CN117203208A - Inhibitors targeting activated and inactivated KRAS G12D - Google Patents

Inhibitors targeting activated and inactivated KRAS G12D Download PDF

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Publication number
CN117203208A
CN117203208A CN202280030233.9A CN202280030233A CN117203208A CN 117203208 A CN117203208 A CN 117203208A CN 202280030233 A CN202280030233 A CN 202280030233A CN 117203208 A CN117203208 A CN 117203208A
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halogen
alkyl
cancer
compound
pharmaceutically acceptable
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张永辉
尚言国
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Tsinghua University
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Tsinghua University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Abstract

A pyridopyrimidine compound, a pharmaceutical composition containing the same, and a preparation method and application thereof, wherein the compound can be targeted to activated and inactivated KRAS G12D and can be used as a reversible inhibitor of KRAS G12D mutant proteins.

Description

Inhibitors targeting activated and inactivated KRAS G12D Technical Field
The invention relates to the field of medicines, and in particular provides a compound capable of reversibly inhibiting KRAS G12D mutant protein, a preparation method and application thereof.
Background
Rat sarcoma homologous gene (RAS) is the first oncogene (oncogene) that has been found to have the highest mutation frequency. RAS proteins act as "molecular switches" regulating a number of signaling pathways involved in cell proliferation and differentiation.
Common mutation sites for KRAS include G12, G13 and Q61, most of which are mutations at the G12 site, accounting for about 83%. Common types of mutations for KRAS G12 include G12D, G V and G12C, with the number of cancer patients carrying KRAS G12D mutations being the greatest. Mutations in KRAS G12D account for 51%, 45%, 17% respectively in ductal carcinoma of the pancreas, colorectal cancer and adenocarcinoma of the lung (Schiripa, M., et al, KRAS G12C Metastatic Colorectal Cancer: specific Features of a New Emerging Target Poplation. Clin Colorectal Cancer, (2020) 219-225). A statistical estimate shows that up to 18 ten thousand new Cancer patients carrying KRAS G12D mutations annually in the united states and europe (Baldus, s.e., et al, prevalence and heterogeneity of KRAS, BRAF, and PIK3CA mutations in primary colorectal adenocarcinomas and their corresponding meta Cancer res.clin Cancer Res 16, (2010) 790-799).
During the last thirty years, all RAS-targeting drug developments failed, with the major difficulty that the guanylate binding pocket of the RAS protein was not suitable for patent and the surface was free of other deeper binding pockets. Since 2013, scientists have found an allosteric pocket in KRAS G12C muteins that can be induced by small molecules, the medical community has raised a hot spot to develop covalent inhibitors of KRAS G12C, whereas inhibitors of the more clinically significant mutein KRAS G12D have rarely been reported to be successful.
Thus, there is an urgent need in the art for safe and effective inhibitors of KRAS G12D muteins.
Disclosure of Invention
Unlike KRAS G12C, the carboxyl group of Asp 12 of KRAS G12D cannot add to the double bond of acrylamide, and thus while covalent inhibitors have been successful on KRAS G12C proteins, such small molecules clearly cannot bind to KRAS G12D. In view of this technical problem, the present invention devised and synthesized inhibitors capable of forming non-covalent bonds with KRAS G12D, and demonstrated that the compounds of the present invention are capable of effectively inhibiting KRAS G12D activity.
In one aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, or isotopic variant thereof:
Wherein,
x is-N (R) -or-CH (R) -;
wherein R is selected from H, - (CH) 2 ) 1-3 Halogen, - (CH) 2 ) 1-3 -OH、-(CH 2 ) 1-3 -CN、-(CH 2 ) 1- 3 -NH 2 、C 1-6 Alkyl or C 1-6 A haloalkyl group;
r is selected from- (CH) 2 ) 0-3 Halogen, - (CH) 2 ) 0-3 -OH、-(CH 2 ) 0-3 -CN or- (CH) 2 ) 0-3 -NH 2 ；
Y is N or CH;
Y 1 is CR (CR) Y1a R Y1b ；
Y 2 Is CR (CR) Y2a R Y2b ；
Y 3 Is CR (CR) Y3a R Y3b Or NR (NR) Y3c ；
r=1 or 2;
s=0 or 1;
wherein R is Y1a 、R Y1b 、R Y2a 、R Y2b 、R Y3a And R is Y3b Independently selected from H, halogen, C 1- 6 Alkyl or C 1-6 A haloalkyl group;
R Y3c selected from H, C 1-6 Alkyl or C 1-6 A haloalkyl group;
or Y 3 And Y adjacent thereto 2 A double bond may be formed therebetween;
R A selected from H, C 6-10 Aryl or 5-14 membered heteroaryl, optionally substituted with 1, 2, 3 or 4R A1 Substitution;
wherein each R is A1 Independently selected from H, halogen, -CN, -OR X 、-SR X 、-NR Y R Z 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
l is selected from a chemical bond, -O-, -S-, or-NH-;
R B selected from H, halogen, -CN, -OR X 、-SR X 、-NR Y R Z 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Aryl or 5-14 membered heteroaryl; optionally substituted with 1, 2, 3 or 4 r#;
wherein R# is selected from H, -C 0-6 Alkylene-halogen, -C 0-6 alkylene-CN, C 1-6 Alkyl, C 1- 6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 alkylene-O-R X 、-C 0-6 alkylene-S-R X 、-C 0-6 alkylene-NR Y R Z 、-C 0-6 alkylene-C (O) R X 、-C 0-6 alkylene-C (O) OR X 、-C 0-6 alkylene-C (O) -NR Y R Z 、-C 0-6 alkylene-C 3-10 Cycloalkyl, -C 0-6 Alkylene-3-10 membered heterocyclyl, -C 0-6 alkylene-C 6-10 Aryl or-C 0-6 Alkylene-5-14 membered heteroaryl; and R# is optionally halogen, -OH, -OC 1-6 Alkyl, -NH 2 、-NH(C 1-6 Alkyl), -N (C) 1-6 Alkyl group 2 、C 1- 6 Alkyl or C 1-6 Haloalkyl substitution;
wherein R is X Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
R Y and R is Z Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2- 6 Alkynyl, or R Y And R is Z The nitrogen atom to which they are attached forms a 3-10 membered heterocyclic group;
R 1 and R is 2 Independently selected from H, halogen, -OH, -NH 2 -CN or- (CR) c R d ) m -R’；
R 3 And R is 4 Independently selected from H, halogen, -OH, -NH 2 -CN or- (CR) c R d ) m -R”；
R 2’ Is H or R 2 、R 2’ Together with the carbon atoms to which they are attached form C 3-6 Cycloalkyl;
or R is 1 And R is 2 、R 3 And R is 4 、R 1 And R is 4 、R 2 And R is 3 Any one of the groups being linked to form- (CR) a R b ) n -；
p=0, 1, 2 or 3;
q=0, 1, 2 or 3;
wherein R is a Selected from H, halogen, C 1-6 Alkyl or C 1-6 A haloalkyl group;
R b selected from H, halogen, C 1-6 Alkyl or C 1-6 A haloalkyl group;
R c selected from H, halogen, C 1-6 Alkyl or C 1-6 A haloalkyl group;
R d selected from H, halogen, C 1-6 Alkyl or C 1-6 A haloalkyl group;
r' is selected from H, halogen, -OH, -SH, -NH 2 、-CN、-C(O)R e 、-C(O)OR e 、-C(O)NR f R g 、C 2-6 Alkenyl or C 2-6 Alkynyl;
r' is selected from H, halogen, -OH, -SH, -NH 2 、-CN、-C(O)R e 、-C(O)OR e 、-C(O)NR f R g 、C 2-6 Alkenyl or C 2-6 Alkynyl;
m=0, 1, 2, 3, 4, 5 or 6;
n=0, 1, 2, 3, 4, 5 or 6;
Wherein R is e Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
R f and R is g Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, or R f And R is g And the nitrogen atom to which they are attached form a 3-10 membered heterocyclic group.
In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention, and optionally a pharmaceutically acceptable excipient.
In another aspect, the invention provides pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable excipient, which also contains an additional therapeutic agent.
In another aspect, the invention provides the use of a compound of the invention in the manufacture of a medicament for the treatment and/or prophylaxis of KRAS G12D mutein mediated diseases.
In another aspect, the invention provides a method of treating and/or preventing KRAS G12D mutein-mediated diseases in a subject comprising administering to the subject a compound of the invention or a composition of the invention.
In another aspect, the invention provides a compound of the invention or a composition of the invention for use in the treatment and/or prevention of KRAS G12D mutein-mediated diseases.
In particular embodiments, the disease treated by the present invention includes a cancer selected from the group consisting of: acute myeloid leukemia, juvenile cancer, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and kaposi's sarcoma), anal carcinoma, appendicular carcinoma, astrocytoma, atypical teratoid, basal cell carcinoma, cholangiocarcinoma, bladder carcinoma, bone carcinoma, brain stem glioma, brain tumor, breast carcinoma, bronchial tumor, burkitt lymphoma, carcinoid tumor, atypical teratoid, embryo tumor, germ cell tumor, primary lymphoma, cervical cancer, childhood cancer, chordoma, heart tumor, chronic Lymphocytic Leukemia (CLL), chronic Myelogenous Leukemia (CML), chronic myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngeal tumor, cutaneous T cell lymphoma, extrahepatic Duct Carcinoma (DCIS), embryo tumor CNS cancers, endometrial cancers, ependymomas, esophageal cancers, olfactory neuroblastomas, ewing's sarcoma, extracranial germ cell tumors, extragonadal germ cell tumors, eye cancers, skeletal fibroblastic tumors, gall bladder cancers, stomach cancers, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), germ cell tumors, gestational trophoblastoma, hairy cell leukemia, head and neck cancers, heart cancers, liver cancers, hodgkin's lymphoma, hypopharynx cancers, intraocular melanoma, islet cell tumors, pancreatic neuroendocrine tumors, kidney cancers, laryngeal cancers, lip and oral cancers, liver cancers, lobular Carcinoma In Situ (LCIS), lung cancers, lymphomas, metastatic squamous neck cancers with harboring primary foci, mesogenic cancers, oral cancers, multiple endocrine tumor syndromes, multiple myeloma/plasmacytoma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic/myeloproliferative neoplasms, multiple myeloma, merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of the bones, nasal and sinus cancers, nasopharyngeal carcinoma, neuroblastoma, non-hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip and oral cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papilloma, paraganglioma, sinus and nasal cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pleural-lung blastoma, primary Central Nervous System (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, gastric cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, cell lymphoma, testicular cancer, laryngeal cancer, thymoma and thymus cancer, thyroid cancer, transitional cell carcinoma of the kidney and ureter, cell tumor, rare cancer, vaginal cancer, uterine sarcoma, cancer of the vulva, cancer of the urinary tract, or virus-induced cancer of the urethra.
Other objects and advantages of the present invention will be apparent to those skilled in the art from the detailed description, examples, and claims that follow.
Drawings
FIG. 1 analysis of binding sites of KRAS G12D protein to TH-Z816.
FIG. 2 TH-Z816 binding pattern analysis to KRAS G12D protein.
FIG. 3 TH-Z816 analysis of protein cavity structure around piperazine ring.
Definition of the definition
Chemical definition
The definition of specific functional groups and chemical terms is described in more detail below.
When numerical ranges are listed, it is intended to include each and every value and subrange within the range. For example "C 1- 6 Alkyl "includes C 1 、C 2 、C 3 、C 4 、C 5 、C 6 、C 1-6 、C 1-5 、C 1-4 、C 1-3 、C 1-2 、C 2-6 、C 2- 5 、C 2-4 、C 2-3 、C 3-6 、C 3-5 、C 3-4 、C 4-6 、C 4-5 And C 5-6 An alkyl group.
“C 1-6 Alkyl "refers to a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, C 1-4 Alkyl and C 1-2 Alkyl groups are preferred. C (C) 1-6 Examples of alkyl groups include: methyl (C) 1 ) Ethyl (C) 2 ) N-propyl (C) 3 ) Isopropyl (C) 3 ) N-butyl (C) 4 ) Tert-butyl (C) 4 ) Sec-butyl (C) 4 ) Isobutyl (C) 4 ) N-pentyl (C) 5 ) 3-pentyl (C) 5 ) Amyl (C) 5 ) Neopentyl (C) 5 ) 3-methyl-2-butyl (C) 5 ) Tert-amyl (C) 5 ) And n-hexyl (C) 6 ). The term "C 1-6 Alkyl "also includes heteroalkyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced with a heteroatom (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Conventional alkyl abbreviations include: me (-CH) 3 )、Et(-CH 2 CH 3 )、iPr(-CH(CH 3 ) 2 )、nPr(-CH 2 CH 2 CH 3 )、n-Bu(-CH 2 CH 2 CH 2 CH 3 ) Or i-Bu (-CH) 2 CH(CH 3 ) 2 )。
“C 2-6 Alkenyl "refers to a straight or branched hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 2-4 Alkenyl groups are preferred. C (C) 2-6 Alkenyl groupsExamples of (a) include: vinyl (C) 2 ) 1-propenyl (C) 3 ) 2-propenyl (C) 3 ) 1-butenyl (C) 4 ) 2-butenyl (C) 4 ) Butadiene group (C) 4 ) Pentenyl (C) 5 ) Pentadienyl (C) 5 ) Hexenyl (C) 6 ) And so on. The term "C 2-6 Alkenyl "also includes heteroalkenyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced with heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). The alkenyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
“C 2-6 Alkynyl "refers to a straight or branched hydrocarbon group having 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 2-4 Alkynyl groups are preferred. C (C) 2-6 Examples of alkynyl groups include, but are not limited to: ethynyl (C) 2 ) 1-propynyl (C) 3 ) 2-propynyl (C) 3 ) 1-butynyl (C) 4 ) 2-butynyl (C) 4 ) Pentynyl (C) 5 ) Hexynyl (C) 6 ) And so on. The term "C 2- 6 Alkynyl "also includes heteroalkynyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced with heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus). Alkynyl groups may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
“C 1-6 Alkylene "means removal of C 1-6 The other hydrogen of the alkyl group forms a divalent group and may be substituted or unsubstituted. In some embodiments, C 1-4 Alkylene, C 2-4 Alkylene and C 1-3 Alkylene groups are preferred. Unsubstituted alkylene groups include, but are not limited to: methylene (-CH) 2 (-), ethylene (-CH) 2 CH 2 (-), propylene (-CH) 2 CH 2 CH 2 -) and butylene (-CH) 2 CH 2 CH 2 CH 2 -) pentylene (-CH) 2 CH 2 CH 2 CH 2 CH 2 (-), hexylene (-CH) 2 CH 2 CH 2 CH 2 CH 2 CH 2 (-), etc. Exemplary substituted alkylene groups, for example, alkylene groups substituted with one or more alkyl (methyl) groups, include, but are not limited to: substituted methylene (-CH (CH) 3 )-、-C(CH 3 ) 2 (-), substituted ethylene (-CH (CH) 3 )CH 2 -、-CH 2 CH(CH 3 )-、-C(CH 3 ) 2 CH 2 -、-CH 2 C(CH 3 ) 2- ) Substituted propylene (-CH (CH) 3 )CH 2 CH 2 -、-CH 2 CH(CH 3 )CH 2 -、-CH 2 CH 2 CH(CH 3 )-、-C(CH 3 ) 2 CH 2 CH 2 -、-CH 2 C(CH 3 ) 2 CH 2 -、-CH 2 CH 2 C(CH 3 ) 2 (-), etc.
“C 0-6 Alkylene "refers to a bond and" C "as described above 1-6 An alkylene group.
“C 2-6 Alkenylene "means removal of C 2-6 The other hydrogen of the alkenyl group forms a divalent group and may be substituted or unsubstituted. In some embodiments, C 2-4 Alkenylene is particularly preferred. Exemplary unsubstituted alkenylenes include, but are not limited to: ethenylene (-ch=ch-) and propenylene (e.g., -ch=chch) 2 -、-CH 2 -ch=ch-). Exemplary substituted alkenylenes, e.g., substituted with one or more alkyl (methyl) groups Alkenylene groups of (a) include, but are not limited to: substituted ethylene (-C (CH) 3 )＝CH-、-CH＝C(CH 3 ) (-), substituted propenylene (-C (CH) 3 )＝CHCH 2 -、-CH＝C(CH 3 )CH 2 -、-CH＝CHCH(CH 3 )-、-CH＝CHC(CH 3 ) 2 -、-CH(CH 3 )-CH＝CH-、 -C(CH 3 ) 2 -CH＝CH-、-CH 2 -C(CH 3 )＝CH-、-CH 2 -CH＝C(CH 3 ) (-), etc.
“C 2-6 Alkynylene "refers to removal of C 2-6 The other hydrogen of the alkynyl group forms a divalent group and may be substituted or unsubstituted. In some embodiments, C 2-4 Alkynylene groups are particularly preferred. Exemplary such alkynylene groups include, but are not limited to: ethynylene (-C.ident.C-), substituted or unsubstituted propynylene (-C.ident.CCH) 2 (-), etc.
"halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).
Thus, "C 1-6 Haloalkyl "means" C "as described above 1-6 Alkyl ", substituted with one or more halo groups. In some embodiments, C 1-4 Haloalkyl is particularly preferred, more preferably C 1-2 A haloalkyl group. Exemplary such haloalkyl groups include, but are not limited to: -CF 3 、-CH 2 F、-CHF 2 、-CHFCH 2 F、-CH 2 CHF 2 、-CF 2 CF 3 、-CCl 3 、-CH 2 Cl、-CHCl 2 2, 2-trifluoro-1, 1-dimethyl-ethyl, and the like. The haloalkyl group may be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
“C 3-10 Cycloalkyl "refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms and zero heteroatoms. In some embodimentsIn case C 4-7 Cycloalkyl and C 3-6 Cycloalkyl is particularly preferred, more preferably C 5-6 Cycloalkyl groups. Cycloalkyl also includes ring systems in which the cycloalkyl ring is fused to one or more aryl or heteroaryl groups, where the point of attachment is on the cycloalkyl ring, and in such cases the number of carbons continues to represent the number of carbons in the cycloalkyl system. Exemplary such cycloalkyl groups include, but are not limited to: cyclopropyl (C) 3 ) Cyclopropenyl (C) 3 ) Cyclobutyl (C) 4 ) Cyclobutenyl (C) 4 ) Cyclopentyl (C) 5 ) Cyclopentenyl (C) 5 ) Cyclohexyl (C) 6 ) Cyclohexenyl (C) 6 ) Cyclohexadienyl (C) 6 ) Cycloheptyl (C) 7 ) Cycloheptenyl (C) 7 ) Cycloheptadienyl (C) 7 ) Cycloheptatrienyl (C) 7 ) And so on. Cycloalkyl groups may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
"3-12 membered heterocyclyl" refers to a group of a 3 to 12 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon. In a heterocyclic group containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as the valence permits. In some embodiments, a 4-12 membered heterocyclic group is preferred, which is a 4-12 membered non-aromatic ring system having a ring carbon atom and 1 to 5 ring heteroatoms; in some embodiments, 3-10 membered heterocyclyl is preferred, which is a 3-10 membered non-aromatic ring system having a ring carbon atom and 1 to 5 ring heteroatoms; in some embodiments, 3-8 membered heterocyclyl is preferred, which is a 3-to 8-membered non-aromatic ring system having a ring carbon atom and 1 to 4 ring heteroatoms; preferably a 3-6 membered heterocyclic group which is a 3 to 6 membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms; preferably a 4-7 membered heterocyclic group which is a 4-7 membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms; more preferably a 5-6 membered heterocyclic group which is a 5-to 6-membered non-aromatic ring system having a ring carbon atom and 1 to 3 ring heteroatoms. Heterocyclyl groups also include Wherein the heterocyclyl ring is fused to one or more cycloalkyl ring(s), wherein the point of attachment is on the cycloalkyl ring, or wherein the heterocyclyl ring is fused to one or more aryl or heteroaryl ring(s), wherein the point of attachment is on the heterocyclyl ring; and in such cases the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to: aziridinyl, oxetanyl, thietanyl (thio). Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to: azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to: tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2, 5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to: dioxolanyl, oxathiolanyl (oxathiolanyl), dithiolanyl (disulfuranyl) and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to: triazolinyl, oxadiazolinyl and thiadiazolinyl. Exemplary 6 membered heterocyclyl groups containing one heteroatom include, but are not limited to: piperidinyl, tetrahydropyranyl, dihydropyridinyl and thianyl (thianyl). Exemplary 6 membered heterocyclyl groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, dithiocyclohexenyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to: hexahydrotriazinyl (triazinyl). Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to: azepanyl, oxepinyl, and thiepanyl. Exemplary AND C 6 Aryl ring fused 5-membered heterocyclyl groups (also referred to herein as 5, 6-bicyclic heterocyclyl groups) include, but are not limited to: indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary AND C 6 Aryl ring fused 6 membered heterocyclyl (also referred to herein as 6, 6-bicyclic heterocyclyl) groups include, but are not limited to: tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. The heterocyclyl group may be optionally substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
“C 6-10 Aryl "refers to a group of a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 pi electrons shared in a cyclic arrangement) having 6 to 10 ring carbon atoms and zero heteroatoms. In some embodiments, the aryl group has six ring carbon atoms ("C 6 Aryl "; for example, phenyl). In some embodiments, aryl groups have ten ring carbon atoms ("C 10 Aryl "; for example, naphthyl groups, such as 1-naphthyl and 2-naphthyl). Aryl also includes ring systems in which the above aryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the aryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the aryl ring system. The aryl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
"5-14 membered heteroaryl" refers to a group of a 5-14 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, as the valency permits. The heteroaryl bicyclic ring system may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the above heteroaryl ring is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring, in which case the number of carbon atoms continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, a 5-10 membered heteroaryl group is preferred, which is a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms. In other embodiments, 5-6 membered heteroaryl groups are particularly preferred, which are 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyrrolyl, furanyl, and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to: imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to: triazolyl, oxadiazolyl (e.g., 1,2, 4-oxadiazolyl), and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to: tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to: a pyridyl group. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to: pyridazinyl, pyrimidinyl and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to: triazinyl and tetrazinyl. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to: azetidinyl, oxepinyl, and thiepinyl. Exemplary 5, 6-bicyclic heteroaryl groups include, but are not limited to: indolyl, isoindolyl, indazolyl, benzotriazole, benzothienyl, isobenzothienyl, benzofuranyl, benzisotofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiadiazolyl, indenazinyl and purinyl. Exemplary 6, 6-bicyclic heteroaryl groups include, but are not limited to: naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl and quinazolinyl. Heteroaryl groups may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, and the like as defined herein are optionally substituted groups.
Exemplary substituents on carbon atoms include, but are not limited to: halogen, -CN, -NO 2 、-N 3 、 -SO 2 H、-SO 3 H、-OH、-OR aa 、-ON(R bb ) 2 、-N(R bb ) 2 、-N(R bb ) 3 + X - 、-N(OR cc )R bb 、-SH、-SR aa 、-SSR cc 、-C(＝O)R aa 、-CO 2 H、-CHO、-C(OR cc ) 2 、-CO 2 R aa 、-OC(＝O)R aa 、-OCO 2 R aa 、-C(＝O)N(R bb ) 2 、-OC(＝O)N(R bb ) 2 、-NR bb C(＝O)R aa 、-NR bb CO 2 R aa 、-NR bb C(＝O)N(R bb ) 2 、-C(＝NR bb )R aa 、-C(＝NR bb )OR aa 、-OC(＝NR bb )R aa 、-OC(＝NR bb )OR aa 、-C(＝NR bb )N(R bb ) 2 、-OC(＝NR bb )N(R bb ) 2 、-NR bb C(＝NR bb )N(R bb ) 2 、-C(＝O)NR bb SO 2 R aa 、-NR bb SO 2 R aa 、-SO 2 N(R bb ) 2 、-SO 2 R aa 、-SO 2 OR aa 、-OSO 2 R aa 、-S(＝O)R aa 、-OS(＝O)R aa 、-Si(R aa ) 3 、-OSi(R aa ) 3 、-C(＝S)N(R bb ) 2 、-C(＝O)SR aa 、-C(＝S)SR aa 、-SC(＝S)SR aa 、-SC(＝O)SR aa 、-OC(＝O)SR aa 、-SC(＝O)OR aa 、-SC(＝O)R aa 、-P(＝O) 2 R aa 、-OP(＝O) 2 R aa 、-P(＝O)(R aa ) 2 、-OP(＝O)(R aa ) 2 、-OP(＝O)(OR cc ) 2 、-P(＝O) 2 N(R bb ) 2 、-OP(＝O) 2 N(R bb ) 2 、-P(＝O)(NR bb ) 2 、-OP(＝O)(NR bb ) 2 、-NR bb P(＝O)(OR cc ) 2 、-NR bb P(＝O)(NR bb ) 2 、-P(R cc ) 2 、-P(R cc ) 3 、-OP(R cc ) 2 、-OP(R cc ) 3 、-B(R aa ) 2 、-B(OR cc ) 2 、-BR aa (OR cc ) Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R dd Group substitution;
or two geminal hydrogen-cover groups on carbon atom=o, =s, =nn (R bb ) 2 、＝NNR bb C(＝O)R aa 、＝NNR bb C(＝O)OR aa 、＝NNR bb S(＝O) 2 R aa 、＝NR bb Or=nor cc Substitution;
R aa independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R aa The groups combine to form a heterocyclyl or heteroaryl ring wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R dd Group substitution;
R bb independently selected from: hydrogen, -OH, -OR aa 、-N(R cc ) 2 、-CN、-C(＝O)R aa 、-C(＝O)N(R cc ) 2 、-CO 2 R aa 、-SO 2 R aa 、-C(＝NR cc )OR aa 、-C(＝NR cc )N(R cc ) 2 、-SO 2 N(R cc ) 2 、-SO 2 R cc 、-SO 2 OR cc 、-SOR aa 、-C(＝S)N(R cc ) 2 、-C(＝O)SR cc 、-C(＝S)SR cc 、-P(＝O) 2 R aa 、-P(＝O)(R aa ) 2 、-P(＝O) 2 N(R cc ) 2 、-P(＝O)(NR cc ) 2 Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R bb The groups combine to form a heterocyclyl or heteroaryl ring wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R dd Group substitution;
R cc independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R cc The groups combine to form a heterocyclyl or heteroaryl ring wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R dd Group substitution;
R dd independently selected from: halogen, -CN, -NO 2 、-N 3 、-SO 2 H、-SO 3 H、-OH、-OR ee 、-ON(R ff ) 2 、-N(R ff ) 2 ,、-N(R ff ) 3 + X - 、-N(OR ee )R ff 、-SH、-SR ee 、-SSR ee 、-C(＝O)R ee 、-CO 2 H、-CO 2 R ee 、-OC(＝O)R ee 、-OCO 2 R ee 、-C(＝O)N(R ff ) 2 、-OC(＝O)N(R ff ) 2 、-NR ff C(＝O)R ee 、-NR ff CO 2 R ee 、-NR ff C(＝O)N(R ff ) 2 、-C(＝NR ff )OR ee 、-OC(＝NR ff )R ee 、-OC(＝NR ff )OR ee 、-C(＝NR ff )N(R ff ) 2 、-OC(＝NR ff )N(R ff ) 2 、-NR ff C(＝NR ff )N(R ff ) 2 、-NR ff SO 2 R ee 、-SO 2 N(R ff ) 2 、-SO 2 R ee 、-SO 2 OR ee 、-OSO 2 R ee 、-S(＝O)R ee 、-Si(R ee ) 3 、-OSi(R ee ) 3 、-C(＝S)N(R ff ) 2 、-C(＝O)SR ee 、-C(＝S)SR ee 、-SC(＝S)SR ee 、-P(＝O) 2 R ee 、-P(＝O)(R ee ) 2 、-OP(＝O)(R ee ) 2 、-OP(＝O)(OR ee ) 2 Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R gg Substituted by a group, or by two gem R dd Substituents may combine to form =o or =s;
R ee independently selected from alkyl, haloalkyl, alkenyl, alkynyl, ringAlkyl, aryl, heterocyclyl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5R gg Group substitution;
R ff independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R ff The groups combine to form a heterocyclyl or heteroaryl ring wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R gg Group substitution;
R gg independently is: halogen, -CN, -NO 2 、-N 3 、-SO 2 H、-SO 3 H、-OH、-OC 1-6 Alkyl, -ON (C) 1-6 Alkyl group 2 、-N(C 1-6 Alkyl group 2 、-N(C 1-6 Alkyl group 3 + X - 、-NH(C 1-6 Alkyl group 2 + X - 、-NH 2 (C 1-6 Alkyl group + X - 、-NH 3 + X - 、-N(OC 1-6 Alkyl) (C) 1-6 Alkyl), -N (OH) (C 1- 6 Alkyl), -NH (OH), -SH, -SC 1-6 Alkyl, -SS (C) 1-6 Alkyl), -C (=o) (C 1-6 Alkyl) -CO 2 H、-CO 2 (C 1-6 Alkyl), -OC (=o) (C 1-6 Alkyl), -OCO 2 (C 1-6 Alkyl), -C (=O) NH 2 、-C(＝O)N(C 1-6 Alkyl group 2 、-OC(＝O)NH(C 1-6 Alkyl), -NHC (=o) (C 1-6 Alkyl), -N (C) 1-6 Alkyl) C (=O) (C 1-6 Alkyl), -NHCO 2 (C 1-6 Alkyl), -NHC (=o) N (C) 1-6 Alkyl group 2 、-NHC(＝O)NH(C 1-6 Alkyl), -NHC (=o) NH 2 、-C(＝NH)O(C 1-6 Alkyl), -OC (=nh) (C 1- 6 Alkyl), -OC (=nh) OC 1-6 Alkyl, -C (=nh) N (C 1-6 Alkyl group 2 、-C(＝NH)NH(C 1-6 Alkyl), -C (=nh) NH 2 、-OC(＝NH)N(C 1-6 Alkyl group 2 、-OC(NH)NH(C 1-6 Alkyl), -OC (NH) NH 2 、-NHC(NH)N(C 1-6 Alkyl group 2 、-NHC(＝NH)NH 2 、-NHSO 2 (C 1-6 Alkyl), -SO 2 N(C 1-6 Alkyl group 2 、-SO 2 NH(C 1-6 Alkyl), -SO 2 NH 2 、-SO 2 C 1-6 Alkyl, -SO 2 OC 1-6 Alkyl, -OSO 2 C 1- 6 Alkyl, -SOC 1-6 Alkyl, -Si (C) 1-6 Alkyl group 3 、-OSi(C 1-6 Alkyl group 3 、-C(＝S)N(C 1-6 Alkyl group 2 、C(＝S)NH(C 1-6 Alkyl), C (=S) NH 2 、-C(＝O)S(C 1-6 Alkyl), -C (=S) SC 1-6 Alkyl, -SC (=s) SC 1-6 Alkyl, -P (=o) 2 (C 1-6 Alkyl), -P (=o) (C 1-6 Alkyl group 2 、-OP(＝O)(C 1-6 Alkyl group 2 、-OP(＝O)(OC 1-6 Alkyl group 2 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C 7 Cycloalkyl, C 6 -C 10 Aryl, C 3 -C 7 Heterocyclyl, C 5 -C 10 Heteroaryl; or two gem R gg Substituents may combine to form =o or =s; wherein X is - Is a counter ion.
Exemplary substituents on nitrogen atoms include, but are not limited to: hydrogen, -OH, -OR aa 、-N(R cc ) 2 、-CN、-C(＝O)R aa 、-C(＝O)N(R cc ) 2 、-CO 2 R aa 、-SO 2 R aa 、-C(＝NR bb )R aa 、-C(＝NR cc )OR aa 、-C(＝NR cc )N(R cc ) 2 、-SO 2 N(R cc ) 2 、-SO 2 R cc 、-SO 2 OR cc 、-SOR aa 、-C(＝S)N(R cc ) 2 、-C(＝O)SR cc 、-C(＝S)SR cc 、-P(＝O) 2 R aa 、-P(＝O)(R aa ) 2 、-P(＝O) 2 N(R cc ) 2 、-P(＝O)(NR cc ) 2 Alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R's attached to a nitrogen atom cc The groups combine to form a heterocyclyl or heteroaryl ring wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R dd Substituted with radicals, and wherein R aa 、R bb 、R cc And R is dd As described above.
Other definitions
The term "KRAS G12D" refers to a mutant form of a mammalian KRAS protein that contains an aspartic acid to glycine amino acid substitution at amino acid position 12.
The term "cancer" includes, but is not limited to, the following cancers: breast, ovary, cervix, prostate, testis, esophagus, stomach, skin, lung, bone, colon, pancreas, thyroid, biliary tract, buccal cavity and pharynx (mouth), lip, tongue, oral cavity, pharynx, small intestine, colorectal, large intestine, rectum, brain and central nervous system cancers, glioblastoma, neuroblastoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, adenocarcinoma, adenoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma, renal carcinoma, myelodisorders, lymphomas, hodgkin's disease, hairy cell carcinoma and leukemia.
The term "treating" as used herein relates to reversing, alleviating, inhibiting the progression or prevention of a disorder or condition to which the term applies, or one or more symptoms of such disorder or condition. The term "treatment" as used herein relates to the action of a verb treatment, the latter as just defined.
The term "pharmaceutically acceptable salts" as used herein means those carboxylate salts, amino acid addition salts of the compounds of the invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response and the like commensurate with a reasonable benefit/risk ratio, and effective for their intended use, including (if possible) zwitterionic forms of the compounds of the invention.
Pharmaceutically acceptable base addition salts are formed with metals or amines, for example alkali metal and alkaline earth metal hydroxides or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N, N' -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine and procaine.
The base addition salts of the acidic compounds may be prepared by contacting the free acid form with a sufficient amount of the desired base to form the salt, in a conventional manner. The free acid can be regenerated by contacting the salt form with the acid in a conventional manner, isolating the free acid. The free acid forms differ somewhat in certain physical properties from their respective salt forms, such as solubility in polar solvents, but for the purposes of the present invention, the salts are also equivalent to their respective free acids.
The salt may be a sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide prepared from an inorganic acid, an acid such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, and the like. Representative salts include: hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, mesylate, glucoheptonate, lactobionate, laurylsulfonate, isethionate, and the like. Salts may also be prepared from organic acids, such as aliphatic mono-and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like. Representative salts include acetates, propionates, octanoates, isobutyrates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzates, dinitrobenzoates, naphthoates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, maleates, tartrates, methanesulfonates, and the like. Pharmaceutically acceptable salts may include cations based on alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Salts of amino acids, such as arginine salts, gluconate salts, galacturonate salts, and the like are also contemplated (see, e.g., berge s.m. et al., "Pharmaceutical Salts," j.pharm.sci.,1977;66:1-19, incorporated herein by reference).
The "subject" to be administered includes, but is not limited to: a human (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle aged adults, or senior adults)) and/or a non-human animal, e.g., a mammal, e.g., a primate (e.g., cynomolgus monkey, rhesus monkey), cow, pig, horse, sheep, goat, rodent, cat, and/or dog. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human", "patient" and "subject" are used interchangeably herein.
"disease," "disorder," and "condition" are used interchangeably herein.
As used herein, unless otherwise indicated, the term "treating" includes an effect that occurs when a subject has a particular disease, disorder, or condition, which reduces the severity of the disease, disorder, or condition, or delays or slows the progression of the disease, disorder, or condition ("therapeutic treatment"), as well as an effect that occurs before the subject begins to have the particular disease, disorder, or condition ("prophylactic treatment").
In general, an "effective amount" of a compound refers to an amount sufficient to elicit a biological response of interest. As will be appreciated by those of ordinary skill in the art, the effective amount of the compounds of the present invention may vary depending on the following factors: for example, biological targets, pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age health and symptoms of the subject. The effective amount includes a therapeutically effective amount and a prophylactically effective amount.
As used herein, unless otherwise indicated, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with a disease, disorder, or condition. A therapeutically effective amount of a compound refers to that amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of a disease, disorder or condition. The term "therapeutically effective amount" may include an amount that improves overall treatment, reduces or avoids symptoms or causes of a disease or disorder, or enhances the therapeutic effect of other therapeutic agents.
As used herein, unless otherwise indicated, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, disorder, or condition, or to prevent one or more symptoms associated with a disease, disorder, or condition, or to prevent recurrence of a disease, disorder, or condition. A prophylactically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other agents, that provides a prophylactic benefit in preventing a disease, disorder, or condition. The term "prophylactically effective amount" may include an amount that improves overall prophylaxis, or an amount that enhances the prophylactic effect of other prophylactic agents.
"combination" and related terms refer to the simultaneous or sequential administration of a compound of the invention and another therapeutic agent. For example, the compounds of the invention may be administered simultaneously or sequentially with other therapeutic agents in separate unit dosage forms, or simultaneously with other therapeutic agents in a single unit dosage form.
Detailed description of the preferred embodiments
Herein, "the compound of the present invention" refers to a compound of the following formula (I) (including sub-formulae, e.g., formula (II), formula (V-2), etc.), pharmaceutically acceptable salts, enantiomers, diastereomers, solvates, hydrates, or isotopic variants thereof, and mixtures thereof.
Compounds are named herein using standard nomenclature. Compounds having asymmetric centers, it is to be understood (unless otherwise indicated) that all optical isomers and mixtures thereof are encompassed. Furthermore, unless otherwise specified, all isomeric compounds encompassed by the present invention may occur with carbon-carbon double bonds in the form of Z and E. Compounds that exist in different tautomeric forms, one of the compounds is not limited to any particular tautomer, but is intended to encompass all tautomeric forms.
In one embodiment, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, or isotopic variant thereof:
Wherein,
x is-N (R) -or-CH (R) -;
wherein R is selected fromH、-(CH 2 ) 1-3 Halogen, - (CH) 2 ) 1-3 -OH、-(CH 2 ) 1-3 -CN、-(CH 2 ) 1- 3 -NH 2 、C 1-6 Alkyl or C 1-6 A haloalkyl group;
r is selected from- (CH) 2 ) 0-3 Halogen, - (CH) 2 ) 0-3 -OH、-(CH 2 ) 0-3 -CN or- (CH) 2 ) 0-3 -NH 2 ；
Y is N or CH;
Y 1 is CR (CR) Y1a R Y1b ；
Y 2 Is CR (CR) Y2a R Y2b ；
Y 3 Is CR (CR) Y3a R Y3b Or NR (NR) Y3c ；
r=1 or 2;
s=0 or 1;
wherein R is Y1a 、R Y1b 、R Y2a 、R Y2b 、R Y3a And R is Y3b Independently selected from H, halogen, C 1- 6 Alkyl or C 1-6 A haloalkyl group;
R Y3c selected from H, C 1-6 Alkyl or C 1-6 A haloalkyl group;
or Y 3 And Y adjacent thereto 2 A double bond may be formed therebetween;
R A selected from H, C 6-10 Aryl or 5-14 membered heteroaryl, optionally substituted with 1, 2, 3 or 4R A1 Substitution;
wherein each R is A1 Independently selected from H, halogen, -CN, -OR X 、-SR X 、-NR Y R Z 、C 1-6 Alkyl, C 1-6 Halogenated compoundsAlkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
l is selected from a chemical bond, -O-, -S-, or-NH-;
R B selected from H, halogen, -CN, -OR X 、-SR X 、-NR Y R Z 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Aryl or 5-14 membered heteroaryl; optionally substituted with 1, 2, 3 or 4 r#;
wherein R# is selected from H, -C 0-6 Alkylene-halogen, -C 0-6 alkylene-CN, C 1-6 Alkyl, C 1- 6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 alkylene-O-R X 、-C 0-6 alkylene-S-R X 、-C 0-6 alkylene-NR Y R Z 、-C 0-6 alkylene-C (O) R X 、-C 0-6 alkylene-C (O) OR X 、-C 0-6 alkylene-C (O) -NR Y R Z 、-C 0-6 alkylene-C 3-10 Cycloalkyl, -C 0-6 Alkylene-3-10 membered heterocyclyl, -C 0-6 alkylene-C 6-10 Aryl or-C 0-6 Alkylene-5-14 membered heteroaryl; and R# is optionally halogen, -OH, -OC 1-6 Alkyl, -NH 2 、-NH(C 1-6 Alkyl), -N (C) 1-6 Alkyl group 2 、C 1- 6 Alkyl or C 1-6 Haloalkyl substitution;
wherein R is X Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
R Y and R is Z Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2- 6 Alkynyl, or R Y And R is Z The nitrogen atom to which they are attached forms a 3-10 membered heterocyclic group;
R 1 and R is 2 Independently selected from H, halogen, -OH, -NH 2 -CN or- (CR) c R d ) m -R’；
R 3 And R is 4 Independently selected from H, halogen, -OH, -NH 2 -CN or- (CR) c R d ) m -R”；
R 2’ Is H or R 2 、R 2’ Together with the carbon atoms to which they are attached form C 3-6 Cycloalkyl;
or R is 1 And R is 2 、R 3 And R is 4 、R 1 And R is 4 、R 2 And R is 3 Any one of the groups being linked to form- (CR) a R b ) n -；
p=0, 1, 2 or 3;
q=0, 1, 2 or 3;
wherein R is a Selected from H, halogen, C 1-6 Alkyl or C 1-6 A haloalkyl group;
R b selected from H, halogen, C 1-6 Alkyl or C 1-6 A haloalkyl group;
R c selected from H, halogen, C 1-6 Alkyl or C 1-6 A haloalkyl group;
R d selected from H, halogen, C 1-6 Alkyl or C 1-6 A haloalkyl group;
r' is selected from H, halogen, -OH, -SH, -NH 2 、-CN、-C(O)R e 、-C(O)OR e 、-C(O)NR f R g 、C 2-6 Alkenyl or C 2-6 Alkynyl;
r' is selected from H, halogen, -OH, -SH, -NH 2 、-CN、-C(O)R e 、-C(O)OR e 、-C(O)NR f R g 、C 2-6 Alkenyl or C 2-6 Alkynyl;
m=0, 1, 2, 3, 4, 5 or 6;
n=0, 1, 2, 3, 4, 5 or 6;
Wherein R is e Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
R f and R is g Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, or R f And R is g And the nitrogen atom to which they are attached form a 3-10 membered heterocyclic group.
X
In a specific embodiment, X is-N (R) -; in another embodiment, X is-NH-; in another specific embodiment, X is-NMe-; in a specific embodiment, X is-CH (R) -; in another embodiment, X is-CH (NH 2 ) -; in another embodiment, X is-CH (CH 2 NH 2 ) -; in another embodiment, X is-CH (CH 2 CH 2 NH 2 ) -; in another embodiment, X is-CH (OH) -; in another embodiment, X is-CH (CH 2 OH) -; in another embodiment, X is-CH (CH 2 CH 2 OH)-。
Y
In a specific embodiment, Y is N; in another embodiment, Y is CH.
(Y 1 ) r
In a specific embodiment, Y 1 Is CR (CR) Y1a R Y1b The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, Y 1 Is CH 2 The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, (Y) 1 ) r Is CH 2 The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, (Y) 1 ) r Is CH 2 CH 2 。
(Y 2 ) s
In a specific embodiment, Y 2 Is CR (CR) Y2a R Y2b The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, Y 2 Is CH 2 The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, (Y) 2 ) s Is CH 2 The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, (Y) 2 ) s Is a chemical bond.
Y 3
In a specific embodiment, Y 3 Is CR (CR) Y3a R Y3b The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, Y 3 Is CH 2 The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, Y 3 Is NR (NR) Y3c The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, Y 3 Is NH; in another embodiment, (Y) 2 ) s -Y 3 Is CH 2 CH 2 The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, (Y) 2 ) s -Y 3 Ch=ch; in another embodiment, (Y) 2 ) s -Y 3 Is CH 2 NH; in another embodiment, (Y) 2 ) s -Y 3 Ch=n.
In a more specific embodiment of the present invention,selected from the following parent nuclei: in a still more specific embodiment of the present invention,is thatIn a still more specific embodiment of the present invention,is thatIn a still more specific embodiment of the present invention,is thatIn a still more specific embodiment of the present invention,is thatIn a still more specific embodiment of the present invention,is thatIn a still more specific embodiment of the present invention,is thatIn a still more specific embodiment of the present invention,is thatIn a still more specific embodiment of the present invention,is thatIn a still more specific embodiment of the present invention,is thatIn a still more specific embodiment of the present invention,is thatIn a still more specific embodiment of the present invention, Is thatIn a still more specific embodiment of the present invention,is thatIn a still more specific embodiment of the present invention,is thatIn a still more specific embodiment of the present invention,is thatIn a still more specific embodiment of the present invention,is thatIn a still more specific embodiment of the present invention,is thatIn a still more specific embodiment of the present invention,is that
R A
In a specific embodiment, R A Selected from H, C 6-10 Aryl or 5-14 membered heteroaryl, optionally substituted with 1, 2, 3 or 4R A1 Substitution; in another embodiment, R A Is H; in another embodiment, R A Is C 6-10 Aryl, optionally substituted with 1, 2, 3 or 4R A1 Substitution; in another embodiment, R A Is phenyl, which is optionally substituted with 1, 2, 3 or 4R A1 Substitution; in another embodiment, R A Is naphthyl, which is optionally substituted by 1, 2, 3 or 4R A1 Substitution; in another embodimentIn the scheme, R A Is a 5-14 membered heteroaryl group, optionally substituted with 1, 2, 3 or 4R A1 And (3) substitution.
In a specific embodiment, R A1 Is H, halogen, -CN, -OR X 、-SR X 、-NR Y R Z 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl; in another embodiment, R A1 Is H; in another embodiment, R A1 Is halogen; in another embodiment, R A1 is-CN; in another embodiment, R A1 is-OR X The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, R A1 is-SR X The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, R A1 is-NR Y R Z The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, R A1 Is C 1-6 An alkyl group; in another embodiment, R A1 Is C 1-6 A haloalkyl group; in another embodiment, R A1 Is C 2-6 Alkenyl groups; in another embodiment, R A1 Is C 2-6 Alkynyl groups.
In a more specific embodiment, R A Selected from the following groups: preferably More preferablyIn another more specific embodiment, R A Is thatIn another more specific embodiment, R A Is thatIn another more specific embodiment, R A Is thatIn another more specific embodiment, R A Is thatIn another more specific embodiment, R A Is thatIn another more specific embodiment, R A Is thatIn another more specific embodiment, R A Is thatIn another more specific embodiment, R A Is thatIn another more specific embodiment, R A Is thatIn another more specific embodiment, R A Is thatIn another more specific embodiment, R A Is thatIn another more specific embodiment, R A Is thatIn another more specific embodiment, R A Is thatIn another more specific embodiment, R A Is thatIn another more specific embodiment, R A Is thatIn another more specificIn embodiments, R A Is that
L
In a specific embodiment, L is a bond; in another embodiment, L is-O-; in another embodiment, L is-S-; in another specific embodiment, L is-NH-.
R B
In a specific embodiment, R B Selected from H, halogen, -CN, -OR X 、-SR X 、-NR Y R Z 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Aryl or 5-14 membered heteroaryl optionally substituted with 1, 2, 3 or 4 r#; in another embodiment, R B Is H; in another embodiment, R B Is halogen; in another embodiment, R B is-CN; in another embodiment, R B is-OR X The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, R B is-SR X The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, R B is-NR Y R Z The method comprises the steps of carrying out a first treatment on the surface of the In another embodiment, R B Is C 1-6 Alkyl optionally substituted with 1, 2, 3 or 4 r#; in another embodiment, R B Is C 1-6 Haloalkyl optionally substituted with 1, 2, 3 or 4 r#; in another embodiment, R B Is C 2-6 Alkenyl optionally substituted with 1, 2, 3 or 4 r#; in another embodiment, R B Is C 2-6 Alkynyl optionally substituted with 1, 2, 3 or 4 r#; in another embodiment, R B Is C 3-10 Cycloalkyl optionally substituted with 1, 2, 3 or 4 r#; in another embodiment, R B Is a 3-10 membered heterocyclyl optionally substituted with 1, 2, 3 or 4 r#; in another embodiment, R B Is C 6-10 Aryl optionally substituted with 1, 2, 3 or 4 r#; in another embodiment, R B Is a 5-14 membered heteroaryl optionally substituted with 1, 2, 3 or 4 r#.
In a more specific embodiment, -L-R B Selected from H, Preferably H, In another more specific embodiment, -L-R B Is H; in another more specific embodiment, -L-R B Is thatIn another more specific embodiment, -L-R B Is thatIn another more specific embodiment, -L-R B Is thatIn another more specific embodiment, -L-R B Is thatIn another more specific embodiment, -L-R B Is thatIn another more specific embodiment, -L-R B Is thatIn another more specific embodiment, -L-R B Is thatIn another more specific embodiment, -L-R B Is that In another more specific embodiment, -L-R B Is thatIn another more specific embodiment, -L-R B Is thatIn another more specific embodiment, -L-R B Is thatIn another more specific embodiment, -L-R B Is thatIn another more specific embodiment, -L-R B Is thatIn another more specific embodiment, -L-R B Is thatIn another more specific embodiment, -L-R B Is thatIn another more specific embodiment, -L-R B Is thatIn another more specific embodiment, -L-R B Is that
R 1 And R is 2
In a specific embodiment, R 1 And R is 2 Independently selected from H, halogen, -OH, -NH 2 -CN or- (CR) c R d ) m -R'; in another embodiment, R 1 And R is 2 Independently selected from H, halogen, -OH, -NH 2 、-CN、-CH 3 or-CH 2 -OH; in another embodiment, R 1 And R is 2 Independently selected from-CH 3 or-CH 2 -OH; in another embodiment, R 1 And R is 2 One is-CH 3 or-CH 2 -OH; in another embodiment, R 1 And R is 2 One of which is-CH of R configuration 3 or-CH 2 -OH。
R 2’
In a specific embodiment, R 2’ Is H; in another embodiment, R 2 、R 2’ Together with the carbon atoms to which they are attached form C 3-6 Cycloalkyl groups.
R 3 And R is 4
In a specific embodiment, R 3 And R is 4 Independently selected from H, halogen, -OH, -NH 2 -CN or- (CR) c R d ) m -R "; in another embodiment, R 3 And R is 4 Independently selected from H, -CH 2 -Cl、-CH 2 -F、-CH 2 -CN、-CH 2 CH 2 -Cl、-CH 2 CH 2 -F、-CH 2 CH 2 -CN; in another embodiment, R 3 And R is 4 Independently selected from H or-CH 2 -CN。
In a more specific embodiment, R 1 And R is 2 Connection to form-CH 2 -、-CH 2 CH 2 -or-CH 2 CH 2 CH 2 -, preferably-CH 2 CH 2 -or-CH 2 CH 2 CH 2 -, more preferably-CH 2 CH 2 -; in another more specific embodiment, R 3 And R is 4 Connection to form-CH 2 -、-CH 2 CH 2 -or-CH 2 CH 2 CH 2 -, preferably-CH 2 CH 2 -or-CH 2 CH 2 CH 2 -, more preferably-CH 2 CH 2 -; in another more specific embodiment, R 1 And R is 4 Connection to form-CH 2 -、-CH 2 CH 2 -or-CH 2 CH 2 CH 2 -, preferably-CH 2 CH 2 -or-CH 2 CH 2 CH 2 -, more preferably-CH 2 CH 2 -; in another more specific embodiment, R 2 And R is 3 Connection to form-CH 2 -、-CH 2 CH 2 -or-CH 2 CH 2 CH 2 -, preferably-CH 2 CH 2 -or-CH 2 CH 2 CH 2 -, more preferably-CH 2 CH 2 -。
p and q
In a specific embodiment, p=0; in another specific embodiment, p=1; in another specific embodiment, p=2; in another specific embodiment, p=3.
In a specific embodiment, q=0; in another specific embodiment, q=1; in another specific embodiment, q=2; in another specific embodiment, q=3.
Any one of the above embodiments or any combination thereof may be combined with any one of the other embodiments or any combination thereof. For example, any one of the technical schemes of X or any combination thereof can be combined with Y, Y 1 、Y 2 、Y 3 、r、s、R A 、L、R B 、R 1 、R 2 、R 2’ 、R 3 、R 4 Any one of the aspects of p and q, etc., or any combination thereof. The invention is intended to include all such combinations, limited to the extent that they are not listed.
In a more specific embodiment, the present invention provides a compound of the above (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof, having the structure:
wherein each group is as defined above.
In a more specific embodiment, the present invention provides a compound of formula (II), or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, or isotopic variant thereof:
wherein,
x is-N (R) -or-CH (R) -;
wherein R is selected from H, C 1-6 Alkyl or C 1-6 A haloalkyl group;
r is selected from- (CH) 2 ) 0-3 -NH 2 Or- (CH) 2 ) 0-3 -OH；
R 1 And R is 2 Independently selected from H, halogen, -OH, -NH 2 -CN or- (CR) c R d ) m -R’；
R 3 And R is 4 Independently selected from H, halogen, -OH, -NH 2 -CN or- (CR) c R d ) m -R”；
R 2’ Is H or R 2 、R 2’ Together with the carbon atoms to which they are attached form C 3-6 Cycloalkyl;
p=0, 1, 2 or 3;
q=0, 1, 2 or 3;
wherein R is c Selected from H, halogen, C 1-4 Alkyl or C 1-4 A haloalkyl group;
R d selected from H, halogen, C 1-4 Alkyl or C 1-4 A haloalkyl group;
R' is selected from H, halogen, -OH, -SH, -NH 2 、-CN、-C(O)R e 、-C(O)OR e or-C (O) NR e R f ；
R' is selected from H, halogen, -OH, -SH, -NH 2 、-CN、-C(O)R e 、-C(O)OR e or-C (O) NR e R f ；
m=0, 1, 2, 3, 4, 5 or 6;
wherein R is e Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
R f and R is g Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, or R f And R is g And the nitrogen atom to which they are attached form a 3-10 membered heterocyclic group.
In a more specific embodiment, the present invention provides a compound of formula (II) as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof, wherein,
x is-N (R) -or-CH (R) -;
wherein R is selected from H, C 1-6 Alkyl or C 1-6 A haloalkyl group;
r is selected from- (CH) 2 ) 0-1 -NH 2 Or- (CH) 2 ) 0-1 -OH；
R 1 And R is 2 Independently selected from H or- (CR) c R d ) m -R’；
R 3 And R is 4 Independently selected from H or- (CR) c R d ) m -R”；
R 2’ Is H or R 2 、R 2’ Together with the carbon atoms to which they are attached form C 3-6 Cycloalkyl;
p=0, 1 or 2;
q=0, 1 or 2;
wherein R is c Is H;
R d is H;
r' is selected from H, halogen or-OH;
r' is selected from H, halogen, -OH, -NH 2 or-CN;
m=0, 1, 2, 3, 4, 5 or 6.
In a more specific embodiment, the present invention provides a compound of formula (III), or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, or isotopic variant thereof:
Wherein,
R 1 and R is 2 Independently selected from H, halogen, -OH, -NH 2 -CN or- (CR) c R d )-R’；
R 3 And R is 4 Independently selected from H, halogen, -OH, -NH 2 -CN or- (CR) c R d ) m -CN；
p=0, 1, 2 or 3;
q=0, 1, 2 or 3;
wherein R is c Selected from H or halogen;
R d selected from H or halogen;
r' is selected from H, halogen, -OH, -SH, -NH 2 or-CN;
m=1 or 2.
In a more specific embodiment, the present invention provides a compound of formula (III) as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof, wherein,
R 1 and R is 2 Independently selected from H or- (CR) c R d )-R’；
R 3 And R is 4 Independently selected from H or- (CR) c R d )-CN；
p=1 or 2;
q=1 or 2;
wherein R is c Is H;
R d is H;
r' is selected from H or-OH.
In a more specific embodiment, the present invention provides a compound of formula (IV), or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, or isotopic variant thereof:
wherein,
R 1 and R is 2 One is- (CR) c R d ) -R', another optionFrom H, halogen, -OH, -NH 2 -CN or- (CR) c R d )-R’；
R 3 And R is 4 Independently selected from H, halogen, -OH, -NH 2 -CN or- (CR) c R d )-R”；
R is selected from H, C 1-6 Alkyl or C 1-6 A haloalkyl group;
p=0, 1, 2 or 3;
q=0, 1, 2 or 3;
wherein R is c Selected from H, halogen, C 1-4 Alkyl or C 1-4 A haloalkyl group;
R d selected from H, halogen, C 1-4 Alkyl or C 1-4 A haloalkyl group;
r' is selected from H, halogen, -OH, -SH, -NH 2 or-CN;
r' is selected from halogen, -OH, -SH, -NH 2 or-CN.
In a more specific embodiment, the present invention provides a compound of formula (IV) as described above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof, wherein,
R 1 and R is 2 One is- (CR) c R d ) -R', the other being H;
R 3 and R is 4 Independently selected from H or- (CR) c R d )-R”；
R is selected from H, C 1-2 Alkyl or C 1-2 A haloalkyl group;
p=1 or 2;
q=1 or 2;
wherein R is c Is H;
R d is H;
r' is selected from H or-OH;
r' is-CN.
In a more specific embodiment, the present invention provides a compound of formula (V), (V-1) or (V-2), or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isomorphous variant thereof:
wherein,
R 1 and R is 2 、R 3 And R is 4 、R 1 And R is 4 、R 2 And R is 3 Any one of the groups being linked to form- (CR) a R b ) n -, the rest of R 1 And R is 2 Independently selected from H or- (CR) c R d ) m -R', the remainder of R 3 And R is 4 Independently selected from H or- (CR) c R d ) m -R”；
R is H, C 1-6 Alkyl or C 1-6 A haloalkyl group;
wherein R is a Selected from H, halogen, C 1-4 Alkyl or C 1-4 A haloalkyl group;
R b Selected from H, halogen, C 1-4 Alkyl or C 1-4 A haloalkyl group;
R c selected from H, halogen, C 1-4 Alkyl or C 1-4 A haloalkyl group;
R d selected from H, halogen, C 1-4 Alkyl or C 1-4 A haloalkyl group;
r' is selected from H, halogen, -CN, -OH, -NH 2 、C 2-4 Alkenyl or C 2-4 Alkynyl;
r' is selected from H, halogen, -CN, -OH, -NH 2 、C 2-4 Alkenyl or C 2-4 Alkynyl;
n=0, 1, 2, 3 or 4;
m=0, 1, 2 or 3.
In a more specific embodiment, the present invention provides a compound of formula (V), (V-1) or (V-2) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof, wherein,
R 1 and R is 2 、R 3 And R is 4 、R 1 And R is 4 、R 2 And R is 3 Any one of the groups being linked to form- (CR) a R b ) n -, the rest of R 1 、R 2 、R 3 Or R is 4 H, halogen, -CN, -OH or-NH respectively 2 ；
R is selected from H, C 1-6 Alkyl or C 1-6 A haloalkyl group;
wherein R is a Selected from H, halogen, C 1-4 Alkyl or C 1-4 A haloalkyl group;
R b selected from H, halogen, C 1-4 Alkyl or C 1-4 A haloalkyl group;
n=0, 1, 2, 3 or 4.
In a more specific embodiment, the present invention provides a compound of formula (V), (V-1) or (V-2) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof, wherein,
R 1 and R is 2 、R 3 And R is 4 、R 1 And R is 4 、R 2 And R is 3 Any one of the groups being linked to form- (CR) a R b ) n -, the rest of R 1 、R 2 、R 3 Or R is 4 Is H;
r is selected from H, C 1-2 Alkyl or C 1-2 A haloalkyl group;
wherein R is a Is H;
R b is H;
n=1, 2 or 3.
In a more specific embodiment, the present invention provides a compound of formula (V), (V-1) or (V-2) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof, wherein,
R 1 and R is 2 、R 3 And R is 4 、R 1 And R is 4 、R 2 And R is 3 Any one of the groups being linked to form- (CR) a R b ) n -, the rest of R 1 And R is 2 Independently selected from H or- (CR) c R d ) m -R', the remainder of R 3 And R is 4 Independently selected from H or- (CR) c R d ) m -R”；
R is H;
wherein R is a Selected from H, halogen, C 1-4 Alkyl or C 1-4 A haloalkyl group;
R b selected from H, halogen, C 1-4 Alkyl or C 1-4 A haloalkyl group;
R c selected from H, halogen, C 1-4 Alkyl or C 1-4 A haloalkyl group;
R d selected from H, halogen, C 1-4 Alkyl or C 1-4 A haloalkyl group;
r' is selected from H, halogen, -CN, -OH, -NH 2 、C 2-4 Alkenyl or C 2-4 Alkynyl;
r' is selected from H, halogen, -CN, -OH, -NH 2 、C 2-4 Alkenyl or C 2-4 Alkynyl;
m=0, 1, 2 or 3;
n=2, 3 or 4.
In a more specific embodiment, the present invention provides a compound of formula (V), (V-1) or (V-2) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof, wherein,
R 1 And R is 2 、R 3 And R is 4 、R 1 And R is 4 、R 2 And R is 3 Any one of the groups being linked to form- (CR) a R b ) n -, the rest of R 1 、R 2 、R 3 Or R is 4 Independently selected from H, halogen, -CN, -OH or-NH 2 ；
R is H;
wherein R is a Selected from H, halogen or C 1-4 An alkyl group;
R b selected from H, halogen or C 1-4 An alkyl group;
n=2, 3 or 4.
In a more specific embodiment, the present invention provides a compound of formula (V), (V-1) or (V-2) above, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof, wherein,
R 1 and R is 2 、R 3 And R is 4 、R 1 And R is 4 、R 2 And R is 3 Any one of the groups being linked to form- (CR) a R b ) n -, the rest of R 1 、R 2 、R 3 Or R is 4 Is H;
r is H;
wherein R is a Is H;
R b is H;
n=2 or 3.
In a more specific embodiment, the present invention provides a compound, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, or isotopic variant thereof, wherein the compound is selected from the group consisting of:
the compounds of the invention may include one or more asymmetric centers and thus may exist in a variety of stereoisomeric forms, for example, enantiomeric and/or diastereomeric forms. For example, the compounds of the invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. The isomers may be separated from the mixtures by methods known to those skilled in the art, including: chiral High Pressure Liquid Chromatography (HPLC), formation and crystallization of chiral salts; alternatively, preferred isomers may be prepared by asymmetric synthesis.
Those skilled in the art will appreciate that the organic compound may form a complex with a solvent in or from which it reacts or from which it precipitates or crystallizes. These complexes are referred to as "solvates". When the solvent is water, the complex is referred to as a "hydrate". The present invention encompasses all solvates of the compounds of the present invention.
The term "solvate" refers to a form of a compound or salt thereof that is bound to a solvent, typically formed by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein may be prepared, for example, in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "solvate" includes both solvates in solution and separable solvates. Representative solvates include hydrates, ethanolates and methanolates.
The term "hydrate" refers to a compound that binds to water. Generally, the ratio of the number of water molecules contained in a hydrate of a compound to the number of molecules of the compound in the hydrate is determined. Thus, the hydrates of the compounds can be used, for example, of the formula R x H 2 O represents, wherein R is the compound, and x is a number greater than 0. A given compound may form more than one hydrate type, including, for example, monohydrate (x is 1), lower hydrate (x is a number greater than 0 and less than 1, e.g., hemihydrate (r.0.5H) 2 O)) and polyhydrates (x is a number greater than 1, e.g., dihydrate (r.2 2H) 2 O) and hexahydrate (r.6H) 2 O))。
The compounds of the present invention may be in amorphous or crystalline form (polymorphs). Furthermore, the compounds of the present invention may exist in one or more crystalline forms. Accordingly, the present invention includes within its scope all amorphous or crystalline forms of the compounds of the present invention. The term "polymorph" refers to a crystalline form (or salt, hydrate or solvate thereof) of a compound of a particular crystal stacking arrangement. All polymorphs have the same elemental composition. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optoelectronic properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors can lead to a crystalline form predominating. Various polymorphs of a compound can be prepared by crystallization under different conditions.
The invention also includes isotopically-labelled compounds (isotopically-variant) which are identical to those recited in formula (I), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, respectively, for example 2 H、 3 H、 13 C、 11 C、 14 C、 15 N、 18 O、 17 O、 31 P、 32 P、 35 S、 18 F and F 36 Cl. The compounds of the invention, prodrugs thereof, and pharmaceutically acceptable salts of the compounds or prodrugs thereof, which contain the isotopes described above and/or other isotopes of other atoms, are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, e.g., for incorporation of a radioisotope (e.g. 3 H and 14 c) Those useful in drug and/or substrate tissue distribution assays. Tritium, i.e. tritium 3 H and carbon-14 14 The C isotopes are particularly preferred because they are easy to prepare and detect. Further, substitution by heavier isotopes, e.g. deuterium, i.e 2 H may be preferred in some cases because higher metabolic stability may provide therapeutic benefits, such as extended in vivo half-life or reduced dosage requirements. Isotopically-labeled compounds of formula (I) of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes and/or examples and preparations below by substituting a readily available isotopically-labeled reagent for a non-isotopically-labeled reagent.
In addition, prodrugs are also included within the context of the present invention. The term "prodrug" as used herein refers to a compound that is converted in vivo by hydrolysis, e.g. in blood, into its active form having a medical effect. Pharmaceutically acceptable prodrugs are described in t.higuchi and v.stilla, prodrugs as Novel Delivery Systems, a.c. s.symposium Series vol.14, edward b.roche, ed., bioreversible Carriers in Drug Design, american Pharmaceutical Association and Pergamon Press,1987, and d.fleisher, s.ramon and h.barbra "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs ", advanced Drug Delivery Reviews (1996) 19 (2) 115-130, each of which is incorporated herein by reference.
Prodrugs are any covalently bonded compounds of the invention which, when administered to a patient, release the parent compound in vivo. Prodrugs are typically prepared by modifying functional groups in such a way that the modification may be performed by conventional procedures or cleavage in vivo to yield the parent compound. Prodrugs include, for example, compounds of the invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when administered to a patient, may cleave to form the hydroxy, amino, or sulfhydryl group. Representative examples of prodrugs therefore include, but are not limited to, acetate, formate and benzoate/amide derivatives of hydroxy, mercapto and amino functional groups of compounds of formula (I). In addition, in the case of carboxylic acid (-COOH), esters such as methyl ester, ethyl ester, and the like can be used. The esters themselves may be active and/or may be hydrolysed under in vivo conditions in the human body. Suitable pharmaceutically acceptable in vivo hydrolysable ester groups include those groups which readily decompose in the human body to release the parent acid or salt thereof.
The invention also provides a pharmaceutical formulation comprising a therapeutically effective amount of a compound of formula (I) or a therapeutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient thereof. All of these forms are within the scope of the invention.
Pharmaceutical compositions and kits
In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition comprises an effective amount of a compound of the present invention. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound of the invention. In some embodiments, the pharmaceutical composition comprises a prophylactically effective amount of a compound of the present invention.
Pharmaceutically acceptable excipients for use in the present invention refer to non-toxic carriers, adjuvants or vehicles that do not destroy the pharmacological activity of the co-formulated compounds. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of the invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.
The invention also includes kits (e.g., pharmaceutical packages). Kits provided can include a compound of the invention, other therapeutic agent, and first and second containers (e.g., vials, ampoules, bottles, syringes, and/or dispersible packages or other suitable containers) containing a compound of the invention, other therapeutic agent. In some embodiments, the provided kits may also optionally include a third container containing pharmaceutically acceptable excipients for diluting or suspending the compounds of the invention and/or other therapeutic agents. In some embodiments, the compounds of the invention and other therapeutic agents provided in the first and second containers are combined to form one unit dosage form.
Administration of drugs
The pharmaceutical compositions provided herein may be administered by a number of routes including, but not limited to: oral, parenteral, inhalation, topical, rectal, nasal, buccal, vaginal, by implantation or other means of administration. For example, parenteral administration as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intramuscularly, and intracranial injection or infusion techniques.
Typically, an effective amount of a compound provided herein is administered. The amount of the compound actually administered may be determined by a physician, according to the circumstances involved, including the condition being treated, the route of administration selected, the compound actually administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the like.
When used to prevent a disorder of the present invention, a subject at risk of developing the disorder is administered a compound provided herein, typically based on physician recommendations and administered under the supervision of a physician, at a dosage level as described above. Subjects at risk for developing a particular disorder generally include subjects having a family history of the disorder, or those subjects determined by genetic testing or screening to be particularly susceptible to developing the disorder.
The pharmaceutical compositions provided herein may also be administered chronically ("chronically"). Chronic administration refers to administration of a compound or pharmaceutical composition thereof over a prolonged period of time, e.g., 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may continue administration indefinitely, e.g., for the remainder of the subject's life. In some embodiments, chronic administration is intended to provide a constant level of the compound in the blood over a prolonged period of time, e.g., within a therapeutic window.
Various methods of administration may be used to further deliver the pharmaceutical compositions of the present invention. For example, in some embodiments, the pharmaceutical composition may be administered as a bolus, e.g., in order to increase the concentration of the compound in the blood to an effective level. Bolus doses depend on the targeted systemic level of active ingredient through the body, e.g., intramuscular or subcutaneous bolus doses cause slow release of the active ingredient, whereas bolus injections delivered directly to veins (e.g., by IV intravenous drip) can be delivered more rapidly, causing the concentration of the active ingredient in the blood to rise rapidly to effective levels. In other embodiments, the pharmaceutical composition may be administered in the form of a continuous infusion, for example, by IV intravenous drip, thereby providing a steady state concentration of the active ingredient in the subject's body. Furthermore, in other embodiments, a bolus dose of the pharmaceutical composition may be administered first, followed by continuous infusion.
Oral compositions may take the form of bulk liquid solutions or suspensions or bulk powders. More typically, however, the compositions are provided in unit dosage form in order to facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human patients and other mammals, each unit containing a predetermined quantity of active material suitable for producing the desired therapeutic effect in association with a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions, or in the case of solid compositions, pills, tablets, capsules and the like. In such compositions, the compound is typically a minor component (about 0.1 to about 50 wt.%, or preferably about 1 to about 40 wt.%) with the remainder being various carriers or excipients and processing aids useful for forming the desired administration form.
For oral doses, a typical regimen is one to five oral doses per day, especially two to four oral doses, typically three oral doses. Using these modes of dosing, each dose provides from about 0.01 to about 20mg/kg of a compound of the invention, with preferred doses each providing from about 0.1 to about 10mg/kg, especially from about 1 to about 5mg/kg.
In order to provide similar blood levels to, or lower than, the use of an injected dose, a transdermal dose is typically selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 10% by weight, and more preferably about 0.5 to about 15% by weight.
From about 1 to about 120 hours, especially 24 to 96 hours, the injection dosage level is in the range of about 0.1 mg/kg/hour to at least 10 mg/kg/hour. To achieve adequate steady state levels, a preloaded bolus of about 0.1mg/kg to about 10mg/kg or more may also be administered. For human patients of 40 to 80kg, the maximum total dose cannot exceed about 2 g/day.
Liquid forms suitable for oral administration may include suitable aqueous or nonaqueous carriers, buffers, suspending and dispersing agents, colorants, flavors, and the like. Solid forms may include, for example, any of the following components, or compounds having similar properties: binders, for example microcrystalline cellulose, gum tragacanth or gelatin; excipients, for example starch or lactose, disintegrants, for example alginic acid, primogel or corn starch; lubricants, for example, magnesium stearate; glidants, for example, colloidal silicon dioxide; sweeteners, for example, sucrose or saccharin; or a flavoring agent, for example, peppermint, methyl salicylate, or orange flavoring.
Injectable compositions are typically based on sterile saline or phosphate buffered saline for injectable use, or other injectable excipients known in the art. As previously mentioned, in such compositions, the active compound is typically a minor component, often about 0.05 to 10% by weight, the remainder being an injectable excipient or the like.
Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient. When formulated as ointments, the active ingredients are typically combined with a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream with, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art and typically include other components for enhancing stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and compositions are included within the scope provided by the present invention.
The compounds of the invention may also be administered via a transdermal device. Transdermal administration may thus be achieved using a reservoir (reservoir) or porous membrane type, or a variety of solid matrix patches.
The above components of the compositions for oral administration, injection or topical administration are merely representative. Other materials and processing techniques, etc. are set forth in Remington's Pharmaceutical Sciences,17th edition,1985,Mack Publishing Company,Easton,Pennsylvania, section 8, incorporated herein by reference.
The compounds of the present invention may also be administered in sustained release form, or from a sustained release delivery system. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.
The invention also relates to pharmaceutically acceptable formulations of the compounds of the invention. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α -, β -and γ -cyclodextrins consisting of 6, 7 and 8 α -1, 4-linked glucose units, respectively, optionally including one or more substituents on the linked sugar moiety, including but not limited to: methylated, hydroxyalkylated, acylated and sulfoalkyl ether substitutions. In some embodiments, the cyclodextrin is a sulfoalkyl ether β -cyclodextrin, e.g., sulfobutyl ether β -cyclodextrin, also known as Captisol. See, for example, U.S.5,376,645. In some embodiments, the formulation comprises hexapropyl- β -cyclodextrin (e.g., 10-50% in water).
Pharmaceutical combination
Many chemotherapeutic agents currently known in the art may be used in combination with the compounds of the present invention. In some embodiments, the chemotherapeutic agent is selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens.
Examples
The starting materials or reagents used herein are commercially available or are prepared by synthetic methods generally known in the art.
Synthesis of intermediate 1-bromo-8-methylnaphthalene
The compound 1, 8-dibromonaphthalene (1 g,3.5 mmol) was dissolved in 20mL of tetrahydrofuran, and 2.6mL of a 1.6M ethereal solution of methyllithium was added thereto, followed by reaction at 0℃for 30 minutes under nitrogen protection. Then 1mL of methyl iodide was slowly added dropwise thereto, and the reaction was further carried out at room temperature for 3 hours. The reaction mixture was then quenched with ice water, extracted 2 times with petroleum ether, and the organic phase was dried and purified by column chromatography on silica gel (eluent: petroleum ether) to give the compound 1-bromo-8-methylnaphthalene (3836 mg,50% yield).
Synthesis of intermediate Compound 7
Step 1: metallic sodium (23 mg,1 mmol) was dissolved in 2mL of anhydrous methanol and reacted at room temperature for 15min, followed by slow addition of sodium methoxide solution to tetrahydrofuran solution (5 mL) of raw material 1 (purchased from Shanghai's Biotechnology Co., ltd., 254 mg,1 mmol) and reaction at room temperature for 2h. Subsequently saturated NH is added 4 Cl was quenched and extracted twice with ethyl acetate, and the organic phase was dried and purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate=5:1) to give compound 2 (260 mg,90% yield).
Step 2: sodium hydride (80 mg,60% purity, 2 mmol) was added to anhydrous tetrahydrofuran, and N-methyl-L-prolyl (230 mg,2 mmol) was added dropwise under nitrogen at 0deg.C. After stirring for 30min, compound 2 (290 mg,1 mmol) was added dropwise. After warming to room temperature, the mixture was heated to 70℃and reacted for 12 hours. Then 1mL of NH is slowly added dropwise at 0 DEG C 4 Saturated Cl solution was stirred for 15min, and 20mL NaHCO was added 3 The saturated solution was extracted twice with ethyl acetate, the organic phase was concentrated and purified by column chromatography on silica gel (eluent: dichloromethane: methanol=10:1) to give compound 3 (284 mg,80% yield).
Step 3: compound 3 (268 mg,1 mmol) was dissolved in 10mL of methanol and 30mg Pd/C was added at H 2 Reacting for 12h at 40 ℃. The Pd/C was removed by filtration, the organic phase was concentrated and purified by column chromatography on silica gel (dichloromethane: methanol=5:1) to give compound 4 (250 mg,90% yield).
Step 4: pd is combined with 2 (dba) 3 (137 mg,0.15 mmol) and BINAP (187 mg,0.3 mmol) were dissolved in 4mL toluene and reacted under nitrogen at 100deg.C for 30min, followed by cooling to room temperature. Compound 4 (278mg,1 mmol) and 1-bromo-8-methylnaphthalene (331 mg,1.5 mmol) and sodium tert-butoxide (240 mg,2.5 mmol) were dissolved in 10mL toluene, and a solution of the catalyst and the ligand was added under nitrogen protection and reacted at 100℃for 18h. Then cooled to room temperature, 40mL of water was added, extracted twice with ethyl acetate, and the organic phase was concentrated and purified by column chromatography on silica gel (eluent: dichloromethane: methanol=15:1) to give compound 5 (293 mg,70% yield).
Step 5: sodium hydride (80 mg,60% purity, 2 mmol) was added to 4mL anhydrous DMF and ethanethiol (124 mg,2 mmol) was slowly added dropwise at 0deg.C, after 30min of reaction, a solution of compound 5 (418 mg,1 mmol) in 5mL DMF was added dropwise. Then heating to 60 ℃ for reaction for 1h, and then slowly dripping 1mL of NH at 0 DEG C 4 Saturated Cl solution. After stirring the reaction for 15min, 20mL of water was added to quench the mixture, which was extracted once with ethyl acetate and dichloromethane, the organic phases were combined and dried by adding an appropriate amount of anhydrous magnesium sulfate. The solution was then filtered and concentrated and the crude product purified by column on silica gel (eluent: dichloromethane: methanol=10:1) to give compound 6 (384 mg,95% yield).
Step 6: compound 6 (404 mg,1 mmol) was dissolved in 20mL of anhydrous dichloromethane, and N-phenylbis (trifluoromethanesulfonyl) imide (428 mg,1.2 mmol) and cesium carbonate (423 mg,1.3 mmol) were added and reacted at room temperature under nitrogen for 2h. The solid was then removed by filtration and the organic phase was concentrated and purified by column chromatography on silica gel (petroleum ether: ethyl acetate=2:1) to give compound 7 (428 mg,80% yield).
Synthesis of intermediate Compound 12
Step 1: compound 8 (9.8 g,146 mmol) was dissolved in a mixed solution of tBuOH/PE (15 mL/57.5 mL) and 23.3g Br was added 2 Dissolved in 15mL of tBuOH, slowly added dropwise to the above mixture, and reacted at 15℃for 30min to obtain intermediate 9.
Step 2: metallic sodium (3.36 g,146 mmol) was dissolved in 85mL EtOH and added slowly dropwise to the reaction mixture of intermediate 9 and reacted for 2h at 15 ℃. Quenched with water, extracted twice with ethyl acetate, and the organic phase concentrated and purified by column to give compound 10 (10.6 g, 50%).
Step 3: n, N-dibenzylethylenediamine (5.75 g,24 mmol) was dissolved in 50mL of toluene, 4.85g of triethylamine was added, followed by dropwise addition of compound 10 at 0℃and further return to room temperature, and the reaction was continued for 12 hours. After filtration, the solvent was removed and purified by column to give compound 11 (3.2 g, 45%).
Step 4: compound 11 (1.64 g,5.36 mmoles) was dissolved in 15mL of DCE, and 1-chloroethyl chloroformate (3.06 g,21.4 mmoles) was added dropwise at 0℃and the temperature was raised to 84℃again for 2 days. 15mL of methanol was added thereto, and the mixture was reacted at 65℃for 1 hour. After the solvent was removed by rotary evaporation under reduced pressure, the solid was washed with methyl tert-butyl ether, and filtered to give compound 12 (0.6 g, 56%).
Synthesis of examples 1 to 38
The following schemes were used to synthesize the compounds of the present invention. For the compounds TH-Z808, TH-Z814, TH-Z815, TH-Z830, TH-Z831 and TH-Z832, the intermediate compound 7 is taken as a starting material, and the final product is obtained through one-step reaction. Other compounds also need to undergo a one-step reaction to remove protecting groups to obtain the final product.
The general synthesis procedure is as follows:
step 1: compound 7 (534 mg,1 mmol) was dissolved in 5ml anhydrous DMF and DIPEA (258 mg,2 mmol) was added together with the various N-Boc protected amine fragments or the N-Boc protected amine fragment (1.05 mmol) was not required and reacted under nitrogen at 100℃for 1-10 h. After cooling, 20mL of water was added, extraction was performed twice with ethyl acetate, the organic phase was concentrated, and the N-Boc protected compound and the target compound without N-Boc protection were obtained by column purification (30-90% yield).
Step 2: N-Boc protected Compound (1 mmol) was dissolved in 2mL of dichloromethane and added1mL of trifluoroacetic acid was reacted at room temperature for 1h. 10mL of Na was added 2 CO 3 The saturated solution was extracted twice with dichloromethane, the organic phase was concentrated and purified by column to give the title compound (80% yield).
Biological Activity test
KRAS protein expression and purification
(1) Protein expression and sample processing
Plasmids carrying the gene of interest (KRAS 4b G D, his tag, truncated sequences 1-169) were transferred to BL21 (DE 3) competent E.coli, transferred to LB medium containing ampicillin resistance, and cultured at 37℃and 220 rpm. When the OD 600nm of the bacterial liquid is about 0.6, the temperature is reduced to 16 ℃, 0.5mM IPTG (isopropyl-. Beta. -D-thiogalactoside) is added to the flask medium, and the culture is carried out at 16℃and 220rpm for about 24 hours. The fermentation broth was centrifuged at 6000g for 10min at 4℃and the supernatant was discarded. The cells were resuspended in Buffer A (25 mM Tris, 150mM NaCl, 10mM imidazole, pH 8.5). The resuspended bacterial liquid was crushed in a high-pressure homogenizing crusher at 4℃and then centrifuged at 16000g at 4℃for 1 hour, the supernatant was collected and the sample was filtered with a 0.22 μm pore size filter.
(2) Affinity chromatography separation
First using 0.1M NiSO 4 Regenerating the Ni-NTA column, balancing with Buffer A to wash out excessive Ni ions, and loading the sample after balancing the column, wherein the flow rate is 3mL/min. After loading, unbound protein and impurities were washed with Buffer A until the A280 value returned to baseline stability, and Buffer A and Buffer B (25 mM Tris, 150mM NaCl, 500mM imidazole, pH 8.5) were mixed using a linear elution strategy, and 6mL of eluate was collected per tube for protein electrophoresis analysis.
(3) Tev enzyme digestion and secondary affinity chromatography separation
An appropriate amount of Tev enzyme was added to the eluate containing KRAS G12D to cleave off the N-piece His-tagged thioredoxin while dialyzing against Buffer C (25 mM Tris, 150mM NaCl, pH 8.5). In the second pass through Ni-NTA column, since the thioredoxin containing His tag is cleaved by Tev enzyme, the target protein can not be combined with the affinity chromatography column, and therefore, when passing through Ni column for the second time, the eluent of the uncombined part is collected for protein electrophoresis analysis.
(4) Concentration, purity and concentration of KRAS G12D
The protein sample buffer contains 25mM Tris, pH 8.5 and 150mM NaCl, the ratio of Crystal observation precipitation of two kits of Crystal Screen I and Crystal Screen II points is tried first, the protein concentration is determined to be 40mg/mL, and the concentrated protein is subjected to electrophoresis analysis to verify the purity.
(5) Preliminary screening of KRAS G12D protein crystallization conditions and optimization of crystallization conditions
Crystal growth was performed in a 96-well plate using a sitting-drop gas phase diffusion method in a constant temperature incubator at a constant temperature of 22 ℃. All 1000 conditions were initially screened, and observed every two days to see if crystals were grown and relevant records were made. The crystallization conditions for KRAS G12D were found to be 0.2M sodium acetate, 0.1M Tris, pH 8.5, 26% (w/v) PEG 3350, and relevant reagents were formulated and optimized for crystallization condition concentration and protein concentration.
(6) Collection and data processing of diffraction data of KRAS G12D
The regular KRAS G12D crystal is subjected to X-ray diffraction data collection, immersed in a compound TH Z816 with a concentration of 2mM for 6 hours, dipped with an antifreeze agent, subjected to X-ray diffraction under crystallization conditions with 10% glycerol, and subjected to data collection, and treated with relevant software such as HKL 2000.
SOS cat Catalytic nucleotide exchange experiments
In a black flat bottom 96-well plate (Corning, # 3686), different concentrations of compound (final DMSO concentration 4%) were reacted with reaction buffer (40 mM HEPES-KOH, 10mM MgCl) 2 1mM DTT, pH 8.5) followed by KRAS G12D mantGDP (2 '/3' -O- (N-methylparaben) guanosine 5' -diphosphate) was added, mixed and incubated for 10min. SOS is carried out cat After the protein was premixed with the GDP solution, the reaction was started by adding to the KRAS protein solution. The total system was 100. Mu.L and the final concentration of each component was KRAS G12D mantGDP 2. Mu. M, SOS cat 2μM、GDP 1mM。
SOS inhibition for TH-Z835 cat Catalytic nucleotide substitution experiments of KRAS G12D mantGCP (polypyrrolone film synthesized from pyromellitic dianhydride and biphenyltetramine). The reaction buffer was unchanged, the total system was 100. Mu.L, and the final concentration of each component was KRAS G12C mantGCP 3. Mu. M, SOS cat 4μM、GCP 2mM、TH-Z 835500μM。
SOS inhibition for TH-Z835 cat Catalytic nucleotide substitution experiments of KRAS G12D GCP. The reaction buffer solution is unchanged, the total system is 100 mu L, and the final concentration of each component is KRAS G12C GCP 3 mu M, SOS cat 2μM、mantGCP 4μM、TH-Z 835 500μM。
After the reaction was started, the fluorescence value was read with an microplate reader (PerkinElmer, enVision) (excitation wavelength 355nm, emission wavelength 460nm, once every 30s, for 1 hour). Fitting the obtained kinetic data with One phase decay equation or One phase association in GraphPad Prism 7.0 software, calculating to obtain rate k value, and plotting corresponding compound concentration gradient to obtain IC 50 A curve.
The experimental results are shown in the following table:
killing of KRAS G12D mutant tumor cells by the Compounds of the invention
We tested the killing effect of three representative compounds on PANC-1 cells and PANC 04.03 cells of pancreatic cancer origin, as well as p53.2.1.1 cells. Both cells were heterozygous for the KRAS gene, i.e. only one allele was the G12D mutation.
PANC-1, PANC 04.03 and p53.2.1.1 cells were purchased from ATCC (American Type Culture Collection). In 96-well plates (Nest, # 701001), 5000 cells (PANC-1 or PANC 04.03) were plated per well in DMEM (10% fetal bovine serum, 1% penicillin/streptomycin). After cell plating, the cells are cultured for 24 hours in an incubator, and then medicines with different concentrations are added for continuous culture for 24 hours. CCK-8 reagent (Biyun, C0042) was then added and incubated for 1h. Absorbance was measured at 450nm using a microplate reader. Data were run using the GraphPad Prism 7.0 software [ Inhibitor ] ]The response-Variable slope (four parameters) model is fitted and calculated to obtain the IC 50 Values.
Killing of three cells by two KRAS G12D inhibitors
Analysis of the Crystal Structure of TH-Z816
We tried to conduct a crystallographic experiment on TH-Z816 and KRAS G12D protein in order to investigate the structure-activity relationship of the compounds.
We obtained a complex crystal of small molecules and KRAS G12D protein by soaking (fig. 1) and resolved. As can be seen from the observation of the crystal structure at the binding site, TH-Z816 binds in the pocket formed under switch II (residues 60-76 of RAS protein), i.e., switch II pocket (SIIP). This is an allosteric site adjacent to the binding site of guanylic acid (GDP or GTP). Electron cloud density (2F) in the vicinity of the compound o -F c 1 sigma) shows that it is seen to be completely covered on the small molecular scaffold. We aligned the crystal of KRAS G12D-TH-Z816 with the crystal of KRAS G12C-MRTX849 (PDB: 6UT 0), and found that the overall conformation of the two proteins was very similar, and that the RMSD of Cα was
Analysis of TH-Z168 binding patterns to KRAS G12D protein revealed four groups of polar interactions: salt bridging of the carboxyl group of Asp 12 with the piperazine terminal secondary amine; hydrogen bonding between O atoms of a main chain of Gly 60 and N atoms of the tail end of piperazine; electrostatic attraction between the carboxyl group of Glu 62 and N-methylpyrrolidine with positively charged side chains; hydrogen bond between the N atom of His 95 and the N atom of the pyrimidine ring of the core skeleton. Nonpolar interactions mainly involve hydrophobic interactions of small molecules with surrounding residues (fig. 2).
It is notable that these polar interactions are directional, especially the hydrogen bond and salt bridge interactions formed by the N atoms at the piperazine ends and the surrounding amino acids, and have stronger directionality, so for small molecules with better activity, the positions of the N atoms at the piperazine ends are relatively fixed, and the conformation (TH-Z816 torsion ship type) and the included angle with the pyrimidine ring are limited.
Figure 3 presents the spatial characteristics of the binding pocket: the spatial characteristics of the binding pocket around the piperazine ring are that the upper space is smaller in volume, the lower space is larger, the proximal space is larger, and the distal space is smaller, so the methyl group on the piperazine ring is directed downward.
The foregoing is a further detailed description of the invention in connection with the preferred embodiments, and it is not intended that the invention be limited to the specific embodiments described. It will be apparent to those skilled in the art that several simple deductions or substitutions may be made without departing from the spirit of the invention, and these should be considered to be within the scope of the invention.

Claims (27)

  1. A compound of formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, or isotopic variant thereof:
    Wherein,
    x is-N (R) -or-CH (R) -;
    wherein R is selected from H, - (CH) 2 ) 1-3 Halogen, - (CH) 2 ) 1-3 -OH、-(CH 2 ) 1-3 -CN、-(CH 2 ) 1- 3 -NH 2 、C 1-6 Alkyl or C 1-6 A haloalkyl group;
    r is selected from- (CH) 2 ) 0-3 Halogen, - (CH) 2 ) 0-3 -OH、-(CH 2 ) 0-3 -CN or- (CH) 2 ) 0-3 -NH 2 ；
    Y is N or CH;
    Y 1 is CR (CR) Y1a R Y1b ；
    Y 2 Is CR (CR) Y2a R Y2b ；
    Y 3 Is CR (CR) Y3a R Y3b Or NR (NR) Y3c ；
    r=1 or 2;
    s=0 or 1;
    wherein R is Y1a 、R Y1b 、R Y2a 、R Y2b 、R Y3a And R is Y3b Independently selected from H, halogen, C 1- 6 Alkyl or C 1-6 A haloalkyl group;
    R Y3c selected from H, C 1-6 Alkyl or C 1-6 A haloalkyl group;
    or Y 3 And Y adjacent thereto 2 A double bond may be formed therebetween;
    R A selected from H, C 6-10 Aryl or 5-14 membered heteroaryl, optionally substituted with 1, 2, 3 or 4R A1 Substitution;
    wherein each R is A1 Independently selected from H, halogen, -CN, -OR X 、-SR X 、-NR Y R Z 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
    l is selected from a chemical bond, -O-, -S-, or-NH-;
    R B selected from H, halogen, -CN, -OR X 、-SR X 、-NR Y R Z 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclyl, C 6-10 Aryl or 5-14 membered heteroaryl; optionally substituted with 1, 2, 3 or 4 r#;
    wherein R# is selected from H, -C 0-6 Alkylene-halogen, -C 0-6 alkylene-CN, C 1-6 Alkyl, C 1- 6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C 0-6 alkylene-O-R X 、-C 0-6 alkylene-S-R X 、-C 0-6 alkylene-NR Y R Z 、-C 0-6 alkylene-C (O) R X 、-C 0-6 alkylene-C (O) OR X 、-C 0-6 alkylene-C (O) -NR Y R Z 、-C 0-6 alkylene-C 3-10 Cycloalkyl, -C 0-6 Alkylene-3-10 membered heterocyclyl, -C 0-6 alkylene-C 6-10 Aryl or-C 0-6 Alkylene-5-14 membered heteroaryl; and R# is optionally halogen, -OH, -OC 1-6 Alkyl, -NH 2 、-NH(C 1-6 Alkyl), -N (C) 1-6 Alkyl group 2 、C 1- 6 Alkyl or C 1-6 Haloalkyl substitution;
    wherein R is X Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
    R Y and R is Z Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2- 6 Alkynyl, or R Y And R is Z The nitrogen atom to which they are attached forms a 3-10 membered heterocyclic group;
    R 1 and R is 2 Independently selected from H, halogen, -OH, -NH 2 、-CN or- (CR) c R d ) m -R’；
    R 3 And R is 4 Independently selected from H, halogen, -OH, -NH 2 -CN or- (CR) c R d ) m -R”；
    R 2’ Is H or R 2 、R 2’ Together with the carbon atoms to which they are attached form C 3-6 Cycloalkyl;
    or R is 1 And R is 2 、R 3 And R is 4 、R 1 And R is 4 、R 2 And R is 3 Any one of the groups being linked to form- (CR) a R b ) n -；
    p=0, 1, 2 or 3;
    q=0, 1, 2 or 3;
    wherein R is a Selected from H, halogen, C 1-6 Alkyl or C 1-6 A haloalkyl group;
    R b selected from H, halogen, C 1-6 Alkyl or C 1-6 A haloalkyl group;
    R c selected from H, halogen, C 1-6 Alkyl or C 1-6 A haloalkyl group;
    R d selected from H, halogen, C 1-6 Alkyl or C 1-6 A haloalkyl group;
    r' is selected from H, halogen, -OH, -SH, -NH 2 、-CN、-C(O)R e 、-C(O)OR e 、-C(O)NR f R g 、C 2-6 Alkenyl or C 2-6 Alkynyl;
    r' is selected from H, halogen, -OH, -SH, -NH 2 、-CN、-C(O)R e 、-C(O)OR e 、-C(O)NR f R g 、C 2-6 Alkenyl or C 2-6 Alkynyl;
    m=0, 1, 2, 3, 4, 5 or 6;
    n=0, 1, 2, 3, 4, 5 or 6;
    Wherein R is e Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
    R f and R is g Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, or R f And R is g And the nitrogen atom to which they are attached form a 3-10 membered heterocyclic group.
  2. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof,
    wherein the method comprises the steps ofSelected from the following parent nuclei:
  3. a compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof,
    wherein R is A Selected from the following groups:
  4. a compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof,
    wherein-L-R B Selected from H,
  5. A compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof, wherein X is-N (R) -, and wherein R is selected from H, C 1-6 Alkyl or C 1-6 Haloalkyl, X is preferably-NH-.
  6. A compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof, wherein R 1 Or R is 2 Selected from H, halogen, -OH, -NH 2 、-CN、-CH 3 or-CH 2 -OH, preferably-CH 3 or-CH 2 -OH; preferably, R 1 And R is 2 One is-CH 3 or-CH 2 -OH; preferably, R 1 And R is 2 One of which is-CH of R configuration 3 or-CH 2 -OH。
  7. A compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof, wherein R 1 And R is 2 、R 3 And R is 4 、R 1 And R is 4 、R 2 And R is 3 Any one of the groups being linked to form-CH 2 -、-CH 2 CH 2 -or-CH 2 CH 2 CH 2 -, preferably-CH 2 CH 2 -or-CH 2 CH 2 CH 2 -。
  8. A compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof, wherein R 3 And R is 4 Independently selected from H, -CH 2 -Cl、-CH 2 -F、-CH 2 -CN、-CH 2 CH 2 -Cl、-CH 2 CH 2 -F、-CH 2 CH 2 -CN, preferably H or-CH 2 -CN。
  9. A compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof, having the structure:
    wherein each group is as defined in any one of claims 1 to 8.
  10. A compound of formula (II) according to claim 9, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof:
    Wherein,
    x is-N (R) -or-CH (R) -;
    wherein R is selected from H, C 1-6 Alkyl or C 1-6 A haloalkyl group;
    r is selected from- (CH) 2 ) 0-3 -NH 2 Or- (CH) 2 ) 0-3 -OH；
    R 1 And R is 2 Independently selected from H, halogen, -OH, -NH 2 -CN or- (CR) c R d ) m -R’；
    R 3 And R is 4 Independently selected from H, halogen, -OH, -NH 2 -CN or- (CR) c R d ) m -R”；
    R 2’ Is H or R 2 、R 2’ Together with the carbon atoms to which they are attached form C 3-6 Cycloalkyl;
    p=0, 1, 2 or 3;
    q=0, 1, 2 or 3;
    wherein R is c Selected from H, halogen, C 1-4 Alkyl or C 1-4 A haloalkyl group;
    R d selected from H, halogen, C 1-4 Alkyl or C 1-4 A haloalkyl group;
    r' is selected from H, halogen, -OH, -SH, -NH 2 、-CN、-C(O)R e 、-C(O)OR e or-C (O) NR e R f ；
    R' is selected from H, halogen, -OH, -SH, -NH 2 、-CN、-C(O)R e 、-C(O)OR e or-C (O) NR e R f ；
    m=0, 1, 2, 3, 4, 5 or 6;
    wherein R is e Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl;
    R f and R is g Independently selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl or C 2-6 Alkynyl, or R f And R is g And the nitrogen atom to which they are attached form a 3-10 membered heterocyclic group.
  11. The compound of formula (II) according to claim 10, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof,
    x is-N (R) -or-CH (R) -;
    wherein R is selected from H, C 1-6 Alkyl or C 1-6 A haloalkyl group;
    r is selected from- (CH) 2 ) 0-1 -NH 2 Or- (CH) 2 ) 0-1 -OH；
    R 1 And R is 2 Independently selected from H or- (CR) c R d ) m -R’；
    R 3 And R is 4 Independently selected from H or- (CR) c R d ) m -R”；
    R 2’ Is H or R 2 、R 2’ Together with the carbon atoms to which they are attached form C 3-6 Cycloalkyl;
    p=0, 1 or 2;
    q=0, 1 or 2;
    wherein R is c Is H;
    R d is H;
    r' is selected from H, halogen or-OH;
    r' is selected from H, halogen, -OH, -NH 2 or-CN;
    m=0, 1, 2, 3, 4, 5 or 6.
  12. A compound of formula (III) according to claim 9, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof:
    wherein,
    R 1 and R is 2 Independently selected from H, halogen, -OH, -NH 2 -CN or- (CR) c R d )-R’；
    R 3 And R is 4 Independently selected from H, halogen, -OH, -NH 2 -CN or- (CR) c R d ) m -CN；
    p=0, 1, 2 or 3;
    q=0, 1, 2 or 3;
    wherein R is c Selected from H or halogen;
    R d selected from H or halogen;
    r' is selected from H, halogen, -OH, -SH, -NH 2 or-CN;
    m=1 or 2.
  13. The compound of formula (III) according to claim 12, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof,
    R 1 and R is 2 Independently selected from H or- (CR) c R d )-R’；
    R 3 And R is 4 Independently selected from H or- (CR) c R d )-CN；
    p=1 or 2;
    q=1 or 2;
    wherein R is c Is H;
    R d is H;
    r' is selected from H or-OH.
  14. A compound of formula (IV) according to claim 9, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof:
    Wherein,
    R 1 and R is 2 One is- (CR) c R d ) -R' another is selected from H, halogen, -OH, -NH 2 -CN or- (CR) c R d )-R’；
    R 3 And R is 4 Independently selected from H, halogen, -OH, -NH 2 -CN or- (CR) c R d )-R”；
    R is selected from H, C 1-6 Alkyl or C 1-6 A haloalkyl group;
    p=0, 1, 2 or 3;
    q=0, 1, 2 or 3;
    wherein R is c Selected from H, halogen, C 1-4 Alkyl or C 1-4 A haloalkyl group;
    R d selected from H, halogen, C 1-4 Alkyl or C 1-4 A haloalkyl group;
    r' is selected from H, halogen, -OH, -SH, -NH 2 or-CN;
    r' is selected from halogen, -OH, -SH, -NH 2 or-CN.
  15. The compound of formula (IV) according to claim 14, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof, wherein,
    R 1 and R is 2 One is- (CR) c R d ) -R', the other being H;
    R 3 and R is 4 Independently selected from H or- (CR) c R d )-R”；
    R is selected from H, C 1-2 Alkyl or C 1-2 A haloalkyl group;
    p=1 or 2;
    q=1 or 2;
    wherein R is c Is H;
    R d is H;
    r' is selected from H or-OH;
    r' is-CN.
  16. A compound of formula (V), (V-1) or (V-2) according to claim 9, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof:
    wherein,
    R 1 and R is 2 、R 3 And R is 4 、R 1 And R is 4 、R 2 And R is 3 Any one of the groups being linked to form- (CR) a R b ) n -, the rest of R 1 And R is 2 Independently selected from H or- (CR) c R d ) m -R', the remainder of R 3 And R is 4 Independently selected from H or- (CR) c R d ) m -R”；
    R is H, C 1-6 Alkyl or C 1-6 A haloalkyl group;
    wherein R is a Selected from H, halogen, C 1-4 Alkyl or C 1-4 A haloalkyl group;
    R b selected from H, halogen, C 1-4 Alkyl or C 1-4 A haloalkyl group;
    R c selected from H, halogen, C 1-4 Alkyl or C 1-4 A haloalkyl group;
    R d selected from H, halogen, C 1-4 Alkyl or C 1-4 A haloalkyl group;
    r' is selected from H, halogen, -CN, -OH, -NH 2 、C 2-4 Alkenyl or C 2-4 Alkynyl;
    r' is selected from H, halogen, -CN, -OH, -NH 2 、C 2-4 Alkenyl or C 2-4 Alkynyl;
    n=0, 1, 2, 3 or 4;
    m=0, 1, 2 or 3.
  17. The compound of formula (V), (V-1) or (V-2) of claim 16, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof, wherein,
    R 1 and R is 2 、R 3 And R is 4 、R 1 And R is 4 、R 2 And R is 3 Any one of the groups being linked to form- (CR) a R b ) n -, the rest of R 1 、R 2 、R 3 Or R is 4 H, halogen, -CN, -OH or-NH respectively 2 ；
    R is selected from H, C 1-6 Alkyl or C 1-6 A haloalkyl group;
    wherein R is a Selected from H, halogen, C 1-4 Alkyl or C 1-4 A haloalkyl group;
    R b selected from H, halogen, C 1-4 Alkyl or C 1-4 A haloalkyl group;
    n=0, 1, 2, 3 or 4.
  18. The compound of formula (V), (V-1) or (V-2) of claim 16, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof, wherein,
    R 1 And R is 2 、R 3 And R is 4 、R 1 And R is 4 、R 2 And R is 3 Any one of the groups being linked to form- (CR) a R b ) n -, the rest of R 1 、R 2 、R 3 Or R is 4 Is H;
    r is selected from H, C 1-2 Alkyl or C 1-2 A haloalkyl group;
    wherein R is a Is H;
    R b is H;
    n=1, 2 or 3.
  19. The compound of formula (V), (V-1) or (V-2) of claim 16, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof, wherein,
    R 1 and R is 2 、R 3 And R is 4 、R 1 And R is 4 、R 2 And R is 3 Any one of the groups being linked to form- (CR) a R b ) n -, the rest of R 1 And R is 2 Independently selected from H or- (CR) c R d ) m -R', the remainder of R 3 And R is 4 Independently selected from H or- (CR) c R d ) m -R”；
    R is H;
    wherein R is a Selected from H, halogen, C 1-4 Alkyl or C 1-4 A haloalkyl group;
    R b selected from H, halogen, C 1-4 Alkyl or C 1-4 A haloalkyl group;
    R c selected from H, halogen, C 1-4 Alkyl or C 1-4 A haloalkyl group;
    R d selected from H, halogen, C 1-4 Alkyl or C 1-4 A haloalkyl group;
    r' is selected from H, halogen, -CN, -OH, -NH 2 、C 2-4 Alkenyl or C 2-4 Alkynyl;
    r' is selected from H, halogen, -CN, -OH, -NH 2 、C 2-4 Alkenyl or C 2-4 Alkynyl;
    m=0, 1, 2 or 3;
    n=2, 3 or 4.
  20. The compound of formula (V), (V-1) or (V-2) of claim 16, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof, wherein,
    R 1 and R is 2 、R 3 And R is 4 、R 1 And R is 4 、R 2 And R is 3 Any one of the groups being linked to form- (CR) a R b ) n -, the rest of R 1 、R 2 、R 3 Or R is 4 Independently selected from H, halogen, -CN, -OH or-NH 2 ；
    R is H;
    wherein R is a Selected from H, halogen or C 1-4 An alkyl group;
    R b selected from H, halogen or C 1-4 An alkyl group;
    n=2, 3 or 4.
  21. The compound of formula (V), (V-1) or (V-2) of claim 16, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof, wherein,
    R 1 and R is 2 、R 3 And R is 4 、R 1 And R is 4 、R 2 And R is 3 Any one of the groups being linked to form- (CR) a R b ) n -, the rest of R 1 、R 2 、R 3 Or R is 4 Is H;
    r is H;
    wherein R is a Is H;
    R b is H;
    n=2 or 3.
  22. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof, wherein said compound is selected from the group consisting of:
  23. a pharmaceutical composition comprising a compound of any one of claims 1-22, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate, or isotopic variant thereof, and a pharmaceutically acceptable excipient; preferably, it also contains other therapeutic agents.
  24. Use of a compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of KRAS G12D mutein mediated diseases.
  25. A method of treating and/or preventing KRAS G12D mutein-mediated diseases in a subject, the method comprising administering to the subject the compound of any one of claims 1-22 or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof or the pharmaceutical composition of claim 23.
  26. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt, enantiomer, diastereomer, solvate, hydrate or isotopic variant thereof, or the pharmaceutical composition of claim 23, for use in the treatment and/or prevention of KRAS G12D mutein-mediated diseases.
  27. The use of claim 24 or the use of the method of claim 25 or the compound or composition of claim 26, wherein the KRAS G12D mutein-mediated disease is selected from acute myeloid leukemia, juvenile cancer, childhood adrenocortical cancer, AIDS-related cancers (e.g., lymphoma and kaposi's sarcoma), anal cancer, appendiceal cancer, astrocytoma, atypical teratoid, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bone cancer, brain stem glioma, brain tumor, breast cancer, bronchogenic tumor, burkitt lymphoma, carcinoid tumor, atypical teratoid, embryonic tumor, germ cell tumor, primary lymphoma, cervical cancer, childhood cancer, chordoma, cardiac tumor, chronic Lymphocytic Leukemia (CLL), chronic Myelogenous Leukemia (CML), chronic myeloproliferative disorder, colon cancer colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic Ductal Carcinoma In Situ (DCIS), embryonic tumors, CNS cancers, endometrial cancer, ependymoma, esophageal cancer, olfactory neuroblastoma, ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, skeletal fibroblastic tumor, gall bladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, gestational trophoblastoma, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, pancreatic neuroendocrine tumor, renal cancer, laryngeal cancer, lip and oral cancer, liver cancer, small Leaf Carcinoma In Situ (LCIS), lung cancer, lymphoma, metastatic squamous neck cancer with suppressed primary focus, mesogenic carcinoma, oral cancer, multiple endocrine tumor syndrome, multiple myeloma/plasmacytoma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic/myeloproliferative neoplasm, multiple myeloma, merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma of the bone, nasal and sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oral cancer, lip and oral cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papilloma, paraganglioma, paranasal and nasal cancers, parathyroid cancer, penile cancer, pharyngeal cancer, pleural-pulmonary blastoma, primary Central Nervous System (CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, gastric cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, cellular lymphoma, testicular cancer, laryngeal cancer, thymoma and thymus cancer, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastoma, rare childhood cancer, urinary tract cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virus-induced cancer.
CN202280030233.9A 2021-04-23 2022-04-22 Inhibitors targeting activated and inactivated KRAS G12D Pending CN117203208A (en)

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JP7039489B2 (en) * 2016-05-18 2022-03-22 ミラティ セラピューティクス， インコーポレイテッド KRAS G12C inhibitor
KR20200100632A (en) * 2017-11-15 2020-08-26 미라티 테라퓨틱스, 인크. KRAS G12C inhibitor
CN112047939B (en) * 2019-06-06 2023-05-02 江苏先声药业有限公司 Tetrahydropyridopyrimidine compound with anti-tumor activity
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