of the compounds of formula (I), the compound is a compound of the formula:wherein R is 1 Is C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 Deuterated alkyl; y is N, CH or CF; each A 1 CH, CD, CMe, CCF independently 3 Cci, CF or N; each R A Independently hydrogen, deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, NHMe or NHCD 3 。
In some embodiments of the compounds of formula (I), the compound is a compound of the formula:wherein R is 1 Is C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 Deuterated alkyl; y is N, CH or CF; each A 1 CH, CD, CMe, CCF independently 3 Cci, CF or N; each R A Independently hydrogen, deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, NHMe or NHCD 3 ；A 2 Is O, NH, NMe or NCD 3 The method comprises the steps of carrying out a first treatment on the surface of the And A is 3 Is N, CH, CF or CD.
In some embodiments of the compounds of formula (I), the compound is a compound of the formula:wherein R is 1 Is C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 Deuterated alkyl; y is N, CH or CF; each A 1 CH, CD, CMe, CCF independently 3 Cci, CF or N; each R A Independently hydrogen, deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, NHMe or NHCD 3 ；A 2 Is O, NH, NMe or NCD 3 The method comprises the steps of carrying out a first treatment on the surface of the And A is 3 Is N, CH, CF or CD.
In some embodiments of the compounds of formula (I), the compound is a compound of the formula: wherein R is 1 Is C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 Deuterated alkyl; y is N, CH or CF; each A is independently CH, CD, CMe, CCF 3 Cci, CF or N; w is CH 2 、CF 2 、CD 2 CHF, CHD; each R 11 Independently hydrogen, deuterium, or halogen; and R is 12 Is C 1 -C 6 Alkyl or C 1 -C 6 Deuterated alkyl.
Also disclosed herein is a compound of formula (II), or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:
wherein:
R 1 is hydrogen, deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Cyanoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl or C 2 -C 6 Alkynyl, cycloalkyl or heterocycloalkyl;
x is N or CR 2 ；
R 2 Is hydrogen, deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl or heterocycloalkyl;
or R is 1 And R is 2 Together forming cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each of which is optionally substituted with deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl or heterocycloalkyl substitution;
z is N or CR 4 ；
R 4 Is hydrogen, deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl or heterocycloalkyl;
y is N or CR 5 ；
R 5 Is hydrogen, deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl or heterocycloalkyl;
R 6 is hydrogen, deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl or heterocycloalkyl;
W 1 is absent as-C (R 7 ) 2 -、-O-、-S-、-NR W1 -、-C(R 7 ) 2 C(R 7 ) 2 -、-C(R 7 ) 2 NR W1 -、-NR W1 C(R 7 ) 2 -、-C(R 7 ) 2 O-、-OC(R 7 ) 2 -、-C(R 7 ) 2 S-or-SC (R) 7 ) 2 -；
Each R 7 Independently hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl or heterocycloalkyl;
or two R 7 Together forming cycloalkyl or heterocycloalkyl; each of which is optionally substituted with deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
R W1 is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 Deuterated alkyl;
ring B is a 3 to 16-membered monocyclic, bicyclic or tricyclic ring, optionally containing 1 to 5 heteroatoms selected from the group consisting of O, N, S, P or B;
each R B Is independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally and independently substituted with one or more R Ba Substitution;
or two R's on the same atom B Together forming oxo;
each R Ba Is independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
or two R's on the same atom Ba Together forming oxo;
p is 0-6;
W 2 is absent as-C (R 9 ) 2 -、-O-、-S-、-NR W2 -、-C(R 9 ) 2 C(R 9 ) 2 -、-C(R 9 ) 2 NR W2 -、-NR W2 C(R 9 ) 2 -、-C(R 9 ) 2 O-、-OC(R 9 ) 2 -、-C(R 9 ) 2 S-or-SC (R) 9 ) 2 -；
Each R 9 Independently hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl or heterocycloalkyl;
or two R 9 Together forming cycloalkyl or heterocycloalkyl; each of which is optionally substituted with deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
R W2 is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 Deuterated alkyl;
each R 11 Is independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl or heterocycloalkyl;
q is 0-3;
each R a Independently C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 Alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
each R b Independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroarylAryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 Alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution; and
each R c And R is d Independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 Alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
or R is c And R is d Together with the atoms to which they are attached form a moiety optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl-substituted heterocycloalkyl;
provided that it isNot->
In some embodiments of the compounds of formula (II), R 1 Is C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Cyanoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl or cycloalkyl. In some embodiments of the compounds of formula (II), R 1 Is C 1 -C 6 An alkyl group.
In some embodiments of the compounds of formula (II), X is CR 2 And Y is CR 5 。
In some embodiments of the compounds of formula (II), X is N and Y is CR 5 。
In some embodiments of the compounds of formula (II), R 5 Is hydrogen, deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Cyanoalkyl, C 1 -C 6 Heteroalkyl or cycloalkyl. In some embodiments of the compounds of formula (II), R 5 Is hydrogen, deuterium, halogen or C 1 -C 6 An alkyl group. In some embodiments of the compounds of formula (II), R 5 Is hydrogen.
In some embodiments of the compounds of formula (II), X is CR 2 And Y is N.
In some embodiments of the compounds of formula (II), R 2 Is hydrogen, deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Cyanoalkyl, C 1 -C 6 Heteroalkyl or cycloalkyl. In some embodiments of the compounds of formula (II), R 2 Is hydrogen, deuterium, halogen or C 1 -C 6 An alkyl group. In some embodiments of the compounds of formula (II), R 2 Is hydrogen.
In some embodiments of the compounds of formula (II), X is N and Y is N.
In some embodiments of the compounds of formula (II), Z is N. In some embodiments of the compounds of formula (II), Z is CR 4 。
In some embodiments of the compounds of formula (II), R 4 Is hydrogen, deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Cyanoalkyl, C 1 -C 6 Heteroalkyl or cycloalkyl. In some embodiments of the compounds of formula (II), R 4 Is hydrogen, deuterium, halogen or C 1 -C 6 An alkyl group. In some embodiments of the compounds of formula (II), R 4 Is hydrogen.
In some embodiments of the compounds of formula (II), R 6 Is hydrogen, deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Cyanoalkyl, C 1 -C 6 Heteroalkyl or cycloalkyl. In some embodiments of the compounds of formula (II), R 6 Is hydrogen, deuterium, halogen or C 1 -C 6 An alkyl group. In some embodiments of the compounds of formula (II), R 6 Is hydrogen.
In some embodiments of the compounds of formula (II), W 1 is-C (R) 7 ) 2 -、-NR W1 -、-C(R 7 ) 2 C(R 7 ) 2 -、-C(R 7 ) 2 NR W1 -or-NR W1 C(R 7 ) 2 -. In some embodiments of the compounds of formula (II), W 1 is-C (R) 7 ) 2 -、-NR W1 -or-C (R) 7 ) 2 NR W1 -. In some embodiments of the compounds of formula (II), W 1 is-C (R) 7 ) 2 -。
In some embodiments of the compounds of formula (II), each R 7 Independently hydrogen, deuterium, halogen, C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group. In some embodiments of the compounds of formula (II), each R 7 Is hydrogen. In some embodiments of the compounds of formula (II), two R 7 Together forming a cycloalkyl group.
In some embodiments of the compounds of formula (II), R W1 Is hydrogen or C 1 -C 6 An alkyl group. In formula (II)In some embodiments of the compounds, R W1 Is hydrogen.
In some embodiments of the compounds of formula (II), W 2 Is absent as-C (R 9 ) 2 -、-NR W2 -、-C(R 9 ) 2 C(R 9 ) 2 -、-C(R 9 ) 2 NR W2 -or-NR W2 C(R 9 ) 2 -。
In some embodiments of the compounds of formula (II), W 1 Absence or-NR W2 -. In some embodiments of the compounds of formula (II), W 2 Is not present. In some embodiments of the compounds of formula (II), W 2 is-O-.
In some embodiments of the compounds of formula (II), each R 9 Independently hydrogen, deuterium, halogen, C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group. In some embodiments of the compounds of formula (II), each R 9 Is hydrogen. In some embodiments of the compounds of formula (II), two R 799 Together forming a cycloalkyl group.
In some embodiments of the compounds of formula (II), R W2 Is hydrogen or C 1 -C 6 An alkyl group. In some embodiments of the compounds of formula (II), R W2 Is hydrogen.
The compound of any one of claims 50-81, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein ring B is a 3 to 7 membered monocyclic ring, optionally comprising 1 to 3 heteroatoms selected from the group consisting of O, N or S.
In some embodiments of the compounds of formula (II), ring B is a 3 to 7 membered cycloalkyl.
In some embodiments of the compounds of formula (II), ring B is a 3 to 7 membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from the group consisting of O, N or S.
In some embodiments of the compounds of formula (II), ring B is piperazinyl.
In some embodiments of the compounds of formula (II), ring B is not piperazinyl.
In some embodiments of the compounds of formula (II), ring B is a 6 to 12 membered bicyclic ring, optionally comprising 1 to 3 heteroatoms selected from the group consisting of O, N or S.
In some embodiments of the compounds of formula (II), ring B is a 6 to 12 membered bicyclic heterocycloalkyl comprising 1 to 3 heteroatoms selected from the group consisting of O, N or S.
In some embodiments of the compounds of formula (II), ring B is a 6 to 12 membered bicyclic heterocycloalkyl containing 1 to 3 heteroatoms that are N.
In some embodiments of the compounds of formula (II), ring B is a 6 to 16 membered tricyclic ring, optionally comprising 1 to 3 heteroatoms selected from the group consisting of O, N or S.
In some embodiments of the compounds of formula (II), ring B is a 6 to 16 membered tricyclic heterocycloalkyl comprising 1 to 3 heteroatoms selected from the group consisting of O, N or S.
In some embodiments of the compounds of formula (II), ring B is a 6 to 16 membered tricyclic heterocycloalkyl containing 1 to 3 heteroatoms that are N.
In some embodiments of the compounds of formula (II), each R B Is independently deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl; or two R's on the same atom B Together forming oxo.
In some embodiments of the compounds of formula (II), each R B Is independently deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 Deuterated alkyl; or two R's on the same atom B Together forming oxo.
In some embodiments of the compounds of formula (II), p is 0-4. In some embodiments of the compounds of formula (II), p is 0 or 1. In some embodiments of the compounds of formula (II), p is 1 or 2. In some embodiments of the compounds of formula (II), p is 1. In some embodiments of the compounds of formula (II), p is 2. In some embodiments of the compounds of formula (II), p is 3. In some embodiments of the compounds of formula (II), p is 4.
In some embodiments of the compounds of formula (II),is->
In some embodiments of the compounds of formula (II),is->
In some embodiments of the compounds of formula (II), each R 11 Is independently deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of formula (II), each R 11 Is independently deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 Deuterated alkyl. In some embodiments of the compounds of formula (II), each R 11 Independent and independentWith halogen or C 1 -C 6 An alkyl group.
In some embodiments of the compounds of formula (II), q is 0 or 1. In some embodiments of the compounds of formula (II), q is 1 or 2. In some embodiments of the compounds of formula (II), q is 1. In some embodiments of the compounds of formula (II), q is 0. In some embodiments of the compounds of formula (II), q is 2. In some embodiments of the compound of formula (II), q is 3.
Also disclosed herein is a compound of formula (III') or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:
wherein:
R C1 is hydrogen, deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally and independently substituted with one or more R Ca Substitution;
each R Ca Is independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
or two R's on the same atom Ca Together forming oxo;
R C2 is hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl or heterocycloalkyl;
R C3 is hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl or heterocycloalkyl;
each R 7 Independently hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl or heterocycloalkyl;
or two R 7 Together forming cycloalkyl or heterocycloalkyl; each of which is optionally substituted with deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
each R 8 Is independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
Or two R's on the same carbon 8 Together forming oxo;
or two R's on the same carbon, adjacent carbon, or opposite carbon 8 Together forming cycloalkyl or heterocycloalkyl; each of which is optionally substituted with one OR more deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
n is 0-6;
R 12 is C 1 -C 6 Alkyl, C 1 -C 6 Deuterated alkyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
each R 11 Is independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl or heterocycloalkyl;
q is 0-3;
each R a Independently C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 Alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
each R b Independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl group(cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 Alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution; and
each R c And R is d Independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 Alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
or R is c And R is d Together with the atoms to which they are attached form a moiety optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl-substituted heterocycloalkyl.
In some embodiments of the compounds of formula (III'), R C1 Is deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally and independently substituted with one or more R Ca And (3) substitution. In some embodiments of the compounds of formula (III'), R C1 Is halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of formula (III'), R C1 Is halogen, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of formula (III'), R C1 Is halogen or cycloalkyl. In some embodiments of the compounds of formula (III'), R C1 Is halogen. In the compounds of formula (III')In some embodiments, R C1 Is cycloalkyl.
In some embodiments of the compounds of formula (III "), each R Ca Is independently deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of formula (III "), each R Ca Is independently deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group.
In some embodiments of the compounds of formula (III'), R C2 Is hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group. In some embodiments of the compounds of formula (III'), R C2 Is hydrogen, deuterium, halogen, C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group. In some embodiments of the compounds of formula (III'), R C2 Is hydrogen, C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group. In some embodiments of the compounds of formula (III'), R C2 Is hydrogen or C 1 -C 6 An alkyl group. In some embodiments of the compounds of formula (III'), R C2 Is hydrogen. In some embodiments of the compounds of formula (III'), R C2 Is C 1 -C 6 An alkyl group.
In some embodiments of the compounds of formula (III'), R C3 Is hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group. In some embodiments of the compounds of formula (III'), R C3 Is hydrogen, deuterium, halogen, C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group. In some embodiments of the compounds of formula (III'), R C3 Is hydrogen, C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group. In some embodiments of the compounds of formula (III'), R C3 Is hydrogen or C 1 -C 6 An alkyl group. In some embodiments of the compounds of formula (III'), R C3 Is hydrogen. In some embodiments of the compounds of formula (III'), R C3 Is C 1 -C 6 An alkyl group.
In some embodiments of the compounds of formula (III "),is that
In some embodiments of the compounds of formula (III "),is thatIn some embodiments of the compounds of formula (III'), the pharmaceutically acceptable salts thereof>Is->In some embodiments of the compounds of formula (III'), the pharmaceutically acceptable salts thereof>Is thatIn some embodiments of the compounds of formula (III'), the pharmaceutically acceptable salts thereof>Is thatIn some embodiments of the compounds of formula (III'), the pharmaceutically acceptable salts thereof>Is thatIn some embodiments of the compounds of formula (III'), the pharmaceutically acceptable salts thereof>Is thatIn some embodiments of the compounds of formula (III'), the pharmaceutically acceptable salts thereof>Is thatIn some embodiments of the compounds of formula (III'), the pharmaceutically acceptable salts thereof>Is thatIn some embodiments of the compounds of formula (III'), the pharmaceutically acceptable salts thereof>Is thatIn some embodiments of the compounds of formula (III'), the pharmaceutically acceptable salts thereof>Is thatIn some embodiments of the compounds of formula (III'), the pharmaceutically acceptable salts thereof >Is->
In some embodiments of the compounds of formula (III "), each R 7 Independently hydrogen, deuterium, halogen, C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group. In some embodiments of the compounds of formula (III "), each R 7 Is hydrogen. In some embodiments of the compounds of formula (III'), two R 7 Together forming a cycloalkyl group.
In some embodiments of the compounds of formula (III "), each R 8 Is C 1 -C 6 An alkyl group; or two R's on the same carbon 8 Together forming oxo. In some embodiments of the compounds of formula (III '), two R's on opposite carbons 8 Together forming a cycloalkyl group. In some embodiments of the compounds of formula (III '), two R's on the same carbon 8 Together forming a cycloalkyl group. In some embodiments of the compounds of formula (III '), two R's on adjacent carbons 8 Together forming a cycloalkyl group.
In some embodiments of the compounds of formula (III "), n is 0. In some embodiments of the compounds of formula (III "), n is 1. In some embodiments of the compounds of formula (III "), n is 2. In some embodiments of the compounds of formula (III "), n is 3. In some embodiments of the compounds of formula (III "), n is 4. In some embodiments of the compounds of formula (III "), n is 5. In some embodiments of the compounds of formula (III "), n is 6. In some embodiments of the compounds of formula (III'), n is 0-3. In some embodiments of the compounds of formula (III'), n is 1-3. In some embodiments of the compounds of formula (III "), n is 1 or 2. In some embodiments of the compounds of formula (III'), n is 1-4. In some embodiments of the compounds of formula (III "), n is 2-4.
In some embodiments of the compounds of formula (III "), each R 11 Is independently deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of formula (III "), each R 11 Is independently deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 Deuterated alkyl. In some embodiments of the compounds of formula (III "), each R 11 Independently halogen or C 1 -C 6 An alkyl group. In some embodiments of the compounds of formula (III "), each R 11 Independently halogen.
In some embodiments of the compounds of formula (III "), q is 0 or 1. In some embodiments of the compounds of formula (III "), q is 1 or 2. In some embodiments of the compounds of formula (III "), q is 0. In some embodiments of the compounds of formula (III "), q is 1. In some embodiments of the compounds of formula (III "), q is 2. In some embodiments of the compounds of formula (III "), q is 3.
In some embodiments of the compounds of formula (III'), R 12 Is C 1 -C 6 Alkyl or cycloalkyl. In some embodiments of the compounds of formula (III'), R 12 Is C 1 -C 6 An alkyl group. In some embodiments of the compounds of formula (III'), R 12 Is cycloalkyl.
Also disclosed herein is a compound of formula (III'), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
wherein:
ring C is a 3 to 16-membered monocyclic, bicyclic or tricyclic ring optionally containing 1 to 5 heteroatoms selected from the group consisting of O, N, S, P or B;
each R C Is independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally and independently substituted with one or more R Ca Substitution;
or two R's on the same atom C Together forming oxo;
each R Ca Is independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
or two R's on the same atom Ca Together forming oxo;
r is 0-6;
W 3 absent, is-C (R) 7 ) 2 -or C 2 Alkynylene;
each R 7 Independently hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl or heterocycloalkyl;
or two R 7 Together forming cycloalkyl or heterocycloalkyl; each of which is optionally substituted with deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
each R 8 Is independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
or two R's on the same carbon 8 Together forming oxo;
or two R's on the same carbon, adjacent carbon, or opposite carbon 8 Together forming cycloalkyl or heterocycloalkyl; each of which is optionally substituted with one OR more deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
n is 0-6;
a is N or CR 11 Or CH;
R 12 is C 1 -C 6 Alkyl or C 1 -C 6 Deuterated alkyl;
each R 11 Is independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl or heterocycloalkyl;
q is 0-3;
each R a Independently C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 Alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
each R b Independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 Alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution; and
each R c And R is d Independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 Alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
or R is c And R is d Together with the atoms to which they are attached form a moiety optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl-substituted heterocycloalkyl;
provided that when n is 0, thenNot be->
Also disclosed herein is a compound of formula (III):
wherein:
ring C is a 3 to 16-membered monocyclic, bicyclic or tricyclic ring optionally containing 1 to 5 heteroatoms selected from the group consisting of O, N, S, P or B;
Each R C Is independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally and independently substituted with one or more R Ca Substitution;
or two R's on the same atom C Together forming oxo;
each R Ca Is independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
or two R's on the same atom Ca Together forming oxo;
r is 0-6;
W 3 absent, is-C (R) 7 ) 2 -or C 2 Alkynylene;
each R 7 Independently hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl or heterocycloalkyl;
or two R 7 Together forming cycloalkyl or heterocycloalkyl; each of which is optionally substituted with deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
each R 8 Is independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
or two R's on the same carbon 8 Together forming oxo;
or two R's on the same carbon, adjacent carbon, or opposite carbon 8 Together forming cycloalkyl or heterocycloalkyl; each of which is optionally substituted with one OR more deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
n is 0-6;
each R 11 Is independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl or heterocycloalkyl;
q is 0-3;
each R a Independently C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 Alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
each R b Independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl,Heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 Alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution; and
each R c And R is d Independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 Alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
or R is c And R is d Together with the atoms to which they are attached form a moiety optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl-substituted heterocycloalkyl;
provided that when n is 0, thenNot be->
In some embodiments of the compounds of formula (III) or (III'), ring C is a 3 to 7 membered monocyclic ring, optionally comprising 1 to 3 heteroatoms selected from the group consisting of O, N or S.
In some embodiments of the compounds of formula (III) or (III'), ring C is phenyl.
In some embodiments of the compounds of formula (III) or (III'), ring C is a 5 to 6 membered heteroaryl group comprising 1 to 3 heteroatoms selected from the group consisting of O, N or S.
In some embodiments of the compounds of formula (III) or (III'), ring a is a 5-membered heteroaryl group comprising 1 to 3 heteroatoms selected from the group consisting of O, N or S.
In some embodiments of the compounds of formula (III) or (III'), ring a is a 6 membered heteroaryl group comprising 1 to 3 heteroatoms that are N.
In some embodiments of the compounds of formula (III) or (III'), ring C is a 3 to 7 membered cycloalkyl.
In some embodiments of the compounds of formula (III) or (III'), ring C is a 3 to 7 membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from the group consisting of O, N or S.
In some embodiments of the compounds of formula (III) or (III'), ring C is a 6 to 12 membered bicyclic ring, optionally comprising 1 to 3 heteroatoms selected from the group consisting of O, N or S.
In some embodiments of the compounds of formula (III) or (III'), ring C is a 6 to 12 membered bicyclic heterocycloalkyl comprising 1 to 3 heteroatoms selected from the group consisting of O, N or S.
In some embodiments of the compounds of formula (III) or (III'), ring C is a 6 to 12 membered bicyclic heteroaryl comprising 1 to 3 heteroatoms selected from the group consisting of O, N or S.
In some embodiments of the compounds of formula (III) or (III'), ring C is an 8 to 16 membered tricyclic ring, optionally comprising 1 to 3 heteroatoms selected from the group consisting of O, N or S.
In some embodiments of the compounds of formula (III) or (III'), ring C is an 8 to 16 membered tricyclic heterocycloalkyl comprising 1 to 3 heteroatoms selected from the group consisting of O, N or S.
In some embodiments of the compounds of formula (III) or (III'), each R C Is independently deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 HeteroalkanesRadical, C 2 -C 6 Alkynyl, cycloalkyl or heterocycloalkyl; or two R's on the same atom C Together forming oxo. In some embodiments of the compounds of formula (III) or (III'), each R C Is independently deuterium, halogen, -CN, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 Deuterated alkyl; or two R's on the same atom C Together forming oxo. In some embodiments of the compounds of formula (III) or (III'), each R C Independently C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Cyanoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkynyl or cycloalkyl. In some embodiments of the compounds of formula (III) or (III'), each R C Independently C 1 -C 6 An alkyl group. In some embodiments of the compounds of formula (III) or (III'), R C Not C 1 -C 6 An alkyl group. In some embodiments of the compounds of formula (III) or (III'), R C Not C 1 -C 6 A haloalkyl group.
In some embodiments of the compounds of formula (III) or (III'), r is 0 to 4. In some embodiments of the compounds of formula (III) or (III'), r is 1-3. In some embodiments of the compounds of formula (III) or (III'), r is 0 or 1. In some embodiments of the compounds of formula (III) or (III'), r is 0-3. In some embodiments of the compounds of formula (III) or (III'), r is 1 or 2. In some embodiments of the compounds of formula (III) or (III'), r is 1 or 2. In some embodiments of the compounds of formula (III) or (III'), r is 1. In some embodiments of the compounds of formula (III) or (III'), r is 2. In some embodiments of the compounds of formula (III) or (III'), r is 3. In some embodiments of the compounds of formula (III) or (III'), r is 4.
In the formulaIn some embodiments of the compounds of (III) or (III'),is that
In some embodiments of the compounds of formula (III) or (III'),is that
In some embodiments of the compounds of formula (III) or (III'), W 3 Is not present. In some embodiments of the compounds of formula (III) or (III'), W 3 Is C 2 Alkynylene groups. In some embodiments of the compounds of formula (III) or (III'), W 3 is-C (R) 7 ) 2 -。
In some embodiments of the compounds of formula (III) or (III'), each R 7 Independently hydrogen, deuterium, halogen, C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group. In some embodiments of the compounds of formula (III) or (III'), each R 7 Is hydrogen. In some embodiments of the compounds of formula (III) or (III'), two R 7 Together forming a cycloalkyl group.
In some embodiments of the compounds of formula (III) or (III'), each R 8 Is C 1 -C 6 An alkyl group; or two R's on the same carbon 8 Together forming oxo. In some embodiments of the compounds of formula (III) or (III '), two R's on opposite carbons 8 Together withForming cycloalkyl groups. In some embodiments of the compounds of formula (III) or (III '), two R's on the same carbon 8 Together forming a cycloalkyl group. In some embodiments of the compounds of formula (III) or (III '), two R's on adjacent carbons 8 Together forming a cycloalkyl group.
In some embodiments of the compounds of formula (III) or (III'), n is 0. In some embodiments of the compounds of formula (III) or (III'), n is 1. In some embodiments of the compounds of formula (III) or (III'), n is 2. In some embodiments of the compounds of formula (III) or (III'), n is 3. In some embodiments of the compounds of formula (III) or (III'), n is 4. In some embodiments of the compounds of formula (III) or (III'), n is 5. In some embodiments of the compounds of formula (III) or (III'), n is 6. In some embodiments of the compounds of formula (III) or (III'), n is 0-3. In some embodiments of the compounds of formula (III) or (III'), n is 1-3. In some embodiments of the compounds of formula (III) or (III'), n is 1 or 2. In some embodiments of the compounds of formula (III) or (III'), n is 1-4. In some embodiments of the compounds of formula (III) or (III'), n is 2-4.
In some embodiments of the compounds of formula (III) or (III'), each R 11 Is independently deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of formula (III) or (III'), each R 11 Is independently deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 Deuterated alkyl. In some embodiments of the compounds of formula (III) or (III'), each R 11 Independently halogen or C 1 -C 6 An alkyl group.
In some embodiments of the compounds of formula (III) or (III'), q is 0 or 1. In some embodiments of the compounds of formula (III) or (III'), q is 1 or 2. In some embodiments of the compounds of formula (III) or (III'), q is 0. In some embodiments of the compounds of formula (III) or (III'), q is 1. In some embodiments of the compounds of formula (III) or (III'), q is 2. In some embodiments of the compounds of formula (III) or (III'), q is 3.
In some embodiments of the compound of formula (III) or (III'), the compound is a compound of the formula:wherein Y is N, CH or CF; a is that 1 Is CH 2 、CF 2 、CHF、CHCH 3 、C(CH 3 ) 2 ；B 1 Is CH 2 、CF 2 、CHF、CHCH 3 、C(CH 3 ) 2 The method comprises the steps of carrying out a first treatment on the surface of the And C 1 Is O or S; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.
In some embodiments of the compound of formula (III) or (III'), the compound is a compound of the formula: Wherein Y is N, CH or CF; a is that 2 Is CH 2 、CF 2 、CHF、CHCH 3 、C(CH 3 ) 2 ；B 2 Is CH 2 、CF 2 、CHF、CHCH 3 、C(CH 3 ) 2 The method comprises the steps of carrying out a first treatment on the surface of the And C 2 Is CH 2 、CF 2 、CHF、CHCH 3 、C(CH 3 ) 2 The method comprises the steps of carrying out a first treatment on the surface of the And D is 2 Is O or S; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.
In some embodiments of the compound of formula (III) or (III'), the compound is a compound of the formula:wherein Y is N, CH or CF; a is that 3 Is hydrogen, halogen or C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or cycloalkyl optionally substituted with halogen; b (B) 3 Is O or S; and C 3 Is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or cycloalkyl optionally substituted with halogen; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.
In some embodiments of the compound of formula (III) or (III'), the compound is a compound of the formula:wherein Y is N, CH or CF; a is that 4 Is hydrogen, C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group; b (B) 4 Is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 A haloalkyl group; and C 4 Is O or S; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.
In some embodiments of the compound of formula (III) or (III'), the compound is a compound of the formula:wherein Y is N, CH or CF; a is that 5 Is O or S; b (B) 5 Is hydrogen, C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group; and C 5 Is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 A haloalkyl group; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.
In some embodiments of the compound of formula (III) or (III'), the compound is a compound of the formula:wherein Y is N, CH or CF; a is that 6 Is hydrogen, C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group;and B is 6 Is O or S; or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.
In some embodiments of the compound of formula (III) or (III'), the compound is a compound of the formula:wherein Y is N, CH or CF; a is that 7 Is O or S; b (B) 7 Is CH 2 、CF 2 、CHF、CHCH 3 、C(CH 3 ) 2 The method comprises the steps of carrying out a first treatment on the surface of the And C 7 Is CH 2 、CF 2 、CHF、CHCH 3 、C(CH 3 ) 2 The method comprises the steps of carrying out a first treatment on the surface of the Or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.
In some embodiments of the compound of formula (III) or (III'), the compound is a compound of the formula:wherein Y is N, CH or CF; a is that 8 Is O or S; b (B) 8 Is CH 2 、CF 2 、CHF、CHCH 3 、C(CH 3 ) 2 ；C 7 Is CH 2 、CF 2 、CHF、CHCH 3 、C(CH 3 ) 2 The method comprises the steps of carrying out a first treatment on the surface of the And D is 8 Is CH 2 、CF 2 、CHF、CHCH 3 、C(CH 3 ) 2 The method comprises the steps of carrying out a first treatment on the surface of the Or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.
In some embodiments of the compound of formula (III) or (III'), the compound is a compound of the formula:wherein Y is N, CH or CF; a is that 9 Is O or S; b (B) 9 Is hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or cycloalkyl optionally substituted with halogen; and C 9 Is hydrogen, halogen or C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or cycloalkyl optionally substituted with halogen; or a pharmaceutically acceptable salt, solvate thereof A drug or a stereoisomer.
In some embodiments of the compound of formula (III) or (III'), the compound is a compound of the formula:wherein Y is N, CH or CF; a is CH, CMe, CCF 3 Cci, CF or N; r is R 12 Is C 1 -C 6 Alkyl, C 1 -C 6 Deuterated alkyl; each R 11 Independently hydrogen, deuterium, or halogen; a is that 10 Is C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 Deuterated alkyl.
Disclosed herein is a compound of formula (IV):
wherein:
R 1 is hydrogen, deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Cyanoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl or heterocycloalkylA base;
x is N or CR 2 ；
R 2 Is hydrogen, deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Cyanoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl or heterocycloalkyl;
or R is 1 And R is 2 Together forming cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each of which is optionally substituted with deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl or heterocycloalkyl substitution;
z is N or CR 4 ；
R 4 Is hydrogen, deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Cyanoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl or heterocycloalkyl;
y is N or CR 5 ；
R 5 Is hydrogen, deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Cyanoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl or heterocycloalkyl;
R 6 is hydrogen, deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Cyanoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl or heterocycloalkyl;
R 7a is deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl or heterocycloalkyl;
R 7b is hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl or heterocycloalkyl;
or R is 7a And R is 7b Together forming cycloalkyl or heterocycloalkyl; each of which is optionally substituted with deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
each R 8 Is independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
or two R's on the same carbon 8 Together forming oxo;
or two R's on the same carbon, adjacent carbon, or opposite carbon 8 Together forming cycloalkyl or heterocycloalkyl; each of which is optionally substituted with one OR more deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
n is 0-6;
each R 11 Is independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl or heterocycloalkyl;
q is 0-3;
each R a Independently C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 Alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
each R b Independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 Alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution; and
each R c And R is d Independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 Alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
or R is c And R is d Together with the atoms to which they are attached form a moiety optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl-substituted heterocycloalkyl.
In some embodiments of the compounds of formula (IV), R 1 Is C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Cyanoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl or cycloalkyl. In some embodiments of the compounds of formula (IV), R 1 Is C 1 -C 6 An alkyl group.
In some embodiments of the compounds of formula (IV), X is CR 2 And Y is CR 5 。
In some embodiments of the compounds of formula (IV)Wherein X is N and Y is CR 5 。
In some embodiments of the compounds of formula (IV), R 5 Is hydrogen, deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Cyanoalkyl, C 1 -C 6 Heteroalkyl or cycloalkyl. In some embodiments of the compounds of formula (IV), R 5 Is hydrogen, deuterium, halogen or C 1 -C 6 An alkyl group. In some embodiments of the compounds of formula (IV), R 5 Is hydrogen.
In some embodiments of the compounds of formula (IV), X is CR 2 And Y is N.
In some embodiments of the compounds of formula (IV), R 2 Is hydrogen, deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Cyanoalkyl, C 1 -C 6 Heteroalkyl or cycloalkyl. In some embodiments of the compounds of formula (IV), R 2 Is hydrogen, deuterium, halogen or C 1 -C 6 An alkyl group. In some embodiments of the compounds of formula (IV), R 2 Is hydrogen.
In some embodiments of the compounds of formula (IV), X is N and Y is N.
In some embodiments of the compounds of formula (IV), Z is N. In some embodiments of the compounds of formula (IV), Z is CR 4 。
In some embodiments of the compounds of formula (IV), R 4 Is hydrogen, deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Cyanoalkyl, C 1 -C 6 Heteroalkyl or cycloalkylA base. In some embodiments of the compounds of formula (IV), R 4 Is hydrogen, deuterium, halogen or C 1 -C 6 An alkyl group. In some embodiments of the compounds of formula (IV), R 4 Is hydrogen.
In some embodiments of the compounds of formula (IV), R 6 Is hydrogen, deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Cyanoalkyl, C 1 -C 6 Heteroalkyl or cycloalkyl. In some embodiments of the compounds of formula (IV), R 6 Is hydrogen, deuterium, halogen or C 1 -C 6 An alkyl group. In some embodiments of the compounds of formula (IV), R 6 Is hydrogen.
In some embodiments of the compounds of formula (IV), R 7a Is deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 Deuterated alkyl. In some embodiments of the compounds of formula (IV), R 7a Is deuterium or C 1 -C 6 An alkyl group. In some embodiments of the compounds of formula (IV), R 7a Deuterium.
In some embodiments of the compounds of formula (IV), R 7b Is hydrogen, deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 Deuterated alkyl. In some embodiments of the compounds of formula (IV), R 7b Is hydrogen, deuterium or C 1 -C 6 An alkyl group.
In some embodiments of the compounds of formula (IV), R 7a And R is 7b Together forming a cycloalkyl group. In some embodiments of the compounds of formula (IV), R 7a And R is 7b Deuterium.
In some embodiments of the compounds of formula (IV), each R 8 Is C 1 -C 6 An alkyl group; or two R's on the same carbon 8 Together forming oxo. Some of the compounds of formula (IV)In embodiments, two R's on opposite carbons 8 Together forming a cycloalkyl group. In some embodiments of the compounds of formula (IV), two R's on the same carbon 8 Together forming a cycloalkyl group. In some embodiments of the compounds of formula (IV), two R on adjacent carbons 8 Together forming a cycloalkyl group.
In some embodiments of the compounds of formula (IV), n is 0. In some embodiments of the compounds of formula (IV), n is 1. In some embodiments of the compounds of formula (IV), n is 2. In some embodiments of the compounds of formula (IV), n is 3. In some embodiments of the compounds of formula (IV), n is 4. In some embodiments of the compounds of formula (IV), n is 5. In some embodiments of the compounds of formula (IV), n is 6. In some embodiments of the compounds of formula (IV), n is 0-3. In some embodiments of the compounds of formula (IV), n is 1-3. In some embodiments of the compounds of formula (IV), n is 1 or 2. In some embodiments of the compounds of formula (IV), n is 1-4. In some embodiments of the compounds of formula (IV), n is 2-4.
In some embodiments of the compounds of formula (IV), each R 11 Is independently deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of formula (IV), each R 11 Is independently deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 Deuterated alkyl. In some embodiments of the compounds of formula (IV), each R 11 Independently halogen or C 1 -C 6 An alkyl group.
In some embodiments of the compounds of formula (IV), q is 0 or 1. In some embodiments of the compounds of formula (IV), q is 1 or 2. In some embodiments of the compounds of formula (IV), q is 0. In some embodiments of the compounds of formula (IV), q is 1. In some embodiments of the compounds of formula (IV), q is 2. In some embodiments of the compounds of formula (IV), q is 3.
Disclosed herein is a compound of formula (V):
wherein:
R 1 is hydrogen, deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Cyanoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl or heterocycloalkyl;
x is N or CR 2 ；
R 2 Is hydrogen, deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Cyanoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl or heterocycloalkyl;
or R is 1 And R is 2 Together forming cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each of which is optionally substituted with deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl or heterocycloalkyl substitution;
z is N or CR 4 ；
R 4 Is hydrogen, deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl group、C 1 -C 6 Aminoalkyl, C 1 -C 6 Cyanoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl or heterocycloalkyl;
y is N or CR 5 ；
R 5 Is hydrogen, deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Cyanoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl or heterocycloalkyl;
R 6 is hydrogen, deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Cyanoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl or heterocycloalkyl;
each R 7 Independently hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl or heterocycloalkyl;
or two R 7 Together forming cycloalkyl or heterocycloalkyl; each of which is optionally substituted with deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
each R 8 Is independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
or two R's on the same carbon 8 Together forming oxo;
or two R's on the same carbon, adjacent carbon, or opposite carbon 8 Together forming cycloalkyl or heterocycloalkyl; each of which is optionally substituted with one OR more deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
n is 1-6;
each R 11 Independently hydrogen, deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl or heterocycloalkyl;
provided that one R 11 And one R 8 Together forming cycloalkyl, heterocycloalkyl, aryl or heteroaryl; each of which is optionally substituted with one OR more deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
each A is independently N or CR 11 ；
R 12 Is C 1 -C 6 Alkyl or C 1 -C 6 Deuterated alkyl;
each R a Independently C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 Alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
each R b Independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 Alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution; and
each R c And R is d Independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 Alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
or R is c And R is d Together with the atoms to which they are attached form a moiety optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl-substituted heterocycloalkyl.
In some embodiments of the compounds of formula (V), R 1 Is C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Cyanoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkynyl or cycloalkyl.
In some embodiments of the compounds of formula (V), R 1 Is C 1 -C 6 An alkyl group.
In some embodiments of the compounds of formula (V), X is N and Y is CR 5 。
In some embodiments of the compounds of formula (V), R 5 Is hydrogen, deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Cyanoalkyl, C 1 -C 6 Heteroalkyl or cycloalkyl. In some embodiments of the compounds of formula (V), R 5 Is hydrogen, deuterium, halogen or C 1 -C 6 An alkyl group. In some embodiments of the compounds of formula (V), R 5 Is hydrogen.
In some embodiments of the compounds of formula (V), X is CR 2 And Y is N.
In some embodiments of the compounds of formula (V), R 2 Is hydrogen, deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Cyanoalkyl, C 1 -C 6 Heteroalkyl or cycloalkyl. In some embodiments of the compounds of formula (V), R 2 Is hydrogen, deuterium, halogen or C 1 -C 6 An alkyl group. In some embodiments of the compounds of formula (V), R 2 Is hydrogen.
In some embodiments of the compounds of formula (V), X is N and Y is N.
In some embodiments of the compounds of formula (V), Z is N. In some embodiments of the compounds of formula (V), Z is CR 4 。
In some embodiments of the compounds of formula (V), R 4 Is hydrogen, deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Cyanoalkyl, C 1 -C 6 Heteroalkyl or cycloalkyl. In some embodiments of the compounds of formula (V), R 4 Is hydrogen, deuterium, halogen or C 1 -C 6 An alkyl group. In some embodiments of the compounds of formula (V), R 4 Is hydrogen.
Some of the compounds of formula (V)In embodiments, R 6 Is hydrogen, deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Cyanoalkyl, C 1 -C 6 Heteroalkyl or cycloalkyl. In some embodiments of the compounds of formula (V), R 6 Is hydrogen, deuterium, halogen or C 1 -C 6 An alkyl group. In some embodiments of the compounds of formula (V), R 6 Is hydrogen.
In some embodiments of the compounds of formula (V), each R 7 Independently hydrogen, deuterium, halogen, C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group. In some embodiments of the compounds of formula (V), each R 7 Is hydrogen. In some embodiments of the compounds of formula (V), two R 7 Together forming a cycloalkyl group.
In some embodiments of the compounds of formula (V), each R 8 Is C 1 -C 6 An alkyl group; or two R's on the same carbon 8 Together forming oxo. In some embodiments of the compounds of formula (V), two R's on opposite carbons 8 Together forming a cycloalkyl group. In some embodiments of the compounds of formula (V), two R's on the same carbon 8 Together forming a cycloalkyl group. In some embodiments of the compounds of formula (V), two R's on adjacent carbons 8 Together forming a cycloalkyl group.
In some embodiments of the compounds of formula (V), n is 0. In some embodiments of the compounds of formula (V), n is 1. In some embodiments of the compounds of formula (V), n is 2. In some embodiments of the compounds of formula (V), n is 3. In some embodiments of the compounds of formula (V), n is 4. In some embodiments of the compounds of formula (V), n is 5. In some embodiments of the compounds of formula (V), n is 6. In some embodiments of the compounds of formula (V), n is 0-3. In some embodiments of the compounds of formula (V), n is 1-3. In some embodiments of the compounds of formula (V), n is 1 or 2. In some embodiments of the compounds of formula (V), n is 1-4. In some embodiments of the compounds of formula (V), n is 2-4.
In some embodiments of the compounds of formula (V), each R 11 Is independently deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds of formula (V), each R 11 Is independently deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 Deuterated alkyl. In some embodiments of the compounds of formula (V), each R 11 Independently halogen or C 1 -C 6 An alkyl group.
In some embodiments of the compounds of formula (V), one A is CR 11 And one is N. In some embodiments of the compounds of formula (V), both A are CR 11 . In some embodiments of the compounds of formula (V), both a are N.
In some embodiments of the compounds of formula (V), R 12 Is C 1 -C 6 An alkyl group. In some embodiments of the compounds of formula (V), R 12 Is deuterated C 1 -C 6 An alkyl group.
In some embodiments of the compounds of formula (V), one R 11 And one R 8 Taken together form cycloalkyl or heterocycloalkyl; each of which is optionally substituted with one OR more deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution.
In some embodiments of the compounds of formula (V), one R 11 And one R 8 Together form a polymer optionally substituted with one OR more of deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl-substituted heterocycloalkyl.
In some embodiments of the compounds of formula (V), one R 11 And one R 8 Together form a polymer optionally substituted with one OR more of deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl-substituted 5-or 6-membered heterocycloalkyl.
In some embodiments of the compounds of formula (V), one R 11 And one R 8 Together form a polymer optionally substituted with one OR more of deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substituted 6 membered heterocycloalkyl.
In some embodiments of the compounds of formula (V), one R 11 And one R 8 Together form a polymer optionally substituted with one OR more of deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl-substituted 5-membered heterocycloalkyl.
In some embodiments of the compound of formula (V), the compound has the formula: wherein R is 1 Is C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 Deuterated alkyl; y is N, CH or CF; each A is independently CH, CD, CMe, CCF 3 Cci, CF or N; b (B) 1 O, S, NH, NMe, NCD of a shape of O, S, NH, NMe, NCD 3 、CH 2 、CHF、CD 2 Or CDH; r is hydrogen, deuterium or halogen; and R is 12 Is C 1 -C 6 Alkyl or C 1 -C 6 Deuterated alkyl.
In some embodiments of the compounds disclosed herein, each R a Independently C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl substitution. In some embodiments of the compounds disclosed herein, each R a Independently C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl substitution. In some embodiments of the compounds disclosed herein, each R a Independently C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds disclosed herein, each R a Independently C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group. In some embodiments of the compounds disclosed herein, each R a Independently C 1 -C 6 An alkyl group.
In some embodiments of the compounds disclosed herein, each R b Independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl substitution. In some embodiments of the compounds disclosed herein, each R b Independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl substitution. In some embodiments of the compounds disclosed herein, each R b Independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, cycloalkyl or heterocycloalkyl. In some embodiments of the compounds disclosed herein, each R b Independently hydrogen, C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group. In some embodiments of the compounds disclosed herein, each R b Independently hydrogen or C 1 -C 6 An alkyl group.
In some embodiments of the compounds disclosed herein, each R c And R is d Independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl substitution. In some embodiments of the compounds disclosed herein, each R c And R is d Independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, cycloalkyl or heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl substitution. In some embodiments of the compounds disclosed herein, each R c And R is d Independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, cycloalkyl or heterocycloalkyl. Some embodiments of the compounds disclosed hereinIn each R c And R is d Independently hydrogen, C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group. In some embodiments of the compounds disclosed herein, each R c And R is d Independently hydrogen or C 1 -C 6 An alkyl group.
In some embodiments of the compounds disclosed herein, R c And R is d Together with the atoms to which they are attached form a moiety optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl-substituted heterocycloalkyl.
In some embodiments of the compounds disclosed herein, each R A 、R B 、R C 、R a 、R b 、R c 、R d When 2R 7 Cycloalkyl or heterocycloalkyl, when taken together, formed when 2R 8 Cycloalkyl or heterocycloalkyl groups formed when taken together, and when R c And R is d The heterocycloalkyl groups formed when taken together are independently substituted with one, two, three or four substituents as defined herein. In some embodiments of the compounds disclosed herein, each R A 、R B 、R C 、R a 、R b 、R c 、R d When 2R 7 Cycloalkyl or heterocycloalkyl, when taken together, formed when 2R 8 Cycloalkyl or heterocycloalkyl groups formed when taken together, and when R c And R is d The heterocycloalkyl groups formed when taken together are independently substituted with one, two or three substituents as defined herein. In some embodiments of the compounds disclosed herein, each R A 、R B 、R C 、R a 、R b 、R c 、R d When 2R 7 Cycloalkyl or heterocycloalkyl, when taken together, formed when 2R 8 Cycloalkyl or heterocycloalkyl groups formed when taken together, and when R c And R is d The heterocycloalkyl groups formed when taken together are independently substituted with one or two substituents as defined herein. In some embodiments of the compounds disclosed herein, each R A 、R B 、R C 、R a 、R b 、R c 、R d When 2R 7 Cycloalkyl or heterocycloalkyl, when taken together, formed when 2R 8 Cycloalkyl or heterocycloalkyl groups formed when taken together, and when R c And R is d The heterocycloalkyl groups formed when taken together are independently substituted with one substituent as defined herein.
Any combination of the above groups of various variables is contemplated herein. Throughout the specification, the groups and substituents thereof are chosen by the skilled person to provide stable moieties and compounds.
In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is selected from the compounds of table 1.
TABLE 1
In some embodiments, the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.
In some embodiments, the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.
In some embodiments, the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.
In some embodiments, the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.
In some embodiments, the compound is selected from the group consisting of: or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.
Other forms of the compounds disclosed herein
Isomers/stereoisomers
In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds provided herein include all cis (cis), trans (trans), cis (syn), trans (anti), trans (entgegen) (E) and cis (zusammen) (Z) isomers and their corresponding mixtures. In some cases, the compounds described herein have one or more chiral centers, and each center exists in either the R configuration or the S configuration. The compounds described herein include all diastereomers, enantiomers and epimeric forms and their corresponding mixtures. In further embodiments of the compounds and methods provided herein, mixtures of enantiomers and/or diastereomers resulting from individual preparation steps, combinations, or interconversions may be used in the applications described herein. In some embodiments, the compounds described herein are prepared as individual stereoisomers thereof by reacting a racemic mixture of the compounds with an optically active resolving agent to form a pair of diastereomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, diastereomers have different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.), and are separated by taking advantage of these differences. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably by separation/resolution techniques based on solubility differences. In some embodiments, the optically pure enantiomer is then recovered along with the resolving agent by any practical means that does not result in racemization.
Labeling compounds
In some embodiments, the compounds described herein are present in their isotopically-labeled form. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically-labeled compounds. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, compounds disclosed herein include isotopically-labeled compounds, which are identical to those described herein, but for the replacement of one or more atoms by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that can be incorporated into compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as respectively 2 H、 3 H、 13 C、 14 C、 l5 N、 18 O、 17 O、 31 P、 32 P、 35 S、 18 F and F 36 Cl. Other isotopies containing the isotopes and/or other atoms described aboveThe compounds described herein of the element and pharmaceutically acceptable salts, solvates or stereoisomers thereof are within the scope of the invention. Certain isotopically-labeled compounds, for example, for incorporation of radioactive isotopes such as 3 H and 14 those of C, useful in drug and/or substrate tissue distribution assays. Tritiated (i.e., 3 h) And carbon-14 (i.e., 14 c) Isotopes because of their ease of preparation and detectability. In addition, the use of heavy isotopes such as deuterium (i.e., 2 h) Substitution may result in certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements.
In some embodiments, the compounds described herein are labeled by other means, including but not limited to using chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.
Pharmaceutically acceptable salts
In some embodiments, the compounds described herein are present in the form of pharmaceutically acceptable salts thereof. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts as pharmaceutical compositions.
In some embodiments, the compounds described herein have acidic or basic groups and thus react with any of a variety of inorganic or organic bases and inorganic and organic acids to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein or solvates or stereoisomers thereof, or by separately reacting the purified compound in its free form with a suitable acid or base and isolating the salt thus formed.
Examples of pharmaceutically acceptable salts include those prepared by reacting the compounds described herein with an inorganic, organic or inorganic base, such salts include acetates, acrylates, adipates, alginates, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1, 4-dioate, camphoronate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, caprate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, glycolate, hemi-sulfate, heptanoate, caprate, hexyne-1, 6-dioate, hydroxybenzoate, gamma-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, pamoate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, undecyl tosylate and xylene sulfonate.
Furthermore, the compounds described herein may be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with pharmaceutically acceptable inorganic or organic acids including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo [2.2.2] oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4' -methylenebis (3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, t-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid. In some embodiments, other acids, such as oxalic acid, while not pharmaceutically acceptable per se, are used to prepare salts useful as intermediates for obtaining the compounds disclosed herein, solvates or stereoisomers thereof, and pharmaceutically acceptable acid addition salts thereof.
In some embodiments, those compounds described herein that contain free acid groups are reacted with a suitable base (such as a hydroxide, carbonate, bicarbonate, sulfate of a pharmaceutically acceptable metal cation), with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include alkali metal salts or alkaline earth metal salts such as lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like. Illustrative examples of the base include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 Alkyl group 4 Etc.
Representative organic amines useful in forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It is to be understood that the compounds described herein also include quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water-soluble or oil-soluble or dispersible products are obtained by such quaternization.
Solvates of the formula
In some embodiments, the compounds described herein exist as solvates. The present invention provides methods of treating diseases by administering such solvates. The invention also provides methods of treating diseases by administering such solvates as pharmaceutical compositions.
Solvates contain a stoichiometric or non-stoichiometric amount of solvent, and in some embodiments are formed with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water or alcoholates are formed when the solvent is an alcohol. Solvates of the compounds described herein may be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein may be conveniently prepared from aqueous/organic solvent mixtures using organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol. Furthermore, the compounds provided herein may exist in unsolvated forms as well as solvated forms. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.
Tautomers
In some cases, the compounds exist in tautomeric forms. The compounds described herein include all possible tautomers within the formulae described herein. Tautomers are compounds that can be interconverted by migration of a hydrogen atom with the transition of a single bond and an adjacent double bond. In a bonding arrangement where tautomerism may occur, there will be a chemical equilibrium of the tautomers. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors, including temperature, solvent and pH.
Therapeutic method
Disclosed herein are methods of treating diseases in which inhibition of PARP is beneficial, comprising administering a compound disclosed herein. Also disclosed herein are methods of treating diseases in which inhibition of PARP1 is beneficial, comprising administering a compound disclosed herein. In some embodiments, the disease is cancer. In some embodiments, the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, hematological cancer, gastrointestinal cancer (such as gastric and colorectal cancer), or lung cancer. In some embodiments, the cancer is breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer. In some embodiments, the cancer is leukemia, colon cancer, glioblastoma, lymphoma, melanoma, or cervical cancer.
In some embodiments, the cancer comprises BRCA1 and/or BRCA2 mutations.
In some embodiments, the cancer comprising BRCA1 and/or BRCA2 mutations is bladder, brain, and CNS cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, hodgkin's lymphoma, non-hodgkin's lymphoma, renal cancer, leukemia, lung cancer, melanoma, myeloma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, gastric cancer, thyroid cancer, or uterine cancer.
In some embodiments, the cancer is a cancer that lacks Flomologous recombination (FIR) dependent DNA DSB repair activity. The FIR-dependent DNA DSB repair pathway repairs Double Strand Breaks (DSBs) in DNA via homology mechanisms to reform a continuous DNA helix. Components of the FIR-dependent DNA DSB repair pathway include, but are not limited to, ATM (NM_ 000051), RAD51 (NM_ 002875), RAD 51L 1 (NM_ 002877), RAD 51C (NM_ 002876), RAD 51L 3 (NM_ 002878), DMC1 (NM_007068), XRCC2 (NM_ 005431), XRCC3 (NM_ 005432), RAD52 (NM_ 002879), RAD54L (NM_ 003579), RAD54B (NM_012315), BRCA1 (NM_ 007295), BRCA2 (NM_ 000059), RAD50 (NM_ 005732), MRE1 1A (NM_ 005590) and NBS1 (NM_ 002485). Other proteins involved in the FIR dependent DNA DSB repair pathway include regulatory factors such as EMSY. In some embodiments, the cancer that lacks FIR-dependent DNA DSB repair comprises one or more cancer cells that have reduced or eliminated the ability to repair DNA DSBs through the pathway relative to normal cells, i.e., the activity of the FIR-dependent DNA DSB repair pathway may be reduced or eliminated in the one or more cancer cells.
In some embodiments, the activity of one or more components of the FIR-dependent DNA DSB repair pathway is abrogated in one or more cancer cells of an individual having a cancer that lacks FIR-dependent DNA DSB repair.
In some embodiments, the cancer cell has a BRCA1 and/or BRCA2 deficient phenotype, i.e., reduced or eliminated BRCA1 and/or BRCA2 activity in the cancer cell. Cancer cells having such a phenotype may lack BRCA1 and/or BRCA2, i.e., expression and/or activity of BRCA1 and/or BRCA2 in the cancer cell may be reduced or eliminated, for example, by a mutation or polymorphism in a coding nucleic acid, or by amplification, mutation or polymorphism of a gene encoding a regulatory factor (e.g., an EMSY gene encoding a BRCA2 regulatory factor). BRCA1 and BRCA2 are known tumor suppressor genes whose wild type alleles are frequently lost in tumors of heterozygous carriers. Amplification of the EMSY gene encoding BRCA2 binding factor is also known to be associated with breast and ovarian cancer. Carriers of BRCA1 and/or BRCA2 mutations are also at high risk for certain cancers, including breast, ovarian, pancreatic, prostate, hematological, gastrointestinal and lung cancers.
In order to minimize the risk of off-target effects, it is desirable that the drug molecule have selectivity for a particular target.
Avoiding inhibition of PARP family isoforms other than PARP1 may be important in minimizing toxicity that may be caused by inhibition of non-PARP 1 isoforms. Pharmacology to inhibit PARP isoforms other than PARP1 may drive toxicity that reduces the therapeutic index of agents that are less selective for PARP1 than PARP isoforms. Like PARP1, PARP3 plays a role in DNA damage, but has also been found to be a critical participant in the integrity of the mitotic spindle and telomerase integrity (Boehler, c., gaucher, LR., mortusewicz o. Et al Poly (ADP-ribose) polymelase 3 (PARP 3), a newcomer in cellular response to DNA damage and mitotic progress. Pnas,2011, 26, 108 (7) 2783-2788). PARP5A, also known as tankyrase 1, plays a key role in Wnt signaling and telomere length (Kulak, O., chen, H., holohan B. Et al Disruption of Wnt/beta-Catenin Signaling and Telomeric Shortening Are Inextricable Consequences of Tankyrase Inhibition in Human cells.mol Cell biol.2015, 7 months; 35 (14), 2425-2435). PARP6 is a microtubule-regulated gene essential in mice, and the elimination of catalytically active germline mutations in PARP6 has a negative effect on human neuronal function (Vermehren-Schmaedick, A., huang J.Y., levinson, M.et al Characterization of PARP6 Function in Knockout Mice and Patients with Developmental delay. Cells,2021, 6 months; 10 (6), 1289). PARP7 catalytic inhibition causes hyperstimulation to type 1 interferons that produce an autoimmune phenotype (Gozgit, j.m., vasbinder, m.m., abo, r.p. et al PARP7 negatively regulates the type I interferon response in cancer cells and its inhibition triggers antitumor immunity volume 39, 9, 2021, 9, 13, pages 1214-1226). Although the exact function of PARP8 has not been determined, its knockout has been shown to induce mitosis and nuclear morphology defects and reduced cell viability (Vyas, s., chesarone-Catado, m., todorova, t. et al A Systematic Analysis of the PARP Protein Family Identifies New Functions Critical for Cell physiolog. PARP10 has been described as a MYC interacting protein with tumor-repressing activity (Yu, m., schreek, s., cerni, c. Et al PARP-10, a novel MYC-interacting protein with poly (ADP-ribose) polymerase activity, inhibition transformation, oncogene, 24, 2005, page 1982-1993).
In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is PARP1 selective over other members of the PARP family, including PARP2, PARP3, PARP6, PARP7, PARP8, PARP10, PARP11, PARP14, PARP15, TNKS1 (PARP 5A), and TNKS2 (PARP 5B). In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is selective for PARP1 over PARP 2. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is selective for PARP1 over PARP 3. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is selective for PARP1 over PARP 6. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is selective for PARP1 over PARP 7. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is selective for PARP1 over PARP 8. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is selective for PARP1 over PARP 10. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is selective for PARP1 over PARP 11. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is selective for PARP1 over PARP 14. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is selective for PARP1 over PARP 15. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is selective for PARP1 over TNKS1 (PARP 5A). In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is selective for PARP1 over TNKS2 (PARP 5B).
In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is more than 10000 times more selective for PARP1 than PARP 2. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, has a PARP1 selectivity of 9000 times greater than PARP 2. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is more than 8000 times more selective for PARP1 than PARP 2. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, has a PARP1 selectivity over more than 7000 times that of PARP 2. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, has a PARP1 selectivity of 6000 times or more than PARP 2. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, has a PARP1 selectivity greater than 5000-fold that of PARP 2. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is more than 4000 times more selective for PARP1 than PARP 2. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, has a PARP1 selectivity greater than 3000 times that of PARP 2. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, has a PARP1 selectivity of more than 2000 times that of PARP 2. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is more than 1000-fold selective for PARP1 over PARP 2. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, has a PARP1 selectivity that is greater than 100-fold that of PARP 2. In some embodiments, the compounds disclosed herein are at least 400-to 600-fold selective for PARP1 over PARP 2. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is at least 400-fold selective for PARP1 over PARP 2. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is at least 500-fold selective for PARP1 over PARP 2.
In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, has a PARP1 selectivity that is greater than 100-fold that of PARP 3. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, has a PARP1 selectivity of greater than 200-fold that of PARP 3.
In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is at least 200-fold to 700-fold selective for PARP1 over PARP 3. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is at least 200-fold selective for PARP1 over PARP 3. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is at least 650-fold selective for PARP1 over PARP 3.
In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, has a PARP1 selectivity of more than 1000-fold that of PARP 6. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is at least 2000-fold to 3000-fold selective for PARP1 over PARP 6. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is at least 2400 fold selective for PARP1 over PARP 6. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is at least 3000-fold selective for PARP1 over PARP 6.
In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, has a PARP1 selectivity of more than 500-fold that of PARP 7. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is at least 600-fold to 900-fold selective for PARP1 over PARP 7. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is at least 600-fold selective for PARP1 over PARP 7. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is at least 800-fold selective for PARP1 over PARP 7.
In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, has a PARP1 selectivity greater than 3000 times that of PARP 8. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is at least 5000-fold to 9000-fold selective for PARP1 over PARP 8. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is at least 8000 times more selective for PARP1 than PARP 8. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is at least 5000-fold selective for PARP1 over PARP 8.
In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, has a PARP1 selectivity of greater than 200-fold that of PARP 10. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is at least 300-fold to 400-fold selective for PARP1 over PARP 10. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is at least 350-fold selective for PARP1 over PARP 10. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is at least 300-fold selective for PARP1 over PARP 10.
In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is more than 5-fold selective for PARP1 over PARP 11. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is at least 5-fold to 270-fold selective for PARP1 over PARP 11. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is at least 6-fold selective for PARP1 over PARP 11. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is at least 270-fold selective for PARP1 over PARP 11.
In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, has a PARP1 selectivity of more than 2000 times that of PARP 14. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is at least 1400-fold to 2600-fold selective for PARP1 over PARP 14. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is at least 1400-fold selective for PARP1 over PARP 14. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is at least 2600-fold selective for PARP1 over PARP 14.
In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, has a PARP1 selectivity of more than 1000-fold that of PARP 15. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is at least 1600-fold selective for PARP1 over PARP 15.
In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, has a PARP1 selectivity that is more than 100-fold that of TNKS1 (PARP 5A). In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is at least 100-fold to 250-fold selective for PARP1 over TNKS1 (PARP 5A). In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is at least 100-fold selective for PARP1 over TNKS1 (PARP 5A). In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is at least 230-fold selective for PARP1 over TNKS1 (PARP 5A).
In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, has a PARP1 selectivity that is more than 100-fold that of TNKS2 (PARP 5B). In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is at least 100-fold to 150-fold selective for PARP1 over TNKS2 (PARP 5B). In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is at least 140-fold selective for PARP1 over TNKS2 (PARP 5B). In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is at least 130-fold selective for PARP1 over TNKS2 (PARP 5B).
Administration of drugs
In certain embodiments, compositions containing the compounds described herein are administered for prophylactic and/or therapeutic treatment. In certain therapeutic applications, the composition is administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially inhibit at least one symptom of the disease or condition. The amount effective for such use will depend on the severity and course of the disease or condition, the previous treatment, the patient's health, weight and response to the drug, and the judgment of the treating physician. The therapeutically effective amount is optionally determined by methods including, but not limited to, up-dosing and/or dose-range clinical trials.
In prophylactic applications, compositions containing the compounds described herein are administered to patients susceptible to or otherwise at risk of a particular disease, disorder, or condition. Such an amount is defined as a "prophylactically effective amount or dose". In this use, the precise amount will also depend on the health, weight, etc. of the patient. When used in a patient, the effective amount for such use will depend on the severity and course of the disease, disorder or condition, previous treatments, the patient's health and response to the drug, and the judgment of the treating physician. In one aspect, prophylactic treatment comprises administering a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, to a mammal that has previously experienced at least one symptom or risk factor of the disease being treated and is currently in remission, to prevent recurrence of symptoms of the disease or condition.
In certain embodiments where the condition of the patient is not improved, administration of the compound is chronically administered, i.e., for an extended period of time, including the entire duration of the patient's life, at the discretion of the physician, to ameliorate or otherwise control or limit the symptoms of the disease or condition in the patient.
In certain embodiments where the patient's condition does improve, the dosage of the administered drug is temporarily reduced or temporarily suspended for a period of time (i.e., a "drug holiday"). In specific embodiments, the length of the drug holiday is between 2 days and 1 year, including, for example, only 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. For example, the dose reduction during drug holidays is only 10% -100%, including, for example, only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% and 100%.
Once the patient condition improves, a maintenance dose is administered as necessary. Subsequently, in specific embodiments, the dosage or frequency of administration, or both, is reduced to a level that maintains an improved disease, disorder, or condition as the symptoms change. However, in certain embodiments, the patient requires long-term intermittent or daily treatment after any recurrence of symptoms.
The amount of a given agent corresponding to such amount varies depending on factors such as the particular compound, the disease condition and its severity, the identity of the subject or host in need of treatment (e.g., body weight, sex), but is nevertheless determined based on the specifics surrounding the case, including, for example, the particular agent administered, the route of administration, the condition being treated, and the subject or host being treated.
However, generally, the dosage for adult treatment is generally in the range of 0.01mg to 5000mg per day. In one aspect, the dosage for adult treatment is from about 1mg to about 1000mg per day. In one embodiment, the desired dose is conveniently provided as a single dose or as divided doses administered simultaneously or at appropriate intervals, for example two, three, four or more sub-doses per day.
In one embodiment, a daily dosage of the compounds described herein, or pharmaceutically acceptable salts thereof, is from about 0.01mg/kg body weight to about 50mg/kg body weight. In some embodiments, the daily dose or the amount of active agent in the dosage form is below or above the ranges indicated herein, based on a number of variables relevant to the individual treatment regimen. In various embodiments, the daily dose and unit dose will vary depending upon a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the needs of the individual subject, the severity of the disease or condition to be treated, and the judgment of the physician.
Toxicity and therapeutic efficacy of such treatment regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including but not limited to LD 10 And ED 90 Is measured. The dose ratio between toxic effect and therapeutic effect is the therapeutic index, expressed as LD 50 With ED 50 The ratio between. In certain embodiments, the data obtained from cell culture assays and animal studies are used in formulating a range of therapeutically effective daily doses and/or a therapeutically effective unit dose for use in a mammal, including a human. In some embodiments, the daily dosage of a compound described herein is in the range of including havingED with minimal toxicity 50 Within a circulating concentration range of (2). In certain embodiments, the daily dose range and/or unit dose varies within this range, depending on the dosage form employed and the route of administration employed.
In any of the foregoing aspects are further embodiments, wherein an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof: (a) systemic administration to a mammal; and/or (b) orally administering to the mammal; and/or (c) intravenously administering to the mammal; and/or (d) administering to the mammal by injection; and/or (e) topical administration to a mammal; and/or (f) non-systemic or topical administration to a mammal.
In any of the foregoing aspects are additional embodiments, including a single administration of an effective amount of a compound, including additional embodiments, wherein (i) the compound is administered once per day; or (ii) administering the compound to the mammal multiple times over the course of a day.
In any of the foregoing aspects are additional embodiments, including multiple administrations of an effective amount of the compound, including additional embodiments, wherein (i) the compound is administered continuously or intermittently: such as in a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) administering the compound to the mammal every 8 hours; (iv) administering the compound to the subject every 12 hours; (v) administering the compound to the subject every 24 hours. In additional or alternative embodiments, the method comprises a drug holiday, wherein administration of the compound is temporarily suspended or the dose of the administered compound is temporarily reduced; at the end of the drug holiday, administration of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year.
Route of administration
Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. Further, for example, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.
In certain embodiments, the compounds as described herein are administered in a local rather than systemic manner, e.g., by direct injection of the compounds into an organ, typically in the form of a depot formulation or sustained release formulation. In particular embodiments, the depot is administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example in liposomes coated with organ specific antibodies. In such embodiments, the liposome targets and is selectively absorbed by the organ. In other embodiments, the compounds as described herein are provided in a quick release formulation, in an extended release formulation, or in an intermediate release formulation. In other embodiments, the compounds described herein are administered topically.
Pharmaceutical composition/formulation
The compounds described herein, alone or in combination with pharmaceutically acceptable carriers, excipients or diluents, are administered to a subject in need thereof in the form of a pharmaceutical composition according to standard pharmaceutical practice. In one embodiment, the compounds of the invention may be administered to an animal. These compounds may be administered orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes of administration.
In another aspect, provided herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient. Pharmaceutical compositions are formulated in conventional manner using one or more pharmaceutically acceptable excipients which facilitate processing of the active compound into a pharmaceutically acceptable formulation. The appropriate formulation depends on the route of administration selected. An overview of the pharmaceutical compositions described herein can be found, for example, in Remington: the Science and Practice of Pharmacy, nineteenth edition (Easton, pa.: mack Publishing Company, 1995); hoover, john e., remington's Pharmaceutical Sciences, mack Publishing co., easton, pennsylvania 1975; liberman, h.a. and Lachman, l. Edit, pharmaceutical Dosage Forms, marcel Decker, new York, n.y.,1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, seventeenth edition (Lippincott Williams & Wilkins 1999), such disclosures being incorporated herein by reference.
In some embodiments, the pharmaceutically acceptable excipient is selected from the group consisting of carriers, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, permeation enhancers, wetting agents, defoamers, antioxidants, preservatives, and any combination thereof.
The pharmaceutical compositions described herein are administered to a subject by suitable routes of administration, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal routes of administration. Pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposome dispersions, aerosols, solid oral dosage forms, powders, immediate release formulations, controlled release formulations, instant formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.
Pharmaceutical compositions comprising the compounds described herein, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, are prepared in a conventional manner, such as, by way of example only, by conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compressing processes.
Pharmaceutical compositions for oral use are obtained by: one or more solid excipients are mixed with one or more of the compounds described herein, the resulting mixture is optionally ground, and the mixture of granules is processed, if necessary, after adding suitable adjuvants, to obtain tablets or dragee cores. Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose; or others such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, disintegrating agents are added, such as crosslinked sodium carboxymethyl cellulose, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. In some embodiments, colorants or pigments are added to the tablet or dragee coating to identify or characterize different combinations of active compound doses.
Pharmaceutical compositions for oral administration include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Push-fit capsules contain the active ingredient in admixture with fillers (such as lactose), binders (such as starches) and/or lubricants (such as talc or magnesium stearate) and, optionally, stabilizers. In soft capsules, the active compounds are dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin or liquid polyethylene glycols. In some embodiments, a stabilizer is added.
Pharmaceutical compositions for parenteral use are formulated as infusions or injections. In some embodiments, pharmaceutical compositions suitable for injection or infusion include sterile aqueous solutions, dispersions, or sterile powders comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the pharmaceutical composition comprises a liquid carrier. In some embodiments, the liquid carrier is a solvent or liquid dispersion medium, including, for example, water, saline, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, and the like), vegetable oils, non-toxic glycerides, and any combination thereof. In some embodiments, the pharmaceutical composition further comprises a preservative to prevent microbial growth.
Combination of two or more kinds of materials
Disclosed herein are methods of treating cancer using a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in combination with an additional therapeutic agent.
In some embodiments, the additional therapeutic agent is an anticancer agent.
In some embodiments, the additional therapeutic agent is administered concurrently with the compounds disclosed herein. In some embodiments, the additional therapeutic agent and the compound disclosed herein are administered sequentially. In some embodiments, the additional therapeutic agent is administered less frequently than the compounds disclosed herein. In some embodiments, the additional therapeutic agent is administered more frequently than the compounds disclosed herein. In some embodiments, the additional therapeutic agent is administered prior to administration of the compounds disclosed herein. In some embodiments, the additional therapeutic agent is administered after administration of the compounds disclosed herein.
Examples
Example 1
Step 1:4- [ 2-cyano-6- (methylcarbamoyl) pyridin-3-yl]Preparation of piperazine-1-carboxylic acid tert-butyl ester：
At room temperature, at N 2 To 4- [ 2-bromo-6- (methylcarbamoyl) pyridin-3-yl under an atmosphere]Piperazine-1-carboxylic acid tert-butyl ester (1.00 g,2.50mmol,1.00 eq.) and Zn (CN) 2 To a stirred solution of (0.44 g,3.76mmol,1.50 eq.) in DMF (10 mL) was added Pd (PPh) 3 ) 4 (0.29 g,0.25mmol,0.10 eq.). The resulting mixture was subjected to N at 120 ℃ 2 Stirring is carried out for 3 hours under an atmosphere. The reaction was monitored by LCMS. By H 2 The resulting mixture was diluted with O (50 mL). The resulting mixture was extracted with EtOAc (3X 100 mL). The combined organic layers were washed with brine (3X 30 mL), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. The pure fractions were concentrated in vacuo to give 4- [ 2-cyano-6- (methylcarbamoyl) pyridin-3-yl as a white solid]Piperazine-1-carboxylic acid tert-butyl ester (460 mg, 53.1%). LC-MS (ES+H, M/z) [ M+H ]] + ＝346.2。
1H NMR(300MHz,DMSO-d6)δ8.60(q,1H),8.13(d,1H),7.76(d,1H),3.52(dd,4H),3.33(d,4H),2.80(d,3H),1.43(s,9H)。
Step 2: preparation of 6-cyano-N-methyl-5- (piperazin-1-yl) pyridine-2-carboxamide HCl salt：
To a stirred solution of tert-butyl 4- [ 2-cyano-6- (methylcarbamoyl) pyridin-3-yl ] piperazine-1-carboxylate (260 mg,0.75mmol,1.00 eq.) in dioxane (2 ml) was added HCl (gas) in 1, 4-dioxane (2 ml,4m in 1, 4-dioxane) dropwise in an ice bath. The resulting mixture was stirred at room temperature for 1 hour. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give 6-cyano-N-methyl-5- (piperazin-1-yl) pyridine-2-carboxamide HCl salt (180 mg, 97.4%). The crude product was used in the next step without further purification.
LC-MS:(ES+H,m/z):[M+H] + ＝245.9。1H NMR(300MHz,DMSO-d6)δ9.32(brs,2H),8.65(d,1H),8.16(d,1H),7.86(d,1H),3.58(dd,4H),3.29(s,4H),2.80(d,3H)。
Step 3: 6-cyano-5- {4- [ (7-ethyl-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl]Piperazin-1-yl } -N-) Preparation of picoline-2-carboxamide：
At room temperature at N 2 To a stirred solution of 7- (chloromethyl) -3-ethyl-1H-1, 5-naphthyridin-2-one (50 mg,0.22mmol,1.00 eq.) and 6-cyano-N-methyl-5- (piperazin-1-yl) pyridine-2-carboxamide (60 mg,0.25mmol,1.10 eq.) and KI (7 mg,0.04mmol,0.20 eq.) in MeCN (3 mL) was added dropwise DIEA (145 mg,1.12mmol,5.00 eq.) under atmosphere. The resulting mixture was subjected to N at 80 ℃C 2 Stirring is carried out for 2 hours under an atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in DMSO (3 mL). The crude product was purified by preparative HPLC. The pure fractions were concentrated and lyophilized to give 6-cyano-5- {4- [ (7-ethyl-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl as a white solid]Piperazin-1-yl } -N-methylpyridine-2-carboxamide (12.9 mg, 13.11%). LC-MS (ES+H, M/z) [ M+H ]] + ＝431.9。1H NMR(300MHz,DMSO-d6)δ11.87(s,1H),8.58(d,1H),8.42(s,1H),8.11(d,1H),7.74(d,2H),7.62(s,1H),3.68(s,2H),3.37(d,4H),2.79(d,3H),2.60-2.56(m,6H),1.19(t,3H)。
The following examples were carried out using a similar procedure to that shown for example 1。
Example 2
Step 1: (3R) -4- [6- (methoxycarbonyl) pyridin-3-yl]Preparation of tert-butyl-3-methylpiperazine-1-carboxylate：
(3R) -3-methylpiperazine-1-carboxylic acid tert-butyl ester (5.00 g,24.96mmol,1.00 eq. [ a ] ] 26 D(c＝1.0，CHCl 3 ): +14.75), methyl 5-bromopyridine-2-carboxylate (5.66 g,26.21mmol,1.05 eq.) Cs 2 CO 3 A mixture of (16.27 g,49.93mmol,2.00 eq.) and RuPhos Palladacycle Gen.3 (1.04 g,1.25mmol,0.05 eq.) in 1, 4-dioxane (50 mL) was stirred overnight at 120deg.C under nitrogen. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with water (100 mL) and then extracted with EtOAc (2X 100 mL). The combined organic layers were washed with brine (2X 50 mL), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give (3R) -4- [6- (methoxycarbonyl) pyridin-3-yl as a white solid]-3-methylpiperazine-1-carboxylic acid tert-butyl ester (5.00 g, 59.71%). LC-MS (ES+H, M/z) [ M+H ]] + ＝336.1。
Step 2: (3R) -3-methyl-4- [6- (methylcarbamoyl) pyridin-3-yl]Preparation of piperazine-1-carboxylic acid tert-butyl ester Preparation method：
(3R) -4- [6- (methoxycarbonyl) pyridin-3-yl]-3-methylpiperazine-1-carboxylic acid tert-butyl ester (2.00 g,5.96mmol,1.00 eq.) and methylamine (8 mL,25 wt% to 30 wt% aqueous solution) in CH 3 The solution in OH (7 mL) was stirred at room temperature under nitrogen for 3 hours. The reaction was monitored by LCMS. With saturated NH 4 Cl (30 mL) quenched the reaction at room temperature. By CH 2 Cl 2 The resulting mixture was extracted (3X 50 mL). The combined organic layers were washed with brine (2X 50 mL), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give (3R) -3-methyl-4- [6- (methylcarbamoyl) pyridin-3-yl as a pale yellow oil]Piperazine-1-carboxylic acid tert-butyl ester (1.70 g, 85.25%). LC-MS (ES+H, M/z) [ M+H ]] + ＝335.3。
Step 3: n-methyl-5- [ (2R) -2-methylpiperazin-1-yl]Preparation of pyridine-2-carboxamide HCl salt：
(3R) -3-methyl-4- [6- (methylcarbamoyl) pyridin-3-yl]A mixture of tert-butyl piperazine-1-carboxylate (500 mg,1.50mmol,1.00 eq.) and HCl (gas) in 1, 4-dioxane (3.7 mL,14.95mmol,10.00 eq., 4.0M) was stirred at room temperature under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give N-methyl-5- [ (2R) -2-methylpiperazin-1-yl as a yellow solid]Pyridine-2-carboxamide HCl salt (400 mg, crude). The crude product was used directly in the next step without further purification. LC-MS (ES+H, M/z) [ M+H ]] + ＝234.9。
Step 4:5- [ (2R) -4- [ (7-ethyl-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl]2-methylpiperazine-1- Base group]Preparation of N-methylpyridine-2-carboxamide：
N-methyl-5- [ (2R) -2-methylpiperazin-1-yl ]A mixture of pyridine-2-carboxamide HCl salt (128 mg, crude product), 7- (chloromethyl) -3-ethyl-1H-1, 5-naphthyridin-2-one (100 mg,0.45mmol,1.00 eq.) and KI (15 mg,0.09mmol,0.20 eq.) and DIEA (290 mg,2.24mmol,5.00 eq.) in MeCN (10 mL) was stirred at 80℃under nitrogen for 3 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was extracted with EtOAc (2X 30 mL). Combining the organic mattersThe layers were washed with brine (2X 20 mL), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the crude product. The crude product was further purified by preparative HPLC. The pure fractions were concentrated under reduced pressure and lyophilized to give 5- [ (2R) -4- [ (7-ethyl-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl as a white solid]-2-methylpiperazin-1-yl]-N-methylpyridine-2-carboxamide (90 mg, 46.89%). LC-MS (ES+H, M/z) [ M+H ]] + ＝421.2。 1 H NMR(400MHz,DMSO-d 6 )δ11.90(s,1H),8.42(d,1H),8.37(d,1H),8.21(d,1H),7.82(d,1H),7.76(s,1H),7.67(d,1H),7.33(dd,1H),4.23(s,1H),3.71(d,1H),3.65–3.52(m,2H),3.14–3.03(m,1H),2.93(d,1H),2.78(d,3H),2.72(d,1H),2.58–2.53(m,2H),2.33(dd,1H),2.29–2.15(m,1H),1.19(t,3H),1.13(d,3H)。
The following examples were carried out using a similar procedure to that shown for example 2。
Example 3A and example 3B
Step 1:5- [6- (methoxycarbonyl) pyridin-3-yl]-2, 5-diazabicyclo [4.1.0]Heptane-2-carboxylic acid tert-butyl ester Preparation of butyl esters：
To 5-bromopyridine-2-carboxylic acid methyl ester (2.5 g,11.57mmol,1 eq.) and 2, 5-diazabicyclo [4.1.0 ] under nitrogen atmosphere at room temperature ]To a stirred mixture of tert-butyl heptane-2-carboxylate (2.41 g,12.15mmol,1.05 eq.) in dioxane (25 ml) was added RuPhos Palladacycle Gen.3 (0.48 g,0.57mmol,0.05 eq.) and Cs 2 CO 3 (7.54 g,23.14mmol,2.00 eq.). The resulting mixture was stirred overnight at 110 ℃ under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with EtOAc (3X 400 mL). The combined organic layers were washed with saturated NaCl (aq) (200 mL), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5- [6- (methoxycarbonyl) pyridin-3-yl as a yellow solid]-2, 5-diazabicyclo [4.1.0]Heptane-2-carboxylic acid tert-butyl ester (1.1 g, y=28.4%). LC-MS (ES+H, M/z) [ M+H ]] + ＝334.1
Step 2:5- [6- (methylcarbamoyl) pyridin-3-yl]-2, 5-diazabicyclo [4.1.0]Heptane-2-carboxylic acid Preparation of tert-butyl ester：
5- [6- (methoxycarbonyl) pyridin-3-yl]-2, 5-diazabicyclo [4.1.0]Heptane-2-carboxylic acid tert-butyl ester (1 g,3.00mmol,1 eq.) and CH 3 NH 2 (2.33 g,75.03mmol,25.01 eq., 40% in H) 2 O) in MeOH (15 ml) was stirred at room temperature under nitrogen atmosphere for 3 hours. The reaction was monitored by LCMS. The resulting mixture was diluted with water (40 mL). With saturated NH 4 The mixture was acidified to pH 6 with Cl (aqueous). By CH 2 Cl 2 The resulting mixture was extracted (3X 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give 5- [6- (methylcarbamoyl) pyridin-3-yl as a yellow crude oil]-2, 5-diazabicyclo [4.1.0]Heptane-2-carboxylic acid tert-butyl ester (1.2 g, crude product). LC-MS (ES+H, M/z) [ M+H ]] + ＝333.1
Step 3:5- {2, 5-diazabicyclo [4.1.0]Hept-2-yl })Preparation of N-methylpyridine-2-carboxamide：
To 5- [6- (methylcarbamoyl) pyridin-3-yl at room temperature under a nitrogen atmosphere]-2, 5-diazabicyclo [4.1.0]To a stirred mixture of tert-butyl heptane-2-carboxylate (1.2 g,3.61mmol,1 eq.) in MeOH (10 mL) was added HCl (gas) in 1, 4-dioxane (6 mL) dropwise. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with diethyl ether (40 mL). The resulting mixture was concentrated under reduced pressure to give 5- {2, 5-diazabicyclo [4.1.0 ] as a yellow crude oil]Hept-2-yl } -N-methylpyridine-2-carboxamide (1 g, crude). LC-MS (ES+H, M/z) [ M+H ]] + ＝232.9
Step 4:5- {5- [ (7-ethyl-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl ]-2, 5-diazabicyclo [4.1.0]Preparation of hept-2-yl } -N-methylpyridine-2-carboxamide：
To 5- {2, 5-diazabicyclo [4.1.0] at room temperature under a nitrogen atmosphere]To a stirred mixture of hept-2-yl } -N-methylpyridine-2-carboxamide (547.67 mg,2.35mmol,1.5 eq.) and 7- (chloromethyl) -3-ethyl-1H-1, 5-naphthyridin-2-one (350 mg,1.57mmol,1.00 eq.) in acetonitrile (5 ml) was added KI (52.19 mg,0.31mmol,0.20 eq.). The resulting mixture was stirred at 80 ℃ under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5- {5- [ (7-ethyl-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl as a white solid]-2, 5-diazabicyclo [4.1.0]Hept-2-yl } -N-methylpyridine-2-carboxamide (180 mg, y=21.3%). LC-MS (ES+H, M/z) [ M+H ]] + ＝419.0
Step 5: rel-5- [ (1R, 6S) -5- [ (7-ethyl-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl]-2, 5-di Azabicyclo [4.1.0]Hept-2-yl]N-methylpyridine-2-carboxamide (example 3A) and rel-5- [ (1R, 6S) -5- [ (7-) ethyl-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl]-2, 5-diazabicyclo [4.1.0]Hept-2-yl]N-methylpyridine Preparation of 2-carboxamide (example 3B)：
Rel-5- [ (1 r,6 s) -5- [ (7-ethyl-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl ] -2, 5-diazabicyclo [4.1.0] hept-2-yl ] -N-methylpyridine-2-carboxamide was purified by prep_chiral_hplc to give rel-5- [ (1 r,6 s) -5- [ (7-ethyl-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl ] -2, 5-diazabicyclo [4.1.0] hept-2-yl ] -N-methylpyridin-2-carboxamide (example 3a,54.8mg, y=30.4%, = 99.28%) and rel-5- [ (1 r,6 s) -5- [ (7-ethyl-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl ] -2, 5-diazabicyclo [4.1.0] hept-2-yl ] -N-methylpyridin-2-carboxamide (example 3a,54.8mg, y=30.4%, y=99.28% > -5- [ (1 r,6 s) -5- [ (7-ethyl-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl ] -2, 5-diazabicyclo [ 4.0 ] hept-2-carboxamide (example 3-2.0 mg, 39.0%). Note that: the stereochemical allocation of example 3A and example 3B was arbitrary.
Example 3A：
LC-MS:(ES+H,m/z):[M+H] + ＝419.2。1H NMR(400MHz,DMSO-d6)δ11.83(s,1H),8.44(d,1H),8.37–8.32(m,1H),8.19(d,1H),7.85(d,1H),7.75(s,1H),7.69–7.65(m,1H),7.27(dd,1H),3.89(q,2H),3.54–3.46(m,1H),3.24–3.16(m,1H),2.81–2.69(m,5H),2.57–2.52(m,4H),1.18(t,3H),0.83–0.74(m,1H),0.44–0.34(m,1H)。
Example 3B：
LC-MS:(ES+H,m/z):[M+H] + ＝419.1。1H NMR(400MHz,DMSO-d6)δ11.83(s,1H),8.46–8.40(m,1H),8.38–8.31(m,1H),8.19(d,1H),7.85(d,1H),7.75(s,1H),7.67(s,1H),7.27(dd,1H),3.99–3.81(m,2H),3.56–3.47(m,1H),3.24–3.18(m,1H),2.85–2.70(m,5H),2.58–2.52(m,4H),1.18(t,3H),0.83–0.74(m,1H),0.44–0.34(m,1H)。
The following examples in table 3 were prepared using similar procedures as shown for example 3A and example 3B.
Table 3.
Example 4
Step 1: (3R) -4- [ 2-bromo-6- (methylcarbamoyl) pyridin-3-yl]-3-methylpiperazine-1-carboxylic acid tert-butyl ester Is prepared from：
To (3R) -3-methyl-4- [6- (methylcarbamoyl) pyridin-3-yl under nitrogen at 0deg.C]To a stirred solution of tert-butyl piperazine-1-carboxylate (2.20 g,6.58mmol,1.00 eq.) in DMF (30 mL) was added NBS (1.29 g,7.24mmol,1.10 eq.). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 3 hours. The desired product was detectable by LCMS. The reaction was quenched by addition of saturated NaHCO3 (aq) (30 mL) at 0 ℃. The resulting mixture was poured into water (100 mL) and extracted with EtOAc (3X 200 mL). The combined organic layers were washed with brine (3X 150 mL), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to give (3R) -4- [ 2-bromo-6- (methylcarbamoyl) pyridin-3-yl as a pale yellow oil]-3-methylpiperazine-1-carboxylic acid tert-butyl ester (1.77 g, 65%). LC-MS (ES+H, M/z) [ M+H ]] + ＝413.0/415.0。 1 H NMR(300MHz,DMSO-d6)δ8.47(d,1H),7.97(d,1H),7.75(d,1H),3.66–3.48(m,4H),3.27-3.18(m,2H),2.80(d,3H),2.73–2.60(m,1H),1.43(s,9H),0.84(d,3H)。
Step 2: (3R) -4- [ 2-cyano-6- (methylcarbamoyl) pyridin-3-yl ]-3-methylpiperazine-1-carboxylic acid tert-butyl ester Preparation of esters：
(3R) -4- [ 2-bromo-6- (methylcarbamoyl) pyridin-3-yl]A mixture of tert-butyl 3-methylpiperazine-1-carboxylate (500 mg,1.21mmol,1.00 eq), zn (CN) 2 (156 mg,1.33mmol,1.10 eq) and Pd (PPh 3) 4 (140 mg,0.12mmol,0.10 eq) in DMF (8 mL) at 120℃CStir overnight under nitrogen. The desired product was detectable by LCMS. The mixture was cooled to room temperature. The resulting mixture was poured into water (100 mL) and extracted with EtOAc (3X 150 mL). The combined organic layers were washed with brine (2X 100 mL), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give (3R) -4- [ 2-cyano-6- (methylcarbamoyl) pyridin-3-yl as a yellow solid]-3-methylpiperazine-1-carboxylic acid tert-butyl ester (428 mg, 98%). LC-MS (ES-H, M/z) [ M-H ]] - ＝358.1。 1 HNMR(400MHz,DMSO-d6)δ8.60(d,1H),8.12(d,1H),7.81(d,1H),3.41–3.33(m,4H),3.21(d,2H),2.80(d,3H),2.52-2.51(m,1H),1.43(s,9H),1.02(d,3H)。
Step 3: 6-cyano-N-methyl-5- [ (2R) -2-methylpiperazin-1-yl]Preparation of pyridine-2-carboxamide HCl salt：
(3R) -4- [ 2-cyano-6- (methylcarbamoyl) pyridin-3-yl]A solution of tert-butyl 3-methylpiperazine-1-carboxylate (135 mg,0.38mmol,1.00 eq) and HCl (gas) in 1, 4-dioxane (5 mL, 4M) in DCM (5 mL) was stirred at room temperature under nitrogen for 3 hours. The desired product was detectable by LCMS. The resulting mixture was concentrated under reduced pressure to give 6-cyano-N-methyl-5- [ (2R) -2-methylpiperazin-1-yl as a pale yellow solid ]Pyridine-2-carboxamide HCl salt (310 mg, crude). The crude product was used directly in the next step without further purification. LC-MS (ES+H, M/z) [ M+H ]] + ＝260.2
Step 4: 6-cyano-5- [ (2R) -4- [ (7-ethyl-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl]-2-methyl group Piperazin-1-yl]Preparation of N-methylpyridine-2-carboxamide：
To 6-cyano-N-methyl-5- [ (2R) -2-methylpiperazin-1-yl at room temperature]To a stirred mixture of pyridine-2-carboxamide HCl salt (250 mg, crude) and DIEA (498 mg,3.86mmol,5.00 eq.) in MeCN (8 mL) was added 7- (chloromethyl) -3-ethyl-1H-1, 5-naphthyridin-2-one (172 mg,0.77mmol,1.00 eq.) and KI (26 mg,0.15mmol,0.20 eq.). The resulting mixture was stirred at 80 ℃ under nitrogen atmosphere for 4 hours. The desired product was detectable by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure.The residue was purified by silica gel chromatography and the pure fractions were concentrated under reduced pressure to give 6-cyano-5- [ (2R) -4- [ (7-ethyl-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl as a pale yellow solid]-2-methylpiperazin-1-yl]-N-methylpyridine-2-carboxamide (135.4 mg,39%, ee=97.6%). LC-MS (ES+H, M/z) [ M+H ]] + ＝446.1。 1 H NMR(400MHz,DMSO-d6)δ11.89(s,1H),8.58(d,1H),8.42(d,1H),8.12(d,1H),7.81(d,1H),7.75(s,1H),7.65(d,1H),4.02(m,1H),3.74–3.58(m,2H),3.47-3.39(m,1H),3.28-3.20(m,1H)2.79(m,4H),2.58–2.53(m,4H),2.42(t,1H),1.19(t,3H),1.13(d,3H)。
Example 5
Step 1: preparation of tert-butyl 4- (5-fluoro-6- (methoxycarbonyl) pyridin-3-yl) piperazine-1-carboxylate ：
Methyl 5-bromo-3-fluoropyridine-2-carboxylate (1.00 g,4.27mmol,1.00 eq.) piperazine-1-carboxylate (0.84 g,4.48mmol,1.05 eq.), ruPhos Palladacycle Gen.3 (0.36 g,0.43mmol,0.10 eq.) and Cs 2 CO 3 A mixture of (2.78 g,8.55mmol,2.00 eq.) in 1, 4-dioxane (16 mL) was stirred overnight at 110deg.C under nitrogen. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl 4- (5-fluoro-6- (methoxycarbonyl) pyridin-3-yl) piperazine-1-carboxylate (1.00 g, 68.96%) as a white solid. LC-MS (ES+H, M/z) [ M+H ]] + ＝339.9。 1 H NMR(300MHz,DMSO-d6)δ8.24(s,1H),7.23(dd,1H),3.81(s,3H),3.56–3.36(m,8H),1.43(s,9H)。
Step 2: preparation of tert-butyl 4- (5-fluoro-6- (methylcarbamoyl) pyridin-3-yl) piperazine-1-carboxylate：
To 4- [ 5-fluoro-6- (methoxycarbonyl) pyridin-3-yl at room temperature]To a stirred solution of piperazine-1-carboxylic acid ethyl ester (1.20 g,3.86mmol,1.00 eq.) in methanol (8 mL) was added CH 3 NH 2 (8mL，25％-30% aqueous solution). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. With saturated NH 4 Cl (aqueous, 100 mL) quenched the reaction at 0deg.C. By CH 2 Cl 2 The resulting mixture was extracted (3X 100 mL). By anhydrous Na 2 SO 4 The combined organic layers were dried. After filtration, the filtrate was concentrated under reduced pressure to give a crude product (1.22 g) as a white solid. The crude product was used directly in the next step without further purification. LC-MS (ES+H, M/z) [ M+H ]] + ＝338.9。 1 H NMR(400MHz,DMSO-d6)δ8.29(q,1H),8.14(d,1H),7.23(d,1H),3.55–3.34(m,8H),2.75(d,3H),1.42(s,9H)。
Step 3: preparation of 3-fluoro-N-methyl-5- (piperazin-1-yl) pyridine amide：
To a stirred solution of 3-fluoro-N-methyl-5- (piperazin-1-yl) pyridine-2-carboxamide (1.22 g,5.12mmol,1.00 eq.) in 1, 4-dioxane (5 mL) was added HCl (gas) (10 mL,4 m) in 1, 4-dioxane dropwise under nitrogen atmosphere at 0 ℃. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with hexane: ether=1:1 (10 ml×3) to give the crude product (1.22 g, hcl salt) as a white solid. The crude product was used directly in the next step. LC-MS (ES+H, M/z) [ M+H ]] + ＝238.9。
Step 4:5- (4- ((7-ethyl-6-oxo-5, 6-dihydro-1, 5-naphthyridin-3-yl) methyl) piperazin-1-yl) -3- Preparation of fluoro-N-picolinamides：
To a stirred solution of 3-fluoro-N-methyl-5- (piperazin-1-yl) pyridine-2-carboxamide (80 mg, assuming 100% yield, 0.34mmol,1.50 eq.) and 7- (chloromethyl) -3-ethyl-1H-1, 5-naphthyridin-2-one (50 mg,0.22mmol,1.00 eq.) in ACN (5 mL) was added KI (7 mg,0.04mmol,0.20 eq.) and DIEA (145 mg,1.12mmol,5.00 eq.) at room temperature. The resulting mixture was stirred at 80 ℃ under nitrogen atmosphere for 3 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by prep_hplc. The pure fractions were concentrated and lyophilized to give a white color Solid 5- (4- ((7-ethyl-6-oxo-5, 6-dihydro-1, 5-naphthyridin-3-yl) methyl) piperazin-1-yl) -3-fluoro-N-methylpyridine amide (34 mg,34.24%, three steps). LC-MS (ES+H, M/z) [ M+H ]] + ＝424.90。 1 H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.40(s,1H),8.27(q,1H),8.13(s,1H),7.75(s,1H),7.62(s,1H),7.22(dd,1H),3.65(s,2H),3.45–3.34(m,4H),2.74(d,3H),2.58–2.51(m,6H),1.18(t,3H)。 19 F NMR(377MHz,DMSO)δ-120.40。
Example 6
Step 1: preparation of tert-butyl 4- (2-bromo-6- (methylcarbamoyl) pyridin-3-yl) piperazine-1-carboxylate：
To 4- [6- (methylcarbamoyl) pyridin-3-yl ] at 0deg.C under nitrogen atmosphere]To a stirred solution of tert-butyl piperazine-1-carboxylate (2.00 g,6.24mmol,1.00 eq.) in DMF (10 ml) was added NBS (1.22 g,6.87mmol,1.10 eq.) in portions. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 3 hours. The reaction was monitored by LCMS. The reaction was quenched at 0deg.C by the addition of saturated NaHCO3 (aq) (5 mL). The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography to give tert-butyl 4- (2-bromo-6- (methylcarbamoyl) pyridin-3-yl) piperazine-1-carboxylate (2.40 g, 96.29%) as a colorless oil. LC-MS (ES+H, M/z) [ M+H ]] + ＝399.1/401.1。 1 H NMR(400MHz,DMSO-d6)δ8.44(q,1H),7.96(d,1H),7.65(d,1H),3.60–3.41(m,4H),3.10–2.98(m,4H),2.80(d,3H),1.43(s,9H)。
Step 2: preparation of tert-butyl 4- (2-cyclopropyl-6- (methylcarbamoyl) pyridin-3-yl) piperazine-1-carboxylate：
4- [ 2-bromo-6- (methylcarbamoyl) pyridin-3-yl]Piperazine-1-carboxylic acid tert-butyl ester (1.20 g,3.00mmol,1.00 eq.) Pd (dppf) Cl 2 (0.22 g,0.30mmol,0.10 eq.) Cs 2 CO 3 (1.96 g,6.01mmol,2.00 eq.) and cyclopropylboronic acid (0.26 g,3.00mmol,1.00 eq.) in toluene/H 2 The mixture in O (10 mL/1 mL) was stirred under nitrogen at 100deg.C for 1.5 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography to give tert-butyl 4- (2-cyclopropyl-6- (methylcarbamoyl) pyridin-3-yl) piperazine-1-carboxylate (900 mg, 83.08%) as a white solid. LC-MS (ES+H, M/z) [ M+H ]] + ＝361.1。 1 H NMR(300MHz,DMSO-d6)δ8.28(q,1H),7.71(d,1H),7.44(d,1H),3.64–3.43(m,4H),3.06–2.89(m,4H),2.80(d,3H),2.45–2.32(m,1H),1.43(s,9H),1.22–1.13(m,2H),1.07–0.88(m,2H)。
Step 3: preparation of 6-cyclopropyl-N-methyl-5- (piperazin-1-yl) pyridine amide HCl salt：
To 4- [ 2-cyclopropyl-6- (methylcarbamoyl) pyridin-3-yl under nitrogen at 0deg.C]To a stirred solution of tert-butyl piperazine-1-carboxylate (900 mg,2.50mmol,1.00 eq.) in 1, 4-dioxane (3 ml) was added HCl (gas) (10.00 ml,4 m) in 1, 4-dioxane. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated in vacuo. The residue was purified by trituration with hexane:diethyl ether=1:1 (10 ml×3) to give 6-cyclopropyl-N-methyl-5- (piperazin-1-yl) pyridine amide HCl salt as a white solid (900 mg, crude). LC-MS (ES+H, M/z) [ M+H ] ] + ＝261.2。
Step 4: 6-cyclopropyl-5- (4- ((7-ethyl-6-oxo-5, 6-dihydro-1, 5-naphthyridin-3-yl) methyl) piperazine- Preparation of 1-yl) -N-methylpyridine amides：
To a stirred mixture of 7- (chloromethyl) -3-ethyl-1H-1, 5-naphthyridin-2-one (100 mg,0.45mmol,1.00 eq.) and 6-cyclopropyl-N-methyl-5- (piperazin-1-yl) pyridine-2-carboxamide HCl salt (200 mg,0.67mmol,1.50 eq.) in MeCN (10 mL) was added KI (15 mg,0.09mmol,0.20 eq.) and DIEA (290 mg,2.25mmol,5.00 eq.) at room temperature. The resulting mixture was stirred at 80 ℃ under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC. Concentrating the pure fraction and lyophilizing to obtain6-cyclopropyl-5- (4- ((7-ethyl-6-oxo-5, 6-dihydro-1, 5-naphthyridin-3-yl) methyl) piperazin-1-yl) -N-methylpyridine amide (31 mg, 15.51%) as a white solid. LC-MS (ES+H, M/z) [ M+H ]] + ＝447.0。 1 H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.41(d,1H),8.32–8.21(m,1H),7.75(s,1H),7.70(d,1H),7.62(s,1H),7.43(d,1H),3.68(s,2H),3.15–2.90(m,4H),2.78(d,3H),2.69–2.54(m,6H),2.36–2.29(m,1H),1.22–1.10(m,5H),1.01–0.91(m,2H)。
Example 7
Step 1:4- [ 3-fluoro-4- (methoxycarbonyl) phenyl]Preparation of piperazine-1-carboxylic acid tert-butyl ester：
To a stirred mixture of methyl 4-bromo-2-fluorobenzoate (1.00 g,4.29mmol,1.00 eq.) and tert-butyl piperazine-1-carboxylate (0.84 g,4.51mmol,1.05 eq.) in dioxane (100 mL) at room temperature was added Cs 2 CO 3 (2.80 g,8.58mmol,2.00 eq.) and RuPhos Palladacycle Gen.3 (0.18 g,0.22mmol,0.05 eq.). The resulting mixture was stirred at 120 ℃ under nitrogen atmosphere for 6 hours. The reaction was monitored by LCMS. The resulting mixture was filtered and the filter cake was washed with EtOAc (3X 100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 4- [ 3-fluoro-4- (methoxycarbonyl) phenyl ] as a yellow solid]Piperazine-1-carboxylic acid tert-butyl ester (1.30 g, 89%). LC-MS (ES+H, M/z) [ M+H ]] + ＝339.2。 1 H NMR(300MHz,DMSO-d6)δ7.72(t,1H),6.84–6.69(m,2H),3.77(s,3H),3.48–3.33(m,8H),1.43(s,9H)。
Step 2:4- [ 3-fluoro-4- (methylcarbamoyl) phenyl]Preparation of piperazine-1-carboxylic acid tert-butyl ester：
To 4- [ 3-fluoro-4- (methoxycarbonyl) phenyl]To a mixture of tert-butyl piperazine-1-carboxylate (1.3 g,3.84mmol,1.00 eq.) in MeOH (5 mL) was added dropwise methylamine (3.5 mL,25 wt% to 30 wt% aqueous solution). And the mixture was stirred overnight at 50 ℃ under nitrogen atmosphere. Monitoring by LCMSThe reaction was measured. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3X 100 mL). By anhydrous Na 2 SO 4 The combined organic layers were dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase combi-flash chromatography. The resulting mixture was concentrated under reduced pressure to give 4- [ 3-fluoro-4- (methylcarbamoyl) phenyl ] as a white solid ]Piperazine-1-carboxylic acid tert-butyl ester (1.00 g, 77%).
LC-MS:(ES+H,m/z):[M+H] + ＝338.2。 1 H NMR(300MHz,DMSO-d6)δ7.78(d,1H),7.58(t,1H),6.85–6.68(m,2H),3.45-3.40(m,4H),3.27(dd,4H),2.76(d,3H),1.43(s,9H)。
Step 3: preparation of 2-fluoro-N-methyl-4- (piperazin-1-yl) benzamide HCl salt：
To 4- [ 3-fluoro-4- (methylcarbamoyl) phenyl group at room temperature under nitrogen atmosphere]Tert-butyl piperazine-1-carboxylate (500 mg,1.48mmol,1.00 eq.) was added dropwise to a stirred mixture of HCl (gas) (2 mL,4 m) in 1, 4-dioxane in DCM (4 mL). The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with hexane: ether=1:1 (4 mL). The resulting mixture was concentrated under reduced pressure to give 2-fluoro-N-methyl-4- (piperazin-1-yl) benzamide HCl salt (500 mg, crude) as a white solid. LC-MS (ES+H, M/z) [ M+H ]] + ＝237.9。 1 H NMR(400MHz,DMSO-d6)δ9.46(s,2H),7.92–7.79(m,1H),7.60(t,1H),6.91–6.72(m,2H),3.54(m,4H),3.17(m,4H),2.75(d,3H)。
Step 4:4- {4- [ (7-ethyl-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl]Piperazin-1-yl } -2-fluoro-N-methyl Preparation of Ylbenzamides：
To a stirred mixture of 7- (chloromethyl) -3-ethyl-1H-1, 5-naphthyridin-2-one HCl salt (100 mg,0.45mmol,1.00 eq.) and 2-fluoro-N-methyl-4- (piperazin-1-yl) benzamide hydrochloride (123 mg,0.45mmol,1.00 eq.) in MeCN (5 mL) was added KI (15 mg,0.09mmol,0.20 eq.) and DIEA (290 mg,2.24mmol,5.00 eq.) at room temperature. The resulting mixture was stirred at 80 ℃ under nitrogen atmosphere for 3 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. Purification of crude material by preparative HPLC The product was concentrated and lyophilized from the pure fractions to give 4- {4- [ (7-ethyl-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl as an off-white solid]Piperazin-1-yl } -2-fluoro-N-methylbenzamide (14 mg, 7%). LC-MS (ES+H, M/z) [ M+H ]] + ＝423.90。 1 H NMR(400MHz,DMSO-d6)δ11.86(s,1H),8.40(d,1H),7.76(d,2H),7.66–7.48(m,2H),6.86–6.66(m,2H),3.64(s,2H),3.30(d,4H),3.28(d,4H),2.74(d,3H),2.56–2.53(m,2H),1.18(t,3H)。 19 F NMR(377MHz,DMSO)δ-111.58。
Example 8
Step 1:3',6' -dihydro- [3,4' -bipyridine]Preparation of 1' - (tert-butyl) 6-methyl-1 ',6 (2 ' H) -dicarboxylic acid Preparation method：
4- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (859 mg,2.78mmol,1.20 eq.), 5-bromopyridine-2-carboxylic acid methyl ester (500 mg,2.31mmol,1.00 eq.), K 2 CO 3 (640 mg,4.63mmol,2.00 eq.) and Pd (dppf) Cl 2 (339 mg,0.46mmol,0.2 eq.) in 1, 4-dioxane (10 mL) and H 2 The solution in O (2 mL) was stirred overnight at 80℃under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. By H 2 The resulting mixture was diluted with O (50 mL). The resulting mixture was extracted with EA (3X 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3',6' -dihydro- [3,4' -bipyridine as a yellow solid]-1',6 (2 ' H) -dicarboxylic acid 1' - (tert-butyl) 6-methyl ester (260 mg, 29.41%). LC-MS (ES+H, M/z) [ M+H ] ] + ＝319.1。 1 HNMR(300MHz,DMSO-d6)δ8.82(dd,1H),8.02(t,2H),6.46(s,1H),4.06(d,2H),3.88(s,3H),3.57(t,2H),2.54(s,2H),1.44(s,9H)。
Step 2:6- (methylcarbamoyl) -3',6' -dihydro- [3,4' -bipyridine]-1 '(2' H) -tert-butyl formate Preparation：
At room temperature, 3',6' -dihydro- [3,4' -bipyridine]To a stirred solution of 1'- (tert-butyl) 6-methyl (210 mg,0.66mmol,1.00 eq.) of-1', 6 (2 'H) -dicarboxylic acid 1' - (tert-butyl) in methanol (3 mL) was added CH 3 NH 2 (3 mL,25 wt% to 30 wt% aqueous solution). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. By addition of saturated NH 4 Cl (aq) (50 mL) quenched the reaction at room temperature. The aqueous layer was extracted with EtOAc (3X 50 mL). The combined organic layers were concentrated under reduced pressure to give 6- (methylcarbamoyl) -3',6' -dihydro- [3,4' -bipyridine as a violet solid]-1 '(2' h) -tert-butyl formate (190 mg, 90.76%). LC-MS (ES+H, M/z) [ M+H ]] + ＝318.2。 1 H NMR(400MHz,DMSO-d6)δ8.76–8.68(m,2H),8.08–7.86(m,2H),6.34(d,1H),4.05(d,2H),3.56(t,2H),2.82(d,4H),2.54(d,1H),1.43(s,9H)。
Step 3: n-methyl-1 ',2',3',6' -tetrahydro- [3,4' -bipyridine]Preparation of the TFA salt of 6-carboxamide：
To 6- (methylcarbamoyl) -3',6' -dihydro-2 'H- [3,4' -bipyridine at room temperature under an air atmosphere]To a stirred solution of tert-butyl 1' -formate (170 mg,0.54mmol,1 eq.) in DCM (5 mL) was added TFA (1 mL) dropwise. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LC-MS (ES+H, M/z) [ M+H ] ] + ＝218.1
Step 4:1' - ((7-ethyl-6-oxo-5, 6-dihydro-1, 5-naphthyridin-3-yl) methyl) -N-methyl-1 ',2', 3',6' -tetrahydro- [3,4' -bipyridine]Preparation of 6-carboxamide：
At room temperature, to N-methyl-1 ',2',3',6' -tetrahydro- [3,4' -bipyridine]To a stirred mixture of 6-carboxamide (101 mg,0.50mmol,1.00 eq.) and 7- (chloromethyl) -3-ethyl-1, 5-naphthyridin-2 (1H) -one (111 mg,0.50mmol,1.00 eq.) in MeCN (5 mL) was added KI (17 mg,0.10mmol,0.20 eq.) and DIEA (323 mg,2.50mmol,5.00 eq.). The resulting mixture was stirred at 80 ℃ under nitrogen atmosphere for 1 hour. Monitoring by LCMSThe reaction was measured. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC. The pure fractions were concentrated and lyophilized to give 1'- ((7-ethyl-6-oxo-5, 6-dihydro-1, 5-naphthyridin-3-yl) methyl) -N-methyl-1', 2',3',6 '-tetrahydro- [3,4' -bipyridine) as a pale yellow solid]6-carboxamide (39.6 mg,18.49%, two steps). LC-MS (ES+H, M/z) [ M+H ]] + ＝404.2。 1 H NMR(400MHz,DMSO-d6)δ11.85(s,1H),8.70(t,2H),8.42(s,1H),8.05–7.93(m,2H),7.76(s,1H),7.65(s,1H),6.42(s,1H),3.73(s,2H),3.16(s,2H),2.81(d,3H),2.71(s,2H),2.60–2.52(m,4H),1.19(t,3H)。
The following examples were carried out using a similar procedure to that shown for example 8。
Example 9
Step 1: preparation of 7- (chloromethyl) -3-ethyl-1H-quinolin-2-one：
SOCl was added dropwise to a stirred mixture of 3-ethyl-7- (hydroxymethyl) -1H-quinolin-2-one (1.00 g,4.92mmol,1.00 eq.) and DMF (18 mg,0.25mmol,0.05 eq.) in DCM (20 mL) at 0deg.C under nitrogen 2 (1.76 g,14.76mmol,3.00 eq.). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give 7- (chloromethyl) -3-ethyl-1H-quinolin-2-one (1.00 g, 91.68%) as an off-white solid. MS (ES+H, M/z) [ M+H ]] + ＝222.1
Step 2:6- {4- [ (3-ethyl-2-oxo-1H-quinolin-7-yl) methyl]Piperazin-1-yl } pyridine-3-carbonitrile Preparation：
To 7- (chloromethyl) -3-ethyl-1H-quinolin-2-one (100 mg,0.45mmol,1.20 eq.) 6- (piperazin-1-yl) pyridin-3 at room temperatureTo a stirred mixture of carbonitrile (71 mg,0.38mmol,1.00 eq.) and KI (12 mg,0.08mmol,0.20 eq.) in MeCN (5 mL) was added DIEA (243 mg,1.88mmol,5.00 eq.). The resulting mixture was stirred at 80 ℃ under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product (100 mg) was purified by preparative HPLC to give 6- {4- [ (3-ethyl-2-oxo-1H-quinolin-7-yl) methyl as an off-white solid]Piperazin-1-yl } pyridine-3-carbonitrile (35.2 mg, 25.07%). MS (ES+H, M/z) [ M+H ]] + ＝374.2。1H NMR(300MHz,DMSO-d6)δ11.68(s,1H),8.48(d,1H),7.84(dd,1H),7.70(s,1H),7.57(d,1H),7.27(s,1H),7.13(d,1H),6.92(d,1H),3.67(s,4H),3.57(s,2H),2.50-2.47(m,6H),1.16(t,3H)。
Example 10
Step 1: preparation of N- (3-bromophenyl) -2-oxocyclopentane-1-carboxamide：
A solution of 4- (cyclopent-1-en-1-yl) morpholine (3.60 g,23.49mmol,1.00 eq.) and phenyl 1-bromo-3-isocyanate (5.58 g,28.19mmol,1.20 eq.) in CHCl3 (100 mL) was stirred at room temperature under nitrogen for 4 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography and the pure fractions were concentrated in vacuo to give N- (3-bromophenyl) -2-oxocyclopentane-1-carboxamide (3.9 g, 58.8%) as a white solid. LC-MS (ES+H, M/z) [ M+H ] ] + ＝281.9/283.9。 1 H NMR (300 MHz, chloroform-d) delta 8.83 (s, 1H), 7.84 (t, 1H), 7.45-7.41 (m, 1H), 7.29-7.15 (m, 2H), 3.20-3.11 (m, 1H), 2.51-2.33 (m, 4H), 2.17-2.05 (m, 1H), 1.96-1.83 (m, 1H).
Step 2: 7-bromo-1H, 2H,3H, 5H-cyclopenta [ c ]]Preparation of quinolin-4-ones：
At 0 ℃ to H 2 SO 4 To a stirred solution (10 mL) of N- (3-bromophenyl) -2-oxocyclopentane-1-carboxamide (3.3 g,11.69mmol,1.00 eq.) was slowly added. The resulting mixture was stirred at room temperature for 4 hours. Through LThe CMS monitors the response. The mixture was basified with aqueous Na2CO3 (200 mL) at 0 ℃. The resulting mixture was extracted with EtOAc (3X 200 mL). The combined organic layers were washed with brine (3X 200 mL), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give 7-bromo-1H, 2H,3H, 5H-cyclopenta [ c ] as a white solid]Quinolin-4-one (2.10 g, 67.9%). The crude product was used directly in the next step without further purification. LC-MS (ES+H, M/z) [ M+H ]] + ＝264.0/266.0。 1 H NMR(300MHz,DMSO-d6)δ11.66(s,1H),7.52–7.43(m,2H),7.33(dd,1H),3.06(t,2H),2.74(t,2H),2.14-1.99(m,2H)。
Step 3: 4-oxo-1H, 2H,3H, 5H-cyclopenta [ c ]]Preparation of quinoline-7-carboxylic acid ethyl ester：
Into a pressure tank 7-bromo-1H, 2H,3H, 5H-cyclopenta [ c ]]Quinolin-4-one (1.50 g,5.67mmol,1.00 eq.) and Et 3 To a solution of N (1.15 g,11.35mmol,2.00 eq.) in EtOH (20 mL) was added Pd (PPh) 3 ) 2 Cl 2 (797 mg,1.13mmol,0.20 eq.). The mixture was purged with nitrogen for 3 minutes and then pressurized with carbon monoxide to 40atm overnight at 120 ℃. The reaction mixture was cooled to room temperature and filtered to remove insoluble solids. The residue was purified by silica gel column chromatography and the pure fractions were concentrated in vacuo to give 4-oxo-1 h,2h,3h,5 h-cyclopenta [ c ] as a pale yellow solid ]Quinoline-7-carboxylic acid ethyl ester (750 mg, 51.33%). LC-MS (ES+H, M/z) [ M+H ]] + ＝258.2
Step 4:7- (hydroxymethyl) -1H,2H,3H, 5H-cyclopenta [ c ]]Preparation of quinolin-4-ones：
At 0℃under a nitrogen atmosphere to 4-oxo-1H, 2H,3H, 5H-cyclopenta [ c ]]Ethyl quinoline-7-carboxylate (650 mg,2.52mmol,1.00 eq.) in THF (3 mL). LiAlH was added dropwise to the above mixture at 0deg.C over 3 minutes 4 (2.02 mL,5.05mmol,2.00 eq., 2.5M in THF). The resulting mixture was stirred at room temperature for an additional 2 hours. The reaction was monitored by LCMS. By adding H at 0 ℃ 2 O (0.3 mL) quenched the reaction. NaOH (15 wt%, 1.4 mL) was then added and stirred at room temperature for 10 minutes. H is added to the reaction 2 O (0.3 mL) and stirred for an additional 10 minutes. Filtering the resulting mixtureThe cake was washed with THF (3X 5 mL) and dried over anhydrous Na 2 SO 4 And (5) drying. The residue was purified by silica gel column chromatography and the pure fractions were concentrated in vacuo to give 7- (hydroxymethyl) -1h,2h,3h,5 h-cyclopenta [ c ] as a white solid]Quinolin-4-one (300 mg, 55.1%). LC-MS (ES+H, M/z) [ M+H ]] + ＝216.2。 1 H NMR(400MHz,DMSO-d6)δ11.56(s,1H),7.47(d,1H),7.33(s,1H),7.12–7.08(m,1H),5.34(t,1H),4.57(d,2H),3.07(t,2H),2.75(t,2H),2.13–2.06(m,2H)。
Step 5:7- (chloromethyl) -1H,2H,3H, 5H-cyclopenta [ c ]]Preparation of quinolin-4-ones：
To 7- (hydroxymethyl) -1H,2H,3H, 5H-cyclopenta [ c ] at 0deg.C]SOCl was added dropwise to a stirred solution of quinolin-4-one (350 mg,1.62mmol,1.00 eq.) and DMF (12 mg,0.16mmol,0.10 eq.) in DCM (2 mL) 2 (967 mg,8.13mmol,5.00 eq.). The resulting mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. The resulting mixture was washed with DCM (3X 30 mL). The resulting mixture was concentrated in vacuo to give 7- (chloromethyl) -3-ethyl-4-fluoro-1H-quinolin-2-one (390 mg, crude) as an orange solid. The crude product was used directly in the next step without further purification. LC-MS (ES+H, M/z) [ M+H ]] + ＝234.0
Step 6: n-methyl-5- [4- ({ 4-oxo-1H, 2H,3H, 5H-cyclopenta [ c ]]Quinolin-7-yl } methyl) piperazin-1- Base group]Preparation of pyridine-2-carboxamide：
To 7- (chloromethyl) -1H,2H,3H, 5H-cyclopenta [ c ] under nitrogen at room temperature]To a stirred solution of quinolin-4-one (150 mg,0.64mmol,1.00 eq.) and N-methyl-5- (piperazin-1-yl) pyridine-2-carboxamide (148 mg,0.67mmol,1.05 eq.) in MeCN (3 mL) was added DIEA (418 mg,3.21mmol,5.00 eq.) dropwise. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography and the pure fractions were concentrated in vacuo to give N-methyl-5- [4- ({ 4-oxo-1 h,2h,3h,5 h-cyclopenta [ c ] as a pale brown solid]Quinolin-7-yl } methyl) piperazin-1-yl ]Pyridine-2-carboxamide (34.1 mg, 12.1%). LC-MS (ES+H, M/z) [ M+H ]] + ＝418.2。 1 H NMR(300MHz,DMSO-d6)δ11.55(s,1H),8.41(d,1H),8.27(d,1H),7.83(d,1H),7.50(d,1H),7.42–7.30(m,2H),7.17(d,1H),3.59(s,2H),3.34-3.32(m,4H)3.08(t,2H),2.78-2.74(m,5H),2.55-2.54(d,4H),2.15-2.05(m,2H)。
Example 11
Step 1: preparation of 3- (furan-3-amide) -4-iodobenzoic acid methyl ester：
Methyl 3-amino-4-iodobenzoate (10.00 g,36.09mmol,1.00 eq.), 3-furoic acid (8.09 g,72.18mmol,2.00 eq.), T 3 A mixture of P (114.84 g,180.46mmol,5.00 eq., 50 wt% in EA) and DIEA (23.32 g,180.46mmol,5.00 eq.) in DCM (100 mL) was stirred overnight at 60℃under a nitrogen atmosphere. The mixture was cooled to room temperature. The reaction was monitored by LCMS. The resulting mixture was diluted with water (150 mL) and extracted with EtOAc (3X 150 mL). The combined organic layers were washed with brine (2X 200 mL), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 3- (furan-3-amide) -4-iodobenzoate (6.80 g, 50.76%) as a white solid. LC-MS (ES+H, M/z) [ M+H ]] + ＝372.0。
Step 2:3- [ N- (tert-Butoxycarbonyl) furan-3-carboxamide]Preparation of methyl-4-iodobenzoate：
A solution of methyl 3- (furan-3-amido) -4-iodobenzoate (6.00 g,16.167mmol,1.00 eq), (Boc) 2O (7.06 g,32.34mmol,2.00 eq) and DMAP (1.98 g,16.17mmol,1.00 eq) in DCE (100 mL) was stirred overnight at room temperature under nitrogen. The reaction was monitored by LCMS. The resulting mixture was diluted with EtOAc (250 mL) and washed with water (2×200 mL). The combined organic layers were washed with brine (2X 200 mL), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3- [ N- (t-butoxycarbonyl) furan-3-amid-yl ] as a white solid]-4-iodoMethyl benzoate (5.00 g, 65.63%). 1 H NMR(300MHz,DMSO-d6)δ8.31(dd,1H),8.13(d,1H),7.90(d,1H),7.79(t,1H),7.69(dd,1H),6.79(dd,1H),3.87(s,3H),1.34(s,9H)。
Step 3: 4-oxo-5H-furo [3,2-c]Preparation of quinoline-7-carboxylic acid methyl ester：
To 3- [ N- (t-butoxycarbonyl) furan-3-amid group at room temperature under nitrogen atmosphere]-4-iodobenzoic acid methyl ester (400 mg,0.85mmol,1.00 eq.) and PCy 3 (48 mg,0.17mmol,0.20 eq.) Pd (OAc) was added to a mixture of DMF (12 mL) 2 (38 mg,0.17mmol,0.20 eq.) and K 2 CO 3 (235 mg,1.70mmol,2.00 eq.). The final reaction mixture was irradiated with microwave radiation at 100 ℃ for 2 hours. The mixture was cooled to room temperature. The reaction was monitored by LCMS. The resulting mixture was diluted with EtOAc (50 mL). The resulting mixture was washed with water (2X 25 mL). The combined organic layers were washed with brine (2×25 mL), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 4-oxo-5H-furo [3,2-c ] as a yellow solid]Quinoline-7-carboxylic acid methyl ester (120 mg, 58.13%). LC-MS (ES+H, M/z) [ M+H ]] + ＝244.0。
Step 4:7- (hydroxymethyl) -5H-furo [3,2-c ]Preparation of quinolin-4-ones：
To 4-oxo-5H-furo [3,2-c ] under nitrogen at 0deg.C]Quinoline-7-carboxylic acid methyl ester (300 mg,1.23mmol,1.00 eq.) LiAlH was added dropwise to a stirred mixture of THF (2 mL) 4 (0.99 mL,2.47mmol,2.00 eq., 2.5M in THF). The resulting mixture was stirred at 0 ℃ under nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The reaction was quenched by the addition of 1M aqueous HCl (1.2 mL) at 0deg.C. The residue was purified by silica gel column chromatography to give 7- (hydroxymethyl) -5H-furo [3,2-c ] as a yellow solid]Quinolin-4-one (220 mg, 82.88%). LC-MS (ES+H, M/z) [ M+H ]] + ＝216.1。
Step 5:7- (chloromethyl) -5H-furo [3,2-c]Preparation of quinolin-4-ones：
At 0 ℃ under nitrogen atmosphere7- (hydroxymethyl) -5H-furo [3,2-c]SOCl was added dropwise to a stirred mixture of quinolin-4-one (300 mg,1.39mmol,1.00 eq.) and DMF (10 mg,0.14mmol,0.10 eq.) in DCM (5 mL) 2 (995 mg,8.36mmol,6.00 eq.). The resulting mixture was stirred overnight at 0 ℃ under a nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 7- (chloromethyl) -5H-furo [3,2-c ] as a white solid ]Quinolin-4-one (240 mg, 73.69%). LC-MS (ES+H, M/z) [ M+H ]] + ＝234.0。
Step 6: n-methyl-5- [4- ({ 4-oxo-5H-furo [3, 2-c)]Quinolin-7-yl } methyl) piperazin-1-yl] Preparation of pyridine-2-carboxamide：
7- (chloromethyl) -5H-furo [3,2-c]A mixture of quinolin-4-one (100 mg,0.43mmol,1.00 eq), N-methyl-5- (piperazin-1-yl) pyridine amide HCl salt (110 mg,0.43mmol,1.00 eq), KI (14 mg,0.09mmol,0.20 eq) and DIEA (276 mg,2.14mmol,5.00 eq) in MeCN (10 mL) was stirred at 80℃under nitrogen for 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give N-methyl-5- [4- ({ 4-oxo-5H-furo [3, 2-c) as a white solid]Quinolin-7-yl } methyl) piperazin-1-yl]Pyridine-2-carboxamide (95 mg, 51.63%). LC-MS (ES+H, M/z) [ M+H ]] + ＝418.20。 1 H NMR(400MHz,DMSO-d6)δ11.70(s,1H),8.40(q,1H),8.27(d,1H),8.08(d,1H),7.89(d,1H),7.83(d,1H),7.46(s,1H),7.39(dd,1H),7.28(dd,1H),7.06(d,1H),3.63(s,2H),3.39–3.34(m,4H),2.78(d,3H),2.56(m,4H)。
Example 12
Step 1:5- {4- [ (7-ethyl-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl]Piperazin-1-yl } pyridin-2-one Preparation of acids：
At room temperature under nitrogen atmosphereNext, 5- {4- [ (7-ethyl-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl group was introduced]To a stirred solution of methyl piperazine-1-yl } pyridine-2-carboxylate (120 mg,0.29mmol,1.00 eq.) in EtOH/THF (1:1, 5 mL) was added aqueous NaOH (3.0 mL, 1N). The resulting mixture was stirred at room temperature for an additional 1 hour. The reaction was monitored by LCMS. Then 1 (N) aqueous HCl (3.0 mL) was added. Concentrating the reaction under reduced pressure to give 5- {4- [ (7-ethyl-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl as a white solid ]Piperazin-1-yl } pyridine-2-carboxylic acid (150 mg). (used without further purification). LC-MS (ES+H, M/z) [ M+H ]] + ＝394.2。
Step 2: n-cyclopropyl-5- {4- [ (7-ethyl-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl]Piperazin-1-yl } Preparation of pyridine-2-carboxamide：
To 5- {4- [ (7-ethyl-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl at room temperature under nitrogen atmosphere]Piperazine-1-yl } pyridine-2-carboxylic acid (120 mg,0.30mmol,1.00 eq.) and DIEA (158 mg,1.22mmol,4.00 eq.) were added dropwise to a stirred solution of HATU (174 mg,0.46mmol,1.50 eq.) in DMF (4 mL). Aminocyclopropane (35 mg,0.61mmol,2.00 eq.) was added to the above mixture and stirred at room temperature overnight. The reaction was monitored by LCMS. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (3X 20 mL). The combined organic layers were washed with brine (1X 5 mL), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase combi-flash chromatography, the pure fractions were concentrated and lyophilized to give N-cyclopropyl-5- {4- [ (7-ethyl-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl as a white solid]Piperazin-1-yl } pyridine-2-carboxamide (23.1 mg, 17%). LC-MS (ES+H, M/z) [ M+H ]] + ＝433.2。 1 H NMR(300MHz,DMSO-d6)δ11.85(s,1H),8.41(s,1H),8.35(s,1H),8.24(s,1H),7.83(d,1H),7.75(s,1H),7.63(s,1H),7.40(d,1H),3.65(s,2H),3.30-3.14(m,6H),2.85(s,1H),2.65–2.53(m,4H),1.18(t,3H),0.69–0.57(m,4H)。
Example 13
Step 1:5- {4- [ (7-ethyl-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl]Piperazin-1-yl } pyridin-2-one Preparation of methyl ester：
To a stirred mixture of methyl 5- (piperazin-1-yl) pyridine-2-carboxylate (280 mg,1.26mmol,1.00 eq.) and DIEA (812 mg,6.32mmol,5.00 eq.) in MeCN (6 mL) was added 7- (chloromethyl) -3-ethyl-1H-1, 5-naphthyridin-2-one (282 mg,1.26mmol,1.00 eq.) and KI (42 mg,0.25mmol,0.20 eq.) at room temperature under nitrogen. The resulting mixture was stirred at 80 ℃ under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography to give methyl 5- {4- [ (7-ethyl-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl ] piperazin-1-yl } pyridine-2-carboxylate (300 mg, 58%) as a white solid. LC-MS (ES+H, M/z) [ M+H ] +=408.1.
Step 2:5- (4- ((7-ethyl-6-oxo-5, 6-dihydro-1, 5-naphthyridin-3-yl) methyl) piperazin-1-yl) pyridine Preparation of formic acid：
To 5- {4- [ (7-ethyl-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl at room temperature under nitrogen atmosphere]To a stirred solution of methyl piperazine-1-yl } pyridine-2-carboxylate (200 mg,0.49mmol,1.00 eq.) in EtOH/THF (5 mL/5 mL) was added 5.0mL of 1 (N) aqueous NaOH. The resulting mixture was stirred at room temperature for an additional 2 hours. The reaction solution was neutralized with 1mol/l hydrochloric acid, and then the organic solvent was distilled off under reduced pressure. After filtering off the resulting residue, washing with water and concentrating under reduced pressure, the title compound (140 mg, 73%) was obtained as a white solid. LC-MS (ES+H, M/z) [ M+H ] ] + ＝394.2。
Step 3: n- (2, 2-difluoroethyl) -5- {4- [ (7-ethyl-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl]Piperazine sheet Preparation of oxazin-1-yl } pyridine-2-carboxamide：
To 5- {4- [ (7-ethyl-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl at room temperature under nitrogen atmosphere]Piperazine-1-yl } pyridine-2-carboxylic acid (220 mg,0.56mmol,1.00 eq.) and DIEA (361 mg,2.80mmol,5.00 eq.) in DMF (5 mL)EDCI (534 mg,2.80mmol,5.00 eq.) and HOBT (227 mg,1.68mmol,3.00 eq.) were added to the stirred solution. The resulting mixture was stirred at 80 ℃ under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (3X 20 mL). The combined organic layers were washed with brine (1X 5 mL), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (80 mg,94% purity) as a white solid. The crude product was purified by reverse phase combi-flash chromatography and the pure fractions concentrated and lyophilized to give N- (2, 2-difluoroethyl) -5- {4- [ (7-ethyl-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl as a white solid]Piperazine-1-yl } pyridine-2-carboxamide (46 mg, 18%). LC-MS (ES+H, M/z) [ M+H ] ] + ＝457.2。 1 H NMR(400MHz,DMSO-d 6 )δ11.86(s,1H),8.70(t,1H),8.41(s,1H),8.30(d,1H),7.86(d,1H),7.76(s,1H),7.63(s,1H),7.41(dd,1H),6.25–5.97(m,1H),3.73–3.60(m,4H),3.37(s,4H),2.61–2.52(m,6H),1.18(t,3H)。
The following examples were carried out using a similar procedure to that shown for example 13。
Example 14
Step 1:4- [ 2-formyl-6- (methylcarbamoyl) pyridin-3-yl]Preparation of piperazine-1-carboxylic acid tert-butyl ester：
To 4- [ 2-bromo-6- (methylcarbamoyl) pyridin-3-yl at room temperature under nitrogen atmosphere]To a stirred solution of tert-butyl piperazine-1-carboxylate (1.73 g,4.33mmol,1.00 eq.) and TMEDA (604 mg,5.20mmol,1.20 eq.) in toluene (60 ml) was added bis (adamantan-1-yl) (butyl) phosphine (311 mg,0.87mmol,0.20 eq.) and Pd (OAc) 2 (97 mg,0.43mmol,0.10 eq.). The resulting mixture was subjected to CO/H at 100deg.C 2 Stirred overnight under atmosphere (1:1, 30 atm). The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography to give 4- [ 2-formyl-6- (methylcarbamoyl) pyridin-3-yl as a yellow solid]Piperazine-1-carboxylic acid tert-butyl ester (1.50 g, crude product). LC-MS (ES-H, M/z) [ M-H ]] - ＝346.8。
Step 2:4- [2- (difluoromethyl) -6- (methylcarbamoyl) pyridin-3-yl]Preparation of piperazine-1-carboxylic acid tert-butyl ester Preparation method：
To 4- [ 2-formyl-6- (methylcarbamoyl) pyridin-3-yl under nitrogen at 0deg.C]To a stirred solution of tert-butyl piperazine-1-carboxylate (1.50 g,4.29mmol,1.00 eq.) in DCM (8 mL) was added BAST (1.20 mL,6.44mmol,1.50 eq.). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 4 hours. The reaction was monitored by LCMS. The reaction was quenched with ice water (40 mL) at room temperature. By CH 2 Cl 2 The resulting mixture was extracted (3X 40 mL). The combined organic layers were washed with brine (3×20 mL), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 4- [2- (difluoromethyl) -6- (methylcarbamoyl) pyridin-3-yl as an off-white solid]Piperazine-1-carboxylic acid tert-butyl ester (580 mg,36.05%, two steps). LC-MS (ES+H, M/z) [ M+H ]] + ＝371.1。 1 H NMR (300 MHz, chloroform-d) delta 8.29 (d, 1H), 7.94 (d, 1H), 7.63 (d, 1H), 7.21-6.80 (m, 1H), 3.69-3.61 (m, 4H), 3.06 (d, 3H), 3.03-2.98 (m, 4H), 1.51 (s, 9H). 19 F NMR(282MHz,CDCl3)δ-116.99,
Step 3:6- (difluoromethyl) -N-methyl-5- (piperazin-1-yl) pyridin-2-Preparation of formamide HCl salt：
To 4- [2- (difluoromethyl) -6- (methylcarbamoyl) pyridin-3-yl at room temperature under nitrogen atmosphere]To a stirred solution of tert-butyl piperazine-1-carboxylate (570 mg,1.54mmol,1.00 eq.) was added HCl (gas) (4 ml,4 m) in 1, 4-dioxane. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 30 minutes. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. This gave 6- (difluoromethyl) -N-methyl-5- (piperazin-1-yl) pyridine-2-carboxamide HCl salt (610 mg, crude) as a red solid. LC-MS (ES+H, M/z) [ M+H ] ] + ＝270.9。 1 H NMR(300MHz,DMSO-d6)δ9.39(s,2H),8.50-8.40(m,1H),8.14(d,1H),7.93(d,1H),7.52-7.06(m,1H),3.31-3.27(m,4H),3.22-3.18(m,4H),2.84(d,3H)。
Step 4:6- (difluoromethyl) -5- {4- [ (7-ethyl-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl]Piperazine-1- Preparation of yl } -N-methylpyridine-2-carboxamide：
To a stirred solution of 6- (difluoromethyl) -N-methyl-5- (piperazin-1-yl) pyridine-2-carboxamide HCl salt (250 mg,0.82mmol,1.40 eq.) and 7- (chloromethyl) -3-ethyl-1H-1, 5-naphthyridin-2-one (130 mg,0.58mmol,1.00 eq.) in MeCN (5 mL) at room temperature under nitrogen was added DIEA (377 mg,2.92mmol,5.00 eq.) and KI (2 mg,0.01mmol,0.02 eq.). The resulting mixture was stirred at 80 ℃ under nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product (366 mg) was purified by preparative HPLC to give 6- (difluoromethyl) -5- {4- [ (7-ethyl-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl as an off-white solid]Piperazin-1-yl } -N-methylpyridine-2-carboxamide (76.0 mg,29.92%, two steps). LC-MS (ES+H, M/z) [ M+H ]] + ＝457.2。 1 H NMR(400MHz,DMSO-d6)δ11.86(s,1H),8.44-8.36(m,2H),8.10(d,1H),7.86(d,1H),7.75(s,1H),7.62(d,1H),7.32-6.99(m,1H),3.68(s,2H),3.06-2.98(m,4H),2.83(d,3H),2.66-2.53(m,6H),1.22-1.15(m,3H)。 19 F NMR(377MHz,DMSO)δ-115.95。
Example 15
Step 1: preparation of ethyl 2-bromo-2-cyclopropylacetate：
LDA (42.9 mL,85.82mmol,1.10 eq., 2.0M in THF) was added dropwise to a stirred solution of ethyl 2-cyclopropylacetate (10.00 g,78.02mmol,1.00 eq.) in THF (100 mL) at-78deg.C under nitrogen. The reaction was stirred for 1 hour, then TMSCl (8.48 g,78.02mmol,1.00 eq.) was added dropwise, and the reaction was stirred for 3 hours while it was warmed to room temperature. The reaction was cooled to-78 ℃ and NBS (15.28 g,85.82mmol,1.10 eq.) was added dropwise to 50mL THF. The reaction was then stirred for 2 hours and allowed to warm to room temperature. The reaction was monitored by LCMS. By addition of saturated NH 4 Cl (aq) (50 mL) quenched the reaction at 0deg.C. With Et 2 The resulting mixture was extracted with O (3X 200 mL). The combined organic layers were washed with brine (3X 200 mL), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase combi-flash chromatography to give ethyl 2-bromo-2-cyclopropylacetate (5.00 g, 30.95%) as a yellow liquid. 1 H NMR (300 MHz, chloroform-d) delta 4.25 (q, 2H), 3.58 (d, 1H), 1.65-1.55 (m, 1H), 1.31 (t, 3H), 0.92-0.76 (m, 2H), 0.61-0.53 (m, 1H), 0.48-0.40 (m, 1H).
Step 2: preparation of ethyl 2-cyclopropyl-2- (diethoxyphosphoryl) acetate：
A solution of ethyl 2-bromo-2-cyclopropylacetate (5.00 g,24.14mmol,1.00 eq.) and triethyl phosphite (5.22 g,31.39mmol,1.30 eq.) was stirred at 130℃under nitrogen atmosphere for 24 hours. The residue was purified by reverse phase combi-flash chromatography to give ethyl 2-cyclopropyl-2- (diethoxyphosphoryl) acetate (2.40 g, 37.61%) as a yellow liquid. 1 H NMR (300 MHz, chloroform-d) delta 4.26-4.07 (m, 6H), 2.19 (dd, 1H), 1.30 (dt, 10H), 0.71 (dddd, 1H), 0.60 (ddddd, 1H), 0.47-0.37 (m, 1H), 0.24 (ddtd, 1H).
Step 3:6- [ (1Z) -2-cyclopropyl-3-ethoxy-3-oxoprop-1-en-1-yl ]-5-nitropyridine-3-carboxylic acid Of methyl estersPreparation：
To a stirred mixture of NaH (0.29 g,7.14mmol,1.50 eq., 60 wt%) in THF (20 mL) was added dropwise ethyl 2-cyclopropyl-2- (diethoxyphosphoryl) acetate (1.89 g,7.14mmol,1.50 eq.) under nitrogen at 0deg.C. The resulting mixture was stirred at 0 ℃ for 10 minutes, then warmed to 40 ℃ and stirred under nitrogen atmosphere for 10 minutes. The resulting mixture was cooled to-78 ℃, followed by dropwise addition of methyl 6-formyl-5-nitropyridine-3-carboxylate (1.00 g,4.76mmol,1.00 eq.) in THF (20 mL). The resulting mixture was stirred at-78 ℃ for 30 minutes under a nitrogen atmosphere. The reaction was monitored by LCMS. By addition of saturated NH 4 Cl (aq) (5 mL) quenched the reaction at 0deg.C. To the resulting mixture was added 20mL of water and extracted with EtOAc (3X 20 mL). The combined organic layers were washed with brine (1X 50 mL), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 6- [ (1Z) -2-cyclopropyl-3-ethoxy-3-oxoprop-1-en-1-yl as a brown oil]-5-nitropyridine-3-carboxylic acid methyl ester (700 mg, 45.93%). LC-MS (ES+H, M/z) [ M+H ]] + ＝320.8。
Step 4: preparation of 7-cyclopropyl-6-oxo-5H-1, 5-naphthyridine-3-carboxylic acid ethyl ester ：
To 6- [ (1Z) -2-cyclopropyl-3-ethoxy-3-oxoprop-1-en-1-yl under nitrogen at room temperature]To a stirred mixture of methyl-5-nitropyridine-3-carboxylate (600 mg,1.87mmol,1.00 eq.) and Fe (1.04 g,18.73mmol,10.00 eq.) in EtOH (10 mL) was added CaCl 2 (1.24 g,11.24mmol,6.00 eq.). The resulting mixture was stirred overnight at 90 ℃ under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was filtered and the filter cake was washed with EtOAc (2X 50 mL). The filtrate was concentrated under reduced pressure. To the resulting mixture was added 50mL of water and extracted with EtOAc (2X 50 mL). The combined organic layers were washed with brine (2X 50 mL), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 7-cyclopropyl-6-oxo-5H-1, 5-naphthyridine-3-carboxylate (200 mg, 41.34%) as a yellow solid. LC-MS (ES)+H,m/z):[M+H] + ＝259.0。
Step 5: preparation of 3-cyclopropyl-7- (hydroxymethyl) -1H-1, 5-naphthyridin-2-one：
To a stirred solution of 7-cyclopropyl-6-oxo-5H-1, 5-naphthyridine-3-carboxylic acid ethyl ester (160 mg,0.62mmol,1.00 eq.) at 0deg.C under nitrogen atmosphere was added LiAlH dropwise 4 (0.50 mL,1.23mmol,2.00 eq. In 2.5M in THF). The resulting mixture was stirred at 0 ℃ under nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The reaction was quenched by the addition of 1M aqueous HCl (1 mL) at 0deg.C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-cyclopropyl-7- (hydroxymethyl) -1H-1, 5-naphthyridin-2-one (100 mg, 74.65%) as a pale yellow solid. LC-MS (ES+H, M/z) [ M+H ] ] + ＝217.2。
Step 6: preparation of 7- (chloromethyl) -3-cyclopropyl-1H-1, 5-naphthyridin-2-one：
SOCl was added dropwise to a stirred mixture of 3-cyclopropyl-7- (hydroxymethyl) -1H-1, 5-naphthyridin-2-one (80 mg,0.37mmol,1.00 eq.) and DMF (3 mg,0.04mmol,0.10 eq.) in DCM (10 mL) at 0deg.C under nitrogen atmosphere 2 (264 mg,2.22mmol,6.00 eq.). The resulting mixture was stirred at room temperature under nitrogen overnight. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give 7- (chloromethyl) -3-cyclopropyl-1H-1, 5-naphthyridin-2-one as a yellow solid. The crude product was used directly in the next step without further purification. LC-MS (ES+H, M/z) [ M+H ]] + ＝235.0。
Step 7:5- {4- [ (7-cyclopropyl-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl]Piperazin-1-yl } -N-methyl Preparation of pyridine-2-carboxamide：
A mixture of 7- (chloromethyl) -3-cyclopropyl-1H-1, 5-naphthyridin-2-one (80 mg,0.34mmol,1.00 eq.), N-methyl-5- (piperazin-1-yl) pyridine-2-carboxamide (75 mg,0.34mmol,1.00 eq.), KI (11 mg,0.07mmol,0.20 eq.) and DIEA (220 mg,1.71mmol,5.00 eq.) in MeCN (10 mL) was stirred at 80℃under nitrogen for 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was treated with water (50 mL) was diluted and extracted with EtOAc (2X 50 mL). The combined organic layers were washed with brine (2X 50 mL), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5- {4- [ (7-cyclopropyl-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl as a white solid]Piperazin-1-yl } -N-methylpyridine-2-carboxamide (85 mg, 58.57%). LC-MS (ES+H, M/z) [ M+H ]] + ＝419.3。 1 H NMR(300MHz,DMSO-d 6 )δ11.89(s,1H),8.43–8.36(m,2H),8.26(d,1H),7.83(d,1H),7.61(d,1H),7.44–7.35(m,2H),3.64(s,2H),3.34–3.28(m,4H),2.78(d,3H),2.56(d,4H),2.21–2.07(m,1H),0.97(dt,2H),0.86–0.77(m,2H)。
Example 16
Step 1:6- (methylcarbamoyl) -3',6' -dihydro- [3,4' -bipyridine]-1 '(2' H) -tert-butyl formate Preparation：
To 5-bromo-N-methylpyridine-2-carboxamide (300 mg,1.40mmol,1.00 eq.) and 4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (518 mg,1.67mmol,1.20 eq.) at room temperature in 1, 4-dioxane/H 2 Pd (dppf) Cl was added to the stirred mixture in O (4/1, 5 mL) 2 (102 mg,0.14mmol,0.10 eq.) and K 2 CO 3 (3836 mg,2.79mmol,2.00 eq.). The resulting mixture was stirred at 80 ℃ under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 6- (methylcarbamoyl) -3',6' -dihydro- [3,4' -bipyridine as a white solid ]-1 '(2' h) -tert-butyl formate (330 mg, 74.53%). LC-MS (ES+H, M/z) [ M+H ]] + ＝318.2。 1 H NMR(400MHz,DMSO-d6)δ8.75–8.67(m,2H),8.04–7.95(m,2H),6.41(s,1H),4.08–4.00(m,2H),3.56(t,2H),2.82(d,3H),2.53(d,2H),1.43(s,9H)。
Step (a)2: preparation of tert-butyl 4- (6- (methylcarbamoyl) pyridin-3-yl) piperidine-1-carboxylate：
To 6- (methylcarbamoyl) -3',6' -dihydro- [3,4' -bipyridine at room temperature under nitrogen atmosphere]To a stirred solution of tert-butyl-1 '(2' H) -carboxylate (330 mg,1.04mmol,1.00 eq.) in methanol (20 mL) was added Pd/C (33 mg,10 wt%). The resulting mixture was stirred at room temperature under an atmosphere of hydrogen overnight. The reaction was monitored by LCMS. The resulting mixture was filtered and the filter cake was washed with MeOH (5X 10 mL). The filtrate was concentrated under reduced pressure to give tert-butyl 4- (6- (methylcarbamoyl) pyridin-3-yl) piperidine-1-carboxylate (320 mg, 96.36%) as a white solid. LC-MS (ES+H, M/z) [ M+H ]] + ＝320.2。 1 H NMR(400MHz,DMSO-d6)δ8.70(d,1H),8.53(d,1H),7.95(d,1H),7.86(dd,1H),4.09(d,2H),2.81(d,6H),1.78(d,2H),1.55(qd,2H),1.42(s,9H)。
Step 3: preparation of TFA salts of N-methyl-5- (piperidin-4-yl) pyridine amides：
To a stirred solution of tert-butyl 4- (6- (methylcarbamoyl) pyridin-3-yl) piperidine-1-carboxylate (310 mg,0.97mmol,1.00 eq.) in DCM (5 mL) at 0deg.C under nitrogen was added TFA (2 mL) dropwise. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product, N-methyl-5- (piperidin-4-yl) pyridine amide TFA salt (510 mg, crude), was used in the next step without further purification. LC-MS (ES+H, M/z) [ M+H ] ] + ＝220.2。
Step 4:5- (1- ((7-ethyl-6-oxo-5, 6-dihydro-1, 5-naphthyridin-3-yl) methyl) piperidin-4-yl) -N- Preparation of picolinamides：
To a stirred mixture of N-methyl-5- (piperidin-4-yl) pyridine-2-carboxamide TFA salt (294 mg, assuming 50% yield, 1.35mmol,2.00 eq.) and 7- (chloromethyl) -3-ethyl-1H-1, 5-naphthyridin-2-one (150 mg,0.67mmol,1.00 eq.) in MeCN (3 mL) at room temperature under nitrogen was added KI (112 mg,0.67mmol,1.00 eq.) and DIEA (435 mg,3.37mmol,5.00 eq.). The resulting mixture was stirred at 80 ℃ under nitrogen atmosphere for 2 hours. Monitoring of the reaction by LCMSShould be. The resulting mixture was concentrated under reduced pressure. The crude product was purified by preparative HPLC. The pure fractions were concentrated and lyophilized to give 5- {1- [ (7-ethyl-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl as a white solid]Piperidin-4-yl } -N-methylpyridine-2-carboxamide (24.6 mg, 9.01%). LC-MS (ES+H, M/z) [ M+H ]] + ＝406.2。 1 H NMR(400MHz,DMSO-d6)δ11.84(s,1H),8.69(d,1H),8.53(d,1H),8.40(d,1H),7.95(d,1H),7.86(dd,1H),7.75(s,1H),7.61(s,1H),3.62(s,2H),2.94(d,2H),2.81(d,3H),2.68(m,1H),2.59–2.53(m,2H),2.13(m,2H),1.82–1.68(m,4H),1.18(t,3H)。
Example 17
Step 1:4- [ 2-cyano-4- (methoxycarbonyl) phenyl]Preparation of piperazine-1-carboxylic acid tert-butyl ester：
To a stirred solution of methyl 4-bromo-3-cyanobenzoate (1.00 g,4.17mmol,1.00 eq.) and tert-butyl piperazine-1-carboxylate (770 mg,4.17mmol,1.00 eq.) in dioxane (10 mL) under nitrogen was added Cs 2 CO 3 (2.70 g,8.33mmol,2.00 eq.) and RuPhos Palladacycle Gen.3 (350 mg,0.42mmol,0.10 eq.). The resulting mixture was stirred overnight at 80 ℃ under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was filtered and the filter cake was washed with ethyl acetate (5X 100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 4- [ 2-cyano-4- (methoxycarbonyl) phenyl ] as a dark oil]Piperazine-1-carboxylic acid tert-butyl ester (1.00 g, 69.50%). LC-MS (ES+H, M/z) [ M+H-tBu ]] + ＝289.8。 1 H NMR (400 MHz, chloroform-d) δ8.24 (d, 1H), 8.11 (dd, 1H), 6.97 (d, 1H), 3.91 (s, 3H), 3.68-3.59 (m, 4H), 3.36-3.28 (m, 4H), 1.39 (s, 9H).
Step 2:4- [ 2-cyano-4- (methylcarbamoyl) phenyl]Preparation of piperazine-1-carboxylic acid tert-butyl ester：
To 4- [ 2-cyano-4- (methoxycarbonyl) phenyl]Piperazine-1-carboxylic acid tert-butyl ester (1.00 g, 2)90mmol,1.00 eq.) and methylamine (5 mL,25 wt% to 30 wt% aqueous solution) in methanol (5 mL). The resulting mixture was stirred overnight at 50 ℃ under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 4- [ 2-cyano-4- (methylcarbamoyl) phenyl ] as a yellow solid ]Piperazine-1-carboxylic acid tert-butyl ester (900 mg, 90.26%). LC-MS (ES+H, M/z) [ M+H-tBu ]]+＝288.9。 1 H NMR (300 MHz, chloroform-d) δ8.01 (d, 1H), 7.98-7.87 (m, 1H), 7.01 (d, 1H), 6.41 (s, 1H), 3.65 (t, 4H), 3.28 (t, 4H), 3.02 (d, 3H), 1.50 (s, 9H).
Step 3: preparation of 3-cyano-N-methyl-4- (piperazin-1-yl) benzamide HCl salt：
At 0℃to 4- [ 2-cyano-4- (methylcarbamoyl) phenyl ]]To a stirred solution of tert-butyl piperazine-1-carboxylate (900 mg,2.61mmol,1.00 eq.) in dichloromethane (3 mL) was added HCl (gas) (7 mL) in 1, 4-dioxane. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 3 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with N-hexane and diethyl ether (1:1) (12 ml. Times.3). The precipitated solid was collected by filtration and washed with diethyl ether (3×5 mL) to give 3-cyano-N-methyl-4- (piperazin-1-yl) benzamide HCl salt (580 mg) as a white solid. LC-MS (ES+H, M/z) [ M+H ]] + ＝244.9。
Step 4: 3-cyano-4- {4- [ (7-ethyl-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl]Piperazin-1-yl } -N-) Preparation of methylbenzamide：
To a stirred solution of 3-cyano-N-methyl-4- (piperazin-1-yl) benzamide HCl salt (150 mg, crude) and 7- (chloromethyl) -3-methyl-1H-1, 5-naphthyridin-2-one (128 mg,0.61mmol,1.00 eq.) in acetonitrile (8 mL) under nitrogen was added DIEA (238 mg,1.84mmol,3.00 eq.) and KI (20 mg,0.12mmol,0.20 eq.). The resulting mixture was stirred at 80 ℃ under nitrogen atmosphere for 1.5 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. By trituration with MeOH (3 mL) The residue was purified. The resulting mixture was stirred at 50 ℃ under nitrogen atmosphere for 1 hour. The precipitated solid was collected by filtration and washed with MeOH (2×1 mL). The pure fractions were concentrated in vacuo to give 3-cyano-4- {4- [ (7-ethyl-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl as a white solid]Piperazin-1-yl } -N-methylbenzamide (125.5 mg, 46.53%). LC-MS (ES+H, M/z) [ M-H ]]+＝431.30。 1 H NMR(400MHz,DMSO-d 6 )δ11.87(s,1H),8.49–8.39(m,2H),8.12(d,1H),8.01(dd,1H),7.75(s,1H),7.62(s,1H),7.19(d,1H),3.68(s,2H),3.29(m,4H),2.77(d,3H),2.61–2.51(m,6H),1.18(t,3H)。
Example 18
Step 1: 4-oxo-2H, 3H, 5H-furo [3,2-c]Preparation of quinoline-7-carboxylic acid methyl ester：
Under nitrogen atmosphere, 4-oxo-5H-furo [3,2-c]To a solution of methyl quinoline-7-carboxylate (480 mg,1.97mmol,1.00 eq.) in MeOH/DCM (80 mL/20 mL) was added Pd/C (200 mg,10 wt%). The mixture was hydrogenated at room temperature under a hydrogen atmosphere for 2 days. The reaction was monitored by LCMS. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure. Purification of the residue by reverse phase combi-flash chromatography gave 4-oxo-2H, 3H, 5H-furo [3,2-c ] as a white solid]Quinoline-7-carboxylic acid methyl ester (170 mg, 35%). LC-MS (ES+H, M/z) [ M+H ]] + ＝246.2。
Step 2:7- (hydroxymethyl) -2H,3H, 5H-furo [3,2-c]Preparation of quinolin-4-ones：
To 4-oxo-2H, 3H, 5H-furo [3,2-c ] under nitrogen at 0deg.C ]Quinoline-7-carboxylic acid methyl ester (170 mg,0.69mmol,1.00 eq.) LiAlH was added dropwise to a stirred solution of THF (8 mL) 4 (0.55 mL,1.39mmol,2.00 eq. In 2.5M in THF). The resulting mixture was stirred at 0 ℃ under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The reaction was quenched by addition of 1M aqueous HCl (10 mL) at 0deg.C. Mixing the obtained mixtureConcentrating under reduced pressure. The residue was purified by silica gel column chromatography to give 7- (hydroxymethyl) -2h,3h,5 h-furo [3,2-c ] as a white solid]Quinolin-4-one (150 mg, 100%). LC-MS (ES+H, M/z) [ M+H ]] + ＝218.0。 1 H NMR(400MHz,DMSO-d 6 )δ11.38(s,1H),7.53(d,1H),7.34(s,1H),7.09(dd,1H),5.40-5.36(m,1H),4.79(t,2H),4.56(s,2H),3.03(t,2H)。
Step 3:7- (chloromethyl) -2H,3H, 5H-furo [3,2-c]Preparation of quinolin-4-ones：
To 7- (hydroxymethyl) -2H,3H, 5H-furo [3,2-c ] under nitrogen at 0deg.C]To a stirred solution of quinolin-4-one (170 mg,0.78mmol,1.00 eq.) and DMF (29 mg,0.39mmol,0.50 eq.) in DCM (6 mL) was added sulfuryl chloride (744 mg,6.26mmol,8.00 eq.) dropwise. The resulting mixture was stirred at room temperature under nitrogen overnight. The reaction was monitored by LCMS. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography to give 7- (chloromethyl) -2h,3h,5 h-furo [3,2-c ] as a white solid]Quinolin-4-one (160 mg, 87%). LC-MS (ES+H, M/z) [ M+H ] ] + ＝236.0。
Step 4: n-methyl-5- [4- ({ 4-oxo-2H, 3H, 5H-furo [3, 2-c)]Quinolin-7-yl } methyl) piperazines 1-yl group]Preparation of pyridine-2-carboxamide：
To a stirred solution of N-methyl-5- (piperazin-1-yl) pyridine-2-carboxamide (200 mg, crude) and DIEA (351 mg,2.72mmol,4.00 eq.) in MeCN (6 mL) at room temperature under nitrogen was added 7- (chloromethyl) -2H,3H, 5H-furo [3,2-c]Quinolin-4-one (160 mg,0.68mmol,1.00 eq.) and KI (22 mg,0.14mmol,0.20 eq.). The resulting mixture was stirred at 80 ℃ under nitrogen atmosphere for 2 hours. The residue was purified by silica gel column chromatography to give N-methyl-5- [4- ({ 4-oxo-2 h,3h,5 h-furo [3, 2-c) as a white solid]Quinolin-7-yl } methyl) piperazin-1-yl]Pyridine-2-carboxamide (56.5 mg, 19%). LC-MS (ES+H, M/z) [ M+H ]] + ＝420.1。 1 H NMR(400MHz,DMSO-d 6 )δ11.36(s,1H),8.40(s,1H),8.27(s,1H),7.83(d,1H),7.56(d,1H),7.43–7.28(m,2H),7.16(d,1H),4.79(t,2H),3.60(s,2H),3.43-3.31(m,4H),3.05(t,2H),2.84-2.73(m,3H),2.61-2.52(m,4H)。
The following examples were carried out using a similar procedure to that shown for example 18。
Example 19
Step 1: 5-bromo-2- (1- { [2- (trimethylsilyl) ethoxy)]Preparation of methyl } imidazol-2-yl) pyridine：
A solution of 5-bromo-2- (1H-imidazol-2-yl) pyridine (1.00 g,4.46mmol,1.00 eq.) and NaH (0.23 g,5.80mmol,1.30 eq., 60 wt%) in DMF (10 mL) was stirred at 0deg.C for 0.5H, then SEMCl (0.97 g,5.80mmol,1.30 eq.) was added dropwise to the above solution at room temperature. And the mixture was stirred for 2 hours. The reaction was monitored by LCMS. The reaction was quenched with water (50 ml) at 0deg.C. The resulting mixture was extracted with EtOAc (3X 100 mL). The combined organic layers were washed with water (3×50 mL) and dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-bromo-2- (1- { [2- (trimethylsilyl) ethoxy) as a brown oil]Methyl } imidazol-2-yl) pyridine (1.20 g, 75.88%). LC-MS (ES+H, M/z) [ M+H ]]+＝353.8/355.8。 1 H NMR (300 MHz, chloroform-d) δ8.65 (d, 1H), 8.14 (d, 1H), 7.91 (d, 1H), 7.24 (d, 1H), 7.20 (d, 1H), 6.01 (s, 2H), 3.59-3.53 (m, 2H), 0.93-0.87 (m, 2H), 0.00 (s, 9H).
Step 2:4- [6- (1- { [2- (trimethylsilyl) ethoxy)]Methyl } imidazol-2-yl) pyridin-3-yl]Piperazine sheet Preparation of t-butyl oxazine-1-carboxylate：
At room temperature, 5-bromo-2- (1- { [2- (trimethylsilyl) ethoxy)]Methyl } imidazol-2-yl) pyridine (900 mg,2.54mmol,1.00 eq.) and piperazine-1-carboxylic acid tert-butyl ester (426 mg,2.29 mmol)To a stirred solution of dioxane (10 mL) was added RuPhos Palladacycle Gen.3 (118 mg,0.25mmol,0.10 eq.) and Cs 1.00 eq.) 2 CO 3 (1.66 g,5.08mmol,2.00 eq.). The resulting mixture was stirred overnight at 100 ℃ under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was filtered using CH 2 Cl 2 The filter cake was washed with MeOH (3:1) (5X 100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 4- [6- (1- { [2- (trimethylsilyl) ethoxy) as an orange oil ]Methyl } imidazol-2-yl) pyridin-3-yl]Piperazine-1-carboxylic acid tert-butyl ester (900 mg, 77.08%). LC-MS (ES+H, M/z) [ M+H ]] + ＝460.2。 1 H NMR (400 MHz, chloroform-d) delta 8.33 (d, 1H), 8.15 (d, 1H), 7.37-7.34 (m, 1H), 7.24 (d, 1H), 7.21 (d, 1H), 6.08 (s, 2H), 3.74-3.64 (m, 4H), 3.63-3.57 (m, 2H), 3.32 (t, 4H), 1.58 (s, 9H), 0.99-0.92 (m, 2H), 0.00 (s, 9H).
Step 3:1- [6- (1- { [2- (trimethylsilyl) ethoxy)]Methyl } imidazol-2-yl) pyridin-3-yl]Piperazine sheet Preparation of oxazines：
At 0deg.C to 4- [6- (1- { [2- (trimethylsilyl) ethoxy)]Methyl } imidazol-2-yl) pyridin-3-yl]To a stirred solution of tert-butyl piperazine-1-carboxylate (1.00 g,2.17mmol,1.00 eq.) and DIEA (5.62 g,43.50mmol,20.00 eq.) in dioxane (20 mL) was added dropwise TMSOTf (4.84 g,21.75mmol,10.00 eq.). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The reaction was quenched by the addition of MeOH (3 mL) at room temperature. The residue was purified by silica gel column chromatography to give 1- [6- (1- { [2- (trimethylsilyl) ethoxy) as an orange oil]Methyl } imidazol-2-yl) pyridin-3-yl]Piperazine (530 mg, 67.76%). LC-MS (ES+H, M/z) [ M+H ]]+＝360.2。 1 H NMR (300 MHz, chloroform-d) delta 8.26 (d, 1H), 8.09-7.97 (m, 1H), 7.28 (d, 1H), 7.16 (d, 1H), 7.12 (d, 1H), 5.99 (s, 2H), 3.56-3.46 (m, 2H), 3.35-3.26 (m, 4H), 3.15-3.08 (m, 4H), 0.93-0.83 (m, 2H), 0.00 (s, 9H).
Step 4: 3-ethyl-7- ({ 4- [6- (1- { [2- (trimethylsilyl) ethoxy)]Methyl } imidazol-2-yl) pyri-dine Pyridin-3-yl]Preparation of piperazin-1-yl } methyl) -1H-1, 5-naphthyridin-2-one：
1- [6- (1- { [2- (trimethylsilyl) ethoxy) was added to the mixture at room temperature under a nitrogen atmosphere]Methyl } imidazol-2-yl) pyridin-3-yl]To a stirred solution of piperazine (160 mg,0.44mmol,1.00 eq.) and 7- (chloromethyl) -3-ethyl-1H-1, 5-naphthyridin-2-one (100 mg,0.44mmol,1.00 eq.) in acetonitrile (8 mL) were added DIEA (172 mg,1.34mmol,3.00 eq.) and potassium iodide (15 mg,0.09mmol,0.20 eq.). The resulting mixture was stirred under nitrogen at 80℃for 1.5 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-ethyl-7- ({ 4- [6- (1- { [2- (trimethylsilyl) oxy) ethoxy) as a brown solid]Methyl } imidazol-2-yl) pyridin-3-yl]Piperazin-1-yl } methyl) -1H-1, 5-naphthyridin-2-one (300 mg, crude). LC-MS (ES+H, M/z) [ M+H ]] + ＝546.0。
Step 5: 3-ethyl-7- ({ 4- [6- (1H-imidazol-2-yl) pyridin-3-yl)]Piperazin-1-yl } methyl) -1H-1,5- Preparation of naphthyridin-2-one：
To 3-ethyl-7- ({ 4- [6- (1- { [2- (trimethylsilyl) oxy) ethoxy ] at 0deg.C under nitrogen atmosphere ]Methyl } imidazol-2-yl) pyridin-3-yl]To a stirred solution of piperazin-1-yl } methyl) -1H-1, 5-naphthyridin-2-one (300 mg,0.55mmol,1.00 eq.) in DCM (7 mL) was added TFA (3 mL) dropwise. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 3 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with diethyl ether (10 mL. Times.3). The residue was basified with NH4 OH. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. The pure fractions were concentrated in vacuo to give 3-ethyl-7- ({ 4- [6- (1H-imidazol-2-yl) pyridin-3-yl) as a white solid]Piperazin-1-yl } methyl) -1H-1, 5-naphthyridin-2-one (80.3 mg, 33.78%). LC-MS (ES+H, M/z) [ M+H ]] + ＝416.30。 1 H NMR(300MHz,DMSO-d6)δ12.45(s,1H),11.87(s,1H),8.42(d,1H),8.27(d,1H),7.87(d,1H),7.76(s,1H),7.64(s,1H),7.44(q,1H),7.05(s,2H),3.66(s,2H),3.34(m,4H),2.59–2.51(m,6H),1.23–1.17(t,3H)。
Implementation of the embodimentsExample 20 and example 21
Step 1: preparation of 7-ethyl-6-oxo-5H-1, 5-naphthyridine-3-carboxylic acid：
To 7-ethyl-6-oxo-5H-1, 5-naphthyridine-3-carboxylic acid methyl ester (1.15 g,4.95mmol,1.00 eq.) in MeOH (15 mL) and H at room temperature 2 NaOH (0.59 g,14.86mmol,3.00 eq.) was added in portions to a stirred solution in O (3 mL). The resulting mixture was stirred at room temperature for 1 hour. The reaction was monitored by LCMS. The resulting mixture was diluted with water (10 mL). The residue was acidified to pH 4 with 6N HCl (aqueous solution). The resulting mixture was filtered, and the solid was concentrated under reduced pressure to give 7-ethyl-6-oxo-5H-1, 5-naphthyridine-3-carboxylic acid (800.0 mg, crude) as a white solid. LC-MS (ES+H, M/z) [ M+H ] ] + ＝218.9。
1 H NMR(400MHz,DMSO-d 6 )δ13.43(s,1H),12.08(s,1H),8.89(d,1H),8.15(d,1H),7.82(s,1H),2.62–2.54(m,2H),1.20(t,3H)。
Step 2: preparation of 7-ethyl-N-methoxy-N-methyl-6-oxo-5H-1, 5-naphthyridine-3-carboxamide：
EDCI (2.10 g,11.00mmol,3.00 eq.) was added portionwise to a solution of 7-ethyl-6-oxo-5H-1, 5-naphthyridine-3-carboxylic acid (800 mg, crude) and N, O-dimethylhydroxylamine (336 mg,5.50mmol,1.50 eq.) in DMF (8 mL) at room temperature under nitrogen. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3X 25 mL). The combined organic layers were washed with brine (3X 50 mL), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 7-ethyl-N-methoxy-N-methyl-6-oxo-5H-1, 5-naphthyridine-3-carboxamide (540 mg, 45.44%) as an off-white solid. LC-MS (ES+H, M/z) [ M+H ]] + ＝262.1。 1 H NMR(400MHz,DMSO-d 6 )δ12.02(s,1H),8.64(d,1H),7.89(dd,1H),7.80(s,1H),3.58(s,3H),3.31(s,3H),2.57(q,2H),1.20(t,3H)。
Step 3: preparation of 7-acetyl-3-ethyl-1H-1, 5-naphthyridin-2-one：
To a solution of 7-ethyl-N-methoxy-N-methyl-6-oxo-5H-1, 5-naphthyridine-3-carboxamide (540 mg,2.07mmol,1.00 eq.) in THF (5 mL) at 0deg.C under nitrogen atmosphere was added CH dropwise 3 MgBr (1.4 mL,4.13mmol,2.00 eq., 3M in THF). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1.5 hours. The reaction was monitored by LCMS. The reaction was quenched with water at 0 ℃. The resulting mixture was diluted with water (15 mL). The resulting mixture was extracted with EtOAc (3X 20 mL). The combined organic layers were washed with brine (2X 60 mL), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 7-acetyl-3-ethyl-1H-1, 5-naphthyridin-2-one (397 mg, 88.83%) as an off-white solid. LC-MS (ES+H, M/z) [ M+H ]] + ＝217.1。 1 H NMR(400MHz,DMSO-d 6 )δ12.06(s,1H),8.98(s,1H),8.09(d,1H),7.84(d,1H),2.67(s,3H),2.58(q,2H),1.20(t,3H)。
Step 4: preparation of 3-ethyl-7- (1-hydroxyethyl) -1H-1, 5-naphthyridin-2-one：
To a solution of 7-acetyl-3-ethyl-1H-1, 5-naphthyridin-2-one (390 mg,1.84mmol,1.00 eq.) in MeOH (5 mL) at 0deg.C under nitrogen was added NaBH in portions 4 (174 mg,4.59mmol,2.50 eq.). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. With saturated NH 4 The reaction was quenched with Cl (aqueous solution) at 0 ℃. The resulting mixture was diluted with water (15 mL). The resulting mixture was extracted with EtOAc (3X 20 mL). The combined organic layers were washed with brine (3X 50 mL), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-ethyl-7- (1-hydroxyethyl) -1H-1, 5-naphthyridin-2-one (335.0 mg, 83.60%) as a brown solid. LC-MS (ES+H, M/z) [ M+H ]] + ＝219.2。
Step 5:7- (1-chloroethyl) -3-ethyl-1H-1, 5-naphthyridine-Preparation of 2-ketones：
To a solution of 3-ethyl-7- (1-hydroxyethyl) -1H-1, 5-naphthyridin-2-one (335 mg,1.54mmol,1.00 eq.) in DCM (10 mL) at 0deg.C under nitrogen 2 (457 mg,3.84mmol,2.50 eq.). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 4 hours. The reaction was monitored by LCMS. The reaction mixture was concentrated under reduced pressure. The residue was used directly in the next step. LC-MS (ES+H, M/z) [ M+H ]] + ＝237.0。
Step 6:5- {4- [1- (7-ethyl-6-oxo-5H-1, 5-naphthyridin-3-yl) ethyl]Piperazin-1-yl } -N-methyl Preparation of pyridine-2-carboxamide：
To a solution of 7- (1-chloroethyl) -3-ethyl-1H-1, 5-naphthyridin-2-one (280 mg,1.18mmol,1.00 eq.) and N-methyl-5- (piperazin-1-yl) pyridine-2-carboxamide (350 mg, crude) in MeCN (6 mL) was added KI (785 mg,4.73mmol,4.00 eq.) and DIEA (917 mg,7.10mmol,6.00 eq.) in portions at room temperature under nitrogen. The resulting mixture was stirred at 80 ℃ under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5- {4- [1- (7-ethyl-6-oxo-5H-1, 5-naphthyridin-3-yl) ethyl as a white solid]Piperazin-1-yl } -N-methylpyridine-2-carboxamide (303.1 mg, 60.91%). LC-MS (ES+H, M/z) [ M+H ]] + ＝421.2。
Step 7: rel-5- {4- [ (1R) -1- (7-ethyl-6-oxo-5H-1, 5-naphthyridin-3-yl) ethyl ]Piperazine-1- Phenyl } -N-methylpyridine-2-carboxamide (example 20) and rel-5- {4- [ (1R) -1- (7-ethyl-6-oxo-5H-1, 5-naphthalene Pyridin-3-yl) ethyl]Preparation of piperazin-1-yl } -N-methylpyridine-2-carboxamide (example 21)：
5- {4- [1- (7-ethyl-6-oxo-5H-1, 5-naphthyridin-3-yl) ethyl ] piperazin-1-yl } -N-methylpyridine-2-carboxamide (300 mg,0.71mmol,1.00 eq.) was isolated by preparative chiral HPLC. This gave rel-5- {4- [ (1R) -1- (7-ethyl-6-oxo-5H-1, 5-naphthyridin-3-yl) ethyl ] piperazin-1-yl } -N-methylpyridine-2-carboxamide (example 20, 130.0mg,43.33%, ee=100%) as a white solid and rel-5- (4- { [ (1 aR) -1 a-ethyl-2-oxo-1H, 3H,7 bH-cyclopropaneo [ c ] quinolin-5-yl ] methyl } piperazin-1-yl) -N-methylpyridin-2-carboxamide (example 21, 122.4mg,40.80%, ee=99.5%) as a white solid. Note that: the stereochemical allocation of example 20 and example 21 was arbitrary.
Example 20：
LC-MS:(ES+H,m/z):[M+H] + ＝421.3。 1 H NMR(300MHz,DMSO-d 6 )δ11.83(s,1H),8.45(s,1H),8.39(q,1H),8.25(d,1H),7.82(d,1H),7.75(s,1H),7.62(s,1H),7.42–7.33(m,1H),3.67–3.64(m,1H),3.35–3.33(m,4H),2.78(dd,3H),2.63–2.59(m,4H),2.55–2.50(m,2H),1.38(d,3H),1.18(t,3H)。
Example 21：
LC-MS:(ES+H,m/z):[M+H] + ＝421.3。 1 H NMR(300MHz,DMSO-d 6 )δ11.83(s,1H),8.45(s,1H),8.39(q,1H),8.25(d,1H),7.82(d,1H),7.75(s,1H),7.62(s,1H),7.42–7.33(m,1H),3.67–3.64(m,1H),3.35–3.33(m,4H),2.78(dd,3H),2.63–2.59(m,4H),2.55–2.50(m,2H),1.38(d,3H),1.18(t,3H)。
Example 22A
Step 1: preparation of (R) -2- (hydroxymethyl) piperazine-1, 4-dicarboxylic acid 4-benzyl 1- (tert-butyl) ester：
To tert-butyl (2R) -2- (hydroxymethyl) piperazine-1-carboxylate (5.00 g,23.11mmol,1.00 eq, [ a ] under nitrogen at 0deg.C] 26 D (c=0.1, meoh): + 54.50) and Et 3 N (7.02 g,69.35mmol,3.00 eq.) Cbz-Cl (7.89 g,46.23mmol,2.00 eq.) was added dropwise to a stirred mixture of DCM (80 mL). The resulting mixture was stirred at room temperature overnight. The reaction was quenched by the addition of water (100 mL) at room temperature. By CH 2 Cl 2 The resulting mixture was extracted (3X 150 mL). The combined organic layers were washed with brine (1X 150 mL), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and the pure fractions were concentrated under reduced pressure to give 4-benzyl 1- (tert-butyl) ester of (R) -2- (hydroxymethyl) piperazine-1, 4-dicarboxylic acid (7.40 g, y= 91.35%) as a colorless oil. LC-MS (ES+H, M/z) [ M- (t-Bu) +H] + ＝294.9。 1 H NMR(300MHz,DMSO-d 6 )δ7.44-7.26(m,5H),5.09(s,2H),4.80-4.70(m,1H),4.18-3.85(m,2H),3.80-3.60(m,2H),3.50-3.35(m,2H),3.15-2.75(m,3H),1.41(s,9H)。
Step 2: (R) -2- (((3-bromo-6- (methoxycarbonyl) pyridin-2-yl) oxy) methyl) piperazine-1, 4-dicarboxylic acid Preparation of 4-benzyl 1- (tert-butyl) ester：
A mixture of PPh3 (19.76 g,75.34mmol,6.00 eq.) and DEAD (10.93 g,62.78mmol,5.00 eq.) in THF (200 mL) was stirred at 0deg.C under nitrogen atmosphere for 1 hour. The mixture was added dropwise to 4-benzyl 1-tert-butyl (2R) -2- (hydroxymethyl) piperazine-1, 4-dicarboxylic acid (4.40 g,12.55mmol,1.00 eq.) and methyl 5-bromo-6-hydroxypyridine-2-carboxylate (2.91 g,12.55mmol,1.00 eq.) in THF (50 mL) at 0deg.C over 10 min. The resulting mixture was stirred at room temperature for an additional 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and the pure fractions were concentrated under reduced pressure to give (R) -2- (((3-bromo-6- (methoxycarbonyl) pyridin-2-yl) oxy) methyl) piperazine-1, 4-dicarboxylic acid 4-benzyl 1- (tert-butyl) ester (5.80 g, y= 81.84%) as a colorless oil. LC-MS (ES+H, M/z) [ M+Na ] ] + ＝586.0/588.0。
Step 3: (R) -3- (((3-bromo-6- (methoxycarbonyl) pyridin-2-yl) oxy) methyl) piperazine-1-carboxylic acid benzyl ester Is prepared from：
To 2- ({ [ 3-bromo-6- (methoxycarbonyl) pyridin-2-yl) at room temperature under a nitrogen atmosphere]4-benzyl 1-tert-butyl oxy } methyl) piperazine-1, 4-dicarboxylic acid (5.60 g,9.62mmol,1.00 eq.) in DCM (100 mL) was added in portions HCl (gas) (50 mL, 4M) in 1, 4-dioxane. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. Concentrating the mixture under reduced pressureAnd (5) shrinking. The residue was purified by trituration with hexane/diethyl ether (1/1, 3X 50 mL). The precipitated solid was collected by filtration and washed with hexane (3×50 mL). The residue was basified with saturated Na2CO3 (aq) to pH 8-9 and extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (1X 200 mL), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. This gave benzyl (R) -3- (((3-bromo-6- (methoxycarbonyl) pyridin-2-yl) oxy) methyl) piperazine-1-carboxylate (3.7 g, y=80.32%) as a pale yellow oil. LC-MS (ES+H, M/z) [ M+H ]] + ＝463.9/465.9。 1 H NMR(300MHz,DMSO-d 6 )δ8.23(d,1H),7.60(d,1H),7.45 -7.25(m,5H),5.08(s,2H),4.45-3.99(m,4H),3.92-3.68(m,4H),3.04-2.54(m,4H)。
Step 4: (R) -1,2,4a, 5-tetrahydropyrazino [1,2-d]Pyrido [2,3-b ][1,4]Oxazine-3, 8 (4H) -dio Preparation of 3-benzyl 8-methyl formate：
To 3- ({ [ 3-bromo-6- (methoxycarbonyl) pyridin-2-yl) at room temperature under a nitrogen atmosphere]Benzyl oxy } methyl) piperazine-1-carboxylate (1.20 g,2.58mmol,1.00 eq.) and Cs 2 CO 3 (2.53 g,7.75mmol,3.00 eq.) in THF (60 mL) was added [ bis (2- (diphenylphosphino) phenyl) ether ]]Palladium (II) dichloride (740 mg,1.03mmol,0.40 eq). The resulting mixture was stirred at 80 ℃ under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and the pure fractions were concentrated under reduced pressure to give (R) -1,2,4a, 5-tetrahydropyrazino [1,2-d ] as a pale yellow oil]Pyrido [2,3-b][1,4]Oxazine-3, 8 (4H) -dicarboxylic acid 3-benzyl 8-methyl ester (560 mg, y= 56.52%). LC-MS (ES+H, M/z) [ M+H ]] + ＝384.1。1H NMR(300MHz,DMSO-d 6 )δ7.63(d,1H),7.46-7.22(m,6H),5.13(s,2H),4.56-4.47(m,1H),4.13-4.06(m,5H),3.78(s,3H),3.17(d,2H)。
Step 5: (R) -8- (methylcarbamoyl) -1,2,4a, 5-tetrahydropyrazino [1,2-d]Pyrido [2,3-b][1, 4]Preparation of oxazine-3 (4H) -carboxylic acid benzyl ester：
In the roomAt the temperature under nitrogen atmosphere, to (R) -1,2,4a, 5-tetrahydropyrazino [1,2-d]Pyrido [2,3-b][1,4]Oxazine-3, 8 (4H) -dicarboxylic acid 3-benzyl 8-methyl ester (560 mg,1.46mmol,1.00 eq.) to a stirred mixture of MeOH (15 mL) was added dropwise methylamine (10 mL,25 wt% to 30 wt% aqueous solution). The resulting mixture was stirred at room temperature overnight. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. Adding saturated NH to the resulting mixture 4 Cl (100 mL) and extracted with EtOAc (3X 100 mL). The combined organic layers were washed with brine (1×100 mL) and dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. This gives (R) -8- (methylcarbamoyl) -1,2,4a, 5-tetrahydropyrazino [1,2-d ] as a white solid]Pyrido [2,3-b][1,4]Oxazine-3 (4H) -carboxylic acid benzyl ester (530 mg, y=94.89%). LC-MS (ES+H, M/z) [ M+H ]] + ＝383.2。
Step 6: (R) -N-methyl-1, 2,3, 4a, 5-hexahydropyrazino [1,2-d]Pyrido [2,3-b][1,4]Oxa-type Preparation of oxazine-8-carboxamides：
To 5- (methylcarbamoyl) -8-oxa-1, 6, 12-triazatricyclo [8.4.0.0 {2,7}, under hydrogen atmosphere at room temperature]Tetradec-2, 4, 6-triene-12-carboxylic acid benzyl ester (500 mg,1.30mmol,1.00 eq.) and NH 3 .H 2 O (3 mL) Pd/C (100 mg,10 wt%) was added to a stirred mixture of i-PrOH (15 mL). The resulting mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The resulting mixture was filtered and the filter cake was washed with MeOH (5X 50 mL). The filtrate was concentrated under reduced pressure. This gives (R) -N-methyl-1, 2,3, 4a, 5-hexahydropyrazino [1,2-d ] as a white solid]Pyrido [2,3-b][1,4]Oxazine-8-carboxamide (290 mg, y= 89.33%). LC-MS (ES+H, M/z) [ M+H ]] + ＝249.0。
Step 7: (R) -3- ((7-ethyl-6-oxo-5, 6-dihydro-1, 5-naphthyridin-3-yl) methyl) -N-methyl-1, 2, 3, 4a, 5-hexahydropyrazino [1,2-d ]]Pyrido [2,3-b][1,4]Preparation of oxazine-8-carboxamide：
To (R) -N-methyl-1, 2,3, 4a, 5-hexahydropyrazino [1,2-d ] at room temperature under nitrogen atmosphere]Pyrido [2,3-b][1,4]Oxazine-8-carboxamide (123 mg,to a stirred mixture of 0.49mmol,1.10 eq.) and 7- (chloromethyl) -3-ethyl-1H-1, 5-naphthyridin-2-one (100 mg,0.45mmol,1.00 eq.) in ACN (4 mL) were added DIEA (290 mg,2.24mmol,5.00 eq.) and KI (7 mg,0.04mmol,0.10 eq.) in portions. The resulting mixture was stirred at 80 ℃ under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was cooled to room temperature. The reaction mixture was poured into water (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3X 50 mL). The combined organic layers were washed with brine (1X 100 mL), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC, the pure fractions concentrated under reduced pressure and lyophilized to give (R) -3- ((7-ethyl-6-oxo-5, 6-dihydro-1, 5-naphthyridin-3-yl) methyl) -N-methyl-1, 2,3, 4a, 5-hexahydropyrazino [1,2-d ] as a white solid]Pyrido [2,3-b][1,4]Oxazine-8-carboxamide (100 mg, ee% = 99.17%, y= 47.62%). LC-MS (ES+H, M/z) [ M+H ] ] + =435.15. Optical rotation: [ a ]] 26 D(c＝0.5,DMF):-3.38。 1 H NMR(300MHz,DMSO-d 6 )δ11.86(s,1H),8.41(d,1H),8.16(d,1H),7.76(s,1H),7.63(d,1H),7.53(d,1H),7.29(d,1H),4.45-4.35(m,1H),4.12-4.00(m,1H),3.86-3.55(m,3H),3.21-3.17(m,1H),3.01-2.71(m,6H),2.61-2.52(m,2H),2.28-2.22(m,1H),1.85-1.81(m,1H),1.20(t,3H)。
The following examples were carried out using a similar procedure to that shown for example 22A。
Example 22B
Step 1: preparation of 4-benzyl 1-tert-butyl (2S) -2- (hydroxymethyl) piperazine-1, 4-dicarboxylic acid：
(2S) -2- (hydroxymethyl) piperazine-1-carboxylic acid tert-butyl ester (5.00 g,23.12mmol,1.00 eq. [ a)] 26 D (c=0.1, meoh): -50.45) solution in DCM (100 mL) NEt 3 (7.02 g,69.35mmol,3 eq.) under nitrogen at 0deg.C for 10 min, followed by dropwise addition of Cbz-Cl (5.92 g,34.68mmol,1.50 eq.) at 0deg.C. The resulting mixture was stirred at room temperature under nitrogen overnight. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with EtOAc (3X 200 mL). The combined organic layers were washed with brine (1X 200 mL), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 4-benzyl 1-tert-butyl (2S) -2- (hydroxymethyl) piperazine-1, 4-dicarboxylic acid 4-ester (7.70 g, 95%) as a colorless oil. LC-MS (ES+H, M/z) [ M-tBu+H ]] + ＝295。 1 H NMR(400MHz,DMSO-d6)δ7.40–7.29(m,5H),5.08(s,2H),4.81(s,1H),4.15–3.99(m,1H),3.95(m,1H),3.84(m,1H),3.73(m,1H),3.40(m,2H),2.97(m,3H),1.40(s,9H)。
Step 2: (2S) -2- ({ [ 3-bromo-6- (methoxycarbonyl) pyridin-2-yl)]Oxy } methyl) piperazine-1, 4-dicarboxylic acid Preparation of acid 4-benzyl 1-tert-butyl ester：
A mixture of PPh3 (11.23 g,42.80mmol,6.00 eq.) and DEAD (6.21 g,35.67mmol,5.00 eq.) in THF (100 mL) was stirred at 0deg.C under nitrogen atmosphere for 1 hour. The mixture was added dropwise to 4-benzyl 1-tert-butyl (2.50 g,7.13mmol,1.00 eq.) and methyl 5-bromo-6-hydroxypyridine-2-carboxylate (1.66 g,7.13mmol,1.00 eq.) in THF (100 mL) at 0 ℃ over 10 min. The resulting mixture was stirred at room temperature for an additional 2 hours. The reaction was monitored by LCMS. The resulting mixture was filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give (2S) -2- ({ [ 3-bromo-6- (methoxycarbonyl) pyridin-2-yl) as a colorless oil]4-benzyl 1-tert-butyl oxy } methyl) piperazine-1, 4-dicarboxylic acid (3.5 g, 86%). LC-MS (ES+H, M/z) [ M+H ]] + ＝564.0/566.0
Step 3: (3S) -3- ({ [ 3-bromo-6- (methoxycarbonyl) pyridin-2-yl)]Oxy } methyl) piperazine-1-carboxylic acid benzyl ester Preparation of esters：
To (2S) -2- ({ [ 3-bromo-6- (methoxycarbonyl) pyridin-2-yl) at room temperature under a nitrogen atmosphere]4-benzyl 1-tert-butyl oxy } methyl) piperazine-1, 4-dicarboxylic acid (3.50 g,6.20mmol,1.00 eq.) in DCM (100 mL) was added in portions HCl (gas) (20 mL, 4M) in 1, 4-dioxane. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with hexane/diethyl ether (1/1, 3X 20 mL). The precipitated solid was collected by filtration and washed with hexane (3×5 mL). The residue was basified with saturated Na2CO3 (aqueous solution) to pH 8-9. To the resulting mixture was added 200mL of water and extracted with EtOAc (3X 200 mL). The combined organic layers were washed with brine (1X 200 mL), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. This gives (3S) -3- ({ [ 3-bromo-6- (methoxycarbonyl) pyridin-2-yl) as a pale yellow oil]Benzyl oxy } methyl) piperazine-1-carboxylate (2.1 g, 72.94%). LC-MS (ES+H, M/z) [ M+H ]] + ＝463.9/465.9。 1 H NMR(400MHz,DMSO-d6)δ8.23(d,1H),7.60(d,1H),7.41–7.28(m,5H),5.07(s,2H),4.34(dd,1H),4.28–4.15(m,1H),4.07(t,1H),3.86 -3.80(m,4H),3.01–2.75(m,4H),2.68–2.56(m,2H)。
Step 4: (S) -1,2,4a, 5-tetrahydropyrazino [1,2-d]Pyrido [2,3-b][1,4]Oxazine-3, 8 (4H) -dio Preparation of 3-benzyl 8-methyl formate：
To (3S) -3- ({ [ 3-bromo-6- (methoxycarbonyl) pyridin-2-yl) at room temperature under a nitrogen atmosphere]Benzyl oxy } methyl) piperazine-1-carboxylate (2.00 g,4.31mmol,1.00 eq.) and Cs 2 CO 3 (4.21 g,12.92mmol,3.00 eq.) in THF (100 mL) was added (II)/[ bis (2- (diphenylphosphino) phenyl) ether]Palladium (II) dichloride (308 mg,0.43mmol,0.10 eq). The resulting mixture was stirred at 80 ℃ under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography. This gives (S) -1,2,4a, 5-tetrahydropyrazino [1,2-d ] as a pale yellow oil]Pyrido [2,3-b][1,4]Oxazine-3, 8 (4H) -dicarboxylic acid 3-benzyl 8-methyl ester(1.5g，91％)。LC-MS:(ES+H,m/z):[M+H] + ＝384.1。 1 H NMR(400MHz,DMSO-d6)δ7.63(d,1H),7.42–7.28(m,6H),5.13(s,2H),4.52(dd,1H),4.08(q,3H),3.89(d,1H),3.78(s,3H),3.31–3.25(m,1H),3.05(s,1H),2.86-2.80(m,1H),2.70-2.68(m,1H)。
Step 5: (S) -8- (methylcarbamoyl) -1,2,4a, 5-tetrahydropyrazino [1,2-d]Pyrido [2,3-b][1, 4]Preparation of oxazine-3 (4H) -carboxylic acid benzyl ester ：
(S) -1,2,4a, 5-tetrahydropyrazino [1,2-d ] under nitrogen at room temperature]Pyrido [2,3-b][1,4]A mixture of oxazine-3, 8 (4H) -dicarboxylic acid 3-benzyl 8-methyl ester (500 mg,1.30mmol,1.00 eq.) and aqueous methylamine (5 mL,25 wt% to 30 wt% aqueous solution) in MeOH (5 mL) was stirred overnight. The resulting mixture was concentrated under reduced pressure. Adding saturated NH to the resulting mixture 4 Cl (200 mL) and extracted with EtOAc (3X 200 mL). The combined organic layers were washed with brine (1X 200 mL), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. This gives (S) -8- (methylcarbamoyl) -1,2,4a, 5-tetrahydropyrazino [1,2-d ] as a white solid]Pyrido [2,3-b][1,4]Oxazine-3 (4H) -carboxylic acid benzyl ester (410 mg, 82%). LC-MS (ES+H, M/z) [ M+H ]] + ＝383.1。 1 H NMR(400MHz,DMSO-d6)δ8.19(q,1H),7.54(d,1H),7.41–7.30(m,6H),5.13(d,2H),4.52(dd,1H),4.16–4.02(m,3H),3.86(d,1H),3.22(td,1H),3.05(s,1H),2.84–2.62(m,5H)。
Step 6: (10S) -N-methyl-8-oxa-1, 6, 12-triazatricyclo [8.4.0.0 {2,7}]The reaction of tetradecane-2, 4, preparation of 6-triene-5-carboxamide：
To (10S) -5- (methylcarbamoyl) -8-oxa-1, 6, 12-triazatricyclo [8.4.0.0 {2,7}, under hydrogen atmosphere at room temperature]To a stirred mixture of tetradecane-2, 4, 6-triene-12-carboxylic acid benzyl ester (400 mg,1.05mmol,1.00 eq.) in MeOH (10 mL) and HOAc (2 mL) was added Pd/C (40 mg). The resulting mixture was stirred at room temperature under an atmosphere of hydrogen overnight. The reaction was monitored by LCMS. The resulting mixture was filtered and the filter cake was washed with MeOH (5X 50 mL). The filtrate was concentrated under reduced pressure. This gives (10S) -N-methyl as a white solid -8-oxa-1, 6, 12-triazatricyclo [8.4.0.0 {2,7}]Tetradec-2, 4, 6-triene-5-carboxamide (220 mg, 85%). LC-MS (ES+H, M/z) [ M+H ]] + ＝249.0。
Step 7: (10S) -12- [ (7-Ethyl-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl]N-methyl-8-oxa-) 1,6, 12-triazatricyclo [8.4.0.0 {2,7}]Preparation of tetradecane-2, 4, 6-triene-5-carboxamide：
To (10S) -N-methyl-8-oxa-1, 6, 12-triazatricyclo [8.4.0.0 {2,7}, under nitrogen atmosphere at room temperature]To a stirred mixture of tetradecane-2, 4, 6-triene-5-carboxamide (200 mg,0.81mmol,1.00 eq.) and 7- (chloromethyl) -3-ethyl-1H-1, 5-naphthyridin-2-one (215 mg,0.97mmol,1.20 eq.) in MeCN (10 mL) was added KI (27 mg,0.16mmol,0.20 eq.) and DIEA (0.70 mL,4.03mmol,5.00 eq.). The resulting mixture was stirred at 80 ℃ under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with MeOH (5 mL). This gives (10S) -12- [ (7-ethyl-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl as a white solid]-N-methyl-8-oxa-1, 6, 12-triazatricyclo [8.4.0.0 {2,7}]Tetradecane-2, 4, 6-triene-5-carboxamide (55.6 mg, y=16%, ee=100%). LC-MS (ES+H, M/z) [ M+H ] ] + = 435.2. Optical rotation: [ a ]] 26 D(c＝0.5,DMF):+3.96。 1 H NMR(400MHz,DMSO-d6)δ11.87(s,1H),8.41(d,1H),8.17(q,1H),7.76(s,1H),7.62(d,1H),7.53(d,1H),7.29(d,1H),4.40(dd,1H),4.05(dd,1H),3.80(d,1H),3.71(d,1H),3.61(d,1H),3.25–3.16(m,1H),3.02–2.86(m,2H),2.84–2.76(m,1H),2.75(d,3H),2.61–2.51(m,2H),2.24(td,1H),1.82(t,1H),1.18(t,3H)。
Example 23
Step 1: 5-fluoro-3 ',6' -dihydro-2 'H- [3,4' -bipyridine]-1', 6-dicarboxylic acid 1' -tert-butyl 6-methyl ester Preparation：
Methyl 5-bromo-3-fluoropyridine-2-carboxylate (550 mg,2.35mmol,1.00 eq) and tert-butyl 4- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -3, 6-dihydro-2H-pyridine-1-carboxylate (872 mg,2.82mmol,1.20 eq) and Pd (dppf) Cl 2 (171 mg,0.23mmol,0.10 eq.) and K 2 CO 3 A mixture of (975 mg,7.05mmol,3.00 eq.) in 1, 4-dioxane (10 mL) and water (0.5 mL) was stirred at 80℃under nitrogen for 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-fluoro-3 ',6' -dihydro-2 'h- [3,4' -bipyridine as a colorless oil]-1', 6-dicarboxylic acid 1' -tert-butyl 6-methyl ester (530 mg, 67.04%). LC-MS (ES+H, M/z) [ M+H ]] + ＝337.2。 1 H NMR (400 MHz, chloroform-d) δ8.52 (d, 1H), 7.40 (dd, 1H), 6.24 (s, 1H), 4.08 (m, 2H), 3.94 (s, 3H), 3.60 (t, 2H), 2.46 (brs, 2H), 1.42 (s, 9H).
Step 2:5- [1- (tert-Butoxycarbonyl) piperidin-4-yl]Preparation of methyl-3-fluoropyridine-2-carboxylate：
To 5-fluoro-3 ',6' -dihydro-2 'H- [3,4' -bipyridine under nitrogen at room temperature ]To a solution of 1', 6-dicarboxylic acid 1' -tert-butyl 6-methyl ester (530 mg,1.57mmol,1.00 eq.) in EtOAc (10 ml) was added Pd/C (100 mg,10 wt%). The mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was filtered and the filter cake was washed with EA (200 mL). Concentrating the filtrate under reduced pressure to give 5- [1- (tert-butoxycarbonyl) piperidin-4-yl as colorless oil]-3-fluoropyridine-2-carboxylic acid methyl ester (500 mg, 93.78%). LC-MS (ES+H, M/z) [ M+H ]] + ＝339.2。 1 H NMR (400 MHz, chloroform-d) delta 8.35 (d, 1H), 7.35-7.26 (dd, 1H), 4.35-4.09 (brs, 2H), 3.93 (s, 3H), 2.94-2.62 (m, 3H), 1.84-1.74 (m, 2H), 1.59-1.48 (m, 2H), 1.41 (s, 9H).
Step 3:4- [ 5-fluoro-6- (methylcarbamoyl) pyridin-3-yl]Preparation of piperidine-1-carboxylic acid tert-butyl ester：
To 5- [1- (tert-butoxycarbonyl) piperidin-4-yl under nitrogen at 0deg.C]In a stirred solution of methyl-3-fluoropyridine-2-carboxylate (500 mg,1.48mmol,1.00 eq.) in MeOH (5 ml)Dropwise adding CH 3 NH 2 (10 mL,25 wt% to 30 wt% aqueous solution). The resulting mixture was stirred at room temperature for an additional 2 hours. The reaction was monitored by LCMS. By addition of saturated NH at 0 DEG C 4 The reaction was quenched with Cl (50 mL). The aqueous layer was extracted with DCM (3X 50 mL). By anhydrous Na 2 SO 4 The combined organic layers were dried. After filtration, the filtrate was concentrated under reduced pressure. This gives 4- [ 5-fluoro-6- (methylcarbamoyl) pyridin-3-yl as a colourless oil]Piperidine-1-carboxylic acid tert-butyl ester (490 mg, 98.29%). LC-MS (ES+H, M/z) [ M+H ]] + ＝337.9。 1 H NMR(400MHz,DMSO-d6)δ8.66–8.49(m,1H),8.39(d,1H),7.84–7.72(m,1H),4.22–3.96(m,2H),2.96–2.86(m,1H),2.86–2.78(m,2H),2.77(d,3H),1.90–1.69(m,2H),1.62–1.49(m,2H),1.42(s,9H)。
Step 4: preparation of 3-fluoro-N-methyl-5- (piperidin-4-yl) pyridine-2-carboxamide TFA salt：
To 4- [ 5-fluoro-6- (methylcarbamoyl) pyridin-3-yl under nitrogen atmosphere at 0 ℃C]To a stirred solution of tert-butyl piperidine-1-carboxylate (460 mg,1.36mmol,1.00 eq.) in DCM (10 mL) was added TFA (3 mL). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with hexane: ether=1:1 (2×5 mL). This gave 3-fluoro-N-methyl-5- (piperidin-4-yl) pyridine-2-carboxamide TFA salt (450 mg, crude) as a colorless oil. LC-MS (ES+H, M/z) [ M+H ]] + ＝238.3。
Step 5:5- {1- [ (7-ethyl-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl]Piperidin-4-yl } -3-fluoro-N-methyl Preparation of alkylpyridine-2-carboxamides：
To a stirred mixture of 3-fluoro-N-methyl-5- (piperidin-4-yl) pyridine-2-carboxamide TFA salt (200 mg, crude) and 7- (chloromethyl) -3-ethyl-1H-1, 5-naphthyridin-2-one (150 mg,0.67mmol,1.00 eq.) and KI (23 mg,0.14mmol,0.20 eq.) in acetonitrile (5 ml) was added DIEA (435 mg,3.37mmol,5.00 eq.) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 ℃ under nitrogen atmosphere for 4 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature . The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give a crude product (250 mg). The crude product was isolated by preparative HPLC and the pure fractions concentrated under reduced pressure and lyophilized to give 5- {1- [ (7-ethyl-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl as a white solid]Piperidin-4-yl } -3-fluoro-N-methylpyridine-2-carboxamide (65.3 mg, 22.89%). LC-MS (ES+H, M/z) [ M+H ]] + ＝423.95。 1 H NMR(400MHz,DMSO-d6)δ11.86(s,1H),8.57(d,1H),8.40(d,2H),7.79–7.71(m,2H),7.60(s,1H),3.62(s,2H),2.98–2.87(m,2H),2.77–2.64(m,4H),2.59–2.53(m,2H),2.19–2.02(m,2H),1.90–1.59(m,4H),1.18(t,3H)。
Example 24
Step 1: preparation of 7- (chloromethyl) -3-cyclopropyl-1H-1, 5-naphthyridin-2-one：
SOCl was added dropwise to a stirred mixture of 3-cyclopropyl-7- (hydroxymethyl) -1H-1, 5-naphthyridin-2-one (1.00 g,4.62mmol,1.00 eq.) and DMF (30 mg,0.46mmol,0.10 eq.) in DCM (10 mL) at 0deg.C under nitrogen atmosphere 2 (3.30 g,27.74mmol,6.00 eq.). The resulting mixture was stirred at room temperature under nitrogen overnight. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give 7- (chloromethyl) -3-cyclopropyl-1H-1, 5-naphthyridin-2-one (1.00 g, crude) as a yellow solid. The crude product was used directly in the next step without further purification. LC-MS (ES+H, M/z) [ M+H ]] + ＝235.0。
Step 2: n-cyclopropyl-5- {4- [ (7-cyclopropyl-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl]Piperazine-1- Preparation of yl } pyridine-2-carboxamide：
To a stirred mixture of N-cyclopropyl-5- (piperazin-1-yl) pyridine-2-carboxamide (115 mg,0.47mmol,1.10 eq.) and DIEA (275 mg,2.13mmol,5.00 eq.) in acetonitrile (5 mL) at room temperature under nitrogen was added KI (14.15 mg,0.09mmol,0.20 eq.) and 7- (chloromethyl) -3-cyclopropyl-1H-1, 5-Naphthyridin-2-one (100 mg,0.43mmol,1.00 eq.). The resulting mixture was stirred at 80℃for 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give N-cyclopropyl-5- {4- [ (7-cyclopropyl-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl as a white solid]Piperazin-1-yl } pyridine-2-carboxamide (91.90 mg, 46.53%). LC-MS (ES+H, M/z) [ M+H ]] + ＝445.2。 1 H NMR(400MHz,DMSO-d 6 )δ11.90(s,1H),8.37(dd,2H),8.23(d,1H),7.83(d,1H),7.60(d,1H),7.43–7.36(m,2H),3.64(s,2H),3.32(m,4H),2.86-2.82(m,1H),2.55(m,4H),2.14(t,1H),1.01–0.93(m,2H),0.85–0.78(m,2H),0.69–0.59(m,4H)。
Example 25
Step 1:5- { [1- (tert-Butoxycarbonyl) azetidin-3-yl]Preparation of methyl oxy } pyridine-2-carboxylate：
A mixture of DEAD (5.69 g,32.65mmol,5.00 eq.) and PPh3 (10.90 g,39.18mmol,6.00 eq.) in THF (100 ml) was stirred at 0deg.C under nitrogen atmosphere for 1 hour. The mixture was added dropwise to methyl 5-hydroxypyridine-2-carboxylate (1.00 g,6.53mmol,1.00 eq.) and tert-butyl 3-hydroxyazetidine-1-carboxylate (1.70 g,9.79mmol,1.50 eq.) in THF (100 ml) under nitrogen atmosphere at 0 ℃. The resulting mixture was stirred at room temperature under nitrogen for 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5- { [1- (tert-butoxycarbonyl) azetidin-3-yl as a yellow solid ]Methyl oxy } pyridine-2-carboxylate (4.5 g, crude, containing TPPO). LC-MS (ES+H, M/z) [ M+H ]] + ＝309.1。
Step 2:3- { [6- (methylcarbamoyl) pyridin-3-yl]Preparation of tert-butyl oxy } azetidine-1-carboxylate Preparation method：
5- { [1- (tert-Butoxycarbonyl) azetidine-3-yl]Methyl oxy } pyridine-2-carboxylate (3.50 g, crude product, TPPO) and CH 3 NH 2 A mixture of (20 mL,25 wt% to 30 wt% aqueous solution) in MeOH (20 mL) was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. Adding saturated NH to the resulting mixture 4 Cl (100 mL) and extracted with DCM (3X 100 mL). The combined organic layers were washed with brine (1×100 mL) and dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. This gives 3- { [6- (methylcarbamoyl) pyridin-3-yl as a yellow solid]Tert-butyl oxy } azetidine-1-carboxylate (3.3 g, crude, containing TPPO). LC-MS (ES+H, M/z) [ M+H ]] + ＝308.1
Step 3: preparation of 5- (azetidin-3-yloxy) -N-methylpyridine-2-carboxamide HCl salt：
To 3- { [6- (methylcarbamoyl) pyridin-3-yl at room temperature under nitrogen atmosphere]Tert-butyl oxy } azetidine-1-carboxylate (3.30 g, crude, TPPO-containing) in DCM (10 mL) was added in portions HCl (gas) in 1, 4-dioxane (10 mL,4m in dioxane). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with EtOAc (3×20 mL). The precipitated solid was collected by filtration and concentrated under reduced pressure. This gave 5- (azetidin-3-yloxy) -N-methylpyridine-2-carboxamide HCl salt (600 mg, crude) as a yellow solid. LC-MS (ES+H, M/z) [ M+H ] ] + ＝208.2。
Step 4:5- ({ 1- [ (7-ethyl-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl]Azetidin-3-yl } oxy Preparation of yl) -N-methylpyridine-2-carboxamide：
To a stirred mixture of 7- (chloromethyl) -3-ethyl-1H-1, 5-naphthyridin-2-one (200 mg,0.90mmol,1.00 eq.) and 5- (azetidin-3-yloxy) -N-methylpyridine-2-carboxamide HCl salt (280 mg, crude) in MeCN (5 mL) was added KI (30 mg,0.18mmol,0.20 eq.) and DIEA (580 mg,4.49mmol,5.00 eq.) at room temperature under nitrogen atmosphere. The resulting mixture was subjected to nitrogen at 80 ℃Stirring was carried out overnight under a gas atmosphere. The mixture was cooled to room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. The pure fractions were concentrated and lyophilized to give 5- ({ 1- [ (7-ethyl-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl) as a white solid]Azetidin-3-yl } oxy) -N-methylpyridine-2-carboxamide (108 mg, 30%). LC-MS (ES+H, M/z) [ M+H ]] + ＝394.20。 1 H NMR(400MHz,DMSO-d6)δ11.85(s,1H),8.56(q,1H),8.37(d,1H),8.23(dd,1H),7.95(dd,1H),7.73(q,1H),7.57(dd,1H),7.41(dd,1H),5.02(p,1H),3.78(dt,4H),3.24–3.09(m,2H),2.79(d,3H),2.55(dd,2H),1.18(t,3H)。
Example 26
Step 1:5- { [1- (tert-Butoxycarbonyl) azetidin-3-yl](methyl) amino } pyridine-2-carboxylic acid methyl ester Preparation：
To a solution of methyl 5-bromopyridine-2-carboxylate (2.00 g,9.26mmol,1.00 eq.) and tert-butyl 3- (methylamino) azetidine-1-carboxylate (2.07 g,11.11mmol,1.20 eq.) in 1, 4-dioxane (20 mL) at room temperature was added Cs 2 CO 3 (9.05 g,27.77mmol,3.00 eq.) and RuPhos Palladacycle Gen.3 (0.77 g,0.93mmol,0.10 eq.). The resulting mixture was stirred overnight at 120 ℃ under nitrogen atmosphere. The reaction was monitored by LCMS. After cooling to room temperature, the resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3X 100 mL). The combined organic layers were washed with brine (1X 100 mL), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography. This gives 5- { [1- (tert-butoxycarbonyl) azetidin-3-yl as a brown oil]Methyl (meth) amino } pyridine-2-carboxylate (1.8 g, 60.50%). LC-MS (ES+H, M/z) [ M+H ]] + ＝322.1。 1 H NMR(300MHz,DMSO-d6)δ8.22(d,1H),7.87(d,1H),7.18(dd,1H),4.85-4.76(m,1H),4.18(t,2H),3.93(dd,2H),3.81(s,3H),3.03(s,3H),1.40(s,9H)。
Step 2:3- { methyl [6- (methylcarbamoyl) pyridin-3-yl]Oxy } azetidine-1-carboxylic acid tert-butyl ester Is prepared from：
5- { [1- (tert-Butoxycarbonyl) azetidin-3-yl](methyl) amino } pyridine-2-carboxylic acid methyl ester (1.00 g,3.11mmol,1.00 eq.) and CH 3 NH 2 (5 mL,25 wt% to 30 wt% aqueous solution) in MeOH (5 mL) was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. Adding saturated NH to the resulting mixture 4 Cl (100 mL) and extracted with DCM (3X 100 mL). The combined organic layers were washed with brine (1×100 mL) and dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. This gives 3- { methyl [6- (methylcarbamoyl) pyridin-3-yl as a brown oil]Amino } azetidine-1-carboxylic acid tert-butyl ester (800 mg, 80.2%).
LC-MS:(ES+H,m/z):[M+H] + ＝321.2。 1 H NMR(300MHz,DMSO-d6)δ8.39(d,1H),8.10(d,1H),7.82(d,1H),7.22(dd,1H),4.77-4.68(m,1H),4.43-4.20(m,2H),3.94-3.89(m,2H),3.00(s,3H),2.78(d,3H),1.40(s,9H)。
Step 3:5- [ azetidin-3-yl (methyl) amino group]Preparation of the TFA salt of-N-methylpyridine-2-carboxamide：
3- { methyl [6- (methylcarbamoyl) pyridin-3-yl]A solution of tert-butyl amino } azetidine-1-carboxylate (800 mg,2.50mmol,1.00 eq.) and TFA (10 mL) in DCM (10 mL) was stirred at room temperature under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. This gives 5- [ azetidin-3-yl (methyl) amino ] as a brown oil]-N-methylpyridine-2-carboxamide TFA salt (2 g, crude). LC-MS (ES+H, M/z) [ M+H ]] + ＝221.2
Step 4:5- ({ 1- [ (7-ethyl-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl]Azetidin-3-yl } (A) Preparation of amino) -N-methylpyridine-2-carboxamide：
At room temperature, to 5- [ azetidine ]3-yl (methyl) amino group]To a stirred solution of the N-methylpyridine-2-carboxamide TFA salt (400 mg, crude) and DIEA (1.56 mL,8.98mmol,10.00 eq.) in MeCN (10 mL) was added 7- (chloromethyl) -3-ethyl-1H-1, 5-naphthyridin-2-one (200 mg,0.90mmol,1.00 eq.) and KI (30 mg,0.18mmol,0.20 eq.). The resulting mixture was stirred at 50 ℃ under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3X 100 mL). The combined organic layers were washed with brine (1X 100 mL), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product (200 mg) was purified by preparative HPLC, the pure fractions concentrated and then lyophilized to give 5- ({ 1- [ (7-ethyl-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl as a white solid]Azetidin-3-yl } (meth) amino) -N-methylpyridine-2-carboxamide (97.0 mg, 26.57%). LC-MS (ES+H, M/z) [ M+H ]] + ＝407.3。1H NMR(300MHz,DMSO-d6)δ11.86(s,1H),8.41-8.32(m,2H),8.04(d,1H),7.80(d,1H),7.74(s,1H),7.58(d,1H),7.16(dd,1H),4.45-4.29(m,1H),3.78-3.63(m,4H),3.13(t,2H),2.98(s,3H),2.78(d,3H),2.60-2.52(m,2H),1.20(t,3H)。
Example 82
Step 1: preparation of tert-butyl 4- (pyridin-2-yl) piperazine-1-carboxylate：
2-bromopyridine (500 mg,3.16mmol,1.00 eq.) piperazine-1-carboxylic acid tert-butyl ester (589 mg,3.16mmol,1.00 eq.) Cs 2 CO 3 A mixture of (2.06 g,6.33mmol,2.00 eq.) and RuPhos Palladacycle Gen.3 (132 mg,0.16mmol,0.05 eq.) in 1, 4-dioxane (10 mL) was stirred at 80℃under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was filtered using CH 2 Cl 2 (3X 10 mL) the filter cake was washed. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl 4- (pyridin-2-yl) piperazine-1-carboxylate (450 mg, 54) as a yellow oil.00％)。LC-MS:(ES+H,m/z):[M+H] + ＝264.1。 1 H NMR(300MHz,DMSO-d 6 )δ8.13–8.11(m,1H),7.58–7.52(m,1H),6.83(d,1H),6.74–6.61(m,1H),3.50-3.44(m,8H),1.43(s,9H)。
Step 2: preparation of pyridylpiperazine HCl salt：
A mixture of tert-butyl 4- (pyridin-2-yl) piperazine-1-carboxylate (450 mg,1.71mmol,1.00 eq.) in HCl (gas) in 1, 4-dioxane (5 mL, 4M) was stirred at room temperature for 30 min. The reaction was monitored by LCMS. The resulting mixture was concentrated in vacuo to give the pyridylpiperazine HCl salt (300 mg, crude) as a yellow solid. LC-MS (ES+H, M/z) [ M+H ] ] + ＝164.25。
Step 3: 3-ethyl-7- { [4- (pyridin-2-yl) piperazin-1-yl]Preparation of methyl } -1H-1, 5-naphthyridin-2-one：
To a stirred mixture of pyridylpiperazine HCl salt (150 mg, crude), 7- (chloromethyl) -3-ethyl-1H-1, 5-naphthyridin-2-one (150 mg,0.67mmol,1.00 eq.) and KI (22 mg,0.14mmol,0.20 eq.) in ACN (5 mL) was added DIEA (261 mg,2.02mmol,3.00 eq.) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80℃for 1 hour. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with water (20 mL). By CH 2 Cl 2 (3X 20 mL) the aqueous layer was extracted. The combined organic layers were concentrated under reduced pressure. Purification of the crude product by preparative HPLC, concentration of the pure fractions under reduced pressure, and then lyophilization gave 3-ethyl-7- { [4- (pyridin-2-yl) piperazin-1-yl as a white solid]Methyl } -1H-1, 5-naphthyridin-2-one (83.2 mg, 35.34%). LC-MS (ES+H, M/z) [ M+H ]] + ＝350.20。 1 H NMR(300MHz,DMSO-d 6 )δ11.85(s,1H),8.40(d,1H),8.12–8.08(m,1H),7.75(s,1H),7.63(d,1H),7.58–7.46(m,1H),6.81(d,1H),6.71–6.59(m,1H),3.63(s,2H),3.49(t,4H),2.60-2.52(m,6H),1.19(t,3H)。
The following examples were carried out using a similar procedure to that shown for example 82。
Example 124 and example 125
Step 1: (E) Preparation of (E) -2- (5-bromo-3-nitropyridin-2-yl) -N, N-dimethylethan-1-amine：
To a stirred solution of 5-bromo-2-methyl-3-nitropyridine (200 g,921.57mmol,1.00 eq.) in NMP (1L) was added DMF-DMA (219.6 g,1843.13mmol,2.00 eq.) at room temperature. The resulting mixture was stirred at 85 ℃ overnight. The reaction was monitored by TLC. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The crude mixture was used directly in the next step without further purification.
Step 2: preparation of 5-bromo-3-nitropyridine aldehyde：
NaIO4 (540 g,2.52mol,2.50 eq.) in EtOH (1L) and H 2 The solution in O (1.85L) was treated at room temperature under nitrogen atmosphere for 30 minutes. To the resulting mixture was added dropwise [ (E) -2- (5-bromo-3-nitropyridin-2-yl) vinyl group in NMP (1L) at room temperature]Dimethylamine (200 g,735.018mmol,1 eq.). The resulting mixture was stirred at room temperature under nitrogen overnight. The reaction was monitored by TLC. Filtering the resulting mixture; the filter cake was washed with EtOAc (3X 1L). The resulting mixture was diluted with water (5L). The resulting mixture was extracted with EtOAc (3X 2L). The combined organic layers were washed with brine (5X 5L). After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and the pure fractions were concentrated under reduced pressure to give the crude product as a yellow solid. The residue was purified by trituration with hexane (1.5L). The precipitated solid was collected by filtration and washed with hexane (3×100 mL). This gave 5-bromo-3-nitropyridine-2-carbaldehyde (80 g,47.12%, two steps) as a yellow solid. LC-MS (ES+H, M/z) [ M+H ]] + ＝229.9/231.90。 1 1HNMR(300MHz,DMSO-d6)δ10.08(d,1H),9.23(d,1H),8.95(d,1H)。
Step 3: (Z) -3- (5-bromo-3-nitroPreparation of ethyl-pyrid-2-yl) -2-methacrylate：
A solution of LiCl (23.49 g,554.10mmol,1.60 eq.) in toluene (350 mL) and pyridine (50 mL) was stirred at 50deg.C under nitrogen for 1 hour. The mixture was cooled to room temperature. TEA (38.55 g,380.94mmol,1.10 eq.) was added to the above mixture. The resulting mixture was stirred at 50℃for a further 15 minutes. 5-bromo-3-nitropyridine-2-carbaldehyde (80 g,346.31mmol,1.00 eq.) and ethyl 2- (diethoxyphosphoryl) propionate (123.75 g,519.47mmol,1.50 eq.) in toluene (200 ml) were added dropwise to the above mixture over 2 hours at 50 ℃. The resulting mixture was stirred at 50℃for a further 30 minutes. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with HCl (0.6 n,600 ml). The resulting mixture was extracted with EtOAc (3X 500 mL). The combined organic layers were washed with brine (1X 500 mL), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude mixture was used directly in the next step without further purification. LC-MS (ES+H, M/z) [ M+H ]] + ＝315.0/317.0。
Step 4: preparation of 7-bromo-3-methyl-1, 5-naphthyridin-2 (1H) -one：
To a stirred solution of Fe (70.89 g,1269.34mmol,5.00 eq.) in AcOH (500 mL) was added dropwise ethyl (2E) -3- (5-bromo-3-nitropyridin-2-yl) -2-methylpropan-2-enoate (55 g,174.54mmol,1.00 eq., crude) at 80℃under nitrogen atmosphere. The resulting mixture was stirred at 75 ℃ for an additional 30 minutes. The reaction was monitored by LCMS. The resulting mixture was filtered at 75 ℃ and the filter cake was washed with AcOH (3 x 200 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was diluted with ice/water (800 mL). The precipitated solid was collected by filtration and washed with water (3×100 mL). The residue was purified by trituration with MTBE (500 mL). The precipitated solid was collected by filtration and washed with MTBE (3X 100 mL). This gave 7-bromo-3-methyl-1H-1, 5-naphthyridin-2-one (26 g,62.83%, two steps) as a brown solid. LC-MS (ES+H, M/z) [ M+H ]] + ＝238.85/240.85。 1 H NMR(300MHz,DMSO-d6)δ11.94(s,1H),8.50(d,1H),7.81(d,1H),7.79(s,1H),2.12(s,3H)。
Step 5: preparation of 7- (1-ethoxyvinyl) -3-methyl-1, 5-naphthyridin-2 (1H) -one：
To a stirred mixture of 7-bromo-3-methyl-1H-1, 5-naphthyridin-2-one (3.00 g,12.54mmol,1.00 eq.) and tributyl (1-ethoxyvinyl) stannane (13.60 g,37.64mmol,3.00 eq.) in 1, 4-dioxane (20 mL) at room temperature was added Pd (PPh) 3 ) 2 Cl 2 (0.44 g,0.62mmol,0.05 eq.). The resulting mixture was stirred at 100 ℃ under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The desired product was detectable by LCMS. The resulting mixture was used directly in the next step without further purification. LC-MS (ES+H, M/z) [ M+H ]] + ＝231.1
Step 6: preparation of 7-acetyl-3-methyl-1, 5-naphthyridin-2 (1H) -one：
The mixture from the last step was cooled to room temperature and concentrated HCl (4 mL) was added dropwise to an ice bath. The resulting mixture was stirred at room temperature for 1 hour. The reaction was monitored by LCMS. The mixture was basified with saturated NaHCO3 (aqueous solution) to pH 8. The resulting mixture was diluted with water (100 mL). By CH 2 Cl 2 The resulting mixture was extracted (3X 200 mL). The combined organic layers were washed with brine (1X 300 mL), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 7-acetyl-3-methyl-1, 5-naphthyridin-2 (1H) -one (1.39 g,54.7%, two steps) as a yellow solid. LC-MS (ES+H, M/z) [ M+H ]] + ＝203.2。
Step 7: n-methyl-5- {4- [1- (7-methyl-6-oxo-5H-1, 5-naphthyridin-3-yl) ethyl]Piperazin-1-yl } Preparation of pyridine-2-carboxamide：
A mixture of N-methyl-5- (piperazin-1-yl) pyridine-2-carboxamide (743 mg,2.23mmol,1.50 eq.) and 7-acetyl-3-methyl-1H-1, 5-naphthyridin-2-one (300 mg,1.48mmol,1.00 eq.) in DCM (2 mL) was stirred at room temperature under nitrogen for 30 min. The resulting mixture was concentrated under reduced pressure. To the above mixture was added tetrakis (prop-2-yloxy) titanium (633 mg,2.23mmol,1.5 eq). The resulting mixture was stirred at 80℃for a further 4 hours . The residue was dissolved in EtOH (2 mL). NaBH was added to the above mixture in portions at room temperature 3 CN (187 mg,2.97mmol,2.00 eq.). The resulting mixture was stirred at 80 ℃ under nitrogen atmosphere for 4 hours. The reaction was monitored by LCMS. The reaction was quenched by the addition of water (5 mL) at room temperature. The resulting mixture was filtered and the filter cake was washed with MeOH/dcm=1:1 (3×50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give N-methyl-5- {4- [1- (7-methyl-6-oxo-5H-1, 5-naphthyridin-3-yl) ethyl as a white solid]Piperazin-1-yl } pyridine-2-carboxamide (260 mg, 43.1%). LC-MS (ES+H, M/z) [ M+H ]] + ＝407.3。
Step 8: rel-N-methyl-5- {4- [ (1R) -1- (7-methyl-6-oxo-5H-1, 5-naphthyridin-3-yl) ethyl]Piperazine sheet Oxazin-1-yl } pyridine-2-carboxamide and rel-N-methyl-5- {4- [ (1R) -1- (7-methyl-6-oxo-5H-1, 5-naphthyridine-3- Radical) ethyl radical]Preparation of piperazin-1-yl } pyridine-2-carboxamide：
The racemate N-methyl-5- {4- [1- (7-methyl-6-oxo-5H-1, 5-naphthyridin-3-yl) ethyl ] piperazin-1-yl } pyridine-2-carboxamide (240 mg) was separated by preparative chiral HPLC to give rel-N-methyl-5- {4- [ (1R) -1- (7-methyl-6-oxo-5H-1, 5-naphthyridin-3-yl) ethyl ] piperazin-1-yl } pyridine-2-carboxamide (example 124, 93.9mg, ee=100%) and rel-N-methyl-5- {4- [ (1R) -1- (7-methyl-6-oxo-5H-1, 5-naphthyridin-3-yl) ethyl ] piperazin-1-yl } pyridine-2-carboxamide (example 125, 66.0mg, ee=100%).
Example 124: LC-MS (ES+H, M/z) [ M+H ]] + ＝407.10。 1 H NMR(300MHz,DMSO-d 6 )δ11.84(s,1H),8.42(d,2H),8.25(d,1H),7.82(d,2H),7.62(d,1H),7.37(dd,1H),3.65(d,1H),3.33–3.28(m,4H),2.78(d,3H),2.64–2.57(m,2H),2.50–2.43(m,2H),2.14(d,3H),1.38(d,3H)。
Example 125: LC-MS (ES+H, M/z) [ M+H ]] + ＝407.25。 1 H NMR(300MHz,DMSO-d 6 )δ11.84(s,1H),8.41(d,2H),8.24(d,1H),7.82(d,2H),7.62(s,1H),7.37(dd,1H),3.65(d,1H),3.34–3.31(m,4H),2.78(d,3H),2.67–2.57(m,2H),2.49–2.41(m,2H),2.14(s,3H),1.37(d,3H)。
The following examples were carried out using similar procedures as shown for examples 124 and 125。
Example 128
Step 1: preparation of 3- (piperazin-1-yl) pyridine-2-carbonitrile：
A solution of 3-fluoropyridine-2-carbonitrile (2.00 g,16.38mmol,1.00 eq.) and piperazine (4.50 g,52.24mmol,3.20 eq.) in DMSO (20 mL) was stirred overnight at 50deg.C under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with brine (300 mL). The resulting mixture was extracted with EtOAc (3X 500 mL). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under reduced pressure to give 3- (piperazin-1-yl) pyridine-2-carbonitrile (2 g, y=64.8%) as a yellow solid. LC-MS (ES+H, M/z) [ M+H ]] + ＝189.00。 1 H NMR(300MHz,DMSO-d6)δ8.26(dd,1H),7.67–7.56(m,2H),3.16–3.09(m,4H),2.92–2.84(m,4H)。
Step 2:3- {4- [ (7-ethyl-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl]Piperazin-1-yl } pyridin-2-one Preparation of nitriles：
To a stirred solution of 3- (piperazin-1-yl) pyridine-2-carbonitrile (150 mg,0.79mmol,1.00 eq.) and 7- (chloromethyl) -3-ethyl-1H-1, 5-naphthyridin-2-one (266 mg,1.19mmol,1.50 eq.) in MeCN (6 mL) was added DIEA (309 mg,2.39mmol,3.00 eq.) and KI (26 mg,0.15mmol,0.20 eq.) in portions at room temperature. The mixture is heated to 80 DEG C Stirring is carried out for 2 hours under nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was filtered using CH 2 Cl 2 The filter cake was washed with MeOH (10:1, 200 mL). The filtrate was concentrated under reduced pressure. Purification of the crude product by HP-FLASH (400 mg), concentration of the pure fractions in vacuo, followed by lyophilization, gave 3- {4- [ (7-ethyl-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl as a white solid]Piperazin-1-yl } pyridine-2-carbonitrile (166.5 mg, y=55.8%). LC-MS (ES+H, M/z) [ M+H ]] + ＝375.25。 1 H NMR(400MHz,DMSO-d6)δ11.86(s,1H),8.41(d,1H),8.28(dd,1H),7.75(s,1H),7.68–7.59(m,3H),3.68(s,2H),3.23(t,4H),2.61(t,4H),2.57–2.52(m,2H),1.19(t,3H)。
The following examples were carried out using a procedure similar to that shown for example 128。
Example 138
Step 1: preparation of 3-bromo-2-methoxy-6-methyl-5-nitropyridine：
To a stirred solution of 3-bromo-2-chloro-6-methyl-5-nitropyridine (20.00 g,79.54mmol,1.00 eq.) in MeOH (50 mL) at 0deg.C under nitrogen was added dropwise NaOMe (15.76 g,87.49mmol,1.10 eq., 30 wt%). The resulting mixture was stirred at room temperature under nitrogen overnight. The reaction was monitored by TLC. The resulting mixture was concentrated under reduced pressure, and water (100 mL) was added. The resulting mixture was extracted with EtOAc (3X 100 mL). The combined organic layers were washed with brine (1X 200 mL), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate is subtracted Concentration under pressure gave 3-bromo-2-methoxy-6-methyl-5-nitropyridine (20 g, y=99%) as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ8.66(s,1H),4.04(s,3H),2.70(s,3H)。
Step 2: (E) Preparation of (E) -2- (5-bromo-6-methoxy-3-nitropyridin-2-yl) -N, N-dimethylethan-1-amine：
A mixture of 3-bromo-2-methoxy-6-methyl-5-nitropyridine (15.00 g,60.72mmol,1.00 eq.) in DMF-DMA (100 mL) and DMF (100 mL) was stirred overnight at 100deg.C under nitrogen. The reaction was monitored by TLC. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.
Step 3: preparation of 5-bromo-6-methoxy-3-nitropyridine aldehyde：
To (E) -2- (5-bromo-6-methoxy-3-nitropyridin-2-yl) vinyl at 0deg.C under nitrogen atmosphere]Dimethylamine (18.01 g, crude) in THF (100 mL) and H 2 NaIO was added in portions to the stirred mixture in O (100 mL) 4 (28.00 g,131.07mmol,2.20 eq.). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The reaction was monitored by TLC. The reaction was quenched at room temperature by the addition of saturated sodium thiosulfate (aqueous) (100 mL). The resulting mixture was extracted with EtOAc (3X 100 mL). The combined organic layers were washed with brine (2X 100 mL), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. 1 H NMR(400MHz,DMSO-d 6 )δ10.16(s,1H),8.87(s,1H),4.10(s,3H)。
Step 4: preparation of 7-bromo-6-methoxy-1, 5-naphthyridine-3-carboxylic acid ethyl ester：
To a stirred mixture of 5-bromo-6-methoxy-3-nitropyridine-2-carbaldehyde (7.00 g, crude) and ethyl 3, 3-diethoxypropionate (20.40 g,107.27mmol,4.00 eq.) in EtOH (100 mL) at room temperature under nitrogen was added in portions 2 (26.25 g,134.09mmol,5.00 eq.). The resulting mixture was stirred overnight at 90 ℃ under a nitrogen atmosphere. The reaction was monitored by LCMS. Allowing the mixture to reactCooled to room temperature. The resulting mixture was concentrated under reduced pressure. The crude mixture was poured into saturated sodium bicarbonate (100 mL). The resulting mixture was extracted with EtOAc (3X 100 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the crude product as a white solid. The crude product was purified by trituration with hexane (50 mL) to give 7-bromo-6-methoxy-1, 5-naphthyridine-3-carboxylic acid ethyl ester (3.50 g, y=18.5%, three steps) as a white solid.
LC-MS:(ES+H,m/z):[M+H] + ＝311.0/313.0。 1 H NMR(400MHz,DMSO-
d 6 )δ9.22(s,1H),8.78(s,1H),8.58(s,1H),4.42(q,2H),4.12(s,3H),1.39(t3H)。
Step 5: preparation of 7-chloro-6-methoxy-1, 5-naphthyridine-3-carboxylic acid ethyl ester：
To a stirred mixture of ethyl 7-bromo-6-methoxy-1, 5-naphthyridine-3-carboxylate (1.20 g,3.85mmol,1.00 eq.) in DMF (10 mL) was added CuCl (0.57 g,5.78mmol,1.50 eq.) at room temperature under nitrogen. The resulting mixture was stirred at 120 ℃ overnight. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with EtOAc (20 mL). The resulting mixture was treated with 3X 30mL of water (10% NH) 3 ×H 2 O) washing. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 7-chloro-6-methoxy-1, 5-naphthyridine-3-carboxylic acid ethyl ester (800 mg, 77.78%) as a white solid. LC-MS (ES+H, M/z) [ M+H ]] + ＝267.0。 1 H NMR(300MHz,DMSO-d6)δ9.27(d,1H),8.63(d,1H),8.57(s,1H),4.41(q,2H),4.12(s,3H),1.37(t,3H)。
Step 6: preparation of 7-chloro-6-oxo-5H-1, 5-naphthyridine-3-carboxylic acid ethyl ester：
To 7-chloro-6-methoxy-1, 5-naphthyridine-3-carboxylic acid ethyl ester (800 mg,3.00mmol,1.00 eq.) in CH at room temperature under nitrogen atmosphere 3 TMSI (1.80 g,9.00mmol,3.00 eq.) was added to a stirred mixture in CN (8 mL). The resulting mixture was stirred at 50℃for 2 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with EtOAc (50 mL). The aqueous layer was purified by 3X 50mL of water (10% Et) 3 N) washingAnd (5) washing. The combined organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 And (5) drying. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 7-chloro-6-oxo-5H-1, 5-naphthyridine-3-carboxylate (740 mg, 97.64%) as a yellow solid. LC-MS (ES+H, M/z) [ M+H ]] + ＝252.9。 1 HNMR(300MHz,DMSO-d6)δ12.61(s,1H),8.94(d,1H),8.37(d,1H),8.20(s,1H),4.39(q,2H),1.36(t,3H)。
Step 7: preparation of 3-chloro-7- (hydroxymethyl) -1H-1, 5-naphthyridin-2-one：
To a stirred solution of 7-chloro-6-oxo-5H-1, 5-naphthyridine-3-carboxylic acid ethyl ester (740 mg,2.92mmol,1.00 eq.) in THF (6 mL) at 0deg.C under nitrogen atmosphere was added LiAlH dropwise 4 (2.5 mL,5.85mmol,2.00 eq.). The resulting mixture was stirred at 0 ℃ for an additional 2 hours. The reaction was monitored by LCMS. The mixture was acidified to pH 5 with 1M HCl. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-chloro-7- (hydroxymethyl) -1H-1, 5-naphthyridin-2-one (250 mg, 40.53%) as a white solid. LC-MS (ES+H, M/z) [ M+H ]] + ＝211.00。 1 H NMR(400MHz,DMSO-d6)δ12.49(s,1H),8.45(d,1H),8.28(s,1H),7.69(d,1H),5.53(t,1H),4.64(d,2H)。
Step 8: preparation of 3-chloro-7- (chloromethyl) -1H-1, 5-naphthyridin-2-one：
To 3-chloro-7- (hydroxymethyl) -1H-1, 5-naphthyridin-2-one (250 mg,1.18mmol,1.00 eq.) in CH under nitrogen at room temperature 2 Cl 2 SOCl was added dropwise to the stirred mixture in (5 mL) 2 (423 mg,3.56mmol,3.00 eq.) and DMF (8 mg,0.11mmol,0.10 eq.). The resulting mixture was stirred at room temperature for 3 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. This gave 3-chloro-7- (chloromethyl) -1H-1, 5-naphthyridin-2-one (280 mg, crude) as a yellow solid. The crude product was used directly in the next step without further purification.
LC-MS:(ES+H,m/z):[M+H] + ＝228.95。
Step 9:5- {4- [ (7-chloro-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl]Piperazin-1-yl } -N-methylpyridine- 2-carboxamide：
A solution of 3-chloro-7- (chloromethyl) -1H-1, 5-naphthyridin-2-one (100 mg,0.43mmol,1.00 eq.), KI (7 mg,0.04mmol,0.10 eq.) and DIEA (225 mg,1.74mmol,4.00 eq.) in acetonitrile (3 mL) was stirred at 50℃under nitrogen for 1 hour. The mixture was cooled to room temperature. The reaction was monitored by LCMS. The resulting mixture was diluted with EtOAc (20 mL) and then washed with water (3×20 mL). The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography to give the crude product. Purification of the crude product by preparative HPLC, concentration of the pure fractions and subsequent lyophilization gave 5- {4- [ (7-chloro-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl as a white solid ]Piperazin-1-yl } -N-methylpyridine-2-carboxamide (73.6 mg, 40.83%). LC-MS (ES+H, M/z) [ M+H ]] + ＝413.10。 1 H NMR(300MHz,DMSO-d 6 )δ12.45(s,1H),8.49(d,1H),8.43-8.36(m,1H),8.29(s,1H),8.27(d,1H),7.83(d,1H),7.70(s,1H),7.40(dd,1H),3.69(s,2H),3.39-3.30(m,4H),2.79(d,3H),2.62-2.54(m,4H)。
The following examples were carried out using a procedure similar to that shown for example 138。
Example 148
Step 1: preparation of methyl 5-nitro-6- (prop-1-en-2-yl) pyridine-3-carboxylate：
6-chloro-5-nitropyridine-3-carboxylic acid methyl ester (10.00 g,46.17mmol,1.00 eq.) 4, 5-tetramethyl-2- (prop-1-en-2-yl) -1,3, 2-dioxaborane (15.52 g,92.34mmol,2.00 g.)Amount, K 2 CO 3 (12.76 g,92.34mmol,2.00 eq.) and Pd (dppf) Cl 2 A mixture of (3.38 g,4.62mmol,0.10 eq.) in dioxane (150 mL) and water (15 mL) was stirred at 100deg.C under nitrogen for 3 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was diluted with water (300 mL) and extracted with EtOAc (3X 300 mL). The combined organic layers were washed with saturated NaCl (aq) (3X 100 mL), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 5-nitro-6- (prop-1-en-2-yl) pyridine-3-carboxylate (5.00 g, 48.74%) as a pale yellow oil.
LC-MS:(ES+H,m/z):[M+H]+＝222.95。1H NMR(300MHz,DMSO-d6)δ9.25(d,1H),8.74(d,1H),5.41–5.47(m,1H),5.13–5.21(m,1H),3.94(s,3H),2.16(dd,3H)。
Step 2: preparation of methyl 5-nitro-6- (prop-1-en-2-yl) pyridine-3-carboxylate ：
To a stirred solution of 5-nitro-6- (prop-1-en-2-yl) pyridine-3-carboxylic acid methyl ester (5.00 g,22.50mmol,1.00 eq.) in MeOH (100 mL) was added NH 4 Cl (25 mL, saturated aqueous solution) and Fe (5.03 g,90.01mmol,4.00 eq.). The reaction was stirred at 80 ℃ under nitrogen atmosphere for 4 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was taken up in CH 2 Cl 2 2-propanol (5:1, 200 mL) was diluted and washed with water (250 mL) and brine (250 mL). The organic layer was treated with anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. This gave methyl 5-amino-6- (prop-1-en-2-yl) pyridine-3-carboxylate (3.90 g, 90.17%) as a pale yellow solid, which was used without further purification. LC-MS (ES+H, M/z) [ M+H ]]+＝193.15。1H NMR(300MHz,DMSO-d6)δ8.29(d,1H),7.60(d,1H),5.51-5.47(m,1H),5.41(s,2H),5.39–5.36(m,1H),3.84(s,3H),2.08(t,3H)。
Step 3: preparation of methyl 8-methyl-6-oxo-5H-1, 5-naphthyridine-3-carboxylate：
A solution of triphosgene (1.54 g,5.20mmol,0.50 eq.) in toluene (20 mL) was stirred under nitrogen at 0deg.CAdded to 5-amino-6- (prop-1-en-2-yl) pyridine-3-carboxylic acid methyl ester (3.90 g,20.29mmol,1.00 eq.) and Et 3 N (6.16 g,60.87mmol,3.00 eq.) in toluene (40 mL). The resulting mixture was stirred overnight at 60 ℃ under nitrogen. The reaction was monitored by LCMS. The reaction was quenched with MeOH (30 mL) at 0deg.C. The resulting mixture was diluted with water (200 mL) and used with CH 2 Cl 2 2-propanol (5:1, 3X 200 mL). The combined organic layers were washed with water (3X 100 mL), dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl 8-methyl-6-oxo-5H-1, 5-naphthyridine-3-carboxylate (1.80 g, 40.66%) as a pale yellow solid. LC-MS (ES+H, M/z) [ M+H ]]+＝219.1。1H NMR(400MHz,DMSO-d6)δ11.92(s,1H),8.92(d,1H),8.15(d,1H),6.79(s,1H),3.93(s,3H),2.48(s,3H)。
Step 4: preparation of 7-chloro-8-methyl-6-oxo-5H-1, 5-naphthyridine-3-carboxylic acid methyl ester：
To 8-methyl-6-oxo-5H-1, 5-naphthyridine-3-carboxylic acid methyl ester (600 mg,2.75mmol,1.00 eq.) and NCS (587 mg,4.40mmol,1.60 eq.) in CH at room temperature under nitrogen atmosphere 3 To a solution of COOH (7 mL) was added dropwise 2, 2-dichloroacetic acid (71 mg,0.55mmol,0.20 eq.). The resulting mixture was stirred overnight at 100 ℃ under a nitrogen atmosphere. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 7-chloro-8-methyl-6-oxo-5H-1, 5-naphthyridine-3-carboxylate (650 mg, 93.5%) as a white solid. LC-MS (ES+H, M/z) [ M+H ]] + ＝253.0。 1 H NMR(300MHz,DMSO-d6)δ8.90(d,1H),8.13(d,1H),3.93(s,3H),2.60(s,3H)。
Step 5: preparation of 3-chloro-7- (hydroxymethyl) -4-methyl-1H-1, 5-naphthyridin-2-one：
To a stirred solution of 7-chloro-8-methyl-6-oxo-5H-1, 5-naphthyridine-3-carboxylic acid ethyl ester (600 mg,2.38mmol,1.00 eq.) in THF (5 mL) at 0deg.C under nitrogen atmosphere was added LiAlH dropwise 4 (2 mL,2.5M in THF, 4.75mmol,2.00 eq.). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 hour. By passing throughLCMS monitored the reaction. The reaction was quenched by addition of HCl (1 mL, 12M) at 0deg.C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-chloro-7- (hydroxymethyl) -4-methyl-1H-1, 5-naphthyridin-2-one (230 mg, 43.1%) as a white solid. LC-MS (ES+H, M/z) [ M+H ]] + ＝225.1。 1 H NMR(300MHz,DMSO-d6)δ12.24(br,1H),8.48(d,1H),7.77(d,1H),5.69(s,1H),4.63(s,2H),2.63(s,3H)。
Step 6: preparation of 3-chloro-7- (chloromethyl) -4-methyl-1H-1, 5-naphthyridin-2-one：
To a stirred solution of 3-chloro-7- (hydroxymethyl) -4-methyl-1H-1, 5-naphthyridin-2-one (200 mg,0.89mmol,1.00 eq.) and DMF (7 mg,0.09mmol,0.10 eq.) in DCM (10 mL) at 0deg.C under nitrogen was added drop wise SOCl 2 (318 mg,2.67mmol,3.00 eq.). The resulting mixture was stirred at room temperature for 10 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-chloro-7- (chloromethyl) -4-methyl-1H-1, 5-naphthyridin-2-one (98 mg, 45.2%) as a white solid. LC-MS (ES+H, M/z) [ M+H ]] + ＝243.0。
Step 7:5- {4- [ (7-chloro-8-methyl-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl]Piperazin-1-yl } -N-methyl Preparation of alkylpyridine-2-carboxamides ：
To a stirred mixture of 3-chloro-7- (chloromethyl) -4-methyl-1H-1, 5-naphthyridin-2-one (120 mg,0.49mmol,1.00 eq.) KI (16 mg,0.09mmol,0.20 eq.) and N-methyl-5- (piperazin-1-yl) pyridine-2-carboxamide (97 mg,0.44mmol,0.90 eq.) in MeCN (5 mL) was added DIEA (319 mg,2.47mmol,5.00 eq.) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80 ℃ under nitrogen atmosphere for 5 hours. The reaction was monitored by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The crude product (120 mg) was purified by preparative HPLC, the pure fractions concentrated and then lyophilized to give 5- {4- [ (7-chloro-8-methyl-6-oxo-5H-1, 5-naphthyridin-3-yl) methyl as a yellow solid]Piperazin-1-yl } -N-methylpyridine-2-carboxamide (26.8 mg, 11.9%). LC-MS (ES+H, M/z) [ M+H ]] + ＝427.15。 1 H NMR(300MHz,DMSO-d6)δ12.31(s,1H),8.53(d,J＝1.9Hz,1H),8.46–8.33(m,1H),8.28(d,J＝2.8Hz,1H),7.83(d,J＝8.8Hz,1H),7.70(d,J＝1.9Hz,1H),7.40(dd,J＝8.8,2.9Hz,1H),3.70(s,2H),3.38–3.33(m,4H),2.78(d,J＝4.8Hz,3H),2.66(s,3H),2.60-2.54(m,4H)。
The following examples were carried out using a similar procedure to that shown for example 148。
The following examples were carried out using similar procedures as shown in the above examples。
Example a: cell growth inhibition assay
The objective of this study was to evaluate the effect of the compounds of the invention on cell proliferation by cell viability assays in the DLD-1BRCA2 (-/-) and parent isogenic pair and MDA-MB-436 (mutated BRCA 1) cell line. Cell viability assays based on CellTiter-Glo (CTG) were designed to determine the number of viable cells in culture due to the influence of a compound by quantifying ATP, which indicates the presence of metabolically active cells.
The DLD-1BRCA2 (-/-) and parent isogenic pair was cultured in RPMI 1640 supplemented with 10% Fetal Bovine Serum (FBS), and MDA-MB-436 cells were cultured in DMEM supplemented with 10% FBS. Both at 37℃and 5% CO 2 And (5) culturing. The compounds of the invention were dispensed into 384 well plates (Corning, 3764) using an Echo sonic liquid processor to give a final concentration of 1:3 serial dilutions, with a maximum dose of 10 μm or 30 μm. Cells were seeded into plates at a density of 50 cells/well (DLD-1 parent), 200 cells/well (DLD-1 BRCA 2-/-), or 500 cells/well (MDA-MB-436). After a short centrifugation time, the cells were incubated in a well-humidified incubator at 37℃and 5% CO 2 The cells were cultured for 7 days without interference. Cell viability was measured by CellTiter Glo 2.0 assay kit (Promega, G9243) and growth inhibition was calculated and plotted against final compound concentration and the data fitted in Xfit to generate IC 50 。
Example B: biochemical (FP) assay
Fluorescence Polarization (FP) based assays have been widely used for drug discovery due to the homogeneous form, robust performance and lack of interference observed in other assays. To characterize our compounds, we utilized an assay that measures the displacement of a commercially available fluorescent-labeled PARP 1/2 inhibitor (PARPi-FL, tocris Biosciences, # 6461), as exemplified in the assays performed in WO2014/064149 and WO 2021/013745 A1. The assay was performed using the following method:
Compounds were dissolved in DMSO and serially expanded in Optiplate-384F plates over the desired concentration range using an Echo550 liquid processor. 100% DMSO was used for high (protein-containing) and low (protein-free) control samples. 20nL of compound or DMSO alone was added to each assay plate well.
In the presence of 50mM Tris pH 8.0, 0.001% Triton X-100, 10mM MgCl 2 PARP1 and PARP2 proteins were expressed, purified and diluted to a final concentration of 20nM in assay buffer of 150mM NaCl. PARPi-FL was then added at a final concentration of 3 nM.
The assay plates were centrifuged at 1000rpm for 1 min and incubated for 4 hours at room temperature.
Fluorescence polarization was read using an Envision microplate reader using the following settings:
excitation filter-FITC FP 480-excitation tank 3
Emission filter-FITC FP P-pol 535-emission tank 4
Emission filter 2-FITC FP S-pol 535-emission tank 3
Mirror Module-FITC FP Dual Enh-tank 1
Using the percentage of permutation mahalanobis distance (mP value) greater than the control sample, the inhibition ratio was calculated according to the following equation:
mP c : mP value of Compound
mP L : low control mP value
mP H : high control mP value
The reported IC50 for each compound was calculated using XLFit (equation 201).
The data for example a and example B are provided in table 2.
TABLE 2
Example C: in vitro human liver clearance in the form of cell relay：
By 100-fold dilution of 10mM stock solution (v: v) prepared in DMSO to ACN/H 2 A working stock solution of each test piece was prepared at a concentration of 100. Mu.M in O (50/50, v: v). Thawing human cryopreserved hepatocytes in a water bath at 37deg.C<For 2 minutes, suspended in thawing medium and centrifuged at 100Xg for 10 minutes. The thawing medium was aspirated and the precipitated hepatocytes were resuspended at 1.5E+06 cells/mL into the incubation medium. Cell viability was determined using acridine orange/propidium iodide stain and hepatocytes were further diluted to 0.5e+06 viable cells/mL with incubation medium. An aliquot of 495 μl of hepatocytes was added to the wells of the 24-well plate, and incubation of the test article was initiated by adding 5 μl of 100 μΜ working stock. The plates were incubated at 37℃with 5% CO 2 Incubate on an orbital shaker at 300rpm under an atmosphere at 95% relative humidity. Incubation was performed in duplicate. At time = 0 hours and 4 hours, aliquots of each incubation were extracted with 6 volumes ACN containing internal standards. After 4 hours, hepatocytes were removed from the incubation via centrifugation and the supernatant was stored frozen until the next day, at which point incubation was restarted by diluting the thawed supernatant containing freshly thawed hepatocytes in the incubation medium, again to a final concentration of 0.5e+06 viable cells/mL. These steps were repeated for a total of 5 incubations, 4 hours each, for a total of 20 hours. Correcting the cell uptake in each relay step, Non-specific binding and dilution induced incubation loss. The supernatants of all incubation aliquots were diluted into ultrapure water prior to analysis via LC/MS. In vitro intrinsic Clearance (CL) in μL/min/1E+06 cells per incubation int ) Determined by calculating in vitro half-life determined using standard log linear regression methods. In vitro CL int The values were amplified using the following physiological scaling factors: 99E+06 cells/g human liver and 25.7g human liver/kg body weight. To calculate the predicted human liver Clearance (CL) in mL/min/kg hep,pred ) Assuming a human liver blood flow of 20.7mL/min/kg and no correction was made for binding of the test sample to erythrocytes, plasma proteins or components of the incubation system, the scaled intrinsic clearance values were finally introduced into a well-stirred liver model. S-warfarin, propidium and diazepam were used as assay controls.
Example D: wider PAPR and TNKS selectivity group determined by FP
In general, all assays were performed according to the BPS PARP and TNKS assay kit protocols with some modifications.
Enzymatic reactions were performed in duplicate in a histone substrate coated 96-well plate at room temperature. The incubation times for PARP 3, 8, 10, 15 and TNKS were one hour and for PARP 6, 7, 11 and 14 were two hours, respectively.
50 μl of the reaction mixture in PARP assay buffer containing NAD+, biotinylated NAD+ enzyme and test or reference compound is incubated for one or two hours at room temperature. Wells were washed five times with PBST and further incubated with 50 μl streptavidin-HRP (prepared with blocking buffer 3) for 30 min. The wells were washed again and 100 μl ELISA ECL substrate was added to each well.
Luminescence was measured using a BioTek synergy tm 2 microplate reader.
Enzyme activity assays were performed in duplicate. Luminescence data was analyzed using computer software Graphpad Prism. In the absence of this compound, luminescence (Lt) in each dataset was defined as 100% activity. In the absence of this enzyme, luminescence (Lb) in each dataset was defined as 0% activity. The percent activity in the presence of each compound was calculated according to the following equation:
% activity = [ (L-Lb)/(Lt-Lb) ]x100;
wherein L = luminescence in the presence of the compound, lb = luminescence in the absence of the enzyme, and Lt = luminescence in the absence of the compound.
Percent inhibition was calculated according to the following equation:
% inhibition = 100-% activity.
The% activity values were then plotted against a range of compound concentrations using a nonlinear regression analysis of the sigmoidal dose-response curve generated by the equation y=b+ (T-B)/1+10 ((log ec 50-X) X Hill slope), where y=percent activity, b=minimum percent activity, t=maximum percent activity, x=log of compound and Hill slope=slope factor or Hill coefficient. IC (integrated circuit) 50 The value is determined by the concentration that gives rise to half the maximum percentage activity.

Claims (47)

1. A compound of formula (III') or a pharmaceutically acceptable salt, solvate or stereoisomer thereof:
wherein:
R C1 is hydrogen, deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-
OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-
S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-
NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-
C(＝O)NR c R d 、C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -
C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally and independently substituted with one or more R Ca Substitution;
each R Ca Is independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-
OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-
S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-
NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-
C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
or two R's on the same atom Ca Together forming oxo;
R C2 is hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、-C(＝O)R a 、-
C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl or heterocycloalkyl;
R C3 is hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl or heterocycloalkyl;
each R 7 Independently hydrogen, deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuteration ofAlkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl or heterocycloalkyl;
or two R 7 Together forming cycloalkyl or heterocycloalkyl; each of which is optionally substituted with deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
each R 8 Is independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl;
or two R's on the same carbon 8 Together forming oxo;
or two R's on the same carbon, adjacent carbon, or opposite carbon 8 Together forming cycloalkyl or heterocycloalkyl; each of which is optionally substituted with one OR more deuterium, halogen, -CN, -OH, -OR a 、-NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
n is 0-6;
R 12 is C 1 -C 6 Alkyl, C 1 -C 6 Deuterated alkyl, cycloalkyl or heterocycloalkyl; wherein the alkyl, cycloalkyl and heterocycloalkyl are optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
each R 11 Is independently deuterium, halogen, -CN, -NO 2 、-OH、-OR a 、-OC(＝O)R a 、-OC(＝O)OR b 、-OC(＝O)NR c R d 、-SH、-SR a 、-S(＝O)R a 、-S(＝O) 2 R a 、-S(＝O) 2 NR c R d 、-NR c R d 、-NR b C(＝O)NR c R d 、-NR b C(＝O)R a 、-NR b C(＝O)OR b 、-NR b S(＝O) 2 R a 、-C(＝O)R a 、-C(＝O)OR b 、-C(＝O)NR c R d 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, cycloalkyl or heterocycloalkyl;
q is 0-3;
each R a Independently C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 Alkyl (heteroaryl); wherein the method comprises the steps of
Each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution;
each R b Independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 Alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, arylAnd heteroaryl are independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl substitution; and
each R c And R is d Independently hydrogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl, C 1 -C 6 Heteroalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C 1 -C 6 Alkyl (cycloalkyl), C 1 -C 6 Alkyl (heterocycloalkyl), C 1 -C 6 Alkyl (aryl) or C 1 -C 6 Alkyl (heteroaryl); wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 HeteroalkanesA group substitution;
or R is c And R is d Together with the atoms to which they are attached form a moiety optionally substituted with one or more oxo, deuterium, halogen, -CN, -OH, -OCH 3 、-S(＝O)CH 3 、-S(＝O) 2 CH 3 、-S(＝O) 2 NH 2 、-S(＝O) 2 NHCH 3 、-S(＝O) 2 N(CH 3 ) 2 、-NH 2 、-NHCH 3 、-N(CH 3 ) 2 、-C(＝O)CH 3 、-C(＝O)OH、-C(＝O)OCH 3 、C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, C 1 -C 6 Hydroxyalkyl, C 1 -C 6 Aminoalkyl or C 1 -C 6 Heteroalkyl-substituted heterocycloalkyl.
2. The compound according to claim 1, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R C1 Is halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Deuterated alkyl, cycloalkyl or heterocycloalkyl.
3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R C1 Is halogen, cycloalkyl or heterocycloalkyl.
4. A compound according to any one of claims 1-3, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R C1 Is halogen or cycloalkyl.
5. The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, wherein R C1 Is halogen.
6. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, solvate or thereofStereoisomers, wherein R C1 Is cycloalkyl.
7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R C2 Is hydrogen, deuterium, halogen, C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group.
8. The compound of any one of claims 1-7, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R C2 Is hydrogen, C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group.
9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R C2 Is hydrogen.
10. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R C2 Is C 1 -C 6 An alkyl group.
11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R C3 Is hydrogen, deuterium, halogen, C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group.
12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R C3 Is hydrogen, C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group.
13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R C3 Is hydrogen or C 1 -C 6 An alkyl group.
14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R C3 Is hydrogen.
15. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein Is->
16. The compound according to claim 1 or 15, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, whereinIs->
17. The compound according to claim 1 or 15, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, whereinIs->
18. According to claimThe compound of claim 1 or 15, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, whereinIs->
19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 7 Independently hydrogen, deuterium, halogen, C 1 -C 6 Alkyl or C 1 -C 6 A haloalkyl group.
20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 7 Is hydrogen.
21. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 8 Is C 1 -C 6 An alkyl group; or two R's on the same carbon 8 Together forming oxo.
22. The compound of any one of claims 1-20, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein two R on opposite carbons 8 Together forming a cycloalkyl group.
23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 0-3.
24. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 2.
25. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 1.
26. The compound of any one of claims 1-23, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein n is 0.
27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 11 Is independently deuterium, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl or C 1 -C 6 Deuterated alkyl.
28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 11 Independently halogen or C 1 -C 6 An alkyl group.
29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein each R 11 Independently halogen.
30. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein q is 0 or 1.
31. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein q is 1.
32. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein q is 0.
33. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 12 Is C 1 -C 6 Alkyl or cycloalkyl.
34. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 12 Is C 1 -C 6 An alkyl group.
35. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein R 12 Is cycloalkyl.
36. The compound of claim 1, wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.
37. The compound of claim 36, wherein the compound is:
or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.
38. The compound of claim 36, wherein the compound is:
or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.
39. The compound of claim 36, wherein the compound is:
or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.
40. The compound of claim 36, wherein the compound is:
or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.
41. The compound of claim 36, wherein the compound is:
or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.
42. The compound of claim 36, wherein the compound is:
or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.
43. A pharmaceutical composition comprising a compound according to any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.
44. A method of treating cancer in a subject in need thereof, the method comprising administering a compound of any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
45. The method of claim 44, wherein the cancer is breast cancer, ovarian cancer, pancreatic cancer, prostate cancer, hematological cancer, gastrointestinal cancer, or lung cancer.
46. A method of treating cancer comprising BRCA1 and/or BRCA2 mutations in a subject in need thereof, the method comprising administering a compound according to any one of claims 1-42, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
47. The method of claim 46, wherein the cancer is bladder, brain, and CNS cancer, breast, cervical, colorectal, esophageal, hodgkin's lymphoma, non-hodgkin's lymphoma, renal, leukemia, lung, melanoma, myeloma, oral cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, gastric cancer, thyroid cancer, or uterine cancer.
CN202280029124.5A 2021-04-19 2022-04-19 PARP1 inhibitors and uses thereof Pending CN117177972A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115702156A (en) * 2021-04-23 2023-02-14 南京明德新药研发有限公司 Pyridine amide compound
CN119019391A (en) * 2024-08-19 2024-11-26 山东轩德医药科技有限公司 Synthesis method and use of a class of azaquinolone compounds

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115702156A (en) * 2021-04-23 2023-02-14 南京明德新药研发有限公司 Pyridine amide compound
CN119019391A (en) * 2024-08-19 2024-11-26 山东轩德医药科技有限公司 Synthesis method and use of a class of azaquinolone compounds

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