Classifications

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  • 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
  • C07D403/12—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 linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • 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
  • C07D403/02—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
  • C07D403/10—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 linked by a carbon chain containing aromatic 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

Definitions

• the present invention relates to a 3-substituted proline derivative having an anticoagulant action or a salt thereof. Specifically, the present invention relates to a 3-position substituted proline derivative that is effective as an FXIa (activated factor XI) inhibitor. Further, the present invention relates to a pharmaceutical use of a 3-position proline derivative effective as an FXIa inhibitor.
• FXIa activated factor XI
• Atherothrombosis that develops due to arteriosclerosis that induces myocardial infarction, cerebral infarction, and the like, and deep vein thrombosis that induces pulmonary embolism occupy many causes of human death.
• the most effective anticoagulant currently has the effect or effect of “treatment and prevention of thromboembolism (venous thrombosis, myocardial infarction, pulmonary embolism, cerebral embolism, slowly progressing cerebral thrombosis, etc.)”
• the warfarin used has a problem that, while exhibiting an excellent antithrombotic action, it is difficult to stop bleeding at the time of bleeding and causes serious side effects such as bleeding complications.
• factor XI factor XI
• FXIa activated factor XI
• a dipeptide analog compound represented by the following formula is disclosed in Patent Document 1.
• A is a C 3-10 carbocycle optionally substituted with a specific substituent, or a 5- to 10-membered heterocycle optionally substituted with a specific substituent, provided that When A is a heterocycle containing one or more nitrogen atoms, A is not bonded to L through any of the nitrogen atoms on the A ring, and L 1 is —CH (R 5 ) CH 2 C (O) NH—, —C (R 5 ) ⁇ CHC (O) NH—, —CH ⁇ C (R 5 ) C (O) NH—, —C (R 5 ) ⁇ C (R 5 ) C (O) NH—, —CH 2 NHC (O) NH—, etc., R 5 is a hydrogen atom, C 1-4 alkyl, etc .; R 11 is a C 1-4 haloalkyl specific substituent.
• R 12 is a hydrogen atom, etc .
• M is a specific substituent A — (CH 2 ) r —C 3-10 carbocycle optionally substituted with a group, or a — (CH 2 ) r —5 to 10 membered heterocycle optionally substituted with a specific substituent. Yes; r is selected from 0, 1, 2, 3, and 4.)
• Patent Document 1 describes that the compound inhibits FXIa and serum kallikrein and is effective in treating or preventing thromboembolism.
• An object of the present invention is to provide a novel compound having excellent FXIa inhibitory activity and useful as a therapeutic agent for thrombosis and thromboembolism. Furthermore, it is providing the pharmaceutical use of this novel compound.
• the present inventors have found that the compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof (hereinafter abbreviated as “the compound of the present invention” as necessary). Because the compound represented by the above formula described in Patent Document 1 does not include a compound in which R 11 or R 12 together with L 1 forms a cyclic group such as a pyrrolidine ring. The present inventors have found that this compound is a novel compound having a chemical structure different from that of the compound and has an excellent FXIa inhibitory activity, thereby completing the present invention.
• ring D represents a phenyl ring or a 5- or 6-membered heteroaryl ring
• m represents 0, 1 or 2
• R a is a halogen atom, a cyano group, a hydroxy group, a carboxyl group, an optionally substituted phenyl group, an optionally substituted 5- to 10-membered heteroaryl group, an optionally substituted 4-membered to 10-membered saturated heterocyclic group, optionally substituted phenoxy group, optionally substituted 5- to 10-membered heteroaryloxy group, optionally substituted 4- to 10-membered saturated heterocyclic oxy Group, optionally substituted amino group, optionally substituted 4- to 10-membered cyclic amino group, optionally substituted C 1-6 alkylcarbonylamino group, optionally substituted C 1 -6 alkoxycarbonylamino group, an optionally substituted C 3-10 cycloalkyl carbonyl amino group, an optionally substituted C 3-10 cycloalkyl alkoxy
• R c represents a halogen atom, a cyano group, a carboxyl group, a hydroxy group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 2-6 alkenyl group, or an optionally substituted C 2 A -6 alkynyl group, an optionally substituted C 1-6 alkoxy group, an optionally substituted C 2-6 alkenyloxy group, an optionally substituted C 3-10 cycloalkyl group, An optionally substituted C 3-10 cycloalkoxy group, an optionally substituted C 1-6 alkylthio group, an optionally substituted C 1-6 alkoxycarbonyl group, an optionally substituted C 6-10 aryl group, substituted 5 may membered to 10-membered heteroaryl group, a saturated heterocyclic group of 4-membered to 10-membered may be substituted, an optionally substituted C 6-10 aryloxy group, Optionally substituted 5- to 10-membered heteroaryloxy group, optionally substituted
• X 1 , X 2 and X 3 each independently represent N or CR 1 ; X 4 and X 5 each independently represent CR 2 , O, S, N, or NR 3 ; A 1 and A 2 each independently represent N or C; Wherein X 1 , X 2 , X 3 , X 4 , X 5 , A 1 , and A 2 are selected such that the ring containing them forms a bicyclic aromatic heterocycle; X 6 and X 9 each independently represent N or CR 4 ; X 7 and X 8 each independently represent N or CR f ; X 10 and X 11 each independently represent N or CR 5 ; R 1 represents a hydrogen atom, a halogen atom, a cyano group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-10 cycloalkyl group, or an optionally substituted C 1 1- 6 represents an alkoxy group (wherein, when 2 or 3 R 1 s are present in the
• An optionally substituted amino group, an optionally substituted 4- to 10-membered cyclic amino group, an optionally substituted aminocarbonyl group, an optionally substituted 4- to 10-membered cyclic amino group Represents a carbonyl group or an optionally substituted C 1-6 alkoxy group (wherein, when two R 4 s are present in the formula, each group represents the same or different group);
• R 5 represents a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-10 cycloalkyl group, or an optionally substituted amino group.
• R g is a hydrogen atom, a halogen atom, a cyano group, a carboxyl group, a hydroxy group, an optionally substituted C 3-10 cycloalkyl group, an optionally substituted C 1-6 alkoxy group, a substituted C 3-10 cycloalkoxy group which may be substituted, C 6-10 aryloxy group which may be substituted, 4-membered to 10-membered heteroaryloxy group which may be substituted, 4-membered which may be substituted 10-membered saturated heterocyclic oxy group, optionally substituted C 1-6 alkylthio group, optionally substituted C 3-10 cycloalkylthio group, optionally substituted C 6-10 arylthio group, substituted An optionally substituted amino group, an optionally substituted aminocarbonyl group, an optionally substituted aminosulfonyl group, an optionally substituted 4 to 10 membered Jo amino group, a substituted ⁇ also be 4-membered optionally 10-member
• R a is (1) a phenyl group (the group is (A) a halogen atom, (B) cyano, (C) hydroxy, (D) carboxyl, (E) C 1-6 alkyl (the group may be substituted with 1 to 3 halogen atoms), (F) C 1-6 alkoxy (the group may be substituted with 1 to 3 halogen atoms), (G) C 1-6 alkoxycarbonylamino, (H) C 1-6 alkylsulfonylamino (the alkyl may be substituted with 1 to 3 halogen atoms), (I) C 3-10 cycloalkyl (the group may be substituted with 1 to 3 halogen atoms, or C 1-6 alkyl), (J) C 1-6 alkylcarbonylamino, (K) amino (the group is (I) C 1-6 alkyl (the group is substituted with 1 to 3 halogen atoms, cyano, hydroxy, C 1-6 alk
• (L) aminocarbonyl (the group may be substituted with 1 or 2 groups of the same or different types selected from the group consisting of (i) to (v) of the above (k)), (M) a 4- to 10-membered cyclic amino (the group is (I) C 1-6 alkyl (the group may be substituted with a halogen atom, hydroxy, or C 1-6 alkoxy), (Ii) C 1-6 alkoxy (the group may be substituted with 1 to 3 halogen atoms), or (iii) C 1-6 alkoxycarbonylamino, (Iv) 1 to 3 halogen atoms, and (v) 1 to 4 groups of the same or different types selected from the group consisting of hydroxy may be substituted.
• a 4- to 10-membered cyclic aminocarbonyl (the group is the same or different 1 to 4 groups selected from the group consisting of (i) to (v) of the above (m)) May be substituted).
• a 5- or 6-membered heteroaryl group (the group is substituted with 1 to 4 groups of the same or different types selected from the group consisting of (a) to (n) of the above (1)
• You may) (3) a 4- to 10-membered saturated heterocyclic group (the group is substituted with 1 to 4 groups of the same or different types selected from the group consisting of (a) to (n) of the above (1) May be)
• (4) a phenoxy group (the group may be substituted with 1 to 4 groups of the same or different types selected from the group consisting of (a) to (n) of (1)), (5) a 5- or 6-membered heteroaryloxy group (the group is substituted with 1 to 4 groups of the same or different types selected from the group consisting of (a) to (n) of (1) above)
• a 4- to 10-membered cyclic amino (the group is (I) C 1-6 alkyl (the group may be substituted with a halogen atom, hydroxy, or 1 to 3 halogen atoms), (Ii) C 1-6 alkoxy (the group may be substituted with 1 to 3 halogen atoms), (Iii) C 1-6 alkoxycarbonylamino, (Iv) 1 to 3 halogens, and (v) 1 to 4 groups of the same or different types selected from the group consisting of hydroxy may be substituted. ) May be substituted.
• R b is independently when m is 2, (1) a hydroxy group, (2) a halogen atom, (3) a cyano group, (4) C 1-6 alkyl group (the group may be substituted with 1 to 3 halogen atoms), or (5) C 1-6 alkoxy group (the group is 1 to 3 Or a pharmaceutically acceptable salt thereof.
• R a is a halogen atom, a 5-membered heteroaryl group (the group is a halogen atom, or C 1-6 alkyl (the group may be substituted with 1 to 3 halogen atoms). ), A C 1-6 alkyl group (the group may be substituted with 1 to 3 halogen atoms), or a C 1-6 alkoxy group (the group is Optionally substituted with 1 to 3 halogen atoms, 5 membered heteroaryl, or 4 to 6 membered saturated heterocycle), When there are a plurality of R b s , each independently represents a halogen atom, a C 1-6 alkoxy group (the group may be substituted with 1 to 3 halogen atoms), or a C 1-6 alkyl.
• L is —CR 61 ⁇ CR 71 —, or —CR 61 R 62 —CR 71 R 72 —, and R 61 , R 62 , R 71 and R 72 are each independently a hydrogen atom, Or a C 1-6 alkyl group (the group may be substituted with 1 to 3 halogen atoms), and R d is a hydrogen atom or a C 1-6 alkyl group, [1] to [6], or a pharmaceutically acceptable salt thereof.
• R C is (1) C 1-6 alkoxy group (the group is a phenyl group (the group is selected from the group consisting of a halogen atom, cyano, C 1-6 alkyl, C 1-6 alkoxycarbonylamino, and C 1-6 alkoxy) Optionally substituted with 1 to 4 groups of the same or different selected from each other), or a pyridyl group (the group is a halogen atom, cyano, C 1-6 alkyl, C 1-6 alkoxycarbonylamino, And optionally substituted with 1 to 4 groups of the same or different types selected from the group consisting of C 1-6 alkoxy.
• a C 3-10 cycloalkyl group (the group is substituted with 1 to 4 groups of the same or different types selected from the group consisting of a halogen atom, C 1-6 alkyl, and C 1-6 alkoxy) May be) (3) a C 3-10 cycloalkoxy group, (4) Phenyl group (this group is (A) a halogen atom, (B) cyano, (C) hydroxy, (D) carboxyl, (E) C 1-6 alkyl (the group may be substituted with 1 to 3 halogen atoms), (F) C 1-6 alkoxy (the group may be substituted with 1 to 3 halogen atoms), (G) C 1-6 alkoxycarbonylamino, (H) C 1-6 alkylsulfonylamino (the alkyl may be substituted with 1 to 3 halogen atoms), (I) C 3-10 cycloalkyl (the group may be substituted with 1 to 3 halogen atoms,
• (L) aminocarbonyl (the group may be substituted with 1 or 2 groups of the same or different types selected from the group consisting of (i) to (v) of the above (k)), (M) a 4- to 10-membered cyclic amino (the group is (I) a halogen atom, (Ii) C 1-6 alkyl (the group may be substituted with C 1-6 alkoxy, hydroxy, or 1 to 3 halogen atoms), (Iii) C 1-6 alkoxy (the group may be substituted with 1 to 3 halogen atoms), and (iv) the same or selected from the group consisting of C 1-6 alkoxycarbonylamino It may be substituted with 1 to 4 different groups.
• a 4- to 10-membered cyclic aminocarbonyl (the group is the same or different 1 to 4 groups selected from the group consisting of (i) to (iv) of (m) above) May be substituted).
• a 5- or 6-membered heteroaryl group (the group is substituted with 1 to 4 groups of the same or different types selected from the group consisting of (a) to (n) of (4) above
• (6) a 4-membered to 10-membered saturated heterocyclic group (the group is substituted with 1 to 4 groups of the same or different types selected from the group consisting of (a) to (n) of the above (4) May be)
• Phenoxy group (the group is (A) a halogen atom, (B) C 1-6 alkyl (the group may be substituted with 1 to 3 halogen atoms), and (c) C 1-6 alkoxy (the group is substituted with 1 to 3 halogen atoms).
• R C is (1) C 1-6 alkoxy group (the group is a phenyl group (the group is the same or different 1-4 selected from the group consisting of a halogen atom, C 1-6 alkyl, and C 1-6 alkoxy) Or may be substituted with a pyridyl group).
• a C 3-6 cycloalkyl group (the group is substituted with 1 to 4 groups of the same or different types selected from the group consisting of a halogen atom, C 1-6 alkyl, and C 1-6 alkoxy) May be) (3) a C 3-6 cycloalkoxy group, (4) Phenyl group (this group is (A) a halogen atom, (B) C 1-6 alkyl (the group may be substituted with 1 to 3 halogen atoms), and (c) C 1-6 alkoxy (the group is substituted with 1 to 3 halogen atoms).
• R C is (1) C 1-6 alkoxy group (the group is a phenyl group (the group is the same or different 1-4 selected from the group consisting of a halogen atom, C 1-6 alkyl, and C 1-6 alkoxy) Or may be substituted with a pyridyl group).
• a cyclohexyl group this group may be substituted with 1 to 4 groups of the same or different types selected from the group consisting of a halogen atom, C 1-6 alkyl, and C 1-6 alkoxy).
• a phenyl group (the group is (A) a halogen atom, (B) C 1-6 alkyl (the group may be substituted with 1 to 3 halogen atoms), or (c) C 1-6 alkoxy (the group is substituted with 1 to 3 halogen atoms). It may be substituted with an atom).
• R C is (1) C 1-6 alkoxy group (the group is a phenyl group (the group is the same or different 1-4 selected from the group consisting of a halogen atom, C 1-6 alkyl, and C 1-6 alkoxy) Or may be substituted with a pyridyl group).
• a cyclohexyl group (this group may be substituted with 1 to 4 groups of the same or different types selected from the group consisting of halogen atoms and C 1-6 alkoxy), (3) a phenyl group (the group is (A) a halogen atom, (B) C 1-6 alkyl (the group may be substituted with 1 to 3 halogen atoms), and (c) C 1-6 alkoxy (the group is substituted with 1 to 3 halogen atoms).
• R C is (1) A cyclohexyl group (this group may be substituted with 1 to 4 groups of the same or different types selected from the group consisting of halogen atoms and C 1-6 alkoxy), (2) a phenyl group (the group is (A) a halogen atom, (B) C 1-6 alkyl (the group may be substituted with 1 to 3 halogen atoms), or (c) C 1-6 alkoxy (the group is substituted with 1 to 3 halogen atoms). It may be substituted with an atom).
• the ring Q is represented by the following formulas (3a) to (3z):
• R 11 , R 12 , R 13 , and R 14 are each independently a hydrogen atom, a halogen atom, a cyano group, an optionally substituted C 1-6 alkyl group, or an optionally substituted group.
• R 21 represents a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, an optionally substituted C 2-6 alkenyl group, an optionally substituted C 2-6 alkynyl group, or an optionally substituted C 1 -6 alkyl group, C 3-10 cycloalkyl group which may be substituted, amino group which may be substituted, C 1-6 alkylcarbonyl group which may be substituted, aminocarbonyl which may be substituted Group, optionally substituted 4- to 10-membered cyclic aminocarbonyl group, optionally substituted C 1-6 alkylsulfonylamin
• R 51 and R 52 each independently represent a hydrogen atom, a halogen atom, a cyano group, an optionally substituted C 1-6 alkyl group, an optionally substituted C 3-10 cycloalkyl group, or a substituted group.
• An optionally substituted amino group, an optionally substituted C 1-6 alkylcarbonyl group, an optionally substituted aminocarbonyl group, an optionally substituted 4- to 10-membered cyclic aminocarbonyl group, substituted is optionally C 1-6 alkylsulfonylamino group, an optionally substituted C 1-6 alkylcarbonylamino group, an optionally substituted C 1-6 alkoxycarbonylamino group, optionally substituted Represents a 4- to 10-membered saturated heterocyclic group, an optionally substituted C 1-6 alkoxycarbonyl group, or a carboxyl group;
• R h , R i and R k are each independently a hydrogen atom, a halogen atom, a cyano group, a carboxyl group, a hydroxy group, an optionally substituted C 3-10 cycloalkyl group, or an optionally substituted A good C 1-6 alkoxy group, an optionally substituted C 3-10 cycloalkoxy
• the ring Q is represented by the formula (3a), (3b), (3c), (3d), (3h), (3j), (3m), (3s), (3t), or (3u). Or a pharmaceutically acceptable salt thereof.
• R 11 , R 12 , R 13 , R 14 , R 41 , and R 42 are each independently a hydrogen atom, a halogen atom, a cyano group, a C 1-6 alkyl group (the group is 1 to Optionally substituted with 3 halogen atoms), a C 1-6 alkoxy group (which group may be substituted with 1 to 3 halogen atoms), or C 3-10 cycloalkyl.
• R 21 is (1) a hydrogen atom, (2) a halogen atom, (3) a cyano group, (4) a C 1-6 alkyl group (the group may be substituted with 1 to 3 halogen atoms), (5) a C 3-10 cycloalkyl group, (6) Amino group (this group may be substituted with the same or different 1-2 C 1-6 alkyl), (7) a C 1-6 alkylcarbonyl group (the group may be substituted with 1 to 3 halogen atoms), (8) C 1-6 alkylcarbonylamino group (the group may be substituted with 1 to 3 halogen atoms), (9) a C 1-6 alkoxycarbonylamino group, (10) a phenyl group (the group is (A) a halogen atom, (B) cyano, (C) hydroxy, (D) carboxyl, (E) C 1-6 alkyl (the group may be substituted with 1 to 3 halogen atoms), (F
• (L) aminocarbonyl (the group may be substituted with 1 or 2 groups of the same or different types selected from the group consisting of (i) to (v) of the above (k)), (M) a 4- to 10-membered cyclic amino (the group is (I) C 1-6 alkyl (the group may be substituted with hydroxy or 1 to 3 halogen atoms), (Ii) C 1-6 alkoxy (the group may be substituted with 1 to 3 halogen atoms), and (iii) the same or a group selected from the group consisting of C 1-6 alkoxycarbonylamino It may be substituted with 1 to 4 different groups.
• a 4- to 10-membered cyclic aminocarbonyl (the group is the same or different 1 to 4 groups selected from the group consisting of (i) to (iii) of (m) above) May be substituted).
• a 5- or 6-membered heteroaryl group (the group is substituted with 1 to 4 groups of the same or different types selected from the group consisting of (a) to (n) of the above (10)
• (12) a 5- or 6-membered saturated heterocyclic group (the group is substituted with 1 to 4 groups of the same or different types selected from the group consisting of (a) to (n) of the above (10) May be)
• Aminocarbonyl (this group may be substituted with 1 or 2 groups of the same or different types selected from the group consisting of (i) to (v) of the above (k)),
• 4- to 10-membered cyclic aminocarbonyl (the group is substituted with 1 to 4 groups selected from
• C 3-10 cycloalkyl (the group may be substituted with 1 to 3 halogen atoms, or C 1-6 alkyl). ), (3) a C 3-10 cycloalkyl group (the group may be substituted with 1 to 3 halogen atoms or C 1-6 alkyl), (4) a C 1-6 alkylcarbonyl group (the group may be substituted with 1 to 3 halogen atoms), or (5) a C 1-6 alkylsulfonyl group (the group is 1 to 3).
• R 51 and R 52 are each independently (1) a hydrogen atom, (2) a halogen atom, (3) a cyano group, (4) a C 1-6 alkyl group (the group may be substituted with 1 to 3 halogen atoms), (5) a C 3-10 cycloalkyl group, (6) Amino group (this group may be substituted with the same or different 1-2 C 1-6 alkyl), (7) a C 1-6 alkylcarbonyl group (the group may be substituted with 1 to 3 halogen atoms), (8) Aminocarbonyl (this group may be substituted with the same or different 1-2 C 1-6 alkyl), (9) 4- to 10-membered cyclic aminocarbonyl (the group is (A) C 1-6 alkyl (the group may be substituted with hydroxy or 1 to 3 halogen atoms), (B) C 1-6 alkoxy (the group may be substituted with 1 to 3 halogen atoms), and (
• a C 1-6 alkylcarbonylamino group (the group is (A) a halogen atom, (B) cyano, (C) hydroxy, (D) carboxyl, (E) C 1-6 alkyl (the group may be substituted with 1 to 3 halogen atoms), (F) C 1-6 alkoxy (the group may be substituted with 1 to 3 halogen atoms), (G) C 1-6 alkoxycarbonylamino, (H) C 1-6 alkylsulfonylamino (the group may be substituted with 1 to 3 halogen atoms), (I) C 3-10 cycloalkyl (the group may be substituted with 1 to 3 halogen atoms, or C 1-6 alkyl), (J) C 1-6 alkylcarbonylamino (the group may be substituted with 1 to 3 halogen atoms), (K) amino (the group may be substituted with the same or different 1-2 C 1-6 alkyl), (L)
• R 11 , R 12 , R 13 , R 14 , R 41 , and R 42 are each independently a hydrogen atom, a halogen atom, or a C 1-6 alkyl group
• R 31 is a hydrogen atom
• 21 , R 51 , and R 52 are each independently a hydrogen atom, a halogen atom, a C 1-6 alkyl group, an amino group (the group is the same or different 1-2 C 1-6 alkyl
• R 11 , R 12 , R 13 , R 14 , R 21 , R 41 , R 42 , R 51 , and R 52 are each independently a hydrogen atom, a halogen atom, or a C 1-6 alkyl group
• R 31 is a hydrogen atom or a C 1-6 alkyl group, or a pharmaceutically acceptable salt thereof according to any one of [1] to [19] above.
• R h , R i , and R k are each independently (1) a hydrogen atom, (2) a cyano group, (3) carboxyl group, (4) Amino group (the amino is (A) C 1-6 alkyl (the group is substituted by 1 to 3 halogen atoms, cyano, hydroxy, carboxyl, C 1-6 alkoxy, C 3-10 cycloalkyl, or C 1-6 alkoxycarbonylamino) May have been) (B) C 3-10 cycloalkyl (the group may be substituted with 1 to 3 halogen atoms, or C 1-6 alkyl), (C) phenyl (the group is the same or different 1 to 4 selected from the group consisting of a halogen atom, cyano, C 1-6 alkyl, C 1-6 alkoxycarbonylamino, and C 1-6 alkoxy; Optionally substituted with a group), (D) 5- or 6-membered heteroaryl (the group is the same or selected from the first or
• an aminocarbonyl group (the amino may be substituted with one or two groups of the same or different types selected from the group consisting of (a) to (e) of (4)); (6) a 4- to 10-membered cyclic amino group (the group is (A) a halogen atom, (B) cyano, (C) hydroxy, (D) C 1-6 alkyl (the group is (I) 1 to 3 halogen atoms, (Ii) carboxyl, (Iii) aminocarbonyl (the amino may be substituted with one or two groups of the same or different types selected from the group consisting of (a) to (e) of (4)); (Iv) 4- to 10-membered cyclic aminocarbonyl (the group is selected from the group consisting of a halogen atom, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, and C 1-6 alkoxycarbonylamino) The same or different 1 to 4 groups may be substituted.), Or (v) 4- to
• C 1-6 alkoxy the group is (I) 1 to 3 halogen atoms, (Ii) carboxyl, (Iii) aminocarbonyl (the amino may be substituted with one or two groups of the same or different types selected from the group consisting of (a) to (e) of (4)); (Iv) 4- to 10-membered cyclic aminocarbonyl (the group is selected from the group consisting of a halogen atom, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, and C 1-6 alkoxycarbonylamino) Optionally substituted with 1 to 4 groups of the same or different types).
• a 4- to 10-membered cyclic aminocarbonyl group (the group is substituted with 1 to 4 groups of the same or different types selected from the group consisting of (a) to (f) of (6) above) May be)
• Phenyl group (this group is (A) a halogen atom, (B) cyano, (C) hydroxy, (D) carboxyl, (E) C 1-6 alkyl (the group is (I) 1 to 3 halogen atoms, (Ii) carboxyl, (Iii) aminocarbonyl (the amino may be substituted with one or two groups of the same or different types selected from the group consisting of (a) to (e) of (4)); (Iv) 4- to 10-membered cyclic aminocarbonyl (the group is selected from the group consisting of a halogen atom, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, and C 1-6 alkoxycarbonylamino)
• C 1-6 alkoxy the group is (I) 1 to 3 halogen atoms, (Ii) carboxyl, (Iii) aminocarbonyl (the amino may be substituted with one or two groups of the same or different types selected from the group consisting of (a) to (e) of (4)); (Iv) 4- to 10-membered cyclic aminocarbonyl (the group is substituted with 1 to 4 groups of the same or different types selected from the group consisting of (a) to (f) of (6) above) Or (v) may be substituted with C 1-6 alkoxycarbonylamino.
• a 5- or 6-membered heteroaryl group (the group is selected from the group consisting of 1 to 4 groups of the same or different types selected from the group consisting of (a) to (o) of (8) above Optionally substituted with 1 to 4 groups of the same or different selected.), (10) a 4- to 10-membered saturated heterocyclic group (the group is substituted with 1 to 4 groups of the same or different types selected from the group consisting of (a) to (o) of (8) above May be) (11) C 1-6 alkyl group (the group is (A) 1 to 3 halogen atoms, (B) carboxyl, (C) cyano, (D) C 1-6 alkoxy, (E) phenyl (this group may be substituted with 1 to 4 groups of the same or different types selected from the group consisting of (a) to (o) of the above (8)); (F) 5-membered or 6-membered heteroaryl (the group is substituted with 1 to 4 groups of the same or different types selected from the
• R h , R i , and R k are each independently (1) a hydrogen atom, (2) carboxyl group, (3) Aminocarbonyl group (the group may be the same or different from 1 to 2 C 1-6 alkyls (the group may be substituted with 1 to 3 halogen atoms or C 1-6 alkoxy) .) May be substituted)), (4) 4- to 6-membered cyclic aminocarbonyl group (the group includes 1 to 3 halogen atoms, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, C 3-10 cyclo Optionally substituted with 1 to 4 groups of the same or different types selected from the group consisting of alkoxy, C 1-6 alkoxycarbonyl, and C 1-6 alkoxycarbonylamino), (5) phenyl group (the group is selected from the group consisting of carboxyl, halogen atom, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxycarbonyl
• (6) 5 or 6 membered heteroaryl group (the group is selected from the group consisting of carboxyl, halogen atom, C 1-6 alkyl, C 1-6 alkoxycarbonyl, and C 1-6 alkoxycarbonylamino) Optionally substituted with 1 to 4 groups of the same or different types), or (7) a 4-membered to 6-membered saturated heterocyclic group (the group is a carboxyl, halogen atom, C 1-6 alkyl, Optionally substituted with 1 to 4 groups of the same or different types selected from the group consisting of C 1-6 alkoxy, C 1-6 alkoxycarbonyl, and C 1-6 alkoxycarbonylamino.
• R h , R i , and R k are each independently (1) a carboxyl group, (2) Aminocarbonyl group (the group may be the same or different 1 to 2 C 1-6 alkyl (the group may be substituted with 1 to 3 halogen atoms or C 1-6 alkoxy) )), Or (3) a 4- to 6-membered cyclic aminocarbonyl group (wherein the group contains 1 to 3 halogen atoms, C 1-6 alkyl, and C 1-6 Or a compound of any one of the above-mentioned [1] to [22], which may be substituted with the same or different 1 to 4 groups selected from the group consisting of alkoxy, or A pharmaceutically acceptable salt.
• R m is (1) a hydrogen atom, (2) a cyano group, (3) carboxyl group, (4) Amino group (the amino is (A) C 1-6 alkyl (the group is substituted by 1 to 3 halogen atoms, cyano, hydroxy, carboxyl, C 1-6 alkoxy, C 3-10 cycloalkyl, or C 1-6 alkoxycarbonylamino) May have been) (B) C 3-10 cycloalkyl (the group may be substituted with 1 to 3 halogen atoms, or C 1-6 alkyl), (C) phenyl (the group is the same or different 1 to 4 selected from the group consisting of a halogen atom, cyano, C 1-6 alkyl, C 1-6 alkoxycarbonylamino, and C 1-6 alkoxy; Optionally substituted with a group), (D) 5- or 6-membered heteroaryl (the group is the same or selected from the group consisting of a halogen atom,
• an aminocarbonyl group (the amino may be substituted with one or two groups of the same or different types selected from the group consisting of (a) to (e) of (4)); (6) a 4- to 10-membered cyclic amino group (the group is (A) a halogen atom, (B) cyano, (C) hydroxy, (D) C 1-6 alkyl (the group is (I) 1 to 3 halogen atoms, (Ii) carboxyl, (Iii) aminocarbonyl (the amino may be substituted with one or two groups of the same or different types selected from the group consisting of (a) to (e) of (4)); (Iv) 4- to 10-membered cyclic aminocarbonyl (which may be substituted with a halogen atom, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkoxycarbonylamino) Or (v) optionally substituted with C 1-6 alkoxycarbonylamino.
• C 1-6 alkoxy the group is (I) 1 to 3 halogen atoms, (Ii) carboxyl, (Iii) aminocarbonyl (the amino may be substituted with one or two groups of the same or different types selected from the group consisting of (a) to (e) of (4)); (Iv) 4- to 10-membered cyclic aminocarbonyl (which may be substituted with a halogen atom, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkoxycarbonylamino) Or (v) optionally substituted with C 1-6 alkoxycarbonylamino.
• C 1-6 alkoxy the group is (I) 1 to 3 halogen atoms, (Ii) carboxyl, (Iii) aminocarbonyl (the amino may be substituted with one or two groups of the same or different types selected from the group consisting of (a) to (e) of (4)); (Iv) 4- to 10-membered cyclic aminocarbonyl (the group is substituted with 1 to 4 groups of the same or different types selected from the group consisting of (a) to (f) of (6) above) Or (v) may be substituted with C 1-6 alkoxycarbonylamino.
• a C 1-6 alkyl group (the group is (A) 1 to 3 halogen atoms, (B) carboxyl, (C) cyano, (D) C 1-6 alkoxy, (E) phenyl (this group may be substituted with 1 to 4 groups of the same or different types selected from the group consisting of (a) to (o) of the above (8)); (F) a 5- to 6-membered heteroaryl (the group is substituted with 1 to 4 groups of the same or different types selected from the group consisting of (a) to (o) of (8) above May be good), (G) a 4- to 10-membered saturated heterocycle (the group is substituted with 1 to 4 groups of the same or different types selected from the group consisting of (a) to (o) of (8) above You may) (H) hydroxy, (I) aminocarbonyl (the amino may be substituted with one or two different groups selected from the group consisting of (a) to (e) in (4)), (J) 4- to 10-member
• R m is (1) a carboxyl group, (2) Aminocarbonyl group (the group may be the same or different 1 to 2 C 1-6 alkyls (the group may be substituted with 1 to 3 halogen atoms or C 1-6 alkoxy) .) May be substituted)), (3) a 4-membered to 6-membered cyclic aminocarbonyl group (the group includes 1 to 3 halogen atoms, C 1-6 alkyl, C 1-6 alkoxy, C 3-10 cycloalkyl, C 3-10 cyclo Optionally substituted with 1 to 4 groups of the same or different types selected from the group consisting of alkoxy, C 1-6 alkoxycarbonyl, and C 1-6 alkoxycarbonylamino), or (4) 4 members A 6-membered saturated heterocyclic group (the group is selected from the group consisting of carboxyl, halogen atom, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, and C 1-6 alkoxycarbon
• C 1-6 alkoxy group (this group may be substituted with a carboxyl group), (6) a 5- or 6-membered heteroaryl group, (7) C 1-6 alkylsulfonylaminocarbonyl group (the group may be substituted with 1 to 3 halogen atoms or C 1-6 alkoxy), or (8) benzenesulfonylaminocarbonyl group ( The group is substituted with 1 to 4 groups of the same or different types selected from the group consisting of carboxyl, halogen atom, C 1-6 alkyl, C 1-6 alkoxy, and C 1-6 alkoxycarbonyl.
• R m is (1) a carboxyl group, (2) a C 1-6 alkoxy group (the group may be substituted with a carboxyl group), (3) a tetrazolyl group, (4) 5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl group, (5) The compound according to any one of [1] to [25] above, which is a C 1-6 alkylsulfonylaminocarbonyl group or (6) a benzenesulfonylaminocarbonyl group, or a pharmaceutically acceptable salt thereof salt.
• R a1 represents a halogen atom or a tetrazolyl group
• R b1 represents a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl group, or an optionally substituted C 1-6 alkoxy group
• R C1 represents an optionally substituted 4- to 6-membered cycloalkyl group, an optionally substituted phenyl group, an optionally substituted pyridyl group, an optionally substituted C 1-6 Represents an alkoxy group, an optionally substituted 4- to 6-membered saturated heterocyclic group, an optionally substituted 4- to 6-membered cyclic amino group, or an optionally substituted amino group
• Ring Q 1 is represented by the following formulas (5a) to (5d):
• R 15 , R 16 , R 17 , and R 18 each independently represents a hydrogen atom, a halogen atom, or an optionally substituted C 1-6 alkyl group;
• R 32 represents a hydrogen atom or an optionally substituted C 1-6 alkyl group;
• R w represents a carboxyl group, an optionally substituted aminocarbonyl group, an optionally substituted 4- to 6-membered cyclic aminocarbonyl group, a tetrazolyl group, 5-oxo-2,5-dihydro-1,2 , 4-oxadiazol-3-yl group, an optionally substituted C 1-6 alkoxy group, a C 1-6 alkylsulfonylaminocarbonyl group, or a benzenesulfonylaminocarbonyl group.
• R a1 is a halogen atom or a tetrazolyl group
• R b1 represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group (the group may be substituted with 1 to 3 halogen atoms), or a C 1-6 alkoxy group (the group includes Optionally substituted with 1 to 3 halogen atoms)
• R C1 is (1) A cyclohexyl group (the group is (A) a halogen atom, (B) C 1-6 alkyl (the group may be substituted with 1 to 3 halogen atoms), and (c) C 1-6 alkoxy (the group is substituted with 1 to 3 halogen atoms).
• R 15 , R 16 , R 17 , and R 18 are each independently a hydrogen atom or a halogen atom;
• R 32 is a hydrogen atom or a C 1-6 alkyl group;
• Rw is (1) a carboxyl group, (2) an aminocarbonyl group (the group is substituted with the same or different 1-2 C 1-6 alkyl group (the alkyl group may be substituted with 1 to 3 halogen atoms))
• You may) (3) a 4- to 6-membered cyclic aminocarbonyl group (the group is (A) a halogen atom, (B) C 1-6 alkyl (the group may be substituted with 1 to 3 halogen atoms), and (c) C 1-6 alkoxy (the group is substituted with 1 to 3 halogen atoms).
• R C1 is (1) A cyclohexyl group (this group may be substituted with 1 to 4 groups of the same or different types selected from the group consisting of a halogen atom, C 1-6 alkyl, and C 1-6 alkoxy). ), (2) phenyl group (the group is (A) a halogen atom, (B) C 1-6 alkyl (the group may be substituted with 1 to 3 halogen atoms), and (c) C 1-6 alkoxy (the group is substituted with 1 to 3 halogen atoms).
• R a1 is a tetrazolyl group
• R C1 is (1) A cyclohexyl group (this group may be substituted with 1 to 4 groups of the same or different types selected from the group consisting of halogen atoms and C 1-6 alkoxy), (2) phenyl group (the group is (A) a halogen atom, (B) C 1-6 alkyl (the group may be substituted with 1 to 3 halogen atoms), and (c) C 1-6 alkoxy (the group is substituted with 1 to 3 halogen atoms).
• a medicament comprising the compound according to any one of [1] to [32] above or a pharmaceutically acceptable salt thereof as an active ingredient.
• a FXIa inhibitor comprising the compound according to any one of [1] to [32] above or a pharmaceutically acceptable salt thereof as an active ingredient.
• a therapeutic agent for thromboembolism comprising the compound according to any one of [1] to [32] above or a pharmaceutically acceptable salt thereof as an active ingredient.
• a therapeutic agent for thrombosis comprising as an active ingredient the compound according to any one of [1] to [32] above, or a pharmaceutically acceptable salt thereof.
• a method for treating thromboembolism comprising administering the compound according to any one of [1] to [32] above or a pharmaceutically acceptable salt thereof to a subject in need thereof.
• a method for treating thrombosis comprising administering the compound according to any one of [1] to [32] above or a pharmaceutically acceptable salt thereof to a subject in need thereof.
• the compound of the present invention has a strong FXIa inhibitory activity, it is useful for the treatment of thromboembolism, thrombosis and the like.
• C 1-6 alkyl is synonymous with an alkyl group having 1 to 6 carbon atoms.
• the substituent in the group defined as “optionally substituted” can be substituted at a substitutable position within the substitutable number range.
• the range of the number of substitutable substituents in the methyl group is 1 to 3.
• the optionally substituted C 6-10 aryl group is a phenyl group
• the number of substitutable substituents in the phenyl group ranges from 1 to 5.
• there are a plurality of substituted groups they may be the same or different.
• the description of each group also applies if the group is part of another group or a substituent.
• Halogen atom includes fluorine atom, chlorine atom, bromine atom or iodine atom.
• C 1-6 alkyl group means a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms.
• a “C 1-4 alkyl group” is preferable.
• Specific examples of “C 1-6 alkyl group” include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl and isohexyl. 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like.
• C 2-6 alkenyl group means a linear or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms and having one or two double bonds.
• Specific examples of “C 2-6 alkenyl group” include, for example, vinyl, propenyl, methylpropenyl, butenyl, methylbutenyl and the like.
• C 2-6 alkynyl group means a linear or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms and having one or two triple bonds.
• Specific examples of “C 2-6 alkynyl group” include, for example, ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, pentynyl, hexynyl and the like.
• the carbon atom constituting the double bond is not a bond of the “group”.
• C 3-10 cycloalkyl group means a monocyclic or polycyclic saturated or partially unsaturated hydrocarbon group of 3-membered to 10-membered. Preferred is “C 3-6 cycloalkyl group”. Specific examples of “C 3-10 cycloalkyl group” include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, decalinyl, adamantyl, norbornyl and the like.
• C 3-10 cycloalkyl group “C 3-10 cycloalkyl” and one or more heteroatoms selected from phenyl or 5- or 6-membered nitrogen, sulfur and oxygen atoms are the same or different.
• a group condensed with a ring containing the above (for example, 1 to 4) is also included. Specific examples of the group include groups represented by the following formulas. These phenyl groups or substituents which may be substituted on rings containing one or more (for example, 1 to 4) heteroatoms selected from 5 or 6-membered nitrogen, sulfur or oxygen atoms. Includes a substituent in the “optionally substituted C 6-10 aryl group” and the “optionally substituted heteroaryl group”.
• the “C 3-10 cycloalkyl group” includes a saturated bicyclo ring. Specific examples include groups represented by the following groups.
• C 6-10 aryl group means an aromatic hydrocarbon group having 6 to 10 carbon atoms. Preferred is a “C 6 aryl group” (phenyl). Specific examples of “C 6-10 aryl group” include, for example, phenyl, 1-naphthyl, 2-naphthyl and the like.
• the “C 6-10 aryl group” contains one or more (for example, 1 to 4) of the same or different heteroatoms selected from phenyl and 5- to 7-membered nitrogen, sulfur or oxygen atoms.
• a ring or a group condensed with a 5- to 7-membered saturated hydrocarbon ring (cyclopentane or cyclohexane) is also included.
• Specific examples of the group include groups represented by the following formulas.
• heteroaryl group examples include a 5- to 10-membered monocyclic or polycyclic aromatic group, and the group includes a heteroatom selected from a nitrogen atom, a sulfur atom or an oxygen atom. 1 or more (for example, 1 to 4) containing the same or different.
• polycyclic heteroaryl group a bicyclic or tricyclic group is preferable, and a bicyclic group is more preferable.
• the polycyclic heteroaryl group includes those in which the monocyclic heteroaryl group is condensed with an aromatic ring (benzene, pyridine, etc.) or a non-aromatic ring (cyclohexyl, piperidine, etc.).
• Specific examples of the “heteroaryl group” include, for example, a group represented by the following formula.
• the bond across the ring means that the “group” is bonded at a substitutable position in the ring.
• heteroaryl group means a 2-furyl group or a 3-furyl group.
• heteroaryl group is a polycyclic group, for example, the following formula
• heteroaryl group In the case of the “polycyclic heteroaryl group” represented by the formula, it means that the “group” is bonded at the 2-, 3-, or 4-position.
• the “heteroaryl group” is preferably a 5- to 10-membered monocyclic or polycyclic aromatic group, more preferably a 5- or 6-membered monocyclic aromatic group.
• the “5-membered or 6-membered heteroaryl ring” in ring D is the same or different hetero atom selected from a nitrogen atom, a sulfur atom or an oxygen atom, or a 5-membered group containing 1 or more (for example 1 to 4) hetero atoms.
• a 6-membered monocyclic aromatic ring may be mentioned.
• pyridine ring pyrimidine ring
• pyrazine ring pyridazine ring
• triazine ring pyrazole ring
• imidazole ring oxazole ring
• thiazole ring isoxazole ring
• isothiazole ring triazole ring oxadiazole ring
• thiadiazole ring Tetrazole and the like.
• the “saturated heterocyclic group” is, for example, a 4- to 10-membered monocyclic or polycyclic saturated heterocycle having 1 to 3 of the same or different atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom.
• a cyclic group etc. are mentioned.
• the nitrogen atom, oxygen atom and sulfur atom are all atoms constituting a ring.
• the heterocyclic group may be either saturated or partially unsaturated.
• a saturated heterocyclic group is preferable, and a 5- or 6-membered saturated heterocyclic group is more preferable.
• the nitrogen atom constituting the ring is not a bond of the “group”. That is
• the “4-membered to 6-membered saturated heterocyclic group” also includes a saturated bicyclo group and a saturated spiro ring group having a “4-membered to 6-membered saturated heterocyclic group” as a basic skeleton. Specific examples include “groups” represented by the following groups.
• the “saturated heterocyclic group” may form a condensed ring with phenyl or 6-membered heteroaryl.
• a group obtained by condensing the above-mentioned 4- to 6-membered saturated heterocyclic group with phenyl or 6-membered heteroaryl is also included.
• 6-membered heteroaryl include pyridine, pyrimidine or pyridazine.
• Examples include quinolinyl, tetrahydronaphthyridinyl, tetrahydropyridazepinyl and the like.
• substituent that may be substituted by these phenyl or 6-membered heteroaryl include “optionally substituted C 6-10 aryl group” and “optionally substituted heteroaryl group”. Substituent
• C 1-6 alkyl part of the “C 1-6 alkoxy group” has the same meaning as the above “C 1-6 alkyl”. Preferred is a “C 1-4 alkoxy group”. Specific examples of “C 1-6 alkoxy group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.
• C 2-6 alkenyl part of the “C 2-6 alkenyloxy group” has the same meaning as the above “C 2-6 alkenyl”. Preferred is a “C 2-5 alkenyl group”. Specific examples of “C 2-6 alkenyloxy group” include, for example, vinyloxy, allyloxy, 3-methylallyloxy and the like.
• C 1-6 alkyl part of the “C 1-6 alkylthio group” has the same meaning as the above “C 1-6 alkyl”.
• a “C 1-4 alkylthio group” is preferable.
• Specific examples of “C 1-6 alkylthio group” include, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, pentylthio, hexylthio and the like.
• C 1-6 alkyl part of the “C 1-6 alkylsulfonyl group” has the same meaning as the above “C 1-6 alkyl”. Preferably, it is “C 1-4 alkylsulfonyl group”. Specific examples of “C 1-6 alkylsulfonyl group” include, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, pentylsulfonyl, hexylsulfonyl and the like.
• C 3-10 cycloalkyl part of the “C 3-10 cycloalkylsulfonyl group” has the same meaning as the above “C 3-10 cycloalkyl”. Specific examples include cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl, cyclohexylsulfonyl and the like.
• C 6-10 aryl part of the “C 6-10 arylsulfonyl group” has the same meaning as the above “C 6-10 aryl”. Specific examples include phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl and the like.
• C 3-10 cycloalkyl part of the “C 3-10 cycloalkoxy group” has the same meaning as the above “C 3-10 cycloalkyl”. Specific examples include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like.
• C 6-10 aryl part of the “C 6-10 aryloxy group” has the same meaning as the above “C 6-10 aryl”. “C 6 aryloxy” (phenoxy) is preferred. Specific examples of the “C 6-10 aryloxy group” include phenoxy, 1-naphthyloxy, 2-naphthyloxy and the like.
• heteroaryl part of the “5- to 10-membered heteroaryloxy group” has the same meaning as the “heteroaryl”.
• Specific examples of the “5- to 10-membered monocyclic or polycyclic heteroaryloxy group” include pyridyloxy, imidazolyloxy, thiazolyloxy and the like.
• the “saturated heterocyclic” part of the “4- to 10-membered saturated heterocyclic oxy group” has the same meaning as the “saturated heterocyclic ring”.
• Preferable examples include “5-membered or 6-membered saturated heterocyclic oxy group”.
• Specific examples of the “4- to 10-membered saturated heterocyclic oxy group” include, for example, tetrahydropyranyloxy, tetrahydrofuryloxy, pyrrolidinyloxy, imidazolidinyloxy, piperidinyloxy, morpholinyloxy and the like. Can be mentioned.
• C 3-10 cycloalkyl part of the “C 3-10 cycloalkylthio group” has the same meaning as the above “C 3-10 cycloalkyl”. Specific examples include cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio and the like.
• C 6-10 aryl part of the “C 6-10 arylthio group” has the same meaning as the above “C 6-10 aryl”. “C 6 arylthio” (phenylthio) is preferred. Specific examples of the “C 6-10 arylthio group” include phenylthio, 1-naphthylthio, 2-naphthylthio and the like.
• C 1-6 alkyl part of the “C 1-6 alkylcarbonyl group” has the same meaning as the above “C 1-6 alkyl”. Preferably, it is “C 1-4 alkylcarbonyl group”. Specific examples of “C 1-6 alkylcarbonyl group” include, for example, methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, pentylcarbonyl, isobutylcarbonyl, butylcarbonyl and the like.
• C 1-6 alkoxy part of the “C 1-6 alkoxycarbonyl group” has the same meaning as the above “C 1-6 alkoxy”.
• Preferable examples include “C 1-4 alkoxycarbonyl group”.
• Specific examples of “C 1-6 alkoxycarbonyl group” include, for example, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, isobutoxycarbonyl and the like.
• the “C 1-6 alkyl” part of the “C 1-6 alkylcarbonylamino group” has the same meaning as the above “C 1-6 alkyl”.
• Preferable examples include “C 1-4 alkylcarbonylamino group”.
• Specific examples of the “C 1-6 alkylcarbonylamino group” include, for example, methylcarbonylamino, ethylcarbonylamino, propylcarbonylamino, tert-butylcarbonylamino and the like.
• C 3-10 cycloalkyl part of the “C 3-10 cycloalkylcarbonylamino group” has the same meaning as the above “C 3-10 cycloalkyl”. Specific examples include cyclopropylcarbonylamino, cyclobutylcarbonylamino, cyclopentylcarbonylamino, cyclohexylcarbonylamino and the like.
• C 6-10 aryl part of the “C 6-10 arylcarbonylamino group” has the same meaning as the above “C 6-10 aryl”. “C 6 arylcarbonylamino” (phenylcarbonylamino) is preferred. Specific examples of the “C 6-10 arylcarbonylamino group” include phenylcarbonylamino, 1-naphthylcarbonylamino, 2-naphthylcarbonylamino and the like.
• heteroaryl part of the “5- to 10-membered heteroarylcarbonylamino group” has the same meaning as the above “heteroaryl”.
• Specific examples of the “5- to 10-membered heteroarylcarbonylamino group” include, for example, pyridylcarbonylamino, imidazolylcarbonylamino, thiazolylcarbonylamino and the like.
• the “saturated heterocycle” part of the “4- to 10-membered saturated heterocycle carbonylamino group” has the same meaning as the above “saturated heterocycle”.
• Preferable examples include “5-membered or 6-membered saturated heterocyclic carbonylamino group”.
• Specific examples of the “4- to 10-membered saturated heterocyclic carbonylamino group” include, for example, tetrahydropyranylcarbonylamino, tetrahydrofurylcarbonylamino, pyrrolidinylcarbonylamino, imidazolidinylcarbonylamino, piperidinylcarbonylamino, And morpholinylcarbonylamino.
• C 1-6 alkoxy part of the “C 1-6 alkoxycarbonylamino group” has the same meaning as the above “C 1-6 alkoxy”.
• C 1-4 alkoxycarbonylamino group and the like can be mentioned.
• Specific examples of “C 1-6 alkoxycarbonylamino group” include, for example, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, tert-butoxycarbonylamino and the like.
• C 3-10 cycloalkyl part of the “C 3-10 cycloalkoxycarbonylamino group” has the same meaning as the above “C 3-10 cycloalkyl”. Specific examples include cyclopropyloxycarbonylamino, cyclobutyloxycarbonylamino, cyclopentyloxycarbonylamino, cyclohexyloxycarbonylamino and the like.
• C 6-10 aryl part of the “C 6-10 aryloxycarbonylamino group” has the same meaning as the above “C 6-10 aryl”. “C 6 aryloxycarbonylamino” (phenoxycarbonylamino) is preferred. Specific examples of the “C 6-10 aryloxycarbonylamino group” include phenoxycarbonylamino, 1-naphthyloxycarbonylamino, 2-naphthyloxycarbonylamino and the like.
• heteroaryl part of the “5- to 10-membered heteroaryloxycarbonylamino group” has the same meaning as the above “heteroaryl”.
• Specific examples of the “5- to 10-membered heteroaryloxycarbonylamino group” include, for example, pyridyloxycarbonylamino, imidazolyloxycarbonylamino, thiazolyloxycarbonylamino and the like.
• saturated heterocycle part of the “4- to 10-membered saturated heterocycle oxycarbonylamino group” has the same meaning as the above “saturate heterocycle”.
• Preferable examples include “5-membered or 6-membered saturated heterocyclic oxycarbonylamino group” and the like.
• the “4- to 10-membered saturated heterocyclic oxycarbonylamino group” include, for example, tetrahydropyranyloxycarbonylamino, tetrahydrofuryloxycarbonylamino, pyrrolidinyloxycarbonylamino, imidazolidinyloxycarbonylamino, Peridinyloxycarbonylamino, morpholinyloxycarbonylamino and the like can be mentioned.
• the “C 1-6 alkyl” part of the “C 1-6 alkylsulfonylamino group” has the same meaning as the above “C 1-6 alkyl”.
• “C 1-4 alkylsulfonylamino group” and the like can be mentioned.
• Specific examples of the “C 1-6 alkylsulfonylamino group” include, for example, methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, tert-butylsulfonylamino and the like.
• C 3-10 cycloalkyl part of the “C 3-10 cycloalkylsulfonylamino group” has the same meaning as the above “C 3-10 cycloalkyl”. Specific examples include cyclopropylsulfonylamino, cyclobutylsulfonylamino, cyclopentylsulfonylamino, cyclohexylsulfonylamino and the like.
• C 6-10 aryl part of the “C 6-10 arylsulfonylamino group” has the same meaning as the above “C 6-10 aryl”. “C 6 arylsulfonylamino” (phenylsulfonylamino) is preferred. Specific examples of the “C 6-10 arylsulfonylamino group” include phenylsulfonylamino, 1-naphthylsulfonylamino, 2-naphthylsulfonylamino and the like.
• heteroaryl part of the “5- to 10-membered heteroarylsulfonylamino group” has the same meaning as the above “heteroaryl”.
• Specific examples of the “5- to 10-membered heteroarylsulfonylamino group” include, for example, pyridylsulfonylamino, imidazolylsulfonylamino, thiazolylsulfonylamino and the like.
• the “saturated heterocyclic” part of the “4- to 10-membered saturated heterocyclic sulfonylamino group” has the same meaning as the “saturated heterocyclic ring”.
• Preferable examples include “5-membered or 6-membered saturated heterocyclic sulfonylamino group” and the like.
• the “4- to 10-membered saturated heterocyclic sulfonylamino group” include, for example, tetrahydropyranylsulfonylamino, tetrahydrofurylsulfonylamino, pyrrolidinylsulfonylamino, imidazolidinylsulfonylamino, piperidinylsulfonylamino, Morpholinylsulfonylamino and the like can be mentioned.
• “4-membered to 10-membered cyclic amino group” means a monocyclic or polycyclic cyclic amino group composed of 4 to 10 members.
• a group in which the nitrogen atom of the ring is a direct bond of the “group” is meant. Preferably, it is 5 to 7 members.
• Specific examples include, for example, azetidino, pyrrolidino, piperidino, morpholino, thiomorpholino, thiomorpholinooxide, thiomorpholinooxide, piperazino, and the “group” represented below.
• the cyclic amino group which is a ring containing partial unsaturation is also contained in this group.
• the “4- to 10-membered cyclic amino group” may form a condensed ring with phenyl or a 5- or 6-membered monocyclic heteroaryl. Specific examples include “groups” shown below. Examples of the substituent which may be substituted by these phenyl or 5-membered or 6-membered heteroaryl include “optionally substituted C 6-10 aryl group” and “optionally substituted heteroaryl group” In the above formula.
• the “5-membered or 6-membered cyclic amino group” includes a saturated bicyclo group and a saturated spiro ring group having a “5-membered or 6-membered saturated heterocycle” as a basic skeleton. Specific examples include “groups” represented by the following groups.
• the “cyclic amino” part has the same meaning as the “cyclic amino”.
• Preferable examples include “5- to 6-membered cyclic aminocarbonylamino group”.
• Specific examples of the “4- to 10-membered cyclic aminocarbonyl group” include azetidinocarbonyl, pyrrolidinocarbonyl, piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, piperazinocarbonyl and the like.
• the “cyclic amino” part has the same meaning as the “cyclic amino”.
• Preferable examples include “5- to 6-membered cyclic aminosulfonylamino group”.
• Specific examples of the “4- to 10-membered cyclic aminosulfonyl group” include, for example, azetidinosulfonyl, pyrrolidinosulfonyl, piperidinosulfonyl, morpholinosulfonyl, thiomorpholinosulfonyl, piperazinosulfonyl and the like.
• C 1-6 alkylsulfonylaminocarbonyl group has the same meaning as the above “C 1-6 alkyl”.
• Preferable examples include “C 1-4 alkylsulfonylaminocarbonyl group” and the like.
• Specific examples of “C 1-6 alkylsulfonylaminocarbonyl group” include, for example, methylsulfonylaminocarbonyl, ethylsulfonylaminocarbonyl, propylsulfonylaminocarbonyl, tert-butylsulfonylaminocarbonyl and the like.
• Examples of the substituent in the “optionally substituted C 1-6 alkyl group” include (a) a halogen atom, (B) a cyano group, (C) a hydroxy group, (D) a C 1-6 alkylcarbonyl group (the group may be substituted with 1 to 3 halogen atoms), (E) a carboxyl group, (F) amino (the amino is (F1) C 1-6 alkyl (the group is (F11) 1 to 3 halogen atoms, (F12) cyano, (F13) hydroxy, (F14) C 1-6 alkoxy, (F15) C 3-10 cycloalkyl, or (f16) C 1-6 alkoxycarbonylamino may be substituted.
• (F2) C 3-10 cycloalkyl (the group may be C 1-6 alkyl, or optionally substituted with 1 to 3 halogen atoms), (F3) phenyl (the group is a halogen atom, cyano, C 1-6 alkyl (the group may be substituted with 1 to 3 halogen atoms), C 1-6 alkoxycarbonylamino, and C 1-6 alkoxy (which group may be substituted with 1 to 3 halogen atoms)), (F4) 5- or 6-membered heteroaryl (the group is a halogen atom, cyano, C 1-6 alkyl (the group may be substituted with 1 to 3 halogen atoms), C 1 -6 alkoxycarbonylamino, and C 1-6 alkoxy (which group may be substituted with 1 to 3 halogen atoms), and (f5) 5-membered or It may be substituted with the same or different 1-2 groups selected from the group consisting of 6-membered saturated heterocycles.
• (G) a 4- to 10-membered cyclic amino (the ring is (G1) a halogen atom, (G2) hydroxy, (G3) C 1-6 alkyl (the group may be substituted with 1 to 3 halogen atoms, hydroxy, or C 1-6 alkoxy (the group may be substituted with 1 to 3 halogen atoms)) And may be substituted with (G4) C 1-6 alkoxy (the group may be substituted with 1 to 3 halogen atoms, hydroxy, or C 1-6 alkoxy (the group may be substituted with 1 to 3 halogen atoms)) And (g5) substituted with mono- or di-C 1-6 alkylamino (wherein the alkyl may be substituted with 1 to 3 halogen atoms).
• (H) a C 1-6 alkoxy group (the group is (H1) hydroxy, (H2) C 1-6 alkoxy (the group may be substituted with 1 to 3 halogen atoms), (H3) C 3-10 cycloalkyl (the group may be substituted with 1 to 3 halogen atoms, or C 1-6 alkyl), or (h4) 1 to 3 halogen atoms May be substituted.
• (M) a 5- to 10-membered heteroaryl group (the group may be substituted with the above (l1) to (l5)), (N) a C 3-10 cycloalkyl group (the group may be substituted with a halogen atom or C 1-6 alkyl), (O) a C 3-10 cycloalkoxy group (the group may be substituted with a halogen atom or C 1-6 alkyl), (P) a C 6-10 aryloxy group (the group may be substituted with the above (l1) to (l5)), (Q) a 5- to 10-membered heteroaryloxy group (the group may be substituted with the above-mentioned (l1) to (l5)), (R) a 4-membered to 10-membered saturated heterocyclic oxy group (this group may be substituted with the above (l1) to (l5)), (S) a mono- or di-C 1-6 alkylaminocarbonyl group (wherein the alkyl may be substituted with 1
• Examples of the substituent in the “ optionally substituted C 6-10 aryl group” include (a) a halogen atom, (B) a cyano group, (C) a hydroxy group, (D) a C 1-6 alkylcarbonyl group (the alkyl may be substituted with 1 to 3 halogen atoms), (E) a carboxyl group, (F) amino (the amino is (F1) C 1-6 alkyl (the group is (F11) 1 to 3 halogen atoms, (F12) cyano, (F13) hydroxy, (F14) C 1-6 alkoxy, (F15) C 3-10 cycloalkyl (the group may be substituted with 1 to 3 halogen atoms, or C 1-6 alkyl), or (f16) C 1-6 alkoxycarbonylamino May be substituted.
• (F2) C 3-10 cycloalkyl (the group may be C 1-6 alkyl, or optionally substituted with 1 to 3 halogen atoms), (F3) phenyl (the group is (F31) a halogen atom, (F32) cyano, (F33) C 1-6 alkyl (the group may be substituted with 1 to 3 halogen atoms), (F34) C 1-6 alkoxycarbonylamino, or (f35) C 1-6 alkoxy (the group may be substituted with 1 to 3 halogen atoms).
• (F4) a 5- or 6-membered heteroaryl (the group may be substituted with the above (f31) to (f35)) and (f5) a group consisting of a 5- or 6-membered saturated heterocycle It may be substituted with 1 or 2 groups of the same or different selected.
• (G) a 4- to 10-membered cyclic amino (the ring is (G1) a halogen atom, (G2) hydroxy, (G3) C 1-6 alkyl (the group may be substituted with 1 to 3 halogen atoms, hydroxy, or C 1-6 alkoxy (the group may be substituted with 1 to 3 halogen atoms)) And may be substituted with (G4) C 1-6 alkoxy (the group may be substituted with 1 to 3 halogen atoms, hydroxy, or C 1-6 alkoxy (the group may be substituted with 1 to 3 halogen atoms)) And (g5) substituted with mono- or di-C 1-6 alkylamino (wherein the alkyl may be substituted with 1 to 3 halogen atoms).
• (H) a C 1-6 alkyl group (the group is (H1) hydroxy, (H2) C 1-6 alkoxy (the group may be substituted with 1 to 3 halogen atoms), (H3) C 3-10 cycloalkyl (the group may be substituted with 1 to 3 halogen atoms, or C 1-6 alkyl), or (h4) 1 to 3 halogen atoms May be substituted.
• Optionally substituted C 1-6 alkoxy group “optionally substituted C 1-6 alkylthio group”, “optionally substituted C 1-6 alkylcarbonyl group”, “substituted” a C 1-6 alkoxycarbonyl group which may "," optionally substituted C 1-6 alkylcarbonylamino group ",” optionally substituted C 1-6 alkylsulfonylamino group “is” substituted Optionally substituted C 1-6 alkoxycarbonylamino group ”,“ optionally substituted C 2-6 alkenyl group ”,“ optionally substituted C 2-6 alkynyl group ”,“ optionally substituted ” C 1-6 alkylsulfonylamino group ", and” the substituent in C 2-6 alkenyloxy group ", optionally substituted, optionally the” substituted C -6 include groups selected from the substituent in the alkyl group. "
• (A) C 1-6 alkyl (the group is (A1) 1 to 3 halogen atoms, (A2) cyano, (A3) hydroxy, (A4) C 1-6 alkoxy (the group may be substituted with 1 to 3 halogen atoms), (A5) C 3-10 cycloalkyl (the group may be substituted with 1 to 3 halogen atoms, or C 1-6 alkyl), or (a6) C 1-6 alkoxycarbonylamino May be substituted.
• (B) C 3-10 cycloalkyl (the group may be C 1-6 alkyl, or optionally substituted with 1 to 3 halogen atoms), (C) phenyl (the group is (C1) a halogen atom, (C2) cyano, (C3) C 1-6 alkyl (the group may be substituted with 1 to 3 halogen atoms), (C4) C 1-6 alkoxycarbonylamino, and (c5) C 1-6 alkoxy (the group may be substituted with 1 to 3 halogen atoms). ), (D) selected from the group consisting of 5- or 6-membered heteroaryl (which may be substituted with the above (c1) to (c5)), and (e) a 5- or 6-membered saturated heterocycle One or two groups are the same or different.
• the compound represented by the formula (1) and pharmaceutically acceptable salts thereof may exist in the form of hydrates and / or solvates, these hydrates and / or solvates (for example, ethanol solvate and the like are also included in the compound of the present invention. Further, the compounds of the present invention include all forms of crystal forms.
• a pharmaceutically acceptable salt when the compound represented by the formula (1) has an acidic functional group, for example, an alkali metal salt such as a sodium salt or a potassium salt; an alkaline earth such as a calcium salt or a magnesium salt Metal salts; inorganic metal salts such as zinc salts; organic base salts such as triethylamine, triethanolamine, trihydroxymethylaminomethane, and amino acids.
• inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate; and acetate, propionic acid Salt, succinate, lactate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate, benzenesulfonate, ascorbate, etc.
• Organic acid salt etc. are mentioned.
• the compound (1) represented by the formula (1) may exist as a tautomer. Therefore, this invention compound also includes the tautomer of the compound represented by Formula (1).
• the compound represented by the formula (1) has at least two asymmetric carbon atoms. Therefore, this invention compound also includes the stereoisomer of these compounds, and its mixture.
• the compound of the present invention includes a racemic form of the compound represented by the formula (1) and an optically active form of the compound.
• trans and cis when the compound represented by the formula (1) and the compound described in the Reference Example are racemic are illustrated as follows.
• the compound represented by the formula (1) may cause atropisomerism based on axial or planar chirality generated by the constraint of intramolecular rotation. Therefore, this invention compound also includes the stereoisomer of these compounds, and its mixture.
• Boc group tert-butoxycarbonyl group
• Cbz group benzyloxycarbonyl group
• Alloc group allyloxycarbonyl group
• Fmoc group 9-fluorenylmethyloxycarbonyl group
• DMF N, N-dimethylformamide
• the compound of the present invention is synthesized by the production method shown below and a method combining a known compound and a known synthesis method.
• Each compound used as a raw material compound may be used as a salt.
• These reactions are merely examples, and the compounds of the present invention can be produced by other methods as appropriate based on the knowledge of those skilled in organic synthesis.
• the desired product may be obtained by deprotection after completion of the reaction or after a series of reactions.
• Protecting groups are described in the literature (TW Greene and PMGM Wuts, “Protective Groups in Organic Synthesis”, 3rd Ed., John Wiley and Sons, Inc., New York et al. (19)). And, more specifically, as an amino group protecting group, for example, benzyloxycarbonyl, tert-butoxycarbonyl, acetyl, benzyl, etc., and as a hydroxy group protection Can include, for example, trialkylsilyl, acetyl, benzyl and the like.
• protecting groups can be carried out by methods commonly used in organic synthetic chemistry (eg, TW Greene and PMGM Wuts, “Protective Groups in Organic Synthesis”, 3rd Ed., John Wiley and Sons). , Inc., New York (1999)) or a similar method.
• Manufacturing method 1 The compound represented by Formula (1) is manufactured by the method shown below, for example.
• R 100 represents C 1-4 alkyl.
• R 101 represents a Cbz group, a Boc group, an Alloc group, a benzyl group, or an Fmoc group.
• Raw material compounds As compounds represented by formula (1-1), formula (1-2), and formula (1-7), commercially available products or known synthesis methods (for example, Tetrahedron Lett. 2010, 51, 6745, Org Lett. 2009, 11, 4056, Bioorg. Med. Chem. 2011, 19, 5833., etc.) can be used.
• the compound (1-3) a commercially available product or a compound produced using a known synthesis method (for example, WO1993 / 005021, WO2009 / 152133, JP55151539, etc.) can be used.
• As the compound (1-6) a commercially available product or a compound produced using a known synthesis method (for example, Chem. Commun. 2009, 48, 7581, WO2008 / 012782, etc.) can be used.
• Step 1-1 using the manufacturing process of Compound (1-2) to (1-1) as a raw material, are described in the literature (Protective Groups in Organic Synthesis 3 rd Edition (John Wiley & Sons, Inc.) , etc.) Compound (1-2) can be produced by a method similar to that described above.
• Step 1-2 Production Step of Compound (1-4)
• Compound (1-2) is reacted with compound (1-3) in an inert solvent using a condensing agent and, if necessary, in the presence of a base.
• a condensing agent By reacting, compound (1-4) can be produced.
• a phase transfer catalyst can also be added as needed.
• the base is not particularly limited as long as it is used as a base in a normal reaction.
• Organic bases such as -ene, 1,4-diazabicyclo [5.4.0] undec-7-ene, pyridine, dimethylaminopyridine, picoline; sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, hydrogen And inorganic bases such as sodium hydride.
• the amount of the base to be used is generally 0.1-100 equivalents, preferably 1-5 equivalents, relative to compound (1-3).
• phase transfer catalyst examples include quaternary ammonium salts such as tetrabutylammonium bromide and benzyltriethylammonium bromide, and crown ethers such as 18-crown-6-ether.
• the amount of the phase transfer catalyst to be used is generally 0.01-100 equivalents, preferably 0.1-3 equivalents, relative to compound (1-3).
• condensing agent examples include those described in Experimental Chemistry Course (edited by Chemical Society of Japan, Maruzen) Vol.
• phosphate esters such as diethyl cyanophosphate and diphenylphosphoryl azide
• carbodiimides such as 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (WSC ⁇ HCl) and dicyclohexylcarbodiimide (DCC);
• DCC dicyclohexylcarbodiimide
• 2 Combinations of disulfides such as 2,2'-dipyridyl disulfide and phosphines such as triphenylphosphine
• Phosphorus halides such as N, N'-bis (2-oxo-3-oxazolidinyl) phosphinic chloride (BOPCl); Azo Combinations of azodicarboxylic acid diesters such as diethyl dicarboxylate and phos
• the inert solvent examples include ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane; hydrocarbon solvents such as hexane, heptane, toluene, benzene, xylene; dichloromethane, chloroform Halogenated hydrocarbon solvents such as dichloroethane; ketone solvents such as acetone; aprotic solvents such as acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide, hexamethylenephosphoamide, and the like. There may be.
• the reaction temperature is not particularly limited, but is preferably selected from the range of about -70 ° C to 100 ° C, more preferably 0 ° C to 40 ° C.
• the compound (1-3) is converted into a halogenating reagent (for example, 1-chloro-N, N, 2-trimethylpropenylamine, phosphorus oxychloride, phosphorus trichloride, thionyl chloride, phosphorus pentachloride, etc.).
• a halogenating reagent for example, 1-chloro-N, N, 2-trimethylpropenylamine, phosphorus oxychloride, phosphorus trichloride, thionyl chloride, phosphorus pentachloride, etc.
• the compound (1-4) can also be produced by leading to an acid halide using and then reacting with the compound (1-2) in an inert solvent, if necessary, in the presence of a base.
• the inert solvent examples include ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane; hydrocarbon solvents such as hexane, heptane, toluene, benzene, xylene; dichloromethane, chloroform , Halogenated hydrocarbon solvents such as dichloroethane; ester solvents such as ethyl acetate and isopropyl acetate; ketone solvents such as methyl ethyl ketone and acetone; non-solvents such as acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide and hexamethylenephosphoamide A protic solvent is mentioned.
• ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane
• hydrocarbon solvents such as
• Examples of the base include N-methylmorpholine, triethylamine, diisopropylethylamine, tributylamine, 1,8-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [5.4.0] undec-7-ene. , Organic bases such as pyridine, dimethylaminopyridine, and picoline.
• the halogenating reagent can be used in an amount of 0.1 to 100 equivalents, preferably 0.8 to 3 equivalents, relative to compound (1-3).
• the reaction temperature is not particularly limited, but is preferably selected from the range of about ⁇ 30 ° C. to 60 ° C.
• Step 1-3 Methods known manufacturing processes compound (1-4) of compound (1-5) (e.g., Protective Groups in Organic Synthesis 3 rd Edition (John Wiley & Sons, Inc), Comprehensive Organic transformation, RC
• the compound (1-5) can be produced by hydrolysis with Laroc et al., VCH publisher Inc., 1989).
• Step 1-4 Process for producing compound represented by formula (1) Using compound (1-5) and compound (1-6), represented by formula (1) in the same manner as in step 1-2 Compounds can be produced.
• Step 1-5 Production Step of Compound (1-7)
• Compound (1-7) can be produced by the same method as in Step 1-3, using Compound (1-1).
• Step 1-6 Step of producing compound (1-8) Using compound (1-7) and compound (1-6), compound (1-8) can be produced by the same method as in step 1-2. it can.
• Step 1-7 Step for Producing Compound (1-9) Using compound (1-8), compound (1-9) can be produced by the same method as in Step 1-1.
• Step 1-8 Production Step of Compound Represented by Formula (1) Using compound (1-9) and compound (1-3), represented by formula (1) in the same manner as in step 1-2 Compounds can be made.
• R c is as defined in the above [1]
• R 100 represents a C 1-4 alkyl group or a benzyl group
• R 300 represents a C 1-6 alkyl, or May combine to form a ring structure.
• R 101 represents a Cbz group, a Boc group, an Alloc group, a benzyl group, or an Fmoc group.
• Raw material compound As a compound represented by the formula (2-1), a commercially available product or 3-hydroxyproline produced by a method known in the literature (for example, Journal of the American Chemical Society, 85 (18), 2832-4; 1963) the known production methods (e.g., protective groups in Organic Synthesis 3 rd Edition (John Wiley & Sons, Inc) , etc.) may be used as the protected appropriately functional groups using. Further, as the compound represented by the formula (2-2), a compound produced by a known production method (for example, Org. Lett. 2007, 9, 4255., Tetrahedron Lett. 1995, 36, 6209., etc.) is used. be able to.
• a known production method for example, Org. Lett. 2007, 9, 4255., Tetrahedron Lett. 1995, 36, 6209., etc.
• Step 2-1 Production step of compound (2-2)
• Compound (2-1) is oxidized by a method similar to a known method (for example, Comprehensive Organic transformation, RC Laroc et al., VCH publisher Inc., 1989 etc.)
• a known method for example, Comprehensive Organic transformation, RC Laroc et al., VCH publisher Inc., 1989 etc.
• compound (2-2) can be produced.
• the oxidation method preferably, Dess-Martin oxidation, Swern oxidation, TPAP oxidation, Parikh oxidation, PCC oxidation or the like is used.
• Step 2-2 Production Step of Compound (2-3)
• Compound (2-2) is reacted with trifluoromethanesulfonic anhydride or N, N-ditrifluoromethanesulfonylaminobenzene in an inert solvent in the presence of a base.
• compound (2-3) can be produced.
• the base is not particularly limited as long as it is used as a base in a normal reaction.
• Organic bases such as -ene, 1,4-diazabicyclo [5.4.0] undec-7-ene, pyridine, dimethylaminopyridine, picoline; sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, lithium diisopropylamide, lithium Bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, lithium amide, n-butyllithium, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate And inorganic bases such as sodium hydroxide, sodium hydroxide and sodium hydride.
• the amount of the base to be used is generally 0.1-
• the inert solvent examples include ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane; hydrocarbon solvents such as hexane, heptane, toluene, benzene, xylene; dichloromethane, chloroform And halogenated hydrocarbon solvents such as dichloroethane; aprotic solvents such as N, N-dimethylformamide, dimethyl sulfoxide, hexamethylenephosphoamide and the like, and a mixed solvent thereof may be used.
• the reaction temperature is not particularly limited, but is preferably selected from the range of about 0 ° C to 40 ° C.
• Step 2-3 Production Step of Compound (2-6)
• Compound (2-3) is prepared in a suitable solvent in an inert solvent in the presence of an appropriate metal reagent, an appropriate ligand and, if necessary, a base.
• Compound (2-6) can be produced by reacting with compound (2-4) or compound (2-5) in an active solvent.
• the reaction temperature ranges from about ⁇ 78 ° C. to the boiling point of the solvent used, preferably 25 ° C. to 120 ° C.
• the reaction time is 10 minutes to 5 days.
• the metal reagent include copper reagents such as copper iodide, palladium (II) acetate, palladium (II) chloride, tetrakis (triphenylphosphine) palladium, tris (dibenzylideneacetone) dipalladium (0), bis (Dibenzylideneacetone) palladium, 1,1'-bis (diphenylphosphino) ferrocenedichloropalladium (II), palladium-carbon, dichlorobis (tri-o-tolylphosphine) palladium (II), bis (tri-tert-butyl Phosphine) palladium (0), bis (triphenylphosphine) palladium (II) dichloride, bis (triphenylphosphine) palladium (II) diacetate, benzylbis (triphenylphosphine) palladium (II) chloride, [1,2-bis (D
• ligand examples include tri-o-tolylphosphine, tri-tert-butylphosphine, triphenylphosphine, 1,1′-bis (diphenylphosphino) ferrocene, tricyclohexylphosphine, and 2,2′-bis.
• the base include organic bases such as triethylamine, N-methylmorpholine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, potassium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, hydrogen Inorganic bases such as potassium iodide, cesium carbonate, sodium carbonate, sodium bicarbonate, potassium phosphate, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) ), Organometallic reagents such as amide, sodium bis (trimethylsilyl) amide, lithium amide, n-butyllithium, and the like.
• potassium carbonate or cesium carbonate is used.
• the amount of the base used is 0.1 to 100 equivalents, preferably 0.5 to 5 equivalents, relative to the equivalent of compound (3-3).
• the inert solvent include acetone, acetonitrile, halogenated hydrocarbons such as chloroform and dichloromethane, aromatic hydrocarbons such as benzene and toluene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, dimethoxyethane.
• ether solvents such as tert-butyl methyl ether and cyclopentyl methyl ether, lower alcohols such as methanol, ethanol and isopropanol, and aprotic polar solvents such as N, N-dimethylformamide, N-methylpyrrolidone and dimethyl sulfoxide. These may be a mixed solvent.
• toluene and N, N-dimethylformamide are used.
• Step 2-4 Step of producing compound (2-7)
• Compound (2-6) is hydrogenated by a method similar to a known method (for example, Bioorg. Med. Chem. Lett. 2008, 18, 1931., etc.) By subjecting to reaction, the compound (2-7) can be selectively obtained in cis form.
• a metal catalyst is used, palladium hydroxide or platinum oxide can be used instead of palladium-carbon.
• Step 2-5 Production Step of Compound (2-8) Reduction of Compound (2-7) by a method similar to a known method (for example, Comprehensive Organic transformation, RC Laroc et al., VCH publisher Inc., 1989 etc.) Thus, compound (2-8) can be produced.
• Step 2-6 Production Step of Compound (2-9)
• Compound (2-8) is oxidized by a method similar to a known method (for example, Comprehensive Organic transformation, RC Laroc et al., VCH publisher Inc., 1989 etc.)
• compound (2-9) can be produced.
• the oxidation method preferably, Dess-Martin oxidation, Swern oxidation, TPAP oxidation, Parikh oxidation, PCC oxidation or the like is used.
• Compound (2-9) can also be obtained directly from compound (2-7) by reducing compound (2-7) with diisobutylaluminum hydride in an inert solvent.
• the reaction temperature is selected from the range of ⁇ 100 ° C. to 100 ° C.
• Specific examples of the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane.
• Step 2-7 Production Step of Compound (2-10)
• Compound (2-9) is converted to 1,8-diazabicyclo [5.4.
• Compound (2-10) can be produced by isomerization by treatment with a base such as undec-7-ene (DBU).
• the reaction temperature is not particularly limited, but is preferably selected from the range of about 0 ° C to 80 ° C.
• Step 2-8 Production Step of Compound (2-11)
• Compound (2-10) is oxidized by a method similar to a known method (for example, Comprehensive Organic transformation, RC Laroc et al., VCH publisher Inc., 1989 etc.)
• compound (2-11) can be produced.
• the oxidation method Pinnick oxidation, PDC oxidation or the like is preferably used.
• Step 2-9 Step of producing compound (2-12) Using compound (2-7), compound (2-12) can be produced by the same method as in step 1-5.
• Production method 3 Of the compounds represented by the formula (1-1), optically active 3-substituted pyrrolidine-2-carboxylic acid esters represented by the formulas (3-10) and (3-13) are shown below, for example. Manufactured by the method.
• R 100c is an optionally substituted C 6-10 aryl, an optionally substituted 5- to 10-membered heteroaryl, an optionally substituted C 1-6 alkyl, a substituted Represents an optionally substituted 4- to 10-membered saturated heterocyclic ring or an optionally substituted C 3-10 cycloalkyl, wherein R 100 and R 103 are a hydrogen atom, a C 1-4 alkyl group, or a benzyl group R 101 represents a Cbz group, a Boc group, an Alloc group, a benzyl group, or an Fmoc group. ]
• Step 3-1 Production Step of Compound (3-2) Compound (3-1) is reacted with Compound (3-14) or Compound (3-15) in the presence of a base in an inert solvent. (3-2) can be manufactured.
• the base is not particularly limited as long as it is used as a base in a normal reaction.
• Organic bases such as -ene, 1,8-diazabicyclo [5.4.0] undec-7-ene, pyridine, dimethylaminopyridine, picoline; sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, hydrogen And inorganic bases such as sodium hydride.
• the amount of the base to be used is generally 0.1-100 equivalents, preferably 0.8-2 equivalents, relative to compound (3-14) or compound (3-15).
• the inert solvent examples include ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane; hydrocarbon solvents such as hexane, heptane, toluene, benzene, xylene; N, N -Aprotic solvents such as dimethylformamide, dimethyl sulfoxide, hexamethylenephosphoamide and the like may be mentioned, and a mixed solvent thereof may be used.
• the reaction temperature is not particularly limited, but is preferably selected from the range of about 0 ° C to 60 ° C.
• Step 3-2 Production Step of Compound (3-3)
• Compound (3-2) is reduced by a method similar to a known method (for example, Comprehensive Organic transformation, RC Laroc et al., VCH publisher Inc., 1989 etc.)
• compound (3-3) can be produced.
• Lithium aluminum hydride is preferably used as the reducing agent, and tetrahydrofuran is preferably used as the inert solvent.
• Step 3-3 Production Step of Compound (3-4)
• Compound (3-3) is oxidized by a method similar to a known method (for example, Comprehensive Organic transformation, RC Laroc et al., VCH publisher Inc., 1989 etc.)
• compound (3-4) can be produced.
• the oxidation method preferably, Dess-Martin oxidation, Swern oxidation, TPAP oxidation, Parikh oxidation, PCC oxidation or the like is used.
• Step 3-4 Production Step of Compound (3-5)
• Compound (3-4) is present in the presence of diphenylprolinol trimethyl ether by a method similar to a known method (for example, Org. Lett. 2009, 11, 4056. etc.) Then, compound (3-5) can be produced by reacting with 2-nitroethanol.
• Step 3-5 Production Step of Compound (3-6)
• Compound (3-5) is subjected to a hydrogenation reaction by a method similar to a known method (for example, Org. Lett. 2009, 11, 4056. etc.).
• a known method for example, Org. Lett. 2009, 11, 4056. etc.
• compound (3-6) can be produced.
• the metal catalyst palladium hydroxide, palladium-carbon, or platinum oxide can be preferably used.
• compound (3-5) is treated with ammonium chloride and iron or zinc in an inert solvent in the same manner as a known method (Comprehensive Organic transformation, RC Larro et al., VCH publisher Inc., 1989).
• Compound (3-6) can be produced by the treatment.
• Step 3-6 using the manufacturing process of Compound (3-7) (3-6), a known method (for example, Protective Groups in Organic Synthesis 3 rd Edition (John Wiley & Sons, Inc) , etc.) and similar Compound (3-7) can be produced by the method.
• a known method for example, Protective Groups in Organic Synthesis 3 rd Edition (John Wiley & Sons, Inc) , etc.
• similar Compound (3-7) can be produced by the method.
• Step 3-7 Step of producing compound (3-8)
• Compound (3-8) can be produced by the same method as in Step 3-3 using compound (3-7).
• Step 3-8 Production Step of Compound (3-9)
• Compound (3-8) is oxidized by a method similar to a known method (for example, Comprehensive Organic transformation, RC Laroc et al., VCH publisher Inc., 1989 etc.)
• compound (3-9) can be produced.
• the oxidation method Pinnick oxidation, PDC oxidation or the like is preferably used.
• Step 3-9 Production Step of Compound (3-10)
• Compound (3-9) is esterified by a method similar to a known method (for example, Comprehensive Organic transformation, RC Laroc et al., VCH publisher Inc., 1989 etc.) To produce the compound (3-10).
• Step 3-10 Production Step of Compound (3-11)
• Compound (3-8) is converted to 1,8-diazabicyclo [5.4.
• DBU undec-7-ene
• the reaction temperature is not particularly limited, but is preferably selected from the range of about 0 ° C to 80 ° C.
• Step 3-11 Step of producing compound (3-12) Oxidation of compound (3-11) by a method similar to a known method (for example, Comprehensive Organic transformation, RC Laroc et al., VCH publisher Inc., 1989 etc.) Thus, compound (3-12) can be produced.
• a known method for example, Comprehensive Organic transformation, RC Laroc et al., VCH publisher Inc., 1989 etc.
• compound (3-12) can be produced.
• the oxidation method Pinnick oxidation, PDC oxidation or the like is preferably used.
• Step 3-12 Production Step of Compound (3-13)
• the compound (3-12) is esterified by a method similar to a known method (for example, Comprehensive Organic transformation, RC Laroc et al., VCH publisher Inc., 1989 etc.) To produce the compound (3-13).
• R 200 represents an optionally substituted C 1-6 alkyl group, an optionally substituted C 1-6 alkoxy group, or a fluorine atom
• n represents 0 to 4
• R 100 represents a hydrogen atom, a C 1-4 alkyl group, or a benzyl group
• R 101 represents a Cbz group, a Boc group, an Alloc group, a benzyl group, or an Fmoc group
• R 104 is substituted.
• Step 4-1 Production Step of Compound (4-2)
• Compound (4-1) is reacted in a hydrogen atmosphere in an inert solvent in the presence of palladium-carbon, palladium hydroxide, or platinum oxide, Compound (4-2) can be produced.
• an acid can also be added as needed.
• Examples of the acid include hydrochloric acid water, hydrogen bromide water, sulfuric acid water, acetic acid, formic acid, trifluoroacetic acid and the like.
• the inert solvent examples include ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane; hydrocarbon solvents such as hexane, heptane, toluene, benzene, xylene; dichloromethane, chloroform And halogenated hydrocarbon solvents such as dichloroethane; alcohol solvents such as ethanol, methanol, and isopropanol; and a mixed solvent thereof may be used.
• the reaction temperature is not particularly limited, but is preferably selected from the range of about 0 ° C. to 100 ° C., more preferably 25 ° C. to 80 ° C.
• Step 4-2 Production Step of Compound (4-3)
• Compound (4) wherein R 104 is an optionally substituted C 1-6 alkyl group or an optionally substituted C 3-10 cycloalkyl group -3) is produced by reacting compound (4-2) with the corresponding aldehyde or ketone in the presence of triacetoxyborohydride or tricyanoborohydride in an inert solvent.
• the inert solvent examples include ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane; halogenated hydrocarbon solvents such as dichloromethane, chloroform, dichloroethane; ethanol, methanol, isopropanol And alcohol solvents such as water, acetic acid and the like, and a mixed solvent thereof may be used.
• the reaction temperature is not particularly limited, but is preferably selected from the range of about 0 ° C to 40 ° C.
• R 104 is an optionally substituted C 1-6 alkylcarbonyl group, an optionally substituted C 3-10 cycloalkylcarbonyl group, an optionally substituted C 6-10 arylcarbonyl group, a substituted Optionally substituted 5- to 10-membered heteroarylcarbonyl group, optionally substituted 4- to 10-membered saturated heterocyclic carbonyl group, optionally substituted C 1-6 alkylsulfonyl group, substituted An optionally substituted C 3-10 cycloalkylsulfonyl group, an optionally substituted C 6-10 arylsulfonyl group, an optionally substituted 5- to 10-membered heteroarylsulfonyl group, an optionally substituted 4 member to 10-membered saturated heterocyclic sulfonyl group, an optionally substituted C 1-6 alkoxycarbonyl group, optionally substituted C 3-10 also be B alkoxycarbonyl group, an optionally substituted C 6-10 aryloxycarbonyl group
• the base is not particularly limited as long as it is used as a base in a normal reaction.
• Organic bases such as -ene, 1,8-diazabicyclo [5.4.0] undec-7-ene, pyridine, dimethylaminopyridine, picoline; sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, hydrogen And inorganic bases such as sodium hydride.
• the amount of the base to be used is generally 0.1-100 equivalents, preferably 0.8-5 equivalents, relative to compound (2-14) or formula (2-15).
• the inert solvent examples include ether solvents such as ethyl acetate, tetrahydrofuran, diethyl ether, 1,4-dioxane and 1,2-dimethoxyethane; hydrocarbon solvents such as hexane, heptane, toluene, benzene and xylene; Halogenated hydrocarbon solvents such as dichloromethane, chloroform and dichloroethane; aprotic solvents such as N, N-dimethylformamide, dimethyl sulfoxide and hexamethylenephosphoamide may be mentioned, and a mixture thereof may be used.
• the reaction temperature is not particularly limited, but is preferably selected from the range of about 0 ° C to 40 ° C.
• R c is as defined in item 1, R 500 represents a C 1-4 alkyl group or a benzyl group, and R 101 represents a Cbz group, a Boc group, an Alloc group, a benzyl group, or an Fmoc group. Represents. ]
• Step 5-1 Production Step of Compound (5-2)
• Compound (5-2) can be produced by reacting compound (5-1) with a base in an inert solvent.
• the reaction temperature is not particularly limited, but is preferably selected from the range of about ⁇ 20 ° C. to 60 ° C.
• the base include organic bases such as triethylamine, N-methylmorpholine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene; potassium carbonate, water Inorganic bases such as sodium oxide, potassium hydroxide, lithium hydroxide, sodium hydride, potassium hydride, cesium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium phosphate; sodium methoxide, sodium tert-butoxide, potassium tert-butoxide , Lithium diisopropylamide, lithium bis (trimethylsilyl) amide, lithium diisopropylamide, potassium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, lithium amide, n-bu Organometallic reagent such as butyllithium and the like.
• lithium diisopropylamide or lithium bis (trimethylsilyl) amide is used
• the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane, aromatic hydrocarbons such as benzene and toluene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, dimethoxyethane, and tert-butyl.
• halogenated hydrocarbons such as chloroform and dichloromethane
• aromatic hydrocarbons such as benzene and toluene
• diethyl ether diethyl ether
• tetrahydrofuran (THF) tetrahydrofuran
• 1,4-dioxane 1,4-dioxane
• dimethoxyethane dimethoxyethane
• tert-butyl examples include ether solvents such as methyl ether and cyclopentyl methyl ether, aprotic polar solvents such as N, N-dimethylformamide, N-methyl
• the optically active trans-3-substituted pyrrolidine-2-carboxylic acid derivative represented by the formula (6-10) is produced, for example, by the method shown below.
• the optically active cis-3-substituted pyrrolidine-2-carboxylic acid ester derivative represented by the formula (6-4) can be obtained by, for example, the following method. Manufactured.
• R 100 represents a C 1-4 alkyl group or a benzyl group
• R 160 represents an optionally substituted C 1-6 alkyl group or an optionally substituted C 2-6 alkenyl group.
• R 101 represents a Cbz group, a Boc group, an Alloc group, a benzyl group, or an Fmoc group
• X represents a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a trifluoro group.
• R 600 represents a tert-butyldimethylsilyl group, a triethylsilyl group, a trimethylsilyl group, a triisopropylsilyl group, a tert-butyldiphenylsilyl group, a triphenylsilyl group, a tetrahydropyranyl group, a trityl group, 2- (trimethylsilyl) ethoxymethyl group and benzyl group.
• Raw material compound As a compound represented by the formula (6-1), a commercially available product or a compound produced by the method of known literature (Journal of Organic Chemistry (1989), 54 (14), 3260-4, etc.) is used.
• hydroxyproline or known production methods, for example, protective groups in Organic Synthesis 3 rd Edition (John Wiley & Sons, Inc) , etc.) can be used 3-hydroxyproline protected appropriately functional groups with.
• Step 6-1 Step for producing compound (6-2)
• Compound (6-1) is converted into a hydroxyl group by a method similar to a known method (for example, Comprehensive Organic transformation, RC Larro et al., VCH publisher Inc., 1989). Is sterically inverted to produce compound (6-2).
• a method for inversion of the hydroxyl group preferably represented by Mitsunobu reaction and a report by Mukaiyama et al. (T. Mukaiyama, T. Shintou, K. Fukumoto, J. Am. Chem. Soc. 2003. 125, 10 538-10 539.)
• a modified Mitsunobu reaction is used.
• the compound (2-2) can also be produced by oxidizing a hydroxyl group with a suitable oxidizing agent and then reducing with a suitable reducing agent.
• suitable oxidizing agent include Dess-Martin oxidation, Swern oxidation, TPAP oxidation, PCC oxidation, oxidation using Parikh oxidation, etc.
• Suitable reducing agents include lithium aluminum hydride, sodium borohydride, triacetoxy hydrogenation.
• Step 6-2 Production Step of Compound (6-4) Compound (6-2) is reacted with the corresponding compound (6-3) in the presence of a base in an inert solvent to give compound (6-4). Can be manufactured.
• the base is not particularly limited as long as it is used as a base in a normal reaction.
• Organic bases such as -ene, 1,4-diazabicyclo [5.4.0] undec-7-ene, pyridine, dimethylaminopyridine, picoline; sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, lithium diisopropylamide, lithium Bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, lithium amide, n-butyllithium, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate And inorganic bases such as sodium hydroxide, sodium hydroxide and sodium hydride.
• the amount of the base to be used is generally 0.1-
• the inert solvent examples include ether solvents such as acetone, acetonitrile, water, tetrahydrofuran, diethyl ether, 1,4-dioxane and 1,2-dimethoxyethane; hydrocarbons such as hexane, heptane, toluene, benzene and xylene.
• Solvents Halogenated hydrocarbon solvents such as dichloromethane, chloroform, dichloroethane, and the like; aprotic solvents such as N, N-dimethylformamide, dimethyl sulfoxide, hexamethylene phosphoamide, etc., and mixed solvents thereof may be used.
• the reaction temperature is not particularly limited, but is preferably selected from the range of about 0 ° C to 80 ° C.
• the alkyl group can be converted to an alkyl group by a method similar to a known method (for example, Comprehensive Organic transformation, RC Laroc et al., VCH publisher Inc., 1989 etc.). It can also be converted.
• Step 6-3 Production Step of Compound (6-5)
• Compound (6-5) can be produced by treating compound (6-1) with an appropriate reducing agent in an inert solvent.
• the reaction temperature ranges from about ⁇ 78 ° C. to the boiling point of the solvent used, preferably 0 ° C. to 60 ° C.
• the reducing agent include, for example, borane-dimethyl sulfide complex, borane-tetrahydrofuran complex, lithium triethylborohydride, lithium aluminum hydride, sodium borohydride, triacetoxyborohydride, tricyanoborohydride, hydrogenation Examples include diisobutylaluminum, lithium tri (sec-butyl) borohydride, sodium tri (sec-butyl) borohydride, potassium tri (sec-butyl) borohydride, and the like.
• the amount of the reducing agent used is 0.25-5 equivalents, preferably 0.8-3 equivalents, relative to the equivalent of compound (6-1).
• the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane, aromatic hydrocarbons such as benzene and toluene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, dimethoxyethane, and tert-butyl.
• halogenated hydrocarbons such as chloroform and dichloromethane
• aromatic hydrocarbons such as benzene and toluene
• diethyl ether diethyl ether
• THF tetrahydrofuran
• 1,4-dioxane 1,4-dioxane
• dimethoxyethane dimethoxyethane
• tert-butyl examples include ether solvents such as methyl ether and cyclopentyl methyl ether, and lower alcohols such as methanol, ethanol, and isopropanol.
• a mixed solvent thereof may be used.
• Step 6-4 methods known production process compound (6-5) of compound (6-6) (e.g., by Protective Groups in Organic Synthesis 3 rd Edition (John Wiley & Sons, Inc , etc.), a hydroxyl group appropriately The compound (6-6) can be obtained by protection.
• Step 6-5 Step of producing compound (6-7) Compound (6-7) is reacted with compound (6-3) in the same manner as in step (6-2) to give compound (6-7) Can be manufactured.
• the alkyl group can be converted to an alkyl group by a method similar to a known method (for example, Comprehensive Organic transformation, RC Laroc et al., VCH publisher Inc., 1989 etc.). It can also be converted.
• Step 6-6 The compound (6-8) production process compound (6-7) a known method (for example, Protective Groups in Organic Synthesis 3 rd Edition (John Wiley & Sons, Inc , etc.), protected hydroxy Can be deprotected to give compound (6-8).
• a known method for example, Protective Groups in Organic Synthesis 3 rd Edition (John Wiley & Sons, Inc , etc.), protected hydroxy Can be deprotected to give compound (6-8).
• Step 6-7 Step of producing compound (6-9)
• Compound (6-9) can be produced by the same method as in Step 3-3 using compound (6-8).
• Step 6-8 Step for producing compound (2-11) Using compound (6-9), compound (6-10) can be produced by the same method as in step 2-8.
• R 100 represents a C 1-4 alkyl group or a benzyl group
• R 160 represents an optionally substituted C 1-6 alkyl group or an optionally substituted C 2-6 alkenyl group.
• R 101 represents a Cbz group, a Boc group, an Alloc group, a benzyl group, or an Fmoc group
• X represents a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a trifluoro group.
• R 600 represents a tert-butyldimethylsilyl group, a triethylsilyl group, a trimethylsilyl group, a triisopropylsilyl group, a tert-butyldiphenylsilyl group, a triphenylsilyl group, a tetrahydropyranyl group, a trityl group, 2- (trimethylsilyl) ethoxymethyl group and benzyl group.
• Raw material compound As the compound represented by the formula (2-2), for example, a compound produced by the method of known literature (Organic Letters (2007), 9 (21), 4255-4258.) Is used, or a known production law (e.g., protective groups in Organic Synthesis 3 rd Edition (John Wiley & Sons, Inc) , etc.) may be used as the protected appropriately functional groups using. Further, as the compound represented by the formula (7-1), for example, a compound produced by the method of a known document (Journal of Medicinal Chemistry (2006), 49 (26), 7596-7599.) Is used or is publicly known. production methods (e.g., protective groups in Organic Synthesis 3 rd Edition (John Wiley & Sons, Inc) , etc.) can be also used suitably those protect functional groups using.
• Step 7-1 Step of producing compound (7-1) Using compound (2-2), a method similar to a known method (for example, Comprehensive Organic transformation, RC Laroc et al., VCH publisher Inc., 1989 etc.)
• the compound (7-1) can be produced by reducing the carbonyl group with an appropriate reducing agent.
• the reducing agent include, for example, sodium borohydride, lithium borohydride, borane-dimethylsulfide complex, borane-tetrahydrofuran complex, lithium triethylborohydride, triacetoxyborohydride, tricyanoborohydride, hydrogenation Examples include diisobutylaluminum, lithium tri (sec-butyl) borohydride, sodium tri (sec-butyl) borohydride, potassium tri (sec-butyl) borohydride, and the like.
• Step 7-2 Step of producing compound (7-3) Using compound (7-1), compound (7-3) can be produced by the same method as in step 6-2.
• the alkyl group can be converted to an alkyl group by a method similar to a known method (for example, Comprehensive Organic transformation, RC Laroc et al., VCH publisher Inc., 1989 etc.). It can also be converted.
• Step 7-3 Production Step of Compound (7-4)
• Compound (7-4) can be produced by the same method as in Step 6-3 using compound (7-1).
• Step 7-4 Production Step of Compound (7-5)
• Compound (7-5) can be produced by the same method as in Step 6-4 using compound (7-4).
• Step 7-5 Step for producing compound (7-6)
• Compound (7-6) can be produced by using compound (7-5) in the same manner as in step 6-5.
• Step 7-6 Step of producing compound (7-7) Using compound (7-6), compound (7-7) can be produced by the same method as in step 6-6.
• Step 7-7 Step of producing compound (7-8) Using compound (7-7), compound (7-8) can be produced by the same method as in step 6-7.
• Step 7-8 Step for producing compound (7-9)
• Compound (7-9) can be produced by the same method as in step 3-10 using compound (7-8).
• Step 7-9 Step for producing compound (7-10)
• Compound (7-10) can be produced by using compound (7-9) in the same manner as in step 6-8.
• R 100 represents a C 1-4 alkyl group or a benzyl group
• R 170 and R 171 each independently represents an optionally substituted C 1-6 alkyl group
• an optionally substituted C 3-10 cycloalkyl group an optionally substituted phenyl group, an optionally substituted 5- to 10-membered heteroaryl group, or an optionally substituted 4- to 10-membered saturation It may be a telocyclic group or may be bonded to each other to form a ring
• R 101 represents a Cbz group, a Boc group, an Alloc group, a benzyl group, or an Fmoc group.
• Step 8-1 Production Step of Compound (8-2)
• a known method for example, Comprehensive Organic Transformation, RC Laroc et al., VCH publisher Inc.
• Compound (2-2) and Compound (8-1) of Production Method 2 1989, etc. can be used to produce compound (8-2).
• a conversion method a reductive amination reaction, or an imination reaction followed by a reduction reaction may be considered.
• cis- and trans geometric isomers may be generated. In this case, they can be separated by various column chromatography and crystallization methods and used for the next reaction.
• Reductive agents for reductive amination reaction or reduction reaction include lithium aluminum hydride, sodium borohydride, triacetoxy borohydride, tricyanoborohydride, diisobutylaluminum hydride, lithium tri (sec-butyl) borohydride , Sodium tri (sec-butyl) borohydride, potassium tri (sec-butyl) borohydride, borane-dimethylsulfide complex, borane-tetrahydrofuran complex, lithium triethylborohydride, ammonium formate, palladium-carbon And a hydrogenation reaction using a metal catalyst such as palladium oxide.
• Additives for reductive amination reaction or reduction reaction include organic acids such as acetic acid, hydrochloric acid, trifluoroacetic acid, methanesulfonic acid, dehydrating agents such as tetramethyl orthosilicate, methyl orthoformate, zinc chloride, titanium tetrachloride , Lanthanum sulfate, magnesium sulfate-pyridinium p-toluenesulfonate, magnesium bromide, indium chloride, zirconium chloride, magnesium triflate, ytterbium (III) triflate, scandium triflate, alumina, copper sulfate, tetraisopropoxide titanate, titanic acid
• Examples include Lewis acids such as tetraethoxide.
• Step 8-2 Step of producing compound (8-3)
• Compound (8-3) can be produced by the same method as in Step 1-3 using compound (8-2). In this step, when isomerization of cis- and trans occurs, it can be separated by various methods such as column chromatography and crystallization and used for the next step.
• the intermediates and final products in the above production method may be converted appropriately in functional groups, and in particular, various side chains may be extended by using amino groups, amidino groups, hydroxy groups, carbonyl groups, halogen groups, etc. as a foothold.
• the transformation of the functional group and the extension of the side chain are carried out by a commonly used general method (for example, Comprehensive Organic transformation, R. C. Lalock, etc.).
• Isolation and purification of intermediates and target compounds in each of the above production methods through purification methods commonly used in organic synthetic chemistry, such as neutralization, filtration, extraction, washing, drying, concentration, recrystallization, and various chromatography. be able to.
• the intermediate can be subjected to the next reaction without any particular purification.
• the optical isomers and atropisomers of the compounds of the present invention are obtained as racemates, or as optically active forms when optically active starting materials and intermediates are used.
• the corresponding raw material, intermediate or final racemate is physically separated by a known separation method such as a method using an optically active column or a fractional crystallization method. Or chemically split into their optical antipodes.
• a known separation method such as a method using an optically active column or a fractional crystallization method.
• two diastereomers are formed from a racemate using an optically active resolving agent, or a diastereomeric salt is formed. Since these different diastereomers generally have different physical properties, they can be resolved by a known method such as fractional crystallization.
• the stereoisomers can be separated by various column chromatography, crystallization and the like.
• the pharmaceutically acceptable salt of the compound of the present invention represented by the formula (1) has a basicity or acidity sufficient to form a salt in a solvent such as water, methanol, ethanol, and acetone. It can be produced by mixing the compound represented by the formula (1) and a pharmaceutically acceptable acid or base.
• the compound of the present invention can be applied to the treatment of various diseases because of its inhibitory action on FXIa.
• the compounds described herein are useful as prophylactic or therapeutic agents for thromboembolism (venous thrombosis, myocardial infarction, pulmonary embolism, cerebral embolism, slowly progressing cerebral thrombosis, etc.). These compounds are expected to be useful for thrombosis caused by exposure of blood to artificial surfaces such as arteries, venous thrombosis, sepsis and prosthetic valves, indwelling catheters, stents, cardiopulmonary, hemodialysis, etc. . These compounds are expected to be useful for inflammatory diseases such as rheumatoid arthritis and ulcerative colitis. In addition, it is effective in improving the therapeutic effect for these diseases.
• the compound of the present invention can be administered orally or parenterally. When administered orally, it can be administered in a commonly used dosage form. Parenterally, it can be administered in the form of topical administration, injection, transdermal preparation, nasal preparation and the like.
• oral or rectal administration agent examples include capsules, tablets, pills, powders, cachets, suppositories, and liquids.
• injections include sterile solutions or suspensions.
• topical administration agent include creams, ointments, lotions, transdermal agents (ordinary patches, matrix agents) and the like.
• the above-mentioned dosage form is formulated by a usual method together with pharmaceutically acceptable excipients and additives.
• pharmaceutically acceptable excipients and additives include carriers, binders, fragrances, buffers, thickeners, colorants, stabilizers, emulsifiers, dispersants, suspending agents, preservatives, and the like. It is done.
• the pharmaceutically acceptable carrier include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting point wax, cocoa butter Etc.
• Capsules can be formulated by placing the compound of the present invention in a pharmaceutically acceptable carrier.
• the compounds of the present invention can be mixed with pharmaceutically acceptable excipients or placed in capsules without excipients. Cachets can be produced in the same manner.
• injection solutions include solutions, suspensions, and emulsions. Examples thereof include an aqueous solution and a water-propylene glycol solution.
• the solution can also be prepared in the form of a solution of polyethylene glycol and / or propylene glycol, which may contain water.
• a solution suitable for oral administration can be produced by adding the compound of the present invention to water and adding a colorant, a fragrance, a stabilizer, a sweetener, a solubilizer, a thickener and the like as necessary.
• a solution suitable for oral administration can also be produced by adding the compound of the present invention together with a dispersant to water to make it viscous.
• the thickener include pharmaceutically acceptable natural or synthetic gum, resin, methylcellulose, sodium carboxymethylcellulose, or a known suspending agent.
• the dose varies depending on the individual compound and the patient's disease, age, weight, sex, symptom, route of administration, etc., but usually 0.1 to 1000 mg of the compound of the present invention for an adult (50 kg body weight).
• / Day preferably 1 to 300 mg / day, once a day or divided into 2 to 3 doses. It can also be administered once every few days to several weeks.
• the compound of the present invention can be used in combination with a drug such as an anticoagulant or an antiplatelet agent (hereinafter abbreviated as a concomitant drug) for the purpose of enhancing its effect.
• a drug such as an anticoagulant or an antiplatelet agent (hereinafter abbreviated as a concomitant drug) for the purpose of enhancing its effect.
• 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 at the same time or may be administered with a time difference. Moreover, it is good also as a mixture of this invention compound and a concomitant drug.
• the dose of the concomitant drug can be appropriately selected based on the clinically used dose.
• the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, the concomitant drug may be
• anticoagulants examples include thrombin inhibitors (eg, dabigatran, AZD-0837, MPC-0920, Org-27306, NU-172, etc.), other FXIa factor inhibitors (eg, ISIS-FXIRx, etc.), etc.
• thrombin inhibitors eg, dabigatran, AZD-0837, MPC-0920, Org-27306, NU-172, etc.
• FXIa factor inhibitors eg, ISIS-FXIRx, etc.
• Plasma kallikrein inhibitors FVIIa factor inhibitors (eg, PCI-27483, etc.), FIXa factor inhibitors (eg, TTP-889, REGI, REG2, etc.) and FXa factor inhibitors (eg, rivaroxaban, apixaban, edoxaban, YM) -150, TAK-442, betrixaban, eribaxaban, LY-517717, AVE-3247, GW-813893, R-1663, DB-772d, etc.).
• FVIIa factor inhibitors eg, PCI-27483, etc.
• FIXa factor inhibitors eg, TTP-889, REGI, REG2, etc.
• FXa factor inhibitors eg, rivaroxaban, apixaban, edoxaban, YM
• Anti-platelet agents include GPIIb / IIIa blockers (eg, Abciximab, Epifibatide, Tirofiban, etc.), P2Y1 and P2Y12 antagonists (eg, clopidogrel, Prasugrel, Ticagrelor, Elinogrel, etc.), thromboxane receptor antagonists, and aspirin receptor antagonists.
• GPIIb / IIIa blockers eg, Abciximab, Epifibatide, Tirofiban, etc.
• P2Y1 and P2Y12 antagonists eg, clopidogrel, Prasugrel, Ticagrelor, Elinogrel, etc.
• thromboxane receptor antagonists eg, aspirin receptor antagonists.
• the combination drug is preferably an antiplatelet agent or the like. Two or more of the above concomitant drugs may be used in combination at an appropriate ratio.
• the amount of these drugs used can be reduced within a safe range considering the side effects of the drug. Therefore, side effects that may be caused by these drugs can be safely prevented.
• the obtained residue was purified by silica gel column chromatography to obtain methyl cis-1-tert-butoxycarbonyl-3-phenylpyrrolidine-2-carboxylate (510 mg, 97%). Subsequently, a THF (1 mL) solution of methyl cis-1-tert-butoxycarbonyl-3-phenylpyrrolidine-2-carboxylate (110 mg, 0.36 mmol) was cooled to ⁇ 78 ° C., and lithium diisopropylamide prepared in advance was used. (0.396 mmol: THF solution) was added and stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with diethyl ether.
• the title compound was obtained from 410-amino-3-bromotoluene (930 mg, 5.0 mmol) according to a known method (for example, WO2008 / 157162) (410 mg, 36%).
• N-methylmorpholine N-oxide (546 mg, 4.65 mmol) and molecular sieves (430 mg) were added to a solution of the compound of Reference Example 15-2 in acetonitrile (4.5 mL), and the mixture was stirred for 10 minutes. Subsequently, tetrapropylammonium perruthenate (270 mg, 0.77 mmol) was added and stirred for 4.5 hours. The reaction solution was filtered using celite and silica gel, and the obtained filtrate was concentrated under reduced pressure to obtain the title compound (366 mg, 83%). MS (ESI +) 294 (M + 1, 19%)
• the compound of Reference Example 15-3 (366 mg, 1.25 mmol) was dissolved in a mixed solvent of tert-butanol and distilled water (3: 1, 6.4 mL), and sodium dihydrogen phosphate dihydrate (583 mg, 3.74 mmol), 2-methyl-2-butene (660 ⁇ l, 6.23 mmol) and sodium chlorite (564 mg, 5.0 mmol) were added and stirred for 6 hours.
• Ethyl acetate and a 1 mol / L aqueous sodium hydroxide solution were added to the reaction solution, the pH was adjusted to 8-9, liquid separation was performed, and the aqueous layer was separated.
• N, N′-carbonyldiimidazole (243 mg, 1.5 mmol) was added to a DMF (5 mL) solution of the compound of Reference Example 22-1 (411 mg, 1.0 mmol), and the mixture was stirred at room temperature for 14 hours. Thereafter, 1,8-diazabicyclo [5.4.0] undec-7-ene (0.152 mL, 1.0 mmol) and tert-butanol (4.75 mL, 50 mmol) were added, and the mixture was stirred at 85 ° C. for 18 hours. After allowing to cool, water was added and the mixture was extracted with chloroform.
• Reference Examples 34-36 Commercially available or in a known manner (for example, Jiangxi Shifan Daxue Xuebao, Ziran Kexueban (2001), 25, (1), 83-86; Journal of Organic Chemistry (2009), 74 (23), 9152-9157.) Using synthesized (E) -2,5-dichlorocinnamic acid, (E) -3-chlorocinnamic acid, and (E) -2-chlorocinnamic acid, according to the method described in Reference Example 21, Reference Example 34 ⁇ 36 compounds were obtained.
• (2S, 3S) -1- (tert-butoxycarbonyl) -3- (2-methylpropoxy) pyrrolidine-2-carboxylic acid was converted from the compound of Reference Example 37-3 in the same manner as in Reference Example 2-3. Synthesized. In the same manner as in Reference Example 3-1, (2S, 3S) -1- (tert-butoxycarbonyl) -3- (2-methylpropoxy) pyrrolidine-2-carboxylic acid (95 mg, 0.330 mmol) and tert-butyl The title compound was obtained from 5-amino-1H-indole-2-carboxylate (84 mg, 0.363 mmol) (39 mg, 23%). MS (ESI +) 502 (M + 1, 62%)
• (2S, 3R) -1- (tert-butoxycarbonyl) -3- (2-methylpropoxy) pyrrolidine-2-carboxylic acid was converted from the compound of Reference Example 38-4 in the same manner as in Reference Example 2-3. Synthesized. Thereafter, in the same manner as in Reference Example 3-1, (2S, 3R) -1- (tert-butoxycarbonyl) -3- (2-methylpropoxy) pyrrolidine-2-carboxylic acid (98 mg, 0.34 mmol) and tert The title compound was obtained from 118-butyl 5-amino-1H-indole-2-carboxylate (87 mg, 0.374 mmol) (118 mg, 70%). MS (ESI +) 502 (M + 1, 93%)
• the compound of Reference Example 43-2 (560 mg, 1.64 mmol) was subjected to hydrolysis to give the title compound (537 mg, 100%).
• RT 2.914 min Shi-pack XR-ODS, 0.1% trifluoroacetic acid in water / acetonitrile, acetonitrile 10-90% 5.7min, 1.0mL / min (condition A)).
• Ethyl 5-nitro-1-benzofuran-2-carboxylate (2.0 g, 8.54 mmol) is suspended in a mixed solvent of methanol (3.2 mL) and THF (3.2 mL), and 4 mol / L aqueous sodium hydroxide solution (3.2 mL) was added and stirred at 70 ° C. for 1 hour.
• a 1 mol / L aqueous hydrochloric acid solution was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and then the solvent was distilled off under reduced pressure to obtain a crude product.
• Reference Example 48-1 tert-butyl trans-2- ⁇ [2- (tert-butoxycarbonyl) -1-benzofuran-5-yl] carbamoyl ⁇ -3-phenylpyrrolidine-1-carboxylate
• the title compound was obtained from the compound of Reference Example 1-1 (110 mg, 0.377 mmol) and the compound of Reference Example 47-2 (80 mg, 0.343 mmol) (173 mg, 99%) .
• Rf value 0.25 (hexane / ethyl acetate 3/1)
• Reference Examples 49-50 According to the method described in Reference Example 47-3 and Reference Example 47-4, the compound of Reference Example 45-1 or (2S, 3R) -1-tert-butoxycarbonyl-3-phenylpyrrolidine-2-carboxylic acid and Reference After synthesizing hydrochloric acid corresponding to Reference Example 47-4 using the compound of Example 47-2, (E) -3- [5-chloro-2- (1H--) was synthesized in the same manner as in Example 2. Reaction with tetrazol-1-yl) phenyl] prop-2-enoic acid gave compounds of Reference Examples 49-50.
• Reference Examples 52-53 In accordance with the methods described in Reference Example 51-2, Reference Example 51-3, Reference Example 51-4 and Reference Example 51-5, the compound of Reference Example 51-1 and the corresponding amine were used as starting materials, and Reference Example 51-5 After synthesizing a pyrrolidine derivative corresponding to this compound, (E) -3- [5-chloro-2- (1H-tetrazol-1-yl) phenyl] prop-2-ene was synthesized in the same manner as in Example 2. Reaction with an acid was performed to obtain the compounds of Reference Example 52 and Reference Example 53.
• Reference Examples 56-59 In accordance with the method described in Reference Example 51-2 and Reference Example 51-3, the compound of Reference Example 51-1 and the corresponding amine were used as starting materials to synthesize the carboxylic acid corresponding to Reference Example 51-3. Then, the compound of Reference Example 51-5 is reacted with tert-butyl 4-aminobenzoate according to the method described in Reference Example 3-1, and de-Cbz converted according to the method described in Reference Example 43-5. After the synthesis of pyrrolidine corresponding to the above, it was finally reacted with (E) -3- [5-chloro-2- (1H-tetrazol-1-yl) phenyl] prop-2-enoic acid. 56-59 compounds were obtained.
• Reference Examples 60-68 In accordance with the method described in Reference Example 51-2 and Reference Example 51-3, the compound of Reference Example 51-1 and the corresponding amine were used as starting materials to synthesize the carboxylic acid derivative corresponding to Reference Example 51-3. Next, after reacting the obtained carboxylic acid derivative or the compound of Reference Example 54-2 with tert-butyl 5-amino-1H-indole-2-carboxylate according to the method described in Reference Example 3-1, The pyrrolidine derivative corresponding to the compound of Reference Example 51-5 was synthesized by de-Cbzation according to the method described in Example 43-5.
• Trifluoroacetic acid (0.4 mL) was added to a solution of the compound of Reference Example 1 (33 mg, 0.26 mmol) in chloroform (1 mL), and then the mixture was warmed to room temperature and stirred for 4 hours. The reaction solution was concentrated under reduced pressure, toluene (2 mL) was added to the residue, and the mixture was concentrated again under reduced pressure. Further, chloroform (3 mL) and hexane (3 mL) were added and concentrated under reduced pressure twice. Thereafter, chloroform-hexane was added to precipitate crystals. The precipitated solid was filtered to obtain the title compound (20 mg, 67%). RT 5.103 min (Condition A) MS (ESI +) 582 (M + 1, 8%).
• Examples 3-8 According to the method described in Example 1, the compounds of Examples 3 to 8 were obtained from the corresponding compounds of Reference Examples 3 to 8.
• Examples 9-11 According to the method described in Example 1, the compounds of Examples 9 to 11 were obtained from the corresponding compounds of Reference Examples 9 to 11.
• Examples 12-14 According to the method described in Example 1, the compounds of Examples 12 to 14 were obtained from the corresponding compounds of Reference Examples 12 to 14.
• Examples 15-19 According to the method described in Example 1, the compounds of Examples 15 to 19 were obtained from the corresponding compounds of Reference Examples 15 to 19.
• Example 20 5-[(2S, 3S) -1- ⁇ (E) -3- [5-Chloro-2- (1H-tetrazol-1-yl) phenyl] prop-2-enoyl ⁇ -3- (tetrahydro-2H- Pyran-4-yl) pyrrolidine-2-carbonylamino] -1H-indole-2-carboxylic acid
• the title compound was obtained from the corresponding compound of Reference Example 20 (9.0 mg, 69%) according to the method described in Example 1. RT 4.792 min (Condition B) MS (ESI +) 590 (M + 1, 100%).
• Examples 21-23 The compounds of Examples 21 to 23 were obtained from the corresponding compounds of Reference Examples 21 to 23 according to the method described in Example 1.
• Example 24 4- [cis-1- ⁇ (E) -3- [5-Chloro-2- (1H-tetrazol-1-yl) phenyl] prop-2-enoyl ⁇ -3-cyclohexylpyrrolidine-2-carbonylamino]- 2-Fluorobenzoic acid
• the title compound was obtained from the corresponding compound of Reference Example 24 (9.0 mg, 69%) according to the method described in Example 1. RT 4.503 min (Condition A) MS (ESI +) 567 (M + 1, 56%).
• Examples 25-28 According to the method described in Example 1, the compounds of Examples 25 to 27 were obtained from the corresponding compounds of Reference Examples 25 to 27. Further, according to the method described in Example 2, the compound of Example 28 was obtained from the corresponding compound of Reference Example 28.
• Examples 29-33 The compounds of Examples 29 to 33 were obtained from the corresponding compounds of Reference Examples 29 to 33 according to the method described in Example 1.
• Examples 34-36 The compounds of Examples 34 to 36 were obtained from the corresponding compounds of Reference Examples 34 to 36 according to the method described in Reference Example 2-3.
• Example 37 In accordance with the method described in Example 1, the compounds of Example 37 and Example 38 were obtained from the corresponding compounds of Reference Example 37 and Reference Example 38.
• Example 39-40 In accordance with the method described in Example 1, the compounds of Example 39 and Example 40 were obtained from the corresponding compounds of Reference Example 39 and Reference Example 40.
• Example 41-42 According to the method described in Example 1, the compounds of Example 41 and Example 42 were obtained from the corresponding compounds of Reference Example 41 and Reference Example 42.
• Example 43-44 In accordance with the method described in Example 1, the compounds of Example 43 and Example 44 were obtained from the corresponding compounds of Reference Example 43 and Reference Example 44.
• Example 45 According to the method described in Example 1, the compound of Example 45 was obtained from the corresponding compound of Reference Example 45. RT 5.295 min (Condition E) MS (ESI +) 626 (M + 1, 100%).
• Example 46 The compound of Example 46 was obtained from the corresponding compound of Reference Example 46 according to the method described in Example 1. RT 5.779 min (Condition E) MS (ESI +) 597 (M + 1, 100%).
• Examples 47-48 According to the method described in Example 1, the compounds of Example 47 and Example 48 were obtained from the corresponding compounds of Reference Example 47 and Reference Example 48.
• Example 49-50 According to the method described in Example 1, the compounds of Example 49 and Example 50 were obtained from the corresponding compounds of Reference Example 49 and Reference Example 50.
• Examples 51-53 According to the method described in Example 1, the compounds of Examples 51 to 53 were obtained from the corresponding compounds of Reference Examples 51 to 53.
• Example 54 According to the method described in Example 1, the compound of Example 54 was obtained from the corresponding compound of Reference Example 54. RT 2.845 min (Condition E) MS (ESI +) 590 (M + 1, 100%).
• Example 55 The compound of Example 55 was obtained from the corresponding compound of Reference Example 55 according to the method described in Example 1. RT 2.841 min (Condition E) MS (ESI +) 590 (M + 1, 100%).
• Examples 56-59 In accordance with the method described in Example 1, from the corresponding compounds of Reference Examples 56 to 59, Examples 56 to 59 To give a compound.
• Examples 60-67 The compounds of Examples 60 to 67 were obtained from the corresponding compounds of Reference Examples 60 to 67 according to the method described in Example 1.
• Examples 69-71 In accordance with the method described in Example 2, from the corresponding compounds of Reference Examples 69 to 71 and (E) -3- [5-chloro-2- (1H-tetrazol-1-yl) phenyl] prop-2-enoic acid The compounds of Examples 69 to 71 were obtained.
• Example 72 4- [cis-1- ⁇ (E) -3- [5-Chloro-2- (1H-tetrazol-1-yl) phenyl] prop-2-enoyl ⁇ -3- (piperidin-1-yl) -2 -[4- (5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl) phenyl] carbamoyl] pyrrolidine According to the method described in Example 2, the title compound was obtained from the corresponding compound of Reference Example 72 and (E) -3- [5-chloro-2- (1H-tetrazol-1-yl) phenyl] prop-2-enoic acid. Got. RT 4.792 min (Condition E). MS (ESI +) 590 (M + 1, 100%).
• Examples 73-78 In accordance with the method described in Reference Example 51, a tert-butyl ester derivative corresponding to Reference Example 51 was synthesized using the compound of Reference Example 51-1 and the corresponding amine as starting materials, and then according to the method described in Example 1. The compounds of Examples 73 to 78 were obtained. However, when N-methylisobutylamine was used as the amine, both cis- and trans-isomers were produced in the reaction corresponding to Reference Example 51-3. The cis- and trans- isomers were separated by column chromatography, and the subsequent reaction was performed to obtain the compounds of Example 75 and Example 76, respectively.
• Examples 79-84 According to the method described in Reference Example 51, a tert-butyl ester derivative corresponding to Reference Example 51 was synthesized using the compound of Reference Example 51-1 and the corresponding amine as starting materials, and then according to the method described in Example 1. The compounds of Examples 79 to 84 were obtained. However, when N-methylisobutylamine was used as the amine, both cis- and trans-isomers were produced in the reaction corresponding to Reference Example 51-3. After isolating the cis- and trans- isomers by column chromatography, the subsequent reaction was performed to obtain the compounds of Example 81 and Example 82, respectively.
• Examples 85-90 According to the method described in Reference Example 51, a tert-butyl ester derivative corresponding to Reference Example 51 was synthesized using the compound of Reference Example 51-1 and the corresponding amine as starting materials, and then according to the method described in Example 1. The compounds of Examples 85 to 90 were obtained. However, when N-methylisobutylamine was used as the amine, both cis- and trans-isomers were produced in the reaction corresponding to Reference Example 51-3. The cis- and trans- isomers were separated by column chromatography and the subsequent reaction was carried out to obtain the compounds of Example 87 and Example 88, respectively.
• Examples 91-105 From a racemic trans-3-hydroxyproline known in the literature (for example, Tetrahedron Letters (1998), 39 (21), 3413-3416.), A method described in the literature (for example, European Journal of Organic Chemistry (2009), ( 20), 3368-3386.) After synthesizing racemic 1-tert-butyl 2-methyl trans-3-hydroxypyrrolidine-1,2-dicarboxylate in the same manner as in Reference Example 37-1 and Racemic 1-tert-butyl 2-methyl cis-3-hydroxypyrrolidine-1,2-dicarboxylate was synthesized according to the method of Reference Example 37-2.
• racemic benzyl trans-2-( ⁇ [tert-butyl (dimethyl) silyl] oxy is prepared from racemic trans-3-hydroxyproline according to the methods of Reference Example 38-1 and Reference Example 38-2.
• ⁇ Methyl) -3-hydroxypyrrolidine-1-carboxylate was synthesized.
• the racemic compound corresponding to Reference Example 37 or Reference Example 38 was prepared according to the method described in Reference Example 37-3, Reference Example 37-4 and Reference Example 38-3 using a halide corresponding to pyrrolidine-1-carboxylate as a starting material.
• the compounds of Examples 91 to 105 were obtained according to the method described in Example 1.
• Examples 106, 107 In accordance with the method described in Reference Example 37-3 and Reference Example 37-4, starting from racemic 1-tert-butyl 2-methyl cis-3-hydroxypyrrolidine-1,2-dicarboxylate and the corresponding halide After synthesizing a racemic tert-butyl ester derivative corresponding to Reference Example 37, the compounds of Examples 106 and 107 were obtained according to the method described in Example 1.
• Examples 108-124 Racemic 1-tert-butyl 2-methyl cis-3-hydroxypyrrolidine-1,2-dicarboxylate or benzyl trans-2-( ⁇ [tert-butyl (dimethyl) silyl] oxy ⁇ methyl) -3-hydroxy
• the racemic compound corresponding to Reference Example 37 or Reference Example 38 is prepared according to the method described in Reference Example 37-3, Reference Example 37-4 and Reference Example 38-3 using a halide corresponding to pyrrolidine-1-carboxylate as a starting material. After synthesizing the tert-butyl ester derivative, the compounds of Examples 108 to 124 were obtained according to the method described in Example 1.
• Examples 125-136 Racemic 1-tert-butyl 2-methyl cis-3-hydroxypyrrolidine-1,2-dicarboxylate or benzyl trans-2-( ⁇ [tert-butyl (dimethyl) silyl] oxy ⁇ methyl) -3-hydroxy
• the racemic compound corresponding to Reference Example 37 or Reference Example 38 is prepared according to the method described in Reference Example 37-3, Reference Example 37-4 and Reference Example 38-3 using a halide corresponding to pyrrolidine-1-carboxylate as a starting material. After synthesizing the tert-butyl ester derivative, the compounds of Examples 125 to 136 were obtained according to the method described in Example 1.
• Test example 1 In vitro FXIa inhibitory activity measurement test To a mixture of HEPES (7.15 g), sodium chloride (8.47 g), potassium chloride (0.372 g), and PEG8000 (2 mL), add 1 mol / L aqueous sodium hydroxide solution. After adjusting to pH 7.4, purified water was added to bring the total volume to 1000 mL, and a buffer solution was prepared. Factor XIa, a substrate, and a test compound were added to the prepared buffer and reacted at 37 ° C. for 15 minutes. Factor XIa was added to a final concentration of 0.35 ⁇ g / mL.
• S-2366 pyroGlu-Pro-Arg-pNA ⁇ HCl
• IC 50 concentration at which the increase in OD value was suppressed by 50%
• the compound of the present invention has a strong FXIa inhibitory activity, it is useful for the treatment of thromboembolism, thrombosis and the like.

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