US 12,404,286 B2
Boron containing pyrazole compounds, compositions comprising them, methods and uses thereof
Alan Long, Warthausen (DE); Chun Yu Liu, Durham, NC (US); Chunliang Liu, Cary, NC (US); Yasheen Zhou, Moraga, CA (US); Shon R. Pulley, Trenton, SC (US); and Keith Andrew Newton Graham, Berlin (DE)
Assigned to BORAH, INC., Nashville, TN (US)
Filed by Borah, Inc., Nashville, TN (US)
Filed on Nov. 16, 2023, as Appl. No. 18/510,888.
Application 18/510,888 is a division of application No. 17/644,023, filed on Dec. 13, 2021, granted, now 11,827,657.
Claims priority of provisional application 63/127,329, filed on Dec. 18, 2020.
Prior Publication US 2024/0352045 A1, Oct. 24, 2024
Int. Cl. C07F 5/02 (2006.01)
CPC C07F 5/025 (2013.01) 18 Claims
 
1. A method for treating a patient having pruritus comprising administering a therapeutically effective amount of a compound of formula (IV):

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt or a stereoisomer or a tautomer thereof,
wherein
X1 is selected from the group consisting of —O—, —N(R6)—, and —C(R7)(R8)—;
X2 is selected from the group consisting of —O—, —N(R6)—, and —C(R7)(R8)—, or
X2 comprises a bond between X1 and X3;
X3 is selected from the group consisting of —O—, —N(R6)—, and —C(R7)(R8)—, except X1 and X2 cannot both be —O—, and X2 and X3 cannot both be —O—;
R1 is selected from the group consisting of hydrogen, halogen (when X3 is —C(R7)(R8)), hydroxy, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkyl(oxy), and C3-7 cycloalkyl(oxy), wherein the last four members of the of the above-mentioned R1 group may optionally be substituted independently of one another with one or more halogen;
R2 is selected from the group consisting of hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkyl(oxy), and C3-7 cycloalkyl(oxy), wherein the last four members of the above-mentioned R2 group may optionally be substituted independently of one another with one or more halogen;
each R3 is independently selected from the group consisting of hydrogen, halogen (when X1 is —C(R7)(R8)), C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkyl(oxy), and C3-7 cycloalkyl(oxy), wherein the last four members of the above-mentioned R3 group may optionally be substituted independently of one another with one or more halogen;
each R4 is independently selected from the group consisting of hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkyl(oxy), and C3-7 cycloalkyl(oxy), wherein the above-mentioned members of each R4 group, except hydrogen, may optionally be substituted independently of one another with one or more halogen;
A is selected from the group consisting of benzo[c][1,2]oxaborol-1 (3H)-ol, 3,4-dihydro-1Hbenzo[c][1,2]oxaborinin-1-ol, and 2H-benzo[e][1,2]oxaborinin-2-ol, or a derivative thereof; or
A is a moiety selected from any one of A1-A6:

OG Complex Work Unit Chemistry
R6 is selected from the group consisting of hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkyl(oxy), C3-7 cycloalkyl(oxy), —COO—C1-6 alkyl, —COO—C3-7-cycloalkyl, —(C1-3-alkyl)-(C3-6-cycloalkyl), —(C2-3-alky(oxy)-(C2-6-alkyl), —(C2-3-alkyl(oxy)-(C3-6-cycloalkyl), 4-7-membered heterocycloalkyl, —(C1-3-alkyl)-(4-7-membered heterocycloalkyl), -heteroaryl, and —(C1-3-alkyl)-(heteroaryl), wherein the above-mentioned members of the R6 group, except hydrogen, may optionally be substituted independently of one another by one or more substituents selected from the group consisting of C1-6 alkyl and halogen, except halogen may not be adjacent to a heteroatom;
R7 and R8 are independently selected from the group consisting of hydrogen, halogen, hydroxy, —N(R9)(R10), —O(R11), C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkyl(oxy), C3-7 cycloalkyl(oxy), —COO—C1-6 alkyl, —COO—C3-7-cycloalkyl, —(C1-3-alkyl)-(C3-6-cycloalkyl), —(C2-3-alkyl(oxy)-(C2-6-alkyl), —(C2-3-alkyl(oxy)-(C3-6-cycloalkyl), 4-7-membered heterocycloalkyl, —(C1-3-alkyl)-(4-7-membered heterocycloalkyl), -heteroaryl, and —(C1-3-alkyl)-(heteroaryl), wherein the last fifteen members of the above-mentioned R7 and R8 groups may optionally be substituted independently of one another by one or more substituents selected from the group consisting of halogen and hydroxy, and wherein R7 and R8 may be linked together to form a ring;
R9 and R10 are independently selected from the group consisting of hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkyl(oxy), C3-7 cycloalkyl(oxy), —COO—C1-6 alkyl, —COO—C3-7-cycloalkyl, —(C1-3-alkyl)-(C3-6-cycloalkyl), —(C2-3-alkyoxyl)-(C2-6-alkyl), —(C2-3-alkyl(oxy)-(C3-6-cycloalkyl), 4-7-membered heterocycloalkyl, —(C1-3-alkyl)-(4-7-membered heterocycloalkyl), -heteroaryl, and —(C1-3-alkyl)-(heteroaryl); wherein the last fourteen members of the above-mentioned R9 and R10 groups may optionally be substituted independently of one another by one or more halogen, or R9 and R10 may be linked together to form a ring;
R11 is selected from the group consisting of hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkyl(oxy), C3-7 cycloalkyl(oxy), —COO—C1-6 alkyl, —COO—C3-7-cycloalkyl, —(C1-3-alkyl)-(C3-6-cycloalkyl), —(C2-3-alkyoxyl)-(C2-6-alkyl), —(C2-3-alkyl(oxy)-(C3-6-cycloalkyl), 4-7-membered heterocycloalkyl, —(C1-3-alkyl)-(4-7-membered heterocycloalkyl), -heteroaryl, and —(C1-3-alkyl)-(heteroaryl), wherein the last thirteen members of the above-mentioned R11 group may optionally be substituted independently of one another by one or more substituents selected from the group consisting of halogen and hydroxy, except that said optional substitution may not be geminal;
each R12 is independently selected from the group consisting of hydrogen, halogen, C1-6 alkyl, C3-7 cycloalkyl, 4-7-membered heterocycloalkyl, C1-6 alkyl(oxy), and C3-7 cycloalkyl(oxy), wherein the last four members of the above-mentioned R12 group may optionally be substituted independently of one another by one or more substituents selected from the group consisting of halogen and hydroxy, except when R12 is adjacent to oxygen, R12 is not halogen, and two adjacent R12 may be connected to provide a fused cycloalkyl; and
R13 and R14 are independently selected from the group consisting of hydrogen, halogen, cyano, C1-6 alkyl, C3-7 cycloalkyl, C1-6 alkyl(oxy), C3-7 cycloalkyl(oxy), —(C1-3-alkyl)-(C3-6-cycloalkyl), —(C2-3-alkyl(oxy)-(C2-6-alkyl), —(C2-3-alkyl(oxy)-(C3-6-cycloalkyl), 4-7-membered heterocycloalkyl, —(C1-3-alkyl)-(4-7-membered heterocycloalkyl), —N—(R6)(R6), —SO2—(R6), —SO2—(R6)(R6), —S(O)—(R6), and —S—(R6), wherein the last fourteen members of the above-mentioned R13 and R14 groups may optionally be substituted independently of one another by one or more substituents selected from the group consisting of halogen and hydroxy,
wherein the pruritus is susceptible to modulation of JAK.