US 12,275,718 B2
Small molecule inhibitors of galectin-3
Jacob Swidorski, Doylestown, PA (US); Brett R. Beno, Yardley, PA (US); David S. Yoon, Yardley, PA (US); and Alicia Regueiro-Ren, Yardley, PA (US)
Assigned to Bristol-Myers Squibb Company, Princeton, NJ (US)
Appl. No. 17/299,325
Filed by BRISTOL-MYERS SQUIBB COMPANY, Princeton, NJ (US)
PCT Filed Dec. 4, 2019, PCT No. PCT/US2019/064366
§ 371(c)(1), (2) Date Jun. 3, 2021,
PCT Pub. No. WO2020/117883, PCT Pub. Date Jun. 11, 2020.
Claims priority of provisional application 62/776,282, filed on Dec. 6, 2018.
Prior Publication US 2022/0009913 A1, Jan. 13, 2022
Int. Cl. C07D 405/14 (2006.01)
CPC C07D 405/14 (2013.01) 16 Claims
 
1. A compound of formula I

OG Complex Work Unit Chemistry
where:
R1 is ((R3)(R4)N)carbonyl or Ar2;
R2 is —O-L1-O—, —OCON(R5)-L2-N(R5)C(O)O—, or —O-(L3)-CON(R5)-L2-N(R5)C(O)-(L3)-O—;
L1 is alkylene;
L2 is alkylene, or —CH2-Ph-CH2—;
or N(R5)-L2-N(R5) taken together is piperazinyl, or homopiperazinyl;
L3 is alkylene;
R3 is hydrogen, alkyl, cycloalkyl, benzyl, or halobenzyl;
R4 is hydrogen or alkyl;
or (R3)(R4)N taken together is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, and is substituted with 0-3 substituents selected from halo, alkyl, and alkylcarbonyl;
R5 is hydrogen or alkyl;
R6 is hydrogen or alkyl;
R7 is hydrogen or alkyl;
or (R6)(R7)N taken together is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, and is substituted with 0-3 substituents selected from halo, alkyl, and hydroxy;
R8 is hydrogen, alkyl, alkylcarbonyl, or alkylsulfonyl;
R9 is hydrogen or alkyl;
or (R8)(R9)N taken together is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, and is substituted with 0-3 substituents selected from halo, alkyl, and alkylcarbonyl;
R10 is cyano, halo, alkoxy, or (R11)(R12)N;
R11 is hydrogen or alkyl;
R12 is hydrogen or alkyl;
or (R11)(R12)N taken together is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
R13 is hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, or alkylsulfonyl;
R14 is hydrogen or alkyl;
or (R13)(R14)N taken together is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, and is substituted with 0-3 substituents selected from halo, alkyl, and hydroxy;
R15 is hydrogen, alkyl, alkylcarbonyl, or alkylsulfonyl;
R16 is hydrogen or alkyl;
or (R15)(R16)N taken together is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, and is substituted with 0-3 substituents selected from halo, alkyl, and alkylcarbonyl;
Ar1 is pyrrolyl, furanyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, phenyl, or indolyl, and is substituted with 0-3 substituents selected from alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, (carboxy)alkyl, (alkoxycarbonyl)alkyl, (H2NCO)alkyl, (Ar3)alkyl, cycloalkyl, hydroxycycloalkyl, alkenyl, alkoxy, alkylthio, alkylsulfonyl, carboxy, alkoxycarbonyl, (alkylNH)carbonyl, (((R6)(R7)N)alkylNH)carbonyl, ((pyridinyl)alkylNH)carbonyl, (R8)(R9)N, and Ar3;
Ar2 is phenyl, pyridinyl, naphthyl, benzoxazolyl, benzothiazolyl, quinolinyl, or quinoxalinyl, and is substituted with 0-5 substituents selected from cyano, halo, alkyl, (R10)alkyl, haloalkyl, cycloalkyl, (R10) cycloalkyl, alkoxy, cycloalkoxy, haloalkoxy, and (R13)(R14)N; and
Ar3 is phenyl, naphthalinyl, biphenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinoxainyl, indolyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzisothiazolyl, benzoxazolyl, benzothiazolyl, benzodioxolyl, dihydrobenzodioxinyl, dihydroquinolinonyl, or dihydrobenzothiophene-2,2-dioxide, and is substituted with 0-5 substituents selected from cyano, nitro, halo, alkyl, haloalkyl, cycloalkyl, alkoxy, haloalkoxy, alkylthio, carboxy, alkoxycarbonyl, CONH2, and (R15)(R16)N;
or Ar3 is pyrrolyl, furanyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, or thiadiazolyl, and is substituted with 0-3 substituents selected from cyano, nitro, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, carboxy, alkoxycarbonyl, CONH2, and (R15)(R16)N;
or Ar3 is (alkylSO2)phenyl, (alkylSO2)(halo)phenyl, (aminoSO2)phenyl, (dialkylaminoSO2)phenyl, ((alkylNHSO2)alkyl)phenyl, (pyrrolyl)phenyl, (imidazolyl)phenyl, (oxazolyl)phenyl, (tetrazolyl)phenyl, ((pyridinyl)methyl)phenyl, phenoxyphenyl, (benzyloxy)phenyl, ((methyl)thiazolyl)phenyl, (thiazolyl)benzenesulfamido, ((methyl)thiadiazolyl)benzenesulfamido, (methyl)benzothiazolonyl, or fluoropyrazolopyrimidinyl;
or a pharmaceutically acceptable salt thereof.