JP2021008407A - Heterocyclic compound - Google Patents

Abstract

To provide a compound having excellent JAK inhibitory action, and useful for prevention or as a therapeutic agent for autoimmune disease (rheumatic arthritis, psoriasis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, multiple sclerosis, systemic lupus erythematosus or the like), cancer (leukemia, uterine smooth muscle sarcoma, prostate cancer, multiple myeloma, cachexia, myelofibrosis or the like) or the like, or a salt thereof.SOLUTION: This invention relates to a compound which is represented by formula (I)[wherein, each symbol is as described in the specifications], or a salt thereof.SELECTED DRAWING: None

Description

The present invention may have an inhibitory effect on Janus kinase (sometimes abbreviated as "JAK" in the present specification) and may have autoimmune diseases (rheumatoid arthritis, psoriasis, inflammatory bowel disease, Schegren's syndrome, Bechet's disease, multiple diseases). Contains heterocyclic compounds that may be useful in the treatment of sclerosis, systemic erythematosus, etc.), cancer (leukemia, uterine smooth muscle tumor, prostate cancer, multiple myeloma, cachexia, myelofibrosis, etc.) Related to pharmaceutical compositions and the like.

(Background of invention)
Cytokines are proteins secreted by cells of the immune system that transmit information to specific cells. There are many types of cytokines, but most of them are related to immunity and inflammation, and are also related to cell proliferation, differentiation, cell death, wound healing, and the like (Non-Patent Document 1).

The Janus kinase (JAK) family plays a role in cytokine-dependent regulation of cellular functions involved in proliferation and immune response. There are four types of Janus kinases in the JAK family (JAK1 (Janus kinase 1), JAK2 (Janus kinase 2), JAK3 (Janus kinase 3) and TYK2 (tyrosine kinase 2)). Among them, JAK1 is IL (interleukin) -2, IL-4, IL-7, IL-15, IL-21, IL-6, OSM (oncostatin M), IL-10 family, IFN (interferon). ) -Α, IFN-β, IFN-γ and the like are known to be involved in cytokine signaling (Non-Patent Document 2). TYK2 is IFN-α, IFN-β, IL-6, IL-10 family (IL-10, IL-19, IL-20, IL-22, IL-28, IL-29), IL-12, IL. It is known to be involved in the signal transduction of cytokines such as -23 (Non-Patent Document 2 and Non-Patent Document 3). In addition, although these cytokines play an important role in the immune response when present in appropriate amounts, overproduction causes rheumatoid arthritis, psoriasis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, multiple sclerosis, and systemic lupus erythematosus. It is involved in many autoimmune diseases such as sexic lupus erythematosus (Non-Patent Document 4, Non-Patent Document 5, Non-Patent Document 6, Non-Patent Document 7).

Tocilizumab, an anti-IL-6 receptor monoclonal antibody, has been approved in Japan, Europe and the United States for the treatment of rheumatoid arthritis, and clinical trials have been conducted in various diseases suggested to be involved in the IL-6 signaling pathway. ing. Based on the above, JAK1 inhibitors can be therapeutic agents for various autoimmune diseases such as rheumatoid arthritis, psoriasis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, multiple sclerosis, and systemic lupus erythematosus (non-patent documents). 8).

In addition, JAK signals are also involved in the differentiation and proliferation of many cancer cells (Non-Patent Document 9), and in particular, JAK1 is constitutively activated in leukemia and uterine leiomyosarcoma and is involved in pathological conditions (Non-Patent Document 9). Non-Patent Document 10, Non-Patent Document 11). In addition, antibodies and low molecular weight compounds targeting IL-6 have been clinically tested in cancer diseases such as prostate cancer, multiple myeloma, cachexia, and myelofibrosis (Non-Patent Document 12, Non-Patent). Document 13). Therefore, the JAK1 inhibitor can be a therapeutic agent for cancer diseases such as leukemia, uterine leiomyosarcoma, prostate cancer, multiple myeloma, cachexia, and myelofibrosis.

On the other hand, the anti-IL-12 / 23 monoclonal antibody ustekinumab has been approved in Europe for the treatment of patients with moderate to severe psoriasis, further suggesting the involvement of the IL-12 / 23 signaling pathway. Clinical trials have been conducted in various diseases (Non-Patent Document 14). It has also been suggested that the IL-23 signaling pathway is involved in central diseases such as Alzheimer's disease (eg, Alzheimer's disease) (Non-Patent Document 15). Based on the above, TYK2 inhibitors are therapeutic agents for various autoimmune diseases such as rheumatoid arthritis, psoriasis, inflammatory bowel disease, Sjogren's syndrome, Bechet's disease, multiple sclerosis, and systemic erythematosus, and Alzheimer's disease (eg, Alzheimer's type). It can be a therapeutic agent for central diseases such as dementia (Non-Patent Document 16).

Examples of the compound having JAK1 inhibition include the compounds described in Patent Documents 1 to 7.

U.S. Patent Publication No. 9085578 U.S. Patent Publication No. 9371320 U.S. Patent Application Publication No. 2016/0251352 U.S. Patent Publication No. 9187453 U.S. Patent Application Publication No. 2016/0159773 U.S. Patent Publication No. 9637843 U.S. Patent Application Publication No. 2017/0174682

Curr Opin Cell Biol. 1991 Apr; 3 (2): 171-5 Nature Immunology 10, 356-360 (2009) New York Academy of Science 1246, 34-40 (2011) Jounal of Allergy and Clinical Immunology 127, 3, 701-721.e70 (2011) Cytokine & Growth Factor Reviews 19, 41-52 (2008) Invest Ophthalmol Vis Sci. 2008 Jul; 49 (7): 3058-3064 Ann Rheum Dis. 2010 Jul; 69 (7): 1325-1328 Clinical Science 122, 143-159 (2012) Trends Biochem. Sci. 33, 122-131 (2008) J Exp Med 205, 751-758 (2008) Oncogene 25, 4016-4026, (2006) Clinical Science 122, 143-159 (2012) The New England Journal of Medicine 363, 1117-1127 (2010) J Immunol. 2010 May 1; 184 (9): 4605-9 Nat Med. 2012 Dec; 18 (12): 1812-9 Front Biosci. 2011 Jun 1; 17: 3214-32

An object of the present invention is that it may have an excellent JAK inhibitory effect, and may have autoimmune diseases (rheumatoid arthritis, cachexia, inflammatory bowel disease, Schegren's syndrome, Bechet's disease, multiple myeloma, systemic erythematosus, etc.), cancer (leukemia). , Uterine smooth muscle tumor, prostate cancer, multiple myeloma, cachexia, myelofibrosis, etc.), etc.) is to provide a compound that can be useful as a prophylactic or therapeutic agent.

As a result of diligent studies to solve the above problems, the present inventors have found that the compound (I) represented by the following formula can have an excellent JAK inhibitory action, and have completed the present invention. ..
That is, the present invention is as follows.
[1] Equation

[In the formula, R ¹ , R ² , R ³ , R ⁴ and R ⁵ each independently indicate a hydrogen atom or a substituent. ] (In this specification, it may be abbreviated as "Compound (I)").
[2] A drug containing the compound according to the above [1] or a salt thereof.
[3] The medicament according to the above [2], which is a Janus kinase inhibitor.
[4] The medicament according to the above [2], which is a prophylactic or therapeutic agent for autoimmune diseases.
[5] The medicament according to the above [4], wherein the autoimmune disease is systemic lupus erythematosus, inflammatory bowel disease, psoriasis, rheumatoid arthritis, Sjogren's syndrome, Behcet's disease, or multiple sclerosis.

Compound (I) can have an excellent JAK inhibitory effect, and can have autoimmune diseases (systemic erythematosus, inflammatory bowel disease (Clone disease, ulcerative colitis, etc.), cachexia, rheumatoid arthritis, Schegren's syndrome, Bechet's disease, etc.) It can be useful as a prophylactic or therapeutic agent for diseases (leukemia, uterine smooth muscle tumor, prostate cancer, multiple myeloma, cachexia, myelofibrosis, etc.) and the like.

(Detailed description of the invention)
In the present specification, the "substituent" refers to the following group.
(1) Halogen atom;
(2) Cyanide group;
(3) Nitro group;
(4) Hydroxy group;
(5) (a) Halogen atom,
(b) Cyanide group and
(c) C _1-6 alkyl group, _optionally substituted with 1 to 3 halogen atoms,
and
(d) A C _3-8 cycloalkyl group optionally substituted with 1 to 3 substituents selected from C _1-6 alkoxy groups optionally substituted with 1 to 3 halogen atoms;
(6) (a) Halogen atom,
(b) Cyanide group,
(c) C _1-6 alkyl groups _optionally substituted with 1 to 3 halogen atoms, and
(d) A C _6-14 aryl group optionally substituted with 1 to 3 substituents selected from C _1-6 alkoxy groups optionally substituted with 1 to 3 halogen atoms;
(7) (a) Halogen atom,
(b) Cyanide group,
(c) C _3-8 cycloalkyl groups _optionally substituted with 1 to 3 halogen atoms,
(d) C _3-8 cycloalkenyl groups _optionally substituted with 1 to 3 halogen atoms,
(e) A C _6-14 aryl group _optionally substituted with 1 to 3 halogen atoms, and
(f) C _1-6 alkoxy group optionally substituted with 1 to 3 substituents selected from 5 or 6 member monocyclic aromatic heterocyclic groups;
(8) C _2-6 alkenyloxy group optionally substituted with 1 to 3 halogen atoms;
(9) C _2-6 alkynyloxy group optionally substituted with 1 to 3 halogen atoms;
(10) C _3-8 cycloalkyloxy group _optionally substituted with 1 to 3 halogen atoms;
(11) C _3-8 cycloalkenyloxy group _optionally substituted with 1 to 3 halogen atoms;
(12) C _6-14 aryloxy group _optionally substituted with 1 to 3 halogen atoms;
(13) C _7-14 aralkyloxy group optionally substituted with 1 to 3 halogen atoms;
(14) (a) (i) C _3-8 cycloalkyl group, (ii) C _1-6 alkoxy group and (iii) may be substituted with 1 to 3 C _1-6 alkyl groups 3 to A C _1-6 alkyl group which may be substituted with 1 to 3 substituents selected from the 8-membered monocyclic non-aromatic heterocyclic group,
(b) C _3-8 cycloalkyl group,
(c) C _6-14 aryl group,
(d) C _1-6 alkoxy group,
(e) 5- or 6-membered monocyclic aromatic heterocyclic group,
(f) 8- to 12-membered condensed aromatic heterocyclic groups,
(g) 3- to 8-membered monocyclic non-aromatic heterocyclic groups, and
(h) A carbamoyl group that may be mono or di-substituted with a substituent selected from 8- to 12-membered condensed non-aromatic heterocyclic groups;
(15) (a) C _1-6 alkyl group,
(b) C _3-8 cycloalkyl group,
(c) C _6-14 aryl group,
(d) C _1-6 alkoxy group,
(e) 5- or 6-membered monocyclic aromatic heterocyclic group,
(f) 8- to 12-membered condensed aromatic heterocyclic groups,
(g) 3- to 8-membered monocyclic non-aromatic heterocyclic groups, and
(h) Sulfamoyl group which may be mono or di-substituted with a substituent selected from 8- to 12-membered condensed non-aromatic heterocyclic groups;
(16) Holmil;
(17) C _1-6 alkyl-carbonyl group optionally substituted with 1 to 3 C _1-6 alkoxy groups;
(18) C _2-6 alkenyl-carbonyl group;
(19) C _2-6 alkynyl-carbonyl group;
(20) C _3-8 cycloalkyl-carbonyl group;
(21) C _3-8 cycloalkenyl-carbonyl group;
(22) C _6-14 aryl-carbonyl group;
(23) C _3-8 cycloalkyl-C _1-6 alkyl-carbonyl group;
(24) C _3-8 cycloalkenyl-C _1-6 alkyl-carbonyl group;
(25) C _7-14 aralkyl-carbonyl group;
(26) 5- or 6-membered monocyclic aromatic heterocyclic carbonyl group;
(27) 8- to 12-membered condensed aromatic heterocyclic carbonyl group;
(28) 3- to 8-membered monocyclic non-aromatic heterocyclic carbonyl group;
(29) 8- to 12-membered condensed non-aromatic heterocyclic carbonyl group (eg, dihydrobenzofuranylcarbonyl);
(30) Substituted with (a) (i) cyano group, (ii) hydroxy group, (iii) C _6-14 aryl group, (iv) C _1-6 alkyl-carbonyl group _optionally substituted with cyano group May be substituted with a 3- to 8-membered monocyclic non-aromatic heterocyclic group, (v) (i') cyano group and (ii') 1 to 3 cyano groups C _{6 From a} 3- to 8-membered monocyclic non-aromatic heterocyclic carbonyl group optionally substituted with 1 to 3 substituents selected from _-14 aryl groups, and (vi) di C _1-6 alkylamino groups. A C _1-6 alkyl group, _optionally substituted with 1 to 3 substituents of choice,
(b) 1 to 3 selected from (i) hydroxy groups, (ii) C _1-6 alkyl groups _optionally substituted with 1 to 3 hydroxy groups, and (iii) C _6-14 aryl groups. C _3-8 cycloalkyl group, which may be substituted with a substituent of
(c) C _6-14 aryl group, _optionally substituted with 1 to 3 halogen atoms,
(d) 5- or 6-membered monocyclic aromatic heterocyclic group,
(e) 8- to 12-membered condensed aromatic heterocyclic group,
(f) 3- to 8-membered monocyclic non-aromatic heterocyclic groups,
(g) 8- to 12-membered condensed non-aromatic heterocyclic group,
(h) C _1-6 alkyl-carbonyl group, _optionally substituted with 1 to 3 halogen atoms,
(i) C _3-8 cycloalkyl-carbonyl group,
(j) C _6-14 aryl-carbonyl group, _optionally substituted with 1 to 3 halogen atoms,
(k) 5- or 6-membered monocyclic aromatic heterocyclic carbonyl group,
(l) 8- to 12-membered condensed aromatic heterocyclic carbonyl group,
(m) 3- to 8-membered monocyclic non-aromatic heterocyclic carbonyl group, and
(n) Amino group which may be mono or di-substituted with a substituent selected from 8- to 12-membered condensed non-aromatic heterocyclic carbonyl groups;
(31) Sulfanil group;
(32) C _1-6 alkylsulfanil group;
(33) C _2-6 alkenylsulfanil group;
(34) C _2-6 alkynyl sulfanil group;
(35) C _3-8 cycloalkylsulfanil group;
(36) C _3-8 cycloalkenyl sulfanil group;
(37) C _6-14 arylsulfanil group;
(38) C _3-8 cycloalkyl-C _1-6 alkyl sulfanil group;
(39) C _3-8 cycloalkenyl-C _1-6 alkylsulfanil group;
(40) C _1-6 alkylsulfinyl group;
(41) C _2-6 alkenylsulfinyl group;
(42) C _2-6 alkynyl sulfinyl group;
(43) C _3-8 cycloalkylsulfinyl group;
(44) C _3-8 cycloalkenylsulfinyl group;
(45) C _6-14 arylsulfinyl group;
(46) C _3-8 cycloalkyl-C _1-6 alkylsulfinyl group;
(47) C _3-8 cycloalkenyl-C _1-6 alkylsulfinyl group;
(48) C _1-6 alkylsulfonyl group;
(49) C _2-6 alkenylsulfonyl group;
(50) C _2-6 alkynylsulfonyl group;
(51) C _3-8 cycloalkylsulfonyl group;
(52) C _3-8 cycloalkenylsulfonyl group;
(53) C _6-14 arylsulfonyl group;
(54) C _3-8 cycloalkyl-C _1-6 alkylsulfonyl group;
(55) C _3-8 cycloalkenyl-C _1-6 alkylsulfonyl group;
(56) C _6-14 aryl-C _1-6 alkylsulfonyl group;
(57) 5- or 6-membered monocyclic aromatic heterocyclic sulfonyl group;
(58) 8- to 12-membered condensed aromatic heterocyclic sulfonyl group;
(59) 3- to 8-membered monocyclic non-aromatic heterocyclic sulfonyl group;
(60) 8- to 12-membered condensed non-aromatic heterocyclic sulfonyl group;
(61) (a) Halogen atom,
(b) C _1-6 alkyl groups _optionally substituted with 1 to 3 halogen atoms, and
(c) A 5- or 6-membered monocyclic aromatic which may be substituted with 1 to 3 substituents selected from C _1-6 alkoxy groups which may be substituted with 1 to 3 halogen atoms. Heterocyclic group;
(62) (a) Halogen atom,
(b) C _1-6 alkyl groups _optionally substituted with 1 to 3 halogen atoms, and
(c) An 8- to 12-membered fused aromatic heterocycle which may be substituted with 1 to 3 substituents selected from the C _1-6 alkoxy groups which may be substituted with 1 to 3 halogen atoms. Group;
(63) (a) Halogen atom,
(b) C _1-6 alkyl groups, optionally substituted with 1 to 3 halogen atoms or hydroxy groups,
(c) C _1-6 alkoxy groups optionally substituted with 1 to 3 halogen atoms, and
(d) A 3- to 8-membered monocyclic non-aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from oxo groups;
(64) (a) Halogen atom,
(b) C _1-6 alkyl groups, _optionally substituted with 1 to 3 halogen atoms,
(c) C _1-6 alkoxy groups optionally substituted with 1 to 3 halogen atoms, and
(d) 8- to 12-membered condensed non-aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from oxo groups;
(65) 5- or 6-membered monocyclic aromatic heterocyclic oxy group;
(66) 8- to 12-membered condensed aromatic heterocyclic oxy group;
(67) 3- to 8-membered monocyclic non-aromatic heterocyclic oxy group;
(68) 8- to 12-membered condensed non-aromatic heterocyclic oxy group;
(69) Carboxy group;
(70) C _1-6 alkoxy-carbonyl group;
(71) C _2-6 alkenyloxy-carbonyl group;
(72) C _2-6 alkynyloxy-carbonyl group;
(73) C _3-8 cycloalkyloxy-carbonyl group;
(74) C _3-8 cycloalkenyloxy-carbonyl group;
(75) C _6-14 aryloxy-carbonyl group;
(76) C _3-8 cycloalkyl-C _1-6 alkoxy-carbonyl group;
(77) C _3-8 cycloalkenyl-C _1-6 alkoxy-carbonyl group;
(78) C _7-14 aralkyloxy-carbonyl group;
(79) Mono C _1-6 alkylthiocarbamoyl group;
(80) Di C _1-6 alkylthiocarbamoyl group;
(81) C _1-6 alkyl-carbonyloxy group;
(82) Imino group optionally substituted with hydroxy group;
(83) C _1-6 alkylenedioxy group.

In the present specification, the “halogen atom” refers to a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

In the present specification, the term "C _1-6 alkyl group" means, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl. , Isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl and the like.

In the present specification, the “C _1-6 alkoxy group” refers to, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, hexyloxy and the like. Shown.
In the present specification, the “C _2-6 alkenyloxy group” refers to, for example, vinyloxy, 1-propenyloxy, 2-propenyloxy, 2-methyl-1-propenyloxy, 1-butenyloxy, 2-butenyloxy, 3-. Butenyloxy, 3-methyl-2-butenyloxy, 1-pentenyloxy, 2-pentenyloxy, 3-pentenyloxy, 4-pentenyloxy, 4-methyl-3-pentenyloxy, 1-hexenyloxy, 3-hexenyloxy, 5 -Indicates hexenyloxy, etc.
In the present specification, the “C _2-6 alkynyloxy group” refers to, for example, ethynyloxy, 1-propynyloxy, 2-propynyloxy, 1-butynyloxy, 2-butynyloxy, 3-butynyloxy, 1-pentynyloxy, 2-Pentynyloxy, 3-Pentynyloxy, 4-Pentynyloxy, 1,1-dimethylprop-2-in-1-yloxy, 1-hexynyloxy, 2-hexynyloxy, 3-hexynyloxy, 4-hexynyloxy, 5 -Indicates hexynyloxy, etc.

In the present specification, the “C _1-6 alkoxy-carbonyl group” refers to, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl and the like.
In the present specification, examples of the "C _2-6 alkenyloxy-carbonyl group" include vinyloxycarbonyl, propenyloxycarbonyl, butenyloxycarbonyl, pentenyloxycarbonyl, hexenyloxycarbonyl and the like.
In the present specification, examples of the "C _2-6 alkynyloxy-carbonyl group" include ethynyloxycarbonyl, propynyloxycarbonyl, butynyloxycarbonyl, pentynyloxycarbonyl, hexynyloxycarbonyl and the like.
In the present specification, examples of the "C _3-8 cycloalkyloxy-carbonyl group" include cyclopropyloxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl and the like.
In the present specification, examples of the "C _3-8 cycloalkenyloxy-carbonyl group" include cyclopropenyloxycarbonyl, cyclobutenyloxycarbonyl, cyclopentenyloxycarbonyl, cyclohexenyloxycarbonyl and the like.
In the present specification, examples of the "C _6-14 aryloxy-carbonyl group" include phenoxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl and the like.
In the present specification, the "C _3-8 cycloalkyl-C _1-6 alkoxy-carbonyl group" includes, for example, cyclopropylmethyloxycarbonyl, cyclopropylethyloxycarbonyl, cyclobutylmethyloxycarbonyl, cyclopentylmethyloxycarbonyl, and the like. Cyclohexylmethyloxycarbonyl, cyclohexylethyloxycarbonyl and the like are shown.
In the present specification, the “C _3-8 cycloalkenyl-C _1-6 alkoxy-carbonyl group” includes, for example, cyclopentenylmethyloxycarbonyl, cyclohexenylmethyloxycarbonyl, cyclohexenylethyloxycarbonyl, cyclohexenylpropyloxycarbonyl. Etc. are shown.
In the present specification, examples of the "C _7-14 aralkyloxy-carbonyl group" include benzyloxycarbonyl, phenethyloxycarbonyl and the like.
In the present specification, examples of the "mono C _1-6 alkylthiocarbamoyl group" include methylthiocarbamoyl, ethylthiocarbamoyl, propylthiocarbamoyl and the like.
In the present specification, examples of the "diC _1-6 alkylthiocarbamoyl group" include dimethylthiocarbamoyl, diethylthiocarbamoyl, dipropylthiocarbamoyl and the like.
In the present specification, examples of the "C _1-6 alkyl-carbonyloxy group" include acetyloxy, propanoyloxy, butanoyloxy, 2-methylpropanoyloxy and the like.
In the present specification, examples of the "C _1-6 alkylenedioxy group" include methylenedioxy and ethylenedioxy.
In the present specification, the “C _1-6 alkyl-carbonyl group” refers to, for example, acetyl, propanoyl, butanoyl, 2-methylpropanoyl and the like.

In the present specification, the “C _1-6 alkylsulfonyl group” refers to, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, tert-butylsulfonyl and the like.
In the present specification, the “C _2-6 alkenylsulfonyl group” refers to, for example, vinylsulfonyl, propenylsulfonyl and the like.
In the present specification, the “C _2-6 alkynylsulfonyl group” refers to, for example, ethynylsulfonyl, propynylsulfonyl and the like.
In the present specification, the “C _3-8 cycloalkylsulfonyl group” refers to, for example, cyclopropylsulfonyl, cyclobutylsulfonyl and the like.
In the present specification, the “C _3-8 cycloalkenylsulfonyl group” refers to, for example, cyclopropenylsulfonyl, cyclobutenylsulfonyl and the like.
In the present specification, examples of the "C _6-14 arylsulfonyl group" include phenylsulfonyl and the like.
In the present specification, examples of the "C _3-8 cycloalkyl-C _1-6 alkylsulfonyl group" include cyclopropylmethylsulfonyl and the like.
In the present specification, examples of the "C _3-8 cycloalkenyl-C _1-6 alkylsulfonyl group" include cyclopentenylmethylsulfonyl and the like.
In the present specification, examples of the "C _6-14 aryl-C _1-6 alkylsulfonyl group" include benzylsulfonyl and the like.
In the present specification, examples of the "5- or 6-membered monocyclic aromatic heterocyclic sulfonyl group" include frill sulfonyl, thienyl sulfonyl, pyridyl sulfonyl and the like.
In the present specification, examples of the "8 to 12-membered condensed aromatic heterocyclic sulfonyl group" include benzofuranylsulfonyl and isobenzofuranylsulfonyl.
In the present specification, examples of the "3- to 8-membered monocyclic non-aromatic heterocyclic sulfonyl group" include oxylanylsulfonyl and azetidinylsulfonyl.
In the present specification, examples of the "8 to 12-membered condensed non-aromatic heterocyclic sulfonyl group" include dihydrobenzofuranylsulfonyl.

In the present specification, examples of the "C _1-6 alkylsulfanil group" include methylsulfanil, ethylsulfanil and the like.
In the present specification, examples of the "C _2-6 alkenylsulfanil group" include vinylsulfanil, propenylsulfanil and the like.
In the present specification, examples of the "C _2-6 alkynyl sulfanyl group" include ethynyl sulfanyl, propynyl sulfanyl and the like.
In the present specification, examples of the "C _3-8 cycloalkylsulfanil group" include cyclopropylsulfanil and cyclobutylsulfanil.
In the present specification, examples of the "C _3-8 cycloalkenylsulfanil group" include cyclopropenylsulfanil, cyclobutenylsulfanil and the like.
In the present specification, examples of the "C _6-14 arylsulfanil group" include phenylsulfanil and the like.
In the present specification, as the "C _3-8 cycloalkyl-C _1-6 alkylsulfanil group", for example, cyclopropylmethylsulfanil and the like are shown.
In the present specification, as "C _3-8 cycloalkenyl-C _1-6 alkylsulfanil group", for example, cyclopentenylmethylsulfanil and the like are shown.

In the present specification, examples of the "C _1-6 alkylsulfinyl group" include methylsulfinyl and ethylsulfinyl.
In the present specification, examples of the "C _2-6 alkenylsulfinyl group" include vinylsulfinyl, propenylsulfinyl and the like.
In the present specification, examples of the "C _2-6 alkynyl sulfinyl group" include ethynyl sulfinyl and propynyl sulfinyl.
In the present specification, examples of the "C _3-8 cycloalkylsulfinyl group" include cyclopropylsulfinyl and cyclobutylsulfinyl.
In the present specification, examples of the "C _3-8 cycloalkenylsulfinyl group" include cyclopropenylsulfinyl and cyclobutenylsulfinyl.
In the present specification, examples of the "C _6-14 arylsulfinyl group" include phenylsulfinyl and the like.
In the present specification, as the "C _3-8 cycloalkyl-C _1-6 alkyl sulfinyl group", for example, cyclopropylmethylsulfinyl and the like are shown.
In the present specification, examples of the "C _3-8 cycloalkenyl-C _1-6 alkylsulfinyl group" include cyclopentenylmethylsulfinyl and the like.

In the present specification, the “C _3-8 cycloalkyl group” refers to, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. Of these, C _3-6 cycloalkyl groups (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) are preferred.

In the present specification, the “C _3-8 cycloalkenyl group” refers to, for example, cyclopropenel (eg, 2-cyclopropene-1-yl), cyclobuteneyl (eg, 2-cyclobutene-1-yl), cyclopentenyl (eg, 2-cyclobutene-1-yl). Examples, 2-cyclopentene-1-yl, 3-cyclopentene-1-yl), cyclohexenyl (eg, 2-cyclohexene-1-yl, 3-cyclohexene-1-yl), cyclohepteneyl (eg, 2-cycloheptene-1). -Il, 3-cycloheptene-1-yl), cycloocteneyl (eg, 2-cyclooctene-1-yl, 3-cyclooctene-1-yl) and the like are shown. Among them, C _3-6 cycloalkenyl group (eg, cyclopropenyl (eg, 2-cyclopropen-1-yl), cyclobutenyl (eg, 2-cyclobutene-1-yl), cyclopentenyl (eg, 2-cyclopentene). -1-yl, 3-cyclopentene-1-yl), cyclohexenyl (eg, 2-cyclohexene-1-yl, 3-cyclohexene-1-yl) are preferred.

In the present specification, the “C _3-8 cycloalkyloxy group” refers to, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy and the like.
In the present specification, the “C _3-8 cycloalkenyloxy group” refers to, for example, cyclopropenyloxy (eg, 2-cyclopropene-1-yloxy), cyclobutenyloxy (eg, 2-cyclobutene-1-yloxy). ), Cyclopentenyloxy (eg, 2-cyclopentene-1-yloxy, 3-cyclopentene-1-yloxy), cyclohexenyloxy (eg, 2-cyclohexene-1-yloxy, 3-cyclohexene-1-yloxy) and the like. ..

In the present specification, the “C _6-14 aryl group” refers to, for example, phenyl, 1-naphthyl, 2-naphthyl and the like. Of these, a C _6-10 aryl group is preferable.
In the present specification, the “C _6-14 aryloxy group” refers to, for example, phenoxy, 1-naphthyloxy, 2-naphthyloxy and the like.
In the present specification, the “C _7-14 aralkyloxy group” refers to, for example, benzyloxy, phenethyloxy and the like.

In the present specification, the "5- or 6-membered monocyclic aromatic heterocyclic group" includes, for example, an oxygen atom, a sulfur atom (which may be oxidized), and a nitrogen atom (which may be oxidized) as ring-constituting atoms in addition to the carbon atom. A 5- or 6-membered monocyclic aromatic heterocyclic group containing 1 to 4 heteroatoms selected from (which may be oxidized), such as frills (eg, 2-furyl, 3-furyl), thienyl. (Example, 2-thienyl, 3-thienyl), pyridyl (eg, 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (eg, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridadinyl (eg, 2-pyrimidinyl) 3-Pyridazinyl, 4-pyridazinyl), pyrazinyl (eg, 2-pyrazinyl), pyrrolyl (eg, 1-pyrrolyl, 2-pyrrolill, 3-pyrrolill), imidazolyl (eg, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl) , 5-Imidazolyl), pyrazolyl (eg, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), thiazolyl (eg, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isothiazolyl (eg, 3-isothiazolyl, 4- Isothiazolyl, 5-isothiazolyl), oxazolyl (eg, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (eg, 3-isooxazolyl, 4-isooxazolyl, 5-isooxazolyl), oxadiazolyl (eg, 1,2,4) -Oxaziazole-5-yl, 1,3,4-oxadiazol-2-yl), thiadiazolyl (eg, 1,3,4-thiazazole-2-yl), triazolyl (eg 1,2,4) -Triazole-1-yl, 1,2,4-triazole-3-yl, 1,2,3-triazole-1-yl, 1,2,3-triazole-2-yl, 1,2,3-triazole -4-yl), tetrazolyl (eg, tetrazol-1-yl, tetrazol-5-yl), triazinyl (eg, 1,2,4-triazine-1-yl, 1,2,4-triazine-3-yl) ) Etc. can be mentioned.

In the present specification, the "8 to 10-membered condensed aromatic heterocyclic group" is, for example, from a ring in which a ring corresponding to the above-mentioned 5- or 6-membered monocyclic aromatic heterocyclic group and a benzene ring are fused. Derived groups; groups derived from rings in which the rings corresponding to the 5- or 6-membered monocyclic aromatic heterocyclic groups are fused together, such as quinolyl (eg, 2-quinolyl, 3-quinolyl, 4-). Kinolyl, 6-quinolyl), isoquinolyl (eg, 3-isoquinolyl), quinazolyl (eg, 2-quinazolyl, 4-quinazolyl), quinoxalyl (eg, 2-quinoxalyl, 6-quinoxalyl), benzofuranyl (eg, 2-benzofuranyl, 3-Benzoflanyl), benzothienyl (eg, 2-benzothienyl, 3-benzothienyl), benzoxazolyl (eg, 2-benzoxazolyl), benzisooxazolyl (eg, 7-benzisooxazoly) Benzimidazole (eg, 2-benzothiazolyl), benzimidazolyl (eg, benzimidazol-1-yl, benzimidazol-2-yl, benzimidazol-5-yl), benzimidazolyl (eg, 1H-1, 1, 2,3-Benzimidazole-5-yl), indrill (eg, indol-1-yl, indol-2-yl, indol-3-yl, indol-5-yl), indazolyl (eg, 1H-imidazole-3) -Il), pyrrolopyrazineyl (eg, 1H-pyrrolo [2,3-b] pyrazine-2-yl, 1H-pyrrolo [2,3-b] pyrazine-6-yl), imidazolepyridyl (eg, 1H-imidazole [ 4,5-b] pyridine-2-yl, 1H-imidazole [4,5-c] pyridine-2-yl, 2H-imidazole [1,2-a] pyridine-3-yl), thienopyridyl (eg, thieno) [2,3-b] pyridine-3-yl), imidazole pyrazinyl (eg, 1H-imidazole [4,5-b] pyrazine-2-yl), pyrazolopyridyl (eg, 1H-pyrazolo [4,) 3-c] pyridine-3-yl), pyrazorotienyl (eg, 2H-pyrazolo [3,4-b] thiophen-2-yl), pyrazorotriadinyl (eg, pyrazolo [5,1-c] [1] , 2,4] Triazine-3-yl) and the like.

In the present specification, the "3- to 8-membered monocyclic non-aromatic heterocyclic group" includes, for example, an oxygen atom, a sulfur atom (which may be oxidized), and a nitrogen atom in addition to a carbon atom as a ring-constituting atom. A 3- to 8-membered (preferably 5- or 6-membered) monocyclic non-aromatic heterocyclic group containing 1 to 4 heteroatoms selected from (which may be oxidized), such as azetidinyl (eg, 5 or 6). , 1-azetidinyl, 2-azetidinyl), pyrrolidinyl (eg, 1-pyrrolidinyl, 2-pyrrolidinyl), piperidil (eg, piperidino, 2-piperidyl, 3-piperidyl, 4-piperidyl), morpholinyl (eg, morpholino), thiomorpholinyl (Example, thiomorpholino), piperazinyl (eg, 1-piperazinyl, 2-piperazinyl, 3-piperazinyl), oxazolidinyl (eg, oxazolidin-2-yl), thiazolidinyl (eg, thiazolidin-2-yl), dihydrothiopyranyl (Eg, dihydrothiopyran-3-yl, dihydrothiopyran-4-yl), imidazolidinel (eg, imidazolidine-2-yl, imidazolidine-3-yl), oxazolinyl (eg, oxazolin-2-yl), Thiazolinyl (eg, thiazolin-2-yl), imidazolinyl (eg, imidazolin-2-yl, imidazolin-3-yl), dioxolyl (eg, 1,3-dioxol-4-yl), dioxolanyl (eg, 1,3) -Dioxoran-4-yl), dihydrooxadiazolyl (eg, 4,5-dihydro-1,2,4-oxadiazol-3-yl), pyranyl (eg, 2-pyranyl, 4-pyranyl), dihydro Pyranyl (eg, dihydropyran-3-yl, dihydropyran-4-yl), tetrahydropyranyl (eg, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl), thiopyranyl (eg, 4) -Thiopyranyl), tetrahydrothiopyranyl (eg, 2-tetrahydrothiopyranyl, 3-tetrahydrothiopyranyl, 4-tetrahydrothiopyranyl), 1-oxide tetrahydrothiopyranyl (eg, 1-oxide tetrahydrothiopyran-) 4-yl), 1,1-dioxide tetrahydrothiopyranyl (eg, 1,1-dioxide tetrahydrothiopyran-4-yl), tetrahydrofuryl (eg, tetrahydrofuran-3-yl, tetrahydrofuran-2-yl) , Oxetanyl (eg, oxetan-2-yl, oxetan-3-yl), pyrazolidinyl (eg, pi) Lazolidine-1-yl, pyrazolidine-3-yl), pyrazolinyl (eg, pyrazolin-1-yl), tetrahydropyrimidinyl (eg, tetrahydropyrimidine-1-yl), dihydrotriazolyl (eg, 2,3-dihydro-) 1H-1,2,3-triazole-1-yl), tetrahydrotriazolyl (eg, 2,3,4,5-tetrahydro-1H-1,2,3-triazole-1-yl), azepanyl (eg) , 1-azepanyl, 2-azepanyl, 3-azepanyl, 4-azepanyl), dihydropyridyl (eg, dihydropyridine-1-yl, dihydropyridine-2-yl, dihydropyridine-3-yl, dihydropyridine-4-yl), tetrahydropyridyl (For example, 1,2,3,4-tetrahydropyridine-1-yl, 1,2,3,4-tetrahydropyridine-2-yl, 1,2,3,4-tetrahydropyridine-3-yl, 1, 2,3,4-Tetrahydropyridine-4-yl) and the like.

In the present specification, as the "8 to 12-membered condensed non-aromatic heterocyclic group", for example, the ring corresponding to the above 3- to 8-membered monocyclic non-aromatic heterocyclic group and the benzene ring are condensed. Ring-derived groups; groups derived from rings in which rings corresponding to the 3- to 8-membered monocyclic non-aromatic heterocyclic groups are fused; the 3- to 8-membered monocyclic non-aromatic heterocyclic groups A group derived from a ring in which a ring corresponding to a ring group and a ring corresponding to the 5- or 6-membered monocyclic aromatic heterocyclic group are condensed; a group obtained by partial saturation of these groups, for example, dihydro Indrills (eg 2,3-dihydro-1H-indole-1-yl), dihydroisoindrills (eg 1,3-dihydro-2H-isoindole-2-yl), dihydrobenzofuranyl (eg, eg) 2,3-Dihydro-1-benzofuran-5-yl), tetrahydrobenzofuranyl (eg, 4,5,6,7-tetrahydro-1-benzofuran-3-yl), dihydrobenzodioxynyl (eg, 2) , 3-Dihydro-1,4-benzodioxin-2-yl), dihydrobenzodioxepinyl (eg, 3,4-dihydro-2H-1,5-benzodioxepin-2-yl), chromenyl (eg, 3,4-dihydro-2H-1,5-benzodioxepin-2-yl) For example, 4H-chromen-2-yl, 2H-chromen-3-yl), dihydrochromenyl (eg, 3,4-dihydro-2H-chromen-2-yl), dihydroquinolinyl (eg, 1, 2). −Dihydroquinolin-4-yl), tetrahydroquinolinyl (eg 1,2,3,4-tetrahydroquinolin-4-yl), dihydroisoquinolinyl (eg 1,2-dihydroisoquinolin-4-yl) ), Tetrahydroisoquinolinyl (eg 1,2,3,4-tetrahydroisoquinolin-4-yl), dihydrophthalazinyl (eg 1,4-dihydrophthalazine-4-yl) and the like.

In the present specification, examples of the "C _2-6 alkenyl-carbonyl group" include acryloyl, butenoyl, pentenoyle, hexenoyl, heptenoyl and the like.
In the present specification, examples of the "C _2-6 alkynyl-carbonyl group" include propioloyl, propynylcarbonyl, butynylcarbonyl, pentynylcarbonyl, hexynylcarbonyl and the like.
In the present specification, examples of the "C _3-8 cycloalkyl-carbonyl group" include cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl and the like.
In the present specification, examples of the "C _3-8 cycloalkenyl-carbonyl group" include cyclopropenylcarbonyl, cyclobutenylcarbonyl, cyclopentenylcarbonyl, cyclohexenylcarbonyl and the like.
In the present specification, examples of the "C _6-14 aryl-carbonyl group" include benzoyl, 1-naphthylcarbonyl, 2-naphthylcarbonyl and the like.
In the present specification, "C _3-8 cycloalkyl-C _1-6 alkyl-carbonyl group" includes, for example, cyclopropyl acetyl, 3-cyclopropyl propionyl, cyclobutyl acetyl, cyclopentyl acetyl, cyclohexyl acetyl, 3-cyclohexyl. Propionyl and the like can be mentioned.
In the present specification, examples of the "C _3-8 cycloalkenyl-C _1-6 alkyl-carbonyl group" include cyclopentenylacetyl, cyclohexenylacetyl, 3-cyclohexenylpropionyl, 3-cyclohexenylpropionyl and the like. ..
In the present specification, examples of the "C _7-14 aralkyl-carbonyl group" include phenylacetyl, 3-phenylpropionyl and the like.
In the present specification, the "5- or 6-membered monocyclic aromatic heterocyclic carbonyl group" includes, for example, frill carbonyl, thienyl carbonyl, pyrrolyl carbonyl, oxazolyl carbonyl, isooxazolyl carbonyl, thiazolyl. Examples thereof include carbonyl, isothiazolylcarbonyl, imidazolylcarbonyl, pyridylcarbonyl, pyrazolylcarbonyl and the like.
In the present specification, the "8 to 12-membered condensed aromatic heterocyclic carbonyl group" includes, for example, benzofuranylcarbonyl, isobenzofuranylcarbonyl, benzothienylcarbonyl, isobenzothienylcarbonyl, indolylcarbonyl, isoin. Examples thereof include drill carbonyl, indazolyl carbonyl, benzimidazolyl carbonyl, and benzoxazolyl carbonyl.
In the present specification, the "3- to 8-membered monocyclic non-aromatic heterocyclic carbonyl group" includes, for example, oxylanylcarbonyl, azetidinylcarbonyl, oxetanylcarbonyl, thietanylcarbonyl, pyrrolidinylcarbonyl, tetrahydro. Examples thereof include frill carbonyl, thiolanyl carbonyl and piperidyl carbonyl.
In the present specification, examples of the "8 to 12-membered condensed non-aromatic heterocyclic carbonyl group" include dihydrobenzofuranylcarbonyl and the like.
In the present specification, the "5- or 6-membered monocyclic aromatic heterocyclic oxy group" includes, for example, frilloxy, thienyloxy, pyrrolyloxy, oxazolyloxy, isooxazolyloxy, thiazolyloxy, isothiazolyl. Examples thereof include oxy, imidazolyloxy, pyridyloxy, pyrazolyloxy and the like. In the present specification, examples of the "8 to 12-membered condensed aromatic heterocyclic oxy group" include benzofuranyloxy, isobenzofuranyloxy and benzothienyl. Examples thereof include oxy, isobenzothienyloxy, indolyloxy, isoindrilloxy, indazolyloxy, benzimidazolyloxy, and benzoxazolyloxy.
In the present specification, the "3- to 8-membered monocyclic non-aromatic heterocyclic oxy group" includes, for example, oxylanyloxy, azetidineyloxy, oxetanyloxy, thietanyloxy, pyrrolidinyloxy, tetrahydrofuryloxy. , Thiolanyloxy, piperidyloxy and the like.
In the present specification, examples of the "8 to 12-membered condensed non-aromatic heterocyclic oxy group" include dihydrobenzofuranyloxy and the like.

Hereinafter, each symbol of the formula (I) will be described.

R ¹ in the formula (I) represents a hydrogen atom or a substituent. A hydrogen atom is preferable as R ¹ .

R ² in the formula (I) represents a hydrogen atom or a substituent. A hydrogen atom is preferable as R ² .

R ³ in formula (I) represents a hydrogen atom or substituent. As R ³ ,
(a) (i) cyano group, (ii) hydroxy group, (iii) C _6-14 aryl group (eg, phenyl), (iv) C _1-6 alkyl-carbonyl group _optionally substituted with cyano group 3- to 8-membered monocyclic non-aromatic heterocyclic groups (eg, pyrrolidinyl) which may be substituted with (eg, acetyl), (v) (i') cyano groups and (ii') 1 to 3 A 3- to 8-membered monocyclic non-aromatic complex which may be substituted with 1 to 3 substituents selected from C _6-14 aryl groups (eg, phenyl) which may be substituted with the cyano group of Substituent with 1 to 3 substituents selected from ring carbonyl groups (eg, azetidinylcarbonyl, piperazinylcarbonyl) and (vi) diC _1-6 alkylamino groups (eg, dimethylamino). _May be C _1-6 alkyl groups (eg, methyl, ethyl, propyl, isopropyl, isobutyl),
(b) (i) hydroxy groups, (ii) C _1-6 alkyl groups _optionally substituted with 1 to 3 hydroxy groups (eg, methyl), and (iii) C _6-14 aryl groups (eg). , Phenyl), C _3-8 cycloalkyl groups (eg, cyclopentyl, cyclohexyl), which may be substituted with 1 to 3 substituents selected from
(c) C _6-14 aryl group, _optionally substituted with 1 to 3 halogen atoms,
(d) 5- or 6-membered monocyclic aromatic heterocyclic group,
(e) 8- to 12-membered condensed aromatic heterocyclic group,
(f) 3- to 8-membered monocyclic non-aromatic heterocyclic groups (eg, tetrahydropyranyl),
(g) 8- to 12-membered condensed non-aromatic heterocyclic group,
(h) C _1-6 alkyl-carbonyl group, _optionally substituted with 1 to 3 halogen atoms,
(i) C _3-8 cycloalkyl-carbonyl group,
(j) C _6-14 aryl-carbonyl group, _optionally substituted with 1 to 3 halogen atoms,
(k) 5- or 6-membered monocyclic aromatic heterocyclic carbonyl group,
(l) 8- to 12-membered condensed aromatic heterocyclic carbonyl group,
(m) 3- to 8-membered monocyclic non-aromatic heterocyclic carbonyl group, and
(n) An amino group which may be mono or di-substituted with a substituent selected from an 8- to 12-membered condensed non-aromatic heterocyclic carbonyl group is preferable.
Among them, as ^{R 3} is,
(a) (i) cyano group, (ii) hydroxy group, (iii) C _6-14 aryl group (eg, phenyl), (iv) C _1-6 alkyl-carbonyl group _optionally substituted with cyano group 3- to 8-membered monocyclic non-aromatic heterocyclic groups (eg, pyrrolidinyl) which may be substituted with (eg, acetyl), (v) (i') cyano groups and (ii') 1 to 3 A 3- to 8-membered monocyclic non-aromatic complex which may be substituted with 1 to 3 substituents selected from C _6-14 aryl groups (eg, phenyl) which may be substituted with the cyano group of Substituent with 1 to 3 substituents selected from ring carbonyl groups (eg, azetidinylcarbonyl, piperazinylcarbonyl) and (vi) diC _1-6 alkylamino groups (eg, dimethylamino). _May be C _1-6 alkyl groups (eg, methyl, ethyl, propyl, isopropyl, isobutyl),
(b) (i) hydroxy groups, (ii) C _1-6 alkyl groups _optionally substituted with 1 to 3 hydroxy groups (eg, methyl), and (iii) C _6-14 aryl groups (eg). C _3-8 cycloalkyl groups (eg, cyclopentyl, cyclohexyl), which may be substituted with 1 to 3 substituents selected from (phenyl), and
(c) 3- to 8-membered monocyclic non-aromatic heterocyclic group (eg, tetrahydropyranyl)
Amino groups that may be mono- or di-substituted with a substituent selected from are preferred.

^{R 4} in formula (I) is a hydrogen atom or a substituent. The R ^4,
(1) Cyanide group;
(2) (a) (i) C _3-8 cycloalkyl group (eg cyclopentyl), (ii) C _1-6 alkoxy group (eg methoxy) and (iii) 1 to 3 C _1-6 alkyl C may be substituted with 1 to 3 substituents selected from 3 to 8 member monocyclic non-aromatic heterocyclic groups (eg, oxetanyl) which may be substituted with a group (eg, methyl). _1-6 alkyl groups (eg, methyl, ethyl, sec-butyl),
(b) C _3-8 cycloalkyl group (eg cyclopentyl),
(c) C _6-14 aryl group,
(d) C _1-6 alkoxy group,
(e) 5- or 6-membered monocyclic aromatic heterocyclic group,
(f) 8- to 12-membered condensed aromatic heterocyclic groups,
(g) 3- to 8-membered monocyclic non-aromatic heterocyclic groups (eg, tetrahydropyranyl), and
(h) A carbamoyl group that may be mono or di-substituted with a substituent selected from 8- to 12-membered condensed non-aromatic heterocyclic groups; or
(3) A C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl) is preferred.
Among them, as ^{R 4} is,
(1) Cyanide group;
(2) (a) (i) C _3-8 cycloalkyl group (eg cyclopropyl), (ii) C _1-6 alkoxy group (eg methoxy) and (iii) 1 to 3 C _1-6 It may be substituted with an alkyl group (eg, methyl) and may be substituted with 1 to 3 substituents selected from a 3- to 8-membered monocyclic non-aromatic heterocyclic group (eg, oxetanyl). C _1-6 alkyl groups (eg, methyl, ethyl, sec-butyl),
(b) C _3-8 cycloalkyl groups (eg, cyclopropyl), and
(c) 3- to 8-membered monocyclic non-aromatic heterocyclic group (eg, tetrahydropyranyl)
Carbamoyl group which may be mono or di-substituted with a substituent selected from;
(3) A C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl) is preferred.

^{R 5} in the formula (I) is a hydrogen atom or a substituent. The R ^5, a hydrogen atom is preferable.

Preferable specific examples of compound (I) include the following.
[Compound A]
R ¹ is a hydrogen atom;
R ² is a hydrogen atom;
R ³
(a) (i) cyano group, (ii) hydroxy group, (iii) C _6-14 aryl group (eg, phenyl), (iv) C _1-6 alkyl-carbonyl group _optionally substituted with cyano group 3- to 8-membered monocyclic non-aromatic heterocyclic groups (eg, pyrrolidinyl) which may be substituted with (eg, acetyl), (v) (i') cyano groups and (ii') 1 to 3 A 3- to 8-membered monocyclic non-aromatic complex which may be substituted with 1 to 3 substituents selected from C _6-14 aryl groups (eg, phenyl) which may be substituted with the cyano group of Substituent with 1 to 3 substituents selected from ring carbonyl groups (eg, azetidinylcarbonyl, piperazinylcarbonyl) and (vi) diC _1-6 alkylamino groups (eg, dimethylamino). _May be C _1-6 alkyl groups (eg, methyl, ethyl, propyl, isopropyl, isobutyl),
(b) (i) hydroxy groups, (ii) C _1-6 alkyl groups _optionally substituted with 1 to 3 hydroxy groups (eg, methyl), and (iii) C _6-14 aryl groups (eg). , Phenyl), C _3-8 cycloalkyl groups (eg, cyclopentyl, cyclohexyl), which may be substituted with 1 to 3 substituents selected from
(c) C _6-14 aryl group, _optionally substituted with 1 to 3 halogen atoms,
(d) 5- or 6-membered monocyclic aromatic heterocyclic group,
(e) 8- to 12-membered condensed aromatic heterocyclic group,
(f) 3- to 8-membered monocyclic non-aromatic heterocyclic groups (eg, tetrahydropyranyl),
(g) 8- to 12-membered condensed non-aromatic heterocyclic group,
(h) C _1-6 alkyl-carbonyl group, _optionally substituted with 1 to 3 halogen atoms,
(i) C _3-8 cycloalkyl-carbonyl group,
(j) C _6-14 aryl-carbonyl group, _optionally substituted with 1 to 3 halogen atoms,
(k) 5- or 6-membered monocyclic aromatic heterocyclic carbonyl group,
(l) 8- to 12-membered condensed aromatic heterocyclic carbonyl group,
(m) 3- to 8-membered monocyclic non-aromatic heterocyclic carbonyl group, and
(n) An amino group which may be mono or di-substituted with a substituent selected from 8- to 12-membered condensed non-aromatic heterocyclic carbonyl groups;
R ⁴
(1) Cyanide group;
(2) (a) (i) C _3-8 cycloalkyl group (eg cyclopentyl), (ii) C _1-6 alkoxy group (eg methoxy) and (iii) 1 to 3 C _1-6 alkyl C may be substituted with 1 to 3 substituents selected from 3 to 8 member monocyclic non-aromatic heterocyclic groups (eg, oxetanyl) which may be substituted with a group (eg, methyl). _1-6 alkyl groups (eg, methyl, ethyl, sec-butyl),
(b) C _3-8 cycloalkyl group (eg cyclopentyl),
(c) C _6-14 aryl group,
(d) C _1-6 alkoxy group,
(e) 5- or 6-membered monocyclic aromatic heterocyclic group,
(f) 8- to 12-membered condensed aromatic heterocyclic groups,
(g) 3- to 8-membered monocyclic non-aromatic heterocyclic groups (eg, tetrahydropyranyl), and
(h) A carbamoyl group that may be mono or di-substituted with a substituent selected from 8- to 12-membered condensed non-aromatic heterocyclic groups; or
(3) C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl);
Compound (I) in which R ⁵ is a hydrogen atom.

[Compound B]
R ¹ is a hydrogen atom;
R ² is a hydrogen atom;
R ³
(a) (i) cyano group, (ii) hydroxy group, (iii) C _6-14 aryl group (eg, phenyl), (iv) C _1-6 alkyl-carbonyl group _optionally substituted with cyano group 3- to 8-membered monocyclic non-aromatic heterocyclic groups (eg, pyrrolidinyl) which may be substituted with (eg, acetyl), (v) (i') cyano groups and (ii') 1 to 3 A 3- to 8-membered monocyclic non-aromatic complex which may be substituted with 1 to 3 substituents selected from C _6-14 aryl groups (eg, phenyl) which may be substituted with the cyano group of Substituent with 1 to 3 substituents selected from ring carbonyl groups (eg, azetidinylcarbonyl, piperazinylcarbonyl) and (vi) diC _1-6 alkylamino groups (eg, dimethylamino). _May be C _1-6 alkyl groups (eg methyl, propyl, isopropyl, isobutyl),
(b) (i) hydroxy groups, (ii) C _1-6 alkyl groups _optionally substituted with 1 to 3 hydroxy groups (eg, methyl), and (iii) C _6-14 aryl groups (eg). C _3-8 cycloalkyl groups (eg, cyclopentyl, cyclohexyl), which may be substituted with 1 to 3 substituents selected from (phenyl), and
(c) 3- to 8-membered monocyclic non-aromatic heterocyclic group (eg, tetrahydropyranyl)
It is an amino group that may be mono- or di-substituted with a substituent selected from;
R ⁴
(1) Cyanide group;
(2) (a) (i) C _3-8 cycloalkyl group (eg cyclopropyl), (ii) C _1-6 alkoxy group (eg methoxy) and (iii) 1 to 3 C _1-6 It may be substituted with an alkyl group (eg, methyl) and may be substituted with 1 to 3 substituents selected from a 3- to 8-membered monocyclic non-aromatic heterocyclic group (eg, oxetanyl). C _1-6 alkyl groups (eg, methyl, ethyl, sec-butyl),
(b) C _3-8 cycloalkyl groups (eg, cyclopropyl), and
(c) 3- to 8-membered monocyclic non-aromatic heterocyclic group (eg, tetrahydropyranyl)
Carbamoyl group which may be mono or di-substituted with a substituent selected from;
(3) C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl);
Compound (I) in which R ⁵ is a hydrogen atom.

[Compound C]
The compound according to Examples 1 to 23 or a salt thereof.

When the compound (I) is a salt, such salts include, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, basic or acidic amino acids. Examples include salt. Preferable examples of the metal salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like. Preferable examples of salts with organic bases include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N'-dibenzyl. Examples include salts with ethylenediamine and the like. Preferable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzene. Examples thereof include salts with succinic acid, p-toluenesulfonic acid and the like. Preferable examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like, and preferred examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. Can be mentioned.
Of these, pharmaceutically acceptable salts are preferable. For example, when the compound has an acidic functional group, it is an inorganic salt such as an alkali metal salt (eg, sodium salt, potassium salt, etc.), an alkaline earth metal salt (eg, calcium salt, magnesium salt, etc.), or an ammonium salt. Etc., and when the compound has a basic functional group, for example, a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitrate, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumaric acid, shu Examples thereof include salts with organic acids such as acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid.

[Production method]
The method for producing the compound (I) of the present invention will be described below.
Compound (I) and its starting compound can be produced by means known per se, for example, by the method shown in the following scheme. In each step of the following production method, "room temperature" usually indicates 10 to 30 ° C., and each symbol in the chemical structural formula described in the scheme has the same meaning as described above unless otherwise specified. In addition, the compound in the formula includes the case where a salt is formed, and examples of such a salt include those similar to the salt of compound (I).

When the compound obtained in each step is a free compound, it can be converted into a target salt by a method known per se. On the contrary, when the compound obtained in each step is a salt, it can be converted into a free form or another kind of salt of interest by a method known per se.

The compound obtained in each step can be used as a reaction solution or as a crude product and then used in the next reaction, or the compound obtained in each step is concentrated from the reaction mixture according to a conventional method. It can be isolated and / or purified by separation means such as crystallization, recrystallization, distillation, solvent extraction, distillation, chromatography and the like.

When a compound of a raw material or a reagent for each step is commercially available, the commercially available product can be used as it is.

In the reaction of each step, the reaction time may vary depending on the reagent and solvent used, but unless otherwise specified, it is usually 1 minute to 48 hours, preferably 10 minutes to 8 hours.

In the reaction of each step, the reaction temperature may vary depending on the reagent and solvent used, but unless otherwise specified, it is usually −78 ° C. to 300 ° C., preferably −78 ° C. to 150 ° C.

In the reaction of each step, the pressure may vary depending on the reagent and solvent used, but unless otherwise specified, it is usually 1 atm to 20 atm, preferably 1 atm to 3 atm.

In the reaction of each step, for example, a microwave synthesizer such as an Initiator manufactured by Biotage may be used. The reaction temperature may vary depending on the reagent and solvent used, but unless otherwise specified, it is usually room temperature to 300 ° C, preferably 50 ° C to 250 ° C. The reaction time may vary depending on the reagent and solvent used, but is usually 1 minute to 48 hours, preferably 1 minute to 8 hours, unless otherwise specified.

In the reaction of each step, the reagent is 0.5 equivalents to 20 equivalents, preferably 0.8 equivalents to 5 equivalents, relative to the substrate, unless otherwise specified. When the reagent is used as a catalyst, the reagent is used in an amount of 0.001 equivalent to 1 equivalent, preferably 0.01 equivalent to 0.2 equivalent, relative to the substrate. When the reagent also serves as a reaction solvent, the solvent amount is used for the reagent.

Unless otherwise specified, in the reaction of each step, these reactions are carried out without solvent or by dissolving or suspending in a suitable solvent. Specific examples of the solvent include the solvents described in the examples, or the following.
Alcohols: methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol, etc .;
Ethers: diethyl ether, diphenyl ether, tetrahydrofuran, 1,2-dimethoxyethane, etc .;
Aromatic hydrocarbons: chlorobenzene, toluene, xylene, etc .;
Saturated hydrocarbons: cyclohexane, hexane, etc .;
Amides: N, N-dimethylformamide, N-methylpyrrolidone, etc .;
Halogenated hydrocarbons: dichloromethane, carbon tetrachloride, etc .;
Nitriles: acetonitrile, etc .;
Sulfoxides: Dimethyl sulfoxide, etc .;
Aromatic organic bases: pyridine, etc .;
Acid anhydrides: acetic anhydride, etc .;
Organic acids: formic acid, acetic acid, trifluoroacetic acid, etc .;
Inorganic acids: hydrochloric acid, sulfuric acid, etc .;
Esters: Ethyl acetate, etc .;
Ketones: acetone, methyl ethyl ketone, etc .;
water.
As the above solvent, two or more kinds may be mixed and used in an appropriate ratio.

When a base is used in the reaction of each step, for example, the base shown below or the base described in Examples is used.
Inorganic bases: sodium hydroxide, magnesium hydroxide, sodium carbonate, calcium carbonate, sodium hydrogen carbonate, etc .;
Organic bases: triethylamine, diethylamine, pyridine, 4-dimethylaminopyridine, N, N-dimethylaniline, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0]- 7-Undecene, imidazole, piperidine, etc .;
Metal alkoxides: sodium ethoxide, potassium tert-butoxide, etc .;
Alkali metal hydrides: sodium hydride, etc .;
Metal amides: sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, etc .;
Organolithium: n-butyllithium, etc.

When an acid or an acidic catalyst is used in the reaction of each step, for example, the acid or acidic catalyst shown below, or the acid or acidic catalyst described in Examples is used.
Inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc .;
Organic acids: acetic acid, trifluoroacetic acid, citric acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc .;
Lewis acid: Boron trifluoride diethyl ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous iron chloride, etc.

Unless otherwise specified, the reaction of each step is a method known per se, for example, 5th Edition Experimental Chemistry Course, Volumes 13-19 (Chemical Society of Japan); New Experimental Chemistry Course, Volumes 14-15 (Japan). Chemical Society of Japan); Precision Organic Chemistry Revised 2nd Edition (LF Tietze, Th. Eicher, Nanedo); Revised Organic Name Reaction Mechanism and Points (Hideo Togo, Kodansha); ORGANIC SYNTHESES Collective Volume I-VII ( John Willey & Sons Inc); Modern Organic Chemistry in the Laboratory A Collection of Standard Experiments Expert Chemistry (Jie Jack Li) by Jie Jack Li, OXF 1-Vol. 14 (Elsevier Japan Co., Ltd.); Organic synthesis strategy learned from name reactions (translated by Kiyoshi Tomioka, published by Kagaku-Dojin); Method described in Comprehensive Organic Transformations (VCH Publicers Inc.), 1989, etc. Alternatively, it is carried out according to the method described in the examples.

Further, in each of the following reactions, when the raw material compound or the intermediate has an amino group, a carboxyl group or a hydroxyl group as a substituent, these groups are protected by a protecting group generally used in peptide chemistry and the like. You may. In this case, the target compound can be obtained by removing the protecting group after the reaction, if necessary. Introduction or removal of these protecting groups, a method known per se, for example, Wiley-Interscience, Inc. 2006 annual ^{"Protective Groups in Organic Synthesis, 4 th} Ed. " (Theodora W. Greene, Peter GM Wuts Author) The method according to And so on.

Examples of the amino group protecting group include a formyl group, a C _1-6 alkyl-carbonyl group, a C _1-6 alkoxy-carbonyl group, a benzoyl group, and a C _7-10 aralkyl-carbonyl group (eg, benzylcarbonyl, etc.). Substituted with C _7-12 aralkyloxy-carbonyl group (eg, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, etc.), trityl group, phthaloyl group, N, N-dimethylaminomethylene group, C _1-6 alkyl group Examples thereof include a silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl, etc.), a C _2-6 alkenyl group (eg, 1-allyl, etc.) and the like. .. These groups may be substituted with 1 to 3 substituents selected from halogen atoms, C _1-6 alkoxy groups and nitro groups.

The carboxyl group protecting group may be substituted with, for example, a C _1-6 alkyl group, a C _7-12 aralkyl group (eg, benzyl, etc.), a phenyl group, a trityl group, or a C _1-6 alkyl group. Examples include groups (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl, etc.), C _2-6 alkenyl groups (eg, 1-allyl, etc.) and the like.

Examples of the hydroxyl group protective group include a C _1-6 alkyl group, a phenyl group, a trityl group, a C _7-12 aralkyl group (eg, benzyl, etc.), a formyl group, a C _1-6 alkyl-carbonyl group, and a benzoyl group. A silyl group optionally substituted with a C _7-12 aralkyl-carbonyl group (eg, benzylcarbonyl, etc.), 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, C _1-6 alkyl group (eg, trimethylsilyl, triethyl). Examples thereof include silyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl, etc.), C _2-6 alkenyl group (eg, 1-allyl, etc.) and the like.

These groups may be substituted with 1 to 3 substituents selected from halogen atoms, C _1-6 alkyl groups, C _1-6 alkoxy groups or nitro groups.
Method for removing the protecting groups described above, a method known per se, for example, Wiley-Interscience, Inc. 2006 annual ^{"Protective Groups in Organic Synthesis, 4 th} Ed. " (Theodora W. Greene, Peter GM Wuts Author) The method according to such Can be mentioned. Specifically, acids, bases, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halide (for example, trimethylsilyl iodide, trimethylsilyl bromide, etc.) and the like are used. The method to be used, the reduction method, etc. are used.

When the reduction reaction is carried out in each step, the reducing agents used include lithium aluminum borohydride, sodium triacetoxyboran borohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), and sodium borohydride. , Metal hydrides such as triacetoxyborohydride tetramethylammonium hydride; boranes such as borane tetrahydrofuran complex; lane nickel; lane cobalt; hydrogen; formic acid; triethylsilane and the like. When reducing a carbon-carbon double bond or triple bond, there is a method using a catalyst such as a palladium-carbon or Lindlar catalyst.

When the oxidation reaction is carried out in each step, the oxidizing agents used include peracids such as m-chloroperbenzoic acid (mCPBA), hydrogen peroxide and tert-butylhydroperoxide; and tetrabutylammonium perchlorate. Perchlorates; Chlorates such as sodium chlorate; Subchlorates such as sodium chlorate; Perioic acids such as sodium periodate; High valence iodine reagents such as iodosylbenzene; Manganese dioxide, excess Manganese-containing reagents such as potassium manganate; Leads such as lead tetraacetate; Chromium-containing reagents such as pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), Jones reagents; N-bromosuccinimide (NBS) Halogen compounds such as; oxygen; ozone; sulfur trioxide / pyridine complex; osmium tetroxide; selenium dioxide; 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and the like.

When the radical cyclization reaction is carried out in each step, the radical initiator used is an azo compound such as azobisisobutyronitrile (AIBN); 4,4'-azobis-4-cyanopentanoic acid (ACPA). Water-soluble radical initiators such as; triethylboron in the presence of air or oxygen; benzoyl peroxide and the like. Examples of the radical reaction reagent used include tributylstanane, tristrimethylsilylsilane, 1,1,2,2-tetraphenyldisilane, diphenylsilane, and samarium iodide.

When the Wittig reaction is carried out in each step, examples of the Wittig reagent used include alkylidene phosphorans and the like. Alkylidene phosphoranes can be prepared by a method known per se, for example, by reacting a phosphonium salt with a strong base.

When the Horner-Emmons reaction is carried out in each step, the reagents used are phosphonoacetic acid esters such as methyl dimethylphosphonoacetate and ethyl diethylphosphonoacetate; bases such as alkali metal hydrides and organolithiums. Can be mentioned.

When the Friedel-Crafts reaction is carried out in each step, the reagents used include a combination of Lewis acid and acid chloride, or a Lewis acid and an alkylating agent (eg, alkyl halides, alcohols, olefins, etc.). The combination of. Alternatively, an organic acid or an inorganic acid can be used instead of Lewis acid, and an acid anhydride such as acetic anhydride can be used instead of acid chloride.

When performing an aromatic nucleophilic substitution reaction in each step, a nucleophile (eg, amines, imidazole, etc.) and a base (eg, organic bases, etc.) are used as reagents.

In each step, when a nucleophilic addition reaction with a carbanion, a nucleophilic 1,4-addition reaction with a carbanion (Michael addition reaction), or a nucleophilic substitution reaction with a carbanion is performed, the base used to generate the carbanion. Examples thereof include organolithiums, metal alkoxides, inorganic bases, and organic bases.

When the Grignard reaction is carried out in each step, examples of the Grignard reagent include arylmagnesium halides such as phenylmagnesium bromide; and alkylmagnesium halides such as methylmagnesium bromide. The Grignard reagent can be prepared by a method known per se, for example, by reacting an alkyl halide or an aryl halide with a metallic magnesium using ether or tetrahydrofuran as a solvent.

When the Knoevenagel condensation reaction is carried out in each step, the reagents include active methylene compounds (eg, malonic acid, diethyl malonate, malononitrile, etc.) and bases (eg, organic bases, etc.) sandwiched between two electron attracting groups. Metal alkoxides, inorganic bases) are used.

When the Vilsmeier-Haack reaction is carried out in each step, phosphoryl chloride and an amide derivative (eg, N, N-dimethylformamide, etc.) are used as reagents.

When the azide reaction of alcohols, alkyl halides and sulfonic acid esters is carried out in each step, examples of the azidizing agent used include diphenylphosphoryl azide (DPPA), trimethylsilyl azide and sodium azide. For example, when azide alcohols, there are a method using diphenylphosphoryl azide and 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), a method using trimethylsilyl azide and Lewis acid, and the like.

When the reductive amination reaction is carried out in each step, examples of the reducing agent used include sodium borohydride, sodium cyanoborohydride, hydrogen and formic acid. When the substrate is an amine compound, examples of the carbonyl compound used include paraformaldehyde, aldehydes such as acetaldehyde, and ketones such as cyclohexanone. When the substrate is a carbonyl compound, the amines used include primary amines such as ammonia and methylamine; secondary amines such as dimethylamine and the like.

When the Mitsunobu reaction is carried out in each step, azodicarboxylic acid esters (eg, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), etc.) and triphenylphosphine are used as reagents.

When an esterification reaction, an amidation reaction, or a urea conversion reaction is carried out in each step, the reagents used are acid halides, acid halides and other halide acylates; acid anhydrides, active esters, and sulfate esters. Examples thereof include activated carboxylic acids. Carboxylic acid activators include carbodiimide-based condensing agents such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSCD); 4- (4,6-dimethoxy-1,3,5- Triazine-2-yl) -4-methylmorpholinium chloride-n-hydrate (DMT-MM) and other triazine condensing agents; 1,1-carbonyldiimidazole (CDI) and other carbonate ester condensing agents; diphenyl Phosphic acid azide (DPPA); benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent); 2-chloro-1-methyl-pyridinium iodide (Mukoyama reagent); thionyl chloride; halogic acid such as ethyl chlorogitate Lower alkyl; O- (7-azabenzotriazole-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate (HATU); sulfuric acid; or a combination thereof. .. When a carbodiimide-based condensing agent is used, additives such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), and dimethylaminopyridine (DMAP) may be further added to the reaction.

When the coupling reaction is carried out in each step, the metal catalysts used are palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) palladium (II), and dichlorobis (triethyl). Palladium compounds such as phosphine) palladium (II), tris (dibenzylideneacetone) dipalladium (0), 1,1'-bis (diphenylphosphino) ferrocene palladium (II) chloride; tetrakis (triphenylphosphine) nickel (0) ) And the like; a rhodium compound such as tris (triphenylphosphine) chloride (III); a cobalt compound; a copper compound such as copper oxide and copper (I) iodide; a platinum compound and the like. Further, a base may be added to the reaction, and examples of such a base include inorganic bases.

When the thiocarbonylation reaction is carried out in each step, diphosphorus pentasulfide is typically used as the thiocarbonylating agent, but in addition to diphosphorus pentasulfide, 2,4-bis (4-methoxyphenyl) ) -1,3,2,4-dithiadiphosphethane-2,4-disulfide (Lawesson's reagent) and other reagents having a 1,3,2,4-dithiadiphosphethane-2,4-disulfide structure May be used.

When the Wohl-Ziegler reaction is carried out in each step, the halogenating agents used include N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfuryl chloride and the like. Can be mentioned. Furthermore, the reaction can be accelerated by adding a radical initiator such as heat, light, benzoyl peroxide, or azobisisobutyronitrile to the reaction.

When the hydroxy group halogenation reaction is carried out in each step, the halogenating agent used is an acid halide of a hydrohalic acid and an inorganic acid, specifically, hydrochloric acid, thionyl chloride, and oxy for chlorination. For bromination such as phosphorus chloride, 48% hydrobromic acid and the like can be mentioned. Further, a method of obtaining an alkyl halide from an alcohol by the action of triphenylphosphine and carbon tetrachloride or carbon tetrabromide may be used. Alternatively, a method may be used in which an alkyl halide is synthesized through a two-step reaction such as converting an alcohol into a sulfonic acid ester and then reacting it with lithium bromide, lithium chloride or sodium iodide.

When the Arbuzov reaction is carried out in each step, the reagents used include alkyl halides such as ethyl bromoacetate; phosphites such as triethyl phosphite and tri (isopropyl) phosphite.

When the sulfonic acid esterification reaction is carried out in each step, examples of the sulfonylating agent used include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic acid anhydride, and p-toluenesulfonic acid anhydride.

When the hydrolysis reaction is carried out in each step, an acid or a base is used as the reagent. Further, when the acid hydrolysis reaction of tert-butyl ester is carried out, formic acid, triethylsilane or the like may be added in order to reduceally trap the tert-butyl cation produced as a by-product.

When the dehydration reaction is carried out in each step, examples of the dehydrating agent used include sulfuric acid, diphosphorus pentoxide, phosphorus oxychloride, N, N'-dicyclohexylcarbodiimide, alumina, polyphosphoric acid and the like.

The compound obtained in each step can be used in the next reaction as a reaction solution or as a crude product, but can also be isolated from the reaction mixture according to a conventional method, and can be used for recrystallization, distillation, chromatography, etc. It can be easily purified by the separation means.

Compound (I) can be produced from compound (II) by the following method.

[In the formula, X represents a halogen atom. ]

Compound (V) can be produced by a cyclization reaction of compound (IV) with a halogenating reagent. Examples of the halogenating reagent include phosphoric acid trichloride and the like. R ¹ , R ² , R ³ , R ⁴ , and R ⁵ can also be converted using methods known per se.

The compound of the present invention obtained by each of the above production methods can be isolated and purified by known means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, transdissolution, and chromatography. In addition, each raw material compound used in each of the above-mentioned production methods can be isolated and purified by the same known means as described above. On the other hand, these raw material compounds may be used as they are as a reaction mixture as a raw material for the next step without isolation.
Compound (I) produced by such a method can be isolated and purified by ordinary separation means such as recrystallization, distillation, chromatography and the like.
When compound (I) contains an optical isomer, a steric isomer, a positional isomer, and a rotational isomer, these are also contained as compound (I), and a synthesis method and a separation method known per se (for example). , Concentration, solvent extraction, column chromatography, recrystallization, etc.), each of which can be obtained as a single product. For example, when the optical isomer is present in the compound (I), the optical isomer separated from the compound is also included in the compound (I).

The optical isomer can be produced by a method known per se. Specifically, an optically active synthetic intermediate is used, or the final racemate is optically resolved according to a conventional method to obtain an optical isomer.
As the optical resolution method, a method known per se, for example, a fractional recrystallization method, a chiral column method, a diastereomer method, or the like is used.

1) Fractional recrystallization method Racemic and optically active compounds (eg, (+)-mandelic acid, (-)-mandelic acid, (+)-tartaric acid, (-)-tartaric acid, (+)-1-phenethylamine, A salt is formed with (-)-1-phenethylamine, cinchonine, (-)-cinchonidine, brucine, etc.), separated by a fractional recrystallization method, and optionally undergoes a neutralization step to obtain a free optical isomer. Method.

2) Chiral column method A method in which a racemate or a salt thereof is separated by applying a column for separating optical isomers (chiral column). For example, in the case of liquid chromatography, a mixture of optical isomers is added to a chiral column such as ENANTIO-OVM (manufactured by Toso) or CHIRAL series (manufactured by Daicel), and water and various buffers (eg, phosphate buffer) are added. The optical isomers are separated by developing the solution as a single solution or a mixture of an organic solvent (eg, ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid, diethylamine, etc.). Further, for example, in the case of gas chromatography, separation is performed using a chiral column such as CP-Chirasil-DeX CB (manufactured by GL Sciences).

3) Diasteromer method A mixture of racemic compounds is made into a mixture of diastereomers by a chemical reaction with an optically active reagent, and this is passed through ordinary separation means (for example, fractional recrystallization, chromatography method, etc.) to form a single substance. Then, a method of obtaining an optical isomer by separating an optically active reagent site by a chemical treatment such as a hydrolysis reaction. For example, if compound (I) has a hydroxy or primary or secondary amino in the molecule, the compound and an optically active organic acid (eg, MTPA [α-methoxy-α- (trifluoromethyl) phenylacetic acid]], ( -) -Mentoxyacetic acid, etc.) and the like are subjected to a condensation reaction to obtain ester or amide diastereomers, respectively. On the other hand, when compound (I) has a carboxylic acid group, diastereomers of amides or esters can be obtained by subjecting the compound to an optically active amine or alcohol reagent in a condensation reaction, respectively. The separated diastereomers are converted into optical isomers of the original compound by subjecting them to an acid hydrolysis or a basic hydrolysis reaction.

Compound (I) may be crystalline.
The crystal of compound (I) can be produced by applying a crystallization method known per se to compound (I) and crystallizing it.
Here, examples of the crystallization method include a crystallization method from a solution, a crystallization method from steam, a crystallization method from a melt, and the like.

The "crystallization method from solution" includes a non-saturated state by changing factors related to the solubility of the compound (solvent composition, pH, temperature, ion intensity, redox state, etc.) or the amount of the solvent. The method of shifting from the above to the supersaturated state is common, and specific examples thereof include a concentration method, a slow cooling method, a reaction method (diffusion method, an electrolytic method), a hydrothermal growth method, and a solvent method. Examples of the solvent used include aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, etc.), saturated hydrocarbons (eg, hexane, heptane, cyclohexane). Etc.), ethers (eg, diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, etc.), nitriles (eg, acetonitrile, etc.), ketones (eg, acetone, etc.), sulfoxides (eg, dimethyl sulfoxide, etc.) ), Acid amides (eg, N, N-dimethylformamide, etc.), esters (eg, ethyl acetate, etc.), alcohols (eg, methanol, ethanol, isopropyl alcohol, etc.), water and the like. These solvents may be used alone or in admixture of two or more at an appropriate ratio (eg, 1: 1 to 1: 100 (volume ratio)). Seed crystals can also be used if desired.

Examples of the "crystallization method from steam" include a vaporization method (sealing method, air flow method), a gas phase reaction method, a chemical transport method, and the like.

Examples of the "crystallization method from a melt" include a normal freezing method (pulling method, temperature gradient method, Bridgeman method), a zone melting method (zone leveling method, float zone method), and a special growth method (VLS method). , Liquid phase epitaxy method) and the like.

A suitable example of the crystallization method is that the compound (I) is dissolved in a suitable solvent (eg, alcohols such as methanol and ethanol) at a temperature of 20 to 120 ° C., and the obtained solution is dissolved. Examples thereof include a method of cooling to a temperature or lower (for example, 0 to 50 ° C., preferably 0 to 20 ° C.).
The crystal of the present invention thus obtained can be isolated by, for example, filtration or the like.
As a method for analyzing the obtained crystal, a method for crystal analysis by powder X-ray diffraction is generally used. Further, as a method for determining the crystal orientation, for example, a mechanical method, an optical method, or the like can be mentioned.

The crystal of compound (I) obtained by the above production method (hereinafter, abbreviated as "crystal of the present invention") has high purity, high quality, low hygroscopicity, and is stored for a long period of time under normal conditions. It does not deteriorate and is extremely stable. In addition, it is expected to be excellent in biological properties (eg, pharmacokinetics (absorption, distribution, metabolism, excretion), expression of drug efficacy, etc.), and may be useful as a medicine.

In the present specification, the specific rotation ([α] _D ) is a ratio measured by using, for example, a rotometer (JASCO Corporation, P-1303 rotometer (No. AP-2)) or the like. It means the degree of optical rotation.
In the present specification, the melting point means a melting point measured by using, for example, a micro melting point measuring device (Yanako, MP-500D type) or a DSC (differential scanning calorimetry) device (SEIKO, EXSTAR6000).

Compound (I) may be used as a prodrug. The prodrug of compound (I) is a compound that is converted into compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo, that is, compound (I) is enzymatically oxidized, reduced, hydrolyzed, or the like. A compound that changes to compound (I) by causing hydrolysis or the like due to gastric acid or the like.

Examples of the prodrug of compound (I) include, for example.
(1) A compound in which the amino of compound (I) is acylated, alkylated, or phosphorylated (for example, the amino of compound (I) is ecosanoyylated, alanylated, pentylaminocarbonylated, (5-methyl-2-). Oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, tert-butylation, ethoxycarbonylation, tert-butoxycarbonylation, acetylation, Cyclopropylcarbonylated compounds, etc.);
(2) The hydroxy of compound (I) is acylated, alkylated, phosphorylated, or booxidized (for example, the hydroxy of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated. , Fumarylation, alanylation, dimethylaminomethylcarbonylated compounds, etc.);
(3) The carboxy of the compound (I) is esterified and amidated (for example, the carboxy of the compound (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pi Valoyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methylesterification, cyclohexyloxycarbonylethyl esterification, methylamide Esterified compounds, etc.);
And so on. These compounds can be produced from compound (I) by a method known per se.

In addition, the prodrug of compound (I) changes to compound (I) under physiological conditions as described in "Development of Pharmaceuticals", Vol. 7, Molecular Design, pp. 163 to 198, published by Hirokawa Shoten, 1990. There may be.

In the present specification, compound (I) and its prodrug may be collectively abbreviated as "compound of the present invention".

Compound (I) may be a hydrate, a non-hydrate, a solvate, or a non-solvate.
Compounds labeled with isotopes (eg, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.) are also included in compound (I).
Further, a deuterium converter obtained by converting ¹ H to ² H (D) is also included in compound (I).
Tautomers are also included in compound (I).
Compound (I) may be a pharmaceutically acceptable co-crystal or co-crystal salt. Here, a co-crystal or a co-crystal salt is unique to two or more at room temperature, each having different physical properties (eg, structure, melting point, heat of fusion, hygroscopicity, solubility and stability). It means a crystalline substance composed of a solid solid. The co-crystal or co-crystal salt can be produced according to a co-crystallization method known per se.
Compound (I) may be used as a PET tracer.

Since the compound of the present invention may have an excellent JAK (JAK1, JAK2, JAK3, TYK2) inhibitory action, it may be useful as a safe drug based on this action.
The compounds of the present invention also have IFN-α inhibitory activity, IFN-β inhibitory activity, IFN-γ inhibitor, IL-2 inhibitor, IL-4 inhibitor, IL-7 inhibitor, IL-15 inhibitor, IL-. 21 inhibitor, IL-6 inhibitor, OSM inhibitor, IL-10 inhibitor, IL-19 inhibitor, IL-20 inhibitor, IL-22 inhibitor, IL-28 inhibitor, IL-29 inhibitor, Since it can have an IL-12 inhibitory action and / or an IL-23 inhibitory action (preferably an IL-23 inhibitory action), it can also be useful as a safe drug based on this action.
For example, the medicament of the present invention containing the compound of the present invention can be used for mammals (for example, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys, humans, etc.) to treat JAK-related diseases. More specifically, it can be used as a prophylactic or therapeutic agent for the diseases described in (1) to (6) below.
(1) Inflammatory diseases (eg, acute pancreatitis, chronic pancreatitis, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease (COPD), inflammatory bone disease, inflammatory lung disease, inflammatory bowel disease, celiac disease, hepatitis , Systemic inflammatory reaction syndrome (SIRS), inflammation after surgery or trauma, pneumonia (such as idiopathic interstitial pneumonia including idiopathic pulmonary fibrosis (IPF)), nephritis, meningitis, cystitis, pharyngolaryngitis , Gastric mucosal injury, meningitis, spondylitis, arthritis, dermatitis, chronic pneumonia, bronchitis, pulmonary infarction, silicopulmonary disease, pulmonary sarcoidosis, vegetation inflammation, purulent sweat adenitis, ischemia-reperfusion injury, gout (eg , Acute gout, etc.), pollinosis, acute renal injury, cryopyrin-related periodic syndrome (CAPS), circular alopecia, white spots, etc.),
(2) Autoimmune diseases (eg, rheumatoid arthritis, psoriasis, inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis, etc.), Schegren's syndrome, Bechet's disease, multiple sclerosis, systemic erythematosus, lupus nephritis, circle Plate erythematosus, Castleman's disease, tonic spondylitis, polymyositis, dermatomyositis (DM), nodular polyarteritis (PN), mixed connective tissue disease (MCTD), strong skin disease, deep Zhizin erythema, chronic thyroiditis, Hashimoto's thyroiditis, Graves' disease, autoimmune gastrointestinal inflammation, type I and type II diabetes, autoimmune hemolytic anemia, autoimmune neutrophilia, thrombocytopenia, atopy Sexual dermatomyositis, chronic active hepatitis, severe myasthenia, organ transplant rejection, transplant-to-host disease, Addison's disease, abnormal immune response, arthritis, dermatomyositis, radiation dermatomyositis, primary biliary cirrhosis, alcohol, etc.) ,
(3) Bone / joint degenerative diseases (eg, rheumatoid arthritis, osteoporosis, osteoarthritis, etc.),
(4) Neoplastic diseases [eg, malignant tumors, angiogenic glaucoma, infantile hemangiomas, multiple myeloma, acute myeloblastic leukemia, chronic sarcoma, multiple myeloma, metastatic sarcoma, caposarcoma, vascular proliferation , Bad fluid, metastasis of breast cancer, cancer (eg, familial sarcoma, hereditary non-polyposis sarcoma, gastrointestinal sarcoma, etc.), lung cancer (eg, non-small cell sarcoma, small cell) Lung cancer, malignant sarcoma, etc.), sarcoma, pancreatic cancer (eg, pancreatic duct cancer, etc.), gastric cancer (eg, papillary adenocarcinoma, mucinous adenocarcinoma, adenoflat epithelial cancer, etc.), breast cancer (eg, invasive mammary duct) Cancer, non-invasive sarcoma, inflammatory sarcoma, etc.), ovarian cancer (eg, epithelial ovarian cancer, extragonadal sarcoma, ovarian sarcoma, low-grade ovarian tumor, etc.), prostate cancer (eg, low-grade ovarian tumor) Hormone-dependent prostate cancer, hormone-independent prostate cancer, etc.), liver cancer (eg, primary liver cancer, extrahepatic bile duct cancer, etc.), thyroid cancer (eg, thyroid sarcoma-like cancer, etc.), kidney cancer (eg, renal cells) Cancer, metastatic epithelial cancer of the renal pelvis and urinary tract), uterine cancer, brain tumor (eg, pineapple sarcoma, hairy cell sarcoma, diffuse sarcoma, degenerative sarcoma, etc.), Black tumor (melanoma), sarcoma, bladder cancer, hematological cancer including multiple myeloma, pituitary adenoma, glioma, acoustic nerve sheath tumor, retinal sarcoma, pharyngeal cancer, laryngeal cancer, tongue cancer, thoracic adenoma, esophageal cancer , Duodenal cancer, colon cancer, rectal cancer, hepatocellular carcinoma, pancreatic endocrine tumor, bile duct cancer, bile sac cancer, penis cancer, urinary tract cancer, testis tumor, genital genital cancer, cervical cancer, uterine body cancer, uterine sarcoma, villi Sexual disorders, vaginal cancer, skin cancer, fungal sarcoma, basal cell tumor, soft sarcoma, malignant lymphoma, Hodgkin's disease, myelodystrophy syndrome, adult T-cell leukemia, chronic myeloproliferative disease, pancreatic endocrine tumor, fibrous tissue Hematoma, smooth sarcoma, horizontal sarcoma, cancer of unknown primary origin, etc.), activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL), leukemia (eg, acute leukemia (eg, acute lymphocytic) Leukemia, acute myeloid leukemia, etc.), chronic leukemia (eg, chronic lymphocytic leukemia, chronic myeloid leukemia, etc.), myelogenesis syndrome, etc.), uterine sarcoma (eg, mesenteric mixed tumor, uterine smooth muscle tumor, uterus) Intimal sarcoma, etc.), myelodystrophy, etc.],
(5) Central diseases (eg, schizophrenia, Alzheimer's disease (eg, Alzheimer's disease)),
(6) Pain (eg, neuropathic pain, diabetic pain, myofiosis, postoperative pain, cancer pain, inflammatory pain, migraine, neuralgia, muscle pain, etc.).

The medicament of the present invention preferably has autoimmune disease, inflammatory disease, bone / joint degenerative disease, central disease or neoplastic disease, more preferably systemic erythematosus, inflammatory bowel disease (preferably Crohn's disease or Ulceral colitis), rheumatoid arthritis, psoriasis, Schegren's syndrome, Bechet's disease, multiple sclerosis, Alzheimer's disease (preferably Alzheimer's dementia), Castleman's disease, leukemia, uterine smooth muscle tumor, prostate cancer, multiple It can be used as a prophylactic or therapeutic agent for myeloma, malaise, or myeloid fibrosis.
Here, "prevention" of the above-mentioned disease means, for example, a patient who has not developed the disease or who has developed the disease but is expected to have a high risk of developing the disease due to some factor related to the disease. It means that a drug containing the compound of the present invention is administered to a patient who does not have the disease, or a drug containing the compound of the present invention is administered to a patient who is concerned about recurrence of the disease after treatment of the disease.

The medicament of the present invention has excellent pharmacokinetics (eg, blood drug half-life), low toxicity (eg, HERG inhibition, CYP inhibition, CYP induction), reduces cytotoxicity, and has side effects based on improved JAK selectivity. Relief and reduction of drug interactions are observed. The compound of the present invention is used as it is or mixed with a pharmacologically acceptable carrier according to a known means generally used in the production method of a pharmaceutical preparation to obtain a pharmaceutical composition and used as the pharmaceutical of the present invention. obtain. The medicament of the present invention is orally or parenterally for mammals (for example, humans, monkeys, cows, horses, pigs, mice, rats, hamsters, rabbits, cats, dogs, sheep, goats, etc.). Can be safely administered.
A drug containing the compound of the present invention allows the compound of the present invention alone or pharmacologically with the compound of the present invention according to a method known per se as a method for producing a pharmaceutical preparation (eg, a method described in the Japanese Pharmacopoeia). It can be used as a pharmaceutical composition mixed with the carrier to be used. Pharmaceuticals containing the compound of the present invention include, for example, tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), suppositories, powders, granules, capsules (soft capsules, microcapsules). Includes capsules), troches, syrups, liquids, emulsions, suspensions, controlled release formulations (eg, fast-release, sustained-release, sustained-release microcapsules), aerosols, films (eg, sustained-release microcapsules) Examples, orally disintegrating film, oral mucosal patch film), injections (eg, subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections), drip, transdermal preparations, creams, Oral or parenteral as ointments, lotions, patches, suppositories (eg, anal suppositories, vaginal suppositories), pellets, nasal agents, transpulmonary agents (eg, inhalants), eye drops, etc. Safely administered (eg, intravenous, intramuscular, subcutaneous, organ, intranasal, intradermal, instillation, brain, rectal, intravaginal, intraperitoneal, intratumor, proximal tumor, lesion, etc.) obtain.
The content of the compound of the present invention in the pharmaceutical product of the present invention is about 0.01% by weight to about 100% by weight of the entire pharmaceutical product. The dose may vary depending on the subject, administration route, disease, etc., and may vary, for example, rheumatoid arthritis, cachexia, inflammatory bowel disease, Schegren's syndrome, Bechet's disease, multiple sclerosis, systemic erythematosus, Castleman's disease. Disease), leukemia, uterine smooth muscle tumor, prostate cancer, multiple myeloma, cachexia, myelofibrosis, etc. (body weight about 60 kg) as an oral preparation, active ingredient (compound (I)) per day As a free body), about 0.01 mg / kg body weight to about 500 mg / kg body weight, preferably about 0.1 mg / kg body weight to about 50 mg / kg body weight, and more preferably about 1 mg / kg body weight to 30 mg / kg body weight. It may be administered once to several times a day.
The pharmacologically acceptable carrier that may be used in the production of the medicament of the present invention may include various organic or inorganic carrier substances commonly used as pharmaceutical materials, for example, excipients and lubricants in solid preparations. , Binders and disintegrants, or solvents, solubilizers, suspending agents, tonicity agents, buffering agents and soothing agents in liquid formulations can be used. Further, if necessary, an appropriate amount of additives such as ordinary preservatives, antioxidants, colorants, sweeteners, adsorbents, and wetting agents can be used.

Examples of excipients include lactose, sucrose, D-mannitol, starch, cornstarch, crystalline cellulose, light anhydrous silicic acid and the like.
Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
Examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methyl cellulose, sodium carboxymethyl cellulose and the like.
Examples of the disintegrant include starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, L-hydroxypropyl cellulose and the like.
Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
Examples of the solubilizing agent include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like.
Examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate; for example, polyvinyl alcohol and polyvinylpyrrolidone. , Hydrophilic polymers such as sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and the like.

Examples of the tonicity agent include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like.
Examples of the buffering agent include buffer solutions such as phosphates, acetates, carbonates and citrates.
Examples of the pain-relieving agent include benzyl alcohol and the like.
Examples of preservatives include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenylethyl alcohol, dehydroacetic acid, sorbic acid and the like.
Examples of the antioxidant include sulfites, ascorbic acid, α-tocopherol and the like.

The compound of the present invention can be used together with other drugs in the prevention and treatment of various diseases. Hereinafter, a drug used when the compound of the present invention is used in combination with another drug is referred to as a "combination agent of the present invention".
For example, the compounds of the present invention are JAK family inhibitors, IFN-α inhibitors, IFN-β inhibitors, IFN-γ inhibitors, IL-2 inhibitors, IL-4 inhibitors, IL-7 inhibitors, IL-15. Inhibitors, IL-21 inhibitors, IL-6 inhibitors, OSM inhibitors, IL-10 inhibitors, IL-19 inhibitors, IL-20 inhibitors, IL-22 inhibitors, IL-28 inhibitors, IL When used as a -29 inhibitor, IL-12 inhibitor, and / or IL-23 inhibitor, it can be used in combination with the following drugs:
(1) Non-steroidal anti-inflammatory drugs (NSAIDs)
(I) Classical NSAIDs
Alcophenac, acecrophenac, sulindac, tolmethin, etodolac, phenoprofen, thiaprofenic acid, meclophenamic acid, meroxycam, teoxycam, lornoxicum, nabmeton, acetaminophen, phenacetin, etenzamid, sulpyrine, antipyrine, efrenin, aspirin, mefenamic acid Diclophenac sodium, loxoprofen sodium, phenylbutazone, indomethacin, ibuprofen, ketoprofen, naproxen, oxaprozin, flurbiprofen, fenbufen, planoprofen, floctaphenin, pyroxicum, epilyzole, thiaramid hydrochloride, zartprofen, gabexate mesilate, camostate mesilate, Urinastatin, corhitin, probenecid, sulinpyrazone, benzbromalone, alloprinol, sodium gold thioappleate, sodium hyaluronate, sodium salicylate, morphine hydrochloride, salicylic acid, atropin, scopolamine, morphine, petidin, levorphanol, oxymorphone or salts thereof etc.
(Ii) Cyclooxygenase inhibitors (COX-1 selective inhibitors, COX-2 selective inhibitors, etc.)
Salicylic acid derivatives (eg, celecoxib, aspirin), etoricoxib, valdecoxib, diclofenac, indomethacin, loxoprofen, etc.
(Iii) Nitric oxide free NSAIDs
(Iv) JAK inhibitors Tofacitinib, Ruxolitinib, etc.

(2) Disease-modifying anti-rheumatic drugs (DMARDs)
(I) Gold preparation Auranofin, etc.
(Ii) Penicillamine D-penicillamine.
(Iii) Aminosalcylic acid preparations Sulfasalazine, mesalamine, orsalazine, balsalazide.
(Iv) Antimalarial drug chloroquine, etc.
(V) Pyrimidine synthesis inhibitor reflunomide, etc.
(Vi) Prograph

(3) Anti-cytocytogene drug (I) Protein preparation (i) TNF inhibitor Eternacept, infliximab, adalimumab, sertrizumab pegor, golimumab, PASSTNF-α, soluble TNF-α receptor, TNF-α binding protein, anti-TNF-α antibody etc.
(Ii) Interleukin-1 inhibitor Anakinra (interleukin-1 receptor antagonist), soluble interleukin-1 receptor, etc.
(Iii) Interleukin-6 inhibitor Tocilizumab (anti-interleukin-6 receptor antibody), anti-interleukin-6 antibody, etc.
(Iv) Interleukin-10 drug Interleukin-10 etc.
(V) Interleukin-12 / 23 inhibitors ustekinumab, briaquinumab (anti-interleukin-12 / 23 antibody), etc.
(II) Non-protein preparation (i) MAPK inhibitor
BMS-582949 etc.
(Ii) Gene regulator
Inhibitors of molecules involved in signal transduction such as NF-κ, NF-κB, IKK-1, IKK-2, AP-1.
(Iii) Cytokine production inhibitor iguratimod, tetomilast, etc.
(Iv) TNF-α converting enzyme inhibitor (v) Interleukin-1β converting enzyme inhibitor
VX-765 etc.
(Vi) Interleukin-6 antagonist
HMPL-004 etc.
(Vii) Interleukin-8 inhibitor
IL-8 antagonist, CXCR1 & CXCR2 antagonist, reparexin, etc.
(Viii) Chemokine antagonist
CCR9 antagonists (CCX-282, CCX-025), MCP-1 antagonists, etc.
(Ix) Interleukin-2 receptor antagonist Deniloukin, Difchitox, etc.
(X) Therapeutic vaccines
TNF-α vaccine, etc.
(Xi) Gene therapy drug A gene therapy drug aimed at enhancing the expression of genes having anti-inflammatory effects such as interleukin-4, interleukin-10, soluble interleukin-1 receptor, and soluble TNF-α receptor. ..
(Xii) Antisense compound
ISIS-104838 etc.

(4) Integrin inhibitors Natalizumab, vedolizumab, AJM300, TRK-170, E-6007, etc.
(5) Immunomodulators (immunosuppressive drugs)
Methotrexate, Cyclophosphamide, MX-68, Atiprimodo dihydrochloride, BMS-188667, CKD-461, Limexolone, Cyclosporine, Tacrolimus, Gusperimus, Azathioprine, Antilymphatic serum, Dry sulfated immunoglobulin, Erythropoietin, Colony stimulation Factors, interleukins, interferons, etc.
(6) Topical steroids Dexamethasone, hexestrol, methimazole, betamesazone, triamcinolone, triamcinolone acetonide, fluocinonide, fluocinolone acetonide, prednisolone, methylprednisolone, cortisone acetate, hydrocortisone, fluorometholone, estriol, propionate, etc.
(7) Angiotensin converting enzyme inhibitor Enalapril, captopril, ramipril, lisinopril, silazapril, perindopril, etc.

(8) Angiotensin II receptor antagonist candesartan, cilexetil (TCV-116), valsartan, irbesartan, olmesartan, eprosartan and the like.
(9) Diuretics Hydrochlorothiazide, spironolactone, furosemide, indapamide, bendrofluazide, cyclopentiazide and the like.
(10) Cardiotonic agents Digoxin, dobutamine, etc.
(11) β-receptor antagonist carvedilol, metoprolol, atenolol and the like.
(12) Ca sensitivity enhancer MCC-135 and the like.
(13) Ca channel antagonist nifedipine, diltiazem, verapamil, etc.
(14) Antiplatelet drug, anticoagulant heparin, aspirin, warfarin, etc.
(15) HMG-CoA reductase inhibitors atrovastatin, simvastatin and the like.

(16) Contraceptives (i) Sex hormones or derivatives thereof (progesterone, 17α-hydroxyprogesterone, medroxyprogesterone, medroxyprogesterone acetate, norethisterone, norethisterone enantate, norethisterone, norethisterone acetate, norethinodorel, levonorgesterone) , Norgestrel, estradiol diacetate, desogestrel, norethisterone, guestden, progestin, etonogestrel, drospyrenone, dienogest, trimegean, nestron, chromadinone acetate, mifepriston, nomegestol acetate, Org-30659, TX-525, EMM-310525) Leprosy hormone or its derivatives and follicular hormone or its derivatives (estradiol, estradiol benzoate, estradiol cypionate, estradiol dipropionate, estradiol enantate, estradiol hexahydrobenzoate, estradiol phenyl propionate, estradiol undecanoate, valeric acid Combination with estradiol, estradiol, ethynyl estradiol, mestranol), etc.
(Ii) Anti-estrogen drugs Ormeroxyphene, mifepristone, Org-33628, etc.
(Iii) Spermicide Uchelsel, etc.

(17) Others (i) T cell inhibitor (ii) Inosinic acid dehydrogenase (IMPDH) inhibitor Mycophenolate mofetil and the like.
(Iii) Adhesion molecule inhibitor
ISIS-2302, selectin inhibitors, ELAM-1, VCAM-1, ICAM-1, etc.
(Iv) Thalidomide (v) Cathepsin inhibitors (vi) Matrix metalloproteinase (MMPs) inhibitors
V-85546 etc.
(Vii) Glucose-6-phosphate dehydrogenase inhibitor (viii) Dihydroorotate dehydrogenase (DHODH) inhibitor (ix) Phosphodiesterase IV (PDEIV) inhibitor Loflumirast, CG-1088, etc.
(X) Phospholipase A ₂ inhibitor (xi) iNOS inhibitor
VAS-203 etc.
(Xii) Microtuble stimulant Paclitaxel, etc.
(Xiii) Microtuble inhibitor Ryumacon, etc.
(Xiv) MHC class II antagonist (xv) Prostacyclin activator Iloprost, etc.
(Xvi) CD4 antagonist Zanolimumab, etc.
(Xvii) CD23 antagonist (xviii) LTD4 receptor antagonist
DW-1305 etc.
(Xix) 5-lipoxygenase inhibitor Giryuton and the like.
(Xx) Cholinesterase inhibitor Galantamine, etc.
(Xxi) Tyrosine kinase inhibitor
TYK2 inhibitor (WO2010 / 142752), etc.
(Xxii) Cathepsin B inhibitor (xxiii) Adenosine deaminase inhibitor Pentostatin and the like.
(Xxiv) Bone formation stimulant (xxv) Dipeptidyl peptidase inhibitor (xxvi) Collagen agonist (xxvii) Capsaicin cream (xxviii) Hyaluronic acid derivative Symbisc (hylan GF 20), orthobisc, etc.
(Xxx) Glucosamine sulfate (xxx) Amiprirose (xxxi) CD-20 inhibitor Rituximab, ibritumomab, tositumomab, ofatumab, etc.
(Xxxii) BAFF inhibitors belimumab, tabalumab, atacicept, A-623, etc.
(Xxxiii) CD52 inhibitor alemtuzumab, etc.
(Xxxiv) IL-17 inhibitor secukinumab (AIN-457), LY-2439821, AMG827, etc.
(Xxxxv) PDE4 inhibitors Roflumilast, Apremilast, etc.

Examples of concomitant drugs other than the above include antibacterial agents, antifungal agents, antigenic insect agents, antibiotics, antitussives / abstinence agents, sedatives, anesthetics, anti-ulcer agents, antiarrhythmic agents, antihypertensive diuretics, and anticoagulants. Drugs, tranquilizers, antipsychic drugs, antitumor drugs, antihyperlipidemic drugs, muscle relaxants, antiepileptic drugs, antidepressants, antiallergic drugs, cardiotonics, antiarrhythmic drugs, vasodilators, vasoconstrictors Drugs, antihypertensive diuretics, antidiabetic drugs, drug antagonists, vitamin drugs, vitamin derivatives, anti-asthmatic drugs, frequent urine / urinary incontinence drugs, antipruritic drugs, atopic dermatitis drugs, allergic rhinitis drugs, pressor Examples thereof include drugs, endotoxin antagonists or antibodies, signal transduction inhibitors, inflammatory mediator action inhibitors, inflammatory mediator action suppressors, anti-inflammatory mediator action inhibitors, anti-inflammatory mediator action suppressors and the like. Specifically, the following can be mentioned.

(1) Antibacterial drug
(i) Sulfa agent Sulfamethizole, sulfisoxazole, sulfamonomethoxyne, sulfamethizole, salazosulfapyridine, silver sulfadiazine, etc.
(ii) Kinolin antibacterial agents Nalidixic acid, pipemidic acid trihydrate, enoxacin, norfloxacin, ofloxacin, tosufloxacin tosilate, ciprofloxacin hydrochloride, lomefloxacin hydrochloride, sparfloxacin, freloxacin, etc.
(iii) Antituberculous agents Isoniazid, ethambutol (ethambutol hydrochloride), para-aminosalicylic acid (calcium para-aminosalicylate), pyrazinamide, etionamide, prothionamide, rifampicin, streptomycin sulfate, canamycin sulfate, cycloserine and the like.
(iv) Acid-fast bacillus diaphenyl sulfone, rifampicin, etc.
(v) Antiviral drugs Idoxuridine, acyclovir, vitaminabin, ganciclovir, etc.

(vi) Anti-HIV drugs zidovudine, didanosine, zalcitabine, indinavir sulfate ethanol adduct, ritonavir, etc.
(vii) Anti-spirochetes
(viii) Antibiotics Tetracycline hydrochloride, ampicillin, piperacillin, gentamycin, dibecasin, canendomycin, ribidomycin, tobramycin, amicacin, fraidomycin, cisomycin, tetracycline, oxytetracycline, lolitetracycline, doxicycline, ticarcillin, cephalotin, cephalotin , Cefacrol, cephalexin, cefloxazine, cefadoroxyl, cefamandole, cephotoam, cefromoxime, cefotiam, cefotiam hexetyl, cefloxim axetyl, cefzinyl, cefditoren pivoxil, ceftadidim, cefpyramid, cefmenoxime, cefmenoxime Cefpirom, cefazoplan, cefepime, cefslogin, cefmenoxime, cefmethazole, cefminox, cefoxitin, cefbuperazone, ratamokinacef, fromoxef, cefazolin, cefotaxim, cefoperazone, ceftizoxime, cefoperazone, ceftizoxime, moxalactam -Antibiotics (J. Antibiotics), 38,877-885 (1985)], azole compounds [2-[(1R, 2R) -2- (2,4-difluorophenyl) -2-hydroxy-1- Methyl-3- (1H-1,2,4-triazol-1-yl) propyl] -4- [4- (2,2,3,3-tetrafluoropropoxy) phenyl] -3- (2H, 4H) -1,2,4-triazolone, fluconazole, itraconazole, etc.] etc.

(2) Antifungal drug
(i) Polyethylene antibiotics (eg, amphotericin B, nystatin, tricomycin)
(ii) Griseofulvin, pyrrolnitrin, etc.
(iii) Cytosine antimetabolite (eg, flucytosine)
(iv) Imidazole derivatives (eg, econazole, clotrimazole, miconazole nitrate, bifonazole, clotrimazole)
(v) Triazole derivatives (eg, fluconazole, itraconazole)
(vi) Thiocarbamic acid derivatives (eg, trinaphthol) and the like.
(3) Antiprotozoal agents Metronidazole, tinidazole, diethylcarbamazine citrate, quinine hydrochloride, quinine sulfate, etc.

(4) Antitussives and abstinence agents Efedrin hydrochloride, noscapine hydrochloride, codeine phosphate, dihydrocodein phosphate, isoproterenol hydrochloride, methylephedrine hydrochloride, allocramide, chlorfedianol, picoperidamine, cloperastin, protoquilol, isoproterenol, salbutamol , Tereptalin, oxypetevanol, morphine hydrochloride, dextropetorphan hydrobromide, oxycodon hydrochloride, dimorphan phosphate, tipepidin hibisate, pentoxiberin citrate, clofedanol hydrochloride, benzonate, guayphenesin, bromhexine hydrochloride, ambroki hydrochloride Sole, acetyl cysteine, ethyl cysteine hydrochloride, carbo cysteine, etc.
(5) Sedatives Chlorpromazine hydrochloride, atropin sulfate, phenobarbital, barbital, amobarbital, pentobarbital, thiopental sodium, thiamiral sodium, nitrazepam, estazolam, flunitrazepam, haloxazolam, triazolam, flunitrazepam, bromvalerylurea Sodium etc.

(6) Anesthetic (6-1) Local anesthetic Cocaine hydrochloride, procaine hydrochloride, lidocaine, dibucaine hydrochloride, tetracaine hydrochloride, mepivacaine hydrochloride, bupivacaine hydrochloride, oxybuprocaine hydrochloride, ethyl aminobenzoate, oxesazein, etc.
(6-2) General anesthetic
(i) Inhalational anesthetics (eg ether, halothane, nitrous oxide, influenza, enflurane),
(ii) Intravenous anesthetics (eg, ketamine hydrochloride, droperidol, sodium thiopental, sodium thiamiral, pentobarbital), etc.
(7) Anti-ulcer agents Histidine hydrochloride, lansoprazole, metclopramide, pirenzepine, cimetidine, ranitidine, famotidine, urogastrin, oxesazein, proglumide, omeprazole, sucralfate, sulpylide, cetraxate, gefarnate, aldioxa, teprenone, prostagland.
(8) Antiarrhythmic drug
(i) Sodium channel blockers (eg, quinidine, procainamide, disopyramide, azimarin, lidocaine, mexiletine, phenytoin),
(ii) Beta blockers (eg, propranolol, alpenolol, bufetrol hydrochloride, oxprenolol, atenolol, acebutolol, metoprolol, bisoprolol, pindolol, carteolol, arotinolol hydrochloride),
(iii) Potassium channel blockers (eg amiodarone),
(iv) Calcium channel blockers (eg verapamil, diltiazem), etc.

(9) Antihypertensive diuretics Hexamethonium bromide, chronidine hydrochloride, hydrochlorothiazide, trichlormethiazide, furosemide, etacrynic acid, bumetanide, mefluside, azosemide, spironolactone, potassium canrenoate, triamterene, amylolide, acetazolamide, D-mannitol, isosorbide, amino etc.
(10) Anticoagulants Sodium heparin, sodium citrate, activated protein C, tissue factor pathway inhibitor, antithrombin III, sodium dalteparin, warfarin potassium, argatroban, gabexate, ozagrel sodium, ethyl icosapentate, sodium veraprost, al Prostadil, ticlopidine hydrochloride, pentoxyphilin, dipyridamole, thisokinase, urokinase, streptokinase, etc.
(11) Mental stabilizers Diazepam, lorazepam, oxazepam, chlordiazepoxide, medazepam, oxazolam, cloxazolam, clotiazepam, bromazepam, etizolam, fludiazepam, hydroxydine and the like.
(12) Antipsychotics Chlorpromazine hydrochloride, prochlorperazine, trifloperazine, thioridazine hydrochloride, perphenazine maleate, fluphenazine enanthate, prochlorperazine maleate, levomepromazine maleate, promethazine hydrochloride, haloperidol, bromperidol , Spiperone, Reselpin, Chlorpromazine hydrochloride, Sulpyride, Zotepine, etc.

(13) Antitumor drug 6-O- (N-chloroacetylcarbamoyl) fumaguilol, bleomycin, methotrexate, actinomycin D, mitomycin C, daunorubicin, adriamycin, neocultinostatin, citocin arabinoside, fluorouracil, tetrahydrofuryl-5 -Fluorouracil, pisibanil, lentinan, levamizol, bestatin, adimexone, glycyrrhizin, doxorubicin hydrochloride, acralubicin hydrochloride, bleomycin hydrochloride, heplomycin sulfate, vincristine sulfate, binblastin sulfate, irinotecan hydrochloride, cyclophosphamide, melphalan, zusulfan, thiotepa , Cisplatin, azathiopurine, mercaptopurine, tegafur, carmofur, citarabin, methyltestosterone, propionate testosterone, enanthate testosterone, mepitiostan, phosfestol, chlormaginone acetate, leuprorelin acetate, bucererin acetate, etc.
(14) Antihyperlipidemic drug clofibrate, 2-chloro-3- [4- (2-methyl-2-phenylpropoxy) phenyl] ethyl propionate [Chem. Pharm. Bull, 38,279-2-2796 (1990) )], Pravastatin, Cymbastatin, Probucol, Bezafibrate, Clinofibrate, Nicomol, Cholestilamine, Sodium dextran sulfate, etc.
(15) Muscle relaxants Pridinol, tubocurarine, pancuronium, tolperisone hydrochloride, chlorphenesine carbamate, baclofen, chlormezanone, mephenesin, clozoxazone, eperisone, tizanidine and the like.
(16) Antiepileptic drugs Phenytoin, ethosuximide, acetazolamide, chlordiazepoxide, trypetadione, carbamazepine, phenobarbital, primidone, sultium, sodium valproate, clonazepam, diazepam, nitrazepam, etc.

(17) Antidepressants Imipramine, chromipramine, noxiptiline, phenelzine, amitriptyline hydrochloride, nortriptyline hydrochloride, amoxapine, myanserin hydrochloride, maprotiline hydrochloride, sulfiride, fluvoxamine maleate, trazodone hydrochloride and the like.
(18) Antiallergic agents diphenhydramine, chlorpheniramine, tryperenamine, metodiramine, cremizol, diphenylpyraline, methoxyphenamine, sodium cromoglycate, tranilast, repyrinast, amlexanox, ibudilast, ketotifen, terphenazine, mequitazine, azelastine hydrochloride, epinastine , Pranlukast hydrate, Ceratrodust, etc.
(19) Cardiotonic agents Transbioxocamphor, terephyllol, aminophylline, etilefrine, dopamine, dobutamine, denopamine, vesinarin, amrinone, pimobendan, ubidecalenone, digitoxin, digoxin, methyldigoxin, lanatoside C, G-strophanthin and the like.
(20) Vasodilators Oxyfedrin, diltiazem, tolazoline, hexobenzine, bamethane, clonidine, methyldopa, guanabenz and the like.
(21) Vasoconstrictor Dopamine, dobutamine denopamine, etc.
(22) Antihypertensive diuretic Hexamethonium bromide, pentolinium, mechamilamine, ecarazine, clonidine, diltiazem, nifedipine and the like.
(23) Antidiabetic agents Tolbutamide, chlorpropamide, acetohexamide, glibenclamide, tolazamide, acarbose, epalrestat, troglitazone, glucagon, glymidin, glypzide, fenformin, pformin, metformin and the like.

(24) Narcotic antagonist levallorphan, nalorphine, naloxone or a salt thereof, etc.
(25) Fat-soluble vitamin drugs
(i) Vitamin A: Vitamin A ₁ , Vitamin A ₂ and retinol palmitate
(ii) Vitamins: Vitamins D ₁ , D ₂ , D ₃ , D ₄ and D ₅
(iii) Vitamin Es: α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, dl-α-tocopherol nicotinate
(iv) Vitamins K: Vitamins K ₁ , K ₂ , K ₃ and K ₄
(v) Folic acid (vitamin M), etc.
(26) Vitamin Derivatives Various vitamin derivatives such as vitamin D ₃ derivatives such as 5,6-trans-choleciferol, 2,5-hydroxycholecalciferol, and 1-α-hydroxycholecalciferol, 5,6- Vitamin D ₂ derivatives such as trans-ergocalciferol.
(27) Anti-asthmatic agents Isoprenalin hydrochloride, salbutamol sulfate, procaterol hydrochloride, terbutaline sulfate, trimetokinol hydrochloride, tulobuterol hydrochloride, orsiprenalin sulfate, phenotelol hydrobromide, ephedrine hydrochloride, iprotropium bromide, oxytropium bromide, bromide Flutropium, theophylline, aminophylline, sodium cromoglycate, tranilast, lepyrinast, anlexanone, ibudilast, ketotiphen, terbutaline, mequitadine, azelastine, ephedrine, ozagrel hydrochloride, planlcast hydrate, ceratrodust, dexamethasone, prednisolone, hydrocorthizone. , Becromethasone propionate, etc.
(28) Frequent urination / urinary incontinence therapeutic agent Flavoxate hydrochloride, etc.
(29) Atopic dermatitis therapeutic agent Sodium cromoglycate and the like.

(30) Therapeutic agent for allergic rhinitis Sodium cromoglycate, chlorpheniramine maleate, alienmemazine tartrate, clemastine fumarate, homochlorcyclizine hydrochloride, fexofenadine, mequitazine and the like.
(31) Pressor agents Dopamine, dobutamine, denopamine, digitoxin, digoxin, methyldigoxin, lanatoside C, G-strophanthin and the like.
(32) Others Hydroxycam, diacelin, megestrol acetic acid, fake logoline, prostaglandins, etc.

In the case of concomitant use, the administration time of the compound of the present invention and the concomitant drug is not limited, and the compound of the present invention and the concomitant drug may be administered to the administration subject at the same time or at a time lag. The dose of the concomitant drug may be based on the dose clinically used, and can be appropriately selected depending on the administration target, administration route, disease, combination and the like.
The administration form of the combination is not particularly limited, and the compound of the present invention and the concomitant drug may be combined at the time of administration. Such administration forms include, for example, (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and the concomitant drug, and (2) obtaining the compound of the present invention and the concomitant drug separately. Simultaneous administration of two preparations on the same route of administration, (3) Administration of two preparations obtained by separately formulating the compound of the present invention and a concomitant drug on the same route of administration, (4) Simultaneous administration of two preparations obtained by separately formulating the compound of the present invention and the concomitant drug by different routes of administration, (5) Differences between the two preparations obtained by separately formulating the compound of the present invention and the concomitant drug Administration with a time lag in the administration route (for example, administration of the concomitant drug after administration of the compound of the present invention, or administration in the reverse order) and the like can be mentioned.
The compounding ratio of the compound of the present invention and the concomitant drug in the concomitant drug of the present invention can be appropriately selected depending on the administration target, administration route, disease and the like.
For example, the content of the compound of the present invention in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, based on the whole preparation. More preferably, it is about 0.5 to 20% by weight.

The content of the concomitant drug in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, more preferably about the entire preparation. It is about 0.5 to 20% by weight.
The content of additives such as carriers in the concomitant drug of the present invention varies depending on the form of the preparation, but is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the whole preparation. ..
Further, when the compound of the present invention and the concomitant drug are separately formulated, the same content may be used.
The dose may vary depending on the type of the compound of the present invention, administration route, symptoms, age of the patient, etc., but for example, rheumatoid arthritis, cachexia, inflammatory bowel disease, Schegren's syndrome, Bechet's disease, multiple sclerosis, systemic When orally administered to patients with erythematosus, leukemia, uterine smooth muscle tumor, prostate cancer, multiple myeloma, cachexia, myelopathy, etc. (body weight about 60 kg), the compound (I) per kg body weight per day As a free form, about 0.1 mg / kg body weight to about 50 mg / kg body weight, preferably about 1 mg / kg body weight to 30 mg / kg body weight may be administered once to several times a day.
When the pharmaceutical composition of the present invention is a sustained-release preparation, the doses include the type and content of compound (I), dosage form, duration of drug release, and target animal (eg, mouse, rat, hamster, guinea pig). , Rabbits, cats, dogs, cows, horses, pigs, sheep, monkeys, humans and other mammals), although it varies depending on the purpose of administration, for example, when applied by parenteral administration, it is about 0.1 per week. About 100 mg of compound (I) may be released from the dosing regimen.

The concomitant drug can be set in any amount as long as side effects are not a problem. The daily dose as a concomitant drug may vary depending on the severity of symptoms, age, gender, body weight, sensitivity difference, time and interval of administration, properties of pharmaceutical product, preparation, type, type of active ingredient, etc. Although not particularly limited, the amount of the drug is usually, for example, about 0.001 to 2000 mg, preferably about 0.01 to 500 mg, and more preferably about 0.1 to 100 mg per 1 kg body weight of the mammal by oral administration. Obtained, which can usually be administered in 1 to 4 divided doses daily.
When administering the concomitant drug of the present invention, the compound of the present invention and the concomitant drug may be administered at the same time or at different times. When administered at different times, the time difference varies depending on the active ingredient to be administered, the dosage form, and the administration method. For example, when the concomitant drug is administered first, it is preferably within 1 minute to 3 days after the concomitant drug is administered. Examples thereof include a method of administering the compound of the present invention within 10 minutes to 1 day, more preferably within 15 minutes to 1 hour. When the compound of the present invention is administered first, a method of administering the concomitant drug within 1 minute to 1 day, preferably within 10 minutes to 6 hours, more preferably within 15 minutes to 1 hour after the administration of the compound of the present invention. Can be mentioned.

The present invention will be further described in detail by the following Examples, Test Examples and Formulation Examples, but these are not limited to the present invention and may be changed without departing from the scope of the present invention.
"Room temperature" in the following examples usually indicates about 10 ° C to about 35 ° C. The ratio shown in the mixed solvent indicates the volume ratio unless otherwise specified. % Indicates weight% unless otherwise specified.
Unless otherwise specified, the elution in the column chromatography of the example was carried out under observation by TLC (Thin Layer Chromatography, thin layer chromatography). In the TLC observation, 60 F ₂₅₄ manufactured by Merck & Co., Inc. was used as the TLC plate, and the solvent used as the elution solvent in the column chromatography was used as the developing solvent. In addition, a UV detector was used for detection. In silica gel column chromatography, aminopropylsilane-bonded silica gel was used when it was described as NH, and 3- (2,3-dihydroxypropoxy) propylsilane-bonded silica gel was used when it was described as Diol. In preparative HPLC (high performance liquid chromatography), when described as C18, octadecyl-bonded silica gel was used. The ratio shown in the elution solvent indicates the volume ratio unless otherwise specified.
^{1 1} H NMR analysis used ACD / SpecManager (trade name) software or the like. Peaks with very gentle proton peaks such as hydroxyl groups and amino groups may not be described.
MS was measured by LC / MS. As the ionization method, the ESI method or the APCI method was used. The data shows the measured value (found). Usually, a molecular ion peak is observed, but it may be observed as a fragment ion. In the case of salts, free molecular ion peaks or fragment ion peaks are usually observed.
The unit of sample concentration (c) in optical rotation ([α] _D ) is g / 100 mL.
The elemental analysis value (Anal.) Is shown as a calculated value (Calcd) and an actually measured value (Found).
The peak by powder X-ray diffraction of the example means a peak measured at room temperature using Cu Kα ray as a radiation source and using Ultima IV (Rigaku Corporation, Japan). The measurement conditions are as follows.
Electric pressure / Electric current: 40 kV / 50 mA
Scan speed: 6 degree / min
Scan range of 2 Theta: 2-35 degree
The crystallinity of the examples by powder X-ray diffraction was calculated by the Hermans method.

The following abbreviations are used in the following examples.
MS: Mass spectrum N: Normality CDCl ₃ : Deuterated chloroform DMSO-d ₆ : Deuterated dimethyl sulfoxide
¹ H NMR: Proton Nuclear Magnetic Resonance LC / MS: Liquid Chromatograph Mass Spectrometer ESI: electrospray ionization, Electrospray Ionization APCI: atomospheric pressure chemical ionization, atmospheric pressure chemical ionization
WSC: N- (3- (dimethylamino) propyl) -N'-ethylcarbodiimide
IPE: 2-isopropoxypropane
DIPEA: N-ethyl-N-isopropylpropan-2-amine
DMF: N, N-dimethylformamide
HOBt: 1H-benzotriazole-1-ol
THF: tetrahydrofuran
MeOH: Methanol
WSC · HCl: N- (3- (dimethylamino) propyl) -N'-ethylcarbodiimide hydrochloride (1: 1)
DMSO: Dimethyl sulfoxide
TEA: Triethylamine
TMSCl: Trimethylsilyl chloride

Example 1
2- (4-((4-Hydroxy-4-phenylcyclohexyl) amino) -2-oxo-1,2-dihydropyridine-3-yl) -1H-thieno [2,3-d] imidazole-5-carbonitrile
A) Methyl 5-amino-4-(((4-iodo-2-methoxypyridin-3-yl) carbonyl) amino) thiophene-2-carboxylate
A mixture of 4-iodo-2-methoxynicotinic acid (5.02 g), methyl 4,5-diaminothiophen-2-carboxylate (3.72 g) and DMF (dry) (90 ml) with HOBt (3.16 g) and WSC. HCl (4.49 g) was added at 0 ° C. The mixture was stirred overnight at room temperature under an argon atmosphere. Water was added to the mixture at room temperature, and the mixture was extracted twice with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (5.81 g).
MS: [M + H] ⁺ 434.

B) Methyl 2- (4-iodo-2-methoxypyridin-3-yl) -1H-thieno [2,3-d] imidazole-5-carboxylate Methyl 5-amino-4-(((4-iodo-) To a mixture of 2-methoxypyridin-3-yl) carbonyl) amino) thiophen-2-carboxylate (3.80 g) and pyridine (17 ml) was added trichloride (28.0 g) phosphate at 0 ° C. The mixture was stirred at 80 ° C. for 2.5 hours under a nitrogen atmosphere. The mixture was poured into ice water, the resulting solid was collected by filtration, washed with water and dried to give the title compound (3.14 g).
MS: [M + H] ⁺ 415.9.

C) 2- (4-Iodo-2-methoxypyridin-3-yl) -1H-thieno [2,3-d] imidazole-5-carboxylic acid methyl 2- (4-iodo-2-methoxypyridin-3-yl) L ) (10.11 g) was added at room temperature. The mixture was stirred at 80 ° C. for 2 hours. Water was added to the mixture at room temperature and THF was distilled off. The mixture was neutralized with 2N hydrochloric acid at 0 ° C and stirred at 0 ° C for 5 minutes. The resulting solid was collected by filtration, washed with water and dried to give the title compound (18.52 g).
MS: [M + H] ⁺ 402.0.

D) 2- (4-Iodo-2-methoxypyridin-3-yl) -1H-thieno [2,3-d] imidazole-5-carboxamide
1H-benzotriazole in a mixture of 2- (4-iodo-2-methoxypyridin-3-yl) -1H-thieno [2,3-d] imidazole-5-carboxylic acid (16.87 g) and DMF (340 ml) -1-Ammonia sum (1: 1) (12.80 g) and WSC / HCl (16.12 g) were added at room temperature. The mixture was stirred at room temperature for 2.5 hours. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained solid was crystallized from DMF / ethyl acetate / IPE to give the title compound (12.14 g).
MS: [M + H] ⁺ 401.1.

E) 2- (4-Iodo-2-methoxypyridin-3-yl) -1H-thieno [2,3-d] imidazol-5-carbonitrile
2- (4-Iodo-2-methoxypyridin-3-yl) -1H-thieno [2,3-d] imidazole-5-carboxamide (12.14 g), pyridine (9.60 g) and THF (240 ml) mixture Trifluoroacetic acid anhydride (17.20 g) was added to the mixture at 0 ° C. The mixture was stirred at room temperature for 1 hour. The mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane) to give the title compound (10.46 g).
MS: [M + H] ⁺ 383.0.

F) 2- (4-iodo-2-oxo-1,2-dihydropyridine-3-yl) -1H-thieno [2,3-d] imidazol-5-carbonitrile
TMSCl (TMSCl (340 ml) in a mixture of 2- (4-iodo-2-methoxypyridin-3-yl) -1H-thieno [2,3-d] imidazole-5-carbonitrile (14.3 g) and CH ₃ CN (340 ml) 32.5 g) and sodium iodide (11.22 g) were added at room temperature. The mixture was stirred at 60 ° C. for 15 hours under an argon atmosphere. Water (150 ml) was added to the mixture at room temperature, the resulting solid was collected by filtration and washed with water and IPE to give the title compound (12.3 g).
MS: 369.0.

G) tert-butyl (4-hydroxy-4-phenylcyclohexyl) carbamate
A butyl ether solution of phenyllithium (30.6 ml) was added to a mixture of tert-butyl (4-oxocyclohexyl) carbamate (4.97 g) and THF (dry) (150 ml) at -78 ° C. The mixture was stirred at −78 ° C. for 1.5 hours under an argon atmosphere. Water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained solid was washed with diethyl ether / hexane to give the title compound (2.5 g).
^{1 1} H NMR (300 MHz, CDCl ₃ ) δ 1.46 (9H, s), 1.59-2.06 (9H, m), 3.29-3.75 (1H, m), 4.48 (1H, brs), 7.21-7.29 (1H, m) ), 7.31-7.40 (2H, m), 7.44-7.52 (2H, m).

H) 4-Amino-1-phenylcyclohexanol hydrochloride
A 2 N hydrogen chloride methanol solution (12.87 ml) was added to a mixture of tert-butyl (4-hydroxy-4-phenylcyclohexyl) carbamate (500 mg) and MeOH (12 ml) at 0 ° C. The mixture was stirred at room temperature for 7 hours. Ethyl acetate (150 ml) and heptane (150 ml) were added to the mixture and the resulting solid was washed with ethyl acetate / heptane (1/1) to give the title compound (257 mg).
^{1 1} H NMR (300 MHz, DMSO-d ₆ ) δ 1.51-2.08 (8H, m), 2.95-3.21 (1H, m), 4.94 (1H, s), 7.15-7.25 (1H, m), 7.25-7.37 (2H, m), 7.42-7.55 (2H, m), 8.17 (3H, brs).

I) 2- (4-((4-Hydroxy-4-phenylcyclohexyl) amino) -2-oxo-1,2-dihydropyridine-3-yl) -1H-thieno [2,3-d] imidazole-5- Carbonitrile
2- (4-Iodo-2-oxo-1,2-dihydropyridine-3-yl) -1H-thieno [2,3-d] imidazol-5-carbonitrile (86.6 mg) and DMF (dry) (1.8 ml) ) To a mixture of TEA (95 mg) and 4-amino-1-phenylcyclohexanol hydrochloride (1: 1) (94 mg) at room temperature. The mixture was stirred at 80 ° C. for 1 hour under an argon atmosphere. Further, the mixture was stirred at 60 ° C. for 15 hours under an argon atmosphere. DMF (3.6 ml) was added to the mixture at 80 ° C. Further, water (0.5 ml) was added to the mixture, and the resulting solid was collected by filtration and washed with DMF / water (1/1) and IPE. The resulting solid was crystallized from DMF / ethyl acetate / heptane to give the title compound (31 mg).
¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.63-2.11 (8H, m), 3.75 (1H, d, J = 7.2 Hz), 4.95 (1H, s), 6.25 (1H, d, J = 7.6) Hz), 7.15-7.27 (1H, m), 7.28-7.42 (3H, m), 7.53 (2H, d, J = 7.2 Hz), 7.85 (1H, brs), 9.90-10.41 (1H, m), 11.28 (1H, brs), 13.43 (1H, brs).

Example compounds are shown in Table 1 below. MS in the table shows the measured value. The compounds of Examples 2 to 23 in the table below were prepared according to the method shown in the above Examples or a method similar thereto.

Formulation Example 1 (manufacturing of capsules)
1) Compound of Example 1 30 mg
2) Fine powdered cellulose 10 mg
3) Lactose 19 mg
4) Magnesium stearate 1 mg
60 mg in total
1), 2), 3) and 4) are mixed and filled in gelatin capsules.

Formulation Example 2 (Manufacturing of tablets)
1) Compound of Example 1 30 g
2) Lactose 50 g
3) Corn starch 15 g
4) Carboxymethyl cellulose calcium 44 g
5) Magnesium stearate 1 g
1000 tablets total 140 g
The whole amount of 1), 2) and 3) and 30 g of 4) are kneaded with water, vacuum dried, and then granulated. 14 g of 4) and 1 g of 5) are mixed with this sized powder and locked with a lock press. In this way, 1000 tablets containing 30 mg of the compound of Example 1 per tablet are obtained.

Test Example 1 JAK1 enzyme inhibition test The JAK1 enzyme inhibition activity of the test compound was measured by the LANCE method (PerkinElmer). First, 2 μL of each test compound diluted with assay buffer (50 mM HEPES (pH 7.5), 10 mM MgCl ₂ , 1 mM EGTA, 2 mM DTT, 0.01% Tween 20, 0.01% BSA) was added to a 384-well plate. .. Next, 2 μL of a solution diluted with 187.5 ng / mL of JAK1 (Invitrogen) and 300 nM of fluorescently labeled peptide substrate (ULight-JAK1, Perkin Elmer) was added, and then the assay was performed to 150 μM. The enzymatic reaction was started by adding 2 μL of the ATP solution prepared in buffer. After reacting at room temperature for 1 hour, 6 μL of Detection Buffer (PerkinElmer) prepared to become a 20 mM EDTA, 4 nM europium-labeled anti-phosphorylated tyrosine antibody (PerkinElmer) was added. After allowing to stand at room temperature for 1 hour, the fluorescence intensity (excitation wavelength 340 nm, fluorescence wavelength 665 nm, delay time 100 microseconds) was measured with a plate reader Envision (PerkinElmer). The inhibitory activity of each compound was calculated as a relative activity value with 100% inhibition of the fluorescence intensity of the well without enzyme. The results are shown in Table 2.

Test Example 2 JAK2 enzyme inhibition test The JAK2 enzyme inhibition activity of the test compound was measured by the LANCE method (PerkinElmer). First, 2 μL of each test compound diluted with assay buffer (50 mM HEPES (pH 7.5), 10 mM MgCl ₂ , 1 mM EGTA, 2 mM DTT, 0.01% Tween 20, 0.01% BSA) was added to a 384-well plate. .. Next, 2 μL of a solution diluted with 6 ng / mL of JAK2 (Invitrogen) and 300 nM of fluorescently labeled peptide substrate (ULight-JAK1, Perkin Elmer) was added, and then with an assay buffer of 45 μM. The enzymatic reaction was started by adding 2 μL of the prepared ATP solution. After reacting at room temperature for 1 hour, 6 μL of Detection Buffer (PerkinElmer) prepared to become a 20 mM EDTA, 4 nM europium-labeled anti-phosphorylated tyrosine antibody (PerkinElmer) was added. After allowing to stand at room temperature for 1 hour, the fluorescence intensity (excitation wavelength 340 nm, fluorescence wavelength 665 nm, delay time 100 microseconds) was measured with a plate reader Envision (PerkinElmer). The inhibitory activity of each compound was calculated as a relative activity value with 100% inhibition of the fluorescence intensity of the well without enzyme. The results are shown in Table 2.

Test Example 3 JAK3 enzyme inhibition test The JAK3 enzyme inhibition activity of the test compound was measured by the LANCE method (PerkinElmer). First, 2 μL of each test compound diluted with assay buffer (50 mM HEPES (pH 7.5), 10 mM MgCl ₂ , 1 mM EGTA, 2 mM DTT, 0.01% Tween 20, 0.01% BSA) was added to a 384-well plate. .. Next, 2 μL of a solution diluted with 12 ng / mL of JAK3 (Invitrogen) and 300 nM of fluorescently labeled peptide substrate (ULight-JAK1, Perkin Elmer) was added, and then with an assay buffer of 15 μM. The enzymatic reaction was started by adding 2 μL of the prepared ATP solution. After reacting at room temperature for 1 hour, 6 μL of Detection Buffer (PerkinElmer) prepared to become a 20 mM EDTA, 4 nM europium-labeled anti-phosphorylated tyrosine antibody (PerkinElmer) was added. After allowing to stand at room temperature for 1 hour, the fluorescence intensity (excitation wavelength 340 nm, fluorescence wavelength 665 nm, delay time 100 microseconds) was measured with a plate reader Envision (PerkinElmer). The inhibitory activity of each compound was calculated as a relative activity value with 100% inhibition of the fluorescence intensity of the well without enzyme. The results are shown in Table 2.

Test Example 4 TYK2 enzyme inhibition test The TYK2 enzyme inhibition activity of the test compound was measured by the LANCE method (PerkinElmer). First, 2 μL of each test compound diluted with assay buffer (50 mM HEPES (pH 7.5), 10 mM MgCl ₂ , 1 mM EGTA, 2 mM DTT, 0.01% Tween 20, 0.01% BSA) was added to a 384-well plate. .. Next, 2 μL of a solution diluted with TYK2 (Invitrogen) at 375 ng / mL and a fluorescently labeled peptide substrate (ULight-JAK1, Perkin Elmer) at 300 nM was added in 2 μL each, and then in an assay buffer at 30 μM. The enzymatic reaction was started by adding 2 μL of the prepared ATP solution. After reacting at room temperature for 1 hour, 6 μL of Detection Buffer (PerkinElmer) prepared to become a 20 mM EDTA, 4 nM europium-labeled anti-phosphorylated tyrosine antibody (PerkinElmer) was added. After allowing to stand at room temperature for 1 hour, the fluorescence intensity (excitation wavelength 340 nm, fluorescence wavelength 665 nm, delay time 100 microseconds) was measured with a plate reader Envision (PerkinElmer). The inhibitory activity of each compound was calculated as a relative activity value with 100% inhibition of the fluorescence intensity of the well without enzyme. The results are shown in Table 2.

The compound of the present invention may have an excellent JAK inhibitory effect, and may have autoimmune diseases (rheumatoid arthritis, cachexia, inflammatory bowel disease, Schegren's syndrome, Bechet's disease, multiple myeloma, systemic erythematosus, etc.), cancer (leukemia, etc.) It may be useful as a prophylactic or therapeutic agent for uterine smooth muscle tumor, prostate cancer, multiple myeloma, cachexia, myelofibrosis, etc.).

Claims (5)

Equation (I):

[In the formula, R ¹ , R ² , R ³ , R ⁴ and R ⁵ each independently indicate a hydrogen atom or a substituent. ] The compound represented by] or a salt thereof. A medicament containing the compound according to claim 1 or a salt thereof. The medicament according to claim 2, which is a Janus kinase inhibitor. The medicament according to claim 2, which is a prophylactic or therapeutic agent for autoimmune diseases. The medicament according to claim 4, wherein the autoimmune disease is systemic lupus erythematosus, inflammatory bowel disease, psoriasis, rheumatoid arthritis, Sjogren's syndrome, Behcet's disease, or multiple sclerosis.