	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

where:

R¹is ((R³)(R⁴)N)carbonyl or Ar²;

R²is —O-L¹-O—, —OCON(R⁵)-L²-N(R⁵)C(O)O—, or —O-(L³)-CON(R⁵)-L²-N(R⁵)C(O)-(L³)-O—;

L¹is alkylene;

L²is alkylene, or —CH₂-Ph-CH₂—;

or N(R⁵)-L²-N(R⁵) taken together is piperazinyl, or homopiperazinyl;

L³is alkylene;

R³is hydrogen, alkyl, cycloalkyl, benzyl, or halobenzyl;

R⁴is 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;

R⁵is hydrogen or alkyl;

R⁶is hydrogen or alkyl;

R⁷is 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;

R⁸is hydrogen, alkyl, alkylcarbonyl, or alkylsulfonyl;

R⁹is 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;

R¹⁰is cyano, halo, alkoxy, or (R¹¹)(R¹²)N;

R¹¹is hydrogen or alkyl;

R¹²is hydrogen or alkyl;

or (R¹¹)(R¹²)N taken together is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;

R¹³is hydrogen, alkyl, alkylcarbonyl, alkoxycarbonyl, or alkylsulfonyl;

R¹⁴is 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;

R¹⁵is hydrogen, alkyl, alkylcarbonyl, or alkylsulfonyl;

R¹⁶is 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;

Ar¹is 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;

Ar²is 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

Ar³is 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 Ar³is 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 Ar³is (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.