Cannabinoid receptor antagonists/inverse agonists useful for treating metabolic disorders, including obesity and diabetes

A method of treating a disease, comprising:

• administering to a mammal in need thereof a therapeutically effective amount of a compound selected from the compounds of Table A and C or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein the disease is selected from obesity, diabetes, dyslipidemia, atherosclerosis, hypertension, stroke, heart attack, cirrhosis, fatty liver disease, and a combination thereof:
• TABLE A
• Number
• Q
• Y″
• X″
• X
• 1
• CH(CH3)CH2CO2Et
• 4-Cl
• H
• Cl
• 2
• CH(CH3)CH2CO2H
• 4-Cl
• H
• Cl
• 3
• CH2CO2Me
• 4-Cl
• H
• Cl
• 4
• CH2CO2H
• 4-Cl
• H
• Cl
• 5
• CH(CH3)CO2Me
• 4-Cl
• H
• Cl
• 6
• CH(CHOHCH3)CO2Me
• 4-Cl
• H
• Cl
• 7
• CH(C(CH3)3)CO2Me
• 4-Cl
• H
• Cl
• 8
• CH2CO2Me
• 4-OMe
• 3-OMe
• Cl
• 10
• CH2CO2Me
• 4-OMe
• 3-Cl
• Cl
• 11
• CH(CH2OH)CO2Me
• 4-Cl
• H
• Cl
• 12
• CH2CONHCH2CO2Me
• 4-Cl
• H
• Cl
• 13
• CH(CH3)CONH—
• 4-Cl
• H
• Cl
• CH2CO2Me
• 14
• CH(CH(CH3)2)CONH—
• 4-Cl
• H
• Cl
• CH2CO2Me
• 15
• CH2CONHCH2CO2Me
• 4-OMe
• H
• Cl
• 16
• CH2CONH2
• 4-Cl
• H
• Cl
• 16
• CH(CH3)CONH2
• 4-Cl
• H
• Cl
• 17
• CH2CH2CONH2
• 4-Cl
• H
• Cl
• 18
• CH(CH3)CH2CONH2
• 4-Cl
• H
• Cl
• 19
• CH(C(CH3)3)CONH2
• 4-Cl
• H
• Cl
• 20
• CH(CH(CH3)2)CONH2
• 4-Cl
• H
• Cl
• 21
• CHCH(CH3)2)—
• 4-Cl
• H
• Cl
• CONHCH3
• 22
• CH(CHOHCH3)CONH2
• 4-Cl
• H
• Cl
• 23
• CH2CONH2
• 4-OMe
• H
• Cl
• 24
• CH(CH3)CONH2
• 4-OMe
• H
• Cl
• 25
• CH(CH3)CONH2
• 4-OCH2—
• H
• Cl
• CN
• 26
• C(CH3)2CONH2
• 4-Cl
• H
• Cl
• 27
• CH2CH(CH3)CONH2
• 4-Cl
• H
• Cl
• 28
• CH(CH3)CONH2
• 4-OMe
• 4-OMe
• Cl
• 29
• CH(CH3)CONH2
• 4-OMe
• 3-Cl
• Cl
• 30
• CH2CONH2
• 4-Cl
• H
• OMe
• 31
• CH(CH(CH3)2)CONH2
• 3-OMe
• H
• Cl
• 32
• CH2CH2CONH2
• 4-Cl
• H
• Cl
• TABLE C
• Number
• Q
• Y″
• X″
• X
• 1
• Me
• 4-OCH2CO2Et
• H
• Cl
• 2
• Me
• 4-CONHOH
• Cl
• Cl.

A method of treating a co-morbidity of obesity, comprising:

• administering to a mammal in need thereof a therapeutically effective amount of a compound of formula I or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the co-morbidity is selected from diabetes, dementia, and heart disease:
• wherein:
• X, Y, X′, Y′, X″, and Y″ are independently selected from:
• H, C1-6 alkyl, halogen, CF3, O—C1-6 alkyl, NO2, NR2, O(CH2)nCO2R, O(CH2)nCN, OCH2CH═CHCO2R, CH2O(CH2)nCO2R, CH2OCH2CH═CHCO2R, O(CH2)nPO(OR)2, CH2O(CH2)nPO(OR)2, NRa(CH2)nCO2R, NRa(CH2)nPO(OR)2, NRaCH2CH═CHCO2R, NRaSO2R, NRaCO(CH2)nCO2R, NRaCO(CH2)nCONRa2, O(CH2)nC6H4CO2R, O(CH2)nC6H4(CH2)nCO2R, CH2O(CH2)nC6H4CO2R, O(CH2)nC6H4CONRa2, O(CH2)nC6H4(CH2)nCONRa2, O(CH2)nC6H4-tetrazole, CH2O(CH2)nC6H4CONRa2, CH2O(CH2)nC6H4-tetrazole, O(CH2)nC6H4(CH2)n-tetrazole, NRa(CH2)nC6H4CO2R, CH2NRa(CH2)nC6H4CO2R, NRa(CH2)nC6H4(CH2)nCO2R, NRa(CH2)nC6H4CONRa2, CH2NRa(CH2)nC6H4CONRa2, NRa(CH2)nC6H4(CH2)nCONRa2, NRa(CH2)nC6H4-tetrazole, CH2NRa(CH2)nC6H4-tetrazole, NRa(CH2)nC6H4(CH2)n-tetrazole, CONHOH, C(NH)NRa2, (CH2)nC(NH)NRa2, O(CH2)nCONRa2, O(CH2)nC(NH)NRa2, O(CH2)nC(NOH)NRa2, CH2O(CH2)nCONRa2, NRa(CH2)nCONRa2, OCH2CH═CHCONRa2, CH2OCH2CH═CHCONRa2, NRaCH2CH═CHCONRa2, (CH2)m-tetrazole, O(CH2)n-tetrazole, O(CH2CH2O)pR, NRa(CH2CH2O)pR, and SO2NHCH3;
• Z is selected from:
• H, C1-6 alkyl, OH, O—C1-6 alkyl, O(CH2CH2O)pR, OC(O)—C1-6 alkyl, O (CH2)nCO2R, OCH2CH═CHCO2R, O(CH2)nPO(OR)2,O(CH2)nCONRa2, O(CH2)nC(NH)NH2, O(CH2)nC(NOH)NRa2, OCH2CH═CHCONRa2, O(CH2)n-phenyl-(CH2)mCO2R, and O(CH2)n-phenyl-(CH2)m-tetrazole;
• Z′ is selected from H, CO2R, and CONRa2;
• Q is selected from:
• (CH2)nCHA(CH2)mC(O)NR2, (CH2)mCAA″(CH2)mC(O)NR2, (CH2)nCHA(CH2)mCO2R, (CH2)mCAA″(CH2)mCO2R, (CH2)mCHA(CH2)mSO2NR2, (CH2)mCHA(CH2)mSO3R, (CH2)mCHA(CH2)mC(NH)NH2, CH2)mCHA(CH2)mC(NOH)NH2, (CH2)mCHA(CH2)mCONHCHA(CH2)mCO2R, (CH2)mCAA″(CH2)mCONHCHA(CH2)mCO2R, (CH2)mCHA(CH2)mCONHCHA(CH2)mCONHCHA(CH2)mCO2R, (CH2)mCHA(CH2)mCONHCHA(CH2)mCONRa2, (CH2)mCAA″(CH2)mCONHCHA(CH2)mCONRa2, (CH2)mCHA(CH2)mCONHCHA(CH2)mCONHCHA(CH2)mCONRa2, C3-C6-cyclic amino-(CH2)mCO2R, C3-C6-cyclic amino-(CH2)mCONRa2, C3-C6-cycloalkylene-(CH2)mCO2R, and C3-C6-cycloalkylene-(CH2)mCONRa2;
• provided that when Q is (CH2)mCAA″(CH2)mC(O)NR2 or (CH2)mCAA″(CH2)mCO2R, then (a) m is other than 0, (b) A is other than H, or (c) both (a) and (b);
• A is selected from H, C1-6 alkyl, (CH2)mC3-6-cycloalkyl, OH, CH2OH, CH(CH3)OH, C(CH3)2OH, (CH2)nCO2Rb, (CH2)nC(O)NRb2, and (CH2)m-phenyl, wherein the phenyl is substituted with 0-3 groups selected from H, C1-4 alkyl, halogen, CF3, O—C1-4 alkyl, and NO2;
• alternatively, Q is CHA(CH2)mC(O)NR2 or CHA(CH2)mCO2R, and (a) A is selected from OH, (CH2)nCO2Rb, and (CH2)nC(O)NRb2;
• (b) R is (CH2)m(CHRb)n(CH2)mOH or CH(CH2OH)2;
• or (c) both (a) and (b);
• A″ is C1-6 alkyl;
• M is C═O or SO2;
• R is independently selected from H, (CH2)m(CHRb)n(CH2)mOH, CH(CH2OH)2, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;
• Ra is independently selected from H, (CH2)m(CHR)n(CH2)mOH, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;
• Rb is independently selected from H, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;
• p is selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12;
• m is selected from 0, 1, 2, 3, and 4;
• and,
• n is selected from 1, 2, 3, and 4.

A method of treating a co-morbidity of obesity, comprising:

• administering to a mammal in need thereof a therapeutically effective amount of a compound of formula I or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the co-morbidity is selected from hypertension;
• gallbladder disease;
• menstrual irregularities;
• degenerative arthritis;
• venous statis ulcers;
• pulmonary hypoventilation syndrome;
• sleep apnea;
• snoring;
• coronary artery disease;
• arterial sclerotic disease;
• pseudotumor cerebri;
• osteoarthritis;
• and, high cholesterol:
• wherein:
• X, Y, X′, Y′, X″, and Y″ are independently selected from:
• H, C1-6 alkyl, halogen, CF3, O—C1-6 alkyl, NO2, NR2, O(CH2)nCO2R, O(CH2)nCN, OCH2CH═CHCO2R, CH2O(CH2)nCO2R, CH2OCH2CH═CHCO2R, O(CH2)nPO(OR)2, CH2O(CH2)nPO(OR)2, NRa(CH2)nCO2R, NRa(CH2)nPO(OR)2, NRaCH2CH═CHCO2R, NRaSO2R, NRaCO(CH2)nCO2R, NRaCO(CH2)nCONRa2, O(CH2)nC6H4CO2R, O(CH2)nC6H4(CH2)nCO2R, CH2O(CH2)nC6H4CO2R, O(CH2)nC6H4CONRa2, O(CH2)nC6H4(CH2)nCONRa2, O(CH2)nC6H4-tetrazole, CH2O(CH2)nC6H4CONRa2, CH2O(CH2)nC6H4-tetrazole, O(CH2)nC6H4(CH2)n-tetrazole, NRa(CH2)nC6H4CO2R, CH2NRa(CH2)nC6H4CO2R, NRa(CH2)nC6H4(CH2)nCO2R, NRa(CH2)nC6H4CONRa2, CH2NRa(CH2)nC6H4CONRa2, NRa(CH2)nC6H4(CH2)nCONRa2, NRa(CH2)nC6H4-tetrazole, CH2NRa(CH2)nC6H4-tetrazole, NRa(CH2)nC6H4(CH2)n-tetrazole, CONHOH, C(NH)NRa2, (CH2)nC(NH)NRa2, O(CH2)nCONRa2, O(CH2)nC(NH)NRa2, O(CH2)nC(NOH)NRa2, CH2O(CH2)nCONRa2, NRa(CH2)nCONRa2, OCH2CH═CHCONRa2, CH2OCH2CH═CHCONRa2, NRaCH2CH═CHCONRa2, (CH2)m-tetrazole, O(CH2)n-tetrazole, O(CH2CH2O)pR, NRa(CH2CH2O)pR, and SO2NHCH3;
• Z is selected from:
• H, C1-6 alkyl, OH, O—C1-6 alkyl, O(CH2CH2O)pR, OC(O)—C1-6 alkyl, O(CH2)nCO2R, OCH2CH═CHCO2R, O(CH2)nPO(OR)2, O(CH2)nCONRa2, O(CH2)nC(NH)NH2, O(CH2)nC(NOH)NRa2, OCH2CH═CHCONRa2, O(CH2)n-phenyl-(CH2)mCO2R, and O(CH2)n-phenyl-(CH2)m-tetrazole;
• Z′ is selected from H, CO2R, and CONRa2;
• Q is selected from:
• (CH2)nCHA(CH2)mC(O)NR2, (CH2)mCAA″(CH2)mC(O)NR2, (CH2)nCHA(CH2)mCO2R, (CH2)mCAA″(CH2)mCO2R, (CH2)mCHA(CH2)mSO2NR2, (CH2)mCHA(CH2)mSO3R, (CH2)mCHA(CH2)mC(NH)NH2, (CH2)mCHA(CH2)mC(NOH)NH2, (CH2)mCHA(CH2)mCONHCHA(CH2)mCO2R, (CH2)mCAA″(CH2)mCONHCHA(CH2)mCO2R, (CH2)mCHA(CH2)mCONHCHA(CH2)mCONHCHA(CH2)mCO2R, (CH2)mCHA(CH2)mCONHCHA(CH2)mCONRa2, (CH2)mCAA″(CH2)mCONHCHA(CH2)mCONRa2, (CH2)mCHA(CH2)mCONHCHA(CH2)mCONHCHA(CH2)mCONRa2, C3-C6-cyclic amino-(CH2)mCO2R, C3-C6-cyclic amino-(CH2)mCONRa2, C3-C6-cycloalkylene-(CH2)mCO2R, and C3-C6-cycloalkylene-(CH2)mCONRa2;
• provided that when Q is (CH2)mCAA″(CH2)mC(O)NR2 or (CH2)mCAA″(CH2)mCO2R, then (a) m is other than 0, (b) A is other than H, or (c) both (a) and (b);
• A is selected from H, C1-6 alkyl, (CH2)mC3-6-cycloalkyl, OH, CH2OH, CH(CH3)OH, C(CH3)2OH, (CH2)nCO2Rb, (CH2)nC(O)NRb2, and (CH2)m-phenyl, wherein the phenyl is substituted with 0-3 groups selected from H, C1-4 alkyl, halogen, CF3, O—C1-4 alkyl, and NO2;
• alternatively, Q is CHA(CH2)mC(O)NR2 or CHA(CH2)mCO2R, and (a) A is selected from OH, (CH2)nCO2Rb, and (CH2)nC(O)NRb2;
• (b) R is (CH2)m(CHRb)n(CH2)mOH or CH(CH2OH)2;
• or (c) both (a) and (b);
• A″ is C1-6 alkyl;
• M is C═O or SO2;
• R is independently selected from H, (CH2)m(CHRb)n(CH2)mOH, CH(CH2OH)2, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;
• Ra is independently selected from H, (CH2)m(CHR)n(CH2)mOH, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;
• Rb is independently selected from H, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;
• p is selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12;
• m is selected from 0, 1, 2, 3, and 4;
• and,
• n is selected from 1, 2, 3, and 4.

A method of treating a disease, comprising:

• administering to a mammal in need thereof a therapeutically effective amount of
• a. a first therapeutic agent that is a compound of formula I or a stereoisomer or pharmaceutically acceptable salt thereof, and
• b. a second therapeutic agent;
• wherein the disease is selected from obesity, diabetes, cirrhosis, fatty liver disease, dyslipidemia, atherosclerosis, hypertension, stroke, heart attack, and a combination thereof and the second therapeutic agent is useful for treating the disease:
• wherein:
• X, Y, X′, Y′, X″, and Y″ are independently selected from:
• H, C1-6 alkyl, halogen, CF3, O—C1-6 alkyl, NO2, NR2, O(CH2)nCO2R, O(CH2)nCN, OCH2CH═CHCO2R, CH2O(CH2)nCO2R, CH2OCH2CH═CHCO2R, O(CH2)nPO(OR)2, CH2O(CH2)nPO(OR)2, NRa(CH2)nCO2R, NRa(CH2)nPO(OR)2, NRaCH2CH═CHCO2R, NRaSO2R, NRaCO(CH2)nCO2R, NRaCO(CH2)nCONRa2, O(CH2)nC6H4CO2R, O(CH2)nC6H4(CH2)nCO2R, CH2O(CH2)nC6H4CO2R, O(CH2)nC6H4CONRa2, O(CH2)nC6H4(CH2)nCONRa2,O(CH2)nC6H4-tetrazole, CH2O(CH2)nC6H4CONRa2, CH2O(CH2)nC6H4-tetrazole, O(CH2)nC6H4(CH2)n-tetrazole, NRa(CH2)nC6H4CO2R, CH2NRa(CH2)nC6H4CO2R, NRa(CH2)nC6H4(CH2)nCO2R, NRa(CH2)nC6H4CONRa2, CH2NRa(CH2)nC6H4CONRa2, NRa(CH2)nC6H4(CH2)nCONRa2, NRa(CH2)nC6H4-tetrazole, CH2NRa(CH2)nC6H4-tetrazole, NRa(CH2)nC6H4(CH2)n-tetrazole, CONHOH, C(NH)NRa2, (CH2)nC(NH)NRa2, O(CH2)nCONRa2, O(CH2)nC(NH)NRa2, O(CH2)nC(NOH)NRa2, CH2O(CH2)nCONRa2, NRa(CH2)nCONRa2, OCH2CH═CHCONRa2, CH2OCH2CH═CHCONRa2, NRaCH2CH═CHCONRa2, (CH2)m-tetrazole, O(CH2)n-tetrazole, O(CH2CH2O)pR, NRa(CH2CH2O)pR, and SO2NHCH3;
• Z is selected from:
• H, C1-6 alkyl, OH, O—C1-6 alkyl, O(CH2CH2O)pR, OC(O)—C1-6 alkyl, O(CH2)nCO2R, OCH2CH═CHCO2R, O(CH2)nPO(OR)2, O(CH2)nCONRa2, O(CH2)nC(NH)NH2, O(CH2)nC(NOH)NRa2, OCH2CH═CHCONRa2, O(CH2)n-phenyl-(CH2)mCO2R, and O(CH2)n-phenyl-(CH2)m-tetrazole;
• Z′ is selected from H, CO2R, and CONRa2;
• Q is selected from:
• (CH2)nCHA(CH2)mC(O)NR2, (CH2)mCAA″(CH2)mC(O)NR2, (CH2)nCHA(CH2)mCO2R, (CH2)mCAA″(CH2)mCO2R, (CH2)mCHA(CH2)mSO2NR2, (CH2)mCHA(CH2)mSO3R, (CH2)mCHA(CH2)mC(NH)NH2, (CH2)mCHA(CH2)mC(NOH)NH2, (CH2)mCHA(CH2)mCONHCHA(CH2)mCO2R, (CH2)mCAA″(CH2)mCONHCHA(CH2)mCO2R, (CH2)mCHA(CH2)mCONHCHA(CH2)mCONHCHA(CH2)mCO2R, (CH2)mCHA(CH2)mCONHCHA(CH2)mCONRa2, (CH2)mCAA″(CH2)mCONHCHA(CH2)mCONRa2, (CH2)mCHA(CH2)mCONHCHA(CH2)mCONHCHA(CH2)mCONRa2, C3-C6-cyclic amino-(CH2)mCO2R, C3-C6-cyclic amino-(CH2)mCONRa2, C3-C6-cycloalkylene-(CH2)mCO2R, and C3-C6-cycloalkylene-(CH2)mCONRa2;
• provided that when Q is (CH2)mCAA″(CH2)mC(O)NR2or (CH2)mCAA″(CH2)mCO2R, then (a) m is other than 0, (b) A is other than H, or (c) both (a) and (b);
• A is selected from H, C1-6 alkyl, (CH2)mC3-6-cycloalkyl, OH, CH2OH, CH(CH3)OH, C(CH3)2OH, (CH2)nCO2Rb, (CH2)nC(O)NRb2, and (CH2)m-phenyl, wherein the phenyl is substituted with 0-3 groups selected from H, C1-4 alkyl, halogen, CF3, O—C1-4 alkyl, and NO2;
• alternatively, Q is CHA(CH2)mC(O)NR2 or CHA(CH2)mCO2R, and (a) A is selected from OH, (CH2)nCO2Rb, and (CH2)nC(O)NRb2;
• (b) R is (CH2)m(CHR b)n(CH2)mOH or CH(CH2OH)2;
• or (c) both (a) and (b);
• A″ is C1-6 alkyl;
• M is C═O or SO2;
• R is independently selected from H, (CH2)m(CHRb)n(CH2)mOH, CH(CH2OH)2, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;
• Ra is independently selected from H, (CH2)m(CHR)n(CH2)mOH, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;
• Rb is independently selected from H, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;
• p is selected from 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12;
• m is selected from 0, 1, 2, 3, and 4;
• and,
• n is selected from 1, 2, 3, and 4.