Nitrogen-containing spirocyclic compounds and pharmaceutical uses thereof

Abstract

To provide novel nitrogen-containing spirocyclic compounds and pharmaceutical uses thereof.SOLUTION: The present invention provides a compound represented by the general formula [I] in the figure, where each symbol is as defined herein, or a pharmaceutically acceptable salt thereof or a solvate thereof, and a pharmaceutical use of the same in treating organ transplant rejection, graft versus host reaction after transplantation, autoimmune disease, allergic disease and chronic myeloproliferative disease.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to novel nitrogen-containing spirocyclic compounds and their pharmaceutical uses. More specifically, it relates to inhibitors of Janus kinase 3 (hereinafter also referred to as JAK3), and compounds for the prevention or treatment of rejection during organ transplantation, graft-versus-host reaction after transplantation, autoimmune diseases and allergic diseases, and their pharmaceutical uses.

[0002] The present invention also relates to inhibitors of Janus kinase 2 (hereinafter also referred to as JAK2), and compounds for the prevention or treatment of chronic myeloproliferative diseases, and their pharmaceutical uses.

Background Art

[0003] JAK3 is a member of the Janus family of protein kinases. Other members of this family are expressed in a wide range of tissues, but JAK3 expression is limited to hematopoietic cells. This limited expression is related to the important role that JAK3 plays in signal transduction via receptors such as IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 by non-covalently associating with the common γ-chain of these multi-chain receptors.

[0004] In patients with severe combined immunodeficiency (SCID; hereinafter also referred to as SCID), a marked decrease in JAK3 protein levels or gene deletion of the common γ-chain is observed. This suggests that immunosuppression occurs by blocking the signal pathway mediated by JAK3. Also, in animal experiments, it has been shown that JAK3 not only plays an important role in the maturation of NK cells, B-lymphocytes and T-lymphocytes, but is also essentially necessary for maintaining the function of T cells.

[0005] Furthermore, it has been reported that CP-690,550 ((3R,4R)-3-[4-methyl-3-[N-methyl-N-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropionitrile), a JAK3 inhibitor, exhibits a disease-improving effect in rheumatoid arthritis and psoriasis, and also shows a rejection-suppressing effect in a monkey kidney transplantation model and an airway inflammation-suppressing effect in a mouse asthma model.

[0006] From these findings, it is considered that controlling immune activity with a JAK3 inhibitor is beneficial for the prevention or treatment of rejection during organ transplantation, graft-versus-host disease after transplantation, autoimmune diseases, and allergic diseases.

[0007] On the other hand, it has been suggested that inhibition of JAK2 is beneficial for patients with chronic myeloproliferative diseases. Chronic myeloproliferative diseases include polycythemia vera, primary myelofibrosis, essential thrombocythemia, chronic myelogenous leukemia, chronic myelomonocytic leukemia, chronic eosinophilic leukemia, chronic neutrophilic leukemia, and systemic mastocytosis.

[0008] Chronic myeloproliferative diseases are thought to be caused by acquired somatic mutations in hematopoietic stem cells, and it has been reported that the majority of patients with polycythemia vera, as well as a significant number of patients with primary myelofibrosis and essential thrombocythemia, have gain-of-function mutations in JAK2. In addition, it has also been reported that inhibition of the JAK2V617F kinase by a small molecule inhibitor leads to inhibition of the proliferation of hematopoietic cells.

[0009] From these findings, it is considered that controlling the proliferation of hematopoietic cells with a JAK2 inhibitor is beneficial for the prevention or treatment of chronic myeloproliferative diseases.

[0010] In addition, as family members of Janus kinase (hereinafter also referred to as JAK), four types are known: Janus kinase 1 (hereinafter also referred to as JAK1), JAK2, JAK3, and tyrosine kinase 2 (hereinafter also referred to as Tyk2), and JAK1 inhibitors and Tyk2 inhibitors are also considered to be beneficial for the prevention or treatment of various diseases, similar to JAK3 inhibitors.

Summary of the Invention

Problems to be Solved by the Invention

[0011] The inventors of the present invention have conducted intensive research to develop a new therapeutic or prophylactic agent for rejection during organ transplantation, graft-versus-host reaction after transplantation, autoimmune diseases, and allergic diseases, which can replace the conventional therapeutic or prophylactic agents. As a result, a novel nitrogen-containing spiro ring compound having a JAK3 inhibitory action has been found, and the present invention has been completed.

[0012] In addition, the inventors of the present invention have found a novel nitrogen-containing spiro ring compound having a JAK2 inhibitory action, and the present invention has been completed.

Means for Solving the Problems

[0013] That is, the present invention is as follows. [1] A compound represented by the following general formula [I], a pharmaceutically acceptable salt thereof, or a solvate thereof:

Chemical Formula

Chemical formula

[0014] [2] In the general formula [I], n1 is an integer from 0 to 2, n2 is an integer from 0 to 2, m1 is an integer from 0 to 3, m2 is an integer from 1 to 3, X is, (1) a nitrogen atom, or (2) C-R d (wherein R d is a halogen atom), R c is a group selected from the following (1) to (6): (1) a hydrogen atom, (2) a C 1-6 alkyl group substituted with one substituent selected from the following Group A, (3) -C(=O)-R c1 , (4) -C(=O)-O-R c2 , (5) -C(=O)-NR c3 R c4 (wherein, R c1 is a C 1-6 alkyl group which may be substituted with one substituent selected from the following Group A, R c2 is a C 1-6 alkyl group, R c3 is a C 1-6 alkyl group which may be substituted with one substituent selected from the following Group A, R c4 is (i) a hydrogen atom, or (ii) a C 1-6 alkyl group), or (6) formula:

Chemical formula

[0015] [3] The compound according to any one of [1] or [2], or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein m1 is an integer of 0 or 1 and m2 is an integer of 1 or 2.

[0016] [4] The compound according to [3], or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the combination of (m1, m2) is (1, 2), and the general formula [II]:

Chemical formula

[0017] [5] The compound according to [3], or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the combination of (m1, m2) is (0, 2), and the general formula [III]:

Chemical formula

[0018] [6] The compound according to [3], or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the combination of (m1, m2) is (0, 1), and the general formula [IV]:

Chemical formula

[0019] [7] The compound according to any one of [1] or [2], or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the combination of (m1, m2) is selected from (0, 3), (2, 1), (2, 2), or (3, 2).

[0020] [8] X a =Xb The compound or a pharmaceutically acceptable salt thereof, or a solvate thereof according to any one of [1] to [7], wherein Z is CH=CH and X is a nitrogen atom.

[0021] The compound or a pharmaceutically acceptable salt thereof, or a solvate thereof according to any one of [1] or [2], wherein the combination of [9] (n1,n2) is (0,0).

[0022] The compound or a pharmaceutically acceptable salt thereof, or a solvate thereof according to any one of [1] or [2], wherein the combination of

[10] (n1,n2) is (1,0).

[0023] The compound or a pharmaceutically acceptable salt thereof, or a solvate thereof according to any one of [1] or [2], wherein the combination of

[11] (n1,n2) is (0,1).

[0024] The compound or a pharmaceutically acceptable salt thereof, or a solvate thereof according to any one of [1] or [2], wherein the combination of

[12] (n1,n2) is (2,0).

[0025] The compound or a pharmaceutically acceptable salt thereof, or a solvate thereof according to any one of [1] or [2], wherein the combination of

[13] (n1,n2) is (0,2).

[0026]

[14] R a The compound or a pharmaceutically acceptable salt thereof, or a solvate thereof according to any one of

[10] or

[12] , wherein R is a methyl group or a fluorine atom.

[0027]

[15] R c The compound or a pharmaceutically acceptable salt thereof, or a solvate thereof according to any one of [1] to

[14] , wherein R is -C(=O)-R c1 The compound or a pharmaceutically acceptable salt thereof, or a solvate thereof according to any one of [1] to

[14] , wherein R is -C(=O)-R

[0028]

[16] R c1 The compound or a pharmaceutically acceptable salt thereof, or a solvate thereof according to any one of [1] to

[14] , wherein R is C substituted with one hydroxyl group or a cyano group 1-6The compound described in

[15] that is an alkyl group, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0029]

[17] R c is -C(=O)-NR c3 R c4 The compound described in any one of [1] to

[14] , or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0030]

[18] R c3 is a C 1-6 alkyl group substituted with one cyano group, and R c4 is a hydrogen atom. The compound described in

[17] , or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0031]

[19] The following chemical structural formula:

Chemical formula

Chemical formula

[0032]

[20] The following chemical structural formula:

Chemical formula

Chemical formula

[0033]

[21] A pharmaceutical composition comprising the compound described in any one of [1] to

[20] , or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier.

[0034]

[22] A Janus kinase inhibitor comprising the compound described in any one of [1] to

[20] , or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0035]

[23] The Janus kinase inhibitor according to

[22] , wherein the Janus kinase is Janus kinase 3.

[0036]

[24] The Janus kinase inhibitor according to

[22] , wherein the Janus kinase is Janus kinase 2.

[0037]

[25] A therapeutic or prophylactic agent for a disease selected from the group consisting of rejection during organ transplantation, graft-versus-host reaction after transplantation, autoimmune diseases, allergic diseases, and chronic myeloproliferative diseases, comprising the compound according to any one of [1] to

[20] or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0038]

[26] A therapeutic or prophylactic agent for rheumatoid arthritis, comprising the compound according to any one of [1] to

[20] or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0039]

[27] A therapeutic or prophylactic agent for psoriasis, comprising the compound according to any one of [1] to

[20] or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0040]

[28] A method for inhibiting Janus kinase, which comprises administering to a mammal a pharmaceutically effective amount of the compound according to any one of [1] to

[20] or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0041]

[29] The inhibition method according to

[28] , wherein the Janus kinase is Janus kinase 3.

[0042]

[30] The inhibition method according to

[28] , wherein the Janus kinase is Janus kinase 2.

[0043]

[31] A method for treating or preventing a disease selected from the group consisting of rejection during organ transplantation, graft-versus-host reaction after transplantation, autoimmune diseases, allergic diseases, and chronic myeloproliferative diseases, which comprises administering to a mammal a pharmaceutically effective amount of the compound according to any one of [1] to

[20] or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0044]

[32] A method for treating or preventing rheumatoid arthritis, which comprises administering to a mammal a pharmaceutically effective amount of the compound according to any one of [1] to

[20] or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0045]

[33] A method for treating or preventing psoriasis, which comprises administering to a mammal a pharmaceutically effective amount of the compound according to any one of [1] to

[20] or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0046]

[34] Use of the compound according to any one of [1] to

[20] or a pharmaceutically acceptable salt thereof, or a solvate thereof, for producing a Janus kinase inhibitor.

[0047]

[35] The use according to

[34] , wherein the Janus kinase inhibitor is a Janus kinase 3 inhibitor.

[0048]

[36] The use according to

[34] , wherein the Janus kinase inhibitor is a Janus kinase 2 inhibitor.

[0049]

[37] Use of the compound according to any one of [1] to

[20] or a pharmaceutically acceptable salt thereof, or a solvate thereof, for producing a therapeutic or prophylactic agent for a disease selected from the group consisting of rejection during organ transplantation, graft-versus-host reaction after transplantation, autoimmune diseases, allergic diseases, and chronic myeloproliferative diseases.

[0050]

[38] Use of the compound according to any one of [1] to

[20] or a pharmaceutically acceptable salt thereof, or a solvate thereof, for producing a therapeutic or prophylactic agent for rheumatoid arthritis.

[0051]

[39] Use of the compound according to any one of [1] to

[20] , or a pharmaceutically acceptable salt thereof, or a solvate thereof, for producing a therapeutic or prophylactic agent for psoriasis.

[0052]

[40] (a) A pharmaceutical composition containing, as an active ingredient, the compound according to any one of [1] to

[20] , or a pharmaceutically acceptable salt thereof, or a solvate thereof, and (b) An attachment regarding the composition, which states that the pharmaceutical composition can be used, or should be used, for the treatment or prevention of rheumatoid arthritis or psoriasis. A commercial kit including the attachment.

[0053]

[41] (a) A pharmaceutical composition containing, as an active ingredient, the compound according to any one of [1] to

[20] , or a pharmaceutically acceptable salt thereof, or a solvate thereof, and (b) An attachment regarding the composition, which states that the pharmaceutical composition can be used, or should be used, for the treatment or prevention of rheumatoid arthritis or psoriasis. A commercial package including the attachment. [Effect of the Invention]

[0054] The nitrogen-containing spiro ring compound of the present invention inhibits JAK3 activity, and thus is effective as a therapeutic or prophylactic agent for rejection during organ transplantation, graft-versus-host reaction after transplantation, autoimmune diseases, allergic diseases, and the like.

[0055] Furthermore, the nitrogen-containing spiro ring compound of the present invention inhibits JAK2 activity, and thus is effective as a therapeutic or prophylactic agent for chronic myeloproliferative diseases. [Modes for Carrying Out the Invention]

[0056] The definitions of the terms in this specification are as follows. "Optionally substituted" includes both the case where the substitutable position of the target group is substituted and the case where it is not substituted (unsubstituted). Here, "unsubstituted" means that all substitutable positions of the target group are hydrogen atoms. For example, "a C alkyl group which may be substituted with the same or different 1 to 5 substituents selected from Group A" 1-6 The "C alkyl group" 1-6 includes both the case where the substitutable positions of the C alkyl group are substituted with the same or different 1 to 5 substituents selected from Group A and the case where they are not substituted (unsubstituted).

[0057] Examples of the "halogen atom" include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc. Preferably, it is a fluorine atom or a chlorine atom. The "C 1-6 alkyl group" means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. For example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a 1-ethylpropyl group, a hexyl group, an isohexyl group, a 1,1-dimethylbutyl group, a 2,2-dimethylbutyl group, a 3,3-dimethylbutyl group, a 2-ethylbutyl group, etc. are included. Preferably, it is a methyl group, an ethyl group, a propyl group, an isopropyl group, etc. The "C 2-6 alkenyl group" means a linear or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms and containing one or more double bonds. For example, a vinyl group, a 1-methylvinyl group, a 1-propenyl group, an allyl group, a methylpropenyl group (1-methyl-1-propenyl group, 2-methyl-1-propenyl group, etc.), a 1-butenyl group, a 2-butenyl group, a 3-butenyl group, a methylbutenyl group (1-methyl-1-butenyl group, 2-methyl-1-butenyl group, 3-methyl-1-butenyl group, etc.), a pentenyl group, a methylpentenyl group, a hexenyl group, etc. are included. Preferably, it is a vinyl group, a 1-methylvinyl group, a 1-propenyl group, a methylpropenyl group, etc.

[0058] The "C 1-6 alkylene" refers to the above linear C 1-6It means a divalent group derived from an alkyl group, and examples thereof include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, etc. Preferably, it is methylene, ethylene, etc. "C 6-10 "aryl group" means an aromatic hydrocarbon group having 6 to 10 carbon atoms, and examples thereof include a phenyl group, a 1-naphthyl group, a 2-naphthyl group, etc. Preferably, it is a phenyl group. "C 3-10 "cycloalkyl group" means a monocyclic saturated hydrocarbon group having 3 to 10 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, etc. Preferably, it is a C 3-6 cycloalkyl group (such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, etc.).

[0059] The "saturated monocyclic heterocyclic group" (the saturated monocyclic heterocyclic group has 1 to 4 heteroatoms selected from nitrogen atoms, oxygen atoms or sulfur atoms in addition to carbon atoms, and the number of atoms constituting the ring is 3 to 7) includes, for example, an oxiranyl group, a thiolanyl group, an aziridinyl group, an azetidinyl group, an oxetanyl group, a pyrrolidinyl group, a pyrrolidino group (1-pyrrolidinyl group), a tetrahydrofuranyl group, a tetrahydrothienyl group, an oxazolinyl group, an oxazolidinyl group, an isoxazolinyl group, an isoxazolidinyl group, a thiazolinyl group, a thiazolidinyl group, an isothiazolinyl group, an isothiazolidinyl group, an imidazolinyl group, an imidazolidinyl group, a pyrazolinyl group, a pyrazolidinyl group, a piperidinyl group, a piperidino group (1-piperidinyl group), a morpholinyl group, a morpholino group (4-morpholinyl group), a thiomorpholinyl group, a thiomorpholino group (4-thiomorpholinyl group), a piperazinyl group, a piperazino group (1-piperazinyl group), a hexahydro-1,3-oxazinyl group, a homomorpholin group, a homopiperazine group, etc.

[0060] "C 1-6The "alkoxy group" refers to a linear or branched alkoxy group having 1 to 6 carbon atoms, specifically, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, an s-butoxy group, a t-butoxy group, a pentyloxy group, an isopentyloxy group, a 2-methylbutoxy group, a neopentyloxy group, a 1-ethylpropoxy group, a hexyloxy group, etc. "C 1-6 The "alkoxycarbonyl group" refers to a group in which a linear or branched alkoxy group having 1 to 6 carbon atoms is bonded to a carbonyl group, specifically, a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, an isobutoxycarbonyl group, an s-butoxycarbonyl group, a t-butoxycarbonyl group, a pentyloxycarbonyl group, an isopentyloxycarbonyl group, a 2-methylbutoxycarbonyl group, a neopentyloxycarbonyl group, a 1-ethylpropoxycarbonyl group, a hexyloxycarbonyl group, a 4-methylpentyloxycarbonyl group, etc.

[0061] "C 1-6 The "alkylcarbonyloxy group" refers to a group in which a group in which an "alkyl group" is bonded to a carbonyl group is bonded to an oxy group, and examples thereof include an acetyloxy group, a propionyloxy group, a butyryloxy group, an isobutyryloxy group, etc. 1-6 The "alkenyloxy group" refers to a group in which an "alkenyl group" is bonded to an oxy group, and examples thereof include an allyloxy group, a 1-butenyloxy group, etc. "C 2-6 The "alkenyloxy group" refers to a group in which an "alkenyl group" is bonded to an oxy group, and examples thereof include an allyloxy group, a 1-butenyloxy group, etc. 2-6 The "alkenyloxy group" refers to a group in which an "alkenyl group" is bonded to an oxy group, and examples thereof include an allyloxy group, a 1-butenyloxy group, etc.

[0062] Preferred embodiments of each group of the compound represented by the general formula [I] (hereinafter also referred to as the compound of the present invention) will be described below.

[0063] R a Preferred specific examples of include (1) a methyl group, or (2) a fluorine atom etc. Preferable specific examples of n1 include integers of 0, 1, or 2. R b Preferable specific examples of include (1) a methyl group, or (2) a fluorine atom and the like. Preferable specific examples of n2 include integers of 0, 1, or 2. Preferable specific examples of m1 include integers from 0 to 3. Preferable specific examples of m2 include integers of 1, 2, or 3.

[0064] Combinations of (m1, m2) include (0, 1), (0, 2), (0, 3), (1, 1), (1, 2), (2, 1), (2, 2), or (3, 2). Preferably, R a and R b can be substituted on the carbon atoms (excluding spiro carbons) constituting each spiro ring of general formula [I], and the carbon atoms not substituted by R a or R b are saturated with hydrogen atoms. When n1 is 2 or more, R a may be the same or different from each other, and may be at the same substitution position or different substitution positions. Also, when n2 is 2 or more, R b may be the same or different from each other, and may be at the same substitution position or different substitution positions.

[0065] X a =X b is (1) CH=CH, (2) N=CH, or (3) CH=N, and preferably (1) CH=CH. Preferable specific examples of X are (1) a nitrogen atom, or (2) C-Cl, and more preferably (1) a nitrogen atom.

[0066] R cPreferred specific examples thereof include a hydrogen atom, a cyanoethyl group, an acetyl group, a benzyl group, a cyanomethylcarbonyl group, a propenyloxyethylcarbonyl group, a 2-propanilcarbonyl group, an ethylcarbonyl group, a methoxycarbonyl group, an (S)-hydroxyethylcarbonyl group, a hydroxymethylcarbonyl group, a 1-hydroxyethylcarbonyl group, an acetoxymethylcarbonyl group, an (S)-acetoxyethylcarbonyl group, a methoxymethylcarbonyl group, a methoxyethylcarbonyl group, an (S)-methoxyethylcarbonyl group, an (R)-methoxyethylcarbonyl group, a 3-cyanopyrrolidinylcarbonyl group, a 3-cyanophenylcarbonyl group, a 4-cyanophenylcarbonyl group, a methoxycarbonylethylcarbonyl group, a p-nitrophenoxycarbonyl group, a 1-cyanomethylcyclopropylcarbonyl group, a t-butoxycarbonyl group, an N-ethylcarbamoyl group, an N-cyanomethylcarbamoyl group, an N-cyanoethylcarbamoyl group, an N,N-methylcyanomethylcarbamoyl group, an N,N-methylcyanoethylcarbamoyl group, an N-propanylcarbamoyl group, etc., and preferably a cyanomethylcarbonyl group, a hydroxymethylcarbonyl group or a cyanoethylcarbamoyl group.

[0067] Preferred embodiments of the compound represented by the general formula [I] include compounds represented by the following formula:

Chemical formula

[0068] Here, as the compound represented by the general formula [II], preferably a compound represented by the general formula [II-A], [II-B] or [II-C].

Chemical formula

[0069] Here, as the compound represented by the general formula [III], preferably a compound represented by the general formula [III-A], [III-B] or [III-C].

Chemical formula

[0070] Here, as the compound represented by the general formula [IV], a compound represented by the general formula [IV-A], [IV-B] or [IV-C] is preferable.

Chemical formula

[0071] As another preferable embodiment of the compound represented by the general formula [I], compounds represented by the following formula can be mentioned.

Chemical formula

[0072] As another preferable embodiment, in addition to the JAK3 inhibitory action, the compound represented by the general formula [I] may have a JAK1 and / or JAK2 and / or Tyk2 inhibitory action. More preferably, it has an inhibitory action against all of JAK1, JAK2, JAK3 and Tyk2.

[0073] The "pharmaceutically acceptable salt" of the compound represented by the general formula [I] (hereinafter also referred to as the compound of the present invention) may be any salt as long as it forms a non-toxic salt with the compound of the present invention. Examples include salts with inorganic acids, salts with organic acids, salts with inorganic bases, salts with organic bases, salts with amino acids, and the like.

[0074] Examples of salts with inorganic acids include salts with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, hydrobromic acid, and the like. Examples of salts with organic acids include salts with oxalic acid, maleic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, gluconic acid, ascorbic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like.

[0075] Examples of salts with inorganic bases include sodium salts, potassium salts, calcium salts, magnesium salts, ammonium salts, and the like. Examples of salts with organic bases include salts with methylamine, diethylamine, trimethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, tris(hydroxymethyl)methylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, guanidine, pyridine, picoline, choline, cinchonine, meglumine, and the like. Examples of salts with amino acids include salts with lysine, arginine, aspartic acid, glutamic acid, and the like.

[0076] Each salt can be obtained by reacting the compound represented by the general formula [I] with an inorganic base, an organic base, an inorganic acid, an organic acid, or an amino acid according to a known method.

[0077] A "solvate" refers to a compound represented by the general formula [I] or a pharmaceutically acceptable salt thereof, in which solvent molecules are coordinated, and hydrates are also included. Pharmaceutically acceptable solvates are preferred. For example, a monohydrate, a 1 / 2 hydrate, or a dihydrate of the compound represented by the general formula [I], a monohydrate of the sodium salt of the compound represented by the general formula [I], a monomethanolate, a monoethanolate, or a monoacetonitrileate of the compound represented by the general formula [I], a 2 / 3 ethanolate of the dihydrochloride of the compound represented by the general formula [I], and the like can be mentioned. More preferably, it is a monohydrate of the compound represented by the general formula [I]. The solvate can be obtained according to a known method.

[0078] In addition, various "isomers" exist in the compound represented by the general formula [I]. For example, the E form and the Z form exist as geometric isomers. When an asymmetric carbon atom exists, enantiomers and diastereomers exist as stereoisomers based on these. Also, when axial asymmetry exists, stereoisomers based on these exist. In some cases, tautomers may exist. Therefore, the scope of the present invention includes all these isomers and mixtures thereof.

[0079] In addition, the compound represented by the general formula [I] may be labeled with isotopes (e.g., 3 H, 14 C, 35 S, etc.). As the compound represented by the general formula [I], its pharmaceutically acceptable salt, or its solvate, a substantially purified compound represented by the general formula [I], its pharmaceutically acceptable salt, or its solvate is preferred. More preferably, it is a compound represented by the general formula [I], its pharmaceutically acceptable salt, or its solvate purified to a purity of 80% or more.

[0080] In the present invention, the prodrug of the compound represented by the general formula [I] can also be a useful drug. A "prodrug" is a derivative of the compound of the present invention having a functional group that can be chemically or metabolically decomposed and, after administration to a living body, is converted into the parent compound, for example, by hydrolysis, solvolysis, or decomposition under physiological conditions, to exhibit the original pharmaceutical effect, and includes non-covalent complexes and salts. Prodrugs are used, for example, for improving absorption in oral administration or for targeting to a target site. Examples of the modification site for forming a prodrug include highly reactive functional groups such as hydroxyl groups, carboxyl groups, amino groups, and thiol groups in the compound of the present invention.

[0081] Specific examples of the modifying group for the hydroxyl group include an acetyl group, a propionyl group, an isobutyryl group, a pivaloyl group, a palmitoyl group, a benzoyl group, a 4-methylbenzoyl group, a dimethylcarbamoyl group, a dimethylaminomethylcarbonyl group, a sulfo group, an alanyl group, a fumaroyl group, or a sodium salt of 3-carboxybenzoyl group or 2-carboxyethylcarbonyl group.

[0082] Specific examples of the modifying group for the carboxyl group include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, pivaloyloxymethyl group, carboxymethyl group, dimethylaminomethyl group, 1-(acetyloxy)ethyl group, 1-(ethoxycarbonyloxy)ethyl group, 1-(isopropyloxycarbonyloxy)ethyl group, 1-(cyclohexyloxycarbonyloxy)ethyl group, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group, benzyl group, phenyl group, o-tolyl group, morpholinoethyl group, N,N-diethylcarbamoylmethyl group, phthalidyl group, and the like.

[0083] Specific examples of the modifying group for the amino group include tert-butyl group, docosanoyl group, pivaloylmethyloxy group, alanyl group, hexylcarbamoyl group, pentylcarbamoyl group, 3-methylthio-1-(acetylamino)propylcarbonyl group, 1-sulfo-1-(3-ethoxy-4-hydroxyphenyl)methyl group, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group, (5-methyl-2-oxo-1,3-dioxol-4-yl)methoxycarbonyl group, tetrahydrofuranyl group, pyrrolidylmethyl group, and the like.

[0084] Examples of the "pharmaceutical composition" include oral preparations such as tablets, capsules, granules, powders, troches, syrups, emulsions, suspensions, etc., or parenteral preparations such as external preparations, suppositories, injections, eye drops, nasal preparations, pulmonary preparations, etc.

[0085] The pharmaceutical composition of the present invention is produced by appropriately mixing, in accordance with a method known in the technical field of pharmaceutical preparations, the compound represented by the general formula [I] or a pharmaceutically acceptable salt thereof, or a solvate thereof, with at least one or more pharmaceutically acceptable carriers, etc., in an appropriate amount. The content of the compound represented by the general formula [I] or a pharmaceutically acceptable salt thereof, or a solvate thereof, in the pharmaceutical composition varies depending on the dosage form, dosage, etc., but is, for example, 0.1 to 100% by weight of the entire composition.

[0086] Examples of the "pharmaceutically acceptable carrier" include various organic or inorganic carrier substances commonly used as formulation materials. For example, excipients, disintegrants, binders, fluidizing agents, lubricants, etc. in solid formulations, or solvents, solubilizing agents, suspending agents, isotonic agents, buffers, soothing agents, etc. in liquid formulations. Furthermore, additives such as preservatives, antioxidants, coloring agents, sweetening agents, etc. are used as necessary.

[0087] Examples of the "excipient" include lactose, sucrose, D-mannitol, D-sorbitol, corn starch, dextrin, microcrystalline cellulose, crystalline cellulose, carmellose, carmellose calcium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, gum arabic, etc. Examples of the "disintegrant" include carmellose, carmellose calcium, carmellose sodium, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose, crystalline cellulose, etc. Examples of the "binder" include hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, crystalline cellulose, sucrose, dextrin, starch, gelatin, carmellose sodium, gum arabic, etc. Examples of the "fluidizing agent" include light anhydrous silicic acid, magnesium stearate, etc. Examples of the "lubricant" include magnesium stearate, calcium stearate, talc, etc.

[0088] Examples of the "solvent" include purified water, ethanol, propylene glycol, macrogol, sesame oil, corn oil, olive oil, etc. Examples of the "solubilizing agent" include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate, etc. Examples of the "suspending agent" include benzalkonium chloride, carmellose, hydroxypropyl cellulose, propylene glycol, povidone, methyl cellulose, glycerin monostearate, and the like. Examples of the "isotonic agent" include glucose, D-sorbitol, sodium chloride, D-mannitol, and the like. Examples of the "buffer" include sodium hydrogen phosphate, sodium acetate, sodium carbonate, sodium citrate, and the like. Examples of the "anesthetic" include benzyl alcohol and the like.

[0089] Examples of the "preservative" include ethyl paraben, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid, and the like. Examples of the "antioxidant" include sodium sulfite, ascorbic acid, and the like. Examples of the "coloring agent" include food coloring (e.g., Food Red No. 2 or 3, Food Yellow No. 4 or 5, etc.), β-carotene, and the like. Examples of the "sweetening agent" include sodium saccharin, dipotassium glycyrrhizinate, aspartame, and the like.

[0090] The pharmaceutical composition of the present invention can also be administered orally or parenterally (e.g., topically, rectally, intravenously, etc.) to mammals other than humans (e.g., mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, pigs, cows, horses, sheep, monkeys, etc.) and humans. The dosage varies depending on the administration subject, disease, symptom, dosage form, administration route, etc. For example, when orally administering to an adult patient (body weight: about 60 kg) suffering from rejection during organ transplantation, graft-versus-host reaction after transplantation, autoimmune disease or allergic disease, the dosage is usually in the range of about 1 mg to 1 g per day with the compound of the present invention as the active ingredient. These amounts can be administered in one or several divided doses.

[0091] The compound represented by the general formula [I], or a pharmaceutically acceptable salt thereof, or a solvate thereof can be used as an active ingredient of a therapeutic or prophylactic agent for the following diseases, etc., since it inhibits JAK3: (a) Rejection during organ transplantation or graft-versus-host disease after transplantation; (b) Autoimmune diseases such as rheumatoid arthritis, psoriasis, psoriatic arthritis, multiple sclerosis, ulcerative colitis, Crohn's disease, systemic lupus erythematosus, type I diabetes, myasthenia gravis, Castleman disease, juvenile idiopathic arthritis, dry eye, etc.; and (c) Allergic diseases such as asthma, atopic dermatitis, rhinitis, etc.

[0092] Preferably, the compound represented by the general formula [I], or a pharmaceutically acceptable salt thereof, or a solvate thereof is used as an active ingredient of a therapeutic or prophylactic agent for rheumatoid arthritis or psoriasis.

[0093] Furthermore, the compound represented by the general formula [I], or a pharmaceutically acceptable salt thereof, or a solvate thereof can be used as an active ingredient of a therapeutic or prophylactic agent for chronic myeloproliferative diseases such as polycythemia vera, primary myelofibrosis, essential thrombocythemia, etc., since it inhibits JAK2.

[0094] "Inhibiting JAK" means inhibiting the function of JAK and disappearing or attenuating its activity, and means inhibiting any enzyme of the JAK family. "Inhibiting JAK" is preferably "inhibiting human JAK". The "JAK inhibitor" is preferably a "human JAK inhibitor".

[0095] "Inhibiting JAK3" means inhibiting the function of JAK3 and disappearing or attenuating its activity. For example, it means inhibiting the function of JAK3 based on the conditions of the test examples described later. "Inhibiting JAK3" is preferably "inhibiting human JAK3". The "JAK3 inhibitor" is preferably a "human JAK3 inhibitor".

[0096] "Inhibiting JAK2" means inhibiting the function of JAK2 to eliminate or attenuate its activity. For example, it means inhibiting the function of JAK2 based on the conditions of the test examples described below. "Inhibiting JAK2" is preferably "inhibiting human JAK2". The "JAK2 inhibitor" is preferably the "human JAK2 inhibitor".

[0097] Next, an example of the method for producing the compound used in the implementation of the present invention will be described, but the production method of the compound of the present invention is not limited thereto. Even if not described in this production method, a protecting group may be introduced into the functional group as necessary and deprotected in a subsequent step; the functional group may be subjected to each step as a precursor and converted into a desired functional group at an appropriate stage; efficient production may be carried out by devising such as changing the order of each production method and step.

[0098] Also, in each step, the treatment after the reaction may be carried out by a commonly used method. For isolation and purification, if necessary, commonly used methods such as crystallization, recrystallization, distillation, liquid separation, silica gel chromatography, preparative HPLC, etc. may be appropriately selected and combined. Note that room temperature is defined as 1°C to 40°C.

[0099] [General production method 1]: General production method of the compound represented by formula [I] [Chemical formula] [In the formula, P N is a protecting group for an amine, preferably a tert-butoxycarbonyl group, a benzyl group, a p-methoxybenzyl group, or a benzyloxycarbonyl group; Q is N (nitrogen atom) substituted with a protecting group, or NH; Hal is a halogen atom; R a , R b , n1, n2, X a , X b , X, m1, m2, and R c have the same meanings as defined in the above formula [I]]

[0100] (The first step) Compound [Vc] can be obtained by reacting compound [Va] with compound [Vb] in a solvent in the presence of a base. Examples of the solvent used in the reaction include ester solvents such as ethyl acetate; ketone solvents such as acetone; amide solvents such as N,N-dimethylformamide; alcohol solvents such as ethanol; ether solvents such as dioxane; hydrocarbon solvents such as toluene; halogenated hydrocarbon solvents such as chloroform; water; etc. These can be used alone or in admixture of two or more. The preferred solvent in this reaction is water. Examples of the base used in the reaction include triethylamine, N,N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, etc. Potassium carbonate is preferably used. The reaction temperature is usually from room temperature to 110 °C, preferably about 80 - 110 °C. The reaction time is usually about 30 minutes to 3 days, preferably about 3 hours to 1 day.

[0101] (Step 2) Compound [Vd] can be obtained by removing P of compound [Vc] using a conventional amine deprotection reaction. The deprotection reaction may be carried out by a known method according to the protecting group employed. N Here, for example, when P N is a tert-butoxycarbonyl group, it may be treated with an acid such as hydrochloric acid or trifluoroacetic acid in a single or mixed solvent of chloroform, dioxane, ethyl acetate, ethanol, methanol, water, etc. Here, for example, when P N is a benzyl group or a benzyloxycarbonyl group, it may be hydrogenated in a single or mixed solvent of chloroform, tetrahydrofuran, dioxane, ethyl acetate, ethanol, methanol, etc. in the presence of a catalyst such as palladium carbon or palladium hydroxide. N Here, for example, when P N is a tert-butoxycarbonyl group, it may be treated with an acid such as hydrochloric acid or trifluoroacetic acid in a single or mixed solvent of chloroform, dioxane, ethyl acetate, ethanol, methanol, water, etc. Also, for example, when P N is a benzyl group or a benzyloxycarbonyl group, it may be hydrogenated in a single or mixed solvent of chloroform, tetrahydrofuran, dioxane, ethyl acetate, ethanol, methanol, etc. in the presence of a catalyst such as palladium carbon or palladium hydroxide. N Here, for example, when P N is a benzyl group or a benzyloxycarbonyl group, it may be hydrogenated in a single or mixed solvent of chloroform, tetrahydrofuran, dioxane, ethyl acetate, ethanol, methanol, etc. in the presence of a catalyst such as palladium carbon or palladium hydroxide.

[0102] (Step 3) In a solvent, R is added to compound [Vd]c By introducing [a certain substance], compound [I] can be obtained. For example, when R c is a cyanoacetyl group, compound [I] can be obtained by reacting compound [Vd] with 1-cyanoacetyl-3,5-dimethylpyrazole in a solvent in the presence of a base. Examples of the solvent used in the reaction include ester solvents such as ethyl acetate; ketone solvents such as acetone; amide solvents such as N,N-dimethylformamide; alcohol solvents such as ethanol; ether solvents such as dioxane; hydrocarbon solvents such as toluene; halogenated hydrocarbon solvents such as chloroform, etc. These can be used alone or in a mixture of two or more. The preferred solvent in this reaction is dioxane. Examples of the base used in the reaction include triethylamine, pyridine, 4-dimethylaminopyridine, N-methylmorpholine, N,N-diisopropylethylamine, etc., and preferably N,N-diisopropylethylamine. The reaction temperature is usually from room temperature to 110 °C, preferably about 80 - 110 °C. The reaction time is usually about 30 minutes to 1 day, preferably about 2 hours to 4 hours.

[0103] Also, for example, when R c is an acyl group, compound [I] can be obtained by a normal amidation reaction of compound [Vd] with a carboxylic acid compound in a solvent in the presence of a condensing agent and a base. Examples of the solvent used in the reaction include amide solvents such as N,N-dimethylformamide; halogenated hydrocarbon solvents such as chloroform, etc. These can be used alone or in a mixture of two or more. The preferred solvent in this reaction is an ether solvent such as tetrahydrofuran or dioxane. Examples of the condensing agent used in the reaction include water-soluble carbodiimide (1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride), N,N'-dicyclohexylcarbodiimide, diphenylphosphoryl azide, carbonyldiimidazole. If necessary, 1-hydroxy-1H-benzotriazole, 4-dimethylaminopyridine, etc. may be added to the reaction mixture. The preferred condensing agent in this reaction is carbonyldiimidazole.

[0104] In the amidation reaction described above, Compound [I] can also be obtained by previously converting the carboxylic acid compound into an acid chloride or a mixed acid anhydride, etc., and then reacting it with Compound [Vd].

[0105] Also, for example, when R c is a propionitrile group, Compound [I] can be obtained by reacting Compound [Vd] with acrylonitrile in an amide solvent such as N,N-dimethylformamide or N,N-dimethylacetamide or acetonitrile in the presence of a base such as triethylamine, pyridine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0106] Also, for example, when R c is an alkoxycarbonyl group, Compound [I] can be obtained by reacting Compound [Vd] with an alkyl chloroformate, etc. using a normal carbamate synthesis method.

[0107] Also, for example, when R c is an alkylaminocarbonyl group, Compound [I] can be obtained by reacting Compound [Vd] with an alkyl isocyanate, etc. using a normal urea synthesis method. In the urea synthesis reaction described above, Compound [I] can also be obtained by reacting an alkylamine compound with 4-nitrophenyl chloroformate to prepare an alkylcarbamic acid 4-nitrophenyl ester in advance and then reacting this with Compound [Vd].

[0108] Also, when N in Q of Compound [Vd] is substituted with a protecting group, an amine deprotection reaction of a conventional method may be appropriately performed after or before the introduction of R c The deprotection reaction may be carried out by a known method according to the protecting group employed. c before the introduction of R.

[0109] For example, when the protecting group is a p-toluenesulfonyl group, the deprotection reaction may be carried out by treating with an alkali such as sodium hydroxide, potassium hydroxide, cesium carbonate, etc. in an ether solvent such as tetrahydrofuran or dioxane; an alcohol solvent such as ethanol or methanol; or water alone or a mixed solvent thereof.

[0110] Also, for example, when the protecting group is a p-methoxybenzyl group, the deprotection reaction may be carried out by treating with an acid such as hydrochloric acid, trifluoroacetic acid, etc. in an ether solvent such as anisole; a halogenated hydrocarbon solvent such as chloroform; an ester solvent such as ethyl acetate; an ether solvent such as dioxane; an alcohol solvent such as ethanol or methanol; or water alone or a mixed solvent thereof. Regarding the synthesis of the compound [Va] of General Production Method 1, an example is shown in the following General Production Methods 2 to 4. In General Production Methods 2 to 4 below, the compounds [VIi] and [VIIo] correspond to the compound [Va].

[0111] [General Production Method 2] [Chemical formula] [In the formula, P N1 , P N2 , P N3 are protecting groups for amines, preferably a tert-butoxycarbonyl group, a benzyl group, a benzyloxycarbonyl group; Y is a hydroxyl group, or a leaving group such as a chlorine atom, a bromine atom, an iodine atom, a mesyloxy group, a tosyloxy group, etc.; m1' is 0 or 1; the carbon atom indicated by * may be substituted with R a within a chemically acceptable range; R a , R b , n1, n2 and m2 are as defined in the above formula [I]]

[0112] (First step 1a) Compound [VIc] can be obtained by subjecting compound [VIa] to an ordinary esterification reaction with compound [VIb] in a solvent. For example, compound [VIa] may be reacted with compound [VIb] in which Y is a hydroxyl group in a solvent in the presence of a condensing agent and a base. Examples of the solvent used in the reaction include amide solvents such as N,N-dimethylformamide; ether solvents such as tetrahydrofuran; halogenated hydrocarbon solvents such as chloroform, etc. These can be used alone or in admixture of two or more. A preferred solvent in this reaction is a halogenated hydrocarbon solvent such as chloroform. The condensing agent used in the reaction is preferably a water-soluble carbodiimide (1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride), etc. The base used in the reaction is preferably an organic base such as 4-dimethylaminopyridine. The reaction temperature is preferably room temperature. The reaction time is usually about 30 minutes to 1 day, preferably about 2 hours to 6 hours.

[0113] Alternatively, for example, compound [VIa] may be reacted with compound [VIb] in which Y is a leaving group in a solvent in the presence of a base. Examples of the leaving group include a chlorine atom, a bromine atom, an iodine atom, a mesyloxy group and a tosyloxy group, and preferably a bromine atom. Examples of the solvent used in the reaction include amide solvents such as N,N-dimethylformamide; ether solvents such as dioxane; hydrocarbon solvents such as toluene, etc. These can be used alone or in admixture of two or more. A preferred solvent in this reaction is N,N-dimethylformamide. Examples of the base used in the reaction include inorganic bases such as sodium carbonate, potassium carbonate, sodium phosphate, potassium phosphate, sodium hydrogen carbonate, etc., and preferably potassium carbonate. The reaction temperature is usually from room temperature to 120 °C, preferably from room temperature to 60 °C. The reaction time is usually about 30 minutes to 1 day, preferably about 2 hours to 6 hours.

[0114] (Step 2a) Compound [VIc] can be reacted in a solvent in the presence of a base by a normal Claisen rearrangement reaction to obtain compound [VId]. The solvent used in the reaction is preferably tetrahydrofuran. Examples of the base used in the reaction include bases such as lithium diisopropylamide, lithium hexamethyldisilazide, potassium hexamethyldisilazide, sodium hexamethyldisilazide, sodium hydride, potassium tert-butoxide, etc., and preferably lithium hexamethyldisilazide. The reaction temperature is preferably about -80°C to 0°C. The reaction time is usually about 30 minutes to 1 day, and preferably about 2 hours to 4 hours.

[0115] (Step 3a) The carboxylic acid of compound [VId] can be subjected to a functional group conversion to a carbamate in a solvent to obtain compound [VIe]. Examples of the method of functional group conversion include, for example, a normal Curtius rearrangement reaction. The reagent used in the reaction is preferably diphenylphosphoryl azide. Examples of the solvent used in the reaction include amide solvents such as N,N-dimethylformamide; alcohol solvents such as benzyl alcohol; ether solvents such as dioxane; hydrocarbon solvents such as toluene, etc. These can be used alone or in a mixture of two or more. The preferred solvent in this reaction is a mixed solution of toluene and benzyl alcohol. The base used in the reaction is preferably triethylamine. The reaction temperature is usually room temperature to 110°C, and preferably about 80°C to 110°C. The reaction time is usually about 30 minutes to 2 days, and preferably about 2 hours to 1 day. In addition, additives such as 4-dimethylaminopyridine may be used as necessary.

[0116] (Step 4a) Compound [VIe] can be obtained by subjecting the olefin thereof to a functional group conversion to a hydroxyl group. An example of the functional group conversion is shown below as Step 4a-1 or 4a-2.

[0117] (Step 4a-1) Compound [VIe] can be obtained by subjecting it to an ozonolysis reaction in a solvent followed by a reduction reaction. The ozonolysis may be carried out according to a conventional method. The solvent used for the ozonolysis reaction is preferably a mixed solution of chloroform and methanol. The reaction temperature of the ozonolysis reaction is usually about -100°C to 0°C, preferably about -80°C to -60°C. The reaction time of the ozonolysis reaction is usually about 5 minutes to 6 hours, preferably about 15 minutes to 3 hours. The reagent used for the reduction reaction is preferably sodium borohydride. The reaction temperature of the reduction reaction is usually about -100°C to room temperature, preferably about -20°C to 0°C. The reaction time of the reduction reaction is usually about 30 minutes to 6 hours, preferably about 1 hour to 3 hours.

[0118] (Step 4a-2) Compound [VIe] can be obtained by subjecting it to a hydroboration reaction in a solvent followed by an oxidation reaction. Examples of the reagent used for the hydroboration reaction include a borane-pyridine complex, a borane-dimethyl sulfide complex, 9-borabicyclo[3.3.1]nonane, or a tetrahydrofuran solution of a borane-tetrahydrofuran complex, and preferably a tetrahydrofuran solution of a borane-tetrahydrofuran complex. The solvent used for the hydroboration reaction is preferably tetrahydrofuran. The reaction temperature of the hydroboration reaction is usually about -20°C to room temperature, preferably 0°C. The reaction time of the hydroboration reaction is preferably about 1 hour to 4 hours.

[0119] Examples of the reagent used in the oxidation reaction include hydrogen peroxide or sodium peroxoborate monohydrate, preferably sodium peroxoborate monohydrate. The reaction temperature of the oxidation reaction is usually about 0 °C to room temperature, preferably room temperature. The reaction time of the oxidation reaction is preferably about 1 hour to 1 day.

[0120] (Step 5a) Similar to the second step of the general production method 1, in a conventional amine deprotection reaction, P of compound [VIf] N1 and P N2 Among them, P N2 can be selectively removed to obtain compound [VIg]. The deprotection reaction may be carried out by a known method according to the protecting group employed.

[0121] (Step 6a) Compound [VIg] can be cyclized in a solvent and then P N3 is introduced to obtain compound [VIh]. Regarding the cyclization reaction, it can be cyclized by introducing a leaving group to the hydroxyl group of compound [VIg] in a solvent in the presence of a base. An example is shown below as Step 6a-1 or 6a-2.

[0122] (Step 6a-1) Compound [VIg] can be reacted with carbon tetrabromide and triphenylphosphine (or methanesulfonyl chloride in place of these two reagents) in a solvent in the presence of a base to perform the introduction of a leaving group and cyclization in one step. The solvent used in the reaction is preferably dichloromethane. The base used in the reaction is preferably triethylamine. The reaction temperature is preferably from 0 °C to room temperature. The reaction time is usually about 10 minutes to 24 hours, preferably about 30 minutes to 12 hours.

[0123] (Step 6a-2) The reaction for introducing a leaving group and the cyclization reaction may be carried out in two steps. The reagent used in the leaving group introduction reaction is preferably methanesulfonyl chloride. The solvent used in the leaving group introduction reaction is preferably chloroform. The base used in the leaving group introduction reaction is preferably triethylamine. The reaction temperature of the leaving group introduction reaction is usually about 0 °C to room temperature, preferably 0 °C. The reaction time of the leaving group introduction reaction is preferably about 30 minutes to 2 hours. The solvent used in the cyclization reaction is preferably N,N-dimethylformamide. The base used in the cyclization reaction is preferably sodium hydride. The reaction temperature of the cyclization reaction is usually about 0 °C to room temperature, preferably 0 °C. The reaction time of the cyclization reaction is preferably about 10 minutes to 2 hours.

[0124] By introducing P N3 into the above cyclized product by a conventional amine protection reaction, compound [VIh] can be obtained. The amine protection reaction may be carried out by a known method according to the protecting group employed. For example, when P N3 is a benzyloxycarbonyl group, it may be reacted with benzyl chloroformate in a halogenated hydrocarbon solvent such as chloroform or dichloromethane in the presence of an organic base such as triethylamine. In addition, the 5a step may be omitted and the 6a step 2 may be carried out.

[0125] (Step 7a) Similar to the second step of the general production method 1, by using a conventional amine deprotection reaction to selectively remove P N1 and P N3 among P N1 from compound [VIh], compound [VIi] can be obtained. The deprotection reaction may be carried out by a known method according to the protecting group employed.

[0126] In addition, in any of the compounds [Va], [Vc], [Vd], [I] of the general production method 1 and the compounds [VId] to [VIi] of the general production method 2, an optically active substance can be obtained by performing optical resolution. Examples of the optical resolution method include a resolution method in which a racemic compound [VId] and an optically active amine compound are mixed in a solvent and crystallized as a single diastereomeric salt. By performing desalting of the obtained diastereomeric salt by a conventional method, an optically active compound [VId] can be obtained. At this time, by selecting an appropriate optically active amine compound, the (+)-form or (-)-form of the compound [VId] can be produced.

[0127] Examples of the optically active amine compound include (S)-(-)-2-amino-3-phenylpropan-1-ol, (R)-(+)-2-amino-3-phenylpropan-1-ol, (S)-(-)-1-(1-naphthyl)ethylamine, (R)-(+)-1-(1-naphthyl)ethylamine, (S)-(+)-2-amino-2-phenyl-ethanol, (R)-(-)-2-amino-2-phenyl-ethanol, and the like.

[0128] Examples of the solvent include ketone solvents such as acetone, methyl ethyl ketone, and methyl isobutyl ketone; ester solvents such as methyl acetate, ethyl acetate, isopropyl acetate, and isobutyl acetate; ether solvents such as isopropyl ether and 1,2-dimethoxyethane; alcohol solvents such as methanol, ethanol, and isopropanol; and water. These can be used alone or in combination of two or more. Preferred solvents include isopropyl acetate, isopropanol, or 1,2-dimethoxyethane.

[0129] In addition, the measures usually taken to increase the optical purity may be carried out as necessary. For example, recrystallization may be repeated. In addition, as another method of optical resolution, for example, there is a method of separating a desired optically active compound [I] from the other isomer by treating a racemic compound [I] with a chiral stationary phase column or the like.

[0130] [General manufacturing method 3] [Chem.]

[0131] [Chem.] [wherein, P N4 , P N5 , P N6 and P N7 are protecting groups for amines, preferably a benzyl group, a tert-butoxycarbonyl group or a benzyloxycarbonyl group; P C1 is a protecting group for carboxylic acids, preferably a tert-butyl ester group, a methyl ester group or an ethyl ester group; Hal is a halogen atom; m1' is 0 or 1; the carbon atom indicated by * may be substituted with R a within a chemically acceptable range; the carbon atom indicated by # may be substituted with R b within a chemically acceptable range; R a , R b , n1, n2 and m2 are synonymous with the definitions in the above formula [I]]

[0132] (Step 1b) Compound [VIIb] can be obtained by introducing P N4 into compound [VIIa] by a conventional amine protection reaction. The amine protection reaction may be carried out by a known method according to the protecting group employed. For example, when P N4 is a benzyl group, it may be subjected to a hydrogenation reaction with benzaldehyde in an alcohol solvent such as methanol or ethanol in the presence of a palladium catalyst such as palladium on carbon.

[0133] (Step 2b) Compound [VIId] can be obtained by reacting compound [VIIb] with compound [VIIc] in a solvent in the presence of a base. The solvent used in the reaction is preferably N,N-dimethylformamide. The base used in the reaction is preferably potassium carbonate. The reaction temperature is usually from room temperature to 120 °C, preferably from room temperature to 60 °C. The reaction time is usually about 30 minutes to 2 days, preferably about 6 hours to 1 day.

[0134] (Step 3b) Compound [VIIe] can be obtained by carrying out a normal halogenation reaction of compound [VIId] in a solvent and then subjecting it to a rearrangement reaction. The reagent used in the halogenation reaction is preferably thionyl chloride. The solvent used in the halogenation reaction is preferably chloroform. The reaction temperature of the halogenation reaction is preferably from room temperature to 60 °C. The reaction time of the halogenation reaction is usually about 30 minutes to 1 day, preferably about 1 hour to 6 hours.

[0135] Here, the rearrangement reaction is as shown in, for example, Step 3b2 below. That is, compound [VIIe3] can be obtained by subjecting compound [VIIe2] obtained by the halogenation reaction to a rearrangement reaction in a solvent.

Chemical formula

[0136] The solvent used in the rearrangement reaction is preferably N,N-dimethylformamide. The reaction temperature of the rearrangement reaction is preferably about 60 °C to 100 °C. The reaction time of the rearrangement reaction is preferably about 30 minutes to 3 days.

[0137] (Step 4b) Compound [VIIf] can be obtained by subjecting compound [VIIe] to an intramolecular cyclization reaction in a solvent in the presence of a base. The base used in the reaction is preferably lithium hexamethyldisilazide. The solvent used in the reaction is preferably a mixed solution of tetrahydrofuran and hexamethylphosphoramide. The reaction temperature is generally about -100 °C to 0 °C, preferably about -80 °C to 0 °C. The reaction time is generally about 30 minutes to 6 hours, preferably about 1 hour to 2 hours.

[0138] (Step 5b) P of compound [VIIf] N4 is converted to P N5 to obtain compound [VIIg]. P N4 can be removed by performing a conventional amine deprotection reaction in the same manner as in the second step of the general production method 1 above. The deprotection reaction may be carried out by a known method according to the protecting group employed.

[0139] Also, the introduction of P N5 can be carried out by performing a conventional amine protection reaction in the same manner as in the first step 1b of the general production method 3 above. The amine protection reaction may be carried out by a known method according to the protecting group employed. For example, when P N4 of compound [VIIf] is a benzyl group and P N5 of compound [VIIg] is a tert-butoxycarbonyl group, compound [VIIf] is hydrogenated with di-tert-butyl dicarbonate in a mixed solvent of tetrahydrofuran and methanol in the presence of a catalyst such as palladium carbon or palladium hydroxide to convert P N4 to P N5 in one step.

[0140] (Step 6b) Compound [VIIi] can be obtained by reacting compound [VIIg] with compound [VIIh] in a solvent in the presence of a base. The base used in the reaction is preferably lithium hexamethyldisilazide. The solvent used in the reaction is preferably tetrahydrofuran. The reaction temperature is generally about -80°C to room temperature, preferably about -80°C to 0°C. The reaction time is generally about 30 minutes to 3 hours, preferably about 30 minutes to 1 hour.

[0141] (Step 7b) Compound [VIIj] can be obtained by subjecting the olefin of compound [VIIi] to an oxidative cleavage reaction in a solvent. Examples of the oxidative cleavage reaction include ozonolysis by a reductive treatment method. The solvent used in the reaction is preferably a mixed solution of chloroform and methanol. The reaction temperature is generally about -100°C to 0°C, preferably about -80°C to 0°C. The reaction time is generally about 5 minutes to 6 hours, preferably about 30 minutes to 2 hours. Examples of the reagent used as the reducing agent include dimethyl sulfide or triphenylphosphine, preferably triphenylphosphine.

[0142] (Step 8b) Compound [VIIk] can be obtained by subjecting compound [VIIj] to a reductive amination reaction in a solvent. The amine used in the reaction is preferably benzylamine. The solvent used in the reaction is preferably tetrahydrofuran. The reaction temperature is preferably room temperature. The reaction time is preferably about 12 hours to 1 day. The reagent used as the reducing agent is preferably sodium triacetoxyborohydride.

[0143] (Step 9b) In the conventional carboxylic acid deprotection reaction and amine deprotection reaction, P of compound [VIIk] C1 and P N5 are simultaneously removed to obtain compound [VIIl]. The deprotection reaction may be carried out by a known method according to the protecting group employed. Here, for example, PC1 is a tert-butyl ester group, and P N5 When is a tert-butoxycarbonyl group, compound [VIIk] may be treated with an acid such as hydrochloric acid or trifluoroacetic acid in a single or mixed solvent such as anisole, chloroform, ethyl acetate, dioxane, water, etc.

[0144] (Step 10b) Compound [VIIm] can be obtained by subjecting compound [VIIl] to an intramolecular cyclization reaction in a solvent. Examples of the cyclization reaction include a normal amidation reaction in the presence of a condensing agent and a base. The condensing agent used in the reaction is preferably O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate. The base used in the reaction is preferably diisopropylethylamine. The solvent used in the reaction is preferably chloroform. The reaction temperature is preferably room temperature. The reaction time is usually about 30 minutes to 1 day, preferably about 1 hour to 6 hours.

[0145] Also, as another method of the cyclization reaction, when P of compound [VIIk] C1 is an ethyl ester or a methyl ester, only P is selectively removed by a normal amine deprotection method while leaving P C1 intact, and then compound [VIIm] can also be obtained by subjecting it to a cyclization reaction at room temperature in 2M aqueous sodium hydroxide solution and an alcoholic solvent such as ethanol. N5

[0146] (Step 11b) After reducing the amide of compound [VIIm] to an amine in a solvent, P is introduced by a conventional amine protection reaction N7 to obtain compound [VIIn]. The reducing agent used in the reduction reaction is preferably a mixture of lithium aluminum hydride and concentrated sulfuric acid. The amount of concentrated sulfuric acid used is preferably 0.5 mol per 1 mol of lithium aluminum hydride. The solvent used in the reduction reaction is preferably tetrahydrofuran. The reaction temperature of the reduction reaction is usually about 0 °C to room temperature, preferably 0 °C. The reaction time of the reduction reaction is usually about 30 minutes to 3 hours, preferably about 1 hour to 2 hours.

[0147] The amine protection reaction may be carried out by a known method according to the protecting group employed, in the same manner as in the first step 1b of the general production method 3. For example, when P N7 is a tert-butoxycarbonyl group, compound [VIIm] may be reacted with di-tert-butyl dicarbonate in tetrahydrofuran.

[0148] (Step 12b) In the same manner as in the second step of the general production method 1, by a conventional amine deprotection reaction, P of compound [VIIn] N6 and P N7 Among them, by selectively removing P N6 , compound [VIIo] can be obtained. The deprotection reaction may be carried out by a known method according to the protecting group employed.

[0149] [General Production Method 4] [Chemical formula] [In the formula, P N8 is a protecting group for the amine, preferably a tert-butoxycarbonyl group; P C2 is a protecting group for the carboxylic acid, preferably a tert-butyl ester group; Hal is a halogen atom; m2' is 1 or 2; the carbon atom indicated by * may be substituted with R a within a chemically acceptable range; the carbon atom indicated by # may be substituted with R b within a chemically acceptable range; R a , R b, n1, n2 and m1 are synonymous with the definitions in the formula [I]

[0150] (Step 1c) Compound [VIIIa] can be reacted with trichloroethanal in a solvent to obtain compound [VIIIb]. The solvent used in the reaction is preferably acetonitrile. The reaction temperature is preferably room temperature. The reaction time is usually about 30 minutes to 3 days, preferably about 6 hours to 1 day.

[0151] (Step 2c) Compound [VIIIb] can be reacted with compound [VIIIc] in a solvent in the presence of a base to obtain compound [VIIId]. The solvent used in the reaction is preferably tetrahydrofuran. The base used in the reaction is preferably lithium diisopropylamide. The reaction temperature is usually about -80°C to room temperature, preferably about -80°C to 0°C. The reaction time is usually about 30 minutes to 1 day, preferably about 1 hour to 3 hours.

[0152] (Step 3c) Compound [VIIId] can be subjected to solvolysis under acidic conditions in an alcoholic solvent to obtain compound [VIIIe]. The solvent used in the reaction is preferably methanol. The acid used in the reaction is preferably concentrated sulfuric acid. The amount of concentrated sulfuric acid used is preferably 0.1 mol to 3 mol per 1 mol of compound [VIIId].[[]] The reaction temperature is preferably room temperature to 65°C. The reaction time is usually about 30 minutes to 3 days, preferably about 6 hours to 1 day.

[0153] (Step 4c) In the same manner as in Step 1b of the general production method 3 above, by a conventional amine protection reaction, P is added to compound [VIIIe]N8 By introducing [VIIIf], compound [VIIIf] can be obtained. The amine protection reaction may be carried out by a known method according to the protecting group employed. For example, when N8 P is a tert-butoxycarbonyl group, compound [VIIIe] may be reacted with di-tert-butyl dicarbonate in tetrahydrofuran.

[0154] (Step 5c) Similar to Step 4a2 of General Production Method 2, compound [VIIIg] can be obtained by subjecting compound [VIIIf] to a hydroboration reaction followed by an oxidation reaction in a solvent.

[0155] (Step 6c) Compound [VIIIh] can be obtained by subjecting compound [VIIIg] to an oxidation reaction in a solvent. Examples of the reagent used in the reaction include sulfur trioxide pyridine complex or Dess-Martin periodinane, preferably Dess-Martin periodinane. The solvent used in the reaction is preferably chloroform. The reaction temperature is preferably about 0 °C to room temperature. The reaction time is usually about 30 minutes to 1 day, preferably about 2 hours to 6 hours.

[0156] Also, as an additive, bases such as sodium hydrogen carbonate may be added as necessary. By reacting the obtained compound [VIIIh] in the same manner as in Step 8b and subsequent steps of General Production Method 3, an amine compound corresponding to compound [VIIo] can be obtained.

Examples

[0157] Next, the production of the compound of the present invention will be specifically described by way of examples. However, the present invention is not limited by these examples. In this example, the stereochemical notations in the chemical structural formula of the compound are omitted.

[0158] The measuring apparatus and conditions used in this example are shown below. HPLC analysis condition 1 Method for preparing solution A: Dissolve 23.4 g of sodium dihydrogen phosphate dihydrate in 3000 mL of water, and adjust the pH to 2.1 using 10.2 mL of phosphoric acid. Measuring instrument: HPLC system, Shimadzu Corporation, High Performance Liquid Chromatograph Prominence Column: Daicel CHIRALPAK AD-3R, 4.6 mm φ × 150 mm Column temperature: 40 °C Mobile phase: (Solution A) 100 mM phosphate (sodium) buffer (pH 2.1), (Solution B) methanol Solution A:Solution B = 30:70 constant, elute for 20 minutes. Elution rate: 0.5 ml / min Detection: UV (220 nm)

[0159] [Production Example 1]: Synthesis of Compound 1

Chemical formula

Chemical formula

[0160] (2) 3-(1-Methyl-allyl)-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester

Chemical Structure

[0161] (3) Optical isomers of 1-tert-butyl 3-(1-methylallyl)piperidine-1,3-dicarboxylate

Chem.

[0162] (3)-(1) Seed crystal of the salt of the optical isomer of 1-tert-butyl 3-(1-methylallyl)piperidine-1,3-dicarboxylate and (R)-(-)-2-amino-2-phenylethanol

Chem.

[0163] (3)-(2) Salt of the optical isomer of 1-tert-butyl 3-(1-methylallyl)piperidine-1,3-dicarboxylate and (R)-(-)-2-amino-2-phenylethanol 1-tert-Butyl 3-(1-methylallyl)piperidine-1,3-dicarboxylate (106.6 g), (R)-(-)-2-amino-2-phenylethanol (31.0 g), isopropyl acetate (480 ml) and isopropanol (480 ml) were mixed and dissolved at room temperature. The seed crystal obtained in (3)-(1) was added to this mixed solution, and the mixture was stirred for 16 hours. This slurry mixture was filtered to obtain the title compound (47.0 g). When this solid was analyzed under HPLC analysis condition 1, the isomer with a shorter retention time was the main component. Isomer with a shorter retention time (retention time 6.48 minutes) Isomer with a longer retention time (retention time 10.70 minutes)

[0164] (3) The optically active form of 1-tert-butyl 3-(1-methylallyl)piperidine-1,3-dicarboxylate recovered from the filtrate of (3)-(3)(3)-(2). (3) The filtrate of (2) was concentrated under reduced pressure, and the resulting residue was mixed with ethyl acetate (500 ml) and water (500 ml), and acidified by adding potassium hydrogen sulfate. The separated organic layer was washed with a saturated aqueous sodium chloride solution and concentrated under reduced pressure. Isopropanol was added to this residue and concentrated under reduced pressure to obtain the title compound (75.0 g). 1 H-NMR (CDCl3) δ: 5.80-5.71 (1H, m), 5.09-5.07 (1H, m), 5.06-5.03 (1H, m), 4.32-4.20 (1H, m), 3.90-3.83 (1H, m), 2.87-2.74 (2H, m), 2.39-2.31 (1H, m), 2.19-2.11 (1H, m), 1.64-1.55 (2H, m), 1.51-1.44 (1H, m), 1.45 (9H, s), 1.07 (3H, d, J = 7.1 Hz).

[0165] (4) The salt of the optically active form of 1-tert-butyl 3-(1-methylallyl)piperidine-1,3-dicarboxylate and (S)-(+)-2-amino-2-phenylethanol [Chemical formula] (3) The residue (75.0 g) obtained in (3) was mixed with (S)-(+)-2-amino-2-phenylethanol (31.0 g), isopropyl acetate (335 ml) and isopropanol (306 ml), and dissolved at room temperature. The seed crystal obtained in (3)-(1) was added to this mixed solution, and the mixture was stirred for 17.5 hours. This slurry mixture was filtered, and the resulting solid was washed with isopropyl acetate (150 ml) to obtain the title compound (54.2 g). When this solid was analyzed under HPLC analysis condition 1, the isomer with a longer retention time was the main component. The isomer with a shorter retention time (retention time 6.48 minutes) Isomer with a long retention time (retention time: 10.70 minutes)

[0166] (5)Optically active form of 1-tert-butyl 3-(1-methylallyl)piperidine-1,3-dicarboxylate

Chemical formula

[0167] (6)Optically active form of tert-butyl 3-benzyloxycarbonylamino-3-(1-methylallyl)piperidine-1-carboxylate

Chemical formula

[0168] (7) Optically active form of 3-benzyloxycarbonylamino-3-(2-hydroxy-1-methylethyl)piperidine-1-carboxylic acid tert-butyl ester

Chemical formula

[0169] (8) Optically active form of tert-butyl 3-amino-3-(2-hydroxy-1-methylethyl)piperidine-1-carboxylate

Chemical formula

[0170] (9) Optically active form of 1-benzyl 6-tert-butyl 3-methyl-1,6-diazaspiro[3,5]nonane-1,6-dicarboxylate

Chemical formula

[0171] (10) Optically active form of 1-benzyl 3-methyl-1,6-diazaspiro[3.5]nonane-1-carboxylate

Chemical formula

[0172] (11) Optically active form of benzyl 3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.5]nonane-1-carboxylate

Chemical formula

[0173] (12) Optically active form of 4-(3-methyl-1,6-diazaspiro[3.5]non-6-yl)-7H-pyrrolo[2,3-d]pyrimidine

Chemical formula

[0174] (13) Optically active form of 3-[3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.5]non-1-yl]-3-oxopropionitrile

Chemical formula

[0175] [Production Example 2]: Synthesis of Compound 2

Chemical Structure

Chem.

[0176] (2) 3-(1-methyl-allyl)-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester

Chem.

[0177] (3) The salt of the optically active form of 3-(1-methyl-allyl)-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester and (S)-(+)-2-amino-2-phenyl-ethanol [Chemical formula] To a solution of 3-(1-methylallyl)piperidine-1,3-dicarboxylic acid 1-tert-butyl ester (3.00 g) in 1,2-dimethoxyethane (30 ml) was added (S)-(+)-2-amino-2-phenyl-ethanol (800 mg), and the mixture was stirred at room temperature overnight. The solid (1.8 g) was obtained by filtering this slurry mixture. 1,2-Dimethoxyethane (45 ml) was added to this solid and dissolved at 80 °C. This mixture was slurried and washed at room temperature for 4 hours to obtain the title compound (1.46 g). When analyzed under HPLC analysis condition 1, the isomer with a longer retention time was the main component. Isomer with a shorter retention time (retention time 6.73 minutes) Isomer with a longer retention time (retention time 13.70 minutes)

[0178] (4) Optically active form of 3-(1-methylallyl)piperidine-1,3-dicarboxylic acid 1-tert-butyl ester [Chemical formula] Ethyl acetate (15 ml) and water (15 ml) were mixed with an optically active form of a salt of 3-(1-methyl-allyl)-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester and (S)-(+)-2-amino-2-phenyl-ethanol (1.5 g), and potassium hydrogen sulfate (567 mg) was added for acidification. The separated aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were washed twice with a 10% aqueous solution of potassium hydrogen sulfate and once with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain the title compound (1.02 g). 1 H-NMR (CDCl3) δ: 5.83 - 5.72 (1H, m), 5.09 - 5.06 (1H, m), 5.05 - 5.02 (1H, m), 4.33 - 3.90 (1H, m), 3.73 - 3.63 (1H, m), 3.31 - 2.73 (2H, m), 2.43 - 2.34 (1H, m), 2.07 - 1.97 (1H, m), 1.64 - 1.56 (2H, m), 1.54 - 1.42 (1H, m), 1.45 (9H, s), 1.05 (3H, d, J = 7.3 Hz).

[0179] (5) Optically active tert-butyl 3-benzyloxycarbonylamino-3-(1-methylallyl)piperidine-1-carboxylate

Chemical formula

[0180] (6) Optically active tert-butyl 3-benzyloxycarbonylamino-3-(2-hydroxy-1-methylethyl)piperidine-1-carboxylate

Chemical formula

[0181] (7) Optically active form of tert-butyl 3-amino-3-(2-hydroxy-1-methylethyl)piperidine-1-carboxylate

Chemical formula

[0182] (8) (R)-3-Methyl-1,6-diazaspiro[3,5]nonane-1,6-dicarboxylic acid 1-benzyl ester 6-tert-butyl ester [Chemical Structure] To a solution of the optically active form of tert-butyl 3-amino-3-(2-hydroxy-1-methylethyl)piperidine-1-carboxylate (258 mg), triphenylphosphine (472 mg) and triethylamine (502 μl) in dichloromethane (7.7 ml) cooled to 0 °C, carbon tetrabromide (596 mg) was added. The reaction mixture was stirred at room temperature for 2.5 hours, cooled to 4 °C, and triethylamine (279 μl) and benzyl chloroformate (267 μl) were added, followed by stirring for 40 minutes. Water was added to this mixture, and the mixture was extracted with ethyl acetate. The separated organic layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 20 / 1 to 2 / 1) to obtain the title compound (85 mg). 1 H-NMR (DMSO-D6) δ: 7.40 - 7.29 (5H, m), 5.07 - 4.98 (2H, m), 4.20 - 4.11 (1H, m), 3.99 - 3.83 (2H, m), 3.39 - 3.20 (1H, m), 3.13 - 2.83 (1H, m), 2.58 - 2.45 (1H, m), 2.44 - 2.32 (1H, m), 2.16 - 2.07 (0.5H, m), 2.01 - 1.82 (1.5H, m), 1.68 - 1.58 (1H, m), 1.39 (9H, s), 1.37 - 1.28 (1H, m), 1.14 - 1.03 (3H, m).

[0183] (9) Optically active 1-benzyl 3-methyl-1,6-diazaspiro[3,5]nonane-1-carboxylate

Chem.

[0184] (10) Optically active benzyl 3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.5]nonane-1-carboxylate

Chem.

[0185] (11) Optically active form of 4-(3-methyl-1,6-diazaspiro[3.5]non-6-yl)-7H-pyrrolo[2,3-d]pyrimidine

Chemical formula

[0186] (12) Optically active form of 3-[3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.5]non-1-yl]-3-oxopropionitrile

Chemical formula

[0187] [Production Example 3]: Synthesis of Compound 3

Chemical Structure

Chem.

[0188] (2) 3-Allyl 1-tert-butyl piperidine-1,3-dicarboxylate

Chem.

[0189] (3) Optically active form of 3-allyl piperidine-1,3-dicarboxylic acid 1-tert-butyl ester

Chemical formula

[0190] (3)-(1)Optical isomer of 1-tert-butyl 3-allylpiperidine-1,3-dicarboxylate and seed crystal of salt of (S)-(-)-2-amino-3-phenyl-1-propanol 1-tert-Butyl 3-allylpiperidine-1,3-dicarboxylate (3.0 g) and isopropyl acetate (30 ml) were mixed and heated to 80 °C for dissolution. To this mixture was added (S)-(-)-2-amino-3-phenyl-1-propanol (1.01 g), and the mixture was stirred at room temperature for 21 hours. This slurry mixture was filtered, and the obtained solid was washed with isopropyl acetate (8 ml) and dried under reduced pressure to obtain the title compound (1.5 g). The filtrate was concentrated under reduced pressure and used in (4)-(1).

[0191] (3)-(2)Salt of optical isomer of 1-tert-butyl 3-allylpiperidine-1,3-dicarboxylate and (S)-(-)-2-amino-3-phenyl-1-propanol [Chemical formula] To a solution of 1-tert-butyl 3-allylpiperidine-1,3-dicarboxylate (73.3 g) in isopropyl acetate (733 ml) heated to 80 °C was added (S)-(-)-2-amino-3-phenyl-1-propanol (24.7 g). This mixed solution was cooled to room temperature, and the seed crystal obtained in (3)-(1) was added, and the mixture was stirred overnight. This slurry mixture was filtered, and the obtained solid was washed with isopropyl acetate (210 ml) to obtain the title compound (37.4 g). When analyzed under HPLC analysis condition 1, the isomer with a shorter retention time was the main component. Isomer with a shorter retention time (retention time: 6.01 minutes) Isomer with a longer retention time (retention time: 8.94 minutes)

[0192] (3)―(3)Optical isomer of 1-tert-butyl 3-allylpiperidine-1,3-dicarboxylate from the filtrate of (3)-(2) (3)-(2)'s filtrate and the washing solution were combined, and an aqueous solution of potassium hydrogen sulfate (22.2 g / 365 ml) was added and stirred. The separated organic layer was successively washed with a 10% aqueous solution of potassium hydrogen sulfate, water, and a saturated aqueous solution of sodium chloride, and concentrated under reduced pressure to obtain the title compound (49 g). 1 H-NMR (CDCl3) δ: 5.81-5.69 (1H, m), 5.14-5.06 (2H, m), 3.93-3.78 (1H, m), 3.54-3.45 (1H, m), 3.29-3.14 (2H, m), 2.43-2.34 (1H, m), 2.29-2.21 (1H, m), 2.07-1.98 (1H, m), 1.65-1.49 (3H, m), 1.45 (9H, s)

[0193] (4) Optical isomer of 3-allylpiperidine-1,3-dicarboxylic acid 1-tert-butyl ester and salt of (R)-(+)-2-amino-3-phenyl-1-propanol

Chemical formula

[0194] (4)-(1) Seed crystal of the salt of the optical isomer of 3-allylpiperidine-1,3-dicarboxylic acid 1-tert-butyl ester and (R)-(+)-2-amino-3-phenyl-1-propanol (3)-(1)'s residue (2.74 g) obtained from the filtrate was added with ethyl acetate (14 ml) and water (14 ml), cooled to 0 °C, and potassium hydrogen sulfate (494 mg) was added. This mixture was stirred at room temperature for 30 minutes and then extracted with ethyl acetate. This organic layer was successively washed with a 10% aqueous solution of potassium hydrogen sulfate, water (twice), and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue (1.94 g) was mixed with isopropyl acetate (20 ml) and heated to 80 °C to dissolve. (R)-(+)-2-Amino-3-phenyl-1-propanol (925 mg) was added to this mixture, and it was stirred at room temperature for 19.5 hours. This slurry mixture was filtered, and the obtained solid was dried under reduced pressure to obtain the title compound (1.85 g).

[0195] (4)-(2) Optical active form of 1-tert-butyl 3-allylpiperidine-1,3-dicarboxylate and salt of (R)-(+)-2-amino-3-phenyl-1-propanol (3) The residue (49 g) obtained in (3) and isopropyl acetate (490 ml) were mixed and heated to 80 °C for dissolution. To this mixture was added (R)-(+)-2-amino-3-phenyl-1-propanol (23.7 g), cooled to room temperature, and the seed crystal obtained in (4)-(1) was added, followed by stirring overnight. This slurry mixture was filtered and washed with isopropyl acetate (150 ml) to obtain the title compound (52 g). When analyzed under HPLC analysis condition 1, the isomer with a longer retention time was the main component. Isomer with a shorter retention time (retention time: 6.01 minutes) Isomer with a longer retention time (retention time: 8.94 minutes)

[0196] (5) Optical active form of 1-tert-butyl 3-allylpiperidine-1,3-dicarboxylate [Chemical formula] (4)-(2) To the salt (52 g) of the optical active form of 1-tert-butyl 3-allylpiperidine-1,3-dicarboxylate and (R)-(+)-2-amino-3-phenyl-1-propanol obtained in (4)-(2) were added ethyl acetate (260 ml) and an aqueous solution of potassium bisulfate (20.2 g / 260 ml), followed by stirring. The separated organic layer was washed successively with a 10% aqueous solution of potassium bisulfate, water, and a saturated aqueous solution of sodium chloride. The separated aqueous layer was extracted again with ethyl acetate (130 ml) and washed successively with water and a saturated aqueous solution of sodium chloride. The combined organic layers were concentrated under reduced pressure to obtain the title compound (32.2 g). 11H-NMR (CDCl3) δ: 5.81 - 5.69 (1H, m), 5.14 - 5.06 (2H, m), 3.93 - 3.78 (1H, m), 3.54 - 3.45 (1H, m), 3.29 - 3.14 (2H, m), 2.43 - 2.34 (1H, m), 2.29 - 2.21 (1H, m), 2.07 - 1.98 (1H, m), 1.65 - 1.49 (3H, m), 1.45 (9H, s).

[0197] (6) Optically active tert-butyl 3-allyl-3-benzyloxycarbonylaminopiperidine-1-carboxylate

Chemical Structure

[0198] (7) Optically active tert-butyl 3-benzyloxycarbonylamino-3-(2-hydroxyethyl)piperidine-1-carboxylate [Chemical formula] Ozone gas stream was passed through a chloroform / methanol solution (493 ml / 493 ml) of the optically active form (39.4 g) of tert-butyl 3-allyl-3-benzyloxycarbonylaminopiperidine-1-carboxylate cooled to -78 °C for 1 hour. Sodium borohydride (19.9 g) was added little by little to this reaction mixture, and the temperature was raised to 4 °C in 50 minutes. A saturated aqueous sodium hydrogen carbonate solution (200 ml) and water (400 ml) were added to this mixture, and the mixture was extracted with chloroform (200 ml). The separated aqueous layer was extracted again with chloroform (300 ml), and the combined organic layers were concentrated under reduced pressure. The obtained residue was slurried and washed with an n-hexane / ethyl acetate (1 / 1, 394 ml) solution to obtain a solid (23.5 g). The residue obtained by concentrating the filtrate under reduced pressure was slurried and washed again with an n-hexane / ethyl acetate (1 / 1) solution to obtain a solid (2.4 g). Next, the residue obtained by concentrating this filtrate under reduced pressure was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 1 / 1 to 0 / 1) to obtain a solid (1.5 g). The solids were combined to obtain the title compound (27.4 g). 1H-NMR (DMSO-D6) δ: 7.39 - 7.26 (5H, m), 6.90 - 6.62 (1H, m), 5.12 - 4.87 (2H, m), 4.36 (1H, t, J = 4.9 Hz), 4.00 - 2.96 (6H, m), 2.15 - 1.72 (2H, m), 1.72 - 1.46 (2H, m), 1.46 - 1.17 (2H, m), 1.36 (9H, s).

[0199] (8) Optically active form of tert-butyl 3-amino-3-(2-hydroxyethyl)piperidine-1-carboxylate

Chemical formula

[0200] (9) Optically active form of 1-benzyl 6-tert-butyl 1,6-diazaspiro[3.5]nonane-1,6-dicarboxylate

Chemical formula

[0201] (10) Optically active form of benzyl 1,6-diazaspiro[3.5]nonane-1-carboxylate

Chemical formula

[0202] (11) Optically active form of 6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.5]nonane-1-carboxylic acid benzyl ester [Chemical formula] The optically active form (2.37 g) of 1,6-diazaspiro[3.5]nonane-1-carboxylic acid benzyl ester was mixed with 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.4 g), potassium carbonate (3.8 g) and water (71 ml), and the mixture was heated with stirring at 100 °C for 3 hours. The mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and concentrated under reduced pressure. The resulting residue was slurried with n-hexane / ethyl acetate (1 / 1) solution to obtain the title compound (2.55 g). 11H-NMR (DMSO-D6) δ: 11.72 (1H, s), 8.13 (1H, s), 7.41 - 7.28 (5H, m), 7.19 (1H, dd, J = 3.5, 2.6 Hz), 6.64 - 6.60 (1H, m), 5.13 - 5.02 (2H, m), 4.96 - 4.89 (1H, m), 4.64 - 4.56 (1H, m), 3.98 - 3.70 (2H, m), 3.46 - 3.28 (1H, m), 3.01 - 2.82 (1H, m), 2.31 - 2.22 (0.5H, m), 2.16 - 2.06 (0.5H, m), 2.03 - 1.90 (3H, m), 1.83 - 1.75 (1H, m), 1.61 - 1.47 (1H, m).

[0203] (12) The optically active form of 4-(1,6-diazaspiro[3.5]non-6-yl)-7H-pyrrolo[2,3-d]pyrimidine

Chemical Structure

[0204] (13) Optical isomers of 3-oxo-3-[6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.5]non-1-yl]-propionitrile [Chemical formula] The optical isomer (1.55 g) of 4-(1,6-diazaspiro[3.5]non-6-yl)-7H-pyrrolo[2,3-d]pyrimidine was mixed with 1-cyanoacetyl-3,5-dimethylpyrazole (1.56 g), N,N-diisopropylethylamine (1.66 ml) and 1,4-dioxane (31 ml), and the mixture was heated with stirring at 100 °C for 2 hours. The mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: ethyl acetate / methanol = 20 / 1 to 9 / 1) to obtain the title compound (1.50 g). 1H-NMR (DMSO-D6) δ: 11.73 (1H, br s), 8.13 (1H, s), 7.22 - 7.18 (1H, m), 6.67 - 6.63 (1H, m), 4.96 (1H, d, J = 12.6 Hz), 4.68 - 4.60 (1H, m), 4.11 - 4.03 (1H, m), 4.01 - 3.93 (1H, m), 3.71 (2H, s), 3.53 (1H, d, J = 12.6 Hz), 2.98 - 2.88 (1H, m), 2.40 - 2.30 (1H, m), 2.03 - 1.90 (3H, m), 1.83 - 1.75 (1H, m), 1.59 - 1.45 (1H, m). [α]D = +210.00° (25 °C, c = 1.01, methanol)

[0205] [Production Example 4]: Synthesis of Compound 4 [Chemical Formula] (1) 1-tert-Butyl 3-(3,3-difluoroallyl) pyrrolidine-1,3-dicarboxylate [Chemical Formula] To a solution of 1-tert-butyl pyrrolidine-1,3-dicarboxylate (3.40 g) in N,N-dimethylformamide (34 ml) were added potassium carbonate (4.37 g) and 3-bromo-3,3-difluoropropene (1.93 ml), and the mixture was stirred at 60 °C for 6 hours. Water was added to this reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 5 / 1) to obtain the title compound (3.73 g). 1 H-NMR (CDCl3) δ: 4.64 - 4.48 (3H, m), 3.67 - 3.42 (3H, m), 3.41 - 3.29 (1H, m), 3.10 - 2.98 (1H, m), 2.18 - 2.04 (2H, m), 1.46 (9H, s).

[0206] (2) 1-tert-Butyl 3-(1,1-difluoroallyl)pyrrolidine-1,3-dicarboxylate

Chem.

[0207] (3) Optically active 1-tert-butyl 3-(1,1-difluoroallyl)pyrrolidine-1,3-dicarboxylate

Chem.

[0208] (4) Salt of an optically active form of 1-tert-butyl 3-(1,1-difluoroallyl)pyrrolidine-1,3-dicarboxylate and (R)-(+)-1-(1-naphthyl)ethylamine

Chemical formula

[0209] (5)Optically active form of 1-tert-butyl 3-(1,1-difluoroallyl)pyrrolidine-1,3-dicarboxylate

Chem.

[0210] (6)Optically active form of tert-butyl 3-benzyloxycarbonylamino-3-(1,1-difluoroallyl)pyrrolidine-1-carboxylate

Chem.

[0211] (7) Optically active form of tert-butyl 3-benzyloxycarbonylamino-3-(1,1-difluoro-2-hydroxyethyl)pyrrolidine-1-carboxylate [Chemical formula] To a chloroform / methanol solution (154 ml / 154 ml) of the optically active form (15.5 g) of tert-butyl 3-benzyloxycarbonylamino-3-(1,1-difluoroallyl)pyrrolidine-1-carboxylate cooled to -78°C, an ozone stream was passed for 30 minutes. Sodium borohydride (4.14 g) was added little by little to this reaction mixture, and then the temperature was raised to 0°C, followed by stirring at the same temperature for 4 hours. A saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution were added to this mixture, and the mixture was extracted with chloroform. The separated aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 3 / 1). The fraction that could not be separated and purified was concentrated under reduced pressure, and the obtained residue was purified again by silica gel column chromatography (developing solvent: n-hexane / chloroform / ethyl acetate = 5 / 4 / 1). By combining and concentrating the purified fractions under reduced pressure, the title compound (12.8 g) was obtained. 1 1H-NMR (CDCl3) δ: 7.42-7.32 (5.0H, m), 5.15-5.07 (2.0H, m), 5.04-4.93 (1.0H, m), 4.02-3.49 (6.0H, m), 3.43-3.30 (1.0H, m), 2.67-2.57 (0.4H, m), 2.45-2.28 (1.6H, m), 1.46 (9.0H, s).

[0212] (8) Optically active form of tert-butyl 3-benzyloxycarbonylamino-3-(1,1-difluoro-2-methanesulfonyloxyethyl)pyrrolidine-1-carboxylate

Chemical formula

[0213] (9) Optically active form of 1-benzyl 6-tert-butyl 3,3-difluoro-1,6-diazaspiro[3.4]octane-1,6-dicarboxylate

Chemical formula

[0214] (10) Optically active form of tert-butyl 3,3-difluoro-1,6-diazaspiro[3,4]octane-6-carboxylate

Chemical Structure

[0215] (11) 3,3-Difluoro-1,6-diazaspiro[3,4]octane dihydrochloride

Chemical Structure

[0216] (12) Optically active form of 4-(3,3-difluoro-1,6-diazaspiro[3,4]oct-6-yl)-7H-pyrrolo[2,3-d]pyrimidine

Chemical formula

[0217] (13) Optical isomer of 3-[3,3-difluoro-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]oct-1-yl]-3-oxopropionitrile [Chemical formula] The optical isomer (170 mg) of 4-(3,3-difluoro-1,6-diazaspiro[3,4]oct-6-yl)-7H-pyrrolo[2,3-d]pyrimidine was mixed with 1-cyanoacetyl-3,5-dimethylpyrazole (209 mg), N,N-diisopropylethylamine (117 μl) and 1,4-dioxane (3.4 ml), and stirred at 100 °C for 75 minutes. The mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The separated aqueous layer was further extracted twice with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: chloroform / ethyl acetate = 2 / 1, then chloroform / methanol = 92 / 8 to 3 / 1). The residue obtained by concentration under reduced pressure was slurried and washed with a mixed solvent of n-heptane / ethanol (3 / 1) to obtain the title compound (177 mg). 1H-NMR (DMSO-D6) δ: 11.68 (1H, br s), 8.11 (1H, s), 7.17 - 7.14 (1H, m), 6.58 (1H, dd, J = 3.3, 1.8 Hz), 4.66 - 4.58 (2H, m), 4.24 - 4.13 (2H, m), 4.12 - 4.02 (1H, m), 3.89 - 3.78 (3H, m), 2.68 - 2.58 (1H, m), 2.56 - 2.45 (1H, m). [α]D = +46.67° (25 °C, c = 0.54, methanol)

[0218] [Production Example 5]: Synthesis of Compound 5

Chemical Structure

Chemical Structure

[0219] (2) 1-tert-Butyl 3-(1,1-difluoroallyl)piperidine-1,3-dicarboxylate

Chem.

[0220] (3) Optically active form of 1-tert-butyl 3-(1,1-difluoroallyl)piperidine-1,3-dicarboxylate

Chem.

[0221] (4) Salt of the optically active form of 1-tert-butyl 3-(1,1-difluoroallyl)piperidine-1,3-dicarboxylate and (S)-(+)-2-amino-2-phenylethanol

Chemical formula

[0222] (5) Optically active form of 3-(1,1-difluoro-allyl)-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester

Chemical formula

[0223] (6) Optically active tert-butyl 3-benzyloxycarbonylamino-3-(1,1-difluoro-allyl)-piperidine-1-carboxylate

Chem.

[0224] (7) Optically active tert-butyl 3-benzyloxycarbonylamino-3-(1,1-difluoro-2-hydroxy-ethyl)-piperidine-1-carboxylate

Chem.

[0225] (8) Optically active form of tert-butyl 3-benzyloxycarbonylamino-3-(1,1-difluoro-2-methanesulfonyloxy-ethyl)-piperidine-1-carboxylate

Chemical formula

[0226] (9) Optically active form of 1-benzyl ester 6-tert-butyl ester of 3,3-difluoro-1,6-diaza-spiro[3.5]nonane-1,6-dicarboxylic acid [Chemical formula] To a suspension of sodium hydride (1.7 g, added with 40% mineral oil) in N,N-dimethylformamide (428 ml) cooled to 0 °C was added a solution of the optically active form (17.1 g) of tert-butyl 3-benzyloxycarbonylamino-3-(1,1-difluoro-2-methanesulfonyloxy-ethyl)-piperidine-1-carboxylate in N,N-dimethylformamide (86 ml), and the mixture was stirred at the same temperature for 15 minutes. Water was added to this reaction mixture, and the mixture was extracted with ethyl acetate. The separated organic layer was successively washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 5 / 1) to obtain the title compound (12.6 g). 1 1H-NMR (CDCl3) δ: 7.41 - 7.30 (5H, m), 5.21 - 5.02 (2H, m), 4.56 - 4.31 (1H, m), 4.25 - 4.14 (2H, m), 4.13 - 3.89 (1H, m), 3.41 - 2.98 (1H, m), 2.80 - 2.41 (1H, m), 2.33 - 2.12 (1H, m), 2.03 - 1.87 (1H, m), 1.80 - 1.67 (1H, m), 1.65 - 1.52 (2H, m), 1.45 (9H, s).

[0227] (10)Optically active form of benzyl 3,3-difluoro-1,6-diaza-spiro[3.5]nonane-1-carboxylate monohydrochloride

Chem.

[0228] (11)Optically active form of benzyl 3,3-difluoro-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diaza-spiro[3.5]nonane-1-carboxylate

Chem.

[0229] (12) Optically active form of 4-(3,3-difluoro-1,6-diaza-spiro[3.5]non-6-yl)-7H-pyrrolo[2,3-d]pyrimidine

Chemical formula

[0230] (13) Optically active form of 3-[3,3-difluoro-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diaza-spiro[3.5]non-1-yl]-3-oxo-propionitrile [Chemical formula] An optically active form (6.6 g) of 4-(3,3-difluoro-1,6-diaza-spiro[3.5]non-6-yl)-7H-pyrrolo[2,3-d]pyrimidine was mixed with 1-cyanoacetyl-3,5-dimethylpyrazole (7.7 g), N,N-diisopropylethylamine (4.3 ml) and 1,4-dioxane (132 ml), and stirred at 100 °C for 2 hours. The mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The separated aqueous layer was further extracted 5 times with ethyl acetate. The combined organic layers were successively washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: chloroform / acetone = 3 / 2 to 2 / 3). n-Heptane was added to the resulting residue, and the mixture was concentrated under reduced pressure. Diethyl ether was added to the resulting residue, and the mixture was washed by slurrying and filtered to obtain a solid (7.5 g). The filtrate was concentrated under reduced pressure, diethyl ether was added to the resulting residue again, and the mixture was washed by slurrying to obtain a solid (0.2 g). The combined solids were purified by silica gel column chromatography (developing solvent: chloroform / methanol = 97 / 3 to 9 / 1). Ethanol was added to the resulting solid, and the mixture was concentrated under reduced pressure to obtain the title compound (7.1 g). 1 H-NMR (DMSO-D6) δ: 11.74 (1H, br s), 8.15 (1H, s), 7.22 - 7.19 (1H, m), 6.65 - 6.62 (1H, m), 5.13 - 5.07 (1H, m), 4.69 - 4.46 (3H, m), 3.83 (1H, d, J = 18.8 Hz), 3.77 (1H, d, J = 19.2 Hz), 3.61 - 3.55 (1H, m), 2.99 - 2.91 (1H, m), 2.39 - 2.29 (1H, m), 2.26 - 2.19 (1H, m), 1.99 - 1.91 (1H, m), 1.63 - 1.48 (1H, m). [α]D=+139.52° (25 °C, c = 1.04, methanol)

[0231] [Production Example 6]: Synthesis of Compound 6 [Chemistry] (1) Optically active form of 2-benzylaminopropan-1-ol [Chemistry] (S)-(+)-2-Aminopropan-1-ol (50.0 g) and benzaldehyde (74 ml) were added to a solution of ethanol (500 ml), and 5% palladium on carbon (5.0 g) was added. The mixture was hydrogenated at room temperature and atmospheric pressure for 8 hours. The reaction mixture was filtered through Celite and concentrated under reduced pressure to obtain the title compound (111.2 g). 1 H-NMR (DMSO-D6) δ: 7.34 - 7.27 (4H, m), 7.23 - 7.18 (1H, m), 4.53 - 4.47 (1H, m), 3.76 (1H, d, J = 13.5 Hz), 3.66 (1H, d, J = 13.5 Hz), 3.29 - 3.24 (2H, m), 2.65 - 2.55 (1H, m), 1.99 (1H, br s), 0.93 (3H, d, J = 6.4 Hz).

[0232] (2) Optically active form of tert-butyl [benzyl-(2-hydroxy-1-methylethyl)-amino]acetate [Chemistry] A mixture of the optically active form of 2-benzylaminopropan-1-ol (111.2 g) cooled to 0 °C, potassium carbonate (111.6 g) and N,N-dimethylformamide (556 ml) was added dropwise with tert-butyl bromoacetate (109 ml) over 20 minutes and stirred at room temperature for 19.5 hours. 2M aqueous hydrochloric acid and 6M aqueous hydrochloric acid were added to this mixture to acidify to pH 2 and washed with toluene (1000 ml). The separated organic layer was extracted with 0.1M aqueous hydrochloric acid (300 ml). The combined aqueous layers were adjusted to pH 10 with 4M aqueous sodium hydroxide and extracted with ethyl acetate (700 ml). This organic layer was washed successively with water (900 ml) and saturated aqueous sodium chloride (500 ml). The separated aqueous layer was extracted again with ethyl acetate (400 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound (160.0 g). 1 1H-NMR (DMSO-D6) δ: 7.37 - 7.26 (4H, m), 7.24 - 7.19 (1H, m), 4.26 (1H, dd, J = 6.9, 3.9 Hz), 3.76 (1H, d, J = 14.1 Hz), 3.68 (1H, d, J = 13.9 Hz), 3.45 - 3.39 (1H, m), 3.29 - 3.20 (1H, m), 3.24 (1H, d, J = 17.2 Hz), 3.13 (1H, d, J = 17.0 Hz), 2.84 - 2.74 (1H, m), 1.37 (9H, s), 0.96 (3H, d, J = 6.8 Hz).

[0233] (3) Optically active form of [benzyl-(2-chloropropyl)-amino]acetic acid tert-butyl ester

Chemical formula

[0234] (3)-(1) Optically active form of [benzyl-(2-chloro-1-methylethyl)-amino]acetic acid tert-butyl ester

Chemical formula

[0235] (3)-(2) Optically active form of tert-butyl [benzyl-(2-chloropropyl)-amino]acetate [Chemical formula] The optically active form (172.9 g) of tert-butyl [[benzyl-(2-chloro-1-methylethyl)-amino]acetate was dissolved in N,N-dimethylformamide (520 ml) and stirred at 80 °C for 140 minutes. The reaction mixture was cooled to 0 °C, water (1200 ml) was added, and extraction was performed with n-hexane / ethyl acetate (2 / 1, 1000 ml). The organic layer was washed successively with water (700 ml) and saturated aqueous sodium chloride solution (400 ml), and the separated aqueous layer was extracted again with n-hexane / ethyl acetate (2 / 1, 600 ml). The combined organic layers were concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 50 / 1 to 40 / 1) to obtain the title compound (127.0 g). 1 H-NMR (CDCl3) δ: 7.37 - 7.29 (4H, m), 7.28 - 7.23 (1H, m), 4.05 - 3.97 (1H, m), 3.91 (1H, d, J = 13.5 Hz), 3.86 (1H, d, J = 13.7 Hz), 3.29 (2H, s), 3.03 (1H, dd, J = 13.9, 6.6 Hz), 2.91 (1H, dd, J = 13.9, 6.8 Hz), 1.50 (3H, d, J = 6.4 Hz), 1.48 (9H, s).

[0236] (4) Optically active form of tert-butyl 1-benzyl-3-methylazetidine-2-carboxylate [Chemical formula] To a solution of the optically active form of benzyl-(2-chloropropyl)-amino]acetic acid tert-butyl ester (60.0 g) and hexamethylphosphoramide (36.0 ml) in tetrahydrofuran (360 ml) cooled to -72 °C, lithium hexamethyldisilazide (1.0 M tetrahydrofuran solution, 242 ml) was added dropwise over 18 minutes, and the temperature was raised to 0 °C over 80 minutes. To this reaction mixture, saturated aqueous ammonium chloride solution (300 ml) and water (400 ml) were sequentially added, and the mixture was extracted with ethyl acetate (500 ml). The organic layer was washed successively with water (700 ml) and saturated aqueous sodium chloride solution (500 ml), and the separated aqueous layer was extracted again with ethyl acetate (300 ml). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 50 / 1 to 4 / 1) to obtain the title compound (50.9 g). 1 H-NMR (CDCl3) δ: 7.34 - 7.21 (5H, m), 3.75 (1H, d, J = 12.6 Hz), 3.70 - 3.67 (1H, m), 3.58 (1H, d, J = 12.6 Hz), 3.05 - 3.01 (1H, m), 2.99 - 2.95 (1H, m), 2.70 - 2.59 (1H, m), 1.41 (9H, s), 1.24 (3H, d, J = 7.1 Hz).

[0237] (5) Optically active form of 3-methylazetidine-1,2-dicarboxylic acid di-tert-butyl ester

Chemical Structure

[0238] (6) Optically active form of di-tert-butyl 3-methyl-2-(3-methylbut-2-enyl)azetidine-1,2-dicarboxylate [Chemical formula] To a solution of the optically active form of di-tert-butyl 3-methylazetidine-1,2-dicarboxylate (48.0 g) and 1-bromo-3-methyl-2-butene (25.4 ml) in tetrahydrofuran (380 ml) cooled to -69 °C was added lithium hexamethyldisilazide (1.0 M solution in tetrahydrofuran, 200 ml). The reaction mixture was warmed to -20 °C in 40 minutes and further stirred at the same temperature for 20 minutes. To this reaction mixture were successively added saturated aqueous ammonium chloride solution (200 ml) and water (300 ml), and the mixture was extracted with n-hexane / ethyl acetate (1 / 1, 500 ml). The separated organic layer was washed successively with water (200 ml) and saturated aqueous sodium chloride solution (200 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 15 / 1 to 8 / 1) to obtain the title compound (44.5 g). 1 H-NMR (CDCl3) δ: 5.29-5.21 (1H, m), 3.77-3.72 (1H, m), 3.49-3.44 (1H, m), 2.73-2.52 (3H, m), 1.76-1.74 (3H, m), 1.66-1.65 (3H, m), 1.51 (9H, s), 1.43 (9H, s), 1.05 (3H, d, J = 7.3 Hz).

[0239] (7)Optically active di-tert-butyl 3-methyl-2-(2-oxoethyl)azetidine-1,2-dicarboxylate

Chem.

[0240] (8)Optically active di-tert-butyl 2-(2-benzylaminoethyl)-3-methylazetidine-1,2-dicarboxylate

Chem.

[0241] (9) Optically active form of 2-(2-benzylaminoethyl)-3-methylazetidine-2-dicarboxylic acid 2 hydrochloride

Chemical formula

[0242] (10) Optically active form of 6-benzyl-3-methyl-1,6-diazaspiro[3.4]octan-5-one

Chemical formula

[0243] (11) Optically active form of tert-butyl 6-benzyl-3-methyl-1,6-diazaspiro[3.4]octane-1-carboxylate

Chemical formula

[0244] (12) Optically active form of tert-butyl 3-methyl-1,6-diazaspiro[3.4]octane-1-carboxylate

Chemical formula

[0245] (13) The optically active form of tert-butyl 3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]octane-1-carboxylate

Chemical formula

[0246] (14) Optically active form of 4-(3-methyl-1,6-diazaspiro[3.4]oct-6-yl)-7H-pyrrolo[2,3-d]pyrimidine dihydrochloride

Chemical Structure

[0247] (15) Optically active form of 3-[3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]oct-1-yl]-3-oxopropionitrile

Chemical Structure

[0248] To the obtained crystal 1 (2.6 g), 1-butanol (39 ml) was added, and the mixture was heated and stirred at 100 °C. After complete dissolution, the solution was cooled to room temperature in 10 °C increments every 30 minutes and further stirred at room temperature overnight. The formed crystals were collected by filtration, washed with 1-butanol (6.2 ml), and dried under reduced pressure to obtain crystal 2 (2.1 g) of the title compound.

[0249] [Production Example 7]: Synthesis of Compound 7

Chemical formula

Chemical formula

[0250] (2) Optically active form of 7a-allyl-3-trichloromethyltetrahydropyrrolo[1,2-c]oxazol-1-one

Chemical formula

[0251] (3)Optical isomers of 2-allylpyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester [Chemical formula] To a solution of 7a-allyl-3-trichloromethyltetrahydropyrrolo[1,2-c]oxazol-1-one (86.1 g) cooled to 0 °C in methanol (430 ml), concentrated sulfuric acid (43 ml) was added dropwise, and then the mixture was stirred for 13.5 hours while refluxing. The mixture was cooled to room temperature and concentrated under reduced pressure. Ethyl acetate (500 ml) was added to the resulting residue, and the mixture was extracted with water (500 ml). The separated organic layer was extracted again with water (300 ml). The combined aqueous layers were neutralized to pH 7.5 with 4M aqueous sodium hydroxide solution. Sodium hydrogen carbonate (55 g) was added to this mixture, and a solution of di-tert-butyl dicarbonate (85.7 g) in tetrahydrofuran (430 ml) was added at room temperature, and the mixture was stirred overnight. Ethyl acetate (800 ml) was added to this mixture for extraction. The separated organic layer was washed successively with water (1000 ml) and saturated aqueous sodium chloride solution (500 ml). The separated aqueous layer was extracted again with ethyl acetate (400 ml). The combined organic layers were dried over anhydrous sodium sulfate and dried under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 30 / 1 to 10 / 1) to obtain the title compound (61.2 g). 1 1H-NMR (CDCl3) δ: 5.82 - 5.70 (1.0H, m), 5.16 - 5.14 (1.0H, m), 5.13 - 5.09 (1.0H, m), 3.73 - 3.66 (0.7H, m), 3.72 (3.0H, s), 3.63 - 3.56 (0.3H, m), 3.42 - 3.31 (1.0H, m), 3.14 - 3.07 (0.3H, m), 2.96 - 2.89 (0.7H, m), 2.65 - 2.57 (1.0H, m), 2.17 - 1.98 (2.0H, m), 1.94 - 1.75 (2.0H, m), 1.46 (3.0H, s), 1.43 (6.0H, s).

[0252] (4)Optically active form of 2-(3-hydroxypropyl)pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester

Chemical formula

[0253] (5) Optically active form of 1-tert-butyl 2-methyl 2-(3-oxopropyl)pyrrolidine-1,2-dicarboxylate [Chemical formula] A suspension of 2-(3-hydroxypropyl)pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (17.4 g) cooled to 0 °C and sodium hydrogen carbonate (12.7 g) in chloroform (175 ml) was added Dess-Martin periodinane (28.3 g). The reaction mixture was warmed to room temperature and stirred for 1.5 hours. To this reaction mixture, Dess-Martin periodinane (1.0 g) was further added and stirred for 50 minutes. To this reaction mixture cooled to 0 °C, Dess-Martin periodinane (15 g) was further added and stirred for 2 hours. To this mixture, 20% sodium thiosulfate (250 ml) and saturated aqueous sodium hydrogen carbonate solution (250 ml) were added and stirred at room temperature for 20 minutes. This mixture was extracted twice with chloroform (200 ml x 2), and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane / ethyl acetate = 4 / 1 to 3 / 2) to obtain the title compound (5.68 g). 1 1H-NMR (CDCl3) δ: 9.78-9.76 (0.5H, m), 9.70-9.68 (0.5H, m), 3.76-3.69 (3.5H, m), 3.61-3.52 (0.5H, m), 3.44-3.32 (1.0H, m), 2.68-2.40 (3.0H, m), 2.29-2.06 (2.0H, m), 2.03-1.76 (3.0H, m), 1.44 (4.0H, s), 1.41 (5.0H, s).

[0254] (6) Optically active form of 2-(3-benzylaminopropyl)pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester

Chemical formula

[0255] (7) Optical isomers of methyl 2-(3-benzylaminopropyl)pyrrolidine-2-carboxylate

Chemical formula

[0256] (8)Optically active form of 7-benzyl-1,7-diazaspiro[4.5]decan-6-one

Chemical formula

[0257] (9)Optically active tert-butyl 7-benzyl-6-oxo-1,7-diazaspiro[4.5]decane-1-carboxylate

Chem.

[0258] (10)Optically active tert-butyl 1,7-diazaspiro[4.5]decane-1-carboxylate

Chem.

[0259] (11)Optically active form of tert-butyl 7-(7H-pyrrolo[2.3-d]pyrimidin-4-yl)-1,7-diazaspiro[4.5]decane-1-carboxylate

Chemical formula

[0260] (12) Optically active form of 4-(1,7-diazaspiro[4.5]dec-7-yl)-7H-pyrrolo[2.3-d]pyrimidine

Chemical Structure

[0261] (13) Optical isomers of 3-oxo-3-[7-(7H-pyrrolo[2.3-d]pyrimidin-4-yl)-1,7-diazaspiro[4.5]decan-1-yl]propionitrile [Chemical formula] 4-(1,7-Diazaspiro[4.5]decan-7-yl)-7H-pyrrolo[2.3-d]pyrimidine (30 mg) was mixed with 1-cyanoacetyl-3,5-dimethylpyrazole (38 mg), N,N-diisopropylethylamine (42 μl) and 1,4-dioxane (1 ml), and stirred at 110 °C for 75 minutes. The mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: chloroform / ethyl acetate = 1 / 2, then chloroform / methanol = 25 / 1 to 20 / 1) to obtain the title compound (32 mg). 11H-NMR (DMSO-D6) δ: 11.69 (1H, br s), 8.09 (1H, s), 7.19 - 7.15 (1H, m), 6.59 - 6.55 (1H, m), 4.74 - 4.66 (1H, m), 4.55 - 4.47 (1H, m), 3.95 (2H, s), 3.86 - 3.78 (1H, m), 3.57 - 3.48 (1H, m), 3.45 - 3.37 (1H, m), 2.99 - 2.82 (2H, m), 1.89 - 1.68 (4H, m), 1.66 - 1.56 (2H, m), 1.55 - 1.47 (1H, m). [α]D = +185.58° (25 °C, c = 1.04, methanol)

[0262] [Production Example 8] The optically active form (Compound 6) of 3-[3-methyl-6-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1,6-diazaspiro[3.4]oct-1-yl]-3-oxopropionitrile was treated according to a conventional method to obtain a monohydrate. 1 1H-NMR (DMSO-D6) δ: 11.60 (1H, br s), 8.08 (1H, s), 7.11 (1H, s), 6.58 (1H, s), 4.16 (1H, dd, J = 8.2, 8.2 Hz), 4.11 - 3.61 (6H, m), 3.57 (1H, dd, J = 7.65, 6.26 Hz), 2.70 - 2.57 (2H, m), 2.24 - 2.10 (1H, m), 1.11 (3H, d, J = 6.9 Hz).

[0263] The following Tables 1 to 3 show the structural formulas of Compounds 1 to 95 produced according to the above Production Examples and 1 1H-NMR spectrum data. 1 The 1H-NMR spectrum was measured using tetramethylsilane as an internal standard in CDCl3 or DMSO-d6, and all δ values are shown in ppm. Unless otherwise specified, the measurement was performed using a 400 MHz NMR apparatus. The symbols in the tables have the following meanings. s: singlet d: doublet t: triplet q: quartet dd: double doublet ddd: double double doublet brs: broad singlet m: multiplet J: coupling constant

[0264]

Table 1-1

Table 1-2

Table 1-3

Table 1-4

Table 1-5

Table 1-6

Table 1-7

Table 1-8

Table 1-9

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

[0265]

Table 2

[0266]

Table 3

[0267] The following Table 4 shows the structural formulas of those optically active compounds in which the absolute configuration has been specified.

[0268]

Table 4

[0269] [Test Example 1] The inhibitory effect of the test compound on JAK3 activity was evaluated by performing the following kinase reaction. The kinase reaction was carried out in Sf21 cells and the fusion protein (hJAK3 kinase domain (aa781-end) fused to a 6His tag) purified by Ni2+ / NTA agarose was used. The following solutions (a) to (c) were added to a 96-well half-area white plate (plate, Corning 3642) to initiate the kinase reaction.

[0270] (a) Kinase buffer (50 mmol / L 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (pH 7.0)), 0.02% sodium azide, 0.1 mmol / L sodium vanadate, 5 mmol / L magnesium chloride, 1 mmol / L dithiothreitol, 0.01% bovine serum albumin)-diluted 5 μmol / L TK substrate-biotin (cisbio), 25 μmol / L ATP, 250 nmol / L Supplement Enzymatic buffer (cisbio) solution: 10 μL / well (b) Test substance solution prepared using kinase buffer containing 5% dimethyl sulfoxide: 10 μL / well (c) 33 ng / mL hJAK3 enzyme diluted with kinase buffer: 30 μL / well

[0271] Wells without adding only ATP were prepared as blank wells. The plate was allowed to stand at room temperature for 10 minutes from the start of the reaction. To each well, 50 μL of a detection buffer (50 mmol / L 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (pH 7.0), 20 mM EDTA, 800 mmol / L potassium fluoride, 0.1% bovine serum albumin) containing TK-Antibody-Cryptate (5 tests / 50 μL) and streptavidin-conjugated XL665 (62.5 nmol / L) reagent was added.

[0272] One hour after the addition of the detection buffer, the fluorescence counts of each well were measured using a fluorescence microplate reader. Specifically, the fluorescence count at 620 nm excited at 337 nm and the fluorescence count at 665 nm excited by the fluorescence at 620 nm were measured.

[0273] From the measured fluorescence counts, the Ratio (fluorescence count at 665 nm / fluorescence count at 620 nm x 10000) of each well was calculated. The value obtained by subtracting the average of the Ratio of the blank wells from the Ratio of each well was used as the data. The IC50 value of the test substance was calculated by calculating the % of control value when the solvent control was 100% and was calculated from the % of control values of two doses sandwiching 50%. Also, the % inhibition (100 - % of control value) at either a dose of 0.1 μmol / L or 1 μmol / L was calculated.

[0274] [Test Example 2] The inhibitory effect of the test compound on JAK2 activity was evaluated by performing the following kinase reaction. For the kinase reaction, a fusion protein (hJAK2 kinase domain (aa808 - end) fused to a 6His tag) expressed in Sf21 cells and purified by Ni2+ / NTA agarose was used. The following solutions (a) - (c) were added to a 96 - well half - area white plate (plate, Corning 3642) to initiate the kinase reaction.

[0275] (a) Kinase buffer (50 mmol / L 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (pH 7.0)), 0.02% sodium azide, 0.1 mmol / L sodium vanadate, 5 mmol / L magnesium chloride, 1 mmol / L dithiothreitol, 0.01% bovine serum albumin)-diluted 5 μmol / L TK substrate-biotin (cisbio), 100 μmol / L ATP, 250 nmol / L Supplement Enzymatic buffer (cisbio) solution: 10 μL / well (b) Test substance solution prepared using kinase buffer containing 5% dimethyl sulfoxide: 10 μL / well (c) 7 ng / mL hJAK2 enzyme diluted with kinase buffer: 30 μL / well

[0276] Wells without adding only ATP were prepared as blank wells. The plate was allowed to stand at room temperature for 10 minutes from the start of the reaction. Detection buffer (50 mmol / L 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (pH 7.0), 20 mM EDTA, 800 mmol / L potassium fluoride, 0.1% bovine serum albumin) containing TK-Antibody-Cryptate (5 test / 50 μL) and streptavidin-conjugated XL665 (62.5 nmol / L) reagent was added to the plate at 50 μL / well.

[0277] One hour after the addition of the detection buffer, the fluorescence counts of each well were measured using a fluorescence microplate reader. Specifically, the fluorescence count at 620 nm excited at 337 nm and the fluorescence count at 665 nm excited by the fluorescence at 620 nm were measured.

[0278] The Ratio (fluorescence count at 665 nm / fluorescence count at 620 nm x 10000) of each well was calculated from the measured fluorescence counts. The value obtained by subtracting the average of the Ratio of the blank wells from the Ratio of each well was used as the data. The IC50 value of the test substance was calculated from the % of control values of two doses straddling 50% after calculating the % of control value with the solvent control set as 100%.

[0279] Tables 5 to 7 below show the JAK3 activity inhibition data or % inhibition data of Compounds 1 to 95.

[0280]

Table 5-1

Table 5-2

Table 5-3

Table 5-4

Table 5-5

[0281]

Table 6

[0282]

Table 7

[0283] Table 8 below shows the JAK2 activity inhibition data or % inhibition data of Compounds 1 to 7.

[0284]

Table 8

[0285] [Formulation Example] Examples of the formulations of the present invention include, for example, the following formulations. However, the present invention is not limited by these formulation examples. Formulation Example 1 (Manufacture of Capsules) 1) Compound 1 30 mg 2) Microcrystalline cellulose 10 mg 3) Lactose 19 mg 4) Magnesium stearate 1 mg Mix 1), 2), 3) and 4) and fill into gelatin capsules.

[0286] Formulation Example 2 (Manufacture of Tablets) 1) Compound 1 10 g 2) Lactose 50 g 3) Corn starch 15 g 4) Calcium carboxymethylcellulose 44 g 5) Magnesium stearate 1 g Mix the total amounts of 1), 2) and 3) and 30 g of 4) with water, perform vacuum drying, and then size reduction. Mix 14 g of 4) and 1 g of 5) with the sized particles and tablet them using a tableting machine. In this way, 1000 tablets each containing Compound 1 (10 mg) per tablet are obtained.

Industrial Applicability

[0287] The present invention is (a) Rejection during organ transplantation, graft-versus-host disease after transplantation; (b) Autoimmune diseases such as rheumatoid arthritis, psoriasis, psoriatic arthritis, multiple sclerosis, ulcerative colitis, Crohn's disease, systemic lupus erythematosus, type I diabetes, myasthenia gravis, Castleman's disease, juvenile idiopathic arthritis, dry eye, etc.; and (c) Allergic diseases such as asthma, atopic dermatitis, rhinitis, etc. useful for the treatment or prevention of etc. In addition, the present invention is useful for the treatment or prevention of chronic myeloproliferative diseases such as polycythemia vera, primary myelofibrosis, essential thrombocythemia, etc.

Claims

1. A compound represented by the following general formula [I], a pharmaceutically acceptable salt thereof, or a solvate thereof: 【Chemical 1】 [In the formula, R ａ are the same or different, (1) C １－６ an alkyl group, or (2) is a halogen atom, n1 is an integer of 0 to 4, R ｂ are the same or different and (1) C １－６ an alkyl group, or (2) is a halogen atom, n2 is an integer of 0 to 4, m1 is an integer of 0 to 3, m2 is an integer of 1 to 4, X ａ = X ｂ is (1) CH=CH, (2) N=CH, or (3) CH=N, X is (1) a nitrogen atom, or (2) C-R ｄ (wherein R ｄ is a hydrogen atom or a halogen atom) R ｃ is a group selected from the following (1) to (6): (1) a hydrogen atom, (2)C which may be substituted with 1 to 5 identical or different substituents selected from the following Group A １－６ an alkyl group, (3)-C(=O)-R ｃ１ , (4)-C(=O)-O-R ｃ２ , (5)-C(=O)-NR ｃ３ R ｃ４ (wherein, R ｃ１ , R ｃ２ , R ｃ３ and R ｃ４ are the same or different, (i) a hydrogen atom, or (ii) C which may be substituted with the same or different 1 to 5 substituents selected from the following Group A １－６ is an alkyl group), or (6) a formula: 【Chemical 2】 {In the formula, Y ａ is a group selected from the following (i) to (iii): (i) C １－６ alkylene, (ii) -C(=O)-, or (iii) -C(=O)-O-, Ring T is (i) C ６－１０ an aryl group, (ii) C ３－１０ cycloalkyl group, or (iii) a saturated monocyclic heterocyclic group (the saturated monocyclic heterocyclic group has 1 to 4 heteroatoms selected from nitrogen atoms, oxygen atoms or sulfur atoms in addition to carbon atoms, and the number of atoms constituting the ring is 3 to 7), R ｃ５ is, independently or identically, (i) a cyano group, or (ii) a nitro group, p is an integer of 0 to 4}[End]] is a group represented by, Group A is (a) a hydroxyl group, (b) C １－６ an alkoxy group (c) a cyano group, (d) C １－６ an alkoxycarbonyl group, (e) C １－６ an alkyloxycarbonyl group, and (f) C ２－６ which is a group consisting of alkenyloxy groups].

2. In general formula [I], n1 is an integer of 0 to 2, n2 is an integer of 0 to 2, m1 is an integer of 0 to 3, m2 is an integer of 1 to 3, X is (1) a nitrogen atom, or (2) C-R ｄ (In the formula, R ｄ is a halogen atom), and R ｃ is a group selected from the following (1) to (6): (1) a hydrogen atom, (2) C substituted with one substituent selected from the following Group A １－６ an alkyl group, (3)-C(=O)-R ｃ１ , (4)-C(=O)-O-R ｃ２ , (5)-C(=O)-NR ｃ３ R ｃ４ (In the formula, R ｃ１ is a C １－６ alkyl group which may be substituted with one substituent selected from the following Group A, R ｃ２ is an alkyl group of C １－６ and R ｃ３ is a C １－６ alkyl group which may be substituted with one substituent selected from the following Group A, R ｃ４ is (i) a hydrogen atom, or (ii) C １－６ is an alkyl group), or (6) a formula: [Chemical Formula 3] {In the formula, Y ａ is a group selected from the following (i) to (iii): (i) C １－６ alkylene, (ii) -C(=O)-, or (iii) -C(=O)-O-, Ring T is (i) a phenyl group, (ii) C ３－６ a cycloalkyl group, or (iii) a pyrrolidinyl group, R ｃ５ is (i) a cyano group, or (ii) a nitro group, p is an integer of 0 or 1}[End]] is a group represented by, Group A is (a) a hydroxyl group, (b) C １－６ an alkoxy group (c) a cyano group, (d) C １－６ an alkoxycarbonyl group, (e) C １－６ an alkyloxycarbonyloxy group, and (f) C ２－６ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, or a solvate thereof, which is a group consisting of alkenyloxy groups.

3. The compound according to any one of Claims 1 or 2, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein m1 is an integer of 0 or 1 and m2 is an integer of 1 or 2.

4. The compound according to Claim 3, a pharmaceutically acceptable salt thereof, or a solvate thereof, represented by general formula [II]: 【Chemical Formula 4】 [In the formula, each symbol has the same meaning as in Claim 1] where the combination of (m1, m2) is (1, 2).

5. The compound according to Claim 3, a pharmaceutically acceptable salt thereof, or a solvate thereof, represented by general formula [III]: 【Chemical Formula 5】 [In the formula, each symbol has the same meaning as in Claim 1] where the combination of (m1, m2) is (0, 2).

6. The compound according to Claim 3, a pharmaceutically acceptable salt thereof, or a solvate thereof, represented by general formula [IV]: 【Chemical Formula 6】 [In the formula, each symbol has the same meaning as in Claim 1] The compound according to claim 3, or a pharmaceutically acceptable salt thereof, or a solvate thereof, as shown by

7. The compound according to any one of claims 1 or 2, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the combination of (m1, m2) is selected from (0, 3), (2, 1), (2, 2) or (3, 2).

8. X ａ = X ｂ wherein X is CH = CH and X is a nitrogen atom, the compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

9. The compound according to any one of claims 1 or 2, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the combination of (n1, n2) is (0, 0).

10. The compound according to any one of claims 1 or 2, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the combination of (n1, n2) is (1, 0).

11. The compound according to any one of claims 1 or 2, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the combination of (n1, n2) is (0, 1).

12. The compound according to any one of claims 1 or 2, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the combination of (n1, n2) is (2, 0).

13. The compound according to any one of claims 1 or 2, or a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the combination of (n1, n2) is (0, 2).

14. R ａ The compound or a pharmaceutically acceptable salt thereof, or a solvate thereof according to any one of claims 10 or 12, wherein R is a methyl group or a fluorine atom.

15. R ｃ is -C(=O)-R ｃ１ The compound or a pharmaceutically acceptable salt thereof, or a solvate thereof according to any one of claims 1 to 14, wherein

16. R ｃ１ is a C １－６ alkyl group substituted with one hydroxyl group or cyano group, the compound according to claim 15, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

17. R ｃ is -C(=O)-NR ｃ３ R ｃ４ The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

18. R ｃ３ is a C alkyl group substituted with one cyano group, and R １－６ is a hydrogen atom, the compound according to claim 17 or a pharmaceutically acceptable salt thereof, or a solvate thereof. ｃ４ ​

19. The following chemical structural formula: 【Chemical Formula 7】 【Chemical 8】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof, selected from

20. The following chemical structural formula: 【Chemical Formula 9】 【Chemical 10】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof, selected from

21. A pharmaceutical composition comprising the compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier.

22. A Janus kinase inhibitor comprising the compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

23. The Janus kinase inhibitor according to claim 22, wherein the Janus kinase is Janus kinase 3.

24. The Janus kinase inhibitor according to claim 22, wherein the Janus kinase is Janus kinase 2.

25. A therapeutic or prophylactic agent for a disease selected from the group consisting of rejection during organ transplantation, graft-versus-host reaction after transplantation, autoimmune diseases, allergic diseases, and chronic myeloproliferative diseases, comprising the compound according to any one of claims 1 to 20, a pharmaceutically acceptable salt thereof, or a solvate thereof.

26. A therapeutic or prophylactic agent for rheumatoid arthritis, comprising the compound according to any one of claims 1 to 20, a pharmaceutically acceptable salt thereof, or a solvate thereof.

27. A therapeutic or prophylactic agent for psoriasis, comprising the compound according to any one of claims 1 to 20, a pharmaceutically acceptable salt thereof, or a solvate thereof.

28. A method for inhibiting Janus kinase, which comprises administering to a mammal a pharmaceutically effective amount of the compound according to any one of claims 1 to 20, a pharmaceutically acceptable salt thereof, or a solvate thereof.

29. The method for inhibition according to claim 28, wherein the Janus kinase is Janus kinase 3.

30. The method for inhibition according to claim 28, wherein the Janus kinase is Janus kinase 2.

31. A method for treating or preventing a disease selected from the group consisting of rejection during organ transplantation, graft-versus-host reaction after transplantation, autoimmune diseases, allergic diseases, and chronic myeloproliferative diseases, which comprises administering to a mammal a pharmaceutically effective amount of the compound according to any one of claims 1 to 20, a pharmaceutically acceptable salt thereof, or a solvate thereof.

32. A method for treating or preventing rheumatoid arthritis, which comprises administering to a mammal a pharmaceutically effective amount of the compound according to any one of claims 1 to 20, a pharmaceutically acceptable salt thereof, or a solvate thereof.

33. A method for treating or preventing psoriasis, which comprises administering to a mammal a pharmaceutically effective amount of the compound according to any one of claims 1 to 20, a pharmaceutically acceptable salt thereof, or a solvate thereof.

34. Use of the compound according to any one of claims 1 to 20, a pharmaceutically acceptable salt thereof, or a solvate thereof, for producing a Janus kinase inhibitor.

35. The use according to claim 34, wherein the Janus kinase inhibitor is a Janus kinase 3 inhibitor.

36. The use according to claim 34, wherein the Janus kinase inhibitor is a Janus kinase 2 inhibitor.

37. Use of a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, or a solvate thereof, for the manufacture of a therapeutic or prophylactic agent for a disease selected from the group consisting of rejection during organ transplantation, graft-versus-host reaction after transplantation, autoimmune diseases, allergic diseases, and chronic myeloproliferative diseases.

38. Use of a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, or a solvate thereof, for the manufacture of a therapeutic or prophylactic agent for rheumatoid arthritis.

39. Use of a compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, or a solvate thereof, for the manufacture of a therapeutic or prophylactic agent for psoriasis.

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