US 12,479,866 B2
Boron-containing rho kinase inhibitors
Robert Eugene Hormann, Melrose Park, PA (US); and Malla Padidam, Chalfont, PA (US)
Assigned to Percipiad, Inc.
Appl. No. 17/627,537
Filed by Percipiad, Inc., Warminster, PA (US)
PCT Filed Jul. 17, 2020, PCT No. PCT/US2020/042538
§ 371(c)(1), (2) Date Jan. 14, 2022,
PCT Pub. No. WO2021/011873, PCT Pub. Date Jan. 21, 2021.
Claims priority of provisional application 62/875,270, filed on Jul. 17, 2019.
Prior Publication US 2022/0389035 A1, Dec. 8, 2022
Int. Cl. C07F 5/02 (2006.01); A61K 45/06 (2006.01); A61P 25/28 (2006.01); A61P 27/06 (2006.01)
CPC C07F 5/025 (2013.01) [A61K 45/06 (2013.01)] 20 Claims
 
1. A compound of Formula 1 or a pharmaceutically acceptable salt or solvate thereof:

OG Complex Work Unit Chemistry
or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein:
E is selected from the group consisting of CH, C—OH, N, or NH,
G is CH, or, when E is NH, G is absent;
J is —(CH2)n-A6, or

OG Complex Work Unit Chemistry
A1, A2, R2 and R3 are each —H or C1-C6 alkyl;
A3 and A4 are each selected from the group consisting of hydrogen, halo, C1-C6 alkyl, nitro, cyano, hydroxy, amino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, alkoxy, alkylthio, alkoxyalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkylaminoalkenyl, dialkylaminoalkenyl,

OG Complex Work Unit Chemistry
R5a and R5b are selected from a side chain of any natural amino acid, C1-C6 alkyl, trifluoro-C1-C6 alkyl, —(CH2)nSH, —(CH2)nNH—C(═NH)NH2, —(CH2)nCO2H, —(CH2)nNH2, —(CH2)nCH(NH2)(CO2H), —(CH2)nSO3H, —(CH2)nNR6R7, —(CH2)n-pyridyl, —(CH2)nONO2;
A6 is —(CR6R7)nB(R8R9),

OG Complex Work Unit Chemistry
or A6 together with either A3 or A4 form
—BR8O(CR6R7)nO—, —BR8O(CR6R7)nNR6—, —BR8O(CR6R7)n—, —BR8NR6(CR6R7)nO—, —BR8NR6(CR6R7)nNR6—, —BR8NR6(CR6R7)n—, —B(R8)2N(R6)2(CR6R7)nO—, —B(R8)2N(R6)2(CR6R7)nNR6—, —B(R8)2N(R6)2(CR6R7)n—, —BR8—O—N═CH—, —BR8NR6N═CH—, —B(R8)2N(R6)2N═CH—, —BR8—O—CR6—N—, —BR8NR6CR6—N—, —BR8—O—C(═O)NR6—, —BR8NR6C(═O)NR6—, —BR8—O—C(NR6)—N—, —BR8NR6C(NR6)═N—, —B(R8)2N(R6)2CR6═N—, —B(R8)2N(R6)2C(═O)—N—, —B(R8)2N(R6)2C(NR6)═N—, —BR8—O—NR6—, —B(OH)—O—NH—C(O)—, —B(OH)NR6NHC(O)—, —B(OH)2N(R6)2NHC(O)—, —OBR8CH═CH—, —NR6BR8CH═CH—, —N(R6)2B(R8)2CH═CH—, —OBR8(CR6R7)nO—, —OBR8(CR6R7)nNR6—, —OBR8(CR6R7)n—, —NR6BR8(CR6R7)nO—, —NR6BR8(CR6R7)nNR6—, —NR6BR8(CR6R7)n, —N(R6)2B(R8)2(CR6R7)nO—, —N(R6)2B(R8)2 (CR6R7)nNR—, —N(R6)2B(R8)2(CR6R7)n—, —BR8—O—CH═CH—, —BR8NR6CH═CH—, —B(R8)2N(R6)2CH═CH—;
R6 and R7 are each H, C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, trifluoro C1-C6 alkyl, acetyl, phenyl, C1-C6 alkylsulfonyl;
R8 and R9 are each fluoro, hydroxy or alkoxy; or —B(R8R9) forms a fluoride adduct, hydroxy acid adduct, or an amino acid adduct;
n and m are each 0, 1, 2, 3, or 4.