CN117126140A - Heterocyclic compounds having protein kinase inhibitory activity, pharmaceutical compositions containing the same, and methods of preparing and using the same - Google Patents

Heterocyclic compounds having protein kinase inhibitory activity, pharmaceutical compositions containing the same, and methods of preparing and using the same Download PDF

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Publication number
CN117126140A
CN117126140A CN202310556246.6A CN202310556246A CN117126140A CN 117126140 A CN117126140 A CN 117126140A CN 202310556246 A CN202310556246 A CN 202310556246A CN 117126140 A CN117126140 A CN 117126140A
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alkyl
cycloalkyl
independently selected
compound
cancer
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Inventor
陈忠辉
韩晓军
田强
宋宏梅
葛均友
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Sichuan Kelun Biotech Biopharmaceutical Co Ltd
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Sichuan Kelun Biotech Biopharmaceutical Co Ltd
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    • 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
    • C07D403/02—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 two hetero rings
    • C07D403/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Abstract

The invention relates to heterocyclic compounds having protein kinase inhibitory activity, pharmaceutical compositions comprising the same, and methods of making and using the same. In particular, the invention relates to compounds of formula I which have good inhibitory effect on RAF and/or RAS kinase, are capable of overcoming the dimer resistance mechanism caused by existing RAF inhibitors, reducing ERK abnormal activation toxicity, and are useful for the prevention or treatment of diseases or conditions associated with RAF and/or RAS kinase activity.

Description

Heterocyclic compounds having protein kinase inhibitory activity, pharmaceutical compositions containing the same, and methods of preparing and using the same
Technical Field
The present invention relates to compounds that are inhibitors of RAF, pharmaceutical compositions comprising the same, methods of preparing the same, and their use for preventing or treating diseases or conditions associated with RAF and/or RAS kinase activity.
Background
Protein kinases are a class of enzymes that catalyze protein phosphorylation reactions. Protein phosphorylation regulates physiological activities of cells, such as survival, proliferation, differentiation, apoptosis, metabolism, etc., by mediating cell signaling processes. Dysfunction of protein kinases is closely related to many diseases including tumors, autoimmune diseases, inflammatory responses, central nervous system diseases, cardiovascular diseases, diabetes, etc.
RAF belongs to ATP kinase, an important component of RAS-RAF-MEK signaling pathway, and is classified into A, B, C subtypes, with high homology and similar domains. RAF exists in the cytoplasm as an inactive monomer. RAS is stimulated by upstream growth factors to convert from an inactive conformation (GDP binding) to an active conformation (GTP binding), thereby recruiting intracellular RAF to the cell membrane and causing dimerization and phosphorylation of the same, which in turn phosphorylates activated MEK and ERK, ultimately regulating proliferation, differentiation, apoptosis and metastasis of the cell (Karoulia Z et al, nat Rev cancer.2017 Nov;17 (11): 676-691). Mutant B-RAF is capable of sustained activation of the MAPK signaling pathway either as monomer (V600 mutation) or as dimer (non-V600 mutation) independent of RAS. RAF inhibitors inhibit RAF monomer and dimer activities, thereby inhibiting RAS-RAF-MEK signaling pathway, for treatment of RAS or RAF mutant tumors, and are useful in about 1/3 of the population of tumor patients. Suitable tumor types mainly include melanoma, NSCLC, CRC, ovarian cancer, endometrial cancer, thyroid cancer, pancreatic cancer, and the like.
The alpha C-OUT RAF inhibitor represented by Vemurafenib can effectively inhibit the kinase activity of the V600 point mutation BRAF. However, for RAS mutant, wild-type B-RAF, and BRAF-driven tumors that are not V600 point mutant, αC-OUT inhibitors are not effective at inhibiting RAF activation and have developed resistance after clinical use.
Disclosure of Invention
The present invention provides novel compounds which are inhibitors of RAF, have good inhibitory effect on RAF and/or RAS kinase, and have good pharmacokinetic properties. The compound can inhibit the activity of RAF dimer, overcome the dimer drug resistance mechanism caused by the prior RAF inhibitor, reduce ERK abnormal activation toxicity, and can be applied to the treatment of RAS or RAF mutant tumor.
One aspect of the present invention provides a compound of formula I, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, isotopically-labeled compound, N-oxide, or prodrug thereof:
wherein:
ring A is a 4-10 membered heterocyclyl;
W 1 、W 2 and W is 3 Each independently selected from N and CR 4 ；
L 1 Selected from-NR 5 -C(＝O)-、-C(＝O)-NR 5 -and-NR 5 -；
R 1 Selected from C 6-10 Aryl and 5-10 membered heteroaryl, wherein each of said aryl and heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of: -NHR 6 Hydroxy, halogen, CN, NO 2 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkoxy, C 1-6 Heteroalkyl (e.g. C 1-6 Alkoxy group), C 3-6 Cycloalkyl and 4-10 membered heterocyclyl; alternatively, the optional two substituents together with the atoms to which they are attached form a 5-10 membered heterocyclic group, said 5-10 membered heterocyclic group optionally being substituted with one or more substituents independently selected from CN, hydroxy, halogen, oxo and C 1-6 Substituent substitution of alkyl;
R 2 and R is 4 Each at each occurrence is independently selected from H, CN, hydroxy, halogen, C 1-6 Alkyl and C 1-6 Alkoxy, wherein each of the alkyl and alkoxy groups is optionally substituted with one or more halogens;
R 3 is L 3 -R 3 ’；
L 3 Each occurrence is independently a direct bond or- (CH) 2 ) n -；
R 3 ' each occurrence is independently selected from H, hydroxy, halogen, CN, NO 2 、C 1-6 Alkyl, C 1-6 Heteroalkyl (e.g. C 1-6 Alkoxy group), C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, -NR 20a R 20b 、-SR 21 、-S(＝O)R 22 、-S(＝O) 2 R 22 、-S(＝O)NR 20a R 20b 、-S(＝O) 2 NR 20a R 20b 、-NR 20a S(＝O)R 20b 、-NR 20a S(＝O) 2 R 20b 、-C(＝O)R 21 、-C(＝O)NR 23a R 23b 、-NR 23a C(＝O)R 23b and-NR 24a C(＝O)NR 25a R 25b Wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocyclyl (e.g., alkoxy), aryl, and heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of: hydroxy, halogen, CN, NO 2 、C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkoxy, C 1-4 Heteroalkyl (e.g. C 1-4 Alkoxy group), C 3-6 Cycloalkyl and 4-10 membered heterocyclyl;
R 5 and R is 6 Each at each occurrence is independently selected from H, C 1-6 Alkyl, C 3-8 Cycloalkyl and 4-10 membered heterocyclyl, wherein each of said alkyl, cycloalkyl and heterocyclyl is optionally substituted with one or more halo;
R 20a 、R 20b 、R 23a 、R 23b 、R 24a 、R 25a And R is 25b Each independently selected from H, OH, -NHCH 3 、-N(CH 3 ) 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl and 4-10 membered heterocyclyl; wherein each of said alkyl, alkoxy, cycloalkyl and heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of: halogen, C 1-6 Alkyl and 4-10 membered heterocyclyl;
R 21 and R is 22 Each independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl and 4-10 membered heterocyclyl, wherein each of said alkyl, alkoxy, cycloalkyl and heterocyclyl is optionally substituted with one or more halo;
m is 1, 2, 3, 4 or 5; and is also provided with
n is 1, 2 or 3.
Another aspect of the invention provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, isotopically-labeled compound, N-oxide, or prodrug thereof, and one or more pharmaceutically acceptable carriers.
Another aspect of the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, isotopically-labeled compound, N-oxide, or prodrug thereof, or a pharmaceutical composition of the invention, in the manufacture of a medicament for the prevention or treatment of a disease or condition associated with RAF and/or RAS kinase activity.
Another aspect of the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, isotopically-labeled compound, N-oxide, or prodrug thereof, or a pharmaceutical composition of the invention, for use in the prevention or treatment of a disease or condition associated with RAF and/or RAS kinase activity.
Another aspect of the invention provides a method of preventing or treating a disease or condition associated with RAF and/or RAS kinase activity, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, isotopically-labeled compound, N-oxide, or prodrug thereof, or a pharmaceutical composition of the invention.
Another aspect of the invention provides a process for preparing the compounds of the invention.
Definition of the definition
Unless defined otherwise hereinafter, all technical and scientific terms used herein are intended to be identical to what is commonly understood by one of ordinary skill in the art. References to techniques used herein are intended to refer to techniques commonly understood in the art, including variations of those that are obvious to those skilled in the art or alternatives to equivalent techniques. While the following terms are believed to be well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.
The terms "comprising," "including," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps, although such additional unrecited elements or method steps do not necessarily exist (i.e., the terms "consist essentially of … …" and "consist of … …").
As used herein, the term "alkyl" is defined as a linear or branched saturated aliphatic hydrocarbon. In some embodiments, the alkyl group has 1 to 12, for example 1 to 6 carbon atoms. For example, as used herein, the term "C 1-6 Alkyl "refers to a linear or branched aliphatic hydrocarbon chain having 1-6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl) optionally substituted with one or more (such as 1 to 3) suitable substituents such as halogen (in which case the group is referred to as" haloalkyl ") (e.g., CH) 2 F、CHF 2 、CF 3 、CCl 3 、C 2 F 5 、C 2 Cl 5 、CH 2 CF 3 、CH 2 Cl or-CH 2 CH 2 CF 3 Etc.). The term "C 1-4 Alkyl "refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).
As used herein, the term "heteroalkyl" refers to an optionally substituted alkyl group having one or more backbone chain atoms independently selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, or a combination thereof. Numerical ranges (e.g. C 1-6 Heteroalkyl) refers to the number of carbons in the chain, and in this example is meant to include 1-6 carbon atoms. For example, -CH 2 OCH 2 CH 3 The radical being referred to as C 3 A heteroalkyl group. Linkage to the remainder of the moleculeThrough a heteroatom or carbon atom in the heteroalkyl chain.
As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more (such as 1 to 3) same or different halogen atoms, the term "C 1-8 Haloalkyl "," C 1-6 Haloalkyl groups "and" C 1-4 Haloalkyl "refers to haloalkyl groups having 1 to 8 carbon atoms, 1 to 6 carbon atoms and 1-4 carbon atoms, respectively, such as-CF 3 、-C 2 F 5 、-CHF 2 、-CH 2 F、-CH 2 CF 3 、-CH 2 Cl or-CH 2 CH 2 CF 3 Etc.
As used herein, the term "hydroxyalkyl" refers to a group formed by substitution of a hydrogen atom in an alkyl group with one or more hydroxyl groups, e.g., C 1-4 Hydroxyalkyl or C 1-3 Hydroxyalkyl groups, examples of which include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, -CH (OH) CH 3 Etc.
As used herein, the term "alkoxy" means a group resulting from the insertion of an oxygen atom at any reasonable position in an alkyl group (as defined above), e.g., C 1-8 Alkoxy, C 1-6 Alkoxy, C 1-4 Alkoxy or C 1-3 An alkoxy group. C (C) 1-6 Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, -CH 2 -OCH 3 Etc., optionally substituted with one or more (such as 1 to 3) identical or different substituents. The term "haloalkoxy" as used herein means that the hydrogen atoms of the alkoxy groups are replaced with one or more (such as 1 to 3) identical or different halogen atoms.
As used herein, the term "alkenyl" means a linear or branched monovalent hydrocarbon radical containing one or more double bonds, preferably having 2 to 6 carbon atoms ("C 2-6 Alkenyl "). The alkenyl group being, for example, -ch=ch 2 、-CH 2 CH＝CH 2 、-C(CH 3 )＝CH 2 、-CH 2 -CH＝CH-CH 3 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl. When the compounds of the present invention contain alkenyl groups, the compounds may exist in pure E (ipsilateral (entgegen)) form, pure Z (ipsilateral (zusammen)) form or any mixture thereof.
As used herein, the term "alkynyl" means a monovalent hydrocarbon radical containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, such as ethynyl, 2-propynyl, 2-butynyl, 1, 3-butadiynyl, and the like. The alkynyl group is optionally substituted with one or more (such as 1 to 3) substituents, which may be the same or different.
As used herein, the term "fused ring" or "fused ring" refers to a ring system formed by two or more cyclic structures sharing two adjacent atoms with each other.
As used herein, the term "spiro" refers to a ring system formed by two or more cyclic structures sharing one ring atom with each other.
As used herein, the term "bridged ring" refers to a ring system formed by two or more ring structures sharing two atoms that are not directly connected to each other.
As used herein, the term "cycloalkyl" refers to a saturated or unsaturated, non-aromatic, monocyclic or polycyclic (such as bicyclic) hydrocarbon cyclic group including, but not limited to, monocyclic alkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and the like) and bicyclic alkyl groups including spiro, fused (fused) or bridged ring systems (i.e., spiro alkyl, fused (fused) alkyl, and bridged cycloalkyl groups such as bicyclo [1.1.1 ]]Amyl, bicyclo [2.2.1]Heptyl, etc.). In the present invention, cycloalkyl groups are optionally substituted with one or more (such as 1 to 3) identical or different substituents. The carbon atom on the cycloalkyl group is optionally substituted with an oxo (oxo) group (i.e., forming c=o). The term "C 3-8 Cycloalkyl "means cycloalkyl having 3 to 8 ring-forming carbon atoms, e.g. C 3-6 Cycloalkyl, which may be a monocycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctylMay also be a bicycloalkyl group, e.g. C 5-8 Spirocycloalkyl, C 5-8 Bridged cycloalkyl, C 5-8 Condensed ring alkyl, C 5-6 Spirocycloalkyl, C 5-6 Bridged cycloalkyl or C 5-6 Condensed ring alkyl.
As used herein, the term "cycloalkoxy" means-O-cycloalkyl, wherein cycloalkyl is as defined above. Representative examples of cycloalkoxy groups include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, and the like.
As used herein, the term "heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated aliphatic monocyclic or polycyclic (e.g., a fused, spiro, or bridged) group having 2 or more (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14) carbon atoms, and one or more (e.g., 1, 2, 3, or 4) heteroatoms, including but not limited to oxygen, nitrogen, and sulfur atoms, which are optionally substituted with oxo groups (e.g., to form c= O, S (=o) or S (=o) 2 )。
As used herein, the term "4-10 membered heterocyclyl" means a heterocyclyl containing 4-10 ring atoms including, but not limited to, 5-10 membered heterocyclyl, 4-9 membered heterocyclyl, 4-8 membered heterocyclyl, 4-7 membered heterocyclyl, 5-6 membered heterocyclyl, 3-8 membered heterocyclyl, 3-7 membered heterocyclyl, 4-7 membered nitrogen containing heterocyclyl, 4-7 membered oxygen containing heterocyclyl, 4-7 membered sulfur containing heterocyclyl, 5-6 membered nitrogen containing heterocyclyl, 5-6 membered oxygen containing heterocyclyl, 5-6 membered sulfur containing heterocyclyl, and the like, each of which optionally also contains one or more additional heteroatoms independently selected from oxygen, nitrogen and sulfur. Examples of 4-10 membered heterocyclyl groups include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidinonyl (e.g) Imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl (tr)ithianyl)。
In the present invention, the heterocyclic group may form a fused ring structure with the heterocyclic group or the cycloalkyl group, and the point of attachment of the fused ring structure to the other group may be on any one of the heterocyclic group or the cycloalkyl group, and thus the heterocyclic group of the present invention also includes, but is not limited to, a heterocyclic-heterocyclic group, a heterocyclic-cycloalkyl group, a mono-heterocyclic-mono-heterocyclic group, a mono-heterocyclic-mono-cycloalkyl group, a 3-7-membered (mono) heterocyclic-3-7-membered (mono) heterocyclic group, a 3-7-membered (mono) heterocyclic-mono-cycloalkyl group, a 3-7-membered (mono) heterocyclic-C 4-6 (mono) cycloalkyl examples include, but are not limited to, pyrrolidinyl-cyclopropyl, cyclopentylazacyclopropyl, pyrrolidinyl-cyclobutyl, pyrrolidinyl-pyrrolidinyl, pyrrolidinyl-piperidinyl, pyrrolidinyl-piperazinyl, piperidinyl-morpholinyl.
As used herein, the term "aryl" or "aromatic ring" refers to an all-carbon monocyclic or fused-polycyclic aromatic group having a conjugated pi-electron system. As used herein, the term "C 6-10 Aryl (aromatic ring) "means an aryl group (aromatic ring) containing 6 to 10 carbon atoms, such as phenyl (benzene ring) or naphthyl (naphthalene ring). Aryl groups optionally substituted with one or more (such as 1 to 3) identical or different substituents (e.g. halogen, OH, CN, NO 2 、C 1 -C 6 Alkyl, etc.) substitution.
As used herein, the term "heteroaryl" or "heteroaromatic ring" refers to a monocyclic or polycyclic aromatic group containing one or more heteroatoms, the same or different, including monocyclic heteroaryl groups and bicyclic or polycyclic ring systems containing at least one heteroaromatic ring (an aromatic ring system containing at least one heteroatom), which may have 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, for example 5, 6, 7, 8, 9, or 10 ring atoms. The heteroatom may be oxygen, nitrogen or sulfur.
As used herein, the term "5-10 membered heteroaryl" or "5-10 membered heteroaryl ring" means a heteroaryl group (heteroaryl ring) containing 5 to 10 (e.g., 5 to 6) ring atoms, including 5-10 membered nitrogen-containing heteroaryl, 5-10 membered oxygen-containing heteroaryl, 5-10 membered sulfur-containing heteroaryl, 5-6 membered nitrogen-containing heteroaryl, 5-6 membered oxygen-containing heteroaryl, 5-6 membered sulfur-containing heteroaryl, and the like. The "nitrogen-containing heteroaryl", "oxygen-containing heteroaryl", and "sulfur-containing heteroaryl" each optionally contain one or more additional heteroatoms independently selected from oxygen, nitrogen, and sulfur. Examples include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, and the like, or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and 5-10 membered bicyclic groups containing these groups.
In the present invention, heteroaryl (e.g., mono-heteroaryl) may form a fused ring structure with aryl (e.g., monocyclic aryl, e.g., phenyl), heterocyclyl (e.g., mono-heterocyclyl), cycloalkyl (e.g., monocyclic alkyl), or another heteroaryl (e.g., another mono-heteroaryl) sharing two adjacent atoms with each other, the point of attachment of which may be on any heteroaryl ring or on other rings, including, but not limited to, (mono) heteroarylo (mono) heteroaryl, (mono) heteroaryl (monocyclic) aryl, (mono) heteroaryl (mono) heterocyclyl, and (mono) heteroarylo (mono) cycloalkyl, e.g., 5-6 membered (mono) heteroaryl, 5-6 membered (mono) heteroarylo phenyl, 5-6 membered (mono) heteroaryl 5-6 membered (mono) heterocyclyl, or 5-6 membered (mono) heteroaryl-C 4-6 (mono) cycloalkyl (e.g., 5-6 membered heteroaryl-cyclobutyl, 5-6 membered heteroaryl-cyclopentyl, or 5-6 membered heteroaryl-cyclohexyl), examples of which include, but are not limited to, indolyl, isoindolyl, indazolyl, benzimidazole, quinolinyl, isoquinolinyl, Etc.
As used herein, the term "halo" or "halogen" group is defined to include F, cl, br or I.
The term "substitution" means that one or more (e.g., one, two, three, or four) hydrogens on the designated atom are replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution forms a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
If a substituent is described as "optionally substituted with one or more … …," the substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as optionally substituted with one or more of the list of substituents, one or more hydrogens on the carbon (to the extent any hydrogens are present) may be replaced with an independently selected optional substituent, alone and/or together. If the nitrogen of a substituent is described as optionally substituted with one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent any hydrogens are present) may each be replaced with an independently selected optional substituent.
If substituents are described as "independently selected from" a group, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.
The term "one or more" as used herein means 1 or more than 1, such as 2, 3, 4, 5 or 10, under reasonable conditions.
As used herein, unless indicated, the point of attachment of a substituent may be from any suitable position of the substituent.
When the bond of a substituent is shown as a bond through the ring connecting two atoms, then such substituent may be bonded to any ring-forming atom in the substitutable ring.
The invention also includes all pharmaceutically acceptable isotopically-labelled compounds which are identical to those of the present invention except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevailing in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium @ 2 H) The tritium is 3 H) A) is provided; isotopes of carbon (e.g 11 C、 13 C, C is a metal alloy 14 C) The method comprises the steps of carrying out a first treatment on the surface of the Isotopes of chlorine (e.g 36 Cl); isotopes of fluorine (e.g 18 F) The method comprises the steps of carrying out a first treatment on the surface of the Isotopes of iodine (e.g 123 I, I 125 I) The method comprises the steps of carrying out a first treatment on the surface of the Isotopes of nitrogen (e.g 13 N is N 15 N); isotopes of oxygen (e.g 15 O、 17 O and O 18 O); isotopes of phosphorus (e.g 32 P) is as follows; isotopes of sulfur (e.g 35 S). Certain isotopically-labeled compounds of the present invention (e.g., those into which a radioisotope is incorporated) are useful in pharmaceutical and/or substrate tissue distribution studies (e.g., assays). Radioisotope tritium (i.e 3 H) Carbon-14 (i.e 14 C) Are particularly useful for this purpose because of easy incorporation and easy detection. Using positron-emitting isotopes (e.g 11 C、 18 F、 15 O and O 13 N) substitution can be used in Positron Emission Tomography (PET) studies to examine substrate receptor occupancy. Isotopically-labeled compounds of the present invention can be prepared by processes analogous to those described in the accompanying schemes and/or in the examples and preparations by substituting an appropriate isotopically-labeled reagent for the non-labeled reagent previously employed. Pharmaceutically acceptable solvates of the invention include those in which the crystallization solvent may be isotopically substituted, e.g., D 2 O, acetone-d 6 Or DMSO-d 6 。
The term "stereoisomer" refers to an isomer formed as a result of at least one asymmetric center. In compounds having one or more (e.g., one, two, three, or four) asymmetric centers, they can produce racemic mixtures, single enantiomers, diastereomeric mixtures, and individual diastereomers. Specific individual molecules may also exist as geometric isomers (cis/trans). Similarly, the compounds of the invention may exist as a mixture of two or more structurally distinct forms (commonly referred to as tautomers) in rapid equilibrium. Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. For example, nitroso-oximes may exist in solution in equilibrium in the following tautomeric forms:
It is to be understood that the scope of the present application encompasses all such isomers in any ratio (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%) or mixtures thereof.
Solid lines may be used hereinWedge shaped->Or virtual wedge +.>Depicting the chemical bond of the compounds of the present application. The use of a solid line to depict a bond to an asymmetric carbon atom is intended to indicate that all possible stereoisomers at that carbon atom (e.g., particular enantiomers, racemic mixtures, etc.) are included. The use of a solid or virtual wedge to depict a bond to an asymmetric carbon atom is intended to indicate the presence of the stereoisomers shown. When present in a racemic mixture, real and imaginary wedges are used to define the relative stereochemistry, not the absolute stereochemistry. Unless otherwise indicated, the compounds of the present application are intended to exist as stereoisomers (which include cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotamers, conformational isomers, atropisomers, and mixtures thereof). The compounds of the present application may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).
The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of any ratio of more than one polymorphs.
Eutectic refers to pharmaceutically active molecules bound in the same lattice with other physiologically acceptable acids, bases, salts, nonionic compounds by hydrogen bonding, pi-pi stacking, van der Waals forces, and other noncovalent bonds.
It will also be appreciated that certain compounds of the invention may exist in free form for use in therapy or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites or prodrugs which, upon administration to a patient in need thereof, are capable of providing the compounds of the invention or metabolites or residues thereof, either directly or indirectly. Thus, when reference is made herein to "a compound of the invention" it is also intended to encompass the various derivative forms of the compounds described above.
Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof. Such as hexafluorophosphate, meglumine salt, and the like. For a review of suitable salts, see Stahl and Wermuth, "Handbook of Pharmaceutical Salts: properties, selection, and Use" (Wiley-VCH, 2002).
As used herein, the term "ester" means an ester derived from each of the compounds of the general formula in the present application, including physiologically hydrolyzable esters (compounds of the present application that can be hydrolyzed under physiological conditions to release the free acid or alcohol form). The compounds of the application may themselves be esters.
The compounds of the present application may exist in the form of solvates (e.g., hydrates) wherein the compounds of the present application comprise a polar solvent, such as water, methanol or ethanol, as a structural element of the compound lattice. The polar solvent, in particular water, may be present in stoichiometric or non-stoichiometric amounts.
Those skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming N-oxides because nitrogen requires available lone pairs to oxidize to oxides. Those skilled in the art will recognize nitrogen-containing heterocycles capable of forming N-oxides. Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include, but are not limited to, oxidizing heterocycles and tertiary amines with peroxyacids such as peroxyacetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl hydrogen peroxide such as t-butyl hydroperoxide, sodium perborate, and dioxiranes (dioxiranes) such as dimethyl dioxirane. These methods for preparing N-oxides have been widely described and reviewed in the literature, see for example: T.L. Gilchrist, comprehensive Organic Synthesis, vol.7, pp 748-750; katritzky and a.j. Boulton, eds., academic Press; and G.W.H.Cheeseman and E.S.G.Werstiuk, advances in Heterocyclic Chemistry, vol.22, pp 390-392, A.R.Katritzky and A.J.Boulton, eds., academic Press.
Also included within the scope of the invention are metabolites of the compounds of the invention, i.e., substances that form in vivo upon administration of the compounds of the invention. Such products may result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the compound being administered. Accordingly, the present invention includes metabolites of the compounds of the present invention, including compounds made by a process of contacting a compound of the present invention with a mammal for a time sufficient to produce the metabolites thereof.
The invention further includes within its scope prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention which may themselves have little or no pharmacological activity, which, when administered into or onto the body, may be converted into the compounds of the invention having the desired activity by, for example, hydrolytic cleavage. Typically such prodrugs will be functional derivatives of the compounds which are readily convertible in vivo into the desired therapeutically active compound. Additional information regarding the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", vol.14, ACS Symposium Series (T.Higuchi and V.stilla). Prodrugs of the invention may be prepared, for example, by replacing the appropriate functional groups present in the compounds of the invention with certain moieties known to those skilled in the art as "pro-moieties" (e.g. "Design of Prodrugs", described in h. Bundegaard (Elsevier, 1985) ".
The invention also encompasses compounds of the invention containing a protecting group. During any process for preparing the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules of interest, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting groups, for example those described in T.W.Greene & P.G.M.Wuts, protective Groups in Organic Synthesis, john Wiley & Sons,1991, which references are incorporated herein by reference. The protecting group may be removed at a suitable subsequent stage using methods known in the art.
The term "about" means within + -10%, preferably within + -5%, more preferably within + -2% of the stated value.
Compounds of formula (I)
In some embodiments, the invention provides a compound of formula I, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, isotopically-labeled compound, N-oxide, or prodrug thereof:
wherein:
ring A is a 4-10 membered heterocyclyl;
W 1 、W 2 and W is 3 Each independently selected from N and CR 4 ；
L 1 Selected from-NR 5 -C(＝O)-、-C(＝O)-NR 5 -and-NR 5 -；
R 1 Selected from C 6-10 Aryl and 5-10 membered heteroaryl, wherein each of said aryl and heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of: -NHR 6 Hydroxy, halogen, CN, NO 2 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkoxy, C 1-6 Heteroalkyl (e.g. C 1-6 Alkoxy group), C 3-6 Cycloalkyl and 4-10 membered heterocyclyl; alternatively, optionally two adjacent substituents together with the atom to which they are attached form a 5-10 membered heterocyclic group, said 5-10 membered heterocyclic group optionally being substituted with one or more independently selected substituentsIn situ selected from CN, hydroxy, halogen, oxo and C 1-6 Substituent substitution of alkyl;
R 2 and R is 4 Each at each occurrence is independently selected from H, CN, hydroxy, halogen, C 1-6 Alkyl and C 1-6 Alkoxy, wherein each of the alkyl and alkoxy groups is optionally substituted with one or more halogens;
R 3 is L 3 -R 3 ’；
L 3 Each occurrence is independently a direct bond or- (CH) 2 ) n -；
R 3 ' each occurrence is independently selected from H, hydroxy, halogen, CN, NO 2 、C 1-6 Alkyl, C 1-6 Heteroalkyl (e.g. C 1-6 Alkoxy group), C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, -NR 20a R 20b 、-SR 21 、-S(＝O)R 22 、-S(＝O) 2 R 22 、-S(＝O)NR 20a R 20b 、-S(＝O) 2 NR 20a R 20b 、-NR 20a S(＝O)R 20b 、-NR 20a S(＝O) 2 R 20b 、-C(＝O)R 21 、-C(＝O)NR 23a R 23b 、-NR 23a C(＝O)R 23b and-NR 24a C(＝O)NR 25a R 25b Wherein each of the alkyl, heteroalkyl (e.g., alkoxy), alkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of: hydroxy, halogen, CN, NO 2 、C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkoxy, C 1-4 Heteroalkyl (e.g. C 1-4 Alkoxy group), C 3-6 Cycloalkyl and 4-10 membered heterocyclyl;
R 5 and R is 6 Each at each occurrence is independently selected from H, C 1-6 Alkyl, C 3-8 Cycloalkyl and 4-10 memberedA heterocyclyl, wherein each of the alkyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more halo;
R 20a 、R 20b 、R 23a 、R 23b 、R 24a 、R 25a and R is 25b Each independently selected from H, OH, -NHCH 3 、-N(CH 3 ) 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl and 4-10 membered heterocyclyl; wherein each of said alkyl, alkoxy, cycloalkyl and heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of: halogen, C 1-6 Alkyl and 4-10 membered heterocyclyl;
R 21 and R is 22 Each independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl and 4-10 membered heterocyclyl, wherein each of said alkyl, alkoxy, cycloalkyl and heterocyclyl is optionally substituted with one or more halo;
m is 1, 2, 3, 4 or 5; and is also provided with
n is 1, 2 or 3.
In certain embodiments, L 1 is-C (=O) -NR 5 -or-NR 5 -C(＝O)-，R 5 Selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl and 4-6 membered heterocyclyl, wherein each of said alkyl, cycloalkyl and heterocyclyl is optionally substituted with one or more halo.
In certain embodiments, L 1 is-C (=O) -NR 5 -or-NR 5 -C(＝O)-，R 5 Selected from H and C 1-4 An alkyl group.
In certain embodiments, L 1 is-C (=O) -NH-or-NH-C (=O) -.
In some embodiments, the compounds of the present invention have the structure shown in formula I-A:
wherein:
R 1 、R 2 、R 3 、W 1 、W 2 and W is 3 As defined in formula I above;
ring A is a 4-10 membered heterocyclyl; and is also provided with
m is 1, 2 or 3.
In certain embodiments, the invention provides for formulas I and I-A wherein ring A is a 4-6 membered heterocyclyl.
In certain embodiments, the present invention provides for formulas I and I-a, wherein ring a is a 5 membered heterocyclyl; preferably, ring A is selected fromAnd->
In certain embodiments, the invention provides compounds of formula I and formula I-A, W 1 、W 2 And W is 3 Each independently selected from N, CF and CH.
In certain embodiments, the invention provides compounds of formula I and formula I-A, W 1 、W 2 And W is 3 Are CH.
In certain embodiments, the invention provides compounds of formula I and formula I-A, R 1 Selected from phenyl, naphthyl, and 5-10 membered heteroaryl, wherein each of the phenyl, naphthyl, and heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of: -NHR 6 Hydroxy, halogen, CN, NO 2 、C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkoxy, C 1-4 Heteroalkyl (e.g. C 1-4 Alkoxy group), C 3-6 Cycloalkyl and 4-10 membered heterocyclyl; alternatively, optionally two adjacent substituents together with the atom to which they are attached form a 5-8 membered heterocyclic group, said 5-8 membered heterocyclic group optionally being substituted with one or more groups independently selected from CN, hydroxy, halo, oxo and C 1-4 The substituent of the alkyl group is substituted.
In certain embodiments, the invention provides compounds of formula I and formula I-A, R 1 Selected from phenyl, naphthyl, pyridyl, pyrazolyl, thiazolyl,Pyrimidinyl and 9-10 membered fused ring heteroaryl, wherein the phenyl, naphthyl, pyridinyl, pyrazolyl, thiazolyl, pyrimidinyl and 9-10 membered fused ring heteroaryl are each optionally substituted with one or more substituents independently selected from the group consisting of: -NHR 6 Hydroxy, halogen, CN, NO 2 、C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkoxy, C 1-4 Heteroalkyl (e.g. C 1-4 Alkoxy group), C 3-6 Cycloalkyl and 4-10 membered heterocyclyl; alternatively, optionally two adjacent substituents together with the atom to which they are attached form a 6 membered heterocyclyl, optionally substituted with one or more groups independently selected from CN, hydroxy, halo, oxo and C 1-4 The substituent of the alkyl group is substituted.
In certain embodiments, the invention provides compounds of formula I and formula I-A, R 1 Selected from phenyl, naphthyl, pyridinyl, pyrazolyl, thiazolyl, pyrimidinyl, and 9-10 membered fused ring heteroaryl, wherein each of said phenyl, naphthyl, pyridinyl, pyrazolyl, thiazolyl, pyrimidinyl, and 9-10 membered fused ring heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of: -NHR 6 Hydroxy, C 1-4 An alkyl group; alternatively, optionally two adjacent substituents together with the atom to which they are attached form a 6 membered heterocyclyl, optionally substituted with one or more substituents independently selected from oxo and C 1-4 The substituent of the alkyl group is substituted.
In certain embodiments, the invention provides compounds of formula I and formula I-A, R 1 Selected from the group consisting of Andwherein said-> And->Each optionally substituted with one or more substituents independently selected from the group consisting of: hydroxy, halogen, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkoxy, C 1-4 Heteroalkyl (e.g. C 1-4 Alkoxy group), C 3-6 Cycloalkyl and 4-10 membered heterocyclyl.
In a preferred embodiment, the invention provides compounds of formula I and formula I-A, R 1 Selected from the group consisting of And->Wherein said->/>And->Each optionally substituted with one or more substituents independently selected from the group consisting of: hydroxy, halogen, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkoxy, C 1-4 Heteroalkyl (e.g. C 1-4 Alkoxy group), C 3-6 Cycloalkyl and 4-10 membered heterocyclyl.
In certain embodiments, the invention provides compounds of formula I and formula I-A, R 6 Independently selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl radicalsAnd 4-6 membered heterocyclyl, wherein each of said alkyl, cycloalkyl and heterocyclyl is optionally substituted with one or more halo; preferably, R 6 H.
In a preferred embodiment, the invention provides compounds of formula I and formula I-A, R 1 Selected from the group consisting of And->
In certain embodiments, the invention provides compounds of formula I and formula I-A, R 2 Selected from H, CN, halogen, C 1-4 Alkyl and C 1-4 Alkoxy, wherein each of the alkyl and alkoxy groups is optionally substituted with one or more halogens; preferably, R 2 Is H or C 1-4 An alkyl group; more preferably, R 2 Is H or methyl.
In certain embodiments, the invention provides compounds of formula I and formula I-A, L 3 Each occurrence is independently a direct bond or-CH 2 -。
In certain embodiments, the invention provides compounds of formula I and formula I-A, R 3 ' each occurrence is independently selected from H, hydroxy, halogen, CN, C 1-4 Alkyl, C 1-4 Heteroalkyl (e.g. C 1-4 Alkoxy group), C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, -NR 20a R 20b 、-SR 21 、-S(＝O)R 22 、-S(＝O) 2 R 22 、-S(＝O)NR 20a R 20b 、-S(＝O) 2 NR 20a R 20b 、-NR 20a S(＝O)R 20b 、-NR 20a S(＝O) 2 R 20b 、-C(＝O)R 21 、-C(＝O)NR 23a R 23b 、-NR 23a C(＝O)R 23b and-NR 24a C(＝O)NR 25a R 25b Wherein each of the alkyl, heteroalkyl (e.g., alkoxy), cycloalkyl, cycloalkoxy, heterocyclyl, phenyl, and heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of: hydroxy, halogen, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkoxy, C 1-4 Heteroalkyl (e.g. C 1-4 Alkoxy group), C 3-6 Cycloalkyl and 4-10 membered heterocyclyl.
In certain embodiments, the invention provides compounds of formula I and formula I-A, R 3 ' each occurrence is independently selected from H, halogen, C 1-4 Alkyl and C 1-4 Alkoxy, wherein the alkyl and alkoxy groups are optionally substituted with one or more halogens or cyano groups.
In certain embodiments, the invention provides compounds of formula I and formula I-A, R 3 ' each occurrence is independently selected from C 1-4 Alkyl and C 1-4 Alkoxy, wherein the alkyl and alkoxy groups are optionally substituted with one or more halogens.
In certain embodiments, the invention provides compounds of formula I and formula I-A, R 3 ' are independently selected at each occurrence from H, F, cl, -CH 3 、-CH 2 CF 3 、-CH 2 CN、-CF 3 and-OCF 3 。
In certain embodiments, the invention provides compounds of formula I and formula I-A, R 3 ' each occurrence is independently selected from-CH 2 CF 3 、-CF 3 and-OCF 3 。
In certain embodiments, the invention provides compounds of formula I and formula I-A, R 3 Each at each occurrence is independently selected from H, F, cl, -CH 3 、-CH 2 CF 3 、-CH 2 CN、-CF 3 and-OCF 3 。
In certain embodiments, the invention provides compounds of formula I and formula I-A, R 3 Each at each occurrence is independently selected from-CH 2 CF 3 、-CF 3 and-OCF 3 。
In certain embodiments, R 20a 、R 20b 、R 23a 、R 23b 、R 24a 、R 25a And R is 25b Each independently selected from H, C 1-6 Alkyl, C 3-8 Cycloalkyl and 4-10 membered heterocyclyl; the alkyl, cycloalkyl and heterocyclyl groups are each optionally substituted with one or more substituents independently selected from the group consisting of: halogen, C 1-6 Alkyl and 4-10 membered heterocyclyl.
In certain embodiments, R 20a 、R 20b 、R 23a 、R 23b 、R 24a 、R 25a And R is 25b Each independently selected from H, C 1-4 Alkyl and C 3-6 Cycloalkyl, wherein each of the alkyl and cycloalkyl groups is optionally substituted with one or more halogens.
In certain embodiments, R 21 And R is 22 Each independently selected from C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl and 4-6 membered heterocyclyl, wherein each of said alkyl, alkoxy, cycloalkyl and heterocyclyl is optionally substituted with one or more halo.
In certain embodiments, m is 1, 2, or 3.
In certain embodiments, n is 1 or 2.
In certain embodiments, the present invention provides compounds of formula I and formula I-A,
Ring A is a 4-10 membered heterocyclyl;
W 1 、W 2 and W is 3 Each independently selected from N, CF and CH;
L 1 is-NH-C (=o) -or-C (=o) -NH-;
R 1 selected from phenyl, naphthyl, and 5-10 membered heteroaryl, wherein each of the phenyl, naphthyl, and heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of: -NHR 6 Hydroxy, halogen, CN, NO 2 、C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkoxy, C 1-4 Heteroalkyl (e.g. C 1-4 Alkoxy group), C 3-6 Cycloalkyl and 4-a 10 membered heterocyclyl; alternatively, optionally two adjacent substituents together with the atom to which they are attached form a 5-8 membered heterocyclic group, said 5-8 membered heterocyclic group optionally being substituted with one or more groups independently selected from CN, hydroxy, halo, oxo and C 1-4 Substituent substitution of alkyl;
R 6 selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl and 4-6 membered heterocyclyl, wherein each of said alkyl, cycloalkyl and heterocyclyl is optionally substituted with one or more halo;
R 2 is H or C 1-4 An alkyl group;
R 3 is L 3 -R 3 ’；
L 3 Each occurrence is independently a direct bond or- (CH) 2 ) n -；
R 3 ' each occurrence is independently selected from H, halogen, C 1-4 Alkyl and C 1-4 Alkoxy, wherein the alkyl and alkoxy groups are optionally substituted with one or more halo or cyano groups;
m is 1, 2 or 3;
n is 1, 2 or 3.
In certain embodiments, the present invention provides compounds of formula I and formula I-A,
ring A is a 4-6 membered heterocyclyl;
W 1 、W 2 and W is 3 Each independently selected from N, CF and CH;
L 1 is-NH-C (=o) -or-C (=o) -NH-;
R 1 selected from the group consisting of And->
R 6 Independently at each occurrence selected from H and C 1-4 Alkyl group；
R 2 Is H or C 1-4 An alkyl group;
R 3 is L 3 -R 3 ’；
L 3 Each occurrence is independently a direct bond, -CH 2 -or-CH 2 CH 2 -；
R 3 ' each occurrence is independently selected from H, halogen, C 1-4 Alkyl and C 1-4 Alkoxy, wherein the alkyl and alkoxy groups are optionally substituted with one or more halo or cyano groups;
m is 1, 2 or 3.
In certain embodiments, the present invention provides compounds of formula I and formula I-A,
ring a is a 5 membered heterocyclyl;
W 1 、W 2 and W is 3 Each is CH;
L 1 is-C (=o) -NH-;
R 1 selected from the group consisting ofAnd->
R 2 Is H or methyl;
R 3 is L 3 -R 3 ’；
L 3 Each occurrence is independently a direct bond;
R 3 ' each occurrence is independently selected from-CH 2 CF 3 、-CF 3 and-OCF 3 ；
m is 1, 2 or 3.
In some embodiments, the compounds of the present invention have the structure shown in formula I-B:
wherein:
R 1 、R 2 、R 3 and ring A is as defined above for formula I or formula I-A; m is 1, 2 or 3.
In some embodiments, the compounds of the present invention have the structure shown in formulas I-C:
Wherein:
R 1 、R 2 、R 3 as defined above for formula I or formula I-A; m is 1, 2 or 3;represents a single bond or a double bond.
The invention encompasses any combination of the above embodiments.
In some embodiments, compounds of the invention include, but are not limited to:
preparation method
In certain embodiments, the present invention provides a process for preparing a compound of formula I-a comprising the steps of:
route A
Wherein:
ring A, R 1 、R 2 、R 3 、W 1 、W 2 、W 3 And m is as defined above for formula I-A。
The first step: the compound I-A-1 and the compound I-A-2 are subjected to condensation reaction to generate a compound I-A-3;
the condensation reaction is preferably carried out in the presence of a condensing agent and a base. Condensing agents which may be used are T 3 P, HATU, CDI, HOBt, DMAP, DCC, DIC, EDC, HBTU, HCTU or PyBOP, etc. The base is pyridine, TEA, DIPEA, t BuOK、 t BuONa、 t BuOLi、NaH、NaOH、Cs 2 CO 3 、K 3 PO 4 Or Na (or) 2 CO 3 Etc. Useful solvents are pyridine, THF, DCM, DCE, meOH, etOH, DMF, DMSO, acetone, CH 3 CN, 1, 4-dioxane, toluene, etc. The reaction temperature is from 0℃to 120℃such as room temperature.
Or preparing the compound I-A-1 into acyl halide, and using acyl halide reagent such as thionyl chloride, oxalyl chloride, etc. The reaction can be carried out under the catalysis of a small amount of DMF or in a system without DMF; the reaction temperature is 0 ℃ to 120 ℃; the acid halide compound is reacted with the compound I-A-2 in the presence of alkali to produce the compound I-A-3. Useful bases are TEA or DIPEA, etc.; useful solvents are THF, DCM, DCE, CH 3 CN, 1, 4-dioxane, toluene, or the like; the reaction may be carried out at 0℃to 120 ℃.
In some embodiments, when R in compound I-A-1 1 When the amino group is contained, the compound I-A-1 needs to be subjected to amino protection (available amino protecting groups are p-methoxybenzyl, 2, 4-dimethoxybenzyl and the like, the conditions of the upper protecting groups are PMB-Cl/NaH/DMF/rt, for example), then the reaction is carried out according to the steps one to four in the scheme A, the product obtained by the reaction in the step four is subjected to deprotection to obtain the compound I-A, and the deprotection usable conditions are TFA/80 ℃ or concentrated hydrochloric acid/80 ℃.
And a second step of: the compound I-A-3 is subjected to reduction reaction to generate a compound I-A-4;
the reducing agent that can be used for the reduction reaction is, for example, zinc powder/acetic acid, iron powder/ammonium chloride solution, iron powder/hydrochloric acid solution, palladium carbon/hydrogen gas, etc.; solvents which can be used are, for example, water, ethanol, methanol or mixtures thereof, etc.; the reaction temperature is 0℃to 90℃such as room temperature, 60℃70℃80℃or 90 ℃.
And a third step of: reacting the compound I-A-4 with triphosgene to generate a compound I-A-5;
solvents usable for the reaction are, for example, THF, DCM or toluene. The reaction temperature is from 0℃to 80℃such as room temperature.
Fourth step: reacting the compound I-A-5 with the compound I-A-6 to generate a compound I-A;
the reaction is preferably carried out in the presence of a base. Useful bases are, for example, DIPEA, TEA, pyridine, or the like. Useful solvents are, for example, toluene, THF, DCM or 1, 4-dioxane etc. The reaction temperature is from 0℃to 120℃such as 100 ℃.
Pharmaceutical compositions, formulations and methods of treatment
In some embodiments, the invention provides pharmaceutical compositions comprising a prophylactically or therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, isotopically-labeled compound, N-oxide, or prodrug thereof, and one or more pharmaceutically acceptable carriers.
In some embodiments, the present invention provides a pharmaceutical formulation, preferably a solid formulation, a semi-solid formulation, a liquid formulation, or a gaseous formulation.
In some embodiments, the pharmaceutical composition or pharmaceutical formulation may further comprise one or more other therapeutic agents.
In some embodiments, the pharmaceutical composition or pharmaceutical formulation may be administered by oral, intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular, or transdermal routes.
In some embodiments, the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, isotopically labeled compound, N-oxide, or prodrug thereof, or a pharmaceutical composition of the invention, or a pharmaceutical formulation of the invention, in the manufacture of a medicament for the prevention or treatment of a disease or condition associated with RAF and/or RAS kinase activity.
In some embodiments, the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, isotopically labeled compound, N-oxide, or prodrug thereof, or a pharmaceutical composition of the invention, or a pharmaceutical formulation of the invention, in the manufacture of a medicament for modulating (e.g., reducing or inhibiting) the activity of RAF and/or RAS kinase.
In some embodiments, the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, isotopically labeled compound, N-oxide, or prodrug thereof, or a pharmaceutical composition of the invention, or a pharmaceutical formulation of the invention, for use in the prevention or treatment of a disease or condition associated with RAF and/or RAS kinase activity.
In some embodiments, the invention provides a method of preventing or treating a disease or condition associated with RAF and/or RAS kinase activity, the method comprising administering to a subject in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, isotopically labeled compound, N-oxide, or prodrug thereof, or a pharmaceutical composition of the invention, or a pharmaceutical formulation of the invention.
In some embodiments, the disease or condition associated with RAF and/or RAS kinase activity is a cancer or tumor.
In some embodiments, the cancer or tumor is lung cancer (e.g., non-small cell lung cancer), breast cancer, ovarian cancer, gastric cancer, liver cancer, kidney cancer, bone cancer, colorectal cancer, pancreatic cancer, head and neck cancer, uterine cancer, esophageal cancer, thyroid cancer, bladder cancer, blood cancer, lymphoma, multiple myeloma, melanoma, glioma, brain tumor, or sarcoma.
In some embodiments, the cancer or tumor is lung cancer (e.g., non-small cell lung cancer), liver cancer, breast cancer, ovarian cancer, colorectal cancer, pancreatic cancer, melanoma, glioma, brain tumor, or sarcoma.
By "pharmaceutically acceptable carrier" is meant a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered, and which is suitable for contacting the tissues of humans and/or other animals within the scope of sound medical judgment without undue toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.
Pharmaceutically acceptable carriers that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).
The pharmaceutical compositions of the present invention may act systematically and/or locally. For this purpose, they may be administered by a suitable route.
For these routes of administration, the pharmaceutical compositions of the present invention may be administered in suitable dosage forms.
The term "effective amount" as used herein refers to the amount of a compound that, upon administration, will alleviate to some extent one or more symptoms of the disorder being treated.
The dosing regimen may be adjusted to provide the best desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the doses may be proportionally reduced or increased as indicated by the urgent need for a therapeutic situation. It is noted that the dosage value may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is further understood that for any particular individual, the particular dosage regimen will be adjusted over time according to the individual needs and the professional judgment of the person administering or supervising the administration of the compositions.
The amount of the compound of the invention administered will depend on the severity of the individual, disorder or condition being treated, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. Generally, an effective dose is about 0.0001 to about 50mg per kg body weight per day. In some cases, dosage levels not higher than the lower limit of the aforementioned range may be sufficient, while in other cases larger doses may still be employed without causing any adverse side effects, provided that the larger dose is first divided into several smaller doses for administration throughout the day.
The compounds of the present invention may be present in the pharmaceutical composition or pharmaceutical formulation in an amount or amount of about 0.01mg to about 1000mg.
As used herein, unless otherwise indicated, the term "treating" means reversing, alleviating, inhibiting the progression of a disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.
The term "preventing" refers to administration to a subject not suffering from a disease to prevent the occurrence of the disease or delay the occurrence or reduce the severity of one or more symptoms of the disorder or condition.
As used herein, "individual" includes human or non-human animals. Exemplary human individuals include human individuals (referred to as patients) or normal individuals suffering from a disease (e.g., a disease described herein). "non-human animals" in the context of the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).
Detailed Description
Examples
The invention is further described below in connection with examples, which are not intended to limit the scope of the invention.
Abbreviations used herein have the following meanings:
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the compounds of the present invention are isolated and purified by preparative TLC, silica gel column chromatography, prep-HPLC and/or Flash column chromatography (Flash column chromatography), the structure of which is described by 1 H NMR and/or MS. Reaction monitoring was performed by TLC or LC-MS.
The separation method comprises the following steps: prep-HPLC purification of the compounds in the examples was carried out using either Aglient type 1260 or Waters 2489 HPLC, separation column model Waters SunFire Prep C 18 OBD(19mm×150mm×5.0μm)、Waters Xbridge Prep C 18 OBD (19 mm. Times.150 mm. Times.5.0 μm) or YMC Actus Triart C 18 (20 mm. Times.150 mm. Times.5.0 μm), the column temperature is 25 ℃, the detection wavelength is 214nm, 254nm or 280nm, the mobile phase A is acetonitrile, the mobile phase B is 0.05% formic acid aqueous solution or 0.05% ammonium bicarbonate aqueous solution or 0.05% TFA aqueous solution, and the volume ratio of the mobile phase is adjusted according to the polarity of the compound; the mobile phase flow rate was 28mL/min.
1 H NMR spectroscopy used a Bruker superconducting nuclear magnetic resonance spectrometer (model AVACE III HD MHz).
LC/MS used Aglient 1260 info/Aglient 6120 Quadrapol.
TLC uses silica gel GF 254 as the stationary phase.
Column chromatography generally uses 200-300 mesh silica gel (Qingdao ocean) as the stationary phase.
Flash column chromatography using a Biotage flash column chromatograph.
Prep-HPLC employed Agilent type 1260 and Waters 2489.
The microwave reaction was performed using a BiotageInitiator microwave reactor.
In the examples below, the temperature of the reaction was room temperature (15-30 ℃ C.) unless otherwise specified.
The reagents used in the present application are available from Acros Organics, aldrich Chemical Company or tertbe chemistry, among others.
Example 1: 4-amino-N- (2-methyl-5- (3- (trifluoromethyl) pyrrolidine-1-carboxamide) phenyl) quinazoline-8-carboxamide (Compound 1)
The first step: preparation of 8-bromoquinazolin-4 (3H) -one (Compound 1 b)
Compound 1a (1.0 g,4.63 mmol) was added to formamide (15 mL), and the mixture was heated to 135℃for 2 hours under nitrogen. After the reaction, a large amount of solid was precipitated, diluted with 60mL of water, filtered under reduced pressure, and the cake was washed with clean water, and the obtained solid was dried under reduced pressure at 50℃to give Compound 1b (800 mg). MS m/z (ESI): 224.9[ M+H ]] + 。
And a second step of: preparation of methyl 4-oxo-3, 4-dihydroquinazoline-8-carboxylate (Compound 1 c)
Into an autoclave were charged compound 1b (780 mg,3.47 mmol), TEA (1.75 g,17.33mmol,2.41 mL), pd (dppf) Cl 2 DCM (283.05 mg, 346.60. Mu. Mol) and MeOH (25 mL), after sealing, carbon monoxide was introduced to 1.0-1.2MPa and then heated to 120℃for reaction for 5 hours. After the reaction was completed, 60mL of water was added for dilution, filtration under reduced pressure, the cake was washed with clear water, and the obtained solid was dried under reduced pressure at 50 ℃. Then, the mixture was slurried with methanol (5 mL), and the mixture was suction-filtered and dried to obtain Compound 1c (400 mg). MS m/z (ESI): 205.0[ M+H ]] + 。
And a third step of: preparation of methyl 4- ((2, 4-dimethoxybenzyl) amino) quinazoline-8-carboxylate (Compound 1 e)
Compound 1c (430.0 mg,2.11 mmol) and BOP (558.8 mg,2.74 mmol) were dissolved in DMF (10 mL), then DBU (1.06 g,4.21mmol,1.04 mL) was added dropwise, after stirring for 10min, compound 1d (528.19 mg,3.16mmol, 474.56. Mu.L) was added, then stirring for 16 hours at 25℃and after LC-MS monitored the completion of the reaction of the starting materials, water quench reaction was added, EA extraction was performed three times, the organic phases were combined, washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 1e (560 mg,1.61 mmol). MS m/z (ESI): 354.1[ M+H ]] + 。
Fourth step: preparation of 4- ((2, 4-dimethoxybenzyl) amino) quinazoline-8-carboxylic acid (compound 1 f)
Compound 1e (570 mg,1.61 mmol) was dissolved in THFTo (15 mL) and MeOH (5 mL) were added an aqueous solution of sodium hydroxide (193.56 mg,4.84 mmol) (5 mL), stirred at 25℃for 16 hours, after the completion of the reaction of the starting materials was monitored by LC-MS, the solvent was removed under reduced pressure, 20mL of water was added to dissolve the resulting solid residue, EA was washed 2 times, the pH of the aqueous phase was adjusted to about 3 with 2M hydrochloric acid, concentrated under reduced pressure, the resulting solid residue was dissolved in methanol, insoluble solids were filtered off, and the filtrate was concentrated to give compound 1f (460 mg). MS m/z (ESI): 340.1[ M+H ] ] + 。
Fifth step: preparation of 4- ((2, 4-dimethoxybenzyl) amino) -N- (2-methyl-5-nitrophenyl) quinazoline-8-carboxamide (Compound 1 h)
Compound 1f (150.00 mg, 442.03. Mu. Mol) was dissolved in 1g (67.25 mg, 442.03. Mu. Mol) of N, N-dimethylformamide (5 mL), followed by addition of HATU (201.69 mg, 530.43. Mu. Mol) and N, N-diisopropylethylamine (114.26 mg, 884.06. Mu. Mol), and after completion of the addition, the temperature was raised to 60℃for 14 hours. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with water 3 times, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by flash column chromatography on silica gel (100% dcm) to give compound 1h (180 mg). MS m/z (ESI): 474.0[ M+H ]] + 。
Sixth step: preparation of N- (5-amino-2-methylphenyl) -4- ((2, 4-dimethoxybenzyl) amino) quinazoline-8-carboxamide (Compound 1 i)
Compound 1h (180 mg, 380.16. Mu. Mol) was added to ethanol (10 mL) and water (2 mL), and iron powder (212.32 mg,3.80 mmol) and ammonium chloride (40.67 mg, 760.33. Mu. Mol) were added and reacted at 80℃for 3 hours after the addition. After completion of the reaction, the mixture was filtered, the filtrate was diluted with water, extracted 3 times with EA, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give Compound 1i (150 mg). MS m/z (ESI): 444.0[ M+H ] ] + 。
Seventh step: preparation of 4- ((2, 4-dimethoxybenzyl) amino) -N- (5-isocyanato-2-methylphenyl) quinazoline-8-carboxamide (Compound 1 j)
Compound 1i (150.00 mg, 338.22. Mu. Mol) was dissolved in anhydrous tetrahydrofuran (6 mL), followed by addition of triphosgene (200.73 mg, 676.44. Mu. Mol) and reaction at 25℃for 2 hours. After the completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed 3 times with a saturated aqueous sodium hydrogencarbonate solution, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give compound 1j (158 mg).
Eighth step: preparation of 4- ((2, 4-dimethoxybenzyl) amino) -N- (2-methyl-5- (3- (trifluoromethyl) pyrrolidine-1-carboxamide) phenyl) quinazoline-8-carboxamide (Compound 1 l)
To the flask were added compound 1j (40 mg, 85.20. Mu. Mol), 1k hydrochloride (23 mg, 127.80. Mu. Mol), DIPEA (22 mg, 170.40. Mu. Mol) and toluene (5 mL) in this order, and the mixture was reacted at 95℃for 16hr under nitrogen. After the reaction was completed, 60mL of water was added to dilute, extracted with EA, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated, and the crude product was purified by silica gel flash column chromatography (DCM: meoh=97:3) to give compound 1l (45 mg). MS m/z (ESI): 609.0[ M+H ]] + 。
Ninth step: preparation of 4-amino-N- (2-methyl-5- (3- (trifluoromethyl) pyrrolidine-1-carboxamide) phenyl) quinazoline-8-carboxamide (Compound 1)
Compound 1l (45 mg, 73.94. Mu. Mol) was dissolved in TFA (3 mL) and reacted at 80℃for 2hr under nitrogen. After the completion of the reaction, 60mL of water was added for dilution, the pH was adjusted to 7-8 with saturated sodium bicarbonate solution, the mixture was extracted with EA, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by Pre-HPLC to give compound 1 (13 mg). MS m/z (ESI): 459.0[ M+H ]] + 。
1 H NMR(400MHz,DMSO-d 6 )δ13.55(s,1H),8.73(dd,J＝7.6,1.6Hz,1H),8.63(s,1H),8.51(dd,J＝8.4,1.6Hz,1H),8.46(d,J＝2.0Hz,1H),8.44–8.32(m,2H),8.25(br,1H),7.71(t,J＝8.0Hz,1H),7.32(dd,J＝8.4,2.4Hz,1H),7.14(d,J＝8.4Hz,1H),3.75–3.68(m,1H),3.62–3.47(m,4H),2.42(s,3H),2.25–2.17(m,1H),2.08–1.99(m,1H).
Example 2: 4-amino-N- (2-methyl-5- (3- (trifluoromethoxy) pyrrolidine-1-carboxamide) phenyl) quinazoline-8-carboxamide (Compound 2)
The first step: preparation of 4- ((2, 4-dimethoxybenzyl) amino) -N- (2-methyl-5- (3- (trifluoromethoxy) pyrrolidine-1-carboxamide) phenyl) quinazoline-8-carboxamide (Compound 2 b)
To the flask were added compound 1j (40 mg, 85.20. Mu. Mol), hydrochloride of 2a (25 mg, 127.80. Mu. Mol), DIPEA (22 mg, 170.40. Mu. Mol) and toluene (5 mL) in this order, and the mixture was reacted at 95℃for 16hr under nitrogen. After the reaction was completed, 60mL of water was added to dilute, extracted with EA, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated, and the crude product was purified by silica gel flash column chromatography (DCM: meoh=97:3) to give compound 2b (45 mg). MS m/z (ESI): 625.0[ M+H ]] + 。
And a second step of: preparation of 4-amino-N- (2-methyl-5- (3- (trifluoromethoxy) pyrrolidine-1-carboxamide) phenyl) quinazoline-8-carboxamide (Compound 2)
Compound 2b (40 mg, 64.04. Mu. Mol) was dissolved in TFA (3 mL) and reacted at 80℃for 2hr under nitrogen. After the completion of the reaction, 60mL of water was added for dilution, the pH was adjusted to 7-8 with saturated sodium bicarbonate solution, the mixture was extracted with EA, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by Pre-HPLC to give compound 2 (15 mg). MS m/z (ESI): 475.0[ M+H ]] + 。
1 H NMR(400MHz,DMSO-d 6 )δ13.55(s,1H),8.74(dd,J＝7.6,1.6Hz,1H),8.63(s,1H),8.51(dd,J＝8.4,1.6Hz,1H),8.46(d,J＝2.0Hz,1H),8.43–8.32(m,2H),8.25(br,1H),7.71(t,J＝8.0Hz,1H),7.32(dd,J＝8.4,2.4Hz,1H),7.15(d,J＝8.0Hz,1H),5.19–5.14(m,1H),3.69(d,J＝2.8Hz,2H),3.66–3.59(m,1H),3.52–3.45(m,1H),2.42(s,3H),2.28–2.14(m,2H).
Example 3: 4-amino-N- (2-methyl-5- (3- (2, 2-trifluoroethyl) -2, 5-dihydro-1H-pyrrole-1-carboxamide) phenyl) quinazoline-8-carboxamide (Compound 3)
The first step: preparation of 3- (2, 2-trifluoroethyl) -2, 5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester (Compound 3 c)
Compounds 3a (1.00 g,3.39 mmol) and 3b (2.13 g,10.16 mmol) were dissolved in 1, 4-dioxane (20 mL) and then 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (392.04 mg, 677.55. Mu. Mol), tris (dibenzylideneacetone) dipalladium (620.44 mg, 677.55. Mu. Mol) and cesium carbonate (2210.00 mg,6.78 mmol) were added and after addition nitrogen protection, heated to 80℃for 16 h. After the completion of the reaction, the reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with water 3 times, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and then purified by silica gel flash column chromatography (PE/ea=3/1) to give compound 3c (495 mg).
And a second step of: preparation of 3- (2, 2-trifluoroethyl) -2, 5-dihydro-1H-pyrrole (Compound 3 d)
Compound 3c (84.98 mg, 338.22. Mu. Mol) was dissolved in a 1, 4-dioxane solution (5 mL, 4M) of hydrochloric acid and reacted at 25℃for 4 hours. After completion of the reaction, the mixture was concentrated to dryness under reduced pressure to give hydrochloride (63 mg) of compound 3 d. MS m/z (ESI): 152.1[ M+H ]] + 。
And a third step of: preparation of 4- ((2, 4-dimethoxybenzyl) amino) -N- (2-methyl-5- (3- (2, 2-trifluoroethyl) -2, 5-dihydro-1H-pyrrole-1-carboxamide) phenyl) quinazoline-8-carboxamide (Compound 3 e)
Compound 1j (158.00 mg, 336.53. Mu. Mol) and 3d hydrochloride (63.13 mg, 336.53. Mu. Mol) were added to toluene (15 mL), followed by N, N-diisopropylethylamine (130.48 mg,1.01 mmol), and after the addition was completed, the temperature was raised to 100℃for 2 hours. After the completion of the reaction, toluene was removed under reduced pressure, and the crude product was purified by silica gel flash column chromatography (dichloromethane/methanol=15/1) to give compound 3e (63 mg). MS m/z (ESI): 621.0[ M+H ]] + 。
Fourth step: preparation of 4-amino-N- (2-methyl-5- (3- (2, 2-trifluoroethyl) -2, 5-dihydro-1H-pyrrole-1-carboxamide) phenyl) quinazoline-8-carboxamide (Compound 3)
Compound 3e (63 mg, 96.44. Mu. Mol) was dissolved in TFA (5 mL) and heated to 70℃for 4hr. After the completion of the reaction, the solvent was removed under reduced pressure, dichloromethane was redissolved, the pH of the solution was adjusted to be basic with triethylamine, and after concentration, it was purified by Pre-HPLC to give Compound 3 (42 mg). MS m/z (ESI): 471.0[ M+H ] ] + 。
1 HNMR(400MHz,DMSO-d 6 )δ13.55(s,1H),8.74(dd,J＝7.6,1.2Hz,1H),8.63(s,1H),8.51(dd,J＝8.0,1.2Hz,1H),8.46(d,J＝2.4Hz,1H),8.40(brs,1H),8.31(s,1H),8.25(brs,1H),7.71(t,J＝8.0Hz,1H),7.34(dd,J＝8.0,2.0Hz,1H),7.15(d,J＝8.4Hz,1H),5.96(s,1H),4.28-4.18(m,4H),3.34-3.28(m,2H),2.42(s,3H).
Example 4: 4-amino-N- (2-methyl-5- (3- (2, 2-trifluoroethyl) pyrrolidine-1-carboxamide) phenyl) quinazoline-8-carboxamide (Compound 4)
Compound 3 (38.00 mg, 80.77. Mu. Mol) was dissolved in methanol (6 mL), palladium on carbon (9.81 mg, 10%) was added, hydrogen was replaced 3 times, and the temperature was raised to 40℃for reaction for 12 hours. Palladium on carbon was removed by filtration after the reaction, and the filtrate was concentrated under reduced pressure and purified by silica gel flash column chromatography (dichloromethane/methanol=10/1) to give compound 4 (20 mg), MS m/z (ESI): 473.0[ M+H ]] + 。
1 HNMR(400MHz,DMSO-d 6 )δ13.53(s,1H),8.73(dd,J＝7.6,1.6Hz,1H),8.63(s,1H),8.51(dd,J＝8.4,1.2Hz,1H),8.44(d,J＝2.0Hz,1H),8.40(brs,1H),8.25(brs,1H),8.23(s,1H),7.71(t,J＝8.0Hz,1H),7.32(dd,J＝8.0,2.0Hz,1H),7.13(d,J＝8.4Hz,1H),3.74-3.68(m,1H),3.59-3.55(m,1H),3.36-3.30(m,2H),3.06(t,J＝9.2Hz,1H),2.51-2.42(m,2H),2.41(s,3H),2.14-2.05(m,1H),1.75-1.60(m,1H).
Example 5: 4-amino-N- (2-methyl-5- (3- (trifluoromethyl) pyrrolidine-1-carboxamide) phenyl) imidazo [2,1-f ] [1,2,4] triazine-7-carboxamide (Compound 5)
The first step: preparation of 7-bromo-N, N-bis (4-methoxybenzyl) imidazo [2,1-f ] [1,2,4] triazin-4-amine (Compound 5 c)
Compound 5a (500 mg,2.34 mmol) was dissolved in DMF (10 mL), naH (373.79 mg,9.34mmol,60% purity) was added to the ice water bath, and after stirring for 30min, the compound was added5b (914.68 mg,5.84 mmol), and stirring for 16hr at 25deg.C. After the reaction, water quenching, ethyl acetate extraction, drying with anhydrous sodium sulfate, filtering and concentrating. The crude product was purified by flash column chromatography on silica gel (PE/ea=23/77) to give compound 5c (770 mg). MS m/z (ESI): 454.1[ M+H ] ] + 。
And a second step of: preparation of methyl 4- (bis (4-methoxybenzyl) amino) imidazo [2,1-f ] [1,2,4] triazine-7-carboxylate (Compound 5 d)
Into an autoclave were charged compound 5c (1.1 g,2.4 mmol), TEA (2.5 g,24.2mmol,13.0 mL), pd (dppf) Cl 2 DCM (197.7 mg, 242.1. Mu. Mol) and MeOH (15 mL), after sealing, carbon monoxide was introduced to 1.0-1.2MPa and then heated to 120℃for reaction for 5 hours. After the reaction was completed, the mixture was directly stirred with silica gel, and purified by flash column chromatography on silica gel (DCM/meoh=10/1) to give compound 5d (650 mg). MS m/z (ESI): 434.0[ M+H ]] + 。
And a third step of: preparation of 4- (bis (4-methoxybenzyl) amino) imidazo [2,1-f ] [1,2,4] triazine-7-carboxylic acid (Compound 5 e)
Compound 5d (650 mg,1.5 mmol) was dissolved in MeOH (3 mL) and THF (3 mL), water (2 mL) and NaOH (780.0 mg,4.5 mmol) were added and reacted at room temperature for 3h. After the completion of the reaction, the pH of the reaction solution was adjusted to about 3 with a 2N hydrochloric acid solution, the organic solvent was distilled off under reduced pressure, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated to give Compound 5e (580.0 mg). MS m/z (ESI): 420.0[ M+H ]] + 。
Fourth step: preparation of 4- (bis (4-methoxybenzyl) amino) -N- (2-methyl-5-nitrophenyl) imidazo [2,1-f ] [1,2,4] triazine-7-carboxamide (Compound 5 g)
Compound 5e (580.0 mg,1.4 mmol) and 5f (252.5 mg,1.7 mmol) were dissolved in pyridine (3.0 mL) and T was added dropwise 3 P (2 mL,50% DMF solution) was reacted at 25℃for 16 hours after the completion of the addition. After completion of the reaction, the solvent was removed by concentration under reduced pressure, the reaction mixture was diluted with ethyl acetate, washed 3 times with a saturated sodium hydrogencarbonate solution, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give 5g (590.0 mg) of a compound. MS m/z (ESI): 554.2[ M+H ]] + 。
Fifth step: preparation of N- (5-amino-2-methylphenyl) -4- (bis (4-methoxybenzyl) amino) imidazo [2,1-f ] [1,2,4] triazine-7-carboxamide (Compound 5 h)
5g (590.0 mg,1.1 mmol) of the compound was dissolved in ethanol (9.0 mL) and water (3.0 mL), and iron powder (297.6 mg,5.3 mmol) and ammonium chloride (57.0 mg,1.1 mmol) were added in this order, and the mixture was heated to 80℃and reacted for 2 hours. After completion of the reaction, the mixture was filtered through celite, and the filtrate was concentrated to give compound 5h (510.0 mg). MS m/z (ESI): 524.2[ M+H ]] + 。
Sixth step: preparation of 4- (bis (4-methoxybenzyl) amino) -N- (5-isocyanato-2-methylphenyl) imidazo [2,1-f ] [1,2,4] triazine-7-carboxamide (Compound 5 i)
Compound 5h (80.0 mg, 152.8. Mu. Mol) was dissolved in anhydrous THF (3.0 mL) and triphosgene (90.7 mg, 305.6. Mu. Mol) was added slowly and reacted at 30℃for 3 hours after the addition. After the completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed 3 times with a saturated aqueous sodium hydrogencarbonate solution, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give compound 5i (80.0 mg).
Seventh step: preparation of 4- (bis (4-methoxybenzyl) amino) -N- (2-methyl-5- (3- (trifluoromethyl) pyrrolidine-1-carboxamide) phenyl) imidazo [2,1-f ] [1,2,4] triazine-7-carboxamide (Compound 5 j)
Compound 5i (80.0 mg, 145.6. Mu. Mol), 1k hydrochloride (28.1 mg, 160.1. Mu. Mol) and DIPEA (37.6 mg, 291.1. Mu. Mol) were added to toluene (5.0 mL) and then reacted at 99℃for 15 hours. After the completion of the reaction, the solvent was removed by concentration under reduced pressure, the reaction mixture was diluted with ethyl acetate, saturated aqueous sodium hydrogencarbonate was washed 3 times, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by flash column chromatography on silica gel (PE/ea=3/1) to give compound 5j (100.0 mg). MS m/z (ESI): 689.0[ M+H ]] + 。
Eighth step: preparation of 4-amino-N- (2-methyl-5- (3- (trifluoromethyl) pyrrolidine-1-carboxamide) phenyl) imidazo [2,1-f ] [1,2,4] triazine-7-carboxamide (Compound 5)
Compound 5j (100.0 mg, 145.2. Mu. Mol) was added to trifluoroacetic acid (3.0 mL) and reacted at 80℃for 16 hours. Concentrating the reaction solution after the reaction is finished, adding saturated sodium bicarbonate aqueous solution for alkalization, extracting with dichloromethane, and performing anhydrous sulfur on an organic phaseSodium acid was dried, filtered and concentrated, and the crude product was isolated and purified by Prep-HPLC to give compound 5 (5.55 mg). MS m/z (ESI): 449.0[ M+H ] ] + 。
1 H NMR(400MHz,DMSO-d 6 ) δ10.47 (s, 1H), 8.71 (d, j=37.6 hz, 2H), 8.42 (s, 1H), 8.38 (s, 1H), 8.31 (d, j=2.4 hz, 1H), 8.22 (s, 1H), 7.34 (dd, j=8.0, 2.2hz, 1H), 7.16 (d, j=8.4 hz, 1H), 3.77-3.66 (m, 1H), 3.62-3.42 (m, 3H), 3.33-3.26 (m, 1H), 2.34 (s, 3H), 2.27-2.15 (m, 1H), 2.11-1.96 (m, 1H). Example 6: 4-amino-N- (2-methyl-5- (3- (trifluoromethoxy) pyrrolidine-1-carboxamide) phenyl) imidazo [2,1-f][1,2,4]Triazine-7-carboxamide (Compound 6)
The first step: preparation of 4- (bis (4-methoxybenzyl) amino) -N- (2-methyl-5- (3- (trifluoromethoxy) pyrrolidine-1-carboxamide) phenyl) imidazo [2,1-f ] [1,2,4] triazine-7-carboxamide (Compound 2 c)
Compound 5i (90.0 mg, 163.8. Mu. Mol) and the hydrochloride salt of 2a (34.5 mg, 180.1. Mu. Mol) were dissolved in toluene (4.0 mL), followed by the addition of DIPEA (42.3 mg, 327.5. Mu. Mol) and reaction at 99℃for 15 hours after the addition. After the completion of the reaction, the solvent was removed by concentration under reduced pressure, the reaction mixture was diluted with ethyl acetate, saturated aqueous sodium hydrogencarbonate was washed 3 times, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was purified by flash column chromatography on silica gel (PE/ea=3/1) to give compound 6a (86.0 mg). MS m/z (ESI): 705.3[ M+H ]] + 。
And a second step of: preparation of 4-amino-N- (2-methyl-5- (3- (trifluoromethoxy) pyrrolidine-1-carboxamide) phenyl) imidazo [2,1-f ] [1,2,4] triazine-7-carboxamide (Compound 6)
Compound 6a (80.0 mg, 113.5. Mu. Mol) was added to trifluoroacetic acid (3.0 mL) and reacted at 80℃for 16 hours. After the reaction, the reaction mixture was concentrated to dryness, alkalified by adding saturated aqueous sodium bicarbonate, extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated, and the crude product was separated and purified by Prep-HPLC to give compound 6 (3.04 mg). MS m/z (ESI): 465.1[ M+H ]] + 。
1 H NMR(400MHz,DMSO-d 6 )δ10.47(s,1H),8.71(d,J＝38.4Hz,2H),8.42(s,1H),8.38(s,1H),8.31(d,J＝2.0Hz,1H),8.22(s,1H),7.34(dd,J＝8.0,2.0Hz,1H),7.16(d,J＝8.4Hz,1H),5.23–5.11(m,1H),3.73–3.57(m,3H),3.52–3.40(m,1H),2.34(s,3H),2.31–2.12(m,2H).
Biological evaluation
Experimental example 1: RAF inhibition assay
The experimental method comprises the following steps: the inhibition of mutant BRAF enzyme (BRAF V600E) activity by the compounds of the invention was determined according to the instructions of the TB-PMAP2K1 (PSER 217/221) kit (ThermoFisher). After preincubation of the RAF enzyme and substrate (fluoroescein-MAP 2K 1) with test compounds at different concentrations for 15min at room temperature, the reaction was initiated by addition of Adenosine Triphosphate (ATP). EDTA and Tb-labeled anti-pMAP2K1[ pS217/221] antibody solution were added after incubation at room temperature for 60min, and fluorescence values were detected after incubation at room temperature for 60 min. The group containing RAF enzyme and no compound was a negative control, the group containing no RAF enzyme and no compound was a blank control, and the relative percent inhibitory activity (i.e., inhibition rate) of the compounds at different concentrations was calculated according to the following formula:
relative percent inhibitory activity = 1- (compound group-placebo)/(negative control-placebo) ×100%
The relative percent inhibitory activity of compounds at different concentrations was plotted against compound concentration, and IC was calculated by fitting a curve according to a four parameter model, by the following formula 50 Value:
y＝min+(max-min)/(1+(x/IC 50 )^(-Hillslope))
wherein y is the relative inhibition activity percentage, max and min are the maximum value and the minimum value of the fitting curve respectively, x is the logarithmic concentration of the compound, and Hillslope is the slope of the curve. The experimental results are shown in table 1.
Table 1: inhibitory Activity of the Compounds of the invention against BRAF V600E enzyme
Numbering of compounds BRAF V600E IC 50 (nM)
1 1.3±0.1
2 1.4±0.2
3 2.1±1.4
4 1.3±0.1
5 1.1±0.1
6 0.6±0.0
Experimental results show that the compound has a strong inhibition effect on BRAF V600E.
Experimental example 2: cancer cell proliferation inhibition experiment
The inhibition of cancer cell proliferation by the compounds of the present invention was further evaluated by testing their effect on cancer cell growth.
In this example, human melanoma cell A375 (BRAF V600E mutation, purchased from China academy of sciences cell bank) and human hepatoma cell HepG2 (NRAS Q61K mutation, purchased from American ATCC) were selected.
In the examples, test compounds at different concentrations were added to the above cells, respectively, and incubated for 72 hours, and the number of living cells was detected by quantitatively determining ATP in the living cells using Cell Titer Glo Kit (Promega).
Background RLU was obtained using CellTiter-Glo without cell-containing medium, and solvent RLU was obtained using CellTiter-Glo with cell-containing medium. Cell inhibition ratio = 1- (sample RLU-background RLU)/(vehicle RLU-background RLU) ×100%, and half Inhibition Concentration (IC) of the compound was calculated according to a four parameter model fitted curve 50 ). IC of the inventive Compound against each test cell 50 The values are as follows:
TABLE 2 inhibitory Activity of the Compounds of the application against proliferation of cancer cells
Numbering of compounds HepG2(IC 50 nM) A375(IC 50 nM)
1 39.9±3.1 361.4±17.5
2 34.6±1.0 248.5±13.7
3 134.6±55.1 331.3±19.9
4 32.1±2.7 178.4±20.4
5 100.9±21.5 1171.1±77.89
6 18.5±2.2 381.0±30.3
Experimental results show that the compound has a strong inhibition effect on A375 (BRAF V600E mutation) cells and HepG2 (NRAS Q61K mutation) cells.
Various modifications of the application, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference cited in this disclosure (including all patents, patent applications, journal articles, books, and any other publications) is hereby incorporated by reference in its entirety.

Claims (13)

1. A compound of formula I or a pharmaceutically acceptable form thereof:
wherein:
ring A is a 4-10 membered heterocyclyl;
W 1 、W 2 and W is 3 Each independently selected from N and CR 4 ；
L 1 Selected from-NR 5 -C(＝O)-、-C(＝O)-NR 5 -and-NR 5 -；
R 1 Selected from C 6-10 Aryl and 5-10 membered heteroaryl, wherein each of said aryl and heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of: -NHR 6 Hydroxy, halogen, CN, NO 2 、C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl group,C 1-6 Haloalkoxy, C 1-6 Heteroalkyl, C 3-6 Cycloalkyl and 4-10 membered heterocyclyl; alternatively, optionally two adjacent substituents together with the atom to which they are attached form a 5-10 membered heterocyclic group, said 5-10 membered heterocyclic group optionally being substituted with one or more groups independently selected from CN, hydroxy, halo, oxo and C 1-6 Substituent substitution of alkyl;
R 2 and R is 4 Each at each occurrence is independently selected from H, CN, hydroxy, halogen, C 1-6 Alkyl and C 1-6 Alkoxy, wherein each of the alkyl and alkoxy groups is optionally substituted with one or more halogens;
R 3 is L 3 -R 3 ’；
L 3 Each occurrence is independently a direct bond or- (CH) 2 ) n -；
R 3 ' each occurrence is independently selected from H, hydroxy, halogen, CN, NO 2 、C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, 4-10 membered heterocyclyl, C 6-12 Aryl, 5-10 membered heteroaryl, -NR 20a R 20b 、-SR 21 、-S(＝O)R 22 、-S(＝O) 2 R 22 、-S(＝O)NR 20a R 20b 、-S(＝O) 2 NR 20a R 20b 、-NR 20a S(＝O)R 20b 、-NR 20a S(＝O) 2 R 20b 、-C(＝O)R 21 、-C(＝O)NR 23a R 23b 、-NR 23a C(＝O)R 23b and-NR 24a C(＝O)NR 25a R 25b Wherein each of the alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of: hydroxy, halogen, CN, NO 2 、C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkoxy, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl and 4-10 membered heterocyclyl；
R 5 And R is 6 Each at each occurrence is independently selected from H, C 1-6 Alkyl, C 3-8 Cycloalkyl and 4-10 membered heterocyclyl, wherein each of said alkyl, cycloalkyl and heterocyclyl is optionally substituted with one or more halo;
R 20a 、R 20b 、R 23a 、R 23b 、R 24a 、R 25a and R is 25b Each independently selected from H, OH, -NHCH 3 、-N(CH 3 ) 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl and 4-10 membered heterocyclyl; wherein each of said alkyl, alkoxy, cycloalkyl and heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of: halogen, C 1-6 Alkyl and 4-10 membered heterocyclyl;
R 21 and R is 22 Each independently selected from C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl and 4-10 membered heterocyclyl, wherein each of said alkyl, alkoxy, cycloalkyl and heterocyclyl is optionally substituted with one or more halo;
m is 1, 2, 3, 4 or 5; and is also provided with
n is 1, 2 or 3;
the pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, co-crystals, solvates, metabolites, isotopically labeled compounds, N-oxides or prodrugs.
2. The compound of claim 1, or a pharmaceutically acceptable form thereof, wherein L 1 is-C (=O) -NR 5 -or-NR 5 -C(＝O)-，R 5 Selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl and 4-6 membered heterocyclyl, wherein each of said alkyl, cycloalkyl and heterocyclyl is optionally substituted with one or more halo; preferably L 1 is-C (=O) -NH-or-NH-C (=O) -.
3. The compound of claim 1 or 2, or a pharmaceutically acceptable form thereof, wherein the compound of formula I has a structure represented by formula I-a:
wherein R is 1 、R 2 、R 3 、W 1 、W 2 、W 3 And ring a is as defined in claim 1 or 2; m is 1, 2 or 3.
4. A compound according to any one of claims 1-3, or a pharmaceutically acceptable form thereof, wherein ring a is 4-6 membered heterocyclyl; preferably, ring a is a 5 membered heterocyclyl; more preferably, ring A is selected from
5. The compound of any one of claims 1-4, or a pharmaceutically acceptable form thereof, wherein W 1 、W 2 And W is 3 Each independently selected from N, CF and CH.
6. The compound or pharmaceutically acceptable form thereof according to any one of claims 1-5, wherein,
R 1 selected from phenyl, naphthyl, and 5-10 membered heteroaryl, wherein each of the phenyl, naphthyl, and heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of: -NHR 6 Hydroxy, halogen, CN, NO 2 、C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkoxy, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl and 4-10 membered heterocyclyl; alternatively, optionally two adjacent substituents together with the atom to which they are attached form a 5-8 membered heterocyclic group, said 5-8 membered heterocyclic group optionally being substituted with one or more groups independently selected from CN, hydroxy, halo, oxo and C 1-4 Substituent substitution of alkyl;
preferably, R 1 Selected from phenyl, naphthyl, pyridinyl, pyrazolyl, thiazolyl, pyrimidinyl, and 9-10 membered fused ring heteroaryl, wherein each of said phenyl, naphthyl, pyridinyl, pyrazolyl, thiazolyl, pyrimidinyl, and 9-10 membered fused ring heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of: -NHR 6 Hydroxy, halogen, CN, NO 2 、C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkoxy, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl and 4-10 membered heterocyclyl; alternatively, the optional two substituents together with the atom to which they are attached form a 6 membered heterocyclyl, the 6 membered heterocyclyl optionally being substituted with one or more substituents independently selected from CN, hydroxy, halogen, oxo and C 1-4 Substituent substitution of alkyl;
more preferably, R 1 Selected from the group consisting of Wherein said-> Each optionally substituted with one or more substituents independently selected from the group consisting of: hydroxy, halogen, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkoxy, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl and 4-10 membered heterocyclyl;
more preferably, R 1 Selected from the group consisting of Wherein said-> Each optionally substituted with one or more substituents independently selected from the group consisting of: hydroxy, halogen, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkoxy, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl and 4-10 membered heterocyclyl;
wherein R is 6 Independently selected from H, C 1-4 Alkyl, C 3-6 Cycloalkyl and 4-6 membered heterocyclyl, wherein each of said alkyl, cycloalkyl and heterocyclyl is optionally substituted with one or more halo; preferably, R 6 Is H;
particularly preferably, R 1 Selected from the group consisting of
7. The compound of any one of claims 1-6, or a pharmaceutically acceptable form thereof, wherein R 2 Selected from H, CN, halogen, C 1-4 Alkyl and C 1-4 Alkoxy, wherein each of the alkyl and alkoxy groups is optionally substituted with one or more halogens; preferably, R 2 Is H or C 1-4 An alkyl group; more preferably, R 2 Is H or methyl.
8. The compound or pharmaceutically acceptable form thereof according to any one of claims 1-7, wherein,
R 3 ' each occurrence is independently selected from H, hydroxy, halogen, CN, C 1-4 Alkyl, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl, C 3-6 Cycloalkoxy, 4-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, -NR 20a R 20b 、-SR 21 、-S(＝O)R 22 、-S(＝O) 2 R 22 、-S(＝O)NR 20a R 20b 、-S(＝O) 2 NR 20a R 20b 、-NR 20a S(＝O)R 20b 、-NR 20a S(＝O) 2 R 20b 、-C(＝O)R 21 、-C(＝O)NR 23a R 23b 、-NR 23a C(＝O)R 23b and-NR 24a C(＝O)NR 25a R 25b Wherein each of the alkyl, heteroalkyl, cycloalkyl, cycloalkoxy, heterocyclyl, phenyl, and heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of: hydroxy, halogen, CN, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Hydroxyalkyl, C 1-4 Haloalkoxy, C 1-4 Heteroalkyl, C 3-6 Cycloalkyl and 4-10 membered heterocyclyl;
preferably, R 3 ' each occurrence is independently selected from H, halogen, C 1-4 Alkyl and C 1-4 Alkoxy, wherein the alkyl and alkoxy groups are optionally substituted with one or more halo or cyano groups;
preferably, R 3 ' each occurrence is independently selected from C 1-4 Alkyl and C 1-4 Alkoxy, wherein the alkyl and alkoxy groups are optionally substituted with one or more halogens;
more preferably, R 3 ' are independently selected at each occurrence from H, F, cl, -CH 3 、-CH 2 CF 3 、-CH 2 CN、-CF 3 and-OCF 3 。
9. The compound or pharmaceutically acceptable form thereof according to any one of claims 1-8, wherein,
R 20a 、R 20b 、R 23a 、R 23b 、R 24a 、R 25a and R is 25b Each independently selected from H, C 1-6 Alkyl, C 3-8 Cycloalkyl and 4-10 membered heterocyclyl; the alkyl, cycloalkyl and heterocyclyl groups are each optionally substituted with one or more substituents independently selected from the group consisting of: halogen, C 1-6 Alkyl and 4-10 membered heterocyclyl;
preferably, R 20a 、R 20b 、R 23a 、R 23b 、R 24a 、R 25a And R is 25b Each independently selected from H, C 1-4 Alkyl and C 3-6 Cycloalkyl, wherein each of the alkyl and cycloalkyl groups is optionally substituted with one or more halogens;
R 21 and R is 22 Each independently selected from C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Cycloalkyl and 4-6 membered heterocyclyl, wherein each of said alkyl, alkoxy, cycloalkyl and heterocyclyl is optionally substituted with one or more halo.
10. A compound or pharmaceutically acceptable form thereof, wherein the compound is selected from the group consisting of:
the pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, co-crystals, solvates, metabolites, isotopically labeled compounds, N-oxides or prodrugs.
11. A pharmaceutical composition comprising a compound of any one of claims 1-10, or a pharmaceutically acceptable form thereof, and one or more pharmaceutically acceptable carriers.
12. Use of a compound according to any one of claims 1-10, or a pharmaceutically acceptable form thereof, or a pharmaceutical composition according to claim 11, in the manufacture of a medicament for the prevention or treatment of a disease or condition associated with RAF and/or RAS kinase activity.
13. The use of claim 12, wherein the disease or condition associated with RAF and/or RAS kinase activity is a cancer or tumor; preferably, the cancer or tumor is selected from lung cancer, breast cancer, ovarian cancer, gastric cancer, liver cancer, kidney cancer, bone cancer, colorectal cancer, pancreatic cancer, head and neck cancer, uterine cancer, esophageal cancer, thyroid cancer, bladder cancer, blood cancer, lymphoma, multiple myeloma, melanoma, glioma, brain tumor, and sarcoma; more preferably, the cancer or tumor is selected from lung cancer, liver cancer, breast cancer, ovarian cancer, colorectal cancer, pancreatic cancer, melanoma, glioma, brain tumor and sarcoma.
CN202310556246.6A 2022-05-27 2023-05-17 Heterocyclic compounds having protein kinase inhibitory activity, pharmaceutical compositions containing the same, and methods of preparing and using the same Pending CN117126140A (en)

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