WO2017010399A1

WO2017010399A1 - COMPOUNDS HAVING RORγt INHIBITORY EFFECTS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME

Info

Publication number: WO2017010399A1
Application number: PCT/JP2016/070151
Authority: WO
Inventors: 敬多幾山; 正英大段; 義一佐々木; 士郎木田; 裕樹立花; 佳世子畑; 加藤　学
Original assignee: 塩野義製薬株式会社
Priority date: 2015-07-10
Filing date: 2016-07-07
Publication date: 2017-01-19

Abstract

Provided are compounds having RORγt inhibitory effects represented by formula (I). Compounds represented by formula (I) (wherein L represents -NR^1ACO-, -SO₂- or the like, A represents a substituted or unsubstituted aromatic carbocyclic group or the like, R¹, R², R^3a, R^4a, R^3b and R^4b represent hydrogen or substituted or unsubstituted alkyl or the like, m is from 0 to 2, n is 0 or 1, ring B represents an aromatic carbocyclic ring, an aromatic heterocyclic ring, etc., R^1A represents hydrogen, etc., E represents SO₂R^10A, etc., R^10A represents substituted or unsubstituted alkyl, etc., X represents =CR⁹- or =N-, R⁵ and R⁸ represent halogen, hydroxy, etc., R⁹ represents hydrogen, halogen, hydroxy, etc., R⁶ and R⁷ represent hydrogen, halogen, substituted or unsubstituted alkyl, etc., p is from 0 to 4 and q is from 0 to 3) or pharmaceutically acceptable salts thereof.

Description

RORγt inhibitory compound and pharmaceutical composition containing them

The present invention relates to a compound useful for treating a disease or condition involving RORγt, and a pharmaceutical composition containing the compound.

Interleukin 17 (IL-17) is an inflammatory cytokine produced from Th17 cells, γδT cells, and the like, and is greatly involved in the pathogenesis of autoimmune diseases such as inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, and psoriasis. It is known that
Retinoid related orphan receptor (ROR) γt expressed in Th17 cells and γδT cells is known to act as a transcription factor of IL-17 and promote differentiation of T cells into Th17 cells.
Therefore, RORγt inhibitors are expected to show preventive and / or therapeutic effects on autoimmune diseases such as inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis and psoriasis by suppressing IL-17 production.
Patent Documents 1 to 29 and Non-Patent Documents 1 to 3 describe compounds that are considered useful for autoimmune diseases such as RORγt inhibitors, RORγt inverse agonists or P2X7 inhibitors, CCR5 agonists, etc. Are different in structure.

WO2013 / 0293338 WO2012 / 100734 publication WO2012 / 100732 publication WO2012 / 028100 publication WO2012 / 027965 WO2013 / 171729 WO2014 / 028669 WO2007 / 109192 publication WO2009 / 010478 WO 2006/130426 WO2014 / 179564 WO2014 / 125426 WO2014 / 086894 WO2014 / 023367 WO2013 / 178362 WO2015 / 002230 WO2013 / 169704 WO2013 / 169588 WO2013 / 169864 WO2015 / 035278 WO2014 / 009447 Publication WO2015 / 082533 WO2015 / 101928 WO2016 / 019588 WO2016 / 039408 WO2015 / 116904 Publication WO2015 / 145371 WO2015 / 082533 WO2015 / 159233

An object of the present invention is to provide a novel compound having a RORγt inhibitory action. More specifically, the present invention relates to a novel compound having a preventive and / or therapeutic effect on autoimmune diseases such as inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis and psoriasis by having an RORγt inhibitory action, and A pharmaceutical composition is provided.

The present invention relates to the following.
(1) Formula (I):

(Wherein L is a single bond, —NR ^1A CO—, —CONR ^1B —, —NR ^1A CONR ^1B —, —OC (═O) NR ^1C —, —CO—, —S—, —SO ₂ — , -SO ₂ NR ^1D- , -NR ^1E SO ₂ -or -NR ^1F-
R ^1A , R ^1B , R ^1C , R ^1D , R ^1E and R ^1F are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted Alkylcarbonyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic A cyclic group,
A represents a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, or a substituted or unsubstituted aromatic heterocyclic ring. A formula group,
When L is —NR ^1A CO—, —OC (═O) NR ^1C —, —SO ₂ —, —SO ₂ NR ^1D — or —NR ^1E SO ₂ — and m is 0, A is substituted Or it may be unsubstituted alkyl (except unsubstituted methyl), substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl,
R ¹ , R ² , R ^3a , R ^4a , R ^3b and R ^4b are each independently hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl , Substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group or substituted or unsubstituted aromatic heterocyclic group And
R ¹ and R ² bonded to the same carbon, together with the carbon atom to which they are bonded, form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring. Well,
R ¹ and R ² bonded to the same carbon may together form ═NR ^1G ,
R ^3a and R ^4a , and R ^3b and R ^4b are each independently, together with the carbon atom to which they are attached, a substituted or unsubstituted non-aromatic carbocycle or substituted or unsubstituted non-aromatic May form a heterocycle,
R ^3a and R ^4a , and R ^3b and R ^4b may each independently form ═NR ^1H ,
R ^1G and R ^1H are each independently substituted or unsubstituted alkyloxy, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted A non-aromatic heterocyclic group or a substituted or unsubstituted aromatic heterocyclic group,
m is an integer from 0 to 2,
n is 0 or 1,
Ring B is a 6-membered non-aromatic carbocycle, 6-membered aromatic carbocycle, 6-membered non-aromatic heterocycle, 6-membered aromatic heterocycle, or

A ring represented by
When the bond a is bonded to —NHC (═O) CR ⁶ R ⁷ —, the bond b is bonded to —CR ^3b Rb ⁴ —, and when the ring B is a condensed ring, R ⁵ is represented by B ¹ and B ² Any ring may be substituted,
B ¹ ring is a 5-membered or 6-membered non-aromatic carbocyclic ring, a 6-membered aromatic carbocyclic ring, a 5-membered or 6-membered non-aromatic heterocyclic ring or a 5-membered or 6-membered aromatic heterocyclic ring,
The B ² ring is a 6-membered non-aromatic carbocycle, a 6-membered aromatic carbocycle, a 6-membered non-aromatic heterocycle or a 6-membered aromatic heterocycle (wherein ring B is not piperidine and indole);
Each R ⁵ is independently halogen, hydroxy, cyano, sulfanyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted Alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted nonaromatic carbocyclic group, substituted Or an unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or Unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic Aromatic heterocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic sulfanyl, substituted or unsubstituted aromatic carbocyclic sulfanyl, substituted or unsubstituted non-aromatic heterocyclic sulfanyl Substituted or unsubstituted aromatic heterocyclic sulfanyl or a group represented by the formula: —NR ⁵¹ R ⁵² , wherein two R ⁵ together may form oxo,
p is an integer from 0 to 4,
E is SO ₂ R ^10A , SOR ^10B or cyano;
R ^10A and R ^10B are each independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, or substituted or unsubstituted A substituted aromatic carbocyclic group,
X is = CR ⁹ -or = N-;
R ⁸ each independently represents halogen, hydroxy, sulfanyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyl Oxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or non-substituted Substituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted Aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocycle Oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic sulfanyl, substituted or unsubstituted aromatic carbocyclic sulfanyl, substituted or unsubstituted non-aromatic heterocyclic sulfanyl, substituted or An unsubstituted aromatic heterocyclic sulfanyl or a group represented by the formula: —NR ⁸¹ R ⁸² ;
R ⁹ is hydrogen, halogen, hydroxy, sulfanyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted Or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic Aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic Carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, Substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic sulfanyl, substituted or unsubstituted aromatic carbocyclic sulfanyl, substituted or unsubstituted non-aromatic heterocyclic sulfanyl, substituted or unsubstituted An aromatic heterocyclic sulfanyl group of the formula: —NR ⁹¹ R ⁹²
R ⁵¹ , R ⁵² , R ⁸¹ , R ⁸² , R ⁹¹ and R ⁹² are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or non-substituted A substituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group or a substituted or unsubstituted aromatic heterocyclic group,
R ⁶ is hydrogen, halogen, hydroxy, sulfanyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted Or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic An aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic heterocyclic group or a group represented by the formula: —NR ⁶¹ R ⁶² ,
R ⁷ is hydrogen, halogen, hydroxy, sulfanyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted Or an unsubstituted alkynyloxy, a substituted or unsubstituted alkylsulfanyl, a substituted or unsubstituted alkenylsulfanyl, a substituted or unsubstituted alkynylsulfanyl, or a group represented by the formula: —NR ⁷¹ R ⁷²
R ⁶ and R ⁷ together with the carbon atom to which they are attached may form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring,
R ⁶¹ , R ⁶² , R ⁷¹ and R ⁷² are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl;
q is an integer from 0 to 3,
However,
[1] When L is —NR ^1A CO—, —CONR ^1B —, —CO— or —NR ^1F —, R ^3b and R ^4b are not simultaneously hydrogen,
[2] When L is a single bond,
(I) m is 0,
(Ii) R ^10A is unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, or substituted or unsubstituted aromatic carbocyclic group And
(Iii) A is a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group or a substituted or unsubstituted aromatic heterocyclic group, and
(Iv) At least one of the following conditions (a) to (c) is satisfied.
(A) at least one of R ^3b and R ^4b is a substituted or unsubstituted alkyl, or R ^3b and R ^4b together with the carbon atom to which they are attached, a substituted or unsubstituted non-aromatic carbon Forming a ring or a substituted or unsubstituted non-aromatic heterocycle, or R ^3b and R ^4b together form ═NR ^1H ,
(B) Ring B is

The ring B ¹ is a 5-membered non-aromatic carbocyclic ring, a 5-membered non-aromatic heterocyclic ring or a 5-membered aromatic heterocyclic ring (provided that ring B is not an indole),
(C) Ring B is benzene, n is 1, and A is substituted or unsubstituted phenyl)
Or a pharmaceutically acceptable salt thereof.

(1 ′) In the above (1),
[1] When L is —NR ^1A CO—, —CONR ^1B —, —CO— or —NR ^1F —, R ^3b and R ^4b are not simultaneously hydrogen,
[2] When L is a single bond,
(I) m is 0,
(Ii) R ^10A is unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, or substituted or unsubstituted aromatic carbocyclic group And
(Iii) A is a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group or a substituted or unsubstituted aromatic heterocyclic group, and
(Iv) satisfy at least one of the following conditions (a) to (c):
(A) at least one of R ^3b and R ^4b is unsubstituted alkyl, or R ^3b and R ^4b together with the carbon atom to which they are attached, a substituted or unsubstituted non-aromatic carbocycle or Forming a substituted or unsubstituted non-aromatic heterocycle, or R ^3b and R ^4b together form ═NR ^1H ;
(B) Ring B is

The ring B ¹ is a 5-membered non-aromatic carbocycle, a 5-membered non-aromatic heterocycle or a 5-membered aromatic heterocycle,
(C) Ring B is benzene, n is 1, and A is substituted or unsubstituted phenyl.
And,
[3] Excluding the following compounds

)
Or a pharmaceutically acceptable salt thereof.

(2) The compound or a pharmaceutically acceptable salt thereof according to the above (1) or (1 ′), wherein L is —NR ^1A CO.
(3) m is 0, n is 0, and R ^3b and R ^4b are each independently hydrogen, halogen or substituted or unsubstituted alkyl, or R ^3b and R ^4b are bonded to each other Or a pharmaceutically acceptable salt thereof according to (1), (1 ′) or (2) above, which forms a substituted or unsubstituted cycloalkane together with a carbon atom.
(4) The compound or a pharmaceutically acceptable salt thereof according to any one of (1), (1 ′), (2) or (3) above, wherein R ^3b is substituted or unsubstituted alkyl.
(5) The compound according to any one of (1), (1 ′), (2) or (3) above, wherein R ^3b and R ^4b are each independently substituted or unsubstituted alkyl, or a pharmaceutical product thereof Top acceptable salt.
(6) The above (1), (1 ′), (2) or (3), wherein R ^3b and R ^4b together with the carbon atom to which they are attached form a substituted or unsubstituted cycloalkane Or a pharmaceutically acceptable salt thereof.
(7) Ring B is a 6-membered aromatic carbocyclic ring, a 6-membered aromatic heterocyclic ring, or

A ring represented by
B ¹ ring is a 5-membered non-aromatic carbocycle, 5-membered non-aromatic heterocycle or 5-membered aromatic heterocycle,
The B ² ring is a 6-membered aromatic carbocyclic ring or a 6-membered aromatic heterocyclic ring, or a pharmaceutically acceptable compound thereof according to any one of the above (1), (1 ′), (2) to (6) Salt.
(8) Ring B is benzene, indazole, benzimidazole, benzothiazole, benzoxazole, dihydrobenzimidazole, dihydrobenzothiazole or dihydrobenzoxazole, p is an integer of 0 to 2, and R ⁵ is independently Any of the above (1), (1 ′), (2) to (6), which is halogen, hydroxy, cyano, alkyl or haloalkyl, and two R ⁵ together may form oxo Or a pharmaceutically acceptable salt thereof.
(9) The above (1), (1 ′), wherein ring B is benzene, p is an integer of 0 to 2, and R ⁵ is each independently halogen, cyano, or substituted or unsubstituted alkyl. , (2) to (6) or a pharmaceutically acceptable salt thereof.
(10) In the above (1), (1 ′), (2) to (9), A is a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group The compound according to any one of the above or a pharmaceutically acceptable salt thereof.

(11) A is the formula:

Each of R ^A is independently halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted monoalkylamino, substituted or unsubstituted dialkylamino, Substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group , Substituted or unsubstituted non-aromatic carbocyclic oxy or substituted or unsubstituted aromatic carbocyclic oxy, wherein r is an integer of 0 to 3, (1), (1 ′), (2) to (9) The compound according to any one of the above or a pharmaceutically acceptable salt thereof.
(12) The compound according to (11) or a pharmaceutically acceptable salt thereof, wherein r is any one of 1 to 3, and R ^A is each independently halogen.
(12 ′) The compound according to the above (11) or a pharmaceutically acceptable salt thereof, wherein r is 1 or 2, and R ^A is each independently halogen.
(13) The compound or a pharmaceutically acceptable salt thereof according to any one of (1), (1 ′), (2) to (12) and (12 ′), wherein X is ═CR ⁹ —.
(14) The above (1), (1 ′), (2) to (12), wherein X is ═CH—, E is SO ₂ R ^10A , and R ^10A is substituted or unsubstituted alkyl. The compound according to any one of (12 ′) or a pharmaceutically acceptable salt thereof.
(15) The above (1), (1 ′), (2) to (12), wherein X is ═N—, E is SO ₂ R ^10A , and R ^10A is a substituted or unsubstituted alkyl. The compound according to any one of (12 ′) or a pharmaceutically acceptable salt thereof.
(16) The compound or a pharmaceutically acceptable salt thereof according to any one of (1), (1 ′), (2) to (15) and (12 ′), wherein q is 0.
(17) Any of (1), (1 ′), (2) to (16) and (12 ′) above, wherein R ⁶ and R ⁷ are each independently hydrogen or substituted or unsubstituted alkyl Or a pharmaceutically acceptable salt thereof.
(18) The compound according to any one of (1), (1 ′), (2) to (16) and (12 ′) above, wherein R ⁶ and R ⁷ are both hydrogen, or a pharmaceutically acceptable salt thereof Salt.

(19) L is —NR ^1A CO—, —CONR ^1B —, —NR ^1A CONR ^1B —, —OC (═O) NR ^1C —, —CO—, —S—, —SO ₂ —, —SO ₂ NR ^1D —, —NR ^1E SO ₂ — or —NR ^1F —,
A is a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group,
m is 0,
Ring B is benzene, 6-membered aromatic heterocycle, indazole, benzimidazole, benzothiazole, benzoxazole, dihydrobenzimidazole, dihydrobenzothiazole or dihydrobenzoxazole;
p is an integer of 0-2, each R ⁵ is independently halogen, hydroxy, cyano, alkyl or haloalkyl, and two R ⁵ together may form oxo,
R ^3b is halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbon A cyclic group, a substituted or unsubstituted non-aromatic heterocyclic group or a substituted or unsubstituted aromatic heterocyclic group,
R ^4b is hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic An aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group or a substituted or unsubstituted aromatic heterocyclic group,
R ^3a and R ^4a and R ^3b and R ^4b are each independently taken together with the carbon atom to which they are attached to form a substituted or unsubstituted non-aromatic carbocycle or substituted or unsubstituted non-aromatic heterocycle. The ring may be formed, and R ^3a and R ^4a and R ^3b and R ^4b may each independently form ═NR ^1H , described in (1) or (1 ′) above Or a pharmaceutically acceptable salt thereof.
(19-1) L is a single bond,
m is 0,
A is a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group or a substituted or unsubstituted aromatic heterocyclic group,
R ^3b is substituted or unsubstituted alkyl,
R ^3b and R ^4b together with the carbon atom to which they are attached form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring, or R ^3b and R ^4b ^4b together form ═NR ^1H ,
R ^10A is unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, or substituted or unsubstituted aromatic carbocyclic group The compound of the above (1) or (1 ′) or a pharmaceutically acceptable salt thereof.
(19-2) L is a single bond,
m is 0,
A is a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group or a substituted or unsubstituted aromatic heterocyclic group,
Ring B is

The ring B ¹ is a 5-membered non-aromatic carbocyclic ring, a 5-membered non-aromatic heterocyclic ring or a 5-membered aromatic heterocyclic ring,
R ^10A is unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, or substituted or unsubstituted aromatic carbocyclic group The compound of the above (1) or (1 ′) or a pharmaceutically acceptable salt thereof.
(19-3) L is a single bond,
m is 0,
A is substituted or unsubstituted phenyl,
Ring B is benzene, n is 1,
R ^10A is unsubstituted alkyl, a substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group or a substituted or unsubstituted aromatic carbocyclic group, The compound of the above (1) or (1 ′) or a pharmaceutically acceptable salt thereof.
(20) Formula (I ′):

(Where
R ^1A is hydrogen or substituted or unsubstituted alkyl;
A is a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group;
R ^3b and R ^4b are each independently hydrogen, halogen or substituted or unsubstituted alkyl, or R ^3b and R ^4b , together with the carbon atom to which they are attached, are substituted or unsubstituted Form a cycloalkane (where R ^3b and R ^4b are not simultaneously hydrogen);
Ring B is a benzene ring,
Each R ⁵ is independently halogen, cyano or substituted or unsubstituted alkyl;
p is an integer from 0 to 2,
R ^10A is substituted or unsubstituted alkyl;
R ⁶ and R ⁷ are each independently hydrogen or substituted or unsubstituted alkyl)
The compound of Claim 1 shown by these, or its pharmaceutically acceptable salt.
(21) (1), (1 ′), (2) to (12), (12 ′), (13) to (19), (19-1), (19-2), (19-3) ) And (20) or a pharmaceutical composition comprising the pharmaceutically acceptable salt thereof.
(22) The pharmaceutical composition according to the above (21), which has a RORγt inhibitory action.

(23) (1), (1 ′), (2) to (12), (12 ′), (13) to (19), (19-1), (19-2), (19-3) ) And a pharmaceutically acceptable salt thereof, or a method for treating or preventing a disease involving RORγt, comprising administering the compound according to any one of
(24) The above (1), (1 ′), (2) to (12), (12 ′), (13) to (19), for producing a therapeutic or prophylactic agent for a disease involving RORγt, Use of the compound according to any one of (19-1), (19-2), (19-3) and (20), or a pharmaceutically acceptable salt thereof.
(25) The above (1), (1 ′), (2) to (12), (12 ′), (13) to (19), (19-) for treating or preventing a disease involving RORγt 1) The compound according to any one of (19-2), (19-3) and (20), or a pharmaceutically acceptable salt thereof.
(26) The above (1), (1 ′), (2) to (12), (12 ′), (13) to (19), (19-1), (19-2) having RORγt inhibitory action ), (19-3) and a composition containing the compound or salt thereof according to any one of (20).
(101) (1), (1 ′), (2) to (12), (12 ′), (13) to (19), (19-1), (19-2), (19-3) ) And a pharmaceutical composition for oral administration comprising the compound according to any one of (20) and (20) or a pharmaceutically acceptable salt thereof.
(102) Tablets, powders, granules, capsules, pills, films, suspensions, emulsions, elixirs, syrups, limonades, spirits, fragrances, extracts, decoctions or tinctures (101) The pharmaceutical composition of description.
(103) Sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, troche tablets, sublingual tablets, buccal tablets, chewable tablets, orally disintegrating tablets, dry syrups, soft capsules, microcapsules or sustained-release capsules The pharmaceutical composition according to (102), wherein
(104) 1), (1 ′), (2) to (12), (12 ′), (13) to (19), (19-1), (19-2), (19-3) And a pharmaceutical composition for parenteral administration comprising the compound according to any one of (20) or a pharmaceutically acceptable salt thereof.
(105) The pharmaceutical composition according to (104), for transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, eye drop, ear drop or intravaginal administration.
(106) Injections, drops, eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, injections, coating agents, gargles, enemas, ointments, plasters, jelly agents, The pharmaceutical composition according to (104) or (105), which is a cream, a patch, a poultice, a powder for external use or a suppository.
(107) 1), (1 ′), (2) to (12), (12 ′), (13) to (19), (19-1), (19-2), (19-3) And a pharmaceutical composition for children or the elderly, comprising the compound according to any of (20) or a pharmaceutically acceptable salt thereof.
(108) (1), (1 ′), (2) to (12), (12 ′), (13) to (19), (19-1), (19-2), (19-3) ) And a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising a combination of an immunosuppressive agent, a steroid agent and / or a cytokine inhibitor.
(109) Above 1), (1 ′), (2) to (12), (12 ′), (13) to (19), (19-1), (19-2), (19-3) And a pharmaceutical composition for combination therapy with an immunosuppressive agent, a steroid agent and / or a cytokine inhibitor, comprising the compound according to any one of (20) and a pharmaceutically acceptable salt thereof.

The compound according to the present invention has RORγ inhibitory activity and is useful as a therapeutic and / or prophylactic agent for autoimmune diseases such as psoriasis.

The meaning of each term used in this specification will be described below. Unless otherwise specified, each term is used in the same meaning when used alone or in combination with other terms.
The term “consisting of” means having only the configuration requirements.
The term “comprising” is not limited to the constituent elements and means that elements not described are not excluded.

“Halogen” includes a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. In particular, a fluorine atom and a chlorine atom are preferable.
“Alkyl” includes straight-chain or branched hydrocarbon groups having 1 to 15 carbon atoms, such as 1 to 10 carbon atoms, such as 1 to 6 carbon atoms, such as 1 to 4 carbon atoms. Specifically, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, Examples include n-octyl, isooctyl, n-nonyl, n-decyl and the like. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or -pentyl, for example, methyl, ethyl, n-propyl, isopropyl or tert-butyl.

“Alkenyl” refers to a straight or branched chain having 2 to 15 carbon atoms, such as 2 to 10 carbon atoms, such as 2 to 6 carbon atoms, such as 2 to 4 carbon atoms, having one or more double bonds at any position. Includes branched hydrocarbon groups. Specifically, vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, tetradecenyl, decenyl, decenyl And pentadecenyl.
Examples of “alkenyl” include vinyl, allyl, propenyl, isopropenyl and butenyl.
“Alkynyl” is a straight or branched chain having 2 to 10 carbon atoms, such as 2 to 8 carbon atoms, such as 2 to 6 carbon atoms, such as 2 to 4 carbon atoms, having one or more triple bonds at any position. -Like hydrocarbon groups. Furthermore, you may have a double bond in arbitrary positions. Specifically, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like are included.
Examples of “alkynyl” include ethynyl, propynyl, butynyl and pentynyl.

“Aromatic carbocycle” means a monocyclic or two or more cyclic aromatic hydrocarbon rings. Examples thereof include benzene, naphthalene, anthracene, phenanthrene and the like. Examples of the “aromatic carbocycle” include benzene.
“6-membered aromatic carbocycle” means benzene.
The “aromatic carbocyclic group” means a cyclic aromatic hydrocarbon group having one or more rings. For example, phenyl, naphthyl, anthryl, phenanthryl and the like can be mentioned.
Examples of the “aromatic carbocyclic group” include phenyl.

“Non-aromatic carbocycle” means a cyclic saturated hydrocarbon or cyclic non-aromatic unsaturated hydrocarbon having one or more rings. The two or more non-aromatic carbocycles include those in which the ring in the above “aromatic carbocycle” is condensed with a single ring or two or more non-aromatic carbocycles.
Furthermore, the “non-aromatic carbocycle” includes a ring that forms a bridge or a spiro ring as described below.

The monocyclic non-aromatic carbocycle has, for example, 3 to 16 carbon atoms, such as 3 to 12 carbon atoms, for example 4 to 8 carbon atoms. Specific examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclohexadiene, and the like.
Examples of the two or more non-aromatic carbocyclic groups include indane, indene, acenaphthene, tetrahydronaphthalene, fluorene and the like.
Examples of the “5-membered or 6-membered non-aromatic carbocycle” include “5-membered non-aromatic carbocycle” such as cyclopentane, cyclopentene and cyclopentadiene, and “6-membered non-aromatic carbon such as cyclohexane, cyclohexene and cyclohexadiene”. Ring ".
In the non-aromatic carbocyclic group having two or more rings, the bond may be present in any ring.
Examples of “cycloalkane” include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane and the like.

The “non-aromatic carbocyclic group” means a cyclic saturated hydrocarbon group or a cyclic non-aromatic unsaturated hydrocarbon group having one or more rings. The non-aromatic carbocyclic group having 2 or more rings also includes those in which the ring in the above “aromatic carbocyclic group” is condensed with a monocyclic or 2 or more non-aromatic carbocyclic groups.
Furthermore, the “non-aromatic carbocyclic group” includes a group that forms a bridge or a spiro ring as described below.

The monocyclic non-aromatic carbocyclic group has, for example, 3 to 16 carbon atoms, for example, 3 to 12 carbon atoms, for example 4 to 8 carbon atoms. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl, and the like.
Examples of the two or more non-aromatic carbocyclic groups include indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, fluorenyl and the like.

“Aromatic heterocycle” means a single ring or two or more aromatic rings having one or more of the same or different heteroatoms arbitrarily selected from O, S and N in the ring.
Two or more aromatic heterocycles include those obtained by condensing the above “aromatic carbocycle” to a single ring or two or more aromatic heterocycles.
The monocyclic aromatic heterocycle is, for example, 5 to 8 members, for example, 5 or 6 members. Specifically, the heterocyclic ring illustrated by said "monocyclic aromatic heterocyclic group" is mentioned.
Specific examples of the bicyclic aromatic heterocycle and the tricyclic or higher aromatic heterocycle include the “bicyclic aromatic heterocyclic group” and “tricyclic aromatic heterocyclic group” described above. Heterocyclic rings.
The “5-membered or 6-membered aromatic heterocycle” means a 5-membered or 6-membered aromatic ring in the above “aromatic heterocycle”. For example, “5-membered aromatic heterocycle” such as pyrrole, imidazole, pyrazole, triazole, triazine, tetrazole, furan, thiophene, isoxazole, oxazole, oxadiazole, isothiazole, thiazole, thiadiazole, and pyridine, pyridazine, pyrimidine, “6-membered aromatic heterocycle” such as pyrazine.
“Aromatic heterocyclic group” means a monocyclic or bicyclic or more aromatic cyclic group having one or more heteroatoms arbitrarily selected from O, S and N in the ring To do.
The aromatic heterocyclic group having two or more rings includes those obtained by condensing a ring in the above “aromatic carbocyclic group” to a monocyclic or two or more aromatic heterocyclic group.
The monocyclic aromatic heterocyclic group is, for example, a 5- to 8-membered cyclic group, for example, 5-membered or 6-membered. Specific examples include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, and the like.
The bicyclic aromatic heterocyclic group is, for example, a cyclic group in which two 5- to 8-membered rings are condensed, for example, indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, Naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotria Examples include zolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridyl, thiazopyridyl and the like.
The aromatic heterocyclic group having three or more rings is, for example, a cyclic group in which three 5- to 8-membered rings are condensed, such as carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, And dibenzofuryl.
In the aromatic heterocyclic group having two or more rings, a bond may be present in any ring.

“Non-aromatic heterocycle” means a single or two or more non-aromatic rings having one or more of the same or different heteroatoms arbitrarily selected from O, S and N in the ring.
The non-aromatic heterocyclic ring having two or more rings is the above-mentioned “aromatic carbocycle”, “non-aromatic carbocycle”, and / or “aromatic heterocycle” in addition to a single ring or two or more non-aromatic heterocyclic rings. Also included are those in which each ring is condensed.
Furthermore, the “non-aromatic heterocycle” includes a ring that forms a bridge or a spiro ring as described below.

The monocyclic non-aromatic heterocyclic ring is, for example, 3 to 8 members, for example, 5 or 6 members. Specific examples include the heterocyclic rings exemplified above for the “monocyclic non-aromatic heterocyclic group”.
Examples of the non-aromatic heterocyclic group having two or more rings include the heterocyclic rings exemplified in the above “two or more non-aromatic heterocyclic groups”.
The “5-membered or 6-membered non-aromatic heterocycle” means a 5-membered or 6-membered non-aromatic ring in the above “non-aromatic heterocycle”. For example, “5-membered non-aromatic heterocycles” such as oxathiolane, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, tetrahydrofuran, dihydrothiazole, tetrahydrothiazole, tetrahydroisothiazole, dioxolane, dioxole and thiolane and dioxane, thiane, “6-membered non-aromatic heterocycles” such as piperidine, piperazine, morpholine, thiomorpholine, dihydropyridine, tetrahydropyridine, tetrahydropyran, dihydrooxazine, tetrahydropyridazine, hexahydropyrimidine, dioxazine, thiazine and thiopyran.
"Non-aromatic heterocyclic group" means a monocyclic or bicyclic or more non-aromatic cyclic group having one or more of the same or different heteroatoms arbitrarily selected from O, S and N in the ring Means.
Two or more non-aromatic heterocyclic groups are
(i) a ring in which the above “aromatic carbocycle”, “non-aromatic carbocycle”, and / or “aromatic heterocycle” are condensed to the above-mentioned “non-aromatic heterocycle” of one or more rings Group, and
(ii) includes a cyclic group in which a “non-aromatic carbocycle” is fused to the above “aromatic heterocycle”.
Furthermore, the “non-aromatic heterocyclic group” includes a group that forms a bridge or a spiro ring as described below.

The monocyclic non-aromatic heterocyclic group is, for example, 3 to 8 members, for example, 5 or 6 members. Specifically, dioxanyl, thiranyl, oxiranyl, oxetanyl, oxathiolanyl, azetidinyl, thianyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholinyl, Tetrahydrofuryl, tetrahydropyranyl, dihydrothiazolyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, dihydrooxazinyl, hexahydroazepinyl, tetrahydrodiazepinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, dioxolanyl, Dioxazinyl, aziridinyl, dioxolyl, oxepanyl, thiolanyl, thiopyranyl, thia Alkylsulfonyl and the like.
Examples of the non-aromatic heterocyclic group having two or more rings include indolinyl, isoindolinyl, chromanyl, isochromanyl, dihydrobenzodioxinyl, dihydrobenzoxazinyl, dihydrobenzoxazolyl, dihydrobenzofuryl, dihydrobenzothiazolyl. , Dihydrobenzimidazolyl, tetrahydroquinolyl, dihydropyrrolopyridyl and the like.
In the non-aromatic heterocyclic group having two or more rings, the bond may be present in any ring.

“Hydroxyalkyl” means a group in which one or more hydroxy groups are replaced with a hydrogen atom bonded to a carbon atom of the above “alkyl”. Examples thereof include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 1,2-hydroxyethyl and the like. Examples thereof include hydroxymethyl and hydroxyethyl.
“Alkyloxy” means a group in which the above “alkyl” is bonded to an oxygen atom. Examples thereof include methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, tert-butyloxy, isobutyloxy, sec-butyloxy, pentyloxy, isopentyloxy, hexyloxy and the like. Examples include methoxy, ethoxy, n-propyloxy, isopropyloxy or tert-butyloxy.
“Alkenyloxy” means a group in which the above “alkenyl” is bonded to an oxygen atom.
Examples thereof include vinyloxy, allyloxy, 1-propenyloxy, 2-butenyloxy, 2-pentenyloxy, 2-hexenyloxy, 2-heptenyloxy, 2-octenyloxy and the like.
“Alkynyloxy” means a group in which the above “alkynyl” is bonded to an oxygen atom.
Examples include ethynyloxy, 1-propynyloxy, 2-propynyloxy, 2-butynyloxy, 2-pentynyloxy, 2-hexynyloxy, 2-heptynyloxy, 2-octynyloxy and the like.

“Haloalkyl” means a group in which one or more of the “halogen” is bonded to the “alkyl”. For example, monofluoromethyl, monofluoroethyl, monofluoropropyl, 2,2,3,3,3-pentafluoropropyl, monochloromethyl, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2, Examples include 2,2-trichloroethyl, 1,2-dibromoethyl, 1,1,1-trifluoropropan-2-yl and the like. Examples thereof include trifluoromethyl and trichloromethyl.
“Haloalkyloxy” means a group in which the above “haloalkyl” is bonded to an oxygen atom. Examples thereof include monofluoromethoxy, monofluoroethoxy, trifluoromethoxy, trichloromethoxy, trifluoroethoxy, trichloroethoxy and the like. Examples include trifluoromethoxy and trichloromethoxy.

“Alkyloxyalkyl” means a group in which the “alkyloxy” is bonded to the “alkyl”. For example, methoxymethyl, methoxyethyl, ethoxymethyl and the like can be mentioned.
“Alkyloxyalkyloxy” means a group in which the “alkyloxy” is bonded to the “alkyloxy”. Examples thereof include methoxymethoxy, methoxyethoxy, ethoxymethoxy, ethoxyethoxy and the like.

“Alkylcarbonyl” means a group in which the above “alkyl” is bonded to a carbonyl group. Examples thereof include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, tert-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, pentylcarbonyl, isopentylcarbonyl, hexylcarbonyl and the like.
“Alkylcarbonyl” includes, for example, methylcarbonyl, ethylcarbonyl, n-propylcarbonyl.
“Alkenylcarbonyl” means a group in which the above “alkenyl” is bonded to a carbonyl group. For example, ethylenylcarbonyl, propenylcarbonyl and the like can be mentioned.
“Alkynylcarbonyl” means a group in which the above “alkynyl” is bonded to a carbonyl group. For example, ethynylcarbonyl, propynylcarbonyl and the like can be mentioned.
“Haloalkylcarbonyl” means a group in which the above “haloalkyl” is bonded to a carbonyl group. For example, monofluoromethylcarbonyl, monofluoroethylcarbonyl, trifluoromethylcarbonyl, trichloromethylcarbonyl, trifluoroethylcarbonyl, trichloroethylcarbonyl and the like can be mentioned. Examples thereof include trifluoromethylcarbonyl and trichloromethylcarbonyl.

“Monoalkylamino” means a group in which the above “alkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group. For example, methylamino, ethylamino, isopropylamino and the like can be mentioned.
Examples of “monoalkylamino” include methylamino and ethylamino.
“Dialkylamino” means a group in which the above “alkyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the amino group. Two alkyl groups may be the same or different. Examples include dimethylamino, diethylamino, N, N-diisopropylamino, N-methyl-N-ethylamino, N-isopropyl-N-ethylamino and the like. For example, dimethylamino and diethylamino are mentioned.

“Alkylsulfonyl” means a group in which the above “alkyl” is bonded to a sulfonyl group. For example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl and the like can be mentioned. For example, methylsulfonyl and ethylsulfonyl are mentioned.
“Alkenylsulfonyl” means a group in which the above “alkenyl” is bonded to a sulfonyl group. For example, ethylenylsulfonyl, propenylsulfonyl and the like can be mentioned.
“Alkynylsulfonyl” means a group in which the above “alkynyl” is bonded to a sulfonyl group. For example, ethynylsulfonyl, propynylsulfonyl and the like can be mentioned.
“Haloalkylsulfonyl” means a group in which the “haloalkyl” is bonded to a sulfonyl group. For example, monofluoromethylsulfonyl, monofluoroethylsulfonyl, trifluoromethylsulfonyl, trichloromethylsulfonyl, trifluoroethylsulfonyl, trichloroethylsulfonyl and the like can be mentioned. Examples thereof include trifluoromethylsulfonyl and trichloromethylsulfonyl.

“Monoalkylcarbonylamino” means a group in which the above “alkylcarbonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group. For example, methylcarbonylamino, ethylcarbonylamino, propylcarbonylamino, isopropylcarbonylamino, tert-butylcarbonylamino, isobutylcarbonylamino, sec-butylcarbonylamino and the like can be mentioned. Examples thereof include methylcarbonylamino and ethylcarbonylamino.
“Dialkylcarbonylamino” means a group in which the above “alkylcarbonyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the amino group. Two alkylcarbonyl groups may be the same or different. For example, dimethylcarbonylamino, diethylcarbonylamino, N, N-diisopropylcarbonylamino and the like can be mentioned. Examples thereof include dimethylcarbonylamino and diethylcarbonylamino.

“Monoalkylsulfonylamino” means a group in which the above “alkylsulfonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group. Examples include methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, tert-butylsulfonylamino, isobutylsulfonylamino, sec-butylsulfonylamino, and the like. Examples include methylsulfonylamino and ethylsulfonylamino. It is done.
“Dialkylsulfonylamino” means a group in which the above “alkylsulfonyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the amino group. Two alkylsulfonyl groups may be the same or different. For example, dimethylsulfonylamino, diethylsulfonylamino, N, N-diisopropylsulfonylamino and the like can be mentioned. Examples thereof include dimethylsulfonylamino and diethylsulfonylamino.

The “alkylimino” means a group in which the “alkyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, methylimino, ethylimino, n-propylimino, isopropylimino and the like can be mentioned.
“Alkenylimino” means a group in which the above “alkenyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. Examples thereof include ethylenylimino and propenylimino.
The “alkynylimino” means a group in which the “alkynyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, ethynylimino, propynylimino and the like can be mentioned.

“Alkylcarbonylimino” means a group in which the above “alkylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, methylcarbonylimino, ethylcarbonylimino, n-propylcarbonylimino, isopropylcarbonylimino and the like can be mentioned.
“Alkenylcarbonylimino” means a group in which the above “alkenylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, ethylenylcarbonylimino, propenylcarbonylimino and the like can be mentioned.
“Alkynylcarbonylimino” means a group in which the above “alkynylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, ethynylcarbonylimino, propynylcarbonylimino and the like can be mentioned.

“Alkyloxyimino” means a group in which the above “alkyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. Examples thereof include methyloxyimino, ethyloxyimino, n-propyloxyimino, isopropyloxyimino and the like.
“Alkenyloxyimino” means a group in which the above “alkenyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, ethylenyloxyimino, propenyloxyimino and the like can be mentioned.
“Alkynyloxyimino” means a group in which the above “alkynyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, ethynyloxyimino, propynyloxyimino and the like can be mentioned.

“Alkylcarbonyloxy” means a group in which the above “alkylcarbonyl” is bonded to an oxygen atom. Examples thereof include methylcarbonyloxy, ethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, tert-butylcarbonyloxy, isobutylcarbonyloxy, sec-butylcarbonyloxy and the like.
Examples of “alkylcarbonyloxy” include methylcarbonyloxy and ethylcarbonyloxy.
“Alkenylcarbonyloxy” means a group in which the above “alkenylcarbonyl” is bonded to an oxygen atom. For example, ethylenylcarbonyloxy, propenylcarbonyloxy and the like can be mentioned.
“Alkynylcarbonyloxy” means a group in which the above “alkynylcarbonyl” is bonded to an oxygen atom. For example, ethynylcarbonyloxy, propynylcarbonyloxy and the like can be mentioned.

“Alkyloxycarbonyl” means a group in which the above “alkyloxy” is bonded to a carbonyl group. For example, methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, tert-butyloxycarbonyl, isobutyloxycarbonyl, sec-butyloxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, hexyloxycarbonyl, etc. It is done. For example, methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl may be mentioned.
“Alkenyloxycarbonyl” means a group in which the above “alkenyloxy” is bonded to a carbonyl group. For example, ethylenyloxycarbonyl, propenyloxycarbonyl and the like can be mentioned.
“Alkynyloxycarbonyl” means a group in which the above “alkynyloxy” is bonded to a carbonyl group. For example, ethynyloxycarbonyl, propynyloxycarbonyl and the like can be mentioned.

“Alkylsulfanyl” means a group in which the above “alkyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. For example, methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl and the like can be mentioned.
“Alkenylsulfanyl” means a group in which the above “alkenyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. For example, ethylenylsulfanyl, propenylsulfanyl and the like can be mentioned.
“Alkynylsulfanyl” means a group in which the above “alkynyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. For example, ethynylsulfanyl, propynylsulfanyl and the like can be mentioned.
The “haloalkylsulfanyl” means a group in which the “haloalkyl” is bonded to a sulfanyl group. Examples thereof include monofluoromethylsulfanyl, monofluoroethylsulfanyl, trifluoromethylsulfanyl, trichloromethylsulfanyl, trifluoroethylsulfanyl, trichloroethylsulfanyl and the like. Examples thereof include trifluoromethylsulfanyl and trichloromethylsulfanyl.

“Alkylsulfinyl” means a group in which the above “alkyl” is bonded to a sulfinyl group. Examples thereof include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl and the like.
“Alkenylsulfinyl” means a group in which the above “alkenyl” is bonded to a sulfinyl group. For example, ethylenylsulfinyl, propenylsulfinyl and the like can be mentioned.
“Alkynylsulfinyl” means a group in which the above “alkynyl” is bonded to a sulfinyl group. For example, ethynylsulfinyl, propynylsulfinyl and the like can be mentioned.

“Monoalkylcarbamoyl” means a group in which the above “alkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the carbamoyl group. Examples thereof include methylcarbamoyl and ethylcarbamoyl.
“Dialkylcarbamoyl” means a group in which the above “alkyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the carbamoyl group. Two alkyl groups may be the same or different. Examples thereof include dimethylcarbamoyl, diethylcarbamoyl and the like.

“Monoalkylsulfamoyl” means a group in which the above “alkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the sulfamoyl group. For example, methylsulfamoyl, dimethylsulfamoyl, etc. are mentioned.
“Dialkylsulfamoyl” means a group in which the above “alkyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the sulfamoyl group. Two alkyl groups may be the same or different. Examples thereof include dimethylsulfamoyl and diethylsulfamoyl.
“Trialkylsilyl” means a group in which three of the above “alkyl” are bonded to a silicon atom. The three alkyls may be the same or different. For example, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl and the like can be mentioned.

“Aromatic carbocyclic alkyl”, “non-aromatic carbocyclic alkyl”, “aromatic heterocyclic alkyl”, and “non-aromatic heterocyclic alkyl”,
“Aromatic carbocyclic alkyloxy”, “non-aromatic carbocyclic alkyloxy”, “aromatic heterocyclic alkyloxy”, and “non-aromatic heterocyclic alkyloxy”,
“Aromatic carbocyclic alkyloxycarbonyl”, “non-aromatic carbocyclic alkyloxycarbonyl”, “aromatic heterocyclic alkyloxycarbonyl”, and “non-aromatic heterocyclic alkyloxycarbonyl”,
“Aromatic carbocyclic alkyloxyalkyl”, “non-aromatic carbocyclic alkyloxyalkyl”, “aromatic heterocyclic alkyloxyalkyl”, and “non-aromatic heterocyclic alkyloxyalkyl”,
“Aromatic carbocyclic alkylcarbamoyl”, “nonaromatic carbocyclic alkylcarbamoyl”, “aromatic heterocyclic alkylcarbamoyl”, and “nonaromatic heterocyclic alkylcarbamoyl”,
“Aromatic carbocyclic alkylamino”, “non-aromatic carbocyclic alkylamino”, “aromatic heterocyclic alkylamino”, and “non-aromatic heterocyclic alkylamino”,
The alkyl moiety of is the same as the above “alkyl”.

“Aromatic carbocyclic alkyl” means an alkyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyl, phenethyl, phenylpropyl, benzhydryl, trityl, naphthylmethyl, groups shown below

Etc. Examples include benzyl, phenethyl, and benzhydryl.

“Non-aromatic carbocyclic alkyl” means alkyl substituted with one or more of the above “non-aromatic carbocyclic groups”. The “non-aromatic carbocyclic alkyl” also includes “non-aromatic carbocyclic alkyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, groups shown below

Etc.

“Aromatic heterocyclic alkyl” means alkyl substituted with one or more of the above “aromatic heterocyclic groups”. “Aromatic heterocyclic alkyl” also includes “aromatic heterocyclic alkyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. . For example, pyridylmethyl, furanylmethyl, imidazolylmethyl, indolylmethyl, benzothiophenylmethyl, oxazolylmethyl, isoxazolylmethyl, thiazolylmethyl, isothiazolylmethyl, pyrazolylmethyl, isopyrazolylmethyl, pyrrolidinylmethyl, benz Oxazolylmethyl, group shown below

Etc.

“Non-aromatic heterocyclic alkyl” means an alkyl substituted with one or more of the above “non-aromatic heterocyclic groups”. In the “non-aromatic heterocyclic alkyl”, the alkyl portion is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”. Also included are “non-aromatic heterocyclic alkyl”. For example, tetrahydropyranylmethyl, morpholinylethyl, piperidinylmethyl, piperazinylmethyl, groups shown below

Etc.

“Aromatic carbocyclic alkyloxy” means alkyloxy substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxy, phenethyloxy, phenylpropyloxy, benzhydryloxy, trityloxy, naphthylmethyloxy, groups shown below

Etc.

“Non-aromatic carbocyclic alkyloxy” means alkyloxy substituted with one or more of the above “non-aromatic carbocyclic groups”. The “non-aromatic carbocyclic alkyloxy” also includes “non-aromatic carbocyclic alkyloxy” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyloxy, cyclobutylmethyloxy, cyclopentylmethyloxy, cyclohexylmethyloxy, groups shown below

Etc.

“Aromatic heterocyclic alkyloxy” means alkyloxy substituted with one or more of the above “aromatic heterocyclic groups”. “Aromatic heterocyclic alkyloxy” also includes “aromatic heterocyclic alkyloxy” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Include. For example, pyridylmethyloxy, furanylmethyloxy, imidazolylmethyloxy, indolylmethyloxy, benzothiophenylmethyloxy, oxazolylmethyloxy, isoxazolylmethyloxy, thiazolylmethyloxy, isothiazolylmethyloxy , Pyrazolylmethyloxy, isopyrazolylmethyloxy, pyrrolidinylmethyloxy, benzoxazolylmethyloxy, groups shown below

Etc.

“Non-aromatic heterocyclic alkyloxy” means alkyloxy substituted with one or more of the above “non-aromatic heterocyclic groups”. In the “non-aromatic heterocyclic alkyloxy”, the alkyl moiety is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”. It also includes “non-aromatic heterocyclic alkyloxy”. For example, tetrahydropyranylmethyloxy, morpholinylethyloxy, piperidinylmethyloxy, piperazinylmethyloxy, groups shown below

Etc.

“Aromatic carbocyclic alkyloxycarbonyl” means alkyloxycarbonyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxycarbonyl, phenethyloxycarbonyl, phenylpropyloxycarbonyl, benzhydryloxycarbonyl, trityloxycarbonyl, naphthylmethyloxycarbonyl, groups shown below

Etc.

“Non-aromatic carbocyclic alkyloxycarbonyl” means alkyloxycarbonyl substituted with one or more of the above “non-aromatic carbocyclic groups”. The “non-aromatic carbocyclic alkyloxycarbonyl” also includes “non-aromatic carbocyclic alkyloxycarbonyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyloxycarbonyl, cyclobutylmethyloxycarbonyl, cyclopentylmethyloxycarbonyl, cyclohexylmethyloxycarbonyl, groups shown below

Etc.

“Aromatic heterocyclic alkyloxycarbonyl” means alkyloxycarbonyl substituted with one or more of the above “aromatic heterocyclic groups”. The “aromatic heterocyclic alkyloxycarbonyl” is an “aromatic heterocyclic alkyloxycarbonyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Is also included. For example, pyridylmethyloxycarbonyl, furanylmethyloxycarbonyl, imidazolylmethyloxycarbonyl, indolylmethyloxycarbonyl, benzothiophenylmethyloxycarbonyl, oxazolylmethyloxycarbonyl, isoxazolylmethyloxycarbonyl, thiazolylmethyl Oxycarbonyl, isothiazolylmethyloxycarbonyl, pyrazolylmethyloxycarbonyl, isopyrazolylmethyloxycarbonyl, pyrrolidinylmethyloxycarbonyl, benzoxazolylmethyloxycarbonyl, groups shown below

Etc.

“Non-aromatic heterocyclic alkyloxycarbonyl” means alkyloxycarbonyl substituted with one or more of the above “non-aromatic heterocyclic groups”. In the “non-aromatic heterocyclic alkyloxycarbonyl”, the alkyl moiety is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”. And “non-aromatic heterocyclic alkyloxycarbonyl”. For example, tetrahydropyranylmethyloxy, morpholinylethyloxy, piperidinylmethyloxy, piperazinylmethyloxy, groups shown below

Etc.

“Aromatic carbocyclic alkyloxyalkyl” means alkyloxyalkyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxymethyl, phenethyloxymethyl, phenylpropyloxymethyl, benzhydryloxymethyl, trityloxymethyl, naphthylmethyloxymethyl, groups shown below

Etc.

“Non-aromatic carbocyclic alkyloxyalkyl” means alkyloxyalkyl substituted with one or more of the above “non-aromatic carbocyclic groups”. In addition, “non-aromatic carbocyclic alkyloxyalkyl” means “non-aromatic carbocyclic alkyloxyalkyl” in which the alkyl moiety to which the non-aromatic carbocycle is bonded is substituted with the above “aromatic carbocyclic group”. Is also included. For example, cyclopropylmethyloxymethyl, cyclobutylmethyloxymethyl, cyclopentylmethyloxymethyl, cyclohexylmethyloxymethyl, groups shown below

Etc.

“Aromatic heterocyclic alkyloxyalkyl” means alkyloxyalkyl substituted with one or more of the above “aromatic heterocyclic groups”. In addition, the “aromatic heterocyclic alkyloxyalkyl” is obtained by replacing the alkyl moiety to which the aromatic heterocyclic ring is bonded with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Also included are “aromatic heterocyclic alkyloxyalkyl”. For example, pyridylmethyloxymethyl, furanylmethyloxymethyl, imidazolylmethyloxymethyl, indolylmethyloxymethyl, benzothiophenylmethyloxymethyl, oxazolylmethyloxymethyl, isoxazolylmethyloxymethyl, thiazolylmethyl Oxymethyl, isothiazolylmethyloxymethyl, pyrazolylmethyloxymethyl, isopyrazolylmethyloxymethyl, pyrrolidinylmethyloxymethyl, benzoxazolylmethyloxymethyl, groups shown below

Etc.

“Non-aromatic heterocyclic alkyloxyalkyl” means alkyloxyalkyl substituted with one or more of the above “non-aromatic heterocyclic groups”. In addition, “non-aromatic heterocyclic alkyloxy” means that the alkyl moiety to which the non-aromatic heterocyclic ring is bonded is the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic”. Also included are “non-aromatic heterocyclic alkyloxyalkyl” substituted with “aromatic heterocyclic group”. For example, tetrahydropyranylmethyloxymethyl, morpholinylethyloxymethyl, piperidinylmethyloxymethyl, piperazinylmethyloxymethyl, groups shown below

Etc.

“Aromatic carbocyclic alkylcarbamoyl” means a group in which the above “aromatic carbocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group of carbamoyl. Examples include benzylcarbamoyl, phenethylcarbamoyl, phenylpropylcarbamoyl, benzhydrylcarbamoyl, tritylcarbamoyl, naphthylmethylcarbamoyl, dibenzylcarbamoyl and the like.
The “non-aromatic carbocyclic alkylcarbamoyl” means a group in which the “non-aromatic carbocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group of carbamoyl. Examples thereof include cyclopropylmethylcarbamoyl, cyclobutylmethylcarbamoyl, cyclopentylmethylcarbamoyl, cyclohexylmethylcarbamoyl and the like.
The “aromatic heterocyclic alkylcarbamoyl” means a group in which the above “aromatic heterocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group of carbamoyl. For example, pyridylmethylcarbamoyl, furanylmethylcarbamoyl, imidazolylmethylcarbamoyl, indolylmethylcarbamoyl, benzothiophenylmethylcarbamoyl, oxazolylmethylcarbamoyl, isoxazolylmethylcarbamoyl, thiazolylmethylcarbamoyl, isothiazolylmethylcarbamoyl , Pyrazolylmethylcarbamoyl, isopyrazolylmethylcarbamoyl, pyrrolidinylmethylcarbamoyl, benzoxazolylmethylcarbamoyl and the like.
“Non-aromatic heterocyclic alkylcarbamoyl” means a group in which the above “non-aromatic heterocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group of carbamoyl. Examples thereof include tetrahydropyranylmethylcarbamoyl, morpholinylethylcarbamoyl, piperidinylmethylcarbamoyl, piperazinylmethylcarbamoyl and the like.

“Aromatic carbocyclic alkylamino” means a group in which the above “aromatic carbocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. Examples include benzylamino, phenethylamino, phenylpropylamino, benzhydrylamino, tritylamino, naphthylmethylamino, dibenzylamino and the like.
“Non-aromatic carbocyclic alkylamino” means a group in which the above “non-aromatic carbocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. For example, cyclopropylmethylamino, cyclobutylmethylamino, cyclopentylmethylamino, cyclohexylmethylamino and the like can be mentioned.
The “aromatic heterocyclic alkylamino” means a group in which the above “aromatic heterocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. For example, pyridylmethylamino, furanylmethylamino, imidazolylmethylamino, indolylmethylamino, benzothiophenylmethylamino, oxazolylmethylamino, isoxazolylmethylamino, thiazolylmethylamino, isothiazolylmethylamino , Pyrazolylmethylamino, isopyrazolylmethylamino, pyrrolidinylmethylamino, benzoxazolylmethylamino and the like.
The “non-aromatic heterocyclic alkylamino” means a group in which the above “non-aromatic heterocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. For example, tetrahydropyranylmethylamino, morpholinylethylamino, piperidinylmethylamino, piperazinylmethylamino and the like can be mentioned.

“Aromatic carbocyclic oxy”, “aromatic carbocyclic carbonyl”, “aromatic carbocyclic oxycarbonyl”, “aromatic carbocyclic carbamoyl”, “aromatic carbocyclic sulfanyl”, and “aromatic carbocyclic sulfonyl” The “aromatic carbocyclic” moiety is the same as the above “aromatic carbocyclic group”.
“Aromatic carbocyclic oxy” means a group in which an “aromatic carbocycle” is bonded to an oxygen atom. For example, phenyloxy, naphthyloxy and the like can be mentioned.
“Aromatic carbocyclic carbonyl” means a group in which an “aromatic carbocycle” is bonded to a carbonyl group. For example, phenylcarbonyl, naphthylcarbonyl and the like can be mentioned.
“Aromatic carbocyclic oxycarbonyl” means a group in which the above “aromatic carbocyclic oxy” is bonded to a carbonyl group. For example, phenyloxycarbonyl, naphthyloxycarbonyl and the like can be mentioned.
“Aromatic carbocyclic carbamoyl” means a group in which the above “aromatic carbocyclic” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group of carbamoyl. For example, phenylcarbamoyl, naphthylcarbamoyl and the like can be mentioned.
“Aromatic carbocyclic sulfanyl” means a group in which an “aromatic carbocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. Examples thereof include phenylsulfanyl and naphthylsulfanyl.
“Aromatic carbocyclic sulfonyl” means a group in which “aromatic carbocycle” is bonded to a sulfonyl group. For example, phenylsulfonyl, naphthylsulfonyl and the like can be mentioned.

“Non-aromatic carbocyclic oxy”, “non-aromatic carbocyclic carbonyl”, “non-aromatic carbocyclic oxycarbonyl”, “non-aromatic carbocyclic carbamoyl”, “non-aromatic carbocyclic sulfanyl”, and “non-aromatic The “non-aromatic carbocyclic” portion of the “aromatic carbocyclic sulfonyl” is the same as the “non-aromatic carbocyclic group”.
“Non-aromatic carbocyclic oxy” means a group in which “non-aromatic carbocycle” is bonded to an oxygen atom. For example, cyclopropyloxy, cyclohexyloxy, cyclohexenyloxy and the like can be mentioned.
“Non-aromatic carbocycle carbonyl” means a group in which “non-aromatic carbocycle” is bonded to a carbonyl group. For example, cyclopropylcarbonyl, cyclohexylcarbonyl, cyclohexenylcarbonyl and the like can be mentioned.
The “non-aromatic carbocyclic oxycarbonyl” means a group in which the above “non-aromatic carbocyclic oxy” is bonded to a carbonyl group. For example, cyclopropyloxycarbonyl, cyclohexyloxycarbonyl, cyclohexenyloxycarbonyl and the like can be mentioned.
The “non-aromatic carbocyclic carbamoyl” means a group in which the above “non-aromatic carbocyclic” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group of carbamoyl. Examples include cyclopropylcarbamoyl, cyclohexylcarbamoyl, cyclohexenylcarbamoyl and the like.
“Non-aromatic carbocyclic sulfanyl” means a group in which a “non-aromatic carbocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. Examples include cyclopropylsulfanyl, cyclohexylsulfanyl, cyclohexenylsulfanyl and the like.
“Non-aromatic carbocycle sulfonyl” means a group in which “non-aromatic carbocycle” is bonded to a sulfonyl group. For example, cyclopropylsulfonyl, cyclohexylsulfonyl, cyclohexenylsulfonyl and the like can be mentioned.

"Aromatic heterocyclic oxy", "aromatic heterocyclic carbonyl", "aromatic heterocyclic oxycarbonyl", "aromatic heterocyclic carbamoyl", "aromatic heterocyclic sulfanyl", and "aromatic heterocyclic sulfonyl" The “aromatic heterocyclic ring” moiety is the same as the above “aromatic heterocyclic group”.
“Aromatic heterocycle oxy” means a group in which “aromatic heterocycle” is bonded to an oxygen atom. For example, pyridyloxy, oxazolyloxy and the like can be mentioned.
“Aromatic heterocycle carbonyl” means a group in which “aromatic heterocycle” is bonded to a carbonyl group. For example, pyridylcarbonyl, oxazolylcarbonyl, etc. are mentioned.
“Aromatic heterocyclic oxycarbonyl” means a group in which the above “aromatic heterocyclic oxy” is bonded to a carbonyl group. For example, pyridyloxycarbonyl, oxazolyloxycarbonyl and the like can be mentioned.
“Aromatic heterocycle carbamoyl” means a group in which the above “aromatic heterocycle” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group of carbamoyl. For example, pyridylcarbamoyl, oxazolylcarbamoyl and the like can be mentioned.
“Aromatic heterocycle sulfanyl” means a group in which an “aromatic heterocycle” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. For example, pyridylsulfanyl, oxazolylsulfanyl and the like can be mentioned.
“Aromatic heterocycle sulfonyl” means a group in which “aromatic heterocycle” is bonded to a sulfonyl group. For example, pyridylsulfonyl, oxazolylsulfonyl and the like can be mentioned.

“Non-aromatic heterocyclic oxy”, “Non-aromatic heterocyclic carbonyl”, “Non-aromatic heterocyclic oxycarbonyl”, “Non-aromatic heterocyclic carbamoyl”, “Non-aromatic heterocyclic sulfanyl”, and “Non-aromatic” The “non-aromatic heterocyclic” part of the “aromatic heterocyclic sulfonyl” is the same as the above “non-aromatic heterocyclic group”.
“Non-aromatic heterocyclic oxy” means a group in which “non-aromatic heterocyclic” is bonded to an oxygen atom. For example, piperidinyloxy, tetrahydrofuryloxy and the like can be mentioned.
“Non-aromatic heterocyclic carbonyl” means a group in which “non-aromatic heterocyclic” is bonded to a carbonyl group. For example, piperidinylcarbonyl, tetrahydrofurylcarbonyl and the like can be mentioned.
The “non-aromatic heterocyclic oxycarbonyl” means a group in which the “non-aromatic heterocyclic oxy” is bonded to a carbonyl group. For example, piperidinyloxycarbonyl, tetrahydrofuryloxycarbonyl and the like can be mentioned.
The “non-aromatic heterocyclic carbamoyl” means a group in which the above “non-aromatic heterocyclic” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group of carbamoyl. For example, piperidinylcarbamoyl, tetrahydrofurylcarbamoyl and the like can be mentioned.
“Non-aromatic heterocyclic sulfanyl” means a group in which a “non-aromatic heterocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. For example, piperidinylsulfanyl, tetrahydrofurylsulfanyl and the like can be mentioned.
“Non-aromatic heterocyclic sulfonyl” means a group in which “non-aromatic heterocyclic” is bonded to a sulfonyl group. For example, piperidinylsulfonyl, tetrahydrofurylsulfonyl and the like can be mentioned.

“Substituted or unsubstituted alkyl”, “substituted or unsubstituted alkenyl”, “substituted or unsubstituted alkynyl”, “substituted or unsubstituted alkyloxy”, “substituted or unsubstituted alkenyloxy”, “substituted or "Unsubstituted alkynyloxy", "substituted or unsubstituted alkylcarbonyl", "substituted or unsubstituted alkenylcarbonyl", "substituted or unsubstituted alkynylcarbonyl", "substituted or unsubstituted monoalkylamino", "substituted Or “unsubstituted dialkylamino”, “substituted or unsubstituted alkylsulfonyl”, “substituted or unsubstituted alkenylsulfonyl”, “substituted or unsubstituted alkynylsulfonyl”, “substituted or unsubstituted alkylsulfanyl”, “substituted” Or unsubstituted alkenyl Rufaniru ", and as the substituent of" substituted or unsubstituted alkylene Nils Alpha alkenyl "include the following substituents. The carbon atom at any position may be bonded to one or more groups selected from the following substituents (a) and (b).
Substituent (a): halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, Nitro, nitroso, azide, hydrazino, ureido, amidino, guanidino, halosulfanyl, trialkylsilyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, monoalkylamino, dialkylamino, alkyl Sulfonyl, alkenylsulfonyl, alkynylsulfonyl, monoalkylcarbonylamino, dialkylcarbonylamino Monoalkylsulfonylamino, dialkylsulfonylamino, alkylimino, alkenylimino, alkynylimino, alkylcarbonylimino, alkenylcarbonylimino, alkynylcarbonylimino, alkyloxyimino, alkenyloxyimino, alkynyloxyimino, alkylcarbonyloxy, alkenylcarbonyloxy, Alkynylcarbonyloxy, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylsulfanyl, alkenylsulfanyl, alkynylsulfanyl, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, monoalkylcarbamoyl, dialkylcarbamoyl, monoalkylsulfamoyl, dialkylsulfamomo Le.
Specifically, as the substituent (a),
Halogen, hydroxy, carboxy, amino, carbamoyl, sulfamoyl, cyano, nitro, trialkylsilyl,
Alkyloxy, haloalkyloxy, alkenyloxy, alkynyloxy, alkyloxyalkyloxy, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, monoalkylamino, dialkylamino, alkylsulfonyl, haloalkylsulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, Alkynyloxycarbonyl, alkylsulfanyl, haloalkylsulfanyl, monoalkylcarbamoyl and dialkylcarbamoyl.

Substituent (b): aromatic carbocyclic group, non-aromatic carbocyclic group, aromatic heterocyclic group, non-aromatic heterocyclic group,
Aromatic carbocyclic oxy, non-aromatic carbocyclic oxy, aromatic heterocyclic oxy, non-aromatic heterocyclic oxy,
Aromatic carbocyclic carbonyl, non-aromatic carbocyclic carbonyl, aromatic heterocyclic carbonyl, non-aromatic heterocyclic carbonyl,
Aromatic carbocyclic oxycarbonyl, non-aromatic carbocyclic oxycarbonyl, aromatic heterocyclic oxycarbonyl, non-aromatic heterocyclic oxycarbonyl,
Aromatic carbocyclic alkyloxy, non-aromatic carbocyclic alkyloxy, aromatic heterocyclic alkyloxy, non-aromatic heterocyclic alkyloxy,
Aromatic carbocyclic alkyloxycarbonyl, non-aromatic carbocyclic alkyloxycarbonyl, aromatic heterocyclic alkyloxycarbonyl, non-aromatic heterocyclic alkyloxycarbonyl,
Aromatic carbocyclic alkylamino, non-aromatic carbocyclic alkylamino, aromatic heterocyclic alkylamino, non-aromatic heterocyclic alkylamino,
Aromatic carbocyclic alkyl carbamoyl, non-aromatic carbocyclic alkyl carbamoyl, aromatic heterocyclic alkyl carbamoyl, non-aromatic heterocyclic alkyl carbamoyl,
Aromatic carbocyclic carbamoyl, non-aromatic carbocyclic carbamoyl, aromatic heterocyclic carbamoyl, non-aromatic heterocyclic carbamoyl,
Aromatic carbocyclic sulfanyl, non-aromatic carbocyclic sulfanyl, aromatic heterocyclic sulfanyl, non-aromatic heterocyclic sulfanyl,
Non-aromatic carbocyclic sulfonyl, aromatic carbocyclic sulfonyl, aromatic heterocyclic sulfonyl, and non-aromatic heterocyclic sulfonyl.
(In the substituent (b), the aromatic carbocycle, non-aromatic carbocycle, aromatic heterocycle and non-aromatic heterocycle are further substituted with one or more groups selected from the substituent (a) and alkyl. May be)

"Substituted or unsubstituted aromatic carbocycle", "Substituted or unsubstituted phenyl", "Substituted or unsubstituted nonaromatic carbocycle", "Substituted or unsubstituted cycloalkane", "Substituted or unsubstituted aromatic Group heterocycle "," substituted or unsubstituted non-aromatic heterocycle ",
“Substituted or unsubstituted aromatic carbocyclic group”, “Substituted or unsubstituted nonaromatic carbocyclic group”, “Substituted or unsubstituted aromatic heterocyclic group”, and “Substituted or unsubstituted aromatic carbocyclic group” Non-aromatic heterocyclic group ",
"Substituted or unsubstituted aromatic carbocyclic oxy", "Substituted or unsubstituted non-aromatic carbocyclic oxy", "Substituted or unsubstituted aromatic heterocyclic oxy", and "Substituted or unsubstituted non-aromatic Heterocyclic oxy ",
"Substituted or unsubstituted aromatic carbocyclic sulfanyl", "Substituted or unsubstituted non-aromatic carbocyclic sulfanyl", "Substituted or unsubstituted aromatic heterocyclic sulfanyl", and "Substituted or unsubstituted non-aromatic Heterocyclic sulfanyl "
Substituents on the ring of “aromatic carbocycle”, “phenyl”, “non-aromatic carbocycle”, “cycloalkane”, “aromatic heterocycle”, and “non-aromatic heterocycle” of And the substituent (c) and the substituent (d). The atom at any position on the ring may be bonded to one or more groups selected from the following substituent (c) and substituent (d).

Substituent (c): halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, Nitro, nitroso, azide, hydrazino, ureido, amidino, guanidino, trialkylsilyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or non-substituted Substituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alky Nylcarbonyl, substituted or unsubstituted monoalkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, monoalkylcarbonylamino, dialkyl Carbonylamino, monoalkylsulfonylamino, dialkylsulfonylamino, alkylimino, alkenylimino, alkynylimino, alkylcarbonylimino, alkenylcarbonylimino, alkynylcarbonylimino, alkyloxyimino, alkenyloxyimino, alkynyloxyimino, alkylcarbonyloxy, alkenyl Carbonyloxy, alkynylcarbonyloxy, alkyloxycarbonyl, alkenyloxyca Bonyl, alkynyloxycarbonyl, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, monoalkylcarbamoyl, dialkylcarbamoyl, monoalkylsulfanyl Moyl, dialkylsulfamoyl and pentafluorosulfanyl.

Specifically, as the substituent (c),
Halogen, hydroxy, carboxy, amino, carbamoyl, sulfamoyl, cyano, nitro, trialkylsilyl,
Alkyl, haloalkyl, hydroxyalkyl, alkyloxyalkyl,
Alkyloxy, haloalkyloxy, alkenyloxy, alkynyloxy, alkyloxyalkyloxy, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, monoalkylamino, dialkylamino, alkylsulfonyl, haloalkylsulfonyl, alkyloxycarbonyl, alkenyloxycarbonyl, Examples include alkynyloxycarbonyl, alkylsulfanyl, haloalkylsulfanyl, monoalkylcarbamoyl, dialkylcarbamoyl, pentafluorosulfanyl and the like.
Substituent (d): aromatic carbocyclic group, non-aromatic carbocyclic group, aromatic heterocyclic group, non-aromatic heterocyclic group, aromatic carbocyclic oxy, non-aromatic carbocyclic oxy, aromatic Aromatic heterocyclic oxy, non-aromatic heterocyclic oxy, aromatic carbocyclic carbonyl, non-aromatic carbocyclic carbonyl, aromatic heterocyclic carbonyl, non-aromatic heterocyclic carbonyl, aromatic carbocyclic oxycarbonyl, non-aromatic carbocyclic Oxycarbonyl, aromatic heterocyclic oxycarbonyl, non-aromatic heterocyclic oxycarbonyl, aromatic carbocyclic alkyl, non-aromatic carbocyclic alkyl, aromatic heterocyclic alkyl, non-aromatic heterocyclic alkyl,
Aromatic carbocyclic alkyloxy, non-aromatic carbocyclic alkyloxy, aromatic heterocyclic alkyloxy, non-aromatic heterocyclic alkyloxy,
Aromatic carbocyclic alkyloxycarbonyl, non-aromatic carbocyclic alkyloxycarbonyl, aromatic heterocyclic alkyloxycarbonyl, non-aromatic heterocyclic alkyloxycarbonyl,
Aromatic carbocyclic alkyloxyalkyl, non-aromatic carbocyclic alkyloxyalkyl, aromatic heterocyclic alkyloxyalkyl, non-aromatic heterocyclic alkyloxyalkyl,
Aromatic carbocyclic alkyl carbamoyl, non-aromatic carbocyclic alkyl carbamoyl, aromatic heterocyclic alkyl carbamoyl, non-aromatic heterocyclic alkyl carbamoyl,
Aromatic carbocyclic alkylamino, non-aromatic carbocyclic alkylamino, aromatic heterocyclic alkylamino, non-aromatic heterocyclic alkylamino,
Aromatic carbocyclic carbamoyl, non-aromatic carbocyclic carbamoyl, aromatic heterocyclic carbamoyl, non-aromatic heterocyclic carbamoyl,
Aromatic carbocyclic sulfanyl, non-aromatic carbocyclic sulfanyl, aromatic heterocyclic sulfanyl, non-aromatic heterocyclic sulfanyl,
Non-aromatic carbocyclic sulfonyl, aromatic carbocyclic sulfonyl, aromatic heterocyclic sulfonyl, and non-aromatic heterocyclic sulfonyl. (The aromatic carbocyclic ring, non-aromatic carbocyclic ring, aromatic heterocyclic ring and non-aromatic heterocyclic ring in the substituent (d) may be further substituted with one or more groups selected from the substituent (c). Good).

In addition, “substituted or unsubstituted non-aromatic carbocyclic ring”, “substituted or unsubstituted non-aromatic heterocyclic ring”, “substituted or unsubstituted non-aromatic carbocyclic group” and “substituted or unsubstituted non-substituted carbocyclic group”. The “aromatic heterocyclic group” may be substituted with “oxo”. In this case, it means a group in which two hydrogen atoms on a carbon atom are substituted as follows.

The above-mentioned “substituted or unsubstituted non-aromatic carbocyclic oxy”, “substituted or unsubstituted non-aromatic heterocyclic oxy”, “substituted or unsubstituted non-aromatic carbocyclic carbonyl”, “substituted or unsubstituted Non-aromatic carbocycles such as “non-aromatic carbocyclic sulfanyl”, “substituted or unsubstituted non-aromatic heterocyclic sulfanyl”, “substituted or unsubstituted non-aromatic carbocyclic sulfonyl”, and non-aromatic heterocyclic moieties May be substituted with “oxo” in the same manner as described above.
“R ¹ and R ² bonded to the same carbon together with the carbon atom to which they are bonded form a substituted or unsubstituted non-aromatic carbocycle or substituted or unsubstituted non-aromatic heterocycle” , “R ^3a and R ^4a and R ^3b and R ^4b are each independently, together with the carbon atom to which they are attached, a substituted or unsubstituted non-aromatic carbocycle or substituted or unsubstituted non-aromatic R ⁶ and R ⁷ together with the carbon atom to which they are attached form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring. "Includes the case where the following ring is formed."

These rings may be substituted with one or more groups listed as substituents on the above-mentioned “substituted or unsubstituted non-aromatic carbocycle” and “substituted or unsubstituted non-aromatic heterocycle”. .
In particular, the case where “R ^3b and R ^4b together with the carbon atom to which they are bonded to form a substituted or unsubstituted cycloalkane” includes the case where the following ring is formed.

These rings may be substituted with one or more groups listed as substituents on the above-mentioned “substituted or unsubstituted non-aromatic carbocyclic ring”.
The case where “R ¹ and R ² bonded to the same carbon together form ═NR ^1G ” includes, for example, the following cases.

The case where “R ^3a and R ^4a and R ^3b and R ^4b are independently combined to form ═NR ^1H ” includes the following cases, for example.

Formula (I) of the present invention:

Examples of each symbol in the compound represented by are shown below. The present invention encompasses all combinations of the following aspects.

A represents, for example, a substituted or unsubstituted alkyl, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, or A substituted or unsubstituted aromatic heterocyclic group.
A represents, for example, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, or a substituted or unsubstituted aromatic It is a heterocyclic group.
A is, for example, a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group (hereinafter referred to as A1).
A is, for example, substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidyl, substituted or unsubstituted pyridazinyl or substituted or unsubstituted pyrazinyl.

A is a “substituted or unsubstituted non-aromatic carbocyclic group”, “substituted or unsubstituted aromatic carbocyclic group”, “substituted or unsubstituted non-aromatic heterocyclic group” or “substituted or non-substituted In the case of `` substituted aromatic heterocyclic group '', examples of the substituent include:
Halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted monoalkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylsulfonyl, pentafluorosulfanyl,
Substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic carbocyclic oxy, substituted or One or more groups selected from unsubstituted non-aromatic heterocyclic groups and oxo.

In A1, the substituent is, for example, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, monoalkylamino, dialkylamino, alkylsulfonyl, pentafluorosulfanyl, aromatic carbocyclic group, One or more groups selected from a non-aromatic heterocyclic group, a non-aromatic carbocyclic oxy, an aromatic carbocyclic oxy and oxo which may be substituted with a halogen.
In A1, the substituent is, for example, one or more groups selected from halogen, cyano, alkyl, haloalkyl, alkyloxy and haloalkyloxy (hereinafter referred to as A2).
In the above A1, the substituent is, for example, one or more groups selected from halogen and cyano.
In A1, the substituent is, for example, one or more groups selected from fluoro and chloro.

A is, for example, the formula:

(In the formula, s is an integer from 0 to 4, for example, u is an integer from 0 to 3, v is an integer from 0 to 2, w is 0 or 1,
R ^A is, for example, each independently
Halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted monoalkylamino, substituted or unsubstituted dialkylamino, substituted or unsubstituted alkylsulfonyl, pentafluorosulfanyl,
A non-aromatic carbocyclic group optionally substituted with one or more groups selected from the substituent (b), an aromatic optionally substituted with one or more groups selected from the substituent (b) Carbocyclic group, non-aromatic carbocyclic oxy optionally substituted with one or more groups selected from substituent (b), substituted with one or more groups selected from substituent (b) Or a non-aromatic heterocyclic group which may be substituted with one or more groups selected from aromatic carbocyclic oxy or substituent (b), or two R ^A together are oxo (Hereinafter referred to as A3))
Indicated by In the bicyclic group, the bond may be present in any ring, and R ^A is a carbon atom of a ring atom or a nitrogen atom (a nitrogen atom represented as —NH— in the above). May be substituted.

In the above A3, w is 0 or 1, and s, u and v are each independently an integer of 0 to 3, for example, an integer of 1 to 3, for example 1 or 2, for example 1, for example 2.
In the above A3, w is 0 or 1, s, u and v are, for example, any integer of 0 to 2, for example 1 or 2, and R ^A is, for example, each independently a halogen , Cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, monoalkylamino, dialkylamino, alkylsulfonyl, pentafluorosulfanyl, aromatic carbocyclic group, non-aromatic optionally substituted with halogen It may be a heterocyclic group, non-aromatic carbocyclic oxy or aromatic carbocyclic oxy, or two R ^A together may form oxo.
In the above A3, w is 0 or 1, s, u and v are each independently an integer of, for example, 0 to 2, for example 1 or 2, and R ^A is, for example, each independently Halogen, cyano, alkyl, haloalkyl, alkyloxy or haloalkyloxy.
In the above A3, w is 0 or 1, s, u and v are each independently an integer of, for example, 0 to 2, for example 1 or 2, and R ^A is, for example, each independently And halogen or cyano (hereinafter referred to as A4).
In the above A4, w is 0 or 1, s, u and v are each independently an integer of, for example, 0 to 2, for example 1 or 2, and R ^A is, for example, each independently Fluoro or chloro.

A is, for example, the formula:

R ^A is substituted with, for example, halogen, cyano, alkyl, haloalkyl, alkyloxy, haloalkyloxy, monoalkylamino, dialkylamino, alkylsulfonyl, pentafluorosulfanyl, aromatic carbocyclic group, halogen Or a non-aromatic heterocyclic group, non-aromatic carbocyclic oxy, aromatic carbocyclic oxy or oxo, and s is an integer from 0 to 2, for example 1 or 2.

A is, for example, the formula:

And each R ^A is independently halogen or cyano (hereinafter referred to as A5).
A is, for example, the formula:

And each R ^A is independently halogen.
A is, for example, the formula:

And R ^A is halogen.
A is, for example, the formula:

And each R ^A is independently halogen.
A is, for example, the formula:

And each R ^A is independently halogen.

For example, L is a single bond, —NR ^1A CO—, —CONR ^1B —, —SO ₂ —, —SO ₂ NR ^1D — or —NR ^1E SO ₂ —, and m and n are each independently 0 or 1 and R ¹ and R ² are both hydrogen;
R ^3a , R ^4a , R ^3b and R ^4b are each independently
Hydrogen, halogen, or substituted or unsubstituted alkyl, R ^3a and R ^4a may each independently be hydroxy, R ^3a and R ^4a and R ^3b and R ^4b are each independently Together with the carbon atoms to which they are attached, they may form a substituted or unsubstituted non-aromatic carbocycle, wherein R ^3a and R ^4a and R ^3b and R ^4b are each independently taken together. = NR ^1H may be formed (hereinafter referred to as L1).
In the above L1, L is, for example, a single bond.
In the above L1, L is, for example, —NR ^1A CO—.
In the above L1, L is, for example, —CONR ^1B .
In the above L1, L is, for example, —SO ₂ —.
In L1, for example, m is 0 and n is 0.
In the above L1, R ^3a , R ^4a , R ^3b and R ^4b are each independently, for example,
Are hydrogen or substituted or unsubstituted alkyl, or R ^3a and R ^4a and R ^3b and R ^4b are each independently, together with the carbon atom to which they are attached, substituted or unsubstituted non-aromatic A carbocycle may be formed.
In the above L1, R ^3a , R ^4a , R ^3b and R ^4b are each independently, for example,
It may be hydrogen or alkyl, or R ^3a and R ^4a and R ^3b and R ^4b may each independently combine with the carbon atom to which they are attached to form a cycloalkane.
In the above L1, R ^3a , R ^4a , R ^3b and R ^4b are both hydrogen, for example.
In L1, for example, R ^3a and R ^4a are hydrogen, and R ^3b and R ^4b are each independently alkyl.
In L1, for example, R ^3a and R ^4a are hydrogen, and R ^3b and R ^4b are both methyl.
In L1, for example, R ^3a and R ^4a are hydrogen, and R ^3b and R ^4b together with the carbon atom to which they are attached form cyclopropane.

formula:

For example,

(In the formula, each symbol has the same meaning as the above item (1)).
(Hereinafter referred to as L1-2).
In L1-2 above, for example, R ^3b and R ^4b are each independently hydrogen or substituted or unsubstituted alkyl, or R ^3b and R ^4b are taken together with the carbon atom to which they are attached. A substituted or unsubstituted non-aromatic carbocyclic ring may be formed (hereinafter referred to as L2).
In L2, for example, R ^3b and R ^4b are each independently hydrogen or alkyl, or R ^3b and R ^4b together with the carbon atom to which they are attached form a cycloalkane. (Hereinafter referred to as L3).
In L2, for example, R ^3b and R ^4b are each independently alkyl (hereinafter referred to as L4).
Specifically, for example,

(Wherein Me is methyl, iPr is isopropyl, iBu is isobutyl, tBu is tert-butyl, cPr is cyclopropyl, cHex is cyclohexyl, and Bn is benzyl)
It is.
More specifically, for example,

(Wherein Me is methyl), more specifically

(Hereinafter referred to as L5).

Ring B is, for example, a 6-membered aromatic carbocycle, a 6-membered non-aromatic heterocycle or a 6-membered aromatic heterocycle, or

The bond a is bonded to —NHC (═O) CR ⁶ R ⁷ —, the bond b is bonded to —CR ^3b Rb ⁴ —,
B ¹ ring is a 6-membered aromatic carbocyclic ring, a 5-membered or 6-membered non-aromatic heterocyclic ring or a 5-membered or 6-membered aromatic heterocyclic ring,
B ² ring is a 6-membered aromatic carbocycle or a 6-membered aromatic heterocycle,
p is, for example, an integer from 0 to 3,
R ⁵ is each independently, for example, halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted aromatic carbocyclic group or substituted or unsubstituted non-aromatic heterocyclic group Two R ⁵ may be combined to form oxo (hereinafter referred to as B1).
In B1, the ring B is, for example, a 6-membered aromatic carbocyclic ring, a 6-membered aromatic heterocyclic ring, or

And
B ¹ ring is a 5-membered or 6-membered non-aromatic heterocyclic ring or a 5-membered or 6-membered aromatic heterocyclic ring,
B ² ring is 6-membered aromatic carbocyclic ring (hereinafter referred to as B2).
In B1 above, ring B is, for example, benzene, pyridine, benzimidazole, indazole, dihydrobenzthiazole.
In the above B1, p is, for example, an integer of 0 to 2, and R ⁵ is each independently, for example, halogen, cyano, alkyl, haloalkyl or a substituted or unsubstituted aromatic carbocyclic group, R ⁵ together may form oxo.
In the above B1, p is an integer of, for example, 0 to 2, and R ⁵ is each independently, for example, halogen, cyano, alkyl, haloalkyl, or phenyl optionally substituted with halogen or haloalkyl, 2 R ⁵ together may form oxo.
In the above B1, p is an integer of, for example, 0 to 2, R ⁵ is, for example, each independently, halogen, cyano, or haloalkyl, and two R ⁵ together form oxo. (Hereinafter referred to as B3).
In B1, p is, for example, an integer from 0 to 2, and R ⁵ is independently, for example, halogen.
In B1 above, p is, for example, 0, for example, 1, for example, 2.

For example, the formula:

(In the formula, t is an integer of 0 to 2, and other symbols have the same meanings as the above item (1)).
(Hereinafter referred to as B4). When ring B is a condensed ring, R ⁵ may be substituted on any ring.

For example, the formula:

Wherein R ⁵ is halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted aromatic carbocyclic group or substituted or unsubstituted non-aromatic heterocyclic group, R ⁵ together may form an oxo, p is an integer from 0 to 2 and t is an integer from 0 to 2)
(Hereinafter referred to as B5).

For example, the formula:

(Wherein R ⁵ is halogen, hydroxy, cyano, substituted or unsubstituted alkyl or substituted or unsubstituted aromatic carbocyclic group)
It is.
In the above B5, R ⁵ is, for example, each independently a halogen, cyano, alkyl, haloalkyl or a substituted or unsubstituted aromatic carbocyclic group.
In B5 above, R ⁵ is, for example, halogen, cyano, haloalkyl, or an aromatic carbocyclic group optionally substituted with halogen or haloalkyl (hereinafter referred to as B6).

For example, the formula:

R ⁵ is, for example, halogen or haloalkyl (hereinafter referred to as B7).

For example, the formula:

And R ⁵ is, for example, halogen or haloalkyl.

R ⁶ is, for example, hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-substituted An aromatic heterocyclic group or a substituted or unsubstituted aromatic heterocyclic group, and R ⁷ is, for example, hydrogen, halogen, hydroxy, or substituted or unsubstituted alkyl (hereinafter referred to as R671).
In the above R671, R ⁶ is, for example, hydrogen, hydroxy, substituted or unsubstituted alkyl, or substituted or unsubstituted non-aromatic heterocyclic group.
In the above R671, R ⁶ is, for example, hydrogen, hydroxy, substituted or unsubstituted alkyl (wherein the substituents are cyano, hydroxy; carboxy; alkyloxy; haloalkyloxy; carbamoyl; alkyloxycarbonyl; monoalkylcarbamoyl; non-substituted) Aromatic carbocyclic alkylcarbamoyl; dialkylcarbamoyl; non-aromatic heterocyclic carbamoyl; aromatic heterocyclic carbamoyl; non-aromatic heterocyclic carbonyl optionally substituted with hydroxy; optionally substituted with carboxy or alkyloxycarbonyl A non-aromatic carbocyclic group; and one or more groups selected from an aromatic heterocyclic group optionally substituted with alkyl) or a substituted or unsubstituted non-aromatic heterocyclic group (wherein the substituent) Is hydroxy, alkyl, haloalkyl And one or more groups selected from hydroxyalkyl).
In the R671, ^{R 6} is, for example, hydrogen, hydroxy, substituted or unsubstituted alkyl (wherein the substituents are cyano, hydroxy, carboxy; one or more groups selected from and carbamoyl) (hereinafter, R672 And).
In R671 above, R ⁶ and R ⁷ are each independently, for example, hydrogen, hydroxy, or unsubstituted alkyl.
In the R671, ^{R 6} and ^{R 7} are both hydrogen (hereinafter referred to as R673).
R ⁶ and R ⁷ , for example, together with the carbon atom to which they are bonded form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring (hereinafter referred to as R674). To do). As the substituent, for example, the substituent is one or more groups selected from hydroxy, alkyl, haloalkyl and hydroxyalkyl.

For example, q is an integer from 0 to 2, R ⁸ is halogen or substituted or unsubstituted alkyl, X is = CR ⁹ -or = N-, and R ⁹ is hydrogen, halogen or substituted or unsubstituted E is SO ₂ R ^10A , and R ^10A is substituted or unsubstituted alkyl (hereinafter referred to as X1).

For example, q is 0 or 1, R ⁸ is halogen, X is ═CR ⁹ — or ═N—, R ⁹ is hydrogen or halogen, E is SO ₂ R ^10A , R ^10A Is substituted or unsubstituted alkyl (hereinafter referred to as X2).
In the above X1 or X2, for example, X is = CH- (hereinafter referred to as X3).
In X1 or X2, for example, X is = N- (hereinafter referred to as X4).
In the above X1 or X2, for example, R ^10A is unsubstituted alkyl or haloalkyl.
In the above X1 or X2, for example, R ^10A is unsubstituted alkyl.
In the above X1 or X2, for example, R ^10A is alkyl having 1 to 3 carbon atoms.
In the above X1 or X2, for example, R ^10A is ethyl.

In the compound represented by the formula (I), A, L, R ¹ , R ² , R ^3a , R ^4a , R ^3b , R ^4b , m, n, ring B, R ⁵ , p, R ⁶ , R ⁷ , Examples of combinations of R ⁸ , q, X and E include the following.
(A1, L1, B1, R671, X1), (A1, L1, B1, R671, X2), (A1, L1, B1, R672, X1), (A1, L1, B1, R672, X2), (A1 , L1, B1, R673, X1), (A1, L1, B1, R673, X2), (A1, L1, B1, R674, X1), (A1, L1, B1, R674, X2), (A1, L1 , B2, R671, X1), (A1, L1, B2, R671, X2), (A1, L1, B2, R672, X1), (A1, L1, B2, R672, X2), (A1, L1, B2 , R673, X1), (A1, L1, B2, R673, X2), (A1, L1, B2, R674, X1), (A1, L1, B2, R674, X2), (A1, L1, B3, R671 , X1), (A1, L1, B3, R671, X2), (A1, L1, B3, R672, X1), (A1, L1, B3, R672, X2), (A1, L1, B3, R673, X1 ), (A1, L1, B3, R673, X2), (A1, L1, B3, R674, X1), (A1, L1, B3, R674, X2), (A1, L1, B4, R671, X1), (A1, L1, B4, R671, X2), (A1, L1, B4, R672, X1), (A1, L1, B4, R672, X2), (A1, L1, B4, R673, X1), (A1 , L1, B4, R673, X2), (A1, L1, B4, R674, X1), (A1, L1, B4, R674, X2), (A1, L1, B5, R671, X1), (A1, L1 , B5, R671, X2), (A1, L1, B5, R672, X1), (A1, L1, B5, R672, X2), (A1, L1, B5, R673, X1), (A1, L1, B5 , R673, X2), (A1, L1, B5, R674, X1), (A1, L1, B5, R674, X2), (A1, L1, B6, R671, X1), (A1, L1, B6, R671 , X2), (A1, L1, B6, R672, X1), (A1, L1, B6, R672, X2), (A1, L1, B6, R673, X1), (A1, L1, B6, R673, X2 ), (A1, L1, B6, R674, X1), (A1, L1, B6, R674, X2), (A1, L1, B7, R671, X1), (A1, L1, B7, R671, X2), (A1, L1, B7, R672, X1), (A1, L1, B7, R672, X2), (A1, L1, B7, R6 73, X1), (A1, L1, B7, R673, X2), (A1, L1, B7, R674, X1), (A1, L1, B7, R674, X2), (A1, L2, B1, R671, X1), (A1, L2, B1, R671, X2), (A1, L2, B1, R672, X1), (A1, L2, B1, R672, X2), (A1, L2, B1, R673, X1) , (A1, L2, B1, R673, X2), (A1, L2, B1, R674, X1), (A1, L2, B1, R674, X2), (A1, L2, B2, R671, X1), ( (A1, L2, B2, R671, X2), (A1, L2, B2, R672, X1), (A1, L2, B2, R672, X2), (A1, L2, B2, R673, X1), (A1, L2, B2, R673, X2), (A1, L2, B2, R674, X1), (A1, L2, B2, R674, X2), (A1, L2, B3, R671, X1), (A1, L2, B3, R671, X2), (A1, L2, B3, R672, X1), (A1, L2, B3, R672, X2), (A1, L2, B3, R673, X1), (A1, L2, B3, R673, X2), (A1, L2, B3, R674, X1), (A1, L2, B3, R674, X2), (A1, L2, B4, R671, X1), (A1, L2, B4, R671, X2), (A1, L2, B4, R672, X1), (A1, L2, B4, R672, X2), (A1, L2, B4, R673, X1), (A1, L2, B4, R673, X2) , (A1, L2, B4, R674, X1), (A1, L2, B4, R674, X2), (A1, L2, B5, R671, X1), (A1, L2, B5, R671, X2), ( (A1, L2, B5, R672, X1), (A1, L2, B5, R672, X2), (A1, L2, B5, R673, X1), (A1, L2, B5, R673, X2), (A1, (L2, B5, R674, X1), (A1, L2, B5, R674, X2), (A1, L2, B6, R671, X1), (A1, L2, B6, R671, X2), (A1, L2, B6, R672, X1), (A1, L2, B6, R672, X2), (A1, L2, B6, R673, X1), (A1, L2, B6, R673, X2), (A1, L2, B6, R674, X1), (A1, L2, B6, R674, X2), (A1, L2, B7, R671, X1), (A1, L 2, B7, R671, X2), (A1, L2, B7, R672, X1), (A1, L2, B7, R672, X2), (A1, L2, B7, R673, X1), (A1, L2, B7, R673, X2), (A1, L2, B7, R674, X1), (A1, L2, B7, R674, X2), (A1, L3, B1, R671, X1), (A1, L3, B1, R671, X2), (A1, L3, B1, R672, X1), (A1, L3, B1, R672, X2), (A1, L3, B1, R673, X1), (A1, L3, B1, R673, X2), (A1, L3, B1, R674, X1), (A1, L3, B1, R674, X2), (A1, L3, B2, R671, X1), (A1, L3, B2, R671, X2) , (A1, L3, B2, R672, X1), (A1, L3, B2, R672, X2), (A1, L3, B2, R673, X1), (A1, L3, B2, R673, X2), ( (A1, L3, B2, R674, X1), (A1, L3, B2, R674, X2), (A1, L3, B3, R671, X1), (A1, L3, B3, R671, X2), (A1, (L3, B3, R672, X1), (A1, L3, B3, R672, X2), (A1, L3, B3, R673, X1), (A1, L3, B3, R673, X2), (A1, L3, B3, R674, X1), (A1, L3, B3, R674, X2), (A1, L3, B4, R671, X1), (A1, L3, B4, R671, X2), (A1, L3, B4, R672, X1), (A1, L3, B4, R672, X2), (A1, L3, B4, R673, X1), (A1, L3, B4, R673, X2), (A1, L3, B4, R674, X1), (A1, L3, B4, R674, X2), (A1, L3, B5, R671, X1), (A1, L3, B5, R671, X2), (A1, L3, B5, R672, X1) , (A1, L3, B5, R672, X2), (A1, L3, B5, R673, X1), (A1, L3, B5, R673, X2), (A1, L3, B5, R674, X1), ( (A1, L3, B5, R674, X2), (A1, L3, B6, R671, X1), (A1, L3, B6, R671, X2), (A1, L3, B6, R672, X1), (A1, L3, B6, R672, X2), (A1, L3, B6, R673, X1), (A1, L3, B6, R673, X2 ), (A1, L3, B6, R674, X1), (A1, L3, B6, R674, X2), (A1, L3, B7, R671, X1), (A1, L3, B7, R671, X2), (A1, L3, B7, R672, X1), (A1, L3, B7, R672, X2), (A1, L3, B7, R673, X1), (A1, L3, B7, R673, X2), (A1 , L3, B7, R674, X1), (A1, L3, B7, R674, X2), (A1, L4, B1, R671, X1), (A1, L4, B1, R671, X2), (A1, L4 , B1, R672, X1), (A1, L4, B1, R672, X2), (A1, L4, B1, R673, X1), (A1, L4, B1, R673, X2), (A1, L4, B1 , R674, X1), (A1, L4, B1, R674, X2), (A1, L4, B2, R671, X1), (A1, L4, B2, R671, X2), (A1, L4, B2, R672 , X1), (A1, L4, B2, R672, X2), (A1, L4, B2, R673, X1), (A1, L4, B2, R673, X2), (A1, L4, B2, R674, X1 ), (A1, L4, B2, R674, X2), (A1, L4, B3, R671, X1), (A1, L4, B3, R671, X2), (A1, L4, B3, R672, X1), (A1, L4, B3, R672, X2), (A1, L4, B3, R673, X1), (A1, L4, B3, R673, X2), (A1, L4, B3, R674, X1), (A1 , L4, B3, R674, X2), (A1, L4, B4, R671, X1), (A1, L4, B4, R671, X2), (A1, L4, B4, R672, X1), (A1, L4 , B4, R672, X2), (A1, L4, B4, R673, X1), (A1, L4, B4, R673, X2), (A1, L4, B4, R674, X1), (A1, L4, B4 , R674, X2), (A1, L4, B5, R671, X1), (A1, L4, B5, R671, X2), (A1, L4, B5, R672, X1), (A1, L4, B5, R672 , X2), (A1, L4, B5, R673, X1), (A1, L4, B5, R673, X2), (A1, L4, B5, R674, X1), (A1, L4, B5, R674, X2 ), (A1, L4, B6, R671, X1), (A1, L4, B6, R671, X2), (A1, L4, B6, R672, X1), (A1, L4, B6, R672, X2), (A1, L4, B6, R673, X1), (A1, L4, B6, R673, X2), (A1, L4, B6, R674, X1), (A1, L4, B6, R674, X2), (A1, L4, B7, R671, X1), (A1, L4, B7, R671, X2), (A1, L4, B7, R672, X1) , (A1, L4, B7, R672, X2), (A1, L4, B7, R673, X1), (A1, L4, B7, R673, X2), (A1, L4, B7, R674, X1), ( (A1, L4, B7, R674, X2), (A2, L1, B1, R671, X1), (A2, L1, B1, R671, X2), (A2, L1, B1, R672, X1), (A2, L1, B1, R672, X2), (A2, L1, B1, R673, X1), (A2, L1, B1, R673, X2), (A2, L1, B1, R674, X1), (A2, L1, (B1, R674, X2), (A2, L1, B2, R671, X1), (A2, L1, B2, R671, X2), (A2, L1, B2, R672, X1), (A2, L1, B2, R672, X2), (A2, L1, B2, R673, X1), (A2, L1, B2, R673, X2), (A2, L1, B2, R674, X1), (A2, L1, B2, R674, X2), (A2, L1, B3, R671, X1), (A2, L1, B3, R671, X2), (A2, L1, B3, R672, X1), (A2, L1, B3, R672, X2) , (A2, L1, B3, R673, X1), (A2, L1, B3, R673, X2), (A2, L1, B3, R674, X1), (A2, L1, B3, R674, X2), ( (A2, L1, B4, R671, X1), (A2, L1, B4, R671, X2), (A2, L1, B4, R672, X1), (A2, L1, B4, R672, X2), (A2, L1, B4, R673, X1), (A2, L1, B4, R673, X2), (A2, L1, B4, R674, X1), (A2, L1, B4, R674, X2), (A2, L1, B5, R671, X1), (A2, L1, B5, R671, X2), (A2, L1, B5, R672, X1), (A2, L1, B5, R672, X2), (A2, L1, B5, R673, X1), (A2, L1, B5, R673, X2), (A2, L1, B5, R674, X1), (A2 , L1, B5, R674, X2), (A2, L1, B6, R671, X1), (A2, L1, B6, R671, X2), (A2, L1, B6, R672, X1), (A2, L1 , B6, R672, X2), (A2, L1, B6, R673, X1), (A2, L1, B6, R673, X2), (A2, L1, B6, R674, X1), (A2, L1, B6 , R674, X2), (A2, L1, B7, R671, X1), (A2, L1, B7, R671, X2), (A2, L1, B7, R672, X1), (A2, L1, B7, R672 , X2), (A2, L1, B7, R673, X1), (A2, L1, B7, R673, X2), (A2, L1, B7, R674, X1), (A2, L1, B7, R674, X2 ), (A2, L2, B1, R671, X1), (A2, L2, B1, R671, X2), (A2, L2, B1, R672, X1), (A2, L2, B1, R672, X2), (A2, L2, B1, R673, X1), (A2, L2, B1, R673, X2), (A2, L2, B1, R674, X1), (A2, L2, B1, R674, X2), (A2 , L2, B2, R671, X1), (A2, L2, 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X2), (A3, L4, B1, R674, X1), (A3, L4, B1, R674, X2), (A3, L4, B2, R671, X1) , (A3, L4, B2, R671, X2), (A3, L4, B2, R672, X1), (A3, L4, B2, R672, X2), (A3, L4, B2, R673, X1), ( (A3, L4, B2, R673, X2), (A3, L4, B2, R674, X1), (A3, L4, B2, R674, X2), (A3, L4, B3, R671, X1), (A3, (L4, B3, R671, X2), (A3, L4, B3, R672, X1), (A3, L4, B3, R672, X2), (A3, L4, B3, R673, X1), (A3, L4, (B3, R673, X2), (A3, L4, B3, R674, X1), (A3, L4, B3, R674, X2), (A3, L4, B4, R671, X1), (A3, L4, B4, R671, X2), (A3, L4, B4, R672, X1), (A3, L4, B4, R672, X2), (A3, L 4, B4, R673, X1), (A3, L4, B4, R673, X2), (A3, L4, B4, R674, X1), (A3, L4, B4, R674, X2), (A3, L4, (B5, R671, X1), (A3, L4, B5, R671, X2), (A3, L4, B5, R672, X1), (A3, L4, B5, R672, X2), (A3, L4, B5, R673, X1), (A3, L4, B5, R673, X2), (A3, L4, B5, R674, X1), (A3, L4, B5, R674, X2), (A3, L4, B6, R671, X1), (A3, L4, B6, R671, X2), (A3, L4, B6, R672, X1), (A3, L4, B6, R672, X2), (A3, L4, B6, R673, X1) , (A3, L4, B6, R673, X2), (A3, L4, B6, R674, X1), (A3, L4, B6, R674, X2), (A3, L4, B7, R671, X1), ( (A3, L4, B7, R671, X2), (A3, L4, B7, R672, X1), (A3, L4, B7, R672, X2), (A3, L4, B7, R673, X1), (A3, L4, B7, R673, X2), (A3, L4, B7, R674, X1), (A3, L4, B7, R674, X2), (A4, L1, B1, R671, X1), (A4, L1, B1, R671, X2), (A4, L1, B1, R672, X1), (A4, L1, B1, R672, X2), (A4, L1, B1, R673, X1), (A4, L1, B1, R673, X2), (A4, L1, B1, R674, X1), (A4, L1, B1, R674, X2), (A4, L1, B2, R671, X1), (A4, L1, B2, R671, X2), (A4, L1, B2, R672, X1), (A4, L1, B2, R672, X2), (A4, L1, B2, R673, X1), (A4, L1, B2, R673, X2) , (A4, L1, B2, R674, X1), (A4, L1, B2, R674, X2), (A4, L1, B3, R671, X1), (A4, L1, B3, R671, X2), ( (A4, L1, B3, R672, X1), (A4, L1, B3, R672, X2), (A4, L1, B3, R673, X1), (A4, L1, B3, R673, X2), (A4, L1, B3, R674, X1), (A4, L1, B3, R674, X2), (A4, L1, B4, R671, X1 ), (A4, L1, B4, R671, X2), (A4, L1, B4, R672, X1), (A4, L1, B4, R672, X2), (A4, L1, B4, R673, X1), (A4, L1, B4, R673, X2), (A4, L1, B4, R674, X1), (A4, L1, B4, R674, X2), (A4, L1, B5, R671, X1), (A4 , L1, B5, R671, X2), (A4, L1, B5, R672, X1), (A4, L1, B5, R672, X2), (A4, L1, B5, R673, X1), (A4, L1 , B5, R673, X2), (A4, L1, B5, R674, X1), (A4, L1, B5, R674, X2), (A4, L1, B6, R671, X1), (A4, L1, B6 , R671, X2), (A4, L1, B6, R672, X1), (A4, L1, B6, R672, X2), (A4, L1, B6, R673, X1), (A4, L1, B6, R673 , X2), (A4, L1, B6, R674, X1), (A4, L1, B6, R674, X2), (A4, L1, B7, R671, X1), (A4, L1, B7, R671, X2 ), (A4, L1, B7, R672, X1), (A4, L1, B7, R672, X2), (A4, L1, B7, R673, X1), (A4, L1, B7, R673, X2), (A4, L1, B7, R674, X1), (A4, L1, B7, R674, X2), (A4, L2, B1, R671, X1), (A4, L2, B1, R671, X2), (A4 , L2, B1, R672, X1), (A4, L2, B1, R672, X2), (A4, L2, B1, R673, X1), (A4, L2, B1, R673, X2), (A4, L2 , B1, R674, X1), (A4, L2, B1, R674, X2), (A4, L2, B2, R671, X1), (A4, L2, B2, R671, X2), (A4, L2, B2 , R672, X1), (A4, L2, B2, R672, X2), (A4, L2, B2, R673, X1), (A4, L2, B2, R673, X2), (A4, L2, B2, R674 , X1), (A4, L2, B2, R674, X2), (A4, L2, B3, R671, X1), (A4, L2, B3, R671, X2), (A4, L2, B3, R672, X1 ), (A4, L2, B3, R672, X2), (A4, L2, B3, R673, X1), (A4, L2, B3, R673, X2), (A4, L2, B3, R674, X1), (A4, L2, B3, R674, X2), (A4, L2, B4, R671, X1), (A4, L2, B4, R671, X2), (A4, L2, B4, R672, X1), (A4, L2, B4, R672, X2), (A4, L2, B4, R673, X1), (A4, L2, B4, R673, X2) , (A4, L2, B4, R674, X1), (A4, L2, B4, R674, X2), (A4, L2, B5, R671, X1), (A4, L2, B5, R671, X2), ( (A4, L2, B5, R672, X1), (A4, L2, B5, R672, X2), (A4, L2, B5, R673, X1), (A4, L2, B5, R673, X2), (A4, (L2, B5, R674, X1), (A4, L2, B5, R674, X2), (A4, L2, B6, R671, X1), (A4, L2, B6, R671, X2), (A4, L2, (B6, R672, X1), (A4, L2, B6, R672, X2), (A4, L2, B6, R673, X1), (A4, L2, B6, R673, X2), (A4, L2, B6, R674, X1), (A4, L2, B6, R674, X2), (A4, L2, B7, R671, X1), (A4, L2, B7, R671, X2), (A4, L2, B7, R672, X1), (A4, L2, B7, R672, X2), (A4, L2, B7, R673, X1), (A4, L2, B7, R673, X2), (A4, L2, B7, R674, X1) , (A4, L2, B7, R674, X2), (A4, L3, B1, R671, X1), (A4, L3, B1, R671, X2), (A4, L3, B1, R672, X1), ( (A4, L3, B1, R672, X2), (A4, L3, B1, R673, X1), (A4, L3, B1, R673, X2), (A4, L3, B1, R674, X1), (A4, (L3, B1, R674, X2), (A4, L3, B2, R671, X1), (A4, L3, B2, R671, X2), (A4, L3, B2, R672, X1), (A4, L3, (B2, R672, X2), (A4, L3, B2, R673, X1), (A4, L3, B2, R673, X2), (A4, L3, B2, R674, X1), (A4, L3, B2, R674, X2), (A4, L3, B3, R671, X1), (A4, L3, B3, R671, X2), (A4 , L3, B3, R672, X1), (A4, L3, B3, R672, X2), (A4, L3, B3, R673, X1), (A4, L3, B3, R673, X2), (A4, L3 , B3, R674, X1), (A4, L3, B3, R674, X2), (A4, L3, B4, R671, X1), (A4, L3, B4, R671, X2), (A4, L3, B4 , R672, X1), (A4, L3, B4, R672, X2), (A4, L3, B4, R673, X1), (A4, L3, B4, R673, X2), (A4, L3, B4, R674 , X1), (A4, L3, B4, R674, X2), (A4, L3, B5, R671, X1), (A4, L3, B5, R671, X2), (A4, L3, B5, R672, X1 ), (A4, L3, B5, R672, X2), (A4, L3, B5, R673, X1), (A4, L3, B5, R673, X2), (A4, L3, B5, R674, X1), (A4, L3, B5, R674, X2), (A4, L3, B6, R671, X1), (A4, L3, B6, R671, X2), (A4, L3, B6, R672, X1), (A4 , L3, B6, R672, X2), (A4, L3, B6, R673, X1), (A4, L3, B6, R673, X2), (A4, L3, B6, R674, X1), (A4, L3 , B6, R674, X2), (A4, L3, B7, R671, X1), (A4, L3, B7, R671, X2), (A4, L3, B7, R672, X1), (A4, L3, B7 , R672, X2), (A4, L3, B7, R673, X1), (A4, L3, B7, R673, X2), (A4, L3, B7, R674, X1), (A4, L3, B7, R674 , X2), (A4, L4, B1, R671, X1), (A4, L4, B1, R671, X2), (A4, L4, B1, R672, X1), (A4, L4, B1, R672, X2 ), (A4, L4, B1, R673, X1), (A4, L4, B1, R673, X2), (A4, L4, B1, R674, X1), (A4, L4, B1, R674, X2), (A4, L4, B2, R671, X1), (A4, L4, B2, R671, X2), (A4, L4, B2, R672, X1), (A4, L4, B2, R672, X2), (A4 , L4, B2, R673, X1), (A4, L4, B2, R673, X2), (A4, L4, B2, R674, X1), (A4, L4, B2, R674, X2), (A4, L4, B3, R671, X1), (A4, L4, B3, R671, X2), (A4, L4, B3, R672, X1) , (A4, L4, B3, R672, X2), (A4, L4, B3, R673, X1), (A4, L4, B3, R673, X2), (A4, L4, B3, R674, X1), ( (A4, L4, B3, R674, X2), (A4, L4, B4, R671, X1), (A4, L4, B4, R671, X2), (A4, L4, B4, R672, X1), (A4, (L4, B4, R672, X2), (A4, L4, B4, R673, X1), (A4, L4, B4, R673, X2), (A4, L4, B4, R674, X1), (A4, L4, (B4, R674, X2), (A4, L4, B5, R671, X1), (A4, L4, B5, R671, X2), (A4, L4, B5, R672, X1), (A4, L4, B5, R672, X2), (A4, L4, B5, R673, X1), (A4, L4, B5, R673, X2), (A4, L4, B5, R674, X1), (A4, L4, B5, R674, X2), (A4, L4, B6, R671, X1), (A4, L4, B6, R671, X2), (A4, L4, B6, R672, X1), (A4, L4, B6, R672, X2) , (A4, L4, B6, R673, X1), (A4, L4, B6, R673, X2), (A4, L4, B6, R674, X1), (A4, L4, B6, R674, X2), ( (A4, L4, B7, R671, X1), (A4, L4, B7, R671, X2), (A4, L4, B7, R672, X1), (A4, L4, B7, R672, X2), (A4, (L4, B7, R673, X1), (A4, L4, B7, R673, X2), (A4, L4, B7, R674, X1), (A4, L4, B7, R674, X2), (A5, L1, (B1, R671, X1), (A5, L1, B1, R671, X2), (A5, L1, B1, R672, X1), (A5, L1, B1, R672, X2), (A5, L1, B1, R673, X1), (A5, L1, B1, R673, X2), (A5, L1, B1, R674, X1), (A5, L1, B1, R674, X2), (A5, L1, B2, R671, X1), (A5, L1, B2, R671, X2), (A5, L1, B2, R672, X1), (A5, L1, B 2, R672, X2), (A5, L1, B2, R673, X1), (A5, L1, B2, R673, X2), (A5, L1, B2, R674, X1), (A5, L1, B2, R674, X2), (A5, L1, B3, R671, X1), (A5, L1, B3, R671, X2), (A5, L1, B3, R672, X1), (A5, L1, B3, R672, X2), (A5, L1, B3, R673, X1), (A5, L1, B3, R673, X2), (A5, L1, B3, R674, X1), (A5, L1, B3, R674, X2) , (A5, L1, B4, R671, X1), (A5, L1, B4, R671, X2), (A5, L1, B4, R672, X1), (A5, L1, B4, R672, X2), ( (A5, L1, B4, R673, X1), (A5, L1, B4, R673, X2), (A5, L1, B4, R674, X1), (A5, L1, B4, R674, X2), (A5, (L1, B5, R671, X1), (A5, L1, B5, R671, X2), (A5, L1, B5, R672, X1), (A5, L1, B5, R672, X2), (A5, L1, (B5, R673, X1), (A5, L1, B5, R673, X2), (A5, L1, B5, R674, X1), (A5, L1, B5, R674, X2), (A5, L1, B6, R671, X1), (A5, L1, B6, R671, X2), (A5, L1, B6, R672, X1), (A5, L1, B6, R672, X2), (A5, L1, B6, R673, X1), (A5, L1, B6, R673, X2), (A5, L1, B6, R674, X1), (A5, L1, B6, R674, X2), (A5, L1, B7, R671, X1) , (A5, L1, B7, R671, X2), (A5, L1, B7, R672, X1), (A5, L1, B7, R672, X2), (A5, L1, B7, R673, X1), ( (A5, L1, B7, R673, X2), (A5, L1, B7, R674, X1), (A5, L1, B7, R674, X2), (A5, L2, B1, R671, X1), (A5, (L2, B1, R671, X2), (A5, L2, B1, R672, X1), (A5, L2, B1, R672, X2), (A5, L2, B1, R673, X1), (A5, L2, (B1, R673, X2), (A5, L2, B1, R674, X1), (A5, L2, B1, R674, X2), ( (A5, L2, B2, R671, X1), (A5, L2, B2, R671, X2), (A5, L2, B2, R672, X1), (A5, L2, B2, R672, X2), (A5, L2, B2, R673, X1), (A5, L2, B2, R673, X2), (A5, L2, B2, R674, X1), (A5, L2, B2, R674, X2), (A5, L2, B3, R671, X1), (A5, L2, B3, R671, X2), (A5, L2, B3, R672, X1), (A5, L2, B3, R672, X2), (A5, L2, B3, R673, X1), (A5, L2, B3, R673, X2), (A5, L2, B3, R674, X1), (A5, L2, B3, R674, X2), (A5, L2, B4, R671, X1), (A5, L2, B4, R671, X2), (A5, L2, B4, R672, X1), (A5, L2, B4, R672, X2), (A5, L2, B4, R673, X1) , (A5, L2, B4, R673, X2), (A5, L2, B4, R674, X1), (A5, L2, B4, R674, X2), (A5, L2, B5, R671, X1), ( (A5, L2, B5, R671, X2), (A5, L2, B5, R672, X1), (A5, L2, B5, R672, X2), (A5, L2, B5, R673, X1), (A5, (L2, B5, R673, X2), (A5, L2, B5, R674, X1), (A5, L2, B5, R674, X2), (A5, L2, B6, R671, X1), (A5, L2, (B6, R671, X2), (A5, L2, B6, R672, X1), (A5, L2, B6, R672, X2), (A5, L2, B6, R673, X1), (A5, L2, B6, R673, X2), (A5, L2, B6, R674, X1), (A5, L2, B6, R674, X2), (A5, L2, B7, R671, X1), (A5, L2, B7, R671, X2), (A5, L2, B7, R672, X1), (A5, L2, B7, R672, X2), (A5, L2, B7, R673, X1), (A5, L2, B7, R673, X2) , (A5, L2, B7, R674, X1), (A5, L2, B7, R674, X2), (A5, L3, B1, R671, X1), (A5, L3, B1, R671, X2), ( (A5, L3, B1, R672, X1), (A5, L3, B1, R672, X2), (A5, L3, B1, R67 3, X1), (A5, L3, B1, R673, X2), (A5, L3, B1, R674, X1), (A5, L3, B1, R674, X2), (A5, L3, B2, R671, X1), (A5, L3, B2, R671, X2), (A5, L3, B2, R672, X1), (A5, L3, B2, R672, X2), (A5, L3, B2, R673, X1) , (A5, L3, B2, R673, X2), (A5, L3, B2, R674, X1), (A5, L3, B2, R674, X2), (A5, L3, B3, R671, X1), ( (A5, L3, B3, R671, X2), (A5, L3, B3, R672, X1), (A5, L3, B3, R672, X2), (A5, L3, B3, R673, X1), (A5, L3, B3, R673, X2), (A5, L3, B3, R674, X1), (A5, L3, B3, R674, X2), (A5, L3, B4, R671, X1), (A5, L3, (B4, R671, X2), (A5, L3, B4, R672, X1), (A5, L3, B4, R672, X2), (A5, L3, B4, R673, X1), (A5, L3, B4, R673, X2), (A5, L3, B4, R674, X1), (A5, L3, B4, R674, X2), (A5, L3, B5, R671, X1), (A5, L3, B5, R671, X2), (A5, L3, B5, R672, X1), (A5, L3, B5, R672, X2), (A5, L3, B5, R673, X1), (A5, L3, B5, R673, X2) , (A5, L3, B5, R674, X1), (A5, L3, B5, R674, X2), (A5, L3, B6, R671, X1), (A5, L3, B6, R671, X2), ( (A5, L3, B6, R672, X1), (A5, L3, B6, R672, X2), (A5, L3, B6, R673, X1), (A5, L3, B6, R673, X2), (A5, L3, B6, R674, X1), (A5, L3, B6, R674, X2), (A5, L3, B7, R671, X1), (A5, L3, B7, R671, X2), (A5, L3, (B7, R672, X1), (A5, L3, B7, R672, X2), (A5, L3, B7, R673, X1), (A5, L3, B7, R673, X2), (A5, L3, B7, R674, X1), (A5, L3, B7, R674, X2), (A5, L4, B1, R671, X1), (A5, L4 , B1, R671, X2), (A5, L4, B1, R672, X1), (A5, L4, B1, R672, X2), (A5, L4, B1, R673, X1), (A5, L4, B1 , R673, X2), (A5, L4, B1, R674, X1), (A5, L4, B1, R674, X2), (A5, L4, B2, R671, X1), (A5, L4, B2, R671 , X2), (A5, L4, B2, R672, X1), (A5, L4, B2, R672, X2), (A5, L4, B2, R673, X1), (A5, L4, B2, R673, X2 ),
(A5, L4, B2, R674, X1), (A5, L4, B2, R674, X2), (A5, L4, B3, R671, X1), (A5, L4, B3, R671, X2), (A5 , L4, B3, R672, X1), (A5, L4, B3, R672, X2), (A5, L4, B3, R673, X1), (A5, L4, B3, R673, X2), (A5, L4 , B3, R674, X1), (A5, L4, B3, R674, X2), (A5, L4, B4, R671, X1), (A5, L4, B4, R671, X2), (A5, L4, B4 , R672, X1), (A5, L4, B4, R672, X2), (A5, L4, B4, R673, X1), (A5, L4, B4, R673, X2), (A5, L4, B4, R674 , X1), (A5, L4, B4, R674, X2), (A5, L4, B5, R671, X1), (A5, L4, B5, R671, X2), (A5, L4, B5, R672, X1 ), (A5, L4, B5, R672, X2), (A5, L4, B5, R673, X1), (A5, L4, B5, R673, X2), (A5, L4, B5, R674, X1), (A5, L4, B5, R674, X2), (A5, L4, B6, R671, X1), (A5, L4, B6, R671, X2), (A5, L4, B6, R672, X1), (A5 , L4, B6, R672, X2), (A5, L4, B6, R673, X1), (A5, L4, B6, R673, X2), (A5, L4, B6, R674, X1), (A5, L4 , B6, R674, X2), (A5, L4, B7, R671, X1), (A5, L4, B7, R671, X2), (A5, L4, B7, R672, X1), (A5, L4, B7 , R672, X2), (A5, L4, B7, R673, X1), (A5, L4, B7, R673, X2), (A5, L4, B7, R674, X1), (A5, L4, B7, R674 , X2),
(A5, L5, B7, R672, X3), (A5, L5, B7, R672, X4), (A5, L5, B7, R673, X3) and (A5, L5, B7, R673, X4).

The compound of formula (I) is not limited to a particular isomer, but all possible isomers (eg keto-enol isomer, imine-enamine isomer, diastereoisomer, optical isomer) , Rotamers, etc.), racemates or mixtures thereof.
One or more hydrogen, carbon and / or other atoms of the compound of formula (I) may be replaced with isotopes of hydrogen, carbon and / or other atoms, respectively. Examples of such isotopes are ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ¹²³ I and ^{Like 36} Cl, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine are included. The compound represented by the formula (I) also includes a compound substituted with such an isotope. The compound substituted with the isotope is also useful as a pharmaceutical, and includes all radiolabeled compounds of the compound represented by the formula (I). A “radiolabeling method” for producing the “radiolabeled product” is also encompassed in the present invention, and is useful as a metabolic pharmacokinetic study, a study in a binding assay, and / or a diagnostic tool.

The radioactive label of the compound represented by the formula (I) can be prepared by a method well known in the art. For example, the tritium-labeled compound represented by the formula (I) can be prepared by introducing tritium into the specific compound represented by the formula (I) by, for example, catalytic dehalogenation reaction using tritium. This method reacts a tritium gas with a precursor in which the compound of formula (I) is appropriately halogen-substituted in the presence of a suitable catalyst such as Pd / C, in the presence or absence of a base. Including that. For suitable methods for preparing other tritium-labeled compounds, reference can be made to “Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)”. ^{The 14} C-labeled compound can be prepared by using a raw material having ¹⁴ C carbon.

As the pharmaceutically acceptable salt of the compound represented by the formula (I), for example, a compound represented by the formula (I), an alkali metal (for example, lithium, sodium, potassium, etc.), an alkaline earth metal (for example, Calcium, barium, etc.), magnesium, transition metals (eg, zinc, iron, etc.), ammonia, organic bases (eg, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, Picolin, quinoline etc.) and salts with amino acids, or inorganic acids (eg hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid etc.) and organic acids (eg formic acid, acetic acid, Propionic acid, trifluoroacetic acid, citric acid, lactic acid Tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, etc.) Salt. Particularly, salts with hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, methanesulfonic acid and the like can be mentioned. These salts can be formed by a commonly performed method.

The compound represented by the formula (I) or a pharmaceutically acceptable salt thereof may form a solvate (for example, hydrate etc.), a co-crystal and / or a crystal polymorph. Various solvates, co-crystals and polymorphs. The “solvate” may be coordinated with an arbitrary number of solvent molecules (for example, water molecules) with respect to the compound represented by the formula (I). When the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is left in the air, it may absorb moisture and adsorbed water may adhere or form a hydrate. In some cases, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof may be recrystallized to form a crystalline polymorph thereof. “Co-crystal” means that the compound or salt represented by the formula (I) and the counter molecule are present in the same crystal lattice, and may be formed with any number of counter molecules.
The compound represented by the formula (I) or a pharmaceutically acceptable salt thereof may form a prodrug, and the present invention includes such various prodrugs. A prodrug is a derivative of a compound of the present invention having a group that can be chemically or metabolically degraded, and is a compound that becomes a pharmaceutically active compound of the present invention by solvolysis or under physiological conditions in vivo. A prodrug is a compound that is enzymatically oxidized, reduced, hydrolyzed, etc. under physiological conditions in vivo to be converted into a compound represented by formula (I), hydrolyzed by gastric acid, etc. The compound etc. which are converted into the compound shown are included. Methods for selecting and producing suitable prodrug derivatives are described, for example, in Design of Prodrugs, Elsevier, Amsterdam 1985. Prodrugs may themselves have activity.

When the compound represented by formula (I) or a pharmaceutically acceptable salt thereof has a hydroxyl group, for example, the compound having a hydroxyl group and a suitable acyl halide, a suitable acid anhydride, a suitable sulfonyl chloride, a suitable Examples thereof include prodrugs such as acyloxy derivatives and sulfonyloxy derivatives produced by reacting sulfonyl anhydride and mixed anhydride or reacting with a condensing agent. For example, CH ₃ COO—, C ₂ H ₅ COO—, tert-BuCOO—, C ₁₅ H ₃₁ COO—, PhCOO—, (m-NaOOCPh) COO—, NaOOCCH ₂ CH ₂ COO—, CH ₃ CH (NH ₂ ) COO—, CH ₂ N (CH ₃ ) ₂ COO—, CH ₃ SO ₃ —, CH ₃ CH ₂ SO ₃ —, CF ₃ SO ₃ —, CH ₂ FSO ₃ —, CF ₃ CH ₂ SO ₃ —, p -CH ₃ O-PhSO _3- , PhSO _3- , p-CH ₃ PhSO ₃ -can be mentioned.

The compound represented by the formula (I) according to the present invention can be produced, for example, by the general synthesis method shown below. Extraction, purification, and the like may be performed in a normal organic chemistry experiment.
The synthesis of the compound of the present invention can be carried out in consideration of techniques known in the art.

(1) Synthesis of compound A-1 (when L = SO ₂ , n = 0)

(Wherein LG is a leaving group such as halogen, p-toluenesulfonyl, alkylsulfonyl, etc., and other symbols are as defined above)
First Step: A thiol synthesized by a commercially available or known method in which a compound a1 synthesized by a commercially available or known method is mixed with a base such as sodium hydride in a solvent such as THF, NMP, or DMF, and 0 to 50 The compound a2 can be obtained by reacting at 0 ° C. for 1 hour to 48 hours, preferably 1 hour to 24 hours.
Second Step Compound a3 can be obtained by reacting compound a2 with an oxidizing agent such as metachloroperbenzoic acid at 0 ° C. to 30 ° C. for 1 hour to 48 hours, preferably 1 hour to 24 hours in a solvent such as dichloromethane.
Step 3 Compound a1 synthesized by a commercially available or known method in a solvent such as methanol, ethanol, THF or the like is substituted with a substituted sodium sulfinate synthesized by a commercially available or known method at 0 to 50 ° C. for 1 hour. The compound a3 can be obtained by reacting for ˜48 hours, preferably 1 hour to 24 hours.
Fourth Step In a solvent such as THF, NMP, DMF, etc., compound a3 is converted to 0 with alkyl halide, alkyl tosylate, alkyl mesylate, etc. in the presence of a base such as sodium hydride, potassium tert-butoxy, sodium hydroxide aqueous solution or the like. Compound a4 can be obtained by reacting at -80 ° C for 1 hour to 48 hours, preferably 1 hour to 24 hours.
When R ^3b and R ^4b together with the carbon atom to which they are attached form a substituted or unsubstituted non-aromatic carbocycle or substituted or unsubstituted non-aromatic heterocycle, a dihalogenated alkyl, What is necessary is just to make it react similarly using ditosylation alkyl, dimesylation alkyl, etc.
Step 5 Compound a4 can be reacted in a mixed solvent of methanol, ethanol, etc. with water in the presence of iron or ammonium chloride at 80-100 ° C. for 1 hour to 48 hours, preferably 1 hour to 24 hours. a5 can be obtained. Compound a4 is reacted in a solvent such as methanol or ethanol in the presence of palladium carbon or palladium hydroxide carbon in a hydrogen atmosphere at 0 ° C. to 30 ° C. for 1 hour to 48 hours, preferably 1 hour to 24 hours. It is also possible to obtain compound a5.
Step 6 In a solvent such as THF, NMP, DMSO, DMF, etc., compound a5 is mixed with a condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, HATU, N, N-diisopropylethylamine, In the presence of a base such as triethylamine, a carboxylic acid synthesized commercially or by a known method is added and reacted at 0 ° C. to 30 ° C. for 0.1 to 24 hours, preferably 0.1 to 6 hours. −1 can be obtained.
In a solvent such as dichloromethane, dichloroethane, or THF, pyridine, triethylamine, N-methylmorpholine, N, N-diisopropylethylamine, or the like is added to compound a5 as a base, and acid chloride or acid anhydride synthesized by a commercially available or known method The compound A-1 is also obtained by sequentially adding the acylating reagents of -20 ° C. to 50 ° C., preferably 0 ° C. to 20 ° C., and reacting for 0.1 to 6 hours, preferably 1 to 3 hours. be able to.
When the target compound is the compound A-1 in which n = 1 in the formula (I), the compound with n = 1 corresponding to the compound a4 synthesized by a commercially available or known method is prepared by the above-mentioned fifth step and step The target compound can be obtained by subjecting to the same reaction as in step 6.

(2) Synthesis of compound A-2 (when L is a single bond)

(Wherein each symbol has the same meaning as above)
Step 1 Compound a6 synthesized by a commercially available or known method in a mixed solvent of methanol, ethanol, and the like and water in the presence of iron and ammonium chloride at 80 to 100 ° C. for 1 to 48 hours, preferably 1 hour By reacting for ˜24 hours, compound a7 can be obtained. Compound a6 is reacted in a solvent such as methanol or ethanol in the presence of palladium carbon or palladium hydroxide carbon in a hydrogen atmosphere at 0 ° C. to 30 ° C. for 1 hour to 48 hours, preferably 1 hour to 24 hours. It is also possible to obtain compound a7.
Second Step In a solvent such as THF, NMP, DMSO, and DMF, compound a7 is mixed with a condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, HATU, N, N-diisopropylethylamine, In the presence of a base such as triethylamine, a carboxylic acid synthesized commercially or by a known method is added and reacted at 0 ° C. to 30 ° C. for 0.1 to 24 hours, preferably 0.1 to 6 hours. -2 can be obtained.
In a solvent such as dichloromethane, dichloroethane, or THF, pyridine, triethylamine, N-methylmorpholine, N, N-diisopropylethylamine, or the like is added to compound a7 as a base, and acid chloride or acid anhydride synthesized by a commercially available or known method The compound A-2 is also obtained by sequentially adding the acylating reagents of -20 ° C to 50 ° C, preferably 0 ° C to 20 ° C, and reacting for 0.1 to 6 hours, preferably 1 to 3 hours. be able to.

(3) Synthesis of compound A-3 (L = —NR ^1A CO—, where n = 0)

(Wherein each symbol has the same meaning as above)
First Step Compound a8 synthesized by a commercially available or known method in a solvent such as THF, NMP, DMF, etc. is converted into an alkyl halide, tosyl in the presence of a base such as sodium hydride, tert-butoxypotassium, sodium hydroxide aqueous solution or the like. Compound a9 can be obtained by reacting with alkyl halide, alkyl mesylate, etc. at 0 to 80 ° C. for 1 to 48 hours, preferably 1 to 24 hours.
When R ^3b and R ^4b together with the carbon atom to which they are attached form a substituted or unsubstituted non-aromatic carbocycle or substituted or unsubstituted non-aromatic heterocycle, a dihalogenated alkyl, What is necessary is just to make it react similarly using ditosylation alkyl, dimesylation alkyl, etc.
Second Step In a mixed solvent of methanol, ethanol, etc. and water, compound a9 is reacted in the presence of iron or ammonium chloride at 80-100 ° C. for 1 hour to 48 hours, preferably 1 hour to 24 hours, to give compound a10. Obtainable. Compound a9 is reacted in a solvent such as methanol or ethanol in the presence of palladium on carbon or palladium hydroxide on carbon in a hydrogen atmosphere at 0 ° C. to 30 ° C. for 1 hour to 48 hours, preferably 1 hour to 24 hours. It is also possible to obtain compound a10.
Third Step In a solvent such as THF, NMP, DMSO, and DMF, compound a10 is mixed with a condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, HATU, N, N-diisopropylethylamine, In the presence of a base such as triethylamine, a carboxylic acid synthesized commercially or by a known method is added and reacted at 0 ° C. to 30 ° C. for 0.1 to 24 hours, preferably 0.1 to 6 hours. Can be obtained.
In a solvent such as dichloromethane, dichloroethane, or THF, pyridine, triethylamine, N-methylmorpholine, N, N-diisopropylethylamine, or the like is added to compound a10 as a base, and acid chloride or acid anhydride synthesized by a commercially available or known method The compound a11 can also be obtained by sequentially adding the acylating reagent and reacting at −20 ° C. to 50 ° C., preferably 0 ° C. to 20 ° C. for 0.1 to 6 hours, preferably 1 to 3 hours. it can.
Step 4 Compound a12 can be obtained by reacting compound a11 with a basic aqueous solution. The reaction temperature is 0 ° C. to 40 ° C., preferably 0 ° C. to 20 ° C. The reaction time is 0.5 to 12 hours, preferably 1 to 6 hours. As the base, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide and the like can be used. Examples of the reaction solvent include methanol, ethanol, water, acetone, acetonitrile, THF and the like, and these can be used alone or in combination.
Fifth Step In a solvent such as THF, NMP, DMSO, and DMF, compound a12 is mixed with a condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, HATU, N, N-diisopropylethylamine, Compound A is prepared by adding a commercially available or publicly known amine compound in the presence of a base such as triethylamine and reacting at 0 ° C. to 30 ° C. for 0.1 to 24 hours, preferably 0.1 to 6 hours. -3 can be obtained.
A halide can be obtained by reacting compound a12 with a halogenating agent. Examples of the halogenating agent include thionyl chloride, phosphorus oxychloride, carbon tetrabromide-triphenylphosphine, and the like, and 1 to 5 molar equivalents can be used with respect to compound a12. The reaction temperature is −80 ° C. to 50 ° C., preferably −20 ° C. to 20 ° C. The reaction time is 0.1 to 24 hours, preferably 0.5 to 12 hours. As the reaction solvent, acetonitrile, THF, toluene, dichloromethane and the like can be used. Compound A-3 can also be obtained by reacting the resulting halide with an amine compound synthesized by a commercially available or known method in the presence of a base. Examples of the base include triethylamine, DIEA, potassium carbonate, sodium hydrogen carbonate, sodium hydride, sodium hydroxide and the like. The reaction temperature is 0 ° C. to 150 ° C., preferably 20 ° C. to 100 ° C. The reaction time is 0.5 to 120 hours, preferably 1 to 72 hours. Examples of the reaction solvent include acetonitrile, THF, toluene, dichloromethane and the like.

When the target compound is the compound A-3 where n = 1 in the formula (I), the compound where n = 1 corresponding to the compound a9 synthesized by a commercially available or known method is used as the second compound. The target compound can be obtained by subjecting it to the same reaction as in Step 5 to Step 5.

(4) Synthesis of Compound A-4 (when L = —CONR ^1B —)

(Wherein each symbol has the same meaning as above)
Step 1 Compound a13 synthesized in a solvent such as methanol, ethanol, THF, DMF or the like by a commercially available or known method is converted to an alkyl halide in the presence of a base such as triethylamine, N-methylmorpholine, N, N-diisopropylethylamine or the like. , Alkyl tosylate, alkyl mesylate and the like, and reacted at 0 to 80 ° C. for 1 hour to 48 hours, preferably 1 hour to 24 hours, to obtain compound a14.
When the target compound is R ^1B = H, the compound a13 may be subjected to the following second step without being subjected to this step.
Second Step In a mixed solvent of methanol, ethanol, etc. and water, compound a14 is reacted in the presence of iron or ammonium chloride at 80-100 ° C. for 1 hour to 48 hours, preferably 1 hour to 24 hours, to give compound a15. Obtainable. Compound a14 is reacted in a solvent such as methanol or ethanol in the presence of palladium carbon or palladium hydroxide carbon in a hydrogen atmosphere at 0 ° C. to 30 ° C. for 1 hour to 48 hours, preferably 1 hour to 24 hours. It is also possible to obtain compound a15.
Third Step In a solvent such as THF, NMP, DMSO, and DMF, compound a15 is mixed with a condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, HATU, N, N-diisopropylethylamine, In the presence of a base such as triethylamine, a carboxylic acid synthesized commercially or by a known method is added and reacted at 0 ° C. to 30 ° C. for 0.1 to 24 hours, preferably 0.1 to 6 hours, to thereby obtain compound a16. Can be obtained.
In a solvent such as dichloromethane, dichloroethane, or THF, pyridine, triethylamine, N-methylmorpholine, N, N-diisopropylethylamine, or the like is added to compound a15 as a base, and acid chloride or acid anhydride synthesized by a commercially available or known method The compound a16 can also be obtained by sequentially adding the acylating reagent and reacting at −20 ° C. to 50 ° C., preferably 0 ° C. to 20 ° C. for 0.1 to 6 hours, preferably 1 to 3 hours. it can.
Fourth Step Compound a17 can be obtained by reacting compound a16 with an acid or a Lewis acid. Examples of the acid include hydrochloric acid-ethyl acetate, hydrochloric acid-methanol, hydrochloric acid-dioxane, sulfuric acid, formic acid, trifluoroacetic acid and the like. Examples of the Lewis acid include trimethylsilyl iodide, BBr ₃ , AlCl ₃ , BF _3. (Et ₂ O), and the like, and 1 to 10 molar equivalents can be used with respect to the compound a16. The reaction temperature is 0 ° C. to 60 ° C., preferably 0 ° C. to 20 ° C. The reaction time is 0.5 to 12 hours, preferably 1 to 6 hours. Examples of the reaction solvent include methanol, ethanol, water, acetone, acetonitrile, DMF and the like, and these can be used alone or in combination.
Fifth Step In a solvent such as THF, NMP, DMSO, and DMF, compound a17 is mixed with a condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, HATU, N, N-diisopropylethylamine, In the presence of a base such as triethylamine, a carboxylic acid synthesized commercially or by a known method is added and reacted at 0 ° C. to 30 ° C. for 0.1 to 24 hours, preferably 0.1 to 6 hours. -4 can be obtained.
In a solvent such as dichloromethane, dichloroethane or THF, pyridine, triethylamine, N-methylmorpholine, N, N-diisopropylethylamine or the like is added as a base to compound a17, and acid chloride or acid anhydride synthesized by a commercially available or known method, etc. The compound A-4 can also be obtained by sequentially adding the acylating reagent and reacting at −20 ° C. to 50 ° C., preferably 0 ° C. to 20 ° C. for 0.1 to 6 hours, preferably 1 to 3 hours. be able to.

(5) Synthesis of compound A-5 (when L = —NR ^1F —)

(Wherein each symbol has the same meaning as above)
In a solvent such as methanol, ethanol, THF, DMF, etc., compound a18 obtained by the same method as in the above production method (4), Step 1 to Step 4, is converted to triethylamine, N-methylmorpholine, N, N-diisopropylethylamine, etc. In the presence of a base, the compound is reacted with a commercially available alkyl halide, tosylated alkyl, mesylated alkyl or the like synthesized by a known method at 0 to 80 ° C. for 1 to 48 hours, preferably 1 to 24 hours. 5 can be obtained.

(6) Synthesis of Compound A-6 (when L = —NR ^1E SO ₂ —, n = 0)

(In the formula, Pro is a protecting group, and other symbols are as defined above.)
First Step Amine compound having a protecting group bonded to a compound a19 synthesized by a commercially available or known method in a solvent such as acetonitrile, THF, toluene, dichloromethane, etc. in the presence of a base. Can be reacted to give compound a20. Examples of the base include triethylamine, DIEA, potassium carbonate, sodium hydrogen carbonate, sodium hydride, sodium hydroxide and the like. The reaction temperature is 0 ° C. to 150 ° C., preferably 20 ° C. to 100 ° C. The reaction time is 0.5 to 120 hours, preferably 1 to 72 hours.
Second Step In a solvent such as THF, NMP, DMF and the like, compound a20 is converted to 0 with alkyl halide, alkyl tosylate, alkyl mesylate, etc. in the presence of a base such as sodium hydride, potassium tert-butoxy, sodium hydroxide aqueous solution or the like. Compound a21 can be obtained by reacting at -80 ° C for 1 hour to 48 hours, preferably 1 hour to 24 hours.
When R ^3b and R ^4b together with the carbon atom to which they are attached form a substituted or unsubstituted non-aromatic carbocycle or substituted or unsubstituted non-aromatic heterocycle, a dihalogenated alkyl, What is necessary is just to make it react similarly using ditosylation alkyl, dimesylation alkyl, etc.

Third Step In a mixed solvent of methanol, ethanol, etc. and water, compound a21 is reacted in the presence of iron or ammonium chloride at 80-100 ° C. for 1 hour to 48 hours, preferably 1 hour to 24 hours to give compound a22. Obtainable. Compound a21 is reacted in a solvent such as methanol or ethanol in the presence of palladium carbon or palladium hydroxide carbon in a hydrogen atmosphere at 0 ° C. to 30 ° C. for 1 hour to 48 hours, preferably 1 hour to 24 hours. It is also possible to obtain compound a22.
Fourth Step In a solvent such as THF, NMP, DMSO, and DMF, compound a22 is mixed with a condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, HATU, N, N-diisopropylethylamine, In the presence of a base such as triethylamine, a carboxylic acid synthesized commercially or by a known method is added and reacted at 0 ° C. to 30 ° C. for 0.1 to 24 hours, preferably 0.1 to 6 hours. Can be obtained.
In a solvent such as dichloromethane, dichloroethane, or THF, pyridine, triethylamine, N-methylmorpholine, N, N-diisopropylethylamine or the like is added to compound a22 as a base, and acid chloride or acid anhydride synthesized by a commercially available or known method The compound a23 can also be obtained by sequentially adding the acylating reagent and reacting at −20 ° C. to 50 ° C., preferably 0 ° C. to 20 ° C. for 0.1 to 6 hours, preferably 1 to 3 hours. it can.
Step 5 The deprotection reaction can be carried out by selecting various conditions depending on the protecting group. For example, a benzyl group or a benzyloxycarbonyl group can be deprotected by catalytic reduction or the like. The tert-butyloxycarbonyl group can be deprotected by an ordinary method using an acid.
When R ^1E of the target compound is a group other than hydrogen, the compound obtained by deprotection is reacted with a halogenated alkyl, tosylated alkyl in the presence of a base in a solvent such as methanol, ethanol, THF, DMF, The target compound A-6 can be obtained by reacting with a mesylated alkyl or the like. Examples of the base include triethylamine, N-methylmorpholine, N, N-diisopropylethylamine and the like. The reaction temperature is 0 to 80 ° C., and the reaction time is 1 to 48 hours, preferably 1 to 24 hours.
When the target compound is compound A-6 where n = 1 in formula (I), the compound where n = 1 corresponding to compound a21 synthesized by a commercially available or known method is used in the third step. The target compound can be obtained by subjecting to the same reaction as in the fifth step.

(7) Synthesis of Compound A-7 (when L = —SO ₂ NR ^1E —)

(Wherein each symbol has the same meaning as above)
First Step In a solvent such as methanol, ethanol, THF, DMF, etc., compound a24 obtained by the same production method as intermediate a17 of the above production method (4) is converted to triethylamine, N-methylmorpholine, N, N-diisopropylethylamine, etc. The compound A-7 can be obtained by reacting with a sulfonyl chloride synthesized by a commercially available or known method at 0-80 ° C. for 1 hour to 48 hours, preferably 1 hour to 24 hours.

(8) Synthesis of compound A-9 (when L = —CO—)

(Wherein each symbol has the same meaning as above)
First Step Compound a28 can be obtained by reacting compound a11 obtained by the above production method (3) with a reducing agent. Examples of the reducing agent include sodium borohydride, lithium borohydride, lithium aluminum hydride and the like, and 1 to 10 molar equivalents can be used with respect to compound a11. The reaction temperature is 0 ° C. to reflux temperature, preferably 20 ° C. to reflux temperature. The reaction time is 0.2 to 48 hours, preferably 1 to 24 hours. Examples of the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, diethyl ether, dichloromethane, water and the like, and these can be used alone or in combination.
Second Step After reacting dimethyl sulfoxide with oxalyl chloride or trifluoroacetic anhydride, reacting with compound a28 and treating with amine, compound a29 can be obtained. The reaction temperature is -78 ° C to -15 ° C, preferably -78 ° C to -40 ° C. The reaction time is 0.1 to 4 hours, preferably 0.5 to 2 hours. Examples of the amine include trimethylamine, triethylamine, tripropylamine, and tributylamine. Examples of the reaction solvent include dichloromethane, THF, dioxane, benzene and the like. Alternatively, compound a29 can be obtained using Dess-Martin reagent as the oxidizing agent.
Step 3 Compound a30 can be obtained by reacting compound a29 with a nucleophile. Examples of nucleophilic agents include lithium reagents such as methyl lithium and ethyl lithium, Grignard reagents such as methyl magnesium bromide, methyl magnesium chloride, methyl magnesium iodide, ethyl magnesium bromide, ethyl magnesium chloride, and ethyl magnesium iodide, and metal salts thereof. And can be used in an amount of 1 to 5 molar equivalents relative to compound a29. The reaction temperature is -78 ° C to the reflux temperature of the solvent, preferably -45 ° C to 0 ° C. The reaction time is 0.5 to 24 hours, preferably 1 to 6 hours. Examples of the reaction solvent include tetrahydrofuran, hexane, diethyl ether, methyl tert-butyl ether, toluene, dichloromethane and the like, and these can be used alone or in combination.
Fourth Step After reacting dimethyl sulfoxide with oxalyl chloride or trifluoroacetic anhydride, reacting with compound a30 and treating with amine, compound A-9 can be obtained. The reaction temperature is -78 ° C to -15 ° C, preferably -78 ° C to -40 ° C. The reaction time is 0.1 to 4 hours, preferably 0.5 to 2 hours. Examples of the amine include trimethylamine, triethylamine, tripropylamine, and tributylamine. Examples of the reaction solvent include dichloromethane, THF, dioxane, benzene and the like. Alternatively, Compound A-9 can also be obtained using Dess-Martin reagent as the oxidizing agent.

Since the compound according to the present invention has RORγt inhibitory action, it is useful as a therapeutic and / or prophylactic agent for immune-related diseases such as autoimmune diseases and allergic diseases. Preferably, it is useful as a therapeutic agent and / or preventive agent for autoimmune diseases. For example, an RORγt inhibitor having an IC50 of 10 μM or less in the human RORγt reporter assay described below is desirable.
Examples of autoimmune diseases include inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, psoriasis, Sjogren's syndrome, systemic lupus erythematosus, scleroderma, thrombocytopenia, myasthenia gravis, ulcerative colitis, Crohn's disease , Graves' disease, polymyositis, type 1 diabetes, asthma, uveitis and the like.

The compound of the present invention has not only an RORγt inhibitory action but also a usefulness as a pharmaceutical, and has any or all of the following excellent characteristics.
a) The inhibitory effect on CYP enzymes (for example, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.) is weak.
b) Good pharmacokinetics such as high bioavailability and moderate clearance.
c) High metabolic stability.
d) Does not show irreversible inhibitory action on CYP enzymes (eg CYP3A4) within the concentration range of the measurement conditions described herein.
e) Not mutagenic.
f) Low cardiovascular risk.
g) High solubility.
h) High RORγt selectivity.

When a pharmaceutical composition containing the compound of the present invention is administered, it can be administered either orally or parenterally. Examples of parenteral administration include transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, eye drop, ear drop, and intravaginal administration.
In the case of oral administration, in accordance with conventional methods, solid preparations for internal use (eg, tablets, powders, granules, capsules, pills, films, etc.), liquids for internal use (eg, suspensions, emulsions, elixirs, Syrups, limonades, spirits, fragrances, extracts, decoctions, tinctures, etc.) may be prepared and administered. Here, the tablet may be a sugar-coated tablet, a film-coated tablet, an enteric-coated tablet, a sustained-release tablet, a troche tablet, a sublingual tablet, a buccal tablet, a chewable tablet or an orally disintegrating tablet, and the powder and granules are dry syrup. The capsule may be a soft capsule, a microcapsule or a sustained release capsule.
For parenteral administration, injections, drops, external preparations (eg eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, injections, coatings, mouthwashes, enemas, Any commonly used dosage form such as an ointment, a plaster, a jelly, a cream, a patch, a patch, a powder for external use, a suppository and the like can be suitably administered. Here, the injection may be an emulsion of O / W, W / O, O / W / O, W / O / W type and the like.
Various pharmaceutical additives such as excipients, binders, disintegrants, lubricants and the like suitable for the dosage form can be mixed with the effective amount of the compound of the present invention as necessary to obtain a pharmaceutical composition. Furthermore, the pharmaceutical composition can be obtained by appropriately changing the effective amount, dosage form, and / or various pharmaceutical additives of the compound of the present invention, so that You can also The pediatric pharmaceutical composition is preferably administered to a patient under the age of 12 or 15 years. In addition, the pediatric pharmaceutical composition can be administered to patients less than 27 days after birth, 28 to 23 months after birth, 2 to 11 years old, or 12 to 16 years old or 18 years old. The elderly pharmaceutical composition is preferably administered to a patient over 65 years of age.

The dose of the compound of the present invention is preferably set in consideration of the patient's age, body weight, type and degree of disease, route of administration, etc., but usually 0.05 to 100 mg / kg / day when administered orally. Preferably, it is within the range of 0.1 to 10 mg / kg / day. In the case of parenteral administration, although it varies greatly depending on the administration route, it is usually 0.005 to 10 mg / kg / day, preferably 0.01 to 1 mg / kg / day. This may be administered once to several times a day.
The compound of the present invention may be used in combination with an immunosuppressant, a steroid agent, a cytokine inhibitor, etc. (hereinafter abbreviated as a concomitant drug) for the purpose of enhancing the action of the compound or reducing the dose of the compound. it can. In this case, the administration time 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. Furthermore, the compound of the present invention and the concomitant drug may be administered as two types of preparations containing each active ingredient, or may be administered as a single preparation containing both active ingredients.
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 used in an amount of 0.01 to 100 parts by weight per 1 part by weight of the compound of the present invention.
Specific examples of the immunosuppressive agent include tacrolimus, cyclosporine, cyclophosphamide, methotrexate and the like.
Specific examples of the steroid include dexamethasone, betamethasone, prednisolone, hydrocortisone and the like.
Cytokine inhibitors include anti-cytokine antibodies, cytokine receptor antagonists, soluble cytokine receptors, MAP kinase inhibitors, cytokine production inhibitors, TASE inhibitors, ICE inhibitors, cytokine gene transcription factor decoys, siRNA, antisense, etc. Specific examples thereof include etanalcept, infliximab, adalimumab, anakinra, tocilizumab, ustekimab and the like.

EXAMPLES The present invention will be described in more detail below with reference to examples and test examples of the present invention, but the present invention is not limited thereto.
Moreover, the abbreviation used in this specification represents the following meaning.
DIEA: N, N-diisopropylethylamine DMSO: dimethyl sulfoxide DMF: dimethylformamide THF: tetrahydrofuran NMP: N-methyl-2-pyrrolidone HATU: 2- (7-azabenzotriazol-1-yl) -1, hexafluorophosphate, 1,3,3-tetramethyluronium M: mol / L

The NMR analysis obtained in each example was performed at 300 MHz or 400 MHz and measured using DMSO-d ₆ or CDCl ₃ . In the examples, RT represents a retention time in LC / MS: liquid chromatography / mass spectrometry, and was measured under the following conditions.
Measurement conditions 1: Column: Shim-pack XR-ODS (2.2 μm, id 50 × 3.0 mm) (Shimadzu)
Flow rate: 1.6 mL / min UV detection wavelength: 254 nm
Mobile phase: [A] is a 0.1% formic acid-containing aqueous solution, [B] is a 0.1% formic acid-containing acetonitrile solution. Gradient: Linear gradient of 10% -100% solvent [B] in 3 minutes. 100% solvent [B] was maintained for 5 minutes.
Measurement condition 2: Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm id 2.1 × 50 mm) (Waters)
Flow rate: 0.55 mL / min UV detection wavelength: 254 nm
Mobile phase: [A] is a 0.1% formic acid-containing aqueous solution, [B] is a 0.1% formic acid-containing acetonitrile solution for 3 minutes, and a linear gradient of 5% -100% solvent [B] is performed. 100% solvent [B] was maintained for minutes.
Measurement condition 3: Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm id 2.1 × 50 mm) (Waters)
Flow rate: 0.8 mL / min UV detection wavelength: 254 nm
Mobile phase: [A] is a 0.1% formic acid-containing aqueous solution, [B] is a 0.1% formic acid-containing acetonitrile solution for 3.5 minutes and linear gradient of 5% -100% solvent [B] is performed. Maintained 100% solvent [B] for 5 minutes.
Measurement condition 4: Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm id 2.1 × 50 mm) (Waters)
Flow rate: 0.8 mL / min UV detection wavelength: 254 nm
Mobile phase: [A] is a 10 mM ammonium carbonate-containing aqueous solution, [B] is a linear gradient of 5% -100% solvent [B] in acetonitrile 3.5 minutes, and then 100% solvent [B ] Was maintained.

Example 1 Synthesis of Compound 3 First Step Synthesis of Compound (2)

4-Fluorobenzenethiol (compound (1), 5 mL, 46.9 mmol) is dissolved in NMP (50 mL), sodium hydride (w / w 60%, 1.9 g, 47.5 mmol) is added, and the mixture is stirred at room temperature for 10 minutes. 1- (Bromomethyl) -4-nitrobenzene (10 g, 46.3 mmol) was added, and the mixture was stirred at room temperature for 3 hours and then allowed to stand overnight at room temperature. Ethyl acetate (300 mL), 2M aqueous sodium hydroxide solution (300 mL) were added, and the organic layer was washed with water and saturated brine, dried over magnesium sulfate, and washed with silica gel chromatography to obtain compound (2) (11.3). g, yield 92.6%).
¹ H-NMR (CDCl ₃ ) δ: 8.10 (d, 2H), 7.31 (d, 2H), 7.23-7.28 (m, 2H), 7.00-6.92 (t, 2H), 4.06 (s, 2H).
Step 2 Synthesis of Compound (3)

Compound (2) (10 g, 38 mmol) was dissolved in dichloromethane (100 mL), metachloroperbenzoic acid (22.9 g, 95 mmol) was slowly added under ice-cooling, and the mixture was warmed to room temperature and stirred for 3 hours. Ice-cooled, dimethyl sulfoxide (10 mL) was added, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate (500 mL), 2M aqueous sodium hydroxide solution (300 mL) were added, and the organic layer was 2M aqueous hydrochloric acid (300 mL), saturated brine. The product was washed with water, dried over magnesium sulfate, and purified by silica gel chromatography to obtain compound (3) (9.3 g, yield 82.7%).
LCMS (ESI): m / z = 294.2 [MH] ^- , RT = 1.83 min
¹ H-NMR (CDCl ₃ ) δ: 8.17 (d, 2H), 7.69 (dd, 3H), 7.32 (d, 2H), 7.18 (t, 2H), 4.40 (s, 2H).
Step 3 Synthesis of Compound (4)

Compound (3) (9 g, 31 mmol), tetrabutylammonium bromide (0.5 g, 0.05 mmol), 1,2-dibromoethane (3.2 mL, 37 mmol) were dissolved in dichloromethane (100 mL), and 50% water An aqueous sodium oxide solution (100 mL) was added and the mixture was stirred at 35 ° C. for 6 hours. 1,2-Dibromoethane (3.2 mL, 37 mmol) was added, and the mixture was stirred at 30 ° C. overnight. Dichloromethane and water were added, and the organic layer was washed with saturated brine, dried over magnesium sulfate, and purified by silica gel chromatography to obtain compound (4) (7.9 g, yield 80.7%).
LCMS (ESI): m / z = 322.26 [M + H] ⁺ , RT = 2.05 min
Step 4 Synthesis of Compound (5)

Compound (4) (5 g, 16 mmol) was added to methanol (50 mL) and stirred, and 10% palladium hydroxide / carbon (0.5 g) was added. The reaction vessel was purged with hydrogen and stirred at room temperature for 1 hour. Palladium was filtered through Celite, and the filtrate was concentrated and purified by silica gel chromatography to obtain compound (5) (3.6 g, yield 78.5%).
LCMS (ESI): m / z = 292.11 [M + H] ⁺ , RT = 1.50 min
Step 5 Synthesis of Compound 3

Compound (5) (1.5 g, 5.3 mmol), 2- (4- (ethylsulfonyl) phenyl) acetic acid (1.0 g, 4.4 mmol) and HATU (2.0 g, 5.3 mmol) were added to DMF (10 mL) and stirred. , N, N-diisopropylethylamine (2.3 mL, 13 mmol) was added. Stir at room temperature for 1 hour and let stand overnight. Ethyl acetate (200 mL) and water (200 mL) were added, and the organic layer was washed with saturated brine, dried over magnesium sulfate, and purified by silica gel chromatography to obtain compound 3 (730 mg, yield 33.2%). Obtained.
¹ H-NMR (CDCl ₃ ) δ: 7.91 (d, 2H), 7.55 (d, 2H), 7.48 (m, 2H), 7.35 (d, 2H), 7.10-7.05 (m, 4H), 3.80 (s , 2H), 3.13 (q, 2H), 1.93 (m, 2H), 1.30 (t, 3H), 1.23 (m, 2H).

Example 2 Synthesis of Compound 5

Compound (3) (1.0 g, 3.4 mmol) and tert-butoxypotassium (1.1 g, 10.2 mmol) were added to THF (10 mL) and stirred, and iodomethane (0.52 mL, 8.5 mmol) was added and stirred at room temperature for 1 hour. . To complete the reaction, potassium tert-butoxy (1.1 g, 10.2 mmol) and iodomethane (0.52 mL, 8.5 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate (50 mL) and water (50 mL) were added to the reaction solution, and the organic layer was washed with saturated brine, dried over magnesium sulfate, and purified by silica gel chromatography to obtain compound (6) (840 mg, yield). Rate 76.4%).
¹ H-NMR (CDCl ₃ ) δ: 8.15 (d, 2H), 7.58 (d, 2H), 7.44 (dd, 2H), 7.08 (t, 2H), 1.88 (s, 6H).
Compound 5 was obtained from compound (6) in the same manner as in Step 4 and Step 5 of Example 1.
¹ H-NMR (CDCl ₃ ) δ: 7.89 (d, 2H), 7.54 (d, 2H), 7.48 (s, 1H), 7.43-7.40 (m, 4H), 7.30 (d, 2H), 7.03 (t , 2H), 3.80 (s, 2H), 3.13 (q, 2H), 1.77 (s, 6H), 1.28 (t, 3H).

Example 3 Synthesis of Compound 2

Sodium hydride (60 w / w%, 100 mg, 0.2 mmol) was added to methanol (500 μl), stirred for 10 minutes, and compound 5 (100 mg, 0.2 mmol) dissolved in 0.5 mL of DMF was added. The mixture was stirred at room temperature for 3 hours, dichloromethane and water were added, the organic layer was washed with saturated brine, dried over magnesium sulfate, and purified by silica gel chromatography to give compound 2 (33 mg, yield 32.0%). .
¹ H-NMR (CDCl ₃ ) δ: 7.89 (d, 2H), 7.54 (t, 2H), 7.46 (s, 1H), 7.41 (d, 2H), 7.33 (t, 4H), 6.82 (d, 2H ), 3.84 (s, 3H), 3.79 (s, 2H), 3.12 (q, 2H), 1.76 (s, 6H), 1.31-1.24 (t, 3H).

Example 4 Synthesis of Compound 9 First Step Synthesis of Compound (7)

Compound (3) (200 mg, 0.68 mmol) and tert-butoxypotassium (190 mg, 1.7 mmol) are dissolved in THF (2 mL), and 1,5-diiodopentane (0.15 mL, 1.0 mmol) is added thereto. Stir for 1 hour at ° C. Ethyl acetate and water were added, and the organic layer was washed with saturated brine, dried over magnesium sulfate, and purified by silica gel chromatography to obtain compound (7) (88 mg, yield 35.6%).
¹ H-NMR (CDCl ₃ ) δ: 8.15 (d, 2H), 7.45 (d, 2H), 7.34 (t, 2H), 7.05 (t, 2H), 2.60 (d, 2H), 2.25 (t, 2H ), 1.79 (d, 2H), 1.62 (d, 1H), 1.39-1.26 (m, 1H), 1.13 (q, 2H).
Step 2 Synthesis of Compound (8)

Compound (7) (86 mg, 0.24 mmol) was added to methanol (1 mL) and stirred, and 10% palladium / carbon (10 mg) was added. The reaction vessel was purged with hydrogen and stirred at room temperature for 3 hours. The palladium was filtered through Celite, and the filtrate was concentrated to dryness to obtain a concentrated residue containing compound (8). The residue was used in the next reaction without further purification.
Step 3 Synthesis of Compound 9

The above residue (30 mg), 2- (4- (ethylsulfonyl) phenyl) acetic acid (21 mg, 0.09 mmol) and HATU (41 mg, 0.11 mmol) were added to DMF (0.5 mL) and stirred, and N, N- Diisopropylethylamine (0.05 mL, 0.27 mmol) was added. Stir at room temperature for 1 hour. Dichloromethane and water were added, and the organic layer was concentrated and purified by silica gel chromatography to obtain Compound 9 (3 mg, yield of the second to third steps: 2.3%).

Example 5 Synthesis of Compound 6

Compound (3) (100 mg, 0.34 mmol) was added to THF (1 mL) and stirred, sodium hydride (w / w 60%, 15 mg, 0.37 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. The mixture was ice-cooled again, iodomethane (0.023 mL, 0.38 mmol) was added, and the mixture was stirred at room temperature for 1 hr. Chloroform and saturated aqueous ammonium chloride solution were added to the reaction solution, and the organic layer was concentrated. Purification by silica gel chromatography gave compound (9) (64 mg, yield 60.9%).
LCMS (ESI): m / z = 308.11 [MH] ^- , RT = 1.95 min
Compound 6 was obtained from Compound (9) in the same manner as in Step 4 and Step 5 of Example 1.
¹ H-NMR (CDCl ₃ ) δ: 7.92 (d, 2H), 7.58-7.54 (m, 4H), 7.40 (2H, d), 7.23 (s, 1H), 7.11-7.07 (m, 4H), 4.19 (q, 1H), 3.81 (s, 2H), 3.12 (q, 2H), 1.73 (d, 3H), 1.30 (t, 3H).

Example 6 Synthesis of Compound 1 First Step Synthesis of Compound (10)

Sodium hydride (w / w 60%, 15 mg, 0.37 mmol) was added to dimethylformamide (0.2 mL) and stirred, and 4-chlorophenylthiol (45 mg, 0.31 mmol) was added and stirred for 10 minutes. To this solution was added a DMF (0.5 mL) solution of compound (6) (100 mg, 0.31 mmol), and the mixture was stirred at room temperature for 1 hour, further heated up and stirred at 40 ° C. for 2 hours. The mixture was cooled to room temperature and washed with ethyl acetate and water. The obtained organic layer was concentrated to dryness to obtain a concentrated residue containing compound (10). The residue was used for the next reaction without purification.
Step 2 Synthesis of Compound (11)

Ethanol (1 mL) was added to the residue and stirred to make a suspension, and half of the residue was transferred to a microwave tube. Ammonium chloride (50 mg) aqueous solution (0.5 mL) and iron (50 mg, 0.9 mmol) were added and sealed, followed by stirring at 80 ° C. for 1 hour. After cooling to room temperature, dichloromethane and water were added, and the organic layer was concentrated to dryness. The crude product was purified by silica gel chromatography to obtain a crude product (11) (6 mg, yield of the first and second steps 7.0%). Used in the next reaction without further purification.
LCMS (ESI): m / z = 278.13 [M + H] ⁺ , RT = 2.07 min
Step 3 Synthesis of Compound (12)

Compound (11) (2 mg, 0.007 mmol), 2- (4- (ethylsulfonyl) phenyl) acetic acid (10 mg, 0.04 mmol) and HATU (20 mg, 0.05 mmol) were added to DMF (0.5 mL) and stirred. , N, N-diisopropylethylamine (23 μL, 0.131 mmol) was added. The mixture was stirred at room temperature for 30 minutes, washed with dichloromethane and water. The obtained organic layer was concentrated and dried to obtain a concentrated residue containing the compound (12). The residue was used for the next reaction without purification.
Step 4 Synthesis of Compound 1

Dichloromethane (1 mL) was added to the above concentrated residue, metachloroperbenzoic acid (20 mg, 0.12 mmol) was added under ice-cooling, the mixture was returned to room temperature, stirred for 1 hour, and allowed to stand overnight at room temperature. DMSO (0.1 mL) was added, and the mixture was stirred at room temperature for 30 minutes, and washed with dichloromethane and water. Purification by silica gel chromatography gave Compound 1 (6 mg, 32.4th step yield 52.4%).
¹ H-NMR (CDCl ₃ ) δ: 7.92 (d, 2H), 7.56 (d, 2H), 7.42 (d, 2H), 7.25-7.29 (m, 6H), 3.82 (s, 2H), 3.13 (q , 2H), 1.77 (s, 6H), 1.30 (t, 3H).

Example 7 Synthesis Step 1 of Compound 11 Synthesis of Compound (13)

1- (Bromomethyl) -4-nitrobenzene (compound (1), 500 mg, 2.3 mmol) is dissolved in ethanol (5 mL), sodium ethanesulfinate (269 mg, 2.3 mmol) is added, and the mixture is sealed and room temperature is 100 ° C. For 2 hours and then cooled to room temperature. After concentration, the precipitated white solid was collected by filtration using ethyl acetate and hexane to obtain Compound (13) (374 mg, yield 70.9%).
LCMS (ESI): m / z = 230.11 [M + H] ⁺ , RT = 1.23 min
Second Step Synthesis of Compound 11

Compound (13) (100 mg, 0.44 mmol) and tert-butoxypotassium (108 mg, 0.96 mmol) were added to THF (1 mL) and stirred, and iodomethane (41 μL, 0.65 mmol) was added and stirred at room temperature for 1 hour. . To complete the reaction, iodomethane (41 μL, 0.65 mmol) was added and stirred at room temperature for 1 hour. Chloroform and water were added to the reaction solution, the organic layer was concentrated, and the resulting residue was purified by silica gel chromatography to obtain compound (14) (51 mg, yield 45.0%).
¹ H-NMR (CDCl ₃ ) δ: 8.25 (d, 2H), 7.85 (d, 2H), 2.69 (q, 2H), 1.25 (t, 3H).
Compound 11 was obtained from compound (14) in the same manner as in Step 4 and Step 5 of Example 1.
¹ H-NMR (CDCl ₃ ) δ: 7.91 (d, 2H), 7.59-7.55 (m, 4H), 7.51 (d, 2H), 3.82 (s, 2H), 3.13 (q, 2H), 2.63 (q , 2H), 1.83 (s, 6H), 1.30 (t, 3H), 1.19 (t, 3H).

Example 8 Synthesis Step 1 of Compound 28 Synthesis of Compound (16)

Compound (15) (200 mg, 1.04 mmol), 2- (4- (ethylsulfonyl) phenyl) acetic acid (248 mg, 1.09 mmol) and HATU (512 mg, 1.35 mmol) were added to DMF (2 mL) and stirred. , Triethylamine (359 μL, 2.59 mmol) was added. The mixture was stirred at room temperature for 1 hour, treated with saturated aqueous ammonium chloride, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated. The concentrated residue was purified by silica gel chromatography to obtain compound (16) (418 mg).
¹ H-NMR (CDCl ₃ ) δ: 7.90 (d, 2H), 7.55 (d, 2H), 7.42 (d, 2H), 7.29 (d, 2H), 7.16 (s, 1H), 3.80 (s, 2H ), 3.63 (s, 3H), 3.12 (q, 2H), 1.29 (t, 3H).
Step 2 Synthesis of Compound (17)

Compound (16) (418 mg, 1.04 mmol) is dissolved in a mixture of THF (2 mL) and methanol (1 mL), 2M aqueous sodium hydroxide solution (0.62 mL, 1.24 mmol) is added, and the mixture is stirred at room temperature for 21 hours. The mixture was further stirred at 50 ° C. for 2 hours. The mixture was neutralized with 2M aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The concentrated residue was purified by silica gel chromatography to obtain compound (17) (317 mg, yield 78.6%).
Step 3 Synthesis of Compound 28

Compound (17) (20 mg, 0.051 mmol), 4-fluoroaniline (11.4 mg, 0.103 mmol) and HATU (29.3 mg, 0.077 mmol) were added to DMF (200 μL) and stirred, and triethylamine (14.2 μL, 0.103 mmol). ) Was added. The mixture was stirred at room temperature for 1 hour, treated with saturated aqueous ammonium chloride, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated. The concentrated residue was purified by silica gel chromatography to give compound 28 (25 mg).
¹ H-NMR (CDCl ₃ ) δ: 8.10 (s, 1H), 7.80 (d, 2H), 7.48 (t, 4H), 7.35-7.28 (m, 4H), 6.98 (s, 1H), 6.92 (t , 2H), 3.74 (s, 2H), 3.10 (t, 2H), 1.62 (s, 6H), 1.26 (t, 3H).

Example 9 Synthesis of Compound 78

Compound (18) (500 mg, 2.07 mmol) was added to ethyl acetate (15 mL) and stirred, and 10% palladium / carbon (466 mg) was added. The reaction vessel was purged with hydrogen and stirred at room temperature for 30 minutes. The palladium was filtered through Celite, and the filtrate was concentrated to dryness to obtain a concentrated residue containing the compound (19).
From the residue, Compound 78 was obtained in the same manner as in First Step, Second Step and Third Step of Example 8.
¹ H-NMR (CDCl ₃ ) δ: 7.88 (d, 2H), 7.65-7.58 (m, 1H), 7.51 (d, 2H), 7.44-7.38 (m, 1H), 7.38-7.30 (m, 3H) , 7.22-7.16 (m, 1H), 7.00-6.92 (m, 3H), 3.78 (s, 2H), 3.13 (q, 2H), 1.63 (s, 6H), 1.29 (t, 3H).

Example 10 Synthesis Step 1 of Compound 113 Synthesis of Compound (21)

Sodium hydride (917 mg, 22.9 mmol) was added to DMF (10 mL), and diethyl methylmalonate (3.0 mL, 22.9 mmol) dissolved in DMF (10 mL) was added to the suspension. After stirring at 0 ° C. for 30 minutes, a DMF solution of compound (20) (2.0 g, 10.4 mmol) was added and stirred at 70 ° C. for 2 hours. The mixture was treated with saturated aqueous ammonia chloride and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The concentrated residue was purified by silica gel chromatography to obtain compound (21) (1.65 g, yield 48.0%).
LCMS (ESI): m / z = 330 [M + H] ⁺ , RT = 2.37 min
¹ H-NMR (CDCl ₃ ) δ: 8.27 (d, 1H), 8.11 (dd, 1H), 7.42 (d, 1H), 4.28 (ddt, 4H), 1.94 (s, 3H), 1.29-1.24 (m , 6H).
Step 2 Synthesis of Compound (22)

Compound (21) (1.65 g, 5.00 mmol) was dissolved in acetic acid (17 mL), concentrated sulfuric acid (4 mL, 75 mmol) diluted with water (6.3 mL) was added, and the mixture was stirred at 100 ° C. for 5 hr. After treating with water, extraction was performed with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated to obtain compound (22) (1.1 g, yield 95.7%). .
¹ H-NMR (CDCl ₃ ) δ: 8.28 (t, 1H), 8.13 (dd, 1H), 7.56 (d, 1H), 4.33 (t, 1H), 1.59 (d, 3H).
Step 3 Synthesis of Compound (23)

Compound (22) (1.1 g, 4.79 mmol) was dissolved in methanol (10 mL), concentrated sulfuric acid (0.077 mL, 1.44 mmol) was added, and the mixture was heated to reflux for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The concentrated residue was purified by silica gel chromatography to obtain compound (23) (1.05 g, yield 90.0%).
¹ H-NMR (CDCl ₃ ) δ: 8.27 (d, 1H), 8.12 (dd, 1H), 7.53 (d, 1H), 4.27 (td, 1H), 3.71 (s, 3H), 1.55 (d, 3H ).
Step 4: Synthesis of Compound 113

Compound (23) (1.05 g, 4.31 mmol) was dissolved in a mixture of DMF (2 mL) and THF (20 mL), tert-butoxypotassium (580 mg, 5.17 mmol) and iodomethane (0.323 mL, 5.17 mmol). And stirred at 50 ° C. for 2 hours. A 1M aqueous hydrochloric acid solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The concentrated residue was purified by silica gel chromatography to obtain compound (24) (1.05 g, yield 94.6%).
¹ H-NMR (CDCl ₃ ) δ: 8.24 (d, 1H), 8.15-8.13 (m, 1H), 7.61 (d, 1H), 3.69 (s, 3H), 1.65 (d, 6H).
Compound 113 was obtained from compound (24) in the same manner as in Step 1 of Example 9 and Steps 1, 2 and 3 of Example 8.
¹ H-NMR (CDCl ₃ ) δ: 7.91-7.85 (m, 2H), 7.59-7.55 (m, 1H), 7.55-7.49 (m, 2H), 7.48-7.45 (m, 2H), 7.35-7.29 ( m, 2H), 7.00-6.93 (m, 2H), 6.91-6.84 (m, 1H), 3.81-3.76 (m, 2H), 3.13 (q, 2H), 1.68 (s, 6H), 1.30 (t, 3H).

Example 11 Synthesis Step 1 of Compound 395 Synthesis of Compound (26)

Compound (25) (300 mg, 1.43 mmol) was added to methylene chloride (3 mL) and stirred, oxalyl chloride (151 μL, 1.72 mmol) and DMF (11.2 μL, 0.143 mmol) were added, and the mixture was stirred at room temperature for 3 hours. . Subsequently, 4-fluoroaniline (239 mg, 2.15 mmol) and pyridine (579 μL, 7.17 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The mixture was treated with saturated aqueous ammonia chloride and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The concentrated residue was purified by silica gel chromatography to obtain compound (26) (400 mg, yield 92.3%).
LCMS (ESI): m / z = 303.15 [M + H] ⁺ , RT = 2.06 min
Step 2 Synthesis of Compound (27)

Compound (26) (20 mg, 0.066 mmol) was added to ethyl acetate (1 mL) and stirred, and 10% palladium / carbon (14.9 mg, 0.066 mmol) was added. The reaction vessel was purged with hydrogen and stirred at room temperature for 30 minutes. The palladium was filtered through Celite, and the filtrate was concentrated to dryness to obtain a concentrated residue containing compound (27).
Step 3 Synthesis of Compound (29)

1-tert-butyl 3-ethyl malonate (151 μL, 0.80 mmol) and tert-butoxypotassium (108 mg, 0.96 mmol) were added to dioxane (1 mL), and the mixture was stirred at room temperature for 3 minutes. Subsequently, compound (28) (100 mg, 0.40 mmol) and [1, 1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (1: 1) (5.85 mg, 0.008 mmol) were added. , And stirred at 70 ° C. for 6 hours. After treatment with saturated aqueous ammonia chloride, extraction with ethyl acetate is performed, and the organic layer is washed with water and saturated brine, dried over magnesium sulfate, and concentrated to dryness to obtain a concentrated residue containing compound (29). It was.
¹ H-NMR (CDCl ₃ ) δ: 9.04 (d, 1H), 8.20 (dd, 1H), 7.74 (d, 1H), 4.96 (s, 1H), 4.31-4.22 (m, 2H), 3.16 (q , 2H), 1.48 (s, 9H), 1.33 (t, 3H), 1.30 (t, 3H).
Step 4 Synthesis of Compound (30)

The concentrated residue containing the compound (29) was dissolved in methylene chloride (1.5 mL), trifluoroacetic acid (1.6 mL, 20.8 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated to dryness and purified by silica gel chromatography to obtain compound (30).
¹ H-NMR (CDCl ₃ ) δ: 9.04 (d, 1H), 8.16 (dd, 1H), 7.54 (d, 1H), 4.21 (q, 2H), 3.97 (s, 2H), 3.16 (q, 2H ), 1.33 (t, 3H), 1.28 (t, 3H).
Step 5: Synthesis of compound (31)

Compound (30) (22.1 mg, 0.086 mmol) is dissolved in a mixture of THF (0.1 mL) and methanol (0.1 mL), 4M aqueous lithium hydroxide solution (24.8 μL, 0.10 mmol) is added, and the mixture is stirred at room temperature for 3 hours. did. The reaction solution was concentrated to dryness to obtain a concentrated residue containing compound (31).
Step 6 Synthesis of Compound 395

The concentrated residue containing Compound (31) and the concentrated residue containing Compound (27), HATU (37.7 mg, 0.099 mmol) were added to DMF (1 mL) and stirred, and triethylamine (18.3 μL, 0.132 mmol) was added. added. The mixture was stirred at room temperature for 1 hour, treated with saturated aqueous ammonium chloride, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated. The concentrated residue was purified by silica gel chromatography to give compound 395 (29.5 mg).
¹ H-NMR (CDCl ₃ ) δ: 9.18 (s, 1H), 9.11 (s, 1H), 8.20 (d, 1H), 7.60-7.54 (m, 3H), 7.43-7.37 (m, 2H), 7.32 -7.27 (m, 1H), 6.94 (t, 2H), 6.74 (s, 1H), 4.01 (s, 2H), 3.18 (q, 2H), 1.64 (6H, s), 1.34 (t, 3H).

Example 12 Synthesis of Compound 466 First Step Synthesis of Compound (32)

Diethylmalonate (34.3 mL, 226 mmol) was gradually added to a DMF (300 mL) suspension of sodium hydride (9 g, 226 mmol) in a nitrogen atmosphere, and the mixture was stirred at 0 ° C. for 1 hour. Subsequently, compound (31) (20 g, 113 mmol) was added, and the mixture was stirred at 0 ° C. for 1 hour and then at room temperature for 2 hours. A 2M aqueous hydrochloric acid solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated to give compound (32) (56.3 g).
LCMS: m / z = 318 [M + H] ⁺
Step 2 Synthesis of Compound (33)

Compound (32) (56.1 g, 177 mmol) was dissolved in acetic acid (400 mL), concentrated sulfuric acid (140 mL) diluted with water (220 mL) was added, and the mixture was stirred at 100 ° C. for 4 hr. After treating with water, extraction with ethyl acetate was performed, and the organic layer was washed with water and saturated brine, dried over sodium sulfate, concentrated and then solidified by adding hexane to give compound (33) (17.7 g, yield). 2 steps 46.1%).
LCMS: m / z = 218.1 [M + H] ⁺
Step 3 Synthesis of Compound (34)

Compound (33) (38.9 g, 179 mmol) was dissolved in methanol (400 mL), concentrated sulfuric acid (5 mL) was added, and the mixture was heated to reflux for 16 hours. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated to obtain compound (34) (38.2 g, yield 92.2%).
LCMS: m / z = 232 [M + H] ⁺
Step 4: Synthesis of compound (35)

Compound (34) (10 g, 43.2 mmol) and iodomethane (12.1 mL, 194.4 mmol) were dissolved in a mixture of DMF (100 mL) and THF (50 mL), and tert-butoxypotassium (5.3 g, 47.47). 5 mmol) was added, and the mixture was stirred at 0 ° C. for 1 hour. Subsequently, tert-butoxypotassium (5.3 g, 47.5 mmol) was further added and stirred at 0 ° C. for 1 hour, and then tert-butoxypotassium (5.3 g, 47.5 mmol) was further added and stirred at 0 ° C. for 1 hour. did. A 2M aqueous hydrochloric acid solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated. The concentrated residue was purified by silica gel chromatography to obtain compound (35) (7.8 g, yield 69.6%).
LCMS: m / z = 260.1 [M + H] ⁺
¹ H-NMR (CDCl ₃ ) δ: 7.78-7.73 (m, 2H), 3.72 (s, 3H), 1.68-1.67 (t, J = 2 Hz, 6H).
Step 5: Synthesis of Compound 466

Compound (35) (4.17 g, 16.1 mmol) was dissolved in a mixture of methanol (40 mL) and THF (5 mL), 4M aqueous lithium hydroxide solution (8.45 mL) was added, and the mixture was stirred at 66 ° C. for 15 hr. After concentration. The concentrated residue was dissolved in water (50 mL), washed twice with ethyl acetate, and 2M hydrochloric acid was added to make the aqueous layer acidic (pH 2). This was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated to obtain compound (36) (2.5 g, yield 63.3%).
LCMS: m / z = 246.1 [M + H] ⁺
¹ H-NMR (CDCl ₃ ) δ: 7.81-7.76 (m, 2H), 1.73 (t, J = 2 Hz, 6H).
Compound 466 was obtained from compound (36) in the same manner as in Step 1 to Step 6 of Example 11.
¹ H-NMR (CDCl ₃ ) δ: 8.24 (d, 1H), 8.15-8.13 (m, 1H), 7.61 (d, 1H), 3.69 (s, 3H), 1.65 (d, 6H).

Example 13 Synthesis of Compound 456

Diethyl 2-methylmalonate (51.3 mL, 301 mmol) was gradually added to a DMF (400 mL) suspension of sodium hydride (12 g, 301 mmol) in a nitrogen atmosphere, and the mixture was stirred at 0 ° C. for 1 hour. Subsequently, compound (36) (40 g, 177 mmol) was added, and the mixture was stirred at 0 ° C. for 1 hour and then at 70 ° C. for 4 hours. A 2M aqueous hydrochloric acid solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated to give compound (37) (83.8 g).
LCMS: m / z = 364 [M + H] ⁺
From compound (37), compound 456 was obtained in the same manner as in the second step, third step, fourth step of Example 10 and second step of Example 12.

Example 14 Synthesis Step 1 of Compound 420 Synthesis of Compound (39)

Compound (38) (10.4 mg, 0.024 mmol) was dissolved in a mixture of THF (0.1 mL) and methanol (0.1 mL), and 4M aqueous lithium hydroxide solution (18.0 μL, 0.072 mmol) was added. , And stirred at 70 ° C. for 2 hours. A saturated aqueous ammonium acetate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated. The concentrated residue is dissolved in DMF (0.2 mL) and 4-fluoroaniline (3.40 μL, 0.036 mmol), HATU (13.7 mg, 0.036 mmol) and triethylamine (6.64 μL, 0.048 mmol) are added. The mixture was stirred at room temperature for 1 hour and further at 60 ° C. for 30 minutes. A saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated. The concentrated residue was purified by silica gel chromatography to obtain compound (39) (7.7 mg, yield 62.6%).
Second Step Synthesis of Compound 420

Compound (39) (7.7 mg, 0.015 mmol) was dissolved in methylene chloride (0.15 mL), TFA (278 μL, 0.096 mmol) was added, and the mixture was stirred at room temperature for 7 hours. A saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated. 2- (4- (Ethylsulfonyl) phenyl) acetic acid (5.1 mg, 0.022 mmol) was dissolved in methylene chloride (0.2 mL), and DMF (0.058 μL, 0.00075 mmol) and oxalyl chloride (2. 5 μL, 0.028 mmol) was added and stirred for 1 hour. Subsequently, the concentrated residue and triethylamine (12.5 μL, 0.090 mmol) were added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated. The concentrated residue was purified by silica gel chromatography to obtain Compound 420 (6.0 mg, yield 82.8%).
¹ H-NMR (CDCl ₃ ) δ: 8.33 (d, 1H), 8.21-8.14 (m, 2H), 7.90 (d, 2H), 7.76 (dd, 1H), 7.55 (d, 2H), 7.36-7.31 (2H, m), 6.97 (t, 2H), 6.86 (s, 1H), 3.84 (s, 2H), 3.12 (q, 2H), 1.33-1.23 (t, 3H).

Example 15 Synthesis of Compound 469

Copper trifluoromethanesulfonate (41.9 mg, 0.116 mmol) and sodium ethylsulfinate (26.9 mg, 0.232 mmol) were dissolved in DMSO (0.3 mL), and N, N′-dimethylethane-1,2, -Diamine (26.1 μL, 0.243 mmol) was added and stirred at room temperature for 5 minutes. Subsequently, a solution of compound (40) (30 mg, 0.116 mmol) in DMSO (0.15 mL) was added, and the mixture was stirred at 120 ° C. for 3 hours. A saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated. The concentrated residue was purified by silica gel chromatography to obtain compound (41) (14 mg, yield 44.4%).
¹ H-NMR (CDCl ₃ ) δ: 7.89 (d, 2H), 7.79 (d, 2H), 3.81 (s, 3H), 3.12 (q, 2H), 1.81 (s, 3H), 1.28 (t, 3H ).
Compound 469 was obtained from compound (41) in the same manner as in Step 5 and Step 6 of Example 11.
¹ H-NMR (CDCl ₃ ) δ: 9.04 (s, 1H), 8.09-8.00 (m, 1H), 7.97-7.88 (m, 2H), 7.84 (d, 2H), 7.77 (d, 2H), 7.66 (d, 1H), 6.89-6.70 (m, 3H), 3.96 (s, 1H), 3.08 (q, 2H), 1.95 (s, 3H), 1.72 (s, 6H), 1.27 (t, 3H).

Example 16 Synthesis Step 1 of Compound 494 Synthesis of Compound (42)

Compound (42) (500 mg, 2.06 mmol) was dissolved in DMF (5 mL), sodium hydride (purity 60%, 99 mg, 2.48 mmol) and 2-bromoacetic acid t-butyl ester (366 μL, 2.476 mmol). And stirred at room temperature for 2 hours. A saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated. The concentrated residue was purified by silica gel chromatography to obtain compound (43) (543 mg, yield 73.8%).
Step 2 Synthesis of Compound (44)

Compound (44) was obtained from compound (43) in the same manner as in Step 5 and Step 6 of Example 11.
Step 3 Synthesis of Compound 494

Compound (44) (85 mg, 0.131 mmol) was dissolved in methylene chloride (1.5 mL), TFA (1.5 mL, 19.5 mmol) was added, and the mixture was stirred at room temperature for 30 min. After adding saturated brine, the mixture was extracted with ethyl acetate, and the organic layer was washed again with saturated brine, dried over sodium sulfate, and concentrated. The concentrated residue was dissolved in THF (1.2 mL), isobutyl chloroformate (36 μL, 0.277 mmol) and triethylamine (51 μL, 0.370 mmol) were added under ice cooling, and the mixture was stirred for 1 hour under ice cooling. Subsequently, a solution of sodium borohydride (21.0 mg, 0.554 mmol) in methanol (0.5 mL) was added and stirred for 1 hour under ice cooling. A saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated. The concentrated residue was purified by silica gel chromatography to give compound 494 (43 mg, yield 40.2%).
¹ H-NMR (CDCl ₃ ) δ: 8.81 (s, 1H), 7.99-7.91 (m, 1H), 7.78 (d, 2H), 7.62-7.58 (m, 1H), 7.55 (d, 1H), 7.51 -7.45 (m, 1H), 7.40 (d, 1H), 7.14 (s, 1H), 6.85-6.71 (m, 2H), 3.94 (t, 1H), 3.68-3.60 (m, 1H), 3.59-3.50 (m, 1H), 3.11 (q, 2H), 2.92-2.75 (m, 1H), 2.46-2.32 (m, 1H), 2.21-2.09 (m, 1H), 2.04-1.94 (m, 2H), 1.66 (s, 6H), 1.26 (t, 3H).

Example 17 Synthesis of Compound 470

From compound (30), compound 470 was obtained in the same manner as in the first, second and third steps of Example 17.
¹ H-NMR (CDCl ₃ ) δ: 9.42 (s, 1H), 9.10-9.08 (m, 1H), 8.25-8.18 (m, 1H), 8.18-8.08 (m, 1H), 7.73-7.67 (m, 1H), 7.63 (d, 1H), 7.58-7.52 (m, 1H), 7.48 (d, 1H), 6.96 (s, 1H), 6.90-6.81 (m, 1H), 6.81-6.72 (m, 1H) , 4.26-4.20 (m, 1H), 3.84-3.75 (m, 1H), 3.72-3.63 (m, 1H), 3.19 (q, 2H), 2.51-2.40 (m, 1H), 2.29-2.17 (m, 1H), 1.73-1.63 (m, 6H), 1.35 (t, 3H).

Example 18 Synthesis Step 1 of Compound 493 Synthesis of Compound (46)

Compound (45) (1.0 g, 6.06 mmol) was dissolved in dichloromethane (12 mL), trimethylcyanide (1.06 mL, 7.87 mmol) and 1M titanium chloride toluene solution (1.30 mL, 1.30 mmol). The mixture was stirred at room temperature for 12 hours and concentrated. The concentrated residue was dissolved in dioxane (15 mL), 12M hydrochloric acid solution (7.5 mL, 90 mmol) was added, and the mixture was heated to reflux for 6 hours. Water was added, followed by extraction with ethyl acetate, and the organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated to obtain compound (46) (1.05 g, yield 82.5%). .
Step 2 Synthesis of Compound (47)

Compound (46) (200 mg, 0.951 mmol) was dissolved in dioxane (10 mL), 12M hydrochloric acid solution (5 mL, 60 mmol) was added, sealed, and heated to reflux for 6 hours. Extraction was performed with chloroform, and the organic layer was washed with saturated brine. Next, the organic layer is extracted with a saturated aqueous sodium hydrogen carbonate solution, and the aqueous layer is acidified with a 1M aqueous hydrochloric acid solution and then extracted with ethyl acetate. The organic layer is then washed with saturated brine, dried over sodium sulfate, and concentrated. Gave compound (47) (96 mg, yield 47.8%).
Step 3 Synthesis of Compound 493

Compound (47) (100 mg, 0.947 mmol) was dissolved in dichloromethane (6 mL), DMF (7.36 μL, 0.095 mmol) and oxalyl chloride (102 μL, 1.23 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Subsequently, 5-fluoro-2-fluoroaniline (128 μL, 1.14 mmol) and DIPEA (827 μL, 4.74 mmol) were added and stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated. The concentrated residue was purified by silica gel chromatography to obtain compound (48) (81 mg, yield 25.2%).
Compound 493 was obtained from compound (48) in the same manner as in Step 4 and Step 5 of Example 1.
¹ H-NMR (CDCl ₃ ) δ: 8.98 (s, 1H), 8.38 (d, 1H), 7.86 (d, 2H), 7.57-7.48 (m, 5H), 7.44 (d, 2H), 7.00 (d , 2H), 3.78 (s, 2H), 3.10 (q, 2H), 1.89 (s, 3H), 1.27 (t, 3H).

The following compounds were synthesized according to the above examples.

Hereinafter, biological test examples of the compounds of the present invention will be described.

Test Example 1 Human RORγt Reporter Assay A gene fused with human binding binding domain of human RORγt and DNA binding domain of GAL4 was introduced into Luc2P luciferase-expressing HEK293 cells to produce a stable expression cell line. A stable expression cell line in which a DMSO solution of the present invention is dispensed at 40-120 nL per well into a 384-well plate and suspended in a medium (DMEM containing bovine serum and antibiotics mixed solution) Was seeded at a rate of 20000-24000 per well and cultured at 37 ° C. under 5% carbon dioxide for 20 hours. The reagent of the luciferase quantification system One Glo Luciferase Assay System (Promega) was added at 20 μL per well and allowed to stand at room temperature for 10 minutes, and then the luminescence of each well was measured with ViewLux (Perkin Elmer). Inhibition of the compound of the present invention was calculated by calculating the concentration (IC ₅₀ ) at which the inhibition rate was 50%, with the value of luminescence intensity without the compound of the present invention being 0% inhibition and 100% inhibition when no cells were added. Activity was evaluated. IC ₅₀ was calculated using Spotfire (manufactured by TIBCO Software).

The test results of the compounds of the present invention are shown in the following table.

The following compounds had an IC ₅₀ of 5 μM or less.
Compound Nos .: 2-11, 13-18, 20-28, 31-43, 45-55, 59-72, 74-80, 82, 84-95, 97-100, 102, 104-112, 115, 117 118, 120-126, 128, 130, 131, 132, 133, 135-138, 141-147, 149-158, 160-168, 170-172, 176, 178-180, 182-187, 189-207 209, 211, 213-235, 237-243, 245-255, 257-264, 266, 281-281, 283-294, 296-301, 303-322, 324, 325, 327-332, 334-337 339-342, 345-348, 350, 351, 353, 355-370, 373, 375-382, 38 ~ 394,400 ~ 404,406 ~ 408,410 ~ 436, 438 ~ 478, 480 ~ 483,487,489 ~ 491, 493 ~ 497,499 and 500.

Test Example 2 Human RORγt binding test A DMSO solution of the compound of the present invention is dispensed into a 96-well plate in a certain amount (22.5 nL, 45 nL, or 205 nL) per well with an automatic dispensing device, and a measurement buffer (50 mM Hepes- Add 200 nM [3H] -Dixoxin diluted with NaOH (pH 7.4), 150 mM NaCl, 5 mM MgCl ₂ , 1 mM DTT, 0.1% BSA) and 20 μL per well of GST-RORγt Ligand Binding Domain. Start and let stand at room temperature for 1-4 hours. At the same time, as a pre-treatment for UniFilter-96 GF / B plate, 50 μL of a measurement buffer was added per well, allowed to stand at 4 ° C. for 1 hour or longer, and filtered with FilterMate (Perkin Elmer). After washing 6 times with washing solution (50 mM Hepes-NaOH (pH 7.4), 150 mM NaCl, 5 mM MgCl ₂ , 1 mM DTT, 0.01% BSA), the plate is dried, and MicroScint-20 is added at 50 μL per well. Then, it was measured for 1 minute with MicroBeta (manufactured by Perkin Elmer). The measured value when the compound of the present invention is not contained is 0% inhibition, 1 to 2 μM, N- {4- (3-chlorophenyl) -5-[(2-chlorophenyl) carbonyl] -1,3- When thiazol-2-yl} -2- [4- (ethylsulfonyl) phenyl] acetamide was added as 100% inhibition, the concentration (IC ₅₀ ) at which the inhibition rate was 50% was calculated, and the inhibitory activity of the compound of the present invention Evaluated. GST-RORgt Ligand Binding Domain was added in such an amount that the measured value in the 0% inhibition condition of this test was about 2000 to 4000 CPM. IC ₅₀ was calculated using Spotfire (manufactured by TIBCO Software).
The following compounds had an IC ₅₀ of 0.5 μM or less.
Compound Nos .: 1 to 18, 20 to 42, 44, 48, 57, 58, 64, 77, 78, 80, 84, 92 to 142, 144 to 216, 223 to 247, 253 to 273, 278 to 281, 285 289, 298, 303 to 317, 320 to 325, 328 to 382, 384 to 390, 392 to 411, 414 to 416, 419, 421 to 443, 446 to 458, 460, 463, 464, 466, 467, 469 ~ 473, 475-490, 493-495 and 497-499.

Test Example 3 TPA induction K14. Action in Stat3C Tg mouse psoriasis model A transgenic mouse (K14. Stat3C Tg mouse) in which an active Stat3 (Signal Transducer and Activator of Transcription 3) is constantly expressed in the epidermis under the human Keratin 14 (K14) promoter. use. K14. After shaving of Stat3C Tg mice (6 weeks old, female), 100 μL of 2 nmol of TPA (12-O-tetradecanoylphorbol-13-acetate, Sigma) acetone solution is shaved once every two days for 10 days. Applying to the eyes causes psoriasis-like dermatitis. The compound of the present invention is dissolved in acetone (concentration 1 or 5%), and 100 μL of the solution is applied twice a day every day from the first day to the tenth day. A group to which acetone was similarly applied is taken as a control group.
The degree of dermatitis was evaluated for three items: erythema, scale, and skin hardness (classified as score 0 to 6, 0: considered, 1: mild, 3: moderate, 6: severe), and the total was total Calculated as dermatitis score.
The skin tissue is removed 3 hours after the final TPA application, and a part thereof is immersed and fixed in a 10% neutral buffered formalin solution for use in histopathological evaluation. Formalin-fixed tissue is stained with hematoxylin and eosin after embedding and slicing, and epidermal thickening is measured by image analysis using Image-Pro Plus.
In addition, in order to evaluate the amount of intradermal cytokine, three skin tissues with a diameter of 8 mm were collected and subjected to T-PER (Tissue Protein Extraction Reagent, Thermo Science) including Protease Inhibitor Cocktail (Thermo Scientific). After centrifugation, the amounts of IL-17 and IL-22 contained in the supernatant are measured with an ELISA kit (R & D).

Test Example 4 Effect on chick Th17 differentiation Blood was collected from a healthy person, and after adjusting peripheral blood mononuclear cells (PBMC) using Ficoll-Paque PLUS solution (GE Healthcare Japan), naive CD4 T cells were naive. Isolate with CD4 T cell isolation kit II (Miltenyi Biotec) and suspend in XVIVO-20 medium (Lonza). In a 96-well BD biocoat T cell activation plate (anti-human CD3) to which 50 μL of the compound of the present invention diluted in a medium was added, add 50000 isolated naive CD4 T cells per well. After seeding with 100 μL, add 50 μL of Th17 differentiation medium. Prepare various antibodies (BD bioscience) and cytokines (R & D) at the following final concentrations in Th17 differentiation medium: 1 μg / mL anti-CD28 antibody, 2 μg / mL anti-IL-4 antibody, 2 μg / mL Anti-IFN-γ antibody, 25 ng / mL IL-23, 25 ng / mL IL-6, 25 ng / mL IL-1β, 10 ng / mL TGF-β. After culturing the cells at 37 ° C. for 3 days, half of the culture solution is replaced with a fresh Th17 differentiation medium containing the same concentration of the compound of the present invention, and IL-2 (Immense, Shionogi & Co.) is added to a final concentration of 20 U / mL. Add as follows. Further, after culturing at 37 ° C. for 4 days, the cells are washed with a medium, transferred to a 96-well round bottom plate, and cultured for 5 hours in the presence of Leukocyte Activation Cocktail, with BD GolgiPlug (BD Bioscience). Cells were stained with Fixable Viability Dye (eBioscience), subjected to membrane permeabilization with Fixation and Permeabilization Solution (BD Bioscience), stained with fluorescently labeled anti-CD4 antibody and anti-IL-17 antibody (eBioscience), and in CD4-positive living cells The ratio of IL-17 positive cells is analyzed with a BD FACSCanto II flow cytometer. In the case of not containing the compound of the present invention, the proportion of IL-17-producing cells is 0% inhibition, and when Th17 differentiation is not induced (anti-CD28 antibody, anti-IL-4 antibody, anti-IFN-γ antibody instead of Th17 differentiation medium) The ratio of IL-17-producing cells (when cultured with the addition of a medium containing only NO) is defined as 100% inhibition, and the concentration (IC ₅₀ ) at which the inhibition rate is 50% is calculated to evaluate the inhibitory activity of the compound of the present invention. . The IC ₅₀ is calculated using Spotfire (registered trademark, manufactured by TIBCO Software).

Test Example 5 Effect on IL-17 production from chick PBMC Blood was collected from a healthy person, and PBMC was prepared using Ficoll-Paque PLUS solution (GE Healthcare Japan), followed by 10% bovine serum (FBS, Equitech- Bio Inc) -containing RPMI 1640 medium (Life Technologies). After seeding 100 μL of the prepared PBMC in a 96-well BD biocoat T cell activation plate (anti-human CD3) to which 50 μL of the compound of the present invention diluted in a medium is added per well, so that there are 100,000 PBMCs per well. Add 50 μL of medium containing anti-CD28 antibody to a final concentration of 2 μg / mL. After culturing the cells at 37 ° C. for 3 days, the culture supernatant is collected, and the amount of IL-17 is measured by an ELISA kit (R & D). Inhibition of the compound of the present invention was calculated by calculating the concentration (IC ₅₀ ) at which the inhibition rate was 50%, with the amount of IL-17 in the absence of the compound of the present invention being 0% inhibition and the case of not adding cells being 100% inhibition. Assess activity. The IC ₅₀ is calculated using Spotfire (registered trademark, manufactured by TIBCO Software).

Test Example 6 Effect on IL-23 Induced Intradermal IL-17 Production 5 μg / mL with phosphate buffered saline on the dorsal skin after shaving of C57BL / 6 mice (Charles River, 8-9 weeks old, female) Recombinant mouse IL-23 (Wako) diluted 50 μL is administered intradermally. The compound of the present invention is dissolved in a solvent (Polysorbate 80 / Polyethylene Glycol 400 / 0.5% Carboxymethylethylcellulose and 20 mmol / L Taurocholic Acid, Japanese Pharmacopoeia Dissolution Test Second Solution = 2.5 / 47.5 / 50) Orally administered twice 30 minutes before and 6 hours after IL-23 administration (dose 30 mg / kg and 100 mg / kg). A group to which only the solvent was similarly administered was used as a control group. Twenty-four hours after the administration of IL-23, skin tissue having a diameter of 12 mm is collected and homogenized with T-PER (Tissue Protein Extraction Reagent, Thermo Scientific) including Protease Inhibitor Cocktail (Thermo Scientific). After centrifugation, the amount of IL-17 contained in the supernatant is measured using an ELISA kit (R & D).

Test Example 7 CYP Inhibition Test O-deethylation of 7-ethoxyresorufin as a typical substrate metabolic reaction of major human CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4) using commercially available pooled human liver microsomes CYP1A2), methyl-hydroxylation of tolbutamide (CYP2C9), 4′-hydroxylation of mephenytoin (CYP2C19), O-demethylation of dextromethorphan (CYP2D6), and hydroxylation of terfenadine (CYP3A4) The degree to which the amount of metabolite produced was inhibited by the compound of the present invention was evaluated.
The reaction conditions are as follows: substrate, 0.5 μmol / L ethoxyresorufin (CYP1A2), 100 μmol / L tolbutamide (CYP2C9), 50 μmol / L S-mephenytoin (CYP2C19), 5 μmol / L dextromethorphan (CYP2D6), 1 μmol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C .; enzyme, pooled human liver microsome 0.2 mg protein / mL; compound concentration of the present invention 1, 5, 10, 20 μmol / L (4 points) .
As a reaction solution in a 96-well plate, each of 5 types of substrate, human liver microsome, and the compound of the present invention are added in the above composition in a 50 mmol / L Hepes buffer solution, and NADPH as a coenzyme is added to make a metabolic reaction as an index. Started. After reacting at 37 ° C. for 15 minutes, the reaction was stopped by adding a methanol / acetonitrile = 1/1 (V / V) solution. After centrifugation at 3000 rpm for 15 minutes, resorufin (CYP1A2 metabolite) in the centrifugation supernatant was quantified with a fluorescent multilabel counter or LC / MS / MS, tolbutamide hydroxide (CYP2C9 metabolite), mephenytoin 4 ′ hydroxylated The body (CYP2C19 metabolite), dextrorphan (CYP2D6 metabolite), and terfenadine alcohol (CYP3A4 metabolite) were quantified by LC / MS / MS.
The control (100%) was obtained by adding only DMSO, which is a solvent in which the drug was dissolved, to the reaction system, the residual activity (%) was calculated, and the IC ₅₀ was calculated by inverse estimation using a logistic model using the concentration and the inhibition rate. Calculated.
Compound 39, 279, 451: 5 species IC ₅₀ > 20 μM

Test Example 8 Pharmacokinetic Test Examination of Oral Absorbability Experimental Materials and Methods (1) Animals Used: Mice or rats were used.
(2) Breeding conditions: Mice or rats were allowed to freely take solid feed and sterilized tap water.
(3) Setting of dosage and grouping: oral administration and intravenous administration at a predetermined dosage. Groups were set up as follows. (Dose may vary for each compound)
Oral administration 1-100 mg / kg (n = 2-3)
Intravenous administration 0.5-10 mg / kg (n = 2-3)
(4) Preparation of administration solution: Oral administration was administered as a solution or suspension. Intravenous administration was solubilized.
(5) Administration method: Oral administration was forcibly administered into the stomach with an oral sonde. Intravenous administration was carried out from the tail vein using a syringe with an injection needle.
(6) Evaluation items: Blood was collected over time, and the concentration of the compound of the present invention in plasma was measured using LC / MS / MS.
(7) Statistical analysis: The plasma concentration-time curve area (AUC) is calculated using the non-linear least squares program WinNonlin (Registered Trademark) for plasma compound concentration transition, and the oral administration group and intravenous administration The bioavailability (BA) of the compound of the present invention was calculated from the AUC of the group. In addition, systemic clearance (CLtot) was calculated by dividing the intravenous dose by AUC after intravenous administration.
Compound 457: BA 56.2%

Test Example 9 Metabolic Stability Test A commercially available pooled human liver microsome and the compound of the present invention were reacted for a certain period of time, and the residual rate was calculated by comparing the reaction sample with the unreacted sample to evaluate the degree of metabolism of the compound of the present invention in the liver. .
In 0.2 mL buffer (50 mmol / L Tris-HCl pH 7.4, 150 mmol / L potassium chloride, 10 mmol / L magnesium chloride) containing 0.5 mg protein / mL human liver microsomes in the presence of 1 mmol / L NADPH The reaction was carried out at 37 ° C. for 0 or 30 minutes (oxidative reaction). After the reaction, 50 μL of the reaction solution was added to 100 μL of a methanol / acetonitrile = 1/1 (v / v) solution, mixed, and centrifuged at 3000 rpm for 15 minutes. The compound of the present invention in the supernatant was quantified by LC / MS / MS or solid phase extraction (SPE) / MS, and the remaining amount of the compound of the present invention after the reaction was defined as 100% at 0 minutes. Calculated.
The residual ratio of the following compounds was 90% or more.
Compound numbers: 32, 39, 56, 57, 79, 84, 116, 118, 130, 156, 158, 172, 176, 192, 204, 206, 211, 212, 214, 236, 240, 241, 242, 243 244, 261, 266, 287, 316, 346, 395, 401, 420, 429, 433, 441, 444, 446, 448, 449, 460, 462, 470, 474, 492-494, 496 and 500.

Test Example 10-1 CYP3A4 (MDZ) MBI Test This test evaluates the mechanism based inhibition (MBI) ability from the enhancement by metabolic reaction with respect to CYP3A4 inhibition of the compounds of the present invention. Pooled human liver microsomes were used to evaluate CYP3A4 inhibition using midazolam (MDZ) 1-hydroxylation as an indicator.
The reaction conditions are as follows: substrate, 10 μmol / L MDZ; pre-reaction time, 0 or 30 minutes; reaction time, 2 minutes; reaction temperature, 37 ° C .; pooled human liver microsomes, pre-reaction 0.5 mg / mL, reaction time 0.05 mg / mL (when diluted 10-fold); concentration at the time of pre-reaction of the compound of the present invention 1, 5, 10, 20 μmol / L (4 points).
Pooled human liver microsomes and the compound solution of the present invention were added to a 96-well plate as a pre-reaction solution in K-Pi buffer (pH 7.4) in the above-mentioned pre-reaction composition, and the substrate and K-Pi buffer were added to another 96-well plate. A part of the solution was transferred so that the solution was diluted to 1/10, and a reaction using NADPH as a coenzyme was started as an index (no pre-reaction). After reaction for a predetermined time, methanol / acetonitrile = 1 The reaction was stopped by adding a 1/1 (V / V) solution. In addition, NADPH is also added to the remaining pre-reaction solution to start the pre-reaction (pre-reaction is present), and after pre-reaction for a predetermined time, one plate is diluted to 1/10 with the substrate and K-Pi buffer. The reaction was started by shifting the part. After the reaction for a predetermined time, the reaction was stopped by adding a methanol / acetonitrile = 1/1 (V / V) solution. The plate subjected to each index reaction was centrifuged at 3000 rpm for 15 minutes, and 1-hydroxymidazolam in the centrifuged supernatant was quantified by LC / MS / MS.
A control (100%) was obtained by adding only DMSO, which is a solvent in which the compound of the present invention was dissolved, to the reaction system, and the residual activity (%) when the compound of the present invention was added at each concentration was calculated. IC was calculated by inverse estimation using a logistic model. Preincubation 0 min IC / Preincubation 30 min IC was defined as the Shifted IC value, and when the Shifted IC was 1.5 or more, Positive, and when the Shifted IC was 1.0 or less, it was defined as Negative.
Compound 32: Negative

Test Example 10-2: CYP3A4 Fluorescence MBI Test The CYP3A4 fluorescence MBI test is a test for examining the enhancement of CYP3A4 inhibition of the compound of the present invention by metabolic reaction. 7-Benzyloxytrifluoromethylcoumarin (7-BFC) is debenzylated by CYP3A4 enzyme (E. coli-expressed enzyme) to produce a fluorescent metabolite 7-hydroxytrifluoromethylcoumarin (7-HFC). CYP3A4 inhibition is evaluated using 7-HFC production reaction as an index.
The reaction conditions are as follows: substrate, 5.6 μmol / L 7-BFC; pre-reaction time, 0 or 30 minutes; reaction time, 15 minutes; reaction temperature, 25 ° C. (room temperature); CYP3A4 content (E. coli expression enzyme), Pre-reaction 62.5 pmol / mL, reaction 6.25 pmol / mL (10-fold dilution); compound concentration of the present invention, 0.625, 1.25, 2.5, 5, 10, 20 μmol / L (6 points) ).
The enzyme and the compound solution of the present invention are added to the 96-well plate as a pre-reaction solution in K-Pi buffer (pH 7.4) in the above-mentioned pre-reaction composition, and the substrate and K-Pi buffer are added to another 96-well plate A part of the solution was transferred so as to be diluted by 1/10, and a reaction using NADPH as a coenzyme was started as an indicator (no pre-reaction). After reaction for a predetermined time, acetonitrile / 0.5 mol / L The reaction is stopped by adding Tris (trishydroxyaminomethane) = 4/1 (V / V). In addition, NADPH is also added to the remaining pre-reaction solution to start the pre-reaction (pre-reaction exists). Start the reaction with the part as the indicator. After the reaction for a predetermined time, the reaction is stopped by adding acetonitrile / 0.5 mol / L Tris (trishydroxyaminomethane) = 4/1 (V / V). The fluorescence value of 7-HFC, which is a metabolite, is measured using a fluorescent plate reader on the plate on which each index reaction has been performed. (Ex = 420nm, Em = 535nm)
A control (100%) was obtained by adding only DMSO, which is a solvent in which the compound of the present invention was dissolved, to the reaction system. Is used to calculate IC ₅₀ by inverse estimation using a logistic model. The case where the difference in IC ₅₀ value is 5 μmol / L or more is (+), and the case where it is 3 μmol / L or less is (−).

Test Example 11 Fluctuation Ames Test
The mutagenicity of the compound of the present invention is evaluated.
20 μL of Salmonella typhimurium TA98 strain, TA100 strain, which has been cryopreserved, is inoculated into 10 mL liquid nutrient medium (2.5% Oxoid nutritive broth No. 2) and cultured at 37 ° C. for 10 hours before shaking. For the TA98 strain, 7.70 mL of the bacterial solution is centrifuged (2000 × g, 10 minutes) to remove the culture solution. 7. 70 mL Micro F buffer (K ₂ HPO ₄ : 3.5 g / L, KH ₂ PO ₄ : 1 g / L, (NH ₄ ) ₂ SO ₄ : 1 g / L, trisodium citrate dihydrate: The cells are suspended in 0.25 g / L, MgSO ₄ · 7H ₂ 0: 0.1 g / L), and 120 mL of Exposure medium (biotin: 8 μg / mL, histidine: 0.2 μg / mL, glucose: 8 mg / mL) To the MicroF buffer). TA100 strain is added to 130 mL of Exposure medium with respect to 3.42 mL bacterial solution to prepare a test bacterial solution. Compound DMSO solution of the present invention (maximum dose of 50 mg / mL to several-fold dilution at 2-3 times common ratio), DMSO as a negative control, and non-metabolic activation conditions as a positive control, 50 μg / mL 4-TA Nitroquinoline-1-oxide DMSO solution, 0.25 μg / mL 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution for TA100 strain, TA98 under metabolic activation conditions 40 μg / mL 2-aminoanthracene DMSO solution for the strain and 20 μg / mL 2-aminoanthracene DMSO solution for the TA100 strain, respectively, and 588 μL of the test bacterial solution (498 μL of the test bacterial solution and S9 under metabolic activation conditions). mix 90 μL of the mixture) and incubate with shaking at 37 ° C. for 90 minutes. 460 μL of the bacterial solution exposed to the compound of the present invention was added 2300 μL of Indicator medium (MicroF buffer solution containing biotin: 8 μg / mL, histidine: 0.2 μg / mL, glucose: 8 mg / mL, bromocresol purple: 37.5 μg / mL). 50 μL aliquots into 48 wells / dose of the microplate and statically cultured at 37 ° C. for 3 days. Since wells containing bacteria that have acquired growth ability by mutation of the amino acid (histidine) synthase gene change from purple to yellow due to pH change, the number of bacteria growth wells that changed to yellow in 48 wells per dose was counted. Evaluation is made in comparison with the negative control group. A negative mutagenicity is indicated as (−), and a positive mutagenicity is indicated as (+).

Test Example 12 hERG Test For the purpose of evaluating the risk of prolonging the electrocardiogram QT interval of the compound of the present invention, CHO cells expressing human ether-a-go-go related gene (hERG) channels are used, The action of the compounds of the present invention on the delayed rectifier K ⁺ current (I _Kr ) playing a role was investigated.
Using a fully automatic patch clamp system (QPatch; Sophion Bioscience A / S), the cell was held at a membrane potential of −80 mV by a whole cell patch clamp method, and after applying a leak potential of −50 mV, a depolarization stimulus of +20 mV for 2 seconds, and further records the _{I Kr} induced repolarization stimulation of -50mV when given 2 seconds. After the generated current is stabilized, an extracellular solution (NaCl: 145 mmol / L, KCl: 4 mmol / L, CaCl ₂ : 2 mmol / L, MgCl ₂ : 1 mmol / L, glucose, in which the compound of the present invention is dissolved at a target concentration) : 10 mmol / L, HEPES (4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid): 10 mmol / L, pH = 7.4) was applied to the cells at room temperature for 10 minutes. Using the analysis software (Falster Patch; Sophion Bioscience A / S), the absolute value of the maximum tail current was measured from the obtained I _{Kr based on} the current value at the holding membrane potential. Furthermore, the inhibition rate with respect to the maximum tail current before application of the compound of the present invention was calculated, and compared with the vehicle application group (0.1% dimethylsulfoxide solution), the effect of the compound of the present invention on I _Kr was evaluated.
Compound 399: 15.4% (5 μM)

Test Example 13 Solubility test The solubility of the compound of the present invention is determined under the condition of addition of 1% DMSO. A 10 mmol / L compound solution is prepared in DMSO. 2 μL of the compound solution of the present invention is added to 198 μL of JP-1 solution and JP-2 solution, respectively, or 6 μL of the compound solution of the present invention is added to JP-1 solution and JP-2 solution 594 μL, respectively. After standing at 25 ° C. for 16 hours (condition 1) or shaking at room temperature for 1 hour (condition 2), the mixed solution is filtered with suction. The filtrate was diluted 10 or 100 times with methanol / water = 1/1 (V / V) or acetonitrile / methanol / water = 1/11/2 (V / V / V), and LC / MS was determined by the absolute calibration curve method. Alternatively, the concentration in the filtrate is measured using solid phase extraction (SPE) / MS.
The composition of JP-1 solution is as follows.
Add water to 2.0 g of sodium chloride and 7.0 mL of hydrochloric acid to make 1000 mL.
The composition of JP-2 solution is one of the following.
Composition 1: About 200 mL of 0.2 mol / L sodium hydroxide test solution is added to 200 mL of 0.2 mol / L potassium dihydrogen phosphate test solution to adjust the pH to 6.8, and then 600 mL of water is added.
Composition 2: 3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium hydrogen phosphate are dissolved in water to make 1000 mL.
Composition 3: 1.40 g of water is added to 1 volume of 3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium hydrogen phosphate dissolved in water to 1000 mL.

Test Example 14 Powder Solubility Test An appropriate amount of the compound of the present invention is put in an appropriate container, and JP-1 solution (2.0 g of sodium chloride, water is added to 7.0 mL of hydrochloric acid to 1000 mL), JP-2 solution ( Dissolve 3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium hydrogen phosphate in water to make 1000 mL, add 1 volume of water to 1 volume), 20 mmol / L sodium taurocholate (TCA) / JP-2 solution (Add JP-2 solution to 1.08 g of TCA to make 100 mL) 200 μL each. When the entire amount is dissolved after the addition of the test solution, the compound of the present invention is appropriately added. After sealing at 37 ° C. for 1 hour, the mixture is filtered, and 100 μL of methanol is added to 100 μL of each filtrate to perform 2-fold dilution. Change the dilution factor as necessary. Check for bubbles and deposits, seal and shake. The compound of the present invention is quantified using HPLC by the absolute calibration curve method.

Formulation Examples Formulation examples shown below are merely illustrative and are not intended to limit the scope of the invention.
Formulation Example 1 Tablet A compound of the present invention, lactose and calcium stearate are mixed, crushed and granulated, and dried to obtain granules of an appropriate size. Next, calcium stearate is added and compressed to form tablets.
Formulation Example 2 Capsules The compound of the present invention, lactose and calcium stearate are mixed and mixed uniformly to form a powder as a powder or fine granules. It is filled into a capsule container to form a capsule.
Formulation Example 3 Granules The compound of the present invention, lactose and calcium stearate are mixed, mixed well, compression-molded, pulverized, sized and sieved to give granules of an appropriate size.
Formulation Example 4 Orally Disintegrating Tablets The compound of the present invention and crystalline cellulose are mixed and compressed after granulation to obtain an orally disintegrating tablet.
Formulation Example 5 Dry Syrup The compound of the present invention and lactose are mixed, pulverized, sized and sieved to obtain a dry syrup of an appropriate size.
Formulation Example 6 Injection The compound of the present invention and a phosphate buffer are mixed to prepare an injection.
Formulation Example 7 Instillation Compound of the present invention and phosphate buffer are mixed to prepare an injection.
Formulation Example 8 Inhalant The compound of the present invention and lactose are mixed and finely pulverized to obtain an inhalant.
Formulation Example 9 Ointment The compound of the present invention and petrolatum are mixed to form an ointment.
Formulation Example 10 Patch A base such as the compound of the present invention and an adhesive plaster is mixed to obtain a patch.

The compound represented by the formula (I) has RORγt inhibitory action and is considered useful for diseases involving RORγt, for example, autoimmune diseases.

Claims

Formula (I):

(Wherein L is a single bond, —NR 1A CO—, —CONR 1B —, —NR 1A CONR 1B —, —OC (═O) NR 1C —, —CO—, —S—, —SO 2 — , -SO 2 NR 1D- , -NR 1E SO 2 -or -NR 1F-
R 1A , R 1B , R 1C , R 1D , R 1E and R 1F are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted Alkylcarbonyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic A cyclic group,
A represents a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, or a substituted or unsubstituted aromatic heterocyclic ring. A formula group,
When L is —NR 1A CO—, —OC (═O) NR 1C —, —SO 2 —, —SO 2 NR 1D — or —NR 1E SO 2 — and m is 0, A is substituted Or it may be unsubstituted alkyl (except unsubstituted methyl), substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl,
R 1 , R 2 , R 3a , R 4a , R 3b and R 4b are each independently hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl , Substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group or substituted or unsubstituted aromatic heterocyclic group And
R 1 and R 2 bonded to the same carbon, together with the carbon atom to which they are bonded, form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring. Well,
R 1 and R 2 bonded to the same carbon may together form ═NR 1G ,
R 3a and R 4a , and R 3b and R 4b are each independently, together with the carbon atom to which they are attached, a substituted or unsubstituted non-aromatic carbocycle or substituted or unsubstituted non-aromatic May form a heterocycle,
R 3a and R 4a , and R 3b and R 4b may each independently form ═NR 1H ,
R 1G and R 1H are each independently substituted or unsubstituted alkyloxy, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted A non-aromatic heterocyclic group or a substituted or unsubstituted aromatic heterocyclic group,
m is an integer from 0 to 2,
n is 0 or 1,
Ring B is a 6-membered non-aromatic carbocycle, 6-membered aromatic carbocycle, 6-membered non-aromatic heterocycle, 6-membered aromatic heterocycle, or

A ring represented by
The bond a is bonded to —NHC (═O) CR 6 R 7 —, the bond b is bonded to —CR 3b R 4b —, and when ring B is a condensed ring, R 5 is B 1 and B 2 Any ring may be substituted,
B 1 ring is a 5-membered or 6-membered non-aromatic carbocyclic ring, a 6-membered aromatic carbocyclic ring, a 5-membered or 6-membered non-aromatic heterocyclic ring or a 5-membered or 6-membered aromatic heterocyclic ring,
The B 2 ring is a 6-membered non-aromatic carbocycle, a 6-membered aromatic carbocycle, a 6-membered non-aromatic heterocycle or a 6-membered aromatic heterocycle (wherein ring B is not piperidine and indole);
Each R 5 is independently halogen, hydroxy, cyano, sulfanyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted Alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted nonaromatic carbocyclic group, substituted Or an unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or Unsubstituted aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic Aromatic heterocyclic oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic sulfanyl, substituted or unsubstituted aromatic carbocyclic sulfanyl, substituted or unsubstituted non-aromatic heterocyclic sulfanyl Substituted or unsubstituted aromatic heterocyclic sulfanyl or a group represented by the formula: —NR 51 R 52 , wherein two R 5 together may form oxo,
p is an integer from 0 to 4,
E is SO 2 R 10A , SOR 10B or cyano;
R 10A and R 10B are each independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, or substituted or unsubstituted A substituted aromatic carbocyclic group,
X is = CR 9 -or = N-;
R 8 each independently represents halogen, hydroxy, sulfanyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyl Oxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or non-substituted Substituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted Aromatic carbocyclic oxy, substituted or unsubstituted non-aromatic heterocycle Oxy, substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic sulfanyl, substituted or unsubstituted aromatic carbocyclic sulfanyl, substituted or unsubstituted non-aromatic heterocyclic sulfanyl, substituted or An unsubstituted aromatic heterocyclic sulfanyl or a group represented by the formula: —NR 81 R 82 ;
R 9 is hydrogen, halogen, hydroxy, sulfanyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted Or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic Aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or unsubstituted aromatic Carbocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, Substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic carbocyclic sulfanyl, substituted or unsubstituted aromatic carbocyclic sulfanyl, substituted or unsubstituted non-aromatic heterocyclic sulfanyl, substituted or unsubstituted An aromatic heterocyclic sulfanyl group of the formula: —NR 91 R 92
R 51 , R 52 , R 81 , R 82 , R 91 and R 92 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or non-substituted A substituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group or a substituted or unsubstituted aromatic heterocyclic group,
R 6 is hydrogen, halogen, hydroxy, sulfanyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted Or unsubstituted alkynyloxy, substituted or unsubstituted alkylsulfanyl, substituted or unsubstituted alkenylsulfanyl, substituted or unsubstituted alkynylsulfanyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic An aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic heterocyclic group or a group represented by the formula: —NR 61 R 62 ,
R 7 is hydrogen, halogen, hydroxy, sulfanyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted Or an unsubstituted alkynyloxy, a substituted or unsubstituted alkylsulfanyl, a substituted or unsubstituted alkenylsulfanyl, a substituted or unsubstituted alkynylsulfanyl, or a group represented by the formula: —NR 71 R 72
R 6 and R 7 together with the carbon atom to which they are attached may form a substituted or unsubstituted non-aromatic carbocyclic ring or a substituted or unsubstituted non-aromatic heterocyclic ring,
R 61 , R 62 , R 71 and R 72 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl;
q is an integer from 0 to 3,
However,
(1) When L is —NR 1A CO—, —CONR 1B —, —CO— or —NR 1F —, R 3b and R 4b are not simultaneously hydrogen,
(2) When L is a single bond,
(I) m is 0,
(Ii) R 10A is unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, or substituted or unsubstituted aromatic carbocyclic group And
(Iii) A is a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group or a substituted or unsubstituted aromatic heterocyclic group, and
(Iv) satisfy at least one of the following conditions (a) to (c):
(A) at least one of R 3b and R 4b is unsubstituted alkyl, or R 3b and R 4b together with the carbon atom to which they are attached, a substituted or unsubstituted non-aromatic carbocycle or Forming a substituted or unsubstituted non-aromatic heterocycle, or R 3b and R 4b together form ═NR 1H ;
(B) Ring B is

The ring B 1 is a 5-membered non-aromatic carbocycle, a 5-membered non-aromatic heterocycle or a 5-membered aromatic heterocycle,
(C) Ring B is benzene, n is 1, A is substituted or unsubstituted phenyl, and
(3) Excluding the following compounds

)
Or a pharmaceutically acceptable salt thereof.
The compound according to claim 1, wherein L is -NR 1A CO-, or a pharmaceutically acceptable salt thereof.
m is 0, n is 0, and R 3b and R 4b are each independently hydrogen, halogen, or substituted or unsubstituted alkyl, or R 3b and R 4b are carbon atoms to which they are attached. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, which, together with, forms a substituted or unsubstituted cycloalkane.
The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R 3b is substituted or unsubstituted alkyl.
The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R 3b and R 4b are each independently substituted or unsubstituted alkyl.
The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R 3b and R 4b together with the carbon atom to which they are bonded form a substituted or unsubstituted cycloalkane. .
Ring B is a 6-membered aromatic carbocyclic ring, a 6-membered aromatic heterocyclic ring, or

A ring represented by
B 1 ring is a 5-membered non-aromatic carbocycle, 5-membered non-aromatic heterocycle or 5-membered aromatic heterocycle,
The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein the B 2 ring is a 6-membered aromatic carbocycle or a 6-membered aromatic heterocycle.
Ring B is benzene, indazole, benzimidazole, benzothiazole, benzoxazole, dihydrobenzimidazole, dihydrobenzothiazole or dihydrobenzoxazole, p is an integer from 0 to 2, and each R 5 is independently halogen, The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, which is hydroxy, cyano, alkyl or haloalkyl, and two R 5 s may together form oxo.
The compound according to any one of claims 1 to 6, wherein ring B is benzene, p is an integer of 0 to 2, and R 5 is each independently halogen, cyano, or substituted or unsubstituted alkyl. Or a pharmaceutically acceptable salt thereof.
10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein A is a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group.
A is the formula:

Each of R A is independently halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted monoalkylamino, substituted or unsubstituted dialkylamino, Substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted non-aromatic heterocyclic group Or a substituted or unsubstituted non-aromatic carbocyclic oxy or substituted or unsubstituted aromatic carbocyclic oxy, wherein r is an integer of 0 to 3, or a compound thereof, Pharmaceutically acceptable salt.
The compound or a pharmaceutically acceptable salt thereof according to claim 11, wherein r is 1 to 3, and R A is each independently halogen.
X is = CR 9 - is a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12.
The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein X is = CH-, E is SO 2 R 10A , and R 10A is substituted or unsubstituted alkyl.
The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein X is = N-, E is SO 2 R 10A , and R 10A is substituted or unsubstituted alkyl.
The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, wherein q is 0.
The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, wherein R 6 and R 7 are each independently hydrogen or substituted or unsubstituted alkyl.
The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, wherein R 6 and R 7 are both hydrogen.
L is —NR 1A CO—, —CONR 1B —, —NR 1A CONR 1B —, —OC (═O) NR 1C —, —CO—, —S—, —SO 2 —, —SO 2 NR 1D — , -NR 1E SO 2 -or -NR 1F-
A is a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group,
m is 0,
Ring B is benzene, 6-membered aromatic heterocycle, indazole, benzimidazole, benzothiazole, benzoxazole, dihydrobenzimidazole, dihydrobenzothiazole or dihydrobenzoxazole;
p is an integer from 0 to 2,
Each R 5 is independently halogen, hydroxy, cyano, alkyl or haloalkyl, and two R 5 together may form an oxo;
R 3b is halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbon A cyclic group, a substituted or unsubstituted non-aromatic heterocyclic group or a substituted or unsubstituted aromatic heterocyclic group,
R 4b is hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic An aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group or a substituted or unsubstituted aromatic heterocyclic group,
R 3a and R 4a , and R 3b and R 4b , independently of each other, together with the carbon atom to which they are attached, are substituted or unsubstituted non-aromatic carbocycle or substituted or unsubstituted non-aromatic The compound according to claim 1, which may form a heterocyclic ring, and R 3a and R 4a , and R 3b and R 4b may each independently form ═NR 1H , or a compound thereof, Pharmaceutically acceptable salt.
Formula (I ′):

(Where
R 1A is hydrogen or substituted or unsubstituted alkyl;
A is a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group;
R 3b and R 4b are each independently hydrogen, halogen or substituted or unsubstituted alkyl, or R 3b and R 4b , together with the carbon atom to which they are attached, are substituted or unsubstituted Form a cycloalkane (where R 3b and R 4b are not simultaneously hydrogen);
Ring B is a benzene ring,
Each R 5 is independently halogen, cyano or substituted or unsubstituted alkyl;
p is an integer from 0 to 2,
R 10A is substituted or unsubstituted alkyl;
R 6 and R 7 are each independently hydrogen or substituted or unsubstituted alkyl)
Or a pharmaceutically acceptable salt thereof.
A pharmaceutical composition comprising the compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof.
The pharmaceutical composition according to claim 21, which has a RORγt inhibitory action.
A method for treating or preventing a disease involving RORγt, which comprises administering the compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof.
The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, for treating or preventing a disease involving RORγt.