Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/404—Indoles, e.g. pindolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/415—1,2-Diazoles
  • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems

Definitions

• the present invention relates to an indole compound and its pharmaceutical use, and more specifically, an inflammatory disease or allergy through suppression of the function of Th2 cells and / or mast cells by inhibition of inducible T cell kinase (ITK).
• ITK inducible T cell kinase
• the present invention relates to compounds for the prevention or treatment of sex diseases, autoimmune diseases and rejection in transplantation, and suppression of rejection in transplantation, and the use thereof.
• ITK is a non-receptor tyrosine kinase belonging to the Tec family essential for T cell activation, and is mainly expressed in T cells, mast cells, and natural killer cells. ITK is activated in T cells when a T cell receptor (TCR) is stimulated, and activated in mast cells when a high affinity immunoglobulin (Ig) E receptor is activated. Following receptor stimulation in T cells, Lck, a member of the Src tyrosine kinase family, phosphorylates Y511 in the kinase domain activation loop of ITK. Activated ITK is required for phosphorylation and activation of PLC- ⁇ along with Zap-70.
• TCR T cell receptor
• Ig immunoglobulin
• PLC- ⁇ catalyzes the formation of inositol 1,4,5-trisphosphate and diacylglycerol, causing calcium mobilization and PKC activation, respectively. These events activate many lower pathways, ultimately leading to cytokine production in T cells and degranulation in mast cells.
• Th2 cells are one type of CD4-positive helper T cells (Th cells), and differentiate from naive T cells by antigen stimulation to produce cytokines.
• Cytokines such as interleukin (IL) -4, IL-5, and IL-13 produced by Th2 cells are called Th2 cytokines, and are a type of granulocyte that enhances antibody production by plasma cells differentiated from B cells. It is known to be involved in mechanisms such as allergic diseases by activating cells such as certain eosinophils.
• Th1 cells that differentiate from naive T cells as well as Th2 cells produce so-called Th1 cytokines such as interferon (IFN) - ⁇ , and Th1 and Th2 cells suppress each other's functions and are called Th1 / Th2 balance. It is thought that a specific disease occurs in each case when this balance is tilted in either direction. ITK knockout mice have been reported to selectively inhibit Th2 cell differentiation and Th2 cytokine production.
• IFN interferon
• ITK Inhibition of ITK inhibits mast cell activation.
• chemical mediators such as histamine in mast cells.
• an antigen binds to IgE bound to the cell surface and the cross-linking is established, it activates the cell as a trigger.
• chemical mediators such as histamine as contents are released (degranulation).
• histamine has bronchial smooth muscle contraction action, vascular permeability enhancement action, mucus secretion action, etc., and causes asthma and allergic diseases.
• ITK inhibitors are involved by suppressing Th2 cell proliferation and Th2 cytokine production and / or suppressing degranulation and histamine production through suppression of mast cell activation. It is expected to be effective as a therapeutic or preventive agent for diseases that occur, such as inflammatory diseases and allergic diseases.
• ITK is also involved in the activation of Th17 cells, which are one type of Th cells, and ITK inhibitors treat or prevent diseases involving Th17 cells, for example, autoimmune diseases such as rheumatism. The effect is also expected as an agent.
• ITK is involved in the mixed lymphocyte reaction, and ITK inhibitors are expected to be effective as inhibitors of rejection in transplantation.
• ITK has been suggested to be involved in HIV infection, and ITK inhibitors are expected to be effective as preventive or therapeutic agents for HIV infection.
• An object of the present invention is to provide a therapeutic or preventive agent for inflammatory diseases based on an ITK inhibitory action, a therapeutic or preventive agent for allergic diseases, a therapeutic or prophylactic agent for autoimmune diseases, an inhibitor of rejection in transplantation, and the like.
• R 1 is (1) a hydrogen atom, (2) a hydroxy group, or (3) a C 1-6 alkoxy group optionally substituted with a C 6-10 aryl group
• R 2 and R 3 are the same or different and are each 1 to 3 substituents selected from (1) a hydrogen atom, or (2) (a) a hydroxy group, and (b) a C 1-6 alkoxy group.
• An optionally substituted C 1-6 alkyl group; R 4 is bonded to the 5th or 6th position of the indole ring.
• R 5 is (1) a hydrogen atom, or (2) a C 1-6 alkyl group
• R 6 is (1) a hydrogen atom, (2) (a) a hydroxy group, (B) a C 1-6 alkoxy group, (C) a carboxy group, (D) a C 1-6 alkoxy-carbonyl group, (E) a C 6-10 aryl group, (F) a C 6-10 aryloxy group, (G) an amino group optionally mono- or di-substituted with a C 1-6 alkyl group, (H) a 5- or 6-membered unsaturated heterocyclic group optionally substituted with a C 1-6 alkyl group, and (i) 1 to 3 substituents selected from a 5- or 6-membered saturated heterocyclic group A C 1-6 alkyl group optionally substituted by (3) a C 1-6 alkoxy group, (4) C 6-10 aryl group, or (5) (a) hydroxy group, and (b) optionally substituted with 1
• a 1-6 alkyl group and R 8 is (1) (a) a hydroxy group, (B) a C 1-6 alkoxy group optionally substituted with a C 6-10 aryl group, (C) a C 3-6 cycloalkyl group optionally substituted with a C 1-6 alkoxy group, (D) a C 6-10 aryl group, (E) a 5- or 6-membered unsaturated heterocyclic group optionally substituted with an oxo group, (F) (i) a hydroxy group, (Ii) a C 1-6 alkyl group which may be substituted with 1 to 3 substituents selected from a hydroxy group and a C 1-6 alkoxy group, (Iii) a C 1-6 alkoxy group, and (iv) a 5- to 8-membered saturated heterocyclic group optionally substituted with 1 to 3 substituents selected from oxo groups, (G) a C 3-6 cycloalkyloxy group, (H) a C 6-10
• R 1 is (1) a hydrogen atom, (2) a hydroxy group, or (3) a C 1-6 alkoxy group optionally substituted with a C 6-10 aryl group
• R 2 and R 3 are the same or different and are each 1 to 3 substituents selected from (1) a hydrogen atom, or (2) (a) a hydroxy group, and (b) a C 1-6 alkoxy group.
• An optionally substituted C 1-6 alkyl group; R 7 ' (A) a hydroxy group, (B) a C 1-6 alkoxy group, and (c) a C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from amino groups optionally mono- or di-substituted.
• a 1-6 alkyl group and R 8 is (1) (a) a hydroxy group, (B) a C 1-6 alkoxy group optionally substituted with a C 6-10 aryl group, (C) a C 3-6 cycloalkyl group optionally substituted with a C 1-6 alkoxy group, (D) a C 6-10 aryl group, (E) a 5- or 6-membered unsaturated heterocyclic group optionally substituted with an oxo group, (F) (i) a hydroxy group, (Ii) a C 1-6 alkyl group which may be substituted with 1 to 3 substituents selected from a hydroxy group and a C 1-6 alkoxy group, (Iii) a C 1-6 alkoxy group, and (1 v selected from i oxo groups) or a 5- to 8-membered saturated heterocyclic group optionally substituted by 3 substituents, (G) a C 3-6 cycloalkyloxy group, (H) a C 6
• R 1 is a hydrogen atom;
• R 7 ′ is a C 1-6 alkyl group
• R 8 is (A) a hydroxy group, (B) a C 1-6 alkoxy group optionally substituted with a C 6-10 aryl group, (C) a C 3-6 cycloalkyl group optionally substituted with a C 1-6 alkoxy group, (D) a C 6-10 aryl group, (E) a 5- or 6-membered unsaturated heterocyclic group optionally substituted with an oxo group, (F) (i) a hydroxy group, (Ii) a C 1-6 alkyl group which may be substituted with 1 to 3 substituents selected from a hydroxy group and a C 1-6 alkoxy group, (Iii) a C 1-6 alkoxy group, and (iv) a 5- to 8-membered saturated heterocyclic group optionally substituted with 1 to 3 substituents selected from oxo groups, (G) a C 3-6 cycloalkyloxy group,
• a pharmaceutical composition comprising the compound according to any one of [1] to [5] above or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
• An ITK inhibitor comprising the compound according to any one of [1] to [5] above or a pharmaceutically acceptable salt thereof.
• a therapeutic or prophylactic agent for inflammatory diseases comprising the compound according to any one of [1] to [5] above or a pharmaceutically acceptable salt thereof.
• the therapeutic or prophylactic agent according to the above [8], wherein the inflammatory disease is rheumatoid arthritis.
• a therapeutic or prophylactic agent for allergic diseases comprising the compound according to any one of [1] to [5] above or a pharmaceutically acceptable salt thereof.
• a therapeutic or prophylactic agent for autoimmune diseases comprising the compound according to any one of [1] to [5] above or a pharmaceutically acceptable salt thereof.
• the therapeutic or prophylactic agent according to the above [11], wherein the autoimmune disease is rheumatoid arthritis.
• An inhibitor of rejection in transplantation comprising the compound according to any one of [1] to [5] above or a pharmaceutically acceptable salt thereof.
• a mammal comprising administering to the mammal a pharmaceutically effective amount of the compound according to any one of [1] to [5] above or a pharmaceutically acceptable salt thereof.
• ITK inhibition method In a mammal, comprising administering to the mammal a pharmaceutically effective amount of the compound according to any one of [1] to [5] above or a pharmaceutically acceptable salt thereof.
• a method for the treatment or prevention of inflammatory diseases [16] The treatment or prevention method according to the above [15], wherein the inflammatory disease is rheumatoid arthritis.
• a mammal comprising administering to the mammal a pharmaceutically effective amount of the compound according to any one of [1] to [5] above or a pharmaceutically acceptable salt thereof. How to treat or prevent allergic diseases.
• a mammal comprising administering to the mammal a pharmaceutically effective amount of the compound according to any one of [1] to [5] above or a pharmaceutically acceptable salt thereof.
• Methods for treating or preventing autoimmune diseases [19] The treatment or prevention method according to the above [18], wherein the autoimmune disease is rheumatoid arthritis.
• [20] In the mammal, comprising administering to the mammal a pharmaceutically effective amount of the compound according to any one of [1] to [5] above or a pharmaceutically acceptable salt thereof.
• a method for suppressing rejection in transplantation [21] Use of the compound according to any one of [1] to [5] above or a pharmaceutically acceptable salt thereof for the manufacture of a therapeutic or prophylactic agent for inflammatory diseases. [22] The use according to [21] above, wherein the inflammatory disease is rheumatoid arthritis. [23] Use of the compound according to any one of [1] to [5] above or a pharmaceutically acceptable salt thereof for producing an agent for treating or preventing allergic diseases.
• R 1 ' (1) a hydrogen atom, (2) a hydroxy group, or (3) a C 1-6 alkoxy group optionally substituted with a C 6-10 aryl group;
• R 2 ′ and R 3 ′ are the same or different and each represents 1 to 3 substituents selected from (1) a hydrogen atom, or (2) (a) a hydroxy group, and (b) a C 1-6 alkoxy group.
• R 4 ′ is bonded to the 5th or 6th position of the indole ring
• R 5 ' (1) a hydrogen atom, or (2) a C 1-6 alkyl group
• R 6 ′ is (1) a hydrogen atom, (2) (a) a hydroxy group, (B) a C 1-6 alkoxy group, (C) a carboxy group, (D) a C 1-6 alkoxy-carbonyl group, (E) a C 6-10 aryl group, (F) a C 6-10 aryloxy group, (G) an amino group optionally mono- or di-substituted with a C 1-6 alkyl group, (H) a 5- or 6-membered unsaturated heterocyclic group optionally substituted with a C 1-6 alkyl group, and (i) 1 to 3 substituents selected from a 5- or 6-membered saturated heterocyclic group
• a C 1-6 alkyl group optionally substituted by (3) a C 1-6 alkoxy group, 5 or 6 which may be substituted with 1 to 3 substituents selected from (4) C 6-10 aryl group,
• a 1-6 alkyl group and R 8 ′ is (1) (a) a hydroxy group, (B) a C 1-6 alkoxy group optionally substituted with a C 6-10 aryl group, (C) a C 3-6 cycloalkyl group optionally substituted with a C 1-6 alkoxy group, (D) a C 6-10 aryl group, (E) a 5- or 6-membered unsaturated heterocyclic group optionally substituted with an oxo group, (F) (i) a hydroxy group, (Ii) a C 1-6 alkyl group which may be substituted with 1 to 3 substituents selected from a hydroxy group and a C 1-6 alkoxy group, (Iii) a C 1-6 alkoxy group, and (iv) a 5- to 8-membered saturated heterocyclic group optionally substituted with 1 to 3 substituents selected from oxo groups, (G) a C 3-6 cycloalkyloxy group, (H) a C
• R 1 ' (1) a hydrogen atom, (2) a hydroxy group, or (3) a C 1-6 alkoxy group optionally substituted with a C 6-10 aryl group
• R 2 ′ and R 3 ′ are the same or different and each represents 1 to 3 substituents selected from (1) a hydrogen atom, or (2) (a) a hydroxy group, and (b) a C 1-6 alkoxy group.
• R 7 ''' (A) a hydroxy group, (B) a C 1-6 alkoxy group, and (c) a C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from amino groups optionally mono- or di-substituted.
• a 1-6 alkyl group and R 8 ′ is (1) (a) a hydroxy group, (B) a C 1-6 alkoxy group optionally substituted with a C 6-10 aryl group, (C) a C 3-6 cycloalkyl group optionally substituted with a C 1-6 alkoxy group, (D) a C 6-10 aryl group, (E) a 5- or 6-membered unsaturated heterocyclic group optionally substituted with an oxo group, (F) (i) a hydroxy group, (Ii) a C 1-6 alkyl group which may be substituted with 1 to 3 substituents selected from a hydroxy group and a C 1-6 alkoxy group, (Iii) a C 1-6 alkoxy group, and (iv) a 5- to 8-membered saturated heterocyclic group optionally substituted with 1 to 3 substituents selected from oxo groups, (G) a C 3-6 cycloalkyloxy group, (H) a C
• a pharmaceutical composition comprising the compound according to [1 ′] or [2 ′] or a pharmaceutically acceptable salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier.
• An ITK inhibitor comprising the compound according to [1 ′] or [2 ′] or a pharmaceutically acceptable salt thereof, or a solvate thereof.
• [7 ′] A therapeutic or prophylactic agent for autoimmune diseases comprising the compound according to [1 ′] or [2 ′] above or a pharmaceutically acceptable salt thereof, or a solvate thereof.
• An inhibitor of rejection in transplantation comprising the compound according to [1 ′] or [2 ′] or a pharmaceutically acceptable salt thereof, or a solvate thereof.
• [9 ′] comprising administering to a mammal a pharmaceutically effective amount of the compound according to the above [1 ′] or [2 ′], or a pharmaceutically acceptable salt thereof, or a solvate thereof, A method for treating or preventing an inflammatory disease in the mammal.
• [10 ′] comprising administering to a mammal a pharmaceutically effective amount of the compound according to [1 ′] or [2 ′] above, or a pharmaceutically acceptable salt thereof, or a solvate thereof, A method for treating or preventing allergic diseases in the mammal.
• [11 ′] comprising administering to a mammal a pharmaceutically effective amount of the compound according to [1 ′] or [2 ′] or a pharmaceutically acceptable salt thereof, or a solvate thereof, A method for treating or preventing an autoimmune disease in the mammal.
• [12 ′] comprising administering to a mammal a pharmaceutically effective amount of the compound according to the above [1 ′] or [2 ′], or a pharmaceutically acceptable salt thereof, or a solvate thereof, A method for suppressing rejection in transplantation in the mammal.
• [13 ′] Use of the compound according to the above [1 ′] or [2 ′] or a pharmaceutically acceptable salt thereof, or a solvate thereof for the manufacture of a therapeutic or prophylactic agent for inflammatory diseases.
• the indole compound of the present invention effectively inhibits ITK activity, suppresses Th2 cell proliferation and activation, and / or suppresses mast cell activation, thereby inhibiting diseases associated with them, for example, It is effective as an agent for treating or preventing inflammatory diseases, an agent for treating or preventing allergic diseases, an agent for treating or preventing autoimmune diseases, and an inhibitor of rejection in transplantation.
• halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
• C 1-6 alkyl group means a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl Group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, 1,2-dimethylpropyl group, 1-ethylpropyl group, hexyl group, isohexyl group, 1,2,2- Examples include trimethylpropyl group, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 3,3-dimethylbutyl group, 2-ethylbutyl group and the like.
• the “C 1-6 alkoxy group” means a hydroxy group substituted with the above “C 1-6 alkyl group”, for example, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group , Sec-butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group, neopentyloxy group, 1,2-dimethylpropyloxy group, 1-ethylpropyloxy group, hexyloxy group, isohexyloxy group, Examples include 1,2,2-trimethylpropyloxy group, 1,1-dimethylbutyloxy group, 2,2-dimethylbutyloxy group, 3,3-dimethylbutyloxy group, 2-ethylbutyloxy group and the like.
• C 3-6 cycloalkyl group means a monocyclic saturated hydrocarbon group having 3 to 6 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
• C 3-6 cycloalkyloxy group means a hydroxy group substituted with the above “C 3-6 cycloalkyl group”, and examples thereof include a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, and a cyclohexyl group. An oxy group etc. are mentioned.
• C 6-10 aryl group means an aromatic hydrocarbon group having 6 to 10 carbon atoms, and examples thereof include a phenyl group, a 1-naphthyl group, and a 2-naphthyl group. Preferably, it is a phenyl group.
• the “C 6-10 aryloxy group” means a hydroxy group substituted with the above “C 6-10 aryl group”, and examples thereof include a phenoxy group, a 1-naphthyloxy group, a 2-naphthyloxy group, and the like. It is done. Preferably, it is a phenoxy group.
• the “5- or 6-membered unsaturated heterocyclic group” has 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom, and the number of atoms constituting the ring is 5 Or 6 monocyclic unsaturated or partially unsaturated heterocyclic groups, and when the group contains a sulfur atom as a hetero atom, the sulfur atom may be mono- or dioxidized.
• Examples of such a group include a furyl group, a thienyl group, a pyrrolyl group, an oxazolyl group, an oxazolinyl group, an isoxazolyl group, an isoxazolinyl group, a thiazolyl group, a thiazolinyl group, an isothiazolyl group, an isothiazolinyl group, an imidazolyl group, and an imidazolinyl group.
• the “5- or 6-membered unsaturated heterocyclic oxy group” means a hydroxy group substituted with the above “5- or 6-membered unsaturated heterocyclic group”, and examples thereof include a furyloxy group, a thienyloxy group, a pyrrolyloxy group.
• the “5- to 8-membered saturated heterocyclic group” has 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom, and the number of atoms constituting the ring is 5 to 5 It means a monocyclic saturated heterocyclic group which is 8 and when the group contains a sulfur atom as a hetero atom, the sulfur atom may be mono- or dioxidized.
• Examples of such groups include pyrrolidinyl group, tetrahydrofuryl group, tetrahydropyranyl group, tetrahydrothienyl group, tetrahydrothiopyranyl group, oxazolidinyl group, isoxazolidinyl group, thiazolidinyl group, isothiazolidinyl group, Imidazolidinyl group, pyrazolidinyl group, piperidyl group (including piperidino group), morpholinyl group (including morpholino group), thiomorpholinyl group (including thiomorpholino group), piperazinyl group, azepanyl group, azocanyl group, 1,1-dioxideisoti Azolidinyl group, 1,1-dioxidetetrahydrothienyl group, 1,1-dioxidetetrahydrothiopyranyl group, 1,1-dioxidethiomorpholinyl group (
• the “5- or 6-membered saturated heterocyclic group” means a group having 5 or 6 atoms constituting the ring in the above “5- to 8-membered saturated heterocyclic group”.
• pyrrolidinyl Group tetrahydrofuryl group, tetrahydropyranyl group, tetrahydrothienyl group, tetrahydrothiopyranyl group, oxazolidinyl group, isoxazolidinyl group, thiazolidinyl group, isothiazolidinyl group, imidazolidinyl group, pyrazolidinyl group, piperidinyl group (piperidino group) Group), morpholinyl group (including morpholino group), thiomorpholinyl group (including thiomorpholino group), piperazinyl group, 1,1-dioxideisothiazolidinyl group, 1,1-dioxidetetrahydrothienyl group, 1 1,
• the “5- or 6-membered saturated heterocyclic oxy group” means a hydroxy group substituted with the above “5- or 6-membered saturated heterocyclic group”, for example, a pyrrolidinyloxy group, a tetrahydrofuryloxy group, Tetrahydropyranyloxy group, tetrahydrothienyloxy group, tetrahydrothiopyranyloxy group, oxazolidinyloxy group, isoxazolidinyloxy group, thiazolidinyloxy group, isothiazolidinyloxy group, imidazolidinyl Oxy group, pyrazolidinyloxy group, piperidyloxy group (including piperidinooxy group), morpholinyloxy group (including morpholinooxy group), thiomorpholinyloxy group (including thiomorpholinooxy group), piperazini Ruoxy group, 1,1-dioxide isothiazolidinyloxy group, 1,1-dioxid
• C 1-6 alkyl-carbonyl group means a carbonyl group to which the above “C 1-6 alkyl group” is bonded, and examples thereof include an acetyl group, a propanoyl group, a butanoyl group, a 2-methylpropanoyl group, , 2-dimethylpropanoyl group, 3-methylbutanoyl group and the like.
• C 1-6 alkoxy-carbonyl group means a carbonyl group to which the above “C 1-6 alkoxy group” is bonded, and examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, Examples include butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl group, isopentyloxycarbonyl group, neopentyloxycarbonyl group, hexyloxycarbonyl group and the like.
• C 3-6 cycloalkyl-carbonyl group means a carbonyl group to which the above “C 3-6 cycloalkyl group” is bonded, and examples thereof include a cyclopropylcarbonyl group, a cyclobutylcarbonyl group, a cyclopentylcarbonyl group and a cyclohexyl group. A carbonyl group etc. are mentioned.
• the “C 6-10 aryl-carbonyl group” means a carbonyl group to which the above “C 6-10 aryl group” is bonded, and examples thereof include a benzoyl group.
• Carboxy -C 1-6 alkoxy group means the carboxy group is bound "C 1-6 alkoxy group", for example, carboxymethoxy group, 2-carboxyethoxy group, 3-carboxy propoxy group, 2 -Carboxy-1-methylethoxy group, 4-carboxybutoxy group and the like.
• a carboxymethoxy group is preferred.
• the “5- or 6-membered cyclic amine” has at least one nitrogen atom in addition to a carbon atom, and further has 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. It may be a saturated heterocyclic ring having 5 or 6 atoms constituting the ring, and a bond is located on a nitrogen atom constituting the ring. When the ring contains a sulfur atom as a hetero atom, the sulfur atom may be mono- or dioxidized.
• rings examples include pyrrolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, imidazolidine, pyrazolidine, piperidine, morpholine, thiomorpholine, piperazine, 1,1-dioxide isothiazolidine, 1,1-dioxide Examples include thiomorpholine.
• the “5- or 6-membered unsaturated heterocyclic ring” has 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom, and the number of atoms constituting the ring is 5 or It means six monocyclic unsaturated or partially unsaturated heterocycles, and when the ring contains a sulfur atom as a hetero atom, the sulfur atom may be mono- or dioxidized.
• rings examples include furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, oxadiazole, thiadiazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine and the like. Can be mentioned.
• R 1 is (1) a hydrogen atom, (2) a C 1-6 alkoxy group (preferably a methoxy group, an isopropoxy group) optionally substituted with a hydroxy group or (3) a C 6-10 aryl group (preferably a phenyl group) And preferably a hydrogen atom.
• R 2 and R 3 are the same or different and are each (1) a hydrogen atom, or (2) (a) a hydroxy group, and (b) a C 1-6 alkoxy group (preferably a methoxy group).
• a C 1-6 alkyl group (preferably a methyl group) which may be substituted with 1 to 3 substituents selected from: preferably the same or different, each having a C 1-6 alkyl group (preferably , Methyl group).
• R 4 is bonded to the 5th or 6th position of the indole ring.
• R 4 is preferably bonded to the 5- or 6-position of the indole ring
• R 5 is (1) a hydrogen atom or (2) a C 1-6 alkyl group (preferably a methyl group or an ethyl group).
• R 6 is (1) a hydrogen atom, (2) (a) a hydroxy group, (B) a C 1-6 alkoxy group (preferably a methoxy group, a propoxy group, an isopropoxy group), (C) a carboxy group, (D) a C 1-6 alkoxy-carbonyl group (preferably a methoxycarbonyl group, a tert-butoxycarbonyl group), (E) a C 6-10 aryl group (preferably a phenyl group), (F) a C 6-10 aryloxy group (preferably a phenoxy group), (G) an amino group optionally mono- or di-substituted with a C 1-6 alkyl group (preferably a methyl group), (H) a 5- or 6-membered unsaturated heterocyclic group (preferably furyl, pyrrolyl, thiazolyl, tetrazolyl, imidazolyl) optionally substituted by a C 1-6 alkyl group (preferably a methyl group
• R 5 and R 6 together with the nitrogen atom to which they are attached, (A) a hydroxy group, (B) a C 1-6 alkyl group (preferably a methyl group, an ethyl group), (C) a C 1-6 alkoxy group (preferably a methoxy group), and (d) a C 1-6 alkoxy-carbonyl group (preferably a tert-butoxycarbonyl group).
• a 5- or 6-membered cyclic amine preferably pyrrolidine, piperidine, piperazine, morpholine
• a heterocycle preferably imidazole
• R 7 is (1) a hydrogen atom, or (2) (a) a hydroxy group, 1 selected from (b) a C 1-6 alkoxy group (preferably a methoxy group), and (c) an amino group optionally mono- or disubstituted with a C 1-6 alkyl group (preferably a methyl group).
• a C 1-6 alkyl group optionally substituted with three substituents (preferably a methyl group, an ethyl group, or a propyl group) And preferably (A) a hydroxy group, 1 selected from (b) a C 1-6 alkoxy group (preferably a methoxy group), and (c) an amino group optionally mono- or disubstituted with a C 1-6 alkyl group (preferably a methyl group).
• a C 1-6 alkyl group optionally substituted with three substituents (preferably a methyl group, an ethyl group, or a propyl group) And more preferably a C 1-6 alkyl group (preferably a methyl group, an ethyl group, or a propyl group).
• R 8 is (1) (a) a hydroxy group, (B) a C 1-6 alkoxy group (preferably a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group) optionally substituted with a C 6-10 aryl group (preferably a phenyl group), (C) a C 3-6 cycloalkyl group (preferably a cyclopentyl group, a cyclohexyl group) optionally substituted with a C 1-6 alkoxy group (preferably a methoxy group), (D) a C 6-10 aryl group (preferably a phenyl group), (E) a 5- or 6-membered unsaturated heterocyclic group (preferably an imidazolyl group, a dihydropyridyl group, a pyrazolyl group) optionally substituted with an oxo group, (F) (i) a hydroxy group, (Ii) a C 1-6 alkyl group (preferably a methyl group
• R 8 More preferably as R 8 , (C) a C 3-6 cycloalkyl group (preferably a cyclopentyl group, a cyclohexyl group) optionally substituted with a C 1-6 alkoxy group (preferably a methoxy group), (D) a C 6-10 aryl group (preferably a phenyl group), (E) a 5- or 6-membered unsaturated heterocyclic group (preferably an imidazolyl group, a dihydropyridyl group, a pyrazolyl group) optionally substituted with an oxo group, and (f) (i) a hydroxy group, (Ii) a C 1-6 alkyl group (preferably a methyl group) optionally substituted with 1 to 3 substituents selected from a hydroxy group and a C 1-6 alkoxy group (preferably a methoxy group); (Iii) a C 1-6 alkoxy group (preferably a methoxy group), and (iv)
• R 8 Particularly preferably as R 8 , (I) a hydroxy group, (Ii) a C 1-6 alkyl group (preferably a methyl group) optionally substituted with 1 to 3 substituents selected from a hydroxy group and a C 1-6 alkoxy group (preferably a methoxy group); (Iii) a C 1-6 alkoxy group (preferably a methoxy group), and (iv) a 5- to 8-membered saturated heterocyclic group optionally substituted with 1 to 3 substituents selected from an oxo group ( Preferably a morpholino group) C 1-6 alkyl group substituted with (preferably methyl group, ethyl group) It is.
• R 7 and R 8 together with the nitrogen and carbon atoms to which they are attached, (A) a hydroxy group, (B) a C 1-6 alkyl group (preferably a methyl group) optionally substituted with a hydroxy group, (C) a C 1-6 alkoxy group (preferably a methoxy group), and (d) a C 3-6 cycloalkyl group (preferably a cyclohexyl group).
• a 5- or 6-membered cyclic amine substituted with an oxo group preferably 2-oxopyrrolidine, 2-oxopiperidine, 2-oxooxazolidine, which may be further substituted with 1 to 3 substituents selected from ) May be formed.
• R 1 is (1) a hydrogen atom, (2) a C 1-6 alkoxy group (preferably a methoxy group, an isopropoxy group) optionally substituted with a hydroxy group or (3) a C 6-10 aryl group (preferably a phenyl group) Is;
• R 2 and R 3 are the same or different and are each (1) a hydrogen atom, or (2) (a) a hydroxy group, and (b) a C 1-6 alkoxy group (preferably a methoxy group).
• a C 1-6 alkyl group (preferably a methyl group) optionally substituted with 1 to 3 substituents selected from: R 4 is bonded to the 5- or 6-position of the indole ring
• R 5 is (1) a hydrogen atom, or (2) a C 1-6 alkyl group (preferably a methyl group, an ethyl group)
• R 6 is (1) a hydrogen atom, (2) (a) a hydroxy group, (B) a C 1-6 alkoxy group (preferably a methoxy group, a propoxy group, an isopropoxy group), (C) a carboxy group, (D) a C 1-6 alkoxy-carbonyl group (preferably a methoxycarbonyl group, a tert-butoxycarbonyl group), (E) a C 6-10 aryl group (preferably a phenyl group), (F) a C 6-10 aryloxy group (preferably a phenoxy group), (G) an amino group optionally mono- or di-substituted with a C 1-6 alkyl group (preferably a methyl group), (H) a 5- or 6-membered unsaturated heterocyclic group (preferably furyl, pyrrolyl, thi
• a 5- or 6-membered cyclic amine (preferably pyrrolidine, piperidine, piperazine, morpholine) optionally substituted with 1 to 3 substituents selected from (the ring is 5- or 6-membered unsaturated) A heterocyclic ring (preferably fused with imidazole));
• R 7 is (1) a hydrogen atom, or (2) (a) a hydroxy group, 1 selected from (b) a C 1-6 alkoxy group (preferably a methoxy group), and (c) an amino group optionally mono- or disubstituted with a C 1-6 alkyl group (preferably a methyl group).
• a C 1-6 alkyl group optionally substituted with three substituents (preferably a methyl group, an ethyl group, or a propyl group)
• substituents preferably a methyl group, an ethyl group, or a propyl group
• R 8 is (1) (a) a hydroxy group, (B) a C 1-6 alkoxy group (preferably a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group) optionally substituted with a C 6-10 aryl group (preferably a phenyl group), (C) a C 3-6 cycloalkyl group (preferably a cyclopentyl group, a cyclohexyl group) optionally substituted with a C 1-6 alkoxy group (preferably a methoxy group), (D) a C 6-10 aryl group (preferably a phenyl group), (E) a 5- or 6-membered unsaturated heterocyclic group (preferably an imidazolyl group, a dihydropyridyl group, a pyrazolyl group)
• a 5- or 6-membered cyclic amine substituted with an oxo group (preferably 2-oxopyrrolidine, 2-oxopiperidine, 2-oxooxazolidine), which may be further substituted with 1 to 3 substituents selected from Are preferred.
• R 1 is (1) a hydrogen atom, (2) a C 1-6 alkoxy group (preferably a methoxy group, an isopropoxy group) optionally substituted with a hydroxy group or (3) a C 6-10 aryl group (preferably a phenyl group) Is;
• R 2 and R 3 are the same or different and are each (1) a hydrogen atom, or (2) (a) a hydroxy group, and (b) a C 1-6 alkoxy group (preferably a methoxy group).
• a C 1-6 alkyl group (preferably a methyl group) optionally substituted with 1 to 3 substituents selected from: R 4 was bonded to position 6 of the indole ring
• R 7 is (A) a hydroxy group, 1 selected from (b) a C 1-6 alkoxy group (preferably a methoxy group), and (c) an amino group optionally mono- or disubstituted with a C 1-6 alkyl group (preferably a methyl group).
• R 8 is (1) (a) a hydroxy group, (B) a C 1-6 alkoxy group (preferably a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group) optionally substituted with a C 6-10 aryl group (preferably a phenyl group), (C) a C 3-6 cycloalkyl group (preferably a cyclopentyl group, a cyclohexyl group) optionally substituted with a C 1-6 alkoxy group (preferably a methoxy group), (D) a C 6-10 aryl group (preferably a phenyl group), (E) a 5- or 6-membered unsaturated heterocyclic group (preferably an imidazolyl group, a dihydropyridyl group, a pyrazolyl group) optional
• a 5- or 6-membered cyclic amine substituted with an oxo group (preferably 2-oxopyrrolidine, 2-oxopiperidine, 2-oxooxazolidine), which may be further substituted with 1 to 3 substituents selected from ), That is, compounds represented by the above general formula [Ia] are particularly preferred.
• R 1 is a hydrogen atom
• R 2 and R 3 are the same or different and each is a C 1-6 alkyl group (preferably a methyl group);
• R 7 ′ is a C 1-6 alkyl group (preferably a methyl group, an ethyl group, a propyl group)
• R 8 is (A) a hydroxy group, (B) a C 1-6 alkoxy group (preferably a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group) optionally substituted with a C 6-10 aryl group (preferably a phenyl group), (C) a C 3-6 cycloalkyl group (preferably a cyclopentyl group, a cyclohexyl group) optionally substituted with a C 1-6 alkoxy group (preferably a methoxy group), (D) a C 6-10 aryl group (preferably a phenyl group), (E) a 5-
• the compound [I] is preferably a compound represented by the above general formula [I ′] (hereinafter sometimes abbreviated as “compound [I ′]”). Each group of the compound [I ′] will be described below.
• R 1 ' (1) a hydrogen atom, (2) a C 1-6 alkoxy group (preferably a methoxy group, an isopropoxy group) optionally substituted with a hydroxy group or (3) a C 6-10 aryl group (preferably a phenyl group) It is.
• R 2 ′ and R 3 ′ are the same or different and are each (1) a hydrogen atom, or (2) (a) a hydroxy group, and (b) a C 1-6 alkoxy group (preferably a methoxy group).
• a C 1-6 alkyl group (preferably a methyl group) which may be substituted with 1 to 3 substituents selected from
• R 4 ′ is bonded to the 5th or 6th position of the indole ring
• R 4 ′ is preferably bonded to the 5- or 6-position of the indole ring
• R 5 ' (1) a hydrogen atom or (2) a C 1-6 alkyl group (preferably a methyl group or an ethyl group).
• R 6 ' (1) a hydrogen atom, (2) (a) a hydroxy group, (B) a C 1-6 alkoxy group (preferably a methoxy group, a propoxy group, an isopropoxy group), (C) a carboxy group, (D) a C 1-6 alkoxy-carbonyl group (preferably a methoxycarbonyl group, a tert-butoxycarbonyl group), (E) a C 6-10 aryl group (preferably a phenyl group), (F) a C 6-10 aryloxy group (preferably a phenoxy group), (G) an amino group optionally mono- or di-substituted with a C 1-6 alkyl group (preferably a methyl group), (H) a 5- or 6-membered unsaturated heterocyclic group (preferably furyl, pyrrolyl, thiazolyl, tetrazolyl, imidazolyl) optionally substituted by a C 1-6 alkyl group (preferably a methyl
• R 5 ′ and R 6 ′ together with the nitrogen atom to which they are attached, (A) a hydroxy group, (B) a C 1-6 alkyl group (preferably a methyl group, an ethyl group), (C) a C 1-6 alkoxy group (preferably a methoxy group), and (d) a C 1-6 alkoxy-carbonyl group (preferably a tert-butoxycarbonyl group).
• a 5- or 6-membered cyclic amine preferably pyrrolidine, piperidine, piperazine, morpholine
• a heterocycle preferably imidazole
• R 7 ′′ is (1) a hydrogen atom, or (2) (a) a hydroxy group, 1 selected from (b) a C 1-6 alkoxy group (preferably a methoxy group), and (c) an amino group optionally mono- or disubstituted with a C 1-6 alkyl group (preferably a methyl group).
• a C 1-6 alkyl group optionally substituted with three substituents (preferably a methyl group, an ethyl group, or a propyl group) And preferably (A) a hydroxy group, 1 selected from (b) a C 1-6 alkoxy group (preferably a methoxy group), and (c) an amino group optionally mono- or disubstituted with a C 1-6 alkyl group (preferably a methyl group). Or a C 1-6 alkyl group optionally substituted with three substituents (preferably a methyl group, an ethyl group, or a propyl group) It is.
• R 8 ' (1) (a) a hydroxy group, (B) a C 1-6 alkoxy group (preferably a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group) optionally substituted with a C 6-10 aryl group (preferably a phenyl group), (C) a C 3-6 cycloalkyl group (preferably a cyclopentyl group, a cyclohexyl group) optionally substituted with a C 1-6 alkoxy group (preferably a methoxy group), (D) a C 6-10 aryl group (preferably a phenyl group), (E) a 5- or 6-membered unsaturated heterocyclic group (preferably an imidazolyl group, a dihydropyridyl group, a pyrazolyl group) optionally substituted with an oxo group, (F) (i) a hydroxy group, (Ii) a C 1-6 alkyl group (preferably a methyl
• R 7 ′′ and R 8 ′ together with the nitrogen and carbon atoms to which they are attached, (A) a hydroxy group, (B) a C 1-6 alkyl group (preferably a methyl group) optionally substituted with a hydroxy group, (C) a C 1-6 alkoxy group (preferably a methoxy group), and (d) a C 3-6 cycloalkyl group (preferably a cyclohexyl group).
• a 5- or 6-membered cyclic amine substituted with an oxo group preferably 2-oxopyrrolidine, 2-oxopiperidine, 2-oxooxazolidine, which may be further substituted with 1 to 3 substituents selected from ) May be formed.
• R 1 ' (1) a hydrogen atom, (2) a C 1-6 alkoxy group (preferably a methoxy group, an isopropoxy group) optionally substituted with a hydroxy group or (3) a C 6-10 aryl group (preferably a phenyl group) Is;
• R 2 ′ and R 3 ′ are the same or different and are each (1) a hydrogen atom, or (2) (a) a hydroxy group, and (b) a C 1-6 alkoxy group (preferably a methoxy group).
• a C 1-6 alkyl group (preferably a methyl group) optionally substituted with 1 to 3 substituents selected from: R 4 ′ is bonded to the 5th or 6th position of the indole ring
• R 5 ' (1) a hydrogen atom, or (2) a C 1-6 alkyl group (preferably a methyl group, an ethyl group), and R 6 ′ is (1) a hydrogen atom, (2) (a) a hydroxy group, (B) a C 1-6 alkoxy group (preferably a methoxy group, a propoxy group, an isopropoxy group), (C) a carboxy group, (D) a C 1-6 alkoxy-carbonyl group (preferably a methoxycarbonyl group, a tert-butoxycarbonyl group), (E) a C 6-10 aryl group (preferably a phenyl group), (F) a C 6-10 aryloxy group (preferably a phenoxy group), (G) an amino group optionally mono- or di-substituted with a C 1-6 alkyl group (preferably a methyl group), (H) a 5- or 6-membered unsaturated heterocyclic group (preferably furyl, pyrrolyl
• a 5- or 6-membered cyclic amine (preferably pyrrolidine, piperidine, piperazine, morpholine) optionally substituted with 1 to 3 substituents selected from (the ring is 5- or 6-membered unsaturated) A heterocyclic ring (preferably fused with imidazole));
• R 7 '' is (1) a hydrogen atom, or (2) (a) a hydroxy group, 1 selected from (b) a C 1-6 alkoxy group (preferably a methoxy group), and (c) an amino group optionally mono- or disubstituted with a C 1-6 alkyl group (preferably a methyl group).
• a C 1-6 alkyl group optionally substituted with three substituents (preferably a methyl group, an ethyl group, or a propyl group)
• substituents preferably a methyl group, an ethyl group, or a propyl group
• R 8 ′ is (1) (a) a hydroxy group, (B) a C 1-6 alkoxy group (preferably a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group) optionally substituted with a C 6-10 aryl group (preferably a phenyl group), (C) a C 3-6 cycloalkyl group (preferably a cyclopentyl group, a cyclohexyl group) optionally substituted with a C 1-6 alkoxy group (preferably a methoxy group), (D) a C 6-10 aryl group (preferably a phenyl group), (E) a 5- or 6-membered unsaturated heterocyclic group (preferably an imidazolyl group, a dihydropyridyl group, a pyrazolyl
• a 5- or 6-membered cyclic amine substituted with an oxo group (preferably 2-oxopyrrolidine, 2-oxopiperidine, 2-oxooxazolidine), which may be further substituted with 1 to 3 substituents selected from Are preferred.
• R 1 ' (1) a hydrogen atom, (2) a C 1-6 alkoxy group (preferably a methoxy group, an isopropoxy group) optionally substituted with a hydroxy group or (3) a C 6-10 aryl group (preferably a phenyl group) Is;
• R 2 ′ and R 3 ′ are the same or different and are each (1) a hydrogen atom, or (2) (a) a hydroxy group, and (b) a C 1-6 alkoxy group (preferably a methoxy group).
• a C 1-6 alkyl group (preferably a methyl group) optionally substituted with 1 to 3 substituents selected from: R 4 'is bonded to the 6-position of the indole ring
• R 7 '' is (A) a hydroxy group, 1 selected from (b) a C 1-6 alkoxy group (preferably a methoxy group), and (c) an amino group optionally mono- or disubstituted with a C 1-6 alkyl group (preferably a methyl group).
• R 8 ′ is (1) (a) a hydroxy group, (B) a C 1-6 alkoxy group (preferably a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group) optionally substituted with a C 6-10 aryl group (preferably a phenyl group), (C) a C 3-6 cycloalkyl group (preferably a cyclopentyl group, a cyclohexyl group) optionally substituted with a C 1-6 alkoxy group (preferably a methoxy group), (D) a C 6-10 aryl group (preferably a phenyl group), (E) a 5- or 6-membered unsaturated heterocyclic group (preferably an imidazolyl group, a dihydropyridyl group, a pyrazolyl group
• a 5- or 6-membered cyclic amine substituted with an oxo group (preferably 2-oxopyrrolidine, 2-oxopiperidine, 2-oxooxazolidine), which may be further substituted with 1 to 3 substituents selected from ), That is, compounds represented by the above general formula [I′-a] are particularly preferred.
• the pharmaceutically acceptable salt of compound [I] may be any salt that forms a non-toxic salt with the compound of the present invention, such as a salt with an inorganic acid, a salt with an organic acid, and an inorganic base. And salts with organic bases, salts with amino acids, and the like.
• Examples of the salt with an inorganic acid include salts with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, hydrobromic acid and the like.
• As salts with organic acids for example, oxalic acid, maleic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, gluconic acid, ascorbic acid, methanesulfonic acid, benzenesulfonic acid And salts with p-toluenesulfonic acid and the like.
• Examples of the salt with an inorganic base include sodium salt, potassium salt, calcium salt, magnesium salt, ammonium salt and the like.
• salts with organic bases include methylamine, diethylamine, trimethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, tris (hydroxymethyl) methylamine, dicyclohexylamine, N, N'-dibenzylethylenediamine, guanidine , Salts with pyridine, picoline, choline, cinchonine, meglumine and the like.
• each salt can be obtained by reacting compound [I] with an inorganic base, organic base, inorganic acid, organic acid, or amino acid according to a known method. .
• the “solvate” is a compound in which a molecule of a solvent is coordinated to Compound [I] or a pharmaceutically acceptable salt thereof, and includes a hydrate.
• the solvate is preferably a pharmaceutically acceptable solvate, and examples thereof include a hydrate of compound [I] or a pharmaceutically acceptable salt thereof, an ethanolate, a dimethylsulfoxide solvate, and the like.
• hemihydrate, monohydrate, dihydrate or monoethanolate of compound [I], or monohydrate or dihydrochloride of sodium salt of compound [I] examples include triethanolate.
• the solvate can be obtained according to a known method.
• the compound [I] or a pharmaceutically acceptable salt thereof, or a solvate thereof is preferably a substantially purified compound [I] or a pharmaceutically acceptable salt thereof or a solvate thereof. More preferably, it is the compound [I] or a pharmaceutically acceptable salt thereof or a solvate thereof purified to a purity of 80% or more.
• a prodrug of compound [I] or a pharmaceutically acceptable salt thereof, or a solvate thereof can also be a useful drug.
• a “prodrug” has a group that can be chemically or metabolically degraded and is administered to a living body and then decomposed under, for example, hydrolysis, solvolysis, or physiological conditions.
• a complex of a compound of the present invention which is restored to the above compound and exhibits the original medicinal effect and does not rely on a covalent bond, and a salt are also conceivable.
• Prodrugs are used, for example, for improving absorption in oral administration or for targeting to a target site. Examples of the modified site include highly reactive functional groups such as a hydroxyl group, a carboxyl group, and an amino group in the compound of the present invention.
• hydroxyl-modifying groups include acetyl, propanoyl, 2-methylpropanoyl, 2,2-dimethylpropanoyl, palmitoyl, benzoyl, 4-methylbenzoyl, dimethylcarbamoyl, dimethylamino
• hydroxyl-modifying groups include acetyl, propanoyl, 2-methylpropanoyl, 2,2-dimethylpropanoyl, palmitoyl, benzoyl, 4-methylbenzoyl, dimethylcarbamoyl, dimethylamino
• examples thereof include a methylcarbonyl group, a sulfo group, an alanyl group, a fumaryl group, a 3-carboxybenzoyl group, a 2-carboxyethylcarbonyl group, and a 3-sodiumcarboxylatobenzoyl group.
• the modifying group of the carboxyl group include methyl group, ethyl group, propanoyl group, 2-methylpropanoyl group, butyl group, isobutyl group, tert-butyl group, 2,2-dimethylpropanoyloxymethyl group, carboxy group Methyl group, dimethylaminomethyl group, 1- (acetyloxy) ethyl group, 1- (ethoxycarbonyloxy) ethyl group, 1- (isopropyloxycarbonyloxy) ethyl group, 1- (cyclohexyloxycarbonyloxy) ethyl group, ( 5-methyl-2-oxo-1,3-dioxol-4-yl) methyl group, benzyl group, phenyl group, o-tolyl group, morpholinoethyl group, N, N-diethylcarbamoylmethyl group, phthalidyl group, etc. It is done.
• amino group modifying group examples include tert-butyl group, docosanoyl group, 2,2-dimethylpropanoylmethyloxy group, alanyl group, hexylcarbamoyl group, pentylcarbamoyl group, 3-methylthio-1- (acetylamino).
• the “pharmaceutical composition” includes tablets, capsules, granules, powders, troches, syrups, emulsions, suspensions and other oral preparations, external preparations, suppositories, injections, eye drops, and nasal preparations. And parenteral agents such as pulmonary agents.
• the pharmaceutical composition of the present invention is produced by appropriately mixing an appropriate amount of the compound of the present invention with at least one pharmaceutically acceptable carrier or the like according to a method known in the technical field of pharmaceutical preparations.
• the content of the compound of the present invention in the pharmaceutical composition varies depending on the dosage form, dosage, etc., and is, for example, 0.1 to 100% by weight of the whole composition.
• the “pharmaceutically acceptable carrier” examples include various organic or inorganic carrier substances commonly used as pharmaceutical materials, such as excipients, disintegrants, binders, fluidizers, lubricants and the like in solid preparations. Or a solvent, a solubilizing agent, a suspending agent, an isotonic agent, a buffering agent, a soothing agent and the like in a liquid preparation. Furthermore, additives such as preservatives, antioxidants, colorants, sweeteners and the like are used as necessary.
• excipient examples include lactose, sucrose, D-mannitol, D-sorbitol, corn starch, dextrin, microcrystalline cellulose, crystalline cellulose, carmellose, carmellose calcium, sodium carboxymethyl starch, low substituted hydroxypropyl
• examples include cellulose and gum arabic.
• disintegrant examples include carmellose, carmellose calcium, carmellose sodium, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, crystalline cellulose and the like.
• binder examples include hydroxypropylcellulose, hydroxypropylmethylcellulose, povidone, crystalline cellulose, sucrose, dextrin, starch, gelatin, carmellose sodium, gum arabic and the like.
• fluidizing agent examples include light anhydrous silicic acid, magnesium stearate and the like.
• lubricant examples include magnesium stearate, calcium stearate, talc and the like.
• solvent examples include purified water, ethanol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
• Examples of the “solubilizing agent” include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, sodium citrate and the like.
• suspending agent examples include benzalkonium chloride, carmellose, hydroxypropylcellulose, propylene glycol, povidone, methylcellulose, glyceryl monostearate and the like.
• isotonic agent examples include glucose, D-sorbitol, sodium chloride, D-mannitol and the like.
• Examples of the “buffering agent” include sodium hydrogen phosphate, sodium acetate, sodium carbonate, sodium citrate and the like.
• Examples of the “soothing agent” include benzyl alcohol and the like.
• Examples of the “preservative” include ethyl paraoxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid and the like.
• Examples of the “antioxidant” include sodium sulfite and ascorbic acid.
• Examples of the “colorant” include food coloring (eg, food red No. 2 or 3, food yellow No. 4 or 5, etc.), ⁇ -carotene and the like.
• Examples of the “sweetening agent” include saccharin sodium, dipotassium glycyrrhizinate, aspartame and the like.
• the pharmaceutical composition of the present invention can be applied not only to humans but also to mammals other than humans (eg, mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, pigs, cows, horses, sheep, monkeys, etc.). Can also be administered orally or parenterally (eg, topical, rectal, intravenous, etc.).
• the dose varies depending on the administration subject, disease, symptom, dosage form, administration route, etc.
• the dose for oral administration to an adult patient is the compound [I], which is an active ingredient As a rule, it is usually in the range of about 1 mg to 1 g per day. These amounts can be administered once to several times.
• the compounds of the present invention have an inhibitory activity on inducible T cell kinase (ITK). Therefore, the compound of the present invention can be used as an active ingredient such as a therapeutic or prophylactic agent for inflammatory diseases, a therapeutic or prophylactic agent for allergic diseases, a therapeutic or prophylactic agent for autoimmune diseases, and an inhibitor of rejection in transplantation. it can.
• ITK inducible T cell kinase
• “Inhibiting ITK” or “having ITK inhibitory activity” means that the function of ITK is inhibited and lost or attenuated, or has such activity. It means that the inhibitory activity of ITK is measured based on the conditions of Example 1, and a compound having the inhibitory activity is administered to mammals including humans to inhibit the function of ITK.
• the “inhibiting ITK” is preferably “inhibiting human ITK”.
• the “ITK inhibitor” is preferably a “human ITK inhibitor”.
• the inflammatory disease is not particularly limited, and examples thereof include rheumatoid arthritis and inflammatory bowel disease. Although it does not restrict
• the autoimmune disease is not particularly limited, and examples thereof include rheumatoid arthritis, systemic lupus erythematosus, psoriasis, and inflammatory bowel disease.
• the compound of the present invention is used (hereinafter also referred to as combination) in combination with one or more other drugs (hereinafter also referred to as concomitant drugs) in a general manner practiced in the pharmaceutical field. Can do.
• the administration timing of the compound of the present invention and the concomitant drug is not limited, and these may be administered to the administration subject as a combination drug, or may be administered as separate preparations simultaneously or at regular intervals. . Moreover, you may use as a kit which consists of the pharmaceutical composition of this invention, and a concomitant drug.
• the dose of the concomitant drug may be determined according to the dose used clinically, and can be appropriately selected depending on the administration subject, disease, symptom, dosage form, administration route, administration time, combination and the like.
• the administration form of the concomitant drug is not particularly limited as long as the compound of the present invention and the concomitant drug are combined.
• the production method of the compound of the present invention is not limited to these. Even if not described in this production method, a protective group is introduced into a functional group as necessary, and deprotection is performed in a post-process; the functional group is treated as a precursor in each step, and the desired functional group is formed at an appropriate stage. You may implement efficient manufacture by devising, such as changing the order of each manufacturing method and process. In each step, post-reaction treatment may be performed by a commonly performed method, and isolation and purification may be performed as necessary by crystallization, recrystallization, distillation, liquid separation, silica gel chromatography, preparative HPLC, etc. These commonly used methods may be appropriately selected and combined.
• R 9 and R 10 are the same or different and each represents a protecting group for an amino group; other symbols have the same meanings as described above.
• Examples of the “amino-protecting group” represented by R 9 or R 10 include a tert-butoxycarbonyl group, an ethoxycarbonyl group, a trityl group, a tetrahydropyranyl group, a methoxymethyl group, a 2- (trimethylsilyl) ethoxymethyl group, p -Toluenesulfonyl group and the like can be mentioned, and a tert-butoxycarbonyl group is preferable.
• Compound [3] can be obtained by subjecting compound [1] and compound [2] to a Suzuki coupling reaction.
• compound [3] can be obtained by reacting compound [1] with compound [2] in the presence of a base and a palladium catalyst in a solvent under heating.
• the reaction is preferably carried out under heating by gradually adding compound [2] in the presence of all other reagents.
• the palladium catalyst used in the reaction include tetrakistriphenylphosphine palladium, (bis (diphenylphosphino) ferrocene) palladium dichloride-methylene chloride complex, and the like.
• Examples of the base used for the reaction include potassium phosphate, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, triethylamine and the like.
• Solvents used in the reaction include ether solvents such as 1,4-dioxane, tetrahydrofuran, diethyl ether and 1,2-dimethoxyethane; alcohol solvents such as methanol, ethanol, n-propanol and isopropanol; toluene, hexane, xylene Hydrocarbon solvents such as: polar solvents such as N, N-dimethylformamide, dimethyl sulfoxide and acetonitrile; or a mixed solvent thereof with water is preferred.
• Compound [1] and compound [2] may be commercially available, or can be obtained by the following production methods 2 and 3, or a conventional method, respectively.
• Compound [I] can be obtained by removing R 9 and R 10 of compound [3] by a conventional deprotection reaction.
• the deprotection reaction if according to the type or combination of R 9 and R 10, may be performed using conditions suitable for each, for example, R 9 and R 10 are both tert- butoxycarbonyl group, the solvent Compound [I] can be obtained by treating compound [3] at room temperature in the presence of a base.
• the base used for the reaction include sodium hydroxide, lithium hydroxide, sodium carbonate and the like.
• Solvents used in the reaction include ether solvents such as 1,4-dioxane and tetrahydrofuran; alcohol solvents such as methanol, ethanol, n-propanol and isopropanol; polar solvents such as N, N-dimethylformamide, dimethyl sulfoxide and acetonitrile Or a mixed solvent of them and water is preferred.
• ether solvents such as 1,4-dioxane and tetrahydrofuran
• alcohol solvents such as methanol, ethanol, n-propanol and isopropanol
• polar solvents such as N, N-dimethylformamide, dimethyl sulfoxide and acetonitrile Or a mixed solvent of them and water is preferred.
• Compound [5] can be obtained by reacting compound [4] with ethyl formate in the presence of a base in a solvent.
• a base used in the reaction include sodium hydride, tert-butoxypotassium, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, lithium diisopropylamide, lithium hexamethyldisilazide and the like.
• solvent used in the reaction examples include ether solvents such as 1,4-dioxane, tetrahydrofuran, diethyl ether and 1,2-dimethoxyethane; alcohol solvents such as methanol, ethanol, n-propanol and isopropanol; N, N-dimethyl Polar solvents such as formamide, dimethyl sulfoxide and acetonitrile are preferred.
• ether solvents such as 1,4-dioxane, tetrahydrofuran, diethyl ether and 1,2-dimethoxyethane
• alcohol solvents such as methanol, ethanol, n-propanol and isopropanol
• N, N-dimethyl Polar solvents such as formamide, dimethyl sulfoxide and acetonitrile are preferred.
• Compound [4] is a commercially available product or can be obtained by a conventional method.
• Compound [6] can be obtained by reacting compound [5] with hydrazine in a solvent at room temperature or under heating. In this step, it may be preferable to react at room temperature to heating. Moreover, you may use an acid for this reaction as needed.
• the solvent used in the reaction alcohol solvents such as methanol, ethanol, n-propanol and isopropanol; polar solvents such as N, N-dimethylformamide, dimethyl sulfoxide and acetonitrile are preferable.
• the acid used for the reaction include hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, pyridium p-toluenesulfonate, and the like.
• Compound [7] can be obtained by reacting compound [6] with iodine in a solvent in the presence of a base at room temperature to under heating.
• the base used for the reaction include potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate and the like.
• Solvents used in the reaction include ether solvents such as 1,4-dioxane and tetrahydrofuran; alcohol solvents such as methanol, ethanol, n-propanol and isopropanol; polar solvents such as N, N-dimethylformamide, dimethyl sulfoxide and acetonitrile Or a mixed solvent of them and water is preferred.
• Compound [1] can be obtained by introducing an amino-protecting group (R 9 ) into compound [7].
• R 9 is a tert-butoxycarbonyl group
• the compound [7] is reacted with di-tert-butyl dicarbonate in a solvent in the presence of a base at room temperature or under heating to give a compound [1 ] Can be obtained.
• the base used in the reaction include tertiary amines such as triethylamine and 4-dimethylaminopyridine.
• solvent used in the reaction examples include ether solvents such as 1,4-dioxane and tetrahydrofuran, ester solvents such as ethyl acetate, hydrocarbon solvents such as toluene, hexane and xylene, N, N-dimethylformamide, dimethyl sulfoxide, A polar solvent such as acetonitrile is preferred.
• Compound [9] can be obtained by introducing an amino-protecting group (R 10 ) into compound [8].
• R 10 is a tert-butoxycarbonyl group
• the compound [8] is reacted with di-tert-butyl dicarbonate in a solvent in the presence of a base at room temperature or under heating to give a compound [ 9] can be obtained.
• the base used in the reaction include tertiary amines such as 4-dimethylaminopyridine and triethylamine, and 4-dimethylaminopyridine is preferred.
• solvent used in the reaction examples include ether solvents such as 1,4-dioxane and tetrahydrofuran; ester solvents such as ethyl acetate; hydrocarbon solvents such as toluene, hexane and xylene; N, N-dimethylformamide, dimethyl sulfoxide, A polar solvent such as acetonitrile is preferred.
• Compound [8] is a commercially available product or can be obtained by a conventional method.
• Compound [2] can be obtained by reacting compound [9] with a borate ester in a solvent in the presence of a base under cooling.
• the reaction is preferably carried out by slowly adding a base dropwise in the presence of a borate ester under cooling.
• boric acid ester used in the reaction include triisopropyl borate and trimethyl borate.
• the base used for the reaction include butyl lithium, lithium diisopropylamide, lithium hexamethyldisilazide and the like.
• ether solvents such as 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane are preferable.
• R 4 was bonded to the 5-position or 6-position of the indole ring.
• Compound [Ib] which is a group represented by the following formula, can also be produced by the following production method 4 or 7.
• R 11 represents a protecting group for a carboxyl group; other symbols have the same meanings as described above.
• Examples of the “carboxyl-protecting group” represented by R 11 include alkyl groups such as a methyl group, an ethyl group and a tert-butyl group, a tert-butyldimethylsilyl group, a benzyl group and a methoxyethoxymethyl group.
• Compound [11] can be obtained by removing R 11 of compound [10] by a deprotection reaction.
• Deprotection reactions depending on the type of R 11, may be performed using conditions suitable, for example, if R 11 is an alkyl group, in a solvent in the presence of a base, at room temperature or compounds under heating [10 ] Is hydrolyzed, and then the resulting solution is acidified to obtain compound [11].
• the base used for the reaction include potassium carbonate, sodium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydride, sodium hydride, potassium hydride and the like.
• the solvent used in the reaction is preferably a mixed solvent of an alcohol solvent such as methanol, ethanol, n-propanol or isopropanol and water; or a mixed solvent of such solvent with an ether solvent such as 1,4-dioxane or tetrahydrofuran.
• an alcohol solvent such as methanol, ethanol, n-propanol or isopropanol and water
• ether solvent such as 1,4-dioxane or tetrahydrofuran.
• Compound [Ib] can be obtained by reacting compound [11] and amine [12] in a solvent in the presence of a condensing agent under cooling to heating.
• a condensing agent used in the reaction, N, N′-carbonyldiimidazole, N, N′-dicyclohexylcarbodiimide, N, N′-diisopropylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride ( EDC) and the like.
• EDC 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride
• the activator used in the reaction include hydroxysuccinimide and 1-hydroxybenzotriazole.
• Solvents used in the reaction include hydrocarbon solvents such as benzene, toluene, hexane, xylene; halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane; 1,4-dioxane, diethyl ether, 1 Ether solvents such as 1,2-dimethoxyethane and tetrahydrofuran; polar solvents such as N, N-dimethylformamide, dimethyl sulfoxide and acetonitrile; pyridine; or a mixed solvent thereof is preferable.
• Amine [12] may be a commercially available product, or can be obtained by a conventional method.
• R 4 was bonded to the 5-position or 6-position of the indole ring.
• Compound [Ic] which is a group represented by the following formula, can also be produced by the following production method 5 or 6.
• R 12 represents an amino-protecting group
• R 13 represents an alkyl group such as a methyl group, an ethyl group or a tert-butyl group, a benzyl group, etc .; other symbols are as defined above.
• Examples of the “protecting group for amino group” represented by R 12 include 2- (trimethylsilyl) ethoxymethyl group, trityl group, tetrahydropyranyl group, methoxymethyl group, p-toluenesulfonyl group, and preferably 2- (Trimethylsilyl) ethoxymethyl group.
• Compound [13] can be obtained by introducing an amino-protecting group (R 12 ) into compound [10].
• R 12 is a 2- (trimethylsilyl) ethoxymethyl group
• the compound [10] is reacted with 2- (trimethylsilyl) ethoxymethyl chloride in a solvent under cooling and in the presence of a base.
• Examples of the base used in the reaction include sodium hydride.
• ether solvents such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, and tetrahydrofuran; polar solvents such as N, N-dimethylformamide, dimethyl sulfoxide, and acetonitrile are preferable.
• Compound [15] can be obtained by converting compound [14] into an isocyanate by Curtius rearrangement using diphenylphosphoryl azide and reacting the resulting isocyanate with an alcohol (R 13 OH).
• the Curtius rearrangement can also be carried out by, for example, reacting the acid chloride of compound [14] with sodium azide to produce an acid azide and then heating. If an alcohol (R 13 OH) is interposed during the Curtius rearrangement, the isocyanate immediately reacts with the alcohol to produce compound [15].
• R 13 is a benzyl group
• compound [14] is reacted by adding diphenylphosphoryl azide dropwise in a solvent in the presence of benzyl alcohol and a tertiary amine under heating to give compound [15].
• tertiary amine used in the reaction include triethylamine.
• hydrocarbon solvents such as benzene, toluene, hexane and xylene
• ether solvents such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane and tetrahydrofuran are preferable.
• compound [16] is obtained by reacting compound [15] with a corresponding alkylating agent in a solvent under ice-cooling to room temperature in the presence of a base to introduce R 7 .
• the alkylating agent used in the reaction is not particularly limited as long as R 7 can be introduced, and examples thereof include methyl iodide, ethyl iodide, benzyloxymethane chloride and the like.
• the base used for the reaction include sodium hydride, butyl lithium, lithium diisopropylamide, lithium hexamethyldisilazide and the like.
• Solvents used in the reaction include hydrocarbon solvents such as benzene, toluene, hexane and xylene; ether solvents such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane and tetrahydrofuran; N, N-dimethylformamide , Polar solvents such as dimethyl sulfoxide and acetonitrile are preferred.
• R 7 is a hydrogen atom
• compound [15] can be directly subjected to step 5 without going through step 4.
• Compound [17] can be obtained by reducing compound [16] by a conventional method.
• compound [17] can be obtained by a conventional method such as catalytic reduction.
• the catalytic reduction can be performed, for example, with hydrogen gas in a solvent in the presence of a metal catalyst, at room temperature to under heating, under normal pressure to under pressure.
• a metal catalyst such as ammonium formate, cyclohexene, dicyclohexene, or the like may be used as a hydrogen source.
• the metal catalyst used for the reaction include palladium carbon, palladium hydroxide, palladium black, Raney nickel and the like.
• the solvent used in the reaction is preferably an alcohol solvent such as methanol, ethanol, n-propanol, or isopropanol; an ether solvent such as 1,4-dioxane or tetrahydrofuran; an ester solvent such as ethyl acetate; or a mixed solvent thereof.
• an alcohol solvent such as methanol, ethanol, n-propanol, or isopropanol
• an ether solvent such as 1,4-dioxane or tetrahydrofuran
• an ester solvent such as ethyl acetate
• the compound [19] can be obtained by condensing the obtained acid halide and the compound [17] in the presence of a tertiary amine or pyridine under cooling to room temperature.
• a tertiary amine or pyridine under cooling to room temperature.
• the halogenating agent used in the reaction include oxalyl chloride, thionyl chloride, phosphorus oxychloride, phosphorus pentachloride and the like.
• the tertiary amine used in the reaction include triethylamine.
• solvent used for the reaction examples include halogen solvents such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; ether solvents such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, and tetrahydrofuran; or A mixed solvent of these and water is preferred.
• Compound [18] may be a commercially available product, or can be obtained by a conventional method. If the corresponding acid halide is a commercial product, it may be used. Alternatively, compound [17] can be obtained by condensing compound [17] and compound [18] in the same manner as in Step 3 of Production Method 4.
• Step 7 Compound [Ic] can be obtained by removing R 12 of compound [19] by a deprotection reaction.
• Deprotection reactions depending on the type of R 12, may be performed using conditions suitable for each, for example, in the case of R 12 is 2- (trimethylsilyl) ethoxymethyl group, in a solvent, under heating, tetra
• Compound [Ic] can be obtained by reacting compound [19] in the presence of butylammonium fluoride and ethylenediamine.
• ether solvents such as 1,4-dioxane and tetrahydrofuran
• polar solvents such as N, N-dimethylformamide, dimethyl sulfoxide and acetonitrile are preferable.
• Compound [Ic] can be obtained by removing the acyl group on the pyrazole ring from compound [22].
• compound [Ic] can be obtained by hydrolyzing compound [22] in the presence of a base at room temperature or under heating in a solvent.
• the base used for the reaction include potassium carbonate, sodium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium hydride, sodium hydride, potassium hydride and the like.
• the solvent used in the reaction is preferably a hydroalcoholic solvent such as methanol, ethanol, n-propanol or isopropanol; or a mixed solvent of these with an ether solvent such as 1,4-dioxane or tetrahydrofuran.
• room temperature means 1 to 40 ° C.
• potassium carbonate 124 g, 900 mmol
• 1H-indole-6-carboxylic acid 121 g, 752 mmol
• N, N-dimethylformamide 360 ml
• iodomethane 56 ml, 900 mmol
• water 1.2 L
• hexane 100 ml
• decan-8-one (10.5 g, 62 mmol) was dissolved in methanolic potassium hydroxide solution (10 w / w%, 60 g). A solution of formaldehyde (37%, 4.6 ml) in methanol (5 ml) was added dropwise to the solution over 20 minutes under ice-cooling, and the mixture was further stirred for 30 minutes. Next, 1N hydrochloric acid and saturated aqueous ammonium chloride solution were added to the reaction solution, and the mixture was extracted 3 times with chloroform. The combined organic layers were dried with magnesium sulfate. Magnesium sulfate was removed by filtration and concentrated under reduced pressure.
• Step 7 N- (2- ⁇ 6,6-dimethyl-1- [2- (trimethylsilyl) ethoxymethyl] -4,5,6,7-tetrahydro-1H-indazol-3-yl ⁇ -1- [2- (trimethylsilyl) ) Ethoxymethyl] -1H-indol-6-yl) -N-methylamine
• Example 1 N- [2- ⁇ 6,6-Dimethyl-1- [2- (trimethylsilyl) ethoxymethyl] -4,5,6,7-tetrahydro-1H-indazol-3-yl obtained in Step 6 ⁇ -1- [2- (Trimethylsilyl) ethoxymethyl] -1H-indol-6-yl) -N-methylcarbamic acid benzyl ester (13 g, 19 mmol) in N, N-dimethylformamide (102 ml) In addition to tetrabutylammonium fluoride (93 ml, 93 ml) concentrated in advance under reduced pressure, ethylenediamine (19 ml) was further added, followed by stirring with heating at 90 ° C.
• Example 1 2- ⁇ 6,6-Dimethyl-1- [2- (trimethylsilyl) ethoxymethyl] -4,5,6,7-tetrahydro-1H-indazol-3-yl ⁇ -1 obtained in Step 4 -[2- (Trimethylsilyl) ethoxymethyl] -1H-indole-6-carboxylic acid (500 mg, 0.88 mmol) in N, N-dimethylformamide (5 ml) solution at room temperature with 1-hydroxybenzotriazole monohydrate Add Japanese (161 mg, 1.1 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (202 mg, 1.1 mmol) and 2-amino-1-propanol (84 mg, 1.1 mmol) And stirred at room temperature for 7 hours.
• the compounds of Examples 9 to 381 were obtained in the same manner as in the above Examples.
• Tables 1-1 to 1-78 show the structural formulas of these compounds and their 1 H-NMR spectral data.
• the optically active compound includes Example No. (Optically active substance) is attached below.
• 1 H-NMR spectra were measured in CDCl 3 or DMSO-D 6 using tetramethylsilane as an internal standard, and all ⁇ values were shown in ppm. Unless otherwise indicated in the table, the resolution was measured at 400 MHz.
• the symbols in the table have the following meanings. s: singlet d: doublet t: triplet q: quartet dd: double doublet (double doublet) ddd: double double doublet (double double doublet) brs: broad singlet m: multiplet J: Coupling constant
• Test Example ITK inhibitory activity (1) Preparation of hITK enzyme The hITK enzyme was prepared by strongly expressing FLAG-tagged full-length hITK in Sf9 cells and purifying with an anti-FLAG antibody column. (2) Preparation of Biotinylated GST-SLP76 Biotinylated GST-SLP76 was prepared by strongly expressing GST-tagged SLP76 (aa95-175) in E. coli and purifying it with a glutathione sepharose column, followed by Biotinization. .
• the kinase reaction was started and the plate was allowed to stand at room temperature for 10 minutes. Thereafter, a detection buffer (50 ⁇ L / well) was added to the plate. Two hours after the addition of the detection buffer, the fluorescence intensity at 620 nm excited at 337 nm and the fluorescence intensity at 665 nm excited by fluorescence at 620 nm were measured with a fluorescence microplate reader. The ratio (fluorescence intensity at 665 nm / fluorescence intensity at 620 nm ⁇ 10000) of each test compound was calculated from the measured fluorescence intensity. Simultaneously, measurement was performed using a blank solution and a control solution, and the% of control value of each test compound was calculated from the following formula.
• the IC 50 value was calculated from the concentration of the test compound at two points across the ITK inhibition rate of 50%. The results are shown in Table 2 as nM values. The numerical value shown in% in the table represents the ITK inhibition rate (%) at the concentration in parentheses.
• Formulation Example 1 (Manufacture of capsules) 1) 30 mg of the compound of Example 1 2) Microcrystalline cellulose 10mg 3) Lactose 19mg 4) Magnesium stearate 1mg 1), 2), 3) and 4) are mixed and filled into gelatin capsules.
• Formulation Example 2 (Manufacture of tablets) 1) 10 g of the compound of Example 1 2) Lactose 50g 3) Corn starch 15g 4) Carmellose calcium 44g 5) Magnesium stearate 1g The total amount of 1), 2) and 3) and 30 g of 4) are kneaded with water, dried in vacuum, and then sized. 14 g of 4) and 1 g of 5) are mixed with the sized powder, and tableted with a tableting machine. In this way, 1000 tablets containing 10 mg of the compound of Example 1 per tablet are obtained.
• the indole compound of the present invention can be an effective drug for the treatment or prevention of inflammatory diseases, allergic diseases, autoimmune diseases, and suppression of rejection in transplantation.

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