HK1244276B - Fused pyrimidine compounds for the treatment of hiv - Google Patents

Description

Fused pyrimidine compounds for treating HIV

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority to U.S. Application Serial No. 62/096,820, filed December 24, 2014, the entire contents of which are incorporated herein by reference.

Background Art

Despite advances in the treatment of HIV and AIDS, HIV infection remains a global health problem. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are often used as part of this treatment, particularly as part of highly active antiretroviral therapy (HAART) regimens. While many known NNRTIs are effective, they have limitations because their use is associated with mutations in the HIV virus that can lead to drug resistance. Therefore, there remains a need for further development of effective NNRTIs.

Described herein are compounds of formula (I) and pharmaceutically acceptable salts thereof, compositions and formulations containing these compounds or their pharmaceutically acceptable salts, and methods of using and preparing these compounds or their pharmaceutically acceptable salts.

Summary of the Invention

In certain embodiments, the present disclosure relates to a compound of formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof,

in:

X is N, Y is CR ³ , and Z is CR ³ ; or X is CR ³ , Y is CR ³ , and Z is N; or X is CR ³ , Y is N, and Z is CR ³ ;

R ¹ is -H, -CN, -OR ^a , C _1-6 haloalkyl or halogen;

R ² is -H, -NR ^a R ^b , -OR ^a or C _1-10 alkyl optionally substituted by, for example, 1, 2, 3, 4 or 5 R ²⁰ groups which may be the same or different;

each R ³ is independently -H, -OR ^a , halogen, -NR ^a R ^b , -C(O)OR ^a , -CN, -NHC(O)NR ^a R ^b , -OC(O)NR ^a R ^b , -CH ₂ C(O)NR ^a R ^b , C 1-10 alkyl optionally substituted, for example, by 1, 2, 3, 4 or 5 R ²⁰ groups which may be the same or different, or C _1-10 heteroalkyl optionally substituted, for example, by 1, 2, 3, ₄ or 5 R ²⁰ groups which may be the same or different;

R ⁴ and R ⁵ are independently halogen, -OR ^a or C _1-10 alkyl optionally substituted by, for example, 1, 2, 3, 4 or 5 R ²⁰ groups which may be the same or different;

Each R ⁶ is independently halogen, -OR ^a or C _1-10 alkyl optionally substituted with, for example, 1, 2, 3, 4 or 5 R ²⁰ groups which may be the same or different;

n is an integer from 0 to 4;

each R ²⁰ is independently C _1-10 alkyl, C _1-10 heteroalkyl, aryl, heteroaryl, halogen, -OR ^a , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -OC(O)NR ^a R ^b , -NR ^a C(O)OR ^b , -S(O) _0-2 R ^a , -S(O) ₂ F, -S(O) ₂ NR ^a R ^b , -NR ^a (O) ₂ R ^b , -N ₃ , -CN or -NO ₂ ,

wherein each C _1-10 alkyl, C _1-10 heteroalkyl, aryl or heteroaryl group is optionally substituted by, for example, 1, 2, 3, 4 or 5 halogen, -OR ^a , -C(O)R ^a , -C(O)OR ^a , C(O)NR ^a R ^b , -OC(O)NR ^a R ^b , -NR ^a C(O)OR ^b , -S(O) _{0- 2} R ^a , -S(O) ₂ F, -S(O) ₂ NR ^a R ^b , -NR ^a S(O) ₂ R ^b , -N ₃ , -CN or -NO ₂ groups, which may be the same or different;

each ^Ra and ^Rb are independently -H, _C1-10 alkyl, _C1-10 heteroalkyl, aryl or heteroaryl, each of which is optionally substituted with 1, 2, 3, 4 or 5 ^R21 groups which may be the same or different; or Ra and ^{Rb ,} together with the atoms to which they are attached, form a _C1-10 heterocycloalkyl; and

R ²¹ is C _1-6 alkyl, -CN, aryl, heteroaryl or halogen.

In certain embodiments, the present disclosure relates to a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In certain embodiments, the present disclosure relates to a preparation comprising a unit dose of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

In certain embodiments, the present disclosure relates to a method of inhibiting reverse transcriptase in an individual in need thereof, comprising administering to the individual a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

In certain embodiments, the present disclosure relates to methods for treating or preventing HIV infection in an individual in need thereof, comprising administering to the individual a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

In certain embodiments, the present disclosure relates to a method for preventing HIV infection in an individual, comprising administering to the individual a compound of formula (I) or a pharmaceutically acceptable salt thereof. In certain embodiments, the individual is at risk of contracting HIV, such as an individual with one or more risk factors known to be associated with contracting HIV.

In certain embodiments, the present disclosure relates to methods for treating or preventing HIV infection in an individual in need thereof, comprising administering to the individual a compound of Formula (I) or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of one or more additional therapeutic agents.

In certain embodiments, the present disclosure relates to a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in medical therapy.

In certain embodiments, the present disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in treating or preventing HIV viral infection in a subject.

In certain embodiments, the present disclosure relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing HIV viral infection in a subject.

Other embodiments of the present disclosure are disclosed herein.

DETAILED DESCRIPTION

The following description is based on the understanding that this disclosure is considered to be an example of the claimed subject matter and is not intended to limit the appended claims to the specific embodiments shown. The headings used in this disclosure are provided for convenience and are not to be construed as limiting the claims in any way. The embodiments set forth under any heading may be combined with the embodiments shown under any other heading.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art. A dash in front of or at the end of a chemical group is used to conveniently indicate the point of attachment to the parent moiety; a chemical group may be described with or without one or more dashes without losing its common meaning. A wavy line drawn through a line in a chemical structure or a dotted line drawn through a line in a chemical structure indicates the point of attachment of a group. A dotted line in a chemical structure indicates an optional bond. A prefix such as " _Cuv " or ( _Cu - _Cv ) indicates that the following group has u to v carbon atoms. For example, " _C1-6alkyl " indicates that the alkyl group has 1-6 carbon atoms.

When a trade name is used herein, it is intended to independently include both the trade name product and the active pharmaceutical ingredient of the trade name product.

As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "the compound" includes a plurality of such compounds, and reference to "the assay" includes reference to one or more assays, etc.

As used herein, an "alkyl" group is a straight or branched chain saturated monovalent hydrocarbon. For example, an alkyl group may have 1 to 20 carbon atoms (i.e., a (Ci _-20 ) alkyl group), or an alkyl group may have 1 to 10 carbon atoms (i.e., a (Ci _-10 ) alkyl group), or an alkyl group may have 1 to 8 carbon atoms (i.e., a (Ci _-8 ) alkyl group), or 1 to 6 carbon atoms (i.e., a (Ci _-6) alkyl group), or 1 to 4 carbon atoms (i.e., a (Ci _-4 ) alkyl group). Examples of alkyl groups include, but are not limited to, methyl (Me, -CH ₃ ), ethyl (Et, -CH ₂ CH ₃ ), 1-propyl (n-Pr, n-propyl, -CH ₂ CH ₂ CH ₃ ), 2-propyl (i-Pr, i-propyl, -CH(CH ₃ ) ₂ ), 1-butyl (n-Bu, n-butyl, -CH ₂ CH ₂ CH ₂ CH ₃ ), 2-methyl-1-propyl (i-Bu, i-butyl, -CH ₂ CH(CH ₃ ) ₂ ), 2-butyl (s-Bu, s-butyl, -CH(CH ₃ )CH ₂ CH ₃ ), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH ₃ ) ₃ ), 1-pentyl (n-pentyl, -CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-pentyl (-CH(CH _{3 ) 2} )CH ₂ CH ₂ CH ₃ ), 3-pentyl (-CH(CH ₂ CH ₃ ) ₂ ), 2-methyl-2-butyl (-C(CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butyl (-CH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-1-butyl (-CH ₂ CH ₂ CH(CH ₃ ) ₂ ), 2-methyl-1-butyl (-CH ₂ CH(CH ₃ )CH ₂ CH ₃ ), 1-hexyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ) _, 2-hexyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl (-CH(CH ₂ CH ₃ )(CH ₂ CH ₂ CH ₃ )), 2-methyl-2-pentyl (-C(CH ₃ ) ₂ CH _{2 3 ) 3 , and octyl ( - ( CH 2 ) 7 CH 3 ) . ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​}

The term "aryl" as used herein refers to a single all-carbon aromatic ring or a plurality of fused all-carbon ring systems, wherein at least one ring is aromatic. For example, in certain embodiments, the aryl group has 6-20 ring carbon atoms, 6-14 ring carbon atoms, or 6-12 ring carbon atoms. Aryl includes phenyl. Aryl also includes a plurality of fused ring systems (e.g., a ring system comprising 2, 3, or 4 rings) with about 9-20 carbon atoms, wherein at least one ring is aromatic, and wherein the other rings may be aromatic or not aromatic (i.e., carbocyclic). Such a plurality of fused ring systems are optionally substituted with one or more (e.g., 1, 2, or 3) oxo groups on any carbocyclic portion of the plurality of fused ring systems. When valence requirements permit, the rings of the plurality of fused ring systems can be interconnected by fusion, spiral, and bridging bonds. It should also be understood that when referring to an aryl group (e.g., a 6-12 membered aryl group) of certain atomic range units, the atomic range is the total ring (cyclic) atoms of the aryl group. For example, a 6-membered aryl group would include phenyl, and a 10-membered aryl group would include naphthyl and 1,2,3,4-tetrahydronaphthyl. Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, anthracenyl, and the like.

"Arylalkyl" refers to an alkyl group as defined herein in which one of the hydrogen atoms bonded to a carbon atom is replaced with an aryl group as described herein (i.e., an arylalkyl moiety). The alkyl group of "aralkyl" includes alkyl groups of 1 to 6 carbon atoms (i.e., aryl( _C1 - _C6 )alkyl). Arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 1-phenylpropan-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, and the like.

"Boronic acid" refers to the group -B(OH) ₂ .

"Borate" refers to an ester derivative of a boronic acid compound. Suitable borate derivatives include those of the formula -B(OR) , wherein each R is independently an alkyl, aryl, aralkyl, heteroalkyl, or heteroaryl group. Additionally, _{the two} R groups of -B(OR) may together form a cyclic ester, such as a cyclic ester having the structure , wherein each R may be the same or different. Examples of borate esters include pinacol borate and catechol borate.

"Cycloalkyl" refers to a single saturated or partially unsaturated full carbocycle (i.e., C3-C20 cycloalkyl) with 3-20 ring carbon atoms, such as 3-12 ring atoms, such as 3-10 ring atoms. The term "cycloalkyl" also includes multiple fused, saturated and partially unsaturated full carbocycle systems (e.g., ring systems comprising 2, 3 or 4 carbocycles). Therefore, cycloalkyl includes polycyclic carbocycles, such as bicyclic carbocycles (e.g., bicyclic carbocycles with about 6-12 ring carbon atoms, such as bicyclo [3.1.0] hexane and bicyclo [2.1.1] hexane) and polycyclic carbocycles (e.g., tricyclic carbocycles and tetracyclic carbocycles with up to about 20 ring carbon atoms). When valence requirements allow, the rings of multiple fused ring systems can be interconnected by fusion, spirals and bridge bonds. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, and 1-cyclohex-3-enyl.

"Halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

"Haloalkyl" refers to an alkyl group substituted with 1, 2, 3, 4, or 5, or in some embodiments, 1, 2, or 3, halogen groups, such as _-CH2Cl , _-CH2F , _-CH2Br , _-CFClBr , _-CH2CH2Cl , _-CH2CH2F , _-CF3 , _-CH2CF3 , _-CH2CC13 , and _{the like} , and also includes those alkyl groups _in which all hydrogen atoms are replaced by fluorine atoms, such as perfluoroalkyl groups.

As used herein, the term "heteroalkyl" refers to an alkyl group as defined herein wherein one or more carbon atoms of the alkyl group are replaced by O, S, or ^NRq (or, if the replaced carbon atom is a terminal carbon, by OH, SH, or N( ^Rq ) ₂ ), wherein each ^Rq is independently H or ( _Ci - _C6 )alkyl. For example, a ( _Ci - _Cs )heteroalkyl group means a heteroalkyl group wherein one or more carbon atoms of the C1 _{- Cs} alkyl group are replaced by heteroatoms (e.g., O, S, ^NRq , OH, SH, or N( ^Rq ) ₂ ), which may be the same or different. Examples of heteroalkyl groups include, but are not limited to, methoxymethyl, ethoxymethyl, methoxy, 2-hydroxyethyl, and N,N'-dimethylpropylamine. The heteroatoms of the heteroalkyl group may be optionally oxidized or alkylated. The heteroatom may be located at any interior position of the heteroalkyl group or at the position where the group is attached to the rest of the molecule. Examples include, but are not limited to –CH ₂ OCH ₃ , –CH ₂ CH ₂ NHCH ₃ , –CH ₂ CH ₂ N(CH ₃ )–CH ₃ , –CH ₂ SCH ₂ CH ₃ , –S(O)CH ₃ , –CH ₂ CH ₂ S(O) ₂ CH ₃ , –CH ₂ CH ₂ OCH ₃ , –CHCHN(CH ₃ )CH _{3 ,} –CH ₂ NHOCH ₃ and –CH ₂ OC(CH ₃ ) ₃ .

As used herein, the term "heteroaryl" refers to a single aromatic ring having at least one atom other than carbon in the ring, wherein the atom is selected from oxygen, nitrogen, and sulfur; the term also includes multiple fused ring systems having at least one such aromatic ring, as further described below. Thus, the term includes single aromatic rings having about 1-6 ring carbon atoms and about 1-4 ring heteroatoms selected from oxygen, nitrogen, and sulfur. The sulfur and nitrogen atoms may also be present in oxidized form, provided that the ring is aromatic. Such rings include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl, or furanyl. The term also includes polyfused ring systems (e.g., ring systems containing 2, 3, or 4 rings), wherein the heteroaryl group as defined above can be fused to one or more rings selected from heteroaryl (to form, for example, naphthyridinyl such as 1,8-naphthyridinyl), heterocycloalkyl (to form, for example, 1,2,3,4-tetrahydronaphthyridinyl such as 1,2,3,4-tetrahydro-1,8-naphthyridine), cycloalkyl (to form, for example, 5,6,7,8-tetrahydroquinolinyl), and aryl (to form, for example, indazolyl) to form a polyfused ring system. Thus, the heteroaryl group (single aromatic ring or polyfused ring system) has about 1-20 ring carbon atoms and about 1-6 ring heteroatoms. Such polyfused ring systems can be optionally substituted with one or more (e.g., 1, 2, 3, or 4) oxo groups on the carbocyclic or heterocyclic portions of the fused rings. When valence requirements permit, the rings of the polyfused ring system can be interconnected by fusion, spiral, and bridge bonds. It should be understood that each ring of the polycondensed ring system can be connected in any order relative to each other.It should also be understood that the connection point (as defined above for heteroaryl) of the polycondensed ring system can be located at any position of the polycondensed ring system, including heteroaryl, heterocycle, aryl or carbocyclic ring moiety of the polycondensed ring system, and any suitable atom located at the polycondensed ring system including carbon atoms and heteroatoms (such as nitrogen).Exemplary heteroaryl includes but is not limited to pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalinyl, quinazolinyl, 5,6,7,8-tetrahydroisoquinolyl, benzofuranyl, benzimidazolyl and thianaphthenyl.

As used herein, "heterocycloalkyl" or "heterocyclyl" refers to a single saturated or partially unsaturated non-aromatic ring or non-aromatic polycyclic ring system having at least one heteroatom in the ring (at least one ring heteroatom selected from oxygen, nitrogen, and sulfur). Unless otherwise indicated, a heterocycloalkyl group has 5 to about 20 ring atoms, such as 5 to 14 ring atoms, such as 5 to 10 ring atoms. Thus, the term includes a single saturated or partially unsaturated ring (e.g., a 3-, 4-, 5-, 6-, or 7-membered ring) having about 1 to 6 ring carbon atoms and about 1 to 3 ring heteroatoms selected from oxygen, nitrogen, and sulfur in the ring. The term also includes a single saturated or partially unsaturated ring (e.g., a 5-, 6-, 7-, 8-, 9-, or 10-membered ring) having about 4 to 9 ring carbon atoms and about 1 to 3 ring heteroatoms selected from oxygen, nitrogen, and sulfur in the ring. When valence requirements permit, the rings of multiple fused ring systems can be interconnected by fusion, spiral, and bridge bonds. Heterocycloalkyl groups include, but are not limited to, azetidine, aziridine, imidazolidine, imino-oxoimidazolidine, morpholine, oxirane (epoxide), oxetane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinuclidine, N-bromopyrrolidine, N-chloropiperidine, and the like.

"Hydroxy" or "hydroxyl" refers to the radical -OH.

"Oxo" refers to a double-bonded oxygen (=O). In a compound where an oxo group is bonded to an ^sp2 nitrogen atom, it represents an N-oxide.

It is understood that combinations of chemical groups can be used and will be recognized by one of ordinary skill in the art.For example, the group "hydroxyalkyl" refers to a hydroxy group attached to an alkyl group.

The term "optional" or "optionally" means that the subsequently described event or circumstance can or need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

As used herein, "tautomers" refer to isomers of a compound that differ from one another in the position of a proton and/or the distribution of electrons. Thus, both proton shift tautomers and valence tautomers are intended and described, and it is understood that more than two tautomers may exist for a given compound. Examples of tautomers include, but are not limited to, enol-keto tautomers, imine-enamine tautomers, lactam-lactim tautomers, amide-imidic acid tautomers, amino-imine tautomers, and tautomeric forms of heteroaryl groups containing ring atoms attached to a cyclic -NH- moiety and a cyclic =N- moiety, such as occurs in pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles (see, e.g., Smith, March's Advanced Organism Chemistry (5th ed.), pp. 1218-1223, Wiley-Interscience, 2001; Katritzky A. and Elguero J, et al., The Tautomerism of Heterocycles, Academic Press (1976)).

"Pharmaceutically acceptable" refers to compounds, salts, compositions, dosage forms, and other materials that can be used to prepare pharmaceutical compositions suitable for veterinary or human pharmaceutical use.

"Pharmaceutically acceptable salts" refers to salts of a compound that are pharmaceutically acceptable and possess the desired pharmacological activity of the parent compound (or can be converted into a form that possesses that activity). These salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, lactic acid, maleic acid, malonic acid, mandelic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, oleic acid, palmitic acid, propionic acid, stearic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, and the like; as well as salts formed when an acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion (e.g., sodium or potassium), an alkaline earth metal ion (e.g., calcium or magnesium), or an aluminum ion; or complexes with organic bases such as diethanolamine, triethanolamine, N-methylglucamine, and the like. Ammonium and substituted or quaternized ammonium salts are also included in this definition. Representative, non-limiting lists of pharmaceutically acceptable salts can be found in S. M. Berge et al., J. Pharma Sci., 66(1), 1-19 (1977) and Remington: The Science and Practice of Pharmacy, R. Hendrickson, ed., 21st ed., Lippincott, Williams & Wilkins, Philadelphia, PA, (2005) p. 732, Table 38-5, both of which are hereby incorporated by reference herein.

"Subject" refers to humans, domestic animals (e.g., dogs and cats), farm animals (e.g., cows, horses, sheep, goats, and pigs), laboratory animals (e.g., mice, rats, hamsters, guinea pigs, pigs, rabbits, dogs, and monkeys), and the like.

As used herein, "treatment" is a method of obtaining a beneficial or desired result. For the purposes of this disclosure, a beneficial or desired result includes, but is not limited to, alleviation of symptoms and/or reduction of the extent of symptoms and/or prevention of worsening of symptoms associated with a disease or condition. In one embodiment, "treatment" includes one or more of the following: a) inhibiting a disease or condition (e.g., reducing one or more symptoms caused by the disease or condition and/or reducing the extent of the disease or condition); b) slowing or preventing the development of one or more symptoms associated with a disease or condition (e.g., stabilizing the disease or condition, delaying worsening or development of the disease or condition); and c) alleviating a disease or condition, such as causing regression of clinical symptoms, improving the disease state, delaying the development of the disease, improving quality of life, and/or prolonging survival.

As used herein, "delaying" the development of a disease or condition means postponing, hindering, slowing down, preventing, stabilizing and/or delaying the development of a disease or condition. This delay can be a change in the length of time, depending on the history of the disease and/or the individual being treated. As will be apparent to those skilled in the art, sufficient or significant delays can actually encompass prevention, since the individual has not developed the disease or condition. For example, a method of "delaying" the development of AIDS is a method of reducing the probability of disease development and/or the extent of the disease within a given timeframe, compared to not using the method. This comparison can be based on clinical studies using statistically significant numbers of individuals. For example, known methods can be used to detect the development of AIDS, such as confirming an individual's HIV ⁺ status and assessing individual T cell counts or other indicators of AIDS development, such as extreme fatigue, weight loss, persistent diarrhea, high fever, swollen lymph nodes in the neck, armpits or groin, or the presence of opportunistic diseases known to be associated with AIDS (e.g., conditions that are not typically present in individuals with a functional immune system but occur in AIDS patients). Development can also refer to disease progression that may not have been initially detected and includes occurrence, recurrence and onset.

As used herein, " prevention " refers to the scheme that prevents disease or disorder outbreak so that clinical symptoms of disease do not develop.Therefore, " prevention " relates to the individual administration of treatment (for example, the administration of therapeutic substance) to individual before signs of disease are detected in individual (for example, in the case of not having detectable infectious agent such as virus in individual), therapeutic substance is administered to individual.Individual can be the individual at risk of disease or disorder development, for example, there is the individual of one or more risk factors related to the development or outbreak of known disease or disorder.Therefore, the term " prevention of HIV infection " refers to the administration of anti-HIV therapeutic substance to the individual without detectable HIV infection.It is understood that the individual of anti-HIV preventive treatment can be the individual at risk of infection with HIV virus.

As used herein, an "at-risk" individual is one who is at risk of developing the condition to be treated. An "at-risk" individual may or may not have a detectable disease or condition, and may or may not have displayed detectable disease prior to treatment with the methods described herein. "At-risk" means that the individual has one or more so-called risk factors, which are measurable parameters associated with the development of a disease or condition and are known in the art. An individual with one or more of these risk factors has a higher probability of developing the disease or disorder than an individual without these risk factors. For example, individuals at risk for AIDS are those who have HIV.

As used herein, the term "effective amount" refers to an amount that effectively triggers a desired biological or medical response, including an amount of a compound that is sufficient to affect the treatment of such a disease when applied to an individual to treat a disease. The effective amount will vary according to the compound, the disease and its severity, and the age, weight, etc. of the individual to be treated. The effective amount may include a range of amounts. As understood in the art, an effective amount may be one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint. An effective amount may be considered in the context of administering one or more therapeutic agents, and if it can achieve or achieve a desired or beneficial result in combination with one or more other agents, a single agent of an effective amount may be considered. Due to the combined effects of the compounds (e.g., additional or synergistic effects), the appropriate dose of any co-administered compound may optionally be reduced.

Unless otherwise expressly defined, the present disclosure includes all tautomers of the compounds described in detail herein, even if only one tautomer is explicitly shown (e.g., both tautomeric forms are intended and described by presenting one tautomeric form, where a pair of two tautomers may exist). For example, if a lactam-containing compound is referred to (e.g., by structure or chemical name), it is understood that the present disclosure includes the corresponding lactim tautomers and is described as if the lactim were explicitly described alone or with the lactam. When more than two tautomers exist, the present disclosure includes all such tautomers even if only a single tautomeric form is described by chemical name and/or structure.

The compositions described in detail herein can comprise compound of the present disclosure as a racemic or non-racemic mixture of stereoisomers, or can comprise compound of the present disclosure as a substantially pure isomer.Stereoisomers include enantiomers and diastereomers. If compound has one or more asymmetric centers or has asymmetrically substituted double bonds, it can exist in stereoisomeric form, and therefore can be produced as independent stereoisomers or mixtures. Unless otherwise indicated, this specification sheets are intended to include independent stereoisomers and mixtures. Methods for determining stereochemistry and separation of stereoisomers are well known in the art (see, for example, Advanced Organism Chemistry, 4th edition, J.March, John Wiley and Sons, New York, 1992, Chapter 4).

One skilled in the art will understand that the present disclosure also encompasses any compound disclosed herein that may be enriched above the naturally occurring isotopic ratio at any or all atoms having one or more isotopes such as, but not limited to, deuterium ( ^2H or D).

Also disclosed are compounds in which 1 to n hydrogen atoms attached to a carbon atom can be replaced by deuterium atoms, or D, where n is the number of hydrogen atoms in the molecule. As is known in the art, a deuterium atom is a non-radioactive isotope of a hydrogen atom. Such compounds may increase resistance to metabolism and, therefore, may be used to increase the half-life of a compound when administered to a mammal. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol. Sci., 5(12): 524-527 (1984). Such compounds are synthesized by methods well known in the art, for example, by using raw materials in which one or more hydrogen atoms are replaced by deuterium.

Unless otherwise specified, descriptions of compounds of a given formula herein encompass the disclosed compounds and all pharmaceutically acceptable salts, esters, stereoisomers, tautomers, prodrugs, solvates, and deuterated forms.

Depending on the specific substituents, compounds of Formula I may exist in tautomeric forms. It should be understood that for a given compound structure, two or more tautomeric forms may exist. For example, a compound of Formula I (wherein ^R is -OH) may exist in at least the following tautomeric forms:

As will be appreciated by those skilled in the art, various other tautomeric forms may exist and are intended to be included in the compounds of Formula I. Some descriptions herein explicitly refer to "tautomers thereof," but it will be understood that even in the absence of such language, the tautomers of a given chemical structure or name are intended to be described. Furthermore, it will be understood that the compounds of Formula I may vary between the various tautomeric forms or exist in varying proportions of the various forms based on the particular circumstances of the compound.

Compounds disclosed herein may contain chiral centers, which may be in the (R) or (S) configuration, or may comprise mixtures thereof. Therefore, the present disclosure includes stereoisomers of the compounds described herein, which, if applicable, may be mixed individually or in any proportion. Stereoisomers may include, but are not limited to, enantiomers, diastereomers, racemic mixtures, and combinations thereof. Conventional techniques may be used to prepare and separate such stereoisomers, by reacting enantiomeric starting materials or by separating isomers of the disclosed compounds.

The compounds of the present disclosure may be compounds of formula (I) having one or more chiral centers, which may be in the (R) or (S) configuration, or may comprise mixtures thereof.

The present disclosure includes racemic mixtures of compounds of Formula I and isolated isomers of Formula (I) or any variants thereof. Where more than one chiral center is present in the compounds of the present disclosure, some, none, or all of the chiral centers may be enantiomerically enriched. Thus, mixtures of compounds of Formula (I) may be racemic with respect to one or more chiral centers and/or enantiomerically enriched with respect to one or more chiral centers.

In certain embodiments, the compound of the present disclosure is a compound of formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof,

in:

X is N, Y is CR ³ , and Z is CR ³ ; or X is CR ³ , Y is CR ³ , and Z is N; or X is CR ³ , Y is N, and Z is CR ³ ;

R ¹ is -H, -CN, -OR ^a , C _1-6 haloalkyl or halogen;

R ² is -H, -NR ^a R ^b , -OR ^a or C _1-10 alkyl optionally substituted by, for example, 1, 2, 3, 4 or 5 R ²⁰ groups which may be the same or different;

each R ³ is independently -H, -OR ^a , halogen, -NR ^a R ^b , -C(O)OR ^a , -CN, -NHC(O)NR ^a R ^b , -OC(O)NR ^a R ^b , -CH ₂ C(O)NR ^a R ^b , C 1-10 alkyl optionally substituted, for example, by 1, 2, 3, 4 or 5 R ²⁰ groups which may be the same or different, or C _1-10 heteroalkyl optionally substituted, for example, by 1, 2, 3, ₄ or 5 R ²⁰ groups which may be the same or different;

R ⁴ and R ⁵ are independently halogen, -OR ^a or C _1-10 alkyl optionally substituted by, for example, 1, 2, 3, 4 or 5 R ²⁰ groups which may be the same or different;

Each R ⁶ is independently halogen, -OR ^a or C _1-10 alkyl optionally substituted with, for example, 1, 2, 3, 4 or 5 R ²⁰ groups which may be the same or different;

n is an integer from 0 to 4;

each R ²⁰ is independently C _1-10 alkyl, C _1-10 heteroalkyl, aryl, heteroaryl, halogen, -OR ^a , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -OC(O)NR ^a R ^b , -NR ^a C(O)OR ^b , -S(O) _0-2 R ^a , -S(O) ₂ F, -S(O) ₂ NR ^a R ^b , -NR ^a (O) ₂ R ^b , -N ₃ , -CN or -NO ₂ ,

wherein each C _1-10 alkyl, C _1-10 heteroalkyl, aryl or heteroaryl is optionally substituted with, for example, 1, 2, 3, 4 or 5 halogen, -OR ^a , -C(O)R ^a , -C(O)OR ^a , C(O)NR ^a R ^b , -OC(O)NR ^a R ^b , -NR ^a C(O)OR ^b , -S(O) _{0- 2} R ^a , -S(O) ₂ F, -S(O) ₂ NR ^a R ^b , , NR ^a S(O) ₂ R ^b , -N ₃ , -CN or -NO ₂ groups, which may be the same or different;

each ^Ra and ^Rb are independently -H, _-NH2 , _C1-10 alkyl, _C1-10 heteroalkyl, aryl, or heteroaryl, each of which is optionally substituted with 1, 2, 3, 4, or 5 ^R21 groups which may be the same or different; or ^Ra and ^Rb, together with the atoms to which they are attached, form _C1-10 heterocycloalkyl; and

R ²¹ is C _1-6 alkyl, -CN, aryl, heteroaryl or halogen.

In certain embodiments of the compound of formula (I), R ² is -H, -NR ^a R ^b or -OH. In certain embodiments of the compound of formula (I), R ² is -NH ₂ or -OH. In certain embodiments of the compound of formula (I), R ² is NH ₂ .

In certain embodiments of the compound of formula (I), each R ^is independently -H, ^-ORa , halogen, ^-NRaRb , -C(O) ^ORa , or ^-C (O) ^NRaRb . In certain embodiments of the compound of formula (I), each ^R is independently -H, C(O) ^ORa , or -C(O) ^NRaRb . In certain embodiments of the compound of formula (I), each R is ^{independently} -H, C(O)ORa, or ^-C (O) ^NRaRb .

In certain embodiments of the compounds of formula (I), R ⁴ and R ⁵ are each independently halogen, -OC _1-6 alkyl, or C _1-6 alkyl optionally substituted with, for example, 1, 2, 3, 4, or 5 R ²⁰ groups, which may be the same or different. In certain embodiments of the compounds of formula (I), R ⁴ and R ⁵ are each independently C _1-3 alkyl. In certain embodiments of the compounds of formula (I), R ⁴ and R ⁵ are each independently C _1-3 alkyl.

In certain embodiments of the compounds of formula (I), R ¹ is -H, -CN, -OC _1-6 alkyl, C _1-3 haloalkyl, or halogen. In certain embodiments of the compounds of formula (I), R ¹ is -H, -CN, -OC _1-3 alkyl, -CF ₃ , or halogen. In certain embodiments of the compounds of formula (I), R ¹ is -CN.

In certain embodiments of the compound of formula (I), n is 4. In certain embodiments of the compound of formula (I), n is 3. In certain embodiments of the compound of formula (I), n is 2. In certain embodiments of the compound of formula (I), n is 1. In certain embodiments of the compound of formula (I), n is 0.

It is to be understood that any of the variables described herein with respect to Formula (I) or variations thereof may be combined as if each and every combination of variables were specifically and individually listed. For example, in certain embodiments of compounds of Formula (I), one or more of the following structural provisions apply: (i) R ² is -H, -NR ^a R ^b , or -OH (e.g., -NH ₂ or -OH); (ii) each R ³ is independently -H, -OR ^a , halogen, -NR ^a R ^b , -C(O)OR ^a , or -C(O)NR ^a R ^b ; (iii) R ⁴ and R ⁵ are each independently halogen, -OC _1-6 alkyl, or C _1-6 alkyl optionally substituted with 1, 2, 3, 4, or 5 R ²⁰ groups which may be the same or different (e.g., R ⁴ and R ⁵ are -CH ₃ ); (iv) R ¹ is -H, -CN, -OC _1-6 alkyl, C _1-3 haloalkyl, or halogen (e.g., R ¹ is -H, -CN, -OC _1-3 alkyl, -CF ₃ , or halogen); and (v) n is 1, 2, 3, or 4. In one such embodiment, any two of the provisions of (i), (ii), (iii), (iv), and (v) apply. In another such embodiment, any three of the provisions of (i), (ii), (iii), (iv), and (v) apply. In another such embodiment, any four of the provisions of (i), (ii), (iii), (iv), and (v) apply. In another embodiment, all of the provisions of (i), (ii), (iii), (iv), and (v) apply.

In certain embodiments, the compound of Formula (I) is a compound of Formula (Ia) or a tautomer thereof or a pharmaceutically acceptable salt thereof:

wherein R ¹ , R ² , R ⁴ and R ⁵ are as defined above. The remarks herein applicable to formula (I) also apply to formula (Ia).

In certain embodiments of the compound of formula (Ia), R ⁴ and R ⁵ are each independently halogen, -OC _1-6 alkyl, or C _1-6 alkyl optionally substituted with, for example, 1, 2, 3, 4, or 5 R ²⁰ groups. In certain embodiments of the compound of formula (Ia), R ⁴ and R ⁵ are each independently C _1-3 alkyl. In certain embodiments of the compound of formula (Ia), R ⁴ and R ⁵ are each independently C _1-3 alkyl.

In certain embodiments of the compound of Formula (Ia), R ² is -H, -NR ^a R ^b or -OH. In certain embodiments of the compound of Formula (Ia), R ² is -NH ₂ or -OH. In certain embodiments of the compound of Formula (Ia), R ² is NH ₂ .

In certain embodiments of the compound of formula (Ia), R ¹ is -H, -CN, -OC _1-6 alkyl, C _1-3 haloalkyl, or halogen. In certain embodiments of the compound of formula (Ia), R ¹ is -H, -CN, -OC _1-3 alkyl, -CF ₃ , or halogen. In certain embodiments of the compound of formula (Ia), R ¹ is -CN.

In certain embodiments of Formula (Ia), R ⁴ and R ⁵ are each independently C _1-3 alkyl; R ² is -H, -NR ^a R ^b or -OH; and R ¹ is -H, -CN, -OC _1-6 alkyl, C _1-3 haloalkyl or halogen.

In certain embodiments of Formula (Ia), R ⁴ and R ⁵ are each independently C _1-3 alkyl; R ² is -NH ₂ or -OH; and R ¹ is -H, -CN, -OC _1-3 alkyl, -CF ₃ or halogen.

It is to be understood that any of the variables described herein with respect to Formula (Ia) may be combined as if each and every combination of variables were specifically and individually listed.

In certain embodiments, the compound of Formula (I) is a compound of Formula (Ib) or a tautomer thereof or a pharmaceutically acceptable salt thereof:

wherein R ¹ , R ² , R ⁴ and R ⁵ are as defined above. The remarks herein applicable to formula (I) also apply to formula (Ib).

In certain embodiments of the compound of formula (Ib), R ⁴ and R ⁵ are each independently halogen, -OC _1-6 alkyl, or C _1-6 alkyl optionally substituted with, for example, 1, 2, 3, 4, or 5 R ²⁰ groups. In certain embodiments of the compound of formula (Ib), R ⁴ and R ⁵ are each independently C _1-3 alkyl. In certain embodiments of the compound of formula (Ib), R ⁴ and R ⁵ are each independently _C 1-3 alkyl.

In certain embodiments of the compound of Formula (Ib), R ² is -H, -NR ^a R ^b or -OH. In certain embodiments of the compound of Formula (Ib), R ² is -NH ₂ or -OH. In certain embodiments of the compound of Formula (Ib), R ² is NH ₂ .

In certain embodiments of the compound of formula (Ib), R ¹ is -H, -CN, -OC _1-6 alkyl, C _1-3 haloalkyl, or halogen. In certain embodiments of the compound of formula (Ib), R ¹ is -H, -CN, -OC _1-3 alkyl, -CF ₃ , or halogen. In certain embodiments of the compound of formula (Ib), R ¹ is -CN.

In certain embodiments of the compound of Formula (Ib), R ⁴ and R ⁵ are each independently C _1-3 alkyl; R ² is -H, -NR ^a R ^b or -OH; and R ¹ is -H, -CN, -OC _1-6 alkyl, C _1-3 haloalkyl or halogen.

In certain embodiments of the compound of Formula (Ib), R ⁴ and R ⁵ are each independently C _1-3 alkyl; R ² is -NH ₂ or -OH; and R ¹ is -H, -CN, -OC _1-3 alkyl, -CF ₃ or halogen.

It is to be understood that any of the variables described herein with respect to Formula (Ib) may be combined as if each and every combination of variables were specifically and individually listed.

In certain embodiments, the compound of formula (I) is a compound of formula (Ic) or a tautomer thereof or a pharmaceutically acceptable salt thereof:

wherein R ¹ , R ² , R ⁴ and R ⁵ are as defined above. The remarks herein applicable to formula (I) also apply to formula (Ic).

In certain embodiments of the compound of formula (Ic), R ⁴ and R ⁵ are each independently halogen, -OC _1-6 alkyl, or C _1-6 alkyl optionally substituted with, for example, 1, 2, 3, 4, or 5 R ²⁰ groups. In certain embodiments of the compound of formula (Ic), R ⁴ and R ⁵ are each independently C _1-3 alkyl. In certain embodiments of the compound of formula (Ic), R ⁴ and R ⁵ are each independently _C 1-3 alkyl.

In certain embodiments of the compound of formula (Ic), R ² is -H, -NR ^a R ^b or -OH. In certain embodiments of the compound of formula (Ic), R ² is -NH ₂ or -OH. In certain embodiments of the compound of formula (Ic), R ² is -NH ₂ .

In certain embodiments of the compound of formula (Ic), R ¹ is -H, -CN, -OC _1-6 alkyl, C _1-3 haloalkyl, or halogen. In certain embodiments of the compound of formula (Ic), R ¹ is -H, -CN, -OC _1-3 alkyl, -CF ₃ , or halogen. In certain embodiments of the compound of formula (Ic), R ¹ is -CN.

In certain embodiments of the compound of Formula (Ic), R ⁴ and R ⁵ are each independently C _1-3 alkyl; R ² is -H, -NR ^a R ^b or -OH; and R ¹ is -H, -CN, -OC _1-6 alkyl, C _1-3 haloalkyl or halogen.

In certain embodiments of the compound of Formula (Ic), R ⁴ and R ⁵ are each independently C _1-3 alkyl; R ² is -NH ₂ or -OH; and R ¹ is -H, -CN, -OC _1-3 alkyl, -CF ₃ or halogen.

It is to be understood that any of the variables described herein with respect to Formula (Ic) may be combined as if each and every combination of variables were specifically and individually listed.

In certain embodiments, the compound of formula (I) is:

or a tautomer thereof; or a pharmaceutically acceptable salt thereof.

Pharmaceutical composition

Pharmaceutical compositions comprising compounds disclosed herein or pharmaceutically acceptable salts thereof can be prepared with conventional carriers (e.g., inactive ingredients or excipient materials) that can be selected according to common practice. Tablets can include excipients, including glidants, fillers, adhesives, etc. Aqueous compositions can be prepared in a sterile form and, when used for delivery by routes other than oral administration, can generally be isotonic. All compositions can optionally contain excipients, such as those described in Rowe et al, Handbook of Pharmaceutical Excipients, 5th edition, American Pharmacists Association, 1986. Excipients can include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose, stearic acid, etc. In certain embodiments, the composition is disclosed as a solid dosage form, including solid oral dosage forms. The pH of the composition can be in the range of about 3 to about 11, but is generally about 7 to 10.

Although the active ingredient can be administered alone, it is preferably present as a pharmaceutical composition. Compositions for veterinary and human use comprise at least one compound of formula (I) and one or more acceptable carriers and optional other therapeutic ingredients. In one embodiment, the pharmaceutical composition comprises a compound of formula (I) or its tautomer or its pharmaceutically acceptable salt, a pharmaceutically acceptable carrier and another therapeutic ingredient. Carrier is "acceptable" in the sense that it is compatible with the other ingredients of the composition and is physiologically harmless to its recipient.

The composition includes compositions suitable for various routes of administration, and the route of administration includes oral administration. The composition can be conveniently present in unit dosage form and can be prepared by any method known in the pharmaceutical field. Such a method includes the step of combining an active ingredient (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) with one or more inactive ingredients (e.g., carriers, pharmaceutical excipients, etc.). The composition can be prepared by uniformly and closely combining the active ingredient with a liquid carrier or a finely dispersed solid carrier or both, and then optionally molding the product. Technology and formulations are generally found in Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006.

Compositions described herein suitable for oral administration may be presented as discrete units (unit dosage forms) including, but not limited to, capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient.

Pharmaceutical compositions disclosed herein comprise one or more compounds disclosed herein or their pharmaceutically acceptable salts and one or more pharmaceutically acceptable carriers or excipients and optional other therapeutic agents. The pharmaceutical composition containing active ingredient can be any form suitable for the intended method of administration. For example, when used for oral administration, tablets, troches, lozenges, water or oil suspensions, dispersible powders or granules, emulsions, hard capsules or soft capsules, syrups or elixirs can be prepared. The composition intended for oral administration can be prepared according to any method for preparing pharmaceutical compositions known in the art, and such compositions can contain one or more reagents, including sweeteners, flavorings, coloring agents and preservatives, to provide a palatable preparation. Tablets containing a mixture of active ingredient and a non-toxic pharmaceutically acceptable excipient suitable for making tablets are acceptable. These excipients can be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, lactose monohydrate, cross-linked sodium carboxymethylcellulose, povidone, calcium phosphate or sodium phosphate; granulating and disintegrants such as corn starch or alginic acid; binders such as cellulose, microcrystalline cellulose, starch, gelatin or gum arabic; and lubricants such as magnesium stearate, stearic acid or talc. Tablets can be uncoated or can be coated by known techniques, including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract, thereby providing a sustained effect over a longer period of time. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate can be used alone or in combination with a wax.

The amount of active ingredient that can be combined with the inactive ingredient to produce a dosage form can vary depending on the intended therapeutic target and the particular mode of administration. For example, in some embodiments, a dosage form for oral administration to a human can contain from about 1 mg to 1000 mg of active substance, formulated together with a suitable and convenient amount of carrier material (e.g., inactive ingredient or excipient material). In certain embodiments, the carrier material varies from about 5% to about 95% (weight:weight) of the total composition.

It should be understood that in addition to the ingredients particularly mentioned above, the compositions of these embodiments may include other agents conventional in the art having regard to the type of composition in question, for example, those suitable for oral administration may include flavoring agents.

In certain embodiments, in one variation, the composition comprising an active ingredient disclosed herein (a compound of formula (I) or a pharmaceutically acceptable salt thereof) does not contain an agent that affects the metabolic rate of the active ingredient. Thus, it should be understood that in certain embodiments, the composition comprising a compound of formula (I) does not contain an agent that affects (e.g., slows, hinders, or delays) the metabolism of the compound of formula (I) or any other active ingredient administered separately, sequentially, or simultaneously with the compound of formula (I). It should also be understood that in certain embodiments, any method, kit, article, etc. described in detail herein does not contain an agent that affects (e.g., slows, hinders, or delays) the metabolism of the compound of formula (I) or any other active ingredient administered separately, sequentially, or simultaneously with any one of the compounds of formula (I).

How to use

Disclosed herein are methods for inhibiting HIV reverse transcriptase in an individual in need thereof, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to the individual. In certain embodiments, the individual in need thereof is a human who has been infected with HIV. In certain embodiments, the individual in need thereof is a human who has been infected with HIV but has not developed AIDS. In certain embodiments, the individual in need thereof is a human who is at risk of developing AIDS. In certain embodiments, the individual in need thereof is a human who has been infected with HIV and has developed AIDS. In certain embodiments of the methods disclosed herein, a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the individual separately, sequentially, or simultaneously with another active ingredient used to treat HIV, such as an HIV protease inhibitory compound, a non-nucleoside inhibitor of HIV reverse transcriptase, a nucleoside inhibitor of HIV reverse transcriptase, a nucleotide inhibitor of HIV reverse transcriptase, an HIV integrase inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, a gp120 inhibitor, a CCR5 inhibitor, a capsid polymerization inhibitor, and other drugs used to treat HIV, as well as combinations thereof.

In certain embodiments, disclosed is a method for treating or preventing HIV viral infection in a subject (eg, a human), comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In certain embodiments, disclosed is a method of inhibiting HIV viral replication, treating AIDS, or delaying the onset of AIDS in an individual (eg, a human) comprising administering to the individual a compound of any of Formula (I) or a pharmaceutically acceptable salt thereof.

In certain embodiments, a method for preventing HIV infection in an individual (e.g., a human) is disclosed, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to the individual. In certain embodiments, the individual is at risk of contracting HIV, such as an individual with one or more risk factors known to be associated with contracting HIV.

In certain embodiments, disclosed is a method for treating HIV infection in an individual (eg, a human) comprising administering to the individual a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

In certain embodiments, a method for treating HIV infection in an individual (e.g., a human) is disclosed, comprising administering to the individual in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of one or more additional therapeutic agents selected from the group consisting of HIV protease inhibiting compounds, non-nucleoside inhibitors of HIV reverse transcriptase, nucleoside inhibitors of HIV reverse transcriptase, nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, and other drugs used to treat HIV, and combinations thereof.

In certain embodiments, a compound of formula (I) or a pharmaceutically acceptable salt thereof is disclosed for use in the medical treatment of HIV viral infection (e.g., HIV-1, or replication of HIV virus (e.g., HIV-1), or AIDS, or delaying the onset of AIDS in an individual (e.g., a human)).

In certain embodiments, the use of any compound of formula (I) or a pharmaceutically acceptable salt thereof for preparing a medicament for treating HIV infection or HIV viral replication or AIDS or delaying the onset of AIDS in an individual (e.g., a human) is disclosed. One embodiment is disclosed, which relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the prophylactic or therapeutic treatment of HIV infection or AIDS or for the therapeutic treatment of AIDS or delaying the onset of AIDS.

In certain embodiments, disclosed is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating HIV infection in an individual (e.g., a human). In certain embodiments, disclosed is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the prophylactic or therapeutic treatment of HIV infection.

In certain embodiments, in the methods of use, administration is to an individual (eg, a human) in need of treatment. In certain embodiments, in the methods of use, administration is to an individual (eg, a human) at risk of developing AIDS.

Disclosed herein are compounds of formula (I) or pharmaceutically acceptable salts thereof for use in treatment. In one embodiment, the compounds of formula (I) or pharmaceutically acceptable salts thereof are used in a method of treating HIV infection or HIV viral replication or AIDS or delaying the onset of AIDS in an individual (e.g., a human).

Also disclosed herein are methods for treating or preventing HIV in individuals in need thereof using a compound of formula (I) or a pharmaceutically acceptable salt thereof. In certain embodiments, the individual in need thereof is a person who has been infected with HIV. In certain embodiments, the individual in need thereof is a person who has been infected with HIV but has not developed AIDS. In certain embodiments, the individual in need thereof is a person who is at risk of developing AIDS. In certain embodiments, the individual in need thereof is a person who has been infected with HIV and has developed AIDS.

Also disclosed herein is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for therapeutically treating AIDS or delaying the onset of AIDS.

Also disclosed herein is a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the prophylactic or therapeutic treatment of HIV infection.

In certain embodiments, compounds of Formula (I) or pharmaceutically acceptable salts thereof are useful as research tools (eg, to study inhibition of HIV reverse transcriptase in a subject in vitro or in vivo).

Route of administration

One or more compounds of formula (I) disclosed herein (also referred to herein as active ingredients) can be administered by any route suitable for the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including oral and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) and the like. It should be understood that the preferred route can vary with, for example, the condition of the recipient. In certain embodiments, the disclosed compounds are orally bioavailable and can be administered orally.

Dosage regimen

Compounds, such as compounds of Formula (I), can be administered to an individual for a desired time or duration, such as at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer, according to an effective dosing regimen. In one variation, the compound is administered daily or intermittently during the life of the individual.

The dosage or frequency of administration of the compound of formula (I) may be adjusted during the course of treatment according to the judgment of the attending physician.

The compound can be administered to an individual (eg, a human) in an effective amount. In certain embodiments, the compound is administered once daily.

The compounds disclosed herein (e.g., any compound of Formula (I)) can be administered at a dosage effective for the compound of Formula I. For example, the dosage can be 10-1000 mg of the compound.

combination

In certain embodiments, a method for treating or preventing HIV infection in a human suffering from or at risk of infection is disclosed, comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents. In one embodiment, a method for treating HIV infection in a human suffering from or at risk of infection is disclosed, comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.

In certain embodiments, the present disclosure relates to methods of treating HIV infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents suitable for treating HIV infection.

Also disclosed herein are methods for treating or preventing HIV using a compound of formula (I) or a pharmaceutically acceptable salt thereof and another active ingredient for treating HIV. In one embodiment, the other active ingredient for treating HIV is selected from the group consisting of HIV protease inhibitory compounds, non-nucleoside inhibitors of HIV reverse transcriptase, nucleoside inhibitors of HIV reverse transcriptase, nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, and other drugs for treating HIV, and combinations thereof.

Also disclosed herein is a method for treating or preventing HIV using a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered separately, sequentially, or simultaneously with another active ingredient for treating HIV. In one embodiment, the other active ingredient for treating HIV is selected from the group consisting of HIV protease inhibitory compounds, non-nucleoside inhibitors of HIV reverse transcriptase, nucleoside inhibitors of HIV reverse transcriptase, nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, and other drugs for treating HIV, and combinations thereof.

The compounds disclosed herein (eg, any compound of Formula (I)) can be combined with one or more additional therapeutic agents at any dose of the compound of Formula I (eg, 10-1000 mg of the compound).

In one embodiment, a pharmaceutical composition is disclosed that comprises a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents and a pharmaceutically acceptable carrier, diluent, or excipient.

In one embodiment, a kit is disclosed comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.

In the above embodiments, the additional therapeutic agent can be an anti-HIV agent. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of: HIV protease inhibitors; non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase; nucleoside or nucleotide inhibitors of HIV reverse transcriptase; HIV integrase inhibitors; HIV non-catalytic site (or allosteric) integrase inhibitors; HIV entry inhibitors (e.g., CCR5 inhibitors, gp41 inhibitors (i.e., fusion inhibitors), and CD4 attachment inhibitors); CXCR4 inhibitors; gp120 inhibitors; G6PD and NADH-oxidase inhibitors; HIV vaccines; HIV maturation inhibitors; potential reversal agents (e.g., histone deacetylase inhibitors, proteasome inhibitors, protein kinase C (PKC) activators, and BRD4 inhibitors); compounds targeting the HIV capsid ("capsid inhibitors"; e.g., capsid polymerization inhibitors or capsid disruption compounds, HIV nucleocapsid p7 (NCp7) inhibitors, HIV p24 capsid protein inhibitors); pharmacokinetic enhancers; immune-based therapies (e.g., Pd-1 modulators, Pd-L1 modulators, toll-like receptor modulators, IL-15 agonists); HIV antibodies; bispecific antibodies; "antibody-like" therapeutic proteins (e.g., Fab derivatives), including those targeting HIV gp120 or gp41; combination drugs for HIV; HIV p17 matrix protein inhibitors; IL-13 antagonists; peptidyl-prolyl cis-trans isomerase A modulators; protein disulfide isomerase inhibitors; complement C5a receptor antagonists; DNA methyltransferase inhibitors, HIV vif gene regulators, HIV-1 viral infection factor inhibitors, TAT protein inhibitors; HIV-1 Nef regulators; Hck tyrosine kinase regulators; mixed lineage kinase-3 (MLK-3) inhibitors; Rev protein inhibitors; integrin antagonists; nuclear protein inhibitors; splicing factor regulators; COMM domain-containing protein 1 regulators; HIV ribonuclease H inhibitors; retrocyclin regulators; CDK-9 inhibitors; dendritic ICAM-3 grasping non-integrin 1 inhibitors; HIV GAG protein inhibitors; HIV POL protein inhibitors; complement factor H regulators; ubiquitin ligase inhibitors; deoxycytidine kinase inhibitors; cyclin-dependent protein kinase inhibitors; proprotein convertase PC9 stimulators; ATP-dependent RNA helicase DDX3X inhibitors; reverse transcriptase initiation complex inhibitors; PI3K inhibitors; such as WO2013/006738 (Gilead Sciences), US2013/0165489 (University of Pennsylvania), WO2009/061096A1(BoehringeRIngelheim), WO2009/062285(BoehringeRIngelheim), US20140221380(JapanTobacco), US20140221378(Japan Tobacco), WO2010/130034 (BoehringeR Ingelheim), WO2013/159064 (Gilead Sciences), WO2012/145728 (Gilead Sciences), WO2012/003497 (Gilead Sciences), WO2014/100323 (Gilead Sciences) Sciences), WO2012/145728 (Gilead Sciences), WO2013/159064 (Gilead Sciences) and WO2012/003498 (Gilead Sciences) Sciences) and WO2013/006792 (Pharma Resources); and other drugs for treating HIV; and combinations thereof.

In certain embodiments, the additional therapeutic agent is selected from the group consisting of HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, pharmacokinetic enhancers, and combinations thereof.

In certain embodiments, the compound of formula (I) is formulated into a tablet, which may optionally contain one or more other compounds for the treatment of HIV. In certain embodiments, the tablet may contain another active ingredient for the treatment of HIV, such as an HIV protease inhibitor, a non-nucleoside or non-nucleotide inhibitor of HIV reverse transcriptase, a nucleoside or nucleotide inhibitor of HIV reverse transcriptase, an HIV integrase inhibitor, an HIV non-catalytic site (or allosteric) integrase inhibitor, a pharmacokinetic enhancer, and combinations thereof.

In certain embodiments, such tablets are suitable for once-daily administration. In certain embodiments, the additional therapeutic agent is one or more selected from the group consisting of:

(1) Combination drugs selected from the group consisting of: (efavirenz + tenofovir disoproxil fumarate + emtricitabine); (, rilpivirine + tenofovir disoproxil fumarate + emtricitabine); (elvitegravir + cobicistat + tenofovir disoproxil fumarate + emtricitabine); dolutegravir + abacavir sulfate + lamivudine; dolutegravir + abacavir sulfate + lamivudine; lamivudine + nevirapine + zidovudine; dolutegravir + rilpivirine; atazanavir sulfate + cobicistat; darunavir + cobicistat; efavirenz + lamivudine + tenofovir disoproxil fumarate; tenofovir alafenamide fumarate + emtricitabine + cobicistat + Elvitegravir; Vacc-4x + romidepsin; darunavir + tenofovir alafenamide hemifumarate + emtricitabine + cobicistat; APH-0812; raltegravir + lamivudine; (lopinavir + ritonavir); atazanavir sulfate + ritonavir; (zidovudine + lamivudine; AZT + 3TC); (abacavir sulfate + lamivudine, ABC + 3TC); (abacavir sulfate + zidovudine + lamivudine; ABC + AZT + 3TC); (tenofovir disoproxil fumarate + emtricitabine; TDF + FTC); tenofovir + lamivudine; and lamivudine + tenofovir disoproxil fumarate;

(2) HIV protease inhibitors selected from the group consisting of amprenavir, atazanavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, ritonavir, nelfinavir, nelfinavir mesylate, saquinavir, saquinavir mesylate, tipranavir, brecanavir, darunavir, DG-17, TMB-657 (PPL-100), and TMC-310911;

(3) a non-nucleoside or non-nucleotide inhibitor of HIV reverse transcriptase selected from the group consisting of: delavirdine; delavirdine mesylate; nevirapine; etravirine; dapivirine; doravirine; rilpivirine; efavirenz; KM-023; VM-1500; lentinan; and AIC-292;

(4) nucleoside or nucleotide inhibitors of HIV reverse transcriptase selected from the group consisting of: and EC (didanosine, ddl), zidovudine, emtricitabine, didanosine, stavudine, zalcitabine, lamivudine, censavudine, abacavir, abacavir sulfate, amdosovir, elvucitabine, alovudine, phosphazid, fozivudine tizumab, aprecitabine, amdosovir, KP-1461, fozivudine tizumab, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir hemifumarate, tenofovir alafenamide, tenofovir hemifumarate, tenofovir alafenamide fumarate, adefovir, adefovir dipivoxil, festinavir;

(5) HIV integrase inhibitors selected from the group consisting of curcumin, curcumin derivatives, chicoric acid, chicoric acid derivatives, 3,5-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid derivatives, aurintricarboxylic acid, aurintricarboxylic acid derivatives, caffeic acid phenethyl ester, caffeic acid phenethyl ester derivatives, tyrosine phosphorylation inhibitors, tyrosine phosphorylation inhibitor derivatives, quercetin, quercetin derivatives, raltegravir, elvitegravir, dolutegravir and cabotegravir;

(6) HIV non-catalytic site or allosteric integrase inhibitor (NCINI) selected from the group consisting of CX-05168, CX-05045 and CX-14442;

(7) HIV gp41 inhibitors selected from the group consisting of enfuvirtide, sifuvirtide and abavita;

(8) HIV entry inhibitors selected from cenicriviroc;

(9) HIV gp120 inhibitors selected from Radha-108 (Receptol) and BMS-663068;

(10) CCR5 inhibitors selected from aplaviroc, vicriviroc, maraviroc, cenicriviroc, PRO-140, Adaptavir (RAP-101), TBR-220 (TAK-220) and vMIP (Haimipu);

(11) a CD4 attachment inhibitor selected from the group consisting of itrazumab;

(12) a CXCR4 inhibitor selected from the group consisting of plerixafor, ALT-1188, vMIP, and Haimipu;

(13) a pharmacokinetic enhancer selected from the group consisting of cobicistat and ritonavir;

(14) Immune-based therapy selected from the group consisting of: leukotriene, interleukin-7, lexgenleucel-T (VRX-496), chloroquine (hydroxychloroquine), aldesleukin (IL-2), interferon alpha, interferon alpha-2b, interferon alpha-n3, pegylated interferon alpha, interferon gamma, hydroxyurea, mycophenolate mofetil (MPA) and mycophenolate mofetil ester derivatives (MMF), WF-10, ribavirin , IL-2, IL-2XL, IL-12, polymer polyethyleneimine (PEI), Gepon, VGV-1, MOR-22, BMS-936559, toll-like receptor modulators (tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12, and tlr13), rintatolimod, and IR-103;

(15) HIV vaccines selected from the group consisting of peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, virus-like particle vaccines (pseudovirion vaccines), CD4-derived peptide vaccines, vaccine combinations, rgp120 (AIDSVAX), ALVAC HIV (vCP1521)/AIDSVAX B/E (gp120) (RV144), Remune, ITV-1, ContreVir, Ad5-ENVA-48, DCVax-001 (CDX-2401), PEP-6409, Vacc-4x, Vacc-C5, VAC-3S, multiple DNA recombinant adenovirus-5 (rAd5), Pennvax-G, VRC-HIV MAB060-00-AB, AVX-101, Tat Oyi vaccine, AVX-201, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3/VSSP ISA-51, multi-ICLC adjuvant vaccine, TatImmune, GTU-multi-HIV (FIT-06), AGS-004, gp140[δ]V2.TV1+MF-59, rVSVIN HIV-1 gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, Ad35-GRIN/ENV, TBC-M4, HIVAX, HIVAX-2, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, Vichrepol, rAAV1-PG9DP, GOVX-B11, GOVX-B21, ThV-01, TUTI-16, VGX-3300, TVI-HIV-1, Ad-4 (Ad4-env Clade C+ad4-mGag), EN41-UGR7C, EN41-FPA2, PreVaxTat, TL-01, SAV-001, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR and DNA-Ad5gag/pol/nef/nev(HVTN505);

(16) HIV antibodies, bispecific antibodies, and “antibody-like” therapeutic proteins (e.g., Fab derivatives), including BMS-936559, TMB-360, and those targeting HIV gp120 or gp41 selected from the group consisting of baviximab, UB-421, C2F5, C2G12, C4E10, C2F5+C2G12+C4E10, 3-BNC-117, KD-247, PGT145, PGT121, MDX010 (ipilimumab), VRC01, A32, 7B2, 10E8, and VRC07;

(17) Potential reversal agents selected from the group consisting of: histone deacetylase inhibitors, such as romidepsin, vorinostat, panobinostat; proteasome inhibitors, such as Velcade; protein kinase C (PKC) activators, such as Indolactam, Prostratin, IngenolB and DAG-lactone, ionomycin, GSK-343, PMA, SAHA, BRD4 inhibitors, IL-15, JQ1, disulfram and amphotericin B;

(18) HIV nucleocapsid p7 (NCp7) inhibitors selected from azodicarbonamide;

(19) HIV maturation inhibitors selected from BMS-955176 and GSK-2838232;

(20) PI3K inhibitors selected from the group consisting of idelalisib, AZD-8186, buparlisib, CLR-457, pictilisib, neratinib, rigosertib, rigosertib sodium, EN-3342, TGR-1202, alpelisib, duvelisib, UCB-5857, taselisib, XL-7 65, gedatolisib, VS-5584, copanlisib, CAI orotic acid, perifosine, RG-7666, GSK-2636771, DS-7423, panulisib, GSK-2269557, GSK-2126458, CUDC-907, PQR-309, INCB-040093, pilaralisib, BAY-1082439, puquitinib mesylate, SAR-245409, AMG-319, RP-6530, ZSTK-474, MLN-1117, SF-1126, RV-1729, sonolisib, LY-3023414, SAR-260301, and CLR-1401;

(21) WO 2004/096286 (Gilead Sciences), WO 2006/110157 (Gilead Sciences), WO 2006/015261 (Gilead Sciences), WO 2013/006738 (Gilead Sciences), US 2013/0165489 (University of Pennsylvania), US20140221380 (Japan Tobacco), US20140221378 (Japan Tobacco), WO 2013/006792 (Pharma Resources), WO 2009/062285 (Boehringer Ingelheim), WO 2010/130034 (Boehringer Ingelheim), WO2013/091096A1 (Boehringer Ingelheim), WO 2013/159064 (Gilead Sciences), WO Compounds disclosed in WO 2012/145728 (Gilead Sciences), WO 2012/003497 (Gilead Sciences), WO 2014/100323 (Gilead Sciences), WO 2012/145728 (Gilead Sciences), WO 2013/159064 (Gilead Sciences) and WO 2012/003498 (Gilead Sciences); and

(22) Other drugs for treating HIV selected from the group consisting of TR-452, MK-8591, REP 9, CYT-107, alisporivir, NOV-205, IND-02, metenkefalin, PGN-007, acetomorphan, Gamimune, SCY-635, Prolastin, 1,5-dicaffeoylquinic acid, BIT-225, RPI-MN, VSSP, Hvviral, IMO-3100, SB-728-T, RPI-MN, VIR-576, HGTV-43, MK-1376, rHIV7-shl-TAR-CCR5RZ, MazF gene therapy agent, BlockAide and PA-1050040 (PA-040).

In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with one, two, three, four, or more additional therapeutic agents. In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with two additional therapeutic agents. In other embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with three additional therapeutic agents. In further embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with four additional therapeutic agents. One, two, three, four, or more additional therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents, and/or they may be therapeutic agents selected from different classes. In one specific embodiment, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with a nucleoside or nucleotide inhibitor of HIV reverse transcriptase and a non-nucleoside inhibitor of HIV reverse transcriptase. In another specific embodiment, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with a nucleoside or nucleotide inhibitor of HIV reverse transcriptase and an HIV protease inhibitory compound. In another embodiment, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with a nucleoside or nucleotide inhibitor of HIV reverse transcriptase, a non-nucleoside inhibitor of HIV reverse transcriptase, and an HIV protease inhibitory compound. In another embodiment, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with nucleoside or nucleotide inhibitors of HIV reverse transcriptase, non-nucleoside inhibitors of HIV reverse transcriptase, and pharmacokinetic enhancers. In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with at least one nucleoside inhibitor of HIV reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with two nucleoside or nucleotide inhibitors of HIV reverse transcriptase.

In a specific embodiment, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with one, two, three, four or more additional therapeutic agents selected from the group consisting of: raltegravir; (tenofovir disoproxil fumarate + emtricitabine; TDF + FTC); maraviroc; enfuvirtide; (abacavir sulfate + lamivudine; ABC + 3TC); (abacavir sulfate + zidovudine + lamivudine; ABC + AZT + 3TC ); Adefovir; Adefovir dipivoxil; (Elvitegravir + Cobicistat + Tenofovir Disoproxil Fumarate + Emtricitabine); Rilpivirine; Rilpivirine Hydrochloride; (Rilpivirine + Tenofovir Disoproxil Fumarate + Emtricitabine); Cobicistat; (Efavirenz + Tenofovir Disoproxil Fumarate + Emtricitabine); Atazanavir; Atazanavir Sulfate; Dolutegravir; Elvitegravir; (Lopinavir + Ritonavir); Ritonavir; Emtricitabine; Atazanavir Sulfate + Ritonavir; Darunavir; Lamivudine; Prolastin; Fosamprenavir; Fosamprenavir calcium; Efavirenz; (Zidovudine + Lamivudine; AZT + 3TC); Etravirine; Nelfinavir; Nelfinavir mesylate; Interferon; Didanosine; Stavudine; Indinavir; Indinavir sulfate; Tenofovir + Lamivudine; Zidovudine; Nevirapine; Saquinavir; Saquinavir mesylate; Aldesleukin; Zalcitabine; Tipranavir; Amprenavir; Delavirdine; Delavirdine mesylate; Radha-108 (Receptol); Hlviral; lamivudine + tenofovir disoproxil fumarate; efavirenz + lamivudine + tenofovir disoproxil fumarate; phosphazid; lamivudine + nevirapine + zidovudine; abacavir; abacavir sulfate; tenofovir; tenofovir disoproxil fumarate; tenofovir alafenamide and tenofovir alafenamide hemifumarate.

In a specific embodiment, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.

In a specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with tenofovir, tenofovir disoproxil, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.

In a specific embodiment, the compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent and a second additional therapeutic agent, the first additional therapeutic agent being selected from the group consisting of abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate; and the second additional therapeutic agent being selected from the group consisting of emtricitabine and lamivudine.

In a specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent and a second additional therapeutic agent, the first additional therapeutic agent being selected from the group consisting of tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate; wherein the second additional therapeutic agent is emtricitabine.

In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with 5-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate or tenofovir alafenamide and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with 5-10 mg, 5-15 mg, 5-20 mg, 5-25 mg, 25-30 mg, 20-30 mg, 15-30 mg or 10-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate or tenofovir alafenamide and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with 10 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate or tenofovir alafenamide and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 25 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of emtricitabine. The compounds disclosed herein (e.g., compounds of Formula (I)) can be combined with the agents disclosed herein at any dose of the compound (e.g., 10-500 mg of the compound) as each combination of doses is specifically listed individually.

In certain embodiments, compound disclosed herein or its pharmaceutically acceptable salt and 200-400mg tenofovir disoproxil fumarate, hemifumarate tenofovir disoproxil or tenofovir disoproxil and 200mg emtricitabine combination.In certain embodiments, compound disclosed herein or its pharmaceutically acceptable salt and 200-250mg, 200-300mg, 200-350mg, 250-350mg, 250-400mg, 350-400mg, 300-400mg or 250-400mg tenofovir disoproxil fumarate, hemifumarate tenofovir disoproxil or tenofovir disoproxil and 200mg emtricitabine combination.In certain embodiments, compound disclosed herein or its pharmaceutically acceptable salt and 300mg tenofovir disoproxil fumarate, hemifumarate tenofovir disoproxil or tenofovir disoproxil and 200mg emtricitabine combination. The compounds disclosed herein (eg, compounds of Formula (I)) may be combined with an agent disclosed herein at any dose of the compound (eg, 10-500 mg of compound) as specifically listed individually for each combination.

In certain embodiments, when the compounds disclosed herein are combined with one or more additional therapeutic agents as described above, the components of the composition are administered in a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more doses.

In certain embodiments, the compounds disclosed herein are combined with one or more additional therapeutic agents in a single dosage form that is administered simultaneously to a patient, for example, as a solid dosage form for oral administration.

In certain embodiments, the compounds disclosed herein are administered with one or more additional therapeutic agents. Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to the simultaneous or sequential administration of a compound disclosed herein and one or more additional therapeutic agents such that a therapeutically effective amount of the compound disclosed herein and one or more additional therapeutic agents are present in the patient's body.

Co-administration includes administering a unit dose of a compound disclosed herein before or after administering a unit dose of one or more additional therapeutic agents, such as administering a compound disclosed herein within seconds, minutes, or hours of administering one or more additional therapeutic agents. For example, in some embodiments, a unit dose of a compound disclosed herein is administered first, followed by administration of a unit dose of one or more additional therapeutic agents within seconds or minutes. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound disclosed herein within seconds or minutes. In some embodiments, a unit dose of a compound disclosed herein is administered first, followed by administration of a unit dose of one or more additional therapeutic agents after a period of time (e.g., 1-12 hours). In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound disclosed herein after a period of time (e.g., 1-12 hours).

In certain embodiments, methods for treating or preventing HIV infection in a human suffering from or at risk of infection are provided, comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents. In one embodiment, methods for treating HIV infection in a human suffering from or at risk of infection are provided, comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.

In one embodiment, a pharmaceutical composition is provided that comprises a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents and a pharmaceutically acceptable carrier, diluent, or excipient.

In certain embodiments, the present disclosure provides methods of treating HIV infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents suitable for treating HIV infection.

In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with one, two, three, four, or more additional therapeutic agents. In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with two additional therapeutic agents. In other embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with three additional therapeutic agents. In further embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with four additional therapeutic agents. The one, two, three, four, or more additional therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents, and/or they may be therapeutic agents selected from different classes.

Administration of HIV combination therapy

In certain embodiments, the compounds disclosed herein are administered together with one or more additional therapeutic agents. Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to the simultaneous or sequential administration of a compound disclosed herein and one or more additional therapeutic agents such that a therapeutically effective amount of the compound disclosed herein and one or more additional therapeutic agents are present in the patient's body. When administered sequentially, the combination can be administered in two or more doses.

Co-administration includes administering a unit dose of a compound disclosed herein before or after administering a unit dose of one or more additional therapeutic agents. For example, a compound disclosed herein can be administered within seconds, minutes, or hours of administering one or more additional therapeutic agents. In some embodiments, a unit dose of a compound disclosed herein is first administered, and then a unit dose of one or more additional therapeutic agents is administered within seconds or minutes. Alternatively, a unit dose of one or more additional therapeutic agents is first administered, and then a unit dose of a compound disclosed herein is administered within seconds or minutes. In other embodiments, a unit dose of a compound disclosed herein is first administered, and then, after a period of time (e.g., 1-12 hours), a unit dose of one or more additional therapeutic agents is administered. In other embodiments, a unit dose of one or more additional therapeutic agents is first administered, and then, after a period of time (e.g., 1-12 hours), a unit dose of a compound disclosed herein is administered.

In certain embodiments, the compounds disclosed herein are combined with one or more additional therapeutic agents in a single dosage form that is administered simultaneously to a patient, for example, as a solid dosage form for oral administration.

In certain embodiments, the compound of formula (I) is formulated into a tablet, which may optionally contain one or more other compounds for the treatment of HIV. In certain embodiments, the tablet may contain another active ingredient for the treatment of HIV, such as an HIV protease inhibitor, a non-nucleoside or non-nucleotide inhibitor of HIV reverse transcriptase, a nucleoside or nucleotide inhibitor of HIV reverse transcriptase, an HIV integrase inhibitor, an HIV non-catalytic site (or allosteric) integrase inhibitor, a pharmacokinetic enhancer, and combinations thereof.

In certain embodiments, such tablets are suitable for once-daily administration.

HIV combination therapy

In the above embodiments, the additional therapeutic agent can be an anti-HIV agent. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of: a combination drug for HIV; other drugs for the treatment of HIV; HIV protease inhibitors; non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase; nucleoside or nucleotide inhibitors of HIV reverse transcriptase; HIV integrase inhibitors; HIV non-catalytic site (or allosteric) integrase inhibitors; HIV entry inhibitors; HIV maturation inhibitors; potential reversal agents; compounds targeting HIV capsid; immune-based therapies; phosphatidylinositol 3-kinase (PI3K) inhibitors; HIV antibodies; bispecific antibodies and "antibody-like" therapeutic proteins; HIV p17 matrix protein inhibitors; IL-13 antagonists; peptidyl-prolyl cis-trans isomerase A modulators; protein disulfide isomerase inhibitors; complement C5a receptor antagonists; DNA methyltransferase inhibitors; HIV vif gene modulators; Vif dimerization antagonists; HIV-1 viral infectious factor inhibitors; TAT protein inhibitors; HIV-1 Nef modulators; Hck tyrosine kinase modulators; mixed lineage kinase-3 (MLK-3) inhibitors; HIV-1 splicing inhibitors; Rev protein inhibitors; integrin antagonists; nuclear protein inhibitors; splicing factor regulators; COMM domain-containing protein 1 regulators; HIV ribonuclease H inhibitors; retrocyclin modulators; CDK-9 inhibitors; dendritic ICAM-3 grasping non-integrin 1 inhibitors; HIV GAG protein inhibitors; HIV Pol protein inhibitors; complement factor H regulators; ubiquitin ligase inhibitors; deoxycytidine kinase inhibitors; cyclin-dependent protein kinase inhibitors; proprotein convertase PC9 stimulators; ATP-dependent RNA helicase DDX3X inhibitors; reverse transcriptase initiation complex inhibitors; G6PD and NADH-oxidase inhibitors; pharmacokinetic enhancers; HIV gene therapy agents; HIV vaccines; and combinations thereof.

HIV combination drugs

Examples of combination drugs include: (efavirenz, tenofovir disoproxil fumarate, emtricitabine); (rilpivirine, tenofovir disoproxil fumarate, emtricitabine); (elvitegravir, cobicistat, tenofovir disoproxil fumarate, emtricitabine); (tenofovir disoproxil fumarate, emtricitabine; TDF+FTC); darunavir, tenofovir alafenamide hemifumarate, emtricitabine and cobicistat; efavirenz, lamivudine and Tenofovir disoproxil fumarate; Lamivudine and tenofovir disoproxil fumarate; Tenofovir and lamivudine; Tenofovir alafenamide and emtricitabine; Tenofovir alafenamide, emtricitabine and rilpivirine; Tenofovir alafenamide hemifumarate and emtricitabine; Tenofovir alafenamide hemifumarate, emtricitabine and rilpivirine; Tenofovir alafenamide hemifumarate, emtricitabine, cobicistat and elvitegravir; (zidovudine and lamivudine; AZT+3TC); (abacavir sulfate and lamivudine; ABC+3TC); (lopinavir and ritonavir); (dolutegravir, abacavir and lamivudine); (abacavir sulfate, zidovudine and lamivudine; ABC+AZT+3TC); atazanavir and cobicistat; atazanavir sulfate and cobicistat; atazanavir sulfate and ritonavir; darunavir and cobicistat; dolutegravir, abacavir and lamivudine; (abacavir sulfate, zidovudine and lamivudine; ABC+AZT+3TC); atazanavir and cobicistat; atazanavir sulfate and cobicistat; atazanavir sulfate and ritonavir; darunavir and cobicistat; dolutegravir lutelutegravir and rilpivirine; dolutegravir and rilpivirine hydrochloride; dolutegravir, abacavir sulfate, and lamivudine; lamivudine, nevirapine, and zidovudine; raltegravir and lamivudine; doravirine, lamivudine, and tenofovir disoproxil fumarate; doravirine, lamivudine, and tenofovir disoproxil fumarate; lopinavir, ritonavir, zidovudine, and lamivudine; Vacc-4x and romidepsin; and APH-0812.

Other HIV drugs

Examples of other drugs used to treat HIV include acetomorph, alisporivir, BanLec, deferiprone, Gamimune, metenkefalin, naltrexone, Prolastin, REP9, RPI-MN, VSSP, H1viral, SB-728-T, 1,5-dicaffeoylquinic acid, rHIV7-shl-TAR-CCR5RZ, AAV-eCD4-Ig gene therapy, MazF gene therapy, BlockAide, ABX-464, AG- 1105, BIT-225, CYT-107, HGTV-43, HS-10234, IMO-3100, IND-02, MK-1376, MK-8507, MK-8591, NOV-205, PA-105004 0(PA-040), PGC-007, SCY-635, TR-452, TEV-90110, TEV-90112, TEV-90111, TEV-90113, RN-18, Immuglo and VIR-576.

HIV protease inhibitors

Examples of HIV protease inhibitors include amprenavir, atazanavir, brecanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir, saquinavir mesylate, tipranavir, DG-17, TMB-657 (PPL-100), T-169, and TMC-310911.

HIV reverse transcriptase inhibitors

Examples of non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase include dapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz, etravirine, lentinan, nevirapine, ritavirine, AIC-292, KM-023, and VM-1500.

Examples of nucleoside or nucleotide inhibitors of HIV reverse transcriptase include adefovir, adefovir dipivoxil, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, and VIDEX (didanosine, ddl), abacavir, abacavir sulfate, alovudine, aprecitabine, sensavudine, didanosine, elvucitabine, festalavir, fosalvudine tidoxil, fozivudine tidoxil, lamivudine, phosphazid, stavudine, zalcitabine, zidovudine, and KP-1461.

HIV integrase inhibitors

Examples of HIV integrase inhibitors include elvitegravir, curcumin, curcumin derivatives, chicoric acid, chicoric acid derivatives, 3,5-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid derivatives, aurintricarboxylic acid, aurintricarboxylic acid derivatives, caffeic acid phenethyl ester, caffeic acid phenethyl ester derivatives, tyrosine phosphorylation inhibitors, tyrosine phosphorylation inhibitor derivatives, quercetin, quercetin derivatives, raltegravir, dolutegravir, JTK-351, and cabotegravir.

Examples of HIV non-catalytic site or allosteric integrase inhibitors (NCINIs) include CX-05045, CX-05168, T-169, and CX-14442.

HIV entry inhibitors

Examples of HIV entry (fusion) inhibitors include cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 attachment inhibitors, gpl20 inhibitors, and CXCR4 inhibitors.

Examples of CCR5 inhibitors include aplaviroc, vicriviroc, maraviroc, cenicriviroc, PRO-140, adaptavir (RAP-101), nifeviroc (TD-0232), TD-0680, and vMIP (Haimipu).

Examples of gp41 inhibitors include abavita, enfuvirtide, and sifuvirtide.

Examples of CD4 attachment inhibitors include ibalizumab.

Examples of gpl20 inhibitors include Radha-108 (receptol) and BMS-663068.

Examples of CXCR4 inhibitors include plerixafor and vMIP (Haimipu).

HIV maturation inhibitors

Examples of HIV maturation inhibitors include BMS-955176 and GSK-2838232.

Potential reversal agents

Examples of potential reversing agents include histone deacetylase (HDAC) inhibitors, proteasome inhibitors such as serine proteases, protein kinase C (PKC) activators, BET-bromodomain 4 (BRD4) inhibitors, ionomycin, PMA, SAHA (simvatidine hydroxamic acid or suberanilohydroxamic acid), IL-15, JQ1, disulfram, amphotericin B, and GSK-343.

Examples of HDAC inhibitors include romidepsin, vorinostat, and panobinostat.

Examples of PKC activators include Indolactam, Prostratin, IngenolB, and DAG-lactone.

Capsid inhibitors

Examples of capsid inhibitors include capsid polymerization inhibitors or capsid disrupting compounds, HIV nucleocapsid p7 (NCp7) inhibitors such as azodicarbonamide, and HIV p24 capsid protein inhibitors.

Immune-based therapeutics

Examples of immune-based therapeutics include: toll-like receptor modulators such as tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12, and tlr13; programmed cell death protein 1 (PD-1) modulators; programmed death ligand 1 (PD-L1) modulators; IL-15 agonists; DermaVir; interleukin-7; chloroquine (hydroxychloroquine); adenovirus; Interleukin (aldesleukin; IL-2); interferon alpha; interferon alpha-2b; interferon alpha-n3; pegylated interferon alpha; interferon gamma; hydroxyurea; mycophenolate mofetil (MPA) and mycophenolate mofetil ester derivatives (MMF); ribavirin; polymer polyethyleneimine (PEI); Gepon; radamacin; IL-12; WF-10; VGV-1; MOR-22; GS-9620; BMS-936559; and IR-103.

Phosphatidylinositol 3-kinase (PI3K) inhibitors

Examples of PI3K inhibitors include itrazole, alpelisib, buparizole, CAI orotic acid, copanlisib, duvelisib, gedatolisib, neratinib, panulisib, perifosine, pictilisib, pilaralisib, rigosertib, rigosertib sodium, sonolisib, taselisib, AMG-319, AZD-8186, BAY-1082439, CLR-14 01. CLR-457, CUDC-907, DS-7423, EN-3342, GSK-2126458, GSK-2269577, GSK-2636771, INCB-040093, LY-3023414, MLN-1117, PQR-309, RG-7666, RP-6530, RV-1729, SAR-245409, SAR-260301, SF-1126, TGR-1202, UCB-5857, VS-5584, XL-765 and ZSTK-474.

HIV antibodies, bispecific antibodies, and “antibody-like” therapeutic proteins

Examples of HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins include Fab derivatives, BMS-936559, TMB-360, and those targeting HIV gpl20 or gp41.

Examples of those targeting HIV gpl20 or gp41 include baviximab, UB-421, C2F5, C2G12, C4E10, C2F5+C2G12+C4E10, 3-BNC-117, PGT145, PGT121, MDX010 (ipilimumab), VRC01, A32, 7B2, 10E8, VRC-07-523, MGD-014, and VRC07.

Pharmacokinetic enhancers

Examples of pharmacokinetic enhancers include cobicistat and ritonavir.

Additional therapeutic agents

Examples of additional therapeutic agents include WO2004/096286 (Gilead Sciences), WO2006/015261 (Gilead Sciences), WO2006/110157 (Gilead Sciences), WO2012/003497 (GileadSciences), WO2012/003498 (Gilead Sciences) Sciences), WO2012/145728 (Gilead Sciences), WO2013/006738 (Gilead Sciences), WO2013/159064 (Gilead Sciences), WO2014/100323 (Gilead Sciences), US2013/0165489 (University of Pennsylvania), US2014/0221378 (Japan Tobacco)、US2014/0221380(Japan Tobacco), WO2009/062285 (Boehringer Ingelheim), WO2010/130034 (Boehringer Ingelheim), WO2013/006792 (Pharma Resources), US20140221356 (Gilead Sciences), WO2013/091096 (Boehringer Ingelheim) and US20100143301 (Gilead Sciences).

HIV vaccine

Examples of HIV vaccines include peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, CD4-derived peptide vaccines, vaccine combinations, rgp120 (AIDSVAX), ALVAC HIV (vCP1521)/AIDSVAX B/E (gp120) (RV144), monomeric gp120 HIV-1 subtype C vaccine, Remune, ITV-1, Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401), Vacc-4x, Vacc-C5, VAC-3S, multiple DNA group adenovirus-5 (rAd5), Pennvax-G, Pennvax-GP, VRC-HIV MAB060-00-AB, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3/VSSP ISA-51, multi-ICLC adjuvant vaccine, TatImmune, GTU-multi-HIV (FIT-06), gp140[δ]V2.TV1+MF-59, rVSVIN HIV-1 gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, ad35-Grin/ENV, TBC-M4, HIVAX, HIVAX-2, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, rAAV1-PG9DP, GOVX-B11, GOVX-B21, TVI-HIV-1, Ad-4 (Ad4-env Clade C+ad4-mGag), EN41-UGR7C, EN41-FPA2, PreVaxTat, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR, DNA-Ad5gag/pol/nef/nev(HVTN505), MVATG-17401, ETV-01, CDX-1401, rcAD26.MOS1.HIV-Env, Ad26.Mod.HIV vaccine, AGS-004, AVX-101, AVX-201, PEP-6409, SAV-001, ThV-01, TL-01, TUTI-16, VGX-3300, IHV-001 and virus-like particle vaccines such as pseudovirion vaccines.

HIV combination therapy

In a specific embodiment, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with one, two, three, four or more additional therapeutic agents selected from (efavirenz, tenofovir disoproxil fumarate and emtricitabine); (rilpivirine, tenofovir disoproxil fumarate and emtricitabine); (elvitegravir, cobicistat, tenofovir disoproxil fumarate and emtricitabine); (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); adefovir; adefovir disoproxil; cobicistat; emtricitabine Tadalafil; Tenofovir; Tenofovir disoproxil; Tenofovir disoproxil fumarate; Tenofovir alafenamide; Tenofovir alafenamide hemifumarate; (Dolutegravir, Abacavir, and Lamivudine); Dolutegravir, Abacavir Sulfate, and Lamivudine; Raltegravir; Raltegravir and Lamivudine; Maraviroc; Enfuvirtide; (Lopinavir and Ritonavir); (Zidovudine and Lamivudine; AZT+3TC); (Abacavir Sulfate and Lamivudine; ABC+3TC); (Abacavir Sulfate, Zidovudine, and Lamivudine) Rilpivirine; ABC+AZT+3TC); Rilpivirine; Rilpivirine hydrochloride; Atazanavir sulfate and cobicistat; Atazanavir and cobicistat; Darunavir and cobicistat; Atazanavir; Atazanavir sulfate; Dolutegravir; Elvitegravir; Ritonavir; Atazanavir sulfate and ritonavir; Darunavir; Lamivudine; Prolastin; Fosamprenavir; Fosamprenavir calcium; Efavirenz; Etravirine; Nelfinavir; Nelfinavir mesylate; Interferon; Didanosine; Stavudine; Indinavir; Sulfur Indinavir disoproxil fumarate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir; delavirdine; delavirdine mesylate; Radha-108 (receptol); Hlviral; lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovir disoproxil fumarate; phosphazid; lamivudine, nevirapine, and zidovudine; abacavir; and abacavir sulfate.

In a specific embodiment, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with a nucleoside or nucleotide inhibitor of HIV reverse transcriptase and a non-nucleoside inhibitor of HIV reverse transcriptase. In another specific embodiment, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with a nucleoside or nucleotide inhibitor of HIV reverse transcriptase and an HIV protease inhibitory compound. In another embodiment, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with a nucleoside or nucleotide inhibitor of HIV reverse transcriptase, a non-nucleoside inhibitor of HIV reverse transcriptase, and a pharmacokinetic enhancer. In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with at least one nucleoside inhibitor of HIV reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with two nucleoside or nucleotide inhibitors of HIV reverse transcriptase.

In a specific embodiment, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.

In a specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.

In a specific embodiment, the compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent and a second additional therapeutic agent, the first additional therapeutic agent being selected from the group consisting of abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate; and the second additional therapeutic agent being selected from the group consisting of emtricitabine and lamivudine.

In a specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent and a second additional therapeutic agent, the first additional therapeutic agent being selected from the group consisting of tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate; wherein the second additional therapeutic agent is emtricitabine.

The compounds disclosed herein (eg, any compound of Formula (I)) can be combined with one or more additional therapeutic agents at any dose of the compound of Formula (I) (eg, 50-1000 mg of the compound).

In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with 5-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate or tenofovir alafenamide and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with 5-10 mg, 5-15 mg, 5-20 mg, 5-25 mg, 25-30 mg, 20-30 mg, 15-30 mg or 10-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate or tenofovir alafenamide and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with 10 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate or tenofovir alafenamide and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 25 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of emtricitabine. The compounds disclosed herein (e.g., compounds of Formula (I)) can be combined with the agents disclosed herein at any dose of the compound (e.g., 10-500 mg of the compound) as each combination of doses is specifically listed individually.

In certain embodiments, compound disclosed herein or its pharmaceutically acceptable salt and 200-400mg tenofovir disoproxil fumarate, hemifumarate tenofovir disoproxil or tenofovir disoproxil and 200mg emtricitabine combination.In certain embodiments, compound disclosed herein or its pharmaceutically acceptable salt and 200-250mg, 200-300mg, 200-350mg, 250-350mg, 250-400mg, 350-400mg, 300-400mg or 250-400mg tenofovir disoproxil fumarate, hemifumarate tenofovir disoproxil or tenofovir disoproxil and 200mg emtricitabine combination.In certain embodiments, compound disclosed herein or its pharmaceutically acceptable salt and 300mg tenofovir disoproxil fumarate, hemifumarate tenofovir disoproxil or tenofovir disoproxil and 200mg emtricitabine combination. The compounds disclosed herein (eg, compounds of Formula (I)) may be combined with an agent disclosed herein at any dose of the compound (eg, 10-500 mg of compound) as specifically listed individually for each combination of doses.

In one embodiment, kits are provided that include a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.

Kits and Products

The present disclosure relates to a kit comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. The kit may also include instructions for use, for example, for inhibiting HIV reverse transcriptase (e.g., for treating HIV infection or AIDS) or as a research tool. Instructions for use are typically written instructions, although electronic storage media (e.g., magnetic disks or optical disks) containing instructions are also acceptable.

The present disclosure also relates to a pharmaceutical kit comprising one or more containers comprising any compound of formula (I) or a pharmaceutically acceptable salt thereof. Alternatively, associated with this container may be a notification of a form prescribed by a government agency managing the manufacture, use or sale of the drug, which notification reflects the approval of the agency managing the manufacture, use or sale of the drug for human use. Each component (if multiple components) may be packaged in a separate container, or some components may be combined in a container allowing cross-reactivity and shelf life. The kit may be in unit dose form, bulk packaging (e.g., multi-dose packaging) or subunit dose. The kit may also include a compound and instructions for use of multiple unit doses, and packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and dispensing pharmacies).

Also disclosed are articles of manufacture suitably packaged for use in the methods described herein, comprising a unit dose of any compound of Formula (I) or a pharmaceutically acceptable salt thereof. Suitable packaging is known in the art and includes, for example, vials, containers, ampoules, bottles, jars, flexible packaging, and the like. The articles of manufacture may be further sterilized and/or sealed.

The present disclosure also relates to processes and intermediates that can be used to prepare the compounds of the present invention or pharmaceutically acceptable salts thereof.

Numerous general references are available that provide conventionally known chemical synthesis protocols and conditions for synthesizing the disclosed compounds (see, for example, Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th ed., Wiley-Interscience, 2013). Angew. Chem. Int. Ed. 2014, 53, 2-21, the entire contents of which are incorporated herein by reference, provides a review of sulfur (VI) fluoride exchange that can also be used in the synthesis protocols.

The compounds described herein can be purified by any method known in the art, including chromatography, such as high performance liquid chromatography (HPLC), preparative thin layer chromatography, flash column chromatography, and ion exchange chromatography. Any suitable stationary phase can be used, including normal and reverse phase and ionic resins. Most commonly, the disclosed compounds are purified by silica gel and/or alumina chromatography. See, for example, Introduction to Modern Liquid Chromatography, 2nd Edition, ed. L.R. Snyde Rand J.J. Kirkland, John Wiley and Sons, 1979 and Thin Layer Chromatography, E. Stahl (ed.), Springer-Verlag, New York, 1969.

During any of the processes for preparing the compounds of the invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by conventional protecting groups as described in standard works, for example, TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis," 4th edition, Wiley, New York 2006. The protecting groups may be removed at a convenient subsequent stage using methods known in the art.

Exemplary chemical entities in the methods for the embodiments will now be described by reference to the exemplary synthetic schemes and specific examples that follow for their general preparation herein. It will be appreciated by those skilled in the art that, in order to obtain the various compounds herein, the starting materials can be appropriately selected so that the final desired substituent will be carried through an appropriate reaction scheme with or without protection to produce the desired product. Alternatively, it is necessary and desirable to replace the final desired substituent with a group that can be carried through the reaction scheme and suitably substituted by the desired substituent. In addition, it will be appreciated by those skilled in the art that the conversions shown in the following schemes can be performed in any order compatible with the functionality of the particular side groups. Each reaction described in the general scheme is preferably carried out at a temperature of about 0°C to the reflux temperature of the organic solvent used. Unless otherwise indicated, the variables are as defined above with reference to formula (I).

Representative syntheses of compounds of the present disclosure are described in the following schemes and in the specific examples that follow.

A representative synthesis of compounds of the embodiments is shown in Scheme 1. This approach is compatible with a wide variety of functional groups.

Solution 1

For the compounds and intermediates of Scheme 1 (e.g., compounds 1-A, 1-B, 1-C, 1-D, 1-E, 1-F, and Formula 1), the values of X, Y, A, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , and n are as disclosed herein for Formula 1. R ^I , R ^II , and R ^III are described below. Starting materials can be obtained from commercial sources or by recognized synthetic procedures.

In Scheme 1, a compound of Formula 1-A is converted to a compound of Formula 1-B by reaction with triphenylphosphine under appropriate conditions, wherein, in certain embodiments, R ^I is halogen or -OC _1-6 alkyl and R ^II is C _1-6 alkyl.

The compound of Formula 1-B is reacted with an isocyanate under suitable conditions, for example, in a suitable solvent such as THF at room temperature. The reaction is then heated to reflux in the presence of ammonia to provide a compound of Formula 1-C.

When ^R is -OC _1-6 alkyl, the compound of formula 1-C is converted to the compound of formula 1-D by halogenation. It should be understood that when ^R is halogen, this conversion of the group is not required. Suitable halogenation conditions include reaction with a halogenating agent such as phosphorus oxychloride.

The compound of Formula 1-D can be converted to the compound of Formula 1-E under appropriate reaction conditions, which vary depending on the nature of ^R. For example, when R _is ^-NH , the reaction of the compound of Formula 1-D with ammonia under appropriate conditions yields the compound of Formula 1-E.

The compound of Formula 1-E can be coupled with an intermediate to form a compound of Formula 1. In some embodiments, the compound of Formula 1-E is reacted with a boronic acid (each R ^III is H) or a boronic ester (each R ^III is C _1-6 alkyl or together form a cyclic boronic ester) of Formula 1-F. In some embodiments, the reaction is carried out in the presence of a suitable base (e.g., tripotassium phosphate) and a suitable palladium-based reagent (e.g., 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride).

The above compounds and intermediates can be separated by methods known to those skilled in the art. In addition, it should be understood that each of the compounds of Formula 1-A, 1-B, 1-C, 1-D, 1-E and 1-F can be prepared by alternative routes or methods that do not change the disclosure of this application. For example, the compound of Formula 1-A wherein R ¹ is halogen can be prepared according to Scheme 2.

Option 2

In Scheme 2, the compound of Formula 2-A is halogenated under suitable conditions to form the compound of Formula 1-A, wherein R ¹ is halogen. In certain embodiments, the compound of Formula 2-A is dissolved in a suitable solvent (eg, aqueous acetic acid) and reacted with bromine (Br ₂ ) to obtain the compound of Formula 1-A.

Additionally, compounds of Formula 1-F (Scheme 1) can be prepared according to Scheme 3.

Option 3

In Scheme 3, the compound of formula 3-A is converted to a compound of formula 3-B. In certain embodiments, Hal is Br. In certain embodiments, 3-A is coupled with acrylonitrile under suitable conditions. In certain embodiments, the coupling is carried out in the presence of a suitable base (e.g., triethylamine) in the presence of a palladium reagent (e.g., palladium (II) acetate) and a phosphine reagent (e.g., tri(o-tolyl)phosphine). The compound of formula 3-B can be further reacted with a suitable borane reagent to form a compound of formula 1-F. In certain embodiments, the reaction is carried out in the presence of a suitable palladium reagent (e.g., palladium (II) acetate), a suitable base (e.g., potassium carbonate), and a suitable phosphine reagent (e.g., dicyclohexyl (2', 6'-dimethoxy-[1,1'-biphenyl]-2-yl) phosphine). In certain embodiments, the borane reagent is a borane ester (e.g., 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-(1,3,2-dioxaborolane)).

In some cases, the above methods also involve the step of forming a salt of the compounds of the present disclosure.The embodiments relate to other methods described herein; and products prepared by any of the methods described herein.

Unless otherwise indicated, the methods and techniques of the present disclosure are generally performed according to conventional methods well known in the art and as described in various general and more specific references cited and discussed throughout the present specification. See, for example, Loudon, OrganiCChemistry, 5th ed., New York: Oxford University Press, 2009; Smith, March's Advanced OrganiCChemistry: Reactions, Mechanisms, and Structure, 7th ed., Wiley-Interscience, 2013.

List of abbreviations and acronyms

Abbreviation-Meaning

Ac-acetyl

B2pin ₂ -4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-(1,3,2-dioxaborolane)

bs-wide single peak

℃-Celsius

d-doublet

DCM-dichloromethane

dd-double double peaks

DIPEA-N,N-diisopropylethylamine

DMF-N,N-dimethylformamide

DMSO-dimethyl sulfoxide

dppf-1,1'-bis(diphenylphosphino)ferrocene

dtbpf-1,1'-bis(di-tert-butylphosphino)ferrocene

_EC50 - half maximal effective concentration

Equiv/eq-equivalent

Et-ethyl

EtOH-ethanol

g-gram

HPLC-High Performance Liquid Chromatography

hrs/H-hours

Hz-Hertz

J-coupling constant

LCMS-Liquid Chromatography-Mass Spectrometry

M-Moore

m-multiplet

m/z - mass-to-charge ratio

M+-mass peak

Me-methyl

mg-milligram

MHz-Megahertz

min-minutes

mL-milliliter

mM - millimolar

mm-millimeter

mmol-millimolar

mol-mole

MS-Mass Spectrometry

MW-Microwave

nM-nanomolar

NMP-N-methyl-2-pyrrolidone

NMR - Nuclear Magnetic Resonance

P(oTol) ₃ -tri(o-tolyl)phosphine

q-quartet

quant

Rf - retention factor

RT/rt/r.t.-room temperature

s-singlet

sat.–saturated

SPhos-dicyclohexyl(2',6'-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine

t-triplet

TFA-trifluoroacetic acid

TMS-trimethylsilyl

Tr/tr-retention time

UV-Ultraviolet

wt.-weight

δ-chemical shift

μL - microliter

μM - micromolar

μmol-micromole

The following examples are illustrative only and are not intended to limit the present disclosure in any way. Unless otherwise indicated, preparative HPLC was performed on a Gilson HPLC system using a 21.2×250 mm 10-micron C18 Phenomenex Gemini semi-preparative column and an acetonitrile/water mobile phase containing 0.1% trifluoroacetic acid at a flow rate of 20 mL/min.

The chemical names of all prepared compounds were generated using ChemBioDraw 12.0 software.

The following methods were used to purify and characterize certain compounds described in the following examples.

LCMS method 1 - Kinetex 2.6μ C18100A, 50×3.00 mm column; acetonitrile containing 0.1% formic acid, water containing 0.1% formic acid; gradient: 0 min-1.4 min 2-100% ACN, 1.4 min-1.8 min 100% ACN, 1.8 min-1.85 min 100-2% ACN, 1.85 min-2 min 2% ACN; flow rate 1.8 mL/min.

LCMS method 2 - Kinetex 2.6μ C18100A, 50×3.00 mm column; acetonitrile containing 0.1% formic acid, water containing 0.1% formic acid; gradient: 0 min-1.5 min 2-100% ACN, 1.5 min-2.8 min 100% ACN, 2.8 min-2.85 min 100%-2% ACN, 2.85 min-3 min 2% ACN; flow rate 1.8 mL/min.

LCMS method 3 - Gemini 5μ 50×4.60 mm 5 micron column; acetonitrile containing 0.1% acetic acid, water containing 0.1% acetic acid; gradient: 0 min-3.5 min 5-100% ACN; flow rate 2 mL/min.

LCMS Method 4 - Phenomenex Gemini-NX3μ 100×2 mm 3 micron column, acetonitrile containing 0.1% formic acid, water containing 0.1% formic acid; 0-100% ACN from 0 min to 7.0 min, flow rate 0.5 mL/min.

Example 1

(E)-4-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)benzonitrile compound 1

Step 1: Synthesis of methyl 3-amino-2-methoxyisonicotinate (Compound 1a)

To a solution of 3-amino-2-methoxyisonicotinic acid (5.0 g, 29.7 mmol, Ark Pharm, Inc.-AK-39940) in dichloromethane (45 mL) and methanol (5 mL) was added a 2.0 M solution of trimethylsilyldiazomethane in hexane (44.6 mL, 89.2 mmol) at 0°C. After the addition was complete, the reaction was quenched with water. The reaction mixture was extracted with dichloromethane. The organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford compound 1a. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.29 (d, J=5.6 Hz, 1H), 7.11 (d, J=5.6 Hz, 1H), 6.45 (bs, 2H), 3.89 (s, 3H), 3.80 (s, 3H). LCMS (m/z) 183.0 [M+H], TR=1.21 min (LCMS method 1).

Step 2: Synthesis of methyl 2-methoxy-3-((triphenylphosphoranylidene)-amino)isonicotinate (Compound 1b)

At 0 ° C, a solution of triphenylphosphine (11.52 g, 43.9 mmol) in dichloromethane (200 mL) was slowly treated with bromine (2.25 mL, 43.9 mmol). The resulting reaction mixture was stirred at 0 ° C for 5 minutes, then treated with triethylamine (12.2 mL, 87.8 mmol), and compound 1a (4.00 g, 22.0 mmol) was immediately added. The cooling bath was removed and the reaction mixture was stirred at 25 ° C for 3 days. The reaction was quenched with water. The layers were separated, and the organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of isohexane/ethyl acetate from 9: 1 to 1: 1 to obtain title compound 1b. ¹ HNMR (400MHz, DMSO-d ₆ )δ7.73–7.46(m,15H),7.31(d,J＝5.2Hz,1H),6.90(d,J＝5.2Hz,1H),3.81(s,3H),3.14(s,3H).LCMS(m/z)443.3[M+H],TR＝1.44min (LCMS method 1).

Step 3: Synthesis of 4-((8-methoxy-4-oxo-3,4-dihydropyrido[3,4-d]pyrimidin-2-yl)amino)benzonitrile (Compound 1c)

To a solution of compound 1b (1500 mg, 3.39 mmol) in tetrahydrofuran (10 mL) was added 4-isocyanatobenzonitrile (538 mg, 3.73 mmol, Sigma-Aldrich) at room temperature, and the reaction mixture was stirred for 1 hour [LCMS (m/z) 326.9 [M+H+water], TR = 1.19 min (LCMS Method 2)]. 2M ammonia in isopropanol (10 mL, 20 mmol) was added, and the reaction mixture was heated to reflux for 18 hours and then concentrated under reduced pressure. The residue was purified by silica gel chromatography using a gradient of isohexane/ethyl acetate from 20:1 to 1:1 to give the title compound 1c. LCMS (m/z) 294.1 [M+H], TR = 1.54 min (LCMS Method 2).

Step 4: Synthesis of 4-((4,8-dichloropyrido[3,4-d]pyrimidin-2-yl)amino)benzonitrile (Compound 1d)

Compound 1c (300 mg, 0.98 mmol) was dissolved in phosphorus oxychloride (5 mL). The reaction was heated to reflux for 18 hours. The reaction was cooled and then concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane and concentrated under reduced pressure to provide crude compound 1d. LCMS (m/z) 316.0 [M+H], TR = 2.09 min (LCMS method 2).

Step 5: Synthesis of 4-((4-amino-8-chloropyrido[3,4-d]pyrimidin-2-yl)amino)benzonitrile (Compound 1e)

Crude compound 1d (323 mg, 1.02 mmol) was added to a 2M solution of ammonia in isopropanol (2.55 mL, 5.10 mmol) in a sealed microwave container. The reaction was heated to 150°C by microwave for 4 hours. The product precipitated from the solution and was collected by filtration. The solid was washed sequentially with water and cold ethanol to give compound 1e. ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.24 (d, J = 8.7 Hz, 1H), 8.11 (s, 1H), 7.70 (d, J = 8.7 Hz, 1H), 7.22–6.95 (m, 4H). LCMS (m/z) 297.1 [M+H], TR = 1.75 min (LCMS method 2).

Step 6: Synthesis of (E)-3-(4-bromo-3,5-dimethylphenyl)acrylonitrile (Compound 1f)

To a solution of 2,5-dibromo-1,3-dimethylbenzene (2640 mg, 10 mmol, Oakwood Products, Inc.-018507) in anhydrous acetonitrile (25 mL) was added palladium (II) acetate (112 mg, 0.5 mmol), acrylonitrile (531 mg, 10 mmol), tri(o-tolyl)phosphine (131 mg, 0.5 mmol) and triethylamine (4 mL, 30 mmol), and the mixture was purged with argon and heated at 110 ° C for 2 hours. The reaction mixture was filtered through celite and the filter pad was washed with tetrahydrofuran (10 mL). The filtrate was evaporated and then redissolved with ethyl acetate (50 mL). The solution was washed with water (50 mL). The aqueous layer was stripped with ethyl acetate (50 mL). The combined organics were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a crude residue. Silica gel chromatography (0-20% ethyl acetate in isohexane gradient) afforded the crude product, which was treated with hexanes (10 mL) in a sonic bath for 10 minutes. The product precipitated from solution and was collected by filtration. The solid was washed with cold hexanes to afford compound 1f. ^1H NMR (400 MHz, CDCl ₃ ) δ 7.25 (d, J = 16.6 Hz, 1H), 7.12 (s, 2H), 5.84 (d, J = 16.6 Hz, 1H), 2.42 (s, 6H). LCMS (m/z) revealed no MS signal, TR = 2.78 min (LCMS Method 3).

Step 7: Synthesis of (E)-3-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylonitrile (Compound 1g)

A mixture of compound 1f (391 mg, 1.66 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-di-(1,3,2-dioxaborolane) (630 mg, 2.48 mmol), potassium carbonate (687 mg, 5 mmol), palladium (II) acetate (19 mg, 0.08 mmol) and dicyclohexyl (2', 6'-dimethoxy-[1,1'-biphenyl]-2-yl) phosphine (SPhos, 85 mg, 0.21 mmol) in dry N, N-dimethylformamide (20 mL) was purged with argon and heated at 100 ° C for 1 hour. The reaction mixture was filtered through celite and the filter pad was washed with tetrahydrofuran (10 mL). The filtrate was evaporated and then redissolved with ethyl acetate (50 mL). The solution was washed with water (50 mL). The aqueous layer was back-extracted with ethyl acetate (50 mL). The combined organics were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a crude residue which was purified by silica gel chromatography (0-20% ethyl acetate in isohexane gradient) to give compound 1g. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.28 (d, J=16.6 Hz, 1H), 7.00 (s, 2H), 5.84 (d, J=16.6 Hz, 1H), 2.39 (s, 6H), 1.37 (s, 12H). LCMS (m/z) 284.3 [M+H], TR=2.85 min (LCMS method 3).

Step 8: (E)-4-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)pyrido[3,4-d]pyrimidin-2-yl)amino)benzonitrile (Compound 1)

Compound 1e (150 mg, 0.54 mmol), compound 1g (229 mg, 0.81 mmol), tripotassium phosphate (172 mg, 0.81 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocenedichloropalladium (35 mg, 0.05 mmol) were dissolved in a dimethylformamide:water mixture (80:20, 5 mL). The reaction mixture was heated to 80 ° C for 2 hours. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated under reduced pressure and then purified by reverse phase chromatography (20-60% acetonitrile in water, 0.1% trifluoroacetic acid) to obtain the TFA salt of compound 1. ¹ HNMR (400MHz, DMSO-d ₆ )δ9.68(s,1H),8.48(d,J＝5.4Hz,1H),8.07(d,J＝5.4Hz,1H),7.76–7.69(m,3H),7.50(s,2H),7.34(d , J=8.5Hz, 2H), 6.54 (d, J=16.7Hz, 1H), 1.89 (s, 6H). LCMS (m/z) 418.4[M+H], TR=1.41min (LCMS method 1).

Example 2

(E)-4-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)pyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile - Compound 2

Step 1: Synthesis of 4-amino-5-bromonicotinic acid (Compound 2a)

A mixture of 4-aminonicotinic acid (2.5 g, 18 mmol, Sigma-Aldrich) in acetic acid (20 mL) and water (20 mL) was heated at 70°C until all the starting material had dissolved. The reaction mixture was then cooled to 50°C and bromine (3.5 mL, 68 mmol) was added. The reaction mixture was stirred at 50°C for 16 hours. The reaction mixture was cooled to room temperature, and the precipitate was filtered and washed with a small amount of cold water to give the title compound 2a. ^1H NMR (400 MHz, DMSO- _d6 ) δ 9.55 (s, _1H ), 8.94 (s, 1H). HRMS: (ESI+) _C6H6O2N2BR [M+H] calcd. 216.96072, found 216.96071. _LCMS (m/z) 216.9 [M+H], TR = 1.32 min (LCMS method ₄ ).

Step 2: Synthesis of methyl 4-amino-5-bromonicotinate (Compound 2b)

Sulfuric acid (2 mL, 37.5 mmol) was added dropwise to an ice-cold mixture of compound 2a (2.5 g, 11.5 mmol) in methanol (20 mL). The reaction mixture was then heated to reflux for 48 hours. The reaction mixture was diluted with ethyl acetate, extracted with saturated sodium bicarbonate solution and brine, and the organic layer was dried over calcium chloride. The solvent was evaporated, and the crude product was subjected to silica gel chromatography (0-40% ethyl acetate in isohexane gradient) to provide the title compound 2b. ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.66 (s, 1H), 8.43 (s, 1H), 3.85 (s, 3H) _. HRMS: (ESI+) _C7H8O2N2BR [M+H] calcd. _230.97637 , found 230.97644. _LCMS (m/z) 231.0 [M+H], TR = 2.36 min (LCMS method 4).

Step 3: Synthesis of methyl 5-bromo-4-((triphenylphosphoranylidene)-amino)nicotinate (Compound 2c)

Triphenylphosphine (2.28 g, 8.7 mmol) was treated with bromine (0.45 mL, 8.7 mmol) at 0°C for 5 minutes. Triethylamine (2.42 mL, 17.4 mmol) was then added followed by compound 2b (1 g, 4.33 mmol). The ice bath was then removed and the reaction mixture was stirred at room temperature for 15 hours. The reaction mixture was diluted with ethyl acetate, extracted with water, and the organic layer was dried over calcium chloride. The solvent was evaporated and the crude product was subjected to silica gel chromatography (0-40% ethyl acetate gradient in isohexane) to give title compound 2c. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.51 (d, J = 1.8 Hz, 1H), 8.40 (s, 1H), 7.64–7.75 (m, 6H), 7.49–7.58 (m, 3H), 7.40–7.49 (m, 6H), 3.21 (s, 3H). HRMS: (ESI+) calcd. for C ₂₅ H ₂₁ O ₂ N ₂ BrP [M+H] 491.05185, found 491.05183. LCMS (m/z) 491.1 [M+H], TR = 3.83 min (LCMS method 4).

Step 4: Synthesis of 4-((8-bromo-4-oxo-3,4-dihydropyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile (Compound 2d)

A mixture of compound 2c (200 mg, 1.02 mmol) and 4-isocyanatobenzonitrile (294 mg, 2.04 mmol, Sigma-Aldrich) was stirred at room temperature for 2 hours. Ammonia was then bubbled through for 2 minutes, and the reaction mixture was stirred for an additional hour. The precipitate was filtered and washed with tetrahydrofuran to yield the title compound 2d. ^H NMR (400 MHz, DMSO-d ₆ ) δ 9.00 (s, 1H), 8.86 (s, 1H), 8.16 (d, J=8.8 Hz, 2H), 7.83 (d, J=8.8 Hz, 2H). HRMS: (ESI+) Calcd. for C ₁₄ H ₉ ON ₅ BR [M+H] 341.99850, found 341.99837. LCMS (m/z) 342.0 [M+H], TR=3.63 min (LCMS method 4).

Step 5: Synthesis of 4-((8-bromo-4-chloropyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile (Compound 2e)

A mixture of compound 2d (200 mg, 0.59 mmol) in phosphorus oxychloride (5 mL, 53.5 mmol) was heated to reflux for 6 hours. The reaction mixture was then poured onto ice, and the mixture was stirred for 2 minutes. The precipitate was filtered and washed with cold water to give the title compound 2e. ^1H NMR (400 MHz, DMSO- _d6 ) δ 11.32 (s, 1H), 9.28 (s, 1H), 9.08 (s, 1H), 8.01 (d, J = 8.8 Hz, 2H), 7.87 (d, J = 8.8 Hz, 2H) _{. HRMS: (ESI+) Calcd. for C14H8N5BrCl [ M} +H] 359.96461, found 359.96455. LCMS (m/z) 360.0 [M+H], TR = 4.28 min (LCMS method 4).

Step 6: Synthesis of 4-((4-amino-8-bromopyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile (Compound 2f)

A solution of ammonia in ethanol (5 mL of a saturated solution) was added to compound 2e (150 mg, 0.42 mmol), and the reaction mixture was stirred at room temperature for 12 hours. The ethanol was evaporated, and the crude product was chromatographed on silica gel (0-10% methanol in chloroform gradient) to provide the title compound 2f. ^1H NMR (400 MHz, DMSO- _d6 ) δ 10.07 (s, 1H), 9.27 (s, 1H), 8.79 (s, 1H), 8.28 (d, J = 8.8 Hz, 2H), 7.73 (d, J = 8.8 Hz, 2H). HRMS: (ESI+) _{Calcd. for C14H10N6BR [} M+H] _341.01448 , found 341.01462. LCMS (m/z) 341.0 [M+H], TR = 4.67 min (LCMS method 4).

Step 7: Synthesis of (E)-4-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)pyrido[4,3-d]pyrimidin-2-yl)amino)benzonitrile (Compound 2)

A solution of compound 2f (40 mg, 0.12 mmol), compound 1g (67 mg, 0.24 mmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (38 mg, 0.06 mmol), and tripotassium phosphate hydrate (135 mg, 0.6 mmol) in dimethylformamide and water (85:15, 5 mL) was purged with argon and heated at 80°C under argon for 2 hours. The solvent was evaporated, and the crude mixture was subjected to silica gel chromatography (ethyl acetate). The product was then purified by reverse phase chromatography (preparative column Phenomenex Gemini 10u C18, 250 × 21.2 mm, 10 mL/min, gradient of 25-100% acetonitrile in water) to give compound 2. ^1H NMR (400 MHz, DMSO- _d6 ) δ 9.77 (s, 1H), 9.39 (s, 1H), 8.38 (s, 1H), 7.79 (d, J = 8.7 Hz, 2H), 7.72 (d, J = 16.6 Hz, 1H), 7.51 (s, 2H), 7.38 (d, J = 8.7 Hz, 2H), 6.54 (d, J = 16.6 Hz, 1H), 1.95 (s, 6H) _{. HRMS: (ESI+) calcd. for C25H20N7 [ M} +H] 418.17747, found 418.17734. LCMS (m/z) 418.2 [M+H], TR = 4.61 min (LCMS method 4).

Example 3

(E)-4-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)pyrido[3,2-d]pyrimidin-2-yl)amino)benzonitrile (Compound 3)

Step 1: Synthesis of 4-((4-amino-8-chloropyrido[3,2-d]pyrimidin-2-yl)amino)benzonitrile (Compound 3a)

A disposable oven-dried 10 ml microwave tube containing a stirring bar was charged with methyl 4-amino-2,8-dichloropyrido[3,2-d]pyrimidine-6-carboxylate (100 mg, 0.37 mmol, Otava Ltd. cat. 3710589) and 4-aminobenzonitrile (65 mg, 0.55 mmol, Sigma-Aldrich). The container was sealed with a septum and purged with argon. Dry NMP was added via a syringe at room temperature, the container was evacuated and backfilled with argon. The reaction mixture was heated in a microwave at 250 ° C for 0.5 hours. The mixture was cooled to room temperature and ether was added. The precipitated product was filtered out and washed twice with ether. The crude residue was extracted 6 times with DCM. The combined organic extracts were evaporated together and the solid residue was treated with ether in a sonic bath. The product was filtered and dried under high vacuum overnight to obtain the title compound 3a as a solid. LCMS (m/z) 297.2 [M+H], TR = 2.35 min (LCMS method 3).

Step 2: Synthesis of (E)-4-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)pyrido[3,2-d]pyrimidin-2-yl)amino)benzonitrile (Compound 3)

Compound 3a (53 mg, 0.18 mmol), compound 1g (202 mg, 0.71 mmol), tripotassium phosphate (227 mg, 1.07 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocenedichloropalladium (23 mg, 0.04 mmol) were dissolved in a dimethylformamide:water mixture (85:15, 5 mL) under argon. The reaction mixture was heated to 90 ° C for 1 hour. The reaction mixture was cooled to room temperature, filtered through celite, diluted with ethyl acetate, extracted with water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated and the crude product was purified by reverse phase chromatography (10-80% acetonitrile in water, 0.1% trifluoroacetic acid) to obtain the TFA salt of compound 3. ¹ HNMR (400MHz, DMSO-d ₆ )δ9.66(s,1H),8.62(d,J＝4.4Hz,1H),7.78–7.70(m,3H),7.58(d,J＝4.4Hz,1H),7.53(s,2H),7.34(d , J=8.5Hz, 2H), 6.56 (d, J=16.7Hz, 1H), 1.95 (s, 6H). LCMS (m/z) 418.3 [M+H], TR=2.61min (LCMS method 3).

Biological Examples

Example A

High-throughput screening of antibodies against HIV-1 RT (reverse transcriptase)

Compounds active against HIV-1 HBX2 (wild-type) and HIV-1 reverse transcriptase mutants K103N and Y181C were screened using a miniaturized, high-throughput cytopathic effect assay. In Tables 1 and 2 below, "w.t." refers to the results of compound testing with wild-type 1, and "w.t. Assay 2" refers to the results of compound testing with wild-type on the same day as the mutants. Therefore, "w.t. Assay 2" was run under the same conditions as the mutants and provides a direct comparison to the results of testing with the mutants.

Ten-point serial dilutions of the compound with half-log steps were generated in DMSO. AZT (5 μM) was used as a positive control and DMSO as a negative control. 200 nL of the serially diluted compound was delivered to a sterile 384-well tissue culture assay plate using an echo dispenser. Two million MT-4 cells were incubated with each of the three viruses at an MOI of 0.0005 in a separate 1 mL infection tube at 37°C for 1 hour. The cells were diluted to 50,000 cells/mL in cell culture medium (RPMI+10% FBS). The infected cells were added to a 384-well assay plate containing the serially diluted compound. The assay plate was incubated in a humidified incubator at 37°C and 5% _CO2 for 5 days. To measure the cytopathic effect of HIV, 40 μL Cell TiterGlo was added to each well and the resulting luminescent signal was read using an Envision plate reader (Perkin Elmer). The data were normalized to the positive and negative controls in each plate and expressed as % CPE protection. _EC50 values were defined as the compound concentration that resulted in a 50% decrease in luminescence signal and were calculated by nonlinear regression using Pipeline Pilot software by applying a four-parameter fitting equation (Accelrys, San Diego, CA). The results are disclosed in Table 1.

High throughput screening was also performed on nevirapine ("NPV"), rilpivirine ("RPV"), and efavirenz ("EFV"). Nevirapine was obtained from Toronto Research Chemicals, Inc. (Toronto, Canada; catalog #N391275). Rilpivirine was obtained from Key Organics Ltd. (Camelford, Cornwall, United Kingdom; catalog #KE-0036). Efavirenz was obtained from Toronto Research Chemicals, Inc. (Toronto, Canada; catalog #E425000). The results are shown in Table 2 below. Further details and background can be found in Janssen et al, J. Med. Chem, 2005, 48, 1901-1909, Das et al., Proc. Nat. Acad. Sci., 2008, vol. 105, no. 5, 1466-1471, and Kuroda et al., Nature Chemistry, 2013, DOI: 10.1038/NCHEM.1559.

*Wild-type assay 2 was performed on the same day as assays with K103N and Y181C mutants.

ND: Not Detected

It should be understood that EC ₅₀ can be assessed by techniques known in the art. In one embodiment, the compound exhibits an EC ₅₀ of less than about 3000 nM in wild type or any HIV RT mutant, as measured by the method disclosed in the "High Throughput Screening Against HIV Mutants K103N and Y181C" assay section discussed above. In one embodiment, the compound exhibits an EC 50 of less than about 1000 nM, 500 nM, 400 nM, 300 nM, 250 nM, 200 nM, 100 nM, 50 nM, 25 nM, 10 nM, 5 nM, or 1 nM in wild type or any HIV RT mutant (e.g., K103N, Y181C ₎ .

Example B

hERG assay

cell:

The AVIVA CHO cell line stably expressing the hERG channel was used in this study. The cells were cultured in DMEM/F12 supplemented with 10% FBS, 1% penicillin/streptomycin, and 500 μg/ml G418. Prior to testing, cells were harvested using Accumax (Innovative Cell Technologies).

Solution:

For electrophysiological recordings, the following solutions were used:

External solution : 2 mM CaCl ₂ ; 2 mM MgCl ₂ ; 4 mM KCl; 150 mM NaCl; 10 mM glucose; 10 mM HEPES; 305-315 mOsm; pH 7.4 (adjusted with 5 M NaOH)

Internal solution : 140 mM KCl, 10 mM MgCl ₂ , 6 mM EGTA, 5 mM HEPES-Na, 5 mM ATP-Mg, 295-305 mOsm, pH 7.25 (adjusted with 1 M KOH).

Electrophysiology:

Whole-cell recordings were performed using a PX 7000A (Axon Instruments) with SealChip ^™ technology from AVIVA. The cell clamp voltage was maintained at -80 mV. The hERG current was then activated to -50 mV by a depolarization step for 300 ms. The first step at -50 mV was used as a baseline for measuring the peak amplitude of the tail current. Next, a voltage step of +20 mV was applied for 5 seconds to activate the channel. Finally, the activation was removed by returning to the -50 mV step for 5 seconds, and the deactivated tail current was recorded.

Test Article Treatment and Dilution:

All test products were prepared from 10 mM DMSO stock solutions. Mix by ultrasonic treatment for 20 minutes, then vortex vigorously. Prior to testing, compounds were diluted to the test concentration using external solution in glass vials. Dilutions were prepared no more than 20 minutes before use.

Electrophysiological procedures

After completing the whole-cell configuration, the cells were monitored for 90 seconds to assess stability, followed by a 66-second wash with external solution. The voltage protocol was then applied to the cells every 12 seconds throughout the procedure. Only stable cells with recording parameters above a threshold were allowed to proceed to the drug addition procedure.

The external solution containing 0.1% DMSO (vehicle) is applied to the cell to establish a baseline. After making the current stable for 3-10 minutes, the test article is applied. In 4 separate additions, the test article solution is added to the cell. The cell is maintained in the test solution until the effect of the test article reaches a steady state, reaching a maximum of 12 minutes. Next, 1 μM cisapride (positive control) is added. Finally, the external solution is rinsed until the recovery current reaches a steady state.

Data Analysis

Data analysis was performed using DataXpress (Axon Instruments), Clampfit (Axon Instruments), and Origin (OriginLab Corporation) software. The results are disclosed in Table 3.

Table 3

A hERG assay for Rilpivirine ("RPV") was also performed. The result was 0.5 μM.

The specific pharmacological responses observed may vary according to and depend on the specific active compound selected or the presence or absence of a pharmaceutical carrier, as well as the type of formulation employed and the mode of administration employed, and expected variations or differences in results are expected from the practice of the present disclosure.

The examples disclosed herein describe the synthesis of the compounds disclosed herein and the intermediates used to prepare the compounds. It should be understood that the various steps described herein can be combined. It should also be understood that separate batches of compounds can be combined and then brought into the next synthesis step.

All references, including publications, patents, and patent documents, are incorporated herein by reference as if individually incorporated by reference. The present disclosure provides references to various embodiments and techniques. However, it should be understood that many variations and modifications can be made within the spirit and scope of the present disclosure.

Claims (19)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, in: X is N, Y is CR ³ , Z is CR ³ ; or X is CR ³ , Y is CR ³ , Z is N; or X is CR ³ , Y is N, Z is CR ³ ; ^R1 is -CN; ^R² is -NR ^a R ^b ; ^R3 is -H; ^R4 and ^R5 are each independently _C1-3 alkyl groups; n is 0; and ^Ra and ^Rb are each independently -H or _C1-3 alkyl groups. 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ^R2 is _-NH2 . 3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ^R4 and ^R5 are each independently _CH3 . 4. The compound according to claim 1, wherein the compound of formula I is a compound of formula Ia or a pharmaceutically acceptable salt thereof: 5. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein ^R4 and ^R5 are _-CH3 . 6. The compound according to claim 4 or 5, or a pharmaceutically acceptable salt thereof, wherein ^R2 is _-NH2 . 7. The compound of claim 1, wherein the compound of formula I is a compound of formula Ib or a pharmaceutically acceptable salt thereof: 8. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein ^R4 and ^R5 are _-CH3 . 9. The compound according to claim 7 or 8 or a pharmaceutically acceptable salt thereof, wherein ^R2 is _-NH2 . 10. The compound of claim 1, wherein the compound of formula I is a compound of formula Ic or a pharmaceutically acceptable salt thereof: 11. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein ^R4 and ^R5 are _-CH3 . 12. The compound of claim 10 or 11 or a pharmaceutically acceptable salt thereof, wherein ^R2 is _-NH2 . 13. The compound according to claim 1, wherein the compound is: Or its pharmaceutically acceptable salt. 14. A pharmaceutical composition comprising the compound of any one of claims 1-13 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 15. An article comprising a unit dose of the compound of any one of claims 1-13 or a pharmaceutically acceptable salt thereof. 16. Use of any compound of claims 1-13 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating or preventing HIV infection in an individual. 17. The use according to claim 16, wherein the medicament further comprises a therapeutically effective amount of one or more adjunctive therapeutic agents selected from the group consisting of: HIV protease inhibitory compounds, HIV reverse transcriptase non-nucleoside inhibitors, HIV reverse transcriptase nucleoside inhibitors, HIV reverse transcriptase nucleotide inhibitors, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, and other medicaments for the treatment of HIV, and combinations thereof. 18. Use of any compound of claims 1-13 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting HIV reverse transcriptase in an individual. 19. Use of the compound of any one of claims 1-13 or a pharmaceutically acceptable salt thereof for in vitro inhibition of HIV reverse transcriptase.