ANTIPROLIFERATION COMPOUNDS AND THEIR USES

Abstract

Claim 1: A compound of formula (1), or a pharmaceutically acceptable salt thereof, wherein: Ring A is a phenyl ring selected from, a saturated or partially unsaturated 5-7 member carbocyclic ring, a saturated or partially unsaturated 8-12 member bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 member heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an 8-10 member bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each R¹ is independently hydrogen or C₁₋₃ aliphatic optionally substituted with 1-6 halogens; or two R¹ groups are optionally taken together with their intervening atoms to form a partially unsaturated fused 5-8 member carbocyclic ring;each of R² is independently hydrogen, halogen, -CN, -NO₂, -C(O)OR, -C(O)NR₂, -NR₂, -NRC(O)R, -NRC(O)OR, -NRS(O)₂R, -OR, -P(O)R₂, -SR, -S(O)R, -S(O)₂R, -S(O)(NH)R, -S(O)₂NR₂, or R; or two R² groups are optionally taken together to form =O; two R² groups are optionally taken together with their intervening atoms to form a saturated 3-8 membered spirocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each R³ is independently hydrogen, -OH, or aliphatic C₁₋₃; or: two R³ groups are optionally taken together to form =O; or two R³ groups are optionally taken together to form =CH₂; or two R³ groups are optionally taken together with their intervening atoms to form a saturated 5-8 membered spirocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;or two R³ groups are optionally taken together with their intervening atoms to form a bridged 5-8 membered saturated bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;each R is independently hydrogen or an optionally substituted group selected from C₁₋₆ aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 7-10 membered saturated heterocyclic spirobicyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 7-10 membered fused, saturated or partially unsaturated bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;or: two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a saturated, partially unsaturated, or heteroaryl 4-7 member ring having 0-3 heteroatoms, in addition to nitrogen, independently selected from nitrogen, oxygen, and sulfur, optionally substituted with 1-2 oxo groups; ⁻ ⁻ ⁻ ⁻ ⁻ is a single or double bond; X is -O-, -N(R)-, -N(S(O)₂(R))-, -S-, -S(O)-, -S(O)₂-, -CH₂-, -CH(R³)-, or -C(R³)₂-; m is 0, 1, or 2; n is 0, 1, 2, 3, 4, or 5; yp is 0, 1, or 2.

Description

ANTIPROLIFERATION COMPOUNDS AND USES THEREOF TECHNICAL FIELD OF THE INVENTION

[0001] The present invention relates to compounds and methods useful for treating cell proliferative disorders (e.g., cancer). The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of various proliferative disorders. BACKGROUND OF THE INVENTION

[0002] Cellular proliferative disorders comprise populations of malignant and non-malignant cells that differentiate from the surrounding tissue morphologically and / or genotypically. Examples of cell proliferative disorders include, for example, solid tumors, cancer, diabetic retinopathy, intraocular neovascular syndromes, macular degeneration, rheumatoid arthritis, psoriasis and endometriosis. Cancer is a group of diseases that involve abnormal cell proliferation with the potential to invade or spread to other parts of the body. According to the Centers for Disease Control and Prevention (CDC), cancer is the second leading cause of death in the United States. Therefore, with additional treatments for cell proliferative disorders we want to provide patients with more options. SUMMARY OF THE INVENTION

[0003] It has now been discovered that the compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful for treating proliferative disorders (e.g., cancer). In one aspect, the present invention provides a compound of Formula I: IF-2019-53902052-APN-ANP#INPI Page 1 of 423 I or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0004] The compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful for treating a variety of proliferative disorders (e.g., cancer), as described herein. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS 1. General description of certain embodiments of the invention:

[0005] The compounds of the present invention, or salts thereof, have been found to exhibit pronounced efficacy in multiple cell line-derived and patient-derived xenograft models. For example, compounds of the invention, or salts thereof, have been found to result in complete and long-lasting regression in models of non-small cell lung cancer (NSCLC), myeloma, hepatocellular carcinoma (HCC), breast cancer and melanoma. It has also been discovered that the compounds of the invention result in greater inhibition of cell viability, particularly cells where Wolframine (WFS1) is overexpressed. Without wishing to subscribe to any specific theory, it is presumed that the compounds of the invention cause calcium release from the endoplasmic reticulum (ER) through a putative Ca2+ channel known as Wolframine (WFS1), which induces ER stress and “unfolded protein response” (UPR) and results in cell death.

[0006] In one aspect, the present invention provides a compound of formula I: IF-2019-53902052-APN-ANP#INPI Page 2 of 423 I or a pharmaceutically acceptable salt thereof, where: Ring A is a ring selected from phenyl, a saturated or partially unsaturated 5-7 membered carbocyclic ring, a saturated or partially unsaturated 8-12 membered bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur , a 5-6 membered heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each R1 is independently hydrogen or aliphatic Cl-3; or two R1 groups are optionally taken together with their intervening atoms to form a partially unsaturated fused carbocyclic 5-8 membered ring; each of R2 is independently hydrogen, halogen, -CN, -NO2, -C(O)OR, C(O)NR2, -NR2, -NRC(O)R, -NRC(O)OR, -NRS(O) 2R, -OR, -P(O)R2, -SR, S(O)R, -S(O)2R, -S(O)(NH)R, or R; or two R2 groups are optionally taken together to form =0; each R3 is independently hydrogen or aliphatic Cl-3; either: two R3 groups are optionally taken together to form =0; two R3 groups are optionally taken together to form =CH2; two R3 groups are optionally taken together with their intervening atoms to form a 5-8 membered saturated spirocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur; either IF-2019-53902052-APN-ANP#INPI Page 3 of 423 two R3 groups are optionally taken together with their intervening atoms to form a bridged saturated 5-8 membered bicyclic ring having 02 heteroatoms independently selected from nitrogen, oxygen or sulfur; each R is independently hydrogen or an optionally substituted group selected from aliphatic Cl-6, a saturated or partially unsaturated monocyclic carbocyclic 3-8 membered ring, phenyl, a saturated heterocyclic spirobicyclic 7-10 membered ring having 1-2 heteroatoms selected independently of nitrogen, oxygen or sulfur, a fused, saturated or partially unsaturated bicyclic heterocyclic 7-10 membered ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a saturated or monocyclic heterocyclic 4-8 membered ring partially unsaturated having 12 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; either: two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen and sulfur, optionally substituted with 1-2 oxo groups; X es -CH(R3)-, or -C(R3)2-; m is 0, 1, or 2; n is 0, 1, 2, 3, 4 or 5; and p is 0, 1, or 2. |0007] In one aspect, the present invention provides a compound of formula Γ: IF-2019-53902052-APN-ANP#INPI Page 4 of 423 Γ or a pharmaceutically acceptable salt thereof, where: Ring A is a ring selected from phenyl, a saturated or partially unsaturated 5-7 membered carbocyclic ring, a saturated or partially unsaturated 8-12 membered bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur , a 5-6 membered heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur ; each R1 is independently hydrogen, or aliphatic Cl-3 optionally substituted with Ιό halogen; or two R1 groups are optionally taken together with their intervening atoms to form a partially unsaturated fused carbocyclic 5-8 membered ring; each of R2 is independently hydrogen, halogen, -CN, -NO2, -C(O)OR, C(O)NR2, -NR2, -NRC(O)R, -NRC(O)OR, -NRS(O) 2R, -OR, -P(O)R2, -SR, S(O)R, -S(O)2R, -S(O)(NH)R, -S(O)2NR2, or R; or two R2 groups are optionally taken together to form = O; or two R2 groups are optionally taken together with their intervening atoms to form a saturated 3-8 membered spirocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur; •5 each R is independently hydrogen, -OH, or aliphatic Cl-3; or two R3 groups are optionally taken together to form =0; or two R3 groups are optionally taken together to form =CH2; or two R3 groups are optionally taken together with their intervening atoms to form a saturated 3-8 membered spirocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur; or two R3 groups are optionally taken together with their intervening atoms to form a bicyclic bridged saturated 5-8 membered ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur; IF-2019-53902052-APN-ANP#INPI Page 5 of 423 each R is independently hydrogen or an optionally substituted group selected from aliphatic Cl-6, a saturated or partially unsaturated monocyclic carbocyclic 3-8 membered ring, phenyl, a saturated heterocyclic spirobicyclic 7-10 membered ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered fused bicyclic, saturated or partially unsaturated heterocyclic ring having 1 -2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 4-8 membered ring saturated or partially unsaturated monocyclic heterocyclic having 12 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; either: two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen and sulfur, optionally substituted with 1-2 oxo groups; ------ is a single bond or a double bond; X es -CH(R3)-, or -C(R3)2-; m is 0, 1, or 2; n is 0, 1, 2, 3, 4 or 5; and p is 0, 1, or 2. 2. Compounds and definitions:

[0008] Compounds of the present invention include those generally described herein, and are further illustrated by the classes, subclasses, and species described herein. As used herein, the following definitions shall apply unless otherwise noted. For the purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. In addition, the general principles of organic chemistry are described in “Organic Chemistry”. , Thomas Sorrell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5° IF-2019-53902052-APN-ANP#INPI Page 6 of 423 Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated by reference.

[0009] The term “aliphatic” or “aliphatic group,” as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or containing one or more unsaturation units, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is fully saturated or that contains one or more unsaturation units, but is not aromatic (also referred to herein as carbocycle, "cycloaliphatic" or "cycloalkyl "), which has a single attachment point to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, the aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, the aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, the aliphatic groups contain 1-3 aliphatic carbon atoms, and in still other embodiments, the aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, "cycloaliphatic" (or "carbocycle" or "cycloalkyl") refers to a C3-C6 monocyclic hydrocarbon that is fully saturated or that contains one or more unsaturation units, but that is not aromatic, that has a unique point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, substituted or unsubstituted linear or branched alkyl, alkenyl, alkynyl groups, and their hybrids such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0010] As used herein, the term “bicyclic ring” or “bicyclic ring system” refers to any bicyclic ring system, that is, carbocyclic or heterocyclic, saturated or having one or more units of unsaturation, having one or more atoms in common between the two rings of the ring system. Thus, the term includes any permissible ring fusion, such as ortho-fused or spirocyclic. As used herein, the term "heterobicyclic" is a subset of "bicyclic" that requires that one or more heteroatoms be present in one or both rings of the bicycle. Such heteroatoms may be present in the ring bonds and are optionally substituted, and may be selected from nitrogen (including noxides), oxygen, sulfur (including oxidized forms, such as sulfones and sulfonates), phosphorus (including oxidized forms, such as phosphates). , boron, etc. In some IF-2019-53902052-APN-ANP#INPI Page 7 of 423 embodiments, a bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, the term “bicyclic bridge” refers to any bicyclic, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated ring system that has at least one bridge. As defined by IUPAC, a “bridge” is an unbranched chain of atoms or an atom or a valence bond connecting two bridgeheads, where a “bridge” is any backbone atom of the ring system that It is bonded to three or more backbone atoms (except hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those groups set forth below, where each group is attached to the rest of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as set forth for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bicyclic rings include: Exemplary bridged bicyclics include: IF-2019-53902052-APN-ANP#INPI Page 8 of 423

[0011] The term "lower alkyl" refers to a straight or branched Cl-4 alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tere-butyl.

[0012] The term "lower haloalkyl" refers to a straight or branched Cl-4 alkyl group that is substituted with one or more halogen atoms.

[0013] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quatemized form of any basic nitrogen or; a nitrogen substitutable of a heterocyclic ring, for example, N (as in 3,4-dihydro-2 / 7-pyrrolyl), NH (as in pyrrolidinyl) or NR+ (as in N-substituted pyrrolidinyl)).

[0014] The term “unsaturated,” as used herein, means that a moiety has one or more unsaturation units.

[0015] As used herein, the term “saturated or unsaturated, linear or branched, bivalent Cl-8 (or Cl-6) hydrocarbon chain” refers to bivalent chains of alkylene, alkenylene, and alkynylene that They are linear or branched as defined herein.

[0016] The term “alkylene” refers to a divalent alkyl group. An “alkylene chain” is a polymethylene group, that is, -(CH2)n-, where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. A substituted alkylene chain is a polymethylene group where one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group. IF-2019-53902052-APN-ANP#INPI Page 9 of 423

[0017] The term “alkenylene” refers to a bivalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond where one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0018] As used herein, the term “cyclopropylenyl” refers to a bivalent cyclopropyl group of the following structure: .

[0019] The term “halogen” means F, Cl, Br, or I.

[0020] The term “aryl,” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic ring systems or bicyclic ring systems having a total of five to fourteen members. ring, where at least one ring in the system is aromatic and where each ring in the system contains 3 to 7 ring members. The term “aryl” can be used interchangeably with the term “aryl ring.” In certain embodiments of the present invention, "aryl" refers to an aromatic ring system including, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may carry one or more substituents. Also included within the scope of the term "aryl", as used herein, is a group where an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthymidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.

[0021] The terms "heteroaryl" and "heteroar-", used alone or as part of a larger moiety, for example, "heteroaralkyl" or "heteroaralkoxy", refer to groups having 5 to 10 atoms in the ring, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 shared π electrons in a cyclic arrangement; and which have, in addition to carbon atoms, from one to five heteroatoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quatemized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl . The terms IF-2019-53902052-APN-ANP#INPI Page 10 of 423 “heteroaryl” and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical attachment point or is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl , and pyrido[2,3-b]-l,4-oxazin-3(4H)-one. A heteroaryl group may be mono- or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring", "heteroaryl group", or "heteroaromatic", any of these terms including rings that are optionally substituted.

[0022] As used herein, the terms "heterocycle", "heterocyclyl", "heterocyclic radical", and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or heterocyclic moiety. 7-10 membered bicyclic that is saturated or partially unsaturated, and that has, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term nitrogen includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen can be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or TslR (as in N-substituted pyrrolidinyl).

[0023] A heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom resulting in a stable structure and any of the ring atoms may be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuc lidinyl. The terms "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclic moiety", and "heterocyclic radical", are used interchangeably herein, and also include groups where a heterocyclyl ring is fused to one IF-2019-53902052-APN-ANP#INPI Page 11 of 423 or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromand, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group may be mono- or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl, where the alkyl and heterocyclyl moieties are independently optionally substituted.

[0024] As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as defined herein.

[0025] As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position in the group, and where more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent can be the same or different in each position. The substituent combinations contemplated by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions that permit their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0026] Each optional substituent on a substitutable carbon is a monovalent substituent independently selected from halogen; -(CH2)o-4R0; -(CH2)(mOR0; 0(CH2)o.4R0, -O-(CH2)0-4C(O)ORo; -(CH2)o-4CH(OR°)2; -(CH2)(mSRo; - (CH2)0_4Ph, which may be substituted with R°; -(CH2)o-40(CH2)o-iPh which may be substituted with R°; o-40(CH2)o_i-pyridyl which may be substituted with R°; -NO2; -N3; ​​-(CH2)o-4N(R0)2; (0)R0; )o-4N(R0)C(0)OR0; IF-2019-53902052-APN-ANP#INPI Page 12 of 423 N(R°)N(R°)C(O)R°; -N(RO)N(R°)C(O)NRO2; -N(R°)N(R°)C(O)OR°; -(CH2)(mC(O)R0; C(S)R°; -(CH2)o-4C(0)OR°; -(CH2)o_4C(0)SR°; -(CH2)<mC(O )OSyRo3; -(CH2)o_ 4OC(O)R°; -OC(0)(CH2)o_4SR- SC(S)SR°; (O)NR°2; C(S)NR°2; -C(S)SR°, -(CH2)(mOC(O)NRo2; -C(O)N(OR) °)R°; -C(O)C(O)R°; -C(O)CH2C(O)Ro; -C(NOR°)R°; O)2Ro; -(CH2)0_4S(O)2OR°; -(CH2)<mOS(O)2R°; -S(O)(NR°)R°; )2N=C(NRo2)2; -(CH2)<mS(O)R°; -N(Ro)S(O)2NR°2; °)R°; -C(NH)NRo2; -P(O)2Ro; -P(O)R°2; -(linear or branched Cl-4 alkylene)O-N(R°)2; or (linear or branched Cl-4 alkylene)C(O)O-N(R°)2.

[0027] Each R° is independently hydrogen, aliphatic Cl-6, -CH2Ph, -0(CH2)o_ iPh, -CH2- (5-6 membered heteroaryl ring), or a partially saturated 5-6 membered ring unsaturated, or aryl having 0 -4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definition, two independent occurrences of R°, taken together with their intervening atoms, form a mono or bicyclic ring of 3-12 membered, saturated, partially unsaturated, or aryl having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted by a divalent substituent on a saturated carbon atom of R° selected from =0 and =S; or each R° is optionally substituted with a monovalent substituent independently selected from halogen, -(CH2)o-2R“, (haloR*), -(CH2)o_2OH, -(CH2)0_2OR·, -(CH2)o_2CH(OR ')2; -O(haloR*), -CN, -N3, (CH2)o_2C(0)R·, -(CH2)o_2C(0)OH, -(CH2)o-2C(0)OR·, ~(CH2) o_2SR·, -(CH2)o-2SH, (CH2)o-2NH2, -(CH2)o-2NHR·, -(CH2)o_2NR2, -NO2, -SiR*3, -OSiR*3, -C(O )SR· (linear or branched Cl-4 alkylene)C(O)OR*, or -SSR*.

[0028] Each Rese independently selected from aliphatic Cl-4, -CH2Ph, 0(CH2)o_]Ph, or a saturated, partially unsaturated or aryl 5-6 membered ring having 0-4 heteroatoms independently selected from nitrogen, oxygen , or sulfur, and where each R is unsubstituted or where preceded by halo is substituted only with one or more halogens; or where an optional substituent on a saturated carbon is a divalent substituent independently selected from =0, =S, =NNR*2, =NNHC(O)R*, =NNHC(0)0R', =NNHS(O)2R' , =NR*, =NOR', -O(C(R*2))2_3O-, or 13 IF-2019-53902052-APN-ANP#INPI Page 13 of 423 LS(C(R*2))2-3S-, or a divalent substituent attached to adjacent substitutable carbons of an “optionally substituted” group is -O(CR*2)2-3O-, where each independent occurrence of R* It is selected from hydrogen, aliphatic Cl-6 or an unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0029] When R is aliphatic Cl-6, R is optionally substituted with halogen, R', -(haloR·), -OH, -OR', -O(haloR*), -CN, -C(O)OH , -C(O)ORe, -NH2, -NHR', -NR'2, or -NO2, where each R* is independently selected from aliphatic Cl-4, -CH2PI1, 0(CH2)o-iPh, or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and where each R* is unsubstituted or where preceded by halo is substituted only with one or more halogens.

[0030] An optional substituent on a substitutable nitrogen is -Rf, -NRt2, -CCOjR1, -C(O)OR·, -QOjCÍOjR1, -QCOCHzCCOjR*, -S(O)2RÍ, -S(O)2NRf2, C(S)NRt2, -CfNHjNR^, or -N(RT)S(O)2R^; wherein each R' is independently hydrogen, aliphatic Cl-6, substituted -OPh, or an unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or , two independent occurrences of R\ taken together with the intervening atom form a 3-12 membered unsubstituted mono- or bicyclic ring, saturated, partially unsaturated, or aryl having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; where when RTis aliphatic Cl-6, R^ is optionally substituted with halogen, -R*, -(haloR*), -OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR', -NH2, -NHR, -NR*2, or -NO2, where each R* is independently selected from aliphatic Cl-4, -CH2PI1, -0(CH2)oiPh, or a ring of 5-6 saturated, partially unsaturated or aryl members having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and where each R· is unsubstituted or where preceded by halo is substituted only with one or more halogens.

[0031] As used herein, the term “pharmaceutically acceptable salt” refers to those salts that are, within the scope of medical judgment, suitable for use in contact with the tissues of humans and lower animals without IF-2019-53902052-APN-ANP#INPI Page 14 of 423 toxicity, irritation, allergic response and the like and are provided with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include salts of adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate. , heptanoate, hexanoate, iodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like.

[0032] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C 1-4 alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additionally, pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

[0033] Unless otherwise indicated, the structures depicted herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and IF-2019-53902052-APN-ANP#INPI Page 15 of 423 Z and E conformational isomers. Therefore, individual stereochemical isomers, as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the compounds herein are within the scope of the invention. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Furthermore, unless otherwise indicated, the structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures, including the replacement of hydrogen with deuterium or tritium, or the replacement of a carbon with a 13C- or 14C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents according to the present invention. 3. Description of exemplary embodiments:

[0034] In one aspect, the present invention provides a compound of formula I: I or a pharmaceutically acceptable salt thereof, where: Ring A is a ring selected from phenyl, a saturated or partially unsaturated 5-7 membered carbocyclic ring, a saturated or partially unsaturated 8-12 membered bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur , a 5-6 membered heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; IF-2019-53902052-APN-ANP#INPI Page 16 of 423 each R1 is independently hydrogen or aliphatic Cl-3; or two R1 groups are optionally taken together with their intervening atoms to form a partially unsaturated fused carbocyclic 5-8 membered ring; each of R2 is independently hydrogen, halogen, -CN, -NO2, -C(O)OR, C(O)NR2, -NR2, -NRC(O)R, -NRC(O)OR, -NRS(O) 2R, -OR, -P(O)R2, -SR, S(O)R, -S(O)2R, -S(O)(NH)R, or R; or two R2 groups are optionally taken together to form =0; each R is independently hydrogen or aliphatic Cl-3; either: two R3 groups are optionally taken together to form =0; two R3 groups are optionally taken together to form = CH2; two R3 groups are optionally taken together with their intervening atoms to form a 5-8 membered saturated spirocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur; or two R3 groups are optionally taken together with their intervening atoms to form a bridged saturated 5-8 membered bicyclic ring having 02 heteroatoms independently selected from nitrogen, oxygen or sulfur; each R is independently hydrogen or an optionally substituted group selected from aliphatic Cl-6, a saturated or partially unsaturated monocyclic carbocyclic 3-8 membered ring, phenyl, a saturated heterocyclic spirobicyclic 7-10 membered ring having 1-2 heteroatoms selected independently of nitrogen, oxygen or sulfur, a fused, saturated or partially unsaturated bicyclic heterocyclic 7-10 membered ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a saturated or monocyclic heterocyclic 4-8 membered ring partially unsaturated having 12 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; either: IF-2019-53902052-APN-ANP#INPI Page 17 of 423 two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, selected independently of nitrogen, oxygen and sulfur, optionally substituted with 1-2 oxo groups; X es -CH(R3)-, or -C(R3)2-; m is 0, 1, or 2; n is 0, 1, 2, 3, 4 or 5; and p is 0, 1, or 2.

[0035] In one aspect, the present invention provides a compound of formula 1': Γ or a pharmaceutically acceptable salt thereof, where: Ring A is a ring selected from phenyl, a saturated or partially unsaturated 5-7 membered carbocyclic ring, a saturated or partially unsaturated 8-12 membered bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur , a 5-6 membered heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur ; each R1 is independently hydrogen, or aliphatic Cl-3 optionally substituted with Ιό halogen; or two R1 groups are optionally taken together with their intervening atoms to form a partially unsaturated fused carbocyclic 5-8 membered ring; IF-2019-53902052-APN-ANP#INPI Page 18 of 423 each of R2is independently hydrogen, halogen, -CN, -NO2, -C(O)OR, C(O)NR2, -NR2, -NRC(O)R, -NRC(O)OR, - NRS(O)2R, -OR, -P(O)R2j-SR, S(O)R, -S(O)2R, -S(O)(NH)R, -S(O)2NR2, or R ; or two R2 groups are optionally taken together to form = O; or two R2 groups are optionally taken together with their intervening atoms to form a saturated 3-8 membered spirocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur; or each R is independently hydrogen, -OH, or aliphatic Cl-3; or two R3 groups are optionally taken together to form =0; or two R3 groups are optionally taken together to form =CH2; or two R3 groups are optionally taken together with their intervening atoms to form a saturated 3-8 membered spirocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur; or two R3 groups are optionally taken together with their intervening atoms to form a bicyclic bridged saturated 5-8 membered ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur; each R is independently hydrogen or an optionally substituted group selected from aliphatic Cl-6, a saturated or partially unsaturated monocyclic carbocyclic 3-8 membered ring, phenyl, a saturated heterocyclic spirobicyclic 7-10 membered ring having 1-2 heteroatoms selected independently of nitrogen, oxygen or sulfur, a fused, saturated or partially unsaturated bicyclic heterocyclic 7-10 membered ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a saturated or monocyclic heterocyclic 4-8 membered ring partially unsaturated having 12 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; either: two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a saturated, partially unsaturated, or heteroaryl 4-7 membered ring having 0-3 heteroatoms in addition to the nitrogen, IF-2019-53902052-APN-ANP#INPI Page 19 of 423 independently selected from nitrogen, oxygen and sulfur, optionally substituted with 1-2 oxo groups; ------is a single bond or a double bond; X es -CH(R3)-, or -C(R3)2-; m is 0, 1, or 2; n is 0, 1, 2, 3, 4 or 5; and p is 0, 1, or 2.

[0036] As generally defined above, ------is a single bond or a double bond.

[0037] In some embodiments, -------= is a simple link. In some embodiments, ------ is a double bond.

[0038] In some embodiments,------ is selected from those represented in the Tables 1, 2, and 2A, below.

[0039] As generally defined above, ring A is a ring selected from phenyl, a saturated or partially unsaturated 5-7 membered carbocyclic ring, a saturated or partially unsaturated 8-12 membered bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0040] In some embodiments, Ring A is phenyl. In some embodiments, Ring A is a 5-7 membered saturated or partially unsaturated carbocyclic ring, an 8-12 membered, saturated or partially unsaturated bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 5-6 membered heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0041] In some embodiments, Ring A is a saturated or partially unsaturated 5-7 membered carbocyclic ring. In some embodiments, Ring A is a ring of 8-12 IF-2019-53902052-APN-ANP#INPI Page 20 of 423 saturated or partially unsaturated heterocyclic bicyclic members having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring A is a 5-6 membered heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, ring A is an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0042] In some embodiments, Ring A is phenyl or , where Ring B is a 5-7 membered partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or Ring B is a 5-6 membered heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Ring B H.N. H.N. HN is selected from: . In some embodiments, Ring B is

[0043] In some embodiments, Ring A is selected from: IF-2019-53902052-APN-ANP#INPI Page 21 of 423

[0044] In some embodiments, Ring A is

[0045] In some embodiments, Ring A is

[0046] In some embodiments, Ring A is selected from:

[0047] In some embodiments, ring A is

[0048] In some embodiments, Ring A is selected from:

[0049] In some embodiments, ring A is

[0050] In some embodiments, Ring A is selected from: IF-2019-53902052-APN-ANP#INPI Page 22 of 423

[0053] In some embodiments, Ring A is selected from:

[0054] In some embodiments, Ring A is selected from:

[0055] In some embodiments, Ring A is selected from: IF-2019-53902052-APN-ANP#INPI Page 23 of 423

[0056] In some embodiments, Ring A is selected from:

[0058] In some embodiments, ring A is one of R2es -OH, and which can also be in the tautomeric form:

[0059] In some embodiments, Ring A is selected from those represented in Tables 1 and 2, below,

[0060] In some embodiments, Ring A is selected from those depicted in Table 2A, below.

[0061] As generally defined above, each R1 is independently hydrogen or aliphatic Cl-3; or two R1 groups are optionally taken together with their intervening atoms to form a partially unsaturated fused carbocyclic 5-8 membered ring. IF-2019-53902052-APN-ANP#INPI Page 24 of 423

[0062] In some embodiments, R1 is hydrogen. In some embodiments, R1 is C1-3 aliphatic. In some embodiments, two R1 groups are optionally taken together with their intervening atoms to form a partially unsaturated fused carbocyclic 5-8 membered ring.

[0063] In some embodiments, R1 is methyl. In some embodiments, R1 is ethyl. In some embodiments, R1 is propyl. In some embodiments, R1 is isopropyl.

[0064] In some embodiments, R1 is attached to the 5-position of the pyrimidine. In some embodiments, R1 is attached to the 6-position of pyrimidine.

[0065] In some embodiments, two R1 groups are optionally taken together with their intervening atoms to form a partially unsaturated fused carbocyclic 5-8 membered ring. In some embodiments, two R1 groups are optionally taken together with their intervening atoms to form a 5-membered partially unsaturated fused carbocyclic ring. In some embodiments, two R1 groups are optionally taken together with their intervening atoms to form a partially unsaturated 6-membered fused carbocyclic ring. In some embodiments, two R1 groups are optionally taken together with their intervening atoms to form a partially unsaturated fused carbocyclic 7-membered ring. In some embodiments, two R1 groups are optionally taken together with their intervening atoms to form a partially unsaturated fused carbocyclic 8-membered ring.

[0066] In some embodiments, R1 is aliphatic Cl-3 optionally substituted 1-6 times by halogen. In some embodiments, R1 is Cl-3 alkyl optionally substituted 1-6 times by halogen. In some embodiments, R1 is Cl-3 alkyl optionally substituted 1-6 times by fluorine. In some embodiments, R1 is Cl-3 alkyl optionally substituted 1-3 times by fluorine. In some embodiments, R1 is -CF3.

[0067] In some embodiments, R1 is selected from those represented in Tables 1 and 2, below.

[0068] In some embodiments, R1 is selected from those represented in Tables 1 and 2A, below.

[0069] As generally defined above, each of R2 is independently hydrogen, halogen (F, Cl, Br, or 1), -CN, -NO2, -C(O)OR, 25 IF-2019-53902052-APN-ANP#INPI Page 25 of 423 C(O)NR2, -NR2, -NRC(O)R, -NRC(O)OR, -NRS(O)2R, -OR, -P(O)R2, -SR, -S(O)R, S(O)2R, -S(O)(NH)R, or R; or two R2 groups are optionally taken together to form =0.

[0070] In some embodiments, R2 is hydrogen. In some embodiments, each of R2 is independently halogen, -CN, -NO2, -C(O)OR, -C(O)NR2, -NR2, NRC(O)R, -NRC(O)OR, -NRS( O)2R, -OR, -P(O)R2, -SR, -S(O)R, -S(O)2R, S(O)(NH)R, or R; or two R2 groups are optionally taken together to form =0.

[0071] In some embodiments, R2 is halogen. In some embodiments, R2 is Cl. In some embodiments, R2 is -CN. In some embodiments, R2 is -NO2. In some embodiments, R2 is -C(O)OR. In some embodiments, R2 is -C(O)NR2. In some embodiments, R2 is -NR2. In some embodiments, R2 is -NRC(O)R. In some embodiments, R2 is -NRC(O)OR. In some embodiments, R2 is -NRS(O)2R. In some embodiments, R2 is independently -OR. In some embodiments, R2 is -P(O)R2. In some embodiments, R2 is -SR. In some embodiments, R2 is -S(O)R. In some embodiments, R2 is -S(O)2R. In some embodiments, R2 is -S(O)(NH)R. In some embodiments, R2 is R. In some embodiments, two groups R2 are optionally taken together to form =0.

[0072] In some embodiments, R2 is -S(O)2NR2. In some embodiments, R2 is S(O)2NH2.

[0073] In some embodiments, R2 is aliphatic Cl-6. In some embodiments, R2 is a saturated monocyclic 3-8 membered carbocyclic ring. In some embodiments, R2 is a 7-10 membered saturated spirobicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R2 is a saturated, bicyclic, fused, heterocyclic, 7-10 membered ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R2 is a 4-8 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R2 is a monocyclic heteroaromatic 5-6 membered ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0074] In some embodiments, each of R2 is selected independently of: IF-2019-53902052-APN-ANP#INPI Page 26 of 423 IF-2019-53902052-APN-ANP#INPI Page 27 of 423 IF-2019-53902052-APN-ANP#INPI Page 28 of 423

[0076] In some embodiments, R2 is aliphatic Cl-6, optionally substituted 1-4 times by halogen, -OH, NH2, -OCH3, -NHC(O)CH3, -S(O)2CH3, or -N(CH3) C(O)CH3. OH In some embodiments, R is selected from CH3, -CF3, -CH2CH3, '

[0077] In some embodiments, R2 is aliphatic Cl-6, optionally substituted 1-4 times by halogen, -OH, NH2, -OCH3, -NHC(O)CH3, -S(O)2CH3, -COOH, -CO2CH3, CO2C2H5, or -N(CH3)C(O)CH3. In some embodiments, R2 is O,

[0078] In some embodiments, R2 is aliphatic Cl-6, optionally substituted by a -S(0)2-(CH2)o-6 group, where (CH2)q_6 is optionally substituted 1-4 times by halogen, -OH, NH2, or -OCH3. In some embodiments, R2 is aliphatic Cl-6, optionally substituted by a -S(0)2-(CH2)o-6 group, where (CH2)o-6 is unsubstituted. In some embodiments, R2 is aliphatic Cl-6, optionally substituted by S(O)2-CH3 or -S(O)2-CH2-CH3. In some embodiments, R2 is aliphatic Cl-6, optionally substituted by -S(O)2-CH3. In some embodiments, R2 is -CH2-S(O)2CH2-CH3. In some embodiments, R2 is -CH2-S(O)2-CH2-CH3. In some embodiments, R2 is -CH2-CH2-S(O)2-CH3. In some embodiments, R2 is -CH2-CH229 IF-2019-53902052-APN-ANP#INPI Page 29 of 423 S(O)2-CH2-CH3. In some embodiments, R2 is selected from

[0079] In some embodiments, R2 is Cl-6unsubstituted aliphatic. In some embodiments, R2 is -C=CH.

[0080] In some embodiments, R2 is a saturated monocyclic carbocyclic 3-6 membered ring. In some embodiments, R2 is

[0081] In some embodiments, R2 is a 7-10 membered saturated spirobicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen or oxygen. In some embodiments, R2

[0082] In some embodiments, R2 is a saturated, bicyclic, fused, heterocyclic, 7-10 membered ring having 1-2 heteroatoms independently selected from nitrogen or oxygen. In some embodiments, R2 is

[0083] In some embodiments, R2 is a saturated monocyclic heterocyclic ring 4-6 members having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, optionally substituted 1-4 times by halogen, -OH, -CH3, -OCH3, or IF-2019-53902052-APN-ANP#INPI Page 30 of 423

[0084] In some embodiments, R2 is a monocyclic heterocyclic 4-6 membered ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, optionally substituted 1-4 times by halogen, -OH, -CH3, -OCH3 ,

[0085] In some embodiments, R2 is a 5-6 membered monocyclic heteroaromatic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R2 is selected from

[0086] In some embodiments, R2 is -C(O)OR, where R is hydrogen or aliphatic Cl-6. In some embodiments, R2 is -C(O)OH. In some embodiments, R2 is aliphatic C(O)OCl-6, where the aliphatic Cl-6 is unsubstituted. In some embodiments, R2es . In some embodiments, R2 is EITHER

[0087] In some embodiments, R2 is -C(O)NR2, where each of R is independently hydrogen, aliphatic Cl-6 which is optionally substituted by N(CH3)2, unsubstituted saturated monocyclic carbocyclic 3-6 membered ring , or unsubstituted monocyclic heterocyclic 4-6 membered ring having 1-2 heteroatoms independently selected from nitrogen or oxygen, or two R's taken together IF-2019-53902052-APN-ANP#INPI Page 31 of 423 with their intervening atoms to form a saturated 4-7-membered heteroaryl ring and not replaced. In some embodiments, R2 is selected from EITHER

[0088] In some embodiments, R2 is -C(O)NR2, where two R's are taken together with their intervening atoms to form a saturated 4-7 membered ring having 0-3 heteroatoms, in addition to nitrogen, selected independently of nitrogen, oxygen and sulfur, optionally substituted with 1-2 oxo groups. In some embodiments, R is -C(O)NR2, where two R's are taken together with their intervening atoms to form a saturated, unsubstituted 4-7 membered ring having 0-3 heteroatoms, other than nitrogen, independently selected. of nitrogen, oxygen and sulfur. In some embodiments, R2 is

[0089] R is -NR2, where each of R is independently: hydrogen; Aliphatic Cl-6 which is optionally substituted 1-2 times by -OH, unsubstituted saturated monocyclic carbocyclic 3-6 membered ring; saturated monocyclic heterocyclic 4-6 membered ring having 1-2 heteroatoms independently selected from nitrogen or oxygen, which is optionally substituted 1-2 times by CH3, -OH, -C(O)OC(CH3)3, or -C (O)CH3; or monocyclic heteroaromatic 6-membered ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, which is optionally substituted 1-2 times by -CH3 or -NH2. IF-2019-53902052-APN-ANP#INPI Page 32 of 423

[0091] In some embodiments, R2 is -NHC(O)R, where R is an aliphatic Cl-6 group optionally substituted 1-3 times by halogen, -OCH3, -N(CH3)2, or -OH, ring of 3 -6-membered saturated monocyclic carbocyclic ring optionally substituted 1-2 times by halogen or -OH, or 4-6-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur optionally substituted 1-2 times by saturated halogen , -OH, or -CH3. In some IF-2019-53902052-APN-ANP#INPI Page 33 of 423

[0092] In some embodiments, R2 is -NHC(O)R, where R is aliphatic Cl-6 optionally substituted 1-3 times by halogen, -OCH3, -N(CH3)2, or -OH. In some embodiments, aliphatic Cl-6 is a straight-chain (i.e., unbranched) or branched, substituted, or saturated unsubstituted hydrocarbon chain. In some embodiments, aliphatic Cl-6 is a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain comprising a monocyclic hydrocarbon. In some embodiments, aliphatic Cl-6 is selected from

[0093] R2 is -NHC(O)OR, where R is unsubstituted aliphatic Cl-6. In some0I HN^CT'' embodiments, R2 is —L- .

[0094] In some embodiments, R2 is -NHS(O)2R, where R is non-aliphatic Cl-6 replaced. In some embodiments, R2 is O.

[0095] In some embodiments, R2 is -OR, where R is H; Aliphatic Cl-6 optionally substituted by a halogen, -OH, O or or saturated monocyclic heterocyclic 4-6 membered ring having 1-2 heteroatoms independently selected from nitrogen or oxygen. In some embodiments, R2se IF-2019-53902052-APN-ANP#INPI Page 34 of 423 OH selects from -OH,

[0096] In some embodiments, R2 is -OR, where R is aliphatic Cl-6 optionally substituted by a halogen, -OH, -C(O)NHC1- 4aliphatic, -COOH, -C(O)OCl-4aliphatic, -CN, -SO2Cl-4aliphatic, or

[0098] In some embodiments, R2 is -OR, where R is unsubstituted aliphatic Cl-6. In some embodiments, R2 is -O-CH2-C=CH.

[0099] In some embodiments, R2 is -P(O)R2, where each of R is EITHER . . Rin independently unsubstituted aliphatic Cl-6. In some embodiments, R2 is I.

[00100] In some embodiments, R2 is -SR, where R is unsubstituted aliphatic Cl-6. In some embodiments, R2 is . IF-2019-53902052-APN-ANP#INPI Page 35 of . 423

[00101] In some embodiments, R2 is -S(O)R, where R is unsubstituted aliphatic Cl-6. or !—S— In some embodiments, R is < .

[00102] In some embodiments, R2 is -S(O)2R, where R is unsubstituted aliphatic Cl-6 or saturated monocyclic carbocyclic 3-6 membered ring. In some embodiments, R O is selected from O

[00103] In some embodiments, R2 is -S(O)(NH)R, where R is non-aliphatic Cl-6 NH HO replaced. In some embodiments, R2 is

[00104] In some embodiments, R2 is a group that increases hydrophilicity. In some embodiments, R2 is selected from the group consisting of -NO2, -C(O)OR, C(O)NR2, -NR2, -NRC(O)R, -NRC(O)OR, -NRS(O)2R , -OR, -P(O)R2, -SR, -S(O)R, S(O)2R, -S(O)(NH)R, or an aliphatic Cl-6 group, where the unit of one or more methylene is replaced by -C(O)-, -S(O)-, -S(O)2-, -P(O)-, or -P(O)2-. In some embodiments, R2 is an aliphatic Cl-6 group, where one or more methylene units are replaced by -C(O)-, S(O)-, -S(O)2-, -P(O)-, or -P(O)2-. In some embodiments, R2 is an aliphatic Cl-6 group, where one or more methylene units are replaced by -S(O)2-. In some embodiments, IF-2019-53902052-APN-ANP#INPI Page 36 of 423 . In some embodiments, R2 is selected from the group consisting of EITHER In some R is selected from the group consisting EITHER Hay , achievements, In some embodiments, R2 is selected from the group consisting In some embodiments, R2 is some realizations, R2 X O \ η S— II In some embodiments, R2 is O. In some embodiments, R2 is EITHER

[00105] In some embodiments, two R2 groups are optionally taken together with their intervening atoms to form a saturated 3-8 membered spirocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, two groups R2 are optionally taken together with IF-2019-53902052-APN-ANP#INPI Page 37 of 423 its intervening atoms to form a saturated spirocyclic 3-8-membered carbocyclic ring. In some embodiments, two R groups are optionally taken together with their intervening atoms to form a 3-membered spirocyclic saturated carbocyclic ring. In some embodiments, two R2 groups are optionally taken together with their intervening atoms to form a 4-, 5-, or 6-membered saturated spirocyclic carbocyclic ring.

[00106] In some embodiments, two R2 groups are joined at the same position. In some embodiments, two R2 groups are attached to a carbon atom. In some embodiments, each of two R2 groups attached to a carbon atom is independently an optionally substituted aliphatic Cl-6 group, as described herein. In some embodiments, each of two R2 groups attached to a carbon atom is independently unsubstituted aliphatic Cl-6. In some embodiments, each of two R2 groups attached to a carbon atom is independently unsubstituted Cl-6 alkyl. In some embodiments, each of two R2 groups attached to a carbon atom is methyl.

[00107] In some embodiments, R2 is selected from those represented in Tables 1 and 2, below.

[00108] In some embodiments, R2 is selected from those represented in Table 2A, below. .

[00109] As generally defined above, each R3 is independently hydrogen or aliphatic Cl-3; either: two R3 groups are optionally taken together to form =0; two R3 groups are optionally taken together to form =CH2; two R3 groups are optionally taken together with their intervening atoms to form a 5-8 membered saturated spirocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur; or two R3 groups are optionally taken together with their intervening atoms to form a bridged saturated 5-8 membered bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[00110] In some embodiments, R3 is hydrogen. In some embodiments, R3 is aliphatic Cl-3; either: IF-2019-53902052-APN-ANP#INPI Page 38 of 423 two R3 groups are optionally taken together to form =0; or two R groups are optionally taken together to form =(2¾ or two R groups are optionally taken together with their intervening atoms to form a 5-8 membered saturated spirocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur; or two R3 groups are optionally taken together with their intervening atoms to form a bridged saturated 5-8 membered bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[00111] In some embodiments, R3 is aliphatic Cl-3. In some embodiments, two R3 groups are optionally taken together to form =0. In some embodiments, two R3 groups are optionally taken together to form =(2¾. In some embodiments, two R3 groups are optionally taken together with their intervening atoms to form a saturated 5-8 membered spirocyclic ring having 0-2 selected heteroatoms. independently of nitrogen, oxygen or sulfur. In some embodiments, two R3 groups are optionally taken together with their intervening atoms to form a bridged saturated 5-8 membered bicyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[00112] In some embodiments, R3 is methyl. In some embodiments, R3 is ethyl. In some embodiments, R3 is propyl. In some embodiments, R3 is isopropyl.

[00113] In some embodiments, two R3 groups are optionally taken together with their intervening atoms to form a 5-membered saturated spirocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, two R3 groups are optionally taken together with their intervening atoms to form a saturated 5-membered spirocyclic ring having 0-2 oxygen atoms. In some embodiments, two R3 groups are taken. . r°> optionally in conjunction with its intervening atoms to form 0'- / , which forms a spirocyclic ring on the carbon atom in position 2.

[00114] In some embodiments, two R3 groups are optionally taken together with their intervening atoms to form a bridged saturated 5-8 membered bicyclic ring having 1-2 heteroatoms independently selected from nitrogen and IF-2019-53902052-APN-ANP#INPI Page 39 of 423 oxygen. In some embodiments, two R3 groups are optionally taken together with their intervening atoms to form a saturated bridged bicyclic ring having 1-2 nitrogen atoms, wherein the bridged saturated bicyclic ring comprises a 6-membered ring and a 7-membered ring. In some embodiments, two groups R together with —X optionally form .

[00115] In some embodiments, R3 is -OH.

[00116] In some embodiments, two R3 groups are optionally taken together with their intervening atoms to form a saturated 3-8 membered spirocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, two R3 groups are optionally taken together with their intervening atoms to form a 3- or 4-membered saturated spirocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, two R3 groups are optionally taken together with their intervening atoms to form a 3- or 4-membered spirocyclic saturated carbocyclic ring. In some embodiments, two R3 groups are optionally taken together with their intervening atoms to form a 3-membered spirocyclic saturated carbocyclic ring.

[00117] In some embodiments, R3 is selected from those represented in Tables 1 and 2, below. .

[00118] In some embodiments, R3 is selected from those represented in Table 2A, below.

[00119] As generally defined above, each R is independently hydrogen or an optionally substituted group selected from aliphatic Cl-6, a 3-8 membered ring, saturated or partially unsaturated monocyclic carbocyclic, phenyl, a 7-membered ring -10-membered saturated spirobicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10-membered fused, saturated, or partially unsaturated bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 4-8 membered saturated monocyclic heterocyclic ring or IF-2019-53902052-APN-ANP#INPI Page 40 of 423 partially unsaturated having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6-membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or: two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen and sulfur, optionally substituted with 1-2 oxo groups.

[00120] In some embodiments, R is hydrogen. In some embodiments, each R is independently an optionally substituted group selected from aliphatic Cl-6, a saturated or partially unsaturated monocyclic carbocyclic 3-8 membered ring, phenyl, a saturated heterocyclic spirobicyclic 7-10 membered ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a fused, saturated, or partially unsaturated bicyclic heterocyclic 7-10 membered ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a monocyclic heterocyclic 4-8 membered ring saturated or partially unsaturated having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or: two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen and sulfur, optionally substituted with 1-2 oxo groups.

[00121] In some embodiments, R is an optionally substituted aliphatic Cl-6 group. In some embodiments, R is an optionally substituted saturated or partially unsaturated carbocyclic monocyclic 3-8 membered ring. In some embodiments, R is an optionally substituted phenyl. In some embodiments, R is an optionally substituted saturated heterocyclic spirobicyclic 7-10 membered ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R is an optionally substituted 7-10 membered ring saturated or IF-2019-53902052-APN-ANP#INPI Page 41 of 423 partially unsaturated fused bicyclic heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R is an optionally substituted 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R is an optionally substituted monocyclic heteroaromatic 6-membered ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a saturated, partially unsaturated, or heteroaryl 4-7 membered ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen and sulfur, optionally substituted with 1-2 oxo groups.

[00122] In some embodiments, R is selected from those represented in Tables 1 and 2, below.

[00123] In some embodiments, R is selected from those represented in Table 2A, below.

[00124] As generally defined above, S(O)2-, -CH2-, -CH(R3)-, or -C(R3)2-,

[00125] In some embodiments, X is -O-. In some embodiments, X is -N(R) -. In some embodiments, X is -N(S(O)2(R))-. In some embodiments, X is S. In some embodiments, X is -S(O)-. In some embodiments, X is S(O)2- In some embodiments, X is -CH2-. In some embodiments, X is -CH(R3)-. In some embodiments, X is C(R3)2-. '

[00126] In some embodiments, X is -N(S(O)2(R))-, where R is aliphatic Cl-6. In some embodiments, X is -N(S(O)2CH3)-. In some embodiments, X is -CH(R3)-, where R3 is aliphatic Cl-6. In some embodiments, X is -CH(CH3)-. In some embodiments, X is -C(R3)2-, where R3 is aliphatic Cl-6. In some embodiments, X is C(CH3)2-.

[00127] In some embodiments, X is selected from those represented in Tables 1 and 2, below. .42 IF-2019-53902052-APN-ANP#INPI Page 42 of 423

[00128] In some embodiments, X is selected from those represented in Table 2A, below.

[00129] As generally defined above, m is 0, 1, or 2.

[00130] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[00131] In some embodiments, m is selected from those represented in Tables 1 and 2, below.

[00132] In some embodiments, m is selected from those represented in Table 2A, below.

[00133] As generally defined above, n is 0, 1, 2, 3, 4 or 5.

[00134] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5 .

[00135] In some embodiments, n is selected from those represented in Tables 1 and 2, below.

[00136] In some embodiments, n is selected from those represented in Table 2A, below.

[00137] As generally defined above, p is 0, 1, or 2.

[00138] In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[00139] In some embodiments, p is selected from those represented in Tables 1 and 2, below.

[00140] In some embodiments, p is selected from those represented in Table 2A, below.

[00141] In some embodiments, the present invention provides a compound of Formulas I-a or I-b: IF-2019-53902052-APN-ANP#INPI Page 43 of 423 IfíΊ\ I-a I-b or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R1, R2, R3, R, X, m, n, and p is as defined above and described in the embodiments herein, both individually as in combination.

[00142] In some embodiments, the present invention provides a compound of Formula II: II or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R1, R2, R3, R, n, and p is as defined above and described in the embodiments herein, both individually and in combination.

[00143] In some embodiments, the present invention provides a compound of Formulas Π-a or Il-b: IF-2019-53902052-APN-ANP#INPI Page 44 of 423 II-a Π-b or a pharmaceutically acceptable salt thereof, wherein each of Ring A, R1, R2, R3, R, n, and p is as defined above and described in the embodiments herein, both individually and in combination .

[00144] In some embodiments, the present invention provides a compound of Formula III III or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R, m, n, and p is as defined above and described in the embodiments herein, both individually and in combination.

[00145] In some embodiments, the present invention provides a compound of Formulas Ill-a or Ill-b: IF-2019-53902052-APN-ANP#INPI Page 45 of 423 / R I \ ΙΙΙ-a Ill-b or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R, m, n, and p is as defined above and described in the embodiments herein, both individually and in combination .

[00146] In some embodiments, the present invention provides a compound of Formula IV IV or a pharmaceutically acceptable salt thereof, wherein each of Ring B, R1, R2, R3, R, m, n, and p is as defined above and described in the embodiments herein, both individually and in combination.

[00147] In some embodiments, the present invention provides a compound of Formulas IV-a or IV-b: IF-2019-53902052-APN-ANP#INPI Page 46 of 423 IV-a IV-b or a pharmaceutically acceptable salt thereof, wherein each of Ring B, R1, R2, R3, R, m, n, and p is as defined above and described in the embodiments herein, both individually as in combination.

[00148] In some embodiments, the present invention provides a compound of Formula V R1 V or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R, X, n, and p is as defined above and described in the embodiments herein, both individually and in combination.

[00149] In some embodiments, the present invention provides a compound of Formulas V-a or V-b: IF-2019-53902052-APN-ANP#INPI Page 47 of 423 Goes V-b 3 or a pharmaceutically acceptable salt thereof, wherein each of R, R, R, R, X, n, and P is as defined above and described in the embodiments herein, both individually and in combination.

[00150] In some embodiments, the present invention provides a compound of Formula VI VI or a pharmaceutically acceptable salt thereof, wherein each of Ring B, R1, R2, R3, R, X, n, and p is as defined above and described in the embodiments herein, both individually and in combination.

[00151] In some embodiments, the present invention provides a compound of Formulas Vl-a or Vl-b: IF-2019-53902052-APN-ANP#INPI Page 48 of 423 VI-b or a pharmaceutically acceptable salt thereof, wherein each of Ring B, R1, R2, R3, R. as in combination.

[00152] In some embodiments, the present invention provides a compound of Formula VII R1 VII or a pharmaceutically acceptable salt thereof, where n' is 1 or 2, and R2 is halogen or aliphatic OC]-3, and where each of R1, R2, R3, R, X, and p is as defined above and is described in embodiments herein, both individually and in combination. In some embodiments, n' is 1. In some embodiments, n' is 2. In some embodiments, R2 is F. In some embodiments, R2 is Cl. In some embodiments, R2 is Br. In some embodiments, R2 is I. In some embodiments, R2is -OCH3. In some embodiments, R2 is -OC2H5. In some embodiments, R2 is OCH2CH2CH3. In some embodiments, R2 is -OCH(CH3)2. IF-2019-53902052-APN-ANP#INPI Page 49 of 423

[00153] In some embodiments, n is selected from those represented in Tables 1, 2, and 2A, below.

[00154] In some embodiments, R2 is selected from those represented in Tables 1, 2, and 2A, below.

[00155] In some embodiments, the present invention provides a compound of VH-a or VH-b formulas: VH-a VH-b or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R2, R3, R, X, p, and n' is as defined above and described in the embodiments herein, both individually and in combination.

[00156] In some embodiments, the present invention provides a compound of Formula VIII: VIII IF-2019-53902052-APN-ANP#INPI Page 50 of 423 or a pharmaceutically acceptable salt thereof, where n” is 0, 1, 2, 3, or 4, and where each of Ring B, R1, R2, R2, R3, R, X, and p is as defined above and described in embodiments herein, both individually and in combination.

[00157] In some embodiments, n" is 0. In some embodiments, n" is 1. In some embodiments, n" is 2. In some embodiments, n" is 3. In some embodiments, n" is 4.

[00158] In some embodiments, n” is selected from those represented in Tables 1, 2, and 2A, below.

[00159] In some embodiments, the present invention provides a compound of Formulas VIII-a or VIII-b: town VIII-b or a pharmaceutically acceptable salt thereof, wherein each of Ring B, R1, R2, R2, R3, R, , both individually and in combination.

[00160] In some embodiments, the present invention provides a compound of Formula IX: IX or a pharmaceutically acceptable salt thereof, where R2 is halogen, and each of R2 and n' is as defined above and described in the embodiments herein, both individually and in combination.

[00161] In some embodiments, the present invention provides a compound of Formulas IX-a or IX-b: IF-2019-53902052-APN-ANP#INPI Page 51 of 423 IX-a IX-b or a pharmaceutically acceptable salt thereof, where R is halogen, and each of R and n' is as defined above and described in the embodiments herein, both individually and in combination,

[00162] In some embodiments, the present invention provides a compound of formulas X, XI or XII: or a pharmaceutically acceptable salt thereof, wherein R2 is halogen, and each of R2 is as defined above and described in the embodiments herein, both individually and in combination.

[00163] In some embodiments, the present invention provides a compound of Formulas Xa, Xb, ΧΙ-a, Xl-b, ΧΙΙ-a, or XH-b: ITEM . IO M z z Z^=4 Z^=4 / --\ / 2 / --\ / Z ( Z^J7 ( z-0j7 ¿ J / η m I / m ΙΌ — X NJ X XJ * Z) . N ) N) H2N^ / N0 ),r2 ü X-b H2N^zN< 0) 0 0 XLb 52 IF-2019-53902052-APN-ANP#INPI Page 52 of 423 or a pharmaceutically acceptable salt thereof, wherein R2 is halogen, and each of R2 is as defined above and described in the embodiments herein, both individually and in combination.

[00164] In some embodiments, the present invention provides a compound of Formulas where R2 is C1 and each of R2 is selected from the group consisting of O a a a Hr halogen (e.g. Cl), -NH2, -CH3, -CF3, A O, -CH2CH3, IF-2019-53902052-APN-ANP#INPI Page 53 of 423 IF-2019-53902052-APN-ANP#INPI Page 54 of 423

[00165] In some embodiments, exemplary compounds of the invention are set forth in Tables 1 and 2, below.

[00166] In some embodiments, exemplary compounds of the invention are set forth in Table 2A, below.

[00167] In some embodiments, the present invention provides a compound selected from those listed in Table 1, or a pharmaceutically acceptable salt thereof.

[00168] In some embodiments, the present invention provides a compound selected from those listed in Table 2, or a pharmaceutically acceptable salt thereof.

[00169] In some embodiments, the present invention provides a compound selected from those listed in Table 2A, or a pharmaceutically acceptable salt thereof.

[00170] In some embodiments, the present invention provides a trifluoroacetate salt of compound D-150. Table 1: Exemplary Compounds IF-2019-53902052-APN-ANP#INPI Page 55 of 423 1-1 \.N NH2 Y Y C|\^. Y¿J Cl ( 2 1-2 V X 1-3 x^NvNH2 ΥΪ Br \ ' / 1-4 rz z CM X 1-8 H2N^N<< « L z-nXCj \__) Br Γ O OO 1-11 NH2 Χϊ 0 VYAnA - 0 1-16 Cl\^\ Y,n^,n^.nh2 Y ¥ AxN 1-17 CIS-\ ΤΧΛΧ \__XN _N^NH2 Y ii X-N X ΙΌ z T> / z=< < z~ z 1-( \__ / A '( £ \ . \ 00 °_XA / z= / IF-2019-53902052-APN-ANP#INPI Page 56 of 423 1-19 C1V rrj o—7 1-20 0 1-23 ίίίίχ^θ V,N^N^NH2 T H kx,N / =Z Tt \___ )\ •7 «Vz ) >-H Z / \ / AZ z CM X 1-25 X0\x-Nx^ NH2 V / V'N> ^° \ / 1-26 \^N NH2 XX Λ 1-27 \^N NH2 y i ,-NxXxj \ ) Ox '—o 1-28 N^NH2 c9? N 0 31 qV Cl (_) Q—' 1-32 \^N^NH2 q1? 1-33 ΗζΝχγΝ^Ζ 1' 1-34 H2N^NíyZ « nA 1-35 h2n^n^ / ' NY r^N 1- 36 Η2Νχ.Ν^ / oA F / \ IF-2019-53902052-APN-ANP#INPI Page 57 of 423 Ck / °' \ £ X f? z '---( tfo / =\ / <\ / )— =o A / / II 00 \—X / —\ 1Γ\--z- ) ι4 z Γ \ / 7Z z - CM T 1-39 iE 1-40 Xo \xN^NH2 (A -° u 1-41 xo Wnh2 (W ^° \ / ^-Ν-χ 1-45 ii Ύ --N Ίί Ύ z-n^jL jL f y ^^ ci ”^z C / z z z=X / \ / z ta- \ \ 00 J^z z 1 1-49 Fx___ N^NHz 1-50 \^N NH2 QcL / ° \ ) 1-51 \,N<5^,NH2 Vo U» A -— LL x~( / z CM X X \__ / / / σι --γ '—< CM 1-54 H 0^NF x) V__nh2 ¥ IF-2019-53902052-APN-ANP#INPI Page 58 of 423 1-55 F ZZ H / γ o Vz^n^nh2 V 58 1-59 clxQ θ'Χ / ' / Y F \___ T ¥ 1-60 H2N N^ T Ύ oo 1-61 ( J ^F eV 1-62 \ / ΝγΝΗ2 -V 1-63 \.N^NH2 z NJ z z=^ V / ZA / £ —< \ -U o—<f~x / z= / 1-65 H2N^zN<?Z cn cNr^ v / Cl °o / zW °z X=\ Ό cn Y Ζ~° SO I '—( 1-67 owo ri=^Y's^ QT 1-68 A Oí \-o 1-69 \^N-,NH2 II Br \ / 1-70 \.Nx_,NH2 XX f rNW V / Cl 1-71 Η2Νυλ Λ^ν-^ν nh2 0\__J 1-72 N zNH2 X / NV no2 IF-2019-53902052-APN-ANP#INPI Page 59 of 423 x F nA JL / ΥΝΥτ^ v\z °\ Φ W ci 1-79 NH2 V A V / Cl VO \AN ' jl y rv <J ci 1-82 O-X / AZ / y o \___.N^N^NHz ¥ 1-83 0 _ ANZ MeOAT H Q-X / ^Z ___.N^N NHj V 1-84 O αΑΛ . A-o 1-85 νΆ, ii A H2N N \ η Ό ρΑχι 1-86 H2Nya ,?A N NH2 1-87 h2A / ^X^A'^N nh2 O\__J 1-88 0 \ / Ν^ΝΗ2 c¥syA N¥ --O \ / 1-89 x^N^ / NH2 Αχ I / CN A-o 1-90 ci-A^A y__ T ii Α,ν IF-2019-53902052-APN-ANP#INPI Page 60 of 423 x ^Z zoz nh2 1-95 Η2Ν'γΝ<¥ / σ9 \-0 NHAc 1-96 1-97 \-N^NH2 XX ^-0 Cl CM bo oo \— / V / σχ / / —' Ο=ω 1-99 0 \-N NH2 To 1-100 'X 'V'N^nh, or—7 1-101 x0 VN^NH2 X? 1-102 h2n^n< pMe X^° z— / O ___ / \ T~ M hQ z \ z Z Z7~Z o \ 1-107 OH VN^NH2 1-108 IF-2019-53902052-APN-ANP#INPI Page 61 of 423 1-109 NH rW Cl \ / 1-110 \,i% / nh2 qx < A— O 1-111 / 0~Oa0~ / Y 0 ν,Ν^,Ν NH2 v 1-112 nh2 Ch N—( 1 -113 Ck ftAr-O ---'N\^N^-NH2 Γ II ¥,N 1-114 z / o V / N N NH2 ¥ 1-115 γγγ \ Y 0 V / NXZ.NX.NH2 ¥ 1- 116 H2N.___N z Τι T 0 1 r n / -'NvxÁsI \__y 1-117 XV-N<^-NH2 CM T z » »-4 z A— z 1 z \_ / \__ / o °Y~Cl ' \== / Q 1-119 ___ o AOA V.N N NH2 γ H 1-120 \.n^znh2 qx ΡνΥυ Cl 1-121 , « ov V Λ ζγ? U Cl 1-123 γΥΝΗ2 V γ U Cl 1-124 NH2 II CpÍyhk 0\ \ / 1-125 n^NH2 |\ ZN ^XxN02 II A-0 1-126 0ΙγΓ==\^ / °'' ο-χ / γ o V___,Ν Νχ.ΝΗ2 \ Η γ,Ν IF-2019-53902052-APN-ANP#INPI Page 62 of 423 1-127 OH VN<?r--NH2 X 1-128 ΟΗ\χΝ<γ-ΝΗ2 Λγ y\.N. 1 \ 1-129 Pl / ''Z ° ci \ N χ / ΝχζΝΗ2 ¥ 1-132 / °γΧΧι V.N N NH2 T II X-N 1-133 cly^X N T II χ,Ν 1-134 HO X H2N. .N^ b-A Y 5 T F Ύ Γ fl U Cl 1-135 X Cl (J o-7 1-139 \^N NH2 TJn °4° T ? 1-142 nh2 N=^ / =:=\_ N—4 1-143 °^jQ / \ -N.-N^NHj ¥ 1-144 Clv-^A N NH2 \ II X^n IF-2019-53902052-APN-ANP#INPI Page 63 of 423 1-145 ho V h2n^,n-^ va Y T 1 rNYr U ci 1-146 HO Fb-FΗ2ΝυνΊγ i f cS 1-147 OH VNAr-NH2 ο-^ 1-148 HZ A z / '-Y' / V 0 V ,N_.N^,NH2 T ΙΪ χ,Ν 1-149 H z / o Ϋ,Ν^,Ν,,ΝΗς r II Αφ-Ν 1-150 Cl^? \___Ν_.Ν^,ΝΗ2 Τ II ίΐ^Ν 1-151 0 V__N^N^.NH2 ¥ 1-152 V ΧΝ Ν ΝΗ2 ¥ 1-153 HAW V,N^,N^,NH2 \ II 1-154 \ _ N ,1+ ,NH, 1 V 1-155 Λ 0 ^nATYci η ϋ JL __ / ΝγΝ η2ν 1-156 .. , νη Η2Ν^ / Νν^0ί^ Η 1 1 (γψ \ / Cl 1-157 H2N ,Ν^ / Αφ,ΝΗ w o 1-158 -^Ό Ο^ΝΗ VN <sr-nh2 1-159 0 ffva \=" / " νη ννγνη2 ^5 0-^ i no - o' -, o 1 q—v y—z zo ü>t / Ό 1-161 V η2ν^ν^ hn-S^ - ^-0 1-162 ,ΝΗ2 Ύ Ύ 7^ Vo / CI IF-2019-53902052-APN-ANP#INPI Page 64 of 423 1-163 Cl H2N- / N^.N.Y H Ύ ! 1 1 / ^\ ζ=ω—<\ / >—o a A / / O —\ 'T Y-z 9 z CM X X z / '''λ z=A / \ / z r ° zZ !± \__ / -— -\ o* \ \ cn}---V ° / / A o— <z y—ω="ζ" - \=" / " 1 z 1-166 m nh : h2n->zN^ / o-g^ i U \ i A. Y\jO 1 C Tei 1 1-167 .. fvNH2 - o— / 1-170 OH Vn^-NH2Cl (_) o—y 1-171 CIY^Z V / Ν^,Ν NH2 ¥ 1-172 : C'yP\ / γ o . V / N^N^NHj T ¥ Y / N 1-173 ciyP\ 0 'US / γ o Z / N N NH2 V 1-174 0 hct^Y NH Vn<^NH2 0—7 oz \ Z 1 z—< \ z -j "· z I M 1-176 o' F-Y^NH VN^NH2 0-^ · 1-177 0 fZnhVn^-nh2 z Cl ( J 1-178 ' XNH νΝ^-ΝΗ2C1 ( ) o-^ 1 -179 \ / N NH2 V °4° oF 1-180 Cl H o—\ / · γ o \___.N N NH2 ¥ IF-2019-53902052-APN-ANP#INPI Page 65 of 423 1-181 1-182 1-183 Η CIA A / N~^ Cl H S- / -NA. cl''r^X ο-\ΑΑ (i 0 ¡ / V\ / ~o0 Τ') ολ-'Ό^ '° V / nx.nx.nh2 \ II νΆ h2ns_nx / V / N^N^NHj An ¥ II Α,ν 1-184 o nh\ / n<^nh2 o—7 1-185 °q^o NH\xN<^NH2 o-7 1-186 z°\ ^n^znh2 y> \L z >N T £ T t / ci A-o 1-187 0 ci\^y^NH2 0-γΜ N Nh2 TJ 1-188 0 ___,N N NH2 lJ 1-189 A ^N^nh? <γ> A 1-190 A . N^NH2 An A? l ) Cl NvN^NH2 ¥ \___.N N^NHj T II Α,ν V_NH2 r H Α4Ί 1-196 NH2 (AL Ji η Un A A 1-197 \.N NH2 oA Il T i A 1-198 \χΝ NH IF-2019-53902052-APN-ANP#INPI Page 66 of 423 1-199 \<n^nh2 A Cl (J 1-200 Ck YVBr NH2 \ II Y-N 1-201 Clx WBr °'A-xY \___-N N NH2 \ II %x-N 1-202 YyNH2 0 1-203 \zN ^NH2 Οςγζ-χ An ζ^χ / ΝΗ A 1-204 ^N^NH2 YN ZX / NH A 1-205 A °—\AY / V.N N^NH2 T it k,N 1-206 \zN^NH2 A 1-207 'Χγ-Ν<^χΝΗ2 A 1-208 Cl\^\ p'xJ¥j¥S''' / y\¥ o o ¥ 1-209 Cl s Ί \ H2N^N Nx J ii Ύ Νχ^ Ρ 1-210 Cl s 1 ) H2N^,N ^ / Nx / V 1-211 ZCI 1-212 zCI Of» 1-213 0 u CIAV oaA / H2N^.N-,N^Y Η Ύ H2N^N Η Ύ Νχ^ hl nh2 A 1-214 0 u c,rA o-x 1-215 A \^Ν^ζΝΗ2 Ϋ \Am ζ^χ,ΝΗ 1-216 Cl A° YVNA \__N NH2 A ' L IJ rNA U ci ¥ IF-2019-53902052-APN-ANP#INPI Page 67 of 423 1-217 0\ Τ / V / Ν^,Ν νη2 V 1 Λ ο~γΤ « * HF 0^7 1-219 V_ΝΗ2 Τ' τ Τ / Ν 1-220 .-Τ'Ο '<ΧΝ Ν^, ΝΗ2 Τ ιΓ kx,N 1-221 i V^> θ'Χ '^ζ^Ν V-N Ν ΝΗ2 τχ 1-222 Cl^\ Τ° p^XCr Χ3 \____.Ν^-Ν^-ΝΗζ Τ' τ ΤζΝ 1-223 / ο ο ν,Ν Ν ΝΗ2 Τ Τ VN 1-224 CI,. \___,Ν Ν ΝΗ2 Τ' II 1-225 c,Y^ry \___·Ν^.ΝΧ.ΝΗ2 τ ” Τ / Ν 1-226 νη2 -Αν Λ''' y---\ 6^ργΝ^ ° 1-227 θ'νγΟ 'ν,Ν^.Ν ΝΗ2 V 1-228 Η2Ν >Νν_ vJ~ cTT 0 ci 1-229 hv Αρ 'W °~Λ Χ^Ο 1-230 ( Χ0 h2nvn^zN^J " IF-2019-53902052-APN-ANP#INPI Page 68 of 423 1-235 ciy^\ JT? o-yj ° V / nx.n^.nh2 ¥ 1-236 ClN¥y_ <oh )-N H2N 1-237 nh2 n^n 0^ / γ 'ΐγ- \^^0H 1-238 ci\^ r % V N ^,NX.NH2 ¥ 1-239 Cly\£\o ~ II N ,° yv ' V .N^N^-NH; ¥ 1-240 'X^N^NHs TX ΛΝ'ΥΧ[^ \__ / Cl 1-244 , Cl ΝγΑΧγ-ο 1 T Νγ,Ν nh2 1-245 Br\-N^NH2 (A Cl (J 1-246 1 N x,N^NH2 Y Ypr I ) Cl ¥-0 1-247 \ / N^zNH2 «1 1 OH V Ν'^^χ nA H °— VVN^X>.0H T Y Cl^^^ 1-250 FvA f / ,NH Vn^nh2 £5 o-7 1-251 NH Vn^NH2 £ α u 1-252 nh2 ο— / '¥γγΝχ^χΌΗ Cl IF-2019-53902052-APN-ANP#INPI Page 69 of 423 1-253 nh2 -A AnAz \ 1 H Ύ i 0H αΆ 1-254 CIAY^x 3o / / Y^N ¿aa ' A / Nx^N-^NH2 V 1-255 CIX^X °·^γΑ^ / ^ / V.N N NH2 T N A / N 1-256 . N_zNH2 V XN ^χ,ΝΗ 'LT rNyr aa ci 1-257 H N . N^NH2 Y 1A ^χ,ΝΗ ( ) Cl N-o 1-258 nh2 nA^ \ 1 H U cr 1-259 r~o cl _ ^7-- / YANA o-^. ., / / / \^xn^n^,nh2 \ H 1-260 °> / Ο-Ν··ΆΑ \^,n^_n^nh2 T II 1-261 CIYA<nO^oh οα·''\ Α A / N^xNx.NH2 V O / 'Z-\ I—1 oJa 8 1-263 \ζΝ^ΝΗ2 γΡ 11 1 1 OH V / N ^rx.NH ' 1 Ϊ rAA Lo> ci 1-264 hv A ? °Λ / OH 1-265 h¡Vn Ap Wn^ A O, J Z-Λ l-H 0^3 ~ i~y° 1-267 CIK^x V / N N^NHj V 1-268 A η2ΡΛν^ AA O Lzl 1 -269 ο-^γΑΑΝΗ2 \__ fl 7 NyN H2N 1-270 νΆ A A z-x η2ν^^ν^ν Ά H Ο^ΝχΖί'χΖ' l TT ρ'^'Άι IF-2019-53902052-APN-ANP#INPI Page 70 of 423 1-271 NY A A h2n n \ __ H ? } Ά 1-272 A A H2N N \ __ η γ ) ΓΧΥ° 1-273 0 ciYa<nO,\7 P'xAY / NH2 V 1-274 ί 1 ν'-Ά] ϊι J ___ h2n^n n A coA 1 -275 .Ck Cl A / )-nh2 An 1-276 —r—OH O^NH h2nAn^nA^ _p 1-277 ' H ?H ύύΆ °Ο / Μ ° V.N N NH2 V 1-278 C'Y^ <N A O-X J J Π F / y \i=^ 0 \___.N ^ / N- / NH2 ¥ 1-279 Ck H \ ) γΑΓΝτΑ-¥ o^\ Ao « / o \__hx / Nx / NH; And if A / N 1-280 Ck Η μ / Q Van M \ o—\ A / Π ( f 0 V___n^xnx.nh2 ¥ 1-281 <·¥¥¥ \__h-vAA \ H 1-282 n° xA V / N^,N^,NH2 ¥ X o •A® z—<\ / 7-° 00 ^.NH2 YA \ J °\ '-o 1-285 F VN<o--NH2 ά¥ _-° z \ 1-286 \y-n<5v^nh2 f M AS o—7 1-287 nh2 V I \ i ^F \__ / ox 1-288 1 t 1 \___N NH2 V IF-2019-53902052-APN-ANP#INPI Page 71 of 423 1-289 \,__ -χ / ΧίΧ . νη2 |\|Αν ΑΤΑη Υν^νη2 0^ 1-295 'XV-N^-NH2Β\ χχ ci W 1-296 Χ / Ν^.ΝΗ2 LX °4-° Τ ΧΤ-ΝΗ ^—0 Cl 1-297 clY ^sC ούΑΧ°° Τ II Y Ν c^° ζ—ζ ο —^Ζ (Κ ' / ' \\ / ) 'Ό Ζχ V__# Q0 Ζ I / =Ο ~ ζ I NJ 1-299 Η2ΝγΝ^ / C# \-ο 1-300 Μ ΝΗ2 Va c>) 1-301 Η2Νχ^Ν^ / XX CNX χ Cl 1-302 Λ \^ΝΗ2 γ \|>.Ν Χν U ci 1-303 \ / Ν.,ΝΗ2 , -y II °ΧθΗ οΧ IF-2019-53902052-APN-ANP#INPI Page 72 of 423 IF-2019-53902052-APN-ANP#INPI Page 73 of 423

[00171] Compounds 1-120 to 1-123 are stereoisomers of the following formulas: Compounds 1-120 to 1-123 can be separated by chiral purification (see, for example, Example 18). Accordingly, in some embodiments, the present invention provides a stereoisomer selected from compounds 1-120 to 1-123, or a pharmaceutically acceptable salt thereof.

[00172] Compounds 1-164 to 1-167 are stereoisomers of the following formulas: NH NH NH NH Compounds 1-164 to 1-167 can be separated by chiral purification (see, for example, Example 41). Accordingly, in some embodiments, the present invention provides a stereoisomer selected from compounds 1-164 to 1-167, or a pharmaceutically acceptable salt thereof.

[00173] Compounds 1-209 and 1-210 are stereoisomers of the following formulas: h2n . Compounds 1-209 and 1-210 can be separated by chiral purification (see, for example, Example 52). Accordingly, in some embodiments, the present invention provides a stereoisomer selected from compounds 1-209 to 1-210, or a pharmaceutically acceptable salt thereof. IF-2019-53902052-APN-ANP#INPI Page 74 of 423.

[00174] Compounds 1-211 and 1-212 are stereoisomers of the following formulas: h2n . Compounds 1-211 and 1-212 can be separated by chiral purification (see, for example, Example 52). Accordingly, in some embodiments, the present invention provides a stereoisomer selected from compounds 1-211 to 1-212, or a pharmaceutically acceptable salt thereof. Table 2. Exemplary Compounds IF-2019-53902052-APN-ANP#INPI Page 75 of 423 IF-2019-53902052-APN-ANP#INPI Page 76 of 423 Page 77 of 423 IF-2019-53902052-APN-ANP#INPI Page 78 of 423 IF-2019-53902052-APN-ANP#INPI Page 79 of 423 IF-2019-53902052-APN-ANP#INPI Page 80 of 423 IF-2019-53902052-APN-ANP#INPI Page 81 of 423 Page 82 of 423 IF-2019-53902052-APN-ANP#INPI Page 83 of 423 h2n n^n NZ \ T \__, °<eZ / r "A—N \= / \=N C p·* A-N C-107 oClv_ o^P \=N C unh2 V-N ex / / / X ° I 2 oo 1 II L ύ ° T λΑ < Έ. O\ C-109 Cl r> / ° A -tA C <rnh2 y-n c-110 ck n ° ,w y="N" 4 anh2 ( x° a^x^o o 2ύζ ¿t s γ? 1 a ' ό c-112 h2n )="N" n__ 0 c c-113 f0f o0u>° _ΧΝγΝΗ2 C-114 h2n An XT^i^0 h2n'z^í:íoi C-115 C-116 C-117 IF-2019-53902052-APN-ANP#INPI Page 84 of 423 IF-2019-53902052-APN-ANP#INPI Page 85 of 423 IF-2019-53902052-APN-ANP#INPI Page 86 of 423 IF-2019-53902052-APN-ANP#INPI Page 87 of 423 Table 2A: Exemplary Compounds IF-2019-53902052-APN-ANP#INPI Page 88 of 423 Page 89 of 423 IF-2019-53902052-APN-ANP#INPI Page 90 of 423 IF-2019-53902052-APN-ANP#INPI Page 91 of 423 IF-2019-53902052-APN-ANP#INPI Page 92 of 423 IF-2019-53902052-APN-ANP#INPI Page 93 of 423 IF-2019-53902052-APN-ANP#INPI Page 94 of 423 SAW IF-2019-53902052-APN-ANP#INPI Page 95 of 423 D-88 D-89 D-90 IF-2019-53902052-APN-ANP#INPI Page 96 of 423 IF-2019-53902052-APN-ANP#INPI Page 97 of 423 IF-2019-53902052-APN-ANP#INPI Page 98 of 423 IF-2019-53902052-APN-ANP#INPI Page 99 of 423 100 IF-2019-53902052-APN-ANP#INPI Page 100 of 423 101 IF-2019-53902052-APN-ANP#INPI Page 101 of 423 102 IF-2019-53902052-APN-ANP#INPI Page 102 of 423 103 IF-2019-53902052-APN-ANP#INPI Page 103 of 423 D-184 D-185 D-186 104 IF-2019-53902052-APN-ANP#INPI Page 104 of 423 4. General methods for providing the compounds herein:

[00175] The compounds of this invention can generally be prepared or isolated by synthetic and / or semi-synthetic methods known to those skilled in the art for analogous compounds and by methods described in detail in the Examples herein.

[00176] In the Schemes below, where a particular protecting group ("PG"), leaving group ("LG"), or transformation condition is depicted, those skilled in the art will appreciate that other protecting groups, leaving groups , and transformation conditions are also appropriate and are contemplated. Such groups and transformations are described in detail in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Μ. B. Smith and J. March, 5 Ed., John Wiley & Sons, 2001, Comprehensive Organic Transformations, R. C. Larock, 2nd Ed., John Wiley & Sons, 1999, and Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts , 3rd ed., John Wiley & Sons, 1999, the entirety of each of which is incorporated herein by reference. 105 IF-2019-53902052-APN-ANP#INPI Page 105 of 423

[00177] As used herein, the term “leaving group” (LG) includes, but is not limited to, halogens (e.g., fluoride, chloride, bromide, iodide), sulfonates (e.g., mesylate, tosylate, benzenesulfonate, brosylate, nosylate, triflate), diazonium, and the like.

[00178] As used herein, the term "oxygen protecting group" includes, for example, carbonyl protecting groups, hydroxyl protecting groups, etc. Hydroxyl protecting groups are well known in the art and include described in detail in Protecting Groups in Organic Synthesis, TW Greene and P. G. M. Wuts, 3rd ed., John Wiley & Sons, 1999, and Philip Kocienski, in "Protecting Groups", Georg Thieme Verlag Stuttgart, New York, 1994, the entire of which are incorporated herein by reference. Examples of suitable hydroxyl protecting groups include, but are not limited to, esters, allyl ethers, ethers, silyl ethers, alkyl ethers, arylalkyl ethers, and alkoxyalkyl ethers. Examples of such esters include formates, acetates, carbonates, and sulfonates. Specific examples include formate, benzoyl formate, chloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, pchlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate, 4,4-(ethylenedithio)pentanoate, pivaloate(trimethylacetyl), crotonate, 4-methoxycrotonate, benzoate, benzyl p-benzoate, 2,4,6-trimethylbenzoate, carbonates such as methyl, 9-fluorenylmethyl, ethyl, 2,2,2trichloroethyl, 2-(trimethylsilyl)ethyl,2-(phenylsulfonyl)ethyl, vinyl, allyl and p-nitrobenzyl. Examples of such silyl ethers include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and other trialkylsilyl ethers. Alkyl ethers include methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, allyl, and allyloxycarbonyl ethers or derivatives. Alkoxyalkyl ethers include acetals such as methoxymethyl, methylthiomethyl, (2-methoxyethoxy)methyl, benzyloxymethyl, beta(trimethylsilyl)ethoxymethyl, and tetrahydropyranyl ethers. Examples of arylalkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, phallobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, and 2- and 4-picolyl.

[00179] Amino protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 ed., John Wiley & Sons, 1999, and Philip Kocienski, in " Protecting Groups”, Georg Thieme Verlag Stuttgart, New York, 1994, all of which are incorporated in the 106 IF-2019-53902052-APN-ANP#INPI Page 106 of 423 present for reference. Suitable amino protecting groups include, but are not limited to, aralkylamines, carbamates, cyclic imides, allyl amines, amides, and the like. Examples of such groups include t-butyloxycarbonyl (BOC), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (CBZ), allyl, phthalimide, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl, dichloroacetyl , trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl, and the like.

[00180] Those skilled in the art will appreciate that the various functional groups present in the compounds of the invention such as aliphatic groups, alcohols, carboxylic acids, esters, amides, aldehydes, halogens and nitriles can be interconverted by techniques well known in the art. technique including, but not limited to, reduction, oxidation, esterification, hydrolysis, partial oxidation, partial reduction, halogenation, dehydration, partial hydration, and hydration. See, for example, "March's Advanced Organic Chemistry", 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entirety of which is incorporated herein by reference. Such Interconversions may require one or more of the aforementioned techniques, and certain methods for synthesizing compounds of the invention are described below.

[00181] In one aspect, the present invention provides a method for synthesizing a compound of Formula I, or partial formulas thereof, or a salt thereof, which (R')mH2N^ Z comprises reacting a compound of formula: , 0 a saj itself, and a compound of formula: where each of Ring A, R1, R2, R3, R, X, m, n, and p is as defined above and described in the embodiments herein, both individually and in combination. 107 IF-2019-53902052-APN-ANP#INPI Page 107 of 423

[00182] In some embodiments, the present invention provides a compound of (R')m formula: agreement H2N , or a salt thereof, where each of R1, R, and m is as defined above and described in the embodiments herein, both individually and in combination.

[00183] In some embodiments, the present invention provides a compound of N (R2)n formula: , or a salt thereof, where each of Ring A, 3 R, R, R, X, n, and p are as defined above and are described in the embodiments herein, both individually and in combination

[00184] In one aspect, the present invention provides a method for synthesizing a compound of Formula Γ, or partial formulas thereof, or a salt thereof, which (R')m , Or a salt of comprises reacting a compound of formula: (R3)Psame, and a compound of formula: where each of Ring A, R1, R2, R3, , or a salt thereof, m, n, and p is as defined above and described in the embodiments herein , both individually and in combination.

[00185] In some embodiments, the present invention provides a compound of (R3)p formula: (R2)n, or a salt thereof, where each of Ring A, 108 IF-2019-53902052-APN-ANP#INPI Page 108 of 423 or 3 · R, R,------, R, X, n, and p are as defined above and described in the embodiments herein, both individually and in combination.

[00186] In some embodiments, the present invention provides a method for synthesizing a compound of Formula VII, or a salt thereof, comprising making . R1h2n-vN^ react a compound of formula: N^z ,0 a sameOjyun^A-(R2)n' H )== / (r3)p^C ΛRcomposed of formula:x, or a salt thereof, where each of R1, R2, R2, R3, R, X, p, and n' is as defined above and described in the embodiments herein, both individually and in combination.

[00187] In some embodiments, the present invention provides a method for synthesizing a compound of formula VIII, or a salt thereof, comprising making R'1h2n^n^ react a compound of formula: ,0 a saj ¿e|same, and a compound of formula: X-—X ,0 a sa| of]same, where each of Ring B, R1, R2, R2, R3, R,

[00188] In some embodiments, the present invention provides a compound of R1 formula: , or a salt thereof, where each of R1 and R is according 109 IF-2019-53902052-APN-ANP#INPI Page 109 of 423 as defined above and described in the embodiments herein, both individually and in combination.

[00189] In some embodiments, the present invention provides a compound of formula:x—Λ, or a salt thereof, where each of R, R, R, R, X, p, and n' are as defined above and are described in the embodiments herein, both individually and in combination.

[00190] In some embodiments, the present invention provides a compound of formula: ,0 a sa] (same, where each of Ring 23 B, R, R, R, R, X, p, and n” is as defined above and is described in the embodiments herein, both individually and in combination. 5. Uses, formulation and administration: Pharmaceutically acceptable compositions

[00191] According to another embodiment, the invention provides a composition comprising a compound of this invention, or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, the amount of compound in the compositions of this invention is such that it is effective in causing the death of cancer cells in a biological sample or in a patient. In certain embodiments, the amount of compound in the compositions of this invention is such that it is effective to induce the UPR in cancer cells in a biological sample or in a patient. In certain embodiments, the amount of compound in the compositions of this invention is such that it is effective to induce ER stress in cancer cells in a biological sample or in a patient. In certain embodiments, the amount 110 IF-2019-53902052-APN-ANP#INPI Page 110 of 423 The compound in the compositions of this invention is such that it is effective in inducing the release of calcium from the ER through WFS1 in cancer cells in a biological sample or in a patient. In certain embodiments, a composition of this invention is formulated for administration to a patient in need of such composition. In some embodiments, a composition of this invention is formulated for oral administration to a patient.

[00192] The term "patient", as used herein, means an animal, preferably a mammal, and most preferably a human being.

[00193] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants, or vehicles that can used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, sorbate potassium, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone , substances based on cellulose, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and lanolin.

[00194] A "pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an active metabolite or residue thereof.

[00195] As used herein, the term active metabolite or residue thereof means that a metabolite or residue thereof also results in cell death.

[00196] The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. The term 111 IF-2019-53902052-APN-ANP#INPI Page 111 of 423 parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrastemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention may be an aqueous or oleaginous suspension. These suspensions can be formulated according to techniques known in the art using dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile fixed oils are conventionally used as a solvent or suspending medium.

[00197] For this purpose, any soft fixed oil can be used including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectables, as they are pharmaceutically acceptable natural oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers that are commonly used in the manufacture of solid, liquid or other pharmaceutically acceptable dosage forms may be used for formulation purposes.

[00198] The pharmaceutically acceptable compositions of this invention may be administered orally in any orally acceptable dosage form including, but not limited to, capsules, tablets, suspensions or aqueous solutions. In the case of tablets for oral use, commonly used carriers include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in capsule form, useful diluents include 112 IF-2019-53902052-APN-ANP#INPI Page 112 of 423 lactose and dry corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents can also be added.

[00199] Alternatively, the pharmaceutically acceptable compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore melts in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[00200] The pharmaceutically acceptable compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs easily accessible by topical application, including diseases of the eyes, skin or lower intestinal tract. Suitable topical formulations are easily prepared for each of these areas or organs.

[00201] Topical application to the lower intestinal tract may be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Transdermal patches can also be used topically.

[00202] For topical applications, the provided pharmaceutically acceptable compositions can be formulated into a suitable ointment containing the active component suspended or dissolved in one or more vehicles. Vehicles for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum jelly, white petroleum jelly, propylene glycol, polyoxyethylene, compound. of polyoxypropylene, emulsifying wax and water. Alternatively, the provided pharmaceutically acceptable compositions may be formulated into a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[00203] For ophthalmic use, the provided pharmaceutically acceptable compositions may be formulated as micronized suspensions in pH-adjusted isotonic sterile saline, or, preferably sterile saline, as 113 IF-2019-53902052-APN-ANP#INPI Page 113 of 423 solutions in isotonic, pH-adjusted solution, either with or without a preservative such as benzalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petroleum jelly.

[00204] The pharmaceutically acceptable compositions of this invention may also be administered by nasal spray or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to improve bioavailability, fluorocarbons and / or other conventional solubilizing agents. or dispersing agents.

[00205] Most preferably, the pharmaceutically acceptable compositions of this invention are formulated for oral administration. Such formulations can be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, the pharmaceutically acceptable compositions of this invention are administered with food.

[00206] The amount of compounds of the present invention that can be combined with the carrier materials to produce a composition in a single dosage form will vary depending on the host treated, the particular mode of administration. Preferably, the compositions provided should be formulated so that a dosage between 0.01 - 100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving these compositions.

[00207] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, rate of excretion, combination of drugs, and judgment of the treating physician and the severity of the particular disease under treatment. The amount of a compound of the present invention in the composition will also depend on the particular compound in the composition. Uses of pharmaceutically acceptable compounds and compositions 114 IF-2019-53902052-APN-ANP#INPI Page 114 of 423

[00208] The compounds and compositions described herein are generally useful for the treatment of cell proliferative disorders. As stated above, the compounds described herein have been found to be capable of causing the release of calcium from the endoplasmic reticulum (ER) through a putative Ca2+ channel known as Wolframine (WFS1), inducing ER stress. and the “unfolded protein response” (UPR), and resulting in cell death.

[00209] In some embodiments, the present invention provides a method of treating a cell proliferative disorder in a patient comprising administering to said patient a compound of the present invention, or a composition comprising said compound. In some embodiments, the present invention provides a compound of the present invention, or a composition comprising said compound, for use in the treatment of a cell proliferative disorder. Such disorders are described in detail herein. In some embodiments, a cell proliferative disorder is a cancer characterized by overexpression of Wolframine (WFS1) in cancer cells. In some embodiments, a cancer characterized by overexpression of Wolframine (WFS1) is selected from non-small cell lung cancer (NSCLC), myeloma, multiple myeloma, hepatocellular carcinoma (HCC), breast cancer, bladder cancer, kidney cancer and melanoma. In some embodiments, a method of treating a cell proliferative disorder as described herein further comprises determining the expression level of Wolframine (WFS1). In some embodiments, the expression level of Wolframine (WFS1) is determined by immunohistochemistry and / or microarray probe intensity.

[00210] As used herein, the terms "treatment", "treating" and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, the treatment may be administered after one or more symptoms have developed. In other embodiments, the treatment may be administered in the absence of symptoms. Treatment may be administered to a susceptible individual before the onset of symptoms (for example, in light of a history of symptoms and / or in light of genetic or other susceptibility factors). 115 IF-2019-53902052-APN-ANP#INPI Page 115 of 423 Treatment can also be continued after symptoms disappear, for example, to prevent or delay their recurrence.

[00211] In some embodiments, the present invention provides a method of inducing ER stress in a patient in need of said treatment, comprising administering a compound of the present invention, or a composition comprising said compound. In some embodiments, the present invention provides a method of inducing the "unfolded protein response" (UPR) in a patient in need of said treatment, comprising administering a compound of the present invention, or a composition comprising said compound. In In some embodiments, the present invention provides a method of causing the release of calcium from the endoplasmic reticulum (ER) through a putative Ca2+ channel known as Wolframine (WFS1) in a patient in need of said treatment, which comprises administering a compound of the present invention, or a composition comprising said compound.

[00212] In some embodiments, the present invention provides a compound of any one of Formulas I-VIII, or a composition comprising said compound, for use to cause the release of calcium from the endoplasmic reticulum (ER) through a putative Ca2+ channel known as Wolframine (WFS1) in a subject in need of such treatment. In some embodiments, the present invention provides a compound of any one of Formulas I-VIII, or a composition comprising said compound, for use in the induction of ER stress in a subject in need of said treatment. In some embodiments, the present invention provides a compound of any one of Formulas I-VIII, or a composition comprising said compound, for use in the induction of the "unfolded protein response" (UPR) in a subject in need of said treatment.

[00213] In some embodiments, the present invention provides a compound of Formula Γ, or a composition comprising such a compound, for use in causing the release of calcium from the endoplasmic reticulum (ER) through a putative Ca2+ channel known as Wolframine (WFS1) in a subject in need of said treatment. In some embodiments, the present invention provides a compound of Formula Γ, or a composition comprising said compound, for use in the induction of ER stress in a subject in need of said treatment. In some embodiments, the present 116 IF-2019-53902052-APN-ANP#INPI Page 116 of 423 invention provides a compound of Formula I, or a composition comprising said compound, for use in the induction of the "unfolded protein response" (LJPR) in a subject in need of said treatment.

[00214] The activity of a compound used in this invention as an inhibitor of cell proliferation can be assessed in vitro or in vivo. Detailed conditions for assaying a compound of this invention are set forth in the following Examples. Proliferative cellular disorders

[00215] The present invention presents methods and compositions for the diagnosis and prognosis of proliferative cellular disorders (e.g., cancer) and the treatment of these disorders. Cellular proliferative disorders described herein include, for example, cancer, obesity, and proliferation-dependent diseases. Such disorders can be diagnosed using methods known in the art. Cancer

[00216] Cancer includes, in one embodiment, without limitation, leukemias (for example, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, leukemia chronic myelocytic leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (e.g., Hodgkin's disease or non-Hodgkin's disease), Waldenstrom's macroglobulinemia, multiple myeloma, heavy chain disease, and solid tumors such as sarcomas and carcinomas ( for example, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer , prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, carcinoma of the bile duct, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, uterine cancer, testicular cancer, lung carcinoma, lung cell carcinoma 117 IF-2019-53902052-APN-ANP#INPI Page 117 of 423 small, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma , neuroblastoma, and retinoblastoma).

[00217] In some embodiments, the cancer is glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma.

[00218] In some embodiments, the cancer is acoustic neuroma, astrocytoma (e.g., Grade I - Pilocytic Astrocytoma, Grade II - Low Grade Astrocytoma, Grade III - Anaplastic Astrocytoma, or Grade IV - Glioblastoma (GBM)), chordoma , CNS lymphoma, craniopharyngioma, brain stem glioma, ependymoma, mixed glioma, optic nerve glioma, subependymoma, medulloblastoma, meningioma, metastatic brain tumor, oligodendroglioma, pituitary tumors, primitive neuroectodermal tumor (PNET), or schwannoma. In some embodiments, the cancer is a type more commonly found in children than adults, such as brain stem glioma, craniopharyngioma, ependymoma, juvenile pilocytic astrocytoma (JPA), medulloblastoma, optic nerve glioma, pineal tumor, neuroectodermal tumors. primitive (PNET), or rhabdoid tumor. In some embodiments, the patient is an adult human being. In some embodiments, the patient is a child or pediatric patient.

[00219] Cancer includes, in another embodiment, without limitation, mesothelioma, hepatobiliary (liver and bile duct), bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cutaneous or intraocular melanoma, cancer ovarian cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal cancer (gastric, colorectal, and duodenal), uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix , carcinoma of the vagina, carcinoma of the vulva, Hodgkin's disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, tissue sarcoma soft, cancer 118 IF-2019-53902052-APN-ANP#INPI Page 118 of 423 of the urethra, penile cancer, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphomas, bladder cancer, kidney or ureter cancer, renal cell carcinoma, carcinoma of the pelvis kidney, non-Hodgkins lymphoma, spinal axis tumors, brainstem glioma, pituitary adenoma, adrenocortical cancer, gallbladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma, or a combination of one or more of the previous cancers.

[00220] In some embodiments, the cancer is selected from hepatocellular carcinoma, ovarian cancer, epithelial ovarian cancer, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; Testicular cancer; gallbladder cancer; hepatocholangiocarcinoma; synovial sarcoma of soft tissue and bones; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; anaplastic thyroid cancer; adrenocortical adenoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal / stomach cancer (GIST); lymphoma; squamous cell carcinoma of the head and neck (SCGHN); salivary gland cancer; glioma, or brain cancer; malignant peripheral nerve sheath tumors associated with neurofibromatosis-1 (MPNST); Waldenstrom macroglobulinemia; or medulloblastoma.

[00221] In some embodiments, the cancer is selected from hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, epithelial ovarian cancer, fallopian tube cancer, papillary serous cystadenocarcinoma, papillary uterine serous carcinoma. (UPSC), hepatocholangiocarcinoma, synovial sarcoma of soft tissue and bones, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical adenoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, malignant peripheral nerve sheath tumors associated with neurofibromatosis-1 (MPNST), Waldenstrom macroglobulinemia, or medulloblastoma.

[00222] In some embodiments, the present invention provides a method of treating a cancer that presents as a solid tumor, such as a sarcoma, carcinoma, or lymphoma, comprising the step of administering a described compound, or a pharmaceutically acceptable salt of the same, to a patient in need of said treatment. Solid tumors generally comprise an abnormal mass of tissue that usually does not include cysts or fluid areas. In some embodiments, the cancer is selected from 119 IF-2019-53902052-APN-ANP#INPI Page 119 of 423 renal cell carcinoma, or kidney cancer; hepatocellular carcinoma (HCC) or hepatoblastoma, or liver cancer; melanoma; breast cancer; colorectal carcinoma, or colorectal cancer; colon cancer; rectal cancer; anal cancer; lung cancer, such as non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC); ovarian cancer, epithelial ovarian cancer, ovarian carcinoma, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; Testicular cancer; gallbladder cancer; hepatocholangiocarcinoma; synovial sarcoma of soft tissue and bones; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; anaplastic thyroid cancer; adrenocortical carcinoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal / stomach cancer (GIST); lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma, or brain cancer; malignant peripheral nerve sheath tumors associated with neurofibromatosis-1 (MPNST); Waldenstrom macroglobulinemia; or medulloblastoma.

[00223] In some embodiments, the cancer is selected from renal cell carcinoma, hepatocellular carcinoma (HCC), hepatoblastoma, colorectal carcinoma, colorectal cancer, colon cancer, rectal cancer, anal cancer, ovarian cancer, epithelial ovarian cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, carcinoma pancreatic ductal, pancreatic adenocarcinoma, glioma, brain cancer, neurofibromatosis -1 associated malignant peripheral nerve sheath tumors (MPNST), Waldenstrom macroglobulinemia, or medulloblastoma.

[00224] In some embodiments, the cancer is selected from hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, epithelial ovarian cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, Uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, soft tissue and synovial bone sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, malignant nerve sheath tumors peripheral 120 IF-2019-53902052-APN-ANP#INPI Page 120 of 423 associated with neurofibromatosis-1 (MPNST), Waldenstrom's macroglobulinemia, or medulloblastoma.

[00225] In some embodiments, the cancer is hepatocellular carcinoma (HCC). In some embodiments, the cancer is hepatoblastoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is rectal cancer. In some embodiments, the cancer is ovarian cancer, or ovarian carcinoma. In some embodiments, the cancer is epithelial ovarian cancer. In some embodiments, the cancer is cancer of the fallopian tube. In some embodiments, the cancer is papillary serous cystadenocarcinoma. In some embodiments, the cancer is uterine papillary serous carcinoma (UPSC). In some embodiments, the cancer is hepatocholangiocarcinoma. In some embodiments, the cancer is synovial sarcoma of soft tissue and bone. In some embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is osteosarcoma. In some embodiments, the cancer is anaplastic thyroid cancer. In some embodiments, the cancer is adrenocortical carcinoma. In some embodiments, the cancer is pancreatic cancer, or pancreatic ductal carcinoma. In some embodiments, the cancer is pancreatic adenocarcinoma. In some embodiments, the cancer is glioma. In some embodiments, the cancer is malignant peripheral nerve sheath tumors (MPNST). In some embodiments, the cancer is MPNST associated with neurofibromatosis1. In some embodiments, the cancer is Waldenstrom's macroglobulinemia. In some embodiments, the cancer is medulloblastoma.

[00226] The present invention further provides methods and compositions for the diagnosis, prognosis and treatment of virus-associated cancers, including human immunodeficiency virus (HIV)-associated solid tumors, human papillomavirus-positive incurable solid tumors. (HPV), and adult T-cell leukemia, which is caused by human T-cell leukemia virus type I (HTLV-I) and is a very aggressive form of CD4+ T-cell leukemia characterized by clonal integration of HTLV -I in · leukemic cells (See https: / / clinicaltrials.gov / ct2 / show / study / NCT02631746); as well as virus-associated tumors in gastric cancer, nasopharyngeal carcinoma, cervical cancer, vaginal cancer, vulvar cancer, head and neck squamous cell carcinoma, and Merkel cell carcinoma. (See https: / / clinicaltrials.gov / ct2 / show / study / NCT02488759; see also 121 IF-2019-53902052-APN-ANP#INPI Page 121 of 423 https: / / clinicaltrials.gov / ct2 / show / study / NCT0240886; https: / / clinicaltrials.gov / ct2 / show / NCT02426892)

[00227] In some embodiments, the present invention provides a method of treating a cancer in a patient in need of said treatment, comprising administering to the patient any of the compounds, salts or pharmaceutical compositions described herein. In some embodiments, the cancer is selected from the cancers described herein. In some embodiments, the cancer is melanoma cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is small cell lung cancer (SCLC). In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the cancer is myeloma. In some embodiments, the cancer is multiple myeloma. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is kidney cancer. In some embodiments, the cancer is hepatocellular carcinoma (HCC). In some embodiments, the cancer is melanoma. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is endometrial cancer. In some embodiments, the cancer is esophageal cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is renal cell carcinoma.

[00228] In some embodiments, the tumor is treated by stopping further growth of the tumor. In some embodiments, the tumor is treated by reducing the size (e.g., volume or mass) of the tumor by at least 5%, 10%, 25%, 50%, 75%, 90% or 99% relative to the tumor size before treatment. In some embodiments, the tumors are treated by reducing the number of the tumors in the patient by at least 5%, 10%, 25%, 50%, 75%, 90% or 99% relative to the number of the tumors. before treatment.

[00229] The compounds and compositions, according to the method of the present invention, can be administered using any amount and any route of administration effective to treat or lessen the severity of a cell proliferative disorder. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease or condition, the particular agent, its mode of administration, and the like. The compounds of the invention are preferably formulated in unit dosage form for ease of administration. 122 IF-2019-53902052-APN-ANP#INPI Page 122 of 423 and dosage uniformity. The term "unit dosage form" as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily use of the compounds and compositions of the The present invention will be decided by the treating physician within the scope of medical judgment. The specific effective dose level for any particular patient or organism will depend on a variety of factors including the disorder being treated and the severity of the disorder. ; the specific composition used; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound used; with the specific compound employed, and similar factors well known in the medical arts. The term "patient", as used herein, means an animal, preferably a mammal, and most preferably a human.

[00230] The pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracystemally, intravaginally, intraperitoneally, topically (such as by powders, ointments or drops), buccal, such as a spray. oral or nasal, or similar, depending on the severity of the disease or disorder to be treated. In certain embodiments, the compounds of the invention can be administered orally or parenterally at dosage levels of about 0.01 mg / kg to about 50 mg / kg and preferably from about 1 mg / kg to about 25 mg / kg, of the subject's body weight per day, one or more times a day, to obtain the desired therapeutic effect.

[00231] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular cottonseed, peanut, corn, germ, olive, castor and sesame oils), glycerol, 123 IF-2019-53902052-APN-ANP#INPI Page 123 of 423 tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan fatty acid esters, and mixtures thereof. In addition to inert diluents, oral compositions may also include adjuvants such as wetting, emulsifying and suspending agents, sweetening agents, flavorings, and perfuming agents.

[00232] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a parenterally acceptable non-toxic diluent or solvent, for example, such as a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution, USP, and isotonic sodium chloride solution. Furthermore, sterile fixed oils are conventionally used as a solvent or suspending medium. For this purpose any soft fixed oil can be used including synthetic mono- or diglycerides. Additionally, fatty acids such as oleic acid are used in the preparation of injectables.

[00233] Injectable formulations can be sterilized, for example, by filtration through a bacterial retention filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium before use. .

[00234] In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved by the use of a liquid suspension of crystalline or amorphous material with poor solubility in water. The absorption rate of the compound then depends on its dissolution rate which, in turn, may depend on the crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered form of the compound is achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsulated matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the nature of the particular polymer employed, the release rate of the compound can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and 124 IF-2019-53902052-APN-ANP#INPI Page 124 of 423 poly(anhydrides). Injectable depot formulations are also prepared by trapping the compound in liposomes or microemulsions that are compatible with body tissues.

[00235] Compositions for rectal or vaginal administration are preferably suppositories that can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax that are solid at room temperature, but liquid. at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[00236] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with excipient or at least one inert pharmaceutically acceptable carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch , alginic acid, certain silicates and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[00237] Solid compositions of a similar type can also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and coatings such as enteric coatings and other coatings well known in the art of pharmaceutical formulation. They may optionally contain opacifying agents and may also be of such a composition 125 IF-2019-53902052-APN-ANP#INPI Page 125 of 423 that release the active ingredient only, or preferably, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of inclusion compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

[00238] The active compounds may also be in micro-encapsulated form with one or more excipients as indicated above. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and coatings such as enteric coatings, controlled release coatings and other coatings well known in the art of pharmaceutical formulation. In such solid dosage forms the active compound may be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, for example, compounding lubricants and other compounding aids such as a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and may also be of such a composition that they release the active ingredient only, or preferably, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of inclusion compositions that can be used include polymeric substances and waxes.

[00239] Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers as required. Ophthalmic formulations, ear drops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the 126 IF-2019-53902052-APN-ANP#INPI Page 126 of 423 composed in the appropriate medium. Absorption enhancers can also be used to increase the flow of the compound through the skin. The rate can be controlled by providing a rate control membrane or by dispersing the compound in a polymer or gel matrix.

[00240] In some embodiments, the invention relates to a method of inducing ER stress in a biological sample comprising the step of contacting said biological sample with a compound of this invention, or a composition comprising said compound.

[00241] In some embodiment, the invention relates to a method of inducing the "unfolded protein response" (UPR) in a biological sample comprising the step of contacting said biological sample with a compound of this invention, or a composition comprising said compound.

[00242] In certain embodiments, the invention relates to a method of causing the release of calcium from the endoplasmic reticulum (ER) through a putative Ca2+ channel known as Wolframine (WFS1) in a biological sample comprising the step of contacting said biological sample with a compound of this invention, or a composition comprising said compound.

[00243] The term "biological sample", as used herein, includes, without limitation, cell cultures or extracts thereof; biopsy material obtained from a mammal or extracts thereof; and blood, saliva, urine , feces, semen, tears, or other bodily fluids or extracts thereof. Co-administration of additional therapeutic agents

[00244] Depending on the particular condition or disease to be treated, additional therapeutic agents that are normally administered to treat that condition may also be present in the compositions of this invention. As used herein, additional therapeutic agents that are typically administered to treat a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated."

[00245] In some embodiments, the present invention provides a method of treating a disclosed disease or condition comprising administering to a 127 IF-2019-53902052-APN-ANP#INPI Page 127 of 423 patient in need of said treatment an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and simultaneously or sequentially co-administer an effective amount of one or more additional therapeutic agents, such as those described in the present. In some embodiments, the method includes coadministration of an additional therapeutic agent. In some embodiments, the method includes co-administration of two additional therapeutic agents. In some embodiments, the combination of the disclosed compound and the additional therapeutic agent(s) act synergistically.

[00246] In some embodiments, the additional therapeutic agent is selected from an immunostimulating therapeutic compound. In some embodiments, the immunostimulatory therapeutic compound is selected from elotuzumab, mifamurtide, a toll-like receptor agonist or activator, or a RORyt activator.

[00247] In some embodiments, the method further comprises administering to said patient a third therapeutic agent, such as an immune checkpoint inhibitor. In some embodiments, the method comprises administering to the patient in need of said treatment three therapeutic agents selected from a compound disclosed herein or a pharmaceutically acceptable salt thereof, an immunostimulating therapeutic compound, and an immune checkpoint inhibitor.

[00248] Other checkpoint inhibitors that can be used in the present invention include 0X40 agonists. 0X40 agonists being studied in clinical trials include PF-04518600 / PF-8600 (Pfizer), an agonist anti-OX40 antibody, in metastatic kidney cancer (NCT03092856) and advanced cancers and malignancies (NCT02554812; NCT05082566); GSK3174998 (Merck & Co.), an agonist anti-OX40 antibody, in Phase 1 cancer trials (NCT02528357); MEDI0562 (Medimmune / AstraZeneca), an agonist anti-OX40 antibody, in advanced solid tumors (NCT02318394 and NCT02705482); MEDI6469, an agonist anti-OX40 antibody (Medimmune / AstraZeneca), in patients with colorectal cancer (NCT02559024), breast cancer (NCTO1862900), head and neck cancer (NCT02274155), and metastatic prostate cancer (NCTO 1303705); and BMS-986178 (Bristol-Myers Squibb), an agonistic anti-OX40 antibody, in advanced cancers (NCT02737475). 128 IF-2019-53902052-APN-ANP#INPI Page 128 of 423

[00249] Other checkpoint inhibitors that can be used in the present invention include CD 137 (also referred to as 41BB) agonists. CD 137 agonists being studied in clinical trials include utomilumab (PF-05082566, Pfizer), an agonistic anti-CD137 antibody, in diffuse large B-cell lymphoma (NCT02951156) and in advanced cancers and malignancies (NCT02554812 and NCT05082566); urelumab (BMS-663513, Bristol-Myers Squibb), an agonist anti-CD137 antibody, in melanoma and skin cancer (NCT02652455) and glioblastoma and gliosarcoma (NCT02658981).

[00250] Other checkpoint inhibitors that can be used in the present invention include CD27 agonists. CD27 agonists being studied in clinical trials include varlilumab (CDX-1127, Celldex Therapeutics), an anti-CD27 antibody agonist, in head and neck squamous cell cancer, ovarian carcinoma, colorectal cancer, renal cell cancer, and glioblastoma (NCT02335918); lymphomas (NCT01460134); and glioma and astrocytoma (NCT02924038).

[00251] Other checkpoint inhibitors that can be used in the present invention include glucocorticoid-induced tumor necrosis factor receptor (GITR) agonists. GITR agonists being studied in clinical trials include TRX518 (Leap Therapeutics), an agonistic anti-GITR antibody, in malignant melanoma and other malignant solid tumors (NCT01239134 and NCT02628574); GWN323 (Novartis), an agonistic anti-GITR antibody, in solid tumors and lymphoma (NCT02740270); INCAGN01876 (Incyte / Agenus), an agonistic anti-GITR antibody, in advanced cancers (NCT02697591 and NCT03126110); MK-4166 (Merck & Co.), an agonist anti-GITR antibody, in solid tumors (NCT02132754) and MEDI1873 (Medimmune / AstraZeneca), an agonist hexameric GITR-ligand molecule with an Fe domain of human IgGl, in solid tumors advanced (NCT02583165).

[00252] Other checkpoint inhibitors that can be used in the present invention include inducible T cell co-stimulator (ICOS, also referred to as CD278) agonists. ICOS agonists being studied in clinical trials include MED1-570 (Medimmune), an agonistic anti-ICOS antibody, in lymphomas (NCT02520791); GSK3359609 (Merck & Co.), an agonist anti-ICOS antibody, in Phase 129 IF-2019-53902052-APN-ANP#INPI Page 129 of 423 (NCT02723955); JTX-2011 (Jounce Therapeutics), an agonist anti-ICOS antibody, in Phase 1 (NCT02904226).

[00253] Other checkpoint inhibitors that can be used in the present invention include IgG-like killer receptor (KIR) inhibitors. KIR inhibitors being studied in clinical trials include lirilumab (IPH2102 / BMS-986015, Innate Pharma / Bristol-Myers Squibb), an anti-KIR antibody, in leukemias (NCT01687387, NCT02399917, NCT02481297, NCT02599649), multiple myeloma (NCT02252263 ) and lymphoma (NCTO 1592370); 1PH2101 (1-7F9, Innate Pharma) in myeloma (NCTO 1222286 and NCTO 1217203); and IPH4102 (Innate Pharma), an anti-KIR antibody that binds to three domains of the cytoplasmic long tail (KIR3DL2), in lymphoma (NCT02593045).

[00254] Other checkpoint inhibitors that can be used in the present invention include CD47 inhibitors of the interaction between CD47 and the signal regulatory protein alpha (SIRPa). CD47 / SIRPa inhibitors being studied in clinical trials include ALX-148 (Alexo Therapeutics), a variant antagonist (SIRPa) that binds to CD47 and prevents CD47 / SIRPa-mediated signaling, in Phase 1 (NCT03013218) ; TTI-621 (SIRPa-Fc, Trillium Therapeutics), a soluble recombinant fusion protein created by ligation of the N-terminal CD47-binding domain of SIRPa to the Fe domain of human IgGl, acts by binding to human CD47, and preventing the delivery of their “do not eat” signal to macrophages, is in Phase 1 clinical trials (NCT02890368 and NCT02663518); CC-90002 (Celgene), an anti-CD47 antibody, in leukemias (NCT02641002); and Hu5F9 -G4 (Forty Seven, Inc.), in colorectal neoplasms and solid tumors (NCT02953782), acute myeloid leukemia (NCT02678338) and lymphoma (NCT02953509).

[00255] Other checkpoint inhibitors that can be used in the present invention include CD73 inhibitors. CD73 inhibitors being studied in clinical trials include MEDI9447 (Medimmune), an anti-CD73 antibody, in solid tumors (NCT02503774); and BMS-986179 (Bristol-Myers Squibb), an anti-CD73 antibody, in solid tumors (NCT02754141).

[00256] Other checkpoint inhibitors that can be used in the present invention include agonists of the stimulator of interferon gene protein (STING, 130 IF-2019-53902052-APN-ANP#INPI Page 130 of 423 also called transmembrane protein 173, or TMEM173). STING agonists being studied in clinical trials include MK-1454 (Merck & Co.), a synthetic cyclic dinucleotide agonist, in lymphoma (NCT03010176); and ADU-S100 (MIW815, Aduro Biotech / Novartis), a synthetic cyclic dinucleotide agonist, in Phase 1 (NCT02675439 and NCT03172936).

[00257] Other checkpoint inhibitors that can be used in the present invention include CSF1R inhibitors. CSF1R inhibitors being studied in clinical trials include pexidartinib (PLX3397, Plexxikon), a small molecule CSF1R inhibitor, in colorectal cancer, pancreatic cancer, metastatic and advanced cancer (NCT02777710) and melanoma, non-small cell lung cancer, head and neck squamous cell cancer, gastrointestinal stromal tumor (GIST), and ovarian cancer (NCT02452424); and IMC-CS4 (LY3022855, Lilly), an antiCSF-1R antibody, in pancreatic cancer (NCT03153410), melanoma (NCT03101254), and solid tumors (NCT02718911); and BLZ945 (4-[2((lR,2R)-2hydroxycyclohexylamino)benzothiazol-6-yloxy]pyridine-2-carboxylic acid methylamide, Novartis), an orally available inhibitor of CSF1R, in advanced solid tumors (NCT02829723) .

[00258] Other checkpoint inhibitors that can be used in the present invention include NKG2A receptor inhibitors. NKG2A receptor inhibitors being studied in clinical trials include monalizumab (IPH2201, Innate Pharma), an anti-NKG2A antibody, in head and neck malignancies (NCT02643550) and chronic lymphocytic leukemia (NCT02557516).

[00259] In some embodiments, the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pidilizumab.

[00260] In another aspect, the present invention provides a method of treating cancer in a patient in need of said treatment, wherein said method comprises administering to said patient a compound described herein or a pharmaceutically acceptable salt thereof in combination with one or plus additional therapeutic agents selected from an indoleamine (2,3)-dioxygenase (IDO) inhibitor, a Poly ADP ribose polymerase (PARP) inhibitor, a histone inhibitor 131 IF-2019-53902052-APN-ANP#INPI Page 131 of 423 deacetylase (HDAC), a CDK4 / CDK6 inhibitor, or a phosphatidylinositol 3-kinase (PI3K) inhibitor.

[00261] In some embodiments, the IDO inhibitor is selected from epacadostat, indoximod, capmanitib, GDC-0919, PF-06840003, BMS:F001287, Phy906 / KD108, or an enzyme that breaks down kynurenine.

[00262] In some embodiments, the PARP inhibitor is selected from olaparib, rucaparib, niraparib, iniparib, talazoparib, or veliparib.

[00263] In some embodiments, the HDAC inhibitor is selected from vorinostat, romidepsin, panobinostat, belinostat, entinostat, or chidamide.

[00264] In some embodiments, the CDK 4 / 6 inhibitor is selected from palbociclib, ribociclib, abemaciclib or trilaciclib.

[00265] In some embodiments, the method further comprises administering to said patient a third therapeutic agent, such as an immune checkpoint inhibitor. In some embodiments, the method comprises administering to the patient in need of said treatment three therapeutic agents selected from a compound disclosed herein or a pharmaceutically acceptable salt thereof, a second therapeutic agent selected from an indoleamine (2,3)-dioxygenase inhibitor (IDO), a Poly ADP ribose polymerase (PARP) inhibitor, a histone deacetylase (HDAC) inhibitor, a CDK4 / CDK6 inhibitor, or a phosphatidylinositol 3-kinase (PI3K) inhibitor, and a third therapeutic agent selected from an immune checkpoint inhibitor. In some embodiments, the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pidilizumab.

[00266] Another immunostimulatory therapeutic that can be used in the present invention is recombinant human interleukin 15 (rhIL-15). rhIL-15 has been clinically tested as a therapy for melanoma and renal cell carcinoma (NCT01021059 and NCT01369888) and leukemias (NCT02689453). Another immunostimulatory therapeutic that can be used in the present invention is recombinant human interleukin 12 (rhlL-12). Another suitable IL-15-based immunotherapeutic is heterodimeric IL-15 (Hetil-15, Novartis / Admune), a fusion complex composed of a synthetic form of endogenous IL-15 in complex with the soluble binding protein IL-15. 132 IF-2019-53902052-APN-ANP#INPI Page 132 of 423 to IL-15 alpha chain receptor (IL15:sIL-15RA), which has been tested in Phase 1 clinical trials for melanoma, renal cell carcinoma, non-small cell lung cancer and carcinoma of head and neck squamous cells (NCT02452268). Recombinant human interleukin 12 (rhIL-12) has been clinically tested for numerous oncological indications, for example, as a therapy for lymphoma (NM-IL12, Neumedicines, Inc.), (NCT02544724 and NCT02542124).

[00267] In some embodiments, the PI3K inhibitor is selected from idelalisib, alpelisib, taselisib, pictilisib, copanlisib, duvelisib, PQR309, or TGR1202.

[00268] In another aspect, the present invention provides a method of treating cancer in a patient in need of said treatment, wherein said method comprises administering to said patient a compound described herein or a pharmaceutically acceptable salt thereof in combination with one or plus additional therapeutic agents selected from a platinum-based therapeutic, a taxane, a nucleoside inhibitor, or a therapeutic agent that interferes with normal DNA synthesis, protein synthesis, cell replication, or otherwise inhibits rapidly proliferating cells .

[00269] In some embodiments, the platinum-based therapeutic is selected from cisplatin, carboplatin, oxaliplatin, nedaplatin, picoplatin, or satraplatin.

[00270] In some embodiments, the taxane is selected from paclitaxel, docetaxel, albumin-bound paclitaxel, cabazitaxel, or SID530.

[00271] In some embodiments, the therapeutic agent that interferes with normal DNA synthesis, protein synthesis, cellular replication, or will interfere with the replication of rapidly proliferating cells is selected from trabectedin, mechlorethamine, vincristine, temozolomide , cytarabine, lomustine, azacitidine, omacetaxine mepesuccinate, asparaginase Erwinia chrysanthemi, eribulin mesylate, capacetrin, bendamustine, ixabepilone, nelarabine, chlorafabine, trifluridine, or tipiracil.

[00272] In some embodiments, the method further comprises administering to said patient a third therapeutic agent, such as an immune checkpoint inhibitor. In some embodiments, the method comprises administering to the patient in need of said treatment three therapeutic agents selected from a compound disclosed herein or a pharmaceutically acceptable salt thereof, a second 133 IF-2019-53902052-APN-ANP#INPI Page 133 of 423 therapeutic agent selected from a therapeutic agent, a platinum-based taxane, a nucleoside inhibitor, or a therapeutic agent that interferes with normal DNA synthesis, protein synthesis, cellular replication, or otherwise inhibits rapidly proliferating cells, and a third therapeutic agent selected from an immune checkpoint inhibitor.

[00273] In some embodiments, the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pidilizumab.

[00274] In some embodiments, any of the above methods further comprises the step of obtaining a biological sample from the patient and measuring the amount of a disease-related biomarker.

[00275] In some embodiments, the biological sample is a blood sample.

[00276] In some embodiments, the disease-related biomarker is selected from circulating CD8+ T cells or the ratio of CD8+ T cells:Treg cells.

[00277] In one aspect, the present invention provides a method of treating an advanced cancer, comprising administering a compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof, either as a single agent (monotherapy ), or in combination with a chemotherapeutic agent, a therapeutic target, such as a kinase inhibitor, and / or an immunomodulatory treatment, such as an immune checkpoint inhibitor. In some embodiments, the immune checkpoint inhibitor is an antibody to PD-1. PD-1 binds to the programmed cell death 1 (PD-1) receptor to prevent the receptor from binding to the inhibitory ligand PDL-1, thereby overriding the ability of tumors to suppress the host anti-tumor immune response.

[00278] In some embodiments, the additional therapeutic agent is a VEGF-R or kinase inhibitor antagonist. Approved VEGF inhibitors and kinase inhibitors useful in the present invention include: bevacizumab (Avastin®, Genentech / Roche) an anti-VEGF monoclonal antibody; ramucirumab (Cyramza®, Eli Lilly), an anti-VEGFR-2 antibody, and ZIV-aflibercept, also called VEGF Trap (Zaltrap®; Regeneron / Sanofi). VEGFR inhibitors, such as regorafenib 134 IF-2019-53902052-APN-ANP#INPI Page 134 of 423 (Stivarga®, Bayer); vandetanib (Caprelsa®, AstraZeneca); axitinib (Inlyta®, Pfizer); and lenvatinib (Lenvima®, Eisai); Raf inhibitors, such as sorafenib (Nexavar®, Bayer AG and Onyx); dabrafenib (Tafinlar®, Novartis); and vemurafenib (Zelboraf®, Genentech / Roche); MEK inhibitors, such as cobimetanib (Cotellic®, Exelexis / Genentech / Roche); trametinib (Mekinist®, Novartis); Bcr-Abl tyrosine kinase inhibitors, such as imatinib (Gleevec®, Novartis); nilotinib (Tasigna®, Novartis); dasatinib (Sprycel®, BristolMyersSquibb); bosutinib (Bosulif®, Pfizer); and ponatinib (Inclusig®, Ariad Pharmaceuticals); Her2 and EGFR inhibitors, such as gefitinib (Iressa®, AstraZeneca); erlotinib (Tarceeva®, Genentech / Roche / Astellas); lapatinib (Tykerb®, Novartis); afatinib (Gilotrif®, Boehringer Ingelheim); osimertinib (activated EGFR target, Tagrisso®, AstraZeneca); and brigatinib (Alunbrig®, Ariad Pharmaceuticals); c-Met and VEGFR2 inhibitors, such as cabozanitib (Cometriq®, Exelexis); and multikinase inhibitors, such as sunitinib (Sutent®, Pfizer); pazopanib (Votrient®, Novartis); ALK inhibitors, such as crizotinib (Xalkori®, Pfizer); ceritinib (Zykadia®, Novartis); and alectinib (Alecenza®, Genentech / Roche); Bruton's tyrosine kinase inhibitors, such as ibrutinib (Imbruvica®, Pharmacyclics / Janssen); and Flt3 receptor inhibitors, such as midostaurin (Rydapt®, Novartis).

[00279] Other VEGF-R kinase inhibitors and antagonists that are under development and may be used in the present invention include tivozanib (Aveo Pharmaecuticals); vatalanib (Bayer / Novartis); lucitanib (Clovis Oncology); dovitinib (TKI258, Novartis); Chiauanib (Chipscreen Biosciences); CEP-11981 (Cephalon); linifanib (Abbott Laboratories); neratinib (HKI-272, Puma Biotechnology); radotinib (Supect®, IY5511, Il-Yang Pharmaceuticals, South Korea); ruxolitinib (Jakafi®, Incyte Corporation); PTC299 (PTC Therapeutics); CP-547,632 (Pfizer); foretinib (Exelexis, GlaxoSmithKline); quizartinib (Daiichi Sankyo) and motesanib (Amgen / Takeda).

[00280] In some embodiments, the additional therapeutic agent is an mTOR inhibitor, which inhibits cell proliferation, angiogenesis, and glucose uptake. Approved mTOR inhibitors useful in the present invention include everolimus (Afinitor®, Novartis); temsirolimus (Torisel®, Pfizer); and sirolimus (Rapamune®, Pfizer).

[00281] In some embodiments, the additional therapeutic agent is a Poly ADP ribose polymerase (PARP) inhibitor. Approved PARP inhibitors useful herein 135 IF-2019-53902052-APN-ANP#INPI Page 135 of 423 invention include olaparib (Lynparza®, AstraZeneca); rucaparib (Rubraca®, Clovis Oncology); and niraparib (Zejula®, Tesaro). Other PARP inhibitors being studied that may be used in the present invention include talazoparib (MDV3800 / BMN 673 / LT00673, Medivation / Pfizer / Biomarin); veliparib (ABT-888, AbbVie); and BGB-290 (BeiGene, Inc.).

[00282] In some embodiments, the additional therapeutic agent is a phosphatidylinositol 3-kinase (P13K) inhibitor. Approved PI3K inhibitors useful in the present invention include idelalisib (Zydelig®, Gilead). Other PI3K inhibitors being studied that may be used in the present invention include alpelisib (BYL719, Novartis); taselisib (GDC-0032, Genentech / Roche); pictilisib (GDC-0941, Genentech / Roche); copanlisib (BAY806946, Bayer); duvelisib (formerly IPI-145, Infinity Pharmaceuticals); PQR309 (Piqur Therapeutics, Switzerland); and TGR1202 (previously RP5230, TG Therapeutics).

[00283] In some embodiments, the additional therapeutic agent is a proteasome inhibitor. Approved proteasome inhibitors useful in the present invention include bortezomib (Velcade®, Takeda); carfilzomib (Kyprolis®, Amgen); and ixazomib (Ninlaro®, Takeda).

[00284] In some embodiments, the additional therapeutic agent is a histone deacetylase (HDAC) inhibitor. Approved HDAC inhibitors useful in the present invention include vorinostat (Zolinza®, Merck & Co.); romidepsin (Istodax®, Celgene); panobinostat (Farydak®, Novartis); and belinostat (Beleodaq®, Spectrum Pharmaceuticals). Other HDAC inhibitors being studied that may be used in the present invention include entinostat (SNDX-275, Syndax Pharmaceuticals) (NCT00866333); and chidamide (Epidaza®, HBI-8000, Chipscreen Biosciences, China).

[00285] In some embodiments, the additional therapeutic agent is a CDK inhibitor, such as a CDK 4 / 6 inhibitor. Approved CDK 4 / 6 inhibitors useful in the present invention include palbociclib (Ibrance®, Pfizer); and ribociclib (Kisqali®, Novartis). Other CDK 4 / 6 inhibitors being studied that may be used in the present invention include abemaciclib (Ly2835219, Eli Lilly); and trilaciclib (G1T28, G1 Therapeutics). 136 IF-2019-53902052-APN-ANP#INPI Page 136 of 423

[00286] In some embodiments, the additional therapeutic agent is an indoleamine (2,3)-dioxygenase (IDO) inhibitor. IDO inhibitors being studied that can be used in the present invention include epacadostat (INCB024360, Incyte); indoximod (NLG-8189, NewLink Genetics Corporation); capmanitib (INC280, Novartis); GDC-0919 (Genentech / Roche); PF-06840003 (Pfizer); BMS: F001287 (Bristol-Myers Squibb); PHY906 / KD108 (Phytoceutica); and an enzyme that breaks down kynurenine (Kynase, Kyn Therapeutics).

[00287] In some embodiments, the additional therapeutic agent is a growth factor antagonist, such as an antagonist of platelet-derived growth factor (PDGF), or epidermal growth factor (EGF) or its receptor (EGFR). Approved PDGF antagonists that can be used in the present invention include olaratumab (Lartruvo®; Eli Lilly). Approved EGFR antagonists that can be used in the present invention include cetuximab (Erbitux®, Eli Lilly); necitumumab (Portrazza®, Eli Lilly), panitumumab (Vectibix®, Amgen); and osimertinib (activated EGFR target, Tagrisso®, AstraZeneca).

[00288] In some embodiments, the additional therapeutic agent is an aromatase inhibitor. Approved aromatase inhibitors that can be used in the present invention include exemestane (Aromasin®, Pfizer); anastazol (Arimidex®, AstraZeneca) and letrozole (Femara, Novartis).

[00289] In some embodiments, the additional therapeutic agent is an antagonist of the hedgehog pathway. Approved hedgehog pathway inhibitors that may be used in the present invention include sonidegib (Odomzo®, Sun Pharmaceuticals); and vismodegib (Erivedge®, Genentech), both for the treatment of basal cell carcinoma.

[00290] In some embodiments, the additional therapeutic agent is a folic acid inhibitor. Approved folic acid inhibitors useful in the present invention include pemetrexed (Alimta®, Eli Lilly).

[00291] In some embodiments, the additional therapeutic agent is a CC chemokine receptor 4 (CCR4) inhibitor. CCR4 inhibitors being studied that may be useful in the present invention include mogamulizumab (Poteligeo®, Kyowa Hakko Kirin, Japan). . 137 IF-2019-53902052-APN-ANP#INPI Page 137 of 423

[00292] In some embodiments, the additional therapeutic agent is an isocitrate dehydrogenase (IDH) inhibitor. IDH inhibitors being studied that can be used in the present invention include AGI20 (Celgene; NCT02677922); AG221 (Celgene, NCT02677922; NCT02577406); BAY1436032 (Bayer, NCT02746081); IDH305 (Novartis, NCT02987010).

[00293] In some embodiments, the additional therapeutic agent is an arginase inhibitor. Arginase inhibitors being studied that may be used in the present invention include AEB1102 (recombinant pegylated arginase, Aeglea Biotherapeutics), which is being studied in Phase 1 clinical trials for acute myeloid leukemia and myelodysplastic syndrome (NCT02732184) and solid tumors (NCT02561234); and CB1158 (Calithera Biosciences).

[00294] In some embodiments, the additional therapeutic agent is a glutaminase inhibitor. Glutaminase inhibitors being studied that can be used in the present invention include CB-839 (Calithera Biosciences).

[00295] In some embodiments, the additional therapeutic agent is an antibody that binds to tumor antigens, that is, proteins expressed on the cell surface of tumor cells. Approved antibodies that bind to tumor antigens that can be used in the present invention include rituximab (Rituxan®, Genentech / BiogenIDEC); ofatumumab (anti-CD20, Arzerra®, GlaxoSmithKline); obinutuzumab (anti-CD20, Gazyva®, Genentech), ibritumomab (anti-CD20 and Yttrium-90, Zevalin®, Spectrum Pharmaceuticals); daratumumab (anti-CD38, Darzalex®, Janssen Biotech), dinutuximab (anti-GD2 glycolipid, Unituxin®, United Therapeutics); trastuzumab (anti-HER2, Herceptin®, Genentech); ado-trastuzumab emtansine (anti-HER2, fused to emtansine, Kadcyla®, Genentech); and pertuzumab (anti-HER2, Perjeta®, Genentech); and brentuximab vedotin (anti-CD30-drug conjugate, Adcetris®, Seattle Genetics).

[00296] In some embodiments, the additional therapeutic agent is a topoisomerase inhibitor. Approved topoisomerase inhibitors useful in the present invention include irinotecan (Onivyde®, Merrimack Pharmaceuticals); topotecan (Hycamtin®, GlaxoSmithKline). Topoisomerase inhibitors being studied 138 IF-2019-53902052-APN-ANP#INPI Page 138 of 423 that can be used in the present invention include pixantrone (Pixuvri®, CTI Biopharma).

[00297] In some embodiments, the additional therapeutic agent is a nucleoside inhibitor, or other therapeutic that interferes with normal DNA synthesis, protein synthesis, cellular replication, or otherwise inhibits rapidly proliferating cells. Such nucleoside inhibitors or other therapeutic agents include trabectedin (guanidine alkylating agent, Yondelis®, Janssen Oncology), mechlorethamine (alkylating agent, Valchlor®, Aktelion Pharmaceuticals); vincristine (Oncovin®, Eli Lilly; Vincasar®, Teva Pharmaceuticals; Marqibo®, Talon Therapeutics); temozolomide (prodrug for alkylating agent 5-(3-methyltriazen-l-yl)-imidazole-4carboxamide (MTIC) Temodar®, Merck & Co.); cytarabine injection (ara-C, antimetabolic cytidine analogue, Pfizer); lomustine (alkylating agent, CeeNU®, BristolMyers Squibb; Gleostine®, NextSource Biotechnology); azacitidine (cytidine pyrimidine nucleoside analogue, Vidaza®, Celgene); omacetaxine mepesuccinate (cephalotaxine ester) (protein synthesis inhibitor, Synribo®; Teva Pharmaceuticals); f asparaginase Erwinia chrysanthemi (asparagine depletion enzyme, Elspar®, Lundbeck; Erwinaze®, EUSA Pharma); eribulin mesylate (microtubule inhibitor, tubulin-based antimitotic, Halaven®, Eisai); cabazitaxel (microtubule inhibitor, tubulin-based antimitotic, Jevtana®, Sanofi-Aventis); capacetrin (thymidylate synthase, Xeloda®, Genentech); bendamustine (bifunctional mechlorethamine derivative, presumed to form between cross-linked DNA strands, Treanda®, Cephalon / Teva); ixabepilone (semi-synthetic analogue of epothilone B, microtubule inhibitor, tubulin-based antimitotic, Ixempra®, Bristol-Myers Squibb); nelarabine (deoxyguanosine analog prodrug, nucleoside metabolic inhibitor, Arranon®, Novartis); chlorafabine (ribonucleotide reductase inhibitor prodrug, competitive deoxycytidine inhibitor, Clolar®, Sanofi-Aventis); and trifluridine and tipiracil (thymidine phosphorylase nucleoside analog and thymidine-based, Lonsurf®, Taiho Oncology).

[00298] In some embodiments, the additional therapeutic agent is a platinum-based therapeutic agent, also referred to as Platins. Platins cause DNA cross-linking, thereby inhibiting DNA repair and / or DNA synthesis, primarily in cells that reproduce rapidly, such as 139 IF-2019-53902052-APN-ANP#INPI Page 139 of 423 cancerous. Approved platinum-based therapeutic agents that may be used in the present invention include cisplatin (Platinol®, Bristol-Myers Squibb); carboplatin (Paraplatin®, Bristol-Myers Squibb; also, Teva; Pfizer); oxaliplatin (Eloxitin® Sanofi-Aventis); and nedaplatin (Aqupla®, Shionogi). Other platinum-based therapeutic agents that have undergone clinical testing and can be used in the present invention include picoplatin (Poniard Pharmaceuticals); and satraplatin (JM-216, Agennix).

[00299] In some embodiments, the additional therapeutic agent is a taxane compound, which causes disruption of microtubules, which are essential for cell division. Approved taxane compounds that can be used in the present invention include paclitaxel (Taxol®, Bristol-Myers Squibb), docetaxel (Taxotere®, SanofiAventis; Docefrez®, Sun Pharmaceutical), albumin-bound paclitaxel (Abraxane®; Abraxis / Celgene) , and cabazitaxel (Jevtana®, Sanofi-Aventis). Other taxane compounds that have undergone clinical testing and can be used in the present invention include SID530 (SK Chemicals, Co.) (NCT00931008).

[00300] In some embodiments, the additional therapeutic agent is an inhibitor of anti-apoptotic proteins, such as BCL-2. Approved anti-apoptotics that can be used in the present invention include venetoclax (Venclexta®, AbbVie / Genentech); and blinatumomab (Blincyto®, Amgen). Other therapeutic agents that target apoptotic proteins that have undergone clinical testing and can be used in the present invention include navitoclax (ABT-263, Abbott), a BCL-2 inhibitor (NCT02079740).

[00301] In some embodiments, the present invention provides a method of treating prostate cancer comprising administering to a patient in need of said treatment an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the same in combination with an additional therapeutic agent that interferes with the synthesis or activity of androgens. Approved androgen receptor inhibitors useful in the present invention include Enzalutamide (Xtandi®, Astellas / Medivation); Approved inhibitors of androgen synthesis include abiraterone (ZYTIGA®, Centocor / Ortho); approved gonadotropin-releasing hormone (GnRH) receptor antagonist (degaralix, Firmagon®, Ferring Pharmaceuticals). 140 IF-2019-53902052-APN-ANP#INPI Page 140 of 423

[00302] In some embodiments, the additional therapeutic agent is a selective estrogen receptor modulator (SERM), which interferes with the synthesis or activity of estrogens. Approved SERMs useful in the present invention include raloxifene (Evista®, Eli Lilly).

[00303] In some embodiments, the additional therapeutic agent is a bone resorption inhibitor. An approved therapeutic LJn that inhibits bone resorption is denosumab (Xgeva®, Amgen), an antibody that binds to RANKL, preventing binding to its RANK receptor, which is found on the surface of osteoclasts, their precursors, and giant cell type. osteoclast, which mediate bone pathology in solid tumors with bone metastases. Other approved therapeutic agents that inhibit bone resorption include bisphosphonates, such as zoledronic acid (ZOMETA®, Novartis).

[00304] In some embodiments, the additional therapeutic agent is an inhibitor of the interaction between the two major p53 suppressor proteins, MDMX and MDM2. Inhibitors of p53 suppression proteins being studied that may be used in the present invention include ALRN-6924 (Aileron), a staple peptide that binds equally potently to and disrupts the interaction of MDMX and MDM2 with p53. ALRN-6924 is currently being evaluated in clinical trials for the treatment of AML, advanced myelodysplastic syndrome (MDS), and peripheral T-cell lymphoma (PTCL) (NCT02909972; NCT02264613).

[00305] In some embodiments, the additional therapeutic agent is a transforming growth factor beta (TGF-beta or TGF) inhibitor. TGF-beta protein inhibitors under study that may be used in the present invention include NIS793 (Novartis), an anti-TGF-beta antibody that is being clinically tested for the treatment of various cancers, including breast, lung, hepatocellular, colorectal, pancreatic, prostate and renal cancer (NCT 02947165). In some embodiments, the TGF-beta protein inhibitor is fresolimumab (GC1008; Sanofi-Genzyme), which is being studied for melanoma (NCT00923169); renal cell carcinoma (NCT00356460); and non-small cell lung cancer (NCT02581787). Furthermore, in some embodiments, the additional therapeutic agent is a TGF-beta trap, as described in Connolly et al. (2012) Int'l J. Biological Sciences 8:964-978. 141 IF-2019-53902052-APN-ANP#INPI Page 141 of 423 Additional Co-Administered Therapeutic Agents - Target Therapeutics and Immunomodulatory Drugs

[00306] In some embodiments, the additional therapeutic agent is selected from a specific therapeutic or immunomodulatory drug. Adjuvant therapies with targeted therapeutic agents or immunomodulatory drugs have shown promising efficacy when administered alone, but are limited by the development of tumor immunity over time or evasion of the immune response.

[00307] In some embodiments, the present invention provides a method of treating cancer, such as a cancer described herein, comprising administering to a patient in need of said treatment an effective amount of a compound described herein or a salt pharmaceutically acceptable thereof or a pharmaceutical composition thereof in combination with an additional therapeutic agent such as a target therapeutic or an immunomodulatory drug. In some embodiments, the immunomodulatory therapeutic agent specifically induces apoptosis of tumor cells. Approved immunomodulatory therapeutics that may be used in the present invention include pomalidomide (Pomalyst®, Celgene); lenalidomide (Revlimid®, Celgene); ingenol mebutate (Picato®, LEO Pharma).

[00308] In other embodiments, the immunomodulatory therapeutic agent is a cancer vaccine. In some embodiments, the cancer vaccine is selected from sipuleucel-T (Provenge®, Dendreon / Valeant Pharmaceuticals), which has been approved for the treatment of asymptomatic, or minimally symptomatic metastatic castration-resistant (refractory) prostate cancer. hormones); and talimogene laherparepvec (Imlygic®, BioVex / Amgen, formerly called T-VEC), a genetically modified oncolytic viral therapy approved for the treatment of unresectable cutaneous, subcutaneous and nodal lesions in melanoma. In some embodiments, the additional therapeutic agent is selected from an oncolytic viral therapy such as pexastimogene devacirepvec (PexaVec / JX-594, SillaJen / formerly Jennerex Biotherapeutics), a vaccinia virus-deficient thymidine kinase (TK) genetically engineered to express GM-CSF. , for hepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312); pelareorep (Reolysin®, Oncolytics Biotech), a variant of the respiratory enteric orphan virus (reovirus) that does not replicate in cells that are not 142 IF-2019-53902052-APN-ANP#INPI Page 142 of 423 activated by RAS, in numerous types of cancer, including colorectal cancer (NCTO1622543); prostate cancer (NCT01619813); head and neck squamous cell cancer (NCTO 1166542); pancreatic adenocarcinoma (NCT00998322); and non-small cell lung cancer (NSCLC) (NCT 00861627); enadenotucirev (NG-348, PsiOxus, formerly called ColoAdl), an adenovirus genetically engineered to express full-length CD80 and an antibody fragment specific for the T-cell receptor protein CD3, in ovarian cancer (NCT02028117); metastatic or advanced epithelial tumors, such as in colorectal cancer, bladder cancer, head and neck squamous cell carcinoma and salivary gland cancer (NCT02636036); ONCOS-102 (Targovax / formerly Oncos), an adenovirus genetically engineered to express GM-CSF, in melanoma (NCT03003676); and peritoneal disease, colorectal cancer, or ovarian cancer (NCT02963831); GL-ONC1 (GLV-lh68 / GLV-lhl53, Genelux GmbH), vaccinia virus genetically engineered to express beta-galactosidase (beta-gal) / beta-glucoronidase or beta-gal / human sodium iodide symporter (hNIS), respectively, it was studied in peritoneal carcinomatosis (NCTO 1443260); fallopian tube cancer, ovarian cancer (NCT 02759588); or CG0070 (Cold Genesys), an adenovirus engineered to express GMCSF, in bladder cancer (NCT02365818).

[00309] In some embodiments, the additional therapeutic agent is selected from JX929 (SillaJen / formerly Jennerex Biotherapeutics), a TK virus and vaccinia growth factor-deficient vaccinia virus genetically engineered to express cytosine deaminase, which is capable of converting the prodrug 5-fluorocytosine in the cytotoxic drug 5-fluorouracil; TG01 and TG02 (Targovax / formerly Oncos), targeted peptide-based immunotherapy agents for difficult-to-treat RAS mutations; and TILT-123 (TILT Biotherapeutics), an engineered adenovirus designated: Ad5 / 3-E2Fdelta24-hTNFa-IRES-hIL20; and VSV-GP (ViraTherapeutics) a vesicular stomatitis virus (VSV) genetically engineered to express the lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP), which can be further engineered to express antigens intended to elevate a CD8+ T cell response. antigen-specific.

[00310] In some embodiments, the present invention comprises administering to said patient a compound disclosed herein or a pharmaceutically acceptable salt of the 143 IF-2019-53902052-APN-ANP#INPI Page 143 of 423 same in combination with a T cell genetically engineered to express a chimeric antigen receptor, or CAR. T cells genetically engineered to express such a chimeric antigen receptor are called CAR-T cells.

[00311] CARs have been constructed that consist of binding domains, which may be derived from natural ligands, single chain variable fragments (scFv) derived from monoclonal antibodies specific for cell surface antigens, fused to endodomains that are the functional end of the T cell receptor (TCR), such as the CD3-zeta signaling domain of TCR, which is capable of generating an activation signal in T lymphocytes. Upon antigen binding, such CARs bind to endogenous signaling pathways in the effector cell and generate activation signals similar to those initiated by the TCR complex.

[00312] For example, in some embodiments the CAR-T cell is one of those described in United States Patent 8,906,682 (June; which is incorporated herein by reference in its entirety), which discloses CAR-T cells. T genetically engineered to comprise an extracellular domain having an antigen binding domain (such as a CD 19 binding domain), fused to an intracellular signaling domain of the zeta chain receptor of the T cell antigen complex (such such as CD3 zeta). When expressed in the T cell, CAR is capable of redirecting antigen recognition based on antigen binding specificity. In the case of CD 19, the antigen is expressed on malignant B cells. More than 200 clinical trials are currently in progress employing CAR-T in a wide range of indications. [https: / / clinicaltrials.gov / ct2 / results?term=chimeric+antigen+receptors&pg=l]. Additional co-administered therapeutic agents - Immunostimulating medications

[00313] In some embodiments, the additional therapeutic agent is an immunostimulant drug. For example, PD-1 and PD-L1 inhibitory axis blocking antibodies can trigger tumor-reactive activated T cells that have been shown in clinical trials to induce durable anti-tumor responses in a growing number of tumor histologies, including some types of tumors that have not conventionally been considered sensitive to immunotherapy. See, for example, Okazaki, T. et al. (2013) Nat. Immunol. 14, 1212-1218; Zou et al. (2016) Sci. Transí. Med. 144 IF-2019-53902052-APN-ANP#INPI Page 144 of 423 8. The anti-PD-1 antibody nivolumab (Opdivo®, Bristol-Myers Squibb, also called ONO-4538, MDX1106 and BMS-936558), has demonstrated its potential to improve overall survival in patients with RCC who had experienced progression of the disease during or after before anti-angiogenic therapy.

[00314] In some embodiments, the present invention provides a method of treating cancer, such as a cancer described herein, comprising administering to a patient in need of said treatment an effective amount of a compound described herein or a salt pharmaceutically acceptable thereof or a pharmaceutical composition thereof in combination with an additional therapeutic agent such as an immunostimulant drug, such as an immune checkpoint inhibitor. In some embodiments, the compound and the checkpoint inhibitor are administered simultaneously or sequentially. In some embodiments, a compound described herein is administered prior to initial dosing with the immune checkpoint inhibitor. In certain embodiments, the immune checkpoint inhibitor is administered prior to initial dosing with the compound disclosed herein.

[00315] In certain embodiments, the immune checkpoint inhibitor is selected from a PD-1 antagonist, a PD-L1 antagonist, or a CTLA-4 antagonist. In some embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is administered in combination with nivolumab (anti-PD-1 antibody, Opdivo®, Bristol-Myers Squibb); pembrolizumab (anti-PD-1 antibody, Keytruda®, Merck & Co.); ipilimumab (anti-CTLA-4 antibody, Yervoy®, Bristol-Myers Squibb); durvalumab (anti-PD-Ll antibody, Imfinzi®, AstraZeneca); or atezolizumab (anti-PD-Ll antibody, Tecentriq®, Genentech).

[00316] Other immune checkpoint inhibitors suitable for use in the present invention include REGN2810 (Regeneren), an anti-PD-1 antibody tested in patients with basal cell carcinoma (NCT03132636); NSCLC (NCT03088540); cutaneous squamous cell carcinoma (NCT02760498); lymphoma (NCT02651662); and melanoma (NCT03002376); pidilizumab (CureTech), also called CT-011, an antibody that binds to PD-1, in clinical trials for diffuse large B-cell lymphoma and multiple myeloma; avelumab (Bavencio®, Pfizer / Merck KGaA), also called MSB0010718C), a fully human anti-PD-Ll IgGl antibody, in trials 145 IF-2019-53902052-APN-ANP#INPI Page 145 of 423 clinical for non-small cell lung cancer, Merkel cell carcinoma, mesothelioma, solid tumors, kidney cancer, ovarian cancer, bladder cancer, head and neck cancer, and gastric cancer; and PDR001 (Novartis), an inhibitory antibody that binds to PD-1, in clinical trials for non-small cell lung cancer, melanoma, triple-negative breast cancer, and advanced or metastatic solid tumors. Tremelimumab (CP-675,206; Astrazeneca) is a fully human monoclonal antibody against CTLA-4 that has been studied in clinical trials for a number of indications, including: mesothelioma, colorectal cancer, kidney cancer, breast cancer, lung cancer and non-small cell lung cancer, pancreatic ductal adenocarcinoma, pancreatic cancer, germ cell cancer, head and neck squamous cell cancer, hepatocellular carcinoma, prostate cancer, endometrial cancer, metastatic liver cancer, liver cancer, lymphoma large B cell cancer, ovarian cancer, cervical cancer, metastatic anaplastic thyroid cancer, urothelial cancer, fallopian tube cancer, multiple myeloma, bladder cancer, soft tissue sarcoma, and melanoma. AGEN-1884 (Agenus) is an anti-CTLA4 antibody that is being studied in Phase 1 clinical trials for advanced solid tumors (NCT02694822).

[00317] Another paradigm for immune stimulation is the use of eneolytic viruses. In some embodiments, the present invention provides a method of treating a patient by administering a compound disclosed herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in combination with an immunostimulatory therapy such as eneolytic viruses. Approved immunostimulant eneolytic viruses that can be used in the present invention include laherparepvec talimogene (live attenuated herpes simplex virus, Imlygic®, Amgen).

[00318] In some embodiments, the additional therapeutic agent is a retinoic acid receptor γ-related orphan receptor activator (RORyt). RORyt is a transcription factor with a key role in the differentiation and maintenance of Type 17 effector subsets of CD4+ (Thl7) and CD8+ (TC17) T cells, as well as the differentiation of IL-17-expressing innate immune cell subpopulations. such as NK cells. An activator of RORyt, which is being studied that can be used in 146 IF-2019-53902052-APN-ANP#INPI Page 146 of 423 The present invention is LYC-55716 (Lycera), which is currently being evaluated in clinical trials for the treatment of solid tumors (NCT02929862).

[00319] In some embodiments, the additional therapeutic agent is an agonist or activator of a toll-like receptor (TLR). Suitable TLR activators include a TLR9 agonist or activator, such as SD-101 (Dynavax). SD-101 is a CpG immunostimulator that is being studied in B cells, follicular and other lymphomas (NCT02254772). TLR8 agonists or activators that may be used in the present invention include motolimod (VTX-2337, VentiRx Pharmaceuticals) which is being studied for head and neck squamous cell cancer (NCT02124850) and ovarian cancer (NCT02431559).

[00320] Other checkpoint inhibitors that can be used in the present invention include mucin inhibitors of T cell immunoglobulin-containing protein-3 (TIM-3). TIM-3 inhibitors that can be used in the present invention include TSR-022, LY3321367 and MBG453. TSR-022 (Tesaro) is an anti-TIM3 antibody, which is being studied in solid tumors (NCT02817633). LY3321367 (Eli Lilly) is an anti-TIM-3 antibody, which is being studied in solid tumors (NCT03099109). MBG453 (Novartis) is an anti-TIM-3 antibody that is being studied in advanced malignant tumors (NCT02608268).

[00321] Other checkpoint inhibitors that can be used in the present invention include T cell immunoreceptor inhibitors with 1g and ITIM domains, or TIGIT, an immune receptor on certain T cells and NK cells. TIGIT inhibitors that can be used in the present invention include BMS-986207 (Bristol-Myers Squibb), an anti-TIGIT monoclonal antibody (NCT02913313); OMP-313M32 (OncoMed); and the anti-TIGIT monoclonal antibody (NCT03119428).

[00322] Checkpoint inhibitors that can be used in the present invention also include Lymphocyte Activation Gene-3 (LAG-3) inhibitors. LAG-3 inhibitors that can be used in the present invention include BMS986016 and REGN3767 and IMP321. BMS-986016 (Bristol-Myers Squibb), an anti-LAG-3 antibody, is being studied in glioblastoma and gliosarcoma (NCT02658981). REGN3767 (Regeneren), is also an anti-LAG-3 antibody, and is being studied in malignancies (NCT03005782). IMP321 (Immutep SA) is a GAL-3-Ig fusion protein, being 147 IF-2019-53902052-APN-ANP#INPI Page 147 of 423 studied in melanoma (NCT02676869); adenocarcinoma (NCT02614833); and metastatic breast cancer (NCT00349934).

[00323] Other immuno-oncology agents that may be used in the present invention in combination with a compound disclosed herein include urelumab (BMS663513, Bristol-Myers Squibb), an anti-CD137 monoclonal antibody; varlilumab (CDX1127, Celldex Therapeutics), an anti-CD27 monoclonal antibody; BMS-986178 (BristolMyers Squibb), an anti-OX40 monoclonal antibody; lirilumab (IPH2102 / BMS-986015, Innate Pharma, Bristol-Myers Squibb), an anti-KIR monoclonal antibody; monalizumab (IPH2201, Innate Pharma, AstraZeneca) an anti-NKG2A monoclonal antibody; andecaliximab (GS-5745, Gilead Sciences), an anti-MMP9 antibody; MK-4166 (Merck & Co.), an anti-GITR monoclonal antibody.

[00324] Additional therapeutic agents that may be used in the present invention include glembatumumab brentuximab-monomethyl auristatin E (MMAE) (Celldex), an anti-NMB glycoprotein (GPNMB) antibody (CR011) linked to cytotoxic MMAE. GPNMB is a protein overexpressed by multiple tumor types associated with the ability of cancer cells to metastasis.

[00325] A compound of the present invention can also be used with advantage in combination with other antiproliferative compounds. Such antiproliferative compounds include, but are not limited to, checkpoint inhibitors; aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active compounds; alkylating compounds; histone deacetylase inhibitors; compounds that induce cellular differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; antineoplastic antimetabolites; platinum compounds; compounds targeting / decreasing a protein or lipid kinase activity and other anti-angiogenic compounds; compounds that target, reduce or inhibit the activity of a protein or lipid phosphatase; gonadorelin agonists; anti-androgens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of oncogenic Ras isoforms; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematological malignancies; compounds that target, 148 IF-2019-53902052-APN-ANP#INPI Page 148 of 423 reduce or inhibit the activity of Flt-3; Hsp90 inhibitors, such as 17-AAG (17allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17desmethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 from Conforma Therapeutics; temozolomide (Temodal®); kinesin spindle protein inhibitors, such as SB715992 or SB743921 from GlaxoSmithKline, or pentamidine / chlorpromazine from CombinatoRx; MEK inhibitors such as ARRY142886 from BioPharma matrix, AZD6244 from AstraZeneca, PD181461 from Pfizer and leucovorin.

[00326] The term "checkpoint inhibitor", as used herein, refers to agents useful in preventing cancer cells from avoiding the patient's immune system. One of the main mechanisms of subversion Anti-tumor immunity is known as “T cell depletion,” which results from chronic exposure to antigens that has led to the downregulation of inhibitory receptors. These inhibitory receptors serve as immune checkpoints to prevent uncontrolled immune reactions.

[00327] PD-1 receptors and co-inhibitors such as cytotoxic T lymphocyte antigen 4 (CTLA-4, B and T Lymphocyte Attenuator (BTLA; CD272), T Cell Immunoglobulin and Mucin Domain-3 (Tim -3), Lymphocyte Activation Gene-3 (LAG-3; CD223), and others are often called checkpoint regulators. These act as molecular “gatekeepers” that allow extracellular information to dictate cell cycle progression. and other intracellular signaling processes must proceed.

[00328] In one aspect, the checkpoint inhibitor is a biological therapeutic or small molecule. In another aspect, the checkpoint inhibitor is a monoclonal antibody, a humanized antibody, a fully human antibody, a fusion protein, or a combination thereof. In a further aspect, the checkpoint inhibitor inhibits a checkpoint protein selected from CTLA-4, PDLL, PDL2, PDL, B7-H3, B7-H4, BTLA, HVEM, TIM3, Gal9, LAG3, VISTA, KIR, 2B4, CD 160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or a combination thereof. In a further aspect, the checkpoint inhibitor interacts with a ligand of a checkpoint protein selected from CTLA-4, PDLL, PDL2, PDL, B7-H3, B7-H4, BTLA, HVEM, TIM3, Gal9, LAG3, VISTA, KIR, 2B4, CD 160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligands or a 149 IF-2019-53902052-APN-ANP#INPI Page 149 of 423 combination of them. In one aspect, the checkpoint inhibitor is an immunostimulatory agent, a T cell growth factor, an interleukin, an antibody, a vaccine, or a combination thereof. In a further aspect, the interleukin is IL-7 or IL-15. In a specific aspect, interleukin is glycosylated IL-7. In a further aspect, the vaccine is a dendritic cell (DC) vaccine.

[00329] Checkpoint inhibitors include any agent that blocks or inhibits in a statistically significant manner inhibitory pathways of the immune system. Such inhibitors may include small molecule inhibitors or may include antibodies, or antigen-binding fragments thereof, that bind and block or inhibit immune checkpoint receptors or antibodies that bind and block or inhibit receptor ligands. immune checkpoint. Illustrative checkpoint molecules that can be targeted for blockade or inhibition include, but are not limited to, CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, Gal9, LAG3 , TIM3, VISTA, KIR , 2B4 (belongs to the CD2 family of molecules and is expressed on all NK, γδ, and memory CD8+(αβ) T cells), CD160 (also called BY55), CGEN15049, CHK 1 and CHK2 kinases , A2aR, and several B-7 family ligands. B7 family ligands include, but are not limited to, B7-1, B7-2, B7-DC, B7-H1, H2-B7, B7H3, H4-B7, B7-H5, H6, and B7-B7- H7. Checkpoint inhibitors include antibodies, or antigen-binding fragments thereof, other binding proteins, biological therapeutic agents, or small molecules, which bind and block or inhibit the activity of one or more of CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3, Gal9, LAG3, VISTA, KIR, 2B4, CD 160 and CGEN-15049. Illustrative immune checkpoint inhibitors include tremelimumab (CTLA-4 blocking antibody), anti-OX40, PD-L1 monoclonal antibody (Anti-B7-Hl; MEDI4736), MK-3475 (PD-1 blocker), Nivolumab ( anti-PDL antibody), CT-011 (anti-PDL antibody), BY55 monoclonal antibody, AMP224 (anti-PDLL antibody), BMS-936559 (anti-PDLL antibody), MPLDL3280A (anti-PDLL antibody), MSB0010718C (anti-PDLL antibody) -PDLL), and ipilimumab (anti-CTLA-4 checkpoint inhibitor). Checkpoint protein ligands include, but are not limited to, PD-L1, PD-L2, B7-H3, B7-H4, CD28, CD86 and TIM-3. 150 IF-2019-53902052-APN-ANP#INPI Page 150 of 423

[00330] In certain embodiments, the immune checkpoint inhibitor is selected from a PD-1 antagonist, a PD-L1 antagonist, and a CTLA-4 antagonist. In some embodiments, the checkpoint inhibitor is selected from the group consisting of nivolumab (Opdivo®), ipilimumab (Yervoy®), and pembrolizumab (Keytruda®).

[00331] In some embodiments, the checkpoint inhibitor is selected from the group consisting of lambrolizumab (MK-3475), nivolumab (BMS-936558), pidilizumab (CT-011), AMP-224, MDX-1105, MEDI4736 , MPDL3280A, BMS-936559, ipilimumab, lirlumab, IPH2101, pembrolizumab (Keytruda®), and tremelimumab.

[00332] The term "aromatase inhibitor" as used herein refers to a compound that inhibits the production of estrogens, for example, the conversion of the substrates androstenedione and testosterone to premiere and estradiol, respectively. The term includes, but is not limited to, steroids, especially atamestane, exemestane and formestane and, in particular, non-steroids, especially aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole and letrozole. marketed under the trade name Aromasin™. Formestane is marketed under the trade name Lentaron™. Fadrozol is marketed under the trade name Afema™. Aminoglutethimide is marketed under the trade name Orimeten™. A combination of the invention comprising a chemotherapeutic agent that is an aromatase inhibitor is particularly useful for the treatment of hormone receptor positive tumors, such as breast tumors.

[00333] The term antiestrogen as used herein refers to a compound that antagonizes the effect of estrogens at the estrogen receptor level. The term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride. Tamoxifen is marketed under the trade name Nolvadex™. Raloxifene hydrochloride is marketed under the trade name Evista™. Fulvestrant may be administered under the brand name Faslodex™. A combination of the invention comprising a chemotherapeutic agent that is an antiestrogen is particularly useful for the treatment of estrogen receptor positive tumors, such as breast tumors. 151 IF-2019-53902052-APN-ANP#INPI Page 151 of 423

[00334] The term anti-androgen as used herein refers to any substance that is capable of inhibiting the biological effects of androgenic hormones and includes, but is not limited to, bicalutamide (Casodex™). The term gonadorelin agonist as used herein includes, but is not limited to, abarelix, goserelin and goserelin acetate. Goserelin may be administered under the brand name Zoladex™.

[00335] The term topoisomerase 1 inhibitor as used herein includes, but is not limited to, topotecan, gimatecan, irinotecan, camptothecian and its analogues, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148. Irinotecan may be administered, for example, in the form in which it is marketed, for example, under the trademark Camptosar™. Topotecan is marketed under the trade name Hycamptin™.

[00336] The term Π-topoisomerase inhibitor as used herein includes, but is not limited to, anthracyclines such as doxorubicin (including liposomal formulation, such as Caelyx™), daunorubicin, epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophyllotoxins etoposide and teniposide. Etoposide is marketed under the trade name Etopophos™. Teniposide is marketed under the trade name VM 26-Bristol. Doxorubicin is marketed under the trade name Acriblastin™ or Adriamycin™. Epirubicin is marketed under the trade name Farmorubicin™. Idarubicin is marketed under the trade name Zavedos™. Mitoxantrone is marketed under the trade name Novantron.

[00337] The term microtubule active agent refers to microtubule stabilizing, microtubule destabilizing and microtubule polymerization inhibitor compounds including, but not limited to, taxanes, such as paclitaxel and docetaxel; vinca alkaloids, such as vinblastine or vinblastine sulfate, vincristine or vincristine sulfate, and vinorelbine; discodermolidas; colchicine and epothilones and derivatives thereof. Paclitaxel is marketed under the trade name Taxol™. Docetaxel is marketed under the trade name Taxotere™. Vinblastine sulfate is marketed under the trade name Vinblastina R.P™. Vincristine sulfate is marketed under the trade name Farmistin™. 152 IF-2019-53902052-APN-ANP#INPI Page 152 of 423

[00338] The term alkylating agent as used herein includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan or nitrosourea (BCNU or Gliadel). Cyclophosphamide is marketed under the trade name Cyclostin™. Ifosfamide is marketed under the trade name Holoxan™.

[00339] The term histone deacetylase inhibitors or HDAC inhibitors refers to compounds that inhibit histone deacetylase and that possess antiproliferative activity. This includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).

[00340] The term antineoplastic antimetabolite includes, but is not limited to, 5fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds, such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folic acid antagonists such as pemetrexed. Capecitabine is marketed under the trade name Xeloda™. Gemcitabine is marketed under the trade name Gemzar™.

[00341] The term platinum compound as used herein includes, but is not limited to, carboplatin, cis-platinum, cisplatin and oxaliplatin. Carboplatin may be administered, for example, in the form as marketed, for example, under the trademark Carboplat™. Oxaliplatin may be administered, for example, in the form as marketed, for example, under the trademark Eloxatin™.

[00342] The term target compounds / decrease in a protein or lipid kinase activity; or a protein or lipid phosphatase activity, or more antiangiogenic compounds as used herein include, but are not limited to, protein tyrosine kinase and / or serine and / or threonine kinase inhibitors or kinase inhibitors of lipids, such as a) compounds that target, reduce or inhibit the activity of platelet-derived growth factor receptors (PDGFR), such as compounds that target, reduce or inhibit the activity of PDGFR, especially compounds that inhibit the PDGF receptor, such as a Nphenyl-2-pyrimidine-amine derivative, such as imatinib, SU101, SU6668 and GFB-111; b) compounds that target, reduce or inhibit the activity of fibroblast growth factor receptors (FGFR); c) compounds that target, reduce or inhibit the activity of the insulin-like growth factor I receptor (IGF-IR), such as compounds that 153 IF-2019-53902052-APN-ANP#INPI Page 153 of 423 target, reduce or inhibit the activity of IGF-1R, especially compounds that inhibit the kinase activity of the IGF-I receptor, or antibodies that target the extracellular domain of the IGF-I receptor or its factors of growth; d) compounds that target, reduce or inhibit the activity of the Trk receptor tyrosine kinase family, or ephrin B4 inhibitors; e) compounds that target, reduce or inhibit the activity of the Axi family of receptor tyrosine kinases; f) compounds that target, reduce or inhibit the activity of Ret receptor tyrosine kinase; g) compounds that target, reduce or inhibit the activity of the Kit / SCFR tyrosine kinase receptor, such as imatinib; h) compounds that target, reduce or inhibit the activity of C-kit tyrosine receptor kinases, which are part of the PDGFR family, such as compounds that target, reduce or inhibit the activity of the receptor family C-Kit tyrosine kinase, especially compounds that inhibit the C-Kit receptor, such as imatinib; i) compounds that target, reduce or inhibit the activity of c-Abl family members, their fusion gene products (e.g. BCR-Abl kinase) and mutants, such as compounds that target, reduce or inhibit the activity of cAbl family members and their gene fusion products, such as an N-phenyl-2-pyrimidinamine derivative, such as imatinib or nilotinib (AMN107); PD180970; AG957; NSC 680410; PD173955 from ParkeDavis; or dasatinib (BMS-354825); j) compounds that target, reduce or inhibit the activity of members of protein kinase C (PKC) and the Raf family of serine / threonine kinases, members of the MEK family, SRC, JAK / pan-JAK, FAK, PDK1 , PKB / Akt, Ras / MAPK, PI3K, SYK, TYK2, BTK and TEC, and / or members of the cyclin-dependent kinase (CDK) family, including staurosporine derivatives, such as midostaurin; examples of other compounds include UCN-01, safingol, BAY 43-9006, Bryostatin 1, Perifosine; llmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531 / LY379196; isocinoline compounds; FTI; PD184352 or QAN697 (a P13K inhibitor) or AT7519 (a CDK inhibitor); k) compounds that target, reduce or inhibit the activity of protein-tyrosine kinase inhibitors, such as compounds that target, reduce or inhibit the activity of protein tyrosine kinase inhibitors include imatinib mesylate (Gleevec ™) or tyrfostina such as Tirfostina A23 / RG-50810; GA 99; Tyrphostin AG 213; Tyrphostin AG 1748; Tyrphostin AG 490; Tyrphostin B44; Tyrphostin B44 enantiomer (+); Tyrphostin AG 555; AG 494; Tyrphostine AG 154 IF-2019-53902052-APN-ANP#INPI Page 154 of 423 556, AG957 and adafostine (4-{[(2,5-dihydroxyphenyl)methyl]amino}benzoic acid adamantyl ester; NSC 680410, adafostine); 1) compounds that target, reduce or inhibit the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFR1 ErbB2, ErbB3, ErbB4 as homo- or heterodimers) and their mutants, such as compounds that target , reduce or inhibit the activity of the epidermal growth factor receptor family are especially compounds, proteins or antibodies that inhibit members of the EGF receptor tyrosine kinase family, such as the EGF receptor, ErbB2, ErbB3 and ErbB4 or are bind EGF or EGF-related ligands, CP 358774, ZD 1839, ZM 105180; trastuzumab (Herceptin™), cetuximab (Erbitux™), Iressa, Tarceva, OS1-774, Cl-1033, EKB-569, GW-2016, ELI, E2.4, E2.5, E6.2, E6. 4, E2.ll, E6.3 or E7.6.3, and 7H-pyrrolo[2,3-d]pyrimidine; m) compounds that target, reduce or inhibit the activity of the c-Met receptor, such as compounds that target, reduce or inhibit the activity of c-Met, especially compounds that inhibit the kinase activity of the c-Met receptor, or antibodies that target the extracellular domain of c-Met or bind HGF, n) compounds that target, reduce or inhibit the kinase activity of one or more members of the JAK family (JAK1 / JAK2 / JAK3 / TYK2 and / or panJAK), including, but not limited to, PRT-062070, SB-1578, baricitinib, pacritinib, momelotinib, VX-509, AZD-1480, TG-101 348, tofacitinib, and ruxolitinib; o) compounds that target, reduce or inhibit the kinase activity of PI3 kinase (PI3K), including, but not limited to, ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK- 474, buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib; and q) compounds that target, reduce or inhibit the signaling effects of the hedgehog protein (Hh) or smoothed (SMO) receptor pathways, including, but not limited to, cyclopamine, vismodegib, itraconazole, erismodegib, and 1PI- 926 (saridegib).

[00343] The term "PI3K inhibitor" as used herein includes, but is not limited to, compounds that have inhibitory activity against one or more enzymes in the phosphatidylinositol-3-kinase family, including, but not limited to a, PI3Ka, ΡΙ3Κγ, ΡΙ3Κδ, ΡΙ3Κβ, PI3K-C2a, ΡΙ3Κ-Ο2β, PI3K-C2y, Vps34, ρ110-α, pl 10-β, pl 10-γ, pl 10-δ, ρ85-α, ρ85-β , ρ55-γ, ρΐ50, plOl, and ρ87 Examples of PI3K inhibitors useful in this invention include, but are not limited to, ATU-027, SF-1126, DS-7423, PBI-05204, 155 IF-2019-53902052-APN-ANP#INPI Page 155 of 423 GSK-2,126,458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL147, XL-765, and idelalisib.

[00344] The term "Bcl-2 inhibitor" as used herein includes, but is not limited to, compounds that have inhibitory activity against B cell lymphoma 2 (Bcl-2) proteins, including, but not limited to, ABT-199, ABT-731, ABT737, apogosipol, Ascenta pan-Bcl-2 inhibitors, curcumin (and analogs thereof), dual Bcl-2 / Bcl-xL inhibitors (Infinity Pharmaceuticals / Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and analogues thereof; see W02008118802), navitoclax (and analogues thereof, see US7390799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and analogues thereof , see W02004106328), S-001 (Gloria Pharmaceuticals), TW series compounds (Univ, of Michigan), and venetoclax. In some embodiments, the Bcl-2 inhibitor is a small molecule therapeutic. Bcl-2 inhibitor is a peptidomimetic.

[00345] The term "BTK inhibitor" as used herein includes, but is not limited to, compounds that have inhibitory activity against Bruton's Tyrosine Kinase (BTK), including, but not limited to, AVL- 292 and ibrutinib.

[00346] The term "SYK inhibitor" as used herein includes, but is not limited to, compounds that have inhibitory activity against spleen tyrosine kinase (SYK), including, but not limited to, PRT-062070 , R-343, R-333, Excellair, PRT-062607 and fostamatinib.

[00347] Other examples of BTK inhibitor compounds, and conditions treatable by said compounds in combination with the compounds of this invention can be found in W02008039218 and WO2011090760, all of which are incorporated herein by reference.

[00348] Other examples of SYK inhibitor compounds, and conditions treatable by such compounds in combination with the compounds of this invention can be found in W02003063794, W02005007623, W02006078846 and, all of which are incorporated herein by reference.

[00349] Other examples of PI3K inhibitor compounds, and conditions treatable by said compounds in combination with the compounds of this invention can be found in W02004019973, W02004089925, W02007016176, US8138347, 156 IF-2019-53902052-APN-ANP#INPI Page 156 of 423 W02002088112, W02007084786, W02007129161, W02006122806, W02005113554 and W02007044729, all of which are incorporated herein by reference.

[00350] Other examples of JAK inhibitor compounds, and conditions treatable by said compounds in combination with the compounds of this invention can be found in W02009114512, W02008109943, W02007053452, W02000142246, W02007070514 and, all of which are incorporated herein as reference.

[00351] Other anti-angiogenic compounds include compounds that have another mechanism for their activity, for example, not related to protein or lipid kinase inhibition, for example, thalidomide (Thalomid™) and TNP-470.

[00352] Examples of proteasome inhibitors useful for use in combination with compounds of the invention include, but are not limited to bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP18770 , and MLN9708. 100353] Compounds that target, reduce or inhibit the activity of a protein or lipid phosphatase are, for example, inhibitors of phosphatase 1, phosphatase 2A, or CDC25, such as okadaic acid or a derivative thereof.

[00354] Compounds that induce cellular differentiation processes include, but are not limited to, retinoic acid, α-γ- or δ-tocopherol or α-γ- or δ-tocotrienol.

[00355] The term cyclooxygenase inhibitor as used herein includes, but is not limited to, Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives, such as celecoxib (Celebrex™) , rofecoxib (Vioxx™), etoricoxib, valdecoxib or a 5-alkyl-2-arylaminophenylacetic acid, such as 5-methyl-2-(2'chloro-6'-fluoroanilino)phenylacetic acid, lumiracoxib.

[00356] The term bisphosphonates, as used herein, includes, but is not limited to, etridonic, clodronic, tiludronic, pamidronic, alendronic, ibadronic, risedronic and zoledronic acid. Etridonic acid is marketed under the trade name Didronel™. Clodronic acid is marketed under the trade name Bonefos™. Tiludronic acid is marketed under the trade name Skelid™. Pamidronic acid is marketed under the trade name Aredia™. Alendronic acid is marketed under the trade name Fosamax™. Ibandronic acid is marketed under the trade name Bondranat™. Risedronic acid is marketed 157 IF-2019-53902052-APN-ANP#INPI Page 157 of 423 under the trade name Actonel™. Zoledronic acid is marketed under the trade name Zometa™. The term mTOR inhibitors refers to compounds that inhibit the mammalian target of rapamycin (mTOR) and have antiproliferative activity such as sirolimus (Rapamune®), everolimus (Certican™), CCI-779 and ABT578.

[00357] The term heparanase inhibitor as used herein refers to compounds that target, reduce or inhibit the degradation of heparin sulfate. The term includes, but is not limited to, PI-88. The term biological response modifier as used herein refers to a lymphokine or interferons.

[00358] The term inhibitor of oncogenic Ras isoforms, such as Η-Ras, KRas, or N-Ras, as used herein, refers to compounds that target, reduce or inhibit the oncogenic activity of Ras; for example, a famesyl transferase inhibitor such as L-744832, DK8G557 or R115777 (Zamestra™). The term telomerase inhibitor as used herein refers to compounds that target, reduce or inhibit the activity of telomerase. Compounds that target, reduce or inhibit telomerase activity are especially compounds that inhibit the telomerase receptor, such as telomestatin.

[00359] The term methionine aminopeptidase inhibitor as used herein refers to compounds that target, reduce or inhibit the activity of methionine aminopeptidase. Compounds that target, reduce or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamide or a derivative thereof.

[00360] The term proteasome inhibitor as used herein refers to compounds that target, reduce or inhibit the activity of the proteasome. Compounds that target, reduce or inhibit proteasome activity include, but are not limited to, Bortezomib (Velcade™) and MLN 341.

[00361] The term matrix metalloproteinase inhibitor or (MMP inhibitor) as used herein includes, but is not limited to, peptidomimetic and non-peptidomimetic collagen inhibitors, tetracycline derivatives, e.g. of peptidomimetic batimastat hydroxamate and its analogue marimastat 158 IF-2019-53902052-APN-ANP#INPI Page 158 of 423 orally bioavailable (BB-2516), prinomastat (AG3340), metastat (NSC 683551) BMS279251, BAY 12-9566, TAA211, MMI270B or AAJ996.

[00362] The term compounds used in the treatment of hematological malignancies as used herein includes, but is not limited to, FMS-like tyrosine kinase inhibitors, which are compounds that target, reduce or inhibit the FMS-like tyrosine kinase receptor (Flt3R) activity; interferon, Ι-β-D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitors, which are compounds that target, reduce, or inhibit anaplastic lymphoma kinase.

[00363] Compounds that target, reduce or inhibit the activity of FMS-like tyrosine kinase receptors (Flt-3R) are especially compounds, proteins or antibodies that inhibit members of the Flt3R receptor kinase family, such as PKC412, midostaurin, a staurosporine derivative, SU11248 and MLN518.

[00364] The term HSP90 inhibitors as used herein includes, but is not limited to, compounds that target, reduce or inhibit the intrinsic ATPase activity of HSP90; degrading, targeting, reducing or inhibiting the corresponding proteins through the ubiquitin proteasome pathway. Compounds that target, reduce or inhibit the intrinsic ATPase activity of HSP90 are especially compounds, proteins or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino, 17-demethoxygeldanamycin (17AAG), a geldanamycin derivative; other compounds related to geldanamycin; radicicol and HDAC inhibitors.

[00365] The term antiproliferative antibodies as used herein includes, but is not limited to, trastuzumab (Herceptin™), Trastuzumab-DMl, Erbitux, bevacizumab (Avastin™), rituximab (Rituxan®), PRO64553 (anti -CD40) and 2C4 antibody. Antibodies are understood as intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least 2 intact antibodies, and antibody fragments provided that they exhibit the desired biological activity.

[00366] For the treatment of acute myeloid leukemia (AML), the compounds of the present invention can be used in combination with standard leukemia therapies, especially in combination with therapies used for the treatment of AML. In 159 IF-2019-53902052-APN-ANP#INPI Page 159 of 423 In particular, the compounds of the present invention can be administered in combination with, for example, famesyl transferase inhibitors and / or other drugs useful for the treatment of AML, such as Daunorubicin, Adriamycin, Ara-C, VP- 16, Teniposide, Mitoxantrone, Idarubicin, Carboplatin and PKC412.

[00367] Other anti-leukemic compounds include, for example, Ara-C, a pyrimidine analog, which is the 2'-alpha-hydroxy ribose (arabinoside) derived from deoxycytidine. Also included are the purine analogue of hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate. Compounds that target, reduce, or inhibit the activity of histone deacetylase (HDAC) inhibitors such as sodium butyrate and suberoylanilide hydroxamic acid (SAHA) inhibit the activity of enzymes known as histone deacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), Trichostatin A and compounds disclosed in US 6,552,065, including, but not limited to, N-hydroxy-3-[4-[[[2-(2 -methyl-lH-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide, or a pharmaceutically acceptable salt thereof and N-hydroxy-3-[4-[(2-hydroxyethyl){2-(lH-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2propenamide, or a pharmaceutically acceptable salt thereof, especially the lactate salt. Somatostatin receptor antagonists as used herein refer to compounds that target, treat or inhibit the somatostatin receptor, such as octreotide, and SOM230. Harmful tumor cell approaches refer to approaches such as ionizing radiation. The term ionizing radiation mentioned above and below means ionizing radiation that is produced by electromagnetic rays (such as X-rays and gamma rays) or particles (such as alpha and beta particles). Ionizing radiation is provided in, but not limited to, radiation therapy and is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., Eds., 4th Ed., Vol. 248-275 (1993).

[00368] Also included are EDG binders and ribonucleotide reductase inhibitors. The term "EDG binders" as used herein refers to a class of immunosuppressants that modulate lymphocyte recirculation, such as FTY720. The term "ribonucleotide reductase inhibitors" refers to pyrimidine nucleoside analogues. or purine including, but not limited to, fludarabine and / or cytosine 160 IF-2019-53902052-APN-ANP#INPI Page 160 of 423 arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C against ALL) and / or pentostatin. Ribonucleotide reductase inhibitors are especially derivatives of hydroxyurea or 2-hydroxy-lHisoindol-l,3-dione. ·

[00369] Also particularly included are those VEGF monoclonal compounds, proteins or antibodies, such as l-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, l-(4) succinate -chloroanilino)-4-(4pyridylmethyl)phthalazine; Angiostatin™; Endostatin™; anthranilic acid amides; ZD4190; Zdg474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies, such as rhuMAb and RHUFab, VEGF aptamer such as Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGl antibodies, Angiozyme (RPI 4610) and Bevacizumab (Avastin™).

[00370] Photodynamic therapy as used herein refers to therapy that uses certain chemicals known as photosensitizing compounds to treat or prevent cancers. Examples of photodynamic therapy include treatment with compounds, such as Visudyne™ and porfimer sodium.

[00371] Angiostatic steroids as used herein refer to compounds that block or inhibit angiogenesis, such as, for example, anecortave, triamcinolone, hydrocortisone, 11-a-epihydrocotisol, cortexolone, 17αhydroxyprogesterone, corticosterone, deoxycorticosterone , testosterone, premiere and dexamethasone.

[00372] Corticosteroid-containing implants refer to compounds, such as fluocinolone and dexamethasone.

[00373] Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormonal compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or miscellaneous compounds or compounds with another or unknown mechanism of action.

[00374] The structure of active compounds identified by code numbers, generic or trade names can be taken from the current edition of the compendium 161 IF-2019-53902052-APN-ANP#INPI Page 161 of 423 standard The Merck Index or databases, for example, International Patents (for example, IMS World Publications).

[00375] A compound of the present invention can also be used in combination with known therapeutic processes, for example, the administration of hormones or radiation. In certain embodiments, a provided compound is used as a radiosensitizer, especially for the treatment of tumors that exhibit poor sensitivity to radiotherapy.

[00376] A compound of the present invention may be administered alone or in combination with one or more other therapeutic compounds, possible combination therapy taking the form of fixed combinations or the administration of a compound of the invention and one or more other therapeutic compounds escalated or administered independently of each other, or the combined administration of fixed combinations and one or more other therapeutic compounds. A compound of the present invention may further or in addition be administered especially for tumor therapy in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination thereof. Long-term therapy is equally possible since it is adjuvant therapy in the context of other treatment strategies, as described above. Other possible treatments are therapies to maintain the patient's condition after tumor regression, or even chemopreventive therapy, for example, in patients at risk.

[00377] Those additional agents may be administered separately from a composition containing the compound of the invention, as part of a multiple dosage regimen. Alternatively, such agents may be part of a single dosage form, mixed together with a compound of this invention in a single composition. If administered as part of a multiple dosage regimen, the two active agents may be presented simultaneously, sequentially, or within a time period of each other typically within five hours of each other.

[00378] As used herein, the term "combination", "combined", and related terms refers to the simultaneous or sequential administration of the therapeutic agents according to this invention. For example, a compound of the present invention can be administered with another therapeutic agent. 162 IF-2019-53902052-APN-ANP#INPI Page 162 of 423 simultaneously or sequentially in separate unit dosage forms or together. in a single unit dosage form. Accordingly, the present invention provides a single unit dosage form comprising a compound of the present invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

[00379] The amount of a compound of the invention and additional therapeutic agent (in those compositions comprising an additional therapeutic agent as described above) that can be combined with the carrier materials to produce a single dosage form will vary depending on the host. treaty and the particular mode of administration. Preferably, the compositions of this invention should be formulated so that a dosage between 0.01 - 100 mg / kg body weight / day of a compound of the invention can be administered.

[00380] In those compositions comprising an additional therapeutic agent, that additional therapeutic agent and the compound of this invention may act synergistically. Therefore, the amount of additional therapeutic agent in such compositions will be less than that required in a monotherapy that uses only the therapeutic agent. In such compositions a dosage between 0.01 and 1000 μg / kg body weight / day of the additional therapeutic agent can be administered.

[00381] The amount of additional therapeutic agent present in the compositions of this invention will not be greater than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in the compositions disclosed herein will vary from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

[00382] The compounds of this invention, or pharmaceutical compositions thereof, may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Vascular stents, for example, have been used to overcome restenosis (renarrowing of the vessel wall after injury). However, patients who use stents or other implantable devices are at risk of clot formation or 163 IF-2019-53902052-APN-ANP#INPI Page 163 of 423 platelet activation. These undesirable effects can be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor. Implantable devices coated with a compound of this invention are another embodiment of the present invention. EXEMPLIFICATION General Synthetic Methods

[00383] The following examples are intended to illustrate the invention and should not be construed as limitations thereof. Unless otherwise indicated, one or more tautomeric forms of the example compounds described below may be prepared in situ and / or isolated. All tautomeric forms of the example compounds described below should be considered disclosed. Temperatures are given in degrees Celsius. If nothing else is mentioned, all evaporations are carried out under reduced pressure, preferably between about 15 mm Hg and 100 mm Hg (= 20133 mbar). The structure of the final products, intermediates and starting materials is confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR, NMR. The abbreviations used are those conventional in the art.

[00384] All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents and catalysts used for the synthesis of the compounds of the present invention are commercially available or can be produced by organic synthesis methods known to those with experience in the technique (Houben-Weyl 4th Ed. 1952, Methods of Organic Synthesis, Thieme, Volume 21). Furthermore, the compounds of the present invention can be produced by organic synthesis methods known to those skilled in the art as shown in the following examples. Abbreviations equiv or eq: molar equivalents o / n: overnight TA: room temperature 164 IF-2019-53902052-APN-ANP#INPI Page 164 of 423 UV: ultraviolet HPLC: high pressure liquid chromatography Rt: retention time LCMS or LC-MS: liquid chromatography-mass spectrometry NMR: nuclear magnetic resonance CC: column chromatography TLC: thin layer chromatography sat: saturated ac: aqueous Ac: acetyl DCM: dichloromethane DCE: dichloroethane DEA: diethylamine DMF: dimethylformamide DMSO : dimethyl sulfoxide ACN or MeCN: acetonitrile DIPEA: diisopropylethylamine EA or EtOAc: ethyl acetate BINAP: (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene TEA: triethylamine THF: tetrahydrofuran TBS: tert-butyldimethylsilyl KHMDS: potassium hexamethyl disilylazide Tf: trifluoromethanesulfonate Ms: methanesulfonyl NBS: N-bromosuccinimide PE: petroleum ether TFA: trifluoroacetic acid FA: formic acid MMPP: magnesium monoperoxyphthalate 165 IF-2019-53902052-APN-ANP#INPI Page 165 of 423 HATU: l-[bis(dimethylamino)methylene]-l / / -l,2,3triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate Cy: cyclohexyl Tol: toluene DMP: Periodinano Dess-Martin IBX: 2-iodoxybenzoic acid PMB: p-methoxybenzyl SEM: [2-(trimethylsilyl)ethoxy]methyl XPhos or X-Phos: 2-dicyclohexylphosphino-2',4',6'-triisopropyl-biphenyl

[00385] General information: All evaporations were carried out under vacuum with a rotary evaporator. Analytical samples were dried under vacuum (1-5 mmHg) at RT. Thin layer chromatography (TLC) was performed on silica gel plates, the spots were visualized using UV light (214 and 254 nm). Purification by column and flash chromatography was performed using silica gel (200-300 mesh). Solvent systems are reported as volume mixtures. All 1H NMR spectra were recorded on a Bruker 400 spectrometer (400 MHz). 1H chemical shifts are reported in δ values ​​in parts per million (ppm) with the deuterated solvent as the internal standard. The data are presented as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, a = width, m = multiplet), coupling constant (Hz), integration (i.e. number of protons). LCMS spectra were obtained on an Agilent 1200 series 6110 or 6120 mass spectrometer with electrospray ionization and except where otherwise noted, the general LCMS condition is: Waters X Bridge Cl8 column (50 mm*4.6 mm*3 .5 pm), Flow Rate: 2.0 ml / min, column temperature: 40 °C. Example 1 Synthetic scheme 1: (i?)-7V-(3-(4-(2-amino-6-methylpyrimidin-4-yl)-l,4-oxazepan-3-yl)-4chlorophenyl)acetamide (6) 1- 10 and (S)- / V-(3-(4-(2-amino-6-methylpyrimidin-4-yl)-l,4oxazepan-3-yl)-4-chlorophenyl)acetamide (7) 1-15 166 IF-2019-53902052-APN-ANP#INPI Page 166 of 423 (a) mol 4A sieves, 2-chloro-5-nitrobenzaldehyde, CH2CI2; (b) 2,6-lutidine, Cu(OTf)2, hexafluoroisopropanol, CH2CI2; c) Boc2O, Et3N, THF; (d) zinc, NH4C1, 2% TPGS-750-M in water, 75 °C; (e) AcCl, Et3N, CH2CI2; (f) TFA, CH2CI2; (g) 2-amino-4-chloro-6methylpyrimidine, NMP, 150 °C; (h) SFC chiral separation Formation of (+ / -)-3-(2-chloro-5-nitrophenyl)-l,4-oxazepam (1)

[00386] To a solution of 3-(tributylstannylmethoxy)propan-l-amine (3.06 g, 8.09 mmol) in anhydrous dichloromethane (15 ml) was added 2-chloro-5-nitrobenzaldehyde (1.50 g, 8.08 mmol) followed by 4A molecular sieves. The mixture was stirred overnight at room temperature, filtered to remove sieves, and diluted with dichloromethane (75 ml). In a separate flask containing hexafluoroisopropanol (22 ml) 2,6lutidine (0.94 ml, 8.10 mmol) was added followed by Cu(OTf)2 (2.93 g, 8.10 mmol). The mixture was stirred for 1 hour and the imine solution prepared above was added in one portion. The reaction was stirred overnight at room temperature. The mixture was diluted with 150 ml of 2:1 saturated aqueous NaHCO3e ammonium hydroxide solution. After stirring for 20 minutes, the organic layer was separated and washed with saturated aqueous NaHCO3 solution, then with brine. The organic layer was passed through a phase separating funnel and concentrated in vacuo. on reverse phase silica gel using ISCO Column - 100 gram cl8-aq - run with 0.2% formic acid / H2O and 0.2% formic acid / CH3CN to give 700 mg of the desired product as residue orange-red color that was used without further purification: 1H(¿76 - DMSO) δ 8.48 (d, J= 2.9 Hz, 1H), 8.11 (dd, J= 8.8, 2, 9 Hz, 1H), 7.73 (d, 1H), 4.38 - 4.21 (m, 1H), 3.90 - 3.66 (m, 3H), 3.34 (dd, J= 12 ,4, 8.5Hz, 167 IF-2019-53902052-APN-ANP#INPI Page 167 of 423 1H), 3.18 - 2.86 (m, 2H), 1.95 - 1.84 (m, 2H); ES1-MS m / z calc. 256.06146, found 257.13 (M+l)+; Retention time: 0.52 minutes. . Formation of (+ / -)-tert-butyl 3-(2-chloro-5-nitrophenyl)-l,4-oxazepan-4-carboxylate (2)

[00387] To a mixture of 3-(2-chloro-5-nitro-phenyl)-l,4-oxazepan (0.50 g, 1.93 mmol) and triethylamine (0.27 ml, 1.94 mmol) In THF (7 ml) di-tert-butyldicarbonate (0.42 g, 1.93 mmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted in saturated aqueous NH4C1 solution and extracted with dichloromethane. The organic phase was passed through a phase separating funnel and concentrated in vacuo. The crude residue was purified by silica gel chromatography using a 40 g ISCO Gold column (0-20% EtOAc / CFLCb gradient) to give 376 mg of the desired product as an off-white solid: ES1-MS m / z cale. 356.1139, found 356, 82 (M+l)+; Retention time: 0.92 minutes. Formation of tere-butyl 3-(5-amino-2-chlorophenyl)-l,4-oxazepan-4-carboxylate (3)

[00388] A suspension of 3-(2-chloro-5-nitro-phenyl)- Terebutyl l,4-oxazepan-4-carboxylate (1.98 g, 5.55 mmol), NH4Cl (1.20 g, 22.43 mmol) and zinc (2.00 g, 30.58 mmol) were stirred. in 2% TPGS-750-M in water (50 ml). The reaction mixture was stirred vigorously and heated at 750C for 23 hours. The mixture was diluted in a saturated aqueous NaHCOa solution and extracted with dichloromethane. The organic phase was dried (MgSC^), filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography with 80 g ISCO column using 10-50% (20% MeOH-CI^Ch / CFLCb gradient) to give 2 g of desired product as a light yellow solid. which was used without further purification; ESI-MS m / z cale. 356.1139, found 227.14 (M-Boc)+; Retention time: 0.64 minutes. Formation of (+ / -)- / ercbutyl 3-(5-acetamido-2-chlorophenyl)-l,4-oxazepan-4-carboxylate (4)

[00389] To a solution of tere-butyl 3-(5-amino-2-chloro-phenyl)-l,4-oxazepan-4-carboxylate, 3, (0.25 g, 0.69 mmol) and triethylamine (0.15 ml, 1.04 mmol) in dichloromethane (3 ml) a solution of acetyl chloride (0.05 ml, 0.75 mmol) was added dropwise in 168 IF-2019-53902052-APN-ANP#INPI Page 168 of 423 dichloromethane (1 ml). The reaction mixture was stirred at room temperature for 1 hour. The mixture was quenched by addition of saturated aqueous NaHCOa solution and extracted twice with dichloromethane. The combined organic phases were filtered through a phase separator and concentrated in vacuo. The crude residue was purified by silica gel chromatography with a 40 g ISCO GOLD column using 0-30% gradient (20% MeOH-CH2Cl2 / CH2Cl2) to provide 185 mg of a white solid, cleaned by LCMS ESI- MS m / z cale. 368.15, found 369.42 (M+l)+; Retention time: 0.8 minutes. Formation of (+ / -)-7V-(4-cIoro-3-(l,4-oxazepan-3-yl)phenyl)acetamide (5)

[00390] To a solution of tere-butyl 3-(5-acetamido-2-chloro-phenyl)-l,4-oxazepan-4-carboxylate, 4, (0.18 g, 0.47 mmol) in dichloromethane (2 ml) trifluoroacetic acid (1.5 ml) was added. The reaction mixture was stirred at room temperature for 30 minutes and then concentrated in vacuo. The residue was diluted with dichloromethane and neutralized with saturated aqueous NaHCO3 solution. The organic phase was passed through a phase separator and the resulting filtrate was concentrated in vacuo to provide 70 mg of product as a white solid which was used without further purification: ESI-MS m / z cale. 268.09, found 269.20 (M+l)+; Retention time: 0.5 minutes; 1HNMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 7.72 (d, J= 2.6 Hz, 1H), 7.64 (dd, J= 8.7, 2.7 Hz, 1H), 7.29 (d, J= 8.7 Hz, 1H), 4.18 (dd, J= 9.2, 3.1 Hz, 1H), 3.90 - 3.73 (m, 2H), 3.67 (dt, J= 11.9, 6.5 Hz, 1H), 3.20 (dd, J= 12.2, 9.1 Hz, 1H), 3.07 (s, 1H), 2.94 - 2.80 (m, 1H), 2.70 - 2.57 (m, 1H), 2.02 (s, 3H), 1.91 -1.80 (m, 2H). Formation of 7V-(3-(4-(2-amino-6-methylpyrimidin-4-yl)-l,4-oxazepan-3-yl)-4chlorophenyljacetamide (R)-isomer (6) and (S)-isomer (7)

[00391] To a solution of A-[4-chloro-3-(l,4-oxazepan-3-yl)phenyl]acetamide, 5, (0.067 g, 0.224 mmol) in NMP (3 ml) was added 4- chloro-6 methyl-pyrimidin-2-amine (0.040 g, 0.279 mmol). The reaction mixture was heated at 1500C for 18 hours. The mixture was cooled to room temperature and loaded directly onto a 50 g ISCO cl8-aq column and purified by reverse phase by running with 0.1% TFA / H2O and 0.1% TFA / CH3CN. The pure fractions were concentrated in vacuo. The residue was diluted with dichloromethane, 169 IF-2019-53902052-APN-ANP#INPI Page 169 of 423 neutralized with saturated aqueous NaHCCh solution. The organic phase was passed through a phase separator and concentrated in vacuo to provide 69 mg of light orange solid: high temperature (360 K) 1H (pho-DMSO) δ 9.75 (s, 1H), 7 .72 - 7.39 (m, 3H), 7.43 - 7.18 (m, 1H), 5.64 - 5.19 (m, 3H), 4.85 - 4.45 (m, 1H) , 4.31 - 4.07 (m, 1H), 4.04 - 3.84 (m, 1H), 3.80 - 3.28 (m, 3H), 3.02 (s, 3H), 2 .00 (s, 3H), 1.91 - 1.72 (m, 2H); ESI-MS m / z cale. 375.15, found 376.31 (M+l)+; Retention time: 0.56 minutes. The racemic mixture was subjected to purification by chiral SFC to obtain the individual enantiomers.

[00392] Peak A (7?)- / V-[3-[4-(2-amino-6-methyl-pyrimidin-4-yl)-l,4-oxazepan-3-yl]-4chloro-phenyl] acetamide: high temperature (360 K) 1H NMR (400 MHz, DMSO-¿6) δ 9.70 (s, 1H), 7.56 (dd, J= 8.6, 2.6 Hz, 1H), 7 .50 (d, J= 2.6 Hz, 1H), 7.31 (d, J = 8.7 Hz, 1H, 5.55 (s, 1H), 5.44 (s, 2H), 5, 34 (s, 1H), 4.67 (d, J = 15.1 Hz, 1H), 4.13 (dd, J = 13.5, 5.0 Hz, 1H), 3.92 - 3.85 (m, 1H), 3.67 (dd, J= 13.5, 10.2 Hz, 1H), 3.63 - 3.49 (m, 1H), 3.40 (q, J = 7.0 Hz, 1H), 1.99 (d, J = 4.4 Hz, 6H), 1.84 - 1.73 (m, 2H); (M+1)+; Retention time: 0.56 minutes.

[00393] Peak B (A)- / V-[3-[4-(2-amino-6-methyl-pyrimidin-4-yl)-l,4-oxazepan-3-yl]-4chloro-phenyl]acetamide : high temperature (360 K) 1H NMR (400 MHz, DMSO-í / 6) δ 9.71 (s, 1H), 7.56 (dd, J= 8.6, 2.6 Hz, 1H), 7 .50 (d, J= 2.6 Hz, 1H), 7.31 (d, J= 8.7 Hz, 1H, 5.55 (s, 1H), 5.44 (s, 2H), 5, 34 (s, 1H), 4.67 (d, J= 15.1 Hz, 1H), 4.13 (dd, J= 13.5, 5.0 Hz, 1H), 3.95 - 3.86 (m, 1H), 3.67 (dd, J= 13.5, 10.2 Hz, 1H), 3.63 - 3.49 (m, 1H), 3.40 (q, J = 7.0 Hz, 1H), 1.99 (d, J = 4.4 Hz, 6H), 1.84 - 1.73 (m, 2H); (m +1)+; Retention time: 0.56 minutes [a]D= +41.2°. The following analogues were prepared according to Synthetic Scheme 1: nY ^.NHAcNY ^XNHAcó1? 9 (+ / -)-JV-(4-(4-(2-amino-6-methylpyrimidin-4-yl)-l,4-oxazepan-3-yl)-3-c!orophenyl)acetamide 1-141

[00394] high temperature (360 K)1H(400 MHz, DMSO-t / 6) δ 9.77 (s, 1H), 7.77 (s, 1H), 7.35 (m, 1H), 7, 21 (d, J= 8.0 Hz, 1H), 5.56 (s, 1H), 5.43 (s, 2H), 5.36-5.30 (m, 1H), 170 IF-2019-53902052-APN-ANP#INPI Page 170 of 423 4.63-4.59 (m, 1H), 4.05 (m, 1H), 3.87 (m, 1H), 3.75-3.48 (m, 3H), 2.02 (s, 3H), 2.00 (s, 3H), 1.78-1.74 (m, 2H), ESI-MS m / z calc. 375.15, found 376.27 (M+l)+; Retention time: 0.55 minutes.

[00395] The racemic material was subjected to SFC chiral separation.

[00396] Peak A: (J?)-7V-(4-(4-(2-amino-6-methylpyrimidin-4-yl)-l,4-oxazepan-3-yl)-3chlorophenyl)acetamide (8) [ü]d = -19.49 (c = 4.1 mg / 0.8 ml of MeOH); high temperature (360 K)1H(400 MHz, DMSO-ifo) δ 9.83 (s, 1H), 7.99 - 7.73 (m, 1H), 7.54 - 7.33 (m, 1H) , 7.34 - 7.12 (m, 1H), 5.83 - 5.23 (m, 4H), 4.88 - 4.54 (m, 1H), 4.28 - 4.02 (m, 1H), 4.07 3.85 (m, 1H), 3.85 - 3.45 (m, 3H), 2.20 - 1.93 (m, 6H), 1.95 - 1.65 (m , 2H); ES1-MS m / z cale. 375.15, found 376.31 (M+l)+; Retention time: 0.55 minutes. 1-310

[00397] Peak B: (S)- / V-(4-(4-(2-amino-6-methylpyrimidin-4-yl)-l,4-oxazepan-3-yl)-3chlorophenyl)acetamide (9) [α]β = 13.75 (c = 4.3 mg / 0.8 ml MeOH); high temperature (360 K)1H(400 MHz, DMSO-46) δ 9.79 (s, 1H), 7.77 (d, J= 2.2 Hz, 1H), 7.35 (dd, J= 8 .7, 2.1 Hz, 1H), 7.21 (d, J = 8.5 Hz, 1H), 5.61 (d, J = 39.5 Hz, 1H), 5.46 (s, 2H ), 5.34 (s, 1H), 4.62 (s, 1H), 4.08 (dd, J= 13.4, 5.2 Hz, 1H), 3.89 (d, J= 12, 3 Hz, 1H), 3.78 - 3.47 (m, 3H), 2.01 (d, J= 8.1 Hz, 6H), 1.83 - 1.46 (m, 2H); ES1-MS m / z cale. 375.15, found 376.31 (M+l)+; Retention time: 0.55 minutes. 1-162 (5)- / V-(4-(4-(2-amino-6-methylpyrimidin-4-yl)-l,4-oxazepan-3-yl)-3chlorophenyl)propionamide (10) 1-204

[00398] SFC chiral separation peak B: 99.8% ee; 1H NMR (400 MHz, MeOD) δ 7.83 (s, 1H), 7.40 (dd, J = 8.5, 2.1 Hz, 1H), 7.23 (d, J= 8.5 Hz , 1H), 6.01-4.90 (br s, 3H), 4.31 4.23 (m, 1H), 4.04 (d, J= 8.4 Hz, 1H), 3.79 - 3.58 (m, 3H), 2.39 (q, J= 7.6 Hz, 2H), 2.10 (s, 3H), 2.00 - 1.78 (m, 2H), 1.24 - 1.16 (m, 3H), ESI-MS m / z cale. 389.2, found 390.4 (M+l)+; Retention time: 0.58 minutes. 171 IF-2019-53902052-APN-ANP#INPI Page 171 of 423 (S)-7V-(4-(4-(2-amino-6-methylpyrimidin-4-yl)-l,4-oxazepan-3-yl)-3chlorophenyl)propionamide (11) 1-207

[00399] SFC chiral separation peak B: 99.8% ee; heating (360K)1H NMR (400 MHz, í / 6-DMSO) δ 10.03 (s, 1H), 7.80 (d, J= 2.0 Hz, 1H), 7.37 (dd, J= 8.5, 2.1 Hz, 1H), 7.21 (d, J= 8.5 Hz, 1H), 5.56 (s, 1H), 5.46 (s, 2H), 5.33 ( s, 1H), 4.63 (d, J= 14.1 Hz, 1H), 4.08 (dd, J= 13.5, 5.0 Hz, 1H), 3.89 (d, J= 12 .0 Hz, 1H), 3.70 (dd, J = 13.4, 10.2 Hz, 1H), 3.66 - 3.50 (m, 2H), 2.00 (s, 3H), 1 .76-1.72 (m, 3H), 0.83-0.75 (m, 4H); ESI-MS m / z calc. 401.2, found 402.3 (M+l)+; Retention time: 0.59 minutes. U I H (+ / r)-Ar-[4-[(-4-yl2-amino-6-methyl-pyrimidin)-l,4-oxazepan-3-yl]-3-chloro-phenyl4-]-2methoxy-acetamide ( 12) I -192

[00400] heating (360K)1H(400 MHz, MeOD) δ 7.74 (s, 1H), 7.35 (d, J = 8.5 Hz, 1H), 7.12 (d, J= 8, 5 Hz, 1H), 5.50 (br s, 3H), 4.14 (dd, J = 13.6, 5.1 Hz, 1H), 3.91 (s, 3H), 3.68 - 3 .43 (m, 3H), 3.35 (s, 3H), 1.97 (s, 3H), 1.75 (m, 2H); ESI-MS m / z calc. 405.2, found 406.3 (M+l)+; Retention time: 0.56 minutes. \ ) Cl (5)-7V-(4-(4-(2-amino-6-methiIpyrimidin-4-yl)-l,4-oxazepan-3-yl)-3chlorophenyl)propionamide (13) 1-197

[00401] SFC chiral separation peak B: 99.4% ee;1H(400 MHz, MeOD) δ 7.75 (s, 1H), 7.38 - 7.31 (m, 1H), 7.12 ( d, J= 8.5 Hz, 1H), 5.45 (s, 3H), 4.15 (dd, J= 13.8, 4.9 Hz, 1H), 3.91 (d, J= 9 .0 Hz, 1H), 3.68 - 3.45 (m, 3H), 1.97 (s, 3H), 1.75 (dd, J= 41.1, 11.5 Hz, 2H), 1 .17 (dd, J= 7.7, 4.5 Hz, 2H), 0.94 (dd, J= Ί,Ί, 4.5 Hz, 2H); ESI-MS m / z calc. 417.2, found 418.3 (M+l)+; Retention time: 0.56 minutes. 15 16 (+ / -)- / V-[5-[4-(2-amino-6-methyl-pyrimidin-4-yl)-l,4-oxazepan-3-yl]-4-chloro-2- fluoro172 IF-2019-53902052-APN-ANP#INPI Page 172 of 423 phenyljacetamide (14) 1-85

[00402] 1H NMR (300 MHz, CDC13) δ 8.36 (d, J= 8.2 Hz, 1H), 7.51 (s, 1H), 7.18 (dd, J= 19.2, 10 .3 Hz, 1H), 6.02 - 5.77 (m, 1H), 5.28 - 5.09 (m, 1H), 4.28 (dt, J= 13.7, 5.1 Hz, 1H), 4.20 - 3.95 (m, 2H), 3.84 - 3.49 (m, 4H), 2.42 - 2.27 (m, 3H), 2.22 (d, J= 0.9 Hz, 3H), 2.03 - 1.82 (m, 2H); ESI-MS m / z calc. 393.1, found 394.1 (M+l)+; Retention time: 0.59 minutes. The racemic material was subjected to SFC chiral separation. Conditions: IC column 20 x250mm, mobile phase: 40% MeOH (5 mM Ammonia), 60% CO2

[00403] Peak A: 7V-[5-[(37?)-4-(-6-methyl-pyrimidin-4-yl2-amino)-l,4-oxazepan-3-yl]-4chloro-2-fluoro -phenyl]acetamide (15): 1H NMR (300 MHz, Methanol- 44) δ 8.00 (d, J = 8.2 Hz, 1H), 7.33 (d, J= 10.4 Hz, 1H) , 5.65 (s, 2H), 4.28 (dd, J= 13.6, 5.1 Hz, 1H), 4.05 (dd, J = 12.0, 4.5 Hz, 1H), 3.88 - 3.54 (m, 3H), 2.15 (s, 3H), 2.12 (s, 3H), 1.90 (d, J= 18.8 Hz, 2H); ES1-MS m / z cale. 393.1, found 394.1 (M+l)+; Retention time: 0.59 minutes; Optical rotation: 5 mg / 1 mL MeOH, C = 1, [a] = -62.24°. 1-270

[00404] Peak B: 7V-[5-[(3S)-4-(2-amino-6-methyl-pyrimidin-4-yl)-l,4-oxazepan-3-yl]-4chloro-2-fluoro -phenyl]acetamide (16): 1H NMR (300 MHz, Methanol- 44) δ 8.00 (d, J = 8.2 Hz, 1H), 7.33 (d, J= 10.4 Hz, 1H) , 5.65 (s, 2H), 4.28 (dd, J= 13.6, 5.1 Hz, 1H), 4.05 (dd, J = 12.0, 4.5 Hz, 1H), 3.88 - 3.54 (m, 3H), 2.15 (s, 3H), 2.12 (s, 3H), 1.90 (d, J= 18.8 Hz, 2H); ESI-MS m / z cale. 393.1, found 394.2 (M+l)+; Optical rotation: 5 mg / 1 ml of MeOH, C=l, [a] = 59.6°. 1-271 (+ / -)-4-[3-[2-chloro-5-(ethylamino)-4-fluoro-phenyl]-l,4-oxazepan-4-yl]-6-methyl-pyrimidin-2amine (17) 1-272

[00405] To a solution of 7V-[5-[4-(2-amino-6-methyl-pyrimidin-4-yl)-l,4-oxazepan-3-yl]4-chloror2-fluoro-phenyl]acetamide , 14, (0.05 g, 0.12 mmol) in tetrahydrofuran (5 ml) was added lithium aluminum hydride (0.08 ml of 2 M, 0.16 mmol) in THF. The cloudy solution was stirred at room temperature overnight. Additional lithium aluminum hydride (0.10 ml) was added and the reaction mixture was heated to 600 C overnight. The mixture was diluted with water (0.25 ml) and stirred for 10 minutes. Dichloromethane was added (10 173 IF-2019-53902052-APN-ANP#INPI Page 173 of 423 ml) and the resulting white solid was filtered and washed with dichloromethane. The combined organic phases were concentrated in vacuo. The resulting residue was purified by silica gel chromatography using a 4g ISCO column eluting a 0-10% MeOH / dichloromethane gradient to provide the desired product as a white solid: 1H NMR (300 MHz, Chloroform-d ) δ 7.02 (d, 10.9 Hz, 1H), 6.45 (d, J= 9.0 Hz, 1H), 5.56 (s, 1H), 4.95 (s, 3H), 4.30 (dd, J= 13.6, 5.0 Hz, 1H), 4.10 (dd, J = 10.8, 6.6 Hz, 1H), 3.83 - 3.39 (m, 5H), 3.10 (qd, J= Ί,ϊ, 5.2 Hz, 2H), 2.17 ( s, 3H), 2.09 - 1.91 (m, 1H), 1.89 - 1.76 (m, 1H), 1.24 (d, J= 7.2 Hz, 3H); ESI-MS m / z cale. 379.2, found 379.8 (M+l)+; Retention time: 0.66 minutes. Example 2 Synthetic Scheme 2: (+ / -)-4-(3-(2-chloro-4-(methylsulfonyl)phenyl)-l,4-oxazepan-4-yl)-6methylpyrimidin-2-amine(19) I -66 a,b Bu1Snx~'Ox''—'''NH, -----------». (a) sieves mol 4A, 4- 2-chloro-benzaldehyde (methylsulfonyl), CH2CI2; (b) 2,6-lutidine, Cu(OTf)2, hexafluoroisopropanol, CH2CI2; c) 2-amino-4-chloro-6-methylpyrimidine, NMP, 150°C; (d) SFC chiral separation Formation of (+ / -)-3-(2-chloro-4-(methylsulfonyl)phenyl)-l,4-oxazepan(18)

[00406] To a solution of 3-(tributylstannylmethoxy)propan-l-amine (2.69 g, 7.11 mmol) in dichloromethane (11 ml) was added 2-chloro-5-methylsulfonyl-benzaldehyde (1.00 g , 4.57 mmol) followed by 4 angstrom molecular sieves. The mixture was stirred for 14 h, filtered to remove the sieves and washed and diluted with dichloromethane (50 ml).

[00407] In a separate flask containing hexafluoroisopropanol (15 ml) 2,6-lutidine (0.53 ml, 4.58 mmol) was added followed by Cu(OTf)2 (1.65 g, 4.56 mmol) . The mixture was stirred for 1 h, then the imine solution prepared above was added in one portion. The reaction was stirred overnight at room temperature. The mixture was diluted with 2:1 mixture of saturated aqueous NaHCCh solution and 10% ammonium hydroxide. 174 IF-2019-53902052-APN-ANP#INPI Page 174 of 423 After stirring for 10 minutes, the organic layer was separated and washed with saturated aqueous NaHCCh solution, then brine. The organic layer was passed through a phase separating funnel and the filtrate was concentrated in vacuo. The residue was purified by reverse phase chromatography using a 100 gram ISCO-cl8-aq Column running with formic acid / H2O and formic acid / CH3CN gradient. The residue was diluted with dichloromethane, neutralized with saturated aqueous NaHCCh solution. The organic phase was passed through a phase separator and concentrated in vacuo to provide 688 mg of desired product: 1H NMR (400 MHz, DMSO-J6) δ 7.93 (dd, J = 1.6, 0, 7 Hz, 1H), 7.90 - 7.87 (m, 2H), 4.31 (dd, J = 8.7, 3.3 Hz, 1H), 3.92 - 3.77 (m, 2H ), 3.71 (dt, J = 12.2, 6.2 Hz, 1H), 3.35 - 3.27 (m, 1H), 3.26 (s, 3H), 3.10 (dt, J = 13.7, 5.1 Hz, 1H), 2.89 (dt, J = 13.3, 6.4 Hz, 2H), 1.93 - 1.81 (m, 2H), ESI-MS m / z cale. 289.05396, found 290.05 (M+l)+; Retention time: 0.5 minutes Formation of (R)-4-(3-(2-chloro-4-(methylsulfonyl)phenyl)-l,4-oxazepan-4-yl)-6methylpyrimidin-2-amine(20) 1-67 and (S) -4-(3-(2-chloro-4-(methylsulfonyl)phenyl)-l,4oxazepan-4-yl)-6-methylpyrimidin-2-amine (21) 1-68

[00408] To a solution of 3-(2-chloro-4-(methylsulfonyl)phenyl)-l,4-oxazepane, 18, (0.67 g, 2.31 mmol) in NMP (7.5 ml) added 4-chloro-6-methyl-pyrimidin-2-amine (0.40 g, 2.79 mmol). The reaction mixture was heated to 1500C overnight. The mixture was cooled to room temperature and loaded directly onto a 100 g ISCO cl8-aq column and purified by reverse phase by running with 0.1% TFA / H2O and 0.1% TFA / CH3CN. The pure fractions were concentrated in vacuo. The resulting residue was diluted with dichloromethane, neutralized with saturated aqueous NaHCOs solution. The mixture was passed through a phase separator and the organic phase was concentrated in vacuo to provide 550 mg of desired product. The racemic mixture was subjected to purification by chiral SFC to provide 155 mg of stereoisomer A and 153 mg of stereoisomer B:

[00409] Peak A: (R)-4-(3-(2-chloro-4-(methylsulfonyl)phenyl)-l,4-oxazepan-4-yl)-6methylpyrimidin-2-amine (20), NMR heating 1H (360K) (400 MHz, DMSO-í / 6) δ 7.97 (t, J= 1.9 Hz, 1H), 7.84 (dt, J= 8.2, 1.9 Hz, 1H) , 7.60 (dd, J= 8.1, 2.0 Hz, 1H), 5.78 - 5.65 (m, 1H), 5.65 - 5.51 (m, 1H), 5.46 (s, 2H), 4.60 - 4.41 (m, 1H), 4.25 - 4.07 (m, 1H), 4.02 3.87 (m, 1H), 3.85 - 3, 68 (m, 2H), 3.68 - 3.44 (m, 1H), 3.24 (s, 3H), 2.10 - 1.99 (m, 3H), 175 IF-2019-53902052-APN-ANP#INPI Page 175 of 423 1.89 - 1.70 (m, 2H); ES1-MS m / z calc. 396.10, found 397.16 (M+l)+; Retention time: 0.57 minutes; [a]D = -71.67 (c = 5.4 mg / 1.5 ml MeOH). 1-67

[00410] Peak B: (S)-4-(3-(2-chloro-4-(methylsulfonyl)phenyl)-l,4-oxazepan-4-yl)-6methylpyrimidin-2-amine (21), NMR heating 1H (360K) (400 MHz, DMSO-i / 6) δ 7.94 (d, J= 2.0 Hz, 1H), 7.80 (dd, J= 8.1, 2.0 Hz, 1H) , 7.56 (d, J= 8.2 Hz, 1H), 5.72 - 5.63 (m, 1H), 5.63 - 5.52 (m, 1H), 5.43 (s, 2H ), 4.58 - 4.37 (m, 1H), 4.14 (dd, J= 13.5, 4.8 Hz, 1H),. 3.97 - 3.85 (m, 1H), 3.85 - 3.64 (m, 2H), 3.57 (dt, J= 12.4, 7.4 Hz, 1H), 3.21 ( s, 3H), 2.03 (s, 3H), 1.90 - 1.70 (m, 2H); ESI-MS m / z calc. 396.10, found 397.16 (M+l)+; Retention time: 0.56 minutes; [a]D = 58.36 (c = 5.3 mg / 1.5 ml MeOH). 1-68

[00411] The following analogues were in accordance with Synthetic Scheme 2: η2ν_Λ h2n (R)-4-(2-(2-fluoro-5-methoxyphenyl)azepan-l-yl)-6-methylpyrimidin-2-amine (22) 1-26 and (5)4-(2-(2- fluoro-5-methoxyphenyl)azepan-l-yl)-6-methylpyrimidin-2-amine (23) 1-27

[00412] The racemic mixture was synthesized in the same way and then subjected to Purification by chiral SFC to obtain the individual enantiomers: Peak A; 98.6% ee; high temperature (360 K) 1H NMR (400 MHz, DMSOY6) δ 7.10 - 6.9 4 (m, 2H), 6 .84 (dd, J = 9.5, 2.8 Hz, 1H), 5 .59 (s, 1H), 5.54 - 5.29 (m, 3H), 4.70 - 4.47 (m, 1H), 4.16 (dd, J = 13.2, 5.1 Hz , 1H), 3.9 9 - 3 .77 (m, 4H), 3.72 - 3.40 (m, 3H ), 2.00 (s , 3H), 1.86 - 1.61 (m, 2H); [a]D= -34.12 (c = 19 mg / 3 mi MeOH). 1-26 Peak B; 97.4% ee; high temperature (360 K) 1H NMR (400 MHz, DMSOY6) δ 7.08 - 6.93 (m, 2H), 6.84 (dd, J= 9.4, 2.8 Hz, 1H), 5, 59 (s, 1H), 5.48 (s, 2H), 5.44 - 5.31 (m, 1H), 4.68 - 4.50 (m, 1H), 4.16 (dd, J= 13.3, 5.1 Hz, 1H), 3.96 - 3.77 (m, 4H), 3.72 - 3.38 (m, 3H), 2.00 (s, 3H), 1.89 - 1.60 (m, 2H); [a]D= +40.44 (c = 19 mg / 3 ml MeOH); ESI-MS m / z cale. 333.21, found 333.18 (M+l)+; Retention time: 0.61 minutes. 1-27 176 IF-2019-53902052-APN-ANP#INPI Page 176 of 423Νθ2v >Cl 4-(3-(2-chloro-5-nitrophenyl)-l,4-oxazepan-4-yl)-6-methylpyrimidin-2-amine (24) 1-72

[00413] high temperature (360 K) 1H NMR (400 MHz, DMSO-J6) δ 8.14 - 8.01 (m, 2H), 7.73 (d, J = 8.7 Hz, 1H), 5.73 (s, 1H), 5.68 - 5.53 (m, 1H), 5.44 (s, 2H), 4.56 - 4.39 (m, 1H), 4.12 (dd, J - 13.6, 4.8 Hz, 1H ), 3.95 - 3.69 (m, 3H), 3.68 - 3.53 (m, 1H), 2.04 (s, 3H), 1.85 - 1.73 (m, 2H); ESI-MS m / z calc. 363.11, found 364.16 (M+l)+; Retention time: 0.61 minutes. cW 25 (+ / -)-4-[3-(2-chloro-4-nitro-phenyl)-l,4-oxazepan-4-yl]-6-methyl-pyrimidin-2-amine (25) I125

[00414] high temperature (360 K) 1H NMR (400 MHz, DMSO-¿6) δ 8.22 (d, J = 2.3 Hz, 1H), 8.08 (dd, J= 8.6, 2 .4 Hz, 1H), 7.58 (d, J= 8.6 Hz, 1H), 5.69 (s, 1H), 5.59 (dd, J= 9.9, 4.7 Hz, 1H ), 5.41 (s, 2H), 4.46 (d, J= 15.7 Hz, 1H), 4.14 (dd, J= 13.5, 4.8 Hz, 1H), 3.90 (dt, J= 11.5, 3.6 Hz, 1H), 3.77 (ddd, J = 16.3, 13.0, 8.2 Hz, 3H), 3.63 - 3.53 (m , 1H), 2.03 (s, 3H), 1.85 - 1.77 (m, 2H); ESI-MS m / z calc. 363.11, found 364.25 (M+l) +; Retention time: 0.6 minutes. (+ / -)-4-[3-(6-chloro-l,3-benzodioxol-5-yl)-l,4-oxazepan-4-yl]-6-methyl-pyrimidin-2-amine (26) 1-113

[00415] heating (360K) 1H NMR (400 MHz, DMSO-¿6) δ 7.00 (s, 1H), 6.79 (s, 1H), 6.09 (s, 2H), 6.01 ( s, 2H), 5.73 (s, 1H), 5.37 (s, 1H), 4.68 - 4.50 (m, 1H), 4.05 (dd, J= 13.6, 4, 9 Hz, 1H), 3.93 - 3.51 (m, 4H), 2.09 (s, 3H), 1.78 (p, J= 4.5, 3.9 Hz, 2H); ESI-MS m / z cale, 362.1, found 363.0 (M+l)+Retention time: 0.71 minutes. 177 IF-2019-53902052-APN-ANP#INPI Page 177 of 423 (+ / -)-4-(3-(2-chloro-6-fluorophenyl)-l,4-oxazepan-4-yl)-6-methylpyrimidin-2-amine (27) 1-59

[00416] 1H NMR (400 MHz, DMSO-í / 6) (heating 360K) δ 7.30 (td, J= 3.8, 2.7 Hz, 2H), 7.10 (ddd, J= 11.3,6.1 ,3.4 Hz, 1H), 5.71 (s, 1H), 5.54 (dd,J= 10.6,5.6 Hz, 1H), 5.41 (s, 2H), 4.48 (d, J= 15.6 Hz, 1H), 4.00 - 3.88 (m, 3H), 3.71 (dd, J= 15.6, 11.2 Hz, 1H), 3.53 ( td, J= 12.1, 3.1 Hz, 1H), 2.02 (s, 3H), 1.82 - 1.57 (m, 2H); ES1-MS m / z calc. 336.12, found 337.0 (M+l)+; Retention time: 0.7 minutes. (+ / -)-4-(3-(2-chloro-4-(12 / -pyrazol-l-yl)phenyl)-l,4-oxazepan-4-yl)-6-methylpyrimidin-2amine 1-133

[00417] 1H NMR (400 MHz, DMSO-d6) (360K heating) δ 8.42 (d, J = 2.5 Hz, 1H), 7.91 (d, J = 2.3 Hz, 1H), 7.79 - 7.67 (m, 2H), 7.43 (d, J= 8.5 Hz, 1H), 6.51 (dd, J = 2.6, 1.8 Hz, 1H), 6 .06 (s, 2H), 5.80 (s, 1H), 5.54 (d, J= 7.6 Hz, 1H), 4.58 (d, J= 15.2 Hz, 1H), 4 .15 (dd, J= 13.5, 4.9 Hz, 1H), 3.96 - 3.80 (m, 2H), 3.80 - 3.69 (m, 1H), 3.68 - 3 .55 (m, 1H), 2.09 (s, 3H), 1.88 - 1.75 (m, 2H); ES1-MS m / z calc. 384.15, found 385.0 (M+l)+; Retention time: 0.72 minutes. (R)-4-(3-(5-chloro-2-methoxyphenyl)-l,4-oxazepan-4-yl)-6-methylpyrimidin-2-amine (29) I131

[00418] 1H NMR (400 MHz, DMSO-í / 6) (heating 360K) δ 7.29 (dd, J = 8.8, 2.7 Hz, 1H), 7.11 (d, J = 2, 7 Hz, 1H), 7.07 (d, J = 8.8 Hz, 1H), 6.97 (s, 2H), 5.95 (d, J= 35.3 Hz, 1H), 5.55 (s, 1H), 4.55 (s, 1H), 4.17 (dd, J = 13.4, 5.2 Hz, 1H), 3.87 (s, 4H), 3.82 - 3, 68 (m, 2H), 3.57 (ddd, J= 12.2, 8.3, 5.7 Hz, 1H), 2.19 (s, 3H), 1.79 (h, 3.9 Hz , 2H), ESIMS m / z calc. 348.14, found 349.0 (M+l)+; Retention time: 0.72 minutes. (*S)-4-(3-(5-chloro-2-methoxyphenyl)-l,4-oxazepan-4-yl)-6-methylpyrimidin-2-amine (30) 1-132 178 IF-2019-53902052-APN-ANP#INPI Page 178 of 423

[00419] 1H NMR (400 MHz, DMSO-í / 6) (heating 360K) δ 7.29 (dd, J = 8.8, 2.7 Hz, 1H), 7.11 (d, J= 2.7 Hz, 1H), 7.07 (d, J= 8.8 Hz, 1H), 6.97 (s, 2H), 5.95 ( d, J= 35.3 Hz, 1H), 5.55 (s, 1H), 4.55 (s, 1H), 4.17 (dd, J= 13.4, 5.2 Hz, 1H), 3.87 (s, 4H) ), 3.82 - 3.68 (m, 2H), 3.57 (ddd, J = 12.2, 8.3, 5.7 Hz, 1H), 2.19 (s, 3H), 1, 79 (h, J= 3.9 Hz, 2H); ESIMS m / z calc. 348.14, found 349.0 (M+l)+; Retention time: 0.72 minutes. (+ / -)-4-(3-(4-bromo-2-chlorophenyl)-l,4-oxazepan-4-yl)-6-methylpyrimidin-2-amine (31) I194

[00420] high temperature (360 K) 1H NMR (400 MHz, DMSO-¿76) δ 7.70 (d, J= 2.1 Hz, 1H), 7.52 (dd, J= 8.4, 2 .1 Hz, 1H), 7.31 (t, J = 6.8 Hz, 3H), 4.15 (dd, J= 13.6, 5.0 Hz, 1H), 3.96 - 3.72 (m, 3H), 3.64 (s, 1H), 2.25 (s, 3H), 1.85 (s, 2H); ESI-MS m / z cale. 396.0, found 397.0 (M+l)+; Retention time: 0.64 minutes.

[00421] The racemic material was subjected to SFC chiral separation.

[00422] Peak A: ESI-MS m / z cale. 396.0, found 399.0 (M+l)+; Retention time: 0.8 minutes; (7?)-4-(3-(4-bromo-2-chlorophenyl)-1,4-oxazepan-4-yl)-6-methylpyrimidin-2-amine (32). 1-200

[00423] Peak B: 1H NMR (400 MHz, DMSO-¿6) δ 7.69 (d, J = 2.0 Hz, 1H), 7.50 (dd, J = 8.4, 2.1 Hz , 1H), 7.29 (d, J= 8.4 Hz, 1H), 6.87 (s, 3H), 6.01 (s, 1H), 5.59 (s, 1H), 4.49 (d, J= 14.9 Hz, 1H), 4.13 (dd, J= 13.6, 4.9 Hz, 1H), 3.91 - 3.78 (m, 3H), 3.62 ( ddd, J= 12.2, 9.4, 4.9 Hz, 1H), 2.19 (s, 4H), 1.82 (dp, J= 10.1, 3.6, 3.1 Hz, 2H); ESI-MS m / z cale. 396.0, found 397.0 (M+l)+; Retention time: 0.8 minutes; [a] = +79 (c - 1, MeOH) 7.1 mg / ml; (S)-4-(3-(4-bromo-2-chlorophenyl)-1,4-oxazepan-4-yl)-6-methylpyrimidin-2-amine (33). 1-201 4-[(35)-3-(5-bromo-2-chloro-phenyl)-l,4-oxazepan-4-iI]-6-methyl-pyrimidjn-2-amine 1-245 179 IF-2019-53902052-APN-ANP#INPI Page 179 of 423

[00424] 1H NMR (300 MHz, DMSO-i / 6) δ 7.47 (m, 3H), 6.52 (brs, 1H), 5.99 (brs, 1H), 3.90 (m, 4H ), 3.66 (br, 2H), 2.30 (s, 3H), 1.89 (m, 2H); ESI-MS m / z calc. 396.03, found 397.01 (M+l)+; Retention time: 0.65 minutes; [<x]d = +66.68° (c = 0.5, MeOH). Example 3 Synthetic Scheme 3: (J?)-4-(2-(2-chlorophenyl)azepan-l-yl)-6-methylpyrimidin-2-amine and (5)-4-(2-(2-chlorophenyl)azepan- l-yl)-6-methylpyrimidin-2-amine) (a) 2-amino-4-chloro-6-methylpyrimidine, nBuOH, 200°C, microwave; (b) HPLC chiral separation Formation of (+ / -)-(2-(2-chlorophenyl)azepan-l-yl)-6-methylpyrimidin-2-amine (34)

[00425] A suspension of 4-chloro-6-methyl-pyrnidin-2-amine (3.02 g, 21.03 mmol), 2(2-chlorophenyl)azepane (3.99 g, 19.01 mmol) in «-butanol (15 ml) was sealed in a microwave tube and irradiated at 200 °C for 2 hours. The crude mixture was concentrated in vacuo and diluted with saturated aqueous KHCO3 solution and extracted twice with dichloromethane. The organic phase was concentrated in vacuo. The residue was then recrystallized from isopropanol and ether to give 3.61 g of racemic product: 1H NMR (400 MHz, CDC13) δ 7.37 (d, J = 8.5 Hz, 1H), 7.16 (d , J = 13.9 Hz, 3H), 5.47 (s, 1H), 4.91 (s, 1H), 4.57 (s, 2H), 3.32 (s, 1H), 2.58 - 2.45 (m, 1H), 2.17 (d, J= 22.1 Hz, 2H), 2.03 (s, 1H), 1.91 (d, J= 10.7 Hz, 2H) , 1.66 (s, 1H), 1.63 (s, 3H), 1.50 - 1.33 (m, 2H); ESI-MS m / z cale. 316.15, found 317.2 (M+l)+; Retention time: 0.8 minutes.

[00426] The racemic mixture was separated by Chiral Analytical HPLC (AD-H, 4.6 x lOOmm, 40% MeOH, 5 mM ammonia, 60% CO2, at 5 ml / min isocratic injection of 10 uM in 1 mg / ml methanol 120 bar UV 254 nM). RT Peak A 0.432 min, ee 97.2%, Peak B at 0.479 min.

[00427] Peak A: 2.10 g, 97.2% ee; optical rotation: [cc]d = -0.096 (c = 1.04, MeOH); 1H NMR (400 MHz, CDC13) δ 7.36 (s, 1H), 7.17 (s, 3H), 5.81 (s, 1H), 5.44 (s, 1H), 4.90 (s , 1H), 4.68 (s, 2H), 4.03 - 3.20 (m, 1H), 2.63 - 2.43 (m, 1H), 2.11 (s, 3H), 2, 02 (s, 1H), 1.97 180 IF-2019-53902052-APN-ANP#INPI Page 180 of 423 1.82 (m, 2H), 1.76-1.51 (m, 2H), 1.51 - 1.31 (m, 2H); ES1-MS m / z calc. 316.15, found 317.24 (M+l)+; Retention time: 0.83 minutes. (7?)-4-(2-(2-chlorophenyl)azepan-1-11)-6methylpyrimidin-2-amine (35) 1-13

[00428] Peak B: 2.09 g, 96% ee; optical rotation: [o.]d - 1.373 (c = 1.02, MeOH); 1H NMR (400 MHz, CDC13) δ 1.46 -1.31 (m, 2H), 1.72 - 1.53 (m, 2H), 1.96 - 1.82 (m, 2H), 2, 04 (d, J = 18.8 Hz, 1H), 2.39 - 2.05 (m, 3H), 2.61 - 2.42 (m, 1H), 4.08 - 3.22 (m, 1H), 4.72 (s, 2H), 4.89 (s, 1H), 5.43 (s, 1H), 5.82 (s, 1H), 7.16 (s, 3H), 7, 35 (s, 1H); ESI-MS m / z calc. 316.15, found 317.2 (M+l)+; Retention time: 0.82 minutes. (S)-4-(2-(2chlorophenyl)azepan-l-yl)-6-methylpyrimidin-2-amine (36) 1-14

[00429] The following analogues were prepared according to Synthetic Scheme 3: (J?)-4-(2-(2-methoxyphenyl)azepan-l-yl)-6-methylpyrimidin-2-amine (37) 1-11 and (5)-4-(2-(2methoxyphenyl)azepan- l-yl)-6-methylpyrimidin-2-amine (38) 1-12

[00430] SFC chiral separation peak A: 1H NMR (400 MHz, CDC13) δ 7.01 (dd, J = 118.6, 38.8 Hz, 4H), 5.60 (2s, 1H), 5, 24 - 4.44 (m, 3H), 3.82 (s, 3H), 3.32 (dd, J = 63.5, 46.9 Hz, 1H), 2.49 (2s, 1H), 2 .30 - 1.91 (m, 3H), 1.94 - 0.56 (m, 9H); ESI-MS m / z cale. 312.20, found 313.13 (M+l)+; Retention time: 0.78 minutes. (38) 1-12

[00431] SFC chiral separation peak B: 1H NMR (400 MHz, CDC13) δ 9.03 - 6.27 (m, 4H), 5.59 (2s, 1H), 5.29 - 4.36 (m , 3H), 3.82 (s, 3H), 3.54 - 2.79 (m, 1H), 2.33 (d, J= 61.8 Hz, 1H), 2.00 (s, 3H) , 1.93 - 0.44 (m, 10H); ESI-MS m / z cale. 312.12, found 313.13 (M+l)+; Retention time: 0.8 minutes. (37) 1-11 ( / ?)-4-(2-(2-bromo)azepan-l-yl)-6-methylpyriinidin-2-amine (41) 1-2 and (5)-4-(2-(2bromo)azepan- l-yl)-6-methylpyrimidin-2-amine (42) 1-3 181 IF-2019-53902052-APN-ANP#INPI Page 181 of 423

[00432] SFC chiral separation peak A: 1H NMR (400 MHz, CDC13) δ 7.46 (d, J= 7.4 Hz, 1H), 7.08 (d, J= 42.6 Hz, 3H) , 5.95 - 5.43 (m, 1H), 5.34 (s, ÍH), 4.77 (d, J= 37.2 Hz, 3H), 3.98 - 3.08 (m, 2H ), 2.46 - 2.32 (m, 1H), 2.08 (d, J= 40.4 Hz, 3H), 1.94 (s, 1H), 1.89 1.75 (m, 2H ), 1.65 - 1.44 (m, 2H), 1.42 - 1.26 (m, 2H); ESI-MS m / z cale. 360.09, found 361.12 (M+l)+; Retention time: 0.91 minutes. (41) 1-2 (00433] SFC chiral separation peak B: 1H NMR (400 MHz, CDCI3) δ 7.46 (s, 1H), 6.99 (t, J= 70.7 Hz, 3H), 6.02 - 5.47 (m, 1H), 5.21 (t, J= 62.8 Hz, 4H), 4.78 (d, J= 17.2 Hz, 1H), 3.96 - 3 .17 (m, 2H), 2.48 - 2.33 (m, 1H), 2.27 - 2.03 (m, 3H), 1.96 - 1.72 (m, 3H), 1.68 - 1.42 (m, 2H), 1.42 - 1.23 (m, 2H); ESI-MS m / z cale. 361.12 (M+l)+; 0.93 minutes (42) 1-3 (+ / -)-4-methyl-6-(2-(2-(methylthio)phenyl)azepan-l-yl)pyrimidin-2-amine (43) 1-5

[00434] 1H NMR (400 MHz, MeOD) δ 7.33 (d, J = 7.8 Hz, 1H), 7.23 (s, 1H), 7.08 (d, J = 5.7 Hz, 2H), 5.45 (s, 1H), 3.41 (s, 1H), 2.58 (s, 3H), 2.38 (d, J = 17.3 Hz, 1H), 2.02 ( d, J = 6.2 Hz, 3H), 1.96 - 1.81 (m, 2H), 1.72 (d, J= 6.7 Hz, 1H), 1.62 - 1.50 (m , 1H), 1.50 1.27 (m, 2H); ESI-MS m / z cale. 328.17, found 329.11 (M+l)+; Retention time: 0.75 minutes. (+ / -) - 4-methyl-6- (2- (2- (methyl) phenyl) azepan-l-yl) pyrimidin-2-amine (44) 1-6 (00435] 1H NMR (400 MHz, Methanol -J4) δ 7.19 - 6.99 (m, 4H), 2.46 (s, 3H), 2.27 (ddd, 14.3, 8.4, 5.1 Hz, 1H), 2.22 - 1.96 (m, 4H), 1.95 - 1.82 (m, 3H), 1.81 - 1.68 ( m, 1H), 1.59 (d, J= 12.0 Hz, 1H), 1.42 (dtt, J = 23.7, 12.2, 6.3 Hz, 2H); ESI-MS m / z cale. 296.20, found 297.14 (M+l)+; Retention time: 0.74 minutes. (+ / -)-4-(2-(2,4-dichlorophenyl)azepan-l-yl)-6-methylpyrimidin-2-amine (45) 1-1 182 IF-2019-53902052-APN-ANP#INPI Page 182 of 423

[00436] 1H NMR (400 MHz, MeOD) δ 7.71 - 7.07 (m, 3H), 6.53 - 5.02 (m, 2H), 4.28 3.43 (m, 2H), 2.66 - 2.37 (m, 1H), 2.25 (2s 3H), 2.17-1.28 (m, 7H); ESI-MS m / z calc. 350.11, found 351.11 (M+l)+; Retention time: 3.13 minutes. nh2 (+ / -)-4-methyl-6-(2-phenylazepan-l-yl)pyrimidin-2-amine (45) 1-4

[00437] 1H NMR (400 MHz, MeOD) δ 7.48 - 7.17 (m, 5H), 6.39 - 5.94 (2s, 1H), 4.04 3.36 (m, 1H), 2.52 (td, J= 14.5, 6.2 Hz, 1H), 2.27 (d, J= 61.1 Hz, 3H), 2.04 - 1.79 (m, 4H), 1 .76- 1.05 (m, 3H). (+ / -)-4-(2-(2-chlorophenyl)azepan-l-yl)-6-isopropylpyrimidin-2-amine 1-16

[00438] 1H NMR (400 MHz, DMSO-¿6) δ 7.47 - 7.34 (m, 1H), 7.34 - 7.17 (m, 3H), 5.57 (s, 1H), 5.46 (s, 2H), 5.21 (s, 1H), 4.55 (d, J= 14.9 Hz, 1H), 3.55 - 3.40 (m,'lH), 2, 57 - 2.52 (m, 1H), 2.34 (ddd, J= 13.8, 8.1, 5.0 Hz, 1H), 1.98 (t, J = 11.2 Hz, 1H) , 1.92 - 1.64 (m, 3H), 1.61 - 1.18 (m, 3H), 1.08 (d, J = 6.9 Hz, 3H), 1.04 (d, J = 6.9 Hz, 3H); ESI-MS found m / z 345. (+ / -)-4-(2-(2-chlorophenyl)azepan-l-yl)-6-ethylpyrimidin-2-amine 1-17

[00439] 1H NMR (400 MHz, DMSO-i / 6) δ 7.45 - 7.32 (m, 1H), 7.28 - 7.13 (m, 3H), 5.56 (s, 1H) , 5.41 (s, 2H), 5.21 (d, J= 12.0 Hz, 1H), 4.49 (d, J = 14.7 Hz, 1H), 3.51 - 3.38 183 IF-2019-53902052-APN-ANP#INPI Page 183 of 423 (m, 1H), 2.52 - 2.49 (m, 1H), 2.38 - 2.22 (τη, 3H), 2.01 - 1.64 (m, 2H), 1 .59 - 1.21 (m, 4H), 1.03 (t, J= 7.5 Hz, 3H); ESI-MS found m / z 331. Example 4 Synthetic scheme 4: (+ / -)-4-(3-(5-amino-2-chloropheniI)-l,4-oxazepan-4-yl)-6methylpyrimidin-2-amine (46) 1-71 to (a) zinc, NH4C1, 2% TPGS-750-M in water, 75°C; (b) SFC chiral separation Formation of (R)-4-(3-(5-amino-2-chlorophenyl)-l,4-oxazepan-4-yl)-6-methylpyrimidin-2amine (47) and (5)-4-(3- (5-amino-2-chlorophenyl)-l,4-oxazepan-4-yl)-6-methylpyrimidin-2amine (48)

[00440] 4-[3-(2-chloro-5-nitro-phenyl)-l,4-oxazepan-4-yl]-6-methyl-pyrimidin-2-amine, 24, (1.00 g, 2 .75 mmol), NH4Cl (0.31 g, 5.85 mmol) and Zn (0.87 g, 13.36 mmol) were stirred in 2% TPGS-750-M in water (28 ml). The reaction mixture was stirred vigorously and heated at 750C for 24 hours. The mixture was cooled to room temperature and diluted in saturated aqueous NaHCCh solution and dichloromethane. The organic phase was dried (MgSCU), filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography with a 40 g ISCO GOLD column using 0-50% (20% MeOHCH2CI2 / CH2CI2) to provide 390 mg of compound 46 as a racemic mixture. The racemic mixture was subjected to chiral separation SFC: prepared in 50% IPA, 50% hexanes, 0.2% diethylamine in AD-H to give the individual stereoisomers.

[00441] Peak A - 99% pure by chiral HPLC; (R)-4-[3-(5-amino-2-chloro-phenyl)-l,4oxazepan-4-yl]-6-methyl-pyrimidin-2-amine (47): high temperature (360 K) NMR 1H (400 MHz, DMSO-¿6) δ 7.01 (d, J = 8.5 Hz, 1H), 6.52 (d, J= 2.7 Hz, 1H), 6.47 (dd, 8 .5, 2.7 Hz, 1H), 5.51 (s, 1H), 5.43 (s, 2H), 5.26 - 5.10 (m, 1H), 4.94 (s, 2H) , 4.82 - 4.64 (m, 1H), 4.10 (dd, J = 13.5, 5.0 Hz, 1H), 3.95 - 3.84 (m, 1H), 3.69 - 3.46 (m, 3H), 1.99 (s, 2H), 1.82 - 1.65 (m, 2H), ESI-MS m / z cale. 333.14, found 334.26 (M+l)+; Retention time: 0.51 minutes; [a]D= -118.67 (c = 12 mg / 4 mi MeOH). 1-86 184 IF-2019-53902052-APN-ANP#INPI Page 184 of 423

[00442] Peak B - 99.9% purity by chiral HPLC; (S)-4-[3-(5-amino-2-chloro-phenyl)l,4-oxazepan-4-yl]-6-methyl-pyrimidin-2-amine (48): high temperature (360 K) 1H NMR (400 MHz, DMSO-í / 6) δ 7.01 (dd, J= 8.5, 1.5 Hz, 1H), 6.52 (d, J= 2.5 Hz, 1H), 6 .47 (dt, J = 8.5, 2.1 Hz, 1H), 5.51 (s, 1H), 5.44 (s, 2H), 5.26 - 5.07 (m, 1H), 4.94 (s, 2H), 4.84 - 4.66 (m, 1H), 4.11 (ddd, J= 13.4, 5.0, 1.5 Hz, 1H), 3.97 - 3.84 (m, 1H), 3.69 - 3.42 (m, 3H), 2.05 - 1.92 (m, 3H), 1.83 - 1.66 (m, 2H), ESI- MS m / z cale. 333.14, found 334.26 (M+l)+; Retention time: 0.51 minutes; [a]D= 175 (c = 8 mg / 4 ml of MeOH). 1-87

[00443] The following analogue was prepared according to Synthetic Scheme 4: h2n^j.n« / Τ (+ / -)-4-[3-(4-amino-2-chloro-phenyl)-l,4-oxazepan-4-yl]-6-methyl-pyrimidin-2-a mine (49) I140

[00444] high temperature (360 K) 1H NMR (400 MHz, DMSO-¿ / 6) δ 7.01 (m, 3H), 6.65 (d, J= 2.3 Hz, 1H), 6.52 (dd, J= 8.5, 2.3 Hz, 1H), 5.95 (br s, 1H), 5.49 - 5.36 (m, 2H), 4.70 - 4.49 (m, 1H), 4.04 (dd, J= 13.5, 5.0 Hz, 1H), 3.83 (dd, J= 10.4, 5.8 Hz, 2H), 3.75 - 3.58 (m, 3H), 2.19 (s, 3H), 1.86 - 1.75 (m, 2H), ESI-MS m / z cale. 333.14, found 334.26 (M+l)+; Retention time: 0.51 minutes. Example 5 Synthetic Scheme 5: (+ / -)-7V-[4-[4-(2-amino-6-methyl-pyrimidin-4-yl)-l,4-oxazepan-3-yl]3-chloro-phenyl] methanesulfonamide 1-139,1-179, e 1-296 1-179 I-296 (a) Methanesulfonyl chloride, NEt3, THF; (B) SFC chiral separation Formation of (+ / -)-3-(2-chloro-5-nitrophenyl)-l,4-oxazepam (50) 1-139

[00445] To a solution of 4-[3-(4-amino-2-chloro-phenyl)-l,4-oxazepan-4-yl]-6-methylpyrimidin-2-amine, 49, (0.034 g, 0.103 mmol) and triethylamine (0.050 ml, 0.360 mmol) in 185 IF-2019-53902052-APN-ANP#INPI Page 185 of 423 φ THF (1.5 ml) methanesulfonyl chloride (0.009 ml, 0.113 mmol) was added. The reaction mixture was stirred overnight at room temperature. An additional 5 uL of methanesulfonyl chloride was added. After 20 minutes, the reaction mixture was concentrated in vacuo. Purification was carried out on a 50 g 1SCO C18-AQ reverse phase column, running with 0.1% TFA / H2O and 0.1% TFA / CH3CN. The pure fractions were concentrated in vacuo and then dissolved in MeOH and passed through two SPE bicarbonate cartridges (Agilent Stratospheres 100 mg / 6 ml) arranged in series and concentrated to give 7.3 mg of the desired product: high temperature (360 K) 1H NMR (400 MHz, DMSO-J6) δ 9.97 - 9.55 (br s, 1H), 7.25-7.21 (m, 2H), 7.09 (dd, J= 8.5, 2.1 Hz, 1H), 5.59 (s, 1H), 5.42 (s, 2H), 5.36 (s, 1H), 4.60 (d, J= 13 .2 Hz, 1H), 4.08 (dd, J = 13.5, 5.0 Hz, 1H), 3.88 (d,J= 12.3 Hz, 1H), 3.70 (dd,J = 13.5, 10.2 Hz, 1H), 3.66 - 3.50 (m, 3H), 2.01 (s, 3H), 1.76 (s, 3H); ESI-MS m / z cale. 411.11, found 412.24 (M+l)+; Retention time: 0.56 minutes.

[00446] Chiral HPLC provided the individual enantiomers

[00447] Peak A: 1H NMR (400 MHz, DMSO-¿76) δ 9.66 (s, 1H), 7.28 - 7.23 (m, 2H), 7.13 (dd, J= 8, 5, 2.2 Hz, 1H), 5.59 (s, 1H), 5.46 (s, 2H), 5.39 (s, 1H), 4.59 (d, J= 14.9 Hz, 1H), 4.09 (dd, J = 13.5, 5.0 Hz, 1H), 3.93 - 3.85 (m, 1H), 3.71 (dd, J = 13.5, 10, 1 Hz, 1H), 3.66 - 3.49 (m, 2H), 2.99 (s, 3H), 2.01 (s, 3H), 1.81 - 1.70 (m, 2H). 1-179

[00448] Peak B: 1H NMR (400 MHz, DMSO-¿6) δ 7.33 - 7.22 (m, 2H), 7.13 (dd, J = 8.5, 2.2 Hz, 1H) , 5.59 (s, 1H), 5.46 (s, 2H), 5.44 - 5.34 (m, 1H), 4.59 (d, J = 15.2 Hz, 1H), 4, 09 (dd, J= 13.4, 5.0 Hz, 1H), 3.93 - 3.84 (m, 1H), 3.71 (dd, J= 13.5, 10.1 Hz, 1H) , 3.67 3.49 (m, 2H), 2.99 (s, 3H), 2.01 (s, 3H), 1.77 (ddt, J= 10.2, 8.0, 3.4 Hz, 2H). 1-296 Example 6 Synthetic scheme 6: (+ / -)- / V-[4-[4-(2-amino-6-methyl-pyrimidin-4-yl)-l,4-oxazepan-3-yl]3-chloro-phenyl ]methanesulfonamide (51) 1-282 II J « I H I cW r?· ’ 51 (a) 3-methyloxetane-3-carboxylic acid, iPr2NEt, HATU, DMF. 186 IF-2019-53902052-APN-ANP#INPI Page 186 of 423 Formation of (+ / -)-2V-(4-(4-(2-amino-6-methylpyrimidin-4-yl)-l,4-oxazepan-3-yl)-3chlorophenyl)-3-methyloxetan-3- carboxamide (51) 1-282

[00449] To a solution of 4-[3-(4-amin.o-2-chloro-phenyl)-l,4-oxazepan-4-yl]-6-methylpyrimidin-2-amine (0.05 g, 0.15 mmol), 3-methyloxetane-3-carboxylic acid (0.02 g, 0.16 mmol) and Α,Α-diisopropylethylamine (0.05 ml, 0.30 mmol) in DMF (1 ml) was added 7V-[(dimethylamino)-lH-l,2,3-triazolo[4,5-b]pyridin-l-ylmethylene]-7Vmethylmethanaminium hexafluorophosphate N-oxide (HATU) (0.08 g, 0.21 mmol ). The reaction mixture was stirred at room temperature overnight. The resulting residue was purified by preparative reverse phase HPLC (CH3CN / 0.1% aq TFA). Fractions containing the desired product were basified with a wash of saturated aqueous NaHCOa solution and extracted with dichloromethane. The organic phase was passed through a phase separator, concentrated in vacuo to provide the desired product.

[00450] The following analogues were prepared according to Synthetic Scheme 6: (31?)-7V-(4-(4-(2-amino-6-methylpyrimidin-4-yl)-l,4-oxazepan-3-yl)-3chlorophenyl)tetrahydrofuran-3-carboxamide (52) 1- 280

[00451] (Oxazepam 3-position racemic mixture) 1H NMR (400 MHz, CDCI3) δ 7.74 (s, 1H), 7.54 (s, 1H), 7.30- 7.21 (m, 1H), 7.15 (d, J = 8.4 Hz, 1H), 5.53 (s, 1H), 4.66 (s, 2H), 4.29 (dd, J = 13.6, 5 .0 Hz, 1H), 4.10 - 3.97 (m, 3H), 3.99 - 3.75 (m, 2H), 3.66 3.43 (m, 3H), 3.11 - 2 .95 (m, 1H), 2.32 - 2.22 (m, 2H), 2.12 (s, 3H), 2.02 - 1.89 (m, 1H), 1.80 (d, J = 14.3 Hz, 3H),- ES1-MS m / z cale. 431.17, found 432.18 (M+l)+; Retention time: 0.57 minutes (35)-7V-(4-(4-(2-amino-6-methylpyrimidin-4-yl)-l,4-oxazepan-3-yl)-3chlorophenyl)tetrahydrofuran-3-carboxamide (53) 1-281 187 IF-2019-53902052-APN-ANP#INPI Page 187 of 423

[00452] (Oxazepam 3-position racemic mixture) 7.74 (s, 1H), 7.54 (s, 1H), 7.30 7.21 (m, 1H), 7.15 (d, J = 8.4 Hz, 1H), 5.53 (s, 1H), 4.64 (s, 2H), 4.30 (dd, J = 13.6, 5.0 Hz, 1H), 4.11 - 3.99 (m, 3H), 3.95 - 3.79 (m, 2H), 3.65 - 3.43 (m, 3H), 3.11 - 2.95 (m, 1H), 2 .32 - 2.19 (m, 2H), 2.12 (s, 3H), 2.04 - 1.89 (m, 1H), 1.87 - 1.72 (m, 3H),- ESI- MS m / z cale. 431.17, found 432.14 (M+l)+; Retention time: 0.57 minutes (+ / -)-7V-(4-(4-(2-amino-6-methylpyrimidin-4-yl)-l,4-oxazepan-3-yl)-3-chlorophenyl)-2,2difluoropropanamide (54) 1-228

[00453] 1H NMR (400 MHz, CDC13) δ 7.91 (s, 1H), 7.78 (s, 1H), 7.36 - 7.31 (m, 1H), 7.22 (d, J = 8.4 Hz, 1H), 5.53 (s, 1H), 4.60 (s, 2H), 4.31 (dd, J= 13.6, 5.0 Hz, 2H), 4.06 (d, J= 12.5 Hz, 1H), 3.65 - 3.47 (m, 4H), 2.13 (s, 3H), 1.89 (t, J= 19.3 Hz, 5H) ; ESI-MS m / z cale. 425.1, found 426.2 (M+l)+; Retention time: 0.64 minutes. (+ / -)-7V-(4-(4-(2-amino-6-methylpyrimidin-4-yl)-l,4-oxazepan-3-yl)-3-cloiPhenyl)-2,2difluoroacetamide (55) 1-278

[00454] 1H NMR (400 MHz, CDC13) δ 7.90 (s, 1H), 7.77 (s, 1H), 7.35 (dd, J= 8.5, 2.2 Hz, 1H), 7.23 (d, J= 8.4 Hz, 1H), 6.01 (t, J= 54.2 Hz, 1H), 5.53 (s, 1H), 4.64 (s, 2H), 4.31 (dd, J= 13.6, 4.9 Hz, 1H), 4.15 - 4.01 (m, 1H), 3.68 - 3.46 (m, 3H), 2.13 ( s, 3H), 2.06 1.91 (m, 2H), 1.88 - 1.76 (m, 2H); ESI-MS m / z cale. 411.1, found 412.1 (M+l)+; Retention time: 0.6 minutes. (+ / -)-7V-(4-(4-(2-amino-6-methylpyrimidin-4-yl)-l,4-oxazepan-3-yl)-3-chlorophenyl)-3fluorotetrahydrofuran-3-carboxamide ( 56) 1-279 188 IF-2019-53902052-APN-ANP#INPI Page 188 of 423

[00455] 1H NMR (400 MHz, CDC13) δ 8.17 (d, J = 7.9 Hz, 1H), 7.81 (d, J = 7.8 Hz, 1H), 7.32 (td, J= 8.3, 2.2 Hz, 1H), 7.20 (d, J= 8.5 Hz, 1H), 5.53 (s, 1H), 4.61 (s, 2H), 4, 30 (dd, J = 13.6, 5.0 Hz, 1H), 4.19 - 4.02 (m, 6H), 3.68 - 3.49 (m, 3H), 2.77 - 2, 56 (m, 1H), 2.44 - 2.27 (m, 1H), 2.12 (s, 3H), 2.03 - 1.90 (m, 1H), 1.88 - 1.74 ( m, 2H); ESI-MS m / z calc. 449.2, found 450.1 (M+l)+; Retention time: 0.6 minutes.

[00456] The following analogues were prepared according to Scheme 6 using 4-(3-(5-amino-2-chlorophenyl)-l,4-oxazepan-4-yl)-6-methylpyrimidin-2-amine 46 as Starting material: (+ / -)-7V-[3-[4-(2-amino-6-methyl-pyriinidin-4-yl)-l,4-oxazepan-3-yl]-4-chloro-phenyl]-2( oxetan-3-yl)acetamide (57) 1-185

[00457] 1H NMR (300 MHz, Methanol-d4) δ 6.07 - 5.93 (m, 1H), 5.75 (br, 2H), 5.26 (s, 1H), 4.27 (s , 1H), 3.87 (br, 2H), 2.80 (m, 4H), 2.52 - 2.21 (m, 5H), 1.74 - 1.35 (m, 2H), 0, 83 (s, 3H), 0.56 (m, 2H); ESI-MS m / z cale. 431.2, found 432.1 (M+l)+; Retention time: 0.55 minutes. (+ / -)-7V-[3-[4-(2-amino-6-methyl-pyrimidin-4-yl)-l,4-oxazepan-3-iI]-4-chlorophenyl]cyclopropanecarboxamide (58) 1 -241

[00458] heating (360K) 1H NMR (300 MHz, DMSO-J6) δ 10.38 (s, 1H), 7.96 (s, 2H), 7.74 - 7.30 (m, 8H), 6 .65 (s, 1H), 5.95 (dd, J = 10.3, 5.4 Hz, 1H), 5.56 (s, 1H), 5.18 (dd, J- 10.1, 4 .9 Hz, 1H), 5.10 - 4.93 (m, 1H), 4.34 - 4.10 (m, 3H), 4.02 - 3.55 (m, 7H), 2.29 ( s, 3H), 2.00 - 1.63 (m, 6H), 0.79 (d, J= 7.3 Hz, 6H); ESI-MS m / z cale. 401.2, found 402.2 (M+l)+; Retention time: 0.62 minutes. 189 IF-2019-53902052-APN-ANP#INPI Page 189 of 423 or (5)- / V-[3-[(3S)-4-(2-amino-6-methyl-pyrimidin-4-yl)-l,4-oxazepan-3-yl]-4-chloro-phenyl] -3hydroxy-propanamide (59) 1-283

[00459] The racemic material was obtained using a similar procedure and then subjected to purification by chiral HPLC (column (OJ-H 20x250m), mobile phase (80% hexanes / 20% IPA / 0.2% diethylamine) , flow rate 20 ml / min).

[00460] Peak B: ee: 91%; [a]D(c = 0.5, MeOH) 32.4; 1H NMR (300 MHz, Methanol-e / 4) δ 7.63 (d, J= 2.6 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.35 (d , J= 8.7 Hz, 1H), 5.46 (br, 3H), 4.30 (dd, J= 13.6, 5.0 Hz, 1H), 4.11 - 3.97 (m, 1H), 3.85 (t, J= 6.2 Hz, 2H), 3.79 - 3.48 (m, 3H), 2.53 (t, J = 6.1 Hz, 2H), 2, 07 (s, 3H), 1.87 (m, 2H); ESI-MS m / z cale. 405.2, found 406.2 (M+l)+; Retention time: 0.58 minutes. EITHER N-(3-(4-(2-amino-6-methylpyrimidin-4-yl)-l,4-oxazepan-3-yl)-4-chlorophenyl)2,2,2trifluoroacetamide (60) I-177

[00461] The racemic material was obtained using a similar procedure and then subjected to purification by chiral HPLC (column (OJ-H 20x250m), mobile phase (80% hexanes / 20% IPA / 0.2% diethylamine) , flow rate 20 ml / min).

[00462] Peak B: ee: 99%; [a]D(c = 0.5, MeOH) 157.3; 1H NMR (300 MHz, Methanol / 4) δ 6.35 (d, J= 2.5 Hz, 2H), 6.16 (d, J= 9.2 Hz, 1H), 4.22 (br, 1H ), 3.02 (dd, J = 13.6, 5.1 Hz, 1H), 2.88 - 2.67 (m, 1H), 2.56 - 2.23 (m, 3H), 2, 03 (m, 2H), 0.59 (m, 2H); ESI-MS m / z cale. 429.1, found 429.9 (M+l)+; Retention time: 0.65 minutes. (+ / -)-7V-[3-[4-(2-amino-6-methyl-pyrimidin-4-yl)-l,4-oxazepan-3-yl]-4-chloro-phenyl]-2( dimethylamino)acetamide (61) 1-168 190 IF-2019-53902052-APN-ANP#INPI Page 190 of 423

[00463] heating (360K) 1H NMR (300 MHz, DMSO-t / 6) δ 9.90 (s, 1H), 7.73 (d, J = 8.7 Hz, 1H), 7.63 (d , J= 2.6 Hz, 1H), 7.38 (d, J= 8.7 Hz, 1H), 5.96 (brs, 2H), 5.03 (br, 2H), 4.11 (s , 1H), 3.94 (m, 1H), 3.74 - 3.47 (m, 3H), 3.33 (s, 6H), 3.04 (s, 2H), 2.25 (s, 3H), 1.98 (br, 2H); ESI-MS m / z cale. 418.2, found 419.1 (M+l)+; Retention time: 0.58 minutes. (+ / -)-7V-[3-[4-(2-amino-6-methyl-pyrimidin-4-yl)-l,4-oxazepan-3-yl]-4-chloro-phenyl]oxetane2-carboxamide (62) 1-184

[00464] 1H NMR (300 MHz, Methanol-í / 4) δ 8.60 (s, 1H), 6.59 - 6.42 (m, 1H), 6.37 - 6.19 (m, 1H), 6.10 (dd, J= 22.6, 8.7 Hz, 1H), 5.20 (s, 0.5H), 4.76 (dd, J= 10.2, 5.2 Hz, 0, 5H), 4.34 (s, 0.5H), 4.04 (dd, J= 10.2, 5.0 Hz, 0.5H), 3.78 (dd, J= 9.1, 6, 7 Hz, 1H), 3.48 - 3.29 (m, 2H), 3.16-2.91 (m, 2H), 2.81 - 2.26 (m, 4H), 1.85 - 1 .25 (m, 2H), 1.02 (s, 1.5H), 0.89 (d, J= 0.8 Hz, 1.5H), 0.61 (m, 2H); ESI-MS m / z cale. 417.2, found 418.0 (M+l)+; Retention time: 0.6 minutes. (+ / -)-7V-[3-[4-(2-amino-6-methyl-pyrimidin-4-yl)-l,4-oxazepan-3-yl]-4-chloro-phenyl]-3hydroxy- 3-methyl-butanamide (63) 1-251

[00465] 1H NMR (300 MHz, Methanol-í / 4) δ 7.75 (t, J = 10.0 Hz, 1H), 7.48 - 7.40 (m, 1H), 7.39 - 7 .29 (m, 1H), 6.52 (s, 0.5H), 6.08 (dd, J= 10.3, 5.3 Hz, 0.5H), 5.65 (d, J= 3 .3 Hz, 0.5H), 5.35 (dd, J= 10.5, 5.1 Hz, 0.5H), 5.20 (d, J= 14.4 Hz, 0.5H), 4 .46 - 4.19 (m, 1.5H), 4.14 - 3.55 (m, 4H), 2.48 (d, J= 1.4 Hz, 1.5H), 2.34 (d , J= 0.8 Hz, 1H), 2.21 (t, J = 0.9 Hz, 1.5H), 2.09 (d, J = 1.1 Hz, 1H), 1.47 - 1 .21 (m, 6H); ESI-MS m / z cale. 433.2, found 434.2 (M+l)+; Retention time: 0.59 minutes. Example 7 Synthetic Scheme 7: (+ / -)-7V-(4-(4-(2-amino-6-methylpyrimidin-4-yl)-l,4-oxazepan-3-yl)3-chlorophenyl)-2-hydroxy -2-methiipropanamide 1-277 191 IF-2019-53902052-APN-ANP#INPI Page 191 of 423 (a) 2-hydroxy-2-methylpropanamide, NaOtBu, tBuXPhos Pd G3, tBuOH, 60°C; (b) SFC chiral separation Formation of (5)-Ar-(4-(4-(2-amino-6-methylpyrimidin-4-yl)-l,4-oxazepan-3-yl)-3chlorophenyl)-2-hydroxy-2-methylpropanamide ( 64) 1-276

[00466] In a microwave tube, a mixture of 4-[3-(4-bromo-2-chloro-phenyl)-l,4oxazepan-4-yl]-6-methyl-pyrimidin-2-amine, 31, (0.77 g, 1.86 mmol), 2-hydroxy-2-methylpropanamide (0.45 g, 4.36 mmol), sodium tert-butoxide (0.56 g, 5.78 mmol), and [2 -(2aminophenyl)phenyl]-methylsulfonyloxy-palladium; Di-tert-butyl-[2-(2,4,6triisopropyl)phenyl]phosphane (tBuXPhos Pd G3) (0.06 g, 0.08 mmol) was evacuated into 2-methyl-2-propanol (14 ml) and It was refilled with nitrogen three times. The tube was then heated at 600C for 3 hours. The reaction mixture was diluted with dichloromethane and washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by reverse phase silica gel chromatography using ISCO 18-C column (150 g) eluting with 0-90% CH3CN / H2O (ammonium formate modifier). The pure fractions were concentrated in vacuo, diluted with dichloromethane and washed with water. The organic phases were passed through a phase separator and concentrated in vacuo to provide 207 mg of desired product. The racemic mixture was subjected to Purification by chiral SFC (lA-column, 20x250mm mobile phase - 20% MeOH (5 mM ammonia), 80% CO2 flow - 80 ml / min).

[00467] Peak B: 1H NMR (400 MHz, CDC13) δ 8.68 (s, 1H), 7.83 (s, 1H), 7.31 (dd, J = 8.4, 2.2 Hz, 1H), 7.16 (d, J= 8.5 Hz, 1H), 5.53 (s, 1H), 4.60 (s, 2H), 4.30 (dd, J= 13.6, 5 .0 Hz, 1H), 4.08 (d, J= 15.8 Hz, 1H), 3.64 - 3.45 (m, 4H), 2.12 (s, 3H), 1.80 (d , J= 14.3 Hz, 4H), 1.54 (s, 6H); ES1-MS m / z cale. 419.2, found 420.2 (M+l)+; Retention time: 0.58 minutes. 192 IF-2019-53902052-APN-ANP#INPI Page 192 of 423 Example 8 Synthetic Scheme 8: (+ / -)-4-(3-(2-chloro-5-(methylsulfonyl)phenyl)-l,4-oxazepan-4-yl)-6methylpyrimidin-2-amine (69) I -311 d (a) TMS-diazomethane, toluene, methanol: (b) NaBFL”, MeOH; (c) Dess-Martin periodinane, dichloromethane; (d) sieves mol 4A, 3-((tributylstannyl)methoxy)propan-l-amine, CH2CI2; then 2,6-lutidine, Cu(OTf)2, hexafluoroisopropanol, CH2CI2; (e) 2-amino-4-chloro-6methylpyrimidine, NMP, 150 °C; (f) SFC chiral separation Formation of methyl-5-2-chlorobenzoate (methylsulfonyl) (65)

[00468] To a solution of 2-chloro-5-methylsulfonyl-benzoic acid (3.0 g, 12.8 mmol) in toluene (45 ml) and MeOH (10 ml) TMS-diazomethane (10, 7 ml of 2 M in hexane, 21.4 mmol). The reaction mixture was stirred for 3 hours and the solvent was concentrated in vacuo to give 3 g of desired product as a tan fluffy solid which was used without further purification: 1H NMR (400 MHz, DMSO-0Z6) δ 8 .32 (d, J= 2.3 Hz, 1H), 8.10 (dd, J= 8.4, 2.4 Hz, 1H), 7.90 (d, J= 8.5 Hz, 1H) , 3.92 (s, 3H), 3.30 (s, 6H); ESI-MS m / z cale. 247.99, found 249.12 (M+l)+; Retention time: 0.71 minutes. Formation of (2-chloro-5-(methylsulfonyl)phenyl)methanol (66)

[00469] To a suspension of methyl 2-chloro-5-methylsulfonyl-benzoate, 65, (3.0 g, 12.1 mmol) in EtOH (45 ml) was added NaBHq (1.83 g, 48.4 mmol). The reaction mixture was stirred at room temperature for 1 hour, then heated to 500C to solubilize the mixture. After 3 hours, the mixture was quenched by slow addition in saturated aqueous NH4Cl solution. The aqueous phase was extracted twice with EtOAc. The combined organic phases were washed with saturated aqueous NaHCO3 solution, dried 193 IF-2019-53902052-APN-ANP#INPI Page 193 of 423 (MgSCL), was filtered and concentrated in vacuo to give 2.5 grams of desired product as an orange oil. The crude residue was purified by silica gel chromatography with a 40 g ISCO column using 0-30% EtOAc / CH2Cl2 gradient to provide 2.0 grams of product as a white solid: ESI-MS m / z cal. 219.99, found 221.06 (M+l)+; Retention time: 0.61 minutes. Formation of 2-chloro-5-(methylsulfonyl)benzaldehyde (67)

[00470] (2-chloro-5-methylsulfonyl-phenyl) methanol, 66, (1.00 g, 4.50 mmol) was dissolved in methylene chloride (23 ml). Dess-Martin periodinane (2.49 g, 5.87 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The solution was diluted in saturated aqueous NaHCCh solution and extracted twice with EtOAc. The combined organic phases were washed with saturated aqueous NaHCOa solution, dried (MgSOy, filtered and concentrated in vacuo. The crude residue was purified by chromatography on silica gel with a 40 g ISCO column using 0-20% gradient of EtOAc / CH2Cl2 to provide 760 mg of desired product: 1H NMR (400 MHz, DMSO-J6) δ 10.36 (s, 1H), 8.31 (d, J= 2.4 Hz, 1H), 8.20 ( dd, J= 8.4, 2.4 Hz, 1H), 7.94 (d, .7=8.4 Hz, 1H), 3.32 (s, 3H). Formation of 3-(2-chloro-5-(methylsulfonyl)phenyl)-l,4-oxazepan (68)

[00471] To a solution of 3-(tributylstannylmethoxy)propan-l-amine (0.88 g, 2.33 mmol) in dichloromethane (6 ml) was added 2-chloro-5-methylsulfonyl-benzaldehyde, 67, (0 .51 g, 2.33 mmol) followed by 4A molecular sieves. The mixture was stirred overnight, filtered to remove the sieves, and diluted with dichloromethane (25 mL).

[00472] In a separate flask containing hexafluoroisopropanol (7 ml) 2,6lutidine (0.28 ml, 2.39 mmol) was added followed by Cu(OTf)2 (0.85 g, 2.34 mmol). The mixture was stirred for 1 hour, then the imine solution prepared above was added in one portion. The reaction was stirred for 3 days at room temperature. The mixture was diluted with 60 ml of 2:1 mixture of saturated aqueous NaHCOa solution and 10% ammonium hydroxide. After stirring for 30 minutes, the organic layer was separated and washed twice with saturated aqueous NaHCCh solution, then with brine. The organic layer was passed through a phase separating funnel and concentrated in vacuo. He 194 IF-2019-53902052-APN-ANP#INPI Page 194 of 423 The resulting residue was purified by reverse phase silica gel chromatography using 100 gram ISCO - cl8-aq Column - running with 0.1% TFA / H2O and 0.1% TFA / CH3CN. The fractions containing the product were concentrated in vacuo and the residue was diluted with dichloromethane and neutralized with a saturated aqueous NaHCO3 solution. The organic phase was passed through a phase separator and concentrated in vacuo. 1H NMR shows desired product plus additional impurity. The product was used without further purification: 1H NMR (400 MHz, DMSO-¿ / 6) δ 8.16 (d, J= 2.4 Hz, 1H), 7.81 (dd, J= 8.4, 2 .4 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 4.29 (dd, J = 9.0 , 3.1 Hz, 1H), 3.91 - 3.76 (m, 2H), 3.76 - 3.63 (m, 1H), 3.22 (s, 3H), 3.12 (dd, J= 12.7, 8.7 Hz, 1H), 2.89 (dt, J= 13.6, 6.8 Hz, 2H), 1.93 - 1.78 (m, 2H); ES1-MS m / z cale. 390.05, found 390.09 (M+1)+; Retention time: 0.50 minutes. Formation of 4-(3-(2-chloro-5-(methylsulfonyl)phenyl)-l,4-oxazepan-4-yl)-6-methylpyrimidin2-amine (69)

[00473] To a solution of 3-(2-chloro-5-methylsulfonyl-phenyl)-l,4-oxazepane, 68, (0.200 g, 0.690 mmol) in NMP (6 ml) was added 4-chloro-6- methyl-pyrimidin-2-amine (0.123 g, 0.857 mmol). The reaction mixture was heated at 1500C for 18 hours. The reaction mixture was cooled to room temperature and the material was loaded directly onto a 50 g ISCO cl8-AQ column and purified by reverse phase silica gel chromatography using a 50 gram ISCO column running with 0. 1% TFA / H2O and 0.1% TFA / CH3CN. The pure fractions were combined and concentrated in vacuo. The residue was diluted with dichloromethane, neutralized with saturated aqueous NaHCOs solution, passed through a phase separator and the resulting organic phase was concentrated in vacuo to provide 84 mg of brown solid: high temperature (360 K) 1H NMR (400 MHz, DMSO-í / 6) δ 7.85 - 7.73 (m, 2H), 7.71 (d, J= 8.3 Hz, 1H), 5.7 5-5.54 (m, 2H), 5.50 - 5.34 (m, 2H), 4.48 (d,J= 14.9 Hz, 1H), 4.11 (dd,J= 13.5,4.9 Hz, 1H), 3.92 - 3.65 (m, 3H), 3.67 - 3.50 (m, 1H), 3.18 - 3.11 (m, 3H), 2.03 (d, J= 5.4 Hz, 3H), 1.80 (s, 2H).

[00474] The racemic mixture was subjected to chiral separation SFC: prepared in 50% IPA, 50% hexanes, 0.2% diethylamine in AD-H 195 IF-2019-53902052-APN-ANP#INPI Page 195 of 423

[00475] Peak A: (7?)-4-(3-(2-chloro-5-(methylsulfonyl)phenyl)-l,4-oxazepan-4-yl)-6methylpyrimidin-2-amine (70), 96 .4% ee by HPLC; heating (360K) 1H NMR (400 MHz, DMSO-í / 6) δ 7.81 (ddd, J= 8.3, 2.3, 1.1 Hz, 1H), 7.78 (d, J= 2 .3 Hz, 1H), 7.71 (dd, J= 8.3, 1.2 Hz, 1H), 5.70 (s, 1H), 5.62 (dd, J= 9.9, 4, 8 Hz, 1H), 5.43 (s, 2H), 4.48 (d, J = 15.4 Hz, 1H), 4.11 (dd, J= 13.4, 4.9 Hz, 1H) , 3.97 - 3.68 (m, 3H), 3.66 - 3.52 (m, 1H), 3.16 (d,J= 1.2 Hz, 3H), 2.04 (d,J = 1.0 Hz, 3H), 1.89- 1.70 (m, 2H); ES1-MS m / z cale. 396.10, found 397.25 (M+l)+; Retention time: 0.56 minutes; [a]o = -42.40 (c = 5 mg / 2 ml of MeOH). 1-102

[00476] Peak B (S)-4-(3-(2-chloro-5-(methylsulfbnyl)phenyl)-l,4-oxazepan-4-yl)-6methylpyrimidin-2-amine (71), 98 +% ee by HPLC; heating (360K) 1H NMR (400 MHz, DMSO-í / 6) δ 7.81 (dd, J= 8.3, 2.3 Hz, 1H), 7.78 (d,J=2.2 Hz, 1H), 7.71 (d,J=8.3 Hz, 1H), 5.70 (s, 1H), 5.62 (dd, J= 9.9, 4.9 Hz, 1H), 5, 42 (s, 2H), 4.48 (d, J= 15.2 Hz, 1H), 4.11 (dd, J= 13.5, 4.9 Hz, 1H), 3.94 - 3.70 (m, 3H), 3.60 (ddd, J= 12.0, 9.5, 4.7 Hz, 1H), 3.15 (s, 3H), 2.04 (s, 3H), 1, 80 (dt, J = 8.3, 4.2 Hz, 2H); ESI-MS m / z cale. 396.10, found 397.20 (M+l)+; Retention time: 0.55 minutes; [cc]d = 77.82 (c = 5.5 mg / 2 ml of MeOH). 1-103

[00477] The following analogue was prepared according to Synthetic Scheme 8: A Y I 72 l-(3-(4-(2-amino-6-methylpyrimidin-4-yl)-l,4-oxazepan-3-yl)-4-chloropheniI)pyrrolidin-2one (72) 1-119

[00478] 1H NMR (400 MHz, DMSO-¿6) δ 7.76 (d, J = 2.7 Hz, 1H), 7.45 (dd, J = 8.7, 2.7 Hz, 1H) , 7.39 (d, J= 8.8 Hz, 1H), 5.59 (s, 1H), 5.42 (s, 3H), 4.63 (d, J= 15.1 Hz, 1H) , 4.12 (dd, J= 13.4, 5.0 Hz, 1H), 3.91 (dt, J= 11.5, 3.8 Hz, 1H), 3.81 - 3.73 (m , 2H), 3.72 3.52 (m, 3H), 2.47 - 2.40 (m, 2H), 2.08 - 2.01 (m, 2H), 2.00 (s, 3H) , 1.80 (ddt, J= 10.9, 7.5, 4.2 Hz, 2H); ESI-MS m / z cale. 401.16, found 402.0 (M+l)+; Retention time: 0.65 minutes. 196 IF-2019-53902052-APN-ANP#INPI Page 196 of 423 Example 9 Synthetic Scheme 9: (+ / -)-4-(2-(2,5-dimethoxyphenyl)azepan-l-yl)-6-methylpyrimidin-2amine (77) 1-25 d (a) DMF, POCI3, CH2CI2, 0°C to 40°C; (b) 2,5-dimethoxyphenylboronic acid, Pd(Ph3P)2C12, DME, 50 °C; (c) Pd / C, HOAc, EtOAc, MeOH; (d) EtMgBr, THF, 0 °C; (E) 2-amino-4chloro-6-methylpyrimidine, NMP, 150°C; (f) SFC chiral separation Formation of 7-chloro-2,3,4,5-tetrahydro-lH-azepin-l-carbaldehyde (73)

[00479] A 3L 3-neck round bottom flask equipped with top stirrer, temperature probe, addition funnel, nitrogen inlet and reflux merge was charged with DMF (360 ml, 4.65 mol) in dichloromethane (500 e) and stirred for 5 minutes and then cooled to 00C. POCI3 (220 ml, 2.36 mol) in dichloromethane (300 ml) was added over 60 minutes maintaining the internal temperature below 70C. The reaction mixture was heated to 400C (the colorless solution observed turned pale orange) and stirred at this temperature for 45 minutes. Azepan-2-one (85 g, 751.2 mmol) in dichloromethane (450 ml) was added for 45 minutes at reflux (Tmax observed 450C). The resulting reaction mixture was stirred at this temperature for 3 h where HPLC analysis revealed the consumption of the starting material. The reaction mixture was cooled to room temperature, poured into crushed ice (3 L), and then left at room temperature for 12 h. The aqueous layer was separated, basified with solid K2CO3 to pH 9, allowed to warm to room temperature and stirred at this temperature for 18 h. The mixture was diluted with dichloromethane (2 L) and the organic layer was separated. The aqueous layer was extracted with dichloromethane (1 L) and the combined organic extracts were washed with water (100 ml), brine (200 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel cartridge using 0% —> 30% acetate 197 IF-2019-53902052-APN-ANP#INPI Page 197 of 423 ethyl / heptane containing 1% EtaN, the fractions containing the desired product were collected, concentrated under reduced pressure to give 7-chloro-2,3,4,5tetrahydroazepin-l-carbaldehyde (110 g , 92%) as a clear, colorless oil. Formation of 7-(2,5-dimethoxyphenyl)-2,3,4,5-tetrahydro-l / / -azepin-l-carbaldehyde (74)

[00480] A 2-neck round bottom flask was charged under nitrogen with 7-chloro2,3,4,5-tetrahydroazepin-l-carbaldehyde, 73, (3.00 g, 18.80 mmol), acid (2, 6-Dimethoxyphenyljboronic acid (4.45 g, 24.44 mmol), DME (24.67 ml) and bis(triphenylphosphine)palladium(II) chloride (0.53 g, 0.75 mmol). stirred overnight at 50°C. The mixture was diluted with water and dichloromethane. The layers were separated through a phase separator and the organic phase was concentrated in vacuo. The crude residue was purified by silica gel chromatography. a 12 g ISCO GOLD column; 10-100% EtOAc in heptane) as a pale yellow oil. 1H NMR (300 MHz, DMSO-Z6) δ 7.79 (s, 1H), 7.27 (t, J= 8.4 Hz, 1H), 6.67 (d, J= 8.4 Hz, 2H), 5.41 (t, J= 6.1 Hz, 1H), 3.74 (s, 6H), 3.69 - 3.48 (m, 2H), 2.31 - 2.12 (m , 2H), 1.83 - 1.48 (m, 4H); ESIMS w / z calc. 261.14, found 262.15 (M+l)+; Retention time: 0.84 minutes. Formation of 2-(2,5-dimethoxyphenyl)azepan-l-carbaldehyde (75)

[00481] To a solution of 7-(2,6-dimethoxyphenyl)2,3,4,5-tetrahydroazepin-l-carbaldehyde, 74, (3.00 g, 11.48 mmol) in MeOH (30 ml) and EtOAc (30 mL), HOAc (9 mL) and Pd / C (0.24 g, 2.30 mmol) were added. The flask was charged with a hydrogen balloon after purging three times with vacuum. The mixture was stirred at room temperature overnight. The mixture was filtered through celite and the solvent was evaporated. The resulting crude oil was used without further purification. Formation of (+ / -)-2-azepan(2,5-dimethoxyphenyl) (76)

[00482] To a solution of 2-(2,4-dimethoxyphenyl)azepan-l-carbaldehyde, 75, (1.80 g, 6.51 mmol) in THF (50 ml) was added ethylmagnesium bromide (2.21 g, 2.17 ml of a 3 M solution in ether, 6.51 mmol) at 00C. The mixture was stirred at 0 °C for 3 hours. The mixture was carefully quenched by the addition of 2N NaOH solution and then extracted with EtOAc. The combined organic layers were washed with brine, and dried 198 IF-2019-53902052-APN-ANP#INPI Page 198 of 423 on MgSO4, they were filtered and concentrated in vacuo. The crude residue was purified by ISCO elution with methanol / dichloromethane gradient. Formation of (R)-4-(2-(2,5-dimethoxyphenyl)azepan-l-yl)-6-methylpyrimidin-2-amine (78) and (5)-4-(2-(2,5- dimethoxypheniI)azepan-l-yl)-6-methylpyrimidin-2-amine (79)

[00483] To a mixture of solids 4-chloro-6-methyl-pyrimidin-2-amine (0.15 g, 1.02 mmol) and 2-(2,4-dimethoxyphenyl)azepane, 76, (0.24 g, 1.02 mmol) EtOH (2 ml) was added to a vial. The vial was placed on the hot plate and heated at 1800C without cap for 2 hrs. The crude residue was purified by silica gel chromatography with a 40 g ISCO column eluting with 20% MeOH-dichloromethane / dichloromethane gradient to provide 32 mg of the desired product: 1H NMR (300 MHz, DMSO-¿6) δ 7.19 (s, 2H), 6.91 (dd, J = 36.7, 8.5 Hz, 1H), 6.61 (s, 1H), 6.52 - 6.36 (m, 2H) , 5.70 (s, 1H), 4.78 (dd, J= 67.0, 11.7 Hz, 2H), 3.88 (s, 3H), 3.73 (d, J= 2.4 Hz, 5H), 3.62 - 3.14 (m, 6H), 2.18 (d, J= 39.5 Hz, 5H), 1.95 - 1.70 (m, 5H), 1.34 (dd, J = 49.7, 10.8 Hz, 3H); ESI-MS m / z cale. 342.21, found 343.32 (M+l)+; Retention time: 0.72 minutes.

[00484] The racemate (4.0 g) was subjected to separation by SFC (column: IC, 4.6x1 OOmrn IC, 20x250mm mobile phase: 40% EtOH (5 mM Ammonia), 60% CO2, 40% EtOH (5 mM Ammonia), 60% CO2, to give:

[00485] Peak A: 1.61 grams of (7?)-4-(2-(2,5-dimethoxyphenyl)azepan-l-yl)-6methylpyrimidin-2-amine (78): ee=98%; [a]D(c = 1.0, MeOH) + 111.98; 1H NMR (300 MHz, DMSO-¿6) δ 6.94 (br, 1H), 6.75 (br, 1H), 6.48 (s, 1H), 5.89 (s, 3H), 4, 76 (brs, 1H), 3.83 (s, 3H), 3.64 (s, 3H), 3.32 (brs, 2H), 1.94 (br, 3H), 1.81 - 0.95 (m, 8H); ESI-MS m / z cale. 342.21, found 343.27 (M+l)+; Retention time: 0.74 minutes. 1-40

[00486] Peak B: 1.21 grams of (5)-4-(2-(2,5-dimethoxyphenyl)azepan-l-yl)-6methylpyrimidin-2-amine (79): ee = 96%; [a]D(c = 1.0, MeOH) -147.32; 1H NMR (300 MHz, DMSO-í / 6) δ 7.56 - 7.10 (br, 2H), 6.89 (br, 2H), 6.64 - 6.39 (m, 1H), 5, 86 - 5.65 (m, 1H), 4.83 (br, 1H), 4.05 (d, J = 15.3 Hz, 0.5H), 3.83 (s, 3H), 3.67 (s, 3H), 3.59 - 3.41 (m, 1.5H), 2.22 (d, J = 37.7 Hz, 3H), 2.00 - 0.94 (m, 8H); ESI-MS m / z cale. 342.21, found 343.32 (M+l)+; Retention time: 0.76 minutes. 1-41

[00487] The following analogues were prepared according to Synthetic Scheme 9: 199 IF-2019-53902052-APN-ANP#INPI Page 199 of 423 (+ / -)-4-(2-(2-chloro-5-methoxyphenyl)azepan-l-yl)-6-methylpyrimidin-2-amine (80) 1-117

[00488] 1H NMR (300 MHz, DMSO-J6) δ 7.77 (s, 1H), 7.52 - 7.28 (m, 2H), 6.90 (ddd, J= 20.8, 8, 8, 2.8 Hz, 1H), 6.58 (s, OH), 5.82 - 5.46 (m, 1H), 5.03 - 4.69 (m, 1H), 4.13 (d , J= 15.2 Hz, 1H), 3.58 - 3.25 (m, 12H), 2.28 (s, 2H), 2.04 - 1.08 (m, 9H); ESI-MS m / z cale. 346.16, found 347.17 (M+l)+; Retention time: 0.72 minutes. 82 (7?)-4-(2-(2-chloro-5-methoxyphenyl)azepan-l-yl)-6-methylpyriinidin-2-ainine (81) 1-135 and (5)4-(2-( 2chloro-5-methoxyphenyl)azepan-l-yl)-6-methylpyrimidin-2-amine (81) 1-136

[00489] 4-[2-(2-chloro-5-methoxy-phenyl)azepan-l-yl]-6-methyl-pyrimidin-2-amine (450 mg, 1.289 mmol) was subjected to separation by SFC. SFC conditions: Column: IC, 20x250mm; mobile phase: 30% MeOH (5 mM Ammonia), 70% CO2; Flow: 75ml / min; Concentrations: ~ 40 mg / ml (MeOH); Injection volume: 500 pL; Wavelength: 214nm; Isocratic Type Method

[00490] Peak A: [a]D(c = 0.5, MeOH) 74.56; 99.4% ee

[00491] (J?)-4-[2-(2-chloro-5-methoxy-phenyl)azepan-l-yl]-6-methyl-pyrimidin-2-amine (81): 1H NMR (300 MHz, DMSO-¿6) δ 7.36 (d, J= 8.8 Hz, 1H), 6.85 (d, J= 8.2 Hz, 1H), 6.62 (s, 1H), 6.07 (br, 2H), 4.78 (brs, 1H), 3.70 (s, 3H), 3.29 (br, 2H), 1.99 (s, 3H), 1.88 - 1.09 ( m, 8H); ESI-MS m / z cale. 346.16, found 347.2 (M+l)+; Retention time: 0.72 minutes. 1-135

[00492] Peak B: [a]D(c = 0.5, MeOH) -76.80; 99% ee

[00493] (S)-4-[2-(2-chloro-5-methoxy-phenyl)azepan-l-yl]-6-methyl-pyrimidin-2-amine (82) (200 mg, 89%): 1H NMR (300 MHz, DMSO-¿ / 6) δ 7.78 (s, 1H), 7.39 (m, 2H), 7.01 - 6.77 (m, 1H), 6.62 (d, 3.0 Hz, 1H), 6.49 (s, 0.5H), 5.72 (dd, J= 12.5, 5.1 Hz, 0.5H), 5.55 (s, 0.5H) ), 5.07 - 4.89 (m, 0.5H), 4.79 (d, J= 13.8 Hz, 0.5H), 4.13 (d, J= 15.3 Hz, 0, 5H), 3.73 (d, J= 3.3 Hz, 3H), 3.57 (t, J= 11.9 Hz, 1H), 3.18 (s, 1H), 2.28 (s, 1.5H), 2.15 (s, 1.5H), 200 IF-2019-53902052-APN-ANP#INPI Page 200 of 423 2.05 - 0.97 (m, 8H); ESI-MS m / z calc. 346.16, found 347.15 (M+l)+; Retention time: 0.72 minutes. 1-136 (+ / -)-4-[2-(2-fluoro-6-methoxy-phenyl)azepan-l-yl]-6-methyl-pyrimidin-2-amine (83) 1-50

[00494] 1H NMR (300 MHz, DMSO-46) δ 7.44 - 6.59 (m, 5H), 5.68 (s, 1H), 5.04 (d, J = 11.0 Hz, 0.5H), 4.67 (d, J= 14.2 Hz, 0.5H), 3.94 (s, 3H), 3.60 - 3.10 (m, 2H), 2.29 - 1.69 (m, 8H), 1.53 - 0.87 (m, 3H); ESI-MS m / z calc. 330.19, found 331.29 (M+l)+; Retention time: 0.72 minutes. (+ / -)-4-[2-(4-chlorophenyl)azepan-l-yl]-6-methyl-pyrimidin-2-amine (1-43)

[00495] 1H NMR (300 MHz, DMSO-46) δ 7.37 (d, J= 8.2 Hz, 2H), 7.28 (d, J= 8.3 Hz, 2H), 6.84 ( s, 2H), 5.81 (s, 1H), 4.76 (br, 1H), 4.00 - 2.99 (m, 2H), 2.20 (s, 3H), 1.95 - 0 .97 (m, 8H); ESI-MS m / z calc. 316.15, found 317.24 (M+l)+; Retention time: 0.72 minutes. (+ / -)-4-[2-(3-chlorophenyl)azepan-l-yl]-6-methyl-pyrimidin-2-amine (1-44)

[00496] 1H NMR (300 MHz, DMSO-46) δ 7.78 - 7.12 (m, 5H), 6.29 (s, 2H), 6.10 - 5.47 (m, 1H), 4 .43 - 3.61 (m, 1H), 3.34 - 2.92 (m, 2H), 2.14 (s, 3H), 1.98 - 0.89 (m, 8H); ESIMS m / z calc. 316.15, found 317.19 (M+l)+; Retention time: 0.72 minutes. 201 IF-2019-53902052-APN-ANP#INPI Page 201 of 423 (+ / -)-4-[2-(3-fluorophenyl)azepan-l-yl]-6-methyl-pyrimidin-2-amine 1-29

[00497] high temperature (360 K) 1H NMR (400 MHz, DMSO-t / 6) δ 7.31 (dd, J = 14.4, 7.7 Hz, 1H), 7.06 (d, J = 7.8 Hz, 1H), 6.95 (dd, J = 14.0, 5.8 Hz, 2H), 5.74 (s, 1H), 5.43 (br s, 3H), 4.07 (br s, 1H), 3.16 (dd, J = 13.4, 11.5 Hz, 1H), 2.46 - 2.35 (m, 1H), 2.04 (s, 3H), 1 .88-1.62 (m, 4H), 1.62 - 1.50 (m, 1H), 1.41 - 1.21 (m, 2H). ESI-MS m / z cale. 300.18, found 301.21 (M+l) +; Retention time: 0.64 minutes. (+ / -) - 4- [2- (2,4-dimethoxyphenyl) azepan-l-yl] -6-methyl-pyrimidin-2-amine (84) 1-51

[00498] 1H NMR (300 MHz, DMSO -¿6) δ 7.19 (s, 2H), 6.91 (dd, J= 36.7, 8.5 Hz, 1H), 6.61 (s, 1H), 6.52 - 6.36 (m, 2H), 5.70 (s, 1H), 4.78 (dd, J= 67.0, 11.7 Hz, 2H), 3.88 (s, 3H), 3.73 (d, J= 2.4 Hz, 5H), 3.62 - 3.14 (m, 6H), 2.18 (d, J = 39.5 Hz, 5H), 1.95 - 1.70 (m, 5H ), 1.34 (dd, J = 49.7, 10.8 Hz, 3H); ESI-MS m / z cale. 342.20, found 343.32 (M+l)+; Retention time: 0.72 minutes. (+ / -)-4-(2-cyclopentylazepan-l-yl)-6-methylpyrimidin-2-amine 1-9

[00499] A suspension of 4-chloro-6-methyl-pyrimidin-2-amine (0.094 g, 0.657 mmol), 2cyclopentylazepane (0.100 g, 0.598 mmol) and 'Pr2NEt (0.230 ml, 1.320 mmol) in IPA (0. 6 mi) was sealed in a microwave tube and irradiated at 1600C for 2 hours. The mixture was concentrated in vacuo and purified by reverse phase chromatography (0.1% TFA / acetonitrile). The material was converted to HC1 salt to give 46 mg of the desired product: 1H NMR (400 MHz, MeOD) δ 6.31 (2s, 1H), 5.06 - 4.91 (m, 1H), 4.48 - 3.34 (m, 2H), 2.35 - 2.27 (m, 3H), 2.27 - 2.15 (m, 1H), 2.02 (qd, J= 16.7, 8, 3 Hz, 1H), 1.92 - 1.15 (m, 14H), 1.14 - 0.96 (m, 1H); ESI-MS m / z cale. 274.22, found 275.18 (M+l)+; Retention time: 2.84 minutes 202 IF-2019-53902052-APN-ANP#INPI Page 202 of 423 (+ / -)-4-methyl-6-[2-(4-pyridyl)azepan-l-yl]pyrimidin-2-amine 1-35

[00500] ESI-MS m / z calc. 283.18, found 284.22 (M+l)+; Retention time: 2.14 minutes. (+ / -)-4-[2-(4-fluorophenyl)azepan-l-yl]-6-methiI-pyrimidin-2-amine 1-34

[00501] high temperature (360 K) 1Η NMR (400 MHz, DMSO-¿ / 6) δ 7.28 - 7.21 (m, 2H), 7.05 (m, 2H), 5.72 (s, 1H), 5.65 (s, 2H), 5.42 (m, 3H), 4.03 (s, 1H), 3.15 (dd, J = 13.3, 11.6 Hz, 1H), 2.44 - 2.34 (m, 1H), 2.03 (s, 3H), 1.90 - 1.65 (m, 4H), 1.63 - 1.48 (m, 1H), 1, 42 1.21 (m, 2H). ESI-MS m / z cale. 300.18, found 301.22 (M+l)+; Retention time: 2.97 minutes. (+ / -)-4-methyl-6-[2-(p-tolyl)azepan-l-yl]pyrimidin-2-amine 1-33

[00502] high temperature (360 K) 1H NMR (400 MHz, DMSO-¿6) δ 7.12 - 7.04 (m, 4H), 5.70 (s, 1H), 5.65 (s, 2H ), 5.39 (s, 1H), 5.39 - 5.20 (m, 1H), 4.08 (s, 1H), 3.18 - 3.07 (m, 1H), 2.42 - 2.32 (m, 1H), 2.24 (s, 3H), 2.02 (s, 3H), 1.88 - 1.66 (m, 4H), 1.63 - 1.50 (m, 1H), 1.31 (m, 2H). ESI-MS m / z cale. 296.20, found 297.25 (M+l)+; Retention time: 3.07 minutes. (+ / -)-4-[2-(4-methoxyphenyl)azepan-l-yl]-6-methyl-pyrimidin-2-amine 1-23

[00503] high temperature (360 K) 1H NMR (400 MHz, DMSO-¿6) δ 7.12 - 7.04 (m, 4H), 5.70 (s, 1H), 5.65 (s, 2H), 5.39 (s, 1H), 5.39 - 5.20 (m, 1H), 4.08 (s, 1H), 3 .18 - 3.07 (m, 203 IF-2019-53902052-APN-ANP#INPI Page 203 of 423 1H), 2.42 - 2.32 (m, 1H), 2.24 (s, 3H), 2.02 (s, 3H), 1.88 - 1.66 (m, 4H), 1.63 - 1.50 (m, 1H), 1.31 (m, 2H); ESI-MS m / z calc. 296.20, found 297.25 (M+l)+; Retention time: 3.07 minutes. Example 10 Synthetic Scheme 10: (+ / -)-4-(2-(2,5-dimethoxy-4-pyridyl)azepan-l-yl]-6-methylpyrimidin-2-amine (88) 1-116 (a) (2,5-dimethoxy-4-pyridyl)boronic acid, Pd(Ph3P)2Cl2, NaHCO3, DME, water, 60 °C; (c) Pd / C, formic acid, EtOAc, MeOH; (d) nBuLi, THF, −78 °C; (e) 2-amino-4-chloro-6methylpyrimidine, NMP, 150°C; (f) SFC chiral separation Formation of 7-(2,5-dimethoxy-4-pyridyl) 2,3,4,5-tetrahydroazepin-l-carbaldehyde (85)

[00504] A 2-neck round bottom flask under nitrogen atmosphere was charged with 7 -chloro-2,3,4,5-tetrahydroazepin-l-carbaldehyde, 73, (0.79 g, 4.95 mmol), (2,5dimethoxy-4-pyridyl)boronic acid (1.00 g, 5, 46 mmol) in DME (10 ml), followed by NaHCO3 (8 ml of 1.2 M solution, 9.6 mmol) and bis(triphenylphosphine)palladium (II) chloride (0.14 g, 0.20 mmol) . It was stirred overnight at 60°C. Water and dichloromethane were added. The layers were separated through a phase separator, and the organics were concentrated in vacuo after a second extraction. Purification by silica gel chromatography (40 g GOLD column; 10-100% EtOAc / heptanes gradient) gave 1 g (47%) of the desired product: 1H NMR (300 MHz, CDC13) δ 7.94 ( s, 1H), 7.75 (s, 1H), 7.28 (d, J= 1.1 Hz, 1H), 6.64 (s, 1H), 3.91 (s, 3H), 3, 84 (s, 3H), 3.80 - 3.69 (m, 2H), 2.43 - 2.29 (m, 2H), 1.87 (dd, J = 8.5, 3.8 Hz, 2H), 1.71 - 1.64 (m, 2H); ESI-MS m / z cale. 262.13, found 263.07 (M+l)+; Retention time: 0.75 minutes. Formation of 2-(2,5-dimethoxy-4-pyridyl)azepan-l-carbaldehyde (86)

[00505] To a solution of 7-(2,5-dimethoxy-4-pyridyl)2,3,4,5-tetrahydroazepine-lcarbaldehyde, 85, (1.0 g, 3.8 mmol) in MeOH (20 ml ) and EtOAc (20 ml) acid was added 204 IF-2019-53902052-APN-ANP#INPI Page 204 of 423 formic (1.7 g, 37.0 mmol) and Pd / C (40 mg, 0.4 mmol) in N2 atmosphere. The reaction mixture was charged with H2(balloon) and stirred at room temperature overnight. Filtered through celite, the solvent was evaporated. The residue was purified by silica gel column (40 g) in 1SCO eluting 0% to 50% EtOAc / heptanes gradient. The desired fractions were collected and evaporated to provide 1.0 grams (51%) of the desired product: ESI-MS m / z cale. 264.15, found 265.14 (M+l)+; Retention time: 0.72 minutes. Formation of 2-(2,5-dimethoxy-4-pyridyl)azepan (87)

[00506] To a solution of 2-(2,5-dimethoxy-4-pyridyl) azepan-l-carbaldehyde, 86, (1.00 g, 3.78 mmol) in THF (20 ml) was added n-butyl -lithium (5.0 ml of 1.6 M, 8.00 mmol) at -78°C. The mixture was stirred at -780C for 2 hours. The reaction mixture was carefully quenched by the addition of MeOH. A 2N HC1 solution was added to the mixture until pH = 2. The resulting solution was then basified by the addition of 6N NaOH until pH = 10. The aqueous solution was extracted with EtOAc and the combined organic layers They were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to provide 230 mg of desired product: ESIMS m / z cale. 236.15, found 237.15 (M+1)+; Retention time: 0.58 minutes. Formation of 4-[2-(2,5-dimethoxy-4-pyridI)azepan-l-yl]-6-methyl-pyrimidin-2-amine (88) 1-116

[00507] To a mixture of solids 4-chloro-6-methyl-pyrimidin-2-amine (0.12 g, 0.81 mmol) and 2-(2,5-dimethoxy-4-pyridyl)azepane (0. 23 g, 0.90 mmol) EtOH (2 ml) was added to a vial. The vial was placed on the hot plate and heated at 1600C without cap for 2 hours. The crude solid was purified by silica gel chromatography (40 g) in ISCO eluting with 20% MeOH / dichloromethane-dichloromethane to provide 6.5 mg of the desired product: 1H NMR (300 MHz, DMSO-J6) δ 7, 85 (s, 1H), 7.56 (br, 2H), 6.48 (s, 0.5H), 6.30 (s, 0.5H), 5.69 (s, 1H), 4.81 (m, 1H), 3.88 (s, 3H), 3.75 (s, 3H), 3.61 - 3.25 (m, 2H), 2.28 (s, 3H), 1.99 - 1.07 (m, 8H); ESI-MS m / z cale. 343.20, found 344.16 (M+l)+; Retention time: 0.65 minutes.

[00508] The following analogues were prepared according to Synthetic Scheme 10: 205 IF-2019-53902052-APN-ANP#INPI Page 205 of 423 4-[2-(2-chloro-5-isopropoxy-phenyl)azepan-l-yl]-6-methyl-pyrimidin-2-amine (89) 1-104

[00509] 1H NMR (300 MHz, DMSOY6) δ 7.78 (s, 1H), 7.50 - 7.25 (m, 2H), 6.88 (ddd, J = 20.5, 8.8, 2.8 Hz, 1H), 6.68 - 6.39 (m, 1H), 5.81 - 5.46 (m, 1H), 5.09 - 4.72 (m, 1H), 4.56 (m, 1H), 4.13 (d, J= 14.6 Hz, 1H), 3.87 - 3.46 (m, 1H), 2.22 (s, 3H), 2.05 - 1.34 (m, 8H), 1.23 (d , J= 5.4 Hz, 6H); ESI-MS m / z calc. 374.19, found 375.07 (M+l)+; Retention time: 0.76 minutes. (R)-4-[2-(2-chloro-5-isopropoxy-phenyl)azepan-l-yl]-6-methyl-pyrimidin-2-amine (90) 1-108

[00510] SFC conditions: column: IC, 4.6x100mm IC, 20x250mm; Mobile phase: 40% EtOH (5 mM Ammonia), 60% CO2.

[00511] Peak A: [a]o (c = 0.5, MeOH) +58.56; 99% ee; (7?)-4-[2-(2-chloro-5-isopropoxyphenyl)azepan-l-yl]-6-methyl-pyrimidin-2-amine (90): 1H NMR (300 MHz, DMSO-¿ / 6 ) δ 7.31 (s, 1H), 6.82 (d, J= 8.9 Hz, 1H), 6.54 (s, 1H), 5.76 (br, 3H), 5.00 - 4 .37 (m, 3H), 4.01 3.81 (m, 1H), 1.95 (s, 3H), 1.86 - 1.29 (m, 8H), 1.21 (m, 6H) ; ESI-MS m / z calc. 374.19, found 375.07 (M+l)+; Retention time: 0.75 minutes. 1-108

[00512] Peak B: [a]D(c = 0.5, MeOH) -70.52; 98.4% ee; (S)-4-[2-(2-chloro-5-isopropoxyphenyl)azepan-l-yl]-6-methyl-pyrimidin-2-amine (91): 1H NMR (300 MHz, DMSO-¿76) δ 7.32 (brs, 1H), 6.83 (brs, 1H), 6.55 (s,_ 1H), 5.83 (br, 3H), 4.96 - 4.43 (m, 2H), 4.02 (br, 2H), 3.17 (s, 3H), 1.95 (s, 3H), 1.86 - 1.31 (m, 8H), 1.26 - 1.15 (m, 6H); ESI-MS m / z calc. 374.19, found 375.12 (M+l)+; Retention time: 0.77 minutes. 1-109. 206 IF-2019-53902052-APN-ANP#INPI Page 206 of 423 3-[l-(2-amino-6-methyl-pyrimidin-4-yl)azepan-2-yl]-4-methoxy-phenoi (92) 1-107

[00513] 1H NMR (300 MHz, DMSO-¿6) δ 8.99 (br, 1H), 7.79 (s, 1H), 7.54 (s, 1H), 6.85 (dd, J = 20.5, 8.7 Hz, 1H), 6.69 - 6.57 (m, 1H), 6.53 - 6.43 (m, 1H), 6.31 (d, J= 2.8 Hz , 0.5H), 5.77 (s, 0.5H), 5.70 (s, 1H), 5.09 - 4.57 (m, 1H), 4.00 (m, 1H), 3, 82 (s, 3H), 3.49 (m, 1H), 2.15 (s, 3H), 1.98 - 1.01 (m, 8H); ESI-MS m / z cale. 328.19, found 329.17 (M+l)+; Retention time: 0.67 minutes. ( / ?)-3-[l-(2-amino-6-methyl-pyrimidin-4-yl)azepan-2-yl]-4-methoxy-phenol (93) 1-127

[00514] SFC Conditions: Column: IC, 4.6x1 OOmrn IC, 20x250mm; Mobile phase: 30% MeOH (5 mM Ammonia), 70% CO2.

[00515] Peak A: [a]D(c = 0.5, MeOH) 100.16; 87.6% ee

[00516] 3-[l-(2-amino-6-methyl-pyrimidin-4-yl)azepan-2-yl]-4-methoxy-phenol (93): 1H NMR (300 MHz, DMSO-í / 6 ) δ 8.84 (br, 1H), 6.81 (s, 1H), 6.55 (s, 1H), 6.39 (s, 1H), 5.80 (s, 2H), 5.32 (s, 1H), 4.74 (s, 1H), 3.79 (m, 3H), 3.30 (m, 2H), 1.92 (s, 3H), 1.82 - 0.64 ( m, 8H); ESI-MS m / z cale. 328.19, found 329.25 (M+l)+; Retention time: 0.65 minutes. 1-127

[00517] Peak B: [a]D(c = 0.5, MeOH) -98.32; 94% ee

[00518] 3-[l-(2-amino-6-methyl-pyrimidin-4-yl)azepan-2-yl]-4-methoxy-phenol (94): 1H NMR (300 MHz, DMSO-c / 6 ) δ 8.85 (br, 1H), 6.82 (s, 1H), 6.56 (s, 1H), 6.40 (s, 1H), 5.80 (s, 2H), 5.32 (s, 1H), 4.74 (s, 1H), 3.79 (s, 3H), 3.30 (m, 2H), 1.92 (s, 3H), 1.83 - 0.84 ( m, 8H); ESI-MS m / z cale. 328.19, found 329.1 (M+l)+; Retention time: 0.65 minutes. 1-128 207 IF-2019-53902052-APN-ANP#INPI Page 207 of 423 (+ / -)-4-methyl-6-(2-(2-methylpyridin-3-yl)azepan-l-yl)pyrimidin-2-amine (95) 1-24

[00519] 1H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 4.6 Hz, 1H), 7.42 (d, J = 7.9 Hz, 1H), 7.12 ( dd, J= ...

Claims

1. A compound of formula I' (FORMULA), characterized in that: Ring A is a phenyl ring selected from, a saturated or partially unsaturated 5-7 membered carbocyclic ring, a saturated or partially unsaturated 8-12 membered bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each R1 is independently hydrogen or C1-3 aliphatic optionally substituted by 1-6 halogens; or two R1 groups are optionally taken together with their intervening atoms to form a partially unsaturated fused 5-8 membered carbocyclic ring;each of R2 is independently hydrogen, halogen, -CN, -NO2, -C(O)OR, -C(O)NR2, -NR2, -NRC(O)R, -NRC(O)OR, -NRS(O)2R, -OR, -P(O)R2, -SR, -S(O)R, -S(O)2R, -S(O)(NH)R, -S(O)2NR2, or R; or two R2 groups are optionally taken together to form =O; two R2 groups are optionally taken together with their intervening atoms to form a saturated 3-8 membered spirocyclic ring having O-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each R3 is independently hydrogen, -OH, or C1-3 aliphatic; or: two R3 groups are optionally taken together to form =O; or two R3 groups are optionally taken together to form =CH2; or two R3 groups are optionally taken together with their intervening atoms to form a saturated 5-8 membered spirocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;or two R 3 groups are optionally taken together with their intervening atoms to form a bridged 5-8 membered saturated bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;each R is independently hydrogen or an optionally substituted group selected from C1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 7-10 membered spirobicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 7-10 membered fused, saturated or partially unsaturated bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 4-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;or: two R groups on the same nitrogen are optionally taken together with their intervening atoms to form a saturated, partially unsaturated, or heteroaryl 4-7 member ring having 0-3 heteroatoms, in addition to nitrogen, independently selected from nitrogen, oxygen, and sulfur, optionally substituted with 1-2 oxo groups; - - - - - - is a single or double bond; X is -O-, -N(R)-, -N(S(O)2(R))-, -S-, -S(O)-, -S(O)2-, -CH2-, -CH(R 3 )-, or -C(R 3 )2-; m is 0, 1, or 2; n is 0, 1, 2, 3, 4, or 5; yp is 0, 1, or 2; or a pharmaceutically acceptable salt thereof. 24 Claims follow;