WO2015081813A1 - Compound with alk inhibitory activity and preparation and use thereof - Google Patents

Abstract

The present invention relates to a compound with an ALK inhibitory activity and a preparation and use thereof. In particular, the present invention relates to a compound as shown by formula (I) or a pharmaceutically acceptable salt thereof, a preparation method thereof and a use thereof. The compound has the ALK inhibitory activity and can be used for treating cancers which are ALK positive, and thus has a wide prospect in medication.

Description

Compound with ALK inhibitory activity and preparation and use thereof Technical field

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a compound having ALK inhibitory activity and preparation and use thereof.

Background technique

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine protein kinase that was first discovered in a subtype of anaplastic large cell lymphoma (ALCL), hence the name anaplastic lymphoma kinase (anaplastic). Lymphoma kinase, ALK) (Morris, SW et al, Science, 1994, 263, 1281-1284; Shiota, M. et al, Oncogene, 1994, 9, 1567-1574). The ALK protein contains 1620 amino acids with a molecular weight of 177 kilodaltons (kDa) and the 254 amino acid kinase domain consists of amino acid residues 1123 to 1376, which was previously a short transmembrane region composed of amino acids. Expression patterns in mice suggest that it plays a role in the development of the central and peripheral nervous systems; ALK is found in Drosophila to promote intestinal muscle tissue formation in the form of ligand binding, mammalian ligands have not been determined; detection in human retina To the ALK protein. There was no significant abnormality in the life cycle and life activities of ALK knockout mice (Webb, TR et al., Expert Rev. Anti-cancer Ther., 2009, 9, 331-356), indicating that ALK inhibition will not cause serious damage to the body. hurt.

In 2007, two independent research groups identified ALK gene rearrangements in non-small cell lung cancer. One group of researchers developed a retroviral cDNA expression library for screening new oncogenes. They transfected a cDNA library extracted from a lung adenocarcinoma of a 62-year-old Japanese male smoker who was pre-screened to show KRAS and EGFR mutations, and designed a transgenic mouse to specifically express EML4-ALK in alveolar cells. This produces many lung adenocarcinoma nodules. Treatment of these transgenic mice with ALK inhibitors resulted in a reduction in tumor burden compared to untreated mice. Most mice die very quickly within 1 month. Treatment with the same ALK inhibitor resulted in no EML4-ALK/3T3 cell infiltration in the lung and prolonged survival. This study strongly confirms that EML4-ALK is the only driving mutation in non-small cell lung cancer, and that inhibition of EML4-ALK activity in vivo leads to a reduction in lung cancer burden (Soda, M., Choi, YL, Enomoto, M., et al., Nature, 2007: 448). EML4-ALK fusion occurs in approximately 3-5% of non-small cell lung cancers, differing between the study population and the ALK assay used, and is the only driver mutation in non-small cell lung cancer.

Experimental data show that inhibition of ALK gene can effectively prevent the growth of ALK-positive lymphoma cells and lung cancer cells, indicating that ALK inhibitors are of great value in the treatment of such tumors (Piva, R. et al, Blood, 2006, 107, 689- 697; Galkin, AV, et al, Proc. Natl. Acad. Sci. USA, 2007, 104, 270-275; Koivunen, JP et al, Clin. Cancer Res., 2008, 14, 4275-4238).

Summary of the invention

During the course of the research, the inventors have found a compound of the formula (I) or a pharmaceutically acceptable salt thereof, which has ALK inhibitory activity and can be used for treating cancers which are positive for ALK, and has broad drug prospects. .

In one aspect, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:

among them:

Ring A is selected from a 5-10 membered cycloalkyl group, a 5-10 membered heterocyclic group, a 5-10 membered aryl group or a 5-10 membered heteroaryl group;

R _{1 is} selected from C _1-6 alkyl, halogen-substituted C _1-6 alkyl, C _3-6 cycloalkyl or 4-tolyl;

R ₂ , R ₃ , R ₄ and R ₅ are each independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, C _1-6 alkyl, halogen substituted C _1-6 alkyl, C _3-8 ring Alkyl, C _1-6 alkoxy, halogen substituted C _1-6 alkoxy, C _3-8 cycloalkoxy, -S(O)pR ₉ , -C(O)R ₉ , -C( O) OR ₉ , -NR ₁₀ R ₁₁ or -C(O)NR ₁₁ ;

R ₆ , R ₇ and R ₈ are each independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _{3 -8} cycloalkyl, 3-8 membered heterocyclic, C _5-10 aryl, 5-10 membered heteroaryl, C _1-6 alkoxy, C _3-8 cycloalkoxy, -S(O ) pR ₉ , -C(O)R ₉ , -C(O)OR ₉ , -NR ₁₀ R ₁₁ or -C(O)NR ₁₁ ,

Wherein the C _1-8 alkyl group, the C _3-8 cycloalkyl group, the 3-8 membered heterocyclic group, the C _5-10 aryl group or the 5-10 membered heteroaryl group are each independently optionally further one or more One selected from the group consisting of halogen, hydroxy, cyano, nitro, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic ring , C _5-10 aryl, 5-10 membered heteroaryl, C _1-6 alkoxy, C _3-8 cycloalkoxy, -S(O)pR ₉ , -C(O)R ₉ , Substituted by a substituent of -C(O)OR ₉ , -NR ₁₀ R ₁₁ or -C(O)NR ₁₁ ;

R ₉ , R ₁₀ and R _{11 are} selected from the group consisting of hydrogen and C _l-4 alkyl;

m, n are 0, 1, 2, 3, 4;

L is 0, 1, 2, 3, 4, 5;

p is 0, 1, or 2.

Preferably, the structure formed by ring A together with its substituent is selected from the following structures:

More preferably, the structure formed by ring A together with its substituent is selected from the following structures:

Wherein R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , m, n, L, p are as defined for the compound of formula (I).

Further preferably, R ₂ and R ₅ are each independently selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, halogen-substituted C _1-6 alkyl; and R ₃ and R ₄ are each independently selected from the group consisting of hydrogen, halogen, and hydroxyl. , cyano, nitro, C _1-6 alkyl, halogen substituted C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 alkoxy, halogen substituted C _1-6 alkoxy , C _3-8 cycloalkoxy, -S(O)pR ₉ , -C(O)R ₉ , -C(O)OR ₉ , -NR ₁₀ R ₁₁ or -C(O)NR ₁₁ ; R ₆ And R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , m, n, L, p are as defined for the compound of formula (I).

Most preferably, the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of:

More preferably, the compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of compounds of formula (II):

among them:

R _{3 is} selected from the group consisting of hydrogen, hydroxy, cyano, nitro, C _3-8 cycloalkyl, C _1-6 alkoxy, halogen substituted C _1-6 alkoxy, C _3-8 cycloalkoxy, -S(O)pR ₉ , -C(O)R ₉ , -C(O)OR ₉ , -NR ₁₀ R ₁₁ or -C(O)NR ₁₁ ;

R ₂ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , m, n, L, p are as defined for the compound of formula (I).

Further preferably, R _{3 is} selected from halogen-substituted C _1-6 alkoxy; R ₂ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , m, n, L, p are as defined for the compound of formula (I).

Most preferably, it is selected from the group consisting of:

According to another aspect of the present invention, there is provided a process for the preparation of a compound of the formula (I), which comprises the steps of: condensing a compound of the formula (III) with a compound of the formula (IV) to give a compound of the formula (I), or a formula (III) The compound is condensed with the formula (IV) and then converted to the corresponding compound of the formula (I) according to a different definition of the substituent or a deprotecting group, the synthesis route of which is as follows:

Wherein ring A, R ₁ , R ₂ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , m, n, L, p are as defined for the compound of formula (I) .

A further aspect of the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the foregoing, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

A further aspect of the invention provides a method of modulating the catalytic activity of a protein kinase comprising contacting the protein kinase with a compound of the foregoing, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the foregoing, selected from the group consisting of a metaplastic lymphocyte Tumor kinase.

A further aspect of the present invention provides the use of the aforementioned compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, for the preparation of a medicament for treating cancer, wherein the cancer is preferably non-small cell lung cancer.

detailed description

DETAILED DESCRIPTION: Unless otherwise stated, the following terms used in the specification and claims have the following meanings.

The "C _1-8 alkyl group" means a linear alkyl group having 1 to 8 carbon atoms and a branched alkyl group, and the alkyl group means a saturated aliphatic hydrocarbon group. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-di Methylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl 1,1,2-Trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethyl Butyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl , 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3 ,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-di Methylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2 -Methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl or various branched isomers thereof.

The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, cyano. , nitro, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclyl, C _5-10 aryl, 5-10 membered heteroaryl, C _1-6 alkoxy, C _3-8 cycloalkoxy, -S(O)pR ₉ , -C(O)R ₉ , -C(O)OR ₉ ,- Substituted by a substituent of NR ₁₀ R ₁₁ or -C(O)NR ₁₁ .

"Cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and "C _3-8 cycloalkyl" refers to a cycloalkyl group of 3 to 8 carbon atoms, "5-10 membered ring.""Alkyl" means a cycloalkyl group of 5 to 10 carbon atoms, for example:

Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptene Alkenyl, cyclooctyl and the like.

Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups. "Spirocycloalkyl" refers to a polycyclic group that shares a carbon atom (called a spiro atom) between the monocyclic rings. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. The spirocycloalkyl group is divided into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group according to the number of shared spiro atoms between the ring and the ring. Non-limiting examples of spirocycloalkyl groups include:

"Fused cycloalkyl" refers to an all-carbon polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or more double bonds, but None of the rings have a fully conjugated π-electron system. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl groups, and non-limiting examples of fused cycloalkyl groups include:

"Bridge cycloalkyl" refers to an all-carbon polycyclic group in which two rings share two carbon atoms that are not directly bonded, which may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system . Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups. Non-limiting examples of bridged cycloalkyl groups include:

The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydrogen Naphthyl, benzocycloheptyl and the like.

The cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of halogen, hydroxy, cyano, nitro, C _1-8 alkane. , C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, C _5-10 aryl, 5-10 membered heteroaryl, C _1-6 alkoxy, C _3-8 cycloalkoxy, -S(O)pR ₉ , -C(O)R ₉ , -C(O)OR ₉ , -NR ₁₀ R ₁₁ or -C(O Substituted by a substituent of NR ₁₁ .

"Heterocyclyl" means a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent wherein one or more of the ring atoms are selected from nitrogen, oxygen or S(O)p (where p is an integer 0, 1, 2 a hetero atom, but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. The "5-10 membered heterocyclic group" means a ring group containing 5 to 10 ring atoms, and the "3-8 membered heterocyclic group" means a ring group containing 3 to 8 ring atoms.

Non-limiting examples of monocyclic cycloalkyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and the like.

Polycyclic cycloalkyl groups include spiro, fused, and bridged heterocyclic groups. "Spiroheterocyclyl" refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between a single ring, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O)p (where p is an integer) The heteroatoms of 0, 1, 2), and the remaining ring atoms are carbon. These may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. The spirocycloalkyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspiroheterocyclic group depending on the number of common spiro atoms between the ring and the ring. Non-limiting examples of spirocycloalkyl groups include:

"Fused heterocyclyl" refers to a polycyclic heterocyclic group in which each ring of the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more double bonds, but none The ring has a fully conjugated pi-electron system in which one or more ring atoms are selected from nitrogen, oxygen or S(O)p (where p is an integer from 0 to 2) heteroatoms, the remaining ring atoms being carbon. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl groups, and non-limiting examples of fused heterocyclic groups include:

"Bridge heterocyclyl" refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly bonded, and these may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system, One or more of the ring atoms are selected from the group consisting of nitrogen, oxygen or S(O)p (where p is an integer 0, 1, 2) heteroatom, and the remaining ring atoms are carbon. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups. Non-limiting examples of bridged cycloalkyl groups include:

The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring wherein the ring to which the parent structure is attached is a heterocyclic group, non-limiting examples comprising:

The heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of halogen, hydroxy, cyano, nitro, C _1-8 alkane. , C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, C _5-10 aryl, 5-10 membered heteroaryl, C _1-6 alkoxy, C _3-8 cycloalkoxy, -S(O)pR ₉ , -C(O)R ₉ , -C(O)OR ₉ , -NR ₁₀ R ₁₁ or -C(O Substituted by a substituent of NR ₁₁ .

"Aryl" means an all-carbon monocyclic or fused polycyclic (ie, a ring that shares a pair of adjacent carbon atoms) groups having a polycyclic ring of a conjugated π-electron system (ie, having a ring adjacent to a carbon atom) a group, "C _5-10 aryl" means an all-carbon aryl group having 5 to 10 carbons, and "5-10 membered aryl group" means an all-carbon aryl group having 5 to 10 carbons, such as phenyl and Naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples comprising:

The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of halogen, hydroxy, cyano, nitro, C _1-8 alkyl, C. _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, C _5-10 aryl, 5-10 membered heteroaryl, C _1-6 Alkoxy, C _3-8 cycloalkoxy, -S(O)pR ₉ , -C(O)R ₉ , -C(O)OR ₉ , -NR ₁₀ R ₁₁ or -C(O)NR ₁₁ Substituted by a substituent.

"Heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms including nitrogen, oxygen and a hetero atom of S(O)p (where p is an integer 0, 1, 2), 5- A 7-membered heteroaryl group means a heteroaromatic system having 5 to 7 ring atoms, and a 5-10 membered heteroaryl group means a heteroaromatic system having 5 to 10 ring atoms, such as furyl, thienyl, pyridyl, Pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples comprising:

The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of halogen, hydroxy, cyano, nitro, C _1-8 alkane. , C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, C _5-10 aryl, 5-10 membered heteroaryl, C _1-6 alkoxy, C _3-8 cycloalkoxy, -S(O)pR ₉ , -C(O)R ₉ , -C(O)OR ₉ , -NR ₁₀ R ₁₁ or -C(O Substituted by a substituent of NR ₁₁ .

"Alkenyl" means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, and a C _2-8 alkenyl group means a straight or branched olefin containing from 2 to 8 carbons base. For example, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, and the like.

The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of halogen, hydroxy, cyano, nitro, C _1-8 alkyl, C. _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, C _5-10 aryl, 5-10 membered heteroaryl, C _1-6 Alkoxy, C _3-8 cycloalkoxy, -S(O)pR ₉ , -C(O)R ₉ , -C(O)OR ₉ , -NR ₁₀ R ₁₁ or -C(O)NR ₁₁ Substituted by a substituent.

"Alkynyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, and _C2-8 alkynyl refers to a straight or branched alkynyl group containing from 2 to 8 carbons. . For example, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like.

The alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of halogen, hydroxy, cyano, nitro, C _1-8 alkyl, C. _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, C _5-10 aryl, 5-10 membered heteroaryl, C _1-6 Alkoxy, C _3-8 cycloalkoxy, -S(O)pR ₉ , -C(O)R ₉ , -C(O)OR ₉ , -NR ₁₀ R ₁₁ or -C(O)NR ₁₁ Substituted by a substituent.

"Alkoxy" means -O-(alkyl) wherein alkyl is as defined above. The C _1-6 alkoxy group means an alkyloxy group having 1 to 6 carbons, and the non-limiting examples include a methoxy group, an ethoxy group, a propoxy group, a butoxy group and the like.

The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent, preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, cyano, nitro, C _1-8 Alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, C _5-10 aryl, 5-10 membered heteroaryl, C _1-6 alkoxy, C _3-8 cycloalkoxy, -S(O)pR ₉ , -C(O)R ₉ , -C(O)OR ₉ , -NR ₁₀ R ₁₁ or -C( O) substituted with a substituent of NR ₁₁ ;

"Cycloalkoxy" refers to -O-(unsubstituted cycloalkyl) wherein cycloalkyl is as defined above. The C _3-8 cycloalkoxy group means a cycloalkyloxy group having 3-8 carbons, and the non-limiting examples include a cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxy group, a cyclohexyloxy group and the like.

The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of halogen, hydroxy, cyano, nitro, C _1-8 alkane. , C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic, C _5-10 aryl, 5-10 membered heteroaryl, C _1-6 alkoxy, C _3-8 cycloalkoxy, -S(O)pR ₉ , -C(O)R ₉ , -C(O)OR ₉ , -NR ₁₀ R ₁₁ or -C(O Substituted by a substituent of NR ₁₁ .

"Halogen-substituted C _1-6 alkyl" means a hydrogen 1-6 alkylalkyl group optionally substituted by fluorine, chlorine, bromine or iodine, such as difluoromethyl or dichloromethyl, on the alkyl group. Base, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, and the like.

The hydrogen on the "halogen-substituted _C1-6 alkoxy"alkyl group is optionally a _1-6 carboalkoxy group substituted with a fluorine, chlorine, bromine or iodine atom. For example, difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy, and the like.

"Halogen" means fluoro, chloro, bromo or iodo.

"Hydroxy" refers to an -OH group.

"Nitro" refers to a -NO ₂ group.

"-S(O)pR ₉ " refers to a sulfur, sulfinyl group, or sulfuryl group substituted with R ₉ .

"-C(O)R ₉ " refers to a carbonyl group substituted with R ₉ .

"-C(O)OR ₉ " refers to an R ₉ -substituted oxycarbonyl group.

"-NR ₁₀ R ₁₁ " refers to an amino group substituted with R ₁₀ and R ₁₁ .

"-C(O)NR ₁₁ " refers to an amide group substituted with R ₁₁ .

"Optional" or "optionally" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may be, but not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group. .

"Substituted" refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.

"Pharmaceutical composition" means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers and excipient. The purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.

The present invention is further described in detail with reference to the accompanying drawings, but by no way of limitation,

Example 1: 5-Chloro-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-(2-(isopropylsulfonyl)pyridin-3-yl Pyrimidine-2,4-diamine

First step: Preparation of 4-(5-isopropoxy-2-methyl-4-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester

1-Chloro-5-isopropoxy-2-methyl-4-nitrobenzene (2.5 g, 10.89 mmol), 4-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (3.7 g, 11.97 mmol), potassium carbonate (4.5 g, 26.78 mmol) and Pd (dppf)Cl ₂ (398 mg, 0.55 mmol) was dissolved in 1,4-dioxane. Nitrogen replacement protection, heating to 150 ° C reaction. After 5 hours, the reaction solvent was stirred, water and dichloromethane were added, and the aqueous layer and organic layer were separated, and the aqueous phase was extracted three times with dichloromethane. The organic phases were combined and dried over anhydrous sodium sulfate. The solvent was distilled off, and the product was separated and purified by column chromatography.

LCMS: t = 4.85 min, 347.1 (M+H ⁺ ).

Second step: Preparation of tert-butyl 4-(4-amino-5-isopropoxy-2-methylphenyl)piperidine-1-carboxylate

The compound 4-(5-isopropoxy-2-methyl-4-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (3.4 g, 0.26 mmol) Dissolved in methanol and added palladium on carbon (400 mg). The hydrogen was replaced and stirred at room temperature overnight under a hydrogen atmosphere. Filtration and evaporation of methanol gave compound 4-(4-amino-5-isopropoxy-2-methylphenyl)piperidine-1-carboxylic acid tert-butyl ester (3.3 g).

LCMS: t = 4.16 min, 349.0 (M+H ⁺ ).

The third step: preparation of 2-isopropyl decyl-3-nitropyridine

2-Fluoro-3-nitropyridine (500 mg, 3.52 mmol), potassium carbonate (973 mg, 7.04 mmol) was placed in a 100 mL round bottom flask, and 15 ml of DMF was added. Under stirring, isopropyl mercaptan (0.36 mL, 3.87 mmol) was added, and the mixture was reacted at room temperature for 1 hour. After completion of the reaction, the reaction solvent was vortexed, and the obtained crude product was washed with water, ethyl acetate, dried and concentrated. Chromatography gave the product 2-isopropylmercapto-3-nitropyridine (660 mg, yield 95%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.61 (dd, J = 4.8, 1.6 Hz, 1H), 8.40 (dd, J = 8.4, 1.6 Hz, 1H), 7.10 (dd, J = 8.4, 4.8 Hz, 1H), 4.13-4.06 (m, 1H), 1.35 (d, J = 6.8 Hz, 6H).

LCMS: t = 4.31 min, 198.9 (M + H ⁺ ).

The fourth step: preparation of 2-isopropylsulfone-3-nitropyridine

2-Isopropylguanidino-3-nitropyridine (660 mg, 3.33 mmol) and mCPBA (85%, 2.2 g, 9.99 mmol) were placed in a 100 mL round bottom flask and 15 mL DCM was added. The mixture is stirred at room temperature overnight. After the reaction is completed, the reaction solvent is evaporated. The obtained crude product is washed with saturated sodium sulfite solution, saturated potassium carbonate solution, saturated brine, dichloromethane, dried, 2-isopropylsulfone-3-nitropyridine (700 mg, yield 91%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.84 (dd, J = 4.4, 1.6 Hz, 1H), 8.06 (dd, J = 8.4, 1.6 Hz, 1H), 7.68 (dd, J = 8.0, 4.4 Hz, 1H), 4.03-3.96 (m, 1H), 1.36 (d, J = 6.8 Hz, 6H).

LCMS: t = 3.39 min, 201.0 (M + H ⁺ ).

Step 5: Preparation of 2-isopropylsulfone-3-aminopyridine

2-Isopropylsulfonyl-3-nitropyridine (700 mg, 2.18 mmol) was placed in a 100 mL hydrogenation flask, and 15 ml of methanol was added. After replacing with nitrogen, 100 mg of palladium/carbon was added to the bottle and replaced with a hydrogen balloon. After stirring overnight, the solution was filtered, and the filtrate was dried under reduced pressure to give a product (600 mg, yield 90%).

LCMS: t = 2.85 min, 201.0 (M+H ⁺ ).

Step 6: Preparation of 2,5-dichloro-N-(2-(isopropylsulfonyl)pyridin-3-yl)pyrimidine-4-amine

2-Isopropylsulfonyl-3-aminopyridine (200 mg, 1.0 mmol) was dissolved in DMF (6 mL)EtOAc. After the addition, the reaction mixture was further stirred at 0 ° C for half an hour, and 2,5,6-trichloropyrimidine (201 mg, 1.1 mmol) was added dropwise to the reaction mixture at 0 °C. After the dropwise addition, the mixture was naturally stirred to room temperature and stirred overnight. After completion, 200 mL of water was added, and extracted with EA (30 mL*3), the organic phase was combined, dried, and the solvent was evaporated. The obtained crude product was obtained by column chromatography (90 mg, yield 26%).

_{^{1 H NMR (400MHz, CDCl 3}} ) δ10.48 (s, 1H), 9.17 (dd, J = 8.4,1.6Hz, 1H), 8.38 (dd, J = 4.4,2.8Hz, 1H), 8.26 (s, 1H), 7.55 (dd, J = 8.8, 3.2 Hz, 1H), 3.90-3.87 (m, 1H), 1.31 (d, J = 6.8 Hz, 6H).

LCMS: t = 3.95 min, 346.9 (M+H ⁺ ).

Step 7: 4-(4-((5-Chloro-4-((2-(isopropylsulfonyl)pyridin-3-yl)amino)pyrimidin-2-yl)amino)-5-isopropyloxy Preparation of tert-butyl 2-methylphenyl) piperidine-1-carboxylate

2,5-Dichloro-N-(2-(isopropylsulfonyl)pyridin-3-yl)pyrimidin-4-amine (90 mg, 0.26 mmol), 4-(4-amino-5-isopropyloxy) Tert-butyl 2-methylphenyl)piperidine-1-carboxylate (100 mg, 0.28 mmol), palladium acetate (6 mg, 20 μmol), Xantphos (17 mg, 22 μmol), cesium acetate (253 mg, 0.78 mmol) In a 10 mL microwave tube, 5 ml of dioxane was added, and after nitrogen substitution, the mixture was microwave-heated to 130 °C for half an hour. After the reaction was completed, the reaction solvent was rotated, and the obtained crude product was subjected to column chromatography to obtain a product (60 mg, yield 35). %).

LCMS: t = 5.47 min, 658.9 (M+H ⁺ ).

Step 8: 5-Chloro-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-(2-(isopropylsulfonyl)pyridin-3-yl Preparation of pyrimidine-2,4-diamine

4-(4-((5-Chloro-4-((2-(isopropylsulfonyl)pyridin-3-yl)amino)pyrimidin-2-yl)amino)-5-isopropoxy-2 -Methylphenyl)piperidine-1-carboxylic acid tert-butyl ester (60 mg, 91 μmol) was dissolved in 4 ml of DCM. EtOAc (1 mL) was added dropwise at room temperature and stirred for half an hour. The obtained crude product was purified by column chromatography and preparative TLC (30 mg, yield 59%).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ10.01 (s, 1H), 9.14 (dd, J = 8.8,1.2Hz, 1H), 8.31 (dd, J = 4.0,2.8Hz, 1H), 7.90 (s , 1H), 7.43 (s, 1H), 7.40-7.37 (m, 1H), 6.76 (s, 1H), 4.55-4.52 (m, 1H), 3.89-3.85 (m, 1H), 3.53-3.50 (m , 2H), 2.96-2.85 (m, 3H), 2.15 (s, 3H), 2.05-2.02 (m, 2H), 1.89-1.86 (m, 2H), 1.33 (d, J = 7.2 Hz, 6H), 1.30 (d, J = 6.4 Hz, 6H).

LCMS: t = 3.69 min, 558.9 (M + H ⁺ ).

Example 2: 5-Difluoromethoxy-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-[2-(propane-2-sulfonyl)- Preparation of phenyl]-pyrimidine-2,4-diamine

First step: Preparation of 2-chloro-N-(2-(isopropylsulfonyl)phenyl)-5-methoxypyrimidine-4-amine

2-isopropylsulfonylaniline (200 mg, 0.99 mmol) was dissolved in DMF (8 mL). NaH (29 mg, 1.2 mmol) was slowly added at 0 ° C. After the addition, the reaction mixture was stirred at 0 ° C for half. After 2 hours, 2,6-dichloro-5-methoxypyrimidine (197 mg, 1.1 mmol) was added dropwise to the reaction mixture at 0 ° C, and the mixture was stirred and the mixture was stirred to room temperature for 4 hours. After completion, 200 mL of water was added and extracted with DCM (30 mL*3). The organic phase was combined, dried, and the solvent was evaporated. The obtained crude product was obtained by column chromatography (90 mg, yield 26%).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ9.50 (s, 1H), 9.87 (s, 1H), 8.68 (d, J = 8.4,1.2Hz, 1H), 7.81 (dd, J = 8.0,1.6Hz , 1H), 7.76 (s, 1H), 7.64-7.60 (m, 1H), 7.17-7.15 (m, 1H), 3.94 (s, 3H), 3.17-3.10 (m, 1H), 1.22 (d, J =6.8Hz, 6H).

LCMS: t = 4.10 min, 341.8 (M+H ⁺ ).

Second step: Preparation of 2-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidine-5-phenol

The compound 2-chloro-N-(2-(isopropylsulfonyl)phenyl)-5-methoxypyrimidin-4-amine (50 mg, 0.15 mmol) was dissolved in anhydrous DCM (10 mL) BBr ₃ (0.2 mL, 4 N in DCM, 0.75 mmol) was slowly added at ° C. After the addition, the reaction mixture was allowed to warm to room temperature overnight. After completion of the reaction, the reaction was quenched by slowly adding methanol (3 mL) at 0 ° C, and then washed with 500 mL of water and extracted with DCM (40 mL*3). The organic phase was combined and dried, and the solvent was evaporated to give a crude product. Light yellow solid (30 mg, yield 52%).

LCMS: t = 3.68 min, 327.9 (M+H ⁺ ).

The third step: preparation of 2-chloro-5-(difluoromethoxy)-N-(2-(isopropylsulfonyl)phenyl)pyrimidine-4-amine

2-Chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-5-phenol (20 mg, 61 μmol), sodium difluoromonochloroacetate (28 mg, 0.18 mmol), potassium carbonate ( 25 mg, 0.18 mmol) was placed in a 10 mL microwave tube, 3 ml of DMF and 3 ml of water were added, and after nitrogen substitution, the mixture was microwave-heated to 120 degrees for 1 hour. After the reaction was completed, the reaction solvent was rotated, and the obtained crude product was obtained by column chromatography. Product (10 mg, yield 43%).

LCMS: t = 4.29 min, 377.8 (M+H ⁺ ).

Fourth step: 4-(4-((5-(difluoromethoxy)-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5- Preparation of tert-butyl isopropoxy-2-methylphenyl)piperidine-1-carboxylate

The compound 2-chloro-5-(difluoromethoxy)-N-(2-(isopropylsulfonyl)phenyl)pyrimidine-4-amine (10 mg, 26 μmol), 4-(4-amino-5) -isopropoxy-2-methylphenyl)piperidine-1-carboxylic acid tert-butyl ester (14 mg, 39 μmol), palladium acetate (1 mg, 2.08 μmol), Xantphos (2 mg, 2.6 μmol), cesium acetate (25 mg) , 79 μmol) was placed in a 10 mL microwave tube, 2 ml of dioxane was added, and after nitrogen substitution, the mixture was microwave-heated to 130 ° C for half an hour. After the reaction was completed, the reaction solvent was spun off, and the obtained crude product was subjected to column chromatography to obtain a product (5 mg). , yield 27%).

LCMS: t = 5.36 min, 89.9 (M+H ⁺ ).

The fifth step: 5-difluoromethoxy-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-[2-(propane-2-sulfonyl)- Preparation of phenyl]-pyrimidine-2,4-diamine

4-(4-((5-(Difluoromethoxy)-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-5-isopropyloxy tert-Butyl 2-methylphenyl)piperidine-1-carboxylate (5 mg, 7.2 μmol) was dissolved in 4 mL of DCM. EtOAc (1 mL) was added dropwise at room temperature and stirred for half an hour. The reaction solvent was removed, and the obtained crude material was purified by column chromatography (yield)

_{^{1 H NMR (400MHz, CDCl 3}} ): δ9.50 (s, 1H), 8.63 (d, J = 8.4Hz, 1H), 8.03 (d, J = 4.8Hz, 2H), 7.83 (dd, J = 8.0 , 2.8 Hz, 1H), 7.55-7.45 (m, 2H), 7.16-7.15 (m, 1H), 6.92 (s, 0.2H), 6.74 (s, 1H), 6.71 (s, 0.2H), 6.53 ( s, 0.4H), 6.35 (s, 0.2H), 4.53-4.50 (m, 1H), 3.48-3.42 (m, 2H), 3.27-3.21 (m, 1H), 2.92-2.78 (m, 3H), 2.13 (s, 3H), 1.99-1.77 (m, 4H), 1.27 (d, J = 6 Hz, 6H).

LCMS: t = 3.64 min, 590.0 (M + H ⁺ ).

Example 3: 5-Chloro-2-[2-isopropoxy-5-methyl-4-(1-methyl-piperidin-4-yl)-phenyl]-4-[2-(propane Preparation of -2-sulfonyl)-pyridin-3-yl]-pyrimidine-2,4-diamine

The compound 5-chloro-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-(2-(isopropylsulfonyl)pyridin-3-yl)pyrimidine -2,4-Diamine (15 mg, 26.8 μmol) was dissolved in dry anhydrous methanol, and paraformaldehyde (4 mg, 134 μmol), sodium cyanoborohydride (3.37 mg, 53.6 μmol) and catalytic amount were added at room temperature. Acetic acid. The mixture was stirred at room temperature overnight and the reaction was checked by TLC and LCMS. The reaction was quenched by dropwise addition of a 1N aqueous NaOH solution. The organic solvent was evaporated under reduced pressure, and the residue was evaporated, evaporated, mjjjjjjjjjjjjjjjj -Chloro-2-[2-isopropoxy-5-methyl-4-(1-methyl-piperidin-4-yl)-phenyl]-4-[2-(propane-2-sulfonyl) )-pyridin-3-yl]-pyrimidine-2,4-diamine (5 mg, 30%).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ10.60 (s, 1H), 10.06 (s, 1H), 9.20 (dd, J = 8.7,1.3Hz, 1H), 8.93 (dd, J = 8.6,1.3Hz , 1H), 8.50 (t, J = 4.3, 1.4 Hz, 2H), 8.38 (d, J = 4.3, 1.4 Hz, 1H), 8.21 (s, 1H), 8.19 (s, 1H), 7.96 (s, 1H), 7.58 (s, 1H), 7.53 (s, 1H), 7.48 (dd, J = 8.7, 4.4 Hz, 1H), 7.42 (dd, J = 8.6, 4.4 Hz, 1H), 6.95 (s, 1H) ), 6.84 (s, 1H), 4.76-4.55 (m, 2H), 4.36 (s, 1H), 4.10-3.87 (m, 2H), 3.68 (s, 4H), 3.12-2.79 (m, 11H), 2.45-2.31 (m, 5H), 2.22 (s, 3H), 2.17 (s, 3H), 2.07-1.99 (m, 6H), 1.46-1.31 (m, 22H).

LCMS: t = 3.60 min, 612.3 (M + K ⁺ ).

Example 4: 1-[4-(4-{5-chloro-4-[2-(propane-2-sulfonyl)-pyridin-3-ylamino]-pyrimidin-2-ylamino}-5-iso Preparation of propoxy-2-methyl-phenyl)-piperidin-1-yl]-ethanone

First step: 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1 (2H Preparation of -) ketone

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester (1.0g, 3.2mmol) was dissolved in dichloromethane, trifluoroacetic acid (4mL) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated to give a colorless oil. Amine (2 mL, 14.3 mmol) was slowly added dropwise EtOAc (1OmL, &lt 30 mL of water and 30 mL of dichloromethane were added to the system, the aqueous phase was separated, and the solvent was evaporated to give an orange solid (700 mg, 86%).

Second step: Preparation of 1-{4-[2-methyl-4-nitro-5-(propan-2-yloxy)phenyl]piperidin-1-yl}-ethanone

1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1 under nitrogen protection 2H)-yl]ethanone (601.4 mg, 2.3 mmol) was dissolved in 10 mL of dioxane/water (3:1), followed by 1-chloro-5-isopropoxy-2-methyl-4 -nitrobenzene (500.0 mg, 2.3 mmol), Pd(dppf)Cl ₂ (80 mg, 0.11 mmol) and potassium carbonate (902 mg, 6.5 mmol). The reaction system was stirred at 150 ° C for 1 hour, and the solvent was evaporated. Column chromatography gave 1-{4-[2-methyl-4-nitro-5-(propan-2-yloxy)phenyl]piperidin-1-yl}-ethanone (600 mg, 77%).

Third step: Preparation of 1-{4-[4-amino-2-methyl-5-(propan-2-yloxy)phenyl]piperidin-1-yl}-ethanone

1-{4-[2-Methyl-4-nitro-5-(propan-2-yloxy)phenyl]piperidin-1-yl}-ethanone (600 mg) was dissolved in 10 mL of methanol. The palladium on carbon catalyst was added under a nitrogen atmosphere, and the mixture was stirred at room temperature overnight, and the solid was filtered, and the filtrate was evaporated to dryness (yield: 530 mg, 95%).

The fourth step: 1-[4-(4-{5-chloro-4-[2-(propane-2-sulfonyl)-pyridin-3-ylamino]-pyrimidin-2-ylamino}-5-iso Preparation of propoxy-2-methyl-phenyl)-piperidin-1-yl]-ethanone

The compound 2-chloro-5-(difluoromethoxy)-N-(2-(isopropylsulfonyl)phenyl)pyrimidine-4-amine (60 mg, Dissolve in dry DMF (2 mL), add N,N-dimethylisopropylamine (89.59 mg, 693 μmol), TBTU (58 mg, 181.9 μmol) at room temperature, stir at room temperature overnight, dilute the reaction solution with water The mixture was extracted with EtOAc. EtOAc (EtOAc m.) 1-{4-[4-Amino-2-methyl-5-(propan-2-yloxy)phenyl]piperidin-1-yl}-ethanone (62.5 mg, 215 μmol) was added thereto, p-toluene The sulfonic acid (46.3 mg, 269 μmol) was heated to 150 ° C overnight and the reaction was monitored by LCMS. The reaction mixture was diluted with ethyl acetate. EtOAc (EtOAc m. -(4-{5-chloro-4-[2-(propane-2-sulfonyl)-pyridin-3-ylamino]-pyrimidin-2-ylamino}-5-isopropoxy-2-methyl -Phenyl)-piperidin-1-yl]-ethanone (23 mg, 21.3%).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ10.11 (s, 1H), 9.22 (dd, J = 8.7,1.2Hz, 1H), 8.39 (dd, J = 4.3,1.3Hz, 1H), 8.18 (s , 1H), 7.92 (s, 1H), 7.57 (s, 1H), 7.45 (dd, J = 8.7, 4.4 Hz, 1H), 6.71 (s, 1H), 4.83 (d, J = 13.3 Hz, 1H) , 4.58-4.53 (m, 1H), 3.98-3.93 (m 2H), 3.23-3.20 (m, 1H), 2.93-2.92 (m 1H), 2.68-2.62 (m, 1H), 2.24 (s, 3H) , 2.16 (s, 3H), 1.87-1.80 (m, 2H), 1.63-1.56 (m, 2H), 1.41-1.36 (m, 12H).

LCMS: t = 4.43 min, 601.2 (M ⁺ ).

Example 5: 5-Chloro-2-{2-isopropoxy-5-methyl-4-[1-(2-morpholin-4-yl-ethyl)-piperidin-4-yl]- Preparation of phenyl}-4-[2-(propane-2-sulfonyl)-pyridin-3-yl]-pyrimidine-2,4-diamine

1-[4-(4-{5-chloro-4-[2-(propane-2-sulfonyl)-pyridin-3-ylamino]-pyrimidin-2-ylamino}-5-isopropoxy 2-Methyl-phenyl)-piperidin-1-yl]-ethanone (20 mg) was dissolved in 2 mL of ethanol, and 1 mL of 6N aqueous NaOH solution was added thereto, heated to 80 ° C and stirred overnight, and the reaction solution was cooled to room temperature. The solvent was evaporated to give a crude product. This crude product was dissolved in 2 mL of dry DMF, and sodium carbonate (8 mg, 75 μmol) and 2-(4-morpholine)ethylbromohydrobromide (14.58 mg, 75 μmol) were added thereto and heated to 60 ° C. Stir overnight. The reaction mixture was diluted with water and extracted with EtOAc. EtOAc was evaporated, evaporated, evaporated, evaporated. -2-{2-isopropoxy-5-methyl-4-[1-(2-morpholin-4-yl-ethyl)-piperidin-4-yl]-phenyl}-4-[ 2-(Proton-2-sulfonyl)-pyridin-3-yl]-pyrimidine-2,4-diamine (12 mg, 71%).

_{^{1 H NMR (400MHz, CDCl 3}} ): δ10.07 (s, 1H), 9.22 (d, J = 8.6Hz, 1H), 8.38 (dd, J = 4.3,1.2Hz, 1H), 8.18 (d, J =3.5Hz,1H),7.86(s,1H),7.57(s,1H),7.45(dd,J=8.6,4.3Hz,1H),6.96(s,1H),4.77-4.58(m,1H) , 4.15 (t, J = 11.6 Hz, 2H), 3.93-3.89 (m, 3H), 3.85-3.66 (m, 1H), 3.58 (d, J = 6.6 Hz, 2H), 3.37 (d, J = 11.4 Hz, 2H), 2.86 (d, J = 3.1 Hz, 5H), 2.68-2.34 (m, 6H), 2.20 (s, 3H), 1.88 (br, 2H), 1.49-1.29 (m, 12H).

LCMS: t = 3.79 min, 672.2 (M ⁺ ).

Example 6: 5-Chloro-2-(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-4-[2-(propane-2-sulfonyl)- Preparation of thiophen-3-yl]-pyrimidine-2,4-diamine

First step: Preparation of 3-nitro-2-(propan-2-ylsulfanyl)thiophene

2-Chloro-3-nitrothiophene (500 mg, 3.05 mmol) was mixed with isopropyl mercaptan (697 mg, 9.16 mmol) in N,N-dimethylformamide, and potassium carbonate solid (843 mg, 9.16 mmol) was added. It was then stirred at room temperature for 2 hours. The mixture was extracted with water and ethyl acetate. EtOAc was evaporated.

Second step: Preparation of 3-nitro-2-(propan-2-ylsulfonyl)thiophene

3-Nitro-2-(propan-2-ylsulfanyl)thiophene was dissolved in dichloromethane, and m-chloroperoxybenzoic acid (3.1 g, 15.2 mmol) was added portionwise, and stirred at room temperature overnight. 30 mL of a saturated aqueous solution of sodium sulfite was added, and the mixture was adjusted to pH=9 with sodium carbonate, extracted with dichloromethane, dried over sodium sulfate, filtered, and evaporated to give a white solid (1.0 g, 80%).

The third step: preparation of 2-(propan-2-ylsulfonyl)thiophen-3-amine

3-Nitro-2-(propan-2-ylsulfonyl)thiophene (200 mg, 0.85 mmol) was dissolved in 5 mL of methanol, and 20 mg of palladium/carbon (10%) was added and hydrogenated at atmospheric pressure for 2 hours. TLC (PE: EA = 3:1) showed the disappearance of the material, the palladium/carbon was removed by filtration, and methanol was evaporated to give a colorless oil (202 mg, 100%).

Step 4: Preparation of 2,5-dichloro-N-[2-(propan-2-ylsulfonyl)thiophen-3-yl]pyrimidin-4-amine

2-(Proton-2-ylsulfonyl)thiophen-3-amine (870 mg, 4.2 mmol) was dissolved in 40 mL of trifluoroethanol, followed by 2,4,5-trichloropyrimidine (3.0 g, 12.6 mmol) and Saturated hydrochloric acid dioxane solution (4.3 mL) was then stirred at 45 °C overnight. The reaction mixture was applied to EtOAcqqqqqqq

_{LC-MS: t R = 4.40min} , [M + H] + = 351.9.

The fifth step: 1-(4-{4-[(5-chloro-4-{[2-(propan-2-ylsulfonyl)thiophen-3-yl]amino}pyrimidin-2-yl)amino]- Preparation of 2-methyl-5-(propane-2-oxy)phenyl}piperidin-1-yl)ethanone

2,5-Dichloro-N-[2-(propan-2-ylsulfonyl)thiophen-3-yl]pyrimidin-4-amine (200 mg, 0.62 mmol) was dissolved in N,N-dimethylformamide DIPEA (0.44 mL, 2.48 mmol) and O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroboric acid (200 mg, 0.62 mmol) were added sequentially, then stirred at room temperature overnight. TLC (PE: EA = 3:1) showed that the starting material 6 disappeared. 20 mL of water and 20 mL of ethyl acetate were added to the system, and the aqueous phase was separated. The organic phase was dried over sodium sulfate and then directly dried.

LC-MS: t _R = 4.34 min, [M+H] ⁺ = 451.0.

Step 6: 5-Chloro-N-2-[5-methyl-4-(piperidin-4-acetyl)-2-(propan-2-oxy)phenyl]-N-4-[2 Preparation of -(propan-2-ylsulfonyl)thiophen-3-yl]pyrimidine-2,4-diamine

The white solid obtained in the previous step (130 mg, 0.28 mmol) and 1-{4-[4-amino-2-methyl-5-(propan-2-yloxy)phenyl]piperidin-1-yl} Ethyl ketone (110 mg, 0.42 mmol) was dissolved in 2 mL of dioxane, and a monohydrate (yield: 90 mg, 0.42 mmol) of p-toluenesulfonic acid was added, and the system was heated to 150 ° C overnight. Direct spin-dry solvent column chromatography gave a yellow solid (50 mg, 28%).

_{LC-MS: t R = 4.64min} , [M + H] + = 606.1.

Step 7: 5-Chloro-N-2-[5-methyl-4-(piperidin-4-yl)-2-(propan-2-oxy)phenyl]-N-4-[2- Preparation of (propan-2-ylsulfonyl)thiophen-3-yl]pyrimidine-2,4-diamine

1-(4-{4-[(5-chloro-4-{[2-(propan-2-ylsulfonyl)thiophen-3-yl]amino}pyrimidin-2-yl)amino]-2-yl 5--5-(propan-2-yloxy)phenyl}piperidin-1-yl)ethanone (10 mg, 0.016 mmol) was dissolved in 0.1 mL of ethanol, added with 30% aqueous sodium hydroxide, then at 100 ° The mixture was stirred for 3 hours. EtOAc was evaporated.

_{^{1 H NMR (400MHz, CDCl 3}} ): δ9.44 (s, 1H), 8.33 (d, J = 5.4Hz, 1H), 8.15 (s, 1H), 8.05 (s, 1H), 7.65 (d, J = 5.4 Hz, 1H), 7.53 (s, 1H), 6.83 (s, 1H), 4.62 (dt, J = 11.8, 6.0 Hz, 1H), 3.69 (d, J = 11.8 Hz, 2H), 3.34 (dt , J=13.7, 6.8 Hz, 1H), 3.06 (t, J = 12.0 Hz, 2H), 2.96 (t, J = 11.8 Hz, 1H), 2.28 (s, 3H), 2.08-1.93 (m, 8H) , 1.48-1.31 (m, 25H).

_{LC-MS: t R = 3.90min} , [M + H] + = 564.1.

Biological evaluation

Experimental Example 1: ALK gene fusion cell proliferation inhibition test

The following in vitro assays can be used to determine the proliferation inhibitory activity of the compounds of the invention against the human lymphoma cell Karpas 299, which is highly expressed by the ALK gene fusion.

The in vitro cell assay described below can determine the proliferation inhibitory activity of the test compound against human lymphoma cell Karpas 299, and its activity can be expressed by the IC ₅₀ value. The general protocol for such an experiment is as follows: First, human lymphoma cell Karpas 299 is selected and seeded on a 96-well culture plate at a suitable cell concentration (for example, 100 μL of medium in 6000 cells/well), followed by addition to each well. A series of gradient test concentrations (generally 6 to 10 concentrations) of the test compound solution diluted in the medium were continuously cultured for 72 hours. After 72 hours, available

Luminescent Cell Viability Assay kit (purchased from Promega). The method measures the activity of a compound to inhibit cell proliferation. The IC ₅₀ value can be calculated by measuring the inhibition of cell proliferation by a test compound at a range of different concentrations.

The biochemical activity of the compounds of the present invention was determined by the above test, and the measured IC ₅₀ values are shown in the following table.

Conclusion: The compounds of the examples of the present invention have significant proliferation inhibitory activity against Karpas 299 cells.

Experimental Example 2: ALK kinase inhibition test

The following in vitro assays may be used to assay the compounds of the present invention to produce and ALK kinase kinase inhibitory activity ALKL1196M variation, which activity can be expressed by IC ₅₀ values. The half-inhibitory concentration IC _{50 of the} compound (the concentration of the compound required to inhibit a certain concentration of the enzyme activity to 50%) is determined by mixing a certain amount of the kinase with a specific substrate and a different concentration of the test compound. of. The ALK kinase used in this experiment is a human recombinant protein in a reaction system containing 50 mM HEPES (pH 7.5), 10 mM MgCl ₂ , 2 M DTT (1000×) buffer solution and 30 μM ATP with polypeptide substrate and different concentrations. The test compounds were co-reacted (25 ° C, 45 min), followed by FAM-labeled antibodies to label the substrate, and finally the ALK kinase activity was quantified by Mobility shift technology based on microfluidic chip technology.

The biochemical activity of the compounds of the present invention was determined by the above test, and the measured IC ₅₀ values are shown in the following table.

Conclusion: The compounds of the examples of the present invention have significant inhibitory effects on the activity of ALK and ALKL1196M kinase.

Claims (12)

1. A compound of the formula (I) or a pharmaceutically acceptable salt thereof:

   

   among them:

   Ring A is selected from a 5-10 membered cycloalkyl group, a 5-10 membered heterocyclic group, a 5-10 membered aryl group or a 5-10 membered heteroaryl group;

   R _{1 is} selected from C _1-6 alkyl, halogen-substituted C _1-6 alkyl, C _3-6 cycloalkyl or 4-tolyl;

   R ₂ , R ₃ , R ₄ and R ₅ are each independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, C _1-6 alkyl, halogen substituted C _1-6 alkyl, C _3-8 ring Alkyl, C _1-6 alkoxy, halogen substituted C _1-6 alkoxy, C _3-8 cycloalkoxy, -S(O)pR ₉ , -C(O)R ₉ , -C( O) OR ₉ , -NR ₁₀ R ₁₁ or -C(O)NR ₁₁ ;

   R ₆ , R ₇ and R ₈ are each independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _{3 -8} cycloalkyl, 3-8 membered heterocyclic, C _5-10 aryl, 5-10 membered heteroaryl, C _1-6 alkoxy, C _3-8 cycloalkoxy, -S(O ) pR ₉ , -C(O)R ₉ , -C(O)OR ₉ , -NR ₁₀ R ₁₁ or -C(O)NR ₁₁ ,

   Wherein the C _1-8 alkyl group, the C _3-8 cycloalkyl group, the 3-8 membered heterocyclic group, the C _5-10 aryl group or the 5-10 membered heteroaryl group are each independently optionally further one or more One selected from the group consisting of halogen, hydroxy, cyano, nitro, C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, C _3-8 cycloalkyl, 3-8 membered heterocyclic ring , C _5-10 aryl, 5-10 membered heteroaryl, C _1-6 alkoxy, C _3-8 cycloalkoxy, -S(O)pR ₉ , -C(O)R ₉ , Substituted by a substituent of -C(O)OR ₉ , -NR ₁₀ R ₁₁ or -C(O)NR ₁₁ ;

   R ₉ , R ₁₀ , and R _{11 are} selected from the group consisting of hydrogen and C _1-4 alkyl;

   m, n are 0, 1, 2, 3, 4;

   L is 0, 1, 2, 3, 4, 5;

   p is 0, 1, or 2.
2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the structure formed by the ring A together with the substituent is selected from the following structures:

   
3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the structure formed by the ring A together with the substituent is selected from the following structures:

   

   Wherein R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , m, n, L, p are as defined in claim 1.
4. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized by:

   R ₂ and R ₅ are each independently selected from the group consisting of hydrogen, halogen, C _1-6 alkyl, halogen-substituted C _1-6 alkyl;

   R ₃ and R ₄ are each independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, C _1-6 alkyl, halogen-substituted C _1-6 alkyl, C _3-8 cycloalkyl, C _{1- 6} alkoxy, halogen substituted C _1-6 alkoxy, C _3-8 cycloalkoxy, -S(O)pR ₉ , -C(O)R ₉ , -C(O)OR ₉ ,- NR ₁₀ R ₁₁ or -C(O)NR ₁₁ ;

   R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , m, n, L, p are as defined in claim 1.
5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

   
6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of compounds of formula (II):

   

   among them:

   R _{3 is} selected from the group consisting of hydrogen, hydroxy, cyano, nitro, C _3-8 cycloalkyl, C _1-6 alkoxy, halogen substituted C _1-6 alkoxy, C _3-8 cycloalkoxy, -S(O)pR ₉ , -C(O)R ₉ , -C(O)OR ₉ , -NR ₁₀ R ₁₁ or -C(O)NR ₁₁ ;

   R ₂ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , m, n, L, p are as defined in claim 1.
7. A compound according to claim 6 or a pharmaceutically acceptable salt thereof, characterized by:

   R _{3 is} selected from a halogen-substituted C _1-6 alkoxy group;

   R ₂ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , m, n, L, p are as defined in claim 1.
8. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of the following compounds:

   
9. A process for the preparation of a compound of the formula (I) according to claim 1, which comprises the step of condensing a compound of the formula (III) with a compound of the formula (IV) to give a compound of the formula (I), or a formula (III) The compound is condensed with the formula (IV) and then converted to the corresponding compound of the formula (I) according to a different definition of the substituent or a deprotecting group, the synthesis route of which is as follows:

   

   Wherein ring A, R ₁ , R ₂ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , m, n, L, p are as defined in claim 1.
10. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
11. A method of modulating the catalytic activity of a protein kinase, comprising the protein kinase and a compound according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 10. Upon contact, the protein kinase is selected from the group consisting of anaplastic lymphoma kinase.
12. The use of a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 10, for the preparation of a medicament for treating cancer, wherein the cancer is preferably a non-small cell Lung cancer.