CN116903626A

CN116903626A - Aryl amide compound, pharmaceutical composition containing same, preparation method and application thereof

Info

Publication number: CN116903626A
Application number: CN202310365734.9A
Authority: CN
Inventors: 陈忠辉; 韩晓军; 田强; 宋宏梅; 葛均友
Original assignee: Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Current assignee: Sichuan Kelun Biotech Biopharmaceutical Co Ltd
Priority date: 2022-04-18
Filing date: 2023-04-07
Publication date: 2023-10-20

Description

Aryl amide compound, pharmaceutical composition containing same, preparation method and application thereof

Technical Field

The present invention relates to aryl amide compounds, 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.2017Nov;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 aryl amide compounds which 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 RAS or RAF mutant tumor treatment.

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 selected from the group consisting of pyrrole ring, 5-6 membered heterocycle, and 5-6 membered carbocycle;

ring B is selected from benzene ring, 5-10 membered heteroaromatic ring, 5-10 membered carbocyclic ring and 4-10 membered heterocyclic ring;

X ¹ and X ² Each independently selected from C and N;

X ³ and X ⁴ Each independently selected from CH and N;

R ¹ selected from H, C _1-6 Alkyl and C _3-6 Cycloalkyl, each of which is optionally substituted with one or more halogens;

R ² selected from H, halogen, C _1-6 Alkyl and C _1-6 Alkoxy, each of said alkyl and alkoxy optionally substituted with one or more halogens;

R ³ is L-R ³ ’；

L is independently at each occurrence 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) ₂ R ²² 、-S(＝O) ₂ NR ^20a 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 The alkyl, heteroalkyl (e.g., alkoxy), alkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocyclyl, aryl, and heteroaryl groups are each 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; or when L is a direct bond and m is greater than 1, two R ³ ' together with the groups to which it is attached form a 4-10 membered heterocyclic ring;

R ⁴ each at 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) ₂ R ²² 、-S(＝O) ₂ NR ^20a 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 The alkyl, heteroalkyl (e.g., alkoxy), alkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocyclyl, aryl, and heteroaryl groups are each optionally substituted with one or more substituents independently selected from the group consisting of: hydroxy, halogen, CN, NH ₂ 、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 ^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; the alkyl, alkoxy, 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;

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, each optionally substituted with one or more halo;

m is 0, 1, 2, 3, 4 or 5;

n is 1 or 2;

p is 0, 1, 2 or 3; and is also provided with

q is 0, 1 or 2;

provided that the conditions are that,not be->And when ring B is a benzene ring, and +.>Is thatWhen (I)>Not be->

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 "and" C _1-4 Alkyl "refers to a line having 1-6 carbon atoms and 1-4 carbon atoms, respectivelyA linear or branched group (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 (this 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 a backbone chain atom having one or more atoms independently selected from the group consisting of atoms other than carbon in the backbone carbon atom of the alkyl group, such as oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. A range of values (e.g. C _1-6 Heteroalkyl) refers to the number of carbons in the chain, including 1-6 carbon atoms in this example. For example, -CH ₂ OCH ₂ CH ₃ The radical being referred to as C ₃ A heteroalkyl group. The attachment to the remainder of the molecule may be through 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 toNot limited to hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, -CH (OH) CH ₃ Etc.

As used herein, the term "alkoxy" means a group, preferably C, inserted at any reasonable position of an alkyl group (as defined above) with an oxygen atom _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, e.g. "C _2-6 Alkenyl "is alkenyl having 2 to 6 carbon atoms. 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" or "carbocycle" refers to a saturated or unsaturated, non-aromatic, monocyclic or polycyclic (such as bicyclic) hydrocarbon ring radical, including, but not limited to, monocycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and the like) and bicycloalkyl, including spirocyclic, fused-ring (fused-ring) or bridged-ring systems (i.e., spirocyclic alkyl, fused-ring (fused-ring) alkyl, and bridged-cycloalkyl radicals, 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, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, or bicycloalkyl, such as 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 unsaturated, non-aromatic, monocyclic or polycyclic (e.g., parallel, 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 includingBut are not limited to oxygen, nitrogen and sulfur atoms, the carbon and heteroatoms on the heterocyclyl being optionally substituted with oxo groups (e.g., to form c= O, S (=o) or S (=o) ₂ ) Or optionally one or more (such as 1 to 3) independently selected from halogen and C _1-3 The substituent of the alkyl group is substituted.

As used herein, the term "4-10 membered heterocyclyl" means a heterocyclyl containing 4-10 ring atoms including, but not limited to, 4-10 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.

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, cyclopentyl-aziridinyl, pyrrolidinyl-cyclobutyl, pyrrolidinyl-pyrrolidinyl, pyrrolidinyl-piperidinyl, pyrrolidinyl-piperazinyl, piperidinyl-morpholinoA pinyl group,

In the present invention, the heterocyclic group also includes bridged heterocyclic groups and spiro heterocyclic groups.

As used herein, the term "bridged heterocyclic ring" refers to a cyclic structure containing one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, nitrogen, and/or sulfur atoms) formed by two saturated rings sharing two ring atoms that are not directly connected, including, but not limited to, 7-10 membered bridged heterocyclic rings, 8-10 membered bridged heterocyclic rings, 7-10 membered nitrogen-containing bridged heterocyclic rings, 7-10 membered oxygen-containing bridged heterocyclic rings, 7-10 membered sulfur-containing bridged heterocyclic rings, and the like, e.g. Etc. The "nitrogen-containing bridged heterocycle", "oxygen-containing bridged heterocycle", "sulfur-containing bridged heterocycle" optionally also contains one or more additional heteroatoms independently selected from oxygen, nitrogen and sulfur.

As used herein, the term "spiroheterocycle" refers to a cyclic structure containing one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, nitrogen, sulfur) formed by two or more saturated rings sharing one ring atom, including but not limited to 5-10 membered spiroheterocycles, 6-10 membered nitrogen-containing spiroheterocycles, 6-10 membered oxygen-containing spiroheterocycles, 6-10 membered sulfur-containing spiroheterocycles, and the like, e.g.

The "nitrogen-containing spiroheterocycle", "oxygen-containing spiroheterocycle", "sulfur-containing spiroheterocycle" optionally further contains oneOr a plurality of other heteroatoms independently selected from oxygen, nitrogen, sulfur. The term "6-10 membered nitrogen-containing spiroheterocyclyl" refers to a spiroheterocyclyl containing a total of 6-10 ring atoms, at least one of which is a nitrogen atom.

Examples of groups resulting from the condensation of a heterocyclyl group with an aryl group include, but are not limited to:

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 _6-12 Aryl (aromatic ring) "means an aryl (aromatic ring) group containing 6 to 12 carbon atoms, preferably C _6-10 Aryl (aromatic ring), preferably 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. The carbon and heteroatoms on the heteroaryl group being optionally substituted with oxo groups (e.g. to form c= O, S (=o) or S (=o) ₂ )。

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 application 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 (-), solid wedges, may be used hereinOr virtual wedge +. >Depicting the chemical bond of the compounds of the present invention. 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 invention 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 invention 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.

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 application may be present in the form of solvates (preferably hydrates) wherein the compounds of the application comprise a polar solvent as a structural element of the compound lattice, in particular for example water, methanol or ethanol. 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:

X ¹ And X ² Each independently selected from C and N;

X ³ and X ⁴ Each independently selected from CH and N;

R ³ is L-R ³ ’；

L is independently at each occurrence a direct bond or- (CH) ₂ ) _n -；

m is 0, 1, 2, 3, 4 or 5;

n is 1 or 2;

p is 0, 1, 2 or 3; and is also provided with

q is 0, 1 or 2;

provided that the conditions are that,not be->And when ring B is a benzene ring, and +.>Is->When (I)>Not be->

In some embodiments, the compounds of the present invention have the structure shown in formula I-A:

wherein:

ring a, ring B, X ¹ 、X ² 、R ¹ 、R ³ 、R ⁴ M and p are as defined in formula I.

In some embodiments, the compounds of the present invention have the structure shown in formula I-B:

wherein:

ring C is selected from pyrrole ring and 5-6 membered heterocycle;

and, a ring B, R ³ 、R ⁴ M and p are as defined in formula I.

In certain embodiments, the present invention provides compounds of formula I and formula I-a wherein when ring a is a 5 membered heterocycle, the heteroatom is not S.

In certain embodiments, the present invention provides compounds of formula I and formula I-A wherein ring A is a pyrrole ring, a 5-6 membered N-containing heterocycle, or a 5-6 membered carbocycle; preferably, ring a is a pyrrole ring, a dihydropyrrole ring, a tetrahydropyridine ring, a dihydro oxazine ring or a cyclohexene ring.

In certain embodiments, the present invention provides compounds of formula I and formula I-a wherein ring a is a pyrrole ring.

In certain embodiments, the present invention provides compounds of formula I-B wherein ring C is a pyrrole ring, a dihydropyrrole ring, a tetrahydropyridine ring, or a dihydro oxazine ring; preferably, ring C is a pyrrole ring, a dihydropyrrole ring or a tetrahydropyridine ring.

In certain embodiments, the present invention provides compounds of formula I, formula I-A and formula I-B wherein ring B is a benzene ring, a 5-6 membered heteroaromatic ring, a 5-6 membered carbocyclic ring and a 4-6 membered heterocyclic ring; preferably, ring B is a benzene ring or a 5-6 membered heteroaryl ring; more preferably, ring B is a benzene ring.

In certain embodiments, the present invention provides compounds of formula I and formula I-A wherein X ¹ C and X ² Is C; or X ¹ C and X ² Is N; or X ¹ Is N and X ² Is C; preferably X ¹ C and X ² Is C; or X ¹ C and X ² Is N.

In certain embodiments, the present invention provides compounds of formula I and formula I-A,selected from-> Wherein R is ¹ 、R ⁴ And p is as defined in formula I.

In certain embodiments, the present invention provides compounds of formula I-B,selected from-> Wherein R is ⁴ And p is as defined in formula I.

In certain embodiments, the present invention provides compounds of formula I wherein X ³ Is CH and X ⁴ Is N.

In certain embodiments, the present invention provides compounds of formula I and formula I-A wherein R ¹ Is H or C _1-6 An alkyl group; preferably, R ¹ Is H or C _1-3 An alkyl group; preferably, R ¹ H.

In certain embodiments, the present invention provides compounds of formula I wherein R ² Selected from H, halogen, C _1-3 Alkyl and C _1-3 Alkoxy, each of said alkyl and alkoxy optionally substituted with one or more halogens; preferably, R ² Selected from halogen and C _1-3 An alkyl group; preferably, R ² Is F or-CH ₃ The method comprises the steps of carrying out a first treatment on the surface of the More preferably, R ² is-CH ₃ 。

In certain embodiments, the present invention provides compounds of formula I wherein q is 0 or 1; preferably q is 1.

In certain embodiments, the present invention provides compounds of formula I, formula I-A and formula I-B wherein L is, at each occurrence, independently a direct bond or-CH ₂ -。

In certain embodiments, the present invention provides compounds of formula I, formula I-A and formula I-B wherein R ³ ' each occurrence is independently selected from H, hydroxy, halogen, CN, NO ₂ 、C _1-4 Alkyl, C _1-4 Heteroalkyl (e.g. C _1-4 Alkoxy group), C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy, 4-6 membered heterocyclyl, C _6-10 Aryl, 5-6 membered heteroaryl, -NR ^20a R ^20b 、-SR ²¹ 、-S(＝O) ₂ R ²² 、-S(＝O) ₂ NR ^20a 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 The alkyl, heteroalkyl (e.g., alkoxy), alkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocyclyl, aryl, and heteroaryl groups are each optionally substituted with one or more substituents independently selected from the group consisting of: hydroxy, halogen, CN, NO ₂ 、C _1-4 Alkyl group、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 4-6 membered heterocyclyl.

In certain embodiments, the present invention provides compounds of formula I, formula I-A and formula I-B wherein R ³ ' each occurrence is independently selected from H, halogen, CN, C _1-4 Alkyl, C _1-4 Heteroalkyl (e.g. C _1-4 Alkoxy) -NR ^20a R ^20b 、-S(＝O) ₂ R ²² And C (=O) R ²¹ The alkyl and heteroalkyl groups (e.g., alkoxy groups) are each optionally substituted with one or more groups independently selected from halogen, C _1-4 Heteroalkyl and 4-6 membered heterocyclyl.

In certain embodiments, the present invention provides compounds of formula I, formula I-A and formula I-B wherein R ³ ' each occurrence is independently selected from H, halogen, C _1-4 Alkyl, C _1-4 Heteroalkyl (e.g. C _1-4 Alkoxy) and-NR ^20a R ^20b The alkyl and heteroalkyl (e.g., alkoxy) groups are each optionally substituted with one or more halogen.

In certain embodiments, the present invention provides compounds of formula I, formula I-A and formula I-B wherein R ³ ' each occurrence is independently selected from H, halogen, C _1-4 An alkyl group; the alkyl groups are each optionally substituted with one or more halogens.

In certain embodiments, the present invention provides compounds of formula I, formula I-A and formula I-B wherein R ³ ' each occurrence is independently selected from halogen and C _1-4 A haloalkyl group; preferably, R ³ ' are independently selected at each occurrence from F, cl and CF ₃ 。

In certain embodiments, the present invention provides compounds of formula I, formula I-A and formula I-B wherein R ^20a 、R ^20b 、R ^23a 、R ^23b 、R ^24a 、R ^25a And R is ^25b Each independently selected from H, -NHCH ₃ 、-N(CH ₃ ) ₂ 、C _1-4 Alkyl, C _1-4 Alkoxy, C _3-6 Cycloalkyl and 4-6 membered heterocyclyl; the alkyl, alkoxy, 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 4-6 membered heterocyclyl.

In certain embodiments, the present invention provides compounds of formula I, formula I-A and formula I-B wherein R ^20a 、R ^20b 、R ^23a 、R ^23b 、R ^24a 、R ^25a And R is ^25b Each independently is H, methyl, ethyl, propyl, or oxetanyl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of: F. cl, br, methyl and oxetanyl.

In certain embodiments, the present invention provides compounds of formula I, formula I-A and formula I-B wherein R ²¹ And R is ²² Each independently selected from C _1-4 Alkyl, C _1-4 Alkoxy and C _3-6 Cycloalkyl, each of which is optionally substituted with one or more halogens.

In certain embodiments, the present invention provides compounds of formula I, formula I-A and formula I-B wherein R ²¹ And R is ²² Each independently is C _1-4 An alkyl group. In a preferred embodiment, R ²¹ And R is ²² Each independently is methyl.

In certain embodiments, the present invention provides compounds of formula I, formula I-A, and formula I-B wherein m is 0, 1, 2, or 3; preferably, m is 1 or 2.

In certain embodiments, the present invention provides compounds of formula I, formula I-A and formula I-B wherein R ⁴ Each at each occurrence is independently selected from H, hydroxy, halogen, CN, NO ₂ 、C _1-4 Alkyl, C _1-4 Heteroalkyl (e.g. C _1-4 Alkoxy group), C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy, 4-6 membered heterocyclyl, C _6-10 Aryl, 5-6 membered heteroaryl, -NR ^20a R ^20b 、-SR ²¹ 、-S(＝O) ₂ R ²² 、-S(＝O) ₂ NR ^20a 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 The alkyl, heteroalkyl (e.g., alkoxy), alkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocyclyl, aryl, and heteroaryl groups are each optionally substituted with one or more substituents independently selected from the group consisting of: hydroxy, halogen, CN, NH ₂ 、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 4-6 membered heterocyclyl;

R ^20a 、R ^20b 、R ^23a 、R ^23b 、R ^24a 、R ^25a and R is ^25b Each independently selected from H, -NHCH ₃ 、-N(CH ₃ ) ₂ 、C _1-4 Alkyl, C _1-4 Alkoxy, C _3-6 Cycloalkyl and 4-6 membered heterocyclyl; the alkyl, alkoxy, 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 4-6 membered heterocyclyl; and is also provided with

R ²¹ And R is ²² Each independently selected from C _1-4 Alkyl, C _1-4 Alkoxy and C _3-6 Cycloalkyl, each of which is optionally substituted with one or more halogens.

In certain embodiments, the present invention provides compounds of formula I, formula I-A and formula I-B wherein R ⁴ Each at each occurrence is independently selected from H, halogen, C _1-4 Alkyl, C _1-4 Heteroalkyl, said alkyl and heteroalkyl (e.g., alkoxy) each optionally substituted with one or more substituents independently selected from the group consisting of: hydroxy, halogen and NH ₂ 。

In certain embodiments, the present invention provides compounds of formula I, formula I-A and formula I-B wherein R ⁴ Each at each occurrence is independently selected from H, halogen and C _1-4 An alkyl group.

In certain embodiments, the present invention provides compounds of formula I, formula I-A and formula I-B wherein R ⁴ Each independently at each occurrence is selected from H and halogen.

In certain embodiments, the present invention provides compounds of formula I, formula I-A and formula I-B wherein R ⁴ Each independently at each occurrence selected from H, F and Cl; preferably, R ⁴ Each independently at each occurrence is selected from H and F.

In certain embodiments, the present invention provides compounds of formula I, formula I-A and formula I-B wherein p is 0, 1 or 2; preferably, p is 0 or 2.

In certain embodiments, the present invention provides compounds of formula I,selected from->

R ¹ Is H;

R ⁴ each independently at each occurrence selected from H and halogen;

X ³ Is CH and X ⁴ Is N;

ring B is benzene ring;

R ³ is H, halogen or C _1-4 An alkyl group; each of said alkyl groups optionally substituted with one or more halogens;

m is 0, 1, 2 or 3;

p is 0, 1 or 2.

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:

PG is an amino protecting group, preferably 2, 4-dimethoxybenzyl or 4-methoxybenzyl;

the remaining groups are as defined above;

the reaction conditions of each step are as follows:

the first step: the compounds I-A-1 and I-A-2 are subjected to substitution reaction or coupling reaction (such as Buchwald or Ullman reaction and the like) to generate a compound I-A-3;

for substitution reactions, the reaction may be carried out in an acid (e.g., trifluoroacetic acid, hydrochloric acid, etc.) or a base (e.g. ^t BuONa、 ^t BuOK、 ^t BuOLi、Cs ₂ CO ₃ 、DIPEA、LiHMDS、LDA、NaHMDS、KHMDS、K ₃ PO ₄ 、Na ₂ CO ₃ 、KOAc、NaHCO ₃ Or K ₂ CO ₃ ) Is carried out in the presence of (3); solvents which can be used are, for example, isopropanol, tert-butanol, toluene, xylene, THF, DME, 1, 4-dioxane, DMF, DMSO or NMP; and the reaction temperature is 40 ℃ to 140 ℃.

For the Buchwald reaction, catalysts which can be used are, for example, pd (OAc) ₂ 、Pd ₂ (dba) ₃ 、Pd(dba) ₂ 、PdCl ₂ 、Pd(PPh ₃ ) ₄ 、Pd(dppf)Cl ₂ 、Pd(acac) ₂ Or Pd (all) ₂ The method comprises the steps of carrying out a first treatment on the surface of the The ligand that can be used is PPh ₃ XPhos, SPhos, ruPhos, xantPhos, dppf, BINOL, BINAP or PCy ₃ Etc.; bases which can be used are, for example ^t BuONa、 ^t BuOK、 ^t BuOLi、Cs ₂ CO ₃ 、LiHMDS、LDA、NaHMDS、KHMDS、K ₃ PO ₄ 、Na ₂ CO ₃ 、KOAc、NaHCO ₃ Or K ₂ CO ₃ The method comprises the steps of carrying out a first treatment on the surface of the Solvents which can be used are, for example, toluene, xylene, THF, DME, 1, 4-dioxane, DMF, DMSO or NMP; and the reaction temperature is 40 ℃ to 140 ℃.

For Ullmann reactions, catalysts which can be used are, for example, cuCl, cuBr, cuI or Cu ₂ O; ligands which can be used are, for example, salicylaldoxime, cyclohexanediamine, N' -dimethylethylenediamine, TMEDA or ethylenediamine; bases which can be used are, for example ^t BuONa、 ^t BuOK、 ^t BuOLi、Cs ₂ CO ₃ 、LiHMDS、LDA、NaHMDS、KHMDS、K ₃ PO ₄ 、Na ₂ CO ₃ 、KOAc、NaHCO ₃ Or K ₂ CO ₃ The method comprises the steps of carrying out a first treatment on the surface of the Solvents which can be used are, for example, toluene, xylene, THF, DME, 1, 4-dioxane, DMF, DMSO or NMP; and the reaction temperature is 40 ℃ to 140 ℃.

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: the compound I-A-4 and the compound I-A-5 are subjected to condensation reaction to generate a compound I-A-6;

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 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-5 into acyl halide, and using acyl halogenating agent such as thionyl chloride and oxalylChlorine, and the like. 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-4 in the presence of alkali to produce the compound I-A-6. 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 ℃.

Fourth step: the compound I-A-6 is subjected to protective group removal under acidic conditions to form a compound of the formula I-A.

The reaction may be carried out in a solvent such as trifluoroacetic acid at a temperature of 25 ℃ to 120 ℃, for example 70 ℃ or 100 ℃.

In certain embodiments, the present invention provides a process for preparing a compound of formula I-B comprising the steps of:

Route B

Wherein:

the remaining groups are as defined above;

the reaction conditions of each step are as follows:

the first step: reacting the compound I-A-4 with triphosgene to generate a compound I-B-1;

solvents which can be used are, for example, THF, DCM or toluene, etc.; the reaction temperature is 25 ℃ to 100 ℃.

And a second step of: reacting the compound I-B-1 with the compound I-B-2 to generate a compound I-B-3;

solvents which can be used are, for example, THF, DCM or toluene, etc.; the reaction temperature is 25 ℃ to 100 ℃; TEA, DIPEA, DMAP, or the like may also be added to promote the reaction.

And a third step of: the compound I-B-3 is subjected to protective group removal under acidic conditions to form a compound of the formula I-B.

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 is preferably administered by oral, intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular, or transdermal route.

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 tumor, preferably a cancer.

In some embodiments, the disease or condition associated with RAF and/or RAS kinase activity is lung cancer (e.g., non-small cell lung cancer), breast cancer, ovarian cancer, gastric cancer, liver cancer, kidney cancer, bone cancer, colorectal cancer, intestinal 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.

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" means preventing or delaying the occurrence of or reducing the intensity of clinical or biochemical manifestations associated with the disease, including not only prevention prior to the development of the disease, but also prevention of recurrence of the disease after treatment.

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.).

In some embodiments, the pharmaceutical compositions or pharmaceutical formulations of the present invention may further comprise one or more additional therapeutic or prophylactic agents (e.g., other agents useful in the treatment of cancer or neoplastic disease). In some embodiments, the methods of treatment of the present invention may further comprise administering one or more additional therapeutic or prophylactic agents (e.g., other agents useful in treating cancer or neoplastic disease).

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.

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, pichia medicine, or terburial chemistry, among others.

Example 1: 4-amino-N- (1- ((3-chloro-2-fluorophenyl) amino) -6-methylisoquinolin-5-yl) -7H-pyrrolo [2,3-d ] pyrimidine-7-carboxamide (Compound 1)

The first step: preparation of N- (3-chloro-2-fluorophenyl) -6-methyl-5-nitroisoquinolin-1-amine (Compound 1 c)

Compound 1a (3.92 g,26.95 mmol) and 1b (5 g,22.46 mmol) were added to isopropanol (25 mL), followed by TFA (3.07 g,26.95mmol,2.00 mL) and stirred in a closed atmosphere at 100deg.C for 18 hours. After the reaction, the reaction solution was naturally cooled to room temperature, suction filtration was performed, the cake was rinsed with isopropyl alcohol, and the obtained solid was dried under reduced pressure to obtain compound 1c (7 g), MS m/z (ESI): 332.0[ M+H ] ] ⁺ 。

And a second step of: n (N) ¹ Preparation of- (3-chloro-2-fluorophenyl) -6-methylisoquinoline-1, 5-diamine (Compound 1 d)

Compound 1c (3.5 g,10.55 mmol) was added to ethanol (50 mL) and water (15 mL), iron powder (2.95 g,52.75 mmol) and concentrated hydrochloric acid (12M, 3 mL) were added, heated to 90℃and stirred for 3.5 hours. After the completion of the reaction, the mixture was filtered through celite while it is hot, the filtrate was concentrated under reduced pressure to remove most of the solvent, then a mixed solvent of chloroform and isopropyl alcohol (chloroform/isopropyl alcohol=4/1, 200 mL) and a saturated sodium carbonate solution (50 mL) were added and stirred well, the lower organic phase was collected after standing and separating, and the aqueous phase was reused with chloroform/isopropyl alcohol=4/1The extracts were combined, dried over anhydrous sodium sulfate, filtered, and concentrated, and the crude product was purified by column chromatography on silica gel (eluent: 100% DCM) to give compound 1d (1.7 g). MS m/z (ESI): 302[ M+H ]] ⁺ 。

And a third step of: preparation of N- (3-chloro-2-fluorophenyl) -5-isocyanate-6-methylisoquinolin-1-amine (Compound 1 e)

Compound 1d (100 mg, 331.41. Mu. Mol) was dissolved in dry THF (8 mL), followed by addition of triphosgene (246 mg, 828.51. Mu. Mol) and reaction was carried out at 25℃for 4hr under nitrogen protection after addition. After the completion of the reaction, the reaction solution was diluted with ethyl acetate, washed with a saturated sodium hydrogencarbonate solution, and the organic phase was dried over anhydrous sodium sulfate and concentrated to give compound 1e (108 mg). MS m/z (ESI): 328.1[ M+H ] ] ⁺ 。

Fourth step: preparation of N- (2, 4-dimethoxybenzyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-amine (Compound 1H)

Compound 1f (500 mg,3.26 mmol) was dissolved in NMP (10 mL) and then 1g (816.59 mg,4.88 mmol) and DIPEA (1.26 g,9.77 mmol) were added and stirred at 120℃for 16hr after addition. After the reaction was completed, the reaction mixture was diluted with ethyl acetate, washed with water 3 times, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by flash column chromatography on silica gel (DCM/meoh=90/10) to give compound 1h (750 mg). MS m/z (ESI): 285.1[ M+H ]] ⁺ 。

Fifth step: preparation of N- (1- ((3-chloro-2-fluorophenyl) amino) -6-methylisoquinolin-5-yl) -4- ((2, 4-dimethoxybenzyl) amino) -7H-pyrrolo [2,3-d ] pyrimidine-7-carboxamide (Compound 1 i)

Compounds 1h (94 mg, 329.53. Mu. Mol) and 1e (108 mg, 329.53. Mu. Mol) were dissolved in toluene (6 mL) and stirred at 100deg.C under nitrogen for 16hr. After the reaction was completed, the reaction mixture was directly purified by flash column chromatography on silica gel (DCM/meoh=90/10) to give compound 1i (30 mg). MS m/z (ESI): 612.2[ M+H ]] ⁺ 。

Sixth step: preparation of 4-amino-N- (1- ((3-chloro-2-fluorophenyl) amino) -6-methylisoquinolin-5-yl) -7H-pyrrolo [2,3-d ] pyrimidine-7-carboxamide (Compound 1)

Compound 1i (30 mg, 49.02. Mu. Mol) was dissolved in TFA (4 mL) and stirred at 85 ℃ 4hr. After the reaction, concentrating the solvent, adding saturated sodium bicarbonate solution dropwise for alkalization, and extracting with EA. The organic phase was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by flash column chromatography on silica gel (DCM/meoh=92/8) followed by Prep-HPLC to give compound 1 (4.09 mg). MS m/z (ESI): 462.1[ M+H ]] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ11.41(s,1H),9.28(s,1H),8.39(d,J＝8.8Hz,1H),8.33(s,1H),7.92(d,J＝6.0Hz,1H),7.69(d,J＝4.0Hz,1H),7.68-7.58(m,3H),7.58–7.51(m,1H),7.39–7.33(m,1H),7.26–7.18(m,2H),6.85(d,J＝4.0Hz,1H),2.46(s,3H).

Example 2: 4-amino-N- (6-methyl-1- ((3- (trifluoromethyl) phenyl) amino) isoquinolin-5-yl) pyrrolo [2,1-f ] [1,2,4] triazine-7-carboxamide (Compound 2)

The first step: preparation of 6-methyl-5-nitro-N- (3- (trifluoromethyl) phenyl) isoquinolin-1-amine (Compound 2 b)

Compounds 2a (731.1 mg,4.45 mmol) and 1b (200.0 mg, 889.4. Mu. Mol) were reacted under solvent-free conditions at 130℃for 5 hours. After the completion of the reaction, the mixture was directly purified by silica gel column chromatography (PE/ea=4/1) to give compound 2b (120.0 mg). MS m/z (ESI): 348.1[ M+H ]] ⁺ 。

And a second step of: 6-methyl-N ¹ Preparation of- (3- (trifluoromethyl) phenyl) isoquinoline-1, 5-diamine (Compound 2 c)

Compound 2b (120.0 mg, 345.5. Mu. Mol), reduced iron powder (59.1 mg,1.04 mmol) and ammonium chloride (37.7 mg, 691.1. Mu. Mol) were added to a mixed solution of ethanol (24.0 mL) and water (8.0 mL), nitrogen was replaced 3 times, and the reaction was warmed to 80℃for 3 hours. After the completion of the reaction, the solid was removed by suction filtration, the filtrate was concentrated, and the crude product was purified by silica gel column chromatography (PE/ea=4/1) to give compound 2c (90.0 mg). MS m/z (ESI): 318.1[ M+H ] ] ⁺ 。

Third step preparation of 7-bromo-N, N-bis (4-methoxybenzyl) pyrrolo [2,1-f ] [1,2,4] triazin-4-amine (Compound 2 f)

Compound 2d (1 g,4.69 mmol) was dissolved in DMF (10 mL), naH (751.05 mg,18.78mmol,60% purity) was added to the ice water bath, and after stirring for 30min compound 2e (2.21 g,14.08 mmol) was added and after the addition was completed, the temperature was naturally raised to 25℃and stirring was continued for 16 hours. 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=3/1) to give compound 2f (1.3 g). MS m/z (ESI): 453.0[ M+H ]] ⁺ 。

Fourth step preparation of methyl 4- (bis (4-methoxybenzyl) amino) pyrrolo [2,1-f ] [1,2,4] triazine-7-carboxylate (Compound 2 g)

Compound 2f (300 mg, 661.77. Mu. Mol), TEA (334.82 mg,3.31 mmol), pd (dppf) Cl ₂ DCM (54.04 mg, 66.18. Mu. Mol) and methanol (14 mL) were added to the autoclave, and after three CO substitutions, the reaction was warmed to 100deg.C under CO pressure of 1.0MPa for 16 hours. After the completion of the reaction, the reaction solution was directly purified by silica gel flash column chromatography (PE/ea=3/1) to obtain 2g (230 mg) of the compound. MS m/z (ESI): 433.1[ M+H ]] ⁺ 。

Fifth step preparation of 4- (bis (4-methoxybenzyl) amino) pyrrolo [2,1-f ] [1,2,4] triazine-7-carboxylic acid (Compound 2 h)

2g (160 mg, 369.97. Mu. Mol) of the compound and LiOH (100 mg,4.18 mmol) were added to THF (5 mL) and water (5 mL) and reacted at room temperature for 16 hours. After the completion of the reaction, the pH of the solution was adjusted to 3-4 with 1N diluted hydrochloric acid, and the solvent was directly concentrated under reduced pressure to give compound 2h (150 mg). MS m/z (ESI): 419.2[ M+H ]] ⁺ 。

Sixth step preparation of 4- (bis (4-methoxybenzyl) amino) -N- (6-methyl-1- ((3- (trifluoromethyl) phenyl) amino) isoquinolin-5-yl) pyrrolo [2,1-f ] [1,2,4] triazine-7-carboxamide (Compound 2 i)

Compounds 2h (47.08 mg, 112.51. Mu. Mol) and 2c (34 mg, 107.15. Mu. Mol) were dissolved in pyridine (1 mL) and T was added dropwise ₃ P (0.3 mL,50% in EA) was reacted at room temperature for 16 hours. Concentrating under reduced pressure to remove solvent after reaction, adjusting pH to about 13 with saturated sodium bicarbonate aqueous solution, extracting with ethyl acetate three times, mixing organic phases, washing with water once, and saturatingOnce washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 2i (70 mg). MS m/z (ESI): 718.2[ M+H ]] ⁺ 。

Seventh step preparation of 4-amino-N- (6-methyl-1- ((3- (trifluoromethyl) phenyl) amino) isoquinolin-5-yl) pyrrolo [2,1-f ] [1,2,4] triazine-7-carboxamide (Compound 2)

Compound 2i (70 mg, 97.53. Mu. Mol) was added to trifluoroacetic acid (10 mL) and heated to 90℃for 16 hours. After the completion of the reaction, the reaction mixture was concentrated to dryness, saturated sodium bicarbonate solution was added, extraction was performed three times with ethyl acetate, the organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated, and the crude product was separated and purified by Prep-HPLC to give compound 2 (32 mg). MS m/z (ESI): 478.2[ M+H ] ] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ10.82(s,1H),9.54(s,1H),8.49(d,J＝8.7Hz,1H),8.37(s,1H),8.34(s,1H),8.31–8.23(m,2H),8.20(s,1H),8.05(d,J＝6.0Hz,1H),7.65(d,J＝8.8Hz,1H),7.56(t,J＝8.0Hz,1H),7.34(d,J＝4.7Hz,1H),7.31(d,J＝7.8Hz,1H),7.23(d,J＝6.1Hz,1H),7.08(d,J＝4.7Hz,1H),2.43(s,3H).

Example 3: 4-amino-N- (1- ((3-chloro-2-fluorophenyl) amino) -6-methylisoquinolin-5-yl) -6, 7-dihydropyridine [2,3-d ] pyrimidine-8 (5H) -carboxamide (Compound 3)

The first step: preparation of N- (2, 4-dimethoxybenzyl) pyridine [2,3-d ] pyrimidin-4-amine (compound 3 b)

Compound 3a (300 mg,2.04 mmol), 1g (357.97 mg,2.14 mmol) and DBU (372.48 mg,2.45 mmol) were dissolved in DMF (8 mL) and PyBOP (1.11 g,2.14 mmol) was added and stirred at 25℃for 16hr after addition. After the completion of the reaction, ethyl acetate was added to dilute the reaction solution, and the mixture was washed with water for 3 times, and the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by flash column chromatography on silica gel (DCM/meoh=94/6) to give compound 3b (150 mg). MS m/z (ESI): 297.0[ M+H ]] ⁺ 。

And a second step of: preparation of N- (2, 4-dimethoxybenzyl) -5,6,7, 8-tetrahydropyridine [2,3-d ] pyrimidin-4-amine (compound 3 c)

Compound 3b (67 mg, 226.10. Mu. Mol) was dissolved in MeOH (5 mL), pd/C (15 mg) was added, and after hydrogen substitution, the mixture was stirred at 25℃for 16hr. After the completion of the reaction, suction filtration was performed, and the filtrate was concentrated to give compound 3c (67 mg). MS m/z (ESI): 301.1[ M+H ]] ⁺ 。

And a third step of: preparation of N- (1- ((3-chloro-2-fluorophenyl) amino) -6-methylisoquinolin-5-yl) -4- ((2, 4-dimethoxybenzyl) amino) -6, 7-dihydropyridine [2,3-d ] pyrimidine-8 (5H) -carboxamide (Compound 3 d)

Compound 3c (98.98 mg, 329.53. Mu. Mol) and 1e (108 mg, 329.53. Mu. Mol) were dissolved in toluene (6 mL) and stirred at 100℃for 16hr under nitrogen. After the reaction was completed, the reaction mixture was directly purified by flash column chromatography on silica gel (DCM/meoh=90/10) to give compound 3d (50 mg). MS m/z (ESI): 628.1[ M+H ]] ⁺ 。

Fourth step: preparation of 4-amino-N- (1- ((3-chloro-2-fluorophenyl) amino) -6-methylisoquinolin-5-yl) -6, 7-dihydropyridine [2,3-d ] pyrimidine-8 (5H) -carboxamide (Compound 3)

Compound 3d (50 mg, 79.61. Mu. Mol) was dissolved in TFA (4 mL) and stirred at 85℃for 4hr. After the reaction, the reaction mixture was concentrated to dryness, quenched with saturated sodium bicarbonate solution, extracted with EA, the organic phase was washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, purified by flash column chromatography on silica gel (DCM/meoh=92/8), and then purified by reverse phase column chromatography on C18 column (acetonitrile/0.5% ammonium bicarbonate solution=65/35) to give compound 3 (4.42 mg). MS m/z (ESI): 478.1[ M+H ]] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ12.59(s,1H),9.18(s,1H),8.27(d,J＝8.8Hz,1H),8.16(s,1H),7.89(d,J＝6.0Hz,1H),7.59–7.50(m,2H),7.39–7.31(m,1H),7.22(td,J＝8.0,1.2Hz,1H),7.14(d,J＝6.0Hz,1H),6.83(br,2H),3.95–3.84(m,2H),2.45(t,J＝6.4Hz,2H),2.39(s,3H),1.97–1.86(m,2H).

Example 4: 4-amino-N- (1- ((3-chloro-2-fluorophenyl) amino) -6-methylisoquinolin-5-yl) -5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidine-7-carboxamide (Compound 4)

The first step: preparation of 4-chloro-N- (1- ((3-chloro-2-fluorophenyl) amino) -6-methylisoquinolin-5-yl) -5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidine-7-carboxamide (Compound 4 b)

The reaction flask was charged with Compound 4a (78 mg, 503.45. Mu. Mol), 1e (150 mg, 457.68. Mu. Mol), DMAP (11 mg, 91.54. Mu. Mol), TEA (93 mg, 915.36. Mu. Mol) and toluene (5 mL), and reacted at 100℃for 16hr under nitrogen. After the completion of the reaction, the reaction mixture was diluted with water, 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 silica gel column chromatography (PE/ea=65/35) to give compound 4b (26 mg). MS m/z (ESI): 483.1[ M+H ]] ⁺ 。

And a third step of: preparation of 4-amino-N- (1- ((3-chloro-2-fluorophenyl) amino) -6-methylisoquinolin-5-yl) -5, 6-dihydro-7H-pyrrolo [2,3-d ] pyrimidine-7-carboxamide (Compound 4)

Compound 4b (26 mg, 53.79. Mu. Mol) was added to ammonia (3 mL) and iPrOH (1 mL), and the mixture was sealed and heated to 120℃for 16hr. After the reaction, the reaction mixture was diluted with water, extracted with EA, and the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by Prep-TLC (DCM/meoh=10/1) followed by Prep-HPLC to give compound 4 (0.8 mg). MS m/z (ESI): 464.0[ M+H ]] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ10.79(s,1H),9.21(s,1H),8.39(br,1H),8.29(d,J＝8.8Hz,1H),7.89(d,J＝6.0Hz,1H),7.59–7.51(m,2H),7.39–7.32(m,1H),7.22(td,J＝8.0,1.6Hz,1H),7.13(d,J＝6.0Hz,1H),6.90(s,2H),4.01(t,J＝8.8Hz,2H),2.86(t,J＝8.8Hz,2H),2.41(s,3H).

Example 5: 4-amino-N- (1- ((3-chloro-2-fluorophenyl) amino) -6-methylisoquinolin-5-yl) pyrrolo [2,1-f ] [1,2,4] triazine-7-carboxamide (Compound 5)

First step preparation of 4- (bis (4-methoxybenzyl) amino) -N- (1- ((3-chloro-2-fluorophenyl) amino) -6-methylisoquinolin-5-yl) pyrrolo [2,1-f ] [1,2,4] triazine-7-carboxamide (Compound 5 a)

Compound 2h (40 mg, 95.59. Mu. Mol) and compound 1d (28.84 mg, 95.59. Mu. Mol) were dissolved in pyridine (3 mL), and T was added dropwise ₃ P (0.5 mL,50% in EA) was reacted at room temperature for 16 hours. After the completion of the reaction, the solvent was removed by concentration under reduced pressure, the pH was adjusted to about 13 with saturated aqueous sodium hydrogencarbonate solution, extraction was performed three times with ethyl acetate, the organic phases were combined and washed once with water, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 5a (60 mg). MS m/z (ESI): 702.3[ M+H ]] ⁺ 。

Second step preparation of 4-amino-N- (1- ((3-chloro-2-fluorophenyl) amino) -6-methylisoquinolin-5-yl) pyrrolo [2,1-f ] [1,2,4] triazine-7-carboxamide (Compound 5)

Compound 5a (60 mg, 85.45. Mu. Mol) was added to trifluoroacetic acid (3 mL) and heated to 90℃for 16 hours. After the completion of the reaction, the reaction mixture was concentrated to dryness, saturated sodium bicarbonate solution was added, extraction was performed three times with ethyl acetate, the organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated, and the crude product was separated and purified by Prep-HPLC to give compound 5 (8.24 mg). MS m/z (ESI): 462.1[ M+H ] ] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ ) δ10.81 (s, 1H), 9.25 (s, 1H), 8.35 (d, j=8.6 hz, 2H), 8.26 (s, 1H), 8.20 (s, 1H), 7.89 (t, j=8.2 hz, 1H), 7.62 (d, j=8.7 hz, 1H), 7.55 (t, j=7.1 hz, 1H), 7.35 (dd, j=11.1, 5.5hz, 2H), 7.23 (t, j=8.1 hz, 1H), 7.16 (d, j=6.0 hz, 1H), 7.08 (d, j=4.4 hz, 1H), 2.43 (s, 3H). Example 6: 4-amino-N- (1- ((4-chloro-2-fluorophenyl) amino) -6-methylisoquinolin-5-yl) -6, 7-dihydropyrido [2,3-d]Pyrimidine-8 (5H) -carboxamide (Compound 6)

The first step: preparation of 4-chloro-2-fluoroaniline (Compound 6 b)

Compound 6a (1.0 g,5.7 mmol) was added to ethanol (12.0 mL) and water (4.0 mL), and iron powder (1.59 g,2.8 mmol) and ammonium chloride (304.7 mg,5.7 mmol) were added sequentially, and the temperature was raised to 80℃for 2 hours. After completion of the reaction, the mixture was filtered through celite, and the filtrate was concentrated to give Compound 6b (800.0 mg). MS m/z (ESI): 146.1[ M+H ]] ⁺ 。

And a second step of: preparation of N- (4-chloro-2-fluorophenyl) -6-methyl-5-nitroisoquinolin-1-amine (Compound 6 c)

Compound 1b (200.0 mg, 898.4. Mu. Mol), 6b (156.9 mg, 1080.0. Mu. Mol) and TFA (102.4 mg, 898.4. Mu. Mol) were added to isopropanol (5.0 mL), and the mixture was heated to 100℃and reacted for 16 hours. After the completion of the reaction, the reaction mixture was adjusted to be alkaline with triethylamine, concentrated, and the crude product was separated and purified by silica gel column chromatography (PE/ea=5/1) to give compound 6c (240.0 mg). MS m/z (ESI): 332.0[ M+H ] ] ⁺ 。

And a third step of: n (N) ¹ Preparation of- (4-chloro-2-fluorophenyl) -6-methylisoquinoline-1, 5-diamine (Compound 6 d)

Compound 6c (100.0 mg, 301.5. Mu. Mol) was added to ethanol (3.0 mL) and water (1.0 mL), and iron powder (84.2 mg, 1510.0. Mu. Mol) and ammonium chloride (16.1 mg, 301.5. Mu. Mol) were added in this order, and the temperature was raised to 80℃for 2 hours. After completion of the reaction, the mixture was filtered through celite, and the filtrate was concentrated to dryness to give compound 6d (85.0 mg). MS m/z (ESI): 302.1[ M+H ]] ⁺ 。

Fourth step: preparation of N- (4-chloro-2-fluorophenyl) -5-isocyanate-6-methylisoquinolin-1-amine (Compound 6 e)

Prepared in the same manner as in the third step of example 1 except that compound 1d was replaced with compound 6d, to obtain compound 6e (144 mg).

Fifth step: preparation of N- (1- ((4-chloro-2-fluorophenyl) amino) -6-methylisoquinolin-5-yl) -4- ((2, 4-dimethoxybenzyl) amino) -6, 7-dihydropyrido [2,3-d ] pyrimidine-8 (5H) -carboxamide (Compound 6 f)

Prepared in the same manner as in the third step of example 3, except that compound 1e was replaced with compound 6e, to obtain compound 6f (50 mg). MS m/z (ESI): 628.3[ M+H ]] ⁺ 。

Fifth step: preparation of 4-amino-N- (1- ((4-chloro-2-fluorophenyl) amino) -6-methylisoquinolin-5-yl) -6, 7-dihydropyrido [2,3-d ] pyrimidine-8 (5H) -carboxamide (Compound 6)

Prepared in the same manner as in the fourth step of example 3 except that compound 3d was replaced with compound 6f, to obtain compound 6 (10 mg). MS m/z (ESI): 478.2[ M+H ]] ⁺ 。

¹ H NMR(400MHz,DMSO-d ₆ )δ12.55(s,1H),9.45(s,1H),8.31(d,J＝8.6Hz,1H),8.19(s,1H),7.87(d,J＝6.1Hz,1H),7.78(dd,J＝6.8,2.6Hz,1H),7.61(d,J＝8.7Hz,1H),7.40–7.33(m,1H),7.29–7.25(m,1H),7.20(s,1H),6.93(s,2H),3.95–3.87(m,2H),2.45(t,J＝6.4Hz,2H),2.41(s,3H),1.97–1.88(m,2H).

Separation method

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.

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 solutions were added after incubation for 60min at room temperature, and fluorescence values of each group of compounds were measured after incubation for 60min at room temperature. The percentage of relative inhibition activity (i.e., inhibition rate) of compounds at different concentrations was calculated as follows using vehicle (DMSO) as negative control and buffer (no RAF enzyme) as blank:

Relative inhibition activity percentage = 1- (compound group fluorescence value at different concentrations-blank fluorescence value)/(negative control fluorescence value-blank fluorescence value) ×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 tables 1 to 2.

Table 1: inhibitory Activity of Compounds against BRAF V600E enzyme

Numbering of compounds	BRAF V600E IC ₅₀ (nM)
		1	11.5±4.4
2	9.4±1.3
		3	10.1±1.0
4	21.5±11.2
		5	4.6±1.4
6	6.3±1.3

Experimental results show that the compound has a strong inhibition effect on BRAF V600E enzyme.

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 the national academy of sciences cell bank) and human hepatoma cell HepG2 (NRAS-Q61K mutation, purchased from American ATCC) were selected.

In the examples, test compounds of different concentrations (100000 nM, 30000nM, 10000nM, 3000nM, 1000nM, 300nM, 100nM, 30nM, 10 nM) were added to the above cells, respectively, and incubated for 72 hours, and the inhibitory activity of the compounds was detected by measurement of ATP in living cells using Cell Titer Glo Kit (Promega).

Determination of the IC of the Compound of the invention against each test cell ₅₀ Values, experimental results are as follows:

table 2: the compound has the inhibitory activity on human melanoma cells A375 and human hepatoma cells HepG2

Numbering of compounds	A375(IC ₅₀ nM)	HepG2(IC ₅₀ nM)
			2	140.5±27.2	66.8±7.3
3	203.3±3.5	47.0±8.3
			5	56.5±5.9	22.5±6.3

Experimental results show that the compound has a strong inhibition effect on a cell line A375 expressing BRAF-V600E and a cell line HepG2 expressing NRAS-Q61K.

Experimental example 3: pharmacokinetic testing of Compounds in Beagle dogs

Pharmacokinetic profiles were examined by administration of the compound to male Beagle dogs via lavage (PO).

The compound 5 of the present invention and HM95573 (prepared according to example 116 of patent CN 104039798B) were PO administered at a dose of 2.5mg/kg in a 20% aqueous hydroxypropyl-beta-cyclodextrin solution as the vehicle. Blood samples were collected before (0 h) and 0.25, 0.5, 1, 2, 4, 6, 8, 24, 48, 72h and 96h post-dose, 1ml was obtained from the vein of the extremities and placed in K ₂ In EDTA anticoagulation tubes, the plasma was separated by centrifugation at 4000rpm for 5min (4 ℃), and stored at-80℃for testing. Plasma samples were subjected to LC-MS/MS analysis after treatment with precipitated proteins. Pharmacokinetic parameters were calculated using the non-compartmental model using WinNonlin 6.3 software and the results are shown in table 3.

Table 3: pharmacokinetic parameters of Compounds in dogs

Conclusion:

the compound 5 of the application is absorbed well in dogs after PO administration, and has high exposure, long half-life and good overall PK property.

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

1. 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:

X ¹ and X ² Each independently selected from C and N;

X ³ and X ⁴ Each independently selected from CH and N;

R ³ is L-R ³ ’；

L is independently at each occurrence 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) ₂ R ²² 、-S(＝O) ₂ NR ^20a 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 The alkyl, heteroalkyl (e.g., alkoxy), alkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocyclyl, aryl, and heteroaryl groups are each 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; or when L is a direct bond and m is greater than 1, two R ³ ' together with the groups to which it is attached form a 4-10 membered heterocyclic ring;

R ⁴ each at 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) ₂ R ²² 、-S(＝O) ₂ NR ^20a 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 The alkyl, heteroalkyl (e.g., alkoxy), alkenyl, alkynyl, cycloalkyl, cycloalkoxy,The heterocyclyl, aryl, and heteroaryl are each optionally substituted with one or more substituents independently selected from the group consisting of: hydroxy, halogen, CN, NH ₂ 、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;

m is 0, 1, 2, 3, 4 or 5;

n is 1 or 2;

p is 0, 1, 2 or 3; and is also provided with

q is 0, 1 or 2;

2. The compound of claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, isotopically-labeled compound, N-oxide, or prodrug thereof, having a structure represented by formula I-a:

Preferably, it has a structure represented by formula I-B:

wherein,,

ring C is selected from pyrrole ring and 5-6 membered heterocycle;

ring a, ring B, X ¹ 、X ² 、R ¹ 、R ³ 、R ⁴ M and p are as defined in claim 1.

3. The compound of claim 1 or 2, 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 pyrrole ring, a 5-6 membered N-containing heterocycle, or a 5-6 membered carbocycle; preferably, ring a is a pyrrole ring, a dihydropyrrole ring, a tetrahydropyridine ring, a dihydro oxazine ring or a cyclohexene ring; more preferably, ring a is a pyrrole ring.

4. The compound of claim 2, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, isotopically-labeled compound, N-oxide, or prodrug thereof, wherein ring C is a pyrrole ring, a dihydropyrrole ring, a tetrahydropyridine ring, or a dihydrooxazine ring; preferably, ring C is a pyrrole ring, a dihydropyrrole ring or a tetrahydropyridine ring.

5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, isotopically-labeled compound, N-oxide, or prodrug thereof, wherein ring B is a benzene ring, a 5-6 membered heteroaryl ring, a 5-6 membered carbocycle, or a 4-6 membered heterocycle; preferably, ring B is a benzene ring or a 5-6 membered heteroaryl ring; more preferably, ring B is a benzene ring.

6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, isotopically-labeled compound, N-oxide, or prodrug thereof, wherein X ¹ C and X ² Is C; or X ¹ C and X ² Is N; or X ¹ Is N and X ² Is C; preferably X ¹ C and X ² Is C; or X ¹ C and X ² Is N.

7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, isotopically-labeled compound, N-oxide, or prodrug thereof, whereinSelected from-> Or,

selected from->Wherein R is ¹ 、R ⁴ And p is as defined in claim 1.

8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, isotopically-labeled compound, N-oxide, or prodrug thereof, wherein X ³ Is CH and X ⁴ Is N.

9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, isotopically-labeled compound, N-oxide, or prodrug thereof, wherein R ¹ Is H or C _1-6 An alkyl group; preferably, R ¹ Is H or C _1-3 An alkyl group; preferably, R ¹ Is H;

R ² selected from H, halogen, C _1-3 Alkyl and C _1-3 Alkoxy, each of said alkyl and alkoxy optionally substituted with one or more halogens; preferably, R ² Selected from halogen and C _1-3 An alkyl group; preferably, R ² Is F or-CH ₃ The method comprises the steps of carrying out a first treatment on the surface of the More preferably, R ² is-CH ₃ 。

10. The compound of any one of claim 1 to 9, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, isotopically-labeled compound, N-oxide, or prodrug thereof,

l is independently at each occurrence a direct bond or-CH ₂ -；

R ³ ' each occurrence is independently selected from H, hydroxy, halogen, CN, NO ₂ 、C _1-4 Alkyl, C _1-4 Heteroalkyl (e.g. C _1-4 Alkoxy group), C _2-6 Alkenyl, C _2-6 Alkynyl, C _3-6 Cycloalkyl, C _3-6 Cycloalkoxy, 4-6 membered heterocyclyl, C _6-10 Aryl, 5-6 membered heteroaryl, -NR ^20a R ^20b 、-SR ²¹ 、-S(＝O) ₂ R ²² 、-S(＝O) ₂ NR ^20a 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 The alkyl, heteroalkyl (e.g., alkoxy), alkenyl, alkynyl, cycloalkyl, cycloalkoxy, heterocyclyl, aryl, and heteroaryl groups are each 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 4-6 membered heterocyclyl;

preferably, R ³ ' each occurrence is independently selected from H, halogen, CN, C _1-4 Alkyl, C _1-4 Heteroalkyl (e.g. C _1-4 Alkoxy) -NR ^20a R ^20b 、-S(＝O) ₂ R ²² And C (=O) R ²¹ The alkyl and heteroalkyl groups (e.g., alkoxy groups) are each optionally substituted with one or more groups independently selected from halogen, C _1-4 Substituents for heteroalkyl and 4-6 membered heterocyclyl;

more preferably, R ³ ' each occurrence is independently selected from H, halogen, C _1-4 Alkyl, C _1-4 Heteroalkyl (e.g. C _1-4 Alkoxy) and-NR ^20a R ^20b Each of the alkyl and heteroalkyl (e.g., alkoxy) is optionally substituted with one or more halo;

R ⁴ each at each occurrence independently of one anotherFrom H, halogen, C _1-4 Alkyl, C _1-4 Heteroalkyl, said alkyl and heteroalkyl (e.g., alkoxy) each optionally substituted with one or more substituents independently selected from the group consisting of: hydroxy, halogen and NH ₂ ；

Preferably, R ⁴ Each at each occurrence is independently selected from H, halogen and C _1-4 An alkyl group.

11. The compound of claim 10, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, isotopically-labeled compound, N-oxide, or prodrug thereof, wherein R ^20a 、R ^20b 、R ^23a 、R ^23b 、R ^24a 、R ^25a And R is ^25b Each independently selected from H, -NHCH ₃ 、-N(CH ₃ ) ₂ 、C _1-4 Alkyl, C _1-4 Alkoxy, C _3-6 Cycloalkyl and 4-6 membered heterocyclyl; the alkyl, alkoxy, 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 4-6 membered heterocyclyl; and is also provided with

12. The compound of any one of claim 1 to 11, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, isotopically-labeled compound, N-oxide, or prodrug thereof,

q is 0 or 1; preferably, q is 1;

m is 0, 1, 2 or 3; preferably, m is 1 or 2;

p is 0, 1 or 2; preferably, p is 0 or 2.

13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, co-crystal, solvate, metabolite, isotopically-labeled compound, N-oxide, or prodrug thereof, wherein the compound is selected from the group consisting of:

14. a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of any one of claims 1 to 13, 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.

15. Use of a compound according to any one of claims 1 to 13, 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 according to claim 14, in the manufacture of a medicament for the prevention or treatment of a disease or condition associated with RAF and/or RAS kinase activity; the disease or condition associated with RAF and/or RAS kinase activity is a tumor, preferably a cancer; more preferably, the disease or condition associated with RAF and/or RAS kinase activity is lung cancer (e.g., non-small cell lung cancer), breast cancer, ovarian cancer, gastric cancer, liver cancer, kidney cancer, bone cancer, colorectal cancer, intestinal 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.

16. A compound according to any one of claims 1 to 13, 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 according to claim 14, for use in the prevention or treatment of a disease or condition associated with RAF and/or RAS kinase activity; the disease or condition associated with RAF and/or RAS kinase activity is a tumor, preferably a cancer; more preferably, the disease or condition associated with RAF and/or RAS kinase activity is lung cancer (e.g., non-small cell lung cancer), breast cancer, ovarian cancer, gastric cancer, liver cancer, kidney cancer, bone cancer, colorectal cancer, intestinal 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.

17. A process for the preparation of a compound of formula I-a comprising the steps of:

route A

Wherein:

the remaining groups are as defined in any one of claims 1 to 13;

the reaction conditions of each step are as follows:

fourth step: removing the protecting group of the compound I-A-6 under acidic conditions to generate a compound of the formula I-A;

alternatively, the process is a process for preparing a compound of formula I-B comprising the steps of:

route B

Wherein:

the remaining groups are as defined in any one of claims 1 to 13;

the reaction conditions of each step are as follows: