US 2007/0191293 A1Published application

Inhibitors of E1 activating enzymes

AssigneeMillennium Pharmaceuticals, Inc.

InventorsSteven Langston, Edward Olhava, Stepan Vyskocil

Life of this patent

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Abstract

This invention relates to compounds that inhibit E1 activating enzymes, pharmaceutical compositions comprising the compounds, and methods of using the compounds. The compounds are useful for treating disorders, particularly cell proliferation disorders, including cancers, inflammatory and neurodegenerative disorders; and inflammation associated with infection and cachexia.

Claims36

Dependent claims

A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
stereochemical configurations depicted at asterisked positions indicate relative stereochemistry;
Ring A is selected from the group consisting of:
wherein one ring nitrogen atom in Ring A optionally is oxidized;
X is —C(Rf1)2, —N(Rf2)—, or —O—;
Y is —O—, —S—, or —C(Rm)(Rn)—;
Ra is selected from the group consisting of hydrogen, fluoro, —CN, —N3, —OR5, —N(R4)2, —NR4CO2R6, —NR4C(O)R5, —C(O)N(R4)2, —C(O)R5, —OC(O)N(R4)2, —OC(O)R5, —OCO2R6, or a C1-4 aliphatic or C1-4 fluoroaliphatic optionally substituted with one or two substituents independently selected from the group consisting of —OR5x, —N(R4x)(R4y), —CO2R5x, or —C(O)N(R4x)(R4y);
or Ra and Rb together form ═O;
or Ra and Rc together form a bond;
Rb is selected from the group consisting of hydrogen, fluoro, C1-4 aliphatic, and C1-4 fluoroaliphatic;
or Rb and Ra together form ═O;
or Rb, taken together with Rd and the intervening carbon atoms, forms a fused cyclopropane ring, which is optionally substituted with one or two substituents independently selected from fluoro or C1-4 aliphatic;
or Rb, taken together with Re and the intervening carbon atoms, forms a fused cyclopropane ring, which is optionally substituted with one or two substituents independently selected from fluoro or C1-4 aliphatic;
Rc is selected from the group consisting of hydrogen, fluoro, —CN, —N3, —OR5, —N(R4)2, —NR4CO2R6, —NR4C(O)R5, —C(O)N(R)2, —C(O)R5, —OC(O)N(R4)2, —OC(O)R5, —OCO2R6, or a C1-4 aliphatic or C1-4 fluoroaliphatic optionally substituted with one or two substituents independently selected from the group consisting of —OR5x, —N(R4x)(R4y), —CO2R5x, or —C(O)N(R4x)(R4y);
or Ra and Rc together form a bond;
or Rc and Rd together form ═O;
Rd is selected from the group consisting of hydrogen, fluoro, C1-4 aliphatic, and C1-4 fluoroaliphatic;
or Rd and Rc together form ═O;
or Rd, taken together with Rb and the intervening carbon atoms, forms a fused cyclopropane ring, which is optionally substituted with one or two substituents independently selected from fluoro or C1-4 aliphatic;
or Rd, taken together with Re′ and the intervening carbon atoms, forms a fused cyclopropane ring, which is optionally substituted with one or two substituents independently selected from fluoro or C1-4 aliphatic;
Re is hydrogen, or C1-4 aliphatic;
or Re, taken together with one Rf and the intervening carbon atoms, forms a 3- to 6-membered spirocyclic ring, which is optionally substituted with one or two substituents independently selected from fluoro or C1-4 aliphatic;
or Re, taken together with Rm and the intervening carbon atoms, forms a fused cyclopropane ring, which is optionally substituted with one or two substituents independently selected from fluoro or C1-4 aliphatic;
or Re, taken together with Rb and the intervening carbon atoms, forms a fused cyclopropane ring, which is optionally substituted with one or two substituents independently selected from fluoro or C1-4 aliphatic;
Re′ is hydrogen or C1-4 aliphatic;
or Re′, taken together with Rm and the intervening carbon atoms, forms a fused cyclopropane ring, which is optionally substituted with one or two substituents independently selected from fluoro or C1-4 aliphatic;
or Re′, taken together with Rd and the intervening carbon atoms, forms a fused cyclopropane ring, which is optionally substituted with one or two substituents independently selected from fluoro or C1-4 aliphatic;
each Rf is independently hydrogen, fluoro, C1-4 aliphatic, or C1-4 fluoroaliphatic, provided that if X is —O— or —NH—, then Rf is not fluoro;
or two Rf taken together form ═O;
or two Rf, taken together with the carbon atom to which they are attached, form a 3- to 6-membered carbocyclic ring;
or one Rf, taken together with Re and the intervening carbon atoms, forms a 3- to 6-membered spirocyclic ring, which is optionally substituted with one or two substituents independently selected from fluoro or C1-4 aliphatic;
or one Rf, taken together with an adjacent Rf1 and the intervening carbon atoms, forms a cyclopropyl ring, which is optionally substituted with one or two substituents independently selected from fluoro or C1-4 aliphatic;
or one Rf and one Rf1 together form a double bond;
each Rf1 is independently hydrogen or fluoro;
or one Rf1, taken together with an adjacent Rf and the intervening carbon atoms forms a cyclopropyl ring, which is optionally substituted with one or two substituents independently selected from fluoro or C1-4 aliphatic;
or one Rf1 and one Rf together form a double bond;
Rf2 is hydrogen, C1-4 aliphatic, or C1-4 fluoroaliphatic;
Rg is hydrogen, halo, —NO2, —CN, —C(R)═C(R)2, —C≡C—R5, —OR5, —SR6, —S(O)R6, —SO2R6, —SO2N(R4)2, —N(R4)2, —NR4C(O)R5, —NR4C(O)N(R4)2, —N(R4)C(═NR4)—N(R)2, —N(R4)C(═NR)—R6, —NR4CO2R6, —N(R4)SO2R6, —N(R4)SO2N(R4)2, —O—C(O)R5, —OCO2R6, —OC(O)N(R4)2, —C(O)R5, —CO2R5, —C(O)N(R4)2, —C(O)N(R4)—OR5, —C(O)N(R4)C(═NR4)—N(R4)2, —N(R4)C(═NR4)—N(R4)—C(O)R5, —C(═NR4)—N(R4)2, —C(═NR4)—OR5, —N(R4)—N(R4)2, —N(R4)—OR5, —C(═NR4)—N(R4)—OR5, —C(R6)═N—OR5, or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl;
each Rh independently is hydrogen, halo, —CN—, —OR5, —N(R4)2, —SR6, or an optionally substituted C1-4 aliphatic group;
Rj is hydrogen, —OR5, —SR6, —N(R4)2, or an optionally substituted aliphatic, aryl, or heteroaryl group;
Rk is hydrogen, halo, —OR5, —SR6, —N(R4)2, or an optionally substituted C1-4 aliphatic group;
Rm is hydrogen, fluoro, —N(R4)2, or an optionally substituted C1-4 aliphatic group;
or Rm and Rn together form ═O or ═C(R5)2;
or Rm and Re, taken together with the intervening carbon atoms, form a fused cyclopropane ring, which is optionally substituted with one or two substituents independently selected from fluoro or C1-4 aliphatic;
or Rm and Re′, taken together with the intervening carbon atoms, form a fused cyclopropane ring, which is optionally substituted with one or two substituents independently selected from fluoro or C1-4 aliphatic;
Rn is hydrogen, fluoro, or an optionally substituted C1-4 aliphatic group;
or Rm and Rn together form ═O or ═C(R5)2;
each R4 independently is hydrogen or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
or two R4 on the same nitrogen atom, taken together with the nitrogen atom, form an optionally substituted 4- to 8-membered heterocyclyl ring having, in addition to the nitrogen atom, 0-2 ring heteroatoms independently selected from N, O, and S;
R4x is hydrogen, C1-4 alkyl, C1-4 fluoroalkyl, or C6-10 ar(C1-4)alkyl, the aryl portion of which may be optionally substituted;
R4y is hydrogen, C1-4 alkyl, C1-4 fluoroalkyl, C6-10 ar(C1-4)alkyl, the aryl portion of which may be optionally substituted, or an optionally substituted 5- or 6-membered aryl, heteroaryl, or heterocyclyl ring;
or
R4x and R4y, taken together with the nitrogen atom to which they are attached, form an optionally substituted 4- to 8-membered heterocyclyl ring having, in addition to the nitrogen atom, 0-2 ring heteroatoms independently selected from N, O, and S;
and
each R5 independently is hydrogen or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
each R5x independently is hydrogen, C1-4 alkyl, C1-4 fluoroalkyl, or an optionally substituted C6-10 aryl or C6-10 ar(C1-4)alkyl;
each R6 independently is an optionally substituted aliphatic, aryl, or heteroaryl group;
and
m is 0, 1, 2, or 3, provided that Y is —C(Rm)(Rn)— when m is 0.

56 more elements

A compound of formula (I-A):

or a pharmaceutically acceptable salt thereof, wherein:
stereochemical configurations depicted at asterisked positions indicate relative stereochemistry;
Ring A is selected from the group consisting of:
wherein one ring nitrogen atom in Ring A optionally is oxidized;
X is —CH2—, —CHF—, —CF2—, —NH—, or —O—;
Y is —O—, —S—, or —C(Rm)(Rn)—;
Ra is selected from the group consisting of hydrogen, fluoro, —CN, —N3, —OR5, —N(R4)2, —NR4CO2R6, —NR4C(O)R5, —C(O)N(R4)2, —C(O)R5, —OC(O)N(R4)2, —OC(O)R5, —OCO2R6, or a C1-4 aliphatic or C1-4 fluoroaliphatic optionally substituted with one or two substituents independently selected from the group consisting of —OR5x, —N(R4x)(R4y), —CO2R5x, or —C(O)N(R4x)(R4y);
or Ra and Rc together form a bond;
Rb is selected from the group consisting of hydrogen, fluoro, C1-4 aliphatic, and C1-4 fluoroaliphatic;
Rc is selected from the group consisting of hydrogen, fluoro, —CN, —N3, —OR5, —N(R4)2, —NR4CO2R6, —NR4C(O)R5, —C(O)N(R4)2, —C(O)R5, —OC(O)N(R4)2, —OC(O)R5, —OCO2R6, or a C1-4 aliphatic or C1-4 fluoroaliphatic optionally substituted with one or two substituents independently selected from the group consisting of —OR5x, —N(R4x)(R4y), —CO2R5x or —C(O)N(R4x)(R4y);
or Ra and Rc together form a bond;
Rd is selected from the group consisting of hydrogen, fluoro, C1-4 aliphatic, and C1-4 fluoroaliphatic;
Re is hydrogen, or C1-4 aliphatic;
or Re, taken together with one Rf and the intervening carbon atoms, forms a 3- to 6-membered spirocyclic ring;
Re′ is hydrogen or C1-4 aliphatic;
each Rf is independently hydrogen, fluoro, C1-4 aliphatic, or C1-4 fluoroaliphatic, provided that if X is —O— or —NH—, then Rf is not fluoro;
or two Rf taken together form ═O;
or two Rf, taken together with the carbon atom to which they are attached, form a 3- to 6-membered carbocyclic ring;
or one Rf, taken together with Re and the intervening carbon atoms, forms a 3- to 6-membered spirocyclic ring;
Rg is hydrogen, halo, —NO2, —CN, —C(R)═C(R)2, —C≡C—R5, —OR5, —SR6, —S(O)R6, —SO2R6, —SO2N(R)2, —N(R4)2, —NR4C(O)R5, —NR4C(O)N(R4)2, —N(R4)C(═NR4)—N(R4)2, —N(R4)C(═NR4)—R6, —NR4CO2R6, —N(R4)SO2R6, —N(R4)SO2N(R4)2, —O—C(O)R5, —OCO2R6, —OC(O)N(R4)2, —C(O)R5, —CO2R5, —C(O)N(R4)2, —C(O)N(R4)—OR5, —C(O)N(R4)C(═NR4)—N(R4)2—N(R4)C(═NR4)—N(R4)—C(O)R5, —C(═NR4)—N(R4)2, —C(═NR4)—OR5, —N(R4)—N(R4)2, —N(R4)—OR5, —C(═NR4)—N(R4)—OR5, —C(R)═N—OR5, or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl;
each Rh independently is hydrogen, halo, —CN—, —OR5, —N(R4)2, —SR6, or an optionally substituted C1-4 aliphatic group;
Rj is hydrogen, —OR5, —SR6, —N(R4)2, or an optionally substituted aliphatic, aryl, or heteroaryl group;
Rk is hydrogen, halo, —OR5, —SR6, —N(R4)2, or an optionally substituted C1-4 aliphatic group;
Rm is hydrogen, fluoro, —N(R4)2, or an optionally substituted C1-4 aliphatic group;
and
Rn is hydrogen, fluoro, or an optionally substituted C1-4 aliphatic group;
or
Rm and Rn together form ═O or ═C(R5)2;
each R4 independently is hydrogen or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
or two R4 on the same nitrogen atom, taken together with the nitrogen atom, form an optionally substituted 4- to 8-membered heterocyclyl ring having, in addition to the nitrogen atom, 0-2 ring heteroatoms independently selected from N, O, and S;
R4x is hydrogen, C1-4 alkyl, C1-4 fluoroalkyl, or C6-10 ar(C1-4)alkyl, the aryl portion of which may be optionally substituted;
R4y is hydrogen, C1-4 alkyl, C1-4 fluoroalkyl, C6-10 ar(C1-4)alkyl, the aryl portion of which may be optionally substituted, or an optionally substituted 5- or 6membered aryl, heteroaryl, or heterocyclyl ring;
or
R4x and R4y, taken together with the nitrogen atom to which they are attached, form an optionally substituted 4- to 8-membered heterocyclyl ring having, in addition to the nitrogen atom, 0-2 ring heteroatoms independently selected from N, O, and S;
and
each R5 independently is hydrogen or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
each R5x independently is hydrogen, C1-4 alkyl, C1-4 fluoroalkyl, or an optionally substituted C6-10 aryl or C6-10 ar(C1-4)alkyl;
each R6 independently is an optionally substituted aliphatic, aryl, or heteroaryl group;
and
m is 1, 2, or 3.

37 more elements

A compound of formula (XI) or formula (XII):

wherein:
depicted stereochemical configurations indicate absolute stereochemistry;
Ring A is selected from the group consisting of:
wherein one ring nitrogen atom in Ring A optionally is oxidized;
Rb is selected from the group consisting of hydrogen, fluoro, C1-4 aliphatic, and C1-4 fluoroaliphatic;
Rd is selected from the group consisting of hydrogen, fluoro, C1-4 aliphatic, and C1-4 fluoroaliphatic;
Re is hydrogen or C1-4 aliphatic;
or Re, taken together with one Rf and the intervening carbon atoms, forms a 3- to 6-membered spirocyclic ring;
each Rf independently is hydrogen, fluoro, C1-4 aliphatic, or Cl, fluoroaliphatic;
or two Rf, taken together with the carbon atom to which they are attached, form a 3- to 6-membered carbocyclic ring;
or one Rf taken together with Re and the intervening carbon atoms, forms a 3- to 6-membered spirocyclic ring;
R8 is hydrogen, halo, —NO2, —CN, —C(R)═C(R)2, —C≡C—R5, —OR5, —SR6, —S(O)R6, —SO2R6, —SO2N(R4)2, —N(R4)2, —NR4C(O)R5, —NR4C(O)N(R4)2, —N(R4)C(═NR4)—N(R4)2, —N(R4)C(═NR4)—R6, —NR4CO2R6, —N(R4)SO2R6, —N(R4)SO2N(R4)2, —O—C(O)R5, —OC(O)N(R4)2, —C(O)R5, —CO2R5, —C(O)N(R4)2, —C(O)N(R4)—OR5, —C(O)N(R4)C(═NR4)—N(R4)2, —N(R4)C(═NR4)—N(R4)—C(O)R5, —C(═NR4)—N(R4)2, —C(═NR4)—OR5, —N(R4)—N(R4)2, —N(R4)—OR5, —C(═NR4)—N(R4)—OR5, —C(R6)═N—OR5, or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl;
each Rh independently is hydrogen, halo, —CN, —OH, —O—(C1-4 aliphatic), —NH2, —NH—(C1-4 aliphatic), —N(C1-4 aliphatic)2, —SH, —S—(C1-4 aliphatic), or an optionally substituted C1-4 aliphatic group;
Rj is hydrogen, —OR5, —SR6, —N(R4)2, or an optionally substituted aliphatic, aryl, or heteroaryl group;
Rk is hydrogen, halo, —OR5, —SR6, —N(R4)2, or an optionally substituted C1-4 aliphatic group;
Raa is hydrogen or a hydroxyl protecting group;
and
Rbb is hydrogen or a hydroxyl protecting group;
Rcc is hydrogen or a hydroxyl protecting group;
or
Raa and Rbb together form a cyclic diol protecting group;
or
Raa and Rcc together form a cyclic diol protecting group.

20 more elements

A pharmaceutical composition, comprising a compound of formula (I-A):

or a pharmaceutically acceptable salt thereof, wherein:
stereochemical configurations depicted at asterisked positions indicate relative stereochemistry;
Ring A is selected from the group consisting of:
wherein one ring nitrogen atom in Ring A optionally is oxidized;
X is —CH2—, —CHF—, —CF2—, —NH—, or —O—;
Y is —O—, —S—, or —C(Rm)(Rn)—;
Ra is selected from the group consisting of hydrogen, fluoro, —CN, —N3, —OR5, —N(R4)2, —NR4CO2R6, —NR4C(O)R5, —C(O)N(R4)2, —C(O)R5, —OC(O)N(R4)2, —OC(O)R5, —OCO2R6, or a C1-4 aliphatic or C1-4 fluoroaliphatic optionally substituted with one or two substituents independently selected from the group consisting of —OR5x, —N(R4x)(R4y), —CO2R5x, or —C(O)N(R4x)(R4y);
or Ra and Rc together form a bond;
Rb is selected from the group consisting of hydrogen, fluoro, C1-4 aliphatic, and C1-4 fluoroaliphatic;
Rc is selected from the group consisting of hydrogen, fluoro, —CN, —N3, —OR5, —N(R4)2, —NR4CO2R6, —NR4C(O)R5, —C(O)N(R4)2, —C(O)R5, —OC(O)N(R4)2, —OC(O)R5, —OCO2R6, or a C1-4 aliphatic or C1-4 fluoroaliphatic optionally substituted with one or two substituents independently selected from the group consisting of —OR5x, —N(R4x)(R4y), —CO2R5x, or —C(O)N(R4x)(R4y);
or Ra and Rc together form a bond;
Rd is selected from the group consisting of hydrogen, fluoro, C1-4 aliphatic, and C1-4 fluoroaliphatic;
Re is hydrogen, or C1-4 aliphatic;
or Re, taken together with one Rf and the intervening carbon atoms, forms a 3- to 6-membered spirocyclic ring;
Re′ is hydrogen or C1-4 aliphatic;
each Rf is independently hydrogen, fluoro, C1-4 aliphatic, or C1-4 fluoroaliphatic, provided that if X is —O— or —NH—, then Rf is not fluoro;
or two Rf taken together form ═O;
or two Rf, taken together with the carbon atom to which they are attached, form a 3- to 6-membered carbocyclic ring;
or one Rf, taken together with Re and the intervening carbon atoms, forms a 3- to 6-membered spirocyclic ring;
Rg is hydrogen, halo, —NO2, —CN, —C(R)═C(R)2, —C≡C—R5, —OR5, —SR6, —S(O)R6, —SO2R6, —SO2N(R4)2, —N(R4)2, —NR4C(O)R5, —NR4C(O)N(R4)2, —N(R4)C(═NR4)—N(R4)2, —N(R4)C(═NR)—R6, —NR4CO2R6, —N(R)SO2R6, —N(R4)SO2N(R4)2, —O—C(O)R5, —OCO2R6, —OC(O)N(R4)2, —C(O)R5, —CO2R5, —C(O)N(R4)2, —C(O)N(R4)—OR5, —C(O)N(R4)C(═NR4)—N(R4)2, —N(R4)C(═NR4)—N(R4)—C(O)R5, —C(═NR4)—N(R4)2, —C(═NR4)—OR5, —N(R4)—N(R4)2, —N(R4)—OR5, —C(═NR4)—N(R4)—OR5, —C(R6)═N—OR5, or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl;
each Rh independently is hydrogen, halo, —CN—, —OR5, —N(R4)2, —SR6, or an optionally substituted C1-4 aliphatic group;
Rj is hydrogen, —OR5, —SR6, —N(R4)2, or an optionally substituted aliphatic, aryl, or heteroaryl group;
Rk is hydrogen, halo, —OR5, —SR6, —N(R4)2, or an optionally substituted C1-4 aliphatic group;
Rm is hydrogen, fluoro, —N(R4)2, or an optionally substituted C1-4 aliphatic group;
and
Rn is hydrogen, fluoro, or an optionally substituted C1-4 aliphatic group;
or
Rm and Rn together form ═O or ═C(R5)2;
each R4 independently is hydrogen or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
or two R4 on the same nitrogen atom, taken together with the nitrogen atom, form an optionally substituted 4- to 8-membered heterocyclyl ring having, in addition to the nitrogen atom, 0-2 ring heteroatoms independently selected from N, O, and S;
R4x is hydrogen, C1-4 alkyl, C1-4 fluoroalkyl, or C6-10 ar(C1-4)alkyl, the aryl portion of which may be optionally substituted;
R4y is hydrogen, C1-4 alkyl, C1-4 fluoroalkyl, C6-10 ar(C1-4)alkyl, the aryl portion of which may be optionally substituted, or an optionally substituted 5- or 6-membered aryl, heteroaryl, or heterocyclyl ring;
or
R4x and R4y, taken together with the nitrogen atom to which they are attached, form an optionally substituted 4- to 8-membered heterocyclyl ring having, in addition to the nitrogen atom, 0-2 ring heteroatoms independently selected from N, O, and S;
and
each R5 independently is hydrogen or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
each R5x independently is hydrogen, C1-4 alkyl, C1-4 fluoroalkyl, or an optionally substituted C6-10 aryl or C6-10 ar(C1-4)alkyl;
each R6 independently is an optionally substituted aliphatic, aryl, or heteroaryl group;
and
m is 1, 2, or 3;
and
a pharmaceutically acceptable carrier.

39 more elements

Dependencies are inferred from the claim text.

Facts

Application: 11/700,614Filed 31 Jan 2007
Priority: 2 Feb 2006
Published: 16 Aug 2007
Term ends: Not estimatedThe source records don’t support an estimate.

Classification21 codes

A61K 31/519
Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim: ortho- or peri-condensed with heterocyclic rings
A61K 31/52
Ortho- or peri-condensed with heterocyclic rings: purines, e.g. adenine
A61P 9/00
Drugs for disorders of the cardiovascular system
A61P 9/14
Drugs for disorders of the cardiovascular system: vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Family

Application60/764,487Us provisional application · filed 2 Feb 2006
US 8,207,177 B2Related patent
US 2007/0191293 A1This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
stereochemical configurations depicted at asterisked positions indicate relative stereochemistry;
Ring A is selected from the group consisting of:
wherein one ring nitrogen atom in Ring A optionally is oxidized;
X is —C(Rf1)2, —N(Rf2)—, or —O—;
Y is —O—, —S—, or —C(Rm)(Rn)—;
Ra is selected from the group consisting of hydrogen, fluoro, —CN, —N3, —OR5, —N(R4)2, —NR4CO2R6, —NR4C(O)R5, —C(O)N(R4)2, —C(O)R5, —OC(O)N(R4)2, —OC(O)R5, —OCO2R6, or a C1-4 aliphatic or C1-4 fluoroaliphatic optionally substituted with one or two substituents independently selected from the group consisting of —OR5x, —N(R4x)(R4y), —CO2R5x, or —C(O)N(R4x)(R4y);
or Ra and Rb together form ═O;
or Ra and Rc together form a bond;
Rb is selected from the group consisting of hydrogen, fluoro, C1-4 aliphatic, and C1-4 fluoroaliphatic;
or Rb and Ra together form ═O;
or Rb, taken together with Rd and the intervening carbon atoms, forms a fused cyclopropane ring, which is optionally substituted with one or two substituents independently selected from fluoro or C1-4 aliphatic;
or Rb, taken together with Re and the intervening carbon atoms, forms a fused cyclopropane ring, which is optionally substituted with one or two substituents independently selected from fluoro or C1-4 aliphatic;
Rc is selected from the group consisting of hydrogen, fluoro, —CN, —N3, —OR5, —N(R4)2, —NR4CO2R6, —NR4C(O)R5, —C(O)N(R)2, —C(O)R5, —OC(O)N(R4)2, —OC(O)R5, —OCO2R6, or a C1-4 aliphatic or C1-4 fluoroaliphatic optionally substituted with one or two substituents independently selected from the group consisting of —OR5x, —N(R4x)(R4y), —CO2R5x, or —C(O)N(R4x)(R4y);
or Ra and Rc together form a bond;
or Rc and Rd together form ═O;
Rd is selected from the group consisting of hydrogen, fluoro, C1-4 aliphatic, and C1-4 fluoroaliphatic;
or Rd and Rc together form ═O;
or Rd, taken together with Rb and the intervening carbon atoms, forms a fused cyclopropane ring, which is optionally substituted with one or two substituents independently selected from fluoro or C1-4 aliphatic;
or Rd, taken together with Re′ and the intervening carbon atoms, forms a fused cyclopropane ring, which is optionally substituted with one or two substituents independently selected from fluoro or C1-4 aliphatic;
Re is hydrogen, or C1-4 aliphatic;
or Re, taken together with one Rf and the intervening carbon atoms, forms a 3- to 6-membered spirocyclic ring, which is optionally substituted with one or two substituents independently selected from fluoro or C1-4 aliphatic;
or Re, taken together with Rm and the intervening carbon atoms, forms a fused cyclopropane ring, which is optionally substituted with one or two substituents independently selected from fluoro or C1-4 aliphatic;
or Re, taken together with Rb and the intervening carbon atoms, forms a fused cyclopropane ring, which is optionally substituted with one or two substituents independently selected from fluoro or C1-4 aliphatic;
Re′ is hydrogen or C1-4 aliphatic;
or Re′, taken together with Rm and the intervening carbon atoms, forms a fused cyclopropane ring, which is optionally substituted with one or two substituents independently selected from fluoro or C1-4 aliphatic;
or Re′, taken together with Rd and the intervening carbon atoms, forms a fused cyclopropane ring, which is optionally substituted with one or two substituents independently selected from fluoro or C1-4 aliphatic;
each Rf is independently hydrogen, fluoro, C1-4 aliphatic, or C1-4 fluoroaliphatic, provided that if X is —O— or —NH—, then Rf is not fluoro;
or two Rf taken together form ═O;
or two Rf, taken together with the carbon atom to which they are attached, form a 3- to 6-membered carbocyclic ring;
or one Rf, taken together with Re and the intervening carbon atoms, forms a 3- to 6-membered spirocyclic ring, which is optionally substituted with one or two substituents independently selected from fluoro or C1-4 aliphatic;
or one Rf, taken together with an adjacent Rf1 and the intervening carbon atoms, forms a cyclopropyl ring, which is optionally substituted with one or two substituents independently selected from fluoro or C1-4 aliphatic;
or one Rf and one Rf1 together form a double bond;
each Rf1 is independently hydrogen or fluoro;
or one Rf1, taken together with an adjacent Rf and the intervening carbon atoms forms a cyclopropyl ring, which is optionally substituted with one or two substituents independently selected from fluoro or C1-4 aliphatic;
or one Rf1 and one Rf together form a double bond;
Rf2 is hydrogen, C1-4 aliphatic, or C1-4 fluoroaliphatic;
Rg is hydrogen, halo, —NO2, —CN, —C(R)═C(R)2, —C≡C—R5, —OR5, —SR6, —S(O)R6, —SO2R6, —SO2N(R4)2, —N(R4)2, —NR4C(O)R5, —NR4C(O)N(R4)2, —N(R4)C(═NR4)—N(R)2, —N(R4)C(═NR)—R6, —NR4CO2R6, —N(R4)SO2R6, —N(R4)SO2N(R4)2, —O—C(O)R5, —OCO2R6, —OC(O)N(R4)2, —C(O)R5, —CO2R5, —C(O)N(R4)2, —C(O)N(R4)—OR5, —C(O)N(R4)C(═NR4)—N(R4)2, —N(R4)C(═NR4)—N(R4)—C(O)R5, —C(═NR4)—N(R4)2, —C(═NR4)—OR5, —N(R4)—N(R4)2, —N(R4)—OR5, —C(═NR4)—N(R4)—OR5, —C(R6)═N—OR5, or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl;
each Rh independently is hydrogen, halo, —CN—, —OR5, —N(R4)2, —SR6, or an optionally substituted C1-4 aliphatic group;
Rj is hydrogen, —OR5, —SR6, —N(R4)2, or an optionally substituted aliphatic, aryl, or heteroaryl group;
Rk is hydrogen, halo, —OR5, —SR6, —N(R4)2, or an optionally substituted C1-4 aliphatic group;
Rm is hydrogen, fluoro, —N(R4)2, or an optionally substituted C1-4 aliphatic group;
or Rm and Rn together form ═O or ═C(R5)2;
or Rm and Re, taken together with the intervening carbon atoms, form a fused cyclopropane ring, which is optionally substituted with one or two substituents independently selected from fluoro or C1-4 aliphatic;
or Rm and Re′, taken together with the intervening carbon atoms, form a fused cyclopropane ring, which is optionally substituted with one or two substituents independently selected from fluoro or C1-4 aliphatic;
Rn is hydrogen, fluoro, or an optionally substituted C1-4 aliphatic group;
or Rm and Rn together form ═O or ═C(R5)2;
each R4 independently is hydrogen or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
or two R4 on the same nitrogen atom, taken together with the nitrogen atom, form an optionally substituted 4- to 8-membered heterocyclyl ring having, in addition to the nitrogen atom, 0-2 ring heteroatoms independently selected from N, O, and S;
R4x is hydrogen, C1-4 alkyl, C1-4 fluoroalkyl, or C6-10 ar(C1-4)alkyl, the aryl portion of which may be optionally substituted;
R4y is hydrogen, C1-4 alkyl, C1-4 fluoroalkyl, C6-10 ar(C1-4)alkyl, the aryl portion of which may be optionally substituted, or an optionally substituted 5- or 6-membered aryl, heteroaryl, or heterocyclyl ring;
or
R4x and R4y, taken together with the nitrogen atom to which they are attached, form an optionally substituted 4- to 8-membered heterocyclyl ring having, in addition to the nitrogen atom, 0-2 ring heteroatoms independently selected from N, O, and S;
and
each R5 independently is hydrogen or an optionally substituted aliphatic, aryl, heteroaryl, or heterocyclyl group;
each R5x independently is hydrogen, C1-4 alkyl, C1-4 fluoroalkyl, or an optionally substituted C6-10 aryl or C6-10 ar(C1-4)alkyl;
each R6 independently is an optionally substituted aliphatic, aryl, or heteroaryl group;
and
m is 0, 1, 2, or 3, provided that Y is —C(Rm)(Rn)— when m is 0.

56 more elements

Facts

Application

11/700,614Filed 31 Jan 2007

Priority

2 Feb 2006

Published

16 Aug 2007

Term ends

Not estimatedThe source records don’t support an estimate.

Classification21 codes

A61K 31/519
Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim: ortho- or peri-condensed with heterocyclic rings
A61K 31/52
Ortho- or peri-condensed with heterocyclic rings: purines, e.g. adenine
A61P 9/00
Drugs for disorders of the cardiovascular system
A61P 9/14
Drugs for disorders of the cardiovascular system: vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers