	US 11,685,745 B2
	Substituted benzoxazole and benzofuran compounds as PDE7 inhibitors
Vincent John Santora, San Diego, CA (US); Mi Chen, San Diego, CA (US); and DeMichael Chung, San Diego, CA (US)
Assigned to Dart Neuroscience, LLC, Dallas, TX (US)
Appl. No. 16/629,922
Filed by Dart NeuroScience, LLC, San Diego, CA (US)
PCT Filed Jul. 11, 2018, PCT No. PCT/US2018/041565 § 371(c)(1), (2) Date Jan. 9, 2020, PCT Pub. No. WO2019/014305, PCT Pub. Date Jan. 17, 2019.
Claims priority of provisional application 62/531,802, filed on Jul. 12, 2017.
Prior Publication US 2022/0267351 A1, Aug. 25, 2022
Int. Cl. C07D 498/10 (2006.01); C07D 519/00 (2006.01)

CPC C07D 498/10 (2013.01) [C07D 519/00 (2013.01)]

32 Claims

1. A compound of Formula (I):

or pharmaceutically acceptable salt thereof,

wherein,

X is —CH or —N;

Y is selected from the group consisting of: —H, halo, and —C_1-4alkyl;

each Z is independently selected from the group consisting of: —H, -halo, and —C_1-4alkyl;

V is selected from the group consisting of: a bond, —(CH₂)_m—, —(CH₂)_mO(CH₂)_n—, —(CH₂)_mO(CH₂)_nC(O)—, —(CH₂)_MN[(CH₂)_NR^1A]—, —(CH₂)_mC(O)O—, —(CH₂)_mC(O)—, —(CH₂)_mC(O)N[(CH₂)_nR^1A]—, -L¹-L²-, -L¹-L²-L³-, -L¹-L²-L³-L⁴-, and -L¹-L⁵;

each m is independently 0, 1, 2 or 3;

each n is independently 0, 1, 2 or 3;

L¹is —C(O)(CH₂)_m—, —[C(R^1A)₂]_m— or —(CH₂)_m—;

L²is —N[(CH₂)_nR^1A]— or —N((CH₂)_nR^1A)(CH₂)_p—;

L³is selected from the group consisting of —(CH₂)_m—C_3-7cycloalkyl, —[C((CH₂)_nR^1B)₂]_m[C((CH₂)_nR^1C)₂]_n—, —[N[(CH₂)_mR^1A](CH₂)_n]—, —[(CH₂)_mN((CH₂)_nR^1A)(CH₂)_p]—, —[(CH₂)_mC(O)N((CH₂)_nR^1B)(CH₂)_p]—, —(CH₂)_mC(O)—, —[C(R^1A)₂]_m— and —[(CH₂)_pO]—;

L⁴is selected from the group consisting of —(CH₂)_mC(O)—, —(CH₂)_mO—, —C_1-6alkyl, —C_3-7cycloalkyl, heteroaryl, aryl, 3-10 membered heterocycloalkyl, and —CH(OH)—, said —C_1-6alkyl, —C_3-7cycloalkyl, heteroaryl, aryl, and 3-10 membered heterocycloalkyl each optionally substituted with one to four R^2A;

L⁵is selected from the group consisting of —C(O)(CH₂)_mN[(CH₂)_nR^1B]—, —C(O)(CH₂)_m—, —CH(OH)— and —(CH₂)_mC(O)O—;

each p is independently 0, 1, 2 or 3;

each R^1Ais independently selected from the group consisting of: —H, —OH, —CN, halo, —C_1-6alkyl, —C_2-6alkenyl, —C_2-6alkynyl, —C_3-7cycloalkyl, aryl, heteroaryl, 3-15 membered heterocycloalkyl, —C_1-6haloalkyl, and —C_1-6alkoxy, said —C_3-7cycloalkyl, aryl, heteroaryl, 3-15 membered heterocycloalkyl, —C_1-6haloalkyl, and —C_1-6alkoxy each optionally substituted with one to four R^2A;

each R^1Bis independently selected from the group consisting of: —H, —OH, —CN, halo, —C_1-6alkyl, —C_2-6alkenyl, —C_2-6alkynyl, —C_3-7cycloalkyl, aryl, heteroaryl, 3-15 membered heterocycloalkyl, —C_1-6haloalkyl, and —C_1-6alkoxy, said —C_3-7cycloalkyl, aryl, heteroaryl, 3-15 membered heterocycloalkyl, —C_1-6haloalkyl, and —C_1-6alkoxy each optionally substituted with one to four R^2A;

each R^1Cis independently selected from the group consisting of: —H, —OH, —CN, halo, —C_1-6alkyl, —C_2-6alkenyl, —C_2-6alkynyl, —C_3-7cycloalkyl, aryl, heteroaryl, 3-15 membered heterocycloalkyl, —C_1-6haloalkyl, and —C_1-6alkoxy, said —C_3-7cycloalkyl, aryl, heteroaryl, 3-15 membered heterocycloalkyl, —C_1-6haloalkyl, and —C_1-6alkoxy each optionally substituted with one to four R^2A;

W is selected from the group consisting of: —H, -halo, —OH, —CN, —C_1-6alkyl, —C_1-6haloalkyl, aryl, heteroaryl, 3-15 membered heterocycloalkyl, —C_3-7cycloalkyl, —SO₂C_1-6alkyl, —(CH₂)_mR^1A, —(CH₂)_mN(R^1B)₂, —(CH₂)_mO(CH₂)_nR^1A, —(CH₂)_mS(CH₂)_nR^1A, —(CH₂)_mC(O)C_1-6alkyl, —(CH₂)_mC(O)heterocycloalkyl, —(CH₂)_mC(O)OH, —(CH₂)_mC(O)OC_1-6alkyl, —(CH₂)_mC(O)NH₂, —(CH₂)_mC(O)N(C_1-4alkyl)₂, and —(CH₂)_mC(O)NH(C_1-4alkyl), said aryl, heteroaryl, 3-15 membered heterocycloalkyl, and —C_3-7cycloalkyl, each optionally substituted with one to five R^3A;

each R^2Ais independently selected from the group consisting of: halo, —CN, ═O, —OH, —SO₂C_1-6alkyl, —C_1-6alkyl, —C_1-6alkoxy, —C_1-6haloalkyl, aryl, heteroaryl, 3-15 membered heterocycloalkyl, —C_3-7cycloalkyl, —(CH₂)_mN(C_1-4alkyl)₂, —OCH₂(CH₂)_mR^2AA, —CH₂(CH₂)_mR^2AA, —C_1-6alkyl-OH, —C_1-6haloalkylOH, —C_1-6haloalkyl-C_3-7cycloalkyl, —C_2-6alkenyl, —C_2-6alkynyl, —C(O)C(CH₃)₃, —OC_3-7cycloalkyl, —C(O)C_1-6alkyl, —C(O)aryl, —C(O)heterocycloalkyl, —C(O)OC_1-6alkyl, —C(O)R^2AA, —NHC(O)R^2AA, —C(O)NH(C_1-4alkyl), —C(O)N(C_1-4alkyl)₂, —CH₂CH(OH)C_3-7cycloalkyl, —C(CH₃)₂OH, —N(R^2AA)₂, —C(CH₃)₂CH₂OCH₃, —CH(CH₃)C(O)N(C_1-4alkyl)₂, and —CH₂CF₂C_3-7cycloalkyl, said aryl, heteroaryl, 3-15 membered heterocycloalkyl, and —C_3-7cycloalkyl, each optionally substituted with one to five substituents each independently selected from the group consisting of: —CN, ═O, —OH, —SO₂C_1-6alkyl, —C_1-6alkyl, —C_1-6alkoxy, —C_1-6haloalkyl, aryl, heteroaryl, 3-15 membered heterocycloalkyl, —C_3-7cycloalkyl, —N(C_1-4alkyl)₂, —NH(C_1-4alkyl), —C_2-6alkenyl, —C_2-6alkynyl, —C(O)C(CH₃)₃, —OC_3-7cycloalkyl, —C(O)C_1-6alkyl, —C(O)aryl, —C(O)heterocycloalkyl, —C(O)OC_1-6alkyl, —C(O)N(C_1-4alkyl)₂, —CH₂CH(OH)C_3-7cycloalkyl, and —C(CH₃)₂OH;

each R^3Ais independently selected from the group consisting of: halo, —CN, ═O, —OH, —SO₂C_1-6alkyl, —C_1-6alkyl, —C_1-6alkoxy, —C_1-6haloalkyl, aryl, heteroaryl, 3-15 membered heterocycloalkyl, —C_3-7cycloalkyl, —(CH₂)_mN(C_1-4alkyl)₂, —OCH₂(CH₂)_mR^3AA, —CH₂(CH₂)_mR^3AA, —C_1-6alkyl-OH, —C_1-6haloalkylOH, —C_1-6haloalkyl-C_3-7cycloalkyl, —C_2-6alkenyl, —C_2-6alkynyl, —C(O)C(CH₃)₃, —OC_3-7cycloalkyl, —C(O)C_1-6alkyl, —C(O)aryl, —C(O)heterocycloalkyl, —C(O)OC_1-6alkyl, —C(O)R^3AA, —NHC(O)R^3AA, —C(O)NH(C_1-4alkyl), —C(O)N(C_1-4alkyl)₂, —CH₂CH(OH)C_3-7cycloalkyl, —C(CH₃)₂OH, —N(R^3AA)₂, —C(CH₃)₂CH₂OCH₃, —CH(CH₃)C(O)N(C_1-4alkyl)₂, and —CH₂CF₂C_3-7cycloalkyl, said aryl, heteroaryl, 3-15 membered heterocycloalkyl, and —C_3-7cycloalkyl, each optionally substituted with one to five substituents each independently selected from the group consisting of: —CN, ═O, —OH, —SO₂C_1-6alkyl, —C_1-6alkyl, —C_1-6alkoxy, —C_1-6haloalkyl, aryl, heteroaryl, 3-15 membered heterocycloalkyl, —C_3-7cycloalkyl, —N(C_1-4alkyl)₂, —NH(C_1-4alkyl), —C_2-6alkenyl, —C_2-6alkynyl, —C(O)C(CH₃)₃, —OC_3-7cycloalkyl, —C(O)C_1-6alkyl, —C(O)aryl, —C(O)heterocycloalkyl, —C(O)OC_1-6alkyl, —C(O)N(C_1-4alkyl)₂, —CH₂CH(OH)C_3-7cycloalkyl, and —C(CH₃)₂OH;

each R^2AAis independently selected from the group consisting of: —H, —OH, —SO₂C_{1 -6}alkyl, halo, —CN, —C_1-6alkoxy, —C_1-6haloalkyl, —N(C_1-4alkyl)₂, —NH(C_1-4alkyl), —NH₂, aryl, heteroaryl, 3-15 membered heterocycloalkyl, —C_2-6alkenyl, —C_2-6alkynyl, —C_3-7cycloalkyl, —C(O)C_1-6alkyl, —C(O)heterocycloalkyl, —C(O)OC_1-6alkyl, —C(O)N(C_1-4alkyl)₂, and —C(O)aryl; and

each R^3AAis independently selected from the group consisting of: —H, —OH, —SO₂C_1-6alkyl, halo, —CN, —C_1-6alkoxy, —C_1-6haloalkyl, —N(C_1-4alkyl)₂, —NH(C_1-4alkyl), —NH₂, aryl, heteroaryl, 3-15 membered heterocycloalkyl, —C_2-6alkenyl, —C_2-6alkynyl, —C_3-7cycloalkyl, —C(O)C_1-6alkyl, —C(O)heterocycloalkyl, —C(O)OC_1-6alkyl, —C(O)N(C_1-4alkyl)₂, and —C(O)aryl.