US 7,402,568 B2Granted

Bicyclic 9a-azalide derivatives

AssigneeEnanta Pharmaceuticals, Inc.

InventorsYat Sun Or, Yao-Ling Qiu, Guoqiang Wang, Deqiang Niu, Ly Tam Phan

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Abstract

The present invention discloses compounds of formulae I and II, 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.

Claims22

Dependent claims

A compound represented by formula (I) or (II):

as well as the pharmaceutically acceptable salts, and esters thereof, wherein V is selected from the group consisting of:
(a) —CH2—C(A)=C(B)-CH2—;
wherein,
A and B are independently selected from the group consisting of:
(i) hydrogen;
(ii) deuterium;
(iii) halogen;
(iv) R1, wherein R1 is dependently selected from C1-C6 alkyl, C2-C6 alkenyl, or 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 the group consisting of:
halogen, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
(v) R2, wherein R2 is independently selected from the group consisting of:
a. aryl;
b. heteroaryl;
c. substituted aryl;
and
d. substituted heteroaryl;
(vi) —(C1-C3-alkyl)-M-(C1-C3-alkyl)-R2, wherein M=—O—, —NH—, —N(CH3)—, —NHC(O)—or —S(O)n—, wherein n =0, 1 or 2, and R2 is as previously defined;
(vii) —(C1-C3-alkyl)-M-R2, wherein M and R2 are as previously defined;
(viii) —C(O)-J-R3, wherein J is absent, O or S, and R3 is H, R1 or R2;
where R1 and R2 are as previously defined, and
(ix) —C(O)—NR4R5, wherein R4 and R5 are each independently selected from the group consisting of:
a. hydrogen;
b. R1, wherein R1 is as previously defined;
c. R2, wherein R2 is as previously defined;
and
d. R4 and R5 taken together with the nitrogen atom to which they are connected form a 3- to 7-membered ring which may optionally contain one or more heterofunctions selected from the group consisting of:
—O—, —NH—, —N(R1)—, —N(R2)—, —S(O)n—, wherein n, R1 and R2 are as previously defined;
(b) —CH2—CH(A)-C(B)═CH—, wherein A and B are as previously defined;
(c) —CH═C(A)-CH(B)-CH2—, wherein A and B are as previously defined;
(d) —CH2—CH(A′)-CH(B′)-CH2—;
wherein A′ and B′ are independently selected from the group consisting of:
(i) A, wherein A is as previously defined;
(ii) —OH;
(iii) —ORp, wherein Rp is a hydroxy protecting group;
(iv) —O—R9, wherein R9 is R1 or R2, and wherein R1 and R2 are as previously defined;
(v) —S(O)nR9, wherein n and R9 are as previously defined;
(vi) —NHC(O)R3, wherein R3 is as previously defined;
(vii) —NHC(O)NR4R5, wherein R4 and R5 are as previously defined;
(viii) —NHS(O)2R9, wherein R9 is as previously defined;
(ix) —NHR13, wherein R13 is an amino protecting group;
and
(x) —NR4R5, wherein R4 and R5 are as previously defined;
wherein:
(i) -Q- is selected from the group consisting of:
—O—;
—O—C(O)—CH(R7)—;
—N(R7)—;
—O—C(O)—N(R7)—;
—O—C(O)—O—;
—N(R7)—N═N—;
—C(R7)═N—O—;
and —CH(R7)—N(R8)—O—;
wherein R7 and R8 are independently selected from R3, wherein R3 is as previously defined;
or
(ii) -Q- taken together with the two carbon atoms it is attached to is selected from the group consisting of:
a. cycloalkylene;
b. cycloalkenylene;
and
c. heterocycloalkylene;
and
(f) —CH2—C(R11)(R12)—CH2—CH2—;
wherein R11 and R12 taken together with the carbon atom to which they are attached are selected from the group consisting of:
(i) C═O;
(ii) C(OR1a)(OR2a), where R1a and R2a are independently R1 or taken together are —(CH2)m—, and where m is 2 or 3;
(iii) C(SR1a)(SR2a), where R1a and R2a are as previously defined;
(iv) C═CHR3, where R3 is as previously defined;
(v) C═N—O—R3, where R3 is as previously defined;
(vi) C═NNHR3, where R3 is as previously defined;
(vii) C═NNHC(O)R3, where R3 is as previously defined;
(viii) C═NNHC(O)NR4R5, where R4 and R5 are as previously defined;
(ix) C═NNHS(O)2R9, where R9 is as previously defined;
(x) C═NNHR13, where R13 is as previously defined;
and
(xi) C═NR9, where R9 is as previously defined;
(g) —C(R14)(R15)—CH2—;
wherein R14 is:
(i) —ORp, where Rp is previously defined;
(ii) —R1, where R1 is as previously described;
(iii) —R2, where R2 is as previously described;
(iv) —OR1, where R1 is as previously defined;
(v) —OR2, where R2 is previously defined;
(vi) —S(O)nR9, where n and R9 are as previously defined;
(vii) —NHC(O)R9, where R9 is as previously defined;
(viii) —NHC(O)NHR9, where R9 is as previously defined;
(ix) —NHS(O)2R9, where R9 is as previously defined;
(x) —NR4R5, where R4 and R5 are as previously defined;
(xi) —NHR13, where R13 is previously defined;
and
R15 is:
(i) deuterium;
(ii) halogen;
(iii) —OH;
(iv) —R1, where R1 is as previously defined;
(v) —R2, where R2 is as previously defined;
or
(vi) —ORp, where Rp is as previously defined, provided that when R15 is halogen, —OH or ORp, R14 is R1 or R2, where R1 and R2 are previously defined;
or, alternatively, R14 and R15 taken together with the carbon atom to which they are attached are:
(i) C═O;
(ii) C(OR1a)(OR2a), where R1a and R2a are independently R1 or taken together are —(CH2)m—, and where m is 2 or 3;
(iii) C(SR1a)(SR2a), where R1a and R2a are as previously defined;
(iv) C═CHR9, where R9 is as previously defined;
(v) C═N—O—R9, where R9 is as previously defined;
(vi) C═NNHR9, where R9 is as previously defined;
(vii) C═NNHC(O)R9, where R9 is as previously defined;
(viii) C═NNHC(O)NHR9, where R9 is as previously defined;
(ix) C∇NNHS(O)2R9, where R9 is as previously defined;
(x) C═NNHR9, where R9 is as previously defined;
or
(xi) C═NR9, where R9 is as previously defined;
(h) —CH2—C(R14)(R15)—CH2—;
wherein R14 and R15 as previously defined;
G and W are independently selected from:
(a) hydrogen;
(b) R10, where R10 is C1-C6-alkyl, C2-C6-alkenyl or C2-C6-alkynyl, containing 0, 1, 2, or 3 heteroatoms, optionally substituted with one or more substituents selected from:
(1) halogen;
(2) aryl;
(3) substituted-aryl;
(4) heteroaryl;
(5) substituted-heteroaryl;
(6) —O—C1-C6-alkyl-R9, where R9 is as previously defined;
and
(7) —N(R1R5), where R4 and R5 are as previously defined;
(c) —C(O)R9, where R9 is as previously defined;
(d) —C(O)O—R9, where R9 is as previously defined;
and
(e) —C(O)N(R4R5), where R4 and R5 are as previously defined;
Or, alternatively, G and W are taken together to form either a carbonyl or a methylene group,
L is:
(a) —CH2CH3;
(b) —CH(OH)CH3;
(c) -R1, where R1 is as previously defined,
D is —N(R19)CH2—, —N(R20)C(O)—, or —N═C(OR20)—, wherein R20 is R9 where R9 is as previously defined;
R19 is
(a) hydrogen;
(b) —C1-C12-alkyl, C2C12-alkenyl, or C2C12alkynyl, containing 0, 1, 2, or 3 heteroatoms, all optionally substituted with one or more substituents independently selected from:
i) halogen;
ii) —OR1, wherein R1 is as previously defined;
iii) —OR2, wherein R2 is as previously defined;
iv) —NR4R5, where R4 and R5 as previously defined or alternatively R4 and R5, together with the atom to which they are attached, form a heterocycloalkyl or substituted heterocycloalkyl moiety;
v) ═N—O—R9, where R9 is as previously defined;
vi) —R1, where R1 is as previously defined;
vii) —C3-C8-cycloalkyl;
viii) substituted —C3-C8-cycloalkyl;
ix) heterocycloalkyl;
x) substituted heterocycloalkyl;
xi) —NHC(O)R9, where R9 is as previously defined;
xii) —NHC(O)OR9, where R9 is as previously defined;
xiii) —NHC(O)NR4R5, where R4 and R5 are as previously defined;
xiv) —OC(O)NR4R5, where R4 and R5 are as previously defined;
xv) —OC(O)R9, where R9 is as previously defined;
xvi) —OC(O)OR9, where R9 is as previously defined;
xvii) —OC(O)NR4R5, where R4 and R5 are as previously defined,
xviii) —C(O)R9, where R9 is as previously defined,
xix) —CO2R9, where R9 is as previously defined, or
xx) —C(O)NR4R5, where R4 and R5 are as previously defined;
Alternatively, D when taken together with G to form a moiety of the following structure:
wherein L, V, W and R2′ are as previously defined and P is C1-C6 alkyl optionally substituted with one or more substituents selected from the group consisting of:
a) R1, where R1 is as previously defined;
b) R2, where R2 is as previously defined;
c) heterocycloalkyl,
d) hydroxyl,
e) C1-C6-alkoxy,
f) Halogen, and
g) NR4R5 where R4 and R5 are as previously defined,
X is hydrogen;
Y is
(a) hydrogen;
(b) —OH;
(c) —ORp, where Rp is as previously defined;
(d) —OR9, where R9 is as previously defined;
(e) —OC(O)R9, where R9 is as previously defined;
(f) —OC(O)NHR9, where R9 is as previously defined;
(g) —S(O)nR9, where n and R9 are as previously defined;
where R3″ is selected from hydrogen or methyl and R4″ is selected from:
(1) hydrogen;
(2) Rp, where Rp is as previously defined;
or
(3) —C(O)(CH2)r-E-R9, wherein R9 is as previously defined, r =1-6 and E is absent or -U(CH2)qU′-, where q =an integer from 2 to 8, and U and U′ are independently selected from:
i) —N(R9)—, where R9 is as previously defined;
ii) —O—;
iii) —S(O)n—, where n =0, 1, or 2;
iv) —N(R9)C(O)—, where R9 is as previously defined;
v) —C(O)N(R9)—, where R9 is as previously defined;
or
vi) —N[C(O)R9]—, where R9 is as previously defined;
and
Alternatively, X and Y taken together are oxo;
Z is
(a) hydrogen;
(b) methyl;
or
(c) halogen;
and
R2′ is hydrogen or Rp, where Rp, is as previously defined.

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Dependencies are inferred from the claim text.

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Abstract

A compound represented by formula (I) or (II):

as well as the pharmaceutically acceptable salts, and esters thereof, wherein V is selected from the group consisting of:
(a) —CH2—C(A)=C(B)-CH2—;
wherein,
A and B are independently selected from the group consisting of:
(i) hydrogen;
(ii) deuterium;
(iii) halogen;
(iv) R1, wherein R1 is dependently selected from C1-C6 alkyl, C2-C6 alkenyl, or 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 the group consisting of:
halogen, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
(v) R2, wherein R2 is independently selected from the group consisting of:
a. aryl;
b. heteroaryl;
c. substituted aryl;
and
d. substituted heteroaryl;
(vi) —(C1-C3-alkyl)-M-(C1-C3-alkyl)-R2, wherein M=—O—, —NH—, —N(CH3)—, —NHC(O)—or —S(O)n—, wherein n =0, 1 or 2, and R2 is as previously defined;
(vii) —(C1-C3-alkyl)-M-R2, wherein M and R2 are as previously defined;
(viii) —C(O)-J-R3, wherein J is absent, O or S, and R3 is H, R1 or R2;
where R1 and R2 are as previously defined, and
(ix) —C(O)—NR4R5, wherein R4 and R5 are each independently selected from the group consisting of:
a. hydrogen;
b. R1, wherein R1 is as previously defined;
c. R2, wherein R2 is as previously defined;
and
d. R4 and R5 taken together with the nitrogen atom to which they are connected form a 3- to 7-membered ring which may optionally contain one or more heterofunctions selected from the group consisting of:
—O—, —NH—, —N(R1)—, —N(R2)—, —S(O)n—, wherein n, R1 and R2 are as previously defined;
(b) —CH2—CH(A)-C(B)═CH—, wherein A and B are as previously defined;
(c) —CH═C(A)-CH(B)-CH2—, wherein A and B are as previously defined;
(d) —CH2—CH(A′)-CH(B′)-CH2—;
wherein A′ and B′ are independently selected from the group consisting of:
(i) A, wherein A is as previously defined;
(ii) —OH;
(iii) —ORp, wherein Rp is a hydroxy protecting group;
(iv) —O—R9, wherein R9 is R1 or R2, and wherein R1 and R2 are as previously defined;
(v) —S(O)nR9, wherein n and R9 are as previously defined;
(vi) —NHC(O)R3, wherein R3 is as previously defined;
(vii) —NHC(O)NR4R5, wherein R4 and R5 are as previously defined;
(viii) —NHS(O)2R9, wherein R9 is as previously defined;
(ix) —NHR13, wherein R13 is an amino protecting group;
and
(x) —NR4R5, wherein R4 and R5 are as previously defined;
wherein:
(i) -Q- is selected from the group consisting of:
—O—;
—O—C(O)—CH(R7)—;
—N(R7)—;
—O—C(O)—N(R7)—;
—O—C(O)—O—;
—N(R7)—N═N—;
—C(R7)═N—O—;
and —CH(R7)—N(R8)—O—;
wherein R7 and R8 are independently selected from R3, wherein R3 is as previously defined;
or
(ii) -Q- taken together with the two carbon atoms it is attached to is selected from the group consisting of:
a. cycloalkylene;
b. cycloalkenylene;
and
c. heterocycloalkylene;
and
(f) —CH2—C(R11)(R12)—CH2—CH2—;
wherein R11 and R12 taken together with the carbon atom to which they are attached are selected from the group consisting of:
(i) C═O;
(ii) C(OR1a)(OR2a), where R1a and R2a are independently R1 or taken together are —(CH2)m—, and where m is 2 or 3;
(iii) C(SR1a)(SR2a), where R1a and R2a are as previously defined;
(iv) C═CHR3, where R3 is as previously defined;
(v) C═N—O—R3, where R3 is as previously defined;
(vi) C═NNHR3, where R3 is as previously defined;
(vii) C═NNHC(O)R3, where R3 is as previously defined;
(viii) C═NNHC(O)NR4R5, where R4 and R5 are as previously defined;
(ix) C═NNHS(O)2R9, where R9 is as previously defined;
(x) C═NNHR13, where R13 is as previously defined;
and
(xi) C═NR9, where R9 is as previously defined;
(g) —C(R14)(R15)—CH2—;
wherein R14 is:
(i) —ORp, where Rp is previously defined;
(ii) —R1, where R1 is as previously described;
(iii) —R2, where R2 is as previously described;
(iv) —OR1, where R1 is as previously defined;
(v) —OR2, where R2 is previously defined;
(vi) —S(O)nR9, where n and R9 are as previously defined;
(vii) —NHC(O)R9, where R9 is as previously defined;
(viii) —NHC(O)NHR9, where R9 is as previously defined;
(ix) —NHS(O)2R9, where R9 is as previously defined;
(x) —NR4R5, where R4 and R5 are as previously defined;
(xi) —NHR13, where R13 is previously defined;
and
R15 is:
(i) deuterium;
(ii) halogen;
(iii) —OH;
(iv) —R1, where R1 is as previously defined;
(v) —R2, where R2 is as previously defined;
or
(vi) —ORp, where Rp is as previously defined, provided that when R15 is halogen, —OH or ORp, R14 is R1 or R2, where R1 and R2 are previously defined;
or, alternatively, R14 and R15 taken together with the carbon atom to which they are attached are:
(i) C═O;
(ii) C(OR1a)(OR2a), where R1a and R2a are independently R1 or taken together are —(CH2)m—, and where m is 2 or 3;
(iii) C(SR1a)(SR2a), where R1a and R2a are as previously defined;
(iv) C═CHR9, where R9 is as previously defined;
(v) C═N—O—R9, where R9 is as previously defined;
(vi) C═NNHR9, where R9 is as previously defined;
(vii) C═NNHC(O)R9, where R9 is as previously defined;
(viii) C═NNHC(O)NHR9, where R9 is as previously defined;
(ix) C∇NNHS(O)2R9, where R9 is as previously defined;
(x) C═NNHR9, where R9 is as previously defined;
or
(xi) C═NR9, where R9 is as previously defined;
(h) —CH2—C(R14)(R15)—CH2—;
wherein R14 and R15 as previously defined;
G and W are independently selected from:
(a) hydrogen;
(b) R10, where R10 is C1-C6-alkyl, C2-C6-alkenyl or C2-C6-alkynyl, containing 0, 1, 2, or 3 heteroatoms, optionally substituted with one or more substituents selected from:
(1) halogen;
(2) aryl;
(3) substituted-aryl;
(4) heteroaryl;
(5) substituted-heteroaryl;
(6) —O—C1-C6-alkyl-R9, where R9 is as previously defined;
and
(7) —N(R1R5), where R4 and R5 are as previously defined;
(c) —C(O)R9, where R9 is as previously defined;
(d) —C(O)O—R9, where R9 is as previously defined;
and
(e) —C(O)N(R4R5), where R4 and R5 are as previously defined;
Or, alternatively, G and W are taken together to form either a carbonyl or a methylene group,
L is:
(a) —CH2CH3;
(b) —CH(OH)CH3;
(c) -R1, where R1 is as previously defined,
D is —N(R19)CH2—, —N(R20)C(O)—, or —N═C(OR20)—, wherein R20 is R9 where R9 is as previously defined;
R19 is
(a) hydrogen;
(b) —C1-C12-alkyl, C2C12-alkenyl, or C2C12alkynyl, containing 0, 1, 2, or 3 heteroatoms, all optionally substituted with one or more substituents independently selected from:
i) halogen;
ii) —OR1, wherein R1 is as previously defined;
iii) —OR2, wherein R2 is as previously defined;
iv) —NR4R5, where R4 and R5 as previously defined or alternatively R4 and R5, together with the atom to which they are attached, form a heterocycloalkyl or substituted heterocycloalkyl moiety;
v) ═N—O—R9, where R9 is as previously defined;
vi) —R1, where R1 is as previously defined;
vii) —C3-C8-cycloalkyl;
viii) substituted —C3-C8-cycloalkyl;
ix) heterocycloalkyl;
x) substituted heterocycloalkyl;
xi) —NHC(O)R9, where R9 is as previously defined;
xii) —NHC(O)OR9, where R9 is as previously defined;
xiii) —NHC(O)NR4R5, where R4 and R5 are as previously defined;
xiv) —OC(O)NR4R5, where R4 and R5 are as previously defined;
xv) —OC(O)R9, where R9 is as previously defined;
xvi) —OC(O)OR9, where R9 is as previously defined;
xvii) —OC(O)NR4R5, where R4 and R5 are as previously defined,
xviii) —C(O)R9, where R9 is as previously defined,
xix) —CO2R9, where R9 is as previously defined, or
xx) —C(O)NR4R5, where R4 and R5 are as previously defined;
Alternatively, D when taken together with G to form a moiety of the following structure:
wherein L, V, W and R2′ are as previously defined and P is C1-C6 alkyl optionally substituted with one or more substituents selected from the group consisting of:
a) R1, where R1 is as previously defined;
b) R2, where R2 is as previously defined;
c) heterocycloalkyl,
d) hydroxyl,
e) C1-C6-alkoxy,
f) Halogen, and
g) NR4R5 where R4 and R5 are as previously defined,
X is hydrogen;
Y is
(a) hydrogen;
(b) —OH;
(c) —ORp, where Rp is as previously defined;
(d) —OR9, where R9 is as previously defined;
(e) —OC(O)R9, where R9 is as previously defined;
(f) —OC(O)NHR9, where R9 is as previously defined;
(g) —S(O)nR9, where n and R9 are as previously defined;
where R3″ is selected from hydrogen or methyl and R4″ is selected from:
(1) hydrogen;
(2) Rp, where Rp is as previously defined;
or
(3) —C(O)(CH2)r-E-R9, wherein R9 is as previously defined, r =1-6 and E is absent or -U(CH2)qU′-, where q =an integer from 2 to 8, and U and U′ are independently selected from:
i) —N(R9)—, where R9 is as previously defined;
ii) —O—;
iii) —S(O)n—, where n =0, 1, or 2;
iv) —N(R9)C(O)—, where R9 is as previously defined;
v) —C(O)N(R9)—, where R9 is as previously defined;
or
vi) —N[C(O)R9]—, where R9 is as previously defined;
and
Alternatively, X and Y taken together are oxo;
Z is
(a) hydrogen;
(b) methyl;
or
(c) halogen;
and
R2′ is hydrogen or Rp, where Rp, is as previously defined.

190 more elements