US 6,645,941 B1Granted

6,11-3C-bicyclic 9a-azalide derivatives

AssigneeEnanta Pharmaceuticals, Inc.

InventorsGuoqiang Wang, Yat Sun Or, Ly Tam Phan, Marina Busuyek

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Abstract

The present invention discloses compounds of formula I, or pharmaceutically acceptable salts, esters, or prodrugs thereof: which exhibit antibacterial properties. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject in need of antibiotic treatment. The invention also relates to methods of treating a bacterial infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention. The invention further includes process by which to make the compounds of the present invention.

Claims14

Dependent claims

A compound of formula I, or a pharmaceutically acceptable salt, ester, or prodrug thereof:

wherein,
A is
i) —OH;
ii) —ORp, where Rp is a hydroxy protecting group;
iii) —R1, where R1 is aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
iv) —OR1, where R1 is as previously defined;
v) —R2, where R2 is
(a) hydrogen;
(b) halogen;
(c) —C1--C6 alkyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
(d) —C2-C6 alkenyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, hetbroaryl, or substituted heteroaryl;
or
(e) —C2-C6 alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
vi) —OR2, where R2 is previously defined;
vii) —S(O)nR11, where n=0, 1 or 2, and R11 is R1 or R2, where R1 and R2 are previously defined;
viii) —NHC(O)R11, where R11 is as previously defined;
ix) —NHC(O)NHR11, where R11 is as previously defined;
x) —NHS(O)2R11, where R11 is as previously defined;
xi) —NR14R15, where R14 and R15 are each independently R11, where R11 is as previously defined;
or
xii) —NHR3, where R3 is an amino protecting group;
B is
i) hydrogen;
ii) deuterium;
iii) halogen;
iv) —OH;
v) —R1, where R1 is as previously defined;
vi) —R2, where R2 is as previously defined;
or
vii) —ORp, where Rp is as previously defined, provided that when B is halogen, —OH or ORp, A is R1 or R2;
or, alternatively, A and B taken together with the carbon atom to which they are attached are
i) C═O;
ii) C(OR2)2, where R2 is as previously defined;
iii) C(SR2)2, where R2 is as previously defined;
iv) C[—O(CH2)m]2, where m=2 or 3;
v) C[—S(CH2)m]2, where m is as previously defined;
vi) C═CHR11, where R11 is as previously defined;
vii) C═N—O—R11, where R11 is as previously defined;
viii) C═NNHR11, where R11 is as previously defined;
ix) C═NNHC(O)R11, where R11 is as previously defined;
x) C═NNHC(O)NHR11, where R11 is as previously defined;
xi) C═NNHS(O)2R11, where R11 is as previously defined;
xii) C═NNHR3, where R3 is as previously defined;
or xiii)C═NR11, where R11 is as previously defined;
L is
i) —CH3;
ii) —CH2CH3;
iii) —CH(OH)CH3;
iv) —C1-C6 alkyl, optionally substituted with one or more substituents selected from aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
v) —C2-C6 alkenyl, optionally substituted with one or more substituents selected from aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
or
vi) —C2-C6 alkynyl, optionally substituted with one or more substituents selected from aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
D is —N(Q)CH2—, —N(R′)C(O)—, or —N═C(OR′)—, wherein R′ is R11 as previously defined and Q is defined herein;
Q is
i) hydrogen;
ii) —C1-C12-alkyl, C3-C12-alkenyl, or C3-C12-alkynyl, all optionally substituted with one or more substituents independently selected from:
(a) halogen;
(b) —OR6, wherein R6 is selected from:
1. hydrogen;
2. —C1-C12-alkyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, optionally substituted with one, two, or three substituents independently selected from aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
3. aryl;
4. substituted aryl;
5. heteroaryl;
and
6. substituted heteroaryl;
(c) —NR4R5, where R4 and R5 are each independently R6, where R6 is as previously defined;
or in the alternative R4 and R5, together with the atom to which they are attached, form a heterocycloalkyl or substituted heterocycloalkyl moiety;
(d) ═N—O—R6, where R6 is as previously defined;
(e) —R1, where R1 is as previously defined;
(f) —C3-C8-cycloalkyl;
(g) substituted —C3-C8-cycloalkyl;
(h) heterocycloalkyl;
(i) substituted heterocycloalkyl;
(j) —NHC(O)R6, where R6 is as previously defined;
(k) —NHC(O)OR7, where R7 is selected from:
1. —C1-C12-alkyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, optionally substituted with one, two, or three substituents independently selected from aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
2. aryl;
3. substituted aryl;
4. heteroaryl;
or
5. substituted heteroaryl;
(i) —NHC(O)NR4R5, where R4 and R5 are as previously defined;
(m) —OC(O)NR4R5, where R4 and R5 are as previously defined;
(n) —OC(O)R7, where R7 is as previously defined;
(o) —OC(O)OR7, where R7 is as previously defined;
(p) —OC(O)NR4R5, where R4 and R5 are as previously defined;
(q) —C(O)R6, where R6 is as previously defined;
(r) —CO2R6, where R6 is as previously defined;
or
(s) —C(O)NR4R5, where R4 and R5 are as previously defined;
X is hydrogen;
Y is
i) hydrogen;
ii) —OH;
iii) —ORp, where Rp is as previously defined;
iv) —OR11, where R11 is as previously defined;
v) —OC(O)R11, where R11 is as previously defined;
vi) —OC(O)NHR11, where R11 is as previously defined;
vii) —S(O)nR11, where n and R11 are as previously defined;
viii) —
where R3″ is hydrogen or methyl;
R4″ is hydrogen or Rp, where Rp is as previously defined;
or
in the alternative X and Y combined together are oxo;
Z is
i) hydrogen;
ii) methyl;
or
iii) halogen;
and
R2′ is hydrogen or Rp, where Rp, is as previously defined.

108 more elements

Dependencies are inferred from the claim text.

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Abstract

A compound of formula I, or a pharmaceutically acceptable salt, ester, or prodrug thereof:

wherein,
A is
i) —OH;
ii) —ORp, where Rp is a hydroxy protecting group;
iii) —R1, where R1 is aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
iv) —OR1, where R1 is as previously defined;
v) —R2, where R2 is
(a) hydrogen;
(b) halogen;
(c) —C1--C6 alkyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
(d) —C2-C6 alkenyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, hetbroaryl, or substituted heteroaryl;
or
(e) —C2-C6 alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, optionally substituted with one or more substituents selected from halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
vi) —OR2, where R2 is previously defined;
vii) —S(O)nR11, where n=0, 1 or 2, and R11 is R1 or R2, where R1 and R2 are previously defined;
viii) —NHC(O)R11, where R11 is as previously defined;
ix) —NHC(O)NHR11, where R11 is as previously defined;
x) —NHS(O)2R11, where R11 is as previously defined;
xi) —NR14R15, where R14 and R15 are each independently R11, where R11 is as previously defined;
or
xii) —NHR3, where R3 is an amino protecting group;
B is
i) hydrogen;
ii) deuterium;
iii) halogen;
iv) —OH;
v) —R1, where R1 is as previously defined;
vi) —R2, where R2 is as previously defined;
or
vii) —ORp, where Rp is as previously defined, provided that when B is halogen, —OH or ORp, A is R1 or R2;
or, alternatively, A and B taken together with the carbon atom to which they are attached are
i) C═O;
ii) C(OR2)2, where R2 is as previously defined;
iii) C(SR2)2, where R2 is as previously defined;
iv) C[—O(CH2)m]2, where m=2 or 3;
v) C[—S(CH2)m]2, where m is as previously defined;
vi) C═CHR11, where R11 is as previously defined;
vii) C═N—O—R11, where R11 is as previously defined;
viii) C═NNHR11, where R11 is as previously defined;
ix) C═NNHC(O)R11, where R11 is as previously defined;
x) C═NNHC(O)NHR11, where R11 is as previously defined;
xi) C═NNHS(O)2R11, where R11 is as previously defined;
xii) C═NNHR3, where R3 is as previously defined;
or xiii)C═NR11, where R11 is as previously defined;
L is
i) —CH3;
ii) —CH2CH3;
iii) —CH(OH)CH3;
iv) —C1-C6 alkyl, optionally substituted with one or more substituents selected from aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
v) —C2-C6 alkenyl, optionally substituted with one or more substituents selected from aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
or
vi) —C2-C6 alkynyl, optionally substituted with one or more substituents selected from aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
D is —N(Q)CH2—, —N(R′)C(O)—, or —N═C(OR′)—, wherein R′ is R11 as previously defined and Q is defined herein;
Q is
i) hydrogen;
ii) —C1-C12-alkyl, C3-C12-alkenyl, or C3-C12-alkynyl, all optionally substituted with one or more substituents independently selected from:
(a) halogen;
(b) —OR6, wherein R6 is selected from:
1. hydrogen;
2. —C1-C12-alkyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, optionally substituted with one, two, or three substituents independently selected from aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
3. aryl;
4. substituted aryl;
5. heteroaryl;
and
6. substituted heteroaryl;
(c) —NR4R5, where R4 and R5 are each independently R6, where R6 is as previously defined;
or in the alternative R4 and R5, together with the atom to which they are attached, form a heterocycloalkyl or substituted heterocycloalkyl moiety;
(d) ═N—O—R6, where R6 is as previously defined;
(e) —R1, where R1 is as previously defined;
(f) —C3-C8-cycloalkyl;
(g) substituted —C3-C8-cycloalkyl;
(h) heterocycloalkyl;
(i) substituted heterocycloalkyl;
(j) —NHC(O)R6, where R6 is as previously defined;
(k) —NHC(O)OR7, where R7 is selected from:
1. —C1-C12-alkyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, optionally substituted with one, two, or three substituents independently selected from aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
2. aryl;
3. substituted aryl;
4. heteroaryl;
or
5. substituted heteroaryl;
(i) —NHC(O)NR4R5, where R4 and R5 are as previously defined;
(m) —OC(O)NR4R5, where R4 and R5 are as previously defined;
(n) —OC(O)R7, where R7 is as previously defined;
(o) —OC(O)OR7, where R7 is as previously defined;
(p) —OC(O)NR4R5, where R4 and R5 are as previously defined;
(q) —C(O)R6, where R6 is as previously defined;
(r) —CO2R6, where R6 is as previously defined;
or
(s) —C(O)NR4R5, where R4 and R5 are as previously defined;
X is hydrogen;
Y is
i) hydrogen;
ii) —OH;
iii) —ORp, where Rp is as previously defined;
iv) —OR11, where R11 is as previously defined;
v) —OC(O)R11, where R11 is as previously defined;
vi) —OC(O)NHR11, where R11 is as previously defined;
vii) —S(O)nR11, where n and R11 are as previously defined;
viii) —
where R3″ is hydrogen or methyl;
R4″ is hydrogen or Rp, where Rp is as previously defined;
or
in the alternative X and Y combined together are oxo;
Z is
i) hydrogen;
ii) methyl;
or
iii) halogen;
and
R2′ is hydrogen or Rp, where Rp, is as previously defined.

108 more elements