US 11,667,644 B2
Disubstituted octahydropyrrolo[3,4-c]pyrroles as orexin receptor modulators
Wenying Chai, San Diego, CA (US); Michael A. Letavic, San Diego, CA (US); Kiev S. Ly, San Diego, CA (US); Daniel J. Pippel, Del Mar, CA (US); Dale A. Rudolph, San Diego, CA (US); Kathleen C. Sappey, San Diego, CA (US); Brad M. Savall, San Diego, CA (US); Chandravadan R. Shah, San Diego, CA (US); Brock T. Shireman, Poway, CA (US); Akinola Soyode Johnson, San Diego, CA (US); Emily M. Stocking, Encinitas, CA (US); and Devin M. Swanson, La Jolla, CA (US)
Assigned to Janssen Pharmaceutica NV, Beerse (BE)
Filed by Janssen Pharmaceutica NV, Beerse (BE)
Filed on Jul. 9, 2021, as Appl. No. 17/372,168.
Application 17/372,168 is a continuation of application No. 16/601,832, filed on Oct. 15, 2019, granted, now 11,059,828.
Application 16/601,832 is a continuation of application No. 15/413,965, filed on Jan. 24, 2017, abandoned.
Application 15/413,965 is a continuation of application No. 14/734,225, filed on Jun. 9, 2015, abandoned.
Application 14/734,225 is a continuation of application No. 14/138,941, filed on Dec. 23, 2013, granted, now 9,079,911, issued on Jul. 14, 2015.
Application 14/138,941 is a continuation of application No. 13/503,231, granted, now 8,653,263, issued on Feb. 18, 2014, previously published as PCT/US2010/053606, filed on Oct. 21, 2010.
Claims priority of provisional application 61/254,509, filed on Oct. 23, 2009.
Prior Publication US 2021/0347781 A1, Nov. 11, 2021
Int. Cl. C07D 487/04 (2006.01); A61K 31/5377 (2006.01); A61K 31/506 (2006.01); A61K 31/428 (2006.01); A61K 31/498 (2006.01); A61K 31/4709 (2006.01); A61K 31/4439 (2006.01); A61K 31/53 (2006.01)
CPC C07D 487/04 (2013.01) [A61K 31/428 (2013.01); A61K 31/4439 (2013.01); A61K 31/4709 (2013.01); A61K 31/498 (2013.01); A61K 31/506 (2013.01); A61K 31/53 (2013.01); A61K 31/5377 (2013.01)] 31 Claims
 
1. A process for preparing a compound of Formula (I):

OG Complex Work Unit Chemistry
wherein:
R1 is selected from the group consisting of:
A) phenyl substituted or unsubstituted with one or two Ra members, and substituted in the ortho position with Rb, wherein:
Ra is independently selected from the group consisting of —H, halo, —C1-4alkyl, —C1-4alkoxy, and —NO2, wherein two adjacent Ra members may come together to form a six membered aromatic ring;
Rb is a member selected from the group consisting of:
a) halo, —C1-4alkoxy, —C1-4alkyl, —CF3, —OCF3, or —CN;
b) 5-membered heteroaryl ring containing one oxygen or one sulfur members;
c) 5-6 membered heteroaryl ring containing one, two or three nitrogen members, optionally containing one oxygen member, substituted or unsubstituted with halo or —C1-4alkyl; and
d) phenyl substituted or unsubstituted with halo, —CH3, or —CF3;
B) pyridine substituted or unsubstituted with one or two Rc members and substituted with Rd, wherein Rd is positioned adjacent to the point of attachment by R1;
Rc is C1-4alkyl;
Rd is a member selected from the group consisting of:
a) 5-6 membered heteroaryl ring selected from the group consisting of 1H-1,2,3-triazol-1-yl, 2H-1,2,3-triazol-2-yl, 1H-pyrazol-5-yl, 3-methyl-1,2,4-oxadiazol-5-yl, pyridinyl, 3-methyl-pyridin-2-yl, 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl), and pyrimidin-2-yl;
b) —CF3, —Br, and —C1-4alkoxy;
C) 5-membered heteroaryl ring selected from the group consisting of 2-methyl-1,3-thiazol-yl, 1H-pyrazol-5-yl, oxazole, isoxazolyl, thiophen-2-yl, and furan-2-yl, each substituted with phenyl substituted or unsubstituted with —F; and
D) 5-13 membered aryl or heteroaryl ring selected from the group consisting of 3-methylfuran-2-yl, 9H-fluorene, quinoline, cinnoline, 3-(1H-pyrrol-1-yl)thiophen-2-yl, 8-[1,2,3]-triazol-2-yl-naphthalen-1-yl, 2,3-dihydro-1,4-benzodioxin-5-yl, 1H-indol-7-yl, 4-fluoronaphthalen-1-yl, and naphthalen-1-yl;
R2 is selected from the group consisting of:
A) 6-membered heteroaryl ring containing two nitrogen members substituted with one or more members independently selected from the group consisting of halo, —C1-4alkyl, —CD3, -D, —C1-4alkoxy, cyclopropyl, morpholin-2-yl, —CO2C1-4alkyl, —CO2H, —CH2OH, —C(O)N(C1-4alkyl)2, —CF3, —CN, —OH, —NO2, —N(C1-4alkyl)2, phenyl, furan-2-yl, thiophen-2-yl, 1H-pyrazol-4-yl, and pyrrolidin-1-yl;
B) pyridine substituted with one or two members independently selected from the group consisting of halo, —C1-4alkyl, —C1-4alkoxy, and —CF3;
C) 9-membered heteroaryl ring selected from the group consisting of benzooxazol-2-yl, 6-fluoro-1,3-benzothiazole, 1,3-benzothiazole, 6-methoxy-1,3-benzothiazole, 6-methyl-1,3-benzothiazole, 6-chloro-benzothiazol-2-yl, and 4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine;
D) 10-membered heteroaryl ring selected from the group consisting of quinoxalin-2-yl, 3-methylquinoxalin-2-yl, 6,7-difluoroquinoxalin-2-yl, 3-(trifluoromethyl)quinoxaline, quinoline, 4-methylquinoline, and 6-fluoroquinazolin-2-yl; and
E) 4-methyl-1,3,5-triazin-2-yl or 2-methylpyrimidin-4(3H)-one,
the process comprising reacting a compound of Formula (I-a):

OG Complex Work Unit Chemistry
wherein, W is benzyl or BOC, with R1CO2H or R1COCl to form a compound of Formula (I-b):

OG Complex Work Unit Chemistry
deprotecting the compound of Formula (I-b) to form a compound of formula (I-c):

OG Complex Work Unit Chemistry
 and
reacting the compound of Formula (I-c) with R2Cl to form the compound of Formula (I).