US009120776B2

(12) United States Patent (10) Patent No.: US 9,120,776 B2 Yamamoto et al. (45) Date of Patent: Sep. 1, 2015

(54) CONDENSED HETEROCYCLIC COMPOUND 2003/0171309 A1 9/2003 Halazy et al. 2003/0212012 A1 1 1/2003 Halazy et al. 2004, OO67988 A1 4/2004 Klein et al. (71) Applicant: Takeda Pharmaceutical Company 2004.0102634 A1 5/2004 Matsuura et al. Limited, Osaka-shi, Osaka (JP) 2006/0247307 A1 11/2006 Kitahara et al. 2006/0264486 A1 11/2006 Ma et al. (72) Inventors: Satoshi Yamamoto, Kanagawa (JP); 2008.0167318 A1 7/2008 Halazy et al. 2008. O176904 A1 7/2008 Govek et al. Junya Shirai, Kanagawa (JP); 2008/0221157 A1 9/2008 Chakravarty et al. Yoshiyuki Fukase, Kanagawa (JP); 2009,0163511 A1 6/2009 Darwish et al. Yoshihide Tomata, Kanagawa (JP); 2009,025.3758 A1 10, 2009 Miller Ayumu Sato, Kanagawa (JP); Atsuko 2009/0275609 A1 11/2009 Yu et al. 2009,0298854 A1 12/2009 Ma et al. Ochida, Kanagawa (JP); Kazuko 2010.0041721 A1 2, 2010 Miller Yonemori, Kanagawa (JP); Hideyuki 2011/0059958 A1 3/2011 Nishida et al. Nakagawa, Kanagawa (JP) 2011/O135650 A1 6/2011 Chackalamannil et al. 2011/0224267 A1 9, 2011 Miller (73) Assignee: Takeda Pharmaceutical Company 2011/0245222 A1 10/2011 Payan et al. Limited, Osaka (JP) 2011/0263.046 A1 10/2011 Deuschle et al. 2011/0319412 A1 12/2011 Sakagami et al. (*) Notice: Subject to any disclaimer, the term of this 2012/0108606 A1 5, 2012 Darwish et al. patent is extended or adjusted under 35 2013,0023660 A1 1/2013 Yu et al. U.S.C. 154(b) by 0 days. (Continued) (21) Appl. No.: 14/346,071 FOREIGN PATENT DOCUMENTS JP 2003-529584 10, 2003 (22) PCT Filed: Sep. 21, 2012 WO 86,067.17 11, 1986 (86). PCT No.: PCT/UP2012/074282 (Continued) S371 (c)(1), (2) Date: Mar. 20, 2014 OTHER PUBLICATIONS Registry STN Database accession No. 736964-37-7, Sep. 2004—1 (87) PCT Pub. No.: WO2013/042782 page. PCT Pub. Date: Mar. 28, 2013 (Continued) (65) Prior Publication Data US 2014/02284.09 A1 Aug. 14, 2014 Primary Examiner — Kristin Vajda (30) Foreign Application Priority Data (74) Attorney, Agent, or Firm — Hamre, Schumann, Mueller & Larson, P.C. Sep. 22, 2011 (JP) ...... 2011-2O7358 (51) Int. Cl. (57) ABSTRACT A6 IK3I/403 (2006.01) A6 IK3I/404 (2006.01) The present invention provides a fused heterocyclic com CO7D 40/12 (2006.01) pound having an RORyt inhibitory action. The present inven CO7D 209/88 (2006.01) tion relates to a compound represented by the formula (I): C07D 209/08 (2006.01) (52) U.S. Cl. (I) CPC ...... C07D401/12 (2013.01); A61 K31/403 --R3A (2013.01); A61 K3I/404 (2013.01); C07D 209/08 (2013.01); C07D 209/88 (2013.01) : Q (58) Field of Classification Search R24 7 B -HCN USPC ...... 514/339, 411, 415: 546/276.7: 548/444, N SA 548/503 A See application file for complete search history. RIA (56) References Cited wherein each symbol is as defined in the specification, pro U.S. PATENT DOCUMENTS vided that 2-(2-((4-cyanophenyl)amino)-2-oxoethoxy)-N- (9-ethyl-9H-carbazol-3-yl)acetamide and N-(4-cyanophe 4,977,153 A 12/1990 Louis et al. nyl)-N'-(9-ethyl-9H-carbazol-3-yl)-3- 6,080,767 A 6, 2000 Klein et al. 6,140,504 A 10, 2000 Klein et al. methylpentanediamide are excluded, or a thereof. 6,277,865 B1 8, 2001 Klein et al. 6,323,227 B1 1 1/2001 Klein et al. 2002fOO16339 A1 2/2002 Klein et al. 12 Claims, 3 Drawing Sheets US 9,120,776 B2 Page 2

(56) References Cited Kumar, et al., “The Benzenesulfoamide T0901317 N-2.2.2 -Trifluoroethyl-N-4-2.2.2-trifluoro-1-hydroxy-1- U.S. PATENT DOCUMENTS (trifluoromethypethyl)ethnylphenyl-benzenesulfonamide Is a Novel Retinoic Acid Receptor-Related Orphan Receptor-O/Y Inverse 2013,011.6288 A1 5, 2013 Miller Agonist'. Mol. Pharmacol., vol. 77. No. 2, 2010, pp. 228-236. 2013/0211075 A1 8, 2013 Ushio et al. Huh, et al., “Digoxin and its derivatives suppress T17 cell differen 2014/0045882 A1 2/2014 Darwish et al. tiation by antagonizing RORytactivity”. Nature, vol. 472, Apr. 2011, pp. 486-490. FOREIGN PATENT DOCUMENTS Wang, et al., “Identification of SR1078, a Synthetic Agonist for the Orphan Nuclear Receptors RORO and RORY”. ACS Chemical Biol WO 97.241.18 7/1997 ogy, vol. 5, No. 11, pp. 1029-1034, 2010. WO 99.00356 1, 1999 Xu, et al., “Ursolic Acid Suppresses Interleukin-17 (IL-17) Produc WO O 1/72705 10, 2001 tion by Selectively Antagonizing the Function of RORyt Protein'. WO O 1/74769 10, 2001 The Journal of Biological Chemistry, vol. 286, 2011, pp. 22707 WO 02/100812 12/2002 22710. WO 2004/074236 9, 2004 Wang, et al., “Modulation of Retinoic Acid Receptor-related Orphan WO 2004/098498 11, 2004 WO 2006/005.941 1, 2006 Receptor C. and Y Activity by 7-Oxygenated Sterol Ligands'. The WO 2006/091496 8, 2006 Journal of Biological Chemistry, vol. 285, 2010, pp. 5013-5025. WO 2009,076631 6, 2009 Wang, et al., “A second class of nuclear receptors for oxysterols: WO 2010/049144 5, 2010 Regulation of RORO and RORY activity by 24S-hydroxycholesterol WO 2010/065717 6, 2010 (cerebrosterol)”. Biochimicaet Biophysica Acta, vol. 1801, 2010, pp. WO 2010, 10 1246 9, 2010 917-923. WO 2011/123681 10, 2011 Jin, et al., “Structural Basis for Hydroxycholesterols as Natural WO 2012/05O159 4/2012 Ligands of Orphan Nuclear receptor RORY”. Mol. Endocrinol, vol. 24, No. 5, 2010, pp. 923-929. OTHER PUBLICATIONS Registry STN Database accession No. 1036688-95-5. Jul. 2008—1 page. Registry STN Database accession No. 737780-18-6, Sep. 2004—1 Registry STN Database accession No. 1327387-55-2, Sep. 2011—1 page. page. Ivanov, et al., “The orphan Nuclear Receptor RORyt Directs the Registry STN Database accession No. 1036676-51-3, Jul. 2008—1 Differentiation Program of Proinflammatory IL-17'T Helper Cells'. page. Cell, vol. 126, Sep. 2006, pp. 1121-1133. Registry STN Database accession No. 1015722-56-1, Apr. 2008—1 Manel, et al., “The differentiation of human T-17 cells requires page. transforming growth factor-fi and induction of the nuclear receptor Registry STN Database accession No. 745025-44-9, Sep. 2004—1 RORyt”. Nature Immunology, vol. 9, No. 6, Jun. 2008, pp. 641-649. page. Solt, et al., “Suppression of T-17 differentiation and autoimmunity Registry STN Database accession No. 568539-93-5, Aug. 2003—1 by a synthetic ROR ligand’, Nature, vol. 472, Apr. 2011, p. 491. page. U.S. Patent Sep. 1, 2015 Sheet 1 of 3 US 9,120,776 B2

Fig. 1 Aouse LAVACTB

2.SE-04 (10) (25) (53) 2.0E-04 15E-04

1.OE-04 5 OE-05 0.0E+00 Normal Control 30 OO 300 The COImpound of Example 14 (mg/kg, p O)

n = 6, mean+SE ##: p < 0.01 vs normal; student's t test, * : p < 0.025 vs control; William's test U.S. Patent Sep. 1, 2015 Sheet 2 of 3 US 9,120,776 B2

Fig. 2

Vouse IFNg/ACTB

6.OE-04 (-3) (2) (3)

S.OE-04

4.OE-04

3.OE-04

2.OE-04

1.OE-04

O.OE-00 Normal Control 30 100 300

The Compound of Example 14 (Ing/kg, po)

n = 6, meanic SE i ! : p < 0.01 vs normal; student's t test, * : p < 0.025 vs control; William's test U.S. Patent Sep. 1, 2015 Sheet 3 of 3 US 9,120,776 B2

Fig. 3

0.02 -17AmRNA

O.O15

(29.4)

S.S. O.01 (61.0) (66.6) t 0.005 -

O rio ------, vocroe, aw,go crg Normal Control 3O 100 300 The Compound of Example 1.4 (mg/kg, po) ?:6, means SE US 9,120,776 B2 1. 2 CONDENSED HETEROCYCLIC COMPOUND wherein rS and rô may together form TECHNICAL FIELD The present invention relates to a fused heterocyclic com \ / pound having an RORyt inhibitory action, a medicament con taining the compound, and the like. Y. W. BACKGROUND OF THE INVENTION 10 Th17 cell and inflammatory cytokine (IL-17A, IL-17F and ^ - the like) produced thereby cause various autoimmune disease such as inflammatory bowel disease (IBD), rheumatoid As a compound having an RORC. and RORY inverse ago arthritis, multiple Sclerosis or psoriasis, and a decrease in 15 nist activity, non-patent document 3 describes a compound QOL as a severe etiology cell and factor accompanying represented by the formula: enhancement of a systemic new immune response. However, the existing therapeutic drugs show only limited effects, and therefore, the earliest possible development of a novel thera peutic drug has been desired. O N H F Involvement of T cells, interalia, Th17 cell and inflamma us us S N F tory cytokines (IL-17A, IL-17F and the like) produced N S / \, OH thereby, in the pathology of these autoimmune disease has 25 F been drawing attention in recent years. F Moreover, it has been recently clarified that a Retinoid related Orphan Receptor (ROR) yt, which is one of the orphan nuclear receptors, plays an important role in the differentia (SR1001) tion of Th17 cells and production of IL-17A/IL-17F. That is, 30 it has been reported that RORyt is mainly expressed in Th17 and non-patent document 4 describes a compound repre cells and functions as a transcription factor of IL-17A and sented by the formula: IL-17F, as well as a master regulator of Th17 cell differentia tion (non-patent documents 1 and 2). Therefore, a medicament that inhibits the action of RORyt 35 R F is expected to show a treatment effect on various autoimmune disease by suppressing differentiation and activation of Th17 F cells. R F As a compound that regulates RORY activity, patent docu N ment 1 describes a compound represented by the formula: 40 s^ F /\, OH F F 45 (TO901317). As a compound that antagonizes an RORyt activity, non patent document 5 describes a compound represented by the formula:

OH

OH US 9,120,776 B2 3 4 (Digoxin). (7C.-hydroxycholesterol) As a compound having an RORC. and RORY agonist activ ity, non-patent document 6' describes a compound repre sented by the formula:

F F F OH 10 F O F (7f8-hydroxycholesterol) F N 15 F OH F F 2O

(SR1078). As a compound that regulates RORC. and RORY activities, (24-ketocholesterol), and non-patent document 9 describes a non-patent document 7 describes a compound represented by 25 compound represented by the formula: the formula:

30

35

(24S-hydroxycholesterol). 40 As a ligand of RORY, non-patent document 10 describes compounds represented by the formulas:

(Ursolic acid). A As a compound that regulates RORC. and RORY activities, 45 non-patent document 8 describes compounds represented by the formulas:

50

HO

Cholesterol 55

60

65 20C-Hydroxycholesterol US 9,120,776 B2 5 6 -continued rheumatoid arthritis, multiple Sclerosis, psoriasis and the like. H The present inventors have conducted intensive studies based on the finding and completed the present invention. Accordingly, present invention relates to 1 a Compound represented by the formula (I'):

(I)

HO Q 22(R)-Hydroxycholesterol B -HCN N SA 15 A. R OH wherein R'' is an optionally substituted hydrocarbon group or an optionally substituted hydrocarbon-oxy group, HO R° and Rare each independently a hydrogen atom, an optionally Substituted hydrocarbon group, an optionally Sub 25-Hydroxycholesterol stituted hydrocarbon-oxy group, an acyl group, a halogen atom, a cyano group, an optionally Substituted hydrocarbon 25 amino group, an optionally Substituted hydrocarbon-sulfanyl group, an optionally Substituted hydrocarbon-Sulfenyl group, DOCUMENT LIST an optionally substituted hydrocarbon-sulfonyl group or a nitro group, or RandR optionally form, together with the Patent Document carbon atoms which they are bonded to, an optionally Substi 30 tuted hydrocarbon ring, patent document 1: WO 2010/049144 R" is a hydrogen atom or a halogen atom, Non-Patent Document Q is a bivalent group selected from non-patent document 1: Cell 126, 1121-1133 (2006) 35 non-patent document 2: Nat. Immunol. 9, 641-649 (2008) non-patent document 3: Nature, 2011, 472, 491 O O non-patent document 4: Mol. Pharmacol., 2010, 77(2): 228 non-patent document 5: Nature, 2011, 472, 486 non-patent document 6: ACS Chem. Biol. 2010, 5(11), 1029 40 H H non-patent document 7: TheJournal of Biological Chemistry, (Ib) 2011, 286, 22707 non-patent document 8: TheJournal of Biological Chemistry, 2010, 285, 5013 non-patent document 9: Biochimica et Biophysica Acta, 1801 45 R4A R4B (2010),917 I non-patent document 10: Mol. Endocrinol, May 2010, 24(5), O O (Ic) 923

SUMMARY OF THE INVENTION 50 NNH --- R4A Problems to be Solved by the Invention O (I'd)I'd The present invention aims to provide a compound having a superior RORyt inhibitory action, and useful as an agent for 55 the prophylaxis or treatment of inflammatory bowel disease H H (I'e) (IBD), ulcerative colitis (UC), Crohn's disease (CD), rheu O O matoid arthritis, multiple Sclerosis, psoriasis and the like.

Means of Solving the Problems 60 N.H H 1N (I'f) The present inventors have found that a compound repre O sented by the following formula (I) and (I) or a salt thereof has a superior RORyt inhibitory action based on the specific N chemical structure thereof and affords Superior efficacy as an 65 N |A), 1 agent for the prophylaxis or treatment of inflammatory bowel O disease (IBD), ulcerative colitis (UC), Crohn's disease (CD), US 9,120,776 B2 7 8 -continued R'' and Rare the same or different and each is an option O (Ig)I ally Substituted hydrocarbon group, X" is an oxygen atom, a Sulfur atom, or an imino group N having an optionally Substituted hydrocarbon group or a NullsNA, 1. hydrogen atom, O n is an integer of 1 to 5. (Ih) n' is an integer of 1 to 4. H n" is an integer of 1 to 3, and N x' and y are each 0 or natural number, and the sum is 0 to NA1 1 10 4, and O O Ring B' is a benzene ring optionally having additional I Substituent(s), or a pyridine ring optionally having additional H (I'i) substituent(s), provided that when Risahalogenatom, then NAIYNs1 Ring B' is a benzene ring optionally having additional Sub 15 stituent(s), O /\, provided that 2-(2-((4-cyanophenyl)amino)-2-oxoethoxy)- O (I) N-(9-ethyl-9H-carbazol-3-yl)acetamide and N-(4-cyanophe nyl)-N'-(9-ethyl-9H-carbazol-3-yl)-3-methylpentanedia mide are excluded (hereinafter sometimes to be referred to as compound (I)) or a salt thereof; Nsu 2 the compound or salt of 1, wherein O R4A (Ik) R" is a hydrogen atom, Q is a bivalent group selected from N NNH All 1 Y 25 O O O (II) O O

30 H H NNH A"),-*N |Aly2 ls N 1. H (Ib) (I'm) O O\/ O O 35 R R YN All 1 NA-1N1H O O (Ic)I O O (In)I N -n. 2 ls 1. N A"), |Aly N 40 H R4A O (I'o) I'd N.-l O (I'd) NA, 1. and 45 H H O (I'e) O (I'p) O O

50 n-s-s-sH H Nsu--> (I'f) O wherein A" are the same or different and each is a methylene group optionally Substituted by Substituent(s) selected from a 55 NNH Al)1 Y hydroxy group, a phenyl group and an optionally substituted O (Ig) C. alkyl group, wherein the two Substituents bonded to the O single carbon atom are optionally combined to each other to H form a hydrocarbon ring, and A are the same or different N ls and each is a methylene group optionally Substituted by Sub 60 A. 1. stituent(s) selected from a hydroxy group and an optionally O Substituted C. alkyl group, wherein the two Substituents (Ih) bonded to the single carbon atom are optionally combined to each other to form a hydrocarbon ring, or the methylene groupinA'or A is optionally combined to the substituent 65 NA1 1 on the adjacent methylene group to form an optionally Sub O O stituted hydrocarbon ring, US 9,120,776 B2 9 10 -continued -continued

(I'i) O NA-1Ns.1 l 1 O / \, N1NAH 1 O O (I) (I) O YN A1So1 10 no O R4A (Ik) O O

N l S l and ls.- 15 NNH A11 Y N-Na?H NA-11 O (In) O (II) O O N. l. YN Al31 Y1A2, HN1 wherein each symbol is as defined in 1: O O O O (I'm) 5 N-(4-cyanophenyl)-N'-(9-ethyl-2,3,4,9-tetrahydro-1H 25 carbazol-6-yl)-3-methylpentanediamide or a salt thereof; Xul 6 N-(3-chloro-4-cyanophenyl)-N'-(9-ethyl-9H-carbazol-3- N1 starStar-N-1H and yl)-3-methylpentanediamide or a salt thereof; 7 N-(4-(3-chloro-4-cyanophenyl)amino-2-methyl-4-ox O O (In)I 30 obutyl-9-ethyl-9H-carbazole-3-carboxamide or a salt thereof; N N A'.11 Sn Aly2 ls N 1. 8 a medicament comprising a compound represented by the formula (I): wherein 35 A") are the same or different and each is a methylene as (I) group optionally Substituted by Substituent(s) selected from a hydroxy group and an optionally Substituted Calkyl group, Q wherein the two substituents bonded to the single carbon 40 R2A / B -HCN atom are optionally combined to each other to form a hydro N SA carbon ring, and AI are the same or different and each is a A R methylene group optionally Substituted by Substituent(s) RIA selected from a hydroxy group and an optionally Substituted C. alkyl group, wherein the two Substituents bonded to the 45 wherein single carbon atom are optionally combined to each other to R'' is an optionally substituted hydrocarbon group or an form a hydrocarbon ring, or the methylene group in A' or optionally substituted hydrocarbon-oxy group, A is optionally combined to the substituent on the adjacent R° and Rare each independently a hydrogen atom, an methylene group to form an optionally Substituted hydrocar optionally Substituted hydrocarbon group, an optionally Sub bon ring, and the other symbols are as defined in 1, and 50 stituted hydrocarbon-oxy group, an acyl group, a halogen Ring B' is a benzene ring optionally further substituted by atom, a cyano group, an optionally Substituted hydrocarbon Substituent(s) excluding cyano; amino group, an optionally Substituted hydrocarbon-sulfanyl group, an optionally Substituted hydrocarbon-Sulfenyl group, (3) the compound or salt of 11, wherein RandR'' are each an optionally substituted hydrocarbon-sulfonyl group or a independently a C- alkyl group, or R'' and R' form, 55 nitro group, or RandR optionally form, together with the together with the carbon atoms which they are bonded to, an carbon atoms which they are bonded to, an optionally Substi optionally substituted hydrocarbon ring; tuted hydrocarbon ring, 4 the compound or salt of 1, wherein Q'is a bivalent group R" is a hydrogen atom or a halogen atom, selected from Q is a bivalent group selected from 60

O O O O

65 N--H H H H US 9,120,776 B2 11 12 -continued -continued (Ib) (In) O O k (Ic) O O 10

H R44

O 15

H H wherein O O A") are the same or different and each is a methylene group optionally Substituted by Substituent(s) selected from a hydroxy group, a phenyl group and an optionally substituted H H C. alkyl group, wherein the two Substituents bonded to the single carbon atom are optionally combined to each other to O 25 form a hydrocarbon ring, and A are the same or different and each is a methylene group optionally substituted by Sub stituent(s) selected from a hydroxy group and an optionally NNH A11 1 Substituted C. alkyl group, wherein the two Substituents O bonded to the single carbon atom are optionally combined to (Ig) 30 each other to form a hydrocarbon ring, or the methylene O group in A' or A is optionally combined to the substituent H on the adjacent methylene group to form an optionally sub N Aful 1. stituted hydrocarbon ring, O RandR are the same or different and each is an option 35 ally Substituted hydrocarbon group, (Ih) H H X" is an oxygen atom, a Sulfur atom, or an imino group N N having an optionally Substituted hydrocarbon group or a NA1 1 hydrogen atom, O O n is an integer of 1 to 5. 40 n' is an integer of 1 to 4. H n" is an integer of 1 to 3, and NAYNs 1 x' and y are each 0 or natural number, and the sum is 0 to O /\, 4, and 45 Ring B' is a benzene ring optionally having additional (I) Substituent(s), or a pyridine ring optionally having additional O substituent(s), provided that when Risahalogenatom, then Ring B' is a benzene ring optionally having additional Sub Nsu stituent(s), 50 or a salt thereof; (Ik) 9 the medicament of 8, which is an RORyt inhibitor; O R4A 10 the medicament of 8, which is an agent for the prophy N laxis or treatment of inflammatory bowel disease (IBD), ulcerative colitis (UC), Crohn's disease (CD), rheumatoid NNH A1 1 55 arthritis, multiple Sclerosis or psoriasis; O 11 a method of inhibiting RORyt, which comprises admin (II) istering an effective amount of the compound or salt of 1 to O O a mammal, X l 12 a method for the prophylaxis or treatment of inflamma YN All1 Y1A2, N1 60 tory bowel disease (IBD), ulcerative colitis (UC), Crohn's H disease (CD), rheumatoid arthritis, multiple Sclerosis or pso riasis, which comprises administering an effective amount of O O O O the compound or salt of 1 to a mammal; 13 use of the compound or salt of 1 for the production of SN ls All.1\/ YA, l 1 65 an agent for the prophylaxis or treatment of inflammatory H bowel disease (IBD), ulcerative colitis (UC), Crohn's disease (CD), rheumatoid arthritis, multiple Sclerosis or psoriasis; US 9,120,776 B2 13 14 14 the compound or salt of 1 for use in the prophylaxis or -continued treatment of inflammatory bowel disease (IBD), ulcerative (Ig) colitis (UC), Crohn's disease (CD), rheumatoid arthritis, multiple Sclerosis or psoriasis; and the like. The present invention also relates to 1A a compound represented by the formula (I): (Ih)

(I) 10

(II) Q N -R2 / B -HCN N 2 15 (I) wherein R" is an optionally substituted hydrocarbon group or an (Ik) optionally substituted hydrocarbon-oxy group, O R4 RandR are each independently an optionally substituted hydrocarbon group, an optionally substituted hydrocarbon oxy group, an acyl group, a halogenatom, a cyano group, an 25 optionally Substituted hydrocarbon-amino group, an option (II) ally Substituted hydrocarbon-sulfanyl group, an optionally O O Substituted hydrocarbon-Sulfenyl group, an optionally Substi tuted hydrocarbon-sulfonyl group or a nitro group, or R and 30 R optionally form, together with the carbon atoms which n-s-s-s-H y H they are bonded to, an optionally substituted hydrocarbon (Im) r1ng, O O O O Q is a bivalent group selected from ls \/ us and 35 SN Al1 YA); N1 (In) (Ia) O O O O O N N ls.-S.-lAl-Na?1SN1. i 1. n-s-s- 40 (Ib) O O wherein A are the same or different and each is a methylene group optionally substituted by substituent(s) selected from a N-1- 45 hydroxy group and an optionally Substituted Calkyl group, R4 R4 wherein the two substituents bonded to the single carbon (Ic) O O atom are optionally combined to each other to form a hydro carbon ring, and A are the same or different and each is a methylene group optionally Substituted by Substituent(s) 50 selected from a hydroxy group and an optionally Substituted NS-S-4 C. alkyl group, wherein the two Substituents bonded to the (Id) single carbon atom are optionally combined to each other to O form a hydrocarbon ring, or the methylene group in A or A is optionally combined to the substituent on the adjacent 55 methylene group to form an optionally Substituted hydrocar Sr.'s bon ring, (Ie) RandR'' are the same or different and each is an option O O ally Substituted hydrocarbon group, X is an oxygen atom, a Sulfur atom, or an imino group Nasra 60 having an optionally Substituted hydrocarbon group or a (If) hydrogen atom, and O X and y are each 0 or natural number, and the Sum is 0 to 4. and ls Ring B is a benzene ring optionally further substituted by YN Al?o 1 65 Substituent(s) excluding cyano, O provided that 2-(2-((4-cyanophenyl)amino)-2-oxoethoxy)- N-(9-ethyl-9H-carbazol-3-yl)acetamide and N-(4-cyanophe US 9,120,776 B2 15 16 nyl)-N'-(9-ethyl-9H-carbazol-3-yl)-3-methylpentanedia -continued mide are excluded (hereinafter sometimes to be referred to as compound (I)) or a salt thereof; (Ib) 2A) the compound or salt of 1A), wherein R and R are each independently a C- alkyl group, or R and R form, together with the carbon atoms which they are bonded to, an optionally substituted hydrocarbon ring; > al 3A the compound or salt of 1A, wherein Q is (Ic) 10 (Ia) SN Ju - ul R4 N N A1-5 N1 (Id) 15 O l (I) Sr.'s- YN A1 No1 (Ie) (II) O O

N N l A.-SS |Alyls N 1 of (If) (In) 25 O O O

N N A.1'N, Aly N 1.

30 (Ig) wherein A, A, X and y are as defined in 1A: 4A a medicament comprising a compound represented by the formula (I):

35

ess (I) (Ih) ? R3 Q / N 40 R2 B -HCN N 2 (II)

45 wherein (I) R" is an optionally substituted hydrocarbon group or an optionally substituted hydrocarbon-oxy group, RandR are each independently an optionally substituted hydrocarbon group, an optionally substituted hydrocarbon 50 oxy group, an acyl group, a halogenatom, a cyano group, an (Ik) optionally Substituted hydrocarbon-amino group, an option O R4 ally Substituted hydrocarbon-sulfanyl group, an optionally Substituted hydrocarbon-Sulfenyl group, an optionally Substi tuted hydrocarbon-sulfonyl group or a nitro group, or R and 55 R optionally form, together with the carbon atoms which they are bonded to, an optionally substituted hydrocarbon (II) ring,

Q is a bivalent group selected from 60

(Ia) (Im) YN Ju-- 65 US 9,120,776 B2 17 18 -continued optionally substituted cycloalkyl group, an optionally Substi (In) tuted cycloalkenyl group and the like. O O In the present specification, examples of the “optionally Substituted alkyl group' include a C- alkyl group (e.g., N ls 1SN us 1. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, N A. (A), N tert-butyl, pentyl, neo-pentyl, hexyl etc.) optionally having substituent(s) selected from wherein (i) a halogen atom (e.g., a fluorine atom, a chlorine atom, a A are the same or different and each is a methylene group bromine atom, an iodine atom), optionally substituted by substituent(s) selected from a 10 (ii) a cyano group, hydroxy group and an optionally Substituted Calkyl group, (iii) a hydroxyl group, wherein the two substituents bonded to the single carbon (iv) a nitro group, atom are optionally combined to each other to form a hydro (v) a formyl group, carbon ring, and A are the same or different and each is a (vi) an amino group, methylene group optionally Substituted by Substituent(s) 15 (vii) a mono- or di-C alkylamino group (e.g., methylamino, selected from a hydroxy group and an optionally Substituted ethylamino, propylamino, dimethylamino, diethylamino, C. alkyl group, wherein the two substituents bonded to the dipropylamino etc.), single carbon atom are optionally combined to each other to (viii) a C- alkyl-carbonylamino group (e.g., acetylamino, form a hydrocarbon ring, or the methylene group in A or ethylcarbonylamino etc.), A is optionally combined to the substituent on the adjacent (ix) a Calkoxy-carbonylamino group (e.g., methoxycarbo methylene group to form an optionally Substituted hydrocar nylamino, ethoxycarbonylamino, propoxycarbonylamino bon ring, etc.), RandR'' are the same or different and each is an option (X) a Cs cycloalkyl group (e.g., cyclopropyl, cyclobutyl, ally Substituted hydrocarbon group, cyclopentyl, cyclohexyl etc.) optionally fused with a benzene X is an oxygen atom, a Sulfur atom, or an imino group 25 r1ng, having an optionally Substituted hydrocarbon group or a (xi) a Cas cycloalkenyl group (e.g., cyclopropenyl, hydrogen atom, and cyclobutenyl, cyclopentenyl, cyclohexenyl etc.) optionally X and y are each 0 or natural number, and the Sum is 0 to 4. fused with a benzene ring, and (xii) a Caryl group (e.g., phenyl, 1-naphthyl 2-naphthyl Ring B is a benzene ring optionally further substituted by 30 etc.) optionally substituted by substituent(s) selected from a Substituent(s) excluding cyano, or a salt thereof. halogen atom (e.g., a fluorine atom, a chlorine atom, a bro 5A the medicament of 4A, which is a RORYt receptor mine atom, an iodine atom) and a C- alkoxy group (e.g., inhibitor. methoxy, ethoxy, propoxy etc.), 6A the medicament of 4A, which is an agent for the (xiii) a C- alkoxy group (e.g., methoxy, ethoxy, propoxy, prophylaxis or treatment of inflammatory bowel disease 35 isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy etc.) (IBD), Crohn's disease (CD), rheumatoid arthritis, multiple optionally Substituted by halogen atom(s) (e.g., a fluorine Sclerosis or psoriasis; atom, a chlorine atom, a bromine atom, an iodine atom), and the like. (xiv) a C7-16 aralkyloxy group (e.g., benzyloxy etc.), (XV) a C-14 aryloxy group (e.g., phenoxy etc.) optionally Effect of the Invention 40 substituted by substituent(s) selected from a C- alkoxy group (e.g., methoxy etc.), a C- alkyl group (e.g., methyl The compound of the present invention has a Superior etc.) and a halogen atom (e.g., a fluorine atom, a chlorine RORyt inhibitory action, and useful as an agent for the pro atom, a bromine atom, an iodine atom), phylaxis or treatment of inflammatory bowel disease (IBD), (Xvi) a carboxyl group, ulcerative colitis (UC), Crohn's disease (CD), rheumatoid 45 (Xvii) a C- alkoxy-carbonyl group (e.g., methoxycarbonyl, arthritis, multiple Sclerosis, psoriasis and the like. ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, tert butoxycarbonyl etc.), BRIEF DESCRIPTION OF THE DRAWINGS (Xviii) a C- aralkyloxy-carbonyl group (e.g., benzyloxy carbonyl etc.), FIG. 1 shows an effect of the compound of Example 14 on 50 (XiX) a Caryloxy-carbonyl group (e.g., phenoxycarbonyl IL-17A gene expression caused by stimulation with anti-CD3 etc.), antibody in mouse colon. (XX) a C- alkyl-carbonyl group (e.g., acetyl, ethylcarbonyl, FIG. 2 shows an effect of the compound of Example 14 on propylcarbonyl, isopropylcarbonyl, 2,2-dimethylpropylcar IFN-Y gene expression caused by stimulation with anti-CD3 bonyl etc.), antibody in mouse colon. 55 (XXi) a Css cycloalkyl-carbonyl group (e.g., cyclopropylcar FIG.3 shows an effect of the compound of Example 14 on bonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexy IL-17A gene expression in lymph node of EAE rat model. lcarbonyl etc.), (XXii) a C- aralkyl-carbonyl group (e.g., benzylcarbonyl DETAILED DESCRIPTION OF THE INVENTION etc.), 60 (XXvii) a carbamoyl group, The present invention is explained in detail in the follow (XXiv) a thiocarbamoyl group, 1ng. (XXV) a mono- or di-C alkyl-carbamoyl group (e.g., meth In the present specification, examples of the “optionally ylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropyl Substituted hydrocarbon group' include an optionally substi carbamoyl, dimethylcarbamoyl, diethylcarbamoyl, dipropy tuted alkyl group, an optionally Substituted alkenyl group, an 65 lcarbamoyl etc.), optionally Substituted alkynyl group, an optionally Substi (XXvi) a mono- or di-C. aralkyl-carbamoyl group (e.g., tuted aralkyl group, an optionally Substituted aryl group, an benzylcarbamoyl, dibenzylcarbamoyl etc.), US 9,120,776 B2 19 20 (XXvii) a thiol group, (XXXXV) a bridged Cz-ocycloalkyl group (e.g., bicyclo3.1.1 (XXviii) a C- alkylthio group (e.g., methylthio, ethylthio. heptyl, adamantyl etc.) optionally substituted by C. alkyl propylthio etc.), group(s) (e.g., methyl etc.). (XXiX) a C- aralkylthio group (e.g., benzylthio etc.), (XXXXVi) a Carylthio group (e.g., phenylthio etc.) and the (XXX) a C- alkylsulfonyl group (e.g., methylsulfonyl, ethyl like. The number of the substituents is 1 to 4, preferably 1 to Sulfonyl, propylsulfonyl, isopropylsulfonyl etc.), 3. When the number of the substituents is 2 or more, the (XXXi) a C-s cycloalkylsulfonyl group (e.g., cyclopropylsul respective substituents may be the same or different. fonyl, cyclobutylsulfonyl, cyclopentylsulfonyl etc.), In the present specification, examples of the “optionally (XXXii) a C- arylsulfonyl group (e.g., phenylsulfonyl, Substituted alkenyl group” include a C- alkenyl group (e.g., 1-naphthylsulfonyl, 2-naphthylsulfonyl etc.), 10 vinyl, 1-propenyl, allyl, isopropenyl, butenyl, isobutenyl etc.) optionally having 1 to 4, preferably 1 to 3, substituents which (XXXiii) a Cz aralkylsulfonyl group (e.g., benzylsulfonyl the alkyl group of the above-defined “optionally substituted etc.). alkyl group' optionally has, and the like. When the number of (XXXiv) a 5- to 8-membered non-aromatic heterocyclic group the Substituents is 2 or more, the respective Substituents may containing, besides carbon atoms, 1 to 4 hetero atoms 15 be the same or different. selected from a nitrogen atom, a Sulfur atom and an oxygen In the present specification, examples of the “optionally atom (e.g., pyrrolidinyl, tetrahydrofuryl, tetrahydrothienyl, Substituted alkynyl group' include a C- alkynyl group (e.g., piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, ethynyl, propargyl, butynyl, 1-hexynyl etc.) optionally hav piperazinyl etc.), wherein the non-aromatic heterocyclic ing 1 to 4, preferably 1 to 3, substituents which the alkyl group group is optionally Substituted by C. alkyl group(s) (e.g., of the above-defined “optionally substituted alkyl group' methyl etc.), optionally has, and the like. When the number of the substitu (XXXV) a 5- to 8-membered aromatic heterocyclic group con ents is 2 or more, the respective substituents may be the same taining, besides carbon atoms, 1 to 4 hetero atoms selected or different. from a nitrogenatom, a Sulfur atom and an oxygenatom (e.g., In the present specification, examples of the “optionally furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, 25 Substituted aralkyl group' include a C-2 aralkyl group (e.g., isothiazolyl, imidazolyl pyrazolyl, 1.2.3-oxadiazolyl, 1,2,4- benzyl, 2-phenylethyl, 1-phenylethyl 3-phenylpropyl and oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1.2.3-thiadiazolyl, the like) optionally having 1 to 4, preferably 1 to 3, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1.2.3-triazolyl, 1,2,4- (i) substituents which the alkyl group of the above-defined triazolyl, tetrazolyl pyridyl, pyridazinyl, pyrimidinyl, “optionally Substituted alkyl group' optionally has, 30 (ii) C alkyl groups (e.g., methyl, ethyl, propyl, isopropyl. pyrazinyl, triazinyl etc.), wherein the aromatic heterocyclic butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neo-pentyl, hexyl group is optionally substituted by halogen atom(s) (e.g., a and the like) optionally substituted by substituent(s) selected chlorine atom etc.) or C. alkyl group(s) (e.g., methyl etc.) from a halogenatom (e.g., a fluorine atom, a chlorine atom, a and optionally fused with a benzene ring (e.g., benzothienyl bromine atom, an iodine atom), a C- alkoxy group (e.g., etc.). 35 methoxy, ethoxy, propoxy and the like), a Carylsulfonyl (XXXVi) a 5- to 8-membered non-aromatic heterocyclyl-car group and a heterocyclic group (e.g., morpholinyl, pyridyl, bonyl group containing, besides carbon atoms, 1 to 4 hetero imidazopyridyl, benzimidazolyl and the like), atoms selected from a nitrogen atom, a Sulfur atom and an (iii) C. aralkyl groups (e.g., benzyl, 2-phenylethyl, 1-phe oxygen atom (e.g., pyrrolidinylcarbonyl, tetrahydrofurylcar nylethyl, 3-phenylpropyl, 4-phenylbutyl and the like), bonyl, tetrahydrothienylcarbonyl, piperidylcarbonyl, tet 40 (iv)5- to 8-membered aromatic heterocyclyl-oxy groups con rahydropyranylcarbonyl, morpholinylcarbonyl, thiomor taining, besides carbon atoms, 1 to 4 hetero atoms selected pholinylcarbonyl, piperazinylcarbonyl etc.), from a nitrogenatom, a Sulfur atom and an oxygenatom (e.g., (XXXVii) a 5- to 8-membered aromatic heterocyclyl-carbonyl furyloxy, thienyloxy, pyrrolyloxy, oxazolyloxy, isoxazoly group containing, besides carbon atoms, 1 to 4 hetero atoms loxy, thiazolyloxy, isothiazolyloxy, imidazolyloxy, pyrazoly selected from a nitrogen atom, a Sulfur atom and an oxygen 45 loxy, 1.2.3-oxadiazolyloxy, 1,2,4-oxadiazolyloxy, 1,3,4-oxa atom (e.g., furylcarbonyl, thienylcarbonyl, pyrrolylcarbonyl, diazolyloxy, furazanyloxy, 1,2,3-thiadiazolyloxy, 1,2,4- oxazolylcarbonyl, isoxazolylcarbonyl, thiazolylcarbonyl, thiadiazolyloxy, 1.3,4-thiadiazolyloxy, 1,2,3-triazolyloxy, isothiazolylcarbonyl, imidazolylcarbonyl, pyrazolylcarbo 1,2,4-triazolyloxy, tetrazolyloxy, pyridyloxy, pyridaziny nyl, 1.2.3-oxadiazolylcarbonyl, 1,2,4-oxadiazolylcarbonyl, loxy, pyrimidinyloxy, pyrazinyloxy, triazinyloxy and the 1,3,4-oxadiazolylcarbonyl, furazanylcarbonyl, 1,2,3-thiadia 50 like), or the like. In the present specification, the substituent of Zolylcarbonyl, 1,2,4-thiadiazolylcarbonyl, 1.3,4-thiadiaz the “optionally substituted aralkyl group” may be present in olylcarbonyl, 1,2,3-triazolylcarbonyl, 1,2,4-triazolylcarbo the aryl part and/or the alkylene part of the aralkyl group. nyl, tetrazolylcarbonyl, pyridylcarbonyl, When the number of the substituents is 2 or more, the respec pyridazinylcarbonyl, pyrimidinylcarbonyl, pyrazinylcarbo tive substituents may be the same or different. nyl, triazinylcarbonyl etc.), 55 In the present specification, examples of the “optionally (XXXViii) an ureido group, Substituted aryl group” include a Caryl group (e.g., phe (XXXix) a C- alkyl-ureido group (e.g., methylureido, ethy nyl, naphthyl and the like) optionally having 1 to 4, preferably lureido, propylureido etc.), 1 to 3, substituents which the aralkyl group of the above (XXXX) a Caryl-ureido group (e.g., phenylureido, 1-naph defined “optionally substituted aralkyl group' optionally has. thylureido, 2-naphthylureido etc.), 60 When the number of the substituents is 2 or more, the respec (XXXXi) a C alkylenedioxy group (e.g., methylenedioxy, tive substituents may be the same or different. ethylenedioxy, propylenedioxy etc.), In the present specification, examples of the “optionally (XXXXii) an aminosulfonyl group, Substituted cycloalkyl group” include a C-s cycloalkyl group (XXXXiii) a mono-N-Cl alkylaminosulfonyl group (e.g., (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl) methylaminosulfonyl, ethylaminosulfonyl etc.), 65 optionally having 1 to 4, preferably 1 to 3, substituents which (XXXXiv) a di-N,N-C alkylaminosulfonyl group (e.g., the aralkyl group of the above-defined “optionally substituted dimethylaminosulfonyl, diethylaminosulfonyl etc.), aralkyl group' optionally has. When the number of the sub US 9,120,776 B2 21 22 stituents is 2 or more, the respective substituents may be the defined “optionally substituted alkyl group' optionally has. same or different. Meanwhile, the substituents for “optionally When the number of the substituents is 2 or more, the respec substituted cycloalkyl group' are optionally bonded to form a tive substituents may be the same or different. ring (a cycloalkane ring (a Cal cycloalkane ring such as a In the present specification, examples of the “optionally cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a Substituted alkenylcarbonyl group” include a Calkenylcar cyclohexane ring), an arene ring (a Co-oarene ring Such as a bonyl group (e.g., vinylcarbonyl, 1-propenylcarbonyl, allyl benzene ring, a naphthalene ring)). carbonyl, isopropenylcarbonyl, butenylcarbonyl, isobutenyl In the present specification, examples of the “optionally carbonyl and the like) optionally having 1 to 4, preferably 1 to Substituted cycloalkenyl group” include Cs cycloalkenyl 3, substituents which the alkyl group of the above-defined group (e.g., cyclopropenyl, cyclobutenyl, cyclopentenyl, 10 cyclohexenyl and the like) optionally having 1 to 4, prefer “optionally substituted alkyl group' optionally has, and the ably 1 to 3, substituents which the aralkyl group of the above like. When the number of the substituents is 2 or more, the defined "optionally substituted aralkyl group' optionally has. respective substituents may be the same or different. When the number of the substituents is 2 or more, the respec In the present specification, examples of the “optionally tive substituents may be the same or different. Meanwhile, the 15 Substituted alkynylcarbonyl group” include a C- alkynyl substituents for the “optionally substituted cycloalkenyl carbonyl group (e.g., ethynylcarbonyl, propargylcarbonyl, group' are optionally bonded to form a ring (a cycloalkane butynylcarbonyl, 1-hexynylcarbonyl and the like) optionally ring (a Cso cycloalkane ring Such as a cyclopropane ring, a having 1 to 4, preferably 1 to 3, substituents which the alkyl cyclobutane ring, a cyclopentane ring and a cyclohexane group of the above-defined “optionally substituted alkyl ring), an arene ring (a Co-oarene ring Such as a benzene ring group' optionally has, and the like. When the number of the and a naphthalene ring)). Substituents is 2 or more, the respective Substituents may be In the present specification, examples of the “optionally, the same or different. Substituted hydrocarbon-oxy group' include a hydrocarbon In the present specification, examples of the “optionally oxy group wherein the optionally Substituted hydrocarbon Substituted aralkylcarbonyl group” include a Czaralkyl moiety is the above-defined “optionally substituted hydrocar 25 carbonyl group (e.g., benzylcarbonyl, 2-phenylethylcarbo bon group'. nyl, 1-phenylethylcarbonyl, 3-phenylpropylcarbonyl and the In the present specification, examples of the “optionally like) optionally having 1 to 4, preferably 1 to 3, substituents Substituted hydrocarbon-amino group' include an amino which the aralkyl group of the above-defined “optionally group optionally mono- or di-substituted by the above-de substituted aralkyl group' optionally has. When the number fined “optionally substituted hydrocarbon group’. When di 30 substituted, two “optionally substituted hydrocarbon groups” of the substituents is 2 or more, the respective substituents may be the same or different. may be the same or different. In the present specification, examples of the “optionally In the present specification, examples of the “optionally substituted hydrocarbon-sulfanyl group' include a hydrocar Substituted arylcarbonyl group' include a Caryl-carbonyl bon-sulfanyl group wherein the optionally substituted hydro 35 group (e.g., phenylcarbonyl, naphthylcarbonyl and the like) carbon moiety is the above-defined “optionally substituted optionally having 1 to 4, preferably 1 to 3, substituents which hydrocarbon group'. the aralkyl group of the above-defined “optionally substituted In the present specification, examples of the “optionally aralkyl group' optionally has. When the number of the sub substituted hydrocarbon-sulfenyl group” include hydrocar stituents is 2 or more, the respective substituents may be the bon-sulfenyl group wherein the optionally substituted hydro 40 same or different. carbon moiety is the above-defined “optionally substituted In the present specification, examples of the “optionally hydrocarbon group'. Substituted cycloalkylcarbonyl group” include a Cs In the present specification, examples of the “optionally cycloalkyl-carbonyl group (e.g., cyclopropylcarbonyl, substituted hydrocarbon-sulfonyl group' include a hydrocar cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbo bon-sulfonyl group wherein the optionally substituted hydro 45 nyl) optionally having 1 to 4, preferably 1 to 3, substituents carbon moiety is the above-defined “optionally substituted which the aralkyl group of the above-defined “optionally hydrocarbon group'. substituted aralkyl group' optionally has. When the number In the present specification, examples of the “acyl group' of the substituents is 2 or more, the respective substituents include an “optionally substituted alkylcarbonyl group', an may be the same or different. “optionally substituted alkenylcarbonyl group', an “option 50 In the present specification, examples of the “optionally ally substituted alkynylcarbonyl group', an “optionally sub Substituted alkoxycarbonyl group' include a C- alkoxy stituted aralkylcarbonyl group', an “optionally substituted carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, pro arylcarbonyl group', an “optionally Substituted cycloalkyl poxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobu carbonyl group', an “optionally Substituted alkoxycarbonyl toxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, group', an “optionally Substituted alkenyloxycarbonyl 55 pentoxycarbonyl, hexyloxycarbonyl and the like) optionally group', an “optionally Substituted alkynyloxycarbonyl having 1 to 4, preferably 1 to 3, substituents which the alkyl group', an “optionally substituted aralkyloxycarbonyl group of the above-defined “optionally substituted alkyl group', an "optionally Substituted aryloxycarbonyl group'. group' optionally has. When the number of the substituents is an “optionally substituted cycloalkyloxycarbonyl group', a 2 or more, the respective Substituents may be the same or “carboxyl group' and the like. 60 different. In the present specification, examples of the “optionally In the present specification, examples of the “optionally Substituted alkylcarbonyl group' include a C- alkyl-carbo Substituted alkenyloxycarbonyl group' include a C- alk nyl group (e.g., methylcarbonyl, ethylcarbonyl, propylcarbo enyl-oxycarbonyl group (e.g., vinyloxycarbonyl, 1-propeny nyl, isopropylcarbonyl, butylcarbonyl, isobutylcarbonyl, sec loxycarbonyl, allyloxycarbonyl, isopropenyloxycarbonyl, butylcarbonyl, tert-butylcarbonyl, pentylcarbonyl, 65 butenyloxycarbonyl, isobutenyloxycarbonyl and the like) hexylcarbonyl and the like) optionally having 1 to 4, prefer optionally having 1 to 4, preferably 1 to 3, substituents which ably 1 to 3, substituents which the alkyl group of the above the alkyl group of the above-defined “optionally substituted US 9,120,776 B2 23 24 alkyl group' optionally has, and the like. When the number of tional substituent(s) include a substituent which the aryl the Substituents is 2 or more, the respective Substituents may group of the above-defined “optionally substituted aryl be the same or different. group' optionally has, an optionally substituted hydrocarbon In the present specification, examples of the “optionally group and the like. The number of the substituents is prefer Substituted alkynyloxycarbonyl group' include a C- alky ably 1 to 4, more preferably 1 to 3, further more preferably 1 nyl-oxycarbonyl group (e.g., ethynyloxycarbonyl, propargy or 2. When the number of the substituents is 2 or more, the loxycarbonyl, butynyloxycarbonyl, 1-hexynyloxycarbonyl respective substituents may be the same or different. and the like) optionally having 1 to 4, preferably 1 to 3, The definition of each symbol in the formula (I') is substituents which the alkyl group of the above-defined explained in detail in the following. “optionally substituted alkyl group' optionally has, and the 10 R'' is an optionally substituted hydrocarbon group or an like. When the number of the substituents is 2 or more, the optionally substituted hydrocarbon-oxy group. respective substituents may be the same or different. The “optionally substituted hydrocarbon group” for R'' is In the present specification, examples of the “optionally preferably a C- alkyl group (e.g., methyl, ethyl, propyl. Substituted aralkyloxycarbonyl group' include a Cz isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neo aralkyl-oxycarbonyl group (e.g., benzyloxycarbonyl, 2-phe 15 pentyl, hexyl etc.) optionally having Substituent(s) selected nylethyloxycarbonyl, 1-phenylethyloxycarbonyl, 3-phenyl from propyloxycarbonyl and the like) optionally having 1 to 4. (i) a halogen atom (e.g., a fluorine atom, a chlorine atom, a preferably 1 to 3, substituents which the aralkyl group of the bromine atom, an iodine atom), above-defined “optionally substituted aralkyl group' option (ii) a cyano group, ally has. When the number of the substituents is 2 or more, the (iii) a hydroxyl group, respective substituents may be the same or different. (iv) a nitro group, In the present specification, examples of the “optionally (v) a formyl group, Substituted aryloxycarbonyl group” include a Caryl-oxy (vi) an amino group, carbonyl group (e.g., phenyloxycarbonyl, naphthyloxycarbo (vii) a mono- or di-C alkylamino group (e.g., methylamino, nyl and the like) optionally having 1 to 4, preferably 1 to 3. 25 ethylamino, propylamino, dimethylamino, diethylamino, substituents which the aralkyl group of the above-defined dipropylamino etc.), “optionally substituted aralkyl group' optionally has. When (viii) a C- alkyl-carbonylamino group (e.g., acetylamino, the number of the substituents is 2 or more, the respective ethylcarbonylamino etc.), substituents may be the same or different. (ix) a Calkoxy-carbonylamino group (e.g., methoxycarbo In the present specification, examples of the “optionally 30 nylamino, ethoxycarbonylamino, propoxycarbonylamino Substituted cycloalkyloxycarbonyl group' include a Cls etc.), cycloalkyl-oxycarbonyl group (e.g., cyclopropyloxycarbo (X) a Cs cycloalkyl group (e.g., cyclopropyl, cyclobutyl, nyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl, cyclo cyclopentyl, cyclohexyl etc.) optionally fused with a benzene hexyloxycarbonyl) optionally having 1 to 4, preferably 1 to 3. r1ng, substituents which the aralkyl group of the above-defined 35 (xi) a Css cycloalkenyl group (e.g., cyclopropenyl, “optionally substituted aralkyl group' optionally has. When cyclobutenyl, cyclopentenyl, cyclohexenyl etc.) optionally the number of the substituents is 2 or more, the respective fused with a benzene ring, substituents may be the same or different. (xii) a Caryl group (e.g., phenyl, 1-naphthyl 2-naphthyl In the present specification, examples of the "halogen etc.) optionally substituted by substituent(s) selected from a atom' include a fluorine atom, a chlorine atom, a bromine 40 halogen atom (e.g., a fluorine atom, a chlorine atom, a bro atom, and an iodine atom. mine atom, an iodine atom) and a C- alkoxy group (e.g., In the present specification, examples of the “optionally methoxy, ethoxy, propoxy etc.), substituted hydrocarbon ring include an “optionally substi (xiii) a C- alkoxy group (e.g., methoxy, ethoxy, propoxy, tuted arene ring, an “optionally substituted cycloalkane isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy etc.) ring, an “optionally substituted cycloalkene ring, corre 45 optionally Substituted by halogen atom(s) (e.g., a fluorine sponding to the above-defined “optionally substituted aryl atom, a chlorine atom, a bromine atom, an iodine atom), group”, “optionally substituted cycloalkyl group”, “option (xiv) a Czaralkyloxy group (e.g., benzyloxy etc.), ally Substituted cycloalkenyl group', and the like. (XV) a C-14 aryloxy group (e.g., phenoxy etc.) optionally Additionally, in the present specification, examples of the substituted by substituent(s) selected from a C- alkoxy “hydrocarbon ring include an “arene ring, a “cycloalkane 50 group (e.g., methoxy etc.), a C- alkyl group (e.g., methyl ring, a “cycloalkene ring, corresponding to the “aryl etc.) and a halogen atom (e.g., a fluorine atom, a chlorine group', the “cycloalkyl group', the “cycloalkenyl group', in atom, a bromine atom, an iodine atom), the above-defined “optionally substituted aryl group', (Xvi) a C- alkoxy-carbonyl group (e.g., methoxycarbonyl, “optionally substituted cycloalkyl group”, “optionally substi ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, tert tuted cycloalkenyl group', and the like. 55 butoxycarbonyl etc.), In the present specification, examples of the “substituent” (xvii) a Czaralkyloxy-carbonyl group (e.g., benzyloxycar of the “benzene ring optionally further substituted by sub bonyl etc.), stituent(s) excluding cyano' include a substituent which the (Xviii) a Caryloxy-carbonyl group (e.g., phenoxycarbo aryl group of the above-defined “optionally substituted aryl nyl etc.), group' optionally has, an optionally Substituted hydrocarbon 60 (XiX) a C- alkyl-carbonyl group (e.g., acetyl, ethylcarbonyl, group and the like. The number of the substituents is prefer propylcarbonyl, isopropylcarbonyl, 2,2-dimethylpropylcar ably 1 to 4, more preferably 1 to 3, further more preferably 1 bonyl etc.), or 2. When the number of the substituents is 2 or more, the (XX) a Cs cycloalkyl-carbonyl group (e.g., cyclopropyl respective substituents may be the same or different. carbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclo In the present specification, examples of the “substituent” 65 hexylcarbonyl etc.), of the “benzene ring optionally having additional (XXi) a C- aralkyl-carbonyl group (e.g., benzylcarbonyl Substituent(s)' and the "pyridine ring optionally having addi etc.), US 9,120,776 B2 25 26 (XXii) a carbamoyl group, (XXXX) a C alkylenedioxy group (e.g., methylenedioxy, (XXiii) a thiocarbamoyl group, ethylenedioxy, propylenedioxy etc.), (XXiv) a mono- or di-C alkyl-carbamoyl group (e.g., meth (XXXXi) an aminosulfonyl group, ylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropyl (XXXXii) a mono-N-Cl alkylaminosulfonyl group (e.g., carbamoyl, dimethylcarbamoyl, diethylcarbamoyl, dipropy methylaminosulfonyl, ethylaminosulfonyl etc.), lcarbamoyl etc.), (XXXXiii) a di-N,N-C alkylaminosulfonyl group (e.g., (XXV) a mono- or di-C7-caralkyl-carbamoyl group (e.g., ben dimethylaminosulfonyl, diethylaminosulfonyl etc.), Zylcarbamoyl, dibenzylcarbamoyl etc.), (XXvi) a thiol group, (XXXXiv) a bridged Czo cycloalkyl group (e.g., bicyclo 10 3.1.1 heptyl, adamantyl etc.) optionally Substituted by C. (XXvii) a C- alkylthio group (e.g., methylthio, ethylthio. alkyl group(s) (e.g., methyl etc.), propylthio etc.), (XXiii) a Czaralkylthio group (e.g., benzylthio etc.), (XXXXV) a Carylthio group (e.g., phenylthio etc.) and the (XXiX) a C- alkylsulfonyl group (e.g., methylsulfonyl, eth like. The number of the substituents is 1 to 4, preferably 1 to ylsulfonyl, propylsulfonyl, isopropylsulfonyl etc.), 3. When the number of the substituents is 2 or more, the (XXX) a Cs cycloalkylsulfonyl group (e.g., cyclopropylsul 15 respective substituents may be the same or different. fonyl, cyclobutylsulfonyl, cyclopentylsulfonyl etc.), R'' is preferably a C- alkyl group (e.g., methyl, ethyl, (XXXi) a C- arylsulfonyl group (e.g., phenylsulfonyl, propyl, isobutyl) optionally substituted by substituent(s) selected from the above-mentioned (i)-(XXXXV), more prefer 1-naphthylsulfonyl, 2-naphthylsulfonyl etc.), ably a C- alkyl group (e.g., methyl, ethyl, propyl, isobutyl), (XXXii) a C- aralkylsulfonyl group (e.g., benzylsulfonyl particularly preferably methyl, ethyl, propyl or isobutyl. etc.). (XXXiii) a 5- to 8-membered non-aromatic heterocyclic group R° and Rare each independently a hydrogen atom, an containing, besides carbon atoms, 1 to 4 hetero atoms optionally Substituted hydrocarbon group, an optionally Sub selected from a nitrogen atom, a Sulfur atom and an oxygen stituted hydrocarbon-oxy group, an acyl group, a halogen atom (e.g., pyrrolidinyl, tetrahydrofuryl, tetrahydrothienyl, 25 atom, a cyano group, an optionally Substituted hydrocarbon piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, amino group, an optionally Substituted hydrocarbon-sulfanyl piperazinyl etc.), wherein the non-aromatic heterocyclic group, an optionally Substituted hydrocarbon-Sulfenyl group, group is optionally substituted by C. alkyl group(s) (e.g., an optionally substituted hydrocarbon-sulfonyl group or a methyl etc.), nitro group, or RandR optionally form, together with the (XXXiv) a 5- to 8-membered aromatic heterocyclic group con 30 carbon atoms which they are bonded to, an optionally Substi taining, besides carbon atoms, 1 to 4 hetero atoms selected tuted hydrocarbon ring. from a nitrogenatom, a Sulfur atom and an oxygenatom (e.g., The “optionally substituted hydrocarbon group” for R' or furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, R" is preferably those similar to the preferable group as the isothiazolyl, imidazolyl pyrazolyl, 1.2.3-oxadiazolyl, 1,2,4- “optionally substituted hydrocarbon group” for R''. oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1.2.3-thiadiazolyl, 35 RandR are preferably each independently a hydrogen 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1.2.3-triazolyl, 1,2,4- atom or an optionally Substituted hydrocarbon group, more triazolyl, tetrazolyl pyridyl, pyridazinyl, pyrimidinyl, preferably a hydrogen atom, or a C- alkyl group (e.g., pyrazinyl, triazinyl etc.), wherein the aromatic heterocyclic methyl) optionally substituted by substituent(s) selected from group is optionally substituted by halogen atom(s) (e.g., a the above-mentioned (i)-(XXXXV) exemplified as the substitu chlorine atom etc.) or C. alkyl group(s) (e.g., methyl etc.) 40 ents which the “optionally substituted hydrocarbon group' and optionally fused with a benzene ring (e.g., benzothienyl for R' optionally has, still more preferably a hydrogenatom etc.). or a C- alkyl group (e.g., methyl), particularly preferably a (XXXV) a 5- to 8-membered non-aromatic heterocyclyl-carbo hydrogen atom or methyl. nyl group containing, besides carbon atoms, 1 to 4 hetero Alternatively, R'' and R' preferably form, together with atoms selected from a nitrogen atom, a Sulfur atom and an 45 the carbon atoms which they are bonded to, an optionally oxygen atom (e.g., pyrrolidinylcarbonyl, tetrahydrofurylcar Substituted arene ring (e.g., a benzene ring) or an optionally bonyl, tetrahydrothienylcarbonyl, piperidylcarbonyl, tet Substituted cycloalkene ring (e.g., a cyclohexene ring), more rahydropyranylcarbonyl, morpholinylcarbonyl, thiomor preferably an arene ring (e.g., a benzene ring) or a cycloalk pholinylcarbonyl, piperazinylcarbonyl (XXXVi) a 5- to enering (e.g., a cyclohexene ring), particularly preferably a 8-membered aromatic heterocyclyl-carbonyl group contain 50 benzene ring or a cyclohexene ring. ing, besides carbon atoms, 1 to 4 hetero atoms selected from a nitrogen atom, a Sulfur atom and an oxygen atom (e.g., In another embodiment, preferably, RandR are each furylcarbonyl, thienylcarbonyl, pyrrolylcarbonyl, oxazolyl independently a C- alkyl group, or R'' and R' form, carbonyl, isoxazolylcarbonyl, thiazolylcarbonyl, isothiaz together with the carbon atoms which they are bonded to, an olylcarbonyl, imidazolylcarbonyl, pyrazolylcarbonyl, 1.2.3- 55 optionally substituted hydrocarbon ring. oxadiazolylcarbonyl, 1,2,4-oxadiazolylcarbonyl, 1.3,4- R" is a hydrogen atom or a halogen atom. oxadiazolylcarbonyl, furazanylcarbonyl, 1,2,3- R is preferably a hydrogenatom or a chlorine atom, more thiadiazolylcarbonyl, 1,2,4-thiadiazolylcarbonyl, 1,3,4- preferably a hydrogen atom. thiadiazolylcarbonyl, 1,2,3-triazolylcarbonyl, 1,2,4- Q is a bivalent group selected from triazolylcarbonyl, tetrazolylcarbonyl, pyridylcarbonyl, 60 pyridazinylcarbonyl, pyrimidinylcarbonyl, pyrazinylcarbo nyl, triazinylcarbonyl etc.), (XXXVii) an ureido group, O O (XXXViii) a C- alkyl-ureido group (e.g., methylureido, ethy lureido, propylureido etc.), 65 (XXXix) a Caryl-ureido group (e.g., phenylureido, 1-naph H H thylureido, 2-naphthylureido etc.), US 9,120,776 B2 27 28 -continued -continued (Ib) (In) O O O O N-sus, N N A'.11 SS |Aly2 l N 1. O (I'o) (Ic) O O Nulls 10 Niall-n1n O H (I'p) 4A O O 15 SN A1So1S

H H wherein O O A") are the same or different and each is a methylene group optionally Substituted by Substituent(s) selected from a H H hydroxy group, a phenyl group and an optionally substituted C. alkyl group, wherein the two Substituents bonded to the O 25 single carbon atom are optionally combined to each other to form a hydrocarbon ring, and A are the same or different NNH A11 1 and each is a methylene group optionally substituted by Sub O stituent(s) selected from a hydroxy group and an optionally (Ig) 30 O Substituted C. alkyl group, wherein the two Substituents H bonded to the single carbon atom are optionally combined to N ul each other to form a hydrocarbon ring, or the methylene Af 1. groupinA'or A is optionally combined to the substituent O 35 on the adjacent methylene group to form an optionally Sub (Ih) H H stituted hydrocarbon ring, N N NA1 1 R'' and Rare the same or different and each is an option O O ally Substituted hydrocarbon group, 40 X" is an oxygen atom, a Sulfur atom, or an imino group H having an optionally Substituted hydrocarbon group or a NAYNs 1 hydrogen atom, O /\, n is an integer of 1 to 5. 45 n' is an integer of 1 to 4. (I) O n" is an integer of 1 to 3, and Nsu x' and y are each 0 or natural number, and the sum is 0 to 50 The “methylene group wherein the two substituents (Ik) O R4A bonded to the single carbon atom are optionally combined to each other to form a hydrocarbon ring in the above-men N tioned definition of A' or AI means, for example, a meth NN A1 1 ylene group represented by H 55 O (II) O O

X l 60 YN All1 Y1A2, HN1

O O O O and the “methylene group in A' or A is optionally com SN ls All.1\/ YA, l 1 65 bined to the Substituent on the adjacent methylene group to H form an optionally Substituted hydrocarbon ring means, for example, a group represented by US 9,120,776 B2 29 30 -continued

O R4A (Ik)

N NNH Al)1 Y O (II) In formula (I), of the two bonds of the bivalent group for O O Q', either the right bond or the left bond may be bonded to 10 Ring B, preferably the right bond is bonded to Ring B. NN Al31 “NA N1 Q is preferably a bivalent group selected from H y H

O O O (I'm) 15 O O O ls \/ ls N1 Nairner-N-H and N----H H O O O (In) (Ib) O O N N A'.11N, sul |Aly2 N 1.

R4A R4B 25 wherein I O O (Ic) A" are the same or different and each is a methylene group optionally Substituted by Substituent(s) selected from a hydroxy group and an optionally Substituted Calkyl group, H 30 wherein the two substituents bonded to the single carbon R44 atom are optionally combined to each other to form a hydro carbon ring, and AI are the same or different and each is a O methylene group optionally Substituted by Substituent(s) selected from a hydroxy group and an optionally Substituted H H 35 C. alkyl group, wherein the two Substituents bonded to the single carbon atom are optionally combined to each other to O O form a hydrocarbon ring, or the methylene group in A' or A is optionally combined to the substituent on the adjacent methylene group to form an optionally Substituted hydrocar H H 40 bon ring, and O (I'f)I the other symbols are as defined above. In another embodiment, Q is preferably a bivalent group ls.- selected from N1SAYH 1 45 O O (Ig)I O O (I'a)I N Nulls 50 YA, 1. n-isH H O (I'f) (Ih) O H N 55 ul NA1 1 N1NAH Y O O O

H (I) N N O Y NA1 X 60 O /\, no (I) O N- A1\o-1 65 US 9,120,776 B2 31 32 -continued alkyl group (e.g., methyl) is preferable, a C- alkyl group (In) (e.g., methyl) is more preferable, and methyl is particularly O O preferable. (f) When Q is (I'f): n is preferably 3. As the substituent for N l Sn l 1. the methylene group in A"), an optionally substituted C N (A'), Atly N alkyl group (e.g., methyl, ethyl) is preferable, a C- alkyl group (e.g., methyl, ethyl) is more preferable, and methyl and wherein ethyl are particularly preferable. In another embodiment, the A") are the same or different and each is a methylene methylene group in A' is preferably unsubstituted. group optionally Substituted by Substituent(s) selected from a 10 (g) When Q'is (Ig): n' is preferably 2. As the substituent for hydroxy group, a phenyl group and an optionally substituted the methylene group in A"), an optionally substituted C C. alkyl group, wherein the two Substituents bonded to the alkyl group (e.g., methyl) is preferable, a C- alkyl group single carbon atom are optionally combined to each other to (e.g., methyl) is more preferable, and methyl is particularly form a hydrocarbon ring, and A are the same or different preferable. 15 (h) When Q'is (I'h): n is preferably 3. As the substituent for and each is a methylene group optionally Substituted by Sub the methylene group in A"), an optionally substituted C. stituent(s) selected from a hydroxy group and an optionally alkyl group (e.g., methyl) is preferable, a C- alkyl group Substituted C. alkyl group, wherein the two Substituents (e.g., methyl) is more preferable, and methyl is particularly bonded to the single carbon atom are optionally combined to preferable. each other to form a hydrocarbon ring, or the methylene (i) When Q is (I'i): n is preferably 3. As the substituent for groupinA'or A is optionally combined to the substituent the methylene group in A"), an optionally substituted C. on the adjacent methylene group to form an optionally Sub alkyl group (e.g., methyl) is preferable, a C- alkyl group stituted hydrocarbon ring, (e.g., methyl) is more preferable, and methyl is particularly n is an integer of 1 to 5, and preferable. x and y are each 0 or natural number, and the sum is 0 to 25 (j) When Q is (I): n is preferably 3. As the substituent for 4. the methylene group in A"), a hydroxy group and an option (a) When Q is (I'a): n is preferably an integer of 2 to 4. As ally substituted C. alkyl group (e.g., methyl) are preferable, the substituent for the methylene group in A"), a phenyl a hydroxy group and a C- alkyl group (e.g., methyl) are group and an optionally Substituted C. alkyl group (e.g., more preferable, and hydroxy and methyl are particularly methyl) are preferable, a phenyl group and a C- alkyl group 30 preferable. In another embodiment, the methylene group in (e.g., methyl) are more preferable, and phenyl and methyl are A") is preferably unsubstituted. particularly preferable. Alternatively, the two substituents (k) When Q'is (I'k): n is preferably 3. The methylene group bonded to the single carbon atom are preferably combined to in A' is preferably unsubstituted. R' is preferably an each other to form a cycloalkane ring (e.g., a cyclopentane optionally substituted C. alkyl group (e.g., ethyl, propyl), 35 more preferably a C- alkyl group (e.g., ethyl, propyl) ring), particularly preferably a cyclopentane ring. Moreover, optionally Substituted by C. alkoxy group(s) (e.g., meth the methylene group is preferably combined to the substituent oxy), particularly preferably ethyl or methoxypropyl. on the adjacent methylene group to form an optionally Sub (1) When Q is (I'l): X" is preferably a sulfur atom (i.e., Q is stituted a cycloalkane ring (e.g., a cyclopropane ring, a (I'l")), or an imino group having a C- alkyl group (e.g., cyclobutane ring), more preferably a cycloalkane ring (e.g., a 40 methyl) or a hydrogen atom, particularly preferably a Sulfur cyclopropane ring, a cyclobutane ring), particularly prefer atom, or an imino group having a C- alkyl group (e.g., ably a cyclopropane ring or a cyclobutane ring. methyl). The methylene group in A' or A is preferably (b) When Q'is (Ib): n is preferably 3. As the substituent for unsubstituted. x' and y are preferably each 1. the methylene group in A"), an optionally substituted C. (m) When Q is (I'm): the methylene group in A' or A alkyl group (e.g., methyl) is preferable, a C- alkyl group 45 is preferably unsubstituted. x' and y are preferably each 1. (e.g., methyl) is more preferable, and methyl is particularly (n) When Q'is (I'n): the methylene group in A' or A is preferable. R* and Rare the same or different and each is preferably unsubstituted. x' and y are preferably each 1. preferably an optionally Substituted C. alkyl group (e.g., (o) When Q is (I'o): n" is preferably 1. As the substituent methyl), more preferably a C- alkyl group (e.g., methyl), for the methylene group in A"), an optionally substituted particularly preferably methyl. 50 C. alkyl group (e.g., methyl) is preferable, a C- alkyl (c) When Q is (Ic): n is preferably 3. As the substituent for group (e.g., methyl) is more preferable, and methyl is particu the methylene group in A"), an optionally substituted C larly preferable. alkyl group (e.g., methyl) is preferable, a C- alkyl group (p) When Q'is (I'p): n' is preferably 2. As the substituent for (e.g., methyl) is more preferable, and methyl is particularly the methylene group in A"), an optionally substituted C. preferable. R' is preferably an optionally substituted C. 55 alkyl group (e.g., methyl) is preferable, a C- alkyl group alkyl group (e.g., propyl), or an optionally substituted C (e.g., methyl) is more preferable, and methyl is particularly aralkyl group (e.g., benzyl), more preferably a C- alkyl preferable. group (e.g., propyl) optionally Substituted by C. alkoxy Ring B' is a benzene ring optionally having additional group(s) (e.g., methoxy), or a C7-12 aralkyl group (e.g., ben Substituent(s), or a pyridine ring optionally having additional Zyl), particularly preferably methoxypropyl or benzyl. 60 substituent(s), provided that when R is a halogen Atom, (d) When Q'is (I'd): n is preferably 3. As the substituent for then Ring B' is a benzene ring optionally having additional the methylene group in A"), an optionally substituted C Substituent(s). alkyl group (e.g., methyl) is preferable, a C- alkyl group As the “substituent of the “benzene ring optionally having (e.g., methyl) is more preferable, and methyl is particularly additional Substituent(s)” for Ring B", a halogen atom, a preferable. 65 cyano group, a C- alkoxy group and an optionally Substi (e) When Q is (I'e): n' is preferably 2. As the substituent for tuted hydrocarbon group are preferable, a halogen atom, a the methylene group in A"), an optionally substituted C cyano group, a C- alkoxy group and an optionally Substi US 9,120,776 B2 33 34 tuted C. alkyl group are more preferable, a halogen atom (I'n): the methylene in A' or A is unsubstituted, and x' (e.g., a chlorine atom), a cyano group, a C- alkoxy group andy" are each 1; (e.g., methoxy), and a C- alkyl group (e.g., methyl) option (I'o): n" is 1, and the methylene group in A' is optionally ally Substituted by 1 to 3 halogenatoms (e.g., a fluorine atom) Substituted by optionally substituted alkyl group(S); and are still more preferable, and a chlorine atom, cyano, meth (I'p): n' is 2, and the methylene group in A' is optionally oxy, methyl and trifluoromethyl are particularly preferable. In Substituted by optionally substituted C. alkyl group(s); and another embodiment, the “benzene ring optionally having Ring B' is (1) a benzene ring optionally having additional additional substituent(s) preferably has no substituent(s). Substituent(s) selected from a halogenatom, a cyano group, a As the “substituent of the “pyridinering optionally having Calkoxy group and an optionally substituted hydrocarbon additional substituent(s)” for Ring B", an optionally substi 10 group, or (2) a pyridine ring optionally having optionally tuted hydrocarbon group is preferable, an optionally Substi Substituted hydrocarbon group(s). tuted C. alkyl group is more preferable, a C- alkyl group Compound (I') is more preferably a compound wherein (e.g., methyl) is still more preferable, and methyl is particu R'' is an optionally substituted C- alkyl group (e.g., larly preferable. In another embodiment, the "pyridine ring 15 methyl, ethyl, propyl, isobutyl); optionally having additional substituent(s) preferably has no RandR are each independently a hydrogenatom oran Substituent(s). optionally Substituted C. alkyl group (e.g., methyl), or Preferable examples of the ring, group, Substituent and the R° and R' form, together with the carbon atoms which like explained in the present specification are more preferably they are bonded to, an optionally substituted arene ring (e.g., used in combination. a benzene ring) or an optionally substituted cycloalkene ring Compound (I') is preferably a compound wherein (e.g., a cyclohexene ring); R'' is an optionally substituted C. alkyl group; R" is a hydrogen atom or a halogen atom (e.g., a chlorine RandR are each independently a hydrogenatom oran atom); optionally substituted hydrocarbon group, or Q is a bivalent group selected from R" and R' form, together with the carbon atoms which 25 (I'a): n is an integer of 2 to 4, and the methylene group in they are bonded to, an optionally substituted arene ring oran A") is optionally substituted by phenyl group(s) or option optionally substituted cycloalkene ring; ally Substituted C. alkyl group(s) (e.g., methyl), or the two R" is a hydrogen atom or a halogen atom; Substituents bonded to the single carbon atom are combined Q is a bivalent group selected from to each other to form a cycloalkane ring (e.g., a cyclopentane (I'a): n is an integer of 2 to 4, and the methylene group in 30 ring), or the methylene group is combined to the Substituent A") is optionally substituted by phenyl group(s) or option on the adjacent methylene group to form an optionally sub ally substituted C. alkyl group(s), or the two substituents stituted cycloalkane ring (e.g., a cyclopropane ring, a bonded to the single carbon atom are combined to each other to form a cycloalkane ring, or the methylene group is com cyclobutane ring); bined to the Substituent on the adjacent methylene group to 35 (Ib): n is 3, the methylene group in A' is optionally form an optionally Substituted a cycloalkane ring; Substituted by optionally substituted Calkyl group(s) (e.g., (Ib): n is 3, the methylene group in A' is optionally methyl), and R' and Rare the same or different and each is Substituted by optionally Substituted C. alkyl group(s), and an optionally Substituted C. alkyl group (e.g., methyl); R'' and Rare the same or different and each is an optionally (Ic): n is 3, the methylene group in A' is optionally Substituted C. alkyl group: 40 Substituted by optionally Substituted Calkyl group(s) (e.g., (Ic): n is 3, the methylene group in A' is optionally methyl), and R' is an optionally substituted C-alkyl group Substituted by optionally substituted C. alkyl group(s), and (e.g., propyl), oran optionally substituted C7 aralkyl group R' is an optionally substituted C-alkyl group oran option (e.g., benzyl); ally Substituted C-2 aralkyl group; (I'd): n is 3, and the methylene group in A' is optionally (I'd): n is 3, and the methylene group in A' is optionally 45 Substituted by optionally Substituted Calkyl group(s) (e.g., Substituted by optionally substituted C. alkyl group(s): methyl); (I'e): n' is 2, and the methylene group in A' is optionally (I'e): n' is 2, and the methylene group in A' is optionally Substituted by optionally substituted C. alkyl group(s): Substituted by optionally Substituted Calkyl group(s) (e.g., (I'f): n is 3, and the methylene group in A' is unsubsti methyl); tuted, or optionally substituted by optionally substituted C 50 (I'f): n is 3, and the methylene group in A' is unsubsti alkyl group(s): tuted, or optionally substituted by optionally substituted C (Ig): n' is 2, and the methylene group in A' is optionally alkyl group(s) (e.g., methyl, ethyl); Substituted by optionally substituted C. alkyl group(s): (Ig): n' is 2, and the methylene group in A' is optionally (I'h): n is 3, and the methylene group in A' is optionally Substituted by optionally substituted Calkyl group(s) (e.g., Substituted by optionally substituted C. alkyl group(s): 55 methyl); (I'i): n is 3, and the methylene group in A' is optionally (I'h): n is 3, and the methylene group in A' is optionally Substituted by optionally substituted C. alkyl group(s): Substituted by optionally Substituted Calkyl group(s) (e.g., (II): n is 3, and the methylene group in A' is optionally methyl); substituted by hydroxy group(s) or optionally substituted (I'i): n is 3, and the methylene group in A' is optionally C. alkyl group(s): 60 Substituted by optionally Substituted Calkyl group(s) (e.g., (I'k): n is 3, the methylene group in A' is unsubstituted, methyl); and R' is an optionally substituted C. alkyl group; (II): n is 3, and the methylene group in A' is optionally (I'l): X is a sulfur atom, or an imino group having a C substituted by hydroxy group(s) or optionally substituted alkyl group or a hydrogenatom, the methylene in A' or A C- alkyl group(s) (e.g., methyl); is unsubstituted, and X’ and y' are each 1; 65 (I'k): n is 3, the methylene group in A' is unsubstituted, (I'm): the methylene in A' or A is unsubstituted, and x' and R' is an optionally substituted C. alkyl group (e.g., andy" are each 1; ethyl, propyl); US 9,120,776 B2 35 36 (I'l): X is a Sulfur atom, or an imino group having a C (I'm): the methylene in A' or A is unsubstituted, and x' alkyl group (e.g., methyl) or a hydrogenatom, the methylene andy" are each 1; in A' or A is unsubstituted, and x' and y are each 1; (I'n): the methylene in A' or A is unsubstituted, and x' (I'm): the methylene in A' or A is unsubstituted, and x' andy" are each 1; andy" are each 1; (I'o): n" is 1, and the methylene group in A' is optionally (I'n): the methylene in A' or A is unsubstituted, and x' Substituted by C. alkyl group(s) (e.g., methyl); and andy" are each 1; (I'p): n' is 2, and the methylene group in A' is optionally (I'o): n" is 1, and the methylene group in A' is optionally Substituted by C. alkyl group(s) (e.g., methyl); and Substituted by optionally Substituted alkyl group(S); and Ring B' is (1) a benzene ring optionally having additional 10 Substituent(s) selected from a halogen atom (e.g., a chlorine (I'p): n' is 2, and the methylene group in A' is optionally atom), a cyano group, a C- alkoxy group (e.g., methoxy). Substituted by optionally substituted alkyl group(s) (e.g., and a C- alkyl group (e.g., methyl) optionally Substituted by methyl); and 1 to 3 halogenatoms (e.g., a fluorine atom), or (2) a pyridine Ring B' is (1) a benzene ring optionally having additional ring optionally having C alkyl group(s) (e.g., methyl). Substituent(s) selected from a halogenatom, a cyano group, a 15 Compound (I) is particularly preferably a compound C. alkoxy group and an optionally Substituted C. alkyl wherein group, or (2) a pyridine ring optionally having optionally R'' is methyl, ethyl, propyl or isobutyl: Substituted C. alkyl group(s). R'' and R are each a hydrogenatom or methyl, or Compound (I) is still more preferably a compound R° and R' form, together with the carbon atoms which wherein they are bonded to, a benzene ring or a cyclohexene ring; R'' is a Calkyl group (e.g., methyl ethyl, propyl, isobu Q is a bivalent group selected from tyl); (I'a): n is an integer of 2 to 4, and the methylene group in R° and Rare each independently a hydrogen atom or a A' is optionally substituted by phenyl or methyl, or the two C. alkyl group (e.g., methyl), or Substituents bonded to the single carbon atom are combined R" and R' form, together with the carbon atoms which 25 to each other to form a cyclopentane ring, or the methylene they are bonded to, an arene ring (e.g., a benzene ring) or a group is combined to the Substituent on the adjacent methyl cycloalkene ring (e.g., a cyclohexene ring); enegroup to form a cyclopropane ring or a cyclobutane ring; Q is a bivalent group selected from (Ib): n is 3, the methylene group in A' is optionally (I'a): n is an integer of 2 to 4, and the methylene group in substituted by methyl, and R'' and R' are each methyl: A") is optionally substituted by phenyl group(s) or C-alkyl 30 (Ic): n is 3, the methylene group in A' is optionally group(s) (e.g., methyl), or the two Substituents bonded to the substituted by methyl, and R' is methoxypropyl or benzyl: single carbon atom are combined to each other to form a (I'd): n is 3, and the methylene group in A' is optionally cycloalkane ring (e.g., a cyclopentane ring), or the methylene substituted by methyl: group is combined to the Substituent on the adjacent methyl (I'e): n' is 2, and the methylene group in A' is optionally ene group to form a cycloalkane ring (e.g., a cyclopropane 35 substituted by methyl: ring, a cyclobutane ring); (I'f): n is 3, and the methylene group in A' is unsubsti (Ib): n is 3, the methylene group in A' is optionally tuted, or optionally substituted by methyl or ethyl: substituted by C1-alkyl group(s) (e.g., methyl), and R' and (Ig): n' is 2, and the methylene group in A' is optionally R" are the same or different and each is a C- alkyl group substituted by methyl: (e.g., methyl); 40 (I'h): n is 3, and the methylene group in A' is optionally (Ic): n is 3, the methylene group in A' is optionally substituted by methyl: Substituted by C. alkyl group(s) (e.g., methyl), and R' is a (I'i): n is 3, and the methylene group in A' is optionally C. alkyl group (e.g., propyl) optionally Substituted by C. substituted by methyl: alkoxy group(s) (e.g., methoxy), or a C7-12 aralkyl group (II): n is 3, and the methylene group in A' is optionally (e.g., benzyl); 45 substituted by hydroxy or methyl: (I'd): n is 3, and the methylene group in A' is optionally (I'k): n is 3, the methylene group in A' is unsubstituted, Substituted by C. alkyl group(s) (e.g., methyl); and R' is ethyl or methoxypropyl; (I'e): n' is 2, and the methylene group in A' is optionally (I'l): X" is a Sulfur atom, or an imino group having methyl, Substituted by C. alkyl group(s) (e.g., methyl); the methylene in A' or A is unsubstituted, and x' and y' (I'f): n is 3, and the methylene group in A' is unsubsti 50 are each 1, tuted, or optionally Substituted by C. alkyl group(s) (e.g., (I'm): the methylene in A' or A is unsubstituted, and x' methyl, ethyl); andy" are each 1; (I'g): n' is 2, and the methylene group in A' is optionally (I'n): the methylene in A' or A is unsubstituted, and x' Substituted by C. alkyl group(s) (e.g., methyl); andy" are each 1; (I'h): n is 3, and the methylene group in A' is optionally 55 (I'o): n" is 1, and the methylene group in A' is optionally Substituted by C. alkyl group(s) (e.g., methyl); substituted by methyl; and (I'i): n is 3, and the methylene group in A' is optionally (I'p): n' is 2, and the methylene group in A' is optionally Substituted by C. alkyl group(s) (e.g., methyl); substituted by methyl; and (II): n is 3, and the methylene group in A' is optionally Ring B' is (1) a benzene ring optionally having additional Substituted by hydroxy group(s) or Ce alkyl group(s) (e.g., 60 Substituent(s) selected from a chlorine atom, cyano, methoxy, methyl); methyl and trifluoromethyl, or (2) a pyridine ring optionally (I'k): n is 3, the methylene group in A' is unsubstituted, having methyl. and R' is a C- alkyl group (e.g., ethyl, propyl) optionally Specific examples of the above-mentioned compound (I) Substituted by C. alkoxy group(s) (e.g., methoxy); include the compounds of Examples. Among them, (I'l): X is a Sulfur atom, or an imino group having a C 65 N-(4-cyanophenyl)-N'-(9-ethyl-2,3,4,9-tetrahydro-1H alkyl group (e.g., methyl), the methylene in A' or A is carbazol-6-yl)-3-methylpentanediamide or a salt thereof (Ex unsubstituted, and X and y' are each 1; ample 4). US 9,120,776 B2 37 38 N-(3-chloro-4-cyanophenyl)-N'-(9-ethyl-9H-carbazol-3- -continued yl)-3-methylpentanediamide or a salt thereof (Example 14), (If) and N-4-(3-chloro-4-cyanophenyl)amino-2-methyl-4-OX obutyl-9-ethyl-9H-carbazole-3-carboxamide or a salt thereof (Example 48) are preferable. (Ig) The definition of each symbol in the formula (I) is explained in detail in the following. R" is an optionally substituted hydrocarbon group or an 10 optionally substituted hydrocarbon-oxy group. R" is preferably an optionally substituted C- alkyl group (e.g., ethyl, propyl, isobutyl), more preferably a C- alkyl (Ih) group (e.g., ethyl, propyl, isobutyl), particularly preferably ethyl, propyl or isobutyl. 15 RandR are each independently an optionally substituted hydrocarbon group, an optionally substituted hydrocarbon (II) oxy group, an acyl group, a halogenatom, a cyano group, an optionally Substituted hydrocarbon-amino group, an option ally Substituted hydrocarbon-sulfanyl group, an optionally Substituted hydrocarbon-Sulfenyl group, an optionally Substi tuted hydrocarbon-sulfonyl group or a nitro group, or R and (I) R optionally form, together with the carbon atoms which they are bonded to, an optionally substituted hydrocarbon 25 r1ng. R and Rare preferably each independently an optionally (Ik) Substituted hydrocarbon group, more preferably an option O R4 ally substituted C. alkyl group (e.g., methyl), still more preferably a C- alkyl group (e.g., methyl), particularly pref 30 erably methyl. Alternatively, RandR preferably form, together with the (II) carbon atoms which they are bonded to, an optionally Substi O O tuted arene ring (e.g., a benzene ring) or an optionally Sub stituted cycloalkene ring (e.g., a cyclohexene ring), more 35 preferably an arene ring (e.g., a benzene ring) or a cycloalk n-s-s-s-H y H enering (e.g., a cyclohexene ring), particularly preferably a (Im) benzene ring or a cyclohexene ring. O O O O Q is a bivalent group selected from 40 SN ls Al1\/ YA); us N1 and (In) (Ia) O O O O O N ls 1SN us 1. ne 45 N A. (A), N (Ib) wherein A are the same or different and each is a methylene group 50 optionally substituted by substituent(s) selected from a hydroxy group and an optionally Substituted Calkyl group, wherein the two substituents bonded to the single carbon (Ic) atom are optionally combined to each other to form a hydro carbon ring, and A are the same or different and each is a 55 methylene group optionally Substituted by Substituent(s) selected from a hydroxy group and an optionally Substituted C. alkyl group, wherein the two Substituents bonded to the (Id) single carbon atom are optionally combined to each other to form a hydrocarbon ring, or the methylene group in A or 60 A is optionally combined to the substituent on the adjacent methylene group to form an optionally Substituted hydrocar bon ring, (Ie) R" and Rare the same or different and each is an option ally Substituted hydrocarbon group, 65 X is an oxygen atom, a Sulfur atom, or an imino group having an optionally Substituted hydrocarbon group or a hydrogen atom, and US 9,120,776 B2 39 40 X and y are each 0 or natural number, and the Sum is 0 to 4. methyl) is preferable, a C- alkyl group (e.g., methyl) is more Q is preferably preferable, and methyl is particularly preferable. (f) When Q is (If): the number of the methylene group in A is preferably 3. The methylene group is preferably unsub (Ia) stituted. (g) When Q is (Ig): the number of the methylene group in A is preferably 2. As the substituent for the methylene N N l A1-5l N1 group, an optionally substituted C. alkyl group (e.g., (I) methyl) is preferable, a C- alkyl group (e.g., methyl) is more O 10 preferable, and methyl is particularly preferable. (h) When Q is (Ih): the number of the methylene group in A is preferably 3. As the substituent for the methylene no group, an optionally substituted C. alkyl group (e.g., (II) O O methyl) is preferable, a C- alkyl group (e.g., methyl) is more 15 preferable, and methyl is particularly preferable. N l 1SS ls 1 or (i) When Q is (Ii): the number of the methylene group in N A. Aly N A is preferably 3. As the substituent for the methylene (In) group, an optionally substituted C. alkyl group (e.g., O O O methyl) is preferable, a C- alkyl group (e.g., methyl) is more N l 1SS ls 1. preferable, and methyl is particularly preferable. N A) |Aly N (j) When Q is (I): the number of the methylene group in A is preferably 3. As the substituent for the methylene group, none, a hydroxy group and an optionally Substituted wherein each symbol is as defined above. 25 Calkyl group (e.g., methyl) are preferable, none, a hydroxy (a) When Q is (Ia): the number of the methylene group in group and a C- alkyl group (e.g., methyl) are more prefer A is preferably 2 to 4. As the substituent for the methylene able, none, and hydroxy and methyl are particularly prefer group, an optionally Substituted C. alkyl group (e.g., able. methyl) is preferable, a C- alkyl group (e.g., methyl) is more (k) When Q is (Ik): the number of the methylene group in preferable, and methyl is particularly preferable. Alterna 30 A is preferably 3. The methylene group is preferably unsub tively, the two substituents bonded to the single carbon atom stituted. R is preferably an optionally substituted C. alkyl are preferably combined to each other to form a cycloalkane group (e.g., ethyl, propyl), more preferably a C- alkyl group ring (e.g., a cyclopentane ring), particularly preferably a (e.g., ethyl, propyl) optionally substituted by C. alkoxy cyclopentane ring. Moreover, the methylene group is prefer group(s) (e.g., methoxy), particularly preferably ethyl or ably combined to the substituent on the adjacent methylene 35 methoxypropyl. group to forman optionally Substituted cycloalkanering (e.g., (1) When Q is (IT): X is preferably a sulfur atom (i.e., Q is a cyclopropane ring), more preferably a cycloalkane ring (II)), or an imino group having a C- alkyl group (e.g., (e.g., a cyclopropane ring), particularly preferably a cyclo methyl) or a hydrogen atom, particularly preferably a Sulfur propane ring. atom, or an imino group having a C- alkyl group (e.g., (b) When Q is (Ib): the number of the methylene group in 40 methyl). A is preferably 3. As the substituent for the methylene The methylene group in A or A is preferably unsubsti group, an optionally substituted C. alkyl group (e.g., tuted. X and y are preferably each 1. methyl) is preferable, a C- alkyl group (e.g., methyl) is more (m) When Q is (Im): the methylene group in A or A is preferable, and methyl is particularly preferable. R* and R' preferably unsubstituted. X and y are preferably each 1. are the same or different and each is preferably an optionally 45 (n) When Q is (In): the methylene group in A or A is Substituted C. alkyl group (e.g., methyl), more preferably a preferably unsubstituted. X and y are preferably each 1. C. alkyl group (e.g., methyl), particularly preferably Ring B is a benzene ring optionally further substituted by methyl. Substituent(s) excluding cyano. (c) When Q is (Ic): the number of the methylene group in As the “substituent of the “benzene ring optionally further A is preferably 3. As the substituent for the methylene 50 substituted by substituent(s) excluding cyano' for Ring B, a group, an optionally Substituted C. alkyl group (e.g., halogen atom and an optionally Substituted hydrocarbon methyl) is preferable, a C- alkyl group (e.g., methyl) is more group are preferable, a halogen atom and an optionally Sub preferable, and methyl is particularly preferable. R is pref stituted C. alkyl group are more preferable, a halogenatom erably an optionally substituted C. alkyl group (e.g., pro (e.g., a chlorine atom), and a C- alkyl group (e.g., methyl) pyl), or an optionally Substituted C-2 aralkyl group (e.g., 55 optionally substituted by 1 to 3 halogenatoms (e.g., a fluorine benzyl), more preferably a C- alkyl group (e.g., propyl) atom) are still more preferable, and a chlorine atom and optionally Substituted by C. alkoxy group(s) (e.g., meth trifluoromethyl are particularly preferable. oxy), or a C-2 aralkyl group (e.g., benzyl), particularly pref Preferable examples of the ring, group, Substituent and the erably methoxypropyl or benzyl. like explained in the present specification are more preferably (d) When Q is (Id): the number of the methylene group in 60 used in combination. A is preferably 3. As the substituent for the methylene Compound (I) is preferably a compound wherein group, an optionally Substituted C. alkyl group (e.g., R" is an optionally substituted C- alkyl group; methyl) is preferable, a Calkyl group (e.g., methyl) is more R° and Rare each independently an optionally substituted preferable, and methyl is particularly preferable. hydrocarbon group, or (e) When Q is (Ie): the number of the methylene group in 65 RandR form, together with the carbonatoms which they A is preferably 2. As the substituent for the methylene are bonded to, an optionally Substituted arene ring or an group, an optionally Substituted C. alkyl group (e.g., optionally substituted cycloalkene ring; US 9,120,776 B2 41 42 Q is a bivalent group selected from group is combined to the Substituent on the adjacent methyl (Ia): the number of the methylene group in A is 2 to 4, and enegroup to form an optionally Substituted cycloalkane ring the methylene group is optionally Substituted by optionally (e.g., a cyclopropane ring); Substituted C. alkyl group(s), or the two Substituents (Ib): the number of the methylene group in A is 3, the bonded to the single carbon atom are combined to each other methylene group is optionally substituted by C. alkyl to form a cycloalkane ring, or the methylene group is com group(s) (e.g., methyl), and RandR' are the same or differ bined to the Substituent on the adjacent methylene group to ent and each is an optionally substituted C. alkyl group form an optionally Substituted a cycloalkane ring; (e.g., methyl); (Ib): the number of the methylene group in A is 3, the (Ic): the number of the methylene group in A is 3, the methylene group is optionally Substituted by optionally Sub 10 methylene group is optionally Substituted by C. alkyl stituted C. alkyl group(s), and R and R' are the same or group(s) (e.g., methyl), and R is an optionally substituted different and each is an optionally substituted C. alkyl C. alkyl group (e.g., propyl), or an optionally Substituted group; C7-12 aralkyl group (e.g., benzyl); (Ic): the number of the methylene group in A is 3, the (Id): the number of the methylene group in A is 3, and the methylene group is optionally Substituted by optionally Sub 15 methylene group is optionally substituted by optionally Sub stituted C- alkyl group(s), and R is an optionally substi stituted C. alkyl group(s) (e.g., methyl); tuted C. alkyl group or an optionally substituted Cz (Ie): the number of the methylene group in A is 2, and the aralkyl group; methylene group is optionally substituted by optionally Sub (Id): the number of the methylene group in A is 3, and the stituted C. alkyl group(s) (e.g., methyl); methylene group is optionally Substituted by optionally Sub (If): the number of the methylene group in A is 3, and the stituted C. alkyl group(s): methylene group is unsubstituted; (Ie): the number of the methylene group in A is 2, and the (Ig): the number of the methylene group in A is 2, and the methylene group is optionally Substituted by optionally Sub methylene group is optionally substituted by optionally Sub stituted C. alkyl group(s): 25 stituted C. alkyl group(s) (e.g., methyl); (If): the number of the methylene group in A is 3, and the (Ih): the number of the methylene group in A is 3, and the methylene group is unsubstituted; methylene group is optionally substituted by optionally Sub (Ig): the number of the methylene group in A is 2, and the stituted C. alkyl group(s) (e.g., methyl); methylene group is optionally Substituted by optionally Sub (Ii): the number of the methylene group in A is 3, and the stituted C. alkyl group(s): 30 methylene group is optionally substituted by optionally Sub (Ih): the number of the methylene group in A is 3, and the stituted C. alkyl group(s) (e.g., methyl); methylene group is optionally substituted by optionally sub (I): the number of the methylene group in A is 3, and the stituted C. alkyl group(s): methylene group is optionally Substituted by hydroxy (Ii): the number of the methylene group in A is 3, and the group(s) or optionally substituted C. alkyl group(s) (e.g., methylene group is optionally Substituted by optionally Sub 35 methyl); stituted C. alkyl group(s): (Ik): the number of the methylene group in A is 3, the (I): the number of the methylene group in A is 3, and the methylene group is unsubstituted, and R is an optionally methylene group is optionally Substituted by hydroxy Substituted C. alkyl group (e.g., ethyl, propyl); group(s) or optionally Substituted C. alkyl group(s): (IT): X is a Sulfur atom, or an imino group having a C (Ik): the number of the methylene group in A is 3, the 40 alkyl group (e.g., methyl) or a hydrogen atom, the methylene methylene group is unsubstituted, and R is an optionally group in A or A is unsubstituted, and X and y are each 1; Substituted C. alkyl group: (Im): the methylene group in A or A is unsubstituted, (IT): X is a Sulfur atom, or an imino group having a C and X and y are each 1; and alkyl group or a hydrogenatom, the methylene group in A or (In): the methylene group in A or A is unsubstituted, A is unsubstituted, and X and y are each 1; 45 and X and y are each 1; and (Im): the methylene group in A or A is unsubstituted, Ring B is a benzene ring optionally further substituted by and X and y are each 1; and halogenatom(s) or optionally substituted Calkyl group(s). (In): the methylene group in A or A is unsubstituted, Compound (I) is still more preferably a compound wherein and X and y are each 1; and R" is a C- alkyl group (e.g., ethyl, propyl, isobutyl); Ring B is a benzene ring optionally further substituted by 50 R and Rare each independently a C- alkyl group (e.g., halogen atom(s) or optionally Substituted hydrocarbon methyl), or group(s). RandR form, together with the carbonatoms which they Compound (I) is more preferably a compound wherein are bonded to, an arene ring (e.g., a benzene ring) or a R" is an optionally substituted Calkyl group (e.g., ethyl, cycloalkene ring (e.g., a cyclohexene ring); propyl, isobutyl); 55 Q is a bivalent group selected from RandR are each independently an optionally substituted (Ia): the number of the methylene group in A is 2 to 4, and Calkyl group (e.g., methyl), or the methylene group is optionally Substituted by C. alkyl RandR form, together with the carbonatoms which they group(s) (e.g., methyl), or the two Substituents bonded to the are bonded to, an optionally Substituted arene ring (e.g., a single carbon atom are combined to each other to form a benzene ring) or an optionally Substituted cycloalkene ring 60 cycloalkane ring (e.g., a cyclopentane ring), or the methylene (e.g., a cyclohexene ring); group is combined to the Substituent on the adjacent methyl Q is a bivalent group selected from ene group to form a cycloalkane ring (e.g., a cyclopropane (Ia): the number of the methylene group in A is 2 to 4, and ring); the methylene group is optionally substituted by C. alkyl (Ib): the number of the methylene group in A is 3, the group(s) (e.g., methyl), or the two Substituents bonded to the 65 methylene group is optionally Substituted by C. alkyl single carbon atom are combined to each other to form a group(s) (e.g., methyl), and Rand Rare the same or differ cycloalkane ring (e.g., a cyclopentane ring), or the methylene ent and each is a C- alkyl group (e.g., methyl); US 9,120,776 B2 43 44 (Ic): the number of the methylene group in A is 3, the (If): the number of the methylene group in A is 3, and the methylene group is optionally substituted by C. alkyl methylene group is unsubstituted; group(s) (e.g., methyl), and R is a C- alkyl group (e.g., (Ig): the number of the methylene group in A is 2, and the propyl) optionally substituted by C. alkoxy group(s) (e.g., methylene group is optionally substituted by methyl; methoxy), or a C7-12 aralkyl group (e.g., benzyl); (Ih): the number of the methylene group in A is 3, and the (Id): the number of the methylene group in A is 3, and the methylene group is optionally substituted by methyl; methylene group is optionally substituted by C. alkyl (Ii): the number of the methylene group in A is 3, and the group(s) (e.g., methyl); methylene group is optionally substituted by methyl; (Ie): the number of the methylene group in A is 2, and the (I): the number of the methylene group in A is 3, and the methylene group is optionally substituted by C. alkyl 10 methylene group is optionally Substituted by hydroxy or group(s) (e.g., methyl); methyl; (If): the number of the methylene group in A is 3, and the (Ik): the number of the methylene group in A is 3, the methylene group is unsubstituted; methylene group is unsubstituted, and R is ethyl or methox (Ig): the number of the methylene group in A is 2, and the 15 ypropyl; methylene group is optionally Substituted by C. alkyl (IT): X is a Sulfur atom, or an imino group having methyl, group(s) (e.g., methyl); the methylene group in A or A is unsubstituted, and X and (Ih): the number of the methylene group in A is 3, and the y are each 1; methylene group is optionally Substituted by C. alkyl (Im): the methylene group in A or A is unsubstituted, group(s) (e.g., methyl); and X and y are each 1; and (Ii): the number of the methylene group in A is 3, and the (In): the methylene group in A or A is unsubstituted, methylene group is optionally Substituted by C. alkyl and X and y are each 1; and group(s) (e.g., methyl); Ring B is a benzene ring optionally further substituted by (I): the number of the methylene group in A is 3, and the chlorine atom(s) or trifluoromethyl. methylene group is optionally Substituted by hydroxy 25 Specific examples of the above-mentioned compound (I) group(s) or C. alkyl group(s) (e.g., methyl); include the compounds of Examples 1 to 35, 37, 38, 40 to 51 (Ik): the number of the methylene group in A is 3, the and 53 to 55. methylene group is unsubstituted, andR is a C- alkyl group Examples of salts of compound (I) and (I) include metal (e.g., ethyl, propyl) optionally substituted by C. alkoxy salts, ammonium salts, salts with organic base, salts with group(s) (e.g., methoxy); 30 inorganic acid, salts with organic acid, salts with basic or (IT): X is a Sulfur atom, or an imino group having a C acidic amino acids, and the like. Preferable examples of the alkyl group (e.g., methyl), the methylene group in A or A metal salt include alkaline metal salts such as sodium salt, potassium salt and the like; alkaline earth metal salts such as is unsubstituted, and X and y are each 1; calcium salt, magnesium salt, barium salt and the like; alu (Im): the methylene group in A or A is unsubstituted, 35 minum salts, and the like. Preferable examples of the salt with and X and y are each 1; and organic base include Salts with trimethylamine, triethy (In): the methylene group in A or A is unsubstituted, lamine, pyridine, picoline, 2.6-lutidine, ethanolamine, and X and y are each 1; and diethanolamine, triethanolamine, cyclohexylamine, dicyclo Ring B is a benzene ring optionally further substituted by hexylamine, N,N'-dibenzylethylenediamine and the like. halogenatom(s) (e.g., a chlorine atom) or C. alkyl group(s) 40 Preferable examples of the salt with inorganic acid include (e.g., methyl) optionally Substituted by 1 to 3 halogen atoms salts with hydrochloric acid, hydrobromic acid, nitric acid, (e.g., a fluorine atom). sulfuric acid, phosphoric acid and the like. Preferable Compound (I) is particularly preferably a compound examples of the salt with organic acid include Salts with wherein formic acid, acetic acid, trifluoroacetic acid, phthalic acid, R" is ethyl, propyl or isobutyl: 45 fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, Succinic acid, malic acid, methanesulfonic acid, benze R and Rare each methyl, or nesulfonic acid, p-toluenesulfonic acid and the like. Prefer RandR form, together with the carbonatoms which they able examples of the salt with basic amino acid include salts are bonded to, a benzene ring or a cyclohexene ring: with arginine, lysine, ornithine and the like. Preferable Q is a bivalent group selected from 50 examples of the salt with acidic amino acid include salt with (Ia): the number of the methylene group in A is 2 to 4, and aspartic acid, glutamic acid and the like. the methylene group is optionally substituted by methyl, or Among them, pharmaceutically acceptable salts are pref the two substituents bonded to the single carbon atom are erable. For example, if the compound has an acidic functional combined to each other to form a cyclopentane ring, or the group therein, examples of the salt include inorganic salts methylene group is combined to the Substituent on the adja 55 Such as alkaline metal salts (e.g., Sodium salt, potassium salt cent methylene group to form a cyclopropane ring; and the like), alkaline earth metal salts (e.g., calcium salt, (Ib): the number of the methylene group in A is 3, the magnesium salt, barium salt and the like) and the like; ammo methylene group is optionally substituted by methyl, and R' nium salt, and the like. If the compound has a basic functional and R' are each methyl; group therein, examples of the salt thereof include salts with 60 inorganic acids such as hydrochloric acid, hydrobromic acid, (Ic): the number of the methylene group in A is 3, the nitric acid, Sulfuric acid, phosphoric acid and the like, and methylene group is optionally substituted by methyl, and R' salts with organic acids such as acetic acid, phthalic acid, is methoxypropyl or benzyl; fumaric acid, oxalic acid, tartaric acid, maleic acid, citric (Id): the number of the methylene group in A is 3, and the acid, Succinic acid, methanesulfonic acid, p-toluenesulfonic methylene group is optionally substituted by methyl; 65 acid and the like. (Ie): the number of the methylene group in A is 2, and the The production methods of the compound (I) or (I) of the methylene group is optionally substituted by methyl; present invention or a salt thereofare explained below. US 9,120,776 B2 45 46 The intermediates produced in the following production The compound (I'a)-compound (I'p) i.e., compound (I), methods may be isolated and purified according to methods wherein Q' in the formula (I') is each the bivalent group Such as column chromatography, recrystallization, distilla (I'a)-(I'p) or a salt thereof of the present invention can be tion and the like, or may be directly used without isolation for produced according to following Method A to Method L. the next step. Method A

o–()-(A), (IIa) HN B CN Step 1

(III)

(IV) (VI) - R3A : NH2 R24 7 RB-L Step 2 Step 5 (VIIb) ?N R SA R (V)

- R3A f H H " 7 N A'. N R1 O All N R24 r B -CN B -HCN O O O O N R54 RIA (Ia) (VIII) R4-L Step 3 6 (VIIa)

- R 4A 4A R4B 7 N (A), N HO All N R24 r B -HCN r B -HCN O O O O N R54 RIA (IX) A. 1 R3A NH2 R24 7 Step 7 N SA A. R RIA US 9,120,776 B2

4A 4B -continued 4B - R3A R R - R3A R RA-L H i N (A), N (VIIa) : N (A), N R24 / r B' --CN - a) - ,R2A / r r B' --CN O O Step 8 O O N R54 N R54 ? M R RIA (Ib) (Ic) wherein R is an optionally substituted hydrocarbon group, L 3-benzotriazine etc.). The amount of the condensing agent to is a leaving group, and the other each symbols are as defined be used is about 1 to 10 mol equivalent, preferably about 1 to above. 2 molequivalent, per 1 mol of compound (IV). The amount of Examples of the leaving group for L include halogenatoms 15 the additive to be used is generally about 1 to 10 mol equiva (a chlorine atom, a bromine atom, an iodine atom etc.). Sub lent, preferably about 1 to 2 mol equivalent, per 1 mol of stituted Sulfonyloxy groups (C. alkylsulfonyloxy groups compound (IV). Such as methanesulfonyloxy, ethanesulfonyloxy and the like; The amount of compound (V) to be used is generally about C. arylsulfonyloxy groups such as benzenesulfonyloxy, 1 to 10 mol equivalent, preferably about 1 to 2 mol equivalent, p-toluenesulfonyloxy and the like: C. aralkylsulfonyloxy per 1 mol of compound (IV). groups such as benzylsulfonyloxy and the like, etc.), acyloxy The above-mentioned reaction is generally performed in a groups (acetoxy, benzoyloxy etc.), oxy groups substituted by Solvent that does not adversely influence the reaction, and a heterocycle oraryl group (Succinimide, benzotriazole, quino base may be added for the progress of the reaction. Examples line, 4-nitrophenyl etc.), heterocycle (imidazole etc.) and the 25 of the solvent include hydrocarbons (benzene, toluene etc.), like. ethers (diethyl ether, dioxane, tetrahydrofuran etc.), esters (Step 1) (ethyl acetate etc.), halogenated hydrocarbons (chloroform, This step is a step of producing compound (IV) or a salt dichloromethane etc.), amides (N.N-dimethylformamide thereof by reacting compound (IIa) or a salt thereof with etc.) and the like, and they may be mixed as appropriate. compound (III) or a salt thereof. 30 Examples of the base include alkali metal hydroxides (so Compound (IIa) and compound (III) may be a commer dium hydroxide, potassium hydroxide etc.), hydrogen car cially available product, or can also be produced according to bonates (sodium hydrogen carbonate, potassium hydrogen a method known perse or a method analogous thereto. carbonate etc.), carbonates (sodium carbonate, potassium When compound (IV) or a salt thereof is produced by carbonate etc.), acetates (sodium acetate etc.), tertiary amines reacting compound (IIa) or a salt thereof with compound (III) 35 (trimethylamine, triethylamine, N-methylmorpholine etc.), or a salt thereof, the reaction can be performed in a solvent aromatic amines (pyridine, picoline, N,N-dimethylaniline that does not adversely influence the reaction. Examples of etc.) and the like. The amount of the base to be used is the solvent include alcohols (methanol, ethanol, propanol, generally about 1 to 100 mol equivalent, preferably about 1 to 2-propanol, butanol, isobutanol, t-butanol etc.), hydrocar 5 mol equivalent, per 1 mol of the substrate. The reaction bons (benzene, toluene etc.), ethers (diethyl ether, dioxane, 40 temperature is generally about -80 to 150° C., preferably tetrahydrofuran etc.), esters (ethyl acetate etc.), halogenated about 0 to 50° C., and the reaction time is generally about 0.5 hydrocarbons (chloroform, dichloromethane etc.), amides to 100 hr, preferably 0.5 to 60 hr. (N,N-dimethylformamide etc.) and the like, and they may be (Step 3) mixed as appropriate. Among these, tetrahydrofuran is pref This step is a step of producing compound (I'b') or a salt erably used. 45 thereof by reacting compound (Ia) or a salt thereof with The amount of compound (III) to be used is generally about compound (VIIa) or a salt thereof in the presence of a base. 0.5 to 10 mol equivalent, preferably about 0.9 to 1.1 mol Compound (VIIa) may be a commercially available prod equivalent, per 1 mol of compound (IIa). uct, or can also be produced according to a method known per The reaction temperature is generally about-80 to 200°C., se or a method analogous thereto. preferably about 25 to 150° C., and the reaction time is 50 Examples of the base used in this step include inorganic generally about 0.5 to 72 hr., preferably 1 to 48 hr. bases (alkali metal hydrides such as sodium hydride, lithium (Step 2) hydride and the like, alkali metal hydroxides such as lithium This step is a step of producing compound (Ia) or a salt hydroxide, Sodium hydroxide, potassium hydroxide and the thereof by reacting compound (IV) or a salt thereof with like, alkali metal hydrogen carbonates Such as sodium hydro compound (V) or a salt thereof in the presence of a condens 55 gen carbonate, potassium hydrogen carbonate and the like, ing agent. alkali metal carbonates Such as lithium carbonate, sodium Compound (V) may be a commercially available product, carbonate, potassium carbonate, cesium carbonate and the or can also be produced according to a method known perse like, alkali metal alkoxides such as Sodium methoxide, or a method analogous thereto. Sodium ethoxide and the like, and the like), organic bases Examples of the condensing agent used in this step include 60 (amines Such as trimethylamine, triethylamine, diisopropyl dicyclohexylcarbodiimide, diisopropylcarbodiimide, ethylamine and the like, cyclic amines such as pyridine, N-ethyl-N'-3-dimethylaminopropylcarbodiimide and a 4-dimethylaminopyridine and the like, and the like) and the hydrochloride thereof, benzotriazol-1-yloxy-tris(dimethy like. Among these, sodium hydride is preferable. While the lamino)phosphonium hexafluorophosphorate, diphenylphos amount of the base to be used varies depending on the kind of phorylazide and the like. They can be used alone or in com 65 the solvent and the other reaction conditions, it is generally bination with an additive (e.g., N-hydroxysuccinimide, about 1 to 10 mol equivalent, preferably about 1 to 5 mol 1-hydroxybenzotriazole, 3-hydroxy-4-oxo-3,4-dihydro-1,2, equivalent, per 1 mol of compound (Ia). US 9,120,776 B2 49 50 The amount of compound (VIIa) to be used is generally Examples of the solvent used for the reaction include aro about 1 to 10 mol equivalent, preferably about 1 to 3 mol matic hydrocarbons (benzene, toluene, Xylene etc.), aliphatic equivalent, per 1 mol of compound (Ia). hydrocarbons (hexane, heptane etc.), halogenated hydrocar This step is performed in a solvent that does not adversely bons (dichloromethane, chloroform etc.), ethers (diethyl influence the reaction. Examples of the solvent that does not ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, adversely influence the reaction include aromatic hydrocar dioxane, dimethoxyethane etc.), nitriles (acetonitrile etc.), bons (benzene, toluene, Xylene etc.), aliphatic hydrocarbons esters (ethyl acetate etc.) and the like. Compound (XXXVI) (hexane, heptane etc.), halogenated hydrocarbons (dichlo may be used as a solvent. romethane, chloroform etc.), ethers (diethyl ether, diisopro 10 The reaction temperature is, for example, within about 0 to pyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane, 200° C., preferably about 25 to 100° C. While the reaction time varies depending on the kind of compound (IV) or a salt dimethoxyethane etc.), nitriles (acetonitrile etc.), esters (ethyl thereof, the reaction temperature and the like, it is, for acetate etc.), amides (N.N-dimethylformamide etc.), sulfox example, about 0.5 to 100 hr, preferably about 0.5 to 24hr. ides (dimethylsulfoxide etc.) and the like. Among these, N.N- 15 Examples of the base used for the reaction of compound dimethylformamide is preferable. These solvent may be used (IV) or a salt thereof with compound (XXXVII) or a salt in a mixture of two or more kinds thereof in an appropriate thereof include inorganic bases (alkali metal hydrides such as ratio. sodium hydride, lithium hydride and the like, alkali metal The reaction temperature is, for example, within about 0 to hydroxides such as lithium hydroxide, sodium hydroxide, 200° C., preferably about 25 to 100° C. While the reaction potassium hydroxide and the like, alkali metal hydrogen car time varies depending on the kind of compound (I'a) or a salt bonates such as Sodium hydrogen carbonate, potassium hydrogen carbonate and the like, alkali metal carbonates Such thereof, the reaction temperature and the like, it is, for as lithium carbonate, Sodium carbonate, potassium carbon example, about 0.5 to 100 hr, preferably about 0.5 to 24hr. ate, cesium carbonate and the like, etc.). While the amount of (Step 4) 25 the base to be used varies depending on the kind of the solvent This step is a step of producing compound (VI) or a salt and the other reaction condition, it is generally about 1 to mol equivalent, preferably about 1 to 5 mol equivalent, per 1 mol thereof by subjecting compound (IV) or a salt thereof to of compound (IV). esterification. 30 The amount of compound (XXXVII) to be used is gener This reaction is a step of producing compound (VI) or a salt ally about 1 to 10 mol equivalent, preferably about 1 to 3 mol thereof by subjecting compound (IV) or a salt thereof to a equivalent, per 1 mol of compound (IV). dehydration reaction with the compound represented by the This step is performed in a solvent that does not adversely formula influence the reaction. Examples of the solvent that does not 35 adversely influence the reaction include aromatic hydrocar R OH (XXXVI) bons (benzene, toluene, Xylene etc.), aliphatic hydrocarbons wherein each symbol is as defined above (hereinafter some (hexane, heptane etc.), halogenated hydrocarbons (dichlo times to be referred to as compound (XXXVI)) or a salt romethane, chloroform etc.), ethers (diethyl ether, diisopro pyl ether, t-butyl methyl ether, tetrahydrofuran, dioxane, thereof in the presence of an acid catalyst, or to an alkylation 40 dimethoxyethane etc.), nitriles (acetonitrile etc.), esters (ethyl reaction with the compound represented by the formula acetate etc.), amides (N.N-dimethylformamide etc.), sulfox ides (dimethylsulfoxide etc.) and the like. These solvent may R-L (XXXVII) be used in a mixture of two or more kinds thereof in an wherein each symbol is as defined above (hereinafter some appropriate ratio. times to be referred to as compound (XXXVII)) in the pres 45 The reaction temperature is, for example, within about 0 to ence of a base. 200° C., preferably about 25 to 100° C. While the reaction Compound (XXXVI) and compound (XXXVII) may be a time varies depending on the kind of compound (IV) or a salt commercially available product, or can also be produced thereof, the reaction temperature and the like, it is, for 50 example, about 0.5 to 100 hr, preferably about 0.5 to 24hr. according to a method known perse or a method analogous (Step 5) thereto. This step is a step of producing compound (VIII) or a salt Examples of the acid catalyst used for the reaction of thereof by reacting compound (VI) or a salt thereof with compound (IV) or a salt thereof with compound (XXXVI) or compound (VIIb) or a salt thereof in the presence of a base. a salt thereof include mineral acids (hydrochloric acid, sulfu 55 This step can be performed in the same manner as in the ric acid etc.), organic Sulfonic acids (methanesulfonic acid, method described in Step 3 of Method A. p-toluenesulfonic acid etc.), Lewis acids (boron fluoride Compound (VIIb) may be a commercially available prod etherate etc.) and the like. While the amount of the acid uct, or can also be produced according to a method known per se or a method analogous thereto. catalyst to be used varies depending on the kind of the solvent 60 and the other reaction condition, it is generally about 0.0001 (Step 6) to 10 mol equivalent, preferably about 0.01 to 0.1 mol equiva This step is a step of converting compound (VIII) or a salt thereof to compound (IX) or a salt thereof by hydrolysis. This lent, per 1 mol of compound (IV). reaction can be performed according to a method known per The amount of compound (XXXVI) to be used is generally 65 se, generally in the presence of an acid or a base, where about 1 to 1000 mol equivalent, preferably about 10 to 100 necessary, in a solvent that does not adversely influence the mol equivalent, per 1 mol of compound (IV). reaction. US 9,120,776 B2 51 52 Examples of the acid include mineral acids (hydrochloric time varies depending on the kind of compound (VIII) or a acid, hydrobromic acid, Sulfuric acid etc.), carboxylic acids salt thereof, the reaction temperature and the like, it is, for example, about 0.5 to 100 hr, preferably about 0.5 to 24hr. (acetic acid, trifluoroacetic acid, trichloroacetic acid etc.), (Step 7) Sulfonic acids (methanesulfonic acid, toluenesulfonic acid This step is a step of producing compound (Ic) or a salt etc.), Lewis acids (aluminium chloride, tin chloride, Zinc thereof by reacting compound (IX) or a salt thereof with bromide etc.) and the like. Where necessary, they may be used compound (V) or a salt thereof in the presence of a condens in a mixture of two or more kinds thereof. While the amount ing agent. This step can be performed in the same manner as of the acid to be used varies depending on the kind of the in the method described in Step 2 of Method A. Solvent and the other reaction condition, it is generally about (Step 8) 0.1 mol equivalent or more per 1 mol of compound (VIII). 10 This step is a step of producing compound (Ib) or a salt The acid may be used as a solvent. thereof by reacting compound (Ic) or a salt thereof with Examples of the base include inorganic bases (alkali metal compound (VIIa) or a salt thereof in the presence of a base. hydroxides such as lithium hydroxide, sodium hydroxide, This step can be performed in the same manner as in the potassium hydroxide and the like, alkali metal hydrogen car method described in Step 3 of Method A. bonates such as Sodium hydrogen carbonate, potassium Method B

HO All pi HO N-1 Allpi r B' CN -e-step 1 B -HCN O O O (IV) (X) s 2 - R3A NH2 R24 7 N SA - R3A A R ? H H RIA H ... / Na1nn-N (V) H. All N R24 B -HCN B -HCN O Step 3 O O N R54 RIA (XI) hydrogen carbonate and the like, alkali metal carbonates Such 40 wherein each symbol is as defined above. as sodium carbonate, potassium carbonate and the like, (Step 1) alkoxides such as sodium methoxide, sodium ethoxide and This step is a step of producing compound (X) or a salt the like, etc.), organic bases (amines Such as trimethylamine, thereof by treating compound (IV) or a salt thereof with a triethylamine, diisopropylethylamine and the like, cyclic reducing agent. amines Such as pyridine, 4-dimethylaminopyridine and the 45 Examples of the reducing agent used in this step include metal hydrides (sodium borohydride, lithium borohydride, like, etc.) and the like. Among these, sodium hydroxide is Zinc borohydride, Sodium cyanoborohydride, Sodium triac preferable. While the amount of the base to be used varies etoxyborohydride, lithium cyanoborohydride, dibutylalumi depending on the kind of the solvent and the other reaction num hydride, aluminiumhydride, lithium aluminium hydride condition, it is generally about 0.1 to 10 mol equivalent, 50 etc.), borane complexs (borane-tetrahydrofuran complex, preferably about 1 to 5 mol equivalent, per 1 mol of com catecholborane etc.) and the like. Among these, borane-tet pound (VIII). rahydrofuran complex is preferable. The amount of the reduc Examples of the solvent that does not adversely influence ing agent to be used is, for example, about 1 to 50 mol the reaction include alcohols (methanol, ethanol, propanol, equivalent, preferably about 1 to 10 mol equivalent, per 1 mol 2-propanol, butanol, isobutanol, t-butanol etc.), hydrocar 55 of compound (IV). Examples of the reaction solvent include bons (benzene, toluene, Xylene, hexane, heptane etc.), halo aromatic hydrocarbons (toluene, Xylene etc.), aliphatic genated hydrocarbons (dichloromethane, chloroform etc.), hydrocarbons (heptane, hexane etc.), halogenated hydrocar ethers (diethyl ether, diisopropyl ether, t-butyl methyl ether, bons (chloroform, dichloromethane etc.), ethers (diethyl tetrahydrofuran, dioxane, dimethoxyethane etc.), nitriles (ac ether, tetrahydrofuran, dioxane etc.), alcohols (methanol, etonitrile etc.), carboxylic acids (acetic acid etc.), amides 60 ethanol. 2-propanol, butanol, benzyl alcohol etc.), nitriles (N,N-dimethylformamide, dimethylacetamide etc.), sulfox (acetonitrile etc.), amides (N.N-dimethylformamide etc.), ides (dimethylsulfoxide etc.), water and the like. Among sulfoxides (dimethylsulfoxide etc.) and the like. Among these, ethanol, tetrahydrofuran and water are preferable. these, tetrahydrofuran is preferable. These solvent may be These solvent may be used in a mixture of two or more kinds used in a mixture thereof in an appropriate ratio. The reaction thereof in an appropriate ratio. 65 temperature is generally about -80°C. to 100° C., preferably The reaction temperature is, for example, within about -50 about 0°C. to 40°C., and the reaction time is generally 5 min to 200° C., preferably about 0 to 100° C. While the reaction to 48 hr, preferably 1 to 24hr. US 9,120,776 B2 53 54 (Step 2) mineral acids (hydrochloric acid, hydrobromic acid, Sulfuric This step is a step of producing compound (XI) or a salt acid etc.), carboxylic acids (formic acid, acetic acid, propi thereof by treating compound (X) or a salt thereof with an oxidizing agent. onic acid, trifluoroacetic acid etc.), Sulfonic acids (methane Examples of the oxidizing agent used in this step include Sulfonic acid, p-toluenesulfonic acid etc.), Lewis acids (alu chromic acids (pyridinium chlorochromate (PCC), pyri minium chloride, Zinc chloride, Zinc bromide, boron dinium dichromate (PDC) etc.), active manganese dioxides, trifluoride, titanium chloride etc.), acetates (sodium acetate, dimethylsulfoxide-electrophiles (examples of the electro potassium acetate etc.), molecular sieves (molecular sieve phile include oxalyl chloride, dicyclohexylcarbodiimide 3A, 4A, 5A etc.), dehydrating agents (magnesium Sulfate (DCC), acetic anhydride, trifluoroacetic anhydride, thionyl 10 etc.) and the like. The amount of the catalyst to be used is chloride, chlorine, N-chlorosuccinimide (NCS) etc.), oxoam monium salts (4-(benzoyloxy)-2.2.6.6-tetramethylpiperidin generally 0.01 to 50 mol equivalent, preferably about 0.1 to 1-oxyl etc.), tetrapropylammonium perruthenates (TPAP)-4- about 10 mol, per 1 mol of compound (XI). methylmorpholine N-oxide, hypervalent iodines (1,1,1- The reaction temperature is generally about 0°C. to about triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess 15 200° C., preferably about 20° C. to about 150° C., and the Martin Periodinane)) and the like. The amount of the oxidizing agent to be used is generally about 1 to about 50 reaction time is generally about 0.5 hr to about 48 hr, prefer mol, preferably about 1 to about 10 mol, per 1 mol of com ably about 0.5 hr to about 24hr. pound (X). The conversion of the imine or iminium ion to compound Examples of the reaction solvent include aromatic hydro (I'd) can be performed according to various reduction reac carbons (toluene, Xylene etc.), aliphatic hydrocarbons (hep tion in a solvent inert to the reaction. The reduction reaction tane, hexane etc.), halogenated hydrocarbons (chloroform, can be performed according to a method known per se, and dichloromethane etc.), ethers (diethyl ether, tetrahydrofuran, examples thereof include a method using a metal hydride, and dioxane etc.), alcohols (methanol, ethanol. 2-propanol, 25 method employing hydrogenation reaction. butanol, benzyl alcohol etc.), nitriles (acetonitrile etc.), Examples of the metal hydride include sodium borohy amides (N.N-dimethylformamide etc.), sulfoxides (dimeth dride, lithium borohydride, zinc borohydride, sodium ylsulfoxide etc.) and the like. These solvent may be used in a cyanoborohydride, sodium triacetoxyborohydride, lithium mixture thereof in an appropriate ratio. 30 cyanoborohydride, dibutylaluminium hydride, aluminium While the reaction temperature varies depending on the hydride, lithium aluminium hydride, borane complexs (bo kind of the oxidizing agent, it is generally about -78°C. to rane-THF complex, catecholborane etc.) and the like, and about 200°C., preferably about 0°C. to about 100°C., and the Sodium borohydride, Sodium cyanoborohydride, Sodium tri reaction time is generally about 0.5 hr to about 48 hr, prefer 35 acetoxyborohydride and the like are preferable. The amount ably about 0.5 hr to about 24hr. of the metal hydride to be used is, for example, about 1 to (Step 3) about 50 mol, preferably about 1 to about 10 mol, per 1 mol of This step is a step of producing compound (I'd) or a salt the imine. thereof by subjecting compound (XI) or a salt thereof to a The reduction reaction using a metal hydride is performed reductive alkylation reaction with compound (V) or a salt 40 generally in a solvent inert to the reaction. Examples of the thereof. Solvent include aromatic hydrocarbons (toluene, Xylene etc.), The reductive alkylation reaction in this step can be per aliphatic hydrocarbons (heptane, hexane etc.), halogenated formed according to a method known perse, for example, by hydrocarbons (chloroform, dichloromethane etc.), ethers (di reacting compound (XI) or a salt thereof with compound (V) 45 ethyl ether, tetrahydrofuran, dioxane etc.), alcohols (metha or a salt thereof, and Subjecting the resulting imine or imi nol, ethanol. 2-propanol, butanol, benzyl alcohol etc.), nium ion to a reduction reaction. nitriles (acetonitrile etc.), N,N-dimethylformamide, dimeth The amount of compound (V) to be used is generally about ylsulfoxide and the like. These solvent may be used in a 1 to 10 mol equivalent, preferably about 1 to 3 molequivalent, 50 mixture thereof in an appropriate ratio. per 1 mol of compound (XI). The reaction temperature is generally about -80° C. to The solvent used for the reaction for producing imine or about 80° C., preferably about -40°C. to about 40°C., and iminium ion is not particularly limited as long as the reaction the reaction time is generally about 5 min to about 48 hr, proceeds. Examples thereof include hydrocarbons (heptane, 55 preferably about 1 hr to about 24hr. hexane, toluene, Xylene etc.), halogenated hydrocarbons The catalytic hydrogenation reaction can be performed in (chloroform, dichloromethane, 1,2-dichloroethane etc.), the presence of a catalyst under hydrogen atmosphere. ethers (diethyl ether, tetrahydrofuran, dioxane etc.), esters Examples of the catalyst include palladiums such as palla (ethyl acetate, t-butyl acetate etc.), alcohols (methanol, etha 60 dium on carbon, palladium hydroxide on carbon, palladium nol, 2-propanol etc.), nitriles (acetonitrile, butyronitrile etc.), oxide and the like; nickels such as Raney-nickel catalyst and amides (N.N-dimethylformamide, dimethylacetamide etc.), the like; platinums such as platinum oxide, platinum on car sulfoxides (dimethylsulfoxide etc.) and the like, and mixed bon and the like; rhodiums such as rhodium on carbon and the solvents thereof. 65 like, and the like. The amount thereof to be used is generally In this step, the reaction can advantageously proceeds by about 0.001 to about 1 mol, preferably about 0.01 to about 0.5 the addition of a catalyst. Examples of the catalyst include mol, per 1 mol of the imine or oxime. US 9,120,776 B2 55 The catalytic hydrogenation reaction is performed gener -continued ally in a solventinert to the reaction. Examples of the solvent include alcohols (methanol, ethanol, propanol, butanol etc.), -a D3AR. H H B i -HCN hydrocarbons (benzene, toluene, Xylene etc.), halogenated N A N hydrocarbons (dichloromethane, chloroform etc.), ethers (di k21-\ ethyl ether, dioxane, tetrahydrofuran etc.), esters (ethyl O O acetate etc.), amides (N.N-dimethylformamide etc.), car N R54 boxylic acids (acetic acid etc.), water and mixtures thereof. RIA The hydrogen pressure for the reaction is generally about 1 to about 50 atm. preferably about 1 to about 10 atm. The 10 reaction temperature is generally about 0°C. to about 150° C. preferably about 20° C. to about 100° C., and the reaction time is generally about 5 minto about 72 hr., preferably about wherein each symbol is as defined above. 0.5 hr to about 40 hr. 15 In this step, by Subjecting the intermediate imine or Oxime (Step 1) without isolation to the next reduction reaction, compound This step is a step of producing compound (XIII) or a salt (I'd) can also be obtained directly from compound (XI). In this case, the pH of the reaction mixture is preferably adjusted thereof by reacting compound (XII) or a salt thereof with to about 4 to about 5. compound (V) or a salt thereof. Method C This step can be performed in the same manner as in the

25 method described in Step 1 of Method A. Compound (XII) may be a commercially available prod uct, or can also be produced according to a method known per

30 se or a method analogous thereto. (Step 2) This step is a step of producing compound (I'e) or a salt 35 thereof by reacting compound (XIII) or a salt thereof with compound (XIV) or a salt thereof in the presence of a con densing agent. 40 This step can be performed in the same manner as in the (XIII) method described in Step 2 of Method A. HN Compound (XIV) may be a commercially available prod 45 Step 2 uct, or can also be produced according to a method known per (XIV) se or a method analogous thereto. Method D

(XV) US 9,120,776 B2 57 58 -continued

B' --CN HO - R3A O R3A f H H N A n O N A NH s: (/ r H B -HCN (XVIII) R2-\ r 2 Step 3 N R54 O p N R54 O A A RIA RIA (If) (XVII) wherein each symbol is as defined above. 15 of the solvent and the other reaction condition, it is generally (Step 1) about 0.1 mol equivalent or more per 1 mol of compound This step is a step of producing compound (XVI) or a salt (XVI). The acid may be used as a solvent. thereof by reacting compound (XV) or a salt thereof with Examples of the solvent that does not adversely influence compound (V) or a salt thereof in the presence of a condens the reaction include alcohols (methanol, ethanol, propanol, ing agent. 2-propanol, butanol, isobutanol, t-butanol etc.), aromatic This step can be performed in the same manner as in the hydrocarbons (benzene, toluene, Xylene etc.), aliphatic method described in Step 2 of Method A. hydrocarbons (hexane, heptane etc.), halogenated hydrocar Compound (XV) may be a commercially available prod 25 bons (dichloromethane, chloroform etc.), ethers (diethyl uct, or can also be produced according to a method known per ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, se or a method analogous thereto. dioxane, dimethoxyethane etc.), nitriles (acetonitrile etc.), (Step 2) esters (ethyl acetate etc.), carboxylic acids (acetic acid etc.), This step is a step of producing compound (XVII) or a salt 30 amides (N.N-dimethylformamide etc.), sulfoxides (dimeth thereof by subjecting compound (XVI) or a salt thereof to a ylsulfoxide etc.), water and the like, and mixed solvents thereof. deprotection reaction. The reaction temperature is, for example, within about -50 The deprotection reaction can be performed according to a 35 to 200° C., preferably about 0 to 100° C. While the reaction known method (e.g., Wiley-Interscience, 1999. “Protective time varies depending on the kind of compound (XVI), the Groups in Organic Synthesis, 3rd Ed. (Theodora W. Greene, reaction temperature and the like, it is, for example, about 0.5 Peter G. m. Wuts)). For example, while the reaction is per to 100 hr, preferably about 0.5 to 24 hr. formed depending on the kind of compound (XVI), it is 40 generally performed in the presence of an acid, where neces (Step 3) sary, in a solvent that does not adversely influence the reac This step is a step of producing compound (I'f) or a salt tion. thereof by reacting compound (XVII) or a salt thereof with Examples of the acid include mineral acids (hydrochloric compound (XVIII) or a salt thereof in the presence of a 45 condensing agent. acid, hydrobromic acid, Sulfuric acid, hydrogen chloride This step can be performed in the same manner as in the etc.), carboxylic acids (acetic acid, trifluoroacetic acid, method described in Step 2 of Method A. trichloroacetic acid etc.), Sulfonic acids (methanesulfonic Compound (XVIII) may be a commercially available prod acid, p-toluenesulfonic acid etc.), Lewis acids (aluminium 50 chloride, tin chloride, zinc bromide etc.) and the like. The acid uct, or can also be produced according to a method known per may be used in a mixture of two or more kinds thereof. While se or a method analogous thereto. the amount of the acid to be used varies depending on the kind Method El

HN B -HCN H B -HCN (XIV) Ben-1A l N Step 1 H r O (XX) US 9,120,776 B2 59 60 -continued R3A O / OH N R54 RIA A l' H B -HCN (XXXIX)Step 3 HN1 --C O

(XXI) wherein each symbol is as defined above. (Step 3) (Step 1) This step is a step of producing compound (I'g) or a salt This step is a step of producing compound (XX) or a salt thereof by reacting compound (XXI) or a salt thereof with thereof by reacting compound (XIX) or a salt thereof with 29 compound (V) or a Salt thereof in the presence of a condens compound (XIV) or a salt thereof in the presence of a con ing agent. densing agent. This step can be performed in the same manner as in the This step can be performed in the same manner as in the method described in Step 2 of Method A. method described in Step 2 of Method A. Method F.

B -HCN HO

O Boc (A), (XVIII) Ben-IA's N- YNH, Step 1 H H B -HCN

(XXII) (XXIII) s 2

- R3A O O O : 1'), as R24 7 N H B -HCN B. H. CN N SA A R RIA (Ih) (XXIV)

55 Compound (XIX) may be a commercially available prod wherein each symbol is as defined above. uct, or can also be produced according to a method known per (Step 1) se or a method analogous thereto. This step is a step of producing compound (XXIII) or a salt 60 thereof by reacting compound (XXII) or a salt thereof with (Step 2) compound (XVIII) or a salt thereof in the presence of a This step is a step of producing compound (XXI) or a salt condensing agent. thereof by subjecting compound (XX) or a salt thereof to a This step can be performed in the same manner as in the deprotection reaction. method described in Step 2 of Method A. 65 Compound (XXII) may be a commercially available prod This step can be performed in the same manner as in the uct, or can also be produced according to a method known per method described in Step 2 of Method D. se or a method analogous thereto. US 9,120,776 B2 61 62 (Step 2) 1 to 10 mol equivalent, preferably about 1 to 5 mol equivalent, This step is a step of producing compound (XXIV) or a salt per 1 mol of compound (XXII). thereof by subjecting compound (XXIII) or a salt thereof to a The amount of compound (XXV) to be used is generally deprotection reaction. about 1 to 10 mol equivalent, preferably about 1 to 3 mol This step can be performed in the same manner as in the equivalent, per 1 mol of compound (XXII). method described in Step 2 of Method D. This reaction is generally performed in a solvent that does (Step 3) not adversely influence the reaction. Examples of the solvent This step is a step of producing compound (Ih) or a salt that does not adversely influence the reaction include aro thereof by reacting compound (XXIV) or a salt thereof with matic hydrocarbons (benzene, toluene, Xylene etc.), aliphatic compound (XXXIX) or a salt thereof in the presence of a 10 hydrocarbons (hexane, heptane etc.), halogenated hydrocar condensing agent. bons (dichloromethane, chloroform etc.), ethers (diethyl This step can be performed in the same manner as in the ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, method described in Step 2 of Method A. dioxane, dimethoxyethane etc.), nitriles (acetonitrile etc.), Method G esters (ethyl acetate etc.), amides (N.N-dimethylformamide

B -HCN C Ns / \, Boc (A), (XXV) n N1 na NH2 H Step 1 B -HCN

(XXII)

(XXVII) wherein each symbol is as defined above. etc.), Sulfoxides (dimethylsulfoxide etc.) and the like. Among (Step 1) 45 these, tetrahydrofuran, acetonitrile and N,N-dimethylforma This step is a step of producing compound (XXVI) or a salt mide are preferable. These solvent may be used in a mixture thereof by reacting compound (XXII) or a salt thereof with of two or more kinds thereof in an appropriate ratio. compound (XXV) or a salt thereof in the presence of a base. The reaction temperature is, for example, within about 0 to Compound (XXV) may be a commercially available prod 200° C., preferably about 50 to 100° C. While the reaction uct, or can also be produced according to a method known per 50 time varies depending on the kind of compound (XXII) or a se or a method analogous thereto. salt thereof, the reaction temperature and the like, it is, for Examples of the base used for this reaction include inor example, about 0.5 to 100 hr, preferably about 0.5 to 24hr. ganic bases (alkali metal hydrides such as Sodium hydride, (Step 2) lithium hydride and the like, alkali metal hydroxides such as 55 This step is a step of producing compound (XXVII) or a lithium hydroxide, Sodium hydroxide, potassium hydroxide salt thereof by subjecting compound (XXVI) or a salt thereof and the like, alkali metal hydrogen carbonates Such as sodium to a deprotection reaction. hydrogen carbonate, potassium hydrogen carbonate and the This step can be performed in the same manner as in the like, alkali metal carbonates Such as lithium carbonate, method described in Step 2 of Method D. Sodium carbonate, potassium carbonate, cesium carbonate 60 and the like, alkali metal alkoxides Such as sodium methox (Step 3) ide, Sodium ethoxide and the like, etc.), organic bases (amines This step is a step of producing compound (I'i) or a salt Such as trimethylamine, triethylamine, diisopropylethy thereof by reacting compound (XXVII) or a salt thereof with lamine and the like, cyclic amines such as pyridine, 4-dim compound (XXXIX) or a salt thereof in the presence of a ethylaminopyridine and the like, etc.) and the like. While the 65 condensing agent. amount of the base to be used varies depending on the kind of This step can be performed in the same manner as in the the solvent and other reaction condition, it is generally about method described in Step 2 of Method A. US 9,120,776 B2 64 Method H This reaction is generally performed in a solvent that does not adversely influence the reaction. Examples of the solvent - R3A that does not adversely influence the reaction include aro NH2 matic hydrocarbons (benzene, toluene, Xylene etc.), aliphatic R-M hydrocarbons (hexane, heptane etc.), halogenated hydrocar N R54 bons (dichloromethane, chloroform etc.), ethers (diethyl IA ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, (A), R 10 O (V) dioxane, dimethoxyethane etc.), nitriles (acetonitrile etc.), O Step 1 esters (ethyl acetate etc.), amides (N.N-dimethylformamide (XXVIII) etc.), sulfoxides (dimethylsulfoxide etc.) and the like. These R3A solvent may be used in a mixture of two or more kinds thereof f All pi OH n1 in an appropriate ratio. R24 7 O The reaction temperature is, for example, within about 0 to S R54 200° C., preferably about 50 to 100° C. While the reaction RIA time varies depending on the kind of compound (XXVIII) or (XXIX) a salt thereof, the kind of compound (V) or a salt thereof, the reaction temperature and the like, it is, for example, about 0.5 B. H-CN Step 2 to 100 hr, preferably about 0.5 to 24 hr. L 25 (Step 2) (XXX) This step is a step of producing compound (I) or a salt - R3A thereof by reacting compound (XXIX) or a salt thereof with ? All pi O n1 compound (XXX) or a salt thereof in the presence of a base. R24 / r B. H-CN Compound (XXX) may be a commercially available prod O N R54 uct, or can also be produced according to a method known per RIA se or a method analogous thereto.

(I) 35 Examples of the base used for this reaction include inor ganic bases (alkali metal hydrides Such as Sodium hydride, wherein each symbol is as defined above. lithium hydride and the like, alkali metal hydroxides such as (Step 1) lithium hydroxide, Sodium hydroxide, potassium hydroxide This step is a step of producing compound (XXIX) or a salt 40 and the like, alkali metal hydrogen carbonates Such as Sodium hydrogen carbonate, potassium hydrogen carbonate and the thereof by reacting compound (XXVIII) or a salt thereof with compound (V) or a salt thereof in the presence of an additive. like, alkali metal carbonates Such as lithium carbonate, Sodium carbonate, potassium carbonate, cesium carbonate Compound (XXVIII) may be a commercially available 45 and the like, alkali metal alkoxides Such as sodium methox product, or can also be produced according to a method ide, Sodium ethoxide, potassium-t-butoxide and the like, known perse or a method analogous thereto. etc.), organic bases (amines Such as trimethylamine, triethy Examples of the additive used for this reaction include lamine, diisopropylethylamine and the like, cyclic amines aluminium reagents (trimethylaluminum, aluminium chlo 50 Such as pyridine, 4-dimethylaminopyridine and the like etc.) ride etc.), tin reagents (tetramethyltin etc.), Grignard reagents and the like. Among these, Sodium hydride and potassium-t- (methylmagnesium chloride, methylmagnesium bromide, butoxide are preferable. While the amount of the base to be methylmagnesium iodide, ethylmagnesium chloride, ethyl used varies depending on the kind of the solvent and other magnesium bromide, ethylmagnesium iodide etc.), bases 55 reaction condition, it is generally about 1 to 10 mol equiva (butyllithium, sodium hydride, sodium methoxide etc.) and lent, preferably about 1 to 5 mol equivalent, per 1 mol of the like. While the amount of the additive to be used varies compound (XXIX). depending on the kind of the solvent and the other reaction The amount of compound (XXX) to be used is generally condition, it is generally about 1 to 10 mol equivalent, pref 60 about 1 to 10 mol equivalent, preferably about 1 to 3 mol erably about 1 to 5 mol equivalent, per 1 mol of compound equivalent, per 1 mol of compound (XXIX). (V). This reaction is generally performed in a solvent that does The amount of compound (V) to be used is generally about not adversely influence the reaction. Examples of the solvent 65 1 to 10 mol equivalent, preferably about 1 to 3 molequivalent, that does not adversely influence the reaction include aro per 1 mol of compound (XXVIII). matic hydrocarbons (benzene, toluene, Xylene etc.), aliphatic US 9,120,776 B2 65 66 hydrocarbons (hexane, heptane etc.), halogenated hydrocar This step can be performed in the same manner as in the bons (dichloromethane, chloroform etc.), ethers (diethyl method described in Step 2 of Method A. Compound (XXXI) may be a commercially available prod ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, uct, or can also be produced according to a method known per dioxane, dimethoxyethane etc.), nitriles (acetonitrile etc.), se or a method analogous thereto. esters (ethyl acetate etc.), amides (N,N-dimethylformamide (Step 2) etc.), Sulfoxides (dimethylsulfoxide etc.) and the like. Among This step is a step of producing compound (XXXIII) or a these, tetrahydrofuran is preferable. These solvent may be salt thereof by reacting compound (XXXII) or a salt thereof with compound (VIIa) or a salt thereof in the presence of a used in a mixture of two or more kinds thereof in an appro 10 base. priate ratio. This step can be performed in the same manner as in the The reaction temperature is, for example, within about 0 to method described in Step 3 of Method A. 200° C., preferably about 50 to 100° C. While the reaction (Step 3) time varies depending on the kind of compound (XXIX) or a 15 This step is a step of converting compound (XXXIII) or a salt thereof to compound (XXXIV) or a salt thereof by salt thereof, the reaction temperature and the like, it is, for hydrolysis. example, about 0.5 to 100 hr, preferably about 0.5 to 24hr. This step can be performed in the same manner as in the Method I method described in Step 6 of Method A.

B -HCN HO O O R6 Y O r All pi YNH, (XVIII) R6 Y O r All pi NN Step 1 H B -HCN O O (XXXI) (XXXII) R4-L Step 2 (VIIa) O O HO A n 61' A n B CN Step 3 B CN O R4A O R4A (XXXIV) (XXXIII) - R3A NH2 R24 / Step 4 N SA A R R14 (V) - R3A O f H N A lin N R24 7 B -HCN O R4A N SA A R RIA (Ik) wherein each symbol is as defined above. 60 (Step 4) (Step 1) This step is a step of producing compound (I'k) or a salt thereof by reacting compound (XXXIV) or a salt thereof with This step is a step of producing compound (XXXII) or a compound (V) or a salt thereof in the presence of a condens salt thereof by reacting compound (XXXI) or a salt thereof 6 s ing agent. with compound (XVIII) or a salt thereof in the presence of a This step can be performed in the same manner as in the condensing agent. method described in Step 2 of Method A. US 9,120,776 B2 67 68 Method J

O O

Yn HO1-sul Al |A OH HN (XXXVa) B -HCN

Step 1 Step 2 III)

HN

B -HCN 2 H O O O HO All Al N N.Y III risk B -HCN AllN AI — Step 3 - 5 O X (XXXVb) (XXXVIII) p 1 R3A : NH2 R2 7 Step 4 AN R54 R14 (V) - R3A H 2 N All Al N / Yx 1 R24 B' --CN O O N R54 RIA (II) /6 6

At - R3A H H N (All Alx-N Step 5 wR24 / S 1 B -HCN O O O ?N R SA RIA (In) -- R3A H / N Al.KS-1A 2 ly NH R24 MV 1 B -HCN O O O O N R54 RIA (I'm) wherein each symbol is as defined above. 60 Examples of the reactant used for this reaction include (Step 1) Sulfuric acid, Sulfonic acids (methanesulfonic acid, p-tolup This step is a step of producing compound (XXXVb) or a enesulfonic acid etc.), thionyl chloride, phosphoryl chloride, thereofsalt thereof to a dehydration by subjecting reaction. compound (XXXVa) or a salt diphosphorus pentaoxide, phosgene, triphosgene, anhydrides Compound (XXXVa) may be a commercially available 65 (acetic anhydride, trifluoroacetic anhydride etc.) and the like. product, or can also be produced according to a method While the amount of the reactant to be used varies depending known perse or a method analogous thereto. on the kind of the solvent and other reaction condition, it is US 9,120,776 B2 69 70 generally about 1 to 100 mol equivalent, preferably about 1 to the oxidizing agent to be used varies depending on the kind of 10 mol equivalent, per 1 mol of compound (XXXVa). the solvent and other reaction condition, it is generally about This reaction is generally performed in a solvent that does 1 to 10 mol equivalent, preferably about 1 to 10 mol equiva not adversely influence the reaction. Examples of the solvent lent, per 1 mol of compound (I'l). that does not adversely influence the reaction include aro This reaction is generally performed in a solvent that does matic hydrocarbons (benzene, toluene, Xylene etc.), aliphatic not adversely influence the reaction. Examples of the solvent hydrocarbons (hexane, heptane etc.), halogenated hydrocar that does not adversely influence the reaction include aro bons (dichloromethane, chloroform, carbon tetrachloride 10 matic hydrocarbons (benzene, toluene, Xylene etc.), aliphatic etc.), ethers (diethyl ether, diisopropyl ether, t-butyl methyl hydrocarbons (hexane, heptane etc.), halogenated hydrocar ether, tetrahydrofuran, dioxane, dimethoxyethane etc.), bons (dichloromethane, chloroform, carbon tetrachloride nitriles (acetonitrile etc.), esters (ethyl acetate etc.), amides 15 etc.), ethers (diethyl ether, diisopropyl ether, t-butyl methyl (N,N-dimethylformamide etc.), sulfoxides (dimethylsulfox ether, tetrahydrofuran, dioxane, dimethoxyethane etc.), ide etc.) and the like. These solvent may be used in a mixture nitriles (acetonitrile etc.), esters (ethyl acetate etc.), amides of two or more kinds thereof in an appropriate ratio. The (N,N-dimethylformamide etc.), sulfoxides (dimethylsulfox reactant may be used as a solvent. ide etc.), water and the like. These solvent may be used in a The reaction temperature is, for example, within about 0 to mixture of two or more kinds thereof in an appropriate ratio. 200° C., preferably about 50 to 100° C. While the reaction The oxidizing agent may be used as a solvent. time varies depending on the kind of compound (XXXVa) or The reaction temperature is, for example, within about -78 a salt thereof, the reaction temperature and the like, it is, for 25 to 200° C., preferably about 0 to 50° C. While the reaction example, about 0.5 to 100 hr, preferably about 0.5 to 24hr. time varies depending on the kind of compound (I'l) or a salt (Step 2) thereof, the reaction temperature and the like, it is, for This step is a step of producing compound (XXVIII) or a example, about 0.5 to 500 hr, preferably about 0.5 to 24hr. salt thereof by reacting compound (XXXVa) or a salt thereof 30 (Step 6) with compound (III) or a salt thereof in the presence of a This step is a step of producing compound (In) or a salt condensing agent. thereof by treating compound (I'l) or a salt thereof with an oxidizing agent. This step can be performed in the same manner as in the 35 method described in Step 2 of Method A. Examples of the oxidizing agent used for this reaction (Step 3) include hydrogen peroxide, peracetic acid, hydroperoxides, This step is a step of producing compound (XXXVIII) or a potassium peroxydisulfate, permanganates, sodium perbo salt thereof by reacting compound (XXXVb) or a salt thereof 40 rate, periodates, metachloroperbenzoic acid, osmium(VII) with compound (III) or a salt thereof. oxide, ruthenium(VII) oxide, nitric acid, chromic acid, This step can be performed in the same manner as in the Sodium dichromate, halogens, sodium hypochlorite, iodo method described in Step 1 of Method A. benzene dichloride, iodobenzene diacetate, oZone, singlet (Step 4) 45 oxygen and the like. While the amount of the oxidizing agent This step is a step of producing compound (I'l) or a salt to be used varies depending on the kind of the solvent and thereof by reacting compound (XXXVIII) or a salt thereof other reaction condition, it is generally about 1 to 10 mol with compound (V) or a salt thereof in the presence of a equivalent, preferably about 1 to 10 mol equivalent, per 1 mol condensing agent. 50 of compound (I'l). This step can be performed in the same manner as in the This reaction is generally performed in a solvent that does method described in Step 2 of Method A. not adversely influence the reaction. Examples of the solvent This step can be performed in the same manner as in the that does not adversely influence the reaction include aro method described in Step 2 of Method A. 55 matic hydrocarbons (benzene, toluene, Xylene etc.), aliphatic (Step 5) hydrocarbons (hexane, heptane etc.), halogenated hydrocar This step is a step of producing compound (I'm) or a salt bons (dichloromethane, chloroform, carbon tetrachloride thereof by treating compound (I'l) or a salt thereof with an etc.), ethers (diethyl ether, diisopropyl ether, t-butyl methyl oxidizing agent. 60 ether, tetrahydrofuran, dioxane, dimethoxyethane etc.), Examples of the oxidizing agent used for this reaction nitriles (acetonitrile etc.), esters (ethyl acetate etc.), amides include hydrogen peroxide, peracetic acid, periodates, (N,N-dimethylformamide etc.), sulfoxides (dimethylsulfox metachloroperbenzoic acid, acyl nitrates, dinitrogen tetraox 65 ide etc.), water and the like. These solvent may be used in a ide, halogen, N-halogen compounds (N-bromosuccinimide, mixture of two or more kinds thereof in an appropriate ratio. N-chlorosuccinimide etc.) and the like. While the amount of The oxidizing agent may be used as a solvent. US 9,120,776 B2 71 72 The reaction temperature is, for example, within about -78 (Step 2) to 200° C., preferably about 0 to 50° C. While the reaction This step is a step of producing compound (XXXXIII) or a time varies depending on the kind of compound (I'l) or a salt salt thereof by subjecting compound (XXXXII) or a salt thereof, the reaction temperature and the like, it is, for thereof to a deprotection reaction. example, about 0.5 to 100 hr, preferably about 0.5 to 24hr. 5 This step can be performed in the same manner as in the Method K method described in Step 2 of Method D.

HO (A): Boc N1 O - R3A N -- R3A ; O i ul -NS R24 7 NH 2 (XXXXI) R24 / NH A.Al Boc Step 1 AN R SA AN RSA RIA RIA (XXXX) (XXXXII) s 2

- R3A

: Y NH2 HO R24 7 NH AlA. B -CN N R54 O RIA (XXXXIV) (XXXXIII) Step 3

- R3A -\ N SA A R RIA (I'o) wherein each symbol is as defined above. (Step 3) (Step 1) 55 This step is a step of producing compound (I'o) or a salt This step is a step of producing compound (XXXXII) or a thereof by reacting compound (XXXXIII) or a salt thereof salt thereof by reacting compound (XXXX) or a salt thereof with compound (XXXXIV) or a salt thereof in the presence of with compound (XXXXI) or a salt thereof in the presence of a condensing agent. a condensing agent. 60 This step can be performed in the same manner as in the This step can be performed in the same manner as in the method described in Step 2 of Method A. method described in Step 2 of Method A. Compound (XXXX) and compound (XXXXI) may be a Compound (XXXXIV) may be a commercially available commercially available product, or can also be produced 65 according to a method known perse or a method analogous product, or can also be produced according to a method thereto. known perse or a method analogous thereto. US 9,120,776 B2

Method L

At w R3A R3A DMB R2. / NH2 2,4-dimethoxybenzaldehyde R. 7 NH Ti(OiPr)4, NaBH4 N R54 Step 1 N R54 RIA RIA (V) (XXXXV) O

Step 2 o={ >=o p (A), (IIb) D3A Mi D3A Mi : N |Ali-OH : N (A) -OH

-\ O - Step 3 ie. M O O N SA N SA A R A R RIA RIA (XXXXVII) (XXXXVI)

L Step 4 B -HCN

(XXXXVIII)

- - DMB -R4 B -HCN : N A. O ' N1 R24 7 O N R54 RIA (XXXXIX) Step

-R4 H B -HCN : N. All O ' N1 R24 7 O N R54 RIA wherein DMB is a 2,4-dimethoxybenzyl group, and the other 0.5 to 1 mol equivalent, per 1 mol of compound (V). The each symbols are as defined above. 55 amount of the titanium(IV) isopropoxide to be used is gener (Step 1) ally about 1 to 10 mol equivalent, preferably about 1 to 3 mol This step is a step of producing compound (XXXXV) or a equivalent, per 1 mol of compound (V). salt thereof by subjecting compound (V) or a salt thereof to a reductive alkylation reaction with 2,4-dimethoxybenzalde The solvent used for the reaction for producing imine is not hyde. The reductive alkylation reaction in this step can be particularly limited as long as the reaction proceeds. performed according to a method known perse. For example, 60 Examples thereof include hydrocarbons (heptane, hexane, compound (XXXXV) or a salt thereof can be produced by toluene, Xylene etc.), halogenated hydrocarbons (chloroform, reacting compound (V) or a salt thereof with 2,4-dimethoxy dichloromethane, 1,2-dichloroethane etc.), ethers (diethyl benzaldehyde in the presence of titanium(IV) isopropoxide, ether, tetrahydrofuran, dioxane etc.), esters (ethyl acetate, and Subjecting the resulting imine to a reduction reaction with t-butyl acetate etc.), nitriles (acetonitrile, butyronitrile etc.), sodium borohydride. 65 amides (N.N-dimethylformamide, dimethylacetamide etc.), The amount of the 2,4-dimethoxybenzaldehyde to be used sulfoxides (dimethylsulfoxide etc.) and the like, and mixed is generally about 0.5 to 5 mol equivalent, preferably about solvents thereof. US 9,120,776 B2 75 76 The reaction temperature is generally about 0°C. to about The production of compound (I) wherein the right bond of 200° C., preferably about 30° C. to about 150° C., and the the bivalent group for Q is bonded to the indole ring and the reaction time is generally about 0.5 hr to about 48 hr, prefer left bond thereof is bonded to Ring B", can be performed ably about 0.5 hr to about 24hr. according to the method described in Method A-Method L The amount of the sodium borohydride used for the reduc mentioned above. tion of the imine to be used is generally about 1 to 10 mol Compound (Ia)-compound (In) compound (I) wherein Q equivalent, preferably about 1 to 3 mol equivalent, per 1 mol in the formula (I) is each the bivalent group (Ia)-(In) or a salt of compound (V). thereof of the present invention can be produced according to The reduction of the imine is performed generally in a the above-mentioned Method A-Method Joramethod analo 10 gous thereto. solvent inert to the reaction. Examples of the solvent include When the object product is obtained in a free form by the aromatic hydrocarbons (toluene, Xylene etc.), aliphatic above-mentioned reaction, it may be converted to a salt by a hydrocarbons (heptane, hexane etc.), halogenated hydrocar conventional method. When it is obtained as a salt, it can also bons (chloroform, dichloromethane etc.), ethers (diethyl be converted to a free form or other salt by a conventional ether, tetrahydrofuran, dioxane etc.), alcohols (methanol, 15 method. The thus-obtained compound (I) or (I) can be iso ethanol. 2-propanol, butanol, benzyl alcohol etc.), nitriles lated and purified from the reaction solution by a known (acetonitrile etc.), N,N-dimethylformamide, dimethylsulfox means, for example, phase transfer, concentration, Solvent ide and the like. These solvent may be used in a mixture extraction, fractionation, crystallization, recrystallization, thereof in an appropriate ratio. chromatography and the like. The reaction temperature is generally about -80° C. to When compound (I) or (I) contains an isomer Such as a about 80° C., preferably about -40°C. to about 40°C., and tautomer, an optical isomer, a stereoisomer, a regioisomer, a the reaction time is generally about 5 min to about 48 hr, rotamerand the like, any isomeranda mixture thereofare also preferably about 1 hr to about 24hr. encompassed in the compound of the present invention. Fur (Step 2) thermore, when compound (I) or (I) has an optical isomer, an This step is a step of producing compound (XXXXVI) or a 25 optical isomer resolved from this compound is also encom salt thereof by reacting compound (XXXXV) or a salt thereof passed in compound (I) or (I). with compound (IIb) or a salt thereof. The compound (I) or (I) may be a crystal. Even if com This step can be performed in the same manner as in the pound (I) or (I') is in a single crystal form or mixed crystal method described in Step 1 of Method A. form, it can be provided as compound (I) or (I) of the present Compound (IIb) may be a commercially available product, 30 invention. or can also be produced according to a method known perse Compound (I) or (I) may be a pharmaceutically acceptable or a method analogous thereto. co-crystal or co-crystal salt. Here, the co-crystal or co-crystal (Step 3) salt means a crystalline Substance consisting of two or more This step is a step of producing compound (XXXXVII) or particular Substances which are solids at room temperature, a salt thereof by treating compound (XXXXVI) or a salt 35 each having different physical properties (e.g., structure, thereof with a reducing agent. melting point, heat of melting, hygroscopicity, Solubility, sta This step can be performed in the same manner as in the bility etc.). The co-crystal and co-crystal salt can be produced method described in Step 1 of Method B. by co-crystallization known per se. (Step 4) The compound (I) or (I) may be a Solvate (e.g., a hydrate) This step is a step of producing compound (XXXXIX) or a 40 or a non-solvate. Any of them can be provided as compound salt thereof by reacting compound (XXXXVII) or a salt (I) or (I) of the present invention. thereof with compound (XXXXVIII) or a salt thereof in the Any of the above compounds may be labeled or substituted presence of a base. with an isotope (e.g., H, H, C, C, F, S, 'I etc.) and This step can be performed in the same manner as in the the like, and provided as compound (I) or (I) of the present method described in Step 2 of Method H. 45 invention. Compound (I) or (I) labeled or substituted with an Compound (XXXXVIII) may be a commercially available isotope can be used, for example, as a tracer (PET tracer) used product, or can also be produced according to a method for positron emission tomography (PET), and is useful in the known perse or a method analogous thereto. field Such as medical diagnosis and the like. (Step 5) The prodrug of compound (I) or (I) means a compound This step is a step of producing compound (I'p) or a salt 50 which can be converted into compound (I) or (I) by reaction thereof by subjecting compound (XXXXIX) or a salt thereof with an enzyme, gastric acid, or the like under physiological to a deprotection reaction. conditions in the living body. In other words, it means a The deprotection reaction can be performed according to a compound which can be converted into compound (I) or (I) known method (e.g., Wiley-Interscience, 1999. “Protective by enzymatic oxidation, reduction, hydrolysis or the like, or a Groups in Organic Synthesis, 3rd Ed. (Theodora W. Greene, 55 compound which can be converted into compound (I) or (I) Peter G. m. Wuts)). For example, the deprotection reaction by hydrolysis with gastric acid or the like. Examples of the can be performed using anisole in trifluoroacetic acid as a prodrug of compound (I) or (I) include a compound in which solvent. amino of compound (I) or (I) is acylated, alkylated, or phos The amount of the trifluoroacetic acid to be used is gener phorylated (e.g., the amino of compound (I) or (I) is ally 1 to 100 mL per 1 g of compound (XXXXIX). The 60 eicosanoylated, alanylated, pentylaminocarbonylated, amount of the anisole to be used is generally 1 to 10 mL per (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, 1 g of compound (XXXXIX). tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxym The reaction temperature is, for example, within about -50 ethylated, tert-butylated etc.); a compound in which hydroxyl to 100° C., preferably about 0 to 30° C. While the reaction of compound (I) or (I') is acylated, alkylated, phosphorylated, time varies depending on the kind of compound (XXXXIX), 65 orborated (e.g., hydroxyl of compound (I) or (I) is acetylated, the reaction temperature and the like, it is, for example, about palmitoylated, propanoylated, pivaloylated. Succinylated, 0.5 to 100 hr, preferably about 0.5 to 48 hr. fumarylated, alanylated, dimethylaminomethylcarbonylated US 9,120,776 B2 77 78 etc.); a compound in which carboxy of compound (I) or (I') is germ cell tumor, ovarian germ cell tumor, ovarian low malig esterified oramidated (e.g., a compound in which carboxy of nant potential tumor and the like), prostate cancer (e.g., hor compound (I) or (I') is ethyl esterified, phenyl esterified, mone-dependent prostate cancer, non-hormone dependent carboxymethyl esterified, dimethylaminomethyl esterified, prostate cancer and the like), liver cancer (e.g., primary liver pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl cancer, extrahepatic bile duct cancer and the like), thyroid esterified, phthalidyl esterified, (5-methyl-2-oxo-1,3-diox cancer (e.g., medullary thyroid carcinoma and the like), kid olen-4-yl)methyl esterified, cyclohexyloxycarbonylethyl ney cancer (e.g., renal cell carcinoma, transitional cell carci esterified, methylamidated etc.). These compounds can be noma in kidney and urinary duct and the like), uterine cancer, produced from compound (I) or (I) by a method known per brain tumor (e.g., pineal astrocytoma, pilocytic astrocytoma, se. The prodrug of compound (I) or (I) may be a compound 10 diffuse astrocytoma, anaplastic astrocytoma and the like), that converts to compound (I) or (I) under physiological melanoma, Sarcoma, urinary bladder cancer, hematologic conditions as described in Development of Pharmaceutical cancer and the like including multiple myeloma, hypophyseal Products, vol. 7, Molecule Design, 163-198, Hirokawa Sho adenoma, glioma, acoustic neurinoma, retinoblastoma, pha ten (1990). ryngeal cancer, laryngeal cancer, cancer of the tongue, thy Since compound (I) or (I) and a prodrug thereofherein 15 moma, esophagus cancer, duodenal cancer, colorectal cancer, after sometimes to be abbreviated as the compound of the rectal cancer, hepatoma, pancreatic endocrine tumor, bile present invention show superior RORyt inhibitory activity, duct cancer, gallbladder cancer, penile cancer, urinary duct they are also useful as safe medicaments based on Such action. cancer, testis tumor, Vulvar cancer, cervix cancer, endometrial For example, the medicament of the present invention con cancer, uterus sarcoma, cholionic disease, vaginal cancer, taining the compound of the present invention can be used for skin cancer, fungoid mycosis, basal cell tumor, Soft tissue a mammal (e.g., mouse, rat, hamster, rabbit, cat, dog, bovine, sarcoma, malignant lymphoma, Hodgkin’s disease, myelod sheep, monkey, human etc.) as a prophylactic or therapeutic ysplastic syndrome, acute lymphocytic leukemia, chronic agent for RORyt associated diseases, Th17 cell associated lymphocytic leukemia, adult T cell leukemia, chronic bone diseases and IL-17A or IL-17F associated diseases, more marrow proliferative disease, pancreatic endocrine tumor, specifically, the diseases described in (1)–(4) below. 25 fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, (1) inflammatory diseases (e.g., rheumatoid arthritis, acute cancer of unknown primary). pancreatitis, chronic pancreatitis, asthma, adult respiratory The medicament of the present invention can be used as a distress syndrome, chronic obstructive pulmonary disease prophylactic or therapeutic agent for preferably autoimmune (COPD), inflammatory bone disease, inflammatory pulmo disease, inflammatory disease, bone or articular disease or nary disease, inflammatory bowel disease, celiac disease, 30 neoplastic disease, particularly preferably, rheumatoid arthri hepatitis, Systemic inflammatory response syndrome (SIRS), tis, inflammatory bowel disease, psoriasis, ankylosing postoperative or posttraumatic inflammation, pneumonia, spondylitis, bronchial asthma, chronic obstructive pulmonary nephritis, meningitis, cystitis, pharyngolaryngitis, gastric diseases, ovarian cancer, non-Small cell lung cancer, breast mucosal injury, meningitis, spondylitis, arthritis, dermatitis, cancer, gastric cancer, cervical cancer, prostate cancer or chronic pneumonia, bronchitis, pulmonary infarction, silico 35 uterine body cancer. sis, pulmonary sarcoidosis etc.), Here, the above-mentioned “prophylaxis' of a disease (2) autoimmune diseases (e.g., rheumatoid arthritis, ankylos means, for example, administration of a medicament contain ing spondylitis, psoriasis, multiple Sclerosis (MS), polymyo ing the compound of the present invention to patients who are sitis, dermatomyositis (DM), polyarteritis nodosa (PN), expected to have a high risk of the onset due to some factor mixed connective tissue disease (MCTD), Sjogren's syn 40 relating to the disease but have not developed the disease or drome nephritis, systemic lupus erythematosus, Scleroderma, patients who have developed the disease but do not have a profundus lupus erythematosus, chronic thyroiditis, Graves Subjective symptom, or administration of a medicament con disease, autoimmune gastritis, type I and type II diabetes, taining the compound of the present invention to patients who autoimmune hemolytic anemia, autoimmune neutropenia, are feared to show recurrence of the disease after treatment of thrombocytopenia, atopic dermatitis, chronic active hepatitis, 45 the disease. myasthenia gravis, inflammatory bowel disease (IBD), ulcer The medicament of the present invention shows superior ative colitis (UC), Crohn's disease (CD), graft versus host pharmacokinetics (e.g., a half-life of the drug in plasma), low disease. Addison's disease, abnormal immunoresponse, toxicity (e.g., HERG inhibition, CYP inhibition, CYP induc arthritis, dermatitis, radiodermatitis etc.), tion), and decreased drug interaction. The compound of the (3) bone or joint degenerative diseases (e.g., rheumatoid 50 present invention can be directly used as a medicament, or as arthritis, osteoporosis, osteoarthritis etc.), the medicament of the present invention by producing a phar (4) neoplastic diseases e.g., malignant tumor, angiogenesis maceutical composition by mixing with a pharmaceutically glaucoma, infantile hemangioma, multiple myeloma, acute acceptable carrier by a means known per se and generally myeloblastic leukemia, chronic sarcoma, multiple myeloma, used in a production method of pharmaceutical preparations. chronic myelogenous leukemia, metastasis melanoma, 55 The medicament of the present invention can be orally or Kaposi's sacroma, Vascular proliferation, cachexia, metasta parenterally administered safely to mammals (e.g., humans, sis of the breast cancer, cancer (e.g., colorectal cancer (e.g., monkeys, cows, horses, pigs, mice, rats, hamsters, rabbits, familial colorectal cancer, hereditary nonpolyposis colorectal cats, dogs, sheep and goats). cancer, gastrointestinal stromal tumor and the like), lung can A medicament containing the compound of the present cer (e.g., non-small cell lung cancer, Small cell lung cancer, 60 invention can be safely administered solely or by mixing with malignant mesothelioma and the like), mesothelioma, pan a pharmacologically acceptable carrier according to a method creatic cancer (e.g., pancreatic duct cancer and the like), known per se (e.g., the method described in the Japanese gastric cancer (e.g., papillary adenocarcinoma, mucinous Pharmacopoeia etc.) as the production method of a pharma adenocarcinoma, adenosquamous carcinoma and the like), ceutical preparation, and in the form of for example, tablet breast cancer (e.g., invasive ductal carcinoma, ductal carci 65 (including Sugar-coated tablet, film-coated tablet, Sublingual noma in situ, inflammatory breast cancer and the like), ova tablet, orally disintegrating tablet, buccal and the like), pill, rian cancer (e.g., ovarian epithelial carcinoma, extragonadal powder, granule, capsule (including soft capsule, microcap US 9,120,776 B2 79 80 Sule), troche, syrup, liquid, emulsion, Suspension, release Examples of the isotonic agent include glucose, D-Sorbitol, control preparation (e.g., immediate-release preparation; Sus Sodium chloride, glycerin, D-mannitol and the like. tained-release preparation, Sustained-release microcapsule). Examples of the buffering agent include buffer solutions aerosol, film (e.g., orally disintegrating film, oral mucosa Such as phosphates, acetates, carbonates, citrates and the like. adhesive film), injection (e.g., Subcutaneous injection, intra Examples of the soothing agent include benzyl alcohol and venous injection, intramuscular injection, intraperitoneal the like. injection), drip infusion, transdermal absorption type prepa Examples of the preservative include parahydroxyben ration, ointment, lotion, adhesive preparation, Suppository Zoates, chlorobutanol, benzyl alcohol, phenylethyl alcohol, (e.g., rectal Suppository, vaginal Suppository), pellet, nasal dehydroacetic acid, Sorbic acid and the like. preparation, pulmonary preparation (inhalant), eye drop and 10 Examples of the antioxidant include Sulfites, ascorbic acid, the like, orally or parenterally (e.g., intravenous, intramuscu C-tocopherol and the like. lar, Subcutaneous, intraorgan, intranasal, intradermal, instil For the prophylaxis or treatment of various diseases, the lation, intracerebral, intrarectal, intravaginal, intraperitoneal compound of the present invention can also be used together and intratumor administrations, administration to the vicinity 15 with other medicaments. In the following, a medicament to be of tumor, and direct administration to the lesion). used when the compound of the present invention is used The content of the compound of the present invention in the together with other drug is referred to as “the combination medicament of the present invention is about 0.01 to 100% by agent of the present invention'. weight of the entire medicament. While the dose varies For example, when the compound of the present invention depending on the Subject of administration, administration is used as an RORyt inhibitor, Th17 cell inhibitor, IL-17A or route, disease and the like, for example, for oral administra IL-17F inhibitor, it can be used in combination with the tion to an adult inflammatory bowel disease (IBD) patient following drugs. (body weight about 60 kg), it is about 0.1 mg/kg body weight (1) Non-Steroidal Anti-Inflammatory Drug (NSAIDs) to 30 mg/kg body weight, preferably about 1 mg/kg body (i) Classical NSAIDs weight to 20 mg/kg body weight as an active ingredient 25 alcofenac, aceclofenac, Sulindac, tolmetin, etodolac, feno (compound (I) or (I)) for one day, which is administered once profen, thiaprofenic acid, meclofenamic acid, meloxicam, to several times (e.g., once to 3 times). tenoxicam, lornoxicam, nabumeton, acetaminophen, phen The pharmaceutically acceptable carrier, which may be acetin, ethenZamide, Sulpyrine, antipyrine, migrenin, aspirin, used for the production of the medicament of the present mefenamic acid, flufenamic acid, diclofenac sodium, loXo invention, may be exemplified by various organic or inor 30 profen Sodium, phenylbutaZone, indomethacin, ibuprofen, ganic carrier materials that are conventionally used as prepa ration materials, for example, excipient, lubricant, binding ketoprofen, naproxen, oxaprozin, flurbiprofen, fenbufen, pra agent and disintegrant for Solid preparations; or solvent, solu noprofen, floctafenine, piroxicam, epirizole, tiaramide bilizing agent, Suspending agent, isotonic agent, buffering hydrochloride, Zaltoprofen, gabexate mesylate, camo.stat agent, soothing agent and the like for liquid preparations. 35 mesylate, ulinastatin, colchicine, probenecid, Sulfinpyrazone, Furthermore, when necessary, ordinary additives such as pre benzbromarone, allopurinol, Sodium aurothiomalate, hyalu servative, antioxidant, colorant, Sweetening agent, adsorbing ronate Sodium, Sodium salicylate, morphine hydrochloride, agent, wetting agent and the like can be also used as appro salicylic acid, atropine, Scopolamine, morphine, pethidine, priate in an appropriate amount. levorphanol, oxymorphone or a salt thereof and the like. Examples of the excipient include lactose, white Sugar, 40 (ii) cyclooxygenase inhibitor (COX-1 selective inhibitor, D-mannitol, Starch, corn starch, crystalline cellulose, light COX-2 selective inhibitor and the like) anhydrous silicic acid and the like. salicylic acid derivatives (e.g., celecoxib, aspirin), etori Examples of the lubricant include magnesium Stearate, coxib, Valdecoxib, diclofenac, indomethacin, loxoprofen and calcium Stearate, talc, colloidal silica and the like. the like. Examples of the binding agent include crystalline cellu 45 (iii) nitric oxide-releasing NSAIDs lose, white Sugar, D-mannitol, dextrin, hydroxypropylcellu (2) Disease-Modifying Anti-Rheumatic Drugs lose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, (DMARDs) starch, Sucrose, gelatin, methylcellulose, carboxymethylcel (i) Gold preparation lulose sodium and the like. auranofin and the like. Examples of the disintegrant include starch, carboxymeth 50 (ii) penicillamine ylcellulose, carboxymethylcellulose calcium, carboxymeth D-penicillamine. ylstarch sodium, L-hydroxypropylcellulose and the like. (iii) aminosalicylic acid preparation Examples of the solvent include water for injection, alco SulfaSalazine, mesalazine, olSalazine, balsalazide. hol, propylene glycol, Macrogol, Sesame oil, corn oil, olive (iv) antimalarial drug oil and the like. 55 chloroquine and the like. Examples of the Solubilizing agent include polyethylene (v) pyrimidine synthesis inhibitor glycol, propylene glycol, D-mannitol, benzylbenzoate, etha leflunomide and the like. nol, trisaminomethane, cholesterol, triethanolamine, sodium (vi) prograf carbonate, sodium citrate and the like. (3) Anti-Cytokine Drug Examples of the Suspending agent include Surfactants such 60 (I) protein drug as Stearyl triethanolamine, Sodium lauryl Sulfate, laurylami (i) TNF inhibitor nopropionic acid, lecithin, benzalkonium chloride, benzeto etanercept, infliximab, adalimumab, certolizumab pegol, nium chloride, glycerin monostearate and the like; hydro golimumab, PASSTNF-ct, soluble TNF-C. receptor, TNF-C. philic polymers such as polyvinyl alcohol, binding protein, anti-TNF-C. antibody and the like. polyvinylpyrrolidone, carboxymethylcellulose Sodium, 65 (ii) interleukin-1 inhibitor methylcellulose, hydroxymethylcellulose, hydroxyethylcel anakinra (interleukin-1 receptor antagonist), Soluble inter lulose, hydroxypropylcellulose and the like; and the like. leukin-1 receptor and the like. US 9,120,776 B2 81 82 (iii) interleukin-6 inhibitor (11) B Receptor Antagonist tocilizumab (anti-interleukin-6 receptor antibody), anti carvedilol, metoprolol, atenolol and the like. interleukin-6 antibody and the like. (12) Ca Sensitizer MCC-135 and the like. (iv) interleukin-10 drug (13) Ca Channel Antagonist interleukin-10 and the like. nifedipine, diltiazem, Verapamil and the like. (v) interleukin-12/23 inhibitor (14) Anti-Platelet Drug, Anticoagulator ustekinumab, briakinumab (anti-interleukin-12/23 anti heparin, aspirin, warfarin and the like. body) and the like. (15) HMG-CoA Reductase Inhibitor (II) non-protein drug atorvastatin, simvastatin and the like. (i) MAPK inhibitor 10 (16) Contraceptive BMS-582949 and the like. (i) sex hormone or derivatives thereof (ii) gene modulator gestagen or a derivative thereof (progesterone, 17C.-hy inhibitor of molecule involved in signal transduction, Such droxy progesterone, medroxyprogesterone, medroxyproges as NF-K, NF-KB, IKK-1, IKK-2, AP-1 and the like, and the terone acetate, norethisterone, norethisterone enanthate, 15 norethindrone, norethindrone acetate, norethynodrel, like. levonorgestrel, norgestrel, ethynodiol diacetate, desogestrel, (iii) cytokine production inhibitor norgestimate, gestodene, progestin, etonogestrel, dro iguratimod, tetomilast and the like. spirenone, dienogest, trimegestone, nestorone, chlormadi (iv) TNF-C. converting enzyme inhibitor none acetate, mifepristone, nomegestrol acetate, Org-30659, (v) interleukin-1B converting enzyme inhibitor TX-525, EMM-310525) or a combination agent of a gestagen VX-765 and the like. or a derivative thereof and an estrogen or a derivative thereof (vi) interleukin-6 antagonist (estradiol, estradiol benzoate, estradiol cypionate, estradiol HMPL-004 and the like. dipropionate, estradiol enanthate, estradiol hexahydroben (vii) interleukin-8 inhibitor Zoate, estradiol phenylpropionate, estradiol undecanoate, IL-8 antagonist, CXCR1 & CXCR2 antagonist, reparixin 25 estradiol Valerate, estrone, ethinylestradiol, mestranol) and and the like. the like. (viii) chemokine antagonist (ii) antiestrogen CCR9 antagonist (CCX-282, CCX-025), MCP-1 antago ormeloxifene, mifepristone, Org-33628 and the like. nist and the like. (iii) Spermatocide (ix) interleukin-2 receptor antagonist 30 ushercell and the like. denileukin, diftitox and the like. (17) Others (x) therapeutic vaccines (i) T cell inhibitors TNF-C. Vaccine and the like. (ii) inosine monophosphate dehydrogenase (IMPDH) inhibi (xi) gene therapy drug tOr gene therapy drugs aiming at promoting the expression of 35 mycophenolate mofetil and the like. gene having an anti-inflammatory action Such as interleukin (iii) adhesion molecule inhibitor 4, interleukin-10, soluble interleukin-1 receptor, soluble ISIS-2302, selectin inhibitor, ELAM-1, VCAM-1, TNF-C. receptor and the like. ICAM-1 and the like. (xii) antisense compound (iv) thalidomide ISIS 104838 and the like. 40 (v) cathepsin inhibitor (4) Integrin Inhibitor (vi) matrix metalloprotease (MMPs) inhibitor natalizumab, vedolizumab, AJM300, TRK-170, E-6007 V-85546 and the like. and the like. (vii) glucose-6-phosphate dehydrogenase inhibitor (5) Immunomodulator (Immunosuppressant) (viii) Dihydroorotate dehydrogenase (DHODH) inhibitor methotrexate, cyclophosphamide, MX-68, atiprimod dihy 45 (ix)phosphodiesterase IV(PDE IV) inhibitor drochloride, BMS-188667, CKD-461, rimexolone, roflumilast, CG-1088 and the like. cyclosporine, tacrolimus, gusperimus, azathiopurine, anti (x) phospholipase A inhibitor lymphocyte serum, freeze-dried Sulfonated normal immuno (xi) iNOS inhibitor globulin, erythropoietin, colony stimulating factor, interleu VAS-203 and the like. kin, interferon and the like. 50 (xii) microtubule stimulating drug (6) Steroid paclitaxel and the like. dexamethasone, hexestrol, methimazole, betamethasone, (xiii) microtuble inhibitor triamcinolone, triamcinolone acetonide, fluocinonide, fluoci reumacon and the like. nolone acetonide, predonisolone, methylpredonisolone, cor (xiv) MHC class II antagonist tisone acetate, hydrocortisone, fluorometholone, beclom 55 (XV) prostacyclin agonist ethasone dipropionate, estriol and the like. iloprost and the like. (7) Angiotensin Converting Enzyme Inhibitor (Xvi) CD4 antagonist enalapril, captopril, ramipril, lisinopril, cilaZapril, perin Zanolimumab and the like. dopril and the like. (xvii) CD23 antagonist (8) Angiotensin II Receptor Antagonist 60 (xviii) LTB4 receptor antagonist candesartan, cilexetil (TCV-116), Valsartan, irbesartan, DW-1305 and the like. olmesartan, eprosartan and the like. (XiX) 5-lipoxygenase inhibitor (9) Diuretic Drug Zileuton and the like. hydrochlorothiazide, Spironolactone, furosemide, indapa (xx) cholinesterase inhibitor mide, bendrofluazide, cyclopenthiazide and the like. 65 galanthamine and the like. (10) Cardiotonic Drug (xxi) tyrosine kinase inhibitor digoxin, dobutamine and the like. Tyk2 inhibitor (WO2010142752) and the like. US 9,120,776 B2 83 84 (xxii) cathepsin B inhibitor cefuroxime, cefotiam, cefotiam hexetil, cefuroxime axetil, (XXiii)adenosine deaminase inhibitor cefdinir, cefditoren pivoxil, ceftazidime, ce?piramide, cefsu pentostatin and the like. lodin, cefinenoXime, cefpodoxime proxetil, cefpirome, cefo (XXiv) osteogenesis stimulator Zopran, cefepime, cefsulodin, cefinenoxime, cefinetazole, (XXV) dipeptidylpeptidase inhibitor cefninox, cefoxitin, cefbuperaZone, latamoxef, flomoxef. (XXvi) collagen agonist cefazolin, cefotaxime, cefoperaZone, ceftizoxime, moxalac (XXvii) capsaicin cream tam, thienamycin, Sulfazecin, aztreonam or a salt a salt (xxviii) hyaluronic acid derivative thereof, griseofulvin, lankacidin-group Journal of Antibiot synvisc (hylan G-F 20), orthovisc and the like. ics (J. Antibiotics), 38,877-885 (1985), azole compound (XXiX) glucosamine Sulfate 10 2-(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3- (XXX) amiprilose (1H-1,2,4-triazol-1-yl)propyl-4-4-(2,2,3,3-tetrafluoropro (xxxi) CD-20 inhibitor poxy)phenyl-3(2H.4H)-1,2,4-triazolone, fluconazole, itra rituximab, ibritumomab, to situmomab, ofätumumab and conazole and the like and the like. the like. (2) Antifungal Agent (xxxi) BAFF inhibitor 15 (i) polyethylene antibiotic (e.g., amphotericin B, nystatin, belimumab, tabalumab, atacicept, A-623 and the like. trichomycin) (xxxiii) CD52 inhibitor (ii) griseofulvin, pyrrolnitrin and the like alemtuzumab and the like. (iii) cytosine metabolism antagonist (e.g., flucytosine) Other concomitant drugs besides the above-mentioned (iv) imidazole derivative (e.g., econazole, clotrimazole, include, for example, antibacterial agent, antifungal agent, miconazole nitrate, bifonazole, croconazole) antiprotozoal agent, antibiotic, antitussive and expectorant (v) triazole derivative (e.g., fluconazole, itraconazole) drug, sedative, anesthetic, antiulcer drug, antiarrhythmic (vi) thiocarbamic acid derivative (e.g., trinaphthol) and the agent, hypotensive diuretic drug, anticoagulant, tranquilizer, like. antipsychotic, antitumor drug, hypolipidemic drug, muscle (3) Antiprotozoal Agent relaxant, antiepileptic drug, antidepressant, antiallergic drug, 25 metronidazole, tinidazole, diethylcarbamazine citrate, qui cardiac stimulants, therapeutic drug for arrhythmia, Vasodi nine hydrochloride, quinine Sulfate and the like. lator, vasoconstrictor, hypotensive diuretic, therapeutic drug (4) Antitussive and Expectorant Drug for diabetes, antinarcotic, vitamin, vitamin derivative, anti ephedrine hydrochloride, noscapine hydrochloride, asthmatic, therapeutic agent for pollakisuria/anischuria, codeine phosphate, dihydrocodeine phosphate, isoproterenol therapeutic agent for atopic dermatitis, therapeutic agent for 30 hydrochloride, ephedrine hydrochloride, methylephedrine allergic rhinitis, hypertensor, endotoxin-antagonist or -anti hydrochloride, noscapine hydrochloride, alloclamide, chlo body, signal transduction inhibitor, inhibitor of inflammatory phedianol, picoperidamine, cloperastine, protokylol, isopro mediator activity, antibody to inhibit inflammatory mediator terenol, Salbutamol, terbutaline, oxymetebanol, morphine activity, inhibitor of anti-inflammatory mediator activity, hydrochloride, dextromethorfan hydrobromide, oxycodone antibody to inhibit anti-inflammatory mediator activity and 35 hydrochloride, dimemorphan phosphate, tipepidine hiben the like. Specific examples thereof include the following. Zate, pentoxyverine citrate, clofedanol hydrochloride, benzo (1) Antibacterial Agent natate, guaifenesin, bromhexine hydrochloride, ambroXol (i) Sulfa drug hydrochloride, acetylcysteine, ethyl cysteine hydrochloride, Sulfamethizole, Sulfisoxazole, Sulfamonomethoxine, Sul carbocysteine and the like. famethizole, Salazosulfapyridine, silver Sulfadiazine and the 40 (5) Sedative like. chlorpromazine hydrochloride, atropine Sulfate, phenobar (ii) quinolone antibacterial agent bital, barbital, amobarbital, pentobarbital, thiopental sodium, nalidixic acid, pipemidic acid trihydrate, enoxacin, nor thiamylal Sodium, nitrazepam, estazolam, flurazepam, halox floxacin, ofloxacin, to Sufloxacin tosylate, ciprofloxacin aZolam, triazolam, flunitrazepam, bromoValerylurea, chloral hydrochloride, lomefloxacin hydrochloride, sparfloxacin, 45 hydrate, triclofos sodium and the like. fleroxacin and the like. (6) Anesthetic (iii) antiphthisic (6-1) Local Anesthetic isoniazid, ethambutol (ethambutol hydrochloride), p-ami cocaine hydrochloride, procaine hydrochloride, lidocaine, nosalicylic acid (calcium p-aminosalicylate), pyrazinamide, dibucaine hydrochloride, tetracaine hydrochloride, mepiv ethionamide, protionamide, rifampicin, Streptomycin Sulfate, 50 acaine hydrochloride, bupivacaine hydrochloride, oxybup kanamycin Sulfate, cycloserine and the like. rocaine hydrochloride, ethyl aminobenzoate, oxethazaine (iv) antiacidfast bacterium drug and the like. diaphenylsulfone, rifampicin and the like. (6–2) General Anesthetic (v) antiviral drug (i) inhalation anesthetic (e.g., ether, halothane, nitrous oxide, idoxuridine, acyclovir, Vidarabine, gancyclovir and the 55 isoflurane, enflurane), like. (ii) intravenous anesthetic (e.g., ketamine hydrochloride, dro (vi) anti-HIV agent peridol, thiopental sodium, thiamylal Sodium, pentobarbital) Zidovudine, didanosine, Zalcitabine, indinavir Sulfate etha and the like. nolate, ritonavir and the like. (7) Antiulcer Drug (vii) antispirochetele 60 histidine hydrochloride, lanSoprazole, metoclopramide, (viii) antibiotic pirenzepine, cimetidine, ranitidine, famotidine, urogastrone, tetracycline hydrochloride, amplicillin, piperacillin, gen oxethazaine, proglumide, omeprazole. Sucralfate, Sulpiride, tamicin, dibekacin, kanendomycin, lividomycin, tobramycin, cetraxate, gefarnate, aldioxa, teprenone, prostaglandin and amikacin, fradiomycin, Sisomicin, tetracycline, Oxytetracy the like. cline, rollitetracycline, doxycycline, amplicillin, piperacillin, 65 (8) Antiarrhythmic Agent ticarcillin, cephalothin, cephapirin, cephaloridine, cefaclor, (i) sodium channel blocker (e.g., quinidine, procainamide, cephalexin, cefroxadine, cefadroxil, cefamandole, cefotoam, disopyramide, ajmaline, lidocaine, mexiletine, phenytoin), US 9,120,776 B2 85 86 (ii) f-blocker (e.g., propranolol, alprenolol, bufetolol hydro (18) Antiallergic Drug chloride, oXprenolol, atenolol, acebutolol, metoprolol, biso diphenhydramine, chlorpheniramine, tripelennamine, prolol, pindolol, carteolol, arotinolol hydrochloride), metodilamine, clemizole, diphenylpyraline, methoxyphe (iii) potassium channel blocker (e.g., amiodarone), namine, sodium cromoglicate, tranilast, repirinast, amlex (iv) calcium channel blocker (e.g., Verapamil, diltiazem) and anox, ibudilast, ketotifen, terfenadine, meduitazine, azelas the like. tine hydrochloride, epinastine, OZagrel hydrochloride, (9) Hypotensive Diuretic Drug pranlukast hydrate, seratrodast and the like. hexamethonium bromide, clonidine hydrochloride, hydro (19) Cardiac Stimulants chlorothiazide, trichlormethiazide, furosemide, ethacrynic trans-U-OXocamphor, terephyllol, aminophylline, etile acid, bumetanide, mefruside, azosemide, Spironolactone, 10 frine, dopamine, dobutamine, denopamine, aminophylline, potassium canrenoate, triamterene, amiloride, acetazola mide, D-mannitol, isosorbide, aminophylline and the like. Vesnarinone, amrinone, pimobendan, ubidecarenone, digi (10) Anticoagulant toxin, digoxin, methyldigoxin, lanatoside C, G-strophanthin heparin Sodium, Sodium citrate, activated protein C, tissue and the like. factor pathway inhibitor, antithrombin III, dalteparin sodium, 15 (20) Vasodilator warfarin potassium, argatroban, gabexate, Sodium citrate, oxyfedrine, diltiazem, tolaZoline, hexobendine, bamethan, oZagrel Sodium, ethyl icosapentate, beraprost sodium, alpros clonidine, methyldopa, guanabenZ, and the like. tadil, ticlopidine hydrochloride, pentoxifylline, dipy (21) Vasoconstrictor ridamole, tisokinase, urokinase, streptokinase and the like. dopamine, dobutamine denopamine and the like. (11) Tranquilizer (22) Hypotensive Diuretic diazepam, lorazepam, oxazepam, chlordiazepoxide, hexamethonium bromide, pentolinium, mecamylamine, medazepam, oxazolam, cloxazolam, clotiazepam, bro ecarazine, clonidine, diltiazem, nifedipine and the like. mazepam, etizolam, fludiazepam, hydroxy Zine and the like. (23) Therapeutic Drug for Diabetes (12) Antipsychotic tolbutamide, chlorpropamide, acetohexamide, glibencla chlorpromazine hydrochloride, prochlorperazine, trifluop 25 mide, tolaZamide, acarbose, epalrestat, troglitaZone, gluca erazine, thioridazine hydrochloride, perphenazine maleate, gon, glymidine, glipizide, phenformin, buformin, metformin fluiphenazine enanthate, prochlorperazine maleate, levome and the like. promazine maleate, promethazine hydrochloride, haloperi (24) Antinarcotic dol, bromperidol, spiperone, reserpine, clocapramine hydro levallorphan, nalorphine, naloxone or a salt thereof and the chloride, Sulpiride, Zotepine and the like. 30 like. (13) Antitumor Drug 6-O-(N-chloroacetylcarbamoyl)fumagillol, bleomycin, (25) Liposoluble Vitamins methotrexate, actinomycin D. mitomycin C, daunorubicin, (i) vitamin A. vitamin A, vitamin A and retinol palmitate adriamycin, neocarzinostatin, cytosine arabinoside, fluorou (ii) Vitamin D: Vitamin D, D, D, D, and Ds racil, tetrahydrofuryl-5-fluorouracil, picibanil, lentinan, 35 (iii) Vitamin E: C-tocopherol, B-tocopherol, Y-tocopherol, levamisole, bestatin, azimexon, glycyrrhizin, doxorubicin 8-tocopherol, dl-C-tocopherol nicotinate hydrochloride, aclarubicin hydrochloride, bleomycin hydro (iv) vitamin K: Vitamin K. K. K. and K chloride, peplomycin Sulfate, Vincristine Sulfate, vinblastine (v) folic acid (vitamin M) and the like. Sulfate, irinotecan hydrochloride, cyclophosphamide, mel (26) Vitamin Derivative phalan, buSulfan, thiotepa, procarbazine hydrochloride, cis 40 various derivatives of vitamins, for example, Vitamin D. platin, azathioprine, mercaptopurine, tegafur, carmofur, cyt derivatives such as 5,6-trans-cholecalciferol, 2.5-hydroxyc arabine, methyltestosterone, testosterone propionate, holecalciferol, 1-O-hydroxycholecalciferol and the like, vita testosterone enanthate, mepitiostane, fosfestrol, chlormadi min D derivatives Such as 5,6-trans-ergocalciferol and the none acetate, leuprorelin acetate, buserelin acetate and the like, and the like. like. 45 (27) Antiasthmatic (14) Hypolipidemic Drug isoprenaline hydrochloride, Salbutamol Sulfate, procaterol clofibrate, ethyl 2-chloro-3-4-(2-methyl-2-phenylpro hydrochloride, terbutaline sulfate, trimetoquinol hydrochlo poxy)phenylpropionate Chemical and Pharmaceutical Bul ride, tulobuterol hydrochloride, orciprenaline sulfate, fenot letin (Chem. Pharm. Bull), 38,2792-2796 (1990), pravasta erol hydrobromide, ephedrine hydrochloride, ipratropium tin, simvastatin, probucol, beZafibrate, clinofibrate, nicomol. 50 bromide, oxitropium bromide, flutropium bromide, theophyl cholestyramine, dextran Sulfate sodium and the like. line, aminophylline, Sodium cromoglicate, tranilast, repiri (15) Muscle Relaxant nast, amlexanox, ibudilast, ketotifen, terfenadine, meduita pridinol, tubocurarine, pancuronium, tolperisone hydro Zine, azelastine, epinastine, oZagrel hydrochloride, pranlkast chloride, chlorphenesin carbamate, baclofen, chlormeza hydrate, seratrodast, dexamethasone, prednisolone, hydro none, mephenesin, chlorZoxazone, eperisone, tizanidine and 55 cortisone, hydrocortisone sodium Succinate, beclometaSone the like. dipropionate and the like. (16) Antiepileptic Drug (28) Therapeutic Agent for Pollakisuria/Anischuria phenytoin, ethoSuximide, acetazolamide, chlordiazep flavoxate hydrochloride and the like. oxide, trimethadione, carbamazepine, phenobarbital, primi (29) Therapeutic Agent for Atopic Dermatitis done, Sulthiame, sodium valproate, clonazepam, diazepam, 60 Sodium cromoglicate and the like. nitrazepam and the like. (30) Therapeutic Agent for Allergic Rhinitis (17) Antidepressant Sodium cromoglicate, chlorpheniramine maleate, alime imipramine, clomipramine, noxiptiline, phenelZine, ami mazine tartrate, clemastine fumarate, homochlorcyclizine triptyline hydrochloride, nortriptyline hydrochloride, amox hydrochloride, fexofenadine, meduitazine and the like. apine, mianserin hydrochloride, maprotiline hydrochloride, 65 (31) Hypertensor Sulpiride, fluvoxamine maleate, traZodone hydrochloride and dopamine, dobutamine, denopamine, digitoxin, digoxin, the like. methyldigoxin, lanatoside C, G-strophanthin and the like. US 9,120,776 B2 87 88 (32) Others mg/kg body weight-20 mg/kg body weight, of compound (I) hydroxycam, diacerein, megestrol acetate, nicergoline, or (I) can be administered once to several portions (e.g., once prostaglandins and the like. to 3 times) per day. For combined use, the administration time of the com The dose of the pharmaceutical composition of the present pound of the present invention and the concomitant drug is invention as a Sustained-release preparation varies depending not restricted, and the compound of the present invention or on the kind and content of compound (I) or (I), dosage form, the concomitant drug can be administered to an administra period of Sustained drug release, Subject animal of adminis tion Subject simultaneously, or may be administered at differ tration (e.g., mammals such as mouse, rat, hamster, guinea ent times. The dosage of the concomitant drug may be deter pig, rabbit, cat, dog, bovine, horse, Swine, sheep, monkey, mined according to the dose clinically used, and can be 10 human and the like), and administration object. For example, appropriately selected depending on an administration Sub for application by parenteral administration, about 0.1 to about 100 mg of compound (I) or (I) needs to be released ject, administration route, disease, combination and the like. from the administered preparation per 1 week. The administration form of the combined use is not par Any amount of the concomitant drug can be adopted as ticularly limited, and the compound of the present invention 15 long as the side effects do not cause a problem. The daily and a concomitant drug only need to be combined on admin dosage in terms of the concomitant drug varies depending on istration. Examples of such administration mode include the the severity, age, sex, body weight, sensitivity difference of following: the Subject, administration period, interval, and nature, phar (1) administration of a single preparation obtained by simul macology, kind of the pharmaceutical preparation, kind of taneously processing the compound of the present invention effective ingredient, and the like, and not particularly and the concomitant drug, (2) simultaneous administration of restricted, and the amount of a drug is, in the case of oral two kinds of preparations of the compound of the present administration for example, generally about 0.001 to 2000 invention and the concomitant drug, which have been sepa mg, preferably about 0.01 to 500 mg, further preferably about rately produced, by the same administration route, (3) admin 0.1 to 100 mg, per 1 kg of a mammal and this is generally istration of two kinds of preparations of the compound of the 25 administered once to 4-times (preferably, once to 3-times) present invention and the concomitant drug, which have been divided in a day. separately produced, by the same administration route in a When the combination agent of the present invention is staggered manner, (4) simultaneous administration of two administered, the compound of the present invention and the kinds of preparations of the compound of the present inven concomitant drug can be administered simultaneously, or tion and the concomitant drug, which have been separately 30 may be administered in a staggered manner. When adminis produced, by different administration routes, (5) administra tered at a time interval, the interval varies depending on the tion of two kinds of preparations of the compound of the effective ingredient, dosage form and administration method, present invention and the concomitant drug, which have been and, for example, when the concomitant drug is administered separately produced, by different administration routes in a first, a method in which the compound of the present inven 35 tion is administered within time range of from 1 minute to 3 staggered manner (e.g., administration in the order of the days, preferably from 10 minutes to 1 day, more preferably compound of the present invention and the concomitant drug, from 15 minutes to 1 hour, after administration of the con or in the reverse order) and the like. comitant drug is an example. When the compound of the The mixing ratio of the compound of the present invention present invention is administered first, a method in which the and a concomitant drug in the combination agent of the 40 concomitant drug is administered within time range of from 1 present invention can be appropriately selected based on the minute to 1 day, preferably from 10 minutes to 6 hours, more Subject of administration, administration route, disease and preferably from 15 minutes to 1 hour after administration of the like. the compound of the present invention is an example. For example, while the content of the compound of the present invention in the combination agent of the present 45 EXAMPLES invention varies depending on the preparation form, it is generally about 0.01-100 wt %, preferably about 0.1-50 wt %, The present invention is explained in more detail in the more preferably about 0.5-20 wt %, of the whole preparation. following by referring to Examples, Preparation Examples The content of the concomitant drug in the combination and Experimental Examples, which are not to be construed as agent of the present invention varies depending on the prepa 50 limitative and may be modified without departing from the ration form, and generally about 0.01 to 100% by weight, Scope of the invention. preferably about 0.1 to 50% by weight, further preferably Unless particularly indicated, the elution in column chro about 0.5 to 20% by weight, of the entire preparation. matography in the Examples was performed under observa While the content of the additive such as a carrier and the tion by TLC (Thin Layer Chromatography). For TLC obser like in the combination agent of the present invention varies 55 vation, 60F254 manufactured by Merck was used as a TLC depending on the form of a preparation, it is generally about plate, and the solvent used as an elution solvent for column 1 to 99.99% by weight, preferably about 10 to 90% by weight, chromatography was used. For detection, moreover, a UV based on the preparation. detector was adopted. As silica gel for column chromatogra When the compound of the present invention and the con phy, silica gel 60 (70-230 mesh) manufactured by Merck was comitant drug are separately prepared, the same content may 60 used. The room temperature generally means a temperature be adopted. about 10°C. to 35° C. For drying extracts, sodium sulfate or The dose of the combination agent varies depending on the magnesium Sulfate was used. kind of the compound of the present invention, administration The abbreviations in the Examples mean as follows. route, symptom, age of patients and the like. For example, for LC: liquid chromatography oral administration to patients (body weight about 60kg) with 65 MS: mass analysis spectrum inflammatory bowel disease (IBD), about 0.1 mg/kg body API: atmospheric pressure ionization method weight—about 30 mg/kg body weight, preferably about 1 M: molecular weight of the compound US 9,120,776 B2 89 90 NMR: nuclear magnetic resonance spectrum hr. The reaction mixture was poured into a mixed solution of HZ: hertz aqueous sodium hydrogen carbonate Solution and ethyl J: coupling constant acetate, and the precipitate was collected by filtration, and m: multiplet recrystallized from methanol and THF to give the title com q: quartet pound (172 mg, 0.392 mmol. 40.4%) as a white powder. t: triplet 'H-NMR (300 MHz, DMSO-d): 81.08 (3H, d, J=6.4 Hz), d: doublet 1.30 (3H, d. J–7.2 Hz), 2.23-2.47 (5H, m), 4.41 (2H, d, J=7.2 s: singlet Hz), 7.13-7.22 (1H, m), 7.32-7.40 (1H, m), 7.40-749 (1H, br: broad m), 7.51-7.62 (4H, m), 7.64-7.73 (1H, m), 7.77-7.87 (1H, m), dt: double triplet 10 8.05 (1H, d, J=7.5 Hz), 8.43 (1H, s), 9.85-10.35 (2H, m) ddd: double double doublet brs: broad singlet Example 2 "Bu: tert-butyl group Boc: tert-butyloxycatbonyl group N-(3-cyanophenyl)-N'-(9-ethyl-9H-carbazol-3-yl)-3- N: normal concentration 15 methylpentanediamide THF: tetrahydrofuran HOBt: 1H-benzod 1.2.3 triazol-1-ol hydrate (Step 1) WSC: N'-((ethylimino)methylene)-N,N-dimethylpro Using 3-aminobenzonitrile, and by the reaction and puri pane-1,3-diamine hydrochloride fication in the same manner as in the method described in Step DMF: N,N-dimethylformamide 1 of Example 1, 5-(3-cyanophenylamino)-3-methyl-5-oxo DMA: dimethylacetamide pentanoic acid was obtained. DMSO: dimethylsulfoxide 'H-NMR (300 MHz, DMSO-d): 80.96 (3H, d, J=6.0 Hz), DIEA: diisopropylethylamine 2.05-2.45 (5H, m), 743-7.62 (2H, m), 7.78 (1H, dt, J=6.7, 2.3 HATU: 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethylu Hz), 8.10 (1H, s), 10.25 (1H, s), 12.10 (1H, brs) ronium hexafluorophosphorate 25 (Step 2) TFA: trifluoroacetic acid A solution of 9-ethyl-9H-carbazol-3-amine (210 mg, 1.00 TEA: triethylamine mmol), the compound obtained in Step 1 (246 mg, 1 mmol), DMAP: dimethylaminopyridine HOBt (306 mg, 2.00 mmol) and WSC (383 mg, 2.00 mmol) mCPBA: m-chloroperbenzoic acid in DMF (5 mL) was stirred at room temperature for 14hr. The DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene 30 reaction mixture was poured into a mixed solution of aqueous The purification by preparative HPLC in the Examples was Sodium hydrogen carbonate solution and ethyl acetate, and performed under the following conditions. the organic layer was separated. The organic layer was equipment: Gilson Inc. High throughput purification sys washed with water and saturated brine, and dried, and the tem solvent was evaporated under reduced pressure. The obtained column: CombiPrep ODS-AS-5 um, 50x20 mm (YMC) 35 residue was purified by silica gel column chromatography solvent: SOLUTIONA; 0.1% trifluoroacetic acid-contain (solvent gradient: 66 to 80% ethyl acetate/hexane) to give the ing water, SOLUTION B: 0.1% trifluoroacetic acid-contain title compound (283 mg, 0.645 mmol. 64.5%) as a white ing acetonitrile powder. gradient cycle: 0.00 min (SOLUTION A/SOLUTION 'H-NMR (300 MHz, DMSO-d): 81.03 (3H, d, J=6.0 Hz), B=95/5), 1.00 min (SOLUTION A/SOLUTION B=95/5), 40 1.23-1.34 (3H, m), 2.23-2.50 (5H, m), 2.72-2.83 (1H, m), 5.20 min (SOLUTION A/SOLUTION B=5/95), 6.40 min 4.41 (1H, d, J=7.2 Hz), 7.13-7.23 (1H, m), 7.52 (7 Ha, J=12.1 (SOLUTION A/SOLUTION B=5/95), 6.50 min (SOLU Hz), 8.04 (1H, d. J=7.5 Hz), 8.13 (1H, s), 8.41 (1H, s), 9.93 TION A/SOLUTION B=95/5), 6.60 min (SOLUTION (1H, s), 10.25-10.34 (1H, m) A/SOLUTION B=95/5) flow rate: mL/min, detection method: UV 220 nm. 45 Example 3 Example 1 N-(4-cyanophenyl)-N'-(1-ethyl-2,3-dimethyl-1H indol-5-yl)-3-methylpentanediamide N-(2-cyanophenyl)-N'-(9-ethyl-9H-carbazol-3-yl)-3- methylpentanediamide 50 (Step 1) A solution of 4-aminobenzonitrile (4.61 g, 39.02 mmol) (Step 1) and 4-methyldihydro-2H-pyran-2.6(3H)-dione (5.0 g, 39.02 A solution of 2-aminobenzonitrile (1.181 g, 10 mmol) and mmol) in THF (50 mL) was stirred at 90° C. for 14 hr. The 4-methyldihydro-2H-pyran-2.6(3H)-dione (1.281 g, 10 reaction solution was concentrated, and the precipitate was mmol) in THF (20 mL) was stirred at 90° C. for 46 hr. The 55 washed with ethyl acetate to give 5-(4-cyanophenylamino)- reaction Solution was concentrated to give 5-(2-cyanopheny 3-methyl-5-oxopentanoic acid (6.23g, 25.3 mmol. 64.8%). lamino)-3-methyl-5-oxopentanoic acid (2.230 g, 9.06 mmol. 'H-NMR (300 MHz, DMSO-d): 80.96 (3H, d, J=6.0 Hz), 91%) as a white powder. 2.01-2.21 (1H, m), 2.21-2.47 (4H, m), 7.62-7.90 (4H, m), H-NMR (300 MHz, DMSO-d): 80.99 (3H, d, J=5.7 Hz), 10.34 (1H, s), 12.11 (1H, brs) 2.08-2.22 (1H, m), 2.22-2.46 (4H, m), 7.30-7.41 (1H, m), 60 (Step 2) 7.52 (1H, d, J=7.9 Hz), 7.63-7.73 (1H, m), 7.80 (1H, d, J=7.9 To a solution of the compound obtained in Step 1 (510 mg. Hz), 10.16 (1H, s), 12.10 (1H, brs) 2.07 mmol), 1-ethyl-2,3-dimethyl-1H-indol-5-amine (390 (Step 2) mg, 2.07 mmol) and DIEA (1.085 mL, 6.21 mmol) in DMF (8 A solution of 9-ethyl-9H-carbazol-3-amine (210 mg, 1.00 mL) was added HATU (1181 mg, 3.11 mmol), and the mix mmol), the compound obtained in Step 1 (239 mg, 0.97 65 ture was stirred at room temperature for 14 hr. The reaction mmol), HOBt (297 mg, 1.94 mmol) and WSC (372 mg, 1.94 mixture was poured into water, and extracted with ethyl mmol) in DMF (5 mL) was stirred at room temperature for 14 acetate. The organic layer was separated, washed with water US 9,120,776 B2 91 92 and Saturated brine, and dried, and the solvent was evaporated residue was purified by silica gel column chromatography under reduced pressure. The obtained residue was purified by (solvent gradient; 5 to 80% ethyl acetate/hexane) to give silica gel column chromatography (Solvent gradient; 10 to crude N-(4-cyanophenyl)-3-methyl-5-oxopentanamide (113 100% ethyl acetate/hexane) to give the title compound (533 mg, 0.492 mmol. 26.3%) as a white powder. MS (API): 229 (M-H) mg, 1.280 mmol. 61.8%) as a white powder. (Step 3) 'H-NMR (300 MHz, DMSO-d): 81.00 (3H, d, J=6.4 Hz) A solution of the compound obtained in Step 2 (110 mg. 1.18 (3H, t, J–7.2 Hz), 2.13 (3H, s), 2.17-2.43 (5H, m), 0.48 mmol) and 3-amino-N-ethylcarbazole (151 mg, 0.72 2.43-2.61 (3H, m), 4.09 (2H, q, J=6.9 Hz), 7.05-7.35 (2H, m), mmol) in TFA (1 mL) and toluene (1 mL) was stirred at room 7.64-789 (5H, m), 9.68 (1H, s), 10.37 (1H, s) temperature for 1 hr. To the reaction mixture was added MS (API):417 (M+H) 10 sodium triacetoxyborohydride (304 mg, 1.43 mmol), and the mixture was stirred at room temperature for additional 14hr. Example 4 The reaction mixture was concentrated under reduced pres sure, and the residue was dissolved in ethyl acetate. The N-(4-cyanophenyl)-N'-(9-ethyl-2.3.4.9-tetrahydro solution was washed with 1N aqueous sodium hydroxide 1H-carbazol-6-yl)-3-methylpentanediamide 15 Solution, water and Saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue To a solution of 5-(4-cyanophenylamino)-3-methyl-5-oxo was purified by silica gel column chromatography (Solvent pentanoic acid (172 mg 0.70 mmol), 9-ethyl-2.3.4.9-tetrahy gradient; 10 to 80% ethyl acetate/hexane) to give the title dro-1H-carbazol-6-amine (150 mg. 0.70 mmol) and DIEA compound (82 mg, 0.193 mmol. 40.5%) as a pale-yellow (0.367 mL, 2.10 mmol) in DMF (8 mL) was added HATU powder. (399 mg, 1.05 mmol), and the mixture was stirred at room 'H-NMR (300 MHz, DMSO-d): 80.97-1.08 (3H, m), 1.26 temperature for 14 hr. The reaction mixture was poured into (3H, t, J=7.0 Hz), 1.49-1.63 (1H, m), 1.66-1.80 (1H, m), water, and extracted with ethyl acetate. The organic layer was 2.13-2.34 (2H, m), 2.41-2.48 (1H, m), 3.15 (2H, brs), 4.31 separated, washed with water and Saturated brine, and dried, (2H, q, J–6.7 Hz), 5.15 (1H, brs), 6.83-6.88 (1H, m), 7.07 and the solvent was evaporated under reduced pressure. The 25 (1H, t, J–7.2 Hz), 7.24 (1H, s), 7.29-7.37 (2H, m), 7.43-7.53 obtained residue was purified by silica gel column chroma (1H, m), 7.71-7.84 (4H, m), 7.96 (1H, d, J=7.6 Hz), 10.34 tography (solvent gradient; 10 to 100% ethyl acetate/hexane) (1H, s) to give the title compound (179 mg, 0.404 mmol, 57.8%) as a white powder. Example 6 'H-NMR (300 MHz, DMSO-d): 80.99 (3H, d, J=6.1 Hz), 30 1.19 (3H, t, J=7.2 Hz), 1.65-1.94 (4H, m), 2.16-2.41 (3H, m), N-(4-cyanophenyl)-N'-(9-ethyl-9H-carbazol-3-yl)-3, 2.41-2.48 (2H, m), 2.57 (2H, t, J=5.3 Hz), 2.63-2.72 (2H, m), 3-dimethylpentanediamide 4.04 (2H, q, J–7.2 Hz), 7.16 (1H, dd, J=8.7, 1.9 Hz), 7.26 (1H, d, J=8.7 Hz), 7.62-7.87 (5H, m), 9.68 (1H, s), 10.37 (1H, s) (Step 1) MS (API): 443 (M+H) 35 Using 4,4-dimethyldihydro-2H-pyran-2,6(3H)-dione, and by the reaction and purification in the same manner as in the Example 5 method described in Step 1 of Example 3, 5-(4-cyanopheny lamino)-3.3-dimethyl-5-oxopentanoic acid was obtained. N-(4-cyanophenyl)-5-[(9-ethyl-9H-carbazol-3-yl) MS (API): 259 (M-H) amino-3-methylpentanamide 40 (Step 2) Using the compound obtained in Step 1, and by the reaction (Step 1) and purification in the same manner as in the method To a solution of 5-(4-cyanophenylamino)-3-methyl-5-oxo described in Step 2 of Example 1, the title compound was pentanoic acid (1.00 g, 4.06 mmol) in THF (15 mL) was obtained. added borane-THF complex (1.2M, THF solution 6.77 mL, 45 'H-NMR (300 MHz, CDC1): 81.06-1.33 (6H, m), 1.42 8.12 mmol) under ice-cooling. The mixture was stirred at (3H, t, J–7.2 Hz), 2.45 (2H, s), 2.56 (2H, s), 4.36 (2H, q, J–7.2 room temperature for 14 hr, and the reaction mixture was Hz), 7.12-7.32(1H, m), 7.32-7.66 (6H, m), 7.76 (2H, d, J=8.7 poured into water. The mixture was extracted with ethyl Hz), 7.94 (1H, s), 8.08 (1H, d, J–7.9 Hz), 8.25 (1H, d, J=1.5 acetate, the organic layer was washed with water and Satu Hz), 10.56 (1H, s) rated brine, and dried, and the solvent was evaporated under 50 reduced pressure. The obtained residue was purified by silica Example 7 gel column chromatography (solvent gradient; 10 to 100% ethyl acetate/hexane) to give N-(4-cyanophenyl)-5-hydroxy 2-(1-2-(4-cyanophenyl)amino-2- 3-methylpentanamide (0.442 g, 1.904 mmol. 46.9%) as a oxoethylcyclopentyl)-N-(9-ethyl-9H-carbazol-3-yl) colorless oil. 55 acetamide 'H-NMR (300 MHz, CDC1): 81.06 (3H, d, J=6.8 Hz), 1.52-1.72 (2H, m), 2.14-2.53 (4H, m), 3.66-3.94 (2H, m), (Step 1) 7.49-7.79 (4H, m), 8.46 (1H, brs) Using 8-oxaspiro4.5 decane-7,9-dione, and by the reac (Step 2) tion and purification in the same manner as in the method To a solution of the compound obtained in Step 1 (435 mg. 60 described in Step 1 of Example 3, 2-(1-(2-(4-cyanopheny 1.87 mmol) in acetonitrile (10 mL) was added Dess-Martin lamino)-2-oxoethyl)cyclopentyl)acetic acid was obtained. Periodinane (953 mg, 2.25 mmol), and the mixture was MS (API): 285 (M-H) stirred at room temperature for 2 hr. The reaction mixture was (Step 2) poured into aqueous Sodium thiosulfate solution, and the Using the compound obtained in Step 1, and by the reaction mixture was extracted with ethyl acetate. The organic layer 65 and purification in the same manner as in the method was washed with water and saturated brine, and dried, and the described in Step 2 of Example 1, the title compound was solvent was evaporated under reduced pressure. The obtained obtained. US 9,120,776 B2 93 94 'H-NMR (300 MHz, CDC1): 81.43 (3H, t, J=7.2 Hz), (Step 1) 1.51-1.70 (3H, m), 1.70-1.95 (5H, m), 2.52 (2H, s), 2.60 (2H, Using methyl 5-(4-cyanophenylamino)-3-methyl-5-oxo s), 4.37 (2H, q, J–7.2 Hz), 7.16-7.31 (1H, m), 7.34-7.63 (6H, pentanoate and 1-bromo-3-methoxypropane, and by the reac m), 7.67-7.89 (3H, m), 8.09 (1H, d, J=7.5 Hz), 8.24 (1H, d, tion and purification in the same manner as in the method J=1.9 Hz), 10.47 (1H, s) described in Step 2 of Example 8, methyl 5-((4-cyanophenyl) (3-methoxypropyl)amino)-3-methyl-5-oxopentanoate was Example 8 obtained. MS (API): 333 (M+H) N-benzyl-N-(4-cyanophenyl)-N'-(9-ethyl-9H-carba (Step 2) Zol-3-yl)-3-methylpentanediamide 10 Using the compound obtained in Step 1, and by the reaction (Step 1) and purification in the same manner as in the method A Solution of 5-(4-cyanophenylamino)-3-methyl-5-oxo described in Step 3 of Example 8, 5-(4-cyanophenyl) pentanoic acid (94.0 mg, 3.82 mmol) and conc. Sulfuric acid (1 (3-methoxypropyl)amino)-3-methyl-5-oxopentanoic acid drop) in methanol (25 mL) was heated with reflux for 14 hr. 15 was obtained as a crude product. The reaction solution was cooled, and ethyl acetate was added MS (API): 317 (M-H) thereto. The solution was washed with water and saturated (Step 3) brine, and dried, and the solvent was evaporated under Using the compound obtained in Step 2, and by the reaction reduced pressure. The obtained residue was purified by silica and purification in the same manner as in the method gel column chromatography (solvent gradient; 10 to 100% described in Step 2 of Example 1, the title compound was ethyl acetate/hexane) to give methyl 5-(4-cyanopheny obtained. lamino)-3-methyl-5-oxopentanoate (557 mg, 2.139 mmol. 'H-NMR (300 MHz, DMSO-d): 80.90 (3H, d, J=6.8 Hz 56.0%) as a white powder. 1.30 (3H, t, J–7.0 Hz), 1.51-1.74 (2H, m), 1.92-2.08 (1H, m), MS (API): 259 (M-H) 2.04-2.32 (3H, m), 2.36-2.48 (1H, m), 3.07-3.19 (3H, m), (Step 2) 25 3.29 (2H, t, J=6.2 Hz), 3.64-3.83 (2H, m), 4.41 (2H, q, J–7.1 To a solution of the compound obtained in Step 1 (228 mg, Hz), 7.37-7.67 (3H, m), 7.85-8.00(5H, m), 8.05 (1H, d, J=7.6 0.88 mmol) in DMF (6 mL) was added sodium hydride (60% Hz), 8.36 (1H, s), 9.80 (1H, s) in oil, 126 mg, 2.63 mmol) at 0°C. The reaction mixture was stirred at room temperature for 30 min, and benzyl bromide Example 10 (0.156 mL, 1.31 mmol) was added thereto at 0°C. The reac 30 tion mixture was stirred at room temperature for 14 hr, to the N-(4-cyanophenyl)-N'-(9-ethyl-9H-carbazol-3-yl) reaction solution was added water, and the mixture was butanediamide extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was Using dihydrofuran-2,5-dione, and by the reaction and evaporated under reduced pressure. The obtained residue was 35 purification in the same manner as in the method described in purified by Silica gel column chromatography (solvent gradi Step 1 of Example 3 and Step 2 of Example 1, the title ent; 5 to 85% ethyl acetate/hexane) to give methyl 5-(benzyl compound was obtained. (4-cyanophenyl)amino)-3-methyl-5-oxopentanoate (81 mg, 'H-NMR (300 MHz, DMSO-d): 81.30 (3H, t, J–7.0 Hz), 0.230 mmol. 26.3%) as a colorless oil. 2.60-2.82 (4H, m), 4.41 (2H, q, J=6.8 Hz), 7.16 (1H, t, J–7.4 MS (API): 351 (M+H) 40 Hz), 7.43 (1H, t, J–7.4 Hz), 7.50-7.64 (3H, m), 7.69-7.89 (4H, (Step 3) m), 8.04 (1H, d, J=8.0 Hz), 8.42 (1H, s), 10.02 (1H, s), 10.48 A solution of the compound obtained in Step 2 (80.0 mg. (1H, s) 0.23 mmol) and 1N aqueous sodium hydroxide solution (1 mL, 1.00 mmol) in methanol (2 mL) and THF (2 mL) was Example 11 stirred at room temperature for 14 hr. The reaction solution 45 was neutralized with 1N hydrochloric acid, and the mixture N-(4-cyanophenyl)-N'-(9-ethyl-9H-carbazol-3-yl) was extracted with ethyl acetate. The organic layer was cyclopropane-1,2-dicarboxamide washed with water and saturated brine, and dried, and the Solvent was evaporated under reduced pressure to give crude Using 3-oxabicyclo(3.1.0)hexane-2,4-dione, and by the 5-(benzyl (4-cyanophenyl)amino)-3-methyl-5-oxopentanoic 50 reaction and purification in the same manner as in the method acid (74.2 mg, 0.221 mmol, 97%) as a white powder. described in Step 1 of Example 3 and Step 2 of Example 1, the MS (API): 335 (M-H) title compound was obtained. (Step 4) 'H-NMR (300 MHz, DMSO-d): 81.20-1.39 (4H, m), Used the compound obtained in Step 3, and by the reaction 1.53-1.71 (1H, m), 2.17-2.41 (2H, m), 4.40 (2H, q, J=6.9 Hz), and purification in the same manner as in the method 55 7.15 (1H, t, J–7.4 Hz), 7.36-7.48 (1H, m), 7.48-7.63 (3H, m), described in Step 2 of Example 1, the title compound was 7.65-7.86 (4H, m), 7.99 (1H, d, J=8.0 Hz), 8.32 (1H, s), 0.10 obtained. (1H, s), 10.50 (1H, s) 'H-NMR (300 MHz, DMSO-d): 80.94 (3H, d, J=6.8 Hz), 1.30 (3H, t, J=7.2 Hz), 2.03-2.43 (4H, m), 4.41 (2H, q, J=6.8 Example 12 Hz), 4.96 (2H, s), 7.09-7.33 (6H, m), 7.36-7.67 (6H, m), 7.84 60 (2H, d, J=8.7 Hz), 8.05 (1H, d, J=7.6 Hz), 8.38 (1H, s), 9.83 N'-(4-cyanophenyl)-N'-(9-ethyl-9H-carbazol-3-yl)- (1H, s) 2-methylbutanediamide Example 9 Using 3-methyldihydrofuran-2,5-dione, and by the reac 65 tion and purification in the same manner as in the method N-(4-cyanophenyl)-N'-(9-ethyl-9H-carbazol-3-yl)-N-(3- described in Step 1 of Example 3 and Step 2 of Example 1, the methoxypropyl)-3-methylpentanediamide title compound was obtained. US 9,120,776 B2 95 96 'H-NMR (300 MHz, DMSO-d): 81.12-142 (6H, m), MS (API): 439 (M+H) 2.53-2.57 (1H, m), 2.82 (1H, dt, J=15.7, 8.0 Hz), 2.98-3.16 'H-NMR (300 MHz, DMSO-d): 81.03 (3H, d, J=6.4 Hz) (1H, m), 4.40 (2H, q, J=6.8 Hz), 7.16 (1H, t, J–74 Hz), 7.43 1.30 (3H, t, J–7.0 Hz), 2.18-2.48 (4H, m), 2.54-2.59 (1H, m), (1H, t, J=7.8 Hz), 7.48-7.64 (3H, m), 7.67-7.90 (4H, m), 8.03 4.41 (2H, q, J=7.2 Hz), 7.17 (1H, t, J=7.2 Hz), 7.34-7.64 (4H, (1H, d, J=7.6 Hz), 8.32-8.51 (1H, m), 10.00 (1H, d, J-3.0 Hz), m), 7.67-7.88 (3H, m), 7.95 (1H, s), 8.03 (1H, d, J=7.6 Hz), 10.45 (1H, d, J=7.6 Hz) 8.40 (1H, s), 9.92 (1H, s), 10.37 (1H, s) (Step 2) Example 13 To a solution of the compound obtained in Step 1 (200 mg. 0.46 mmol) in DMF (6 mL) were added sodium hydride (60% N'-(4-cyanophenyl)-N'-(9-ethyl-9H-carbazol-3-yl)- 10 in oil, 219 mg, 4.56 mmol) and methyl iodide (0.142 mL, 2.28 2,2-dimethylbutanediamide mmol), and the mixture was stirred at room temperature for Using 3.3-dimethyldihydrofuran-2,5-dione, and by the 14 hr. The reaction solution was cooled to 0°C., water was reaction and purification in the same manner as in the method added thereto, and the mixture was extracted with ethyl described in Step 1 of Example 3 and Step 2 of Example 1, the 15 acetate. The organic layer was washed with water and Satu title compound was obtained. rated brine, and dried, and the solvent was evaporated under 'H-NMR (300 MHz, DMSO-d): 81.21-1.36 (3H, m), 1.39 reduced pressure. The obtained residue was purified by silica (6H, s), 2.80 (2H, s), 4.42 (2H, q, J–6.9 Hz), 7.04-7.28 (1H, gel column chromatography (solvent gradient; 10 to 100% m), 7.37-7.68 (4H, m), 7.68-7.89 (4H, m), 8.04 (1H, d. J–7.6 ethyl acetate/hexane) to give the title compound (30.7 mg, Hz), 8.34 (1H, d, J=1.9 Hz), 9.36 (1H, s), 10.50 (1H, s) 0.066 mmol. 14.43%) as a pale-yellow powder. MS (API): 467 (M+H) Example 14 Example 16 N-(3-chloro-4-cyanophenyl)-N'-(9-ethyl-9H-carba Zol-3-yl)-3-methylpentanediamide 25 N-(4-cyanophenyl)-N'-(9-ethyl-9H-carbazol-3-yl) pentanediamide (Step 1) A solution of 4-amino-2-chlorobenzonitrile (500 mg, 3.28 (Step 1) mmol) and 4-methyldihydro-2H-pyran-2.6(3H)-dione (420 A solution of dihydro-2H-pyran-2,6(3H)-dione (483 mg, mg, 3.28 mmol) in THF (15 mL) was stirred at 90° C. for 14 30 4.23 mmol) and 4-aminobenzonitrile (500 mg, 4.23 mmol) in hr. The reaction solution was concentrated to give 5-(3- THF (15 mL) was heated with reflux for 14 hr. The reaction chloro-4-cyanophenylamino)-3-methyl-5-oxopentanoic acid solution was concentrated under reduced pressure, and the (1143 mg, 4.07 mmol. 124%) as a crude product. precipitate was washed with ethyl acetate to give 5-(4-cy 'H-NMR (300 MHz, DMSO-d): 80.82-1.07 (3H, m), anophenylamino)-5-oxopentanoic acid (782 mg, 3.37 mmol. 2.05-2.42 (5H, m), 7.60 (1H, dd, J=8.7, 1.9 Hz), 7.88 (1H, d, 35 80%) as a pale-yellow powder. J=8.7 Hz), 8.06 (1H, d, J=1.5 Hz), 10.50 (1H, s), 12.08 (1H, 'H-NMR (300 MHz, DMSO-d): 81.81 (2H, quin, J–7.4 s) Hz), 2.17-2.35 (2H, m), 2.41 (2H, t, J=7.4 Hz), 7.56-7.96 (4H, (Step 2) m), 10.33 (1H, s), 12.08 (1H, brs) To a solution of the compound obtained in Step 1 (300 mg. (Step 2) 1.07 mmol), 3-amino-9-ethylcarbazole (270 mg, 1.28 mmol) 40 To a solution of the compound obtained in Step 1 (200 mg. and DIEA (0.560 mL, 3.21 mmol) in DMF (6 mL) was added 0.97 mmol), 9-ethyl-9H-carbazol-3-amine (217 mg, 1.03 HATU (610 mg, 1.60 mmol), and the mixture was stirred at mmol) and DIEA (0.451 mL, 2.58 mmol) in DMF (6 mL) was room temperature for 14 hr. To the reaction solution was added HATU (491 mg, 1.29 mmol), and the mixture was added water, and the mixture was extracted with ethyl acetate. stirred at room temperature for 14 hr. The reaction mixture The organic layer was washed with water and Saturated brine, 45 was poured into water, and extracted with ethyl acetate. The and dried, and the solvent was evaporated under reduced organic layer was washed with water and Saturated brine, and pressure. The obtained residue was purified by silica gel dried, and the solvent was evaporated under reduced pressure. column chromatography (solvent gradient; 5 to 75% ethyl The obtained residue was purified by silica gel column chro acetate/hexane) to give the title compound (225 mg, 0.476 matography (solvent gradient; 5 to 75% ethyl acetate/hexane) mmol. 44.5%) as a white powder. 50 to give the title compound (229 mg 0.540 mmol, 62.7%) as a 'H-NMR (300 MHz, DMSO-d): 81.03 (3H, d, J=6.0 Hz), white powder. 1.20-1.40 (4H, m), 2.19-2.48 (3H, m), 2.54 (1H, brs), 4.41 'H-NMR (300 MHz, DMSO-d): 81.30 (3H, t, J–7.0 Hz), (2H, q, J=7.1 Hz), 7.07-7.27 (1H, m), 7.36-7.69 (5H, m), 7.87 1.85-2.11 (2H, m), 2.31-2.44 (1H, m), 2.49-2.63 (3H, m), (1H, d, J=8.7 Hz), 7.97-8.14 (2H, m), 8.39 (1H, s), 9.91 (1H, 4.41 (2H, q, J=6.8 Hz), 7.17 (1H, t, J=7.4 Hz), 7.36-7.65 (4H, s), 10.54 (1H, s) 55 m), 7.69-7.90 (4H, m), 8.04 (1H, d. J=7.6 Hz), 8.43 (1H, s), 9.92 (1H, s), 10.37 (1H, s) Example 15 Example 17 N'-(4-cyanophenyl)-N'-(9-ethyl-9H-carbazol-3-yl)- N',N.3-trimethylpentanediamide 60 N-(4-cyanophenyl)-N'-(9-ethyl-9H-carbazol-3-yl) hexanediamide (Step 1) Using 5-(4-cyanophenylamino)-3-methyl-5-oxopentanoic (Step 1) acid, and by the reaction and purification in the same manner Using adipic anhydride, and by the reaction and purifica as in the method described in Step 2 of Example 1, N'-(4- 65 tion in the same manner as in the method described in Step 1 cyanophenyl)-N'-(9-ethyl-9H-carbazol-3-yl)-3-methylpen of Example 3, 6-(4-cyanophenylamino)-6-oxohexanoic acid tanediamide was obtained. was obtained. US 9,120,776 B2 97 98 'H-NMR (300 MHz, DMSO-d): 81.42-1.70 (4H, m), ethyl acetate/hexane) to give 6-nitro-9-propyl-2.3.4.9-tet 2.13-2.30 (2H, m), 2.36 (2H, t, J=7.0 Hz), 7.58-7.95 (4H, m), rahydro-1H-carbazole (279 mg, 1.081 mmol, 93%) as a yel 10.32 (1H, d, J-3.0 Hz), 12.00 (1H, brs) low powder. (Step 2) 'H-NMR (300 MHz, CDC1): 80.95 (3H, t, J=7.4 Hz), Using the compound obtained in Step 1 and 9-ethyl-9H 1.66-2.05 (6H, m), 2.60-2.85 (4H, m), 3.89-4.11 (2H, m), carbazol-3-amine, and by the reaction and purification in the 7.15-7.33 (1H, m), 8.03 (1H, dd, J=8.7, 2.3 Hz), 8.41 (1H, d, same manner as in the method described in Step 2 of Example J=2.3 Hz) 3, the title compound was obtained. (Step 2) 'H-NMR (300 MHz, DMSO-d): 81.30 (3H, t, J=7.0 Hz), A solution of the compound obtained in Step 1 (270 mg. 1.68 (4H, brs) 2.27-2.46 (4H, m), 4.41 (2H, q, J=7.1 Hz), 10 1.05 mmol) and 10% palladium on carbon (50% wet, 10 mg. 7.07-7.25 (1H, m), 7.36-7.63 (4H, m), 7.68-7.85 (4H, m), 0.09 mmol) in a mixed solvent of methanol (4 mL) and ethyl 8.04 (1H, d, J=7.6 Hz), 8.40 (1H, s), 9.89 (1H, s), 10.35 (1H, acetate (4 mL) was stirred at room temperature for 14hr under s) 1 atm of hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced Example 18 15 pressure to give 9-propyl-2.3.4.9-tetrahydro-1H-carbazol-6- amine (230 mg, 1.006 mmol, 96%) as a brown oil. N-4-cyano-3-(trifluoromethyl)phenyl)-N'-(9-ethyl MS (API): 229 (M+H) 9H-carbazol-3-yl)-3-methylpentanediamide (Step 3) To a solution of the compound obtained in Step 2 (229 mg, (Step 1) 1.00 mmol), 5-(4-cyanophenylamino)-3-methyl-5-oxopen A solution of 4-amino-2-(trifluoromethyl)benzonitrile tanoic acid (247 mg, 1.00 mmol) and DIEA (0.525 mL, 3.01 (500 mg, 2.69 mmol) and 4-methyldihydro-2H-pyran-2.6 mmol) in DMF (6 mL) was added HATU (572 mg, 1.50 (3H)-dione (344 mg, 2.69 mmol) in THF (15 mL) was stirred mmol), and the mixture was stirred at room temperature for at 90° C. for 14hr. The reaction solution was concentrated to 14 hr. To the reaction solution was added water, and the give 5-(4-cyano-3-(trifluoromethyl)phenylamino)-3-methyl 25 mixture was extracted with ethyl acetate. The organic layer 5-oxopentanoic acid (964 mg, 3.07 mmol. 114%) as a crude was washed with water and saturated brine, and dried, and the product. solvent was evaporated under reduced pressure. The obtained 'H-NMR (300 MHz, DMSO-d): 80.80-1.08 (3H, m), residue was purified by silica gel column chromatography 2.08-2.47 (5H, m), 7.88-8.16 (2H, m), 8.28 (1H, d. J–1.9 Hz), (solvent gradient; 5 to 75% ethyl acetate/hexane) to give the 10.68 (1H, s), 12.09 (1H, s) 30 title compound (151 mg, 0.332 mmol. 33.1%) as a white (Step 2) powder. To a solution of the compound obtained in Step 1 (300 mg. 'H-NMR (300 MHz, DMSO-d): 80.84 (3H, t, J=74 Hz), 0.95 mmol), 3-amino-9-ethylcarbazole (241 mg, 1.15 mmol) 1.00 (3H, d, J=6.4 Hz), 1.51-1.71 (2H, m), 1.71-1.94 (4H, m), and DIEA (0.500 mL, 2.86 mmol) in DMF (6 mL) was added 2.19-2.39 (3H, m), 2.41-2.48 (2H, m), 2.57 (2H, t, J=5.5 Hz), HATU (544 mg, 1.43 mmol), and the mixture was stirred at 35 2.68 (2H, t, J=5.7 Hz), 3.96 (2H, t, J=7.2 Hz), 7.15 (1H, dd, room temperature for 14 hr. To the reaction solution was J=8.7, 19 Hz), 7.25 (1H, d, J=8.3 Hz), 7.67 (1H, d, J=1.9 Hz), added water, and the mixture was extracted with ethyl acetate. 7.70-7.87 (4H, m), 9.66 (1H, s), 10.35 (1H, s) The organic layer was washed with water and Saturated brine, and dried, and the solvent was evaporated under reduced Example 20 pressure. The obtained residue was purified by silica gel 40 column chromatography (solvent gradient; 5 to 75% ethyl N-(4-cyanophenyl)-3-methyl-N'-9-(2-methylpro acetate/hexane), and then NH-silica gel column chromatog pyl)-2.3.4.9-tetrahydro-1H-carbazol-6-ylpentanedia raphy (solvent gradient; 5 to 100% ethyl acetate/hexane) to mide give the title compound (189 mg 0.372 mmol. 39.0%) as a white powder. 45 (Step 1) 'H-NMR (300 MHz, DMSO-d): 81.05 (3H, d, J=6.0 Hz), To a solution of 6-nitro-2.3.4.9-tetrahydro-1H-carbazole 1.30 (3H, t, J=7.0Hz), 2.24-2.48 (3H, m), 2.56 (2H, d, J=10.6 (250 mg, 1.16 mmol) and potassium carbonate (479 mg, 3.47 Hz), 4.41 (2H, q, J=6.8 Hz), 7.17 (1H, t, J=7.4 Hz), 7.33-7.67 mmol) in DMF (8 mL) was added 1-bromo-2-methylpropane (4H, m), 7.89-8.16 (3H, m), 8.30 (1H, s), 8.41 (1H, s), 9.93 (0.314 mL, 2.89 mmol), and the mixture was stirred at 70° C. (1H, s), 10.72 (1H, s) 50 for 14hr. The reaction mixture was cooled, and to the reaction solution was added water, and the mixture was extracted with Example 19 ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated N-(4-cyanophenyl)-3-methyl-N'-(9-propyl-2.3.4.9- under reduced pressure. The obtained residue was purified by tetrahydro-1H-carbazol-6-yl)pentanediamide 55 silica gel column chromatography (solvent gradient; 5 to 55% ethyl acetate/hexane) to give 9-isobutyl-6-nitro-2.3.4.9-tet (Step 1) rahydro-1H-carbazole (296 mg, 1.087 mmol, 94%) as a yel To a solution of 6-nitro-2.3.4.9-tetrahydro-1H-carbazole low powder. (250 mg, 1.16 mmol) and potassium carbonate (479 mg, 3.47 H-NMR (300 MHz, CDC1): 80.93 (6H, d, J=6.8 Hz), mmol) in DMF (8 mL) was added 1-bromopropane (0.263 60 1.77-2.05 (4H, m), 2.05-2.28 (1H, m), 2.62-2.84 (4H, m), mL, 2.89 mmol), and the mixture was stirred at 70° C. for 14 3.83 (2H, d, J=7.6 Hz), 7.14-7.32 (1H, m), 8.03 (1H, dd, hr. The reaction mixture was cooled, and to the reaction J=9.1, 2.3 Hz), 8.41 (1H, d, J=2.3 Hz) solution was added water, and the mixture was extracted with (Step 2) ethyl acetate. The organic layer was washed with water and A solution of the compound obtained in Step 1 (290 mg. saturated brine, and dried, and the solvent was evaporated 65 1.06 mmol) and 10% palladium on carbon (50% wet, 10 mg. under reduced pressure. The obtained residue was purified by 0.09 mmol) in a mixed solvent of methanol (4 mL) and ethyl silica gel column chromatography (solvent gradient; 5 to 55% acetate (4 mL) was stirred at room temperature for 14hr under US 9,120,776 B2 99 100 1 atm of hydrogen atmosphere. The catalyst was removed by (Step 2) filtration, and the filtrate was concentrated under reduced A solution of the compound obtained in Step 1 (1.0g, 2.53 pressure to give 9-isobutyl-2,3,4,9-tetrahydro-1H-carbazol mmol) and 4M hydrogen chloride/ethyl acetate (4 mL, 16.00 6-amine (237 mg, 0.977 mmol. 92%) as a brown oil. mmol) in ethyl acetate (10 mL) was stirred at room tempera MS (API): 243 (M+H) ture for 14hr. The precipitate was collected by filtration, and (Step 3) washed with ethyl acetate to give 4-amino-N-(9-ethyl-9H To a solution of the compound obtained in Step 2 (235 mg. carbazol-3-yl)butanamide hydrochloride (0.622 g, 1.875 0.97 mmol), 5-(4-cyanophenylamino)-3-methyl-5-oxopen mmol. 74.2%) as a white powder. tanoic acid (239 mg, 0.97 mmol) and DIEA (0.508 mL, 2.91 MS (API): 296 (M-HC1+H) mmol) in DMF (6 mL) was added HATU (553 mg, 1.45 10 (Step 3) mmol), and the mixture was stirred at room temperature for To a solution of the compound obtained in Step 2 (150 mg. 14 hr. To the reaction solution was added water, and the 0.45 mmol), 4-cyanobenzoic acid (80 mg. 0.54 mmol) and mixture was extracted with ethyl acetate. The organic layer DIEA (0.395 mL, 2.26 mmol) in DMF (6 mL) was added was washed with water and saturated brine, and dried, and the 15 HATU (258 mg 0.68 mmol), and the mixture was stirred at solvent was evaporated under reduced pressure. The obtained room temperature for 14 hr. To the reaction solution was residue was purified by silica gel column chromatography added water, and the mixture was extracted with ethyl acetate. (solvent gradient; 5 to 75% ethyl acetate/hexane) to give the The organic layer was washed with water and Saturated brine, title compound (242 mg, 0.515 mmol. 53.1%) as a white and dried, and the solvent was evaporated under reduced powder. pressure. The obtained residue was purified by silica gel 'H-NMR (300 MHz, DMSO-d): 80.84 (6H, d, J=6.4 Hz), column chromatography (solvent gradient; 10 to 100% ethyl 1.00 (3H, d. J=6.4 Hz), 1.81 (4H, dt, J=13.3, 6.6 Hz), 1.94 acetate/hexane) to give the title compound (141 mg, 0.332 2.16 (1H, m), 2.16-2.41 (3H, m), 2.41-2.48 (2H, m), 2.53 mmol. 73.5%) as a white powder. 2.75 (4H, m), 3.79 (2H, d, J=7.6 Hz), 7.14 (1H, dd, J=8.7, 1.9 'H-NMR (300 MHz, DMSO-d): 81.30 (3H, t, J–7.0 Hz), Hz), 7.24 (1H, d, J=8.7 Hz), 7.67 (1H, d, J=1.9 Hz), 7.70-7.86 25 1.78–2.00 (2H, m), 2.42 (2H, t, J–7.4 Hz), 3.34-3.47 (2H, m), (4H, m), 9.66 (1H, s), 10.35 (1H, s) 4.41 (2H, q, J=6.9 Hz), 7.17 (1H, t, J=7.2 Hz), 737-748 (1H, m), 7.48-7.65 (3H, m), 7.87-8.11 (5H, m), 8.39 (1H, s), 8.78 Example 21 (1H, t, J=5.5 Hz), 9.92 (1H, s) N'-(4-cyanobenzyl)-N'-(9-ethyl-9H-carbazol-3-yl)- 30 Example 23 2-methylbutanediamide N-(3-(4-cyanophenyl)sulfonyl)amino-2-methyl Using 3-methyldihydrofuran-2,5-dione, and by the reac propyl)-9-ethyl-9H-carbazole-3-carboxamide tion and purification in the same manner as in the method 35 (Step 1) described in Step 1 of Example 3 and Step 2 of Example 1, the To a solution of tert-butyl (3-amino-2-methylpropyl)car title compound was obtained. bamate (200 mg, 1.06 mmol) and TEA (0.444 mL, 3.19 'H-NMR (300 MHz, DMSO-d): 81.08-1.43 (6H, m), mmol) in THF (5 mL) was added 4-cyanobenzene-1-sulfonyl 2.23-2.48 (1H, m), 2.58-2.78 (1H, m), 2.78-3.00 (1H, m), chloride (214 mg, 1.06 mmol), and the mixture was stirred at 4.41 (2H, q, J=6.9 Hz), 7.17 (1H, t, J=7.6 Hz), 7.35-7.65 (4H, 40 room temperature for 16 hr. To the reaction solution was m), 8.05 (1H, d, J=7.9 Hz), 8.33-8.52 (1H, m), 9.95 (1H, s), added water, and the mixture was extracted with ethyl acetate. 12.14 (1H, brs) The organic layer was washed with water and Saturated brine, and dried, and the solvent was evaporated under reduced Example 22 pressure. The obtained residue was purified by silica gel 45 column chromatography (solvent gradient; 10 to 100% ethyl 4-cyano-N-(4-(9-ethyl-9H-carbazol-3-yl)amino-4- acetate/hexane) to give tert-butyl (3-(4-cyanophenylsulfona oxobutylbenzamide mido)-2-methylpropyl)carbamate (273 mg 0.772 mmol. 72.7%) as a white powder. (Step 1) 'H-NMR (300 MHz, DMSO-d): 80.77 (3H, d, J=6.8 Hz), To a solution of 3-amino-9-ethylcarbazole (500 mg, 2.38 50 1.34 (9H, s), 1.53-1.71 (1H, m), 2.52-2.57 (1H, m), 2.64-2.89 mmol), 4-(tert-butoxycarbonylamino)butyric acid (483 mg, (3H, m), 6.78 (1H, t, J=5.8 Hz), 7.84 (1H, s), 7.90-7.97 (2H, 2.38 mmol) and DIEA (1.246 mL, 7.13 mmol) in DMF (12 m), 8.05-8.12 (2H, m) mL) was added HATU (1085 mg, 2.85 mmol), and the mix (Step 2) ture was stirred at room temperature for 3 days. To the reac A solution of the compound obtained in Step 1 (273 mg, tion solution was added water, and the mixture was extracted 55 0.77 mmol) in TFA (1 mL, 12.98 mmol) was stirred at room with ethyl acetate. The organic layer was washed with water temperature for min, and the mixture was concentrated under and Saturated brine, and dried, and the solvent was evaporated reduced pressure. To the residue were added ethyl acetate and under reduced pressure. The obtained residue was purified by 1Naqueous sodium hydroxide solution, and the organic layer silica gel column chromatography (Solvent gradient; 10 to was separated. The organic layer was washed with water and 75% ethyl acetate/hexane) to give crude tert-butyl 4-(9-ethyl 60 saturated brine, and dried, and the solvent was evaporated 9H-carbazol-3-ylamino)-4-oxobutylcarbamate (1080 mg. under reduced pressure to give N-(3-amino-2-methylpropyl)- 2.73 mmol. 1.15%) as a pale-yellow powder. 4-cyanobenzenesulfonamide (128 mg, 0.505 mmol. 65.4%) 'H-NMR (300 MHz, CDC1): 81.29-1.59 (12H, m), 1.92 as a white powder. (2H, quin, J=6.6 Hz), 2.43 (2H, t, J–7.0 Hz), 3.26 (2H, q, 'H-NMR (300 MHz, DMSO-d): 80.77 (3H, d, J=6.4 Hz), J=6.0 Hz), 4.29 (2H, q, J–7.2 Hz), 7.09-7.23 (1H, m), 7.23 65 141-1.55 (1H, m), 2.32-2.45 (2H, m), 2.61 (1H, dd, J=12.5, 7.50 (3H, m), 7.55 (1H, d, J=7.9 Hz), 7.94-8.08 (2H, m), 8.37 6.8 Hz), 2.74-2.84 (1H, m), 3.59 (3H, brs), 7.91-7.98 (2H, m), (1H, s), 8.77 (1H, brs) 8.05-8.12 (2H, m) US 9,120,776 B2 101 102 (Step 3) Example 25 A solution of the compound obtained in Step 2 (65.7 mg, N-(3-chloro-4-cyanophenyl)-N'-(9-ethyl-9H-carba 0.26 mmol), 9-ethyl-9H-carbazole-3-carboxylic acid (62.1 Zol-3-yl)-3-methylpentanediamide (Optically Active mg, 0.26 mmol), HATU (128 mg, 0.34 mmol) and TEA Form Having a Shorter Retention Time) (0.108 mL, 0.78 mmol) in DMF (1.25 mL) was stirred at room temperature for 16 hr. To the reaction solution was added Example 26 water, and the mixture was extracted with ethyl acetate. The N-(3-chloro-4-cyanophenyl)-N'-(9-ethyl-9H-carba organic layer was washed with water and Saturated brine, and 10 dried, and the solvent was evaporated under reduced pressure. Zol-3-yl)-3-methylpentanediamide (Optically Active The obtained residue was purified by silica gel column chro Form Having a Longer Retention Time) matography (solvent gradient; 10 to 50% ethyl acetate/hex N-(3-Chloro-4-cyanophenyl)-N'-(9-ethyl-9H-carbazol-3- ane) to give the title compound (81 mg, 0.170 mmol. 65.7%) 15 yl)-3-methylpentanediamide (0.500 g) was subjected to opti as a white powder. cal resolution by chiral column chromatography. The pre parative fraction having a shorter retention time was H-NMR (300 MHz, DMSO-d): 80.89 (3H, d, J=6.4 Hz), concentrated to give the title compound (0.195 g) of Example 1.33 (3H, t, J=7.2 Hz), 1.81-1.98 (1H, m), 2.60-2.74 (1H, m), 25, and the preparative fraction having alonger retention time 2.79-2.91 (1H, m), 3.10-3.26 (2H, m), 4.48 (2H, q, J–6.9 Hz), was concentrated to give the title compound (0.203 g) of 7.27 (1H, t, J=7.2 Hz), 7.45-7.55 (1H, m), 7.66 (2H, d, J=8.7 Example 26, each as a white powder. Hz), 7.86-8.07 (6H, m), 8.18 (1H, d, J–7.6 Hz), 8.40 (1H, t, purification condition by chiral column chromatography J=5.7 Hz), 8.65 (1H, d, J=1.5 Hz) column: CHIRALPAKAD 50 mm IDX500 mL. solvent: hexane/ethanol=500/500 (v/v) 25 flow rate: 80 mL/min Example 24 temperature: 40°C. detection: UV 220 mm 2-(2-(4-cyanophenyl)amino)-2-oxoethylsulfanyl)- The Title Compound of Example 25 N-(9-ethyl-9H-carbazol-3-yl)acetamide optical purity: >99.9% ee, chemical purity: >99.9% 30 MS (API): 473 (M+H) The Title Compound of Example 26 (Step 1) optical purity: >99.9% ee, chemical purity: >99.9% A solution of 4-aminobenzonitrile (500 mg, 4.23 mmol), MS (API): 473 (M+H) 2,2'-thiodiacetic acid (3.18 g. 21.2 mmol), WSC (4.87 g. 25.4 mmol), DMAP (258 mg 0.21 mmol) and DIEA (5.47g, 42.3 35 Example 27 mmol) in THF (200 mL) was stirred at room temperature for 5-(3-chloro-4-cyanophenoxy)-N-(9-ethyl-9H-carba 60 hr. To the reaction solution was added water, and the Zol-3-yl)pentanamide mixture was extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid, and dried, and the 40 (Step 1) To a solution of 9-ethyl-9H-carbazol-3-amine (300 mg. solvent was evaporated under reduced pressure. The obtained 1.43 mmol) in toluene (4 mL) was added trimethylaluminium residue was purified by preparative HPLC to give 2-((2-((4- (1.8M in toluene solution, 1.189 mL, 2.14 mmol), and the cyanophenyl)amino)-2-oxoethyl)thio)acetic acid (162 mg, mixture was stirred at room temperature for 30 min. To the 15.3%) as a pale-yellow powder. 45 reaction mixture was added a solution of Ö-Valerolactone (0.129 mL, 1.43 mmol) in toluene (4 mL) at room tempera 'H-NMR (300 MHz, DMSO-d): 83.42 (2H, s), 3.47 (2H, ture, and the mixture was stirred at 80° C. for 4 hr. The s), 7.75 (2H, d, J=9.0 Hz), 7.78 (2H, d, J=9.0 Hz), 10.53 (1H, reaction mixture was cooled to 0°C., neutralized with 1N s), 12.64 (1H, s) hydrochloric acid, and extracted with ethyl acetate. The (Step 2) 50 organic layer was washed with water and Saturated brine, and dried, and the solvent was evaporated under reduced pressure A solution of the compound obtained in Step 1 (145 mg. to give N-(9-ethyl-9H-carbazol-3-yl)-5-hydroxypentana 0.58 mmol), 9-ethyl-9H-carbazol-3-amine (122 mg, 0.58 mide (420 mg, 1.352 mmol. 95%) as a pale-yellow powder. mmol), HATU (330 mg. 0.87 mmol) and DIEA (225 mg, 1.74 MS (API): 311 (M+H) mmol) in DMF (4 mL) was stirred at room temperature for 16 55 (Step 2) hr. To the reaction solution was added dilute hydrochloric To a solution of the compound obtained in Step 1 (150 mg. acid, and the mixture was extracted with ethyl acetate. The 0.48 mmol) and 2-chloro-4-fluorobenzonitrile (75 mg, 0.48 organic layer was washed with dilute hydrochloric acid, and mmol) in THF (6 mL) was added potassium t-butoxide (136 dried, and the solvent was evaporated under reduced pressure. mg, 1.21 mmol), and the mixture was stirred at room tem The obtained residue was purified by silica gel column chro 60 perature for 3 days. Water was poured into the reaction mix matography to give the title compound (150 mg, 0.339 mmol. ture, and the mixture was extracted with ethyl acetate. The 59%) as a white powder. organic layer was washed with water and Saturated brine, and 'H-NMR (300 MHz, DMSO-d): 81.30 (3H, t, J=7.2 Hz), dried, and the solvent was evaporated under reduced pressure. 3.53 (2H, s), 3.60 (2H, s), 4.41 (2H, q, J–7.2 Hz), 7.15-7.20 The obtained residue was purified by silica gel column chro (1H, m), 7.42-7.47 (1H, m), 7.53-7.60 (3H, m), 7.73-7.80 65 matography (solvent gradient; 5 to 85% ethyl acetate/hexane) (4H, m), 8.01 (1H, d. J=7.5 Hz), 8.37 (1H, t like), 10.13 (1H, to give the title compound (79 mg, 0.178 mmol. 36.8%) as a s), 10.59 (1H, s) white powder. US 9,120,776 B2 103 104 'H-NMR (300 MHz, CDC1): 81.42 (3H, t, J=7.2 Hz), Example 29 1.86-2.06 (4H, m), 2.42-2.59 (2H, m), 4.07 (2H, s), 4.35 (2H, q, J=7.1 Hz), 6.85 (1H, dd, J=8.7, 2.3 Hz), 7.01 (1H, d, J–2.6 4-cyano-N-(4-(9-ethyl-9H-carbazol-3-yl)amino-4- Hz), 7.14-7.26 (2H, m), 7.29-7.61 (5H, m), 8.06 (1H, d. J–7.6 oxobutyl-N-(3-methoxypropyl)benzamide Hz), 8.30 (1H, d, J=1.9 Hz) (Step 1) Example 28 Using ethyl 4-(4-cyanobenzamido)butanoate and 1-bromo-3-methoxypropane, and by the reaction and purifi cation in the same manner as in the method described in Step 4-cyano-N-ethyl-N-(4-(9-ethyl-9H-carbazol-3-yl) 10 2 of Example 28, 4-(4-cyano-N-(3-methoxypropyl)benza aminol-4-oxobutylbenzamide mido)butanoic acid was obtained. MS (API): 303 (M-H) (Step 1) (Step 2) 15 Using the compound obtained in Step 1, and by the reaction To a solution of 4-cyanobenzoic acid (2.0 g, 13.59 mmol), and purification in the same manner as in the method ethyl 4-aminobutyrate hydrochloride (2.507 g. 14.95 mmol), described in Step 3 of Example 28, the title compound was HOBt (0.918 g. 6.80 mmol) and TEA (6.63 mL, 47.58 mmol) obtained. in DMF (20 mL) was added WSC (3.26g, 16.99 mmol), and 'H-NMR (300 MHz, CDC1): 81.40 (3H, t, J=7.0 Hz), the mixture was stirred at room temperature for 14hr. Water 1.66-1.86 (2H, m), 1.97 (1H, brs), 2.08-2.20 (1H, m), 2.24 was poured into the reaction mixture, and the mixture was (1H, brs), 2.52(1H, t, J=6.2 Hz), 3.04-3.27 (4H, m), 3.27-3.42 extracted with ethyl acetate. The organic layer was washed (2H, m), 3.49 (1H, brs), 3.56-3.82 (2H, m), 4.33 (2H, q, J–7.2 with water and saturated brine, and dried, and the solvent was Hz), 7.16-7.56 (7H, m), 7.61 (2H, d, J=7.9 Hz), 8.03 (1H, d, evaporated under reduced pressure. The obtained residue was J=7.9 Hz), 8.37 (1H, s), 8.49 (1H, brs) purified by Silica gel column chromatography (solvent gradi 25 ent; 5 to 75% ethyl acetate/hexane) to give ethyl 4-(4-cy Example 30 anobenzamido)butanoate (1.558 g. 5.99 mmol. 44.0%) as a white powder. 5-(3-chloro-4-cyanophenoxy)-N-(9-ethyl-9H-carba 'H-NMR (300 MHz, CDC1): 81.25 (3H, t, J=7.0Hz), 1.98 Zol-3-yl)-3-hydroxy-3-methylpentanamide (2H, quin, J–6.6 Hz), 2.48 (2H, t, J–6.6 Hz), 3.42-3.62 (2H, 30 (Step 1) m), 4.14 (2H, q, J–7.2 Hz), 6.96 (1H, brs), 7.68-7.81 (2H, m), To a solution of 9-ethyl-9H-carbazol-3-amine (300 mg, 7.85-7.97 (2H, m) 1.43 mmol) in toluene (4 mL) was added trimethylaluminium (Step 2) (1.8M in toluene solution, 1.189 mL, 2.14 mmol), and the To a solution of the compound obtained in Step 1 (200 mg. 35 mixture was stirred at room temperature for 30 min. To the 0.77 mmol) in DMF (4 mL) were added sodium hydride (50% reaction mixture was added a solution of 4-hydroxy-4-meth oil, 111 mg, 2.31 mmol) and ethyl iodide (0.093 mL, 1.15 yltetrahydro-2H-pyran-2-one (186 mg, 1.43 mmol) in tolu mmol) at room temperature, and the mixture was stirred at ene (4 mL) at room temperature, and the mixture was stirred 60° C. for 14 hr. To the reaction solution was added 1N at 80° C. for 4 hr. The reaction mixture was cooled to 0°C., aqueous Sodium hydroxide solution (3 mL, 3.00 mmol), and 40 neutralized with 1N hydrochloric acid, and extracted with the mixture was stirred at 60° C. for additional 2 hr. The ethyl acetate. The organic layer was washed with water and reaction solution was cooled, and neutralized with 1N hydro saturated brine, and dried, and the solvent was evaporated chloric acid. The reaction mixture was extracted with ethyl under reduced pressure. The obtained residue was purified by acetate. The organic layer was washed with water and Satu silica gel column chromatography (Solvent gradient; 10 to rated brine, and dried, and the solvent was evaporated under 45 100% ethyl acetate/hexane) to give N-(9-ethyl-9H-carbazol reduced pressure to give 4-(4-cyano-N-ethylbenzamido)bu 3-yl)-3,5-dihydroxy-3-methylpentanamide (359 mg, 1.056 tanoic acid (0.23g, 0.76 mmol. 98.7%) as a crude product. mmol. 74.0%) as a colorless oil. (Step 3) 'H-NMR (300 MHz, CDC1): 81.33-1.53 (6H, m), 1.71 2.01 (2H, m), 2.49 (1H, d. J=14.7 Hz), 2.73 (1H, d. J=14.3 To a solution of the compound obtained in Step 1 (0.23 g, 50 Hz), 2.83-3.03 (1H, m), 3.81-4.06 (2H, m), 4.33 (2H, q, J–7.2 0.76 mmol), 3-amino-N-ethylcarbazole (159 mg, 0.76 mmol) Hz), 4.90 (1H, s), 7.16-7.55 (5H, m), 7.97-8.12 (1H, m), 8.27 and DIEA (0.396 mL, 2.27 mmol) in DMF (6 mL) was added (1H, d, J=1.9 Hz), 8.36 (1H, s) HATU (359 mg, 0.94 mmol), and the mixture was stirred at (Step 2) room temperature for 14hr. Water was poured into the reac To a solution of the compound obtained in Step 1 (348 mg, tion mixture, and the mixture was extracted with ethyl 55 1.02 mmol) and 2-chloro-4-fluorobenzonitrile (159 mg, 1.02 acetate. The organic layer was washed with water and Satu mmol) in THF (10 mL) was added potassium t-butoxide (287 rated brine, and dried, and the solvent was evaporated under mg, 2.56 mmol), and the mixture was stirred at room tem reduced pressure. The obtained residue was purified by silica perature for 14hr. Water was poured into the reaction mixture, gel column chromatography (solvent gradient; 10 to 100% and the mixture was extracted with ethyl acetate. The organic ethyl acetate/hexane) to give the title compound (43.4 mg. 60 layer was washed with water and saturated brine, and dried, 0.087 mmol, 11.56%) as a white powder. and the solvent was evaporated under reduced pressure. The 'H-NMR (300 MHz, CDC1): 81.40 (3H, t, J–7.0 Hz), obtained residue was purified by silica gel column chroma 1.66-1.86 (2H, m), 1.97 (1H, brs), 2.08-2.20 (1H, m), 2.24 tography (solvent gradient; 10 to 100% ethyl acetate/hexane) (1H, brs), 2.52(1H, t, J=6.2 Hz), 3.04-3.27 (4H, m), 3.27-3.42 to give the title compound (236 mg, 0.496 mmol. 48.5%) as a (2H, m), 3.49 (1H, brs), 3.56-3.82 (2H, m), 4.33 (2H, q, J–7.2 65 white powder. Hz), 7.16-7.56 (7H, m), 7.61 (2H, d, J–7.9 Hz), 8.03 (1H, d, H-NMR (300 MHz, CDC1): 81.30-1.54 (6H, m), 1.85 J=7.9 Hz), 8.37 (1H, s), 8.49 (1H, brs) 2.24 (2H, m), 2.45-2.78 (2H, m), 4.03-4.43 (4H, m), 4.64 (1H, US 9,120,776 B2 105 106 s), 6.83 (1H, dd, J=8.9, 2.5 Hz), 7.00 (1H, d. J=2.3 Hz), The organic layer was dried, and the solvent was evaporated 7.17-7.55 (6H, m), 7.77-7.95 (1H, m), 7.96-8.10 (1H, m), under reduced pressure. The obtained residue was purified by 8.24 (1H, d. J=1.9 Hz) silica gel column chromatography (Solvent gradient; 20 to 100% ethyl acetate/hexane) to give the title compound (200 Example 31 mg, 0.456 mmol, 50.0%) as a white powder. 2-(2-(4-cyanophenyl)amino)-2-oxoethylsulfonyl)- 'H-NMR (300 MHz, DMSO-d): 80.95 (3H, d, J=6.8 Hz N-(9-ethyl-9H-carbazol-3-yl)acetamide 1.33 (3H, t, J–7.2 Hz), 2.02-2.16 (1H, m), 3.19-3.37 (3H, m), 4.48 (2H, q, J=6.9 Hz), 7.26 (1H, t, J=7.2 Hz), 7.46-7.55 (1H, To a solution of 2-(2-(4-cyanophenyl)amino-2- 10 m), 7.66 (2H, d. J=8.7 Hz), 7.92-8.06 (5H, m), 8.18 (1H, d, oxoethylsulfanyl)-N-(9-ethyl-9H-carbazol-3-yl)acetamide J=7.5 Hz), 8.50 (1H, t, J=5.8 Hz), 8.70 (1H, d, J=1.5 Hz), 8.79 (60 mg, 0.14 mmol) in DMF (1.5 mL) was added mOPBA (1H, t, J=5.8 Hz) (73.5 mg, 0.30 mmol), and the mixture was stirred at room temperature for 3 hr. Aqueous Sodium thiosulfate Solution Example 33 was poured into the reaction mixture, and the mixture was 15 extracted with ethyl acetate. The organic layer was washed with aqueous sodium carbonate Solution, and dried, and the N-3-(4-cyanobenzyl)amino-2-methyl-3-oxopro solvent was evaporated under reduced pressure. The obtained pyl-9-ethyl-9H-carbazole-3-carboxamide residue was purified by silica gel column chromatography to give the title compound (42 mg, 0.088 mmol. 65%) as a pale-yellow powder. (Step 1) 'H-NMR (300 MHz, CDC1): 81.31 (3H, t, J=7.2 Hz), 4.43 A solution of 3-((tert-butoxycarbonyl)amino)-2-methyl (2H, q, J–7.2 Hz), 4.51 (2H, s), 4.60 (2H, s), 7.17-7.22 (1H, propanoic acid (200 mg. 0.98 mmol), 4-(aminomethyl)ben m), 743-749 (1H, m), 7.53-7.62 (3H, m), 7.77-7.85 (4H, m), Zonitrile (130 mg. 0.98 mmol), HATU (486 mg, 1.28 mmol) 8.09 (1H, d, J=7.8 Hz), 8.44 (1H, d, J=1.8 Hz), 10.52 (1H, s), 25 and TEA (0.411 mL, 2.95 mmol) in DMF (5 mL) was stirred 10.92 (1H, s) at room temperature for 16 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl Example 32 acetate. The organic layer was dried, and the solvent was evaporated under reduced pressure. The obtained residue was N-(3-(4-cyanophenyl)carbonyl)amino-2-methyl 30 purified by silica gel column chromatography (solvent gradi propyl)-9-ethyl-9H-carbazole-3-carboxamide ent; 20 to 67% ethyl acetate/hexane) to give tert-butyl (3-((4- cyanobenzyl)amino)-2-methyl-3-oxopropyl)carbamate (221 (Step 1) A solution of tert-butyl (3-amino-2-methylpropyl)carbam mg, 0.696 mmol, 70.8%) as a white powder. ate (200 mg, 1.06 mmol), 4-cyanobenzoic acid (156 mg, 1.06 35 'H-NMR (300 MHz, DMSO-d): 81.00 (3H, d, J=7.2 Hz), mmol), HATU (525 mg, 1.38 mmol) and TEA (0.444 mL, 1.37 (9H, s), 2.90 (1H, dt, J=13.2, 6.6Hz), 3.03-3.16 (1H, m), 3.19 mmol) in DMF (5 mL) was stirred at room temperature 4.23-4.42 (2H, m), 6.77 (1H, t, J=5.5 Hz), 7.42 (2H, d, J–8.3 for 16 hr. Water was poured into the reaction mixture, and the Hz), 7.72-7.82 (2H, m), 8.44 (1H, t, J–6.0 Hz) mixture was extracted with ethyl acetate. The organic layer (Step 2) was dried, and the solvent was evaporated under reduced 40 pressure. The obtained residue was purified by silica gel A solution of the compound obtained in Step 1 (221 mg. column chromatography (solvent gradient; 10 to 50% ethyl 0.70 mmol) in TFA (1 mL, 12.98 mmol) was stirred at room acetate/hexane) to give tert-butyl (3-(4-cyanobenzamido)-2- temperature for 15 min, and concentrated under reduced pres methylpropyl)carbamate (311 mg, 0.980 mmol, 92%) as a sure. To the residue were added ethyl acetate and 1 Naqueous white powder. 45 Sodium hydroxide Solution, and the organic layer was sepa 'H-NMR (300 MHz, CDC1): 80.83 (3H, d, J=6.8 Hz), rated. The organic layer was washed with water and Saturated 1.37 (9H, s), 1.74-193 (1H, m), 2.76-3.00 (2H, m), 3.05-3.25 brine, and dried, and the solvent was evaporated under (2H, m), 6.82 (1H, t, J=5.7 Hz), 7.93-8.02 (4H, m), 8.65 (1H, reduced pressure to give 3-amino-N-(4-cyanobenzyl)-2-me t, J=5.5 Hz) thylpropanamide (112 mg, 0.515 mmol. 74.0%) as a white (Step 2) 50 powder. A solution of the compound obtained in Step 1 (311 mg, (Step 3) 0.98 mmol) in TFA (1 mL, 12.98 mmol) was stirred at room temperature for 15 min, and concentrated under reduced pres A solution (2.5 mL) of the compound obtained in Step 2 sure. To the residue were added ethyl acetate and 1N aqueous (112 mg, 0.52 mmol), 9-ethyl-9H-carbazole-3-carboxylic Sodium hydroxide Solution, and the organic layer was sepa 55 acid (123 mg, 0.52 mmol), HATU (255 mg 0.67 mmol) and rated. The organic layer was washed with water and Saturated TEA (0.216 mL, 1.55 mmol) in DMF was stirred at room brine, and dried, and the solvent was evaporated under temperature for 16 hr. Water was poured into the reaction reduced pressure to give N-(3-amino-2-methylpropyl)-4-cy mixture, and the mixture was extracted with ethyl acetate. anobenzamide (198 mg, 0.911 mmol. 93%) as a white pow The organic layer was dried, and the solvent was evaporated der. 60 under reduced pressure. The obtained residue was purified by (Step 3) silica gel column chromatography (solvent; ethyl acetate) to A solution of the compound obtained in Step 2 (198 mg, give the title compound (158 mg, 0.360 mmol. 69.9%) as a 0.91 mmol), 9-ethyl-9H-carbazole-3-carboxylic acid (218 white powder. mg, 0.91 mmol), HATU (450 mg, 1.18 mmol) and TEA 'H-NMR (300 MHz, DMSO-d): 81.11 (3H, d, J=6.8 Hz), (0.381 mL, 2.73 mmol) in DMF (4.5 mL) was stirred at room 65 1.34 (3H, t, J–7.2 Hz), 2.75-2.89 (1H, m), 3.33-3.49 (2H, m), temperature for 16 hr. Water was poured into the reaction 4.19-4.32 (1H, m), 4.39-4.56 (3H, m), 7.26 (1H, t, J–7.3 Hz), mixture, and the mixture was extracted with ethyl acetate. 7.38 (2H, d, J=8.7 Hz), 7.46-7.60 (3H, m), 7.66 (2H, d, J=8.3 US 9,120,776 B2 107 108 Hz), 7.99 (1H, dd, J=8.7, 1.5 Hz), 8.15 (1H, d, J=7.9 Hz), 8.51 added water, and the mixture was extracted with ethyl acetate. (2H, q, J=5.8 Hz), 8.71 (1H, d, J=1.5 Hz) The organic layer was washed with water and Saturated brine, and dried, and the solvent was evaporated under reduced Example 34 pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10 to 60% ethyl 2-((2-((4-cyanophenyl)amino)-2-oxoethyl)sulfinyl)- acetate/hexane), and crystallized from ethyl acetate and hex N-(9-ethyl-9H-carbazol-3-yl)acetamide ane to give tert-butyl (1-(((9-ethyl-9H-carbazol-3-yl)methyl) amino)-1-oxopropan-2-yl)carbamate (324 mg. 0.819 mmol. To a solution of 2-(2-(4-cyanophenyl)amino-2- 78%) as a white powder. oxoethylsulfanyl)-N-(9-ethyl-9H-carbazol-3-yl)acetamide 10 'H-NMR (300 MHz, DMSO-d): 81.19-143 (15H, m), (55 mg, 0.12 mmol) in a mixed solvent of acetonitrile (4 mL) 3.95-4.09(1H, m), 4.35-4.50 (4H, m), 6.93 (1H, d. J–7.6 Hz), and water (2 mL) was added sodium periodate (29.2 mg, 0.14 mmol), and the mixture was stirred at room temperature for 7.12-7.21 (1H, m), 7.35 (1H, d, J=9.1 Hz), 7.43 (1H, td, J=7.7, 18 days. Aqueous sodium thiosulfate Solution was poured 1.1 Hz), 7.56 (2H, dd, J=13.2, 8.3 Hz), 8.03 (1H, s), 8.11 (1H, into the reaction mixture, and the mixture was extracted with 15 d, J=7.6 Hz), 8.27 (1H, t, J=5.7 Hz). ethyl acetate. The organic layer was washed with aqueous (Step 2) Sodium carbonate Solution, and dried, and the solvent was A solution of the compound obtained in Step 1 (324 mg. evaporated under reduced pressure. The obtained residue was 0.82 mmol) in TFA (1 mL, 12.98 mmol) was stirred at room purified by preparative HPLC to give the title compound (13 temperature for 15 min, and concentrated under reduced pres mg, 0.028 mmol, 23%) as a pale-yellow powder. sure. To the residue were added ethyl acetate and 1 Naqueous 'H-NMR (300 MHz, DMSO-d): 81.31 (3H, t, J=6.9 Hz), Sodium hydroxide Solution, and the organic layer was sepa 4.01 (2H, t, J=13.8 Hz), 4.19 (2H, t, J=13.8 Hz), 4.43 (2H, q, rated. The organic layer was washed with water and Saturated J=6.9 Hz), 7.19 (1H, t, J=7.8 Hz), 7.46 (1H, t, J–7.5 Hz), brine, and dried, and the solvent was evaporated under 7.55-7.61 (3H, m), 7.81 (4H, s), 8.07 (1H, d, J=7.5 Hz), 8.45 reduced pressure to give 2-amino-N-((9-ethyl-9H-carbazol (1H, s), 10.43 (1H, s), 10.85 (1H, s) 25 3-yl)methyl)propanamide (242 mg, 0.819 mmol. 100%) as a white powder. Example 35 'H-NMR (300 MHz, DMSO-d): 81.11-1.21 (3H, m), 1.22-1.33 (3H, m), 1.81-2.14 (2H, m), 3.19-3.42 (1H, m), 2-((2-((4-cyanophenyl)amino)-2-oxoethyl)(methyl) 4.29-4.51 (4H, m), 7.05-7.25 (1H, m), 7.30-7.63 (4H, m), amino)-N-(9-ethyl-9H-carbazol-3-yl)acetamide 30 7.93-8.16 (2H, m), 8.22-8.35 (1H, m). (Step 3) (Step 1) A solution of the compound obtained in Step 2 (242 mg, A mixture of 2,2'-(methylazanediyl)diacetic acid (500 mg. 0.82 mmol), 2-(4-cyanophenyl)acetic acid (198 mg, 1.23 3.40 mmol) and acetic anhydride (5 mL) was stirred at 165° mmol), HATU (46.8 mg, 1.23 mmol) and TEA (0.343 mL, C. for 30 min. The reaction mixture was concentrated under 35 2.46 mmol) in DMF (3 mL) was stirred at room temperature reduced pressure to give 4-methylmorpholine-2,6-dione as a for 16 hr. To the reaction solution was added dilute hydro crude product. The obtained crude product was dissolved in chloric acid, and the mixture was extracted with ethyl acetate. THF (10 mL), and p-aminobenzonitrile (401 mg, 3.40 mmol) The organic layer was washed with dilute hydrochloric acid, was added thereto. The mixture was heated with reflux for 22 and dried, and the solvent was evaporated under reduced hr, and concentrated under reduced pressure to give 2-((2-((4- 40 pressure. The obtained residue was purified by silica gel cyanophenyl)amino)-2-oxoethyl)(methyl)amino)acetic acid column chromatography (solvent: ethyl acetate) to give the (467 mg, 56%) as a pale-brown powder. title compound (50.3 mg 0.115 mmol, 14%) as a white pow H-NMR (300 MHz, DMSO-d): 82.42 (3H, s), 3.41 (4H, der. s), 7.76-7.85 (4H, m), 10.30 (1H, s) 'H-NMR (300 MHz, DMSO-d): 81.23-1.40 (6H, m), 3.61 (Step 2) 45 (2H, s), 4.24-4.52 (5H, m), 7.11-7.21 (1H, m), 7.33 (1H, dd, Using the compound obtained in Step 1 and 9-ethyl-9H J=8.3, 1.5 Hz), 7.39-7.61 (5H, m), 7.67-7.75 (2H, m), 7.97 carbazol-3-amine, and by the reaction and purification in the 8.10 (2H, m), 8.37-8.51 (2H, m). same manner as in the method described in Step 2 of Example 3, the title compound was obtained. Example 37 H-NMR (300 MHz, DMSO-d): 81.31 (3H, t, J=7.2 Hz), 50 2.49 (3H, s), 3.43 (2H, s), 3.48 (2H, s), 4.42 (2H, q, J–7.2 Hz), 4-cyano-N-(3-(9-ethyl-9H-carbazol-3-yl)methyl 7.19 (1H, t, J=7.5 Hz), 7.42-7.48 (1H, m), 7.56-7.67 (3H, m), amino-2-methyl-3-oxopropyl)benzamide 7.81 (2H, d, J=8.7 Hz), 7.91 (2H, d, J–8.7 Hz), 8.07 (1H, d, J=7.8 Hz), 8.44 (1H, d, J=2.1 Hz), 10.07 (1H, s), 10.55 (1H, (Step 1) s) 55 Using 3-((tert-butoxycarbonyl)amino)-2-methylpro panoic acid and (9-ethyl-9H-carbazol-3-yl)methanamine, Example 36 and by the reaction and purification in the same manner as in the method described in Step 1 of Example 36, tert-butyl N-(4-cyanophenyl)acetyl-N-(9-ethyl-9H-carba (3-(((9-ethyl-9H-carbazol-3-yl)methyl)amino)-2-methyl-3- Zol-3-yl)methylalanine amide 60 Oxopropyl)carbamate was obtained. 'H-NMR (300 MHz, DMSO-d): 81.02 (3H, d, J=6.8 Hz), (Step 1) 1.29 (3H, t, J–7.0 Hz), 1.36 (9H, s), 2.53-2.58 (1H, m), A solution of 2-((tert-butoxycarbonyl)amino)propanoic 2.90-2.99 (1H, m), 3.14 (1H, dt, J=13.0, 6.3 Hz), 4.33-4.51 acid (200 mg, 1.06 mmol), (9-ethyl-9H-carbazol-3-yl)metha (4H, m), 6.75 (1H, t, J=5.5 Hz), 7.14-7.22 (1H, m), 7.36 (1H, namine (237 mg, 1.06 mmol), HATU (522 mg, 1.37 mmol) 65 dd, J=8.5, 1.7 Hz), 7.44 (1H, ddd, J=8.3, 7.2, 1.1 Hz), 7.56 and TEA (0.442 mL, 3.17 mmol) in DMF (5 mL) was stirred (2H, dd, J=12.1, 8.3 Hz), 8.00 (1H, d. J–0.8 Hz), 8.11 (1H, d, at room temperature for 16 hr. To the reaction mixture was J=7.6 Hz), 8.34 (1H, t, J=5.7 Hz). US 9,120,776 B2 109 110 (Step 2) stirred for 14hr. To the reaction mixture was added water, and Using the compound obtained in Step 1, and by the reaction the mixture was extracted with ethyl acetate. The organic and purification in the same manner as in the method layer was washed with water and saturated brine, and dried, described in Step 2 of Example 36, 3-amino-N-((9-ethyl-9H and the solvent was evaporated under reduced pressure. The carbazol-3-yl)methyl)-2-methylpropanamide was obtained. obtained residue was purified by silica gel column chroma 'H-NMR (300 MHz, DMSO-d): 81.02 (3H, d, J=6.8 Hz), tography (solvent gradient; 5 to 75% ethyl acetate/hexane) to 1.25-1.32 (3H, m), 1.47-1.89 (1H, m), 2.25-2.40 (1H, m), give the title compound (458 mg, 0.996 mmol. 64.6%) as a 2.53-2.60 (1H, m), 2.67-2.77 (1H, m), 4.32-4.52 (4H, m), colorless powder. 7.12-7.22 (1H, m), 7.29-7.64 (4H, m), 7.94-8.14 (2H, m), 'H-NMR (300 MHz, DMSO-d): 81.03 (3H, d, J=6.0 Hz), 8.32-8.47 (1H, m). 10 1.20-1.42 (3H, m), 1.56-1.79 (1H, m), 1.79-2.00 (1H, m), (Step 3) 2.14-2.33 (2H, m), 2.33-2.48 (1H, m), 4.04-4.31 (2H, m), Using the compound obtained in Step 2 and 4-cyanoben 4.41 (2H, q, J=6.9 Hz), 7.00-7.26 (2H, m), 7.35 (1H, d. J–2.3 Zoic acid, and by the reaction and purification in the same Hz), 7.38-749 (1H, m), 7.49-7.66(3H, m), 7.85 (1H, d, J=8.7 manner as in the method described in Step 3 of Example 36, Hz), 8.04 (1H, d, J–7.9 Hz), 8.40 (1H, s), 9.91 (1H, s). the title compound was obtained. 15 'H-NMR (300 MHz, DMSO-d): 81.09 (3H, d, J=6.8 Hz), Example 39 1.27 (3H, t, J–7.0 Hz), 2.67-2.81 (1H, m), 3.32-3.46 (2H, m), 4.28 (1H, dd, J=14.7, 4.9 Hz), 4.40 (2H, q, J–7.2 Hz), 4.58 N-(3-chloro-4-cyanophenyl)-N'-(9-ethyl-9H-carba (1H, dd, J=14.7, 6.8 Hz), 7.12-7.20 (1H, m), 7.27-7.33 (1H, Zol-3-yl)-3-phenylpentanediamide m), 7.36-7.47 (2H, m), 7.58 (1H, d, J=8.3 Hz), 7.77-7.84 (2H, m), 7.88-8.04 (4H, m), 8.41 (1H, t, J=5.9 Hz), 8.79 (1H, t, (Step 1) J=5.5 Hz). A solution of 3-phenylpentanedicarboxylic acid (1.0 g, 4.80 mmol) in acetic anhydride (0.453 mL, 4.80 mmol) was Example 38 stirred at 100° C. for 14hr. The reaction mixture was concen 25 trated, to the residue was added toluene (10 mL), and 5-(3-chloro-4-cyanophenoxy)-N-(9-ethyl-9H-carba 4-amino-2-chlorobenzonitrile (0.733 g, 4.80 mmol) and TEA Zol-3-yl)-3-methylpentanamide (0.669 mL, 4.80 mmol) were added thereto. The mixture was stirred at 80° C. for 3 hr, brine was added thereto at room (Step 1) temperature, and the mixture was extracted with ethylacetate. To a solution of 9-ethyl-9H-carbazol-3-amine (4.21 g, 20 30 The organic layer was washed with water and Saturated brine, mmol) in THF (40 mL) was added 3-methylglutaric anhy and dried, and the solvent was evaporated under reduced dride (2.56g, 20.00 mmol), and the mixture was stirred at 90° pressure. The obtained residue was purified by silica gel C. for 4 hr. To the reaction mixture was added water, and the column chromatography (solvent gradient; 10 to 100% ethyl mixture was extracted with ethyl acetate. The organic layer acetate/hexane) to give 5-((3-chloro-4-cyanophenyl)amino)- was washed with water and saturated brine, and dried, and the 35 5-oxo-3-phenylpentanoic acid (1.200 g, 3.50 mmol, 72.9%) solvent was evaporated under reduced pressure to give 5-(9- as a pale-yellow powder. ethyl-9H-carbazol-3-ylamino)-3-methyl-5-oxopentanoic MS (API): 341 (M-H) acid (6.23g, 18.41 mmol, 92%) as a white powder. (Step 2) 'H-NMR (300 MHz, DMSO-d): 81.00 (3H, d, J=6.1 Hz), A solution of the compound obtained in Step 1 (1.2g, 3.50 1.30 (3H, t, J–7.0 Hz), 2.07-2.32 (2H, m), 2.32-2.46 (3H, m), 40 mmol), 9-ethyl-9H-carbazol-3-ylamine (0.736 g, 3.50 4.41 (2H, q, J=6.9 Hz), 7.17 (1H, t, J–74 Hz), 7.43 (1H, t, mmol), HATU (1.464 g, 3.85 mmol) and TEA (0.537 mL, J=7.6 Hz), 7.49-7.63 (3H, m), 8.05 (1H, d, J=8.0 Hz), 8.41 3.85 mmol) in DMF (10 mL) was stirred at room temperature (1H, s), 9.91 (1H, s), 12.09 (1H, brs) for 3 hr. To the reaction mixture was added brine at room (Step 2) temperature, and the mixture was extracted with ethylacetate. To a solution of the compound obtained in Step 1 (1.0 g, 45 The organic layer was washed with water and Saturated brine, 2.96 mmol) in THF (10 mL) was added a THF (5.91 mL, 5.91 and dried, and the solvent was evaporated under reduced mmol) solution of 1M borane-tetrahydrofuran complex at pressure. The obtained residue was purified by silica gel room temperature, and the mixture was stirred for 14 hr. To column chromatography (solvent gradient; 10 to 50% ethyl the reaction mixture was added water, and the mixture was acetate/hexane), and crystallized from ethyl acetate to give extracted with ethyl acetate. The organic layer was washed 50 the title compound (0.187 g., 0.350 mmol, 9.98%) as white with water and saturated brine, and dried, and the solvent was crystals. evaporated under reduced pressure. The obtained residue was 'H-NMR (300 MHz, DMSO-d): 81.28 (3H, t, J=7.2 Hz), purified by Silica gel column chromatography (solvent gradi 2.66-2.96 (4H, m), 3.77 (1H, t, J=7.6 Hz), 4.39 (2H, d, J=7.2 ent; 10 to 100% ethyl acetate/hexane) to give N-(9-ethyl-9H Hz), 7.16 (2H, td, J=6.9, 4.3 Hz), 7.23-7.66 (9H, m), 7.82(1H, carbazol-3-yl)-5-hydroxy-3-methylpentanamide (0.514 g. 55 d, J–8.7 Hz), 7.91-8.11 (2H, m), 8.29 (1H, d, J=1.5 Hz), 9.88 1.586 mmol. 53.7%) as a colorless powder. (1H, s), 10.52 (1H, s). 'H-NMR (300 MHz, DMSO-d): 80.95 (3H, d, J=6.4 Hz), 1.21-1.46 (4H, m), 1.47-1.73 (1H, m), 2.01-2.24 (2H, m), Example 40 2.24-2.44 (1H, m), 3.40-3.58 (2H, m), 4.27-4.53 (3H, m), 7.17 (1H, t, J=7.2 Hz), 7.43 (1H, td, J=7.7, 1.1 Hz), 7.49-7.65 60 N-(3-chloro-4-cyanophenyl)-N'-(9-ethyl-9H-carba (3H, m), 8.05 (1H, d, J=7.6 Hz), 8.41 (1H, d, J=1.5 Hz), 9.85 Zol-3-yl)cyclobutane-1,2-dicarboxamide (1H, s). (Step 3) (Step 1) To a solution of the compound obtained in Step 2 (500 mg. A solution of 4-amino-2-chlorobenzonitrile (1229 mg, 1.54 mmol) and 2-chloro-4-fluorobenzonitrile (240 mg, 1.54 65 8.06 mmol), 3-oxabicyclo[3.2.0]heptane-2,4-dione (1016 mmol) in THF (15 mL) was added potassium t-butoxide (432 mg, 8.06 mmol) and TEA (1.123 mL, 8.06 mmol) in toluene mg, 3.85 mmol) at room temperature, and the mixture was (10 mL) was stirred at 80°C. for 14hr. To the reaction mixture US 9,120,776 B2 111 112 was added brine at room temperature, and the mixture was rated brine, and dried, and the solvent was evaporated under extracted with ethyl acetate. The organic layer was washed reduced pressure. The obtained residue was purified by silica with water and saturated brine, and dried, and the solvent was gel column chromatography (solvent gradient; 10 to 85% evaporated under reduced pressure. The obtained residue was ethyl acetate/hexane), and purified by NH-silica gel column purified by COOH-silica gel column chromatography (sol chromatography (solvent gradient; 10 to 100% ethyl acetate/ vent gradient; 10 to 100% ethyl acetate/hexane), and crystal hexane) to give the title compound (0.788 g, 1.681 mmol. lized from ethyl acetate to give 2-((3-chloro-4-cyanophenyl) 38.7%) as a colorless powder. carbamoyl)cyclobutanecarboxylic acid (795 mg, 2.85 mmol. 'H-NMR (300 MHz, DMSO-d): 81.04 (3H, d, J=6.0 Hz), 35.4%) as colorless crystals. 1.30 (3H, t, J–7.0 Hz), 2.22-2.49 (4H, m), 2.53-2.64 (1H, m), MS (API): 277 (M-H) 10 (Step 2) 3.86 (3H, s), 4.41 (2H, q, J–7.2 Hz), 7.07-7.34 (2H, m), A solution of the compound obtained in Step 1 (795 mg. 7.36-7.70 (6H, m), 8.04 (1H, d, J=7.6Hz), 8.31-8.50 (1H, m), 2.85 mmol), 9-ethyl-9H-carbazol-3-amine (600 mg, 2.85 9.94 (1H, s), 10.39 (1H, s). mmol), HATU (1085 mg, 2.85 mmol) and TEA (0.437 mL, Example 42 3.14 mmol) in DMF (5 mL) was stirred at room temperature 15 for 14 hr. To the reaction mixture was added brine at room temperature, and the mixture was extracted with ethylacetate. N-(3-chloro-4-cyanophenyl)-N'-(9-ethyl-9H-carba The organic layer was washed with water and Saturated brine, Zol-3-yl)-2-methylpentanediamide and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel Example 43 column chromatography (solvent gradient; 10 to 100% ethyl acetate/hexane), and crystallized from ethyl acetate and etha N'-(3-chloro-4-cyanophenyl)-N'-(9-ethyl-9H-carba nol to give the title compound (82 mg, 0.174 mmol, 6.10%) as Zol-3-yl)-2-methylpentanediamide colorless crystals. 'H-NMR (300 MHz, DMSO-d): 81.28 (3H, t, J=7.0 Hz), 25 (Step 1) 2.07-2.25 (1H, m), 2.25-2.45 (4H, m), 3.47-3.74 (1H, m), A solution of 3-methyldihydro-2H-pyran-2.6(3H)-dione 4.39 (2H, d, J=7.2 Hz), 7.15 (1H, t, J=70 Hz), 7.33-749 (3H, (876 mg, 6.84 mmol), 4-amino-2-chlorobenzonitrile (1044 m), 7.50-7.66 (2H, m), 7.80 (1H, d, J=8.7 Hz), 7.90 (1H, d, mg, 6.84 mmol) and TEA (0.953 mL, 6.84 mmol) in toluene J=7.6 Hz), 8.01 (1H, d, J=1.9 Hz), 8.16 (1H, d, J=1.1 Hz), (10 mL) was stirred at 70° C. for 3 hr. To the reaction mixture 9.64 (1H, brs), 10.28 (1H, brs). 30 was added brine at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed Example 41 with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was N-(4-cyano-3-methoxyphenyl)-N'-(9-ethyl-9H-car purified by COOH-silica gel column chromatography (sol bazol-3-yl)-3-methylpentanediamide 35 vent gradient; 10 to 100% ethyl acetate/hexane) to give a (Step 1) mixture (750 mg, 2.67 mmol. 39.1%) of 5-((3-chloro-4-cy A solution of 2-methoxy-4-nitrobenzonitrile (750 mg, 4.21 anophenyl)amino)-2-methyl-5-oxopentanoic acid and 5-((3- mmol) and palladium on carbon (50 mg, 0.47 mmol) in chloro-4-cyanophenyl)amino)-4-methyl-5-oxopentanoic methanol (15 mL) was stirred at room temperature for 48 hr 40 acid, as a colorless powder. under hydrogen atmosphere (1 atm). The catalyst was MS (API): 279 (M-H) removed by filtration, and the filtrate was concentrated under (Step 2) reduced pressure to give 4-amino-2-methoxybenzonitrile A solution of the mixture obtained in Step 2 (750 mg, 2.67 (679 mg, 4.58 mmol, quantitative) as a brownish-red powder. mmol), HATU (1117 mg, 2.94 mmol), 3-amino-9-ethylcar H-NMR (300 MHz, DMSO-d): 83.32 (3H, s), 6.05-6.29 45 bazole (590 mg, 2.81 mmol) in DMF (5 mL) was stirred at (4H, m), 7.23 (1H, d. J=8.3 Hz). room temperature for 14 hr. To the reaction mixture was (Step 2) added brine at room temperature, and the mixture was A solution of the compound obtained in Step 1 (670 mg. extracted with ethyl acetate. The organic layer was washed 4.52 mmol) and 3-methylglutaric anhydride (579 mg, 4.52 with water and saturated brine, and dried, and the solvent was mmol) in THF (20 mL) was heated with reflux for 14hr. The 50 evaporated under reduced pressure. The obtained residue was reaction Solution was concentrated under reduced pressure to purified by silica gel column chromatography (solvent gradi give 5-((4-cyano-3-methoxyphenyl)amino)-3-methyl-5- ent; 10 to 100% ethyl acetate/hexane), and purified by pre oXopentanoic acid (1.35 g, 4.89 mmol, quantitative) as a parative HPLC (column: L-Column 2 ODS, eluent: 0.1% brownish-red oil. TFA-containing acetonitrile/water) to give the compound of 'H-NMR (300 MHz, DMSO-d): 80.75-1.12 (3H, m), 55 1.58-1.91 (1H, m) 2.08-2.19 (1H, m), 2.22-2.46 (2H, m), Example 42 (42.0 mg, 0.089 mmol. 3.32%) and the com 2.48-2.55 (1H, m), 2.65-2.94 (1H, m), 3.36 (1H, brs), 3.60 pound of Example 43 (20.00 mg 0.042 mmol. 1.583%), each (1H, t, J=6.4Hz), 7.25 (1H, dd, J=8.3, 1.5 Hz), 7.45-7.76 (2H, as a white powder. m), 10.34 (1H, s), 12.11 (1H, brs). The Compound of Example 42 (Step 3) 60 H-NMR (300 MHz, CDC1): 81.29-142 (6H, m), 1.86 To a solution of the compound obtained in Step 2 (1.20 g, 2.02 (2H, m), 2.31-2.52 (2H, m), 2.62 (1H, d, J=6.8 Hz), 4.34 mmol), 9-ethyl-9H-carbazol-3-amine (0.913 g, 4.34 4.18-4.44 (2H, m), 7.14-7.25 (2H, m), 7.28-7.41 (4H, m), mmol) and DIEA (1.896 mL, 10.86 mmol) in DMF (15 mL) 742-7.51 (1H, m), 7.67-7.81 (2H, m), 7.87 (1H, d, J=4.5 Hz), was added HATU (1.982 g, 5.21 mmol), and the mixture was 8.12 (1H, d. J=1.5 Hz), 9.18 (1H, brs). stirred at room temperature for 4 hr. To the reaction mixture 65 The Compound of Example 43 was added water, and the mixture was extracted with ethyl H-NMR (300 MHz, CDC1): 81.24-1.48 (6H, m), 1.78 acetate. The organic layer was washed with water and Satu 1.98 (1H, m), 2.05-2.19 (1H, m), 2.36-2.63 (2H, m), 2.67 US 9,120,776 B2 113 114 2.94 (1H, m), 4.35 (2H, q, J=6.9 Hz), 7.12-7.24 (1H, m), 'H-NMR (300 MHz, DMSO-d): 81.02 (3H, d, J=6.2 Hz), 7.29-7.73 (7H, m), 7.88-8.09 (2H, m), 8.21 (1H, s), 9.66 (1H, 1.29 (3H, t, J=7.1 Hz), 1.70-1.73 (1H, m), 1.87-191 (1H, m), S). 2.24-2.28 (2H, m), 2.38-2.49 (1H, m), 4.23-4.27 (2H, m), 4.41 (2H, q, J–7.0 Hz), 7.16 (1H, t, J–7.0 Hz), 7.43 (1H, t, Example 44 5 J=7.1 Hz), 7.52 (2H, brs), 7.58-7.62 (2H, m), 7.98 (1H, d, 5-(4-cyano-3-methylphenoxy)-N-(9-ethyl-9H-carba J=8.6Hz), 8.04 (1H, d. J–7.7 Hz), 8.38 (1H, brs), 8.44 (1H, d, Zol-3-yl)-3-methylpentanamide J=2.8 Hz), 9.91 (1H, brs). To a solution of N-(9-ethyl-9H-carbazol-3-yl)-5-hydroxy Example 48 3-methylpentanamide (0.34g, 1.05 mmol) in DMF (8.0 mL) 10 was added potassium-t-butoxide (0.258 g, 2.31 mmol) under N-4-(3-chloro-4-cyanophenyl)amino-2-methyl-4- argon atmosphere. The mixture was stirred at room tempera oxobutyl-9-ethyl-9H-carbazole-3-carboxamide ture for 15 min, and 4-fluoro-2-methylbenzonitrile (0.212 g, 1.57 mmol) was added thereto. The reaction solution was (Step 1) stirred at room temperature for 14 hr, and ethyl acetate (80 15 A solution of crotonic acid (8.24 mL. 98.31 mmol) and mL) was added thereto. The organic layer was washed with thionyl chloride (7.18 mL. 98.31 mmol) in DMA (150 mL) cold water (2x20 mL) and saturated brine (2x20 mL), and was stirred at 0°C. for 1 hr. To the reaction mixture was added dried, and the solvent was evaporated under reduced pressure. 4-amino-2-chlorobenzonitrile (15g, 98.31 mmol), and the The obtained residue was purified by silica gel column chro mixture was stirred at room temperature for additional 14hr. matography (solvent gradient; 20 to 30% ethyl acetate/hex- 20 To the reaction solution was added brine at room temperature, ane) to give the title compound (0.16 g., 35%) as a white and the mixture was extracted with ethyl acetate. The organic powder. layer was washed with 1N aqueous sodium hydroxide solu H-NMR (300 MHz, DMSO-d): 81.01 (3H, d, J=6.1 Hz), tion and 1N hydrochloric acid, and dried, and the solvent was 1.29 (3H, t, J=7.2 Hz), 1.66-1.70 (1H, m), 1.84-1.87 (1H, m), evaporated under reduced pressure to give (E)-N-(3-chloro 2.23-2.27 (2H, m), 2.40-2.44 (4H, m), 4.14 (2H, dd, J=10.9, as 4-cyanophenyl)but-2-enamide (21.69 g, 98.31 mmol, quan 6.6 Hz), 4.41 (2H, q, J=7.1 Hz), 6.93 (1H, dd, J–2.4, 8.6 Hz), titative) as a brownish-red powder. 7.04 (1H, d, J=2.2 Hz), 7.16 (1H, t, J=7.2 Hz), 741-7.45 (1H, MS (API): 229 (M-H) m), 7.53 (2H, brs), 7.57 (1H, d, J=8.2 Hz), 7.65 (1H, d, J=8.6 (Step 2) Hz), 8.04 (1H, d, J=7.7 Hz), 8.39 (1H, brs), 9.91 (1H, brs). The compound obtained in Step 1 (21.69 g, 98.31 mmol), Example 45 30 DBU (16.30 mL. 108.14 mmol) and nitromethane (6.00 g, 98.31 mmol) were stirred at room temperature for 14 hr. To 5-(5-cyano-6-methylpyridin-2-yl)oxy-N-(9-ethyl the reaction solution was added brine at room temperature, 9H-carbazol-3-yl)-3-methylpentanamide and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, Using 2-fluoro-5-cyano-6-methylpyridine, and by the 35 and the solvent was evaporated under reduced pressure. The reaction and purification in the same manner as in the method obtained residue was purified by silica gel column chroma described in Example 44, the title compound was obtained. tography (solvent gradient; 5 to 30% ethyl acetate/hexane) to 'H-NMR (300 MHz, DMSO-d): 81.01 (3H, d, J=6.1 Hz), give N-(3-chloro-4-cyanophenyl)-3-methyl-4-nitrobutana 1.29 (3H, t, J=7.1 Hz), 1.66-1.69 (1H, m.), 1.84-1.87 (1H, m), mide (21.20 g, 75 mmol. 77%) as a pale-orange powder. 2.20-2.26 (2H, m), 2.37-2.40 (1H, m), 2.53 (3H, s), 4.38-4.45 40 'H-NMR (300 MHz, CDC1): 81.18 (3H, d, J–7.2 Hz), (4H, m), 6.80 (1H, d, J=8.6 Hz), 7.16 (1H, t, J–74 Hz), 7.43 2.35-2.69 (2H, m), 2.75-3.06 (1H, m), 4.50 (2H, t, J=5.7 Hz), (1H, t, J=7.6 Hz), 7.52 (2H, brs), 7.57 (1H, d, J=8.2 Hz), 8.03 741-7.54 (1H, m), 7.53-7.69 (1H, m), 7.71-7.83 (1H, m), (2H, d, J=8.6 Hz), 8.38 (1H, brs), 9.91 (1H, brs). 7.91 (1H, d, J=2.3 Hz). (Step 3) Example 46 45 A solution of the compound obtained in Step 2 (21.2g, 5-(5-cyanopyridin-2-yl)oxy-N-(9-ethyl-9H-carba 75.26 mmol), iron powder (21.01 g, 376.29 mmol) and cal Zol-3-yl)-3-methylpentanamide cium chloride (25.06 g. 225.78 mmol) in a mixed solvent of methanol (100 mL) and water (20 mL) was stirred at 60° C. Using 5-cyano-2-fluoropyridine, and by the reaction and for 3 hr. To the reaction solution was added brine at room purification in the same manner as in the method described in 50 temperature, and the mixture was extracted with ethylacetate. Example 44, the title compound was obtained. The organic layer was washed with water and Saturated brine, 'H-NMR (300 MHz, DMSO-d): 81.01 (3H, d, J=6.2 Hz), and dried, and the solvent was evaporated under reduced 1.29 (3H, t, J=7.1 Hz), 1.65-1.70 (1H, m), 1.87-190 (1H, m), pressure. The obtained residue was purified by NH-silica gel 2.21-2.26 (2H, m), 2.37-2.41 (1H, m), 4.38-4.47 (4H, m), column chromatography (solvent gradient; 10 to 50% ethyl 6.99 (1H, d, J=8.7 Hz), 7.16 (1H, t, J=7.4 Hz), 7.41 (1H, t, 55 acetate/hexane) to give 4-amino-N-(3-chloro-4-cyanophe J=7.3 Hz), 7.52-7.58 (3H, m), 8.04 (1H, d, J=7.7 Hz), 8.12 nyl)-3-methylbutanamide (6.02 g, 23.92 mmol, 31.8%) as a (1H, dd, J=2.3,8.7 Hz), 8.38 (1H, brs), 8.67 (1H, d, J-2.0 Hz), brown oil. 9.90 (1H, brs). MS (API): 252 (M+H) (Step 4) Example 47 60 A solution of the compound obtained in Step 3 (158 mg, 0.63 mmol), 9-ethyl-9H-carbazole-3-carboxylic acid (150 5-(6-cyanopyridin-3-yl)oxy-N-(9-ethyl-9H-carba mg, 0.63 mmol), HATU (262 mg, 0.69 mmol) and TEA Zol-3-yl)-3-methylpentanamide (0.096 mL, 0.69 mmol) in DMF (5 mL) was stirred at 50° C. for 14 hr. To the reaction solution was added brine at room Using 2-cyano-5-fluoropyridine, and by the reaction and 65 temperature, and the mixture was extracted with ethylacetate. purification in the same manner as in the method described in The organic layer was washed with water and Saturated brine, Example 44, the title compound was obtained. and dried, and the solvent was evaporated under reduced US 9,120,776 B2 115 116 pressure. The obtained residue was purified by silica gel Example 50 column chromatography (solvent gradient; 10 to 80% ethyl acetate/hexane) to give the title compound (156 mg, 0.330 N-(5-cyanopyridin-2-yl)-N'-(9-ethyl-9H-carbazol-3- mmol, 52.6%) as white crystals. yl)-3-methylpentanediamide 'H-NMR (300 MHz, DMSO-d): 80.99 (3H, d, J=6.8 Hz), 1.33 (3H, t, J=7.2 Hz), 2.13-2.43 (2H, m), 3.24-3.31 (1H, m), (Step 1) 4.47 (2H, d, J=7.2 Hz), 7.25 (1H, t, J=74 Hz), 742-7.69 (4H, A solution of 6-aminonicotinonitrile (100.0 mg. 0.839 m), 7.77 (1H, d, J=8.7 Hz), 7.93-8.03 (2H, m), 8.13 (1H, d, mmol) and 4-methyldihydro-2H-pyran-2.6(3H)-dione (118 J=7.9 Hz), 8.47 (1H, t, J=5.7 Hz), 8.66 (1H, d, J=1.5 Hz), 10 mg, 0.923 mmol) in a mixed solvent of toluene (3 mL) and 10.54 (1H, s). DMSO (0.3 mL) was stirred at 120° C. for 24 hr. To the reaction mixture was added cold water, and the mixture was MS (API): 473 (M+H) extracted with ethyl acetate (4x30 mL). The organic layer was washed with water, and dried, and the solvent was evaporated Example 49 15 under reduced pressure. The obtained solid was washed with 50% dichloromethane/hexane solution to give 4-(5-cyanopy N-(6-cyanopyridin-3-yl)-N'-(9-ethyl-9H-carbazol-3- ridin-2-ylcarbamoyl)-3-methylbutyric acid (30 mg, 14.49%) yl)-3-methylpentanediamide as a pale-yellow powder. 'H-NMR (300 MHz, DMSO-d): 80.94 (3H, d, J=6.1 Hz), (Step 1) 2.06-2.50 (5H, m), 7.01 (1H, s), 8.23 (1H, s), 8.77 (1H, s), 10.98 (1H, s), 12.09 (1H, brs). A solution of 5-aminopyridine-2-carbonitrile (300.0 mg. (Step 2) 2.518 mmol) and 4-methyldihydro-2H-pyran-2,6(3H)-dione To a solution of 9-ethyl-9H-carbazol-3-ylamine (306.5 (354.931 mg, 2.77 mmol) in a mixed solvent of toluene (7 mg, 1.457 mmol) in DMF (7 mL) were added the compound mL) and DMSO (0.7 mL) was stirred at 110° C. for 16 hr. To 25 obtained in Step 1 (300 mg, 1.215 mmol), HATU (554.14 mg. the reaction mixture was added cold water, and the mixture 1.457 mmol) and DIPEA (0.632 mL, 3.644 mmol) at room was extracted with ethyl acetate (4x30 mL). The organic layer temperature, and the mixture was stirred at room temperature was washed with water, and dried, and the solvent was evapo for 16 hr. To the reaction mixture was added water, and the rated under reduced pressure. The obtained solid was washed mixture was extracted with ethyl acetate (2x50 mL). The with 50% dichloromethane/hexane solution to give 4-(6-cy 30 organic layer was dried, and the solvent was evaporated under anopyridin-3-ylcarbamoyl)-3-methylbutyric acid (300 mg. reduced pressure. The obtained residue was purified by pre 48.2%) as a pale-yellow powder. parative HPLC to give the title compound (220 mg, 41.21%) 'H-NMR (300 MHz, DMSO-d): 80.96 (3H, d, J=5.8 Hz), as a colorless powder. 2.12-2.50 (5H, m), 7.97 (1H, d, J=8.6 Hz), 8.27 (1H, dd, 'H-NMR (300 MHz, DMSO-d): 81.01 (3H, d, J=6.0 Hz) J=8.60, 2.2 Hz), 8.84 (1H, d, J-2.0 Hz), 10.59 (1H, s), 12.12 35 1.29 (3H, t, J–7.0 Hz), 2.27-2.50 (5H, m), 4.38-444 (2H, m), (1H, brs). 7.16 (1H, t, J=7.6 Hz), 7.43 (1H, t, J–7.4 Hz), 7.53-7.58 (3H, (Step 2) m), 8.03 (1H, d, J–7.7 Hz), 8.21-8.28 (2H, m), 8.40 (1H, s), To a solution of 9-ethyl-9H-carbazol-3-ylamine (306.5 8.77 (1H, s), 9.92 (1H, s), 11.03 (1H, s). mg, 1.457 mmol) in DMF (7 mL) were added the compound Purification Condition by Preparative HPLC obtained in Step 1 (300 mg, 1.215 mmol), HATU (554.14 mg. 40 The Same as Example 49 1.457 mmol) and DIPEA (0.632 mL, 3.644 mmol) at room Example 51 temperature, and the mixture was stirred at room temperature for 16 hr. To the reaction mixture was added water, and the N-4-(3-chloro-4-cyanophenyl)amino-1-ethyl-2- mixture was extracted with ethyl acetate (2x50 mL). The 45 methyl-4-oxobutyl-9-ethyl-9H-carbazole-3-car organic layer was dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by pre boxamide parative HPLC to give the title compound (260 mg, 48.71%) (Step 1) as a colorless powder. A solution of the compound obtained in Step 1 of Example 'H-NMR (300 MHz, DMSO-d): 81.03 (3H, d, J=6.2 Hz), 50 48 (1.2g, 5.44 mmol) and DBU (0.984 mL, 6.53 mmol) in 1.29 (3H, t, J–7.0 Hz), 2.29-2.50 (5H, m), 4.38-4.44 (2H, m), 1-nitropropane (2.420 mL. 27.19 mmol) was stirred at 60° C. 7.17 (1H, t, J=7.4 Hz), 7.44 (1H, t, J=7.6 Hz), 7.51-7.58 (3H, for 2 hr. To the reaction solution was added brine at room m), 7.96 (1H, d, J=8.6 Hz), 8.03 (1H, d, J=7.6 Hz), 8.28 (vdd, temperature, and the mixture was extracted with ethylacetate. J=8.6, 2.4 Hz), 8.40 (1H, s), 8.86 (1H, s), 9.93 (1H, s), 10.64 The organic layer was washed with water and Saturated brine, (1H, s). 55 and dried, and the solvent was evaporated under reduced Purification Condition by Preparative HPLC pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10 to 30% ethyl equipment: Waters Semi-Preparative HPLC instrument acetate/hexane) to give N-(3-chloro-4-cyanophenyl)-3-me column: Prep Scalar 10 um C18 (250x30 mm) thyl-4-nitrohexanamide (1.420 g, 4.58 mmol. 84%) as a pale solvent: A=0.05% aqueous formic acid solution, 60 yellow oil. B-acetonitrile 'H-NMR (300 MHz, CDC1): 80.88-1.18 (6H, m), 1.66 solvent gradient: 60% A/B (0 min)->40% A/B 1.94 (1H, m), 2.09-2.74 (4H, m), 4.38-4.59 (1H, m), 7.49 (1H, (60 min)->5% A/B (61 min)->5% A/B (70 min)->60% A/B td, J=4.2.2.1 Hz), 7.55-7.67 (1H, m), 7.92 (2H, dd, J–4.7, 2.1 (71 min) Hz). 65 (Step 2) flow rate: 30 mL/min Using the compound obtained in Step 1, and by the reaction temperature: room temperature and purification in the same manner as in the method US 9,120,776 B2 117 118 described in Step 3 of Example 48, 4-amino-N-(3-chloro-4- ture for 15 min, and 4-fluorophthalonitrile (0.270 g, 1.85 cyanophenyl)-3-methylhexanamide was obtained as a crude mmol) was added thereto. The reaction solution was stirred at product. room temperature for 14 hr, and ethyl acetate (100 mL) was MS (API): 278 (M-H) added thereto. The organic layer was washed with cold water (Step 3) (2x25 mL) and saturated brine (2x25 mL), and dried, and the Using the compound obtained in Step 2, and by the reaction solvent was evaporated under reduced pressure. The obtained and purification in the same manner as in the method residue was purified by preparative HPLC to give the title described in Step 4 of Example 48, the title compound was compound (0.285 g, 51%) as a white powder. obtained. 'H-NMR (300 MHz, DMSO-d): 80.99 (3H, d, J=5.9 Hz), MS (API): 501 (M+H) 10 1.26 (3H, t, J–7.0 Hz), 1.64-1.69 (1H, m), 1.83-1.88 (1H, m), 2.21-2.25 (2H, m), 2.37-2.39 (1H, m), 4.18-4.21 (2H, m), Example 52 4.37 (2H, q, J=6.8 Hz), 7.13 (1H, t, J=7.2 Hz), 7.38-743 (2H, N-(3-chloro-4-cyanophenyl)-N'-(6-chloro-1-methyl m), 7.49-7.55 (3H, m), 7.74 (1H, d, J=2.20 Hz), 7.99 (2H, t, 15 J=9.2 Hz), 8.34 (1H, s), 9.86 (1H, brs). 1H-indol-5-yl)-3-methylpentanediamide Purification Condition by Preparative HPLC Using 5-(3-chloro-4-cyanophenylamino)-3-methyl-5- equipment: Waters Semi-Preparative HPLC instrument oxopentanoic acid and 6-chloro-1-methyl-1H-indol-5- column: Prep Scalar 10 um C18 (250x30 mm) amine, and by the reaction and purification in the same man Solvent: A 5 mM aqueous ammonium acetate solution, ner as in the method described in Step 2 of Example3, the title B-acetonitrile compound was obtained. solvent gradient: 50% A/B (0 min)->30% A/B MS (API): 443 (M+H) (60 min)->5% A/B (65 min)->5% A/B (75 min)->50% A/B (76 min) Example 53 flow rate: 30 mL/min 25 temperature: room temperature 5-(4-cyano-3-methoxyphenoxy)-N-(9-ethyl-9H-car bazol-3-yl)-3-methylpentanamide Example 56 Using N-(9-ethyl-9H-carbazol-3-yl)-5-hydroxy-3-meth 4-((4-cyanobenzyl)oxy)-N-(9-ethyl-9H-carbazol-3- ylpentanamine and 4-fluoro-2-methoxybenzonitrile, and by 30 yl)-3-methylbutanamide the reaction and purification in the same manner as in the method described in Example 44, the title compound was (Step 1) obtained. To a solution of 2,4-dimethoxybenzaldehyde (4 g. 24.07 H-NMR (300 MHz, DMSO-d): 81.01 (3H, d, J=6.0 Hz), mmol) in toluene (440 mL) was added 9-ethyl-9H-carbazol 1.29 (3H, t, J=7.1 Hz), 1.65-1.70 (1H, m), 1.86-1.89 (1H, m), 35 3-ylamine (7.58 g. 36.1 mmol), and titanium(IV) isopro 2.24-2.28 (2H, m), 2.38-2.43 (1H, m), 3.9 (3H, s), 4.15-4.19 poxide (10.8 mL, 36.1 mmol) was added dropwise thereto. (2H, m), 4.41 (2H, q, J–7.0 Hz), 6.7 (1H, dd, J-2.0, 8.7 Hz), The mixture was heated with reflux for 14 hr, cooled, and 6.73-6.74 (1H, m), 7.17 (1H, t, J=7.5 Hz), 7.43 (1H, d, J=7.6 concentrated under reduced pressure. The obtained residue Hz), 7.53-7.62 (4H, m), 8.04 (1H, d, J=7.7 Hz), 8.39 (1H, s), was dissolved in dichloromethane (440 mL), methanol (440 9.91 (1H, brs). 40 mL) was added thereto, and the mixture was cooled to 0°C. Sodium borohydride (1.82 g, 48.14 mmol) was slowly added Example 54 thereto, the mixture was stirred for 30 min, and cold water (200 mL) was added thereto. The insoluble substance was 5-(4-cyano-3,5-dimethylphenoxy)-N-(9-ethyl-9H removed by filtration through Celite, and washed with dichlo carbazol-3-yl)-3-methylpentanamide 45 romethane (100 mLX2). The organic layer was separated, and the aqueous layer was extracted with dichloromethane (100 Using N-(9-ethyl-9H-carbazol-3-yl)-5-hydroxy-3-meth mLX3). The organic layers were combined, washed with Satu ylpentanamine and 4-fluoro-2,6-dimethylbenzonitrile, and rated brine, and dried, and the solvent was evaporated under by the reaction and purification in the same manner as in the reduced pressure. The obtained residue was purified by silica method described in Example 44, the title compound was 50 gel column chromatography (solvent; 30% ethyl acetate/hex obtained. ane) to give 2,4-dimethoxybenzyl)-(9-ethyl-9H-carbazol-3- 'H-NMR (300 MHz, DMSO-d): 81.01 (3H, d, J=6.0 Hz), yl)-amine (8g, 92.2%) as a white powder. 1.29 (3H, t, J–7.0 Hz), 1.64-1.69 (1H, m), 1.85-1.86 (1H, m), 'H-NMR (300 MHz, DMSO-d): 81.24 (3H, t, J=7.1 Hz), 2.23-2.27 (3H, m), 2.38 (6H, s), 4.11-4.12 (2H, m), 4.41 (2H, 3.71 (3H, s), 3.85 (3H, s), 4.22 (2H, d, J=6.0 Hz), 4.31 (2H, q, q, J=6.8 Hz), 6.84 (2H, s), 7.16 (1H, t, J=7.26 Hz), 7.43 (1H, 55 J=7.1 Hz), 5.54 (1H, t, J=6.1 Hz), 6.44 (1H, dd, J–2.3, 8.3 d, J=7.2 Hz), 7.53-7.58 (3H, m), 8.03 (1H, d, J=7.5 Hz), 8.39 Hz), 6.57 (1H, d, J=2.2 Hz), 6.87 (1H, dd, J=2.1, 8.7 Hz), 7.05 (1H, s), 9.91 (1H, brs) (1H, t, J=7.5 Hz), 7.24-7.26 (2H, m), 7.30-7.35 (2H, m), 7.45 (1H, d, J=8.2 Hz), 7.93 (1H, d, J=7.6 Hz). Example 55 (Step 2) 60 To a solution of the compound obtained in Step 1 (8 g. 5-(3,4-dicyanophenoxy)-N-(9-ethyl-9H-carbazol-3- 22.22 mmol) in dichloromethane (100 mL) was added 3-me yl)-3-methylpentanamide thyldihydrofuran-2,5-dione (2.78 g. 24.44 mmol) at 0°C., and the mixture was stirred at room temperature for 4 hr. The To a solution of N-(9-ethyl-9H-carbazol-3-yl)-5-hydroxy reaction solution was concentrated under reduced pressure, 3-methylpentanamine (0.40g, 1.23 mmol) in DMF (10.0 mL) 65 and the precipitate was triturated with 20% ethyl acetate/ was added potassium-t-butoxide (0.304 g, 2.71 mmol) under hexane to give a mixture (10.4 g. 98.6%) of N-(2,4- argon atmosphere. The mixture was stirred at room tempera dimethoxybenzyl)-N-(9-ethyl-9H-carbazol-3-yl)-2-methyl US 9,120,776 B2 119 120 Succinamidic acid and a regioisomer thereof, as a white ane) to give a mixture (1 g, 40%) of 4-(4-cyanobenzyloxy)- powder. The regioisomeric mixture was used for the next step N-(2,4-dimethoxybenzyl)-N-(9-ethyl-9H-carbazol-3-yl)-3- without purification. methylbutylamide and a regioisomer thereof, as a white (Step 3) powder. The regioisomeric mixture was used for the next step without further purification. To a solution of the regioisomeric mixture (10.4g, 21.94 (Step 5) mmol) obtained in Step 2 in THF (300 mL) was added 2M To a solution of the regioisomeric mixture (1 g, 1.74 mmol) borane-dimethyl sulfide THF solution (10.75 mL, 21.5 obtained in Step 4 in TFA (20 mL) was added anisole (2 mL) mmol) at 0°C., and the mixture was stirred at room tempera at 0°C., and the mixture was stirred at 50° C. for 16 hr, and ture for 4 hr. The reaction solution was concentrated under 10 then stirred at room temperature for 24hr. The reaction solu reduced pressure, and the residue was dissolved in ethyl tion was concentrated under reduced pressure, and the acetate (200 mL). The solution was washed with water (100 obtained residue was purified by preparative HPLC to give mL) and saturated brine (100 mL), and dried, and the solvent the title compound (0.035 g, 4.7%) as a white powder. was evaporated under reduced pressure. The obtained residue 'H-NMR (300 MHz, DMSO-d): 81.00 (3H, d, J=6.6 Hz), was purified by silica gel column chromatography (solvent; 15 1.29 (3H, t, J–7.0 Hz), 2.19-2.25 (1H, m), 2.31-2.34 (1H, m), 4% methanol/dichloromethane) to give a mixture (6 g. 2.44-2.47 (1H, m), 3.41 (2H, t, J=5.2 Hz), 4.41 (2H, q, J–7.0 59.4%) of N-(2,4-dimethoxybenzyl)-N-(9-ethyl-9H-carba Hz), 4.59 (2H, s), 7.16 (1H, t, J=7.4 Hz), 7.43 (1H, t, J=7.6 Zol-3-yl)-4-hydroxy-3-methylbutylamide and a regioisomer Hz), 7.50-7.58 (5H, m), 7.77 (2H, d, J=8.1 Hz), 8.03 (1H, d, thereof, as a white powder. The regioisomeric mixture was J=7.4 Hz), 8.39 (1H, s), 9.89 (1H, s). used for the next step without further purification. Purification Condition by Preparative HPLC (Step 4) equipment: Waters Semi-Preparative HPLC instrument To a solution of the regioisomeric mixture (2g, 4.35 mmol) column: Prep Scalar 10 um C18 (250x30 mm) obtained in Step 3 in DMF (25 mL) was added sodium Solvent: A 5 mM aqueous ammonium acetate solution, hydride (60% oil, 261 mg, 6.52 mmol) at 0°C., and the B-acetonitrile mixture was stirred at the same temperature for 30 min. 4-Cy 25 solvent gradient: 50% A/B (0 min)->45% A/B (15 min) anobenzyl bromide (2.55g, 13.05 mmol) was added thereto at -->40% A/B (60 min)->5% A/B (61 min)->5% A/B (70 min) 0°C., and the mixture was stirred at room temperature for 24 ->50% A/B (71 min) hr. To the reaction solution was added water (50 mL), and the flow rate: 30 mL/min mixture was extracted with ethyl acetate (100 mLx2). The temperature: room temperature organic layer was dried, and the solvent was evaporated under 30 The compounds described in Examples 1 to 56 are as reduced pressure. The obtained residue was purified by silica follows (Table 1). The “free” shown in Table 1 means a free gel column chromatography (solvent; 30% ethyl acetate/hex form.

US 9,120,776 B2 137 138 Experimental Example 1 The results (signal value inhibitory rate attest compound 1 uM) measured by the above-mentioned method are shown in RORyt Binding Test Table 3.

The binding activity of the test compound to RORyt was TABLE 3 measured by a time resolved fluorescence resonance energy transfer method (TR-FRET) utilizing histidine-tagged Test compound RORyt, fluorescent-labeled cholesterol (BODIPY-choles (Example No.) inhibitory rate (%) terol. AVIVA) and terbium-labeled anti-histidinetagantibody 3 99.7 (Invitrogen). First, a test compound diluted with an assay 10 4 O1.O buffer (20 mM Tris-HCl (pH 7.5), 100 mMNaCl, 1 mM DTT, 14 O1.O 0.1% BSA) was added to a 384 well plate by 3 ul, each. Then, 16 98.6 RORyt diluted with an assay buffer to 240 nM was added by 18 O1.O 3 uL each, after which fluorescent-labeled cholesterol diluted 19 O1.O 15 2O O1.O with the assay buffer to 12 uM was added by 3 ul. each, and 24 O1.O the mixture was stood at room temperature for 20 min. There 25 OO.O after, a terbium-labeled anti-histidine tag antibody diluted 26 O1.O with the assay buffer to 8 nM was added by 3 uI, each. The 30 OO.O mixture was stood at room temperature for 20 min, and fluo 34 O3.O rescence intensity (excitation wavelength 320 nm, fluores 38 O2.O cence wavelength 520 nm, delay time 100 microseconds) was 39 O2.O measured by Envision (PerkinElmer). 40 O2.O The results (binding inhibitory rate of fluorescent-labeled 41 OO.O cholesterol to RORyt attest compound 1 uM) measured by the 42 O1.O above-mentioned method are shown in Table 2. 25 43 O2.O 44 98.7 48 O6.O TABLE 2 49 O4.O 50 O3.O Test compound 55 O4.O (Example No.) binding inhibitory rate (%) 30 3 88.2 4. 99.4 14 101.0 16 97.8 Experimental Example 3 18 87.2 19 98.9 35 2O 98.7 Jurkat Reporter Test 24 98.9 25 101.0 26 99.7 The Jurkat cells used for the reporter test were cultured in 30 944 a culture medium (RPMI (Invitrogen), 10% FCS (Aus 34 94.6 40 38 91.9 GeneX), 100 U/mL penicillin, 100 g/mL streptomycin). On 39 91.4 the day of the test, 4x10" cells were recovered by a centrifugal 40 96.3 operation (1000 rpm, 5 min.) and suspended in PBS (phos 41 93.4 42 101.0 phate buffered saline) (Invitrogen). Thereafter, the cells were 43 1OO.O 45 recovered again by a centrifugal operation, and Suspended in 44 62.9 48 104.O 2 mL of R buffer (NEON transfection kit, Invitrogen). Then, 49 93.9 a reporter vector (53 ug) wherein a human IL-17 ROR 50 88.8 response element was inserted into the upstream of luciferase 55 82.2 of pCL 4.28 (Promega), and a vector (27 Jug) wherein RORyt 50 sequence was inserted into the downstream of CMV promoter were added to the cell Suspension. Gene transfer was per Experimental Example 2 formed by Electroporation apparatus (NEON, Invitrogen) under the conditions of pulse voltage 1350 V, interval 10 Cofactor Recruitment Test milliseconds, number of times 3. The cells after gene transfer 55 were suspended in 40 mL of a reaction medium (RPMI, 10% Cofactor recruitment test was performed by Alpha Screen Lipid reduced FCS (HyClone), 10 mM HEPES (pH 7.5), 100 (Histidine Detection Kit, PerkinElmer) method. First, a test U/mL penicillin, 100 ug/mL streptomycin, 5uM lovastatin), compound diluted with an assay buffer (50 mM Tris-HCl (pH and plated in a 96 well plate by 90 uL each. A test compound 7.5), 50 mMKC1, 1 mM DTT, 0.1% BSA) was added to a 384 diluted with the reaction medium was added by 10 uL each, well plate by 5 uL each. Then, RORyt diluted with an assay 60 and the cells were cultured overnight in an incubator. Bright buffer to 125 nM was added by 10 ul, each, after which solutions of 25 nM biotinylated SRC-1 peptide (biotin Glo (Promega) was added by 100 uL each, and the mixture CLTARHKILHRLLQEGSPSD), 12.5 g/mL acceptor beads was stirred at room temperature for 10 min, and the lumines and 12.5 g/mL donor beads, which was prepared with the cence level was measured by Envision (PerkinElmer). assay buffer, were added by 10 u, each. The mixture was 65 The results (luminescence level inhibitory rate at test com stood in a dark place for 1 hr., and the signal value was pound 3 uM) measured by the above-mentioned method are measured by Envision (PerkinElmer). shown in Table 4. US 9,120,776 B2 139 140 TABLE 4 Experimental Example 5 Test compound (Example No.) inhibitory rate (%) Human Th17 Cell Differentiation Test 3 82.6 4 103.0 CD4 positive naive T cells were isolated from peripheral 14 103.0 blood mononuclear cells (PBMC) collected from human 16 1OOO 18 1OOO peripheral blood by a density gradient centrifugation method. 19 103.0 The CD4 positive naive T cells were seeded in a 96 well plate 2O 102.0 10 (2x10 cells/well), and stimulated (37° C. for culture) with 24 1OOO anti-CD3/28Ab Dynabeads (Invitrogen) for 6 days in the 25 103.0 26 102.0 presence of IL-1B, IL-6, IL-23, TGFB, anti-IFNY Ab (BioLe 30 92.5 gend) and anti-IL-4 Ab (BioLegend) to differentiate into 34 82.7 Th17 cells. The compound was dissolved in DMSO and then 38 99.4 15 added thereto. After culture for 6 days, the concentration of 39 93.2 40 99.3 IL-17A in the culture supernatant obtained by centrifugation 41 96.4 was measured by ELISA to evaluate differentiation of the 42 104.O Th17 cells. 43 104.O 44 77.8 The results (inhibitory rate at 10 uM of test compound) 48 11S.O evaluated by the above-mentioned method are shown in Table 49 109.0 6. 50 11O.O 55 102.0 TABLE 6

25 Test compound (Example No.) inhibitory rate (%) Experimental Example 4 3 80.0 4 1OOO Mouse Th17 Cell Differentiation Test 14 99.3 16 96.2 CD4 positive naive T cells were collected from the spleen 30 18 98.5 19 95.2 cells of BALB/c mice (female, 8-11W, Charles River Labo 2O 89.9 ratories Japan, Inc.) using CD4+CD62L + T Cell Isolation kit 30 1OOO II (Miltenyi Biotec). The CD4 positive naive T cells in a 96 well plate (3x10 cells/well) were stimulated (37° C. for culture) with anti-mouse CD3e antibody (Bio X cell) (10 35 ug/mL, solid phase) and anti-CD28 antibody (Bio X cell) (5 Experimental Example 6 ug/mL) for 4 days in the presence of anti-IFN-Y antibody (BioLegend), anti-IL-4 antibody (BioLegend), anti-IL-2 anti body (BioLegend), IL-6, TGF-3 and IL-23 to differentiate IL17 Production Test in Human PBMC into Th17 cells. The compound was dissolved in DMSO and 40 then added thereto. The cells were cultured under these con Peripheral blood mononuclear cells (PBMC) collected ditions for 4 days, and differentiation of the Th17 cells was from human peripheral blood by a density gradient centrifu evaluated by using the concentration of IL-17A, which was gation method were stimulated by Dynabeads (registered measured by ELISA, in the culture supernatant obtained by trade mark; anti-CD3/CD28 antibody) and cultured at 37°C. centrifugation. 45 for 3 days. The compound was dissolved in DMSO and then The results (inhibitory rate at 10 uM of test compound) added thereto. After culture for 3 days under such conditions, evaluated by the above-mentioned method are shown in Table the concentration of IL-17A in the culture supernatant 5. obtained by centrifugation was measured by ELISA to evalu 50 ate the effect of the compound on IL-17 production. TABLE 5 The results (inhibitory rate at 10 uM of test compound) evaluated by the above-mentioned method are shown in Table Test compound 7. (Example No.) inhibitory rate (%)

3 97.1 55 TABLE 7 4 97.0 14 96.O Test compound Step 1 of Example 15 93.2 (Example No.) inhibitory rate (%) 16 96.O 18 95.8 3 73.3 19 95.8 4 88.3 2O 95.8 60 14 95.0 24 96.O 16 91.O 25 96.1 18 96.O 26 96.1 19 87.O 30 96.1 2O 84.O 34 96.3 30 1OOO 48 96.9 65 48 97.6 US 9,120,776 B2 141 142 Experimental Example 7 Incomplete adjuvant (DIFCO), and 5 mg of MBP (Sigma) was dissolved in 1.25 mL of saline (Otsuka). These two Effect on IL-17A Gene Expression Induced by Solutions were mixed at the ratio of 1:1 using glass syringe Anti-CD3 Antibody Stimulation in Mouse Colon with a three-way stopcock until emulsion was obtained. The emulsion was intracutaneously administered to the bottom of the rightfoot of Lewis rats (male, 7 weeks old) at 0.1 mL/rat. 1. Stimulation with Anti-CD3 Antibody and Collection of 2. Compound Administration Colon Tissue A suspension of the compound of Example 14 in 0.5% An anti-CD3 antibody (5 g/500 uL/mouse, BioXcell) or methylcellulose was orally administered twice a day from the saline (500 uL/mouse) was intraperitoneally administered to day of sensitization at the dose of 30, 100 or 300 mg/kg. The Balb/c mice (female, 8 weeks old). Three hours after the 10 last administration was performed on the 5" day after sensi administration, the mice were anesthetized by ether inhala tization, and an autopsy was performed 4 hours after the last tion, and euthanized by cervical spine fracture dislocation. administration. 3. Analysis of IL-17A Expression Then, the mice underwent laparotomy, and colons were iso The autopsy was performed on the 5" day after the sensi lated. The obtained colons were washed with saline, and then, 15 tization, and popliteal lymph nodes of the right leg were immersed in RNA stabilization buffer (RNAlater, QIAGEN) collected. The lymph nodes were immersed in RNA later at 4°C. for 18 hours or longer. Meanwhile, a suspension of a (Applied Biosystems), stored at 4°C. overnight, and then, the compound in 0.5% methylcellulose was orally administered lymph nodes were homogenized with a homogenizer in 1 mL an hour before administration of anti-CD3 antibody. of Isogen (Wako), and total RNA was purified. cDNA was 2. RNA Extraction from Colon Tissue and RT-PCR synthesized by reverse transcription reaction using High The colon tissues were retrieved from RNAlater, and Capacity cDNA Reverse Transcription Kit with RNase immediately immersed in 5 mL of RIT buffer (RNeasy Mini Inhibitor (Applied Biosystems). The synthesized cDNA was detected by PCR reaction using Taqman Gene Expression Kit, QIAGEN). Then, the tissues were homogenized at room Master Mix (Applied Biosystems) and 7900HT Fast realtime temperature. Total RNA was extracted from the homogenized 25 PCR system (Applied Biosystems) (Stage 1: 50° C., 2 min, solution in accordance with the protocol of RNeasy Mini Kit Stage 2: 95°C., 10 min, Stage 3: 95°C., 15 sec, 60°C., 1 min, (QIAGEN), and cDNA was prepared using high capacity 40 cycle). The primers and probes used in the reaction are as follows. RNA-to-cDNA Kit (Applied biosystems). mRNAs of various rat IL-17A: cytokines were detected by realtime-PCR (TaqMan PCR) using the obtained cDNA as a template. TaqMan universal 30 Forward primer: master mixII (Applied biosystems) was used as PCR buffer, (SEQ ID NO: 1) and TaqMan Gene Expression Assays (Applied biosystems): 5 - GCTCCAGAAGGCCCTCAGA-3 Mm004396.19 m1 (IL-17A), MmO0801778 m1 (IFN-Y) and Reverse primer: 43252341 E(B-actin) were used for detection of each cytokine 35 (SEQ ID NO: 2) gene, respectively. The expression levels of each gene were s' - GTCCTCATTGCGGCTCAGA-3' shown as normalized values calculated using B-actin expres Probe: sion level. (SEQ ID NO : 3) s" - TACCTCAACCGTTCCACTTCACCCTGG-3' 3. Statistical Analysis 40 All the data were shown as mean values-ESE. Statistical rat GAPDH: analyses were performed by Student's t test and Williams test. It was found that there was a significant difference Forward primer: (SEQ ID NO : 4) between two groups when P value is P<0.05 or P-0.025. 45 s" - GTGTTCCTACCCCCAATGTATCC-3' 4. Result of Experiment Reverse primer: It was confirmed that mRNA expressions of IL-17A and (SEO ID NO; 5) IFN-Y in colon tissue were significantly enhanced by intrap s' - GATGTCATCATACTTGGCAGGTTT-3' eritoneally administering an anti-CD3 antibody to Balb/c 50 Probe: mice, compared with the saline-administered group. Regard (SEQ ID NO : 6) ing these increases of expression, the compound of Example s' - TTGTGGATCTGACATGCCGCCTG-3' 14 (30, 100 and 300 mg/kg, po) significantly suppressed 4. Result of Experiment IL-17A expression in a dose-dependent manner, and the inhi The compound of Example 14 (30, 100 and 300 mg/kg, po) 55 tended to Suppress the increase in IL-17A gene expression in bition rates were 10, 25 and 53%, respectively (FIG. 1). On lymph node of EAE-sensitized rat in a dose-dependent man the other hand, it did not affect IFN-Y expression (FIG. 2). ner (FIG. 3). Experimental Example 8 INDUSTRIAL APPLICABILITY 60 The compound of the present invention has a Superior Effect on IL-17A Gene Expression in Lymph Node RORyt inhibitory action, and useful as an agent for the pro of EAE Rat Model phylaxis or treatment of inflammatory bowel disease (IBD), ulcerative colitis (UC), Crohn's disease (CD), rheumatoid 1. EAE (Experimental Allergic Encephalomyelitis) Sensiti arthritis, multiple Sclerosis, psoriasis and the like. Zation 65 This application is based on patent application No. 207358/ A killed Mycobacterium tuberculosis, H37Ra (DIFCO), 2011 filed in Japan, the contents of which are encompassed in was suspended at the concentration of 2 mg/mL in Freund full herein. US 9,120,776 B2 143 144

SEQUENCE LISTING

<16O is NUMBER OF SEO ID NOS: 6

<210s, SEQ ID NO 1 &211s LENGTH: 19 &212s. TYPE: DNA <213> ORGANISM: Artificial 22 Os. FEATURE: <223> OTHER INFORMATION: Forward primer for rat IL-17A

<4 OOs, SEQUENCE: 1 gctic Cagaag gcc ct caga 19

<210s, SEQ ID NO 2 &211s LENGTH: 19 &212s. TYPE: DNA <213> ORGANISM: Artificial 22 Os. FEATURE: <223> OTHER INFORMATION: Reverse primer for rat IL-17A

<4 OOs, SEQUENCE: 2 gtcct cattg cggct Caga 19

<210s, SEQ ID NO 3 &211s LENGTH: 27 &212s. TYPE: DNA <213> ORGANISM: Artificial 22 Os. FEATURE: <223 is OTHER INFORMATION: Probe for rat IL-17A

<4 OOs, SEQUENCE: 3 tacct caa.cc gttccactitc accctgg 27

<210s, SEQ ID NO 4 &211s LENGTH: 23 &212s. TYPE: DNA <213> ORGANISM: Artificial 22 Os. FEATURE: <223> OTHER INFORMATION: Forward primer for rat GAPDH

<4 OOs, SEQUENCE: 4 gtgttcctac ccc caatgta t co 23

<210s, SEQ ID NO 5 &211s LENGTH: 24 &212s. TYPE: DNA <213> ORGANISM: Artificial 22 Os. FEATURE: <223> OTHER INFORMATION: Reverse primer for rat GAPDH

<4 OOs, SEQUENCE: 5 gatgtcatca tacttggcag gttt 24

<210s, SEQ ID NO 6 &211s LENGTH: 23 &212s. TYPE: DNA <213> ORGANISM: Artificial 22 Os. FEATURE: 223 OTHER INFORMATION: Prole for at GAPDH

<4 OOs, SEQUENCE: 6 ttgttggat.ct gaCatgcc.gc ctg 23 US 9,120,776 B2 145 146 The invention claimed is: -continued 1. A compound represented by the formula (I): (Ig)

(I) R34 (Ih) Q R2A / B -HCN 10

N SA A R RIA wherein 15 R'' is an optionally substituted hydrocarbon group or an (I) optionally substituted hydrocarbon-oxy group, R" and Rare each independently a hydrogen atom, an optionally substituted hydrocarbon group, an optionally Ik Substituted hydrocarbon-oxy group, an acyl group, a O R4A (Ik) halogen atom, a cyano group, an optionally substituted hydrocarbon-amino group, an optionally substituted hydrocarbon-sulfanyl group, an optionally substituted hydrocarbon-sulfenyl group, an optionally substituted 25 hydrocarbon-sulfonyl group or a nitro group, or R'' and R' optionally form, together with the carbon atoms (II) which they are bonded to, an optionally substituted hydrocarbon ring, 30 R" is a hydrogen atom or a halogen atom, Q is a bivalent group selected from

35 I O O (I'a) (In)

N-asH H (Ib) 40

45 (Ic)

50

wherein A") are the same or different and each is a methylene group optionally Substituted by Substituent(s) selected 55 from a hydroxy group, a phenyl group and an optionally Substituted C. alkyl group, wherein the two Substitu ents bonded to the single carbon atom are optionally combined to each other to form a hydrocarbon ring, and A are the same or different and each is a methylene 60 group optionally Substituted by Substituent(s) selected from a hydroxy group and an optionally substituted C. alkyl group, wherein the two substituents bonded to the single carbon atom are optionally combined to each other to form a hydrocarbon ring, or the methylene 65 group in A' or A is optionally combined to the Substituent on the adjacent methylene group to form an optionally Substituted hydrocarbon ring, US 9,120,776 B2 147 148 R'' and Rare the same or different and each is an option -continued ally Substituted hydrocarbon group, (I'i) X" is an oxygen atom, a Sulfur atom, or an imino group having an optionally substituted hydrocarbon group or a hydrogen atom, n is an integer of 1 to 5. n' is an integer of 1 to 4. (I) n" is an integer of 1 to 3, and x and y are each 0 or natural number, and the sum is 0 to 4, and 10 Ring B' is a benzene ring optionally having additional (Ik) Substituent(s), or a pyridine ring optionally having addi O R4A tional substituent(s), provided that when R is a halo gen atom, then Ring B' is a benzene ring optionally having additional Substituent(s), provided that 2-(2-((4- 15 cyanophenyl)amino)-2-oxoethoxy)-N-(9-ethyl-9H-car bazol-3-yl)acetamide and N-(4-cyanophenyl)-N'-(9- (II) ethyl-9H-carbazol-3-yl)-3-methylpentanediamide are excluded, or a salt thereof. 2. The compound or salt of claim 1, wherein R is a hydrogen atom, (I'm) Q is a bivalent group selected from

25

O O (In)

N-asH H 30 (Ib) O O wherein A" are the same or different and each is a methylene N-1- 35 R4A R4B group optionally Substituted by Substituent(s) selected (Ic) from a hydroxy group and an optionally substituted C. O O alkyl group, wherein the two substituents bonded to the single carbon atom are optionally combined to each N-AllH al 40 other to form a hydrocarbon ring, and AI are the same R4A or different and each is a methylene group optionally substituted by substituent(s) selected from a hydroxy O group and an optionally Substituted C. alkyl group, wherein the two substituents bonded to the single carbon 45 atom are optionally combined to each other to form a N-a-H H hydrocarbon ring, or the methylene group in A' or A O O is optionally combined to the Substituent on the adjacent methylene group to form an optionally substituted hydrocarbon ring, and the other symbols are as defined N-usH H 50 in claim 1, and (I'f) O Ring B' is a benzene ring optionally further substituted by Substituent(s) excluding cyano. 3. The compound or salt of claim 1, wherein R'' and R' N1AH 1 55 are each independently a C- alkyl group, or R'' and R' O form, together with the carbon atoms which they are bonded O (Ig)I to, an optionally Substituted hydrocarbon ring. 4. The compound or salt of claim 1, wherein Q'is a bivalent Rul group selected from YA1S1\H 60 O H H (Ih) N N O O Y (A), 1 65 O O n-isH H US 9,120,776 B2 149 150 -continued -continued (I'f) (Ib) O O O NN l (A), 1 H N-- O (I) (Ic) O O O

10 nor N-alH (II) O 15

(In) n-isH H

O O

N-a-s-sH H wherein each symbol is as defined in claim 1. O 5. N-(4-Cyanophenyl)-N'-(9-ethyl-2.3.4.9-tetrahydro-1H carbazol-6-yl)-3-methylpentanediamide or a salt thereof. 25 l 6. N-(3-Chloro-4-cyanophenyl)-N'-(9-ethyl-9H-carbazol NNH A11 1 3-yl)-3-methylpentanediamide or a salt thereof. 7. N-(4-(3-Chloro-4-cyanophenyl)amino-2-methyl-4- (Ig) oxobutyl-9-ethyl-9H-carbazole-3-carboxamide or a salt thereof. 30 8. A medicament comprising a compound represented by the formula (I"): (Ih)

- - - - (I) 35

Q R2A / B -HCN 40 N SA A R RIA (I) wherein R'' is an optionally substituted hydrocarbon group or an 45 optionally substituted hydrocarbon-oxy group, R" and Rare each independently a hydrogen atom, an (Ik) optionally substituted hydrocarbon group, an optionally O R4A Substituted hydrocarbon-oxy group, an acyl group, a halogen atom, a cyano group, an optionally substituted 50 hydrocarbon-amino group, an optionally substituted hydrocarbon-sulfanyl group, an optionally substituted hydrocarbon-sulfenyl group, an optionally substituted (II) hydrocarbon-sulfonyl group or a nitro group, or R' and R optionally form, together with the carbon atoms 55 which they are bonded to, an optionally substituted hydrocarbon ring, R" is a hydrogen atom or a halogen atom, Q is a bivalent group selected from 60

(In) O O

65 N-asH H US 9,120,776 B2 151 152 -continued R'' and Rare the same or different and each is an option (I'o) ally Substituted hydrocarbon group, O X" is an oxygen atom, a Sulfur atom, or an imino group H ls having an optionally substituted hydrocarbon group or a N a A. N1N and 5 hydrogen atom, H n is an integer of 1 to 5. O n' is an integer of 1 to 4. (I'p) n" is an integer of 1 to 3, and l x' and y are each 0 or natural number, and the sum is 0 to 10 4, and YN 1N1N Ring B' is a benzene ring optionally having additional Substituent(s), or a pyridine ring optionally having addi tional substituent(s), provided that when R is a halo wherein gen atom, then Ring B' is a benzene ring optionally A") are the same or different and each is a methylene 15 having additional Substituent(s), or a salt thereof. group optionally Substituted by Substituent(s) selected 9. The medicament of claim 8, which is an RORyt inhibitor. from a hydroxy group, a phenyl group and an optionally 10. The medicament of claim 8, which is an agent for the Substituted C. alkyl group, wherein the two Substitu- treatment of inflammatory bowel disease (IBD), ulcerative ents bonded to the single carbon atom are optionally colitis (UC), Crohn's disease (CD), rheumatoid arthritis, combined to each other to form a hydrocarbon ring, and 20 multiple Sclerosis or psoriasis. A are the same or different and each is a methylene 11. A method of inhibiting RORyt, which comprises group optionally Substituted by Substituent(s) selected administering an effective amount of the compound or salt of from a hydroxy group and an optionally substituted C. claim 1 to a mammal. alkyl group, wherein the two substituents bonded to the 12. A method for the treatment of inflammatory bowel single carbon atom are optionally combined to each disease (IBD), ulcerative colitis (UC), Crohn's disease (CD), other to form a hydrocarbon ring, or the methylene rheumatoid arthritis, multiple Sclerosis or psoriasis, which group in A' or A is optionally combined to the comprises administering an effective amount of the com Substituent on the adjacent methylene group to form an pound or salt of claim 1 to a mammal. optionally substituted hydrocarbon ring, k . . . .