OA18583A

OA18583A - Quinazoline derivatives used to treat HIV

Info

Publication number: OA18583A
Application number: OA1201700237
Authority: OA
Inventors: Yunfeng Eric Hu; Richard L. Mackman; LANSDON E (c/o Gilead Sciences, Inc.); Petr Jansa; Petr Simon; Ondrej Baszczynski; Milan Dejmek
Original assignee: Gilead Sciences, Inc.; Institute Of Organic Chemistry And Biochemistry Of The As Cr
Priority date: 2014-12-24
Filing date: 2015-12-23
Publication date: 2018-12-28

Abstract

Described herein are compounds of Formula

Description

QUINAZOLINE DERIVATIVES USED TO TREAT IIIV

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority benefit to U.S. Application Serial No. 62/096,748, filed December24,2014, the disclosure of which is herein incorporated by reference in its entirety.

BACKGROUND [0002] While progress has been made jn treating HIV and AIDS, HIV infection remains a global health concem. As part of such treatments, non-nucleoside reverse transcriptase inhibitors (NNRTIs) hâve often been employed, particularly as part of highly active antirétroviral therapy (IIAART) treatment regimens. Though potent, drawbacks exist for many of the known NNRTIs as their use has been associated with mutations in the HIV virus that may resuit in drug résistance. As such, there remains a need for further development of potent NNTRIs.

[0003] Described herein are compounds of Formula (I) and pharmaceutically acceptable salts thereof, compositions and formulations containing such compounds, or pharmaceutically acceptable salts thereof, and methods of using and making such compounds, or pharmaceutically acceptable salts thereof

SUMMARY [0004]

In certain embodiments, the présent disclosure relates to compounds of Formula (I) or a tautomer thereof,

R⁴ R³

wherein

I

X*, X², and X³ are each independently N or C(Rⁿ), provided that, at most 2 ofX¹, X², and X³ are N;

R¹ is -H, -CN, -OR*, -C(O)OR*, halogen, Ci^alkyl, C₃-iocycloalkyl, or Ciôheteroalkyl, wherein each Ci-ealkyl, C₃. locycloalkyl, and Ci^heteroalkyl is optionally substituted with 1,2, 3,4, or 5 R¹² groups, which may be same or different;

R² is -H, -CN, -OR·, -NR*R^b, -C(O)OR·, halogen, Ci^alkyl, C₃.iocycloalkyl, or Cw heteroalkyl, wherein each Ci-&alkyl, C₃.iocycloalkyl, and Ci^heteroalkyl is optionally substituted with 1, 2,3, 4, or 5 R¹² groups, which may be same or different,

R³ is -H, -OR*, -SR*, -NR*R^b, -NHC(O)NR*R^b, Ci^alkyl, C₃.i₀cycloalkyl, or Ci^ heteroalkyl, wherein each Ci-ealkyl, C₃.iocycloalkyl, and Cizheteroalkyl is optionally substituted with 1,2,3, 4, or 5 R¹² groups, which may be same or different;

R⁴ is -H, -OR·, halogen, -NO2, -CN, -NR*R^b, -NHC(O)NR*R^b, -OC(O)NR*R^b, CH2C(0)NR*R^b, Ci^alkyl, C3.iocycloalkyl, or Ci^ heteroalkyl, wherein each Ci^alkyl, C₃iccycloalkyl, and Ci^, heteroalkyl is optionally substituted with 1,2,3,4, or 5 R¹² groups, which may be same or different;

R³ is -H, -OR·, halogen, -NO2, -CN, -NR’R^b, -Ni IC(O)NR*R^b, -OC(O)NR*R^b, CH2C(O)NR*R^b, Ci^alkyl, C₃.iocycloalkyl, or Ci-6 heteroalkyl, wherein each Ci^alkyl, C₃. locycloalkyl, and Ci^ heteroalkyl is optionally substituted with 1,2,3,4, or 5 R¹² groups, which may be same or different;

R⁶ is -H, -OR·, halogen, -NO2, -CN, -NR’R^b, -NHC(O)NR*R^b, -OC(O)NR'R^b, CH2C(O)NR*R^b, Ci^alkyl, C₃-iocycloalkyl, or Ci4heteroalkyl, wherein each Ci-oalkyl, C₃. locycloalkyl, and Ci4 heteroalkyl is optionally substituted with 1,2, 3, 4, or 5 R¹² groups, which may be same or different;

R⁷ is Ci^alkyl, C₃.iocycloalkyl, Ci^heteroalkyl, halogen, -OR, -CN, or -NO₂, wherein each Ci^alkyl, C₃.locycloalkyl, and Ci-e heteroalkyl is optionally substituted with 1, 2,3, 4, or 5 R¹² groups, which may be same or different;

R⁸ is Ci^alkyl, C₃-iocycloalkyl, Ci^heteroalkyl, halogen, -OR*,-CN, or -NÛ2, wherein each Ci^alkyl, C₃-iocycloalkyl, and C14 heteroalkyl is optionally substituted with 1, 2,3,4, or 5 R¹² groups, which may be same or different;

R⁹ is -H, Ci^alkyl, or C₃-iocycloalkyl, wherein each Ci-salkyl and C₃-iocycloalkyl is optionally substituted with 1,2,3,4, or 5 R¹² groups, which may be same or different;

R¹⁰ is -H, Cj-ealkyl, or Ci.iocycloalkyl, wherein each Ci^alkyl and Cnocycloalkyl is optionally substituted with 1,2,3, 4, or 5 R¹² groups, which may be same or different;

each R¹¹ is independently -H, -CN, -OR*. -C(O)OR·, halogen, Ci^alkyl, C?. îocycloalkyl, or Ci-cheteroalkyl, which may be same or different, wherein each Ci-calkyl, Cjîocycloalkyl, and Cwheteroalkyl is optionally substituted with 1,2,3,4, or 5 R¹² groups, which may be same or different;

each R¹² is independently Ci.«alkyl, Cj-iocycloalkyl, Ci-cheteroalkyl, 5-10 membered heterocyclyl, Ce-ioaryl, 5-10 membered heteroaryl, halogen, -OR‘, -C(O)R‘, -C(O)OR‘, C(O)NR'R^b, -OC(O)NR*R^b, -NR*C(O)OR^b, -SR’, -S(O)i-;R·, -S(O)2F, -S(O)2NR'R^b, NRS(O)iR^b, -Nj, -CN, or-NO2; wherein each Ci^alkyl, Cj-iocycloalkyl, Ci-cheteroalkyl, and 5-10 membered heterocyclyl is optionally substituted with 1,2,3,4, or 5 substituents selected from halogen, -OR*. -C(O)R\ -C(O)OR', -C(O)NR^,R^b. -OC(O)NR*R^b, NR*C(O)OR^b, -SR‘, -SÎOJhîR·, -S(O)2F, -S(O)2NR*R^b, -NR*S(O)2R^b, -Nj, -CN, and NO₂, groups, which may be same or different;

each R* and R^b is independently -H, -NIh. Ci .«alkyl, Cj-iocycloalkyl, Cj-«heteroalkyl, 5-10 membered heterocyclyl, Ce-ioaryl, or 5-10 membered heteroaryl, wherein each Ci«alkyl. Cî-iocycloalkyl, Ci^hcteroalkyl, 5-10 membered heterocyclyl, Ce-ioaryl, and 5-10 membered heteroaryl is optionally substituted with 1, 2,3,4, or 5 Rⁿ groups, which may be same or different; or R* and R^b together with the atoms to which they are attached form a 510 membered heterocycle; and each R¹³ is independently -CN, halogen, Cj.«alkyl, Cj-iocycloalkyl, Ci^heteroalkyl, or 5-10 membered heterocyclyl;

or a pharmaceutically acceptable sait thereof.

[0005] In certain embodiments, the current disclosure relates to a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable sait thereof, and a pharmaceutically acceptable carrier.

[0006] In certain embodiments, the current disclosure relates to an article of manufacture comprising a unit dosage of a compound of Formula (I), or a pharmaceutically acceptable sait thereof.

[0007] In certain embodiments, the current disclosure relates to a method of inhibiting reverse transcriptase in a subject in need thereof, comprising administering a compound of Formula (I), or a pharmaceutically acceptable sait thereof, to the subject [0008] In certain embodiments, the current disclosure relates to a method for treating or preventing an HIV infection in a subject in need thereof, comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable sait thereof [0009] In certain embodiments, the cunent disclosure relates to a method for preventing an HIV infection in a subject, comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable sait thereof. In certain embodiments, the subject is at risk of contracting the HIV virus, such as a subject who has one or more risk factors known to be associated with contracting the HIV virus.

[0010] In certain embodiments, the current disclosure relates to a method for treating or preventing an HIV infection in a subject in need thereof, comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable sait thereof, in combination with a therapeutically effective amount of one or more additional therapeutic

agents. [0011]

In certain embodiments, the current disclosure relates to a compound of Formula

(I), or a pharmaceutically acceptable sait thereof, for use in medical therapy.

[0012]

In certain embodiments, the current disclosure relates to a compound of Formula

(I), or a pharmaceutically acceptable sait thereof, for use in treating or preventing an HIV virus infection in a subject.

[0013]

In certain embodiments, the current disclosure relates to the use ofa compound

of Formula (I), or a pharmaceutically acceptable sait thereof, for the manufacture ofa médicament for treating or preventing an HIV virus infection in a subject.

[0014]	Additional embodiments of the présent disclosure are disclosed herein. BRIEF DESCRIPTION OF THE DRAWINGS
[0015]	Figure 1 shows results of résistance profile against IIIV-1 RT (Reverse

Transcriptase) mutants of certain compounds.

[0016]

DETAILED DESCRIPTION The description below is made with the understanding that the présent disclosure

is to be considered as an exemplification of the claimed subject matter, and is not intended to 1 imit the appended daims to the spécifie embodiments illustrated. The headings used throughout this disclosure are provided for convenience and are not to be construed to limit the daims in any way. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading.

[0017] Unless defined otherwise, ail technical and scientific terms used herein hâve the same meaning as commonly understood by one of ordinary skill in the art A dash at the front or end of a chemical group is a matter of convenience to indicate the point of attachment to a parent moiety; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning A wavy line drawn through a line in a chemical structure or a dashed line drawn through a line in a chemical structure indicates a point of attachment of a group. A dashed line within a chemical structure indicates an optional bond. A prefïx such as “Cu-_V or (C_u-C_v) indicates that the following group has from u to v carbon atoms. For example, “Ci-ealkyl” indicates that the alkyl group has from I to 6 carbon atoms [0018] When trade names are used herein, it is intended to independently include the tradename product and the active pharmaceutical ingredient(s) ofthe tradename product. [0019] As used herein and in the appended daims, the singular forms a and an, and the include plural referents unless the context clearly dictâtes otherwise Thus, e.g., reference to the compound includes a plurality of such compounds and reference to the assay includes reference to one or more assays, and so forth.

[0020] “Alkyl” as used herein is a linear or branched saturated monovalent hydrocarbon. For example, an alkyl group can hâve 1 to 20 carbon atoms (Le., (Ci-₂o)alkyl) or an alkyl group can hâve 1 to 10 carbon atoms (Le., (Ci-io)alkyl), or an alkyl group can hâve 1 to 8 carbon atoms (Le., (Cj-s)alkyl), or 1 to 6 carbon atoms (i.e., (Cj-β alkyl), or 1 to 4 carbon atoms (Le., (Ci-j)a!ky 1 ). Examples of alkyl groups include, but are not limited to, methyl (Me, -CIL), ethyl (Et, -CH₂CHj), 1-propyl (zi-Pr, n-propyl, -CH₂CH₂Clh), 2-propyl (/-Pr, ί-propyl, -CH(CH₃)₂), l-butyl (n-Bu, π-butyl, -ClfeCFhClhCHj), 2-methyl-l -propyl (/-Bu, /-butyl, -CH₂CH(CH₃)2), 2-butyl (s-Bu, s-butyl, -CH(CHj)CH₂CHj), 2-methyl-2-propyl (/Bu, /-butyl, -CiCHj)?), 1-pentyl (n-pentyl, -ClbCIhCIhCIhCHj), 2-pentyl (-CH(CH3)CH₂CH₂CHj), 3-pentyl (-CH(CH₂CHj)₂), 2-methyl-2-butyl (-C(CH₃)2CH₂CHj),

3-methyl-2-butyl (-CH(CHj)CH(CH₃)₂), 3-methyl-l -butyl (-CH₂CH₂CH(CHi)₂), 2-methyl l-butyl(-CH2CH(CHj)CH2CHj), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CHÎCHjXZHîCHzCHîCHj), 3-hexyl (-CHiCHîClhMClhClhCHj)), 2-methyl-2-pentyl (-CtCIhhClhClhCIh), 3-methyl-2-pentyl (-CH(CH3)CH(CHj)CH2CHj), 4-methyl-2pentyl (-CH(CHj)CH2CH(CHjh), 3-methyl-3-pentyl (-C(CH3)(CH₂CH3)2), 2-methyl-3pentyl (-CHiCHiCHjJCHtCIh):), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CIh)j), 3,3-dimethyl-2-butyl (-CHiCHjJCfCÎhh, and octyl (-(CHjJtCHj).

[0021 ] The term “aryl” as used herein refers to a single ail carbon aromatic ring or a multiple condensed ail carbon ring system wherein at least one of the rings is aromatic. For example, in certain embodiments, an aryl group has 6 to 20 annular carbon atoms, 6 to 14 annular carbon atoms, or 6 to 12 annular carbon atoms. Aryl includes a phenyl radical. Aryl also includes multiple condensed ring Systems (e.g., ring Systems comprising 2,3 or 4 rings) having about 9 to 20 carbon atoms in which at least one ring is aromatic and wherein the other rings may be aromatic or not aromatic (i.e., carbocycle). Such multiple condensed ring Systems are optionally substituted with one or more (e.g., 1, 2 or 3) oxo groups on any carbocycle portion of the multiple condensed ring system. The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements It is also to be understood that when reference is made to a certain atom-range membered aryl (e g, 6-12 membered aryl), the atom range is for the total ring (annular) atoms of the aryl. For example, a 6-membered aryl would include phenyl and a 10-membered aryl would include naphthyl and 1,2,3,4tetrahydronaphthyl. Non-limiting examples ofaryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2.3,4-tetrahydronaphthyl, anthracenyl, and the like.

[0022] “Arylalkyl” refers to an alkyl radical as defined herein in which one of the hydrogen atoms bonded to a carbon atom is replaced with an aryl radical as described herein (i.e., an aryl-alkyl- moiety) The alkyl group of the “arylalkyl” includes alkyl groups that are 1 to 6 carbon atoms (i.e. aryl(Ci-Ce)alkyl) Arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-l-yl, 1-phenylpropan-1-yl, naphthylmethyl, 2-naphthylethan-l-yl and the like.

[0023] “Doronic acid” refers to the group -B(OH)2.

[0024] “Boronic acid ester” refers to an ester dérivative of a boronic acid compound. Suitable boronic acid ester dérivatives include those of the formula -B(OR)2 where each R is independently alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl. Additionally, the two R groups of-B(0R)2 may be taken together to form a cychc ester, e.g. having the structure

o—r_t where each R may be the same or different. Examples of boronic acid ester include boronic acid pinacol ester and boronic acid catechol ester.

[0025] “Cycloalkyl refers to a single saturated or partially unsaturated ail carbon ring having 3 to 20 annular carbon atoms (i.e., C3-C20 cycloalkyl), for example from 3 to 12 annular atoms, for example from 3 to 10 annular atoms. The term ‘‘cycloalkyl” also includes multiple condensed, saturated and partially unsaturated al! carbon ring Systems (e.g-, ring Systems comprising 2,3 or 4 carbocyclic rings) Accordingly, cycloalkyl includes multicyclic carbocycles such as a bicyclic carbocycles (e.g., bicyclic carbocycles having about 6 to 12 annular carbon atoms such as bicyclo[3.1.0]hexane and bicyclo[2.1.1 ]hexane), and polycyclic carbocycles (e.g., tricyclic and tetracyclic carbocycles with up to about 20 annular carbon atoms) The rings of a multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. Nonlimiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, Icyclopent-1-enyl, l-cyclopent-2-enyl, l-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-l-enyl, Icyclohex-2-enyl and l-cyclohex-3-enyl [0026] “Halo” or “halogen” refers to fluoro, chloro, bromo and iodo.

[0027] The term “heteroalkyl” as used herein refers to an alkyl as defined herein, wherein one or more of the carbon atoms of the alkyl are replaced by an O, S, or NR^q, (or if the carbon atom being replaced is a terminal carbon with an OH, SH or N(R^q)2) wherein each R^q is independently H or (Ci-Ce)alkyl. For example, (Ci-Ce)heteroalkyl intends a heteroalkyl wherein one or more carbon atoms of a Ci-Cs alkyl is replaced by a heteroatom (e.g., O, S, NR^q, OH, SH or N(R^q)i), which may the same or different. Examples of heteroalkyls include but are not limited to methoxymethyl, ethoxymethyl, methoxy, 2hydroxyethyl and Ν,Ν’-dimethylpropylamine. A heteroatom of a heteroalkyl may optionally be oxidized or alkylated. A heteroatom may be placed at any interior position of the heteroalkyl group orat a position at which the group is attached to the remainder of the molécule. Examples include, but are not limited to, -CH2OCH3, -CH2CH2NHCH3, 7

CH₂CH₂N(CH₃) -CHj, -CH₂SCH₂CHj, -S(O)CHj, -CH₂CH₂S(O)₂CHj, -CH;CH_:OCIb, CHCHN(CIb)CHi,-CH₂NHOCHj and -CH₂OC(CIÎ3)₃.

[0028] The terni “heteroaryl” as used herein refers to a single aromatic ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur; the term also includes multiple condensed ring Systems that hâve at least one such aromatic ring, which multiple condensed ring Systems are further described below. Thus, the term includes single aromatic rings of from about 1 to 6 annular carbon atoms and about 1-4 annular heteroatoms selected from the group consisting ofoxygen, nitrogen and sulfur in the rings. The sulfur and nitrogen atoms may also be présent in an oxidized form provided the ring is aromatic. Such rings include but are not limited to pyridyl, pyrimidinyl, oxazolyl or furyl. The term also includes multiple condensed ring Systems (e.g., ring Systems comprising 2, 3 or 4 rings) wherein a heteroaryl group, as defined above, can be condensed with one or more rings selected from heteroaryls (to form for example a naphthyridinyl such as 1,8-naphthyridinyl), heterocycloalkyls, (to form for example a 1,2,3,4-tetrahydronaphthyridinyl such as 1,2,3,4-tetrahydro-1,8naphthyridinyl), cycloalkyls (to form for example 5,6,7,8-tetrahydroquinolyl) and aryls (to form for example indazolyl) to form the multiple condensed ring system. Thus, a heteroaryl (a single aromatic ring or multiple condensed ring system) has about 1 -20 annular carbon atoms and about 1-6 annular heteroatoms. Such multiple condensed ring Systems may be optionally substituted with one or more (e g., 1, 2,3 or 4) oxo groups on the carbocycle or heterocycle portions of the condensed ring. The rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is to be understood that the individual rings of the multiple condensed ring System may be connected in any order relative to one another. It is also to be understood that the point of attachment of a multiple condensed ring system (as defined above for a heteroaryl) can be at any position of the multiple condensed ring System including a heteroaryl, heterocycle, aryl or carbocycle portion of the multiple condensed ring system and at any suitable atom of the multiple condensed ring system including a carbon atom and heteroatom (e g, a nitrogen). Exemplary heteroaryls include but are not limited to pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quînoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinyl benzofuranyl, benzimidazolyl and thianaphthenyl.

[0029] “Heterocycloalkyl or ‘’heterocydyl” as used herein refers to a single saturated or partîally unsaturated non-aromatic ring or a non-aromatic multiple ring system that has at least one heteroatom in the ring (at least one annular heteroatom selected from oxygen, nitrogen, and sulfur) Unless otherwîse specified, a heterocycloalkyl group has from 5 to about 20 annular atoms, for example from 5 to 14 annular atoms, for example from 5 to 10 annular atoms. Thus, the term includes single saturated or partîally unsaturated rings (e.g., 3,4, 5,6 or 7-membered rings) having from about 1 to 6 annular carbon atoms and from about 1 to 3 annular heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring. The term also includes single saturated or partîally unsaturated rings (e.g., 5, 6, 7,8,9, or 10-membered rings) having from about 4 to 9 annular carbon atoms and from about 1 to 3 annular heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring The rings of the multiple condensed ring System can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. Heterocycloalkyl groups include, but are not limited to. azetidine, aziridîne, imidazolidine, imino-oxoimidazolidine, morpholine, oxirane (epoxide), oxetane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidinone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinuclidine, N-bromopyrrolidîne, N-chloropiperidine, and the like. · [0030] [0031] “Hydroxy” or “hydroxyl'' refers to the group -OH “Oxo refers to a double-bonded oxygen (=O) , In compounds where an oxo group is bound to an sp² nitrogen atom, an TV-oxide is indicated.

[0032]

It is understood that combinations of chemical groups may be used and will be recognized by persons of ordinary skill in the art For instance, the group “hydroxyalkyl” would refer to a hydroxyl group attached to an alkyl group.

[0033] The terms “optional or “optionally” mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.

[0034] “Tautomers” as used herein refers to isomers of a compound that difîer from each other in the position of a proton and/or in electronic distribution. Thus, both proton migration tautomers and valence tautomers are intended and described and it is understood that more than two tautomers may exist fora given compound. Examples oftautomers include, but are not limited to, enol-keto tautomers:

NHR*

lactam-lactim tautomers:

’lactanT

; amide-imidic acid tautomers:

amino-imine tautomers:

ami ne’

W’ imine . _anc] ta_utomeric forms of heteroaryl groups containing a ring atom attached to both a ring-NH- moiety and a ring =N- moiety such as présent in pyrazoles, imidazoles, benzimidazoles, triazoles and tetrazoles (see, e.g., Smith, March's Advanced Organic Chemistry (5^lh ed.), pp. 1218-1223, Wiley-ïnterscience, 2001; Katritzky A. and Elguero J, et al., The Tautomerism of Heterocycles, Academie Press (1976)) [0035] “Pharmaceutically acceptable” refers to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.

[0036] “Pharmaceutically acceptable sait” refers to a sait ofa compound that is pharmaceutically acceptable and that possesses (or can be converted to a form that possesses) the desired pharmacological activity ofthe parent compound Such 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 formed 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-napththalenesulfonic acid, oleic acid, palmîtic acid, propionic acid, stearic acid, succinic acid, tartane acid, p-toluenesulfonic acid, trimethylacetic acid, and the like, and salts formed when an acidic proton présent in the parent compound is replaced by either a métal ion, e.g., an alkali métal ion (e.g. a sodium or potassium), an alkaline earth ion (e.g. calcium or magnésium), or an aluminum ion; or coordinates with an organic base such as diethanolamine, triethanolamine, Nmethylglucamine and the like. Also included in this définition are ammonium and substituted or quatemized ammonium salts Représentative non-limiting lists of pharmaceutically acceptable salts can be found in S.M, Berge et al., J. Pharma Sci.» 66(1), 119 (1977), and Remington: The Science and Practice of Pharmacy, R. Hendrickson, ed., 21 st édition, Lippincott, Williams & Wilkins, Philadelphia, PA, (2005), at p. 732, Table 38-5, both of which are hereby incorporated by reference herein.

[0037] “Subject and “subjects” refers to humans, domestic animais (e.g., dogs and cats), farm animais (e.g., cattle, horses, sheep, goats and pigs), laboratory animais (e.g., mice, rats, hamsters, guinea pigs, pigs, rabbits, dogs, and monkeys), and the like.

[0038] As used herein, “treatment” or“treatîng” is an approach for obtaining bénéficiai or desired results. For purposes of the présent disclosure, bénéficiai or desired results include, but are not limited to, alleviation of a symptom and/or diminishment of the extent of a symptom and/or preventing a worsening of a symptom assocîated with a disease or condition. In one embodiment, “treatment” or “treating” includes one or more of the following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition); b) slowing or anesting the development of one or more symptoms associated with the disease or condition (e.g., stabiIizing the disease or condition, delaying the worsenîng or progression ofthe disease or condition); and c) relieving the disease or condition, e g, causingthe régression ofclinical symptoms, ameliorating the disease state, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival.

[0039] As used herein, “delaying” development ofa disease or condition means to defer, hinder, slow, retard, stabilize and/or postpone development of the disease or condition. This delay can be of varying lengths oftime, depending on the history ofthe disease and/or individual being treatcd. As is évident to one skillcd in the art, a sufficient or significant delay can, in effect, encompass prévention, in that the individual does not develop the disease or condition. For example, a method that “delays” development of AIDS is a method that reduces the probability of disease development in a given time frame and/or reduces extent of the disease in a given time frame, when compared to not using the method. Such comparisons may be based on clinical studies, using a statistically significant number of subjects. For example, the development of AIDS can be detected using known methods, such as confirming an indtvidual’s HIV* status and assessing the individuaFs T-cell count or other indication of AIDS development, such as extreme fatigue, weight loss, persistent diarrhea, high fever, swollen lymph nodes in the neck, armpits or groin, or presence of an opportunisme condition that is known to be associated with AIDS (e.g., a condition that ts generally not présent in individuals with functioning immune Systems but does occur in AIDS patients). Development may also refer to disease progression that may be initially undetec table and includes occurrence, récurrence and onset.

[0040] As used herein, “prévention” or“preventing” refers to a regimen that protects against the onset of the disease or disorder such that the clinical symptoms of the disease do not develop. Thus. “prévention” relates to administration ofa therapy (e.g, administration of a therapeutic substance) to a subject before signs of the disease are détectable in the subject (e g., administration of a therapeutic substance to an subject in the absence of détectable infectious agent (e.g., virus) in the subject). The subject may be an individual at risk of developing the discase or disorder, such as an individual who has one or more risk factors known to be associated with development or onset of the disease or disorder. Thus, the term “preventing HIV infection” refers to administering to a subject who does not hâve a détectable HIV infection an anti-HIV therapeutic substance. It is understood that the subject for anti-HIV preventative therapy may be an individual at risk of contracting the HIV virus. [004 ! ] As used herein, an “at risk” individual is an individual who is at risk of developing a condition to be treated. An individual “at risk may or may not hâve détectable disease or condition, and may or may not hâve displayed détectable disease prior to the treatment of methods described herein. “At risk dénotés that an individual has one or more so-called risk factors, which are measurable parameters that correlate with development of a disease or condition and are known in the art. An individual having one or more of these risk factors has a higher probability of developing the disease or condition than an individual without these risk factor(s) For example, individuals at risk for AIDS are those having HIV.

[0042] As used herein, the term “effective amount” refers to an amount that is effective to elicit the desired biologica! or medical response. including the amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The effective amount will vary depending on the compound, the disease, and its severity and the âge. weight, etc., of the subject to be treated. The effective amount can include a range of amounts As is understood in the art, an effective amount may be in 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 a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a désirable or bénéficiai resuit may be or is achieved Suitable doses ofany co-administered compounds may optionally be lowered due to the combined action (e.g., additive or synergistic effects) ofthe compounds.

[0043 ] Except as expressly defined otherwise. the présent disclosure includes al! tautomers of compounds detailed herein. even if only one tautomer is expressly represented (e.g., both tautomeric forms are intended and described by the présentation of one tautomeric form where a pair of two tautomers may exist) For example, if reference is made to a compound containing a lactam (e.g., by structure or chemical name), it is understood that the correspondîng lactim tautomer is included by this disclosure and described the same as if the lactim were expressly recited either alone or together with the lactam. Where more than two tautomers may exist, the présent disclosure includes al! such tautuomers even if only a single tautomeric form is depicted by chemical name and/or structure.

[0044] Compositions detailed herein may comprise a compound of the présent disclosure in a racemic or non-racemic mixture of stereoisomers or may comprise a compound ofthe présent disclosure as a substantially pure isomer. Stereoisomers include enantiomers and diastereomers The compounds may exist in stereoisomeric form if they possess one or more asymmetric centers or a double bond with asymmetric substitution and, therefore, can be produced as individual stereoisomers or as mixtures. Unless otherwise indicated, the description is intended to include individual stereoisomers as well as mixtures. The methods for the détermination of stereochemistry and the séparation of stereoisomers are well-known in the art (see, e.g., Chapter 4 of Advanced Organic Chemistry, 4th ed , J. March, John Wiley and Sons, New York, 1992) [0045] It is understood by one skilled in the art that this disclosure also includes any compound disclosed herein that may be enriched at any or ail atoms above naturally occurring isotopic ratios with one or more isotopes such as, but not limited to, deuterium (²H orD) [0046] Disclosed are also compounds in which from 1 to n hydrogen atoms attached to a carbon atom may be replaced by a deuterium atom or D, in which n is the number of hydrogen atoms in the molécule. As known in the art, the deuterium atom is a nonradioactive isotope ofthe hydrogen atom. Such compounds may increase résistance to metabolism, and thus may be useful for increasing the half-life ofthe compounds when administered to a mammal. See, e.g., Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism”, Trends Pharmacol. Sci., 5( 12) 524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogen atoms hâve been replaced by deuterium.

[0047] Compounds of a given formula described herein encompasses the compound disclosed and al! pharmaceutically acceptable salts, esters, stereoisomers, tautomers, prodrugs, solvatés, and deuterated forms thereof, unless otherwise specified.

[0048] Depending on the particular substituents, the compounds of Formula I may exist in tautomeric forms. It is understood that two or more tautomeric forms may exist fora given compound structure For example, a compound of Formula I (where R³ is -OH) may exist in at least the following tautomeric forms:

[0049]

As is understood by those of skiîl in the art, various other tautomeric forms may exist and are intended to be encompassed by the compounds of Formula I. Some descriptions herein expressly refer to “tautomers thereof' but it is understood that, even in the absence of such language, tautomers are intended and described. Further, it is understood that the compounds of Formula I may shift between various tautomeric forms or exist in various ratios of each form based on the particular environment of the compound [0050] The compounds disclosed herein may contain chiral centers, which may be either of the (/Î) or (5) configuration, or which may comprise a mixture thereof. Accordingly, the présent disclosure includes stereoisomers of the compounds described herein, where applicable, either individually or admixed in any proportions Stereoisomers may include, but are not limited to, enantiomers, diastereomers, racemic mixtures, and combinations thereof. Such stereoisomers can be prepared and separated using conventional techniques, either by reactîng enantiomeric starting materials, or by separating isomers of compounds of the présent disclosure.

[0051]

The compounds of the présent disclosure may be compounds according to

Formula (I) with one or more chiral centers, which may be either of the (R) or (S) configuration, or which may comprise a mixture thereof [0052]

The présent disclosure includes both racemic mixtures of a compound of formula

I and isolated isomers of Formula (I) or any variation thereof. Where more than one chiral center is présent in a compound of the présent disclosure, some, none, or ali of the chiral centers may be enantiomerically enriched. Thus, mixtures ofa compound ofFormula (I) may be racemic with respect to one or more chiral centers and/or enantiomerically enriched with respect to one or more chiral centers.

[0053] The présent disclosure relates to a compound of formula (I)

R⁵^	R⁴	R³
rïr
R⁶' ^Rx	U ô
	Q	χψχ²
		R² (I)
wherein
t	N
Ji
Q is N or R¹⁰	*

X¹, X², and X³ are each independently N or C(R”), provided that, at most 2 of X¹, X², and X³ are N;

R¹ is -H, -CN, -OR*, -C(O)OR*, halogen, Ct-ealkyl, Cî-iocycloalkyl, or Cteheteroalkyl, wherein each Ci-calkyl, Cî-iocycloalkyl, and Ci-eheteroalkyl is optionally substituted with 1,2,3,4, or 5 R¹² groups, which may be same or different;

R² is -H, -CN, -OR*, -NR*R^b, -C(O)OR*, halogen, Ci^alkyl, Cî.iocycloalkyl, or Ci-e heteroalkyl, wherein each Ci^alkyl, Cî-iocycloalkyl, and Ci-eheteroalkyl is optionally substituted with 1, 2,3,4, or 5 R¹² groups, which may be same or different;

R³ is -H, -OR*, -SR*. -NR*R^b,-NHC(O)NR*R^b, Ci^alkyl, Cs-iocycloalkyl. or Ci^ heteroalkyl, wherein each Ci^alkyl, Cî-iocycloalkyl, and Ci^heteroalkyl is optionally substituted with 1,2,3,4, or 5 R¹² groups, which may be same or different;

R⁴ is -H, -OR*, halogen, -NO;, -CN, -NR*R^b, -NHC(O)NR*R^b, -OC(O)NR*R^b, CHîC(O)NR*R^b, Ci^alkyl, C3-iocycloalkyl, or Ci-6 heteroalkyl, wherein each Ci^alkyl, C3· locycloalkyl,and C1-6heteroalkyl is optionally substituted with 1,2,3,4, or 5 R¹² groups, which may be same or different;

R’ is -H, -OR*, halogen, -NO2, -CN, -NR'R^b, -NHC(O)NR'R^b, -OC(O)NR'R^b, Cll2C(O)NR*R^b, Ci-ealkyl, Cî-iocycloalkyl, or CMheteroalkyl, wherein each Ci^alkyl, C3locycloalkyl, and CMheteroalkyl is optionally substituted with 1,2,3,4, or 5 R¹² groups, which may be same or different;

R⁶ is -H, -OR*, halogen, -NO2, -CN, -NR’R^b, -NHC(O)NR'R^b, -OC(O)NR*R^b, CH2C(0)NR’R^b, Ci-ealkyl, C3-iocycloalkyl, or Ci-e heteroalkyl, wherein each Ci^alkyl, C3îocycloalkyl, and Cm heteroalkyl is optionally substituted with 1,2,3,4, or 5 R¹² groups, which may be same or different;

R⁷ is Ci.6alky1, Cs-iocycloalkyl, CMheteroalkyl, halogen, -OR*,-CN, or-NÛ2, wherein each Ci^alkyl, Cs-iocycloalkyl, and Cm heteroalkyl is optionally substituted with 1, 2,3, 4, or 5 R¹² groups, which may be same or different;

R⁸ is CMalkyl, Cs-iocycloalkyl, CMheteroalkyl, halogen, -OR', -CN, or -NO2, wherein each Ci-ealkyl, C3-iocycloalkyl, and Cm heteroalkyl is optionally substituted with 1, 2, 3,4, or 5 R¹² groups, which may be same or different,

R⁹ is -H, Ci-ealkyl, or C3-iocycloalkyl, wherein each Ci-ealkyl and C3-iocycloalkyl is optionally substituted with 1,2,3,4, or 5 R¹² groups, which may be same or different;

R¹⁰ is -H, Ct^alkyl, or Cj-iocycloalkyl, wherein each CMalkyl and C3-iocycloalkyl is optionally substituted with 1,2,3,4, or 5 R¹² groups, which may be same or different;

each R¹¹ is independently -H, -CN, -OR*. -C(O)OR', halogen, CMalkyl, C3locycloalkyl, or Cmheteroalkyl, which may be same or different, wherein each CMalkyl, C3locycloalkyl, and CMheteroalkyl is optionally substituted with 1,2,3,4, or 5 R¹² groups, which may be same or different, each R¹² is independently CMalkyl, C3-iocycloalkyl, CMheteroalkyl, 5-10 membered heterocyclyl, Cs-toaryl, 5-10 membered heteroaryl, halogen, -OR, -C(O)R', -C(O)OR, C(O)NR*R^b, -OC(O)NR'R^b, -NR*C(O)OR^b, -SR*. -S(O)i-2R*, -S(O)2F, -S(O)2NR'R^b, NR'S(O)2R^b, -N3, -CN, or -NO2; wherein each CMalkyl, C3-iocycloalkyl, CMheteroalkyl, and 5-10 membered heterocyclyl is optionally substituted with 1,2,3,4, or 5 substituents selected from halogen, -OR*, -C(O)R', -C(O)OR', -C(O)NR'R^b, -OC(O)NR'R^b, NR*C(O)OR^b, -SR*, -S(O)i.2R*, -S(O)2F, -S(OhNR*R^b, -NR'S(O)2R^b, -N₃, -CN, and NO2, groups, which may be same or different;

each R* and R^bis independently -H, -NHxCi-ealkyl, Ca-iocycloalkyl, Ci^heteroalkyl, 5-10 membered heterocyclyl, Ce-ioaryl, or 5-10 membered heteroaryl, wherein each Citalkyl, Ca-iocycloalkyl, Ci^heteroalkyl, 5-10 membered heterocyclyl, Ce-ioaryl, and 5-10 membered heteroaryl is optionally substituted with I, 2,3,4, or 5 R¹³groups, which may be same or different; or R* and R^b together with the atoms to which they are attached form a 510 membered heterocycle; and each R¹³ is independently -CN, halogen, Ci^alkyl, Cs-iocycloalkyl, Ci-Jieteroalkyl, or 5-10 membered heterocyclyl;

or a tautomer or a pharmaceutically acceptable sait thereof.

[0054] In certain embodiments in formula (I), R² is -II, -CN, -OR, or Ci-ealkyl.

[0055] In certain embodiments in formula (I), R² is -CN.

[0056] In one variation, the présent disclosure relates to compounds of formula (II), which are compounds of formula (I)·

R⁴ R³

II N (II) wherein

I

X¹, X², and X³ are each independently N or C(R¹¹), provided that, at most 2 of X¹, X², and X³ are N;

R¹ is -H, -CN, -OR*, -C(O)OR*. halogen, or Ci^alkyl, wherein Ci^alky 1 is optionally substituted with 1,2,3,4, or 5 R¹² groups, which may be same or different;

R³ is -H, -OR*, -NR'R^b, -NHC(0)NR'R^b, Ci.«alkyl, or CiJieteroalkyl, wherein each Ci^alkyl and Ci^heteroalkyl is optionally substituted with 1,2,3,4, or 5 R¹² groups, which may be same or different;

R⁴ is -H, -OR*, halogen, -NO2, -CN, -NR*R^b, Cj^alkyl, or Ci-« heteroalkyl, wherein each Ci-ealkyl and Ct-β heteroalkyl is optionally substituted with 1,2,3,4, or 5 R¹² groups, which may be same or different;

R’ is -H, -OR’, halogen, -NO2, -CN, -NR*R^b, Ci-«alkyl, or Ci-e heteroalkyl, wherein each Ci^alkyl and Ci-βheteroalkyl is optionally substituted with 1, 2,3,4, or 5 R¹² groups, which may be same or different;

R⁶ is -H, -OR’, halogen, -NO₂, -CN, -NR*R^b, Ci^alkyl, or Ci^s heteroalkyl, wherein each Ci-ealkyl and Ci« heteroalkyl is optionally substituted with 1, 2,3, 4, or 5 R¹² groups, which may be same or different;

R⁷ is Ci.6alkyl, Ci-eheteroalkyl, halogen, -OR*, -CN, or-NOî, wherein each Ci«alkyl is optionally substituted with 1, 2,3,4, or 5 R¹² groups, which may be same or different;

R⁸ is Ci^alkyl, Ci-eheteroalkyl, halogen, -OR*, -CN, or-NO;, wherein each Ci«alkyl is optionally substituted with 1, 2, 3,4, or 5 R¹² groups, which may be same or different;

R⁹ is -H or Ci.«alkyl, wherein Ci^alkyl is optionally substituted with 1,2, 3,4, or 5 R¹² groups, which may be same or different;

R¹⁰ is -H or Ci-ealkyl wherein Ci-«alkyl is optionally substituted with 1,2, 3,4, or 5 R¹² groups, which may be same or different;

each R¹¹ is independently -H, -CN, -OR*, -C(O)OR*, halogen, or Ci^alkyl, which may be same or different, wherein Ci-«alkyl is optionally substituted with 1, 2,3,4, or 5 R¹²groups, which may be same or different;

each R¹² is independently Ci^alkyl, Cj-iocycloalkyl, Ci-eheteroalkyl, 5-10 membered heterocyclyl, C«-ioaryl, 5-10 membered heteroaryl, halogen,-OR*, -C(O)R*, -C(O)OR*, C(O)NR*R^b, -OC(O)NR*R^b, -NR*C(O)OR^b, -SR*, -S(O)i-2R*. -S(O)2F, -S(O)2NR*R^b, NR*S(O)2R^b, -Nî, -CN, or-NO;; wherein each Cwalkyl, Cj-iocycloalkyl, Ci .«heteroalkyl, and 5-10 membered heterocyclyl is optionally substituted with 1, 2,3,4, or 5 substituents selected from halogen, -OR*, -C(O)R*, -C(O)OR*, -C(O)NR*R^b, -OC(O)NR*R^b, NR*C(O)OR^b, -SR*, -S(O)t.2R*, -S(O)2F, -S(O)?NR*R^b, -NR*S(O)2R^b, -Nj, -CN, and NO2, groups, which may be same or different;

each R* and R^bis independently -H, Ci^alkyl, C₃-iocycloalkyl, Ci^heteroalkyl, 5-10 membered heterocyclyl, Ce-ioaryl, or 5-10 membered heteroaryl, wherein each Ci^alkyl, C₃locycloalkyl, Ci-eheteroalkyl, 5-10 membered heterocyclyl, Cô-ioaryl, and 5-10 membered heteroaryl is optionally substituted with 1,2,3,4, or 5 R¹³ groups, which may be same or different; or R* and R^b together with the atoms to which they are attached form a 5-10 membered heterocycle; and each R¹³ is independently-CN, halogen, Cnalkyl, C₃-iocycloalkyl, Ci-ôheteroalkyl, or 5-10 membered heterocyclyl, or a tautomer or a pharmaceutically acceptable sait thereof.

[0057]

In certain embodiments in formula (I) and (II), Q is

R¹ [0058] In certain embodiments in formula (I) and (II), Q is R¹⁰ .

[0059] In certain embodiments in formula (I) and (II), X’, X², and X³ are each independently N or C(R¹¹), wherein 2 of X¹, X², and X³ are N. In certain embodiments, X¹, X², and X³ are each independently N or C(R¹¹), wherein one of X’, X², and X³ is N. In certain embodiments, X’, X², and X³ are each independently N or C(R”), wherein none of X¹, X², and X³ is N.

[0060] In certain embodiments in formula (I) and (II), X’, X², and X³ are each C(R^U). In certain embodiments in formula (I) and (II), X¹, X², and X³ are each CH. In certain embodiments, X¹ is N; X² is C(Rⁿ), and X³ is C(Rⁿ) In certain embodiments, X’ is N; X²is CH, and X³ isCH.

[0061] In certain embodiments in formula (l)and (II), X’ is N; X² is N; and X³ is C(Rⁿ). In certain embodiments, X¹ is N; X² is C(Rⁿ); and X³ is N. In certain embodiments, X¹ is C(Rⁿ); X² is N; and X³ is C(Rⁿ).

[0062] In certain embodiments in formula (I) and (II), R¹ is -H or Ci-«alkyl. In certain embodiments, R’ is -H. In certain embodiments, R¹ is Ci^alkyl In certain embodiments, R¹ is methyl.

[0063] In certain embodiments in formula (I) and (II), X¹, X², and X³ are C(R“); each R¹¹ are independently selected from -II, -CN, -OR*, halogen, and Ci^alky 1; and R¹ is selected from -H, -CN, -OR¹, halogen, and Ci-calkyl. In certain embodiments, X¹, X², and X³ are C(Rⁿ); each R are -H; and R¹ is -H.

[0064] In certain embodiments in formula (I) and (II), X’ is N; X² is C(R^l ’); and X³ is C(R¹¹); each R¹¹ are independently selected from -H, -CN, -OR¹, halogen, and Ci^alkyI; and R¹ is selected from -H, -CN, -OR¹, halogen, and Ci^alkyl. In certain embodiments, X¹ is N; X¹ is C(R¹¹); and X³ is C(Rⁿ); each R'¹ are -H; and R¹ is selected from -H and Ci-ealkyl. In certain embodiments, X¹ is N; X² is C(R^H); and X³ is C(R¹¹); each R” are -H; and R¹ is -H.

X²

R² [0065]

In certain embodiments in formula (I) and (II), of formula (I) or (II) is

In certain embodiments in formula (I) and (II), [0066]

In certain embodiments, ^'NH

R³ certain embodiments,

XyX³

R³ 'NH

M of formula (I) or (II) is of formula (I) or (II) is

[0067] In certain embodiments in formula (I) and (II), R³ is -H, -OR, -NR*R^b, NHC(O)NR’R^b, Ci-ôalkyl, or Ci-eheteroalkyl. In certain embodiments, R³ is H, -OR*. -NR*R^b, or -NHC(O)NR*R^b.

[0068] In certain embodiments in formula (I) and (II), R³ is -NR'R^b or -OR*. In certain embodiments, R³ is -N H 2 or-OH.

[0069] In certain embodiments, R³ is —NR'R^b. In certain embodiments, R³ is -NR*R^b, wherein each R' and R^b is independently -H or Ct^alkyl, wherein the Ci^alkyl is optionally substituted with 1,2,3,4, or 5 R¹³ groups. In certain embodiments, R³ is -NR*R^b, wherein each R' and R^b is independently -H or Ct-6alkyl. In certain embodiments, R³ is -NR*R^b, wherein each R* and R^b is independently -H, methyl, butyl, or cyclopropyl methyl. In certain embodiments, R³ is -NH2.

[0070] In certain embodiments in formula (I) and (H), R³ is -OR*. In certain embodiments, R³ is -OH.

[0071 ] In certain embodiments in formula (I) and (II), R³ is -H. In certain embodiments, R³ is -NHC(O)NR'R^b. In certain embodiments, R³ is -NHC(O)NIh.

[0072] In certain embodiments in formula (I) and (H), R⁴ is -H, -OR*, halogen, -NO2, CN, -NR'R^b, -NIIC(O)NR’R^b, or C^lkyl. In certain embodiments, R⁴ is -H or -OR’.

[0073] In certain embodiments in formula (I) and (II), R⁵ is -H, -OR*, halogen, -NO2, CN, -NR*R^b, -NHC(O)NR’R^b, or Ct^alkyl. In certain embodiments, R’ is -H, -OR*, halogen, -NO2, -CN, -NR*R^b, or Ci-talky 1.

[0074] In certain embodiments in formula (I) and (II), R⁶ is -H, -OR, halogen, -NÛ2, CN, -NR*R^b, -NHC(O)NR*R^b, or Ci-talkyl. In certain embodiments in formula (I) and (II), R⁶ is -H.

[0075] In certain embodiments in formula (I) and (II), two of R⁴, R^s, and R⁶ are -H and one of R⁴, R’, and R® is -H, -OR*, halogen, -NO₂, -CN, -NR*R^b, -NHC(O)NR*R^b, or Ci. ealkyl. In certain embodiments, two of R⁴, R⁵, and R⁶ are -H and one of R⁴, R⁵, and R⁶ is H, -OR*, halogen, -NO2, -NR*R^b, or Ci-ealkyI. In certain embodiments, two of R⁴, R’, and R⁶ are -H and one of R⁴, R\ and R® is 41, -OCH3, halogen, -NO2, -NH2, or methyl.

[0076] In certain embodiments in formula (I) and (II), R⁴, R®, and R® are -H.

[0077] In certain embodiments in formula (I) and (II), R⁷ is Ci^alkyl, Ci^heteroalkyl, halogen, -OR*, -CN, or -NO2. In certain embodiments, R⁷ is Ci^alkyl, halogen, or-OR*. [0078] In certain embodiments in formula (I) and (II), R⁸ is Ci-6alkyl, Ci^heteroalkyl, halogen, -OR*, -CN, or-NOz In certain embodiments, R⁸ is Ci^alkyl, halogen, or-OR*. [0079] In certain embodiments tn formula (I) and (II), R⁷ and R⁸ are the same and are selected from Ci^alkyl, Ci^hetcroalkyl, halogen, -OR*, -CN, and -NO2 In certain embodiments, R⁷ and R⁸ are the same and are selected from Ci^alkyl, halogen, or-OR*.

[0080] In certain embodiments in formula (I) and (II), R⁷ and R⁸ are Ci^alkyl. In certain embodiments, R⁷and R⁸ are methyl.

[0081 ] In certain embodiments in formula (I) and (II), R⁷ and R⁸ are -OR*. In certain embodiments, R⁷and R⁸ are -OCH3.

[0082] In certain embodiments in formula (I) and (Π), R⁷ and R⁸ are halogen. In certain embodiments, R⁷ and R⁸ are fluoro.

[0083] In certain embodiments in formula (I) and (II), R⁹ is 41 or Ci^alkyl. In certain embodiments, R⁹ is 41 or methyl.

[0084] In certain embodiments in formula (I) and (II), R¹⁰ ts 41 or Ct-ealkyl. In certain embodiments in formula (I) and (II), R¹⁰ is -H or methyl.

[0085] In certain embodiments in formula (I) and (II), R⁹ is -H or Ci-ealkyl; and R¹⁰ is H or Ci-ealkyl. In certain embodiments, R⁹ is -H or methyl, and R¹⁰ is -H or methyl. In certain embodiments in formula (I) and (II), R⁹ and R¹⁰ are -H.

I ' ι/vw AW

[0086] In certain embodiments in formula (I) and (II), Q is selected from N, N ,

AW

A

rfVW

[0087] [0088]

In certain embodiments in formula (I) and (II), Q is N,

It is understood that any variable for Q of formula (I) and (II) may be combined with any variable of R³ in formula (I) and (II), the same as if each and every combination were specifically and indivîdually listed. For example, in one variation of formula (I) and ili . ili , .

N and R³ is -NH2. In another variation, Q is N and R³ is -OH.

It is understood that any variable for R⁷ of formula (I) and (II) may be combined (II), Q is [0089] with any variable of R³ in formula (I) and (II), the same as if each and every combination were specifically and indivîdually listed. For example, in one variation of formula (I) and (Π), R⁷ is methyl and R³ is -NIh. In another variation, R⁷ is methyl and R³ is -OH [0090] It is understood that any variable for R⁸ of formula (I) and (II) may be combined with any variable of R³ in formula (I) and (II), the same as if each and every combination were specifically and indivîdually listed. For example, in one variation of formula (I) and (Π), R⁸ is methyl and R³ is -NIE In another variation, R⁸ is methyl and R³ is -OH.

[0091 ] It is understood that any variable for R⁴, R³, and R⁶ of formula (I) and (II) may be combined with any variable of R³ in formula (I) and (II), the same as if each and every combination were specifically and indivîdually listed. For example, in one variation of formula (I) and (II), R⁴, R^s, and R⁶ are each -H; and R³ is -NH₂. In another variation, R⁴, R^s, and R⁶ are each -H; and R³ is -OH.

[0092] It is understood that any variable for X¹, X², and X³ of formula (I) and fil) may be combined with any variable of R³ in formula (I) and (II), the same as if each and eveiy combination were specifically and individually listed. For example, in one variation of formula (I) and (II), X¹, X², and X³ are each CH; and R³ is -NH2. In one variation of formula (I) and (II), X¹ is N; X² is CH, and X³ is CH; and R³ is -NH2. In another variation, X¹ is N; X² is CH; and X³ is CH, and R³ is -OH. In another variation, X¹, X², and X³ are each CH; and R³ is -OH.

[0093] It is understood that any variable for R¹ of formula (1) and (11) may be combined with any variable of R³ in formula (I) and (II), the same as if each and evety combination were specifically and individually listed. For example, in one variation of formula (I) and (II), R¹ is hydrogen and R³ is -NH₂. In another variation, R¹ is hydrogen and R³ is -OH.

[0094] In certain embodiments of formula (I) and (II), where R³ is -NH₂, the compounds may hâve any one or more of the following structural features:

a) X¹, X², and X³ are each CH,

b) R⁷ is methyl,

c) R⁸ is methyl;

II

d) Q is N; and

e) R⁴, R^s, and R^s are each -H.

[0095] In one variation, the compounds conform to at least one of features (a)-(e). In another variation, the compounds conform to two or more (and in certain variations, ail) of features (a)-(e). In a particular variation, the compounds conform to feature (a) In another variation, the compounds conform to features (a), (b), and (c). In another variation, the compounds conform to features (a) and (d) In another variation, the compounds conform to features (a) and (e).

[0096] In certain embodiments of formula (I) and (11), where R³ is -OH, the compounds may hâve any one or more of the following structural features:

a) X¹ is N; X² is CH; and X³ is CH;

b) R⁷ is methyl;

c) R* is methyl;

t ww

II

d) Qis N;and

e) R⁴, R³, and R⁶ are each -H.

[0097] In one variation, the compounds conform to at least one of features (a)-(e) In another variation, the compounds conform to two or more (and in certain variations, ail) of features (a)-(e). In a particular variation, the compounds conform to feature (a) In another variation, the compounds conform to features (a), (b), and (c) In another variation, the compounds conform to features (a) and (d) In another variation, the compounds conform to features (a) and (e).

WW . Il [0098] In certain embodiments of formula (I) and (II), where Qis N, the compounds may have any one or more of the following structural features:

a) X¹, X², and X³ are each CH or X¹ is N; X² is CH; and X³ is CH,

b) R³ is -Nlb or -OH;

c) R⁷ and R⁸ are methyl;

d) R⁴, R\ and R⁶ are each -H.

[0099] In one variation, the compounds conform to at least one of features (a)-(d) In another variation, the compounds conform to two or more (and in certain variations, ail) of features (a)-(d) In a particular variation, the compounds conform to feature (a). In another variation, the compounds conform to features (a) and (b). In another variation, the compounds conform to features (a), (b), and (c). In another variation, the compounds conform to features (a), (b), and (d).

[0100] The présent disclosure relates to the following compounds or a pharmaceutically acceptable sait thereof.

[0101] The présent disclosure relates to the following compound or a tautomer or a pharmaceutically acceptable sait thereof.

[0102] The présent disclosure relates to the following compound or a pharmaceutically acceptable sait thereof:

O OH

N , and tautomers thereof such as N .

Pharmaceutical Compositions [0103] Pharmaceutical compositions comprising the compounds disclosed herein, or pharmaceutically acceptable salts thereof, may be prepared with conventional carriers (e.g., inactive ingrédient or excipient material) which may be selected in accord with ordinary practice. Tablets may contain excipients including glidants, fillers, bînders and the like. Aqueous compositions may be prepared in stérile form, and when intended for delivery by other than oral administration generally may be isotonie. Ail compositions may optionally contain excipients such as those set forth in the Rowe et al, Handbook of Pharmaceutical Excipients, 5°¹ édition, American Pharmacists Association, 1986. Excipients can include ascorbic acid and other antîoxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like. In certain embodiments, the composition relates to a solid dosage form, includinga solid oral dosage form. The pH of a composition may range from about 3 to about 11, but is ordinarily about 7 to 10.

[0104] While it is possible for the active ingrédients to be administered alone, it may be préférable to présent them as pharmaceutical compositions. The compositions, both for veterinary and for human use, comprise at least one compound of formula (I), together with one or more acceptable carriers and optionally other therapeutic ingrédients In one embodiment, the pharmaceutical composition comprises a compound of formula (I), or a tautomer or a pharmaceutically acceptable sait thereof, a pharmaceutically acceptable carrier and one other therapeutic ingrédient. The carrierfs) are “acceptable in the sense of being compatible with the other ingrédients of the composition and physiologically innocuous to the récipient thereof.

[0105] The compositions include those suitable for various administration routes, including oral administration. The compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingrédient (e.g., a compound of formula (I) or a pharmaceutical sait thereof) with one or more inactive ingrédients (e.g., a carrier, pharmaceutical excipient, etc.) The compositions may be prepared by uniformly and intimately bringing into association the active ingrédient with liquid carriers or fïnely divided solid carriers or both, and then, if necessary, shaping the product. Techniques and formulations generally are found in Remington: The Science and Practice of Pharmacy, 21 Edition, Lippincott Wiliams and Wilkins, Philadelphia, Pa, 2006. [0106] Compositions described herein that are suitable for oral administration may be presented as discrète units (a unit dosage form) including but not limited to capsules, cachets or tablets each containing a predetermined amount of the active ingrédient.

(0107] Pharmaceutical compositions disclosed herein comprise one or more compounds disclosed herein, or a pharmaceutically acceptable sait thereof, together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. Pharmaceutical compositions containing the active ingrédient may be in any form suitable for the intended method of administration. When used for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, émulsions, hard or soft capsules, syrups or élixirs may be prepared. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable préparation Tablets containing the active ingrédient in admïxture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid, binding agents, such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricating agents, such as magnésium stéarate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceiyl monostearate or glyceryl distearate alone or with a wax may be employed. [0108| The amount of active ingrédient that may be combined with the inactive ingrédients to produce a dosage form may vary depending upon the intended treatment subject and the particular mode of administration. For example, in some embodiments, a dosage form for oral administration to humans may contain approximately 1 to 1000 mg of active material formulated with an appropriate and convenient amount of carrier material (e.g., inactive ingrédient or excipient material) In certain embodiments, the carrier material varies from about 5 to about 95% ofthe total compositions (weightiweight).

[0109] It should be understood that in addition to the ingrédients 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.

]0110| In certain embodiments, a composition comprising an active ingrédient disclosed herein (a compound of formula (I) or a pharmaceutically acceptable sait thereof) in one variation does not contain an agent that affects the rate at which the active ingrédient is metabolized. Thus, it is understood that compositions comprising a compound of formula (I) in certain embodiments do not comprise an agent that would affect (e.g., slow, hinder or retard) the metabolism of a compound of formula (I) or any other active ingrédient administered separately, sequentially or simultaneously with a compound of formula (I). It is also understood that any of the methods, kits, articles of manufacture and the like detailed herein in certain embodiments do not comprise an agent that would affect (e.g., slow, hinder or retard) the metabolism of a compound of formula (I) or any other active ingrédient administered separately, sequentially or simultaneously with a compound of any one of formula (I).

Methods of Use [0111] Disclosed herein is a method of inhibiting an HIV reverse transcriptase in an individual in need thereof, comprising administering a compound of Formula (I), or a pharmaceutically acceptable sait 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 IIIV but who has not developed AIDS. In certain embodiments, the individual in need thereof is an individual at risk fordeveloping AIDS. In certain embodiments, the individual in need thereof is a human who has been infected with HIV and who has developed AIDS. In certain embodiments of the methods disclosed herein, a compound of Formula (I), or a pharmaceutically acceptable sait thereof, is administered to the individual separately, sequentially orsimultaneously with another active ingrédient for treating HIV, such as HIV protease inhibiting compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, IIIV nucléotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp4l inhibitors, CXCR4 inhibitors, gp!20 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, and other drugs for treating HIV, and combinations thereof [0112] In certain embodiments, a method for treating orpreventing an HIV viral infection in an individual (e.g., a human), comprising administering a compound of formula (I), or a pharmaceutically acceptable sait thereof, to the individual is disclosed.

|0113] In certain embodiments, a method for inhibiting the réplication of the HIV virus, treating AIDS or delaying the onset of AIDS in an individual (e.g., a human), comprising administering a compound of any formula (I), or a pharmaceutically acceptable sait thereof, to the individual is disclosed.

[01141 In certain embodiments, a method for preventing an HIV infection in an individual (e.g., a human), comprising administering a compound of formula (I), or a pharmaceutically acceptable sait thereof, to the individual is disclosed. In certain embodiments, the individual is at risk of contracting the HIV virus, such as an individual who has one or more risk factors known to be associated with contracting the HIV virus. [0115| In certain embodiments, a method for treating an HIV infection in an individual (e.g., a human), comprising administering a compound of formula (I), or a pharmaceutically acceptable sait thereof, to the individual is disclosed [0116| In certain embodiments, a method for treating an HIV infection in an individual (e.g., a human), comprising administering to the individual in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable sait 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, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucléotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp4l inhibitors, CXCR4 inhibitors, gpl 20 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, and other drugs for treating HIV, and combinations thereof is disclosed.

10117] In certain embodiments, a compound of formula (I), or a pharmaceutically acceptable sait thereof for use in medical therapy ofan HIV viral infection (e.g. HIV-I or the réplication of the HIV virus (e.g. HIV-1) or AIDS or delaying the onset of AIDS in an individual (e.g., a human)) is disclosed.

[0118] In certain embodiments, a compound ofany of formula (I), or a pharmaceutically acceptable sait thereof for use in the manufacture of a médicament for treating an HIV viral infection or the réplication of the HIV virus or AIDS or delaying the onset of AIDS in an individual (e.g., a human) is disclosed. One embodiment relates to a compound of formula (I), or a pharmaceutically acceptable sait thereof, for use in the prophylactic or therapeutic treatment ofan HIV infection or AIDS or for use in the therapeutic treatment or delaying the onset of AIDS is disclosed.

[0119] In certain embodiments, the use of a compound of formula (I), or a pharmaceutically acceptable sait thereof, for the manufacture of a médicament for an HIV virus infection in an individual (e.g., a human) is disclosed In certain embodiments, a compound of any of formula (I), or a pharmaceutically acceptable sait thereof, for use in the prophylactic or therapeutic treatment of an HIV virus infection is disclosed.

[0120] In certain embodiments, in the methods of use, the administration is to an individual (e.g., a human) in need of the treatment. In certain embodiments, in the methods of use, the administration is to an individual (e.g., a human) who is at risk of developing AIDS

10121] Disclosed herein is a compound of formula (I), or a pharmaceutically acceptable sait thereof, for use in therapy. In one embodiment, the compound of formula (I), or a pharmaceutically acceptable sait thereof, is for use in a method of treating an HIV viral infection or the réplication of the HIV virus or AIDS or delaying the onset of AIDS in an individual (e.g., a human).

10122] Also disclosed herein is a compound of formula (I), or a pharmaceutically acceptable sait thereof, for use in a method of treating or preventing HIV in an individual in need thereof. 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 who has not developed AIDS In certain embodiments, the individual in need thereof is an individual at risk for developing AIDS In certain embodiments, the individual in need thereof is a human who has been infected with HIV and who has developed AIDS |0123[ Also disclosed herein is a compound of formula (I), or a pharmaceutically acceptable sait thereof, for use in the therapeutic treatment or delaying the onset of AIDS. |0124] Also disclosed herein is a compound of formula (I), or a pharmaceutically acceptable sait thereof, for use in the prophylactic or therapeutic treatment of an HIV infection.

[0I25| In certain embodiments, a compound of formula (I), or a pharmaceutically acceptable sait thereof can be used as a research tool (e.g. to study the inhibition of HIV reverse transcriptase in a subject or in vitro)

Routes of Ad ministration [0126( One or more compounds disclosed herein which are of the Formula (I) (also referred to herein as the active ingrédients) can be administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal and parentéral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and épidural), and the like. It will be appreciated that the preferred route may vary with, for example, the condition of the récipient. In certain embodiments, the compounds disclosed are orally bioavailable and can be dosed orally.

Dosing Regimen [0127] The compound, such as a compound of Formula (I), may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer. In one variation, the compound is administered on a daily or intermittent schedule for the duration of the individual’s life.

[0128] The dosage or dosîng frequency of a compound of Formula (I) may be adjusted over the course of the treatment, based on the judgment of the ad minis te ring physician. [0129] The compound may be administered to an individual (e.g., a human) in an effective amount. In certain embodiments, the compound is administered once daily.

J0130] A compound as disclosed herein (e.g., any compound of Formula (I)) may be administered in a dosage amount of the compound of Formula I that is effective. For example, the dosage amount can be from 10 mg to 1000 mg of compound, such as 75 mg to 100 mg of the compound.

Combinations [0131] In certain embodiments, a method for treating or preventing an HIV infection in a human having or at risk of having the infection is disclosed, comprising administering to the human a therapeutically effective amount ofa compound disclosed herein, or a pharmaceutically acceptable sait 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 an HIV infection in a human having orat risk of having the infection ïs disclosed, comprising administering to the human a therapeutically effective amount ofa compound disclosed herein, or a pharmaceutically acceptable sait 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.

[0132] In certain embodiments, the présent disclosure relates to a method for treating an HIV infection, comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable sait, thereof, in combination with a therapeutically effective amount ofone or more additional therapeutic agents which are suitable for treating an HIV infection.

[0133] Also disclosed herein is a compound of formula (I), or a pharmaceutically acceptable sait thereof, and another active ingrédient for treating HTV, for use in a method of treating or preventing HIV. In one embodiment, the another active ingrédient for treating HIV is selected from the group consisting of HIV protease inhibiting compounds, HIV nonnucleoside inhibitors of reverse transcriptase, HIV nucleoside inhîbitors of reverse transcriptase, HIV nucléotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp4I inhibitors, CXCR4 inhibitors, gpl20 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, and other drugs for treating HIV, and combinations thereof. [0134] Also disclosed herein is a compound of formula (I), or a pharmaceutically acceptable sait thereof, for use in a method of treating or preventing HIV, wherein the compound of formula (I) or a pharmaceutically acceptable sait thereof is administered simultaneously, separately or sequentially with another active ingrédient for treating HIV. In one embodiment, the another active ingrédient for treating HIV is selected from the group consisting of HIV protease inhibiting compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucléotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gpl 20 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, and other drugs for treating

HIV, and combinations thereof.

[0135] A compound as disclosed herein (e g, any compound of Formula (I)) may be combined with one or more additional therapeutic agents in any dosage amount of the compound of Formula I (e g , from 10 mg to 1000 mg of compound or 75 mg to 100 mg of compound).

[0136] In one embodiment, pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable sait 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 are disclosed.

[0137] In one embodiment, kits comprising a compound disclosed herein, or a pharmaceutically acceptable sait thereof, in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents are disclosed.

[0138] In the above embodiments, the additional therapeutic agent may be an anti-HIV agent For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucléotide inhibitors of reverse transcriptase, HIV integrase inhibitors, 1IIV 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, gpl 20 inhibitors, G6PD and

NADH-oxidase inhibitors, HIV vaccines, HIV maturation inhibitors, latency reversing agents (e.g, histone deacetylase inhibitors, protéasome inhibitors, protein kinase C (PKC) activators, and BRD4 inhibitors), compounds that target the HIV capsid (“capsid inhibitors”; e g, capsid polymerization inhibitors or capsid disrupting compounds, HIV nucleocapsid p7 (NCp7) inhibitors, HIV p24 capsid protein inhibitors), pharniacokînetic enhancers, immune-based thérapies (e.g, Pd-1 modulators, Pd-LI modulators, toll like receptors modulators,, IL-15 agonists, ), HIV antibodies, bispecific antibodies and “antibody-like” therapeutic proteins (e.g., DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs ®, Fab dérivatives) induding those targeting HIV gpl20 or gp41, combination drugs for HIV, HIV pl7 matrix protein inhibitors, IL-13 antagonists, Peptidyl-prolyl cistrans isomerase A modulators, Protein disulfide isomerase inhibitors, Complément C5a receptor antagonists, DNA methyltransferase inhibitor, HIV vif gene modulators, HIV-1 viral infectivity factor inhibitors, T AT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, Rev protein inhibitors, Integrin antagonists, Nucleoprotein inhibitors, Splicing factor modulators, COMM domain containing protein I modulators, HIV Ribonucléase II inhibitors, Retrocyclin modulators, CDK-9 inhibitors, Dendritic ICAM-3 grabbingnonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, Complément Factor H modulators, Ubiquitin ligase inhibitors, Deoxycytidine kinase inhibitors, Cyclin dépendent kinase inhibitors Proprotein convertase PC9 stimulators, ATP dépendent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, PI3K inhibitors, compounds such as those disclosed in WO 2013/006738 (Gilead Sciences), US 2013/0165489 (University of Pennsylvania), WO 2013/091096Al (Boehringer Ingelheim), WO 2009/062285 (Boehringer Ingelheim), US20140221380 (Japan Tobacco). US20140221378 (Japan Tobacco), WO 2010/130034 (Boehringer Ingelheim), WO 2013/159064 (Gilead Sciences), WO 2012/145728 (Gilead Sciences), W02012/003497 (Gilead Sciences), WO20I4/100323 (Gilead Sciences), WO2012/145728 (Gilead Sciences), WO20I3/159064 (Gilead Sciences) and WO 2012/003498 (Gilead Sciences) and WO 2013/006792 (Pharma Resources), and other drugs for treating HIV, and combinations thereof.

(0139] In certain embodiments, the additional therapeutic is selected from the group consisting of HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucléotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, pharmacokinetic enhancers, and combinations thereof.

[0140] In certain embodiments a compound of Formula (I) is formulated as a tablet, which may optionally contain one or more other compounds useful for treating HIV. In certain embodiments, the tablet can contain another active ingrédient for treating HIV, such as HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucléotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, pharmacokinetic enhancers, and combinations thereof.

[0141] In certain embodiments, such tablets are suitable for once daily dosing. In certain embodiments, the additional therapeutic agent is selected from one or more of.

(1 ) Combination drugs selected from the group consisting of ATRIPLA® (efavirenz+tenofovir disoproxil fumarate +emtricitabîne), COMPLERA® (EVIPLERA®, rilpivirine+tenofovïr disoproxil fumarate +emtricitabine), STRIBILD® (elvitegraviri-cobicistat+tenofovir disoproxil fumarate +emtricitabine), dolutegravir+abacavir sulfate +lamivudine, dolutegravir + abacavir sulfate + lamivudine, lamivudine + nevirapine + zidovudine, dolutegravirt-rilpivirine, atazanavir sulfate + cobicistat, darunavir + cobicistat, efavirenz + lamivudine + tenofovir disoproxil fumarate, tenofovir alafenamide hemifumarate + emtricitabîne + cobicistat + elvitegravir, Vacc-4x + romidepsin, darunavir + tenofovir alafenamide hemifumarate+ emtricitabîne + cobicistat, APH-0812, raltegravir+ lamivudine, KALETRA® (ALUVIA®, lopinavir+ritonavir), atazanavir sulfate + ritonavir, COMBIVIR® (zidovudine+lamivudine, AZT+3TC), EPZICOM® (Livexa®, abacavir sulfate +lamivudine, ABC+3TC), TR1ZIVIR® (abacavir sulfate+zidovudine+ lamivudine, ABC+AZT+3TC), TRUVADA® (tenofovir disoproxil fumarate +emtricitabine, TDF+FTC), tenofovir + lamivudine and lamivudine + tenofovir disoproxil fumarate;

(2) HIV protease inhibitors selected from the group consisting ofamprenavir, 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) HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase selected from the group consisting of delavirdine, delavirdine mesylate, nevirapine, etravirine, dapivirine, doravirine, rilpivirine, efàvirenz, KM-023, VM-1500, lentinan and AIC-292;

(4) HIV nucleoside or nucléotide inhibitors of reverse transcriptase selected from the group consisting of VIDEX® and VIDEX® EC (didanosine, ddl), zidovudine, emtricitabine, didanosine, stavudine, zalcitabine, lamivudine, censavudine, abacavir, abacavir sulfate, amdoxovir, elvucitabine, alovudine, phosphazid, fozivudine tidoxil, apricitabine, amdoxovir, KP-1461, fosalvudine tidoxil, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovîr disoproxil hemifumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, tenofovir alafenamide fumarate, adefovir, adefovir dipivoxil, and festinavir;

(5) HIV integrase inhibitors selected from the group consisting of curcumin, dérivatives of curcumin, chîcoric acid, dérivatives ofchicoric acid, 3,5-dicaffeoylquinic acid, dérivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, dérivatives of aurintricarboxylic acid, cafieic acid phenethyl ester, dérivatives of cafieic acid phenethyl ester, tyrphostin, dérivatives oftyrphostin, quercetin, dérivatives ofquercetin, raltegravir, elvitegravir, dolutegravir andcabotegravir, (6) HIV non-catalytic site, or allosteric, integrase inhibitors (NCINI) selected from the group consisting ofCX-05168, CX-05045 and CX-14442;

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

(8) HIV entry inhibitors selected from the group consisting ofcenicriviroc;

(9) HIV gpl20 inhibitors selected from the group consistingof Radha-108 (Receptol) and BMS-663068;

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

(11) CD4 attachaient inhibitors selected from the group consisting of ibalizumab;

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

(13) Pharmacokinetic enhancers selected from the group consisting of cobicistat and ritonavir;

(14) Immune-based thérapies selected from the group consisting of dermaVir, interleukin-7, !exgenleucel-T (VRX-496), plaquenil (hydroxychloroquine), proleukin (aldesleukin, IL-2), interferon alfa, interferon alfa-2b, interferon alfâ-n3, pegylated interferon alfa, interferon gamma, hydroxyurea, mycophenolate mofetil (MPA) and its ester dérivative mycophenolate mofetil (MMF), WF-10, ribavirin, IL-2, IL-2 XL, IL-12, polymer polyethyleneimine (PE1), Gepon, VGV-1, MOR-22, BMS-936559, toll-like receptors modulators (tlrl, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlrlO, tlrl 1, tlrl 2 and tlr!3), rintatolimod and IR-103;

(15) HIV vaccines selected from the group consisting of peptide vaccines, recombinant subunit protein vaccines, 1 ive vector vaccines, DNA vaccines, virus-like particle vaccines (pseudovirion vaccine), CD4-derived peptide vaccines, vaccine combinations, rgpl20 (AIDSVAX), ALVAC HlV(vCP1521)/AIDSVAX B/E (gpl 20) (RV144), Remune, ITV-1, Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401), PEP6409,Vacc-4x, Vacc-C5, VAC-3S, multiclade DNA recombinant adenovirus-5 (rAd5), Pennvax-G, VRC-HIV MAB060-00-AB, AVX-101, Tat Oyi vaccine, AVX-201, HIVLAMP-vax, Ad35, Ad35-GRÏN, NAcGM3/VSSP ISA-51, poly-ICLC adjuvanted vaccines, Tatlmmune, GTU-multiHlV (FIT-06), AGS-004, gpl40[delta]V2.TVI+ MF-59, rVSVlN HIV-1 gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, Ad35-GRIN/ENV, TBC-M4, HIVAX , HIVAX-2, NYVAC-HIV-PTI, NYVAC-HIV-PT4, DNA-HIV-PT 123, Vichrepol, rAAVl-PG9DP, GOVX-B! I, GOVX-B21, ThV-01, TUTI-16, VGX-33OO, TVI-HIV-1, Ad4 (Ad4-env Clade C 4- Ad4-mGag), EN41-UGR7C, EN41-FPA2, PreVaxTat, TL-01, SAV001, AE-H, MYM-V101, CombiHlVvac, ADVAX, MYM-V201, MVA-CMDR and DNAAd5 gag/pol/nef/nev (HVTN5O5);

(16) HIV antibodies, bispecific antibodies and “antibody-like” therapeutic proteins (such as DARTs®, Duobodies®, Dites®, XmAbs®, TandAbs ®, Fab dérivatives) including BMS-936559, TMB-360 and those targeting HIV gpl 20 or gp41 selected from the group consisting of bavituximab, UB-421, C2F5, C2G12, C4E10, C2F5+C2G12+C4E10, 3-BNC117, KD-247, PGT145, PGT121, MDX010 (ipilimumab), VRC01, A32,7B2,10E8 and VRC07;

(17) latency reversing agents selected from the group consisting of Histone deacetylase inhibitors such as Romidepsin, vorinostat, panobinostat; Protéasome inhibitors such as Velcade; protein kinase C (PKC) activators such as Indolactam, Prostratin, Ingenol B and DAG-lactones, lonomycin, GSK-343, PMA, SAHA, BRD4 inhibitors, IL-15, JQ1, disulfram, and amphotericin B;

(18) HIV nucleocapsid p7 (NCp7) inhibitors selected from the group consisting of azodicarbonamide;

(19) HIV maturation inhibitors selected from the group consisting of BMS-955176 and GSK-2838232;

(20) PI3K inhibitors selected from the group consisting of idelalisib, AZD-8186, buparlisib, CLR-457, picttlisib, neratinib, rigosertib, rigosertib sodium, EN-3342, TGR-

1202, alpelisîb, duvelisib, UCB-5857, taselisib, XL-765, gedatolisib, VS-5584, copanlisib, CAI orotate, 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-l 126, RV-1729, sonolisib, LY-3023414, SAR-260301 and CLR-1401;

(21 ) the compounds disclosed in 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), WO 2013/091096A1 (Boehringer Ingelheim), WO 2013/159064 (Gilead Sciences), WO 2012/145728 (Gilead Sciences), W02012/003497 (Gilead Sciences), WO2014/100323 (Gilead Sciences), WO2012/145728 (Gilead Sciences), WO2013/159064 (Gilead Sciences) and WO 2012/003498 (Gilead Sciences); and (22) other drugs for treating HIV selected from the group consisting of TR-452, MK8591, REP 9, CYT-I07, alisporivir, NOV-205, IND-02, metenkefalin, PGN-007, Acemannan, Gamimune, SCY-635, Prolastin, 1,5-dicafleoylquinicacid, ΒΓΓ-225, RPI-MN, VSSP, Hlviral, IMO-3100, SB-728-T, RPI-MN, VIR-576, HGTV-43, MK-1376, rHlV7-shlTAR-CCR5RZ, MazF gene therapy, BlockAide and PA-1050040 (PA-040) [0142] In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable sait thereof, is combined with one, two, three, four or more additional therapeutic agents. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable sait thereof, is combined with two additional therapeutic agents. In other embodiments, a compound disclosed herein, or a pharmaceutically acceptable sait thereof, is combined with three additional therapeutic agents. In further embodiments, a compound disclosed herein, or a pharmaceutically acceptable sait thereof, is combined with four additional therapeutic agents. The one, two, three, four or more additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents, and/or they can be selected from different classes of therapeutic agents. In a spécifie embodiment, a compound disclosed herein, or a pharmaceutically acceptable sait thereof, is combined with an HIV nucleoside or nucléotide inhibitor of reverse transcriptase and an HIV non-nucleoside inhibitor of reverse transcriptase. In another spécifie embodiment, a compound disclosed herein, or a pharmaceutically acceptable sait thereof, is combined with an HIV nucleoside or nucléotide inhibitor of reverse transcriptase, and an HIV protease inhibiting compound. In a further embodiment, a compound disclosed herein, or a pharmaceutically acceptable sait thereof, is combined with an HIV nucleoside or nucléotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and an HIV protease inhibiting compound In an additional embodiment, a compound disclosed herein, or a pharmaceutically acceptable sait thereof, is combined with an HIV nucleoside or nucléotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable sait thereof, is combined with at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, a compound disclosed herein, or a pharmaceutically acceptable sait thereof, is combined with two HIV nucleoside or nucléotide inhibitors of reverse transcriptase.

[0143] In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable sait thereof, is combined with one, two, three, four or more additional therapeutic agents selected from raltegravir, Truvada® (tenofovir disoproxil fumarate +emtricitabine, TDF+FTC), maraviroc, enfuvirtide, Epzicom® (Livexa®, abacavir sulfate -Hamîvudine,

ABC+3TC), Trizivir® (abacavir sulfate+zidovudineH-lamivudine, ABC+AZT+3TC), adefovir, adefovir dîpivoxil, Stribild ® (elvitegraviH-cobicistat+tenofovir disoproxil fumarate +emtricitabine), rilpivirine, riIpivirine hydrochloride, Comptera® (Eviplera®, rilpivirînei-tenofovir disoproxil fumarate +emtricitabine), Cobicistat, Atripla® (efavirenz+tenofovir disoproxil fumarate +emtricitabine), atazanavir, atazanavir.sulfàte, dolutegravir, elvitegravir, Aluvia® (Kaletra®, lopinaviH-ritonavir), ritonavir, emtricitabine , atazanavir.sulfate + ritonavir, darunavir, lamivudine, Prolastin, fosamprenavir, fosamprenavir calcium, efavirenz, Combivîr® (zidovudine+lamivudine, AZT+3TC), etravirine, nelftnavir, nelfinavir mesylate, interferon, didanosine, stavudine, indinavir, indinavir sulfate, tenofovir + lamivudine, zidovudine, nevîraptne, saquinavir, saquinavir mesylate, aldesleukin, zalcitabine, tipranavir, amprenavir, delavirdine, delavirdine mesylate, Radha-108 (Receptol), Hlviral, lamivudine + tenofovirdisoproxil fumarate, efavirenz + lamivudine + tenofovir disoproxil fumarate, phosphazid, lamivudine + nevirapine + zidovudine, abacavir, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide and tenofovir alafenamide hemifumarate.

[0144] In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable sait thereof, is combined with abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofoviralafenamide or tenofovir alafenamide hemifumarate.

{0145] In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable sait thereof, is combined with tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.

{01461 In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable sait thereof, is combined with a first additional therapeutic agent selected from the group consisting of: abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate and a second additional therapeutic agent selected from the group consisting of emtricitabine and lamivudine.

[0147] In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable sait thereof, is combined with a first additional therapeutic agent selected from the group consisting of: tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate and a second additional therapeutic agent, wherein the second additional therapeutic agent is emtricitabine.

[0148| In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable sait thereof, is combined with 5-30 mg tenofovir alafenamide fumaratc, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable sait thereof, is combined with 5-10; 5-15; 5-20; 5-25; 25-30; 20-30; 15-30, or 10-30 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable sait thereof, is combined with 10 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable sait thereof, is combined with 25 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg emtricitabine. A compound as disclosed herein (e.g., a compound of formula (I)) may be combined with the agents disclosed herein in any dosage amount of the compound (e g, from 10 mg to 1000 mg of compound, 10 mg to 500 mg, or 75 mg to 100 mg of compound) the same as ifeach combination of dosages were specifically and individually listed [0149] In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable sait thereof, is combined with 200-400 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200 mg emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable sait thereof, is combined with 200-250; 200-300; 200-350; 250-350; 250-400; 350-400; 300400; or 250-400 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200 mg emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable sait thereof, is combined with 300 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200 mg emtricitabine. A compound as disclosed herein (e.g., a compound of formula (I)) may be combined with the agents disclosed herein in any dosage amount of the compound (e.g, from lOmgto 1000mgofcompound, 10mgto500mg, or75mgto 100 mg of compound) the same as if each combination of dosages were specifically and individually listed. · [0150] In certain embodiments, when a compound disclosed herein is combined with one or more additiona! therapeutic agents as described above, the components of the composition are administered as a simultaneous or sequentîal regimen When administered sequentially, the combination may be administered in two or more administrations. [0151] In certain embodiments, a compound disclosed herein is combined with one or more additiona! therapeutic agents in a unitary dosage form for simultaneous administration to a patienL for example as a solid dosage form for oral administration.

[0152] In certain embodiments, a compound disclosed herein is 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 simultaneous or sequentîal administration of a compound disclosed herein and one or more additional therapeutic agents, such that therapeutically effective amounts of the compound disclosed herein and one or more additional therapeutic agents are both présent in the body of the patient.

[0153] Co-administration includes administration of unit dosages of the compounds disclosed herein before or after administration of unit dosages of one or more additional therapeutic agents, for example, administration ofthe compound disclosed herein within seconds, minutes, or hours of the administration of one or more additional therapeutic agents. For example, in some embodiments, a unit dose of a compound disclosed herein is administered first, followed within seconds or minutes by administration of a unit dose of one or more additional therapeutic agents. Altematively, in other embodiments, a unit dose of one or more additiona! 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, after a period of hours (e g., 1-12 hours), by administration ofaunit dose of one or more additional therapeutic agents. In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed, after a period of hours (e.g., 1 -12 hours), by administration of a unit dose of a compound disclosed herein [0154] In certain embodiments, a method for treating or preventing an HIV infection in a human having or at risk of having the infection is provided, comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable sait 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 an HIV infection in a human having orat risk of having the infection is provided, comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable sait 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. [0155| ïn one embodiment, pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable sait 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 are provided.

[0156] ïn certain embodiments, the présent disclosure provides a method for treating an HIV infection, comprising administering to a patient in need thereofa therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable sait thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents which are suitable for treating an HIV infection.

[0157| In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable sait thereof, is combined with one, two, three, four, or more additional therapeutic agents. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable sait thereof, is combined with two additional therapeutic agents. In other embodiments, a compound disclosed herein, or a pharmaceutically acceptable sait thereof, is combined with three additional therapeutic agents In further embodiments, a compound disclosed herein, or a pharmaceutically acceptable sait thereof, is combined with four additional therapeutic agents. The one, two, three, four, or more additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents, and/or they can be selected from different classes of therapeutic agents.

Administration of HIV Combination Therapy [0158[ In certain embodiments, a compound disclosed herein is 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 simultaneous or sequential administration of a compound disclosed herein and one or more additional therapeutic agents, such that therapeutically effective amounts of the compound disclosed herein and the one or more additional therapeutic agents are both présent in the body of the patient. When administered sequentially, the combination may be administered in two or more administrations.

[0159[ Co-administration includes administration of unit dosages of the compounds disclosed herein before or after administration of unit dosages of one or more additional therapeutic agents. For example, the compound disclosed herein may be administered within seconds, minutes, or hours of the administration of the one or more additional therapeutic agents. In some embodiments, a unit dose of a compound disclosed herein is administered first, followed within seconds or minutes by administration ofa unit dose ofone or more additional therapeutic agents. Altematively, a unit dose ofone or more additional therapeutic agents is administered first, followed by administration ofa unit dose ofa compound disclosed herein within seconds or minutes. In other embodiments, a unit dose of a compound disclosed herein is administered first, followed, after a period of hours (e.g, 112 hours), by administration of a unit dose of one or more additional therapeutic agents. In yet other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed, after a period of hours (e.g., 1 -12 hours), by administration of a unit dose of a compound disclosed herein.

[0160] In certain embodiments, a compound disclosed herein is combined with one or more additional therapeutic agents in a unitary dosage form for simultaneous administration to a patient, for example as a solid dosage form for oral administration.

[0161] In certain embodiments, a compound of Formula (I) is formulated as a tablet, which may optionally contain one or more other compounds useful for treating HIV. In certain embodiments, the tablet can contain another active ingrédient for treating HIV, such as HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucléotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (orallosteric) integrase inhibitors, pharmacokinetic enhancers, and combinations thereof.

[0162] In certain embodiments, such tablets are suitable for once daily dosing.

HIV Combination Therapy [0163] In the above embodiments, the additional therapeutic agent may be an anti-HIV agent For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors. HTV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucléotide inhibitors of reverse transcriptase, HIV integrase inhibitors. HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors. HIV maturation inhibitors, latency reversing agents, compounds that target the HIV capsid, immune-based thérapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and “antibody-like” therapeutic proteins, HIV pl 7 matrix protein inhibitors, IL-13 antagonists, peptidy 1-prolyl cis-trans isomerase A modulators. protein disulfide isomerase inhibitors, complément C5a receptor antagonists, DNA methyltransferase inhibitor, HIV vif gene modulators. Vif dimerization antagonists, HIV-I viral infectivity factor inhibitors, TAT protein inhibitors, HIV-l Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors. HIV-l splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain containing protein 1 modulators, HIV ribonucléase H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG protein inhibitors. HIV POL protein inhibitors, Complément Factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin dépendent kinase inhibitors, proprotein convertase PC9 stimulators, ATP dépendent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADII-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines, and combinations thereof

HIV Combination Drtigs [0164] Examples of combination drugs include ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA* (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD* (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine), TRUVADA® (tenofovir disoproxil fumarate and 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; COMBIVIR* (zidovudine and lamivudine; AZT+3TC); EPZICOM® (LIVEXA®; abacavir sulfate and lamivudine; ABC+3TC); KALETRA* (ALUVIA*; lopinavir and ritonavir); TRIUMEQ® (dolutegravir, abacavir, and lamivudine); TRIZIVIR* (abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); atazanavir and cobicistat; atazanavir sulfate and cobicistat; atazanavir sulfate and ritonavir; darunavir and cobicistat; dolutegravir 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; lopinavir, ritonavir, zidovudine and lamivudine; Vacc-4x and romidepsin; and APH-0812.

Other HIV Drugs [0165] Examples of other drugs for treating HIV include acemannan, alisporivir,

BanLec, deferiprone, Gamimune, metenkefalin, naltrexone, Prolastin, REP 9, RPI-MN, VSSP, HI viral, SB-728-T, 1,5-dicafîeoylquinic acid, rHIV7-shl-TAR-CCR5RZ, AAVeCD4-lg gene therapy, MazF gene therapy, BlockAide, ABX-464, AG-1105, ΒΓΓ-225, CYT-107, HGTV-43, HS-10234, IMO-3100, IND-02, MK-1376, MK-8507, MK-8591, NOV-205, PA-1050040 (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 [0166] 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 [0167] Examples of HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase include dapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz, etravirine, lentinan, nevirapine, rilpivirîne, AIC-292, KM-023, and VM-1500.

[0168] Examples of HIV nucleoside or nucléotide inhibitors of reverse transcriptase include adefovir, adefovir dipivoxil, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, VIDEX* and VIDEX EC* (didanosine, ddl), abacavir, abacavir sulfate, alovudine, apricitabine, censavudine, didanosine, elvucitabine, festinavir, fosalvudine tidoxil, fozivudine tidoxil, lamivudine, phosphazid, stavudîne, zalcitabine, zidovudine, and KP-1461.

HIVIntegrase Inhibitors [0169|

Examples of HIV integrase inhibitors include elvitegravir, curcumin, dérivatives of curcumin, chicoric acid, dérivatives of chîcoric acid, 3,5-dicafTeoylquinic acid, dérivatives of 3,5-dicafTeoylquinic acid, aurintricarboxylic acid, dérivatives of aurintricarboxylic acid, cafTeic acid phenethyl ester, dérivatives of cafTeic acid phenethyl ester, tyrphostin, dérivatives oftyrphostin, quercetin, dérivatives of quercetin, raltegravir, dolutegravir, JTK-351, and cabotegravir.

[0170] Examples ofHIV non-catalytic site, or allosteric, integrase inhibitors (NCINI) include CX-05045, CX-05168, T-169, and CX-14442.

HIV Entry Inhibitors [0171]

Examples ofHIV entry (fusion) inhibitors include cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 attachment inhibitors, gpl 20 inhibitors, and CXCR4 inhibitors.

[0172] Examples of CCR5 inhibitors include aplaviroc, vicriviroc, maraviroc, cenicriviroc, PRO-140, adaptavir (RAP-101 ), nifeviroc (TD-0232), TD-0680, and vMIP (Haimipu).

[0173] Examples of gp41 inhibitors include albuvirtide, enfuvirtide, and sifuvirtide. [0174] Examples of CD4 attachment inhibitors include ibalizumab.

[0175| Examples of gpl20 inhibitors include Radha-108 (receptol) and BMS-663068 [0176] Examples of CXCR4 inhibitors include plerixafor, and vMIP (Haimipu)

HIV Maturation Inhibitors [0177] Examples of HIV maturation inhibitors include BMS-955176 and GSK-2838232.

Latency Ileversing Agents [0178] Examples of latency reversing agents include histone deacetylase (HDAC) inhibitors, protéasome inhibitors such as velcade, protein kinase C (PKC) activators, BETbromodomain 4 (BRD4) inhibitors, ionomycin, PMA, SAHA (suberanilohydroxamic acid, or suberoyl, anilide, and hydroxamic acid), IL-15, JQ1, disulfram, amphotericin B, and GSK-343.

[0179] Examples ofHDAC inhibitors include romidepsin, vorinostat, and panobinostat. [0180] Examples of PKC activators include indolactam, prostratin, ingenol B, and DAGlactones.

Capsid Inhibitors [0181 ] 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 Thérapies [0182] Examples of immune-based thérapies include toll-like receptors modulators such as tlrl, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlrlO, tlrl 1, tlrl2, and tlrl3; programmed cell death protein 1 (Pd-1) modulators; programmed death-ligand 1 (Pd-Ll ) modulators; IL-15 agonists; DermaVir; interleukin-7; plaquenil (hydroxychloroquine); proleukin (aldesleukin, IL.-2); interferon alfa; interferon alfa-2b; interferon alfa-n3; pegylated interferon alfa; interferon gamma; hydroxyurea; mycophenolate mofetil (MPA) and its ester dérivative mycophenolate mofetil (MMF); ribavirin; polymer polyethyleneimine (PEI); gepon; rintatolimod, IL-12; WF-10; VGV-1; MOR-22; GS-9620, BMS-936559; and IR-103.

Phosphatidylinositol 3-kinase (PI3K) Inhibitors [0183] Examples of PI3K inhibitors include idelalisib, alpelisib, buparlisib, CAI orotate, copanlisib, duvelisib, gedatolisib, neratinib, panulisib, perifosine, pictilisib, pilaralisib, puquitinib mesylate, rigosertib, rigosertib sodium, sonolisib, taselisib, AMG-319, AZD8186, BAY-1082439, CLR-1401, CLR-457, CUDC-907, DS-7423, EN-3342, GSK2126458, GSK-2269577, GSK-2636771, INCB-040093, LY-3023414, MLN-1117, PQR309, RG-7666, RP-6530, RV-1729, SAR-245409, SAR-260301, SF-1126, TGR-1202, UCB-5857, VS-5584, XL-765, and ZSTK-474.

HIl' Antibodies, Bispecific Antibodies, and Antibody-hke ” Iherapeutic Proteins [0184] Examples of HIV antibodies, bispecific antibodies, and “antibody-like” therapeutic proteins include DARTs®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab dérivatives, BMS-936559, TMB-360, and those targeting HIV gpl20 or gp41.

[0185] Examples ofthosetargetingHIVgpl20orgp4I includebavituximab,UB-421, C2F5, C2G12, C4E10, C2F5+C2G12+C4EI0, 3-BNC-l I7,PGTI45, PGT121, MDX010 (ipilimumab), VRC0I, A32, 7B2,10E8, VRC-07-523, MGD-014 and VRC07.

Pharmacokinetic Enhancers [0186]

Examples of pharmacokinetic enhancers include cobicistat and ritonavir.

Additional Therapeutic Agents (0187] Examples of additional therapeutic agents include the compounds disclosed in

WO 2004/096286 (Gilead Sciences), WO 2006/015261 (Gilead Sciences), WO 2006/110157 (Gilead Sciences), WO 2012/003497 (Gilead Sciences), WO 2012/003498 (Gilead Sciences). WO 2012/145728 (Gilead Sciences). WO 2013/006738 (Gilead Sciences), WO 2013/159064 (Gilead Sciences), WO 2014/100323 (Gilead Sciences), US 2013/0165489 (University of Pennsylvania), US 2014/0221378 (Japan Tobacco), US 2014/0221380 (Japan Tobacco), WO 2009/062285 (Boehringer Ingelheim), WO 2010/130034 (Boehringer Ingelheim), WO 2013/006792 (Pharma Resources), US 20140221356 (Gilead Sciences); WO 2013/091096 (Boehringer Ingelheim), and U.S. 20100143301 (Gilead Sciences)

HIV Vaccines [0188| Examples of HIV vaccines include peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, CD4-derived peptide vaccines, vaccine combinations, rgpl20 (AIDSVAX), ALVAC HIV(vCP1521)/AIDSVAX B/E (gpl20) (RV144), monomeric gpl 20 HIV-1 subtype C vaccine, Remune, ITV-1, Contre Vir, Ad5ENVA-48, DCVax-001 (CDX-2401), Vacc-4x, Vacc-C5, VAC-3S, multiclade DNA recombinant adenovirus-5 (rAd5), Pennvax-G, Pennvax-GP, VRC-HIV MAB060-00-AB, HlV-TriMix-mRNA vaccine, IIlV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3/VSSP ISA51, poly-ICLC adjuvanted vaccines, Tatlmmune, GTU-multiHIV (FIT-06), gpl40[delta]V2.TVI+MF-59, rVSVIN HIV-1 gag vaccine, SeV-Gag vaccine, AT-20, DNK4, ad35-Grin/ENV, TBC-M4, HIVAX, HIVAX-2, NYVAC-HIV-PTI, NYVAC-HIV-PT4, DNA-HIV-PT 123, rAAVI-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, AD VAX, MYM-V201, MVA-CMDR, DNA-Ad5 gag/pol/nef/nev (HVTN5O5), MVATG-17401, ETV-01, CDX-1401, rcAD26MOSl.HIV-Env, Ad26.Mod.HIV vaccine, AGS-004, AVX-10I, AVX-201, PEP-6409, SAV-001, ThV-01, TL-0I, TUTI-16, VGX-3300, IHV-001, and virus-lîke particle vaccines such as pseudovirion vaccine.

HIV Combination Therapy [0189| In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable sait thereof, is combined with one, two, three, four or more additional therapeutic agents selected from ATRIPLA* (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD* (elvitegravir, cobicîstat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF +FTC), adefovir; adefovir dipîvoxil, cobicîstat, emtricitabine; tenofovir; tenofovir disoproxil; tenofovir disoproxil fumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate; TRIUMEQ* (dolutegravir, abacavir, and lamivudine); dolutegravîr, abacavir sulfate, and lamivudine; raltegravir; raltegravir and lamivudine; maraviroc;enfuvirtide; ALUVIA® (KALETRA®; lopinavirand ritonavir); COMBIVIR® (zidovudine and lamivudine; AZT+3TC); EPZICOM* (LIVEXA*; abacavir sulfate and lamivudine; ABC+3TC), TRIZIVIR® (abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); rilpivirine; rilpivirine hydrochloride; atazanavir sulfate and cobicîstat; atazanavir and cobicîstat; darunavir and cobicîstat; atazanavir, atazanavir sulfate; dolutegravir; elvitegravir, ritonavir; atazanavir sulfate and ritonavir; darunavir; lamivudine, prolastin; fosamprenavir, fosamprenavir calcium efavirenz; etravirine; nelfinavir; nelfinavir mesylate; interferon; didanosîne; stavudine; indinavîr, indinavir sulfate; tenofovir and lamivudine; zidovudine; nevîrapine; saquinavir, saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir, delavirdine, delavirdine mesylate; Radha-108 (receptol); HIviral; lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovir disoproxil fumarate; phosphazid; lamivudine, nevirapine, and zidovudine; abacavir; and abacavir sulfate.

[0190] In a spécifie embodiment, a compound disclosed herein, or a pharmaceutically acceptable sait thereof, is combined with an IIIV nucleoside or nucléotide inhibitor of reverse transcriptase and an HIV non-nucleoside inhibitor of reverse transcriptase. In another spécifie embodiment, a compound disclosed herein, or a pharmaceutically acceptable sait thereof, is combined with an IIIV nucleoside or nucléotide inhibitor of reverse transcriptase, and an HIV protease inhibiting compound In an additional embodiment, a compound disclosed herein, or a pharmaceutically acceptable sait thereof, is combined with an HIV nucleoside or nucléotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable sait thereof, is combined with at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, a compound disclosed herein, or a pharmaceutically acceptable sait thereof, is combined with two HIV nucleoside or nucléotide inhibitors of reverse transcriptase.

[0191] In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable sait thereof, is combined with abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.

[0192| In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable sait thereof, is combined with tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.

[0193] In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable sait thereof, is combined with a first additional therapeutic agent selected from the group consisting of abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent selected from the group consisting of emtricitabine and lamivudine.

[0194] In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable sait thereof, is combined with a first additional therapeutic agent selected from the group consisting of tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent, wherein the second additional therapeutic agent is emtricitabine.

[0195]

A compound as disclosed herein (e.g., any compound of Formula (I)) may be combined with one or more additional therapeutic agents in any dosage amount of the compound of Formula (I) (e.g., from 50 mg to 1000 mg of compound) [0196] In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable sait thereof, is combined with 5-30 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable sait thereof, is combined with 5-10, 5-15, 5-20, 5-25, 25-30, 20-30,15-30,or 10-30 mgtenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable sait thereof, is combined with 10 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable sait thereof, is combined with 25 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg emtricitabine. A compound as disclosed herein (e.g, a compound of formula (I)) may be combined with the agents provided herein in any dosage amount of the compound (e.g, from 50 mg to 500 mg of compound) the same as if each combination of dosages were specifically and individually listed.

[0197] In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable sait thereof, is combined with 200-400 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil, and 200 mg emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable sait thereof, is combined with 200-250, 200-300, 200-350, 250-350, 250-400, 350-400, 300-400, or 250-400 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil, and 200 mg emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable sait thereof, is combined with 300 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil, and 200 mg emtricitabine. A compound as disclosed herein (e.g., a compound of formula (I)) may be combined with the agents provided herein in any dosage amount of the compound (e.g, from 50 mg to 500 mg of compound) the same as if each combination of dosages were specifically and individually listed.

[0198] In one embodiment, kits comprising a compound disclosed herein, or a pharmaceutically acceptable sait thereof, in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents are provided.

Kits and Articles of Manufacture [0199] The présent disclosure relates to a kit comprising a compound of formula (I), or a pharmaceutically acceptable sait thereof. The kit may further comprise instructions for use, e.g., for use in inhibiting an HIV reverse transcriptase, such as for use in treating an HIV infection or AIDS or as a research tool. The instructions for use are generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable.

|0200] The présent disclosure also relates to a pharmaceutical kit comprising one or more containers comprising a compound of any of formula (I), or a pharmaceutically acceptable sait thereof. Optionally associated with such containers) can be a notice in the form prescribed by a govemmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice reflects approval by the agency for the manufacture, use or sale for human administration. Each component (if there is more than one component) can be packaged in separate containers or some components can be combined in one container where cross-reactivity and shelf life permit The kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or sub-unit doses. Kits may also include multiple unit doses ofthe compounds and instructions for use and be packaged in quantifies sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies) [0201] Also disclosed are articles of manufacture comprising a unit dosage ofa compound of any of formula (I), or a pharmaceutically acceptable sait thereof, in suitable packaging for use in the methods described herein. Suitable packaging is known in the art and includes, for example, vials, vessels, amputes, bottles, jars, flexible packaging and the like. An article of manufacture may further be sterilized and/or sealed [0202] The présent disclosure is also directed to processes and intermediates useful for preparing the subject compounds or pharmaceutically acceptable salts thereof.

|0203] Many general référencés providing commonly known chemical synthetic schemes and conditions useful for synthesizing the disclosed compounds are available (see, e.g., Smith, March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7⁰¹ édition, Wiley-Interscience, 2013.) [0204[ Compounds as described herein can be purified by any ofthe means known in the art, including chromatographie means, such as high performance liquid chromatography (HPLC), préparative thin layer chromatography, flash column chromatography and ion exchange chromatography. Any suitable stationary phase can be used, including normal and reversed phases as well as ionic resins. Most typically the disclosed compounds are purified via silica gel and/or alumina chromatography. See, e.g., Introduction to Modem Liquid

Chromatography, 2nd ed., ed. L. R. Snyderand J. J. Kirkland, John Wiley and Sons, 1979; and Thin Layer Chromatography, E. Stahl (ed ), Springer-Verlag, New York, 1969.

[0205] During any of the processes for préparation of the subject compounds, it may be necessary and/or désirable to protect sensitive or reactive groups on any of the molécules concemed. This may be achieved by means of conventional protecting groups as described in standard works, such as T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis,” 4^Λ ed., Wiley, New York 2006. The protecting groups may be removed at a convenient subséquent stage using methods known from the art.

[0206] Exemplary chemical entities useful in methods of the embodiments will now be described by reference to illustrative synthetic schemes for their general préparation herein and the spécifie examples that follow. Artisans will recognize that, to obtain the various compounds herein, starting matériels may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product Alternatively, it may be necessary or désirable to employ, in the place ofthe ultimately desired substituent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent Furthermore, one of skill in the art will recognize that the transformations shown in the schemes below may be performed in any order that is compatible with the functionality of the particular pendant groups. Each ofthe reactions depicted in the general schemes is preferably run at a température from about 0 °C to the reflux température of the organic solvent used. Unless otherwise specified, the variables are as defined above in reference to formula (I).

[0207] Représentative synthèses of compounds of the présent disclosure are described in schemes below, and the particular examples that follow.

[0208] The embodiments are also directed to processes and intermediates useful for preparing the subject compounds or pharmaceutically acceptable salts thereof.

]0209] Many general référencés providing commonly known chemical synthetic schemes and conditions useful for synthesizing the disclosed compounds are available (see, e.g., Smith, March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7¹¹¹ édition, Wiley-Interscience, 2013.) Angew. Chem. Int. Ed. 2014,53,2-21, which is herein încorporated by reference in its entirety, provides a review of sulfur (VI) fluoride exchange, which can also be useful in the synthetic schemes.

[0210] Compounds as described herein can be purified by any of the means known in the art, including chromatographie means, such as high performance liquid chromatography (HPLC), préparative thin layer chromatography, flash column chromatography and ion exchange chromatography. Any suitable stationary phase can be used, including normal and reversed phases as well as ionic resins. Most typically the disclosed compounds are purified via silica gel and/or alumina chromatography. See, e.g., Introduction to Modem Liquid Chromatography, 2nd ed , ed. L. R. Snyder and J. J. Kirkland, John Wiley and Sons, 1979; and Thin Layer Chromatography, E. Stah! (ed.), Springer-Verlag, New York, 1969.

[0211] During any of the processes for préparation of the subject compounds, it may be necessary and/or désirable to protect sensitive or reactive groups on any of the molécules concemed. This may be achieved by means of conventional protecting groups as described in standard works, such as T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis,” 4^,h ed., Wiley, New York 2006. The protecting groups may be removed at a convenient subséquent stage using methods known from the art.

[0212] Exemplary chemical entities useful in methods of the embodiments will now be described by reference to illustrative synthetic schemes for their general préparation herein and the spécifie examples that follow. Artisans will recognize that, to obtain the various compounds herein, starting materials may be suitably selected so that the ultimately desired substituents will be carried through the réaction scheme with or without protection as appropriate to yield the desired product Alternatively, it may be necessary or désirable to employ, in the place of the ultimately desired substituent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent Furthermore, one of skill in the art will recognize that the transformations shown in the schemes below may be performed in any order that is compatible with the functionality of the particular pendant groups. Each of the reactions depicted in the general schemes may be run at a température from about 0 °C to the reflux température of the organic solvent used. Unless otherwise specified, the variables are as defined above in reference to formula (I).

[0213] Représentative synthèses of compounds of the présent disclosure are described in schemes below, and the particular examples that follow.

[0214] Scheme 1 shows a représentative synthesis of the compounds ofthe embodiments. The methodology is compatible with a wide variety of functionalities.

Scheme 1

R⁴ R³

[0215] In Scheme 1, R’, R², R³, R⁴, R^s, R⁶, R⁷, R’, X', X², X³, and Q are as defined herein. Also in Scheme 1, as discussed below, Y¹', Z¹*, and Z²* are precursor moieties to fonning the proper bonds and moieties in formula (1) Starting materials may be obtained from commercial sources or via well-established synthetic procedures. The synthesis of formula l-D is discussed below in Schemes 4 and 5.

[0216] In Scheme l.a nucleophilic substitution reaction between formula l-Aand l-B occurs to produce a compound of formula 1-C. The amino group of fonnula l-B reacts with formula l-A to displace Y¹*, which is a leaving group, such as halogen, triflate, mesylate, and tosylate. In certain instances. Y¹* is halogen, such as iodo, bromo, or chloro.

[0217]

With continued reference to Scheme 1, a coupling reaction between fonnula 1-C and l-D occurs to produce a compound of fonnula (I) In certain instances, a palladium catalyzed reaction between an aryl halideand an organoboron compound (e.g., Suzuki coupling reaction) can be used. With a Suzuki coupling reaction, Z¹* in fonnula 1 -C can be a halide, such as iodo or bromo and Z²* in fonnula l-D can be a boronic acid or boronic acid ester. In certain instances, Z²* is

In certain instances, the coupling step includes a palladium catalyst, such as l,r-bis(di’/€77-butylphosphino)ferrocene palladium dichloride or l,r-bis(diphenylphosphino)ferrocenepalladiumdichloride.

[0218] With continued reference to Scheme 1, as an alternative coupling reaction between formula 1-C and 1 -D, a palladium-catalyzed reaction between an organotin compound and an aryl halide (e.g., Stille coupling reaction) can be used to produce a compound of formula (I). With the Stille reaction, Z¹* in formula 1 -C can be an organotin moiety (-SnR*. where R is an alkyl group) and Z²* in formula 1 -D can be a halide, such as iodo, or bromo. In certain instances, the coupling step includes a palladium catalyst, such as bïs(tri-/t’r/-butylphosphine)palladium(0).

[0219] Scheme 2 is another représentative synthesis of the compounds of the embodiments. The methodology is compatible with a wide variety of functionalities.

Scheme 2

2-A 2-B

R³

2-E [0220] In Scheme 2, R¹, R², R³, R⁴, R³, R⁶, R⁷, R⁸, R⁹, R¹⁰, X¹, X², X³, and Q are as defmed herein. Also in Scheme 2, as discussed below. Y’*, Z¹', and Z²* are precursor moieties to forming the proper bonds and moieties in formula (I) Starting materials may be obtained from commercial sources or via well-established synthetic procedures.

|0221] In Scheme 2, a nucleophilic substitution reaction between formula 2-A and 2-B occurs to produce a compound of formula 2-C. The amino group of formula 2-B reacts with formula 2-A to displace Y¹*, which is a leaving group, such as halogen, triflate, mesylate, and tosylate. In certain instances, Y¹* is halogen, such as iodo, bromo, or chloro.

|0222| With continued reference to Scheme 2, a coupling reaction between formula 2-C and 2-D occurs to produce formula 2-E. In certain instances, a palladium-catalyzed reaction between an aryl halide and an organoboron compound (e.g, Suzuki coupling reaction) can be used. With a Suzuki coupling reaction, Z¹* in formula 2-C can be a halide, such as iodo or bromo and Z²· in formula 2-D can be a boronic acid or boronic acid ester. In certain instances, Z² is <λ \ . In certain instances, the coupling step includes a palladium catalyst, such as 1 ,l’-bis(di-/t’rt-butylphosphino)ferrocene palladium dichloride or 1,1 'bis(diphenylphosphino)ferrocene palladium dichloride.

[0223] With continued reference to Scheme 2, as an alternative coupling reaction between formula 2-C and 2-D, a palladium-catalyzed reaction between an organotin compound and an aryl halide (e.g, Stille coupling reaction) can be used to produce a compound of formula (I). With the Stille reaction, Z¹* in formula 2-C can be an organotin moiety (-SnRi, where R is an alkyl group) and Z²· in formula 2-D can be a halide, such as iodo or bromo. In certain instances, the coupling step includes a palladium catalyst, such as bis(tri-/c’rr-butylphosphine)palladium(0)

With continued reference to Scheme 2, a coupling reaction between formula 2-D and 2-E occurs to produce a compound of formula (I). In certain instances, a coupling réaction between a stabilized phosphonate carbanion and an aldéhyde (e.g., HomerWadsworth-Emmons reaction) can be used.

[0225] Scheme 3 is another représentative synthesis of the compounds ofthe embodiments. The methodology is compatible with a wide variety of functionalities.

Scheme 3

R

In Scheme 3, R*. R², R³, R⁴, R⁵, R^s, R⁷, R⁸, X¹, X², X³, and Q are as defined [0226] herein. Also in Scheme 3, as discussed below, Y¹¹, Z¹*, and Z²* are precursor moieties to forming the proper bonds and moieties in formula (I). Starting materials may be obtained from commercial sources or via well-established synthetic procedures. The synthesis of formula I-D is discussed below in Schemes 4 and 5.

[0227] With reference to Scheme 3, a coupling reaction between formula 3-A and 1 -D occurs to produce formula 3-B. In certain instances, a palladium-catalyzed réaction between an aryl halide and an organoboron compound (e g, Suzuki coupling reaction) can be used With a Suzuki coupling reaction, Z¹* in formula 3-A can be a halide, such as iodo or bromo and Z²¹ in formula I-D can be a boronic acid or boronic acid ester. In certain instances, Z²¹ . In certain instances, the coupling step includes a palladium catalyst, such as 1,1 ^l-bis(di-rert-butylphosphino)ferrocene palladium dichloride or 1,1 bis(diphenylphosphino)ferrocene palladium dichloride.

[0228( With continued reference to Scheme 3, as an alternative coupling reaction between formula 3-A and 1 -D, a palladium-catalyzed reaction between an organotin compound and an aryl halide (e.g., Stille coupling reaction) can be used to produce a compound of formula (I) With the Stille reaction, Z¹· in formula 1 -C can be an organotin moiety (-SnRj, where R is an alkyl group) and Z²* in formula 1 -D can be a halide, such as iodo, or bromo. In certain instances, the coupling step includes a palladium catalyst, such as bis(tri-r<?/7-butylphosphine)palladium(0) [0229] With continued reference to Scheme 3, a nucleophilic substitution reaction between formula 3-B and 3-C occurs to produce a compound of formula (I) The amino group of formula 3-C reacts with formula 3-B to displace Y¹*, which is a leaving group, such as halogen, triflate, mesylate, and tosylate. In certain instances, Y¹* is halogen, such as iodo, bromo, or chloro.

[0230] Scheme 4 shows a représentative synthesis of formula 1 -D. The methodology is compatible with a wide variety of functionalities.

Scheme 4

4-B

4-A 4-C 1-D [0231 ] In Scheme 4, R⁷, R’, R⁹, R¹⁰, and Q are as defined herein Also in Scheme 4, as discussed below, Q’*, X¹*, and X²* are precursor moieties to forming the proper bonds and moieties in formula 1-D. Starting materials may be obtained from commercial sources or via well-established synthetic procedures.

[0232] In Scheme 4, a coupling reaction between formula 4-A and 4-B occurs to produce formula 4-C. In certain instances, a palladium-catalyzed reaction between an aryl halide and an alkene compound (e.g., Ileck coupling reaction) can be used. With a Heck coupling reaction, X¹· in formula 4-A can be a halide, such as iodo, or bromo and X²* in formula 4-B can be hydrogen. The Heck coupling reaction can be carried out in the presence of a palladium catalyst, such as palladium(Il) acetate in a combination with tri(otolyl)phosphine.

[0233] With continued reference to Scheme 4, Q¹* in formula 4-A and 4-C is a precursor moiety to a boronîc acid or boronic acid ester in formula 1-D, wherein Z²* is a boronic acid or boronic acid ester. A borylation reaction of formula 4-C occurs to produce a compound of formula 1 -D. In certain instances, a cross-coupling reaction of 4,4,4',4',5,5,5‘,5'octamethyI-2,2'-bi(l,3,2-dioxaborolane) with an aryl halide (e.g., Miyaura borylation reaction) can be used. With a Miyaura borylation reaction, Q¹* in formula 4-C can be a halide, such as iodo, or bromo. In certain instances, Formula 4-C can react with 4>4j4^,t4',5,5,5',5'-octamethy!-2,2'-bi(l,3,2-dioxaborolane) to provide for formula 1-D, in which Z²* is Vx . In certain instances, the borylation step includes a palladium catalyst, such as palladium(II) acetate in a combination with dicyclohexyl(2*,6’-dimethoxy[1 ,r-biphenyl]-2-yl)phosphine. Other borylation reactions can be used.

1023-4] Scheme 5 shows another représentative synthesis of formula 1 -D. The methodology is compatible with a wide variety of functionalities.

Scheme 5

Q¹’

5-A

Q

5-C

1-D [0235] In Scheme 5, R⁷, R*, R⁹, R¹⁰, and Q are as defined herein. Also in Scheme 5, as discussed below, Q¹* and X¹* are precursor moieties to forming the proper bonds and moieties in formula 1-D. Starting materials may be obtained from commercial sources or via well-established synthetic procedures.

[0236] In Scheme 5, a coupling reaction between formula 5-A and 5-B occurs to produce formula 5-C. In certain instances, a coupling reaction between a stabilized phosphonate carbanion and an aldéhyde (e.g., Horner-Wadsworth-Emmons reaction) can be used. With a Horner-Wadsworth-Emmons reaction, X¹· in formula 4-A can be an aldéhyde or ketone (e.g., X¹· is -CHO or-C(O)R⁹) [0237] With continued référencé to Scheme 5, Q¹* in formula 5-A and 5-C is a precursor moiety to a boronic acid in formula 1 -D, wherein Z² is a boronic acid. A borylation reaction of formula 5-C occurs to produce a compound of formula l-D. In certain instances, a cross-coupling reaction of4,4,4',4’,5,5,5’,5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) with an aryl halide (e g, Miyaura Borylation reaction) can be used. With a Miyaura Borylation reaction, Q¹* in formula 5-C can be a halide, such as iodo, or bromo In certain instances, Formula 5-C can react with 4,4,4’,4',5,5,5’,5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) to includes a palladium catalyst, such as palladium(II) acetate in a combination with dicycIohexyl(2'.6^,-dimethoxy-[l,r-biphenyl]-2-yl)phosphine. Other borylation reactions can be used.

[0238] Accordingly, and as described in more detail herein, the présent disclosure relates to a process of preparing a compound of the présent disclosure, the process involving:

R⁴ R³ reacting a compound of formula: Z^2a

Ri -R⁸

R² (1-C) with a compound of fonnula: Q (l-D); thereby producing a compound of formula

(I), wherein R¹, R². R’, R*. R’, R⁶, R’. R¹. X', X², X’. Z¹·, Z²·, and

Q are as defined herein.

[0239] Accordingly, and as described in more detail herein, the présent disclosure relates to a process of preparing a compound of the présent disclosure, the process involving:

	R⁴	R³
^Rx

R⁶'	O
^RX		^r⁸

reacting a compound of formula:	Q	(3-B) with a compound of

formula:

(3-C); thereby producing a compound of formula

are as defined herein (I), wherein R¹, R², R³, R⁴, R³. R⁶, R⁷, R, X¹, X². X³. Y, and Q [0240] In certain instances, the above processes further involve the step of forming a sait ofa compound ofthe présent disclosure. Embodiments are directed to the other processes described herein; and to the product prepared by any of the processes described herein.

[0241|

Except as otherwise noted, the methods and techniques ofthe présent embodiments are generally performed according to conventional methods well known in the art and as described in various general and more spécifie references that are cited and discussed throughout the présent spécification. See, e.g., Loudon, Organic Chemistry, 5°¹édition, New York: Oxford University Press, 2009; Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7°* édition, Wiley-Interscience, 2013.

LIST OF ABBREVIATIONS AND ACRONYMS

Abbreviation - Meaning

Ac - Acetyl

B2pin2 - 4,4,4',4^,,5,5,5',5'-Octamethyl-2,2'-bi(l 3,2-dioxaborolane) bs - B road singlet ° C Degree Celsius d - Doublet

DCM - Dichloromethane dd - Doublet of doublet

DIPEA - 7V,/V-Diisopropylethy!amine

DMF -ΛζΛΑ-Di methyl formamide

DMSO - Dimethylsulfoxide dppf- l,l’-Bis(diphenylphosphino)ferrocene dtbpf- l,r-Bis(di-/er/-butylphosphino)ferrocene

ECso - Half maximal effective concentration

Equiv/eq - Equivalents

Et - Ethyl

EtOH - Ethanol g - Grams

HPLC - High-performance liquid chromatography hrs/h - Hours

Hz - Hertz

J· Coupling constant

LCMS - Liquid chromatography-mass spectrometry

M - Molar m - Multiplet m/z - mass-to-charge ratio

M+ - Mass peak

Me - Methyl mg - Milligram

MHz - Mégahertz min - Minute mL - Milliliter mM - Millimolar mm - Millimeter mmol - Millimole mol-Mole

MS - mass spectrometry

MW - Microwave nM-Nanomolar

NMP - 2V-Methyl-2-pyrrolidone

NMR - Nuclear magnetic résonance

P(oTol)3 - Tri(o-tolyl)phosphine

P(/-Bu)a - Tri-rert-butylphosphine

Pd2(dba)j - Tris(dibenzylideneacetone)palladtum(0) q - Quartet quant - Quantitative

Rf- Rétention factor

RT/rt/r t - Room température s -Singlet sat. - Saturated

SPhos - Dicyclohexyl(2',6'-dimethoxy-[l ,l'-biphenyl]-2-yl)phosphine t-Triplet

TFA - Trifluoroacetic acid

TMS - Trimethylsilyl

Tr/tr - Rétention time

UV - Ultraviolet wt. - Weight

Xantphos- (9,9-Dimethyl-9H-xantheneA5-diyl)bis(diphenylpbosphine) δ - Chemical shift pL - Microliter μΜ - Micromolar pmol - Micromole [0242] The following examples are merely illustrative, and do not limit this disclosure in any way. Unless otherwise stated, préparative HPLC was performed on a Gilson HPLC System, using a 21.2x250 mm 10 micron Cl 8 Phenomenex Gemini semi-preparative column and gradient 0-100% acetonitrile in water mobile phase with 0.1% trifluoroacetic acid at a flow rate of 20 mL/min.

[0243] Chemical names for ail prepared compounds were generated using ChemBioDraw 12.0 software.

[0244] While the structures in the examples below are drawn as certain géométrie isomers, a certain géométrie isomer (e.g., E or Z isomer) or a ratio of the E and Z isomers may be indicated in the title and/or description of the example to represent the results of the example [0245] The following methods were used for the purification and characterization of certain compounds described in the following Examples.

|0246] LCMS method 1 - Phenomenex Gemini-NX 3u C18 1 lOA, 100 x 2 mm 3 micron column, Acetonitrile with 0.1% formic acid, Water with 0.1% formic acid; 0 min-7.0 min ΟΙ 00% ACN, flow rate 0.5 mL/min.

[0247] LCMS method 2 - Gemini 5u Cl 8 1 lOA, 50 x 4 60 mm 5 micron column; Acetonitrile with 0.1% acetic acid, Water with 0.1% acetîc acid; Gradient: 0 min-3.5 min 5100% ACN; flow rate 2 mL/min.

[0248] LCMS method 3 -Kinetex2 6μ Cl 8 100A, 50 x 3.00 mm column; Acetonitrile with 0.1% formic acid, Water with 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.

EXAMPLE 1 (£)-4-((8-(4-(2-Cyanovinyl)-2,6-dimethylphenyl)qiiinazo!in-2-yl)amino)benzonÎtri!eCompound 1

Step 1: Synthesis of4-((8-bromoquinazolin-2-yl)amÎno)benzonitrile (Compound la)

[0249] A mixture of 8-bromo-2-chloroquinazoline (1.0 g, 4.10 mmol, Ark Pharm Inc, AK-27609) and 4-cyanoaniline (533 mg, 4.52 mmol, Sigma-Aldrich) in isopropanol (15 mL) was heated under reflux for 15 hours. The solid product was filtered off and washed twice with cold isopropanol (2x10 mL). The product was dried on air to afîord the title compound la. Ή NMR (400 MHz, DMSO-î/ô) δ 10.76 (s, 1 H), 9.47 (s, 1H), 8.41 (d, J= 8 8 Hz, 211), 8.28 (dd, 7 = 7.8, 1.2 Hz, 1H), 8.06 (dd, 7 = 7.8, 1.2 Hz, 1 H), 7.85 (d, 7=8.8 Hz, 2H), 7.44 (t, 7= 7.8 Hz, 1H) HRMS: (ESI+) calculated for CisHtoNiBr [M+H] 325.00834, found 325.00821. LCMS (m/z) 325.0 [M+H], Tr = 4 69 min (LCMS method 1 )

Step 2: synthesis of (E)-3-(4-bromo-3^-dimethylphenyl)acrylonitri!e (compound lb)

N Compound lb [0250| To a solution of 2,5-dibromo-l J-dimethylbenzene (2640 mg, 10 mmol, Oakwood Products, Inc. - 018507) in anhydrous acetonitrile (25 mL) was added palladium(ll) acetate (112 mg, 0.5 mmol), acrylonitrîle (531 mg, 10 mmol), tri(otolyl)phosphine (131 mg, 0.5 mmol) and triethylamine (4 mL, 30 mmol) then 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 then re-dissolved with ethyl acetate (50 mL). The solution was washed with water (50 mL) The water 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. This was subjected to silica gel chromatography (gradient from 0-20% ethyl acetate in /.ro-hexanes) to afford the crude product which was treated in sonie bath with hexane (10 mL) for 10 minutes. The product precipitated out of solution and was collected by filtration. The solids were washed with cold hexane to afford compound lb. ^lH NMR (400 MHz, CDClj) 5 7.25 (d, J= 16 6 Hz, 1 H), 7.12 (s, 2H), 5.84 (d, J= 16 6 Hz, 1H), 2.42 (s, 6H). LCMS (m/z) no MS signal, Tr = 2.78 min (LCMS method 2).

Step 3: synthesis of (E)-3-(3,5-diinethy!-4-(4^4,5,5-tetramethy!-13»2*dioxaboroIan-2yl)pheny!)acrylonitrile (compound le)

N Compound le [0251] A mixture ofcompound lb (391 mg, 1.66 mmol), 4,4,4',4',5,5,5',5'-octamethyl2,2’-bi(l,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-[l ,Γ-biphenyl]2-yl)phosphine (SPhos. 85 mg, 0.21 mmol) in dry A/3/-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 then re-dissolved with ethyl acetate (50 mL) The solution was washed with water (50 mL) The water 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 (gradient from 0-20% ethyl acetate in /so-hexanes) to afford compound le. ’ H NMR (400 MHz, CDCb) δ 7.28 (d, J = 16 6 Hz, 1 H), 7.00 (s, 2H), 5.84 (d, J = 16 6 Hz, 1 H), 2.39 (s, 6H), 1.37 (s, 12H) LCMS (m/z) 284.3 [M+H], Tr = 2.85 min (LCMS method

2).

Step 4: synthesis of (E)-4-((8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)qumazolin-2yl)amino)benzonitrile (compound 1)

O O 'B'

N Compound 1 [0252] A mixture of compound 1 a (50 mg, 0.15 mmol), compound 1 c ( 129 mg, 0.45 mmol), [l,l’-bis(diphenylphosphino)fenOcene] dichloropalladium(II), complex with dichloromethane (100 mg, 0.12 mmol), potassium carbonate (64 mg, 0.45 mmol), and copper(I) acetate (19 mg, 0.15 mmol) in dry /VA-dimethylformamide (5 mL) was purged with argon and heated at 100 °C for 15 hours Solvent was removed under reduced pressure and crude mixture was subjected to silica gel chromatography (gradient from 0-30% ethyl acetate in /.ro-hexanes). The crude product was then re-purified on HPLC (préparative column Phenomenex Gemini 10 micron C18, 250 x 21.2 mm, 10 mL/min, gradient from ΙΟΙ 00% acetonitrile in water) to afford the title compound 1. ’H NMR (400 MHz, DMSO-t/s) δ 10.48 (s, 1 H), 9.50 (s, 1 H), 8.09 (d, J = 7.8 Hz, 1 H), 7.70-7.87 (m, 4H), 7.63 (t, J = 7.8 Hz, I H), 7.61 (s, 2H), 7.40 (d, J = 8.8 Hz, 2H), 6.62 (d, J = 16.7 Hz, 1 H), 1.94 (s, 6H) HRMS: (ESI+) calculated for CzeHjoNs [M+H] 402.17132, found 402.17126. LCMS (m/z) 402.2 [M+H], Tr = 4.91 min (LCMS method 1 ).

EXAMPLE 2 (E)-4-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethyIphenyl)quÎnazolÎn-2yl)amino)benzonitrile- Compound 2

NHî

Step 1: Synthesis of(£7-3-(4-(4-amino-2-chloroquinazolin-8-yl)-3,5<!imethylphenyl)acrylonitrile (Compound 2a)

80°C η

N Compound 2a [0253] A mixture of 8-bromo-2-chloroquinazolin-4-amine (129 mg, 0.5 mmol, Ark Pharm Inc, AK-28702), compound le (184 mg, 0.65 mmol), potassium phosphate tribasic (159 mg, 0.75 mmol)and l,r-bis(di-tert-butylphosphino)ferrocene palladium dichloride (65 mg, 0.10 mmol) was dissolved in A^-di methyl forma mi de: water mixture (85:15,40 mL) under argon. The reaction was heated to 80°C for 30 minutes. The reaction mixture was cooled down to room température and diluted with water and ethyl acetate. The organic layer was separated and washed twice with brine, dried over magnésium sulfate, 0.5 volume équivalent of hexane added and this mixture was filtered through a 2 cm layer of silica gel which was washed with additional ethyl acetate. Combined organics were concentrated down under reduced pressure and the residue was treated with diethyl ether in a sonie bath The solid product was filtered off and washed twice with diethyl ether and once with hexane to afford the title compound 2a. Ή NMR (400 MHz, DMSO-î/ô) δ 8.38 (bs, 2H), 8,28 (dd, J = 8.1, 1.6 Hz, I H), 7.66 - 7.52 (m, 3H), 7.43 (s, 2H), 6 46 (d, J = 16.7 Hz, 1 H), 1.86 (s, 6H) LCMS (m/z) 335.2 [M+H], Tr = 2.48 min (LCMS method 2)

Step 2: synthesis of (E)-4-((4-amino-8-(4-(2-cyanoviny 1)-2,6dimethylphenyl)qiiinazoIin-2-yI)amino)benzonitriIe (compound 2)

[0254] A mixture of compound 2a ( 100 mg, 0.30 mmol), 4-cyanoaniIine (46 mg, 0.388 mmol, Sigma-Aldrich) and hydrogen chloride solution in 1,4-dioxane (4M, 7 pL, 0 03 mmol) in dry 7V-methyl-2-pyrroIidone (2 mL) was heated at 120 °C for 2 hours. The reaction mixture was cooled down to room température and triethylamine (0.1 mL, 0.72 mmol) was added. After 15 minutes, water (5 mL) was added and the solid product was filtered off and washed with water. The crude residue was taken up in a mixture of dichloromethane and diethyl ether (1:1, 5 mL) and then treated in a sonie bath for 3 minutes. The solid compound was filtered off and washed with diethyl ether (5 mL) to afford the title compound 2. *H NMR (400 MHz, DMSO-î/ô) δ 9.44 (s, 1 H), 8.18 (dd, J = 8.2, 1.5 Hz, 1 H), 7.74 (d, J = 16 7 Hz, 1 H), 7.70 (d, J = 8.9 Hz, 2H), 7.51 (s, 2H), 7.48 (dd, J = 7.1, L3 Hz, 1 H), 7.34 (dd, J = 8.2, 7.1 Hz, 1H), 7.26 (d,J= 8.9 Hz,2H), 6.54 (d,J= 16.7 Hz, 1H), 1.91 (s,6H) HRMS: (ES1+) calculated for CîôHhNô [M+H] 417.1822, found 417.1820. LCMS (m/z) 417.2 [M+H], Tr= 4.68 min (LCMS method 1)

EXAMPLE3 (E)-4-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolm-2-yl)amino)-2methoxybenzonitrile- Compound 3

Step 1: Synthesis of 4-((4-amino-8-bromoquinazolin-2-yl)amino)-2methoxybenzonitrile hydrochloride (Compound 3a)

N Compound 3a [02S5| A mixture of 8-bromo-2-chloroquinazolin-4-amine (259 mg, 1 mmol, Ark Pharm Inc, AK-28702) and 4-amino-2-methoxybenzonitrile (222 mg, 1.5 mmol, Ark Pharm Inc, AK-77827) in isopropanol (7 mL) was heated in microwave at 180 °C for 8 hours. The reaction mixture was cooled down to room température and the solid product was filtered offand washed with cold isopropanol and then with diethyl ether and hexane to afford the compound 3a as the HCl sait. 'H NMR (400 MHz, DMSO-î/o) Ô 8 24 (d, J= 8.1 Hz, 1 H), 8.07 (d, J =7.6 Hz, 111),7.59 (d, J = 8.5 Hz, 111),7.42 (dd,J = 8.6, 1.9 Hz, III), 7.37-7.04 (m, 5H), 3.99 (s, 3H) LCMS (m/z) 370.3 [M+H], Tr = 2.43 min (LCMS method 2).

S(ep 2: synthesis of (£)-4-((4-amino-8-(4-(2-cyanovinyl)-2,6dimethylphenyl)qiiînazolin-2-yl)amino)-2-methoxybenzonitrile (compound 3)

K3PO4, CuOAc, DMF, 120°C

[0256] A mixture ofcompound 3a (50 mg, 0.14 mmol), compound le (76 mg, 0.27 mmol), [],l'-bis(diphenylphosphino)ferrocene] dich)oropalladium(Il), complex with dichloromethane (33 mg, 0 04 mmol), potassium phosphate tribasic (86 mg, 0 41 mmol), and copper (I) acetate (2 mg, 0.01 mmol) in dry N^V-dimethylformamide (5 mL) was purged with argon and heated at 120 °C for 3 hours. The reaction mixture was cooled down to room température and diluted with water and ethyl acetate. The organic layer was separated and washed twice with brine, dried over magnésium sulfate, 1 volume équivalent of hexane added and this mixture was filtered through a 3 cm layer of si 1 ica gel which was washed with additional ethyl acetate. Combined organics were concentrated down under reduced pressure and the crude mixture was subjected to silica gel chromatography (gradient from 550% ethyl acetate in wo-hexanes) Product was then re-purified by reverse phase chromatography (5-100% acetonitrile in water with 0.1% trifluoroacetic acid) to afîord the TFA sait of compound 3, *H NMR (400 MHz, DMSO-î/ô) 5 8.25 (bs, 1H), 7.74 - 7.65 (m, 2H), 7.62 - 7.42 (m, 5H), 7.3 0 (d, J = 9.0 Hz, 2H), 7.26 - 6.95 (m, I H), 6.53 (d, J = 17.0 Hz, 1H), 3.41 (s, 3H), 1.93 (s, 6H). LCMS (m/z) 447.4 [M+H], Tr = 2.39 min (LCMS method 2).

EXAMPLE 4 (E)-4-((8-(4-(2-Cyanovinyl)-2,6-dimethylphenyl)-6-nuoroquinazolm-2yl)amino)benzonitrile- Compound 4

Step 1: Synthesis of 4-((8-bromo-6-iliioroqiiinazolin-2-yl)amino)bcnzonitrile (Compound 4a)

N Compound 4a |0257] A mixture of 8-bromo-2-chloro-6-fluoroquinazoline (500 mg, 1.91 mmol, Ark Pharm Inc, AK-93358) and 4-aminobenzonitrile (250 mg, 2.12 mmol, Sigma-Aldrich) in dry jV-methylpyrrolidone was heated in microwave at 200 °C for 5 hours The reaction mixture was cooled down to room température and subjected to silica gel chromatography (gradient from 5-50% ethyl acetate in /.ro-hexanes) to afïord the title compound 4a. ’H NMR (400 MHz, DMSO-Je) δ 10.69 (s, 1 H), 9.37 (s, I H), 8.32 (d, J = 8.7 Hz, 2H), 8.26 (dd. J = 8.5, 2.7 Hz, 1H), 7.86 (dd, J= 8.5, 2.7 Hz, IH), 7.78 (d, J= 8.7 Hz,2H). LCMS (m/z) 343.0 [M+H], Tr = 4.72 min (LCMS method 1 )

Step 2: synthesis of (E)-4-((8-(4-(2-cyanovinyl)-2,6-dÎmethylphenyl)-6-nuoroqiiinazolin2-yl)amino)benzonitrile (compound 4)

Compound 4 [0258] A mixture of compound 4a (50 mg, 0,14 mmol), 4,4,4',4',5,5,5',5^,-octamethyl2,2'-bi(l,3,2-dioxaborolane) (40 mg, 0.16 mmol), potassium acetate(60 mg, 0.61 mmol)and [I,I*-bis(diphenylphosphino)ferrocene] dichloropalladium(H), complex with dichloromethane (50 mg, 0.061 mmol) in dry 7VJV-dimethy!formamide (5 mL) was purged with argon and heated at 100°C for I hour. A mixture of compound lb (33 mg, 0.14 mmol), [l,r-bis(diphenylphosphino)ferrocene] dichloropalladium(H), complex with dichloromethane (50 mg, 0.061 mmol) and potassium carbonate (90 mg, 0.65 mmol) was added to the reaction mixture. The reaction mixture was heated to I00°C for 5 hours, cooled down to room température, concentrated down under reduced pressure and subjected to silica gel chromatography (gradient from 5-50% ethyl acetate in /.w-hexanes). The crude product was then re-purified on HPLC (préparative column Phenomenex Gemini 10 micron CI8, 250 x 21.2 mm, 10 mL/min, gradient from 10-100% acetonitrile in water) to afford the title compound 4 *H NMR (400 MHz, DMSO-Jô) δ 9.45 (s, 1 H), 7.92 - 7.86 (m, 1 H), 7.82 - 7.76 (m, 2H), 7.72 (s, 1H), 7.68 (d, 8.9 Hz, 2H), 7.58 (s, 2H), 7.36 (d, J = 8.9 Hz, 2H),

6.60 (d, J = 16.7 Hz, 1 H), 1.92 (s, 6H) LCMS (m/z) 420.1 [M+H], Tr = 4.85 min (LCMS method 1)

EXAMPLE5 (E)-4-((8-(4-(2-Cyanovinyl)-2^-dinuorophenyI)qiiinazolin-2-yl)amino)benzonitr!leCompound 5 (mixture E!Z= 4/1)

Step 1: Synthesis of4-((8-(2^-dinuoro-4-formylphenyl)quinazolin-2yl)amino)benzonitrile (Compound 5a)

[0259] A mixture of compound la (40 mg, 0.12 mmol), 3,5-difluoro-4-(4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-yl)benzaldehyde (66 mg, 0.24 mmol, Sigma-Aldrich), and potassium fluoride (24 mg, 0.4 mmol) in a tetrahydrofuran/water mixture (10.1,10 mL) was purged with argon and tris(dibenzylideneacetone)palladium(0) (68 mg, 0.07 mmol) was added followed by tri-terï-butylphosphine (36 pL, 0.14 mmol) This mixture was heated at 80°C for 4 hours. The solvent was removed under reduce pressure and the residue was purified by silica gel chromatography (gradient from 20-80% ethyl acetate in /aï?-hexanes) to afford the title compound 5a. *H NMR (400 MHz, DMSO-ί/ό) δ 10.55 (s, 1H), 10.15 (s, 1H), 9.51 (s, 1 H), 8.16 (d, J = 8 0 Hz, 1 H), 8 03 (d, J = 7.0 Hz, 1 H), 7.90 (d, J = 6.9 Hz, 2H), 7.83 (d, J = 8.8 Hz, 2H), 7.67-7.58 (m, 1 H), 7.53 (d, J = 8.8 Hz, 2H). LCMS (m/z) 387.1 [M+H], Tr= 4.67 min (LCMS method 1).

Step 2: synthesis of (E)-4-((8-(4-(2-cyanovinyl}-2,6-diniiorophenyl)qiiinazolin-2yl)amino)benzonitrile (compound 5) (mixture E!Z= 4/1)

CsjCOj ch₂ci₂r.t.

[0260] Césium carbonate (1.5 g, 4.6 mmol) was added to a solution of compound 5a (70 mg, 0.18 mmol) and diethyl (cyanomethyl)phosphonate (32 pL, 0.2 mmol) in dry dichloromethane (25 mL) and the solvent was slowly removed under reduced pressure at 30 °C. The resulting reaction mixture was allowed to stand ovemight at room température. Dichloromethane was added to the residue and the solids were filtered ofî. The solvent was removed under reduced pressure and the residue was purified by HPLC (préparative column Phenomenex Gemini 10 micron CI8,250x 21.2 mm, 10 mL/min, gradient from 10-100% acetonitrile in water) to afford the title compound 5 as a mixture of FJZ isomers 4/1. ’H NMR for the E isomer (400 MHz, DMSO-î/₆) δ 10 54 (s, 1 H), 9.49 (s, 1 H), 8.16 - 8.12 (m, 1 H), 8 0 (d, J = 7.3 Hz, 1 H), 7.87 - 7.83 (m, 3H), 7.73 (d, J = 8.0 Hz, 2H), 7.63 -7.58 (m, 1 H), 7.56-7.52 (m, 211),6.81 (d, J= 16.7 Hz, 1H) LCMS (m/z) 410.1 [M+H], Tr = 4.76 min (LCMS method 1)

EXAMPLE 6 (E)-4-((8-(4-(2-Cyanovinyl)-2,6-dimethylphenyl)-4((cyclopropylmethyl)amino)quinazolin-2-yl)amino)benzonitrile - Compound 6

Step 1: Synthesis of 8-bromo-2-chloro-/V-(cyclopropylmethyl)quinazolin-4-amme (Compound 6a)

[0261 ] Cyclopropylmethanamine (95 pL, 1.1 mmol) and /V-ethyldiisopropylamine (0.35 mL, 2 mmol) were added to a solution of 8-bromo-2,4-dichloroquinazoline (278 mg, 1 mmol, Ark Pharm Inc., AK-28703) in isopropanol (5 mL) The réaction mixture was stirced at room température for 30 minutes. The solid product was filtered off and washed with water (2x5 mL) and pentane (3x5 mL) to give the title compound 6a. ’H NMR (400 MHz, DMSO^A) 5 9.03 (s, 1 H), 8.30 (dd, 8.3 Hz, J = 1.3 Hz, 1 H), 8.12 (dd, J = 7.7 Hz, J = 1.3 Hz, 1H), 7.44 (t, J=8.0 Hz, 111),3.41 -3.35 (m,211), 1.23-1.H (m, 1 H), 0,52-0.45 (m, 2H), 0.34 -0 28 (m, 2H) HRMS: (ES 1+) calculated for CnHuNaBrCI [M+H] 311.9898, found 311.9898. LCMS (m/z) 312 0 [M+H], Tr 4.59 min (LCMS method 1 )

Step 2: Synthesis of4-((8-bromo-4-((cycIopropylmethyl)amino)qiiinazolin-2yl)amino)benzonitrile hydrochloride (Compound 6b)

N Compound 6b [0262] A mixture of compound 6a (156 mg. 0.5 mmol) and 4-aminobenzonitrile (71 mg, 0.6 mmol, Sigma-Aldrich) in isopropanol (5 mL) was heated in microwave at 180 °C for 2 hours. The reaction mixture was cooled down to room température and the solid product was filtered off and washed twice with cold isopropanol and then three times with pentane to afford the compound 6b as the HCl sait. *H NMR (400 MHz, DMSO-t/â) δ 8.39 (d, J- 7.7 Hz, 1 H), 8.15 - 7.99 (m, 3H), 7.81 (d, J = 8.4 Hz, 2H), 7.33 (t, J = 7.9 Hz, 1 H), 3.53 - 3.45 (m, 2H), 1.30- 1.17 (m, 1H), 0.54-0.48 (m, 2H), 0.37-0.32 (m, 2H). HRMS: (ESI+) calculated for CwHnNsBr [M+H] 394.0662, found 394 0661. LCMS (m/z) 394.0 [M+H], Tr 4 29 min (LCMS method 1 )

Step 3: synthesis of(E)-4-((8-(4-(2-cyanovinyl)-2,6-dinietIiyIphenyl)-4((cyclopropylmetliyl)ammo)quinazolin-2-yl)amino)benzonitrile (compound 6)

II

PdCI₂(dppf),K₂CO₃

1,4-dioxane/H₂0 (10:1) 100C

N Compound 6 [0263] A mixture of compound 6b (65 mg, 0.15 mmol), compound 1 c (64 mg, 0.23 mmol), [l,r-bis(diphenylphosphino)ferrocene] dichloropalladium(II), complex with dichloromethane (37 mg, 0.05 mmol) and potassium carbonate (104 mg, 0.75 mmol) in the mixture of 1,4-dioxane and water ( 10:1, 5 mL) was purged with argon and heated at 100 °C for 1 hour. Solvents were removed under reduced pressure and the residue was purified by silica gel chromatography (gradient from 20-40% ethyl acetate in /w-hexanes) to afford the title compound 6. Ή NMR (400 MHz, DMSO-î/₆) δ 9.49 (s, 1 H), 8.39 (t, J = 5.6 Hz, 1 H), 8.24 - 8.13 (m, 2H), 7.74 - 7.69 (m, 2H), 7.51 (s, 2H), 7.46 (dd, J= 7.2 Hz, J = 1.4 Hz, 1 H), 7.35 (t,J=8.2 Hz, 1H), 7.26 (d, J =8.9 Hz, 2H), 6.54 (d,J= 16.7 Hz, 111),3.47 - 3.43 (m,

2H). 1.90 (s, 6H), 1.30-1.21 (m, 1H), 0.53 - 0.47 (m, 2H), 0.35-0 30(m,2H). HRMS: (ESI+) calculated for CjoFhiNs [M+H] 471.2292, found 471.2292. LCMS (m/z) 471.2 [M+H], Tr4 05 min (LCMS method 1).

EXAMPLE 7 (E)-4-((4-(ButyIamÎnoh8-(4-(2-cyanovinyI)-2,6-dimethyIphenyI)quÎnazoIin-2 yl)amino)benzonitrile - Compound 7

Step 1: Synthesis ofS-bromo-yV-butyl-Z-chloroquinazolîn^-amine (Compound 7a)

[0264| n-Butylamine (109 pL, 1.1 mmol) and V-ethyldiisopropylamine (0.35 mL, 2 mmol) were added to a solution of 8-bromo-2,4-dichloroquinazoline (278 mg, 1 mmol, Ark Pharm Inc., AK-28703) in isopropanol (5 mL) The reaction mixture was stirred at room température for 30 minutes. The solid product was filtered offand washed with water (2x5 mL) and pentane (3x5 mL) to give the title compound 7a ¹II NMR (400 MHz, DMSO-ί/ό) δ 8.87 (s, 1 H), 8.27 (dd, J = 8 3 Hz, J = 1.2 Hz, 1 H), 8.12 (dd, J = 7.7 Hz, J = 1.2 Hz, 1 H), 7.43 (t, J = 7.9 Hz, 1 H), 3.55 - 3 48 (m, 2H), 1.66 - 1.57 (m, 2H), 1.41 - 1.31 (m, 2H), 0.92 (t, J= 7.3 Hz, 311). HRMS: (ESI+) calculated for CnHuNjBrCl [M+H] 314.0054, found 314.0055. LCMS (m/z) 314.0 [M+H], Tr 4.76 min (LCMS method 1 )

Step 2: Synthesis of 4-((8-bromo-4-(biitylammo)qiiinazolin-2-yl)amino)benzonitrile hydrochloride (Compound 7b)

Compound 7b [0265] A mixture of compound 7a (157 mg, 0.5 mmol) and 4-aminobenzonitrile (71 mg, 0.6 mmol, Sigma-Aldrich) in isopropanol (5 mL) was heated in microwave at 180 °C for 2 hours. The reaction mixture was cooled down to room température and the solid product was filtered off and washed twice with cold isopropanol and then three times with pentane to afford the compound 7b as the HCl sait ^lH NMR (400 MHz, DMSO-Je) δ 8.32 (d, J-7.8 Hz, 1H), 8.21-7.79 (m, 3H), 7.79 (d, J=8.3 Hz»2H), 7.29 (t, J=7.8 Hz, III), 3.65-3.63 (m, 2H), 1.74- 1.59 (m, 2H), 1.43 - 1.33 (m.2H), 0.92 (t, J =7.4 Hz, 3H) HRMS: (ESI+) calculated for CwHuNjBr [M+H] 396.0818, found 396 0816. LCMS (m/z)396.1 [M+H],Tr 4.34 min (LCMS method 1)

Step 3: synthesis of (E)-4-((4-(butylamino)-8-(4-(2-cyanoviny 1)-2,6dimethylphenyl)qiiinazolin-2-yl)amino)benzonîtrîle (compound 7)

N Compound 7 [0266] A mixture of compound 7b (65 mg, 0.15 mmot), compound 1 c {64 mg, 0.23 mmol), [l,r-bis(diphenylphosphino)ferrocene] dtchloropalladium(II), complex with dichloromethane (37 mg, 0.05 mmol) and potassium carbonate (104 mg, 0.75 mmol) in the mixture of 1,4-dioxane and water (101, 5 mL) was purged with argon and heated at 100 °C for 1 hour. Solvents were removed under reduced pressure and the residue was purified by silica gel chromatography (gradient from 20-40% ethyl acetate in /.vo-hexanes) to afford the title compound 7. Ή NMR (400 MHz, DMSO-î/₆) δ 9.45 (s, 1H), 8.25 - 8.16 (m, 2H), 7.78 — 7.69 (m, 3H), 7.51 (s, 2H), 7.46 (dd, J = 7.1 Hz, J =1.3 Hz, 1 H), 7.34 (t, J = 8.2 Hz, 1H), 7.27 (d, J = 8.9 Hz, 2H),6.54 (d, J =16.7 Hz, 1 H), 3.63-3.51 (m,2H), 1.90 (s, 6H), 1.721.65 (m,2H), 1.46- 1.38 (m,2H), 0.95 (t, J = 7.4 Hz,3H) MS-EST m 'z (%) 473 (100, Μ+1Γ), 495 (20, M+Na⁺); HRMS: (ESI+) calculated for CjolhsNe [M+H] 473.2448, found 473.2448. LCMS (m/z) 473.3 [M+H], Tr 4.14 min (LCMS method 1 ).

EXAMPLE 8 (E)-4-((4-Amino-8-(4-(2-cyanovinyl)-2,6-diniiorophenyl)quinazo[in-2yl)amino)benzonitrile - Compound 8 (mixture £7Z = 3/2)

Step 1: Synthesis of 4-((4-amino-8-bromoquinazolin-2-yl)amino)benzonitrile (Compound 8a)

N Compound 8a [0267] A mixture of 8-bromo-2-ch)oroquinazo)in-4-amine (259 mg, 1 mmol, Ark Pharm

Inc, AK-28702)and4-aminobenzonitrile(130 mg, 1.1 mmol, Sigma-Aldrich) in isopropanol (5 mL) was heated in microwave at 160 °C for 3 hours The reaction mixture was cooled down to room température and the solid product was filtered off and washed with cold isopropanol and then with diethyl ether to afford the compound 2a. ’H NMR (400 MHz, DMSO-tZs) δ 9.74 (s, 1H), 8.35 (d, J= 8.8 Hz, 2H), 8.16 (d,J= 8.0 Hz. 1H). 8 01 (d, J= 7.5 Hz, 1H), 7.71 (d, 8.8 Hz, 2H), 7,16 (t, J = 7.8 Hz, 1H). HRMS: (ESI+) calculated for

CisHnNsBr [M+H] 340.0192, found 340.0192. LCMS (m/z) 340.0 [M+H], Tr = 4.06 min (LCMS method 1)

Step 2: Synthesis of 4-((4-amino-8-(2,6-diniioro-4-formylphenyl)quinazolin-2yl)amino)benzonitri!e (Compound 8b) nh.

Pd₂(dba)₃, P(EBu)₃KF,THF/H₂O (10/1) 80“C

NH,

N Compound 8b [0268] A mixture ofcompound 8a (l 20 mg, 0.36 mmol), 3,5-difluoro-4-(4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-yl)benzaldehyde(285 mg, 1.06 mmol, Sigma-Aldrich), and potassium fluoride(102 mg, 1.76 mmol) in a tetrahydrofuran/water mixture (10.1,30 mL) was purged with argon and tris(dibenzylideneacetone)pa11adium(0) (195 mg, 0.213 mmol) was added followed by tri-ferr-butylphosphine (103 pL, 0.43 mmol) The mixture was heated at 80°C for 4 hours. The solvent was removed under reduce pressure and the residue was purified by silica gel chromatography (gradient from 20-80% ethyl acetate in /so-hexanes) to afford the title compound 8b. *H NMR (400 MHz, DMSO-î/s) δ 10.12 (s, 1H), 9.56 (s, 1H), 8.29 (dd, J= 8 2 Hz, J = 1.1 Hz, 2H), 7.87-7.73 (m, 6H), 7.44-7.34 (m, 3H) LCMS (m/z) 401.9 [M+H], Tr= 4.28 min (LCMS method 1)

Step 3: synthesis of (E)-4-((4-amino-8-(4-(2-cyanovinyI)-2,6-dinuorophenyl)quinazolin 2-yl)amîno)benzonitrile (compound 8) (mixture E!Z~ 3/2)

Cs₂CO₃ch₂ci₂r.t.

[0269] Césium carbonate (2,5 g, 7.69 mmol) was added to a solution of compound 8b (74 mg, 0.18 mmol) and diethyl (cyanomethyl)phosphonate (30 pL, 0.18 mmol) in dry dichloromethane (25 mL) and the solvent was slowly removed under reduced pressure at 30 °C. The resulting reaction mixture was allowed to stand ovemight at room température. Dichloromethane was added to the residue and the solids were filtered ofT. The solvent was removed under reduced pressure and the residue was purified by HPLC (préparative column Phenomenex Gemini 10 micron Cl8, 250 x 21.2 mm, 10 mL/min, gradient from 10-100% acetonitrile in water) to afîord the title compound 8 as a mixture of FJZ isomers 3/2. ’H NMR for the E isomer (400 MHz, DMSCWs) δ 9.54 (s, I H), 8.29 - 8.24 (m, 2H), 7.84 (d, J = 2.4 Hz, 1 H), 7.82-7.78 (m, 2H), 7.72 (d, J = 7.3,2H), 7.66 (d, J =7.8 Hz, 2H), 7.43 -7.39 (m, 2H), 7.38-7.33 (m, 1H), 6.77 (d, J= 16.7 Hz, 1H). LCMS (m/z) 424.9 [M+H], Tr = 3.46 min (LCMS method 1)

EXAMPLE 9 (E)-5-((4-AmÎno-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2yl)amino)picolïnonitrile - Compound 9

N

Step 1: Synthesis of5-((4-amino-8-bromoqiitnazolin-2-yl)amino)pîcolinonitrile (compound 9a)

Isopropanol

180 °C

N Compound 9a [0270] A mixture of 8-bromo-2-chloroquinazolin-4-amine (500 mg, 1.9 mmol, Ark Pharm Inc, AK-28702) and 5-aminopicolinonitrile (253 mg, 2.1 mmol, Ark Pharm Inc, AK26123) in isopropanol (10 mL) was heated under argon in microwave at 180 °C for 8 hours. The reaction mixture was cooled down to room température and the solid product was filtered offand washed with cold isopropanol and then with diethyl ether and hexane to afford the compound 9a. Ή NMR (400 MHz, DMSCWô) δ 9.98 (s, 1 H), 9.35 (dd,J= 2.6, 0.7 Hz, 1H), 8.85 (dd, J= 8.7, 2.6 Hz, 1H), 8.17 (dd, J= 8.2, 1.3 Hz, 1 H), 8 03 (dd, J= 7.6, 1.3 Hz, 1H), 7.95 - 7.91 (m, 2H), 7.23 - 7.10 (m, 2H) LCMS (m/z) 343.2 [M+H], Tr= 2.31 min (LCMS method 2)

Step 2: synthesis of (E)-5-((4-amino-8-(4-(2-cyanovinyI)-2,6(lÎmethyIphenyI)quinazoIin-2-yl)amino)picoIinonitnle (compound 9)

K₃PO<

PdCI₂(dtbpf) DMF:H₂O (85:15) 90°C

100 [0271] Compound 9a (150 mg, 0.44 mmol), compound le (498 mg, 1.76 mmol), potassium phosphate tribasic (560 mg, 2,64 mmol) and 1,1 -bis(di-f«?r/~ butylphosphinojferrocene palladium dichloride (57 mg, 0.09 mmol) were dissolved in Ν,Νdimethylformamide: water mixture (85:15,25 mL) under argon. The reaction was heated at 90°C for 1 hour. The reaction mixture was cooled down to room température and diluted with water and ethyl acetate. The organic layer was separated. The water layer was washed with additional ethyl acetate. Combined organics were washed twice with brine and dried over magnésium sulfate. Solvents were removed under reduced pressure and the residue was purified by silica gel chromatography (gradient from 0-40% ethyl acetate and methanol (4/1) in ûo-hexanes) Solvents were removed under reduced pressure and the solid residue was treated with the mixture of hexane/diethyl ether (5:1) in the sonie bath for 5 minutes, filtered off and washed with hexane to afford the title compound 9. *H NMR (400 MHz, DMSO-Je) δ 9.70 (s, 1 H), 8.74 (d, J = 2.5 Hz, 1 H), 8.24 - 8.15 (m, 2H), 7.72 (d, J = 16.7 Hz, 1 H), 7.49 (d, J = 7.6 Hz, 3H), 7.40 - 7.30 (m, 2H), 6 51 (d, J = 16 7 Hz, 1 H), 1.90 (s, 6H). LCMS (m/z) 418.3 [M+H], Tr = 2.47 min (LCMS method 2).

EXAMPLE 10 (£)-6-((4-Amino-8-(4-(2-cyanovînyl)-2,6-dimethylphenyl)quinazolin-2yl)amino)nîcotinonîtri!e- Compound 10

NH₂

LL x

Synthesis of (£>6-((4-amino-8-(4-(2-cyanovinyl)-2,6-dÎmethylphenyl)quinazolin-2y!)amino)nicotinonitrile (compound 10)

101

N

Nt-h

N

Pd(OAc)₂Xantphos DIPEA NMP 120°C

[0272| Compound 2a (820 mg, 2.45 mmol), 6-aminonicotinonitrile (875 mg, 7.35 mmol, Ark Pharm Inc, AK-32349), TV/Z-diisopropylethylamine (2.53 g, 19.6 mmol), (9,9-dimethyl9H-xanthene-4,5-dîyl)bis(diphenylphosphine) (142 mg, 0.25 mmol) and palladium (II) acetate (55 mg, 0.25 mmol) were combined under argon in N-methyl-2-pyaolidone (40 mL) The reaction was heated at 120°C in a sealed vessel for 4 hours. The reaction mixture was cooled down to room température and diluted with water and ethyl acetate. The organic layer was separated and washed twice with brine, dried over magnésium sulfate, 0.05 volume équivalent of hexane added and this mixture was filtered through a 2 cm layer of silica gel which was washed with additional ethyl acetate Combined organics were concentrated down under reduced pressure. The crude residue was treated with diethyl ether/dichloromethane mixture (1:1 ) in the sonie bath for 5 minutes. The solid compound was filtered offand washed twice with diethyl ether and once with hexane to afford the title compound 10. ’H NMR (400 MHz, DMSO-î/₆) δ 9.58 (s, 1H), 8.57 (dd, J= 2.4,0.8 Hz, 1 H), 8.20 (dd, J = 8.3,1.4 Hz, 1 H), 7.95 (dd, J = 9.0, 0.8 Hz, 1 H), 7.73 (d, J = 16.7 Hz, 1 H), 7.55 -7.51 (m,3H), 7.44-7.36 (m, 2H), 6.53 (d,J= 16.7 Hz, 1H), 1.90(s, 6H) LCMS (m/z) 418.3 [M+H], Tr= 1.82 min (LCMS method 2).

EXAMPLE 11 (E)-6-((4-Amino-8-(4-(2-cyanovinyI}-2,6-dimethyIpIienyl)quinazoIin-2yl)amino)pyridazine-3-carbonitrile- Compound 11

102

Synthesis of (E)-6-((4-amino-8-(4-(2-cyanovmyI)-2_i6-dimethylphenyl)qitinazolÎn-2yl)amino)pyridazine-3-carbonitriIe (compound 11)

II N

N

Pd(OAc)j Xantphos DI PEA NMP 120°C

[0273] Compound 2a (20 mg, 0.06 mmol). 6-aminopyridazine-3-carbonitrile (22 mg. 0.18 mmol, Matrix Scientific, 112287), TV^-diisopropylethylamine (62 mg, 0.47 mmol), (9,9-dimethyl-9//-xanthene-4,5-diyl)bis(diphenylphosphine) (3 mg, 0.006 mmol) and palladium (II) acetate (I mg, 0.006 mmol) were combined under argon in 7V-methyl-2pyrrolidone (2 mL) The reaction was heated at I20°C in a sealed vessel for I hour. The reaction mixture was cooled down to room température and purified by HPLC reverse phase chromatography (0-100% acetonitrile in water with 0.1% trifluoroacetic acid) to aflord the TFA sait of compound 11. '11 NMR (400 MHz, DMSO-c/s) δ 8.35 (bs, I H), 8 09 (bs, 1 H), 7.78-7.39 (m, 6H), 6.54 (d, J = 16.7 Ηζ,ΙΗ), 1.93 (s,6H) LCMS (m/z)419.3 [M+H],Tr = 2.03 min (LCMS method 2)

EXAMPLE 12

103 (E)-5-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylplienyl)qiiinazolin-2yl)amino)pyrazîne-2-carbonîtrile- Compound 12

Synthesis of(E)-5-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2 yl)amino)pyrazine-2-carbonitrile (compound 12)

NH₂

-------►

Pd(OAc)₂Xantphos DI PEA NMP 120°C

[0274] Compound 2a (20 mg, 0.06 mmol), 5-aminopyrazine-2-carbonitriîe (22 mg, 0.18 mmol, Ark Pharm Inc, AK-21935), /VA-diisopropylethylamine (62 mg, 0.47 mmol), (9,9dimethyI-9//-xanthene-4,5-diyî)bis(diphenylphosphine) (3 mg, 0.006 mmol) and palladium (II) acetate (1 mg, 0,006 mmol) were combined under argon in jV-methyl-2-pyrroIidone (I mL). The reaction was heated at 120°C in a sealed vessel for 3 hours. The reaction mixture was cooled down to room température and purified by reverse phase chromatography (ΟΙ 00% acetonitrile in water with 0.1% trifluoroacetic acid) to afford the TFA sait of compound 12. Ή NMR (400 MHz, DMSO-J₆) δ 8.98 (bs, I H), 8 36 (bs, I H), 7.85 - 7.28 (m, 6H), 6.59 (d, J = 15.6 Hz, I H), 1.94 (s, 6H). LCMS (m/z) 419.3 [M+H], Tr = 1.89 min (LCMS method 2).

104

EXAMPLE 13 (E)-6-((8-(4-(2-Cyanovinyl)-2A-<liniethylphenyl)quinazolin-2-yl)aniino)nicotinonitrileCompound 13

Step 1: Synthesis of(E)-3-(4-(2-chloroquinazolin-8-yl)-3,5-dimethylphenyl)aci'ylonitrile (Compound 13a)

N Compound 13a [0275] A mixture of 8-bromo-2-chloroquinazoline (500 mg, 2.05 mmol, Ark Pharm Inc, AK-27609), compound le (776 mg. 2.67 mmol), potassium phosphate tribasic (633 mg, 3.08 mmol) and 1 ,r-bis(di-/t’rt-butylphosphino)feiTocene palladium dichloride (134 mg, 0.21 mmol) was dissolved in ΛζΛΓ-dimethylformamide: water mixture (85:15,10 mL) under argon. The reaction was heated to 50°C for 2 hours. The reaction mixture was cooled down to room température and diluted with water and ethyl acetate. The organic layer was

105 separated and washed twice with brine, dried over magnésium sulfate, 0.5 volume équivalent ofhexane added and this mixture was filtered through a 2 cm layer of silica gel which was washed with additional hexane/ethyl acetate mixture (]/]) Combined organics were concentrated down under reduced pressure and the residue was treated with diethyl ether in a sonie bath. The solid product was filtered off and washed twice with diethyl ether and once with hexane to afford the title compound 13a. ’H NMR (400 MHz, DMSO-î/î) δ 9.70 (s, 1 H), 8.30 (dd, J = 7.1,2.5 Hz, 1 H), 7.99 - 7.84 (m, 2H), 7.66 (d, J = 16.7 Hz, 1 H), 7.49 (s, 2H), 6.50 (d, J= 16.7 Hz, ]H), 1.85 (s, 6H) LCMS (m/z) 320.1 [M+H],Tr= 1.40 min (LCMS method 3).

Step 2: Synthesis of (£)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6dimethylphenyl)quinazolin-2-yl)amino)nicotinonitrile (compound 13)

Pd(OAc)₂Xantphos DIPEA NMP 80°C

[0276] Compound 13a (508 mg, 1.60 mmol), 6-aminonicotinonitrile (567 mg, 4.77 mmol, Ark Pharm Inc, AK-32349), Λζ/V-diisopropylethylamine (1.64 g, 12.71 mmol), (9,9dimethyl-9/7-xanthene4,5-diyl)bis(diphenylphosphine) (93 mg, 0.16 mmol) and palladium (II) acetate (36 mg, 0.16 mmol) were combined under argon in/V-methyl-2-pyrrolidone(10 mL). The reaction was heated at 80°C in a sealed vessel for 30 minutes. The réaction mixture was cooled down to room température and diluted with water and ethyl acetate. The organic layer was separated and washed twice with brine, dried over magnésium sulfate, 0.5 volume équivalent of hexane added and this mixture was filtered through a 2 cm layer of silica gel which was washed with additional hexane/ethyl acetate mixture (1/1 ) Combined organics were concentrated down under reduced pressure. The crude residue was treated with diethyl ether in the sonie bath for 5 minutes. The solid compound was filtered off and

106 washed twice with diethyl ether and once with hexane to afford the title compound 13. ’H NMR (400 MHz, DMSCMs) δ 10.85 (s, 1 H), 9.52 (s, 1 H), 8.66 (dd, J = 2.3,0.9 Hz, I H).

8.10 (dd, J = 8.0, 1.4 Hz, 1 H), 7.92 (dd, J = 8.9,0.9 Hz, 1 H), 7.85 - 7.70 (m, 2H), 7.65 (dd, J = 8.1,7.1 Hz, 1 H), 7.57 - 7.48 (m, 3 H), 6.56 (d, J = 16.7 Hz, 1 H), 1.89 (s, 6H). LCMS (m/z) 403.2 [M+H], Tr = 1.48 min (LCMS method 3)

EXAMPLE 14 (E)-6-((8-(4-(2-Cy a nov iny l)-2,6-d imethyl phenyl)-6-nuoroq u in azolin-2 yl)amino)nicotinonitrile- Compound 14

Step 1: (E)-3-(4-(2-cliloro-6-fhioroqtiinazolÎn-8-yI)-3,5-dimethylplienyl)acrylonitnIe (Compound 14a)

DMF:H₂O (10;1) eo°c

107 |0277| A mixture ofcompound le (100 mg, 0.35 mmol), 8-bromo-2-chloro-6fluoroquinazoline (100 mg, 0.38 mmol, Ark Pharm Inc, AK-93358), 1,1 '-bis(di-rer/butylphosphino)ferrocene palladium dichloride (50 mg, 0.08 mmol) and potassium phosphate tribasic monohydrate (200 mg, 0.77 mmol) in A/.A/’-dimethylformamide (3 mL) and water (0.3 mL) was heated under argon at 80°C for 30 minutes. The reaction mixture was evaporated to dryness and the residue was purified by silica gel chromatography This was subjected to silica gel chromatography (gradient from 0-100% ethyl acetate in isohexanes) to afford compound 14a LCMS (m/z) 337.9 [M+H], Tr = 4 52 min (LCMS method 1).

Step 2: Synthesis of (E)-6-((8-(4-(2-cyanovinyl)-2,6-diinethyIphenyl)-6fluoroquinazolin-2-yl)amino)nicotinonitrile (compound 14)

NH₂

Pd(OAc)₂Xantphos DIPEA NMP 100°C

[0278] Compound 14aa (100 mg, 0.30 mmol), 6-aminonicotinonitrile (200 mg, 1.68 mmol, Ark Pharm Inc, AK-32349), WJV-diisopropylethylamine (0.5 mL, 2 86 mmol), (9,9dimethyl-9/7-xanthene-4,5-diyl)bis(diphenylphosphine) (180 mg, 0.31 mmol) and palladium (II) acetate (40 mg, 0.18 mmol) were combined under argon in A/-methy1-2-pyrro1idone (3 mL). The reaction was heated at 100°C in a sealed vessel for 1 hour. The reaction mixture was cooled down to room température and dîrectly purified by silica gel chromatography (gradient from 60-100% ethyl acetate in /.vo-hexanes and then gradient from 0-20% methanol in ethyl acetate) to afford the title compound 14. Ή NMR (400 MHz, DMSO-ί/β) δ 9.62 (s,1 H), 8.77 (dd, J = 2.3, 0.8 Hz, I H), 8.08-7.99 (m, 1H), 7.99-7.91 (m, 1H), 7.87 (d, J = 16 7 Hz, 1Π), 7.68 (s, 2H), 7.65 -7.60 (m, 111), 7.60-7.53 (m, III), 7.36 (d, J= 8.2,

108

Hz, 1H), 6.68 (d, J= 16.7 Hz, 1H), 2.01 (s, 6H). LCMS (m/z) 420.9 [M+H], Tr = 4.62 min (LCMS method 1).

EXAMPLE 15 (E)-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethyIphenyI)quinazoIin-2-yl)amino)-2,4' dimethylnicotinonitrile- Compound 15

Synthesis of (E)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)qiiinazolin-2yl)amino)-2,4-dimethylnicotinonitriIe (compound 15)

Pd(OAc)₂Xantphos DIPEA NMP 120°C

N Compound 15 [0279] Compound 2a (20 mg, 0.06 mmol), 6-amino-2,4-dimethylnicotinonitrile (26 mg, 0.18 mmol, Key Organics Ltd, 1X-0933), NA/-diisopropylethylamine (622 mg, 0,48 mmol), (9,9-dimethyl-9H-xantheneA5-diyl)bis(diphenylphosphine) (4 mg, 0.006 mmol)and palladium (II) acetate (I mg, 0.006 mmol) were combined under argon in 7V-methyl-2pyrrolidone (I mL). The reaction was heated at 120°C in a sealed vessel for 4 hours. The reaction mixture was cooled down to room température and diluted with water and ethyl

109 acetate. The organic layer was separated and washed twice with brine, dried over magnésium sulfate and this solution was filtered through a 2 cm layer of silica gel which was washed with additional ethyl acetate. Combined organics were concentrated down under reduced pressure. The crude residue was treated with diethyl ether in the sonie bath for 5 minutes. The solid compound was filtered off and washed twice with diethyl ether and once with hexane to afford the title compound 15. Ή NMR (400 MHz, DMSO-Jô) δ 9.56 (bs, 1 H), 9.29 (bs, I H), 8.44 (d, J = 8 0 Hz, 1H), 7,99-7.47 (m, 5H), 7.41-7.10 (m, 1H), 6.55 (d, J = 16.7 Hz, 1 H), 2.41 (bs, 3H), 1.96 (s, 6H), 1.62 (bs, 3H) LCMS (m/z) 446 4 [M+H], Tr= 1.19 min (LCMS method 3).

EXAMPLE 16 (£>-6-((4-Amino-8-(4-(2-€yanovinyl)-2,6-diniethylphenyl)quinazolÎn-2-yl)aniino)-2methylnicotinonitrile- Compound 16

N

Synthesis of(E)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2yl)amino)-2-methylnicotinonitrile (compound 16)

110 [0280] Compound 2a (20 mg, 0.06 mmol), 6-amino-2-methylnicotinonitrile (24 mg, 0.18 mmol, Ark Pharm Inc, AK-78835), A/AMiisopropylethylamine (622 mg, 0.48 mmol), (9,9-dimethyl-9//-xanthene-4,5-diyl)bis(diphenylphosphine) (4 mg, 0 006 mmol) and palladium (II) acetate (1 mg, 0.006 mmol) were combined under argon in jV-methyl-2pyrrolidone (1 mL). The reaction was heated at 120°C in a sealed vessel for 4 hours. The reaction mixture was cooled down to room température and diluted with water and ethyl acetate. The organic layer was separated and washed twice with brine, dried over magnésium sulfate and this solution was filtered through a 2 cm layer of silica gel which was washed with additional ethyl acetate. Combined organics were concentrated down under reduced pressure. The crude residue was treated with diethyl ether in the sonie bath for 5 minutes. The solid compound was filtered off and washed twice with diethyl ether and once with hexane to afford the title compound 16. *11 NMR (400 MHz, DMSO-ί/β) δ 10.92 (s, 1 H), 9.55 (s, 1 H), 9.10 (s, 1 H), 8.46 (dd, J = 8.3,1.3 Hz, 1 H), 8.19 (d, J = 2.2 Hz, 1 H), 7.89 - 7.73 (m, 3H), 7.69 (s, 2H), 7.32 (d, J = 2.2 Hz, 1 H), 6 68 (d, J = 16.7 Hz, 1H), 2.37 (s, 3H), 1.95 (s, 6H). LCMS (m/z) 432.4 [M+H], Tr= 1.15 min (LCMS method 3)

EXAMPLE 17 (£)-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimetliyIphenyl)quinazoIin-2-yI)amino)-5methylnicotinonitrile- Compound 17

Synthesis of (E)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyI)quÎnazolin-2yl)amino)-5-methylnicotinonitrile (compound 17)

111

II

N

Pd(OAc)₂Xantphos DIPEA NMP 120°C

NH,

N Compound 17 [0281] Compound 2a (20 mg, 0.06 mmol), 6-amino-5-methylnicotinonitrile (24 mg, 0.18 mmol, Ark Pharm Inc, AK-25043), NJV-diisopropylethylamine (622 mg, 0 48 mmol), (9,9-dimethyl-9//-xanthene-4,5-diyl)bis(dipheny!phosphine) (4 mg, 0.006 mmol) and palladium (II) acetate (1 mg, 0.006 mmol) were combined under argon in Mmethyl-2pyrrolidone (1 mL). The reaction was heated at 120°C in a sealed vessel for 4 hours. The reaction mixture was cooled down to room température and diluted with water and ethyl acetate. The organic layer was separated and washed twice with brine, dried over magnésium sulfate and this solution was filtered through a 2 cm layer of silica gel which was washed with additional ethyl acetate. Combined organics were concentrated down under reduced pressure. The crude residue was treated with diethyl ether in the sonie bath for 5 minutes. The solid compound was filtered oflf and washed twice with diethyl ether and once with hexane to afford the title compound 17. *H NMR (400 MHz, DMSO-ΐ/ά) δ 10.92 (s, 1H), 9,55 (s, 1H), 9.10 (s, 1H), 8.46 (dd, J = 8.3,1.3 Hz, IH), 8.25-8.13 (m, 1H), 7.91 7.72 (m, 3H), 7.69 (s, 2H), 7.35 - 7.29 (m, 1 H), 6 68 (d, J = 16.7 Hz, 1 H), 2.37 (s, 3H), 1.95 (s, 6H) LCMS (m/z) 432.4 [M+H], Tr = 1.19 min (LCMS method 3)

EXAMPLE 18 (E)-6-((4-AmÎno-8-(4-(2-cyanovmyl)-2,6-diînethylphenyl)qitinazolin-2-yl)anuno)-4mcthylnicotinonitrile- Compound 18

112

Synthesis of (£}-6-((4-amino-8-(4-(2-cyanoviny 1)-2,6-dimethylphenyl)qiiinazolin-2 yt)amino)-4-methytnicotinonitriIe (compound 18)

II

N

II N

Pd(OAc)₂Xantphos DIPEA NMP 120°C

N Compound 18 [0282] Compound 2a (20 mg, 0,06 mmol), 6-amino-4-methylnicotinonitrile (24 mg, 0.18 mmol. Ark Pharm Inc. AK-80I25), A^V-diisopropylethylamine (622 mg, 0.48 mmol), (9,9-dimethyl-9/7-xanthene-4.5-diyl)bis(diphenylphosphine) (4 mg, 0.006 mmol) and palladium (II) acetate (I mg. 0.006 mmol) were combined under argon in V-methyl-2pyrrolidone (I mL) The reaction was heatcd at I20°C in a sealed vessel for 4 hours. The reaction mixture was cooled down to room température and diluted with water and ethyl acetate. The organic layer was separated and washed twice with brine, dried over magnésium sulfate and this solution was filtered through a 2 cm layer of silica gel which was washed with additional ethyl acetate. Combined organics were concentrated down under reduced pressure. The crude residue was treated with diethyl ether in the sonie bath for 5 minutes. The solid compound was filtered offand washed twice with diethyl ether and once with hexane to afford the title compound 18. ’ll NMR (400 MHz, DMSO-ί/β) δ 11.97

113 (bs, 1 H), 9.55 (bs, 1 H), 9.32 (bs, 1 H), 8.48 - 8.37 (m, 1 H), 7.90 - 7.62 (m, 5H), 7.52 - 7.43 (m, 1 H), 7.32 - 7.23 (m, 1 H), 6.69 (d, J = 16.7 Hz, 1 H), 2.45 (s, 3H), 1.96 (s, 6H). LCMS (m/z) 432.3 [M+H], Tr = 1.25 min (LCMS method 3)

EXAMPLE 19 (E)-4-((4-Amino-6-chloro-8-(4-(2-cyanovinyl)-2,6-<lïmethyIplienyl)quÎnazolin-2 yl)amino)benzonitrile- Compound 19

NH->

Step 1: Synthesis or2-amino-3-bromo-5-chIorobenzoic acid (Compound 19a)

OH	OH
	NBS	- ^0ΙΥΊι	^O
^nh₂	DMF, r.t.		^NH₂
		Br	Compound 19a

[0283] A mixture of 2-amino-5-chlorobenzoic acid (5 g, 29 mmol, Ark Pharm Inc, AK26989) and /V-bromosuccinimide (5.4 g, 30 mmol) in A^N'tliniethylformamide (100 mL) was stirred at room température for 14 hours. The reaction mixture was poured into water (400 mL) and product was extracted with diethylether (400 mL) The organic phase was washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated down under reduced pressure to afford the title compound 19a. LCMS (m/z) 250.0 [M+H], Tr = 4 05 min (LCMS method I )

Step 2: synthesis of 8-bromo-6-chloroqiiinazoIine-2<4(l/A3/7)-dione (compound 19b)

114

[0284] A mixture of compound 19a (5.3 g, 21 mmol) and urea (30 g, 500 mmol) was heated at 200 °C for 3 hours. The reaction mixture was cooled down, diluted with methanol (100 mL)and the product was filtered off. The solid was washed with water (50 mL) and methanol (50 mL) to afiord the title compound 19b LCMS (m/z) 275.0 [M+H], Tr = 3.32 min (LCMS method 1 )

Step 3: synthesis of8-bromo-2,6-dich!oroquinazolin-4-amme (compound 19c)

Compound 19c [0285] A mixture of compound 19b (5.3 g, 21 mmol), phosphorus(V) oxychloride (15 mL) and A//-dimethylformamide (3 drops) was heated at 120 °C for 14 hours. The reaction mixture was cooled down, poured into water (200 mL) and the product was filtered off. The solid was dried in vacuo for 2 hours, suspended in saturated ethanolic solution of ammonia (50 mL) and stirred at room température for 14 hours. The solid product was filtered off to a fiord the title compound 19c. Ή NMR (400 MHz, DMSO-c/ô) δ 8 65 (s, 2H), 8,47 (d, J = 2.2 Hz, 1H), 8.25 (d.J = 2.2 Hz, 1H) LCMS (m/z) 291.9 [M+H], Tr = 3.86 min (LCMS method 1).

Step 4: synthesis of (E)-3-(4-(4-aniino-2,6-dichloroquinazolm-8-yl)-3,5dimethylpheny!)acrylonitrite (compound !9d)

115

Κ₃ΡΟ,

PdCI₂(dtbpf) DMF:H₂O (10:1) 80°C

[0286] A mixture ofcompound 19c (146 mg, 0.5 mmol), compound le (170 mg, 0 6 mmol), potassium phosphate tribasic monohydrate (230 mg, 1 mmol) and [1,1bis(diphenylphosphino)ferrocene] dichloropalladium(ll), complex with dichloromethane (65 mg, 0.1 mmol) was dissolved in a mixture of/V^-dimethylformamide and water(10:l, 5.5 mL) under argon and this mixture was stirred at 80°C for 30 minutes. The product was isolated by silica gel chromatography (gradient from 80-100% ethyl acetate in /.w-hexanes) to afford the title compound 19d. LCMS (m/z) 369.0 [M+H], Tr = 4.30 (LCMS method 1 ).

Step 5: synthesis of (E)-4-((4-amÎno-6-ch1oro-8-(4-(2-cyanovÎnyl)-2^dimethylphenyl)quinazolm-2-yl)amino)benzonitrile (compound 19)

Pd(OAc)₂Xantphos DIPEA NM P 100°C

N Compound 19 [0287|

A mixture of compound 19d (85 mg, 0.23 mmol), 4-amînobenzonitrile (33 mg,

0.28 mmol, Sigma-Aldrich), palladium(II) acetate (10 mg, 0.046 mmol) and (9,9-dimethyl116

9//-xanthene-4,5-diyl)bis(diphenylphosphine) (27 mg, 0.046 mmol) was dissolved in Nmethyl-2-pyrrolidone (2 mL) under argon. AUV-Dîisopropylethylamine (174 pL, 1 mmol) was then added via syringe and the reaction mixture was stirTed at 100°C for 1 hour. The product was isoiated by silica gel flash chromatography (gradient from 40-60% ethyl acetate in /.vo-hexanes) and then repurified by reverse phase flash chromatography (5.5 g C-l 8 RediSep pre-packed column, gradient 5-100%, acetonitrile in water) to afford the title compound 19. Ή NMR (400 MHz, DMSO-t/e) δ 9.55 (s, 1 H), 8.34 (d, J = 2.3 Hz, 1 H), 7.74 (d, J = 16.7 Hz, 1 H), 7.66 (d, J = 8.9 Hz, 2H), 7.55 (d, J = 2.3 Hz, 1 H), 7.52 (s, 2H), 7.40 7.35 (m, 2H), 7.26 (d, J= 8.9 Hz, 2H), 6.55 (d, J= 16.7 Hz, 1H), 1.93 (s, 6H) LCMS (m/z) 451.2 [M+H], Tr = 4 25 min (LCMS method 1 ).

EXAMPLE 20 (E)-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-fluoroquinazolÎn-2yl)amino)nicotinonitrile- Compound 20

II

N

Step 1: Synthesis of 2-amino-3-bromo-5-fltiorobenzoic acid (Compound 20a)

OH ^Fy^A₀	OH
NBS		^O
^^x^nh₂	DMF, r.t.	M	^nh₂ '
		Br	Compound 20a

[0288] A mixture of 2-amino-5-fluorobenzoic acid (10 g, 65 mmol, Ark Pharm Inc, AK35193) and /V-bromosuccinimide (12 g, 67 mmol) in AUV-dimethylformamide (100 mL) was stirred at room température for 14 hours. The reaction mixture was poured into water (500

117 mL), the solid product was filtered ofT and washed with water to afiord the title compound

20a. LCMS (m/z) 233.7 [M+H], Tr= 3.75 min (LCMS method 1)

Step 2: synthesis of 8-bromo-6-fIiioroquinazoline-2,4(l/A3//)-dione (compound 20b)

	OH	O A	O
	A,	h₂n nh₂		^NH
V	^xnh₂	200 ^eC	V
Br			Br	Compound 20b

[0289] A mixture of compound 20a (12 g, 51 mmol) and urea (20 g, 333 mmol) was heated at 200 °C for 3 hours. The reaction mixture was cooled down and diluted with water (100 mL). The solid product was filtered ofTand washed with methanol (50 mL) to afiord the title compound 20b. LCMS (m/z) 259.0 [M+H], Tr = 3.23 min (LCMS method 1 ).

Step 3: synthesis of8-bromo-2-chloro-6-fltioroquinazolin-4-amine (compound 20c)

POCiyDMF

120 *C

Cl	nh₂
		nh₃
O	^XN^CI	éthanol	U
Br		rt	Br

Compound 20c [0290] A mixture of compound 20b (3 g, 20 mmol), phosphorus(V) oxychloride (20 mL) and/<A/-dimethylformamide (3 drops) was heated at 120°C for 14 hours. The reaction mixture was cooled down, poured into ice water mixture (200 mL) and the solid product was filtered ofT. The solid was dried in vacuo for 2 hours, suspended in saturated ethanolic solution ofammonia (100 mL) and stirred at room température for 14 hours. The reaction mixture was evaporated to dryness and the solid residue was suspended in water. The solid product was filtered ofTto afiord the title compound 20c. *H NMR (400 MHz, DMSO-c/ό) δ 8.59 (s, 1 H), 8.46 (s, 1 H), 8.19 (dd, J = 8 3, 2.7 Hz, 1 H), 8.13 (dd, J = 9.2,2.7 Hz, 1 H) LCMS (m/z) 275.7 [M+H], Tr = 3.74 min (LCMS method 1 )

Step 4: synthesis of(E)-3-(4-(4-amino-2*chloro-6-ni!oroqiiinazolin-8-yl)-3,5dimethylpheny!)acrylonitrile (compound 20d)

118

Κ₃ΡΟ₄

PdCI₂(dtbpf) DMF:H₂O (10:1) 80°C

[0291] A mixture ofcompound 20c (276 mg, 1 mmol), compound le (340 mg, 1.2 mmol), potassium phosphate tribasic monohydrate (460 mg, 2mmol) and [1,1bis(dipheny)phosphîno)ferrocene] dichloropalladium(II), complex with dichloromethane (65 mg, 0.1 mmol) was dissolved in a mixture of Λ/^V-dimethylformamide and water (10.1, 11 mL) under argon and this mixture was stirred at 80°C for 30 minutes. The product was isolated by silica gel chromatography (gradient from 80-100% ethyl acetate in i.w-hexanes) to afford the title compound 20d. LCMS (m/z) 352.9 [M+H], Tr = 4.12 min (LCMS method DStep 5: synthesis of (£)-6-((4-ammo-8-(4-(2-cyanovinyl)-2,6-dimethyIplienyl)-6fliioroquinazoIin-2-yl)amino)nicotinonitrile (compound 20)

II

N

Pd(OAc)₂Xantphos DI PEA NMP 100°C

N Compound 20

119 |0292] A mixture of compound 20d (176 mg, 0.5 mmol), 6-aminonicotinonitrile (178 mg, 1.5 mmol, Ark Pharm Inc, AK-32349), palladium(II) acetate (22 mg, 0.1 mmol) and (9,9-dimethyl-9/7-xanthene-4,5-diyl)bis(diphenylphosphine) (58 mg, 0.1 mmol) was dissolved in Mmethyl-2-pyrrolidone (5 mL) under argon. NW-Diisopropylethylamine (348 pL, 2 mmol) was then added via syringe and the reaction mixture was stirred at 100°C for 1 hour. The product was isolated by silica gel chromatography (gradient from 40-100% ethyl acetate in /.w-hexanes) and then repurified by reverse phase flash chromatography (5.5 g ΟΙ 8 RediSep prepacked column, gradient 5-100%, acetonitrile in water with 0 1% TFA) to afïbrd the title compound 20 as the TFA sait. *H NMR (400 MHz, DMSO-ί/β) δ 9.56 (bs, 1 H), 9.46 (bs, 1 H), 8.40-8.20 (m, 2H), 8.02 - 7.84 (m, 1 H), 7.82 (d, J= 16.6 Hz, 1H), 7.69 (s, 2H), 7.51 (bs, IH), 7.42 (bs, IH), 6.69 (d, J= 16.6 Hz, 1 H), 1.98 (s, 6H) LCMS (m/z)

435.8 [M+H], Tr = 3.45 min (LCMS method I).

EXAMPLE 21 (E)-6-((4-Amino-8-(4-(2-cyanovinyl)-2^-dimethylphenyI)-6-methyIqiiinazolÎn-2· yl)amino)nicotinonitrile- Compound 21

Step 1: Synthesis of 2-amino-3-bromo-5-methylbenzoic acid (Compound 21a)

NBS

DMF, r.t.

Compound 21a |0293|

A mixture of 2-amino-5-methylbenzoic acid (10 g, 66 mmol, Ark Pharm, Inc

AK-34555) and ΛΖ-bromosuccinimide (12 g, 67 mmol) in jV//-dimethylformamide (100 mL)

120 was stirred at room température for 14 hours. The reaction mixture was poured into water (500 mL) and the solid product was filtered off and washed with water to afford the title compound 21a. LCMS (m/z) 229.80 [M+H], Tr = 3.87 min (LCMS method l)

Step 2: synthesis or8-bromo-6-methylquinazoline-2,4(l/Z3ff)*dione (compound 21b)

[0294] A mixture of compound 21a (5 g, 22 mmol) and urea (30 g, 500 mmol) was heated at 200 °C for 3 hours. The reaction mixture was cooled down, and diluted with water (100 mL) The solid product was filtered off and washed with methanol (50 mL) and water (50 mL) to afford the title compound 21b LCMS (m/z) 254.7 [M+H], Tr = 3.19 min (LCMS method 1 )

Step 3: synthesis of 8-bromo-2-chloro-6-methylquinazolin-4-amine (compound 21c)

Br

Compound 21c [0295] A mixture of compound 21b (5 g, 20 mmol), phosphorus(V) oxychloride (15 mL) and A^/V-dimethylformamide (3 drops) was heated at 120 °C for 14 hours. The reaction mixture was cooled down, poured into ice water mixture (200 mL) and the solid product was filtered off. The solid was dried in vacuo for 2 hours, suspended in saturated ethanolic solution ofammonia (100 mL) and stirred at room température for 14 hours. The solid product was filtered off to afford the title compound 21c. ^lH NMR (400 MHz, DMSO-î/ô) δ 8.41 (s, 2H), 8.06 (d, J « 1.7 Hz, 1H),8O1 (d,J=1.7Hz, 1H), 2.42 (s, 3H) LCMS (m/z)

271.8 [M+H], Tr = 3.65 min (LCMS method 1 ).

Step 4: synthesis of (E)-3-(4-(4-amino-2-chIoi*o-6-methyIquinazolin-8-yl)-3,5dimethylphenyl)acrylonitrile (compound 21 d)

121

DMF;H₂O(10;1) 80°C

[0296] A mixture of compound 2 ) c (273 mg, 1 mmol), compound 1 c (340 mg, 1.2 mmol), potassium phosphate tribasic monohydrate (460 mg, 2 mmol)and [1,1bis(diphenylphosphino)ferrocene] dichloropalladium(ll), complex with dichloromethane (65 mg, 0.1 mmol) was dissolved in a mixture of NjV-dimethylformamide and water (10.1, 5.5 mL) under argon and this reaction mixture was stirred at 80°C for 30 minutes. The product was isolated by silica gel chromatography (gradient from 40-100% ethyl acetate in iso· hexanes) to afford the tîtle compound 21d. LCMS (m/z) 348.9 [M+H], Tr = 4.17 min (LCMS method 1 )

Step 5: synthesis of (£)-6-((4-amino-8-(4-(2-cyanovînyl)-2,6-dime(hylphenyl)-6methylquinazolin-2-yl)amino)nïcotinonitrile (compound 21)

NH₂

Pd(OAc)₂Xantphos DIPEA NMP 110°C

122 [0297] A mixture of compound 21 d (175 mg, 0.5 mmol), 6-aminonicotinonitrile (298 mg, 2.5 mmol, Ark Pharm Inc, AK-32349), palladium(II) acetate (23 mg, 0.1 mmol) and (9,9-dimethyl-9//-xanthene-4,5-diyl)bis(diphenylphosphine) (58 mg, 0.1 mmol) was dissolved in /V-methyl-2-pyrrolidone (5 mL) under argon. TVJV-Diisopropylethylamine (435 pL, 2.5 mmol) was then added via syringe and the reaction mixture was stirred at 110°C for 6 hours The product was isolated by silica gel chromatography (gradient from 40-100% ethyl acetate in z.w-hexanes) and then repurified by reverse phase flash chromatography (5 5 g C-18 RediSep prepacked column, gradient 5-100%, acetonitrile in water with 0.1% TFA) to afiord the title compound 21 as the TFA sait ’H NMR (400 MHz, DMSO-îZs) δ 9.51 (s, 1 H), 9.31 (s, 1 H), 8.33 - 8.24 (m, 2H), 7.82 (d, J = 16.7 Hz, 1 H), 7.77 - 7.66 (m, 3H), 7.58 - 7.50 (m, 1H), 7.45 - 7.36 (m, 1 H), 6.69 (d, J= 16.7 Hz, 1 H), 2.54 (s, 3H), 1.96 (s, 6H) LCMS (m/z) 432.0 [M+H], Tr= 3.56 min (LCMS method 1)

EXAMPLE 22 (E)-6-((4-Ammo-8-(4-(2-cyanovmyl)-2,6-dÎmethylphenyl)-6-nitroqiiinazolin-2’ yl)amino)nicotinonitrile- Compound 22

Step 1: Synthesis or2-amino-3-bromo-5-nitrobenzoic acid (Compound 22a)

O* OH	0'	OH
	NBS	_ O-'⁴*-		A
U-_NH2	DMF, r.t.		V	^xnh₂
			Br	Compound 22a

[0298] A mixture of 2-amino-5-nitrobenzoic acid (5 g, 27 mmol, Sigma-Aldrich) and Nbromosuccinimide (6 g, 34 mmol) in /VJV-dimethylformamide (100 mL) was stirred at room

123 température for 14 hours. The reaction mixture was poured into water (500 mL) and the solid product was filtered offand washed with water to afford the title compound 22a. LCMS (m/z) 261.03 [M+H], Tr = 3.70 min (LCMS method 1)

Step 2: synthesis of 8-bromo-6-nitroquinazoline-2,4(17Z,3/0^_d'^one (compound 22b)

[0299] A mixture of compound 22a (5 g, 22 mmol) and urea (20 g, 333 mmol) was heated at 200 °C for 3 hours. The reaction mixture was cooled down, and diluted with water (100 mL). The solid product was filtered offand washed with methanol (50 mL) and water (50 mL) to afford the title compound 22b. LCMS (m/z) 286.2 [M+H], Tr = 3.21 min (LCMS method 1)

Step 3: synthesis of 8-bromo-2-ch!oro-6-nitroquinazolin-4-amine (compound 22c)

Compound 22c [0300] A mixture of compound 22b (5 g, 17 mmol), phosphorus(V) oxychloride ( 15 mL) and A/JV-dimethylformamide (4 drops) was heated at 120 °C for 14 hours. The reaction mixture was cooled down, poured into ice water mixture (200 mL) and the solid product was filtered off. The solid was dried in vacuo for 2 hours, suspended in saturated ethanolic solution ofammonia (100 mL) and stirred at room température for 14 hours. The reaction mixture was concentrated down under reduced pressure and water was added. The solid product was filtered offto afford the title compound 22c. Ή NMR (400 MHz, DMSO-</<>) δ 9.34 (d, J = 2 4 Hz, 1 H). 8.79 (d, J = 2.4 Hz, 1 H) LCMS (m/z) 303.0 [M+H], Tr = 3.97 min (LCMS method 1)

Step 4: synthesis of (E)-3-(4-(4-amino-2-chloro-6-nitroqiiinazolm-8-yl)-3,5dimethylphenyl)acrylonitri!e (compound 22d)

124

Κ₃ΡΟ₄

PdCI₂(dtbpf) DMF:H₂O (10:1) 80°C

[0301 ] A mixture ofcompound 22c (152 mg, 0.5 mmol), compound le (170 mg, 0.6 mmol), potassium phosphate tribasic monohydrate (230 mg, 1 mmol) and [1,1bis(diphenylphosphino)ferrocene] dichloropalladium(ll), complex with dichloromethane (33 mg, 0.05 mmol) was dissolved in a mixture ofA/,N-dimethylformamide and water (10:1,5.5 mL) under argon and this reaction mixture was stirred at 80°C for 7 hours. The product was isolated by silica gel chromatography (gradient from 40-100% ethyl acetate in /.w-hexanes) to afford the title compound 22d. LCMS (m/z) 379.9 [M+H], Tr = 4.40 min (LCMS method 1)

Step 5: synthesis of (£)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6nitroqumazolin-2-yl)amino)nicotinomtrile (compound 22)

Pd(OAc)₂Xantphos DIPEA NMP 100°C

125 [0302] A mixture of compound 22d (110 mg, 0.29 mmol), 6-aminonicotinonitrile (171 mg, 1.45 mmol, Ark Pharm Inc, AK-32349), palladiumfll) acetate (13 mg, 0.06 mmol) and (9,9-dimethyl-9Jf-xanthene-4,5-diyl)bis(diphenylphosphine) (34 mg, 0.06 mmol) was dissolved in /V-methyl^-pyrrolidone (5 mL) under argon. A^MDiisopropylethylamine (514 pL, 2.95 mmol) was then added via syringe and the reaction mixture was stirred at 100°C for 1 hour. The product was isolated by silica gel chromatography (gradient from 40-100% ethyl acetate in Ao-hexanes) and then repurified by reverse phase flash chromatography (5.5 g C-18 RediSep prepacked column, gradient 5-100%, acetonitrile in water with 0.1% TFA) to afford the title compound 22 as the TFA sait. ’H NMR (400 MHz, DMSO-îA) δ 9.43 (bs, 2H), 7,80 (d, J = 16.7 Hz, 1 H), 7.77 - 7.50 (m, 7H), 7.48 (bs, 1 H), 6.53 (d, J = 16.7 Hz, 1 H), 1.97 (s, 6H). LCMS (m/z) 463.0 [M+H], Tr= 3.98 min (LCMS method 1).

EXAMPLE 23 (E)-6-((4,6-Diamino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2yl)amino)nicotinonitrile- Compound 23

Synthesis of (E}-6-((4,6-diammo-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2 yl)amino)nicotinonitrile (compound 23)

126

[0303] Compound 22 (20 mg, 0 043 mmol) was dissolved in the methanol-acetic acid mixture (10:1,2 mL), iron dust (20 mg, 0.358 mmol) was added in one portion and the reaction mixture was stirred at room température for 24 hours. The product was isolated by silica gel chromatography (gradient from 10-30% methanol in ethyl acetate) and then repurified by reverse phase flash chromatography (5 5 g C-18 RediSep prepacked column, gradient 5-100%, acetonitrile in water with 0.1% TFA) to afFord the title compound 23 as the TFA sait. Ή NMR (400 MHz, DMSCWè) δ 9.22 (s, 1 H), 9.04 (s, 1 H), 8.26 - 8,21 (m, I H), 7.82 (d,J= 16.6 Hz, 1 H), 7.83 - 7.74 (m, 1 H), 7.68 (s, 2H), 7.51 (s, 1H), 7.38-7.32 (m, 1 H), 7.11 (s, 1H), 6.69 (d, J= 16.6 Hz, IH), 1.98 (s. 6H). LCMS (m/z) 433.1 [M+H], Tr - 3.68 min (LCMS method 1 )

EXAMPLE 24 (E)-6-((4-Amîno-8-(4-(2-cyanovinyl}-2,6-dimethy]phenyl)-6-methoxyquÎnazolîn-2y])amino)nicotinonitrile- Compound 24

NH,

Step 1: Synthesis of 2-amino-3-bromo-5-methoxybenzoic acid (Compound 24a)

127

OH	OH
	NBS
^^νη₂	DMF, r.t.	V	^x-nh₂
		Br	Compound 24a

|0304] A mixture of 2-amino-5-methoxybenzoic acid (3.95 g, 23.6 mmol, SigmaAldrich) and W-bromosuccinimide (4.2 g, 23.6 mmol) in Λ/JV-dimethylfonnamide (80 mL) was stirred at room température for 14 hours. The reaction mixture was poured into water (400 mL) and the solid product was filtered off and washed with water to afford the title compound 24a. LCMS (m/z) 245.8 [M+H], Tr = 4.06 min (LCMS method 1 )

Step 2: synthesis or8’bromo-6-methoxyquinazoline-2,4(l/73//)^'^one (compound 24b)

	OH	O A	O
°Y^îAï	Â_o	h₂n nh₂	^x Άΐι	^NH
V	^nh₂	200 “C	V
Br			Br	Compound 24b

103051 A mixture of compound 24a (2.19 g, 8.9 mmol) and urea (12 g, 200 mmol) was heated at 200 °C for 3 hours. The reaction mixture was cooled down, and diluted with water (100 mL) The solid product was filtered off and washed with water (50 mL) to afford the title compound 24b.

Step 3: synthesis of 8-bromo-2-ch1oro-6-methoxyquinazo1in-4-amine (compound 24c)

O	Cl	nh₂
°YYi	POCiyDMF	vAr ^N	NH₃		Άν
	120’C		éthanol rt	1D	N^CI
		Br		Br

Compound 24c [0306] A mixture of compound 24b (2.45 g, 9 mmol), phosphorus(V) oxychloride ( 10 mL) and WJV-dimethylformamide (5 drops) was heated at 120 °C for 14 hours. The reaction mixture was cooled down, poured into ice water mixture (200 mL) and the solid product was filtered off. The solid was dried in vacuo for 2 hours, suspended in saturated ethanolic solution of ammonia (100 mL) and stirred at room température for 14 hours. The reaction mixture was concentrated down under reduced pressure and water (20 mL) was added. The

128 solid product was filtered off to aflord the title compound 24c. LCMS (m/z) 287.7 [M+H], Tr = 4.33 min (LCMS method 1).

Step 4: synthesis of (E)“3-(4-(4-amino-2-chloro-6-methoxyqitinazoltn-8-yl)-3,5dimethylphenyl)acrylonitrile (compound 24d)

Br

NH

N Cl

N

K₃PO₄

PdCI₂(dtbpf) DMF:H₂O (10:1) 80°C

Compound 24d [0307[ A mixture ofcompound 24c (30 mg, 0.1 mmol), compound le (34 mg, 0.12 mmol), potassium phosphate tribasic monohydrate (46 mg, 0.2 mmol) and [1,1'bis(diphenylphosphino)ferrocene] dichloropalladium(II), complex with dichloromethane (13 mg, 0.02 mmol) was dissolved in a mixture of JVJV-dimethylformamide and water (10.1,2 mL) under argon and this reaction mixture was stined at 80°C for 30 minutes The product was isolated by silica gel chromatography (gradient from 50-100% ethyl acetate in isohexanes) to afïord the title compound 24d. LCMS (m/z) 364.9 [M+H], Tr = 4.65 min (LCMS method 1).

Step 5: synthesis of(E)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimetliylpIienyl)-6methoxyqiiinazolin-2-yl)amino)mcotinonîtrile (compound 24)

129

Compound 24 [0308] A mixture of compound 24d (15 mg, 0.041 mmol), 6-aminonicotinonitrile (24 mg, 0.21 mmol, Ark Pharm Inc, AK-32349), palladium(II) acetate (4 mg, 0 016 mmol) and (9,9-dimethyl-9/7-xanthene-4,5-diyl)bis(diphenylphosphine) (10 mg, 0.016 mmol) was dissolved in TV-methyl-2-pyrrolidone (1 mL) under argon. ΛζΝ-Diisopropylethylamine (37 pL, 0,21 mmol) was then added via syringe and the reaction mixture was stirred at 100°C for 2 hours. The product was isolated by silica gel chromatography (gradient from 60-100% ethyl acetate in /so-hexanes) and then repurified by reverse phase flash chromatography (5,5 g C-18 RediSep prepacked column, gradient 5-100%, acetonitrile in water with 0.1% TFA) to afford the title compound 24 as the TFA sait, *H NMR (400 MHz, DMSO-îA) δ 13.52 (bs, l H), 11.99 (bs, 1 H), 9.46 (bs, 1 H), 9.26 (bs, 1 H), 8.28 (s. 1 H), 7.97 (s, 1 H), 7.83 (d, J = 16.7 Hz, 1 H), 7.70 (s, 2H), 7.62 - 7.48 (m, 2H), 7.42 - 7.36 (m, 1 H), 6,69 (d, J = 16.7 Hz, 1 H), 3.95 (s, 3H), 1.98 (s, 6H). LCMS (m/z) 448.0 [M+H], Tr = 3.95 min (LCMS method 1 )

EXAMPLE 25 (E)-4-((4-Amino-6-bromo-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quïnazolin-2jl)iimino)benzonitrile- Compound 25

130

NH,

Step 1: Synthesis of 2-amino-5-bromo-3-iodobenzoic acid (Compound 25a)

NI S

DMF, r.t.

[0309] A mixture of 2-amino-5-bromobenzoic acid (1 g, 4 6 mmol, Sigma-Aldrich) and AModosuccinimide (1.9 g, 8.4 mmol) in ?///-dimethylformamide (30 mL) was stirred at room température for 48 hours. The reaction mixture was poured into water (100 mL). The solid product was filtered offand washed with water to afford the title compound 25a. LCMS (m/z) 341.9 [M+H], Tr = 4.53 min (LCMS method I).

Step 2: synthesis of 6-bromo-8-iodoquinazoline-2<1(l//_T3//)-d'one (compound 25b)

[0310] Amixtureofcompound25a(l.2g, 3.5 mmol)andurea(10g. 166 mmol) was heated at 200 °C for 3 hours The reaction mixture was cooled down, and diluted with water (100 mL). The solid product was filtered offand washed with methanol (50 mL) and water (50 mL) to afford the title compound 25b.

Step 3: synthesis of6-bromo-2-chloro-8-iodoquinazolin-4-amine (compound 25c)

131

Br

Cl

Compound 25c [0311| A mixture of compound 25b (5.33 g, 14.5mmol), phosphorus(V) oxychloride (30 mL) and JVJV-dimethylformamide (3 drops) was heated at 120 °C for 14 hours. The reaction mixture was cooled down, poured into ice water mixture (200 mL) and the solid product was filtered off. The solid was dried in vacuo for 2 hours, suspended in saturated ethanolic solution of ammonia (100 mL) and stirred at room température for 14 hours. The réaction mixture was concentrated down under reduced pressure and subjected to silica gel column chromatography (gradient from 10-50% ethyl acetate in wo-hexanes) to afford the title compound 25c. ’H NMR (400 MHz, DMSO-<Zs) δ 7.97 (d, J = 2.4 Hz, 1 H), 7.86 (d, J = 2.4 Hz, 1H), 6.78 (bs, 2H) LCMS (m/z) 383.9 [M+H], Tr = 5.98 min (LCMS method 1) Step 4: synthesis of (E)-3-(4-(4-amîno-6-bromo-2-chloroqiiinazolin-8-yl)-3,5dimethylphenyl)acrylonitrile (compound 25d)

Br

N Cl

K₃PO₄PdCI₂(dtbpf) DMF:H₂O (10:1) r.t.

Br-

N Cl

Compound 25d

A mixture of compound 25c (120 mg, 0.31 mmol), compound lc(106mg, 0.37 mmol), potassium phosphate tribasîc monohydrate (143 mg, 0.62 mmol) and [1,1bis(dipheny1phosphino)ferrocene] dichloropalladium(n), complex with dichloromethane (40 mg, 0.062 mmol) was dissolved in a mixture ofW,A/-dirnethy1forrnamide and water (10.1,3

132 mL) under argon and this reaction mixture was stirred at room température for 24 hours The reaction was quenched by addition of saturated ammonium chloride and the product was isolated by silica gel chromatography (gradient from 30-60% ethyl acetate in /w-hexanes) to afford the title compound 25d LCMS (m/z) 412,8 [M+H], Tr = 4.62 min (LCMS method 1 ).

Step 5: synthesis of (E)-4-((4-amino-6-bromo-8-(4-(2-cyanovinyl)-2,6dimethylphenyI)qi!mazoIin-2-yl)amino)benzonitriIe (compound 25)

N Compound 25 [0313] A mixture of compound 25d (55 mg, 0,13 mmol) and 4-aminobenzonitrile (20 mg, 0.17 mmol, Sigma-Aldrich) in isopropanol (2 mL) was heated under microwave conditions at 170 °C for 30 minutes. The reaction mixture was concentrated down under reduced pressure and purified by silica gel column chromatography (gradient from 0-100% ethyl acetate in /sohexanes) to afford the title compound 25. ‘H NMR (400 MHz, DMSOA) δ 9.57 (s, 1H), 8.47 (d, J= 2.2 Hz, IH), 7.75 (d, J= 16.7 Hz, 1H), 7.68 - 7,63 (m, 3H), 7.52 (s, 2H), 7.32 - 7.21 (m, 2H), 6.56 (d, J= 16.7 Hz, 1H), 1.92 (s, 6H). LCMS (m/z) 495.1 [M+H], Tr = 4.58 min (LCMS method 1)

EXAMPLE 26 (E)-5-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-fluoroquinazo!in-2yl)amino)pyrazinc-2-carbonitri!e- Compound 26

133

Synthesis of (E)-5-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6fliioroquinazolÎn-2-yl)amino)pyrazme-2-carbonitrile (compound 26)

Pd(OAc)₂Xantphos DIPEA NMP 100°C

[0314] Compound 20d (92 mg, 0.21 mmol), 5-aminopyrazine-2-carbonitrile (60 mg,

0,50 mmol, Ark Pharm Inc, AK-21935), ΑΛ-diisopropylethylamine (174 pL. 1.0 mmol), (9,9-dimethyl-9/7-xanthene-4,5-diyl)bis(diphenylphosphine) (24 mg, 0.042 mmol) and palladium (II) acetate (9 mg,’ 0.042 mmol) were combined under argon in /V-methyl-2pyrrolidone (2 mL). The reaction was heated at 100°C in a sealed vessel for 7 hours. The reaction mixture was cooled down to room température, purified by silica gel chromatography (gradient from 50-100% ethyl acetate in /.w-hexanes) and then re-purified by reverse phase chromatography (5-100% acetonitrile in water with 0.1 % triiluoroacetic acid) to afford the TFA sait of compound 26. Ή NMR (400 MHz, DMSCMe) 6 9.10 (s, 1 H), 8.20 (s, 1 H), 7.74 (d, J = 16.7 Hz, 1 H), 7.77 - 7.60 (m, 211), 7.57 (s, 2H), 6.56 (d, J = 16.7 Hz, III), 1.94 (s, 611). LCMS (m/z) 436.9 [M+H], Tr = 3.59 min (LCMS method 1)

EXAMPLE 27

134 (E)-6-((4-Amino-8-(4-(2-€yanovinyl)-2,6-dimethylphenyl)-6-niioroqiiinazolin-2yl)amino)pyridazine-3-carbonitrile- Compound 27

Synthesis of (E)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-dÎmethylphenyl)-6· fluoroquinazolin-2-yl)amino)pyridazine-3-€arbonitrile (compound 27)

Pd(OAc)₂Xantphos DIPEA NMP 100°C

NH,

N Compound 27 (0315] Compound 20d (92 mg, 0.21 mmol), 6-aminopyridazine-3-carbonitrile (60 mg, 0.50 mmol. Matrix Scientiftc, 1 12287), TVW-diisopropylethylamine ( 174 pL, 1.0 mmol), (9,9-dimethyl-9/f-xanthene-4,5-diyl)bis(diphenylphosphine) (24 mg, 0.042 mmol) and palladium (II) acetate (9 mg, 0.042 mmol) were combined under argon in V-methyl-2pyrrolidone (2 mL) The reaction was heated at 100°C in a sealed vessel for 7 hours. The réaction mixture was cooled down to room température, purified by silica gel chromatography (gradient from 50-100% ethyl acetate in iro-hexanes) and then re-purified by reverse phase chromatography (5-100% acetonitrile in water with 0.1% trifluoroacetic acid) to afford the TFA sait of compound 27. ’H NMR (400 MHz, DMSO-ί/ό) δ 8.18 (bs.

135

H), 8.06 (bs, 1H), 7.73 (d, J= 16.7 Hz, 1H), 7.71 -7.58 (m, 2H), 7.54 (s, 2H), 6.55 (d, J =

16.7 Hz, 1 H), 1.93 (s, 6H) LCMS (m/z) 436 9 [M+H], Tr = 3.73 min (LCMS method 1 )

EXAMPLE 28 (£7)-4-( (4-Amino-8-(4-(2-cyanovinyl)-2,6-dÎmcthylphenyl)-5-mcthoxyquinazolin-2 yl)ammo)benzonitrtle- Compound 28

Step 1: synthesis of 8-bromo-5-mcthoxyquinazolinc-2,4(l/73/£)-dione (compound 28a)

O OH ¥*»	O 11 h₂n nh₂	'''O A	O Ah A Π Compound 28a
	200’C	V
Br		Br

[0316] A mixture of 2-amino-3-bromo-6-methoxybenzoic acid (2 g, 8.1 mmol, Ark Pharm Inc, AK137474) and urea (12 g, 200 mmol) was heated at 200 °C for 2 hours. The reaction mixture was cooled down, and diluted with water (100 mL). The solid product was filtered offand washed with water (50 mL) to afford the title compound 28a.

Step 2: synthesis 8-bromo-2-chloro-5-methoxyquinazolin-4-amine (compound 28b)

Cl

Br

NH₃ éthanol rt

Compound 28b

136 [0317] A mixture of compound 28a (4.67 g, 17 mmol), phosphorus(V) oxychloride (20 mL) and TV^-dimethylformamide (3 drops) was heated at 120 °C for 14 hours. The reaction mixture was cooled down, poured into ice water mixture (200 mL) and the solid product was filtered off. The solid was dried in vacuo for 2 hours, suspended in saturated ethanolic solution ofammonia (100 mL) and stirred at room température for 14 hours. The reaction mixture was concentrated down under reduced pressure and the solid residue was subjected to extraction with acetone. The acetone solution was concentrated down under reduced pressure to afford the title compound 28b ^lH NMR (400 MHz, DMSO-î/î) δ 8 66 (s, 1H), 8.26 (s, 1 H), 8.02 (d, J = 8.7 Hz, 1 H), 6.95 (d, J = 8.7 Hz, 1 H), 3.98 (s, 3H) LCMS (m/z) 288.1 [M+H], Tr = 3.74 min (LCMS method 1).

Step 3: synthesis of (E)-3-(4-(4-amino-2-chloro-5-methoxyqiiÎnazo!in-8-yl)-3,5dimethylphenyl)acrylonitrile (compound 28c)

Compound 28c [0318] A mixture ofcompound 28b (100 mg, 0.35 mmol), compound le (118 mg, 0.42 mmol), potassium phosphate tribasic monohydrate (159 mg, 0 69 mmol) and [1,1bis(diphenylphosphino)ferTocene] dichloropalladium(Il), complex with dichloromethane (23 mg, 0.035 mmol) was dissolved in a mixture of/VJV-dimethylformamide and water (10:1, 5 mL) under argon and this reaction mixture was stirred at 80°C for 30 minutes. The product was isolated by silica gel chromatography (gradient from 60-100% ethyl acetate in iso

137 hexanes) to afford the title compound 28c. LCMS (m/z) 364.9 [M+H], Tr = 4.38 min (LCMS method 1)

Step 4: synthesis of (E)-4-((4-ammo-8-(4-(2-cyanovinyI)-2,6-dimethylphenyl)-5metl»oxyqiiinazolin-2-yl)amino)benzonitrile (compound 28)

Pd(OAc)₂Xantphos DI PEA NM P 110°C

N Compound 28 [0319] A mixture of compound 28c (37 mg, 0.1 mmol), 4-aminobenzonitrile (60 mg, 0.5 mmol, Sigma-Aldrich), palladium(II) acetate (4 mg, 0.02 mmol) and (9,9-dimethy1-9/fxanthene*4,5-diyl)bis(dipheny!phosphine) (12 mg, 0.02 mmol) was dissolved in A/-methyl-2pyrrolidone (2 mL) under argon. A/ZZ-Diisopropylethylamine (87 pL, 0.5 mmol) was then added via syringe and the reaction mixture was stirred at 110°C for 6 hours. The product was isolated by silica gel chromatography (gradient from 50-100% ethyl acetate in isohexanes) and then repurified by reverse phase flash chromatography (5.5 g C-l 8 RediSep prepacked column, gradient 5-100%, acetonitrile in water with 0.1% TFA) to afford the title compound 28 as the TFA sait. *H NMR (400 MHz, DMSO-ί/ό) δ 7.90 - 7.65 (m, 3H), 7.71 (d, J= 16.7 Hz, 1 H), 7.58 -7.45 (m, 4H), 7.07 (s, 1H), 6.55 (d, J= 16.7 Hz, 1H), 4.07 (s, 3H), 1.95 (s. 6H) LCMS (m/z) 447.0 [M+H], Tr = 3.85 min (LCMS method 1 ).

EXAMPLE 29 (E)-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethyIphenyI)-5-metIioxyqiiinazolin-2yl)amino)nicotinonitrile- Compound 29

138

Synthesis of (E)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-5metlioxyqiiinazolin-2-yl)amino)nicotinonîtnle (compound 29)

Pd(OAc)₂Xantphos DIPEA NMP 110°C

N Compound 29 (0320] Compound 28c (37 mg, 0.1 mmol), 6-aminonicotinonitrile (60 mg, 0.5 mmol, Ark Pharm Inc, AK-32349), MA-diisopropylethylamine (87 pL, 0.5 mmol), (9,9-dimethyl9f/-xanthene-4,5-diy1)bis(diphenylphosphine) (12 mg, 0.02 mmol) and palladium (II) acetate (4 mg, 0.02 mmol) were combined under argon in A/-methyl-2-pyrro1idone (2 mL) The reaction was heated at 110°C in a sealed vessel for 6 hours. The reaction mixture was cooled down to room température, purified by silica gel chromatography (gradient from 50100% ethyl acetate in wo-hexanes) and then re-purified by reverse phase chromatography (5-100% acetonitrile in water with 0.1% trifluoroacetic acid) to aftord the TFA sait of compound 29. *H NMR (400 MHz, DMSO-îA) δ 13.31 (bs. 1H), 11.92 (bs, 1H), 9.49 (s, 1H), 9.09 (s, 1H), 8.27 (d, J =8.4 Hz, 1H), 7.82 (d, J= 16.7 Hz, 1H), 7.77 (d, J= 9.2 Hz, 1H), 7.68 (s, 2H), 7.55 - 7.40 (m, 2H), 7.30 (d, J= 8.4 Hz, 1H), 6.69 (d, J= 16.7 Hz, 1H), 4.13 (s, 3H), 1.97 (s, 6H). LCMS (m/z) 448.0 |M+H], Tr = 3.60 min (LCMS method 1)

139

EXAMPLE 30 (E)-4-((8-(4-(2-Cyanovinyl)-2,6-dimethylphenyl)-4-(niethylamino)quinazolÎn-2 yl)amino)benzonitrile - Compound 30

N H

Step 1: Synthesis of 8-bromo-2-chloro-7V-methylquinazolin-4-amine (compound 30a)

[03211 8-Bromo-2,4-dichloroquinazoline (556 mg, 2 mmol, Ark Pharm Inc., AK-28703) was dissolved in 6 mL of 20% solution of methylamine in éthanol and the reaction was stirred at room température for 15 minutes. Volatiles were removed under reduced pressure and the solid residue was suspended in water. The solid product was filtered off and washed with water (3x5 mL) and pentane (3x5 mL) to give the title compound 30a. ’H NMR (400 MHz, DMSO-Je) δ 8 96 (d, J = 4.7 Hz. 1 H), 8.19 (dd, J = 8.3 Hz, J = 1.2 Hz, 1 H), 8.11 (dd, J = 7.7Hz,J= 1.2 Hz, 1H), 7.42(t, J = 7.9 Hz, 111),3.00 (d, J= 4 3 Hz, 3H). HRMS: (ESI+) calculated for CçHgNjBrCl [M+H] 271.9585, found 271.9585. LCMS (m/z) 272.0 [M+H], Tr 3.80 min (LCMS method 1 ).

Step 2: Synthesis of (£>3-(4-(2-chloro-4-(niethylamino)quinazolin-8-yl)-3,5dimethylphenyl)acrylonitrile (compound 30b)

140

Κ₃ΡΟ₄

PdCI₂(dtbpf) DMF:H₂O (85:15) 80°C

N Compound 30b [0322] A mixture of compound 30a (l I0 mg, 0 4 mmol), compound le (147 mg, 0.52 mmol), potassium phosphate tribasic monohydrate (138 mg, 0.6 mmol) and [Ι.Γbis(diphenylphosphino)ferrocene] dichloropalladium(ll), complex with dichloromethane (26 mg, 0.04 mmol) was dissolved in a mixture of/VJV-dimethylformamide and water (85:15,5 mL) under argon and this reaction mixture was stirred at 80°C for 20 minutes. The reaction mixture was concentrated down under reduced pressure and the product was isolated by silica gel chromatography (gradient from 50-80% ethyl acetate in /.w-hexanes) to afford the title compound 30b ‘H NMR (400 MHz, DMSO-Jô) δ 8.88 (d, J = 4.4 Hz, 1 H), 8.25 (dd, J = 8.2 Hz,J= 1.5 Hz, IH), 7.67-7.58 (m, 2H), 7.53 (dd, J= 7.2 Hz, J= 1.5 Hz, 1H), 7.43 (s,2H),6.46 (d, J = 16.7 Hz, 1 H), 3.01 (d, J = 4.4 Hz, 3H), 1.85 (s, 6H) HRMS: (ESI+) calculated for CjoHigN^Cl [M+H] 349.1215, found 349.1216. LCMS (m/z) 349.1 [M+H], Tr 4.51 min (LCMS method 1 ).

Step 3: synthesis of(E)-4-((8-(4-(2-cyanovinyl}-2Î6-diniethylphenyl)-4(methylamino)quinazolin-2-yl)amino)benzonitrile (compound 30)

141 ^XNH

Pd(OAc)₂Xantphos DIPEA NMP 110°C

[0323] A mixture of compound 30b (52 mg, 0.15 mmol), 4-aminobenzonitrile (90 mg,

0.75 mmol, Sigma-Aldrich), palladium(II) acetate (20 mg, 0.064 mmol) and (9,9-d i methyl9W-xanthene-4,5-diyl)bis(diphenylphosphine) (40 mg, 0.064 mmol) was dissolved in Nmethyl-2-pynolidone (3 mL) under argon. N/V-Diisopropylethylamine (150 pL, 0.85 mmol) was then added via syringe and the reaction mixture was stined at 110°C for 3 hours. The reaction mixture was concentrated down under reduced pressure and the product was isolated by silica gel chromatography (gradient from 80-100% ethyl acetate in /.vo-hexanes) and then repurified by reverse phase flash chromatography (5.5 g C-18 RediSep prepacked column, gradient 0-100%, acetonitrile in water) to aflord the title compound 30. *H NMR (400 MHz, DMSO-Jî) δ 9.54 (s, 1 H), 8.31 (d, J = 4.3 Hz, 1 H), 8.11 (d, J = 8 4 Hz, 1 H), 7.77 - 7.70 (m, 3H), 7.51 (s, 2H), 7.46 (d, J= 7.5 Hz, 1H), 7.35 (t, J= 7.7 Hz, 1H), 7.27 (d, J =

8.8 Hz, 2H), 6 54 (d, 16.7 Hz, 1H), 3.06 (d, J = 4.3 Hz, 3H), 1.90 (s, 6H). HRMS:

(ESI+) calculated for CivlENs [M+H] 431.1979, found 431.1977. LCMS (m/z) 431.2 [M+H], Tr 3.67 min (LCMS method 1 ).

EXAMPLE 31 (E)-6-((8-(4-(2-Cyanovinyl)-2,6-dimethy!phenyl)-4-(methylamino)quinazolin-2yl)amino)nicotinonitrile - Compound 31

142

Synthesis of (E)-6-((8-(4-(2-cyanovinyl)-2,6-dimetliylplienyl)-4(methylamino)quinazolin-2-yl)amino)nicotinonitrile (compound 31)

Pd(OAc)₂Xantphos DIPEA NMP 110°C ^XNH

N Compound 31 [0324] A mixture of compound 30b (52 mg, 0,1 5 mmol), 6-aminonicotinonitrile (90 mg,

0.75 mmol, Ark Pharm ïnc. AK-32349), palladium(ll) acetate (20 mg, 0.064 mmol) and (9,9-dimethyl-9/f-xanthene-4,5-diyl)bis(diphenylphosphine) (40 mg, 0.064 mmol) was dissolved in JV-methyl-2-pynOlidone (3 mL) under argon. W^V-Diisopropylethylamine (150 pL, 0.85 mmol) was then added via syringe and the reaction mixture was stirred at 110°C for 4 hours. The reaction mixture was concentrated down under reduced pressure and the product was isolated by silica gel chromatography (gradient from 80-100% ethyl acetate in /so-hexanes) and then repurified by reverse phase flash chromatography (5.5 g C-18 RediSep prepacked column, gradient 0-100%, acetonitrile in water with 0.1% trîfluoroacetic acid) to afford the TFA sait of the title compound 31. *H NMR (400 MHz, DMSO-î/ô) δ 13.53 (s, 1H), 12.28 (s, 1H), 10.13 (s, 1 H), 8.41 (d,J=8.4 Hz, 1 H), 8.29 (d,J=8.8 Hz,

143

1H). 7,88-7.80 (m, 2H), 7.80 - 7.72 (m, 1H), 7,71 (s, 2H), 7.59 - 7.49 (m, 1H), 7.46-7.41 (m, 1 H), 6.70 (d, J = 16.7 Hz, 1 H), 3.21 (d. J = 4 4 Hz, 3H), 1.96 (s, 6H). HRMS: (ESI+) calculated for C26H22N7 [M+H] 432.1931, found 432.1929. LCMS (m/z) 432.2 [M+H], Tr 3.53 min (LCMS method I)

EXAMPLE 32 (£)-4-((4-Amino-8-(4-(2-cyanovÎnyl)-2,6-dimethoxyphenyl)quinazoIin-2yl)amino)benzomtrîle - Compound 32

Step 1·. Synthesis of 4-((4-amino-8-(trimethyIstannyl)qumazolm-2 yl)amino)benzonitrile (compound 32a)

NH

I I —Sn-Sn—

I I

Pd(PPh3)₄dioxane 100’C

N Compound 32a |0325| To a mixture of 8a (1000 mg, 2.94 mmol) and tetrakis(triphenylphosphîne)palladium(0) (200 mg, 0.17 mmol) in dry dioxane (5 mL) was added hexamethylditin (I mL, 4.82 mmol) under argon The reaction mixture was heated to 100°C for 14 hours under argon, then cooled down to room température and directly purified by silica gel chromatography (gradient from 25-50% ethyl acetate in Ao-hexanes) to afford the title compound 32a. Ή NMR (400 MHz, DMSO-Je) Ô 9.42 (s, 1H), 8.08 - 8.18 (m, 3H),

144

7.73 (d, J= 9.9 Hz, 1H), 7.64 (d, J= 8.9 Hz, 2H), 7.51 (bs, 2H), 7.20-7.28 (m, 1H), 0.36 (s, 9H) LCMS (m/z) 424.0 [M-H], Tr = 4.84 min (LCMS method 1 ).

Step 2: Synthesis of (E)-3-(4-bromo-3,5-dimethoxyphenyl)acrylonitrile (compound 32b)

t-BuOK, 2-MeTHF

0°Cto r.t.

Br

[0326| To a solution of 4-bromo-3,5-dimethoxybenzaldehyde (24.5 g, 100 mmol, Ark Pharm Inc., AK-34641)and diethylcyanomethyl phosphonate (18 6 g, 105 mmol) in anhydrous 2-methyltetrahydrofuran (400 mL) was slowly added potassium t-butoxide (12.3 g, 110 mmol) at 0°C under argon. The reaction mixture was vigorously stirred at 0°C for 1 hour and then at room température for 3 hours. The reaction mixture was diluted with ethyl acetate and washed twice with water and once with brine. The organic layer was dried over

MgSCh and, filtered through a 3 cm layer of silica gel which was washed with additional ethyl acetate. The combined organics were concentrated down under reduced pressure and the solid residue was treated in sonie bath with hexane/diethyl ether mixture (1/3) for 3 minutes. The solid product was filtered off and washed with hexane to afford the title compound 32b. Ή NMR (400 MHz, DMSO-Je) δ 7 61 (d, 16.7 Hz, I H), 7.06 (s, 2H),

65 (d, J= 16.7 Hz, 1H), 3.87 (s, 6H). LCMS (m/z) no MS signal, Tr 2.50 min (LCMS method 2)

Step 3: synthesis of (£)-4-((4-amino-8-(4-(2-cyanovinyl)-2,6dimethoxyphenyl)quinazolin-2-yl)amino)benzonÎtrile (compound 32)

145

[0327] A mixture of compound 32a (20 mg, 0.047 mmol), compound 32b (20 mg, 0.075 mmol) and bis(tri-/er/-butylphosphine)palladium(0) (20 mg, 0 039 mmol) in N,Ndimethylformamide (2 mL) was heated under argon at 100°C for 2 hours. The reaction mixture was concentrated down under reduced pressure, purified by silica gel chromatography (gradient from 50-100% ethyl acetate in Zio-hexanes) and then repurified by reverse phase flash chromatography (5.5 g C-l 8 RediSep prepacked column, gradient ΟΙ 00%, acetonitrile in water with 0.1% TFA) to afford the TFA sait of the title compound 32. *H NMR (400 MHz, DMSO-î/û) δ 10.53 (bs, 1H). 9.72-9.53 (m, 2H), 7.88-7.83 (m, 2H), 7.77 (d, J= 16.7 Hz, 1H), 7.71 (d, J= 7.8 Hz, 2H), 7.58 (bs, 1H), 7.54 (bs, 1H), 7.41 -7.34 (m, 1 H), 7.16 (s, 2H), 6.76 (d, J = 16.7 Hz, 1 H), 3.72 (s, 6H). LCMS (m/z) 449.0 [M+H], Tr = 3.48 min (LCMS method 1)

EXAMPLE 33 (E}-4-((8-(4-(2-Cyanovinyl)-2,6-dimcthoxyphenyl)qiiinazolin-2-yl)amino)benzonitrileCompound 33

146

Step 1: Synthesis of 4-((8-(trimethyIstannyI)quinazoIin-2-yl)amino)benzonitrile (compound 33a)

Pd(PPh₃)₄dioxane 110C

N Compound 33a [0328] To a mixture of la (1000 mg, 3.07 mmol) and tetrakis(triphenylphosphine)palIadium(0) (200 mg, 0.17 mmol) in dry dioxane (5 mL) was added hexamethylditin (1 mL, 4 82 mmol) under argon. The reaction mixture was heated to 110°C for 4 hours under argon, then cooled down to room température and directly purified by silica gel chromatography (gradient from 0-30% ethyl acetate in / w-hexanes) to afford the title compound 33a ’H NMR (400 MHz, DMSO-î/ô) δ 10.53 (s, 1 H), 9.47 (s, 1 H), 8.34 (d, J= 8.8 Hz, I H), 8.31 - 8.24 (m, 2H), 8,09 - 8 02 (m, 1 H), 7.90 - 7.85 (m, 2H), 7.60 7.51 (m, 1 H), 0.05 (s, 9H) LCMS (m/z) 409.0 [M+H], Tr = 5.54 min (LCMS method 1).

Step 2: synthesis of (E)-4-((8-(4-(2-cyanovinyl)-2,6-dimethoxyphenyl)quînazolin-2yl)amino)benzonitrile (compound 33)

Br

N Compound 33 (0329] A mixture of compound 33a (20 mg, 0.048 mmol), compound 32b (20 mg, 0.075 mmol) and bis(tri-/cr/-butylphosphine)palIadium(0) (20 mg, 0.039 mmol) in N,N

147 dimethylformamide (2 mL) was heated under argon at 100°C for 2 hours. The réaction mixture was concentrated down under reduced pressure, purified by silica gel chromatography (gradient from 0-50% ethyl acetate in z.w-hexanes) and then repurified by reverse phase flash chromatography (5.5 g C-18 RediSep prepacked column, gradient ΟΙ 00%, acetonitrile in water with 0.1% TFA) to afford the TFA sait of the title compound 33 *H NMR (400 MHz, DMSO-î/ô) δ 10.38 (s, IH), 9.40 (s.l H), 7.96 (dd, 8.1,1.4 Hz, IH), 7.78-7.85 (m, 3H), 7.71 (dd,J=7.2, 1.4 Hz, 1 H), 7.44-7.54 (m,3H), 7.21 (s, 2H), 6.77 (d, J= 16.7 Hz, 1 H), 3.62 (s, 6H). LCMS (m/z) 433.98 [M+H], Tr = 4.39 min (LCMS method 1).

EXAMPLE 34 (E)-6-((8-(4-(2-CyanovinyI)-2,6-diniethylphenyl)-4-oxo-3,4-dihydroqiiînazolm-2yl)ammo)nicotinonitrile- Compound 34

Step 1: Synthesis of8-bromo-2-chloroquÎnazolin-4(3//)-one (Compound 34a)

O

Br Compound 34a [0330] Aqueous sodium hydroxide (30 mL, 0.2 M, 6 mmol) was added into a solution of 8-bromo-2,4-dich1oroquinazoline (556 mg, 2 mmol, Ark Pharm Inc., AK-28703) in tetrahydrofuran (30 mL). The reaction mixture was stirred at room température for 0.5 hour. Then the reaction mixture was acidified with glacial acetic acid to pH = 5 and concentrated down under reduced pressure. Water was added and the solid product was filtered off and

148 washed with water (3 x 20 ml) to afford the title compound 34a *H NMR (400 MHz, DMSO-t/s) δ 13.51 (s, 1 H), S. 15 (d, J = 7.8 Hz, 1 H), 8.09 (d, J = 7.8 Hz, 1 H), 7.42 - 7.51 (m, 1 H). HRMS: (ES 1+) calculated for CgH-iONîBrClNa [M+Na] 280.9088, found 280.9089. LCMS (m/z) 259.0 [M+H], Tr 3.58 min (LCMS method I)

Step 2: synthesis or(E)-3-(4-(2-chloro-4-oxo-3,4-dÎhydroquinazolin-8-yl)-33 dïmethylphenyl)acrylonitrile (compound 34b)

[0331] A mixture of compound 34a (74 mg, 0.28 mmol), compound le (120 mg, 0.42 mmol), potassium phosphate tribasic monohydrate (200 mg, 0.87 mmol) and [1,1’bis(dipheny!phosphino)ferrocene] dichloropalladium(II), complex with dichloromethane (30 mg, 0.05 mmol) was dissolved in a mixture of TVJV-dimethylformamide and water (10:1,3.3 mL) under argon and this mixture was stirTed at 80°C for 2 hours. The product was isoiated by silica gel chromatography (gradient from 0-100% ethyl acetate in Mo-hexanes) to afford the title compound 34b. *H NMR (400 MHz, DMSOA) 613.30 (bs, 1 H), 8.16 (dd, J = 7.7,

1.8 Hz, 1 H), 7.67-7.51 (m,3H), 7.43 (s,2H), 6.46 (d, J = 16.7 Hz, 1H), 1.88 (s, 6H). LCMS (m/z) 336.1 [M+H], Tr = 4.24 (LCMS method 1 ).

Step 3: synthesis of (E)-6-((8-(4-(2-cyanovinyl)-2,6-dimethylplienyl)-4-oxo-3,4dihydroquinazolin-2-yI)ainino)nicotÎnonitrile (compound 34)

149

Ο

Pd(OAc)₂Xantphos DIPEA NMP 100°C

O

Compound 34 [0332] A mixture of compound 34b (80 mg, 0.24 mmol), 6-aminonicotinonitriIe (200 mg, 1.68 mmol, Ark Pharm Inc, AK-32349), paIIadium(II) acetate (20 mg, 0.09 mmol) and (9,9-dimethyl-9/f-xanthene-4,5-diyl)bis(diphenylphosphine) (100 mg, 0.17 mmol) was dissolved in AAmethyl-2-pyrrolidone (3 mL) under argon. N,/V-Diisopropylethylamine (1 mL, 5.7 mmol) was then added via syringe and the reaction mixture was stirred at 100°C for 1 hour. The product was isolated by silica gel flash chromatography (gradient from 0-100% ethyl acetate in Ao-h exan es) and then repurified by reverse phase flash chromatography (5.5 g C-18 RediSep pre-packed column, gradient 0-100% acetonitrile in water with 0.1% trifluoroacetic acid) to afford the TFA sait of compound 34. *H NMR (400 MHz, DMSO-Je) 512.16 (bs, 1 H), 10.26 (bs, 1 H), 8 74 (bs, 1 H), 8.10 (dd, J = 7.8,1.6 Hz, 1 H), 7.94 - 7.81 (m, 1 H), 7.69 (d, J = 16.7 Hz, 1 H), 7.59 - 7.36 (m, 5H), 6 51 (d, J = 16.7 Hz, 1 H), 1.94 (s, 6H) LCMS (m/z) 418.9 [M+H[, Tr = 4.11 min (LCMS method 1 ).

EXAMPLE 35 (E)-4-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dîethylphenyl)qiiinazo]in-2· yl)amino)benzonitrile- Compound 35

150

NH,

Step 1: synthesis of (E)-3-(4-bromo-3,5-diethyIphenyI)acrylonÎtrile (compound 35a)

70^eC

[0333] To a solution of 2.5-dibromo-l 3-diethylbenzene (2920 mg, 10 mmol, Oakwood Products, Inc. - 034265) in anhydrous acetonitrile (25 mL) was added palladium(II) acetate (224 mg, 1 mmol), acrylonitrile (1060 mg, 20 mmol), tri(o-tolyl)phosphine (913 mg, 3 mmol) and triethylamine (4 mL, 30 mmol) then the mixture was purged with argon and heated at 70 °C for 3 hours. The reaction mixture was filtered through Celite and the filter pad was washed with tetrahydrofuran (10 mL) The filtrate was evaporated then re-dissolved with ethyl acetate (50 mL). The solution was washed with water (50 mL). The water 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 crade residue. This was subjected to silica gel chromatography (gradient from 020% ethyl acetate in ira-hexanes) to afford the title compound 35a. ^lH NMR (400 MHz, CDCh)57.31 (d, J= 16.6 Hz, 1H), 7.12(s, 2H), 5.86(d,J = 166Hz, 1H), 2.79 (q,J=7.5 Hz, 4H), 1.22 (t, J =7.5 Hz,6H) LCMS (m/z) no MS signal, Tr = 3.07 min (LCMS method

2).

Step 2: synthesis of (£)-3-(3^-diethyl-4-(4^1^^-tetrametliyl-13»2-dÎoxaborolan-2yl)phenyl)acrylonitrile (compound 35b)

151

Br

Pd(OAc)₂SPhos K₂CO₃DMF, 100 C

B₂pin₂

Compound 35b [0334] A mixture of compound 35a (300 mg, 1.14 mmol), 4,4,4',4',5,5,5’,5'-octamethyl2Z'-bi(l,3,2-dioxaborolane) (432 mg, 1.70 mmol), potassium carbonate (471 mg, 3.4 mmol), palladium(ll)acetate (13 mg, 0.06 mmol)and dicyclohexyl(2',6'-dimethoxy-[1,l'biphenyl]-2-yl)phosphine (SPhos, 58 mg, 0.14 mmol) in dry AJV-diniethylformamide (20 mL) was purged with argon and heated at 100 °C for 2 hour. The reaction mixture was filtered through Celite and the filter pad was washed with tetrahydrofuran (10 mL). The filtrate was evaporated then re-dissolved with ethyl acetate (50 mL). The solution was washed with water (50 mL). The water 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 (gradient from 0-15% ethyl acetate in ho-hexanes) to afford compound 35b. *H NMR (400 MHz, CDCb) S 7.33 (d, J= 16.6 Hz, 1H), 7.04 (s, 2H), 5.85 (d, J = 16 6 Hz, 1 H), 2.67 (q, J = 7.6 Hz, 4H). 1.38 (s, 12H), 1.20 (t, J = 7.6 Hz, 6H) LCMS (m/z) no MS signal, Tr = 3.07 min (LCMS method 2)

Step 3: Synthesis of (E)-3-(4-(4-itmino-2-chloroquÎnazolin-8-yl)-3,5diethylphenyl)acrylonitrile (Compound 35c)

152

[0335] A mixture of 8-bromo-2-chloroquînazolin-4-amine (90 mg, 0.35 mmol, Ark Pharm Inc, AK-28702), compound 35b (130 mg, 042 mmol), potassium phosphate tribasîc (96 mg, 0.45 mmol) and I ,r-bis(di-rerr-butylphosphino)ferrocene palladium dichloride (23 mg, 0.04 mmol) was dissolved in JV^V-di methyl forma mi de: water mixture (80:20, 5 mL) under argon The reaction was heated at 80°C for 60 minutes. The réaction mixture was cooled down to room température and diluted with water and ethyl acetate. The organic layer was separated and washed twice with brine, dried over magnésium sulfate, 1 volume équivalent of hexane added and this mixture was filtered through a 2 cm layer ofsilica gel which was washed with additional ethyl acetate. Combined organics were concentrated down under reduced pressure and the residue was treated with hexane in a sonie bath. The solid product was filtered oif and washed twice with hexane to afford the title compound 35c. Ή NMR (400 MHz, DMSCMù) δ 8.39 (bs, 2H), 8.29 (dd, J= 7.2, 2.5 Hz, 1 H), 7.67 (d, J = 16.7 Hz, 1 H), 7.61 - 7,54 (m, 2H), 7.46 (s, 2H), 6.52 (d, J= 16.7 Hz, 1 H), 2.22 - 2.01 (m, 4H), 0.91 (t, J= 7.5 Hz, 6H). LCMS (m/z) 363.3 [M+H], Tr = 2.68 min (LCMS method

2)

Step 4: synthesis of (E)-4-((4-amino-8-(4-(2-cyanovÎny1)-2,6-dÎetbylphenyl)quinazolin2-yl)amino)benzonitrile (compound 35)

153

[0336| A mixture of compound 35c (40 mg, 0.11 mmol), 4-cyanoaniline (18 mg, 0.154 mmol, Sigma-Aldrich) and hydrogen chloride solution in 1,4-dioxane (4M, 3 pL, 0.011 mmol) in dry N-methyl-2-pyrrolidone (1 mL) was heated under argon at 120°C for 12 hours. The reaction mixture was cooled down to room température and purified directly by HPLC reverse phase chromatography (gradient 0-100% acetonitrile in water with 0.1% trifluoroacetic acid) to afford the TFA sait of compound 35. ’H NMR (400 MHz, DMSO-t/s) 6 10.57-9.84 (m, 1 H), 9.82 - 8.84 (m, 2H), 8.27 (bs, 1 H), 7.86-7.22 (m, 7H), 6.62 (d, J =

16.8 Hz, 1 H), 2.40 - 1.98 (m, 4H), 0.94 (t, J= 7.2 Hz, 6H). LCMS (m/z) 445.4 [M+H], Tr =

2.59 min (LCMS method 2)

EXAMPLE 36 (E)-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-diethylphenyl)quinazolin-2yl)amino)nicotinonitrile- Compound 36

Synthesis or(E)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-dicthylphenyl)qi!inazolin-2yl)amino)nicotinonitrile (compound 36)

154

BrettPhos G3 DIPEA NMP 120°C

[0337] Compound 35c (40 mg, 0.11 mmol), 6-aminonicotinonitrile (53 mg, 0 44 mmol, Ark Pharm Inc, AK-32349), TV^V-diisopropylethylamine (28 mg, 0.22 mmol) and [(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'- triisopropyl-1,1 -biphenyl)-2-(2'-amino-t ,Γ biphenyl)Jpalladium(II) methanesulfonate (9 mg, 0.011 mmol) were combined under argon in 7V-methyl-2-pyrrolidone (1 mL). The reaction was heated at 120°C in a sealed vessel for 4 hours. The reaction mixture was cooled down to room température and purified directly by HPLC reverse phase chromatography (gradient 0-100% acetonitrile in water with 0.1% trifluoroacetic acid) to afford the TFA sait of compound 36. ’H NMR (400 MHz, DMSO-<A>) δ 13.54 (bs, 1H), 12.09 (bs, 1H), 9.62 (bs, 1 H), 9.38 (bs, IH), 8 46(d, J= 8.2 Hz, ÏH), 8.37 - 8.15 (m, 1 H), 7.94 - 7.83 (m, 2H), 7.80 - 7.66 (m, 311), 7.56 - 7.27 (m, 2H), 6.76 (d, J= 16.7 Hz, IH), 2.40-2.01 (m,4H), 0.94 (t, J= 7.5 Hz, 6H) LCMS (m/z) 446.4 [M+H], Tr = 1.98 min (LCMS method 2).

EXAMPLE 37 (£)-1-(2-( (4-Cyanophenyl)amino)-8-(4-(2-cyanoviny!)-2,6-dimethylphenyl)quinazolin-4 yl)tirea- Compound 37

155

Ο

Synthesis of (E)-l-(2-((4-cyanop!icnyI)amino)-8-(4-(2-cyanovinyI)-2,6 dimethylphenyI)qtiinazolin-4-yl)itrea (compound 37)

2) NHj r.t.

1)COCI₂DIPEA/DCM 50 °C

O

N Compound 37 [0338] Compound 2 (42 mg, 0.10 mmol) was suspended in dry dichloromethane (2 mL), and ^^-diisopropylethylamine (0.1 mL, 0.57 mmol) was added to the suspension followed by dropwise addition of phosgene (0.5 mL, 20% solution in toluene). The mixture was stirred at 50 °C for 1 hour. Another portion of A^V-diisopropylethylamine (0.1 mL, 0.57 mmol) and phosgene (0.2 mL, 20% solution in toluene) was added to the reaction mixture and this mixture was stirred at 50 °C for another lhour. The mixture was cooled down to room température and saturated aqueous ammonia (1 mL) was added. Volatiles were removed under reduced pressure and the crude residue was purified by HPLC using gradient from 50-100% acetonitrile in water (HPLC préparative column Phenomenex Gemini 10u, Cl 8, 250 x 21.2 mm, 10 mL/min) to afford the title compound 37. *H NMR (400 MHz, DMSO-îL) δ 9.35 (bs, 1 H), 8 26 - 8 07 (m, 1 H), 7.78 - 7.65 (m. 3H), 7.62 - 7.45 (m, 3H),

156

7.44-7.30 (m, 3H), 7.29-7.16 (m, 3H), 6.43 (d,J=16.7Hz, 1H), 1.81 (s, 6H). LCMS (m/z) 460.3 [M+H], Tr = 3.98 min (LCMS method 1 )

EXAMPLE 38 (E)-4*((4-Amino-8-(4-(l-cyanoprop-l-en-2-yl)-2,6-dimethylphenyl)quinazolin-2yl)amino)benzonitrile* Compound 38

Step 1: Synthesis of 4-bromo-3,5-dimethylbenzoic acid (Compound 38a)

NaOH Br

EtOH and H₂O,

120°C θ θΗ Compound 38a f0339J 4-Bromo-3,5-dimethylbenzonitrile (630 mg, 3 mmol, Ark Pharm Inc, AK-44760) was dissolved in éthanol (1 mL), and 8M sodium hydroxide solution (5 mL) was added and this reaction mixture was stirred in a sealed vessel at 120°C for 12 hours. The reaction mixture was diluted with water (100 mL) and washed with diethylether (2x 50 mL). aqueous layer was acidified with concentrated hydrochloric acid (to pH=3) and extracted with diethylether (2x 100 mL) Combined organic layers were dried over sodium sulfate and concentrated down under reduced pressure to afford the title compound 38a. *H NMR (600 MHz, DMSO-Je) δ 7.72 (s, 2H), 2 41 (s, 6H)

Step 2: synthesis of l-(4-bromo-3,5-dimethylphcnyl)etlianone (compound 38b)

157

[0340] Compound 38a (100 mg, 0.44 mmol) was suspended in dry 1,4-dioxane (5 mL) and methyllithium (0.8 mL, 1.6 M solution in diethyl ether) was added dropwise under argon. The mixture was stirred at room température for 1 hour. The reaction was quenched by addition of methanol (10 mL) and concentrated down under reduced pressure. The solid residue was extracted with ethyl acetate (3x10 mL) Combined organic solutions were concentrated down under reduced pressure to afford the title compound 38b. LCMS (m/z) 227.0 [M+H], Tr = 4.65 min (LCMS method 1 )

Step 3; synthesis or(E)-3-(4-bromo-3,5-dimethylphenyl)bi!t-2-enenitrile and (2)-3-(4bromo-3,5-dimcthylphenyl)but-2-encnitrile (compound 38c and compound 38d)

Compound 38c Compound 38d [0341 [ Compound 38b (95 mg, 0.42 mmol) and diethyl (cyanomethyl)phosphonate (70 pL, 0.40 mmol) were dissolved in dry dichloromethane (5 mL). Césium carbonate (1 g, 3.07 mmol) was added and the solution was slowly concentrated down under reduced pressure at 30 °C. The resulting solid was allowed to stand at room température for 4 hours. Dichloromethane was added to the residue and the solids were filtered off The solvent was removed under reduced pressure and the crude product was purified by silica gel chromatography using gradient from 0-10% ethyl acetate in /.ro-hexanes to afford the title compound 38c LCMS (m/z) 250.0 [M+H], Tr = 5.01 min (LCMS method 1); and the title compound 38d LCMS (m/z) 250 0 [M+H], Tr = 4.48 min (LCMS method 1 )

158

Step 4: synthesis of(E)-4-((4-amino-8-(4-(l-cyanoprop-l-en-2-yl)-2^dimethylpheny!)quinazolîn-2-yl)amino)benzonitri!e (compound 38)

Br

N Compound 38 [0342] A mixture of compound 32a (20 mg, 0.047 mmol), compound 38c (20 mg, 0 080 mmol) and bis(tri-/er/-butylphosphine)palladium(0) (20 mg, 0.039 mmol) in N.Ndimethylformamide (2 mL) was heated under argon at 100°C for 14 hours. The reaction mixture was concentrated down under reduced pressure, purified by silica gel chromatography (gradient from 50-100% ethyl acetate in κο-hexanes) and then re-purified on HPLC (préparative column Phenomenex Gemini 10 micron Cl 8. 250 x 21.2 mm, 10 mL/min, gradient from 10-100% acetonitrile in water) to afford the title compound 38. ’H NMR (600 MHz, DMSOW₆) δ 8 23 (bs, 1H), 7.83 - 7.72 (m, 2H), 7.60-7.29 (m, 7H), 6.17 (q. J = 1.0 Hz, 1 H), 2.52 - 2.51 (m, 3H), 1.96 (s, 6H). LCMS (m/z) 430,9 [M+H], Tr = 3.83 min (LCMS method 1).

EXAMPLE 39 (Z}4-((4-Amino-8-(4-(l-cyanoprop-l-en-2-yl)-2,6-dimethylphenyl)quinazolin-2yl)amino)benzonitri!e- Compound 39

159

Synthesis of (Z)-4-((4-amino-8-(4-(l-cyanoprop-l-en-2-yl)-2,6dimethy!pheny!)quinazolin-2-yl)amino)benzonitrile (compound 39)

[0343] A mixture of compound 32a (20 mg, 0.047 mmol), compound 38d (18 mg, 0.072 mmol) and bis(tri-ft?rAbutylphosphine)palladium(0) (20 mg, 0.039 mmol) in N,Ndimethylformamide (2 mL) was heated under argon at 100°C for 14 hours. The reaction mixture was concentrated down under reduced pressure, purified by silica gel chromatography (gradient from 50-100% ethyl acetate in wo-hexanes) and then re-purified on HPLC (préparative column Phenomenex Gemini 10 micron Cl8, 250 x 21.2 mm, 10 mL/min, gradient from 10-100% acetonitrile in water) to afford the title compound 38 *H NMR (600 MHz, DMSO-J₆) δ 8.22 (bs, 1H), 7.84 - 7.71 (m, 4H). 7.62 - 7.29 (m, 5H), 5.89 - 5.79 (m, 1 H), 2.36 (d, J = 1.5 Hz, 3H), 1.97 (s, 6H) LCMS (m/z) 430.9 [M+H], Tr = 3.76 mîn (LCMS method 1 )

EXAMPLE 40

4-((4-Amino-8-(4-(2-cyanoprop-l-en-l-yI)-2,6-dimethylphenyl)qiiÎnazoIÎn-2yl)amino)benzonitrile - Compound 40 (mixture E!Z- 1/1)

160

Step I: Synthesis of 4-bromo-3^-dimethylbenzaldehyde (Compound 40a)

DIBAL-H

CH₂CI₂ °C to r.t.

Compound 40a [0344] A mixture of 4-bromo-3.5-dimethylbenzonitrile (2 g, 9.57 mmol, Ark Pharm Inc, AK-44760) in dichloromethane (25 mL) was cooled to -62 °C. A solution of diisobutylaluminium hydride (IM in dichloromethane, 11 mL) was added dropwise and the reaction was left to reach room température during 2 hours. After that, 5% aqueous solution of hydrochloric acid (10 mL) was added and the reaction mixture was heated to reflux for 30 minutes. Then, the reaction mixture was diluted with dichloromethane, washed with brine.

The organic layer was dried over calcium chloride. The solvent was removed under reduced pressure and the crude product was subjected to silica gel chromatography (gradient from 010% ethyl acetate in iso-hexanes) to afford the title compound 40a. *H NMR (400 MHz, CDCb) δ 9.93 (s, 1 H), 7.57 (s, 2H), 2.50 (s, 6H). IIRMS: (TOF CI+) calculated for CgHioBrO [M+H] 212.9915, found 212.9913. LCMS (m/z) 213.0 [M+H], Tr = 4.59 min (LCMS method 1 ).

Step 2: synthesis of 3-(4-bromo-3,5-dimethylphenyl)-2-methylacrylonitrile (compound

40b) mixture E!Z- 1/1

161

Br Br

(mixture) Compound 40b [0345] Compound 40a (100 mg, 0.47 mmol) and diethyl (l-cyanoethyl)phosphonate (70 pL, 0.40 mmol) were dissolved in dry dichloromethane (5 mL). Césium carbonate (1 g, 3.07 mmol) was added and the solution was slowly concentrated down under reduced pressure at 30 °C. The resulting solid was allowed to stand at room température for 4 hours. Dichloromethane was added to the residue and the solids were filtered off. The solvent was removed under reduced pressure and the crude product was purified by silica gel chromatography using gradient from 0-10% ethyl acetate in wo-hexanes to afford the title compound 40b as a 1:1 mixture of E!Z isomers. LCMS (m/z) 250.0 [M+H], Tr = 5.07 and 5.10 min (LCMS method 1)

Step 4: synthesis of4-((4-amino-8-(4-(2-cyanoprop-l-en-l-y 1)-2,6dimethylphenyl)quinazolin-2-yl)amino)benzonitri!e (compound 40) mixture FJZ~ 1/1

Br Br

Compound 40 [0346|

A mixture of compound 32a (20 mg, 0.047 mmol), compound 40b (20 mg, 0 080 mmol) and bis(tri-rt'r/-butylphosphine)palladium(0) (20 mg, 0 039 mmol) in N,N·

162 dimethylformamide (2 mL) was heated under argon at 100°C for 8 hours. The reaction mixture was concentrated down under reduced pressure, purified by silica gel chromatography (gradient from 50-100% ethyl acetate in fro-hexanes) and then re-purifîed on HPLC (préparative column Phenomenex Gemini 10 micron Cl 8, 250 x 21.2 mm, 10 mL/min, gradient from 10-100% acetonitrile in water) to afïbrd the title compound 40 as a 1:1 mixture ofÆ/Z isomers. Ή NMR (600 MHz, DMSO-î/₆) δ 8.26 (s, 1H), 7.82-7.74 (m, 2H), 7.64 - 7.23 (m, 7H), 2.23 - 2.19 (m, 3H), 1.96 (s, 6H) LCMS (m/z) 430.8 [M+H], Tr = 3.86 min (LCMS method 1)

EX AMPLE 41 (E)-4-((8-(4-(2-Cyanovmyl)-2^-<limethyIphenyl)-4-oxo-3/l-<lihydroqiiinazolin-2yl)amino)benzonitrilc- Compound 41

O

Step 1: Synthesis or4-((8-bromo-4-oxo-34-dihydroquinazoIin-2-yI)amino)benzonitriIe (Compound 41a)

163 nh₂

N Compound 41a [0347] A mixture of compound 34a (260 mg, 1 mmol) and 4-aminobenzonitrile (130 mg, 1.1 mmol, Sigma-Aldrich) in isopropanol (5 mL) was heated in microwave at 130 °C for 30 minutes. The reaction mixture was cooled down to room température and diethyl ether (10 mL) was added. The solid product was filtered off and washed with diethyl ether (3x 20 mL) to afford the title compound 41a. *H NMR (400 MHz, DMSO-t/ΰ) δ 11.13 (bs, 1 H), 9,41 (bs, 1 H), 8.11 (d, J = 8.8 Hz, 2H), 8.04 - 7.96 (m, 2H), 7.80 (d, J = 8.8 Hz, 2H), 7.19 (t, J= 7.8 Hz, IH). HRMS: (ESI+) calculated for CisHioONiBr [M+H] 341.0033, found 341.0033. LCMS (m/z) 341.1 [M+H], Tr4.52 min (LCMS method 1)

Step 2: synthesis of (E)-4-((8-(4-(2-cyanovinyl}*2Xi-dÎmethylphenyI)-4-oxo-3,4dÎhydroquinazolin-2-yl)amino)benzonitrile (compound 41)

164

Compound 41 [0348] A mixture ofcompound 41a (68 mg, 0.2 mmol), compound le (85 mg, 0.3 mmol), potassium phosphate tribasic (92 mg, 0.4 mmol) and 1,1 '-bis(di-ft.’rA butylphosphino)ferrocene palladium dichloride (26 mg, 0.04 mmol) was dissolved in NJ/dimethylformamîde: water mixture (85:15, 40 mL) under argon. The reaction was heated to 80°C for 3 hours. The reaction mixture was concentrated down under reduced pressure and the residue was purified by silica gel chromatography (gradient from 50-80% ethyl acetate in iso-hexanes) and then repurified by HPLC reverse phase chromatography (gradient 5100% acetonitrile in water with 0.1% trifluoroacetic acid) to afiord the TFA sait of compound 41.¹H NMR (400 MHz, DMSO-J₆) δ 10.96 (bs, 1H), 9.15 (bs, 1H), 8 05 (dd, J = 7.9,1.6 Hz, 1H), 7.75 (d,J= 16.7 Hz, 1H), 7.57 (dd, J = 7.3, 1.6 Hz, 1H), 7.53 (s,2H), 7.48 -7.29 (m, 6H), 6.56 (d, J= 16.7 Hz, 1H), 1.93 (s, 6H) LCMS (m/z) 418.3 [M+H],Tr =

2.72 min (LCMS method 2)

EXAMPLE 42

Alternative synthesis of (E)-3-(4-bromo-3,5-dimethylphenyl)acrylonitrile - Compound lb

165

Br

Alternative synthesis of (E)-3-(4-bromo-3,5-diinethylphenyl)acrylonitrile (compound lb)

[0349] To a solution of diethyl cyanomethylphosphonate (266 mg, 1.5 mmol) in tetrahydrofuran (10 mL) was added potassium /-butoxide (168 mg, 1.5 mmol)at 0°C with stîrring for 30 minutes. After that, compound 40a (212 mg, 1 mmol) in tetrahydrofuran (10 mL) was added dropwise into the reaction mixture at room température and the reaction mixture was stirred at room température ovemight. The reaction mixture was quenched with water. Ethyl acetate was added and the organic layer was washed with brine, dried over anhydrous calcium chloride and concentrated down under reduced pressure. The residue was purified by silica gel column chromatography (gradient from 0-20% ethyl acetate in isohexanes) to afford the title compound lb. ’H NMR (400 MHz, CDCh) δ 7.25 (d, J= 16.6 Hz, 1 H), 7.12 (s, 2H), 5.84 (d, J = 16 6 Hz, 1H), 2.42 (s, 6H). LCMS (m/z) no MS signal, Tr = 2.78 min (LCMS method 2).

EXAMPLE 43

Alternative synthesis of 4-((4-amino-8-bromoquinazolin-2-yl)amino)bcnzonitrile Compound 8a

166

Step 1: synthesis or3-bromo-2-((triplienylphosphoranylidene)amîno)benzonitrile (compound 43a)

PPh₃, Br₂, Et₃N .........

ch₂ci₂

r.t.

[0350] A solution oftriphenylphosphine (10.65 g, 40.6 mmol) in dichlormomethane (200 mL) was treated slowly with bromine (6.49 g, 40 6 mmol ) at 0 °C for 5 minutes Then triethylamine (8.22 g, 81.2 mmol) was added followed by addition of 2-amino-3bromobenzonitrile (4.00 g. 20.3 mmol, Abblis, AB 1000095) Then, the ice bath was removed and the reaction mixture was stirred at room température for 8 hours. The reaction mixture was poured onto water and extracted two times with dichloromethane. The combined organics were wahsed with brine and dried over megnesium sufate. Solvent was removed under reduced presure and the residue was subjected to silica gel chromatography (gradient from 0-30% ethyl acetate in /.vo-hexanes) to afford the title compound 43a. *H NMR (400 MHz, DMSO-îA) δ 7.80 - 7.70 (m. 6H), 7.66 (dt, J = 7.9,1.4 Hz, 1 H), 7.64 7.58 (m, 311), 7.57 - 7.47 (m, 6H), 7.40 (dt, J= 7.7,1.5 Hz, 1 H), 6.64 (td, J= 7.8,1.5 Hz, 1 H). LCMS (m/z) 457.1 [M+H], Tr = 2.99 min (LCMS method 2)

Step 2: alternative synthesis 4-((4-amino-8-bromoquînazolin-2-yl)amino)benzonitrile (Compound 8a)

167

[0351J To a solution of compound 43a (500 mg, 1.09 mmol) in 2-methyltetrahydrofuran (10 mL) was added 4-isocyanatobenzonitrile (173 mg, 1.20 mmol, Sigma-Aldrich) at 0 °C and the reaction mixture was stirred at 0 C for 30 minutes. 2M ammonia in isopropanol (3.3 mL, 6.6 mmol) was added and the reaction mixture was heated to reflux for 3 hours then concentrated down under reduced pressure. The residue was purified by silica gel chromatography (gradient from 0-40% ethyl acetate in /.ro-hexanes) to afford the title compound 8a. Ή NMR (400 MHz, DMSO-J_fi) δ 9.74 (s, 1H). 8.35 (d, J = 8.8 Hz, 2H), 8 16 (d, J = 8.0 Hz, 1 H), 8 01 (d, J = 7.5 Hz, 1 H). 7.71 (d, J = 8.8 Hz, 2H), 7.16 (t, J = 7.8 Hz, 1 H) LCMS (m/z) 340.0 [M+H], Tr = 4.06 min (LCMS method 1 ).

Biological Examples

Example A

High Throughput Screening of anti-lHV-1 RT (Reverse Transcriptase) [0352] Compounds were screened in a miniaturized, high throughput cytopathic effect assay for activity against HIV-1 HBX2 (wild type) and HIV-1 reverse transcriptase mutants K103N and Y181C. In Tables 1 and 2 below, “w.t.” refers to results ofthe tested compounds run with the wildtype 1 and “w.t. assay 2” refers results ofthe tested compounds run with the wildtype on the same day as the testing of the compounds with the mutants Thus, “w.t. assay 2” was run under the same conditions as the testing of the compounds with the mutants and provides a direct comparison with the results from the testing with the mutants

168 [0353[ Ten-point serial dilutions of compounds with half-log step size were generated in DMSO. AZT (5μΜ) was used as the positive control and DMSO as the négative control. The Echo acoustîc dispenser was used to deliver 200nL of serial ly diluted compound into stérile 384 well tissue culture assay plates Two million MT-4 cells were incubated with each of the 3 viruses at MOI of 0.0005 in separate 1 mL infection tubes for 1 hour at 37^OC. The cells were diluted in cell culture medium (RPMI + 10% FBS) to 50,000 cells/mL. The infected cells were added to 384 well assay plates containing serially dilute compounds. Assay plates were incubated for 5 days in a humidified încubator set at 37°C and 5% CO₂. To measure the cytopathic effect of HIV, 40 gL Cell TiterGlo was added to each well and the resulting luminescence signal is read with the Envision plate reader (Perkin Elmer) Data were normalized to positive and négative controls in each plate and expressed as % CPE Protection. ECso values were defined as the compound concentration that caused a 50% decrease in luminescence signal, and were calculated by non-linear régression using Pipeline Pilot software by applyîng a four parameter fit équation (Accelrys, San Diego, CA). Results are disclosed in Table 1.

Table 1	MT4 ECso (nM) against	MT4 ECîo (nM) against	FC against mutant
Compound ID	w.t	w.t assay 2*	Kl 03 N	Y181C	K103N	YI81C
1	3.0	6.2	8.8	17.8	1.4	2.9
2	3.7	3.6	4.0	10.9	l.l	3.0
3	NA	12.9	12.0	50.2	0.9	3.9
4	9.2	9.8	19.1	47.0	2.0	4.8
5	1.3	1.5	2.5	12.0	1.7	8.2
6	99.3	82.6	81.1	469.5	1.0	5.7
7	122.2	1168	130.5	>500	1.1	>4 3
8	2.7	2.8	3.7	21.7	1.3	7.8
9	3.4	3.2	3.5	10.8	1.1	3.4
10	2.8	3.0	2.9	29.3	1.0	98
11	4.7	4.2	52	126.4	1.2	29.8

169

Table 1	MT4 ECw (nM) against	MT4 ECjo (nM) against	FC against mutant
Compound ID	w.t.	w.t. assay 2*	KI03N	Y181C	K103N	Y181C
12	1.8	1.8	1.7	12.5	0.9	6.9
13	3.2	43	5.9	27.4	1.4	6.4
14	8.1	12.7	15.1	121.9	1.2	9.6
15	22.6	33.2	72.2	179.5	2.2	5.4
16	6.3	7.5	12 5	42.6	1.7	5.7
17	229.1	189.9	150 8	>500	08	>2 6
18	21.9	13.1	12.1	112.3	0.9	8.6
19	27.5	29.0	30.3	79.7	1.0	2.7
20	7.0	6.6	7.1	69.9	II	10.5
21	10.1	10 6	10.8	187.0	1.0	17.6
22	69.3	87.5	101.4	>500	1.2	>5.7
23	8.7	NA	NA	NA	NA	NA
24	27.8	27.8	32.5	478.5	1.2	17.2
25	39.1	28.3	44.1	159.8	1.6	5.6
26	2.7	2.0	2.4	27.2	1.2	13.5
27	6.3	3.8	5.3	399.7	1.4	105.9
28	11.4	9.1	14.3	57.2	1.6	6.3
29	22.1	18.6	33.4	>500	1.8	>26.9
30	15.9	13.0	17.0	55.6	1.3	4.3
31	10.5	8.6	17.6	4325	2.1	50.5
32	1.9	1.3	1.5	10.5	1.2	8.3
33	2.1	1.5	3.2	12.3	2.1	7.9
34	2.4	3.0	3.2	11.3	1.0	3.7
35	12.8	16 8	16.9	38.6	1.0	2.3
36	7.7	10.5	10.1	87.3	1.0	8.3
37	4.7	6 8	7.8	22,1	1.2	3.3
38	6.0	7.9	7.0	18 6	0.9	2.4

170

Table 1	MT 4 ECso (nM) against	MT4 ECso (nM) against	FC against mutant
Compound ID	w.t.	w.t. assay 2*	KI03N	Y181C	K103N	Y181C
39	5,9	8 9	12.1	27.2	1,4	3.0
40 (mixture of isomers)	68	9.9	16 3	36.1	1,7	3.7
41	6.3	9,5	15.7	32.8	1.6	3.4

* w t. assay 2 were run on the same day as the assays with K103 N and Y181C mutants.

[0354] The high-throughput screening was also run for nevirapine (“NPV”), rilpivirine (“RPV”), and efavirenz (“EFV”) Nevirapine was obtained from Toronto Research Chemicals, Inc. (Toronto, Canada; Catalogue #N391275). Rilpivirine was obtained from Key Organics Ltd. (Camelford, Comwall, United Kingdom; Catalogue #KE-0036) Efavirenz was obtained from Toronto Research Chemicals, Inc, (Toronto, Canada;

Catalogue #E425000). The results are shown below in Table 2.

Table 2	MT4 EC» (nM) against	MT4 EC» (nM) against	FC against mutant
Compound	w.t.	w.t assay 2*	K103N	YI8IC	K103N	Y18IC
Nevirapine (“NVP”)	65 0	ND	ND	ND	ND	ND
Rilpivirine (“RPV’)	0.9	1.3	1.5	3.8	1,2	3,1
Efavirenz (“EFV”)	1,3	1.6	46 4	3.8	28.9	2.3

* w t. assay 2 were run on the same day as the assays with K103N and Y181C mutants. ND nol determined [0355| It is understood that ECso may be evaluated by techniques known in the art In one embodiment the compounds exhibit an ECso of less than about 3000 nM in the wildtype or any of the HIV RT mutants, as measured by the method disclosed in the “high throughput screening ofanti-HIV mutants K103N and Y181C” assay section discussed above. In one embodiment, the compounds exhibit an ECso of less than about 1000 nM, 500

171 nM, 400 nM, 300 nM, 250 nM, 200 nM, 100 nM, 50 nM, 25 nM. 10 nM, 5 nM, or 1 nM in the wild-type or any of the HIV RT mutants (eg, K103N, Y181C).

Example B

Résistance Profile Against IIIV-l RT (Reverse Transcriptase) Mutants [0356] Compounds were tested for antiviral activity against a panel of NNRTÏ résistant viruses. A panel of 8 clonal site-directed mutant viruses representing the major résistance development pathways against rilpivirine (“RPV”), efavirenz (“EFV”), and nevirapine (“NVP”), containing both single and double mutations within HIV-1 reverse transcriptase was employed. Further details and background can be found in Janssen et al, J. Med. Chem, 2005,48,1901-1909; Das étal., Proc. Nat. Acad. Sci., 2008, vol., 105, no. 5,1466-1471; and Kurodaeta!, Nature Chemistry, 2013, DOI: 10.1038/NCHEM 1559. Rétention offull antiviral potency against the KI03N mutation relative to the wild type virus was considered especially désirable as this mutation is présent in a minor subset of treatment-naïve patients (1.4%). HIV-1 recombinant strains encoding reverse transcriptase mutations K103N, Y181C, Y188L, G190A, K103N/YI81C, L100I/YI81C, Ε138Κ.ΟΓ EI38K/M184V were constructed by site-directed mutagenesis Wild-type and mutant viruses were prepared by transfecting infectious proviral HXB2-based cDNA clones into MT-2 cells and harvesting the ce!! supematants. MT-2 cells were infected with wild-type and mutant HIV-1 strains at a multiplicity of infection (MOI) of 0.005 by gentle mixing for 3 hours at 37°C and then added ata density of 16,667 cells per well in 50 pL complété RPMI cell culture media (containing 10% fêtai bovine sérum (FBS) and 10% penicillin-streptomycin) to 96-well plates containing 50 pL ofa 3-fold serial dilution of test compounds in RPMI medium. After 5 days of incubation at 37°C in a humidified incubator in the presence of 5% CO₂,100 pL of Cell Titer-Glo™ Reagent (Promega Biosciences, Inc., Madison, WI) was added to each well and the relative light units (RLU) measured on an Envision plate reader. The virus-induced cytopathic effect was determined as a percentage of the RLU measurements from samples with fully suppressed virus réplication after subtracting the signa! from untreated (DMSO) controls. The EC50 value was defined as the compound concentration inducing a 50% decrease in virus réplication. Data analysis for the antiviral activity observed in MT-2 cells was performed using XL-fït™ software (IDBS, Guildford, Surrey, UK) to calculate ECso from an 8-poînt dose-response curve using the following équation:

172

-_Λ/ (Μ-Η)χΕ^ (EC^+x) wherey = virus inhibition, x = drug concentration, M = maximum inhibition, H= minimum inhibition and n = HilI coefficient ECso values (mean ± standard déviation) were calculated from at least three independent experiments performed in triplicate. The level of résistance was calculated as a ratio ofthe mean EC» for each mutant/WT virus. Results are disclosed in Figure 1 and in Tables 3 and 4 below.

Table 3	Biology résistance pancl-low throughput fold change (1-C)
Compound	KI03N	YI81C	1.1001/ Y181C	K103N/ Y181C	Y1881.	GI90A	E138K/ M184V
1	13	5.7	69	148	152	06	ND
2	09	40	1 6	4 1	100	1.6	50
3	1.0	34	1 0	3.4	13.7	ND	ND
4	1 4	49	54	12 8	169	ND	ND
5	16	15 4	189	208 0	174 0	ND	ND
9	1 0	5.7	40	14 7	11.4	ND	ND
10	09	11.9	38	19 9	53 6	ND	ND
II	2 1	1540	85 0	157.0	161 0	ND	ND
34	1 4	34	1 7	12 4	187	ND	42

ND: not determined [0357] The résistance profile against HIV-l RT mutants was also run for nevirapine (“NPV”), rilpivtrine (“RPV”), and efavirenz (EFV”). Nevirapine was obtained from Toronto Research Chemicals, Inc. (Toronto, Canada; Catalogue#N39I275) Rilpivirîne was obtained from Key Organics Ltd (Camelford, Comwall, United Kingdom; Catalogue #KE-0036). Efavirenz was obtained from Toronto Research Chemicals, Inc. (Toronto, Canada; Catalogue #E425000). The results are shown below in Table 4.

Table 4	Biology résistance pancl-low throughput fold change (1· C)
Compound	Kl 03 N	Y181C	L1001/ Y181C	K103N/ Y181C	YI88L	G190 A	E138K/ Ml 84 V
Ncvtraptnc (NVP”)	870	>229	>229	ND	>229	183 0	ND
Rilpivtrine (RPV”)	1 0	4 6	18 1	77	22 8	08	30
Efavirenz	48 1	3 6	>200	83.5	132 5	148	ND

173

I <~ίΐ·ν·> II II II I ~

ND, not determined

Example C hERG assay

Cells:

[0358| AVIVA’s CHO cell line, which stably expresses hERG channels, was used for the study. Cells were cultured in DMEM/F12 containing 10% FBS, 1% penicillin/streptomycin and 500 pg/ml G418. Before testing, cells were harvested using Accumax (Innovative Cell Technologies)

Solutions:

[0359] For electrophysiological recordings, the following solutions were used:

Extemal Solution: 2 mM CaCh; 2 mM MgCh; 4 mM KC1; 150 mM NaCl; 10 mM Glucose; 10 mM HEPES; 305-315 mOsm; pH 7.4 (adjusted with 5M NaOH.)

Internai Solution: 140 mM KCI; 10 mM MgCh; 6 mM EGTA; 5 mM HEPES-Na; 5mM ATP-Mg; 295-305 mOsm; pH 7.25 (adjusted with IMKOH)

Electrophysiology:

[0360] Whole cell recordings were performed using PX 7000A (Axon Instruments) with AVIVA’s SealChip™ technology. Cells were voltage clamped at a holding potential of-80 mV. The hERG current was then activated by a depolarizing step to -50 mV for 300 ms. This first step at -50 mV was used as a baseline for measuring peak amplitude of the tail current. Next, a voltage step to +20 mV was applied for 5 s to activate the channels. Finally, a step back to -50 mV for 5 s removed activation and the deactivating tail current was recorded.

Test Article Handlingand Dilutions:

[0361 ] Ail test articles were prepared from 10 mM DMSO stock solutions. Solutions were mixed by sonication for 20 min, followed by vigorous vortexing. Prior to testing, compounds were diluted to test concentrations in glass vials using Extemal Solution. Dilutions were prepared no longer than 20 min prior to use.

Electrophysiology Procedures [0362] After achieving whole cell configuration, cells were monitored for 90 s to assess stability and then washed with Extemal Solution for 66 s. The voltage protocol was then

174 applied to the cells every 12 s throughout the procedure, Only stable cells with recording parameters above threshold were allowed to enter the drug addition procedure.

[0363] External solution containing 0.1% DMSO (vehicle) was applied to the cells to establish a baseline. After allowing the current to stabilize for 3 to 10 min, test articles were applied. Test article solutions were added to cells in 4 separate additions. Cells were kept in test solution until eflect of the test article reached steady state, to a maximum of 12 min. Next, 1 μΜ cisapride (positive control) was added. Finally, washout with External Solution was performed until the recovery current reached steady state.

Data Analysis [0364| Data analysis was performed using DataXpress (Axon Instruments), Clampfit (Axon Instruments) and Orîgin (OriginLab Corporation) software. Results are disclosed in Table 5. The greater than values in Table 5 indicate the maximum achievable concentration in the assay (e.g., coupounds achieving their solubility limit)

Table 5.

Compound No	hERG (μΜ)
2	>1
9	>3
10	>3
11	>3
12	>3
13	1.3
34	>3

[0365] The hERG assay was also run for rilpivirine (“RPV). The resuit was 0.5 μΜ.

|0366] The spécifie pharmacological responses observed may vary according to and depending on the particular active compound selected or whether there are présent pharmaceutical carriers, as well as the type of formulation and mode ofadministration employed, and such expected variations or différences in the results are contemplated in accordance with practice ofthe présent disclosure.

[0367] The Examples disclosed herein describe the synthesis of compounds disclosed herein as well as intermediates used to préparé the compounds. It is to be understood that

175 individual steps described herein may be combined. It is also to be understood that separate batches of a compound may be combined and then carried forth in the next synthetic step. [0368] Ail references, including publications, patents, and patent documents are incorporated by reference herein, as though individually incorporated by reference. The présent disclosure provides reference to various embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope ofthe présent disclosure.

Claims

What is claimed is:

1.

A compound of formula (I):

R⁴

R⁵R³

R^e

R⁷

I,

R² (I) wherein

X¹, X², and X³ are each independently N or C(R^U), provided that, at most 2 ofX¹, X², and X³ are N;

R¹ is -H, -CN, -OR*. -C(O)OR*, halogen, Ci-ealkyl, Cî-iocycloalkyl, or Ci ^heteroalkyl, wherein each Ci^alkyl, Cî-iocycloalkyl, and Ci-ôheteroalkyl is optionally substituted with 1,2,3, 4, or 5 R¹² groups, which may be same or different;

R² is -H, -CN, -OR*, -NR*R^b, -C(O)OR*, halogen, Ci^alkyl, Cwocycloalkyl, or Ci-6 heteroalkyl, wherein each Ci-&alkyl, Cs-tocycloalkyl, and Cusheteroalky! is optionally substituted with !, 2,3,4, or 5 R¹² groups, which may be same or different;

R³ is -H, -OR*, -SR*, -NR*R^b, -NHC(O)NR*R^b, Ci^lkyl, Cî-iocycloalkyl, or Ci-6 heteroalkyl, wherein each Ci^Ikyl, Cj-mcycloalkyl, and Ci-eheteroalkyl is optionally substituted with 1,2,3,4, or 5 R¹² groups, which may be same or different;

R⁴ is -H, -OR*, halogen, -NO2, -CN, -NR*R^b, -NHC(O)NR*R^b, -OC(O)NR*R^b, CH2C(O)NR*R^b, Ci^alkyl, Cs-iocycloalkyl, or Ci-6 heteroalkyl, wherein each Ci^alkyl, C3. locycloalkyl, and Ci-6heteroalkyl is optionally substituted with 1,2, 3,4, or 5 R¹² groups, which may be same or different;

-46+18583

R⁵ is -H, -OR*, halogen, -NO₂, -CN, -NR*R^b, -NHC(O)NR’R^b, -OC(O)NR*R^b, CH2C(O)NR*R^b, Ci-6alkyl, Cî-iocycloalkyl, or Cm heteroalkyl, wherein each Ci^alkyl, C3locycloalkyl, and CMheteroalkyl is optionally substituted with 1,2,3,4, or 5 R¹² groups, which may be same or different;

R⁶ is -H, -OR*, halogen, -NO2, -CN, -NR’R^b, -NHC(O)NR’R^b, -OC(O)NR^,R^b, CH2C(0)NR*R^b, CMalkyl, C3-iocycloalkyl, or Cm heteroalkyl, wherein each CMalkyl, C3locycloalkyl, and CMheteroalkyl is optionally substituted with 1,2,3,4, or 5 R¹² groups, which may be same or different;

R⁷ is Ci-ealkyl, C3-iocycloalkyl, Ci-eheteroalkyl, halogen,-OR*. -CN, ΟΓ-ΝΟ2, wherein each Cj-éalkyl, Cs-iocycloalkyl,and CMheteroalkyl is optionally substituted with 1,2,3,4, or 5 R¹² groups, which may be same or different;

R⁸ is Cr-ealkyl, C3-iocycloalkyl, CMheteroalkyl, halogen, -OR*, -CN, or -NO2, wherein each Cj-éalkyl, Cs-jocycloalkyl, and Cm heteroalkyl is optionally substituted with 1,2,3,4, or 5 R¹² groups, which may be same or different;

R⁹ is -H, CMalkyl, or C3-iocycloalkyl, wherein each Ci-6alkyl and Cs-tocycloalkyl is optionally substituted with 1,2,3,4, or 5 R¹² groups, which may be same or different;

R¹⁰ is -H, Cj-6alkyl, or C3-iocycloalkyl, wherein each CMalkyl and C3-iocycloalkyl is optionally substituted with 1,2,3,4, or 5 R¹² groups, which may be same or different;

each R¹¹ is independently -H, -CN, -OR*, -C(O)OR*, halogen, Cj-6alkyl, Cs-iocycloalkyl, or CMheteroalkyl, which may be same or different, wherein each CMalkyl, Cj-iocycloalkyl, and CMheteroalkyl is optionally substituted with 1,2,3,4, or 5 R¹² groups, which may be same or different;

each R¹² is independently CMalkyl, Cs-iocycloalkyl, CMheteroalkyl, 5-10 membered heterocyclyl, Ce-ioaryl, 5-10 membered heteroaryl, halogen, -OR*,-C(O)R*, -C(O)OR·, — C(O)NR*R^b, -OC(O)NR*R^b, -NR*C(O)OR^b, -SR·, -S(O)i.₂R·, -S (O) 2F, -S(O)2NR*R^b, NR*S(O)2R^b, -N3, -CN, or-NO2; wherein each Ci-6alkyl, Cs-iocycloalkyl, CMheteroalkyl, and 5-10 membered heterocyclyl is optionally substituted with 1,2,3,4, or 5 substituents selected from halogen, -OR·, -C(O)R', -C(O)OR·, -C(O)NR’R^b, -OC(O)NR’R^b, -NR’C(O)OR^b, -SR*, S(O)i-2R·, -S(O)2F, -S(O)zNR*R^b, -NR*S(O)2R^b, -Nj. -CN, and -NO2, groups, which may be same or different;

164 each R* and R^b is independently -H, -NH2. Ci^alkyl, Cj-iocycloalkyl, Ci^heteroalkyl, 510 membered heterocyclyl, Ce-ioaryl, or 5-10 membered heteroaryl, wherein each Ci^alkyl, C3îocycloalkyl, Ci^heteroalkyl, 5-10 membered heterocyclyl, Ce-ioaryl, and 5-10 membered heteroaryl is optionally substituted with 1,2, 3,4, or 5 R¹³ groups, which may be same or different; or R* and R^b together with the atoms to which they are attached form a 5-10 membered heterocycle; and each R¹³ is independently-CN, halogen, Ci^alkyl, Cj-iocycloalkyl, Ci^heteroalkyl, or 510 membered heterocyclyl, or a tautomer or a pharmaceutically acceptable sait thereof.
2. The compound of claim 1, or a tautomer or a pharmaceutically acceptable sait thereof, wherein R² is -H, -CN, -OR*, or Ci-ealkyl.
3. The compound of daims 1 or 2, or a tautomer or a pharmaceutically acceptable sait thereof, wherein R² is -CN.
4.

A compound of formula (II):

wherein

Q is

X¹, X², and X³ are each independently N or C(Rⁿ), provided that, at most2 ofX¹, X², and X³ are N;

R* is -H, -CN, -OR*, -C(O)OR*, halogen, or Ct-ealkyl, wherein Ci^alkyl is optionally substituted with 1,2,3,4, or 5 R¹² groups, which may be same or different;

165

R³ is -H, -OR*, -NR*R^b, -NHC(O)NR*R^b, C^lkyl, or Ci^heteroalkyl, wherein each C_b«alkyl and Ci^heteroalkyl is optionally substituted with 1,2,3,4, or 5 R¹¹ groups, which may be same or different;

R⁴ ts -H, -OR*, halogen, -NO2, -CN, -NR*R^b, Ci-calkyl, or Cm heteroalkyl, wherein each Ci^alkyl and Cm heteroalkyl is optionally substituted with 1,2,3,4, or 5 R¹² groups, which may be same or different;

R³ is -H, -OR*, halogen, -NO2, -CN, -NR*R^b, Ci^alkyl, or Cm heteroalkyl, wherein each Ci^alkyl and Cm heteroalkyl is optionally substituted with 1,2,3,4, or 5 R¹² groups, which may be same or different;

R⁶ is -H, -OR*, halogen, -NO2, -CN, -NR*R^b, Ci^alkyl, or Cm heteroalkyl, wherein each Ci^alkyl and Cm heteroalkyl is optionally substituted with 1,2,3,4, or 5 R¹² groups, which may be same or different;

R⁷ is Ci^alkyl, Ci-cheteroalkyl, halogen,-OR*, -CN, or-NO2, wherein each Ci^alkyl is optionally substituted with 1,2,3,4, or 5 R¹² groups, which may be same or different;

R⁸ is Ci^alkyl, Ci-éheteroalkyl, halogen,-OR*,-CN, or-NO2, wherein each CMalkyl is optionally substituted with 1,2,3,4, or 5 R¹² groups, which may be same or different;

R⁹ is -H or Ci-«alkyl, wherein Ci^alkyl is optionally substituted with 1, 2, 3,4, or 5 R¹²groups, which may be same or different;

R¹⁰ is -H or Ci-6alkyl wherein Ci-eal ky 1 is optionally substituted with 1,2,3,4, or 5 R¹²groups, which may be same or different;

each R¹¹ is independently -H, -CN, -OR’, -C(O)OR*, halogen, or Ci^alkyl, which may be same or different, wherein CMalkyl is optionally substituted with 1,2,3,4, or 5 R’² groups, which may be same or different;

each R¹² is independently Ci-talky 1, Cî-iocycloalkyl, CMheteroalkyl, 5-10 membered heterocyclyl, Ce-ioaryl, 5-10 membered heteroaryl, halogen, -OR*. -C(O)R*, -C(O)OR*, C(0)NR*R^b, -OC(O)NR*R^b, -NR*C(0)0R^b, -SR*. -S(O)i .2R·, -StOJzF, -S(O)2NR*R^b, NR*S(O)2R^b, -Nî, -CN, or-NÛ2; wherein each Cj^alkyl, Cj-iocycloalkyl, Cj^heteroalkyl, and 5-10 membered heterocyclyl is optionally substituted with 1,2,3,4, or 5 substituents selected from halogen, -OR*, -C(0)R*. -C(O)OR‘, -C(0)NR‘R^b, -OC(O)NR*R^b, -NR*C(0)0R^b, -SR*, S(O)i.2R*. -S(O)2F, -S(O)2NR*R^b, -NR*S(O)2R^b, -Na, -CN, and -NO2, groups, which may be same or different;

166 each R’ and R^b is independently -H, Ci-calkyl, Cî-iocycloalkyl, Ci^heteroalkyl, 5-10 membered heterocyclyl, Ce-ioaryl, or 5-10 membered heteroaryl, wherein each Ci^alkyl, C3. îocycloalkyl, Ci^heteroalkyl, 5-10 membered heterocyclyl, Ce-ioaryl, and 5-10 membered heteroaryl is optionally substituted with 1,2,3,4, or 5 R¹³ groups, which may be same or different; or R* and R^b together with the atoms to which they are attached form a 5-10 membered heterocycle; and each R¹³ is independently -CN, halogen, Ci^alkyl, Cî-iocycloalkyl, Ci-ôheteroalkyl, or 510 membered heterocyclyl, or a tautomer or a pharmaceutically acceptable sait thereof.
5. The compound of any of claims 1 -4, or a tautomer or a pharmaceutically acceptable sait thereof, wherein Q is N .
6. The compound of claims 1 -4, or a tautomer or a pharmaceutically acceptable sait thereof, wherein Q is R¹⁰ .
7. The compound of any of claims 1-6, or a tautomer or a pharmaceutically acceptable sait thereof, wherein X¹, X², and X³ are each CH.
8. The compound of any of claims 1 -6, or a tautomer or a pharmaceutically acceptable sait thereof, wherein X’ is N; X² is CH; and X³ is CH.
9. The compound of any of claims 1 -6, or a tautomer or a pharmaceutically acceptable sait thereof, wherein X¹, X¹, and X³ are C(R¹¹); each R*¹ are independently selected from -H, -CN, -OR*, halogen, and Ci^alkyI; and R¹ is selected from -H, -CN, -OR*, halogen, and Ci^alkyl.
10. The compound of any of claims 1 -6, or a tautomer or a pharmaceutically acceptable sait thereof, wherein X’, X¹, and X³ are C(R¹¹); each R¹¹ are -H; and R¹ is -H.
11. The compound of any of claims 1 -10, or a tautomer or a pharmaceutically acceptable sait thereof, wherein R³ is -H, -OR‘, -NR*R^b, -NHC(0)NR*R^b, Ci^alkyl, or Ci-e heteroalkyl.
12. The compound of any of claims 1-11, or a tautomer or a pharmaceutically acceptable sait thereof, wherein R³ is -H, -OR*, -NR’R^b, or -NHC(O)NRR^b.

167
13. The compound ofany ofdaims 1-12, ora tautomerora pharmaceutically acceptable sait thereof, wherein R³ is -NH₂ or -OH.
14. The compound of any of daims 1-12, ora tautomerora pharmaceutically acceptable sait thereof, wherein R³ is -NH₂.
15. Thecompound ofany ofdaims 1-12, ora tautomerora pharmaceutically acceptable sait thereof, wherein R³ is -OH.
16. The compound of any of daims 1-15, ora tautomerora pharmaceutically acceptable sait thereof, wherein R⁴ is -H, -OR, halogen, -NO₂, -CN, -NR*R^b, -NHC(O)NR’R^b, or Ci^alkyl.
17. The compound of any of daims 1-16, ora tautomerora pharmaceutically acceptable sait thereof, wherein R^J is -H, -OR, halogen, -NO₂, -CN, -NR*R^b, -NHC(O)NR*R^b, or Ct-ôalkyl.
18. The compound of any of daims 1-17, or a tautomerora pharmaceutically acceptable sait thereof, wherein R^s is -H, -OR*, halogen, -NO₂, -CN, -NR*R^b, -NHC(O)NR*R^b, or Ci-ealkyl.
19. The compound of any of daims 1 -18, or a tautomer or a pharmaceutically acceptable sait thereof, wherein two of R⁴, R^J, and R⁶ are -H and one of R⁴, R⁵, and R⁶ is -H, OR*, halogen, -NO₂, -CN, -NR*R^b, -NHC(O)NR*R^b, or Ci^alky 1.
20. The compound of any of daims 1-18, or a tautomer or a pharmaceutically acceptable sait thereof, wherein two of R⁴, R³, and R⁶ are -H and one of R⁴, R³, and R⁶ is -H, — OR*, halogen,-NO₂, -NR'R^b, or Ci-ealkyl.
21. The compound of any of daims 1 -20, or a tautomer or a pharmaceutically acceptable sait thereof, wherein R⁶ is -H.
22. The compound of any of daims 1-21, or a tautomer or a pharmaceutically acceptable sait thereof, wherein R⁴, R³, and R^s are -H.
23. The compound of any of daims 1-22, or a tautomer ora pharmaceutically acceptable sait thereof, wherein R⁷ is Ci^alkyl, Ci-eheteroalkyl, halogen, -OR*. -CN, or -NO₂.
24. The compound of any of daims 1 -23, or a tautomer or a pharmaceutical ly acceptable sait thereof, wherein R* is Cusalkyl, Ci-eheteroalkyl, halogen, -OR*, -CN, or -NO₂.

168
25. The compound of any of claims 1 -24, or a tautomer or a pharmaceutically acceptable sait thereof, wherein R⁷ and R* are the same and are selected from Ci^alkyl, Ci. eheteroalkyl, halogen, -OR*, -CN, and -NO₂.
26. The compound of any of claims 1 -25, or a tautomer or a pharmaceutically acceptable sait thereof, wherein R⁷ and R⁸ are the same and are selected from Ci^alkyl, halogen, and -OR*.
27. The compound of any of claims 1 -26, or a tautomer or a pharmaceutically acceptable sait thereof, wherein R⁷ and R⁸ are Ci-éalkyl.
28. The compound of any of claims 1 -27, or a tautomer or a pharmaceutically acceptable sait thereof, wherein R⁷ and R⁸ are methyl.
29. The compound of any of claims 1 -28, or a tautomer or a pharmaceutically acceptable sait thereof, wherein R⁹ is -H or Ci-aalkyl.
30. The compound of any of claims 1 -29, or a tautomer or a pharmaceutically acceptable sait thereof, wherein R¹⁰ is -H or Ci-calkyl.
31. The compound of any of claims 1-30, or a tautomer or a pharmaceutically acceptable sait thereof, wherein R⁹ is -H or Ci^alkyl; and R¹⁰ is -H or Ci-*alkyl.
32. The compound of any of claims 1 -31, or a tautomer or a pharmaceutically acceptable sait thereof, wherein R⁹ and R¹⁰ are -H,
33. The compound of any of claims 1-31, or a tautomer or a pharmaceutically acceptable saitthereof, Q is selected from N, N , ,and N.
34. The compound of any of claims 1 -33, or a tautomer or a pharmaceutically acceptable sait thereof, wherein Q is N.
35. A compound selected from the group consisting of:

Structure

Compound ID

169

170

171

172

173

174

175

176

177

178

179 or a tautomer or a pharmaceutically acceptable sait thereof.
37. A compound of formula:

N or N or a tautomer or a pharmaceutically acceptable sait thereof.
38. A compound of formula:

180 or a tautomer or a pharmaceutically acceptable sait thereof.
39. A pharmaceutical composition comprising a compound of any of daims 1 -38, or a tautomer or a pharmaceutically acceptable sait thereof, and a pharmaceutically acceptable carrier.
40. The pharmaceutical composition of claim 39, further comprising at least one or more additional therapeutic agent.
41. The pharmaceutical composition of daim 40, wherein the at least one or more additional therapeutic agent is selected from the group consisting of HIV protease inhibiting compounds, HTV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HTV nucléotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gpl 20 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, and other drugs for treating HIV, and combinations thereof.
42. A kit comprising a compound of any of daims 1-38, or a tautomer or a pharmaceutically acceptable sait thereof.
43. An article of manufacture comprising a unit dosage of a compound ofany of daims 1 -38 or a tautomer or a pharmaceutically acceptable sait thereof
44. A compound ofany of daims 1 -38, or a tautomer or a pharmaceutically acceptable sait thereof, for use in inhibiting a reverse transcriptase in a subject in need thereof
45. A compound ofany of claims 1-38, or a tautomer or a pharmaceutically acceptable sait thereof, for use in treating or preventing an HIV infection in a subject.
46. A compound ofany of claims 1-38, or a tautomer or a pharmaceutically acceptable sait thereof, for use in treating or preventing an HIV infection in a subject, in combination with a therapeutically effective amount of one or more additional therapeutic agents

181 selected from the group consisting ofHIV protease inhibiting compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucléotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gpl20 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, and other drugs for treating or preventing HIV, and combinations thereof.
47. A compound of any of daims 1-38, or a tautomer or a pharmaceutically acceptable sait thereof, for use in medical therapy.
48. A compound ofany of daims 1-38, or a tautomer or a pharmaceutically acceptable sait thereof, for use in treating or preventing an HIV virus infection in a subject.
49. Use of a compound of any of daims 1 -38, or a tautomer or a pharmaceutically acceptable sait thereof, for the manufacture of a médicament for treating or preventing an HIV virus infection in a subject.
50. Use of a compound of any of daims 1 -38, or a tautomer or a pharmaceutically acceptable sait thereof, for the manufacture ofa médicament for inhibiting HIV reverse transcriptase in a subject.
51. Use of a compound of any of daims 1 -38, or a tautomer or a pharmaceutically acceptable sait thereof, for the manufacture of a médicament for inhibiting HIV reverse transcriptase in vitro.