Pyrimidinecarboxamide derivatives
This disclosure relates to novel HIV integrase inhibitors their derivatives, pharmaceutically acceptable salts thereof. This disclosure also provides compositions comprising a compound of this disclosure and the use of such compositions in methods of treating HIV infections.
1. A compound of Formula I-A:
or a pharmaceutically acceptable salt thereof, wherein:
each of R 1 , R 2a , R 2b , and R 3 is independently selected from —CH 3 , —CDH 2 , —CD 2 H, and —CD 3 ;
Y 1 and Y 2 are each independently selected from H and D;
R 4 is selected from:
and
R 6 is selected from the group consisting of —C(R 7 )(R 8 )—O—Z and —(CH 2 ) q —C(O)—R 12 , wherein:
q is 1 or 0;
R 12 is C 6 -C 10 aryl optionally substituted with deuterium, or C 1 -C 7 alkyl optionally substituted with one or two R 10 and further optionally substituted with deuterium, wherein
(a)(i) one carbon unit in the C 1 -C 7 alkyl, wherein the carbon unit is bound to a —C(O)— of the —C(O)—C 1 -C 7 alkyl, is optionally replaced with —C(O)—, —O—, —S—, —NH, or —N(C 1 -C 3 alkyl);
a(ii) one carbon unit in the C 1 -C 7 alkyl, wherein the carbon unit is not bound to a —C(O)— of the —C(O)—C 1 -C 7 alkyl, is optionally replaced with —C(O)—, —S(O)—, —S(O) 2 , —O—, —S—, —NH, or —N(C 1 -C 3 alkyl);
(b)(i) when a first carbon unit in the C 1 -C 7 alkyl is replaced with —C(O)—, —S(O)—, or —S(O) 2 , a second carbon unit is optionally replaced with —O—, —S—, —NH, or —N(C 1 -C 3 alkyl); and
(b)(ii) when a first carbon unit in the C 1 -C 7 alkyl is replaced with —O—, —S—, —NH, or —N(C 1 -C 3 alkyl), a second carbon unit, separated by at least two carbon units from the first carbon unit replaced with —O—, —S—, —NH, or —N(C 1 -C 3 alkyl), is optionally replaced with —O—, —S—, —NH, or —N(C 1 -C 3 alkyl);
each R 10 is independently a C 3 -C 7 carbocyclyl or a 3-7-membered heterocyclyl, wherein each R 10 is optionally and independently substituted with C 1 -C 3 alkyl or deuterium and optionally and independently benzofused;
R 7 and R 8 are each independently hydrogen, deuterium, or C 1 -C 3 alkyl optionally substituted with deuterium; or
R 7 and R 8 taken together with the carbon to which they are attached form a C 3 -C 7 saturated or partially saturated carbocyclic ring or a saturated or partially saturated 3-7-membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with deuterium; and
Z is C 1 -C 6 alkyl optionally substituted with deuterium,
provided that when each of Y 1 and Y 2 is H, then at least one of R 1 , R 2a , R 2b , R 3 and R 4 comprises deuterium.
2. A compound of claim 1 , wherein R 6 is —(CH 2 ) q —C(O)—R 12 , wherein q is 1 or 0; and R 12 is —C 1 -C 7 alkyl optionally substituted with one R 10 and further optionally substituted with deuterium, wherein each R 10 is optionally and independently substituted with C 1 -C 3 alkyl or deuterium, and wherein the first and the second carbon units in (b)(ii) are each optionally replaced with —O—.
3. A compound of claim 1 or 2 , wherein R 12 is isobutyl, neopentyl, isoamyl, —CH 2 —CH 2 —O—CH 3 , —CH 2 —CH 2 —O—CH 2 —CH 2 —O—CH 3 ,
wherein R 12 and the heterocyclyl substituent of R 12 are each optionally and independently substituted with deuterium.
4. A compound of claim 1 , wherein each of R 1 , R 2a , R 2b , and R 3 is independently selected from —CH 3 and —CD 3 .
5. A compound of claim 1 or 4 , wherein Y 1 and Y 2 are the same.
6. A compound of claim 5 , wherein each of Y 1 and Y 2 is hydrogen.
7. A compound of claim 1 or 4 , wherein R 2a and R 2b are the same and are selected from —CH 3 and —CD 3 .
8. A compound of claim 1 or 4 , wherein R 4 is selected from
9. A compound of claim 1 , wherein R 4 is
Y 1 and Y 2 are the same; R 2a and R 2b are the same; R 6 is —C(O)—CH 2 —CH 2 —O—CH 3 , and the compound is selected from any one of the compounds set forth in the table below:
Compound
R 1
R 2a /R 2b
R 3
Y 1 /Y 2
101
CD 3
CH 3
CH 3
H
102
CH 3
CD 3
CH 3
H
103
CH 3
CH 3
CD 3
H
10 4
CH 3
CH 3
CH 3
D
105
CD 3
CD 3
CH 3
H
106
CD 3
CH 3
CD 3
H
107
CD 3
CH 3
CH 3
D
108
CH 3
CD 3
CD 3
H
109
CH 3
CD 3
CH 3
D
110
CH 3
CH 3
CD 3
D
111
CD 3
CD 3
CD 3
H
112
CD 3
CH 3
CD 3
D
113
CH 3
CD 3
CD 3
D
114
CD 3
CD 3
CD 3
D.
10. A compound of claim 1 or claim 4 , wherein any atom not designated as deuterium is present at its natural isotopic abundance.
11. A pyrogen-free pharmaceutical composition comprising a compound of claim 1 or claim 4 and a pharmaceutically acceptable carrier.
12. The composition of claim 11 , further comprising a second therapeutic agent selected from an antiviral agent, an anti-infective, an immunomodulator, an antibiotic, a CCR5 receptor antagonist, a vaccine, a viral protease inhibitor, a nucleoside reverse transcriptase inhibitor and a non-nucleoside reverse transcriptase inhibitor.
13. The composition of claim 12 , wherein the second therapeutic agent is selected from one or more of darunavir, ritonavir, and etravirine.