Novel Phosphinic Acid-Containing Thyromimetics
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Abstract
The present invention relates to compounds of phosphonic acid-containing T3 mimetics and monoesters thereof, stereoisomers, pharmaceutically acceptable salts, co-crystals, and prodrugs thereof and pharmaceutically acceptable salts and co-crystals of the prodrugs, as well as their preparation and uses for preventing and/or treating metabolic diseases such as obesity, NASH, hypercholesterolemia and hyperlipidemia, as well as associated conditions such as atherosclerosis, coronary heart disease, impaired glucose tolerance, metabolic syndrome x and diabetes.
119 Citations
96 Claims
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1-2. -2. (canceled)
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9-26. -26. (canceled)
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27. A compound of Formula VIII:
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wherein; G is selected from the group consisting of —
O—
, —
S—
, —
Se—
, —
S(═
O)—
, —
S(═
O)2—
, —
Se—
, —
CH2—
, —
CF2—
, —
CHF—
, —
C(O)—
, —
CH(OH)—
, —
CH(C1-C4 alkyl)-, —
CH(C1-C4 alkoxy)-, —
C(═
CH2)—
, —
NH—
, and —
N(C1-C4 alkyl)-, or CH2 linked to any of the preceding groups;or G is R50-R51 wherein; R50-R51 together are —
C(R52)═
C(R52)—
or alternatively R50 and R51 are independently selected from O, S and —
CH(R53)—
, with the provisos that at least one R50 and R51 is —
CH(R53)—
, and when one of R50 and R51 is O or S, then R53 is R54;R54 is hydrogen, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, fluoromethyl, difluoromethyl, or trifluoromethyl; R53 is selected from hydrogen, halogen, hydroxyl, mercapto, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio; and R52 is selected from hydrogen, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio; T is selected from the group consisting of (CRa2)k—
, —
CRb═
CRb (CRa2)n—
, —
(CRa2)n—
CRb═
CRb—
, —
(CRa2)—
CRb═
CRb—
(CRa2)—
, —
O(CRb2)(CRa2)n—
, —
S(CRb2)(CRa2)n—
, —
N(Rc)(CRb2)(CRa2)n—
, —
N(Rb)C(O)(CRa2)n—
, —
(CRa2)nC(Rb)(NRbRc)—
, —
C(O)(CRa2)m—
, —
(CRa2)mC(O)—
, —
(CRb2)—
O—
(CRb2)—
(CRa2)p—
, —
(CRb2)—
S—
(CRb2)—
(CRa2)p—
, —
(CRb2)—
N(Rc)—
(CRb2)—
(CRa2)p—
, —
(CRa2)p—
(CRb2)—
O—
(CRb2)—
, —
(CRa2)p—
(CRb2)—
S—
(CRb2)—
, —
(CRa2)p—
(CRb2)—
N(Rc)—
(CRb2)—
, —
(CRa2)1-2—
O—
(CRa2)1-2—
, —
(CH2)pC(O)N(Rb)C(Ra2)—
, —
(CRa2)nC(Rb2)O—
, —
(CRa2)nC(Rb2)N(Rb)—
, —
(CRa2)nC(Rb2)S—
, —
C(O)(CRa2)pC(Rb2)O—
, —
C(O)(CRa2)pC(Rb2)N(Rb)—
, —
C(O)(CRa2)pC(Rb2)S—
, —
(CRa2)pC(O)C(Rb2)O—
, —
(CRa2)pC(O)C(Rb2)N(Rb)—
, and —
(CRa2)pC(O)C(Rb2)S—
;k is an integer from 0-4; m is an integer from 0-3; n is an integer from 0-2; p is an integer from 0-1; Each Ra is independently selected from the group consisting of hydrogen, optionally substituted —
C1-C4 alkyl, halogen, —
OH, optionally substituted —
O—
C1-C4 alkyl, —
OCF3, —
OCHF2, —
OCH2F, optionally substituted —
S—
C1-C4 alkyl, —
NRbRc, optionally substituted —
C2-C4 alkenyl, and optionally substituted —
C2-C4 alkynyl;
with the proviso that when one Ra is attached to C through an O, S, or N atom, then the other Ra attached to the same C is a hydrogen, or attached via a carbon atom;Each Rb is independently selected from the group consisting of hydrogen and optionally substituted —
C1-C4 alkyl;Each Rc is independently selected from the group consisting of hydrogen and optionally substituted —
C1-C4 alkyl, optionally substituted —
C(O)—
C1-C4 alkyl, and —
C(O)H;R1, R2, R6, and R7 are each independently selected from the group consisting of hydrogen, halogen, optionally substituted —
C1-C4 alkyl, optionally substituted —
S—
C1-C3 alkyl, optionally substituted —
C2-C4 alkenyl, optionally substituted —
C2-C4 alkynyl, —
CF3, —
CHF2, —
CH2F, —
OCF3, —
OCHF2, —
OCH2F, optionally substituted-O—
C1-C3 alkyl, and cyano;
with the proviso that at least one of R1 and R2 is not hydrogen;R8 and R9 are each independently selected from the group consisting of hydrogen, halogen, optionally substituted —
C1-C4 alkyl, optionally substituted —
S—
C1-C3 alkyl, optionally substituted —
C2-C4 alkenyl, optionally substituted —
C2-C4 alkynyl, —
CF3, —
CHF2, —
CH2F, —
OCF3, —
OCHF2, —
OCH2F, optionally substituted —
O—
C1-C3 alkyl, hydroxy, —
(CRa2)aryl, —
(CRa2)cycloalkyl, —
(CRa2)heterocycloalkyl, —
C(O)aryl, —
C(O)cycloalkyl, —
C(O)heterocycloalkyl, —
C(O)alkyl and cyano;
orR6 and T are taken together along with the carbons they are attached to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations including 0 to 2 heteroatoms independently selected from —
NRi—
, —
O—
, and —
S—
, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different than nitrogen then both heteroatoms have to be separated by at least one carbon atom; and
X is attached to this ring by a direct bond to a ring carbon, or by —
CRa2)—
or —
C(O)—
bonded to a ring carbon or a ring nitrogen;Ri is selected from the group consisting of hydrogen, —
C(O)C1-C4 alkyl, and —
C1-C4 alkyl;
orR1 and R7 are taken together along with the carbons to which they are attached to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation on the ring to which R1 and R7 are attached, including 0 to 2 heteroatoms independently selected from —
NRh—
, —
O—
, and —
S—
, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different than nitrogen then both heteroatoms have to be separated by at least one carbon atom;R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, —
CF3, —
CHF2, —
CH2F, —
OCF3, —
OCHF2, —
OCH2F, cyano, optionally substituted —
C1-C12 alkyl, optionally substituted —
C2-C12 alkenyl, optionally substituted —
C2-C12 alkynyl, optionally substituted —
(CRa2)maryl, optionally substituted —
(CRa2)mcycloalkyl, optionally substituted —
(CRa2)mheterocycloalkyl, C(Rb)═
C(Rb)-aryl, C(Rb)═
C(Rb)-cycloalkyl, —
C(Rb)═
C(Rb)-heterocycloalkyl, —
C≡
C(aryl), —
C≡
C(cycloalkyl), —
C≡
C(heterocycloalkyl), —
(CRa2)n(CRb2)NRfRg, —
ORd, —
SRd, —
S(═
O)Re, —
S(═
O)2Re, —
S(═
O)2NRfRg, —
C(O)NRfRg, —
C(O)ORh, —
C(O)Re, —
N(Rb)C(O)Re, —
N(Rb)C(O)NRfRg, —
N(Rb)S(═
O)2Re, —
N(Rb)S(═
O)2NRfRg, and —
NRfRg;Each Rd is selected from the group consisting of optionally substituted —
C1-C12 alkyl, optionally substituted —
C2-C12 alkenyl, optionally substituted —
C2-C12 alkynyl, optionally substituted —
(CRb2)naryl, optionally substituted —
(CRb2)ncycloalkyl, optionally substituted —
(CRb2)nheterocycloalkyl, and —
C(O)NRfRg;Each Re is selected from the group consisting of optionally substituted —
C1-C12 alkyl, optionally substituted —
C2-C12 alkenyl, optionally substituted —
C2-C12 alkynyl, optionally substituted —
(CRa2)naryl, optionally substituted —
(CRa2)ncycloalkyl, and optionally substituted —
(CRa2)nheterocycloalkyl;Rf and Rg are each independently selected from the group consisting of hydrogen, optionally substituted —
C1-C12 alkyl, optionally substituted —
C2-C12 alkenyl, optionally substituted —
C2-C12 alkynyl, optionally substituted —
(CRb2)naryl, optionally substituted —
(CRb2)ncycloalkyl, and optionally substituted —
(CRb2)nheterocycloalkyl, or Rf and Rg may together form an optionally substituted heterocyclic ring of 3-8 atoms containing 0-4 unsaturations, said heterocyclic ring may contain a second heterogroup within the ring selected from the group consisting of O, NRc, and S, wherein said optionally substituted heterocyclic ring may be substituted with 0-4 substituents selected from the group consisting of optionally substituted —
C1-C4 alkyl, —
ORb, oxo, cyano, —
CF3, —
CHF2, —
CH2F, optionally substituted phenyl, and —
C(O)ORh;Each Rh is selected from the group consisting of optionally substituted —
C1-C12 alkyl, optionally substituted —
C2-C12 alkenyl, optionally substituted —
C2-C12 alkynyl, optionally substituted —
(CRb2)naryl, optionally substituted —
(CRb2)ncycloalkyl, and optionally substituted —
(CRb2)nheterocycloalkyl;
orR3 and R8 are taken together along with the carbon atoms to which they are attached to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation on the ring to which R3 and R8 are attached, including 0 to 2 heteroatoms independently selected from —
NRh—
, —
O—
, and —
S—
, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different than nitrogen then both heteroatoms have to be separated by at least one carbon atom;
orR8 and G are taken together along with the carbon atoms to which they are attached to form an optionally substituted ring comprising —
CH═
CH—
CH═
, —
N═
CH—
CH═
, —
CH═
N—
CH═
or —
CH═
CH—
N═
;R5 is selected from the group consisting of —
OH, optionally substituted —
OC1-C6 alkyl, —
OC(O)Re, —
OC(O)ORh, —
NHC(O)ORh, —
OC(O)NH(Rh), —
F, —
NHC(O)Re, —
NHS(═
O)Re, —
NHS(═
O)2Re, —
NHC(═
S)NH(Rh), and —
NHC(O)NH(Rh);
orR3 and R5 are taken together along with the carbons they are attached to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation on the ring to which R3 and R5 are attached, including 0 to 2 heteroatoms independently selected from —
NRh—
, —
O—
, and —
S—
, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different than nitrogen then both heteroatoms have to be separated by at least one carbon atom;X is P(O)(YR11)Y″
;Y″
is selected from the group consisting of hydrogen, optionally substituted —
C1-C6-alkyl, —
CF3, —
CHF2, —
CH2F, —
CH2OH, optionally substituted —
C2-C6 alkenyl, optionally substituted —
C2-C6 alkynyl, optionally substituted —
(CRa2)ncycloalkyl, optionally substituted (CRa2)nheterocycloalkyl, —
(CRa2)kS(═
O)Re, —
(CRa2)kS(═
O)2Re, —
(CRa2)kS(═
O)2NRfRg, —
(CRa2)kC(O)NRfRg, and —
(CRa2)kC(O)Re;Y is selected from the group consisting of —
O—
, and —
NRv—
;when Y is —
O—
, R11 attached to —
O—
is selected from the group consisting of —
H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloakyl wherein the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, —
C(Rz)2OC(O)NRz2, —
NRz—
C(O)—
Ry, —
C(Rz)2—
OC(O)Ry, —
C(Rz)2—
O—
C(O)ORy, —
C(Rz)2OC(O)SRy, -alkyl-S—
C(O)Ry, -alkyl-S—
S-alkylhydroxy, and -alkyl-S—
S—
S-alkylhydroxy;when Y is —
NRv—
, then R11 attached to —
NRv—
is selected from the group consisting of —
H, —
[C(Rz)2]q—
C(O)ORy, —
C(Rx)2C(O)ORy, —
[C(Rz)2]q—
C(O)SRy, and -cycloalkylene-C(O)ORy;q is an integer 2 or 3; Each Rz is selected from the group consisting of Ry and —
H;Each Ry is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl; Each Rx is independently selected from the group consisting of —
H, and alkyl, or together Rx and Rx form a cyclic alkyl group;Each Rv is selected from the group consisting of —
H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl;with the proviso that; a) when G is —
O—
, —
S—
, —
Se—
, —
S(═
O)—
, —
S(═
O)2—
, —
CH2—
, —
C(O)—
, —
NH— and
, T is —
(CH2)0-4—
or —
C(O)NH(CRb2)—
, R1 and R2 are independently chosen from the group consisting of hydrogen, halogen, —
C1-C4 alkyl, R8 and R9 are each independently selected from hydrogen, halogen and C1-4alkyl, R6 and R7 are each independently selected from hydrogen, halogen O—
C1-3alkyl, hydroxy, cyano and C1-4alkyl, R3 is C(O)NR25R26, —
CH2—
NR25R26, —
NR25—
C(O)R26, —
OR27, R28, or, R4 is hydrogen, halogen, cyano or alkyl, and R5 is —
OH, R25 and R26 are each independently selected from the group consisting of hydrogen, aryl, heteroaryl, alkyl, cycloalkyl, aralkyl or heteroaralkyl, R27 is aryl, heteroaryl, alkyl, aralkyl, or heteroaralkyl, R28 is aryl, heteroaryl, or cycloalkyl, R29 is hydrogen, aryl, heteroaryl, alkyl, aralkyl, heteroaralkyl, then X is not —
P(O)(OH)C1-C6 alkyl or —
P(O)(O-lower alkyl)C1-C6 alkyl;b) when G is —
O—
, —
S—
, —
Se—
, —
S(═
O)—
, —
S(═
O)2—
, —
CH2—
, —
CF2—
, —
C(O)—
, —
NH— and
, T is —
C(O)NH(CRb2)—
, R1 and R2 are independently halogen, cyano, —
C1-C4 alkyl, R8 and R9 are each independently selected from hydrogen, halogen and C1-4alkyl, R6 and R7 are each independently selected from hydrogen, halogen O—
C1-3alkyl, hydroxy, cyano and C1-4alkyl, R3 is halogen, —
C1-C6 alkyl, —
C2-C6 alkynyl, C4-C7 cycloalkenyl, —
C3-C7 cycloalkoxy, —
S(═
O)2(NR14R15), —
N(R16)S(═
O)2R17, —
SR17, —
S(═
O)R17, —
S(═
O)2R17, —
C(O)R16, or —
CR18(OR16)R19, R4 is halogen, cyano or alkyl, and R5 is —
OH, optionally substituted —
OC1-C6 alkyl, aroyl or alkanoyl, R14, R15, R16, R18 and R19 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroalkyl, arylalkyl, and heteroarylalkyl, or R14 and R15 may be joined so as to comprise a chain of 3 to 6 methylene groups to form a ring of 4 to 7-membered in size, R17 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroalkyl, arylalkyl, and heteroarylalkyl, then X is not —
P(O)(OH)C1-C6 alkyl or —
P(O)(O-lower alkyl)C1-C6 alkyl;and pharmaceutically acceptable salts and prodrugs thereof and pharmaceutically acceptable salts of said prodrugs. - View Dependent Claims (3, 4, 5, 6, 7, 8, 28, 29, 30, 31, 32, 33, 34, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 60, 61, 63, 64, 65, 66, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 80, 81, 82, 83, 84)
wherein; G is selected from the group consisting of —
O—
, —
S—
, —
Se—
, —
S(═
O)—
, —
S(═
O)2—
, —
CH2—
, —
CF2—
, —
CHF—
, —
C(O)—
, —
CH(OH)—
, —
NH—
, and —
N(C1-C4 alkyl)-, or CH2 linked to any of the preceding groups;or G is R50-R51 wherein; R50-R51 together are —
C(R52)═
C(R52)—
or alternatively R50 and R51 are independently selected from O, S and —
CH(R53)—
, with the provisos that at least one R50 and R51 is —
CH(R53)—
, and when one of R50 and R51 is O or S, then R53 is R54;R54 is hydrogen, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, fluoromethyl, difluoromethyl, or trifluoromethyl; R53 is selected from hydrogen, halogen, hydroxyl, mercapto, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio; R52 is selected from hydrogen, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, methylthio, fluoromethylthio, difluoromethylthio and trifluoromethylthio; T is selected from the group consisting of —
(CRa2)k, —
CRb═
CRb—
(CRa2)n—
, —
(CRa2)CRb═
CRb—
, —
(CRa2)—
CRb═
CRb—
(CRa2)—
, —
O(CRb2)(CRa2)n—
, —
S(CRb2)(CRa2)n—
, —
N(Rc)(CRb2)(CRa2)n—
, —
N(Rb)C(O)(CRa2)n—
, —
(CRa2)mC(Rb)(NRbRc)—
, C(O)(CRa2)m—
, —
(CRa2)mC(O)—
, —
(CRb2)—
O—
(CRb2)—
(CRa2)p—
, —
(CRb2)—
S—
(CRb2)—
(CRa2)p—
, —
(CRb2)—
N(Rc)—
(CRb2)—
(CRa2)p—
, —
(CRa2)p—
(CRb2)—
O—
(CRb2)—
, —
(CRa2)p—
(CRb2)—
S—
(CRb2)—
, —
(CRa2)p—
(CRb2)—
N(Rc)—
(CRb2)—
—
(CH2)pC(O)N(Rb)C(Ra2)—
, —
(CRa2)nC(Rb2)O—
, —
(CRa2)nC(Rb2)N(Rb)—
, —
(CRa2)nC(Rb2)S—
, —
C(O)(CRa2)pC(Rb2)O—
, —
C(O)(CRa2)pC(Rb2)N(Rb)—
, —
C(O)(CRa2)pC(Rb2)S—
, —
(CRa2)pC(O)C(Rb2)O—
, —
(CRa2)pC(O)C(Rb2)N(Rb)—
, and —
(CRa2)pC(O)C(Rb2)S—
;k is an integer from 0-4; m is an integer from 0-3; n is an integer from 0-2; p is an integer from 0-1; Each Ra is independently selected from the group consisting of hydrogen, optionally substituted —
C1-C4 alkyl, halogen, —
OH, optionally substituted —
O—
C1-C4 alkyl, —
OCF3, —
OCHF2, —
OCH2F, optionally substituted —
S—
C1-C4 alkyl, —
NRbRc, optionally substituted —
C2-C4 alkenyl, and optionally substituted —
C2-C4 alkynyl;
with the proviso that when one Ra is attached to C through an O, S, or N atom, then the other Ra attached to the same C is a hydrogen, or attached via a carbon atom;Each Rb is independently selected from the group consisting of hydrogen and optionally substituted —
C1-C4 alkyl;Each Rc is independently selected from the group consisting of hydrogen and optionally substituted —
C1-C4 alkyl, optionally substituted —
C(O)—
C1-C4 alkyl, and —
C(O)H;R1 and R2 are each independently selected from the group consisting of halogen, optionally substituted —
C1-C4 alkyl, optionally substituted —
S—
C1-C3 alkyl, optionally substituted —
C2-C4 alkenyl, optionally substituted —
C2-C4 alkynyl, —
CF3, —
CHF2, —
CH2F, —
OCF3, —
OCHF2, —
OCH2F, optionally substituted —
O—
C1-C3 alkyl, and cyano;R3 and R4 are each independently selected from the group consisting of hydrogen, halogen, —
CF3, —
CHF2, —
CH2F, —
OCF3, —
OCHF2, —
OCH2F, cyano, optionally substituted —
C1-C12 alkyl, optionally substituted —
C2-C12 alkenyl, optionally substituted —
C2-C12 alkynyl, optionally substituted —
(CRa2)maryl, optionally substituted —
(CRa2)mcycloalkyl, optionally substituted —
(CRa2)mheterocycloalkyl, —
C(Rb)═
C(Rb)-aryl, —
C(Rb)═
C(Rb)-cycloalkyl, —
C (b)═
C(Rb)-heterocycloalkyl, —
C≡
C(aryl), —
C≡
C(cycloalkyl), —
C≡
C(heterocycloalkyl), —
(CRa2)n(CRb2)NRfRg, —
ORd, —
SRd, —
S(═
O)Re, —
S(═
O)2Re, —
S(═
O)2NRfRg, —
C(O)NRfRg, —
C(O)ORh, —
C(O)Re, —
N(Rb)C(O)Re, —
N(Rb)C(O)NRfRg, N(Rb)S(═
O)2Re, —
N(Rb)S(═
O)2NRfRg, and —
NRfRg;Each Rd is selected from the group consisting of optionally substituted —
C1-C12 alkyl, optionally substituted —
C2-C12 alkenyl, optionally substituted —
C2-C12 alkynyl, optionally substituted —
(CRb2)naryl, optionally substituted —
(CRb2)ncycloalkyl, optionally substituted —
(CRb2)nheterocycloalkyl, and —
C(O)NRfRg;Each Re is selected from the group consisting of optionally substituted —
C1-C12 alkyl, optionally substituted —
C2-C12 alkenyl, optionally substituted —
C2-C12 alkynyl, optionally substituted —
(CRa2)naryl, optionally substituted —
(CRa2)ncycloalkyl, and optionally substituted —
(CRa2)nheterocycloalkyl;Rf and Rg are each independently selected from the group consisting of hydrogen, optionally substituted —
C1-C12 alkyl, optionally substituted —
C2-C12 alkenyl, optionally substituted —
C2-C12 alkynyl, optionally substituted —
(CRb2)naryl, optionally substituted —
(CRb2)ncycloalkyl, and optionally substituted —
(CRb2)nheterocycloalkyl, or Rf and Rg may together form an optionally substituted heterocyclic ring of 3-8 atoms containing 0-4 unsaturations, which may contain a second heterogroup selected from the group consisting of O, NRc, and S, wherein said optionally substituted heterocyclic ring may be substituted with 0-4 substituents selected from the group consisting of optionally substituted —
C1-C4 alkyl, —
ORb, oxo, cyano, —
CF3, —
CHF2, —
CH2F, optionally substituted phenyl, and —
C(O)ORh;Each Rh is selected from the group consisting of optionally substituted —
C1-C12 alkyl, optionally substituted —
C2-C12 alkenyl, optionally substituted —
C2-C12 alkynyl, optionally substituted —
(CRb2)naryl, optionally substituted —
(CRb2)ncycloalkyl, and optionally substituted —
(CRb2)nheterocycloalkyl;R5 is selected from the group consisting of —
OH, optionally substituted —
OC1-C6 alkyl, —
OC(O)Re, —
OC(O)ORh, —
F, —
NHC(O)ORh, —
OC(O)NH(Rh), —
NHC(O)Re, —
NHS(═
O)Re, —
NHS(═
O)2Re, —
NHC(═
S)NH(Rh), and —
NHC(O)NH(Rh);
orR3 and R5 are taken together along with the carbons they are attached to form an optionally substituted ring of 5 to 6 atoms with 0-2 unsaturations, not including the unsaturation on the ring to which R3 and R5 are attached, including 0 to 2 heteroatoms independently selected from —
NRh—
, —
O—
, and —
S—
, with the proviso that when there are 2 heteroatoms in the ring and both heteroatoms are different than nitrogen then both heteroatoms have to be separated by at least one carbon atom;X is P(O)(YR11)Y″
;Y″
is selected from the group consisting of hydrogen, optionally substituted —
C1-C6 alkyl, —
CF3, —
CHF2, —
CH2F, —
CH2OH, optionally substituted —
C2-C6 alkenyl, optionally substituted —
C2-C6 alkynyl, optionally substituted —
(CRa2)ncycloalkyl, optionally substituted (CRa2)nheterocycloalkyl, —
(CRa2)kS(═
O)Re, —
(CRa2)kS(═
O)2Re, —
(CRa2)kS(═
O)2NRfRg, —
(CRa2)kC(O)NRfRg, and —
(CRa2)kC(O)Re;Y is selected from the group consisting of —
O—
, and —
NRv—
;when Y is —
O—
, R11 attached to —
O—
is selected from the group consisting of —
H, alkyl, optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted CH2-heterocycloalkyl wherein the cyclic moiety contains a carbonate or thiocarbonate, optionally substituted -alkylaryl, —
C(Rz)2OC(O)NRz2, —
NRz—
C(O)—
Ry, —
C(Rz)2—
OC(O)Ry, —
C(Rz)2—
O—
C(O)ORy, —
C(Rz)2OC(O)SRy, -alkyl-S—
C(O)Ry, -alkyl-S—
S-alkylhydroxy, and -alkyl-S—
S—
S-alkylhydroxy;when Y is —
NRv—
, then R11 attached to —
NRv—
is selected from the group consisting of —
H, —
[C(Rz)2]q—
C(O)ORy, —
C(Rx)2C(O)ORy, —
[C(Rz)2]q—
C(O)SRy, and -cycloalkylene-C(O)ORy;q is an integer 2 or 3; Each Rz is selected from the group consisting of Ry and —
H;Each Ry is selected from the group consisting of alkyl, aryl, heterocycloalkyl, and aralkyl; Each Rx is independently selected from the group consisting of —
H, and alkyl, or together Rx and Rx form a cycloalkyl group;Each Rv is selected from the group consisting of —
H, lower alkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl, and lower acyl;with the proviso that; a) when G is —
O—
, —
S—
, —
Se—
, —
S(═
O)—
, —
S(═
O)2—
, —
CH2—
, —
C(O)—
, —
NH— and
, T is —
(CH2)0-4—
or —
C(O)NH(CRb2)—
, R1 and R2 are independently chosen from the group consisting of hydrogen, halogen, —
C1-C4 alkyl, R3 is —
C(O)NR25R26, —
CH2—
NR25R26—
, —
NR25—
C(O)R26, —
OR27, R28, or, R4 is hydrogen, halogen, cyano or alkyl, and R5 is —
OH, R25 and R26 are each independently selected from the group consisting of hydrogen, aryl, heteroaryl, alkyl, cycloalkyl, aralkyl or heteroaralkyl, R27 is aryl, heteroaryl, alkyl aralkyl, or heteroaralkyl, R28 is aryl, heteroaryl, or cycloalkyl, R29 is hydrogen, aryl, heteroaryl, alkyl, aralkyl, heteroaralkyl, then X is not —
P(O)(OH)C1-C6 alkyl or —
P(O)(O-lower alkyl)C1-C6 alkyl;b) when G is —
O—
, —
S—
, —
Se—
, —
S(═
O)—
, —
S(═
O)2—
, —
CH2—
, —
CF2—
, —
C(O)—
, —
NH— and
, T is —
C(O)NH(CRb2)—
, R1 and R2 are independently halogen, cyano, —
C1-C4 alkyl, R3 is halogen, —
C1-C6 alkyl, —
C2-C6 alkynyl, —
C4-C7 cycloalkenyl, —
C3-C7 cycloalkoxy, —
S(═
O)2(NR14R15), —
N(R16)S(═
O)2R17—
SR17, —
S(═
O)R17, —
S(═
O)2R17, —
C(O)R16, or —
CR18(OR16)R19, R4 is halogen, cyano or alkyl, and R5 is —
OH, optionally substituted —
OC1-C6 alkyl, aroyl or alkanoyl, R14, R15, R16, R18 and R19 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroalkyl, arylalkyl, and heteroarylalkyl, or R14 and R15 may be joined so as to comprise a chain of 3 to 6 methylene groups to form a ring of 4 to 7-members in size, R17 is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroalkyl, arylalkyl, and heteroarylalkyl, then X is not —
P(O)(OH)C1-C6 alkyl or —
P(O)(O-lower alkyl)C1-C6 alkyl;and pharmaceutically acceptable salts and prodrugs thereof and pharmaceutically acceptable salts of said prodrugs.
-
-
4. The compound of claim 3 wherein G is —
- O—
;
T is —
CH2CH(NH2)—
;
R1 and R2 are each iodo;
R4 is selected from the group consisting of hydrogen and iodo;
R5 is —
OH; and
R3 is iodo.
- O—
-
5. The compound of claim 3 wherein G is —
- O—
;
T is —
N(H)C(O)—
;
R1 and R2 are each methyl;
R4 is hydrogen;
R5 is —
OH; and
R3 is —
CH(OH)(4-fluorophenyl).
- O—
-
6. The compound of claim 3 wherein G is —
- CH2—
;
T is —
OCH2—
;
R1 and R2 are each methyl;
R4 is hydrogen;
R5 is —
OH; and
R3 is iso-propyl.
- CH2—
-
7. The compound of claim 3 wherein G is —
- O—
;
T is —
CH2—
;
R1 and R2 are each chloro;
R4 is hydrogen;
R5 is —
OH; and
R3 is iso-propyl.
- O—
-
8. The compound of claim 3 wherein G is —
- O—
;
T is —
CH2CH2—
;
R1 and R2 are each chloro;
R4 is hydrogen;
R5 is —
OH; and
R3 is iso-propyl.
- O—
-
28. The compound of claim 27 wherein T is selected from the group consisting of —
- (CRa2)n—
, O(CRb2)(CRa2)p—
, —
N(Rc)(CRb2)(CRa2)p—
, —
S(CRb2)(CRa2)p—
, —
N(Rb)C(O)—
, and —
CH2CH(NRcRb)—
.
- (CRa2)n—
-
29. The compound of claim 28 wherein T is —
- (CRa2)n—
, —
O(CRb2)(CRa2)p—
or —
N(Rc)(CRb2)(CRa2)p—
.
- (CRa2)n—
-
30. The compound of claim 27 wherein G is —
- O—
;
T is —
CH2CH(NH2)—
;
R1 and R2 are each iodo;
R4 is selected from the group consisting of hydrogen and iodo;
R5 is —
OH; and
R3 is iodo.
- O—
-
31. The compound of claim 27 wherein G is —
- O—
;
T is —
N(H)C(O)—
;
R1 and R2 are each methyl;
R4 is hydrogen;
R5 is —
OH; and
R3 is —
CH(OH)(4-fluorophenyl).
- O—
-
32. The compound of claim 27 wherein G is —
- CH2—
;
T is —
OCH2—
;
R1 and R2 are each methyl;
R4 is hydrogen;
R5 is —
OH; and
R3 is iso-propyl.
- CH2—
-
33. The compound of claim 27 wherein G is —
- O—
;
T is —
CH2—
;
R1 and R2 are each chloro;
R4 is hydrogen;
R5 is —
OH; and
R3 is iso-propyl.
- O—
-
34. The compound of claim 27 wherein G is —
- O—
;
T is —
CH2CH2—
;
R1 and R2 are each chloro;
R4 is hydrogen;
R5 is —
OH; and
R3 is iso-propyl.
- O—
-
42. The compound of claim 27 wherein G is selected from the group consisting of —
- O—
, —
CH2— and
R50-R51.
- O—
-
43. The compound of claim 27 wherein T is selected from the group consisting of —
- (CRa2)nC(Rb)2O—
, —
(CRa2)nC(Rb)2N(Rb)—
, —
C(O)(CRa2)pC(Rb)2O—
, —
C(O)(CRa2)pC(Rb)2N(Rb)—
, and —
(CRa2)pC(O)C(Rb)2O—
.
- (CRa2)nC(Rb)2O—
-
44. The compound of claim 43 wherein T is —
- (CRa2)nC(Rb)2O—
, or —
C(O)(CRa2)pC(Rb)2O—
.
- (CRa2)nC(Rb)2O—
-
45. The compound of claim 27 wherein R1 and R2 are the same and are selected from the group consisting of halogen, —
- C1-C4 alkyl, —
CF3, and cyano.
- C1-C4 alkyl, —
-
46. The compound of claim 45 wherein R1 and R2 are both alkyl.
-
47. The compound of claim 27 wherein R1 and R2 are different and are selected from the group consisting of halogen, —
- C1-C4 alkyl, —
CF3, and cyano.
- C1-C4 alkyl, —
-
48. The compound of claim 47 wherein R1 and R2 are not both halogen.
-
49. The compound of claim 27 wherein R4 is selected from the group consisting of hydrogen, halogen, —
- C1-C4 alkyl, cyano and CF3.
-
50. The compound of claim 49 wherein R4 is hydrogen.
-
51. The compound of claim 27 wherein R6 and R7 are independently selected from the group consisting of hydrogen, halogen, —
- C1-C4 alkyl, cyano and CF3.
-
52. The compound of claim 51 wherein R6 and R7 are independently hydrogen, halogen, or methyl.
-
53. The compound of claim 27 wherein R8 and R9 are independently selected from the group consisting of hydrogen, halogen, —
- C1-C4 alkyl, —
C1-C4 alkylaryl, cyano and CF3.
- C1-C4 alkyl, —
-
54. The compound of claim 53 wherein R8 and R9 are independently hydrogen, halogen, methyl, benzyl, and benzoate.
-
55. The compound of claim 27 wherein R5 is selected from the group consisting of —
- OH, —
OC(O)Re, —
OC(O)ORh, —
F, and —
NHC(O)Re.
- OH, —
-
56. The compound of claim 55 wherein R5 is —
- OH.
-
57. The compound of claim 27 wherein R3 is selected from the group consisting of halogen, optionally substituted —
- C1-C6 alkyl, —
CF3, cyano, —
C(O)NRfRg, optionally substituted —
(CRa2)naryl, —
SO2NRfRg, and —
SO2Re.
- C1-C6 alkyl, —
-
58. The compound of claim 57 wherein R3 is isopropyl or 4-fluorobenzyl.
-
60. The compound of claim 27 wherein X is selected from the group consisting of —
- P(O)(OH)(Y″
), —
P(O)(ORy)(Y″
), —
P(O)[—
OCRz2OC(O)Ry](Y″
), —
P(O)[—
OCRz2OC(O)ORy](Y″
), and —
P(O)[—
N(H)CRz2C(O)ORy](Y″
).
- P(O)(OH)(Y″
-
61. The compound of claim 60 wherein X is selected from the group consisting of —
- P(O)(OH)(CH3), —
P(O)(OH)(CH2CH3), —
P(O)[—
OCH2OC(O)-t-butyl](CH3), —
P(O)[—
OCH2OC(O)O-iso-propyl](CH3), P(O)[—
OCH(CH3)OC(O)-t-butyl](CH3), —
P(O)[—
OCH(CH3)OC(O)O-iso-propyl](CH3), —
P(O)[—
N(H)CH(CH3)C(O)OCH2CH3](CH3), —
P(O)[—
N(H)CH2C(O)OCH2CH3](CH3) and —
P(O)[—
N(H)C(CH3)2C(O)OCH2CH3](CH3).
- P(O)(OH)(CH3), —
-
63. A compound of claims 27 or 62, wherein said compound is in the form of a co-crystal.
-
64. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of claims 27 or 62.
-
65. The pharmaceutical composition of claim 64 wherein said pharmaceutical composition in a form selected from the group consisting of a controlled release composition, transdermal patch, tablet, hard capsule, and soft capsule.
-
66. The pharmaceutical composition of claim 64 wherein said pharmaceutical composition comprises a crystalline form or a salt form of said compound.
-
68. The pharmaceutical composition of claim 64 wherein said pharmaceutical composition is administered orally in a unit dose of about 0.375 μ
- g/kg to 3.75 mg/kg.
-
69. The pharmaceutical composition of claim 64 wherein said pharmaceutical composition is administered orally in a total daily dose of about 0.375 μ
- g/kg/day to about 3.75 mg/kg/day, equivalent of the free acid.
-
70. A method of preventing or treating a metabolic disease comprising administering to an animal a pharmaceutically effective amount of a phosphinic acid-containing compound of claims 27 or 62, a pharmaceutically acceptable salt thereof, or prodrugs thereof or pharmaceutically acceptable salts of said prodrugs, wherein said phosphinic acid-containing compound binds to a thyroid receptor.
-
71. The method of claim 70 wherein said phosphinic acid-containing compound binds to a thyroid receptor with a Ki of ≦
- 1 μ
M.
- 1 μ
-
72. The method of claim 71 wherein said thyroid receptor is TRα
- 1.
-
73. The method of claim 71 wherein said thyroid receptor is TRβ
- 1.
-
74. The method of claim 71 wherein said phosphinic acid-containing compound binds to a thyroid receptor with a Ki of ≦
- 100 nM.
-
75. The method of claim 74 wherein said thyroid receptor is TRα
- 1.
-
76. The method of claim 74 wherein said thyroid receptor is TRβ
- 1.
-
77. The method of claim 70 wherein said metabolic disease is selected from the group consisting of obesity, hypercholesterolemia, hyperlipidemia, atherosclerosis, coronary heart disease, and hypertension.
-
78. The method of claim 77 wherein said metabolic disease is selected from the group consisting of obesity, hypercholesterolemia, and hyperlipidemia.
-
80. The method of claim 70 wherein said metabolic disease is NASH.
-
81. The method of claim 70 wherein said metabolic disease is selected from the group consisting of impaired glucose tolerance, diabetes, and metabolic syndrome X.
-
82. The method of claim 70, wherein said phosphinic acid-containing compound activates said thyroid receptor.
-
83. The method of claim 82 wherein said thyroid receptor is TRα
- 1.
-
84. The method of claim 82 wherein said thyroid receptor is TRβ
- 1.
-
35-41. -41. (canceled)
-
59. (canceled)
-
62. A compound selected from the group consisting of:
and pharmaceutically acceptable salts and prodrugs thereof.
-
67. (canceled)
-
79. (canceled)
-
85-93. -93. (canceled)
-
94. A method of increasing the liver specificity of a T3 mimetic having a carboxylic acid moiety comprising the preparation of a compound that is an analog of said T3 mimetic wherein said carboxylic acid moiety is replaced by phosphinic acid or prodrugs thereof.
-
95. A method of selecting a T3 mimetic having enhanced liver specificity comprising the steps of:
-
a) measuring the liver specificity of a T3 mimetic having a carboxylic acid moiety; b) measuring the liver specificity of a compound that is an analog of said T3 mimetic having a carboxylic acid moiety wherein the carboxylic acid moiety is replaced by a phosphinic acid or prodrug thereof; and comparing the liver specificities of steps a) and b).
-
-
96. A method of screening T3 mimetics comprising the steps of:
-
a) measuring a biological effect of T3 mimetic having a carboxylic acid moiety wherein said biological effect is selected from the group consisting of the Ki relative to T3, effects on blood glucose level, effects on serum cholesterol level, effects on fat in the liver, liver specificity, and therapeutic index; b) measuring the same biological effect measured in a) of a T3 mimetic having a phosphinic acid or prodrug moiety thereof; and c) comparing the results in steps a) and b); and d) selecting the T3 mimetic of step b) for further scientific evaluation.
-
Specification