EA041413B1 - 4,6-DIAMINOPYRIDO[3,2-d]PYRIMIDINE COMPOUNDS MODULATING TOLL-LIKE RECEPTORS - Google Patents

Description

Cross-reference to related applications

This patent application claims priority on U.S. Provisional Application Nos. 62/128397 filed March 4, 2015 and 62/250403 filed November 3, 2015, both of which are incorporated herein in their entirety for all purposes. .

Technical field

The invention relates generally to compounds that are modulators of toll-like receptors, including diaminopyrido[3,2-d]pyrimidine compounds, and pharmaceutical compositions that modulate toll-like receptors in particular (e.g., TLR-8), and how to obtain and use them.

State of the art

The toll-like receptor (TLR) family plays a fundamental role in pathogen recognition and activation of innate immunity. Toll-like receptor 8 (TLR-8) is predominantly expressed by myeloid immune cells and activation of this receptor stimulates a broad immunological response. TLR-8 agonists activate myeloid dendritic cells, monocytes, monocyte-derived dendritic cells, and Kupffer cells, leading to the production of pro-inflammatory cytokines and chemokines such as interleukin-18 (IL-18), interleukin-12 (IL-12) factor tumor necrosis-alpha (TNF-α) and interferon-gamma (IFN-γ). Such agonists also increase the expression of co-stimulatory molecules such as CD8+ cells, major histocompatibility complex molecules (MAIT, NK cells), and chemokine receptors.

Together, activation of these innate and adaptive immune responses induces an immune response and provides therapeutic benefit in various conditions associated with autoimmunity, inflammation, allergy, asthma, graft rejection, graft-versus-host disease (GvHD), infection, cancer, and immunodeficiency.

For example, in relation to hepatitis B, TLR8 activation on professional antigen presenting cells (pAPC) and other intrahepatic immune cells is associated with the induction of IL-12 and pro-inflammatory cytokines, which is expected to increase HBV-specific T cell responses, activate intrahepatic NK cells, and will stimulate the restoration of antiviral immunity. See Wille-Reece, U. et al. J Exp Med 203, 1249-1258 (2006); Peng, G. et al., Science 309, 1380-1384 (2005); Jo, J. et al., PLoS Pathogens 10, e1004210 (2014) and Watashi, K. et al., J Biol Chem 288, 31715-31727 (2013).

Given the potential to treat a wide range of diseases, there remains a need for new toll-like receptor modulators, such as TLR-8. Particularly desirable are active and selective TLR-8 modulators that would reduce the incidence of off-target reactions.

The essence of the invention

Provided herein is a compound of formula (J) ^R4 \

NH

R ² ^^N^NH ₂ ^R3 C) or a pharmaceutically acceptable salt thereof, where

X is N or CR ¹⁰ ;

R ¹ is selected from the group consisting of hydrogen, halogen, C1.6 alkyl, CN, -NR ^a R ^b , -S(O)1.2 R ^a and OR ^a where C ₁ . ₆ alkyl is optionally substituted with 1-5 R ²⁰ groups;

R ² is selected from the group consisting of hydrogen, halogen, C1.6 alkyl, CN, -NR ^a R ^b , -S(O)1.2 R ^a and OR ^a where C ₁ . ₆ alkyl is optionally substituted with 1-5 R ²⁰ groups;

R ³ is selected from the group consisting of hydrogen, halogen, C1.6 alkyl, CN, -NR ^a R ^b , -S(O)1.2 R ^a and OR ^a where C ₁ . ₆ alkyl is optionally substituted with 1-5 R ²⁰ groups;

R ⁴ is C1.12 alkyl which is optionally substituted with 1-5 substituents independently selected from halo, -OR ^a , -NR ^a R ^b , CN, -C(O)R ^a , -C(O)OR ^a , - C(O)NR ^a R ^b , -OC(O)NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)NR ^b , -NR ^a C(O)OR ^b , - SR ^a , -S(O) R ^a , -S(O)2NR ^a R ^b , -NR ^a S(ObR ^b , C1.6 haloalkyl, _C3.6 cycloalkyl, 3-6-membered heterocyclyl, where 3-6- the membered heterocyclyl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur, C _{6 10} aryl and 5-10-membered heteroaryl, where the 5-10-membered heteroaryl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur;

where each C ₃ . ₆ cycloalkyl, 3-6 membered heterocyclyl, C ₆ . ₁₀ aryl and 5-10 membered heteroaryl are optionally substituted with 1-5 R ²¹ groups;

R ¹⁰ is selected from hydrogen, halogen, C1.6 alkyl, CN, -NR ^a R ^b , -S(O)1.2 R ^a and OR ^a where C ₁ . ₆ alkyl is optionally substituted with 1-5 R ²⁰ groups;

each R ²⁰ is independently selected from the group consisting of halogen, C ₁ . ₆ haloalkyl, CN, -NR ^a R ^b , S(O) 2Ra and OR ^a ;

each R ²¹ is independently selected from the group consisting of halogen, C1.6 alkyl, C1.6 haloalkyl, CN, -NR ^a R ^b , S(O) 1.2 R ^a and OR ^a ; And

- 1 041413 each R ^a and R ^b is independently selected from the group consisting of hydrogen and C ₁ . ₆ alkyl; where everyone

_C1 . ₆ alkyl is optionally substituted with 1-5 substituents independently selected from halogen, hydroxyl, amino, 5-10 membered heteroaryl, where 5-10 membered heteroaryl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur, and C ₁ _ ₆ haloalkyl;

provided that when X is N, R ¹ is Cl, R ² is H and R ³ is H, then R ⁴ is not CH ₂ CH ₂ OMe or CH ₂ CH ₂ SO ₂ Me.

Provided herein is a compound of formula (I) e NH _r 2

R ³ (I) or a pharmaceutically acceptable salt thereof, where:

R ¹ is selected from the group consisting of hydrogen, halogen, C1_6alkyl, CN, -NR ^a R ^b , -S(O)1_2R ^a and OR ^a where C ₁ . ₆ alkyl is optionally substituted with 1-5 R ²⁰ groups;

R ² is selected from the group consisting of hydrogen, halogen, C1_6 alkyl, CN, -NR ^a R ^b , -S(O)1.2R ^a and OR ^a where C ₁ . ₆ alkyl is optionally substituted with 1-5 R ²⁰ groups;

R ³ is selected from the group consisting of hydrogen, halogen, C1_6alkyl, CN, -NR ^a R ^b , -S(O)1_2R ^a and OR ^a where C ₁ . ₆ alkyl is optionally substituted with 1-5 R ²⁰ groups;

R ⁴ is C _1-12 alkyl which is optionally substituted with 1-5 substituents independently selected from halo, -OR ^a , -NR ^a R ^b , CN, -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -OC(O)NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)NR ^b , -NR ^a C(O)OR ^b , -SR ^a , -S(O)1-2R ^a , -S(OhNR ^a R ^b , -NR ^a S(O)2R ^b , C1_6 haloalkyl,

_C3 . ₆ cycloalkyl, 3-6-membered heterocyclyl, where 3-6-membered heterocyclyl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur, C ₆ _ ₁₀ aryl and 5-10-membered heteroaryl, where 5-10-membered heteroaryl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur;

where each C ₃ . ₆ cycloalkyl, 3-6 membered heterocyclyl, C ₆ . ₁₀ aryl and 5-10 membered heteroaryl are optionally substituted with 1-5 R ²¹ groups;

each R ²⁰ is independently selected from the group consisting of halogen, C ₁ . ₆ haloalkyl, CN, -NR ^a R ^b , S(O)1-2R ^a and OR ^a ;

each R ²¹ is independently selected from the group consisting of halo, C1.6 alkyl, C1.6 haloalkyl, CN, -NR ^a R ^b , S(O) 1-2R ^a and OR ^a ; and each R ^a and R ^b is independently selected from the group consisting of hydrogen and C ₁ . ₆ alkyl; where each C ₁ _ ₆ alkyl is optionally substituted with 1-5 substituents independently selected from halogen, hydroxyl, amino, 5-10 membered heteroaryl, where 5-10 membered heteroaryl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur , and C ₁ . ₆ haloalkyl;

provided that when R ¹ is Cl, R ² is H and R ³ is H, then R ⁴ is not CH ₂ CH ₂ OMe or CH ₂ CH ₂ SO ₂ Me.

Provided herein is a compound of formula (IV)

R ³ _t (IV) where R ¹ is selected from the group consisting of hydrogen, halogen, C1.6 alkyl, CN and OR ^a , where C1. ₆ alkyl is optionally substituted with 1-5 R ²⁰ groups;

R ² is selected from the group consisting of hydrogen, halogen, C1-6alkylα, CN and OR ^a , where C1. ₆ alkyl is optionally substituted with 1-5 R ²⁰ groups;

R ³ is selected from the group consisting of hydrogen, halogen, C1.6 alkyl, CN and OR ^a , where C1. ₆ alkyl is optionally substituted with 1-5 R ²⁰ groups;

R ¹¹ is selected from the group consisting of C ₁ _ ₂ alkyl, C ₃ _ ₆ cycloalkyl and C ₁ _ ₃ haloalkyl;

R ¹² is selected from C1.3 alkyl, halogen, -OR ^a , -NR ^a R ^b , CN, -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -OC (O)NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)NR ^b , -NR ^a C(O)OR ^b , -SR ^a , -S(O)1-2R ^a , -S(O)2NR ^a R ^b , -NR ^a S(O)2R ^b , C1_ ₃ haloalkyl, C ₃ _ ₆ cycloalkyl, 3-6 membered heterocyclyl, where 3-6 membered heterocyclyl contains 1-3 heteroatom selected from oxygen, nitrogen and sulfur, C ₆ . ₁₀ aryl and 5-10-membered heteroaryl, where 5-10-membered heteroaryl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur, where C ₁ . _{The 3} alkyl group is optionally substituted with 1 or 2 substituents independently selected from halo, -OR ^a , -NR ^a R ^b , CN, -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -OC(O)NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)NR ^b , -NR ^a C(O)OR ^b , -SR ^a , -S( O)1.2R ^a , -S(O)2NR ^a R ^b , -NR ^a S(O)2R ^b , C1. ₃ haloalkyl, C ₃ . ₆ cycloalkyl, 3-6-2 041413 membered heterocyclyl, where the 3-6 membered heterocyclyl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur, C ₆ . ₁ oaryl and 5-10-membered heteroaryl, where 5-10-membered heteroaryl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur;

R ¹³ is selected from C1.6 alkyl, halogen, -OR ^a , -NR ^a R ^b , CN, -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -OC (O)NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)NR ^b , -NR ^a C(O)OR ^b , -SR ^a , -S(O)1-2R ^a , -S(OhNR ^a R ^b , -NR ^a S(O)2R ^b , C1. ₆ haloalkyl, C ₃ . ₆ cycloalkyl, 3-6-membered heterocyclyl, where 3-6-membered heterocyclyl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur, C _6.10 aryl and 5-10-membered heteroaryl, where _5-10 -membered heteroaryl contains 1-3 heteroatoms selected from _{oxygen, nitrogen and sulfur, where C 1.6 alkyl} is optional substituted with 1-2 substituents independently selected from halo, -OR ^a , -NR ^a R ^b , CN, -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , - OC(O)NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)NR ^b , -NR ^a C(O)OR ^b , -SR ^a , -S(O)1- 2R ^a , -S(O) ₂ NR ^a R ^b _, -NR ^a S(O)2R ^b , _C1.6 haloalkyl, C _3.6 cycloalkyl, 3-6 membered heterocyclyl, where 3-6 membered heterocyclyl contains 1- 3 heteroatoms selected _from oxygen, nitrogen and sulfur, C _6.10 aryl and 510-membered hetero oaryl, where 5-10-membered heteroaryl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur; each R ²⁰ is independently selected from the group consisting of halogen, CN, -NR ^a R ^b and OR ^a ; and each R ^a and R ^b is independently selected from the group consisting of hydrogen and C ₁ . ₃ αkil, where each C ₁ . The ₃ αalkyl is optionally substituted with 1-3 substituents independently selected from halogen, -OH and NH2. In some embodiments, provided herein is a pharmaceutical composition comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition contains one or more additional therapeutic agents.

In some embodiments, a method for modulating TLR-8 is provided, comprising administering a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, to an individual (eg, human).

In some embodiments, a method of treating or preventing a disease or condition responsive to TLR-8 modulation is provided, comprising administering to an individual (e.g., human) in need thereof a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In some embodiments, a method for treating or preventing a disease or condition responsive to TLR-8 modulation comprises administering one or more additional therapeutic agents.

In some embodiments, a method of treating or preventing a viral infection is provided, comprising administering to an individual (eg, human) in need thereof a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof.

In some embodiments, a method for treating or preventing a hepatitis B viral infection is provided, comprising administering to an individual (eg, human) in need thereof a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In some embodiments, a method for treating or preventing a hepatitis B viral infection comprises administering one or more additional therapeutic agents. In some embodiments, the individual is a human infected with the hepatitis B virus.

In some embodiments, a method of treating or preventing HIV infection is provided, comprising administering to an individual (eg, human) in need thereof a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In some embodiments, a method for treating or preventing HIV infection comprises administering one or more additional therapeutic agents. In some embodiments, the individual is a human infected with an HIV virus (eg, HIV-1).

In some embodiments, a method for treating a hyperproliferative disease (eg, cancer) is provided, comprising administering to an individual (eg, human) in need thereof a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In some embodiments, a method for treating a hyperproliferative disease (eg, cancer) comprises administering one or more additional therapeutic agents. In some embodiments, the individual is a human.

In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is provided for use in medical therapy.

In some embodiments, there is provided a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease or condition responsive to TLR-8 modulation. In some embodiments, the disease or condition is a viral infection.

- 3 041413

In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is provided for use in the treatment or prevention of hepatitis B.

In some embodiments, the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is provided for the manufacture of a medicament for the treatment or prevention of a disease or condition responsive to TLR-8 modulation.

In some embodiments, the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is provided for the manufacture of a medicament for the treatment or prevention of hepatitis B.

Also provided are kits containing the compounds, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions described above. Also provided are articles containing a unit dose of the compounds or their pharmaceutically acceptable salts described above. Methods for preparing compounds according to the present disclosure are also provided.

Detailed description

The following description is made with the understanding that the present description is to be considered as an example of the claimed subject matter and is not intended to limit the appended claims to the specific embodiments illustrated. The headings used in this specification are for convenience and should not be construed as limiting the claims in any way. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading.

Definitions

Unless otherwise indicated, all technical and scientific terms used in this document have the same meaning as generally understood by a person skilled in the art. The dash before or at the end of the chemical group is given for convenience to indicate the point of attachment to the original fragment; chemical groups may be shown with or without one or more dashes without losing their usual meaning. A prefix such as C _uv or (C _u -C _v ) indicates that the next group contains u to v carbon atoms, where u and v are integers. For example, _{C1_6} alkyl means that the alkyl group contains from 1 to 6 carbon atoms.

Alkyl is a linear or branched saturated monovalent hydrocarbon. For example, an alkyl group may contain 1 to 10 carbon atoms (i.e. ( _{C1_10} ) alkyl) or 1 to 8 carbon atoms (i.e. ( _C1-8 ) alkyl) or 1 to 6 carbon atoms carbon (i.e. (C _{1 .6} alkyl), or 1 to 4 carbon atoms (i.e. (C1_ 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, -CH2CH2CH3), 2-propyl (i-Pr, isopropyl, -CH(CH ₃ ) ₂ ), 1-butyl (n -Bu, n-butyl, -Ch ₂ CH ₂ Ch ₂ CH ₃ ), 2-methyl-1-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, t-butyl, -C(CH ₃ ) ₃ ), 1-pentyl (npentyl, -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-2butyl ( -C (CH ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butyl (-CH (CH ₃ )CH (CH ₃ ) ₂ ), 3-methyl-1-butyl (-CH ₂ CH ₂ CH ( CH ₃ ) ₂ ), 2methyl-1-butyl (-CH ₂ CH (CH ₃ )CH ₂ CH ₃ ), 1-hexyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2-hexyl (- CH (CH ₃ ) CH ₂ CH ₂ CH ₂ C H ₃ ), 3-hexyl (-CH (CH ₂ CH ₃ ) (CH ₂ CH ₂ CH ₃ )), 2-methyl-2-pentyl (-C (CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ), Z -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 ), Z- 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 (CH3) C (CH3) and octyl (- (CH ^ CH3).

Alkenyl is a linear or branched monovalent hydrocarbon radical with at least one carbon-carbon double bond. For example, an alkenyl group may contain 2 to 8 carbon atoms (i.e. C ₂ - ₈ alkenyl), or 2 to 6 carbon atoms (i.e. C _2-6 alkenyl), or 2 to 4 carbon atoms (i.e. C ₂ .4 alkenyl). Examples of suitable alkenyl groups include, but are not limited to, ethylene or vinyl (-CH=CH ₂ ), allyl (-CH ₂ CH=CH ₂ ), 5-hexenyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH=CH ₂ ) and 3-hexenyl (-CH ₂ CH ₂ CH=CHCH ₂ CH ₂ ).

Alkynyl is a linear or branched monovalent hydrocarbon radical with at least one carbon-carbon triple bond. For example, an alkynyl group may contain 2 to 8 carbon atoms (i.e. C ₂ _ ₈ alkine), or 2 to 6 carbon atoms (i.e. C ₂ _ ₆ alkynyl), or 2 to 4 carbon atoms (i.e. C ₂ _ ₄ alkynyl). Examples of alkynyl groups include, but are not limited to, acetylenyl (-C^CH), propargyl (-CHSCH^CH) and -CH ₂ -C=C-CH ₃ .

As used herein, the term halo or halogen refers to fluorine (-F), chlorine (-Cl), bromine (-Br), and iodine (-I).

As used herein, the term haloalkyl refers to alkyl, as defined herein, wherein one or more hydrogen atoms of the alkyl are independently substituted with a halogen substituent, which may be the same or different. For example, _C1-8 haloalkyl is C1. ₈ alkyl, where one or more _C1-8 alkyl hydrogen atoms have been replaced by a halogen substituent. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, fluorochloromethyl, difluoromethyl, difluorochloromethyl, trifluoromethyl, 1,1,1-trifluoroethyl, and pentafluoroethyl.

As used herein, the term heteroalkyl refers to alkyl, as defined herein, where one or more carbons of the alkyl are substituted with O, S, or NR ^q , where each R ^q is independently H or C1-6 alkyl. For example, C1.8heteroalkyl refers to a heteroalkyl with one to eight carbon atoms, where one or more carbon atoms 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, 2hydroxyethyl, and N,N'-dimethylpropylamine. The heteroalkyl heteroatom may optionally be oxidized or alkylated. The heteroatom may be at any internal position of the heteroalkyl group or at the position at which said group is attached to the rest of the molecule. Examples include, but are not limited to, -CH2OCH3, -CH2CH2NHCH3, -CH2CH ₂ N(CH ₃ )-CH ₃ , -CH2SCH2CH3, -S(O)CH3, -CH2CH2S(O)2CH3, -CHCHOCH3, -CH2CHNOCH3, - CHCHN(CH3)CH3, -CH2NHOCH3 and -CH2OS(CH3)3.

As used herein, the term aryl refers to a single all-carbon aromatic ring or a fused all-carbon multi-ring system in which at least one of the rings is aromatic. For example, in some embodiments, the aryl group contains 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Aryl includes a phenyl radical. Aryl also includes fused multi-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 (t .e. carbocycle). Such a fused multi-ring system is optionally substituted with one or more (eg 1, 2 or 3) oxo groups on any carbocycle moiety in the fused multi-ring system. The rings of a fused multi-ring system may be connected to each other by condensation, spiro, and bridging if allowed by valence requirements. It should also be understood that when referring to a specific range of aryl atoms (eg, 6-10 membered aryl), the range of atoms is given for all ring atoms of the aryl. For example, a 6-membered aryl will include phenyl and a 10-membered aryl will include naphthyl and 1,2,4,3-tetrahydronaphthyl. Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4tetrahydronaphthyl, anthracenyl, and the like.

As used herein, the term heteroaryl refers to a single aromatic ring that contains at least one atom other than carbon in the ring, wherein said atom is selected from the group consisting of oxygen, nitrogen, and sulfur; heteroaryl also includes fused multi ring systems that contain at least one such aromatic ring, the fused multi ring systems of which are described below. Thus, heteroaryl includes single aromatic rings with from about 1 to 6 carbon atoms and about 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. The sulfur and nitrogen atoms may also be present in oxidized form if the ring is aromatic. Exemplary heteroaryl ring systems include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl, or furyl. Heteroaryl also includes fused multi-ring systems (e.g., ring systems containing 2, 3, or 4 rings) wherein the heteroaryl group, as defined above, is fused to one or more rings selected from heteroaryls (to form, for example, 1,8-naphthyridinyl ), heterocycles (to form, for example, 1,2,3,4-tetrahydro-1,8naphthyridinyl), carbocycles (to form, for example, 5,6,7,8-tetrahydroquinolyl) and aryls (to form, for example, indazolyl ) with the formation of a condensed multi-ring system. Thus, a heteroaryl (single aromatic ring or fused multi-ring system) contains about 1-20 carbon atoms and about 1-6 heteroatoms in the heteroaryl ring. Such fused multi-ring systems may be optionally substituted with one or more (eg 1, 2, 3 or 4) oxo groups on the carbocyclic or heterocyclic portions of the fused ring. The rings of a fused multi-ring system may be connected to each other by condensation, spiro, and bridging if allowed by valency requirements. It should be understood that the individual rings in fused multi-ring systems may be connected in any order relative to each other. It should be understood that the point of attachment of the heteroaryl or heteroaryl fused multi ring system may be at any suitable atom of the heteroaryl or heteroaryl fused multi ring system, including a carbon atom and a heteroatom (eg, nitrogen). It should also be understood that when referring to a certain range of the number of atoms of heteroaryl members (eg, 5-10 membered heteroaryl), this range of atoms is specified for all heteroaryl ring atoms and includes carbon atoms and heteroatoms. For example, a 5-membered heteroaryl will include thiazolyl and a 10-membered heteroaryl will include quinolinyl. Examples of heteroaryls include, but are not limited to, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl , indazolyl, quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinylbenzofuranyl, benzimidazolyl, thianaphenyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl-4(3H)-one, triazolyl, 4,5,6,7- tetrahydro-1H-indazole; and 3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazole.

The term cycloalkyl refers to a single saturated or partially unsaturated all-carbon ring containing from 3 to 20 ring carbon atoms (i.e. C _{3 .20} cycloalkyl), for example from 3 to 12 ring atoms, for example from 3 to 10 ring atoms. The term cycloalkyl also includes fused saturated and partially unsaturated all-carbon multi-ring systems (eg, ring systems containing 2, 3, or 4 carbocyclic rings). Accordingly, cycloalkyl includes polycyclic carbocycles such as bicyclic carbocycles (for example, bicyclic carbocycles containing from about 6 to 12 ring carbon atoms, such as bicyclo[3.1.0]hexane and bicyclo[2.1.1]hexane) and polycyclic carbocycles (for example , tricyclic and tetracyclic carbocycles with up to about 20 ring carbon atoms). Rings in fused multi-ring systems may be connected to each other by condensation, spiro, and bridging if allowed by valency requirements. 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.

As used herein, the term heterocyclyl or heterocycle refers to a single saturated or partially unsaturated non-aromatic ring or non-aromatic multi-ring system that contains at least one heteroatom in the ring (i.e., at least one ring heteroatom selected from oxygen, nitrogen, and sulfur ). Unless otherwise indicated, a heterocyclyl group contains 5 to about 20 ring atoms, eg 3 to 12 ring atoms, eg 5 to 10 ring atoms. Thus, the term includes single saturated or partially unsaturated rings (for example, 3, 4, 5, 6 or 7-membered rings) containing from about 1 to 6 ring carbon atoms and from 1 to 3 ring heteroatoms selected from the group, consisting of oxygen, nitrogen and sulfur in the ring. The rings of a fused multi-ring system may be connected to each other by condensation, spiro, and bridging if allowed by valency requirements. Heterocycles include, but are not limited to, azetidine, aziridine, imidazolidine, morpholine, oxirane (epoxide), oxetane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidinone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinuclidine, N-bromopyrrolidine, N -chlorpiperidine and the like.

As used herein, the term oxo refers to =O.

As used herein, the term treatment or treat is an approach to obtain beneficial or desired results. For the purposes of this disclosure, advantageous or desired 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, treating or treating comprises one or more of the following: a) inhibiting the disease or condition (eg, reducing one or more symptoms caused by the disease or condition and/or reducing the severity of the disease or condition); b) slowing or stopping the development of one or more symptoms associated with the disease or condition (eg, stabilizing the disease or condition, delaying the worsening or progression of the disease or condition); and c) alleviating the disease or condition, for example, causing regression of clinical symptoms, improvement in disease status, slowing down disease progression, improved quality of life, and/or prolongation of survival.

The compound according to the present description includes the compounds disclosed herein, for example, the compound according to the present description includes compounds of formula (J), (I), (Ia), (Ib), (II), (IIa), (IIb), ( III), (IIIa), (IIIb) and the compounds listed in table. 1. The compound according to the present description also includes compounds of formula (J), (I), (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (VI), (IVa), (IVb), (IVc), (IVd), compounds of examples 1-113 and compounds listed in table. 1 and 3. The compound according to the present description also includes the compounds of examples 1-118.

As used herein, the term delaying the development of a disease or condition means delaying, hindering, slowing, holding back, stabilizing, and/or postponing the development of a disease or condition. Said delay may be of varying lengths of time depending on the medical history and/or the individual being treated. As will be appreciated by one of skill in the art, a sufficient or significant delay may, in essence, include prevention as long as 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 period of time and/or reduces the severity of the disease in a given period of time compared to not using the method. Such comparisons may be based on clinical studies using a statistically significant number of subjects. For example, the development of AIDS can be detected using known methods such as confirming a person's HIV+ status and

- 6 041413 assessment of the number of human T-cells or other signs of the development of AIDS, such as excessive fatigue, weight loss, persistent diarrhea, high fever, swollen lymph nodes in the neck, armpits or groin, or the presence of an opportunistic condition associated with AIDS (for example, a condition that is usually absent in people with a functioning immune system, but which occurs in patients with AIDS). Development may also refer to the progression of a disease, which may be initially undetectable and includes onset, recurrence, and onset.

As used herein, the term prevent or prevent refers to a regimen that protects against the onset of a disease or disorder such that clinical symptoms of the disease do not develop. Thus, prevention refers to the administration of a therapy (eg, administration of a therapeutic agent) to a subject before signs of a disease are detected in the subject (eg, administration of 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, such as an individual who has one or more risk factors known to be associated with the development or onset of the disease or disorder. Thus, in some embodiments, the term prevention of HBV infection refers to administering an anti-HBV drug to a subject who does not have a detectable HBV infection. It should be understood that the subject for prophylactic therapy against HBV may be an individual at risk of infection with the HBV virus. Thus, in some embodiments, the term prevention of HIV infection refers to administering to a subject who does not have detectable HIV infection an anti-HIV therapeutic agent. It should be understood that the subject for prophylactic therapy against HIV may be an individual at risk of exposure to the HIV virus.

As used herein, an individual at risk is an individual at risk of developing a condition to be treated. An individual at risk may or may not have a detectable disease or condition, and may or may not have a detectable disease 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 these risk factors. For example, an individual at risk for AIDS is an individual with HIV.

As used herein, the term therapeutically effective amount or effective amount refers to an amount that is effective to elicit 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 effect such treatment of the disease. The effective amount will vary depending on the compound, the disease and its severity, age, weight, etc. the subject to be treated. An effective amount may include a range of amounts. As is understood in the art, the effective amount may be in one or more doses, i.e., a single dose or multiple 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 one agent may be considered to be indicated in an effective amount if, in combination with one or more other agents, a desired or beneficial result can occur or be achieved. Suitable doses of any co-administered compounds may optionally be reduced due to the combined action (eg, additive or synergistic effects) of the compounds.

As used herein, the term agonist is a substance that stimulates its binding partner, usually a receptor. Stimulation is defined in relation to a particular quantitative assay or may be apparent from the literature from the discussion in this document, which provides a comparison with a factor or substance that is accepted as an agonist or antagonist of a particular binding partner under essentially similar conditions understood by specialists in this field of technology . Stimulation can be defined in relation to an increase in a particular effect or function that is induced by the interaction of an agonist or partial agonist with a binding partner, and may include allosteric effects.

As used herein, the term antagonist is a substance that inhibits its binding partner, usually a receptor. Inhibition is defined in relation to a particular quantitative assay or may be evident from the literature from the discussion in this document, which is compared with a factor or substance that is accepted as an agonist or antagonist of a particular binding partner under essentially similar conditions understood by specialists in this field of technology . Inhibition may be defined in relation to the reduction of a particular effect or function that is induced by the interaction of an antagonist with a binding partner, and may include allosteric effects.

As used herein, the term partial agonist or partial antagonist is a substance that provides a level of stimulation or inhibition, respectively, of its binding partner, which is not fully or fully agonistic or antagonistic, respectively. It will be appreciated that stimulation, and hence inhibition, is defined per se for any substance or category of substances to be defined as agonists, antagonists, or partial agonists.

As used herein, the term intrinsic activity or efficacy refers to some measure of the biological efficacy of a complex with a binding partner. With respect to receptor pharmacology, the conditions under which intrinsic activity or efficacy must be determined will depend on the particular binding partner complex (eg, receptor/ligand) and consideration of the activity relevant to the particular biological outcome. For example, in some circumstances, native activity may vary depending on the particular second messenger system involved in the process. It will be apparent to one of ordinary skill in the art in which the specific assessments given in accordance with a particular situation are appropriate and how they may be relevant to the present description.

A pharmaceutically acceptable excipient includes, but is not limited to, an adjuvant, a carrier, an excipient, a lubricant, a sweetening agent, a diluent, a preservative, a dye/coloring agent, a flavor enhancer, a surfactant, a wetting agent, a dispersing agent, a suspending agent, a stabilizer, an isotonic agent, diluent, or emulsifier that has been approved by the US Food and Drug Administration as acceptable for use in humans or pets.

As used herein, the term receptor modulation includes agonism, partial agonism, antagonism, partial antagonism, or inverse agonism of a receptor.

The nomenclature used herein to refer to the compounds in question is illustrated in the examples and elsewhere in this document.

As used herein, the term co-administration includes administering unit doses of the compounds described herein before or after administration of unit doses of one or more additional therapeutic agents, e.g., administering a compound disclosed herein within seconds, minutes, or hours after administering one or more additional therapeutic agents. For example, in some embodiments, a single dose of a compound as described herein is first administered, followed by a single dose of one or more additional therapeutic agents over seconds or minutes. Alternatively, according to other implementation options, a single dose of one or more additional therapeutic agents is first administered, and then a single dose of a compound according to the present description is administered over seconds or minutes. In some embodiments, a single dose of a compound as described herein is first administered, followed by a single dose of one or more additional therapeutic agents after a period of time (eg, 1-12 hours). In other embodiments, a single dose of one or more additional therapeutic agents is first administered, followed by a single dose of a compound as described herein after a period of time (eg, 1-12 hours).

Also provided are pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein. Pharmaceutically acceptable or physiologically acceptable refers to compounds, salts, compositions, dosage forms and other materials that are suitable for the preparation of a pharmaceutical composition suitable for veterinary pharmaceutical use or pharmaceutical use in the human body.

The compounds described herein may be prepared and/or formulated as pharmaceutically acceptable salts. Pharmaceutically acceptable salts are non-toxic salts of the free base form of the compound that have the desired pharmacological activity of the free base. Said salts may be derived from inorganic or organic acids or bases. For example, a compound that contains a basic nitrogen can be obtained as a pharmaceutically acceptable salt by contacting the compound with an inorganic or organic acid. Non-limiting examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexane-1,6dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, methylsulfonates, propylsulfonates, besilates, xylenesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates,

- 8 041413 lactates, γ-hydroxybutyrates, glycolates, tartrates and mandelates. For lists of other suitable pharmaceutically acceptable salts, see Remington: The Science and Practice of Pharmacy, ^21st Edition,

Lippincott Williams and Wilkins, Philadelphia, Pa., 2006.

Examples of pharmaceutically acceptable salts of the compounds described herein also include salts derived from an appropriate base such as alkali metal (eg sodium, potassium), alkaline earth metal (eg magnesium), ammonium, and NX ₄ ⁺ (wherein X is C1- _C4 -alkyl). Also included are base addition salts such as sodium or potassium salts.

Also provided are compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, in which 1 to n hydrogen atoms attached to a carbon atom can be replaced by a deuterium atom or D, in which 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 thus may be useful in increasing the half-life of the compounds described herein, or a pharmaceutically acceptable salt, isomer or mixture thereof, when administered to a mammal. See, for example, Foster, Deuterium Isotope Effects in Studies of Drug Metabolism, Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by methods known in the art, for example using starting materials in which one or more hydrogen atoms are replaced by deuterium.

Examples of isotopes that may be included in the disclosed compounds also include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as ² H, ³ H, ⁿ C, ¹³ C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ³⁶ Cl, ¹²³ I, and ¹²⁵ I, respectively. Substitution with positron emitting isotopes such as ⁿ C, ¹⁸ F, ¹⁵ O and ¹³ N can be useful in positron emission topography (PET) to study substrate receptor activity. Isotopically labeled compounds of formula (I) can generally be prepared by conventional methods known to those skilled in the art, or by methods analogous to those described in the examples, as set forth below, using an appropriate isotopically labeled reagent instead of an unlabeled reagent. previously used.

Compounds of the embodiments disclosed herein, or pharmaceutically acceptable salts thereof, may contain one or more asymmetric centers and thus may form enantiomers, diastereomers, and other stereoisomeric forms, which may be defined in terms of absolute stereochemistry as (R)- or ( S)- or as (D)- or (L)- for amino acids. The present description includes all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)- or (D)- and (L)-isomers can be obtained using chiral synthons or chiral reagents or separated using traditional methods, for example, with using chromatography and fractional crystallization. Conventional methods for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise indicated, said compounds are intended to include both E and Z geometric isomers. Likewise, all tautomeric forms are also included.

A stereoisomer refers to a compound composed of the same atoms linked by the same bonds, but having different three-dimensional structures that are not interchangeable. The present description contemplates various stereoisomers and mixtures thereof, and includes enantiomers that refer to two stereoisomers whose molecules are non-superimposable mirror images of each other.

Tautomer refers to the proton shift from one atom of a molecule to another atom of the same molecule. The present description includes tautomers of any of these compounds.

The solvate is formed by the interaction of a solvent and a compound. Solvates of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.

A prodrug includes any compound that becomes a compound described herein when administered to a subject, for example, upon metabolic processing of the prodrug.

The terms combination antiretroviral therapy (cART) refer to combinations or cocktails of antiretroviral drugs used to treat human viral infections, including HIV infections. As used herein, the terms combination antiretroviral therapy and cART include combinations and regimens often referred to as highly active antiretroviral therapy (HAART). HAART and cART combinations and regimens typically include multiple, often two or more drugs, such as nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), fusion inhibitors, CCR5 agonists, and/or inhibitors integrases.

- 9 041413

The terms latent HIV reservoir, latent HIV reservoir, HIV reservoir, latent reservoir, and latent HIV infection refer to a state in which resting CD4+ T-lymphocytes or other cells are infected with HIV, but do not actively produce HIV. Currently, inactive HIV-infected cells are referred to as latently infected cells. Antiretroviral therapy (APT) can reduce blood levels of HIV to undetectable levels while latent HIV reservoirs continue to survive. When a latently infected cell is reactivated, the cell begins to produce HIV (HIV replication).

Connections

Provided herein is a compound of formula (J) ^R4 \

NH

R ^{2 R3} (L or a pharmaceutically acceptable salt thereof, where

X is N or CR ¹⁰ ;

R ¹ is selected from the group consisting of hydrogen, halogen, C1.6 alkyl, CN, -NR ^a R ^b , -S(O)1.2 R ^a and OR ^a where C ₁ . ₆ alkyl is optionally substituted with 1-5 R ²⁰ groups;

R ² is selected from the group consisting of hydrogen, halogen, C1.6 alkyl, CN, -NR ^a R ^b , -S(O)1.2 R ^a and OR ^a where C ₁ . ₆ alkyl is optionally substituted with 1-5 R ²⁰ groups;

R ³ is selected from the group consisting of hydrogen, halogen, C1.6 alkyl, CN, -NR ^a R ^b , -S(O)1.2 R ^a and OR ^a where C ₁ . ₆ alkyl is optionally substituted with 1-5 R ²⁰ groups;

R ⁴ is C1.12 alkyl which is optionally substituted with 1-5 substituents independently selected from halo, -OR ^a , -NR ^a R ^b , CN, -C(O)R ^a , -C(O)OR ^a , - C(O)NR ^a R ^b , -OC(O)NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)NR ^b -NR ^a C(O)OR ^b , -SR ^a , -S(O)1. ₂ R ^a , -S(O)2NR ^a R ^b , -NR ^a S(O)2R ^b , C ₁ . ₆ haloalkyl,

_C3 . ₆ cycloalkyl, 3-6 membered heterocyclyl, where the 3-6 membered heterocyclyl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur, C ₆ . ₁₀ aryl and 5-10-membered heteroaryl, where 5-10-membered heteroaryl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur;

where each C ₃ . ₆ cycloalkyl, 3-6 membered heterocyclyl, C ₆ . ₁₀ aryl and 5-10 membered heteroaryl are optionally substituted with 1-5 R ²¹ groups;

R ¹⁰ is selected from hydrogen, halogen, C1.6 alkyl, CN, -NR ^a R ^b , -S(O)1.2 R ^a and OR ^a where C ₁ . ₆ alkyl is optionally substituted with 1-5 R ²⁰ groups;

each R ²⁰ is independently selected from the group consisting of halogen, C ₁ . ₆ haloalkyl, CN, -NR ^a R ^b , S(O) 2R ^a and OR ^a ;

each R ²¹ is independently selected from the group consisting of halogen, C ₁ . ₆ alkyl, C ₁ . ₆ haloαalkyl, CN, -NR ^a R ^b , S(O) 2R ^a and OR ^a ; and each R ^a and R ^b is independently selected from the group consisting of hydrogen and C ₁ . ₆ alkyl; where each C ₁ . ₆ alkyl is optionally substituted with 1-5 substituents independently selected from halogen, hydroxyl, amino, 5-10 membered heteroaryl, where 5-10 membered heteroaryl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur, and C ₁ . ₆ haloalkyl;

provided that when X is N, R ¹ is Cl, R ² is H and R ³ is H, then R ⁴ is not CH ₂ CH ₂ OMe or CH ₂ CH ₂ SO ₂ Me.

In some embodiments of Formula (J), X is CR ¹⁰ . In some embodiments of Formula (J), X is N.

Provided herein is a compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein:

R ¹ is selected from the group consisting of hydrogen, halogen, C1.6alkyl, CN, -NR ^a R ^b , -S(O)1.2R ^a and OR ^a where C ₁ . ₆ alkyl is optionally substituted with 1-5 R ²⁰ groups;

R ² is selected from the group consisting of hydrogen, halogen, C1.6 alkyl, CN, -NR ^a R ^b , -S(O)1.2 R ^a and OR ^a where C ₁ . ₆ alkyl is optionally substituted with 1-5 R ²⁰ groups;

R ³ is selected from the group consisting of hydrogen, halogen, C1.6 alkyl, CN, -NR ^a R ^b , -S(O)1.2 R ^a and OR ^a where C1. ₆ alkyl is optionally substituted with 1-5 R ²⁰ groups;

R ⁴ is C ₁ . ₁₂ alkyl which is optionally substituted with 1-5 substituents independently selected from halo, -OR ^a , -NR ^a R ^b , CN, -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -OC(O)NR ^a R ^b , -NR ^a C(O)R ^b ,

- 10 041413

-NR ^a C(O)NR ^b -NR ^a C(O)OR ^b , -SR ^a , -S(O)i-2R ^a , -S(O)2NR ^a R ^b , -NR ^a S(O) 2R ^b , C^ haloalkyl,

C _3-6 cycloalkyl, 3-6 membered heterocyclyl, where the 3-6 membered heterocyclyl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur, C ₆ . ₁₀ aryl and 5-10-membered heteroaryl, where 5-10-membered heteroaryl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur;

where each C ₃ . ₆ cycloalkyl, 3-6 membered heterocyclyl, C ₆ . ₁₀ aryl and 5-10 membered heteroaryl are optionally substituted with 1-5 R ²¹ groups;

each R ²⁰ is independently selected from the group consisting of halogen, C1.6 haloalkyl, CN, -NR ^a R ^b , S(O) 1-2R ^a and OR ^a ; each R ²¹ is independently selected from the group consisting of halogen, C1. ₆ alkyl, C ₁ . ₆ haloalkyl, CN, -NR ^a R ^b , S(O)1_2R ^a and OR ^a ; and each R ^a and R ^b is independently selected from the group consisting of H and C ₁ . ₆ alkyl; where each C ₁ . ₆ alkyl is optionally substituted with 1-5 substituents independently selected from halogen, hydroxyl, amino, 5-10 membered heteroaryl, where 5-10 membered heteroaryl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur, and C ₁ . ₆ haloalkyl;

provided that when R ¹ is Cl, R ² is H and R ³ is H, then R ⁴ is not CH ₂ CH ₂ OMe or CH ₂ CH ₂ SO ₂ Me.

In some embodiments of a compound of formula (J) or (I), R ⁴ is C1.8 alkyl which is optionally substituted with 1-5 substituents independently selected from the group consisting of halo, -OR ^a , -NR ^a R ^b , CN, -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -OC(O)NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C (O)NR ^b -NR ^a C(O)OR ^b , -SR ^a , -S(O)1-2R ^a , -S(ObNR ^a R ^b , -NR ^a S(O)2R ^b , C1.6 haloalkyl , Сз_6Cycloalkyl, 3-6-membered heterocyclyl, where 3-6-membered heterocyclyl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur, C _6.10 aryl and _5-10 -membered heteroaryl, where 5-10-membered heteroaryl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur, and wherein each C _3.6 cycloalkyl, _3-6 membered heterocyclyl, C _6.10 aryl and _5-10 membered heteroaryl are optionally substituted with 1-5 R ²¹ groups.

In some embodiments of a compound of formula (J) or (I), R ⁴ is C1.6αalkyl optionally substituted with 1-5 substituents independently selected from the group consisting of halo, -OR ^a , -C(O)OR ^a , - C(O)NR ^a R ^b , -SR ^a , C1. ₆ haloalkyl, C ₃ . ₆ cycloalkyl, 3-6 membered heterocyclyl and C ₆ . ₁₀ arila; where each C ₃ . ₆ cycloalkyl, 3-6 membered heterocyclyl and C ₆ . ₁₀ aryl is optionally substituted with 1-5 R ²¹ groups. In some embodiments of a compound of formula (J) or (I), R ⁴ is C3_8 alkyl optionally substituted with 1-5 substituents independently selected from the group consisting of halo, -OR ^a , -C(O)OR ^a , -NR ^a C(O)R ^b , -SR ^a , C1. ₆ haloalkyl, C ₃ . ₆ cycloalkyl, 3-6 membered heterocyclyl and C ₆ . ₁₀ arila; where each C ₃ . ₆ cycloalkyl, 3-6 membered heterocyclyl and C ₆ . ₁₀ aryl is optionally substituted with 1-5 R ²¹ groups.

In some embodiments of a compound of formula (J) or (I), R ⁴ is C1.6αalkyl optionally substituted with 1-3 substituents independently selected from the group consisting of halo, -OR ^a , -C(O)OR ^a , - C(O)NR ^a R ^b , -SR ^a , -C1. ₃ haloalkyl, C ₃ . ₆ cukloalkulα, 3-6-membered heterocyclyl and C ₆ . ₁₀ arila; where each C ₃ . ₆ cycloalkyl and C ₆ . ₁₀ aryl is optionally substituted with 1-3 R ²¹ groups. In some embodiments of a compound of formula (J) or (I), R ⁴ is C3-8 alkyl optionally substituted with 1-3 substituents independently selected from the group consisting of halo, -OR ^a , -C(O)OR ^a , - NR ^a C(O)R ^b , -SR ^a , -C1. ₃ haloalkyl, C ₃ . ₆ cycloalkyl, 3-6 membered heterocyclyl and C ₆ . ₁₀ arila; where each C ₃ . ₆ cycloalkyl and C ₆ . ₁₀ aryl is optionally substituted with 1-3 R ²¹ groups.

In some embodiments of a compound of formula (J) or (I), R ⁴ is C1.6αalkyl optionally substituted with 1 or 2 substituents independently selected from halo, -OR ^a , -C(O)OR ^a , -C(O) NR ^a R ^b , -SR ^a , C1. ₃ haloalkyl, C ₃ . ₆ cycloalkyl, 3-6 membered heterocyclyl and C ₆ . ₁₀ arila; where each C ₃ . ₆ cycloalkyl and C ₆ . ₁₀ aryl is optionally substituted with 1-3 R ²¹ groups and where each R ^a and R ^b is independently hydrogen or C1.4 alkyl, where C1.4 alkyl is optionally substituted with -NH2, OH or pyridyl. In some embodiments of a compound of formula (J) or (I), R ⁴ is C3. ₈ alkyl which is optionally substituted with 1 or 2 substituents independently selected from the group consisting of halo, -OR ^a , -C(O)OR ^a , -NR ^a C(O)R ^b , -SR ^a , C1_3 haloalkyl, C3- 6 cycloalkyl, 3-6 membered heterocyclyl and C6_10 aryl; where each C3_6cycloalkyl and C6_10aryl is optionally substituted with 1-3 R ²⁰ groups and where each R ^a and R ^b is independently hydrogen or C1_4 alkyl, where each _{C1_4} alkyl is optionally substituted with -NH2, OH or pyridyl.

In some embodiments of a compound of formula (J) or (I), R ⁴ is C1_6 alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of OH, CF3, -C(O)OH, -C(O)OCH3 , -C(O)NH2, SCH3, -C(O)NHCH3, -C(O)NHCH2CH2NH2, -C(O)NHCH2CH2OH, -C(O)NHCH2-pyridyl, phenyl, tetrahydrofuranyl and cyclopropyl. In some embodiments of a compound of formula (J) or (I), R ⁴ is _{C3_8} alkyl which is optionally substituted with 1 or 2 substituents independently selected from OH, CF3, -C(O)OH, -C(O)OCH3, SCH3, -NHC(O)CH3, -NHC(O)CH2CH2NH2, -NHC(O)CH2CH2OH, -NHC(O)CH2-pyridyl, phenyl, tetrahydrofuranyl and cyclopropyl.

In some embodiments of a compound of formula (J) or (I), R ⁴ is C _{3 -6} alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of OH, CF3, -C(O)OH, -C (O)OCH3, -C(O)NH2, SCH3, -C(O)NHCH3, -C(O)NHCH2CH2NH2, -C(O)NHCH ₂ CH ₂ OH, and -C(O)NHCH ₂ -pyridyl. According to some embodiments of the connection

- 11 041413 of formula (J) or (I) R ⁴ is C3-6 alkyl which is optionally substituted with 1 or 2 substituents independently selected from OH, CF3, -C(O)OH, -C(O)OCH3, SCH3, -NHC(O)CH3,

-NHC(O)CH2CH2NH2, -NHC(O)CH2CH2OH, -NHC(O)CH2-pyridyl, phenyl, tetrahydrofuranyl and cyclopropyl.

In some embodiments of a compound of formula (J) or (I), R ⁴ is C 1-6 alkyl which is optionally substituted with OH. In some embodiments of a compound of formula (J) or (I), R ⁴ is C3-8 alkyl which is optionally substituted with OH. In some embodiments of a compound of formula (J) or (I), R ⁴ is C ₃ .galkyl which is substituted with -NHC(O)CH3.

In some embodiments of a compound of formula (J) or (I), R ⁴ is C3.6 alkyl which is optionally substituted with OH. In some embodiments of a compound of formula (J) or (I), R ⁴ is C3. ₆ alkyl which is substituted with -NHC(O)CH ₃ .

In some embodiments of a compound of formula (J) or (I), R ⁴ contains at least one chiral center. In some embodiments, at least one chiral center is in the S configuration. In some embodiments, at least one chiral center is in the R configuration.

In some embodiments of a compound of formula (J) or (I), R ⁴ is selected from the group consisting of:

In some embodiments of a compound of formula (J) or (I), R ⁴ is selected from the group consisting of:

- 12 041413

- 13 041413

In some embodiments of a compound of formula (J) or (I), R ⁴ is selected from the group consisting of:

- 14 041413

In some embodiments of a compound of formula (J) or (I), R ⁴ is selected from the group consisting of:

In some embodiments of a compound of formula (J) or (I), R ⁴ is selected from the group consisting of:

In some embodiments of a compound of formula (J) or (I), R ⁴ is selected from the group consisting of:

- 15 041413

According to some embodiments of a compound of formula (J) or (I) R ⁴ consisting of:

selected from the group

- 16 041413

In some embodiments of a compound of formula (J) or (I), R ⁴ is selected from the group consisting of:

- 17 041413

and F.

In some embodiments of a compound of formula (J) or (I), R ⁴ is selected from the group consisting of:

In some embodiments of a compound of formula (J) or (I), R ⁴ is selected from the group consisting of:

In some embodiments of a compound of formula (J) or (I), R ⁴ is selected from the group consisting of:

In some embodiments of a compound of formula (J) or (I), R ⁴ is selected from the group consisting of:

- 18 041413

Consisting of:

In some embodiments of a compound of formula (J) or (I), R ⁴ is selected from the group consisting of:

in some embodiments of a compound of formula (J) or (I), R ⁴ is selected from the group,

In some embodiments of a compound of formula (J) or (I), R ⁴ is selected from the group consisting of:

In some embodiments of a compound of formula (J) or (I), R ⁴ is selected from the group,

- 19 041413

In some embodiments of a compound of formula (J) or (I), R ⁴ is

O

In some embodiments of a compound of formula (J) or (I), R ⁴ is

O

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

II or a pharmaceutically acceptable salt thereof, wherein

R ⁵ is selected from the group consisting of hydrogen, halogen and methyl;

R ⁶ is selected from the group consisting of hydrogen, halogen and methyl; or

R ⁵ and R ⁶ together form an oxo group;

R ⁷ is selected from the group consisting of hydrogen, halogen, OR ^a and NR ^a R ^b ;

R ⁸ is selected from the group consisting of hydrogen and methyl;

R ⁹ is selected from the group consisting of C ₁ . ₄ alkyl, C ₃ . ₅ cycloalkyl and -SC ₁ . ₄ alkyl;

R ^a and R ^b are independently selected from the group consisting of hydrogen and C ₁ . ₆ alkyl; where each C ₁ . ₆ alkyl is optionally substituted with 1-3 substituents independently selected from the group consisting of halogen,

- 20 041413 hydroxyl and pyridyl; and R ¹ , R ² and R ³ are as defined herein.

For example, in formulas (II), (IIa) and (IIb), R ¹ is selected from the group consisting of hydrogen, halogen, C1.6 alkyl, CN, -NR ^a R ^b , -S(O) 1.2 R ^a and OR ^a , where C ₁ . ₆ alkyl is optionally substituted with 1-5 R ²⁰ groups; R ² is selected from the group consisting of hydrogen, halogen, C1.6 alkyl, CN, -NR ^a R ^b , -S(O)1.2 R ^a and OR ^a where C ₁ . ₆ alkyl is optionally substituted with 1-5 R ²⁰ groups; and R ³ is selected from the group consisting of hydrogen, halogen, C1.6 alkyl, CN, -NR ^a R ^b , -S(O)1.2 R ^a and OR ^a , where C _1-6 alkyl is optionally substituted with 1-5 R groups ²⁰ ;

In some embodiments, a compound of formula (II) is a compound of formula (IIa)

In some embodiments, a compound of formula (II) is a compound of formula (IIb)

R

^R6

R

^R3

IIb.

In some embodiments of a compound of formula (II), (IIa), or (IIb), R ⁵ is hydrogen; R ⁶ is hydrogen; or R ⁵ and R ⁶ together form an oxo group; R ⁷ is OR ^a or NR ^a R ^b ; R ⁸ is hydrogen; R ⁹ is C1.4 alkyl, cyclopropyl or -SCH3; R ^a and R ^b are independently selected from the group consisting of hydrogen and C1. ₄ alkyl; where each C ₁ . ₄ alkyl is optionally substituted with 1-3 substituents independently selected from halogen, hydroxyl, pyrid-2-yl and CF ₃ , and R ¹ , R ² and R ³ are as defined herein. In some embodiments, R ^a and R ^b are hydrogen. In some embodiments, R ⁷ is OH or NH2. In some embodiments, R ¹ and R ² are hydrogen.

In some embodiments of a compound of formula (IIa)

selected from

In some embodiments, the compound of formula (IIa) is selected from

- 21 041413

In some embodiments of a compound of formula (II), (IIa) or (IIb), R ⁵ is hydrogen, R ⁶ is hydrogen, or R ⁵ and R ⁶ together form an oxo group, R ⁷ is OR ^a or NR ^a R ^b , R ⁸ is hydrogen, R ⁹ is C1-4 alkyl, cyclopropyl, or —SCH3, and R ^a and R ^b are independently selected from the group consisting of hydrogen and C 1-4 alkyl; where each € _1-4 alkyl is optionally substituted with 1-3 substituents independently selected from halogen, hydroxyl, pyrid-2-yl and CF3. In some embodiments of a compound of formula (II), (IIa) or (IIb), R ⁷ is OH or NH ₂ .

In some embodiments of a compound of formula (J), formula (I), or formula (II), said compound is a compound of formula (III)

- 22 041413

(III) where R ⁵ represents hydrogen;

R ⁶ is hydrogen; or

R ⁵ and R ⁶ together form an oxo group;

R ⁷ is selected from the group consisting of OR ^a and NR ^a R ^b ;

R ^a and R ^b are independently selected from the group consisting of hydrogen and C ₁ _ ₃ alkyl; where each C ₁ _ ₃ alkyl is optionally substituted with 1-3 substituents independently selected from the group consisting of halogen and hydroxyl and R ¹ , R ² and R ³ are as defined herein.

In some embodiments, a compound of formula (III) is a compound of formula (IIIa)

In some embodiments, a compound of formula (III) is a compound of formula (IIIb)

In some embodiments of a compound of formula (III), (IIIa) or (IIIb), both R ⁵ and R ⁶ are hydrogen and R ⁷ is OR ^a , where R ^a is hydrogen or C _1-3 alkyl. In some embodiments of a compound of formula (III), (IIIa) or (IIIb), R ⁵ and R ⁶ are both hydrogen and R ⁷ is OH. In some embodiments of a compound of formula (III), (IIIa) or (IIIb), each R ¹ , R ² , R ⁵ and R ⁶ is hydrogen and R ⁷ is OH.

In some embodiments of a compound of formula (III), (IIIa) or (IIIb), R ⁵ and R ⁶ together form an oxo group and R ⁷ is selected from the group consisting of OR ^a and NR ^a R ^b , where R ^a and R ^{b are} independently selected from the group consisting of hydrogen and C ₁ _ ₃ alkyl. In some embodiments of a compound of formula (III), (IIIa) or (IIIb), R ⁵ and R ⁶ together form an oxo group and R ⁷ is selected from the group consisting of OR ^a and NR ^a R ^b , where R ^a and R ^{b are} independently selected from the group consisting of hydrogen and methyl.

In some embodiments of a compound of formula (J) or formula (I), said compound is a compound of formula (IV)

The R ¹ , R ² and R ³ groups of formula (IV) are as defined above for formula (J) or (I). The groups R ¹¹ , R ¹² and R ¹³ are as defined above for R ⁴ in formula (J) or formula (I).

In some embodiments, a compound of formula (IV), or a pharmaceutically acceptable salt thereof, is a compound of formula (IVa)

- 23 041413

In some embodiments, a compound of formula (IV), or a pharmaceutically acceptable salt thereof, is a compound of formula (IVb)

The groups R ¹ , R ² , R ³ , R ¹¹ , R ¹² and R ¹³ of formula (IVa) and (IVb) are as defined for formula (J), (I) or (IV) above, or as defined below , or any combination of them.

R ¹ of formula (IV), (IVa) and (IVb) may be any suitable group selected from hydrogen, halogen, C1.6 alkyl, CN, -NR ^a R ^b , -S(O) 1 . ₂ R ^a and OR ^a , where C1.6alkyl is optionally substituted with 1-5 R ²⁰ groups. In some embodiments, R ¹ is selected from hydrogen, halogen, C1. ₆ alkyl, CN and OR ^a , where C1.6 alkyl is optionally substituted with 1-5 R ²⁰ groups. In some embodiments, R ¹ may be hydrogen, halogen, and C1. ₃ alkyl, where C ₁ . ₃ alkyl is optionally substituted with 1-5 halogen groups. In some embodiments, R ¹ may be hydrogen, fluorine, chlorine, bromine, methyl, or ethyl, where each methyl or ethyl group is optionally substituted with 1-5 halogen groups. In some embodiments, R ¹ may be hydrogen, fluorine, chlorine, bromine, methyl, or ethyl, where each methyl or ethyl group is optionally substituted with 1-5 fluorine groups. In some embodiments, R ¹ may be hydrogen, methyl, fluorine, chlorine, and CF3. In some embodiments, R ¹ may be hydrogen. In some embodiments, R ¹ is selected from hydrogen, halogen, NH2, C ₁ . ₆ alkyl, CN and OR ^a where C ₁ . ₆ alkyl is optionally substituted with 1-5 R ²⁰ groups.

R ² of formula (IV), (IVa) and (IVb) may be any suitable group selected from hydrogen, halogen, C1.6 alkyl, CN, -NR ^a R ^b , -S(O)1. ₂ R ^a and OR ^a , where C1.6alkyl is optionally substituted with 1-5 R ²⁰ groups. In some embodiments, R ² is selected from hydrogen, halogen, C1. ₆ αalkyl, CN and OR ^a , where C1.6alkyl is optionally substituted with 1-5 R ²⁰ groups. In some embodiments, R ² is selected from hydrogen, halogen, C1. ₃ alkyl, CN and OR ^a , where C1-3 alkyl is optionally substituted with 1-5 halogen groups. In some embodiments, R ² is selected from hydrogen, methyl, ethyl, fluorine, chlorine, bromine, CF3, CN, OH, OMe, and OEt. In some embodiments, R ² is selected from hydrogen, methyl, fluorine, and chlorine. In some embodiments, R ² is selected from hydrogen and fluorine. In some embodiments, R ² is selected from hydrogen, halogen, NH2, C1.6 alkyl, CN, and OR ^a , where C1. ₆ alkyl is optionally substituted with 1-5 R ²⁰ groups. In some embodiments, R ² is selected from hydrogen, methyl, ethyl, NH ₂ , fluorine, chlorine, bromine, CF ₃ , CN, OH, OMe, and OEt.

R ³ of formula (IV), (IVa) and (IVb) may be any suitable group selected from hydrogen, halogen, C1.6 alkyl, CN, -NR ^a R ^b , -S(O)1. ₂ R ^a and OR ^a , where C1.6alkyl is optionally substituted with 1-5 R ²⁰ groups. In some embodiments, R ³ is selected from hydrogen, halogen, C1. ₆ αalkyl, CN and OR ^a , where C1.6alkyl is optionally substituted with 1-5 R ²⁰ groups. In some embodiments, R ³ may be selected from hydrogen, halogen and C1. ₃ alkyl. In some embodiments, R ³ may be selected from hydrogen, methyl, fluorine, and chlorine. In some embodiments, R ³ may be selected from hydrogen and methyl. In some embodiments, R ³ is selected from hydrogen, halogen, NH2, C1.6 alkyl, CN, and OR ^a , where C1. ₆ alkyl is optionally substituted with 1-5 R ²⁰ groups.

In some embodiments, a compound of formula (IV), (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, is a compound wherein R ¹ is selected from the group consisting of hydrogen, halogen, C1.6 alkyl, CN, -NR ^a R ^b , -S(O)1.2R ^a and OR ^a , where C1. ₆ alkyl is optionally substituted with 1-5 R ²⁰ groups, R ² is selected from the group consisting of hydrogen, halogen, C ₁ . ₆ alkylα, CN, -NRaRb, -S(O) ₁ . ₂ R ^a and OR ^a , where C ₁ . ₆ alkyl is optionally substituted with 1-5 R ²⁰ groups and R ³ is selected from the group consisting of hydrogen, halogen, C1.6 alkyl, CN, -NR ^a R ^b , -S(O) 1.2 R ^a and OR ^a where C1. ₆ alkyl is optionally substituted with 1-5 R ²⁰ groups.

In some embodiments, a compound of formula (IV), (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, is a compound wherein R ¹ is selected from the group consisting of

- 24 041413 hydrogen, halogen and C ₁ . ₃ alkyl, where C _1-3 alkyl is optionally substituted with 1-5 halogen groups, R ² is selected from the group consisting of hydrogen, halogen, C _1-3 alkyl, CN and OR ^a , where C _1-3 alkyl is optionally substituted

1-5 halogen groups and R ³ is selected from the group consisting of hydrogen, halogen and C _1-3 αalkyl.

In some embodiments, a compound of formula (IV), (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, is a compound wherein R ¹ is selected from the group consisting of hydrogen, methyl, fluorine, chlorine and CF3, R ² is selected from the group , consisting of hydrogen, methyl, ethyl, fluorine, chlorine, bromine, CF3, CN, OH, OMe, and OEt, and R ³ is selected from the group consisting of hydrogen, methyl, fluorine and chlorine.

In some embodiments, a compound of formula (IV), (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, is a compound wherein R ¹ is selected from the group consisting of hydrogen, methyl, fluoro and chlorine and CF3, R ² is selected from the group , consisting of hydrogen, methyl, ethyl, NH2, fluorine, chlorine, bromine, CF3, CN, OH, OMe and OEt, and R ³ is selected from the group consisting of hydrogen, methyl, fluorine and chlorine.

In some embodiments, a compound of formula (IV), (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, is a compound wherein R ¹ is hydrogen, R ² is selected from the group consisting of hydrogen, methyl, ethyl, fluorine, chlorine and bromine, and R ³ is selected from the group consisting of hydrogen and methyl.

In some embodiments, a compound of formula (IV), (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, is a compound wherein R ¹ is hydrogen. R ² is selected from the group consisting of hydrogen and fluorine, and R ³ is selected from the group consisting of hydrogen and methyl.

In some embodiments, R ¹¹ of formula (IV), (IVa), and (IVb) may be any suitable group selected from hydrogen, C1.2αkyl, C3.6cycloalkyl, and C1.3haloalkyl. In some embodiments, a compound of formula (IV), (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, is a compound wherein R ¹¹ is selected from the group consisting of hydrogen, C1. ₂ αalkyl and C ₁ _ ₂ haloalkyl. In some embodiments, a compound of formula (IV), (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, is a compound wherein R ¹¹ is selected from the group consisting of C1.2αkyl and C1_2 haloalkyl. In some embodiments, a compound of formula (IV), (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, is a compound wherein R ¹¹ can be selected from hydrogen, methyl, ethyl, or CF3. In some embodiments, a compound of formula (IV), (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, is a compound wherein R ¹¹ can be selected from methyl, ethyl, or CF3. In some embodiments, a compound of formula (IV), (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, is a compound wherein R ¹¹ can be selected from hydrogen, methyl, or CF3. In some embodiments, a compound of formula (IV), (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, is a compound wherein R ¹¹ can be selected from methyl or CF3. In some embodiments, a compound of formula (IV), (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, is a compound wherein R ¹¹ can be selected from hydrogen or methyl. In some embodiments, a compound of formula (IV), (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, wherein R ¹¹ is selected from the group consisting of methyl and CF ₃ . In some embodiments, a compound of formula (IV), (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, is a compound wherein R ¹¹ is methyl. In some embodiments, a compound of formula (IV), (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, is a compound wherein R ¹¹ is hydrogen.

R ¹² of formula (IV), (IVa) and (IVb) may be any suitable group selected from C1_zalkyl, halogen, -OR ^a , -NR ^a R ^b , CN, -C(O)R ^a , -C( O)OR ^a , -C(O)NR ^a R ^b , -OC(O)NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)NR ^b , -NR ^a C( O)OR ^b , -SR ^a , -S(O)1-2R ^a , -S(O)2NR ^a R ^b , -NR ^a S(O)2R ^b , C1_zhaloalkyl,

C ₃ .bcycloalkyl, 3-6-membered heterocyclyl, where 3-6-membered heterocyclyl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur, C ₆ _ ₁₀ aryl and 5-10-membered heteroaryl, where 5-10 -membered heteroaryl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur, where C ₁ . _{The 3αalkylα} group is optionally substituted with 1-5 substituents independently selected from halo, -OR ^a , -NR ^a R ^b , CN, C(O)R ^a ,

-C(O)OR ^a , -C(O)NR ^a R ^b , -OC(O)NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)NR ^b , -NR ^a C(O)OR ^b , -SR ^a , -S(O)1-2R ^a , -S(O) ₂ NR ^a R ^b , -NR ^a S(O)2R ^b , C1_ ₃ haloalkyl, C _{3- 6} cycloalkyl, 3-6 membered heterocyclyl, where 3-6 membered heterocyclyl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur, C ₆ . ₁₀ aryl and 510-membered heteroaryl, where 5-10-membered heteroaryl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur.

In some embodiments, a compound of formula (IV), (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, wherein R ¹² can be selected from C1.2αkyl, -C(O)NR ^a R ^b and a 5-membered heteroaryl containing 1 to 3 nitrogen heteroatoms, where C1. ₂ αkyl is optionally substituted with 1-5 substituents independently selected from halogen, -OH, -NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a S(O) 2 R ^b and C1_ ₃ haloalkyl, and each R ^a and R ^b are independently selected from the group consisting of hydrogen and C ₁ _ ₃ αalkyl, where each C ₁ _ ₃ αalkyl

- 25 041413 is optionally substituted with 1-3 substituents independently selected from hydroxyl and amino. In some embodiments, a compound of formula (IV), (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, wherein R ¹² is C1.2 alkyl optionally substituted with 1-3 substituents independently selected from halo, -OH, -NH2, -NHC(O)-C1.3 alkyl, -NHS(O)2-C1.3 alkyl and C1.3 haloalkyl. In some embodiments, a compound of formula (IV), (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, wherein R ¹² is methyl or ethyl, each optionally substituted with 1 or 2 substituents independently selected from halo, -OH, -NH2, -NHC(O)-C _1-3 alkyl and C _1-3 haloalkyl. In some embodiments, a compound of formula (IV), (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, wherein R ¹² is methyl or ethyl, where methyl or ethyl is substituted with 1 or 2 substituents independently selected from -OH and -NHC (O)CH3. In some embodiments, a compound of formula (IV), (IVa) or (IVb), or a pharmaceutically acceptable salt _thereof , wherein R ¹² can be selected from CH2OH, _CH2CH2OH , CH(Me)OH, CH(CH2F)OH, CH(CHF2)OH, CH(CF3)OH, CF3, CH2NH2, CH2NHC(O)Me, CH(CH2F)NHC(O)Me, CHNHS(O)2Me, C(O)NH2, C(O)NHMe, C(O)NH-CH2CH2OH, C(O)NH-CH2CH2NH2, C(O)NH-(pyridin-2ylmethyl), imidazolyl and triazolyl. In some embodiments, a compound of formula (IV), (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, wherein R ¹² can be selected from CH2OH, CH(Me)OH, CH(CH2F)OH, and CH2NHC(O)Me. In some embodiments, a compound of formula (IV), (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, wherein R ¹² may be selected from CH2OH, CH(Me)OH, and _CH2NHC (O)Me. In some embodiments, a compound of formula (IV), (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, wherein R ¹² is —CH ₂ OH or —CH2NC(O)CH3.

In some embodiments, a compound of formula (IV), (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, wherein R ¹² is C1.2 alkyl substituted with -NR ^a C(O)R ^b , where Ra and R ^b are each independently selected from the group consisting of hydrogen and C1. ₃ alkyl, where each C ₁ . ₃ alkyl is optionally substituted with 1-3 substituents independently selected from hydroxyl and amino.

R ¹³ of formulas (IV), (IVa) and (IVb) may be any suitable group selected from C1.6 alkyl, halogen, -ORa, -NRaRb, CN, -C(O)R ^a , -C(O) OR ^a , -C(O)NR ^a R ^b , -OC(O)NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)NR ^b , -NR ^a C(O) OR ^b , -SRa, -S(O)1-2R ^a , -S(O)2NR ^a R ^b , -NR ^a S(O)2R ^b , C1.6 haloalkyl,

C ₃ _ ₆ cycloalkyl, 3-6 membered heterocyclyl, where 3-6 membered heterocyclyl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur, C ₆ . ₁₀ aryl and 5-10-membered heteroaryl, where 5-10-membered heteroaryl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur, where C ₁ . ₆ alkyl is optionally substituted with 1-5 substituents independently selected from halo, -ORa, -NRaRb, CN, -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -OC (O)NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)NR ^b , -NR ^a C(O)OR ^b , -SRa, -S(O)1-2R ^a , -S(O)2NR ^a R ^b , -NR ^a S(O)2R ^b , C1. ₆ haloalkyl, C ₃ . ₆ cycloalkyl, 3-6 membered heterocyclyl, where 3-6 membered heterocyclyl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur, C ₆ . ₁₀ aryl and 5-10 membered heteroaryl, where 5-10 membered heteroaryl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur.

In some embodiments, a compound of formula (IV), (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, is a compound wherein R ¹³ is C3.6 alkyl optionally substituted with 1-2 substituents independently selected from halo and —OH. In some embodiments, a compound of formula (IV), (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, is a compound wherein R ¹³ is C3. ₆ alkyl optionally substituted with 1-2 halogen substituents. In some embodiments, a compound of formula (IV), (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, is a compound wherein R ¹³ is C ₃ . ₆ alkyl. Typical C ₃ . _{The 6} alkyl groups for R ¹³ include, but are not limited to, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl, t-pentyl, neopentyl, isopentyl, sec-pentyl, and 3-pentyl . In some embodiments, a compound of formula (IV), (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, is a compound wherein R ¹³ is propyl, butyl, or pentyl. In some embodiments, a compound of formula (IV), (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, is a compound wherein R ¹³ is n-propyl, n-butyl, or n-pentyl. In some embodiments, a compound of formula (IV), (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, is a compound wherein R ¹³ is propyl or butyl.

R ²⁰ of formula (IV), (IVa) and (IVb) may be any suitable group selected from halo, C1.6 haloalkyl, CN, -NRaRb, S(O)1_2R ^a and ORa. In some embodiments, each R ²⁰ may be independently selected from halo, CN, -NRaRb, and ORa. In some embodiments, each R ²⁰ may be independently selected from halo, CN, -NRaRb, and ORa. In some embodiments, each R ²⁰ may independently be halogen. In some embodiments, each R ²⁰ may be independently selected from fluorine, chlorine, bromine, CN, -NH2, OH, OMe, and OEt. In some embodiments, each R ²⁰ may be independently selected from fluorine and chlorine.

Each R ^a and R ^b of formulas (IV), (IVa) and (IVb) may independently represent any suitable

- 26 041413 a driving group selected from the group consisting of hydrogen and C ₁ . ₆ alkyl; where each C ₁ . ₆ alkyl is optionally substituted with 1-5 substituents independently selected from halogen, hydroxyl, amino, 5-10 membered heteroaryl, where 5-10 membered heteroaryl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur, and C ₁ _ ₆ haloalkyl . In some embodiments, R ^a and R ^b can each be independently selected from hydrogen and C1_3 alkyl, where each C1.3αalkyl is optionally substituted with 1-3 substituents independently selected from halo, hydroxyl, amino, and C1_6 haloalkyl. In some embodiments, R ^a and R ^b can each be independently selected from hydrogen and C1. ₃ αalkyl, where each C ₁ _ ₃ alkyl is optionally substituted with 1-3 substituents independently selected from hydroxyl and amino. In some embodiments, R ^a and R ^b can each be independently selected from hydrogen and C1.3 alkyl, where each C1.3 alkyl is optionally substituted with 1 substituent selected from hydroxyl and amino. In some embodiments, R ^a and R ^b can each be independently selected from hydrogen and C1. ₃ alkyla. In some embodiments, R ^a and R ^b can each be independently selected from hydrogen, methyl, ethyl, propyl, butyl, CF3, CH2CF3, CH2CH2CF3, CH2OH, CH2CH2OH, CH2NH2, and CH2CH2NH2. In some embodiments, R ^a and R ^b can each be independently selected from hydrogen, methyl, ethyl, CF3, CH2OH, CH2CH2OH, CH2NH2 and CH2CH ₂ NH ₂ . In some embodiments, R ^a and R ^b can each be independently selected from hydrogen, methyl, ethyl, CH ₂ CH ₂ OH, and CH ₂ CH ₂ NH ₂ . In some embodiments, R ^a and R ^b can each be independently selected from hydrogen, methyl, and ethyl. In some embodiments, R ^a and R ^b can each be independently selected from hydrogen and methyl.

In some embodiments, a compound of formula (IV), (IVa), or (IVb), or a pharmaceutically acceptable salt thereof, is a compound wherein:

R ¹ is selected from the group consisting of hydrogen, halogen, C1.6αkyl, CN, -NR ^a R ^b , -S(O)1_2R ^a and OR ^a where C1. ₆ αkyl is optionally substituted with 1-5 R ²⁰ groups;

R ² is selected from the group consisting of hydrogen, halogen, C1.6alkyl, CN, -NR ^a R ^b , -S(O)1_2R ^a and OR ^a where C1. ₆ αkyl is optionally substituted with 1-5 R ²⁰ groups;

R ³ is selected from the group consisting of hydrogen, halogen, C1.6alkyl, CN, -NR ^a R ^b , -S(O)1_2R ^a and OR ^a where C1. ₆ αkyl is optionally substituted with 1-5 R ²⁰ groups;

R ¹¹ is selected from the group consisting of hydrogen, C ₁ . ₂ alkyl, C ₃ . ₆ cycloalkyl and _C1-3 haloalkyl;

R ¹² is selected from C1.3 alkyl, halogen, -OR ^a , -NR ^a R ^b , CN, -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -OC (O)NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)NR ^b , -NR ^a C(O)OR ^b , -SR ^a , -S(O)1-2R ^a , -S(O)2NR ^a R ^b , -NR ^a S(O)2R ^b , C1. ₃ haloalkyl, C ₃ . ₆ cycloalkyl, 3-6 membered heterocyclyl, where 3-6 membered heterocyclyl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur, C ₆ . ₁₀ aryl and 5-10-membered heteroaryl, where 5-10-membered heteroaryl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur, where C ₁ . _{The 3} αalkyl group is optionally substituted with 1-5 substituents independently selected from halo, -OR ^a , -NR ^a R ^b , CN, -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -OC(O)NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)NR ^b , -NR ^a C(O)OR ^b , -SR ^a , -S( O)1-2R ^a , -S(O)2NR ^a R ^b , -NR ^a S(O)2R ^b , C1.3-haloalkyl, C3.6-Cycloalkyl, 3-6-membered heterocyclyl, where 3-6-membered heterocyclyl contains 1- 3 heteroatoms selected from oxygen, nitrogen and sulfur, C ₆ _ ₁₀ aryl and 5-10 membered heteroaryl, where 5-10 membered heteroaryl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur;

R ¹³ is selected from C1.6 alkyl, halogen, -OR ^a , -NR ^a R ^b , CN, -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -OC (O)NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)NR ^b , -NR ^a C(O)OR ^b , -SR ^a , -S(O)1-2R ^a , -S(O)2NR ^a R ^b , -NR ^a S(O)2R ^b , C1. ₆ haloalkyl, C ₃ . ₆ cycloalkyl, 3-6 membered heterocyclyl, where 3-6 membered heterocyclyl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur, C ₆ . ₁₀ aryl and 5-10-membered heteroaryl, where 5-10-membered heteroaryl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur, where C ₁ . ₆ alkyl is optionally substituted with 1-5 substituents independently selected from halo, -OR ^a , -NR ^a R ^b , CN, -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -OC(O)NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)NR ^b , -NR ^a C(O)OR ^b , -SR ^a , -S(O )1-2R ^a , -S(O)2NR ^a R ^b , -NR ^a S(O)2R ^b , C ₁ . ₆ haloalkyl, C ₃ . ₆ cycloalkyl, 3-6 membered heterocyclyl, where 3-6 membered heterocyclyl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur, C ₆ . ₁₀ aryl and 510-membered heteroaryl, where 5-10-membered heteroaryl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur; each R ²⁰ is independently selected from the group consisting of halogen, CN, -NR ^a R ^b and OR ^a ; and each R ^a and R ^b is independently selected from the group consisting of hydrogen and C ₁ _ ₃ αkyl, where each C ₁ . ₃ αalkyl is optionally substituted with 1-3 substituents independently selected from halogen, hydroxyl, amino and C ₁ _ ₆ haloalkyl.

In some embodiments, a compound of formula (IV), (IVa), or (IVb), or a pharmaceutically acceptable salt thereof, is a compound wherein:

R ¹ is selected from the group consisting of hydrogen, halogen, C1.6αkyl, CN, -NR ^a R ^b , -S(O)1_2R ^a and OR ^a where C ₁ . ₆ αkyl is optionally substituted with 1-5 R ²⁰ groups;

R ² is selected from the group consisting of hydrogen, halogen, C1.6alkyl, CN, -NR ^a R ^b , -S(O)1_2R ^a and OR ^a where C ₁ . ₆ αkyl is optionally substituted with 1-5 R ²⁰ groups;

R ³ is selected from the group consisting of hydrogen, halogen, C1.6alkyl, CN, -NR ^a R ^b , -S(O)1_2R ^a and OR ^a where C ₁ . ₆ αkyl is optionally substituted with 1-5 R ²⁰ groups;

- 27 041413

R ¹¹ is selected from the group consisting of C _1-2 alkyl, O ₃ . ₆ cycloalkyl and C _1-3 haloalkyl;

R ¹² is selected from C1-zalkyl, halogen, -OR ^a , -NR ^a R ^b , CN, -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -OC (O)NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)NR ^b , -NR ^a C(O)OR ^b , -SR ^a , -S(O)1-2R ^a , -S(OhNR ^a R ^b , -NR ^a S(O)2R ^b , C1.3 haloalkyl, C3.6 cycloalkyl, 3-6 membered heterocyclyl, where 3-6 membered heterocyclyl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur, C6.10 aryl and 5-10-membered heteroaryl, where the 5-10-membered heteroaryl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur, where the C1.3αkylα group is optionally substituted with 1-5 substituents, independently selected from halogen, -OR ^a , -NR ^a R ^b , CN, -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -OC(O)NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)NR ^b , -NR ^a C(O)OR ^b , -SR ^a , -S(O)1-2R ^a , -S( O) 2NR ^a R ^b , -NR ^a S (O) 2 R ^b , C ^ haloalkyl, C3-6 Cycloalkyl, 3-6 membered heterocyclyl, where 3-6 membered heterocyclyl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur , _C6.10 aryl and 5-10-membered heteroaryl, where 5 -10-membered heteroaryl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur;

R ¹³ is selected from C1_6alkyl, halogen, -OR ^a , -NR ^a R ^b , CN, -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -OC(O )NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)NR ^b -NR ^a C(O)OR ^b , -SR ^a , -S(O)1-2R ^a , - S(O)2NR ^a R ^b , -NR ^a S(O)2R ^b , C1.6 haloalkyl, C3.6 cycloalkyl, 3-6 membered heterocyclyl, where the 3-6 membered heterocyclyl contains 1-3 heteroatoms selected from oxygen , nitrogen and sulfur, C6_10 aryl and 5-10-membered heteroaryl, where 5-10-membered heteroaryl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur, where C1.6 alkyl is optionally substituted with 1-5 substituents independently selected from halogen , -OR ^a , -NR ^a R ^b , CN, -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -OC(O)NR ^a R ^b , - NR ^a C(O)R ^b , -NR ^a C(O)NR ^b , -NR ^a C(O)OR ^b , -SR ^a , -S(O)1-2R ^a , -S(O)2NR ^a R ^b , -NR ^a S(O)2R ^b , C1_ ₆ haloalkyl, C ₃ . ₆ cycloalkyl, 3-6 membered heterocyclyl, where 3-6 membered heterocyclyl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur, C ₆ . ₁₀ aryl and 510-membered heteroaryl, where 5-10-membered heteroaryl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur; each R ²⁰ is independently selected from the group consisting of halogen, CN, -NR ^a R ^b and OR ^a ; and each R ^a and R ^b is independently selected from the group consisting of hydrogen and C ₁ . ₃ αkil, where each C ₁ . ₃ αalkyl is optionally substituted with 1-3 substituents independently selected from halogen, hydroxyl, amino and C ₁ _ ₆ haloalkyl.

In some embodiments, a compound of formula (IV), (IVa), or (IVb), or a pharmaceutically acceptable salt thereof, is a compound wherein:

R ¹ is selected from the group consisting of hydrogen, halogen, C1.6 alkyl, CN and OR ^a , where C1. ₆ αkyl is optionally substituted with 1-5 R ²⁰ groups;

R ² is selected from the group consisting of hydrogen, halogen, C1.6 alkyl, CN and OR ^a , where C1. ₆ αkyl is optionally substituted with 1-5 R ²⁰ groups;

R ³ is selected from the group consisting of hydrogen, halogen, C1.6 alkyl, CN and OR ^a , where C1. ₃ αkyl is optionally substituted with 1-5 R ²⁰ groups;

R ¹¹ is selected from the group consisting of hydrogen, C ₁ . ₂ alkyl, O ₃ . ₆ cycloalkyl and C ₁ . ₃ haloalkyl;

R ¹² is selected from C1_zalkyl, halogen, -OR ^a , -NR ^a R ^b , CN, -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -OC(O )NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)NR ^b , -NR ^a C(O)OR ^b , -SR ^a , -S(O)1-2R ^a , -S(O)2NR ^a R ^b , -NR ^a S(O)2R ^b , C1.3 haloalkyl, C3.6 cycloalkyl, 3-6 membered heterocyclyl, where the 3-6 membered heterocyclyl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur, C6_10 aryl and 5-10-membered heteroaryl, where 5-10-membered heteroaryl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur, where the C1.3αkylα group is optionally substituted with 1-5 substituents independently selected from halogen, -OR ^a , -NR ^a R ^b , CN, -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -OC(O)NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)NR ^b , -NR ^a C(O)OR ^b , -SR ^a , -S(O)1-2R ^a , -S(O) 2NR ^a R ^b , -NR ^a S(O)2R ^b , C1_3 haloalkyl, C3-6 Cycloalkyl, 3-6 membered heterocyclyl, where the 3-6 membered heterocyclyl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur, C6. ₁₀ aryl and 5-10-membered heteroaryl, where 5-10-membered heteroaryl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur;

R ¹³ is selected from C1_6alkyl, halogen, -OR ^a , -NR ^a R ^b , CN, -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -OC(O )NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)NR ^b , -NR ^a C(O)OR ^b , -SR ^a , -S(O)1-2R ^a , -S(O)2NR ^a R ^b , -NR ^a S(O)2R ^b , C1.6 haloalkyl, C3.6 cycloalkyl, 3-6 membered heterocyclyl, where 3-6 membered heterocyclyl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur, C6_10 aryl and 5-10-membered heteroaryl, where 5-10-membered heteroaryl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur, where C1.6 alkyl is optionally substituted with 1-5 substituents independently selected from halogen, -OR ^a , -NR ^a R ^b , CN, -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -OC(O)NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)NR ^b , -NR ^a C(O)OR ^b , -SR ^a , -S(O)1-2R ^a , -S(O)2NR ^a R ^b , -NR ^a S(O)2R ^b , C1. ₆ haloalkyl, O ₃ . ₆ cycloalkyl, 3-6 membered heterocyclyl, where 3-6 membered heterocyclyl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur, C ₆ . ₁₀ aryl and 510-membered heteroaryl, where 5-10-membered heteroaryl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur; each R ²⁰ is independently selected from the group consisting of halogen, CN, -NR ^a R ^b and OR ^a ; and each R ^a and R ^b is independently selected from the group consisting of hydrogen and C ₁ . ₃ αkil, where each C ₁ . ₃ αalkyl is optionally substituted with 1-3 substituents independently selected from halogen, hydroxyl, amino and C ₁ _ ₆ haloalkyl.

- 28 041413

In some embodiments, a compound of formula (IV), (IVa), or (IVb), or a pharmaceutically acceptable salt thereof, is a compound wherein:

R ¹ is selected from the group consisting of hydrogen, halogen, C ₁ . ₆ alkyl, CN and ORa, where C ₁ . ₆ αkyl is optionally substituted with 1-5 R ²⁰ groups;

R ² is selected from the group consisting of hydrogen, halogen, C ₁ . ₆ alkyl, CN and ORa, where C ₁ . ₆ αkyl is optionally substituted with 1-5 R ²⁰ groups;

R ³ is selected from the group consisting of hydrogen, halogen, C ₁ . ₆ alkyl, CN and ORa, where C ₁ . ₆ αkyl is optionally substituted with 1-5 R ²⁰ groups;

R ¹¹ is selected from the group consisting of C ₁ . ₂ alkyl, C ₃ . ₆ cycloalkyl and C ₁ . ₃ haloalkyl;

R ¹² is selected from C1.zalkyl, halogen, -ORa, -NRaRb, CN, -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -OC(O)NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)NR ^b -NR ^a C(O)OR ^b , -SRa, -S(O)1-2Ra, -S(O) 2NR ^a R ^b , -NR ^a S (O) 2 R ^b , Cl. , C6.10aryl and 5-10-membered heteroaryl, where 5-10-membered heteroaryl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur, where C1.3αalkylα group is optionally substituted with 1-5 substituents independently selected from halogen, -ORa, -NRaRb, CN, -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -OC(O)NR ^a R ^b , -NR ^a C(O )R ^b , -NR ^a C(O)NR ^b , -NR ^a C(O)OR ^b , -SRa, -S(O)1- ₂ R ^a , -S(O) ₂ NR ^a R ^b , - NR ^a S(O)2R ^b , C1. ₃ haloalkyl, C ₃ . ₆ cycloalkyl, 3-6 membered heterocyclyl, where the 3-6 membered heterocyclyl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur, C ₆ . ₁₀ aryl and 5-10-membered heteroaryl, where 5-10-membered heteroaryl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur;

R ¹³ is selected from C1.6 alkyl, halogen, -ORa, -NRaRb, CN, -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -OC(O)NR ^a R ^b , -NR ^a C(O)R ^b , -NR ^a C(O)NR ^b , -NR ^a C(O)OR ^b , -SRa, -S(O)1-2R ^a , -S( O)2NR ^a R ^b , -NR ^a S(O)2R ^b , C1.6 haloalkyl, C3.6 cycloalkyl, 3-6 membered heterocyclyl, where 3-6 membered heterocyclyl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur, C6.10 aryl and 5-10 membered heteroaryl, where the 5-10 membered heteroaryl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur, where C1.6 alkyl is optionally substituted with 1-5 substituents independently selected from halogen , -ORa, -NRaRb, CN, -C(O)R ^a , -C(O)OR ^a , -C(O)NR ^a R ^b , -OC(O)NR ^a R ^b , -NR ^a C( O)R ^b , -NR ^a C(O)NR ^b , -NR ^a C(O)OR ^b , -SRa, -S(O)1-2R ^a , -S(O)2NR ^a R ^b , -NR ^a S(O)2R ^b , C1. ₆ haloalkyl, C ₃ . ₆ cycloalkyl, 3-6 membered heterocyclyl, where 3-6 membered heterocyclyl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur, C ₆ . ₁₀ aryl and 510-membered heteroaryl, where 5-10-membered heteroaryl contains 1-3 heteroatoms selected from oxygen, nitrogen and sulfur; each R ²⁰ is independently selected from the group consisting of halogen, CN, -NRaRb and ORa; and each Ra and R ^b is independently selected from the group consisting of hydrogen and C ₁ . ₃ αkil, where each C ₁ . ₃ αkyl is optionally substituted with 1-3 substituents independently selected from halogen, hydroxyl, amino and C ₁ . ₆ haloalkyl.

In some embodiments, a compound of formula (IV), (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, wherein R ¹¹ is methyl or CF3, R ¹² is -CH2OH, -CH(Me)OH, or _-CH2NHC (O)CH ₃ , and R ¹³ is selected from the group consisting of propyl, butyl and pentyl.

In some embodiments, a compound of formula (IV), (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, wherein R ¹¹ is methyl or CF3, R ¹² is —CH2OH, —CH(Me)OH, _CH2NHCH ( CH ₃ )(CF ₃ ) or -CH ₂ NHC(O)CH ₃ , and R ¹³ is selected from the group consisting of propyl, butyl and pentyl.

In some embodiments, a compound of formula (IV), (IVa) or (IVb), or a pharmaceutically acceptable salt thereof, wherein R ¹¹ is methyl, R ¹² is -CH2OH or -CH ₂ NHC(O)CH ₃ and R ¹³ is selected from the group consisting of propyl and butyl.

In some embodiments, a compound of formula (IV), or a pharmaceutically acceptable salt thereof, r- _R ¹¹ x/'r ¹² , wherein moiety x is

- 29 041413

In some embodiments, a compound of formula (IV), or a pharmaceutically acceptable salt thereof, wherein the moiety

from R ¹¹ * ¹² _ _ .

represents

In some embodiments, the compound of formula (IV) or (IVa), 4^^2 _w

In some embodiments, a compound of formula (IV) or (IVa) is 4e ^X _R 12 .

a classically acceptable salt, where the moiety x is or its pharmaceutical

In some embodiments, a compound of formula (IV) or (IVa) is a commercially acceptable salt, wherein the moiety \ is or a pharmaceutically acceptable salt thereof.

In some embodiments, a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt ^thereof , wherein the χ moiety is

In some embodiments, a compound of formula (IV) or (IVa) or a pharmaceutically acceptable salt thereof, R^*, wherein the X ^R moiety can also be depicted as a moiety

In some embodiments, the compound of formula (IV) or (IVb) or pharmaceuticals thereof is

a tistically acceptable salt, where the fragment

In some embodiments, a compound of formula (IV) or (IVb), or a pharmaceutically acceptable salt thereof, wherein the moiety \ can also be depicted as a moiety

Ir _V ^r11 y^R ¹²

In some embodiments, a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt thereof, is a compound of formula (IVc)

The R ² , R ¹² and R ¹³ groups of formula (IVc) are as defined above for formula (J), (I), (IV) or (IVa), or any combination thereof. For example, R ² may be selected from hydrogen, halogen, C1-3 alkyl, CN, and OR ^a where C1-3 alkyl is optionally substituted with 1-5 halo groups, R ¹² may be selected from C1-2 alkyl, -C(O)NR ^a R ^b , and a 5-membered heteroaryl containing from 1 to 3 nitrogen heteroatoms, where C1-2 alkyl is optionally substituted with 1-5 substituents independently selected from halogen, -OH, -NR ^a R ^b , -NR ^a C(O) R ^b , -NR ^a S(O)2R ^b , and C1-3 haloalkyl, and R ¹³ may be C3-6 alkyl optionally substituted with 1-2 substituents independently selected from halo and -OH. In some embodiments, a compound of formula (IV), (IVa), or (IVc), or a pharmaceutically acceptable salt thereof, is a compound where R ² can be selected from hydrogen, methyl, ethyl, fluorine, chlorine, bromine, CF3, CN, OH, OMe and OEt, and R ¹² can be selected from CH2OH, CH2CH2OH, CH(Me)OH, CH(CH2F)OH, CH(CHF2)OH, CH(CF3)OH, CF3, CH2NH2, CH2NHC(O)Me , CH(CH2F)NHC(O)Me, CH2NHS(O)2Me, C(O)NH2, C(O)NHMe, C(O)NH-CH2CH2OH, C(O)NH-CH2CH2NH2, C(O)NH -(pyridin-2ylmethyl), imidazolyl and triazolyl, and R ¹³ may be propyl, butyl or pentyl. In some embodiments, a compound of formula (IV), (IVa) or (IVc), or a pharmaceutically acceptable salt thereof, is a compound wherein R ² may be selected from hydrogen, methyl, fluorine, and chlorine, and R ¹² may be selected from CH2OH, CH(Me)OH, CH(CH ₂ F)OH and CH ₂ NHC(O)Me, and R ¹³ may be propyl, butyl or pentyl. In some embodiments, a compound of formula (IV), (IVa), or (IVc), or a pharmaceutically acceptable salt thereof, is a compound wherein R ² is hydrogen or fluorine, R ¹² is -CH2OH or -CH2NHC(O)CH3, and R ¹³ is selected from propyl and butyl. In some embodiments, a compound of formula (IV), (IVa) or (IVc), or a pharmaceutically acceptable salt thereof, is a compound wherein R ² is hydrogen, chlorine, or fluorine, R ¹² is —CH2OH or _—CH2NHC (O )CH ₃ , and R ¹³ is selected from butyl or pentyl.

In some embodiments, a compound of formula (IV) or (IVa), or a pharmaceutically acceptable salt thereof, is a compound of formula (IVd)

R ³ (IVd) .

The groups R ¹ , R ² , R ³ , R ¹¹ , R ¹³ , R ^a and R ^b of formula (IVd) may be as defined above for formula (J), (I), (IV), or (IVa) , or any combination of them. R ^12a may be any suitable group selected from hydrogen, C1.2 alkyl and C1.3 haloalkyl. In some embodiments, a compound of formula (IV), (IVa) or (IVd), or a pharmaceutically acceptable salt thereof, is a compound wherein R ^12a can be selected from hydrogen, C1. ₂ alkyl and C ₁ . ₃ haloalkyl. In some embodiments, a compound of formula (IV), (IVa) or (IVd), or a pharmaceutically acceptable salt thereof, is a compound wherein R ^12a can be selected from hydrogen, methyl, ethyl, and CF ₃ . In some embodiments, a compound of formula (IV), (IVa) or (IVd), or a pharmaceutically acceptable salt thereof, is a compound wherein R ^12a may be hydrogen.

In some embodiments, a compound of formula (IVd), or a pharmaceutically acceptable salt thereof, is a compound wherein R ¹ is selected from the group consisting of hydrogen, halogen, C1.6 alkyl, CN, and OR ^a , where C 1-6 alkyl is optionally substituted with 1-5 groups R ²⁰ , R ² is selected from the group consisting of hydrogen, halogen, C1.6 alkyl, CN and OR ^a , where C1. ₆ alkyl is optionally substituted with 1-5 R ²⁰ groups, R ³ is selected from the group consisting of hydrogen, halogen, C1.6 alkyl, CN and OR ^a , where C1. ₆ alkyl is optionally substituted with 1-5 R ²⁰ groups, R ¹¹ is C1.2 alkyl or CF3, R ^12a is selected from the group consisting of hydrogen, C1. ₂ alkyl and C ₁ . ₃ haloalkyl, R ¹³ is C3.6 alkyl optionally substituted with 1-2 halogen substituents, each R ²⁰ is independently selected from the group consisting of halo, C1. ₆ haloalkyl, CN, -NR ^a R ^b , S(O)1.2R ^a and OR ^a , and each R ^a and R ^b is independently selected from the group consisting of hydrogen and C1. ₃ alkyl, where each C ₁ . ₃ alkyl is optionally substituted with 1-3 substituents independently selected from halo, hydroxyl, amino and C ₁ . ₆ haloalkyl.

In some embodiments, a compound of formula (IVd), or a pharmaceutically acceptable salt thereof, is a compound wherein R ¹ is selected from the group consisting of hydrogen, halogen and C1.3 alkyl, R ² is selected from the group consisting of hydrogen, halogen and C1. ₃ alkyl, R ³ is selected from the group consisting of hydrogen, halogen and C1.3 alkyl, R ¹¹ is C1. ₂ alkyl or CF ₃ , R ^12a is selected from the group consisting of hydrogen, C1.2 alkyl and C1.3 haloalkyl, R ¹³ is C3. ₆ alkyl optionally substituted with 1-2 halo substituents, and each R ^a and R ^b is independently selected from the group consisting of hydrogen and C ₁ . ₃ alkyl, where each C ₁ . ₃ alkyl is optionally substituted with 1-3 substituents independently selected from halo, hydroxyl, amino and C ₁ . ₆ haloalkyl.

In some embodiments, a compound of formula (IVd), or a pharmaceutically acceptable salt thereof, has the structure:

where R ² is selected from the group consisting of hydrogen, methyl, fluorine and chlorine, R ³ is selected from the group consisting of hydrogen and methyl, R ^12a is selected from the group consisting of hydrogen, C1.2 alkyl and C1.3 haloalkyl, R ¹³ is a C3. ₆ alkyl, and R ^b is methyl or ethyl, each of which is optionally substituted with hydroxyl or amino.

In some embodiments, a compound of formula (IVd), or a pharmaceutically acceptable salt thereof, has the structure:

where R ² is selected from the group consisting of hydrogen, methyl, fluorine and chlorine, R ^12a is selected from the group consisting of hydrogen, C1.2 alkyl and C1.3 haloalkyl, R ¹³ is C3. ₆ alkyl, and R ^b is methyl or ethyl, each of which is optionally substituted with hydroxyl or amino. In some embodiments, R ² and R ¹³ may be as defined above for formula (J),

- 32 041413 (I), (IV) or (IVa), or any combination thereof.

In some embodiments, a compound of formula (IVd), or a pharmaceutically acceptable salt thereof, has the structure:

where R ³ is selected from the group consisting of hydrogen and methyl, R ^12a is selected from the group consisting of hydrogen, C1-2 alkyl and C1-3 haloalkyl, R ¹³ is C3-6 alkyl, and R ^b is methyl or ethyl, each of which is optionally substituted with hydroxyl or amino.

In some embodiments, a compound of formula (IVd), or a pharmaceutically acceptable salt thereof, has the structure:

R

R ³ where R ¹³ is C _3-6 alkyl. R ¹ , R ² and R ³ may be as defined above for formula (J), (I), (IV), (IVa) or (IVd).

In some embodiments, a compound of formula (IVd), or a pharmaceutically acceptable salt thereof, has the structure:

R ² where R ² is selected from the group consisting of hydrogen and F, and R ¹³ is C _3-6 alkyl. In some embodiments, R ² and R ¹³ may be as defined above for formula (J), (I), (IV) or (IVa), or any combination thereof.

In some embodiments, a compound of formula (IVd), or a pharmaceutically acceptable salt thereof, has the structure:

R ² where R ² is selected from the group consisting of hydrogen, Cl and F, and R ¹³ is C _3-6 alkyl. In some embodiments, R ² and R ¹³ may be as defined above for formula (J), (I), (IV) or (IVa), or any combination thereof.

In some embodiments, a compound of formula (IVd), or a pharmaceutically acceptable salt thereof, has the structure:

where R ³ is selected from the group consisting of hydrogen and methyl, and R ¹³ represents C _3-6 alkyl. In some embodiments, a compound of formula (J), (I), or (IV) is selected from:

- 33 041413 or a pharmaceutically acceptable salt thereof.

In some embodiments, a compound of formula (J), (I), or (IV) is selected from:

or a pharmaceutically acceptable salt thereof.

In some embodiments, a compound of formula (J), (I), or (IV), or a pharmaceutically acceptable salt thereof, is a compound of the following formula:

where R ¹ is selected from the group consisting of hydrogen, halogen, C1.6 alkyl, CN and OR ^a , where C1. ₆ alkyl is optionally substituted with 1-5 R ²⁰ groups, R ² is selected from the group consisting of hydrogen, halogen, C1.6 alkyl, CN and OR ^a , where C1. ₆ alkyl is optionally substituted with 1-5 R ²⁰ groups, R ³ is selected from the group consisting of hydrogen, halogen, C1.6 alkyl, CN and OR ^a , where C1. ₆ alkyl is optionally substituted with 1-5 r ²⁰ groups, R ^12a is selected from the group consisting of hydrogen, C ₁ . ₂ αlkylα and C ₁ . ₃ haloalkyl, R ¹³ is C3.6 alkyl optionally substituted with 1-2 halogen substituents, each R ²⁰ is independently selected from the group consisting of halo, C1. ₆ haloalkyl, CN, -NR ^a R ^b , S(O)1. ₂ R ^a and OR ^a , and each R ^a and R ^b is independently selected from the group consisting of hydrogen and C ₁ . ₃ alkyl, where each C ₁ . ₃ alkyl is optionally substituted with 1-3 substituents independently selected from halo, hydroxyl, amino and C ₁ . ₆ haloalkyl. In some embodiments, a compound of formula (J), (I), or (IV), or a pharmaceutically acceptable salt thereof, is a compound of the following formula:

where R ¹ is selected from the group consisting of hydrogen, halogen and C1.3 alkyl, R ² is selected from the group consisting of hydrogen, halogen and C1. ₃ alkyl, R ³ is selected from the group consisting of hydrogen, halogen and C1.3 alkyl, R ^12a is selected from the group consisting of hydrogen, C1. ₂ alkyl and C ₁ . ₃ haloalkyl, R ¹³ is C3.6 alkyl optionally substituted with 1-2 halo substituents, and each R ^a and R ^b is independently selected from the group consisting of hydrogen and C1. ₃ alkyl, where each C ₁ . ₃ alkyl is optionally substituted with 1-3 substituents independently selected from halo, hydroxyl, amino and C ₁ . ₆ haloalkyl.

In some embodiments, a compound of formula (J), (I), or (IV), or a pharmaceutically acceptable salt thereof, is a compound of the following formula:

R

R ³ where R ¹³ is C ₃ . ₆ alkyl. R ¹ , R ² and R ³ may be as defined above for formula (J), (I), (IV), (IVa) or (IVd).

In some embodiments of a compound of formula (J), (I), (II), (IIa), (IIb), (III), (IIIa) or (IIIb), R ¹ is hydrogen, halogen, or C ₁ . ₆ alkyl optionally substituted with 1-5 R ²⁰ groups. In some embodiments of a compound of formula (J), (I), (II), (IIa), (IIb), (III),

- 34 041413 (IIIa), (IIIb), (IV), (IVa), (IVb), or (IVd), R ¹ is hydrogen, halogen or C ₁ . ₆ alkyl optionally substituted with 1-5 R ²⁰ groups.

In some embodiments of a compound of formula (J), (I), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), R ¹ is hydrogen, halogen, or C1.3 alkyl, optionally substituted with 1-5 halogens. In some embodiments of a compound of formula (J), (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), or (IVd), R ¹ is hydrogen, halogen or C1-3 alkyl optionally substituted with 1-5 halogens.

In some embodiments of a compound of formula (J), (I), (II), (IIa), (IIb), (III), (IIIa) or (IIIb), R ¹ is hydrogen, Cl, CH ₃ or CF ₃ . In some embodiments of a compound of formula (J), (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), or (IVd) R ¹ is hydrogen, Cl, CH3 or CF3.

In some embodiments of a compound of formula (J), (I), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), R ² is hydrogen, halogen, CN, or C1- 6alkyl optionally substituted with 1-5 R ²⁰ groups. In some embodiments of a compound of formula (J), (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc) or (IVd) R ² is hydrogen, halogen, CN or C1-6αkyl optionally substituted with 1-5 R ²⁰ groups.

In some embodiments of a compound of formula (J), (I), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), R ² is hydrogen, halogen, CN, or C 1-3 alkyl , optionally substituted with 1-5 halogens. In some embodiments of a compound of formula (J), (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc) or (IVd) R ² is hydrogen, halogen, CN or C1_ ₃ alkyl optionally substituted with 1-5 halogens.

In some embodiments of a compound of formula (J), (I), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), R ² is hydrogen, CH ₃ , —CH ₂ CH ₃ , F, Br, Cl or CN. In some embodiments of a compound of formula (J), (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc) or (IVd) R ² is hydrogen, CH3, -CH2CH3, F, Br, Cl or CN.

In some embodiments of a compound of formula (J), (I), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), R ³ is hydrogen, halogen, or C1_6αalkyl optionally substituted with 1 -5 groups R ²⁰ . In some embodiments of a compound of formula (J), (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), or (IVd) R ³ is hydrogen, halogen or C1_ ₆ alkyl optionally substituted with 1-5 R ²⁰ groups.

In some embodiments of a compound of formula (J), (I), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), R ³ is hydrogen, halogen, or C1.3αalkyl, optionally substituted with 1-5 R ²⁰ groups. In some embodiments of a compound of formula (J), (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), or (IVd) R ³ is hydrogen, halogen or C1. ₃ alkyl optionally substituted with 1-5 R ²⁰ groups.

In some embodiments of a compound of formula (J), (I), (II), (IIa), (IIb), (III), (IIIa), or (IIIb), R ³ is hydrogen, Cl, or CH3. In some embodiments of a compound of formula (J), (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), or (IVd) R ³ is hydrogen, Cl or CH ₃ .

In some embodiments of a compound of formula (J), R ¹⁰ is hydrogen, F, Cl, or CH ₃ .

In some embodiments of a compound of formula (J), R ¹⁰ is hydrogen.

In some embodiments of a compound of formula (J), (I), (II), (IIa), (IIb), (III), (IIIa) or (IIIb), R ¹ , R ² and R ³ are hydrogen. In some embodiments of a compound of formula (J), (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc) or (IVd) R ¹ , R ² , and R ³ are hydrogen.

In some embodiments of a compound of formula (J), (I), (II), (IIa), (IIb), (III), (IIIa) or (IIIb), R ¹ and R ³ are hydrogen and R ² is F. In some embodiments of a compound of formula (J), (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb ), (IVc) or (IVd), R ¹ and R ³ are hydrogen and R ² is F.

It should be understood that each of the variables (for example, R ¹ , R ² , R ³ , R ⁴ ) can be combined with any other variables for formula (J), (I), (II), (IIa) or (IIb) (for example, R ¹ , R ² , R ³ , R ⁴ ). In addition, when describing a compound of formula (J) or (I), it should be understood that the variables also describe compounds of other formulas (for example, formulas (II), (IIa), (IIb), (III), (IIIa) and (IIIb)) which fall within the scope of formula (J) or (I).

It should be understood that any variable for R ¹ of formula (J), (I), (II), (IIa), (IIb), (III), (IIIa) or (IIIb) can be combined with any R ⁴ variable in formula (J), (I), (II), (IIa), (IIb), (III), (IIIa), or (IIIb) as well as if each combination were specifically and separately listed. For example, in one embodiment of formula (J) or (I), R ¹ is hydrogen, Cl, CH3 or CF3 and R ⁴ is C _{1_6} alkyl which is optionally substituted with 1 or 2 substituents _{independently} selected from OH, CF3 , -C(O)OH, -C(O)OCH3, -C(O)NH ₂ , SCH3, -C(O)NHCH3, -C(O)NHCH2CH2NH2,

- 35 041413

-C(O)NHCH2CH2OH, -C(O)NHCH ₂ -pyridyl, phenyl, tetrahydrofuranyl and cyclopropyl.

It should be understood that any variable for R2 of formula (J), (I), (II), (IIa), (IIb), (III), (IIIa) or (IIIb) may be combined with any ^R4 variable in formula (J), (I), (II), (IIa), (IIb), (III), (IIIa), or (IIIb) as well as if each combination were specifically and separately listed. For example, in one embodiment of formula (J) or (I), R2 is hydrogen, CH3, -CH2CH3, F, Br, Cl or CN and ^R4 is O^alkyl which is optionally substituted with 1 or 2 substituents independently selected from OH, CF3, -C(O)OH, -C(O)OCH ₃ , -C(O)NH ₂ , SCH ₃ , -C(O)NHCH ₃ , -C(O)NHCH ₂ CH ₂ NH ₂ , -C(O)NHCH ₂ CH ₂ OH, -C(O)NHCH ₂ -pyridyl, phenyl, tetrahydrofuranyl and cyclopropyl.

It should be understood that any variable for R ³ of formula (J), (I), (II), (IIa), (IIb), (III), (IIIa) or (IIIb) may be combined with any R ⁴ variable in formula (J), (I), (II), (IIa), (IIb), (III), (IIIa) or (IIIb) as well as if each combination were specifically and separately listed. For example, in one embodiment of formula (J) or (I), R ³ is hydrogen, Cl, or CH3 and R ⁴ is C ₁ . ₆ alkyl which is optionally substituted with 1 or 2 substituents independently selected from OH, CF ₃ , -C(O)OH, -C(O)OCH3, -C(O)NH2, SCH3, -C(O)NHCH3, - C(O)NHCH2CH2NH2, -C(O)NHCH2CH2OH, -C(O)NHCH ₂ -pyridyl, phenyl, tetrahydrofuranyl and cyclopropyl.

In some embodiments, a compound of formula (J) or (I), or a pharmaceutically acceptable salt thereof, has one or more features selected from:

(a) R ⁴ is C1-6 alkyl which is optionally substituted with 1 or 2 substituents independently selected from halo, -ORa, -C(O)OR ^a , -C(O)NR ^a R ^b , -SR ^a , C1 -3 haloalkyl, C ₃ . ₆ cycloalkyl, 3-6 membered heterocyclyl and C ₆ . ₁₀ arila; where each C ₃ . ₆ cycloalkyl and C ₆ . ₁₀ aryl is optionally substituted with 1-3 R ²¹ groups and where each Ra and R ^b is independently hydrogen or C _1-4 alkyl, where each C _1-4 alkyl is optionally substituted with -NH2, OH or pyridyl;

(b) R ¹ is hydrogen, halogen or C ₁ . ₆ alkyl optionally substituted with 1-5 R ²⁰ groups;

(c) R ² is hydrogen, halogen, CN, or C ₁ . ₆ alkyl optionally substituted with 1-5 R ²⁰ groups; and (d) R ³ is hydrogen, halogen or C ₁ . ₃ alkyl optionally substituted with 1-5 _R 20 groups _.

In some embodiments, a compound of formula (J) or (I), or a pharmaceutically acceptable salt thereof, has two or more of the features selected from (a)-(d) as listed above. In some embodiments, a compound of formula (J) or (I), or a pharmaceutically acceptable salt thereof, has three or more of the features selected from (a)-(d) as listed above. In some embodiments, a compound of formula (J) or (I), or a pharmaceutically acceptable salt thereof, has four features selected from (a)-(d) as listed above.

In some embodiments, a compound of formula (J) or (I), or a pharmaceutically acceptable salt thereof, has one or more features selected from:

(e) R ⁴ is C ₁ . ₆ alkyl which is optionally substituted with 1 or 2 substituents independently selected from OH, CF3, -C(O)OH, -C(O)OCH3, -C(O)NH2, SCH3, -C(O)NHCH3, -C (O)NHCH ₂ CH ₂ NH ₂ , -C(O)NHCH ₂ CH ₂ OH, -C(O)NHCH ₂ -pyridyl, phenyl, tetrahydrofuranyl and cyclopropyl.

(f) R ¹ is hydrogen, halogen or C ₁ . ₃ alkyl optionally substituted with 1-5 halogens;

(g) R ² is hydrogen, halogen, CN or C ₁ . ₃ alkyl optionally substituted with 1-5 halogens; and (h) R ³ is hydrogen, halogen or C ₁ . ₃ alkyl.

In some embodiments, a compound of formula (J) or (I), or a pharmaceutically acceptable salt thereof, has two or more of the features selected from (e)-(h) as listed above. In some embodiments, a compound of formula (J) or (I), or a pharmaceutically acceptable salt thereof, has three or more of the features selected from (e)-(h) as listed above. In some embodiments, a compound of formula (J) or (I), or a pharmaceutically acceptable salt thereof, has two or more of the features selected from (e)-(h) as listed above.

In some embodiments, the compound of formula (J) or (I) is selected from:

- 36 041413

- 37 041413

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula (J) or (I) is selected from:

- 38 041413

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula (J) or (I) is selected from:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula (J) is selected from:

- 39 041413

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula (J) or (I) is selected from:

CI

- 40 041413

- 41 041413

- 42 041413

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula (J), (I), (IV), or (IVa) is selected from:

- 43 041413

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula (J), (I), (IV), or (IVa) is selected from:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula (J), (I), (IV), or (IVa) is selected from:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula (J), (I), (IV), or (IVa) is selected from:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of formula (J), (I), (IV), or (IVa) is selected from:

- 44 041413

or a pharmaceutically acceptable salt thereof.

As used herein, a compound of formula (I) includes compounds of formula (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc) or (IVd).

Compositions

In some embodiments, provided herein is a pharmaceutical composition comprising a compound of formula (J), (I), (II), (IIa), (IIb), (III), (IIIa), ( IIIb), (IV), (IVa), (IVb), (IVc) or (IVd)) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

In some embodiments, the pharmaceutical composition contains one or more additional therapeutic agents, as set forth in more detail below.

Pharmaceutical compositions containing the compounds disclosed herein, or pharmaceutically acceptable salts thereof, may be prepared with one or more pharmaceutically acceptable excipients, which may be selected in accordance with normal practice. Tablets may contain excipients, including lubricants, fillers, binders, and the like. Aqueous compositions may be prepared in sterile form, and when intended to be delivered by a method other than oral, may generally be isotonic. All formulations may optionally contain excipients such as those described in Rowe et al., Handbook of Pharmaceutical Excipients, ^6th edition, American Pharmacists Association, 2009. Excipients may include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like. In some embodiments, a composition is provided in the form of a solid dosage form, including a solid oral dosage form.

The compositions include compositions suitable for various routes of administration, including oral administration. The compositions may be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient (eg, a compound of the present disclosure or a pharmaceutical salt thereof) with one or more pharmaceutically acceptable excipients. Compositions can be prepared by uniformly and thoroughly combining the active ingredient with liquid excipients or finely divided solid excipients or both, and then, if necessary, shaping the product. Methods and formulations are generally described in The Science and Practice of Pharmacy, ^21st Edition, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006.

The compositions described herein, which are suitable for oral administration,

- 45 041413 can be presented as discrete units (single dosage form), including, but not limited to, capsules, cachets or tablets, each containing a given amount of the active ingredient. In one embodiment, the pharmaceutical composition is a tablet.

The pharmaceutical compositions provided herein comprise one or more of the compounds described herein, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient and optionally other therapeutic agents. Pharmaceutical compositions containing the active ingredient may be in any form suitable for the intended route of administration. When used for oral administration, for example, tablets, lozenges, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs can be prepared. Compositions intended for oral use 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 excipients, including sweetening agents, flavoring agents, coloring agents, and preservatives, to provide a pleasant formulation. . Acceptable are tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients, which are suitable for the manufacture of tablets. Said excipients may be, for example, inert diluents such as calcium or sodium carbonate, lactose, lactose monohydrate, sodium croscarmellose, povidone, calcium or sodium phosphate; granulating and disintegrating agents such as cornstarch or alginic acid; binding agents such 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 by known methods, including microencapsulation, to retard disintegration and absorption in the gastrointestinal tract and thereby provide sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with wax may be used.

The amount of active ingredient that may be combined with the inactive ingredients to form the dosage form may vary depending on the subject being treated 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 the active agent formulated with a suitable and convenient amount of a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutically acceptable excipient ranges from about 5% to about 95% of the total compositions (w:w).

In some embodiments, a composition comprising a compound as described herein (e.g., a compound of formula (J), (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV ), (IVa), (IVb), (IVc) or (IVd)) or a pharmaceutically acceptable salt thereof, in one embodiment, does not contain an agent that adversely affects the rate of metabolism of the active ingredient. Thus, it should be understood that compositions containing a compound of the present disclosure, in one aspect, do not contain an agent that will interfere with (eg, slow, interfere with, or stop) the metabolism of the compound of the present disclosure or any other active ingredient administered alone, sequentially, or concurrently with the connection of the present description. It should also be understood that any of the methods, kits, articles, and the like detailed herein, in one aspect, does not contain an agent that will affect (e.g., slow, interfere with, or stop) the metabolism of a compound as described herein. or any other active ingredient administered alone, sequentially or simultaneously with a compound of the present disclosure.

Ways

The present invention relates to methods for treating diseases or conditions responsive to the modulation of toll-like receptors (eg, TLR-8 receptors). Although not limited to any one theory, it is believed that the compounds disclosed herein modulate TLR-8 receptors as agonists. As will be appreciated by those skilled in the art, TLR-8 modulators can modulate other toll-like receptors (eg, TLR-7) to some extent. As such, in some embodiments, the compounds disclosed herein may also modulate TLR-7 to a measurable extent. In some embodiments, those compounds that modulate TLR-8 to a higher extent than TLR-7 are considered selective TLR-8 modulators. Typical methods for measuring each compound for TLR-7 and TLR-8 modulation are described in the examples provided herein. In some embodiments, the compounds disclosed herein are TLR-8 selective modulators.

In some embodiments, a method for modulating TLR-8 is provided, comprising

- 46 041413 administering a compound according to the present disclosure, or a pharmaceutically acceptable salt thereof, to an individual (eg, a human).

In some embodiments, a method for modulating TLR-8 in vitro is provided.

In some embodiments, provided herein is a compound as described herein, or a pharmaceutically acceptable salt thereof, for use as a research tool, for example, for use in identifying TLR-8 modulators.

In some embodiments, the present invention relates to methods for treating or preventing diseases or conditions in an individual (eg, human) in need thereof, comprising administering a compound of the present disclosure or a pharmaceutically acceptable salt thereof. In some embodiments, the methods include administering one or more additional therapeutic agents. Treatment with a compound as described herein typically results in stimulation of an immune response to the particular disease or condition being treated. The diseases or conditions contemplated herein include those affected by the modulation of toll-like receptors (eg, TLR-8). In some embodiments, a method for treating or preventing a disease or condition responsive to TLR-8 modulation is provided, comprising administering to a human a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. Typical diseases, disorders, and conditions include, but are not limited to, those associated with autoimmunity, inflammation, allergies, asthma, transplant rejection, graft-versus-host disease (GvHD), infectious diseases, cancer, and immunodeficiency.

In some embodiments, infectious diseases include diseases such as hepatitis A, hepatitis B (HBV), hepatitis C (HCV), hepatitis D (HDV), HIV, human papillomavirus (HPV), respiratory syncytial virus (RSV), severe acute respiratory syndrome (SARS), influenza, parainfluenza, cytomegalovirus, dengue fever, herpes simplex virus-1, herpes simplex virus2, leishmania infection, and respiratory syncytial virus. In some embodiments, infectious diseases include diseases such as hepatitis A, hepatitis B (HBV), hepatitis D (HDV), HIV, human papillomavirus (HPV), respiratory syncytial virus (RSV), severe acute respiratory syndrome (SARS), influenza, parainfluenza, cytomegalovirus, dengue fever, herpes simplex virus-1, herpes simplex virus-2, leishmania infection, and respiratory syncytial virus.

In some embodiments, a method of treating or preventing a viral infection is provided, comprising administering to an individual (eg, a human) a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In one embodiment, the method can be used to induce an immune response against multiple epitopes of a human viral infection. The induction of an immune response against a viral infection can be assessed using any technique known to those skilled in the art to determine if an immune response has occurred. Suitable methods for detecting an immune response for the present disclosure include, inter alia, detecting a decrease in viral load or antigen in a subject's serum, detecting IFN-gamma-secreting peptide-specific T cells, and detecting elevated levels of one or more liver enzymes such as alanine transferase (ALT) and aspartate transferase (AST). In one embodiment, detection of IFN-gamma-secreting peptide-specific T cells is performed using an ELISPOT assay. Another embodiment includes a reduction in viral load associated with HBV infection, including a reduction that is measured by PCR testing.

In some embodiments, the present invention provides a method of improving vaccine efficacy by co-administering a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, to an individual (eg, human) with the vaccine. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, can be co-administered with a vaccine to enhance the immune response, allowing more antibodies to be produced or providing longer lasting protection. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, may be used as vaccine adjuvants to improve efficacy and response to immunization with a particular antigen. In some embodiments, co-administration of compounds of the present disclosure, or a pharmaceutically acceptable salt thereof, with a vaccine may affect how the vaccine antigen is presented to the immune system and enhance the effectiveness of the vaccine.

In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is provided for use in medical therapy. In some embodiments, there is provided a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease or condition responsive to TLR-8 modulation. In some embodiments, the disease or condition is a viral infection as defined herein.

In some embodiments, the use of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is provided for the manufacture of a medicament for the treatment or prevention of a disease or condition responsive to TLR-8 modulation.

In some embodiments, the present disclosure also provides methods for treating a hepatitis B viral infection, comprising administering to an individual (e.g., a human) infected with the hepatitis B virus a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof. Typically, the subject suffers from chronic hepatitis B infection, although it is within the scope of the present disclosure to treat individuals with acute hepatitis B virus infection.

Also provided herein are methods of treating a hepatitis C virus infection comprising administering to an individual (eg, human) infected with the hepatitis C virus a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. As a rule, the individual suffers from a chronic hepatitis C infection, although the present description includes the treatment of people with acute HCV infection.

Treatment of HBV or HCV as described herein generally results in stimulation of an immune response against HBV or HCV in an individual (human) infected with HBV or HCV, respectively, and a subsequent decrease in the HBV or HCV viral load in the infected individual. Examples of immune responses include the production of antibodies (eg, IgG antibodies) and/or the production of cytokines such as interferons, which modulate the activity of the immune system. The response of the immune system may be a new elicited response or may be an enhancement of an existing immune response. In particular, the systemic immune response may be seroconversion against one or more HBV or HCV antigens.

As described in more detail herein, the compounds of the present disclosure may be administered with one or more additional therapeutic agents to an individual (eg, human) infected with HBV or HCV. Additional therapeutic agents can be administered to an infected individual (eg, a human) at the same time as the compound according to the present description, or before or after administration of the compound according to the present description. For example, in some embodiments, when used to treat or prevent HCV, a compound of the present disclosure may be administered with one or more additional therapeutic agents selected from the group consisting of interferons, ribavirin or analogs thereof, HCV NS3 protease inhibitors, HCV NS4 protease inhibitors, HCV NS3/NS4 protease inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectors, nucleoside or nucleotide inhibitors of HCV NS5B polymerase, non-nucleoside inhibitors of HCV NS5B polymerase, HCV NS5A inhibitors, TLR-7 agonists, cyclophilin inhibitors, HCV IRES inhibitors, pharmacokinetic enhancers, and other drugs agents for the treatment of HCV or mixtures thereof. Specific examples are described in more detail below.

In addition, in some embodiments, when used to treat or prevent HBV, a compound of the present disclosure may be administered with one or more additional therapeutic agents selected from the group consisting of HBV DNA polymerase inhibitors, toll-like receptor 7 modulators, toll-like receptor modulators 8, toll-like receptor modulators 7 and 8, toll-like receptor modulators 3, interferon-alpha ligands, HBsAg inhibitors, HbcAg targeting compounds, cyclophilin inhibitors, HBV therapeutic vaccines, HBV prophylactic vaccines, HBV entry inhibitors, NTCP inhibitors , antisense oligonucleotide targeting viral mRNA, short interfering RNAs (siRNAs), hepatitis B e antigen inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies, including anti-HBV antibodies targeting hepatitis B surface antigens, thymosin agonists, cytokines , nucleoprotein inhibitors (inhibito HBV core or capsid protein), retinoic acid inducible gene 1 stimulators, NOD2 stimulators, inhibitors of recombinant thymosin alpha-1 replication and hepatitis B virus, and combinations thereof. Specific examples are described in more detail below.

In some embodiments, provided herein is a method for alleviating a symptom associated with HBV infection or HCV infection, comprising administering to an individual (human) infected with hepatitis B virus or hepatitis C virus, a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is sufficient to relieve a symptom associated with HBV infection or HCV infection. Such symptoms include the presence of HBV virus particles (or HCV virus particles) in the blood, inflammation of the liver, jaundice, muscle pain, weakness, and fatigue.

In some embodiments, provided herein is a method for reducing the rate of progression of a hepatitis B virus infection or hepatitis C virus infection in an individual (e.g., human), comprising administering to an individual (e.g., human) infected with hepatitis B virus or hepatitis C virus. C, a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is sufficient to reduce the rate of progression of a hepatitis B virus infection or hepatitis C virus infection. blood.

In some embodiments, provided herein is a method for reducing viral load associated with an HBV or HCV infection, comprising administering to an individual (e.g., human) infected with HBV or HCV, a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, wherein the therapeutically an effective amount is sufficient to reduce the HBV viral load or HCV viral load in an individual.

In some embodiments, provided herein is a method for inducing or enhancing an immune response against hepatitis B virus or hepatitis C virus in a (human) subject, comprising administering a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, to the subject, wherein a novel immune response is induced in the subject. a reaction against hepatitis B virus or hepatitis C virus, or an immune response against hepatitis B virus or hepatitis C virus is enhanced in the individual. Seroconversion against HBV or HCV can be induced in the individual. Examples of immune responses include the production of antibodies, such as IgG antibody molecules, and/or the production of cytokine molecules that modulate the activity of one or more components of the human immune system.

In some embodiments, an immune response may be induced against one or more HBV or HCV antigens. For example, an immune response can be induced against the HBV surface antigen (HBsAg) or against the small form of the HBV surface antigen (small S antigen) or against the medium form of the HBV surface antigen (medium S antigen), or against a combination of both. Again, by way of example, an immune response can be induced against the HBV surface antigen (HBsAg) as well as against other HBV derived antigens such as nuclear polymerase or x-protein.

The induction of an immune response against HCV or HBV can be assessed using any method known to those skilled in the art to determine if an immune response has occurred. Suitable methods for detecting an immune response for the present disclosure include, inter alia, detecting a decrease in viral load in human serum, for example, by measuring the amount of HBV DNA or HCV DNA in the subject's blood using PCR analysis and/or by measuring the amount of anti-HBV antibodies or anti-HCV antibodies in the subject's blood using a method such as ELISA.

In some embodiments, a compound of the present disclosure (eg, a compound of formula (I)) or a pharmaceutically acceptable salt thereof is provided for use in the treatment or prevention of an HBV infection. In some embodiments, a compound of the present disclosure (eg, a compound of formula (I)) or a pharmaceutically acceptable salt thereof is provided for use in the treatment or prevention of HCV infection. In some embodiments, a compound of the present disclosure (eg, a compound of formula (I)) or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for the treatment or prevention of HBV infection. In some embodiments, there is provided a compound of the present disclosure (eg, a compound of formula (I)) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of HCV infection.

In some embodiments, the present disclosure also provides methods for treating a Retroviridae viral infection (eg, HIV viral infection) in an individual (eg, human), comprising administering a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, to the individual.

In some embodiments, the present disclosure also provides methods for treating an HIV infection (e.g., an HIV-1 infection) comprising administering to an individual (e.g., a human) infected with the HIV virus, a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In some embodiments, the individual in need thereof is a human who has been infected with HIV. In some embodiments, the individual in need thereof is a human who has been infected with HIV but has not developed AIDS. In some embodiments, the individual in need thereof is an individual at risk of developing AIDS. In some embodiments, the individual in need thereof is a human who has been infected with the HIV virus and has developed AIDS.

In some embodiments, a method for treating or preventing an HIV viral infection in a subject (eg, a human) is provided, comprising administering a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, to the subject.

- 49 041413

In some embodiments, a method for inhibiting viral replication is provided.

HIV, treating AIDS, or delaying the onset of AIDS in a subject (eg, a human), comprising administering a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, to the subject.

In some embodiments, a method for preventing HIV infection in an individual (eg, a human) is provided, comprising administering a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, to the individual. In some embodiments, the individual is an individual at risk for contracting the HIV virus, such as an individual who has one or more risk factors known to be 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 the present disclosure, or a pharmaceutically acceptable salt thereof, to the individual.

In some embodiments, a method of treating an HIV infection in an individual (e.g., a human) is provided, comprising administering to an individual in need thereof a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents, selected from the group consisting of HIV protease inhibitors, 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 drugs for the treatment of HIV and their combinations.

In some embodiments, a compound of the present disclosure is administered to a patient whose expression of an active HIV gene has been suppressed by administration of antiretroviral therapy (including combination antiretroviral therapy or cART).

In some embodiments, a method is provided for reducing a latent HIV reservoir in an HIV-infected human, comprising administering to the human a pharmaceutically effective amount of a compound as described herein. In some embodiments, the method further comprises administering one or more anti-HIV agents. In some embodiments, the method further comprises administering antiretroviral therapy (including combination antiretroviral therapy) or cART). In some embodiments, expression of an active HIV gene in a human has been suppressed by administration of antiretroviral therapy (including combination antiretroviral therapy) or cART).

In some embodiments, there is provided a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in the medical treatment of an HIV viral infection (e.g., HIV-1 or HIV virus replication (e.g., HIV-1) or AIDS or delayed onset of AIDS in an individual (e.g., person).

In some embodiments, there is provided a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of an HIV viral infection or the replication of an HIV or AIDS virus or delaying the onset of AIDS in an individual (eg, human). One embodiment provides a compound of the present disclosure, 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 onset of AIDS.

In some embodiments, the use of a compound of the present disclosure (eg, a compound of formula (I)) or a pharmaceutically acceptable salt thereof is provided for the manufacture of a medicament for the treatment of an HIV viral infection in an individual (eg, human). In some embodiments, there is provided a compound of the present disclosure (eg, a compound of formula (I)) or a pharmaceutically acceptable salt thereof, for use in the prophylactic or therapeutic treatment of an HIV viral infection.

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

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

Also provided herein is a compound of the present disclosure (e.g., a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in a method of treating or preventing HIV in an individual in need thereof. In some embodiments, an individual in need of is a human who has been infected with the HIV virus.In some embodiments, the individual in need is a human who has been infected with the HIV virus but has not developed AIDS.In some embodiments, the individual in need is is an individual at risk of developing AIDS In some embodiments, the individual in need thereof is a human who has been infected with the HIV virus and has developed AIDS.

Also provided herein is a compound as described herein (e.g., 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 provided herein is a compound as described herein (e.g., 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, the HIV infection is an HIV-1 infection.

In addition, the compounds according to the present description are suitable for the treatment of cancer or tumors (including dysplasias such as uterine dysplasia). These include hematologic malignancies, oral carcinomas (eg, lips, tongue, or pharynx), digestive organs (eg, esophagus, stomach, small intestine, colon, hindgut, or rectum), peritoneum, liver and bile ducts, pancreas , respiratory system, such as the larynx or lungs (small cell and non-small cell), bones, connective tissue, skin (such as melanoma), breasts, reproductive organs (fallopian tube, uterus, cervix, testicles, testicles, or prostate), urinary tract (such as , bladder or kidneys), brain and endocrine glands such as the thyroid gland. Thus, the compounds of the present disclosure are useful in the treatment of any neoplasm, including not only hematologic malignancies, but solid tumors of all kinds. In some embodiments, the compounds are suitable for treating a form of cancer selected from ovarian cancer, breast cancer, head and neck cancer, kidney cancer, bladder cancer, liver cancer, and colorectal cancer.

Hematologic malignancies are broadly defined as proliferative disorders of blood cells and/or their progenitors in which said cells proliferate in an uncontrolled manner. Anatomically, hematologic malignancies are divided into two primary groups: lymphomas, malignant masses of lymphoid cells primarily but not exclusively in the lymph nodes, and leukemias, a neoplasm originating usually from lymphoid or myeloid cells and primarily affecting the bone marrow and peripheral blood. Lymphomas can be divided into Hodgkin's disease and non-Hodgkin's lymphoma (NHL). The latter group includes several different members that may be distinguished clinically (eg, aggressive lymphoma, indolent lymphoma), histologically (eg, follicular lymphoma, mantle cell lymphoma), or based on the origin of the malignant cell (eg, B-lymphocytic, T-lymphocytic). ). Leukemias and related malignancies include acute myelocytic leukemia (AML), chronic myelocytic leukemia (CML), acute lymphoblastic leukemia (ALL), and chronic lymphoblastic leukemia (CLL). Other hematologic malignancies include plasma cell dyscrasias, including multiple myeloma and myelodysplastic syndromes.

In some embodiments, the compounds of the present disclosure are suitable for the treatment of B-cell lymphoma, lymphoplasmacytic lymphoma, fallopian tube cancer, head and neck cancer, ovarian cancer, and peritoneal cancer.

In some embodiments, the compounds of the present disclosure are suitable for the treatment of hepatocellular carcinoma, gastric cancer, and/or colorectal cancer. In some embodiments, the compounds of the present disclosure are suitable for the treatment of prostate cancer, breast cancer, and/or ovarian cancer. In some embodiments, the compounds of the present disclosure are suitable for the treatment of recurrent or metastatic squamous cell carcinoma.

In some embodiments, a method for treating a hyperproliferative disease is provided, comprising administering to an individual (eg, human) in need thereof a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In some embodiments, the hyperproliferative disease is cancer. In some embodiments, the cancer is a solid tumor. In some embodiments, the cancer is selected from ovarian cancer, breast cancer, head and neck cancer, kidney cancer, bladder cancer, hepatocellular cancer, and colorectal cancer. In some embodiments, the cancer is a lymphoma. In some embodiments, the cancer is Hodgkin's lymphoma. In some embodiments, the cancer is non-Hodgkin's lymphoma. In some embodiments, the cancer is a B-cell lymphoma. In some embodiments, the cancer is selected from B-cell lymphoma; fallopian tube cancer, head and neck cancer, ovarian cancer, and abdominal cancer. In some embodiments, the method further comprises administering one or more additional therapeutic agents, which are more fully described herein.

In some embodiments, the cancer is prostate cancer, breast cancer, ovarian cancer, hepatocellular carcinoma, gastric cancer, colorectal cancer, and/or recurrent or metastatic squamous cell carcinoma. In some embodiments, the cancer is prostate cancer, breast cancer, and/or ovarian cancer. In some embodiments, the cancer is hepatocellular carcinoma, gastric cancer, and/or colorectal cancer. In some embodiments, the cancer is recurrent or metastatic squamous cell carcinoma.

Introduction

In some embodiments of the methods, the administration is administered to an individual (eg, human) in need of treatment.

Additional examples of diseases, disorders or conditions include psoriasis, systemic lupus erythematosus and allergic rhinitis.

In one embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is for use in a method of treating a hyperproliferative disease (eg, cancer) in an individual (eg, human).

Also provided herein is the use of a compound of the present disclosure (eg, a compound of formula (I) or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of a hyperproliferative disease (eg, cancer).

Introduction.

One or more compounds according to the present description (also referred to herein as active ingredients) can be administered by any route suitable for the condition being treated. Suitable methods 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 may vary, for example, depending on the condition of the recipient. Some of the compounds disclosed herein have the advantage that they are orally bioavailable and can be dosed orally.

A compound of the present disclosure, such as a compound of formula (I), may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, e.g., at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer. In one embodiment, the compound is administered on a daily or intermittent basis for the lifetime of the individual.

The dosage or dosing frequency of a compound as described herein may be adjusted during treatment based on the judgment of the prescribing 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.

In some embodiments, methods are provided for treating or preventing a disease or condition in a human, comprising administering to a human a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents. Since TLR-8 modulators can be used to treat a variety of diseases or conditions, the specific representatives of additional therapeutic agents will depend on the particular disease or condition being treated.

A compound of formula (J), (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc) or (IVd) may be administered by any suitable route and routes such as oral or parenteral (eg, intravenous) administration. A therapeutically effective amount of a compound of formula (J), (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), ( IVc) or (IVd) is from about 0.00001 mg/kg body weight per day to about 10 mg/kg body weight per day, or for example from about 0.0001 mg/kg body weight per day to about 10 mg/kg body weight per day, or for example from about 0.001 mg/kg of body weight per day to about 1 mg/kg of body weight per day, or for example from about 0.01 mg/kg of body weight per day to about 1 mg/kg of body weight per day, or for example from about 0.05 mg/kg of body weight per day to about 0.5 mg/kg of body weight per day, or for example from about 0.3 μg to about 30 mg per day, or for example from about 30 mcg to about 300 mcg per day.

A compound as described herein (e.g., any compound of formula (I) may be combined with one or more additional therapeutic agents in any dosage amount of a compound as described herein (e.g., 1 to 1000 mg of a compound). Therapeutically effective amounts of a compound of formula (J) , (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc) or (IVd) are from about 0.01 mg per dose up to about 1000 mg per dose, for example from about 0.01 mg per dose to about 100 mg per dose, or for example from about 0.1 mg per dose to about 100 mg per dose , or for example from about 1 mg per dose to about 100 mg per dose, or for example from about 1 mg per dose to about 10 mg per dose Other therapeutically effective amounts of a compound of formula (J), (I), (II), ( IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc), or (IVd) are about 1 mg per dose, or about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20 , 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or about 100 mg per dose. Other therapeutically effective amounts of a compound of formula (J), (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc) or (IVd) is about 1θ0 mg per dose, or about 125, 150, 175, 200, 225, 250, 275, 3θ0, 350, 400, 450, or about 500 mg per dose. A single dose can be administered hourly, daily or weekly. For example, a single dose may be administered once every 1 hour, 2, 3, 4, 6, 8, 12, 16, or once every 24 hours. A single dose may be administered once every 1 day, 2, 3, 4, 5, 6 or once every 7 days. A single dose can be administered once a week, 2, 3 or once every 4 weeks. In some embodiments, a single dose may be administered once per week. A single dose can be administered once a month.

Dosing frequency of a compound of formula (J), (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc ) or (IVd) will be determined by the needs of the individual patient and may be, for example, once a day or twice or more times a day. Administration of the compound is continued for as long as necessary to treat the HBV or HCV infection. For example, Compound I can be administered to a human infected with HBV or HCV over a period of 20 days to 180 days, or, for example, over a period of 20 days to 90 days, or, for example, over a period of 30 days to 60 days.

The administration may be intermittent, with a period of several or more days, during which the patient receives a daily dose of a compound of formula (J), (I), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (IVc) or (IVd) followed by a period of several or more days during which the patient does not receive a daily dose of the compound. For example, a patient may receive a dose of the compound every other day or three times a week. Again, by way of example, a patient may receive a dose of the compound each day for a period of 1 to 14 days followed by a period of 7 to 21 days during which the patient does not receive a dose of the compound, followed by a period (e.g., 1 to 14 days) , during which the patient again receives a daily dose of the compound. Alternate periods of compound administration followed by no compound administration may be repeated as clinically indicated to treat the patient.

In one embodiment, pharmaceutical compositions are provided comprising a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, four, one or two, one to three, or one to four ) additional therapeutic agents, and a pharmaceutically acceptable excipient.

In one embodiment, kits are provided containing a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents.

In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four, or more additional therapeutic agents. In some embodiments, a compound as described herein, or a pharmaceutically acceptable salt thereof, is combined with two additional therapeutic agents. In other embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with three additional therapeutic agents. In additional embodiments, a compound as described herein, or a pharmaceutically acceptable salt thereof, is combined with four additional therapeutic agents. One, two, three, four or more additional therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents and/or they may be selected from different classes of therapeutic agents.

In some embodiments, when a compound of the present disclosure is combined with one or more additional therapeutic agents described herein, the components of the composition are administered in a simultaneous or sequential fashion. When administered sequentially, the combination may be administered over two or more administrations.

In some embodiments, a compound of the present disclosure is combined with one or more additional therapeutic agents in a unit dosage form for simultaneous administration to a patient, eg, as a solid oral dosage form.

In some embodiments, a compound of the present disclosure is administered with one or more additional therapeutic agents. Co-administration of a compound of the present disclosure with one or more additional therapeutic agents is typically

- 53 041413 refers to the simultaneous or sequential administration of a compound as described herein and one or more additional therapeutic agents such that a therapeutically effective amount of the compound disclosed herein and one or more additional therapeutic agents are present in the patient's body.

Co-administration includes administering unit doses of the compounds described herein before or after administration of unit 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. For example, in some embodiments, a single dose of a compound as described herein is first administered, followed by a single dose of one or more additional therapeutic agents over several seconds or minutes. Alternatively, according to other implementation options, a single dose of one or more additional therapeutic agents is first administered, and then a single dose of a compound according to the present description is administered over several seconds or minutes. In some embodiments, a single dose of a compound as described herein is first administered, followed by a single dose of one or more additional therapeutic agents after a period of time (eg, 1-12 hours). In other embodiments, a single dose of one or more additional therapeutic agents is first administered, followed by a single dose of a compound as described herein after a period of time (eg, 1-12 hours).

Combination therapy for HBV

In some embodiments, a method of treating or preventing an HBV infection in a human having or at risk of developing an infection is provided, comprising administering to a human a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents. In one embodiment, there is provided a method of treating an HBV infection in a human having or at risk of developing an infection, comprising administering to a human a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two , three, four, one or two, one to three, or one to four) additional therapeutic agents.

In some embodiments, provided herein is a method of treating an HBV infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents suitable for treating the infection. HBV. In some embodiments, the one or more additional therapeutic agents include, for example, one, two, three, four, one or two, one to three, or one to four additional therapeutic agents.

In the above embodiments, the additional therapeutic agent may be an anti-HBV agent. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of HBV combination drugs, HBV DNA polymerase inhibitors, immunomodulators, toll-like receptor modulators (TLR-1, TLR-2, TLR-3, TLR-4, TLR-5, TLR-6, TLR-7, TLR-8, TLR-9, TLR-10, TLR-11, TLR-12 and TLR-13), interferon-alpha receptor ligands, hyaluronidase inhibitors, recombinant IL-7 , hepatitis B surface antigen inhibitors, hepatitis B internal antigen (HbcAg) targeting compounds, cyclophilin inhibitors, HBV therapeutic vaccines, HBV prophylactic vaccines, HBV virus entry inhibitors, NTCP (Na+taurocholate co-transporting polypeptide) inhibitors, antisense oligonucleotide , targeting viral mRNA, short interfering RNA (siRNA), miRNA agents for gene therapy, endonuclease modulators, ribonucleotide reductase inhibitors, inhibitors of hepatitis e antigen recombinant phagocytic receptor A (SRA) proteins, Src kinase inhibitors, HBx inhibitors, cccDNA inhibitors, short hairpin RNAs (sshRNAs), HBV antibodies, including anti-HBV antibodies targeting hepatitis B surface antigens and bispecific antibodies and antibody-like therapeutic proteins (such as DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs®, Fab derivatives), CCR2 chemokine antagonists, thymosin agonists, cytokines, nucleoprotein inhibitors (HBV core or capsid protein inhibitors), retinoic acid inducible gene 1 stimulators , NOD2 stimulators, NOD1 stimulators, arginase-1 inhibitors, STING agonists, PI3K inhibitors, lymphotoxin-beta receptor activators, natural killer cell 2B4 receptor inhibitors, lymphocyte activation gene 3 inhibitors, CD160 inhibitors, cytotoxic T-lymphocyte protein 4 inhibitors, inhibitors CD137, Lectin-Like Natural Killer Receptor Inhibitors (Member 1 of Subfamily G), Ingi TIM-3 inhibitors, B- and T-54 inhibitors 041413 lymphocyte attenuators, CD305 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, PEGinterferon lambda, recombinant thymosin alfa-1, BTK inhibitors, TIGIT modulators, CD47 modulators, SIRPalpha modulators, ICOS modulators, CD27 modulators, CD70 modulators, OX40 modulators, NKG2D modulators, Tim-4 modulators, B7-H4 modulators, B7-I3 modulators, NKG2A modulators, GITR modulators, CD160 modulators, HEVEM modulators, CD161 modulators, Axl modulators, Meg modulators , Tyro modulators, gene modifiers or editors such as CRISPR (including CRISPR Cas9), zinc finger nucleases or synthetic nucleases (TALENs), Hepatitis B virus replication inhibitors, compounds such as those described in US Patent Application Publication No. 2010/0143301 (Gilead Sciences), U.S. Patent Application Publication No. 2011/0098248 (Gilead Sciences), U.S. Patent Application Publication No. 2009/0047249 (Gilead Sciences), U.S. Patent Application 8722054 (Gilead Science es), US Patent Application Publication No. 2014/0045849 (Janssen), US Patent Application Publication No. 2014/0073642 (Janssen), WO 2014/056953 (Janssen), wO 2014/076221 (Janssen), WO 2014/128189 ( Janssen), US Patent Application Publication No. 2014/0350031 (Janssen), WO 2014/023813 (Janssen), US Patent Application Publication No. 2008/0234251 (Array Biopharma), US Patent Application Publication No. 2008/0306050 (Array Biopharma ), US Patent Application Publication No. 2010/0029585 (Ventirx Pharma), US Patent Application Publication No. 2011/0092485 (Ventirx Pharma), US 2011/0118235 (Ventirx Pharma), US Patent Application Publication No. 2012/0082658 (Ventirx Pharma), US Patent Application Publication No. 2012/0219615 (Ventirx Pharma), US Patent Application Publication No. 2014/0066432 (Ventirx Pharma), US Patent Application Publication No. 2014/0088085 (Ventirx Pharma), US Patent Application Publication No. No. 2014/0275167 (Novira Therapeutics), U.S. Patent Application Publication No. 2013/0251673 (Novira Therapeutics), U.S. Patent 8,513,184 ( Gilead Sciences), US Patent Application Publication No. 2014/0030221 (Gilead Sciences), US Patent Application Publication No. 2013/0344030 (Gilead Sciences), US Patent Application Publication No. 2013/0344029 (Gilead Sciences), Patent Application Publication US No. 2014/0343032 (Roche), WO 2014037480 (Roche), US Patent Publication No. 2013/0267517 (Roche), WO 2014131847 (Janssen), WO 2014033176 (Janssen), WO 2014033170 (Janssen), WO 2014033167 (Janssen) ), US Patent Application Publication No. 2014/0330015 (Ono Pharmaceutical), US Patent Application Publication No. 2013/0079327 (Ono Pharmaceutical), US Patent Application Publication No. 2013/0217880 (Ono pharmaceutical), and other drugs for the treatment of HBV and their combinations. In some embodiments, the additional therapeutic agent is further selected from hepatitis B surface antigen (HBsAg) secretion or assembly inhibitors, TCR-like antibodies, IDO inhibitors, cccDNA epigenetic modifiers, IAPs inhibitors, SMAC mimetics, and compounds such as those described in US20100015178 ( Incyte).

In some embodiments, the additional therapeutic agent is selected from the group consisting of HBV combination drugs, HBV DNA polymerase inhibitors, toll-like receptor 7 modulators, toll-like receptor 8 modulators, toll-like receptor 7 and 8 modulators, toll-like receptor modulators. receptor 3, interferon-alpha receptor ligands, HBsAg inhibitors, HbcAg targeting compounds, cyclophilin inhibitors, HBV therapeutic vaccines, HBV prophylactic vaccines, HBV entry inhibitors, NTCP inhibitors, antisense oligonucleotide targeting viral mRNA, short interfering RNA (siRNA) ), hepatitis B virus e antigen inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies, including anti-HBV antibodies targeting hepatitis B surface antigens, thymosin agonists, cytokines, nucleoprotein inhibitors (inhibitors of the HBV core or capsid protein), stimulants of inducible retinoic acid gene 1, NOD2 stimulators, NOD1 stimulators, recombinant alpha-1 thymosin, BTK inhibitors, and inhibitors of hepatitis B virus replication, and combinations thereof. In some embodiments, the additional therapeutic agent is selected from hepatitis B surface antigen (HBsAg) secretion or assembly inhibitors and IDO inhibitors.

In some embodiments, a compound of the present disclosure (e.g., a compound of formula (I) is provided in the form of a tablet, which may optionally contain one or more other compounds suitable for the treatment of HBV. In some embodiments, the tablet may contain another active ingredient for the treatment of HBV, such as HBV DNA polymerase inhibitors, immunomodulators, toll-like receptor modulators (modulators TLR-1, TLR2, TLR-3, TLR-4, TLR-5, TLR-6, TLR-7, TLR-8, TLR-9, TLR -10, TLR-11, TLR-12 and TLR-13), tlr7 modulators, tlr8 modulators, tlr7 and tlr8 modulators, interferon-alpha receptor ligands, hyaluronidase inhibitors, hepatitis B surface antigen inhibitors, compounds targeting internal viral antigen hepatitis B (HbcAg), cyclophilin inhibitors, HBV virus entry inhibitors, NTCP (Na+-taurocholate co-transporting polypeptide) inhibitors, endonuclease modulators, ribonucleotide reductase inhibitors, EAN inhibitors HBV tigen, Src kinase inhibitors, HBx inhibitors, cccDNA inhibitors, CCR2 chemokine antagonists, thymosin agonists, nucleoprotein inhibitors (HBV core or capsid protein inhibitors), retinoic acid inducible gene 1 stimulators, NOD2 stimulators, NOD1 stimulators, arginase-1 inhibitors , agonists

- 55 041413

STING, PI3K inhibitors, lymphotoxin-beta receptor activators, natural killer cell 2B4 receptor inhibitors, lymphocyte activation gene 3 inhibitors, CD160 inhibitors, cytotoxic T-lymphocyte protein 4 inhibitors, CD137 inhibitors, lectin-like natural killer receptor (subfamily member 1) inhibitors G), TIM-3 inhibitors, B and T cell attenuator inhibitors, CD305 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, BTK inhibitors, TIGIT modulators, CD47 modulators, SIRP alpha modulators, ICOS modulators, CD27 modulators, CD70 modulators, OX40 modulators, NKG2D modulators, Tim-4 modulators, B7H4 modulators, B7-I3 modulators, NKG2A modulators, GITR modulators, CD160 modulators, HEVEM modulators, CD161 modulators, Axl modulators, Mer modulators, Tyro modulators, and inhibitors of hepatitis B virus replication, and their combinations. In some embodiments, the tablet may contain another active ingredient for the treatment of HBV, such as inhibitors of hepatitis B surface antigen (HBsAg) secretion or assembly, cccDNA epigenetic modifiers, IAPs inhibitors, SMAC mimetics, and IDO inhibitors.

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

In some embodiments, the additional therapeutic agent is selected from one or more of:

(1) combination drugs selected from the group consisting of tenofovir disoproxil fumarate + emtricitabine (TRUVADA®); adefovir + clevudine and GBV-015, as well as combination drugs selected from ABX-203 + lamivudine + PEG-IFNalpha, ABX203 + adefovir + PEG-IFNalpha and INO-9112 + RG7944 (INO-1800);

(2) HBV DNA polymerase inhibitors selected from the group consisting of besifovir, entecavir (Baraclude®), adefovir (Hepsera®), tenofovir disoproxil fumarate (Viread®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir dipivoxil, tenofovir dipivoxil fumarate, tenofovir octadecyloxyethyl ether, telbivudine (Tyzeka®), pradefovir, clevudine, emtricitabine (Emtriva®), ribavirin, lamivudine (Epivir-HBV®), phosphazide, famciclovir, SNC-01CA, SNC-01CA97 fusolin, AGX-1009 and metacavir, as well as HBV DNA polymerase inhibitors selected from AR-II-04-26 and HS-10234;

(3) immunomodulators selected from the group consisting of rintatolimod, imidol hydrochloride, Ingaron, dermaVir, plaquenil (hydroxychloroquine), proleukin, hydroxyurea, mycophenolate mofetil (MPA) and mycophenolate mofetil ester derivative (MMF), WF-10, ribavirin, IL -12, polymeric polyethyleneimine (PEI), Gepon, VGV-1, MOR-22, BMS-936559 and IR-103, and immunomodulators selected from INO-9112, polymeric polyethyleneimine (PEI), Gepon, VGV-1, MOR -22, BMS-936559, RO-7011785, RO-6871765 and IR-103;

(4) toll-like receptor modulators 7 selected from the group consisting of GS-9620, GSK2245035, imiquimod, resiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, 3M-051, SB-9922, 3M052, Limtop, TMX-30X, TMX-202 RG-7863 and RG-7795;

(5) toll-like receptor modulators 8 selected from the group consisting of motolimod, resiquimod, 3M-051, 3M-052, MCT-465, IMO-4200, VTX-763, VTX-1463;

(6) toll-like receptor modulators 3 selected from the group consisting of rinthatolimod, poly-ICLC, MCT-465, MCT-475, Riboxxon, Riboxxim, and ND-1.1;

(7) interferon-alpha receptor ligands selected from the group consisting of interferon alfa-2b (Intron A®), pegylated interferon alfa-2a (Pegasys®), interferon alfa-1b (Hapgen®), Veldona, Infradure, Roferon-A , YPEG-interferon alfa-2a (YPEG-rhIFNalpha-2a), P-1101, Algeron, Alfarona, Ingaron (interferon gamma), rSIFN-co (recombinant supercomponent interferon), peg-interferon alfa-2b (YPEG-rhIFNalpha-2b ), MOR-22, peginterferon alfa-2b (PEGIntron®), Bioferon, Novaferon, Inmutag (Inferon), Multiferon®, interferon alfa-nl (Humoferon®), interferon beta-1a (Avonex®), Shaferon, interferon alfa- 2b (AXXO), Alfaferon, interferon alfa-2b (BioGeneric Pharma), interferon-alpha 2 (CJ), Laferonum, VIPEG, BLAUFERON-B, BLAUFERON-A, Intermax Alpha, Realdiron, Lanstion, Pegaferon, PDferon-B PDferon- B, interferon alfa-2b (IFN, Laboratorios Bioprofarma), alfainterferona 2b, Calferon, Pegnano, Feronsure, PegiHep, interferon alfa-2b (Zydus-Cadila), Optipeg A, Realfa 2B , Reliferon, interferon alfa-2b (Amega), interferon alfa-2b (Virchow), peginterferon alfa-2b (Amega), Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon alfa-2b (Changchun Institute of Biological Products), Anterferon , Shanferon, Layfferon, Shang Sheng Lei Tai, INTEFEN, SINOGEN, Fukangtai, Pegstat, rHSA-IFN alpha-2b and Interapo (Interapa);

(8) hyaluronidase inhibitors selected from the group consisting of astodrimer;

(9) IL-10 modulators;

(10) HBsAg inhibitors selected from the group consisting of HBF-0259, PBHBV-001, PBHBV-215, PBHBV-2-1, REP 9AC, REP-9C and REP 9AC, and HBsAg inhibitors selected from REP-9 , REP2139, REP-2139-Ca, REP-2165, REP-2055, REP-2163, REP-2165, REP-2053, REP-2031 and REP-006 and REP-

- 56 041413

9AC;

(11) toll-like receptor modulators 9 selected from CYT003 as well as toll-like receptor modulators 9 selected from CYT-003, IMO-2055, IMO-2125, IMO-3100, IMO-8400, IMO-9200, agatolimod, DIMS -9054, DV-1179, AZD-1419, MGN-1703 and CYT-003-QbG10;

(12) cyclophilin inhibitors selected from the group consisting of OSV-030, SCY-635 and NVP018;

(13) HBV prophylactic vaccines selected from the group consisting of Hexaxim, Heplisav, Mosquirix, DTwP-HBV vaccine, Bio-Hep-B, D/T/P/HBV/M (LBVP-0101; LBVW-0101), DTwP vaccine -HepbHib-IPV, Heberpenta L, DTwP-HepB-Hib, V-419, CVI-HBV-001, Tetrabhay, hepatitis B prophylactic vaccine (Advax Super D), Hepatrol-07, GSK-223192A, Engerix B®, recombinant hepatitis B vaccine (IM, Kangtai Biological Products), recombinant hepatitis B vaccine (Yeast Hansenual polymorpha, IM, Hualan Biological Engineering), Bimmugen, Euforavac, Eutravac, anrix-DTaP-IPV-Hep B, Infanrix-DTaP-IPV- Hep B-Hib, Pentabio Vaksin DTP-HB-Hib, Comvac 4, Twinrix, Euvax-B, Tritanrix HB, Infanrix Hep B, Comvax, DTP-Hib-HBV vaccines, DTPHBV vaccines, Yi Tai, Heberbiovac HB, Trivac HB, GerVax, DTwP-Hep B-Hib, Bilive, Hepavax-Gene, SUPERVAX, Comvac5, Shanvac-B, Hebsulin, Recombivax HB, Revac B mcf, Revac B+, Fendrix, DTwP-HepBHib, DNA-001, Shan6, rhHBsAG vaccines and DT vaccines aP-rHB-Hib;

(14) HBV therapeutic vaccines selected from the group consisting of HBsAG-HBIG complex, Bio-Hep-B, NASVAC, abi-HB (intravenous), ABX-203, Tetrabhay, GX-110E, GS-4774, peptide vaccine ( epsilonPA-44), Hepatrol-07, NASVAC (NASTERAP), IMP-321, BEVAC, Revac B mcf, Revac B+, MGN1333, KW-2, CVI-HBV-002, AltraHepB, VGX-6200, FP-02, TG -1050, NU-500, HBVax, im/TriGrid/antigen vaccines, Mega-CD40L adjuvant vaccine, HepB-v, NO-1800, recombinant VLP-based therapeutic vaccine (HBV infection, VLP Biotech), AdTG-17909, AdTG -17910 AdTG-18202, ChronVac-B, and Lm HBV, as well as HBV therapeutic vaccines selected from FP-02.2 and RG7944 (INO1800);

(15) HBV entry inhibitors selected from the group consisting of Myrcludex B;

(16) an antisense oligonucleotide targeting viral mRNA selected from the group consisting of ISIS-HBVRx;

(17) short interfering RNAs (siRNAs) selected from the group consisting of TKM-HBV (TKM-HepB), ALN-HBV, SR-008, ddRNAi and ARC-520;

(18) endonuclease modulators selected from the group consisting of PGN-514;

(19) ribonucleotide reductase inhibitors selected from the group consisting of Trimidox;

(20) hepatitis B e antigen inhibitors selected from the group consisting of wogonin;

(21) anti-HBV antibodies targeting hepatitis B surface antigens selected from the group consisting of GC-1102, XTL-17, XTL-19, XTL-001, KN-003 and fully human monoclonal antibody therapy (hepatitis virus infection B, Humabs BioMed) as well as HBV antibodies targeted to hepatitis B surface antigens selected from IV Hepabulin SN;

(22) anti-HBV antibodies, including monoclonal antibodies and polyclonal antibodies selected from the group consisting of Zutectra, Shang Sheng Gan Di, Uman Big (Hepatitis B Hyperimmune), Omri-Hep-B, Nabi-HB, Hepatect CP, HepaGam B , igantibe, Niuliva, CT-P24, hepatitis B immunoglobulin (intravenous, pH4, HBV infection, Shanghai RAAS Blood Products) and Fovepta (BT-088);

(23) CCR2 chemokine antagonists selected from the group consisting of propgermanium;

(24) thymosin agonists selected from the group consisting of thymalfasin;

(25) cytokines selected from the group consisting of recombinant IL-7, CYT-107, interleukin-2 (IL-2, Immunex); recombinant human interleukin-2 (Shenzhen Neptunus) and celloleukin, as well as cytokines selected from IL-15, IL-21, IL-24;

(26) nucleoprotein inhibitors (HBV core or capsid protein inhibitors) selected from the group consisting of NVR-1221, NVR-3778, BAY 41-4109, morphothiadine mesylate, and DVR-23;

(27) retinoic acid inducible gene 1 stimulators selected from the group consisting of SB-9200, SB-40, SB-44, ORI-7246, ORI-9350, ORI-7537, ORI-9020, ORI-9198 and ORI- 7170;

(28) NOD2 stimulants selected from the group consisting of SB-9200;

(29) recombinant alpha-1 thymosin selected from the group consisting of NL-004 and PEGylated alpha-1 thymosin;

(30) inhibitors of hepatitis B virus replication selected from the group consisting of isothiafludine, IQP-HBV, RM-5038 and Xingantie;

(31) PI3K inhibitors selected from the group consisting of idelalisib, AZD-8186, buparlisib, CLR-457, pictilisib, neratinib, rigosertib, rigosertib sodium, EN-3342, TGR-1202, alpelisib, duvelisib, UCB-5857, tazelisib , XL-765, Gedatolisib, VS-5584, Copanlysib, Orotate CAI, Perifosin, RG-7666, GSK-2636771, DS-7423, Panulisib, GSK-2269557, GSK-2126458, CUDC-907, PQR-309, INCB- 040093, pilaralisiba, BAY-1082439, puquitinib mesylate, SAR-245409, AMG-319, RP-6530, ZSTK474, MLN-1117, SF-1126, RV-1729, sonolisiba, LY-3023414, SAR-260301 and CLR-1401 ;

(32) cccDNA inhibitors selected from the group consisting of BSBI-25;

- 57 041413 (33) PD-L1 inhibitors selected from the group consisting of MEDI-0680, RG-7446, durvalumab,

KY-1003, KD-033, MSB-0010718C, TSR-042, ALN-PDL, STI-A1014 and BMS-936559;

(34) PD-1 inhibitors selected from the group consisting of nivolumab, pembrolizumab, pidilizumab, BGB-108 and mDX-400;

(35) BTK inhibitors selected from the group consisting of ACP-196, dasatinib, ibrutinib, PRN-1008, SNS-062, ONO-4059, BGB-3111, MSC-2364447, X-022, spebrutinib, TP-4207, HM-71224, KBP-7536, AC-0025;

(36) other drugs for the treatment of HBV selected from the group consisting of gentiopicrin (gentiopicroside), nitazoxanide, birinapant, NOV-205 (Molixan; BAM-205), oligotide, mivotilate, feron, levamisole, Ka Shu Ning, alloferon, WS -007, Y-101 (Ti Fen Tai), rSIFN-co, PEGIIFNm, KW-3, BP-Inter-014, oleanolic acid, HepB-nRNA, cTP-5 (rTP-5), HSK-II-2, HEISCO-106-1, HEISCO-106, Hepbama, IBPB-006IA, Hepuyinfen, DasKloster 0014-01, Jiangantai (Ganxikang), picroside, GA5 NM-HBV, DasKloster-0039, hepulantai, IMB-2613, TCM-800B and ZH -2N, as well as other drugs for the treatment of HBV, selected from reduced glutathione and RO-6864018; and (37) compounds described in US 20100143301 (Gilead Sciences), US 20110098248 (Gilead Sciences), US 20090047249 (Gilead Sciences), US 8722054 (Gilead Sciences), US 20140045849 (Janssen), US 20140073642 (Janssen), WO 2014 /056953 (Janssen), WO 2014/076221 (Janssen), WO 2014/128189 (Janssen), US 20140350031 (Janssen), WO 2014/023813 (Janssen), US 20080234251 (Array Biopharma), US 20080306050 (Array Biopharma), US 20100029585 (Ventirx Pharma), US 20110092485 (Ventirx Pharma), US 20110118235 (Ventirx Pharma), US 20120082658 (Ventirx Pharma), US 20120219615 (Ventirx Pharma), US 20140066432 (Ventirx Pharma), US 20140088085 (VentirxPharma), US 20140275167 (Novira therapeutics) ), US 20130267517 (Roche), WO 2014131847 (Janssen), WO 2014033176 (Janssen), WO 2014033170 (Janssen), WO 2014033167 (Janssen), US 20140330015 (Ono pharmaceutical), US 20130079327 (Ono pharmaceutical), and US 20130217880 (Ono pharmaceutical), and the compounds described in US 20100015178 (Incyte). Also included in the list above are:

(38) IDO inhibitors selected from the group consisting of epacadostat (INCB24360), F-001287, resminostat (4SC-201), SN-35837, NLG-919, GDC-0919 and indoxymod;

(39) arginase inhibitors selected from CB-1158, C-201 and resminostat; and (40) cytotoxic inhibitors of T-lymphocyte protein 4 (ipi4) selected from ipilumimab, belatacept, PSI-001, PRS-010, tremelimumab and JHL-1155.

In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four, or more additional therapeutic agents. In some embodiments, a compound as described herein, or a pharmaceutically acceptable salt thereof, is combined with two additional therapeutic agents. In other embodiments, a compound as described herein, or a pharmaceutically acceptable salt thereof, is combined with three additional therapeutic agents. In additional embodiments, a compound as described herein, or a pharmaceutically acceptable salt thereof, is combined with four additional therapeutic agents. One, two, three, four or more additional therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents and/or they may be selected from different classes of therapeutic agents.

In a specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with an inhibitor of HBV DNA polymerase. In another specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with an inhibitor of HBV DNA polymerase and at least one additional therapeutic agent selected from the group consisting of: immunomodulators, toll-like receptor modulators (TLR-1 modulators, TLR -2, TLR-3, TLR-4, TLR-5, TLR-6, TLR7, TLR-8, TLR-9, TLR-10, TLR-11, TLR-12 and TLR-13), interferon receptor ligands- alpha, hyaluronidase inhibitors, recombinant IL-7, HBsAg inhibitors, HbcAg targeting compounds, cyclophilin inhibitors, HBV therapeutic vaccines, HBV prophylactic vaccines HBV entry inhibitors, NTCP inhibitors, antisense oligonucleotide targeting viral mRNA, short interfering RNA (siRNA ), miRNA agents for gene therapy, endonuclease modulators, inhibitors of ribonucleotide reductase, inhibitors of hepatitis B virus e antigen, proteins of the recombinant phagocytic receptor A (SRA ), Src kinase inhibitors, HBx inhibitors, cccDNA inhibitors, short hairpin RNAs (sshRNAs), HBV antibodies, including anti-HBV antibodies targeting hepatitis B surface antigens, and bispecific antibodies and antibody-like therapeutic proteins (such as DARTs®, Duobodies® , Bites®, XmAbs®, TandAbs®, Fab derivatives), CCR2 chemokine antagonists, thymosin agonists, cytokines, nucleoprotein inhibitors (HBV core or capsid protein inhibitors), retinoic acid inducible stimulants

- 58 041413 gene 1, NOD2 stimulators, NOD1 stimulators, arginase-1 inhibitors, STING agonists, PI3K inhibitors, lymphotoxin-beta receptor activators, natural killer cell 2B4 receptor inhibitors, lymphocyte activation gene 3 inhibitors, CD160 inhibitors, cytotoxic T-lymphocyte protein inhibitors 4, CD137 inhibitors, lectin-like natural killer receptor (G subfamily member 1) inhibitors, TIM-3 inhibitors, B- and T-lymphocyte attenuator inhibitors, CD305 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, PEG interferon lambda , recombinant thymosin alpha-1, BTK inhibitors, TIGIT modulators, CD47 modulators, SIRPalpha modulators, ICOS modulators, CD27 modulators, CD70 modulators, OX40 modulators, NKG2D modulators, Tim-4 modulators, B7-H4 modulators, B7-H3 modulators, modulators NKG2A, GITR modulators, CD160 modulators, HEVEM modulators, CD161 modulators, Axl modulators, Mer modulators, Tyro modulators, modifiers or gene editors such as CRISPR (including CRISPR Cas9), zinc finger nucleases or synthetic nucleases (TALENs), and inhibitors of hepatitis B virus replication. In some embodiments, the at least one additional therapeutic agent is further selected from inhibitors of surface antigen secretion or assembly. hepatitis B virus (HBsAg), TCR-like antibodies, cccDNA epigenetic modifiers, IAPs inhibitors, SMAC mimetics and IDO inhibitors.

In another specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with an inhibitor of HBV DNA polymerase and at least one additional therapeutic agent selected from the group consisting of: HBV entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting hepatitis B surface antigens, short interfering RNAs (siRNAs), miRNAs, gene therapy agents, short hairpin RNAs (sshRNAs), and nucleoprotein inhibitors (inhibitors of the HBV core or capsid protein).

In another specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with an inhibitor of HBV DNA polymerase, one or two additional therapeutic agents selected from the group consisting of: immunomodulators, toll-like receptor modulators (TLR-1 modulators, TLR- 2, TLR-3, TLR-4, TLR5, TLR-6, TLR-7, TLR-8, TLR-9, TLR-10, TLR-11, TLR-12 and TLR-13), HBsAg inhibitors, therapeutic vaccines HBV, HBV antibodies, including HBV antibodies targeting hepatitis B surface antigens and bispecific antibodies and antibody-like therapeutic proteins (such as DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs®, Fab derivatives), cyclophilin inhibitors, retinoic acid inducible gene 1 stimulators, PD-1 inhibitors, PD-L1 inhibitors, arginase-1 inhibitors, PI3K inhibitors and NOD2 stimulators, and one or two additional therapeutic agents selected from the group consisting of: entry site for HBV, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting hepatitis B surface antigens, short interfering RNAs (siRNAs), microRNA gene therapy agents, short hairpin RNAs (sshRNAs), and nucleoprotein inhibitors (Inhibitors). core or capsid protein of HBV). In some embodiments, the one or two additional therapeutic agents are further selected from hepatitis B surface antigen (HBsAg) secretion or assembly inhibitors, TCR-like antibodies, and IDO inhibitors.

In a specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four or more additional therapeutic agents selected from adefovir (Hepsera®), tenofovir disoproxil fumarate + emtricitabine (TRUVADA®), tenofovir disoproxil fumarate (Viread ®), entecavir (Baraclude®), lamivudine (Epivir-HBV®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide gemifumarate, telbivudine (Tyzeka®), clevudine®, emtricitabine (Emtriva®), pegynudine alfa -2b (PEG-Intron®), Multiferon®, interferon alfa-1b (Hapgen®), interferon alfa-2b (Intron A®), pegylated interferon alfa-2a (Pegasys®), interferon alfa-n1 (Humoferon®), ribavirin , interferon beta-1a (Avonex®), Bioferon, Ingaron, Inmutag (Inferon), Algeron, Roferon-A, Oligotide, Zutectra, Shaferon, interferon alfa-2b (AXXO), Alfaferon, interferon alfa-2b (B ioGeneric Pharma), Feron, interferon-alpha 2 (CJ), BEVAC, Laferonum, VIPEG, BLAUFERON-B, BLAUFERON-A, Intermax Alpha, Realdiron, Lanstion, Pegaferon, PDferon-B, interferon alfa-2b (IFN, Laboratorios Bioprofarma ), interferon alfa 2b, Calferon, Pegnano, Feronsure, PegiHep, interferon alfa 2b (Zydus-Cadila), Optipeg A, Realfa 2B, Reliferon, interferon alfa-2b (Amega), interferon alfa-2b (Virchow), peginterferon alfa-2b (Amega), Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon alfa-2b (Changchun Institute of Biological Products), Anterferon, Shanferon, MOR-22, interleukin-2 (IL-2, Immunex), recombinant human interleukin-2 (Shenzhen Neptunus), Layfferon, Ka Shu Ning, Shang Sheng Lei Tai, INTEFEN, SINOGEN, Fukangtai, Alloferon and celloleukin.

In a specific embodiment, a compound as described herein, or a pharmaceutically acceptable salt thereof, is combined with entecavir (Baraclude®), adefovir (Hepsera®),

- 59 041413 tenofovir disoproxil fumarate (Viread®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine (Tyzeka®) or lamivudine (Epivir-HBV®)

In a specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with entecavir (Baraclude®), adefovir (Hepsera®), tenofovir disoproxil fumarate (Viread®), tenofovir alafenamide hemifumarate, telbivudine (Tyzeka®), or lamivudine (Epivir-HBV®). ).

In a specific embodiment, a compound as described herein, or a pharmaceutically acceptable salt thereof, is combined with a PD-1 inhibitor. In a specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with a PD-L1 inhibitor. In a specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with an IDO inhibitor. In a specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with an IDO inhibitor and a PD-1 inhibitor. In a specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with an IDO inhibitor and a PD-L1 inhibitor. In a specific embodiment, a compound as described herein, or a pharmaceutically acceptable salt thereof, is combined with a TLR7 modulator such as GS-9620.

In a specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with a TLR7 modulator and an IDO inhibitor. In a specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with a TLR7 modulator such as GS-9620 and an IDO inhibitor such as epacadostat.

In a specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with (4-amino-2-butoxy-8-({3-[(pyrrolidin-1yl)methyl]phenyl}methyl)-7,8-dihydropteridine-6 (5H)-one) or a pharmaceutically acceptable salt thereof.

Herein, GS-9620 (4-amino-2-butoxy-8-({3-[(pyrrolidin-1yl)methyl]phenyl}methyl)-7,8-dihydropteridin-6(5H)-one) includes it pharmaceutically acceptable salts. J. Med. Chem., 2013, 56 (18), pp 7324-7333.

In a specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of: entecavir (Baraclude®), adefovir (Hepsera®), tenofovir disoproxil fumarate (Viread®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine (Tyzeka®), or lamivudine (Epivir-HBV®), and at least one additional therapeutic agent selected from the group consisting of immunomodulators, toll-like receptor modulators ( modulators TLR-1, TLR-2, TLR-3, TLR-4, TLR-5, TLR-6, TLR-7, TLR-8, TLR-9, TLR-10, TLR-11, TLR-12 and TLR -13), interferon-alpha receptor ligands, hyaluronidase inhibitors, recombinant IL-7, HBsAg inhibitors, HbcAg targeting compounds, cyclophilin inhibitors, HBV therapeutic vaccines, HBV prophylactic vaccines, viral entry inhibitors HBV, NTCP inhibitors, antisense oligonucleotide targeting viral mRNA, short interfering RNA (siRNA), microRNA gene therapy agents, endonuclease modulators, ribonucleotide reductase inhibitors, hepatitis B e antigen inhibitors, recombinant phagocytic receptor A (SRA) proteins, Src inhibitors kinases, HBx inhibitors, cccDNA inhibitors, short hairpin RNAs (sshRNAs), HBV antibodies, including anti-HBV antibodies targeting hepatitis B surface antigens and bispecific antibodies and antibody-like therapeutic proteins (such as DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs®, Fab derivatives), CCR2 chemokine antagonists, thymosin agonists, cytokines, nucleoprotein inhibitors (HBV core or capsid protein inhibitors), retinoic acid inducible gene 1 stimulators, NOD2 stimulators, NOD1 stimulators, recombinant thymosin alfa-1, inhibitors arginase-1, STING agonists, PI3K inhibitors, lymphocyte receptor activators xina-beta, natural killer cell 2B4 receptor inhibitors, lymphocyte activation gene 3 inhibitors, CD160 inhibitors, cytotoxic T-lymphocyte protein 4 inhibitors, CD137 inhibitors, natural killer cell lectin-like receptor (G subfamily member 1) inhibitors, TIM-3 inhibitors, inhibitors B- and T-lymphocyte attenuators, CD305 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, PEG interferon lambda, BTK inhibitors, TIGIT modulators, CD47 modulators, SIRPalpha modulators, ICOS modulators, CD27 modulators, CD70 modulators, OX40 modulators, NKG2D modulators, Tim-4 modulators, B7-H4 modulators, B7-H3 modulators, NKG2A modulators, GITR modulators, CD160 modulators, HEVEM modulators, CD161 modulators, Axl modulators, Mer modulators, Tyro modulators, gene modifiers, or gene editors, such as CRISPR (including CRISPR Cas9), zinc finger nucleases or synthetic nucleases (TALENs), and inhibitors of hepatitis B virus replication. in which embodiments the at least one additional therapeutic agent is further selected from inhibitors of hepatitis B surface antigen (HBsAg) secretion or assembly,

TCR-like antibodies, IDO inhibitors, cccDNA epigenetic modifiers, IAPs inhibitors, and SMAC mimetics.

In a specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of: entecavir (Baraclude®), adefovir (Hepsera®), tenofovir disoproxil fumarate (Viread®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine (Tyzeka®) or lamivudine (Epivir-HBV®) and at least one additional therapeutic agent selected from the group consisting of peginterferon alfa-2b (PEG-Intron® ), Multiferon®, interferon alfa-1b (Hapgen®), interferon alfa-2b (Intron A®), pegylated interferon alfa-2a (Pegasys®), interferon alfa-n1 (Humoferon®), ribavirin, interferon beta-1a (Avonex ®), Bioferon, Ingaron, Inmutag (Inferon), Algeron, Roferon-A, Oligotide, Zutectra, Shaferon, interferon alfa-2b (AXHO), Alfaferon, interferon alfa-2b (BioGener ic Pharma), Feron, interferon-alpha 2 (CJ), BEVAC, Laferonum, VIPEG, BLAUFERON-B, BLAUFERON-A, Intermax Alpha, Realdiron, Lanstion, Pegaferon, PDferon-B, interferon alfa-2b (IFN, Laboratorios Bioprofarma ), interferon alfa 2b, Calferon, Pegnano, Feronsure, PegiHep, interferon alfa 2b (Zydus-Cadila), Optipeg A, Realfa 2B, Reliferon, interferon alfa-2b (Amega), interferon alfa-2b (Virchow), peginterferon alfa-2b (Amega), Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon alfa-2b (Changchun Institute of Biological Products), Anterferon, Shanferon, MOR-22, interleukin-2 (IL-2, Immunex), recombinant human interleukin-2 (Shenzhen Neptunus), Layfferon, Ka Shu Ning, Shang Sheng Lei Tai, INTEFEN, SINOGEN, Fukangtai, Alloferon and celloleukin.

In a specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of: entecavir (Baraclude®), adefovir (Hepsera®), tenofovir disoproxil fumarate (Viread®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine (Tyzeka®) or lamivudine (Epivir-HBV®), and at least one additional therapeutic agent selected from the group consisting of HBV entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting hepatitis B surface antigens, short interfering RNAs (siRNAs), miRNAs, gene therapy agents, short hairpin RNAs (sshRNAs), and nucleoprotein inhibitors (inhibitors of the HBV core or capsid protein).

In a specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of: entecavir (Baraclude®), adefovir (Hepsera®), tenofovir disoproxil fumarate (Viread®), tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine (Tyzeka®), or lamivudine (Epivir-HBV®), one or two additional therapeutic agents selected from the group consisting of: immunomodulators, toll-like receptor modulators (modulators TLR1, TLR-2, TLR-3, TLR-4, TLR-5, TLR-6, TLR-7, TLR-8, TLR-9, TLR-10, TLR-11, TLR-12 and TLR-13) , HBsAg inhibitors, HBV therapeutic vaccines, HBV antibodies, including anti-HBV antibodies targeting hepatitis B surface antigens and bispecific antibodies and antibody-like therapeutic proteins (such as DARTs®, Duobodies®, Bites®, XmA bs®, TandAbs®, Fab derivatives), cyclophilin inhibitors, retinoic acid inducible gene 1 stimulators, PD-1 inhibitors, PD-L1 inhibitors, arginase-1 inhibitors, PI3K inhibitors, and NOD2 stimulators, and one or two additional therapeutic agents selected from the group consisting of: HBV entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting hepatitis B surface antigens, short interfering RNAs (siRNAs), microRNA gene therapy agents, short hairpin RNAs (sshRNAs ), and nucleoprotein inhibitors (HBV core or capsid protein inhibitors). In some embodiments, the one or two additional therapeutic agents are further selected from hepatitis B surface antigen (HBsAg) secretion or assembly inhibitors, TCR-like antibodies, and IDO inhibitors.

In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with 5-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In some embodiments, a compound as described herein, or a pharmaceutically acceptable salt thereof, is combined with 5-10; 5-15; 5-20; 5-25; 25-30; 20-30; 15-30; or 10-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with 10 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with 25 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. A compound of the present disclosure (e.g., a compound of formula (I)) may be combined with the agents described herein at any dosage of the compound (e.g., 50 to 500 mg of the compound) as if each dosage combination were specifically and separately listed. A compound of the present disclosure (e.g., a compound of formula (I)) may be combined with the agents described herein at any dosage of the compound (e.g., about 1 to about 150 mg of the compound) as if each dosage combination were specifically and separately listed.

In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with 100-400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. In some embodiments, a compound as described herein, or a pharmaceutically acceptable salt thereof, is combined with 100-150; 100-200, 100-250; 100-300; 100-350; 150-200; 150-250; 150-300; 150-350; 150-400; 200-250; 200-300; 200-350; 200-400; 250-350; 250-400; 350-400 or 300-400 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate or tenofovir disoproxil. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with 300 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with 250 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with 150 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil. A compound of the present disclosure (e.g., a compound of formula (I)) may be combined with the agents described herein at any dosage of the compound (e.g., 50 to 500 mg of the compound) as if each dosage combination were specifically and separately listed. A compound of the present disclosure (e.g., a compound of formula (I)) may be combined with the agents described herein at any dosage of the compound (e.g., about 1 to about 150 mg of the compound) as if each dosage combination were specifically and separately listed.

Also provided herein is a compound of the present disclosure (eg, a compound of formula (I)) or a pharmaceutically acceptable salt thereof, and one or more additional active ingredients for treating HBV, for use in a method for treating or preventing HBV.

Also provided herein is a compound of the present disclosure (e.g., a compound of formula (I)) or a pharmaceutically acceptable salt thereof, for use in a method for treating or preventing HBV, wherein said compound or a pharmaceutically acceptable salt thereof is administered simultaneously, separately, or sequentially with one or more additional therapeutic agents for the treatment of HBV.

Combination therapy for HCV

In some embodiments, a method of treating or preventing an HCV infection in a human having or at risk of developing an infection is provided, comprising administering to a human a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one , two, three, one or two, or one to three) additional therapeutic agents. In one embodiment, a method of treating an HCV infection in a human having or at risk of developing an infection is provided, comprising administering to a human a therapeutically effective amount of a compound of the present disclosure, 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, provided herein is a method of treating an HCV infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents suitable for treating the infection. HCV.

In the above embodiments, the additional therapeutic agent may be an anti-HCV agent. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of interferons, ribavirin or analogs thereof, HCV NS3 protease inhibitors, HCV NS4 protease inhibitors, HCV NS3/NS4 inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectors, nucleoside or nucleotide inhibitors. HCV NS5B polymerase, non-nucleoside inhibitors of HCV NS5B polymerase, HCV NS5A inhibitors, TLR-7 agonists, cyclophilin inhibitors, HCV IRES inhibitors and pharmacokinetic enhancers, compounds such as those described in US 2010/0310512, US 2013/0102525 and WO 2013/185093, or combinations thereof.

In some embodiments, a compound of the present disclosure (eg, a compound of formula (I)) is provided as a tablet, which may optionally contain one or more other compounds suitable for the treatment of HCV. In some embodiments, the tablet may contain another active ingredient for the treatment of HCV, such as interferons, ribavirin or analogues thereof, HCV NS3 protease inhibitors, HCV NS4 protease inhibitors, HCV NS3/NS4 inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectors, nucleoside or nucleotide HCV NS5B polymerase inhibitors, non-nucleoside HCV NS5B polymerase inhibitors, HCV NS5A inhibitors, TLR-7 agonists, cyclophilin inhibitors, HCV IRES inhibitors, and pharmacokinetic enhancers, or combinations thereof.

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

In some embodiments, the additional therapeutic agent is selected from one or more of:

(1) interferons selected from the group consisting of pegylated rIFN-alpha 2b (PEGIntron), pegylated rIFN-alpha 2a (Pegasys), rIFN-alpha 2b (Intron A), rIFN-alpha 2a (RoferonA), interferon alfa (MOR -22, ORS-18, Alfaferon, Alfanative, Multiferon, Subalin), interferon alfacon-1 (Infergen), interferon alpha-n1 (Wellferon), interferon alpha-n3 (Alferon), interferon-beta (Avonex, DL-8234) , interferon-omega (omega DUROS, Biomed 510), albinterferon alpha-2b (Albuferon), IFN alpha XL, BLX-883 (Locteron), DA-3021, glycosylated interferon alpha-2b (AVI-005), PEG-Infergen, Pegylated interferon lambda (PEGylated IL29) or beleforon, IFN alfa-2b XL, rIFN-alpha 2a, consensus IFN alfa, infergen, rebif, pegylated IFN-beta, oral interferon alfa, feron, reaferon, intermax alfa, r-IFN-beta and infergen + actimmunribavirin and ribaviria analogues eg rebetol, copegus, VX-497 and viramidine (taribavirin);

(2) ribavirin and analogues thereof selected from the group consisting of ribavirin (Rebetol, Copegus) and taribavirin (Viramidin);

(3) NS5A inhibitors selected from the group consisting of Compound A.1 (described below), Compound A.2 (described below), Compound A.3 (described below), ABT-267, Compound A.4 (described below) ), JNJ-47910382, daclatasvir (BMS-790052), ABT-267, Samatasvir, MK-8742, MK-8404, EDP-239, IDX-719, PPI-668, GSK-2336805, ASN-3102, A-831 , A-689, AZD-2836 (A-831), AZD-7295 (A689) and BMS-790052;

(4) NS5B polymerase inhibitors selected from the group consisting of sofosbuvir (GS-7977), Compound A.5 (described below), Compound A.6 (described below), ABT-333, Compound A.7 (described below) , ABT-072, Compound A.8 (described below), tegobuvir (GS-9190), GS-9669, TMC647055, ABT-333, ABT-072, setrobuvir (ANA-598), IDX-21437, filibuvir (PF- 868554) VX-222 IDX-375 IDX-184 IDX-102 BI-207127 BILB 1941, MK-0608, NM-107, R7128, VCH-759, GSK625433, XTL-2125, VCH-916, JTK-652, MK-3281, VBY-708, A848837, GL59728, A-63890, A-48773 , A-48547, BC-2329, BMS791325, BILB-1941, AL-335, AL-516, and ASN-3422;

(5) protease inhibitors (NS3, NS3-NS4) selected from the group consisting of Compound A.9, Compound A.10, Compound A.11, ABT-450, Compound A.12 (described below), simeprevir (TMC435 ), boceprevir (SCH-503034), narlaprevir (SCH-900518), vaniprevir (MK7009), MK-5172, danoprevir (ITMN-191), sovaprevir (ASN-1625), netceprevir (ASN-2684), Telaprevir (VX- 950), VX-813, VX-500, faldaprevir (BI-201335), asunaprevir (BMS-650032), BMS-605339, VBY-376, PHX-1766, YH5531, BILN-2065, and BILN-2061;

(6) alpha-glucosidase 1 inhibitors selected from the group consisting of celgosivir (MX3253), Miglitol and UT-231B;

(7) hepatoprotectors selected from the group consisting of emrikasan (IDN-6556), ME-3738, GS9450 (LB-84451), silibilin and MitoQ;

(8) TLR-7 agonists selected from the group consisting of imiquimod, 852A, GS-9524, ANA-773, ANA-975, AZD-8848 (DSP-3025) and SM-360320;

(9) cyclophilin inhibitors selected from the group consisting of DEBIO-025, SCY-635 and NIM811;

(10) HCV IRES inhibitors selected from the group consisting of MCI-067;

(11) pharmacokinetic enhancers selected from the group consisting of BAS-100, SPI-452, PF4194477, TMC-41629, GS-9350, GS-9585 and roxithromycin; and (12) other anti-HCV agents selected from the group consisting of thymosin alpha 1 (Zadaxin), nitazoxanide (Alinea, NTZ), BIVN-401 (virostat), PYN-17 (altirex), KPE02003002, actilone (CPG10101), GS-9525, KRN-7000, civatsira, GI-5005, XTL-6865, BIT225, PTX-111, ITX2865, TT-033i, ANA 971, NOV-205, tarvacina, EHC-18, VGX-410C, EMZ-702 , AVI 4065, BMS-650032, BMS-791325, Bavituk-

- 63 041413 simaba, MDX-1106 (ONO-4538), Oglufanide, VX-497 (merimepodib) NIM811, benzimidazole derivatives, benzo-1,2,4-thiadiazine derivatives and phenylalanine derivatives;

Compound A.1 is an inhibitor of the NS5A protein of HCV and is represented by the following chemical structure:

(See, for example, US Patent Application Publication No. 20100310512 A1).

Compound A.2 is an NS5A inhibitor and is represented by the following chemical

Compound A.3 is an NS5A inhibitor and is represented by the structure:

next chemical

next chemical

Compound A.4 is an NS5A inhibitor and is represented by the structure:

(See U.S. Patent Application Publication No. 2013/0102525 and references therein.)

Compound A.5 is an inhibitor of NS5B Thumb II polymerase and has the following chemical structure:

Compound A.6 is a nucleotide inhibitor prodrug designed to inhibit viral RNA replication by HCV NS5B polymerase and has the following chemical structure:

Compound A.7 is an HCV polymerase inhibitor and is represented by the following structure:

(See U.S. Patent Application Publication No. 2013/0102525 and references therein.)

- 64 041413

Compound A.8 is an HCV polymerase inhibitor and is represented by the following structure:

(See U.S. Patent Application Publication No. 2013/0102525 and references therein.)

Compound A.9 is an HCV polymerase inhibitor and is represented by the following chemical structure:

Compound A.10 is an HCV polymerase inhibitor and is represented by the following chemical structure:

O

Compound A.11 is an inhibitor of HCV polymerase and is represented by the following chemical structure:

Compound A.12 is an inhibitor of HCV polymerase and is represented by the following chemical structure:

(See U.S. Patent Application Publication No. 2013/0102525 and references therein.)

In one embodiment, the additional therapeutic agent used in combination with the pharmaceutical compositions described herein is an HCV NS3 protease inhibitor. Non-limiting examples include the following:

- 65 041413

In another embodiment, the additional therapeutic agent used in combination with the pharmaceutical compositions described herein is a cyclophilin inhibitor, including, for example, the cyclophilin inhibitor disclosed in WO 2013/185093. Non-limiting examples, in addition to those listed above, include the following:

and stereoisomers and mixtures of their stereoisomers.

In a specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with an inhibitor of HCV NS5B polymerase. In a particular embodiment, a compound as described herein or pharmaceutically

- 66 041413 an acceptable salt is combined with an HCV NS5B polymerase inhibitor and an HCV NS5A inhibitor. In another specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with an HCV NS5B polymerase inhibitor, an HCV NS3 protease inhibitor, and an HCV NS5A inhibitor. In another specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with an HCV NS5B polymerase inhibitor, an HCV NS4 protease inhibitor, and an HCV NS5A inhibitor. In another specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with an HCV NS5B polymerase inhibitor, an HCV NS3/NS4 protease inhibitor, and an HCV NS5A inhibitor. In another specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with an HCV NS3 protease inhibitor and an HCV NS5A inhibitor. In another specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with an HCV NS4 protease inhibitor and an HCV NS5A inhibitor. In another specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with an HCV NS3/NS4 protease inhibitor and an HCV NS5A inhibitor. In another specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with an HCV NS3 protease inhibitor, a pharmacokinetic enhancer, and an HCV NS5A inhibitor. In another specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with an HCV NS4 protease inhibitor, a pharmacokinetic enhancer, and an HCV NS5A inhibitor. In another specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with an HCV NS3/NS4 protease inhibitor, a pharmacokinetic enhancer, and an HCV NS5A inhibitor.

In a specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four or more additional therapeutic agents selected from simeprevir, MK-8742, MK-8408, MK-5172, ABT-450, ABT- 267, AVT-333, sofosbuvir, sofosbuvir + ledipasvir, sofosbuvir + GS-5816, sofosbuvir + GS-9857 + ledipasvir, AVT-450 + AVT-267 + ritonavir, AVT-450 + AVT-267 + ribavirin + ritonavir, AVT- 450 + АВТ-267 + ribavirin + АВТ-333 + ritonavir, АВТ-530 + АВТ-493, MK-8742 + MK5172, MK-8408 + MK-3682 + MK-5172, MK-8742 + MK-3682 + MK- 5172, daclatasvir, interferon, pegylated interferon, ribavirin, samatasvir, MK-3682, ACH-3422, AL-335, IDX-21437, IDX21459, tegobuvir, setrobuvir, valopicitabine, boceprevir, narlaprevir, vaniprevir, danoprevir, sovaprevir, telaprevir, necevaprevir , faldaprevir, asunaprevir, ledipasvir, GS-5816, GS-9857, ACH-3102, ACH-3422 + ACH-3102, ACH-3422 + sovaprevir + ACH-3102 , asunaprevir, asunaprevir + daclatasvir, AL-516 and vedroprevir.

In some embodiments, a compound as described herein, or a pharmaceutically acceptable salt thereof, is co-administered with simeprevir. In some embodiments, a compound as described herein, or a pharmaceutically acceptable salt thereof, is co-administered with MK-8742 or MK-8408. In some embodiments, a compound as described herein, or a pharmaceutically acceptable salt thereof, is co-administered with MK-5172. In some embodiments, a compound as described herein, or a pharmaceutically acceptable salt thereof, is co-administered with ABT-450, ABT-267, or ABT-333. In some embodiments, a compound as described herein, or a pharmaceutically acceptable salt thereof, is co-administered with Viekirat (combination of ABT-450, ABT-267 and ritonavir). In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with daclatasvir. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with sofosbuvir. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with Harvoni (sofosbuvir + ledipasvir). In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with sofosbuvir and GS-5816. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with sofosbuvir + GS-9857 + ledipasvir. In some embodiments, a compound as described herein, or a pharmaceutically acceptable salt thereof, is co-administered with ABT-450 + ABT-267 + ribavirin + ritonavir. In some embodiments, a compound as described herein, or a pharmaceutically acceptable salt thereof, is co-administered with ABT-450 + ABT-267 + ribavirin + ABT-333 + ritonavir. In some embodiments, a compound as described herein, or a pharmaceutically acceptable salt thereof, is co-administered with ABT-530 + ABT-493. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with MK-8408 + MK-3682 + MK-5172. In some embodiments, a compound as described herein, or a pharmaceutically acceptable salt thereof, is co-administered with MK-8742 + MK-5172. According to some

- 67 041413 embodiments, a compound according to the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with MK-3682. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with ACH-3422. In some embodiments, a compound as described herein, or a pharmaceutically acceptable salt thereof, is co-administered with AL-335. In some embodiments, a compound as described herein, or a pharmaceutically acceptable salt thereof, is co-administered with ACH-3422 + ACH-3102. In some embodiments, a compound as described herein, or a pharmaceutically acceptable salt thereof, is co-administered with ACH-3422 + covaprevir + ACH-3102. In some embodiments, a compound as described herein, or a pharmaceutically acceptable salt thereof, is co-administered with GS-5816. In some embodiments, a compound as described herein, or a pharmaceutically acceptable salt thereof, is co-administered with GS-9857. In some embodiments, a compound as described herein, or a pharmaceutically acceptable salt thereof, is co-administered with IDX-21459. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with boceprevir. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is co-administered with ledipasvir. In some embodiments, a compound as described herein, or a pharmaceutically acceptable salt thereof, is co-administered with AL-516.

In various ways, compound A.1 is administered in an amount ranging from about 10 mg/day to about 200 mg/day. For example, the amount of Compound A.1 may be about 30 mg/day, about 45 mg/day, about 60 mg/day, about 90 mg/day, about 120 mg/day, about 135 mg/day, about 150 mg/day , approximately 180 mg/day. In some methods, Compound A.1 is administered at about 90 mg/day. In various ways, Compound A.2 is administered in an amount ranging from about 50 mg/day to about 800 mg/day. For example, the amount of compound A.2 may be about 100 mg/day, about 200 mg/day, or about 400 mg/day. In some methods, the amount of compound A.3 is from about 10 mg/day to about 200 mg/day. For example, the amount of Compound A.3 may be about 25 mg/day, about 50 mg/day, about 75 mg/day, or about 100 mg/day.

In various routes, sofosbuvir is administered in an amount ranging from about 10 mg/day to about 1000 mg/day. For example, the amount of sofosbuvir may be about 100 mg/day, about 200 mg/day, about 300 mg/day, about 400 mg/day, about 500 mg/day, about 600 mg/day, about 700 mg/day, about 800 mg/day. In some methods, sofosbuvir is administered at about 400 mg/day.

Also provided herein is a compound of the present disclosure (eg, a compound of formula (I)) or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents for treating HCV, for use in a method for treating or preventing HCV.

Also provided herein is a compound of the present disclosure (e.g., a compound of formula (I)) or a pharmaceutically acceptable salt thereof, for use in a method for treating or preventing HCV, wherein the compound or pharmaceutically acceptable salt thereof is administered simultaneously, separately, or sequentially with one or more additional therapeutic agents for the treatment of HCV.

Combination therapy for HIV

In some embodiments, a method is provided for treating or preventing an HIV infection in a human having or at risk of developing an infection, comprising administering to a human a therapeutically effective amount of a compound of the present disclosure, 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, there is provided a method of treating an HIV infection in a human having or at risk of developing an infection, comprising administering to a human a therapeutically effective amount of a compound of the present disclosure, 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, provided herein is a method of treating an HIV infection comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents suitable for treating the infection. HIV. In some embodiments, the one or more additional therapeutic agents include, for example, one, two, three, four, one or two, one to three, or one to four additional therapeutic agents.

In the above embodiments, the additional therapeutic agent may be an anti-HIV agent. For example, according to some embodiments of the additional

The body therapeutic agent is selected from the group consisting of HIV protease inhibitors, non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, nucleoside or nucleotide inhibitors of HIV reverse transcriptase, inhibitors of HIV integrase, inhibitors of the non-catalytic site of HIV integrase (allosteric inhibitors), inhibitors of HIV entry ( e.g., CCR5 inhibitors, gp41 inhibitors (i.e., fusion inhibitors) and CD4 attachment inhibitors), CXCR4 inhibitors, gp120 inhibitors, G6PD and NADPH oxidase inhibitors, HIV vaccines, inhibitors of HIV maturation, latency reversal agents (e.g., histone deacetylase inhibitors , proteasome inhibitors, protein kinase C (PKC) activators and BRD4 inhibitors), HIV capsid-targeting compounds (capsid inhibitors; e.g. capsid of HIV), pharmacokinetic mustache agents, immunological therapies (eg, Pd-1 modulators, Pd-L1 modulators, toll-like receptor modulators, IL-15 agonists), HIV antibodies, bispecific antibodies, and antibody-like therapeutic proteins (eg, DARTs®, Duobodies®, Bites® , XmAbs®, TandAbs®, Fab derivatives), including those targeting HIV gp120 or gp41, HIV combination drugs, HIV matrix p17 protein inhibitors, IL-13 antagonists, peptidyl-prolyl-cis-trans isomerase A modulators , protein disulfide isomerase inhibitors, C5a complement receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, HIV-1 viral infection factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed-origin kinase 3 (MLK- 3), HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, domain-containing protein 1 modulators COMM, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3 capture non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent inhibitors kinases, protein convertase-PC9 stimulators, DDX3X ATP-dependent RNA helicase inhibitors, complex reverse transcriptase inhibitors, PI3K inhibitors, compounds such as those disclosed in WO 2013/006738 (Gilead Sciences), US 2013/0165489 (University of Pennsylvania), WO 2013/091096A1 (Boehringer Ingelheim), WO 2009/062285 (Boehringer Ingelheim), US20140221380 (Japan Tobacco), US20140221378 (Japan Tobacco), WO 2010/130034 (Boehringer Ingelheim) ), WO 2012/145728 (Gilead Sciences), WO 2012/003497 (Gilead Sciences), WO 2014/100323 (Gilead Sciences), WO 2012/145728 (Gilead Sciences), WO 2013/159064 (Gilead Sciences) and WO 2012/003498 (Gilead Sciences) and WO 2013/006792 (Pharma Resources) and other drugs for the treatment of HIV and combinations thereof. In some embodiments, the additional therapeutic agent is further selected from Vif dimerization antagonists and anti-HIV gene therapy.

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 non-catalytic site inhibitors (allosteric inhibitors), pharmacokinetic enhancers, and their combinations.

In some embodiments, a compound of the present disclosure is in the form of a tablet, which may optionally contain one or more compounds suitable for 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 inhibitors of HIV reverse transcriptase, nucleoside or nucleotide HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV inhibitors of the non-catalytic site of HIV integrase (allosteric inhibitors) , pharmacokinetic enhancers, and combinations thereof.

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

In some embodiments, the additional therapeutic agent is selected from one or more of:

(1) combination medicines 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), dolutegravir + abacavir sulfate + lamivudine, TRIUMEQ® (dolutegravir + abacavir + lamivudine), lamivudine + nevirapine + zidovudine, dolutegravir + rilpivirine, atazanavir sulfate + cobicistat, darunavir + cobicistat, efavirenz + lamivudine + tenofovir fumarate, tenofovir fumarate, tenofovir fumarate, tenofoviramidumate hemifumarate + emtricitabine + cobicistat + elvitegravir, Vacc-4x + romidepsin, darunavir + tenofovir alafenamide hemifumarate + emtricitabine + cobicistat, APH-0812, raltegravir + lamivudine, KALETRA® (ALUVIA®, lopinavir + ritonavir), atazanavir sulfate, COMBIR® (zidovudine+lamivudine, AZT+3TC), EP

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ZICOM® (Livexa®, abacavir sulfate + lamivudine, ABC+3TC), TRIZIVIR® (abacavir sulfate + zidovudine + lamivudine, ABC+AZT+3TC), TRUVADA® (tenofovir disoproxil fumarate + emtricitabine, TDF+FTC), tenofovir + lamivudine и ламивудин + тенофовир дизопроксил фумарат, а также combinations drugs выбранных из долутегравир+рилпивирин гидрохлорид, атазанавир + кобицистат, тенофовир алафенамид гемифумарат + эмтрицитабин, тенофовир алафенамид + эмтрицитабин, тенофовир алафенамид гемифумарат + эмтрицитабин + рилпивирин, тенофовир алафенамид + эмтрицитабин + рилпивирин, доравирин + lamivudine + tenofovir disoproxil fumarate, doravirine + lamivudine + tenofovir disoproxil;

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

(3) non-nucleoside or non-nucleotide HIV reverse transcriptase inhibitors selected from the group consisting of delavirdine, delavirdine mesylate, nevirapine, etravirine, dapivirine, doravirine, 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, censavudine, abacavir, abacavir sulfate, amdoxovir, 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, тенофовира алафенамида фумарата, адефовира, адефовира дипивоксила и фестиавира ;

(5) HIV integrase inhibitors selected from the group consisting of curcumin, curcumin derivatives, chicory acid, chicory acid derivatives, 3,5-dicofeylquinic acid, 3,5-dicofeylquinic acid derivatives, aurine tricarboxylic acid, aurine tricarboxylic acid derivatives, caffeic phenethyl ester acids, caffeic acid phenethyl ester derivatives, tyrphostin, tyrphostin derivatives, quercetin, quercetin derivatives, raltegravir, elvitegravir, dolutegravir and cabotegravir, as well as HIV integrase inhibitors selected from JTK351;

(6) HIV integrase non-catalytic site inhibitors (NCINIs or allosteric inhibitors) 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 albuvirtide;

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

(9) HIV gp120 inhibitors 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), nifeviroc (TD-0232), TD-0680 and vMIP (Haimipu);

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

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

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

(14) immunological therapies selected from the group consisting of dermaVir, interleukin-7, Plaquenil (hydroxychloroquine), proleukin (aldesleukin, IL-2), interferon alfa, interferon alfa2b, interferon alfa-n3, pegylated interferon alfa, interferon gamma, hydroxyurea, mycophenolate mofetil (MPA) and mycophenolate mofetil ester (MMF), WF-10, ribavirin, IL-2, IL-12, polymeric polyethyleneimine (PEI), Gepon, VGV-1, MOR-22, BMS936559, Toll modulators -like receptors (TLR-1, TLR-2, TLR-3, TLR-4, TLR-5, TLR-6, TLR-7, TLR-8, TLR-9, TLR-10, TLR-11, TLR- 12 and TLR-13), rinthatolimod and IR-103;

(15) HIV vaccines selected from the group consisting of peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, virus-like particle (pseudovirion) vaccines, CD4-derived peptide vaccines, 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, recombinant adenovirus-5 (rAd5) multiclade DNA, Pennvax-G, VRC-HIV MAB060-00-AB, AVX-101, Tat Oyi vaccines, AVX-201, HIV-LAMP-vax , Ad35, Ad35-GRIN, NAcGM3/VSSP ISA-51, poly-ICLC adjuvant vaccines, TatImmune, GTU-multiHIV (FIT-06), AGS-004, gp140[delta]V2.TV1+ MF-59, rVSVIN Gag HIV vaccines -1, vaccines SeV-Gag, AT-20, DNK-4, Ad35-GRIN/ENV, TBC-M4, HIVAX, HIVAX-2, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, Vichrepol, rAAV1-PG9DP, GOVX-B11, GOVX-B21, ThV-01, TUTI-

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16, VGX-3300, TVI-HIV-1, Ad-4 (Ad4-env Clade C + Ad4-mGag), EN41-UGR7C, EN41-FPA2, PreVaxTat,

TL-01, SAV-001, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR, ETV-01 and DNAAd5 gag/pol/nef/nev (HVTN505), as well as HIV vaccines, selected from monomeric gp120 vaccine

HIV-1 subtype C (Novartis), HIV-TriMix-mRNA, MVATG-17401, ETV-01, CDX-1401 and rcAd26.MOS1.

HIV Env;

(16) HIV antibodies, bispecific antibodies, and antibody-like therapeutic proteins (e.g., DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs®, Fab derivatives), including BMS-936559, TMB-360 and those targeting gp120 or HIV gp41 selected from the group consisting of bavituximab, UB-421, C2F5, C2G12, C4E10, C2F5+C2G12+C4E10, 3-BNC-117, PGT145, PGT121, MDX010 (ipilimumab), VRC01, A32, 7B2, 10E8 and VRC07 as well as HIV antibodies such as VRC-07-523;

(17) latency reversing 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 DAG lactones, Ionomycin, GSK-343, PMA, SAHA, BRD4, IL-15, JQ1 inhibitors, disulfiram and amphotericin B;

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

(19) HIV maturation inhibitors selected from the group consisting of BMS-955176 and GSK2838232;

(20) PI3K inhibitors selected from the group consisting of idelalisib, AZD-8186, buparlisib, CLR-457, pictilisib, neratilisib, rigosertib, rigosertib sodium, EN-3342, TGR-1202, alpelisib, duvelisib, UCB-5857, tazelisib , XL-765, Gedatolisib, VS-5584, Copanlysib, Orotate CAI, Perifosin, RG-7666, GSK-2636771, DS-7423, Panulisib, GSK-2269557, GSK-2126458, CUDC-907, PQR309, INCB-040093, pilaralisiba, BAY-1082439, puquitinib mesylate, SAR-245409, AMG-319, RP-6530, ZSTK-474, MLN-1117, SF-1126, RV-1729, sonolisiba, LY-3023414, SAR-260301 and CLR-1401 ;

(21) compounds described 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 2013/016 Ingelheim), WO 2013/159064 (Gilead Sciences), WO 2012/145728 (Gilead Sciences), WO 2012/003497 (Gilead Sciences), WO 2014/100323 (Gilead Sciences), WO 2012/145728 (Gilead Sciences), WO 2013 /159064 (Gilead Sciences) and WO 2012/003498 (Gilead Sciences); and (22) other HIV medicines selected from the group consisting of BanLec, MK-8507, AG-1105, TR-452, MK-8591, REP 9, CYT-107, Alisporivir, NOV-205, IND- 02, methenkephalin, PGN-007, acemannan, gamimun, prolastin, 1,5-dicapheoylquinic acid, BIT-225, RPI-MN, VSSP, Hlviral, IMO-3100, SB-728-T, RPI-MN, VIR-576 , HGTV-43, MK-1376, rBH47-shl-TARCCR5RZ, MazF gene therapy, BlockAide, ABX-464, SCY-635, naltrexone, and RA-1050040 (RA-040); and other HIV medicines selected from AAV-eCD4-Ig gene therapy, TEV90110, TEV-90112, TEV-90111, TEV-90113, deferiprone and HS-10234.

In some embodiments, the additional therapeutic agent is a compound described in US 2014-0221356 (Gilead Sciences, Inc.), e.g. (2R,5S,13aR)-N-(2,4difluorobenzyl)-8-hydroxy-7,9- dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine -10-carboxamide, (2S,5R,13aS)-N-(2,4-difluorobenzyl)-8-hydroxy-7,9-dioxo2,3,4,5,7,9,13,13a-octahydro-2 ,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide, (1S,4R,12aR)-N-(2,4-difluorobenzyl )-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4methanodipyrido[1,2-a:1',2'-d]pyrazine- 9-carboxamide, (1R,4S,12aR)-7-hydroxy-6,8-dioxo-N-(2,4,6trifluorobenzyl)-1,2,3,4,6,8,12,12a-octahydro- 1,4-methanodipyrido[1,2-а:1',2'-d]pyrazine-9-carboxamide, (2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4 ,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1 ,3]oxazepine-10-carboxamide and (1R,4S,12aR)-N-(2,4-difluorobenzyl)-7hydroxy-6,8-dioxo-1,2,3,4,6,8,12,1 2a-octahydro-1,4-methanodipyrido[1,2-a:1',2'-d]pyrazine-9carboxamide, US 2015-0018298 (Gilead Sciences, Inc.) and US 2015-0018359 (Gilead Sciences, Inc. ).

In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four, or more additional therapeutic agents. In some embodiments, a compound as described herein, or a pharmaceutically acceptable salt thereof, is combined with two additional therapeutic agents. In other embodiments, a compound as described herein, or a pharmaceutically acceptable salt thereof, is combined with three additional therapeutic agents. In additional embodiments, a compound as described herein, or a pharmaceutically acceptable salt thereof, is combined with four additional therapeutic agents. One, two, three, four or more additional therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents and/or they may be selected from different classes of therapeutic agents.

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In a specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with a nucleoside or nucleotide HIV reverse transcriptase inhibitor and a non-nucleoside HIV reverse transcriptase inhibitor. In another specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with a nucleoside or nucleotide inhibitor of HIV reverse transcriptase and an HIV protease-inhibiting compound. In a further embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined 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 of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined 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 of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with at least one HIV nucleoside reverse transcriptase inhibitor, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with two nucleoside or nucleotide inhibitors of HIV reverse transcriptase.

In a specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four or more additional therapeutic agents selected from Triumeq® (dolutegravir+abacavir+lamivudine), dolutegravir+abacavir sulfate+lamivudine, 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 + tenofovir disoproxil fumarate + emtricitabine), cobicistat, Atripla® emtricitabine), atazanavir, atazanavir sulfate, dolutegravir, elvitegravir, Aluvia® (Kaletra®, lopinavir+ritonavir), ritonavir, emtricitabine, atazanavir with sulfate+ritonavir, darunavir, lamivudine, prolastin, fosamprenavir, fosamprenavir calcium, efavirenz, Combivir® (zidovudine+lamivudine, AZT+3TC), etravirine, nelfinavir, nelfinavir mesylate, interferon, didanosine, stavudine, indinavir, indinavir sulfate, tenofovir+lamivudine , zidovudine, nevirapine, saquinavir, saquinavir mesylate, aldesleukin, zalcitabine, tipranavir, amprenavir, delavirdine, delavirdine mesylate, Radha-108 (Receptol), Hlviral, lamivudine+tenofovir disoproxil fumarate, efavirenz+lamivudine+tenofovir disoproxilate, flosamidine disoproxil, nevirapine + zidovudine, abacavir, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide and tenofovir alafenamide hemifumarate. In some embodiments, the one, two, three, four or more additional therapeutic agents are further selected from raltegravir+lamivudine, atazanavir sulfate+cobicistat, atazanavir+cobicistat, darunavir+cobicistat, darunavir+cobicistat, atazanavir sulfate+cobicistat, atazanavir+cobicistat.

In a specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four or more additional therapeutic agents selected from Triumeq® (dolutegravir+abacavir+lamivudine), dolutegravir+abacavir sulfate+lamivudine, 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 + tenofovir disoproxil fumarate + emtricitabine), cobicistat, Atripla® (efavirenz + tenofovir disoproxil emtricitabine), atazanavir, atazanavir sulfate, dolutegravir, elvitegravir, Aluvia® (Kaletra®, lopinavir + ritonavir), ritonavir, emtricitabine, atazanavir sulfate + ritonavir ira, darunavir, lamivudine, Prolastin, fosamprenavir, fosamprenavir calcium, efavirenz, Combivir® (zidovudine+lamivudine, AZT+3TC), etravirine, nelfinavir, nelfinavir mesylate, interferon, didanosine, stavudine, indinavir, indinavir sulfate, tenofovir+lamivudine, zidovudine , nevirapine, saquinavir, saquinavir mesylate, aldesleukin, zalcitabine, tipranavir, amprenavir, delavirdine, delavirdine mesylate, Radha-108 (Receptol), Hlviral, lamivudine+tenofovir disoproxil fumarate, efavirenz+lamivudine+tenofovir disoproxil+fumarate, nelamivudine, fosfamidine zidovudine, (2R,5S,13aR)-N-(2,4-difluorobenzyl)-8-hydroxy-7,9-dioxo2,3,4,5,7,9,13,13a-octahydro-2,5- methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide,

- 72 041413 (2S,5R,13aS)-N-(2,4-difluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2 ,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide, (1S,4R,12aR)-N-(2,4-difluorobenzyl )-7hydroxy-6,8-dioxo-1,2,3,4,6,8D2,12a-octahydro-1,4-methanodipyrido[1,2-a:D,2'-1]pyrazine-9-carboxamide , (1R,4S,12aR)-7-hydroxy-6,8-dioxo-N-(2,4,6-fluorobenzyl)-1,2,3,4,6,8,12,12a-octahydro-1 ,4methanodipyrido[1,2-a:G,2'-1]pyrazine-9-carboxamide, (2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6trifluorobenzyl)- 2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine10-carboxamide , and (1R,4S,12aR)-N-(2,4-difluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12а-octahydro-1, 4-Methanodipyrido[1,2-a:D,2'-1]pyrazine-9-carboxamide, abacavir, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate.

In a specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.

In a specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.

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

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

In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with 5-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg of emtricitabine. In some embodiments, a compound as described herein, or a pharmaceutically acceptable salt thereof, is combined with 5-10; 5-15; 5-20; 5-25; 25-30; 20-30; 15-30; or 10-30 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg emtricitabine. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with 10 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of emtricitabine. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with 25 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of emtricitabine. A compound of the present disclosure (e.g., a compound of formula (I)) may be combined with the agents described herein at any dosage of the compound (e.g., 1 to 500 mg of the compound), as well as if each dosage combination were specifically or separately listed.

In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with 200-400 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200 mg emtricitabine. In some embodiments, a compound as described herein, or a pharmaceutically acceptable salt thereof, is combined with 200-250; 200-300; 200-350; 250-350; 250-400; 350-400; 300-400 or 250-400 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate or tenofovir disoproxil and 200 mg emtricitabine. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with 300 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200 mg of emtricitabine. A compound of the present disclosure (e.g., a compound of formula (I)) may be combined with the agents described herein at any dosage of the compound (e.g., 50 to 500 mg of the compound) as if each dosage combination were specifically and separately listed. A compound of the present disclosure (e.g., a compound of formula (I)) may be combined with the agents described herein at any dosage of the compound (e.g., about 1 to about 150 mg of the compound) as if each dosage combination were specifically and separately listed.

In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with (2R,5S,13aR)-N-(2,4-difluorobenzyl)-8-hydroxy-7,9

- 73 041413 dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1, 3]oxazepine-10carboxamide, (2S,5R,13aS)-N-(2,4-difluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a- octahydro2,5-methanopyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazepine-10-carboxamide, (1S,4R,12aR)-N-(2,4- g-fluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-methanodipyrido[1,2-a:1',2'-d ]pyrazine-9-carboxamide, (1R,4S,12aR)-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4,6,8,12 ,12aoctahydro-1,4-methanodipyrido[1,2-a:1',2'L]pyrazine-9-carboxamide, (2R,5S,13aR)-8-hydroxy-7,9dioxo-N-(2,4 ,6-trifluorobenzyl)-2,3,4,5,7,9,13,13а-octahydro-2,5-methanopyrido[1',2':4,5]pyrazino[2,1b][1,3 ]oxazepine-10-carboxamide or (1R,4S,12aR)-N-(2,4-difluorobenzyl)-7-hydroxy-6,8-dioxo1,2,3,4,6,8,12,12a-octahydro -1,4-methanodipyrido[1,2-a:1',2'N]pyrazine-9-carboxamide.

Also provided herein is a compound of the present disclosure (eg, a compound of formula (I)) or a pharmaceutically acceptable salt thereof, and one or more additional HIV therapeutic agents for use in a method of treating or preventing HIV.

Also provided herein is a compound of the present disclosure (e.g., a compound of formula (I)) or a pharmaceutically acceptable salt thereof, for use in a method for treating or preventing HIV, wherein the compound or pharmaceutically acceptable salt thereof is administered simultaneously, separately, or sequentially with one or more additional therapeutic agents for the treatment of HIV.

In some embodiments, a method of treating a hyperproliferative disorder, such as cancer, in a human is provided, comprising administering to a human a therapeutically effective amount of a compound of the present disclosure, 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, there is provided a method of treating a hyperproliferative disorder, such as cancer, in a human, comprising administering to a human a therapeutically effective amount of a compound of the present disclosure, 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.

Combination therapy for cancer

In some embodiments, provided herein is a method of treating a hyperproliferative disorder, such as cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound as described herein, or a pharmaceutically acceptable salt, in combination with a therapeutically effective amount of one or more additional therapeutic agents suitable for the treatment of a hyperproliferative disorder such as cancer.

In the above embodiments, the additional therapeutic agent may be an anti-cancer agent. For example, in some embodiments, the additional therapeutic agent is selected from the group consisting of chemotherapeutic agents, immunotherapeutic agents, radiotherapeutic agents, anticancer agents, antihormonal agents, antiangiogenic agents, antifibrotic agents, therapeutic antibodies, tyrosine kinase inhibitors, JAK inhibitors, Hedgehog inhibitors, HDAC inhibitors. , discoidin domain receptor (DDR) inhibitors, MMP9 inhibitors, LOXL inhibitors, ASK1 inhibitors, PI3K inhibitors, BTK inhibitors, SYK inhibitors, mTOR inhibitors, AKT inhibitors, mitogen or extracellularly regulated kinase (MEK) inhibitors, Raf kinase (rafk) blockers, CDK inhibitors, JNK inhibitors, MAPK inhibitors, Raf inhibitors, ROCK inhibitors, Tie2 inhibitors, myo-inositol signaling inhibitors, phospholipase C blockers, anti-CD19 antibodies, anti-CD20 antibodies, anti-MN-14 antibodies, anti-TRAIL DR4 and DR5 antibodies , anti-CD74 antibodies, cancer vaccines based on the genetic composition of the individual patient's tumor, IDH1 inhibitors, BRD4 inhibitors, TPL2 inhibitors; A2B inhibitors; TBK1 inhibitors; IKK inhibitors; BCR inhibitors, agents that inhibit the RAS/RAF/ERK pathway, protein kinase C (PKC) modulators, growth factor receptor modulators such as epidermal growth factor receptor (EGFr), platelet-derived growth factor receptor (PDGFr), erbB2, erbB4, ret, vascular endothelial growth factor receptor (VEGFr), tyrosine kinase with immunoglobulin-like domains homologous to epidermal growth factor (TIE-2), insulin growth factor-I receptor (IGF), macrophage colony-stimulating factor (cfms), BTK, ckit, cmet, receptors fibroblast growth factor (FGF), Trk receptors (TrkA, TrkB, and TrkC), ephrin (eph) receptors and the RET proto-oncogene, tyrosine kinase modulators including cSrc, Lck, Fyn, Yes, cAbl, FAK (Focal Adhesion Kinase) and Bcr- Abl, modulators of the PKB kinase family, modulators of TGF beta receptor kinases, inhibitors of the Ras oncogene, including inhibitors of farnesyl transferase, geranyl geranyl transferase and CAAX proteases, antisense oligonucleotides, ribozymes, protein inhibitors the Bcl-2 family, proteasome inhibitors, HSP90 heat shock protein inhibitors, combination drugs and immunotherapies, and other drugs for the treatment of hyperproliferative disorders such as cancer, and combinations thereof.

- 74 041413

In some embodiments, a compound of the present disclosure is provided in the form of a tablet, which may optionally contain one or more other compounds useful in the treatment of cancer. In some embodiments, the tablet may contain another active ingredient for the treatment of cancer, such as chemotherapeutic agents, immunotherapeutic agents, radiotherapeutic agents, antitumor agents, antifibrotic agents, antihormonal agents, antiangiogenic agents, tyrosine kinase inhibitors, JAK inhibitors, Hedgehog inhibitors, HDAC inhibitors, inhibitors discoidin domain receptor (DDR), MMP9 inhibitors, LOXL inhibitors, ASK1 inhibitors, PI3K inhibitors, BTK inhibitors, SYK inhibitors, mTOR inhibitors, AKT inhibitors, mitogen or extracellularly regulated kinase (MEK) inhibitors, Raf kinase (rafk) blockers, CDK inhibitors , JNK inhibitors, MAPK inhibitors, Raf inhibitors, ROCK inhibitors, Tie2 inhibitors, myo-inositol signaling inhibitors, phospholipase C blockers, IDH1 inhibitors, BRD4 inhibitors, TPL2 inhibitors; A2B inhibitors; TBK1 inhibitors; IKK inhibitors; BCR inhibitors, RAS/RAF/ERK pathway inhibitory agents, protein kinase C (PKC) modulators, growth factor receptor modulators such as epidermal growth factor receptor (EGFr), platelet-derived growth factor receptor (PDGFr), erbB2, erbB4 , ret, vascular endothelial growth factor receptor (VEGFr), tyrosine kinase with immunoglobulin-like domains homologous to epidermal growth factor (TIE-2), insulin growth factor-I receptor (IGFI), macrophage colony-stimulating factor (cfms), BTK, ckit, cmet, fibroblast growth factor (FGF) receptors, Trk receptors (TrkA, TrkB, and TrkC), ephrin (eph) receptors and RET proto-oncogene, tyrosine kinase modulators including cSrc, Lck, Fyn, Yes, cAbl, FAK (Focal Adhesion Kinase) and Bcr -Abl, modulators of the PKB kinase family, modulators of TGF beta receptor kinases, inhibitors of the Ras oncogene, including inhibitors of farnesyl transferase, geranyl geranyl transferase and CAAX proteases, antisense oligonucleotides, ribozymes, inhibitors of protein families Bcl-2 properties, proteasome inhibitors, HSP90 heat shock protein inhibitors, combination drugs and immunotherapies, and other drugs for the treatment of hyperproliferative disorders such as cancer, and combinations thereof.

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

(1) chemotherapeutic agents selected from the group consisting of the following: antimetabolites/anticancer agents such as pyrimidine analogs (floxuridine, capecitabine and cytarabine); purine analogs, folic acid antagonists and related inhibitors, antiproliferative/antimitotic agents, including natural products such as vinca alkaloid (vinblastine, vincristine) and microtubules such as taxane (paclitaxel, docetaxel), vinblastine, nocodazole, epothilones and navelbine, epididophyllotoxins ( etoposide, teniposide); DNA destroying agents (actinomycin, amsacrine, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide, cytoxan, dactinomycin, daunorubicin, doxorubicin, epirubicin, ifosfamide, melphalan, mechlorethamine, mitomycin, mitoxantrone, nitrosourea, procarbazine, taxol, etoposide, teniposide , triethylenethiophosphoramide); antibiotics such as dactinomycin (actinomycin D), daunorubicin, doxorubicin (adriamycin), idarubicin, anthracyclines, mitoxantrone, bleomycins, plicamycin (mitramycin), and mitomycin; enzymes (L-asparaginase, which systemically metabolizes L-asparagine and impoverishes cells that are unable to synthesize their own asparagine); antiplatelet agents; antiproliferative/antimitotic alkylating agents such as nitrogen mustard, cyclophosphamide and analogs, melphalan, chlorambucil) and (hexamethylmelamine and thiotepa), alkylnitrosoureas (BCNU) and analogs, streptozocin, trazene-dacarbazinine (DTIC); antiproliferative/antimitotic antimetabolites such as folic acid analogs (methotrexate); platinum coordination complexes (cisplatin, oxyloplatin, carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide; hormones, hormone analogs (estrogen, tamoxifen, goserelin, bicalutamide, nilutamide) and aromatase inhibitors (letrozole, anastrozole); anticoagulants (heparin, synthetic heparin salts and other thrombin inhibitors); fibrinolytic agents (such as tissue plasminogen activator, streptokinase and urokinase), aspirin, dipyridamole, ticlopidine, clopidogrel; anti-migration means; antisecretory agents (breveldin); immunosuppressants tacrolimus, sirolimus azathioprine, mycophenolate; compounds (TNP-470, genistein) and growth factor inhibitors (vascular endothelial growth factor inhibitors, fibroblast growth factor inhibitors); angiotensin receptor blocker, nitric oxide donors; antisense oligonucleotides; cell cycle inhibitors and differentiation inducers (tretinoin); inhibitors, topoisomerase inhibitors (doxorubicin (adriamycin), daunorubicin, dactinomycin, eniposide, epirubicin, idarubicin, irinotecan and mitoxantrone, topotecan, irinotecan), corticosteroids (cortisone, dexamethasone, hydrocortisone, methylpeptizolone, prednisone and prednisolone); growth factor signal transduction kinase inhibitors; dysfunction inducers, toxins such as cholera toxin, ricin, Pseudomonas exotoxin, pertussis adenylate cyclase toxin or diphtheria toxin and caspase activators, chromatin, alkylating agents such as thiotepa and cyclophosphamide (Cytoxan, Endoxan, Endoxan, Cyclostine), alkylsulfonates such as

- 75 041413 busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carbokwon, meturedopa and uredopa; ethyleneimines and methylamelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolomelamin; acetogenins (especially bullatacin and bullatacinone); camptothecin (including the synthetic analog of topotecan); bryostatin; callistatin; CC-1065 (including synthetic analogues of adoselesin, carzelesin and bizelesin); cryptophycins (articular cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including synthetic analogues, KW-2189 and CBI-TMI); eleutherobin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphasine, holofosfamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembihin, phenesterin, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as endiine antibiotics (e.g. calicheamycin, especially calicheamycin gamma-II and calicheamycin fi-II (see, e.g., Agnew, Chem. Intl. Ed. Engl, 33:183-186 (1994); dynemycin, including dynemycin A; bisphosphonates such as clodronate, esperamycin, as well as the neocarcinostatin-based chromophore and similar chromoprotein chromophores based on endiine antibiotics), aclacinomysins, actinomycin, autramycin, azaserine, bleomycins, sactinomycin, carabicin, carminomycin, carcinophilin, chromomycin, dactorubinomycin, daunocrunomycin , detorubicin, 6-diazo-5oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolin-doxorubicin, PEGylated liposomal doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marsellomycin, mitomycin C, such as mitomycins, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rhodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as demopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprin, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, dideoxyuridine, doxyfluridine, enocytabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; antiadrenals such as aminoglutethimide, mitotane, trilostane; folic acid compensator such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraksat; defofamine; demecolcin; diaziquon; elfornitin; elliptinium acetate; epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; leucovorin; lonidamine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pyrarubicin; losoxantrone; fluoropyrimidine; folinic acid; podophyllic acid; 2-ethylhydrazide; procarbazine; PSK®; razoxane; rhizoxin; sisofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2''-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anhidine); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; hacytosine; arabinoside (Ara-C); cyclophosphamide; thiotepa; taxoids, paclitaxel (taxol) and docetaxel (taxotere); chlorambucil; gemcitabine (Gemzar); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; platinum; ifosfamide; mitoxantrone; vincristine; vinorelbine (Navelbine); novantron; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; SRT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFAO); retinoids such as retinoic acid; capecitabine and FOLFIRI (fluorouracil, leucovorin and irinotecan);

(2) anti-hormonal agents selected from the group consisting of the following:

antiestrogen and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including Nolvadex), raloxifene, droloxifene, 4-hydroxy tamoxifen, trioxifene, keoxifene, LY117018, onapriston, and toremifene; inhibitors of the aromatase enzyme, which regulates the formation of estrogens in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, megestrol acetate, exemestane, formestane, fadrozole, vorozol, letrozole and anastrozole and antiandrogens, such as flutamide, nilutamide, bicalutamide, leuprolide and goserelin;

(3) anti-angiogenic agents selected from the group consisting of the following:

retinoic acid and its derivatives, 2-methoxyestradiol, angiostatin, endostatin, suramin, squalamine, tissue metalloproteinase-1 inhibitors, tissue metalloproteinase-2 inhibitors, plasminogen activator-1 inhibitor, plasminogen activator-2 inhibitor, cartilage inhibitor, paclitaxel (nab-paclitaxel ), platelet factor 4, protamine sulfate (lupein), sulfated chitin derivatives (derived from king crab shells), sulfated peptidoglycan polysaccharide complex (sp-pg), staurosporine, modulators of matrix metabolism, including, for example, proline analogs ((1-azetidine- 2-carboxylic acid (LACA), cidroxyproline, d,I-3,4-dehydroproline, thiaproline, alpha-dipyridyl, beta-aminopropionitrile fumarate, 4-propyl-5-(4-pyridinyl)-2(3b)oxazolone, methotrexate, mitoxantrone, heparin, interferons, serum 2 macroglobulin, chemp-3, chymostatin, beta-cyclodextrintetradecasulfate, epineomycin, fumagillin, sodium gold thiomalate, d-penicillamine (CDPT), serum beta-1-antic allagenase, alpha-2-antiplasmin, bisanthen, disodium lobenzarite, disodium N-2-carboxyphenyl-4-chloroanthronilic acid or CCA, thalidomide; angiostatic steroid, carbohexinaminolimidazole; metalloproteinase inhibitors such as BB94,

- 76 041413 antibodies, preferably monoclonal antibodies to the indicated angiogenic growth factors: betaFGF, alpha-FGF, FGF-5, VEGF isoforms, VEGF-C, HGF/SF, Ang-1/Ang-2 and compounds described in

Ferrara N. and Alitalo, K. Clinical application of angiogenic growth factors and their inhibitors (1999) Nature

Medicine 5:1359-1364;

(4) antifibrotic agents selected from the group consisting of the following: beta-aminopropionitrile (BAPN), primary amines that react with the carbonyl group of the active site of lysyl oxidases, and in particular which, after binding to the carbonyl, produce a resonance-stabilized product such as the following primary amines : ethylenediamine, hydrazine, phenylhydrazine and their derivatives, semicarbazide and urea derivatives, aminonitriles such as beta-aminopropionitrile (BAPN) or 2-nitroethylamine, unsaturated or saturated haloamines such as 2-bromoethylamine, 2-chloroethylamine, 2-trifluoroethylamine, 3-bromopropylamine , phalogenbenzylamines, selenohomocysteine lactone, copper chelating agents, indirect inhibitors such as compounds that block aldehyde derivatives resulting from the oxidative deamination of lysine and hydroxylysyl residues by lysyl oxidases, such as thiolamines, in particular D-penicillamine or its analogues, such as 2-amino- 5-mercapto-5-methylhexanoic acid a, D-2-amino-3-methyl-3-((2-acetamidoethyl)dithio)butanoic acid, p-2-amino-3-methyl-3-((2-aminoethyl)dithio)butanoic acid, 4- ((p-1-dimethyl-2-amino-2-carboxyethyl)dithio)sodium butanesulfinate, 2-acetamidoethyl-2-acetamidoethanethiolsulfonate, sodium 4-mercaptobutanesulfinate trihydrate disclosed in US Patent No. 4,965,288, US Patent No. 4,997,854, US Patent No. 4,943,593, US Patent No. 5,021,456; US patent No. 55059714; US patent No. 5120764; US Pat. No. 5,182,297; US Pat. No. 5,252,608 and US Patent Application No. 2004/0248871;

(5) therapeutic antibodies selected from the group consisting of the following: abagovomab, adecatumumab, afutuzumab, alemtuzumab, altumomab, amatuximab, anatumomab, arcitumomab, bavituximab, bektumomab, bevacizumab, bivatuzumab, blinatumomab, brentuximab, cantuzumab, catumaxumab, cetuzumab, citutuzumab циксутумумаб, кливатузумаб, конатумумаб, даратумумаб, дрозитумаб, дулиготумаб, дусигитумаб, детумомаб, дацетузумаб, далотузумаб, экромексимаб, элотузумаб, энситуксимаб, эртумаксомаб, этарацизумаб, фарлетузумаб, фиклатузумаб, фигитумумаб, фланвотумаб, футуксимаб, ганитумаб, гемтузумаб, гирентуксимаб, глембатумумаб, ибритумомаб, иговомаб, имгатузумаб, индатуксимаб, инотузумаб, интетумумаб, ипилимумаб, иратумумаб, лабетузумаб, лексатумумаб, линтузумаб, лорвотузумаб, лукатумумаб, мапатумумаб, матузумаб, милатузумаб, минретумомаб, митумомаб, моксетумомаб, нарнатумомаб, наптумомаб, нецитумумаб, нимотузумаб, нофетумомаб, оцаратузумаб офатумумаб, оларатумаб , onartuzumab, oportuzumab, oregoma б, панитумумаб, парсатузумаб, патритумаб, пемтумомаб, пертузумаб, пинтумомаб, притумумаб, ракотумомаб, радретумаб, рилотумумаб, ритуксимаб, робатумумаб, сатумомаб, сибротузумаб, силтуксимаб, симтузумаб, солитомаб, такатузумаб, таплитумомаб, тенатумомаб, тепротумомаб, тигатузумаб, тозитумомаб, трастузумаб, tucotuzumab, ublituximab, veltuzumab, vorsetuzumab, votumumab, zalutumumab, alemtuzumab, veltuzumab, apolizumab, bevacizumab, epratuzumab, tositumumab, galiximab, ibritumomab, lumiliximab, milatuzumab, obinutuzumab, ofatumumab, CC49, and where 3F or antibodies can be combined a radioisotope particle such as indium In 111, yttrium Y 90, iodine I-131;

(6) JAK inhibitors selected from the group consisting of: ruxolitinib, fedratinib, tofacitinib, baricitinib, lestaurtinib, pacritinib, momelotinib, XL019, AZD1480, INCB039110, LY2784544, BMS911543 and NS018;

(7) Hedgehog inhibitors selected from the group consisting of: saridegib;

(8) histone deacetylase (HDAC) inhibitors selected from the group consisting of: pracinostat, romidepsin, vorinostat and panobinostat;

(9) tyrosine kinase inhibitors selected from the group consisting of lestaurtinib, gefinitib, erlotinib, and sunitinib;

(10) Discoidin domain receptor (DDR) inhibitors selected from the group consisting of: inhibitors described in US 2009/0142345, US 2011/0287011, WO 2013/027802, WO 2013/034933 and US Provisional Application No. 61/ 705044;

(11) MMP9 inhibitors selected from the group consisting of: marimastat (BB-2516), cypemastat (Ro 32-3555) and inhibitors described in WO 2012/027721;

(12) LOXL inhibitors selected from the group consisting of: antibodies described in WO 2009/017833, antibodies described in WO 2009/017833, WO 2009/035791 and WO/2011/097513;

(13) ASK1 inhibitors selected from the group consisting of: compounds described in WO 2011/008709 and WO/2013/112741;

(14) PI3K inhibitors selected from the group consisting of: the compounds described in US Pat. No. 7,932,260, US Provisional Application No. 61/543,176; 61/581528; 61/745429; 61/745437; and 61/835333, PI3K II, TGR-1202, AMG-319, GSK2269557, X-339, X-414, RP5090, KAR4141, XL499, OXY111A, duvelisiba, IPI-443, GSK2636771, BAY 10824391, RGTGX-226, , CUDC-907, PQR-309, DS-7423, panulisib, AZD-8186, CLR-457, pictilisiba, neratinib, rigosertiba, rigosertiba sodium, EN-3342, uCb-5857, tazeliciba, INCB-040093, pilaralisiba, BAY- 1082439, puquitinib mesi-

- 77 041413 lats, XL-765, gedatolisib, VS-5584, copanlisib, CAI orotata, alpelisib, buparlisib, BAY 80-6946,

BYL719, RX-866, RG7604, MLN1117, WX-037, AEZS-129, PA799, ZSTK474, RP-6530, AS252424,

LY294002, TG100115, LY294002, BEZ235, XL147 (SAR245408), SAR-245409, GDC-0941, VKM120,

CH5132799, XL756, MLN-1117, SF-1126, RV-1729, sonolisib, GDC-0980, CLR-1401, perifosin, and wortmannin;

(15) BTK inhibitors selected from the group consisting of: ibrutinib, HM71224, ONO-4059 and CC-292;

(16) SYK inhibitors selected from the group consisting of: tamatinib (R406), fostamatinib (R788), PRT062607, BAY-61-3606, NVP-QAB 205 AA, R112, R343, and compounds described in US Pat. No. 8,450,321;

(17) mTOR inhibitors selected from the group consisting of: temsirolimus, everolimus, ridaforolimus, deforolimus, OSI-027, AZD2014, CC-223, RAD001, LY294002, BEZ235, rapamycin, Ku0063794 and PP242;

(18) AKT inhibitors selected from the group consisting of: perifosin, MK-2206, GDC-0068 and GSK795;

(19) MEK inhibitors selected from the group consisting of: trametinib, selumetinib, cobimetinib, MEK162, PD-325901, PD-035901, AZD6244 and CI-1040;

(20) CDK inhibitors selected from the group consisting of: AT-7519, alvocidib, palbociclib and SNS-032;

(21) JNK inhibitors selected from the group consisting of: CC-401;

(22) MAPK inhibitors selected from the group consisting of: VX-702, SB203580 and SB202190;

(23) Raf inhibitors selected from the group consisting of: PLX4720;

(24) ROCK inhibitors selected from the group consisting of: Rho-15;

(25) Tie2 inhibitors selected from the group consisting of: AMG-Tie2-1;

(26) myo-inositol signaling inhibitors such as phospholipase C blockers and myoinositol analogs described in Powis, G., and Kozikowski A., (1994) New Molecular Targets for Cancer Chemotherapy ed., Paul Workman and David Kerr, CRC press 1994, London;

(27) Bcl-2 family protein inhibitors selected from the group consisting of: ABT-263, ABT-199 and ABT-737;

(28) IKK inhibitors selected from the group consisting of: BMS-345541;

(29) proteasome inhibitors selected from the group consisting of: bortezomib;

(30) protein kinase C (PKC) inhibitors selected from the group consisting of: bryostatin 1 and enzastaurin;

(31) HSP90 heat shock protein inhibitors selected from the group consisting of: Geldanamycin;

(32) combination medicines selected from the group consisting of: FR (fludarabine, rituximab), FCR (fludarabine, cyclophosphamide, rituximab), R-CHOP (rituximab plus CHOP), R-CVP (rituximab plus CVP), R- FCM (rituximab plus FCM), R-ICE (rituximab-ICE), CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), CVP (cyclophosphamide, vincristine and prednisone), FCM (fludarabine, cyclophosphamide, mitoxantrone), hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine), ICE (ifosfamide, carboplatin and etoposide), MCP (mitoxantrone, chlorambucil and prednisolone) and R MCP (R MCP); and (33) other cancer drugs selected from the group consisting of the following: aldesleukin, alvocidib, CHIR-12.12, ha20, tiuxetan, PRO131921, SGN-40, WT-1 analog peptide vaccine, WT1 peptide vaccine 126-134 , autologous human tumor derived HSPPC-96, GTOP-99 (MyVax®), antineoplaston AS2-1, antineoplaston A10, antithymocyte globulin, beta-alethine, arsenic trioxide, amifostine, aminocamptothecin, lenalidomide, casfofungin, clofarabine, ixabepilone, cladribine, chlorambucil, curcumin, vinorelbine, tipifarnib, tanespimycin, sildenafil citrate, denileukin diftitox, simvastatin, epoetin alfa, fenretinide, filgrastim, mesna, mitoxantrone, lenalidomide, fludarabine, mycophenolate mofetil, nelarabine, octreotide, oxaliplatin, pegfilgrastim, recombinant2 interleukin-11, recombinant flt3 ligand, recombinant human thrombopoietin, sargramostim, lymphokine-activated killer cells, omega-3 fatty acids, recombinant and interferon alfa, therapeutic allogeneic lymphocytes and cyclosporine analogues.

In a specific embodiment, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four, or more additional therapeutic agents selected from the following: ibrutinib, aldesleukin, alvocidib, antineoplaston AS2-1, antineoplaston A10, antithymocyte globulin, amifostine trihydrate, aminoscamptothecin, arsenic trioxide, beta-alethine, ABT-263, ABT-199, ABT-737, BMS-345541, bortezomib, bryostatin 1, busulfan, carboplatin, campat-1H, CC-5103, carmustine, caspofungin acetate, clofarabine , cisplatin, cladribine (Leustarin), chlorambucil (leukeran), curcumin, cyclosporine, cyclophosphamide (Cycloxan, Endoxan, Endoxan, Cyclostine), denileukine diftitox, dexamethasone, DT

- 78 041413

PACE, docetaxel, dolastatin 10, doxorubicin (Adriamycin®, Adriblastine), doxorubicin hydrochloride, enzastaurin, epoetin alfa, etoposide, everolimus (RAD001), fenretinide, filgrastim, melphalan, mesna, flavopiridol, fludarabine (Fludara), geldanamycin (17 AAG) , ifosfamide, irinotecan hydrochloride, ixabepilone, lenalidomide (Revlimid®), lymphokine-activated killer cells, melphalan, methotrexate, mitoxantrone hydrochloride, gadolinium motexafine, mycophenolate mofetil, nelarabine, Obatoclax oblimersen, oblimersen, octreotide acetate, omega-3 fatty acids, oxaliplatin , paclitaxel, PD0332991, PEGylated liposomal doxorubicin hydrochloride, pegfilgrastim, pentstatin (Nipent), perifosin, prednisolone, prednisone, selicilib, recombinant interferon alfa, recombinant interleukin-12, recombinant interleukin-11, recombinant flt3 ligand, recombinant thrombogrampoietin, human, ritmogrampoietin , sildenafil citrate, simvastatin, sirolimus, styryl sulfones, tacrolimus, ta nespimycin, temsirolimus, thalidomide, therapeutic allogeneic lymphocytes, thiotepa, tipifarnib, vincristine, vincristine sulfate, vinorelbine ditartrate, vorinostat (SAHA), vorinostat, FR (fludarabine, rituximab), CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), CVP (cyclophosphamide) , vincristine and prednisone), FCM (fludarabine, cyclophosphamide, mitoxantrone), FCR (fludarabine, cyclophosphamide, rituximab), hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine), ICE (ifosfamide, carboplatin and etoposide), MCP (mitoxantrone, chlorambucil and prednisolone), RCHOP (rituximab plus CHOP), R-CVP (rituximab plus CVP), R-FCM (rituximab plus FCM), RICE (rituximab-ICE), and R MCP (R MCP).

Any of the proposed methods of treatment can be used to treat cancer at different stages. For example, the stage of cancer includes, but is not limited to, early, advanced, locally advanced, remission, refractory, re-remission, and progressive.

In addition, the subject may be a human who is undergoing one or more conventional therapies such as chemotherapy, radiation therapy, immunotherapy, surgery, or a combination thereof. Accordingly, one or more anti-cancer agents may be administered before, during, or after the administration of chemotherapy, radiation therapy, immunotherapy, surgery, or a combination thereof.

Therapeutic treatment may be supplemented or combined with any of the aforementioned stem cell transplant or treatment therapies. One example of a modified approach is radioimmunotherapy, in which a monoclonal antibody is combined with a radioisotope particle such as indium In 111, yttrium Y 90, iodine I-131. Examples of combination therapy include, but are not limited to, iodine-131 tositumomab (Bexxar®), yttrium-90 ibritumomab tiuxetan (Zevalin®), Bexxar® with CHOP.

Other therapeutic procedures include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biological therapy, enzyme inhibitor therapy, total body irradiation, stem cell infusion, bone marrow ablation with stem cell support, stem cell transplantation in vitro treated peripheral blood, cord blood transplantation, enzyme immunoassay, pharmacological testing, low LET cobalt-60 gamma therapy, bleomycin, conventional surgery, radiotherapy, and non-myeloablative allogeneic hematopoietic stem cell transplantation.

Also provided herein is a compound of the present disclosure (eg, a compound of formula (I)) or a pharmaceutically acceptable salt thereof, and one or more additional cancer therapeutic agents, for use in a method of treating cancer.

Also provided herein is a compound of the present disclosure (e.g., a compound of formula (I)) or a pharmaceutically acceptable salt thereof, for use in a method of treating cancer, wherein said compound or a pharmaceutically acceptable salt thereof is administered simultaneously, separately, or sequentially with one or more additional therapeutic agents for the treatment of cancer.

Sets

Provided herein is a kit containing a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. The kit may further contain instructions for use, eg, for use to modulate a toll-like receptor (eg, TLR8), eg, for use in the treatment of a disease, disorder, or condition. In some embodiments, the kit is for the treatment of HIV, HBV, or HCV infection. In some embodiments, the kit is for the treatment of HBV infection. Instructions for use are typically written instructions, although electronic media (eg, magnetic diskette or optical disk) containing instructions are also acceptable.

The present disclosure also provides a pharmaceutical kit containing one or more containers containing a compound of the present disclosure or a pharmaceutically acceptable salt thereof. Optionally associated with such container(s) may be a notification in

- 79 041413 the form prescribed by a government agency that regulates the manufacture, use or sale of pharmaceuticals, reflecting the approval of the said agency for the manufacture, use or sale for administration to humans. Each component (if there is more than one component) may be packaged in separate containers, or some components may be combined into one container where cross-reactivity and shelf life are allowed. Kits may be in unit dosage forms, multi-dose packs (eg, multi-dose packs), or sub-unit doses. Kits may also include multiple unit doses of the compounds and instructions for use, and be packaged in quantities sufficient for storage and use in pharmacies (eg, hospital pharmacies and industrial pharmacies).

Getting connections

Also provided are articles containing a unit dose of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, in suitable packaging 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 product can be further sterilized and/or sealed.

Embodiments also relate to methods and intermediates suitable for the preparation of said compounds or their pharmaceutically acceptable salts.

Many general references are available containing 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 using any of the methods 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 phase may be used, including normal and reversed phases, as well as ionic resins. Most typically, the compounds described are purified by silica gel and/or alumina chromatography. See, for example, Introduction to Modern Liquid Chromatography, 2nd ed., ed. L. R. Snyder and J. J. Kirkland, John Wiley and Sons, 1979; and Thin Layer Chromatography, E. Stahl (ed.), Springer-Verlag, New York, 1969.

During any of the processes for the preparation of these compounds, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the respective molecules. This can be achieved with traditional protecting groups as described in standard works such as T. W. Greene and PGM Wuts, Protective Groups in Organic Synthesis, ^4th ed., Wiley, New York 2006. The protecting groups can be removed at convenient subsequent step using methods known in the art.

Examples

Exemplary chemical compounds suitable for the methods of the embodiments will be described with reference to illustrative synthetic schemes for general preparation herein and the following specific examples. Those skilled in the art will appreciate that for the preparation of the various compounds described herein, the starting materials may be appropriately selected such that the desired substituents will eventually pass through the reaction scheme with or without protection as necessary to obtain the desired product. Alternatively, it may be necessary or desirable to use, in place of the final desired substituent, a suitable group that can be carried through the reaction scheme and replaced as appropriate by the desired substituent. In addition, one of skill in the art will appreciate that the transformations shown in the schemes below may be performed in any order that is compatible with the functionality of the particular side groups. Each of the reactions depicted in the General schemes, preferably carried out at a temperature of from about 0°C to the boiling point of the organic solvent used. Unless otherwise indicated, the variables are defined above with reference to formulas (I) or (J).

Typical syntheses of compounds according to the present description are given below in the schemes, followed by a description of specific examples.

Scheme 1 shows a typical synthesis of compounds according to embodiments. The methodology is compatible with a wide range of functional groups.

- 80 041413

In Scheme 1, compounds of formula A1 (wherein R ¹ , R ² and R ³ are as defined herein or are suitably protected derivatives of R ¹ , R ² and R ³ ) are converted to the corresponding 4-amino, 2-chloroheterocycle by reaction with a nucleophilic amine in the presence of a suitable base (such as DIPEA) at room temperature. The compound of formula A2 is then treated with 2,4-dimethoxybenzylamine at elevated temperature to give 2,4-diaminopyrimidine of formula A3. In cases where R ¹ , R ² and R ³ are a diversifiable chemical group such as Cl or Br, further substitution of R ¹ , R ² and R ³ is carried out in various ways, including cyanidation, nucleophilic aromatic substitution and cross-coupling reactions catalyzed metal, such a combination of Suzuki, to obtain products of formula A4. Treatment with a suitable acid (eg trifluoroacetic acid) results in certain compounds of formula (I) or (J). Where appropriate, other leaving groups may be used in place of the Cl group(s) in Al.

Scheme 2 shows the general route that is used to prepare some of the compounds of formula (I) or (J).

The 2,4-dichloropyripyrimidines of formula A1 (wherein R ¹ , R ² and R ³ are as defined herein or are suitably protected derivatives of R ¹ , R ² and R ³ ) are converted to the corresponding 4-amino, 2- chlorheterocycle by reacting with an amino acid ester (such as L-norvaline methyl ester) in the presence of a suitable base (such as DIPEA) at room temperature to give a compound of formula B1 wherein G is the amino acid side chain. The compound of formula B1 is then treated with 2,4-dimethoxybenzylamine in a microwave reactor at a suitable temperature (eg, about 135° C.) to give 2,4-diaminopyrimidine of formula B2. Hydrolysis of the ester group by treatment with sub-

- 81 041413 a walking base (such as aqueous KOH/THF) results in a product of formula B3, where Z is hydroxyl. Additional reaction of the resulting carboxylic acid leads to the modification of Z through the formation of a HATU-promoted amide with various amines. Removal of the protecting group with a suitable acid (eg trifluoroacetic acid) at room temperature then leads to certain compounds of formula (J) or (I).

Scheme 3 shows a typical synthesis of compounds according to embodiments. Methodology

are suitably protected derivatives of R ¹ , R ² and R ³ and Z ¹ is NH ² or O-alkyl) are converted to a compound of formula C2 under suitable reaction conditions. For example, a compound of formula C1 is contacted with chloroformamidine hydrochloride under suitable conditions to give C2. The hydroxyl group can be further modified, for example by introducing any suitable leaving group, such as a tosyl group, prior to contacting R4-NH2. Alternatively, R4-NH2 can be directly coupled to C2 in the presence of a suitable coupling agent, such as a BOP reagent, under suitable conditions.

Additionally, a compound of formula A1 (wherein R ¹ , R ² and R ³ are as defined herein or are suitably protected derivatives of R ¹ , R ² and R ³ ) can be prepared as described in the scheme below. It should be understood that A1 can be further modified to obtain compounds of formula (I), as described more fully herein.

As described above, C1 is contacted with a suitable agent such as triphosgene and dioxane to give compound D1. Compound D1 may be further halogenated under suitable conditions, such as treatment with POCl ₃ and PCl5, to give a compound of formula A1.

In some instances, the above methods further include the step of forming a salt of a compound of the present disclosure. Embodiments refer to other methods described herein; and to a product obtained by any of the methods described herein.

Unless otherwise indicated, the methods and techniques of the present embodiments are generally performed in accordance with conventional methods well known in the art and described in the various general and specific references cited and discussed herein. See, for example, Loudon, Organic Chemistry, ^5th edition, New York: Oxford University Press, 2009; Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, ^7th edition, WileyInterscience, 2013.

The examples provided herein describe the synthesis of the compounds described herein as well as the intermediates used to prepare the compounds. It should be understood that the individual steps described herein may be combined. It should also be understood that individual batches of a compound may be pooled and then carried on to the next step in the synthesis.

In the following description of examples, specific embodiments are described. These embodiments are described in sufficient detail to enable those skilled in the art to make certain embodiments of the present disclosure. Other implementations may be used and logical and other changes may be made without departing from the scope of the disclosure. Accordingly, the following description is not intended to limit the scope of the present disclosure.

The methods of the present invention generally provide a particular enantiomer or diastereomer as the desired product, although the stereochemistry of the enantiomer or diastereomer is not

- 82 041413 is determined in all cases. When the stereochemistry of a particular stereocenter in an enantiomer or diastereomer is not defined, the compound is shown without depicting the stereochemistry at that particular stereocenter, even though the compound may be substantially enantiomerically or desatheromericly pure.

Example 1

Synthesis of N ⁴ -butyl-N ² -(2,4-dimethoxybenzyl)pyrido[3,2-d]pyrimidine-2,4-diamine (1A). Butane-1- amine (0.03 ml, 0.28 mmol) and N,N-diisopropylethylamine (0.13 ml, 0.75 mmol). After stirring at room temperature for 30 minutes, 2,4-dimethoxybenzylamine (0.19 ml, 1.25 mmol) and N,N-diisopropylethylamine (0.13 ml, 0.75 mmol) were added and the mixture was heated to 100°C. After 16 h the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried over Na ₂ SO ₄ and concentrated in vacuo. Product (1A) was obtained after flash chromatography. MS (m/z): 368.14 [M+H]+.

Synthesis of N ⁴ -butylpyrido[3,2-d]pyrimidine-2,4-diamineα (1B): 1B was dissolved in trifluoroacetic acid (3 ml). After 30 minutes the reaction mixture was diluted with water and methanol. After 60 minutes the mixture was concentrated in vacuo. The residue was then co-evaporated with methanol three times and filtered through methanol to give the title product 1B as the trifluoroacetic acid salt.

1H NMR (400 MHz, methanol-d4) δ 8.59 (dd, J=4.4, 1.4 Hz, 1H), 7.82 (dd, J=8.5, 1.4 Hz, 1H) , 7.72 (dd, J=8.5, 4.4 Hz, 1H), 3.66 (t, J=7.3 Hz, 2H), 1.78-1.62 (m, 2H), 1.43 (dq, J=14.7, 7.4 Hz, 2H), 0.98 (t, J=7.4 Hz, 3H). MS (m/z): 218.10 [M+H]+.

¹⁹ F NMR (377 MHz, methanol-d4) δ -77.6.

Example 2

'2

2B

Synthesis of N ² -(2,4-dimethoxybenzyl)-N ⁴ -(pentan-2-yl)pyrido[3,2-d]pyrimidin-2,4-diαmine (2A): 2A was synthesized according to the procedure described above to obtain 1A, replacing butane-1-amine with 2-aminopentane. MS (m/z) 382.17 [M+H]+.

Synthesis of N ⁴ -(pentan-2-yl)pyrido[3,2-d]pyrimidine-2,4-diamine (2B): 2B was prepared according to the procedure described for 1B to give the title compound (2B) in the form of TFA salt.

1H NMR (400 MHz, methanol-d4) δ 8.61 (dd, J=4.4, 1.4 Hz, 1H), 7.84 (dd, J=8.5, 1.4 Hz, 1H) , 7.74 (dd, J=8.5, 4.4 Hz, 1H), 4.60-4.46 (m, 1H), 1.74 (dtd, J=13.5, 8.3, 6.7 Hz, 1H), 1.68-1.55 (m, 1H), 1.44 (d, J=7.4 Hz, 2H), 1.32 (d, J=6.6 Hz, 3H), 0.95 (t, J=7.4 Hz, 3H). MS (m/z) 232.11 [M+H]+.

¹⁹ F NMR (377 MHz, methanol-d4) δ -77.5.

Example 3

Synthesis of (S)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-4 methylpentan-1-ol (3A): 3A was synthesized in accordance with the procedure above for 1A, replacing butane-1amine with (S)-(+)-leucinol. MS (m/z) 412.19 [M+H]+.

Synthesis of (S)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-4-methylpentan-1-ol (3B): 3B was synthesized using the procedure described above for preparation of 1B , to give the title compound (3B) as a TFA salt.

¹ H NMR (400 MHz, methanol-ide) δ 8.62 (dd, J=4.4, 1.3 Hz, 1H), 7.84 (dd, J=8.5, 1.4 Hz, 1H ), 7.74 (dd, J=8.5, 4.4 Hz, 1H), 4.74-4.58 (m, 1H), 3.71 (h, J=6.2 Hz, 2H) , 1.76-1.58 (m, 2H), 1.52 (tq, J=10.6, 3.5 Hz, 1H), 0.98 (t, J=6.4 Hz, 6H). MS (m/z) 262.15 [M+H]+.

- 83 041413 ¹⁹ F NMR (377 MHz, methanol^) δ -77.6.

Example 4

Synthesis

(S)-3-cyclopropyl-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4 yl)amino)propan-1-ol (4A): 4A was obtained using the procedure described above for preparation of 1A, replacing butan-1-amine with the HCl salt of (2S)-2-amino-3-cyclonpropylpron-1-ol. MS (m/z) 410.20 [M+H]+.

Synthesis of (S)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-3-cyclopropylpropan-1-ol (4B): 4B was synthesized according to the procedure described above for 1B , to give the title compound (4B) as a TFA salt.

1H NMR (400 MHz, methanol-d ₄ ) δ 8.62 (dd, J=4.4, 1.3 Hz, 1H), 7.85 (dd, J=8.5, 1.4 Hz, 1H ), 7.75 (dd, J=8.5, 4.4Hz, 1H), 4.63 (dq, J=7.3, 5.5Hz, 1H), 3.81 (d, J= 5.2 Hz, 2H), 1.65 (h, J=7.1 Hz, 2H), 0.78 (dddd, J=15.0, 10.1, 5.1, 2.1 Hz, 1H ), 0.45 (dddd, J=11.1, 9.4, 7.9, 4.6 Hz, 2H), 0.19-0.07 (m, 2H). MS (m/z) 260.15 [M+H] ⁺ .

¹⁹ F NMR (377 MHz, methanol-d ₄ ) δ -77.6

Example 5

Synthesis of (S)-methyl-2-((2-((2,4-dimethoxybenzyl)amino)n-irido[3,2-d]n-pyrimidin-4-yl)amino)pentanoate (5A): 5A was obtained in accordance with the general by the procedure described above for 1A, replacing butane-1amine with (S)-methyl-2-aminopentanoate. MS (m/z) 426.19 [M+H] ⁺ .

Synthesis of (S)-methyl-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)pentanoate (5B): 5B was prepared according to the procedure described above for 1B to give the indicated in the title compound (5B) as a TFA salt.

1 H NMR (400 MHz, methanol-d ₄ ) δ 8.66 (dd, J=4.4, 1.4 Hz, 1H), 7.88 (dd, J=8.5, 1.4 Hz, 1H ), 7.79 (dd, J=8.5, 4.4Hz, 1H), 5.02 (dd, J=8.7, 5.3Hz, 1H), 3.78 (s, 3H) , 2.13-1.92 (m, 2H), 1.56-1.39 (m, 2H), 0.99 (t, J=7.4 Hz, 3H). MS (m/z) 276.13 [M+H] ⁺ .

¹⁹ F NMR (377 MHz, methanol-d ₄ ) δ -77.8.

Example 6

Synthesis of (S)-2-((8-chloro-2-((2,4-dimethoxybenzyl)amino)-6-methylpyrido[3,2-d]pyrimidin-4yl)amino)pentan-1-ol (6A) : 6A was prepared according to the procedure described above for 1A, replacing butane-1-amine with (S)-methyl-2-aminopentanoate and starting with 2,4,8-trichloro-6-methylpyrido[3,2d]pyrimidine instead of 2,4-dichloropyrido[3,2-d]-pyrimidine. MS (m/z) 446.20 [M+H] ⁺ .

Synthesis of (S)-2-((2-amino-8-chloro-6-methylpyrido[3,2-d]pyrimidin-4-yl)amino)pentan-1-ol (6B): 6B was obtained according to the procedure described above for 1B to give the title compound (6B) as a TFA salt.

1H NMR (400 MHz, methanol^) δ 7.84 (s, 1H), 4.55 (ddd, J=12.6, 7.2, 5.2 Hz, 1H), 3.75 (d, J =5.3 Hz, 3H), 1.79-1.67 (m, 3H), 1.51-1.35 (m, 3H), 0.98 (t, J=7.4 Hz, 4H) . MS (m/z) 296.18 [M+H] ⁺ .

¹⁹ F NMR (377 MHz, methanol-d ₄ ) δ -77.6.

- 84 041413

Example 7

Compound 7, (S)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-2-phenylethanol, was prepared according to the procedure for compound 1B above, replacing butane-1- amine on (S)-2-amino-2-phenylethanol to give the title compound (7) as a TFA salt.

1H NMR (400 MHz, methanol-d4) δ 8.68 (dd, J=4.3, 1.5 Hz, 1H), 7.84 (dd, J=8.5, 1.5 Hz, 1H) , 7.77 (dd, J=8.5, 4.4 Hz, 1H), 7.49-7.43 (m, 2H), 7.38-7.31 (m, 2H), 7.31 -7.24 (m, 1H), 5.57 (dd, J=7.4, 4.8 Hz, 1H), 4.123.93 (m, 2H).

¹⁹ F NMR (376 MHz, methanol-^) δ -77.7. MS (m/z) 282.1 [M+H]+.

Example 8

Compound 8, (R)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)pentan-1-ol, was prepared according to the procedure for the synthesis of compound 1B described above, replacing butan- 1-amine on (R)-2aminopentan-1-ol to give the title compound (8) as a TFA salt.

1H NMR (400 MHz, methanol^) δ 8.64 (dd, J=4.4, 1.4 Hz, 1H), 7.83 (dd, J=8.5, 1.5 Hz, 1H), 7.76 (dd, J=8.5, 4.4 Hz, 1H), 4.55 (dq, J=7.4, 5.4 Hz, 1H), 3.78-3.69 (m, 2H), 1.77-1.65 (m, 2H), 1.52-1.36 (m, 2H), 0.98 (t, J=7.3 Hz, 3H).

¹⁹ F NMR (376 MHz, methanol-d4) δ -77.56. MS (m/z) 248.1 [M+H]+.

Example 9

Compound 9, (2S,3S)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-3-methylpentan-1-ol, was prepared according to the procedure for compound 1B described above, replacing butan-1-amine with (2S,3S)-2-amino-3-methylpentan-1-ol to give the title compound (9) as a TFA salt.

1H NMR (400 MHz, methanol-d4) δ 8.64 (dd, J=4.4, 1.4 Hz, 1H), 7.84 (dd, J=8.5, 1.4 Hz, 1H) , 7.76 (dd, J=8.5, 4.4Hz, 1H), 4.39 (dt, J=8.1, 5.0Hz, 1H), 3.83 (d, J=5 .0 Hz, 2H), 1.97-1.82 (m, 1H), 1.58 (dddd, J=16.8, 11.2, 7.6, 3.8 Hz, 1H), 1, 33-1.16 (m, 2H), 1.03 (d, J=6.8 Hz, 3H), 0.94 (t, J=7.4 Hz, 3H).

¹⁹ F NMR (376 MHz, methanol-d4) δ -77.71. MS (m/z) 262.1 [M+H]+.

Example 10

Compound 10, (S)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-4-(methylthio)butan-1-ol, was prepared according to Step 2 of the compound procedure 1B above, replacing butan-1amine with (S)-2-amino-4-(methylthio)butan-1-ol to give the title compound (10) as a TFA salt.

1H NMR (400 MHz, methanol-d4) δ 8.64 (dd, J=4.4, 1.4 Hz, 1H), 7.83 (dd, J=8.5, 1.4 Hz, 1H) , 7.76 (dd, J=8.5, 4.4Hz, 1H), 4.66 (dq, J=8.1, 5.4Hz, 1H), 3.76 (d, J=5 .3 Hz, 2H), 2.65-2.52 (m, 2H), 2.11-1.98 (m, 5H).

¹⁹ F NMR (376 MHz, methanol-d ₄ ) δ -77.63. MS (m/z) 280.1 [M+H]+.

- 85 041413

Example 11

Compound 11, N ⁴ -pentylpyrido[3,2-d]pyrimidine-2,4-diamine, was prepared according to the procedure for compound 1B above, replacing butan-1-amine with n-pentylamine, to give the title compound (11) in the form of TFA salt.

1H NMR (400 MHz, methanol-d4) δ 8.62 (dd, J=4.4, 1.4 Hz, 1H), 7.81 (dd, J=8.5, 1.4 Hz, 1H) , 7.74 (dd, J=8.5, 4.4 Hz, 1H), 3.67 (dd, J=7.8, 6.8 Hz, 2H), 1.80-1.66 (m , 2H), 1.49-1.32 (m, 4H), 0.99-0.85 (m, 3H).

¹⁹ F NMR (376 MHz, methanol-d4) δ -77.58. MS (m/z) 232.1 [M+H]+.

Example 12

Compound 12, 2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)ethanol, was prepared according to the procedure for compound 1B above, replacing butan-1-amine with ethanolamine, to give the title compound (12) as a TFA salt.

¹ H NMR (400 MHz, methanol^) δ 8.64 (dd, J=4.3, 1.5 Hz, 1H), 7.88-7.72 (m, 2H), 3.82 (d, J=2.3Hz, 4H).

¹⁹ F NMR (376 MHz, methanol-d ₄ ) δ -77.58. MS (m/z) 206.0 [M+H]+.

Example 13

Compound 13, 3-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)propan-1-ol, was prepared according to Step 2 of the procedure for compound 1B above, replacing butan-1- amine to propanolamine to give the title compound (13) as a TFA salt.

1H NMR (400 MHz, methanol^) δ 8.62 (td, J=4.6, 1.4 Hz, 1H), 7.87-7.70 (m, 2H), 3.80 (dt, J =11.7, 6.8 Hz, 2H), 3.70 (t, J=6.0 Hz, 2H), 2.00-1.88 (m, 2H).

¹⁹ F NMR (376 MHz, methanol-d4) δ -77.58. MS (m/z) 220.1 [M+H]+.

Example 14

Compound 14, (S)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol, was prepared according to the procedure for compound 1B above, replacing butane- 1-amine on (S)-2aminohexan-1-ol to give the title compound (14) as a TFA salt.

1H NMR (400 MHz, methanol-d ₄ ) δ 8.63 (dd, J=4.4, 1.4 Hz, 1H), 7.84 (dd, J=8.5, 1.4 Hz, 1H ), 7.76 (dd, J=8.5, 4.4 Hz, 1H), 4.53 (dq, J=8.6, 5.4 Hz, 1H), 3.79-3.68 ( m, 2H), 1.87-1.61 (m, 2H), 1.52-1.31 (m, 4H), 1.010.85 (m, 3H).

¹⁹ F NMR (376 MHz, methanol-d4) δ -77.63. MS (m/z) 262.2 [M+H]+.

Example 15

Compound 15, (R)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol, was prepared according to the procedure for compound 1B above, replacing butane- 1-amine on (R)-2aminohexan-1-ol to give the title compound (15) as a TFA salt.

- 86 041413 ¹ H NMR (400 MHz, methanol^) δ 8.66-8.59 (m, 1H), 7.84 (dd, J=8.5, 1.4 Hz, 1H), 7.77 (td, J=8.8, 4.4 Hz,

1H), 4.59-4.42(m, 1H), 3.81-3.68(m, 2H), 1.90-1.65(m, 2H), 1.49-1.35( m, 4H), 1.03-0.82 (m, 3H).

¹⁹ F NMR (376 MHz, methanol-d4) δ -77.60. MS (m/z) 262.2 [M+H]+.

Example 16

Compound 16, N ⁴ -((tetrahydrofuran-2-yl)methyl)pyrido[3,2-d]pyrimidin-2,4-diamine, was prepared according to the procedure for compound 1B above, replacing butan-1-amine on (tetrahydrofuran-2-yl)methanamine to give the title compound (16) as a TFA salt.

¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.62 (dd, J=4.4, 1.4 Hz, 1H), 7.83 (dd, J=8.5, 1.4 Hz, 1H), 7.75 (dd, J=8.5, 4.4 Hz, 1H), 4.24 (qd, J=6.8, 4.8 Hz, 1H), 3.93 (dt, J =8.3, 6.5 Hz, 1H), 3.84-3.68 (m, 3H), 2.16-1.82 (m, 3H), 1.71 (ddt, J=11.6 , 8.0, 6.5 Hz, 1H).

¹⁹ F NMR (376 MHz, methanol^) δ -77.50. MS (m/z) 246.1 [M+H]+.

Example 17

Compound 17, 2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)propan-1,3-diol, was prepared according to the procedure for compound 1B above, replacing butane-1- amine on 2-aminopropane 1,3-diol to give the title compound (17) as a TFA salt.

1H NMR (400 MHz, methanol-d4) δ 8.64 (dd, J=4.4, 1.4 Hz, 1H), 7.85 (dd, J=8.5, 1.4 Hz, 1H) , 7.77 (dd, J=8.5, 4.4 Hz, 1H), 4.54 (p, J=5.5 Hz, 1H), 3.84 (d, J=5.5 Hz, 4H).

¹⁹ F NMR (376 MHz, methanol-d4) δ -77.66. MS (m/z) 236.1 [M+H]+.

Example 18

Synthesis of 3-amino-5-bromopicolinamide (18B). To a solution of 3-amino-5-bromopicolinic acid 18A (300 mg, 1.38 mmol, 1 eq) in DMF (11 ml, 0.1 M) was added HATU (598 mg, 1.57 mmol, 1.1 eq .) followed by the addition of DIPEA (0.48 ml, 2.76 mmol, 2 eq.) and ammonium hydroxide (0.8 ml, 5.55 mmol, 4 eq.). The mixture was left to stir overnight. Water (50 ml) was added and the mixture was then extracted with EtOAc (3 times). The organic layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Product (18B) was obtained after flash chromatography. MS (m/z): 216.8 [M+H]+.

Synthesis of 2-amino-7-bromopyrido[3,2-d]pyrimidin-4-ol (18C). To a flask containing 3-amino-5-bromopicolinamide (18B) (205 mg, 0.1 mmol, 1 eq.) was added chloroformamidine hydrochloride (140 mg, 1.3 eq.). The mixture was heated to 165° C. overnight. It was left to cool to room temperature, then filtered and washed with water and ethyl ether. The residue was allowed to air dry to give 2-amino-7-bromopyrido[3,2-d]pyrimidin-4-ol (1C) which was used without further purification. MS (m/z): 239.9 [M+H]+.

Synthesis of N-(7-bromo-4-hydroxypyrido[3,2-d]pyrimidin-2-yl)acetamide (18D). Acetic anhydride (3 mL) was added to a flask containing 2-amino-7-bromopyrido[3,2-d]pyrimidin-4-ol (1C) (155 mg, 0.64 mmol, 1 eq.). The mixture was heated to 115° C. for 4 hours. It was concentrated under reduced pressure. It was filtered and washed with diethyl ether and hexane and left to air dry to give N-(7-bromo-4-hydroxypyrido[3,2-d]pyrimidin-2-yl)acetamide (18D). MS (m/z): 282.9 [M+H]+.

Synthesis of N-(7-bromo-4-chloropyrido[3,2-d]pyrimidin-2-yl)acetamide (18E). Acetonitrile (2 ml) and POCl ₃ (1 ml), followed by the addition of DIPEA (0.12 ml, 0.71 mmol., 1 eq.). The mixture was refluxed for 6 hours. The mixture was concentrated under reduced pressure. Water (20 ml) was added thereto, followed by extraction with EtOAc (3 times). The organic layer was separated, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the title product N-(7-bromo-4-chloropyrido[3,2-d]pyrimidin-2-yl) acetamide (18E). MS(m/z): 298.9

[M+H]+.

Synthesis of (S)-2-((2-amino-7-bromopyrido[3,2-d]pyrimidin-4-yl)amino)pentan-1-ol (18F). DMF (1.5 ml) was added to a solution of N-(7-bromo-4-chloropyrido[3,2-d]pyrimidin-2-yl)acetamide (18E) (215 mg, 0.71 mmol, 1 eq.) , followed by the addition of DIPEA (0.38 ml, 2.1 mmol, 3 eq.) and (S)-(+)-2-amino-1-pentanol (55 mg, 3.6 mmol, 5 eq.). The reaction mixture was allowed to stir overnight. It was concentrated under reduced pressure and purified by reverse phase HPLC to give the title compound (18F) as a TFA salt.

1H NMR (400 MHz, methanol^) δ 8.41 (d, J=2.0 Hz, 1H), 7.83 (d, J=2.0 Hz, 1H), 4.34 (dd, J= 8.5, 5.4 Hz, 1H), 3.65-3.53 (m, 3H), 1.67-1.49 (m, 3H), 1.41 - 1.24 (m, 3H) , 0.86 (t, J=7.4 Hz, 5H).

¹⁹ F NMR (377 MHz, CD ₃ OD) δ -77.52. MS (m/z): 368.2 [M+H].

Example 19

19B 19A 19C

19D 19E

Synthesis of 2,4,7-trichloropyrido[3,2-d]pyrimidine (19B): pyrido[3,2-d]pyrimidine-2,4-diol (19A) (200 mg, 1.2 mmol , 1 eq.) was added POCl ₃ (2.5 ml) and PCl ₅ (1.53 g, 7.4 mmol, 6 eq.). The mixture was heated to 160° C. for 3 hours in a microwave reactor. The reaction mixture was concentrated under reduced pressure and partitioned between EtOAc and H2O. Organic matter was separated, dried and removed in vacuo. The residue was purified by silica gel column chromatography to give the title compound. MS (m/z): 236.6 [M+H] ⁺ .

Synthesis of (S)-2-((2,7-dichloropyrido[3,2-d]-pyrimidin-4-yl)-amino)-pentan-1-ol (19C). To a solution of 2,4,7-trichloropyrido[3,2-d]pyrimidine (19B) (160 mg, 0.68 mmol, 1 eq.) was added dioxane (4 ml), followed by DIPEA (0.18 ml, 1.2 mmol, 1.5 eq.) and (S)-(+)-2-amino-1-pentanol (85 mg, 0.82 mmol, 1.1 eq.). The reaction mixture was allowed to stir for one hour. It was concentrated under reduced pressure and used as is to give the title compound. MS (m/z): 301.1 [M+H] ⁺ .

Synthesis of (S)-2-((7-chloro-2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)pentan1-ol (19D). To a solution of (R)-2-((2,7-dichloropyrido[3,2-d]pyrimidin-4-yl)amino)pentan-1-ol (19C) (206 mg, 0.68 mmol, 1 equiv.) dioxane (4 ml) was added, followed by DIPEA (0.24 ml, 1.4 mmol, 2 eq.) and 2,4-dimethoxybenzylamine (0.30 ml, 2.0 mmol, 3 eq.). The reaction mixture was left to warm at 120° C. overnight. The reaction mixture was partitioned between EtOAc and H ₂ O. The organics were separated, dried and removed in vacuo. The residue was purified by silica gel column chromatography to give the title compound. MS (m/z): 432.2 [M+H] ⁺ .

Synthesis of (S)-2-((2-amino-7-chloropyrido[3,2-d]pyrimidin-4-yl)amino)pentan-1-ol (19E). To a solution of (S)-2-((7-chloro-2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)pentan-1-ol (19D) (35 mg, 0.08 mmol, 1 eq.) DCM (2 ml) and TFA (0.5 ml) were added. After 3 hours, the reaction mixture was concentrated under reduced pressure and purified by reverse phase HPLC to give the title compound (19E) as a TFA salt.

1H NMR (400 MHz, methanol-^) δ 8.48 (d, J=2.0 Hz, 1H), 7.78 (d, J=2.1 Hz, 1H), 4.48 (dd, J = 8.6, 5.3 Hz, 1H), 3.93-3.74 (m, 2H), 3.71 (d, J=5.2 Hz, 3H), 1.77-1.57 ( m, 2H), 1.50-1.36 (m, 1H), 1.28 (s, 2H), 0.97 (t, J=7.4 Hz, 4H).

¹⁹ F NMR (377 MHz, methanol-d4) δ -77.59 (d, J=80.2 Hz). MS (m/z): 282.1 [M+H] ⁺ .

General scheme of examples 20-22

- 88 041413

Example 20

O^ ^he χΰ. Ν ΝΗ ₂

Synthesis of (S)-2-((2-((2,4-dimethoxybenzyl)amino)-7-methylpyrido[3,2-d]pyrimidin-4-yl)amino)pentan-1-ol (19F). In a vial containing (S)-2-((7-chloro-2-((2,4-dimethoxybenzyl)amino)pyrido[3,2d]pyrimidin-4-yl)amino)pentan-1-ol (19D) (25 mg, 0.06 mmol, 1 eq.) was added methylboronic acid (8 mg, 0.14 mmol, 2.5 eq.), potassium orthophosphate (37 mg, 0.17 mmol, 3 eq.), palladium ( 0) tetrakis(triphenylphosphine) (7 mg, 0.006 mmol, 0.1 eq.) together with dioxane (2 ml) and water (2 ml). The mixture was heated to 150° C. for 1 hour in a microwave reactor. The reaction mixture was partitioned between EtOAc and H ₂ O. The organics were separated, dried and removed in vacuo to give the title compound which was used directly. MS (m/z): 474.3 [M+H]+.

Synthesis of (S)-2-((2-amino-7-methylpyrido[3,2-d]pyrimidin-4-yl)amino)pentan-1-ol (20). To a flask containing 19F was added THF (2 mL), water (2 mL), followed by 2,3-dichloro-5,6dicyanobenzoquinone (26 mg, 20.11 mmol, 2 eq.) After stirring overnight, the reaction the mixture was partitioned between EtOAc and H ₂ O. The organics were separated, dried and removed in vacuo. Purification was carried out using flash column chromatography to give the title compound (20).

1H NMR (400 MHz, methanol-a ₄ ) δ 8.35 (d, J=1.1 Hz, 1H), 7.49 (s, 1H), 4.54-4.34 (m, 1H), 3.70 (d, J=5.0 Hz, 2H), 1.84-1.61 (m, 2H), 1.56-1.35 (m, 2H), 0.97 (t, J= 7.3 Hz, 3H). MS (m/z): 262.1 [M+H] ⁺ .

Example 21

ΑΛ Ν ΝΗ ₂

Synthesis of (S)-2-((2-amino-7-ethylpyrido[3,2-d]pyrimidin-4-yl)amino)pentan-1-ol (21) was prepared according to the procedure used for 20 using ethylboronic acid instead of methylboronic acid.

¹ H NMR (400 MHz, methanol^) δ 8.65-8.30 (m, 1H), 7.62 (s, 1H), 4.61-4.38 (m, 1H), 3.80- 3.64 (m, 2H), 2.84 (q, J=7.6 Hz, 2H), 1.71 (tdd, J=8.3, 6.5, 2.2 Hz, 2H), 1 .43 (dddd, J=12.4, 7.4, 5.1, 2.5 Hz, 2H), 1.39-1.23 (m, 4H), 0.97 (t, J=7, 3 Hz, 3H). MS (m/z): 276.2 [M+H] ⁺ .

Example 22

Synthesis of (S)-2-amino-4-((1-hydroxypentan-2-yl)amino)pyrido[3,2-d]pyrimidine-7-carbonitrile (22) was prepared according to the two-step procedure used for 20, using Zn(CN) ₂ instead of methylboronic acid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 7.93 (d, J=1.7 Hz, 1H), 7.24 (d, J=1.7 Hz, 1H), 2.95-2, 68 (m, 3H), 0.76 (d, J=7.3 Hz, 2H), 0.47 (d, J=7.6 Hz, 1H), 0.02 (t, J=7.4 Hz, 4H). MS (m/z): 273.3 [M+H] ⁺ .

Example 23

19V 23A

Synthesis of (R)-2-((2,7-dichloropyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol (23A). To the solution

2,4,7-trichloropyrido[3,2-d]pyrimidine (19B) (45 mg, 0.19 mmol, 1 eq.) was added dioxane (4 ml) followed by the addition of DIPEA (41 μl, 0 .23 mmol, 1.2 eq.) and (R)-(-)-2-Amino-1-hexanol 97% (24.7 mg, 0.21 mmol, 1.1 eq.). The reaction mixture was allowed to stir for one hour. It was concentrated under reduced pressure and used as is to give the title compound. MS (m/z): 316.2[M+H]+.

Synthesis of (R)-2-((7-chloro-2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)hexan1-ol (23B). To a solution of (R)-2-((2,7-dichloropyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol (23A) (60 mg, 0.19 mmol, 1 eq. ) was added dioxane (4 ml) followed by the addition of DIPEA (68 μl, 0.38 mmol, 2 eq.) and 2,4-dimethoxybenzylamine (85 μl, 3.0 mmol, 3 eq.). The reaction mixture was left to warm at 120° C. overnight. The reaction mixture was partitioned between EtOAc and H ₂ O. The organics were separated, dried and removed in vacuo. The residue was purified by silica gel column chromatography to give the title compound. MS (m/z): 446.9 [M+H] ⁺ .

Synthesis of (R)-2-((2-amino-7-chloropyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol (23C). To a solution of (R)-2-((7-chloro-2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol (20V) (50 mg, 0.11 mmol, 1 eq.) DCM (2 ml) and TFA (0.5 ml) were added. After 3 hours, the reaction mixture was concentrated under reduced pressure and purified by reverse phase HPLC to give the title compound (23C) as a TFA salt.

¹ H NMR (400 MHz, methanol^) δ 8.60 (d, J=2.1 Hz, 1H), 7.90 (d, J=2.1 Hz, 1H), 4.58-4.44 (m, 1H), 3.79

3.63 (m, 3H), 1.86-1.61 (m, 2H), 1.52-1.24 (m, 5H), 1.01-0.79 (m, 4H).

¹⁹ F NMR (377 MHz, methanol-d4) δ -77.61. MS (m/z): 296.2 [M+H] ⁺ .

Example 24

Synthesis of methyl 3-amino-6-bromo-5-fluoropicolinate (24V).

To a solution of methyl-3-amino-5-fluoropicolinate (24A) (270 mg, 0.22 mmol, 1 eq.) was added acetonitrile (5 ml) and N-bromosuccinimide (310 mg, 0.24 mmol, 1.1 eq. ). The reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was partitioned between EtOAc and H ₂ O. The organics were separated, dried and removed in vacuo. The residue was purified by silica gel column chromatography to give the title compound. MS (m/z): 250.2 [M+H] ⁺ .

Synthesis of 2-amino-6-chloro-7-fluoropyrido[3,2-d]pyrimidin-4-ol (24C). Chloroformamidine hydrochloride (185 mg, 1.61 mmol, 2 eq.) was added to a flask containing methyl 3-amino-6-bromo-5-fluoropicolinate (24B) (200 mg, 0.80 mmol, 1 eq.). The mixture was heated to 165° C. overnight. It was left to cool to room temperature, filtered and washed with water and ethyl ether. The residue was allowed to air dry to give the title compound (24C). Approximately 25% of the product was the corresponding by-product 2-amino-6-bromo-7-fluoropyrido[3,2c]pyrimidin-4-ol. The material was used without further purification. MS (m/z): 260.0 [M+H] ⁺ .

Synthesis Synthesis of 2-amino-6-chloro-7-fluoropyrido[3,2-d]pyrimidin-4-ol (24D). To a flask of 2-amino-6chloro-7-fluoropyrido[3,2-d]pyrimidin-4-ol (24C) (50 mg, 0.23 mmol, 1 eq.) hexafluorophosphate 97% (BOP Reagent) (123 mg, 0.28 mmol, 1.2 eq.), (S)-(+)-2-Amino-1-pentanol, 97% (48 mg, 0.47 mmol, 2 eq. .) and DBU (105 µl, 0.70 mmol, 3 eq.) and DMF (3 ml). The mixture was allowed to stir at room temperature overnight and purified by reverse phase HPLC to give the title compound (24D) as a TFA salt.

1H NMR (400 MHz, methanol-d4) δ 7.86-7.63 (m, 1H), 4.64-4.47 (m, 1H), 3.72 (d, J=5.5 Hz, 2H), 1.82-1.61 (m, 3H), 1.56-1.35 (m, 2H), 0.97 (t, J=7.4 Hz, 3H).

¹⁹ F NMR (377 MHz, methanol-d4) δ -77.54, -110.63 (d, J=8.2 Hz). MS (m/z): 300.2 [M+H] ⁺ .

- 90 041413

Example 25

Synthesis of N ⁴ -butyl-8-methylpyrido[3,2-d]pyrimidine-2,4-diamine (25E). Starting with Intermediate 25A, work up 1.05 eq. butan-1-amine in THF/DIPEA at RT resulted in 25V which was concentrated to a residue and carried over directly. Heating with an excess of 2,4dimethoxybenzylamine in THF/DIPEA gave compound 25C, MS (m/z): 416.2 [M+H]+. Following the procedure described by Hasnik et. al in Synthesis, 2009, 1309-1317, instead of the expected 6-methylation by potassium methyltrifluoroborate, protonolysis of the intermediate heteroaryl-Pd complex led mainly to the isolation of 25D, and finally to N ⁴ -butyl-8-methylpyrido[3,2

d]pyrimidine-2,4-diamine 25E after treatment with 25D in excess TFA and final purification with

HPLC to give the title compound (25E) as the TFA salt.

1H NMR (400 MHz, methanol^) δ 8.48 (d, J=1.1 Hz, IH), 7.61 (d, J=1.1 Hz, 1H), 3.67 (d, J= 7.2 Hz, 2H), 2.52 (s, 3H), 1.75-1.68 (m, 2H), 1.46-1.35 (m, 2H), 0.98 (t, J =7.3 Hz, 3H).

¹⁹ F NMR (377 MHz, methanol^) δ -77.6. MS (m/z): 232.1 [M+H] ⁺ .

Example 26

Synthesis of (S)-2-((2-amino-8-methylpyrido[3,2-d]pyrimidin-4-yl)amino)pentan-1-ol (26E). Starting with intermediate 25A and following the synthesis sequence described above for the synthesis of 25E, but using L-norvalinol instead of butan-1-amine, 26E was obtained as a TFA salt.

1H NMR (400 MHz, methanol-d ₄ ) δ 8.50 (d, J=4.6 Hz, 1H), 7.63 (dq, J=4.5, 0.8 Hz, 1H), 4, 60-4.49 (m, 1H), 3.78-3.70 (m, 2H), 2.53 (s, 3H), 1.81-1.64 (m, 2H), 1.52- 1.34 (m, 2H), 0.97 (t, J=7.3 Hz, 3H).

ⁱ⁹ F NMR (377 MHz, methanol-d4) δ -77.7. MS (m/z): 262.2 [M+H] ⁺ .

Example 27

Synthesis of (S)-2-((2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)pentan-1-ol (27C). THF (4 mL) was added to a solution of 2,4dichloropyrido[3,2-d]pyrimidine (160 mg, 0.68 mmol, 1 eq.) followed by DIPEA (0.18 mL, 1.2 mmol, 1.5 eq.) and (S)-(+)-2-amino-1-pentanol (85 mg, 0.82 mmol, 1.1 eq.). The reaction mixture was allowed to stir for 1 hour. The reaction mixture was concentrated under reduced pressure and used as is to give 27A. MS (m/z): 267.1[M+H] ⁺ .

Synthesis of (S)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)pentan-1-ol (27B). To a solution of (S)-2-((2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)pentan-l-ol (27A) (206 mg, 0.68 mmol, 1 eq.) was added THF (4 ml) followed by the addition of DIPEA (0.24 ml, 1.4 mmol, 2 eq.) and 2,4-dimethoxybenzylamine (0.30 ml, 2.0 mmol, 3 eq.). The reaction mixture was heated at 135°C using a microwave reactor for 30 min. The reaction mixture was partitioned between EtOAc and H ₂ O.

- 91 041413

Organic matter was separated, dried and removed in vacuo. The residue was purified by silica gel column chromatography to give 27B. MS (m/z): 398.2 [M+H]+.

Synthesis of ^)-2-((2-amino-[3,2^]pyrimidin-4-yl)amino)pentan-1-ol (27C). To a solution of (S)-2-((2-((2,4dimethoxybenzyl)αmino)pyrido[3,2-d]pyrimidin-4-yl)amino)pentan-1-ol (27B) (35 mg, 0. 08 mmol, 1 eq.) DCM (2 ml) and TFA (0.5 ml) were added. After 3 hours, the reaction mixture was concentrated under reduced pressure and purified by reverse phase HPLC to give the title compound (27C) as a TFA salt.

1H NMR (400 MHz, methanol^) δ 8.65 (dd, J=4.3, 1.5 Hz, 1H), 7.85-7.73 (m, 2H), 4.55 (s, 1H ), 3.76-3.70 (m, 2H), 1.77-1.66 (m, 2H), 1.44 (td, J=7.3, 4.2 Hz, 2H), 0, 98 (t, J=7.4 Hz, 3H).

¹⁹ F NMR (377 MHz, methanol-d ₄ ) δ -77.6. MS (m/z): 248.2 [M+H] ⁺ .

Example 28

Following the general procedure described above for the synthesis of 1B, 2,4-dichloropyrido[3,2d]pyrimidine was reacted with 1.1 eq. (S)-1,1,1-trifluoropentan-2-amine instead of 1-butanamine and then carried out the steps as described above in example 1, obtaining (S)-N ⁴ -(1,1,1 trifluoropentan-2-yl )pyrido[3,2-d]pyrimidine-2,4-diamine (28).

1H NMR (400 MHz, DMSO-d6) δ 9.87 (s, 1H), 8.67 (dd, J=4.4, 1.5 Hz, 1H), 7.95-7.81 (m, 2H), 5.13 (t, J=8.9 Hz, 1H), 2.21-2.10 (m, 1H), 1.74 (dd, J=12.1, 7.1 Hz, 1H ), 1.44-1.36 (m, 1H), 1.27 (dq, J=13.7, 7.1 Hz, 1H), 0.89 (t, J=7.3 Hz, 3H) .

¹⁹ F NMR (377 MHz, methanol-d4) δ -73.9, -74.1. MS (m/z): 286.1 [M+H] ⁺ .

Example 29

Following the general procedure described above for the synthesis of 1B, 2,4-dichloropyrido[3,2d]pyrimidine was reacted with 1.1 eq. 4,4,4-trifluorobutylamine instead of 1-butane-amine and then carried out the steps as described above for example 1, obtaining N ⁴ -(4,4,4trifluorobutyl)pyrido[3,2-d]pyrimidine-2,4 -diamine (29) after HPLC purification as TFA salt.

¹ H NMR (400 MHz, DMSO-d6) δ 9.74 (t, J=6.0 Hz, 1H), 8.63 (dd, J=4.4, 1.4 Hz, 1H), 8, 18-7.50 (m, 2H), 3.62 (q, J=6.7 Hz, 1H), 2.39-2.27 (m, 1H), 1.93-1.84 (m, 1H).

¹⁹ F NMR (377 MHz, methanol-0 ₄ ) δ -65.5, 75.6. MS (m/z): 272.1 [M+H] ⁺ .

Example 30

Synthesis of (S)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)pentanamide (30B). Starting with 50 mg of intermediate 5A described above, treatment with 1 eq. aq. KOH in THF/MEOH (4 ml) for 1 h led, after removal of the solvent, to intermediate compound 30A, MS (m/z): 399.1 [M+H] ⁺ . 30A was treated with 1.5 eq. HATU and 3 equiv. DIPEA in 2 ml DMF, quenched with excess 2,4-dimethoxybenzylamine (DMB) to give the amide intermediate. After complete removal of DMB by treatment with TFA, HPLC purification of the product residue yielded the title compound 30B as a TFA salt.

¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.67 (ddd, J=9.2, 4.3, 1.5 Hz, 1H), 7.89-7.73 (m, 2H), 4.00-3.59 (m, 1H), 2.81 (s, 2H), 2.22-1.79 (m, 2H), 1.48 (tt, J=9.8, 7.4 Hz, 2H), 0.99 (t, J=7.4 Hz, 3H).

¹⁹ F NMR (377 MHz, methanol^) δ -77.6. MS (m/z): 261.1 [M+H] ⁺ .

- 92 041413

Example 31

Synthesis of (S)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-N-methylpentanamide (31). 50 mg 30A was treated with 1.5 eq. HATU and 3 equiv. DIPEA in 2 ml DMF, quenched with 1.0 M methylamine in THF to give the methylamide intermediate. After routine removal of DMB by treatment with TFA, HPLC purification of the product residue provided the title compound 31 as the TFA salt.

¹ H NMR (400 MHz, methanol^) δ 8.68 (dd, J=4.3, 1.5 Hz, 1H), 7.89-7.76 (m, 2H), 4.85 (m, 1H), 2.76 (s, 3H), 2.08-1.85 (m, 2H), 1.45 (dddd, J=16.5, 13.8, 11.5, 7.4 Hz, 2H), 0.98 (t, J=7.4 Hz, 3H). ¹⁹ F NMR (377 MHz, methanol-a ₄ ) δ -77.9. MS (m/z): 275.1 [M+H]+.

Example 32

1B kt to 55°С 32

Synthesis of N ⁴ -butyl-6-(trifluoromethyl)pyrido[3,2-d]pyrimidine-2,4-diamine (32). Starting with 10 mg of compound 1B, the synthesis of which is described in example 1, and in accordance with the chemistry described by Yining et al. in PNAS, 2011, 108, 14411, 1B was heated at 55°C in DMSO in the presence of 10 equivalents of zinc trifluoromethanesulfonate and 10 equivalents of zinc trifluoromethanesulfonate. 70% aq. tert-butyl hydroperoxide solution. After 24 hours, the reaction mixture was injected directly into HPLC for a final purification to give the title compound (32) as the corresponding TFA salt.

'and NMR (400 MHz, methanol-d ₄ ) δ 8.15 (d, J=8.7 Hz, 1H), 8.01 (dd, J=8.8, 0.8 Hz, 1H), 3 .82-3.56 (m, 2H), 1.83-1.61 (m, 2H), 1.58-1.31 (m, 2H), 0.99 (t, J=7.4 Hz , 3H).

¹⁹ F NMR (377 MHz, methanol-d ₄ ) δ - 69.0, -77.6. MS (m/z): 286.1 [M+H] ⁺ .

Example 33

Cl

6B 33

Synthesis of (S)-2-((2-amino-6-methylpyrido[3,2-d]pyrimidin-4-yl)amino)pentan-1-ol (33). 50 mg of compound 6B, (0.11 mmol, 1 equiv) in 10 ml (1:1 EtOH/EtOAc) was reacted with 28 mg of 5% Pd/C at 70°C under a pressure of 1 atm and ₂ . After overnight, the reaction mixture was filtered to remove the catalyst and the product was chromatographed on silica gel eluting with 25% MeOH/75% EtOAc to give the title compound (33) as the TFA salt.

1i NMR (400 MHz, methanol-d ₄ ) δ 7.74 (d, J=8.6 Hz, 1H), 7.65 (d, J=8.6 Hz, 1H), 4.54 (ddd, J=12.4, 7.3, 5.2 Hz, 1H), 3.75 (d, J=5.2 Hz, 2H), 2.65 (s, 3H), 1.73 (q, J =7.5 Hz, 2H), 1.44 (ddt, J=14.6, 7.4, 4.2 Hz, 2H), 0.98 (t, J=7.3 Hz, 3i).

¹⁹ F NMR (377 MHz, methanol-d ₄ ) δ -77.7. MS (m/z) 262.14 [M+H]+.

Example 34

Synthesis of (S)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-N-(2-hydroxyethyl)pentanamide (34): The title compound was synthesized in a manner analogous to 30B, as described in Example 30, replacing the methanolic ammonia with ethanolamine to give the title compound (34) as a TFA salt.

1H NMR (400 MHz, methanol-d ₄ ) δ 8.68 (dd, J=4.3, 1.5 Hz, 1H), 7.86 (dd, J=8.6, 1.5 Hz, 1H ), 7.80 (dd,

- 93 041413

J=8.5, 4.4 Hz, 1H), 4.88 (d, J=5.5 Hz, 1H), 3.27-3.22 (m, 2H), 2.11-1.90 (m, 3H), 1.70-1.40 (m, 5H), 1.00 (t,

J=7.4 Hz, 3H).

¹⁹ F NMR (377 MHz, methanol-d ₄ ) δ -77.5. MS (m/z) 305.21 [M+H]+.

Example 35

Synthesis of (S)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-N-(2-hydroxy-2-methylpropyl)pentanamide (35). Compound (35) was synthesized in a manner analogous to 30B as described in Example 30, replacing the methanolic ammonia with 1-amino-2-methyl-2-propanol to give the title compound (35) as a TFA salt.

¹ H NMR (400 MHz, methanol-04) δ 8.67 (dd, J=4.4, 1.4 Hz, 1H), 7.87 (dd, J=8.5, 1.4 Hz, 1H ), 7.79 (dd, J=8.5, 4.4 Hz, 1H), 4.84-4.78 (m, 1H), 3.61 (td, J=5.9, 5.5 , 1.5 Hz, 2H), 2.09-1.85 (m, 2H), 1.48 (dddd, J=18.0, 13.7, 9.7, 7.3 Hz, 2H), 1.29 (s, 6H), 0.99 (t, J=7.4 Hz, 3H).

¹⁹ F NMR (377 MHz, methanol^) δ -77.5. MS (m/z) 333.25 [M+H]+.

Example 36

Synthesis of (S)-N-(2-aminoethyl)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)pentanamide (36). Compound 36 was synthesized in a manner analogous to 30B, replacing the methanolic ammonia with N-Bocethylenediamine. Complete deprotection with TFA resulted in the title compound (36) as its bis-TFA salt.

1H NMR (400 MHz, methanol-d4) δ 8.68 (dd, J=4.4, 1.4 Hz, 1H), 7.88 (dd, J=8.5, 1.4 Hz, 1H) , 7.81 (dd, J=8.5, 4.3 Hz, 1H), 4.92 (dd, J=8.6, 5.1 Hz, 1H), 3.56 (ddd, J=13 .9, 12.8, 6.7 Hz, 1H), 3.45 (dt, J=14.3, 6.1 Hz, 1H), 3.08 (hept, J=6.4 Hz, 2H) , 2.13-2.00 (m, 1H), 2.00-1.85 (m, 1H), 1.55-1.41 (m, 2H), 0.99 (t, J=7, 4 Hz, 3H).

¹⁹ F NMR (377 MHz, methanol-d4) δ -77.6. MS (m/z) 304.05 [M+H]+.

Example 37

An

Synthesis of (S)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-N-(pyridin-2-ylmethyl)pentanamide (37). Compound 37 was synthesized in a manner analogous to 30B, replacing the methanolic ammonia with 2-picolylamine to give the title compound (37) as its bis-TFA salt.

1H NMR (400 MHz, methanol-d4) δ 8.69 (dd, J=4.4, 1.5 Hz, 1H), 8.65-8.62 (m, 1H), 8.22 (td, J=7.8, 1.7Hz, 1H), 7.88(dd, J=8.5, 1.4Hz, 1H), 7.81(dd, J=8.5, 4.4Hz , 1H), 7.73 (d, J=8.0 Hz, 1H), 7.67 (dd, J=7.5, 5.7 Hz, 1H), 4.93 (dd, J=8, 8, 5.2 Hz, 1H), 4.65 (s, 2H), 2.13-1.94 (m, 3H), 1.57-1.40 (m, 3H), 1.00 (t , J=7.4 Hz, 3H).

¹⁹ F NMR (377 MHz, methanol-d4) δ -77.8. MS (m/z) 352.04 [M+H]+.

Example 38

Χά

_NH2

38C

Synthesis of (R)-2-((8-chloro-2-((2,4-dimethoxybenzyl)amino)-6-methylpyrido[3,2-d]pyrimidin-4yl)amino)pentan-1-ol (38A) : 38A was synthesized in a manner similar to 6A, replacing (S)-norvalinol with (R)-2-aminopentanol and 2,4-dichloropyrido[3,2-d]pyrimidine with 2,4,8-trichloro-6-methylpyrido[3 ,2d]pyrimidine. MS (m/z) 446.24 [M+H]+.

Synthesis of (R)-2-((2-((2,4-dimethoxybenzyl)amino)-6-methylpyrido[3,2-d]pyrimidin-4yl)amino)pentan-1-ol (38B): 38B was synthesized as follows , similar to 6V. MS (m/z) 412.22 [M+H]+.

Synthesis of (R)-2-((2-amino-6-methylpyrido[3,2-d]pyrimidin-4-yl)amino)pentan-1-ol (38C). Compound 38C was synthesized in a manner analogous to 33 to give the title compound

- 94 041413 (38C) in the form of a TFA salt.

¹ H NMR (400 MHz, methanol-d4) δ 7.69 (d, J=8.5 Hz, 1H), 7.59 (d, J=8.4 Hz, 1H), 4.49 (qd, J=7.9, 6.9, 4.1

Hz, 1H), 3.71 (d, J=5.0 Hz, 2H), 2.60 (s, 3H), 1.68 (q, J=7.5 Hz, 2H), 1.44- 1.33 (m, 2H), 0.93 (t, J=7.3 Hz, 3H).

¹⁹ F NMR (377 MHz, methanol^) δ -77.3. MS (m/z) 262.15 [M+H]+.

Example 39

ΝΗ ₂

39C

Synthesis of (R)-2-((8-chloro-2-((2,4-dimethoxybenzyl)amino)-6-methylpyrido[3,2-d]pyrimidin-4yl)amino)hexan-1-ol (39A) : 39A was synthesized in a manner similar to 1A, replacing butane-1-amine with (R)-2-aminohexanol and 2,4-dichloropyrido[3,2-d]pyrimidine with 2,4,8-trichloro-6-methylpyrido[3 ,2d]pyrimidine. MS (m/z) 460.21 [M+H]+.

Synthesis of (R)-2-((2-((2,4-dimethoxybenzyl)amino)-6-methylpyrido[3,2-d]pyrimidin-4yl)amino)hexan-1-ol (39B): 39B was synthesized as follows , similar to 33. MS (m/z) 426.24 [M+H]+.

Synthesis of (R)-2-((2-αmino-6-methylpyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-olα (39C). Compound 39C was synthesized in a manner similar to 1B to give the title compound (39C) as a TFA salt.

1H NMR (400 MHz, methanol^) δ 7.72 (d, J=8.5 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 4.50 (dt, J= 8.4, 5.2 Hz, 1H), 3.73 (d, J=5.1 Hz, 2H), 2.63 (s, 3H), 1.80-1.67 (m, 2H), 1.44-1.32 (m, 5H), 0.93-0.86 (m, 3H).

¹⁹ F NMR (377 MHz, methanol-d4) δ -77.3. MS (m/z) 276.17 [M+H]+.

Example 40

40C

Synthesis of (S)-2-((8-chloro-2-((2,4-dimethoxybenzyl)amino)-6-methylpyrido[3,2-d]pyrimidin-4yl)amino)hexan-1-ol (40A) : 40A was synthesized in a manner similar to 1A, replacing butane-1-amine with (S)-2-αminohexanol and 2,4-dichloropyrido[3,2-d]pyrimidine with 2,4,8-trichloro-6-methylpyrido[3 ,2d]pyrimidine. MS (m/z) 460.26 [M+H]+.

Synthesis of (S)-2-((2-((2,4-dimethoxybenzyl)amino)-6-methylpyrido[3,2-d]pyrimidin-4yl)amino)hexan-1-ol (40b): 40b was synthesized as follows similar to 33. MS (m/z) 426.24 [M+H]+.

Synthesis of (S)-2-((2-amino-6-methylpyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol (40C). Compound 40C was synthesized in a manner analogous to 1B. to give the title compound (40C) as a TFA salt.

1H NMR (400 MHz, methanol-d ₄ ) δ 7.73 (d, J=8.6 Hz, 1H), 7.63 (d, J=8.6 Hz, 1H), 4.51 (dq, J=8.5, 6.1, 5.4 Hz, 1H), 3.75 (d, J=5.2 Hz, 2H), 2.64 (s, 3H), 1.84-1.65 (m, 3H), 1.38 (qd, J=8.0, 6.4, 2.9 Hz, 5H), 0.95-0.87 (m, 4H).

¹⁹ F NMR (377 MHz, methanol^) δ -77.6. MS (m/z) 276.16 [M+H]+.

Example 41

N ⁴ -butyl-7-chloropyrido[3,2-d]pyrimidine-2,4-diamine (41).

Compound 41 was synthesized according to the procedure described above for the preparation of 19E, reacting intermediate 19B with 1-butane-amine and following the sequence described to give the title compound (41) as a TFA salt after final purification by HPLC.

1H NMR (400 MHz, methanol-d4) δ 8.56 (d, J=2.1 Hz, 1H), 7.90 (d, J=2.0 Hz, 1H), 3.66 (t, J = 7.3 Hz, 2H), 1.76-1.64 (m, 2H), 1.59 (s, 0H), 1.43 (dq, J=14.7, 7.4 Hz, 2H) , 0.98 (t, J=7.4 Hz, 3H).

¹⁹ F NMR (376 MHz, methanol-d4) δ -77.55. MS (m/z) 252.2 [M+H]+.

- 95 041413

Example 42

(S)-2-((2-amino-7-methoxypyrido[3,2-d]pyrimidin-4-yl)amino)pentan-1-ol (42B) was obtained according to the following scheme:

ci

19D he

NaOMe

MeOH

42A

HE

TFU

42B (S)-2-((2-((2,4-dimethoxybenzyl)amino)-7-methoxypyrido[3,2-d]pyrimidin-4-yl)amino)pentan-1ol (42A). In a vial containing (S)-2-((7-chloro-2-((2,4-dimethoxybenzyl)amino)pyrido[3,2d]pyrimidin-4-yl)amino)pentan-1-ol (19D) (50 mg, 0.11 mmol, 1 eq.), NaOMe (65 μl, 1.1 mmol, 10 eq.) and methanol (2 ml) were added. The mixture was heated to 150°C for 30 min in a microwave reactor. The reaction mixture was partitioned between EtOAc and H ₂ O. The organic layer was separated, dried and removed in vacuo. The residue was purified by silica gel column chromatography to give the title compound. MS (m/z): 428.2 [M+H]+.

Compound 42B was synthesized by treatment with TFA 42A to give the title compound (42B) as a TFA salt after final HPLC purification.

¹ H NMR (400 MHz, methanol-44) δ 8.32 (d, J=2.5 Hz, 1H), 7.21 (d, J=2.5 Hz, 1H), 4.57-4, 45 (m, 1H), 4.00 (s, 3H), 3.77-3.67 (m, 2H), 1.80-1.63 (m, 2H), 1.50-1.39 ( m, 2H), 0.97 (t, J=7.4 Hz, 3H).

¹⁹ F NMR (377 MHz, methanol-d4) δ -77.52. MS (m/z) 278.2 [M+H] ⁺ .

Example 43

43С

Synthesis of (S)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)pentan-1-ol (43C):

43A 43B

Methyl 3-amino-5-fluoropicolinate (43A) (830 mg, 4.88 mmol), chloroformamidine hydrochloride (1121.64 mg, 9.76 mmol), dimethyl sulfone (4592.09 mg, 48.78 mmol) and stirrer was loaded into a sealed tube and heated to 160°C for 1 h. After which the reaction mixture was left to cool, 50 ml of water was added and the solution was stirred with heating for 30 min. The precipitates were filtered off and the mother liquor was purified by reverse phase HPLC using ACN/H2O with 0.1% TFA as eluent on a Hydro-RP column with a gradient of 2-5% ACN. The solvents were removed under reduced pressure and the residue was azeotroped 2x with methanol, 2x with DCM before sonication in ether. The precipitates were filtered and air dried to give 210 mg (23.9%) of 2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-ol (43B) as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.43 (d, J=2.5 Hz, 1H), 7.48 (dd, J=10.1, 2.5 Hz, 1H), 7, 23(s, 2H). ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -75.15, -119.96. MS (m/z) 181.0 [M+H] ⁺ .

Compound 43C was synthesized by BOP-Cl promoted coupling of 43B with (S)norvalinol to give the title compound (43C) as a TFA salt after final HPLC purification.

1H NMR (400 MHz, methanol-d4) δ 8.56 (d, J=2.4 Hz, 1H), 7.61 (dd, J=8.8, 2.5 Hz, 1H), 4.56 (dq, J=12.7, 6.4, 6.0 Hz, 1H), 3.80-3.69 (m, 2H), 1.78 (ddd, J=18.8, 11.4, 3.7 Hz, 2H), 1.53-1.33 (m, 2H), 0.97 (t, J=7.4 Hz, 3H).

¹⁹ F NMR (377 MHz, methanol-d4) δ -77.64, -118.17 (d, J=8.8 Hz). MS (m/z) 266.2 [M+H]+.

- 96 041413

Example 44

(R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol (44). Compound 44 was synthesized according to the procedure described above for the preparation of 43C, reacting intermediate 43B with (R)-norleucinol and following the sequence described above to give the title compound (44) as a TFA salt after final purification by HPLC.

¹ H NMR (400 MHz, methanol-J4) δ 8.57 (d, J=2.4 Hz, 1H), 7.60 (dd, J=8.8, 2.4 Hz, 1H), 4, 53 (dq, J=8.7, 5.6 Hz, 1H), 3.72 (d, J=5.4 Hz, 2H), 1.72 (m, 2H), 1.52-1.28 (m, 4H), 1.04-0.82 (m, 3H).

¹⁹ F NMR (377 MHz, methanol-d ₄ ) δ -77.60, -118.13 (d, J=8.6 Hz). MS (m/z) 280.2 [M+H]+.

Example 45

(S)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol (45). Compound 45 was synthesized according to the procedure described above for the preparation of 43C, reacting intermediate 43B with (S)-norleucinol and following the sequence described above to give the title compound (45) as a TFA salt after final purification by HPLC.

¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.57 (d, J=2.4 Hz, 1H), 7.60 (dd, J=8.8, 2.4 Hz, 1H), 4 .53 (dq, J=8.7, 5.6 Hz, 1H), 3.72 (d, J=5.4 Hz, 2H), 1.72 (m, 2H), 1.52-1, 28 (m, 4H), 1.04-0.82 (m, 3H).

¹⁹ F NMR (376 MHz, methanol-d4) δ -77.60, -118.13 (d, J=8.6 Hz). MS (m/z) 280.2 [M+H]+.

Example 46

Synthesis of (R)-2-((2-amino-6,7-difluoroquinazolin-4-yl)amino)hexan-1-ol (46C):

O

'2 nh ₂ he

NH HCl dimethylsulfone i, 140°C

hour

46A ^46B

2-Amino-6,7-difluoroquinazolin-4-ol (46B) was synthesized according to the procedure described above for 43B, reacting intermediate 46A instead of 43A and following the sequence described above to give the title compound (46C) in as a TFA salt after final HPLC purification.

1 H NMR (400 MHz, DMSO-d6) δ 7.83 (t, J=9.7 Hz, 1H), 7.31-7.22 (m, 1H), 7.19 (s, 1H).

¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -74.93, -128.78, -144.35. MS (m/z) 198.0 [M+H]+.

Compound (46C) was synthesized by BOP-Cl promoted coupling of 46B with (R)norleucinol to give the title compound (46C) as a TFA salt after final HPLC purification.

1H NMR (400 MHz, methanol-d4) δ 8.29 (dd, J=11.0, 7.9 Hz, 1H), 7.35 (dd, J=10.6, 6.8 Hz, 1H) , 4.67-4.53(m, 1H), 3.80-3.59(m, 2H), 1.77-1.63(m, 2H), 1.49-1.30(m, 4H), 0.91 (td, J=7.0, 6.3, 2.2 Hz, 3H).

¹⁹ F NMR (376 MHz, methanol-d4) δ -77.71, -127.97 (ddd, J=21.5, 10.6, 7.9 Hz), -142.27 (ddd, J=21 .4, 11.0, 6.9 Hz). MS (m/z) 297.2 [M+H]+.

- 97 041413

Example 47

47A 47B (R)-2-((2-aminoquinazolin-4-yl)amino)hexan-1-ol (47B) was synthesized by BOP-Cl promoted coupling of 47A with (R)-norleucinol to give the title compound ( 47B) as TFA salt after final HPLC purification.

'H NMR (400 MHz, methanol^) δ 8.22 (ddd, J=8.3, 1.3, 0.6 Hz, 1H), 7.78 (ddd, J=8.4, 7.3 , 1.3 Hz, 1H), 7.50-7.33 (m, 2H), 4.71-4.56 (m, 1H), 3.80-3.61 (m, 2H), 1, 81-1.64 (m, 2H), 1.47-1.31 (m, 4H), 0.92 (h, J=3.2 Hz, 3H).

¹⁹ F NMR (376 MHz, methanol-d ₄ ) δ -77.69. MS (m/z) 261.1 [M+H]+.

Example 48

Synthesis of (S)-2-((2-aminoquinazolin-4-yl)amino)hexan-1-ol. (48) was prepared in a manner similar to 47B using (S)-norleucinol instead of (R)-norleucinol.

'H NMR (400 MHz, methanol^) δ 8.22 (ddd, J=8.3, 1.3, 0.6 Hz, 1H), 7.78 (ddd, J=8.4, 7.3 , 1.3 Hz, 1H), 7.50-7.33 (m, 2H), 4.71-4.56 (m, 1H), 3.80-3.61 (m, 2H), 1, 81-1.64 (m, 2H), 1.47-1.31 (m, 4H), 0.92 (h, J=3.2 Hz, 3H).

¹⁹ F NMR (376 MHz, methanol^) δ -77.69. MS (m/z) 261.1 [M+H] ⁺ .

Example 49

Synthesis of (S)-tert-butyl-(2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4yl)amino)propyl)carbamate (49A). A solution of 2,4-dichloropyrido[3,2-d]pyrimidine (100 mg, 0.5 mmol) in THF (2 mL) was treated with butane-1-amine (S)-tert-butyl-(2-aminopropyl)carbamate hydrochloride (CAS# 959833-70-6, Fluorochem Ltd. UK), (0.03 ml, 0.56 mmol) and N,N-diisopropylethylamine (0.25 ml, 1.15 mmol). The mixture was stirred at rt for 30 min, 2,4-dimethoxybenzylamine (0.19 ml, 1.25 mmol) and Ν,Ν-diisopropylethylamine (0.13 ml, 0.75 mmol) were added and the mixture was heated to 100° C. After 16 h the reaction mixture was cooled to rt, diluted with EtOAc, washed with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting residue was chromatographed on silica gel eluting with 0-100% EtOAc in hexanes to give, after devolatilization in vacuo, compound 49A. LCMS (m/z): 469.18 [M+H] ⁺ .

Synthesis of (S)-N ⁴ -(1-aminopropan-2-yl)pyrido[3,2-d]pyrimidine-2,4-diamine (49). 49A (50 mg, 0.11 mmol) was dissolved in TFA (3 ml). After 30 minutes the reaction mixture was diluted with water and methanol. After 60 minutes the mixture was concentrated in vacuo. The residue was then dissolved in methanol and filtered to give, after devolatilization in vacuo, compound 49 as the TFA salt.

'H NMR (400 MHz, methanol^) δ 8.67 (ddd, J=9.0, 4.2, 1.6 Hz, 1H), 7.85-7.68 (m, 2H), 4, 82 (m, 1H), 3.34 (d, 2H), 1.39 (d, 3H).

¹⁹ F NMR (377 MHz, methanol^) δ -77.8. LCMS (m/z): 219.03 [M+H] ⁺ ; tR = 0.29 min. (LC/MS HPLC method B).

- 98 041413

Example 50

Synthesis of (R)-2-(2-aminohexyl)isoindoline-1,3-dione hydrochloride (50a). To phthalimide 51c (180 mg, 0.53 mmol) was added 4N HCl in dioxane (20 ml). The reaction mixture was stirred at rt for 6 h and then the volatiles were removed in vacuo to give crude 50a, which was taken directly to the next step without further purification. LCMS (m/z): 246.93 [M+H]+.

Synthesis of (R)-methyl-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)hexanoate (50b). A solution of 2,4-dichloropyrido[3,2^]pyrimidine (100 mg, 0.5 mmol) in THF (2 mL) was treated with 50a (150 mg, 0.53 mmol) and N,N-diisopropylethylamine (0.25 mL , 1.15 mmol). The mixture was stirred at rt for 30 min and 2,4-dimethoxybenzylamine (0.38 ml, 2.5 mmol) and N,N-diisopropylethylamine (0.13 ml, 0.75 mmol) were added and the mixture was heated to 125°C. After 24 h the reaction mixture was cooled to rt, diluted with EtOAc (50 ml), washed with water (25 ml), brine (25 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting residue was chromatographed on silica gel eluting with 0-100% EtOAc in hexanes to give, after devolatilization in vacuo, compound 50b.

Synthesis of (R)-N ⁴ -(1-aminohexan-2-yl)pyrido[3,2-d]pyrimidine-2,4-diamine (50). 50b (15 mg, 0.04 mmol) was dissolved in TFA (3 ml). After 60 min the mixture was concentrated to a residue in vacuo followed by co-evaporation with MeOH to give the title compound 50 as its bis-TFA salt.

¹ H NMR (400 MHz, MeOH-d ₄ ) δ 8.68 (m, 1H), 7.81-7.83 (m, 2H), 4.89 (m, 1H), 3.91 (m, 2H), 3.61 (m, 1H) 1.92-1.79 (m, 2H), 1.55-1.48 (m, 4H), 0.98 (t, J=7.4 Hz, 3H).

¹⁹ F NMR (377 MHz, MeOH-d4) δ -77.9. LCMS (m/z): 261.14 [M+H] ⁺ ; tR=0.30 min.

Example 51

(R)-norleucinol (0.5 g, 4.3 mmol) was treated with Boc ₂ O (1.2 equiv, 5.2 mmol) and excess N,N-diisopropylethylamine in DCM (20 mL). The reaction mixture was stirred for 3 h and then filtered through a plug of silica gel. Removal of volatiles gave 51b as a crude residue, which was used without further purification. LCMS (m/z): 218.23 [M+H] ⁺ .

Compound 51b (0.7 g, 3.22 mmol) was reacted with PPh ₃ (1.1 g, 3.9 mmol), phthalimide (573 mg, 3.9 mmol) and DIAD (810 mg, 4.0 mmol ) in THF (30 ml). The mixture was stirred for 3 hours and then partitioned between EtOAc (200 ml) and water (200 ml). The organic layer was separated, washed with brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 0-100% EtOAc in hexanes to give 51c. LCMS (m/z): 347.24 [M+H] ⁺ .

Imide 51c (300 mg, 0.87 mmol) was treated with an excess of hydrazine hydrate (0.2 ml, 6.25 mmol) in

- 99 041413

EtOH (30 mL) and refluxed for 16 h. The mixture was concentrated in vacuo to give intermediate 51d as a crude residue which was taken up directly. Intermediate 51d (0.87 mmol) was dissolved in DCM (10 ml) and treated with AcCl (0.1 ml, 1.2 mmol) followed by TEA (0.26 ml, 1.8 mmol). The mixture was stirred for 3 h and then the reaction mixture was diluted with DCM (50 ml). The mixture was then washed with water (50 ml), brine (50 ml), dried over Na ₂ SO ₄ , filtered and then concentrated under reduced pressure to obtain 51e. LCMS (m/z): 259.21 [M+H]+.

Intermediate 51e (0.3 g) was treated with 4N HCl in dioxanes (20 ml) and stirred for 4 h at rt. The volatiles were removed in vacuo to give the hydrochloride 51 f, which was used without further purification. LCMS (m/z): 159.45 [M+H]+.

Synthesis of (R)-N-(2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimigin-4-yl)amino)hexyl)acetamide (51a). A solution of 2,4-dichloropyrido[3,2-d]pyrimidine (100 mg, 0.5 mmol) in THF (2 mL) was treated with 51f (200 mg, 0.53 mmol) and N,N-diisopropylethylamine (0.53 mmol). 25 ml, 1.15 mmol). After stirring the mixture for 30 minutes, 2,4-dimethoxybenzylamine (0.38 ml, 2.5 mmol) and N,N-diisopropylethylamine (0.13 ml, 0.75 mmol) were added and the mixture was heated to 115°C. After heating for 16 h, the reaction mixture was cooled to rt, diluted with EtOAc (100 ml), washed with water (100 ml), brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting residue was flash chromatographed on silica gel eluting with 0-100% EtOAc in hexanes to give 51a. LCMS (m/z): 453.33 [M+H]+.

Synthesis of (R)-N-(2-((2-aminopyrigo[3,2-d]pyrimigin-4-yl)amino)hexyl)acetαmide (51). 51a (60 mg, 0.133 mmol) was dissolved in TFA (3 ml). After 60 minutes the mixture was concentrated in vacuo. The residue was diluted in MeOH, filtered and concentrated in vacuo to give the title compound 51 as the TFA salt.

¹ H NMR (400 MHz, MeOH-d4) 8.65 (dd, J=4.3, 1.5 Hz, 1H), 7.86-7.73 (m, 2H), 4.68-4, 55 (m, 4H), 3.59 (dd, J=13.9, 4.3 Hz, 4H), 3.34-3.23 (m, 3H), 1.88 (s, 3H), 1 .78-1.67 (m, 2H), 1.39 (ddd, J=7.7, 5.1, 2.4 Hz, 4H), 0.91 (ddt, J=8.3, 4, 7, 3.0 Hz, 3H).

¹⁹ F NMR (377 MHz, MeOH-d ₄ ) δ -77.7. LCMS (m/z): 303.15 [M+H]+; t _R \u003d 0.68 min. (LC/MS HPLC method B).

Example 52

(/-Pr) ₂ NEt

N-Boc-protected intermediate 51d (188 mg, 0.87 mmol) was dissolved in DCM (10 ml) and treated with methanesulfonyl chloride (0.78 μl, 114 mg, 1 mmol) and TEA (0.26 ml, 1.8 mmol). After 3 h EtOAc (100 ml) was added and the resulting mixture was washed with water (100 ml), brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to obtain 52b. LCMS (m/z): 295.24 [M+H]+.

Following the synthesis of 51f from 51e, intermediate 52b (0.87 mmol) was converted to the crude hydrochloride salt 52c, which was then carried on without purification.

Synthesis of (R)-N-(2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimigin-4-yl)amino)hexyl)methanesulfonamide (52A). A solution of 2,4-dichloropyrido[3,2-b]pyrimidine (50 mg, 0.25 mmol) in THF (2 mL) was treated with crude 52c (85 mg, 0.43 mmol) and N,N-diisopropylethylamine (0 .25 ml, 1.15 mmol). The mixture was stirred at rt for 30 min, 2,4-dimethoxybenzylamine (0.19 ml, 1.25 mmol) and N,N-diisopropylethylamine (0.13 ml, 0.75 mmol) were added and the mixture was heated to 115°C . After 16 h, the reaction mixture was cooled to rt, diluted with EtOAc (100 ml), washed with deionized water (100 ml), brine (100 ml), dried over Na2SO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 0-100% EtOAc in hexanes to give 52A. LCMS (m/z): 489.25 [M+H]+.

Synthesis of (R)-N-(2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)hexyl)methanesulfonamide (52). 52A (30 mg, 0.06 mmol) was dissolved in TFA (3 ml). After 60 minutes the mixture was concentrated in vacuo. The residue was then diluted with MeOH, filtered and concentrated in vacuo to give the title

- 100 041413 in the form of product 52 in the form of a TFA salt.

1H NMR (400 MHz, MeOHSA) δ 8.65 (dd, J=4.4, 1.4 Hz, 1H), 7.84 (dd, J=8.5, 1.4 Hz, 1H), 7 .76 (dd, J=8.5, 4.4 Hz, 1H), 4.58 (t, J=6.1 Hz, 1H), 3.52-3.26 (m, 2H), 2, 93 (s, 3H), 1.75 (dd, J=9.6, 4.0 Hz, 2H), 1.39 (td, J=8.5, 7.6, 3.5 Hz, 4H) , 0.91 (m, 3H).

¹⁹ F NMR (377 MHz, MeOH-d^ δ -77.7. LCMS (m/z): 339.21 [M+H]+; tR=0.83 min. (LC/MS HPLC method B).

Example 53

(i-Pr) ₂ NEt

Compound 61C (0.22 g, 0.69 mmol) was mesylated according to the procedure for the formation of 61D, but replacing the acetyl chloride with methanesulfonyl chloride (0.06 ml, 0.8 mmol) to give a quantitative yield of the corresponding mesylated intermediate. The resulting sulfonamide was then subjected to Pd/C hydrogenation followed by N-BOC removal as described in the preparation of 61E from 61D to give the crude product 53A as its hydrochloride salt. LCMS (m/z): 209.1 [M+H] ⁺ .

Synthesis of (R)-N-(2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-2methylhexyl)methanesulfonamide (53B). A solution of 2,4-dichloropyrido[3,2-d]pyrimidine (100 mg, 0.5 mmol) in THF (4 mL) was treated with crude 53A (0.69 mmol) and N,N-diisopropylethylamine (0.5 mL, 2.3 mmol). After heating at 75° C. for 4 h, 2,4-dimethoxybenzylamine (0.4 ml, 2.5 mmol) and additional N,N-diisopropylethylamine (0.26 ml, 1.5 mmol) were added and the mixture heated to 115°C. After 16 h, the reaction mixture was cooled to rt, diluted with EtOAc (100 ml), washed with deionized water (100 ml), brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 0100% EtOAc to give 53B. LCMS (m/z): 503.28 [M+H] ⁺ .

Synthesis of (R)-N-(2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexyl)methanesulfonamide (53). 53B (75 mg, 0.15 mmol) was dissolved in TFA (3 ml). After 60 minutes the mixture was concentrated in vacuo. The residue was dissolved in MeOH, filtered and the volatiles removed in vacuo to give the title product 53, as the TFA salt.

1H NMR (400 MHz, MeOH-d ₄ ) δ 8.63 (dd, J=4.3, 1.4 Hz, 1H), 7.79 (dd, J=8.4, 1.5 Hz, 1H ), 7.73 (dd, J=8.4, 4.3 Hz, 1H), 3.78 (m, 2H), 2.93 (s, 3H), 2.25 (m, 1H), 1 .82 (dd, J=9.6, 4.0 Hz, 2H), 1.56 (s, 3H), 1.37 (td, J=8.4, 7.5, 3.4 Hz, 4H ), 0.93(m,3H).

¹⁹ F NMR (377 MHz, MeOH-d4) δ -77.6. LCMS (m/z): 353.18 [M+H] ⁺ ; tR=0.83 min. (LC/MS HPLC method B).

Example 54

(/-Pr) ₂ NEt

Synthesis of (R)-methyl-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4yl)amino)hexanoate (54A). D-norleucine methyl ester hydrochloride (454 mg, 2.5 mmol) and N,N-diisopropylethylamine (1.3 ml, 7.5 mmol). After stirring at rt for 30 min, 2,4-dimethoxybenzylamine (1.9 ml, 12.5 mmol) and N,N-diisopropylethylamine (1.3 ml, 7.5 mmol) were added and the mixture was heated to 100°C. After 16 hours the reaction mixture

- 101 041413 was cooled to rt, diluted with EtOAc (100 ml), washed with water (100 ml), brine (100 ml), dried over Na2SO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexanes-EtOAc to give 54A.

1H NMR (400 MHz, chloroform-d) δ 8.33 (dd, J=4.2, 1.5 Hz, 1H), 7.68 (d, J=7.6 Hz, 1H), 7.43 (dd, J=8.5, 4.2 Hz, 1H), 7.28 (s, 1H), 6.46 (d, J=2.3 Hz, 1H), 6.41 (dd, J= 8.2, 2.4 Hz, 1H), 4.88 (q, J=7.3 Hz, 1H), 4.59 (d, J=6.0 Hz, 2H), 3.85 (s, 3H), 3.79 (s, 3H), 3.75 (s, 3H), 2.04-1.95 (m, 1H), 1.88 (dq, J=14.8, 7.6 Hz , 1H), 1.40 (dddd, J=26.8, 15.8, 6.9, 2.6 Hz, 5H), 0.91 (t, J=7.1 Hz, 3H). LCMS (m/z): 440.49 [M+H]+; tR=0.77 min on LC/MS Method A.

Synthesis of (R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)hexanoic acid (54B). To a solution of 54A (750.7 mg, 1.71 ml) in THF (3.6 ml) and MeOH (3.6 ml) was added 1N KOH( _AQHO ) (3.6 ml). After 4 hours, the reaction mixture was neutralized to pH 7 using 1 M HCl( _AQHO ). Concentration of the mixture in vacuo gave the crude product 54B.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.34 (d, J=4.1 Hz, 1H), 7.77 (s, 1H), 7.61 (d, J=6.5 Hz , 1H), 7.53 (dd, J=8.5, 4.2 Hz, 1H), 7.10 (s, 1H), 6.53 (d, J=2.3 Hz, 1H), 6 .42 (dd, J=7.9, 2.0 Hz, 1H), 4.65 (s, 1H), 4.44 (s, 2H), 3.81 (s, 3H), 3.71 ( s, 3H), 1.90 (s, 2H), 1.30 (s, 4H), 0.84 (s, 3H). LCMS (m/z): 426.16 [M+H]+; tR=0.67 min on LC/MS Method A.

Synthesis of (R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-N-(2hydroxyethyl)hexanamide (54C). To a solution of crude 54B (50 mg, 0.12 mmol), N,N-diisopropylethylamine (0.15 ml, 0.86 mmol) and 2-aminoethanol (0.05 ml, 0.59 mmol) in NMP (12 ml) was added HATU (96 mg, 0.25 mmol). After 16 hours, the mixture was subjected to preparative HPLC (Synergi 4u PolarRP 80A, Axia; gradient 10% aq. acetonitrile - 70% aq. acetonitrile with 0.1% TFA, over 20 min) to give 54C as the TFA salt. LCMS (m/z): 469.23 [M+H]+; t _R =0.70 min on LC/MS Method A.

Synthesis of (R)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-N-(2-hydroxyethyl)hexanamide (54). TFA (3 ml) was added to 54C (10 mg, 0.02 mmol). After 4 hours, MeOH (2 ml) and water (2 ml) were added to the mixture. After 16 h the mixture was concentrated in vacuo and then co-evaporated with MeOH three times. The residue was subjected to preparative HPLC (Synergi 4u Polar-RP 80A, Axia; gradient 10% aq. acetonitrile - 60% aq. acetonitrile with 0.1% TFA, over 20 min) to give 54 as the TFA salt.

1H NMR (400 MHz, MeOH-d^ δ 8.68 (dd, J=4.4, 1.5 Hz, 1H), 7.86 (dd, J=8.5, 1.5 Hz, 1H) , 7.80 (dd, J=8.5, 4.4 Hz, 1H), 4.81 (dd, J=8.2, 5.7 Hz, 1H), 3.66-3.56 (m , 2H), 3.43-3.32 (m, 2H), 2.12-1.90 (m, 2H), 1.491.36 (m, 4H), 0.98-0.89 (m, 3H ).

¹⁹ F NMR (377 MHz, MeOH-d^ δ -77.83. LCMS (m/z): 319.23 [M+H]+; tR=0.49 min on LC/MS Method A.

Example 55

Synthesis of (R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol (55A). To a solution of 2,4-dichloropyrido[3,2-d]pyrimidine (500 mg, 2.5 mmol) in THF (15 ml) was added (R) norleucinol (293 mg, 2.5 mmol) and N,N-diisopropylethylamine (1.3 ml, 7.5 mmol). After stirring at rt for 30 min, 2,4-dimethoxybenzylamine (1.9 ml, 12.5 mmol) and N,N-diisopropylethylamine (1.3 ml, 7.5 mmol) were added and the mixture was heated to 100°C. After 16 h the reaction mixture was cooled to rt, diluted with EtOAc (100 ml), washed with water (100 ml), brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexanes-EtOAc to give 55A.

1H NMR (400 MHz, chloroform-d) δ 8.32 (s, 1H), 7.74 (s, 1H), 7.46 (s, 1H), 6.49-6.37 (m, 3H) , 4.60 (d, J=5.9 Hz, 3H), 3.86 (s, 5H), 3.79 (s, 5H), 1.55 (s, 2H), 1.45-1, 33 (m, 6H), 0.91 (t, J=7.0 Hz, 4H). LCMS (m/z): 412.20 [M+H]+; t _R =0.89 min on LC/MS Method A.

Synthesis of (R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)hexanal (55B). Dess-Martin periodinan (248 mg, 0.58 mmol) was added to a solution of 55A (100 mg, 0.24 mmol) in DCM (5 ml) at 0°C. The reaction mixture was heated to rt and stirred for 24 hours. The reaction mixture was diluted with DCM (5 ml) and then quenched with a mixture of sat. Na ₂ S ₂ Oz ( _BODH ) (5 ml) and sat. NaHCO ₃ ( _aq ) (5

- 102 041413 ml). The organic layer was separated and the aqueous layer was extracted with DCM (2x10 ml). The combined organics were washed with brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexanes-EtOAc to give 55B. LCMS (m/z): 410.19 [M+H]+; tR=0.97 min on LC/MS Method A.

Synthesis of (R)-N ⁴ -(1-(1H-imidazol-2-yl)pentyl)-N ² -(2,4-dimethoxybenzyl)pyrido[3,2-d]pyrimidine2,4-diamine (55C). To a solution of 55B (50 mg, 0.12 mmol) in MeOH (2 ml) was added glyoxal trimer dihydrate (12 mg, 0.06 mg) and ammonia in MeOH (2M, 0.28 ml, 0.55 mmol). After 24 hours, additional glyoxal trimer dihydrate (12 mg, 0.06 mg) and ammonia in MeOH (2M, 0.28 mL, 0.55 mmol) were added. After 18 h the mixture was concentrated in vacuo. The residue was diluted with water (10 ml) and extracted with EtOAc (4x10 ml). The combined organics were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give crude 55C. LCMS (m/z): 448.15 [M+H]+; t _R =0.62 min on LC/MS Method A.

Synthesis of (R)-N ⁴ -(1-(1H-imidazol-2-yl)pentyl)pyrido[3,2-d]pyrimidin-2,4-diamine (55). TFA (2 ml) was added to 55C (50 mg, 0.11 mmol). After 90 min MeOH (2 ml) and water (2 ml) were added to the mixture. After 16 hours the mixture was concentrated in vacuo and co-evaporated with MeOH (x3). The residue was subjected to preparative HPLC (Synergi 4u Polar-RP 80A, Axia; gradient 10% aq. acetonitrile - 60% aq. acetonitrile with 0.1% TFA, over 20 min) to give 55 as the TFA salt 1H NMR (400 MHz , MeOH-d ₄ ) δ 8.70 (dd, J=4.4, 1.4 Hz, 1H), 7.93 (dd, J=8.5, 1.4 Hz, 1H), 7.83 (dd, J=8.5, 4.4 Hz, 1H), 7.52 (s, 2H), 5.92-5.71 (m, 1H), 2.30 (td, J=9.3 , 8.7, 4.3 Hz, 2H), 1.64-1.34 (m, 4H), 0.95 (t, J=7.0 Hz, 3H).

¹⁹ F NMR (377 MHz, MeOH-dd δ -77.73. LCMS (m/z): 298.05 [M+H]+; tR=0.46 min on LC/MS Method A.

Example 56

Synthesis of (R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)hexanamide (56A). To a solution of 54B (50 mg, 0.12 mmol), N,N-diisopropylethylamine (0.1 ml, 0.57 mmol) and ammonia in dioxane (0.5 M, 1.2 ml, 0.59 mmol) in NMP (6 ml) was added HATU (174 mg, 0.46 mmol). After 4 hours, the mixture was subjected to preparative HPLC (Synergi 4u Polar-RP 80A, Axia; gradient 10% aq. acetonitrile - 70% aq. acetonitrile with 0.1% TFA, over 20 min) to give 56A as the TFA salt. LCMS (m/z): 425.18 [M+H]+; t _R =0.69 min on LC/MS Method A.

Synthesis of (R)-N ⁴ -(1-(4H-1,2,4-triazol-3-yl)pentyl)-N ² -(2,4-dimethoxybenzyl)pyrido[3,2d]pyrimidine-2,4 -diamine (56V). A mixture of 56A (70 mg, 0.17 mmol) and N,N-dimethylformamide dimethylacetal (2 ml, 16 mmol) was heated to 120°C. After 2 h the mixture was cooled to rt and concentrated in vacuo. The crude residue was dissolved in AcOH (2 ml) and treated with hydrazine monohydrate (0.02 ml, 0.42 mmol). The mixture was heated to 90° C. for 24 hours. The mixture was concentrated in vacuo to give crude 56B which was used without further purification. LCMS (m/z): 449.23 [M+H]+; tR=0.83 min on LC/MS Method A.

Synthesis of (R)-N ⁴ -(1-(4H-1,2,4-triazol-3-yl)pentyl)pyrido[3,2-d]pyrimidin-2,4-diamine (56). TFA (3 ml) was added to crude 56B. After 60 minutes the mixture was concentrated in vacuo and the residue was diluted with MeOH (3.5 ml) and water (3.5 ml). After 90 min, the mixture was concentrated and then subjected to preparative HPLC (Synergi 4u Polar-RP 80A, Axia; gradient 10% aq. acetonitrile - 60% aq. acetonitrile with 0.1% TFA, over 20 min) to give 56 as salt TFU.

¹ H NMR (400 MHz, MeOH-d4) δ 8.67 (dd, J=4.4, 1.4 Hz, 1H), 8.47 (s, 1H), 7.86 (dd, J=8 .5, 1.4Hz, 1H), 7.79 (dd, J=8.5, 4.4Hz, 1H), 5.72 (dd, J=8.4, 6.3Hz, 1H) , 2.30-2.09 (m, 2H), 1.49-1.34 (m, 4H), 0.96-0.89 (m, 3H).

¹⁹ F NMR (377 MHz, MeOH-dd δ -77.98. LCMS (m/z): 299.15 [M+H]+; t _R = 0.62 min on LC/MS Method A.

- 103 041413

Example 57

Pd(dppf)CI ₂ ,

_Et3N , MeOH

POCI ₃ , DIPEA, ci

125°C

Cl

Cl

25A

2-Chloro-4-methyl-5-nitropyridine (10.0 g, 57.8 mmol) was dissolved in EtOH (100 ml) and Raney nickel (3 g) was added. The reaction mixture was stirred under H ₂ atmosphere overnight. The mixture was filtered, concentrated in vacuo, and washed with petroleum ether/EtOAc=5:1 (50 ml) to give crude 6-chloro-4-methylpyridine-3-amine.

6-Chloro-4-methylpyridin-3-amine (22.0 g, 154.9 mmol) was dissolved in DMF (150 ml) and treated with NIS (41.8 g, 185.9 mmol). The reaction mixture was stirred at rt overnight, then water (200 ml) was added and the mixture was extracted with EtOAc (3x200 ml). The combined organics were concentrated in vacuo and the residue flash chromatographed on silica gel eluting with Et2O-EtOAc to give 6-chloro-2-iodo-4-methylpyridine-3-amine.

1 H NMR (DMSO-H6, 400 MHz): δ 7.11 (s, 1H), 5.23 (s, 2H), 2.15 (s, 3H) ppm.

Pd(dppf)Cl ₂ (4.09 g, 5.5 mmol), Et ₃ N (45.1 g, 447 mmol) and the reaction mixture was stirred at rt overnight. The residue was chromatographed on silica gel eluting with Et ₂ O-EtOAc to give 6chloro-2-iodo-4-methylpyridine-3-amine.

1H NMR (DMSO-H6, 400 MHz): δ 7.33 (d, J=0.8, 1H), 6.74 (s, 2H), 3.82 (s, 3H), 3.18 (d , J=0.4, 3H) ppm.

MeOH (10 ml) was added to a solution of 6-chloro-2-iodo-4-methylpyridin-3-amine (18.8 g, 94 mmol) in NH4OH (180 ml) and the reaction mixture was stirred at rt overnight. The mixture was filtered and the collected solid was washed with petroleum ether/EtOAc (5:1, 50 mL) to give 3-amino-6chloro-4-methylpicolinamide.

1 H NMR (DMSO-d ₆ , 400 MHz): δ 7.76 (s, 1H), 7.43 (s, 1H), 7.27 (s, 1H), 6.92 (s, 2H), 2 .15 (s, 3H)ppm.

A solution of 3-amino-6-chloro-4-methylpicolinamide (10 g, 54.1 mmol) and CDI (8.02 g; 27.02 mmol) in 1,4-dioxane (200 ml) was stirred at 110°C for 30 min. The mixture was filtered and the collected solids were washed with EtOAc (30 ml). The organics were concentrated in vacuo to give the crude 6-chloro-8-methylpyrido[3,2-d]pyrimidine-2,4(1H,3H)-dione.

1 H NMR (CDCl3, 400 MHz) δ 7.70 (d, J=1.2 Hz, 1H), 2.76 (d, J=0.8 Hz, 3H) ppm.

Synthesis of 2,4,6-trichloro-8-methylpyrido[3,2-d]pyrimidine (25A). Solution of 6-chloro-8-methylpyrido[3,2d]pyrimidine-2,4(1H,3H)-dione (32 g, 151.6 mmol) and N,N-diisopropylethylamine (50 ml) in POCl ₃ (320 ml ) was stirred at 125°C overnight. The mixture was concentrated in vacuo and the residue was flash chromatographed on silica gel eluting with Et ₂ O-EtOAc to give 25A.

1 H NMR (CDCl ₃ , 400 MHz) δ 7.70 (d, J=1.2 Hz, 1H), 2.76 (d, J=0.8 Hz, 3H) ppm.

(R)-2-((6-chloro-2-((2,4-dimethoxybenzyl)amino)-8-methylpyrido[3,2-d]pyrimidin-4Synthesyl)amino)hexan-1-ol (57A) . To a solution of 25A (50 mg, 0.20 mmol) in THF (15 mL) was added D-104 041413 norleucinol (24 mg, 0.20 mmol) and N,N-diisopropylethylamine (1.1 mL, 6.0 mmol) . After stirring at rt for 30 min, 2,4-dimethoxybenzylamine (0.2 ml, 1.1 mmol) and additional N,N-diisopropylethylamine (0.26 ml, 1.5 mmol) were added and the mixture was heated to 100° C. After 16 h the reaction mixture was cooled to rt, diluted with EtOAc (100 ml), washed with water (100 ml), brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude residue was chromatographed on silica gel eluting with hexanes-EtOAc to give 57A.

¹ H NMR (400 MHz, chloroform-d) δ 7.30 (d, J=8.2 Hz, 1H), 7.25 (s, 1H), 6.75 (d, J=6.0 Hz, 1H), 6.46 (d, J=2.3 Hz, 1H), 6.41 (dd, J=8.2, 2.4 Hz, 1H), 5.39 (s, 1H), 4, 57(d, J=6.0Hz, 2H), 3.85(s, 4H), 3.81(d, J=3.1Hz, 1H), 3.79(s, 4H), 3, 68 (q, J=7.7, 7.2 Hz, 1H), 2.51 (s, 3H), 1.72-1.60 (m, 3H), 1.46-1.30 (m, 5H), 0.95-0.86 (m, 4H). LCMS (m/z): 460.25 [M+H]+; t _R =1.26 min on LC/MS Method A.

Synthesis of (R)-2-((2-((2,4-dimethoxybenzyl)amino)-8-methylpyrido[3,2-d]pyrimidin-4-yl)amino)hexan1-ol (57B). A solution of 57A (35 mg, 0.08 mmol) in EtOAc (4 ml) and EtOH (4 ml) was purged with Ar and then Pd/C (Degussa 10 wt%, 25 mg) was added. The mixture was then purged with H ₂ and heated to 70°C. After 1 h the reaction mixture was cooled, purged with Ar, filtered through celite and the celite was washed with EtOAc. The organics were concentrated in vacuo and the residue was chromatographed on silica gel eluting with EtOAcMeOH to give 57B. LCMS (m/z): 426.16 [M+H]+; t _R =1.18 min on LC/MS Method A.

Synthesis of (R)-2-((2-amino-8-methylpyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol (57). TFA (3 ml) was added to 57B (21 mg, 0.05 mmol). After 60 min MeOH (5 ml) and water (5 ml) were added to the mixture. After 4 hours the mixture was concentrated in vacuo and co-evaporated with MeOH (x3). The residue was subjected to preparative HPLC (Synergi 4u Polar-RP 80A, Axia; gradient 10% aq. acetonitrile - 70% aq. acetonitrile with 0.1% TFA, over 20 min) to give 57 as the TFA salt.

1H NMR (400 MHz, MeOH-d4) δ 8.50 (d, J=4.6 Hz, 1H), 7.63 (dd, J=4.6, 1.0 Hz, 1H), 4.53 (dq, J=8.6, 5.2 Hz, 1H), 3.74 (d, J=5.3 Hz, 2H), 2.53 (d, J=0.8 Hz, 4H), 1 .83-1.64 (m, 3H), 1.45-1.33 (m, 5H), 0.97-0.87 (m, 4H).

¹⁹ F NMR (377 MHz, MeOH-d4) δ -77.78. LCMS (m/z): 276.26 [M+H]+; tR=0.88 min on LC/MS Method A.

Example 58

Synthesis of (S)-2-((2-αmino-8-methylpyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol (58). 58 was synthesized in a three-step procedure similar to that described for example 57, replacing D-norleucinol with L-norleucinol (24 mg, 0.204 mmol) to give 58 as a TFA salt.

¹ H NMR (400 MHz, MeOH-04) δ 8.48 (d, J=4.6 Hz, 1H), 7.60 (dd, J=4.6, 1.0 Hz, 1H), 4, 52 (dq, J=8.7, 5.4Hz, 1H), 3.74 (d, J=5.8Hz, 2H), 2.52 (d, J=0.8Hz, 3H), 1.86-1.61 (m, 3H), 1.47-1.32 (m, 5H), 0.95-0.86 (m, 4H).

¹⁹ F NMR (377 MHz, MeOH-d4) δ -77.64. LCMS (m/z): 276.17 [M+H]+; tR=0.88 min on LC/MS Method A.

Example 59

Synthesis of (R)-2-amino-2-methylhexan-1-ol (59A). To (2R)-2-Amino-2-methylhexanoic acid hydrochloride (250 mg, 1.4 mmol, supplied by Astatech) in THF (5 ml) was added a solution of boranetetrahydrofuran complex in THF (1 M, 5.5 ml) dropwise in within 5 min. After 24 hours the reaction mixture was quenched with MeOH (1 ml) and concentrated in vacuo. The residue was diluted with DCM, filtered and concentrated in vacuo to give crude 59A which was transferred directly to

- 105 041413 next step. LCMS (m/z): 131.92 [M+H]+; tR=0.58 min on LC/MS Method A.

Synthesis of (R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-2methylhexan-1-ol (59B). 59A (50 mg, 0.38 mmol) and N,N-diisopropylethylamine (0.13 ml, 0.75 mmol). After stirring at 80°C for 18 h, 2,4-dimethoxybenzylamine (0.19 ml, 1.25 mmol) was added and the mixture was heated to 100°C. After 18 h the reaction mixture was cooled to rt, diluted with EtOAc, washed with water and brine, dried over Na ₂ SO ₄ then filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexanes-EtOAc to give 59B. LCMS (m/z): 426.21 [M+H] ⁺ ; t _R =0.91 min on LC/MS Method A.

Synthesis of (R)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol (59). TFA (3 ml) was added to 59B. After 2 hours the reaction mixture was concentrated in vacuo. The residue was subjected to preparative HPLC (Synergi 4u Polar-RP 80A, Axia; gradient 10% aq. acetonitrile - 70% aq. acetonitrile with 0.1% TFA, over 20 min) to give 59 as the TFA salt.

1H NMR (400 MHz, methanol-J4) δ 8.62 (dd, J=4.2, 1.6 Hz, 1H), 7.81 (dd, J=8.5, 1.6 Hz, 1H) , 7.77 (dd, J=8.5, 4.2 Hz, 1H), 3.97 (d, J=11.2 Hz, 1H), 3.72 (d, J=11.2 Hz, 1H), 2.18-2.03 (m, 1H), 1.99-1.86 (m, 1H), 1.54 (s, 3H), 1.41-1.30 (m, 4H) , 0.92 (t, J=6.9 Hz, 2H).

¹⁹ F NMR (377 MHz, MeOH-d4) δ -77.98. LCMS (m/z): 276.13 [M+H] ⁺ ; tR=0.65 min on LC/MS Method A.

Example 60

0ά Ν ΝΗ ₂ 60

Synthesis of (S)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol (60). Compound 60 was synthesized following a procedure similar to that described for 59, replacing (2R)-2-Amino-2-methylhexanoic acid hydrochloride with (2S)-2-Amino-2-methylhexanoic acid hydrochloride (250 mg, 1.38 mmol, supplied by Astatech , Inc.). A final purification by preparative HPLC (Synergi 4u Polar-RP 80A, Axia; gradient 10% aq. acetonitrile - 70% aq. acetonitrile with 0.1% TFA, over 20 min) gave 60 as the TFA salt.

1H NMR (400 MHz, methanol-d4) δ 8.63 (dd, J=4.3, 1.5 Hz, 1H), 7.82 (dd, J=8.5, 1.5 Hz, 1H) , 7.77 (dd, J=8.5, 4.3Hz, 1H), 3.98 (d, J=11.2Hz, 1H), 3.73 (d, J=11.2Hz, 1H), 2.19-2.04 (m, 1H), 2.01-1.88 (m, 1H), 1.55 (s, 3H), 1.50-1.29 (m, 4H) , 0.93 (t, J=6.9 Hz, 3H).

¹⁹ F NMR (377 MHz, MeOH-d4) δ -77.98. LCMS (m/z): 276.10 [M+H] ⁺ ; tR=0.65 min on LC/MS Method A.

Example 61

Synthesis of (R)-tert-butyl-(1-hydroxy-2-methylhexan-2-yl)carbamate (61A). To a solution of 59A (1 g, 7.6 mmol) in THF (35 ml) was added us. NaHCO ₃ ( _aq ) (35 ml) followed by the addition of di-t-butyl dicarbonate (3.33 g, 15.24 mmol). After 24 hours the organic solvents were removed in vacuo. The resulting suspension was diluted with water (50 ml), extracted with EtOAc (100 ml), washed with brine (10 ml), dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed on silica gel using ELSD eluting with hexanes-EtOAc to give 61A. LCMS (m/z): 231.61 [M+H] ⁺ ; t _R =1.09 min on LC/MS Method A.

- 106 041413

Synthesis of (R)-tert-butyl-(2-methyl-1-oxohexan-2-yl)carbamate (61B). To a solution of 61A (2.1 g, 9.0 mmol) in DCM (100 ml) was added Dess-Martin periodinan (5.7 g, 14 mmol). After 2 hours the reaction mixture was quenched with sat. Na ₂ S ₂ O ₃ ( _aq ) (75 ml). The mixture was separated and the aqueous layer was extracted with DCM (100 ml). The combined organics were washed with water (100 ml) and brine (100 ml), dried over Na ₂ SO ₄ then filtered and concentrated in vacuo. The residue was chromatographed on silica gel using ELSD eluting with hexanes-EtOAc to give 61B. LCMS (m/z): 173.75 [M+H-(t-Bu)] ⁺ ; t _R =1.18 min on LC/MS Method A.

Synthesis of (N)-tert-butyl-(1-(benzylamino)-2-methylhexan-2-yl)carbamate (61C). To a solution of 61B (1.9 g, 8.4 mmol) in dry MeOH (50 ml) was added benzylamine (1.0 ml, 8.35 mmol). After 18 h, sodium borohydride (500 mg, 13 mmol) was added in portions. After 60 minutes the mixture was concentrated in vacuo. The resulting residue was dissolved in EtOAc (50 ml), washed with 1 M NaOH( _aq ) (50 ml), 10% aqueous solution of Rochelle's salt (50 ml, solid, supplied by Sigma-Aldrich), and brine (50 ml), dried over Na ₂ SO ₄ then filtered and concentrated in vacuo to give 61C. LCMS (m/z): 321.03 [M+H] ⁺ ; t _R =0.94 min on LC/MS Method A.

Synthesis of (R)-tert-butyl-(1-(N-benzylacetamido)-2-methylhexan-2-yl)carbamate (61D). To a solution of 61C (2.2 g, 6.9 mmol) in THF (50 ml) was added N,N-diisopropylethylamine (2.4 ml, 14 mmol) followed by the addition of acetyl chloride (0.75 ml, 11 mmol). After 60 min the mixture was diluted with EtOAc (150 ml), washed with sat. NaHCO ₃ ( _aq ) (100 ml) and brine (100 ml), dried over Na ₂ SO ₄ then filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexanes-EtOAc to give 61D. LCMS (m/z): 362.82 [M+H] ⁺ ; t _R =1.32 min on LC/MS Method A.

Synthesis of (R)-N-(2-amino-2-methylhexyl)acetamide (61E). Palladium hydroxide on charcoal (20 wt%, 2 .0 g). The mixture was purged with H2 and heated to 60°C. After 24 h, the reaction mixture was filtered through Celite, washed with EtOAc, and concentrated in vacuo to give 61E as the HCl salt. LCMS (m/z): 172.92 [M+H] ⁺ ; t _R =0.50 min on LC/MS Method A.

Synthesis of (R)-N-(2-((2-((2,4-dimethoxybenzyl)amino)-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2methylhexyl)acetamide (61F) . To a solution of 2,4-dichloropyrido[3,2-d]pyrimidine (30 mg, 0.15 mmol) in THF (10 ml) was added 61E (25 mg, 0.15 mmol) and N,N-diisopropylethylamine (0.15 mmol). 08 ml, 0.44 mmol). After stirring at 80°C for 18 h, 2,4-dimethoxybenzylamine (0.1 ml, 0.73 mmol) was added and the mixture was heated to 100°C. After 18 h the reaction mixture was cooled to rt, diluted with EtOAc, washed with water and brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was chromatographed on silica gel eluting with EtOAc-MeOH to give 61F. LCMS (m/z): 467.24 [M+H] ⁺ ; t _R =1.02 min on LC/MS Method A.

Synthesis of (R)-N-(2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexyl)acetamide (61). TFA (3 ml) was added to 61F (33 mg, 0.07 mmol). After 60 minutes the mixture was concentrated in vacuo and co-evaporated with MeOH (x3). The residue was suspended in MeOH, filtered and concentrated in vacuo to give 61 as the TFA salt.

¹ H NMR (400 MHz, MeOH-64) δ 8.63 (dd, J=4.4, 1.4 Hz, 1H), 7.84 (dd, J=8.5, 1.4 Hz, 1H ), 7.76 (dd, J=8.5, 4.4Hz, 1H), 3.95 (d, J=14.0Hz, 1H), 3.57 (d, J=14.0Hz , 1H), 2.25-2.12 (m, 1H), 1.95 (s, 3H), 1.95-1.86 (m, 1H), 1.54 (s, 3H), 1, 41-1.32 (m, 4H), 0.95-0.90 (m, 3H).

¹⁹ F NMR (377 MHz, MeOH-d4) δ -77.77. LCMS (m/z): 317.24 [M+H] ⁺ ; tR=0.71 min on LC/MS Method A.

Example 62

Synthesis of (R)-N-(2-((6-chloro-2-((2,4-dimethoxybenzyl)amino)-8-methylpyrido[3,2-d]pyrimidin-4yl)amino)-2-methylhexyl) acetamide (62A). To a solution of 25A (37 mg, 0.15 mmol) in THF (5 ml) was added 61E (25 mg, 0.15 mmol) and N,N-diisopropylethylamine (0.4 ml, 0.43 mmol). After stirring at 80° C. for 18 h, 2,4-dimethoxybenzylamine (0.1 ml, 0.63 mmol) was added and the mixture was heated to

- 107 041413

100°C. After 18 h the reaction mixture was cooled to rt, diluted with EtOAc, washed with water (50 ml) and brine (50 ml), dried over Na ₂ SO ₄ then filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with EtOAc-MeOH to give 62A (49 mg, 75%).

LCMS (m/z): 515.17 [M+H]+; tR=0.86 min on LC/MS Method A.

Synthesis of (R)-N-(2-((2-((2,4-dimethoxybenzyl)amino)-8-methylpyrido[3,2-d]pyrimidin-4-yl)αmino)-2methylhexyl)acetamide (62B) . To a solution of 62A (49 mg, 0.1 mmol) in EtOAc (4 ml) and EtOH (4 ml), which was purged with Ar, was added Pd/C (Degussa 10 wt%, 25 mg). The mixture was then purged with H2 and heated to 70°C. After 1 h, the reaction mixture was allowed to cool to rt, purged with Ar, filtered through celite, washed with EtOAc (50 mL) and concentrated in vacuo to give 62B (46 mg, 100%). LCMS (m/z): 481.25 [M+H] ⁺ ; t _R =1.10 min on LC/MS Method A.

Synthesis of (R)-2-((2-amino-8-methylpyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol (62). TFA (3 ml) was added to 62B (46 mg, 0.1 mmol). After 18 h the mixture was concentrated in vacuo and co-evaporated with MeOH (3x10 ml). The residue was suspended in 10 ml MeOH, filtered and concentrated in vacuo to give 62 as the TFA salt.

¹ H NMR (400 MHz, MeOH-d4) δ 8.48 (d, J=4.6 Hz, 1H), 7.61 (dd, J=4.7, 1.0 Hz, 1H), 3, 95 (d, J=14.0 Hz, 1H), 3.56 (d, J=14.0 Hz, 1H), 2.52 (d, J=0.8 Hz, 3H), 2.18 ( ddd, J=13.5, 11.3, 4.5 Hz, 1H), 1.95 (s, 3H), 1.89 (ddd, J=13.5, 11.6, 4.8 Hz, 1H), 1.54 (s, 3H), 1.42-1.31 (m, 5H), 0.96-0.89 (m, 4H).

¹⁹ F NMR (377 MHz, MeOH-d4) δ -77.85. LCMS (m/z): 331.16 [M+H] ⁺ ; tR=0.79 min on LC/MS Method A.

Example 63

Synthesis of methyl 2-amino-2-methylhexanoate (63A). To a mixture of (2R)-2-amino-2-methylhexanoic acid hydrochloride (50 mg, 0.28 mmol) and (25)-2-amino-2-methylhexanoic acid hydrochloride (50 mg, 0.28 mmol) in MeOH (5, 0 ml) was added dropwise (trimethylsilyl)diazomethane in hexanes (2 M, 0.41 ml, 0.83 mmol). After 6 hours the reaction mixture was quenched with AcOH (100 pL). The mixture was concentrated in vacuo to give 63A which was used without further isolation. LCMS (m/z): 159.91 [M+H] ⁺ ; t _R =0.57 min on LC/MS Method A.

Synthesis of methyl 2-((2-((2,4-dimethoxybenzyl)amino)-7-fluoropyrido[3,2-d]pyrimidin-4-yl)αmino)-2methylhexanoate (63B). To a solution of 84E (120 mg, 0.55 mmol) in THF (5 ml) was added 63A (88 mg, 0.55 mmol) and N,N-diisopropylethylamine (0.3 ml, 1.7 mmol). After stirring at 80°C for 18 h, the reaction mixture was cooled to rt, diluted with EtOAc (50 ml), washed with water (50 ml) and brine (50 ml), dried over Na ₂ SO ₄ , then filtered and concentrated in vacuo . The crude residue was then diluted with THF (10 ml) and 2,4-dimethoxybenzylamine (0.4 ml, 2.6 mmol) and N,N-diisopropylethylamine (0.3 ml, 1.7 mmol) were added. After stirring at 100°C for 18 h the reaction mixture was cooled to rt, diluted with EtOAc (50 ml), washed with water and brine, dried over Na ₂ SO ₄ then filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexanes-EtOAc to give 63B.

1H NMR (400 MHz, chloroform-d) δ 8.14 (d, J=2.5 Hz, 1H), 7.36 (s, 1H), 7.28-7.24 (m, 2H), 6 .46 (d, J=2.3 Hz, 1H), 6.41 (dd, J=8.3, 2.4 Hz, 1H), 4.54 (dd, J=6.2, 2.7 Hz, 2H), 3.84 (s, 3H), 3.78 (s, 3H), 3.69 (s, 3H), 2.27-2.16 (m, 1H), 2.02 (s , 1H), 1.71 (s, 3H), 1.34-1.23 (m, 5H), 0.88 (t, J=6.9 Hz, 3H).

¹⁹ F NMR (376 MHz, chloroform-d) δ -121.51 (d, J=422.9 Hz). LCMS (m/z): 472.21 [M+H] ⁺ ; tR=0.91 min on LC/MS Method A.

Synthesis of 2-((2-((2,4-dimethoxybenzyl)amino)-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2methylhexan-1-ol (63C). To a solution of 63B (104 mg, 0.22 mmol) in THF (5 ml) was added lithium aluminum hydride in Et ₂ O (2M, 0.30 ml, 0.60 mmol). After 5 h the reaction mixture was quenched with H2O (1 ml) and 2 M NaOH( _BODH ) and then filtered. The mother liquor was then diluted with EtOAc (30 ml), washed with sat. Rochelle's salt solution (25 ml), H ₂ O (25 ml) and brine (25 ml), dried over Na ₂ SO ₄ then filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane

- 108 041413 mi-EtOAc to give 63C.

1H NMR (400 MHz, chloroform-d) δ 8.12 (d, J=2.5 Hz, 1H), 7.32 (s, 1H), 7.28 (s, 1H), 6.46 (d , J=2.4Hz, 1H), 6.42(dd, J=8.2, 2.4Hz, 1H), 4.57-4.52(m, 2H), 3.84(s, 3H), 3.79 (s, 4H), 3.75 (s, 2H), 1.92 (d, J=14.1 Hz, 1H), 1.74 (t, J=12.6 Hz, 1H), 1.40-1.37 (m, 3H), 1.32 (td, J=13.4, 12.4, 6.3 Hz, 4H), 0.91 (t, J=7, 0 Hz, 3H).

¹⁹ F NMR (377 MHz, chloroform-d) δ -121.34. LCMS (m/z): 444.20 [M+H] ⁺ ; t _R =0.94 min on LC/MS Method A.

Synthesis of 2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol (63). TFA (3 ml) was added to 63C (22 mg, 0.05 mmol). After 30 minutes the reaction mixture was diluted with MeOH (5 ml). After stirring for 18 hours, the mixture was filtered and concentrated in vacuo. Co-evaporation with MeOH (x3) gave 63 as the TFA salt.

1H NMR (400 MHz, MeOH-d4) δ 8.53 (d, J=2.4 Hz, 1H), 8.20 (s, 1H), 7.65 (dd, J=8.8, 2, 4 Hz, 1H), 3.95 (s, 1H), 3.70 (d, J=11.2 Hz, 1H), 2.09 (ddd, J=13.9, 10.9, 5.3 Hz, 1H), 1.96-1.86 (m, 1H), 1.53 (s, 3H), 1.42-1.28 (m, 6H), 0.95-0.87 (m, 3H).

¹⁹ F NMR (377 MHz, MeOH-d4) δ -77.47, -118.23 (d, J=8.6 Hz). LCMS (m/z): 294.12 [M+H] ⁺ ; tR=-0.68 min on LC/MS Method A.

Example 64

Synthesis of (S)-2-amino-2-methylhexan-1-ol (64A). To (28)-2-amino-2-methylhexanoic acid hydrochloride (250 mg, 1.4 mmol, supplied by Astatech) in THF (5 ml) was added dropwise a solution of boranetetrahydrofuran complex in THF (1 M, 5.5 ml) in within 5 min. After 24 hours the reaction mixture was quenched with MeOH (1 ml) and concentrated in vacuo. The residue was diluted in DCM (10 ml), filtered and concentrated in vacuo to give crude 64A. LCMS (m/z): 131.92 [M+H]+; t _R =0.57 min on LC/MS Method A.

Synthesis of (S)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol (64). To a solution of 43B (140 mg, 78 mmol) and 64A (125 mg, 0.95 mmol) in NMP (7.5 ml) was added DBU (0.35 ml, 2.4 mmol) followed by BOP (419 mg , 0.95 mmol). After 16 hours, the reaction mixture was subjected to prep HPLC (Gemini 10u C18 110A, AXIA; gradient 10% aq. acetonitrile - 50% aq. acetonitrile with 0.1% TFA, over 20 min) to obtain, after removal of volatiles in vacuum, 64 as TFA salt.

¹ H NMR (400 MHz, MeOH-d ₄ ) δ 8.55 (d, J=2.4 Hz, 1H), 8.22 (s, 1H), 7.64 (dd, J=8.7, 2.5 Hz, 1H), 3.97 (d, J=11.2 Hz, 1H), 3.71 (d, J=11.2 Hz, 1H), 2.09 (ddd, J=13, 9, 10.8, 5.2 Hz, 1H), 1.92 (ddd, J=13.6, 10.9, 5.4 Hz, 1H), 1.54 (s, 4H), 1.40 -1.31 (m, 5H), 1.00-0.85 (m, 3H).

¹⁹ F NMR (377 MHz, MeOH-d4) δ -77.62, -118.22 (d, J=8.7 Hz). LCMS (m/z) 294.09 [M+H] ⁺ ; tR=0.79 min on LC/MS Method A.

Example 65

Synthesis of (R)-N-(2-((2-amino-7-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexyl)acetamide (65A). To a solution of 19B (112 mg, 0.48 mmol) in THF (5 ml) was added 61E (100 mg, 0.48 mmol) and N,N-diisopropylethylamine (0.25 ml, 1.4 mmol). After stirring at 80°C for 18 h, 2,4-dimethoxybenzylamine (0.75 ml, 5.0 mmol) was added and the mixture was heated to 100°C. After 18 hours the reaction

- 109 041413 the mixture was cooled to rt, diluted with EtOAc (50 ml), washed with water (50 ml) and brine (50 ml), dried over Na2SO4, then filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexanes-EtOAc to give 65A LCMS (m/z): 509.30 [M+H]+;

tR=0.89 min on LC/MS Method A.

Synthesis of (R)-N-(2-((2-amino-7-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexyl)acetamide (65). TFA (3 ml) was added to 65A (21 mg, 0.04 mmol). After 30 min the mixture was concentrated in vacuo and the residue co-evaporated with MeOH (10 mlx3). The resulting residue was suspended in MeOH (10 ml), filtered and concentrated in vacuo to give 65 as the TFA salt.

1H NMR (400 MHz, MeOH-d ₄ ) δ 8.59 (d, J=2.1 Hz, 1H), 8.58 (s, 1H), 7.91 (d, J=2.1 Hz, 1H), 3.93 (d, J=14.0 Hz, 1H), 3.52 (d, J=14.0 Hz, 1H), 2.22-2.10 (m, 1H), 1, 96 (s, 3H), 1.95-1.87 (m, 1H), 1.54 (s, 3H), 1.34 (dd, J=7.5, 3.9Hz, 5H), 0 .94-0.89 (m, 3H).

¹⁹ F NMR (377 MHz, MeOH-d4) δ -77.91. LCMS (m/z): 351.29 [M+H] ⁺ ; tR=0.69 min on LC/MS Method A.

Example 66

Synthesis of (R)-N-(2-((2-((2,4-dimethoxybenzyl)amino)-7-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-2methylhexyl)acetamide (66A) . Methylboronic acid (61 mg, 1.0 mmol), tetrakis(triphenylphosphine)palladium(0) (51 mg, 0.05 mmol and potassium orthophosphate (163 mg, 0.77 mmol) The reaction mixture was heated to 150°C in a microwave reactor for 30 min. The reaction mixture was diluted with water (50 ml) and extracted with EtOAc (3x25 ml). The combined organics were washed with water (50 ml) and brine (50 ml), dried over Na ₂ SO ₄ and concentrated in vacuo.The residue was chromatographed on silica gel eluting with EtOAc-MeOH to give 66A. LCMS (m/z): 481.30 [M+H] ⁺ t _R = 0.89 min on LC/MS Method A.

Synthesis of (R)-N-(2-((2-amino-7-methylpyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexyl)acetamide (66). TFA (3 ml) was added to 66A (54 mg, 0.11 mmol). After 60 minutes, the mixture was concentrated in vacuo and co-evaporated with MeOH (10 mlx3). The resulting residue was suspended in MeOH (10 ml), filtered and concentrated in vacuo to give 66 as the TFA salt.

1H NMR (400 MHz, MeOH-d4) δ 8.48 (d, J=1.8 Hz, 1H), 7.64 (s, 1H), 3.94 (d, J=14.0 Hz, 1H ), 3.57 (d, J=13.9 Hz, 1H), 2.50 (s, 3H), 2.17 (ddd, J=13.4, 11.4, 4.7 Hz, 1H) , 1.95 (s, 3H), 1.88 (ddd, J=16.1, 8.9, 4.4 Hz, 1H), 1.53 (s, 3H), 1.39-1.29 (m, 4H), 0.97-0.86 (m, 3H).

¹⁹ F NMR (377 MHz, MeOH-d4) δ -77.86. LCMS (m/z): 331.34 [M+H] ⁺ ; tR=0.93 min on LC/MS Method A.

Example 67

Synthesis of methyl 3-amino-6-bromo-5-fluoropicolinate (67B). NBS (311 mg , 2.2 mmol, 1.1 equiv.) for 2 min at rt. After 18 h the reaction mixture was quenched with water (50 ml) and the mixture was extracted with EtOAc (50 ml), washed with water (50 ml) and brine (50 ml), then dried over Na ₂ SO ₄ , filtered and then concentrated in vacuo. The residue was subjected to silica gel column chromatography eluting with 0-100% EtOAc in hexanes to give 67B. LCMS (m/z): 250.1 [M+H]+; tR=0.71 min on LC/MS Method A.

Synthesis of methyl 3-amino-5-fluoro-6-methylpicolinate (67С). Methyl 3-amino-6-bromo-5-fluoropicolinate 67B (50 mg, 0.2 mmol, 1 eq.) in a microwave vial was treated with dioxane (2 ml) and water (2 ml), together with methylboronic acid (36, 05 mg, 0.06 mmol, 3 eq.), potassium orthophosphate (85.23 mg, 0.4 mmol, 2 eq.) and palladium(0) tetrakis(triphenylphosphine) (46.4 mg, 0.04 mmol, 0.2 equiv.). The mixture was heated to 120°C for 20 min and the reaction mixture was partitioned between EtOAc (20 ml) and H2O (20 ml). The organic layers were combined, dried over MgSO ₄ then filtered and the volatiles were removed in vacuo. The resulting residue was chromatographed on silica gel eluting with 0-100% EtOAc in hexanes to give 67C. LCMS (m/z): 184.88 [M+H]+; t _R =0.54 min on LC/MS Method A.

Synthesis of 2-amino-7-fluoro-6-methylpyrido[3,2-d]pyrimidin-4-ol (67D). A flask containing methyl 3-amino-5-fluoro-6-methylpicolinate 67C (95 mg, 0.52 mmol) was treated with chloroformamidine hydrochloride (118 mg, 1.03 mmol, supplied by Oakwood Scientific, Inc.). The mixture was heated to 160° C. overnight. The mixture was allowed to cool to rt, diluted with EtOAc (100 ml), filtered and then the collected solids were washed with water (50 ml) and diethyl ether (50 ml). The solid was allowed to air dry to give 67D which was used without further purification. LCMS (m/z): 195.03 [M+H]+; t _R =0.31 min on LC/MS Method A.

Synthesis of (S)-2-((2-amino-7-fluoro-6-methylnirido[3,2-d]pyrimidin-4-yl)amino)pentan-1-ol (67). To a flask containing 2-amino-7-fluoro-6-methylpyrido[3,2-d]pyrimidin-4-ol 67D (5 mg, 0.026 mmol) was added DMF (2 ml) together with a 1 M solution with 1.8 -diazabicyclo[5,4.0]undec-7-ene in THF (0.01 ml, 0.08 mmol), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (22.78 mg, 0.05 mmol) and (S)-(+)-2-amino-1-pentanol, (10.63 mg, 0.1 mmol). The reaction mixture was allowed to stir overnight and then subjected to HPLC (10-70% MeCN in water with 0.1% TFA using a Hydro-RP column) to give, after devolatilization in vacuo, 67 as the TFA salt; tR=0.57 min on LC/MS Method A.

¹ H NMR (400 MHz, MeOH-d4) 5 7.52 (d, J=9.4 Hz, 1H), 4.54 (s, 1H), 3.73 (d, J=5.3 Hz, 2H), 2.61 (d, J=2.9 Hz, 3H), 1.71 (q, J=7.6 Hz, 2H), 1.49-1.37 (m, 1H), 1, 29 (s, 5H), 0.97 (t, J=7.4 Hz, 3H).

¹⁹ F NMR (377 MHz, MeOH-d4) δ -77.42; LCMS (m/z): 280.1 [M+H]+.

Example 68

70V 68A ₆₈

Synthesis of (R)-2-((2,4-dimethoxybenzyl)amino)-4-((1-hydroxyhexan-2-yl)amino)pyrido[3,2d]pyrimidin-7-ol (68A). In a microwave vial containing (R)-2-((7-chloro-2-((2,4dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol 70V ( 22 mg, 0.049 mmol, 1 eq.) was added 2-(dicyclohexylphosphino)-2',4',6'-triisopropylbiphenyl (2.35 mg, 0.01 mmol), tris(dibenzylideneacetone)diialladium(0) (0, 9 mg, 0.005 mmol, 20 mol%) together with dioxane (2.5 ml) and KOH( _aq ) (1 ml, 0.08M). The mixture was heated to 150°C for 30 min in a microwave reactor. The reaction mixture was partitioned between EtOAc (50 ml) and H2O (50 ml). The organic layer was separated, dried over MgSO ₄ , filtered and concentrated in vacuo. Crude 68A was used without further purification. LCMS (m/z): 428.2 [M+H]+; t _R =0.78 min on LC/MS Method A.

Synthesis of (R)-2-amino-4-((1-hydroxyhexan-2-yl)amino)pyrido[3,2-d]pyrimidin-7-ol (68). Solution of (R)-2-((2,4-dimethoxybenzyl)amino)-4-((1-hydroxyhexan-2-yl)amino)pyrido[3,2-d]pyrimidin-7-ol 68A (21 mg, 0.05 mmol, 1 eq.) in DCM (2 ml) was treated with TFA (0.5 ml). After 3 hours, the reaction mixture was concentrated under reduced pressure and the residue was subjected to reverse phase HPLC (10-70% MeCN in water with 0.1% TFA using a Hydro-RP column) to give, after collection of the product fraction and removal of volatiles in vacuo , 68 as TFA salt. LCMS (m/z): 278.3 [M+H]+; t _R =0.55 min on LC/MS Method A.

1H NMR (400 MHz, MeOH-d ₄ ) δ 8.61-8.34 (m, 1H), 8.19-7.98 (m, 1H), 4.39 (ddd, J=18.0, 9.2, 5.3 Hz, 2H), 3.77 (dt, J=8.3, 6.5 Hz, 1H), 1.74-1.50 (m, 6H), 1.34-1 .09 (m, 10H), 0.79 (tt, J=6.9, 1.3 Hz, 6H), 0.59 (d, J=5.6 Hz, 2H).

¹⁹ F NMR (377 MHz, MeOH-d4) δ -77.55.

- 111 041413

Example 69

^69A 69B ⁶⁹

Synthesis of 2-amino-7-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4-ol (69B). Methyl 3-amino-5(trifluoromethyl)picolinate 69A (300 mg, 0.001 mol, 1 eq, supplied by J&W Pharmlab, LLC) was treated with chloroformamidine hydrochloride (390 mg, 0.003 mmol, 2.5 eq) and dimethyl sulfone (1. 28 g, 0.014 mol, 10 eq.). The mixture was heated to 200° C. overnight. The reaction mixture was left to cool to rt, filtered and washed with water (50 ml) and diethyl ether (50 ml). The residue was left to air dry to give 69B, which was used without further purification. LCMS (m/z): 231 [M+H]+; tR=0.48 min on LC/MS Method A.

Synthesis of (S)-2-((2-amino-7-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol (69). 2amino-7-(trifluoromethyl)pyrido[3,2-d]pyrimidin-4-ol, 69B (100 mg, 0.44 mmol, 1 eq.) was treated with a 1 M solution of 1,8-diazabicyclo[5.4.0]undec -7-ene in THF (0.19 ml, 1.3 mmol, 3 eq.). (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (249.83 mg, 0.56 mmol, 1.3 eq) was added followed by (S)-(+)-2-amino-1-pentanol (112.06 mg, 1.09 mmol, 2.5 eq.) and DMF (5 ml). After stirring for 16 hours, the reaction mixture was diluted with water (5 ml) and subjected to reverse phase HPLC (10-70% MeCN in water with 0.1% TFA using a Hydro-RP column) to give, after collecting product fractions and removing volatiles in vacuo, indicated in the title compound 69 as a TFA salt. LCMS (m/z): 316.16 [M+H]+; t _R =0.59 min on LC/MS Method A.

¹ H NMR (400 MHz, MeOH-d4) δ 8.94-8.53 (m, 1H), 8.01 (dd, J=1.8, 0.9 Hz, 1H), 4.45 (t , J=6.5 Hz, 1H), 3.71-3.54 (m, 2H), 3.42-3.24 (m, 2H), 2.72-2.55 (m, 2H), 1.59 (td, J=8.2, 6.6 Hz, 3H), 1.37-1.20 (m, 2H), 0.85 (t, J=7.3 Hz, 4H).

¹⁹ F NMR (377 MHz, MeOH-d ₄ ) δ -64.83, -77.69.

Example 70 and Example 71

Synthesis of (R)-2-((2,7-dichloropyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol (70A). A solution of 2,4,7trichloropyrido[3,2-d]pyrimidine 19B (250 mg, 1.06 mmol, 1 eq.) in dioxane (4 mL) was treated with N,Ndiisopropylethylamine (0.22 mL, 1.2 mmol, 1 .5 eq.) and (R)-(-)-2-amino-1-hexanol (312.38 mg, 3.02 mmol, 2.5 eq.). The reaction mixture was allowed to stir for 1 hour and the resulting product, 70A, was taken directly to the next reaction without isolation.

Synthesis of (R)-2-((7-chloro-2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)hexan1-ol (70V). Solution of (R)-2-((2,7-dichloropyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol 70A (315 mg, 1.06 mmol, 1 eq.) as described, treated with dioxane (4 ml) followed by N,N-diisopropylethylamine (0.38 ml, 2 mmol, 2 eq.) and 2,4-dimethoxybenzylamine (0.47 ml, 3.1 mmol, 3 eq. ). The reaction mixture was heated at 120°C overnight. The reaction mixture was partitioned between EtOAc (50 ml) and H2O (50 ml). The organic layer was separated, dried over Na ₂ SO ₄ then filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 0-100% EtOAc in hexanes to give the title compound 70B. LCMS (m/z): 446.9 [M+H]+; t _R =0.78 min on LC/MS Method A.

Synthesis of (R)-2-((2-((2,4-dimethoxybenzyl)amino)-7-vinylpyrido[3,2-d]pyrimidin-4yl)amino)hexan-1-ol (70C). Microwave vial containing (R)-2-((7-chloro-2-((2,4dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol 70V (50 mg, 0.11 mmol, 1 eq.), treated with potassium vinyl trifluoroborate (26.59 mg, 0.28 mmol, 2.5 eq.), potassium orthophosphate (71.4 mg, 0.34 mmol, 3 eq.) , palladium(0) tetrakis(triphenylphosphine) (25.91 mg, 0.02 mmol, 0.2 eq.), dioxane (2.0 ml) and water (2 ml). The mixture was heated to 150°C for 60 min in a microwave reactor. The reaction mixture was partitioned between EtOAc (50 ml) and H2O (50 ml). The organic layer was separated, dried

- 112 041413 over Na2SO4, filtered and concentrated in vacuo to give the crude 70C, which was used without further purification. LCMS (m/z): 438.27 [M+H]+; tR=0.82 min on LC/MS

Method A.

Synthesis of (R)-2-((2-amino-7-vinylpyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol (70). (R)2-((2-((2,4-dimethoxybenzyl)amino)-7-vinylpyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol solution, 70C (49 mg, 0.08 mmol, 1 eq.) in DCM (2 ml) was treated with TFA (0.5 ml). After 3 hours, the reaction mixture was concentrated under reduced pressure and the residue was subjected to reverse phase HPLC (10-70% MeCN in water with 0.1% TFA using a Hydro-RP column) to give, after collecting product fractions and removing volatiles in vacuo , 70 as TFA salt. LCMS (m/z): 288.17 [M+H]+; t _R =0.61 min on LC/MS Method A.

1H NMR (400 MHz, MeOH-d ₄ ) δ 8.61 (d, J=1.8 Hz, 1H), 7.75-7.62 (m, 1H), 6.80 (dd, J=17 .7, 11.1 Hz, 1H), 6.05 (d, J=17.7 Hz, 1H), 5.54 (d, J=11.1 Hz, 1H), 4.47-4.31 (m, 1H), 3.71-3.51 (m, 2H), 1.77-1.47 (m, 2H), 1.35-1.16 (m, 5H), 0.93-0 .71 (m, 4H).

¹⁹ F NMR (377 MHz, MeOH-d ₄ ) δ -77.60.

Synthesis of (R)-2-((2-amino-7-ethylpyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol (71). (R)-2-((2amino-7-vinylpyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol, 70 (25mg, 0.09mmol, 1eq) was treated with Pd /C (Degussa 10 wt.%, 50 mg) and EtOH (5 ml) and the mixture was stirred under hydrogen atmosphere. After a few hours the solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was subjected to reverse phase HPLC (10-50% MeCN in water with 0.1% TFA using a Gemini C18 column) to give, after collection of product fractions and removal of volatiles in vacuo, 71 as the TFA salt. LCMS (m/z): 290.42 [M+H]+; t _R =0.70 min on LC/MS Method A.

1H NMR (400 MHz, MeOH-d4) δ 8.60-8.42 (m, 1H), 7.63 (td, J=1.6, 0.9 Hz, 1H), 4.61-4, 44 (m, 1H), 3.823.63 (m, 2H), 2.85 (q, J=7.6 Hz, 2H), 1.84-1.64 (m, 3H), 1.46-1 .15 (m, 9H), 0.97-0.81 (m, 4H).

¹⁹ F NMR (377 MHz, MeOH-d4) δ -77.47.

Example 72

Synthesis of (3R,5R,6S)-tert-butyl-3-(but-3-en-1-yl)-2-oxo-5,6-diphenylmorpholine-4-carboxylate (72B). Starting with a stirred solution of (2S,3R)-tert-butyl-6-oxo-2,3-diphenylmorpholine-4-carboxylate 72A (1500 mg, 4 mmol, 1 eq., supplied by Sigma-Aldrich) and 4-iodobutene (3862.41 mg, 0.02 mol, 5 eq., supplied by Sigma-Aldrich) in anhydrous THF (24 ml) and HMPA (2.5 ml) cooled to -78°C, 1 M sodium bis(trimethylsilyl)amide in THF ( 6.37 ml, 6.37 mmol, 1.5 eq.) was added dropwise under argon. After 10 min, the reaction mixture was stirred at -40°C for 4 h. The reaction mixture was quenched with EtOAc (50 ml) and poured into a mixture of EtOAc (50 ml) and an aqueous solution of 1 M NH ₄ Cl (50 ml). The organic layer was separated, washed with water (50 ml) and brine (50 ml), dried over Na2SO4, filtered and the volatiles removed in vacuo to give a residue. The residue was chromatographed on silica gel eluting with 0-100% EtOAc in hexanes to give the title compound 72B. LCMS (m/z): 307.98 [M+H-Boc]+; t _R =1.28 min on LC/MS Method A.

Synthesis of (R)-methyl-2-aminohex-5-enoate (72C). A 2-necked flask containing lithium (91.98 mg, 13.25 mmol, 15 eq.) was cooled to -40° C. before liquid ammonia (15 ml) was added to the flask via condensation using cold finger devices. Intermediate 72B (360 mg, 0.88 mmol, 1 eq.) in THF (2 mL) was then added. The reaction mixture was maintained at -40°C for 1 h, and then slowly extinguished with a solution of NH ₄ Cl (5 ml), after which it was left to warm to rt. The reaction mixture was then diluted with diethyl ether (50 ml) and water (50 ml) and a layer of diethyl

- 113 041413 ether was separated. 1N HCl was then added to the aqueous layer until pH 5 followed by extraction with EtOAc (50 ml). The organic layers were each washed with saturated NH4Cl (50 ml) separately and then combined, dried over MgSO ₄ , filtered and concentrated in vacuo. DCM (10 ml) was added to the residue followed by MeOH (1 ml), (trimethylsilyl)diazomethane (2.0 M solution in hexanes) (0.29 ml, 2.20 mmol, 12 eq.). After stirring for 1 hour, the reaction mixture was concentrated under reduced pressure. The crude residue was treated with DCM (5 ml) and TFA (5 ml). After stirring for 2 hours, the reaction mixture was concentrated under reduced pressure to give 72C, which was used without further purification.

Synthesis of (R)-2-((2,7-dichloropyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol (72D). A solution of 2,4dichloropyrido[3,2-b]pyrimidine (110 mg, 0.55 mmol, 1.1 equiv) in dioxane (4 ml) was treated with N,N-diisopropylethylamine (0.14 ml, 0.9 mmol, 2 equiv. ) and then crude (R)-methyl-2-aminopent-4-enoate 72C (112 mg, 0.46 mmol, 1 eq.). The reaction mixture was allowed to stir for 1 hour to give 72D, which was used directly in solution. LCMS (m/z): 307.80 [M+H]+; t _R =1.09 min on LC/MS Method A.

Synthesis of (R)-methyl-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)hex-5enoate (72E). Crude solution containing (R)-2-((2,7-dichloropyrido[3,2-d]pyrimidin-4yl)amino)hexan-1-ol 72D (128 mg, 0.42 mmol, 1 eq.), treated with additional N,Ndiisopropylethylamine (0.15 ml, 0.84 mmol, 2 eq.) and then 2,4-dimethoxybenzylamine (0.47 ml, 0.85 mmol, 2 eq.). The reaction mixture was heated at 120°C overnight. The reaction mixture was then partitioned between EtOAc (50 ml) and H ₂ O (50 ml). The organic layer was separated, dried over Na ₂ SO ₄ , filtered and then concentrated in vacuo. The residue was chromatographed on silica gel eluting with 0100% EtOAc in hexanes to give the title compound 72E. LCMS (m/z): 438.52 [M+H] ⁺ ; t _R =0.91 min on LC/MS Method A.

Synthesis of (R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)hex-5-en-1-ol (72F). (R)-methyl-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)hex-5-enoate 72E (43 mg, 0, 1 mmol, 1 eq.) was dissolved in THF (5 ml) and 1 M lithium aluminum hydride in diethyl ether (0.29 ml, 0.29 mmol, 3 eq.) was added. The reaction mixture was stirred at rt for 2 h. The reaction mixture was quenched with water (50 ml) and extracted with EtOAc (50 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and then concentrated in vacuo. The crude residue 72F (40 mg) was then used without further purification. LCMS (m/z): 410.52 [M+H]+; t _R =0.85 min on LC/MS Method A.

Synthesis of (R)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)hex-5-en-1-ol (72). (R)-2-((2-((2,4dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)hex-5-en-1-ol 72F (40 mg, 0, 09 mmol, 1 eq.) was treated with DCM (2 ml) and TFA (0.5 ml). After 3 hours, the reaction mixture was concentrated under reduced pressure and subjected to reverse phase HPLC (10-70% MeCN in water with 0.1% TFA using a Hydro-RP column) to give, after collecting product fractions and removing volatiles in vacuo, 72 as TFA salt. LCMS (m/z): 260.14 [M+H]+; t _R =0.58 min on LC/MS Method A.

1H NMR (400 MHz, MeOH-d4) δ 8.66 (ddd, J=10.3, 4.2, 1.5 Hz, 1H), 7.94-7.65 (m, 2H), 5, 86 (ddt, J=16.9, 10.3, 6.7 Hz, 1H), 5.15-4.90 (m, 2H), 4.63-4.43 (m, 1H), 2, 29-2.06 (m, 2H), 2.00-1.71 (m, 2H).

¹⁹ F NMR (377 MHz, methanol-d4) δ -77.31, -77.69.

Example 73

Synthesis of (2R)-methyl-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-5fluorohexanoate (73A). Iron(III) oxalate hexahydrate (172 mg, 0.36 mmol, 2 equiv.) was stirred in water (10 ml) until complete dissolution (usually 1-2 hours). The clear yellow solution was cooled to 0°C and degassed for 10 min. Selectfluor (126 mg, 0.36 mmol, 2 eq.) and MeCN (5 ml) were added to the reaction mixture. Solution of (R)-methyl-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4yl)amino)hex-5-enoate 72E (78 mg, 0.18 mmol, 1 eq.) in MeCN (5 ml) was added to the reaction mixture, followed by the addition of sodium borohydride (23.6 mg, 0.62 mmol, 3.5 eq.) at 0°C. After 2 min the reaction mixture was treated with additional NaBH ₄ (24 mg, 0.62 mmol, 3.5 eq.). The resulting mixture was stirred for 30 min and then quenched by adding 28-30% aqueous NH ₄ OH

- 114 041413 (4 ml). The mixture was extracted with 10% MeOH in CH2C12 and the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 0-100% EtOAc in hexanes to give 73A. LCMS (m/z): 458.63 [M+H]+; t _R \u003d 0.91 min per

LC/MS Method A.

Synthesis of (2R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-5fluorohexan-1-ol (73B). (2R)-methyl-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4yl)amino)-5-fluorohexanoate 73A (43 mg, 0.1 mmol, 1 eq.) was treated with THF (5 ml) and 1 M lithium aluminum hydride in ether (0.29 ml, 0.29 mmol, 3 eq.). The reaction mixture was allowed to stir at rt for 2 h. The reaction mixture was quenched with water (50 ml) and extracted with EtOAc (50 ml). The organics were combined, dried over Na ₂ SO ₄ and concentrated in vacuo. Crude 73B was used without further purification. LCMS (m/z): 430.19 [M+H]+; t _R =0.82 min on LC/MS Method A.

Synthesis of (2R)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-5-fluorohexan-1-ol (73). (2R)-2-((2((2,4-dimethoxybenzyl)αmino)pyrido[3,2-d]pyrimidin-4-yl)amino)-5-fluorohexan-1-ol 73B (40 mg, 0. 09 mmol, 1 eq.) was treated with DCM (2 ml) and TFA (0.5 ml). After 3 hours, the reaction mixture was concentrated under reduced pressure and the residue was subjected to reverse phase HPLC (10-70% MeCN in water with 0.1% TFA using a Hydro-RP column) to give, after collecting product fractions and removing volatiles in vacuo , 73 as TFA salt. LCMS (m/z): 280.12 [M+H]+; t _R =0.59 min on LC/MS Method A.

1H NMR (400 MHz, methanol-d4) δ 8.64 (dd, J=4.3, 1.4 Hz, 1H), 7.84 (dd, J=8.5, 1.4 Hz, 1H) , 4.63-4.50 (m, 1H), 4.47 (t, J=6.0 Hz, 1H), 4.35 (t, J=6.0 Hz, 1H), 3.74 ( d, J=5.3 Hz, 2H), 1.89-1.61 (m, 4H), 1.60-1.39 (m, 2H).

¹⁹ F NMR (377 MHz, methanol^) δ -77.66, -220.85 (ddd, J=47.6, 25.5, 22.1 Hz).

Example 74

Synthesis of (3R,5R,6S)-tert-butyl-3-(4-fluorobutyl)-2-oxo-5,6-diphenylmorpholine-4-carboxylate (74B). A stirred solution of (2S,3R)-mpem-butyl-6-oxo-2,3-diphenylmorpholine-4-carboxylate 72A (1000 mg, 2.8 mmol, 1 eq.) and 1-bromo-4-fluorobutane (2, 57 g, 13.5 mmol, 4.5 eq., supplied by Sigma-Aldrich) in anhydrous THF (10 ml) and HMPA (1 ml) were cooled to -78°C and treated dropwise with 1M lithium bis(trimethylsilyl)amide in THF (4.2 ml, 4.2 mmol, 1.5 eq) under argon. After 10 min, the reaction mixture was stirred at -40°C for 4 h. The reaction mixture was quenched with EtOAc and poured into a mixture of EtOAc (50 ml) and aqueous NH ₄ Cl solution (50 ml, 1 M). The organic layer was separated and concentrated in vacuo to give a crude residue which was chromatographed on silica gel eluting with 0-100% EtOAc in hexanes to give the title compound 74B LCMS (m/z): 328.9 [M+H-Boc ]+; t _R =1.38 min on LC/MS Method A.

Synthesis of (R)-methyl-2-amino-6-fluorohexanoate (74C). A 2-necked flask containing lithium (170 mg, 24.5 mmol, 15 eq.) was cooled at -40° C. before adding liquid ammonia (15 ml) with a cold finger. To the dark blue mixture was added (3R,5R,6S)-tert-butyl-3-(4-fluorobutyl)-2-oxo5,6-diphenylmorpholine-4-carboxylate 74B (700 mg, 1.6 mmol, 1 eq. .). The reaction mixture was maintained at the same temperature for 1 h and then allowed to warm to rt. The reaction mixture was slowly quenched with NH ₄ Cl solution and diluted with diethyl ether and the organic layer was separated. The aqueous layer was adjusted to pH 5 with 1N HCl and then extracted with EtOAc. The organic layers were washed with saturated NH4Cl, dried over MgSO4, filtered and concentrated under reduced pressure. The organic residues were combined and treated with DCM (10 ml) and MeOH (1 ml) together with (trimethylsilyl)diazomethane (2.0 M solution in hexanes, 0.50 ml, 3.2 mmol, 4 eq.). After 1 h, the reaction mixture was concentrated under reduced pressure. The crude material was treated with DCM (5 ml) and TFA

- 115 041413 (5 ml). The mixture was stirred for 2 hours and then concentrated under reduced pressure to give crude 74C which was used without further purification.

Synthesis of (R)-methyl-2-((2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-6-fluorohexanoate (74D). 2,4dichloropyrido[3,2H]pyrimidine (163 mg, 0.82 mmol, 1.1 eq.) was dissolved in dioxane (6 ml), N,N-diisopropylethylamine (0.53 ml, 2.9 mmol, 4 eq.) and (R)-methyl-2-amino-6-fluorohexanoate 74C (205 mg, 0.74 mmol, 1 eq.). The reaction mixture was stirred for 1 hour and then mixture 74D was used directly. LCMS (m/z): 326.80 [M+H]+; t _R =1.04 min on LC/MS Method A.

Synthesis of (R)-methyl-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-6fluorohexanoate (74E). Solution of (R)-methyl-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4yl)amino)-6-fluorohexanoate 74D (243 mg, 0.74 mmol , 1 eq.), obtained as described, was treated with 2,4-dimethoxybenzylamine (0.22 ml, 1.49 mmol, 2 eq.). The reaction mixture was heated at 120°C overnight. The reaction mixture was partitioned between EtOAc (50 ml) and H2O (50 ml). The organic layer was separated, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 0-100% EtOAc in hexanes to give 74E. LCMS (m/z): 445.61 [M+H] ⁺ ; t _R =0.87 min on LC/MS Method A.

Synthesis of (R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-6-fluorohexan1-ol (74F). (R)-methyl-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-6fluorohexanoate 74E (236 mg, 0.52 mmol, 1 equiv) was treated with THF (5 ml) and 1 M lithium aluminum hydride in ether (1.5 ml, 1.54 mmol, 3 equiv.). The reaction mixture was stirred at rt. After 2 hours the reaction mixture was quenched with water (50 ml) and extracted with EtOAc (50 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo. The crude material 74F was used without further purification. LCMS (m/z): 430.52 [M+H] ⁺ ; t _R =0.79 min on LC/MS Method A.

Synthesis of (R)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-6-fluorohexan-1-ol (74). (R)-2-((2((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-6-fluorohexan-1-ol 74F (80 mg, 0. 18 mmol, 1 eq.) was treated with DCM (2 ml) and TFA (0.5 ml). After 3 hours, the reaction mixture was concentrated under reduced pressure and subjected to reverse phase HPLC (10-70% MeCN in water with 0.1% TFA using a Hydro-RP column) to give, after collecting product fractions and removing volatiles in vacuo, 74 as TFA salt. LCMS (m/z): 280.15 [M+H] ⁺ ; t _R =0.56 min on LC/MS Method A.

¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.64 (dd, J=4.3, 1.4 Hz, 1H), 7.84 (dd, J=8.5, 1.4 Hz, 1H), 4.63-4.50 (m, 1H), 4.47 (t, J=6.0 Hz, 1H), 4.35 (t, J=6.0 Hz, 1H), 3, 74 (d, J=5.3 Hz, 2H), 1.89-1.61 (m, 4H), 1.60-1.39 (m, 2H).

¹⁹ F NMR (377 MHz, methanol-d ₄ ) δ -77.66, -220.85 (ddd, J=47.6, 25.5, 22.1 Hz).

Example 75

Synthesis of (3R,5R,6S)-tert-butyl-2-oxo-3-pentyl-5,6-diphenylmorpholine-4-carboxylate (75B). A stirred solution of (2S,3R)-tert-butyl-6-oxo-2,3-diphenylmorpholine-4-carboxylate 72A (1000 mg, 2.8 mmol, 1 eq., supplied by Sigma-Aldrich) and 1-iodopentane (1 .8 ml, 14.2 mmol, 5 equiv., supplied by Sigma-Aldrich) in anhydrous THF (15 ml) and HMPA (1.5 ml), cooled to -78°C, was treated dropwise with 1 M bis(trimethylsilyl) lithium amide in THF (4.2 ml, 1.5 equiv.) under argon. After 10 min, the reaction mixture was stirred at -40°C for 4 h. The reaction mixture was quenched with EtOAc and poured into a mixture of EtOAc (50 ml) and aqueous NH ₄ Cl solution (50 ml, 1 M). The organic layer was separated and concentrated in vacuo to give a crude residue which was chromatographed on silica gel eluting with 0-100% EtOAc in hexanes to give 75B. LCMS (m/z): 310.08 [M+H] ⁺ ; t _R =0.1.33 min on LC/MS Method A.

- 116 041413

Synthesis of (R)-methyl-2-aminoheptanoate (75C). A 2-neck flask containing lithium (110 mg, 15.9 mmol, 15 eq.) was cooled at -40°C before adding liquid ammonia (15 ml) with a cold finger. To the dark blue mixture was added (3R,5R,6S)-tert-butyl-2-oxo-3-pentyl-5,6-diphenylmorpholine-4-carboxylate 75B (450 mg, 1.06 mmol, 1 eq.). The reaction mixture was maintained at the same temperature for 1 h and then allowed to warm to rt. The reaction mixture was slowly quenched with a solution of NH ₄ Cl (5 ml) and diluted with ether (50 ml) and separated. 1N HCl was added to the aqueous layer until pH 5, which was then extracted with EtOAc (50 ml). Each of the organic layers was then washed separately with saturated NH4Cl, then combined, dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was treated with DCM (10 ml) and MeOH (1 ml) together with (trimethylsilyl)diazomethane, 2.0 M solution in hexanes (1.1 ml, 2.1 mmol, 4 eq.). After 1 h the reaction mixture was concentrated under reduced pressure and the residue was dissolved in DCM (5 ml) and TFA (5 ml). The mixture was stirred for 2 hours and then concentrated under reduced pressure to give crude 75°C which was used without further purification.

Synthesis of (R)-methyl-2-((2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)heptanoate (75D). A solution of 2,4,dichloropyrido[3,2-d]pyrimidine (89 mg, 0.44 mmol, 1.2 eq.) in THF (5 mL) was treated with N,N-diisopropylethylamine (0.26 mL, 1.76 mmol, 4 eq.) and (R)-methyl-2-aminoheptanoate 75C (71 mg, 0.44 mmol, 1 eq., TFA salt). The reaction mixture was stirred for 1 hour and then the mixture containing 75D was used without purification. LCMS (m/z): 323.8 [M+H]+; t _R =1.32 min on LC/MS Method A.

Synthesis of (R)-methyl-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4yl)amino)heptanoate (75E). To a solution containing (R)-methyl-2-((2-chloropyrido[3,2-d]pyrimidin-4yl)amino)heptanoate 75D (120 mg, 0.37 mmol, 1 eq) prepared as described, 2,4-dimethoxybenzylamine (0.17 ml, 1.1 mmol, 3 eq.) was added. The reaction mixture was heated at 120°C overnight. The reaction mixture was partitioned between EtOAc (50 ml) and H2O (50 ml). The organic layer was separated, dried, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 0100% EtOAc in hexanes to give the title compound 75E. LCMS (m/z): 454.6 [M+H]+; t _R =1.02 min on LC/MS Method A.

Synthesis of (R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)heptan-1-ol (75F). (R)-methyl-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)heptanoate 75E (169 mg, 0.37 mmol, 1 eq.) was dissolved in THF (5 ml) and treated with 1 M lithium aluminum hydride in ether (1.1 ml, 1.1 mmol, 3 eq.). The reaction mixture was stirred at rt. After 2 h the reaction mixture was quenched with water and extracted with EtOAc. The organics were separated, dried and concentrated in vacuo. The crude product 75F was used without further purification. LCMS (m/z): 426.4 [M+H]+; t _R =0.95 min on LC/MS Method A.

Synthesis of (R)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)heptan-1-ol (75). (R)-2-((2-((2,4dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)heptan-1-ol 75F (20 mg, 0.05 mmol, 1 eq.) was dissolved in DCM (2 ml) and TFA (0.5 ml). After 3 hours, the reaction mixture was concentrated under reduced pressure and the residue was subjected to reverse phase HPLC (10-70% MeCN in water with 0.1% TFA using a Hydro-RP column) to give, after collecting product fractions and removing volatiles in vacuo , 75 as TFA salt. LCMS (m/z): 276.4 [M+H]+; t _R =0.71 min on LC/MS Method A.

¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.65 (dd, J=4.3, 1.6 Hz, 1H), 7.92-7.66 (m, 2H), 4.66- 4.43 (m, 1H), 3.73 (d, J=5.3 Hz, 2H), 1.81-1.57 (m, 2H), 1.51-1.20 (m, 9H) , 0.89 (t, J=7.0 Hz, 3H).

¹⁹ F NMR (377 MHz, methanol-d ₄ ) δ -77.55.

- 117 041413

Example 76 and Example 77

Synthesis of (S)-methyl-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (76B). (R)-methyl-2-((tert-butoxycarbonyl)amino)-3-hydroxypropanoate 76A (6 g, 27.37 mmol, supplied by Sigma-Aldrich) was treated with DMF (100 ml) and cooled to 0°C before slowly adding methyltriphenoxyphosphonium iodide (16.1 g, 35.58 mmol, 1.3 eq., supplied by Sigma-Aldrich). The reaction mixture was stirred overnight and solid NaHCO ₃ (14 g) and water (100 ml) were added to the reaction mixture. The reaction mixture was stirred for 15 minutes. and then the mixture was extracted with hexanes in diethyl ether, (1:1) (2x250 ml). The combined organic extracts were washed with 0.5 M NaOH (3x75 ml) and saturated NH ₄ Cl (75 ml), dried over MgSO ₄ , filtered and concentrated under reduced pressure to give the crude product 76B. LCMS (m/z): 331.13 [M+H]+; t _R =1.16 min on LC/MS Method A.

Synthesis of (R)-methyl-2-((tert-butoxycarbonyl)amino)-5-methylhex-5-enoate (76С). Zinc dust (2.4 g, 36.4 mmol, 4 eq.) was added to iodine (93 mg, 0.37 mmol, 0.04 eq.) in a three-necked round bottom flask and heated under vacuum for 10 minutes. The flask was purged with nitrogen and evacuated three times. (S)methyl 2-((tert-butoxycarbonyl)amino)-3-iodopropanoate 76B (3000 mg, 9.11 mmol) was dissolved in dry DMF (5 ml) and added to the zinc suspension at 0°C. The reaction mixture was stirred at rt for 1 h. Copper(I) bromide-dimethylsulfide complex (187.39 mg, 0.91 mmol, 0.1 equiv., supplied by Sigma-Aldrich) was placed in a separate three-necked flask and dried carefully under vacuum until the color change from white to green is observed. Dry DMF (4 ml) and 3-chloro-2-methylpropene (1.34 ml, 13.67 mmol, supplied by Sigma-Aldrich) were added and the reaction mixture was cooled to -15°C. After completion of the introduction of zinc in the first stage, the stirring was stopped and the zinc was left to settle. The supernatant was removed with a syringe and added dropwise to the electrophilic and Cu-catalytic

- 118 041413 mixtures at -15°C. The cold bath was removed and the reaction mixture was stirred at rt for 2 days. EtOAc (100 ml) was added and the reaction mixture was stirred for 15 minutes. The reaction mixture was washed with 1 M Na ₂ S ₂ O ₃ (100 ml), water (2x100 ml) and brine (100 ml), dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 0-100% EtOAc in hexane to give 76C. LCMS (m/z): 157.95 [M+H-Boc]+; t _R =1.16 min on LC/MS Method A.

Synthesis of (R)-methyl-2-amino-5-methylhex-5-enoate (76D). N)-methyl-2-((tert-butoxycarbonyl)amino)heptanoate 76C (655 mg, 3 mmol) was treated with DCM (5 ml) and TFA (5 ml) and stirred for 2 h. The mixture was then concentrated under reduced pressure with obtaining 76D, which was used without further purification.

Synthesis of (R)-methyl-2-((2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-5-methylhex-5-enoate (76E). 2,4,Dichloropyrido[3,2-d]pyrimidine (466 mg, 2 mmol, 1 eq.) was treated with THF (10 ml) followed by the addition of N,N-diisopropylethylamine (1.66 ml, 9 mmol, 4 eq. ) and then (R)-methyl-2-amino-5-methylhex5-enoate 76D (593 mg, 2 mmol, 1 eq., TFA salt). The reaction mixture was stirred for 1 hour and then the product 76E was used directly. LCMS (m/z): 321.2 [M+H]+; t _R =1.19 min on LC/MS Method A.

Synthesis of (R)-methyl-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-5methylhex-5-enoate (76F). A solution of (R)-methyl-2-((2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-5-methylhex5-enoate 76E (748 mg, 2 mmol, 1 eq) prepared as described, was treated with 2,4-dimethoxybenzylamine (0.69 ml, 5 mmol, 2 eq.) and N,N-diisopropylethylamine (1.66 ml, 9 mmol, 4 eq.). The reaction mixture was heated at 120°C overnight. The reaction mixture was partitioned between EtOAc (50 ml) and H2O (50 ml). The organic layer was separated, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 0-100% EtOAc in hexane to give the title compound 76F (LCMS (m/z): 452.55 [M+H]+; t _R = 0.97 min on LC/ MS Method A.

Synthesis of (R)-methyl-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-5methylhexanoate (76G). (R)-methyl-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4yl)amino)-5-methylhex-5-enoate 76F (35 mg, 0 .08 mmol) was treated with Pd/C (50 mg) and EtOH (5 ml) and then stirred under a hydrogen atmosphere. After 4 h, the solid was removed by filtration and the filtrate was concentrated under reduced pressure. The resulting residue 76G was used without further purification. LCMS (m/z): 454.24 [M+H]+; t _R =1.06 min on LC/MS Method A.

Synthesis of (R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-5methylhexan-1-ol (76H). (R)-methyl-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4yl)amino)-5-methylhexanoate 76G (32 mg, 0.37 mmol, 1 eq.) was treated with THF (5 ml) and 1 M lithium aluminum hydride in ether (0.2 ml, 0.2 mmol, 3 eq.). The reaction mixture was stirred for 2 h and then quenched with water (50 ml) and extracted with EtOAc (50 ml). The organic layer was separated, dried over MgSO4 and concentrated in vacuo. The crude 76H was used without further purification. LCMS (m/z): 426.23 [M+H]+; t _R =0.96 min on LC/MS Method A.

Synthesis of (R)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-5-methylhexan-1-ol. (R)-2-((2-((2,4dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-5-methylhexan-1-ol (76). Compound 76H (25 mg, 0.05 mmol, 1 eq.) was treated with DCM (2 ml) and TFA (0.5 ml). After 3 hours, the reaction mixture was concentrated under reduced pressure and subjected to reverse phase HPLC (10-70% MeCN in water with 0.1% TFA using Hydro-RP) to give, after collection of product fractions and removal of volatiles in vacuo, 76 LCMS (m/z): 276.13 [M+H]+; t _R =0.70 min on LC/MS Method A.

Synthesis of (R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-5-methylhex5-en-1-ol (77A) . (R)-methyl-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-5methylhex-5-enoate 76F (40mg, 90 mmol, 1 eq.) was treated with THF (5 ml) and 1 M lithium aluminum hydride in ether (0.27 ml, 0.27 mmol, 3 eq.). The reaction mixture was stirred for 2 h and then quenched with water (50 ml) and extracted with EtOAc (50 ml). The organics were separated, dried and concentrated in vacuo to give residue 77A, which was used without further purification. LCMS (m/z): 424.20 [M+H]+; t _R =0.88 min on LC/MS Method A.

Synthesis of (R)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-5-methylhex-5-en-1-ol (77). 77A (40 mg, 0.095 mmol, 1 eq.) was treated with DCM (2 ml) and TFA (0.5 ml). After 3 hours, the reaction mixture was concentrated under reduced pressure and subjected to reverse phase HPLC (10-70% MeCN in water with 0.1% TFA using a Hydro-RP column) to give, after collecting product fractions and removing volatiles in vacuo, the title compound 77 as a TFA salt. LCMS (m/z): 274.43 [M+H]+; t _R =0.65 min on LC/MS Method A.

¹ H NMR (400 MHz, methanol^) δ 8.59-8.42 (m, 1H), 7.75-7.52 (m, 2H), 4.45-4.13 (m, 1H), 3.87-3.69 (m, 1H), 3.65-3.44 (m, 2H), 2.30 (dq, J=15.0, 7.1 Hz, 1H), 2.01- 1.73 (m, 2H), 1.68-1.41 (m, 4H), 1.26-1.05 (m, 6H).

¹⁹ F NMR (377 MHz, methanol-d4) δ -77.52.

- 119 041413

Example 78

Synthesis of (R)-methyl-2-((tert-butoxycarbonyl)amino)-5-oxohexanoate (78A). (R)-methyl-2-((tert-butoxycarbonyl)amino)-5-methylhex-5-enoate 76C (775 mg, 3.01 mmol) was treated with DCM (20 ml) and MeOH (5 ml) before cooling to -78° C. Ozone was bubbled through the reaction mixture. After 10 min, the mixture was quenched with dimethyl sulfide (0.90 ml, 12 mmol, 4 eq.) and allowed to warm to rt. EtOAc (100 ml) was added and the reaction mixture was stirred for 15 minutes. The mixture was washed with 1 M Na ₂ S ₂ O ₃ (100 ml), water (2x100 ml) and brine (100 ml) and dried over MgSO ₄ . The organic solution was filtered and concentrated under reduced pressure and the resulting residue was subjected to silica gel chromatography eluting with 0-100% EtOAc in hexane to give 78A 1H NMR (400 MHz, chloroform-d) δ 5.11 (d, J=8.3 Hz, 1H), 4.33-4.20(m, 1H), 3.73(s, 4H), 2.63-2.42(m, 3H), 2.14(s, 4H), 2 .12-2.05 (m, 1H), 1.94-1.81 (m, 1H), 1.42 (s, 13H).

Synthesis of (R)-methyl-2-((tert-butoxycarbonyl)amino)-5,5-difluorohexanoate (78B). (R)-methyl-2((tert-butoxycarbonyl)amino)-5-oxohexanoate 78A (235 mg, 0.91 mmol) was dissolved in DCM (10 ml) then treated with DAST 95% (0.36 ml, 2. 72 mmol). The reaction mixture was stirred for 16 hours. EtOAc (50 ml) and NaHCO ₃ solution (5 ml) were added and the reaction mixture was stirred for 5 minutes. The reaction mixture was washed with 1 M Na ₂ S ₂ O ₃ (100 ml), water (2x100 ml) and brine (100 ml) and dried over MgSO ₄ . The solvent was removed under reduced pressure and the residue was chromatographed on silica gel eluting with 0-100% EtOAc in hexanes to give 78B.

¹ H NMR (400 MHz, chloroform-d) δ 5.04 (s, 1H), 4.32 (s, 1H), 3.76 (s, 5H), 2.16-1.99 (m, 2H ), 1.98-1.75 (m, 5H), 1.69-1.52 (m, 7H), 1.44 (s, 16H), 1.34-1.20 (m, 2H), 0.92-0.80 (m, 1H).

¹⁹ F NMR (377 MHz, chloroform-d) δ -92.14 (dq, J=50.1, 17.0 Hz).

Synthesis of (R)-methyl-2-amino-5,5-difluorohexanoate (78C). (R)-methyl-2-((tert-butoxycarbonyl)amino)-5,5-difluorohexanoate 78B (36 mg, 0.13 mmol, 1 eq) was treated with DCM (2 ml) and TFA (0.5 ml) . After 3 hours the reaction mixture was concentrated under reduced pressure and the crude product 78C was used without further purification.

Synthesis of (R)-methyl-2-((2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-5,5-difluorohexanoate (78D). 2,4,Dichloropyrido[3,2-d]pyrimidine (33 mg, 0.16 mmol, 1.25 eq.) was treated with THF (10 mL) followed by the addition of N,N-diisopropylethylamine (0.18 mL, 1.25 equiv.). 0 mmol, 8 eq.) and (R)-methyl-2-amino-5,5-difluorohexanoate 78C (36 mg, 0.13 mmol, 1 eq., TFA salt). The reaction mixture was stirred for 1 hour to give 78D, and then this mixture was used directly. LCMS (m/z): 345.13 [M+H]+; t _R =1.08 min on LC/MS Method A.

Synthesis of (R)-methyl-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-5,5difluorohexanoate (78E). (R)-methyl-2-((2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-5,5-difluorohexanoate 78D (45 mg, 0.13 mmol, 1 eq) obtained treated as described with 2,4-dimethoxybenzylamine (0.077 ml, 0.52 mmol, 4 eq.). The reaction mixture was heated at 120°C overnight. The reaction mixture was partitioned between EtOAc (100 ml) and H2O (100 ml). The organics were separated, dried and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 0-100% EtOAc in hexanes to give the title compound 78E. LCMS (m/z): 476.13 [M+H]+; t _R =0.99 min on LC/MS Method A.

Synthesis of (R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-5,5difluorohexan-1-ol (78F). (R)-methyl-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4yl)amino)-5,5-difluorohexanoate 78E (26 mg, 0.055 mmol, 1 eq.) was treated with THF (5 ml) and 1 M lithium aluminum hydride in ether (0.2 ml, 0.2 mmol, 4 eq.). The reaction mixture was stirred at rt for 2 h

- 120 041413 and then the reaction mixture was extinguished with water (50 ml) and was extracted with EtOAc (50 ml). The organics were separated, dried and concentrated in vacuo. Crude 78E was used without further purification. LCMS (m/z): 448.12 [M+H]+; tR=0.91 min on LC/MS Method A.

Synthesis of (R)-2-((2-aminopyrido[3,2-d]pyrimigin-4-yl)amino)-5,5-g-fluorohexan-1-ol (78). (R)-2-((2((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-5,5-difluorohexan-1-ol 78F (24mg, 0.055 mmol, 1 eq.) was treated with DCM (2 ml) and TFA (0.5 ml). After 3 hours, the reaction mixture was concentrated under reduced pressure and subjected to reverse phase HPLC (10-70% MeCN in water with 0.1% TFA using a Hydro-RP column) to give, after collecting product fractions and removing volatiles in vacuo, 78. LCMS (m/z): 298.10 [M+H]+; t _R =0.60 min on LC/MS Method A.

¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.66 (dd, J=4.3, 1.5 Hz, 5H), 7.86-7.73 (m, 10H), 4.55 ( dd, J=9.0, 4.7 Hz, 5H), 4.30 (s, 1H), 3.83 (s, 2H), 3.76 (t, J=5.1 Hz, 12H), 3.34 (s, 3H), 2.05-1.85 (m, 23H), 1.58 (t, J=18.5 Hz, 17H), 1.41-1.26 (m, 17H) , 1.14 (s, 1H), 0.96-0.88 (m, 4H), 0.87 (s, 2H).

¹⁹ F NMR (377 MHz, methanol-d ₄ ) δ -77.67, -92.96 (p, J=17.4 Hz).

Example 79

79F79

Synthesis of (R)-methyl-2-((tert-butoxycarbonyl)amino)-4-oxohexanoate (79A). Zinc dust (1.58 g, 24.3 mmol, 4 eq.) was added to iodine (61 mg, 0.24 mmol, 0.04 eq.) in a three-necked round bottom flask and heated under vacuum for 10 minutes. The flask was purged with nitrogen and evacuated three times. After cooling, benzene (10 ml) and DMA (1 ml) were added. Then 1,2-bromoethane (0.05 ml, 0.61 mmol) and chlorotrimethylsilane (33.01 mg, 0.3 mmol) were added successively and the process was repeated three times for 1 hour. (S)-methyl-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate 76B (2400 mg, 0.6 mmol, 1 eq.) was dissolved in benzene (10 ml) and DMA (1 ml) and added to zinc suspensions. After about 1 hour, bis(triphenylphosphine)palladium(II) dichloride (106.62 mg, 0.025 eq.) and tetrakis(triphenylphosphine)palladium(0) (175.68 mg, 0.025 eq.) were added, followed by the addition of propionyl chloride (0.025 eq.) .8 ml, 0.01 mol, 1.5 eq.). The reaction mixture was heated to 70° C. and stirred for 1 h. EtOAc (100 ml) was added and the reaction mixture was filtered through a pad of celite. The filtrate was washed with water (2x100 ml), brine (100 ml), dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 0-100% EtOAc in hexane to give 79A.

1H NMR (400 MHz, chloroform-d) δ 5.48 (d, J=8.6 Hz, 1H), 4.46 (dt, J=8.7, 4.4 Hz, 1H), 3.69 (s, 3H), 3.10 (dd, J=18.0, 4.5 Hz, 1H), 2.89 (dd, J=17.9, 4.4 Hz, 1H), 2.40 ( qd, J=7.3, 1.7 Hz, 2H), 1.40 (s, 10H), 1.01 (t, J=7.3 Hz, 3H).

Synthesis of (R)-methyl-2-((tert-butoxycarbonyl)amino)-4,4-difluorohexanoateα (79B). (R)-methyl-2((tert-butoxycarbonyl)amino)-4-oxohexanoate 79A (475 mg, 1.8 mmol, 1 eq.) was treated with DAST (0.97 ml, 7.3 mmol, 4 eq.) . The reaction mixture was stirred for 16 hours. EtOAc (50 ml) and NaHCO ₃ solution (5 ml) were added and the reaction mixture was stirred for 5 minutes. The reaction mixture was washed with 1 M Na ₂ S ₂ O ₃ (100 ml), water (2x100 ml), brine (100 ml), dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 0-100% EtOAc in hexane to give 79B.

1H NMR (400 MHz, chloroform-d) δ 5.20 (d, J=8.3 Hz, 1H), 4.51 (d, J=7.0 Hz, 1H), 3.82 (s, 1H ), 3.75 (d, J=0.5 Hz, 5H), 3.35-3.17 (m, 2H), 3.11 (q, J=7.1 Hz, 2H), 2.52 -2.27 (m, 3H), 1.89 (ddt, J=24.1, 16.8, 7.5Hz, 3H), 1.44 (d, J=0.6Hz, 15H), 1.23-1.13 (m, 4H), 1.00 (dt, J=10.7, 7.5 Hz, 6H).

- 121 041413 ¹⁹ F NMR (377 MHz, chloroform-d) δ -93.56 - -109.28 (m).

Synthesis of (R)-methyl-2-amino-5,5-difluorohexanoate. (R)-methyl-2-((tert-butoxycarbonyl)amino)-4,4difluorohexanoate (79C). Compound 79B (98 mg, 0.35 mmol, 1 eq) was treated with DCM (2 ml) and TFA (0.5 ml). After 3 h the reaction mixture was concentrated under reduced pressure and the crude product

79С in the form of TFA salt was used without further purification.

Synthesis of (R)-methyl-2-((2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-4,4-difluorohexanoate (79D). 2,4,Dichloropyrido[3,2-d]pyrimidine (80 mg, 0.39 mmol, 1 eq.) was treated with THF (10 mL) followed by N,N-diisopropylethylamine (0.28 mL, 1.5 mmol , 4 eq.) and then (R)-methyl-2-amino-5,5-difluorohexanoate 79C (110 mg, 0.39 mmol, 1 eq., TFA salt). The reaction mixture was stirred for 1 hour to give 79D and then this solution was used directly. LCMS (m/z): 345.11 [M+H]+; t _R =1.09 min on LC/MS Method A.

Synthesis of (R)-methyl-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-4,4difluorohexanoate (79E). a solution of (R)-methyl-2-((2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-5,5difluorohexanoate 79D prepared as described was treated with 2,4-dimethoxybenzylamine (0.077 mL, 0 .52 mmol, 4 eq.). The reaction mixture was heated at 120°C overnight. The reaction mixture was partitioned between EtOAc (50 ml) and H2O (50 ml). The organics were separated, dried over MgSO ₄ and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 0-100% EtOAc in hexanes to give 79E. LCMS (m/z): 476.32 [M+H]+; t _R =0.96 min on LC/MS Method A.

Synthesis of (R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-4,4difluorohexan-1-ol (79F). (R)-methyl-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4yl)amino)-4,4-difluorohexanoate 79E (35 mg, 0.074 mmol, 1 eq.) was treated with THF (5 ml) and 1 M lithium aluminum hydride in ether (0.29 ml, 0.29 mmol, 4 eq.). The reaction mixture was stirred for 2 h and then the reaction mixture was quenched with water (50 ml) and was extracted with EtOAc (50 ml). The organic layer was separated, dried over MgSO ₄ and concentrated in vacuo. Crude 79F was used without further purification. LCMS (m/z): 448.20 [M+H]+; t _R =0.86 min on LC/MS Method A.

Synthesis of (R)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-4,4-difluorohexan-1-ol (79). (R)-2-((2((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-4,4-difluorohexan-1-ol 79F (24mg, 0.055 mmol, 1 eq.) was treated with DCM (2 ml) and TFA (0.5 ml). After 3 hours, the reaction mixture was concentrated under reduced pressure and subjected to reverse phase HPLC (10-70% MeCN in water with 0.1% TFA using a Hydro-RP column) to give, after collecting product fractions and removing volatiles in vacuo, 79 as TFA salt. LCMS (m/z): 298.11 [M+H]+; t _R =0.63 min on LC/MS Method A.

1H NMR (400 MHz, methanol-d4) δ 8.51 (dd, J=4.3, 1.5 Hz, 1H), 7.77-7.54 (m, 2H), 3.60 (d, J=5.7 Hz, 2H), 2.37-2.11 (m, 2H), 1.93-1.69 (m, 2H), 0.87 (t, J=7.5 Hz, 3H ).

¹⁹ F NMR (377 MHz, methanol-d ₄ ) δ -77.80, -98.15, -105.45 (m).

Example 80 and Example 81 ci nm 1

Fmoc-N<Rj,COOH _{1 TMSDM} d _XM H ₂ N CO ₂ Me C Vj*DIPEA ' piperidine

80A

Synthesis of (R)-methyl-2-amino-2-methylpent-4-enoate (80B). (R)-2-((((9H-fluoren-9-yl)methoxy)

- 122 041413 carbonyl)amino)-2-methylpent-4-enoic acid 80A (1 g, 2.8 mmol, 1 eq., obtained from Okeanos Inc.) was treated with DCM (10 ml) and MeOH (1 ml), together with (trimethylsilyl)diazomethane (2.0M solution in hexanes, 2.3 ml, 5.6 mmol, 2.5 eq.). After 1 hour, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was treated with THF (10 ml) followed by the addition of piperidine (0.56 ml, 0.006 mol, 2 eq.). The mixture was stirred for 2 hours and then concentrated under reduced pressure to give 80V, which was used without further purification.

Synthesis of (R)-methyl-2-((2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylpent-4-enoate (80C). 2,4,Dichloropyrido[3,2-d]pyrimidine (540 mg, 2.71 mmol, 1 eq.) was treated with dioxane (15 mL) followed by N-diisopropylethylamine (1.9 mL, 10.8 mmol, 4 eq.) and then (R)-methyl-2amino-2-methylpent-4-enoatom 80B (486 mg, 2.71 mmol, 1 eq.). The reaction mixture was stirred at 80° C. for 15 min, then additional 2,4,-dichloropyrido[3,2d]pyrimidine (250 mg, 1.25 mmol) was added. The mixture was stirred at 80° C. overnight to give 80° C., which was then used directly. LCMS (m/z): 307.12 [M+H]+; t _R =1.14 min on LC/MS Method A.

Synthesis of (R)-methyl-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-2methylpent-4-enoate (80D). a solution of (R)-methyl-2-((2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-2methylpent-4-enoate 80C, obtained as described, was treated with 2,4-dimethoxybenzylamine (0. 80 ml, 5.0 mmol, 2 eq.). The reaction mixture was heated at 120°C overnight. The reaction mixture was partitioned between EtOAc (50 ml) and H2O (50 ml). The organics were separated, dried over MgSO ₄ and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 0-100% EtOAc in hexane to give 80D. LCMS (m/z): 438.20 [M+H]+; t _R =1.04 min on LC/MS Method A.

Synthesis of (R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylpent4-en-1-ol (80E) . (R)-methyl-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-2methylpent-4-enoate 80D (634 mg, 1 44 mmol, 1 eq.) was treated with THF (20 ml) and 1 M lithium aluminum hydride in ether (3.6 ml, 3.62 mmol, 2.5 eq.). The reaction mixture was stirred for 2 h and then the reaction mixture was quenched with water (100 ml) and was extracted with EtOAc (100 ml). The organic layer was separated, dried over MgSO ₄ and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 0-100% EtOAc in hexane to give 80E. LCMS (m/z): 410.17 [M+H]+; t _R =0.97 min on LC/MS Method A.

Synthesis of (R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-2methylpentan-1-ol (80F). (R)-methyl-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4yl)amino)-5-methylhex-5-enoate 80E (35 mg, 0 .09 mmol) was treated with Pd/C (60 mg) and EtOH (5 ml) and then stirred under a hydrogen atmosphere. After 24 hours the solid was filtered off and the filtrate was concentrated under reduced pressure. The resulting 80F residue was used without further purification. LCMS (m/z): 454.24 [M+H]+; t _R =1.06 min on LC/MS Method A.

Synthesis of (R)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylpentan-1-ol (80). (R)-2-((2((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylpentan-1-ol 80F (35 mg, 0. 09 mmol, 1 eq.) was treated with DCM (2 ml) and TFA (0.5 ml). After 3 hours, the reaction mixture was concentrated under reduced pressure and subjected to reverse phase HPLC (10-70% MeCN in water with 0.1% TFA using a Hydro-RP column) to give, after collecting product fractions and removing volatiles in vacuo, 80 as TFA salt. LCMS (m/z): 262.13 [M+H]+; t _R =0.64 min on LC/MS Method A.

Synthesis of (R)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylpent-4-en-1-ol (81). (R)methyl-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-5-methylhex-5-enoate 80E (40 mg, 0.10 mmol, 1 eq.) was treated with DCM (2 ml) and TFA (0.5 ml). After 4 hours, the reaction mixture was concentrated under reduced pressure and subjected to reverse phase HPLC (10-70% MeCN in water with 0.1% TFA using a Hydro-RP column) to give, after collecting product fractions and removing volatiles in vacuo, 81 as TFA salt. LCMS (m/z): 260.10 [M+H]+; t _R =0.63 min on LC/MS Method A.

¹ H NMR (400 MHz, methanol-d4) δ 8.59 (dd, J=4.4, 1.4 Hz, 1H), 7.84 (dd, J=8.5, 1.4 Hz, 1H ), 7.75 (dd, J=8.5, 4.4 Hz, 1H), 5.87 (ddt, J=17.5, 10.1, 7.4 Hz, 1H), 5.33- 4.94 (m, 2H), 3.94 (d, J=11.2 Hz, 1H), 3.78 (d, J=11.2 Hz, 1H), 2.97-2.76 (m , 1H), 2.70 (ddt, J=13.9, 7.3, 1.2 Hz, 1H), 1.55 (s, 3H).

¹⁹ F NMR (377 MHz, methanol-d4) δ -77.56.

- 123 041413

Example 82

82B 82

Synthesis of 2-amino-7-bromopyrido[3,2-d]pyrimidin-4-ol (82A). A mixture of 3-amino-5-bromopyridine-2-carboxamide (3.0 g, 13.9 mmol, 1 eq., supplied by Combi-Blocks Inc.), chloroformamidine hydrochloride (3192.9 mg, 27.8 mmol, 2 eq.) , methylsulfone (13.1 g, 139 mmol, 10 eq.) in sulfolane (1 ml) in a sealed tube was heated at 165°C. After 24 h the mixture was diluted with water and then cooled to rt. The reaction mixture was adjusted to pH 12 using NH4OH and stirred for 20 min. The precipitates were then filtered, washed with water, hexanes and ether, and dried in a vacuum oven at 100° C. overnight to give 82A, which was used without further purification. LCMS (m/z): 242.92 [M+H]+; tR=0.55 min on LC/MS Method A.

Synthesis of 2-amino-7-bromopyrido[3,2-d]pyrimidin-4-yl 4-methylbenzenesulfonate (82B). 2-amino-7-bromopyrido[3,2-d]pyrimidin-4-ol 82A (1000 mg, 4.2 mmol, 1 eq.) was treated with acetonitrile (40 ml) followed by potassium carbonate (1433.4 mg, 10 37 mmol, 2.5 eq.) and ptoluenesulfonyl chloride (1186.38 mg, 6.22 mmol, 1.5 eq.). The reaction mixture was heated to 100°C and stirred overnight. The mixture was left to cool and then diluted with EtOAc, washed with water and saturated NH ₄ Cl. The organic layer was dried over MgSO ₄ , filtered and concentrated under reduced pressure to give 82B which was used without further purification. LCMS (m/z): 396.98 [M+H] ⁺ ; tR=1.15 min on LC/MS Method A.

Synthesis of (R)-2-((2-amino-7-bromopyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol (82). 2-Amino-7-bromopyrido[3,2-d]pyrimidin-4-yl 4-methylbenzenesulfonate 82B (50 mg, 0.13 mmol, 1 eq.) was treated with acetonitrile (5 ml), N,N-diisopropylethylamine (0.07 ml, 0.38 mmol, 3 eq.) and (R)-(-)2-amino-1-hexanol (44.48 mg, 0.38 mmol, 3 eq.). After 16 hours, the reaction mixture was concentrated under reduced pressure and subjected to reverse phase HPLC (10-70% MeCN in water using a Hydro-RP column) to give, after collection of product fractions and removal of volatiles in vacuo, 82 as the TFA salt. LCMS (m/z): 342.1 [M+H] ⁺ ; t _R =0.90 min on LC/MS Method A.

¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.69 (d, J=1.9 Hz, 1H), 8.06 (d, J=1.9 Hz, 1H), 4.52 (dq , J=8.7, 5.5 Hz, 1H), 3.86-3.54 (m, 2H), 1.95-1.63 (m, 2H), 1.57-1.29 (m , 5H), 1.11-0.76 (m, 3H).

¹⁹ F NMR (377 MHz, methanol-d ₄ ) δ -77.42.

Example 83

Synthesis of (R)-methyl-2-amino-2-methylhex-5-enoate (83B). (R)-methyl-2-((((9H-fluoren-9yl)methoxy)carbonyl)amino)-2-methylhex-5-enoate 83A (2 g, 5.5 mmol, 1 eq., obtained from Okeanos Inc. .) was treated with DCM (20 ml) and MeOH (4 ml), together with (trimethylsilyl)diazomethane (2.0 M solution in hexanes, 4.4 ml, 11.0 mmol, 2.5 eq.). After 30 minutes, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was treated with THF (33 ml) followed by piperidine (1.9 ml, 0.02 mol, 3.5 eq.). The mixture was stirred for 3 days and then concentrated

- 124 041413 under reduced pressure. The residue was chromatographed on silica gel eluting with 0-20% MeOH in

DXM, yielding 83B. LCMS (m/z): 157.91 [M+H]+; tR=0.59 min on LC/MS Method A.

Synthesis of (R)-methyl-2-((2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhex-5-enoate (83C). 2,4,Dichloropyrido[3,2-d]pyrimidine (55 mg, 0.28 mmol, 1 eq) was treated with dioxane (15 mL) followed by N,N-diisopropylethylamine (0.25 mL, 1.4 mmol , 4 eq.) and then (R)-methyl-2-amino-2-methylhex-5-enoatom 83B (47.6 mg, 0.30 mmol, 1 eq.). The mixture was stirred at 80°C overnight to give 83C, which was used directly. LCMS (m/z): 321.14 [M+H]+; t _R =1.21 min on LC/MS Method A.

Synthesis of (R)-methyl-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-2methylhex-5-enoate (83D). a solution of (R)-methyl-2-((2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-2methylhex-5-enoate 83C, obtained as described, was treated with 2,4-dimethoxybenzylamine (0. 10 ml, 0.69 mmol, 2.5 eq.). The reaction mixture was heated at 120°C overnight. The reaction mixture was partitioned between EtOAc (50 ml) and H2O (50 ml). The organics were separated, dried over MgSO ₄ and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 0-100% EtOAc in hexane to give 83D. LCMS (m/z): 452.21 [M+H]+; t _R =1.22 min on LC/MS Method A.

Synthesis of (R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhex5-en-1-ol (83E) . (R)-methyl-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-2methylhex-5-enoate 83D (25 mg, 0 06 mmol, 1 eq.) was treated with THF (20 ml) and 1 M lithium aluminum hydride in ether (0.14 ml, 0.14 mmol, 2.5 eq.). The reaction mixture was stirred for 2 h and then the reaction mixture was quenched with water (100 ml) and was extracted with EtOAc (100 ml). The organic layer was separated, dried over MgSO ₄ and concentrated in vacuo to give 83E, which was used without further purification. LCMS (m/z): 424.14 [M+H]+; t _R =1.12 min on LC/MS Method A.

Synthesis of (R)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhex-5-en-1-ol (83). (R)-2-((2((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhex-5-en-1-ol 83E (23 mg, 0.05 mmol, 1 eq) were treated with DCM (2 ml) and TFA (0.5 ml). After 3 hours, the reaction mixture was concentrated under reduced pressure and subjected to reverse phase HPLC (10-70% MeCN in water with 0.1% TFA using a Hydro-RP column) to give, after collecting product fractions and removing volatiles in vacuo, 83 (10 mg, 65%) as TFA salt. LCMS (m/z): 274.7 [M+H]+; t _R =0.73 min on LC/MS Method A.

1H NMR (400 MHz, methanol-d ₄ ) δ 9.01 (d, J=4.5 Hz, 1H), 8.33-8.09 (m, 2H), 6.23 (ddt, J=16 .4, 11.0, 5.8 Hz, 1H), 5.42 (d, J=17.1 Hz, 1H), 4.40 (d, J=11.3 Hz, 1H), 4.26 -4.03 (m, 2H), 2.57 (ddd, J=29.2, 14.7, 8.4 Hz, 3H), 2.42 (dq, J=10.9, 6.9 Hz , 1H), 1.96 (s, 3H).

¹⁹ F NMR (377 MHz, methanol-d4) δ -77.19 (d, J=144.5 Hz).

Example 84

Synthesis of intermediate compound 84E o

< ^N y ^Br ZnCN2, Pd(PPh3)4 A ^η 2°2 K2CO ₃ f ^N Y^ ^NH2

P^^MH ₂ F^^NH ₂ ^{F NH} 2

84A 84B 84C

84D 84E

Synthesis of 3-amino-5-fluoropicolinonitrile (84B). 3-amino-2-bromo-5-fluoropyridine 84A (25 g, 131 mmol, Asstatech Chemical, Inc) was treated with ZnCN ₂ (16.9 g, 1.1 eq., 144 mmol), Pd(Ph ₃ ) ₄ ( 11.3 g, 0.075 eq., 9.8 mmol) and DMF (200 ml) and then heated to 115°C. After 6 h the reaction mixture was left to cool and then concentrated under reduced pressure to a solid. The solid was washed with EtOAc (2x100 ml). The organic layers were combined and washed with water (3x100 ml), saturated NH ₄ Cl solution (100 ml), dried over MgSO ₄ , filtered and concentrated under reduced pressure to give 84B, which was used without further purification. LCMS (m/z): 138.87 [M+H]+; tR=0.59 min on LC/MS Method A.

Synthesis of 3-amino-5-fluoropicolinamide (84С). Compound 84B (2.6 g, 19.0 mmol, 1 eq.) was treated with DMSO (10 ml) and cooled to 0°C before adding K ₂ CO ₃ (524 mg, 0.2 eq., 3.8 mmol) . Then H ₂ O ₂ (2.3 ml, 1.2 eq., 22.8 mmol, 30% water) was added slowly. The cooling bath was removed and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with water (100 ml) and extracted with EtOAc (3x100). The combined organic layers were washed with water (3x500) and saturated NH ₄ Cl solution (500 ml), dried over MgSO ₄ , filtered and concentrated under reduced pressure. The crude 84C was used without further purification. LCMS (m/z): 155.87 [M+H]+;

- 125 041413 tR=0.62 min on LC/MS Method A.

The following procedure has been adapted from De Jonghe, WO 2006/1359931.

Synthesis of 7-fluoropyrido[3,2-d]-pyrimidine-2,4-diol (84D). Carboxamide 84C (1 g, 1 eq., 6.4 mmol) was treated with triphosgene (1.9 g, 1.0 eq., 6.4 mmol) and dioxane (20 ml). The reaction mixture was heated to 110°C for 30 min. The reaction mixture was left to cool and concentrated under reduced pressure. The crude solid was washed with DCM and diethyl ether and left to air dry to give 84D. LCMS (m/z): 181.95 [M+H]+; tR=0.62 min on LC/MS Method A.

Synthesis of 2,4-dichloro-7-fluoropyrido[3,2-d]pyrimidine (84E). Dione 84D (13.7 g, 75.6 mmol, 1 eq.) was treated with phosphorus pentachloride (63.0 g, 302.6 mmol, 4 eq.) and phosphorus(Y) oxychloride (141 ml, 20 eq.) and heated to 110° C. under reflux for 8 hours. The reaction mixture was concentrated under reduced pressure and azeotroped with toluene. The resulting solid was treated with EtOAc (500 ml) and ice water (500 ml). The organic layer was separated and washed with saturated NaHCO ₃ solution (500 ml), water (500 ml) and saturated NH ₄ Cl (500 ml). The organic solution was dried over MgSO ₄ , filtered and concentrated under reduced pressure to give the crude product 84E. LCMS (m/z): 213.9 [M+H+2(OMe)-2Cl] ⁺ ; tR=0.82 min on LC/MS Method A.

¹ H NMR (400 MHz, chloroform-d) δ 9.01 (d, J=2.6 Hz, 1H), 7.94 (dd, J=7.9, 2.7 Hz, 1H).

¹⁹ F NMR (377 MHz, chloroform-d) δ -111.79 (d, J=7.9 Hz).

Synthesis of compound 84 _N ? DIPEA HN-V ⁰ -- DMBNH ₂

H ₂ N^CO ₂ Me G ----* n A O *

UCH J L L S Si N„ ' ⁺ F^^N^CI L D A ^{120 C}

83B 84E84F

Synthesis of (R)-methyl-2-((2-chloro-7-fluoro-irido[3,2-d]pyrimidin-4-yl)amino)-2-methylhex-5-enoate (84F). 2,4-dichloro-7-fluoropyrido[3,2-d]pyrimidine 84E (75 mg, 0.34 mmol, 1 eq.) was treated with dioxane (15 ml) followed by N,N-diisopropylethylamine (0.31 ml , 1.7 mmol, 5 eq.) and then (R)-methyl-2-amino-2-methylhex-5-enoate 83B (59.5 mg, 0.38 mmol, 1 eq.). The mixture was stirred at 80° C. overnight to give 84F in solution, which was then used directly. LCMS (m/z): 339.1 [M+H] ⁺ ; t _R =1.23 min on LC/MS Method A.

Synthesis of (R)-methyl-2-((2-((2,4-dimethoxybenzyl)amino)-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)2-methylhex-5-enoate ( 84G). a solution of (R)-methyl-2-((2-chloro-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2methylhex-5-enoate 84F prepared as described was treated with 2,4- dimethoxybenzylamine (0.10 ml, 0.69 mmol, 2.5 eq.). The reaction mixture was heated at 120°C overnight. The reaction mixture was partitioned between EtOAc (50 ml) and H2O (50 ml).

The organics were separated, dried over MgSO ₄ and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 0-100% EtOAc in hexane to give 84G. LCMS (m/z): 470.25 [M+H] ⁺ ; t _R =1.12 min on LC/MS Method A.

Synthesis of (R)-2-((2-((2,4-dimethoxybenzyl)amino)-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2methylhex-5-en-1-ol (84H). (R)-methyl-2-((2-((2,4-dimethoxybenzyl)amino)-7-fluoropyrido[3,2d]pyrimidin-4-yl)amino)-2-methylhex-5-enoate 83G (85 mg, 0.18 mmol, 1 eq.) was treated with THF (5 ml) and 1 M lithium aluminum hydride in ether (0.54 ml, 0.54 mmol, 3 eq.). The reaction mixture was stirred for 2 h and then the reaction mixture was quenched with water (100 ml) and was extracted with EtOAc (100 ml). The organic layer was separated, dried over MgSO ₄ and concentrated in vacuo to give 84H, which was used without further purification. LCMS (m/z): 442.16 [M+H] ⁺ ; t _R =1.07 min on LC/MS Method A.

Synthesis of (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhex-5-en-1-ol (84). (R)-2-((2-((2,4-dimethokCybenzyl)amino)-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhex-5-en-1ol 84Н (35 mg, 0.08 mmol, 1 eq) was treated with DCM (2 ml) and TFA (0.5 ml). After 3 hours, the reaction mixture was concentrated under reduced pressure and subjected to reverse phase HPLC (10-70% MeCN in water with 0.1% TFA using a Hydro-RP column) to give, after collecting product fractions and removing volatiles in vacuo, in the form of TFA salt. LCMS (m/z): 292.13 [M+H] ⁺ ; t _R =0.62 min on LC/MS Method A.

¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.55 (d, J=2.4 Hz, 1H), 8.25 (s, 1H), 7.63 (dd, J=8.7, 2.5Hz, 1H), 5.83

- 126 041413 (ddt, J=16.6, 10.2, 6.2Hz, 1H), 5.02 (dq, J=17.1, 1.5Hz, 1H), 4.92 (ddt, J=10.2, 2.1, 1.1 Hz, 8H), 4.08-3.88 (m,

1H), 3.69 (d, J=11.3 Hz, 1H), 2.34-1.90 (m, 4H), 1.56 (s, 3H).

¹⁹ F NMR (377 MHz, methanol-d4) δ -77.54, -118.17 (dd, J=8.8, 4.3 Hz).

Example 85

Synthesis of ethyl 2-((2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-2-ethylhexanoate (85B). 2,4,Dichloropyrido[3,2-d]pyrimidine (1068 mg, 5.34 mmol, 1 eq.) was treated with dioxane (10 mL), followed by N,N-diisopropylethylamino (5.7 mL, 32.0 mmol, 6 eq.) and then 2-amino-2-ethyl-hexanoic acid ethyl ester 85A (1000 mg, 5.34 mmol, 1 eq., supplied by J&W Pharmlab, LLC). The mixture was stirred at 80°C overnight. The reaction mixture was partitioned between EtOAc (50 ml) and H2O (50 ml). The organics were separated, dried over MgSO ₄ and concentrated in vacuo to give 85B, which was then used directly. LCMS (m/z): 351.23 [M+H]+; tR=1.43 min on LC/MS Method A.

Synthesis of ethyl 2-((2-((2,4-diethylbenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-2ethylhexanoate (85C). Ethyl 2-((2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-2-ethylhexanoate 85B, obtained as described, was treated with dioxane (10 ml), N,N-diisopropylethylamine (1.7 ml, 9.5 mmol, 3 eq.) and 2,4-dimethoxybenzylamine (0.94 ml, 6.3 mmol, 2 eq.). The reaction mixture was heated at 120°C overnight. The reaction mixture was partitioned between EtOAc (50 ml) and H2O (50 ml). The organics were separated, dried over MgSO ₄ and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 0-100% EtOAc in hexane to give 85C. LCMS (m/z): 482.27 [M+H]+; tR=1.02 min on LC/MS Method A.

Synthesis of 2-((2-((2,4-diethylbenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-2-ethylhexan-1-ol (85D). Ethyl 2-((2-((2,4-diethylbenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-2-ethylhexanoate 85C (111 mg, 0.23 mmol, 1 eq. .) was treated with THF (10 ml) and 1 M lithium aluminum hydride in ether (0.92 ml, 0.92 mmol, 4 eq.). The reaction mixture was stirred for 2 h and then the reaction mixture was quenched with water (100 ml) and was extracted with EtOAc (100 ml). The organic layer was separated, dried over MgSO ₄ and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 0-100% EtOAc in hexane to give 85D. LCMS (m/z): 440.24 [M+H]+; tR=0.94 min on LC/MS Method A.

Synthesis of 2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-2-ethylhexan-1-ol (85). 2-((2-((2,4Diethylbenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-2-ethylhexan-1-ol 85D (16 mg, 0.04 mmol, 1 eq .) were treated with DCM (2 ml) and TFA (0.5 ml). After 6 hours, the reaction mixture was concentrated under reduced pressure and subjected to reverse phase HPLC (10-70% MeCN in water with 0.1% TFA using a Hydro-RP column) to give, after collecting product fractions and removing volatiles in vacuo, 85 as TFA salt. LCMS (m/z): 290.15 [M+H]+; t _R =0.73 min on LC/MS Method A.

¹ H NMR (400 MHz, methanol-d4) δ 8.62 (dd, J=4.4, 1.4 Hz, 1H), 7.93-7.61 (m, 2H), 3.98 (s , 3H), 3.91 (s, 2H), 2.10-1.82 (m, 4H), 1.46-1.20 (m, 4H), 1.10-0.71 (m, 5H ).

¹⁹ F NMR (377 MHz, methanol-d ₄ ) δ -77.69 (d, J=231.2 Hz).

- 127 041413

Example 86

BnBr, K ₂ CO ₃ (COC02 DM-CO-.

MeCN * [ _he Et ₃ N, -78 °C *

Bn ₂ N ⁴ '' Βη ₂ N''

86b 86s

Synthesis of (R)-2-(dibenzylα-mino)hexan-1-ol (86b). (R)-norleucinol (86a, 2046.4 mg, 17.46 mmol) was treated with acetonitrile (40 ml) and K ₂ CO ₃ (4842.4 mg, 35.04 mmol), followed by benzyl bromide (6.222 ml, 52 .39 mmol) at 0°C. The resulting mixture was stirred at rt. After 18 hours the precipitate was filtered and the solids were washed with EtOAc (30 ml). The filtrates were concentrated under reduced pressure and the resulting residue was subjected to silica gel chromatography eluting with 0-70% EtOAc in hexanes to give 86b LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C ₂₀ H ₂₈ NO: 298 .22; found: 298.16; t _R =0.82 min on LC/MS Method A.

Synthesis of (R)-2-(dibenzylαmino)hexanal (86c). Oxalyl chloride (0.18 ml, 2.10 mmol) in DCM (3 ml) was cooled in an acetone-dry ice bath and then treated with DMSO (0.3 ml, 4.22 mmol) in DCM (1 ml) dropwise over 2 minutes. After 10 minutes, a solution of compound 86b (503.5 mg, 1.69 mmol) in DCM (2 ml) was added and the resulting mixture was allowed to stir for 30 minutes. before adding triethylamine (1.2 ml, 8.61 mmol). After 1 h at -70 ~ -55°C, the reaction mixture was allowed to warm to rt, diluted with EtOAc (30 ml) and washed with water (30 mlx2). The aqueous fractions were extracted with EtOAc (x1) and the combined organic fractions were then dried (MgSO ₄ ), concentrated under reduced pressure and the residue dried in vacuo to give compound 86c, which was used without further purification. LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C ₂₀ H ₂₆ NO): 296.20; found: 296.16; t _R =1.12 min on LC/MS Method A.

Synthesis of (2S,3R)-3-(dibenzylamino)heptan-2-ol (86d) and (2R,3R)-3-(dibenzylamino)heptan-2-ol (86f). Compound 86c (134.87 mg, 0.457 mmol) in diethyl ether (4 ml) was stirred at -15°C and a 1.6 M solution of methyllithium in diethyl ether (4.2 ml, 6.72 mmol) was added. After 0.5 h the reaction mixture was quenched with saturated aqueous ammonium chloride (10 ml) and water (10 ml) and the product was extracted with EtOAc (20 mlx2). The organic extracts were washed with water (20 mlx1), combined, dried (MgSO ₄ ) and then concentrated under reduced pressure. The crude residue was chromatographed on silica gel eluting with 5-30% EtOAc in hexanes to give 86d (first eluting compound) and compound 86e, second eluting compound.

(2S,3R)-3-(Dibenzylamino)heptan-2-ol (86d): 1H NMR (400 MHz, chloroform-d) δ 7.37-7.17 (m, 10H), 4.33 (s, 1H), 3.86 (d, J=13.3 Hz, 1.9H), 3.73 (d, J=13.7 Hz, 0.1H), 3.67-3.55 (m, 1H ), 3.45 (d, J=13.3 Hz, 2H), 2.64 (d, J=5.8 Hz, 0.05H), 2.33 (dt, J=9.3.5, 5 Hz, 0.95H), 1.72 (ddd, J=14.8, 12.0, 6.5 Hz, 1H), 1.50-1.20 (m, 6H), 1.18 (d , J=6.7 Hz, 0.15H), 1.09 (d, J=6.0 Hz, 2.85H), 0.96 (t, J=7.1 Hz, 3H). LCMS-ESr (m/z): [M+H] ⁺ calculated for C ₂₁ H ₃₀ NO: 312.23; found: 312.16; t _R =0.98 min on LC/MS Method A.

(2R,3R)-3-(Dibenzylamino)heptan-2-ol (86e): 1H NMR (400 MHz, chloroform-d) δ 7.44-7.13 (m, 10H), 3.88 (dt, J=8.6, 5.8 Hz, 1H), 3.73 (d, J=13.6 Hz, 2H), 3.63 (d, J=13.6 Hz, 2H), 2.65 ( td, J=6.5, 4.3 Hz, 1H), 2.31 (s, 1H), 1.73 (td, J=11.0, 9.8, 5.8 Hz, 1H), 1 .50-1.22 (m, 6H), 1.18 (d, J=6.6 Hz, 3H), 0.92 (t, J=7.0 Hz, 3H). LCMS-ESF (m/z): [M+H] ⁺ calculated for C ₂₁ H ₃₀ NO: 312.23; found: 312.16; t _R =0.93 min on LC/MS Method A.

Synthesis of (2S,3R)-3-aminoheptan-2-ol (86f). Diastereomer 86d (108.9 mg, 0.349 mmol) and 20% palladium hydroxide on carbon (25.3 mg) in EtOH (4 ml) were stirred under H ₂ for 16 h. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure with obtaining compound 86f contaminated with some EtOH, which was used without further purification.

- 128 041413

1H NMR (400 MHz, methanol-a ₄ ) δ 3.51 (p, J=6.3 Hz, 1H), 2.49 (ddd, J=8.2, 6.0, 4.0 Hz, 1H ), 1.57-1.20 (m,

6H), 1.15 (d, J=6.4 Hz, 3H), 0.97-0.87 (m, 3H).

Synthesis of (2S,3R)-3-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)heptan-2ol (86g). Compound 86f prepared as described and 2,4-dichloropyrido[3,2-b]pyrimidine (73.2 mg, 0.350 mmol, Astatech, Inc.) in THF (3 mL) were treated with N,N-diisopropylethylamine (0. 19 ml, 1.091 mmol) and the resulting mixture was stirred for 1.5 h. Additional THF (3 ml), N,N-diisopropylethylamine (0.19 ml, 1.091 mmol) and 2,4-dimethoxybenzylamine (0.27 ml, 1.797 mmol). The reaction mixture was stirred at 100°C for 15.5 h and then cooled to rt. The reaction mixture was diluted with DCM (30 ml), washed with water (30 mlx2). The aqueous fractions were then extracted with DCM (20 mlx1) and the combined organic fractions were dried (MgSO ₄ ) and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 0-20% methanol in DCM to give a crude 86g. The crude 86g was further subjected to preparative HPLC (Gemini 10u C18 110A, AXIA; gradient 10% aq. acetonitrile - 80% aq. acetonitrile with 0.1% TFA, over 20 min). The collected fractions were neutralized with NaHCO ₃ prior to concentration. The residue was dissolved in EtOAc, washed with water, dried (MgSO ₄ ) and concentrated under reduced pressure to give compound 86g. LCMS-E81+ (m/z): [M+H] ⁺ calculated for C ₂₃ H ₃₂ N ₅ O ₃ : 426.25; found: 426.14; t _R =1.23 min on LC/MS Method A.

Synthesis of (2S,3R)-3-(2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)heptan-2-ol (86). Compound 86g (76.0 mg, 0.179 mmol) was dissolved in TFA (2 ml) and stirred at rt for 1 h. The reaction mixture was concentrated and co-evaporated with methanol (10 mlx1). The resulting residue was dissolved in methanol (2 ml) and concentrated ammonium hydroxide (0.2 ml) was added to the solution. After 10 min at rt, the mixture was concentrated to dryness and the residue was dissolved in methanol (3 ml) and water (3 ml). The insoluble matter was removed by filtration and the filtrate was subjected to preparative HPLC (Gemini 10u C18 110A, AXIA; gradient 10% aq. acetonitrile - 70% aq. acetonitrile with 0.1% TFA, over 20 min) to obtain, after collecting the product fractions and removing volatiles in vacuo, compound 86 as TFA salt.

1H NMR (400 MHz, methanol^) δ 8.64 (dd, J=4.4, 1.4 Hz, 1H), 7.84 (dd, J=8.5, 1.5 Hz, 1H), 7.77 (dd, J=8.5, 4.4Hz, 1H), 4.37 (td, J=7.2, 3.4Hz, 1H), 3.99 (qd, J=6, 4, 3.4 Hz, 1H), 1.76 (q, J=7.4 Hz, 2H), 1.48-1.26 (m, 4H), 1.18 (d, J=6.4 Hz, 3H), 0.97-0.82 (m, 3H). LCMS-E81+ (m/z): [M+H] ⁺ calculated for C _i4 H ₂₂ N ₅ O: 276.18; found: 276.15; t _R =0.67 min on LC/MS Method A.

Example 87

Synthesis of (2S,3R)-3-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)heptan-2-ol (87). A solution of 2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-ol (43B, 20.0 mg, 0.068 mmol), compound 86f (27.2 mg, 0.207 mmol), and (benzotriazole-1 - yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP, 58.9 mg, 0.133 mmol) in DMF (3 ml) was stirred at rt and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0. 05 ml, 0.333 mmol). After stirring for 24 h at rt, the reaction mixture was diluted with water (2 ml) and 1N HCl (1 ml) and the resulting solution was filtered. The filtrate was subjected to preparative HPLC (Gemini 10u C18 110A, AXIA; gradient 10% aq. acetonitrile - 70% aq. acetonitrile with 0.1% TFA, over 20 min). The concentrated fractions containing the product were concentrated, co-evaporated with methanol (10 ml x3) and then dried in vacuo to give compound 87 as a TFA salt.

1H NMR (400 MHz, methanol-b ₄ ) δ 8.56 (d, J=2.4 Hz, 1H), 7.64 (dd, J=8.8, 2.4 Hz, 1H), 4, 36 (td, J=7.2, 3.6 Hz, 1H), 4.03-3.91 (m, 1H), 1.82-1.69 (m, 2H), 1.37 (tddd, J=12.8, 10.3, 7.7, 5.0 Hz, 4H), 1.18 (d, J=6.4 Hz, 3H), 0.94-0.85 (m, 3H) .

¹⁹ F NMR (376 MHz, methanol-d ₄ ) δ -77.82, -117.98 (d, J=8.8 Hz). LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C14H21FN5O: 294.17; found: 294.13; tR=0.71 min on LC/MS Method A.

- 129 041413

Example 88

Synthesis of (3R)-3-(dibenzylamino)-1-fluoro-1-(phenylsulfonyl)heptan-2-ol (88a). A solution of fluoromethylphenylsulfone (935.6 mg, 5.371 mmol) in THF (3 ml) was stirred in an acetone-dry ice bath and 2.5 M n-butyllithium in hexane (2.15 ml) was added. After 30 min, crude compound 86c (393.9 mg, 1.333 mmol) in THF (2 ml) was added and the resulting solution was stirred with cooling using an acetone-dry ice bath. After 30 min the reaction mixture was quenched with saturated NH4Cl (15 ml), diluted with EtOAc (30 ml) and heated to rt to separate two fractions. The aqueous fraction was extracted with EtOAc (20 mlx1) and the organic fractions were then washed with water (30 mlx1) until combined, dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 0-40% EtOAc in hexanes to give compound 88a as a mixture of 4 diastereomers. LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C ₂₇ H ₃₃ FNO ₃ S: 470.22; found: 470.24; t _R \u003d 1.40-1.45 min.

Synthesis of (2R,3R)-3-(dibenzylamino)-1-fluoroheptαn-2-ol and (2S,3R)-3-(dibenzylamino)-1-fluoroheptan2-ol (88b and 88c). A suspension of compound 88a (635.4 mg, 1.333 mmol) and Na ₂ HPO ₄ (1325.9 mg, 9.340 mmol) in methanol (10 ml) was stirred in a -30-40°C bath, after which mercury sodium amalgam was added (1853 .9 mmol, 8.060 mmol). The reaction mixture was slowly heated to ~5°C for 2 h and then stirred for 1 h at ~5°C. The mixture was then filtered through a pad of celite and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc and water (20 ml each) and two fractions were separated. The aqueous fraction was extracted with EtOAc (20 mlx1). The organic fractions were washed with water (30 ml x 1), then combined, dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was rechromatographed on silica gel eluting with 5-20% EtOAc in hexanes to give compound 88b as a first eluting fraction and compound 88c as a second eluting fraction.

Compound 88b: 1H NMR (400 MHz, chloroform-d) δ 7.63-6.91 (m, 10H), 4.53-4.27 (m, 2H), 4.16 (s, 1H), 3 .90 (d, J=13.2Hz, 2H), 3.66 (dt, J=22.5, 5.7Hz, 1H), 3.49 (d, J=13.3Hz, 2H) , 2.69 (dt, J=9.2, 5.3 Hz, 1H), 1.90-1.70 (m, 1H), 1.39 (tdd, J=12.6, 8.2, 5.5 Hz, 5H), 0.97 (t, J=7.0 Hz, 3H).

¹⁹ F NMR (376 MHz, chloroform-d) δ -230.59 (td, J=47.8, 23.5 Hz). LCMS-ESF (m/z): [M+H] ⁺ calculated for C ₂₁ H ₂₉ FNO: 330.22; found: 330.17; t _R =0.96 min on LC/MS Method A.

Compound 88c: ¹ H NMR (400 MHz, chloroform-d) δ 7.54-6.94 (m, 10H), 4.54 (ddd, J=47.2, 9.4, 3.4 Hz, 1H ), 4.25 (ddd, J=48.2, 9.4, 7.3 Hz, 1H), 4.01 (d, J=18.6 Hz, 1H), 3.66 (d, J= 2.5 Hz, 4H), 2.68 (q, J=6.1 Hz, 1H), 2.35 (s, 1H), 1.88-1.70 (m, 1H), 1.53- 1.21 (m, 5H), 1.00-0.80 (m, 3H).

¹⁹ F NMR (376 MHz, chloroform-d) δ -228.21 (td, J=47.7, 18.4 Hz). LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C ₂₁ H ₂₉ FNO: 330.22; found: 330.13; t _R \u003d 1.07 min per LC / mS Method A.

Synthesis of (3R)-3-amino-1-fluoroheptan-2-ol (88d). A mixture of compound 88b (38.25 mg, 0.116 mmol) and 20% palladium hydroxide on carbon (15.61 mg) in EtOH (2 ml) was stirred under H ₂ atmosphere. After 20.5 h the reaction mixture was filtered and the solids washed with EtOH (10 ml). Then the filtrate and washing were concentrated, the residue was co-evaporated with toluene (5 ml x 2) to give compound 88d. LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C ₇ H ₁₇ FNO: 150.13; found: 149.97; t _R =0.40 min on LC/MS Method A.

Synthesis of (3R)-3-((2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-1-fluoroheptan-2-ol (88e). N,N-diisopropylethylαmin (0 .1 ml, 0.574 mmol). The mixture was stirred at rt for 1.5 h and at 50°C for 30 min. The reaction mixture was then concentrated in vacuo and the residue was chromatographed on silica gel eluting with 20-70% EtOAc in hexanes to give compound 88e. LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C ₁₄ H ₁₉ ClFN ₄ O: 313.12; found: 313.14; t _R =1.06 min on LC/MS Method A.

Synthesis of (3I.)-3-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2^]pyrimidin-4-yl)amino)-1fluoroheptan-2-ol (88f). To a solution of compound 88e (22.0 mg, 0.070 mmol) in dioxane (2 ml) was added N,N-diisopropylethylamine (0.06 ml, 0.344 mmol) and 2,4-dimethoxybenzylamine (0.04 ml, 0.266 mmol). The resulting solution was refluxed at 110° C. for 19 hours. Then the reaction mixture was concentrated, the residue was subjected to silica gel chromatography, eluting with hexanes - EtOAc, to obtain the crude product 88f. The crude product was then subjected to preparative HPLC (Gemini 10u C18 110A, AXIA; gradient 10% aq. acetonitrile - 80% aq. acetonitrile with 0.1% TFA, over 20 minutes). The combined product fractions were neutralized by adding saturated aqueous NaHCO ₃ (1 ml), concentrated to remove acetonitrile and then extracted with EtOAc (20 mlx2). The organic extracts were washed with water (x 1), combined, dried (MgSO ₄ ) and concentrated under reduced pressure to give compound 88f LCMS-ESI ⁺ (m/z): [M+H-C2H4] ⁺ calculated for C23H ₃₁ FN5O ₃ : 444.24; found: 444.18; t _R =0.95 min on LC/MS Method A.

Synthesis of (3R)-3-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-1-fluoroheptan-2-ol (88). Compound 88f (8.7 mg, 30.44 µmol) was dissolved in TFA (1 ml) and stirred at rt for 1 h. The reaction mixture was concentrated in vacuo and co-evaporated with methanol (10 ml). The residue was dissolved in methanol (1 ml) and concentrated ammonium hydroxide (0.1 ml) was added. The resulting mixture was stirred at rt for 10 min, concentrated under reduced pressure. The residue was triturated in 1N HCl (0.5 ml) and methanol (2 ml), filtered and diluted with water (3 ml) before preparative HPLC (Gemini 10u C18 110A, AXIA; gradient 10% aq. acetonitrile - 70% aq. acetonitrile with 0.1% TFA, for 20 minutes). The product fractions were combined, concentrated in vacuo, co-evaporated with methanol (10 ml x 3) and dried in vacuo to give compound 88 as the TFA salt.

1H NMR (400 MHz, methanol-d ₄ ) δ 8.64 (dd, J=4.4, 1.4 Hz, 1H), 7.84 (dd, J=8.5, 1.4 Hz, 1H ), 7.77 (dd, J=8.5, 4.4 Hz, 1H), 4.59 (ddd, J=8.0, 6.5, 3.0 Hz, 1H), 4.51- 4.38 (m, 1H), 4.38-4.26 (m, 1H), 4.04 (dddd, J=16.2, 6.1, 4.9, 3.1 Hz, 1H), 1.89-1.73 (m, 2H), 1.39 (dtd, J=10.4, 6.9, 6.3, 3.4 Hz, 4H), 0.96-0.84 (m , 3H).

¹⁹ F NMR (376 MHz, methanol-d4) δ -77.56, -231.26 (td, J=47.3, 16.2 Hz). LCMS-ESF (m/z): [M+H] ⁺ calculated for C14H ₂₁ FN ₅ O: 294.17; found: 294.15; t _R \u003d 0.69 min per LC / mS Method A.

Example 89

Synthesis of (28.3R)-3-(dibenzylamino)-1,1,1-trifluoroheptan-2-ol (89a) and (2R,3R)-3-(dibenzylamino)1,1,1-trifluoroheptan-2-ol (89b). A solution of compound 86c (492.7 mg, 1.668 mmol) and tetrabutylammonium fluoride (TBAF, 21.8 mg, 0.083 mmol) in THF (4 mL) was stirred at 0°C and trimethyl(trifluoromethyl)silane (0.76 mL, 5.17 mmol). After the resulting mixture was stirred at 0°C for 30 min, additional TBAF (87.2 mg, 0.334 mmol) was added and the reaction mixture was stirred for 1 h at rt. The reaction mixture was quenched with saturated aqueous NH ₄ Cl (10 ml). The resulting solution was diluted with EtOAc (20 ml) and the two layers were separated. The aqueous fraction was extracted with EtOAc (20 mlx3) and the organic fractions were washed with brine (20 mlx1), combined, dried (MgSO ₄ ) and concentrated in vacuo. The residue was then subjected to silica gel chromatography eluting with 0-20% EtOAc in hexanes to give compound 89a as the first eluted product and compound 89b as the second eluted product.

Compound 89a: ¹ H NMR (400 MHz, chloroform-d) δ 7.36-7.26 (m, 10H), 5.30 (s, 1H), 3.90 (d, J=13.1 Hz, 2H), 3.74-3.64 (m, 1H), 3.60 (d, J=13.1 Hz, 2H), 2.97 (d, J=9.3 Hz, 1H), 1, 94-1.80 (m, 1H), 1.60-1.44 (m, 3H), 1.38 (h, J=7.4 Hz, 2H), 0.98 (t, J=7, 2 Hz, 3H).

- 131 041413 ¹⁹ F NMR (376 MHz, chloroform-d) δ -76.57 (d, J=6.3 Hz). LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for

C ₂₁ H ₂₇ F ₃ NO: 366.20; found: 366.15; tR=1.46 min.

Compound 89b: 1H NMR (400 MHz, chloroform-d) δ 7.32 (d, J=4.8 Hz, 10H), 4.22 (s, 1H), 3.82 (d, J=13.6 Hz, 2H), 3.50 (d, J=13.6 Hz, 2H), 3.00 (d, J=9.4 Hz, 1H), 2.66 (s, 1H), 1.79 ( q, J=9.1 Hz, 1H), 1.49 (s, 2H), 1.35-1.11 (m, 4H), 0.87 (t, J=7.2 Hz, 3H).

¹⁹ F NMR (376 MHz, chloroform-d) δ -76.53 (d, J=8.3 Hz). LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C ₂₁ H ₂₇ F ₃ NO: 366.20; found: 366.15; t _R =1.49 min on LC/MS Method A.

Synthesis of (2R,3R)-3-amino-1,1,1-trifluoroheptan-2-ol (89c). To a stirred solution of compound 89a (121.35 mg, 0.332 mmol) in EtOH (4 ml) was added 20% palladium hydroxide on carbon (52 mg, 0.074 mmol). The resulting mixture was stirred under H ₂ atmosphere for 20 hours. The reaction mixture was then filtered and washed with ethanol (10 ml). The filtrate was then concentrated in vacuo to give compound 89c. LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C ₇ H _i5 F ₃ NO: 186.11; found: 185.96; tR=0.55 min on LC/MS Method A.

Synthesis of (2R,3R)-3-((2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-1,1,1-trifluoroheptan-2-ol (89d). N,N-diisopropylethylamine (0.151 ml, 0.865 mmol) and the mixture was heated to 80°C. After 2 h the reaction mixture was allowed to cool to rt and then concentrated in vacuo and the residue was subjected to silica gel chromatography eluting with 0-100% EtOAc in hexanes to give compound 89d.

Synthesis of (2R,3R)-3-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-1,1,1trifluoroheptan-2-ol ( 89e). To a solution of compound 89d (106.7 mg, 0.346 mmol) in dioxane (3 ml) was added N,N-diisopropylethylamine (0.160 ml, 0.918 mmol) and 2,4-dimethoxybenzylamine (0.230 ml, 1.530 mmol). The resulting solution was refluxed at 110°C and stirred for 20 h. The reaction mixture was then cooled to rt and diluted with EtOAc (20 ml), washed with water (20 mlx3) and brine (20 mlx1), dried (MgSO ₄ ) , filtered and then concentrated in vacuo.

The residue was chromatographed on silica gel eluting with 0-100% EtOAc in hexanes to give compound 89e. LCMS-ESI ⁺ (m/z): [M+H-C2H4] ⁺ calculated for C23H ₂₉ F ₃ N ₅ O ₃ : 480.22; found: 480.17; t _R =1.03 min on LC/MS Method A.

Synthesis of (2R,3R)-3-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-1,1,1-trifluoroheptan-2-ol (89). Compound 89e (12 mg, 25.0 μmol) was dissolved in TFA (1 ml) and stirred at rt for 1 h. The reaction mixture was concentrated in vacuo and co-evaporated with methanol (10 ml). The resulting residue was dissolved in aqueous methanol (1 ml), filtered through a celite membrane filter to remove insoluble matter, and the filtrate was subjected to preparative HPLC (Gemini 10u C18 110A, AXIA; gradient 10% aq. acetonitrile - 70% aq. acetonitrile with 0. 1% TFA, for 20 min). The collected product fractions were concentrated in vacuo and the residue was co-evaporated with methanol (10 mlx3) and dried in vacuo overnight to give compound 89 as a TFA salt.

1H NMR (400 MHz, methanol-d4) δ 8.65 (dd, J=4.4, 1.4 Hz, 1H), 7.85 (dd, J=8.5, 1.4 Hz, 1H) , 7.79 (dd, J=8.5, 4.4 Hz, 1H), 4.82 (ddd, J=8.3, 6.5, 2.1 Hz, 1H), 4.22 (qd , J=7.3, 1.9 Hz, 1H), 1.92-1.74 (m, 2H), 1.50-1.31 (m, 4H), 0.96-0.87 (m , 3H).

¹⁹ F NMR (376 MHz, methanol-d4) δ -77.56, -79.32 (d, J=7.3 Hz). LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C14H19F3N5O: 330.15; found: 330.15; tR=0.77 min on LC/MS Method A.

Example 90

86s

Na/Hg Na ₂ HPO ₄ MeOH

90a

Bn ₂ N''

CHF ₂ 90s

Cl

1) DIPEA, THF ____________

2) DMB-NH ₂ , DIPEA, 100 °C

H ₂ , Pd(OH) ₂ /C EtOH

Synthesis of (2R,3R)-3-(dibenzylamino)-1,1-difluoro-1-(phenylsulfonyl)heptan-2-ol and (2S,3R)-3(dibenzylamino)-1,1-difluoro-1-( phenylsulfonyl)heptan-2-ol (90a and 90b). A solution of compound 86c (235.6

- 132 041413 mg, 0.798 mmol) and difluoromethylphenylsulfone (153.3 mg, 0.80 mmol) in THF (5 ml) were stirred at 78°C and then 1.0 M LHMDS in THF (1.60 ml, 1 .60 mmol). The reaction mixture was stirred for 2 h at -78°C and heated to rt. To quench with saturated aqueous NH ₄ Cl (15 ml). The resulting solution was diluted with EtOAc (25 ml) and the two layers were separated. The separated aqueous fraction was back-extracted with EtOAc (15 ml x 2). The separated organic fractions were washed with water (25 mlx2), brine (25 ml), then combined, dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 0-30% EtOAc in hexanes to give compound 90a as the first eluting isomer and compound 90b as the second eluting isomer.

Compound 90a. LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C ₂₇ H ₃₂ F ₂ NO ₃ S: 488.21; found: 488.20; t _R =1.50 min on LC/MS Method A.

Compound 90b. LCMS-ESI+ (m/z): [M+H] ⁺ calculated for C ₂₇ H ₃₂ F ₂ NO ₃ S: 488.21; found: 488.23; t _R =1.52 min on LC/MS Method A.

Synthesis of (3R)-3-(dibenzylamino)-1,1-difluoroheptan-2-ol (90c). To a solution of compound 90a (132.9 mg, 0.273 mmol) in methanol (2 ml) at -40°C was added Na ₂ HPO ₄ (236.3 mg, 1.664 mmol) and granules of 5% sodium mercury amalgam (646.1 mg , 1.41 mmol). The resulting mixture was stirred for 2 hours in an ice bath and then filtered through a pad of celite. The filtrate was concentrated in vacuo and the residue was treated with EtOAc (20 ml) and water (20 ml). The two layers were separated and the aqueous layer was extracted with EtOAc (20 mlx2). The organic fractions were washed with water (20 mlx1), then combined, dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 0-30% EtOAc in hexanes to give compound 90c. LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C ₂₁ H ₂₈ F ₂ NO: 348.21; found: 348.16; t _R =1.26 min on LC/MS Method A.

Synthesis of (3R)-3-amino-1,1-difluoroheptan-2-ol (90d). To a solution of compound 90c (27.2 mg, 0.078 mmol) in EtOH (1 ml) was added 20% palladium hydroxide on carbon (15.9 mg, 0.023 mmol). The resulting mixture was stirred under H2 atmosphere for 20 h. The reaction mixture was then filtered and washed with EtOH (5 ml). The filtrate was concentrated in vacuo to give compound 90d. LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C ₇ H ₁₁₆ F ₂ NO: 168.12; found: 167.94; t _R =0.49 min on LC/MS Method A.

Synthesis of (3R)-3-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-1,1difluoroheptan-2-ol (90e). To a solution of compound 90d (12.4 mg, 0.074 mmol) and 2,4-dichloropyrido[3,2d]pyrimidine (11.8 mg, 0.059 mmol) in THF (1 ml) 0.222 mmol). The mixture was stirred for 2 h at rt, then additional THF (1 ml), N,N-diisopropylethylamine (0.039 ml, 0.222 mmol), and 2,4-dimethoxybenzylamine (0.056 ml, 0.371 mmol) were added and the resulting mixture was heated to 100°C for 20 h. The reaction mixture was cooled to rt, diluted with EtOAc (~20 ml), washed with water (20 mlx3) and brine (20 mlx1), dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 0-100% EtOAc in hexanes to give dirty 90s. The impure material was then purified by preparative HPLC (column, Gemini 10u C18 110A, AXIA; gradient 10% aq. acetonitrile - 80% aq. acetonitrile with 0.1% TFA, over 20 min) to give compound 90e LCMSESI ⁺ ( m/z): [M+H] ⁺ calculated for C ₂₃ H ₃₀ F ₂ N ₅ O ₃ : 462.23; found: 462.17; t _R =1.00 min on LC/MS Method A.

Synthesis of (3R)-3-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-1,1-difluoroheptan-2-ol (90). Compound 90e (16 mg, 34.67 µmol) was dissolved in TFA (1 ml) and stirred at rt. After 1 h the mixture was concentrated in vacuo and the residue was triturated in methanol (1 ml x 3), filtered and diluted with water (~6 ml). The mixture was subjected to preparative HPLC (Gemini 10u C18 110A, AXIA; gradient 10% aq. acetonitrile - 70% aq. acetonitrile with 0.1% TFA, over 20 min). Collected product fractions were concentrated in vacuo, co-evaporated with methanol (10 ml x 3) and dried in vacuo to give compound 90 as the TFA salt.

¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.64 (dd, J=4.3, 1.4 Hz, 1H), 7.84 (dd, J=8.5, 1.5 Hz, 1H), 7.78 (dd, J=8.5, 4.3 Hz, 1H), 5.73 (td, J=55.6, 4.9 Hz, 1H), 4.70 (t, J = 7.4 Hz, 1H), 3.98-3.82 (m, 1H), 1.90-1.72 (m, 2H), 1.54-1.31 (m, 4H), 1, 00-0.82 (m, 3H).

¹⁹ F NMR (376 MHz, methanol-d4) δ -77.78, -129.57 (ddd, J=289.8, 55.1, 8.6 Hz), -132.42 (ddd, J=290 .1, 56.0, 12.5 Hz). LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C ₁₄ H ₂₀ F ₂ N ₅ O: 312.16; found: 312.15; t _R =0.74 min on LC/MS Method A.

- 133 041413

Example 91

Cl

Synthesis of (3R)-3-amino-1-fluoroheptan-2-ol (91a). A mixture of compound 88b (300.1 mg, 0.911 mmol) and 20% palladium hydroxide on carbon (30.9 mg) in EtOH (5 ml) was stirred under H ₂ atmosphere. The reaction mixture was stirred for 20 h, filtered and the solids washed with EtOH (10 ml). The filtrate was concentrated in vacuo and the residue co-evaporated with toluene (10 mlx2) to give compound 91a. LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C ₇ H ₁₇ FNO: 150.13; found: 149.95; t _R =0.47 min on LC/MS Method A.

Synthesis of (3R)-3-((2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-1-fluoroheptan-2-ol (91b). A solution of 91a (133.7 mg, 0.896 mmol) and 2,4-dichloropyrido[3,2^]pyrimidine (201.6 mg, 1.008 mmol) in THF (6 mL) was treated with N,N-diisopropylethylamine (0.48 mL , 2.756 mmol). The mixture was stirred at rt for 2.75 hours. The reaction mixture was concentrated in vacuo and the residue was subjected to silica gel chromatography eluting with 20-70% EtOAc in hexanes to give compound 91b after removing the solvent in vacuo. LCMS-ESC (m/z): [M+HC ₂ H ₄ ] ⁺ calculated for C ₁₄ H ₁₉ ClFN ₄ O: 313.12; found: 313.14; t _R =1.04 min on LC/MS Method A.

Synthesis of (3R)-3-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-1fluoroheptan-2-ol (91c). To a solution of compound 91b (233.6 mg, 0.747 mmol) in dioxane (7 ml) was added N,N-diisopropylethylamine (0.64 ml, 3.674 mmol) and 2,4-dimethoxybenzylamine (0.45 ml, 2.995 mmol). The resulting solution was refluxed at 110° C. bath for 24 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in DCM (30 ml) and washed with water (30 mlx1). The aqueous layer was extracted with DCM (30 mlx1) and the organic layers were combined, dried (MgSO ₄ ), filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 20-100% EtOAc in hexanes. The collected fractions were concentrated under reduced pressure and the residue was subjected to preparative HPLC (Gemini 10u C18 110A, AXIA; gradient 10% aq. acetonitrile - 80% aq. acetonitrile with 0.1% TFA, over 20 min). The collected product fractions were combined, neutralized with saturated aqueous NaHCO ₃ (1 ml), partially concentrated in vacuo to remove acetonitrile and then extracted with EtOAc (20 mlx2). The organic extracts were washed with water (20 ml), combined, dried over MgSO ₄ , filtered and concentrated in vacuo to give compound 91c. LCMS-ESI ⁺ (m/z): [M+H-C2H4] ⁺ calculated for C23H ₃₁ FN ₅ O ₃ : 444.24; found: 444.19; t _R =0.97 min on LC/MS Method A.

Synthesis of 2-((3R)-3-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-1fluoroheptan-2-yl)isoindoline-1 ,3-diones (91d). Diisopropyl azidocarboxylate (0.697 ml , 3.539 mmol). The reaction mixture was heated to rt and stirred for 2 h. After concentrating the reaction mixture under reduced pressure, the residue was chromatographed on silica gel eluting with 0-100% EtOAc in hexanes to give, after devolatilization in vacuo, compound 91d. LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C ₃₁ H ₃₄ FN ₆ O ₄ : 573.26; found: 573.20; t _R =1.27 min on LC/MS Method A.

Synthesis of N ⁴ -((3R)-2-amino-1-fluoroheptan-3-yl)-N ² -(2,4-dimethoxybenzyl)pyrido[3,2-d]pyrimidine2,4-diamine (91e). To a solution of compound 91d (489.3 mg, 0.854 mmol) in EtOH (5 ml) was added hydrazine hydrate (0.07 ml, 1.28 mmol) at rt. The reaction mixture was refluxed for 3.5 h, the precipitates were removed by filtration and then the solid was washed with EtOH (15 ml). The filtrates were concentrated in vacuo and the residue was dissolved in DCM (30 ml), washed with water (30 ml x 2), dried over MgSO4, filtered and concentrated in vacuo to give compound 91e. LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C23H ₃₂ FN ₆ O ₂ : 443.26; found: 443.20; t _R =0.79 min on LC/MS Method A.

Synthesis of N-((3R)-3-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-1fluoroheptan-2-yl)acetamide (91f ). To a solution of 91e (395.3 mg, 0.893 mmol) and N,N-diisopropylethylamine (0.311 mL, 1.787 mmol) in THF (8 mL) was added acetic anhydride (0.127 mL, 1.340 mmol) and the reaction mixture was stirred for 30 min. at ct. The mixture was then diluted with EtOAc (30 ml), washed with saturated aqueous NaHCO ₃ (30 ml), brine (30 ml), dried over MgSO ₄ , filter

- 134 041413 was triturated and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 0-100% EtOAc in hexanes followed by 0-20% methanol in EtOAc. The collected product fractions were concentrated in vacuo and then subjected to preparative HPLC purification (Gemini 10u C18 110A, AXIA; gradient 10% aq. acetonitrile - 70% aq. acetonitrile with 0.1% TFA, over 20 min) to obtain, after removal of volatiles substances in vacuum, compound 91f. LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C ₂₅ H ₃₄ FN ₆ O ₃ : 485.27; found: 485.23; tR=1.28 min on LC/MS Method A.

Synthesis of N-((3R)-3-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-1-fluoroheptan-2-yl)acetamide (91). Compound 91f (50 mg, 0.103 mmol) was dissolved in TFA (3 ml) and stirred at rt for 11 h. The mixture was concentrated under reduced pressure and the residue was triturated with methanol (1 ml×3). After the insoluble matter was removed by filtration and the filtrate was diluted with water (3 ml), the resulting solution was subjected to preparative HPLC (Gemini 10u C18 110A, AXIA; gradient 10% aq. acetonitrile - 70% aq. acetonitrile with 0.1% TFA, in for 20 minutes). Product-containing fractions were combined, concentrated under reduced pressure to dryness, co-evaporated with methanol (x3), and finally dried under high vacuum to give 91 as the TFA salt.

1H NMR (400 MHz, methanol-d ₄ ) δ 8.67 (ddd, J=4.3, 1.4, 0.6 Hz, 1H), 7.96-7.69 (m, 2H), 4 .82-4.67 (m, 1H), 4.60 (d, J=5.1 Hz, 1H), 4.48 (d, J=5.0 Hz, 1H), 4.41 (dq, J=21.7, 5.1Hz, 1H), 1.96(d, J=4.2Hz, 3H), 1.78(td, J=8.6, 4.6Hz, 1H), 1.48-1.24 (m, 4H), 0.90 (tt, J=5.5, 2.3 Hz, 3H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C16H27FN6O: 335.19; found: 335.19; tR=0.82 min on LC/MS Method A.

Example 92

92g

Synthesis of (S)-methyl-2-((tert-butoxycarbonyl)amino)-2-methylhexanoate (92b). Thionyl chloride (1.62 ml) was added dropwise to a suspension of (S)-2-amino-2-methylhexanoic acid 92a (2018.9 mg, 11.11 mmol, Asiba Pharmatech Inc.) in methanol (30 ml) and the resulting solution was boiled with reflux for 41 hours. The solution was concentrated under reduced pressure and the residue was co-evaporated with methanol (30 mlx2). The residue was treated with NaHCO ₃ (4.6964 g, 55.90 mmol) in water (30 ml) and methanol (5 ml) and stirred at rt. Di-tert-butyl dicarbonate ( ₂₉₃₂ mg, 13.43 mmol) was added and the mixture was stirred for 4 h. mg, 5.654 mmol) and the resulting suspension was stirred at rt overnight. The reaction mixture was then diluted with water (100 ml) and extracted with EtOAc (100 mlx2). The organic extracts were washed with water (100 ml), then combined, dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 020% EtOAc in hexanes to give compound 92b. LCMS-ESI ⁺ (m/z): [M+HC ₄ H ₈ ] ⁺ calculated for C9H18NO4: 204.12; found: 203.68; tR=1.24 min on LC/MS Method A.

Synthesis of (S)-tert-butyl-(1-hydroxy-2-methylhexan-2-yl)carbamate (92c). To a stirred solution of compound 92b (2515.4 mg, 9.699 mmol) in THF (20 ml) and methanol (2.8 ml) at 0°C was added 2.0 M LiBH ₄ in THF (9.7 ml, 19.4 mmol). The solution was stirred at rt for 5 h and then diluted with water (100 ml) at 0°C and extracted with EtOAc (100 mlx2). The combined extracts were washed with water (100 ml), dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 0-40% EtOAc in hexanes to give compound 92c LCMS-ESI ⁺ (m/z):

- 135 041413

[M+HC ₄ H ₈ ]+ calculated for C ₁₂ H ₂₆ NO ₃ : 232.19; found: 231.60; t _R =1.07 min on LC/MS Method A.

Synthesis of (S)-tert-butyl-(2-methyl-1-oxohexan-2-yl)carbamate (92d). To a solution of compound 92c (543.3 mg, 2.349 mmol) in DCM (20 ml) was added Dess-Martin periodinan (1495.1 mg, 3.525 mmol) and the resulting mixture was stirred for 3 h. The reaction mixture was diluted with DCM (30 ml) and filtered through a pad of celite. The filtrate was washed with saturated aqueous Na ₂ S ₂ O ₃ (50 ml), water (50 ml) and brine (50 ml). The aqueous layer was re-extracted with DCM (30 mlx2) and the combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 0-70% EtOAc in hexanes to give compound 92d. LCMS-ESI ⁺ (m/z): [M+HC ₄ H ₈ ]+ calculated for C ₈ H ₁₆ NO ₃ : 174.11; found: 174.76, t _R = 1.28 min on LC/MS Method A.

Synthesis of tert-butyl-((3S)-2-hydroxy-3-methylheptan-3-yl)carbamate (92e). To a solution of compound 92d (511.8 mg, 2.232 mmol) in diethyl ether (5 ml), cooled in an ice bath with salt (-15°C), was added a 1.6 M solution of MeLi in diethyl ether (5.58 ml, 8.927 mmol) drop by drop over 5 min. After 30 minutes the reaction mixture was quenched with saturated aqueous NH ₄ Cl (15 ml). The resulting mixture was diluted with water and the product was extracted with EtOAc (25 mlx2). The combined extracts were dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was then subjected to silica gel chromatography eluting with 0-70% EtOAc in hexanes to give compound 92e as a mixture of two diastereomers. LCMS-ESI ⁺ (m/z): [M+H]+ calculated for C ₁₃ H ₂₈ NO ₃ : 246.21; found: 245.63; t _R =1.28 min on LC/MS Method A.

Synthesis of (3S)-3-((2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-3-methylheptan-2-ol (92f). Compound 92e (347 mg, 1.414 mmol) was dissolved in 4 M HCl in dioxane (3.1 ml) and stirred at rt for 4 h. The reaction mixture was then concentrated in vacuo. The residue in THF (10.5 ml) was treated with 2,4dichloropyrido[3,2-d]pyrimidine (259.1 mg, 1.295 mmol) and N,N-diisopropylethylamine (1.18 ml, 6.77 mmol) and placed at 80°C bath for 1 h. The reaction mixture was cooled to rt, concentrated under reduced pressure, and the residue was subjected to chromatography on silica gel, eluting with 0-70% EtOAc in hexanes, to obtain compound 92f. LCMS-ESI ⁺ (m/z): [M+H]+ calculated for C ₁₅ H ₂₁ ClN ₄ O: 309.15; found: 309.12; t _R =1.32 min on LC/MS Method A.

Synthesis of (2R,3S)-3-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-3methylheptan-2-ol and (2S,3S )-3-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-3methylheptan-2-ol (92g and 92h). To a solution of compound 92f (331.8 mg, 1.074 mmol) in dioxane (11 ml) was added N,N-diisopropylethylamine (0.561 ml, 3.223 mmol) and 2,4-dimethoxybenzylamine (0.807 ml, 5.372 mmol). The resulting mixture was refluxed at 110°C bath for 17 hours. The mixture was then concentrated in vacuo and the resulting residue was dissolved in EtOAc (50 ml) and washed with water (50 mlx2) and brine (50 ml). The organic layer was dried over Na ₂ SO ₄ , filtered and then concentrated in vacuo. The resulting residue was chromatographed on silica gel eluting with 0-100% EtOAc in hexanes. The collected product was then concentrated in vacuo and re-subjected to silica gel column chromatography eluting with 0-20% MeOH in DCM to give a mixture of compound 92g and 92h. The mixture was then concentrated in vacuo and the residue was subjected to preparative chiral SFC (SFC IC-5 um-4.6×100 mm, 40% EtOH-ammonia) to give, after devolatilization in vacuo, compound 92g eluted first and compound 92h, eluted second.

Compound 92g: 1H NMR (400 MHz, chloroform-d) δ 8.29 (dd, J=4.5, 1.5 Hz, 1H), 7.71 (d, J=8.4 Hz, 1H), 7.44 (dd, J=8.5, 4.3Hz, 1H), 7.29 (d, J=8.2Hz, 1H), 6.46 (d, J=2.4Hz, 1H ), 6.42 (dd, J=8.2, 2.4Hz, 1H), 4.56 (d, J=5.8Hz, 2H), 3.84 (s, 3H), 3.79 (s, 3H), 2.13 (t, J=12.7 Hz, 1H), 1.88 (t, J=11.5 Hz, 1H), 1.45 (ddd, J=12.9, 9.7, 5.5 Hz, 1H), 1.38 (s, 3H), 1.35-1.22 (m, 2H), 1.21 (d, J=6.3 Hz, 4H), 0.87 (t, J=7.2 Hz, 3H). LCMSESI+ (m/z): [M+H]+ calculated for C ₂₄ H ₃₄ N ₅ O ₃ : 440.27; found: 440.18; t _R =1.29 min on LC/MS Method A.

Compound 92h: 1H NMR (400 MHz, chloroform-d) δ 8.29 (dd, J=4.3, 1.5 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.43 (dd, J=8.5, 4.3 Hz, 1H), 7.29 (d, J=8.2 Hz, 1H), 7.20 (s, 1H), 6.46 (d , J=2.4Hz, 1H), 6.42 (dd, J=8.2, 2.4Hz, 1H), 4.56 (d, J=5.7Hz, 2H), 3.84 (s, 3H), 3.79 (s, 3H), 1.97 (d, J=10.6Hz, 1H), 1.59 (dt, J=13.9, 7.2Hz, 1H) , 1.48 (s, 3H), 1.36 (qd, J=7.2, 6.7, 4.0 Hz, 4H), 1.26 (d, J=1.4 Hz, 1H), 1.18 (d, J=6.4 Hz, 3H), 0.97-0.90 (m, 3h). LCMS-ESI ⁺ (m/z): [M+H]+ calculated for C ₂₄ H ₃₄ N ₅ O ₃ : 440.27; found: 440.18; t _R =1.28 min on LC/MS Method A.

Synthesis of (3S)-3-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-3-methylheptan-2-ol (92). Compound 92g (74.1 mg, 0.169 mmol) was dissolved in TFA (3 ml) and stirred at rt for 0.75 h. The reaction mixture was carefully concentrated under reduced pressure to dryness. The residue was triturated with 50% aq. methanol and filtered through a celite-filled membrane filter. The filtrate was then subjected to preparative HPLC (Gemini 10u C18 110A, AXIA; gradient 10% aq. acetonitrile - 70% aq. acetonitrile with 0.1% TFA, over 20 min). The product fractions were combined, concentrated in vacuo, then co-evaporated with methanol (10 ml x 3) and dried in vacuo to give compound 92 as the TFA salt.

1H NMR (400 MHz, methanol-d ₄ ) δ 8.61 (dd, J=4.4, 1.4 Hz, 1H), 7.84 (dd, J=8.5, 1.4 Hz, 1H ), 7.76 (dd,

- 136 041413

J=8.5, 4.4 Hz, 1H), 4.36 (q, J=6.5 Hz, 1H), 2.30 (dt, J=16.4, 6.8 Hz, 1H), 1.91-1.78 (m, 1H), 1.56 (s, 3H), 1.461.29 (m, 4H), 1.23 (d, J=6.5 Hz, 3H), 0.97 - 0.85 (m, 3H).

¹⁹ F NMR (376 MHz, methanol-d4) δ -77.60. LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C15H ₂₄ N ₅ O: 290.20; found: 290.14; tR=0.82 min on LC/MS Method A.

Example 93 ^p \ph,

- ^h ΩH ⁺ A ---- HnOo NaBH _4> GA

BocHN^^ FgC^COzEt Toluene, reverse _X%O^ ^Me0H CPN cold. ^F 3 ^C P F ₃ C^^

93a 93b O 93d

93s

Synthesis of (4R)-ethyl-4-phenyl-2-(trifluoromethyl)oxazolidine-2-carboxylate (93c). A solution of (R)-N-Bocphenylglycinol 93a (522.4 mg, 2.249 mmol, Combi-Blocks, Inc.), ethyl trifluoropyruvate 93b (0.328 mL, 2.474 mmol, Oakwood Products), and pyridinium p-toluenesulfonate (113.1 mg, 0.450 mmol) in toluene (20 ml) was refluxed with a Dean-Stark apparatus for 20 h. The reaction mixture was then cooled to 0° C. using an ice bath and filtered through a pad of celite. After concentrating the filtrate in vacuo, the residue was chromatographed on silica gel eluting with 0-30% EtOAc in hexanes to give compound 93c. LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C ₁₃ H ₁₅ F ₃ NO ₃ : 290.10; found: 289.84; tR=1.21 min on LC/MS Method A.

Synthesis of ((4R)-4-phenyl-2-(trifluoromethyl)oxazolidin-2-yl)methanol (93d). Sodium borohydride (50.3 mg, 1.331 mmol) was added to a solution of compound 93c (384.9 mg, 1.331 mmol) in MeOH (6 ml) at 0°C. The reaction mixture was heated to rt and stirred for 30 min. before quenching with aqueous saturated NH ₄ Cl (15 ml). After removal of methanol under reduced pressure, the resulting aqueous solution was extracted with EtOAc (25 mlx3). The organic extracts were washed with water (25 mlx2) and brine (25 ml), combined, dried over MgSO ₄ , filtered and then concentrated in vacuo. The residue was chromatographed on silica gel eluting with 0-40% EtOAc in hexanes to give compound 93d LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C11H13F3NO2: 248.09; found: 247.90; tR=0.96 min on LC/MS Method A.

Synthesis of (R)-2-(((R)-2-hydroxy-1-phenylethyl)amino)-2-(trifluoromethyl)hexan-1-ol (93e). To a solution of compound 93d (264.7 mg, 1.071 mmol) in THF (13 ml) at -78°C was added n-butyllithium (2.5 M in hexane, 1.713 ml, 4.283 mmol) dropwise. The resulting solution was stirred in an ice bath for 2 h before quenching with aqueous saturated NH ₄ Cl (30 ml). The mixture was extracted with EtOAc (30 mlx3) and the extracts were washed with water (30 mlx2) and brine (30 mlx1). The organic fractions were combined, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 0-70% EtOAc in hexanes to give compound 93e LCMS-ESC (m/z): [M+H] ⁺ calculated for C ₁₅ H ₂₃ F ₃ NO ₂ : 306.17; found: 305.90, t _R = 1.13 min on LC/MS Method A.

Synthesis of (R)-2-amino-2-(trifluoromethyl)hexan-1-ol hydrochloride (93f).

To a solution of compound 93e (146.5 mg, 0.480 mmol) in EtOH (1 ml) and concentrated with HCl (0.3 ml) was added palladium hydroxide on carbon (67.4 mg) and the resulting mixture was stirred under H ₂ atmosphere for 24 h. The reaction mixture was filtered through a pad of celite and then the solids were washed with EtOH (25 ml). The eluents were concentrated under reduced pressure, diluted with water (20 ml) and then extracted with EtOAc (20 mlx2). The organic extracts were combined and concentrated under reduced pressure to give compound 93f as its HCl salt. LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C7H ₁₅ F ₃ NO: 186.11; found: 185.95; tR=0.51 min on LC/MS Method A.

Synthesis of (R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-2-(trifluoromethyl)hexan-1-ol (93h ). To a solution of compound 93f (123.84 mg, 0.480 mmol) and 2,4-dichloropyrido[3,2d]pyrimidine (96.0 mg, 0.480 mmol) in THF (4 ml) was added Ν,Ν-diisopropylethylamine (0.251 ml, 1.439 mmol). The reaction mixture was stirred and heated to 80° C. for 18 hours. The reaction mixture was allowed to cool and concentrated in vacuo. The resulting residue was chromatographed on silica gel eluting with 0-100% EtOAc in hexanes to give compound 93g (109.9 mg, 66%). To a solution of compound 93g (109.9 mg, 0.315 mmol) in dioxane (3.5 ml) was added N,N-diisopropylethylamine (0.165 ml, 0.945 mmol) and 2,4-dimethoxybenzylamine (0.237 ml, 1.576 mmol). The mixture was refluxed at 110°C for 20 h, left to cool to rt, diluted with EtOAc (30 ml), washed with water (30 mlx3) and brine (30 ml), dried over MgSO ₄ , filtered and concentrated in vacuo . The resulting residue was chromatographed on silica gel eluting with 0-100% EtOAc in hexanes. The collected fractions were concentrated in vacuo to a residue which was purified by preparative HPLC (Gemini 10u C18 110A, AXIA; gradient 10% aq. acetonitrile - 80% aq. acetonitrile with 0.1% TFA, over 20 min) to give compound 93h LCMS -ESI ⁺ (m/z): [M+H] ⁺ calculated for C ₂₃ H ₂₉ F ₃ N ₅ O ₃ : 480.22; found: 480.17; tR=0.96 min on LC/MS Method A.

Synthesis of (K)-2-((2-aminopyrido[3,2^]pyrimidin-4-yl)amino)-2-(trifluoromethyl)hexan-1-ol (93). Compound 93h (7.8 mg, 16.27 µmol) was dissolved in TFA (1 ml) and stirred at rt for 1 h. The reaction mixture was then concentrated in vacuo and the residue co-evaporated with methanol (5 mlx3). The residue was triturated with 50% aq. methanol and filtered through a celite-filled membrane filter. The filtrate was subjected to preparative HPLC (Gemini 10u C18 110A, AXIA; gradient 10% aq. acetonitrile - 70% aq. acetonitrile with 0.1% TFA, over 20 min). The product fractions were combined, concentrated under reduced pressure, co-evaporated with methanol (10 mlx3), and dried under vacuum to give compound 93 as the TFA salt.

¹ H NMR (400 MHz, methanol^) δ 8.67 (dd, J=4.4, 1.4 Hz, 1H), 7.89 (dd, J=8.5, 1.4 Hz, 1H) , 7.82 (dd, J=8.5, 4.4 Hz, 1H), 4.11 (d, J=12.2 Hz, 1H), 4.06-3.97 (m, 1H), 2.81 (ddd, J=13.8, 11.0, 4.4 Hz, 1H), 1.99-1.85 (m, 1H), 1.38 (m, 4H), 0.92 ( t, J=7.0 Hz, 3H).

¹⁹ F NMR (376 MHz, methanol^4) δ -75.96 (s, 3F), -77.39(s, 3F). LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C14H ₁₉ F ₃ N ₅ O: 330.15; found: 330.16; tR=0.76 min per LC/mS Method A.

Example 94

Synthesis of (K)-3-methyl-5-phenyl-5,6-dihydro-2H-1,4-oxazin-2-one (94c) and 3-methyl-5-phenyl-3,6dihydro-2H-1, 4-oxazin-2-one (94d). To a mixture of (K)-(-)-2-phenylglycinol 94a, (Sigma-Aldrich, 98%, 99% ee, 3.6296 g, 172.25 mmol) and molecular sieves (86.03 g) in 2.2 ,2-trifluoroethanol (500 mL) was added ethyl pyruvate 94b (19.2 mL, 172.29 mmol) and the resulting mixture was heated to reflux. After 24 hours

- 138 041413 the mixture was cooled to rt, filtered through a pad of celite and washed with EtOAc (50 ml). The orange filtrate and EtOAc washes were divided into two flasks and each concentrated under reduced pressure.

Each of the residues obtained was subjected to silica gel chromatography eluting with 0-40% EtOAc in hexanes. The product fractions from the two chromatographies were combined, concentrated under reduced pressure and dried in vacuo to give compound 94c and later eluting compound 94d.

Compound 94c: 1H NMR (400 MHz, chloroform-d) δ 7.45-7.38 (m, 2H), 7.38-7.32 (m, 3H), 4.85 (ddd, J=10, 9, 4.6, 2.4 Hz, 1H), 4.57 (dd, J=11.6, 4.5 Hz, 1H), 4.26 (dd, J=11.6, 10.9 Hz , 1H), 2.41 (d, J=2.4 Hz, 3H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C _n H ₁₂ NO ₂ : 190.09; found: 189.92; tR=0.88 min on LC/MS Method A.

Compound 94d: 1H NMR (400 MHz, chloroform-d) δ 7.81-7.71 (m, 2H), 7.55-7.41 (m, 3H), 5.47 (dd, J=16, 0, 1.2Hz, 1H), 5.25(dd, J=16.0, 2.8Hz, 1H), 4.31(qdd, J=7.1, 3.0, 1.1Hz , 1H), 1.72 (d, J=7.3 Hz, 3H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for CnH ₁₂ NO ₂ : 190.09; found: 189.94; tR=0.83 min on LC/MS Method A.

Synthesis of (3R,5R)-3-butyl-3-methyl-5-phenylmorpholin-2-one (94e). A solution of compound 94c (14.84 g, 78.43 mmol) in THF (500 ml) was stirred in a -78°C bath under argon atmosphere and boron trifluoride diethyl etherate (20.5 ml, 161.11 mmol) was added slowly over 30 min. The reaction mixture was allowed to stir at -78°C for 1.5 h. for 2 h before adding saturated ammonium chloride (300 ml) followed by heating to rt. The mixture was diluted with water (200 ml) and extracted with EtOAc (300 mlx3). The organic extracts were washed with water (500 mlx3), brine (300 ml), combined, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. After dissolving the residue in DCM (150 ml, heating), the insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure to a small volume and chromatographed on silica gel eluting with 0-20% EtOAc in hexanes to give compound 94e. LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C ₁₅ H ₂₂ NO ₂ : 248.17; found: 248.02; t _R =1.07 min on LC/MS Method A.

Synthesis of (R)-2-(((R)-2-hydroxy-1-phenylethyl)amino)-2-methylhexan-1-ol (94f). To a stirred solution of compound 94e (14.01 g, 56.64 mmol) in THF (100 ml) at 0°C was added 2.0 M LiBH ₄ in THF (57 ml, 114 mmol). The solution was stirred at rt for 2 h, cooled in an ice bath and quenched with water (500 ml). The product was extracted with EtOAc (300 mlx3) and the extracts were washed with water (500 ml) and brine (100 ml). The combined extracts were dried (Na2SO4) and concentrated under reduced pressure to give 94f LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C ₁₅ H ₂₆ NO ₂ : 252.20; found: 252.05; tR=0.68 min on LC/MS Method A.

Synthesis of (R)-2-amino-2-methylhexan-1-ol hydrochloride (94g). To a mixture of compound 94f (14.24 g, 56.65 mmol) and 20% Pd(OH) ₂ on carbon (2.847 g) in EtOH (210 ml) was added 4N HCl in dioxane (21.5 ml, 86.0 mmol ) The resulting mixture was purged with gaseous H ₂ (3 times) and then stirred in an atmosphere of H ₂ at 70°C for 8 hours. The reaction mixture was left to cool and additional 20% Pd(OH) ₂ on carbon (0.71 g) was added . The resulting mixture was purged with gaseous H ₂ (3 times) and then stirred in an atmosphere of H ₂ at 70°C for 2 hours, the Reaction mixture was cooled and filtered through a pad of celite and the removed solids were washed with EtOH (50 ml). The filtrate and EtOH washes were combined and concentrated under reduced pressure. The residue was co-evaporated with DCM (100 mlx3) and dried under vacuum to give compound 94g. The residue was triturated with DCM (50 ml) and toluene (50 ml) and then concentrated under reduced pressure. The residue was co-evaporated with toluene (50 mlx1) and dried under vacuum at 40° C. for 1 h and rt overnight to give compound 94g as its HCl salt. LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C ₇ H ₁₈ NO: 132.14; found: 131.90; t _R =0.42 min on LC/MS Method A.

Synthesis of (R)-tert-butyl-(1-hydroxy-2-methylhexan-2-yl)carbamate (94h). To a solution of 94g (3.1403 g, 16.01 mmol) in methanol (7 ml) and water (45 ml) was added sodium bicarbonate (4.05 g, 48.21 mmol) and ditert-butyl dicarbonate (Boc ₂ O, 4 .25 g, 19.47 mmol). The resulting mixture was stirred at rt for 3 h and then additional sodium bicarbonate (0.68 g, 8.095 mmol) and di-tert-butyl dicarbonate (1.752 g, 8.028 mmol) were added. The mixture was stirred for 48 h and then additional sodium bicarbonate (0.808 g, 9.618 mmol) and di-tert-butyl dicarbonate (1.92 g, 8.797 mmol) were added. The reaction mixture was stirred for 4 h, diluted with water (100 ml) and extracted with EtOAc (100 mlx2). The extracts were washed with water (100 ml), dried over MgSO ₄ , filtered and then concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 0-40% EtOAc in hexanes to give compound 94h LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C ₁₂ H ₂₆ NO ₃ : 232.19; found: 231.65; t _R =1.08 min on LC/MS Method A.

Synthesis of (R)-tert-butyl-(2-methyl-1-oxohexan-2-yl)carbamate (94i). To a solution of compound 94h (446.7 mg, 1.931 mmol) in DCM (15 ml) was added Dess-Martin periodinan (1230.6 mg, 2.901 mmol) and the resulting mixture was stirred for 3 hours. The reaction mixture was filtered through a pad of celite and then the filtrate was washed with saturated aqueous Na ₂ S ₂ O ₃ (30 ml) followed by washing with water

- 139 041413 (30 mlx2). The aqueous fractions were back-extracted with DCM (30 ml) and then all organic fractions were combined, dried over MgSO ₄ , filtered and concentrated in vacuo. The resulting residue was chromatographed on silica gel eluting with 0-30% EtOAc in hexanes to give compound 94i.

LCMS-ESI ⁺ (m/z): [M+H-C4H8] ⁺ calculated for C8H ₁₆ NO ₃ : 174.11; found: 173.77; t _R \u003d 1.17 min per

LC/MS Method A.

Synthesis of tert-butyl-((3R)-2-hydroxy-3-methylheptan-3-yl)carbamate (94j). To a solution of compound 94i (322.4 mg, 1.406 mmol) in diethyl ether (5 ml) in an ice-NaCl bath was added 1.6 M MeLi in diethyl ether (3.6 ml, 5.76 mmol) dropwise over 2 min. After 30 minutes, the reaction mixture was quenched with saturated aqueous ammonium chloride (20 ml). The two phases were separated and the aqueous fraction was extracted with DCM (30 ml). The organic fractions were washed with water (30 ml), combined, dried over MgSO4, filtered and then concentrated in vacuo. The residue was then subjected to silica gel chromatography eluting with 0-40% EtOAc in hexanes to give compound 94j. LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C ₁₃ H ₂₈ NO ₃ : 246.21; found: 245.70; t _R \u003d 1.14 min. and t _R = 1.16 min on LC/MS Method A.

Synthesis of (3R)-3-((2-chloro-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-3-methylheptan-2-ol (94k). Compound 94j (119.8 mg, 0.488 mmol) was dissolved in 4 M HCl in dioxane (3 ml) and stirred at rt for 1 h. The reaction mixture was concentrated in vacuo and the residue was then treated with THF (10.5 ml) followed by treatment 2,4-dichloro-7-fluoropyrido[3,2-d]pyrimidine 84E (110.9 mg, 0.508 mmol) and N,N-diisopropylethylamine (0.36 ml, 2.067 mmol). The mixture was heated in an 80°C bath for 3 h. The reaction mixture was allowed to cool to rt, concentrated in vacuo and the residue was chromatographed on silica gel eluting with 0-100% EtOAc in hexanes to give compound 94k as a mixture of two diastereomers (~2 :3 ratio).

¹ H NMR (400 MHz, chloroform-d) δ 8.55 (dd, J=2.6, 1.2 Hz, 1H), 7.66 (dd, J=8.8, 2.6 Hz, 1H ), 7.35 (d, J=10.9 Hz, 1H), 5.29 (br, 1H), 3.97 (q, J=6.1 Hz, 0.4H), 3.91 (q , J=6.4 Hz, 0.6H), 2.09 (ddd, J=13.8, 12.3, 4.4 Hz, 0.6H), 2.03-1.88 (m, 1H ), 1.67 (dt, J=14.2, 7.0 Hz, 0.4H), 1.51 (s, 1.2H), 1.43 (s, 1.8H), 1.49- 1.136 (m, 4H), 1.22 (d, J=6.5 Hz, 1.8H), 1.20 (d, J=6.5 Hz, 1.2H), 0.99-0.91 (m, 1.2H), 0.88 (t, J=7.3 Hz, 1.8H).

¹⁹ F NMR (376 MHz, chloroform-d) δ -117.38 (t, J=8.9 Hz). LCMS-EST (m/z): [M+H] ⁺ calculated for C ₁₅ H ₂₁ ClFN ₄ O: 327.14; found: 327.11; t _R = 1.23 min on LC/MS Method A.

Synthesis of (2R,3R)-3-((2-((2,4-dimethoxybenzyl)amino)-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-3methylheptan-2-ol and ( 2S,3R)-3-((2-((2,4-dimethoxybenzyl)amino)-7-fluoropyrido[3,2-d]pyrimidin-4yl)amino)-3-methylheptan-2-ol (94l and 94m ). To a solution of compound 94k (128.5 mg, 0.416 mmol) in dioxane (5 ml) was added N,N-diisopropylethylamine (0.22 ml, 1.263 mmol) and 2,4-dimethoxybenzylamine (0.16 ml, 1.065 mmol) and the resulting mixture was refluxed at 110° C. bath for 20 hours. The reaction mixture was allowed to cool to rt, diluted with EtOAc (30 ml) and then washed with water (30 mlx2). The aqueous fractions were then back extracted with EtOAc (30 ml). The organic fractions were combined, dried over MgSO ₄ and concentrated under reduced pressure. The residue was then subjected to silica gel chromatography eluting with 0-100% EtOAc in hexanes to give a mixture of compounds 94l and 94m.

The mixture of compounds was further subjected to preparative chiral SFC (SFC IC-5 um-4.6×100 mm, 30% EtOH-ammonia, flow rate = 3 ml/min) to give compound 941 eluting first and compound 94m eluting second.

Compound 94l: 1H NMR (400 MHz, chloroform-d) δ 8.14 (d, J=2.5 Hz, 1H), 7.32 (s, 1H), 7.28 (d, J=8.3 Hz, 1H), 6.46 (d, J=2.4 Hz, 1H), 6.42 (dd, J=8.3, 2.4 Hz, 1H), 4.55 (d, J=5 .7 Hz, 2H), 3.84 (s, 3H), 3.79 (s, 3H), 4.0-3.7 (m, 1H), 1.97 (s, 1H), 1.59 (s, 2H), 1.47 (s, 3H), 1.36 (d, J=5.2 Hz, 4H), 1.17 (d, J=6.4 Hz, 3H), 1.00 -0.89 (m, 3H).

¹⁹ F NMR (376 MHz, chloroform-d) δ -121.41. LCMS-EST (m/z): [M+H] ⁺ calculated for C ₂₄ H ₃₃ FN ₅ O ₃ : 458.26; found: 458.17; t _R =1.19 min on LC/MS Method A.

Compound 94m: 1H NMR (400 MHz, chloroform-d) δ 8.14 (d, J=2.6 Hz, 1H), 7.33 (s, 1H), 7.28 (d, J=8.3 Hz, 1H), 6.46 (d, J=2.3 Hz, 1H), 6.42 (dd, J=8.3, 2.4 Hz, 1H), 4.55 (d, J=5 .8 Hz, 2H), 3.84 (d, J=1.1 Hz, 3H), 3.79 (s, 3H), 3.9-3.6 (m, 1H), 2.09 (d , J=14.1Hz, 1H), 1.87(s, 1H), 1.57(s, 1H), 1.43(m, 1H), 1.37(s, 3H), 1.30 (m, 2H), 1.20 (d, J=6.4 Hz, 3H), 0.87 (t, J=7.2 Hz, 3H).

¹⁹ F NMR (376 MHz, Chloroform-d) δ -121.40. LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C ₂₄ H ₃₃ FN ₅ O ₃ : 458.26; found: 458.16; t _R =1.22 min on LC/MS Method A.

Synthesis of (3R)-3-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-3-methylheptan-2-ol (94). Compound 94m (9.0 mg, 20.5 μmol) was dissolved in TFA (1 ml) and stirred at rt for 1 h. The reaction mixture was carefully concentrated under reduced pressure to dryness and then the residue was triturated with 50% aq. methanol and filtered through a celite-filled membrane filter. The filtrate was subjected to preparative HPLC (Gemini 10u C18 110A, AXIA; gradient 10% aq. acetonitrile - 70% aq. acetonitrile with 0.1% TFA, over 20 min). The product fractions were combined, concentrated under reduced pressure, co-evaporated with methanol (10 mlx3), and dried under vacuum to give compound 94 as the TFA salt.

1H NMR (400 MHz, methanol-d ₄ ) δ 8.54 (d, J=2.4 Hz, 1H), 8.31 (s, 1H), 7.62 (dd, J=8.8, 2 .5 Hz, 1H), 4.39-

- 140 041413

4.29 (m, 1H), 2.29 (dt, J=15.7, 6.7 Hz, 1H), 1.84 (dt, J=16.0, 6.9 Hz, 1H), 1 .55 (s, 3H), 1.44-1.30 (m, 4H), 1.23 (d, J=6.5 Hz, 3H), 0.96-0.84 (m, 3H).

¹⁹ F NMR (376 MHz, methanol-d4) δ -77.53 (s, 3F), -118.19 (dd, J=8.8, 4.0 Hz, 1F). LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C15H ₂₃ FN ₅ O: 308.19; found: 308.12; t _R =1.46 min on LC/MS Method A.

Example 95

Synthesis of (2R,3R)-3-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-3-methylheptan-2-ol (95). Compound 94l (10.3 mg, 23.4 μmol) was dissolved in TFA (1 ml) and stirred at rt for 1 h. After the reaction mixture was carefully concentrated to dryness in vacuo, the residue was triturated with 50% aq. methanol and filtered through a membrane filter with celite. The filtrate was subjected to preparative HPLC (Gemini 10u C18 110A, AXIA; gradient 10% aq. acetonitrile - 70% aq. acetonitrile with 0.1% TFA, over 20 min). The product fractions were combined, concentrated under reduced pressure, co-evaporated with methanol (10 ml x 3) and dried under vacuum overnight to give compound 95 as the TFA salt.

1H NMR (400 MHz, methanol^) δ 8.53 (d, J=2.4 Hz, 1H), 8.41 (s, 1H), 7.62 (dd, J=8.7, 2.5 Hz, 1H), 4.24 (q, J=6.4 Hz, 1H), 2.14 (ddd, J=15.0, 11.3, 4.2 Hz, 1H), 2.04 (dq , J=14.3, 5.2 Hz, 1H), 1.48 (s, 3H), 1.39-1.24 (m, 4H), 1.22 (d, J=6.4 Hz, 3H), 0.89 (t, J=7.0 Hz, 3H).

¹⁹ F NMR (376 MHz, methanol-d4) δ -77.52 (s, 3F), -118.31 (dd, J=8.7, 4.1 Hz, 1F). LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C15H ₂₃ FN ₅ O: 308.19; found: 308.12; t _R =1.47 min on LC/MS Method A.

Example 96

Synthesis of (3R)-3-((2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-3-methylheptan-2-ol (96a). Compound 94j (195.7 mg, 0.798 mmol) was dissolved in 4 M HCl in dioxane (3 ml) and stirred at rt for

h.

The reaction mixture was then concentrated in vacuo. The residue was treated with 2 methyltetrahydrofuran (5 ml), 2,4-dichloropyrido[3,2-d]pyrimidine (160 mg, 0.525 mmol) and N,N-diisopropylethylamine (0.57 ml, 3.272 mmol) and heated at 80°C bath in over 3 hours. The reaction mixture was cooled to rt, concentrated under reduced pressure, and the residue was subjected to silica gel chromatography, eluting with 0-100% EtOAc in hexanes, to give compound 96a as a mixture of two diastereomers (~2:3 ratio). LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C ₁₅ H ₂₂ ClN ₄ O: 309.15; found: 309.08; t _R =1.41 min on LC/MS Method A.

Synthesis of (2S,3R)-3-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-3methylheptan-2-ol and (2R,3R )-3-((2-((2,4-dimethocCybenzyl)amino)pyrido[3,2-d]n-yrimidin-4-yl)amino)-3methylheptan-2-ol (96b and 96c). To a solution of compound 96a (132.6 mg, 0.429 mmol) in dioxane (5 ml) was added N,N-diisopropylethylamine (0.23 ml, 1.320 mmol) and 2,4-dimethoxybenzylamine (0.16 ml, 1.065 mmol) and the resulting mixture was refluxed at 110° C. for 20 hours. The reaction mixture was diluted with EtOAc (30 ml) and washed with water (30 mlx2). The aqueous fractions were back-extracted with EtOAc (50 ml). The organic fractions were combined, dried over MgSO ₄ , filtered and then

- 141 041413 was concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 0-100% EtOAc in hexanes to give a mixture of compounds 96b and 96c. The mixture was further subjected to chiral SFC (SFC IC-5 um-4.6×100 mm, 40% EtOH-ammonia, flow rate = 3 ml/min) to give compound 96b eluting first and compound 96c eluting second.

Compound 96b: ¹ H NMR (400 MHz, chloroform-d) δ 8.28 (dd, J=4.2, 1.5 Hz, 1H), 7.69 (d, J=8.4 Hz, 1H) , 7.43 (dd, J=8.5, 4.3 Hz, 1H), 7.29 (d, J=8.2 Hz, 1H), 7.19 (s, 1H), 6.46 ( d, J=2.4 Hz, 1H), 6.42 (dd, J=8.2, 2.4 Hz, 1H), 5.3 (br, 1H), 4.56 (d, J=5 .7 Hz, 2H), 3.86 (m, 1H), 3.83 (s, 3H), 3.79 (s, 3H), 1.98 (m, 1H), 1.661.53 (m, 1H ), 1.48 (s, 3H), 1.44-1.30 (m, 4H), 1.17 (d, J=6.4 Hz, 3H), 0.98-0.89 (m, 3H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C ₂₄ H ₃₄ N ₅ O ₃ : 440.27; found: 440.25; tR=0.99 min on LC/MS Method A.

Compound 96c: ¹ H NMR (400 MHz, chloroform-d) δ 8.29 (dd, J=4.2, 1.5 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H) , 7.43 (dd, J=8.5, 4.2 Hz, 1H), 7.30 (d, J=8.2 Hz, 1H), 7.16 (s, 1H), 6.46 ( d, J=2.3Hz, 1H), 6.42(dd, J=8.2, 2.4Hz, 1H), 5.25(s, 1H), 4.56(d, J=5 .7 Hz, 2H), 3.84 (s, 3H), 3.79 (s, 3H), 3.86-3.75 (m, 1H), 2.13 (t, J=13.0 Hz , 1H), 1.93-1.79 (m, 1H), 1.52-1.40 (m, 1H), 1.38 (s, 3H), 1.35-1.15 (m, 3H ), 1.20 (d, J=6.4 Hz, 3H), 0.87 (t, J=7.2 Hz, 3H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C24H34N5O3: 440.27; found: 440.25; tR=1.00 min on LC/MS Method A.

Synthesis of (3R)-3-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-3-methylheptan-2-ol (96). Compound 96b (8.7 mg, 19.79 µmol) was dissolved in TFA (1 ml) and stirred at rt for 1 h. The reaction mixture was concentrated under reduced pressure to dryness and then co-evaporated with methanol (10 ml). The resulting residue was dissolved in methanol (1 ml) and concentrated ammonium hydroxide (0.1 ml). The reaction mixture was stirred for 10 min and then concentrated under reduced pressure to dryness and co-evaporated with methanol (10 ml). The residue was triturated with 50% aq. MeOH (10 ml) and filtered through a celite membrane filter. The filtrate was subjected to preparative HPLC (Gemini 10u C18 110A, AXIA; gradient 10% aq. acetonitrile - 70% aq. acetonitrile with 0.1% TFA, over 20 min). The product fractions were combined, concentrated in vacuo, co-evaporated with methanol (10 ml x 3), and dried under high vacuum to give compound 96 as the TFA salt.

L NMR (400 MHz, methanol^) δ 8.61 (dd, J=4.4, 1.5 Hz, 1H), 7.82 (dd, J=8.5, 1.5 Hz, 1H), 7.76 (dd, J=8.5, 4.4 Hz, 1H), 4.36 (q, J=6.5 Hz, 1H), 2.30 (dt, J=16.3, 6, 8 Hz, 1H), 1.91-1.78 (m, 1H), 1.56 (s, 3H), 1.431.30 (m, 4H), 1.23 (d, J=6.5 Hz, 3H), 0.98-0.85 (m, 3H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C ₁₅ H ₂₄ N ₅ O: 290.20; found: 290.11; t _R =0.74 min on LC/MS Method A.

Example 97

Synthesis of (3R)-3-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-3-methylheptan-2-ol (97). Compound 96c (9.0 mg, 20.5 µmol) was dissolved in TFA (1 ml) and stirred at rt for 1 h. The reaction mixture was carefully concentrated under reduced pressure to dryness and co-evaporated with methanol (10 ml). The residue was dissolved in methanol (1 ml) and concentrated ammonium hydroxide (0.1 ml). The reaction mixture was stirred for 10 minutes. and then concentrated under reduced pressure to dryness and then co-evaporated with methanol (10 ml). The resulting residue was triturated with 50% aq. methanol and filtered through a celite-filled membrane filter. The filtrate was then subjected to preparative HPLC (Gemini 10u C18 110A, AXIA; gradient 10% aq. acetonitrile - 70% aq. acetonitrile with 0.1% TFA over 20 minutes). The product fractions were combined, concentrated under reduced pressure, co-evaporated with methanol (10 mlx3), and dried under high vacuum to give compound 97 as the TFA salt.

¹ H NMR (400 MHz, methanol-d4) δ 8.61 (dd, J=4.3, 1.3 Hz, 1H), 7.82 (dd, J=8.5, 1.4 Hz, 1H ), 7.76 (dd, J=8.5, 4.3Hz, 1H), 4.26 (q, J=6.4Hz, 1H), 2.11 (dddd, J=24.9, 19.8, 12.8, 7.0 Hz, 2H), 1.49 (s, 3H), 1.40-1.24 (m, 4H), 1.22 (d, J=6.4 Hz , 3H), 0.89 (t, J=6.9 Hz, 3H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C15H ₂₄ N ₅ O: 290.20; found: 290.10; t _R =0.74 min on LC/MS Method A.

Example 98

NMP 43V ⁹⁸

Synthesis of (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol (98). Intermediate 43B (101 mg, 0.56 mmol) and (R)-α-Menorleucinol 59A (109 mg, 0.83 mmol)

- 142 041413 was added to NMP (5.5 ml) followed by BOP reagent (0.36 g, 0.83 mmol) and DBU (0.25 ml, 1.67 mmol). The reaction mixture was stirred at rt for 16 h and then diluted with EtOH (2 ml) and water (2 ml). The resulting mixture was directly subjected to HPLC purification (Gemini 10u C18 110A, AXIA; gradient 10% aq. acetonitrile - 80% aq. acetonitrile with 0.1% TFA, over 20 min) to obtain, after collecting the product fractions and removing the solvent in vacuo , compounds 98 in the form of a TFA salt.

1H NMR (400 MHz, methanol-d ₄ ) δ 8.55 (d, J=2.4 Hz, 1H), 8.22 (s, 1H), 7.64 (dd, J=8.7, 2 .5 Hz, 1H), 3.97 (d, J=11.2 Hz, 1H), 3.71 (d, J=11.2 Hz, 1H), 2.09 (m, 1H), 1, 92 (m, 1H), 1.54 (s, 3H), 1.40-1.31 (m, 4H), 1,000.85 (m, 3H).

¹⁹ F NMR (376 MHz, methanol^) δ -77.68, -118.20 (d, J=8.8 Hz). LCMS-ESr (m/z): [M+H]+ calculated for C ₁₄ H ₂₀ FN ₅ O: 293.34; found: 294.1; t _R \u003d 0.68 min.

Example 99

PPh ₃ , l ₂ CF ₃ (CH ₂ ) ₃ OH ——----UUM , imidazole

Ph

CF ₃ (CH ₂ ) ₃ I ₊ BocN-^' ^Ph

72A°

Synthesis of (3R,5R,6S)-tert-butyl-2-oxo-5,6-diphenyl-3-(4,4,4-trifluorobutyl)morpholine-4-carboxylate (99a). Imidazole (1.75 g, 0.03 mol) and triphenylphosphine 99+% (6.08 g, 0.02 mol) were stirred in DCM (100 ml) under argon and cooled to 0°C over 10 min. Iodine (5.94 g, 0.02 mol) was added over 5 min and the reaction mixture was stirred at 0° C. for 20 min. A solution of 4,4,4-trifluoro-1-butanol 97% (2.48 ml, 0.02 mol) was added slowly. The reaction mixture was stirred and allowed to warm to rt. After 16 h, pentane (200 ml) was added and the resulting solids were filtered off. The solvent was partially removed under reduced pressure and then additional cold pentane (50 ml) was added. The solids were filtered off and the eluent was concentrated under reduced pressure to give 1,1,1-trifluoro-4-iodobutane.

(2S,3R)-tert-butyl-6-oxo-2,3-diphenylmorpholine-4-carboxylate, 72A (1 g, 2.83 mmol) and 1,1,1 trifluoro-4-iodobutane (2.02 g, 8.49 mmol) was dissolved in THF (24 ml) and HMPA (2.5 ml) and then the mixture was cooled to -78° C. under argon. 1M lithium hexamethyldisilazide (1.0 M THF in THF, 4.24 ml) was added and the reaction mixture was transferred to a -40° C. bath. The cold bath was refilled with dry ice and the reaction mixture was allowed to warm to room temperature with stirring overnight. The reaction mixture was quenched with EtOAc (25 ml) and poured into a mixture of EtOAc (100 ml) and saturated aqueous NH4Cl (50 ml). The organic layer was separated and washed with water (100 ml), brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with hexanes-EtOAc to give (3R,5R,6S)-tert-butyl-2-oxo-5,6-diphenyl-3-(4,4,4-trifluorobutyl)morpholine-4-carboxylate 99a .

Synthesis of (R)-2-((tert-butoxycarbonyl)amino)-6,6,6-trifluorohexanoic acid (99b). Lithium (granular) (157.24 mg, 22.65 mmol) was cooled in a -40° C. bath. Ammonia gas was slowly condensed through a cold finger into the reaction mixture over 15-20 min. After 20 min additional (3R,5R,6S)-tert-butyl-2-oxo-5,6-diphenyl-3-(4,4,4-trifluorobutyl)morpholine-4-carboxylate, 99a (700 mg, 1.51 mmol) in THF (10 ml) and EtOH (0.5 ml). The reaction mixture was allowed to warm to rt and the liquid ammonia was allowed to evaporate with stirring overnight. The resulting residue was treated with THF (50 ml) and water (50 ml) and stirred until all solids were dissolved. Added saturated aq. ammonium chloride solution (50 ml) followed by the addition of 1N NaOH to adjust the pH to basic. The reaction mixture was washed with diethyl ether (100 ml) and then the pH of the aqueous layer was adjusted with 1N HCl to ~ pH 4. The aqueous layer was then extracted with EtOAc (3x50 ml). The combined organics were then washed with ammonium chloride (50 ml), water (50 ml), brine (50 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure to give 99b.

- 143 041413

Synthesis of (R)-methyl-2-amino-6,6,6-trifluorohexanoate (99c). Compound 99b (230 mg, 0.81 mmol) was dissolved in DCM (10 ml) and MeOH (1 ml). A solution of 2 M (trimethylsilyl)diazomethane, 2 M solution in hexanes (0.6 ml, 1.2 mmol) was added dropwise. The reaction mixture was allowed to stir for 20 minutes and then 2 drops of acetic acid were added. The reaction mixture was concentrated under reduced pressure and the resulting residue was treated with DCM (5 ml) and TFA (5 ml). The mixture was stirred for 90 minutes and then concentrated under reduced pressure. The residue was co-evaporated with

DCM (20 ml x 2) to give 99c as TFA salt.

Synthesis of (R)-methyl-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-6,6,6trifluorohexanoate (99d). 99d was synthesized in a manner similar to compound 63B, replacing 63A with TFA salt of (R)-methyl-2-amino-6,6,6-trifluorohexanoate 99c (100 mg, 0.75 mmol) to give 99d. MS (m/z) 494.2 [M+H]+; tR=0.95 min.

Synthesis of (R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-6,6,6trifluorohexan-1-ol (99е) . Compound 99d (100 mg, 0.2 mmol) was treated with THF (15 ml) and cooled to 0° C. under argon. To this solution was added 1 M LiAlH ₄ in THF (0.61 ml, 0.61 mmol) and the reaction mixture was stirred at 0°C. After completion, the reaction mixture was diluted with

EtOAc/H ₂ O and extracted with EtOAc (50 mlx3). The combined organics were then washed with aq. ammonium chloride (50 ml), water (50 ml), brine (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude residue was chromatographed on silica gel eluting with hexanes-EtOAc to give 99e. LCMS (m/z) 466.1 [M+H]+. t _R \u003d 1.14 min.

Synthesis of (R)-2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-6,6,6-trifluorohexan-1-ol (99). Compound 99e (75 mg, 0.16 mmol) was dissolved in TFA (5 ml) and left to stir for 1 h. TFA was removed under reduced pressure and MeOH (10 ml) was added. The mixture was stirred for 1 hour and then filtered. The eluent was removed in vacuo and the residue was treated with MeOH (10 ml). The mixture was stirred for 16 h and then concentrated under reduced pressure. The residue was co-evaporated with MeOH (10 ml x 3) and the resulting residue was dried under high vacuum to give compound 99 as a TFA salt.

¹ H NMR (400 MHz, methanol^) δ 8.65 (dd, J=4.4, 1.4 Hz, 1H), 7.84 (dd, J=8.5, 1.4 Hz, 1H) , 7.77 (dd, J=8.5, 4.4 Hz, 1H), 4.56 (ddt, J=10.9, 5.5, 3.1 Hz, 1H), 3.75 (d , J=5.3 Hz, 2H), 2.40-2.07 (m, 2H), 1.94-1.76 (m, 2H), 1.66 (dddd, J=19.0, 16 .1, 8.7, 5.9 Hz, 2H).

¹⁹ F NMR (376 MHz, methanol^) δ -68.49 (t, J=11.0 Hz), -77.91. LCMS-EST (m/z): [M+H] ⁺ calculated for C ₁₃ H ₁₆ F ₃ N ₅ O: 315.29; found: 316.2; t _R \u003d 0.82 min.

Example 100

Synthesis of (E)-tert-butyl-hept-2-enoate (100a). To a solution of valeric aldehyde (2.82 ml, 26.57 mmol) in THF (50 ml) was added (tert-butoxycarbonylmethylene)triphenylphosphorane (10 g, 26.57 mmol) and the reaction mixture was stirred for 16 h at rt. Then the solvents were removed under reduced pressure and the residue was suspended in diethyl ether and filtered. The filtrate was concentrated in

- 144 041413 vacuum and the residue was subjected to chromatography on silica gel, eluting with hexanes-EtOAc, to obtain

100a.

1H NMR (400 MHz, methanol^) δ 6.85 (dt, J=15.5, 7.0 Hz, 1H), 5.73 (dt, J=15.6, 1.6 Hz, 1H), 2.26-2.11 (m, 2H), 1.52-1.25 (m, 13H), 0.93 (t, J=7.2 Hz, 3H).

Synthesis of (R)-tert-butyl-3-(benzyl((S)-1-phenylethyl)amino)hentanoate (100b). 2.5 M Butyl lithium (2.5 M in hexanes, 14.33 ml) was added to a stirred solution of (R)-(+)-N-benzyl-alpha-methylbenzylamine (7.99 ml, 38.2 mmol) in THF (100 ml) at -78°C. The reaction mixture was stirred for 30 min and then 100a (4.4 g, 23.88 mmol) in THF (50 ml) was slowly added to the reaction mixture. Then the reaction mixture was stirred at -78°C for 2 h, quenched sat. aq. NH ₄ Cl solution (100 ml) and allowed to warm to rt. EtOAc (200 ml) and water (100 ml) was added and the organic layer was separated. The aqueous layer was extracted with EtOAc (3x50 ml) and the combined organics were washed with brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting residue was chromatographed on silica gel eluting with hexanes-EtOAc to give 100b.

¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.41 (d, J=7.2 Hz, 2H), 7.36-7.10 (m, 8H), 3.87-3.73 ( m, 2H), 3.50 (d, J=15.0 Hz, 1H), 3.24 (tt, J=9.4, 4.2 Hz, 1H), 2.04 (dd, J=14 .4, 3.6 Hz, 1H), 1.89 (dd, J=14.4, 9.4 Hz, 1H), 1.571.43 (m, 3H), 1.38 (s, 8H), 1 .33-1.12 (m, 7H), 0.87 (t, J=7.3 Hz, 3H).

Synthesis of (R)-3-(benzyl((S)-1-phenylethyl)amino)heptanoic acid (100s). (R)-tert-Butyl-3(benzyl((S)-1-phenylethyl)amino)heptanoate 100b (6.4 g, 16.18 mmol) was dissolved in DCM (40 ml) and treated with TFA (20 ml). The reaction mixture was allowed to stir at 40°C for 24 h and then concentrated under reduced pressure to give 100s. LCMS (m/z) 340.0 [M+H]+. t _R \u003d 0.94 min.

Synthesis of (R)-3-(benzyl((S)-1-phenylethyl)amino)hentan-1-ol (100d). (R)-3-(benzyl(((S)-1phenylethyl)amino)heptanoic acid 100c (5.5 g, 16.2 mmol) was dissolved in THF (100 ml) under argon and 1M borane-tetrahydrofuran was added slowly in THF (64.81 mL, 64.81 mmol) The reaction mixture was allowed to stir for several hours at rt MeOH was added slowly to quench the reaction mixture and the mixture was allowed to stir for an additional 20 min. 14 ml) and the mixture was concentrated under reduced pressure to give a white solid. The solid was suspended in DCM (100 ml) and filtered. The filter cake was washed with DCM (25 ml). The mother liquor was concentrated under reduced pressure to give a light yellow oil, which chromatographed on silica gel eluting with DCM-MeOH to give 100 d MS (m/z) 326.1 [M+H] + t _R = 0.82 min.

Synthesis of (R)-3-aminoheptan-1-ol (100e). (R)-3-(benzyl((S)-1-phenylethyl)amino)hentan-1-ol 100d (0.78 g, 2.4 mmol) was treated with EtOH (25 ml) and 20% Pd(OH) ₂ /C (300 mg, 0.43 mmol). The reaction vessel was purged with 3x H ₂ gas and then allowed to stir for 2 days under an H ₂ atmosphere. The reaction mixture was filtered and the solvents were removed under reduced pressure to give 100e.

1H NMR (400 MHz, methanol-d ₄ ) δ 3.90-3.68 (m, 2H), 3.39-3.27 (m, 1H), 1.98-1.72 (m, 2H) , 1.72-1.57 (m, 3H), 1.39 (h, J=4.5, 4.0 Hz, 4H), 1.03-0.86 (m, 3H).

NNHO'

N NH ₂ 100

Synthesis of (R)-3-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)heptan-1-ol (100). 2,4dichloropyrido[3,2-d]pyrimidine (100 mg, 0.5 mmol) was reacted with 100e (65.6 mg, 0.5 mmol) followed by the addition of 2,4-dimethoxybenzylamine, (150.21 µl, 1 mmol) as described for the synthesis of 59B from 59A to give 100f. Compound 100f was then subjected to TFA (3 ml) for 1 h as described in the preparation of compound 59 from 59B to give 100 as the TFA salt. MS (m/z) 276.1 [M+H] ⁺ ; t _R =0.64 min; 1H NMR (400 MHz, methanol ^) δ 8.63 (dd, J=4.4, 1.5 Hz, 1H), 7.82 (dd, J=8.5, 1.5 Hz, 1H) , 7.76 (dd, J=8.5, 4.4 Hz, 1H), 4.64 (tt, J=7.9, 5.6 Hz, 1H), 3.72-3.59 (m , 2H), 1.99-1.83 (m, 2H), 1.81-1.66 (m, 2H), 1.46-1.29 (m, 4H), 0.97-0.82 (m, 3H).

¹⁹ F NMR (376 MHz, methanol^) δ -77.56.

Example 101

101

Synthesis of (R)-N-(2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexyl)acetamide (101). Compound 101 was prepared according to the procedure described in Example 84 using 2,4-dichloro-7-fluoropyrido[3,2-d]pyrimidine 84E (30 mg, 0.14 mmol) followed by reaction with (R)-N-(2-amino-2-methylhexyl)acetamide hydrochloride 61E (28.72 mg, 0.14 mmol), followed by reaction with 2,4-dimethoxybenzylamine (82.69 µl, 0.55 mmol) . The resulting product was then treated with TFA as described in the preparation of 84 from 84G to give 101 as a TFA salt.

MS (m/z) 335.2 [M+H]+; t _R \u003d 0.64 min.

1H NMR (400 MHz, methanol^) δ 8.54 (t, J=2.9 Hz, 2H), 7.62 (dd, J=8.8, 2.5 Hz, 1H), 3.99- 3.86 (m, 1H), 3.51 (d, J=14.0 Hz, 1H), 2.26-2.05 (m, 1H), 1.95 (s, 4H), 1.54 (s, 3H), 1.45-1.27 (m, 4H), 0.99-0.80 (m, 3H).

¹⁹ F NMR (376 MHz, methanol-d ₄ ) δ -78.04, -118.27 (d, J=8.8 Hz).

Example 102

Synthesis of (3R)-3-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-1-fluoroheptan-2-ol (102). A solution of compound 43B (131.5 mg, 0.730 mmol), compound 88d (212.2 mg, 1.415 mmol) and BOP (392.7 mg, 0.888 mmol) in DMF (7 ml) was stirred at rt while adding DBU (0. 33 ml, 2.209 mmol). The reaction mixture was stirred at rt for 17.5 h, diluted with water (7 ml) and then the mixture was filtered. The filtrate was subjected to preparative HPLC (Gemini 10u C18 110A, AXIA; gradient 10% aq. acetonitrile - 70% aq. acetonitrile with 0.1% TFA, over 20 min) and the product fractions were combined, concentrated under reduced pressure to obtain the crude product. The crude product was resubjected to preparative HPLC (Gemini 10u C18 110A, AXIA; gradient 10% aq. acetonitrile - 70% aq. acetonitrile with 0.1% TFA, over 20 min) and the combined product fractions were concentrated under reduced pressure, co evaporated with methanol (10 mlx4) and dried to give compound 102 as a TFA salt.

¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.67 (d, J=9.6 Hz, 0H), 8.55 (d, J=2.4 Hz, 1H), 7.65 (dd , J=8.8, 2.5Hz, 1H), 4.63-4.54(m, 1H), 4.51-4.39(m, 1H), 4.39-4.26(m , 1H), 4.03 (dddd, J=16.5, 6.0, 4.9, 3.2 Hz, 1H), 1.871.73 (m, 2H), 1.49-1.28 (m , 4H), 0.98-0.83 (m, 3H).

¹⁹ F NMR (376 MHz, methanol-d ₄ ) δ -77.71, -117.85 (d, J=8.3 Hz), -231.37 (td, J=47.3, 16.5 Hz ). LCMSESI+ (m/z): [M+H]+ calculated for C ₁₄ H ₂₀ F ₂ N ₅ O: 312.16; found: 312.16; t _R \u003d 0.70 min.

Example 103

Synthesis of (R)-benzyl (1-hydroxyhexan-2-yl)carbamate (103a). A solution of (R)-2-aminohexan-1-ol (1.853 g, 15.81 mmol) and sodium bicarbonate (1961.6 mg, 31.63 mmol) in water (80 ml) was stirred at rt and benzyl chloroformate (2, 7 ml, 95% pure, 18.98 mmol). After stirring for 1 h at rt, the mixture was extracted with EtOAc (100 ml x 1, 80 ml x 2). The combined extracts were washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 0-100% EtOAc in hexanes to give 103a.

1 H NMR (400 MHz, methanol-d ₄ ) δ 7.44-7.18 (m, 5H), 6.75 (d, J=8.7 Hz, 0H), 5.07 (d, J=2 .2 Hz, 2H), 3.57 (dt, J=11.1, 5.4 Hz, 1H), 3.48 (d, J=5.6 Hz, 2H), 1.58 (dq, J =14.0, 8.4, 6.4 Hz, 1H), 1.35 (dq, J=14.3, 7.4, 6.4 Hz, 5H), 0.91 (t, J=5 .6 Hz, 3H). LCMS-ESI ⁺ (m/z): [M+H]+ calculated for C ₁₄ H ₂₂ NO ₃ : 252.16; found: 251.80; tR=0.90 min.

Synthesis of benzyl (1-oxohexan-2-yl)carbamate (103b). To a stirred solution of oxalyl chloride (0.125 ml, 1.432 mmol) in DCM (10 ml) cooled to -78°C in a bath was added DMSO (0.203 ml, 2.865 mmol) in DCM (2 ml) over 8 minutes. After 15 min, a solution of compound 103a (300 mg, 1.194 mmol)

- 146 041413 in DCM (4 ml) was added to the reaction mixture. The mixture was stirred at -78°C for 30 minutes. and then triethylamine (0.832 ml, 5.968 mmol) was added with vigorous stirring. The resulting mixture was allowed to warm to rt, diluted with DCM (20 ml), washed with water (30 mlx3), brine (20 ml), dried (MgSO ₄ ), filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 0-50% EtOAc in hexanes to give 103b.

1H NMR (400 MHz, methanol-d ₄ ) δ 9.41 (d, J=80.7 Hz, 0H), 7.51-7.06 (m, 5H), 5.08 (d, J=2 .1 Hz, 2H), 4.43 (d, J=3.9 Hz, 1H), 3.57 (dd, J=9.8, 5.1 Hz, 1H), 1.65 (dd, J =11.3, 6.7 Hz, 1H), 1.46-1.20 (m, 5H), 0.90 (t, J=6.3 Hz, 3H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C ₁₄ H ₂₀ NO ₃ : 250.14; found: 249.83; tR=0.93 min.

Synthesis of benzyl (2-hydroxyheptan-3-yl) carbamate (103c). To a solution of compound 103b (277.0 mg, 1.111 mmol) dissolved in diethyl ether (10 ml) and cooled to -78°C, 1.57 M methyllithium in diethyl ether (1.557 ml, 2.444 mmol) was added dropwise. After 10 min, saturated ammonium chloride (10 ml) was added to the reaction mixture and the resulting mixture was allowed to warm to rt over 45 min. The mixture was extracted with EtOAc (50 mlx3), the combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 0-70% EtOAc in hexanes to give compound 103c as a mixture of 4 diastereomers.

¹ H NMR (400 MHz, methanol-d4) δ 7.44-7.19 (m, 5H), 5.08 (d, J=3.0 Hz, 2H), 3.83-3.57 (m , 1H), 3.54-3.40 (m, 1H), 1.76-1.41 (m, 2H), 1.43-1.24 (m, 6H), 1.12 (dd, J =9.4, 6.4 Hz, 3H), 0.90 (dd, J=7.9, 4.9 Hz, 3H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C15H ₂₄ NO ₃ : 266.18; found: 265.81; tR=0.93 min.

Synthesis of 3-aminoheptan-2-ol (103d). Compound 103c (59.6 mg, 0.225 mmol) and 20% Pd(OH) ₂ on charcoal (15.2 mg) were dissolved in EtOH (2 ml) and stirred under H ₂ atmosphere. After 2 h the reaction mixture was filtered through a pad of celite and the removed solid was washed with EtOH (10 ml). The filtrate and washing were concentrated under reduced pressure and the crude compound, 103d, was used without further purification. LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C ₇ H ₁₈ NO: 132.14; found: 131.91; t _R \u003d 0.37 min.

Synthesis of 3-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)heptan-2-ol (103e). N,N-diisopropylethylamine (0 .05 ml, 0.281 mmol). After 20 min additional N,N-diisopropylethylamine (0.080 ml, 0.449 mmol) and 2,4-dimethoxybenzylamine (0.10 ml, 0.674 mmol) were added and the resulting mixture was heated at a 115° C. bath for 7 h. The reaction mixture was allowed to cool to rt, diluted with water (50 ml), extracted with DCM (25 mlx2). The combined organic extracts were washed with water (25 mlx2), dried over MgSO4, filtered and then concentrated in vacuo. The residue was chromatographed on silica gel eluting with 0-100% EtOAc in hexanes to give compound 103e.

1 H NMR (400 MHz, methanol-d ₄ ) δ 8.31 (dt, J=4.3, 1.0 Hz, 0.85H), 8.05 (s, 0.15H), 7.63 (s , 1H), 7.48 (dd, J=8.5, 4.2 Hz, 1H), 7.18 (dd, J=8.3, 1.9 Hz, 1H), 6.52 (d, J=2.3Hz, 1H), 6.48-6.38(m, 1H), 4.64-4.47(m, 2H), 4.35-4.21(m, 1H), 4 .00-3.87 (m, 1H), 3.83 (two s, 3H), 3.76 (two s, 3H), 3.35 (s, 1H), 1.90-1.52 (m , 2H), 1.33 (m, 4H), 1.16 (m, 3H), 0.97-0.78 (m, 3H). LCMS-eST (m/z): [M+H] ⁺ calculated for C ₂₃ H ₃₄ N ₅ O ₃ : 426.25; found: 426.17; t _R =1.00 min.

Synthesis of 3-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)heptan-2-ol (103). Compound 103e (17.4 mg, 40.9 μmol) was dissolved in TFA (1 ml) and stirred at rt for 1 h. The reaction mixture was concentrated under reduced pressure and co-evaporated with MeOH (10 ml). The resulting residue was dissolved in MeOH (1 ml) and concentrated ammonium hydroxide (0.1 ml). The mixture was stirred for 10 minutes. at rt and then concentrated under reduced pressure to dryness. The residue was dissolved in DMF-water (1:1, 5 ml) and filtered through celite/membrane filter. The filtrate was subjected to preparative HPLC (Gemini 10u C18 110A, AXIA; gradient 10% aq. acetonitrile - 70% aq. acetonitrile with 0.1% TFA, over 20 min). The product fractions were combined, concentrated under reduced pressure, co-evaporated with methanol (10 ml x 3) and dried under high vacuum to give compound 103 as the TFA salt.

1H NMR (400 MHz, methanol-d ₄ ) δ 8.64 (dt, J=4.4, 1.2 Hz, 1H), 7.84 (dt, J=8.5, 1.4 Hz, 1H ), 7.77 (ddd, J=8.5, 4.4, 1.5 Hz, 1H), 4.47-4.31 (m, 1H), 3.99 (tq, J=6.5 , 3.5 Hz, 0.5H), 3.94 (dd, J=6.6, 5.5 Hz, 0.5H), 1.951.82 (m, 0.5H), 1.82-1, 72 (m, 1H), 1.72-1.63 (m, 0.5H), 1.48-1.25 (m, 4H), 1.22 (d, J=6.4 Hz, 1, 5H), 1.19 (d, J=6.4 Hz, 1.5H), 0.89 (two d, J=6.9, Hz each, 3H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C ₁₄ H ₂₂ N ₅ O: 276.18; found: 276.15; t _R \u003d 0.68 min.

- 147 041413

Example 104

Synthesis of (S)-benzyl (1-hydroxyhexan-2-yl)carbamate (104a). Benzyl chloroformate (0.74 ml , 95% pure, 5.17 mmol). The resulting mixture was vigorously stirred at rt overnight. The solid was dissolved in EtOAc (75 ml) and the mixture was extracted with EtOAc (75 ml x2). The organic extracts were combined, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give white solids. The solids were chromatographed on silica gel eluting with 0100% EtOAc in hexanes to give compound 104a.

1 H NMR (400 MHz, methanol-d ₄ ) δ 7.42-7.22 (m, 5H), 5.07 (d, J=2.1 Hz, 2H), 3.59 (d, J=8 .0 Hz, 1H), 3.48 (d, J=5.6 Hz, 2H), 1.59 (d, J=10.8 Hz, 1H), 1.34 (td, J=15.4 , 11.8, 7.3 Hz, 6H), 0.91 (t, J=6.0 Hz, 3H). LCMSESI ⁺ (m/z): [M+H] ⁺ calculated for C ₁₄ H ₂₂ NO ₃ : 252.16; found: 251.78; tR=0.88 min.

Synthesis of benzyl (1-oxohexan-2-yl)carbamate (104b). To a stirred solution of oxalyl chloride (0.052 ml, 0.602 mmol) in DCM (1.5 ml) at -78°C was added DMSO (0.086 ml, 1.205 mmol) in DCM (2 ml) over 8 minutes. After 15 min, a solution of compound 104a (108.1 mg, 0.430 mmol) in DCM (1.5 ml) was added to the reaction mixture. The mixture was stirred at -78°C for 30 minutes and then triethylamine (0.174 ml, 1.248 mmol) was added with vigorous stirring. The resulting mixture was allowed to warm to rt over 45 min. The mixture was diluted with DCM (30 ml), washed with water (30 mlx3), brine (25 ml), dried over MgSO ₄ , filtered and concentrated under reduced pressure to obtain a mixture of 104b. LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C ₁₄ H ₂₀ NO ₃ : 250.14; found: 249.79; t _R \u003d 0.91 min.

Synthesis of benzyl-(2-hydroxyheptan-3-yl)carbamate (104c). To a solution of compound 104b (107.3 mg, 0.430 mmol) dissolved in diethyl ether (4 ml) and cooled to -78°C, 1.57 M methyllithium in diethyl ether (0.685 ml, 1.076 mmol) was added dropwise. After 10 minutes, saturated aq. ammonium chloride (7 ml) was added to the reaction mixture and the resulting mixture was allowed to warm to rt over 45 min. The mixture was extracted with EtOAc (25 ml x2) and the combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 0-70% EtOAc in hexanes to give compound 104c as a mixture of 4 diastereomers.

¹ H NMR (400 MHz, methanol-d4) δ 7.42-7.20 (m, 5H), 6.63 (dd, J=102.5, 9.6 Hz, 1H), 5.08 (d , J=3.3 Hz, 2H), 3.80-3.54 (m, 1H), 3.52-3.41 (m, 1H), 1.75-1.42 (m, 2H), 1.42-1.27 (m, 5H), 1.12 (dd, J=9.3, 6.4 Hz, 3H), 0.90 (d, J=3.5 Hz, 3H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C15H24NO3: 266.18; found: 265.81; tR=1.06 min.

[Synthesis of 3-aminoheptan-2-ol (104d) Compound 104c (71.68 mg, 0.270 mmol) and 20% Pd(OH) ₂ on charcoal (19 mg) were dissolved in EtOH (2 ml) and stirred under H2 atmosphere. After 2 h the reaction mixture was filtered through a pad of celite and the removed solids were washed with EtOH (5 ml). The filtrate and washings were concentrated under reduced pressure to give 104d, which was used without further purification. LCMS-ESP (m/z): [M+H] ⁺ calculated for C ₇ H ₁₈ NO: 132.14; found: 131.91; tR=0.51 min.

Synthesis of 3-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)heptan-2-ol (104e). N,N-diisopropylethylamine (0 .06 ml, 0.338 mmol). After 20 min additional N,N-diisopropylethylamine (0.096 ml, 0.540 mmol) and 2,4-dimethoxybenzylamine (0.120 ml, 0.811 mmol) were added and the resulting mixture was heated at 115° C. bath for 6 h. The reaction mixture was cooled to rt, diluted water (30 ml) and extracted with DCM (20 ml x 2). The organic extracts were combined, washed with water (30 mlx2), brine (25 ml), dried

- 148 041413 over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 0-100% EtOAc in hexanes to give compound 104e.

Ή NMR (400 MHz, methanol-d ₄ ) δ 8.31 (ddd, J=4.2, 1.5, 0.8 Hz, 1H), 7.63 (d, J=8.4 Hz, 1H ), 7.48 (dd, J=8.5, 4.2 Hz, 1H), 7.25-7.08 (m, 1H), 6.60-6.37 (m, 2H), 4, 84 (s, 3H), 4.54 (d, J=5.3 Hz, 2H), 4.35-4.22 (m, 1H), 3.83 (d, J=10.3 Hz, 3H ), 3.79-3.73 (m, 3H), 1.88-1.52 (m, 2H), 1.46-1.28 (m, 4H), 1.23-1.12 (m , 3H), 0.86 (td, J=7.0, 2.2 Hz, 3H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C ₂₃ H ₃₄ N ₅ O ₃ : 426.25; found: 426.19; t _R \u003d 0.97 min.

Synthesis of 3-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)heptan-2-ol (104). Compound 104e (27.3 mg, 64.2 μmol) was dissolved in TFA (1 ml) and stirred at rt for 1 h. The reaction mixture was concentrated under reduced pressure and co-evaporated with MeOH (10 ml). The resulting residue was dissolved in MeOH (1 ml) and concentrated ammonium hydroxide (0.1 ml). The reaction mixture was stirred at rt and then concentrated under reduced pressure to dryness. The residue was treated with DMF-water (1:1, 5 ml). The insoluble matter was removed by filtration through a Celite/membrane filter and the filtrate was subjected to preparative HPLC (Gemini 10u C18 110A, AXIA; gradient 10% aq. acetonitrile - 70% aq. acetonitrile with 0.1% TFA, over 20 min). The fractions were combined, concentrated under reduced pressure, co-evaporated with methanol (10 ml x 3) and dried in vacuo overnight to give 104 as the TFA salt.

¹ H NMR (400 MHz, methanol-d4) δ 8.64 (dt, J=4.4, 1.2 Hz, 1H), 7.84 (dt, J=8.5, 1.4 Hz, 1H ), 7.77 (ddd, J=8.5, 4.4, 1.5 Hz, 1H), 4.46-4.40 (m, 0.5H), 4.37 (m, 1H), 4.00 (m, 0.5H), 3.97-3.88 (m, 0.5H), 1.88 (m, 0.5H), 1.82-1.72 (m, 1H), 1.72-1.62 (m, 0.5H), 1.48-1.25 (m, 4H), 1.22 (d, J=6.4 Hz, 1.5H), 1.19 ( d, J=6.4Hz, 1.5H), 0.89 (two t, J=6.8Hz each, 3H). LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C ₁₄ H ₂₂ N ₅ O: 276.18; found: 276.15; t _R \u003d 0.68 min.

Example 105

Synthesis of 2,4,7-trichloropyrido[3,2-d]n-pyrimidine (105a). A mixture of pyrido[3,2-d]pyrimidine-2,4(1H,3H)dione 19A (supplied by Astatech, Inc., 2.00 g, 12.26 mmol), phosphorus pentachloride (15.32 g, 73.56 mmol) and phosphorus oxychloride (22.86 ml, 245.20 mmol) in a sealed thick-walled reaction tube was stirred at 160°C for 5 hours. The mixture was concentrated in vacuo and the residue was dissolved in DCM (100 ml). The organic solution was washed with water (100 ml), brine (100 ml), dried over MgSO ₄ , filtered and then concentrated in vacuo. The residue was chromatographed on silica gel eluting with 0-50% EtOAc in hexanes to give compound 105a.

1 H NMR (400 MHz, chloroform-d) δ 9.02 (d, J=2.2 Hz, 21H), 8.29 (d, J=2.2 Hz, 21H). LCMS-ESI' (m/z): t _R =0.86 min.

Synthesis of (R)-2-((7-chloro-2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)hexan1-ol (105b). N,N-diisopropylethylamine (0.23 ml , 1.292 mmol). The mixture was stirred for 40 minutes and then additional N,N-diisopropylethylamine (0.38 ml, 2.132 mmol) and 2,4-dimethoxybenzylamine (0.473 ml, 3.198 mmol) were added. The resulting mixture was heated at 115° C. for 2 hours. The reaction mixture was cooled to rt, diluted with water (30 ml) and extracted with DCM (30 ml). The organic extracts were washed with water (30 ml), brine (30 ml), dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 0-100% EtOAc in hexanes to give compound 105b. LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C ₂₂ H ₂₉ ClN ₅ O ₃ : 446.20; found: 446.23, t _R =0.80 min.

Synthesis of (R)-2-((2-((2,4-dimethoxybenzyl)amino)-7-methoxypyrido[3,2-d]pyrimidin-4yl)amino)hexan-1-ol (105c). To a solution of compound 105b (50 mg, 0.113 mmol) in dioxane (2 ml) was added sodium methoxide (25 wt%, 0.064 ml, 0.280 mmol) in a microwave vial. The resulting mixture was heated at 120°C for 45 min in a microwave reactor. The reaction mixture was concentrated

- 149 041413 in vacuo and the residue was dissolved in methanol (2 ml) and sodium methoxide (25 wt.%, 0.2 ml, 0.874 mmol). The resulting mixture was heated at 150° C. for 1 hour in a microwave reactor. The reaction mixture was diluted with water (25 ml) and extracted with EtOAc (25 mlx2). The combined extracts were washed with saturated aqueous ammonium chloride (25 ml), dried over MgSO ₄ , filtered and concentrated under reduced pressure to give the crude compound 105c. LCMS-E81 ⁺ (m/z): [M+H] ⁺ calculated for C ₂₃ H ₃₂ N ₅ O ₄ : 442.25; found: 442.23; tR=0.82 min.

Synthesis of (R)-2-((2-amino-7-methoxypyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol (105). Compound 105c was dissolved in TFA (1 ml) and stirred at rt for 1 h. The reaction mixture was concentrated under reduced pressure and co-evaporated with MeOH (10 ml). The resulting residue was subjected to preparative HPLC (Gemini 10u C18 110A, AXIA; gradient 5% aq. acetonitrile - 50% aq. acetonitrile with 0.1% TFA, over 20 min). The product fractions were concentrated in vacuo, co-evaporated with methanol (10 ml x 3) and dried in vacuo to give compound 105 as the TFA salt.

¹ H NMR (400 MHz, methanol-J4) δ 8.32 (d, J=2.5 Hz, 1H), 7.22 (d, J=2.6 Hz, 1H), 4.58-4, 39 (m, 1H), 4.00 (s, 4H), 3.77-3.60 (m, 3H), 1.72 (dtd, J=14.7, 8.5, 8.0, 5 .4 Hz, 2H), 1.51-1.22 (m, 5H), 1.00-0.80 (m, 4H).

¹⁹ F NMR (376 MHz, methanol-d4) δ -77.51. LCMS-E81 ⁺ (m/z): [M+H] ⁺ calculated for C14H ₂₂ N ₅ O ₂ : 292.18; found: 292.19; tR=0.45 min.

Example 106

Synthesis

(R)-2-((2-((2,4-dimethoxybenzyl)amino)-7-etkCipirido[3,2-d]pyrimidin-4yl)amino)hexan-1-ol (106a). To a solution of compound 105 c (40 mg, 0.090 mmol) in EtOH (3 ml) was added sodium ethoxide (21 wt%, 0.335 ml, 0.897 mmol) in a microwave vial. The resulting mixture was heated at 120°C for 45 min in a microwave reactor. The reaction mixture was concentrated in vacuo and then the residue was dissolved in water (25 ml) and EtOAc (25 ml). The organic layer was separated and washed with saturated aqueous ammonium chloride, dried over MgSO4, filtered and then concentrated in vacuo to give crude compound 106a. LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C24H34N5O4: 456.26; found: 456.23; tR=0.76 min.

Synthesis of (R)-2-((2-amino-7-ethoxypyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol (106). Compound 106a was dissolved in TFA (1 ml) and stirred at rt for 1 h. The reaction mixture was concentrated in vacuo and co-evaporated with MeOH (10 ml). The resulting residue was dissolved in MeOH (1 ml) and concentrated ammonium hydroxide (0.1 ml). The mixture was stirred at 50°C for 10 min. and then concentrated under reduced pressure. The resulting residue was subjected to preparative HPLC (Gemini 10u C18 110A, AXIA; gradient 5% aq. acetonitrile - 50% aq. acetonitrile with 0.1% TFA, over 20 min). The product fractions were concentrated in vacuo, co-evaporated with methanol (10 ml x 3) and then dried under high vacuum to give compound 106 as the TFA salt.

1H NMR (400 MHz, methanol-d ₄ ) δ 7.94 (d, J=2.6 Hz, 1H), 6.83 (d, J=2.6 Hz, 1H), 4.02 (q, J=7.0Hz, 3H), 3.55(d, J=4.9Hz, 3H), 1.33(t, J=7.0Hz, 4H), 1.30-1.15( m, 4H), 0.91-0.63 (m, 3H).

¹⁹ F NMR (377 MHz, methanol-d4) δ -77.50. LCMS-ESf (m/z): [M+H] ⁺ calculated for C15H ₂₄ N ₅ O ₂ : 306.19; found: 306.20; t _R \u003d 0.51 min.

Example 107

Synthesis of (R)-2-((2-((2,4-dimethoxybenzyl)amino)-7-methylpyrido[3,2-d]pyrimidin-4yl)amino)hexan-1-ol (107a). Mixture of compound 105c (35 mg, 0.078 mmol), methylboronic acid (18.8 mg, 0.314 mmol), potassium orthophosphate (50.0 mg, 0.235 mmol) and tetrakis(triphenylphosphine)palladium (18.14 mg, 0.016 mmol) in water (2 ml) and dioxane (2 ml) were stirred at 150°C for 45 min in a microwave reactor. The reaction mixture was diluted with water (25 ml) and extracted with EtOAc (25 ml).

The organic layer was washed with water (25 ml), brine (25 ml), dried over MgSO ₄ , filtered and then concentrated under reduced pressure to obtain the crude compound 107a.

LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C ₂₃ H ₃₂ N ₅ O ₃ : 292.18; found: 426.22; t _R \u003d 0.70 min.

Synthesis of (R)-2-((2-amino-7-methylpyrido[3,2-d]pyrimidin-4-yl)amino)hexan-1-ol (107). Compound 107a was dissolved in TFA (1 ml) and stirred at rt for 1 h. The reaction mixture was concentrated in vacuo and the residue co-evaporated with MeOH (10 ml). The resulting residue was dissolved in MeOH (1 ml) and concentrated ammonium hydroxide (0.1 ml). The mixture was stirred for 10 min at 50°C and then concentrated under reduced pressure. The resulting residue was subjected to preparative HPLC (Gemini 10u C18 110A, AXIA; gradient 5% aq. acetonitrile - 50% aq. acetonitrile with 0.1% TFA, over 20 min). Product fractions were concentrated in vacuo, co-evaporated with methanol (10 ml x 3) and dried under high vacuum to give compound 107 as the TFA salt.

1H NMR (400 MHz, methanol-d ₄ ) δ 8.53-8.46 (m, 1H), 7.62 (tt, J=1.9, 1.0 Hz, 1H), 4.51 (dtd , J=9.0, 5.5, 3.1 Hz, 1H), 3.72 (d, J=5.3 Hz, 2H), 2.51 (d, J=2.2 Hz, 3H) , 1.83-1.62 (m, 2H), 1.49-1.29 (m, 4H), 0.98-0.86 (m, 3H).

¹⁹ F NMR (376 MHz, methanol-d4) δ -77.52. LCMS-ESI* (m/z): [M+H] ⁺ calculated for C14H ₂₂ N ₅ O: 276.18; found: 276.16; tR=0.50 min.

Example 108ci

C* DIPEA/1,4-dioxane_______

OH then DMB-NH ₂ , DIPEA * _Z „ 120 °C

108a

Synthesis of (R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)pent-4-en-1ol (108b). To a solution of 2,4-dichloropyrido[3,2-d]pyrimidine (50 mg, 0.250 mmol) and (R)-2aminopent-4-en-1-ol hydrochloride 108a (26.6 mg, 0.280 mmol, Chiralix BV, Netherland) in dioxane (2 ml) was added N,N-diisopropylethylamine (0.09 ml, 0.500 mmol). The mixture was stirred overnight and then additional N,N-diisopropylethylamine (0.09 ml, 0.500 mmol) and 2,4-dimethoxybenzylamine (0.403 ml, 2.727 mmol) were added. The resulting mixture was heated at 120°C overnight. The reaction mixture was allowed to cool to rt, diluted with water (25 ml) and extracted with EtOAc (25 mlx3). The organic extracts were washed with water (25 ml), brine (25 ml), dried over MgSO), filtered and then concentrated in vacuo to give crude compound 108b. LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C ₂₁ H ₂₆ N ₅ O ₃ : 396.20; found: 396.14, t _R =0.69 min.

Synthesis of (R)-2-((2-αminopyrido[3,2-d]pyrimidin-4-yl)amino)pent-4-en-1-olα (108). Compound 108b (99 mg) was dissolved in TFA (3 ml) and stirred at rt for 3 h. The reaction mixture was concentrated under reduced pressure and co-evaporated with MeOH (10 ml). The resulting residue was subjected to preparative HPLC (Gemini 10u C18 110A, AXIA; gradient 5% aq. acetonitrile - 50% aq. acetonitrile with 0.1% TFA, over 20 min). Product fractions were concentrated in vacuo, co-evaporated with methanol (10 mlx3), and dried under high vacuum to give compound 108 as a TFA salt.

1H NMR (400 MHz, methanol-d ₄ ) δ 8.64 (dd, J=4.3, 1.5 Hz, 1H), 7.89-7.65 (m, 2H), 6.02-5 .70 (m, 1H), 5.24-5.10 (m, 1H), 5.11-4.99 (m, 1H), 4.63-4.45 (m, 1H), 3.76 (d, J=5.3 Hz, 2H), 2.68-2.35 (m, 2H).

¹⁹ F NMR (376 MHz, methanol-d4) δ -77.49. LCMS-ESr (m/z): [M+H] ⁺ calculated for C12H ₁₆ N ₅ O: 246.14; found: 246.09, tR=0.45 min.

Example 110

Synthesis of (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylheptan-1-ol (110). TFA (3 ml) was added to 77A (40 mg, 0.09 mmol) and the mixture was stirred for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was subjected to preparative HPLC (Synergi 4u PolarRP 80A, Axia; gradient 10% aq. acetonitrile - 70% aqueous acetonitrile with 0.1% TFA, for 20 min) s

- 151 041413 obtaining 110 in the form of TFA salt. LCMS (m/z): 292.12 [M+H]+; t _R =0.50 min on LC/MS Method A.

1H NMR (400 MHz, methanol-d ₄ ) δ 8.63 (dd, J=4.4, 1.4 Hz, 1H), 7.87 (dd, J=8.5, 1.4 Hz, 1H ), 7.76 (dd, J=8.5, 4.4 Hz, 1H), 4.61-4.34 (m, 1H), 3.76 (d, J=5.3 Hz, 2H) , 1.96-1.70 (m, 2H), 1.64-1.51 (m, 2H), 1.19 (s, 6H).

¹⁹ F NMR (377 MHz, methanol-d ₄ ) δ -77.52.

Example 111

Synthesis of (3R,5R)-3-methyl-3-nentyl-5-phenylmorpholin-2-one (111A). To a solution of 94c (2 g, 10.57 mmol) in THF (50 mL) at -78°C was added 2 M boron trifluoride diethyl etherate in THF (2.76 mL, 22.39 mmol, 2.1 eq.) over 10 min. After 90 minutes, a 2M solution of pentylmagnesium chloride in THF (11.19 mL, 22.38 mmol, 2.1 eq.) was added slowly. The reaction mixture was stirred for 2 hours and then quenched with sat. NH ₄ Cl (200 ml). The mixture was allowed to warm to rt and then diluted with water (200 ml). The mixture was extracted with EtOAc (3x300 ml) and the combined extracts were washed with water (3x500 ml), brine (300 ml), dried over NaSO ₄ and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with hexanes-EtOAc to give 111A. LCMS (m/z): 262.06 [M+H]+; t _R =1.14 min on LC/MS Method A.

Synthesis of (R)-2-(((R)-2-hydroxy-1-phenylethyl)amino)-2-methylheptan-1-ol (111B). To a solution of 111A (1.65 g, 6.31 mmol) in THF (100 mL) was added 2 M lithium borohydride in THF (6.35 mL, 12.7 mmol, 2 eq) at 0°C. The reaction mixture was heated to rt and stirred overnight. The mixture was then quenched with water (100 ml) and extracted with EtOAc (3x300 ml). The combined organics were washed with water (500 ml), brine (100 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give 111B, which was used without further purification. LCMS (m/z): 266.05 [M+H]+; tR=0.64 min on LC/MS Method A.

Synthesis of (R)-2-amino-2-methylheptan-1-ol (111C). To a solution of 111B (1.66 g, 6.25 mmol) in EtOH (20 ml) was added Pd(OH) ₂ /C (20% wt.%, 0.92 g) and 4 M HCl in dioxane (2.37 ml, 9.50 mmol, 1.5 eq.). The mixture was stirred under H2 atmosphere at 70° C. overnight. The reaction mixture was then filtered through celite and concentrated to give 111C, which was used without further purification. LCMS (m/z): 145.95 [M+H]+; t _R =0.57 min on LC/MS Method A.

Synthesis of (R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylheptan-1-ol (111D). 111C (135 mg, 0.74 mmol, 1.25 eq.) and N ,N-diisopropylethylamine (0.78 ml, 4.46 mmol, 7.5 eq.). The reaction mixture was stirred at 80°C overnight. 2,4-dimethoxybenzylamine (0.27 mL, 1.85 mmol, 3.1 eq.) was added and the mixture was heated to 100°C for 6 h. The reaction mixture was allowed to cool, diluted with EtOAc (50 mL), washed with water ( 50 ml) saturated with NH ₄ Cl (50 ml), dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with hexanes-EtOAc to give 111D. LCMS (m/z): 440.30 [M+H]+; t _R =0.93 min on LC/MS Method A.

Synthesis of (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylheptan-1-ol (111). TFA (3 ml) was added to 111D (155 mg, 0.35 mmol). After 1 h, the reaction mixture was concentrated under reduced pressure and the residue was subjected to preparative HPLC (Synergi 4u Polar-RP 80A, Axia; gradient 10% aq. acetonitrile - 70% aq. acetonitrile with 0.1% TFA, over 20 min) to obtain 111

- 152 041413 in the form of TFA salt. LCMS (m/z): 290.15 [M+H]+; tR=0.72 min on LC/MS Method A.

1H NMR (400 MHz, methanol^) δ 8.63 (dd, J=4.3, 1.5 Hz, 1H), 7.86-7.80 (m, 1H), 7.77 (dd, J =8.5, 4.3 Hz, 1H), 3.98 (d, J=11.2 Hz, 1H), 3.72 (d, J=11.2 Hz, 1H), 2.16-2 .04 (m, 1H), 1.92 (tt, J=11.1, 4.9 Hz, 1H), 1.55 (s, 3H), 1.42-1.28 (m, 7H), 0.93-0.85 (m, 3H).

¹⁹ F NMR (377 MHz, methanol-d ₄ ) δ -77.58.

Example 112 h ₂ n

112

Synthesis of (R)-2-((2-((2,4-dimethoxybenzyl)amino)-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2methylheptan-1-ol (112A). To a solution of 84E (119.98 mg, 0.55 mmol) in dioxane (10 ml) was added 111C (125 mg, 0.69 mmol, 1.25 eq.) and N,N-diisopropylethylamine (0.72 ml, 4 .13 mmol, 6 eq.). The mixture was stirred at 80°C overnight. 2,4-dimethoxybenzylamine (0.2 ml, 1.38 mol, 2.5 eq.) was added and the reaction mixture was heated to 100°C for 6 h. The reaction mixture was left to cool, diluted with EtOAc (50 ml), washed with water (50 ml), sat. NH4Cl (50 ml), dried over MgSO ₄ , filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with hexanes-EtOAc to give 112A. LCMS (m/z): 458.26 [M+H] ⁺ ; t _R =1.00 min on LC/MS Method A.

Synthesis of (R)-2-((2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylheptan-1-ol (112). TFA (3 ml) was added to 112A (105 mg, 0.23 mmol). After 1 h, the reaction mixture was concentrated under reduced pressure and subjected to preparative HPLC (Synergi 4u Polar-RP 80A, Axia; gradient 10% aq. acetonitrile - 70% aq. acetonitrile with 0.1% TFA, over 20 min) to give 112 in the form of TFA salt. LCMS (m/z): 308.14 [M+H] ⁺ ; tR=0.75 min on LC/MS Method A.

1H NMR (400 MHz, methanol-d ₄ ) δ 8.54 (d, J=2.5 Hz, 1H), 8.22 (s, 1H), 7.62 (ddd, J=8.7, 2 .4, 0.8 Hz, 1H), 3.96 (d, J=11.2 Hz, 1H), 3.70 (d, J=11.2 Hz, 1H), 2.13-2.02 (m, 1H), 1.91 (s, 1H), 1.53 (s, 3H), 1.41-1.28 (m,

7H), 0.93-0.84 (m, 3H).

¹⁹ F NMR (377 MHz, methanol-d ₄ ) δ -77.56, -118.19 (dd, J=8.7, 4.2 Hz).

Example 113

Synthesis of N-(7-fluoro-4-hydroxypyrido[3,2-d]pyrimidin-2-yl)acetamide (113а). The acetic anhydride was cooled to 0° C. under nitrogen and 2-amino-7-fluoropyrido[3,2-d]pyrimidin-4-ol 43B (200 mg, 1.11 mmol; supplied by Medicilon, Shanghai) was added. The reaction mixture was then heated to 110° C. for 4 hours. The mixture was cooled and concentrated under reduced pressure. The residue was triturated with DCM (20 ml) and the solids were removed by filtration and air dried to give compound 113a as a solid. LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C ₉ H ₇ FN ₄ O ₂ : 223.06; found: 222.96; tR=0.58 min.

Synthesis of N ⁴ -(tert-butyl)-7-methoxypyrido[3,2-d]pyrimidine-2,4-diamine (113). 113a was suspended in POCl ₃ (5 ml) and heated to 110°C for 1 h. The reaction mixture was then cooled and POCl ₃ was removed under reduced pressure. The residue was co-evaporated with toluene (15 ml) and then treated with THF (5 ml). tert-Butylamine (70 μl, 0.66 mmol) was added and the mixture was stirred at rt for 15 min. 25% Sodium methoxide in methanol (100 μl, 0.45 mmol) was added and the reaction mixture was heated in a sealed vessel at 80°C. The reaction mixture was allowed to cool to rt and directly subjected to preparative HPLC (Synergi 4u Polar-RP 80A, Axia; gradient 10% aq. acetonitrile - 70% aq. acetonitrile with 0.1% TFA, over 20 min). Product fractions were concentrated in vacuo to give 113 as the TFA salt.

- 153 041413

1H NMR (400 MHz, methanol^) δ 8.30 (d, J=2.5 Hz, 1H), 8.04 (s, 1H), 7.18 (d, J=2.6 Hz, 1H) , 3.99(s,

3H), 1.61(s, 9H).

¹⁹ F NMR (376 MHz, methanol-d4) δ -77.51. LCMS-ESI ⁺ (m/z): [M+H] ⁺ calculated for C12H ₁₇ N ₅ O: 248.14; found: 248.09; tR=0.81 min.

Example 114

Synthesis of (R)-2-((2,7-dichloropyrido[3,2-d]n-yrimidin-4-yl)amino)-2-methylhexan-1-ol (114A). To a solution of 94G (75 mg, 0.30 mmol) and 19B (51 mg, 0.30 mmol) in THF (5 ml) was added N,N-diisopropylethylamine (0.16 ml, 0.90 mmol). After stirring at 80°C for 23 h, the reaction mixture was cooled to room temperature, diluted with EtOAc (50 ml), washed with water (50 ml) and brine (50 ml), dried over Na ₂ SO ₄ , then filtered and concentrated in vacuum. The residue was chromatographed on silica gel eluting with hexanes-EtOAc (0-75%) to give 114A. LCMS (m/z): 329.11 [M+H] ⁺ ; t _R =1.27 min on LC/MS Method A.

Synthesis of (R)-2-((7-chloro-2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]n-yrimidin-4-yl)amino)-2methylhexan-1-ol (114B) . To a solution of 114A in THF (5 mL) was added N,N-diisopropylethylamine (0.16 mL, 0.90 mmol) followed by 2,4-dimethoxybenzylamine (0.25 mL, 1.5 mmol). After stirring at 100°C for 18 h, the reaction mixture was cooled to room temperature, diluted with EtOAc (100 ml), washed with water (100 ml) and brine (100 ml), dried over Na ₂ SO ₄ , then filtered and concentrated in vacuum. The residue was chromatographed on silica gel eluting with hexanes-EtOAc (15-100%) to give 114B. LCMS (m/z): 460.29 [M+H] ⁺ ; t _R =0.94 min on LC/MS Method A.

Synthesis of (R)-2-((2-αmino-7-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol (114). TFA (3 ml) was added to 114B (11 mg, 0.02 mmol). After 4 h the reaction mixture was concentrated in vacuo and co-evaporated with MeOH (3x20 ml). The residue was suspended in MeOH (20 ml) and filtered. After stirring overnight, the solution was concentrated in vacuo to give 114 as the TFA salt. LCMS (m/z): 310.12 [M+H] ⁺ ; tR=0.98 min on LC/MS Method A.

1H NMR (400 MHz, methanol-d4) δ 8.59 (d, J=2.1 Hz, 1H), 8.25 (s, 1H), 7.91 (d, J=2.1 Hz, 1H ), 3.97 (d, J=11.3 Hz, 1H), 3.71 (d, J=11.2 Hz, 1H), 2.10 (ddd, J=13.9, 10.9, 5.0 Hz, 1H), 1.96-1.82 (m, 1H), 1.54 (s, 3H), 1.35 (qt, J=6.8, 2.8 Hz, 4H), 0.95-0.88 (m, 3H).

¹⁹ F NMR (377 MHz, methanol-d ₄ ) δ -77.61.

- 154 041413

Example 115

Synthesis of (R)-2-((2-chloro-7-fluoropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol (115A). To a solution of 94G (55 mg, 0.30 mmol) and 84E (65 mg, .30 mmol) in THF (5 ml) was added N,Ndiisopropylethylamine (0.16 ml, 0.90 mmol). After stirring at 80°C for 18 h, the reaction mixture was cooled to room temperature, diluted with EtOAc (50 ml), washed with water (50 ml) and brine (50 ml), dried over Na2SO4, then filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexanes-EtOAc to give 115A. LCMS (m/z): 313.08 [M+H] ⁺ ; t _R =1.19 min on LC/MS Method A.

Synthesis of (R)-2-((2,7-bis((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-2 methylhexan-1-ol (115V) . To a solution of 115A in THF (5 mL) was added Ν,N-diisopropylethylamine (0.16 mL, 0.90 mmol), followed by 2,4-dimethoxybenzylamine (0.25 mL, 1.5 mmol). After stirring at 140°C for 18 h, the reaction mixture was cooled to room temperature, diluted with EtOAc (100 ml), washed with water (100 ml) and brine (100 ml), dried over Na ₂ SO ₄ , then filtered and concentrated in vacuum. The residue was chromatographed on silica gel eluting with hexanes-EtOAc (0-100%) to give 115B. LCMS (m/z): 444.23 [M+H] ⁺ ; t _R =0.90 min on LC/MS Method A.

Synthesis of (R)-2-((2,7-diaminopyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylhexan-1-ol (115). TFA (3 ml) was added to 115B (14 mg, 0.02 mmol). After 4 h the reaction mixture was concentrated in vacuo and co-evaporated with MeOH (3x20 ml). The residue was suspended in MeOH (20 ml) and filtered. After stirring overnight, the solution was concentrated in vacuo to give 115 as the bisTFA salt. LCMS (m/z): 291.19 [M+H] ⁺ ; tR=0.93 min on LC/MS Method A.

1H NMR (400 MHz, methanol^) δ 8.02 (d, J=2.4 Hz, 1H), 6.69 (d, J=2.4 Hz, 1H), 3.94 (d, J= 11.2 Hz, 1H), 3.69 (d, J=11.2 Hz, 1H), 2.06 (ddd, J=13.4, 11.0, 5.0 Hz, 1H), 1, 91-1.79 (m, 1H), 1.49 (s, 3H), 1.35 (td, J=7.4, 4.2 Hz, 4H), 0.92 (t, J=7, 0 Hz, 3H).

¹⁹ F NMR (377 MHz, methanol^) δ -77.58.

- 155 041413

Example 116

Synthesis of tert-butyl-(R)-(1-hydroxy-2-methylheptan-2-yl)carbamate (116A). To 111C (315 mg, 2.17 mmol) in THF (30 ml) was added 1 M aqueous NaOH (2.2 ml), followed by the addition of DIPEA (1.7 ml, 9.76 mmol) and Boc ₂ O (2 .17 g, 9.94 mmol). After 18 hours the mixture was diluted with water (50 ml) and extracted with EtOAc (2x50 ml). The combined organics were washed with brine (100 ml), dried over Na ₂ SO ₄ and concentrated in vacuo. The material was purified by flash chromatography equipped with ELSD using hexane-EtOAc (0-50%) to give 116A. LCMS (m/z): 245.77 [M+H]+; t _R =1.15 min on LC/MS Method A.

Synthesis of tert-butyl-(R)-(2-methyl-1-oxoheptan-2-yl)carbamate (116B). To a solution of 116A (378 mg, 1.54 mmol) in DCM (15 ml) was added Dess-Martin periodinan (981 g, 2.31 mmol). After 90 min, the reaction mixture was quenched with sat. Na ₂ S ₂ O ₃ ( _BOdH ) (20 ml). The layers were separated and the aqueous was extracted with DCM (25 ml). The combined organics were washed with water (50 ml) and brine (50 ml), dried over Na ₂ SO ₄ and concentrated in vacuo. The material was purified by flash chromatography equipped with ELSD using hexane-EtOAc (0-50%) to give 116B. LCMS (m/z): 143.95 [M+H]+; tR=1.23 min on LC/MS Method A.

Synthesis of tert-butyl-(R)-(1-(benzylamino)-2-methylheptan-2-yl)carbamate (116C). To a solution of 116B (351 mg, 1.44 mmol) in MeOH (6 ml) was added benzylamine (0.16 ml, 1.44 mmol). After 18 h, sodium borohydride (91 mg, 2.17 mmol) was added to the reaction mixture. After 90 minutes the mixture was concentrated in vacuo. The residue was diluted with EtOAc (25 ml), washed with 1 M NaOH( _BODH ) (20 ml), dried over Na ₂ SO ₄ and concentrated in vacuo to give crude 116C, which was used without further purification. LCMS (m/z): 335.02 [M+H]+; t _R =0.95 min on LC/MS Method A.

Synthesis of tert-butyl-(R)-(1-(N-benzylacetamido)-2-methylheptan-2-yl)carbamate (116D). To a solution of 116C (519 mg, 1.55 mmol) in THF (15 mL) was added N,N-diisopropylethylamine (0.54 mL, 3.10 mmol) followed by acetyl chloride (0.17 mL, 2.33 mmol) . After 60 min the reaction mixture was diluted with EtOAc (50 ml), washed with water (30 ml), sat. NaHCO ₃ ( _BODH ) (30 ml) and brine (30 ml), dried over Na ₂ SO ₄ and concentrated in vacuo. The material was purified by flash chromatography equipped with ELSD using hexane-EtOAc (0-100%) to give 116D. LCMS (m/z): 376.82 [M+H]+; tR=1.36 min on LC/MS Method A.

Synthesis of (R)-N-(2-amino-2-methylheptyl)acetamide (116E). To a solution of 116D (584 mg, 1.55 mmol) in EtOH (15 ml) was added a solution of HCl (0.78 ml, 3.10 mmol, 4 M in 2,4-dioxane). The solution was then purged with Ar and Pd(OH) ₂ (441 mg) was added. The mixture was purged with H ₂ and heated to 75°C. After 18 hours the mixture was cooled to room temperature, purged with Ar, filtered and concentrated in vacuo to give crude 116E (288 mg) as the HCl salt. LCMS (m/z): 186.96 [M+H]+; t _R =0.52 min on LC/MS Method A.

- 156 041413

Synthesis of (R)-N-(2-((2-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylheptyl)acetamide (116F). To a solution of 116E (50 mg, 0.22 mmol) and 2,4-dichloropyrido[3,2-d]pyrimidine (45 mg, 0.22 mmol) in THF (3 ml) was added N,N-diisopropylethylamine (0 12 ml, 0.67 mmol). After stirring at 80°C for 18 h, the reaction mixture was cooled to room temperature, diluted with EtOAc (25 ml), washed with water (25 ml) and brine (25 ml), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexanes-EtOAc (0-100%) to give 116F. LCMS (m/z): 350.06 [M+H]+; t _R =1.09 min on LC/MS Method A.

Synthesis of (R)-N-(2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-2methylheptyl)acetamide (116G). To a solution of 116F (58 mg, 0.17 mmol) in 2-MeTHF (3 mL) was added potassium carbonate (46 mg, 0.33 mmol) followed by 2,4-dimethoxybenzylamine (0.05 mL, 0.33 mmol ). After stirring at 85°C for 18 h, the reaction mixture was cooled to room temperature, diluted with EtOAc (25 ml), washed with water (20 ml) and brine (20 ml), dried over Na2SO4, then filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexanes-EtOAc (20-100%) to give 116G. LCMS (m/z): 481.27 [M+H]+; t _R =0.94 min on LC/MS Method A.

Synthesis of (R)-N-(2-((2-aminopyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylheptyl)acetamide (116). TFA (3 ml) was added to 116G (53 mg, 0.11 mmol). After 2 h the reaction mixture was concentrated in vacuo and co-evaporated with MeOH (3x20 ml). The residue was suspended in MeOH and filtered. The solution was concentrated in vacuo to give 116 as the TFA salt. LCMS (m/z): 331.25 [M+H]+; t _R =0.72 min on LC/MS Method A.

¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.63 (dd, J=4.4, 1.4 Hz, 1H), 7.85 (dd, J=8.5, 1.4 Hz, 1H), 7.76 (ddd, J=8.5, 4.4, 1.2 Hz, 1H), 3.95 (d, J=14.0 Hz, 1H), 3.56 (d, J =13.9 Hz, 1H), 2.22-2.12 (m, 1H), 1.95 (s, 3H), 1.941.85 (m, 1H), 1.54 (s, 3H), 1 .41-1.30 (m, 6H), 0.88 (t, J=6.3 Hz, 3H).

¹⁹ F NMR (377 MHz, methanol-d ₄ ) δ -77.86.

- 157 041413

Example 117

O

116E 19V 117A

Synthesis of (R)-N-(2-((2,7-dichloropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylheptyl)acetamide (117A). To a solution of 116E (50 mg, 0.22 mmol) and 19B (53 mg, 0.22 mmol) in THF (3 ml) was added N,Ndiisopropylethylamine (0.12 ml, 0.67 mmol). After stirring at 80°C for 18 h, the reaction mixture was cooled to room temperature, diluted with EtOAc (25 ml), washed with water (25 ml) and brine (25 ml), dried over Na ₂ SO ₄ , then filtered and concentrated in vacuum. The residue was chromatographed on silica gel eluting with hexanes-EtOAc (0-100%) to give 117A. LCMS (m/z): 384.01 [M+H]+; t _R =1.77 min on LC/MS Method A.

Synthesis of (R)-N-(2-((7-chloro-2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-2methylheptyl)acetamide (117B ). To a solution of 117A (33 mg, 0.09 mmol) in 2-MeTHF (3 mL) was added potassium carbonate (24 mg, 0.17 mmol), followed by 2,4-dimethoxybenzylamine (0.05 mL, 0.17 mmol). After stirring at 85°C for 18 h, the reaction mixture was cooled to room temperature, diluted with EtOAc (50 ml), washed with water (20 ml) and brine (20 ml), dried over Na ₂ SO ₄ , then filtered and concentrated in a vacuum. The residue was chromatographed on silica gel eluting with hexanes-EtOAc (0-100%) followed by EtOAc-MeOH (0-25%) to give 117B. LCMS (m/z): 515.26 [M+H]+; t _R =1.06 min on LC/MS Method A.

Synthesis of (R)-N-(2-((2-amino-7-chloropyrido[3,2-d]pyrimidin-4-yl)amino)-2-methylheptyl)acetamide (117). TFA (3 ml) was added to 117B (38 mg, 0.07 mmol). After 2 h the reaction mixture was concentrated in vacuo and co-evaporated with MeOH (3x20 ml). The residue was suspended in MeOH and filtered. The solution was concentrated in vacuo to give 117 as the TFA salt. LCMS (m/z): 632.22 [M+H]+; tR=0.89 min on LC/MS Method A.

Ή NMR (400 MHz, methanol^) δ 8.59 (dd, J=3.5, 2.1 Hz, 1H), 7.92 (d, J=1.9 Hz, 1H), 3.93 ( d, J=14.0 Hz, 1H), 3.51 (d, J=14.0 Hz, 1H), 2.21-2.10 (m, 1H), 1.96 (s, 3H), 1.95-1.87 (m, 1H), 1.54 (s, 3H), 1.35 (dd, J=17.6, 5.4 Hz, 6H), 0.88 (t, J= 6.4 Hz, 3H).

¹⁹ F NMR (377 MHz, methanol-d ₄ ) δ -77.80.

Example 118

59V 118A

Synthesis of (R)-2-((2-((2,4-dimethoxybenzyl)amino)pyrido[3,2-d]pyrimidin-4-yl)amino)-2methylhexanal (118A). To a solution of 59B (548 mg, 1.29 mmol) in DCM (24 ml) was added Dess-Martin periodinan (829 mg, 1.93 mmol). After 60 min, the reaction mixture was quenched with sat. Na ₂ S ₂ Oz ( _BODH ) (20 ml),

- 158 041413 the layers were separated and the aqueous was extracted with DCM (25 ml). The combined organics were washed with water (50 ml), sat. NaHCO ₃ ( _BODH ) (50 ml) and brine (50 ml), dried over Na ₂ SO ₄ and concentrated in vacuo. The material was purified by flash chromatography using hexane EtOAc (25-100%) followed by EtOAc-MeOH (0-20%) to give 118A. LCMS (m/z): 424.18

[M+H]+; tR=1.04 min on LC/MS Method A.

Synthesis of N ² -(2,4-dimethoxybenzyl)-N ⁴ -((R)-2-methyl-1 -(((S)-1,1,1-trifluoropropan-2-yl)amino)hexan2-yl) pyrido[3,2-d]pyrimidine-2,4-diamine (118B). To a solution of 118A (70 mg, 0.17 mmol) in MeOH (1 ml) was added (S)-1,1,1-trifluoro-2-propylamine (39 mg, 0.33 mmol, supplied by Oakwood Chemical). After 5 hours the reaction mixture was concentrated in vacuo. The residue was diluted with THF (2 ml) and a solution of lithium aluminum hydride (0.82 ml, 0.82 mmol, 1 M in THF) was added. After 30 min the reaction mixture was quenched with water (20 ml) and extracted with EtOAc (2x20 ml). The combined organics were dried over Na ₂ SO ₄ and concentrated in vacuo to give crude 118B. LCMS (m/z): 521.24 [M+H]+; t _R =1.26 min on LC/MS Method A.

Synthesis of N ⁴ -((R)-2-methyl-1 -(((S)-1,1,1 -trifluoropropan-2-yl)amino)hexan-2-yl)pyrido[3,2d]pyrimidin-2 ,4-diamine (118). TFA (3 ml) was added to 118B (66 mg, 0.13 mmol). After 4 hours the reaction mixture was concentrated in vacuo. The residue was suspended in 50% EtOH( _bogn ) (6 ml) and filtered. The solution was purified by preparative HPLC (Synergi 4u Polar-RP 80A, Axia; gradient 20% aq. acetonitrile - 60% aq. acetonitrile with 0.1% TFA, over 20 min) to give 122 as the bis-TFA salt. LCMS (m/z): 371.10 [M+H]+; t _R =1.14 min on LC/MS Method A.

¹ H NMR (400 MHz, methanol-d ₄ ) δ 8.62 (dd, J=4.4, 1.4 Hz, 1H), 7.87 (dd, J=8.5, 1.4 Hz, 1H), 7.78 (dd, J=8.5, 4.4 Hz, 1H), 3.75 (hept, J=7.1 Hz, 1H), 3.64 (d, J=12.8 Hz, 1H), 3.28 (d, J=12.8 Hz, 1H), 2.17 (ddd, J=13.6, 11.4, 4.6 Hz, 1H), 1.95 (ddd , J=16.1, 12.3, 4.1 Hz, 1H), 1.61 (s, 3H), 1.42 (d, J=6.9 Hz, 3H), 1.40-1, 26 (m, 4H), 0.92 (t, J=6.9 Hz, 3H).

¹⁹ F NMR (376 MHz, methanol-d ₄ ) δ -76.47 (d, J=7.1 Hz), -77.87.

Unless otherwise noted, the LC/MS retention time (t _R ) described above was measured using the LC/MS method Method A.

Method for LC/MS HPLC (Method A): HPLC LC/MS chromatograms were obtained using a Thermo Scientific LCQ LC/MS system, eluting with Kinetex 2.6u C18 100 A, 5x30 mm HPLC columns using a 1.85 minute gradient elution from 2% aq. acetonitrile - 98% aq. acetonitrile with 0.1% formic acid modifier.

Method for LC/MS HPLC (Method B): HPLC LC/MS chromatograms were obtained using a Thermo Scientific LCQ LC/MS system, eluting with a Kinetex 2.6u C18 100 A, 5x30 mm HPLC column using a 2.85 minute gradient elution from 2% aq. acetonitrile - 98% aq. acetonitrile with 0.1% formic acid modifier.

Biological Example 1 - PBMC assays for IFNa, XE12-p40 and TNFa.

Some of the compounds described herein were tested according to the procedure described below. In addition, some control compounds were obtained and tested in conjunction with the compounds according to the present description. For example, compound X was prepared in a manner similar to that described in PCT Application Publication No. WO 2012/156498 (where the compound is identified as compound 72). Compound Y was prepared in a manner similar to that described in PCT Application Publication No. WO 2015/014815 (where the compound is identified as Compound 6).

Compounds were dissolved and stored in DMSO (Sigma-Aldrich, St. Louis, MO) at 10 mM.

Cells and reagents.

Cryopreserved human PBMCs isolated from healthy donors were purchased from StemCell Technologies (Vancouver, Canada). The culture medium used was L-glutamine RPMI (Mediatech, Manassas, VA) supplemented with 10% fetal bovine serum (Hyclone, GE Healthcare, Logan, UT) and penicillin-streptomycin (Mediatech). 384-well plates, standards, buffers, and reagents for assaying human TNFa, IL12p40, and IFNa2a were obtained from MesoScale Discovery Technologies (MSD; Rockville, MD).

Cryopreserved human PBMCs (1x10e8 cells/ml) were thawed at 37°C and resuspended in 25 ml of warm cell culture medium. Cells were pelleted at 200xg (Beckman Avanti J-E) for 5 min and resuspended in 20 ml of fresh culture medium. Cells were counted using a Cellometer (Nexcelcom Bioscience), adjusted to 2x10e6 cells and incubated for 2 h in an incubator set at 37°C, 5% CO2 to recover after

- 159 041413 cryopreservation. Compounds were serially diluted in DMSO by a factor of 3.16 (semi-log dilution) to give a 10-point dose range. Using a Bravo pipette fitted with a 384-well head (Agilent), 0.4 μl of the compound was transferred into each well of a 384-well black clear bottom plate (Greiner Bio-One, Germany) containing 30 μl of cell culture medium. The reconstituted PBMCs were then dispensed into the assay plate at 50 μl per well (100 cells/well) using a MicroFlow multichannel dispenser (Biotek). The final concentration of DMSO was 0.5%. DMSO was used as a negative control. The plates were incubated for 24 h at 37°C. The PBMCs in the assay plate were pelleted by centrifugation (Beckman Avanti J-E) at 200xg for 5 min.

Using a Biomek FX 384 pipette station (Beckman), conditioned culture medium (CCM) from the assay plate was transferred to MSD capture plates configured for each cytokine. For detection of IFNa and IL12-p40, 25 μl and 20 μl of CCM were added directly to each capture plate, respectively. For TNFa detection, CCM was diluted 1:9 in fresh culture medium and 20 µl of diluted CCM was used. Serially diluted calibration standards for each cytokine were used to generate calibration curves and establish linearity of the assay. The plates were sealed and incubated overnight at 4°C in a tablet shaker (Titer Plate) set at 200 rpm. The next day, antibodies specific for each cytokine were diluted 1:50 in MSD Diluent 100 dilution buffer. The diluted antibodies were added to the respective capture plates at a concentration of 10 µl/well and incubated at room temperature for 1-2 hours on a shaker. The plates were washed with PBST buffer (3X, 60 μl/well) using a Biotek Multiflow plate washer. MSD Reading Buffer diluted to 2X in deionized water and at 35 µl/well was added using a Biomek FX instrument. The plates were read directly into the MSD6000 reader. Data were normalized to positive and negative controls for each assay plate. AC50 values are compound concentrations at half maximal effect based on normalized percent activation and calculated by non-linear regression using Pipeline Pilot software (Accelrys, San Diego, CA).

The results of the analysis of cytokine profiling are presented in table. 1, 2 and 3 below.

Table 1

Compound TNFa ACso (µM) IL12p40 ACso (µM) IFNa ACso (µM) IB 3.9 2 2.7 2B 5.4 2.8 4.3 SW 29.4 15.5 14.5 4B 9.1 5.4 5.9 5B >50 >50 41 6B >50 >50 >50 7 >50 >50 34 8 20.2 19.4 >50 9 1.9 1.1 7.2 10 29.2 23.8 >50 eleven 10.1 6 6.9 12 >50 >50 >50 13 >50 >50 >50 14 1.1 0.94 1.6 15 1.6 1.2 >200 16 >50 >50 >50 17 >50 >50 >50 18F 16.1 15.2 30.6 19E 3.3 2.5 21.6 20 3.2 2.8 5.4 21 3.1 2.3 4.8 22 >50 >50 35.9

- 160 041413

23C 24.7 25.7 >50 24D 3.4 3.1 18.4 25E 20 19.7 12.3 26E 2.3 1.7 13.5 27C 0.52 0.42 2 28 28.6 28.2 45 29 18.3 15.5 3.9 CALL 10.6 8.6 >50 31 4.7 4.7 32.9 32 >50 >50 >50 33 0.92 0.85 5.9 34 12.2 10.9 >50 35 39.4 22.6 >50 36 21.5 10.8 >50 37 >50 >50 >50 38C >50 >50 >50 39С >50 41.5 >50 40С 0.94 0.87 2.4 41 AND 9.1 13 42V 1.1 0.9 3.6 43C 1.1 1 10.9 44 3 2.4 >50 45 1.6 1.3 8.3 46C 28.6 28.5 >50 47V 2.70 2.0 >50 48 0.85 0.71 0.57 Compound X Y Compound 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 ΤΝΕα AC ₅ o (μM) 1.2 I.2 ΤΝΕα ACeo (μM) 22.4 26.9 0.37 3.2 0.26 34.0 23.9 3.6 11.0 3.9 0, 18 2.6 0.02 1.0 0.41 3.1 o.i 0.04 6.3 I.1 31.0 3.3 2.6 7.2 1.3 IL12p40 ACso (μM) 0.97 13.0 IL12p40 ACeo (μM) 18.1 23.1 0.33 3.6 0.28 42.5 21.5 3.4 9.7 3.8 0.17 2.3 0.02 0.91 0.43 3.2 0.09 0.03 3.9 14.2 30.8 2.7 2.7 7.0 1.3 table 2 ΙΕΝα ACso (µM) 7.1 >50 Table 3 IFNa ACso (μM) 41.6 >50 >200 >50 3.9 >50 28.8 1.9 >50 4.1 15.0 7.9 42.1 >50 22.4 37.9 >50 1.6 23.0 >50 34.8 >50 >50 >50 >50 74 9.1 9.6 >50 75 4.0 3.3 20.3 76 36.9 31.8 36.9 77 43.6 43.6 43.6 78 16.0 14.2 >50 79 9.1 I,5 >50 80 2.7 2.4 >50 81 7.6 7.8 >50

- 161 041413

82 16.6 14.3 >50 83 1.7 1.8 43.1 84 h, o 3.9 >50 85 0.86 0.80 4.0 86 2.9 2.4 37.4 87 5.0 4.5 >50 88 0.4 0.37 35.6 89 2.2 1.7 >50 90 0.86 0.62 7.8 91 2.0 1.9 >50 92 4.3 4.7 >50 93 0.44 0.40 >50 94 1.0 0.7 2.2 95 0.15 0.15 >50 96 1.1 1.0 2.8 97 0.14 0.13 26.0 98 0.24 0.23 134 99 3.4 3.6 >50 100 3.8 3.5 4.6 101 0.10 0.11 >50 102 0.81 0.76 >50 103 3.3 2.6 10.3 104 2.1 1.9 4.2 105 3.5 3.4 >50 106 13.8 10.2 >50 107 2.8 1.8 >50 108 38.7 22.0 >50 110 32.6 32.6 32.6 111 0.61 0.47 19.8 112 0.36 0.33 >50 113 12.5 13.6 >50 114 0.34 0.20 34.1 115 0.024 0.027 9.0 116 0.036 oh and >50 117 0.37 0.33 >50 118 9.3 9.1 >50

In some embodiments, some compounds described herein have an AC50 for TNFa of less than about 100 μM, less than about 50 μM, less than about 40 μM, less than about 30 μM, less than about 25 μM, less than about 20 μM, less than about 15 μM, less than about 10 μM, less than about 5 μM, less than about 4 μM, less than about 3 μM, less than about 2 μM, or less than about 1 μM. In some embodiments, some of the compounds described herein have an AC50 for TNFa of greater than about 25 μM or greater than about 50 μM. In some embodiments, some of the compounds described herein have an AC50 for TNFa of less than about 0.75 μM, less than about 0.5 μM, or less than about 0.25 μM. Those skilled in the art will appreciate that TNFa induction is associated with TLR8 agonism.

In some embodiments, some of the compounds described herein have an AC ₅₀ for IL12p40 of less than about 100 μM, less than about 50 μM, less than about 40 μM, less than about 30 μM, less than about 25 μM, less than about 20 μM, less than about 15 μM, less than about 10 μM, less than about 5 μM, less than about 4 μM, less than about 3 μM, less than about 2 μM, less than about 1 μM, or less than about 0.5 μM. In some embodiments, some of the compounds described herein have an AC ₅₀ for IL12p40 of greater than about 25 μM or greater than about 50 μM. Those skilled in the art will appreciate that IL12p40 induction is associated with TLR8 agonism.

In some embodiments, some of the compounds described herein have an AC50 for IFNa of less than about 200 μM, less than about 100 μM, less than about 50 μM, less than about 40 μM, less than about 30 μM, less than about 25, μM, less than about 20 μM, less than about 15 μM, less than about 10 μM, less than about 5 μM, less than about 4 μM, less than about 3 μM, less than about 2 μM, or less than about 1 μM. In some embodiments, some of the compounds described herein have an AC ₅₀ for IFNa of greater than about 25 μM, greater than about 50 μM, greater than about 100 μM, greater than about 150 μM, or greater than about 200 μM. Those skilled in the art will appreciate that IFNa induction is associated with TLR7 agonism.

In some embodiments, the compounds described herein are selective TLR8 agonists. Compounds that are selective TLR8 agonists

- 162 041413 produce a cytokine effect associated with the induction of TLR8 (eg TNFa and IL12p40) at a lower concentration than the effect associated with the induction of TLR7 (eg IFNa). In some embodiments, in a cytokine profiling assay, the compounds induce IFNa at a concentration of at least about 2-fold higher than the concentration at which TNFa and/or IL12p40 are induced; in some embodiments, the compounds induce IFNa at a concentration of at least about 4 times higher than the concentration at which TNFa and/or IL12p40 are induced; in some embodiments, the compounds induce IFNa at a concentration at least about 6 times higher than the concentration at which TNFa and/or IL12p40 are induced; in some embodiments, the compounds induce IFNa at a concentration of at least about 8 times higher than the concentration at which TNFa and/or IL12p40 are induced; in some embodiments, the compounds induce IFNa at a concentration of at least about 10 times higher than the concentration at which TNFa and/or IL12p40 are induced; in some embodiments, the compounds induce IFNa at a concentration at least about 20 times higher than the concentration at which TNFa and/or IL12p40 are induced; in some embodiments, the compounds induce IFNa at a concentration at least about 30 times higher than the concentration at which TNFa and/or IL12p40 are induced; in some embodiments, the compounds induce IFNa at a concentration of at least about 40 times higher than the concentration at which TNFa and/or IL12p40 are induced; in some embodiments, the compounds induce IFNa at a concentration of at least about 50 times higher than the concentration at which TNFa and/or IL12p40 are induced; in some embodiments, the compounds induce IFNa at a concentration of at least about 75 times higher than the concentration at which TNFa and/or IL12p40 are induced; in some embodiments, the compounds induce IFNa at a concentration of at least about 100 times higher than the concentration at which TNFa and/or IL12p40 are induced; in some embodiments, the compounds induce IFNa at a concentration of at least about 125 times higher than the concentration at which TNFa and/or IL12p40 are induced; in some embodiments, the compounds induce IFNa at a concentration of at least about 150 times higher than the concentration at which TNFa and/or IL12p40 are induced; in some embodiments, the compounds induce IFNa at a concentration of at least about 175 times higher than the concentration at which TNFa and/or IL12p40 are induced; and in some embodiments, the compounds induce IFNa at a concentration at least about 200 times higher than the concentration at which TNFa and/or IL12p40 are induced.

Those skilled in the art will appreciate that each compound as described herein may have AC ₅₀ values for each cytokine tested (eg, TNFa, IL12p40, and IFNa) that include various combinations of the ranges described above. Thus, such combinations are provided herein. In addition, the ability of any particular compound or group of compounds to selectively modulate a particular receptor can be extrapolated from the AC ₅₀ data disclosed herein. One skilled in the art will certainly appreciate the varying selectivities of any particular compound or group of compounds.

Biological Example 2 - Study of efficacy in WHV-infected woodchucks.

The antiviral efficacy of the compound described herein was evaluated in vivo in the CHB (Chronic Hepatitis B Virus) woodchuck model. Woodchucks chronically infected with woodchuck hepatitis virus (WHV) (n=23) were divided into a placebo group (n=11), a 1 mg/kg dose group (n=6), and a 3 mg/kg dose group (n= 6) based on gender and basic antiviral parameters. The placebo group included animals with high levels of gamma-glutamyl transferase (GGT) (which correlate with an increased risk of hepatocellular carcinoma (HCC)) and/or with liver tumors observed at the preliminary study of the biopsy. This division has been made so that adverse events (including death) associated with HCC do not skew the safety assessment of the dosage groups treated with the compound disclosed herein. The design of this ongoing study was as follows: animals were administered p.o. compound or vehicle once a week for 8 weeks followed by an observation period of 24 weeks. Animals were monitored for safety and vital parameters (blood chemistry/hematology/temperature), pharmacokinetics (serum PK), pharmacodynamics (whole blood MARCO mRNA levels and WHV-specific T-cell levels), and antiviral efficacy (WHV DNA, hepatitis virus surface antigen marmots (WHsAg) in serum and antibodies against sAg and cccDNA, DNA and mRNA of liver WHV).

An interim analysis of this ongoing study indicated that animals treated with vehicle or 1 mg/kg for 8 weeks had no change in WHV DNA levels.

- 163 041413 or WHsAg in serum. In contrast, there was a strong reduction in both viral endpoints in 4/6 animals in the 3 mg/kg dose group. Serum levels of WHV DNA and WHsAg for three of these animals did not return at week 12, four weeks after cessation of treatment. Of note, three animals had detectable levels of anti-WHsAg starting at week 4, which were still increasing, stabilizing or decreasing by week 12. These intermediate data show that the compound of the present disclosure has antiviral and anti-HBsAg activity, as well as the ability to induce an anti-HBsAg antibody in vivo in a STRN model in woodchucks.

Biological example 3 - non-target toxicity.

To assess the potential off-target toxicity of some of the compounds described herein, the in vitro cytotoxicity of these compounds was profiled using a panel of 5 cell lines with different tissue origins. The cytotoxicity of the compound was studied in Huh-7 and HepG2 cells derived from hepatoma, PC-3 cells derived from prostate carcinoma, MT-4 cells derived from lymphoma, and the normal diploid MRC5 cell line. The HepG2 and PC-3 cells used were adapted for growth in a medium containing galactose and not containing glucose. These cells have a relatively high sensitivity to inhibitors of mitochondrial oxidative phosphorylation compared to the same cells contained in a standard glucose-containing culture medium (Marroquin et al., Toxicol. Sci. 2007;97(2):539-47). Cell viability was determined by measuring intracellular ATP levels after five days of continuous incubation with test compounds.

Cell cultures.

The Huh-7 cell line from human hepatoma was obtained from ReBLikon GmbH (Mainz, Germany) {20879}. The MT-4 cell line (HTLV-1 transformed, human T-lymphoblastoid cells) was obtained from the NIH AIDS Reagent program (Bathesda, MD). The human hepatoblastoma cell line HepG2, the human prostate carcinoma cell line PC-3, and normal fetal lung MRC-5 cells were obtained from the American Type Culture Collection (ATCC, Manassas, VA).

Huh-7 cells were maintained in Dulbecco's Modified Eagle's Medium (DMEM) supplemented with 10% fetal bovine serum (FBS, Hyclone, Logan, UT), 1% essential amino acids (Gibco, Carlsbad, CA). PC-3 and HepG2 cells were adapted to grow in 0.2% galactose-free glucose-modified Dulbecco's Eagle's medium (DMEM) supplemented with 10% fetal bovine serum (FBS, Hyclone, Logan, UT), 1% essential amino acids ( Gibco, Carlsbad, CA), 1% pyruvate (Cellgro), 1% glutamax (Invitrogen, Carlsbad, CA). Galactose-adapted cells were kept in the same culture medium. MRC-5 cells were maintained in Eagle's Minimal Medium (EMEM) supplemented with 10% fetal bovine serum (FBS, Hyclone, Logan, UT). MT-4 cells were maintained in RPMI-1640 supplemented with 10% fetal bovine serum (FBS, Hyclone, Logan, UT). All cell culture media were also supplemented with 100 units/ml penicillin, 100 µg/ml streptomycin (Gibco).

Cytotoxicity assays.

Using a Biotek uFlow workstation (Biotek, Winooski, VT), 1500 HepG2 cells, 1500 PC-3 cells, 500 Huh7 cells, or 1500 MRC-5 cells in 90 µl of culture medium were dispensed into each well of a black polystyrene 384-well plate treated with tissue culture. Placed in the tablet cells were incubated for 24 h in an incubator at 37°C, 5% CO ₂ and 90% humidity. Compound serial dilutions were performed in 100% DMSO in 384-well polypropylene (high performance) plates on a Biomek FX workstation (Beckman Coulter, Fullerton, Calif.). After 3-fold serial dilutions, 0.4 µl of compounds were transferred to 384-well plates containing cells using a Velocity 11 system equipped with a Bravo 384 pipette. The concentration of DMSO in the final assay plates was 0.44% (v/v) . Cells were incubated with compound(s) for five days at 37°C. Puromycin (44 mM final concentration) and DMSO (0.44%, v/v) were used as positive and negative controls, respectively.

At the end of the incubation period, cytotoxicity analysis was performed as follows. The medium from the 384-well cell culture plates was aspirated using a Biotek EL405 plate washer (Biotek) and the cells were washed once with 100 μl of PBS. Twenty microliters of Celltiter Glo (Promega, Madison, WI) was added to each well of the plate using a Biotek uFlow liquid dispenser. The plates were incubated for 15 minutes at room temperature before measuring luminescence using a Perkin Elmer Envision plate reader (Perkin Elmer, Waltham, MA).

For cytotoxicity assay in MT-4, 0.4 μl of serially diluted compounds were added to 40 μl of cell maintenance medium in a 384-well black hard bottom plate using a Biomek FX workstation (Beckman Coulter). Two thousand cells in 35 μl were added to each well using a Biotek uFlow workstation (Biotek). Each assay plate contained 10 μM puromycin (final concentration) and 0.5% DMSO in RPMI-1640 as positive and

- 164 041413 negative controls, respectively. Assay plates were incubated for five days at

37°C in an incubator set at 5% CO2 and 90% humidity. After 5 days, 22 µl of CellTiter Glo reagent (Promega) was added to the assay plates using a Biotek uFlow workstation. The plates were then placed on a Perkin Elmer Envision plate reader for 5 min until the luminescence signal was read.

Data analysis.

CC ₅₀ values were defined as the concentration of compounds that caused a 50% reduction in luminescence signal and were calculated by non-linear regression using Pipeline Pilot software using a four parameter equation (Accelrys, San Diego, CA). The results are shown in the table below. Individual CC ₅₀ values are given as concentration in μM.

Compound CC50 GALHEPG2 CTG 5D CC50 GALPC3 CTG 5D SS50 HUH7 CTG 5D SS50 MRC5 CTG 5D SS50 (MT4) 15 1.23 0.69. 10.70 7.60 8.62 44 1.07 0.52 9.64 3.72 1.97 59 8.88 5.20 35.39 40.31 31.40 98 6.70 4.53 21.90 24.42 16.17 51 44.44 37.23 44.44 44.44 57.14 102 27.42 19.08 44.44 44.44 57.14 61 44.44 44.44 44.44 44.44 212.39 62 44.44 29.74 44.44 44.44 19.23 93 7.73 3.63 44.44 38.80 18.55 64 3.56 1.55 10.36 6.97 0.79 101 44.44 44.44 44.44 44.44 50.0 65 44.44 44.44 44.44 44.44 50.0 95 28.06 16.76 31.34 44.44 44.11 97 33.01 27.51 44.44 44.44 50.0 X 7.85 6.79 16.91 20.95 53.77 Y 0.19 0.18. 2.31 0.95 1.42

As one of skill in the art will appreciate, a high ratio of CC ₅₀ from a cytotoxicity assay to AC ₅₀ (eg, TNFa and/or IL12p40) indicates a potential good in vivo safety.

All references, including publications, patents, and patent documents, are incorporated herein by reference as if they were individually incorporated by reference. The present description contains reference to various implementations and methods. However, it should be understood that many variations and modifications can be made while remaining within the spirit and scope of the present description.

- 165 -

Claims (10)

CLAIM 1. Compound of formula (IVa) or a pharmaceutically acceptable salt thereof, wherein R ¹ is hydrogen; R ² is selected from the group consisting of hydrogen, methyl, fluorine and chlorine; R ³ is selected from the group consisting of hydrogen and methyl; and where fragment Y represents 2. The compound according to claim 1 or its pharmaceutically acceptable salt, where R ¹ represents hydrogen; R ² is selected from the group consisting of hydrogen and fluorine; And R ³ is selected from the group consisting of hydrogen and methyl. 3. The compound according to claim 1, which is or a pharmaceutically acceptable salt thereof. or a pharmaceutically acceptable salt thereof. 4. A compound according to claim 1, which is or a pharmaceutically acceptable salt thereof. 5. The compound according to claim 1, which is 6. The compound according to claim 1, which is - 166 041413 7. The compound according to claim 1, which is 8. Connection, which is or a pharmaceutically acceptable salt thereof. 9. Connection, which is - 167 041413 - 168 041413 - 169 041413 or a pharmaceutically acceptable salt thereof. 10. A pharmaceutical composition for the treatment or prevention of a disease or condition responsive to toll-like receptor (TLR-8) modulation, comprising a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2 - 170 -