EA040107B1 - QUINAZOLINE DERIVATIVES USED FOR THE TREATMENT OF HIV - Google Patents

Description

and their tautomers, pharmaceutically acceptable salts, compositions and dosage forms containing such compounds, and methods of using and obtaining such compounds.

Cross-reference to related applications

This application claims priority from U.S. Provisional Application Serial No. 62/096,748, filed December 24, 2014, the contents of which are hereby incorporated by reference in their entirety.

State of the art

Although some progress has been made in the treatment of HIV and AIDS, HIV infection remains a global public health problem. Non-nucleoside reverse transcriptase inhibitors (NNRTIs, NNRTIs) are often used as part of this treatment, particularly in highly active antiretroviral therapy (HAART, HAART) regimens. HIV mutations that can lead to drug resistance.Accordingly, there is a need for further development of effective NNRTIs.Compounds of formula (I) and their pharmaceutically acceptable salts, compositions and dosage forms containing such compounds or their pharmaceutically acceptable salts, and methods of using and preparing such compounds or their pharmaceutically acceptable salts.

Short description

In some embodiments, the present description refers to compounds of formula (I) or a tautomer of such a compound,

where pYu I ill ^R9 \

Q is ^{N or R} >

X ¹ , X ² and X ³ are each independently N or C(R11), provided that at most 2 of X ¹ , X ² and X ³ are N,

R ¹ is -H, -CN, -OR ^a , -C(O)OR ^a , halogen, C ₁ . ₆ alkyl, C ₃ . ₁₀ cycloalkyl or C _1-6 heteroalkyl, each C1. ₆ alkyl, C ₃ . ₁₀ cycloalkyl and C ₁ . ₆ heteroalkyl optionally substituted with 1, 2, 3, 4 or 5 R ¹² groups, which may be the same or different,

R ² is -H, -CN, -OR ^a , -NR ^a R ^b , -C(O)OR ^a , halogen, C1. ₆ alkyl, C ₃ . ₁₀ cycloalkyl or C ₁ . ₆ heteroalkyl, each C1. ₆ alkyl, C ₃ . ₁₀ cycloalkyl and C1. ₆ heteroalkyl optionally substituted with 1, 2, 3, 4 or 5 R ¹² groups, which may be the same or different,

R ³ is -H, -OR ^a , -SR ^a , -NR ^a R ^b , -NHC(O)NR ^a R ^b , C1. ₆ alkyl, C ₃ . ₁₀ cycloalkyl or C1. ₆ heteroalkyl, each C1. ₆ alkyl, C ₃ . ₁₀ cycloalkyl and C1. ₆ heteroalkyl optionally substituted with 1, 2, 3, 4 or 5 R ¹² groups, which may be the same or different,

R ⁴ is -H, -OR ^a , halogen, -NO2, -CN, -NR ^a R ^b , -NHC(O)NR ^a R ^b , -OC(O)NR ^a R ^b , -CH2C(O) NR ^a R ^b , C1. ₆ alkyl, C ₃ . ₁₀ cycloalkyl or C1. ₆ heteroalkyl, each C1. ₆ alkyl, C ₃ . ₁₀ cycloalkyl and C1. ₆ heteroalkyl optionally substituted with 1, 2, 3, 4 or 5 R ¹² groups, which may be the same or different,

R ⁵ is -H, -OR ^a , halogen, -NO2, -CN, -NR ^a R ^b , -NHC(O)NR ^a R ^b , -OC(O)NR ^a R ^b , -CH2C(O) NR ^a R ^b , C1. ₆ alkyl, C ₃ . ₁₀ cycloalkyl or C1. ₆ heteroalkyl, each C1. ₆ alkyl, C ₃ . ₁₀ cycloalkyl and C1. ₆ heteroalkyl optionally substituted with 1, 2, 3, 4 or 5 R ¹² groups, which may be the same or different,

R ⁶ is -H, -OR ^a , halogen, -NO2, -CN, -NR ^a R ^b , -NHC(O)NR ^a R ^b , -OC(O)NR ^a R ^b , -CH2C(O) NR ^a R ^b , C1. ₆ alkyl, C ₃ . ₁₀ cycloalkyl or C1. ₆ heteroalkyl, each C1. ₆ alkyl, C ₃ . ₁₀ cycloalkyl and C1. ₆ heteroalkyl optionally substituted with 1, 2, 3, 4 or 5 R ¹² groups, which may be the same or different,

R ⁷ is C1.6alkyl, C3.10cycloalkyl, C1.6heteroalkyl, halogen, -OR ^a , -CN or -NO2, each C1.6alkyl, _C3 . ₁₀ cycloalkyl and C1. ₆ heteroalkyl optionally substituted with 1, 2, 3, 4 or 5 R ¹² groups, which may be the same or different,

R ⁸ is C1.6alkyl, C3.10cycloalkyl, C1.6heteroalkyl, halogen, -OR ^a , -CN or -NO2, each C1.6alkyl, _C3 . ₁₀ cycloalkyl and C1. ₆ heteroalkyl optionally substituted with 1, 2, 3, 4 or 5 R ¹² groups, which may be the same or different,

R ⁹ is -H, C1. ₆ alkyl or C ₃ . ₁₀ cycloalkyl, each C1. ₆ alkyl and C ₃ . ₁₀ cycloalkyl optionally substituted with 1, 2, 3, 4 or 5 R ¹² groups which may be

- 1 040107 identical or different,

R ¹⁰ is -H, C _1-6 alkyl or C ₃ .l ₀ cycloalkyl, each C _1-6 alkyl and C _3-10 cycloalkyl optionally substituted with 1, 2, 3, 4 or 5 R ¹² groups , which may be the same or different, each R ¹¹ independently represents -H, -CN, -OR ^a , -C(O)OR ^a , halogen, C ₁ . ₆ αkyl, C ₃ . ₁₀ cycloalkyl or ^^heteroalkyl, which may be the same or different, each C ₁ .6 alkyl, C ₃ . ₁₀ cycloalkyl and C ₁ . ₆ heteroalkyl optionally substituted with 1, 2, 3, 4 or 5 R ¹² groups, which may be the same or different, each R ¹² is independently C1.6 alkyl, C3.10 cycloalkyl, C1.6 heteroalkyl, 5-10 membered heterocyclyl, C6.10aryl, 5-10 membered heteroaryl, halogen, -OR ^a , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -OC(O)NR ^a R ^b , -NR ^a C(O)OR ^b , -SR ^a , -S(O)1-2R ^a , -S(O)2F, -S(O)2NR ^a R ^b , -NR ^a S(O )2R ^b , -N3, -CN or -NO2, each C1.6alkyl, C3.10cycloalkyl, C1.6heteroalkyl and 5-10 membered heterocyclyl optionally having 1, 2, 3, 4 or 5 substituents selected from the following groups : halogen, -OR ^a , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -OC(O)NR ^a R ^b , -NR ^a C(O) OR ^b , -SR ^a , -S(O)1-2R ^a , -S(O)2F, -S(O)2NR ^a R ^b , -NR ^a S(O)2R ^b , -N3, -CN, and -NO ₂ , which may be the same or different, each R ^a and R ^b independently represents -H, -NH2, C ₁ . ₆ αkyl, C ₃ . ₁₀ cycloalkyl, C ₁ . ₆ heteroalkyl, 5-10 membered heterocyclyl, C ₆ . ₁₀ aryl or 5-10 membered heteroaryl, each C ₁ . ₆ alkyl, C ₃ . ₁₀ cycloalkyl, C ₁ . ₆ heteroalkyl, 5-10 membered heterocyclyl, C ₆ . ₁₀ aryl and 5-10 membered heteroaryl optionally substituted as substituents 1, 2, 3, 4 or 5 R ¹³ groups, which may be the same or different, or R ^a and R ^b together with the atom to which they are attached form 5-10 membered heterocycle, and each R ¹³ is independently -CN, halogen, C ₁ .6αkyl, C ₃ . ₁₀ cycloalkyl, C ₁ .6 heteroalkyl or 5-10 membered heterocyclyl, or pharmaceutically acceptable salts thereof.

In some embodiments, the present disclosure relates to a pharmaceutical composition containing a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In some embodiments, the present disclosure relates to a product containing a dosage unit of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In some embodiments, the present 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 salt thereof to the subject.

In some embodiments, the present disclosure relates to a method of treating or preventing HIV infection in a subject in need thereof, comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt thereof.

In some embodiments, the present disclosure relates to a method for treating or preventing HIV infection in a subject, comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is at risk of becoming infected with HIV, as in the case of a subject having one or more known risk factors associated with infection with the HIV virus.

In some embodiments, the present disclosure relates to a method of treating or preventing HIV infection in a subject in need thereof, comprising administering to the subject a compound of formula (I), or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents. In some embodiments, the present disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in medical therapy.

In some embodiments, the present disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of HIV infection in a subject. In some embodiments, the present disclosure relates to the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of HIV infection in a subject.

Additional embodiments of the present disclosure are described herein.

Brief description of the drawings

The figure shows the results of a resistance profile study against HIV-1 reverse transcriptase mutants (HIV-1 RT, HIV-1 RT) for some compounds.

Detailed description

The following description is written with the understanding that the present disclosure is to be considered as an example of the claimed subject matter and is not intended to limit the accompanying claims to the specific illustrative embodiments. The headings used in this specification are for convenience only and should not be construed as limiting the claims in any way. Implementations given after any heading may be combined with implementations given after any other heading.

- 2 040107 dexterity.

Unless otherwise indicated, all technical and scientific terms used in the present description have the meaning usually given to them by one of ordinary skill in the art. A dash at the beginning or end of a chemical group is used to conveniently indicate the point of attachment to the parent molecule, chemical groups can be shown with or without one or more dashes without losing their usual meaning. A wavy line drawn through a line in a chemical structure indicates the point of attachment of the group. A dotted line in a chemical structure indicates an optional bond. A prefix such as C _u - _v or (C _u - C _v ) indicates that the next group contains u to v carbon atoms. For example, C _1-6 alkyl means that the alkyl group contains from 1 to 6 carbon atoms.

When trade names are used herein, they are meant to independently include the product of that trade name and the active pharmaceutical ingredient(s) of the product of that trade name.

In this document and in the accompanying claims, the singular forms include the plural of the same term, unless the context clearly requires otherwise. Accordingly, for example, an indication of a compound includes a plurality of such compounds, and an indication of an assay includes an indication of one or more assays, and so on.

Alkyl as used herein is a linear or branched monovalent hydrocarbon. For example, an alkyl group may contain 1 to 20 carbon atoms (i.e. (C _1-20 )alkyl), or an alkyl group may contain 1 to 10 carbon atoms (i.e. (C _{1_10} )alkyl), or the alkyl group may contain from 1 to 8 carbon atoms (i.e. (C ₁ - ₈ )alkyl), or from 1 to 6 carbon atoms (i.e. (C _1-6 alkyl), or from 1 to 4 atoms carbon (i.e. (C _1-4 )alkyl) Examples of alkyl groups include, but are not limited to: methyl (Me, -CH ₃ ), ethyl (Et, -CH2CH3), 1-propyl (n-Pr , n-propyl, -CH ₂ CH ₂ CH ₃ ), 2-propyl (i-Pr, isopropyl, -CH (CH ₃ ) ₂ ), 1-butyl (n-Bu, n-butyl, -CH ₂ CH ₂ CH ₂ CH ₃ ), 2-methyl1-propyl (i-Bu, isobutyl, -CH ₂ CH (CH ₃ ) ₂ ), 2-butyl (s-Bu, sec-butyl, -CH (CH ₃ )CH ₂ CH ₃ ), 2-methyl-2-propyl (t-Bu, tert-butyl, -C (CH 3 ) _{3 )} , 1-pentyl (n-pentyl, -CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2 -pentyl (-CH (CH ₃ )CH ₂ CH ₂ CH ₃ ), 3-pentyl (-CH (CH ₂ CH ₃ ) ₂ ), 2-methyl-2-butyl (-C (CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butyl (-CH (CH ₃ )CH (CH ₃ ) ₂ ), 3methyl-1-butyl (-CH ₂ CH ₂ CH (CH ₃ ) ₂ ), 2-methyl-1-butyl (-CH ₂ CH (CH ₃ )CH ₂ CH ₃ ), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3) , 3-hexyl (-CH(CH2CH ₃ )(CH2CH2CH ₃ )), 2methyl-2-pentyl (-C(CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ), 3-methyl-2-pentyl (-CH(CH ₃ ) CH (CH ₃ ) CH ₂ CH ₃ ), 4-methyl-2-pentyl (-CH ( _CH 3 ) CH ₂ CH (CH ₃ ) ₂ ), 3-methyl-3-pentyl (-C (Ch ₃ )(cH ₂ CH ₃ ) ₂ ), 2-methyl-3-pentyl (-CH(CH ₂ CH ₃ )CH(CH ₃ ) ₂ ), 2,3-dimethyl-2-butyl (-C(CH ₃ ) ₂ CH( _CH 3 ) ₂ ), 3,3-dimethyl-2-butyl (-CH(CH ₃ )C(CH ₃ ) ₃ and octyl (-(CH ₂ ) ₇ CH ₃ ).

The term aryl as used herein refers to a single all-carbon ring or a system of multiple all-carbon rings, where at least one of the rings is aromatic. For example, in some embodiments, the aryl group has 6 to 20 ring carbons, 6 to 14 ring carbons, or 6 to 12 ring carbons. Aryl includes a phenyl radical. Aryl also includes multiple fused ring systems (e.g., ring systems containing 2, 3, or 4 rings) containing from about 9 to 20 carbon atoms, in which at least one ring is aromatic and the other rings may be aromatic or non-aromatic (i.e. carbocycles). Such multiple fused ring systems are optionally substituted with one or more (eg, 1, 2, or 3) oxo groups on any carbocyclic moiety of the multiple fused ring system. The rings of a system of several fused rings can be connected to each other by conjugated, spiro- and bridging bonds, where this is permissible from the point of view of valency requirements. It should also be understood that when a specific (range of atoms)-membered aryl (eg, 6-12 membered aryl) is mentioned, said atomic range refers to the total number of ring atoms(s) in said aryl. For example, a 6-membered aryl would include phenyl, and a 10-membered aryl would include naphthyl and 1,2,3,4-tetrahydronaphthyl. Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4tetrahydronaphthyl, anthracenyl, and the like.

Arylalkyl refers to an alkyl radical as defined herein in which one of the hydrogen atoms associated with a carbon atom is replaced by an aryl radical as described herein (ie, an aryl-alkyl moiety). The arylalkyl alkyl group includes alkyl groups which contain from 1 to 6 carbon atoms (ie, aryl(C1-C ₆ )alkyl). Arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 1-phenylpropan-1-yl, naphthylmethyl, 2-naphthylethane-1-yl, and the like.

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

Boronic acid ester refers to an ester derivative of a compound containing a boronic acid group. Suitable ester derivatives of boronic acids include compounds of the formula -B(OR) ₂ where each R is independently alkyl, aryl, arylalkyl, heteroalkyl or heteroaryl. In addition, the two R groups in -B(OR) ₂ can be connected to form 3 040107

by naming a cyclic ether, for example, having the structure ^{0 R} , each R being the same as the others or different. Examples of boronic acid esters include boronic acid pinacol ester and boronic acid catechol ester.

Cycloalkyl refers to a single saturated or partially unsaturated all-carbon ring containing 3 to 20 carbons per ring (i.e. C ₃ -C ₂₀ cycloalkyl), e.g. 3 to 12 ring atoms, e.g. 3 to 10 ring atoms. The term cycloalkyl also includes systems of multiple fused, saturated, and partially unsaturated all-carbon rings (eg, ring systems containing 2, 3, or 4 carbocyclic rings). Accordingly, cycloalkyl includes polycyclic carbocycles, such as bicyclic carbocycles (e.g., bicyclic carbocycles containing from about 6 to about 12 carbon atoms in the ring, such as bicyclo[3.1.0]hexane and bicyclo[2.1.1]hexane) , and polycyclic carbocycles (eg, tricyclic and tetracyclic carbocycles containing up to about 20 ring carbon atoms). Rings of a system of several condensed rings can be connected to each other by conjugated, spiro- and bridging bonds, if this is permissible from the point of view of the valence requirement. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2 -enyl and 1-cyclohex-3-enyl.

Halo or halogen refers to sec, chlorine, bromine, and iodine.

The term heteroalkyl as used herein refers to an alkyl as defined herein in which one or more of the carbon atoms in the alkyl is replaced by O, S, or NR ^q (or, if the carbon atom replaced is terminal, then by OH, SH, or N(R ^q )2), wherein each R ^q is independently H or (C1-C6)alkyl. For example, (C1-C8)heteroalkyl means a heteroalkyl in which one or more carbon atoms in C1-C8-alkyl are replaced by a heteroatom (for example, O, S, NR ^q , OH, SH or N(R ^q )2) which may be the same or different. Examples of heteroalkyls include, but are not limited to, methoxymethyl, ethoxymethyl, methoxy, 2-hydroxyethyl, and N,N'dimethylpropylamine. The heteroatom in a heteroalkyl may optionally be oxidized or alkylated. The heteroatom may be placed at any internal position of the heteroaryl group or at the position at which this group is attached to the rest of the molecule. Examples include, but are not limited to: -CH2OCH3, -CH2CH2NHCH3, -CH2CH2N(CH ₃ )-CH ₃ , -CH2SCH2CH3, -S(O)CH3, -CH2CH2S(O)2CH3, -CH2CH2OCH3, -CHCHN(CH3) CH3, -CH2NHOCH3 and -CH2OC(CH ₃ ) ₃ .

The term heteroaryl as used herein refers to a single heterocyclic ring that contains at least one atom other than carbon in the ring, which atom is selected from the group consisting of oxygen, nitrogen and sulfur, this term also includes systems of multiple fused rings , which contain at least one such aromatic ring, said systems of multiple fused rings being described in more detail below. Accordingly, the term includes single aromatic rings containing from about 1 to 6 ring carbon atoms and about 1 to 4 ring heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring. The sulfur and nitrogen atoms may also be present in oxidized form, provided that the ring is aromatic. Such rings include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl, or furyl. The term also includes multiple fused ring systems (e.g., ring systems containing 2, 3, or 4 rings) where a heteroaryl group as defined above can be fused to one or more rings selected from heteroaryls (to form, for example, naphthyridinyl , such as 1,8-naphthyridinyl), heterocycloalkyls (to form, for example, 1,2,3,4-tetrahydronaphthyridinyl, such as 1,2,3,4tetrahydro-1,8-naphthyridinyl), cycloalkyls (to form, for example, 5,6,7,8-tetrahydroquinolyl) and aryls (to form, for example, indazolyl), to form a system of several fused rings. Accordingly, a heteroaryl (a single aromatic ring or a system of multiple fused rings) contains about 1-20 carbon atoms per ring and about 1-6 heteroatoms per ring. Such multiple fused ring systems may optionally be substituted with one or more (eg 1, 2, 3 or 4) oxo groups on the carbocyclic or heterocyclic portion of the fused ring. The rings of a system of several fused rings can be connected to each other by conjugated, spiro- and bridging bonds, where this is permissible from the point of view of valence requirements. It is understood that the individual rings of the system of several condensed rings can be connected to each other in any order. It should also be understood that the point of attachment of the multi-fused ring system (as defined above for heteroaryl) may be at any position of said multi-fused ring system, including the heteroaryl, heterocyclic, aryl, or carbocyclic portion of the multi-fused ring system, and at any suitable atom of a system of several fused rings, including a carbon atom and a heteroatom (for example, nitrogen). Examples of heteroaryls include, but are not limited to: pyridyl, pyrrolyl, pyrazinyl, pyrimidium

- 4 040107 nil, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8-tetrabenzohydroisoquinolinyl, benzimidazolyl and tianaphthenil.

Heterocycloalkyl or heterocyclyl as used herein refers to a single saturated or partially unsaturated non-aromatic ring or non-aromatic multi-ring system containing at least one ring heteroatom (at least one ring heteroatom selected from oxygen, nitrogen and sulfur). Unless otherwise indicated, a heterocycloalkyl group contains 5 to about 20 ring atoms, eg 5 to 14 ring atoms, eg 5 to 10 ring atoms. Accordingly, this term includes individual saturated or partially unsaturated rings (for example, 3-, 4-, 5-, 6-, or 7-membered rings) containing from about 1 to 6 carbon atoms in the ring and from about 1 to 3 heteroatoms in cycle selected from the group consisting of oxygen, nitrogen and sulfur in the ring. The term also includes individual saturated or partially unsaturated rings (e.g., 5-, 6-, 7-, 8-, 9-, or 10-membered rings) containing from about 4 to 9 carbon atoms per ring and from about 1 to 3 heteroatoms in the ring selected from the group consisting of oxygen, nitrogen and sulfur in the ring. Rings of a system of several fused rings may be connected to each other by fused, spiro- and bridging bonds, where this is permissible from the point of view of valency requirements. Heterocycloalkyl groups include, but are not limited to, azetidine, aziridine, imidazolidine, imino-oxoimidazolidine, morpholine, oxirane (epoxide), oxetane, piperazine, piperidine, pyrrazolidine, piperidine, pyrrolidine, pyrrolidinone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinuclidine , N-bromopyrrolidine, N-chloropiperidine, and the like.

Hydroxy or hydroxyl refers to the -OH group. Oxo refers to the double bonded oxygen (=O). In those compounds where the oxo group is bonded to the sp ² nitrogen atom, the N-oxide is indicated. It is understood that combinations of chemical groups may be used and that such combinations will be recognized by one skilled in the art. For example, a hydroxyalkyl group refers to a hydroxyl group attached to an alkyl group.

The terms optional or optional mean that the event or circumstance described below may or may not occur, and that the description includes cases where the event or circumstance occurs and cases where the event or circumstance does not occur. The term tautomers as used herein refers to isomers of a compound that differ from one another in proton position and/or electron distribution. Accordingly, both tautomers whose existence is due to proton migration and tautomers whose existence is due to valence changes are contemplated and described, and it should be understood that more than two tautomers may exist for a particular compound. Examples of tautomers include, but are not limited to: keto-enol tautomers:

imine-enamine tautomers:

lactam-lactim tautomers:

."lactam" "lactim"

- 5 040107 amide-imidic acid tautomers:

amino-imine tautomers:

and tautomeric forms of heteroaryl groups containing a ring atom attached to both the -NH- ring moiety and the =N- ring moiety, such as those present in pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles (see, for example, Smith, March's Advanced Organic Chemistry (5th ed.), pp. 1218-1223, Wiley-Interscience, 2001, Katritzky A., Elguero J, et al., The Tautomerism of Heterocycles, Academic Press (1976)).

Pharmaceutically acceptable refers to compounds, salts, compositions, dosage forms and other materials suitable for the preparation of a pharmaceutical composition suitable for pharmaceutical use in veterinary or human applications.

A pharmaceutically acceptable salt refers to a salt of a compound that is pharmaceutically acceptable and that possesses (or can be converted to a form that possesses) the intended pharmacological activity of the 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, mundalic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, oleic acid, palmitic acid, propionic acid, stearic acid , succinic acid, tartaric acid, ptoluenesulfonic acid, trimethylacetic acid, and the like, and salts formed when an acidic proton present in a compound is either replaced by a metal ion, such as an alkali metal ion (such as sodium or potassium), an alkaline ion metal (such as calcium or magnesium) or an aluminum ion, or coordinates with an organic base such as diethanolamine, triethanolamine, N-methylglucamine, and the like. Also included in this definition are ammonium and substituted or quaternized ammonium salts. Representative non-limiting lists of pharmaceutical salts can be found in S.M. Berge et al., J. Pharma Sci., 66(1), 1-19 (1977), and Remington: The Science and Practice of Pharmacy, R. Hendrickson, ed., 21st edition, Lippincott, Williams & Wilkins, Philadelphia, PA, (2005), at p. 732, in tab. 38-5; both of these sources are incorporated herein by reference.

Subject and Subjects refers to humans, pets (e.g., dogs and cats), farm animals (e.g., cattle, sheep, goats, and pigs), laboratory animals (e.g., mice, rats, hamsters, guinea pigs, rabbits, dogs and monkeys), etc.

As used herein, a treatment or treatment process is an approach to producing beneficial or desirable results. For purposes of this disclosure, useful or desirable results include, but are not limited to, alleviation of a symptom, and/or reduction in the severity of a symptom, and/or prevention of worsening of a symptom associated with a disease or condition. In one embodiment, the treatment or treatment process comprises one or more of the following: a) suppressing the disease or condition (e.g., reducing one or more symptoms caused by the disease or condition and/or reducing the severity of the disease or condition), b) slowing down or stopping the development of one or more symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, delaying the worsening or progression of the disease or condition), and c) alleviating the disease or condition, e.g. disease progression, improved quality of life, and/or extended survival.

- 6 040107

As used herein, delaying the development of a disease or condition means to delay, impede, slow, delay, stabilize, and/or delay the development of a disease or condition. This delay may be of varying duration depending on the history of the disease and/or the individual being treated. As is apparent to one of skill in the art, sufficient or significant delay may in practice include prevention, in which case the individual does not develop the disease or condition. For example, a method that delays the development of AIDS is a method that reduces the likelihood of developing a disease in a given time period and/or reduces the degree of the disease in a given time period, compared to a situation in which this method is not used. Such comparisons may be based on clinical studies in a significant number of subjects. For example, the development of AIDS can be detected using known methods, such as checking the HIV ⁺ status of an individual and assessing the number of T cells in the subject or other indicators of AIDS development, such as extreme fatigue, weight loss, persistent diarrhea, high fever, swollen lymph nodes on neck, armpits, or groin, or the presence of an opportunistic condition known to be associated with AIDS (eg, a condition that is not normally seen in individuals with a functioning immune system but occurs in patients with AIDS). Development can also refer to the progression of a disease, which may not be detectable at first, and includes onset, relapse, and onset.

As used herein, prevention or the process of prevention refers to a scheme that protects against the occurrence of a disease or disorder in such a way that the clinical symptoms of the disease do not develop. Accordingly, prevention refers to the application of therapy (eg, administering a therapeutic agent) to a subject prior to the onset of detectable signs of disease in the subject (eg, administering a therapeutic agent to a subject in the absence of a detectable infectious agent (eg, virus) in the subject). The subject may be an individual at risk for developing a disease or disorder, as in the case of an individual having one or more known risk factors associated with the development or occurrence of the disease or disorder. Accordingly, the term preventing HIV infection refers to administering to a subject who does not have detectable HIV infection an anti-HIV therapeutic substance. It is clear that the subject for the application of preventive therapy directed against HIV, may be an individual at risk of infection with the HIV virus. In the present text, an at-risk individual is an individual at risk of developing the disease being treated. An individual at risk may or may not have a detectable disease or condition, and the detectable disease may or may not have manifested prior to treatment with the methods described herein. At risk means that an individual has one or more so-called risk factors, which are measurable parameters that correlate with the development of a disease or condition and are known in the art. An individual with one or more of these risk factors is more likely to develop a disease or condition than an individual without (or without) that risk factor. For example, individuals at risk of developing AIDS are individuals with HIV. As used herein, the term effective amount refers to an amount that effectively provides a desired biological or medical response, including an amount of a compound that, when administered to a subject for the treatment of a disease, is sufficient to provide such treatment for the disease. The effective amount will vary depending on the compound, the disease and its severity, as well as the age, weight and other parameters of the subject being treated. An effective amount may include a range of amounts. It is understood in the art that the effective amount may be in one or more doses, i. a single dose or a number of doses may be required to achieve the desired endpoint of treatment. 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 administered in an effective amount if, in combination with one or more other agents, a desired or beneficial result can be achieved or achieved. Suitable doses of any co-administered compounds may be (optionally) reduced by the combined action (eg, additive or synergistic effects) of the compounds.

Unless expressly stated otherwise, this disclosure includes all tautomers of the compounds of the present invention described herein, even if only one tautomer is expressly indicated (e.g., reference to one tautomeric form is intended to include both tautomeric forms where a pair may exist. from two tautomeric forms). For example, when referring to a compound containing a lactam (eg, by structure or chemical name), it is understood that the corresponding lactim tautomer is also included in this disclosure and is described as if lactim were explicitly listed alone or together with lactam. Where more than two tautomers may exist, the present disclosure includes all such tautomers, even if the chemical name and/or structure reflects only one tautomer.

The compositions described herein may include a compound of the present disclosure as a racemic or non-racemic mixture of stereoisomers, or may include compounds

- 7 040107 in accordance with the present disclosure as an essentially pure isomer. Stereoisomers include enantiomers and diastereomers. Compounds can exist in stereoisomeric form if they contain one or more asymmetric centers or a double bond with an asymmetric substitution, and accordingly can be obtained as single stereoisomers or mixtures. Unless otherwise indicated, the description is intended to include individual stereoisomers as well as mixtures. Methods for determining stereochemistry and separating stereoisomers are well known in the art (see, for example, Chapter 4 of Advanced Organic Chemistry, 4e ed., J. March, John Wiley and Sons, New York, 1992).

One of skill in the art will also appreciate that this disclosure also includes any compound disclosed herein that can be enriched in any or all atoms to isotope ratios in excess of natural ones in one or more isotopes, such as, but not limited to, deuterium ( ² H or D).

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

Compounds having the specific formula described herein encompass the disclosed compound and all pharmaceutically acceptable salts, esters, stereoisomers, tautomers, prodrugs, solvates, and deuterated forms thereof, unless otherwise indicated.

Depending on the specific substituents, the compounds of formula I may exist in tautomeric forms. It is understood that for a particular compound structure, two or more tautomeric forms may exist. For example, a compound of formula I (where R ³ is —OH) may exist in at least the following tautomeric forms:

As one skilled in the art will appreciate, various other tautomeric forms may exist and are intended to be included within the scope of the compounds of formula I. Some of the descriptions herein explicitly refer to their tautomers, but it should be understood that even in the absence of such expression, tautomers are contemplated and described. Further, it is understood that the compounds of formula I may change from one tautomeric form to another or exist at different form ratios depending on the specific environment of the compound.

The compounds disclosed herein may contain chiral centers, which may be in the (R)- or ^-configuration, or which may include a mixture of them. Accordingly, the present disclosure includes stereoisomers of the compounds described herein, as appropriate, either alone or mixed in any proportion. Stereoisomers may include, but are not limited to, enantiomers, diastereomers, racemic mixtures, and combinations thereof. Such stereoisomers can be obtained and separated using conventional techniques, either by carrying out reactions of enantiomeric starting materials, or by separating isomers of the compounds of the present invention disclosed herein.

The compounds disclosed herein may be compounds of formula (I) with one or more chiral cents, which may have the (R)- or ^-configuration, or which may include a mixture of them.

The present disclosure includes both racemic mixtures of a compound of formula I and isolated isomers of formula (I) or any variant thereof. In cases where a compound disclosed herein contains more than one chiral center, some, none, or all of the chiral centers may be enantiomerically enriched. Accordingly, mixtures of a compound of formula (I) may be racemic at one or more chiral centers and/or enantiomerically enriched at one or more chiral centers. The present description relates to a compound of formula (I)

Where

Q represents

X ¹ , X ² and X ³ are each independently N or C(R ⁿ ), provided that at most 2 of X ¹ , X ² and X ³ are N,

R ¹ is -H, -CN, -OR ^a , -C(O)OR ^a , halogen, C ₁ . ₆ alkyl, C ₃ . ₁₀ cycloalkyl or

_C1 . ₆ heteroalkyl, each C ₁ . ₆ alkyl, C ₃ . ₁₀ cycloalkyl and C ₁ . ₆ heteroalkyl optionally substituted with 1, 2, 3, 4 or 5 R ¹² groups, which may be the same or different,

R ² is -H, -CN, -OR ^a , -NR ^a R ^b , -C(O)OR ^a , halogen, C ₁ . ₆ alkyl, C ₃ . ₁₀ cycloalkyl or C ₁ . ₆ heteroalkyl, each C _1-6 alkyl, C _3-10 cycloalkyl and C _1-6 heteroalkyl optionally substituted with 1, 2, 3, 4 or 5 R ¹² groups which may be the same or different,

R ³ is -H, -OR ^a , -SR ^a , -NR ^a R ^b , -NHC(O)NR ^a R ^b , C _1-6 alkyl, C _3-10 cycloalkyl or C _1-6 heteroalkyl, and each C _1-6 alkyl, C _3-10 cycloalkyl and C _1-6 heteroalkyl optionally has 1, 2, 3, 4 or 5 R ¹² groups as substituents, which may be the same or different,

R ⁴ is -H, -OR ^a , halogen, -NO2, -CN, -NR ^a R ^b , -NHC(O)NR ^a R ^b , -OC(O)NR ^a R ^b , -CH2C(O) NR ^a R ^b , C1-6 alkyl, C _3-10 cycloalkyl or C _1-6 heteroalkyl, each C _1-6 alkyl, C _3-10 cycloalkyl and C _1-6 heteroalkyl optionally having 1, 2, 3 as substituents , 4 or 5 R ¹² groups, which may be the same or different,

R ⁵ is -H, -OR ^a , halogen, -NO2, -CN, -NR ^a R ^b , -NHC(O)NR ^a R ^b , -OC(O)NR ^a R ^b , -CH2C(O) NR ^a R ^b , C 1-6 alkyl, C _3-10 cycloalkyl or C _1-6 heteroalkyl, each C _1-6 alkyl, C _3-10 cycloalkyl and C _1-6 heteroalkyl optionally having 1, 2, 3 as substituents , 4 or 5 R ¹² groups, which may be the same or different,

R ⁶ is -H, -OR ^a , halogen, -NO2, -CN, -NR ^a R ^b , -NHC(O)NR ^a R ^b , -OC(O)NR ^a R ^b , -CH2C(O) NR ^a R ^b , C 1-6 alkyl, C _3-10 cycloalkyl or C _1-6 heteroalkyl, each C _1-6 alkyl, C _3-10 cycloalkyl and C _1-6 heteroalkyl optionally having 1, 2, 3 as substituents , 4 or 5 R ¹² groups, which may be the same or different,

R ⁷ is C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 heteroalkyl, halogen, -OR ^a , -CN or -NO 2 , wherein each C _1-6 alkyl, C _3-10 cycloalkyl and C _1-6 heteroalkyl optionally contains as substituents 1, 2, 3, 4 or 5 R ¹² groups, which may be the same or different,

R ⁸ represents C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 heteroalkyl, halogen, -OR ^a , -CN or -NO 2, and each C _1-6 alkyl, C _3-10 cycloalkyl and C _1-6 heteroalkyl optionally contains in as substituents 1, 2, 3, 4 or 5 R ¹² groups, which may be the same or different,

R ⁹ is -H, C _1-6 alkyl or C _3-10 cycloalkyl, each C _1-6 alkyl and C _3-10 cycloalkyl optionally having 1, 2, 3, 4 or 5 R ¹² groups as substituents, which may be the same or different,

R ¹⁰ is —H, C _1-6 alkyl or C _3-10 cycloalkyl, each C _1-6 alkyl and C _3-10 cycloalkyl optionally having 1, 2, 3, 4 or 5 R ¹² groups as substituents, which may be the same or different, each R ¹¹ is independently -H, -CN, -OR ^a , -C(O)OR ^a , halogen, C _1-6 alkyl, C _3-10 cycloalkyl or C _1-6 heteroalkyl , which may be the same or different, with each C _1-6 alkyl, C _3-10 cycloalkyl and C _1-6 heteroalkyl optionally having 1, 2, 3, 4 or 5 R ¹² groups as substituents, which may be the same or different, each R ¹² is independently C1-6 alkyl, C3-10 cycloalkyl, C1-6 heteroalkyl, 5-10 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, halogen, -OR ^a , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -OC(O)NR ^a R ^b , -NR ^a C(O)OR ^b , -SR ^a , -S(O)1 -2R ^a , -S(O)2F, -S(O)2NR ^a R ^b , -NR ^a S(O)2R ^b , -N3, -CN or -NO2, each C1-6 alkyl, C _3-10 cycloalkyl, C _1-6 heteroalkyl and 5-10 membered hetero cyclyl optional

- 9 040107 contains 1, 2, 3, 4 or 5 substituents selected from the following groups: halogen, -OR ^a , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -OC(O)NR ^a R ^b , -NR ^a C(O)OR ^b , -SR ^a , -S(O)1-2R ^a , -S(OhF, -S(O)2NR ^a R ^b , -NR ^a S(O)2R ^b , -N ₃ , -CN and -NO ₂ which may be the same or different, each R ^a and R ^b independently represents -H, -NH ₂ ;C _{1 .6} alkyl , C _{3.10 cycloalkyl} , C _1-6 heteroalkyl, _{5-10 membered heterocyclyl, C 6.10 aryl or 5-10 membered heteroaryl, each C 1.6 alkyl} , C _3.1 ocycloalkyl, C _{1- 6} heteroalkyl, 5-10 membered heterocyclyl, C _6-10 aryl and 5-10 membered heteroaryl are optionally substituted with 1, 2, 3, 4 or 5 R ¹³ groups which may be the same or different, or R ^a and R ^b together with the atom to which they are attached form a 5-10 membered heterocycle, and each R ¹³ is independently -CN, halogen, C _1-6 alkyl, C _3-10 cycloalkyl, C _1-6 heteroalkyl, or 5-10-membered heterocyclyl, or its tautomer or pharmaceutical vticheski acceptable salt.

In some embodiments, in formula (I), R ² is -H, -CN, -OR ^a or C _1-6 αl kil.

In some embodiments, in formula (I), R ² is -CN.

In one embodiment, the present description relates to compounds of formula (II), which are compounds of formula (I)

Where

Q represents

X ¹ , X ² and X ³ are each independently N or C(R11), provided that at most 2 of X ¹ , X ² and X ³ are N,

R ¹ is -H, -CN, -ORa, -C(O)OR ^a , halogen or C _1-6 alkyl, with C _1-6 alkyl optionally substituted with 1, 2, 3, 4 or 5 groups R ¹² which may be the same or different,

R ³ is -H, -OR ^a , -NR ^a R ^b , -NHC(O)NR ^a R ^b , C _1-6 alkyl or C _1-6 heteroalkyl, each C _1-6 alkyl and C _{1- 6} heteroalkyl optionally substituted with 1, 2, 3, 4 or 5 R ¹² groups, which may be the same or different,

R ⁴ is -H, -OR ^a , halogen, -NO2, -CN, -NR ^a R ^b , C1-6 alkyl or C _1-6 heteroalkyl, each C _1-6 alkyl and C _1-6 heteroalkyl optionally containing as substituents 1, 2, 3, 4 or 5 R ¹² groups, which may be the same or different,

R ⁵ is -H, -OR ^a , halogen, -NO2, -CN, -NR ^a R ^b , C1-6 alkyl or C _1-6 heteroalkyl, each C _1-6 alkyl and C _1-6 heteroalkyl optionally containing as substituents 1, 2, 3, 4 or 5 R ¹² groups, which may be the same or different,

R ⁶ is -H, -OR ^a , halogen, -NO2, -CN, -NR ^a R ^b , C1-6 alkyl or C _1-6 heteroalkyl, each C _1-6 alkyl and C _1-6 heteroalkyl optionally containing as substituents 1, 2, 3, 4 or 5 R ¹² groups, which may be the same or different,

R ⁷ is C 1-6 alkyl, C 1-6 heteroalkyl, halogen, -OR ^a , -CN or -NO 2 , each C _1-6 alkyl is optionally substituted with 1, 2, 3, 4 or 5 R ¹² groups which may be the same or different

R ⁸ is C 1-6 alkyl, C 1-6 heteroalkyl, halogen, -OR ^a , -CN or -NO 2 , each C _1-6 alkyl is optionally substituted with 1, 2, 3, 4 or 5 R ¹² groups which may be the same or different

R ⁹ is -H or C _1-6 alkyl, with C _1-6 alkyl optionally substituted with 1, 2, 3, 4 or 5 R ¹² groups which may be the same or different,

R ¹⁰ is —H or C _1-6 alkyl, whereby C _1-6 alkyl optionally has as substituents 1, 2, 3, 4 or 5 R ¹² groups which may be the same or different, each R ¹¹ is independently -H, -CN, -OR ^a , -C(O)OR ^a , halogen or C _1-6 alkyl, which may be the same or different, with C _1-6 alkyl optionally containing as a batch

- 10 040107 bodies of 1, 2, 3, 4 or 5 R ¹² groups, which may be the same or different, each R ¹² is independently C1.6αlkyl, C3.10cycloalkyl, C1-6heteroalkyl, 5-10 membered heterocyclyl, C6-10aryl , 5-10 membered heteroaryl, halogen, -OR ^a , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -OC(O)NR ^a R ^b , -NR ^a C(O)OR ^b , -SR ^a , -S(O)1-2R ^a , -S(O)2F, -S(O)2NR ^a R ^b , -NR ^a S(O)2R ^b , -N3, -CN or -NO2, wherein each C ₁ _ ₆ alkyl, C ₃ _ ₁₀ cycloalkyl, C ₁ _ ₆ heteroalkyl and 5-10 membered heterocyclyl optionally contains 1, 2, 3, 4 or 5 substituents chosen from the following groups: halogen, -OR ^a , -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -OC(O)NR ^a R ^b , -NR ^a C (O)OR ^b , -SR ^a , -S(O)1-2R ^a , -S(O)2F, -S(O)2NR ^a R ^b , -NR ^a S(O)2R ^b , -N3, -CN and -NO2, which may be the same or different, each R ^a and R ^b independently represents -H, C ₁ .6αkyl, C ₃ . ₁₀ cycloalkyl, C ₁ .6 heteroalkyl, 510-membered heterocyclyl, C6. ₁₀ aryl or 5-10 membered heteroaryl, each C ₁ . ₆ alkyl, C ₃ _ ₁₀ cycloalkyl, C ₁ .6 heteroalkyl, 5-10 membered heterocyclyl, C6. ₁₀ aryl and 5-10 membered heteroaryl optionally substituted as substituents 1, 2, 3, 4 or 5 R ¹³ groups, which may be the same or different, or R ^a and R ^b together with the atom to which they are attached form 5-10 membered heterocycle, and each R ¹³ is independently -CN, halogen, C ₁ . ₆ alkyl, C ₃ . ₁₀ cycloalkyl, C ₁ .6 heteroalkyl or 5-10 membered heterocyclyl, or a tautomer or pharmaceutically acceptable salt thereof.

In some embodiments in formulas (I) and (II), Q is

In some embodiments in formulas (I) and (II), Q is

W.W.N

^R10 .

In some embodiments in formulas (I) and (II), X ¹ , X ² and X ³ are each independently N or C(R11), with 2 of X ¹ , X ² and X ³ being N. In some embodiments implementations of X ¹ , X ² and X ³ are each independently N or C(R11), with one of X ¹ , X ² and X ³ being N. In some embodiments of X ¹ , X ² and X ³ , each independently is N or C(R11), and none of X ¹ , X ² and X ³ is N.

In some embodiments, in formulas (I) and (II), X ¹ , X ² and X ³ are each C(R11). In some embodiments, in formulas (I) and (II), X ¹ , X ² and X ³ are each CH. In some embodiments, X ¹ is N, X ² is C(R11), and X ³ is C(R11). In some embodiments, X ¹ is N, X ² is CH, and X ³ is CH.

In some embodiments in formulas (I) and (II), X ¹ is N, X ² is N, and X ³ is C(R11). In some embodiments, X ¹ is N, X ² is C(R11), and X ³ is N. In some embodiments, X ¹ is C(R11), X ² is N, and X ³ is C(R11).

In some embodiments of formulas (I) and (II), R ¹ is —H or C1_6alkyl. In some embodiments, R ¹ is -H. In some embodiments, R ¹ is C1. ₆ alkyl. In some embodiments, R ¹ is methyl.

In some embodiments in formulas (I) and (II), X ¹ , X ² and X ³ are C(R11), each R ¹¹ is independently selected from -H, -CN, -OR ^a , halo and C1.6 alkyl, and R ¹ is selected from -H, -CN, -OR ^a , halo and C1. ₆ alkyl. In some embodiments, X ¹ , X ² and X ³ are C(R11), each R ¹¹ is -H, and R ¹ is -H.

In some embodiments in formulas (I) and (II), X ¹ is N, X ² is C(R ⁿ ), and X ³ is C(R 11 ), each R ¹¹ is independently selected from -H, -CN , -OR ^a , halogen and C1_6 alkyl, and R ¹ is selected from -H, -CN, -OR ^a , halogen and C1_ ₆ αalkyl. In some embodiments, X ¹ is N, X ² is C(R ⁿ ), and X ³ is C(R ⁿ ), each R ¹¹ is -H, and R ¹ is selected from -H and C ₁ . ₆ αlkulα. In some embodiments, X ¹ is N, X ² is C(R11), and X ³ is C(R11), each R ¹¹ is H, and R ¹ is -H.

In some embodiments, in formulas (I) and (II)

formulas (I) or (II) are selected from

- 11 040107

In some embodiments, in formulas (I) and (II)

formula (I) or (II) is

In some embodiments of formula (I) or (II), is

In some embodiments of formula (I) or (II), is

In some embodiments in formulas (I) and (II), R ³ is -H, -OR ^a , -NR ^a R ^b , -NHC(O)NR ^a R ^b , C _1-6 αkyl, or C _1-6 heteroalkyl. In some embodiments, R ³ is -H, -OR ^a , -NR ^a R ^b , or -NHC(O)NR ^a R ^b . In some embodiments, in formulas (I) and (II), R ³ is -NR ^a R ^b or -OR ^a . In some embodiments, R ³ is -NH2 or -OH.

In some embodiments, R ³ is -NR ^a R ^b . In some embodiments, R ³ is -NR ^a R ^b , where R ^a and R ^b are each independently -H or C _1-6 αkyl, where C _1-6 alkyl is optionally substituted with 1, 2, 3, 4 or 5 groups R ¹³ . In not

- 12 040107 in which embodiments R ³ is -NR ^a R ^b , wherein R ^a and R ^b are each independently -H or C ₁ . ₆ alkyl. In some embodiments, R ³ is -NR ^a R ^b , where R ^a and R ^b are each independently -H, methyl, butyl, or cyclopropylmethyl. In some embodiments, R ³ is -NH2.

In some embodiments, in formulas (I) and (II), R ³ is -OR ^a . In some embodiments, R ³ is -OH.

In some embodiments, in formulas (I) and (II), R ³ is -H. In some embodiments, R ³ is -NHC(O)NR ^a R ^b .

In some embodiments, R ³ is -NHC(O)NH2.

In some embodiments in formulas (I) and (II), R ⁴ is -H, -OR ^a , halogen, -NO2, -CN, -NR ^a R ^b , -NHC(O)NR ^a R ^{b ,} or C ₁ . ₆ alkyl. In some embodiments, R ⁴ is -H or -OR ^a .

In some embodiments in formulas (I) and (II), R ⁵ is -H, -OR ^a , halo, -NO2, -CN, -NR ^a R ^b , -NHC(O)NR ^a R ^{b ,} or C1. 6alkyl. In some embodiments, R ⁵ is -H, -OR ^a , halo, -NO2, -CN, -NR ^a R ^b or C1. ₆ alkyl.

In some embodiments in formulas (I) and (II), R ⁶ is -H, -OR ^a , halogen, -NO2, -CN, -NR ^a R ^b , -NHC(O)NR ^a R ^b , or C ₁ . ₆ alkyl. In some embodiments, in formulas (I) and (II), R ⁶ is -H.

In some embodiments in formulas (I) and (II), two of R ⁴ , R ⁵ and R ⁶ are -H and one of R ⁴ , R ⁵ and R ⁶ is -H, OR ^a , halogen, - NO2, -CN, -NR ^a R ^b , -NHC(O)NR ^a R ^b or C1.6αkyl. In some embodiments, two of R ⁴ , R ⁵ and R ⁶ are -H and one of R ⁴ , R ⁵ and R ⁶ is -H, -OR ^a , halogen, -NO2, -NR ^a R ^b or C1 . ₆ alkyl. In some embodiments, two of R ⁴ , R ⁵ and R ⁶ are -H and one of R ⁴ , R ⁵ and R ⁶ is -H, -OCH3, halo, -NO2, -NH2 or methyl.

In some embodiments, in formulas (I) and (II), R ⁴ , R ⁵ and R ⁶ are -H.

In some embodiments in formulas (I) and (II), R ⁷ is C1.6 alkyl, C1.6 heteroalkyl, halo, -OR ^a , -CN, or -NO2. In some embodiments, R ⁷ is C1. ₆ αkyl, halogen or -OR ^a .

In some embodiments in formulas (I) and (II), R ⁸ is C1.6 alkyl, C1.6 heteroalkyl, halo, -OR ^a , -CN, or -NO2. In some embodiments, R ⁸ is C1. ₆ αkyl, halogen or -OR ^a .

In some embodiments in formulas (I) and (II), R ⁷ and R ⁸ are the same and are selected from C ₁ . ₆ alkyl, C ₁ . ₆ heteroalkyl, halogen, -OR ^a , -CN and -NO2.

In some embodiments, R ⁷ and R ⁸ are the same and are selected from C ₁ . ₆ alkyl, halogen or -OR ^a .

In some embodiments, in formulas (I) and (II), R ⁷ and R ⁸ are C ₁ . ₆ alkyl. In some embodiments, R ⁷ and R ⁸ are methyl.

In some embodiments, in formulas (I) and (II), R ⁷ and R ⁸ are -OR ^a . In some embodiments, R ⁷ and R ⁸ are -OCH ₃ .

In some embodiments, in formulas (I) and (II), R ⁷ and R ⁸ are halogen. In some embodiments, R ⁷ and R ⁸ are fluoro.

In some embodiments, in formulas (I) and (II), R ⁹ is -H or C ₁ . ₆ alkyl. In some embodiments, R ⁹ is -H or methyl.

In some embodiments, in formulas (I) and (II), R ¹⁰ is -H or C ₁ . ₆ alkyl. In some embodiments, in formulas (I) and (II), R ¹⁰ is -H or methyl.

In some embodiments in formulas (I) and (II), R ⁹ is -H or C1.6 alkyl, and R ¹⁰ is -H or C1. ₆ alkyl. In some embodiments, R ⁹ is -H or methyl, and R ¹⁰ is -H or methyl. In some embodiments, in formulas (I) and (II), R ⁹ and R ¹⁰ are —H.

In some embodiments in formulas (I) and (II), Q is selected from

In some embodiments in formulas (I) and (II), Q is ^N ,

It is understood that any variable for Q of formulas (I) and (II) can be combined with any variable R ³ in formulas (I) and (II), just as if each combination were given explicitly and from - 13 040107 sensibly. For example, in one embodiment of formulas (I) and (II), Q is R ³ is -NH ₂ .

And

In another embodiment, Q is and R ³ is -OH.

It is understood that any variable for R ⁷ formulas (I) and (II) can be combined with any R ³ variable in formulas (I) and (II), just as if each combination were given explicitly and separately. For example, in one embodiment of formulas (I) and (II), R ⁷ is methyl and R ³ is -NH ₂ . In another embodiment, R ⁷ is methyl and R ³ is —OH. It is understood that any variable for R ⁸ of formulas (I) and (II) can be combined with any R ³ variable in formulas (I) and (II), just as if each combination were given explicitly and separately. For example, in one embodiment of formulas (I) and (II), R ⁸ is methyl and R ³ is -NH2. In another embodiment, R ⁸ is methyl and R ³ is —OH.

It is understood that any variable for R ⁴ , R ⁵ and R ⁶ of formulas (I) and (II) can be combined with any variable R ³ in formulas (I) and (II), just as if each combination were given in explicitly and separately. For example, in one embodiment of formulas (I) and (II), R ⁴ , R ⁵ and R ⁶ are each —H, and R ³ is —NH ₂ . In another embodiment, R ⁴ , R ⁵ and R ⁶ are each -H, and R ³ is -OH.

It is understood that any variable for X ¹ , X ² and X ³ of formulas (I) and (II) can be combined with any variable R ³ in formulas (I) and (II), just as if each combination were given in explicitly and separately. For example, in one embodiment of formulas (I) and (II), X ¹ , X ² and X ³ are each CH and R ³ is -NH2. In one embodiment of formulas (I) and (II), X ¹ is N, X ² is CH, and X ³ is CH and R ³ is -NH2. In another embodiment, X ¹ is N, X ² is CH, and X ³ is CH, and R ³ is —OH. In another embodiment, X ¹ , X ² and X ³ are each CH and R ³ is —OH. It is understood that any variable for R ¹ of formulas (I) and (II) can be combined with any variable of R ³ in formulas (I) and (II), just as if each combination were given explicitly and separately. For example, in one embodiment of formulas (I) and (II), R ¹ is hydrogen and R ³ is —NH ₂ . In another embodiment, R ¹ is hydrogen and R ³ is —OH. In some embodiments of formulas (I) and (II), where R ³ is -NH 2 , the compound may have one or more of the following structural features:

a) X ¹ , X ² and X ³ are each CH,

b) R ⁷ is methyl,

c) R ⁸ is methyl,

d) Q is

e) R ⁴ , R ⁵ and R ⁶ are each -H.

In one embodiment, the compounds correspond to at least one of features (a)-(e). In another embodiment, the compounds correspond to two or more (and in some embodiments, all) of features (a)-(e). In a particular embodiment, the compounds correspond to feature (a). In another embodiment, the compounds correspond to features (a), (b) and (c). In another embodiment, the compounds correspond to features (a) and (d). In another embodiment, the compounds correspond to features (a) and (e). In some embodiments of formulas (I) and (II) wherein R ³ is —OH, the compound may have one or more of the following structural features:

a) X ¹ is N, X ² is CH, and X ³ is CH,

b) R ⁷ is methyl,

c) R ⁸ is methyl,

d) Q is ^N , and

e) R ⁴ , R ⁵ and R ⁶ are each -H.

In one embodiment, the compounds correspond to at least one of features (a)-(e). In another embodiment, the compounds correspond to two or more (features (a)-(e), and in some embodiments

- 14 040107 to all). In a particular embodiment, the compounds correspond to feature (a). In another embodiment, the compounds correspond to features (a), (b) and (c). In another embodiment, the compounds correspond to features (a) and (d). In another embodiment, the compounds correspond to features (a) and (e). In some embodiments of formulas (I) and (II), where Q is ^N , the compound may have one or more of the following structural features:

a) X ¹ , X ² and X ³ are each CH or X ¹ is N, X ² is CH and X ³ is CH,

b) R ³ is -NH ₂ or -OH,

c) R ⁷ and R ⁸ are methyl,

d) R ⁴ , R ⁵ and R ⁶ are each -H.

In one embodiment, the compounds correspond to at least one of features (a)-(d). In another embodiment, the compounds correspond to two or more features (a)-(d) (and in some embodiments all). In a particular embodiment, the compounds correspond to feature (a). In another embodiment, the compounds correspond to features (a) and (b). In another embodiment, the compounds correspond to features (a), (b) and (c). In another embodiment, the compounds correspond to features (a), b) and (d). The present disclosure relates to the following compounds or their pharmaceutically acceptable salts.

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hh ₂ 15 kJ ^N II 'NH if I I II N 11 N hh ₂ ^N II Ί\Γ 'NH kJ _x if 16 I I II N 11 N hh ₂ ^iT*** ^N N^ 'NH jj |J ^N 17 I I II N 11 N hh ₂ ^N N^ 'NH [Γ A _n h 18 I I II N 11 N

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nh ₂ NA L jj* rc II N NH II N 35 hh ₂ II NH g c ^N 36 I I II N 11 N 0 A HN hh ₂ || NH c 37 I I II N 11 N hh ₂ || NH V ^jj 38 I I II N 11 N

- 24 040107

The present disclosure relates to the following compound, or a tautomer or pharmaceutically acceptable salt thereof:

The present disclosure relates to the following compound, or a pharmaceutically acceptable salt thereof:

- 25 040107

ABOUT

N

N and its tautomers such as

HE

N

N.

Pharmaceutical compositions

Pharmaceutical compositions containing the compounds disclosed herein, or pharmaceutically acceptable salts thereof, may be prepared using conventional carriers (eg, inactive ingredient or auxiliary material), which may be selected in accordance with normal practice. Tablets may contain excipients, including lubricants, fillers, binders, and the like. Aqueous compositions may be formulated in sterile form and, when intended for delivery by a route other than oral, may generally be isotonic. All formulations may additionally contain excipients such as those described by Rowe et al., Handbook of Pharmaceutical Excipients, ^5th edition, American Pharmacists Association, 1986. Excipients may contain ascorbic acid and other antioxidants, chelating agents such as EDTA, hydrocarbons such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid, and the like. In some embodiments, the composition refers to a solid dosage form, including a solid oral dosage form. The pH of the composition may range from about 3 to about 11, but is usually about 7 to 10.

While the active ingredients may be administered separately, it may be preferred if they are presented in the form of pharmaceutical compositions. Compositions, both for veterinary use and for use in humans, contain at least one compound of formula (I), together with one or more pharmaceutically acceptable carriers and optionally other therapeutic ingredients. In one embodiment, the pharmaceutical composition comprises a compound of formula (I), or a tautomer or pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, and one other therapeutic ingredient. The carrier(s) are acceptable in the sense that they are compatible with the other ingredients of the composition and are physiologically safe for the recipient of the composition.

The compositions are compositions suitable for various routes of administration, including oral administration. The compositions may be presented in a convenient dosage form and may be prepared by any of the methods well known in the pharmaceutical art. Such methods include the step of bringing into association an active ingredient (eg a compound of formula (I) or a pharmaceutical salt thereof) with one or more inactive ingredients (eg a carrier, pharmaceutical excipient, etc.). Compositions can be prepared by uniformly and thoroughly mixing the active ingredient with liquid carriers or finely divided solid carriers, or both, followed by shaping the product (if necessary). Manufacturing techniques are generally described in Remington: The Science and Practice of Pharmacy, ^21st edition, Lippincott Wiliams & Wilkins, Philadelphia, PA, 2006 (USA). The compositions described herein suitable for oral administration may be presented as discrete units (dosage dosage form), including, without limitation: capsules, sachets

- 26 040107 or tablets, each containing a predetermined amount of the active ingredient.

The pharmaceutical compositions disclosed herein comprise one or more of the compounds disclosed herein, or pharmaceutically acceptable salts thereof, together with one or more pharmaceutically acceptable carriers or excipients, and optionally other therapeutic agents. Pharmaceutical compositions containing the active ingredient may be presented in any form suitable for the intended route of administration. When used for oral administration, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs can be prepared. Compositions intended for oral administration may be prepared in accordance with any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more agents, including sweeteners, flavoring agents, coloring agents and preservatives, which allow you to get a edible preparation. Suitable tablets are those containing the active ingredient in admixture with a non-toxic pharmaceutically acceptable excipient suitable for the manufacture of tablets. These excipients can be, for example, inert diluents such as sodium or calcium carbonate, lactose, lactose monohydrate, sodium croscarmellose, povidone, calcium or sodium phosphate, granulating agents and disintegrants such as corn starch or alginic acid, binders such as as cellulose, microcrystalline cellulose, starch, gelatin or gum arabic and lubricants such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated using any of the known techniques, including microencapsulation, to delay disintegration and absorption in the gastrointestinal tract, resulting in sustained action over a longer period. For example, a retarding material such as glyceryl monostearate can be used alone or in combination with a wax. The amount of active ingredient that can be combined with inactive ingredients to form a dosage form may vary depending on the intended subject of treatment and the particular route of administration. For example, in some embodiments, a dosage form for oral administration to humans may contain from about 1 to 1000 mg of active material combined with a suitable and convenient amount of carrier material (eg, inactive ingredient or auxiliary material). In some embodiments, the carrier material ranges from about 5% to about 95% of the total composition (w:w). It should be understood that, in addition to the ingredients specifically mentioned above, compositions according to these embodiments may include other agents commonly used in the art, depending on the type of particular composition, for example, compositions suitable for oral administration may include flavoring agents.

In some embodiments, a composition containing an active ingredient disclosed herein (a compound of formula (I) or a pharmaceutically acceptable salt thereof) in one embodiment does not contain agents that affect the rate at which the active ingredient is metabolized. Accordingly, it is understood that compositions containing a compound of formula (I) in some embodiments do not contain agents that would interfere with (e.g., slow, impede or delay) the metabolism of the compound of formula (I) or any other active ingredient, administered separately, sequentially or simultaneously with the compound of formula (I). It is also understood that any of the methods, kits, articles, and the like detailed herein, in some embodiments, does not contain agents that would affect (e.g., slow, hinder, or delay) the metabolism of a compound of formula (I ) or any other active ingredient administered separately, sequentially or simultaneously with the compound of any formula (I).

Application methods

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

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In some embodiments, a method of treating or preventing HIV infection in an individual (eg, a human) is disclosed, comprising administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, to that individual.

In some embodiments, a method is disclosed for inhibiting HIV virus replication, treating AIDS, or delaying the onset of AIDS in an individual (e.g., human), comprising administering a compound of any of Formula (I), or a pharmaceutically acceptable salt thereof, to that individual. In some embodiments, a method of treating or preventing HIV infection in an individual (eg, a human) is disclosed, comprising administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, to that individual. In some embodiments, the individual is at risk of infection with the HIV virus, as in the case of a subject having one or more known risk factors associated with infection with the HIV virus. In some embodiments, a method for treating an HIV infection in an individual (eg, a human) is provided, comprising administering a compound of formula (I), or a pharmaceutically acceptable salt thereof, to that individual.

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

In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is disclosed for use in the medical therapy of HIV infection (e.g., HIV-1) or replication of an HIV (e.g., HIV-1) or AIDS virus, or delaying the onset of AIDS in an individual ( e.g. a person). In some embodiments, a compound of any of formulas (I), or a pharmaceutically acceptable salt thereof, is disclosed for use in the manufacture of a medicament for the treatment of HIV infection, or HIV replication, or AIDS, or delaying the onset of AIDS in an individual (e.g., human). One embodiment relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the prophylactic or therapeutic treatment of HIV infection or AIDS, or for use in the therapeutic treatment or delay of the onset of AIDS. In some embodiments, the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of HIV infection in an individual (eg, human) is disclosed. In some embodiments, a compound of any of formulas (I), or a pharmaceutically acceptable salt thereof, is disclosed for use in the prevention or therapeutic treatment of HIV infection.

In some embodiments, the methods of use are administered to an individual (eg, human) in need of treatment. In some embodiments, the methods of use are administered to an individual (eg, a human) at risk of developing AIDS.

Disclosed herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy. In one embodiment, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is for use in a method of treating HIV infection, or replication of HIV, or AIDS, or delaying the onset of AIDS in an individual (eg, human).

Also disclosed herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in a method for treating or preventing HIV in an individual in need thereof. In some embodiments, the individual in need thereof is a human infected with HIV. In some embodiments, the individual in need thereof is a human infected with HIV who has not yet developed AIDS. In some embodiments, the individual in need thereof is an individual at risk for developing AIDS. In some embodiments, the individual in need thereof is a human infected with HIV and who has already developed AIDS.

Also disclosed herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the therapeutic treatment or delay of the onset of AIDS.

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

In some embodiments, a compound of formula (I), or a pharmaceutically acceptable salt thereof, may be used as a research tool (eg, to study inhibition of HIV reverse transcriptase in a subject or in vitro).

Routes of administration

One or more of the compounds of formula (I) disclosed herein (also referred to herein as active ingredients) may be administered using any route.

- 28 040107 administration suitable for the disease being treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) and the like. It is understood that the preferred route of administration may vary depending on, for example, the condition of the recipient. In some embodiments, the disclosed compounds are orally bioavailable and may be administered orally.

Application scheme

Compounds, such as a compound of formula (I), may be administered to an individual in accordance with an effective dosage 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 more. In one embodiment, the compound is administered on a daily or intermittent schedule for the lifetime of the individual.

The dosage or frequency of administration of a compound of formula (I) may be adjusted during the course of treatment based on the judgment of the administering physician.

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

A compound disclosed herein (eg, any compound of formula (I)) may be administered at a dosage level of a compound of formula I that is effective. For example, the dosage amount may be from 10 to 1000 mg of the compound, for example from 75 to 100 mg of the compound.

Combinations

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

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

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

Also disclosed herein is a compound of formula (1), or a pharmaceutically acceptable salt thereof, for use in a method for treating or preventing HIV, wherein the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered simultaneously, separately, or sequentially with another HIV treatment active ingredient. In one embodiment, the other HIV treatment active ingredient is selected from the group consisting of HIV protease inhibitory compounds, non-nucleoside HIV reverse transcriptase inhibitors, HIV nucleoside reverse transcriptase inhibitors, HIV nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, and other HIV drugs, and combinations thereof.

A compound disclosed herein (e.g., any compound of formula (I)) may be used in combination with one or more additional therapeutic agents at any dosage of a compound of formula I (e.g., 10 to 1000 mg of a compound or 75 to 100 mg of a compound ).

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

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In one embodiment, kits are disclosed containing a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (eg, one, two, three, one or two, or one to three) additional therapeutic agents. In the embodiments described above, 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, non-nucleoside or non-nucleotide HIV reverse transcriptase inhibitors, nucleoside or nucleotide HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV integrase inhibitors not binding at the catalytic site (or allosteric), inhibitors of HIV cell entry (eg, CCR5 inhibitors, gp41 inhibitors (i.e., fusion inhibitors) and CD4 binding inhibitors), CXCR4 inhibitors, gp120 inhibitors, NADH oxidase and G6PD inhibitors, HIV vaccines, inhibitors of HIV maturation latency reversal agents (e.g., histone deacetylase inhibitors, proteasome inhibitors, protein kinase C activators (PKC), and BRD4 inhibitors), HIV capsid-targeting compounds (capsid inhibitors, e.g., capsid polymerization inhibitors or capsid disrupting compounds, nucleocapsid inhibitors p7 (NCp7) VI H, p24 capsid protein inhibitors), pharmacokinetic enhancers, immunotherapeutics (e.g., Pd-1 modulators, Pd-L1 modulators, toll-like receptor modulators, IL-15 agonists), HIV antibodies, bispecific antibodies, and antibody-like therapeutic proteins (e.g. , DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs®, Fab derivatives), including molecules targeting HIV glycoprotein gp120 or gp41, HIV combination drugs, HIV p17 matrix protein inhibitors, IL-13 antagonists, modulators peptidyl prolylcis/trans-isomerase A, protein disulfide isomerase inhibitors, C5a receptor antagonists, DNA methyltransferase inhibitor, HIV vif gene modulators, HIV-1 virus infectious factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators , mixed line kinase-3 (MLK-3) inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, mo COMM protein 1 domain-containing protein 1 dulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, ICAM-3-binding non-integrin 1 dendritic cell inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors , deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, PC9 proprotein convertase stimulators, DDX3X ATP-dependent RNA helicase inhibitors, reverse transcriptase priming complex inhibitors, PI3K inhibitors, compounds disclosed in WO 2013/006738 (Gilead Sciences), US 2013/0165489 ( University of Pennsylvania), WO 2013/091096 A1 (Boehringer Ingelheim), WO 2009/062285 (Boehringer Ingelheim), US20140221380 (Japan Tobacco), US20140221378 (Japan Tobacco), WO 2010/130034 (Boehringer Ingelheim), WO596 (Gilead 2013) Sciences), WO 2012/145728 (Gilead Sciences), WO2012/003497 (Gilead Sciences), WO2014/100323 (Gilead Sciences), WO2012/145728 (Gilead Sciences), WO2013/159 064 (Gilead Sciences) and WO 2012/003498 (Gilead Sciences) and WO 2013/006792 (Pharma Resources) and other drugs for the treatment of HIV and combinations thereof. In some embodiments, the additional therapeutic agent is selected from the group consisting of HIV protease inhibitors, non-nucleoside or non-nucleotide HIV reverse transcriptase inhibitors, nucleoside or nucleotide HIV reverse transcriptase inhibitors, HIV integrase inhibitors, non-catalytic (or allosteric) binding HIV integrase inhibitors , substances that improve pharmacokinetics, and their combinations.

In some embodiments, the compound of formula (I) is presented in the form of a tablet, which may optionally contain one or more other compounds useful in the treatment of HIV. In some embodiments, the tablet may contain another active ingredient for the treatment of HIV, such as HIV protease inhibitors, non-nucleoside or non-nucleotide HIV reverse transcriptase inhibitors, nucleoside or nucleotide HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV integrase inhibitors not binding at the catalytic site ( or allosteric), substances that improve pharmacokinetics and their combinations.

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

(1) a combination drug selected from the group consisting of ATRIPLA® (efavirenz + tenofovir disoproxil fumarate + emtricitabine), COMPLERA® (EVIPLERA®, rilpivirine + tenofovir disoproxil fumarate + emtricitabine), STRIBILD® (elvitegravir + cobicistat + tenofovir disoproxil fumarate) + emtricitabine), combinations of dolutegravir + abacavir sulfate + lamivudine, dolutegravir + abacavir sulfate + lamivudine, lamivudine + nevirapine + zidovudine, dolutegravir + rilpivirine, atazanavir sulfate + cobicistat, darunavir + cobicistat, efavirenz + lamivudine + tenofovir disoproxylamifenamidov emtricitabine + cobicistat + elvitegravir, Vacc-4x + romidepsin, darunavir + tenofovir alafenamide hemifumarate + emtricitabine

- 30 040107 + cobicistat, APH-0812, raltegravir + lamivudine, KALETRA® (ALUVIA®, lopinavir + ritonavir), atazanavir sulfate + ritonavir, COMBIVIR® (zidovudine + lamivudine, AZT+3TC), EPZICOM® (Livexa®, abacavir sulfate) + lamivudine, ABC+3TS), TRIZIVIR® (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 of amprenavir, atazanavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, ritonavir, neflinavir, neflavir mesylate, saquinavir, saquinavir mesylate, tipranavir, brecanavir, darunavir, DG-17, TMB-657 (PPL-100) and TMC-310911, (3) non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase selected from the group consisting of delaviridine, delaviridine mesylate, nevirapine, etravirine, dapivirine, doravinir, rilpivirine, efavirenz, KM-023 , VM-1500, lentinan and AIC-292, (4) HIV nucleoside or nucleotide reverse transcriptase inhibitors selected from the group consisting of VIDEX® and VIDEX® EC (didanosine, ddl), zidovudine, emtricitabine, didanosine, stavudine, zalcitabine, lamivudine , ценсавудина, абакавира, абакавира сульфата, амдоксовира, элвуцитабина, аловудина, фосфазида, фозивудина тидоксила, априцитабина, амдоксовира, KP-1461, фосалвудина тидоксила, тенофовира, тенофовира дизопроксила, тенофовира дизопроксила фумарата, тенофовира дизопроксила гемифумарата, тенофовира алафенамида, тенофовира алафенамида гемифумарата, tenofovir alafenamide fumarate, adefovir, adefovir dipivoxil and festinavir, (5) HIV integrase inhibitors selected from the group consisting of curcumin, curcumin derivatives, chicoryic acid, chicoryic acid derivatives, 3,5-dicaffeloylquinic acid, 3,5-dicaffeloylquinic acid derivatives , aurine carboxylic acid, aurine carboxylic acid derivatives, caffeic acid phenethyl ester, caffeic acid phenethyl ester derivatives, tyrphostin, tyrphostin derivatives, quercetin, quercetin derivatives, raltegravir, elvitegravir, dolutegravir and cabotegravir, (6) non-catalytic site-binding (allosteric) HIV integrase inhibitors (NCINI) selected from the group consisting of CX- 05168, CX-05045 and CX-14442, (7) HIV gp41 inhibitors selected from the group consisting of enfuvirtide, sifuvirtide and albuviride, (8) HIV cell entry inhibitors selected from the group consisting of cenicriviroc, (9) inhibitors HIV gp120 selected from the group consisting of Radha-108 (Receptol) and BMS663068, (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 binding inhibitors selected from the group consisting of ibalizumab, (12) CXCR4 inhibitors selected from the group consisting of plerixaphor, ALT-1188, vMIP and Haimipu , (13) substances, improved pharmacokinetic agents selected from the group consisting of cobicistat and ritonavir, (14) immunotherapeutic agents selected from the group consisting of dermaVir, interleukin-7, lexgenleucel-T (VRX-496), 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 derivative mycophenolate mofetil (MMF), WF-10, ribavirin, IL-2 , IL-2 XL, IL-12, polyethyleneimine (PEI) polymer, hepon, VGV-1, MOR-22, BMS-936559, modulators of toll-like receptors (tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlrl2 and tlr13), rintatolimod and IR-103, (15) HIV vaccines selected from the group consisting of peptide vaccines, recombinant protein subunit vaccines, live vector vaccines, DNA vaccines, based on virus-like particles (pseudovirion vaccines), peptide vaccines based on nove CD4, vaccine combinations, rgp120 (AIDSVAX), ALVAC HIV (vCP1521)/AIDSVAX B/E (gp120) (RV144), Remune, ITV-1, Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401 ), PEP-6409, Vacc-4x, Vacc-C5, VAC-3S, adenovirus-5 recombinant vaccine with DNA from different taxa (rAd5), Pennvax-G, VRC-HIV MAB060-00-AB, AVX101, vaccines Tat Oyi, AVX-201, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3/VSSP ISA-51, poly-ICLC adjuvanted vaccines, TatImmune, GTU-multiHIV (FIT-06), AGS-004, gp140δV2.TV1+ MF-59, rVSVIN HIV-1 gag vaccines, SeV-Gag, AT-20, DNK-4, Ad35-GRIN/ENV, TBC-M4, HIVAX, HIVAX-2, NYVAC-HIV-PT1, NYVAC vaccines -HIV-PT4, DNA-HIV-PT123, Vichrepola, rAAV1-PG9DP, GOVXB11, GOVX-B21, ThV-01, TUTI-16, VGX-3300, TVI-HIV-1, Ad-4 (Ad4-env Clade C + Ad4-mGag), EN41UGR7C, EN41-FPA2, PreVaxTat, TL-01, SAV-001, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYMV201, MVA-CMDR and DNA-Ad5 gag/pol/nef/nev (HVTN505), (16) HIV antibodies, bispecific antibodies and antibody-like therapeutic proteins (such as DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs®, Fab derivatives), including BMS-936559,

- 31 040107

TMB-360 and molecules targeting HIV glycoprotein gp120 or gp41 selected from the group consisting of bavituximab, UB-421, C2F5, C2G12, C4E10, C2F5+C2G12+C4E10, 3-BNC-117, KD-247, PGT145, PGT121, MDX010 (ipilimumab), VRC01, A32, 7B2, 10E8 and VRC07, (17) latency reversal agents selected from the group consisting of histone deacetylase inhibitors such as romidepsin, vorinostat, panobinostat, proteasome inhibitors such as velcade, protein kinase C (PKC) activators such as indolactam, prostratin, ingenol B and diacylglycerol lactones, ionomycin, GSK-343, PMA, SAHA, BRD4, IL-15, JQ1 inhibitors, disulfram and amphotericin B, (18) p7 protein inhibitors HIV nucleocapsid (NCp7) selected from the group consisting of azodicarbonamide, (19) HIV maturation inhibitors selected from the group consisting of BMS-955176 and GSK2838232, (20) PI3K inhibitors selected from the group consisting of Idelalisib, AZD-8186 , buparlisib, CLR-457, pictilisiba, neratinib, rigosertiba, rigosertiba sodium, EN-3342, TGR-1202, alpelisib, duvelisib, UCB-5857, taselisib, XL-765, gedatolisib, VS-5584, copanlisib, carboxyamidotriazole orotate, perifosine, RG-7666, GSK-2636771, DS-7423, panulisib, GSK -2269557, GSK-2126458, CUDC-907, PQR-309, INCB-040093, Pilaralisib (pilaralisib), BAY-1082439, Piquitinib (puquitinib) mesylate, SAR-245409, AMG-319, RP-6530, ZSTK-474, MLN-1117, SF-1126, RV-1729, sonolisib, LY3023414, SAR-260301 and CLR-1401, (21) 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), US 20140221380 (Japan Tobacco), US 20140221378 (Japan Tobacco), WO 2013/006792 (Pharma Resources), WO 2009/062285 (Boehringer Ingelheim), WO 2010/130034 (Boehringer Ingelheim), WO 2013/091096 A1 (Boehringer Ingelheim), WO 2013/159064 (Gilead Sciences), WO 2012/145728 (Gilead Sciences), WO2012/003497 (Gilead Sciences), WO2014/100323 (Gilead Scie nces), WO2012/145728 (Gilead Sciences), WO2013/159064 (Gilead Sciences) and WO 2012/003498 (Gilead Sciences), and (22) other HIV drugs selected from the group consisting of TR-452, MK -8591, REP 9, CYT-107, Alisporovir, NOV-205, IND-02, Methenkephalin, PGN-007, Acemannan, Gamimun, SCY-635, Prolastin, 1,5-dicaffeloylquinic acid, BIT-225, RPI-MN , VSSP, Hlviral (H1viral), IMO-3100, SB-728-T, RPI-MN, VIR-576, HGTV-43, MK-1376, rHIV7-shl-TAR-CCR5RZ, gene therapy agent MazF, BlockAide (Blockade) and RA-1050040 (RA-040).

In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is used in combination with one, two, three, or more additional therapeutic agents. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is used in combination with two additional therapeutic agents. In other embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is used in combination with three additional therapeutic agents. In further embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is used in combination with four additional therapeutic agents. These one, two, three, four or more additional therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents and/or they may be selected from different classes of therapeutic agents. In one particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is used in combination with an HIV nucleoside or nucleotide reverse transcriptase inhibitor and a non-nucleoside HIV reverse transcriptase inhibitor. In another specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is used in combination with an HIV nucleoside or nucleotide reverse transcriptase inhibitor and an HIV protease inhibitor compound. In another embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is used in combination with an HIV nucleoside or nucleotide reverse transcriptase inhibitor, a non-nucleoside HIV reverse transcriptase inhibitor, and an HIV protease inhibitory compound. In a further embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is used in combination with an HIV nucleoside or nucleotide reverse transcriptase inhibitor, a non-nucleoside HIV reverse transcriptase inhibitor, and a pharmacokinetic enhancer. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is used in combination with at least one HIV nucleoside reverse transcriptase inhibitor, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is used in combination with two nucleoside or nucleotide inhibitors of HIV reverse transcriptase. In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is used in combination with one, two, three,

- 32 040107 four or more additional therapeutic agents selected from raltegravir, Truvada® (tenofovir disoproxil fumarate + emtricitabine, TDF+FTC), maraviroc, enfuvirtide, Epzicom® (Livexa®, abacavir sulfate + lamivudine, ABC+3TC), Trizivir® (abacavir sulfate + zidovudine + lamivudine, ABC+AZT+3TC), adefovir, adefovir dipivoxil, Stribild® (elvitegravir + cobicistat + tenofovir disoproxil fumarate + emtricitabine), rilpivirine, rilpivirine hydrochloride, Complera® (Eviplera®, rilpivirine + tenofoxyl dimarsoproate + emtricitabine), cobicistat, Atripla® (efavirenz + tenofovir disoproxil fumarate + emtricitabine), atazanavir, atazanavir sulfate, dolutegravir, elvitegravir, Aluvia® (Kaletra®, lopinavir + ritonavir), ritonavir, emtricitabine, atazanavir sulfate + ritonavir, daramivir , prolastin, fosamprenavir, fosamprenavir calcium, efavirenz, Combivir® (zidovudine + lamivudine, AZT+3TC), etravirine, neflinavir, neflinavir mesylate, int erferon, didanosine, stavudine, indinavir, indinavir sulfate, tenofovir + lamivudine combinations, zidovudine, nevirapine, saquinavir, saquinavir mesylate, aldesleukin, zalcitabine tipranavir, amprenavir, delaviridine, delaviridine mesylate, Radha-108 (Receptol), Hlamivudine + lamivudine combinations disoproxil fumarate, efavirenz + lamivudine + tenofovir disoproxil fumarate combinations, phosphazid, lamivudine + nevirapine + zidovudine combinations, abacavir, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamigemide, and alafenofovidine.

In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is used in combination with abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate. In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is used in combination with tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate. In a specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is used in combination 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.

In a specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is used in combination 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 an additional therapeutic agent, wherein the second additional therapeutic agent is emtricitabine.

In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is used in combination with 5-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg of emtricitabine. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is used in combination 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 some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is used in combination with 10 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of emtricitabine. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is used in combination with 25 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of emtricitabine. A compound disclosed herein (e.g., a compound of formula (I)) may be used in combination with agents disclosed herein at any dosage of the compound (e.g., 10 to 1000 mg of a compound, 10 to 500 mg, or 75 to 100 mg of compound), just as if each dosage combination were given specifically and explicitly.

In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is used in combination with 200-400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200 mg of emtricitabine. In some embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is used in combination 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 some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is used in combination with 300 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofo

- 33 040107 disoproxil vir and 200 mg emtricitabine. A compound disclosed herein (e.g., a compound of formula (I)) may be used in combination with agents disclosed herein at any dosage of the compound (e.g., 10 to 1000 mg of the compound, 10 to 500 mg, or 75 to 100 mg of the compound), just as if each dosage combination were given specifically and explicitly.

In some embodiments, if a compound disclosed herein is used in combination with one or more additional therapeutic agents as described above, the components of the composition are administered in a simultaneous or sequential mode. In the case of sequential administration, the combination may be administered over two or more administrations. In some embodiments, a compound disclosed herein is combined (used in combination) with one or more additional therapeutic agents in a single dosage form for simultaneous administration to a patient, eg, as a solid oral dosage form.

In some embodiments, the compound is administered with one or more other therapeutic agents. Co-administration of a compound disclosed herein with one or more other therapeutic agents generally refers to the simultaneous or sequential administration of a compound disclosed herein and one or more additional therapeutic agents in which therapeutically effective amounts of a compound disclosed herein , and one or more additional therapeutic agents are simultaneously present in the patient's body. Co-administration includes administering single doses of the compounds disclosed herein before or after administration of single doses of one or more additional therapeutic agents, for example, administering a compound disclosed herein within seconds, minutes, or hours of administration of one or more additional therapeutic agents. agents. For example, in some embodiments, a single dose of a compound disclosed herein is administered first, followed by a single dose of one or more additional therapeutic agents over seconds or minutes. Alternatively, in other embodiments, a single dose of one or more additional therapeutic agents is administered first, followed by a single dose of a compound disclosed herein within seconds or minutes. In some embodiments, a single dose of a compound disclosed herein is administered first, followed by a single dose of one or more additional therapeutic agents following a period measured in hours (eg, 1-12 hours). In other embodiments, a single dose of one or more additional therapeutic agents is administered first, then after a period measured in hours (eg, 1-12 hours), a single dose of a compound disclosed herein is administered.

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

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

In some embodiments, disclosed herein is a method of 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 salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents, suitable for the treatment of HIV infection. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is used in combination with one, two, three, or more additional therapeutic agents. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is used in combination with two additional therapeutic agents. In other embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is used in combination with three additional therapeutic agents. In further embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is used in combination with four additional therapeutic agents. These one

- 34 040107 two, three or more additional therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents, and/or they may be selected from different classes of therapeutic agents.

Use of combination therapy for HIV

In some embodiments, the compound is administered with one or more other therapeutic agents. Co-administration of a compound disclosed herein with one or more other therapeutic agents generally refers to the simultaneous or sequential administration of a compound disclosed herein and one or more additional therapeutic agents in which a therapeutically effective amount of a compound disclosed herein , and one or more additional therapeutic agents are simultaneously present in the patient's body. In the case of sequential administration, the combination may be administered over two or more administrations. Co-administration includes the administration of single doses of the compounds disclosed herein before or after the administration of single doses of one or more additional therapeutic agents. For example, a compound disclosed herein may be administered within seconds, minutes or hours of administration of one or more additional therapeutic agents. In some embodiments, a single dose of a compound disclosed herein is administered first, followed by a single dose of one or more additional therapeutic agents over seconds or minutes. Alternatively, a single dose of one or more additional therapeutic agents is administered first, followed by a single dose of a compound disclosed herein within seconds or minutes. In other embodiments, a single dose of a compound disclosed herein is administered first, then, after a period measured in hours (eg, 1-12 hours), a single dose of one or more additional therapeutic agents is administered. In other embodiments, a single dose of one or more additional therapeutic agents is administered first, then after a period measured in hours (eg, 1-12 hours), a single dose of a compound disclosed herein is administered. In some embodiments, a compound disclosed herein is combined (used in combination) with one or more additional therapeutic agents in a single dosage form for simultaneous administration to a patient, for example, as a solid dosage form for oral administration.

In some embodiments, the compound of formula (I) is presented in the form of a tablet, which may optionally contain one or more other compounds useful in the treatment of HIV. In some embodiments, the tablet may contain another active ingredient for the treatment of HIV, such as HIV protease inhibitors, non-nucleoside or non-nucleotide HIV reverse transcriptase inhibitors, nucleoside or nucleotide HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV integrase inhibitors not binding at the catalytic site ( or allosteric), pharmacokinetic enhancing agents, and combinations thereof.

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

Combination therapy for HIV

In the embodiments described above, 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 the treatment of HIV, other drugs for the treatment of HIV, HIV protease inhibitors, non-nucleoside or non-nucleotide HIV reverse transcriptase inhibitors, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, inhibitors HIV integrase, non-catalytic (or allosteric) HIV integrase inhibitors, inhibitors of HIV cell entry, inhibitors of HIV maturation, latency reversal agents, HIV capsid-targeting compounds, immunotherapies, phosphainositol 3-kinase inhibitors ( PI3K), anti-HIV antibodies, bispecific antibodies and antibody-like therapeutic proteins, HIV matrix protein p17 inhibitors, IL-13 antagonists, peptidyl prolyl cis/trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, inhibitor ra DNA methyltransferase, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed-line kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors 1, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, modulators of protein 1 COMM domain, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, ICAM-3-binding non-integrin 1 dendritic cell inhibitors, GAG protein inhibitors HIV, HIV POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, PC9 proprotein convertase inhibitors, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, NADH oxidase and G6PD inhibitors, substances that improve pharmacokinetics, genetically and HIV therapy, HIV vaccines and combinations thereof.

- 35 040107

Combination drugs for the treatment of HIV

Examples of combination medicines 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 дизопроксил фумарат и эмтрицитабин, TDF+FTC), дарунавир, тенофовир алафенамид гемифумарат, эмтрицитабин и кобицистат, эфавиренз, ламивудин и тенофовир дизопроксил фумарат, ламивудин и тенофовир дизопроксил фумарат, тенофовир и ламивудин, тенофовир алафенамид и эмтрицитабин, тенофовир алафенамид, эмтрицитабин и рилпивирин, 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® ), KALETRA® (ALUVIA®, lopinavir and ritonavir), TRIUMEQ® (dolutegravir, abacavir and la mivudine), 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, doraviner, lamivudine and tenofovir disoproxil fumarate, doravidin, lamivudine and tenofovir disoproxil, lopinavir, ritonavir, zidovudine and lamivudine, Vacc-4x and romidepsin and ARN-0812.

Other HIV medicines

Examples of other HIV medicines include acemannan, alisporovir, Banlec, deferiprone, Gamimun, methenkephalin, naltrexone, Prolastin, REP 9, RPI-MN, VSSP, Hlviral (H1viral), SB-728-T, 1,5-dicaffeloylquinic acid , rHIV7-shl-TAR-CCR5RZ, AAVeCD4-Ig gene therapy, MazF gene therapy, BlockAide, ABX-464, AG-1105, BIT-225, CYT-107, HGTV-43, HS-10234, IMO- 3100, IND-02, MK-1376, MK-8507, MK-8591, NOV-205, RA-1050040 (RA-040), PGC-007, SCY-635, TR-452, TEV-90110, TEV-90112 , TEV-90111, TEV-90113, RN-18, Immuglo and VIR576.

HIV protease inhibitors

Examples of HIV protease inhibitors include amprenavir, atazanavir, brecanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, neflavir, neflanavir mesylate, ritonavir, saquinavir, saquinavir mesylate, tipranavir, DG-17, TMB-657 (PPL100), T-169 and TMS-310911.

HIV reverse transcriptase inhibitors

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

Примеры нуклеозидных и нуклеотидных ингибиторов обратной транскриптазы ВИЧ включают адефовир, адефовира дипивоксил, эмтрицитабин, тенофовир, тенофовир алафенамид, тенофовир алафенамид фумарат, тенофовир алафенамид гемифумарат, тенофовир дизопроксил, тенофовир дизопроксил фумарат, тенофовир дизопроксил гемифумарат, VIDEX® и VIDEX ЕС® (диданозин, ddl ), abacavir, abacavir sulfate, alovudine, apricitabine, censavudine, didanosine, elvucitabine, festinavir, fosalvudine tidoxil, fozivudine tidoxil, lamivudine, phosphazide, stavudine, zalcitabine, zidovudine, and KP-1461.

HIV integrase inhibitors

Examples of HIV integrase inhibitors include elvitegravir, curcumin, curcumin derivatives, chicory acid, chicory acid derivatives, 3,5-dicaffeloylquinic acid, 3,5-dicaffeloylquinic acid derivatives, aurine carboxylic acid, aurine carboxylic acid derivatives, caffeic acid phenethyl ester, caffeic acid phenethyl ester derivatives. acids, tyrphostin, tyrphostin derivatives, quercetin, quercetin derivatives, raltegravir, dolutegravir, JTK351 and cabotegravir.

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

Inhibitors of HIV entry into the cell

Examples of HIV cell entry (fusion) inhibitors include cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 binding inhibitors, gp120 inhibitors, and CXCR4 inhibitors.

Examples of CCR5 inhibitors include aplaviroc, vicriviroc, maraviroc, cenicriviroc, PRO140, adaptavir (RAP-101), nifeviroc (TD-0232), TD-0680 and vMIP (Haimipu).

Examples of gp41 inhibitors include albuviride, enfuvirtide and sifuvirtide.

Examples of CD4 binding inhibitors include ibalizumab.

Examples of gp120 inhibitors include Radha-108 (Receptol) and BMS-663068.

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

HIV maturation inhibitors

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

- 36 040107

Means that reverse the latent state

Examples of latency reversal agents include histone deacetylase (HDAC) inhibitors, proteasome inhibitors such as velcade, protein kinase C (PKC) activators, BET bromodomain 4 (BRD4) inhibitors, ionomycin, PMA, SAHA (suberanilohydroxamic acid or suberoyl, anilide, and hydroxamic acid), IL-15, JQ1, disulfram, amphotericin B and GSK-343. Examples of histone deacetylase inhibitors include romidepsin, vorinostat and panobinostat.

Examples of PKC activators include indolactam, prostratin, ingenol B, and diacylglycerol lactones.

Capsid inhibitors

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

Immunotherapeutic agents

Examples of immunotherapeutic agents include toll-like receptor modulators such as tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12 and tlr13, modulators of programmed cell death protein 1 (Pd-1), programmed cell death ligand 1 (Pd-L1) modulators, IL15 agonists, DermaVir, interleukin-7, plaquenil (hydroxychloroquine), proleukin (aldesleukin, IL-2), interferon alfa, interferon alfa-2b, interferon alfa-n3, pegylated interferon alpha, interferon gamma, hydroxyurea, mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF), ribavirin, polymer polyethyleneimine (PEI), hepon, rintatolimod, IL-12, WF-10, VGV1, MOR-22, GS- 9620, BMS-936559 and IR-103.

Phosphatidylinositolkinase (PI3K) inhibitors

Examples of PI3K inhibitors include idelalisib, alpelisib, buparlisib, carboxyamidotriazole orotate, copanlisib, duvelisib, gedatolisib, neratinib, panulisib, perifosine, pictilisib, pilaralisib, piquitinib (puquitinib) mesylate, rigosertib, rigosertib sodium, sonolisib, AMG-319 , AZD-8186, BAY-1082439, CLR-1401, CLR-457, CUDC-907, DS-7423, EN-3342, GSK-2126458, GSK-2269577, GSK-2636771, INCB-040093, LY-3023414, MLN -1117, PQR-309, RG-7666, RP-6530, RV1729, SAR-245409, SAR-260301, SF-1126, TGR-1202, UCB-5857, VS-5584, XL-765 and ZSTK-474.

HIV antibodies, bispecific antibodies and antibody-like therapeutic proteins

Examples of HIV antibodies, bispecific antibodies, and antibody-like therapeutic proteins include DARTs®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives, BMS-936559, TMB-360, and molecules targeting HIV glycoprotein gp120 or gp41.

Examples of molecules targeting HIV glycoprotein gp120 or gp41 include bavituximab, UB421, C2F5, C2G12, C4E10, C2F5+C2G12+C4E10, 3-BNC-117, PGT145, PGT121, MDX010 (ipilimumab), VRC01, A32, 7B2, 10E8, VRC-07-523, MGD-014 and VRC07.

Substances that improve pharmacokinetics,

Examples of pharmacokinetic enhancing agents include cobicistat and ritonavir.

Additional Therapeutic Agents

Examples of additional therapeutic agents include those 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) , WO 2013/091096 (Boehringer Ingelheim) and U.S. 20100143301 (Gilead Sciences).

HIV vaccines

Examples of HIV vaccines include peptide vaccines, recombinant protein subunit vaccines, live vector vaccines, DNA vaccines, CD4-based peptide vaccines, vaccine combinations, rgp120 (AIDSVAX), ALVAC HIV (vCP1521)/AIDSVAX B/E (gp120) (RV144 ), vaccine based on monomeric gp120 HIV-1 subtype C, Remune, ITV-1, Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401), Vacc-4x, Vacc-C5, VAC-3S, recombinant vaccine based on adenovirus-5 with DNA from different taxa (rAd5), Pennvax-G, Pennvax-GP, VRC-HIV MAB060-00-AB, HIV-TriMix mRNA vaccine, HIV-LAMP-vax, Ad35, Ad35-GRIN , NAcGM3/VSSP ISA-51, poly-ICLC adjuvanted vaccines, TatImmune, GTU-multiHIV (FIT-06), gp140δV2.TV1+MF-59, rVSVIN HIV-1 gag vaccine, SeVGag vaccine, AT-20, DNK-4, ad35-Grin/ENV, TBC-M4, HIVAX, HIVAX-2, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, rAAV1-PG9DP, GOVX-B11, GOVX-B21, TVI-HIV-1, Ad-4 (Ad4-env Clade C+Ad4mGag), EN41-UGR7C, EN41-FPA2, PreVaxTat, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR , DNA-Ad5 gag/pol/nef/nev (HVTN505), MVATG-17401, ETV-01, CDX-1401, rcAD26.MOS1.HIV-Env, Ad26.Mod.HIV vaccine, AGS-004, AVX-101, AVX-201, PEP-6409, SAV-001, ThV-01, TL-01, TUTI-16, VGX-3300, IHV-001 and virus-like particle vaccines such as

- 37 040107 pseudovirion vaccine.

Combination therapy for HIV

In a specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is used in combination 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, cobicistat, tenofovir disoproxil fumarate and emtricitabine), TRUVADA® (tenofovir disoproxil fumarate and emtricitabine, TDF+FTC), adefovir, adefovir dipivoxil, cotricitofibirate , тенофовира дизопроксила, тенофовира дизопроксила фумарата, тенофовира алафенамида, тенофовира алафенамид агемифумарата, TRIUMEQ® (долутегравир, абакавир и ламивудин), долутегравира, абакавира сульфата и ламивудина, ралтегравира, ралтегравира и ламивудина, маравирока, энфувиртида, ALUVIA® (KALETRA®, лопинавир и 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 cobicistat, atazanavir and cobicistat, darunavir and cobicistat, atazanavir, atazanavir sulfate , долутегравира, элвитегравира, ритонавира, атазанавира сульфата и ритонавира, дарунавира, ламивудина, проластина, фосампренавира, фосампренавира кальция, эфавиренза, этравирина, нефлинавира, нефлинавира мезилата, интерферона, диданозина, ставудина, индинавира, индинавира сульфата, тенофовира и ламивудина, зидовудина, невирапина , saquinavir, saquinavir mesylate, aldesleukin, zalcitabine, tipranavir, amprenavir, delaviridine, delaviridine mesylate, Radha-108 (receptol), H1viral (H1viral), lamivudine and tenofovir disoproxil fumarate, efavirenz, lamivudine and tenofovir famirafu disoproxydine, and zidovudine, abacavir, and abacavir sulfate.

In one particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is used in combination with an HIV nucleoside or nucleotide reverse transcriptase inhibitor and a non-nucleoside HIV reverse transcriptase inhibitor. In another specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is used in combination with an HIV nucleoside or nucleotide reverse transcriptase inhibitor and an HIV protease inhibitory compound. In a further embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is used in combination with an HIV nucleoside or nucleotide reverse transcriptase inhibitor, a non-nucleoside HIV reverse transcriptase inhibitor, and a pharmacokinetic enhancer. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is used in combination with at least one HIV nucleoside reverse transcriptase inhibitor, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is used in combination with two nucleoside or nucleotide inhibitors of HIV reverse transcriptase. In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is used in combination with abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate. In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is used in combination with tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate. In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is used in combination 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.

In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is used in combination 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, and the second additional therapeutic agent is emtricitabine. The compound disclosed herein (eg, any compound of formula (I)) may be used in combination with one or more additional therapeutic agents at any dosage of the compound of formula (I) (eg, 50 to 1000 mg of the compound).

In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is used in combination with tenofovir alafenamide fumarate 5-30 mg,

- 38 040107 tenofovir alafenamide hemifumarate or tenofovir alafenamide and 200 mg emtricitabine. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is used in combination 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 some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is used in combination with 10 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of emtricitabine. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is used in combination with 25 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of emtricitabine. A compound disclosed herein (e.g., a compound of formula (I)) may be combined (used in combination) with the agents provided herein at any dosage level (e.g., 50 to 500 mg of the compound) as well as if each combination dosage was given specifically and explicitly.

In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is used in combination with 200-400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200 mg of emtricitabine. In some embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is used in combination with 200-250, 200-300, 200-350, 250-350, 250-400, 350-400, 300-400, or 400 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate or tenofovir disoproxil and 200 mg emtricitabine. In some embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is used in combination with 300 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200 mg of emtricitabine. A compound disclosed herein (e.g., a compound of formula (I)) may be combined (used in combination) with the agents provided herein at any dosage level (e.g., 50 mg to 500 mg of the compound) as well as if each the combination of dosages has been given specifically and explicitly.

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

Kits and products

The present disclosure relates to a kit containing a compound of formula (I) or a pharmaceutically acceptable salt thereof. The kit may further contain instructions for use, for example for use in HIV reverse transcriptase inhibition, as in the case of use in the treatment of HIV or AIDS, or as a research tool. Instructions for use are usually written instructions, although electronic storage media (eg, magnetic floppy disk or optical disk) are also acceptable.

The present disclosure also relates to a pharmaceutical kit containing one or more containers containing a compound of any of formulas (I) or a pharmaceutically acceptable salt thereof. Optionally, such container(s) may be accompanied by a notice in the form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, reflecting that authority's approval for manufacture, use, or sale for human use. Each component (in case more than one component is present) may be packaged in a separate container, or some components may be combined in one container if this is acceptable in terms of cross-reactivity and shelf life. Kits may be presented in unit dosage forms, non-dose packages (eg, multi-dose packages), or in substandard doses. Kits may also include multiple unit doses of the compounds and instructions for use, and may be packaged in quantities sufficient for storage and use in pharmacies (eg hospital pharmacies or prescription pharmacies).

Also disclosed is an article of manufacture containing a dosage unit of a compound of any formula (I) or a pharmaceutically acceptable salt thereof in a suitable package for use in the methods described herein. Suitable packaging is known in the art and includes, for example, vials, vials, ampoules, bottles, jars, flexible packaging, and the like. The article may also be sterilized and/or sealed.

The present disclosure also relates to methods and intermediates that can be used to treat the described compounds or their pharmaceutically acceptable salts.

Many general sources are available describing well-known chemical synthesis schemes and conditions suitable for the synthesis of the disclosed compounds (see, for example, Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, ^7th edition, Wiley-Interscience, 2013.)

The compounds described herein may be purified by any means known

- 39 040107 in the art, including chromatographic tools such as high performance liquid chromatography (HPLC), preparative thin layer chromatography, flash column chromatography and ion exchange chromatography. Any suitable stationary phases may be used, including conventional and reversed phases and ionic resins. Most commonly, the disclosed compounds are purified by silica gel and/or alumina chromatography. See, for example, Introduction to Modern Liquid Chromatography, 2nd ed., ed. L. R. Snyder, J. J. Kirkland, John Wiley and Sons, 1979, and Thin Layer Chromatography, E. Stahl (ed.), Springer-Verlag, New York, 1969.

During any process for the preparation of the described compounds, it may be necessary or desirable to protect sensitive or reactive groups on any of the molecules involved. Such protection can be achieved through the use of conventional protecting groups as described in standard works such as T. W. Greene, PGM Wuts, Protective Groups in Organic Synthesis, 4th ^ed ., Wiley, New York 2006 (New York , USA). The protecting groups may be removed at a suitable subsequent step by methods known in the art. Examples of chemicals that can be used in methods according to embodiments of the present invention will be described below with reference to illustrative synthetic schemes describing in general the way they are prepared according to this document, and the following specific examples. Those skilled in the art will appreciate that in order to prepare the various compounds of the present case, starting materials can be easily selected in such a way as to pass the substituents whose presence is desired in the final compound through the reaction scheme, with or without protecting groups, as the case may be, to obtain the desired product. Alternatively, it may be necessary or desirable to use a suitable group in place of the final target substituent, which can be carried through the reaction scheme and replaced by a suitable target substituent. In addition, one skilled in the art will appreciate that the transformations shown in the schemes below can be performed in any order that is compatible with the given functional or pendant groups. Preferably, each of the reactions shown in the general schemes is carried out at a temperature from about 0° C. to the reflux temperature of the organic solvent used. Unless otherwise indicated, the variables have the meanings defined above for formula (I).

Representative synthetic routes for the compounds disclosed herein are described in the Schemes below, and in particular in the following examples.

Embodiments also relate to methods and intermediates that can be used to prepare the described compounds or their pharmaceutically acceptable salts.

Many general sources are available describing well-known chemical synthesis schemes and conditions suitable for the synthesis of the disclosed compounds (see, for example, Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7e ed., Wiley-Interscience, 2013.). Angew. Chem. Int. Ed. 2014, 53, 2-21, which is incorporated herein by reference in its entirety, provides an overview of the copper(VI) fluoride exchange reaction, which can also be used in synthetic schemes.

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

During any process for the preparation of the described compounds, it may be necessary or desirable to protect sensitive or reactive groups on any of the molecules involved. Such protection can be achieved through the use of conventional protecting groups as described in standard works such as T. W. Greene, PGM Wuts, Protective Groups in Organic Synthesis, 4th ^ed ., Wiley, New York 2006 (New York, USA). The protecting groups may be removed at a suitable subsequent step by methods known in the art. Examples of chemicals that can be used in methods according to embodiments of the present invention will be described below with reference to illustrative synthetic schemes describing in general the route from preparation according to this document, and the following specific examples. Those skilled in the art will appreciate that in order to prepare the various compounds of the present case, starting materials can be easily selected in such a way as to pass the substituents whose presence is desired in the final compound through the reaction scheme, with or without protecting groups, as the case may be, to obtain the desired product. Alternatively, it may be necessary or desirable to use a suitable group in place of the final target substituent, which can be carried through the reaction scheme and replaced by a suitable target substituent. In addition, one skilled in the art will appreciate that the transformations shown in the schemes below can be performed in any order that is compatible with the given functional or pendant groups. Each of the reactions shown in the general schemes can be carried out at a temperature from about 0°C to reflux temperature

- 40 040107 of the organic solvent used. Unless otherwise indicated, the variables have the meanings defined above for formula (I).

Representative synthetic routes for the compounds disclosed herein are described in the Schemes below, and in particular in the following examples.

Scheme 1 shows a representative example of the synthesis of compounds according to implementation options. This methodology is compatible with a large number of different functional groups.

Scheme 1

R ⁴ R ³

In Scheme 1, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , X ¹ , X ² , X ³ and Q are as defined herein. Also in Scheme 1, as discussed below, Y ^1a , Z ^1a and Z ^2a are precursor groups to form the necessary bonds and groups in formula (I). Starting materials can be obtained from commercial suppliers or by well-known synthetic procedures. The synthesis of Formula 1-D is discussed below in Schemes 4 and 5. In Scheme 1, a nucleophilic substitution reaction is performed between a compound of Formula 1-A and 1-B to give a compound of Formula 1-C. The amino group of formula 1-B reacts with a compound of formula 1-A and displaces Y ^1a which is a leaving group such as halogen, triflate, mesylate and tosylate. In some cases Y ^1a is a halogen such as iodine, bromine or chlorine.

Further in Scheme 1, a coupling reaction occurs between formulas 1-C and 1-D to obtain a compound of formula (I). In some cases, a palladium-catalyzed reaction of an aryl halide and an organoboron compound (eg, a Suzuki coupling reaction) can be used. In a Suzuki coupling reaction, Z ^1a in formula 1-C may be a halide such as iodine or bromine, and Z ^2a in formula 1-D may be boronic acid or a boronic acid ester. In some cases, Z ^2a is

In some cases, the coupling step includes a palladium catalyst such as 1,1'-bis(ditert-butylphosphino)ferrocene palladium dichloride or 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride.

Further in Scheme 1, as an alternative coupling reaction between formulas 1-C and 1-D, a palladium-catalyzed reaction between an organotin compound and an aryl halide (eg, a Stille coupling reaction) can be used to obtain a compound of formula (I). In the Stille reaction, Z ^1a in formula 1-C may be an organic tin compound (-S11R4 where R is an alkyl group) and Z ^2a in formula 1-D may be a halide such as iodine or bromine. In some cases, the coupling step includes a palladium catalyst such as bis(tritert-butylphosphine)palladium(0).

Scheme 2 is a representative example of the synthesis of compounds according to embodiments of the invention. This methodology is compatible with a large number of different functional groups.

- 41 040107

Scheme 2

2-E

In Scheme 2, R ^{1 ,} R ² , R 3 , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , X ¹ , X ² , X ³ and Q are as defined herein. Also in Scheme 2, as discussed below, Y ^1a , Z ^1a and Z ^2a are precursor groups to form the necessary bonds and groups in formula (I). Starting materials can be obtained from commercial suppliers or by well known synthetic procedures.

In Scheme 2, a nucleophilic substitution reaction is carried out between a compound of formula 2-A and 2-B to give a compound of formula 2-C. The amino group of formula 2-B reacts with a compound of formula 2-A and displaces Y ^1a which is a leaving group such as halogen, triflate, mesylate and tosylate. In some cases Y ^1a is a halogen such as iodine, bromine or chlorine.

Further in Scheme 2, a coupling reaction between formulas 2-C and 2-D is carried out to form a compound of formula 2-E. In some cases, a palladium-catalyzed reaction of an aryl halide and an organoboron compound (eg, a Suzuki coupling reaction) can be used. In a Suzuki coupling reaction, Z ^1a in formula 2-C may be a halide such as iodine or bromine, and Z ^2a in formula 2-D may be boronic acid or a boronic acid ester. In some cases, Z ^2a is 'οΆ

In some instances, the coupling step includes a palladium catalyst such as palladium 1,1'-bis(ditert-butylphosphino)ferrocene dichloride or palladium 1,1'-bis(diphenylphosphino)ferrocene dichloride.

Further in scheme 2, as an alternative coupling reaction between formulas 2-C and 2-D, a palladium-catalyzed reaction between an organotin compound and an aryl halide (eg, a Stille coupling reaction) can be used to obtain a compound of formula (I). In the Stille reaction, Z ^1a in formula 2-C may be an organic tin compound (-S11R4 where R is an alkyl group) and Z ^2a in formula 2-D may be a halide such as iodine or bromine. In some cases, the coupling step includes a palladium catalyst such as bis(tri-tert-butylphosphine)palladium(0). Further, in Scheme 2, a coupling reaction between formulas 2-D and 2-E is carried out to obtain a compound of formula (I). In some cases, a coupling reaction between a stabilized phosphonate carbanion and an aldehyde can be used (eg Horner-Wadsworth-Emmons reaction).

Scheme 3 is a representative example of the synthesis of compounds according to embodiments of the invention. This methodology is compatible with a large number of different functional groups.

- 42 040107

Scheme 3

In Scheme 3, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , X ¹ , X ² , X ³ and Q are as defined herein. Also in Scheme 3, as discussed below, Y ^1a , Z ^1a and Z ^2a are precursor groups to form the necessary bonds and groups in formula (I). Starting materials can be obtained from commercial suppliers or by well-known synthetic procedures. The synthesis of formula 1-D is discussed below in schemes 4 and 5. In scheme 3, a coupling reaction between formulas 3-A and 1-D is carried out to form a compound of formula 3-B. In some cases, a palladium-catalyzed reaction of an aryl halide and an organoboron compound (eg, a Suzuki coupling reaction) can be used. In a Suzuki coupling reaction, Z ^1a in formula 3-A may be a halide such as iodine or bromine, and Z ^2a in formula 1-D may be boronic acid or a boronic acid ester. In some cases, Z ^2a is

In some cases, the coupling step includes a palladium catalyst such as 1,1'-bis(ditert-butylphosphino)ferrocene palladium dichloride or 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride.

Further in scheme 3, as an alternative coupling reaction between formulas 3-A and 1-D, a palladium-catalyzed reaction between an organotin compound and an aryl halide (eg, a Stille coupling reaction) can be used to obtain a compound of formula (I). In the Stille reaction, Z ^1a in formula 1-C may be an organic tin compound (-S11R4 where R is an alkyl group) and Z ^2a in formula 1-D may be a halide such as iodine or bromine. In some cases, the coupling step includes a palladium catalyst such as bis(tri-tert-butylphosphine)palladium(0). Further, in Scheme 3, a nucleophilic substitution reaction is performed between a compound of formula 3-B and 3-C to give a compound of formula (I). An amino group of formula 3-C reacts with a compound of formula 3-B and displaces Y ^1a which is a leaving group such as halogen, triflate, mesylate and tosylate. In some cases Y ^la is a halogen such as iodine, bromine or chlorine.

Scheme 4 shows a representative example of the synthesis of formula 1-D. This methodology is compatible with a large number of different functional groups.

Scheme 4

In scheme 4, R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and Q are as defined herein. Also in Scheme 4, as discussed below, Q ^1a , X ^1a and X ^2a are precursor groups for

- 43 040107 the formation of the necessary bonds and groups in the formula 1-D. Starting materials can be obtained from commercial suppliers or by well-known synthetic procedures.

In Scheme 4, a coupling reaction between formulas 4-A and 4-B is carried out to form a compound of formula 4-C. In some cases, aryl halides and alkene compounds can be used (eg Heck coupling reaction). In the case of a Heck coupling reaction, X ^1a in formula 4-A may be a halide such as iodine or bromine, and X ^2a in formula 4-B may be hydrogen. The Heck coupling reaction can be carried out in the presence of a palladium catalyst such as palladium(II) acetate in combination with tri(o-tolyl)phosphine.

Further in Scheme 4, Q ^1a in formula 4-A and 4-C is a precursor group of boronic acid or boronic acid ester in formula 1-D, where Z ^2a is boronic acid or ester of boronic acid. A borylation reaction of formula 4-C is carried out to give a compound of formula 1-D. In some cases, the coupling reaction of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) with an aryl halide can be used (for example, the reaction borylation Mayar (Miyaura)). In the Miyaura borylation reaction, Q ^la in formula 4-C may be a halide such as iodine or bromine. In some cases, it is possible to react a compound of formula 4-C with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) with obtaining a compound of formula 1-D, in which Z ^2a represents

In some cases, the borylation step includes a palladium catalyst such as palladium(II) acetate in combination with dicyclohexyl(2',6'-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine. Other borylation reactions may be used. Scheme 5 shows another representative example of the synthesis of formula 1-D. This methodology is compatible with a large number of different functional groups.

Scheme 5

In scheme 5, R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and Q are as defined herein. Also in Scheme 5, as discussed below, Q ^1a and X ^1a are precursor groups to form the necessary bonds and groups in formula 1-D. Starting materials can be obtained from commercial suppliers or by well-known synthetic procedures. In Scheme 5, a coupling reaction between formulas 5-A and 5-B is carried out to form a compound of formula 5-C. In some cases, a coupling reaction between a stabilized phosphonate carbanion and an aldehyde can be used (eg Horner-Wadsworth-Emmons reaction). In the Horner-Wadsworth-Emmons reaction, X ^1a in formula 4-A can be an aldehyde or a ketone (eg, X ^1a is -CHO or -C(O)R ⁹ ).

Further, in Scheme 5, Q ^1a in Formula 5-A and 5-C is a boronic acid precursor group in Formula 1-D, where Z ^2a is boronic acid. A borylation reaction of formula 5-C is carried out to give a compound of formula 1-D. In some cases, a cross-coupling reaction of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) with an aryl halide can be used (for example , Maillard borylation reaction). In a Miyaura borylation reaction, Q ^la in formula 5-C may be a halide such as iodine or bromine. In some cases, formula 5-C may be reacted with 4,4,4',4',5,5, 5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) to give a compound of formula 1-D wherein Z ^2a is

In some cases, the borylation step includes a palladium catalyst such as palladium(II) acetate in combination with dicyclohexyl(2',6'-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine. Other borylation reactions may be used.

Accordingly, as detailed herein, the present disclosure relates to a process for preparing a compound of the present disclosure, comprising:

carrying out the reaction of a compound of the formula:

- 44 040107 with a compound of the formula:

resulting in a compound of the formula

R ⁴ R ³

where R ¹ , R ² , R ^{3 ,} R 4 , R ⁵ , R ⁶ , R ⁷ , R ⁸ , X ¹ , X ² , X ³ , Z ^1a , Z ^2a and Q are as defined herein. Accordingly, as detailed herein, the present disclosure relates to a process for preparing a compound of the present disclosure, comprising:

carrying out the reaction of a compound of the formula:

with formula compound:

resulting in a compound of the formula

wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , X ¹ , X ² , X ³ , Y ^1a and Q are as defined herein.

In some cases, the methods described above further include the step of forming a salt of the compound disclosed herein. Embodiments refer to other methods described herein and to a product obtained by any of the methods described herein. Except where otherwise indicated, the methods and techniques according to embodiments of the present invention are generally carried out in accordance with conventional techniques well known and described in various general and more specific sources and discussed herein. See, for example, Loudon, Organic Chemistry, ^5th edition, New York: Oxford Univer.

- 45 040107 sity Press, 2009, Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, ^7th edition, Wiley-Interscience, 2013.

List of abbreviations and abbreviations Abbreviation - meaning Ac - acetyl

B ₂ pin ₂ - 4,4,4',4',5,5,5',5'-oxtamethyl-2,2'-bi(1,3,2-dioxaborolane) bs - wide singlet °C - degrees Celsius d - doublet

DCM - dichloromethane dd - doublet of doublets DIPEA - N,N-diisopropylethylamine DMF - N,N-dimethylformamide DMSO - dimethyl sulfoxide dppf - 1,1'-bis(diphenylphosphino)ferrocene dtbpf - 1,1'-bis(di-tert-butylphosphino ) ferrocene EC ₅₀ - concentration providing half of the maximum effect eff./eq. - Et equivalents - ethyl EtOH - ethanol g - grams

HPLC - high performance liquid chromatography h/h - h Hz - Hertz J - binding constant

HPLC - Liquid Chromatography - Mass Spectrometry M - mol m - multiplet m/z - mass-to-charge ratio M+ - mass peak Me - methyl mg - milligram MHz - megahertz min - minute ml - milliliter mM - millimol mm - millimeter mmol - millimole - mole

MS - mass spectrometry MW (MB) - microwave nM - nanomolar NMP - N-methyl-2-pyrrolidone NMR - nuclear magnetic resonance P(oTol) ₃ - tri(o-tolyl)phosphine P(t-Bu) ₃ - three -tert-butylphosphine Pd ₂ (dba) ₃ - tris (dibenzylideneacetone) palladium (0) q- quartet quant. - quantitative Rf - retention factor RT/kt/k.t. - room temperature s - singlet us. - saturated

SPhos - dicyclohexyl(2',6'-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine t- triplet

TFA - trifluoroacetic acid TMS - trimethylsilyl Tr/tr - retention time UV - ultraviolet mass. - mass (weight)

Xantphos - (9,9-dimethyl-9H-xanthine-4,5-diyl) bis(diphenylphosphine) δ - chemical shift

- 46 040107 µl - microliter µm - micromolar µmol - micromol

The following examples are purely illustrative and do not limit the present invention in any way. Unless otherwise stated, preparative HPLC is performed on a Gilson HPLC system using a 21.2x250 mm 10 micron C18 Phenomenex Gemini semi-preparative column and a gradient of 0-100% acetonitrile in water as the mobile phase with 0.1% trifluoroacetic acid at flow rate 20 ml/min. Chemical names for all obtained compounds were generated using ChemBioDraw 12.0 software.

Although the structures in the examples below are depicted as specific geometric isomers, a specific geometric isomer (eg, E or Z isomer) or some ratio of E and Z isomers may be given in the title and/or description of an example.

The following methods were used to purify and analyze some of the compounds described in the following examples.

HPLC method 1 - Phenomenex Gemini-NX 3µ C18 110A column, 100x2 mm 3 µm, acetonitrile with 0.1% formic acid, water with 0.1% formic acid, 0-7.0 min 0-100% acetonitrile, flow rate 0.5 ml/min. HPLC Method 2 - Column Gemini 5µ C18 110A, 50x4.60 mm 5 µm, acetonitrile with 0.1% acetic acid, water with 0.1% acetic acid, gradient: 0-3.5 min 5-100% acetonitrile, speed flow 2 ml/min. HPLC method 3 - column Kinetex 2.6mk C18 100A, 50x3.00 mm, acetonitrile with 0.1% formic acid, water with 0.1% formic acid, gradient: 0-1.4 min 2-100% acetonitrile, 1 4-1.8 min 100% acetonitrile, 1.8-1.85 min 100-2% acetonitrile, 1.85-2 min 2% acetonitrile, flow rate 1.8 ml/min.

Example 1 (E)-4-((8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)benzonitrile Compound 1

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) heated at reflux for 15 hours. The resulting solid was filtered and washed twice with cold isopropanol (2x10 ml). The product was air dried to give the title compound 1a.

1H-NMR (400 MHz, DMSO-d ₆ ) δ 10.76 (s, 1H), 9.47 (s, 1H), 8.41 (d, J=8.8 Hz, 2H), 8.28 (dd, J=7.8, 1.2Hz, 1H), 8.06 (dd, J=7.8, 1.2Hz, 1H), 7.85 (d, J=8.8Hz, 2H), 7.44 (t, J=7.8 Hz, 1H). High resolution mass spectroscopy (electrospray ionization - ESI+) calc. for C ₁₅ H ₁₀ N ₄ Br [M+H] 325.00834, exp. 325.00821. HPLC (m/z) 325.0 [M+H], retention time=4.69 min (HPLC method 1).

- 47 040107

Step 2: Synthesis of (E)-3-(4-bromo-3,5-dimethylphenyl)acrylonitrile (compound 1b)

Vg = \ ? ^Г ifV ^N - ξΎ

I Pd(OAc) ₂ +P(oTol) ₃ Τ

Vg

NEt ₃ /CH ₃ CN

110°C ||

N connection 1b

To a solution of 2,5-dibromo-1,3-dimethylbenzene (2640 mg, 10 mmol, Oakwood Products, Inc. - 018507) in anhydrous acetonitrile (25 mL) was added palladium(II) acetate (112 mg, 0.5 mmol) , acrylonitrile (531 mg, 10 mmol), tri(o-tolyl)phosphine (131 mg, 0.5 mmol) and triethylamine (4 ml, 30 mmol), then the mixture was purged with argon and heated at 110°C for 2 h The reaction mixture was filtered through celite and washed with tetrahydrofuran (10 ml) filter media. The filtrate was evaporated, then redissolved with ethyl acetate (50 ml). The solution was washed with water (50 ml). The aqueous layer was subjected to back extraction 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 chromatographed on silica gel (0-20% ethyl acetate in iso-hexanes gradient) to give a crude product which was sonicated in 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 give compound 1b.

¹ H-NMR (400 MHz, CDCl3) δ 7.25 (d, J=16.6 Hz, 1H), 7.12 (s, 2H), 5.84 (d, J=16.6 Hz, 1H ), 2.42 (s, 6H). HPLC (m/z) no MS signal, retention time = 2.78 min (HPLC method 2).

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

Compound 1b mixture (391 mg, 1.66 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (630 mg, 2.48 mmol), potassium carbonate (687 mg, 5 mmol), palladium(II) acetate (19 mg, 0.08 mmol), and dicyclohexyl(2',6'-dimethoxy-[1,1' -biphenyl]-2-yl)phosphine (SPhos, 85 mg, 0.21 mmol) in dry N,N-dimethylformamide (20 ml) was purged with argon and heated at 100° C. for 1 h. The reaction mixture was filtered through celite and washed filter media with tetrahydrofuran (10 ml). The filtrate was evaporated, then redissolved with ethyl acetate (50 ml). The solution was washed with water (50 ml). The aqueous layer was subjected to back extraction with ethyl acetate (50 ml). The combined organics were washed with brine (30 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a crude residue which was purified by silica gel chromatography (0-20% ethyl acetate in iso-hexanes gradient) to resulting in compound 1c.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.28 (d, J=16.6 Hz, 1H), 7.00 (s, 2H), 5.84 (d, J=16.6 Hz, 1H), 2.39(s, 6H), 1.37(s, 12H). HPLC (m/z) 284.3 [M+H], retention time=2.85 min (HPLC method 2).

- 48 040107

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

PdCl2(dppf).CH ₂ Cl2

K ₂ CO ₃ , SiOAc,

DMF 100 °C

N

N

A mixture of compound 1a (50 mg, 0.15 mmol), compounds

Compound 1

1c (129 mg, 0.45 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(11), complexed with dichloromethane, (100 mg, 0.12 mmol), potassium carbonate (64 mg, 0 .45 mmol) and copper(1) acetate (19 mg, 0.15 mmol) in dry Ν,N-dimethylformamide (5 ml) were purged with argon and heated at 100°C for 15 h. The solvent was removed under reduced pressure and subjected to silica gel chromatography crude mixture (gradient from 0-30% ethyl acetate in iso-hexanes). The crude product was again purified by HPLC (Phenomenex Gemini 10 micron C18 preparative column, 250x21.2 mm, 10 ml/min, gradient from 10-100% acetonitrile in water) to give the title compound 1.

1H-NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H), 9.50 (s, 1H), 8.09 (d, J=7.8 Hz, 1H), 7.70- 7.87 (m, 4H), 7.63 (t, J=7.8 Hz, 1H), 7.61 (s, 2H), 7.40 (d, J=8.8 Hz, 2H), 6.62 (d, J=16.7 Hz, 1H), 1.94 (s, 6H). High resolution mass spectroscopy (electrospray ionization -ESI+) calc. for C ₂₆ H2 ₀ N ₅ [M+H] 402.17132, exp. 402.17126. HPLC (m/z) 402.2 [M+H], retention time = 4.91 min (HPLC method 1).

Example 2

Co-

Stage 1: synthesis of (E)-3-(4-(4-amino-2-chloroquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile (compound 2a)

- 49 040107

A mixture of 8-bromo-2-chloroquinazolin-4-amine (129 mg, 0.5 mmol, Ark Pharm Inc, AK-28702), compound 1c (184 mg, 0.65 mmol), tribasic potassium phosphate (159 mg, 0 .75 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (65 mg, 0.10 mmol) were dissolved in N,N-dimethylformamide:water (85:15, 40 mL) under argon. The reaction mixture was heated to 80°C for 30 min. The reaction mixture was cooled to room temperature and diluted with water and ethyl acetate. The organic layer was separated and washed twice with brine, dried over magnesium sulfate, 0.5 volume equivalent of hexane was added, and the mixture was filtered through a 2 cm pad of silica gel, which was washed with additional ethyl acetate. The combined organics were concentrated under reduced pressure and the residue was treated with diethyl ether in an ultrasonic bath. The resulting solid was filtered off and washed twice with diethyl ether and once with hexane to give the title compound 2a.

¹ H-NMR (400 MHz, DMSO-de) δ 8.38 (bs, 2H), 8.28 (dd, J=8.1, 1.6 Hz, 1H), 7.66-7.52 ( m, 3H), 7.43 (s, 2H), 6.46 (d, J=16.7 Hz, 1H), 1.86 (s, 6H). HPLC (m/z) 335.2 [M+H], retention time=2.48 min (HPLC method 2).

Step 2: Synthesis of (E)-4-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)benzonitrile (compound 2)

A mixture of compound 2a (100 mg, 0.30 mmol), 4-cyanoaniline (46 mg, 0.388 mmol, Sigma-Aldrich) and a solution of hydrogen chloride in 1,4-dioxane (4 M, 7 μl, 0.03 mmol) in dry K-methyl-2-pyrrolidone (2 ml) was heated at 120° C. for 2 hours. The reaction mixture was cooled to room temperature and triethylamine (0.1 ml, 0.72 mmol) was added. After 15 min water (5 ml) was added, the solid was filtered off and washed with water. The crude residue was diluted in dichloromethane/diethyl ether (1:1.5 ml) and then sonicated for 3 minutes. The solid compound was filtered off and washed with diethyl ether (5 ml) to give the title compound 2.

¹ H-NMR (400 MHz, DMSO-d6) δ 9.44 (s, 1H), 8.18 (dd, J=8.2, 1.5 Hz, 1H), 7.74 (d, J= 16.7 Hz, 1H), 7.70 (d, J=8.9 Hz, 2H), 7.51 (s, 2H), 7.48 (dd, J=7.1, 1.3 Hz, 1H), 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). High resolution mass spectroscopy (electrospray ionization - ESI+) calc. for C2 ₆ H ₂₁ N ₆ [M+H] 417.1822, exp.417.1820. HPLC (m/z) 417.2 [M+H], retention time=4.68 min (HPLC method 1).

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

N

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

- 50 040107

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 by microwave radiation at 180°C for 8 h. The reaction mixture was cooled to room temperature, the solid was filtered off and washed with cold isopropanol and then with diethyl ether and hexane, which gave compound 3a as a salt with HCl.

¹ H-NMR (400 MHz, DMSO-dg) δ 8.24 (d, J=8.1 Hz, 1H), 8.07 (d, J=7.6 Hz, 1H), 7.59 (d , J=8.5Hz, 1H), 7.42(dd, J=8.6, 1.9Hz, 1H), 7.37-7.04(m, 5H), 3.99(s, 3H). HPLC (m/z) 370.3 [M+H], retention time=2.43 min (HPLC method 2).

Step 2: Synthesis of (E)-4-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)-2methoxybenzonitrile (compound 3)

A mixture of compound 3a (50 mg, 0.14 mmol), compound 1c (76 mg, 0.27 mmol), [1,1'bis(diphenylphosphino)ferrocene]dichloropalladium(II), in complex with dichloromethane, (33 mg, 0.04 mmol), tribasic potassium phosphate (86 mg, 0.41 mmol) and copper(I) acetate (2 mg, 0.01 mmol) in dry N,Ndimethylformamide (5 ml) was purged with argon and heated at 120°C within 3 hours the Reaction mixture was cooled to room temperature and diluted with water and ethyl acetate. The organic layer was separated and washed twice with brine, dried over magnesium sulfate, 1 volume equivalent of hexane was added and the mixture was filtered through a three cm pad of silica gel, which was washed with additional ethyl acetate. The combined organics were concentrated under reduced pressure and the crude mixture was chromatographed on silica gel (550% ethyl acetate in iso-hexanes gradient). The product was then repurified by reverse phase chromatography (5-100% acetonitrile in water with 0.1% trifluoroacetic acid) to give the trifluoroacetic acid salt of compound 3.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.25 (bs, 1H), 7.74-7.65 (m, 2H), 7.62-7.42 (m, 5H), 7 .30 (d, J=9.0 Hz, 2H), 7.26 - 6.95 (m, 1H), 6.53 (d, J=17.0 Hz, 1H), 3.41 (s, 3H), 1.93(s, 6H). HPLC (m/z) 447.4 [M+H], retention time = 2.39 min (HPLC method 2).

Example 4 (E)-4-((8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-fluoroquinazolin-2-yl)amino)benzonitrile Compound 4

- 51 040107

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 N- methylpyrrolidone was heated by microwave at 200° C. for 5 hours. The reaction mixture was cooled to room temperature and subjected to silica gel chromatography (5-50% ethyl acetate in iso-hexanes gradient) to give the title compound 4a.

¹ H-NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 9.37 (s, 1H), 8.32 (d, J=8.7 Hz, 2H), 8.26 (dd, J=8.5, 2.7Hz, 1H), 7.86 (dd, J=8.5, 2.7Hz, 1H), 7.78 (d, J=8.7Hz, 2H). HPLC (m/z) 343.0 [M+H], retention time=4.72 min (HPLC method 1).

Step 2: Synthesis of (E)-4-((8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-fluoroquinazolin-2-yl)amino)benzonitrile (compound 4)

B ₂ pin ₂

1) PdCI ₂ (dppf). CH ₂ CI ₂ KOAc, DM ^f A, Yu0 "S

2) PdCI ₂ (dppf). CH ₂ CI ₂ K ₂ CO ₃ , DMF, 100 ° C

Br

N Connection 4

A mixture of compound 4a (50 mg, 0.14 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (40 mg, 0.16 mmol), potassium acetate (60 mg, 0.61 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexed with dichloromethane, (50 mg, 0.061 mmol ), in dry N,N-dimethylformamide (5 ml) was purged with argon and heated at 100°C for 1 h. A mixture of compound 1b (33 mg, 0.14 mmol), [1,1'-bis (diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (50mg, 0.061mmol) and potassium carbonate (90mg, 0.65mmol). The reaction mixture was heated to 100°C for 5 h, cooled to room temperature, concentrated under reduced pressure and subjected to chromatography on silica gel (gradient from 5-50% ethyl acetate in iso-hexanes). The crude product was again purified by HPLC (Phenomenex Gemini 10 micron C18 preparative column, 250x21.2 mm, 10 ml/min, gradient from 10-100% acetonitrile in water) to give the title compound 4.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.45 (s, 1H), 7.92-7.86 (m, 1H), 7.82-7.76 (m, 2H), 7 .72 (s, 1H), 7.68 (d, J=8.9 Hz, 2H), 7.58 (s, 2H), 7.36 (d, J=8.9 Hz, 2H), 6 .60 (d, J=16.7 Hz, 1H), 1.92 (s, 6H). HPLC (m/z) 420.1 [M+H], retention time = 4.85 min (HPLC method 1).

- 52 040107

Example 5 (E)-4-((8-(4-(2-cyanovinyl)-2,6-difluorophenyl)quinazolin-2-yl)amino)benzonitrile Compound 5 (mixture E/Z = 4/1)

N

II

N

Step 1: Synthesis of 4-((8-(2,6-difluoro-4-formylphenyl)quinazolin-2-yl)amino)benzonitrile (compound 5 a)

O _h / O V

A mixture of compound 1a (40 mg, 0.12 mmol), 3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzaldehyde (66 mg, 0.24 mmol, Sigma-Aldrich) and potassium fluoride (24 mg, 0.4 mmol) in tetrahydrofuran/water (10:1, 10 mL) was purged with argon and tris(dibenzylideneacetone)palladium(0) (68 mg, 0.07 mmol) followed by tri-tert-butylphosphine (36 µl, 0.14 mmol). This mixture was heated at 80° C. for 4 hours. The solvent was removed under reduced pressure, the residue was purified by silica gel chromatography (20-80% ethyl acetate in iso-hexanes gradient) to give the title compound 5a.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 10.55 (s, 1H), 10.15 (s, 1H), 9.51 (s, 1H), 8.16 (d, J=8 .0 Hz, 1H), 8.03 (d, J=7.0 Hz, 1H), 7.90 (d, J=6.9 Hz, 2H), 7.83 (d, J=8.8 Hz, 2H), 7.67-7.58 (m, 1H), 7.53 (d, J=8.8 Hz, 2H). HPLC (m/z) 387.1 [M+H], retention time=4.67 min (HPLC method 1).

Step 2: Synthesis of (E)-4-((8-(4-(2-cyanovinyl)-2,6-difluorophenyl)quinazolin-2-yl)amino)benzonitrile (compound 5) (mixture E/Z = 4/ 1)

N Connection 5

Cesium 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 μl, 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 overnight at room temperature. Dichloromethane was added to the residue and the solids were filtered off. The solvent was removed under reduced pressure and the residue was purified by HPLC (Phenomenex Gemini 10 micron C18 preparative column, 250 x 21.2 mm, 10 ml/min, gradient from 10-100% acetonitrile in water) to give the title compound 5 as a mixture of E/Z isomers 4/1.

¹ H-NMR for E isomer (400 MHz, DMSO-d ₆ ) δ 10.54 (s, 1H), 9.49 (s, 1H), 8.16-8.12 (m, 1H), 8 .0 (d, J=7.3 Hz, 1H), 7.87-7.83 (m, 3H), 7.73 (d, J=8.0 Hz, 2H), 7.63-7, 58 (m, 1H), 7.56-7.52 (m, 2H), 6.81 (d, J=16.7 Hz, 1H). HPLC (m/z) 410.1 [M+H], retention time=4.76 min (HPLC method 1).

- 53 040107

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-N-(cyclopropylmethyl)quinazoline-4-amine (compound 6a)

Cyclopropylmethanamine (95 µl, 1.1 mmol) and N-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 temperature for 30 minutes. The resulting solid was filtered and washed with water (2x5 ml) and pentane (3x5 ml) to give the title compound 6a.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.03 (s, 1H), 8.30 (dd, J=8.3 Hz, J=1.3 Hz, 1H), 8.12 ( dd, J=7.7 Hz, J=1.3 Hz, 1H), 7.44 (t, J=8.0 Hz, 1H), 3.41-3.35 (m, 2H), 1, 23-1.11 (m, 1H), 0.52-0.45 (m, 2H), 0.34-0.28 (m, 2H). High resolution mass spectroscopy (electrospray ionization - ESI+) calc. for C ₁₂ H ₁₂ N ₃ BrCl [M+H] 311.9898, exp. 311.9898. HPLC (m/z) 312.0 [M+H], retention time 4.59 min (HPLC method 1).

Step 2: Synthesis of 4-((8-bromo-4-((cyclopropylmethyl)amino)quinazolin-2-yl)amino)benzonitrile hydrochloride (compound 6b)

N Compound 6b

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 by microwave radiation at 180°C for 2 h. The reaction mixture was cooled to room temperature, the solid was filtered off and washed twice with cold isopropanol and then three times with pentane, resulting in compound 6b as a salt with HCl.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.39 (d, J=7.7 Hz, 1H), 8.15-7.99 (m, 3H), 7.81 (d, J = 8.4 Hz, 2H), 7.33 (t, J=7.9 Hz, 1H), 3.53-3.45 (m, 2H), 1.30-1.17 (m, 1H) , 0.54-0.48 (m, 2H), 0.37-0.32 (m, 2H). High resolution mass spectroscopy (electrospray ionization - ESI+) calc. for C ₁₉ H ₁₇ N ₅ Br [M+H] 394.0662, exp. 394.0661. HPLC (m/z) 394.0 [M+H], retention time 4.29 min (HPLC method 1).

Step 3: Synthesis of (E)-4-((8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-4-((cyclopropylmethyl)amino)quinazolin-2-yl)amino)benzonitrile (compound 6 )

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A mixture of compound 6b (65 mg, 0.15 mmol), compound 1c (64 mg, 0.23 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(11), in complex with dichloromethane, (37 mg, 0.05 mmol) and potassium carbonate (104 mg, 0.75 mmol) in a mixture of 1,4-dioxane and water (10:1.5 ml) was purged with argon and heated at 100°C for 1 h. Solvents removed under reduced pressure and purified the residue by silica gel chromatography (20-40% ethyl acetate in iso-hexanes gradient) to give the title compound 6.

¹ H-NMR (400 MHz, DMSO-06) δ 9.49 (s, 1H), 8.39 (t, J=5.6 Hz, 1H), 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, 1H), 7.35 ( t, J=8.2 Hz, 1H), 7.26 (d, J=8.9 Hz, 2H), 6.54 (d, J=16.7 Hz, 1H), 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). High resolution mass spectroscopy (electrospray ionization - ESI+) calc. for C ₃₀ H ₂₇ N ₆ [M+H] 471.2292, exp. 471.2292. HPLC (m/z) 471.2 [M+H], retention time 4.05 min (HPLC method 1).

Example 7 (E)-4-((4-(butylamino)-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)benzonitrile Compound 7

N-butylamine (109 µl, 1.1 mmol) and N-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 temperature for 30 minutes. The resulting solid was filtered off and washed with water (2x5 ml) and pentane (3x5 ml) to give the title compound 7a.

¹ H-NMR (400 MHz, DMSO-dg) δ 8.87 (s, 1H), 8.27 (dd, J=8.3 Hz, J=1.2 Hz, 1H), 8.12 (dd , J=1.1 Hz,

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J=1.2Hz, 1H), 7.43(t, J=7.9Hz, 1H), 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, 3H). High resolution mass spectroscopy (electrospray ionization - ESI+) calc. for C ₁₂ H ₁₄ N ₃ BrCl [M+H] 314.0054, exp. 314.0055. HPLC (m/z) 314.0 [M+H], retention time 4.76 min (HPLC method 1).

Step 2: Synthesis of 4-((8-bromo-4-(butylamino)quinazolin-2-yl)amino)benzonitrile hydrochloride (compound 7b)

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 by microwave radiation at 180°C for 2 h. The reaction mixture was cooled to room temperature, the solid was filtered off and washed twice with cold isopropanol and then three times with pentane to give compound 7b as the HCl salt.

¹ H-NMR (400 MHz, DMSO-d ₆ ) 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, 1H), 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). High resolution mass spectroscopy (electrospray ionization - ESI+) calc. for C ₁₉ H ₁₉ N ₅ Br [M+H] 396.0818, exp. 396.0816. HPLC (m/z) 396.1 [M+H], retention time 4.34 min (HPLC method 1).

Step 3: Synthesis of (E)-4-((4-(butylamino)-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)benzonitrile (compound 7)

A mixture of compound 7b (65 mg, 0.15 mmol), compound 1c (64 mg, 0.23 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), in complex with dichloromethane, (37 mg , 0.05 mmol) and potassium carbonate (104 mg, 0.75 mmol) in a mixture of 1,4-dioxane and water (10:1.5 ml) was purged with argon and heated at 100°C for 1 h. The solvents were removed under reduced pressure and purify the residue by silica gel chromatography (20-40% ethyl acetate in iso-hexanes gradient) to give the title compound 7.

¹ H-NMR (400 MHz, DMSO-d6) 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, 1H), 7.34 (t, J=8.2 Hz, 1H), 7.27 ( d, J=8.9 Hz, 2H), 6.54 (d, J=16.7 Hz, 1H), 3.63-3.51 (m, 2H), 1.90 (s, 6H), 1.72-1.65 (m, 2H), 1.46-1.38 (m, 2H), 0.95 (t, J=7.4 Hz, 3H). MS-ESI+ m/z (%): 473 (100, M+H+), 495 (20, M+Na ⁺ ), high resolution Macc spectroscopy (electrospray ionization - ESI+) calc. for C ₃₀ H ₂₉ N ₆ [M+H] 473.2448, exp. 473.2448. HPLC (m/z) 473.3 [M+H], retention time 4.14 min (HPLC method 1).

Example 8 (E)-4-((4-Amino-8-(4-(2-cyanovinyl)-2,6-difluorophenyl)quinazolin-2-yl)amino)benzonitrile Compound 8 (E/Z mixture = 3 /2)

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A mixture of 8-bromo-2-chloroquinazolin-4-amine (259 mg, 1 mmol, Ark Pharm Inc, AK-28702) and 4-aminobenzonitrile (130 mg, 1.1 mmol, Sigma-Aldrich) in isopropanol (5 ml) was heated by microwave irradiation at 160°C for 3 hours. The reaction mixture was cooled to room temperature, the solid was filtered off and washed with cold isopropanol and then with diethyl ether, resulting in compound 2a.

¹ H-NMR (400 MHz, DMSO-a ₆ ) 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, J=8.8 Hz, 2H), 7.16 (t, J=7.8 Hz, 1H). High resolution mass spectroscopy (electrospray ionization - ESI+) calc. for C ₁₅ HnN ₅ Br [M+H] 340.0192, exp. 340.0192. HPLC (m/z) 340.0 [M+H], retention time = 4.06 min (HPLC method 1).

Step 2: Synthesis of 4-((4-amino-8-(2,6-difluoro-4-formylphenyl)quinazolin-2-yl)amino)benzonitrile (compound 8b)

N Compound 8b

A mixture of compound 8a (120 mg, 0.36 mmol), 3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)benzaldehyde (285 mg, 1.06 mmol, Sigma-Aldrich) and potassium fluoride (102 mg, 1.76 mmol) in tetrahydrofuran/water (10:1, 30 mL) was purged with argon and tris(dibenzylideneacetone)palladium(0) (195 mg, 0.213 mmol) was added and then tri-tert-butylphosphine (103 µl, 0.43 mmol). The mixture was heated at 80° C. for 4 hours. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (20-80% ethyl acetate in iso-hexanes gradient) to give the title compound 8b.

¹ H-NMR (400 MHz, DMSO-d6) 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). HPLC (m/z) 401.9 [M+H], retention time = 4.28 min (HPLC method 1).

Step 3: Synthesis of (E)-4-((4-Amino-8-(4-(2-cyanovinyl)-2,6-difluorophenyl)quinazolin-2-yl)α-mino)benzonitrile (compound 8) (mixture E/ Z=3/2)

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N, F

N

N Connection 8

Cesium 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 μl, 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 overnight at room temperature. Dichloromethane was added to the residue and the solids were filtered off. The solvent was removed under reduced pressure and the residue was purified by HPLC (Phenomenex Gemini 10 micron C18 preparative column, 250x21.2 mm, 10 ml/min, gradient from 10-100% acetonitrile in water) to give the title compound 8 in as a mixture of E/Z isomers 3/2.

¹ H-NMR for E-isomer (400 MHz, DMSOCH) δ 9.54 (s, 1H), 8.29-8.24 (m, 2H), 7.84 (d, J=2.4 Hz, 1H), 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). HPLC (m/z) 424.9 [M+H], retention time = 3.46 min (HPLC method 1).

Example 9 (E)-5-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)picolinonitrile Compound 9

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, AK-26123) in isopropanol (10 ml) was heated in an argon atmosphere with microwave radiation at 180°C for 8 h. The reaction mixture was cooled to room temperature, the solid was filtered off and washed with cold isopropanol and then with diethyl ether and hexane, resulting in compound 9a.

¹ H-NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 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, 1H), 8.03 (dd, J=7.6, 1.3 Hz, 1H ), 7.95-7.91 (m, 2H), 7.23-7.10 (m, 2H). HPLC (m/z) 343.2 [M+H], retention time = 2.31 min (HPLC method 2).

Step 2: Synthesis of (E)-5-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)picolinonitrile (compound 9)

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Compound 9a (150 mg, 0.44 mmol), compound 1c (498 mg, 1.76 mmol), tribasic potassium phosphate (560 mg, 2.64 mmol) and 1,1'-bis(di-tert-butylphosphino) ferrocenepalladium dichloride (57 mg, 0.09 mmol) was dissolved in N,N-dimethylformamide: water (85:15, 25 mL) under argon. The reaction mixture was heated at 90° C. for 1 hour. The reaction mixture was cooled to room temperature and diluted with water and ethyl acetate. The organic layer was separated. The aqueous layer was washed with more ethyl acetate. The combined organics were washed twice with brine and dried over magnesium sulfate. The solvents were removed under reduced pressure and the residue was purified by silica gel chromatography (gradient 0 to 40% ethyl acetate and methanol (4/1) in iso-hexanes). The solvents were removed under reduced pressure and the solid residue was treated with hexane/diethyl ether (5:1) in an ultrasonic bath for 5 min, filtered and washed with hexane to give the title compound 9.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.70 (s, 1H), 8.74 (d, J=2.5 Hz, 1H), 8.24-8.15 (m, 2H ), 7.72 (d, J=16.7 Hz, 1H), 7.49 (d, J=7.6 Hz, 3H), 7.40-7.30 (m, 2H), 6.51 (d, J=16.7 Hz, 1H), 1.90 (s, 6H). HPLC (m/z) 418.3 [M+H], retention time = 2.47 min (HPLC method 2).

Example 10 (E)-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)nicotinonitrile Compound 10

N

Synthesis of (E)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)nicotinonitrile (compound 10)

Compound 2a (820 mg, 2.45 mmol), 6-aminonicotinonitrile (875 mg, 7.35 mmol, Ark Pharm Inc, AK-32349), N,N-diisopropylethylamine (DIPEA) (2.53 g, 19.6 mmol), (9,9-dimethyl-9H-xanthine-4,5diyl)bis(diphenylphosphine) (Xantphos) (Xantphos) (142 mg, 0.25 mmol) and palladium(II) acetate (55 mg, 0.25

- 59 040107 mmol) were combined under argon in N-methyl-2-pyrrolidone (40 ml). The reaction mixture was heated at 120° C. in a closed vessel for 4 hours. The reaction mixture was cooled to room temperature and diluted with water and ethyl acetate. The organic layer was separated and washed twice with brine, dried over magnesium sulfate, 0.05 volume equivalents of hexane, and filtered the mixture through a 2 cm plug of silica gel, which was washed with additional ethyl acetate.

The combined organics were concentrated under reduced pressure. The crude residue was treated with diethyl ether/dichloromethane (1:1) in an ultrasonic bath for 5 minutes. The solid was filtered off and washed twice with diethyl ether and once with hexane to give the title compound 10.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.58 (s, 1H), 8.57 (dd, J=2.4, 0.8 Hz, 1H), 8.20 (dd, J =8.3, 1.4Hz, 1H), 7.95 (dd, J=9.0, 0.8Hz, 1H), 7.73 (d, J=16.7Hz, 1h), 7 .55-7.51 (m, 3H), 7.44-7.36 (m, 2H), 6.53 (d, J=16.7 Hz, 1H), 1.90 (s, 6H). HPLC (m/z) 418.3 [M+H], retention time = 1.82 min (HPLC method 2).

Example 11 (E)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)pyridazin-3-carbonitrile Compound 11

Synthesis of (E)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)pyridazin-3carbonitrile (compound 11)

Compound 2a (20 mg, 0.06 mmol), 6-aminopyridazine-3-carbonitrile (22 mg, 0.18 mmol, Matrix Scientific, 112287), N,N-diisopropylethylamine (DIPEA) (62 mg, 0.47 mmol ), (9,9-dimethyl-9H-xanthine-4,5diyl)bis(diphenylphosphine) (Xantphos) (Xantphos) (3 mg, 0.006 mmol) and palladium(II) acetate (1 mg, 0.006 mmol) were combined under atmosphere argon in N-methyl-2-pyrrolidone (2 ml). The reaction mixture was heated at 120° C. in a closed vessel for 1 hour. The reaction mixture was cooled to room temperature and purified by reverse phase HPLC chromatography (0-100% acetonitrile in water with 0.1% trifluoroacetic acid) to give trifluoroacetate of compound 11.

1H-NMR (400 MHz, DMSO-d ₆ ) δ 8.35 (bs, 1H), 8.09 (bs, 1H), 7.78-7.39 (m, 6H), 6.54 (d, J=16.7 Hz, 1H), 1.93 (s, 6H). HPLC (m/z) 419.3 [M+H], retention time = 2.03 min (HPLC method 2).

Example 12 (E)-5-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)pyrazine-2-carbonitrile Compound 12

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

Compound 2a (20 mg, 0.06 mmol), 5-aminopyrazine-2-carbonitrile (22 mg, 0.18 mmol, Ark Pharm Inc, AK-21935), N,N-diisopropylethylamine (DIPEA) (62 mg, 0 .47 mmol), (9,9-dimethyl-9H-xanthine-4,5diyl)bis(diphenylphosphine) (Xantphos) (Xantphos) (3 mg, 0.006 mmol) and palladium(II) acetate (1 mg, 0.006 mmol) combined under argon in N-methyl-2-pyrrolidone (1 ml). The reaction mixture was heated at 120° C. in a closed vessel for 3 hours. The reaction mixture was cooled to room temperature and purified by reverse phase chromatography (0-100% acetonitrile in water with 0.1% trifluoroacetic acid) to give the trifluoroacetate of the compound 12.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.98 (bs, 1H), 8.36 (bs, 1H), 7.85-7.28 (m, 6H), 6.59 (d , J=15.6 Hz, 1H), 1.94 (s, 6H). HPLC (m/z) 419.3 [M+H], retention time = 1.89 min (HPLC method 2).

Example 13 (E)-6-((8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)nicotinonitrile Compound 13

N

Stage 1: synthesis of (E)-3-(4-(2-chloroquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile (compound 13a)

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Mixture of 8-bromo-2-chloroquinazoline (500 mg, 2.05 mmol, Ark Pharm Inc, AK-27609), compound 1c (776 mg, 2.67 mmol), tribasic potassium phosphate (633 mg, 3.08 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (134mg, 0.21mmol) was dissolved in N/N-dimethylformamide:water (85:15, 10mL) under argon. The reaction mixture was heated to 50° C. for 2 hours. The reaction mixture was cooled to room temperature and diluted with water and ethyl acetate. The organic layer was separated and washed twice with brine, dried over magnesium sulfate, 0.5 volume equivalents of hexane was added and the mixture was filtered through a 2 cm pad of silica gel, which was washed with additional hexane/ethyl acetate (1/1). The combined organics were concentrated under reduced pressure and the residue was treated with diethyl ether in an ultrasonic bath. The resulting solid was filtered and washed twice with diethyl ether and once with hexane to give the title compound 13a.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.70 (s, 1H), 8.30 (dd, J=7.1, 2.5 Hz, 1H), 7.99-7.84 (m, 2H), 7.66 (d, J=16.7 Hz, 1H), 7.49 (s, 2H), 6.50 (d, J=16.7 Hz, 1H), 1.85 (s, 6H). HPLC (m/z) 320.1 [M+H], retention time = 1.40 min (HPLC method 3).

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

Compound 13a (508 mg, 1.60 mmol), 6-aminonicotinonitrile (567 mg, 4.77 mmol, Ark Pharm Inc, AK-32349), N/N-diisopropylethylamine (DIPEA) (1.64 g, 12.71 mmol), (9,9-dimethyl-9H-xanthine-4,5diyl)bis(diphenylphosphine) (Xantphos) (Xantphos) (93 mg, 0.16 mmol) and palladium(II) acetate (36 mg, 0.16 mmol) were combined under argon in N-methyl-2-pyrrolidone (10 ml). The reaction mixture was heated at 80°C in a closed vessel for 30 min. The reaction mixture was cooled to room temperature and diluted with water and ethyl acetate. The organic layer was separated and washed twice with brine, dried over magnesium sulfate, 0.5 volume equivalents of hexane was added and the mixture was filtered through a 2 cm pad of silica gel, which was washed with additional hexane/ethyl acetate (1/1). The combined organics were concentrated under reduced pressure. The crude residue was treated with diethyl ether in an ultrasonic bath for 5 minutes. The solid was filtered off and washed twice with diethyl ether and once with hexane to give the title compound 13.

¹ H-NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 9.52 (s, 1H), 8.66 (dd, J=2.3, 0.9 Hz, 1H) , 8.10 (dd, J=8.0, 1.4 Hz, 1H), 7.92 (dd, J=8.9, 0.9 Hz, 1H), 7.85-7.70 (m , 2H), 7.65 (dd, J=8.1, 7.1 Hz, 1H), 7.57-7.48 (m, 3H),

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6.56 (d, J=16.7 Hz, 1H), 1.89 (s, 6H). HPLC (m/z) 403.2 [M+H], retention time = 1.48 min (HPLC method 3).

Example 14 (E)-6-((8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-fluoroquinazolin-2-yl)amino)nicotinonitrile Compound 14

A mixture of compound 1c (100 mg, 0.35 mmol), 8-bromo-2-chloro-6-fluoroquinazoline (100 mg, 0.38 mmol, Ark Pharm Inc, AK-93358), 1,1'-bis(di -tert-butylphosphino)ferrocenepalladium dichloride (50mg, 0.08mmol) and tribasic potassium phosphate monohydrate (200mg, 0.77mmol) in N,N-dimethylformamide (3mL) and water (0.3mL) were heated in argon atmosphere at 80°C for 30 min. The reaction mixture was evaporated to dryness and the residue was purified by silica gel chromatography. This was chromatographed on silica gel (gradient from 0-100% ethyl acetate in iso-hexanes) to give compound 14a. HPLC (m/z) 337.9 [M+H], retention time = 4.52 min (HPLC method 1).

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

Compound 14aa (100 mg, 0.30 mmol), 6-aminonicotinonitrile (200 mg, 1.68 mmol, Ark Pharm Inc, AK-32349), N,N-diisopropylethylamine (DIPEA) (0.5 ml, 2.86 mmol), (9,9-dimethyl-9H-xanthine-4,5-diyl)bis(diphenylphosphine) (Xantphos) (Xantphos) (180 mg, 0.31 mmol) and palladium(I) acetate (40 mg, 0 .18 mmol) were combined under argon in N-methyl-2-pyrrolidone (3 ml). The reaction mixture was heated at 100° C. in a closed vessel for 1 h. The reaction mixture was cooled to room temperature and immediately purified by silica gel chromatography (gradient from 60-100% ethyl acetate in iso-hexanes followed by a gradient from 0-20% methanol in ethyl acetate) to give the title compound 14.

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1H-NMR (400 MHz, DMSO^) δ 9.62 (s, 1H), 8.77 (dd, J=2.3, 0.8 Hz, 1H), 8.08-7.99 (m, 1H), 7.99-7.91 (m, 1H), 7.87 (d, J=16.7 Hz, 1H), 7.68 (s, 2H), 7.65-7.60 (m , 1H), 7.60-7.53 (m, 1H), 7.36 (d, J=8.2, Hz, 1H), 6.68 (d, J=16.7 Hz, 1H), 2.01 (s, 6H). HPLC (m/z) 420.9 [M+H], retention time = 4.62 min (HPLC method 1).

Example 15 (E)-6-((4-Amino-8-(4-(2-cyαnovinyl)-2,6-dimethylphenyl)quinαzolin-2-yl)amino)-2,4-dimethylnicotinonitrile Compound 15

Synthesis of (E)-6-((4-αmino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)-2,4-dimethylnicotinonitrile (compound 15)

Compound 2a (20 mg, 0.06 mmol), 6-amino-2,4-dimethylnicotinonitrile (26 mg, 0.18 mmol, Key Organics Ltd, 1X-0933), N,N-diisopropylethylamine (DIPEA) (622 mg , 0.48 mmol), (9,9-dimethyl-9Hxanthine-4,5-diyl)bis(diphenylphosphine) (Xantphos) (Xantphos) (4 mg, 0.006 mmol) and palladium(II) acetate (1 mg, 0.006 mmol) were combined under argon in N-methyl-2-pyrrolidone (1 ml). The reaction mixture was heated at 120° C. in a closed vessel for 4 hours. The reaction mixture was cooled to room temperature and diluted with water and ethyl acetate. The organic layer was separated and washed twice with brine, dried over magnesium sulfate and this solution was filtered through a two cm pad of silica gel, which was washed with additional ethyl acetate. The combined organics were concentrated under reduced pressure. The crude residue was treated with diethyl ether in an ultrasonic bath for 5 minutes. The solid was filtered off and washed twice with diethyl ether and once with hexane to give the title compound 15.

¹ H-NMR (400 MHz, DMSO-d6) δ 9.56 (bs, 1H), 9.29 (bs, 1H), 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, 1H), 2.41 (bs, 3H), 1, 96 (s, 6H), 1.62 (bs, 3H). HPLC (m/z) 446.4 [M+H], retention time = 1.19 min (HPLC method 3).

Example 16 (E)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)-2-methylnicotinonitrile Compound 16

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

Compound 2a (20 mg, 0.06 mmol), 6-amino-2-methylnicotinonitrile (24 mg, 0.18 mmol, Ark Pharm Inc, AK-78835), N,N-diisopropylethylamine (DIPEA) (622 mg, 0 .48 mmol), (9,9-dimethyl-9H-xanthine-4,5diyl)bis(diphenylphosphine) (Xantphos) (Xantphos) (4 mg, 0.006 mmol) and palladium(II) acetate (1 mg, 0.006 mmol) combined under argon in N-methyl-2-pyrrolidone (1 ml). The reaction mixture was heated at 120° C. in a closed vessel for 4 hours. The reaction mixture was cooled to room temperature and diluted with water and ethyl acetate. The organic layer was separated and washed twice with brine, dried over magnesium sulfate and this solution was filtered through a two cm pad of silica gel, which was washed with additional ethyl acetate. The combined organics were concentrated under reduced pressure. The crude residue was treated with diethyl ether in an ultrasonic bath for 5 minutes. The solid was filtered off and washed twice with diethyl ether and once with hexane to give the title compound 16.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 10.92 (s, 1H), 9.55 (s, 1H), 9.10 (s, 1H), 8.46 (dd, J=8 .3, 1.3 Hz, 1H), 8.19 (d, J=2.2 Hz, 1H), 7.89-7.73 (m, 3H), 7.69 (s, 2H), 7 .32 (d, J=2.2 Hz, 1H), 6.68 (d, J=16.7 Hz, 1H), 2.37 (s, 3H), 1.95 (s, 6H). HPLC (m/z) 432.4 [M+H], retention time = 1.15 min (HPLC method 3).

Example 17 (E)-6-((4-αmino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)-5-methylnicotinonitrile Compound 17

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

Compound 2a (20 mg, 0.06 mmol), 6-amino-5-methylnicotinonitrile (24 mg, 0.18 mmol, Ark Pharm Inc, AK-25043), N,N-diisopropylethylamine (DIPEA) (622 mg, 0 .48 mmol), (9,9-dimethyl-9H-xanthine-4,5-65 040107 diyl) bis (diphenylphosphine) (Xantphos) (Xantphos) (4 mg, 0.006 mmol) and palladium(II) acetate (1 mg , 0.006 mmol) were combined under argon in N-methyl-2-pyrrolidone (1 ml). The reaction mixture was heated at 120° C. in a closed vessel for 4 hours. The reaction mixture was cooled to room temperature and diluted with water and ethyl acetate. The organic layer was separated and washed twice with brine, dried over magnesium sulfate and this solution was filtered through a two cm pad of silica gel, which was washed with additional ethyl acetate. The combined organics were concentrated under reduced pressure. The crude residue was treated with diethyl ether in an ultrasonic bath for 5 minutes. The solid was filtered off and washed twice with diethyl ether and once with hexane to give the title compound 17.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 10.92 (s, 1H), 9.55 (s, 1H), 9.10 (s, 1H), 8.46 (dd, J=8 .3, 1.3 Hz, 1H), 8.25-8.13 (m, 1H), 7.91-7.72 (m, 3H), 7.69 (s, 2H), 7.35- 7.29 (m, 1H), 6.68 (d, J=16.7 Hz, 1H), 2.37 (s, 3H), 1.95 (s, 6H). HPLC (m/z) 432.4 [M+H], retention time = 1.19 min (HPLC method 3).

Example 18 (E)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)-4-methylnicotinonitrile Compound 18

Synthesis of (E)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)-4-methylnicotinonitrile (compound 18)

Compound 2a (20 mg, 0.06 mmol), 6-amino-4-methylnicotinonitrile (24 mg, 0.18 mmol, Ark Pharm Inc, AK-80125), N,N-diisopropylethylamine (DIPEA) (622 mg, 0 .48 mmol), (9,9-dimethyl-9H-xanthine-4,5diyl)bis(diphenylphosphine) (Xantphos) (Xantphos) (4 mg, 0.006 mmol) and palladium(II) acetate (1 mg, 0.006 mmol) combined under argon in N-methyl-2-pyrrolidone (1 ml). The reaction mixture was heated at 120° C. in a closed vessel for 4 hours. The reaction mixture was cooled to room temperature and diluted with water and ethyl acetate. The organic layer was separated and washed twice with brine, dried over magnesium sulfate and this solution was filtered through a two cm pad of silica gel, which was washed with additional ethyl acetate. The combined organics were concentrated under reduced pressure. The crude residue was treated with diethyl ether in an ultrasonic bath for 5 minutes. The solid was filtered off and washed twice with diethyl ether and once with hexane to give the title compound 18.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 11.97 (bs, 1H), 9.55 (bs, 1H), 9.32 (bs, 1H), 8.48-8.37 (m , 1H), 7.907.62 (m, 5H), 7.52-7.43 (m, 1H), 7.32-7.23 (m, 1H), 6.69 (d, J=16.7 Hz, 1H), 2.45(s, 3H), 1.96(s, 6H). HPLC (m/z) 432.3 [M+H], retention time = 1.25 min (HPLC method 3).

Example 19 (E)-4-((4-amino-6-chloro-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)benzonitrile Compound 19

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A mixture of 2-amino-5-chlorobenzoic acid (5 g, 29 mmol, Ark Pharm Inc, AK-26989) and N-bromosuccinimide (5.4 g, 30 mmol) in N,N-dimethylformamide (100 ml) was stirred at room temperature for 14 hours. The reaction mixture was poured into water (400 ml) and the product was extracted with diethyl ether (400 ml). The organic phase was washed with brine (200 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound 19a. HPLC (m/z) 250.0 [M+H], retention time = 4.05 min (HPLC method 1).

Step 2: Synthesis of 8-bromo-6-chloroquinazolin-2,4(1H,3H)-dione (compound 19b)

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

Step 3: Synthesis of 8-bromo-2,6-dichloroquinazolin-4-amine (compound 19c)

A mixture of compound 19b (5.3 g, 21 mmol), phosphorus(V) oxychloride (15 ml) and N,N-dimethylformamide (3 drops) was heated at 120°C for 14 h. The reaction mixture was cooled, poured into water ( 200 ml) and filtered the product. The solid was dried under vacuum for 2 h, suspended in saturated ammonia in ethanol (50 ml) and stirred at room temperature for 14 h. The resulting solid was filtered to give the title compound 19c.

¹ H-NMR (400 MHz, DMSO-db) δ 8.65 (s, 2H), 8.47 (d, J=2.2 Hz, 1H), 8.25 (d, J=2.2 Hz , 1H). HPLC (m/z) 291.9 [M+H], retention time = 3.86 min (HPLC method 1).

Step 4: Synthesis of (E)-3-(4-(4-amino-2,6-dichloroquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile (compound 19d)

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A mixture of compound 19c (146 mg, 0.5 mmol), compound 1c (170 mg, 0.6 mmol), tribasic potassium phosphate monohydrate (230 mg, 1 mmol) and [1,H-bis(diphenylphosphino)ferrocene]dichloropalladium( P), in complex with dichloromethane, (65 mg, 0.1 mmol) was dissolved in a mixture of N,N-dimethylformamide and water (10:1, 5.5 ml) under argon and this mixture was stirred at 80°C for 30 min. The product was isolated by silica gel chromatography (gradient from 80-100% ethyl acetate in iso-hexanes) to give the title compound 19d. HPLC (m/z) 369.0 [M+H], retention time = 4.30 (HPLC method 1).

Step 5: Synthesis of (E)-4-((4-amino-6-chloro-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)benzonitrile (compound 19)

A mixture of compound 19d (85 mg, 0.23 mmol), 4-aminobenzonitrile (33 mg, 0.28 mmol, Sigma-Aldrich), palladium(II) acetate (10 mg, 0.046 mmol) and (9,9-dimethyl- 9H-xanthine-4,5-diyl)bis(diphenylphosphine) (27 mg, 0.046 mmol) was dissolved in N-methyl-2-pyrrolidone (2 ml) under argon. N/N-diisopropylethylamine (DIPEA) (174 µl, 1 mmol) was then added via syringe at 100°C for 1 h. The product was isolated by flash chromatography on silica gel (gradient from 40-60% ethyl acetate in iso-hexanes), and then purified again by reverse phase flash chromatography (5.5 g C-18 prepacked column, 5-100% gradient, acetonitrile in water) to give the title compound 19.

¹ H-NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 8.34 (d, J=2.3 Hz, 1H), 7.74 (d, J=16.7 Hz , 1H), 7.66 (d, J=8.9 Hz, 2H), 7.55 (d, J=2.3 Hz, 1H), 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). HPLC (m/z) 451.2 [M+H], retention time = 4.25 min (HPLC method 1).

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

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A mixture of 2-amino-5-fluorobenzoic acid (10 g, 65 mmol, Ark Pharm Inc, AK-35193) and N-bromosuccinimide (12 g, 67 mmol) in N,N-dimethylformamide (100 ml) was stirred at room temperature in over 14 hours. The reaction mixture was poured into water (500 ml), the solid was filtered off and washed with water to give the title compound 20a. HPLC (m/z) 233.7 [M+H], retention time = 3.75 min (HPLC method 1).

Step 2: Synthesis of 8-bromo-6-fluoroquinazoline-2,4(1H,3H)-dione (compound 20b)

A mixture of compound 20a (12 g, 51 mmol) and urea (20 g, 333 mmol) was heated at 200°C for 3 h. The reaction mixture was cooled and diluted with water (100 ml). The resulting solid was filtered off and washed with methanol (50 ml) to give the title compound 20b. HPLC (m/z) 259.0 [M+H], retention time = 3.23 min (HPLC method 1).

Step 3: Synthesis of 8-bromo-2-chloro-6-fluoroquinazolin-4-amine (compound 20c)

Connection 20s

A mixture of compound 20b (3 g, 20 mmol), phosphorus(V) oxychloride (20 ml) and N,N-dimethylformamide (3 drops) was heated at 120°C for 14 h. The reaction mixture was cooled, poured into a mixture of ice and water (200 ml), the solid product was filtered off. The solid was dried under vacuum for 2 h, suspended in a saturated solution of ammonia in ethanol (100 ml) and stirred at room temperature for 14 h. The reaction mixture was evaporated to dryness and the solid residue was suspended in water. The resulting solid was filtered off to give the title compound 20c.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.59 (s, 1H), 8.46 (s, 1H), 8.19 (dd, J=8.3, 2.7 Hz, 1H ), 8.13 (dd, J=9.2, 2.7 Hz, 1H). HPLC (m/z) 275.7 [M+H], retention time = 3.74 min (HPLC method 1).

Step 4: Synthesis of (E)-3-(4-(4-amino-2-chloro-6-fluoroquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile (compound 20d)

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A χθ B

N Connection 20d

Mixture of compound 20c (276 mg, 1 mmol), compound 1c (340 mg, 1.2 mmol), tribasic potassium phosphate monohydrate (460 mg, 2 mmol) and [1,H-bis(diphenylphosphino)ferrocene]dichloropalladium(II) , in complex with dichloromethane, (65 mg, 0.1 mmol) was dissolved in a mixture of N,N-dimethylformamide and water (10:1, 11 ml) under argon atmosphere and this mixture was stirred at 80°C for 30 min. The product was isolated by silica gel chromatography (gradient from 80-100% ethyl acetate in iso-hexanes) to give the title compound 20d. HPLC (m/z) 352.9 [M+H], retention time = 4.12 min (HPLC method 1).

Step 5: Synthesis of (E)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-fluoroquinazolin-2-yl)amino)nicotinonitrile (compound 20)

Compound 20

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-9H-xanthine-4,5-diyl)bis(diphenylphosphine) (58 mg, 0.1 mmol) was dissolved in N-methyl-2-pyrrolidone (5 ml) under argon. N,N-diisopropylethylamine (DIPEA) (348 µl, 2 mmol) was then added via syringe at 100°C for 1 h. The product was isolated by silica gel chromatography (gradient from 40-100% ethyl acetate in isohexanes) and then again was purified by reverse phase flash chromatography (5.5 g C-18 RediSep prepacked column, gradient 5-100%, acetonitrile in water with 0.1% TFA) to give the title compound 20 as a salt with trifluoroacetic acid.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.56 (bs, 1H), 9.46 (bs, 1H), 8.40-8.20 (m, 2H), 8.02-7 .84 (m, 1H), 7.82 (d, J=16.6 Hz, 1H), 7.69 (s, 2H), 7.51 (bs, 1H), 7.42 (bs, 1H) , 6.69 (d, J=16.6 Hz, 1H), 1.98 (s, 6H). HPLC (m/z) 435.8 [M+H], retention time = 3.45 min (HPLC method 1).

Example 21 (E)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-methylquinazolin-2-yl)amino)nicotinonitrile Compound 21

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N

N

Stage 1: synthesis of 2-amino-3-bromo-5-methylbenzoic acid (compound 21a)

A mixture of 2-amino-5-methylbenzoic acid (10 g, 66 mmol, Ark Pharm, Inc AK-34555) and N-bromosuccinimide (12 g, 67 mmol) in N,N-dimethylformamide (100 ml) was stirred at room temperature in over 14 hours. The reaction mixture was poured into water (500 ml), the solid was filtered off and washed with water, whereby the title compound 21a was obtained. HPLC (m/z) 229.80 [M+H], retention time = 3.87 min (HPLC method 1).

Step 2: Synthesis of 8-bromo-6-methylquinazoline-2,4(1H,3H)-dione (compound 21b)

Compound 21b

A mixture of compound 21a (5 g, 22 mmol) and urea (30 g, 500 mmol) was heated at 200°C for 3 h. The reaction mixture was cooled and diluted with water (100 ml). The resulting solid was filtered off and washed with methanol (50 ml) and water (50 ml) to give the title compound 21b. HPLC (m/z) 254.7 [M+H], retention time = 3.19 min (HPLC method 1).

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

Compound 21s

A mixture of compound 21b (5 g, 20 mmol), phosphorus(V) oxychloride (15 ml) and N,N-dimethylformamide (3 drops) was heated at 120°C for 14 h. The reaction mixture was cooled, poured into a mixture of ice and water (200 ml), the solid product was filtered off. The solid was dried under vacuum for 2 h, suspended in saturated ammonia in ethanol (100 ml) and stirred at room temperature for 14 h. The resulting solid was filtered to give the title compound 21c.

¹ H-NMR (400 MHz, DMSO-d6) δ 8.41 (s, 2H), 8.06 (d, J=1.7 Hz, 1H), 8.01 (d, J=1.7 Hz , 1H), 2.42(s, 3H). HPLC (m/z) 271.8 [M+H], retention time = 3.65 min (HPLC method 1).

Step 4: Synthesis of (E)-3-(4-(4-amino-2-chloro-6-methylquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile (compound 21d)

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A mixture of compound 21c (273 mg, 1 mmol), compound 1c (340 mg, 1.2 mmol), tribasic potassium phosphate monohydrate (460 mg, 2 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II ), in complex with dichloromethane, (65 mg, 0.1 mmol) was dissolved in a mixture of N,N-dimethylformamide and water (10:1, 5.5 ml) under argon atmosphere and this reaction mixture was stirred at 80°C for 30 min. The product was isolated by silica gel chromatography (40-100% ethyl acetate in iso-hexanes gradient) to give the title compound 21d. HPLC (m/z) 348.9 [M+H], retention time = 4.17 min (HPLC method 1).

Step 5: Synthesis of (E)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-methylquinazolin-2yl)amino)nicotinonitrile (compound 21)

A mixture of compound 21d (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-9H-xanthine-4,5-diyl)bis(diphenylphosphine) (58 mg, 0.1 mmol) was dissolved in N-methyl-2-pyrrolidone (5 ml) under argon. N,N-diisopropylethylamine (DIPEA) (435 µl, 2.5 mmol) was then added via syringe at 110° C. for 6 hours. The product was isolated by silica gel chromatography (40-100% ethyl acetate in isohexanes gradient) followed purified again by reverse phase flash chromatography (5.5 g C-18 RediSep prepacked column, gradient 5-100%, acetonitrile in water with 0.1% TFA) to give the title compound 21 as salt with trifluoroacetic acid.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.51 (s, 1H), 9.31 (s, 1H), 8.33-8.24 (m, 2H), 7.82 (d , J=16.7 Hz, 1H), 7.77-7.66 (m, 3H), 7.58-7.50 (m, 1H), 7.45-7.36 (m, 1H), 6.69 (d, J=16.7 Hz, 1H), 2.54 (s, 3H), 1.96 (s, 6H). HPLC (m/z) 432.0 [M+H], retention time = 3.56 min (HPLC method).

Example 22 (E)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-nitroquinazolin-2-yl)amino)nicotinonitrile Compound 22

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A mixture of 2-amino-5-nitrobenzoic acid (5 g, 27 mmol, Sigma-Aldrich) and N-bromosuccinimide (6 g, 34 mmol) in N/N-dimethylformamide (100 mL) was stirred at room temperature for 14 h. The reaction mixture was poured into water (500 ml), the solid was filtered off and washed with water to give the title compound 22a. HPLC (m/z) 261.03 [M+H], retention time = 3.70 min (HPLC method 1).

Step 2: Synthesis of 8-bromo-6-nitroquinazoline-2,4(1H,3H)-dione (compound 22b)

A mixture of compound 22a (5 g, 22 mmol) and urea (20 g, 333 mmol) was heated at 200°C for 3 h. The reaction mixture was cooled and diluted with water (100 ml). The resulting solid was filtered off and washed with methanol (50 ml) and water (50 ml) to give the title compound 22b. HPLC (m/z) 286.2 [M+H], retention time = 3.21 min (HPLC method 1).

Step 3: Synthesis of 8-bromo-2-chloro-6-nitroquinazolin-4-amine (compound 22c)

A mixture of compound 22b (5 g, 17 mmol), phosphorus(V) oxychloride (15 ml) and N,N-dimethylformamide (4 drops) was heated at 120°C for 14 h. The reaction mixture was cooled, poured into a mixture of ice and water (200 ml), the solid product was filtered off. The solid was dried under vacuum for 2 h, suspended in saturated ammonia in ethanol (100 ml) and stirred at room temperature for 14 h. The reaction mixture was concentrated under reduced pressure and water was added. The resulting solid was filtered off to give the title compound 22c.

¹ H-NMR (400 MHz, DMSO-d6) δ 9.34 (d, J=2.4 Hz, 1H), 8.79 (d, J=2.4 Hz, 1H). HPLC (m/z) 303.0 [M+H], retention time = 3.97 min (HPLC method 1).

Step 4: Synthesis of (E)-3-(4-(4-amino-2-chloro-6-nitroquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile (compound 22d)

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A mixture of compound 22c (152 mg, 0.5 mmol), compound 1c (170 mg, 0.6 mmol), tribasic potassium phosphate monohydrate (230 mg, 1 mmol) and [1,H-bis(diphenylphosphino)ferrocene]dichloropalladium( P) in complex with dichloromethane (33 mg, 0.05 mmol) was dissolved in a mixture of N,N-dimethylformamide and water (10:1, 5.5 ml) under argon atmosphere and this reaction mixture was stirred at 80°C for 7 h. The product was isolated by chromatography on silica gel (gradient from 40-100% ethyl acetate in iso-hexanes), resulting in the title compound 22d. HPLC (m/z) 379.9 [M+H], retention time = 4.40 min (HPLC method 1).

Step 5: Synthesis of (E)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-nitroquinazolin-2-yl)amino)nicotinonitrile (compound 22)

A mixture of compound 22d (110 mg, 0.29 mmol), 6-aminonicotinonitrile (171 mg, 1.45 mmol, Ark Pharm Inc, AK-32349), palladium(II) acetate (13 mg, 0.06 mmol) and ( 9,9-dimethyl-9H-xanthine-4,5diyl)bis(diphenylphosphine) (34 mg, 0.06 mmol) was dissolved in N-methyl-2-pyrrolidone (5 ml) under argon. N,N-diisopropylethylamine (DIPEA) (514 µl, 2.95 mmol) was then added via syringe at 100° C. over 1 hour. The product was isolated by silica gel chromatography (gradient from 40-100% ethyl acetate in iso-hexanes), and then purified again by reverse phase flash chromatography (prepacked 5.5 g C-18 RediSep column, gradient 5-100%, acetonitrile in water with 0.1% TFA) to give the title compound 22 in the form of a salt with trifluoroacetic acid.

1H-NMR (400 MHz, DMSO-d ₆ ) δ 9.43 (bs, 2H), 7.80 (d, J=16.7 Hz, 1H), 7.77-7.50 (m, 7H) , 7.48 (bs, 1H), 6.53 (d, J=16.7 Hz, 1H), 1.97 (s, 6H). HPLC (m/z) 463.0 [M+H], retention time = 3.98 min (HPLC method 1).

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

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

Compound 22 (20 mg, 0.043 mmol) was dissolved in methanol:acetic acid (10:1, 2 ml), iron powder (20 mg, 0.358 mmol) was added in one portion at room temperature over 24 h. The product was isolated by chromatography on silica gel (10-30% methanol in ethyl acetate gradient) and then purified again by reverse phase flash chromatography (5.5 g C-18 RediSep prepacked column, 5-100% gradient, acetonitrile in water with 0.1% TFA ) to give the title compound 23 as a salt with trifluoroacetic acid.

¹ H-NMR (400 MHz, DMSO-de) δ 9.22 (s, 1H), 9.04 (s, 1H), 8.26-8.21 (m, 1H), 7.82 (d, J=16.6Hz, 1H), 7.83-7.74(m, 1H), 7.68(s, 2H), 7.51(s, 1H), 7.38-7.32(m , 1H), 7.11 (s, 1H), 6.69 (d, J=16.6 Hz, 1H), 1.98 (s, 6H). HPLC (m/z) 433.1 [M+H], retention time = 3.68 min (HPLC method 1).

Example 24 (E)-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-methoxyquinazolin-2-yl)amino)nicotinonitrile Compound 24

A mixture of 2-amino-5-methoxybenzoic acid (3.95 g, 23.6 mmol, Sigma-Aldrich) and N-bromosuccinimide (4.2 g, 23.6 mmol) in K,K-dimethylformamide (80 mL) was stirred at room temperature for 14 hours. The reaction mixture was poured into water (400 ml), the solid was filtered off and washed with water to give the title compound 24a. HPLC (m/z) 245.8 [M+H], retention time = 4.06 min (HPLC method 1).

Step 2: Synthesis of 8-bromo-6-methoxyquinazoline-2,4(1H,3H)-dione (compound 24b)

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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 and diluted with water (100 ml). The resulting solid was filtered off and washed with water (50 ml) to give the title compound 24b.

Step 3: Synthesis of 8-bromo-2-chloro-6-methoxyquinazoline-4-amine (compound 24c)

A mixture of compound 24b (2.45 g, 9 mmol), phosphorus(V) oxychloride (10 ml) and N,N-dimethylformamide (5 drops) was heated at 120°C for 14 h. The reaction mixture was cooled, poured into a mixture of ice with water (200 ml), the solid product was filtered off. The solid was dried under vacuum for 2 h, suspended in saturated ammonia in ethanol (100 ml) and stirred at room temperature for 14 h. The reaction mixture was concentrated under reduced pressure and water (20 ml) was added. The resulting solid was filtered off to give the title compound 24c. HPLC (m/z) 287.7 [M+H], retention time = 4.33 min (HPLC method 1).

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

Mixture of compound 24c (30 mg, 0.1 mmol), compound 1c (34 mg, 0.12 mmol), tribasic potassium phosphate monohydrate (46 mg, 0.2 mmol) and [1,1'-bis(diphenylphosphino)ferrocene ]dichloropalladium(II) complexed with dichloromethane (13 mg, 0.02 mmol) was dissolved in a mixture of K,K-dimethylformamide and water (10:1, 2 ml) under argon and this reaction mixture was stirred at 80°C in within 30 min. The product was isolated by silica gel chromatography (gradient 50 to 100% ethyl acetate in iso-hexanes) to give the title compound 24d. HPLC (m/z) 364.9 [M+H], retention time = 4.65 min (HPLC method 1).

Step 5: Synthesis of (E)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-methoxyquinazolin-2yl)amino)nicotinonitrile (compound 24)

- 76 040107

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-9H-xanthine-4,5-diyl)bis(diphenylphosphine) (10 mg, 0.016 mmol) was dissolved in N-methyl-2-pyrrolidone (1 ml) under argon. N,N-diisopropylethylamine (DIPEA) (37 µl, 0.21 mmol) was then added via syringe at 100° C. over 2 hours. The product was isolated by silica gel chromatography (gradient from 60-100% ethyl acetate in iso-hexanes), and then purified again by reverse phase flash chromatography (5.5 g C-18 RediSep prepacked column, gradient 5-100%, acetonitrile in water with 0.1% TFA) to give the title compound 24 in salt form with trifluoroacetic acid.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 13.52 (bs, 1H), 11.99 (bs, 1H), 9.46 (bs, 1H), 9.26 (bs, 1H), 8.28 (s, 1H), 7.97 (s, 1H), 7.83 (d, J=16.7 Hz, 1H), 7.70 (s, 2H), 7.62-7.48 (m, 2H), 7.42-7.36 (m, 1H), 6.69 (d, J=16.7 Hz, 1H), 3.95 (s, 3H), 1.98 (s, 6H). HPLC (m/z) 448.0 [M+H], retention time = 3.95 min (HPLC method 1).

Example 25 (E)-4-((4-amino-6-bromo-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)benzonitrile Compound 25

Stage 1: synthesis of 2-amino-5-bromo-3-iodobenzoic acid (compound 25a)

A mixture of 2-amino-5-bromobenzoic acid (1 g, 4.6 mmol, Sigma-Aldrich) and N-iodosuccinimide (1.9 g, 8.4 mmol) in N,N-dimethylformamide (30 mL) was stirred at room temperature for 48 hours. The reaction mixture was poured into water (100 ml). The resulting solid was filtered off and washed with water to give the title compound 25a. HPLC (m/z) 341.9 [M+H], retention time = 4.53 min (HPLC method 1).

Step 2: Synthesis of 6-bromo-8-iodoquinazoline-2,4(1H,3H)-dione (compound 25b)

A mixture of compound 25a (1.2 g, 3.5 mmol) and urea (10 g, 166 mmol) was heated at 200° C. for 3 hours. The reaction mixture was cooled and diluted with water (100 ml). The resulting solid was filtered off and washed with methanol (50 ml) and water (50 ml) to give the title compound 25b.

- 77 040107

Step 3: Synthesis of 6-bromo-2-chloro-8-iodoquinazoline-4-amine (compound 25c)

Connection 25s

A mixture of compound 25b (5.33 g, 14.5 mmol), phosphorus(V) oxychloride (30 ml) and N,N-dimethylformamide (3 drops) was heated at 120°C for 14 h. The reaction mixture was cooled, poured into ice-water mixture (200 ml), the solid product was filtered off. The solid was dried under vacuum for 2 h, suspended in saturated ammonia in ethanol (100 ml) and stirred at room temperature for 14 h. The reaction mixture was concentrated under reduced pressure and subjected to silica gel column chromatography (gradient from 10-50 % ethyl acetate in isohexanes) to give the title compound 25c.

¹ H-NMR (400 MHz, DMSO-d6) δ 7.97 (d, J=2.4 Hz, 1H), 7.86 (d, J=2.4 Hz, 1H), 6.78 (bs , 2H). HPLC (m/z) 383.9 [M+H], retention time = 5.98 min (HPLC method 1).

Step 4: Synthesis of (E)-3-(4-(4-amino-6-bromo-2-chloroquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile (compound 25d)

O _h / O V

N Connection 25d

Mixture of compound 25c (120 mg, 0.31 mmol), compound 1c (106 mg, 0.37 mmol), tribasic potassium phosphate monohydrate (143 mg, 0.62 mmol) and [1,1'-bis(diphenylphosphino)ferrocene ]dichloropalladium(II) complexed with dichloromethane (40 mg, 0.062 mmol) was dissolved in a mixture of N,Ndimethylformamide and water (10:1, 3 mL) under argon and the reaction mixture was stirred at room temperature for 24 h. The reaction was quenched by adding saturated ammonium chloride and isolating the product by silica gel chromatography (gradient from 30-60% ethyl acetate in iso-hexanes) to give the title compound 25d. HPLC (m/z) 412.8 [M+H], retention time = 4.62 min (HPLC method 1).

Step 5: Synthesis of (E)-4-((4-amino-6-bromo-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)benzonitrile (compound 25)

A mixture of compound 25d (55 mg, 0.13 mmol) and 4-aminobenzonitrile (20 mg, 0.17 mmol, SigmaAldrich) in isopropanol (2 mL) was heated under microwave irradiation at 170°C for 30 min. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (0-100% ethyl acetate in iso-hexanes gradient) to give the title compound 25.

- 78 040107

Ή-NMR (400 MHz, DMSO-d6) δ 9.57 (s, 1H), 8.47 (d, J=2.2 Hz, 1H), 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). HPLC (m/z) 495.1 [M+H], retention time = 4.58 min (HPLC method 1).

Example 26 (E)-5-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-fluoroquinazolin-2-yl)amino)pyrazine-2carbonitrile Compound 26

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

Compound 20d (92 mg, 0.21 mmol), 5-aminopyrazine-2-carbonitrile (60 mg, 0.50 mmol, Ark Pharm Inc, AK-21935), N,N-diisopropylethylamine (174 µl, 1.0 mmol ), (9,9-dimethyl-9H-xanthine-4,5diyl)bis(diphenylphosphine) (Xantphos) (Xantphos) (24 mg, 0.042 mmol) and palladium(II) acetate (9 mg, 0.042 mmol) were combined under atmosphere argon in N-methyl-2-pyrrolidone (2 ml). The reaction mixture was heated at 100° C. in a closed vessel for 7 hours. The reaction mixture was cooled to room temperature, purified by silica gel chromatography (50 to 100% ethyl acetate in iso-hexanes gradient), and then repurified by reverse phase chromatography (5 -100% acetonitrile in water with 0.1% trifluoroacetic acid) to give compound 26 trifluoroacetate.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.10 (s, 1H), 8.20 (s, 1H), 7.74 (d, J=16.7 Hz, 1H), 7, 77-7.60 (m, 2H), 7.57 (s, 2H), 6.56 (d, J=16.7 Hz, 1H), 1.94 (s, 6H). HPLC (m/z) 436.9 [M+H], retention time = 3.59 min (HPLC method 1).

Example 27 (E)-6-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-fluoroquinazolin-2-yl)amino)pyridazin-3carbonitrile Compound 27

Synthesis of (E)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-fluoroquinazolin-2-yl)amino)pyridazine-3-carbonitrile (compound 27)

- 79 040107

Compound 20d (92 mg, 0.21 mmol), 6-aminopyridazine-3-carbonitrile (60 mg, 0.50 mmol, Matrix Scientific, 112287), K,K-diisopropylethylamine (DIPEA) (174 µl, 1.0 mmol ), (9,9-dimethyl-9H-xanthine4,5-diyl)bis(diphenylphosphine) (Xantphos) (Xantphos) (24 mg, 0.042 mmol) and palladium(II) acetate (9 mg, 0.042 mmol) were combined under atmosphere argon in K-methyl-2-pyrrolidone (2 ml). The reaction mixture was heated at 100° C. in a closed vessel for 7 hours. The reaction mixture was cooled to room temperature, purified by silica gel chromatography (50% to 100% ethyl acetate in iso-hexanes gradient), and then repurified by reverse phase chromatography (5 -100% acetonitrile in water with 0.1% trifluoroacetic acid) to give compound 27 trifluoroacetate.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.18 (bs, 1H), 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, 1H), 1.93 (s, 6H). HPLC (m/z) 436.9 [M+H], retention time = 3.73 min (HPLC method 1).

Example 28 (E)-4-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-5-methoxyquinazolin-2-yl)amino)benzonitrile Compound 28

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 h. The reaction mixture was cooled and diluted with water (100 ml). The resulting solid was filtered off and washed with water (50 ml) to give the title compound 28a.

Step 2: Synthesis of 8-bromo-2-chloro-5-methoxyquinazoline-4-amine (compound 28b)

Compound 28b

A mixture of compound 28a (4.67 g, 17 mmol), phosphorus(V) oxychloride (20 ml) and N,N-dimethylformamide (3 drops) was heated at 120°C for 14 h. The reaction mixture was cooled, poured into a mixture of ice with water (200 ml), the solid product was filtered off. The solid was dried under vacuum in

- 80 040107 for 2 hours, suspended in a saturated solution of ammonia in ethanol (100 ml) and stirred at room temperature for 14 hours, the Reaction mixture was concentrated under reduced pressure and the solid residue was extracted with acetone. The acetone solution was concentrated under reduced pressure to give the title compound 28b.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.66 (s, 1H), 8.26 (s, 1H), 8.02 (d, J=8.7 Hz, 1H), 6, 95 (d, J=8.7 Hz, 1H), 3.98 (s, 3H). HPLC (m/z) 288.1 [M+H], retention time = 3.74 min (HPLC method 1).

Step 3: Synthesis of (E)-3-(4-(4-amino-2-chloro-5-methoxyquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile (compound 28c)

Mixture of compound 28b (100 mg, 0.35 mmol), compound 1c (118 mg, 0.42 mmol), tribasic potassium phosphate monohydrate (159 mg, 0.69 mmol) and [1,1'-bis(diphenylphosphino)ferrocene ]dichloropalladium(II), complexed with dichloromethane (23 mg, 0.035 mmol) was dissolved in a mixture of N,N-dimethylformamide and water (10:1.5 mL) under argon and the reaction mixture was stirred at 80°C for 30 min. The product was isolated by silica gel chromatography (gradient from 60-100% ethyl acetate in iso-hexanes) to give the title compound 28c. HPLC (m/z) 364.9 [M+H], retention time = 4.38 min (HPLC method 1).

Step 4: Synthesis of (E)-4-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-5-methoxyquinazolin-2yl)amino)benzonitrile (compound 28)

NH

Compound 28

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- dimethyl-9H-xanthine-4,5-diyl)bis(diphenylphosphine) (12 mg, 0.02 mmol) was dissolved in N-methyl-2-pyrrolidone (2 ml) under argon. N,N-diisopropylethylamine (DIPEA) (87 µl, 0.5 mmol) was then added via syringe at 110° C. over 6 hours. The product was isolated by silica gel chromatography (gradient 50 to 100% ethyl acetate in isohexanes), and then purified again by reverse phase flash chromatography (5.5 g C-18 RediSep prepacked column, gradient 5-100%, acetonitrile in water with 0.1% TFA) to give the title compound 28 in salt form with trifluoroacetic acid.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 7.90-7.65 (m, 3H), 7.71 (d, J=16.7 Hz, 1H), 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). HPLC (m/z) 447.0 [M+H], retention time = 3.85 min (HPLC method 1).

Example 29 (E)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-5-methoxyquinazolin-2-yl)amino)nicotinonitrile Compound 29

- 81 040107

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

Compound 28c (37 mg, 0.1 mmol), 6-aminonicotinonitrile (60 mg, 0.5 mmol, Ark Pharm Inc, AK32349), N,N-diisopropylethylamine (DIPEA) (87 µl, 0.5 mmol), ( 9,9-dimethyl-9H-xanthine-4,5diyl)bis(diphenylphosphine) (Xantphos) (Xantphos) (12 mg, 0.02 mmol) and palladium(II) acetate (4 mg, 0.02 mmol) were combined in argon atmosphere in N-methyl-2-pyrrolidone (2 ml). The reaction mixture was heated at 110° C. in a closed vessel for 6 hours. The reaction mixture was cooled to room temperature, purified by silica gel chromatography (gradient 50 to 100% ethyl acetate in iso-hexanes), and then repurified by reverse phase chromatography (5 -100% acetonitrile in water with 0.1% trifluoroacetic acid) to give compound 29 trifluoroacetate.

¹ H-NMR (400 MHz, DMSO-d6) δ 13.31 (bs, 1H), 11.92 (bs, 1H), 9.49 (s, 1H), 9.09 (s, 1H), 8 .27 (d, J=8.4Hz, 1H), 7.82 (d, J=16.7Hz, 1H), 7.77 (d, J=9.2Hz, 1H), 7.68 (s, 2H), 7.55-7.40 (m, 2H), 7.30 (d, J=8.4Hz, 1H), 6.69 (d, J=16.7Hz, 1H) , 4.13 (s, 3H), 1.97 (s, 6H). HPLC (m/z) 448.0 [M+H], retention time = 3.60 min (HPLC method 1).

Example 30 (E)-4-((8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-4-(methylamino)quinazolin-2-yl)amino)benzonitrile Compound 30

8-Bromo-2,4-dichloroquinazoline (556 mg, 2 mmol, Ark Pharm Inc., AK-28703) was dissolved in 6 mL of 20% methylamine in ethanol and the reaction mixture was stirred at room temperature for 15 min. The volatiles were removed under reduced pressure and the solid residue was suspended in water. The resulting solid was filtered and washed with water (3x5 ml) and pentane (3x5 ml),

- 82 040107 whereby the title compound 30a was obtained.

1H-NMR (400 MHz, DMSO-d6) δ 8.96 (d, J=4.7 Hz, 1H), 8.19 (dd, J=8.3 Hz, J=1.2 Hz, 1H) , 8.11 (dd, J=7.7 Hz, J=1.2 Hz, 1H), 7.42 (t, J=7.9 Hz, 1H), 3.00 (d, J=4, 3 Hz, 3H). High resolution mass spectroscopy (electrospray ionization - ESI+) calc. for C ₉ H ₈ N ₃ BrCl [M+H] 271.9585, exp.271.9585. HPLC (m/z) 272.0 [M+H], retention time 3.80 min (HPLC method 1).

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

Οχ χθ in

N Connection 30b

Mixture of compound 30a (110 mg, 0.4 mmol), compound 1c (147 mg, 0.52 mmol), tribasic potassium phosphate monohydrate (138 mg, 0.6 mmol) and [1,1'-bis(diphenylphosphino)ferrocene ]dichloropalladium(II) in complex with dichloromethane (26 mg, 0.04 mmol) was dissolved in a mixture of N,N-dimethylformamide and water (85:15, 5 ml) under argon atmosphere and this reaction mixture was stirred at 80°C for 20 minutes. The reaction mixture was concentrated under reduced pressure and the product was isolated by silica gel chromatography (50 to 80% ethyl acetate in iso-hexanes gradient) to give the title compound 30b.

¹ H-NMR (400 MHz, DMSO-d6) δ 8.88 (d, J=4.4 Hz, 1H), 8.25 (dd, J=8.2 Hz, J=1.5 Hz, 1H ), 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, 1H), 3.01 (d, J=4.4 Hz, 3H), 1.85 (s, 6H). High resolution mass spectroscopy (electrospray ionization - ESI+) calc. for C ₂₀ H ₁₈ N ₄ Cl [M+H] 349.1215, exp. 349.1216. HPLC (m/z) 349.1 [M+H], retention time 4.51 min (HPLC method 1).

Step 3: Synthesis of (E)-4-((8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-4-(methylamino)quinazolin-2yl)amino)benzonitrile (compound 30)

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-dimethyl- 9H-xanthine-4,5-diyl)bis(diphenylphosphine) (40 mg, 0.064 mmol) was dissolved in N-methyl-2-pyrrolidone (3 ml) under argon. N,N-diisopropylethylamine (DIPEA) (150 μl, 0.85 mmol) was then added via syringe at 110°C for 3 hours. The reaction mixture was concentrated under reduced pressure and the product was isolated by chromatography on silica gel (80-100% gradient ethyl acetate in iso-hexanes) and then purified again by reverse phase flash chromatography (5.5 g C-18 RediSep prepacked column, 0-100% acetonitrile in water gradient) to give the title compound 30.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.54 (s, 1H), 8.31 (d, J=4.3 Hz, 1H), 8.11 (d, J=8.4 Hz, 1H), 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, J=16.7 Hz, 1H), 3.06 (d, J=4 .3 Hz, 3H), 1.90 (s, 6H). High resolution mass spectroscopy (electrospray ionization - ESI+) calc. for C ₂ 7H ₂ 3N ₆ [M+H] 431.1979, exp. 431.1977. HPLC (m/z) 431.2 [M+H], time

- 83 040107 retention 3.67 min (HPLC method 1).

Example 31 (E)-6-((8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-4-(methylamino)quinazolin-2-yl)amino)nicotinonitrile - Compound 31 ^NH

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

A mixture of compound 30b (52 mg, 0.15 mmol), 6-aminonicotinonitrile (90 mg, 0.75 mmol, Ark Pharm Inc, AK-32349), palladium(II) acetate (20 mg, 0.064 mmol) and (9, 9-dimethyl-9H-xanthine-4,5diyl)bis(diphenylphosphine) (40 mg, 0.064 mmol) was dissolved in N-methyl-2-pyrrolidone (3 ml) under argon. N,N-diisopropylethylamine (DIPEA) (150 μl, 0.85 mmol) was then added via syringe at 110°C for 4 h. The reaction mixture was concentrated under reduced pressure and the product was isolated by chromatography on silica gel (80-100% gradient ethyl acetate in iso-hexanes) and then further purified by reverse phase flash chromatography (5.5 g C-18 RediSep prepacked column, 0-100% gradient, acetonitrile in water with 0.1% trifluoroacetic acid), resulting in which gave the trifluoroacetate of the title compound 31.

¹ H-NMR (400 MHz, DMSO-a ₆ ) δ 13.53 (s, 1H), 12.28 (s, 1H), 10.13 (s, 1H), 8.41 (d, J=8 .4 Hz, 1H), 8.29 (d, J=8.8 Hz, 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, 1H), 6.70 (d, J=16.7 Hz, 1H), 3.21 (d, J=4.4 Hz, 3H), 1.96 (s, 6H). High resolution mass spectroscopy (electrospray ionization - ESI+) calc. for C26H22N- [M+H] 432.1931, exp.432.1929. HPLC (m/z) 432.2 [M+H], retention time 3.53 min (HPLC method 1).

Example 32 (E)-4-((4-Amino-8-(4-(2-cyanovinyl)-2,6-dimethoxyphenyl)quinαzolin-2-yl)αmino)benzonitrile Compound 32

Step 1: Synthesis of 4-((4-amino-8-(trimethylstannyl)quinazolin-2-yl)amino)benzonitrile (compound 32a)

- 84 040107

To a mixture of 8a (1000 mg, 2.94 mmol) and tetrakis(triphenylphosphine)palladium(0) (200 mg, 0.17 mmol) in dry dioxane (5 ml) was added hexamethylditin (1 ml, 4.82 mmol) under atmosphere argon. The reaction mixture was heated to 100° C. for 14 h under argon, then cooled to room temperature and immediately purified by silica gel chromatography (25-50% ethyl acetate in iso-hexanes gradient) to give the title compound 32a.

Ή-NMR (400 MHz, DMSO-d ₆ ) δ 9.42 (s, 1H), 8.08 - 8.18 (m, 3H), 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). HPLC (m/z) 424.0 [M-H], retention time = 4.84 min (HPLC method 1).

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

To a solution of 4-bromo-3,5-dimethoxybenzaldehyde (24.5 g, 100 mmol, Ark Pharm Inc., AK-34641) and diethylcyanomethylphosphonate (18.6 g, 105 mmol) in anhydrous 2-methyltetrahydrofuran (400 ml) slowly potassium tert-butoxide (12.3 g, 110 mmol) was added at 0° C. under argon. The reaction mixture was vigorously stirred at 0° C. for 1 h and then at room temperature for 3 h. The reaction mixture was diluted with ethyl acetate and washed twice with water and once with brine. The organic layer was dried over MgSO ₄ and filtered through a three cm pad of silica gel, which was washed with more ethyl acetate. The combined organics were concentrated under reduced pressure and the solid residue was sonicated with hexane/diethyl ether (1/3) for 3 minutes. The resulting solid was filtered off and washed with hexane to give the title compound 32b.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 7.61 (d, J=16.7 Hz, 1H), 7.06 (s, 2H), 6.65 (d, J=16.7 Hz, 1H), 3.87(s, 6H). HPLC (m/z) no MS signal, retention time 2.50 min (HPLC method 2).

Step 3: Synthesis of (E)-4-((4-amino-8-(4-(2-cyanovinyl)-2,6-dimethoxyphenyl)quinazolin-2-yl)amino)benzonitrile (compound 32)

A mixture of compound 32a (20 mg, 0.047 mmol), compound 32b (20 mg, 0.075 mmol) and bis(tri-tert-butylphosphine)palladium(0) (20 mg, 0.039 mmol) in N,N-dimethylformamide (2 ml) was heated in argon atmosphere at 100° C. for 2 h. The reaction mixture was concentrated under reduced pressure, purified by silica gel chromatography (gradient 50 to 100% ethyl acetate in iso-hexanes), and then purified again by reverse phase flash chromatography (prepacked column 5.5 g C-18 RediSep, gra

- 85 040107 dient 0-100%, acetonitrile in water with 0.1% TFA) to give the trifluoroacetate of the title compound 32.

1H-NMR (400 MHz, DMSO-d ₆ ) 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, 1H), 7.16 (s, 2H), 6.76 (d, J=16.7 Hz, 1H), 3.72 (s, 6H). HPLC (m/z) 449.0 [M+H], retention time = 3.48 min (HPLC method 1).

Example 33 (E)-4-((8-(4-(2-cyanovinyl)-2,6-dimethoxyphenyl)quinazolin-2-yl)amino)benzonitrile Compound 33

To a mixture of compound 1a (1000 mg, 3.07 mmol) and tetrakis(triphenylphosphine)palladium(0) (200 mg, 0.17 mmol) in dry dioxane (5 ml) was added hexamethylditin (1 ml, 4.82 mmol) in argon atmosphere. The reaction mixture was heated to 110° C. for 4 hours under argon, then cooled to room temperature and immediately purified by silica gel chromatography (0-30% ethyl acetate in isohexanes gradient) to give the title compound 33a.

¹ H-NMR (400 MHz, DMSOCH) δ 10.53 (s, 1H), 9.47 (s, 1H), 8.34 (d, J=8.8 Hz, 1H), 8.31-8 .24 (m, 2H), 8.09-8.02 (m, 1H), 7.90-7.85 (m, 2H), 7.60-7.51 (m, 1H), 0.05 (s, 9H). HPLC (m/z) 409.0 [M+H], retention time = 5.54 min (HPLC method 1).

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

Vg

N Connection 33

A mixture of compound 33a (20 mg, 0.048 mmol), compound 32b (20 mg, 0.075 mmol) and bis(tri-tert-butylphosphine)palladium(0) (20 mg, 0.039 mmol) in X,X-dimethylformamide (2 ml) was heated in argon atmosphere at 100°C for 2 h. The reaction mixture was concentrated under reduced pressure, purified by silica gel chromatography (gradient from 0-50% ethyl acetate in iso-hexanes), and then again purified by reverse phase flash chromatography (prepacked column 5.5 g C-18 RediSep, gradient 0-100%, acetonitrile in water with 0.1% TFA) to give the trifluoroacetate of title compound 33.

1H-NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 9.40 (s, lH), 7.96 (dd, J=8.1, 1.4 Hz, 1H), 7.78-7.85 (m, 3H), 7.71 (dd, J=7.2, 1.4 Hz, 1H), 7.44-7.54 (m, 3H), 7.21 ( s, 2H), 6.77 (d, J=16.7 Hz, 1H), 3.62 (s, 6H). HPLC

- 86 040107 (m/z) 433.98 [M+H], retention time = 4.39 min (HPLC method 1).

Example 34 (E)-6-((8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)nicotinonitrile Compound 34

Water sodium hydroxide (30 ml, 0.2 M, 6 mmol) was added to a solution of 8-bromo-2,4-dichloroquinazoline (556 mg, 2 mmol, Ark Pharm Inc., AK-28703) in tetrahydrofuran (30 ml). The reaction mixture was stirred at room temperature for 0.5 h. The reaction mixture was then acidified with crystalline acetic acid to pH=5 and concentrated under reduced pressure. Water was added, the solid was filtered off and washed with water (3x20 ml) to give the title compound 34a.

¹ H-NMR (400 MHz, DMSO-d6) δ 13.51 (s, 1H), 8.15 (d, J=7.8 Hz, 1H), 8.09 (d, J=7.8 Hz , 1H), 7.42-7.51 (m, 1H). High resolution mass spectroscopy (electrospray ionization -ESI+) calc. for C ₈ H ₄ ON ₂ BrClNa [M+Na] 280.9088, exp. 280.9089. HPLC (m/z) 259.0 [M+H], retention time 3.58 min (HPLC method 1).

Step 2: Synthesis of (E)-3-(4-(2-chloro-4-oxo-3,4-dihydroquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile (compound 34b)

O. / O V

N Connection 34b

Mixture of compound 34a (74 mg, 0.28 mmol), compound 1c (120 mg, 0.42 mmol), tribasic potassium phosphate monohydrate (200 mg, 0.87 mmol) and [1,1'-bis(diphenylphosphino)ferrocene ]dichloropαlladium(II), in complex with dichloromethane, (30 mg, 0.05 mmol) was dissolved in a mixture of N,H-dimethylformamide and water (10:1, 3.3 ml) under argon and this mixture was stirred at 80 °C for 2 hours. The product was isolated by silica gel chromatography (gradient from 0-100% ethyl acetate in iso-hexanes) to give the title compound 34b.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 13.30 (bs, 1H), 8.16 (dd, J=7.7, 1.8 Hz, 1H), 7.67-7.51 (m, 3H), 7.43 (s, 2H), 6.46 (d, J=16.7 Hz, 1H), 1.88 (s, 6H). HPLC (m/z) 336.1 [M+H], retention time = 4.24 min (HPLC method 1).

Step 3: Synthesis of (E)-6-((8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2yl)amino)nicotinonitrile (compound 34)

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A mixture of compound 34b (80 mg, 0.24 mmol), 6-aminonicotinonitrile (200 mg, 1.68 mmol, Ark Pharm Inc, AK-32349), palladium(II) acetate (20 mg, 0.09 mmol) and ( 9,9-dimethyl-9H-xanthine-4,5diyl)bis(diphenylphosphine) (100 mg, 0.17 mmol) was dissolved in N-methyl-2-pyrrolidone (3 ml) under argon. N,N-diisopropylethylamine (DIPEA) (1 ml, 5.7 mmol) was then added via syringe at 100°C for 1 h. The product was isolated by flash chromatography on silica gel (0-100% ethyl acetate in iso-hexanes gradient ) and then purified again by reverse phase flash chromatography (5.5 g C-18 RediSep prepacked column, gradient 0-100% acetonitrile in water with 0.1% trifluoroacetic acid) to give compound 34 trifluoroacetate.

¹ H-NMR (400 MHz, DMSOCH) δ 12.16 (bs, 1H), 10.26 (bs, 1H), 8.74 (bs, 1H), 8.10 (dd, J=7.8, 1.6 Hz, 1H), 7.94-7.81 (m, 1H), 7.69 (d, J=16.7 Hz, 1H), 7.59-7.36 (m, 5H), 6.51 (d, J=16.7 Hz, 1H), 1.94 (s, 6H). HPLC (m/z) 418.9 [M+H], retention time = 4.11 min (HPLC method 1).

Example 35 (E)-4-((4-amino-8-(4-(2-cyanovinyl)-2,6-diethylphenyl)quinazolin-2-yl)amino)benzonitrile Compound 35

Step 1: Synthesis of (E)-3-(4-bromo-3,5-diethylphenyl)acrylonitrile (compound 35a)

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 h. The reaction mixture was filtered through celite and the filter media was washed with tetrahydrofuran (10 ml). The filtrate was evaporated, then redissolved with ethyl acetate (50 ml). The solution was washed with water (50 ml). The aqueous layer was subjected to back extraction 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 chromatographed on silica gel (0-20% ethyl acetate in iso-hexanes gradient) to give the title compound 35a.

¹ H-NMR (400 MHz, CDCl3) δ 7.31 (d, J=16.6 Hz, 1H), 7.12 (s, 2H), 5.86 (d, J=16.6 Hz, 1H ), 2.79 (q, J=7.5 Hz, 4H), 1.22 (t, J=7.5 Hz, 6H). HPLC (m/z) no MS signal, retention time = 3.07 min (HPLC method 2).

Step 2: Synthesis of (E)-3-(3,5-diethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylonitrile (compound 35b)

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N

N Connection 35b

A mixture of compound 35a (300 mg, 1.14 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2dioxaborolane) (432 mg, 1.70 mmol), potassium carbonate (471 mg, 3.4 mmol), palladium(II) acetate (13 mg, 0.06 mmol), and dicyclohexyl(2',6'-dimethoxy-[1,1' -biphenyl]-2-yl)phosphine (SPhos, 58 mg, 0.14 mmol) in dry N,N-dimethylformamide (20 ml) was purged with argon and heated at 100° C. for 2 h. The reaction mixture was filtered through celite and washed filter media with tetrahydrofuran (10 ml). The filtrate was evaporated, then redissolved with ethyl acetate (50 ml). The solution was washed with water (50 ml). The aqueous layer was subjected to back extraction with ethyl acetate (50 ml). The combined organics were washed with brine (30 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure to give a crude residue which was purified by silica gel chromatography (0-15% ethyl acetate in iso-hexanes gradient) to resulting in compound 35b.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.33 (d, J=16.6 Hz, 1H), 7.04 (s, 2H), 5.85 (d, J=16.6 Hz, 1H), 2.67 (q, J=7.6 Hz, 4H), 1.38 (s, 12H), 1.20 (t, J=7.6 Hz, 6H). HPLC (m/z) no MS signal, retention time = 3.07 min (HPLC method 2).

Step 3: Synthesis of (E)-3-(4-(4-amino-2-chloroquinazolin-8-yl)-3,5-diethylphenyl)acrylonitrile (compound 35c)

O _h χθ V

Ν Connection 35s

A mixture of 8-bromo-2-chloroquinazolin-4-amine (90 mg, 0.35 mmol, Ark Pharm Inc, AK-28702), compound 35b (130 mg, 0.42 mmol), tribasic potassium phosphate (96 mg, 0 .45 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (23 mg, 0.04 mmol) were dissolved in N,Ndimethylformamide:water (80:20, 5 mL) under argon. The reaction mixture was heated at 80°C for 60 min. The reaction mixture was cooled to room temperature and diluted with water and ethyl acetate. The organic layer was separated and washed twice with brine, dried over magnesium sulfate, 1 volume equivalent of hexane was added, and the mixture was filtered through a 2 cm pad of silica gel, which was washed with additional ethyl acetate. The combined organics were concentrated under reduced pressure and the residue was treated with hexane in an ultrasonic bath. The resulting solid was filtered and washed twice with hexane to give the title compound 35c.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.39 (bs, 2H), 8.29 (dd, J=7.2, 2.5 Hz, 1H), 7.67 (d, J =16.7 Hz, 1H), 7.61-7.54 (m, 2H), 7.46 (s, 2H), 6.52 (d, J=16.7 Hz, 1H), 2.22 -2.01 (m, 4H), 0.91 (t, J=7.5 Hz, 6H). HPLC (m/z) 363.3 [M+H], retention time = 2.68 min (HPLC method 2).

Step 4: Synthesis of (E)-4-((4-amino-8-(4-(2-cyanovinyl)-2,6-diethylphenyl)quinazolin-2-yl)amino)benzonitrile (compound 35)

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A mixture of compound 35c (40 mg, 0.11 mmol), 4-cyanoaniline (18 mg, 0.154 mmol, Sigma-Aldrich) and a solution of hydrogen chloride in 1,4-dioxane (4 M, 3 μl, 0.011 mmol) in dry K- methyl-2-pyrrolidone (1 ml) was heated under argon at 120°C for 12 h. , 1% trifluoroacetic acid), resulting in the formation of compound 35 trifluoroacetate.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 10.57-9.84 (m, 1H), 9.82-8.84 (m, 2H), 8.27 (bs, 1H), 7 .86-7.22 (m, 7H), 6.62 (d, J=16.8 Hz, 1H), 2.40-1.98 (m, 4H), 0.94 (t, J=7 .2 Hz, 6H). HPLC (m/z) 445.4 [M+H], retention time = 2.59 min (HPLC method 2).

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

Synthesis of (E)-6-((4-amino-8-(4-(2-cyanovinyl)-2,6-diethylphenyl)quinazolin-2-yl)amino)nicotinonitrile (compound 36)

Compound 35c (40 mg, 0.11 mmol), 6-aminonicotinonitrile (53 mg, 0.44 mmol, Ark Pharm Inc, AK-32349), K,K-diisopropylethylamine (DIPEA) (28 mg, 0.22 mmol) and [(2-di-cyclohexylphosphino-3,6dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium( P) methanesulfonate (9 mg, 0.011 mmol) was combined under argon in N-methyl-2-pyrrolidone (1 ml). The reaction mixture was heated at 120° C. in a closed vessel for 4 hours. The reaction mixture was cooled to room temperature and purified without further treatment by reverse phase HPLC chromatography (gradient 0-100% acetonitrile in water with 0.1% trifluoroacetic acid), as a result, compound 36 trifluoroacetate was obtained.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 13.54 (bs, 1H), 12.09 (bs, 1H), 9.62 (bs, 1H), 9.38 (bs, 1H), 8.46 (d, J=8.2 Hz, 1H), 8.37-8.15 (m, 1H), 7.94-7.83 (m, 2H), 7.80-7.66 ( m, 3H), 7.56-7.27 (m, 2H), 6.76 (d, J=16.7 Hz, 1H), 2.40-2.01 (m, 4H), 0.94 (t, J=7.5 Hz, 6H). HPLC (m/z) 446.4 [M+H], retention time = 1.98 min (HPLC method 2).

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Example 37 (E)-1-(2-((4-cyanophenyl)amino)-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinazolin-4-yl)urea Compound 37

Synthesis of (E)-1-(2-((4-cyanophenyl)amino)-8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)quinαzolin-4-yl)urea (compound 37)

Compound 2 (42 mg, 0.10 mmol) was suspended in dry dichloromethane (2 ml) and N,N-diisopropylethylamine (DIPEA) (0.1 ml, 0.57 mmol) was added to this suspension, after which phosgene was added dropwise (0.5 ml, 20% solution in toluene). The mixture was stirred at 50°C for 1 h. Another portion of N,N-diisopropylethylamine (0.1 ml, 0.57 mmol) and phosgene (0.2 ml, 20% solution in toluene) was added to the reaction mixture and stirred this mixture at 50° C. for another 1 hour. The mixture was cooled to room temperature, and saturated aqueous ammonia (1 ml) was added. The volatiles were removed under reduced pressure and purified. The crude residue was purified by HPLC using a gradient of 50 to 100% acetonitrile in water (HPLC Phenomenex Gemini 10µ preparative column, C18, 250 x 21.2 mm, 10 ml/min) to give the title compound 37.

¹ H-NMR (400 MHz, DMSO-d6) δ 9.35 (bs, 1H), 8.26-8.07 (m, 1H), 7.78-7.65 (m, 3H), 7, 62-7.45 (m, 3H), 7.44-7.30 (m, 3H), 7.29-7.16 (m, 3H), 6.43 (d, J=16.7 Hz, 1H), 1.81(s, 6H). HPLC (m/z) 460.3 [M+H], retention time = 3.98 min (HPLC method 1).

Example 38 (E)-4-((4-amino-8-(4-(1-cyanoprop-1-en-2-yl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)benzonitrile Compound 3 8

Stage 1: synthesis of 4-bromo-3,5-dimethylbenzoic acid (compound 38a)

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4-bromo-3,5-dimethylbenzonitrile (630 mg, 3 mmol, Ark Pharm Inc, AK-44760) was dissolved in ethanol (1 ml), 8M sodium hydroxide solution (5 ml) was added and the reaction mixture was stirred in a closed vessel at 120°C for 12 hours. The reaction mixture was diluted with water (100 ml) and washed with diethyl ether (2x50 ml), the aqueous layer was acidified with concentrated hydrochloric acid (to pH=3) and was extracted with diethyl ether (2x100 ml). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to give the title compound 38a.

¹ H-NMR (600 MHz, DMSO-06) δ 7.72 (s, 2H), 2.41 (s, 6H).

Step 2: Synthesis of 1-(4-bromo-3,5-dimethylphenyl)ethanone (compound 38b)

Compound 38a (100 mg, 0.44 mmol) was suspended in dry 1,4-dioxane (5 ml) and methyl lithium (0.8 ml, 1.6 M solution in diethyl ether) was added dropwise under argon. The mixture was stirred at room temperature for 1 hour. The reaction was quenched by adding methanol (10 ml) and concentrated under reduced pressure. The solid residue was extracted with ethyl acetate (3x10 ml). The combined organic solutions were concentrated under reduced pressure to give the title compound 38b. HPLC (m/z) 227.0 [M+H], retention time = 4.65 min (HPLC method 1).

Step 3: Synthesis of (E)-3-(4-bromo-3,5-dimethylphenyl)but-2-ennitrile and (Z)-3-(4-bromo-3,5-dimethylphenyl)but-2-ennitrile ( compounds 38c and compounds 38d)

Connection 38c Connection 38d

Compound 38b (95 mg, 0.42 mmol) and diethyl(cyanomethyl)phosphonate (70 μl, 0.40 mmol) were dissolved in dry dichloromethane (5 ml). Cesium carbonate (1 g, 3.07 mmol) was added and the solution was slowly concentrated under reduced pressure at 30°C. The resulting solid was allowed to stand at room temperature 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 a gradient of 0-10% ethyl acetate in iso-hexanes to give the title compound 38c HPLC (m/z) 250.0 [M+H], retention time = 5.01 min (HPLC method 1) and title compound 38d HPLC (m/z) 250.0 [M+H], retention time = 4.48 min (HPLC method 1).

Step 4: Synthesis of (E)-4-((4-amino-8-(4-(1-cyanoprop-1-en-2-yl)-2,6-dimethylphenyl)quinazolin-2yl)amino)benzonitrile (compound 38)

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A mixture of compound 32a (20 mg, 0.047 mmol), compound 38c (20 mg, 0.080 mmol) and bis(tri-tert-butylphosphine)palladium(0) (20 mg, 0.039 mmol) in N,N-dimethylformamide (2 ml) was heated in under argon at 100°C for 14 h. The reaction mixture was concentrated under reduced pressure, purified by silica gel chromatography (50 to 100% ethyl acetate in iso-hexanes gradient), and then repurified by HPLC (Phenomenex Gemini 10 micron C18 preparative column). , 250x21.2 mm, 10 ml/min, gradient from 10-100% acetonitrile in water) to give the title compound 38.

¹ H-NMR (600 MHz, DMSO-d6) δ 8.23 (bs, 1H), 7.83-7.72 (m, 2H), 7.60-7.29 (m, 7H), 6, 17 (q, J=1.0 Hz, 1H), 2.52-2.51 (m, 3H), 1.96 (s, 6H). HPLC (m/z) 430.9 [M+H], retention time = 3.83 min (HPLC method 1).

Example 39 (2)-4-((4-amino-8-(4-(1-cyanoprop-1-en-2-yl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)benzonitrile - Compound 39

Synthesis of (2)-4-((4-amino-8-(4-(1-cyanoprop-1-en-2-yl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)benzonitrile (compound 39 )

A mixture of compound 32a (20 mg, 0.047 mmol), compound 38d (18 mg, 0.072 mmol) and bis(tri-tert-butylphosphine)palladium(O) (20 mg, 0.039 mmol) in N,N-dimethylformamide (2 ml) was heated in under argon at 100°C for 14 h. The reaction mixture was concentrated under reduced pressure, purified by silica gel chromatography (50 to 100% ethyl acetate in iso-hexanes gradient), and then repurified by HPLC (Phenomenex Gemini 10 micron C18 preparative column). , 250x21.2 mm, 10 ml/min, gradient from 10-100% acetonitrile in water) to give the title compound 38.

¹ H-NMR (600 MHz, DMSO-d ₆ ) δ 8.22 (bs, 1H), 7.84-7.71 (m, 4H), 7.62-7.29 (m, 5H), 5 .89-5.79 (m, 1H), 2.36 (d, J=1.5 Hz, 3H), 1.97 (s, 6H). HPLC (m/z) 430.9 [M+H], retention time = 3.76 min (HPLC method 1).

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Example 40

4-((4-amino-8-(4-(2-cyanoprop-1-en-1-yl)-2,6-dimethylphenyl)quinazolin-2-yl)amino)benzonitrile Compound 40 (mixture E/Z= 1/1)

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 diisobutylaluminum hydride (1 M in dichloromethane, 11 ml) was added dropwise and the reaction mixture was allowed to come to room temperature for 2 h. After that, 5% aqueous hydrochloric acid solution (10 ml) was added and the reaction mixture was heated under reflux for 30 min. The reaction mixture was then 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 0-10% ethyl acetate in iso-hexanes) to give the title compound 40a.

1H-NMR (400 MHz, CDCl3) δ 9.93 (s, 1H), 7.57 (s, 2H), 2.50 (s, 6H). High resolution mass spectroscopy (TOF CI+) calc. for C ₉ H ₁₀ BrO [M+H] 212.9915, exp.212.9913. HPLC (m/z) 213.0 [M+H], retention time = 4.59 min (HPLC method 1).

Step 2: Synthesis of 3-(4-bromo-3,5-dimethylphenyl)-2-methylacrylonitrile (compound 40b): mixture E/Z=1/1

^(mixture) Compound 40b

Compound 40a (100 mg, 0.47 mmol) and diethyl (1-cyanoethyl)phosphonate (70 μl, 0.40 mmol) were dissolved in dry dichloromethane (5 ml). Cesium carbonate (1 g, 3.07 mmol) was added and the solution was slowly concentrated under reduced pressure at 30°C. The resulting solid was allowed to stand at room temperature 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 a gradient of 0-10% ethyl acetate in iso-hexanes to give the title compound 40b as a 1:1 mixture of E/Z isomers. HPLC (m/z) 250.0 [M+H], retention time = 5.07 and 5.10 min (HPLC method 1).

Step 4: Synthesis of 4-((4-amino-8-(4-(2-cyanoprop-1-en-1-yl)-2,6-dimethylphenyl)quinazolin-2yl)amino)benzonitrile (compound 40): mixture E/Z=1/1

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A mixture of compound 32a (20 mg, 0.047 mmol), compound 40b (20 mg, 0.080 mmol) and bis(tri-tert-butylphosphine)palladium(O) (20 mg, 0.039 mmol) in N,N-dimethylformamide (2 ml) was heated in argon atmosphere at 100°C for 8 h. The reaction mixture was concentrated under reduced pressure, purified by silica gel chromatography (50 to 100% ethyl acetate in iso-hexanes gradient), and then repurified by HPLC (Phenomenex Gemini 10 micron C18 preparative column). , 250x21.2 mm, 10 ml/min, gradient from 10-100% acetonitrile in water) to give the title compound 40 as a 1:1 mixture of E/Z isomers.

¹ H-NMR (600 MHz, DMSO-d6) 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). HPLC (m/z) 430.8 [M+H], retention time = 3.86 min (HPLC method 1).

Example 41 (E)-4-((8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2-yl)amino)benzonitrile Compound 41

Step 1: Synthesis of 4-((8-bromo-4-oxo-3,4-dihydroquinazolin-2-yl)amino)benzonitrile (compound 41a)

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 by microwave at 130°C for 30 min. The reaction mixture was cooled to room temperature and diethyl ether (10 ml) was added. The resulting solid was filtered off and washed with diethyl ether (3x20 ml) to give the title compound 41a.

¹ H-NMR (400 MHz, DMSO-06) δ 11.13 (bs, 1H), 9.41 (bs, 1H), 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, 1H). High resolution mass spectroscopy (electrospray ionization - ESI+) calc. for С^НшО^Вг [M+H] 341.0033, exp. 341.0033. HPLC (m/z) 341.1 [M+H], retention time 4.52 min (HPLC method 1).

Step 2: Synthesis of (E)-4-((8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-4-oxo-3,4-dihydroquinazolin-2yl)amino)benzonitrile (compound 41)

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Οχ ,0 in

N Connection 41

A mixture of compound 41a (68 mg, 0.2 mmol), compound 1c (85 mg, 0.3 mmol), tribasic potassium phosphate (92 mg, 0.4 mmol) and 1,1'-bis(di-tert-butylphosphino )ferrocenepalladium dichloride (26 mg, 0.04 mmol) was dissolved in N,N-dimethylformamide:water (85:15, 40 mL) under argon. The reaction mixture was heated to 80° C. for 3 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (gradient 50 to 80% ethyl acetate in iso-hexanes) and then purified by reverse phase HPLC (gradient 5- 100% acetonitrile in water with 0.1% trifluoroacetic acid) to give compound 41 trifluoroacetate.

¹ H-NMR (400 MHz, DMSO-b ₆ ) 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). HPLC (m/z) 418.3 [M+H], retention time = 2.72 min (HPLC method 2).

Example 42 alternative synthesis of (E)-3-(4-bromo-3,5-dimethylphenyl)acrylonitrile - Compounds 1b

To a solution of diethylcyanomethylphosphonate (266 mg, 1.5 mmol) in tetrahydrofuran (10 mL) was added potassium tert-butoxide (168 mg, 1.5 mmol) at 0°C with stirring for 30 min. Thereafter, compound 40a (212 mg, 1 mmol) in tetrahydrofuran (10 ml) was added dropwise to the reaction mixture at room temperature overnight. The reaction mixture was neutralized with water. Ethyl acetate was added, the organic layer was washed with brine, dried over anhydrous calcium chloride and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (gradient from 0-20% ethyl acetate in iso-hexanes) to give the title compound 1b.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.25 (d, J=16.6 Hz, 1H), 7.12 (s, 2H), 5.84 (d, J=16.6 Hz, 1H), 2.42(s, 6H). HPLC (m/z) no MS signal, retention time = 2.78 min (HPLC method 2).

Example 43 alternative synthesis of 4-((4-amino-8-bromoquinazolin-2-yl)amino)benzonitrile - Compound 8a

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Step 1: Synthesis of 3-bromo-2-((triphenylphosphoranylidene)amino)benzonitrile (compound 43a)

A solution of triphenylphosphine (10.65 g, 40.6 mmol) in dichloromethane (200 ml) was treated slowly with bromine (6.49 g, 40.6 mmol) at 0° C. for 5 minutes. Triethylamine (8.22 g, 81.2 mmol) was then added followed by 2-amino-3-bromobenzonitrile (4.00 g, 20.3 mmol, Abblis, AB1000095). The ice bath was then removed at room temperature for 8 hours. The reaction mixture was poured onto water and extracted twice with dichloromethane. The combined organics were washed with brine and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was subjected to silica gel chromatography (gradient from 0-30% ethyl acetate in iso-hexanes) to give the title compound 43a.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 7.80-7.70 (m, 6H), 7.66 (dt, J=7.9, 1.4 Hz, 1H), 7.64 -7.58 (m, 3H), 7.577.47 (m, 6H), 7.40 (dt, J=7.7, 1.5Hz, 1H), 6.64 (td, J=7.8 , 1.5 Hz, 1H). HPLC (m/z) 457.1 [M+H], retention time = 2.99 min (HPLC method 2).

Step 2: alternative synthesis of 4-((4-amino-8-bromoquinazolin-2-yl)amino)benzonitrile (compound 8a)

Compound 8a

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 over 30 min. 2 M ammonia in isopropanol (3.3 ml, 6.6 mmol) was added and the reaction mixture was heated under reflux for 3 h, then concentrated under reduced pressure. The residue was purified by silica gel chromatography (gradient 0 to 40% ethyl acetate in iso-hexanes) to give the title compound 8a.

¹ H-NMR (400 MHz, DMSO-d ₆ ) 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, J=8.8 Hz, 2H), 7.16 (t, J=7.8 Hz, 1H). HPLC (m/z) 340.0 [M+H], retention time = 4.06 min (HPLC method 1).

Biological examples

Example A High throughput screening for anti-HIV-1 activity with reverse transcriptase mutation (HIV-1 RT).

The compounds were screened for cytopathic effect in a miniaturized high throughput assay, thus determining activity against HIV-1 HBX2 (wild type) and HIV-1 mutants by reverse transcriptase K103N and Y181C. In table. 1 and 2 below, d.t. refers to the results of the study of compounds with wild type 1, and d.t. in Test 2 refers to the results of testing wild-type compounds on the same day as testing the mutants. Accordingly, d.t. test 2 was carried out under the same conditions as the study of compounds with mutants, i.e. it gives a direct comparison with the results of the study with mutants.

- 97 040107

Ten semi-log serial dilutions of the compounds of the present invention were prepared in DMSO. AZT was used as a positive control and DMSO was used as a negative control. Using an Echo sonic pipette, 200 nl serial dilutions of the compound were placed into sterile 384-well tissue culture plates. Two million MT-4 cells were incubated with each of the three viruses at an MOI (multiplicity of infection) of 0.0005 in separate 1 ml infectious tubes for 1 hour at 37°C. Cells were diluted in culture medium (RPMI + 10% FBS) to 50,000 cells/ml. Infected cells were added to 384-well assay plates containing serial dilutions of the compounds. Assay plates were incubated for 5 days in a humidified incubator set at 37° C. and 5% CO2. To measure the cytopathic effect of HIV, 40 μl of TiterGlo was added to each well and the final luminescent signal was read on an Envision plate reader (Perkin Elmer). Data were normalized to the positive and negative controls in each plate and expressed as % protection against cytopathic effect. EC ₅₀ values were defined as the compound concentration that provided a 50% reduction in luminescence signal and were calculated by non-linear regression using the Pipeline Pilot program with a four-parameter fit (Accelrys, San Diego, CA, USA). The results are disclosed in table. 1.

Table 1

ec ₅₀ (nM) in MT4 cells against ECzo (nM) in MT4 cells vs. CI (multiple change) against mutant Connection ID D.T. D.t. in test 2* K103N Y181C K103N Y181C 1 3.0 6.2 8.8 17.8 1.4 2.9 2 3.7 3.6 4.0 10.9 1.1 h, o 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 7 122.2 116.8 130.5 >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 9.8 eleven 4.7 4.2 5.2 126.4 1.2 29.8 12 1.8 1.8 1.7 12.5 0.9 6.9 13 3.2 4.3 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 0.8 >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 1.1 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

- 98 040107

* test 2 with d.t. were performed on the same days as the test with the K103N and Y181C mutants.

High throughput screening was also performed for nevirapine (NPV), rilpivirine (RPV) and efavirenz (EFV). Nevirapine was obtained from Toronto Research Chemicals, Inc. (Toronto, Canada, catalog # N391275). Rilpivirine was obtained from Key Organics Ltd. (Camelford, Cornwall, UK, Cat. No. KE-0036). Efavirenz was obtained from Toronto Research Chemicals, Inc. (Toronto, Canada, catalog # E425000). The results are shown below in table. 2.

table 2

EC ₅₀ (nM) in MT4 cells vs. ECso (nM) in MT4 cells vs. KN (fold change) vs. mutant Compound d.t. d.t. in test 2* K103N Y181C K103N Y181C Nevirapine ("NVP") 65.0 BUT BUT BUT BUT BUT 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

* test 2 with d.t. were performed on the same days as the test with the K103N and Y181C mutants. N/A: not determined

It is understood that the EC ₅₀ can be estimated by techniques known in the art. In one embodiment, the compounds exhibited an EC ₅₀ of less than about 3000 nM in wild-type or in any of the HIV reverse transcriptase mutants as measured by the method disclosed in the High Throughput Screen for K103N and Y181C Anti-HIV Mutants discussed above. In one embodiment, the compounds exhibited an EC ₅₀ less than about 1000 nM, 500 nM, 400 nM, 300 nM, 250 nM, 200 nM, 100 nM, 50 nM, 25 nM, 10 nM, 5 nM, or 1 nM in wild type or in any of the HIV reverse transcriptase mutants (eg K103N, Y181C).

Example B Resistance profile against HIV-1 reverse transcriptase mutants (HIV-1 RT).

Investigated the antiviral activity of the compounds against a panel of viruses resistant to NNRTIs. A panel of 8 clonal mutant viruses obtained by site-directed mutagenesis was used, representing the main pathways for the development of resistance against rilpivirine (RPV), efavirenz (EFV) and nevirapine (NVP), including single and double mutations in HIV-1 reverse transcriptase. Additional details and related prior art can be found in Janssen et al., J. Med. Chem, 2005, 48, 1901-1909, Das et al., Proc. Nat. Acad. Sci., 2008, vol. 105, no. 5, 1466-1471, and Kuroda et al., Nature Chemistry, 2013, DOI: 10,103 type, as this mutation represents a minor subset of previously untreated patients (1.4%). Recombinant HIV-1 strains encoding K103N, Y181C, Y188L, G190A, K103N/Y181C, L100I/Y181C, E138K, or E138K/M184V reverse transcriptase mutations were constructed by site-directed mutagenesis. Wild-type and mutant viruses were prepared by transfection of infectious proviral cDNA clones based on MT-2 cells and collection of cell supernatants. MT-2 cells were infected with HIV-1 mutant strains and di virus

- 99 040107 co-type at a MOI of 0.005 by gently mixing for 3 hours at 37°C and then added at a density of 16,667 cells per well to 50 µl of complete RPMI cell culture medium (containing 10 % fetal bovine serum (FBS) and 10% penicillin-streptomycin) into 96-well plates containing 50 µl of 3-fold dilutions of test compounds in RPMI. After 5 days of incubation at 37°C in a humidified incubator with 5% CO2, 100 µl of Cell Titer-Glo™ reagent (Promega Biosciences, Inc., Madison, Wisconsin, USA) was added to each well and the relative light units (RLU) were measured on tablet reader Envision. The virus-induced cytopathic effect was defined as a percentage of the measured RLU values in samples with completely suppressed viral replication minus the signal from untreated controls (DMSO). The EC ₅₀ value was defined as the compound concentration giving a 50% reduction in viral replication. Analysis of data on antiviral activity observed in MT-2 cells was performed using XL-fit™ software (TDBS, Guildford, Surrey, UK) to calculate EC ₅₀ from an 8-point dose-response curve using the following equation:

(m-n^ec ₅ ;

y=M-~-------(EC ₅₀ ⁿ +x) where y=virus inhibition, x=drug concentration, M=maximum inhibition, H=minimum inhibition, and n=Hill's coefficient. EC ₅₀ values (mean ± standard deviation) were calculated from at least three independent triplicate experiments. The level of resistance was defined as the ratio of the average EC ₅₀ for each mutant/wild type virus. The results are disclosed in the figure in table. 3 and 4 below.

________________________________________________________________________ Table 3

Bioresistance fold change (KI) in a low performance panel Connections e K103N Y181C L100I/ Y181C K103N/ Y181C Y188L G190A E138K/ M184V 1 1.3 5.7 6.9 14.8 15.2 0.6 BUT 2 0.9 4.0 1.6 4.1 10.0 1.6 5.0 3 1.0 3.4 1.0 3.4 13.7 BUT BUT 4 1.4 4.9 5.4 12.8 16.9 BUT BUT 5 1.6 15.4 18.9 208.0 174.0 BUT BUT 9 1.0 5.7 4.0 14.7 I,4 BUT BUT 10 0.9 I,9 3.8 19.9 53.6 BUT BUT eleven 2.1 154.0 85.0 157.0 161.0 BUT BUT 34 1.4 3.4 1.7 12.4 18.7 BUT 4.2

N/A: not defined

The resistance profile against HIV-1 reverse transcriptase mutants was also investigated for nevirapine (NPV), rilpivirine (RPV) and efavirenz (EFV). Nevirapine was obtained from Toronto Research Chemicals, Inc. (Toronto, Canada, catalog # N391275). Rilpivirine was obtained from Key Organics Ltd. (Camelford, Cornwall, UK, Cat. No. KE-0036). Efavirenz was obtained from Toronto Research Chemicals, Inc. (Toronto, Canada, catalog # E425000). The results are shown below in table. 4.

Table 4

Multiple change (CI) in a low-performance panel Connections e K103N Y181C L100I/ Y181C K103N/ Y181C Y188L G190A E138K/ M184V Nevirapine ("NVP") 87.0 >229 >229 BUT >229 183.0 BUT Rilpiviri n ("RPV") 1.0 4.6 18.1 7.7 22.8 0.8 3.0 Efavirenz ("EFV") 48.1 3.6 >200 83.5 132.5 14.8 BUT

N/A: not defined

Example C Analysis with hERG

Cells:

For this study, a Chinese Hamster Ovary cell line from AVIVA, which stably expresses hERG channels, was used. Cells were cultured in DMEM/F12 medium containing 10% FBS, 1% penicillin/streptomycin, and 500 μg/ml G418. Prior to testing, cells were collected using Accumax pipettes (Innovative Cell Technologies).

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Solutions:

The following solutions were used to record electrophysiological readings:

External solution: 2 mM CaCl ₂ , 2 mM MgCl ₂ , 4 mM KCl, 150 mM NaCl, 10 mM glucose, 10 mM HEPES, 05-315 mOsm, pH 7.4 (adjusted with 5 M NaOH.).

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

Electrophysiological studies:

Whole cell data recording was performed using a PX 7000A instrument (Axon Instruments) using the AVIVA SealChip™ technique.

The cells were subjected to the voltclamp method at a holding potential of -80 mV.

Then, the current of the hERG channels was activated by a depolarization step up to -50 mV for 300 ms. This step at -50 mV was used as a baseline for measuring the trace current peak amplitude. Then a sharp change in potential up to +20 mV was applied for 5 s to activate the channels. Then, by changing the potential back to -50 mV for 5 s, the activation was removed and the residual deactivation current was recorded.

Preparation and dilution of study drugs:

All studied preparations were prepared from 10 mM solutions in DMSO.

The solutions were mixed by ultrasonic treatment for 20 min, followed by vigorous vortex mixing. Prior to analysis, compounds were diluted to test concentrations using an external solution. Dilutions were prepared no more than 20 min before use.

Electrophysiological procedures

After reaching the configuration of whole cells, the cells were monitored for 90 s until stability was achieved, and then washed with an external solution for 66 s. The strain protocol was then applied to the cells every 12 s throughout the procedure. Only stable cells with fixation parameters above the threshold were selected for the drug addition procedure.

An external solution containing 0.1 DMSO was applied to the cells to set the background level. The current was allowed to stabilize for 3-10 min, after which the test products were applied. Test product solutions were added to the cells in 4 separate additions. The cells were kept in the assay solution until the effect of the test product reached steady state, maximum 12 min. Then 1 μM cisapride (positive control) was added. Finally, flushing with an external solution was carried out until the recovery current reached a steady state.

Data analysis

Data analysis was performed using DataXpress (Axon Instruments), Clampfit (Axon Instruments), and Origin (OriginLab Corporation) software. The results are disclosed in table. 5. Higher values in table. 5 indicates the maximum concentration achieved in this assay (eg, compounds that have reached their solubility limit).

An hERG test was also performed for rilpivirine (RPV). The result was 0.5 μM.

The specific pharmacological responses observed may vary according to and depending on the particular active compound selected and whether pharmaceutical carriers are present, as well as the type of dosage form and route of administration employed, and the practice of the present invention contemplates such expected variations or differences in results. The examples disclosed herein describe the synthesis of compounds of the present invention, as well as intermediates used to prepare such compounds. It is contemplated that the individual steps described herein may be combined. It is also contemplated that individual batches of the compound may be pooled and then used further in the next step in the synthesis. All references cited, including publications, patents, and patent documents, are incorporated herein by reference, as if each were individually incorporated by reference. The present disclosure indicates various implementations and techniques. Nevertheless,

- 101 040107 it is to be understood that many changes and modifications can be made without departing from the spirit and scope of the present disclosure.

Claims (24)

CLAIM 1. Pharmaceutical composition containing a compound of formula (I) Where Q represents X ¹ , X ² and X ³ are each independently N or C(R11), provided that at most 2 of X ¹ , X ² and X ³ are N, R ¹ is -H, -CN, -OR ^a , halo or C ₁ . ₆ alkyl, R ² is -H, -CN, -OR ^a , or C _1-6 alkyl, R ³ is -H, -OR ^a , -NR ^a R ^b , -NHC(O)NR ^a R ^b or C ₁ . ₆ alkyl, R ⁴ is -H, -OR ^a , halogen, -NO2, -CN, -NR ^a R ^b , -NHC(O)NR ^a R ^b or C1. ₆ alkyl, R ⁵ is -H, -OR ^a , halogen, -NO2, -CN, -NR ^a R ^b , -NHC(O)NR ^a R ^b or C1. ₆ alkyl, R ⁶ is -H, -OR ^a , halogen, -NO2, -CN, -NR ^a R ^b , -NHC(O)NR ^a R ^b or C1. ₆ alkyl, R ⁷ is C1.6 alkyl, halo, -OR ^a , -CN or -NO2, R ⁸ is C1.6 alkyl, halogen, -OR ^a , -CN or -NO2, R ⁹ is -H or C ₁ . ₆ alkyl, R ¹⁰ is -H or C1.6alkyl, each R ¹¹ is independently -H, -CN, -OR ^a , halogen or C1-6αkyl, and each R ^a and R ^b is independently -H, C ₁ . ₆ alkyl or C ₃ . ₁₀ cycloalkyl, or a pharmaceutically acceptable salt thereof; and one, two, three or four additional therapeutic agents. 2. Pharmaceutical composition according to 3. Pharmaceutical composition according to Q represents 1, where R ² represents -CN. item 1 or 2, where 4. Pharmaceutical composition according to claim 1 or 2, where Q is R ¹⁰ . 5. Pharmaceutical composition according to any one of claims 1-4, where each X ¹ , X ² and X ³ represents CH. 6. Pharmaceutical composition according to any one of paragraphs.1-4, where X ¹ represents N; X ² is CH; and X ³ is CH. 7. Pharmaceutical composition according to any one of paragraphs.1-4, where X ¹ , X ² and X ³ represent C(R11); each R ¹¹ is independently selected from -H, -CN, -OR ^a , halo and C1.6 alkyl; and R ¹ is selected from -H, -CN, -OR ^a , halo and C1. ₆ alkyl. 8. Pharmaceutical composition according to any one of paragraphs.1-4, where X ¹ , X ² and X ³ represent C(R11); each R ¹¹ is -H; and R ¹ is -H. 9. A pharmaceutical composition according to any one of claims 1 to 8, wherein R ³ is -H, -OR ^a , -NR ^a R ^b , or -NHC(O)NR ^a R ^b . 10. Pharmaceutical composition according to any one of claims 1 to 9, wherein R ³ is -NH ₂ or -OH. 11. A pharmaceutical composition according to any one of claims 1 to 9, wherein R ³ is -NH ₂ . 12. Pharmaceutical composition according to any one of claims 1 to 9, wherein R ³ is -OH. 13. Pharmaceutical composition according to any one of claims 1-12, where two of R ⁴ , R ⁵ and R ⁶ are -H, and one of R ⁴ , R ⁵ and R ⁶ is -H, -OR ^a , halogen , -NO2, -CN, -NR ^a R ^b , -NHC(O)NR ^a R ^b or C ₁ . ₆ alkyl. 14. Pharmaceutical composition according to any one of claims 1-12, where two of R ⁴ , R ⁵ and R ⁶ are -H, and one of R ⁴ , R ⁵ and R ⁶ is -H, -OR ^a , halogen , -NO2, -NR ^a R ^b or C1. ₆ alkyl. - 102 040107 15. A pharmaceutical composition according to any one of claims 1 to 14, wherein R ⁶ is -H. 16. A pharmaceutical composition according to any one of claims 1 to 15, wherein R ⁴ , R ⁵ and R ⁶ are -H. 17. Pharmaceutical composition according to any one of claims 1-16, wherein R ⁷ and R ⁸ are the same and are selected from C _1-6 αkyl, halogen, -OR ^a , -CN and -NO2. 18. Pharmaceutical composition according to any one of claims 1-17, wherein R ⁷ and R ⁸ are the same and are selected from C _1-6 αkyl, halogen and -OR ^a . 19. Pharmaceutical composition according to any one of claims 1-18, where R ⁷ and R ⁸ represent Cl _-6 αkil. 20. A pharmaceutical composition according to any one of claims 1 to 19, wherein R ⁷ and R ⁸ are methyl. 21. A pharmaceutical composition according to any one of claims 1 to 20, wherein R ⁹ and R ¹⁰ are -H. 22. Pharmaceutical composition according to any one of claims 1-21, where Q is selected from > I JVW JWV JUW II II II N, N, HCH and N. 23. Pharmaceutical composition according to any one of claims 1-22, where Q is ^N 24. Pharmaceutical composition according to claim 1, containing a compound selected from the group consisting of: