Substituted phenylpyrrolecarboxamides with therapeutic activity in HIV

This application is a continuation of U.S. patent application Ser. No. 16/777,559, filed Jan. 30, 2020, now U.S. Pat. No. 10,869,856, which is a continuation of U.S. patent application Ser. No. 16/521,327, filed Jul. 24, 2019, now U.S. Pat. No. 10,576,059, which is a continuation of U.S. patent application Ser. No. 16/178,277, filed Nov. 1, 2018, now U.S. Pat. No. 10,413,527, which is a continuation of U.S. patent application Ser. No. 15/512,493, filed Mar. 17, 2017, now U.S. Pat. No. 10,137,107, which is a 35 U.S.C. 371 national phase entry of PCT/US2015/051086, filed Sep. 18, 2015, which claims the benefit of U.S. Provisional Patent Application Nos. 62/209,619, filed on Aug. 25, 2015, 62/209,268, filed Aug. 24, 2015, and 62/052,974, filed Sep. 19, 2014. The entire content of each of these applications is herein incorporated by reference.

This invention was made with government support under Grant/Contract Number 1R01AI104416-01A1 awarded by the National Institutes of Health. The government has certain rights in the invention.

Human immunodeficiency virus (HIV) is known to cause AIDS. Human immunodeficiency virus type 1 (HIV-1) cell entry process is thought to start when its surface envelope glycoproteins gp120 bind to the host cell primary receptor CD4. The binding triggers conformational changes in gp120 that facilitate its binding to the host cell coreceptor (secondary) CCR5 or CXCR4. There is no drug available yet that targets HIV-1 gp120.

Phe43 cavity of HIV-1 gp120 may be a target for developing entry inhibitors for AIDS therapy and prophylaxis.

Disclosed herein are anti-HIV compounds.

Some embodiments include a pharmaceutical composition, such as an antiviral composition, comprising a compound represented by the following formula:

wherein Ph is optionally substituted phenyl; Py is optionally substituted pyrrolyl; or Ph-Py is optionally substituted indolyl; R 1 is H or C 1-6 hydrocarbyl; A is H, optionally substituted imidazolyl, optionally substituted thiazolyl, optionally substituted pyrrolyl, morpholine-4-carbonyl, ((2-(methylsulfonamido)ethyl)carbamoyl), optionally substituted piperazin-1-ylcarbamoyl, or optionally substituted morpholinocarbamoyl, or (2-hydroxyethyl)carbamoyl); and B is optionally substituted aminomethyl, optionally substituted amino(C 1-3 alkyl) (such as optionally substituted aminomethyl, aminoethyl, aminopropyl, etc.), optionally substituted alkylamino(C 1-3 )alkyl (such as —CH 2 NHCH 3 , —CH 2 N(CH 3 ) 2 , —CH 2 CH 2 NHCH 3 , —CH 2 CH 2 N(CH 3 ) 2 , acetaminomethyl, piperidinyl, optionally substituted guanidino, optionally substituted guanidino(C 1-3 alkyl) (such as optionally substituted guanidinomethyl, optionally substituted guanidinoethyl, or optionally substituted guanidinopropyl), optionally substituted phenyl, optionally substituted furanyl, optionally substituted triazolyl, optionally substituted pyrazolyl, or optionally substituted phenylmethyl; or

is optionally substituted pyrimidinyl.

Some embodiments include a method of inhibiting HIV comprising administering a compound described herein to a human being infected with HIV virus.

Some embodiments include a method of treating HIV infection comprising administering a compound described herein to a human being infected with HIV virus.

Disclosed herein are compounds useful for treating and preventing HIV infection, and methods of using of those compounds. Some of the compounds described herein may target and inhibit gp120 from binding to the host cell receptor, CD4.

Unless otherwise indicated, when a compound or chemical structural feature such as aryl is referred to as being “optionally substituted,” it includes a feature that has no substituents (i.e. unsubstituted), or a feature that is “substituted,” meaning that the feature has one or more substituents. The term “substituent” has the broadest meaning known to one of ordinary skill in the art, and includes a moiety that replaces one or more hydrogen atoms in a parent compound or structural feature. The term “replaces” is merely used herein for convenience, and does not require that the compound be formed by replacing one atom with another. In some embodiments, a substituent may be any ordinary organic moiety known in the art, which may have a molecular weight (e.g. the sum of the atomic masses of the atoms of the substituent) of 15 Da to 50 Da, 15 Da to 100 Da, 15 Da to 150 Da, 15 Da to 200 Da, 15 Da to 300 Da, or 15 Da to 500 Da. In some embodiments, a substituent comprises, or consists of: 0-30, 0-20, 0-10, or 0-5 carbon atoms; 0-62, 0-41, 0-21, or 0-11 hydrogen atoms; and 0-30, 0-20, 0-10, or 0-5 heteroatoms, wherein each heteroatom may independently be: N, O, P, S, Si, F, Cl, Br, or I; provided that the substituent includes one C, N, O, P, S, Si, F, Cl, Br, or I atom.

Examples of substituents include, but are not limited to, hydrocarbyl, such as alkyl, alkenyl, alkynyl; heteroalkyl, including any moiety wherein one or more heteroatoms replaces one or more carbon atoms of an alkyl moiety, and some accompanying hydrogen atoms (e.g. N replaces CH, O replaces CH 2 , Cl replaces CH 3 , etc.), such as alkoxy, alkylthio, haloalkyl, haloalkoxy, amino, etc.; heteroalkenyl, including any moiety wherein one or more heteroatoms replaces one or more carbon atoms of an alkenyl moiety, and some accompanying hydrogen atoms, such as acyl, acyloxy, thiocarbonyl, alkylcarboxylate, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, sulfinyl, isocyanato, isothiocyanato, etc; heteroalkynyl, including any moiety wherein one or more heteroatoms replaces one or more carbon atoms of an alkynyl moiety, and some accompanying hydrogen atoms, such as cyano, thiocyanato, cyanato, etc.; aryl; heteroaryl; hydroxy; aryloxy; thiol; halo; S-sulfonamido; N-sulfonamido; nitro; silyl; sulfonyl; trihalomethanesulfonyl; trihalomethanesulfonamido; etc.

For convenience, the term “molecular weight” is used with respect to a moiety or part of a molecule to indicate the sum of the atomic masses of the atoms in the moiety or part of a molecule, even though it may not be a complete molecule. If a substituent is anionic or cationic, only the covalently bonded atoms are counted in the molecular weight. Although counter-ions can be present, they are not included in the determination of molecular weight. Thus, —CO 2 − Na + would be considered have a molecular weight of about 44 Da and not about 67 Da.

The structures associated with some of the chemical names referred to herein are depicted below. These structures may be unsubstituted, as shown below, or a substituent may independently be in any position normally occupied by a hydrogen atom when the structure is unsubstituted. Unless a point of attachment is indicated by , attachment may occur at any position normally occupied by a hydrogen atom.

As used herein, the term “alkyl” has the broadest meaning generally understood in the art, and may include a moiety composed of carbon and hydrogen containing no double or triple bonds. Alkyl may be linear alkyl, branched alkyl, cycloalkyl, or a combination thereof, and in some embodiments, may contain from one to thirty-five carbon atoms. In some embodiments, alkyl may include C 1-10 linear alkyl, such as methyl (—CH 3 ), ethyl (—CH 2 CH 3 ), n-propyl (—CH 2 CH 2 CH 3 ), n-butyl CH 2 CH 2 CH 2 CH 3 ), n-pentyl (—CH 2 CH 2 CH 2 CH 2 CH 3 ), n-hexyl (—CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), etc.; C 3-10 branched alkyl, such as C 3 H 7 (e.g. iso-propyl), C 4 H 9 (e.g. branched butyl isomers), C 5 H 11 (e.g. branched pentyl isomers), C 6 H 13 (e.g. branched hexyl isomers), C 7 H 15 (e.g. branched heptyl isomers), etc.; C 3-10 cycloalkyl, such as C 3 H 5 (e.g. cyclopropyl), C 4 H 7 (e.g. cyclobutyl isomers such as cyclobutyl, methylcyclopropyl, etc.), C 5 H 9 (e.g. cyclopentyl isomers such as cyclopentyl, methylcyclobutyl, dimethylcyclopropyl, etc.) C 6 H 11 (e.g. cyclohexyl isomers), C 7 H 13 (e.g. cycloheptyl isomers), and the like.

As used herein the term “aryl” has the broadest meaning generally understood in the art, and includes a ring or a ring system having at least one aromatic ring, such as phenyl, naphthyl, etc.

The term “heteroaryl” also has the meaning understood by a person of ordinary skill in the art, and in some embodiments, may refer to an “aryl” that has one or more heteroatoms in the ring or ring system. Examples of “heteroaryl” may include, but are not limited to, pyridinyl, furyl, thienyl, oxazolyl, thiazolyl, imidazolyl, indolyl, quinolinyl, benzofuranyl, benzothienyl, benzooxazolyl, benzothiazolyl, benzoimidazolyl, etc.

As used herein, the term “hydrocarbyl” has the broadest meaning generally understood in the art, and may include a moiety composed of carbon and hydrogen. Some examples may include alkyl, alkenyl, alkynyl, aryl, etc., and combinations thereof, and may be linear, branched, cyclic, or a combination thereof. Hydrocarbyl may be bonded to any other number of moieties (e.g. be bonded to 1 other group, such as CH 3 , —CH═CH 2 , etc.; 2 other groups, such as -phenyl-, —C≡C—, etc.; or any number of other groups) that the structure may bear, and in some embodiments, may contain from one to thirty-five carbon atoms. Examples of hydrocarbyl groups include but are not limited to C 1 alkyl, C 2 alkyl, C 2 alkenyl, C 2 alkynyl, C 3 alkyl, C 3 alkenyl, C 3 alkynyl, C 4 alkyl, C 4 alkenyl, C 4 alkynyl, C alkyl, C alkenyl, C alkynyl, C alkyl, C alkenyl, C alkynyl, phenyl, etc.

Unless otherwise indicated, any reference to a compound or any structural feature herein by structure, name, or any other means, includes pharmaceutically acceptable salts, such as sodium, potassium, and ammonium salts; prodrugs, such as ester prodrugs; alternate solid forms, such as polymorphs, solvates, hydrates, etc.; tautomers; or any other chemical species that may rapidly convert to a compound described herein under conditions in which the compounds are used as described herein.

With respect to any relevant formula or structural depiction herein, such as Formula A, Ph is optionally substituted phenyl. Ph may have 0, 1, 2, 3, or 4 substituents. Any substituent may be included on Ph. In some embodiments, some or all of the substituents on the ring or ring system may have: from 0 to 10 carbon atoms and from 0 to 10 heteroatoms, wherein each heteroatom is independently: O, N, S, F, Cl, Br, or I (provided that there is at least one non-hydrogen atom); and/or a molecular weight of 15 Da to 500 Da. For example, the substituents may be C 1-10 optionally substituted alkyl, such as CH 3 , C 2 H 5 , C 3 H 7 , cyclic C 3 H 5 , C 4 H 9 , cyclic C 4 H 7 , C 5 H 11 , cyclic C 5 H 9 , C 6 H 13 , cyclic C 6 H 11 , etc., which may be optionally substituted; C 1-10 optionally substituted alkoxy, such as optionally substituted methoxy, optionally substituted ethoxy, etc.; halo, such as F, Cl, Br, I; OH; CN; NO 2 ; C 1-6 fluoroalkyl, such as CF 3 , CF 2 H, C 2 F 5 , etc.; a C 1-10 ester such as —OCOCH 3 , —CO 2 CH 3 , —OCOC 2 H 5 , —CO 2 C 2 H 5 , OCO-phenyl, —CO 2 -phenyl, etc.; a C 1-10 ketone such as —COCH 3 , —COC 2 H 5 , —COC 3 H 7 , CO-phenyl, etc.; or a C 1-10 amine such as NH 2 , NH(CH 3 ), N(CH 3 ) 2 , N(CH 3 )C 2 H 5 , etc.

In some embodiments, Ph may be:

With respect to any relevant formula or structural depiction herein, such as Formula A, Py is optionally substituted pyrrolyl, which may have 0, 1, 2, or 3 substituents. Py may have any suitable substituent. In some embodiments, some or all of the substituents of Py may have: from 0 to 10 carbon atoms and from 0 to 10 heteroatoms, wherein each heteroatom is independently: O, N, S, F, Cl, Br, or I (provided that there is at least one non-hydrogen atom); and/or a molecular weight of 15 Da to 500 Da. For example, the substituents may be C 1-10 optionally substituted alkyl, such as CH 3 , C 2 H 5 , C 3 H 7 , cyclic C 3 H 5 , C 4 H 9 , cyclic C 4 H 7 , C 5 H 11 , cyclic C 5 H 9 , C 6 H 13 , cyclic C 6 H 11 , etc., which may be optionally substituted; C 1-10 optionally substituted alkoxy, such as optionally substituted methoxy, optionally substituted ethoxy, etc.; halo, such as F, Cl, Br, I; OH; CN; NO 2 ; C 1-6 fluoroalkyl, such as CF 3 , CF 2 H, C 2 F 5 , etc.; a C 1-10 ester such as —OCOCH 3 , —CO 2 CH 3 , —OCOC 2 H 5 , —CO 2 C 2 H 5 , —OCO-phenyl, —CO 2 -phenyl, etc.; a C 1-10 ketone such as —COCH 3 , —COC 2 H 5 , —COC 3 H 7 , —CO-phenyl, etc.; or a C 1-10 amine such as NH 2 , NH(CH 3 ), N(CH 3 ) 2 , N(CH 3 )C 2 H 5 , etc.

In some embodiments, Py may be:

With respect to any relevant formula or structural depiction herein, such as Formula A, R 1 can be H; or C 1-6 hydrocarbyl, such as alkyl (e.g. CH 3 , C 2 H 5 , C 3 H 7 , cyclic C 3 H 5 , C 4 H 9 , cyclic C 4 H 7 , C 5 H 11 , cyclic C 5 H 9 , C 6 H 13 , cyclic C 6 H 11 ), alkenyl, (e.g. C 2 H 3 , C 3 H 5 , etc.) alkynyl, (e.g. C 2 H, C 2 H 3 , etc.), phenyl, etc.

With respect to any relevant formula or structural depiction herein, such as Formula A, A can be H, optionally substituted imidazolyl, optionally substituted thiazolyl, optionally substituted pyrrolyl, morpholine-4-carbonyl, ((2-(methylsulfonamido) ethyl)carbamoyl), optionally substituted piperazin-1-ylcarbamoyl, optionally substituted morpholinocarbamoyl, and/or (2-hydroxyethyl)carbamoyl. A may have any suitable substituent. In some embodiments, some or all of the substituents of A may have: from 0 to 10 carbon atoms and from 0 to 10 heteroatoms, wherein each heteroatom is independently: O, N, S, F, Cl, Br, or I (provided that there is at least one non-hydrogen atom); and/or a molecular weight of 15 Da to 500 Da. For example, the substituents may be C 1-10 optionally substituted alkyl, such as CH 3 , C 2 H 5 , C 3 H 7 , cyclic C 3 H 5 , C 4 H 9 , cyclic C 4 H 7 , C 5 H 11 , cyclic C 5 H 9 , C 6 H 13 , cyclic C 6 H 11 , etc., which may be optionally substituted; C 1-10 optionally substituted alkoxy, such as optionally substituted methoxy, optionally substituted ethoxy, etc.; halo, such as F, Cl, Br, I; OH; CN; NO 2 ; C 1-6 fluoroalkyl, such as CF 3 , CF 2 H, C 2 F 5 , etc.; a C 1-10 ester such as —OCOCH 3 , —CO 2 CH 3 , —OCOC 2 H 5 , —CO 2 C 2 H 5 , —OCO-phenyl, —CO 2 -phenyl, etc.; a C 1-10 ketone such as —COCH 3 , —COC 2 H 5 , —COC 3 H 7 , —CO-phenyl, etc.; or a C 1-10 amine such as NH 2 , NH(CH 3 ), N(CH 3 ) 2 , N(CH 3 )C 2 H 5 , etc.

With respect to any relevant formula or structural depiction herein, such as Formula A, B can be optionally substituted aminomethyl; optionally substituted guanidino; optionally substituted guanidino(C 1-3 alkyl), such as optionally substituted guanidinomethyl, optionally substituted guanidinoethyl, optionally substituted guanidinopropyl; optionally substituted phenyl; optionally substituted furanyl; optionally substituted triazolyl; optionally substituted pyrazolyl; and/or optionally substituted phenylmethyl. B may have any suitable substituent. In some embodiments, some or all of the substituents of B may have: from 0 to 10 carbon atoms and from 0 to 10 heteroatoms, wherein each heteroatom is independently: O, N, S, F, Cl, Br, or I (provided that there is at least one non-hydrogen atom); and/or a molecular weight of 15 Da to 500 Da. For example, the substituents may be C 1-10 optionally substituted alkyl, such as CH 3 , C 2 H 5 , C 3 H 7 , cyclic C 3 H 5 , C 4 H 9 , cyclic C 4 H 7 , C 5 H 11 , cyclic C 5 H 9 , C 6 H 13 , cyclic C 6 H 11 , etc., which may be optionally substituted; C 1-10 optionally substituted alkoxy, such as optionally substituted methoxy, optionally substituted ethoxy, etc.; halo, such as F, Cl, Br, I; OH; CN; NO 2 ; C 1-6 fluoroalkyl, such as CF 3 , CF 2 H, C 2 F 5 , etc.; a C 1-10 ester such as —OCOCH 3 , —CO 2 CH 3 , —OCOC 2 H 5 , —CO 2 C 2 H 5 , —OCO-phenyl, —CO 2 -phenyl, etc.; a C 1-10 ketone such as —COCH 3 , —COC 2 H 5 , —COC 3 H 7 , —CO-phenyl, etc.; or a C 1-10 amine such as NH 2 , NH(CH 3 ), N(CH 3 ) 2 , N(CH 3 )C 2 H 5 , etc.

If stereochemistry is not indicated, such as in Formulas 1-13 and Formula A, a name or structural depiction includes any stereoisomer or any mixture of stereoisomers.

In some embodiments, Formula A may be further described by any of the following Formulas 1-13.

With respect to any relevant structural representation, such as Formulas 1 and 2, in some embodiments, Y is C 1-3 hydrocarbyl, including C 1-3 alkyl, such as —CH 2 , —C 2 H 4 —, —C 3 H 6 —, etc, or C 2-3 alkenyl or alkynyl. In some embodiments Y is a bond.

With respect to any relevant structural representation, R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 13 , R 14 , R 15 , R 15a , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , and R 28 , may independently be H, a halide, or a substituent having a molecular weight of 15 Da to 300 Da or 15 Da to 150 Da and consisting of 2 to 5 chemical elements, wherein the chemical elements are independently C, H, O, N, S, P, F, Cl, Br, or I. In some embodiments, R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , and R 28 are independently R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , CONR A R B , etc. In some embodiments, R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 13 , R 14 , R 15 , R 15a , R 16 , R 17 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 and R 28 are independently H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, propyl isomers (e.g. n-propyl and isopropyl), cyclopropyl, butyl isomers, cyclobutyl isomers (e.g. cyclobutyl and methylcyclopropyl), pentyl isomers, cyclopentyl isomers ; hexyl isomers, cyclohexyl isomers, etc.; or C 1-6 alkoxy, such as -O-methyl, -O-ethyl, isomers of -O-propyl, -O-cyclopropyl, isomers of -O-butyl, isomers of -O-cyclobutyl, isomers of -O-pentyl, isomers of -O-cyclopentyl, isomers of -O-hexyl, isomers of -O-cyclohexyl, etc.

With respect to any relevant structural representation, each R A may independently be H, or C 1-12 alkyl, including: linear or branched alkyl having a formula C a H a+1 , or cycloalkyl having a formula C a H a−1 , wherein a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, such as linear or branched alkyl of a formula: CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , C 5 H 11 , C 6 H 13 , C 7 H 15 , C 8 H 17 , C 9 H 19 , C 10 H 21 , etc., or cycloalkyl of a formula: C 3 H 5 , C 4 H 7 , C 5 H 9 , C 6 H 11 , C 7 H 13 , C 8 H 15 , C 9 H 17 , C 10 H 19 , etc. In some embodiments, R A may be H or C 1-6 alkyl. In some embodiments, R A may be H or C 1-3 alkyl. In some embodiments, R A may be H or CH 3 . In some embodiments, R A may be H.

With respect to any relevant structural representation, each R B may independently be H, or C 1-12 alkyl, including: linear or branched alkyl having a formula C a H a+1 , or cycloalkyl having a formula C a H a , wherein a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, such as linear or branched alkyl of a formula: CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , C 5 H 11 , C 6 H 13 , C 8 H 17 , C 7 H 15 , C 9 H 19 , C 10 H21, etc., or cycloalkyl of a formula: C 3 H 5 , C 4 H 7 , C 5 H 9 , C 6 H 11 , C 7 H 13 , C 8 H 15 , C 9 H 17 , C 10 H19, etc. In some embodiments, R B may be H or C 1-3 alkyl. In some embodiments, R B may be H or CH 3 . In some embodiments, R B may be H.

With respect to Formulas 1-14, in some embodiments, R 4 is H, F, Cl, NH 2 , CH 3 , SO 2 NH 2 , OCH 3 , CH 2 OH, N(C 2 H 5 ) 2 . In some embodiments, R 4 is H. Additionally, for any embodiments recited in this paragraph, R 5 , R 6 , R 7 , and R 8 can independently be: R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , OR A , CO 2 RA, OCOR A , NR A COR B , or CONR A R B ; or H, F, Cl, CN, CF 3 , OH, NH 2 , C 1-6 alkyl, or C 1-6 alkoxy.

With respect to Formulas 1-13, in some embodiments, R 5 is H, F, Cl, NH 2 , CH 3 , SO 2 NH 2 , OCH 3 , CH 2 OH, N(C 2 H 5 ) 2 . In some embodiments, R 5 is H. In some embodiments, R 5 is F. Additionally, for any embodiments recited in this paragraph, R 4 , R 6 , R 7 , and R 8 can independently be: R A , F, C, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCO A , NR A O B , or CONRARB; or H, F, Cl, CN, CF 3 , OH, NH 2 , C 1-6 alkyl, or C 1-6 alkoxy.

With respect to Formulas 1-14, in some embodiments, R 6 is H, F, Cl, NH 2 , CH 3 , SO 2 NH 2 , OCH 3 , CH 2 OH, N(C 2 H 5 ) 2 . In some embodiments, R 6 is H. In some embodiments, R 6 is Cl. In some embodiments, R 6 is CH 3 . Additionally, for any embodiments recited in this paragraph, R 4 , R 5 , R 7 , and R 8 can independently be: R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , or CONR A R B ; or H, F, Cl, CN, CF 3 , OH, NH 2 , C 1-6 alkyl, or C 1-6 alkoxy.

With respect to Formulas 1-14, in some embodiments, R 7 is H, F, Cl, NH 2 , CH 3 , SO 2 NH 2 , OCH 3 , CH 2 OH, N(C 2 H 5 ) 2 . In some embodiments, R 7 is H. In some embodiments, R 7 is F. Additionally, for any embodiments recited in this paragraph, R 4 , R 5 , R 6 , and R 8 can independently be: R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCO A , NR A C B , or CONR A R B ; or H, F, Cl, CN, CF 3 , OH, NH 2 , C 1-6 alkyl, or C 1-6 alkoxy.

With respect to Formulas 1-14, in some embodiments, R 8 is H, F, Cl, NH 2 , CH 3 , SO 2 NH 2 , OCH 3 , CH 2 OH, N(C 2 H 5 ) 2 . In some embodiments, R 8 is H. Additionally, for any embodiments recited in this paragraph, R 4 , R 5 , R 6 , and R 7 can independently be: R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , or CONR A R B ; or H, F, Cl, CN, CF 3 , OH, NH 2 , C 1-6 alkyl, or C 1-6 alkoxy.

With respect to Formulas 1-13, in some embodiments, R 4 and R 5 are H. In some embodiments, R 5 and R 6 are H. In some embodiments, R 6 and R 7 are H. In some embodiments, R 7 and R 8 are H. In some embodiments, R 4 , R 5 , R 6 , R 7 , and R 8 are H.

With respect to Formulas 1-14, in some embodiments, R 9 is H, F, Cl, NH 2 , CH 3 , SO 2 NH 2 , OCH 3 , CH 2 OH, N(C 2 H 5 ) 2 . In some embodiments, R 9 is H. Additionally, for any embodiments recited in this paragraph, R 10 , and R 11 can independently be: R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , OR A , CO 2 R A , OCOR A , NR A COR B , or CONR A R B ; or H, F, Cl, CN, CF 3 , OH, NH 2 , C 1-6 alkyl, or C 1-6 alkoxy.

With respect to Formulas 1-14, in some embodiments, R 10 is H, F, Cl, NH 2 , CH 3 , SO 2 NH 2 , OCH 3 , CH 2 OH, N(C 2 H 5 ) 2 . In some embodiments, R 10 is H. Additionally, for any embodiments recited in this paragraph, R 9 , and R 11 can independently be: R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , or CONR A R B ; or H, F, Cl, CN, CF 3 , OH, NH 2 , C 1-6 alkyl, or C 1-6 alkoxy.

With respect to Formulas 1-14, in some embodiments, R 11 is H, F, Cl, NH 2 , CH 3 , SO 2 NH 2 , OCH 3 , CH 2 OH, N(C 2 H 5 ) 2 . In some embodiments, R 11 is H. Additionally, for any embodiments recited in this paragraph, R 9 , and R 10 can independently be: R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A OOR B , or CONR A R B ; or H, F, Cl, CN, CF 3 , OH, NH 2 , C 1-6 alkyl, or C 1-6 alkoxy.

With respect to Formulas 1-14, in some embodiments, R 12 is H, F, Cl, NH 2 , CH 3 , SO 2 NH 2 , OCH 3 , CH 2 OH, N(C 2 H 5 ) 2 . In some embodiments, R 12 is H. Additionally, for any embodiments recited in this paragraph, R 15 and R 16 can independently be: R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , OR A , CO 2 R A , OCOR A , NR A OOR B , or CONR A R B , or H, F, Cl, CN, CF 3 , OH, NH 2 , C 1-6 alkyl, or C 1-6 alkoxy.

With respect to Formulas 1-14, in some embodiments, R 13 is H, F, Cl, NH 2 , CH 3 , SO 2 NH 2 , OCH 3 , CH 2 OH, N(C 2 H 5 ) 2 . In some embodiments, R 13 is H. In some embodiments, R 13 is —CH 2 OH. Additionally, for any embodiments recited in this paragraph, R 14 and R 22 can independently be: R A , F, C, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A C B , or CONR A R B ; or H, F, Cl, CN, CF 3 , OH, NH 2 , C 1-6 alkyl, or C 1-6 alkoxy.

With respect to Formulas 1-14, in some embodiments, R 14 is H, F, Cl, NH 2 , CH 3 , SO 2 NH 2 , OCH 3 , CH 2 OH, N(C 2 H 5 ) 2 . In some embodiments, R 14 is H. In some embodiments, R 14 is CH 3 . Additionally, for any embodiments recited in this paragraph, R 13 and R 22 can independently be: R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A O B , or ONR A R B ; or H, F, Cl, CN, CF 3 , OH, NH 2 , C 1-6 alkyl, or C 1-6 alkoxy.

With respect to Formulas 1-14, in some embodiments, R 15 is H, F, Cl, NH 2 , CH 3 , SO 2 NH 2 , OCH 3 , CH 2 OH, N(C 2 H 5 ) 2 . In some embodiments, R 15 is H. In some embodiments, R 15 and R 15a may together form a ring, such as, but not limited to piperidinyl. In some embodiments, R 15 is CH 3 . In some embodiments, R 15 is acetyl. In some embodiments, R 15 is carbamimidoyl. Additionally, for any embodiments recited in this paragraph, R 12 , R 15a , and R 16 can independently be: R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A OR B , or CONR A R B ; or H, F, Cl, CN, CF 3 , OH, NH 2 , C 1-6 alkyl, or C 1-6 alkoxy.

With respect to Formulas 1-14, in some embodiments, R 15a is H, F, Cl, NH 2 , CH 3 , SO 2 NH 2 , OCH 3 , CH 2 OH, N(C 2 H 5 ) 2 . In some embodiments, R 15a is H. In some embodiments, R 15a and R 15a may together form a ring, such as, but not limited to piperidinyl. In some embodiments, R 15 is CH 3 . In some embodiments, R 15a is acetyl. In some embodiments, R 15 is carbamimidoyl. Additionally, for any embodiments recited in this paragraph, R 12 , R 15 , and R 16 can independently be: R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A OR B , or CONR A R B ; or H, F, Cl, CN, CF 3 , OH, NH 2 , C 1-6 alkyl, or C 1-6 alkoxy.

With respect to Formulas 1-14, in some embodiments, R 16 is H, F, Cl, NH 2 , CH 3 , SO 2 NH 2 , OCH 3 , CH 2 OH, N(C 2 H 5 ) 2 . In some embodiments, R 16 is H. Additionally, for any embodiments recited in this paragraph, R 12 , R 15 and, where applicable, R 23 can independently be: R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , or CONR A R B ; or H, F, Cl, CN, CF 3 , OH, NH 2 , C 1-6 alkyl, or C 1-6 alkoxy.

With respect to Formulas 1-14, in some embodiments, R 17 is H, F, Cl, NH 2 , CH 3 , SO 2 NH 2 , OCH 3 , CH 2 OH, N(C 2 H 5 ) 2 . In some embodiments, R 17 is H. In some embodiments, R 17 is methoxy. Additionally, for any embodiments recited in this paragraph, R 18 , R 19 , R 20 , and R 21 can independently be: R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , or CONR A R B ; or H, F, Cl, CN, CF 3 , OH, NH 2 , C 1-6 alkyl, or C 1-6 alkoxy.

With respect to Formulas 1-14, in some embodiments, R 18 is H, F, Cl, NH 2 , CH 3 , SO 2 NH 2 , OCH 3 , CH 2 OH, N(C 2 H 5 ) 2 . In some embodiments, R 18 is H. In some embodiments, R 18 is guanidino. In some embodiments, R 18 is (diethylamino)methyl. Additionally, for any embodiments recited in this paragraph, R 17 , R 19 , R 20 , and R 21 can independently be: R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A NR A COR B , or CONR A R B ; or H, F, Cl, CN, CF 3 , OH, NH 2 , C 1-6 alkyl, or C 1-6 alkoxy.

With respect to Formulas 1-14, in some embodiments, R 19 is H, F, Cl, NH 2 , CH 3 , SO 2 NH 2 , OCH 3 , CH 2 OH, N(C 2 H 5 ) 2 . In some embodiments, R 19 is H. Additionally, for any embodiments recited in this paragraph, R 17 , R 18 , R 20 , and R 21 can independently be: R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A OR B ; or CONR A R B ; or H, F, Cl, CN, CF 3 , OH, NH 2 , C 1-6 alkyl, or C 1-6 alkoxy.

With respect to Formulas 1-14, in some embodiments, R 20 is H, F, Cl, NH 2 , CH 3 , SO 2 NH 2 , OCH 3 , CH 2 OH, N(C 2 H 5 ) 2 . In some embodiments, R 20 is H. In some embodiments, R 20 is methylamino. In some embodiments, R20 is (diethylamino)methyl. In some embodiments, R 20 is SO 2 NH 2 . Additionally, for any embodiments recited in this paragraph, R 17 , R 18 , R 19 , and R 21 can independently be: R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A OR B , or CONR A R B ; or H, F, Cl, CN, CF 3 , OH, NH 2 , C 1-6 alkyl, or C 1-6 alkoxy.

With respect to Formulas 1-14, in some embodiments, R 21 is H, F, Cl, NH 2 , CH 3 , SO 2 NH 2 , OCH 3 , CH 2 OH, N(C 2 H 5 ) 2 . In some embodiments, R 21 is H. In some embodiments, R 21 is methoxy. Additionally, for any embodiments recited in this paragraph, R 17 , R 18 , R 19 , and R 20 can independently be: R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , OR A , CO 2 R A , OCOR A , NR A OR B , or CONR A R B ; or H, F, Cl, CN, CF 3 , OH, NH 2 , C 1-6 alkyl, or C 1-6 alkoxy.

With respect to Formulas 1-14, in some embodiments, R 22 is H, F, Cl, NH 2 , CH 3 , SO 2 NH 2 , OCH 3 , CH 2 OH, N(C 2 H 5 ) 2 . In some embodiments, R 22 is H. Additionally, for any embodiments recited in this paragraph, R 13 and R 14 can independently be: R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , or CONR A R B ; or H, F, Cl, CN, CF 3 , OH, NH 2 , C 1-6 alkyl, or C 1-6 alkoxy.

With respect to Formulas 1-14, in some embodiments, R 23 is H, F, Cl, NH 2 , CH 3 , SO 2 NH 2 , OCH 3 , CH 2 OH, N(C 2 H 5 ) 2 . In some embodiments, R 23 is H. Additionally, for any embodiments recited in this paragraph, R 16 can independently be: R A , F, Cl, CN, OR A , CF 3 , NO 2 , NRARB, COR A , CO 2 R A , OCORA, NRACORB, or CONR A R B ; or H, F, Cl, CN, CF 3 , OH, NH 2 , C 1-6 alkyl, or C 1-6 alkoxy.

With respect to Formulas 1-14, in some embodiments, R 24 is H, F, Cl, NH 2 , CH 3 , SO 2 NH 2 , OCH 3 , CH 2 OH, N(C 2 H 5 ) 2 . In some embodiments, R 24 is H. Additionally, for any embodiments recited in this paragraph, R 25 can independently be: R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , or CONR A R B ; or H, F, Cl, CN, CF 3 , OH, NH 2 , C 1-6 alkyl, or C 1-6 alkoxy.

With respect to Formulas 1-14, in some embodiments, R 25 is H, F, Cl, NH 2 , CH 3 , SO 2 NH 2 , OCH 3 , CH 2 OH, N(C 2 H 5 ) 2 . In some embodiments, R 25 is H. Additionally, for any embodiments recited in this paragraph, R 24 can independently be: R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A OOR B , or CONR A R B ; or H, F, Cl, CN, CF 3 , OH, NH 2 , C 1-6 alkyl, or C 1-6 alkoxy.

With respect to Formulas 1-14, in some embodiments, R 26 is H, F, Cl, NH 2 , CH 3 , SO 2 NH 2 , OCH 3 , CH 2 OH, N(C 2 H 5 ) 2 . In some embodiments, R 26 is H. In some embodiments, R 26 is NH 2 . Additionally, for any embodiments recited in this paragraph, R 27 and R 28 can independently be: R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , OR A , CO 2 R A , OCOR A , NR A O B , or ONR A R B ; or H, F, Cl, CN, CF 3 , OH, NH 2 , C 1-6 alkyl, or C 1-6 alkoxy.

With respect to Formulas 1-14, in some embodiments, R 27 is H, F, Cl, NH 2 , CH 3 , SO 2 NH 2 , OCH 3 , CH 2 OH, N(C 2 H 5 ) 2 . In some embodiments, R 27 is H. Additionally, for any embodiments recited in this paragraph, R 26 and R 28 can independently be: R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , OR A , CO 2 R A , OCOR A , NR A OOR B , or CONR A R B ; or H, F, Cl, CN, CF 3 , OH, NH 2 , C 1-6 alkyl, or C 1-6 alkoxy.

With respect to Formulas 1-14, in some embodiments, R 28 is H, F, Cl, NH 2 , CH 3 , SO 2 NH 2 , OCH 3 , CH 2 OH, N(C 2 H 5 ) 2 . In some embodiments, R 28 is H. In some embodiments, R 28 is CH 3 . Additionally, for any embodiments recited in this paragraph, R 26 and R 27 can independently be: R A , F, Cl, CN, OR A , CF 3 , NO 2 , NR A R B , COR A , CO 2 R A , OCOR A , NR A COR B , or CONR A R B ; or H, F, Cl, CN, CF 3 , OH, NH 2 , OC 1-6 alkyl, or C 1-6 alkoxy.

In some embodiments, a compound of Formula 1 can be:

In some embodiments, a compound of Formula 2 can be:

In some embodiments, a compound of Formula 3 can be:

In some embodiments, a compound of Formula 4 can be:

In some embodiments, a compound of Formula 5 can be:

In some embodiments, a compound of Formula 6 can be:

In some embodiments, a compound of Formula 7 can be:

In some embodiments, a compound of Formula 8 can be:

In some embodiments, a compound of Formula 9 can be:

In some embodiments, a compound of Formula 10 can be:

In some embodiments, a compound of Formula 11 can be:

In some embodiments, a compound of Formula 12 can be:

In some embodiments, a compound of Formula 13 can be:

The compounds described herein, such as compounds of Formulas A and 1-13 (referred to hereafter as “subject compounds” or “subject compound”) may be used as inhibitors of human immunodeficiency virus (HIV) and/or for treating associated diseases, disorders, and conditions. A pharmaceutical composition comprising at least one subject compound may be administered to individuals suffering from or susceptible to HIV-1 infection.

Appropriate excipients for use in a pharmaceutical composition comprising a subject compound (referred to hereafter as “subject compositions” or “subject composition”) may include, for example, one or more carriers, binders, fillers, vehicles, disintegrants, surfactants, dispersion or suspension aids, thickening or emulsifying agents, isotonic agents, preservatives, lubricants, and the like or combinations thereof, as suited to a particular dosage from desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. This document is incorporated herein by reference in its entirety.

A subject composition may be formulated for any desirable route of delivery including, but not limited to, parenteral, intravenous, intradermal, subcutaneous, oral, inhalative, transdermal, topical, transmucosal, rectal, interacisternal, intravaginal, intraperitoneal, buccal, and intraocular.

In certain aspects, parenteral, intradermal or subcutaneous formulations may be sterile injectable aqueous or oleaginous suspensions. Acceptable vehicles, solutions, suspensions and solvents may include, but are not limited to, water or other sterile diluent; saline; Ringer's solution; sodium chloride; fixed oils such as mono- or diglycerides; fatty acids such as oleic acid; polyethylene glycols; glycerine; propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol; antioxidants such as ascorbic acid; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates; and agents for the adjustment of tonicity such as sodium chloride or dextrose.

Solutions or suspensions used for parenteral, intradermal, or subcutaneous application may include one or more of the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine; propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfate; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation may be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

Pharmaceutical compositions suitable for injectable use may include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include, but are not limited to, saline, bacteriostatic water, CREMOPHOR EL® (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). The solvent or dispersion medium may contain, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Preventing growth of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. The composition may also include isotonic agents such as, for example, sugars; polyalcohols such as manitol; sorbitol; or sodium chloride. Prolonged absorption of injectable compositions can be enhanced by addition of an agent that delays absorption, such as, for example, aluminum monostearate or gelatin.

Oral compositions may include an inert diluent or an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets. Tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose; a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

In addition to oral or injected administration, systemic administration may be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants may be used. Such penetrants are generally known in the art, and include, for example, detergents, bile salts, and fusidic acid derivatives. Transdermal administration may include a bioactive agent and may be formulated into ointments, salves, gels, or creams as generally known in the art. Transmucosal administration may be accomplished through the use of nasal sprays or suppositories.

A subject compound may be administered in a therapeutically effective amount, according to an appropriate dosing regiment. As understood by a skilled artisan, an exact amount required may vary from subject to subject, depending on a subject's species, age and general condition, the severity of the infection, the particular agent(s) and the mode of administration. In some embodiments, about 0.001 mg/kg to about 50 mg/kg, of the pharmaceutical composition based on the subject's body weight is administered, one or more times a day, to obtain the desired therapeutic effect. In other embodiments, about 0.01 mg/kg to about 25 mg/kg, of the pharmaceutical composition based on the subject's body weight is administered, one or more times a day, to obtain the desired therapeutic effect.

A total daily dosage of a subject compound can be determined by the attending physician within the scope of sound medical judgment. A specific therapeutically effective dose level for any particular patient or subject will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient or subject; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and other factors well known in the medical arts.

Although there are many ways in which Formula A might be prepared, Formula A can be synthesized by a peptide coupling reaction, as follows, which couples Precursor 1 with Intermediate 1 to form Formula A.

In some embodiments Intermediate 1 is pretreated with tetraphenylborate before the peptide coupling reaction is carried out to avoid unintended coupling of amino substituents (see U.S. Pat. No. 5,262,567).

Although there are many ways that Intermediate 1 can be prepared,

Intermediate 1, having a structure H 2 N can be prepared as shown in Scheme 1.

Although there are many ways that Intermediate 1 can be prepared,

Intermediate 1, having a structure H 2 N can be prepared as shown in Scheme 2.

Although there are many ways that Intermediate 1 can be prepared,

Intermediate 1, having a structure H 2 N can be prepared as shown in Scheme 3.

Although there are many ways that Intermediate 1 can be prepared,

Intermediate 1, having a structure H 2 N can be prepared as shown in Scheme 4.

Single-cycle infection assay in TZM-bl cells. The inhibitory activity of test compounds was measured on HIV-1 pseudotyped viruses expressing HIV-1HXB-2 ENV or ENV from the panel of standard reference subtype A, A/D, A2/D, A/E, A/G, B, C and D. Pseudoviruses were obtained by transfecting HEK 293T cells with a mixture of an Env-deleted backbone proviral plasmid pSG3Δenv and an Env expression vector DNA. Briefly, 100 μl of TZM-bl cells at 1×105 cells/ml was added to the wells of a 96 well tissue culture plate and cultured at 37° C. overnight. 50 μl of a test compound at graded concentrations was mixed with 50 μl of the HIV-1 pseudovirus at about 100 TCID50. After incubation at 37° C. for 30 min, the mixture was added to the cells and incubated at 37° C. for 3 days. Cells were washed 2 times with PBS and lysed with 50 μl of cell culture lysis reagent. 20 μl of lysates were transferred to a white 96 well plate and mixed with 100 μl of luciferase assay reagent. The luciferase activity was immediately measured with a Tecan infinite M1000 reader and the percent inhibition by the compounds and IC 50 values were calculated using the GraphPad Prism software. (see Table 1 & 2)